Heterocyclic compounds and their uses

Abstract

The present invention provides heterocyclic compounds having orexin type 2 receptor agonist activity. Formula (I): JPEG2025539434000134.jpg51127 [wherein each symbol is as defined in the specification] The compound or a salt thereof has orexin type 2 receptor agonist activity and is useful as an agent for the prophylaxis or treatment of narcolepsy.

Description

[Technical Field]

[0001] The present invention relates to heterocyclic compounds, particularly heterocyclic compounds having orexin type 2 receptor agonist activity.

[0002] BACKGROUND OF THE INVENTION Orexin is a neuropeptide specifically produced by certain neurons scattered throughout the lateral hypothalamus and its surrounding areas, and consists of two subtypes: orexin A and orexin B. Both orexin A and orexin B are endogenous ligands for orexin receptors, which are G protein-coupled receptors found primarily in the brain, and two subtypes of orexin receptors, type 1 and type 2, are known (Non-Patent Document 1).

[0003] Orexin-producing neurons (orexin neurons) are localized near the feeding center, and intracerebroventricular administration of orexin peptides increases food intake. Therefore, when orexin was first discovered, it attracted attention as a neuropeptide with an appetite-regulating effect. However, it was later reported that canine narcolepsy is caused by a genetic mutation in the orexin type 2 receptor (Non-patent Document 2), and the role of orexin in regulating sleep and wakefulness also began to attract attention.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice, which were crossbred with transgenic mice overexpressing orexin, have demonstrated that sustained expression of orexin eliminates narcolepsy-like symptoms caused by degeneration of orexin neurons. Similarly, intracerebroventricular administration of orexin peptides to transgenic mice with degenerated orexin neurons also improved narcolepsy-like symptoms (Non-Patent Document 3). Furthermore, studies of orexin type 2 receptor knockout mice suggest that the orexin type 2 receptor is important for maintaining wakefulness (Non-Patent Documents 4 and 5). Based on these findings, orexin type 2 receptor agonists have been suggested as potential therapeutic agents for narcolepsy and other sleep disorders characterized by hypersomnia (Non-Patent Document 6).

[0005] It has also been suggested that a peptide agonist that selectively acts on the orexin type 2 receptor ameliorates obesity induced by a high-fat diet in mice (Non-Patent Document 7). It has also been suggested that intracerebroventricular administration of orexin peptides shortens the time of general anesthesia in rats (Non-Patent Document 8). It has also been suggested that patients with sleep apnea syndrome have low plasma orexin A concentration levels (Non-Patent Document 9). It has also been suggested that intracerebroventricular administration of orexin peptides improves memory retention in senescence-accelerated mouse model (SAMP8) with cognitive impairment (Non-Patent Document 10). Furthermore, it has been suggested that orexin type 2 receptor agonists could be used as therapeutic agents for heart failure (Patent Document 1, Non-Patent Document 11). It has also been suggested that daytime sleepiness in Parkinson's disease patients is caused by loss of orexin neurons (Non-Patent Document 12). Furthermore, orexin regulates bone formation and bone loss, and it has been suggested that orexin type 2 receptor agonists could be used to treat diseases associated with bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2). Furthermore, a significant improvement in mortality rate was observed in a mouse model of septic shock simply by continuous peripheral administration of orexin, suggesting that orexin receptor agonists are useful for the prevention or treatment of sepsis, severe sepsis, and septic shock (Patent Document 3).

[0006] Therefore, compounds having orexin type 2 receptor agonist activity are expected to be useful as novel therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, and the like, as well as anesthetic antagonists and agents for preventing or treating side effects and complications caused by anesthesia.

[0007] On the other hand, sulfonamide derivatives include: formula

[0008] [ka]

[0009] (The symbols in the formula are as described in the literature.) A compound represented by the following formula (Patent Document 4) has been reported.

[0010] Furthermore, the following compounds have been reported to have orexin type 2 receptor agonist activity. formula

[0011] [ka]

[0012] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 5). formula

[0013] [ka]

[0014] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 6). formula

[0015] [ka]

[0016] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 7). formula

[0017] [ka]

[0018] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 8). formula

[0019] [ka]

[0020] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 9). formula

[0021] [ka]

[0022] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 10). formula

[0023] [ka]

[0024] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 11). formula

[0025] [ka]

[0026] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 12). formula

[0027] [ka]

[0028] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 13). formula

[0029] [ka]

[0030] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 14). formula

[0031] [ka]

[0032] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 15). formula

[0033] [ka]

[0034] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 16). formula

[0035] [ka]

[0036] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 17).

[0037] There is a need for the development of novel compounds that have orexin type 2 receptor agonist activity. [Prior art documents] [Patent documents]

[0038] [Patent Document 1] WO2015 / 073707A1 [Patent Document 2] WO2015 / 048091A1 [Patent Document 3] WO2015 / 147240A1 [Patent Document 4] WO2012 / 137982A9 [Patent Document 5] WO2017 / 135306A1 [Patent Document 6] WO2018 / 164191A1 [Patent Document 7] WO2018 / 164192A1 [Patent Document 8] WO2019 / 027003A1 [Patent Document 9] WO2019 / 027058A1 [Patent Document 10] WO2020 / 004536A1

Patent document 11

Patent document 12

Patent document 13

Patent document 14

Patent document 15

Patent document 16

Patent document 17

Non-licensed literature

[0039] [Non-licensed document 1] Cell, Vol. 92, 573-585, 1998 [Non-licensed document 2] Cell, Vol. 98, 365-376, 1999 [Non-licensed document 3] Proc. Natl. Acad. Sci. USA, Vol.101, 4649-4654, 2004

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

[0040] An object of the present invention is to provide a heterocyclic compound having orexin type 2 receptor agonist activity. [Means for solving the problem]

[0041] The present inventors have found that a compound represented by the following formula (I) or a salt thereof (also referred to as compound (I) in this specification) has orexin type 2 receptor agonist activity, and as a result of further research, have completed the present invention.

[0042] That is, the present invention relates to the following: [1] Formula (I)

[0043] [ka]

[0044] [In the formula, R 1 is C 1-6 Alkyl group, C 3-7 Cycloalkyl group, or mono- or di-C 1-6 alkylamino group, wherein the C 1-6 Alkyl group, C 3-7Cycloalkyl groups, and mono- or di-C 1-6 Each alkylamino group may be optionally substituted; Each R 2 are the same or different and may be substituted C 1-6 is an alkyl group; Each R 3 are the same or different and may be substituted C 1-6 an alkyl group, or a halogen atom; R A represents an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 an aryl group or an optionally substituted C 3-10 is a cycloalkyl group; L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group; L 2 is a bond or -CH2-; X 1 is N or CR 3’ and; X 2 is N or CR 4b and; X 3 is N or C; X 4 is N or CR 4c and; X 5 is N or CR 4d and; However, X 2 , X 3 , X 4 , and X 5 of which no more than two are N; R 3’ is a hydrogen atom, optionally substituted C 1-6 an alkyl group, or a halogen atom; R 4a , R 4b , R 4c, and R 4d are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 3-7 a cycloalkyl group, a halogen atom, or an optionally substituted C 1-6 is an alkoxy group; m is an integer from 0 to 3; n is an integer from 0 to 3; o is an integer from 0 to 3; p is an integer of 0 or 1; and

[0045] [ka]

[0046] contains one single bond and one double bond when p is 0, and one single bond and two double bonds when p is 1, providing an aromatic ring structure; or a salt thereof (hereinafter referred to as "compound (I)").

[0047] [2] R A But the following structure:

[0048] [ka]

[0049] [In the formula, X 6 is N or CR 5’ and; Each R 5 are the same or different and are halogen atoms or C 1-6 is an alkoxy group; R 5’ is a hydrogen atom or a halogen atom; q is an integer from 0 to 7; and

[0050] [ka]

[0051] are identical and either both single bonds or both double bonds; The compound according to [1], or a salt thereof, having the formula:

[0052] [3] X 1 is CR 3’ wherein m is an integer from 0 to 2 and n is 0; The compound according to [1] or [2], or a salt thereof.

[0053] [4] X 1 is N; The compound according to [1] or [2], or a salt thereof.

[0054] [5] R 1 But C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl groups, halo-C 1-6 alkyl group, cyclopropyl group, halo-cyclopropyl group, or mono- or di-C 1-6 is an alkylamino group; Each R 2 However, the same or different, C 1-6 Alkyl groups, halo-C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, or hydroxy-C 1-6 is an alkyl group; Each R 3 However, the same or different, C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 an alkyl group, or a halogen atom; R 4a is a hydrogen atom, C 1-6 Alkyl group, cyclopropyl group, C 1-6 Alkoxy group, halo-C 1-6 an alkyl group, or a halogen atom; and q is an integer from 0 to 4; [2]-[4] A compound or a salt thereof according to any one of [2]-[4].

[0055] [6] (i)X 2 is CR 4b and X 3 is N and X 4 is N and p is 0; or (ii) X 2 is N and X 3 is N and X 4 is CR 4c and p is 0; The compound according to any one of [1] to [5], or a salt thereof, wherein

[0056] [7] X 2 is CR 4b and X 3 is C and X 4 is CR 4c and X 5 is CR 4d and p is 1; the compound according to any one of [1] to [5], or a salt thereof.

[0057] [8] X 2 is N and X 3 is C and X 4 is CR 4c and X 5 is CR 4d and p is 1; the compound according to any one of [1] to [5], or a salt thereof.

[0058] [9] X 2 is CR 4b and X 3 is C and X 4 and X 5 is N and p is 1; the compound according to any one of [1] to [5], or a salt thereof.

[0059]

[10] X 2 is CR 4b and X 3 is C and X 4 is CR4c and X 5 is N and p is 1; the compound according to any one of [1] to [5], or a salt thereof.

[0060]

[11] X 2 and X 4 is N and X 3 is C and X 5 is CR 4d and p is 1; the compound according to any one of [1] to [5], or a salt thereof.

[0061]

[12] X 2 is CR 4b and X 3 is C and X 4 is N and X 5 is CR 4d and p is 1; the compound according to any one of [1] to [5], or a salt thereof.

[0062]

[13] X 6 is CR 5’ and

[0063] [ka]

[0064] are both single bonds; the compound according to any one of [2] to

[12] , or a salt thereof.

[0065]

[14] X 6 is CR 5’ and

[0066] [ka]

[0067] are both double bonds; the compound according to any one of [2] to

[12] , or a salt thereof.

[0068]

[15] X 6N ’ and

[0069] [ka]

[0070] are both double bonds; the compound according to any one of [2] to

[12] , or a salt thereof.

[0071]

[16] Part:

[0072] [ka]

[0073] but:

[0074] [ka]

[0075] Selected from the group consisting of: where * indicates R A indicates the binding site for R 4a , R 4b , R 4c , and R 4d is as defined in [1]; [1]-[5] A compound or a salt thereof according to any one of [1]-[5].

[0076]

[17] Part:

[0077] [ka]

[0078] but:

[0079] [ka]

[0080] Selected from the group consisting of: where: * is R A indicates the binding site for; R 1 But C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl groups, halo-C 1-6 alkyl group, cyclopropyl group, halo-cyclopropyl group, or mono- or di-C 1-6 is an alkylamino group; Each R 2 However, the same or different, C 1-6 Alkyl groups, halo-C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 Alkyl group, or hydroxy-C 1-6 is an alkyl group; Each R 3 However, the same or different, C 1-6 Alkyl group, C 1-6 Alkoxy-C 1-6 an alkyl group, or a halogen atom; L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom, or C 1-6 is an alkyl group; L 2 is a bond or -CH2-; X 1 But N or CR 3’ where R 3’ is a hydrogen atom; R 4a is a hydrogen atom, C 1-6 Alkyl group, cyclopropyl group, C 1-6 Alkoxy group, halo-C 1-6 an alkyl group, or a halogen atom; X 2 But N or CR 4b where R 4b is a hydrogen atom or a halogen atom; X4 But N or CR 4c where R 4c is a hydrogen atom or a halogen atom; X 5 But N or CR 4d where R 4d is a hydrogen atom; m is an integer from 0 to 3; n is an integer from 0 to 3; o is an integer from 0 to 3; and portion:

[0081] [ka]

[0082] but:

[0083] [ka]

[0084] Selected from the group consisting of: where: Each R 5 are the same or different and are halogen atoms or C 1-6 is an alkoxy group; R 5’ is a hydrogen atom or a halogen atom; and q is an integer from 0 to 4; [2]-[5] A compound or a salt thereof according to any one of [2]-[5].

[0085]

[18] The compound represented by formula (Ia):

[0086] [ka]

[0087] [In the formula, q is an integer from 0 to 4; and Other symbols are as defined in [2];] The compound according to any one of [2] to [5], or a salt thereof, wherein the compound is

[0088]

[19] The compound represented by formula (Ib):

[0089] [ka]

[0090] [In the formula, q is an integer from 0 to 4; and Other symbols are as defined in [2];] The compound according to any one of [2] to [5], or a salt thereof, wherein the compound is

[0091]

[20] The compound represented by formula (Ic):

[0092] [ka]

[0093] [In the formula, R 2a is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group; q is an integer from 0 to 4; and Other symbols are as defined in [2];] The compound according to any one of [2] to [5], or a salt thereof, wherein the compound is

[0094]

[21] The compound has the formula (Id):

[0095] [ka]

[0096] [In the formula, R 2ais a hydrogen atom or an optionally substituted C 1-6 is an alkyl group; R 3a and R 3b are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 an alkyl group, or a halogen atom; q is an integer from 0 to 4; and Other symbols are as defined in [2];] The compound according to any one of [2] to [5], or a salt thereof, wherein the compound is

[0097]

[22] The compound represented by formula (Ie):

[0098] [ka]

[0099] [In the formula, R 1 is C 1-6 Alkyl group, or halo-C 1-6 is an alkyl group; R 2a is a hydrogen atom, C 1-6 Alkyl group, or halo-C 1-6 is an alkyl group; R 3a and R 3b are the same or different, respectively, C 1-6 an alkyl group, or a halogen atom; R 4a is C 1-6 an alkyl group, or a halogen atom; X 2 is N or CR 4b where R 4b is a halogen atom; and R A is a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are each optionally substituted with 1 to 3 halogen atoms; The compound according to any one of [1] to [5], or a salt thereof, wherein the compound is a compound represented by the formula:

[0100]

[23] R 1 But C 1-6 Alkyl group, or halo-C 1-6 is an alkyl group; R 2a is a hydrogen atom, C 1-6 Alkyl group, or halo-C 1-6 is an alkyl group; R 3a and R 3b are each a halogen atom; R 4a But C 1-6 an alkyl group, or a halogen atom; X 2 But N or CR 4b where R 4b is a halogen atom; and R A is a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are each optionally substituted with 1 to 3 halogen atoms;

[22] The compound or a salt thereof according to

[22] .

[0101]

[24] R 1 But C 1-6 Alkyl group, or halo-C 1-6 is an alkyl group; R 2a But C 1-6 Alkyl group, or halo-C 1-6 is an alkyl group; R 3a and R 3b are each a halogen atom; R 4a is a halogen atom; X 2 is N; and R A is a phenyl group optionally substituted by 1 to 3 halogen atoms;

[22] The compound or a salt thereof according to

[22] .

[0102]

[25] R 1 But C 1-6 is an alkyl group; R 2a But, Halo-C 1-6 is an alkyl group; R 3a and R 3b are each a halogen atom; R 4a is a halogen atom; X 2 is N; and R A is a phenyl group optionally substituted by 1 to 3 halogen atoms; A compound according to any one of [1] to [5] and

[22] to

[24] , or a salt thereof.

[0103]

[26] The compound: N-[(3R)-4,4-difluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide; N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide; N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide; and N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide The compound according to [1], or a salt thereof, selected from the group consisting of:

[0104]

[27] A pharmaceutical composition comprising a compound defined in any one of [1]-

[26] or a salt thereof, and a pharmacologically acceptable carrier.

[0105]

[28] A pharmaceutical comprising a compound defined in any one of [1]-

[26] or a salt thereof, or a pharmaceutical composition defined in

[27] .

[29] The pharmaceutical agent according to

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

[30] The pharmaceutical described in

[28] , which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, or side effects or complications caused by anesthesia.

[31] The pharmaceutical agent according to

[28] , which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[32] The pharmaceutical agent according to

[28] , which is a preventive or therapeutic agent for narcolepsy.

[0106]

[33] A method for preventing or treating a disease or disorder associated with the orexin type 2 receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound defined in any one of [[1]-

[26] or a salt thereof, or a pharmaceutical composition defined in

[27] .

[34] The method described in

[33] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects or complications of anesthesia.

[35] The method according to

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

[36] The method according to

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

[0107]

[37] A compound as defined in any one of [1]-

[26] or a salt thereof for use in therapy.

[38] The compound or salt according to

[37] , wherein the therapeutic method comprises treating a disease or disorder associated with the orexin type 2 receptor.

[39] The compound or salt according to

[38] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects or complications of anesthesia.

[40] The compound or salt according to

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

[41] The compound or salt according to

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

[0108]

[42] Use of a compound defined in any one of [1]-

[26] or a salt thereof in the manufacture of a medicament for the treatment of a disease or disorder associated with the orexin type 2 receptor.

[43] The use described in

[42] , wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects and complications of anesthesia.

[44] The use according to

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

[45] The use according to

[42] , wherein the disease or disorder is narcolepsy. [Effects of the Invention]

[0109] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for certain diseases such as narcolepsy.

[0110] [Detailed Description of the Invention] The definition of each substituent used in the present specification will be described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. As used herein, "optionally halogenated C 1-6 The "alkyl group" includes, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include alkyl groups, such as methyl, chloromethyl, difluoromethyl, trichloromethyl, 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, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. In this specification, "C 2-6Examples of the "alkenyl 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. In this specification, "C 2-6 Examples of the "alkynyl 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. In this specification, "C 3-10 Examples of the "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. As used herein, "optionally halogenated C 3-10 The "cycloalkyl group" includes, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples include cycloalkyl groups, such as cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl. In this specification, "C 7-16Examples of the "aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0111] In this specification, "C 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. As used herein, "optionally halogenated C 1-6 The "alkoxy group" includes, for example, a C alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include alkoxy groups, such as methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. In this specification, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. In this specification, "C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. As used herein, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, a C alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0112] In this specification, "C1-6 Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl. As used herein, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, a C alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of alkyl-carbonyl groups include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl and 2-naphthoyl. In this specification, "C 7-16 Examples of the "aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl. As used herein, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0033] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0113] As used herein, "mono- or di-C 1-6Examples of the "alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl. As used herein, "mono- or di-C 7-16 Examples of the "aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

[0114] In this specification, "C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. As used herein, "optionally halogenated C 1-6 The alkylsulfonyl group includes, for example, a C alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include alkylsulfonyl groups, such as methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0115] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted 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 group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups and C 7-16 Examples include aralkyl groups.

[0116] In the present specification, examples of the "optionally substituted hydrocarbon group" include hydrocarbon groups which may have a substituent selected from the following Substituent Group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 alkoxy groups, (7) C 6-14 aryloxy groups (e.g., phenoxy, naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., morpholinyloxy, piperidinyloxy), (11)C 1-6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy); (12)C 6-14 aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13)C 1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C 1-6alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19)C 1-6 C optionally substituted with alkyl group 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) Optionally halogenated C 1-6 alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 alkyl-carbonyl groups, (26)C 6-14 aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 alkoxy-carbonyl groups, (30)C 6-14 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (31)C 7-16aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 alkyl-carbamoyl groups, (35)C 6-14 aryl-carbamoyl groups (e.g., phenylcarbamoyl); (36) 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 alkylsulfonyl groups, (39)C 6-14 arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl groups, (42)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl); (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino); (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16aralkylamino groups (e.g., benzylamino), (49) formylamino group, (50)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (52)C 6-14 arylcarbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with alkyl group 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino); (57) Optionally halogenated C 1-6 alkyl groups, (58)C 2-6 alkenyl groups, (59)C 2-6 alkynyl groups, (60)C 3-10 cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0117] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0118] In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0119] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and 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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0120] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydrofuranyl, and the like. 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as diisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrobenzo[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydro ... and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0121] In the present specification, suitable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" that contain at least one nitrogen atom as a ring-constituting atom.

[0122] In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent Group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0123] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C, each of which may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Aralkyl groups, 5- to 14-membered aromatic heterocyclic groups, 3- to 14-membered non-aromatic heterocyclic groups, amino groups, and mono- or di-C 1-6 Examples of the alkyl-amino group include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which may have "1 or 2 substituents selected from an alkyl-amino group." The term "acyl group" also includes hydrocarbon-sulfonyl groups, heterocyclic-sulfonyl groups, hydrocarbon-sulfinyl groups and heterocyclic-sulfinyl groups. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Suitable examples of the "acyl group" include a formyl group, a carboxy group, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C3-10 Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), NC 1-6 Alkyl-N',N'-di-C 1-6 Alkylhydrazine-carbonyl group, thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, and mono- or di-C 1-6 Examples include alkylphosphono groups (eg, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0124] As used herein, examples of the "optionally substituted amino group" include "amino groups each optionally having 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an amino group which may have one or two substituents selected from an arylsulfonyl group. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6Alkenylamino group (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino group (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 Aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methyl sulfonyl amino, ethyl sulfonyl amino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), and (C 1-6 Alkyl)(C 6-14 and aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0125] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and carbamoyl groups which may have one or two substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0126] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and a thiocarbamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group. Suitable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14Examples thereof include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl), and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0127] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which optionally has 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and a sulfamoyl group which may have one or two substituents selected from an aralkyl-carbamoyl group. Suitable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0128] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from Substituent Group A, each of which may have 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups. Suitable examples of the optionally substituted hydroxy group include a hydroxy group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy groups (e.g., benzyloxy, phenethyloxy), C 1-6Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), and C 6-14 Examples include arylsulfonyloxy groups (eg, phenylsulfonyloxy).

[0129] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from Substituent Group A, each of which may have 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Examples thereof include a sulfanyl group which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, and a halogenated sulfanyl group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, C 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C3-10 Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0130] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from Substituent Group A, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0131] As used herein, the term "hydrocarbon ring" refers to, for example, C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes and C 3-10 Cycloalkenes are examples. In this specification, "C 6-14 Examples of the "aromatic hydrocarbon ring" include benzene and naphthalene. In this specification, "C 3-10 "Cycloalkanes" include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10"Cycloalkenes" include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. As used herein, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0132] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Preferable 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-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidin and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzophenone, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0133] As used herein, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane; Examples thereof include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the term "nitrogen-containing heterocycle" includes "heterocycles" that contain at least one nitrogen atom as a ring-constituting atom.

[0134] In this specification, "C 3-7 Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As used herein, "mono- or di-C 1-6 Examples of the "alkylamino group" include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neo-pentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, and 2-ethylbutylamino.

[0033] In the present specification, examples of the "3- to 8-membered non-aromatic heterocyclic group" in the definition of "optionally substituted 3- to 8-membered non-aromatic heterocyclic group" include 3- to 8-membered (preferably 5- or 6-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "3- to 8-membered non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisothiazolyl ... Examples thereof include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as hydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl.

[0033] In the present specification, examples of the "5- or 6-membered aromatic heterocyclic group" in the definition of "optionally substituted 5- or 6-membered aromatic heterocyclic group" include 5- or 6-membered aromatic heterocyclic groups containing, as ring-constituting atoms, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "5- or 6-membered aromatic heterocyclic group" include monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl.

