Heterocyclic compound and use thereof

Abstract

The present invention provides a heterocyclic compound having an orexin type 2 receptor agonist activity. Provided is a compound of formula (I): # imgabs0 # wherein each symbol is as described in the specification, or a salt thereof, which has orexin type 2 receptor agonist activity and is useful as an agent for preventing or treating hypersomnia.

Description

Technical Field

[0001] The present invention relates to a heterocyclic compound, in particular to a heterocyclic compound having orexin type 2 receptor agonist activity. Background Art

[0002] Orexin is a neuropeptide produced specifically in specific neurons sparsely located in 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 primarily present 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 located near the feeding center, and intracerebroventricular administration of orexin peptides leads to increased food intake. Orexin initially attracted attention as a neuropeptide that regulates feeding behavior. However, since it was reported that genetic mutations in the orexin type 2 receptor are the cause of canine narcolepsy (Non-Patent Document 2), the role of orexin in controlling sleep and wakefulness has also attracted attention.

[0004] By using the transgenic mice with degenerated orexin neurons and the research of the double transgenic mice obtained by hybridizing this mouse with the transgenic mice of overexpressing orexin, it has been illustrated that the narcolepsy-like symptoms that occur due to the degeneration of orexin neurons disappear due to the continuous expression of orexin. Similarly, when administering orexin peptides to the intracerebroventricular administration of transgenic mice with degenerated orexin neurons, the improvement of narcolepsy-like symptoms has also been observed (non-patent literature 3). Research on orexin type 2 receptor knockout mice has shown that orexin type 2 receptor is important for maintaining wakefulness (non-patent literature 4, non-patent literature 5). Such background shows that orexin type 2 receptor agonists become the therapeutic drugs for narcolepsy or show the therapeutic drugs (non-patent literature 6) of other sleep disorders of excessive sleepiness.

[0005] Furthermore, it has been proposed that a peptide agonist that selectively acts on the orexin type 2 receptor improves obesity induced by a high-fat diet in mice (Non-Patent Document 7).

[0006] Furthermore, it has been suggested that intracerebroventricular administration of orexin peptide shortens the duration of general anesthesia in rats (Non-Patent Document 8).

[0007] Furthermore, it has been suggested that patients with sleep apnea syndrome show low orexin A concentration levels in plasma (Non-Patent Document 9).

[0008] Furthermore, it has been proposed that intracerebroventricular administration of orexin peptide improves memory retention in senescence-accelerated model mice (SAMP8) with cognitive impairment (Non-Patent Document 10).

[0009] Furthermore, orexin type 2 receptor agonists have been proposed as therapeutic drugs for heart failure (Patent Document 1, Non-Patent Document 11).

[0010] Furthermore, it has been suggested that daytime sleepiness in Parkinson's disease patients is caused by the neuronal deposition of orexin (Non-Patent Document 12).

[0011] Furthermore, it has been proposed that orexin regulates bone formation and bone loss, and that orexin type 2 receptor agonists would be therapeutic drugs for diseases associated with bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2).

[0012] Furthermore, it has been suggested that orexin receptor agonists can be used to prevent or treat sepsis, severe sepsis, and septic shock, because mortality was significantly improved in septic shock model mice simply by continuous peripheral administration of orexin (Patent Document 3).

[0013] Therefore, compounds having orexin type 2 receptor agonist activity are expected to be useful as novel therapeutic drugs for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbances of consciousness such as coma, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barre syndrome, and Kleine Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, and the like, and furthermore, as anesthetic antagonists, i.e., preventive or therapeutic drugs for side effects and complications due to anesthesia.

[0014] As a sulfonamide derivative, a compound represented by the following formula has been reported:

[0015]

[0016] The symbols are as described in the document (Patent Document 4).

[0017] In addition, the following compounds have been reported as compounds having orexin type 2 receptor agonist activity.

[0018] A compound represented by the formula:

[0019]

[0020] The symbols are as described in the document (Patent Document 5).

[0021] A compound represented by the formula:

[0022]

[0023] The symbols are as described in the document (Patent Document 6).

[0024] A compound represented by the formula:

[0025]

[0026] The symbols are as described in the document (Patent Document 7).

[0027] A compound represented by the formula:

[0028]

[0029] The symbols are as described in the document (Patent Document 8).

[0030] A compound represented by the formula:

[0031]

[0032] The symbols are as described in the document (Patent Document 9).

[0033] A compound represented by the formula:

[0034]

[0035] The symbols are as described in the document (Patent Document 10).

[0036] A compound represented by the formula:

[0037]

[0038] The symbols are as described in the document (Patent Document 11).

[0039] A compound represented by the formula:

[0040]

[0041] The symbols are as described in the document (Patent Document 12).

[0042] A compound represented by the formula:

[0043]

[0044] The symbols are as described in the document (Patent Document 13).

[0045] A compound represented by the formula:

[0046]

[0047] The symbols are as described in the document (Patent Document 14).

[0048] A compound represented by the formula:

[0049]

[0050] The symbols are as described in the document (Patent Document 15).

[0051] A compound represented by the formula:

[0052]

[0053] The symbols are as described in the document (Patent Document 16).

[0054] A compound represented by the formula:

[0055]

[0056] The symbols are as described in the document (Patent Document 17).

[0057] It is desirable to develop novel compounds having orexin type 2 receptor agonist activity.

[0058] [Reference List]

[0059] [Patent Document]

[0060] [Patent Document 1] WO 2015 / 073707 A1

[0061] [Patent Document 2] WO 2015 / 048091 A1

[0062] [Patent Document 3] WO 2015 / 147240 A1

[0063] [Patent Document 4] WO 2012 / 137982 A9

[0064] [Patent Document 5] WO 2017 / 135306 A1

[0065] [Patent Document 6] WO 2018 / 164191 A1

[0066] [Patent Document 7] WO 2018 / 164192 A1

[0067] [Patent Document 8] WO 2019 / 027003 A1

[0068] [Patent Document 9] WO 2019 / 027058 A1

[0069] [Patent Document 10] WO 2020 / 004536 A1

[0070] [Patent Document 11] WO 2020 / 004537 A1

[0071] [Patent Document 12] WO 2020 / 122092 A1

[0072] [Patent Document 13] WO 2020 / 122093 A1

[0073] [Patent Document 14] WO 2020 / 158958 A1

[0074] [Patent Document 15] WO 2020 / 167701 A1

[0075] [Patent Document 16] WO 2020 / 167706 A1

[0076] [Patent Document 17] WO 2021 / 106975 A1

[0077] [Non-patent literature]

[0078] [Non-patent document 1] Cell, Vol. 92, 573-585, 1998

[0079] [Non-patent document 2] Cell, Vol. 98, 365-376, 1999

[0080] [Non-patent document 3] Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004

[0081] [Non-patent document 4] Cell, Vol. 98, 437-451, 1999

[0082] [Non-patent document 5] Neuron, Vol. 38, 715-730, 2003

[0083] [Non-patent document 6] CNSDrugs, Vol. 27, pp. 83-90, 2013

[0084] [Non-patent document 7] Cell Metabolism, Vol. 9, 64-76, 2009

[0085] [Non-patent document 8] Neuroscience, Vol. 121, 855-863, 2003

[0086] [Non-patent document 9] Respiration, Vol. 71, pp. 575-579, 2004

[0087] [Non-patent document 10] Peptides, Vol. 23, 1683-1688, 2002

[0088] [Non-patent document 11] Journal of the American College of Cardiology. Vol. 66, 2015, pp. 2522-2533

[0089] [Non-patent document 12] Brain. Vol. 130, 2007, pp. 1586-1595 Summary of the Invention

[0090] Problems to be solved by the present invention

[0091] The present invention aims to provide a heterocyclic compound having orexin type 2 receptor agonist activity.

[0092] Means for solving the problem

[0093] The present inventors have discovered that a compound represented by the following formula (I) or a salt thereof (sometimes referred to as Compound (I) in this specification) has orexin type 2 receptor agonist activity. As a result of further studies, they have completed the present invention.

[0094] Therefore, the present invention relates to the following.

[0095] [1] A compound of formula (I):

[0096]

[0097] in

[0098] R 1 C 1-6 Alkyl, C 3-7 Cycloalkyl or mono- or di-C 1-6 Alkylamino, where C 1-6 Alkyl, C 3-7 Cycloalkyl and mono- or di-C 1-6 Each of the alkylamino groups is optionally substituted;

[0099] Each R 2 are the same or different and are optionally substituted C 1-6 alkyl;

[0100] Each R 3 are the same or different and are optionally substituted C 1-6 an alkyl group or a halogen atom;

[0101] R Ais an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- to 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 Aryl or optionally substituted C 3-10 Cycloalkyl;

[0102] L 1 For the key, -NR 6 -or-O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl;

[0103] L 2 is a bond or –CH2-;

[0104] X 1 N or CR 3’ ;

[0105] X 2 N or CR 4b ;

[0106] X 3 N or C;

[0107] X 4 N or CR 4c ;

[0108] X 5 N or CR 4d ;

[0109] The prerequisite is X 2 、X 3 、X 4 and X 5 No more than two of them are N;

[0110] R 3’ is a hydrogen atom, an optionally substituted C 1-6 an alkyl group or a halogen atom;

[0111] R 4a 、R 4b 、R 4c and R 4d are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, halogen atom or optionally substituted C 1-6 alkoxy;

[0112] m is an integer from 0 to 3;

[0113] n is an integer from 0 to 3;

[0114] o is an integer from 0 to 3;

[0115] p is an integer 0 or 1; and

[0116] contains one single bond and one double bond when p is 0, or contains one single bond and two double bonds when p is 1, to provide an aromatic ring structure;

[0117] or a salt thereof (hereinafter referred to as "Compound (I)").

[0118] [2] The compound according to [1], wherein R A Has the following structure:

[0119]

[0120] in

[0121] X 6 N or CR 5’ ;

[0122] Each R 5 are the same or different and are halogen atoms or C 1-6 alkoxy;

[0123] R 5’ is a hydrogen atom or a halogen atom;

[0124] q is an integer from 0 to 7; and

[0125] are identical and all have single bonds or all have double bonds;

[0126] or a salt thereof.

[0127] [3] The compound according to [1] or [2], wherein X 1 CR 3' , m is an integer from 0 to 2, and n is 0; or a salt thereof.

[0128] [4] The compound according to [1] or [2], wherein X 1 is N; or a salt thereof.

[0129] [5] The compound according to any one of [2] to [4], wherein

[0130] R 1 C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyclopropyl, halogenated cyclopropyl or mono- or di-C 1-6 Alkylamino;

[0131] Each R 2 are the same or different and are C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl or hydroxy-C 1-6 alkyl;

[0132] Each R 3 are the same or different and are C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 an alkyl group or a halogen atom;

[0133] R 4a For hydrogen atoms, C 1-6 Alkyl, cyclopropyl, C 1-6 Alkoxy, halogenated C 1-6 an alkyl group or a halogen atom; and

[0134] q is an integer from 0 to 4;

[0135] or a salt thereof.

[0136] [6] The compound according to any one of [1] to [5], wherein

[0137] (i)X 2 CR 4b , X 3 N, X 4 is N, and p is 0; or

[0138] (ii)X 2 N, X 3 N, X 4 CR 4c , and p is 0;

[0139] or a salt thereof.

[0140] [7] The compound according to any one of [1] to [5], wherein X 2 CR 4b , X 3 C, X 4 CR 4c , X 5 CR 4d , and p is 1; or a salt thereof.

[0141] [8] The compound according to any one of [1] to [5], wherein X 2 N, X 3 C, X 4 CR 4c , X 5 CR 4d , and p is 1; or a salt thereof.

[0142] [9] The compound according to any one of [1] to [5], wherein X 2 CR 4b , X 3 C, X 4 and X 5 is N, and p is 1; or a salt thereof.

[0143]

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

[0144]

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

[0145]

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

[0146]

[13] The compound according to any one of [2] to

[12] , wherein X 6 CR 5’ ,and are all single bonds; or their salts.

[0147]

[14] The compound according to any one of [2] to

[12] , wherein X 6 CR 5’ ,and are double bonds; or their salts.

[0148]

[15] The compound according to any one of [2] to

[12] , wherein X 6 N ′ ,and are double bonds; or their salts.

[0149]

[16] The compound according to any one of [1] to [5], wherein the compound is:

[0150]

[0151] Selected from the group consisting of:

[0152]

[0153]

[0154] in

[0155] * indicates the same as R A bonding sites; and

[0156] R 4a 、R 4b 、R 4c and R 4d As defined in claim 1;

[0157] or a salt thereof.

[0158]

[17] The compound according to any one of [2] to [5], wherein

[0159] part:

[0160]

[0161] Selected from the group consisting of:

[0162]

[0163] * indicates the same as R A The bonding site of

[0164] R 1 C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyclopropyl, halogenated cyclopropyl or mono- or di-C 1-6 Alkylamino;

[0165] Each R 2 are the same or different and are C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl or hydroxy-C 1-6 alkyl;

[0166] Each R 3 are the same or different and are C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 an alkyl group or a halogen atom;

[0167] L1 For the key, -NR 6 -or-O-; where R 6 A hydrogen atom or C 1-6 alkyl;

[0168] L 2 is a bond or -CH2-;

[0169] X 1 N or CR 3' ; where R 3' is a hydrogen atom;

[0170] R 4a For hydrogen atoms, C 1-6 Alkyl, cyclopropyl, C 1-6 Alkoxy, halogenated C 1-6 an alkyl group or a halogen atom;

[0171] X 2 N or CR 4b ; where R 4b is a hydrogen atom or a halogen atom;

[0172] X 4 N or CR 4c ; where R 4c is a hydrogen atom or a halogen atom;

[0173] X 5 N or CR 4d ; where R 4d is a hydrogen atom;

[0174] m is an integer from 0 to 3;

[0175] n is an integer from 0 to 3;

[0176] o is an integer from 0 to 3; and

[0177] part:

[0178]

[0179] Selected from the group consisting of:

[0180]

[0181] in

[0182] Each R 5 are the same or different and are halogen atoms or C 1-6 alkoxy;

[0183] R 5’ is a hydrogen atom or a halogen atom; and

[0184] q is an integer from 0 to 4;

[0185] or a salt thereof.

[0186]

[18] The compound according to any one of [2] to [5], wherein the compound is a compound of formula (Ia):

[0187]

[0188] in

[0189] q is an integer from 0 to 4; and

[0190] Other symbols are as defined in [2];

[0191] or a salt thereof.

[0192]

[19] The compound according to any one of [2] to [5], wherein the compound is a compound of formula (Ib):

[0193]

[0194] in

[0195] q is an integer from 0 to 4; and

[0196] Other symbols are as defined in [2];

[0197] or a salt thereof.

[0198]

[20] The compound according to any one of [2] to [5], wherein the compound is a compound of formula (Ic):

[0199]

[0200] in

[0201] R 2a is a hydrogen atom or an optionally substituted C 1-6 alkyl;

[0202] q is an integer from 0 to 4; and

[0203] Other symbols are as defined in [2];

[0204] or a salt thereof.

[0205]

[21] The compound according to any one of [2] to [5], wherein the compound is a compound of formula (Id):

[0206]

[0207] in

[0208] R2a is a hydrogen atom or an optionally substituted C 1-6 alkyl;

[0209] R 3a and R 3b are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 an alkyl group or a halogen atom;

[0210] q is an integer from 0 to 4; and

[0211] Other symbols are as defined in [2];

[0212] or a salt thereof.

[0213]

[22] The compound according to any one of [1] to [5], wherein the compound is a compound of formula (Ie):

[0214]

[0215] in

[0216] R 1 C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0217] R 2a For hydrogen atoms, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0218] R 3a and R 3b are the same or different, and each is C 1-6 an alkyl group or a halogen atom;

[0219] R 4a C 1-6 an alkyl group or a halogen atom;

[0220] X 2 N or CR 4b ; where R 4b is a halogen atom; and

[0221] R A is phenyl or pyridyl, wherein each of said phenyl and pyridyl is optionally substituted with one to three halogen atoms;

[0222] or a salt thereof.

[0223]

[23] The compound according to

[22] , wherein

[0224] R 1 C 1-6 Alkyl or halogenated C 1-6alkyl;

[0225] R 2a For hydrogen atoms, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0226] R 3a and R 3b Each is a halogen atom;

[0227] R 4a C 1-6 an alkyl group or a halogen atom;

[0228] X 2 N or CR 4b ; where R 4b is a halogen atom; and

[0229] R A is phenyl or pyridyl, wherein each of said phenyl and pyridyl is optionally substituted with one to three halogen atoms;

[0230] or a salt thereof.

[0231]

[24] The compound according to

[22] , wherein

[0232] R 1 C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0233] R 2a C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0234] R 3a and R 3b Each is a halogen atom;

[0235] R 4a is a halogen atom;

[0236] X 2 is N; and

[0237] R A is phenyl optionally substituted by one to three halogen atoms;

[0238] or a salt thereof.

[0239]

[25] The compound according to any one of [1]-[5] and

[22] -

[24] , wherein

[0240] R 1 C 1-6 alkyl;

[0241] R 2aHalogenated C 1-6 alkyl;

[0242] R 3a and R 3b Each is a halogen atom;

[0243] R 4a is a halogen atom;

[0244] X 2 is N; and

[0245] R A is phenyl optionally substituted by one to three halogen atoms;

[0246] or a salt thereof.

[0247]

[26] The compound according to [1], wherein the compound is selected from the group consisting of:

[0248] 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;

[0249] 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;

[0250] 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

[0251] 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,

[0252] or a salt thereof.

[0253]

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

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

[0254]

[28] A medicament comprising a compound or a salt thereof as defined in any one of [1] to

[26] , or a pharmaceutical composition as defined in

[27] .

[0255]

[29] The drug according to

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

[0256]

[30] The drug according to

[28] , which is an agent for preventing or treating the following diseases: 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 associated with bone loss, sepsis, impaired consciousness, or side effects and complications due to anesthesia.

[0257]

[31] The drug according to

[28] , which is an agent for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[0258]

[32] The drug according to

[28] , which is an agent for preventing or treating narcolepsy.

[0259]

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

[26] , or a pharmaceutical composition as defined in

[27] .

[0260]

[34] The method according to

[33] , wherein the disease or condition is selected from the group consisting of: hypersomnia, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, hypersomnia syndrome with narcolepsy-like 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 and complications due to anesthesia.

[0261]

[35] The method according to

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

[0262]

[36] The method according to

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

[0263]

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

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

[0264]

[38] The compound or salt of

[37] , wherein the therapy comprises treating a disease or condition associated with orexin type 2 receptor.

[0265]

[39] The compound or salt according to

[38] , wherein the disease or condition 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 associated with bone loss, sepsis, impaired consciousness, and side effects and complications due to anesthesia.

[0266]

[40] The compound or salt according to

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

[0267]

[41] The compound or salt according to

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

[0268]

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

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

[0269]

[43] The use according to

[42] , wherein the disease or condition 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 associated with bone loss, sepsis, impaired consciousness, and side effects and complications due to anesthesia.

[0270]

[44] The use according to

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

[0271]

[45] The use according to

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

[0272] Effects of the Invention

[0273] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as an agent for preventing or treating certain diseases such as narcolepsy. DETAILED DESCRIPTION

[0274] The definition of each substituent used in this specification is described in detail below. Unless otherwise specified, each substituent has the following definition.

[0275] In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0276] In this manual, “C1-6 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.

[0277] In this specification, "optionally halogenated C 1-6 Examples of the "alkyl group" include C optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples thereof include 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.

[0278] In this manual, “C 2-6 Examples 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.

[0279] In this manual, “C 2-6 Examples of “alkynyl” 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.

[0280] In this manual, “C 3-10 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0281] In this specification, "optionally halogenated C 3-10 Examples of "cycloalkyl" include C 3-10 Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0282] In this manual, “C 3-10Examples of "cycloalkenyl" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0283] In this manual, “C 6-14 Examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0284] In this manual, “C 7-16 Examples of "aralkyl" include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0285] In this manual, “C 1-6 Examples of the "alkoxy" group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0286] In this specification, "optionally halogenated C 1-6 Examples of the "alkoxy group" include C 1-6 Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.

[0287] In this manual, “C 3-10 Examples of the "cycloalkyloxy" group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0288] In this manual, “C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

[0289] In this specification, "optionally halogenated C 1-6 Examples of the "alkylthio group" include C 1-6 Specific examples thereof include a methylthio group, a difluoromethylthio group, a trifluoromethylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a 4,4,4-trifluorobutylthio group, a pentylthio group, and a hexylthio group.

[0290] In this manual, “C 1-6 Examples of "alkyl-carbonyl" include acetyl, propionyl, butyryl, 2-methylpropionyl, pentanoyl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl and heptanoyl.

[0291] In this specification, "optionally halogenated C 1-6Examples of "alkyl-carbonyl" include C 1-6 Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and hexanoyl.

[0292] In this manual, “C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0293] In this manual, “C 6-14 Examples of "aryl-carbonyl" include benzoyl, 1-naphthoyl and 2-naphthoyl.

[0294] In this manual, “C 7-16 Examples of "aralkyl-carbonyl" include phenylacetyl and phenylpropionyl.

[0295] In the present specification, examples of the "5- to 14-membered aromatic heterocyclic carbonyl group" include a nicotinoyl group, an isonicotinoyl group, a thenoyl group, and a furoyl group.

[0296] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclic carbonyl group" include a morpholinylcarbonyl group, a piperidinylcarbonyl group, and a pyrrolidinylcarbonyl group.

[0297] In this specification, "mono- or di-C 1-6 Examples of the “alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

[0298] In this specification, "mono- or di-C 7-16 Examples of the "aralkyl-carbamoyl" group include benzylcarbamoyl and phenethylcarbamoyl.

[0299] In this manual, “C 1-6 Examples of the “alkylsulfonyl group” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a sec-butylsulfonyl group and a tert-butylsulfonyl group.

[0300] In this specification, "optionally halogenated C 1-6 Examples of the "alkylsulfonyl group" include C 1-6Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[0301] In this manual, “C 6-14 Examples of the “arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0302] 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 hydroxyl group, an optionally substituted sulfanyl group (SH) and an optionally substituted silyl group.

[0303] In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" of the "optionally substituted hydrocarbon group") include C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl and C 7-16 Aralkyl.

[0304] In the present specification, examples of the “optionally substituted hydrocarbon group” include hydrocarbon groups optionally having one or more substituents selected from Substituent Group A below.

[0305] [Substituent Group A]

[0306] (1) halogen atoms,

[0307] (2) nitro,

[0308] (3) cyano group,

[0309] (4) oxo group,

[0310] (5) hydroxyl groups,

[0311] (6) optionally halogenated C 1-6 Alkoxy,

[0312] (7)C 6-14 aryloxy (e.g., phenoxy, naphthoxy),

[0313] (8)C 7-16 Aralkyloxy (e.g., benzyloxy),

[0314] (9) a 5- to 14-membered aromatic heterocyclic oxy group (e.g., a pyridyloxy group),

[0315] (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy),

[0316] (11)C 1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy),

[0317] (12)C 6-14 aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),

[0318] (13)C 1-6 Alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

[0319] (14) Single or Double C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

[0320] (15)C 6-14 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy),

[0321] (16) a 5- to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyloxy),

[0322] (17) a 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

[0323] (18) optionally halogenated C 1-6 alkylsulfonyloxy (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),

[0324] (19) optionally C 1-6 Alkyl substituted C 6-14 arylsulfonyloxy (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

[0325] (20) optionally halogenated C 1-6 Alkylthio,

[0326] (21) a 5- to 14-membered aromatic heterocyclic group,

[0327] (22) a 3- to 14-membered non-aromatic heterocyclic group,

[0328] (23) formyl group,

[0329] (24) carboxyl group,

[0330] (25) optionally halogenated C 1-6 Alkyl-carbonyl,

[0331] (26)C 6-14 Aryl-carbonyl,

[0332] (27) a 5- to 14-membered aromatic heterocyclic carbonyl group,

[0333] (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group,

[0334] (29)C 1-6 Alkoxy-carbonyl,

[0335] (30)C 6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

[0336] (31)C 7-16 Aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethoxycarbonyl),

[0337] (32) Carbamoyl,

[0338] (33) thiocarbamoyl,

[0339] (34) Single or Double C 1-6 Alkyl-carbamoyl,

[0340] (35)C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl),

[0341] (36) a 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., a pyridylcarbamoyl group, a thienylcarbamoyl group),

[0342] (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),

[0343] (38) optionally halogenated C 1-6 Alkylsulfonyl,

[0344] (39)C 6-14 Arylsulfonyl,

[0345] (40) a 5- to 14-membered aromatic heterocyclic sulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl),

[0346] (41) optionally halogenated C 1-6 Alkylsulfinyl,

[0347] (42)C 6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),

[0348] (43) a 5- to 14-membered aromatic heterocyclic sulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl),

[0349] (44) amino group,

[0350] (45) Single or Double C 1-6 Alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

[0351] (46) Single or Double C 6-14 arylamino (e.g., phenylamino),

[0352] (47) a 5- to 14-membered aromatic heterocyclic amino group (e.g., a pyridylamino group),

[0353] (48)C 7-16 aralkylamino (e.g., benzylamino),

[0354] (49) formylamino group,

[0355] (50)C 1-6 Alkyl-carbonylamino (e.g., acetylamino, propionylamino, butyrylamino),

[0356] (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino),

[0357] (52)C 6-14 aryl-carbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino),

[0358] (53)C 1-6 Alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),

[0359] (54)C 7-16 Aralkyloxy-carbonylamino (e.g., benzyloxycarbonylamino),

[0360] (55)C 1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino),

[0361] (56) optionally C 1-6 Alkyl substituted C 6-14 arylsulfonylamino (e.g., phenylsulfonylamino, toluenesulfonylamino),

[0362] (57) optionally halogenated C 1-6 alkyl,

[0363] (58)C 2-6 alkenyl,

[0364] (59)C 2-6 Alkynyl,

[0365] (60)C 3-10 Cycloalkyl,

[0366] (61)C 3-10 Cycloalkenyl and

[0367] (62)C 6-14 Aryl.

