Heterocyclic compound

Abstract

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

Description

Technical Field

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

[0003] Orexin is a neuropeptide specifically produced by specific neurons sparsely distributed in the lateral hypothalamus and its surrounding regions, and consists of two subtypes, namely orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of orexin receptors, which are G protein-coupled receptors mainly present in the brain, and orexin receptors are known to have two subtypes, type 1 and type 2 (Non-Patent Document 1).

[0004] Since orexin-producing neurons (orexin neurons) are located near the feeding center, and intracerebroventricular administration of orexin peptides results in an increase in food intake, orexin was initially regarded as a neuropeptide with regulation of feeding behavior and attracted attention. However, thereafter, it was reported that the cause of narcolepsy in dogs is a genetic variation in the orexin type 2 receptor (Non-Patent Document 2), and the role of orexin in controlling sleep and wakefulness has also been studied.

[0005] According to studies using transgenic mice with degenerated orexin neurons and double transgenic mice obtained by crossing such mice with transgenic mice overexpressing orexin, it was observed that narcolepsy-like symptoms caused by degeneration of orexin neurons disappeared due to continuous expression of orexin. Similarly, when orexin peptides were intracerebroventricularly administered to transgenic mice with degenerated orexin neurons, improvement of narcolepsy-like symptoms was observed (Non-Patent Document 3). Studies on orexin type 2 receptor knockout mice have shown that the orexin type 2 receptor is important for maintaining wakefulness (Non-Patent Document 4, Non-Patent Document 5). Such background indicates that orexin type 2 receptor agonists become therapeutic drugs for narcolepsy or therapeutic drugs for other sleep disorders showing excessive sleepiness (Non-Patent Document 6).

[0006] In addition, it was shown that a peptide agonist selectively acting on the orexin type 2 receptor improves obesity in mice caused by a high-fat diet load (Non-Patent Document 7).

[0007] In addition, it was shown that intracerebroventricular administration of orexin peptides shortens the general anesthesia time in rats (Non-Patent Document 8).

[0008] In addition, it was shown that patients with sleep apnea syndrome showed a lower concentration level of orexin A in plasma (Non-Patent Document 9).

[0009] In addition, it was shown that intracerebroventricular administration of orexin peptides improves memory retention in senescence-accelerated model mice (SAMP8) with cognitive dysfunction (Non-Patent Document 10).

[0010] In addition, it has been shown that orexin type 2 receptor agonists will become therapeutic agents for heart failure (Patent Document 1, Non-Patent Document 11).

[0011] In addition, it has been shown that daytime sleepiness in patients with Parkinson's disease is caused by orexin neuropathy (Non-Patent Document 12).

[0012] In addition, it has been shown that orexin regulates bone formation and bone loss, and that orexin type 2 receptor agonists will become therapeutic agents for diseases associated with bone loss, such as osteoporosis, rheumatoid arthritis, etc. (Patent Document 2).

[0013] In addition, it has been shown that orexin receptor agonists can be used for the prevention or treatment of sepsis, severe sepsis, and septic shock, because the mortality can be significantly improved simply by continuously administering orexin peripherally to septic shock model mice (Patent Document 3).

[0014] Therefore, compounds having orexin type 2 receptor agonist activity are expected to be used as therapeutic agents for treating the following diseases: narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness (such as coma, etc.), narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with 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, etc. In addition, orexin type 2 receptor agonists can be used as anesthetic antagonists or as preventive or therapeutic agents for side effects and complications caused by anesthesia.

[0015] As sulfonamide derivatives, compounds represented by the following formula have been reported

[0016]

[0017] wherein each symbol is as described in the literature (Patent Document 4).

[0018] In addition, as compounds having orexin type 2 receptor agonist activity, the following compounds have been reported.

[0019] Compounds represented by the following formula

[0020]

[0021] wherein each symbol is as described in the literature (Patent Document 5).

[0022] A compound represented by the following formula

[0023]

[0024] wherein each symbol is as described in the document (Patent Document 6).

[0025] A compound represented by the following formula

[0026]

[0027] wherein each symbol is as described in the document (Patent Document 7).

[0028] A compound represented by the following formula

[0029]

[0030] wherein each symbol is as described in the document (Patent Document 8).

[0031] A compound represented by the following formula

[0032]

[0033] wherein each symbol is as described in the document (Patent Document 9).

[0034]

[0035] wherein each symbol is as described in the document (Patent Document 10).

[0036] A compound represented by the following formula

[0037]

[0038] wherein each symbol is as described in the document (Patent Document 11).

[0039] A compound represented by the following formula

[0040]

[0041] wherein each symbol is as described in the document (Patent Document 12).

[0042] A compound represented by the following formula

[0043]

[0044] wherein each symbol is as described in the document (Patent Document 13).

[0045] A compound represented by the following formula

[0046]

[0047] Each symbol is as described in the document (Patent Document 14).

[0048] A compound represented by the following formula

[0049]

[0050] Each symbol is as described in the document (Patent Document 15).

[0051] A compound represented by the following formula

[0052]

[0053] Each symbol is as described in the document (Patent Document 16).

[0054] A compound represented by the following formula

[0055]

[0056] Each symbol is as described in the document (Patent Document 17).

[0057] However, these compounds are considered to be insufficient in terms of activity, pharmacokinetics, or safety, and there is still a desire to develop compounds with orexin type 2 receptor agonist activity.

[0058] [List of Documents]

[0059] [Patent Documents]

[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 Document]

[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] CNS Drugs, Vol. 27, 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, 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 Invention]

[0091] An object of the present invention is to provide a heterocyclic compound having orexin type 2 receptor agonist activity.

[0092] [Means for Solving the Problems]

[0093] The present inventors have found 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. The present invention has been completed through further research.

[0094] Therefore, the present invention provides the following.

[0095] [1] A compound represented by formula (I):

[0096]

[0097] Wherein

[0098] X 1 is NR 8 or CR 9 ;

[0099] X 2 is O, NR 10 or S;

[0100] X 3 and X 4 are both C, or one of X 3 and X 4 is N and the other is C;

[0101] X 5 is CR 11 or N;

[0102] X 6 is CR 12 ;

[0103] X7 is CR 13 or N;

[0104] X 8 is CR 14 or N;

[0105] X 9 is CR 2 or N;

[0106] X 10 is CR 15 or N;

[0107] R 1 is optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl or optionally substituted mono- or di-C 1-6 alkylamino;

[0108] R 2 and R 3 are each independently a hydrogen atom or optionally substituted C 1-6 alkyl, or

[0109] when r is 0, then R 2 and R 3 can combine together to form a bond, or

[0110] when X 10 is CR 15 then R 3 can combine with R 15 to form a bond;

[0111] R 4 is a hydrogen atom, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy or hydroxy;

[0112] R 5 is an optionally substituted 4-, 5- or 6-membered monocyclic group;

[0113] R 6 and R 7 are each independently a hydrogen atom, a halogen atom or optionally substituted C 1-6 alkyl;

[0114] m is 0 or 1;

[0115] q is 1 or 2;

[0116] r is 0 or 1;

[0117] R 9 、R 11 、R 12 and R13 Each independently is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group;

[0118] R 8 and R 10 each independently do not exist, or are selected from a hydrogen atom and an optionally substituted C 1-6 alkyl group; and

[0119] R 14 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group;

[0120] R 15 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group, or

[0121] R 15 can combine with R 3 to form a bond;

[0122] or a salt thereof.

[0123] [2] The compound according to [1] above, wherein m is 0; q is 1; and r is 0; or a salt thereof.

[0124] [3] The compound according to [1] above, wherein m is 1; q is 1; and r is 0; or a salt thereof.

[0125] [4] The compound according to [1] above, wherein m is 0; q is 1; and r is 1; or a salt thereof.

[0126] [5] The compound according to [1] above, wherein m is 0; q is 2; and r is 0; or a salt thereof.

[0127] [6] The compound according to [1] above, wherein

[0128] X 1 is NR 8 wherein R 8 does not exist;

[0129] X 2 is O;

[0130] X 3 and X 4 are both C;

[0131] X 5 is CR 11 or N, wherein R 11 is a hydrogen atom;

[0132] X 6 is CR 12 , where R 12 is a hydrogen atom, C 1-6 alkyl or a halogen atom; and

[0133] X 7 is CR 13 , where R 13 is a hydrogen atom or a halogen atom;

[0134] or a salt thereof.

[0135] [7] The compound according to [1] above, wherein

[0136] X 8 is N;

[0137] X 9 is CR 2 , where R 2 is a hydrogen atom, or when r is 0, then R 2 can combine with R 3 to form a bond; and

[0138] X 10 is N;

[0139] or a salt thereof.

[0140] [8] The compound according to [1] above, wherein

[0141] R 1 is

[0142] (1) Optionally substituted by 1 to 3 substituents independently selected from the following: C 1-6 alkyl:

[0143] (i) A halogen atom,

[0144] (ii) C 1-6 alkoxy, and

[0145] (iii) C 3-6 cycloalkyl,

[0146] (2) C 3-10 cycloalkyl, or

[0147] (3) Mono- or di-C 1-6 alkylamino;

[0148] R 2 and R 3 are each independently a hydrogen atom or C 1-6 alkyl, or

[0149] when r is 0, then R2 and R 3 may combine with each other to form a bond, or

[0150] when X 10 is CR 15 then R 3 combines with R 15 to form a bond;

[0151] R 4 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or hydroxy;

[0152] R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl or cyclobutyl, any of which is optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halogen atom, halo(C 1-6 )alkyl and C 1-6 alkoxy;

[0153] R 6 and R 7 are each independently a hydrogen atom, halogen atom or C 1-6 alkyl;

[0154] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are selected to form a ring system, and the ring system is one of the following:

[0155] (i) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 ,and X 7 is CR 13 ;

[0156] (ii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6is CR 12 and X 7 is CR 13 ;

[0157] (iii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is N;

[0158] (iv) X 1 is NR 8 and R 8 is absent, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 and X 7 is CR 13 ;

[0159] (v) X 1 is NR 8 and R 8 is absent, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ;

[0160] (vi) X 1 is NR 8 and X 2 is NR 10 and R 8 and R 10 one of them is absent and R 8 and R 10 the other one is C 1-6 alkyl, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR13 ;

[0161] (vii) X 1 is CR 9 X 2 is NR 10 and R 10 is absent, X 3 is N, X 4 is C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ; and

[0162] (viii) X 1 is CR 9 X 2 is NR 10 and R 10 is absent, X 3 is C, X 4 is N, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ;

[0163] X 8 、X 9 、X 10 、m, q and r are selected to form a ring system which is one of the following:

[0164] (i) X 8 is N, X 9 is CR 2 X 10 is N, m is 0, q is 1, and r is 0;

[0165] (ii) X 8 is N, X 9 is CR 2 X 10 is N, m is 1, q is 1, and r is 0;

[0166] (iii) X 8 is N, X 9 is CR 2 X 10 is N, m is 0, q is 1, and r is 1;

[0167] (iv) X 8 is N, X 9 is N, X 10is CR 15 , m is 0, q is 1, and r is 0;

[0168] (v) X 8 is CR 14 , X 9 is CR 2 , X 10 is N, m is 0, q is 1, and r is 0; and

[0169] (vi) X 8 is N, X 9 is CR 2 , X 10 is N, m is 0, q is 2, and r is 0;

[0170] R 9 、R 11 、R 12 and R 13 are each independently selected from a hydrogen atom, C 1-6 alkyl, a halogen atom, C 3-6 cycloalkyl, C 3-6 cycloalkyl(C 1-6 )alkoxy, halo(C 1-6 )alkyl, halo(C 1-6 )alkoxy, C 1-6 alkoxy(C 1-6 )alkyl, azetidinyl, C 1-6 alkoxy, a hydroxyl group, and hydroxyl(C 1-6 )alkyl; and

[0171] R 14 is a hydrogen atom, a halogen atom, or C 1-6 alkyl; and

[0172] R 15 and R 3 together form a bond;

[0173] or a salt thereof.

[0174] [9] The compound according to [1] above, wherein the partial structure represented by the following formula:

[0175]

[0176] wherein each symbol is as defined in [1] above,

[0177] is one of the partial structures represented by the following formula:

[0178]

[0179] and

[0180]

[0181] Each symbol is defined as described above in [1].

[0182]

[10] A compound according to [1] above, wherein said compound is represented by formula (Ia):

[0183] wherein

[0184] R 1 is C 1-6 alkyl, C 3-10 cycloalkyl or mono-C 1-6 alkylamino;

[0185] r is 0 or 1;

[0186] R 2 and R 3 are each independently a hydrogen atom, or when r is 0, then R 2 and R 3 may be joined together to form a bond;

[0187] R 4 is a hydrogen atom;

[0188] R 5 is phenyl optionally substituted with 1 to 3 halogen atoms;

[0189] R 6 and R 7 are each independently a hydrogen atom or a halogen atom;

[0190] X 5 is CH or N; and

[0191] R 12 and R 13 are each independently a hydrogen atom, C 1-6 alkyl or a halogen atom; or a salt thereof.

[0192]

[11] A compound according to

[10] above, wherein

[0193] R 1 is C 1-6 alkyl;

[0194] r is 0 or 1;

[0195] R 2 and R 3 are each a hydrogen atom, or

[0196] when r is 0, then R 2 and R 3can be combined together to form a bond;

[0197] R 4 is a hydrogen atom;

[0198] R 5 is a phenyl group substituted by 1 to 3 halogen atoms;

[0199] R 6 and R 7 are each a halogen atom;

[0200] X 5 is CH; and

[0201] R 12 and R 13 are each independently a hydrogen atom or a halogen atom;

[0202] or a salt thereof.