[0135] The definition of each symbol in formula (I) is explained in detail below. In formula (I), R 1 is C 1-6 Alkyl group, C 3-7 Cycloalkyl group, or mono- or di-C 1-6 alkylamino group, wherein the C 1-6 Alkyl group, C 3-7 Cycloalkyl groups, and mono- or di-C 1-6 Each alkylamino group may be optionally substituted. The above "Optionally substituted C 1-6 alkyl group," "optionally substituted C 3-7 "cycloalkyl group," and "optionally substituted mono- or di-C 1-6 Examples of the substituent of the alkylamino group include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0136] In some embodiments of Formula (I), R 1 teeth, (1) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, halo-C1-6 Alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl), or C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (2) optionally substituted C 3-7 Cycloalkyl groups (e.g., cyclopropyl or halo-C 3-7 a cycloalkyl group (e.g., fluorocyclopropyl), or (3) optionally substituted mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) is. In some embodiments of Formula (I), R 1 is preferably (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl); (4) a cyclopropyl group, (5) a halocyclopropyl group (e.g., fluorocyclopropyl), or (6) Mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) is. In some embodiments of Formula (I), R 1 is more preferably (1)C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) is. In some embodiments of Formula (I), R 1 More preferably, C 1-6 It is an alkyl group (e.g., methyl).

[0137] In formula (I), each R 2are the same or different and may each be substituted C 1-6 It is an alkyl group. The above "Optionally substituted C 1-6 Examples of the substituent of the "alkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0138] In some embodiments of Formula (I), each R 2 are the same or different and may be substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, halo-C 1-6 Alkyl groups (e.g., fluoromethyl, difluoromethyl), C 1-6 Alkoxy-C 1-6 Alkyl group (e.g., methoxymethyl), or hydroxyl-C 1-6 It is an alkyl group (e.g., hydroxymethyl). In some embodiments of Formula (I), each R 2 are the same or different, preferably (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Hydroxyl-C 1-6 Alkyl groups (e.g., hydroxymethyl) is. In some embodiments of Formula (I), each R 2 are the same or different, more preferably (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) is. In some embodiments of Formula (I), each R 2are the same or different, and more preferably halo-C 1-6 It is an alkyl group (eg, fluoromethyl).

[0139] The symbol "o" represents the substituent R 2 and is an integer between 0 and 3 (i.e., 0, 1, 2, or 3). In some embodiments of formula (I), the symbol "o" is preferably 0 or 1. In some embodiments of formula (I), the symbol "o" is more preferably an integer of one. In some embodiments of formula (I), when "o" is an integer of 0 or 1, (R 2 ) o is preferably R 2a is.

[0140] In formula (I), or formula (Ic), (Id), or (Ie) described herein, R 2a is a hydrogen atom or an optionally substituted C 1-6 It is an alkyl group. The above "Optionally substituted C 1-6 Examples of the substituent of the "alkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0141] In some embodiments of Formula (I), (Ic) or (Id), R 2a teeth, (1) a hydrogen atom, or (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, halo-C 1-6 Alkyl groups (e.g., fluoromethyl, difluoromethyl), C 1-6 Alkoxy-C 1-6 Alkyl group (e.g., methoxymethyl), or hydroxyl-C 1-6 It is an alkyl group (e.g., hydroxymethyl). In some embodiments of Formula (I), (Ic) or (Id), R 2ais preferably (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (4) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (5) Hydroxyl-C 1-6 Alkyl groups (e.g., hydroxymethyl) is. In some embodiments of Formula (I), (Ic), (Id), or (Ie), R 2a is more preferably (1) a hydrogen atom, (2) C 1-6 an alkyl group (e.g., methyl, ethyl), or (3) Halo-C 1-6 Alkyl groups (e.g., fluoromethyl, difluoromethyl) is. In some embodiments of Formula (I), (Ic), (Id), or (Ie), R 2a is more preferably (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) is. In some embodiments of Formula (I), (Ic), (Id), or (Ie), R 2a is even more preferably halo-C 1-6 It is an alkyl group (eg, fluoromethyl).

[0142] In formula (I), each R 3 are the same or different and may be substituted C 1-6 It is an alkyl group or a halogen atom. The above "Optionally substituted C 1-6Examples of the substituent of the "alkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0143] In some embodiments of Formula (I), each R 3 are the same or different, (1) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, or C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (2) Halogen atoms (e.g., fluorine) is. In some embodiments of Formula (I), each R 3 are the same or different, preferably (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) is.

[0144] The symbol "n" represents the substituent R 3 and is an integer between 0 and 3 (i.e., 0, 1, 2, or 3). In some embodiments of formula (I), the symbol "n" is preferably the integer 2. In some embodiments of formula (I), when "n" is an integer of 2, (R 3 ) n is preferably R 3a and R 3b is. In formula (I), or formula (Id) described herein, R 3a and R 3b are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 It is an alkyl group or a halogen atom. The above "Optionally substituted C1-6 Examples of the substituent of the "alkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0145] In some embodiments of Formula (I) or (Id), R 3a and R 3b are the same or different, respectively. (1) a hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) is. In some embodiments of Formula (I) or (Id), R 3a and R 3b are the same or different, and each is preferably (1) a hydrogen atom, (2) C 1-6 Alkyl groups (e.g., methyl, ethyl) (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Halogen atoms (e.g., fluorine) is. In some embodiments of Formula (I), (Id), or (Ie), R 3a and R 3b are the same or different, and each is more preferably (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine) is. In some embodiments of Formula (I), (Id), or (Ie), R 3a and R 3b and are each more preferably a halogen atom (eg, each fluorine).

[0146] In formula (I), R 4a is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-7 a cycloalkyl group, a halogen atom, or an optionally substituted C 1-6 It is an alkoxy group. The above "Optionally substituted C 1-6 alkyl group," "optionally substituted C 3-7 "Cycloalkyl group", and "optionally substituted C 1-6 Examples of the substituents of "alkoxy" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0147] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), R 4a teeth, (1) Hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl); (3) optionally substituted C 3-7 cycloalkyl groups (e.g., cyclopropyl), (4) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), or (5) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy) is. In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), R 4a is preferably (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) is. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R 4a is more preferably (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine or chlorine) is. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R 4a is more preferably a halogen atom (eg, fluorine).

[0148] In formula (I), R A represents an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 an aryl group or an optionally substituted C 3-10 It is a cycloalkyl group. The above-mentioned "optionally substituted 3- to 8-membered non-aromatic heterocyclic group", "optionally substituted 5- to 6-membered aromatic heterocyclic group", and "optionally substituted C 6-14 "aryl group," and "optionally substituted C 3-10 Examples of the substituent of the "cycloalkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0149] In some embodiments of Formula (I), R A preferably has the following structure:

[0150] [ka]

[0151] [In the formula, X 6 is N or CR 5’ and; Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); q is an integer from 0 to 7 (e.g., 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3); and

[0152] [ka]

[0153] are the same and are both single bonds or both double bonds. It has.

[0154] In some embodiments of Formula (I), R A preferably has the following structure:

[0155] [ka]

[0156] [In the formula, X 6 is N or CR 5’ and; Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine), or C 1-6 an alkoxy group (e.g., methoxy); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); q is an integer from 0 to 7 (e.g., 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3); and

[0157] [ka]

[0158] are the same and are both single bonds or both double bonds. It has.

[0159] In some embodiments of Formula (I), R A is preferably (1)X 6 is CR 5’ and

[0160] [ka]

[0161] are both single bonds (i.e., R A represents an optionally substituted 1-cyclohexyl group), (2)X 6 is CR 5’ and

[0162] [ka]

[0163] are both double bonds (i.e., R A represents an optionally substituted phenyl group), or (3)X 6 is N, and

[0164] [ka]

[0165] are both double bonds (i.e., R A represents an optionally substituted 2-pyridyl group) is a 6-membered cyclic group having the structure

[0166] In some embodiments of Formula (I), the structure:

[0167] [ka]

[0168] is preferably:

[0169] [ka]

[0170] Selected from the group consisting of: where: Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine), or C 1-6 an alkoxy group (e.g., methoxy); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and q is an integer from 0 to 4.

[0171] In some embodiments of Formula (I), R A is more preferably (1) The same or different halogen atoms (e.g., fluorine, chlorine) and C 1-6 a phenyl group optionally substituted by 1 to 3 substituents selected from alkoxy groups (e.g., methoxy), or (2) a 2-pyridyl group optionally substituted with 1 to 3 identical or different halogen atoms (e.g., fluorine); is. In some embodiments of Formula (I), R A is more preferably (1) a phenyl group optionally substituted with 1 to 3 identical or different halogen atoms (e.g., fluorine, chlorine, preferably fluorine), or (2) a 2-pyridyl group optionally substituted with 1 to 3 identical or different halogen atoms (e.g., fluorine); is. In some embodiments of Formula (I), R Ais even more preferably a phenyl group optionally substituted with 1 to 3 identical or different halogen atoms (eg, fluorine). In some embodiments of Formula (I), R A is even more preferably a phenyl group substituted with 1 to 3 fluorines or a 2-pyridyl group substituted with 1 to 3 fluorines. In some embodiments of Formula (I), R A is more preferably 2,6-difluorophenyl, 2,4,6-trifluorophenyl, or 4,6-difluoropyridin-2-yl. In some embodiments of Formula (I), R A is even more preferably 2,6-difluorophenyl or 2,4,6-trifluorophenyl. In some embodiments of Formula (I), R A is particularly preferably 2,6-difluorophenyl.

[0172] In formula (I), L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 It is an alkyl group. The above "Optionally substituted C 1-6 Examples of the alkyl group include substituents selected from substituent group A. The number of substituents is preferably 1 to 3, and when the number of substituents is 2 or more, the respective substituents may be the same or different.

[0173] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), L 1 is preferably (1) combination; (2)-NR 6 -, where R 6 is a hydrogen atom or C 1-6 an alkyl group (e.g., methyl), or (3)-O- is. In some embodiments of Formula (I), (Ia), (Ib), or (Ic), L 1 is more preferably a bond.

[0174] In formula (I), L 2 is a bond or -CH2-. In some embodiments of Formula (I), (Ia), (Ib), or (Ic), L 2 is preferably a bond.

[0175] In formula (I), X 1 is N or CR 3’ where R 3’ is a hydrogen atom, optionally substituted C 1-6 It is an alkyl group or a halogen atom. The above "Optionally substituted C 1-6 Examples of the substituent of the "alkyl group" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0176] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), R 3’ teeth, (1) a hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, or C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) is. In some embodiments of Formula (I), (Ia), (Ib), or (Ic), R 3’ is preferably (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Halogen atoms (e.g., fluorine) is. In some embodiments of Formula (I), (Ia), (Ib), or (Ic), R 3’ is more preferably a hydrogen atom.

[0177] The symbol "m" refers to the number of methylene groups (-CH2-) and is an integer from 0 to 3 (ie, 0, 1, 2, or 3) that form a 4- to 7-membered carbocyclic or N-containing ring.

[0178] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), X 1 teeth, (1) N (i.e., a 4- to 7-membered N-containing ring) is R 3 azetidine, pyrrolidine, piperidine, or azepane, optionally substituted with (2)CR 3’ (i.e., each of the 4- to 7-membered carbocyclic rings is R 3’ and R 3 cyclobutane, cyclopentane, cyclohexane, or cycloheptane, optionally substituted with is. In some embodiments of Formula (I), (Ia), (Ib), or (Ic), X 1 is preferably (1) N (i.e., a 4- to 7-membered N-containing ring) is R 3 azetidine, pyrrolidine, piperidine, or azepane, optionally substituted with (2) CH (i.e., 4- to 7-membered carbocyclic rings) are preferably R 3 cyclobutane, cyclopentane, cyclohexane, or cycloheptane, optionally substituted with is. In some embodiments of Formula (I), (Ia), (Ib), or (Ic), X 1 is more preferably N (i.e., a 4- to 7-membered N-containing ring), 3Azetidine, pyrrolidine, piperidine, or azepane, optionally substituted with R 3a and R 3b is pyrrolidine optionally substituted with

[0179] In formula (I), X 2 is N or CR 4b where R 4b is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-7 a cycloalkyl group, a halogen atom, or an optionally substituted C 1-6 It is an alkoxy group. The above "Optionally substituted C 1-6 alkyl group," "optionally substituted C 3-7 "Cycloalkyl group", and "optionally substituted C 1-6 Examples of the substituents of "alkoxy" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0180] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), X 2 teeth, (1) N, or (2)CR 4b where R 4b teeth, (1) a hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, halo-C 1-6 alkyl groups (e.g., fluoromethyl, trifluoromethyl); (3) optionally substituted C 3-7 cycloalkyl groups (e.g., cyclopropyl), (4) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), or (5) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy) is. In some embodiments of Formula (I), R 4b is preferably (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine) is.

[0181] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), X 2 is preferably (1) N, or (2)CR 4b where R 4b is a hydrogen atom or a halogen atom (e.g., fluorine). In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X 2 is more preferably (1) N, or (2)CR 4b where R 4b is a halogen atom (e.g., fluorine). In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X 2 is more preferably N or —CF. In some embodiments of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X 2 is even more preferably N.

[0182] In formula (I), X 3 is N or C. In some embodiments of Formula (I) or (Ia), X 3 is preferably C.

[0183] In formula (I), X 4 is N or CR 4c where R 4c is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-7a cycloalkyl group, a halogen atom, or an optionally substituted C 1-6 It is an alkoxy group. The above "Optionally substituted C 1-6 alkyl group," "optionally substituted C 3-7 "Cycloalkyl group", and "optionally substituted C 1-6 Examples of the substituents of "alkoxy" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0184] In some embodiments of Formula (I) or (Ia), X 4 teeth, (1) N, or (2)CR 4c where R 4c teeth, (1) a hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, halo-C 1-6 alkyl groups (e.g., fluoromethyl, trifluoromethyl); (3) optionally substituted C 3-7 cycloalkyl groups (e.g., cyclopropyl), (4) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), or (5) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy) is. In some embodiments of Formula (I) or (Ia), R 4c is preferably (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine) is.

[0185] In some embodiments of Formula (I) or (Ia), X 4 is preferably (1) N, or (2)CR 4c where R 4cis a hydrogen atom or a halogen atom (e.g., fluorine). In some embodiments of Formula (I) or (Ia), X 4 is more preferably (1) N, or (2)CR 4c where R 4c is a hydrogen atom. In some embodiments of Formula (I) or (Ia), X 4 Preferably, CR 4c where R 4c is as defined above. In some embodiments of Formula (I) or (Ia), X 4 More preferably, CR 4c where R 4c is a hydrogen atom or a halogen atom (e.g., fluorine). In some embodiments of Formula (I) or (Ia), X 4 is more preferably —CH.

[0186] In formula (I), X 5 is N or CR 4d where R 4d is a hydrogen atom, optionally substituted C 1-6 alkyl group, optionally substituted C 3-7 a cycloalkyl group, a halogen atom, or an optionally substituted C 1-6 It is an alkoxy group. The above "Optionally substituted C 1-6 alkyl group," "optionally substituted C 3-7 "Cycloalkyl group", and "optionally substituted C 1-6 Examples of the substituents of "alkoxy" include substituents selected from Substituent Group A. The number of substituents is preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0187] In some embodiments of Formula (I) or (Ia), X 5 teeth, (1) N, or (2)CR 4d where R 4d teeth, (1) a hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, halo-C 1-6 alkyl groups (e.g., fluoromethyl, trifluoromethyl); (3) optionally substituted C 3-7 cycloalkyl groups (e.g., cyclopropyl), (4) a halogen atom (e.g., fluorine, chlorine, bromine, iodine), or (5) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy) is. In some embodiments of Formula (I), R 4d is preferably (1) a hydrogen atom, or (2) Halogen atoms is. In some embodiments of Formula (I), (Ib), (Ic), or (Id), R 4d is more preferably a hydrogen atom.

[0188] In some embodiments of Formula (I) or (Ia), X 5 is preferably (1) N, or (2)CR 4d where R 4d is a hydrogen atom. In some embodiments of Formula (I) or (Ia), X 5 Preferably, CR 4d where R 4d is as defined above. In some embodiments of Formula (I) or (Ia), X 5 is more preferably —CH.

[0189] In formula (I), the moiety:

[0190] [ka]

[0191] is X 2 , X 3 , X 4 , and X 5 Of which no more than two are N. In some embodiments of formula (I), the moiety is preferably X 2 , X 3 , X 4 , and X 5 At most one of these is N. In some embodiments of formula (I), the moiety is more preferably X 2 , X 3 , X 4 , and X 5 One of them is N.

[0192] In formula (I), the symbol "p" represents X 5 is an integer of 0 or 1, and

[0193] [ka]

[0194] When p is 0, X contains one single bond and one double bond, and when p is 1, X contains one single bond and two double bonds, providing an aromatic ring structure. 5 is absent, providing a 5-membered aromatic ring. When p is 1, X 5 is present, providing a 6-membered aromatic ring.

[0195] In some embodiments of Formula (I) or (Ia), X 2 , X 3 , X 4 , X 5 , and the combination of p is (1)X 2 is CR 4b and X 3 is N and X4 is N and p is 0; (2)X 2 is N and X 3 is N and X 4 is CR 4c and p is 0; (3)X 2 is CR 4b and X 3 is C and X 4 is CR 4c and X 5 is CR 4d and p is 1; (4)X 2 is N and X 3 is C and X 4 is CR 4c and X 5 is CR 4d and p is 1; (5)X 2 is CR 4b and X 3 is C and X 4 and X 5 is N and p is 1; (6)X 2 is CR 4b and X 3 is C and X 4 is CR 4c and X 5 is N and p is 1; (7)X 2 and X 4 is N and X 3 is C and X 5 is CR 4d and p is 1; or (8)X 2 is CR 4b and X 3 is C and X 4 is N and X 5 is CR 4d and p is 1.

[0196] In some embodiments of Formula (I) or (Ia), the moiety

[0197] [ka]

[0198] is preferably:

[0199] [ka]

[0200] Selected from the group consisting of: where: * indicates R A indicates the binding site for R 4a , R 4b , R 4c , and R 4d is as defined above.

[0201] In this embodiment, R 4a , R 4b , R 4c , and R 4d The combinations are preferably as follows: R 4a but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) and; R 4b but, (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine) and; R 4c but, (1) a hydrogen atom, or (2) Halogen atoms (e.g., fluorine) and R 4d is a hydrogen atom.

[0202] In some embodiments of Formula (I), R 1 , R 2 , R 3 , R 4a , and R A The combinations are preferably as follows: R 1 but, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl); (4) a cyclopropyl group, (5) a halocyclopropyl group (e.g., fluorocyclopropyl), or (6) Mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) and; Each R 2 But the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Hydroxyl-C 1-6 Alkyl groups (e.g., hydroxymethyl) and; Each R 3 But the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) and; R 4a but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) and R A But the following structure:

[0203] [ka]

[0204] and the structure comprises:

[0205] [ka]

[0206] Selected from the group consisting of: where: q is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4); and The other symbols are as defined above.

[0207] In some embodiments, the preferred compound (I) is R 1 but, (1) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, halo-C 1-6 Alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl), or C 1-6Alkoxy- C1-6 alkyl groups (e.g., methoxymethyl), (2) optionally substituted C 3-7 Cycloalkyl groups (e.g., cyclopropyl or halo-C 3-7 a cycloalkyl group (e.g., fluorocyclopropyl), or (3) optionally substituted mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) and; Each R 2 are the same or different and may be substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, halo-C 1-6 Alkyl groups (e.g., fluoromethyl, difluoromethyl), C 1-6 Alkoxy-C 1-6 Alkyl group (e.g., methoxymethyl), or hydroxyl-C 1-6 an alkyl group (e.g., hydroxymethyl); Each R 3 But the same or different, (1) optionally substituted C 1-6 Alkyl groups (e.g., methyl, ethyl, or C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (2) Halogen atoms (e.g., fluorine) and; R A is an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 an aryl group or an optionally substituted C 3-10 is a cycloalkyl group; L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group (e.g., methyl); L 2 is a bond or -CH2-; X 1But N or CR 3’ and; X 2 But N or CR 4b and; X 3 is N or C; X 4 But N or CR 4c and; X 5 But N or CR 4d and; However, X 2 , X 3 , X 4 , and X 5 of which no more than two are N; R 3’ but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Halogen atoms (e.g., fluorine) and; R 4a , R 4b , R 4c , and R 4d are the same or different, respectively, (1) a hydrogen atom, (2) optionally substituted C 1-6 Alkyl groups (e.g., methyl, halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl); (3) optionally substituted C 3-7 cycloalkyl groups (e.g., cyclopropyl), (4) a halogen atom (e.g., fluorine, chlorine, bromine), or (5) optionally substituted C 1-6 Alkoxy groups (e.g., methoxy) and; m is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); n is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); o is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); p is an integer of 0 or 1; and

[0208] [ka]

[0209] contains one single bond and one double bond when p is 0, and one single bond and two double bonds when p is 1, providing an aromatic ring structure. It is a compound.

[0210] In some embodiments, the more preferred compound (I) is R 1 but, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl); (4) a cyclopropyl group, (5) a halocyclopropyl group (e.g., fluorocyclopropyl), or (6) Mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) is. Each R 2 But the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Hydroxyl-C 1-6 Alkyl groups (e.g., hydroxymethyl) and; Each R 3 But the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) and; R A But the following structure:

[0211] [ka]

[0212] [In the formula, X 6 But N or CR 5’ and; Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine), or C 1-6 an alkoxy group (e.g., methoxy); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); q is an integer from 0 to 7 (e.g., 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1 to 3); and

[0213] [ka]

[0214] are the same and are both single bonds or both double bonds. having; L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group (e.g., methyl); L 2 is a bond or -CH2-; X1 But N or CR 3’ and; X 2 But N or CR 4b and; X 3 is N or C; X 4 But N or CR 4c and; X 5 But N or CR 4d and; However, X 2 , X 3 , X 4 , and X 5 of which no more than two are N; R 3’ but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Halogen atoms (e.g., fluorine) and; R 4a , R 4b , R 4c , and R 4d are the same or different, respectively. (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) and; m is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); n is an integer from 1 to 3 (i.e., 1, 2, or 3); o is an integer from 1 to 3 (i.e., 1, 2, or 3); and p is an integer of 0 or 1; and

[0215] [ka]

[0216] contains one single bond and one double bond when p is 0, and one single bond and two double bonds when p is 1, providing an aromatic ring structure. It is a compound.

[0217] In some embodiments, further preferred compounds (I) are portion:

[0218] [ka]

[0219] but:

[0220] [ka]

[0221] Selected from the group consisting of: where * is R A indicates the binding site for; R 1 but, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl); (4) a cyclopropyl group, (5) a halocyclopropyl group (e.g., fluorocyclopropyl), or (6) Mono- or di-C1-6 Alkylamino group (e.g., dimethylamino) and; Each R 2 But the same or different, the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Hydroxy-C 1-6 Alkyl groups (e.g., hydroxymethyl) and; Each R 3 But the same or different, the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) and; R 4a , R 4b , R 4c , and R 4d are the same or different, respectively. (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) and; R A But the following structure:

[0222] [ka]

[0223] and the structure comprises:

[0224] [ka]

[0225] Selected from the group consisting of: where: Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine), or C 1-6 an alkoxy group (e.g., methoxy); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and q is an integer from 0 to 4 (e.g., 0, 1, 2, 3, 4); L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group (e.g., methyl); L 2 is a bond or -CH2-; X 1 But N or CR 3’ and; R 3’ but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Halogen atoms (e.g., fluorine) and; m is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); n is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); and o is an integer from 0 to 3 (i.e., 0, 1, 2, or 3); The compound is a compound, or a salt thereof.