[0368] 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 the substituents is two or more, the respective substituents may be the same or different.

[0369] In the present specification, examples of the “heterocyclic group” (including the “heterocyclic group” of 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 containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as a ring-constituting atom in addition to carbon atoms.

[0370] In the present specification, examples of the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as ring-constituting atoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms.

[0371] Preferred examples of the “aromatic heterocyclic group” include a 5- or 6-membered monocyclic aromatic heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

[0372] 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups, such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl , furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0373] In the present specification, examples of the “non-aromatic heterocyclic group” (including the “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 hetero atoms selected from nitrogen atoms, sulfur atoms and oxygen atoms as ring-constituting atoms.

[0374] Preferable examples of the “non-aromatic heterocyclic group” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrothiophenyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazacanyl and the like; and

[0375] 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quinolizinyl, dihydroindolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthanenyl, octahydroisoquinolinyl and the like.

[0376] In the present specification, preferred examples of the "7- to 10-membered bridged heterocyclic group" include a quinuclidinyl group and a 7-azabicyclo[2.2.1]heptanyl group.

[0377] In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.

[0378] In the present specification, examples of the “optionally substituted heterocyclic group” include heterocyclic groups optionally having one or more substituents selected from Substituent Group A described above.

[0379] The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0380] In the present specification, examples of the "acyl group" include formyl, carboxyl, carbamoyl, thiocarbamoyl, sulfinyl, sulfo, sulfamoyl and phosphono groups, each optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, C 7-16 Aralkyl, 5- to 14-membered aromatic heterocyclic group, 3- to 14-membered non-aromatic heterocyclic group, amino group and mono- or di-C 1-6 The substituents of the alkyl-amino group each optionally have 1 to 3 groups selected from halogen atoms, optionally halogenated C 1-6 Alkoxy, hydroxy, nitro, cyano, amino and carbamoyl substituents".

[0381] Examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclylsulfinyl group.

[0382] Here, the hydrocarbon-sulfonyl group refers to a sulfonyl group bonded to a hydrocarbon group, the heterocyclylsulfonyl group refers to a sulfonyl group bonded to a heterocyclyl group, the hydrocarbon-sulfinyl group refers to a sulfinyl group bonded to a hydrocarbon group, and the heterocyclylsulfinyl group refers to a sulfinyl group bonded to a heterocyclyl group.

[0383] Preferred examples of "acyl" include formyl, carboxyl, C 1-6 Alkyl-carbonyl, C 2-6 Alkenyl-carbonyl (e.g., crotonyl), C 3-10 Cycloalkyl-carbonyl (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl, C 7-16Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, C 6-14 Aryloxy-carbonyl (e.g., phenoxycarbonyl, naphthoxycarbonyl), C 7-16 Aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethoxycarbonyl), carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl, 5- to 14-membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl), NC 1-6 Alkyl-N',N'-di-C 1-6 Alkylhydrazine-carbonyl, thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridylthiocarbamoyl), sulfinyl, C 1-6 Alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl), sulfo, C 1-6 Alkylsulfonyl, C 6-14 Arylsulfonyl, phosphonyl and mono- or di-C 1-6 Alkylphosphono (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0384] In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aralkyl-carbamoyl, C 1-6 Alkylsulfonyl and C 6-14 substituents of the arylsulfonyl group (each of which optionally has 1 to 3 substituents selected from Substituent Group A)" an amino group.

[0385] Preferred examples of the optionally substituted amino group include amino, mono- or di-(optionally halogenated C 1-6 alkyl)amino (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino (eg, benzylamino, dibenzylamino), mono- or di- (optionally halogenated C 1-6 Alkyl)-carbonylamino (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino (e.g., tert-butyloxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (e.g., pyridylamino), carbamoylamino, (mono- or di-C 1-6 Alkyl-carbamoyl)amino (e.g., methylcarbamoylamino), (mono- or di-C 7-16 Aralkyl-carbamoyl)amino (e.g., benzylcarbamoylamino), C 1-6 Alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino (e.g., N-benzoyl-N-methylamino).

[0386] In the present specification, examples of the "optionally substituted carbamoyl group" include a group optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 a carbamoyl group "a substituent of an aralkyl-carbamoyl group (each of the substituents optionally has 1 to 3 substituents selected from Substituent Group A)".

[0387] Preferred examples of the optionally substituted carbamoyl group include carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-carbamoyl (e.g., benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclylcarbamoyl (e.g., pyridylcarbamoyl).

[0388] In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a group optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl and mono- or di-C 7-16 a thiocarbamoyl group "a substituent of an aralkyl-carbamoyl group (each of the substituents optionally has 1 to 3 substituents selected from Substituent Group A)".

[0389] Preferred examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl)

[0390] In the present specification, examples of the "optionally substituted sulfamoyl group" include a group optionally having "1 or 2 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6Alkyl-carbamoyl and mono- or di-C 7-16 a sulfamoyl group "a substituent of the aralkyl-carbamoyl group (each of the substituents optionally has 1 to 3 substituents selected from Substituent Group A)".

[0391] Preferred examples of the optionally substituted sulfamoyl group include sulfamoyl, mono- or di-C 1-6 Alkyl-sulfamoyl (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Aryl-carbonyl-sulfamoyl (e.g., benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl (e.g., pyridylsulfamoyl).

[0392] In the present specification, examples of the "optionally substituted hydroxyl group" include a group optionally having "selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclylcarbonyl, 3- to 14-membered non-aromatic heterocyclylcarbonyl, C 1-6 Alkoxy-carbonyl, 5- to 14-membered aromatic heterocyclic group, carbamoyl, mono- or di-C 1-6 Alkyl-carbamoyl, mono- or di-C 7-16 Aralkyl-carbamoyl, C 1-6 Alkylsulfonyl and C 6-14 a hydroxyl group "a substituent of the arylsulfonyl group (the substituents each optionally have 1 to 3 substituents selected from Substituent Group A)".

[0393] Preferred examples of the optionally substituted hydroxy group include hydroxy, C 1-6 Alkoxy, C 2-6Alkenyloxy (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy (e.g., cyclohexyloxy), C 6-14 Aryloxy (e.g., phenoxy, naphthoxy), C 7-16 Aralkyloxy (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclyloxy (e.g., pyridyloxy), carbamoyloxy, C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy (e.g., benzylcarbamoyloxy), C 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy) and C 6-14 Arylsulfonyloxy (eg, phenylsulfonyloxy).

[0394] In the present specification, examples of the "optionally substituted sulfanyl group" include a group optionally having "a group selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-16 Aralkyl, C 1-6 Alkyl-carbonyl, C 6-14 aryl-carbonyl and a substituent of a 5- to 14-membered aromatic heterocyclic group (the substituents each optionally having 1 to 3 substituents selected from Substituent Group A)", a sulfanyl group, and a halogenated sulfanyl group.

[0395] Preferred examples of the optionally substituted sulfanyl group include sulfanyl (—SH), C 1-6 Alkylthio, C 2-6 Alkenylthio (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio (e.g., cyclohexylthio), C 6-14 Arylthio (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio (e.g., benzylthio, phenethylthio), C 1-6Alkyl-carbonylthio (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 an aryl-carbonylthio group (eg, benzoylthio), a 5- to 14-membered aromatic heterocyclic thio group (eg, pyridylthio), and a halogenated thio group (eg, pentafluorothio).

[0396] In the present specification, examples of the “optionally substituted silyl group” include a group optionally having “1 to 3 groups selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 6-14 Aryl and C 7-16 a silyl group "a substituent of the aralkyl group (each of the substituents optionally has 1 to 3 substituents selected from Substituent Group A)".

[0397] Preferred examples of the optionally substituted silyl group include tri-C 1-6 Alkylsilyl group (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0398] In the present specification, examples of the "hydrocarbon ring" include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes and C 3-10 Cyclic olefins.

[0399] In this manual, “C 6-14 Examples of the "aromatic hydrocarbon ring" include benzene and naphthalene.

[0400] In this manual, “C 3-10 Examples of "cycloalkanes" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.

[0401] In this manual, “C 3-10 Examples of "cycloalkanes" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.

[0402] In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as ring-constituting atoms in addition to carbon atoms.

[0403] In the present specification, examples of the “aromatic heterocycle” include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring atoms in addition to carbon atoms. Preferred 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, triazine, and the like; and

[0404] 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles, such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine , furanopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiol, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine, etc.

[0405] In the present specification, examples of the "non-aromatic heterocycle" include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms as ring-constituting atoms in addition to carbon atoms. Preferred examples of the “non-aromatic heterocycle” include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiol, 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, azooctane, diazaoctane, heterocycloheptane and the like; and

[0406] 9- to 14-membered fused polycyclic (preferably bicyclic 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, octahydroisoquinoline, and the like.

[0407] In the present specification, examples of the "nitrogen-containing heterocycle" include a heterocycle containing at least one nitrogen atom derived from the "heterocycle" as a ring-constituting atom.

[0408] In this manual, “C 3-7 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0409] In this specification, "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, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, 2-ethylbutylamino, and the like.

[0410] In the present specification, examples of the “3- to 8-membered non-aromatic heterocyclic group” in the definition of the “optionally substituted 3- to 8-membered non-aromatic heterocyclic group” include a 3- to 8-membered (preferably 5- to 6-membered) non-aromatic heterocyclic group containing, as ring-constituting atoms, 1 to 4 hetero atoms selected from nitrogen atoms, sulfur atoms and oxygen atoms in addition to carbon atoms.

[0411] Preferable examples of the “3- to 8-membered non-aromatic heterocyclic group” include a 3- to 8-membered monocyclic non-aromatic heterocyclic group such as aziridinyl, oxiranyl, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrothiophenyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazaoctanyl and the like.

[0412] In the present specification, examples of the “5- to 6-membered aromatic heterocyclic group” in the definition of the “optionally substituted 5- to 6-membered aromatic heterocyclic group” include a 5- to 6-membered aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as ring-constituting atoms.

[0413] Preferred examples of the “5- to 6-membered aromatic heterocyclic group” include monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like.

[0414] The definition of each symbol in formula (I) is described in detail below.

[0415] In formula (I), R 1 C 1-6 Alkyl, C 3-7 Cycloalkyl or mono- or di-C 1-6 Alkylamino, where C 1-6 Alkyl, C 3-7 Cycloalkyl and mono- or di-C 1-6 Each of the alkylamino groups is optionally substituted.

[0416] The above-mentioned "optionally substituted C 1-6 Alkyl", "optionally substituted C 3-7 Cycloalkyl" 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 the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0417] In some embodiments of Formula (I), R 1 for

[0418] (1) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl) or C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0419] (2) optionally substituted C 3-7 Cycloalkyl (e.g., cyclopropyl or halo-C 3-7 cycloalkyl (e.g., fluorocyclopropyl)), or

[0420] (3) optionally substituted mono- or di-C 1-6Alkylamino (eg, dimethylamino).

[0421] In some embodiments of Formula (I), R 1 Preferably

[0422] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0423] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0424] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl),

[0425] (4) cyclopropyl,

[0426] (5) a halogenated cyclopropyl group (e.g., a fluorocyclopropyl group), or

[0427] (6) Single or Double C 1-6 Alkylamino (eg, dimethylamino).

[0428] In some embodiments of Formula (I), R 1 More preferably

[0429] (1)C 1-6 alkyl (e.g., methyl, ethyl), or

[0430] (2) Halogenated C 1-6 Alkyl (eg, fluoromethyl).

[0431] In some embodiments of Formula (I), R 1 More preferably, C 1-6 Alkyl (eg, methyl).

[0432] In formula (I), each R 2 are the same or different and each is an optionally substituted C 1-6 alkyl.

[0433] The above-mentioned "optionally substituted C 1-6 Examples of the substituent of the "alkyl" group include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0434] In some embodiments of Formula (I), each R 2 are the same or different and are optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl), C1-6 Alkoxy-C 1-6 Alkyl (e.g., methoxymethyl) or hydroxy-C 1-6 alkyl (e.g., hydroxymethyl)).

[0435] In some embodiments of Formula (I), each R 2 are the same or different, and preferably

[0436] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0437] (2) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0438] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0439] (4) Hydroxyl-C 1-6 Alkyl (eg, hydroxymethyl).

[0440] In some embodiments of Formula (I), each R 2 are the same or different, and more preferably

[0441] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0442] (2) Halogenated C 1-6 Alkyl (eg, fluoromethyl).

[0443] In some embodiments of Formula (I), each R 2 are the same or different, and further more preferably are halogenated C 1-6 Alkyl (eg, fluoromethyl).

[0444] The symbol "o" represents a substituent R 2 and is an integer from 0 to 3 (ie, 0, 1, 2 or 3).

[0445] In some embodiments of formula (I), the symbol "o" is preferably 0 or 1.

[0446] In some embodiments of formula (I), the symbol "o" is more preferably the integer 1.

[0447] In some embodiments of Formula (I), when "o" is an integer of 0 or 1, (R 2 ) o Preferably R 2a .

[0448] In Formula (I) or Formula (Ic), (Id) or (Ie) described herein, R 2a is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0449] The above-mentioned "optionally substituted C 1-6 Examples of the substituent of the "alkyl" group include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0450] In some embodiments of Formula (I), (Ic), or (Id), R 2a for

[0451] (1) a hydrogen atom, or

[0452] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl), C 1-6 Alkoxy-C 1-6 Alkyl (e.g., methoxymethyl) or hydroxy-C 1-6 alkyl (e.g., hydroxymethyl)).

[0453] In some embodiments of Formula (I), (Ic), or (Id), R 2a Preferably

[0454] (1) Hydrogen atoms,

[0455] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0456] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0457] (4)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0458] (5) Hydroxyl-C 1-6 Alkyl (eg, hydroxymethyl).

[0459] In some embodiments of Formula (I), (Ic), (Id), or (Ie), R 2a More preferably

[0460] (1) Hydrogen atoms,

[0461] (2)C 1-6 alkyl (e.g., methyl, ethyl), or

[0462] (3) Halogenated C1-6 Alkyl (eg, fluoromethyl, difluoromethyl).

[0463] In some embodiments of Formula (I), (Ic), (Id), or (Ie), R 2a Further more preferably

[0464] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0465] (2) Halogenated C 1-6 Alkyl (eg, fluoromethyl).

[0466] In some embodiments of Formula (I), (Ic), (Id), or (Ie), R 2a Still more preferably halogenated C 1-6 Alkyl (eg, fluoromethyl).

[0467] In formula (I), each R 3 are the same or different and are optionally substituted C 1-6 an alkyl group or a halogen atom.

[0468] The above-mentioned "optionally substituted C 1-6 Examples of the substituent of the "alkyl" group include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0469] In some embodiments of Formula (I), each R 3 are the same or different and are

[0470] (1) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl or C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0471] (2) Halogen atom (eg, fluorine).

[0472] In some embodiments of Formula (I), each R 3 are the same or different, and preferably

[0473] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0474] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0475] (3) Halogen atom (eg, fluorine).

[0476] The symbol "n" represents a substituent R 3 and is an integer from 0 to 3 (ie, 0, 1, 2 or 3).

[0477] In some embodiments of formula (I), the symbol "n" is preferably the integer 2.

[0478] In some embodiments of Formula (I), when "n" is an integer of 2, (R 3 ) n Preferably R 3a and R 3b .

[0479] In Formula (I) or Formula (Id) described herein, R 3a and R 3b are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 an alkyl group or a halogen atom.

[0480] The above-mentioned "optionally substituted C 1-6 Examples of the substituent of the "alkyl" group include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0481] In some embodiments of Formula (I) or (Id), R 3a and R 3b are the same or different and each is

[0482] (1) Hydrogen atoms,

[0483] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl, C 1-6 Alkoxy-C 1-6 alkyl (e.g. methoxymethyl), or

[0484] (3) Halogen atom (eg, fluorine).

[0485] In some embodiments of Formula (I) or (Id), R 3a and R 3b are the same or different and each is preferably

[0486] (1) Hydrogen atoms,

[0487] (2)C 1-6 Alkyl (e.g., methyl, ethyl)

[0488] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0489] (4) Halogen atom (eg, fluorine).

[0490] In some embodiments of Formula (I), (Id), or (Ie), R 3a and R 3b are the same or different and each is more preferably

[0491] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0492] (2) Halogen atom (eg, fluorine).

[0493] In some embodiments of Formula (I), (Id), or (Ie), R 3a and R 3b More preferably, each is a halogen atom (for example, each is fluorine).

[0494] In formula (I), R 4a is a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, halogen atom or optionally substituted C 1-6 Alkoxy.

[0495] The above-mentioned "optionally substituted C 1-6 Alkyl", "optionally substituted C 3-7 Cycloalkyl" and "optionally substituted C 1-6 Examples of the substituent of the "alkoxy group" include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0496] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), R 4a for

[0497] (1) Hydrogen atoms,

[0498] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl),

[0499] (3) optionally substituted C 3-7 cycloalkyl (e.g., cyclopropyl),

[0500] (4) halogen atoms (e.g., fluorine, chlorine, bromine, iodine), or

[0501] (5) optionally substituted C 1-6 Alkoxy (eg, methoxy).

[0502] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), R 4a Preferably

[0503] (1) Hydrogen atoms,

[0504] (2)C 1-6 an alkyl group (e.g., methyl),

[0505] (3) cyclopropyl,

[0506] (4)C 1-6 alkoxy (e.g., methoxy),

[0507] (5) Halogenated C 1-6 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or

[0508] (6) Halogen atoms (e.g., fluorine, chlorine, bromine).

[0509] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R 4a More preferably

[0510] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0511] (2) Halogen atom (for example, fluorine or chlorine).

[0512] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), R 4a Even more preferred is a halogen atom (eg, fluorine).

[0513] In formula (I), R A is an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- to 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 Aryl or optionally substituted C 3-10 Cycloalkyl.

[0514] The above-mentioned "optionally substituted 3- to 8-membered non-aromatic heterocyclic group", "optionally substituted 5- to 6-membered aromatic heterocyclic group", "optionally substituted C 6-14 Aryl" and "optionally substituted C 3-10 Examples of the substituent of the "cycloalkyl group" include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0515] In some embodiments of Formula (I), R A Preferably, it has the following structure:

[0516]

[0517] in

[0518] X 6 N or CR 5’ ;

[0519] Each R 5 are the same or different and are halogen atoms (e.g., fluorine, chlorine);

[0520] R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine);

[0521] 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

[0522] are the same and are either all single bonds or all double bonds.

[0523] In some embodiments of Formula (I), R A Preferably, it has the following structure:

[0524]

[0525] in

[0526] X 6 N or CR 5’ ;

[0527] Each R 5 are the same or different and are halogen atoms (eg, fluorine, chlorine) or C 1-6 alkoxy (e.g., methoxy);

[0528] R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine);

[0529] 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

[0530] are the same and are either all single bonds or all double bonds.

[0531] In some embodiments of Formula (I), R A Preferably, it is a 6-membered cyclic group having the following structure, wherein

[0532] (1)X 6 CR 5' ,and are all single bonds (i.e., R A is an optionally substituted 1-cyclohexyl),

[0533] (2)X 6 CR 5' ,and are double bonds (i.e., R A is optionally substituted phenyl), or

[0534] (3)X 6 is N, and are double bonds (i.e., R A is an optionally substituted 2-pyridyl group).

[0535] In some embodiments of Formula (I), the structure:

[0536]

[0537] Preferably selected from the group consisting of:

[0538]

[0539] in

[0540] Each R 5 are the same or different and are halogen atoms (eg, fluorine, chlorine) or C 1-6 alkoxy (e.g., methoxy);

[0541] R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and

[0542] q is an integer from 0 to 4.

[0543] In some embodiments of Formula (I), R A More preferably

[0544] (1) optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms (e.g., fluorine, chlorine) and C 1-6 a phenyl group substituted with an alkoxy group (e.g., a methoxy group), or

[0545] (2) 2-pyridyl optionally substituted by 1 to 3 identical or different halogen atoms (eg, fluorine).

[0546] In some embodiments of Formula (I), R A Further more preferably

[0547] (1) a phenyl group optionally substituted by 1 to 3 identical or different halogen atoms (e.g., fluorine, chlorine, preferably fluorine), or

[0548] (2) 2-pyridyl optionally substituted by 1 to 3 identical or different halogen atoms (eg, fluorine).

[0549] In some embodiments of Formula (I), R A Still more preferred is a phenyl group optionally substituted by 1 to 3 identical or different halogen atoms (eg, fluorine).

[0550] In some embodiments of Formula (I), R A Still more preferred is phenyl substituted by 1 to 3 fluorine groups, or 2-pyridyl substituted by 1 to 3 fluorine groups.

[0551] In some embodiments of Formula (I), R A Even more preferably, it is 2,6-difluorophenyl, 2,4,6-trifluorophenyl or 4,6-difluoropyridin-2-yl. In some embodiments of formula (I), R A Even more preferably, it is 2,6-difluorophenyl or 2,4,6-trifluorophenyl. In some embodiments of formula (I), R A Particularly preferred is 2,6-difluorophenyl.

[0552] In formula (I), L 1 For the key, -NR 6 -or-O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0553] The above-mentioned "optionally substituted C 1-6 Examples of the substituent of the "alkyl" group include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0554] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), L 1 Preferably

[0555] (1) key,

[0556] (2)-NR 6 -, where R 6 A hydrogen atom or C 1-6 an alkyl group (e.g., a methyl group), or

[0557] (3)-O-.

[0558] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), L 1 More preferably, it is a bond.

[0559] In formula (I), L 2 It is a bond or -CH2-.

[0560] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), L2 Preferably it is a bond.

[0561] In formula (I), X 1 N or CR 3' , where R 3' is a hydrogen atom, an optionally substituted C 1-6 an alkyl group or a halogen atom.

[0562] The above-mentioned "optionally substituted C 1-6 Examples of the substituent of the "alkyl" group include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0563] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), R 3’ for

[0564] (1) Hydrogen atoms,

[0565] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl or C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0566] (3) Halogen atom (eg, fluorine).

[0567] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), R 3’ Preferably

[0568] (1) Hydrogen atoms,

[0569] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0570] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0571] (4) Halogen atom (eg, fluorine).

[0572] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), R 3’ More preferably, it is a hydrogen atom.

[0573] The symbol "m" represents the number of methylene groups (-CH2-) and is an integer from 0 to 3 (ie, 0, 1, 2, or 3) to form a 4- to 7-membered carbon ring or N-containing ring.

[0574] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), X 1 for

[0575] (1) N (i.e., the 4- to 7-membered N-containing ring is azetidine, pyrrolidine, piperidine, or azepane, each of which is optionally replaced by R 3 replaced), or

[0576] (2)CR 3’ (i.e., the 4- to 7-membered carbocyclic ring is cyclobutane, cyclopentane, cyclohexane, or cycloheptane, each of which is replaced by R 3’ substituted and optionally by R 3 replace).

[0577] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), X 1 Preferably

[0578] (1) N (i.e., the 4- to 7-membered N-containing ring is azetidine, pyrrolidine, piperidine, or azepane, each of which is optionally replaced by R 3 replaced), or

[0579] (2) CH (i.e., a 4- to 7-membered carbocyclic ring preferably cyclobutane, cyclopentane, cyclohexane or cycloheptane, each of which is optionally replaced by R 3 replace).

[0580] In some embodiments of Formula (I), (Ia), (Ib), or (Ic), X 1 More preferably, N (i.e., the 4- to 7-membered N-containing ring is azetidine, pyrrolidine, piperidine, or azepane, each of which is optionally replaced by R 3 substituted, particularly preferably optionally by R 3a and R 3b substituted pyrrolidines).

[0581] In formula (I), X 2 N or CR 4b , where R 4b is a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, halogen atom or optionally substituted C 1-6 Alkoxy.