[0203]

[12] The compound according to [1] above, wherein the compound is represented by formula (Ib):

[0204]

[0205] wherein

[0206] R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group or an optionally substituted mono- or di-C 1-6 alkylamino group;

[0207] R 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group, or

[0208] R 2 and R 3 are combined together to form a bond;

[0209] R 4 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group;

[0210] R 5 is an optionally substituted 5- or 6-membered monocyclic group;

[0211] R 6 and R 7 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group;

[0212] m is 0 or 1;

[0213] q is 1 or 2;

[0214] X 1 is NR 8 or CR 9 ;

[0215] X 2 is O, NR 10 or S;

[0216] X 3 and X 4 are both C, or X 3 and X 4 one of them is N and the other is C;

[0217] X 5 is CR 11 or N;

[0218] X 6 is CR 12 ;

[0219] X 7 is CR 13 or N;

[0220] R 9 、R 11 、R 12 and R 13 each independently is a hydrogen atom, an optionally substituted C 1-6 alkyl, a halogen atom, an optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy or a hydroxyl group; and

[0221] R 8 and R 10 each independently does not exist, or is selected from a hydrogen atom and an optionally substituted C 1-6 alkyl;

[0222] or a salt thereof.

[0223] [12a] The compound according to

[12] above, wherein R 2 and R 3 are each a hydrogen atom; or a salt thereof.

[0224] [12b] The compound according to

[12] above, wherein R 2 and R 3 together form a bond; or a salt thereof.

[0225] [12c] The compound according to

[12] above, wherein m is 0; and q is 1; or a salt thereof.

[0226] [12d]Compound (I) according to

[12] above, wherein m is 1; and q is 1; or a salt thereof.

[0227] [12e]Compound according to

[12] above, wherein R 1 is C 1-6 alkyl; or a salt thereof.

[0228] [12f]Compound according to

[12] above, wherein

[0229] X 1 is NR 8 and R 8 is absent;

[0230] X 2 is O;

[0231] X 3 and X 4 are both C;

[0232] X 5 is CH or N;

[0233] X 6 is CR 12 and R 12 is a hydrogen atom, C 1-6 alkyl or a halogen atom; and

[0234] X 7 is CR 13 and R 13 is a hydrogen atom or a halogen atom;

[0235] or a salt thereof.

[0236]

[13] Compound according to

[12] above, wherein

[0237] R 1 is

[0238] (1) C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from:

[0239] (i) a halogen atom,

[0240] (ii) C 1-6 alkoxy, and

[0241] (iii) C 3-6 cycloalkyl,

[0242] (2) C 3-10 cycloalkyl, or

[0243] (3) mono- or di-C1-6 Alkylamino;

[0244] R 2 and R 3 each independently is a hydrogen atom or C 1-6 alkyl, or R 2 and R 3 together with each other form a bond;

[0245] R 4 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or hydroxy;

[0246] R 5 is phenyl, pyrazolyl, furyl, thienyl or thiazolyl, any one of which is optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halogen atom, halo(C 1-6 )alkyl and C 1-6 alkoxy;

[0247] m is 0 or 1;

[0248] q is 1 or 2;

[0249] R 6 and R 7 each independently is a hydrogen atom, halogen atom or C 1-6 alkyl;

[0250] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are selected to form a ring system, and the ring system is one of the following:

[0251] (i) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 ,and X 7 is CR 13 ;

[0252] (ii) X 1 is NR 8 and R 8 is absent, X 2 is O, X3 and X 4 are both C, X 5 is N, X 6 is CR 12 and X 7 is CR 13 ;

[0253] (iii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is N;

[0254] (iv) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 and X 7 is CR 13 ;

[0255] (v) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ;

[0256] (vi) X 1 is NR 8 and X 2 is NR 10 and R 8 and R 10 one of which does not exist and R 8 and R 10 the other is C 1-6 alkyl, X 3 and X 4 are both C, X 5 is CR 11, X 6 is CR 12 , and X 7 is CR 13 ;

[0257] (vii) X 1 is CR 9 , X 2 is NR 10 and R 10 is absent, X 3 is N, X 4 is C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and

[0258] (viii) X 1 is CR 9 , X 2 is NR 10 and R 10 is absent, X 3 is C, X 4 is N, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and

[0259] R 9 、R 11 、R 12 and R 13 each independently is selected from a hydrogen atom, C 1-6 alkyl, a halogen atom, C 3-6 cycloalkyl, C 3-6 cycloalkyl(C 1-6 )alkoxy, halo(C 1-6 )alkyl, halo(C 1-6 )alkoxy, C 1-6 alkoxy(C 1-6 )alkyl, azetidinyl, C 1-6 alkoxy, hydroxy and hydroxy(C 1-6 )alkyl;

[0260] or a salt thereof.

[0261]

[14] The compound according to [1] above, wherein the compound is represented by formula (Ic):

[0262]

[0263] wherein

[0264] R 1 is C 1-6 alkyl or mono-C 1-6 alkylamino;

[0265] R 2 and R 3 are each a hydrogen atom, or R 2 and R 3 together with each other form a bond;

[0266] R 4 is a hydrogen atom;

[0267] R 5 is phenyl optionally substituted by 1 to 3 halogen atoms;

[0268] R 6 and R 7 are each independently a hydrogen atom or a halogen atom;

[0269] X 5 is CH or N; and

[0270] R 12 and R 13 are each independently a hydrogen atom, C 1-6 alkyl or a halogen atom;

[0271] or a salt thereof.

[0272]

[15] The compound according to

[14] above, wherein

[0273] R 1 is C 1-6 alkyl;

[0274] R 2 and R 3 are each a hydrogen atom, or R 2 and R 3 together with each other form a bond;

[0275] R 4 is a hydrogen atom;

[0276] R 5 is phenyl substituted by 1 to 3 halogen atoms;

[0277] R 6 and R 7 are each a halogen atom;

[0278] X 5 is CH; and

[0279] R 12 and R 13Each independently is a hydrogen atom or a halogen atom;

[0280] or a salt thereof.

[0281]

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

[0282] N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0283] N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0284] N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0285] N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0286] N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0287] N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0288] N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0289] N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide;

[0290] N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide;

[0291] N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and

[0292] N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0293] or a salt thereof.

[0294]

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

[16] above.

[0295]

[18] The medicament according to

[17] above, said medicament being an orexin type 2 receptor agonist.

[0296]

[19] The medicament according to

[17] above, said medicament being 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 related to bone loss, sepsis, disturbance of consciousness, or side effects and complications caused by anesthesia.

[0297]

[20] The medicament according to

[17] above, said medicament being an agent for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia or sleep apnea syndrome.

[0298]

[21] The medicament according to

[17] above, said medicament being an agent for preventing or treating narcolepsy.

[0299]

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

[16] above.

[0300]

[23] According to the method of

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

[0301]

[24] According to the method of

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

[0302]

[25] According to the method of

[22] above, wherein the disease or disorder is narcolepsy.

[0303]

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

[16] above, said compound or a salt thereof being for use in therapy.

[0304]

[27] According to the compound or salt of

[26] above, wherein the therapy comprises treating a disease or disorder associated with the orexin type 2 receptor.

[0305]

[28] According to the compound or salt of

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

[0306]

[29] According to the compound or salt of

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

[0307]

[30] According to the compound or salt of

[27] above, wherein the disease or disorder is narcolepsy.

[0308]

[31] Use of a compound or a salt thereof as defined in any one of [1] to

[16] above for the manufacture of a medicament for treating a disease or disorder associated with the orexin type 2 receptor.

[0309]

[32] For the use according to

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

[0310]

[33] For the use according to

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

[0311]

[34] For the use according to

[31] above, wherein the disease or disorder is narcolepsy.

[0312] [Function of the present invention]

[0313] The compounds of the present invention have orexin type 2 receptor agonist activity and can be used as agents for preventing or treating certain diseases such as narcolepsy. Detailed Description of the Invention

[0314] The definitions of each substituent used in this specification are described in detail below. Unless otherwise specified, each substituent has the following definition.

[0315] In this specification, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.

[0316] In this specification, "C 1-6 alkyl" examples 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.

[0317] In this specification, "optionally halogenated C 1-6 alkyl" examples include C 1-6 alkyl optionally having 1 to 7, preferably 1 to 5, more preferably 1 to 3 halogen atoms. 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.

[0318] In this specification, "halo C1-6 Examples of "alkyl" include the above-mentioned "optionally halogenated C 1-6 alkyl" in "halogenated C 1-6 alkyl".

[0319] In this specification, examples of "C 2-6 alkenyl" include vinyl, 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.

[0320] In this specification, examples of "C 2-6 alkynyl" include ethynyl, 1-propynyl, 2-propynyl, 2-methyl-1-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butenyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-3-pentenyl, 1-hexynyl, 3-hexynyl, and 5-hexynyl.

[0321] In this specification, examples of "C 2-6 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.

[0322] In this specification, examples of "C 3-10 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.

[0323] In this specification, examples of "optionally halogenated C 3-10 cycloalkyl" include C 3-10 cycloalkyl optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0324] In this specification, examples of "C 3-10 cycloalkenyl" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0325] In this specification, examples of "C 7-16 arylalkyl" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0326] In this specification, examples of "C 1-6 alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0327] In this specification, examples of "optionally halogenated C 1-6 alkoxy" include C 1-6 alkoxy optionally having 1 to 7, preferably 1 to 5, more preferably 1 to 3 halogen atoms. 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.

[0328] In this specification, examples of "halo C 1-6 alkoxy" include "halogenated C 1-6 alkoxy" in the above "optionally halogenated C 1-6 alkoxy".

[0329] In this specification, examples of "C 3-10 cycloalkoxy" include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0330] In this specification, examples of "C 1-6 alkylthio" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0331] In this specification, examples of "optionally halogenated C 1-6 alkylthio" include C 1-6 alkylthio optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0332] In this specification, examples of "C 1-6 alkyl-carbonyl" include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl, and heptanoyl.

[0333] In this specification, examples of "optionally halogenated C 1-6 alkyl-carbonyl" include C 1-6Alkyl-carbonyl. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0334] In this specification, "C 1-6 Alkoxy-carbonyl" examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0335] In this specification, "C 6-14 Aryl-carbonyl" examples include benzoyl, 1-naphthoyl, and 2-naphthoyl.

[0336] In this specification, "C 7-16 Aralkyl-carbonyl" examples include phenylacetyl and phenylpropionyl.

[0337] In this specification, "5- to 14-membered aromatic heterocyclic group carbonyl" examples include nicotinoyl, isonicotinoyl, thiophenecarbonyl, and furancarbonyl.

[0338] In this specification, "3- to 14-membered non-aromatic heterocyclic group carbonyl" examples include morpholinocarbonyl, piperidinocarbonyl, and pyrrolidinocarbonyl.

[0339] In this specification, "mono- or di-C 1-6 Alkyl-carbamoyl" examples include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0340] In this specification, "optionally substituted mono- or di-C 1-6 Alkylamino" examples include an amino group having one or two C 1-6 Alkyl groups. The C 1-6 Alkyl moiety of the amino group may optionally have 1 or 2 substituents selected from the following: 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 heterocyclic group carbonyl, 3- to 14-membered non-aromatic heterocyclic group carbonyl, 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 6-14An arylsulfonyl group, each optionally having 1 to 3 substituents selected from Substituent Group A.

[0341] In the present specification, examples of "optionally substituted amino" include amino optionally having: "1 or 2 substituents selected from the following: 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 heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, 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 arylsulfonyl, each optionally having 1 to 3 substituents selected from Substituent Group A".

[0342] Preferred examples of the optionally substituted amino 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 (e.g., 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., piperidylcarbonylamino), mono- or di-C 1-6 alkoxy-carbonylamino (e.g., tert-butoxycarbonylamino), 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 (arylalkyl-carbamoyl)amino (e.g., benzylcarbamoylamino), C 1-6 (alkylsulfonyl)amino (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 (arylsulfonyl)amino (e.g., phenylsulfonylamino), (C 1-6 (alkyl)(C 1-6 (alkyl-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).

[0343] In this specification, "hydroxyl" means -OH. In this specification, "hydroxyl" and "hydroxy" are the same.

[0344] In this specification, examples of "4-, 5- or 6-membered monocyclic group" include 4-, 5- or 6-membered monocyclic groups selected from cycloalkyl, C 3-10 cycloalkenyl, C 3-10 aryl and heterocyclic group (e.g., aromatic heterocyclic group or non-aromatic heterocyclic group). 6-14

[0345] In this specification, examples of "C 6-14 aryl" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0346] In this specification, examples of "heterocycle" include aromatic heterocycles and non-aromatic heterocycles, each containing 1 to 4 (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen atom, sulfur atom, oxygen atom and combinations thereof as ring-forming atoms other than carbon atoms.

[0347] In this specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered, more preferably 5- to 6-membered) aromatic heterocycles, which contain 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof as ring-forming atoms other than carbon atoms. 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, etc.; and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thiophenopyridine, furanopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thiophenopyrimidine, furanopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine, etc.