[0226] In some embodiments of formula (I), preferred compounds (I) are portion

[0227] [ka]

[0228] but:

[0229] [ka]

[0230] Selected from the group consisting of: where * is R A indicates the binding site for; R 1 but, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl); (4) a cyclopropyl group, (5) a halocyclopropyl group (e.g., fluorocyclopropyl), or (6) Mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) and; Each R 2 But the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (3) C 1-6Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Hydroxyl-C 1-6 Alkyl groups (e.g., hydroxymethyl) and; Each R 3 But the same or different, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (3) Halogen atoms (e.g., fluorine) is. L 1 is the bond, -NR 6 -, or -O-; where R 6 is a hydrogen atom, or C 1-6 is an alkyl group (e.g., methyl); L 2 is a bond or -CH2-; X 1 But N or CR 3’ where R 3’ is a hydrogen atom; R 4a but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) and; X 2 But N or CR 4b where R 4b is a hydrogen atom or a halogen atom (e.g., fluorine); X 4 But N or CR 4c where R4c is a hydrogen atom or a halogen atom (e.g., fluorine); X 5 But N or CR 4d where R 4d is a hydrogen atom; m is an integer from 0 to 3; n is an integer from 0 to 3; o is an integer from 0 to 3; and R A But the following structure:

[0231] [ka]

[0232] and the structure comprises:

[0233] [ka]

[0234] Selected from the group consisting of: where: Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine), or C 1-6 an alkoxy group (e.g., methoxy); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and q is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4); The compound is a compound, or a salt thereof.

[0235] In some embodiments, preferred compounds (I) have the formula (Ia):

[0236] [ka]

[0237] [In the formula, q is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4); and Other symbols are as defined above;] or a salt thereof.

[0238] In some embodiments, preferred compounds (I) have the formula (Ib):

[0239] [ka]

[0240] [In the formula, q is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4); and Other symbols are as defined above;] or a salt thereof.

[0241] In some embodiments, preferred compounds (I) have the formula (Ic):

[0242] [ka]

[0243] [In the formula, R 2a is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group; q is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4); and Other symbols are as defined above;] or a salt thereof.

[0244] In some embodiments, preferred compounds (I) have the formula (Id):

[0245] [ka]

[0246] [In the formula, R 2a is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group; R 3a and R 3b are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 an alkyl group, or a halogen atom; q is an integer from 0 to 4; and Other symbols are as defined in claim 2; or a salt thereof (hereinafter referred to as "compound (Id)").

[0247] In some embodiments, the preferred compound (Id) is R 1 but, (1)C 1-6 alkyl groups (e.g., methyl, ethyl); (2) C 1-6 Alkoxy-C 1-6 alkyl groups (e.g., methoxymethyl), (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl, fluoroethyl); (4) a cyclopropyl group, (5) a halocyclopropyl group (e.g., fluorocyclopropyl), or (6) Mono- or di-C 1-6 Alkylamino group (e.g., dimethylamino) and; R 2a but, (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) Halo-C 1-6 alkyl groups (e.g., fluoromethyl, difluoromethyl); (4) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (5) Hydroxyl-C 1-6Alkyl groups (e.g., hydroxymethyl) and; R 3a and R 3b are the same or different, respectively. (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl, ethyl); (3) C 1-6 Alkoxy-C 1-6 an alkyl group (e.g., methoxymethyl), or (4) Halogen atoms (e.g., fluorine) and; X 2 But N or CR 4b and; R 4a , R 4b , R 4c , and R 4d are the same or different, respectively. (1) a hydrogen atom, (2) C 1-6 alkyl groups (e.g., methyl); (3) a cyclopropyl group, (4) C 1-6 Alkoxy groups (e.g., methoxy), (5) Halo-C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) Halogen atoms (e.g., fluorine, chlorine, bromine) and; X 6 But N or CR 5’ and; Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine); R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and q is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4); The compound is a compound, or a salt thereof.

[0248] In some embodiments, preferred compounds (I) have the formula (Ie):

[0249] [ka]

[0250] [In the formula, R 1 teeth, (1)C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) and; R 2a teeth, (1) a hydrogen atom, (2) C 1-6 an alkyl group (e.g., methyl), or (3) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) and; R 3a and R 3b are the same or different, respectively. (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine) and; R 4a teeth, (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine, chlorine) and; X 2 is N or CR 4b where R 4b is a halogen atom (e.g., fluorine); and R A is a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are each optionally substituted with 1 to 3 halogen atoms (e.g., fluorine) (including 2,6-difluorophenyl, 2,4,6-trifluorophenyl, and 4,6-difluoropyridin-2-yl). or a salt thereof (hereinafter referred to as "compound (Ie)").

[0251] In some embodiments, the preferred compound (Ie) is R 1 but, (1)C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) and; R 2a but, (1) a hydrogen atom, (2) C 1-6 an alkyl group (e.g., methyl), or (3) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) and; R 3a and R 3b are each a halogen atom (e.g., fluorine); R 4a but, (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine, chlorine) and; X 2 But N or CR 4b where R 4b is a halogen atom (e.g., fluorine); and R A is a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are each optionally substituted with 1 to 3 halogen atoms (e.g., fluorine) (including 2,6-difluorophenyl, 2,4,6-trifluorophenyl, and 4,6-difluoropyridin-2-yl); The compound is a compound, or a salt thereof.

[0252] In some embodiments, the more preferred compound (Ie) is R 1 but, (1)C 1-6an alkyl group (e.g., methyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) and; R 2a but, (1)C 1-6 an alkyl group (e.g., methyl), or (2) Halo-C 1-6 Alkyl group (e.g., fluoromethyl) and; R 3a and R 3b are each a halogen atom (e.g., fluorine); R 4a is a halogen atom (e.g., fluorine); X 2 is N; and R A is a phenyl group (including 2,6-difluorophenyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine); The compound is a compound, or a salt thereof.

[0253] In some embodiments, the further preferred compound (Ie) is R 1 But C 1-6 is an alkyl group (e.g., methyl); R 2a But, Halo-C 1-6 an alkyl group (e.g., fluoromethyl); R 3a and R 3b are each a halogen atom (e.g., each fluorine); R 4a is a halogen atom (e.g., fluorine); X 2 is N; and R A is a phenyl group (including 2,6-difluorophenyl) optionally substituted by 1 to 3 halogen atoms (e.g., fluorine); The compound is a compound, or a salt thereof.

[0254] Specific examples of Compound (I) include the compounds of Examples 1 to 93 and 96 to 178 described below. In one embodiment, compound (I) is preferably N-[(3R)-4,4-difluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide or a salt thereof (Example 11); N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer) or a salt thereof (Example 39); N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide (optical isomer) or a salt thereof (Example 42); N-[(3R)-1-{5-[5-chloro-3-(2,6-difluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer) or a salt thereof (Example 49); N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide or a salt thereof (Example 109); N-[(3R)-4,4-difluoro-1-{5-(fluoromethyl)-5-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide (optical isomer) or a salt thereof (Example 147); N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide or a salt thereof (Example 149); N-[(3R)-1-{5-[2-(3,5-difluoropyridin-2-yl)-6-fluoro-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide or a salt thereof (Example 154); and N-{(3R,4S)-4-fluoro-4-methyl-1-[(5S)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide, or N-{(3S,4R)-4-fluoro-4-methyl-1-[(5S)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide, or N-{(3R,4 S)-4-Fluoro-4-methyl-1-[(5R)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or an optical isomer of N-{(3S,4R)-4-fluoro-4-methyl-1-[(5R)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide, or a salt thereof (Example 164) is.

[0255] In one embodiment, compound (I) is preferably N-[(3R)-4,4-difluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide or a salt thereof (Example 11); N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide or a salt thereof (Example 109); N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide or a salt thereof (Example 149); and N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide or a salt thereof (Example 165) is.

[0256] As the salt of the compound of formula (I), a pharmacologically acceptable salt is preferred, and examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids 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, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0257] The method for producing the compound of the present invention is explained below.

[0258] The starting compounds and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt, such as the salt of the compound of formula (I).

[0259] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. When the compound obtained in each step is a salt, it can be converted into the desired free form or another type of salt by a method known per se.

[0260] The compound obtained in each step can be used in the next reaction directly as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture according to a known separation method, for example, concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, or the like.

[0261] When the raw material compounds and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0262] In the reaction of each step, the reaction time varies depending on the reagents and solvent used, and unless otherwise specified, the reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0263] In the reactions of each step, the reaction temperature varies depending on the reagents and solvents used, and unless otherwise specified, the reaction temperature is usually from -78°C to 300°C, preferably from -78°C to 150°C.

[0264] In the reaction of each step, the pressure varies depending on the reagents and solvents used, and unless otherwise specified, the pressure is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0265] In the reactions of each step, a microwave synthesis apparatus such as Biotage's Initiator+ can be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0266] In the reactions of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in the amount of the solvent.

[0267] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending the raw material compounds in an appropriate solvent. Specific examples of the solvent include those described in the Examples and the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents can be used alone or in combination of two or more in an appropriate ratio.

[0268] When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the Examples are used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0269] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples can be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0270] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University Press); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc., 1989, or in accordance with the method described in the Examples.

[0271] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G.M. Wuts), published by Wiley-Interscience, 2007; "Protecting Groups, 3rd Ed." (P.J. Kocienski), published by Thieme, 2004, or the method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of thiol-protecting groups include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or the like, or a reduction method.

[0272] When a reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon or Lindlar's catalyst can be used.

[0273] In the oxidation reactions carried out in each step, examples of oxidizing agents that can be used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0274] When a radical cyclization reaction is carried out in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0275] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0276] When the Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0277] In each step, when a Friedel-Crafts reaction is carried out, a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.) is used as a reagent. Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0278] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0279] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is carried out, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0280] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0281] In each step, when a Knoevenagel condensation reaction is carried out, a compound having an active methylene group sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0282] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0283] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, for the azidation reaction of alcohols, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a method using trimethylsilyl azide and a Lewis acid is employed.

[0284] When a reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include aldehydes such as paraformaldehyde and acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amine used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0285] When Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0286] When an esterification reaction, amidation reaction, or urea reaction is performed in each step, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, activated esters, and sulfates. Examples of carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-Chloro-1-methyl-pyridinium iodide (Mukaiyama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be added to the reaction system.

[0287] When a coupling reaction is carried out in each step, 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), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases.

[0288] When a thiocarbonylation reaction is carried out in each step, diphosphorus 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-disulfide (Lawesson's reagent)) may be used in addition to diphosphorus pentasulfide.

[0289] When the Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by providing the reaction system with a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile.

[0290] When a halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent used include hydrohalic acids and acid halides of inorganic acids. Specific examples of chlorination include hydrochloric acid, thionyl chloride, and phosphorus oxychloride, and examples of bromination include 48% hydrobromic acid. Alternatively, a method for producing alkyl halides by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method for producing alkyl halides via a two-step reaction including converting the alcohol to the corresponding sulfonic acid ester and then reacting it with lithium bromide, lithium chloride, or sodium iodide may be used.

[0291] When Arbuzov reaction is carried out in each step, examples of the reagent used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite.

[0292] When a sulfonate esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0293] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. In addition, for the acid hydrolysis reaction of a tert-butyl ester, formic acid, triethylsilane, or the like may be added to reductively trap the by-product tert-butyl cation.

[0294] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, and the like.

[0295] Compound (I) can be produced from compound (1) according to the method shown in Scheme 1 below. 7 is a halogen atom, and P 1is a protecting group, and LG 1 is a leaving group, and the other symbols are as defined above.

[0296] [ka]

[0297] P 1 Examples of the "protecting group" include those exemplified above as "protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole." LG 1 Examples of the "leaving group" include a halogen atom, an optionally halogenated C 1-6 Alkyl sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with alkyl 6-14 Examples thereof include arylsulfonyloxy (eg, benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0298] Compound (I) can be produced by subjecting compound (1) to a nucleophilic substitution reaction with compound (2) and a base. Examples of the base to be used include inorganic bases, organic bases, and alkali metal hydrides. Compound (4) can be produced by subjecting compound (1) to a nucleophilic substitution reaction with compound (3). Compound (5) can be produced by subjecting compound (4) to a deprotection reaction. Compound (I) can also be produced by subjecting compound (5) to a sulfonylation reaction with compound (6). Examples of compound (6) include the corresponding sulfonyl chloride and the corresponding sulfamoyl chloride. Compound (1) is a readily available commercial product, or can be prepared according to the method shown in Scheme 3, 5 or 7 or a method known per se. Compound (2) is a readily available commercial product, or can be prepared according to the method shown in Scheme 4 or a method known per se. Compounds (3) and (6) are readily available commercially, or can be prepared according to known methods.

[0299] Compound (I)-1, in which p is 1 in Compound (I), can be produced from Compound (7) according to the method shown in Scheme 2 below. 8 is a halogen atom, and the other symbols are as defined above.

[0300] [ka]

[0301] Compound (8) can be produced by subjecting compound (7) to a nucleophilic substitution reaction with compound (2) and a base. Examples of the base to be used include inorganic bases, organic bases, and alkali metal hydrides. Compound (I)-1 can be produced by subjecting compound (8) to a coupling reaction with compound (9). Compound (2) is a readily available commercial product, or can be prepared according to the method shown in Scheme 4 or a method known per se. Compound (7) is a readily available commercial product, or can be prepared according to the method shown in Scheme 8 or 9 or a method known per se. Compound (9) is a commercially available product that is readily available, or can be prepared according to a method known per se.

[0302] Compounds (1)-2, (1)-4, and (1)-5 can be prepared from compound (1)-1 according to the method shown in Scheme 3 below. 7 is C 1-6 is an alkyl group, and the other symbols are as defined above.

[0303] [ka]

[0304] Compound (1)-2 can be produced by subjecting compound (1)-1 to a fluorination reaction. Examples of the fluorination reagent used include (diethylamino)sulfur trifluoride and bis(2-methoxyethyl)aminosulfur trifluoride. Compound (1)-3 can be produced by subjecting compound (1)-1 to an oxidation reaction. The compound (1)-4 can be produced by subjecting the compound (1)-3 to a fluorination reaction. Compound (1)-5 can be produced by subjecting compound (1)-1 to an alkylation reaction with compound (10). Compounds (1)-1 and (10) are readily available commercially, or can be prepared according to known methods.

[0305] Compound (2)-1 can be prepared from compound (11) or compound (13) according to the method shown in Scheme 4 below. 2 is a protecting group, and R 8 may be substituted C 1-6 alkyl group or optionally substituted C 6-14 An aryl group, and the other symbols are as defined above.

[0306] [ka]

[0307] Compound (12) can be produced by subjecting compound (11) to a sulfonylation reaction with compound (6). Compound (2)-1 can be produced by subjecting compound (12) to a deprotection reaction. Compound (14) can be produced by subjecting compound (13) to a sulfonation reaction. Examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and trifluoromethanesulfonic anhydride. Compound (12) can also be produced by subjecting compound (14) to an alkylation reaction with compound (15). Compound (17) can be produced by subjecting compound (13) to Mitsunobu reaction with compound (16). Compound (2)-1 can also be produced by subjecting compound (17) to a deprotection reaction. Compounds (6), (11), (13), (15) and (16) are readily available commercially or can be prepared according to known methods.

[0308] Compound (1)-6 and compound (4)-1 can be prepared from compound (18) according to the method shown in Scheme 5 below. 9 and R 10 and R 11 Each of the groups is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, and the other symbols are as defined above.

[0309] [ka]

[0310] Compound (1)-6 can be produced by subjecting compound (18) to a cycloaddition reaction with compound (19) and a base. The base used can be, for example, an inorganic base or an organic base. Compound (4)-1 can be produced by subjecting compound (18) to a cycloaddition reaction with compound (20) and a base. Examples of the base used include inorganic bases and organic bases. Compound (18) is a readily available commercial product, or can be prepared according to the method shown in Scheme 6 or a method known per se. Compounds (19) and (20) are either readily available commercially or can be prepared according to known methods.

[0311] Compound (18)-1 can be prepared from compound (21), compound (26), or compound (28) according to the method shown in Scheme 6 below. 9 and X 10 are each a halogen atom, and the other symbols are as defined above.

[0312] [ka]

[0313] Compound (22) can be produced by subjecting compound (21) to a coupling reaction with compound (9). Compound (24) can be produced by subjecting compound (22) to a Sandmeyer reaction with compound (23). The Sandmeyer reaction is carried out according to a method known per se, for example, a method described in Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin), or a method described in the Examples. Compound (24) can also be produced by subjecting compound (26) to a coupling reaction with compound (27). Compound (24) can also be produced by subjecting compound (28) to a coupling reaction with compound (9). Compound (18)-1 can be produced by subjecting compound (24) to a coupling reaction with compound (25). Compounds (9), (21), (23) and (25)-(28) are readily available commercially or can be prepared according to known methods.

[0314] Compound (1)-7 can be prepared from compound (29) according to the method shown in Scheme 7 below. 11 is a halogen atom, and the other symbols are as defined above.

[0315] [ka]

[0316] Compound (30) can be produced by subjecting compound (29) to a coupling reaction with compound (9). Compound (31) can be produced by subjecting compound (30) to a coupling reaction with compound (25). Compound (32) can be produced by subjecting compound (31) to a cycloaddition reaction with compound (19) and a base. Examples of the base used include inorganic bases and organic bases. Compound (33) can be produced by subjecting compound (32) to a deprotection reaction. Compound (1)-7 can be produced by subjecting compound (33) to a Sandmeyer reaction with compound (23)-1. Compounds (9), (19), (23)-1, (25) and (29) are readily available commercially or can be prepared according to known methods.

[0317] Compounds (7)-2, (7)-4, and (7)-5 can be prepared from compound (7)-1 according to the method shown in Scheme 8 below, where each symbol is as defined above.

[0318] [ka]

[0319] The compound (7)-2 can be produced by subjecting the compound (7)-1 to a fluorination reaction. The compound (7)-3 can be produced by subjecting the compound (7)-1 to an oxidation reaction. The compound (7)-4 can be produced by subjecting the compound (7)-3 to a fluorination reaction. Compound (7)-5 can be produced by subjecting compound (7)-1 to an alkylation reaction with compound (10). Compounds (7)-1 and (10) are readily available commercially, or can be prepared according to known methods.

[0320] Compound (7)-6 can be prepared from compound (28) according to the method shown in Scheme 9 below: wherein each symbol is as defined above.

[0321] [ka]

[0322] Compound (34) can be produced by subjecting compound (28) to a coupling reaction with compound (25). Compound (7)-6 can be produced by subjecting compound (34) to a cycloaddition reaction with compound (19) and a base. The base used can be, for example, an inorganic base or an organic base. Compounds (19), (25) and (28) are readily available commercially or can be prepared according to known methods.

[0323] Compound (22) can be produced from compound (21)-1 according to the method shown in Scheme 10 below: wherein each symbol is as defined above.

[0324] [ka]

[0325] Compound (22) can be produced by subjecting compound (21-1) to a coupling reaction with compound (27). Compounds (21)-1 and (27) are either readily available commercially or can be prepared according to known methods.

[0326] In the compound (I) thus obtained, the functional groups in the molecule can be converted to the desired functional groups by combining known chemical reactions, such as oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0327] In the above-mentioned production methods, when the 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 commonly used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0328] Compound (I) obtained by the above-mentioned production method can be isolated and purified by known means, such as solvent extraction, liquid conversion, dissolution transfer, crystallization, recrystallization, chromatography, and the like. When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or separation method known per se. For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also included in compound (I). Here, the optical isomers can be produced by methods known per se. Compound (I) may be crystalline. The crystals of Compound (I) (hereinafter sometimes abbreviated as the crystals of the present invention) can be produced by crystallizing Compound (I) using a crystallization method known per se.

[0329] In this specification, the melting point refers to the melting point measured using, for example, a micromelting point analyzer (Yanaco, MP-500D model or Buchi, B-545 model) or a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1). Generally, the melting point may vary depending on the measuring instrument, measuring conditions, etc. The crystals in this specification may be crystals that exhibit a melting point different from that described in this specification, as long as it is within the normal error range. The crystals of the present invention have excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), pharmacological efficacy), and are extremely useful as pharmaceuticals.

[0330] Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, or the like. Prodrugs of compound (I) include: a compound in which the amino group of compound (I) has been acylated, alkylated or phosphorylated (e.g., a compound in which the amino group of compound (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., compounds in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); Examples include compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, cyclohexyloxycarbonylethyl-esterified, or methylamidized). These compounds can be produced from compound (I) by methods known per se.

[0331] Furthermore, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Hirokawa Shoten, 1990, Vol. 7, Molecular Design, pp. 163 to 198. In the present specification, the prodrug may be in the form of a salt, and examples of such salts include those exemplified as salts of the compound represented by formula (I) above. Compound (I) may also contain isotopes (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, 125 I) or the like. Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) for use in positron emission tomography (PET), and is useful in fields such as medical diagnosis. Furthermore, Compound (I) may be a hydrate, a non-hydrate, a non-solvate (eg, anhydrous), or a solvate (eg, hydrate). moreover, 1 H 2 Deuterium-converted compounds converted to H(D) are also encompassed by Compound (I). Furthermore, Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared by a known cocrystallization method.

[0332] Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) can be used as a prophylactic or therapeutic agent for various diseases described below in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys) either as such or in the form of a pharmaceutical composition (also referred to as a medicine) by mixing it with a pharmacologically acceptable carrier or the like. Here, various organic or inorganic carrier substances commonly used as pharmaceutical ingredients are used as pharmacologically acceptable carriers, and are incorporated as excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. Furthermore, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners, etc. can also be used as needed.

[0333] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose. Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Suitable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate. Suitable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Suitable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. A suitable example of a soothing agent is benzyl alcohol. Suitable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acids. Suitable examples of coloring agents include water-soluble food tar dyes (e.g., food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide). Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.

[0334] Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), capsules (including soft capsules and microcapsules), pills, granules, powders, troches, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal patch films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. The compound of the present invention and the medicament of the present invention can be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, subcutaneously, intraorgan, intranasally, intradermally, by eye drop, intracerebrally, intravaginally, intraperitoneally, inside a tumor, in the vicinity of a tumor, or directly to a lesion). These formulations may be immediate release formulations or controlled release formulations such as sustained release formulations (eg, sustained release microcapsules).

[0335] The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical formulation, for example, a method described in the Japanese Pharmacopoeia. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight. When producing oral preparations, coating may be carried out, if necessary, for the purposes of taste masking, enteric coating, or sustained release.

[0336] Examples of coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination. Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L (Eudragit L (trade name)), methacrylic acid copolymer LD (Eudragit L-30D55 ​​(trade name)), and methacrylic acid copolymer S (Eudragit S (trade name)); and natural products such as shellac. Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)). The above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. Furthermore, a light-shielding agent such as titanium oxide or iron sesquioxide may be used during coating.