[0582] The above-mentioned "optionally substituted C 1-6 Alkyl", "optionally substituted C 3-7 Cycloalkyl" and "optionally substituted C 1-6 Examples of the substituent of the "alkoxy group" include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0583] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), X 2 for

[0584] (1) N, or

[0585] (2)CR 4b , where R 4b for

[0586] (1) Hydrogen atoms,

[0587] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, halo 1-6 Alkyl (e.g., fluoromethyl, trifluoromethyl),

[0588] (3) optionally substituted C 3-7 cycloalkyl (e.g., cyclopropyl),

[0589] (4) halogen atoms (e.g., fluorine, chlorine, bromine, iodine), or

[0590] (5) optionally substituted C 1-6 Alkoxy (eg, methoxy).

[0591] In some embodiments of Formula (I), R 4b Preferably

[0592] (1) a hydrogen atom, or

[0593] (2) Halogen atom (eg, fluorine).

[0594] In some embodiments of Formula (I), (Ia), (Ib), (Ic), or (Id), X 2 Preferably

[0595] (1) N, or

[0596] (2)CR 4b , where R 4b is a hydrogen atom or a halogen atom (eg, fluorine).

[0597] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X 2 More preferably

[0598] (1) N, or

[0599] (2)CR 4b , where R 4b is a halogen atom (eg, fluorine).

[0600] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X 2 Even more preferably, it is N or -CF.

[0601] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), X 2 Still more preferably, it is N.

[0602] In formula (I), X 3 N or C.

[0603] In some embodiments of Formula (I) or (Ia), X 3 Preferred is C.

[0604] In formula (I), X 4 N or CR 4c , where R 4c is a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, halogen atom or optionally substituted C 1-6 Alkoxy.

[0605] The above-mentioned "optionally substituted C 1-6 Alkyl", "optionally substituted C 3-7 Cycloalkyl" and "optionally substituted C 1-6 Examples of the substituent of the "alkoxy group" include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0606] In some embodiments of Formula (I) or (Ia), X 4 for

[0607] (1) N, or

[0608] (2)CR 4c , where R 4c for

[0609] (1) Hydrogen atoms,

[0610] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, halo 1-6 Alkyl (e.g., fluoromethyl, trifluoromethyl),

[0611] (3) optionally substituted C 3-7 cycloalkyl (e.g., cyclopropyl),

[0612] (4) halogen atoms (e.g., fluorine, chlorine, bromine, iodine), or

[0613] (5) optionally substituted C 1-6 Alkoxy (eg, methoxy).

[0614] In some embodiments of Formula (I) or (Ia), R 4c Preferably

[0615] (1) a hydrogen atom, or

[0616] (2) Halogen atom (eg, fluorine).

[0617] In some embodiments of Formula (I) or (Ia), X 4 Preferably

[0618] (1) N, or

[0619] (2)CR 4c , where R 4c is a hydrogen atom or a halogen atom (eg, fluorine).

[0620] In some embodiments of Formula (I) or (Ia), X 4 More preferably

[0621] (1) N, or

[0622] (2)CR 4c , where R 4c A hydrogen atom.

[0623] In some embodiments of Formula (I) or (Ia), X 4 Preferably CR 4c , where R 4c As defined above.

[0624] 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 (eg, fluorine).

[0625] In some embodiments of Formula (I) or (Ia), X 4 Even more preferably, it is -CH.

[0626] In formula (I), X 5 N or CR 4d , where R 4d is a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, halogen atom or optionally substituted C 1-6 Alkoxy.

[0627] The above-mentioned "optionally substituted C1-6 Alkyl", "optionally substituted C 3-7 Cycloalkyl" and "optionally substituted C 1-6 Examples of the substituent of the "alkoxy group" include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the corresponding substituents may be the same or different.

[0628] In some embodiments of Formula (I) or (Ia), X 5 for

[0629] (1) N, or

[0630] (2)CR 4d , where R 4d for

[0631] (1) Hydrogen atoms,

[0632] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, halo 1-6 Alkyl (e.g., fluoromethyl, trifluoromethyl),

[0633] (3) optionally substituted C 3-7 cycloalkyl (e.g., cyclopropyl),

[0634] (4) halogen atoms (e.g., fluorine, chlorine, bromine, iodine), or

[0635] (5) optionally substituted C 1-6 Alkoxy (eg, methoxy).

[0636] In some embodiments of Formula (I), R 4d Preferably

[0637] (1) a hydrogen atom, or

[0638] (2) Halogen atoms.

[0639] In some embodiments of Formula (I), (Ib), (Ic), or (Id), R 4d More preferably, it is a hydrogen atom.

[0640] In some embodiments of Formula (I) or (Ia), X 5 Preferably

[0641] (1) N, or

[0642] (2)CR 4d , where R 4d A hydrogen atom.

[0643] In some embodiments of Formula (I) or (Ia), X 5 Preferably CR4d , where R 4d As defined above.

[0644] In some embodiments of Formula (I) or (Ia), X 5 More preferably, it is -CH.

[0645] In formula (I), the moiety:

[0646]

[0647] Make X 2 、X 3 、X 4 and X 5 No more than two of them are N.

[0648] In some embodiments of formula (I), the moiety is preferably such that X 2 、X 3 、X 4 and X 5 No more than one of them is N.

[0649] In some embodiments of formula (I), the moiety is more preferably such that X 2 、X 3 、X 4 and X 5 One of them is N.

[0650] In formula (I), the symbol "p" represents X 5 and is an integer 0 or 1, and When p is 0, it contains one single bond and one double bond, or when p is 1, it contains one single bond and two double bonds, to provide an aromatic ring structure. When p is 0, then X 5 is absent to provide a 5-membered aromatic ring. When p is 1, then X 5 Present to provide a 6-membered aromatic ring.

[0651] In some embodiments of Formula (I) or (Ia), X 2 、X 3 、X 4 、X 5 The combination of and p is

[0652] (1)X 2 CR 4b , X 3 N, X 4 is N, and p is 0;

[0653] (2)X 2 N, X 3 N, X 4 CR 4c, and p is 0;

[0654] (3)X 2 CR 4b , X 3 C, X 4 CR 4c , X 5 CR 4d , and p is 1;

[0655] (4)X 2 N, X 3 C, X 4 CR 4c , X 5 CR 4d , and p is 1;

[0656] (5)X 2 CR 4b , X 3 C, X 4 and X 5 is N, and p is 1;

[0657] (6)X 2 CR 4b , X 3 C, X 4 CR 4c , X 5 is N, and p is 1;

[0658] (7)X 2 and X 4 N, X 3 C, X 5 CR 4d , and p is 1; or

[0659] (8)X 2 CR 4b , X 3 C, X 4 N, X 5 CR 4d , and p is 1.

[0660] In some embodiments of Formula (I) or (Ia), part

[0661]

[0662] Preferably selected from the group consisting of:

[0663]

[0664] in

[0665] * indicates the same as RA The bonding site of R 4a 、R 4b 、R 4c and R 4d As defined above.

[0666] In this embodiment, R 4a 、R 4b 、R 4c and R 4d The combination of R is preferably as follows: 4a for

[0667] (1) Hydrogen atoms,

[0668] (2)C 1-6 an alkyl group (e.g., methyl),

[0669] (3) cyclopropyl,

[0670] (4)C 1-6 alkoxy (e.g., methoxy),

[0671] (5) Halogenated C 1-6 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or

[0672] (6) halogen atoms (e.g., fluorine, chlorine, bromine);

[0673] R 4b for

[0674] (1) a hydrogen atom, or

[0675] (2) halogen atoms (e.g., fluorine);

[0676] R 4c for

[0677] (1) a hydrogen atom, or

[0678] (2) halogen atoms (e.g., fluorine); and

[0679] R 4d A hydrogen atom.

[0680] In some embodiments of Formula (I), R 1 、R 2 、R 3 、R 4a and R A The preferred combination is as follows:

[0681] R 1 for

[0682] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0683] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0684] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl),

[0685] (4) cyclopropyl,

[0686] (5) a halogenated cyclopropyl group (e.g., a fluorocyclopropyl group), or

[0687] (6) Single or Double C 1-6 Alkylamino (e.g., dimethylamino);

[0688] Each R 2 are the same or different and are

[0689] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0690] (2) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0691] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0692] (4) Hydroxyl-C 1-6 alkyl (e.g., hydroxymethyl);

[0693] Each R 3 are the same or different and are

[0694] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0695] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0696] (3) halogen atoms (e.g., fluorine);

[0697] R 4a for

[0698] (1) Hydrogen atoms,

[0699] (2)C 1-6 an alkyl group (e.g., methyl),

[0700] (3) cyclopropyl,

[0701] (4)C 1-6alkoxy (e.g., methoxy),

[0702] (5) Halogenated C 1-6 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) a halogen atom (e.g., fluorine, chlorine, bromine); and R A Has the following structure:

[0703]

[0704] It is selected from the group consisting of:

[0705]

[0706] in

[0707] q is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4); and

[0708] Other symbols are as defined above.

[0709] In some embodiments, preferred compound (I) is a compound wherein

[0710] R 1 for

[0711] (1) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl) or C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0712] (2) optionally substituted C 3-7 Cycloalkyl (e.g., cyclopropyl or halo-C 3-7 cycloalkyl (e.g., fluorocyclopropyl)), or

[0713] (3) optionally substituted mono- or di-C 1-6 Alkylamino (e.g., dimethylamino);

[0714] Each R 2 are the same or different and are optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl), C 1-6 Alkoxy-C 1-6 Alkyl (e.g., methoxymethyl) or hydroxy-C 1-6 alkyl (e.g., hydroxymethyl);

[0715] Each R 3 are the same or different and are

[0716] (1) optionally substituted C 1-6 Alkyl (e.g., methyl, ethyl or C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0717] (2) halogen atoms (e.g., fluorine);

[0718] R A is an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- to 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 Aryl or optionally substituted C 3-10 Cycloalkyl;

[0719] L 1 For the key, -NR 6 -or-O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl (e.g., methyl);

[0720] L 2 is a bond or -CH2-;

[0721] X 1 N or CR 3’ ;

[0722] X 2 N or CR 4b ;

[0723] X 3 N or C;

[0724] X 4 N or CR 4c ;

[0725] X 5 N or CR 4d ;

[0726] The prerequisite is X 2 、X 3 、X 4 and X 5 No more than two of them are N;

[0727] R 3’ for

[0728] (1) Hydrogen atoms,

[0729] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0730] (3)C 1-6 Alkoxy-C 1-6alkyl (e.g., methoxymethyl), or

[0731] (4) halogen atoms (e.g., fluorine);

[0732] R 4a 、R 4b 、R 4c and R 4d are the same or different and each is

[0733] (1) Hydrogen atoms,

[0734] (2) optionally substituted C 1-6 Alkyl (e.g., methyl, halo 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl),

[0735] (3) optionally substituted C 3-7 cycloalkyl (e.g., cyclopropyl),

[0736] (4) halogen atoms (e.g., fluorine, chlorine, bromine), or

[0737] (5) optionally substituted C 1-6 alkoxy (e.g., methoxy);

[0738] m is an integer from 0 to 3 (i.e., 0, 1, 2 or 3);

[0739] n is an integer from 0 to 3 (i.e., 0, 1, 2 or 3);

[0740] o is an integer from 0 to 3 (i.e., 0, 1, 2 or 3);

[0741] p is an integer 0 or 1; and

[0742] It contains one single bond and one double bond when p is 0, or one single bond and two double bonds when p is 1, to provide an aromatic ring structure.

[0743] In some embodiments, more preferred compounds (I) are compounds wherein

[0744] R 1 for

[0745] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0746] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0747] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl),

[0748] (4) cyclopropyl,

[0749] (5) a halogenated cyclopropyl group (e.g., a fluorocyclopropyl group), or

[0750] (6) Single or Double C 1-6 Alkylamino (eg, dimethylamino).

[0751] Each R 2 are the same or different and are

[0752] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0753] (2) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0754] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0755] (4) Hydroxyl-C 1-6 alkyl (e.g., hydroxymethyl);

[0756] Each R 3 are the same or different and are

[0757] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0758] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0759] (3) halogen atoms (e.g., fluorine);

[0760] R A Has the following structure:

[0761]

[0762] in

[0763] X 6 N or CR 5’ ;

[0764] Each R 5 are the same or different and are halogen atoms (eg, fluorine, chlorine) or C 1-6 alkoxy (e.g., methoxy);

[0765] R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine);

[0766] q is an integer from 0 to 7 (e.g., 0, 1, 2, 3, 4, 5, 6 or 7, preferably 1 to 3); and

[0767] are identical and all have single bonds or all have double bonds;

[0768] L 1 For the key, -NR 6 -or-O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl (e.g., methyl);

[0769] L 2 is a bond or -CH2-;

[0770] X 1 N or CR 3’ ;

[0771] X 2 N or CR 4b ;

[0772] X 3 N or C;

[0773] X 4 N or CR 4c ;

[0774] X 5 N or CR 4d ;

[0775] The prerequisite is X 2 、X 3 、X 4 and X 5 No more than two of them are N;

[0776] R 3’ for

[0777] (1) Hydrogen atoms,

[0778] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0779] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0780] (4) halogen atoms (e.g., fluorine);

[0781] R 4a 、R 4b 、R 4c and R 4d are the same or different and each is

[0782] (1) Hydrogen atoms,

[0783] (2)C 1-6 an alkyl group (e.g., methyl),

[0784] (3) cyclopropyl,

[0785] (4)C 1-6 alkoxy (e.g., methoxy),

[0786] (5) Halogenated C 1-6 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or

[0787] (6) halogen atoms (e.g., fluorine, chlorine, bromine);

[0788] m is an integer from 0 to 3 (i.e., 0, 1, 2 or 3);

[0789] n is an integer from 1 to 3 (i.e., 1, 2 or 3);

[0790] o is an integer from 1 to 3 (i.e., 1, 2, or 3); and

[0791] p is an integer 0 or 1; and

[0792] It contains one single bond and one double bond when p is 0, or one single bond and two double bonds when p is 1, to provide an aromatic ring structure.

[0793] In some embodiments, further more preferred compounds (I) are compounds wherein

[0794] part:

[0795]

[0796] Selected from the group consisting of:

[0797]

[0798] * indicates the same as R A The bonding site of

[0799] R 1 for

[0800] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0801] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0802] (3) Halogenated C 1-6Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl),

[0803] (4) cyclopropyl,

[0804] (5) a halogenated cyclopropyl group (e.g., a fluorocyclopropyl group), or

[0805] (6) Single or Double C 1-6 Alkylamino (e.g., dimethylamino);

[0806] Each R 2 are the same or different, and are the same or different, and are

[0807] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0808] (2) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0809] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0810] (4) Hydroxyl-C 1-6 alkyl (e.g., hydroxymethyl);

[0811] Each R 3 are the same or different, and are the same or different, and are

[0812] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0813] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0814] (3) halogen atoms (e.g., fluorine);

[0815] R 4a 、R 4b 、R 4c and R 4d are the same or different and each is

[0816] (1) Hydrogen atoms,

[0817] (2)C 1-6 an alkyl group (e.g., methyl),

[0818] (3) cyclopropyl,

[0819] (4)C 1-6 alkoxy (e.g., methoxy),

[0820] (5) Halogenated C 1-6 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or

[0821] (6) halogen atoms (e.g., fluorine, chlorine, bromine);

[0822] R A Has the following structure:

[0823]

[0824] It is selected from the group consisting of:

[0825]

[0826] in

[0827] Each R 5 are the same or different and are halogen atoms (eg, fluorine, chlorine) or C 1-6 alkoxy (e.g., methoxy);

[0828] R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and

[0829] q is an integer from 0 to 4 (e.g., 0, 1, 2, 3, 4);

[0830] L 1 For the key, -NR 6 -or-O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl (e.g., methyl);

[0831] L 2 is a bond or -CH2-;

[0832] X 1 N or CR 3’ ;

[0833] R 3’ for

[0834] (1) Hydrogen atoms,

[0835] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0836] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0837] (4) halogen atoms (e.g., fluorine);

[0838] m is an integer from 0 to 3 (i.e., 0, 1, 2 or 3);

[0839] n is an integer from 0 to 3 (i.e., 0, 1, 2 or 3); and

[0840] o is an integer from 0 to 3 (i.e., 0, 1, 2 or 3);

[0841] or a salt thereof.

[0842] In some embodiments of formula (I), preferred compounds (I) are compounds wherein

[0843] part

[0844]

[0845] Selected from the group consisting of:

[0846]

[0847]

[0848] * indicates the same as R A The bonding site of

[0849] R 1 for

[0850] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0851] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0852] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl), (4) cyclopropyl,

[0853] (5) a halogenated cyclopropyl group (e.g., a fluorocyclopropyl group), or

[0854] (6) Single or Double C 1-6 Alkylamino (e.g., dimethylamino);

[0855] Each R 2 are the same or different and are

[0856] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0857] (2) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0858] (3)C 1-6 Alkoxy-C 1-6alkyl (e.g., methoxymethyl), or

[0859] (4) Hydroxyl-C 1-6 alkyl (e.g., hydroxymethyl);

[0860] Each R 3 are the same or different and are

[0861] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0862] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0863] (3) Halogen atom (eg, fluorine).

[0864] L 1 For the key, -NR 6 -or-O-; where R 6 A hydrogen atom or C 1-6 alkyl (e.g., methyl);

[0865] L 2 is a bond or -CH2-;

[0866] X 1 N or CR 3’ ; where R 3’ is a hydrogen atom;

[0867] R 4a for

[0868] (1) Hydrogen atoms,

[0869] (2)C 1-6 an alkyl group (e.g., methyl),

[0870] (3) cyclopropyl,

[0871] (4)C 1-6 alkoxy (e.g., methoxy),

[0872] (5) Halogenated C 1-6 alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or

[0873] (6) halogen atoms (e.g., fluorine, chlorine, bromine);

[0874] X 2 N or CR 4b ; where R 4b is a hydrogen atom or a halogen atom (e.g., fluorine);

[0875] X 4 N or CR4c ; where R 4c is a hydrogen atom or a halogen atom (e.g., fluorine);

[0876] X 5 N or CR 4d ; where R 4d is a hydrogen atom;

[0877] m is an integer from 0 to 3;

[0878] n is an integer from 0 to 3,

[0879] o is an integer from 0 to 3; and

[0880] R A Has the following structure:

[0881]

[0882] It is selected from the group consisting of:

[0883]

[0884] in

[0885] Each R 5 are the same or different and are halogen atoms (eg, fluorine, chlorine) or C 1-6 alkoxy (e.g., methoxy);

[0886] R 5’ is a hydrogen atom or a halogen atom (e.g., fluorine); and

[0887] q is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4),

[0888] or a salt thereof.

[0889] In some embodiments, the preferred compound (I) is a compound of formula (Ia):

[0890] in

[0891] q is an integer from 0 to 4 (i.e., 0, 1, 2, 3 or 4); and

[0892] Other symbols are as defined above;

[0893] or a salt thereof.

[0894] In some embodiments, the preferred compound (I) is a compound of formula (Ib):

[0895] in

[0896] q is an integer from 0 to 4 (i.e., 0, 1, 2, 3 or 4); and

[0897] Other symbols are as defined above;

[0898] or a salt thereof.

[0899] In some embodiments, the preferred compound (I) is a compound of formula (Ic):

[0900] where R 2a is a hydrogen atom or an optionally substituted C 1-6 alkyl;

[0901] q is an integer from 0 to 4 (i.e., 0, 1, 2, 3 or 4); and

[0902] Other symbols are as defined above;

[0903] or a salt thereof.

[0904] In some embodiments, the preferred compound (I) is a compound of formula (Id):

[0905] in

[0906] R 2a is a hydrogen atom or an optionally substituted C 1-6 alkyl;

[0907] R 3a and R 3b are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 an alkyl group or a halogen atom;

[0908] q is an integer from 0 to 4; and

[0909] Other symbols are as defined in claim 2;

[0910] or a salt thereof (hereinafter referred to as "Compound (Id)").

[0911] In some embodiments, preferred compound (Id) is a compound wherein

[0912] R 1 for

[0913] (1)C 1-6 Alkyl (e.g., methyl, ethyl),

[0914] (2)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl),

[0915] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl, fluoroethyl),

[0916] (4) cyclopropyl,

[0917] (5) a halogenated cyclopropyl group (e.g., a fluorocyclopropyl group), or

[0918] (6) Single or Double C 1-6 Alkylamino (e.g., dimethylamino);

[0919] R 2a for

[0920] (1) Hydrogen atoms,

[0921] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0922] (3) Halogenated C 1-6 Alkyl (e.g., fluoromethyl, difluoromethyl),

[0923] (4)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0924] (5) Hydroxyl-C 1-6 alkyl (e.g., hydroxymethyl);

[0925] R 3a and R 3b are the same or different and each is

[0926] (1) Hydrogen atoms,

[0927] (2)C 1-6 Alkyl (e.g., methyl, ethyl),

[0928] (3)C 1-6 Alkoxy-C 1-6 alkyl (e.g., methoxymethyl), or

[0929] (4) halogen atoms (e.g., fluorine);

[0930] X 2 N or CR 4b ;

[0931] R 4a 、R 4b 、R 4c and R 4d are the same or different and each is

[0932] (1) Hydrogen atoms,

[0933] (2)C 1-6 an alkyl group (e.g., methyl),

[0934] (3) cyclopropyl,

[0935] (4)C 1-6 alkoxy (e.g., methoxy),

[0936] (5) Halogenated C 1-6 an alkyl group (e.g., fluoromethyl, difluoromethyl, trifluoromethyl), or (6) a halogen atom (e.g., fluorine, chlorine, bromine);

[0937] X 6 N or CR 5’ ;

[0938] Each R 5 are the same or different and are halogen atoms (eg, fluorine, chlorine); R 5’ is a hydrogen atom or a halogen atom (eg, fluorine); and q is an integer from 0 to 4 (ie, 0, 1, 2, 3, or 4).

[0939] In some embodiments, the preferred compound (I) is a compound of formula (Ie):

[0940] in

[0941] R 1 for

[0942] (1)C 1-6 alkyl (e.g., methyl, ethyl), or

[0943] (2) Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0944] R 2a for

[0945] (1) Hydrogen atoms,

[0946] (2)C 1-6 an alkyl group (e.g., a methyl group), or

[0947] (3) Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0948] R 3a and R 3b are the same or different and each is

[0949] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0950] (2) halogen atoms (e.g., fluorine);

[0951] R 4a for

[0952] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0953] (2) halogen atoms (e.g., fluorine, chlorine);

[0954] X 2 N or CR 4b ; where R 4b is a halogen atom (e.g., fluorine); and

[0955] R A is phenyl or pyridyl, wherein each of phenyl and pyridyl is optionally substituted with one to three halogen atoms (e.g., fluorine) (including 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 4,6-difluoropyridin-2-yl),

[0956] or a salt thereof (hereinafter referred to as "Compound (Ie)").

[0957] In some embodiments, preferred compound (Ie) is a compound wherein

[0958] R 1 for

[0959] (1)C 1-6 alkyl (e.g., methyl, ethyl), or

[0960] (2) Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0961] R 2a for

[0962] (1) Hydrogen atoms,

[0963] (2)C 1-6 an alkyl group (e.g., a methyl group), or

[0964] (3) Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0965] R 3a and R 3b are each a halogen atom (e.g., fluorine);

[0966] R 4a for

[0967] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0968] (2) halogen atoms (e.g., fluorine, chlorine);

[0969] X 2 N or CR 4b ; where R 4b is a halogen atom (e.g., fluorine); and

[0970] R A is phenyl or pyridyl, wherein each of phenyl and pyridyl is optionally substituted with one to three halogen atoms (e.g., fluorine) (including 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 4,6-difluoropyridin-2-yl);

[0971] or a salt thereof.

[0972] In some embodiments, more preferred compound (Ie) is a compound wherein

[0973] R 1 for

[0974] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0975] (2) Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0976] R 2a for

[0977] (1)C 1-6 an alkyl group (e.g., a methyl group), or

[0978] (2) Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0979] R 3a and R 3b are each a halogen atom (e.g., fluorine);

[0980] R 4a is a halogen atom (e.g., fluorine);

[0981] X 2 is N; and

[0982] R A is phenyl (including 2,6-difluorophenyl) optionally substituted by one to three halogen atoms (e.g., fluorine);

[0983] or a salt thereof.

[0984] In some embodiments, further more preferred compound (Ie) is a compound wherein

[0985] R 1 C 1-6 alkyl (e.g., methyl);

[0986] R 2a Halogenated C 1-6 alkyl (e.g., fluoromethyl);

[0987] R 3a and R 3b are each a halogen atom (e.g., each is fluorine);

[0988] R 4a is a halogen atom (e.g., fluorine);

[0989] X 2 is N; and

[0990] R A is phenyl (including 2,6-difluorophenyl) optionally substituted by one to three halogen atoms (e.g., fluorine);

[0991] or a salt thereof.

[0992] Specific examples of Compound (I) include the compounds of Examples 1 to 93 and 96 to 178 described below.

[0993] In one aspect, compound (I) is preferably

[0994] 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);

[0995] 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);

[0996] 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);

[0997] 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);

[0998] 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);

[0999] 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);

[1000] 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);

[1001] 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

[1002] 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).

[1003] In one aspect, compound (I) is preferably

[1004] 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);

[1005] 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);

[1006] 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

[1007] 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).

[1008] As the salt of the compound of formula (I), pharmacologically acceptable salts are 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 and the like.