[0348] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered, more preferably 5- to 6-membered) non-aromatic heterocycles, which contain 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, and combinations thereof as ring-forming atoms other than carbon atoms. Examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles, such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyrazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepatriene, azocane, diazocane, oxepane, etc.; and 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocycles, such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepatriene, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophtalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydro-phenazine, tetrahydrothioxanthene, octahydroisoquinoline, etc.

[0349] In the present specification, examples of the "3- to 7-membered nitrogen-containing heterocycle" include the 3- to 7-membered "heterocyclic group" as described herein that contains at least one (e.g., 1, 2, 3, etc.) nitrogen atom as a ring-forming atom.

[0350] In the present specification, examples of the "acyl group" include formyl, carboxyl, carbamoyl, thiocarbamoyl, sulfinyl, sulfonyl, sulfamoyl, and phosphonyl, each optionally having "1 or 2 substituents selected from the following: 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, and 3- to 14-membered non-aromatic heterocyclic group, each optionally having 1 to 3 substituents selected from a halogen atom, optionally halogenated C 1-6 alkoxy, hydroxyl, nitro, cyano, amino, and carbamoyl".

[0351] Examples of the "acyl group" also include hydrocarbon-sulfonyl, heterocyclic group-sulfonyl, hydrocarbon-sulfinyl, and heterocyclic group-sulfinyl.

[0352] Herein, hydrocarbon-sulfonyl means a sulfonyl group bonded to a hydrocarbon group, heterocyclic-sulfonyl means a sulfonyl group bonded to a heterocyclic group, hydrocarbon-sulfinyl means a sulfinyl group bonded to a hydrocarbon group, and heterocyclic-sulfinyl means a sulfinyl group bonded to a heterocyclic group.

[0353] Examples of "acyl group" 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 7-16 aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclic-carbonyl, 3- to 14-membered non-aromatic heterocyclic-carbonyl, C 1-6 alkoxy-carbonyl, C 6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl), C 7-16 aralkoxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), 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), 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), sulfo, C 1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl), sulfonyl, C 1-6 alkylsulfonyl, C 6-14Aryl sulfonyl, phosphonyl, and mono- or di-C 1-6 alkylphosphonyl (e.g., dimethylphosphonyl, diethylphosphonyl, diisopropylphosphonyl, dibutylphosphonyl).

[0354] In this specification, examples of "5- to 14-membered aromatic heterocyclic carbonyl" include nicotinoyl, isonicotinoyl, thiophenecarbonyl, and furancarbonyl.

[0355] In this specification, examples of "3- to 14-membered non-aromatic heterocyclic carbonyl" include morpholinocarbonyl, piperidinocarbonyl, and pyrrolidinocarbonyl.

[0356] In this specification, examples of "optionally substituted carbamoyl" include carbamoyl optionally having the following: "1 or 2 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-16 arylalkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocycle, carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, and mono- or di-C 7-16 arylalkyl-carbamoyl, each optionally having 1 to 3 substituents selected from substituent group A".

[0357] Preferred examples of optionally substituted carbamoyl 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 arylalkyl-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 heterocyclic carbamoyl (e.g., pyridylcarbamoyl).

[0358] In this specification, examples of "optionally substituted thiocarbamoyl" include thiocarbamoyl optionally having the following: "1 or 2 substituents selected from the following: 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 heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, 5- to 14-membered aromatic heterocycle, carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl and mono- or di-C 7-16 aralkyl-carbamoyl, each optionally having 1 to 3 substituents selected from substituent group A".

[0359] Preferred examples of optionally substituted thiocarbamoyl 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 (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridylthiocarbamoyl).

[0360] In this specification, examples of "optionally substituted sulfamoyl" include sulfamoyl optionally having the following: "1 or 2 substituents selected from the following: 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 6-14Aryl-carbonyl, C 7-16 Aralkyl-carbonyl, 5- to 14-membered aromatic heterocyclic-carbonyl, 3- to 14-membered non-aromatic heterocyclic-carbonyl, 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 Aralkyl-carbamoyl, each optionally having 1 to 3 substituents selected from substituent group A”.

[0361] Preferred examples of optionally substituted sulfamoyl groups 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).

[0362] In this specification, examples of “optionally substituted hydroxy” include hydroxy optionally having the following: “substituents 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 heterocyclic-carbonyl, 3- to 14-membered non-aromatic heterocyclic-carbonyl, 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 Arylsulfonyl, each optionally having 1 to 3 substituents selected from substituent group A”.

[0363] Preferred examples of the optionally substituted hydroxy group include hydroxy, C 1-6 alkoxy, C 2-6 alkenyloxy (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 cycloalkoxy (e.g., cyclohexyloxy), C 6-14 aryloxy (e.g., phenoxy, naphthyloxy), C 7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy), C 1-6 alkyl-carbonyloxy (e.g., acetoxy, 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 heterocyclic group carbonyloxy (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclic group carbonyloxy (e.g., piperidinylcarbonyloxy), C 1-6 alkoxy-carbonyloxy (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (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 (e.g., phenylsulfonyloxy).

[0364] In the present specification, examples of the "optionally substituted thioalkyl" include thioalkyl optionally having the following: "substituents selected from the following: 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 5- to 14-membered aromatic heterocyclic groups, each optionally having 1 to 3 substituents selected from substituent group A", and halogenated thioalkyl.

[0365] Preferred examples of the optionally substituted thioalkyl include thioalkyl (-SH) groups, 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 7-16Arylalkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 alkyl-carbonothioyl groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonothioyl groups (e.g., benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (e.g., pyridylthio), and halogenated thio groups (e.g., pentafluorothio).

[0366] In the present specification, examples of "optionally substituted silyl groups" include silyl groups optionally having the following: "1 to 3 substituents selected from the following: C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 aryl, and C 7-16 arylalkyl, each optionally having 1 to 3 substituents selected from substituent group A".

[0367] Preferred examples of optionally substituted silyl groups include tri-C 1-6 alkylsilyl groups (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0368] In the present specification, examples of "hydrocarbon rings" include C 6-14 aromatic hydrocarbon rings, C 3-10 cycloalkanes, and C 3-10 cycloalkenes.

[0369] In the present specification, examples of "mono- or di-C 7-16 arylalkyl-carbamoyl" include benzylcarbamoyl and phenethylcarbamoyl.

[0370] In the present specification, examples of "C 1-6 alkylsulfonyl" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

[0371] In the present specification, examples of "optionally halogenated C 1-6 alkylsulfonyl" include C 1-6 alkylsulfonyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0372] In the present specification, examples of "C 6-14 arylsulfonyl" include phenylsulfonyl, 1-naphthalenesulfonyl, and 2-naphthalenesulfonyl.

[0373] In this specification, examples of "hydrocarbyl" (including "hydrocarbyl" in "optionally substituted hydrocarbyl") 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 arylalkyl.

[0374] In this specification, examples of "heterocyclic group" (including "heterocyclic group" in "optionally substituted heterocyclic group") include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered bridged heterocyclic groups, each containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom as ring-forming atoms other than carbon atoms.

[0375] In this specification, examples of "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, which contain 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom as ring-forming atoms other than carbon atoms.

[0376] Preferred examples of "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.; and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridyl, thienopyridyl, furanopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0377] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups, which contain 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom as ring-forming atoms other than carbon atoms.

[0378] Preferred examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuryl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridyl, dihydropyridyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepatrieneyl, oxepanyl, azocanyl, diazocanyl, etc.; and 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, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzazepatrieneyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophtalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolinyl, etc.

[0379] In the present specification, preferred examples of the "7- to 10-membered bridged heterocyclic group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptyl.

[0380] In the present specification, examples of the "nitrogen-containing heterocyclic group" include "heterocyclic groups" containing at least one nitrogen atom as a ring-forming atom.

[0381] In the present specification, examples of the "optionally substituted heterocyclic group" include heterocyclic groups optionally having one or more substituents selected from the above substituent group A.

[0382] 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, each substituent may be the same or different.

[0383] In the present specification, "C 6-14Examples of the "aromatic hydrocarbon ring" include benzene and naphthalene.

[0384] In this specification, "C 3-10 Examples of the "cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0385] In this specification, "C 3-10 Examples of the "cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.

[0386] In this specification, examples of the "nitrogen-containing heterocycle" include heterocycles containing at least one nitrogen atom as a ring-forming atom selected from the "heterocycles".

[0387] In this specification, examples of the "4- to 6-membered heterocyclic group" include aromatic or non-aromatic 4- to 6-membered heterocyclic groups. Specific examples thereof include oxetanyl, furyl, pyrazolyl, pyridyl, and pyrimidinyl.

[0388] In this specification, examples of the "ring" include "hydrocarbon rings" and "heterocycles".

[0389] In this specification, certain portions may be "optionally substituted", meaning that the group optionally has one or more substituents selected from the following substituent group A.

[0390] [Substituent group A]

[0391] (1) A halogen atom,

[0392] (2) A nitro group,

[0393] (3) A cyano group,

[0394] (4) An oxo group,

[0395] (5) A hydroxyl group,

[0396] (6) Optionally halogenated C 1-6 An alkoxy group,

[0397] (7) C 6-14 An aryloxy group (e.g., phenoxy, naphthyloxy),

[0398] (8) C 7-16 An aralkyloxy group (e.g., benzyloxy),

[0399] (9) A 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy),

[0400] (10) A 3- to 14-membered non-aromatic heterocyclic oxy group (e.g., tetrahydropyranyloxy, morpholinooxy, piperidinooxy),

[0401] (11) C 1-6Alkyl-carbonyloxy (e.g., acetoxy, propionyloxy),

[0402] (12)C 6-14 Aryl-carbonyloxy (e.g., benzoyloxy, 1-naphthoyl-oxy, 2-naphthoyloxy),

[0403] (13)C 1-6 Alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

[0404] (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

[0405] (15)C 6-14 Aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy),

[0406] (16) 5- to 14-membered aromatic heterocyclic group carbonyloxy (e.g., nicotinoyloxy),

[0407] (17) 3- to 14-membered non-aromatic heterocyclic group carbonyloxy (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

[0408] (18) Optionally halogenated C 1-6 Alkylsulfonyloxy (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy),

[0409] (19) Optionally substituted by C 1-6 Alkyl-substituted C 6-14 Arylsulfonyloxy (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

[0410] (20) Optionally halogenated C 1-6 Alkylthio,

[0411] (21) 5- to 14-membered aromatic heterocyclic group,

[0412] (22) 3- to 14-membered non-aromatic heterocyclic group,

[0413] (23) Formyl,

[0414] (24) Carboxyl,

[0415] (25) Optionally halogenated C 1-6 Alkyl-carbonyl,

[0416] (26)C 6-14 Aryl-carbonyl,

[0417] (27) 5- to 14-membered aromatic heterocyclic group carbonyl,

[0418] (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group

[0419] (29) C 1-6 alkoxy-carbonyl

[0420] (30) C 6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl)

[0421] (31) C 7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl)

[0422] (32) carbamoyl

[0423] (33) thiocarbamoyl

[0424] (34) mono- or di-C 1-6 alkyl-carbamoyl

[0425] (35) C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl)

[0426] (36) a 5- to 14-membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl, thienylcarbamoyl)

[0427] (37) a 3- to 14-membered non-aromatic heterocyclic carbamoyl (e.g., morpholinocarbamoyl, piperidinocarbamoyl)

[0428] (38) optionally halogenated C 1-6 alkylsulfonyl

[0429] (39) C 6-14 arylsulfonyl

[0430] (40) a 5- to 14-membered aromatic heterocyclic sulfonyl (e.g., pyridylsulfonyl, thienylsulfonyl)

[0431] (41) optionally halogenated C 1-6 alkylsulfinyl

[0432] (42) C 6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl)

[0433] (43) a 5- to 14-membered aromatic heterocyclic sulfinyl (e.g., pyridylsulfinyl, thienylsulfinyl)

[0434] (44) amino

[0435] (45) mono- or di-C 1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

[0436] (46) mono- or di-C 6-14 arylamino (e.g., phenylamino),

[0437] (47) 5- to 14-membered aromatic heterocyclic amino (e.g., pyridylamino),

[0438] (48) C 7-16 aralkylamino (e.g., benzylamino),

[0439] (49) formylamino,

[0440] (50) C 1-6 alkyl-carbonylamino (e.g., acetylamino, propionylamino, butyrylamino),

[0441] (51) (C 1-6 alkyl)(C 1-6 alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino),

[0442] (52) C 6-14 aryl-carbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino),

[0443] (53) C 1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),

[0444] (54) C 7-16 aralkoxy-carbonylamino (e.g., benzyloxycarbonylamino),

[0445] (55) C 1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino),

[0446] (56) optionally C 1-6 alkyl-substituted C 6-14 arylsulfonylamino (e.g., phenylsulfonylamino, toluenesulfonylamino),

[0447] (57) optionally halogenated C 1-6 alkyl,

[0448] (58) C 2-6 alkenyl,

[0449] (59) C2-6 alkynyl

[0450] (60)C 3-10 cycloalkyl

[0451] (61)C 3-10 cycloalkenyl, and

[0452] (62)C 6-14 aryl

[0453] In some aspects, examples of "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted thioalkyl (SH) group, and an optionally substituted silyl group.

[0454] The number of the above substituents is, for example, 1 to 5 (e.g., 1, 2, 3, 4, or 5), preferably 1 to 3 (e.g., 1, 2, or 3). When the number of substituents is two or more, each substituent may be the same or different.

[0455] A detailed explanation of the definition of each symbol in compound (I) is provided.