[0337] The compound of the present invention has low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as a preventive or therapeutic agent or diagnostic agent for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0338] Furthermore, the compounds of the present invention are expected to have excellent central nervous system transfer properties.

[0339] The compound of the present invention has excellent orexin type 2 receptor agonist activity and can treat, prevent, and alleviate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor. The compound of the present invention can be used to treat, prevent, and alleviate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor, for example, narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, U-12 encephalitis, and other conditions. Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, pituitary obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as coma, side effects and complications from anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms convulsions, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunkenness, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, Cardiac arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormonal abnormalities, sexual and reproductive dysfunction such as reduced fertility, infertility, male hypogonadism, and female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity-hypoventilation syndrome (Pickwickian syndrome),Reduces the risk of respiratory disorders such as shortness of breath, inflammation such as systemic inflammation of the vascular system, secondary consequences of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flashes, night sweats, genital / urinary system disorders, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as cerebral defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, and spinal cord trauma. The compounds are useful as preventive or therapeutic agents for various diseases, such as head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury (TBI). ,

[0340] In particular, the compound of the present invention is useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, side effects and complications caused by anesthesia, and the like, or as an anesthetic antagonist.

[0341] In some embodiments, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness, and side effects or complications of anesthesia. In some embodiments, the compounds of the present invention are useful as agents for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea. In some embodiments, the compounds of the present invention are useful as agents for the prevention or treatment of narcolepsy.

[0342] Central hypersomnia (CDH) is characterized by excessive daytime sleepiness in the absence of other sleep disorders and despite the establishment of adequate and regular sleep habits. Central hypersomnia (CDH) includes narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. Kleine-Levin syndrome and insufficient sleep syndromes or hypersomnia caused by medical conditions, drugs or substances, or psychiatric conditions are also considered central hypersomnia. Evaluation of CDH includes sleep testing in a sleep laboratory (polysomnography, PSG) followed by multiple sleep latency testing (MSLT). Symptoms associated with narcolepsy include abnormal intrusions of REM sleep characteristics into wakefulness, such as sleep-related hallucinations, sleep paralysis, or vivid dreams and confusion between dreams and reality. These symptoms can occur even in people without a sleep disorder. Some people with narcolepsy experience cataplexy (narcolepsy type 1), a loss of muscle tone that is triggered by emotions, typically laughter or anticipation. Cataplexy can be generalized or partial and does not involve loss of consciousness. This muscle weakness usually improves within seconds to minutes. Patients with idiopathic hypersomnia (IDH) often complain of excessive daytime sleepiness, prolonged sleep duration (more than 10-11 hours of sleep per night), and severe difficulty waking in the morning (sleep inertia). In contrast to narcolepsy, patients with IDH often take long, unrefreshing naps. Another common symptom of IDH is "brain fog," a feeling of daytime cognitive clouding. Kleine-Levin syndrome is a rare disorder of periodic hypersomnia.

[0343] One aspect of the disclosure is a method of treating a subject having one or more central hypersomnias (CDH), comprising administering to the subject a compound of the invention. Another aspect of the present disclosure is the use of a compound of the present invention for the manufacture of a medicament for the treatment of one or more central hypersomnias (CDH) in a subject. Another aspect of the present disclosure is a compound of the present invention for use in treating one or more central hypersomnias (CDH) in a subject. Another embodiment is the method or use of the previous embodiment, wherein the subject has narcolepsy. In one embodiment, the subject has been diagnosed with narcolepsy type 1. In another embodiment, the subject has been diagnosed with narcolepsy type 2. In yet another embodiment, the subject has been diagnosed with idiopathic hypersomnia.

[0344] Another embodiment is a method or use of any of the preceding embodiments, wherein administering a compound of the invention reduces daytime sleepiness, reduces instances of loss of muscle control, and / or reduces instances of sleep disruption in a subject. Another aspect is a method or use wherein a compound of the invention is administered in an amount effective to reduce excessive daytime sleepiness in adults with narcolepsy. Another aspect is the method or use, wherein a compound of the invention is administered in an amount effective to increase mean sleep latency. Another aspect is a method or use, wherein a compound of the invention is administered in an amount effective to reduce cataplexy events. Another aspect is a method or use, wherein a compound of the invention is administered in an amount effective to reduce nocturnal sleep disruption in a subject.

[0345] The dosage of the compound of the present invention varies depending on the subject, administration route, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the single dose is usually about 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight, and more preferably 0.5 to 20 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

[0346] The compound of the present invention can be used in combination with other drugs (hereinafter abbreviated as concomitant drugs). By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to when the compound of the present invention or a concomitant drug is administered alone. (2) Drugs to be used in combination with the compound of the present invention can be selected depending on the patient's symptoms (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0347] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as the "concomitant drug of the present invention." When using the combination drug of the present invention, the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof may be administered to a subject simultaneously or at staggered times. The dosage of the concomitant drug may be in accordance with the dosage used clinically and can be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug via different administration routes with a time lag (e.g., administration in the order of the compound of the present invention and the concomitant drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage, and the mixing ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc. For example, the content of the compound of the present invention in the combination drug of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total weight of the formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight of the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the formulation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total weight of the formulation. Furthermore, when the compound of the present invention and the concomitant drug are formulated separately, the contents may be similar.

[0348] Concomitant medications include, for example, the following: narcolepsy medications (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drugs (amphetamine, benzphetamine, bromocloptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), antidementia drugs (e.g., memantine), inhibitors of beta-amyloid protein production, secretion, accumulation, aggregation and / or deposition, beta-secretase inhibitors (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-(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-yl)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, their optically active forms, their salts and their hydrates,OM99-2 (International Publication No. 01 / 00663)), gamma-secretase inhibitors, beta-amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (JP Patent Publication No. Hei 11-514333), PPI-558 (JP Patent Publication No. 2001-500852), SKF-74652 (Biochem.J.(1999),340(1),283-289)), beta-amyloid vaccines, beta-amyloid degrading enzymes, etc., brain function enhancers (e.g., aniracetam, nicergoline), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-dopa , bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline (remacemide), riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], drugs for treating amyotrophic lateral sclerosis (e.g., riluzole, neurotrophic factors), drugs for treating abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), Neuronal differentiation and regeneration promoters (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-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, propylphenyl)-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 its optically active forms, salts, hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drugs (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors,MAP kinase inhibitors), drugs for treating urinary incontinence and frequent urination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil citrate), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), drugs for treating osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, salmon calciton nin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, drugs for treating insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, orexin receptor antagonists), drugs for treating schizophrenia (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole) drugs acting on metabotropic glutamate receptors or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines (chlordiazepoxide, diazepam, clorazepate potassium, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin Reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT, 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, 5-HT3 antagonists (cyamemazine, etc.), non-cardioselective beta-blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, beta3-adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel blockers, type 2 carbonic anhydrase inhibitors, NM DA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), drugs for treating bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, phenelzine sulfate ... benzodiazepines (e.g., benzodiazepines), cannabinoid CB1 antagonists (e.g., rimonabant), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (e.g., methylphenidate hydrochloride, methamphetamine hydrochloride), drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for smoking cessation, drugs for treating myasthenia gravis, drugs for treating cerebral infarction, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating dysthymia, drugs for treating autonomic nervous system disorders, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling, and drugs for treating leg immobility drugs for treating impotence syndrome, drugs for treating substance dependence, drugs for treating alcohol-related diseases, drugs for treating irritable bowel syndrome, drugs for treating dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or drugs to suppress wanderlust due to dementia (sedatives, anti-anxiety drugs, etc.), drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating high blood pressure, drugs for treating low blood pressure, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anticancer agents, etc.

[0349] The above concomitant drugs may be used in combination of two or more kinds in an appropriate ratio. Furthermore, when the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in combination with a biological product (e.g., an antibody drug, a nucleic acid or a nucleic acid derivative, an aptamer drug, or a vaccine preparation), and can also be used in combination with a gene therapy or the like, or with a drug-free psychiatric therapy. Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, TNFα antibodies, antibodies against other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., Peptor's DIAPEP-277), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in the blood coagulation and fibrinolysis systems, antibodies or vaccine preparations against proteins involved in glucose metabolism and insulin resistance, etc. In addition, they can also be used in combination with biological preparations related to growth factors such as GH and IGF. Examples of gene therapy methods include therapies using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes; treatments using DNA decoys such as NFκB decoys; treatments using antisense; treatments using genes related to enzymes and proteins involved in blood lipid metabolism (e.g., genes related to the metabolism, excretion, and absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids); treatments using genes related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular occlusion and the like (e.g., growth factors such as HGF and VEGF); treatments using genes related to proteins involved in glucose metabolism and insulin resistance; and antisense against cytokines such as TNF. Non-drug psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy, including cognitive behavioral therapy. Furthermore, the compound of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (e.g., artificial blood vessels, cardiomyocyte sheets). [Example]

[0350] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these do not limit the present invention and may be modified within the scope of the present invention. In the following examples, "room temperature" generally refers to a temperature of about 10° C. to about 35° C. The ratio of mixed solvents is by volume unless otherwise specified. % is by weight unless otherwise specified.

[0351] Unless otherwise specified, elution in column chromatography in the examples was carried out under observation by TLC (Thin Layer Chromatography). In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The solvent used in column chromatography was used as the eluent. A UV detector was used for detection. In silica gel column chromatography, the abbreviation NH indicates the use of aminopropylsilane-bonded silica gel, and the abbreviation Diol indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high-performance liquid chromatography), the abbreviation C18 indicates the use of octadecyl-bonded silica gel. Unless otherwise specified, the ratio of elution solvents is expressed by volume.

[0352] 1 H NMR analysis was performed using ACD / SpecManager (trade name) software. Peaks with very gentle proton peaks, such as those of hydroxyl groups and amino groups, may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shown are actual measurements (found values). Molecular ion peaks are usually observed, but fragment ions may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0353] The unit of sample concentration (c) for the optical rotation ([α]D) is g / 100 mL. Elemental analysis values ​​(Anal.) are reported as calculated values ​​(Calcd) and found values ​​(Found). In the examples, retention times were measured by liquid chromatography under the following conditions unless otherwise specified. Column: YMC PackPro C18 2.0mm idx75mm (3μm) Mobile phase: A solution prepared by adding 0.04 M Britton-Robinson buffer (pH 6.5) to methanol (5:2), mixing well, and adjusting the pH to 7.4 with 0.2 M sodium hydroxide solution. In the examples, the peaks measured by powder X-ray diffraction are those measured at room temperature using an Ultima IV (Rigaku Corporation) with CuKα radiation as the radiation source. The measurement conditions are as follows: Voltage / Current: 40kV / 50mA Scan speed: 6° / min 2-theta scan range: 2-35° In the examples, the crystallinity measured by powder X-ray diffraction was calculated by the Hermans method.

[0354] The following abbreviations are used in the following examples: mp: melting point MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization Et2O: Diethyl ether DIPEA: Diisopropylethylamine IPE: Diisopropyl ether NBS: N-bromosuccinimide CPME: Cyclopentyl methyl ether DIAD: Diisopropylethylamine NMP: N-methyl-2-pyrrolidone TFA: Trifluoroacetic acid THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) TEA: Triethylamine DPPA: Diphenylphosphoryl azide MeOH: Methanol EtOH: ethanol IPA: 2-propanol EtOAc: ethyl acetate CH2Cl2: Dichloromethane t-BuOH: tert-butyl alcohol DAST: (Diethylamino)sulfur trifluoride NCS: N-chlorosuccinimide Pd(Ph3P)4: Tetrakis(triphenylphosphine)palladium(0) Pd(OAc)2: Palladium(II) acetate Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(dppf)Cl2·CH2Cl2:[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct SFC: Supercritical Fluid Chromatography

[0355] Example 8 N-{(3S)-1-[5-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}ethanesulfonamide

[0356] A) tert-Butyl (3S)-3-[(ethanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (1.00 g) and triethylamine (2.10 mL) in THF (22 mL) was added ethanesulfonyl chloride (0.712 mL) dropwise at room temperature. The mixture was stirred at room temperature overnight. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.28 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.18 (3H, t, J = 7.4 Hz), 1.39 (9H, s), 1.70-1.84 (1H, m), 1.98-2.09 (1H, m), 3.00-3.25 (4H, m), 3.33-3.39 (1H, m), 3.46 (1H, dd, J = 10.9, 6.5 Hz), 3.83 (1H, br s), 7.38 (1H, d, J = 6.3 Hz).

[0357] B) N-[(3S)-pyrrolidin-3-yl]ethanesulfonamide hydrochloride A mixture of tert-butyl (3S)-3-[(ethanesulfonyl)amino]pyrrolidine-1-carboxylate (2.84 g) and 4 M hydrogen chloride in EtOAc (12.8 mL) was stirred at room temperature overnight. To the resulting suspension was added heptane with stirring, and the precipitate was collected, washed with EtOAc, and dried under reduced pressure at 50 °C to give the title compound (2.09 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.3 Hz), 1.87 (1H, dq, J = 13.5, 6.7 Hz), 2.04-2.22 (1H, m), 2.92-3.35 (6H, m), 3.99 (1H, sxt, J = 6.2 Hz), 7.56 (1H, d, J = 6.4 Hz), 9.31 (2H, br s).

[0358] C) 3-bromo-5-(2-bromo-4-methylphenyl)-4,5-dihydro-1,2-oxazole Sodium bicarbonate (128 mg) was added to a mixture of 2-bromo-4-methyl-1-vinylbenzene (150 mg) and hydroxycarbonimide dibromide (232 mg) in EtOAc (3.05 mL) at room temperature. The mixture was stirred at 70°C for 7 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (216 mg). 1 H NMR (400 MHz, CDCl3) δ 2.34 (3H, s), 3.03 (1H, dd, J = 17.4, 7.6 Hz), 3.80 (1H, dd, J = 17.4, 11.0 Hz), 5.89 (1H, dd, J = 11.0, 7.7 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.32-7.51 (2H, m).

[0359] D) N-{(3S)-1-[5-(2-bromo-4-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}ethanesulfonamide A mixture of 3-bromo-5-(2-bromo-4-methylphenyl)-4,5-dihydro-1,2-oxazole (55 mg), N-[(3S)-pyrrolidin-3-yl]ethanesulfonamide hydrochloride (48.1 mg), and sodium carbonate (91 mg) was stirred at 130° C. for 24 hours. The mixture was poured into water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / EtOAc) to give the title compound (62 mg). MS: [M+H] + 416.0.

[0360] E) N-{(3S)-1-[5-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}ethanesulfonamide Tri-tert-butylphosphonium tetrafluoroborate (4.32 mg) and Pd2(dba)3 (4.28 mg) were added to a mixture of N-{(3S)-1-[5-(2-bromo-4-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}ethanesulfonamide (62.0 mg), (2,6-difluorophenyl)boronic acid (47.0 mg), potassium fluoride (17.3 mg) in THF (1.24 mL) and water (0.248 mL). The mixture was stirred at 140 °C under microwave irradiation for 1 hour. The crude product was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fractions were then concentrated to give the title compound (13.0 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.18 (3H, td, J = 7.3, 1.1 Hz), 1.74-1.86 (1H, m), 2.08-2.13 (1H, m), 2.33 (3H, s), 2.80-3.29 (7H, m), 3.41 (1H, ddd, J = 12.4, 10.4, 6.5 Hz), 3.81-3.92 (1H, m), 5.03 (1H, t, J = 9.3 Hz), 7.07 (1H, s), 7.23 (2H, td, J = 8.6, 2.6 Hz), 7.32 (1H, d, J = 7.8 Hz), 7.39 (1H, d, J = 5.0 Hz), 7.47-7.60 (2H, m).

[0361] Example 11 N-[(3R)-4,4-difluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide

[0362] A) 5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-amine Tri-tert-butylphosphonium tetrafluoroborate (1.63 g) and Pd2(dba)3 (1.61 g) were added to a mixture of 3-bromo-5-methylpyridin-2-amine (7.00 g), (2,4,6-trifluorophenyl)boronic acid (9.87 g), and potassium fluoride (4.35 g) in THF (104 mL) and water (20.8 mL) at room temperature. The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was poured into brine, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, passed through a pad of NH silica gel, and concentrated under reduced pressure. The solid was triturated with IPE to give the title compound (9.15 g). MS: [M+H] + 239.0.

[0363] B) 2-chloro-5-methyl-3-(2,4,6-trifluorophenyl)pyridine A solution of sodium nitrite (7.95 g) in water (5 mL) was added dropwise to a solution of 5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-amine (9.15 g) in concentrated aqueous hydrogen chloride (80 mL) at -10°C. The mixture was stirred at -10°C for 10 minutes. Copper(I) chloride (22.8 g) was added portionwise to the mixture at -10°C. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine and water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (5.50 g). MS: [M+H] + 257.9.

[0364] C) 2-ethenyl-5-methyl-3-(2,4,6-trifluorophenyl)pyridine Pd(dppf)Cl2·CHCl2 (190 mg) was added to a mixture of 2-chloro-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (400 mg), potassium vinyltrifluoroborate (475 mg), potassium carbonate (429 mg) in DME (8.63 mL) and water (1.73 mL) at room temperature. The mixture was stirred at 110 °C under microwave irradiation under an argon atmosphere for 2 hours. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (358 mg). MS: [M+H] + 250.0.

[0365] D) 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-methyl-3-(2,4,6-trifluorophenyl)pyridine Sodium bicarbonate (241 mg) was added to a mixture of 2-ethenyl-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (358 mg) and hydroxycarbonimide dibromide (437 mg) in EtOAc (5.75 mL) at room temperature. The mixture was stirred at 75°C overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (293 mg). MS: [M+H] + 371.0.

[0366] E) 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-5-methyl-3-(2,4,6-trifluorophenyl)pyridine 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (9.0 g) was optically resolved by SFC to give the title compound with a shorter retention time (4.3 g). Chiral separation conditions Column: Chiral PAK IC (trademark) (250mm*50mm, 10μm) Mobile phase: CO2 / IPA containing 0.1% ammonium hydroxide = 750 / 250 (v / v) MS: [M+H] + 371.0.

[0367] F) N-[(3R)-4,4-difluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (1.10 g) and N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (1.40 g) in pyridine (7.41 mL) was stirred in a sealed tube at 135° C. for 15 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) and NH silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOAc / hexane to give the title compound (667 mg). 1 H NMR (400 MHz, CDCl3) δ 2.40 (3H, s), 3.08 (3H, s), 3.15 (1H, dd, J = 15.7, 9.9 Hz), 3.24-3.32 (1H, m), 3.66-4.03 (4H, m), 4.33 (1H, dquin, J = 14.0, 8.9 Hz), 4.84 (1H, d, J = 9.8 Hz), 5.49 (1H, t, J = 9.1 Hz), 6.78 (2H, dtt, J = 17.3, 8.8, 2.3 Hz), 7.40-7.42 (1H, m), 8.53 (1H, d, J = 1.8 Hz).

[0368] Example 12 N-[(3R)-1-{5-[1-(2,6-difluorophenyl)-4-methyl-1H-imidazol-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide

[0369] A) 2-bromo-1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1H-imidazole Potassium carbonate (1.72 g) was added to a solution of 2-bromo-4-methyl-1H-imidazole (1.00 g) and 1,2,3-trifluoro-5-nitrobenzene (1.65 g) in DMF (15 mL) at room temperature. The mixture was stirred at 60° C. overnight. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.40 g) as a mixture with regioisomers. MS: [M+H] + 317.9.

[0370] B) 4-(2-bromo-4-methyl-1H-imidazol-1-yl)-3,5-difluoroaniline Iron (1.23 g) was added to a solution of 2-bromo-1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1H-imidazole (1.40 g, including regioisomer) and 1M aqueous hydrogen chloride solution (2 mL) in EtOH (15 mL) at room temperature. The mixture was stirred at 80° C. for 1 hour. The precipitate was removed by filtration through Celite™. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine and water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.12 g). MS: [M+H] + 287.9.

[0371] C) 2-Bromo-1-(2,6-difluorophenyl)-4-methyl-1H-imidazole To a solution of n-pentyl nitrite (1.03 mL) in THF (38.9 mL) was added 4-(2-bromo-4-methyl-1H-imidazol-1-yl)-3,5-difluoroaniline (1.12 g) portionwise at 0°C. The mixture was stirred at 0°C for 15 minutes. Then, hypophosphorous acid (2.13 mL) was added to the solution, and the mixture was stirred at 0°C for 30 minutes. The mixture was neutralized with saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with EtOAc. The 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) to give the title compound (595 mg). 1 H NMR (400 MHz, CDCl3) δ 2.28 (3H, s), 6.80 (1H, s), 7.09 (2H, t, J = 8.3 Hz), 7.46 (1H, quin, J = 7.3 Hz).

[0372] D) 1-(2,6-difluorophenyl)-4-methyl-2-(prop-1-en-2-yl)-1H-imidazole Pd(dppf)Cl2·CHCl2 (93.0 mg) was added to a mixture of 2-bromo-1-(2,6-difluorophenyl)-4-methyl-1H-imidazole (205 mg), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (191 mg), potassium carbonate (235 mg) in DME (4 mL) and water (0.800 mL) at room temperature. The mixture was stirred at 110 °C under microwave irradiation under an argon atmosphere for 2 hours. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (125 mg). MS: [M+H] + 235.0.

[0373] E) 3-bromo-5-[1-(2,6-difluorophenyl)-4-methyl-1H-imidazol-2-yl]-5-methyl-4,5-dihydro-1,2-oxazole Sodium bicarbonate (134 mg) was added to a solution of 1-(2,6-difluorophenyl)-4-methyl-2-(prop-1-en-2-yl)-1H-imidazole (125 mg) and hydroxycarbonimide dibromide (216 mg) in EtOAc (3 mL) at room temperature. The mixture was stirred at 70°C for 5 hours. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (71.0 mg). MS: [M+H] + 355.9.

[0374] F) N-[(3R)-1-{5-[1-(2,6-difluorophenyl)-4-methyl-1H-imidazol-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide A mixture of 3-bromo-5-[1-(2,6-difluorophenyl)-4-methyl-1H-imidazol-2-yl]-5-methyl-4,5-dihydro-1,2-oxazole (71 mg), (N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (70.8 mg) in pyridine (0.498 mL) was stirred at 140° C. overnight. The residue was purified by silica gel column chromatography (EtOAc / hexane) and preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fractions were then concentrated to give the title compound (46.3 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.49 (3H, d, J = 2.3 Hz), 2.12 (3H, d, J = 0.8 Hz), 2.99 (3H, d, J = 0.6 Hz), 3.03-3.26 (2H, m), 3.43-3.91 (4H, m), 4.07-4.48 (1H, m), 6.97 (1H, dd, J = 1.7, 1.1 Hz), 7.18-7.37 (2H, m), 7.47-7.72 (1H, m), 7.95 (1H, dd, J = 9.1, 4.1 Hz).

[0375] Example 20 N-[(1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutyl]methanesulfonamide

[0376] A) 2-chloro-3-(2,6-difluorophenyl)-5-methylpyridine Tri-tert-butylphosphonium tetrafluoroborate (0.703 g) and Pd2(dba)3 (1.11 g) were added to a mixture of 3-bromo-2-chloro-5-methylpyridine (5.00 g), (2,6-difluorophenyl)boronic acid (4.97 g), and potassium fluoride (2.81 g) in THF (67.3 mL) and water (13.5 mL) at room temperature. The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was poured into brine, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (5.55 g). MS: [M+H] + 239.9.