[1009] Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; aluminum salt, ammonium salt and the like.

[1010] Preferable examples of the salt with an organic base 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.

[1011] Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[1012] Preferable examples of the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

[1013] Preferable examples of the salt with a basic amino acid include salts with arginine, lysine, ornithine and the like.

[1014] Preferable examples of the salt with an acidic amino acid include salts with aspartic acid, glutamic acid and the like.

[1015] The production method of the compound of the present invention is explained below.

[1016] In the following production methods, the starting compounds and reagents used and the compound obtained in each step may each be in the form of a salt, and examples of such salts include those similar to the salts of the compound of formula (I), and the like.

[1017] When the compound obtained in each step is a free form, it can be converted into the target salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted into the target free form or other salt according to a method known per se.

[1018] The compound obtained in each step can be used directly as a reaction mixture, or can be used in the next reaction as a crude product. Alternatively, the compound obtained in each step can be separated and purified from the reaction mixture according to methods known per se, such as separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, column chromatography, etc.

[1019] When the starting compounds and reagents used in each step are commercially available, the commercially available products can be used directly.

[1020] In the reaction in each step, although the reaction time varies depending on the kinds of the reagent and solvent to be used, it is generally 1 minute to 48 hours, preferably 10 minutes to 8 hours, unless otherwise specified.

[1021] In the reaction in each step, although the reaction temperature varies depending on the kinds of the reagent and solvent to be used, it is generally -78°C to 300°C, preferably -78°C to 150°C, unless otherwise specified.

[1022] In the reaction in each step, although the pressure varies depending on the kinds of the reagent and solvent to be used, it is generally 1 atm to 20 atm, preferably 1 atm to 3 atm, unless otherwise specified.

[1023] A microwave synthesizer such as the Initiator manufactured by Biotage can be used for the reactions in each step. Although the reaction temperature varies depending on the types of reagents and solvents to be used, it is generally room temperature to 300°C, preferably 50°C to 250°C, unless otherwise specified. Although the reaction time varies depending on the types of reagents and solvents to be used, it is generally 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[1024] In the reaction in 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 a solvent amount.

[1025] Unless otherwise specified, the reaction in each step is carried out in the absence of a solvent, or by dissolving or suspending the starting compound in an appropriate solvent. Examples of the solvent include those described in the Examples and the following solvents.

[1026] Alcohols: methanol, ethanol, tert-butanol, 2-methoxyethanol, etc.;

[1027] Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.;

[1028] Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.;

[1029] Saturated hydrocarbons: cyclohexane, hexane, etc.;

[1030] Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.;

[1031] Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

[1032] Nitriles: acetonitrile, etc.

[1033] Sulfoxides: dimethyl sulfoxide, etc.

[1034] Aromatic organic bases: pyridine, etc.;

[1035] Acid anhydride: acetic anhydride, etc.;

[1036] Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;

[1037] Inorganic acids: hydrochloric acid, sulfuric acid, etc.;

[1038] Esters: ethyl acetate, etc.

[1039] Ketones: acetone, methyl ethyl ketone, etc.

[1040] water.

[1041] The above-mentioned solvents may be used as a mixture of two or more of them at an appropriate ratio.

[1042] When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases.

[1043] Inorganic alkali: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.;

[1044] 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.

[1045] Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.;

[1046] Alkali metal hydrides: sodium hydride, etc.

[1047] Metal amide compounds: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.;

[1048] Organic lithium: n-butyl lithium, etc.

[1049] When an acid or an acid catalyst is used for the reaction in each step, examples thereof include those described in Examples and the following acids and acid catalysts.

[1050] Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;

[1051] Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.;

[1052] Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[1053] Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, Jikken Kagaku Kouza, 5th edition, vol. 13-19 (edited by the Chemical Society of Japan); Shin Jikken Kagaku Kouza, vol. 14-15 (edited by the Chemical Society of Japan); Fine Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective, vol. I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, vol. 1-vol. 14 (Elsevier Japan); Strategic Applications of Named Reactions in The method described in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989 etc., or the method described in Examples.

[1054] In each step, protection or deprotection reaction of the functional group is carried out according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th edition”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G.M. Wuts); “Protecting Groups 3rd edition” Thieme, 2004 (P.J. Kocienski) or the like, or the method described in Examples.

[1055] Examples of the protecting groups for the hydroxyl group and the phenolic hydroxyl group of alcohol etc. include ether type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether etc.; carboxylate type protecting groups such as acetate etc.; sulfonate type protecting groups such as methanesulfonate etc.; carbonate type protecting groups such as tert-butyl carbonate etc.

[1056] Examples of the protecting group for the carbonyl group of aldehyde include acetal type protecting groups such as dimethyl acetal and the like; cyclic acetal type protecting groups such as 1,3-dioxane and the like.

[1057] Examples of the protecting group for the carbonyl group of ketone include ketal-type protecting groups such as dimethylketal, cyclic ketal-type protecting groups such as 1,3-dioxane, oxime-type protecting groups such as O-methyloxime, hydrazone-type protecting groups such as N,N-dimethylhydrazone, and the like.

[1058] Examples of the protecting group for the carboxyl group include ester type protecting groups such as methyl ester and the like; amide type protecting groups such as N,N-dimethylamide and the like.

[1059] Examples of the protecting group for thiol include ether-type protecting groups such as benzyl sulfide and the like; ester-type protecting groups such as thioacetate, thiocarbonate, thiocarbamate and the like.

[1060] Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, indole, etc. include carbamate type protecting groups such as benzyl carbamate, etc.; amide type protecting groups such as acetamide, etc.; alkylamine type protecting groups such as N-triphenylmethylamine, etc.; sulfonamide type protecting groups such as methanesulfonamide, etc.

[1061] The protecting group can be removed according to a method known per se, for example, by a method using an acid, a base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method, or the like.

[1062] When the 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, tetramethylammonium triacetoxyborohydride, etc.; boranes such as borane tetrahydrofuran complex, etc.; 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, Lindlar's catalyst, etc. can be used.

[1063] When the oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide, etc.; perchlorates such as tetrabutylammonium perchlorate, etc.; chlorates such as sodium chlorate, etc.; chlorites such as sodium chlorite, etc.; periodates such as sodium periodate, etc.; hypervalent iodine reagents such as iodosobenzene, etc.; manganese-containing reagents such as manganese dioxide, potassium permanganate, etc.; lead such as lead tetraacetate, etc.; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent, etc.; halogen compounds such as N-bromosuccinimide (NBS), etc.; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), etc.

[1064] When performing the radical cyclization reaction in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanovaleric acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical agent to be used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[1065] When the Wittig reaction is performed in each step, examples of the Wittig reagent to be used include alkylenephosphoranes, etc. Alkylenephosphoranes can be prepared according to a method known per se, for example, by reacting a phosphonium salt with a strong base.

[1066] When the Horner-Emmons reaction is carried out in each step, examples of the reagent to be used include phosphonoacetic acid esters such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organic lithium and the like.

[1067] When the Friedel-Crafts reaction is performed in each step, a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an alcohol, an olefin, etc.) is used as a reagent. Alternatively, an organic acid or an inorganic acid may be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride may be used instead of the acid chloride.

[1068] When the aromatic nucleophilic substitution reaction is carried out in each step, a nucleophilic agent (eg, amine, imidazole, etc.) and a base (eg, organic base, etc.) are used as reagents.

[1069] When the nucleophilic addition reaction of the carbanion, the nucleophilic 1,4-addition reaction (Michael addition reaction) of the carbanion, or the nucleophilic substitution reaction of the carbanion is performed in each step, examples of the base to be used to generate the carbanion include organic lithium, metal alkoxide, inorganic base, organic base, and the like.

[1070] When the Grignard reaction is performed in each step, examples of the Grignard reagent to be used include aryl magnesium halides such as phenylmagnesium bromide, etc.; and alkyl magnesium halides such as methylmagnesium bromide, etc. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[1071] When the Knoevenagel condensation reaction is performed in each step, a compound having an activated methylene group with two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., an organic base, a metal alkoxide, an inorganic base) are used as reagents.

[1072] When the Vilsmeier-Haack reaction is performed in each step, phosphorus oxychloride and an amide derivative (for example, N,N-dimethylformamide, etc.) are used as reagents.

[1073] When the azidation reaction of an alcohol, an alkyl halide, or a sulfonic acid ester is performed in each step, examples of the azidating agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, for the azidation reaction of an alcohol, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, etc. are employed.

[1074] When a reductive amination reaction is performed in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[1075] When the Mitsunobu reaction is performed in each step, azodicarboxylic acid ester (for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[1076] When esterification reaction, amidation reaction or urea formation reaction is carried out in each step, examples of the reagent to be used include acid halides such as acid chloride, acid bromide and the like; activated carboxylic acids such as acid anhydride, activated ester, sulfuric ester and the like. Examples of the activating agent for carboxylic acid include carbodiimide condensation agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensation agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensation agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformate such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; combinations thereof and the like. When a carbodiimide condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), etc. may be added to the reaction system.

[1077] When the 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), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride, etc.; nickel compounds such as tetrakis (triphenylphosphine) nickel (0), etc.; rhodium compounds such as tris (triphenylphosphine) rhodium (III) chloride, etc.; cobalt compounds; copper compounds such as copper oxide, copper (I) iodide, etc.; platinum compounds, etc. In addition, a base may be added to the reaction system, and examples thereof include inorganic bases, etc.

[1078] When the thiocarbonylation reaction is performed in each step, phosphorus pentasulfide is generally 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 reagent)) may be used instead of phosphorus pentasulfide.

[1079] When the Wohl-Ziegler reaction is performed in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. In addition, the reaction can be accelerated by subjecting the reaction system to a free radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile, etc.

[1080] When the halogenation reaction of the hydroxyl group is performed in each step, examples of the halogenating agent to be used include hydrohalic acids and acyl halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. for chlorination, and 48% hydrobromic acid, etc. for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. can be used. Alternatively, a method of producing an alkyl halide by converting an alcohol into the corresponding sulfonic acid ester and then reacting the sulfonic acid ester with lithium bromide, lithium chloride, or sodium iodide can also be used.

[1081] When the Arbuzov reaction is performed in each step, examples of the reagent to be used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[1082] When the sulfonic acid ester esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.

[1083] When performing the hydrolysis reaction in each step, an acid or a base is used as a reagent. For the acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane, etc. can be added to reductively capture the by-produced tert-butyl cation.

[1084] When the dehydration reaction is performed in each step, examples of the dehydrating agent to be used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, aluminum oxide, polyphosphoric acid and the like.

[1085] Compound (I) can be produced from compound (1) according to the method shown in the following Scheme 1. In the formula, X 7 is a halogen atom, P 1 is a protecting group, LG 1 is a leaving group, and other symbols are as defined above.

[1086] Solution 1

[1087]

[1088] P 1 Examples of the "protecting group" include those exemplified for the above-mentioned "protecting group for amino group and aromatic heterocycle (such as imidazole, pyrrole, indole etc.)".

[1089] LG 1 Examples of the "leaving group" include a halogen atom, an optionally halogenated C 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, trifluoromethanesulfonyloxy), optionally substituted by C 1-6 Alkyl substituted C 6-14 Arylsulfonyloxy (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the like.

[1090] 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, alkali metal hydrides and the like.

[1091] Compound (4) can be produced by subjecting compound (1) to a nucleophilic substitution reaction with compound (3).

[1092] Compound (5) can be produced by subjecting compound (4) to a deprotection reaction.

[1093] Compound (I) can also be produced by subjecting compound (5) to a sulfonylation reaction with compound (6). Examples of compound (6) to be used include corresponding sulfonyl chloride, corresponding sulfamoyl chloride and the like.

[1094] Compound (1) can be easily obtained commercially, or can be produced according to the method shown in Scheme 3, 5 or 7 or a method known per se.

[1095] Compound (2) can be readily obtained commercially, or can be produced according to the method shown in Scheme 4 or a method known per se.

[1096] Compounds (3) and (6) are easily commercially available or can be produced according to a method known per se.

[1097] Compound (I)-1, which is a compound (I) wherein p is 1, can be produced from compound (7) according to the method shown in the following Scheme 2. In the formula, X 8 is a halogen atom, and other symbols are as defined above.

[1098] Option 2

[1099]

[1100] 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, alkali metal hydrides and the like.

[1101] Compound (I)-1 can be produced by subjecting compound (8) and compound (9) to a coupling reaction.

[1102] Compound (2) can be readily obtained commercially, or can be produced according to the method shown in Scheme 4 or a method known per se.

[1103] Compound (7) can be readily obtained commercially, or can be produced according to the method shown in Scheme 8 or 9 or a method known per se.

[1104] Compound (9) can be easily commercially obtained, or can be produced according to a method known per se.

[1105] Compounds (1)-2, (1)-4 and (1)-5 can be produced from compound (1)-1 according to the method shown in the following Scheme 3. In the formula, R 7 C 1-6 Alkyl, and other symbols are as defined above.

[1106] Option 3

[1107]

[1108] Compound (1)-2 can be produced by subjecting compound (1)-1 to a fluorination reaction. Examples of the fluorination agent to be used include (diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, and the like.

[1109] Compound (1)-3 can be produced by subjecting compound (1)-1 to an oxidation reaction.

[1110] Compound (1)-4 can be produced by subjecting compound (1)-3 to a fluorination reaction.

[1111] Compound (1)-5 can be produced by subjecting compound (1)-1 to an alkylation reaction with compound (10).

[1112] Compounds (1)-1 and (10) are easily commercially available or can be produced according to a method known per se.

[1113] Compound (2)-1 can be produced from compound (11) or compound (13) according to the method shown in the following Scheme 4. In the formula, P 2 is a protecting group, R 8 is optionally substituted C 1-6 Alkyl, or optionally substituted C 6-14 The aryl group and other symbols are as defined above.

[1114] Option 4

[1115]

[1116] Compound (12) can be produced by subjecting compound (11) to a sulfonylation reaction with compound (6).

[1117] Compound (2)-1 can be produced by subjecting compound (12) to a deprotection reaction.

[1118] Compound (14) can be produced by subjecting compound (13) to a sulfonate esterification reaction. Examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride and the like.

[1119] Compound (12) can also be produced by subjecting compound (14) to an alkylation reaction with compound (15).

[1120] Compound (17) can be produced by subjecting compound (13) and compound (16) to a Mitsunobu reaction.

[1121] Compound (2)-1 can also be produced by subjecting compound (17) to a deprotection reaction.

[1122] Compounds (6), (11), (13), (15) and (16) are easily commercially available or can be produced according to a method known per se.

[1123] Compound (1)-6 and compound (4)-1 can be produced from compound (18) according to the method shown in the following Scheme 5. In the formula, R 9 and R 10 and R 11 Each is a hydrogen atom or an optionally substituted C 1-6 Alkyl, and other symbols are as defined above.

[1124] Option 5

[1125]

[1126] Compound (1)-6 can be produced by subjecting compound (18) to a cycloaddition reaction with compound (19) and a base. Examples of the base to be used include inorganic bases, organic bases and the like.

[1127] Compound (4)-1 can be produced by subjecting compound (18) to a cycloaddition reaction with compound (20) and a base. Examples of the base to be used include inorganic bases, organic bases and the like.

[1128] Compound (18) can be readily obtained commercially, or can be produced according to the method shown in Scheme 6 or a method known per se.

[1129] Compounds (19) and (20) are easily commercially available or can be produced according to methods known per se.

[1130] Compound (18)-1 can be produced from compound (21), compound (26) or compound (28) according to the method shown in the following Scheme 6. In the formula, X 9 and X 10 Each is a halogen atom, and other symbols are as defined above.

[1131] Option 6

[1132]

[1133] Compound (22) can be produced by subjecting compound (21) to a coupling reaction with compound (9).

[1134] 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, the 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 the method described in Examples.

[1135] Compound (24) can also be produced by subjecting compound (26) to a coupling reaction with compound (27).

[1136] Compound (24) can also be produced by subjecting compound (28) to a coupling reaction with compound (9).

[1137] Compound (18)-1 can be produced by subjecting compound (24) to a coupling reaction with compound (25).

[1138] Compounds (9), (21), (23) and (25) to (28) are readily commercially available or can be produced according to methods known per se.

[1139] Compound (1)-7 can be produced from compound (29) according to the method shown in the following Scheme 7. In the formula, X 11 is a halogen atom, and other symbols are as defined above.

[1140] Option 7

[1141]

[1142] Compound (30) can be produced by subjecting compound (29) to a coupling reaction with compound (9).

[1143] Compound (31) can be produced by subjecting compound (30) to a coupling reaction with compound (25).

[1144] Compound (32) can be produced by subjecting compound (31) to a cycloaddition reaction with compound (19) and a base. Examples of the base to be used include inorganic bases, organic bases and the like.

[1145] Compound (33) can be produced by subjecting compound (32) to a deprotection reaction.

[1146] Compound (1)-7 can be produced by subjecting compound (33) to a Sandmeyer reaction with compound (23)-1.

[1147] Compounds (9), (19), (23)-1, (25) and (29) are easily commercially available or can be produced according to a method known per se.

[1148] Compounds (7)-2, (7)-4 and (7)-5 can be produced from compound (7)-1 according to the method shown in the following Scheme 8. In the formula, each symbol is as defined above.

[1149] Option 8

[1150]

[1151] Compound (7)-2 can be produced by subjecting compound (7)-1 to a fluorination reaction.

[1152] Compound (7)-3 can be produced by subjecting compound (7)-1 to an oxidation reaction.

[1153] Compound (7)-4 can be produced by subjecting compound (7)-3 to a fluorination reaction.

[1154] Compound (7)-5 can be produced by subjecting compound (7)-1 to an alkylation reaction with compound (10).

[1155] Compounds (7)-1 and (10) are easily commercially available or can be produced according to a method known per se.

[1156] Compound (7)-6 can be produced from compound (28) according to the method shown in the following Scheme 9. In the formula, each symbol is as defined above.

[1157] Option 9

[1158]

[1159] Compound (34) can be produced by subjecting compound (28) to a coupling reaction with compound (25).

[1160] Compound (7)-6 can be produced by subjecting compound (34) to a cycloaddition reaction with compound (19) and a base. Examples of the base to be used include inorganic bases, organic bases and the like.

[1161] Compounds (19), (25) and (28) are easily commercially available or can be produced according to methods known per se.

[1162] Compound (22) can be produced from compound (21)-1 according to the method shown in the following Scheme 10. In the formula, each symbol is as defined above.

[1163] Plan 10

[1164]

[1165] Compound (22) can be produced by subjecting compound (21-1) to a coupling reaction with compound (27).

[1166] Compounds (21)-1 and (27) are easily commercially available or can be produced according to a method known per se.

[1167] In the compound (I) thus obtained, the intramolecular functional groups can also be converted into the target functional groups by a combination of chemical reactions known per se. Examples of chemical reactions include oxidation, reduction, alkylation, acylation, ureidation, hydrolysis, amination, esterification, aromatic coupling, deprotection, and the like.

[1168] In the above production method, when the starting compound has an amino group, a carboxyl group, a hydroxyl group, a carbonyl group or a mercapto group as a substituent, a protecting group commonly used in peptide chemistry can be introduced into these groups, and the target compound can be obtained by removing the protecting group as needed after the reaction.

[1169] The compound (I) obtained by the above-mentioned production method can be isolated and purified by known means such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.

[1170] When compound (I) contains optical isomers, stereoisomers, regioisomers, and rotational isomers, these compounds are also included in compound (I), and each can be obtained as a single product by a known synthesis method or separation method. For example, when optical isomers exist in compound (I), optical isomers resolved from the compound are also included in compound (I).

[1171] Here, optical isomers can be produced by a method known per se.

[1172] Compound (I) may be crystalline.

[1173] The crystal of compound (I) (hereinafter sometimes simply referred to as the crystal of the present invention) can be produced by crystallizing compound (I) using a crystallization method known per se.

[1174] In the present specification, the melting point refers to a melting point measured, for example, by a micro melting point apparatus (Yanako, MP-500D or Buchi, B-545), a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1) or the like.

[1175] In general, the melting point sometimes varies depending on the measuring device, measuring conditions, etc. The crystal in this specification may be a crystal showing a melting point different from the value described in this specification as long as the difference is within a general error range.

[1176] The crystal of the present invention is excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression), and is therefore very suitable as a drug.

[1177] Compound (I) can be used as a prodrug. A prodrug of Compound (I) refers to a compound that is converted into Compound (I) of the present invention by a reaction caused by an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that is converted into Compound (I) of the present invention by oxidation, reduction, hydrolysis, or the like by an enzyme; or a compound that is converted into Compound (I) of the present invention by hydrolysis, or the like by gastric acid, or the like.

[1178] The prodrug of compound (I) may be a compound obtained by acylation, alkylation or phosphorylation of the amino group in compound (I) (for example, a compound obtained by eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylation, tetrahydrofurylation, pyrrolidinylmethylation, pivaloyloxymethylation and tert-butylation of the amino group in compound (I); a compound obtained by acylation, alkylation, phosphorylation or borylation of the hydroxyl group in compound (I) (for example, a compound obtained by acetylation of the hydroxyl group in compound (I)); , palmitoylation, propionylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); a compound obtained by esterifying or amidating the carboxyl group in compound (I) (for example, a compound obtained by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, and methylamidation, etc.). Any of these compounds can be produced from compound (I) by a method known per se.

[1179] The prodrug of compound (I) may also be a prodrug that is converted into compound (I) under physiological conditions, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), vol. 7, Design of Molecules, pp. 163-198, published by HIROKAWASHOTEN (1990).

[1180] In the present specification, the prodrug may form a salt, and as such a salt, those exemplified as the salts of the compound represented by the above-mentioned formula (I) can be mentioned.

[1181] Isotopes (e.g. 3 H. 13 C. 14 C. 18 F. 35 S. 125 I) and the like labeled compound (I).

[1182] Compound (I) labeled with an isotope or substituted with an isotope can be used as a tracer (PET tracer) used in, for example, positron emission tomography (PET), and can be used in medical diagnosis and the like.

[1183] Furthermore, compound (I) may be a hydrate or a non-hydrate, or a non-solvate (eg, an acid anhydride), or a solvate (eg, a hydrate).

[1184] Compound (I) also encompasses deuterated forms, wherein 1 H is converted into 2 H(D).

[1185] In addition, compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. A co-crystal or co-crystal salt refers to a crystalline substance composed of two or more specific solids at room temperature, each solid having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Co-crystals or co-crystal salts can be produced by co-crystallization methods known per se.

[1186] Compound (I) or a prodrug thereof (hereinafter sometimes referred to as the compound of the present invention) can be used as it is, or by mixing with a pharmacologically acceptable carrier or the like in the form of a pharmaceutical composition (also referred to as a drug) as an agent for preventing or treating the following various diseases for mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys).

[1187] As pharmacologically acceptable carriers, various organic or inorganic carrier substances commonly used as preparation materials can be used. These can be incorporated into solid preparations as excipients, lubricants, binders, and disintegrants; or incorporated into liquid preparations as solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents; and formulation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can be added as needed.

[1188] Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminum metasilicate.

[1189] Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silicon dioxide.

[1190] Preferable examples of the binder include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.

[1191] Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low-substituted hydroxypropylcellulose.

[1192] 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.

[1193] Preferable 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, sodium acetate and the like.

[1194] Preferred examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as poly(vinyl alcohol), polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, polysorbate; and polyoxyethylene hydrogenated castor oil.

[1195] Preferable examples of the isotonic agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.

[1196] Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.

[1197] Preferred examples of soothing agents include benzyl alcohol.

[1198] Preferable examples of the preservative include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

[1199] Preferred examples of the antioxidant include sulfites and ascorbic acid salts.

[1200] Preferred examples of colorants include aqueous edible tar pigments (e.g., food pigments such as food pigments Red No. 2 and No. 3, food pigments Yellow No. 4 and No. 5, food pigments Blue No. 1 and No. 2, and similar food pigments), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned aqueous edible tar pigments), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide), and the like.

[1201] Preferable examples of the sweetener include saccharin sodium, dipotassium glycyrrhizate, aspartame and stevia.

[1202] Examples of the dosage form of the above-mentioned pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets), capsules (including soft capsules, microcapsules), pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, films (e.g., orally disintegrating films, oral mucosal adhesive films), etc.; and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external preparations (e.g., transdermal absorption preparations, ointments, lotions, adhesive preparations), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. The compounds and drugs of the present invention can be safely administered orally or parenterally (e.g., intrarectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorganally, intranasally, intradermally, by instillation, intracerebrally, intravaginally, intraperitoneally, intratumorally, proximal to tumors, and to lesions), respectively.

[1203] These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations, sustained-release preparations, and the like.

[1204] The pharmaceutical composition can be produced according to methods commonly used in the field of pharmaceutical formulation, for example, methods described in the Japanese Pharmacopoeia.

[1205] The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dosage, etc. of the compound of the present invention, and is, for example, about 0.1 to 100 wt %.

[1206] When producing oral preparations, coatings may be applied if necessary for the purposes of taste masking, enteric solubility or sustainability.

[1207] 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.