[0456] R 1 is an optionally substituted C 1-6 alkyl, an optionally substituted C 3-10 cycloalkyl, or an optionally substituted mono- or di-C 1-6 alkylamino.

[0457] In some aspects, R 1 is

[0458] (1) C 1-6 alkyl (e.g., methyl, ethyl) optionally substituted with 1 to 3 substituents independently selected from:

[0459] (i) a halogen atom (e.g., a fluorine atom),

[0460] (ii) C 1-6 alkoxy (e.g., methoxy), and

[0461] (iii) C 3-6 cycloalkyl (e.g., cyclopropyl),

[0462] (2) C 3-10 cycloalkyl (e.g., cyclopropyl), or

[0463] (3) mono- or di-C 1-6 alkylamino (e.g., methylamino, dimethylamino).

[0464] In some aspects, R 1 is C 1-6 alkyl (e.g., methyl, ethyl), C 3-10 cycloalkyl (preferably C 3-6 cycloalkyl, such as cyclopropyl) or mono-C 1-6 alkylamino (e.g., methylamino).

[0465] In some aspects, R 1 is C 1-6 alkyl (e.g., methyl, ethyl) or mono-C 1-6 alkylamino (e.g., methylamino).

[0466] In some aspects, R 1 is C 1-6 alkyl (e.g., methyl, ethyl).

[0467] R 2 and R 3 are each independently a hydrogen atom or optionally substituted C 1-6 alkyl. Alternatively, when r is 0, then R 2 and R 3 can combine together to form a bond. Alternatively, when X 10 is R 15 then R 3 can combine with R 15 to form a bond.

[0468] In some aspects, R 2 and R 3 are each independently a hydrogen atom or C 1-6 alkyl (e.g., methyl), or when r is 0, then R 2 and R 3 can combine together to form a bond, or when X 10 is R 15 then R 3 combines with R 15 to form a bond.

[0469] In some aspects, R 2 and R 3 are each a hydrogen atom, or when r is 0, then R 2 and R 3 can combine together to form a bond, or when X 10 is R 15 then R 3 combines with R 15 to form a bond.

[0470] In some aspects, in the case where X 10 is N, R 2 and R3 Each independently is a hydrogen atom, or when r is 0, then R 2 and R 3 may combine with each other to form a bond.

[0471] In some aspects, when X 10 is N, R 2 and R 3 are each a hydrogen atom, or when r is 0, then R 2 and R 3 may combine with each other to form a bond.

[0472] When R 2 and R 3 combine with each other to form a bond, the ring containing X 8 、X 9 and X 10 includes a double bond between the carbons connected to R 2 and R 3 .

[0473] R 4 is a hydrogen atom, an optionally substituted C 1-6 alkyl, an optionally substituted C 1-6 alkoxy or a hydroxyl group.

[0474] In some aspects, R 4 is a hydrogen atom, a C 1-6 alkyl (e.g., methyl), a C 1-6 alkoxy (e.g., ethoxy) or a hydroxyl group.

[0475] In some aspects, R 4 is a hydrogen atom.

[0476] R 5 is an optionally substituted 4-membered, 5-membered or 6-membered monocyclic group.

[0477] In some aspects, R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl or cyclobutyl, any of which is optionally substituted by one or more (e.g., 1, 2, 3, etc.) substituents independently selected from C 1-6 alkyl (e.g., methyl), a halogen atom (e.g., fluorine atom, chlorine atom), a halo(C 1-6 )alkyl (e.g., trifluoromethyl) and C 1-6 alkoxy (e.g., methoxy).

[0478] In some aspects, R 5 is phenyl optionally substituted by 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms).

[0479] In some aspects, R 5 is a phenyl group substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms).

[0480] In some aspects, R 5 is a phenyl group substituted with 2 or 3 fluorine atoms (e.g., 2,6-substituted or 2,4,6-substituted).

[0481] In some aspects, R 5 is a phenyl group substituted with 3 fluorine atoms (e.g., 2,4,6-substituted).

[0482] R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group.

[0483] In some aspects, R 6 and R 7 are each independently a hydrogen atom, a halogen atom (e.g., fluorine atom), or a C 1-6 alkyl group (e.g., methyl group).

[0484] In some aspects, R 6 and R 7 are each independently a hydrogen atom or a halogen atom (e.g., fluorine atom).

[0485] In some aspects, R 6 and R 7 are each a hydrogen atom, or each is a halogen atom (e.g., fluorine atom).

[0486] In some aspects, R 6 and R 7 are each a halogen atom (e.g., fluorine atom).

[0487] The subscript “m” together with “q” is 0 (to form a 5-membered or 6-membered ring) or 1 (to form a 6-membered or 7-membered ring).

[0488] The subscript “q” together with “m” is 1 (to form a 5-membered or 6-membered ring) or 2 (to form a 6-membered or 7-membered ring).

[0489] In some aspects, m is 0; and q is 1 to form a 5-membered ring.

[0490] In some aspects, m is 1; and q is 1 to form a 6-membered ring.

[0491] The subscript “r” is 0 (to form a 5-membered ring) or 1 (to form a 6-membered ring).

[0492] In some aspects, the combination of m, q, and r is: m is 0; q is 1; and r is 0.

[0493] In some aspects, the combination of m, q, and r is: m is 1; q is 1; and r is 0.

[0494] In some aspects, the combination of m, q, and r is: m is 0; q is 1; and r is 1.

[0495] In some aspects, the combination of m, q, and r is: m is 0; q is 2; and r is 0.

[0496] X 1 is NR 8 or CR 9 , where R 8 is absent (i.e., = N-), or is selected from a hydrogen atom and an optionally substituted C 1-6 alkyl, and R 9 is a hydrogen atom, an optionally substituted C 1-6 alkyl, a halogen atom, an optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy, or a hydroxyl group.

[0497] In some aspects, X 1 is NR 8 , where R 8 is absent (i.e., = N-), or is a C 1-6 alkyl (e.g., methyl).

[0498] In some aspects, X 1 is NR 8 , where R 8 is absent (i.e., = N-).

[0499] In some aspects, X 1 is CR 9 , where R 9 is a hydrogen atom or a C 1-6 alkyl (e.g., methyl).

[0500] X 2 is O, NR 10 or S, where R 10 is absent (i.e., = N-), or is selected from a hydrogen atom and an optionally substituted C 1-6 alkyl.

[0501] In some aspects, X 2 is O.

[0502] In some aspects, X 2 is NR 10 , where R 10 is absent, or is a C 1-6 alkyl (e.g., methyl).

[0503] In some aspects, X 2 is S.

[0504] X 3 and X 4 (i) are both C, or (ii) one of X 3 and X 4 is N and the other is C.

[0505] In some aspects, X 3 and X 4 are both C.

[0506] In some aspects, X 3 is N, and X 4 is C.

[0507] In some aspects, X 3 is C, and X 4 is N.

[0508] X 5 is CR 11 or N, where R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl, a halogen atom, an optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy or a hydroxyl group.

[0509] In some aspects, X 5 is N.

[0510] In some aspects, X 5 is CR 11 where R 11 is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or C 1-6 alkyl (e.g., methyl).

[0511] In some aspects, X 5 is CR 11 or N, where R 11 is a hydrogen atom.

[0512] X 6 is CR 12 where R 12 is a hydrogen atom, an optionally substituted C 1-6 alkyl, a halogen atom, an optionally substituted C 3-6 cycloalkyl, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy or a hydroxyl group.

[0513] In some aspects, R 12is a hydrogen atom, C 1-6 alkyl (e.g., methyl, ethyl), halogen atom (e.g., fluorine atom, chlorine atom, bromine atom), C 3-6 cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl(C 1-6 )alkoxy (e.g., cyclopropylmethoxy), halo(C 1-6 )alkyl (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 )alkoxy (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 alkoxy(C 1-6 )alkyl (e.g., methoxymethyl), azetidinyl, C 1-6 alkoxy (e.g., methoxy, ethoxy), hydroxy or hydroxy(C 1-6 )alkyl (e.g., hydroxymethyl, 2-hydroxyethyl);

[0514] In some aspects, R 12 is a hydrogen atom, C 1-6 alkyl (e.g., methyl) or halogen atom (e.g., chlorine atom or fluorine atom).

[0515] In some aspects, R 12 is a hydrogen atom or halogen atom (e.g., fluorine atom).

[0516] X 7 is CR 13 or N, where R 13 is a hydrogen atom, optionally substituted C 1-6 alkyl, halogen atom, optionally substituted C 3-6 cycloalkyl, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, optionally substituted C 1-6 alkoxy or hydroxy.

[0517] In some aspects, X 7 is N.

[0518] In some aspects, X 7 is CR 13 where R 13 is a hydrogen atom or halogen atom (e.g., fluorine atom, chlorine atom).

[0519] In some aspects, X 1 X 2 X 3 X 4 X 5 X 6 and X 7Selected to form a ring system, which is pyrazolopyridine, 1,2-benzoxazole, indazole, imidazopyridine, 1,2-benzothiazole, [1,2]oxazolo[4,5-c]pyridine, isoxazolo[5,4-b]pyridine or isothiazolo[5,4-b]pyridine.

[0520] In these aspects, R 9 , R 11 , R 12 and R 13 are each independently selected from a hydrogen atom, C 1-6 alkyl (e.g., methyl, ethyl), a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom), C 3-6 cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl(C 1-6 )alkoxy (e.g., cyclopropylmethoxy), halo(C 1-6 )alkyl (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 )alkoxy (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 alkoxy(C 1-6 )alkyl (e.g., methoxymethyl), azetidinyl, C 1-6 alkoxy (e.g., methoxy, ethoxy), hydroxyl and hydroxyl(C 1-6 )alkyl (e.g., hydroxymethyl, 2-hydroxyethyl); and

[0521] R 8 and R 10 each independently do not exist (i.e., =N-), or are selected from a hydrogen atom and C 1-6 alkyl (e.g., methyl).

[0522] In some aspects,

[0523] X 1 is NR 8 , where R 8 does not exist (i.e., =N-);

[0524] X 2 is O;

[0525] X 3 and X 4 are both C;

[0526] X 5 is CR 11 or N, where R 11 is a hydrogen atom;

[0527] X 6 is CR 12 , where R 12 is a hydrogen atom, C1-6 an alkyl group (e.g., a methyl group) or a halogen atom (e.g., a chlorine atom or a fluorine atom); and

[0528] X 7 is CR 13 wherein R 13 is a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0529] In some aspects, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are selected to form a ring system, and the ring system is one of the following:

[0530] (i) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 ,and X 7 is CR 13 ;

[0531] (ii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 ,and X 7 is CR 13 ;

[0532] (iii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 ,and X 7 is N;

[0533] (iv) X 1 is NR 8 and R8 Absent, X 2 Is S, X 3 And X 4 Both are C, X 5 Is N, X 6 Is CR 12 , and X 7 Is CR 13 ;

[0534] (v) X 1 Is NR 8 And R 8 Absent, X 2 Is S, X 3 And X 4 Both are C, X 5 Is CR 11 , X 6 Is CR 12 , and X 7 Is CR 13 ;

[0535] (vi) X 1 Is NR 8 And X 2 Is NR 10 , and R 8 And R 10 One of them is absent and R 8 And R 10 The other is C 1-6 Alkyl (e.g., methyl), X 3 And X 4 Both are C, X 5 Is CR 11 , X 6 Is CR 12 , and X 7 Is CR 13 ;

[0536] (vii) X 1 Is CR 9 , X 2 Is NR 10 And R 10 Absent, X 3 Is N, X 4 Is C, X 5 Is CR 11 , X 6 Is CR 12 , and X 7 Is CR 13 ; and

[0537] (viii) X 1 Is CR 9 , X2 is NR 10 and R 10 does not exist, X 3 is C, X 4 is N, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 .

[0538] In some aspects, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are selected to form a ring system, and the ring system is one of the following:

[0539] (i)X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and

[0540] (ii)X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 .

[0541] In some aspects, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are selected to form a ring system, where (i)X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3and X 4 are both C, and X 5 is CR 11 , and X 6 is CR 12 , and furthermore X 7 is CR 13 .

[0542] In some aspects, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are selected to form a ring system, where (i) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 , and X 4 are both C, X 5 is CH, X 6 is CR 12 , and furthermore X 7 is CR 13 .

[0543] In these aspects, R 9 , R 11 , R 12 , and R 13 are each independently selected from a hydrogen atom, C 1-6 alkyl (e.g., methyl, ethyl), a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom), C 3-6 cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl(C 1-6 )alkoxy (e.g., cyclopropylmethoxy), halo(C 1-6 )alkyl (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 )alkoxy (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 alkoxy(C 1-6 )alkyl (e.g., methoxymethyl), azetidinyl, C 1-6 alkoxy (e.g., methoxy, ethoxy), hydroxy, and hydroxy(C 1-6 )alkyl (e.g., hydroxymethyl, 2-hydroxyethyl).

[0544] X 8 is CR 14 or N, where R 14 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl.

[0545] In some aspects, X 8 is N.

[0546] In some aspects, X 8 is CR 14 , where R 14 is a hydrogen atom.

[0547] X 9 is CR 2 or N, where R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl, or when r is 0, then R 2 can combine with R 3 to form a bond.

[0548] In some aspects, X 9 is CR 2 , where R 2 is a hydrogen atom or C 1-6 alkyl (e.g., methyl), or when r is 0, then R 2 can combine with R 3 to form a bond.