[0377] B) 3-(2,6-difluorophenyl)-2-ethenyl-5-methylpyridine Pd(dppf)Cl2·CHCl2 (0.562 g) was added to a mixture of 2-chloro-3-(2,6-difluorophenyl)-5-methylpyridine (1.10 g), potassium vinyltrifluoroborate (1.35 g), potassium carbonate (1.27 g) in DME (17 mL) and water (3 mL) at room temperature. The mixture was stirred at 110 °C under microwave irradiation under an argon atmosphere for 3.5 hours. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (6.10 g). MS: [M+H] + 232.0.

[0378] C) 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-methylpyridine Sodium bicarbonate (7.34 g) was added to a mixture of 3-(2,6-difluorophenyl)-2-ethenyl-5-methylpyridine (5.05 g) and hydroxycarbonimide dibromide (8.86 g) in EtOAc (87 mL) at room temperature. The mixture was stirred at 70° C. overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (6.37 g). 1 H NMR (400 MHz, CDCl3) δ 2.41 (3H, s), 3.41 (1H, dd, J = 17.1, 11.0 Hz), 3.89 (1H, dd, J = 17.1, 9.0 Hz), 5.55-5.71 (1H, m), 6.95-7.09 (2H, m), 7.30-7.48 (2H, m), 8.57 (1H, d, J = 1.8 Hz).

[0379] D) tert-Butyl [(1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutyl]carbamate To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (31.8 mg) in THF (0.5 mL) was added sodium hydride (60% in oil, 6.80 mg) at room temperature. After stirring at room temperature for 30 minutes, 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-methylpyridine (40 mg) in THF (0.1 mL) was added to the reaction mixture. The mixture was refluxed overnight. The mixture was quenched with saturated aqueous ammonium chloride at room temperature, and the resulting 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 column chromatography (EtOAc / hexane) to give the title compound (29.4 mg). MS: [M+H] + 460.1.

[0380] E) (1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutan-1-amine trifluoroacetic acid To a solution of tert-butyl [(1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutyl]carbamate (29.4 mg) in toluene (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the title compound (30.3 mg). MS: [M+H-(TFA)] + 360.1.

[0381] F) N-[(1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutyl]methanesulfonamide (1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutan-1-amine To a cooled (0°C) mixture of trifluoroacetic acid (30.3 mg) and TEA (0.089 mL) in THF (1 mL), methanesulfonic anhydride (14.5 mg) was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (23.5 mg). 1 H NMR (400 MHz, CDCl3) δ 2.06-2.15 (2H, m), 2.40 (3H, s), 2.93 (3H, s), 2.94-3.12 (3H, m), 3.56-3.76 (2H, m), 4.44 (1H, d, J = 8.8 Hz), 4.60 (1H, t, J = 7.0 Hz), 5.52 (1H, t, J = 9.7 Hz), 6.95-7.05 (2H, m), 7.34-7.44 (2H, m), 8.56 (1H, d, J = 1.8 Hz).

[0382] Example 22 N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide

[0383] A) 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-methylpyridine (253 mg) was optically resolved by HPLC. The fraction with a shorter retention time was concentrated under reduced pressure to give the title compound (111 mg). Chiral separation conditions Column: Chiral PAK IH (trademark) (20mmID*250mmL, 5μm) Mobile phase: Hexane / IPA = 800 / 200 (v / v) MS (found): 353.1, 355.1.

[0384] B) N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (50.0 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride (71.0 mg) in pyridine (0.354 mL) was stirred in a sealed tube at 140° C. for 15 hours. The residue was purified by silica gel column chromatography (EtOAc / hexane). The desired fraction was concentrated under reduced pressure. The residue was triturated with IPE to give the title compound (22.1 mg). 1 H NMR (400 MHz, CDCl3) δ 1.42 (3H, t, J = 7.3 Hz), 2.40 (3H, s), 3.09-3.21 (3H, m), 3.27 (1H, t, J = 9.6 Hz), 3.69-3.86 (3H, m), 3.91 (1H, dd, J = 9.9, 7.9 Hz), 4.11-4.41 (1H, m), 4.66 (1H, d, J = 9.5 Hz), 5.51 (1H, t, J = 9.0 Hz), 6.76-7.11 (2H, m), 7.29-7.47 (2H, m), 8.54 (1H, d, J = 2.0 Hz).

[0385] Example 23 N-[(1s,3s)-3-{5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}cyclobutyl]methanesulfonamide

[0386] A) tert-Butyl [(1s,3s)-3-{5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}cyclobutyl]carbamate A mixture of tert-butyl ((1s,3s)-3-formylcyclobutyl)carbamate (1.24 g), hydroxylamine hydrochloride (0.388 mL), and pyridine (1.01 mL) in EtOH (10 mL) and water (3 mL) was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue and NCS (0.831 g) in DMF (15 mL) was stirred at room temperature for 1 hour. The mixture was diluted with water, and the resulting mixture was extracted with EtOAc. The organic layer was washed three times with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. TEA (0.380 mL) was added to a mixture of 5-methyl-3-(2,4,6-trifluorophenyl)-2-vinylpyridine (200 mg) and the residue (339 mg) in THF (2 mL) at room temperature. The mixture was stirred at 50°C for 1 hour. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (355 mg). MS: [M+H] + 462.1.

[0387] B) N-[(1s,3s)-3-{5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}cyclobutyl]methanesulfonamide A mixture of tert-butyl [(1s,3s)-3-{5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}cyclobutyl]carbamate (355 mg) in TFA (1 mL) was stirred at room temperature for 20 minutes. The mixture was concentrated under reduced pressure. To a solution of the residue and TEA (0.537 mL) in THF (2 mL) was added methanesulfonyl chloride (132 mg). The mixture was stirred at 0°C for 10 minutes. Then, TEA (0.3 mL) and methanesulfonyl chloride (30.0 mg) were added to the mixture at room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (265 mg). 1 H NMR (300 MHz, CDCl3) δ 2.14-2.28 (2H, m), 2.39 (3H, s), 2.63-2.78 (2H, m), 2.81-2.96 (4H, m), 3.10 (1H, dd, J = 16.8, 10.7 Hz), 3.53 (1H, dd, J = 16.9, 7.9 Hz), 3.96 (1H, sxt, J = 8.2 Hz), 4.84-5.04 (1H, m), 5.45 (1H, dd, J = 10.2, 8.7 Hz), 6.64-6.90 (2H, m), 7.34-7.45 (1H, m), 8.52 (1H, d, J = 2.3 Hz).

[0388] Example 30 N-[(3S)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]-1-fluorocyclopropane-1-sulfonamide

[0389] A) tert-Butyl (3S)-3-[(tert-butoxycarbonyl)(1-fluorocyclopropane-1-sulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl ((1-fluorocyclopropyl)sulfonyl)carbamate (479 mg), tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (374 mg), and triphenylphosphine (1.05 g) in toluene (20 mL) was added 1.9 M DIAD in toluene (2.63 mL) at 0° C. The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and poured into water at room temperature. 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 column chromatography (EtOAc / hexane) to give the title compound (587 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.39 (9H, s), 1.48 (9H, s), 1.61-1.83 (4H, m), 2.07-2.19 (1H, m), 2.20-2.33 (1H, m), 3.12-3.28 (1H, m), 3.36-3.59 (3H, m), 4.77-4.96 (1H, m).

[0390] B) 1-Fluoro-N-[(3S)-pyrrolidin-3-yl]cyclopropane-1-sulfonamide hydrochloride tert-Butyl (3S)-3-[(tert-butoxycarbonyl)(1-fluorocyclopropane-1-sulfonyl)amino]pyrrolidine-1-carboxylate (587 mg) was dissolved in 4 M hydrogen chloride in CPME (6 mL). The mixture was stirred at room temperature under a dry atmosphere overnight. The mixture was concentrated. The residue was triturated with EtOAc and filtered to give the title compound (364 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.34-1.62 (4H, m), 1.89 (1H, td, J = 13.6, 7.2 Hz), 2.18 (1H, dq, J = 13.6, 7.0 Hz), 3.01 (1H, dd, J = 12.0, 6.0 Hz), 3.13-3.30 (2H, m), 3.35-3.46 (1H, m), 4.15 (1H, quin, J = 6.4 Hz), 8.26-8.72 (1H, m), 9.10 (2H, br s).

[0391] C) N-[(3S)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]-1-fluorocyclopropane-1-sulfonamide To a mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (43.3 mg) and DIPEA (0.143 mL) in NMP (0.50 mL) was added 1-fluoro-N-[(3S)-pyrrolidin-3-yl]cyclopropane-1-sulfonamide hydrochloride (20 mg). The mixture was stirred at 120°C for 3 hours. The mixture was quenched with water, and the resulting 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 column chromatography (EtOAc / hexane and NH, EtOAc / hexane) to give the title compound (18 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.58 (4H, m), 1.82-1.93 (1H, m), 2.09-2.19 (1H, m), 2.36 (3H, s), 3.09 (1H, dd, J = 10.4, 5.5 Hz), 3.17-3.28 (3H, m), 3.45 (1H, dd, J = 10.4, 6.6 Hz), 3.70 (1H, dd, J = 15.6, 8.8 Hz), 4.03-4.09 (1H, m), 5.21 (1H, t, J = 9.2 Hz), 7.19-7.29 (2H, m), 7.49-7.60 (1H, m), 7.62 (1H, d, J = 1.9 Hz), 8.33 (1H, d, J = 7.9 Hz), 8.54 (1H, d, J = 1.9 Hz).

[0392] Example 39 N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer)

[0393] A) tert-butyl [6-chloro-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate Tri-tert-butylphosphonium tetrafluoroborate (0.755 g) and Pd2(dba)3 (0.794 g) were added to a mixture of tert-butyl (5-bromo-6-chloropyridin-3-yl)carbamate (5.34 g), (2,4,6-trifluorophenyl)boronic acid (3.66 g), and potassium fluoride (2.02 g) in THF (55 mL) and water (11 mL) at room temperature. The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was poured into water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (5.58 g). 1 H NMR (300 MHz, CDCl3) δ 1.52 (9H, s), 6.59 (1H, br s), 6.78 (2H, dd, J = 8.7, 7.3 Hz), 8.09 (1H, br s), 8.27 (1H, d, J = 2.8 Hz).

[0394] B) tert-butyl [6-ethenyl-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate Pd(dppf)Cl2·CHCl2 (221 mg) was added to a mixture of tert-butyl [6-chloro-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate (648 mg), potassium vinyltrifluoroborate (532 mg), and potassium carbonate (749 mg) in DME (10 mL) and water (2.00 mL) at room temperature. The mixture was stirred at 110 °C under microwave irradiation under an argon atmosphere for 3.5 hours. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (510 mg). MS: [M+H] + 351.0.

[0395] C) tert-Butyl [6-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate Sodium bicarbonate (489 mg) was added to a mixture of tert-butyl [6-ethenyl-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate (510 mg) and hydroxycarbonimide dibromide (591 mg) in EtOAc (6.0 mL) at room temperature. The mixture was stirred at 70°C overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (577 mg). MS: [M+H] + 472.0.

[0396] D) 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,4,6-trifluorophenyl)pyridine TFA (3 mL) was added to tert-butyl [6-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate (577 mg) in a flask at 0° C. The mixture was stirred at room temperature for 30 minutes. After the solvent was evaporated under reduced pressure, the residue was dissolved in conc. hydrochloric acid (5 mL). To the mixture, sodium nitrite (253 mg) in water (1 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 10 minutes. Copper(I) chloride (726 mg) was added portionwise. The mixture was stirred at 0° C. for 1 hour. EtOAc and water were added to the mixture, and the mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (270 mg). MS: [M+H] + 390.9.

[0397] E) N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide A mixture of 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,4,6-trifluorophenyl)pyridine (100 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (121 mg) in pyridine (0.638 mL) was stirred in a sealed tube at 140° C. for 15 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (95 mg). 1H NMR (400 MHz, CDCl3) δ 3.09 (3H, s), 3.12-3.41 (2H, m), 3.69-3.95 (4H, m), 4.34 (1H, dtd, J = 13.3, 8.9, 4.3 Hz), 4.80-4.95 (1H, m), 5.49 (1H, t, J = 8.8 Hz), 6.63-7.05 (2H, m), 7.62 (1H, d, J = 2.3 Hz), 8.53-8.79 (1H, m).

[0398] F) N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer) N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (77.5 mg) was optically resolved by HPLC. The longer retention fraction was concentrated under reduced pressure to give the title compound (40.2 mg). Chiral separation conditions Column: Chiral PAK IB-N5 (trademark) (20mmID*250mmL, 5μm) Mobile phase: Hexane / EtOH = 600 / 400 (v / v) 1 H NMR (300 MHz, CDCl3) δ 3.09 (3H, s), 3.14-3.39 (2H, m), 3.64-3.98 (4H, m), 4.34 (1H, dt, J = 13.8, 8.9 Hz), 4.75 (1H, d, J = 9.8 Hz), 5.50 (1H, t, J = 8.8 Hz), 6.72-6.87 (2H, m), 7.59-7.64 (1H, m), 8.65 (1H, d, J = 2.3 Hz).

[0399] Example 42 N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide (optical isomer)

[0400] A) tert-butyl (4R)-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate To a solution of tert-butyl (R)-4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.13 g) and TEA (3.53 mL) in DME (20 mL) was added ethanesulfonyl chloride (0.675 mL) at 5° C. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc and poured into saturated aqueous sodium bicarbonate at 0° C. 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 column chromatography (EtOAc / hexane) to give the title compound (0.708 g). 1 H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.3 Hz), 1.46 (9H, s), 3.06-3.26 (3H, m), 3.62-3.90 (2H, m), 3.91-4.09 (1H, m), 4.12-4.36 (1H, m), 4.57 (1H, d, J = 9.8 Hz).

[0401] B) N-[(3R)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride To a solution of tert-butyl (4R)-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate (708 mg) in EtOAc (5.0 mL) was added 4M hydrogen chloride in EtOAc (10 mL) at room temperature. The mixture was stirred at room temperature over the weekend. The precipitated solid was collected by filtration, washed with EtOAc, and dried under reduced pressure to give the title compound (513 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (3H, m), 2.98-3.16 (3H, m), 3.58-3.88 (3H, m), 4.23-4.52 (1H, m), 8.07 (1H, d, J = 9.0 Hz), 9.15-9.77 (2H, m).

[0402] C) N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide A mixture of 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,4,6-trifluorophenyl)pyridine (100 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride (128 mg) in pyridine (0.638 mL) was stirred in a sealed tube at 140° C. for 15 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (115 mg). 1 H NMR (400 MHz, CDCl3) δ 1.42 (3H, t, J = 7.3 Hz), 2.97-3.44 (4H, m), 3.63-3.99 (4H, m), 4.22-4.44 (1H, m), 4.70 (1H, t, J = 10.6 Hz), 5.49 (1H, t, J = 8.7 Hz), 6.57-6.93 (2H, m), 7.62 (1H, d, J = 2.2 Hz), 8.64 (1H, dd, J = 2.2, 1.5 Hz).

[0403] D) N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide (optical isomer) N-[(3R)-1-{5-[5-chloro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide (101 mg) was optically resolved by HPLC. The fraction with a longer retention time was concentrated under reduced pressure. The residue was washed with IPE to give the title compound (38.7 mg). Chiral separation conditions Column: Chiral PAK IB-N5 (trademark) (20mmID*250mmL, 5μm) Mobile phase: hexane / ethanol = 700 / 300 (v / v) 1 H NMR (300 MHz, CDCl3) δ 1.42 (3H, t, J = 7.3 Hz), 3.04-3.35 (4H, m), 3.64-4.00 (4H, m), 4.21-4.42 (1H, m), 4.63 (1H, d, J = 10.2 Hz), 5.49 (1H, t, J = 8.7 Hz), 6.70-6.88 (2H, m), 7.58-7.64 (1H, m), 8.65 (1H, d, J = 2.3 Hz).

[0404] Example 49 N-[(3R)-1-{5-[5-chloro-3-(2,6-difluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer)

[0405] A) 5-chloro-3-(2,6-difluorophenyl)pyridin-2-amine A mixture of 3-bromo-5-chloro-pyridin-2-amine (15.0 g), (2,6-difluorophenyl)boronic acid (14.8 g), Pd(dba) (3.31 g), tri-tert-butylphosphonium tetrafluoroborate (3.15 g), and potassium fluoride (8.40 g) in THF (150 mL) and water (30 mL) was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water, and the resulting mixture was extracted with EtOAc. The combined organic layers were 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 title compound (17.0 g). 1 H NMR (400 MHz, DMSO-d6) δ 5.98 (2H, s), 7.16-7.24 (2H, m), 7.46-7.57 (2H, m), 8.03 (1H, d, J = 2.4 Hz).

[0406] B) 5-chloro-3-(2,6-difluorophenyl)-2-iodopyridine To a mixture of 5-chloro-3-(2,6-difluorophenyl)pyridin-2-amine (8.50 g), diiodomethane (37.8 g), and copper(I) iodide (10.1 g) in THF (90 mL) was added n-pentyl nitrite (8.28 g) at room temperature. The mixture was stirred at 70°C for 5 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (6.70 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.26-7.32 (2H, m), 7.60-7.69 (1H, m), 8.10 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 2.4 Hz).

[0407] C) 5-chloro-3-(2,6-difluorophenyl)-2-ethenylpyridine To a mixture of 5-chloro-3-(2,6-difluorophenyl)-2-iodopyridine (6.70 g), potassium vinyltrifluoroborate (5.11 g), and potassium carbonate (5.27 g) in DME (100 mL) and water (20 mL) was added Pd(dppf)Cl2·CHCl2 (2.33 g). The mixture was stirred at 100 °C under a nitrogen atmosphere for 14 hours. The reaction mixture was diluted with water, and the resulting mixture was extracted with EtOAc. The combined organic layers were 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 title compound (3.20 g). 1 H NMR (400 MHz, DMSO-d6) δ 5.46-5.51 (1H, m), 6.35-6.40 (1H, m), 6.41-6.48 (1H, m), 7.27-7.32 (2H, m), 7.57-7.66 (1H, m), 8.05 (1H, d, J = 2.4 Hz), 8.73 (1H, d, J = 2.4 Hz).

[0408] D) 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine To a solution of hydroxycarbonimide dibromide (11.1 g) and 5-chloro-3-(2,6-difluorophenyl)-2-ethenylpyridine (6.90 g) in EtOAc (70 mL) was added sodium bicarbonate (9.21 g). The mixture was stirred at 60° C. for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (8.50 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.62-3.75 (2H, m), 5.48-5.55 (1H, m), 7.30 (2H, q, J = 9.2 Hz), 7.58-7.67 (1H, m), 8.17 (1H, d, J = 2.4 Hz), 8.84 (1H, d, J = 2.4 Hz).

[0409] E) 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine (optical isomer) 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine (8.50 g) was resolved by SFC. The longer retention fraction was concentrated under reduced pressure to give the title compound (4.02 g). Chiral separation conditions Column: Chiral PAK AY (trademark) (250 mm*50 mm, 10 μm) Mobile phase: CO2 / EtOH containing 0.1% ammonium hydroxide = 850 / 150 (v / v) 1 H NMR (400 MHz, DMSO-d6) δ 3.66-3.72 (2H, m), 5.48-5.54 (1H, m), 7.30 (2H, q, J = 9.2 Hz), 7.58-7.67 (1H, m), 8.17 (1H, d, J = 2.4 Hz), 8.84 (1H, d, J = 2.4 Hz).

[0410] F) N-[(3R)-1-{5-[5-chloro-3-(2,6-difluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer) A mixture of 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine (optical isomer) (1.00 g), N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (1.27 g) in pyridine (9 mL) was stirred at 140° C. overnight in a sealed tube. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 1M aqueous hydrogen chloride and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / hexane) to give the title compound (671 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.99 (3H, s), 3.12-3.23 (1H, m), 3.27-3.37 (1H, m), 3.56-3.87 (4H, m), 4.23-4.42 (1H, m), 5.29 (1H, t, J = 9.0 Hz), 7.23-7.32 (2H, m), 7.55-7.66 (1H, m), 7.98 (1H, s), 8.12 (1H, d, J = 2.1 Hz), 8.80 (1H, d, J = 2.4 Hz).

[0411] Example 50 N-[(3S)-1-{5-[2-(3,5-difluoropyridin-2-yl)-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide

[0412] A) 2-(2-chloro-5-methylphenyl)-3,5-difluoropyridine A mixture of (2-chloro-5-methylphenyl)boronic acid (527 mg), 2-bromo-3,5-difluoropyridine (500 mg), Pd(PhP) (149 mg), and sodium carbonate (546 mg) in DME (10 mL) and water (2.50 mL) was stirred at 80 °C for 3.5 hours under an argon atmosphere. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water 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 (544 mg). MS: [M+H] + 239.9.

[0413] B) 2-(2-ethenyl-5-methylphenyl)-3,5-difluoropyridine A mixture of 2-(2-chloro-5-methylphenyl)-3,5-difluoropyridine (540 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.956 mL), Pd(dba) (206 mg), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (278 mg), and sodium carbonate (478 mg) in toluene (10 mL) and water (2.3 mL) was heated at 110 °C for 8 h under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water 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 (504 mg). MS: [M+H] + 231.9.

[0414] C) 2-[2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-methylphenyl]-3,5-difluoropyridine A mixture of 2-(2-ethenyl-5-methylphenyl)-3,5-difluoropyridine (500 mg), hydroxycarbonimide dibromide (877 mg), and sodium bicarbonate (727 mg) in EtOAc (7.5 mL) was stirred at 65° C. for 7 hours under a nitrogen atmosphere. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (617 mg). MS: [M+H] + 352.9.

[0415] D) N-[(3S)-1-{5-[2-(3,5-difluoropyridin-2-yl)-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide A mixture of 2-[2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-methylphenyl]-3,5-difluoropyridine (20.0 mg), N-[(3S)-pyrrolidin-3-yl]methanesulfonamide hydrochloride (28.4 mg), and DIPEA (0.099 mL) in NMP (0.35 mL) was stirred in a sealed tube at 120 °C for 6 hours. The mixture was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fraction was collected, extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (3.2 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.73-1.90 (1H, m), 2.03-2.17 (1H, m), 2.34 (3H, s), 2.85-2.92 (1H, m), 2.94 (3H, s), 2.99-3.08 (1H, m), 3.13-3.28 (3H, m), 3.38-3.49 (1H, m), 3.85-3.98 (1H, m), 5.15-5.25 (1H, m), 7.16 (1H, s), 7.31-7.39 (2H, m), 7.54 (1H, d, J = 7.9 Hz), 8.08 (1H, td, J = 9.4, 2.5 Hz), 8.61 (1H, d, J = 2.4 Hz).

[0416] Example 59 N-[(3R)-1-{5-(difluoromethyl)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer)

[0417] A) 2-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]prop-2-en-1-ol Pd(dppf)Cl2·CHCl2 (348 mg) was added to a mixture of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (783 mg), 2-chloro-3-(2,6-difluorophenyl)-5-methylpyridine (510 mg), potassium carbonate (588 mg) in DME (12 mL) and water (2.4 mL) at room temperature. The mixture was stirred at 110 °C under microwave irradiation under an argon atmosphere for 3 hours. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (616 mg). MS: [M+H] + 262.0.