[1208] As the sugar coating base, sucrose is used, and one or more selected from talc and precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be further used in combination.

[1209] Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinyl pyrrolidone, etc.; and polysaccharides such as pullulan, etc.

[1210] Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc.; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], etc.; and naturally occurring substances such as shellac, etc.

[1211] Examples of the sustained-release film coating base include cellulose polymers such as ethylcellulose, and the like; and acrylic polymers such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)], and the like.

[1212] Two or more of the above coating bases may be mixed and used in an appropriate ratio. In addition, for example, a sunscreen such as titanium oxide, red iron oxide, etc. may also be used during coating.

[1213] Since the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and fewer side effects, it 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, rats).

[1214] Furthermore, the compounds of the present invention are expected to be excellent in center migration.

[1215] The compounds of the present invention have excellent orexin type 2 receptor agonist activity and can treat, prevent or reduce the risk of various neurological and psychiatric diseases associated with orexin type 2 receptors. The compounds of the present invention can be used as agents for preventing or treating various diseases, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with hypersomnia-like symptoms, hypersomnia syndrome with daytime excessive sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, Lewy body dementia, 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-Barre syndrome, Las Vegas, spondylosis, schizophrenia, leukemia ... Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperpancreatic obesity, protoplasmic obesity, pituitary obesity, hypoprotoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects due to anesthesia and Complications, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, interrupted rapid eye movement sleep, jet lag, jet lag syndrome, alternating worker sleep disorder, sleep disorders, night terrors, depression, major depressive disorder, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight, diseases related to circadian rhythm, fibromyalgia, disorders caused by decreased sleep quality, binge eating, compulsive eating disorders, obesity-related diseases, hypertension, diabetes, increased plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer Cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary disease, craniopharyngioma, Froelich's syndrome, growth hormone deficiency, normal mutant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual and reproductive dysfunction such as hirsutism in women, fetal defects related to maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux,Obesity hypoventilation syndrome (Pickwick syndrome), respiratory disorders such as dyspnea, inflammatory conditions such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, risk of obesity secondary outcomes such as reduced risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, disorders of the genital / urinary system, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as post-bypass and transplant brain defects, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemia, nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, conditions associated with muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorders, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced parkinsonism, Jill-Doula Tourette's syndrome La Tourette's syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury (TBI).

[1216] In particular, the compound of the present invention can be used as an agent for preventing or treating the following diseases: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (for example, 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, etc., side effects and complications due to anesthesia, etc., or can be used as an anesthetic antagonist.

[1217] In some aspects, the compounds of the present invention can be used as agents for preventing or treating the following diseases: 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 associated with bone loss, sepsis, impaired consciousness, side effects and complications due to anesthesia.

[1218] In some aspects, the compounds of the present invention can be used as agents for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

[1219] In some aspects, the compounds of the present invention can be used as agents for preventing or treating narcolepsy.

[1220] Central disorders of hypersomnolence (CDH) are characterized by excessive daytime sleepiness in the absence of other sleep disorders but in the presence of adequate and regular sleep habits. Central disorders of hypersomnia (CDH) include hypersomnia type 1, hypersomnia type 2, and idiopathic hypersomnia. Kleine-Levin syndrome and insufficient sleep syndrome and hypersomnia caused by medical conditions, medications or substances, or psychiatric conditions are also considered core symptoms of narcolepsy. Evaluation of central disorders of hypersomnia (CDH) includes sleep testing (polysomnography, PSG) in a sleep laboratory followed by a multiple sleep latency test (MSLT).

[1221] Symptoms associated with hypersomnia include unusual intrusions of REM sleep characteristics into the waking state: for example, sleep-related hallucinations, sleep paralysis, or vivid dreams and confusion between dreams and reality. These symptoms can also occur in people without a sleep disorder.

[1222] Some people with narcolepsy also experience cataplexy (narcolepsy type 1), a loss of muscle tone triggered by emotion (usually laughter or anticipation). Cataplexy can be generalized or partial and does not cause any loss of consciousness. This muscle weakness usually improves within seconds to minutes.

[1223] Patients with idiopathic hypersomnia (IDH) often describe excessive daytime sleepiness, prolonged sleep duration (more than 10-11 hours per night), and difficulty waking up in the morning (sleep inertia). Unlike narcolepsy, patients with IDH often describe long, non-refreshing daytime naps. Another common symptom of IDH is "brain fog," or a feeling of confusion during the day. Kleine-Levin syndrome is a rare, periodic hypersomnia disorder.

[1224] One aspect of the present disclosure is a method for treating a subject suffering from one or more central disorders of hypersomnia (CDH), the method comprising administering to the subject a compound of the present invention.

[1225] Another aspect of the present disclosure is the use of a compound of the present invention for the manufacture of an agent for treating one or more central disorders of hypersomnia (CDH) in a subject.

[1226] Another aspect of the present disclosure is a compound of the present invention for use in treating one or more central disorders of hypersomnia (CDH) in a subject.

[1227] Another aspect is the method or use of the aforementioned aspect, wherein the subject suffers from narcolepsy. In one aspect, the subject has been diagnosed with narcolepsy type 1. In another aspect, the subject has been diagnosed with narcolepsy type 2. In yet another aspect, the subject has been diagnosed with idiopathic hypersomnia.

[1228] Another aspect is the method or use of the preceding aspect, wherein administration of a compound of the invention reduces daytime sleepiness, reduces loss of muscle control, and / or reduces sleep disruption in a subject.

[1229] 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 an adult suffering from narcolepsy.

[1230] Another aspect is a method or use wherein a compound of the invention is administered in an amount effective to increase mean sleep latency.

[1231] Another aspect is a method or use wherein a compound of the invention is administered in an amount effective to reduce cataplexy events.

[1232] 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.

[1233] The dosage of the compounds of the present invention varies depending on the subject of administration, route of administration, target disease, symptoms, etc. For example, when the compounds of the present invention are administered orally or parenterally to adult patients, the dosage is, for example, about 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose, more preferably 0.5 to 20 mg / kg body weight per dose. This amount is ideally administered in 1 to 3 portions per day.

[1234] The compound of the present invention can be used in combination with other drugs (hereinafter referred to as concomitant drugs).

[1235] Excellent effects can be achieved by combining the compound of the present invention with concomitant drugs, for example,

[1236] (1) Compared with single administration of the compound of the present invention or concomitant drug, the dosage can be reduced,

[1237] (2) The drug to be used in combination with the compound of the present invention can be selected according to the patient's disease (mild case, severe case, etc.),

[1238] (3) A longer treatment period can be set by selecting a concomitant drug with a different action and mechanism from the compound of the present invention,

[1239] (4) Sustained therapeutic effects can be designed by selecting concomitant drugs with different actions and mechanisms from the compounds of the present invention,

[1240] (5) A synergistic effect or the like can be provided by using the compound of the present invention in combination with a concomitant drug.

[1241] In the present specification, the compound of the present invention and a concomitant drug used in combination are referred to as "the combination agent of the present invention."

[1242] When using the combination of the present invention, the administration time of the compounds of this invention and the concomitant drug is not limited, and the compounds of this invention or its pharmaceutical composition or the concomitant drug or its pharmaceutical composition can be applied to the subject at the same time, or can be applied at different times. The dosage of the concomitant drug can be determined according to the dosage used clinically, and can be appropriately selected according to the subject, route of administration, disease, combination, etc.

[1243] There is no particular limitation on the mode of administration of the combination agent of the present invention and the concomitant drug, and the compound of the present invention and the concomitant drug only need to be combined at the time of administration. Examples of such modes of administration include the following:

[1244] (1) administering a single preparation obtained by simultaneously processing the compound of the present invention and a concomitant drug, (2) administering two preparations of the compound of the present invention and a concomitant drug that have been produced separately simultaneously through the same administration route, (3) administering two preparations of the compound of the present invention and a concomitant drug that have been produced separately through the same administration route in a staggered manner, (4) administering two preparations of the compound of the present invention and a concomitant drug that have been produced separately simultaneously through different administration routes, (5) administering two preparations of the compound of the present invention and a concomitant drug that have been produced separately through different administration routes in a staggered manner (for example, administering in the order of the compound of the present invention and the concomitant drug or in the reverse order), etc.

[1245] The dosage of the concomitant drug can be appropriately determined based on the dosage used in clinical situations. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined depending on the administration subject, administration route, target disease, symptoms, combination, and the like.

[1246] For example, the content of the compound of the present invention in the combination varies depending on the form of the preparation and is generally about 0.01 to about 100 wt %, preferably about 0.1 to about 50 wt %, further preferably about 0.5 to about 20 wt % based on the entire preparation.

[1247] The content of the concomitant drug in the combination of the present invention varies depending on the form of the preparation and is usually about 0.01 to about 100 wt %, preferably about 0.1 to about 50 wt %, further preferably about 0.5 to about 20 wt % based on the entire preparation.

[1248] The content of additives such as carriers and the like in the combination of the present invention varies depending on the form of the preparation and is usually about 1 to about 99.99 wt %, preferably about 10 to about 90 wt %, based on the preparation.

[1249] Even when the compound of the present invention and the concomitant drug are formulated separately, similar contents can be used.

[1250] Examples of concomitant drugs include the following: therapeutic drugs for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), anti-obesity drugs (amphetamine, benzphetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, cyclohexetine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., , donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia agents (e.g., memantine), inhibitors of beta-amyloid production, secretion, accumulation, aggregation and / or deposition, beta-secretase inhibitors (e.g., 6-(4-biphenyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-Biphenyl)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 (WO01 / 00663)), γ-secretase inhibitors, β-amyloid aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 2001-500852), SKF-74652 (Biochem.J.(1999), 340(1), 283-289), amyloid-β vaccine, amyloid-β degrading enzyme, etc., brain function enhancers (e.g., aniracetam, nicergoline), therapeutic drugs for Parkinson's disease [(e.g., dopamine receptor agonists (e.g., levodopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline, rimaracetamide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], therapeutic drugs for amyotrophic lateral sclerosis (e.g., riluzole etc., neurotrophic factors), therapeutic drugs for abnormal behavior associated with dementia progression, wandering mind, etc. (e.g., sedatives, antianxiety drugs), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation-regeneration promoters (e.g., leteprinim, zaliroden; SR-57746-A), SB-216763, Y-128, VX-853, neurotrophic peptides, 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]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and optically active forms, salts or hydrates thereof), nonsteroidal anti-inflammatory agents (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), therapeutic agents for 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), therapeutic agents for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, therapeutic drugs for insomnia (e.g., benzodiazepines, Non-benzodiazepines drugs, melatonin agonists, orexin receptor antagonists), therapeutic drugs for schizophrenia (e.g., typical antipsychotics such as haloperidol, etc.; atypical antipsychotics such as clozapine, olanzapine, risperidone, aripiprazole, etc.; drugs acting on metabotropic glutamate receptors or ion channel-conjugated glutamate receptors; phosphodiesterase inhibitors), benzodiazepines drugs (chlordiazepoxide, diazepam, potassium chlorpheniramine, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-norepinephrine reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, septiline maleate, 5-HT 1A Agonists (buspirone hydrochloride, tandospirone citrate, omozotan hydrochloride, etc.), 5-HT 2A Antagonists, 5-HT 2A Inverse agonists, 5-HT3 antagonists (cyanomemazine, etc.), cardiac non-selective β inhibitors (propranolol hydrochloride, oxprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists, other antianxiety drugs (tranquilizers, etc.), tachykinin antagonists (MK-869, saredutan, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3 adrenergic antagonists (amiberon hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel inhibitors, carbonic anhydrase II inhibitors, NMDA glycine partial agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepines 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.), therapeutic drugs for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimo Naban, etc.), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), therapeutic drugs for alcoholism, therapeutic drugs for autism, therapeutic drugs for chronic fatigue syndrome, therapeutic drugs for spasticity, therapeutic drugs for fibromyalgia syndrome, therapeutic drugs for headaches, therapeutic drugs for smoking cessation, therapeutic drugs for myasthenia gravis, therapeutic drugs for cerebral infarction, therapeutic drugs for mania, Therapeutic drugs for excessive sleep, therapeutic drugs for pain, therapeutic drugs for dysthymia, therapeutic drugs for autonomic ataxia, therapeutic drugs for male and female sexual dysfunction, therapeutic drugs for migraine, therapeutic drugs for pathological gamblers, therapeutic drugs for restless legs syndrome, therapeutic drugs for substance addiction, therapeutic drugs for alcohol-related syndrome, therapeutic drugs for irritable bowel syndrome, therapeutic drugs for dyslipidemia such as cholesterol-lowering drugs (statins (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthetase inhibitors), therapeutic drugs for abnormal behavior or inhibitors of delusions due to dementia (sedatives, antianxiety drugs, etc.), therapeutic drugs for diabetes, therapeutic agents for diabetic complications, therapeutic drugs for hypertension, therapeutic drugs for hypotension, diuretics, chemotherapeutic agents, immunotherapeutic agents, antithrombotic agents, anticancer agents, etc.

[1251] Two or more of the above-mentioned concomitant drugs may be used in combination at an appropriate ratio.

[1252] When the compound of the present invention is applied to the above-mentioned various diseases, it can also be used in combination with biological preparations (for example, antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), or can be used in combination with gene therapy methods, or can also be used in combination with psychiatric treatments without the use of drugs.

[1253] Examples of antibody drugs and vaccine preparations include vaccine preparations for angiotensin II, vaccine preparations for CETP, CETP antibodies, antibodies to TNFα and antibodies to other cytokines, amyloid β vaccine preparations, vaccines for type 1 diabetes (e.g., Peptor's DIAPEP-277), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies or vaccine preparations for cytokines, renin-angiotensin type enzymes and their products, antibodies or vaccine preparations for enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in coagulation or fibrinolysis systems, antibodies or vaccine preparations for proteins involved in sugar metabolism and insulin resistance, etc. In addition, it can also be used in combination with biological preparations related to growth factors such as GH, IGF, etc.

[1254] Examples of gene therapy methods include therapy methods using genes related to cytokines, renin-angiotensin type enzymes and their products, G proteins, G protein-conjugated receptors and their phosphorylases, therapy methods using DNA baits such as NFκB baits, therapy methods using antisense, therapy methods using genes related to enzymes or proteins involved in blood lipid metabolism (for example, genes related to the metabolism, excretion and absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids), therapy methods using genes related to enzymes or proteins involved in angiogenesis therapy for peripheral vascular obstruction (for example, growth factors such as HGF, VEGF, etc.), therapy methods using genes related to proteins involved in glucose metabolism and insulin resistance, antisense against cytokines such as TNF, etc., etc.

[1255] Examples of treatment methods in the field of psychiatry without using drugs include modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, psychotherapy including cognitive behavioral therapy, and the like.

[1256] The compounds of the present invention can also 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-derived monocytes, bone marrow stem cells), or artificial organs using tissue engineering (e.g., artificial blood vessels, myocardial cell sheets).

[1257] Example

[1258] The present invention will be described in detail below with reference to Examples, Experimental Examples and Formulation Examples. However, the examples do not limit the present invention, and the examples can be modified within the scope of the present invention.

[1259] The “room temperature” in the following examples is generally about 10° C. to about 35° C. Unless otherwise specified, the ratio of the mixed solvents is a volume mixing ratio, and % means wt % unless otherwise specified.

[1260] Unless otherwise specified, elution by column chromatography in the Examples was performed under observation by TLC (thin layer chromatography). In the observation by TLC, 60F manufactured by Merck 254 The solvent used as the elution solvent for TLC plates and column chromatography was used as the eluent, and a UV detector was used for detection. In silica gel column chromatography, the NH designation indicates the use of aminopropylsilane-bonded silica gel, and the Diol designation indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography), the C18 designation indicates the use of octadecyl-bonded silica gel. Unless otherwise stated, the ratio of the elution solvents is a volume mixing ratio.

[1261] for 1 H NMR analysis uses ACD / SpecManager (trade name) software, etc. Peaks of hydroxyl groups, amino groups, etc., which have very mild proton peaks, may not be described.

[1262] MS is measured by LC / MS. As ionization method, ESI method or APCI method is used. The data indicate actual measured values ​​(measured values). Although molecular ion peaks are usually observed, fragment ions are sometimes observed. In the case of salt, molecular ion peaks or fragment ion peaks of free form are usually observed.

[1263] The optical rotation ([α]) of the sample concentration (c) D ) is in g / 100mL.

[1264] Elemental analysis values ​​(Anal.) are described as calculated values ​​(Calcd) and found values ​​(Found).

[1265] The retention times in the examples were measured by liquid chromatography. Unless otherwise specified, the measurement conditions were as follows.

[1266] Column: YMC PackPro C18 2.0mm idx 75mm (3μm)

[1267] 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.

[1268] The peaks obtained by powder X-ray diffraction in the examples are peaks measured at room temperature using Cu Kα radiation by Ultima IV (Rigaku Corporation, Japan), and the measurement conditions are as follows.

[1269] Voltage / current: 40kV / 50mA

[1270] Scanning speed: 6 degrees / minute

[1271] 2θ scanning range: 2-35 degrees

[1272] The crystallinity obtained by powder X-ray diffraction in the examples was calculated by the Hermans method.

[1273] In the following examples, the following abbreviations are used.

[1274] mp: melting point

[1275] MS: mass spectrometry

[1276] M: molar concentration

[1277] N: equivalent concentration

[1278] CDCl3: deuterated chloroform

[1279] DMSO-d6: deuterated dimethyl sulfoxide

[1280] 1 H NMR: proton nuclear magnetic resonance

[1281] LC / MS: Liquid Chromatography Mass Spectrometry

[1282] ESI: electrospray ionization

[1283] APCI: Atmospheric Pressure Chemical Ionization

[1284] Et2O: diethyl ether

[1285] DIPEA: diisopropylethylamine

[1286] IPE: diisopropyl ether

[1287] NBS: N-bromosuccinimide

[1288] CPME: Cyclopentyl methyl ether

[1289] DIAD: diisopropylethylamine

[1290] NMP: N-methyl-2-pyrrolidone

[1291] TFA: trifluoroacetic acid

[1292] THF: Tetrahydrofuran

[1293] DMSO: dimethyl sulfoxide

[1294] DMA: N,N-dimethylacetamide

[1295] DME: 1,2-dimethoxyethane

[1296] DMF: N,N-dimethylformamide

[1297] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[1298] TEA: triethylamine

[1299] DPPA: diphenylphosphoryl azide

[1300] MeOH: methanol

[1301] EtOH: ethanol

[1302] IPA: 2-propanol

[1303] EtOAc: ethyl acetate

[1304] CH2Cl2: dichloromethane

[1305] t-BuOH: tert-butyl alcohol

[1306] DAST: (diethylamino)sulfur trifluoride

[1307] NCS: N-chlorosuccinimide

[1308] Pd(Ph3P)4:Tetrakis(triphenylphosphine)palladium(0)

[1309] Pd(OAc)2: Palladium(II) acetate

[1310] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[1311] Pd(dppf)Cl2·CH2Cl2:[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct

[1312] SFC: Supercritical fluid chromatography

[1313] Example 8

[1314] 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

[1315] A) tert-Butyl (3S)-3-[(ethylsulfonyl)amino]pyrrolidine-1-carboxylate

[1316] At room temperature to (S) -3- aminopyrrolidine -1- tert-butyl formate (1.00g) and triethylamine (2.10mL) in THF (22mL) in solution of ethylsulfonyl chloride (0.712mL) is added dropwise. The mixture is stirred at room temperature overnight. Insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. Residue is passed through silica gel column chromatography (EtOAc / hexane) purification to obtain title compound (1.28g).

[1317] 1 H NMR(300MHz,DMSO-d6)δ1.18(3H,t,J=7.4Hz),1.39(9H,s),1.70-1.84(1H,m),1.98-2.0 9(1H,m),3.00-3.25(4H,m),3.33-3.39(1H,m),3.46(1H,dd,J=10.9,6.5Hz),3.83(1H,br s), 7.38 (1H, d, J = 6.3Hz).

[1318] B) N-[(3S)-Pyrrolidin-3-yl]ethanesulfonamide hydrochloride

[1319] A mixture of tert-butyl (3S)-3-[(ethylsulfonyl)amino]pyrrolidine-1-carboxylate (2.84 g) and 4 M hydrogen chloride in EtOAc (12.8 mL) was stirred at room temperature overnight. Heptane was added to the resulting suspension 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).

[1320] 1 H NMR(300MHz,DMSO-d6)δ1.20(3H,t,J=7.3Hz),1.87(1H,dq,J=13.5,6.7Hz),2.04-2.22 (1H,m),2.92-3.35(6H,m),3.99(1H,sxt,J=6.2Hz),7.56(1H,d,J=6.4Hz),9.31(2H,br s).

[1321] C) 3-Bromo-5-(2-bromo-4-methylphenyl)-4,5-dihydro-1,2-oxazole

[1322] At room temperature, sodium bicarbonate (128mg) is added to a mixture of 2-bromo-4-methyl-1-vinylbenzene (150mg) and dibromo-hydroxycarbonimidic dibromide (232mg) in EtOAc (3.05mL). The mixture is stirred at 70°C for 7 hours. The precipitation is removed by filtration and the filtrate is concentrated under reduced pressure. Residue is passed through silica gel column chromatography (EtOAc / hexane) purification to obtain title compound (216mg).

[1323] 1 H NMR (400MHz, CDCl3) δ2.34 (3H, s), 3.03 (1H, dd, J = 17.4, 7.6Hz), 3.80 (1H, dd, J = 17. 4, 11.0Hz), 5.89 (1H, dd, J = 11.0, 7.7Hz), 7.16 (1H, d, J = 7.8Hz), 7.32-7.51 (2H, m).

[1324] D) N-{(3S)-1-[5-(2-bromo-4-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]pyrrolidin-3-yl}ethanesulfonamide

[1325] 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).

[1326] MS:[M+H] + 416.0.

[1327] 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

[1328] Tri-tert-butylphosphonium tetrafluoroborate (4.32 mg) and Pd2(dba)3(4.28 mg) are 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)boric acid (47.0 mg), potassium fluoride (17.3 mg) in THF (1.24 mL) and water (0.248 mL). The mixture is stirred at 140 ° C for 1 hour under microwave irradiation. The crude material is purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile). The desired fraction is then concentrated to give the title compound (13.0 mg).

[1329] 1 H NMR (400MHz, DMSO-d6) δ1.18 (3H, td, J = 7.3, 1.1Hz), 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. 5Hz),3.81-3.92(1H,m),5.03(1H,t,J=9.3Hz),7.07(1H,s),7.23(2H,td,J= 8.6, 2.6Hz), 7.32 (1H, d, J = 7.8Hz), 7.39 (1H, d, J = 5.0Hz), 7.47-7.60 (2H, m).

[1330] Example 11

[1331] 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

[1332] A) 5-Methyl-3-(2,4,6-trifluorophenyl)pyridin-2-amine

[1333] At room temperature, 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)boric acid (9.87 g) and potassium fluoride (4.35 g) in THF (104 mL) and water (20.8 mL). 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 an NH silica gel pad and concentrated under reduced pressure. The solid was ground with IPE to obtain the title compound (9.15 g).

[1334] MS:[M+H] + 239.0.

[1335] B) 2-Chloro-5-methyl-3-(2,4,6-trifluorophenyl)pyridine

[1336] At -10 ° C, a solution of sodium nitrite (7.95g) in water (5mL) is added dropwise to a solution of 5-methyl-3-(2,4,6-trifluorophenyl) pyridine-2-amine (9.15g) in concentrated aqueous hydrogen chloride solution (80mL). The mixture is stirred at -10 ° C for 10 minutes. Copper chloride (I) (22.8g) is added to the mixture in batches at -10 ° C. The mixture is stirred at room temperature overnight. The mixture is diluted with EtOAc and water, and the resulting mixture is extracted with EtOAc. The organic layer is separated, washed with salt water and water, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (5.50g).

[1337] MS:[M+H] + 257.9.

[1338] C) 2-vinyl-5-methyl-3-(2,4,6-trifluorophenyl)pyridine

[1339] At room temperature, 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 vinyl trifluoroborate (475 mg), potassium carbonate (429 mg) in DME (8.63 mL) and water (1.73 mL). The mixture was stirred at 110 ° C for 2 hours under an argon atmosphere under microwave irradiation. 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).

[1340] MS:[M+H] + 250.0.

[1341] D) 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-methyl-3-(2,4,6-trifluorophenyl)pyridine

[1342] At room temperature, sodium bicarbonate (241mg) is added to a mixture of 2-vinyl-5-methyl-3-(2,4,6-trifluorophenyl)pyridine (358mg) and dibrominated hydroxycarbonimide (437mg) in EtOAc (5.75mL). The mixture is stirred overnight at 75 ° C. The precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is passed through silica gel column chromatography (EtOAc / hexane) to obtain the title compound (293mg).

[1343] MS:[M+H] + 371.0.

[1344] E) 2-[(5S)-3-Bromo-4,5-dihydro-1,2-oxazol-5-yl]-5-methyl-3-(2,4,6-trifluorophenyl)pyridine

[1345] 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 (4.3 g) with a shorter retention time.