[0549] In some aspects, X 9 is CR 2 , where R 2 is a hydrogen atom, or when r is 0, then R 2 can combine with R 3 to form a bond.

[0550] In some aspects, X 9 is CR 2 , where R 2 is a hydrogen atom.

[0551] In some aspects, X 9 is CR 2 , r is 0, and R 2 combines with R 3 to form a bond.

[0552] In some aspects, X 9 is N.

[0553] X 10 is CR 15 or N, where R 15 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl, or R 15 can combine with R 3 to form a bond.

[0554] In some aspects, X 10 is N.

[0555] In some aspects, X 10 is CR 15 , where R 15 and R 3 together form a bond.

[0556] In some aspects,

[0557] X 8 is N;

[0558] X 9 is CR 2 , where R 2 is a hydrogen atom, or when r is 0, then R 2 can combine with R 3 together to form a bond; and

[0559] X 10 is N.

[0560] In some aspects,

[0561] X 8 is N;

[0562] X 9 is CR 2 , where R 2 is a hydrogen atom; and

[0563] X 10 is N.

[0564] In some aspects,

[0565] X 8 is N;

[0566] X 9 is CR 2 , where r is 0 and R2 combines with R 3 together to form a bond; and

[0567] X 10 is N.

[0568] In some aspects, X 8 , X 9 , X 10 , m, q and r are selected to form a ring system, and the ring system is one of the following:

[0569] (i) X 8 is N, X 9 is CR 2 , X 10 is N, m is 0, q is 1, and r is 0;

[0570] (ii) X 8 is N, X9 is CR 2 and X 10 is N, m is 1, q is 1, and r is 0;

[0571] (iii) X 8 is N, X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 1;

[0572] (iv) X 8 is N, X 9 is N, X 10 is CR 15 and m is 0, q is 1, and r is 0;

[0573] (v) X 8 is CR 14 and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 0; and

[0574] (vi) X 8 is N, X 9 is CR 2 and X 10 is N, m is 0, q is 2, and r is 0.

[0575] In some aspects, X 8 , X 9 , X 10 , m, q, and r are selected to form a ring system that is one of the following:

[0576] (i) X 8 is N, X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 0; and

[0577] (iii) X 8 is N, X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 1.

[0578] In these aspects,

[0579] R 2 is a hydrogen atom or C 1-6 alkyl (e.g., methyl), or when r is 0, then R 2 can combine with R 3 to form a bond;

[0580] R 14 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group; and

[0581] R 15 and R 3 together form a bond;

[0582] In some aspects, a partial structure represented by the following formula:

[0583]

[0584] where each symbol is as defined above,

[0585] is one of the partial structures represented by the following formula:

[0586]

[0587] and

[0588] where each symbol is as defined above.

[0589] In some aspects of compound (I),

[0590] R 1 is

[0591] (1) C 1-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 substituents independently selected from:

[0592] (i) a halogen atom (e.g., fluorine atom),

[0593] (ii) C 1-6 alkoxy group (e.g., methoxy), and

[0594] (iii) C 3-6 cycloalkyl group (e.g., cyclopropyl),

[0595] (2) C 3-10 cycloalkyl group (e.g., cyclopropyl), or

[0596] (3) mono- or di-C 1-6 alkylamino group (e.g., methylamino, dimethylamino);

[0597] R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (e.g., methyl), or

[0598] when r is 0, then R 2 and R 3can be joined together to form a bond with each other, or

[0599] When X 10 is CR 15 then R 3 joins with R 15 to form a bond;

[0600] R 4 is a hydrogen atom, C 1-6 alkyl (e.g., methyl), C 1-6 alkoxy (e.g., ethoxy) or hydroxyl;

[0601] R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl or cyclobutyl, any of which is optionally substituted by one or more (e.g., 1, 2, 3, etc.) substituents independently selected from C 1-6 alkyl (e.g., methyl), halogen atom (e.g., fluorine atom, chlorine atom), halo (C 1-6 ) alkyl (e.g., trifluoromethyl) and C 1-6 alkoxy (e.g., methoxy);

[0602] R 6 and R 7 are each independently a hydrogen atom, halogen atom (e.g., fluorine atom) or C 1-6 alkyl (e.g., methyl);

[0603] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are selected to form a ring system, and the ring system is one of the following:

[0604] (i) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 ,X 6 is CR 12 ,and X 7 is CR 13 ;

[0605] (ii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3and X 4 are both C, X 5 is N, X 6 is CR 12 and X 7 is CR 13 ;

[0606] (iii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is N;

[0607] (iv) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 and X 7 is CR 13 ;

[0608] (v) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ;

[0609] (vi) X 1 is NR 8 and X 2 is NR 10 and one of R 8 and R 10 does not exist and the other of R 8 and R 10 is C 1-6 alkyl (e.g., methyl), X 3 and X 4 are both C, X 5 is CR 11 X6 is CR 12 and X 7 is CR 13 ;

[0610] (vii)X 1 is CR 9 X 2 is NR 10 and R 10 does not exist, X 3 is N, X 4 is C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ; and

[0611] (viii)X 1 is CR 9 X 2 is NR 10 and R 10 does not exist, X 3 is C, X 4 is N, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ;

[0612] X 8 X 9 X 10 , m, q and r are selected to form a ring system, and the ring system is one of the following:

[0613] (i)X 8 is N, X 9 is CR 2 X 10 is N, m is 0, q is 1, and r is 0;

[0614] (ii)X 8 is N, X 9 is CR 2 X 10 is N, m is 1, q is 1, and r is 0;

[0615] (iii)X 8 is N, X 9 is CR 2 X 10 is N, m is 0, q is 1, and r is 1;

[0616] (iv)X8 is N, X 9 is N, X 10 is CR 15 , m is 0, q is 1, and r is 0;

[0617] (v) X 8 is CR 14 , X 9 is CR 2 , X 10 is N, m is 0, q is 1, and r is 0; and

[0618] (vi) X 8 is N, X 9 is CR 2 , X 10 is N, m is 0, q is 2, and r is 0;

[0619] R 9 、R 11 、R 12 and R 13 each independently selected from a hydrogen atom, C 1-6 alkyl (e.g., methyl, ethyl), a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom), C 3-6 cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl(C 1-6 ) alkoxy (e.g., cyclopropylmethoxy), halo(C 1-6 ) alkyl (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 ) alkoxy (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 alkoxy(C 1-6 ) alkyl (e.g., methoxymethyl), azetidinyl, C 1-6 alkoxy (e.g., methoxy, ethoxy), hydroxy and hydroxy(C 1-6 ) alkyl (e.g., hydroxymethyl, 2-hydroxyethyl); and

[0620] R 14 is a hydrogen atom; and

[0621] R 15 combines with R 3 to form a bond.

[0622] In some aspects, the compound (I) is represented by formula (Ia):

[0623]

[0624] wherein

[0625] R 1 is C 1-6Alkyl (e.g., methyl, ethyl), C 3-10 Cycloalkyl (preferably C 3-6 Cycloalkyl, such as cyclopropyl) or mono-C 1-6 Alkylamino (e.g., methylamino);

[0626] r is 0 or 1;

[0627] R 2 and R 3 are each independently a hydrogen atom, or

[0628] when r is 0, then R 2 and R 3 can combine with each other to form a bond;

[0629] R 4 is a hydrogen atom;

[0630] R 5 is a phenyl group optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms);

[0631] R 6 and R 7 are each independently a hydrogen atom or a halogen atom (e.g., fluorine atom);

[0632] X 5 is CH or N; and

[0633] R 12 and R 13 are each independently a hydrogen atom, C 1-6 alkyl (e.g., methyl) or a halogen atom (e.g., fluorine atom, chlorine atom);

[0634] or a salt thereof (sometimes referred to as compound (Ia)).

[0635] In some aspects of compound (Ia),

[0636] R 1 is C 1-6 alkyl (e.g., methyl, ethyl);

[0637] r is 0 or 1;

[0638] R 2 and R 3 are each a hydrogen atom, or

[0639] when r is 0, then R 2 and R 3 can combine with each other to form a bond;

[0640] R 4 is a hydrogen atom;

[0641] R 5 is a phenyl group substituted by 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms);

[0642] R 6 and R 7 are each a halogen atom (e.g., fluorine atom);

[0643] X 5 is CH; and

[0644] R 12 and R 13 are each independently a hydrogen atom or a halogen atom (e.g., fluorine atom).

[0645] In some aspects, compound (I) is represented by formula (Ib):

[0646]

[0647] wherein

[0648] R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group or an optionally substituted mono- or di-C 1-6 alkylamino;

[0649] R 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group, or

[0650] R 2 and R 3 together form a bond;

[0651] R 4 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group;

[0652] R 5 is an optionally substituted 5- or 6-membered monocyclic group;

[0653] R 6 and R 7 are each independently a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group;

[0654] m is 0 or 1;

[0655] q is 1 or 2;

[0656] X 1 is NR8 or CR 9 ;

[0657] X 2 is O, NR 10 or S;

[0658] X 3 and X 4 are both C, or X 3 and X 4 one of them is N and the other is C;

[0659] X 5 is CR 11 or N;

[0660] X 6 is CR 12 ;

[0661] X 7 is CR 13 or N;

[0662] R 9 、R 11 、R 12 and R 13 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; and

[0663] R 8 and R 10 each independently do not exist, or are selected from a hydrogen atom and an optionally substituted C 1-6 alkyl group;

[0664] or a salt thereof (sometimes referred to as compound (Ib)).

[0665] In some aspects of compound (Ib),

[0666] R 1 is

[0667] (1) a C 1-6 alkyl group (e.g., methyl, ethyl) optionally substituted with 1 to 3 substituents independently selected from the following:

[0668] (i) a halogen atom (e.g., fluorine atom),

[0669] (ii) a C 1-6 alkoxy group (e.g., methoxy), and

[0670] (iii) a C 3-6Cycloalkyl (e.g., cyclopropyl),

[0671] (2) C 3-10 Cycloalkyl (e.g., cyclopropyl), or

[0672] (3) Mono- or di-C 1-6 Alkylamino (e.g., methylamino, dimethylamino);

[0673] R 2 and R 3 are each independently a hydrogen atom or C 1-6 alkyl (e.g., methyl), or R 2 and R 3 together with each other form a bond;

[0674] R 4 is a hydrogen atom, C 1-6 alkyl (e.g., methyl), C 1-6 alkoxy (e.g., ethoxy) or hydroxy;

[0675] R 5 is phenyl, pyrazolyl, furyl, thienyl or thiazolyl, any one of which is optionally substituted by one or more substituents independently selected from C 1-6 alkyl (e.g., methyl), halogen atom (e.g., fluorine atom, chlorine atom), halo (C 1-6 ) alkyl (e.g., trifluoromethyl) and C 1-6 alkoxy (e.g., methoxy);

[0676] m is 0 or 1;

[0677] q is 1 or 2;

[0678] R 6 and R 7 are each independently a hydrogen atom, halogen atom (e.g., fluorine atom) or C 1-6 alkyl (e.g., methyl);

[0679] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are selected to form a ring system, and the ring system is one of the following:

[0680] (i) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ;

[0681] (ii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ;

[0682] (iii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is N;

[0683] (iv) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ;

[0684] (v) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ;

[0685] (vi) X 1 is NR8 and X 2 is NR 10 , and R 8 and R 10 in which one does not exist and R 8 and R 10 in which the other is C 1-6 alkyl (e.g., methyl), X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ;

[0686] (vii) X 1 is CR 9 , X 2 is NR 10 and R 10 does not exist, X 3 is N, X 4 is C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and

[0687] (viii) X 1 is CR 9 , X 2 is NR 10 and R 10 does not exist, X 3 is C, X 4 is N, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and

[0688] R 9 , R 11 , R 12 and R 13 are each independently selected from a hydrogen atom, C 1-6 alkyl (e.g., methyl, ethyl), a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom), C 3-6 cycloalkyl (e.g., cyclopropyl), C 3-6 cycloalkyl(C 1-6 ) alkoxy (e.g., cyclopropylmethoxy), halo(C 1-6)Alkyl (e.g., difluoromethyl, trifluoromethyl), halogen (C 1-6 )alkoxy (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 alkoxy(C 1-6 )alkyl (e.g., methoxymethyl), azetidinyl, C 1-6 alkoxy (e.g., methoxy, ethoxy), hydroxy and hydroxy(C 1-6 )alkyl (e.g., hydroxymethyl, 2-hydroxyethyl).

[0689] In some aspects, compound (I) is represented by formula (Ic):

[0690]

[0691] wherein

[0692] R 1 is C 1-6 alkyl (e.g., methyl, ethyl) or mono-C 1-6 alkylamino (e.g., methylamino);

[0693] R 2 and R 3 are each a hydrogen atom, or R 2 and R 3 together with each other form a bond;

[0694] R 4 is a hydrogen atom;

[0695] R 5 is phenyl optionally substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms);

[0696] R 6 and R 7 are each independently a hydrogen atom or a halogen atom (e.g., fluorine atom);

[0697] X 5 is CH or N; and

[0698] R 12 and R 13 are each independently a hydrogen atom, C 1-6 alkyl (e.g., methyl) or a halogen atom (e.g., fluorine atom, chlorine atom);

[0699] or a salt thereof (sometimes referred to as compound (Ic)).