[0418] B) {3-bromo-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol Sodium bicarbonate (3.01 g) was added to a mixture of 2-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]prop-2-en-1-ol (2.34 g) and hydroxycarbonimide dibromide (3.63 g) in EtOAc (35.8 mL) at room temperature. The mixture was stirred at 70° C. overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.14 g). MS: [M+H] + 382.9.

[0419] C) 2-[3-bromo-5-(difluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine Oxalyl chloride (0.110 mL) was added to a solution of DMSO (0.119 mL) in THF (4.18 mL) at −78° C. The mixture was stirred at −78° C. for 10 minutes under a nitrogen atmosphere. {3-bromo-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol (160 mg) in THF (5 mL) was added. The mixture was stirred at −78° C. for 30 minutes under a nitrogen atmosphere. TEA (0.291 mL) was added. The mixture was stirred from −78° C. to room temperature for 30 minutes. The mixture was quenched with saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. DAST (0.089 mL) was added to a solution of the residue in CHCl (4 mL) at 0° C. The mixture was gradually warmed to room temperature and stirred at room temperature under a nitrogen atmosphere over the weekend. The mixture was quenched with water at room temperature, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (76 mg). MS: [M+H] + 402.9.

[0420] D) N-[(3R)-1-{5-(difluoromethyl)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide A mixture of 2-[3-bromo-5-(difluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (76 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (89 mg) in pyridine (0.47 mL) was stirred in a sealed tube at 140° C. for 15 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (41 mg). 1 H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 3.07 (3H, s), 3.13-3.29 (1H, m), 3.49-3.99 (5H, m), 4.30 (1H, dt, J = 14.1, 8.8 Hz), 4.76 (1H, dd, J = 9.8, 3.4 Hz), 5.68-6.32 (1H, m), 6.84-7.11 (2H, m), 7.30-7.43 (2H, m), 8.48 (1H, s).

[0421] E) N-[(3R)-1-{5-(difluoromethyl)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer) N-[(3R)-1-{5-(difluoromethyl)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (40.2 mg) was optically resolved by HPLC. The fraction with a shorter retention time was concentrated under reduced pressure to give the title compound (17.8 mg). Chiral separation conditions Column: Chiral PAK IG (trademark) (20mmID*250mmL, 5μm) Mobile phase: Hexane / EtOH = 500 / 500 (v / v) 1H NMR (300 MHz, CDCl3) δ 2.39 (3H, s), 3.07 (3H, s), 3.20 (1H, t, J = 9.4 Hz), 3.52 (1H, d, J = 16.9 Hz), 3.64 (2H, dd, J = 19.0, 8.5 Hz), 3.82 (1H, dd, J = 10.7, 7.7 Hz), 3.90-4.02 (1H, m), 4.25-4.42 (1H, m), 4.72 (1H, d, J = 10.5 Hz), 5.87-6.31 (1H, m), 6.91-7.06 (2H, m), 7.34-7.42 (2H, m), 8.46-8.52 (1H, m).

[0422] Example 64 N-(4,4-difluoro-3-methyl-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl)methanesulfonamide

[0423] A) Benzyl 3-[(tert-butoxycarbonyl)amino]-4,4-difluoro-3-methylpyrrolidine-1-carboxylate To a solution of 1-((benzyloxy)carbonyl)-4,4-difluoro-3-methylpyrrolidine-3-carboxylic acid (161 mg) in t-BuOH (2 mL), TEA (0.150 mL) and DPPA (0.175 mL) were added at room temperature. The mixture was stirred at 100° C. overnight. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (130 mg). MS: [M+Na] + 393.1.

[0424] B) Benzyl 3,3-difluoro-4-[(methanesulfonyl)amino]-4-methylpyrrolidine-1-carboxylate A mixture of benzyl 3-[(tert-butoxycarbonyl)amino]-4,4-difluoro-3-methylpyrrolidine-1-carboxylate (130 mg) and 4 M hydrogen chloride in CPME (1 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was combined with THF (2 mL), and then methanesulfonyl chloride (0.136 mL) and TEA (0.391 mL) were added. The mixture was stirred at room temperature overnight. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (37.2 mg). MS: [M+Na] + 371.0.

[0425] C) N-(4,4-difluoro-3-methylpyrrolidin-3-yl)methanesulfonamide Under a hydrogen atmosphere, a mixture of benzyl 3,3-difluoro-4-[(methanesulfonyl)amino]-4-methylpyrrolidine-1-carboxylate (45.6 mg), 10% palladium on carbon (10 mg), and MeOH (1 mL) was stirred at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was combined with 20% palladium hydroxide on carbon (10 mg) and MeOH (1 mL). The mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (26.5 mg). 1 H NMR (300 MHz, CDCl3) δ 1.56 (3H, d, J = 3.0 Hz), 3.12 (3H, s), 3.15-3.51 (4H, m).

[0426] D) N-(4,4-difluoro-3-methyl-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl)methanesulfonamide A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (45.9 mg), N-(4,4-difluoro-3-methylpyrrolidin-3-yl)methanesulfonamide (26.5 mg), and pyridine (0.3 mL) was stirred in a sealed tube at 140 °C overnight. The mixture was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fraction was then concentrated to give the title compound (6.8 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.51 (3H, s), 2.36 (3H, s), 3.03 (3H, d, J = 1.9 Hz), 3.22-3.31 (1H, m), 3.41-3.51 (1H, m), 3.59-3.84 (4H, m), 5.27 (1H, t, J = 9.6 Hz), 7.28-7.44 (2H, m), 7.54-8.02 (2H, m), 8.54 (1H, d, J = 1.8 Hz).

[0427] Example 72 N-[(3R)-4,4-Difluoro-1-{5-[6-methoxy-4-(2,4,6-trifluorophenyl)pyridin-3-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide

[0428] A) 2-Methoxy-4-(2,4,6-trifluorophenyl)pyridine To a solution of 4-bromo-2-methoxypyridine (1.59 g) and (2,4,6-trifluorophenyl)boronic acid (2.97 g) in DME (20 mL) and water (10.0 mL) were added potassium fluoride (1.47 g), Pd(dba) (0.581 g), and tri-t-butylphosphonium tetrafluoroborate (0.491 g), and the reaction mixture was stirred at 100 °C for 1 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.67 g). MS: [M+H] + 240.0.

[0429] B) 5-bromo-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine To a solution of 2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (900 mg) in DMF (20 mL) was added NBS (1.01 g), and the reaction mixture was stirred at 100° C. for 3 hours. After cooling to room temperature, the mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (300 mg). MS: [M+H] + 317.9.

[0430] C) 5-ethenyl-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine A mixture of 5-bromo-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (300 mg), potassium vinyltrifluoroborate (253 mg), potassium carbonate (261 mg), and Pd(dppf)Cl₂·C₂Cl₂ (116 mg) in DME (4 mL) and water (1.00 mL) was heated at 110°C for 2 hours under microwave irradiation. After cooling to room temperature, potassium carbonate (130 mg), potassium vinyltrifluoroborate (126 mg), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (95 mg) were added to the mixture, and the mixture was heated at 120°C for 2 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (223 mg). MS: [M+H] + 265.9.

[0431] D) 5-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine To a solution of 5-ethenyl-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (220 mg) and hydroxycarbonimide dibromide (336 mg) in EtOAc (10 mL) was added sodium bicarbonate (279 mg), and the reaction mixture was stirred at 70° C. for 10 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (226 mg). 1 H NMR (300 MHz, DMSO-d6) δ 3.24 (1H, dd, J = 17.5, 9.6 Hz), 3.59 (1H, dd, J = 17.5, 11.5 Hz), 3.91 (3H, s), 5.49 (1H, t, J = 10.4 Hz), 6.77-7.01 (1H, m), 7.27-7.49 (2H, m), 8.38 (1H, s).

[0432] E) N-[(3R)-4,4-difluoro-1-{5-[6-methoxy-4-(2,4,6-trifluorophenyl)pyridin-3-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide To a solution of 5-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (50 mg) and N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (45.8 mg) in NMP (0.5 mL), DIPEA (0.226 mL) was added, and the reaction mixture was stirred in a sealed tube at 130 °C for 24 hours. The crude product was then purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile), and the desired fraction was concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (11 mg). 1 H NMR (300 MHz, CDCl3) δ 2.78-2.98 (1H, m), 3.07 (3H, s), 3.10-3.30 (2H, m), 3.62-3.87 (3H, m), 3.95-4.01 (3H, m), 4.22-4.43 (1H, m), 5.03-5.18 (1H, m), 5.25-5.41 (1H, m), 6.62 (1H, s), 6.75-6.90 (2H, m), 8.45 (1H, s).

[0433] Example 73 N-[1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-3-(methoxymethyl)pyrrolidin-3-yl]methanesulfonamide (optical isomer)

[0434] A) Benzyl 3-[(methanesulfonyl)amino]-3-(methoxymethyl)pyrrolidine-1-carboxylate A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)pyrrolidine-1-carboxylate (2.00 g) and 4 M hydrogen chloride in CPME (30 mL) was stirred at room temperature for 2 hours. After evaporation, methanesulfonyl chloride (0.637 mL) was added to a mixture of the residue and TEA (1.53 mL) in THF (20 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The mixture was neutralized with saturated aqueous sodium bicarbonate at 0° C., and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.61 g). MS: [M+H] + 365.0.

[0435] B) N-[1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-3-(methoxymethyl)pyrrolidin-3-yl]methanesulfonamide Under a hydrogen atmosphere, a mixture of benzyl 3-[(methanesulfonyl)amino]-3-(methoxymethyl)pyrrolidine-1-carboxylate (1.61 g) and 10% palladium on carbon (1 g) in MeOH (15 mL) was stirred at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. A mixture of the residue (83.0 mg) and 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (70.0 mg) in NMP (0.6 mL) was stirred in a sealed tube at 120°C for 6 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) to give the title compound (75.7 mg). MS: [M+H] + 481.1

[0436] C) N-[1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-3-(methoxymethyl)pyrrolidin-3-yl]methanesulfonamide (optical isomer) N-[1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}-3-(methoxymethyl)pyrrolidin-3-yl]methanesulfonamide (100 mg) was optically resolved by HPLC. The longer retention fraction was concentrated under reduced pressure to give the title compound (48.2 mg). Chiral separation conditions Column: Chiral PAK IC (trademark) (20 mmID*250 mmL, 5 μm) Mobile phase: Hexane / EtOH = 250 / 750 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ 1.90-2.04 (1H, m), 2.06-2.17 (1H, m), 2.36 (3H, s), 2.94 (3H, s), 3.13-3.37 (7H, m), 3.44 (1H, d, J = 11.3 Hz), 3.49 (2H, d, J = 1.1 Hz), 3.66 (1H, dd, J = 15.4, 8.7 Hz), 5.21 (1H, t, J = 9.0 Hz), 7.24 (2H, q, J = 8.9 Hz), 7.33 (1H, s), 7.48-7.59 (1H, m), 7.62 (1H, d, J = 1.9 Hz), 8.53 (1H, d, J = 1.5 Hz)

[0437] Example 82 1-Fluoro-N-[(3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide

[0438] A) Benzyl [(3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]carbamate A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (250 mg), DIPEA (1.18 mL), and benzyl ((3R,4S)-4-fluoropyrrolidin-3-yl)carbamate hydrochloride (278 mg) in NMP (2.0 mL) was stirred in a sealed tube at 140° C. overnight. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (138 mg). MS: [M+H] + 529.1.

[0439] B) (3R,4S)-4-Fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-amine To a mixture of benzyl [(3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]carbamate (137 mg) in EtOH (2 mL) was added 10% palladium on carbon (20 mg). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (98 mg). MS: [M+H] + 395.0.

[0440] C) 1-fluoro-N-[(3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide To a stirred solution of (3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-amine (30 mg) and DIPEA (0.027 mL) in THF (2 mL) was added fluoromethanesulfonyl chloride (12.1 mg). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile) and silica gel column chromatography (EtOAc / hexane) to give the title compound (18.5 mg). 1 H NMR (300 MHz, CDCl3) δ 2.40 (3H, s), 3.11-3.24 (1H, m), 3.26-3.37 (1H, m), 3.58-3.77 (2H, m), 3.78-3.93 (2H, m), 4.18-4.36 (1H, m), 5.02-5.16 (2H, m), 5.17-5.27 (2H, m), 5.49 (1H, t, J = 9.3 Hz), 6.70-6.85 (2H, m), 7.39-7.46 (1H, m), 8.50-8.57 (1H, m).

[0441] Example 99 N-[(3S)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]-1-fluoroethane-1-sulfonamide

[0442] A) tert-Butyl (3S)-3-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate 4-Methoxybenzyl chloride (3.90 mL) was added to a suspension of tert-butyl (3S)-3-[(ethanesulfonyl)amino]pyrrolidine-1-carboxylate (6.67 g) and potassium carbonate (9.93 g) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature over the weekend. The mixture was poured into water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (9.55 g). MS: [M+Na] + 421.1.

[0443] B) tert-Butyl (3S)-3-{(1-fluoroethanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate n-Butyllithium (1.6 M in hexane, 17.3 mL) was added dropwise to a solution of tert-butyl (3S)-3-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate (5.0 g) in THF (50 mL) at -78 °C. The mixture was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. A solution of N-fluorobis(phenylsulfonyl)amine (8.70 g) in THF (10 mL) was added to the mixture, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was quenched with saturated aqueous ammonium chloride at 0 °C, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fraction was then concentrated to give the title compound (1.60 g). 1H NMR (300 MHz, DMSO-d6) δ 1.35 (9H, br s), 1.53-1.70 (3H, m), 1.84-3.70 (6H, m), 3.74 (3H, s), 4.31-4.50 (3H, m), 5.67-5.96 (1H, m), 6.88-6.96 (2H, m), 7.28 (2H, d, J = 8.3 Hz).

[0444] C) 1-Fluoro-N-[(3S)-pyrrolidin-3-yl]ethane-1-sulfonamide A mixture of tert-butyl (3S)-3-{(1-fluoroethanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate (1.58 g), TFA (20 mL), and water (1.00 mL) was stirred at 60° C. over the weekend. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (340 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.51-1.65 (3H, m), 1.71-1.83 (1H, m), 2.03-2.16 (1H, m), 2.85 (1H, td, J = 12.3, 5.7 Hz), 2.97-3.17 (2H, m), 3.24 (1H, ddd, J = 11.6, 7.0, 4.2 Hz), 3.94-4.02 (1H, m), 4.89-6.48 (2H, m), 5.51-5.72 (1H, m).

[0445] D) N-[(3S)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]-1-fluoroethane-1-sulfonamide A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (50 mg), 1-fluoro-N-[(3S)-pyrrolidin-3-yl]ethane-1-sulfonamide (50.0 mg), and DIPEA (0.247 mL) in NMP (0.4 mL) was stirred in a sealed tube at 120° C. for 6 hours. The mixture was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (18.0 mg). 1 H NMR (300 MHz, CDCl3) δ 1.62-1.75 (3H, m), 1.97-2.12 (2H, m), 2.14-2.27 (1H, m), 2.38 (3H, s), 3.16 (1H, dd, J = 15.6, 9.6 Hz), 3.27-3.40 (2H, m), 3.42-3.59 (2H, m), 3.74 (1H, ddd, J = 15.7, 8.9, 3.2 Hz), 4.12-4.23 (1H, m), 5.11-6.38 (2H, m), 6.93-7.07 (2H, m), 7.30-7.44 (2H, m), 8.50 (1H, dd, J = 4.1, 1.9 Hz).

[0446] Example 107 Optical isomers of 1-fluoro-N-[(3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]cyclopropane-1-sulfonamide or 1-fluoro-N-[(3S,4R)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]cyclopropane-1-sulfonamide

[0447] A) rac-tert-butyl (3S,4S)-3-fluoro-4-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate To a mixture of rac-tert-butyl (3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (528 mg), pyridine (0.6 mL), and acetonitrile (10 mL) was added trifluoromethanesulfonic anhydride (0.6 mL) at -10 °C, and the mixture was stirred at -10 °C for 1 hour. The mixture was quenched with aqueous ammonium chloride solution, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (833 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (9H, s), 3.46-3.89 (4H, m), 5.39-5.64 (1H, m), 5.70-5.86 (1H, m).

[0448] B) 1-Fluorocyclopropane-1-sulfonamide A mixture of tert-butyl ((1-fluorocyclopropyl)sulfonyl)carbamate (893 mg) and TFA (3 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure to give the title compound (580 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.30-1.56 (4H, m), 7.51 (2H, s).

[0449] C) rac-tert-butyl (3S,4R)-3-fluoro-4-[(1-fluorocyclopropane-1-sulfonyl)amino]pyrrolidine-1-carboxylate To a solution of 1-fluorocyclopropane-1-sulfonamide (575 mg) and DMF (9 mL) was added sodium hydride (60% in oil, 179 mg) at 0°C, and the mixture was stirred at 0°C for 10 minutes. A solution of rac-tert-butyl (3S,4S)-3-fluoro-4-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate (1.23 g) in DMF (3 mL) was added dropwise at 0°C, and the mixture was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was quenched with aqueous ammonium chloride, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.575 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.32-1.63 (13H, m), 3.13 (1H, td, J = 10.1, 3.6 Hz), 3.41-3.49 (1H, m), 3.53-3.69 (2H, m), 4.08-4.34 (1H, m), 4.84-5.16 (1H, m), 8.49 (1H, d, J = 8.7 Hz).

[0450] D) rac-1-fluoro-N-((3R,4S)-4-fluoropyrrolidin-3-yl)cyclopropane-1-sulfonamide hydrochloride A mixture of rac-tert-butyl (3S,4R)-3-fluoro-4-[(1-fluorocyclopropane-1-sulfonyl)amino]pyrrolidine-1-carboxylate (575 mg) and 4 M hydrogen chloride in CPME (4.5 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure, and the solid was collected by filtration and washed with IPE / EtOAc to give the title compound (411 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.39-1.66 (4H, m), 3.04 (1H, t, J = 11.3 Hz), 3.43-3.67 (3H, m), 4.16-4.43 (1H, m), 4.99-5.26 (1H, m), 8.69 (1H, br s), 9.43 (2H, br s).

[0451] E) Optical isomers of 1-fluoro-N-[(3R,4S)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]cyclopropane-1-sulfonamide or 1-fluoro-N-[(3S,4R)-4-fluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]cyclopropane-1-sulfonamide A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (59.2 mg), rac-1-fluoro-N-((3R,4S)-4-fluoropyrrolidin-3-yl)cyclopropane-1-sulfonamide hydrochloride (62.2 mg), cesium carbonate (144 mg), and t-BuOH (0.8 mL) was stirred in a sealed tube at 140° C. for 5 hours. The mixture was quenched with aqueous ammonium chloride solution, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The desired fraction was concentrated under reduced pressure. The residue was solidified with IPE to give the title compound (19.1 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.63 (4H, m), 2.36 (3H, s), 3.13-3.27 (2H, m), 3.42-3.79 (4H, m), 4.10-4.35 (1H, m), 4.94-5.19 (1H, m), 5.25 (1H, t, J = 9.4 Hz), 7.27-7.42 (2H, m), 7.63 (1H, d, J = 1.9 Hz), 8.49-8.61 (2H, m).

[0452] Example 109 N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide

[0453] A) 2-chloro-3-(2,6-difluorophenyl)-5-fluoropyridine Tri-tert-butylphosphonium tetrafluoroborate (0.414 g) and Pd2(dba)3 (0.653 g) were added to a mixture of 3-bromo-2-chloro-5-fluoropyridine (3.00 g), (2,6-difluorophenyl)boronic acid (2.93 g), and potassium fluoride (1.66 g) in THF (39.6 mL) and water (7.92 mL) at room temperature. The mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was poured into brine, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (3.11 g). MS: [M+H] + 243.9.

[0454] B) 2-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]prop-2-en-1-ol Pd(dppf)Cl2·CHCl2 (0.654 g) was added to a mixture of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (1.96 g), 2-chloro-3-(2,6-difluorophenyl)-5-fluoropyridine (1.30 g), and potassium carbonate (2.21 g) in DME (15 mL) and water (3.0 mL) at room temperature. The mixture was stirred at 120 °C under microwave irradiation and an argon atmosphere for 10 hours. The mixture was diluted with EtOAc and water, and the insoluble material was removed by filtration through Celite™. The organic layer was separated, dried over anhydrous sodium sulfate, passed through an NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.850 g). MS: [M+H] + 266.0.

[0455] C) {3-bromo-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol Sodium bicarbonate (1.77 g) was added to a mixture of 2-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]prop-2-en-1-ol (1.40 g) and hydroxycarbonimide dibromide (2.14 g) in EtOAc (21.1 mL) at room temperature. The mixture was stirred at 70° C. overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.871 g). 1 H NMR (300 MHz, CDCl3) δ 3.10 (1H, dd, J = 7.7, 7.0 Hz), 3.37-3.61 (1H, m), 3.66-3.86 (2H, m), 4.14-4.16 (1H, m), 6.72-7.12 (2H, m), 7.30-7.48 (2H, m), 8.48 (1H, d, J = 2.6 Hz).

[0456] D) 2-[3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine DAST (0.743 mL) was added to a solution of {3-bromo-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol (871 mg) in CHCl (15 mL) at 0°C. The mixture was gradually warmed to room temperature and stirred at room temperature for 6 hours under a nitrogen atmosphere. DAST (0.149 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature overnight under a nitrogen atmosphere. The mixture was quenched with saturated aqueous sodium bicarbonate at room temperature, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (580 mg). 1 H NMR (300 MHz, CDCl3) δ 3.52-3.67 (1H, m), 3.71-3.95 (1H, m), 4.58-5.11 (2H, m), 6.80-7.09 (2H, m), 7.30-7.54 (2H, m), 8.49 (1H, d, J = 2.6 Hz).

[0457] E) 2-[(5S)-3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine 2-[3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine (6.00 g) was resolved by SFC. The longer retention fraction was concentrated under reduced pressure to give the title compound (2.78 g). Chiral separation conditions Column: Chiral CEL OJ (trademark) (250 mm*50 mm, 10 μm) Mobile phase: CO2 / EtOH containing 0.1% ammonium hydroxide = 850 / 150 (v / v) 1 H NMR (400 MHz, DMSO-d6) δ 3.51-3.57 (1H, m), 3.64-3.71 (1H, m), 4.76-4.86 (1H, m), 4.87-4.97 (1H, m), 7.14-7.22 (2H, m), 7.50-7.59 (1H, m), 7.96 (1H, dd, J = 9.2, 2.8 Hz), 8.75 (1H, d, J = 2.8 Hz).

[0458] F) tert-Butyl (4R)-3,3-difluoro-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate To a mixture of tert-butyl (R)-4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.65 g), TEA (3.10 mL), and THF (35 mL) was added a solution of methanesulfonic anhydride (1.94 g) in THF (5 mL) at 0°C. The mixture was stirred at room temperature overnight under an argon atmosphere. Saturated aqueous sodium bicarbonate solution was added to the mixture at 0°C, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.63 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.41 (9H, s), 2.99 (3H, s), 3.08-3.19 (1H, m), 3.60-3.76 (2H, m), 3.76-3.85 (1H, m), 4.23-4.44 (1H, m), 7.93 (1H, d, J = 9.0 Hz).