[1346] Chiral separation conditions

[1347] Column: CHIRALPAK IC (trade name) (250 mm*50 mm, 10 μm)

[1348] Mobile phase: CO2 / IPA (containing 0.1% ammonium hydroxide) = 750 / 250 (v / v)

[1349] MS:[M+H] + 371.0.

[1350] 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

[1351] 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).

[1352] 1 H NMR (400MHz, CDCl3) δ2.40(3H,s),3.08(3H,s),3.15(1H,dd,J=15.7,9.9Hz),3.24-3.32(1H,m),3.66-4.03(4H,m),4.33(1H,dquin,J=1 4.0, 8.9Hz), 4.84 (1H, d, J = 9.8Hz), 5.49 (1H, t, J = 9.1Hz), 6.78 (2H, dtt, J = 17.3, 8.8, 2.3Hz), 7.40-7.42 (1H, m), 8.53 (1H, d, J = 1.8Hz).

[1353] Example 12

[1354] 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

[1355] A) 2-Bromo-1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1H-imidazole

[1356] 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 of positional isomers.

[1357] MS:[M+H] + 317.9.

[1358] B) 4-(2-Bromo-4-methyl-1H-imidazol-1-yl)-3,5-difluoroaniline

[1359] At room temperature, iron (1.23 g) is added to a solution of 2-bromo-1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1H-imidazole (1.40 g, including positional isomers) and 1M aqueous hydrogen chloride solution (2 mL) in EtOH (15 mL). The mixture is stirred at 80 ° C for 1 hour. The precipitate is removed by Celite (trade name). The filtrate is concentrated under reduced pressure. The residue is dissolved in EtOAc and aqueous sodium bicarbonate solution, and the mixture is extracted with EtOAc. The organic layer is separated, washed with brine and water, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (1.12 g).

[1360] MS:[M+H] + 287.9.

[1361] C) 2-Bromo-1-(2,6-difluorophenyl)-4-methyl-1H-imidazole

[1362] At 0 ° C, 4- (2- bromo -4- methyl -1H- imidazole -1- bases) -3,5- difluoroaniline (1.12 g) was added in batches to a solution of n-amyl nitrite (1.03 mL) in THF (38.9 mL). The mixture was stirred at 0 ° C for 15 minutes. Then hypophosphoric 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 sodium bicarbonate aqueous solution, 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).

[1363] 1 H NMR (400MHz, CDCl3) δ2.28 (3H, s), 6.80 (1H, s), 7.09 (2H, t, J = 8.3Hz), 7.46 (1H, quin, J = 7.3Hz).

[1364] D) 1-(2,6-difluorophenyl)-4-methyl-2-(prop-1-en-2-yl)-1H-imidazole

[1365] At room temperature, 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-ene-2-yl) -1,3,2-dioxaborolane (191 mg), potassium carbonate (235 mg) in DME (4 mL) and water (0.800 mL). The mixture was stirred at 110 ° C for 2 hours under an argon atmosphere under microwave irradiation. 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).

[1366] MS:[M+H] + 235.0.

[1367] E) 3-Bromo-5-[1-(2,6-difluorophenyl)-4-methyl-1H-imidazol-2-yl]-5-methyl-4,5-dihydro-1,2-oxazole

[1368] At room temperature, sodium bicarbonate (134 mg) was added to a solution of 1-(2,6-difluorophenyl)-4-methyl-2-(prop-1-ene-2-yl)-1H-imidazole (125 mg) and dibromide hydroxycarbonimide (216 mg) in EtOAc (3 mL). 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).

[1369] MS:[M+H] + 355.9.

[1370] 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

[1371] 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).

[1372] 1 H NMR (300MHz, DMSO-d6) δ1.49(3H,d,J=2.3Hz),2.12(3H,d,J=0.8Hz),2.99(3H,d,J=0.6Hz),3.03-3.26(2H,m),3.43-3.91 (4H,m),4.07-4.48(1H,m),6.97(1H,dd,J=1.7,1.1Hz),7.18-7.37(2H,m),7.47-7.72(1H,m),7.95(1H,dd,J=9.1,4.1Hz).

[1373] Example 20

[1374] N-[(1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutyl]methanesulfonamide

[1375] A) 2-Chloro-3-(2,6-difluorophenyl)-5-methylpyridine

[1376] At room temperature, tri-tert-butylphosphonium tetrafluoroborate (0.703g) and Pd2(dba)3(1.11g) are added to a mixture of 3-bromo-2-chloro-5-methylpyridine (5.00g), (2,6-difluorophenyl)boric acid (4.97g) and potassium fluoride (2.81g) in THF (67.3mL) and water (13.5mL). The mixture is stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture is poured into salt water and the resulting mixture is extracted with EtOAc. The organic layer is separated, washed with salt water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by NH silica gel column chromatography (EtOAc / hexane) to obtain the title compound (5.55g).

[1377] MS:[M+H] + 239.9.

[1378] B) 3-(2,6-Difluorophenyl)-2-vinyl-5-methylpyridine

[1379] At room temperature, 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 vinyl trifluoroborate (1.35 g), potassium carbonate (1.27 g) in DME (17 mL) and water (3 mL). The mixture was stirred at 110 ° C for 3.5 hours under an argon atmosphere under microwave irradiation. 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).

[1380] MS:[M+H] + 232.0.

[1381] C) 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-methylpyridine

[1382] At room temperature, sodium bicarbonate (7.34g) is added to a mixture of 3-(2,6-difluorophenyl)-2-vinyl-5-methylpyridine (5.05g) and dibrominated hydroxycarbonimide (8.86g) in EtOAc (87mL). The mixture is stirred overnight at 70°C. The precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (6.37g).

[1383] 1 H NMR(400MHz, CDCl3) δ2.41(3H,s),3.41(1H,dd,J=17.1,11.0Hz),3.89(1H,dd,J=17.1, 9.0Hz),5.55-5.71(1H,m),6.95-7.09(2H,m),7.30-7.48(2H,m),8.57(1H,d,J=1.8Hz).

[1384] 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

[1385] At room temperature, sodium hydride (60% in oil, 6.80 mg) was added to a solution of tert-butyl ((1s, 3s)-3-hydroxycyclobutyl)carbamate (31.8 mg) in THF (0.5 mL). 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).

[1386] MS:[M+H] + 460.1.

[1387] E)(1s,3s)-3-({5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}oxy)cyclobutane-1-amine trifluoroacetic acid

[1388] 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 obtain the title compound (30.3 mg).

[1389] MS:[M+H-(TFA)] + 360.1.

[1390] 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

[1391] To a cooled (0°C) mixture of (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 (30.3 mg) and TEA (0.089 mL) in THF (1 mL) was added methanesulfonic anhydride (14.5 mg), and the mixture was stirred at room temperature for 1 hour. After the resulting mixture was concentrated, the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (23.5 mg).

[1392] 1 H NMR (400MHz, CDCl3) δ2.06-2.15(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=8.8Hz), 4.60(1H,t,J=7.0Hz), 5.52(1H,t,J=9.7Hz), 6.95-7.05(2H,m), 7.34-7.44(2H,m), 8.56(1H,d,J=1.8Hz).

[1393] Example 22

[1394] 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

[1395] A) 2-[(5S)-3-Bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine

[1396] 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-methylpyridine (253 mg) was optically resolved by HPLC, and fractions with shorter retention time were concentrated under reduced pressure to obtain the title compound (111 mg).

[1397] Chiral separation conditions

[1398] Column: CHIRALPAK IH (trade name) (20 mm ID*250 mm L, 5 μm)

[1399] Mobile phase: Hexane / IPA = 800 / 200 (v / v)

[1400] MS (found): 353.1, 355.1.

[1401] 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

[1402] A mixture of 2-[(5S)-3-bromo-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (50.0 mg) and N-[(3R)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride (71.0 mg) in pyridine (0.354 mL) was stirred at 140 ° C. for 15 hours in a sealed tube. 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).

[1403] 1H NMR (400MHz, CDCl3) δ1.42(3H,t,J=7.3Hz),2.40(3H,s),3.09-3.21(3H,m),3.27(1H,t,J=9.6Hz),3.69-3.86(3H,m),3.91(1H,dd,J=9. 9,7.9Hz),4.11-4.41(1H,m),4.66(1H,d,J=9.5Hz),5.51(1H,t,J=9.0Hz),6.76-7.11(2H,m),7.29-7.47(2H,m),8.54(1H,d,J=2.0Hz).

[1404] Example 23

[1405] 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

[1406] 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

[1407] 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. At room temperature, TEA (0.380 mL) was added to a mixture of 5-methyl-3-(2,4,6-trifluorophenyl)-2-vinylpyridine (200 mg) and 339 mg of the residue in THF (2 mL). 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).

[1408] MS:[M+H] + 462.1.

[1409] 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

[1410] A mixture of [(1s, 3s)-3-{5-[5-methyl-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-3-yl}cyclobutyl] tert-butyl carbamate (355 mg) in TFA (1 mL) was stirred at room temperature for 20 minutes. The mixture was concentrated under reduced pressure. Methanesulfonyl chloride (132 mg) was added to a solution of the residue and TEA (0.537 mL) in THF (2 mL). The mixture was stirred at 0 ° C for 10 minutes. TEA (0.3 mL) and methanesulfonyl chloride (30.0 mg) were then 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).

[1411] 1 H NMR (300MHz, CDCl3) δ2.14-2.28(2H,m),2.39(3H,s),2.63-2.78(2H,m),2.81-2.96(4H,m),3.10(1H,dd,J=16.8,10.7Hz),3.53(1H,dd,J=16.9 ,7.9Hz),3.96(1H,sxt,J=8.2Hz),4.84-5.04(1H,m),5.45(1H,dd,J=10 .2,8.7Hz),6.64-6.90(2H,m),7.34-7.45(1H,m),8.52(1H,d,J=2.3Hz).

[1412] Example 30

[1413] 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

[1414] A) tert-Butyl (3S)-3-[(tert-Butoxycarbonyl)(1-fluorocyclopropane-1-sulfonyl)amino]pyrrolidine-1-carboxylate

[1415] At 0 ° C, 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), 1.9 M DIAD in toluene (2.63 mL) was added. The mixture was stirred at room temperature overnight. At room temperature, the mixture was diluted with EtOAc and poured into water. 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 obtain the title compound (587 mg).

[1416] 1 H NMR(300MHz,DMSO-d6)δ1.39(9H,s),1.48(9H,s),1.61-1.83(4H,m),2.07-2.19(1 H,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).

[1417] B) 1-Fluoro-N-[(3S)-pyrrolidin-3-yl]cyclopropane-1-sulfonamide hydrochloride

[1418] Tert-butyl (3S)-3-[(tert-butyloxycarbonyl)(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).

[1419] 1 H NMR(300MHz,DMSO-d6)δ1.34-1.62(4H,m),1.89(1H,td,J=13.6,7.2Hz),2.18(1H,dq,J=13.6,7.0Hz),3.01(1H,d d,J=12.0,6.0Hz),3.13-3.30(2H,m),3.35-3.46(1H,m),4.15(1H,quin,J=6.4Hz),8.26-8.72(1H,m),9.10(2H,br s).

[1420] 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

[1421] 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).

[1422] 1 H NMR(300MHz,DMSO-d6)δ1.40-1.58(4H,m),1.82-1.93(1H,m),2.09-2.19(1H,m),2.36( 3H,s),3.09(1H,dd,J=10.4,5.5Hz),3.17-3.28(3H,m),3.45(1H,dd,J=10.4,6.6Hz),3. 70(1H,dd,J=15.6,8.8Hz),4.03-4.09(1H,m),5.21(1H,t,J=9.2Hz),7.19-7.29(2H,m) ,7.49-7.60(1H,m),7.62(1H,d,J=1.9Hz),8.33(1H,d,J=7.9Hz),8.54(1H,d,J=1.9Hz).

[1423] Example 39

[1424] 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)

[1425] A) tert-Butyl [6-chloro-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate

[1426] At room temperature, tri-tert-butyl phosphonium tetrafluoroborate (0.755g) and Pd(dba) (0.794g) are added to a mixture of (5-bromo-6-chloropyridin-3-yl) tert-butyl carbamate (5.34g), (2,4,6-trifluorophenyl) boric acid (3.66g) and potassium fluoride (2.02g) in THF (55mL) and water (11mL). The mixture is stirred at 80 DEG C for 2 hours under a nitrogen atmosphere. The mixture is poured into water and the resulting mixture is extracted with EtOAc. The organic layer is separated, washed with salt water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Residue is purified by NH silica gel column chromatography (EtOAc / hexane) to obtain title compound (5.58g).

[1427] 1 H NMR (300MHz, CDCl3) δ1.52 (9H, s), 6.59 (1H, br s), 6.78 (2H, dd, J = 8.7, 7.3Hz), 8.09 (1H, br s), 8.27 (1H, d, J = 2.8Hz).

[1428] B) tert-Butyl [6-vinyl-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate

[1429] At room temperature, 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 vinyl trifluoroborate (532 mg), potassium carbonate (749 mg) in DME (10 mL) and water (2.00 mL). The mixture was stirred at 110 ° C for 3.5 hours under an argon atmosphere under microwave irradiation. 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).

[1430] MS:[M+H] + 351.0.

[1431] C) tert-Butyl [6-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-(2,4,6-trifluorophenyl)pyridin-3-yl]carbamate

[1432] At room temperature, sodium bicarbonate (489mg) is added to a mixture of [6-vinyl-5-(2,4,6-trifluorophenyl)pyridin-3-yl] tert-butyl carbamate (510mg) and dibrominated hydroxycarbonimide (591mg) in EtOAc (6.0mL). The mixture is stirred overnight at 70°C. The precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (577mg).

[1433] MS:[M+H] + 472.0.

[1434] D) 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,4,6-trifluorophenyl)pyridine

[1435] At 0 ° C, 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. The mixture was stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in concentrated hydrochloric acid (5 mL). At 0 ° C, sodium nitrite (253 mg) in water (1 mL) was added dropwise to the mixture. The mixture was stirred at 0 ° C for 10 minutes. Copper (I) chloride (726 mg) was added in batches. The mixture was stirred at 0 ° C for 1 hour. EtOAca 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 obtain the title compound (270 mg).

[1436] MS:[M+H] + 390.9.

[1437] 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

[1438] A mixture of 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,4,6-trifluorophenyl)pyridine (100 mg) and 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).

[1439] 1 H NMR (400MHz, CDCl3) δ3.09(3H,s),3.12-3.41(2H,m),3.69-3.95(4H,m),4.34(1H,dtd,J=13.3,8.9,4.3H z),4.80-4.95(1H,m),5.49(1H,t,J=8.8Hz),6.63-7.05(2H,m),7.62(1H,d,J=2.3Hz),8.53-8.79(1H,m).

[1440] 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)

[1441] 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. Fractions with a longer retention time were concentrated under reduced pressure to obtain the title compound (40.2 mg).

[1442] Chiral separation conditions

[1443] Column: CHIRALPAK IB-N5 (trade name) (20 mm ID*250 mm L, 5 μm)

[1444] Mobile phase: Hexane / EtOH = 600 / 400 (v / v)

[1445] 1 H NMR(300MHz, CDCl3)δ3.09(3H,s),3.14-3.39(2H,m),3.64-3.98(4H,m),4.34(1H,dt,J=13.8,8.9Hz),4 .75(1H,d,J=9.8Hz), 5.50(1H,t,J=8.8Hz), 6.72-6.87(2H,m), 7.59-7.64(1H,m), 8.65(1H,d,J=2.3Hz).

[1446] Example 42

[1447] 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)

[1448] A) tert-Butyl (4R)-4-[(ethylsulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate

[1449] To a solution of (R)-4-amino-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (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. At 0 ° C, the mixture was diluted with EtOAc and poured into a saturated aqueous sodium bicarbonate solution. 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).

[1450] 1 H NMR(300MHz, CDCl3)δ1.42(3H,t,J=7.3Hz),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=9.8Hz).

[1451] B) N-[(3R)-4,4-Difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride

[1452] At room temperature, to a solution of (4R)-4-[(ethylsulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (708 mg) in EtOAc (5.0 mL) was added 4M hydrogen chloride in EtOAc (10 mL). 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).

[1453] 1 H NMR (300MHz, DMSO-d6) δ1.15-1.30(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=9.0Hz),9.15-9.77(2H,m).

[1454] 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

[1455] A mixture of 2-(3-bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,4,6-trifluorophenyl)pyridine (100 mg) and 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).

[1456] 1 H NMR(400MHz, CDCl3)δ1.42(3H,t,J=7.3Hz),2.97-3.44(4H,m),3.63-3.99(4H,m),4.22-4.44(1H,m),4.70(1 H,t,J=10.6Hz),5.49(1H,t,J=8.7Hz),6.57-6.93(2H,m),7.62(1H,d,J=2.2Hz),8.64(1H,dd,J=2.2,1.5Hz).

[1457] 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)

[1458] 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 longer-retaining fraction was concentrated under reduced pressure. The residue was washed with IPE to obtain the title compound (38.7 mg).

[1459] Chiral separation conditions

[1460] Column: CHIRALPAK IB-N5 (trade name) (20 mm ID*250 mm L, 5 μm)

[1461] Mobile phase: hexane / ethanol = 700 / 300 (v / v)

[1462] 1H NMR(300MHz, CDCl3)δ1.42(3H,t,J=7.3Hz),3.04-3.35(4H,m),3.64-4.00(4H,m),4.21-4.42(1H,m),4. 63(1H,d,J=10.2Hz), 5.49(1H,t,J=8.7Hz), 6.70-6.88(2H,m), 7.58-7.64(1H,m), 8.65(1H,d,J=2.3Hz).

[1463] Example 49

[1464] 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)

[1465] A) 5-Chloro-3-(2,6-difluorophenyl)pyridin-2-amine

[1466] A mixture of 3-bromo-5-chloro-pyridin-2-amine (15.0 g), (2,6-difluorophenyl) boronic acid (14.8 g), Pd2(dba)3(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 layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (17.0 g).

[1467] 1 H NMR (400MHz, DMSO-d6) δ5.98(2H,s),7.16-7.24(2H,m),7.46-7.57(2H,m),8.03(1H,d,J=2.4Hz).

[1468] B) 5-Chloro-3-(2,6-difluorophenyl)-2-iodopyridine

[1469] At room temperature, n-amyl nitrite (8.28g) is added to a mixture of 5-chloro-3-(2,6-difluorophenyl)pyridine-2-amine (8.50g), diiodomethane (37.8g) and copper (I) iodide (10.1g) in THF (90mL). The mixture is stirred at 70 DEG C for 5 hours. Solids are removed by filtration, and the filtrate is concentrated in vacuo. Residue is purified by silica gel column chromatography (EtOAc / petroleum ether) to obtain title compound (6.70g).

[1470] 1 H NMR (400MHz, DMSO-d6) δ7.26-7.32(2H,m), 7.60-7.69(1H,m), 8.10(1H,d,J=2.4Hz), 8.58(1H,d,J=2.4Hz).

[1471] C) 5-Chloro-3-(2,6-difluorophenyl)-2-vinylpyridine

[1472] To a mixture of 5-chloro-3-(2,6-difluorophenyl)-2-iodopyridine (6.70 g), potassium vinyl trifluoroborate (5.11 g) and potassium carbonate (5.27 g) in DME (100 mL) and water (20 mL) was added Pd(dppf)Cl2·CH2Cl2 (2.33 g). The mixture was stirred at 100 ° C for 14 hours 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 (3.20 g).

[1473] 1 H NMR(400MHz,DMSO-d6)δ5.46-5.51(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=2.4Hz),8.73(1H,d,J=2.4Hz).

[1474] D) 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine

[1475] To a solution of dibromohydroxycarbonimide (11.1 g) and 5-chloro-3-(2,6-difluorophenyl)-2-vinylpyridine (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 obtain the title compound (8.50 g).

[1476] 1H NMR (400MHz, DMSO-d6) δ3.62-3.75(2H,m),5.48-5.55(1H,m),7.30(2H,q,J=9.2Hz),7.58-7.67(1H,m),8.17(1H,d,J=2.4Hz),8.84(1H,d,J=2.4Hz).

[1477] E) 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine (optical isomer)

[1478] 2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-(2,6-difluorophenyl)pyridine (8.50 g) was optically resolved by SFC. The fractions with a longer retention time were concentrated under reduced pressure to give the title compound (4.02 g).

[1479] Chiral separation conditions

[1480] Column: CHIRALPAK AY (trade name) (250 mm*50 mm, 10 μm)

[1481] Mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide) = 850 / 150 (v / v)

[1482] 1 H NMR (400MHz, DMSO-d6) δ3.66-3.72(2H,m),5.48-5.54(1H,m),7.30(2H,q,J=9.2Hz),7.58-7.67(1H,m),8.17(1H,d,J=2.4Hz),8.84(1H,d,J=2.4Hz).

[1483] 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)

[1484] 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

[1485] g) in pyridine (9 mL) was stirred in a sealed tube at 140 ° C overnight. 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 solution 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).

[1486] 1 H NMR(300MHz,DMSO-d6)δ2.99(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=9.0Hz),7.23-7.32(2H,m),7.55-7.66(1H,m),7.98(1H,s),8.12(1H,d,J=2.1Hz),8.80(1H,d,J=2.4Hz).

[1487] Example 50

[1488] N-[(3S)-1-{5-[2-(3,5-difluoropyridin-2-yl)-4-methylphenyl]-4,5-dihydro-1,2-oxazol-3-yl}pyrrolidin-3-yl]methanesulfonamide

[1489] A) 2-(2-chloro-5-methylphenyl)-3,5-difluoropyridine

[1490] A mixture of (2-chloro-5-methylphenyl)boronic acid (527 mg), 2-bromo-3,5-difluoropyridine (500 mg), Pd(Ph3P)4 (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).

[1491] MS:[M+H] + 239.9.

[1492] B) 2-(2-vinyl-5-methylphenyl)-3,5-difluoropyridine

[1493] 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), Pd2(dba)3(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 hours 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).

[1494] MS:[M+H] + 231.9.

[1495] C) 2-[2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-methylphenyl]-3,5-difluoropyridine

[1496] A mixture of 2-(2-vinyl-5-methylphenyl)-3,5-difluoropyridine (500 mg), dibromide hydroxycarbonimide (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 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 (617 mg).

[1497] MS:[M+H] + 352.9.

[1498] 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

[1499] 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 fractions were collected and 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).

[1500] 1 H NMR(300MHz,DMSO-d6)δ1.73-1.90(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 = 7.9Hz), 8.08 (1H, td, J = 9.4, 2.5Hz), 8.61 (1H, d, J = 2.4Hz).

[1501] Example 59

[1502] 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)

[1503] A) 2-[3-(2,6-Difluorophenyl)-5-methylpyridin-2-yl]prop-2-en-1-ol

[1504] At room temperature, 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). The mixture was stirred at 110 ° C for 3 hours under an argon atmosphere under microwave irradiation. 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).

[1505] MS:[M+H] + 262.0.

[1506] B) {3-Bromo-5-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol

[1507] At room temperature, sodium bicarbonate (3.01g) is added to a mixture of 2-[3-(2,6-difluorophenyl)-5-methylpyridin-2-yl]prop-2-ene-1-ol (2.34g) and dibrominated hydroxycarbonimide (3.63g) in EtOAc (35.8mL). The mixture is stirred at 70°C overnight. The precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (2.14g).

[1508] MS:[M+H] + 382.9.

[1509] C) 2-[3-Bromo-5-(difluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine

[1510] At -78 ° C, oxalyl chloride (0.110 mL) was added to a solution of DMSO (0.119 mL) in THF (4.18 mL). 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 at -78 ° C to room temperature for 30 minutes. The mixture was quenched with saturated sodium bicarbonate aqueous solution, 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. At 0 ℃, DAST (0.089mL) is added to the solution of residue in CH 2 Cl 2 (4mL).The mixture is gradually warmed to room temperature and stirred at room temperature over the weekend under a nitrogen atmosphere.The mixture is quenched with water at room temperature and extracted with EtOAc.The organic layer is separated, washed with salt water, dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue is purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (76mg).

[1511] MS:[M+H] + 402.9.

[1512] 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

[1513] A mixture of 2-[3-bromo-5-(difluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-methylpyridine (76 mg) and 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).

[1514] 1 H NMR (300MHz, CDCl3) δ2.39(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, 8.8Hz), 4.76 (1H, dd, J = 9.8, 3.4Hz), 5.68-6.32 (1H, m), 6.84-7.11 (2H, m), 7.30-7.43 (2H, m), 8.48 (1H, s).

[1515] 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)

[1516] 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. Fractions with a shorter retention time were concentrated under reduced pressure to obtain the title compound (17.8 mg).