[0700] In some aspects of compound (Ic),

[0701] R 1 is C 1-6 alkyl (e.g., methyl, ethyl);

[0702] R 2 and R 3 each is a hydrogen atom, or R 2 and R 3 together with each other form a bond;

[0703] R 4 is a hydrogen atom;

[0704] R 5 is a phenyl group substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms);

[0705] R 6 and R 7 each is a halogen atom (e.g., fluorine atom);

[0706] X 5 is CH; and

[0707] R 12 and R 13 each independently is a hydrogen atom or a halogen atom (e.g., fluorine atom).

[0708] Exemplary examples of compound (I) (including compounds (Ia), (Ib) and (Ic)) include the compounds listed in the Examples and Table 1.

[0709] In some aspects, the present disclosure provides a compound selected from the group consisting of:

[0710] N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0711] N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0712] N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0713] N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0714] N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0715] N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0716] N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide;

[0717] N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide;

[0718] N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide;

[0719] N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and

[0720] N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide;

[0721] or a salt thereof.

[0722] In some aspects, the present disclosure provides a compound that is N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide or a salt thereof.

[0723] In some aspects, the present disclosure provides a compound that is N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0724] In some aspects, the present disclosure provides a compound that is N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide or a salt thereof.

[0725] In some aspects, the present disclosure provides a compound that is N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide or a salt thereof.

[0726] In some aspects, the present disclosure provides a compound that is N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0727] In some aspects, the present disclosure provides a compound that is N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0728] In some aspects, the present disclosure provides a compound that is N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide or a salt thereof.

[0729] In some aspects, the present disclosure provides a compound that is N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide or a salt thereof.

[0730] In some aspects, the present disclosure provides a compound that is N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide or a salt thereof.

[0731] In some aspects, the present disclosure provides a compound that is N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide or a salt thereof.

[0732] In some aspects, the present disclosure provides a compound that is N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide or a salt thereof.

[0733] As salts of the compounds represented by formula (I), pharmaceutically 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.

[0734] Examples of salts with inorganic bases include alkali metal salts such as sodium salts, potassium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.; aluminum salts, ammonium salts, etc.

[0735] Examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like.

[0736] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0737] Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0738] Examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0739] The method for producing the compounds of the present invention is explained below.

[0740] The starting compound, reagent, and obtained compound used in each step of the following production method may each be in the form of a salt, and examples of such salts include those similar to the salts of the compound represented by formula (I) and the like.

[0741] When the compound obtained in each step is in the free form, it can be converted into the target salt according to a known method. When the compound obtained in each step is a salt, it can be converted into the target free form or another salt according to a known method.

[0742] The compound obtained in each step can be directly used as a reaction mixture or as a crude product in the next reaction. Alternatively, the compound obtained in each step can be separated and purified from the reaction mixture according to a known method, such as a separation method, such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography, etc.

[0743] When the starting compound and / or reagent used in each step is commercially available, the commercially available product can also be directly used.

[0744] In the reaction of each step, the reaction time varies depending on the types of reagents and solvents used. Generally, unless otherwise specified, the reaction time is 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0745] In the reaction of each step, the reaction temperature varies depending on the types of reagents and solvents used. Generally, unless otherwise specified, the reaction temperature is -78°C to 300°C, preferably -78°C to 150°C.

[0746] In the reaction of each step, the pressure varies depending on the types of reagents and solvents used. Generally, unless otherwise specified, the pressure is 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0747] The reaction of each step can use a microwave synthesizer, such as Initiator+ manufactured by Biotage. Although the reaction temperature varies depending on the types of reagents and solvents used, generally, unless otherwise specified, it is room temperature to 300°C, preferably 50°C to 250°C. Although the reaction time varies depending on the types of reagents and solvents used, generally, unless otherwise specified, it is 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0748] In the reaction of each step, unless otherwise specified, the amount of reagent used is 0.5 equivalent to 20 equivalents relative to the substrate, preferably 0.8 equivalent to 5 equivalents. When the reagent is used as a catalyst, the amount of reagent used is 0.001 equivalent to 1 equivalent relative to the substrate, preferably 0.01 equivalent to 0.2 equivalent. When the reagent is used as a reaction solvent, the reagent is used in the amount of the solvent.

[0749] Unless otherwise specified, the reaction of each step is carried out without a solvent or by dissolving or suspending the starting compound in a suitable solvent. Examples of solvents include those described in the examples and the following solvents:

[0750] Alcohols: methanol, ethanol, tert-butanol, 2-methoxyethanol, etc.;

[0751] Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.;

[0752] Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.;

[0753] Saturated hydrocarbons: cyclohexane, hexane, etc.;

[0754] Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.;

[0755] Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.;

[0756] Nitriles: acetonitrile, etc.;

[0757] Sulfoxides: dimethyl sulfoxide, etc.;

[0758] Aromatic organic bases: pyridine, etc.;

[0759] Acid anhydrides: acetic anhydride, etc.;

[0760] Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;

[0761] Inorganic acids: hydrochloric acid, sulfuric acid, etc.;

[0762] Esters: ethyl acetate, etc.;

[0763] Ketones: acetone, methyl ethyl ketone, etc.; and

[0764] Water.

[0765] The above solvents can be used alone or in the form of a mixture of two or more of their types in an appropriate ratio.

[0766] When a base is used in the reaction of each step, examples thereof include those described in the examples and the following bases:

[0767] Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.;

[0768] 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.;

[0769] Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.;

[0770] Alkali metal hydrides: sodium hydride, etc.;

[0771] Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; and

[0772] Organolithiums: n-butyllithium, etc.

[0773] When an acid or an acid catalyst is used in the reaction of each step, examples thereof include those described in the examples and the following acids and acid catalysts:

[0774] Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;

[0775] Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.;

[0776] Lewis acids: boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0777] Unless otherwise specified, the reaction of each step is carried out according to known methods, for example, the methods described in Jikken Kagaku Kouza, 5th Edition, Volumes 13-19 (edited by Chemical Society of Japan); Shin Jikken Kagaku Kouza, Volumes 14-15 (edited by Chemical Society of Japan); Fine Organic Chemistry, Revised 2nd Edition (L.F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); the combined volumes of ORGANIC SYNTHESES Volumes 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, Volumes 1-14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, etc., or the methods described in the examples.

[0778] In each step, the protection or deprotection reaction of functional groups is carried out according to known methods, for example, the methods described in "Protective Groups in Organic Synthesis, 4th Ed", Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G.M. Wuts); "Protecting Groups 3rd Ed." Thieme, 2004 (P.J. Kocienski), etc., or the methods described in the examples.

[0779] Examples of protecting groups for hydroxyl groups such as those of alcohols and phenolic hydroxyl groups include, for example, ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether, etc.; carboxylate ester-type protecting groups such as acetate, etc.; sulfonate ester-type protecting groups such as methanesulfonate, etc.; and carbonate ester-type protecting groups such as tert-butyl carbonate, etc.

[0780] Examples of protecting groups for the carbonyl group of aldehydes include, for example, acetal-type protecting groups such as dimethyl acetal, etc.; and cyclic acetal-type protecting groups such as 1,3-dioxane, etc.

[0781] Examples of protecting groups for the carbonyl group of ketones include, for example, ketal-type protecting groups such as dimethyl ketal, etc.; cyclic ketal-type protecting groups such as 1,3-dioxane, etc.; oxime-type protecting groups such as O-methyl oxime, etc.; and hydrazone-type protecting groups such as N,N-dimethyl hydrazone, etc.

[0782] Examples of protecting groups for carboxyl groups include, for example, ester-type protecting groups such as methyl ester, etc.; and amide-type protecting groups such as N,N-dimethyl amide, etc.

[0783] Examples of protecting groups for thiols include, for example, ether-type protecting groups such as benzyl thioether, etc.; and ester-type protecting groups such as thioacetate, thiocarbonate, thiocarbamate, etc.

[0784] Examples of protecting groups for amino groups and aromatic heterocycles (such as imidazole, pyrrole, indole, etc.) include, for example, carbamate-type protecting groups such as benzyl carbamate, etc.; amide-type protecting groups such as acetamide, etc.; alkylamine-type protecting groups such as N-tritylamine, etc.; and sulfonamide-type protecting groups such as methanesulfonamide, etc.

[0785] Protecting groups can be removed according to known methods, for example, by using methods such as those using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), etc., reduction methods, etc.

[0786] When carrying out a reduction reaction in each step, examples of reducing agents 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; and so on. When reducing a carbon-carbon double bond or triple bond, methods using catalysts such as palladium-carbon, Lindlar's catalyst, etc. can be employed.

[0787] When an oxidation reaction is carried out in each step, examples of the oxidizing agent used include, for example, 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 iodobenzene dichloride, 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.

[0788] When a radical cyclization reaction is carried out in each step, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), etc.; water-soluble radical initiators such as 4,4'-azobis-4-cyanovaleric acid (ACPA), etc.; in the presence of air or oxygen, triethylboron; benzoyl peroxide, etc. Examples of the radical reagent used include tributylstannane, tris(trimethylsilyl)silane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0789] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes, etc. The alkylidenephosphoranes can be prepared according to known methods, for example, by reacting a phosphonium salt with a strong base.

[0790] When a Horner-Emmons reaction is carried out in each step, examples of the reagent used include phosphonylacetates such as methyl dimethylphosphonylacetate, ethyl diethylphosphonylacetate, etc.; and bases such as alkali metal hydrides, organolithiums, etc.

[0791] When a Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid and an acid chloride or a combination of a Lewis acid and an alkylating agent (for example, an alkyl halide, an alcohol, an alkene, etc.) is used as the reagent. Alternatively, an organic acid or an inorganic acid as described herein can also be used in place of the Lewis acid, and an acid anhydride such as acetic anhydride, etc. can also be used in place of the acid chloride.

[0792] When an aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (for example, an amine, an imidazole, etc.) and a base (for example, an organic base, etc.) are used as the reagents.

[0793] When a nucleophilic addition reaction is carried out by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) is carried out by a carbanion, or a nucleophilic substitution reaction is carried out by a carbanion in each step, examples of the base used to generate the carbanion include organolithium, metal alkoxide, inorganic base, organic base, etc.

[0794] When a Grignard reaction is carried out in each step, examples of the Grignard reagent used include arylmagnesium halides such as phenylmagnesium bromide, etc.; and alkylmagnesium 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 diethyl ether or tetrahydrofuran as a solvent.

[0795] When a Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with two electron-withdrawing groups (for example, malonic acid, diethyl malonate, malononitrile, etc.) and a base (for example, an organic base, a metal alkoxide, an inorganic base, each as described herein) are used as reagents.

[0796] When a Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (for example, N,N-dimethylformamide, etc.) are used as reagents.

[0797] When an azidation reaction of an alcohol, an alkyl halide or a sulfonate ester is carried out in each step, examples of the azidating agent 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 adopted.

[0798] When a reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde; aldehydes such as acetaldehyde, etc.; and ketones such as cyclohexanone, etc. When the substrate is a carbonyl compound, examples of the amine used include ammonia; primary amines such as methylamine, etc.; secondary amines such as dimethylamine, etc.; and so on.

[0799] When performing the Mitsunobu reaction in each step, a diester of azodicarboxylic acid (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0800] When performing an esterification reaction, an amidation reaction, or a urea formation reaction in each step, examples of the reagents used include acyl halides such as acid chlorides, acid bromides, etc.; activated carboxylic acids such as acid anhydrides; activated esters; sulfates; and the like. Examples of the activators of carboxylic acids include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD), etc.; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), etc.; carbonate condensing agents such as 1,1'-carbonyldiimidazole (CDI), etc.; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl halides of formic acid such as ethyl chloroformate, etc.; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; combinations thereof, and the like. When using a carbodiimide condensing agent, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), etc. can be added to the reaction system.

[0801] When performing a coupling reaction in each step, examples of the metal catalysts 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.; and platinum compounds, etc. Additionally, a base can be added to the reaction system, and examples thereof include inorganic bases as described herein.

[0802] When the thiocarbonylation reaction is carried out 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 (for example, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent), etc.) can also be used to replace phosphorus pentasulfide.

[0803] When the Wohl-Ziegler reaction is carried out in each step, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, thionyl chloride, etc. In addition, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile, etc. to the reaction of the reaction system.

[0804] When the halogenation reaction of a hydroxyl group is carried out in each step, examples of the halogenating agent used include hydrohalic acids and acid halides of inorganic acids. Specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc. for chlorination, 48% hydrobromic acid, etc. for bromination. In addition, a method of generating an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. can be adopted. Alternatively, a method of generating an alkyl halide via two steps can also be adopted, and these two steps include converting the alcohol into the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide.

[0805] When the Arbuzov reaction is carried out in each step, examples of the reagents used include alkyl halides such as ethyl bromoacetate, etc.; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite, etc.

[0806] When the sulfonation reaction is carried out in each step, examples of the sulfonating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc.

[0807] When the hydrolysis reaction is carried out in each step, an acid or a base is used as the reagent. For the acid hydrolysis reaction of a tert-butyl ester, formic acid, triethylsilane, etc. can be added to reductively capture the by-product tert-butyl cation.

[0808] When the dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid, etc.

[0809] Compound (7) used in the following Process 2 can be produced from compound (1) according to the method shown in the following Process 1. In the formula, P 1 and P2 each is a protecting group or a hydrogen atom, LG 1 is a leaving group, R 16 is an optionally substituted C 1-6 alkyl or an optionally substituted C 6-14 aryl, and other symbols are as defined above.