[0459] G) N-[(3R)-4,4-Difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride A mixture of tert-butyl (4R)-3,3-difluoro-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (1.62 g) and 4 M hydrogen chloride in EtOAc (30 mL) was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. A mixture of EtOAc / hexane (1 / 1) was added to the residue. The resulting solid was collected by filtration and washed with EtOAc / hexane (1 / 1) to give the title compound (1.07 g). 1 H NMR (300 MHz, DMSO-d6) δ 3.02 (3H, s), 3.06-3.18 (1H, m), 3.68-3.82 (3H, m), 4.35-4.49 (1H, m), 8.11 (1H, d, J = 9.2 Hz), 9.81 (2H, br s).

[0460] H) N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide A mixture of 2-[(5S)-3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine (1.70 g), N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (2.07 g), and pyridine (10.9 mL) was stirred in a sealed tube at 135 °C overnight. The mixture was purified by silica gel column chromatography (EtOAc / hexane) and NH silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOAc / hexane to give the title compound (924 mg). 1H NMR (400 MHz, CDCl3) δ 3.07 (3H, s), 3.12-3.19 (1H, m), 3.46 (1H, dd, J = 16.4, 0.9 Hz), 3.54-3.71 (3H, m), 3.77 (1H, dd, J = 9.9, 8.3 Hz), 4.15-4.39 (1H, m), 4.58-4.89 (3H, m), 6.91-7.06 (2H, m), 7.28-7.38 (2H, m), 8.49 (1H, d, J = 2.8 Hz).

[0461] Example 131 N-[(3R)-1-{5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(methoxymethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide

[0462] A) 2-[3-bromo-5-(methoxymethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine To a solution of {3-bromo-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol (150 mg) and N,N,N',N'-tetramethyl-1,8-naphthalenediamine (415 mg) in EtOAc (5 mL) was added trimethyloxonium tetrafluoroborate (229 mg) at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was filtered and quenched with saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (134 mg). MS: [M+H] + 400.9.

[0463] B) N-[(3R)-1-{5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(methoxymethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide A mixture of 2-[3-bromo-5-(methoxymethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine (30.0 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (35.4 mg) in pyridine (0.25 mL) was stirred in a sealed tube at 140 °C for 6 hours. The mixture was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fraction was then concentrated to give the title compound (23.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.98 (3H, s), 3.00-3.10 (1H, m), 3.18-3.23 (3H, m), 3.36-3.74 (7H, m), 4.20-4.37 (1H, m), 7.08-7.19 (2H, m), 7.42-7.53 (1H, m), 7.76-7.82 (1H, m), 7.93 (1H, br s), 8.69 (1H, dd, J = 2.8, 1.5 Hz).

[0464] Example 147 N-[(3R)-4,4-difluoro-1-{5-(fluoromethyl)-5-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide (optical isomer)

[0465] A) 5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-amine Tri-tert-butylphosphonium tetrafluoroborate (0.304 g) and Pd2(dba)3 (0.301 g) were added to a mixture of 3-bromo-5-fluoropyridin-2-amine (2.00 g), (2,4,6-trifluorophenyl)boronic acid (3.32 g), and potassium fluoride (1.22 g) in THF (29.1 mL) and water (5.82 mL) at room temperature. The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was poured into brine, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, passed through a pad of NH silica gel, and concentrated under reduced pressure. The solid was triturated with IPE to give the title compound (1.81 g). MS: [M+H] + 242.9.

[0466] B) 5-Fluoro-2-iodo-3-(2,4,6-trifluorophenyl)pyridine To a stirred mixture of 5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-amine (1.70 g), diiodomethane (4.52 mL), and copper(I) iodide (2.01 g) in THF (35 mL) was added n-pentyl nitrite (3.73 mL) at room temperature. The mixture was stirred at 70°C for 5 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.58 g). 1 H NMR (300 MHz, CDCl3) δ 6.76-6.87 (2H, m), 7.29 (1H, dd, J = 8.2, 3.0 Hz), 8.37 (1H, d, J = 3.0 Hz).

[0467] C) 2-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]prop-2-en-1-ol A mixture of 5-fluoro-2-iodo-3-(2,4,6-trifluorophenyl)pyridine (900 mg), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (704 mg), potassium carbonate (1.06 g), PdCl2 (dppf) (187 mg), DME (15 mL), and water (3.00 mL) was heated at 110 °C for 1 hour under microwave irradiation. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (546 mg). MS: [M+H] + 283.9.

[0468] D) {3-Bromo-5-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol Sodium bicarbonate (485 mg) was added to a mixture of 2-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]prop-2-en-1-ol (545 mg) and hydroxycarbonimide dibromide (781 mg) in EtOAc (10 mL) at room temperature. The mixture was stirred at 75°C overnight. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / hexane) to give the title compound (586 mg). MS: [M+H] + 404.9.

[0469] E) 2-[3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-fluoro-3-(2,4,6-trifluorophenyl)pyridine DAST (0.477 mL) was added to a solution of {3-bromo-5-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol (585 mg) in CHCl (10 mL) at 0 °C. The mixture was gradually warmed to room temperature and stirred at room temperature for 6 hours under a nitrogen atmosphere. The mixture was quenched with saturated aqueous sodium bicarbonate at room temperature, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 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 (375 mg). 1 H NMR (300 MHz, CDCl3) δ 3.57-3.83 (2H, m), 4.62-4.94 (2H, m), 6.73-6.85 (2H, m), 7.33 (1H, dd, J = 8.3, 2.8 Hz), 8.51 (1H, d, J = 2.8 Hz).

[0470] F) 2-[3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-fluoro-3-(2,4,6-trifluorophenyl)pyridine (optical isomer) 2-[3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-fluoro-3-(2,4,6-trifluorophenyl)pyridine (4.00 g) was resolved by SFC. The desired fraction with the shorter retention time was concentrated in vacuo to give the title compound (1.74 g). Chiral separation conditions Column: Chiral PAK IG (trademark) (250 mm*50 mm, 10 μm) Mobile phase: CO2 / MeOH containing 0.1% ammonium hydroxide = 900 / 100 (v / v) 1H NMR (400 MHz, DMSO-d6) δ 3.47-3.55 (1H, m), 3.66-3.74 (1H, m), 4.76-4.86 (1H, m), 4.88-4.98 (1H, m), 7.28-7.36 (2H, m), 7.99 (1H, dd, J = 8.8, 2.8 Hz), 8.76 (1H, d, J = 2.8 Hz).

[0471] G) N-[(3R)-4,4-difluoro-1-{5-(fluoromethyl)-5-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide (optical isomer) A mixture of 2-[3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-fluoro-3-(2,4,6-trifluorophenyl)pyridine (optical isomer) (90.0 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (105 mg), and pyridine (0.553 mL) was stirred in a sealed tube at 135 °C overnight. The mixture was purified by silica gel column chromatography (EtOAc / hexane). The residue was triturated with IPE / EtOAc to give the title compound (38.4 mg). 1 H NMR (400 MHz, CDCl3) δ 3.07 (3H, s), 3.13-3.23 (1H, m), 3.47 (1H, dd, J = 16.4, 0.9 Hz), 3.58-3.71 (3H, m), 3.80 (1H, dd, J = 9.9, 8.2 Hz), 4.19-4.36 (1H, m), 4.56-4.68 (1H, m), 4.69-4.77 (2H, m), 6.66-6.82 (2H, m), 7.28 (1H, dd, J = 8.4, 2.8 Hz), 8.51 (1H, d, J = 2.7 Hz).

[0472] Example 149 N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide

[0473] A) tert-Butyl (4R)-3,3-difluoro-4-[(fluoromethanesulfonyl)amino]pyrrolidine-1-carboxylate To a solution of tert-butyl (R)-4-amino-3,3-difluoropyrrolidine-1-carboxylate (250 mg) in pyridine (4 mL) was added dropwise fluoromethanesulfonyl chloride (179 mg) at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with 1M aqueous hydrogen chloride and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (321 mg). 1 H NMR (300 MHz, CDCl3) δ 1.47 (9H, s), 3.20-3.33 (1H, m), 3.60-3.91 (2H, m), 3.92-4.07 (1H, m), 4.19-4.41 (1H, m), 5.08 (1H, s), 5.23 (1H, s), 5.31 (1H, br s).

[0474] B) N-[(3R)-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide hydrochloride To a solution of tert-butyl (4R)-3,3-difluoro-4-[(fluoromethanesulfonyl)amino]pyrrolidine-1-carboxylate (321 mg) in EtOAc (5 mL) was added 4M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with EtOAc to give the title compound (217 mg). 1H NMR (300 MHz, DMSO-d6) δ 3.05-3.23 (1H, m), 3.61-3.89 (3H, m), 4.29-4.58 (1H, m), 5.17-5.70 (2H, m), 8.45-9.13 (1H, m), 9.95 (2H, br s).

[0475] C) N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide A mixture of 2-[(5S)-3-bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine (50.0 mg), N-[(3R)-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide hydrochloride (49.1 mg) in pyridine (0.40 mL) was stirred overnight at 140 ° C. in a sealed tube. The mixture was purified by NH silica gel column chromatography (MeOH / EtOAc) and silica gel column chromatography (EtOAc / hexane) to give the title compound (23.0 mg). 1 H NMR (300 MHz, CDCl3) δ 3.15-3.27 (1H, m), 3.41-3.78 (5H, m), 4.18-4.38 (1H, m), 4.59-4.73 (1H, m), 4.76-4.89 (1H, m), 5.06 (1H, s), 5.21 (1H, s), 5.37-5.54 (1H, m), 6.91-7.04 (2H, m), 7.29-7.44 (2H, m), 8.49 (1H, d, J = 2.7 Hz).

[0476] Example 154 N-[(3R)-1-{5-[2-(3,5-difluoropyridin-2-yl)-6-fluoro-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide

[0477] A) 3-bromo-5-(2-bromo-6-fluoro-4-methylphenyl)-4,5-dihydro-1,2-oxazole Hydroxycarbonimide dibromide (943 mg) was added to a mixture of 1-bromo-3-fluoro-5-methyl-2-vinylbenzene (500 mg), sodium bicarbonate (1.56 g), and EtOAc (10 mL) at room temperature. The mixture was stirred at 70°C for 1.5 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (793 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.32 (3H, s), 3.40 (1H, td, J = 8.8, 1.2 Hz), 3.80 (1H, ddd, J = 17.6, 12.2, 2.3 Hz), 6.02-6.10 (1H, m), 7.19 (1H, dt, J = 11.9, 0.7 Hz), 7.40 (1H, s).

[0478] B) N-{(3R)-1-[5-(2-bromo-6-fluoro-4-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide N-[(3R)-4,4-Difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (492 mg) was added to a solution of 3-bromo-5-(2-bromo-6-fluoro-4-methylphenyl)-4,5-dihydro-1,2-oxazole (500 mg) in pyridine (3.71 mL). The mixture was stirred overnight at 140° C. in a sealed tube. The mixture was poured into saturated aqueous sodium bicarbonate at room temperature, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (309 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.31 (3H, s), 3.00 (3H, s), 3.15-3.29 (2H, m), 3.39-3.56 (1H, m), 3.68-3.90 (3H, m), 4.25-4.46 (1H, m), 5.79 (1H, t, J = 10.3 Hz), 7.14 (1H, d, J = 11.6 Hz), 7.37 (1H, s), 7.99 (1H, dd, J = 9.1, 4.2 Hz).

[0479] C) N-[(3R)-1-{5-[2-(3,5-difluoropyridin-2-yl)-6-fluoro-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide Hexa-n-butylditin (0.391 mL) was added to a mixture of 2-bromo-3,5-difluoropyridine (100 mg), tricyclohexylphosphine (14.5 mg), and Pd(dba) (47.2 mg) in DME (1.5 mL) at room temperature. The mixture was heated to 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and directly filtered through Celite™ with EtOAc. The filtrate was concentrated under reduced pressure. The residue was suspended in DMF (1.5 mL) and added to a flask containing N-{(3R)-1-[5-(2-bromo-6-fluoro-4-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide (25.0 mg) and Pd(PhP) (12.7 mg) at room temperature. The mixture was heated to 110°C under an argon atmosphere for 6 hours. The mixture was filtered through Celite™, the filtrate was diluted with water, and the resulting mixture was extracted with EtOAc. The combined organic layer was then washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile) and NH silica gel column chromatography (EtOAc / hexane) to give the title compound (5.0 mg). 1 H NMR (300 MHz, DMSO-d6) δ 2.36 (3H, s), 2.99 (3H, s), 3.08-3.27 (2H, m), 3.35-3.46 (1H, m), 3.53-3.83 (3H, m), 4.24-4.41 (1H, m), 5.18-5.32 (1H, m), 7.02 (1H, s), 7.23 (1H, d, J = 12.4 Hz), 7.98 (1H, s), 8.07 (1H, td, J = 9.3, 1.7 Hz), 8.58 (1H, t, J = 2.4 Hz).

[0480] Example 164 N-{(3R,4S)-4-fluoro-4-methyl-1-[(5S)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or N-{(3S,4R)-4-fluoro-4-methyl-1-[(5S)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or N - an optical isomer of {(3R,4S)-4-fluoro-4-methyl-1-[(5R)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or N-{(3S,4R)-4-fluoro-4-methyl-1-[(5R)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide

[0481] A) Ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-2-fluoro-3-hydroxy-2-methylbutanoate Under an argon atmosphere, n-butyllithium (1.6 M in hexane, 97 mL) was added dropwise to a solution of diisopropylamine (15.8 g) in THF (150 mL) at 0°C, and the mixture was stirred for 15 minutes. The mixture was then cooled to -78°C, and a solution of ethyl 2-fluoropropanoate (15.6 g) in THF (50 mL) was added dropwise at the same temperature. The mixture was stirred at -78°C for 30 minutes. A solution of tert-butyl (4-methoxybenzyl)(2-oxoethyl)carbamate (14.5 g) in THF (50 mL) was added dropwise, and the mixture was stirred at -78°C for 1 hour, then slowly warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride at 0°C, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (13.3 g). MS: [M+Na] + 422.2.

[0482] B) rac-(3R,4S)-3-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one A mixture of ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-2-fluoro-3-hydroxy-2-methylbutanoate (13.3 g) and 4 M hydrogen chloride in EtOAc (130 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. A mixture of the residue, DIPEA (17.5 mL), and EtOH (400 mL) was stirred at 80° C. for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.22 g). MS: [M+H] + 254.1.

[0483] C) rac-(3R,4R)-4-azido-3-fluoro-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one Under an argon atmosphere, trifluoromethanesulfonic anhydride (14.6 mL) was added dropwise to a solution of rac-(3R,4S)-3-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one (8.73 g) and pyridine (13.9 mL) in acetonitrile (150 mL), and the mixture was stirred at 0°C for 2 hours. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A mixture of the residue, tetra-n-butylammonium azide (30.6 g), and acetonitrile (150 mL) was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was quenched with water at room temperature, and the resulting mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (8.80 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.35-1.61 (3H, m), 3.08 (1H, ddd, J = 10.7, 4.0, 1.1 Hz), 3.50 (1H, dd, J = 10.9, 6.0 Hz), 3.74 (3H, s), 4.20-4.37 (2H, m), 4.39-4.61 (1H, m), 6.85-6.99 (2H, m), 7.08-7.21 (2H, m).

[0484] D) rac-(3R,4R)-4-amino-3-fluoro-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one Under a hydrogen atmosphere, a mixture of rac-(3R,4R)-4-azido-3-fluoro-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one (8.80 g) and 10% palladium on carbon (880 mg) in MeOH (90 mL) was stirred at room temperature for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (7.80 g). MS: [M+H] + 253.1.

[0485] E) rac-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide To a solution of rac-(3R,4R)-4-amino-3-fluoro-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one (7.80 g) in THF (80 mL), methanesulfonic anhydride (8.08 g) and triethanolamine (8.62 mL) were added at 0° C., and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et0Ac / hexane) to give the title compound (8.60 g). MS: [M+H] + 331.1.

[0486] F) rel-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide (optical isomer) rac-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide (10 g) was resolved by SFC. The desired longer retention fraction was concentrated in vacuo to give the title compound (4.77 g). Chiral separation conditions Column: Chiral PAK AY™ (250 x 30 mm ID, 10 μm) Mobile phase: CO2 / EtOH =750 / 250 (v / v) MS: [M+H] + 331.1.

[0487] G) rel-N-{(3R,4S)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methylpyrrolidin-3-yl}methanesulfonamide (optical isomer) To a solution of rel-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide (enantiomer) (1.00 g) in THF (10 mL) was added dropwise borane dimethyl sulfide complex in THF (1.9 M, 7.97 mL) at room temperature. The mixture was stirred at 50°C for 5 hours. After the reaction mixture was cooled to room temperature, MeOH (10 mL) and 1M aqueous sodium hydroxide solution (10 mL) were added dropwise. The mixture was stirred at 65°C for 3 hours. After cooling to room temperature, water and brine were added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with EtOAc / hexane (1 / 1) to give the title compound (653 mg). MS: [M+H] + 317.0.

[0488] H) rel-N-[(3R,4S)-4-fluoro-4-methylpyrrolidin-3-yl]methanesulfonamide (optical isomer) Under a hydrogen atmosphere, a mixture of rel-N-{(3R,4S)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methylpyrrolidin-3-yl}methanesulfonamide (enantiomer) (653 mg) and 10% palladium on carbon (439 mg) in THF (40 mL) and MeOH (40 mL) was stirred at room temperature for 14 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with hexane / EtOAc (1 / 4) to give the title compound (350 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.28-1.44 (3H, m), 2.59-2.70 (1H, m), 2.87-2.96 (4H, m), 2.98-3.02 (1H, m), 3.07-3.18 (1H, m), 3.23-3.60 (2H, m), 7.03-7.39 (1H, m).

[0489] I) 2-ethenyl-2',3,5,6'-tetrafluoro-1,1'-biphenyl A mixture of 1-bromo-3,5-difluoro-2-vinylbenzene (0.816 mL), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.52 g), cesium carbonate (6.84 g), copper(I) chloride (0.520 g), Pd(OAc) (0.059 g), and 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.431 g) in DMF (27 mL) was stirred at 100 °C for 10 h. The reaction mixture was diluted with EtOAc, washed twice with water, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (0.500 g). 1 H NMR (400 MHz, DMSO-d6) δ 5.42 (1H, dt, J = 11.8, 1.6 Hz), 5.55 (1H, dt, J = 17.9, 1.3 Hz), 6.25 (1H, dd, J = 17.9, 11.7 Hz), 7.17-7.69 (5H, m).

[0490] J) 3-Bromo-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazole Sodium bicarbonate (1.67 g) was added to a mixture of 2-ethenyl-2',3,5,6'-tetrafluoro-1,1'-biphenyl (500 mg) and hydroxycarbonimide dibromide (804 mg) in EtOAc (7.93 mL) at room temperature. The mixture was stirred at 70°C for 2 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (540 mg). 1H NMR (400 MHz, DMSO-d6) δ 3.37 (1H, ddd, J = 17.6, 9.2, 1.0 Hz), 3.70 (1H, ddd, J = 17.5, 12.2, 2.2 Hz), 5.42 (1H, dd, J = 11.5, 9.9 Hz), 7.21-7.33 (3H, m), 7.49-7.65 (2H, m).

[0491] K) 3-Bromo-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazole (optical isomer) 3-Bromo-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazole (1.50 g) was optically resolved by SFC to give the title compound with a shorter retention time (601 mg). Chiral separation conditions Column: Chiral CEL OJ (trademark) (250mm*50mm, 10μm) Mobile phase: CO2 / MeOH containing 0.1% ammonium hydroxide = 900 / 100 (v / v) 1 H NMR (400 MHz, DMSO-d6) δ 3.35-3.47 (1H, m), 3.63-3.75 (1H, m), 5.37-5.46 (1H, m), 7.21-7.32 (3H, m), 7.47-7.64 (2H, m)

[0492] L) N-{(3R,4S)-4-fluoro-4-methyl-1-[(5S)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or N-{(3S,4R)-4-fluoro-4-methyl-1-[(5S)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or N - an optical isomer of {(3R,4S)-4-fluoro-4-methyl-1-[(5R)-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide or N-{(3S,4R)-4-fluoro-4-methyl-1-[(5R]-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}methanesulfonamide A mixture of 3-bromo-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazole (optical isomer) (37.4 mg), rel-N-[(3R,4S)-4-fluoro-4-methylpyrrolidin-3-yl]methanesulfonamide (optical isomer) (39.2 mg), and DIPEA (0.052 mL) in t-BuOH (0.3 mL) was heated at 140 °C for 14 hours under microwave irradiation. After cooling to room temperature, the mixture was purified by silica gel column chromatography (EtOAc / hexane) and NH silica gel column chromatography (EtOAc / hexane) to give the title compound (26.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.52 (3H, m), 2.97 (3H, s), 3.10-3.22 (1H, m), 3.26-3.30 (2H, m), 3.36-3.41 (1H, m), 3.48 (1H, s), 3.60-3.71 (1H, m), 3.73-3.96 (1H, m), 5.07 (1H, t, J = 10.4 Hz), 7.09-7.36 (3H, m), 7.38-7.69 (3H, m).

[0493] Example 165 N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide

[0494] A) 2-(3-bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-fluoropyridine To a mixture of 2-chloro-3-(2,6-difluorophenyl)-5-fluoropyridine (78.0 g), potassium isopropenyltrifluoroborate (142 g), potassium carbonate (133 g), and copper(I) iodide (3.05 g) in DME (780 mL) and water (156 mL) was added Pd(dppf)Cl2·CHCl2 (39.2 g) at 20 °C. The mixture was stirred at 110 °C under a nitrogen atmosphere for 4 hours. 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 on a silica gel column (EtOAc / petroleum ether) to give 3-(2,6-difluorophenyl)-5-fluoro-2-(prop-1-en-2-yl)pyridine (73 g, crude). To a mixture of 3-(2,6-difluorophenyl)-5-fluoro-2-(prop-1-en-2-yl)pyridine (73.0 g, crude) and hydroxycarbonimide dibromide (42.8 g) in EtOAc (800 mL) was added sodium bicarbonate (29.5 g). The mixture was stirred at 60° C. for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the crude title compound, which was dissolved in EtOAc. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (36.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.63 (3H, s), 3.46-3.50 (1H, m, overlapped with water's signal), 3.78-3.83 (1H, m), 7.08-7.24 (2H, m), 7.44-7.59 (1H, m), 7.85-7.88 (1H, m), 8.72 (1H, d, J = 2.8 Hz).

[0495] B) 2-[(5S)-3-bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine 2-(3-Bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-fluoropyridine (37.8 g) was resolved by SFC. The desired fraction with the longer retention time was concentrated under vacuum. The residue was again resolved by SFC. The desired fraction with the longer retention time was concentrated. The residue 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 to give the title compound (9.33 g). Chiral separation conditions Column: Chiral CEL OJ (trademark) (250mm*50mm, 10μm) Mobile phase: CO2 / IPA containing 0.1% ammonium hydroxide = 800 / 200 (v / v) 1 H NMR (400 MHz, DMSO-d6) δ 1.62 (3H, s), 3.45-3.50 (1H, m), 3.78-3.82 (1H, m), 7.14-7.20 (2H, m), 7.48-7.56 (1H, m), 7.84-7.87 (1H, m), 8.71 (1H, d, J = 2.8 Hz).