[1517] Chiral separation conditions

[1518] Column: CHIRALPAK IG (trade name) (20 mm ID * 250 mm L, 5 μm)

[1519] Mobile phase: Hexane / EtOH = 500 / 500 (v / v)

[1520] 1H NMR (300MHz, CDCl3) δ2.39(3H,s),3.07(3H,s),3.20(1H,t,J=9.4Hz),3.52(1H,d,J=16.9Hz),3.64(2H,dd,J=19.0,8.5Hz),3.82(1H,dd,J=10.7, 7.7Hz),3.90-4.02(1H,m),4.25-4.42(1H,m),4.72(1H,d,J=10.5Hz),5. 87-6.31(1H,m),6.91-7.06(2H,m),7.34-7.42(2H,m),8.46-8.52(1H,m).

[1521] Example 64

[1522] 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

[1523] A) Benzyl 3-[(tert-Butoxycarbonyl)amino]-4,4-difluoro-3-methylpyrrolidine-1-carboxylate

[1524] To a solution of 1-((benzyloxy)carbonyl)-4,4-difluoro-3-methylpyrrolidine-3-carboxylic acid (161 mg) in t-BuOH (2 mL) was added TEA (0.150 mL) and DPPA (0.175 mL) 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).

[1525] MS:[M+Na] + 393.1.

[1526] B) Benzyl 3,3-difluoro-4-[(methylsulfonyl)amino]-4-methylpyrrolidine-1-carboxylate

[1527] A mixture of 3-[(tert-butoxycarbonyl)amino]-4,4-difluoro-3-methylpyrrolidine-1-formic acid benzyl ester (130 mg) and 4M hydrogen chloride in CPME (1 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was merged 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).

[1528] MS:[M+Na] + 371.0.

[1529] C) N-(4,4-Difluoro-3-methylpyrrolidin-3-yl)methanesulfonamide

[1530] Under a hydrogen atmosphere, a mixture of 3,3-difluoro-4-[(methylsulfonyl)amino]-4-methylpyrrolidine-1-carboxylic acid benzyl ester (45.6 mg), 10% palladium on carbon (10 mg) and MeOH (1 mL) was stirred at room temperature overnight. The catalyst was filtered off 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 at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (26.5 mg).

[1531] 1 H NMR (300MHz, CDCl3) δ1.56 (3H,d,J=3.0Hz), 3.12 (3H,s), 3.15-3.51 (4H,m).

[1532] 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

[1533] 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 overnight at 140° C. in a sealed tube. The mixture 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 (6.8 mg).

[1534] 1 H NMR (300MHz, DMSO-d6) δ1.51(3H,s),2.36(3H,s),3.03(3H,d,J=1.9Hz),3.22-3.31(1H,m),3.41-3.51(1H ,m),3.59-3.84(4H,m),5.27(1H,t,J=9.6Hz),7.28-7.44(2H,m),7.54-8.02(2H,m),8.54(1H,d,J=1.8Hz).

[1535] Example 72

[1536] 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

[1537] A) 2-Methoxy-4-(2,4,6-trifluorophenyl)pyridine

[1538] To a solution of 4-bromo-2-methoxypyridine (1.59 g) and (2,4,6-trifluorophenyl)boric acid (2.97 g) in DME (20 mL) and water (10.0 mL) was added potassium fluoride (1.47 g), Pd2(dba)3 (0.581 g) and tri-tert-butylphosphonium tetrafluoroborate (0.491 g), and the reaction mixture was stirred at 100 ° C for 1 hour 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).

[1539] MS:[M+H] + 240.0.

[1540] B) 5-Bromo-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine

[1541] To a solution of 2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (900mg) in DMF (20mL) was added NBS (1.01g), and the reaction mixture was stirred at 100°C for 3 hours. After cooling to room temperature, the mixture was quenched with water and 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 (300mg).

[1542] MS:[M+H] + 317.9.

[1543] C) 5-vinyl-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine

[1544] A mixture of 5-bromo-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (300 mg), potassium trifluoroborate (253 mg), potassium carbonate (261 mg) and Pd(dppf)Cl2.CH2Cl2 (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 trifluoroborate (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).

[1545] MS:[M+H] + 265.9.

[1546] D) 5-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine

[1547] To a solution of 5-vinyl-2-methoxy-4-(2,4,6-trifluorophenyl)pyridine (220 mg) and dibrominated hydroxycarbonimide (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 obtain the title compound (226 mg).

[1548] 1 H NMR(300MHz,DMSO-d6)δ3.24(1H,dd,J=17.5,9.6Hz),3.59(1H,dd,J=17.5,11.5Hz),3 .91(3H,s),5.49(1H,t,J=10.4Hz),6.77-7.01(1H,m),7.27-7.49(2H,m),8.38(1H,s).

[1549] 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

[1550] 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) was added DIPEA (0.226 mL), and the reaction mixture was stirred in a sealed tube at 130° C. for 24 hours. The crude material was then purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile), the desired fractions were concentrated, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (11 mg).

[1551] 1 H NMR (300MHz, CDCl3) δ2.78-2.98(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).

[1552] Example 73

[1553] 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)

[1554] A) Benzyl 3-[(methylsulfonyl)amino]-3-(methoxymethyl)pyrrolidine-1-carboxylate

[1555] A mixture of 3-((tert-butoxycarbonyl)amino)-3-(methoxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (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 a saturated aqueous sodium bicarbonate solution 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).

[1556] MS:[M+H] + 365.0.

[1557] 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

[1558] Under hydrogen atmosphere, a mixture of 3- [(methylsulfonyl) amino] -3- (methoxymethyl) pyrrolidine -1- benzyl formate (1.61g) and 10% palladium / carbon (1g) in MeOH (15mL) 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 83.0mg residue and 2- [(5S) -3- bromo -4,5- dihydro -1,2- oxazole -5- bases] -3- (2,6- difluorophenyl) -5- methylpyridine (70.0mg) in NMP (0.6mL) was stirred at 120 ° C for 6 hours in a sealed tube. The mixture was purified by silica gel column chromatography (EtOAc / hexane and MeOH / EtOAc) to give the title compound (75.7mg).

[1559] MS:[M+H] + 481.1

[1560] 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)

[1561] 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 fractions with a longer retention time were concentrated under reduced pressure to obtain the title compound (48.2 mg).

[1562] Chiral separation conditions

[1563] Column: CHIRALPAK IC (trade name) (20 mm ID*250 mm L, 5 μm)

[1564] Mobile phase: Hexane / EtOH = 250 / 750 (v / v)

[1565] 1H NMR(300MHz,DMSO-d6)δ1.90-2.04(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=11.3Hz),3.49(2H,d,J=1.1Hz) ,3.66(1H,dd,J=15.4,8.7Hz),5.21(1H,t,J=9.0Hz),7.24(2H,q,J=8.9Hz), 7.33(1H,s),7.48-7.59(1H,m),7.62(1H,d,J=1.9Hz),8.53(1H,d,J=1.5Hz)

[1566] Example 82

[1567] 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

[1568] 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

[1569] 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).

[1570] MS:[M+H] + 529.1.

[1571] 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

[1572] To a mixture 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-yl] benzyl carbamate (137 mg) in EtOH (2 mL) was added 10% palladium on carbon (20 mg). The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (98 mg).

[1573] MS:[M+H] + 395.0.

[1574] 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

[1575] 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 and 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).

[1576] 1 H NMR(300MHz, CDCl3)δ2.40(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(1 H,m),5.02-5.16(2H,m),5.17-5.27(2H,m),5.49(1H,t,J=9.3Hz),6.70-6.85(2H,m),7.39-7.46(1H,m),8.50-8.57(1H,m).

[1577] Example 99

[1578] 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

[1579] A) tert-Butyl (3S)-3-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate

[1580] At room temperature, 4-methoxybenzyl chloride (3.90 mL) was added to a suspension of (3S)-3-[(ethylsulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (6.67 g) and potassium carbonate (9.93 g) in DMF (50 mL). 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 obtain the title compound (9.55 g).

[1581] MS:[M+Na] + 421.1.

[1582] B) (3S)-tert-Butyl 3-{(1-fluoroethanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate

[1583] At -78 ° C, n-butyl lithium (1.6M in hexane, 17.3mL) was added dropwise to a solution of (3S) -3- { (ethylsulfonyl) [ (4-methoxyphenyl) methyl] amino} pyrrolidine -1- carboxylic acid tert-butyl ester (5.0g) in THF (50mL). The mixture was stirred at -78 ° C for 30 minutes under a nitrogen atmosphere. A solution of N- fluorobis (phenylsulfonyl) amine (8.70g) in THF (10mL) was added to the mixture, and the mixture was stirred at room temperature under a nitrogen atmosphere 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 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 10mM ammonium bicarbonate) / acetonitrile). The desired fractions were then concentrated to give the title compound (1.60 g).

[1584] 1H NMR(300MHz,DMSO-d6)δ1.35(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=8.3Hz).

[1585] C) 1-Fluoro-N-[(3S)-pyrrolidin-3-yl]ethane-1-sulfonamide

[1586] 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).

[1587] 1 H NMR(400MHz,DMSO-d6)δ1.51-1.65(3H,m),1.71-1.83(1H,m),2.03-2.16(1H,m),2.85(1H,td,J=12.3,5.7Hz), 2.97-3.17(2H,m),3.24(1H,ddd,J=11.6,7.0,4.2Hz),3.94-4.02(1H,m),4.89-6.48(2H,m),5.51-5.72(1H,m).

[1588] 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

[1589] 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 / hexanes) to give the title compound (18.0 mg).

[1590] 1H NMR(300MHz, CDCl3)δ1.62-1.75(3H,m),1.97-2.12(2H,m),2.14-2.27(1H, m),2.38(3H,s),3.16(1H,dd,J=15.6,9.6Hz),3.27-3.40(2H,m),3.42-3.5 9(2H,m),3.74(1H,ddd,J=15.7,8.9,3.2Hz),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=4.1,1.9Hz).

[1591] Example 107

[1592] 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

[1593] A) tert-Butyl (3S,4S)-3-fluoro-4-[(trifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate

[1594] To a mixture of racemic -(3S, 4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (528 mg), pyridine (0.6 mL) and acetonitrile (10 mL) was added trifluoromethanesulfonic anhydride (0.6 mL) dropwise at -10 ° C, and the mixture was stirred at -10 ° C for 1 hour. 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 (833 mg).

[1595] 1 H NMR (300MHz, DMSO-d6) δ1.41(9H,s),3.46-3.89(4H,m),5.39-5.64(1H,m),5.70-5.86(1H,m).

[1596] B) 1-Fluorocyclopropane-1-sulfonamide

[1597] 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).

[1598] 1 H NMR (300MHz, DMSO-d6) δ1.30-1.56 (4H, m), 7.51 (2H, s).

[1599] C) tert-Butyl (3S,4R)-3-fluoro-4-[(1-fluorocyclopropane-1-sulfonyl)amino]pyrrolidine-1-carboxylate

[1600] To a solution of 1-fluorocyclopropane-1-sulfonamide (575mg) and DMF (9mL) was added sodium hydride (60% in oil, 179mg), and the mixture was stirred at 0°C for 10 minutes. A solution of racemic-(3S, 4S)-3-fluoro-4-[(trifluoromethanesulfonyl) oxy] pyrrolidine-1-carboxylic acid tert-butyl ester (1.23g) in DMF (3mL) was added dropwise at 0°C, the mixture was warmed to room temperature and stirred overnight under a nitrogen atmosphere. 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 (0.575g).

[1601] 1 H NMR(300MHz,DMSO-d6)δ1.32-1.63(13H,m),3.13(1H,td,J=10.1,3.6Hz),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=8.7Hz).

[1602] D) rac-1-fluoro-N-((3R,4S)-4-fluoropyrrolidin-3-yl)cyclopropane-1-sulfonamide hydrochloride

[1603] 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).

[1604] 1H NMR (300MHz, DMSO-d6) δ1.39-1.66(4H,m),3.04(1H,t,J=11.3Hz),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).

[1605] 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

[1606] 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), racemic-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 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 by IPE to give the title compound (19.1 mg).

[1607] 1 H NMR(300MHz,DMSO-d6)δ1.40-1.63(4H,m),2.36(3H,s),3.13-3.27(2H,m),3.42-3.79(4H,m),4.10-4.35(1 H,m),4.94-5.19(1H,m),5.25(1H,t,J=9.4Hz),7.27-7.42(2H,m),7.63(1H,d,J=1.9Hz),8.49-8.61(2H,m).

[1608] Example 109

[1609] 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

[1610] A) 2-Chloro-3-(2,6-difluorophenyl)-5-fluoropyridine

[1611] At room temperature, tri-tert-butylphosphonium tetrafluoroborate (0.414 g) and Pd2(dba)3 (0.653 g) are added to a mixture of 3-bromo-2-chloro-5-fluoropyridine (3.00 g), (2,6-difluorophenyl)boric acid (2.93 g) and potassium fluoride (1.66 g) in THF (39.6 mL) and water (7.92 mL). The mixture is stirred at 80 ° C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture is poured into brine and the resulting mixture is extracted with EtOAc. The organic layer is separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by NH silica gel column chromatography (EtOAc / hexane) to obtain the title compound (3.11 g).

[1612] MS:[M+H] + 243.9.

[1613] B) 2-[3-(2,6-Difluorophenyl)-5-fluoropyridin-2-yl]prop-2-en-1-ol

[1614] At room temperature, 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), potassium carbonate (2.21 g) in DME (15 mL) and water (3.0 mL). The mixture was stirred at 120 ° C for 10 hours under an argon atmosphere under microwave irradiation. The mixture was diluted with EtOAc and water, and the insoluble material was removed by Celite (trade name). 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).

[1615] MS:[M+H] + 266.0.

[1616] C) {3-Bromo-5-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol

[1617] At room temperature, sodium bicarbonate (1.77g) is added to a mixture of 2-[3-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]prop-2-ene-1-ol (1.40g) and dibrominated hydroxycarbonimide (2.14g) in EtOAc (21.1mL). The mixture is stirred at 70°C overnight. The precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.871g).

[1618] 1 H NMR(300MHz, CDCl3)δ3.10(1H,dd,J=7.7,7.0Hz),3.37-3.61(1H,m),3.66-3.86(2H,m),4.14-4.16(1H,m),6.72-7.12(2H,m),

[1619] 7.30-7.48(2H,m),

[1620] 8.48 (1H, d, J = 2.6 Hz).

[1621] D) 2-[3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine

[1622] At 0 ° C, 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-oxazole-5-yl}methanol (871 mg) in CH2Cl2 (15 mL). 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 sodium bicarbonate aqueous solution 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).

[1623] 1 H NMR (300MHz, CDCl3) δ3.52-3.67(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=2.6Hz).

[1624] E) 2-[(5S)-3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine

[1625] 2-[3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine (6.00 g) was optically resolved by SFC. The fractions with a longer retention time were concentrated under reduced pressure to give the title compound (2.78 g).

[1626] Chiral separation conditions

[1627] Column: CHIRALCEL OJ (trade name) (250 mm*50 mm, 10 μm)

[1628] Mobile phase: CO2 / EtOH (containing 0.1% ammonium hydroxide) = 850 / 150 (v / v)

[1629] 1 H NMR(400MHz,DMSO-d6)δ3.51-3.57(1H,m),3.64-3.71(1H,m),4.76-4.86(1H,m),4.87-4.97(1 H,m),7.14-7.22(2H,m),7.50-7.59(1H,m),7.96(1H,dd,J=9.2,2.8Hz),8.75(1H,d,J=2.8Hz).

[1630] F)(4R)-tert-Butyl 3,3-difluoro-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate

[1631] At 0 ° C, to a mixture of (R) -4-amino-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (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). The mixture was stirred at room temperature overnight under an argon atmosphere. Saturated sodium bicarbonate aqueous 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).

[1632] 1H NMR(300MHz,DMSO-d6)δ1.41(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=9.0Hz).

[1633] G) N-[(3R)-4,4-Difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride

[1634] A mixture of 4M hydrogen chloride in (4R)-3,3-difluoro-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (1.62 g) and 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).

[1635] 1 H NMR (300MHz, DMSO-d6) δ3.02 (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).

[1636] 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

[1637] 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 overnight at 135 ° C in a sealed tube. 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).

[1638] 1H NMR (400MHz, CDCl3) δ3.07(3H,s),3.12-3.19(1H,m),3.46(1H,dd,J=16.4,0.9Hz),3.54-3.71(3H,m),3.77(1H,dd,J=9.9,8.3Hz),4.15-4.39

[1639] (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=2.8Hz).

[1640] Example 131

[1641] 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

[1642] A) 2-[3-Bromo-5-(methoxymethyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine

[1643] At 0 ° C, trimethyloxonium tetrafluoroborate (trime thyloxoniumtetrafluoroborate) (229 mg) 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 (150 mg) and N,N,N',N'-tetramethyl-1,8-naphthalenediamine (415 mg) in EtOAc (5 mL). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was filtered, quenched with saturated aqueous ammonium chloride solution and 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).

[1644] MS:[M+H] + 400.9.

[1645] 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

[1646] 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) and 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 fractions were then concentrated to give the title compound (23.6 mg).

[1647] 1 H NMR(300MHz,DMSO-d6)δ2.98(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, 1.5Hz).

[1648] Example 147

[1649] 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)

[1650] A) 5-Fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-amine

[1651] At room temperature, tri-tert-butylphosphonium tetrafluoroborate (0.304g) and Pd2(dba)3(0.301g) are added to a mixture of 3-bromo-5-fluoropyridine-2-amine (2.00g), (2,4,6-trifluorophenyl)boric acid (3.32g) and potassium fluoride (1.22g) in THF (29.1mL) and water (5.82mL). The mixture is stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture is poured into brine and the resulting mixture is extracted with EtOAc. The organic layer is separated, washed with brine, dried over anhydrous sodium sulfate, passed through a NH silica gel pad and concentrated under reduced pressure. The solid is ground with IPE to obtain the title compound (1.81g).

[1652] MS:[M+H] + 242.9.

[1653] B) 5-Fluoro-2-iodo-3-(2,4,6-trifluorophenyl)pyridine

[1654] At room temperature, n-amyl nitrite (3.73 mL) was added 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). 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 obtain the title compound (1.58 g).

[1655] 1 H NMR (300MHz, CDCl3) δ6.76-6.87 (2H, m), 7.29 (1H, dd, J = 8.2, 3.0Hz), 8.37 (1H, d, J = 3.0Hz).

[1656] C) 2-[5-Fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]prop-2-en-1-ol

[1657] A mixture of 5-fluoro-2-iodo-3-(2,4,6-trifluorophenyl)pyridine (900 mg), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)prop-2-ene-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 and 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).

[1658] MS:[M+H] + 283.9.

[1659] D) {3-Bromo-5-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]-4,5-dihydro-1,2-oxazol-5-yl}methanol

[1660] At room temperature, sodium bicarbonate (485mg) is added to a mixture of 2-[5-fluoro-3-(2,4,6-trifluorophenyl)pyridin-2-yl]prop-2-ene-1-ol (545mg) and dibrominated hydroxycarbonimide (781mg) in EtOAc (10mL). The mixture is stirred overnight at 75°C. The precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (EtOAc / hexane) to give the title compound (586mg).

[1661] MS:[M+H] + 404.9.

[1662] E) 2-[3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-fluoro-3-(2,4,6-trifluorophenyl)pyridine

[1663] At 0 ° C, 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-oxazole-5-yl}methanol (585 mg) in CH2Cl2 (10 mL). 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 sodium bicarbonate aqueous solution 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).

[1664] 1 H NMR (300MHz, CDCl3) δ3.57-3.83(2H,m), 4.62-4.94(2H,m), 6.73-6.85(2H,m), 7.33(1H,dd,J=8.3,2.8Hz), 8.51(1H,d,J=2.8Hz).

[1665] F) 2-[3-Bromo-5-(fluoromethyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-fluoro-3-(2,4,6-trifluorophenyl)pyridine (optical isomer)

[1666] 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 optically resolved by SFC. The desired fractions with shorter retention time were concentrated in vacuo to give the title compound (1.74 g).

[1667] Chiral separation conditions

[1668] Column: CHIRALPAK IG (trade name) (250 mm*50 mm, 10 μm)

[1669] Mobile phase: CO2 / MeOH (containing 0.1% ammonium hydroxide) = 900 / 100 (v / v)

[1670] 1H NMR(400MHz,DMSO-d6)δ3.47-3.55(1H,m),3.66-3.74(1H,m),4.76-4.86(1H,m),4.8 8-4.98(1H,m),7.28-7.36(2H,m),7.99(1H,dd,J=8.8,2.8Hz),8.76(1H,d,J=2.8Hz).

[1671] 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)

[1672] 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 overnight in a sealed tube at 135° C. 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).

[1673] 1 H NMR (400MHz, CDCl3) δ3.07(3H,s),3.13-3.23(1H,m),3.47(1H,dd,J=16.4,0.9Hz),3.58-3.71(3H,m),3.80(1H,dd,J=9.9,8.2Hz),4.19-4.36

[1674] (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=8.4,2.8Hz),8.51(1H,d,J=2.7Hz).

[1675] Example 149

[1676] 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

[1677] A) tert-Butyl (4R)-3,3-difluoro-4-[(fluoromethylsulfonyl)amino]pyrrolidine-1-carboxylate

[1678] To a solution of (R) -4- amino -3,3- difluoropyrrolidine -1- tert-butyl formate (250 mg) in pyridine (4 mL) was added fluoromethanesulfonyl chloride (179 mg) dropwise 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 solution 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).

[1679] 1 H NMR(300MHz, CDCl3)δ1.47(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).

[1680] B) N-[(3R)-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide hydrochloride

[1681] To a solution of tert-butyl (4R)-3,3-difluoro-4-[(fluoromethylsulfonyl)amino]pyrrolidine-1-carboxylate (321 mg) in EtOAc (5 mL) was added 4 M 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).

[1682] 1 H NMR (300MHz, DMSO-d6) δ3.05-3.23(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).

[1683] 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

[1684] 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) and N-[(3R)-4,4-difluoropyrrolidin-3-yl]-1-fluoromethanesulfonamide hydrochloride (49.1 mg) in pyridine (0.40 mL) was stirred in a sealed tube at 140° C. overnight. 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).

[1685] 1 H NMR (300MHz, CDCl3) δ3.15-3.27(1H,m),3.41-3.78(5H,m),4.18-4.38(1H,m),4.59-4.73(1H,m),4.76-4.89(1 H,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=2.7Hz).

[1686] Example 154

[1687] 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

[1688] A) 3-Bromo-5-(2-bromo-6-fluoro-4-methylphenyl)-4,5-dihydro-1,2-oxazole

[1689] At room temperature, dibrominated hydroxy carbon imine (943mg) is added into the mixture of 1-bromo-3-fluoro-5-methyl-2-vinylbenzene (500mg), sodium bicarbonate (1.56g) and EtOAc (10mL).Mixture is stirred at 70 ℃ for 1.5 hours.Precipitation is removed by filtration, and the filtrate is concentrated under reduced pressure.Residue is passed through silica gel column chromatography (EtOAc / hexane) purification, obtain title compound (793mg).

[1690] 1 H NMR(300MHz,DMSO-d6)δ2.32(3H,s),3.40(1H,td,J=8.8,1.2Hz),3.80(1H,ddd,J= 17.6, 12.2, 2.3Hz), 6.02-6.10 (1H, m), 7.19 (1H, dt, J = 11.9, 0.7Hz), 7.40 (1H, s).

[1691] 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

[1692] N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide hydrochloride (492 mg) is 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 is stirred in a sealed tube at 140 ° C overnight. The mixture is poured into a saturated sodium bicarbonate aqueous solution at room temperature, and the resulting mixture is extracted with EtOAc. The organic layer is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (309 mg).

[1693] 1 H NMR(300MHz,DMSO-d6)δ2.31(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=10.3Hz),7.14(1H,d,J=11.6Hz),7.37(1H,s),7.99(1H,dd,J=9.1,4.2Hz).

[1694] 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

[1695] At room temperature, hexa-n-butylditin (0.391 mL) was added to a mixture of 2-bromo-3,5-difluoropyridine (100 mg), tricyclohexylphosphine (14.5 mg) and Pd2(dba)3 (47.2 mg) in DME (1.5 mL). The mixture was heated to 80° C. over 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered directly through Celite (trade name) using EtOAc. The filtrate was concentrated under reduced pressure. At room temperature, 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(Ph3P)4 (12.7 mg). The mixture was heated to 110° C. under an argon atmosphere for 6 hours. The mixture was filtered through Celite (trade name), the filtrate was diluted with water and the resulting mixture was extracted with EtOAc. The combined organic layers were 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).

[1696] 1 H NMR(300MHz,DMSO-d6)δ2.36(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=12.4Hz),7.98(1H,s),8.07(1H,td,J=9.3,1.7Hz),8.58(1H,t,J=2.4Hz).

[1697] Example 164

[1698] 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- Optical isomers 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

[1699] A) Ethyl 4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-2-fluoro-3-hydroxy-2-methylbutanoate

[1700] Under argon atmosphere, at 0 DEG C, to the solution of diisopropylamine (15.8g) in THF (150mL), n-butyl lithium (1.6M in hexane, 97mL) is dropwise added, and the mixture is then stirred for 15 minutes.Then the mixture is cooled to-78 DEG C, and the solution of 2-fluoropropionic acid ethyl ester (15.6g) in THF (50mL) is dropwise added at the same temperature.The mixture is stirred at-78 DEG C for 30 minutes.A solution of (4-methoxybenzyl) (2-oxoethyl) tert-butyl carbamate (14.5g) in THF (50mL) is dropwise added, and the mixture is stirred at-78 DEG C for 1 hour, then it is slowly warming up to room temperature and stirred at room temperature overnight.The mixture is quenched with saturated ammonium chloride aqueous solution at 0 DEG C and the mixture extracted with EtOAc.The organic layer is separated, washed with salt water, 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 (13.3 g).