[0810]

[0811] P 1 Examples of the "protecting group" of P include those exemplified as the "protecting group for amino and aromatic heterocycles (such as imidazole, pyrrole, indole, etc.)" above.

[0812] P 2 Examples of the "protecting group" of P include those exemplified as the "protecting group for the hydroxyl group of alcohols, etc." above.

[0813] LG 1 Examples of the "leaving group" of LG include a halogen atom, an optionally halogenated C 1-6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), a C 1-6 optionally substituted by C 6-14 arylsulfonyloxy (e.g., benzenesulfonyloxy, toluenesulfonyloxy), etc.

[0814] Compound (1) can be easily commercially available or can be produced according to methods known per se.

[0815] Compound (3) can be produced by subjecting compound (1) to a sulfonamidation reaction with compound (2). Examples of compound (2) used include sulfonyl chloride, sulfamoyl chloride, etc. Compound (2) can be easily commercially available or can be produced according to methods known per se.

[0816] Compound (7) can be produced, for example, by subjecting compound (5) in which X 8 is a nitrogen atom to a condensation reaction with compound (6)-1 or compound (6)-2. Compound (6)-1 and compound (6)-2 can be easily commercially available or can be produced according to methods known per se.

[0817] Compound (I) can be produced from compound (7) according to the method shown in Scheme 2 below. In the formula, R 17 is an optionally substituted C 1-6 alkyl or an optionally substituted C 6-14 aryl, and other symbols are as defined above.

[0818]

[0819] Compound (8) can be produced by subjecting compound (7) to a sulfonation reaction. Examples of the sulfonating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, and the like.

[0820] Compound (9) can be produced, for example, by subjecting compound (7) in which R 4 is a hydrogen atom to an oxidation reaction.

[0821] Compound (I) can be produced, for example, by subjecting compound (8) to a nucleophilic substitution reaction in the presence of a base. Examples of the base used include inorganic bases, organic bases, alkali metal hydrides, and the like.

[0822] wherein X 9 is CR 2 , r is 0, and R 2 and R 3 together form a bond can be produced, for example, by subjecting compound (9) to a dehydration reaction.

[0823] wherein X 10 is CR 15 and R 3 and R 15 together form a bond can be produced, for example, by subjecting compound (9) to a dehydration reaction.

[0824] In compound (I), the intramolecular functional groups can also be converted into target functional groups by a combination of known chemical reactions. Examples of the chemical reactions include oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, ureation reaction, hydrolysis reaction, amination reaction, esterification reaction, aryl coupling reaction, deprotection reaction, and the like.

[0825] In the 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 generally used in peptide chemistry can be introduced into these groups, and if necessary, the target compound can be obtained by removing the protecting group after the reaction.

[0826] Compound (I) can be separated and purified by known methods such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography, and the like.

[0827] When compound (I) contains optical isomers, stereoisomers, regioisomers, or rotamers, these compounds are also included in compound (I), and each can be obtained as a single product by a synthetic method or a separation method. For example, when compound (I) has optical isomers, the optical isomers resolved from the compound are also covered by compound (I).

[0828] The optical isomers can be produced by known methods.

[0829] Compound (I) can be crystalline.

[0830] The crystal of compound (I) (sometimes abbreviated hereinafter as the crystal of the present invention) can be produced by crystallizing compound (I) by applying known crystallization methods.

[0831] In this specification, the melting point means the 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), etc.

[0832] Generally, the melting point can vary depending on the measuring apparatus, measuring conditions, etc. The crystal in this specification can be a crystal with a melting point different from the value described in this specification, as long as the difference is within the general error range.

[0833] The crystal of the present invention is excellent in terms of physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), efficacy expression), and can be particularly used as a medicament.

[0834] Compound (I) can be used as a prodrug. The prodrug of compound (I) means a compound that is converted into the compound (I) of the present invention via reactions of enzymes, gastric acid, etc. under physiological conditions in vivo. For example, the prodrug of compound (I) can be a compound that is converted into the compound (I) of the present invention by oxidation, reduction, hydrolysis, etc. in the presence of an enzyme, or a compound that is converted into the compound (I) of the present invention by hydrolysis, etc. via gastric acid, etc.

[0835] The prodrug of compound (I) can be:

[0836] Compounds obtained by acylating, alkylating or phosphorylating the amino group in compound (I) (e.g., compounds obtained by eicosanoylating, alanylating, pentylaminocarbonylating, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylating, tetrahydrofuranylating, pyrrolidinylmethylating, pivaloyloxymethylating and tert-butylating, etc. the amino group in compound (I));

[0837] Compounds obtained by acylating, alkylating, phosphorylating or borylating the hydroxyl group in compound (I) (e.g., compounds obtained by acetylating, palmitoylating, propionylating, pivaloylating, succinylating, fumaroylating, alanylating, dimethylaminomethylcarbonylating, etc. the hydroxyl group in compound (I)); or

[0838] Compounds obtained by esterifying or amidating the carboxyl group in compound (I) (for example, compounds obtained by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthaloyl esterification, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, methyl amidation, etc. of the carboxyl group in compound (I)).

[0839] Any of these compounds can be produced from compound (I) by known methods.

[0840] Prodrugs of compound (I) can also be prodrugs that are converted to 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 HIROKAWA SHOTEN (1990).

[0841] In this specification, prodrugs can form salts, and as such salts, those exemplified as salts of the compounds represented by the above formula (I) can be mentioned.

[0842] Compound (I) can be labeled with isotopes (for example, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I), etc.

[0843] Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer for positron emission tomography (PET) (PET tracer), and can be used in the field of medical diagnosis, etc.

[0844] In addition, compound (I) can be a hydrate or non-hydrate, or a non-solvate (for example, an acid anhydride), or a solvate (for example, a hydrate).

[0845] Compound (I) also encompasses the deuterium-converted form in which 1 H is converted to 2 H (D).

[0846] In addition, compound (I) can be a pharmaceutically acceptable cocrystal or cocrystal salt. A cocrystal or cocrystal salt means a crystalline substance composed of two or more special solids at room temperature, each solid having different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Cocrystals or cocrystal salts can be produced by known cocrystallization methods.

[0847] Compound (I) or its prodrug (hereinafter sometimes simply referred to as the compound of the present invention) can be used in the form of a pharmaceutical composition (also called a medicament) as it is or by mixing with a pharmaceutically acceptable carrier, etc., for mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys), as an agent for preventing or treating the following various diseases.

[0848] Various organic or inorganic carrier substances conventionally used as preparation materials can be used as pharmaceutically acceptable carriers. These substances are incorporated as excipients, lubricants, binders, and disintegrants for solid preparations; or solvents, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents for liquid preparations; etc.; and formulation additives such as preservatives, antioxidants, coloring agents, sweetening agents, etc. can be added as necessary.

[0849] Examples of excipients 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.

[0850] Examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.

[0851] Examples of binders include gelatinized starch, sucrose, gelatin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone.

[0852] Examples of disintegrants include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

[0853] Examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

[0854] Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[0855] Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.; polysorbates; and polyoxyethylene hydrogenated castor oil.

[0856] Examples of isotonizing agents include sodium chloride, glycerol, D-mannitol, D-sorbitol, and glucose.

[0857] Examples of buffering agents include buffering agents such as phosphates, acetates, carbonates, citrates, etc.

[0858] An example of an emollient is benzyl alcohol.

[0859] Examples of preservatives include parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0860] Examples of antioxidants include sulfites and ascorbates.

[0861] Examples of coloring agents include water-soluble food tar pigments (e.g., food colors such as Food Color Red No. 2 and 3, Food Color Yellow No. 4 and 5, Food Color Blue No. 1 and 2, and similar food colors), water-insoluble lake dyes (e.g., aluminum salts of the above water-soluble food tar pigments), natural dyes (e.g., β-carotene, chlorophyll, iron oxide red), etc.

[0862] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0863] Examples of dosage forms of the above pharmaceutical compositions 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 mucoadhesive films), etc.; and parenteral agents such as injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion), external preparations (e.g., transdermal absorption-type preparations, ointments, lotions, adhesive preparations), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. The compounds and agents of the present invention can be safely administered orally or parenterally, respectively (e.g., rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, by infusion, intracranially, intravaginally, intraperitoneally, intratumorally, proximal tumor administration, and administration to the lesion).

[0864] These preparations may be controlled-release preparations (e.g., sustained-release microcapsules), such as immediate-release preparations, sustained-release preparations, etc.

[0865] The pharmaceutical composition can be produced according to methods commonly used in the field of pharmaceutical formulation, for example, the methods described in the Japanese Pharmacopoeia, etc.

[0866] Although the content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, dose, etc. of the compound of the present invention, the content is, for example, about 0.1 wt% to 100 wt%.

[0867] When producing oral preparations, coating may be applied as necessary for the purposes of taste masking, enteric solubility, and / or sustainability.

[0868] Examples of coating matrices for coating include sugar coating matrices, water-soluble film coating matrices, enteric film coating matrices, and sustained-release film coating matrices.

[0869] As the sugar coating matrix, sucrose can be used, and one or more species selected from talc and precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. can be further used in combination.

[0870] Examples of water-soluble film coating matrices 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)], polyvinylpyrrolidone, etc.; and polysaccharides such as pullulan, etc.

[0871] Examples of enteric film coating matrices include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc.; acrylic 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.

[0872] Examples of sustained-release film coating matrices include cellulose polymers such as ethyl cellulose, etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)], etc.

[0873] Two or more kinds of the above coating bases can be used in the form of a mixture at an appropriate ratio. Additionally, for example, during coating, an opacifying agent such as titanium oxide, iron oxide red, etc. can also be used.

[0874] Since the compounds of the present invention exhibit low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and fewer side effects, the compounds can be used as prophylactic agents, therapeutic agents, or diagnostic agents for various diseases in mammals (e.g., humans, cattle, horses, dogs, cats, monkeys, mice, rats).

[0875] The compounds of the present invention have excellent orexin type 2 receptor agonist activity and can treat, prevent or improve the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor. 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 narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinemic obesity, hypertrophic obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, diet-induced obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness (such as coma, etc.), side effects and complications caused by anesthesia, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorders of shift workers, sleep disorders, night terrors, depression, major depressive disorder, somnambulism, enuresis, sleep disorders, Alzheimer's dusk, diseases related to the circadian rhythm, fibromyalgia, diseases caused by decreased sleep quality, overeating, compulsive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart diseases, abnormal heartbeats, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Froelich'ssyndrome), growth hormone deficiency, normal variant short stature, Turner's syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, reduced fertility, infertility, male hypogonadism, sexual and reproductive dysfunctions (such as hirsutism in women), fetal defects associated with maternal obesity, gastrointestinal motility disorders (such as obesity-related gastroesophageal reflux), obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases (such as dyspnea), inflammation (such as systemic inflammation of the vascular system), arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, renal cancer, risk of secondary obesity outcomes (such as reducing the risk of left ventricular hypertrophy), migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, flushing, night sweats, reproductive / urinary system diseases, diseases related to sexual function or fertility, major depressive disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neuropsychiatric disorders (such as brain defects after coronary artery bypass surgery and transplantation), stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, conditions related to muscle spasm, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, motor disability, chronic fatigue syndrome, fatigue, drug-induced parkinsonism, Gilles de la Tourette's syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, motor disability, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy and traumatic brain injury.

[0876] In particular, the compounds of the present invention can be used as agents for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness (such as coma, etc.), side effects and complications caused by anesthesia, etc., or as anesthetic antagonists.

[0877] 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, disorders of consciousness, side effects and complications caused by anesthesia.

[0878] 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.

[0879] In some aspects, the compounds of the present invention can be used as agents for preventing or treating narcolepsy.

[0880] Central hypnogenic disorders (CDH) are characterized by excessive daytime sleepiness in the absence of other sleep disorders but with adequate and regular sleep habits. Central hypnogenic disorders (CDH) include narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. Kleine-Levin syndrome, as well as sleep deprivation syndrome and hypersomnia caused by medical disorders, drugs or substances, or mental disorders, are also considered central hypnogenic disorders. The assessment of central hypnogenic disorders (CDH) includes sleep testing (polysomnography, PSG) in a sleep laboratory, followed by a multiple sleep latency test (MSLT).

[0881] Symptoms associated with narcolepsy involve abnormal intrusion of REM sleep characteristics into the waking state: for example, sleep-related hallucinations, sleep paralysis, or vivid dreams, as well as confusion between dreams and reality. These symptoms may also occur in people without sleep disorders.

[0882] Some narcolepsy patients also experience cataplexy (narcolepsy type 1), which is a loss of muscle tone triggered by emotions (usually laughter or anticipation). Cataplexy can be generalized or partial and is not associated with any loss of consciousness. This muscle weakness usually improves within seconds to minutes.

[0883] Patients with idiopathic hypersomnia (IDH) typically describe excessive daytime sleepiness, prolonged sleep duration (more than 10 - 11 hours of sleep per night), and severe difficulty waking up in the morning (sleep inertia). In contrast to narcolepsy, patients with IDH typically describe long daytime naps and lethargy. Another common symptom of IDH is "brain fog", a feeling of cognitive blurriness during the day. Kleine - Levin syndrome is a rare disorder of periodic hypersomnia.

[0884] One aspect of the present disclosure is a method for treating a subject having one or more central disorders of hypersomnolence (CDH), the method comprising administering a compound of the invention to the subject.