[0496] C) N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide To a mixture of 2-[(5S)-3-bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine (50.0 mg) in pyridine (1 mL) was added N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (63.8 mg). The mixture was stirred at 140°C under microwave irradiation for 4 hours. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fractions were then concentrated to give the title compound (23.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.53 (3H, s), 2.98 (3H, s), 3.06 (1H, t, J = 9.3 Hz), 3.17 (1H, d, J = 16.4 Hz), 3.50-3.65 (2H, m), 3.65-3.78 (2H, m), 4.16-4.36 (1H, m), 7.07-7.18 (2H, m), 7.40-7.53 (1H, m), 7.73-7.78 (1H, m), 7.93 (1H, br s), 8.68 (1H, d, J = 2.8 Hz).

[0497] Example 167 N-[(3R)-1-{5-[2-(3,5-difluoropyridin-2-yl)-6-fluoro-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (optical isomer)

[0498] N-[(3R)-1-{5-[2-(3,5-difluoropyridin-2-yl)-6-fluoro-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (110 mg) was optically resolved by SFC to give the title compound with a longer retention time (36 mg). Chiral separation conditions First separation Column: Chiral PAK AD (trademark) (250*30mm ID, 10μm) Mobile phase: CO2 / IPA = 750 / 250 (v / v) Second separation Column: Chiral PAK AS (trademark) (250*30mm ID, 10μm) Mobile phase: CO2 / EtOH = 850 / 150 (v / v) 1 H NMR (300 MHz, DMSO-d6) δ 2.36 (3H, s), 2.99 (3H, s), 3.08-3.30 (2H, m), 3.36-3.48 (1H, m), 3.77 (3H, s), 4.25-4.43 (1H, m), 5.24 (1H, t, J = 10.7 Hz), 7.03 (1H, s), 7.23 (1H, d, J = 12.1 Hz), 7.99 (1H, d, J = 9.2 Hz), 8.03-8.11 (1H, m), 8.58 (1H, d, J = 2.4 Hz).

[0499] Example 171 N-[(3R)-1-{5-[4-chloro-2-(3,5-difluoropyridin-2-yl)-6-fluorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide

[0500] A) 4-chloro-2-(3,5-difluoropyridin-2-yl)-6-fluoroaniline A mixture of 4-chloro-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (233 mg), 2-bromo-3,5-difluoropyridine (183 mg), Pd(dba) (157 mg), cesium fluoride (261 mg), and tri-tert-butylphosphonium tetrafluoroborate (124 mg) in THF (4 mL) was stirred at 60 °C for 4 hours under an argon atmosphere. The reaction mixture was directly filtered through Celite™, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and NH silica gel column chromatography (EtOAc / hexane) to give the title compound (117 mg). MS: [M+H] + 258.8.

[0501] B) 2-(5-chloro-3-fluoro-2-iodophenyl)-3,5-difluoropyridine To a stirred solution of 4-chloro-2-(3,5-difluoropyridin-2-yl)-6-fluoroaniline (113 mg) in THF (4 mL) was added copper(I) iodide (125 mg), diiodomethane (0.282 mL), and n-pentyl nitrite (0.232 mL). The mixture was stirred at 70°C for 6 hours under an argon atmosphere. After cooling to room temperature, the mixture was dissolved in EtOAc and washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The 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) to give the title compound (28.0 mg). MS: [M+H] + 369.9.

[0502] C) 2-[2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-fluorophenyl]-3,5-difluoropyridine A mixture of 2-(5-chloro-3-fluoro-2-iodophenyl)-3,5-difluoropyridine (28 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.014 mL), potassium carbonate (31.4 mg), PdCl(dppf) (5.54 mg), and DME (1 mL) / water (0.20 mL) was heated at 90 °C for 1.5 h under microwave irradiation. The mixture was filtered, and the resulting residue was purified by silica gel column chromatography (EtOAc / hexane) to give 2-(5-chloro-2-ethenyl-3-fluorophenyl)-3,5-difluoropyridine (19 mg, crude). To the crude product was added EtOAc (1 mL), followed by sodium bicarbonate (63.7 mg) and hydroxycarbonimide dibromide (30.7 mg) at room temperature. The mixture was stirred at 70 °C for 1.5 h. The mixture was filtered, and the resulting residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (19 mg). 1 H NMR (300 MHz, CD3OD) δ 3.42-3.80 (2H, m), 5.61-5.78 (1H, m), 7.28-7.34 (1H, m), 7.46 (1H, dd, J = 10.8, 2.1 Hz), 7.75 (1H, ddd, J = 9.4, 8.5, 2.4 Hz), 8.49 (1H, d, J = 2.4 Hz).

[0503] D) N-[(3R)-1-{5-[4-chloro-2-(3,5-difluoropyridin-2-yl)-6-fluorophenyl]-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide N-[(3R)-4,4-Difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (17.2 mg) was added to a mixture of pyridine (0.3 mL) and 2-[2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-fluorophenyl]-3,5-difluoropyridine (19 mg). The mixture was heated in a sealed tube at 140 °C overnight. The crude product was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile) to give the title compound (2.3 mg). 1 H NMR (300 MHz, CD3OD) δ 3.05 (3H, s), 3.27 (1H, d, J = 9.9 Hz), 3.43-3.91 (5H, m), 4.45 (1H, dd, J = 14.4, 8.1 Hz), 5.57 (1H, td, J = 10.6, 5.4 Hz), 7.28 (1H, dd, J = 1.9, 1.0 Hz), 7.45 (1H, dd, J = 10.7, 2.1 Hz), 7.74 (1H, td, J = 8.9, 2.4 Hz), 8.41-8.50 (1H, m).

[0504] The example compounds are shown in the following tables. In these tables, MS represents the observed molecular ion (measured value). The compounds described in Examples 1-7, 9, 10, 13-19, 21, 24-29, 31-38, 40, 41, 43-48, 51-58, 60-63, 65-71, 74-81, 83-93, 96-98, 100-106, 108, 110-130, 132-146, 148, 150-153, 155-163, 166, 168-170, and 172-178 were synthesized using the same reactions and purification methods as those described in the above examples.

[0505] [Table 1-1]

[0506] [Table 1-2]

[0507] Table 1-3-1

[0508] Table 1-3-2

[0509] Table 1-4

[0510] Table 1-5

[0511] Table 1-6

[0512] Table 1-7

[0513] Table 1-8

[0514] Table 1-9

[0515] Table 1-10

[0516] Table 1-11

[0517] Table 1-12

[0518] Table 1-13

[0519] Table 1-14

[0520] Table 1-15

[0521] Table 1-16

[0522] Table 1-17

[0523] Table 1-18

[0524] Table 1-19

[0525] Table 1-20

[0526] Table 1-21

[0527] Table 1-22

[0528] Table 1-23

[0529] Table 1-24

[0530] Table 1-25

[0531] Table 1-26

[0532] Table 1-27

[0533] Table 1-28

[0534] Table 1-29

[0535] Table 1-30

[0536] Table 1-31

[0537] Test Example 1: Obtaining cells stably expressing human orexin type 2 receptor (hOX2R) To obtain cell clones stably expressing human orexin type 2 receptor, human orexin type 2 (residues 1-444, NCBI reference sequence: AK314279) was constructed in the pcDNA3.1(+) vector (Invitrogen) and expressed in mammalian cells. This plasmid DNA was transfected into CHO-K1 cells by electroporation, and stable clones were obtained by limiting dilution using G418 resistance as a selection marker.

[0538] Test Example 2: Measurement of orexin type 2 receptor agonist activity CHO cells overexpressing human OX2 receptor were seeded at 10,000 cells / well in a 384-well black clear-bottom plate (BD Falcon) and incubated at room temperature for 30 minutes, followed by incubation at 37°C and 5% CO2 for 1 day. After removing the cell plate medium, 30 μL / well of assay buffer containing calcium indicator A (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4AM (Dojindo Laboratories), 0.08% Pluronic F127 (Dojindo Laboratories), 1.25 mM probenecid (Dojindo Laboratories)) was added. The plates were incubated at 37°C for 30 minutes in a 5% CO2 incubator, followed by another 30 minutes at room temperature. Test compounds diluted in assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) were added at 10 μL / well, and fluorescence values ​​were measured every 1 second for 1 minute, then every 2 seconds for 1 minute using an FDSS μCELL (Hamamatsu Photonics). Measurements were performed for 1 minute and 40 seconds. The fluorescence value when DMSO was added instead of the test compound was set to 0%, and the fluorescence value when orexin A (human) (Peptide Institute) was added at a final concentration of 10 nM was set to 100%. The activity (%) of the test compounds was calculated. Table 2 shows the activity of each compound at a concentration of 3 μM. As is clear from these results, the compounds of the present invention were shown to have orexin type 2 receptor agonist activity.

[0539] [Table 2-1]

[0540] [Table 2-2]

[0541] [Table 2-3]

[0542] [Table 2-4]

[0543] [Table 2-5]

[0544] [Table 2-6]

[0545] [Table 2-7]

[0546] Test Example 3: Evaluation of wake-promoting effect in cynomolgus monkeys The wake-promoting effect was evaluated by measuring electroencephalogram (EEG), electromyogram (EMG), and locomotor activity in cynomolgus monkeys. Under isoflurane anesthesia (0.5–5%, Pfizer Japan, Tokyo, Japan), male cynomolgus monkeys (2–3 years old, Hamuri Co., Ltd., Ibaraki, Japan) were surgically implanted with a radiotelemetry transmitter (L03-F3, Data Sciences International, MN, USA). Two EEG electrodes were stereotactically placed on the parietal area, in contact with the dura mater, and fixed to the skull with stainless steel screws. Bilateral EMG electrodes were implanted in the muscles at the back of the neck. After a recovery period of at least 1 month in their home cages, monkeys were habituated to a recording chamber (acrylic cage, 60cm W x 55cm D x 75cm H) in a soundproof, electrically shielded room until they were fully asleep in the experimental room. Cortical EEG, EMG, and locomotor activity were recorded using a telemetry system (PhysioTel Digital Telemetry Platform, Data Science International). Signals were scored semi-automatically in 20-second epochs using a sleep scoring system (SleepSign, Kissei Comtec Co., Ltd., Nagano, Japan). Test compound (3 mg / kg) suspended in 0.5% methylcellulose solution or vehicle (i.e., 0.5% methylcellulose solution) was orally administered (po) to monkeys (n = 2) at Zeitgeber time 12 in a volume of 5 mL / kg body weight in a pretest-posttest design, and EEG, EMG, and locomotor activity were recorded. SleepSign was used to calculate the wakefulness time (% of vehicle treatment) 4 hours after administration. The results are shown in Table 3.

[0547] [Table 3]

[0548] As is clear from Table 3, the test compounds of the present invention increased the wakefulness time in cynomolgus monkeys compared to the vehicle-treated group, suggesting that these compounds may be potential therapeutic agents for narcolepsy.

[0549] Formulation Example 1 (Capsule Production) 1) 30 mg of the compound of Example 1 2) Finely powdered cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg Total 60mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0550] Formulation Example 2 (Tablet Production) 1) 30 g of the compound of Example 1 2) Lactose 50g 3) 15g corn starch 4) Carboxymethylcellulose calcium 44g 5) Magnesium stearate 1g 1000 tablets total 140g The total amount of 1), 2), 3) and 30 g of 4) are mixed with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and compressed into tablets using a tablet press. 1000 tablets containing 30 mg of the compound of Example 1 per tablet are thus obtained. [Industrial Applicability]

[0551] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as an agent for the prevention or treatment of narcolepsy.

[0552] This application is based on U.S. Patent Application No. 63 / 385,598, filed on November 30, 2022, the contents of which are incorporated herein in their entirety.

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, R １ is C １－６ Alkyl group, C ３－７ a cycloalkyl group, or a mono- or di-C １－６ alkylamino group, wherein the C １－６ Alkyl group, C ３－７ Cycloalkyl groups, and mono- or di-C １－６ Each alkylamino group may be optionally substituted; Each R ２ are the same or different and optionally substituted C １－６ is an alkyl group; Each R ３ are the same or different and optionally substituted C １－６ an alkyl group or a halogen atom; R Ａ represents an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted C ６－１４ an aryl group or an optionally substituted C ３－１０ is a cycloalkyl group; L １ is a bond, -NR ６ -, or -O-; where R ６ represents a hydrogen atom or an optionally substituted C １－６ is an alkyl group; L ２ is a bond or -CH ２ - and; X １ is N or CR ３’ and X ２ is N or CR ４ｂ and X ３ is N or C; X ４ is N or CR ４ｃ and X ５ is N or CR ４ｄ and However, X ２ , X ３ , X ４ , and X ５ where no more than two of are N; R ３’ represents a hydrogen atom, an optionally substituted C １－６ an alkyl group or a halogen atom; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ are the same or different and each represents a hydrogen atom, an optionally substituted C １－６ alkyl group, optionally substituted C ３－７ a cycloalkyl group, a halogen atom, or an optionally substituted C １－６ is an alkoxy group; m is an integer from 0 to 3; n is an integer from 0 to 3; o is an integer from 0 to 3; p is an integer of 0 or 1; and 【Chemistry 2】 contains one single bond and one double bond when p is 0, and one single bond and two double bonds when p is 1, to provide an aromatic ring structure; or a salt thereof.

2. R Ａ but has the following structure: 【Transformation 3】 [In the formula, X ６ is N or CR ５’ and Each R ５ are the same or different and each represents a halogen atom or C １－６ is an alkoxy group; R ５’ is a hydrogen atom or a halogen atom; q is an integer from 0 to 7; and 【Chemistry 4】 are the same and are both single bonds or both double bonds; 2. The compound of claim 1, or a salt thereof, having the formula:

3. X １ is CR ３’ wherein m is an integer from 0 to 2 and n is 0; The compound of claim 1, or a salt thereof.

4. X １ is N; The compound of claim 1, or a salt thereof.

5. R １ But C １－６ Alkyl group, C １－６ Alkoxy-C １－６ Alkyl group, halo-C １－６ an alkyl group, a cyclopropyl group, a halo-cyclopropyl group, or a mono- or di-C １－６ an alkylamino group; Each R ２ However, the same or different, C １－６ Alkyl group, halo-C １－６ Alkyl group, C １－６ Alkoxy-C １－６ alkyl group, or hydroxy-C １－６ is an alkyl group; Each R ３ However, the same or different, C １－６ Alkyl group, C １－６ Alkoxy-C １－６ an alkyl group or a halogen atom; R ４ａ is a hydrogen atom, C １－６ Alkyl group, cyclopropyl group, C １－６ Alkoxy group, halo-C １－６ an alkyl group, or a halogen atom; and q is an integer from 0 to 4; The compound according to claim 2, or a salt thereof.

6. (i) X ２ is CR ４ｂ and X ３ is N and X ４ is N and p is 0; or (ii) X ２ is N and X ３ is N and X ４ is CR ４ｃ and p is 0; The compound according to claim 1, or a salt thereof,

7. X ２ is CR ４ｂ and X ３ is C and X ４ is CR ４ｃ and X ５ is CR ４ｄ and p is 1; or a salt thereof.

8. X ２ is N and X ３ is C and X ４ is CR ４ｃ and X ５ is CR ４ｄ and p is 1; or a salt thereof.

9. X ２ is CR ４ｂ and X ３ is C and X ４ and X ５ is N and p is 1; or a salt thereof.

10. X ２ is CR ４ｂ and X ３ is C and X ４ is CR ４ｃ and X ５ is N and p is 1; or a salt thereof.

11. X ２ and X ４ is N and X ３ is C and X ５ is CR ４ｄ and p is 1; or a salt thereof.

12. X ２ is CR ４ｂ and X ３ is C and X ４ is N and X ５ is CR ４ｄ and p is 1; or a salt thereof.

13. X ６ is CR ５’ and 【Transformation 5】 and are both single bonds; or a salt thereof.

14. X ６ is CR ５’ and 【Transformation 6】 and R are double bonds; or a salt thereof.

15. X ６ N ’ and 【Transformation 7】 and R are double bonds; or a salt thereof.

16. portion: 【Transformation 8】 but: 【Chemistry 9】 selected from the group consisting of: where * indicates R Ａ indicates a binding site for R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ is as defined in claim 1; The compound of claim 1, or a salt thereof.

17. portion: 【Chemistry 10】 but: 【Chemistry 11】 selected from the group consisting of: where: * is R Ａ indicates the binding site for R １ But C １－６ Alkyl group, C １－６ Alkoxy-C １－６ Alkyl group, halo-C １－６ an alkyl group, a cyclopropyl group, a halo-cyclopropyl group, or a mono- or di-C １－６ an alkylamino group; Each R ２ However, the same or different, C １－６ Alkyl group, halo-C １－６ Alkyl group, C １－６ Alkoxy-C １－６ alkyl group, or hydroxy-C １－６ is an alkyl group; Each R ３ However, the same or different, C １－６ Alkyl group, C １－６ Alkoxy-C １－６ an alkyl group or a halogen atom; L １ is a bond, -NR ６ -, or -O-; where R ６ is a hydrogen atom, or C １－６ is an alkyl group; L ２ is a bond or -CH ２ - and; X １ But N or CR ３’ where R ３’ is a hydrogen atom; R ４ａ is a hydrogen atom, C １－６ Alkyl group, cyclopropyl group, C １－６ Alkoxy group, halo-C １－６ an alkyl group or a halogen atom; X ２ But N or CR ４ｂ where R ４ｂ is a hydrogen atom or a halogen atom; X ４ But N or CR ４ｃ where R ４ｃ is a hydrogen atom or a halogen atom; X ５ But N or CR ４ｄ where R ４ｄ is a hydrogen atom; m is an integer from 0 to 3; n is an integer from 0 to 3; o is an integer from 0 to 3; and portion: 【Chemistry 12】 but: 【Chemistry 13】 selected from the group consisting of: where: Each R ５ are the same or different and are a halogen atom or C １－６ is an alkoxy group; R ５’ is a hydrogen atom or a halogen atom; and q is an integer from 0 to 4; The compound according to claim 2, or a salt thereof.

18. The compound has the formula (Ia): 【Chemistry 14】 [In the formula, q is an integer from 0 to 4; and Other symbols are as defined in claim 2; 3. The compound according to claim 2, which is a compound of the formula:

19. The compound has the formula (Ib): 【Chemistry 15】 [In the formula, q is an integer from 0 to 4; and Other symbols are as defined in claim 2; 3. The compound according to claim 2, which is a compound of the formula:

20. The compound has the formula (Ic): 【Chemistry 16】 [In the formula, R ２ａ represents a hydrogen atom or an optionally substituted C １－６ is an alkyl group; q is an integer from 0 to 4; and Other symbols are as defined in claim 2; 3. The compound according to claim 2, which is a compound of the formula:

21. The compound has the formula (Id): 【Chemistry 17】 [In the formula, R ２ａ represents a hydrogen atom or an optionally substituted C １－６ is an alkyl group; R ３ａ and R ３ｂ are the same or different and each represents a hydrogen atom, an optionally substituted C １－６ an alkyl group or a halogen atom; q is an integer from 0 to 4; and Other symbols are as defined in claim 2; 3. The compound according to claim 2, which is a compound of the formula:

22. The compound has the formula (Ie): [Chemistry 18] [In the formula, R １ is C １－６ alkyl group, or halo-C １－６ is an alkyl group; R ２ａ is a hydrogen atom, C １－６ alkyl group, or halo-C １－６ is an alkyl group; R ３ａ and R ３ｂ are the same or different, and each represents C １－６ an alkyl group or a halogen atom; R ４ａ is C １－６ an alkyl group or a halogen atom; X ２ is N or CR ４ｂ where R ４ｂ is a halogen atom; and R Ａ is a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are each optionally substituted with 1 to 3 halogen atoms; 2. The compound of claim 1, wherein the compound is:

23. R １ But C １－６ alkyl group, or halo-C １－６ is an alkyl group; R ２ａ is a hydrogen atom, C １－６ alkyl group, or halo-C １－６ is an alkyl group; R ３ａ and R ３ｂ are each a halogen atom; R ４ａ But C １－６ an alkyl group or a halogen atom; X ２ But N or CR ４ｂ where R ４ｂ is a halogen atom; and R Ａ is a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are each optionally substituted with 1 to 3 halogen atoms; 23. The compound of claim 22, or a salt thereof.

24. R １ But C １－６ alkyl group, or halo-C １－６ is an alkyl group; R ２ａ But C １－６ alkyl group, or halo-C １－６ is an alkyl group; R ３ａ and R ３ｂ are each a halogen atom; R ４ａ is a halogen atom; X ２ is N; and R Ａ is a phenyl group optionally substituted by 1 to 3 halogen atoms; 23. The compound of claim 22, or a salt thereof.

25. R １ But C １－６ is an alkyl group; R ２ａ But, Halo-C １－６ is an alkyl group; R ３ａ and R ３ｂ are each a halogen atom; R ４ａ is a halogen atom; X ２ is N; and R Ａ is a phenyl group optionally substituted by 1 to 3 halogen atoms; 23. The compound of claim 22, or a salt thereof.

26. The compound is: N-[(3R)-4,4-difluoro-1-{(5S)-5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide; N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide; N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide; and N-[(3R)-1-{(5S)-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl}-4,4-difluoropyrrolidin-3-yl]methanesulfonamide 2. The compound of claim 1, or a salt thereof, selected from the group consisting of:

27. 27. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 26, or a salt thereof, and a pharmaceutically acceptable carrier.

28. 27. A medicament comprising a compound as defined in any one of claims 1 to 26 or a salt thereof.

29. The pharmaceutical agent according to claim 28, which is an orexin type 2 receptor agonist.

30. The pharmaceutical agent according to claim 28, which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcoleptic symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness, or side effects or complications caused by anesthesia.

31. The pharmaceutical agent according to claim 28, which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

32. The pharmaceutical agent according to claim 28, which is a preventive or therapeutic agent for narcolepsy.

33. 27. A method for preventing or treating a disease or disorder associated with the orexin type 2 receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound defined in any one of claims 1 to 26 or a salt thereof.

34. The method of claim 33, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness, and side effects or complications caused by anesthesia.

35. 34. The method of claim 33, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea.

36. 34. The method of claim 33, wherein the disease or disorder is narcolepsy.

37. 27. A compound as defined in any one of claims 1 to 26, or a salt thereof, for use in therapy.

38. 38. The compound or salt of claim 37, wherein the therapy comprises treatment of a disease or disorder associated with the orexin type 2 receptor.

39. 39. The compound or salt of claim 38, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disturbance of consciousness, and side effects or complications due to anesthesia.

40. 39. The compound or salt of claim 38, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

41. 39. The compound or salt of claim 38, wherein the disease or disorder is narcolepsy.

42. 30. Use of a compound as defined in any one of claims 1 to 26, or a salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with the orexin type 2 receptor.

43. The use according to claim 42, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcoleptic symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects or complications of anesthesia.

44. 43. The use of claim 42, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea.

45. 43. The use of claim 42, wherein the disease or disorder is narcolepsy.

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