[1701] MS:[M+Na] + 422.2.

[1702] B) rac-(3R,4S)-3-fluoro-4-hydroxy-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one

[1703] A mixture of 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).

[1704] MS:[M+H] + 254.1.

[1705] C) rac-(3R,4R)-4-azido-3-fluoro-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one

[1706] Under an argon atmosphere, trifluoromethanesulfonic anhydride (14.6 mL) was added dropwise to a solution of racemic-(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 (EtOAc / hexane) to give the title compound (8.80 g).

[1707] 1 H NMR(300MHz,DMSO-d6)δ1.35-1.61(3H,m),3.08(1H,ddd,J=10.7,4.0,1.1Hz),3.50(1H,dd,J=10.9 ,6.0Hz),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).

[1708] D) rac-(3R,4R)-4-amino-3-fluoro-1-[(4-methoxyphenyl)methyl]-3-methylpyrrolidin-2-one

[1709] 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 / 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).

[1710] MS:[M+H] + 253.1.

[1711] E) rac-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide

[1712] 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) was added methanesulfonic anhydride (8.08 g) and TEA (8.62 mL) at 0°C. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (8.60 g).

[1713] MS:[M+H] + 331.1.

[1714] F)rel-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide (optical isomer)

[1715] Racemic-N-{(3R,4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide (10 g) was optically resolved by SFC. The desired fractions with a longer retention time were concentrated in vacuo to give the title compound (4.77 g).

[1716] Chiral separation conditions

[1717] Column: CHIRALPAK AY (trade name) (250×30 mm ID, 10 μm)

[1718] Mobile phase: CO2 / EtOH=750 / 250 (v / v)

[1719] MS:[M+H] + 331.1.

[1720] G)rel-N-{(3R,4S)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methylpyrrolidin-3-yl}methanesulfonamide (optical isomer)

[1721] At room temperature, to a solution of rel-N-{(3R, 4R)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methyl-5-oxopyrrolidin-3-yl}methanesulfonamide (optical isomer) (1.00 g) in THF (10 mL) was added dropwise a THF solution of borane dimethyl sulfide complex (1.9 M, 7.97 mL). The mixture was stirred at 50 ° C for 5 hours. The reaction mixture was cooled to room temperature, and then 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).

[1722] MS:[M+H] + 317.0.

[1723] H)rel-N-[(3R,4S)-4-fluoro-4-methylpyrrolidin-3-yl]methanesulfonamide (optical isomer)

[1724] Under a hydrogen atmosphere, a mixture of rel-N-{(3R, 4S)-4-fluoro-1-[(4-methoxyphenyl)methyl]-4-methylpyrrolidin-3-yl}methanesulfonamide (optical isomer) (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).

[1725] 1 H NMR(300MHz,DMSO-d6)δ1.28-1.44(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).

[1726] I) 2-vinyl-2',3,5,6'-tetrafluoro-1,1'-biphenyl

[1727] 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) 2 (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 hours. 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).

[1728] 1 H NMR (400MHz, DMSO-d6) δ5.42(1H,dt,J=11.8,1.6Hz), 5.55(1H,dt,J=17.9,1.3Hz), 6.25(1H,dd,J=17.9,11.7Hz), 7.17-7.69(5H,m).

[1729] J) 3-bromo-5-(2',3,5,6'-tetrafluoro-[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazole was added to a mixture of 2-vinyl-2',3,5,6'-tetrafluoro-1,1'-biphenyl (500 mg) and dibrominated hydroxycarbonimide (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).

[1730] 1 H NMR(400MHz,DMSO-d6)δ3.37(1H,ddd,J=17.6,9.2,1.0Hz),3.70(1H,ddd,J=17.5, 12.2, 2.2Hz), 5.42 (1H, dd, J = 11.5, 9.9Hz), 7.21-7.33 (3H, m), 7.49-7.65 (2H, m).

[1731] K) 3-Bromo-5-(2',3,5,6'-tetrafluoro[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,2-oxazole (optical isomer)

[1732] 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 (601 mg) with a shorter retention time.

[1733] Chiral separation conditions

[1734] Column: CHIRALCEL OJ (trade name) (250 mm*50 mm, 10 μm)

[1735] Mobile phase: CO2 / MeOH (containing 0.1% ammonium hydroxide) = 900 / 100 (v / v)

[1736] 1 H NMR(400MHz,DMSO-d6)δ3.35-3.47(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)

[1737] 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 Optical isomers 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

[1738] 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).

[1739] 1 H NMR(300MHz,DMSO-d6)δ1.35-1.52(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=10.4Hz),7.09-7.36(3H,m),7.38-7.69(3H,m).

[1740] Example 165

[1741] 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

[1742] A) 2-(3-Bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-fluoropyridine

[1743] To a mixture of 2-chloro-3-(2,6-difluorophenyl)-5-fluoropyridine (78.0 g), potassium isopropenyl trifluoroborate (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.CH2Cl2 (39.2 g) at 20 ° C. The mixture was stirred at 110 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (EtOAc / petroleum ether) to give 3-(2,6-difluorophenyl)-5-fluoro-2-(prop-1-en-2-yl)pyridine (73 g, crude product). To a mixture of 3-(2,6-difluorophenyl)-5-fluoro-2-(prop-1-ene-2-yl)pyridine (73.0g, crude product) and dibromohydroxycarbonimide (42.8g) in EtOAc (800mL) was added sodium bicarbonate (29.5g). 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 obtain a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to obtain a crude title compound, which was dissolved in EtOAc. The combined organic layer was washed with brine and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (36.5g).

[1744] 1 H NMR (400 MHz, DMSO-d6) δ 1.63 (3H, s), 3.46-3.50 (1H, m, overlapped with the signal of water), 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).

[1745] B) 2-[(5S)-3-Bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl]-3-(2,6-difluorophenyl)-5-fluoropyridine

[1746] 2-(3-bromo-5-methyl-4,5-dihydro-1,2-oxazol-5-yl)-3-(2,6-difluorophenyl)-5-fluoropyridine (37.8 g) was optically resolved by SFC. The desired fraction with a longer retention time was concentrated in vacuo. The residue was optically resolved again by SFC. The desired fraction with a 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).

[1747] Chiral separation conditions

[1748] Column: CHIRALCEL OJ (trade name) (250 mm*50 mm, 10 μm)

[1749] Mobile phase: CO2 / IPA (containing 0.1% ammonium hydroxide) = 800 / 200 (v / v)

[1750] 1 H NMR(400MHz,DMSO-d6)δ1.62(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=2.8Hz).

[1751] 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

[1752] 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. for 4 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The crude material 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).

[1753] 1 H NMR (300MHz, DMSO-d6) δ1.53(3H,s),2.98(3H,s),3.06(1H,t,J=9.3Hz),3.17(1H,d,J=16.4Hz),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 = 2.8Hz).

[1754] Example 167

[1755] 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)

[1756] Optical resolution of 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 performed by SFC to give the title compound (36 mg) with a longer retention time.

[1757] Chiral separation conditions

[1758] First separation

[1759] Column: CHIRALPAK AD (trade name) (250*30 mm ID, 10 μm)

[1760] Mobile phase: CO2 / IPA=750 / 250 (v / v)

[1761] Second separation

[1762] Column: CHIRALPAK AS (trade name) (250*30 mm ID, 10 μm)

[1763] Mobile phase: CO2 / EtOH=850 / 150 (v / v)

[1764] 1 H NMR (300MHz, DMSO-d6) δ2.36(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=10.7Hz),

[1765] 7.03 (1H, s), 7.23 (1H, d, J = 12.1Hz), 7.99 (1H, d, J = 9.2Hz), 8.03-8.11 (1H, m), 8.58 (1H, d, J = 2.4Hz).

[1766] Example 171

[1767] 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

[1768] A) 4-Chloro-2-(3,5-difluoropyridin-2-yl)-6-fluoroaniline

[1769] By 4- chloro- 2- fluoro- 6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) aniline (233mg), 2- bromo- 3,5- difluoropyridine (183mg), Pd2 (dba) 3 (157mg), cesium fluoride (261mg) and tri- tert-butylphosphonium tetrafluoroborate (124mg) in THF (4mL) mixture under argon atmosphere at 60 DEG C stirred 4 hours. Directly through celite (trade name) filter reaction mixture and under reduced pressure concentrate filtrate. Residue is passed through silica gel column chromatography (EtOAc / hexane) and NH silica gel column chromatography (EtOAc / hexane) purification, obtain title compound (117mg).

[1770] MS:[M+H] + 258.8.

[1771] B) 2-(5-chloro-3-fluoro-2-iodophenyl)-3,5-difluoropyridine

[1772] 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-amyl 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% sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution. 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).

[1773] MS:[M+H] + 369.9.

[1774] C) 2-[2-(3-Bromo-4,5-dihydro-1,2-oxazol-5-yl)-5-chloro-3-fluorophenyl]-3,5-difluoropyridine

[1775] By 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), PdCl2 (dppf) (5.54 mg) and DME (1 mL) / water (0.20 mL) mixture was heated at 90 ° C for 1.5 hours 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- vinyl -3- fluorophenyl) -3,5- difluoropyridine (19 mg, crude product). EtOAc (1 mL) was added to the crude product, and sodium bicarbonate (63.7 mg) and dibromide hydroxycarbonimide (30.7 mg) were then added at room temperature. The mixture was stirred at 70 ° C for 1.5 hours. The mixture was filtered and the resulting residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (19 mg).

[1776] 1 H NMR(300MHz,CD3OD)δ3.42-3.80(2H,m),5.61-5.78(1H,m),7.28-7.34(1H,m),7.4 6(1H,dd,J=10.8,2.1Hz), 7.75(1H,ddd,J=9.4,8.5,2.4Hz), 8.49(1H,d,J=2.4Hz).

[1777] 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

[1778] 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 material was purified by preparative HPLC (C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / acetonitrile) to give the title compound (2.3 mg).

[1779] 1H NMR(300MHz,CD3OD)δ3.05(3H,s),3.27(1H,d,J=9.9Hz),3.43-3.91(5H,m),4.45(1H,dd,J=14.4,8.1Hz),5.57(1H,td,J =10.6,5.4Hz),7.28(1H,dd,J=1.9,1.0Hz),7.45(1H,dd,J=10.7,2.1Hz),7.74(1H,td,J=8.9,2.4Hz),8.41-8.50(1H,m).

[1780] The compounds of the examples are shown in the following tables. In these tables, MS represents the observed molecular ions (measured values). 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 in the same manner as the reactions and purifications described in the above examples.

[1781] Table 1-1

[1782]

[1783] Table 1-2

[1784]

[1785] Table 1-3

[1786]

[1787]

[1788] Table 1-4

[1789]

[1790]

[1791] Table 1-5

[1792]

[1793]

[1794] Table 1-6

[1795]

[1796]

[1797] Table 1-7

[1798]

[1799]

[1800] Table 1-8

[1801]

[1802]

[1803] Table 1-9

[1804]

[1805]

[1806] Table 1-10

[1807]

[1808]

[1809] Table 1-11

[1810]

[1811]

[1812] Table 1-12

[1813]

[1814]

[1815] Table 1-13

[1816]

[1817]

[1818] Table 1-14

[1819]

[1820]

[1821] Table 1-15

[1822]

[1823]

[1824] Table 1-16

[1825]

[1826]

[1827] Table 1-17

[1828]

[1829]

[1830] Table 1-18

[1831]

[1832]

[1833] Table 1-19

[1834]

[1835]

[1836] Table 1-20

[1837]

[1838]

[1839] Table 1-21

[1840]

[1841]

[1842] Table 1-22

[1843]

[1844]

[1845] Table 1-23

[1846]

[1847]

[1848] Table 1-24

[1849]

[1850]

[1851] Table 1-25

[1852]

[1853]

[1854] Table 1-26

[1855]

[1856]

[1857] Table 1-27

[1858]

[1859] Table 1-28

[1860]

[1861] Table 1-29

[1862]

[1863] Table 1-30

[1864]

[1865] Table 1-31

[1866]

[1867] Experimental Example 1: Obtaining cells stably expressing human orexin type 2 receptor (hOX2R)

[1868] 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 a pcDNA3.1(+) vector (Invitrogen) for expression 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.

[1869] Experimental Example 2: Measurement of orexin type 2 receptor agonist activity

[1870] CHO cells forced to express the human OX2 receptor were seeded at 10,000 cells / well in a 384-well black clear-bottom plate (BD Falcon). After incubation at room temperature for 30 minutes, the plate was incubated at 37°C, 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-4 AM (Dojin Kagaku), 0.08% Pluronic F127 (Dojin Kagaku), 1.25 mM probenecid (Dojin Kagaku)) was added. The plate was incubated in a 37°C, 5% CO₂ incubator for 30 minutes, followed by an additional 30 minutes at room temperature. Add 10 μ L / wells of test compound diluted with assay buffer B (HBSS, 20mM HEPES, 0.1% BSA), and use FDSSμCELL (Hamamatsu Photonics) to measure fluorescence value every 1 second for 1 minute, then measure fluorescence value every 2 seconds for 1 minute. The measurement lasts for 1 minute and 40 seconds. The amount of fluorescence value when adding DMSO instead of the test compound is defined as 0%, and the amount of fluorescence value when adding orexin A (people) (Peptide Institute) with a final concentration of 10nM is defined as 100%. Calculate the activity (%) of the test compound. Table 2 shows the activity of each compound at a concentration of 3 μ M. From this result, it is clear that the compound of the present invention shows orexin type 2 receptor activating activity.

[1871] Table 2-1

[1872]

[1873]

[1874] Table 2-2

[1875]

[1876]

[1877] Table 2-3

[1878] Test compound OX2R agonist activity (3 μM, %) 61 98 62 17 63 101 64 100 65 97 66 99 67 98 68 104 69 95 70 94 71 108 72 105 73 102 74 58 75 105 76 108 77 102 78 102 79 100 80 97 81 100 82 98 83 103 84 97 85 99 86 95 87 104 88 112 89 93 90 98

[1879] Table 2-4

[1880] Test compound OX2R agonist activity (3 μM, %) 91 98 92 92 93 99 96 99 97 103 98 108 99 101 100 99 101 98 102 95 103 96 104 102 105 97 106 108 107 98 108 105 109 101 110 100 111 102 112 98 113 100 114 87 115 100 116 100 117 105 118 100 119 101 120 102 121 98 122 102

[1881] Table 2-5

[1882]

[1883]

[1884] Table 2-6

[1885]

[1886]

[1887] Table 2-7

[1888] Test compound OX2R agonist activity (3 μM, %) 165 100 166 102 167 102 168 103 169 98 170 102 171 109 172 99 173 100 174 107 175 112 176 109 177 106 178 111

[1889] Experimental Example 3: Evaluation of the wake-promoting effect in cynomolgus monkeys

[1890] The wake-promoting effect was evaluated by measuring the electroencephalogram (EEG), electromyogram (EMG), and motor activity of cynomolgus monkeys. Male cynomolgus monkeys (2-3 years old, Hamri Co., Ltd., Ibaraki, Japan) were surgically implanted with a radiotelemetry transmitter (L03-F3, Data Sciences International Inc., MN, USA) under isoflurane anesthesia (0.5–5%, Pfizer Japan Inc., Tokyo, Japan). Two EEG electrodes were stereotactically positioned in the parietal region and fixed to the skull with stainless steel screws in contact with the dura mater. Bilateral EMG electrodes were implanted in the posterior cervical muscles.

[1891] After a recovery period of at least 1 month in the home cage, when the monkeys had adequate sleep in the laboratory, they were habituated to the recording chamber (60W x 55D x 75H (cm) acrylic cage) located in a soundproof and electrically shielded room. Cortical EEG, EMG, and motor activity were recorded using a telemetry system (PhysioTel Digital telemetry platform, Data Sciences International Inc.). Signals were semi-automatically scored in 20-second epochs using a sleep scoring system (SleepSign, Kissei Comtec Co., Ltd., Nagano, Japan).

[1892] In a pretest-posttest design (n=2), monkeys were orally administered (po) a test compound (3 mg / kg) or vehicle (i.e., 0.5% methylcellulose aqueous solution) suspended in a 0.5% methylcellulose aqueous solution at zeitgeber time 12 in a volume of 5 mL / kg body weight, followed by recording EEG, EMG, and motor activity. Calculations of wakefulness (vehicle-treated %) were performed for 4 hours after administration using SleepSign. The results are shown in Table 3.

[1893] Table 3

[1894]

[1895] As can be clearly seen from Table 3, the test compounds of the present invention increased the wakefulness time in cynomolgus monkeys compared with the vehicle-treated group. That is, these compounds are considered to be potential therapeutic agents for narcolepsy.

[1896] Formulation Example 1 (Production of Caps...

Claims

1. A compound of formula (I) in R 1 C 1-6 Alkyl, C 3-7 Cycloalkyl or mono- or di-C 1-6 Alkylamino, where C 1-6 Alkyl, C 3-7 Cycloalkyl and mono- or di-C 1-6 Each of the alkylamino groups is optionally substituted; Each R 2 are the same or different and are optionally substituted C 1-6 alkyl; Each R 3 are the same or different and are optionally substituted C 1-6 an alkyl group or a halogen atom; R A is an optionally substituted 3- to 8-membered non-aromatic heterocyclic group, an optionally substituted 5- to 6-membered aromatic heterocyclic group, an optionally substituted C 6-14 Aryl or optionally substituted C 3-10 Cycloalkyl; L 1 For the key, -NR 6 -or-O-; where R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl; L 2 is a bond or -CH2-; X 1 N or CR 3’ ; X 2 N or CR 4b ; X 3 N or C; X 4 N or CR 4c ; X 5 N or CR 4d ; The prerequisite is X 2 、X 3 、X 4 and X 5 No more than two of them are N; R 3’ is 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 are each a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 Cycloalkyl, halogen atom or optionally substituted C 1-6 alkoxy; 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 0 or 1; and contains one single bond and one double bond when p is 0, or contains one single bond and two double bonds when p is 1, to provide an aromatic ring structure; or a salt thereof.

2. The compound according to claim 1, wherein R A Has the following structure: in X 6 N or CR 5’ ; Each R 5 are the same or different and are halogen atoms or C 1-6 alkoxy; R 5’ is a hydrogen atom or a halogen atom; q is an integer from 0 to 7; and and are identical and all have single bonds or all have double bonds; or a salt thereof.

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

4. The compound according to claim 1, wherein X 1 is N; or a salt thereof.

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

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

7. The compound according to claim 1, wherein X 2 CR 4b , X 3 C, X 4 CR 4c , X 5 CR 4d , and p is 1; or a salt thereof.

8. The compound according to claim 1, wherein X 2 N, X 3 C, X 4 CR 4c , X 5 CR 4d , and p is 1; or a salt thereof.

9. The compound according to claim 1, wherein X 2 CR 4b , X 3 C, X 4 and X 5 is N, and p is 1; or a salt thereof.

10. The compound according to claim 1, wherein X 2 CR 4b , X 3 C, X 4 CR 4c , X 5 is N, and p is 1; or a salt thereof.

11. The compound according to claim 1, wherein X 2 and X 4 N, X 3 C, X 5 CR 4d , and p is 1; or a salt thereof.

12. The compound according to claim 1, wherein X 2 CR 4b , X 3 C, X 4 N, X 5 CR 4d , and p is 1; or a salt thereof.

13. The compound according to claim 2, wherein X 6 CR 5’ ,and and are all single bonds; or their salts.

14. The compound according to claim 2, wherein X 6 CR 5’ ,and and are double bonds; or their salts.

15. The compound according to claim 2, wherein X 6 N ′ ,and and are double bonds; or their salts.

16. The compound according to claim 1, wherein the portion: Selected from the group consisting of: * indicates the same as R A The bonding site of R 4a 、R 4b 、R 4c and R 4d As defined in claim 1; or a salt thereof.

17. The compound according to claim 2, wherein the portion: Selected from the group consisting of: * indicates the same as R A The bonding site of R 1 C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyclopropyl, halogenated cyclopropyl or mono- or di-C 1-6 Alkylamino; Each R 2 are the same or different and are C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl or hydroxy-C 1-6 alkyl; Each R 3 are the same or different and are C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 an alkyl group or a halogen atom; L 1 For the key, -NR 6 -or-O-; where R 6 A hydrogen atom or C 1-6 alkyl; L 2 is a bond or –CH2-; X 1 N or CR 3' ; where R 3' is a hydrogen atom; R 4a For hydrogen atoms, C 1-6 Alkyl, cyclopropyl, C 1-6 Alkoxy, halogenated C 1-6 an alkyl group or a halogen atom; X 2 N or CR 4b ; where R 4b is a hydrogen atom or a halogen atom; X 4 N or CR 4c ; where R 4c is a hydrogen atom or a halogen atom; X 5 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 part: Selected from the group consisting of: in Each R 5 are the same or different and are halogen atoms or C 1-6 alkoxy; R 5’ is a hydrogen atom or a halogen atom; and q is an integer from 0 to 4; or a salt thereof.

18. The compound or salt thereof according to claim 2, wherein the compound is a compound of formula (Ia): in q is an integer from 0 to 4; and Other symbols are as defined in claim 2; or a salt thereof.

19. The compound according to claim 2, wherein the compound is a compound of formula (Ib): in q is an integer from 0 to 4; and Other symbols are as defined in claim 2; or a salt thereof.

20. The compound according to claim 2, wherein the compound is a compound of formula (Ic): in R 2a is a hydrogen atom or an optionally substituted C 1-6 alkyl; q is an integer from 0 to 4; and Other symbols are as defined in claim 2; or a salt thereof.

21. The compound according to claim 2, wherein the compound is of formula (Id): in R 2a is a hydrogen atom or an optionally substituted C 1-6 alkyl; R 3a and R 3b are the same or different and are each 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.

22. The compound according to claim 1, wherein the compound is of formula (Ie): in R 1 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 2a For hydrogen atoms, C 1-6 Alkyl or halogenated C 1-6 alkyl; R 3a and R 3b are the same or different, and each is C 1-6 an alkyl group or a halogen atom; R 4a C 1-6 an alkyl group or a halogen atom; X 2 N or CR 4b ; where R 4b is a halogen atom; and R A is phenyl or pyridyl, wherein each of said phenyl and pyridyl is optionally substituted with one to three halogen atoms; or a salt thereof.

23. The compound according to claim 22, wherein R 1 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 2a For hydrogen atoms, C 1-6 Alkyl or halogenated C 1-6 alkyl; R 3a and R 3b Each is a halogen atom; R 4a C 1-6 an alkyl group or a halogen atom; X 2 N or CR 4b ; where R 4b is a halogen atom; and R A is phenyl or pyridyl, wherein each of said phenyl and pyridyl is optionally substituted with one to three halogen atoms; or a salt thereof.

24. The compound according to claim 22, wherein R 1 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 2a C 1-6 Alkyl or halogenated C 1-6 alkyl; R 3a and R 3b Each is a halogen atom; R 4a is a halogen atom; X 2 is N; and R A is phenyl optionally substituted by one to three halogen atoms; or a salt thereof.

25. The compound according to claim 22, wherein R 1 C 1-6 alkyl; R 2a Halogenated C 1-6 alkyl; R 3a and R 3b Each is a halogen atom; R 4a is a halogen atom; X 2 is N; and R A is phenyl optionally substituted by one to three halogen atoms; or a salt thereof.

26. The compound of claim 1, wherein the compound is selected from the group consisting of: 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, or a salt thereof.

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

28. A medicament comprising a compound as defined in any one of claims 1 to 26 or a salt thereof. The drug according to claim 28 , which is an orexin type 2 receptor agonist.

30. The drug according to claim 28, which is an agent for preventing or treating 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 associated with bone loss, sepsis, impaired consciousness, or side effects and complications due to anesthesia. The medicament according to claim 28, which is an agent for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia or sleep apnea syndrome.

32. The medicine according to claim 28, which is an agent for preventing or treating narcolepsy.

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

34. The method of claim 33, wherein the disease or condition 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 associated with bone loss, sepsis, impaired consciousness, and side effects and complications due to anesthesia.

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

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

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

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

39. The compound or salt of claim 38, wherein the disease or condition 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 associated with bone loss, sepsis, impaired consciousness, and side effects and complications due to anesthesia.

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

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

42. 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 treating a disease or condition associated with the orexin type 2 receptor.

43. The use according to claim 42, wherein the disease or condition 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 associated with bone loss, sepsis, impaired consciousness, and side effects and complications due to anesthesia.

44. The use according to claim 42, wherein the disease or condition is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia and sleep apnea syndrome.

45. The use according to claim 42, wherein the disease or disorder is narcolepsy.

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