[0885] Another aspect of the present disclosure is the use of a compound of the invention for the manufacture of an agent for treating one or more central disorders of hypersomnolence (CDH) in a subject.

[0886] Another aspect of the present disclosure is a compound of the invention for treating one or more central disorders of hypersomnolence (CDH) in a subject.

[0887] Another aspect is the method or use of the previous aspect, wherein the subject has 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.

[0888] Another aspect is the method or use of the previous aspect, wherein administering the compound of the invention reduces daytime sleepiness in the subject, reduces the occurrence of loss of muscle control, and / or reduces the occurrence of sleep disruptions.

[0889] Another aspect is the method or use, wherein the compound of the invention is administered in an amount effective to reduce excessive daytime sleepiness in adults with narcolepsy.

[0890] Another aspect is the method or use, wherein the compound of the invention is administered in an amount effective to increase the mean sleep latency.

[0891] Another aspect is the method or use, wherein the compound of the invention is administered in an amount effective to reduce the occurrence of cataplexy events.

[0892] Another aspect is the method or use, wherein the compound of the invention is administered in an amount effective to reduce nocturnal sleep disruptions in the subject.

[0893] Although the dosage of the compounds of the present invention varies depending on the subject to which it is administered, the route of administration, the target disease, symptoms, etc., for example, when the compound of the present invention is administered orally or parenterally to an adult patient, the dosage of the compound is, for example, about 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose, and more preferably 0.5 to 20 mg / kg body weight per dose. Such an amount is desirably administered in 1 to 3 portions per day.

[0894] The compounds of the present invention can be used in combination with other medicaments (abbreviated hereinafter as concomitant medicaments).

[0895] By combining the compounds of the present invention with concomitant medicaments, excellent effects can be achieved. For example,

[0896] (1) Compared with administering the compound of the present invention or the concomitant medicament alone, the dosage can be reduced.

[0897] (2) The medicament combined with the compound of the present invention can be selected according to the patient's disease (mild, severe, etc.).

[0898] (3) By selecting a concomitant medicament having a different action and mechanism from the compound of the present invention, the treatment period can be set longer.

[0899] (4) By selecting a concomitant medicament having a different action and mechanism from the compound of the present invention, a continuous therapeutic effect can be designed.

[0900] (5) By using the compound of the present invention in combination with a concomitant medicament, etc., a synergistic effect can be provided.

[0901] In this specification, the compound of the present invention and the concomitant medicament used in combination are referred to as "the combination agent of the present invention".

[0902] When using the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant medicament is not limited, and the compound of the present invention or its pharmaceutical composition or the concomitant medicament or its pharmaceutical composition can be administered to the subject to be administered simultaneously, or can be administered at different times. The dosage of the concomitant medicament can be determined according to the dosage used in clinical practice, and can be appropriately selected depending on the subject to which it is administered, the route of administration, the disease, the combination, etc.

[0903] There is no particular limitation on the administration mode of the combination agent of the present invention and the concomitant medicament, and the compound of the present invention and the concomitant medicament only need to be combined at the time of administration. Examples of such administration modes include the following:

[0904] (1) Administering a single preparation obtained by simultaneously treating the compound of the present invention and the concomitant medicament.

[0905] (2) The two preparations of the compound of the present invention and the concomitant drug, which have been produced independently, are administered simultaneously by the same route of administration.

[0906] (3) The two preparations of the compound of the present invention and the concomitant drug, which have been produced independently, are administered in an alternating manner by the same route of administration.

[0907] (4) The two preparations of the compound of the present invention and the concomitant drug, which have been produced independently, are administered simultaneously by different routes of administration.

[0908] (5) The two preparations of the compound of the present invention and the concomitant drug, which have been produced independently, are administered in an alternating manner (e.g., in the order of the compound of the present invention and the concomitant drug or in the reverse order) by different routes of administration.

[0909] The dose of the concomitant drug can be appropriately determined based on the dose used in the clinical situation. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately determined depending on the subject to be administered, the route of administration, the target disease, the symptoms, the combination, etc.

[0910] For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the preparation form, and is generally about 0.01 wt% to about 100 wt%, preferably about 0.1 wt% to about 50 wt%, and more preferably about 0.5 wt% to about 20 wt% based on the entire preparation.

[0911] The content of the concomitant drug in the combination agent of the present invention varies depending on the preparation form, and is generally about 0.01 wt% to about 100 wt%, preferably about 0.1 wt% to about 50 wt%, and more preferably about 0.5 wt% to about 20 wt% based on the entire preparation.

[0912] The content of additives (such as carriers, etc.) in the combination agent of the present invention varies depending on the preparation form, and is generally about 1 wt% to about 99.99 wt%, preferably about 10 wt% to about 90 wt% based on the preparation.

[0913] Even when the compound of the present invention and the concomitant drug are independently formulated into preparations, similar contents can be used.

[0914] Examples of concomitant drugs include the following: therapeutic drugs for narcolepsy (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), weight loss drugs (amphetamine, benzfetamine, bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, Lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galanthamine, zanapezil, idebenone, tacrine), anti-dementia agents (e.g., memantine), inhibitors of β-amyloid production, secretion, accumulation, aggregation and / or deposition, β-secretase inhibitors (e.g.,6-(4-Biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylaminomethyl)tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylaminomethyl)tetralin, 2-(N,N-dimethylaminomethyl)-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, their optically active forms, their salts and their hydrates, OM99-2 (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)), β-amyloid vaccines, β-amyloid degrading enzymes, etc., brain function enhancers (e.g., aniracetam, nicergoline), therapeutic drugs for Parkinson's disease [(e.g., dopamine receptor agonists (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine)), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], therapeutic drugs for amyotrophic lateral sclerosis (e.g.,Therapeutic drugs for abnormal behaviors accompanied by dementia, wandering, etc. (e.g., sedatives, anti-anxiety drugs), neurotrophic factors (e.g., riluzole, etc.), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation-regeneration promoters (e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active forms, salts or hydrates), non-steroidal anti-inflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying anti-rheumatic 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), anti-arrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), therapeutic agents for osteoporosis (e.g.,Alfacalcidol, Calcitriol, Elcatonin, Calcitonin Salmon, Estriol, Ipriflavone, Pamidronate Disodium, Alendronate Sodium Hydrate, Incadronate Disodium, Parathyroid Hormone (PTH), Calcium Receptor Antagonist, Therapeutic Drugs for Insomnia (e.g., Benzodiazepine Drugs, Non-Benzodiazepine 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-coupled glutamate receptors; phosphodiesterase inhibitors), benzodiazepine drugs (chlordiazepoxide, diazepam, potassium clorazepate, 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 hydrobromide, 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, setiptiline maleate, 5-HT, 1AAgonists (buspirone hydrochloride, tando spirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A antagonists, 5-HT 2AInverse agonists, 5-HT3 antagonists (such as cyamemazine), cardiac non-selective β-blockers (such as propranolol hydrochloride, oxprenolol hydrochloride), histamine H1 antagonists (such as hydroxyzine hydrochloride), CRF antagonists, other anxiolytic drugs (such as meprobamate), tachykinin antagonists (such as MK-869, saredutant), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3-adrenergic antagonists (such as amibegron hydrochloride), GAT-1 inhibitors (such as tiagabine hydrochloride), N-type calcium channel inhibitors, carbonic anhydrase II inhibitors, NMDA glycine partial agonists, NMDA antagonists (such as memantine), peripheral benzodiazepine receptor agonists, antidiuretic hormone antagonists, antidiuretic hormone V1b antagonists, antidiuretic hormone V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (such as phenelzine sulfate, tranylcypromine sulfate, moclobemide), therapeutic drugs for bipolar disorder (such as lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate), cannabinoid CB1 antagonists (such as rimonabant), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (such as methylphenidate hydrochloride, methamphetamine hydrochloride)Therapeutic drugs for amphetamine hydrochloride), alcoholism, autism, chronic fatigue syndrome, spasticity, fibromyalgia syndrome, headache, smoking cessation, myasthenia gravis, cerebral infarction, mania, hypersomnia, pain, dysthymia, autonomic ataxia, male and female sexual dysfunction, migraine, pathological gambling, restless legs syndrome, substance addiction, alcohol-related syndromes, irritable bowel syndrome, lipid abnormalities (such as cholesterol-lowering drugs (statins series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.)), fibrates (clofibrate, etc.), squalene synthase inhibitors)), therapeutic drugs for abnormal behaviors caused by dementia or wandering inhibitors (sedatives, anti-anxiety 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.

[0915] Two or more kinds of the above concomitant drugs can be used in the form of a mixture at an appropriate ratio.

[0916] When the compound of the present invention is used for treating the above diseases, the compound can also be used in combination with biological agents (e.g., antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), or can be used in combination with gene therapy methods, etc., or can also be used in combination with treatments in the field of psychiatry that do not use drugs.

[0917] Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibodies and other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., DIAPEP-277 of Peptor), anti-HIV antibodies and HIV vaccine preparations, and antibodies or vaccine preparations against cytokines, renin-angiotensin type enzymes and their products, antibodies or vaccine preparations against enzymes or proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in the coagulation or fibrinolytic system, antibodies or vaccine preparations against proteins involved in glucose metabolism and insulin resistance, and so on. In addition, it can also be used in combination with biological agents related to growth factors, such as GH, IGF, etc.

[0918] Examples of gene therapy methods include treatment methods using genes related to cytokines, renin-angiotensin type enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylases, treatment methods using DNA decoys (such as NFκB decoys, etc.), treatment methods using antisense, treatment methods using genes related to enzymes or proteins involved in blood lipid metabolism (e.g., genes related to the metabolism, excretion and absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids), treatment methods using genes related to enzymes or proteins in angiogenesis therapies related to peripheral vascular occlusion, etc. (e.g., growth factors, such as HGF, VEGF, etc.), treatment methods using genes related to proteins involved in glucose metabolism and insulin resistance, antisense against cytokines (such as TNF, etc.).

[0919] 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), etc.

[0920] The compounds of the present invention can also be used in combination with various organ regeneration methods, such as heart regeneration, kidney regeneration, pancreas regeneration, vascular reconstruction, etc., cell transplantation therapies using bone marrow cells (monocytes derived from bone marrow, bone marrow-derived stem cells), or artificial organs using tissue engineering (e.g., artificial blood vessels, myocardial cell sheets).

[0921] [Examples]

[0922] The present invention will be explained 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.

[0923] "Room temperature" in the following examples generally refers to about 10°C to about 35°C. Unless otherwise specified, the ratio of the mixed solvents is a volume mixing ratio, and unless otherwise specified, % means wt%.

[0924] Unless otherwise specified, elution is performed by column chromatography in the examples under TLC (thin layer chromatography) observation. In the TLC observation, 60F manufactured by Merck is used 254 As the saturated LC plate, the solvent used as the eluent in column chromatography is used as the eluent, and detection is performed using a UV detector. In silica gel column chromatography, the indication of NH means using silica gel bonded with aminopropylsilane, and the indication of DIOL means using silica gel bonded with 3-(2,3-dihydroxypropoxy)propylsilane. Preparative HPLC (high performance liquid chromatography) is performed under the following conditions; column: Boston Prime C18 (150mm×30mm, 5μm), Xtimate C18 (100mm×30mm, 3μm), Gemini NX C18 (150mm×30mm, 5μm), YMC Triart C18 (250mm×50mm, 7μm), Exsil plus C18 (150mm×50mm, 5μm) or Water Xbridge C18 (150mm×30mm, 5μm), mobile phase: ammonia water / MeCN, water / MeCN (both containing 0.1% TFA), water / MeCN containing ammonia hydroxide. The indication of C18 means using octadecyl-bonded silica gel. Unless otherwise specified, the ratio of the eluent is a volume mixing ratio.

[0925] For 1 For the analysis of 1H NMR, ACD / SpecManager (trade name) software etc. are used. Sometimes the peaks of hydroxyl groups, amino groups etc. with extremely flat proton peaks are not described.

[0926] MS is measured by LC / MS. As the ionization method, the ESI method or the APCI method is used. The data indicate the actual measured values (measured values). Although the molecular ion peak is generally observed, sometimes fragment ion peaks are observed. In the case of salts, generally the molecular ion peak or fragment ion peak in the free form is observed.

[0927] In the following examples, the following abbreviations are used.

[0928] MS: Mass spectrometry

[0929] M: Molar concentration

[0930] N: Normal concentration

[0931] CDCl3: Deuterochloroform

[0932] DMSO-d6: Deuterated dimethyl sulfoxide

[0933] 1 H NMR: Proton nuclear magnetic resonance

[0934] LC / MS: Liquid chromatography - mass spectrometry

[0935] ESI: Electrospray ionization

[0936] APCI: Atmospheric pressure chemical ionization

[0937] Boc: tert - Butyloxycarbonyl

[0938] CPME: Cyclopentyl methyl ether

[0939] DBU: 1,8 - Diazabicyclo[5.4.0]undec - 7 - ene

[0940] Dess Martin periodinane: 3 - Oxo - 1,1,1(3H) - triacetoxy - 1,2 - benziodoxol - 3(1H) - one

[0941] DMA: N,N - Dimethylacetamide

[0942] DME: 1,2 - Dimethoxyethane

[0943] DMF: N,N - Dimethylformamide

[0944] EtOAc: Ethyl acetate

[0945] EtOH: Ethanol

[0946] IPE: Diisopropyl ether

[0947] MeCN: Acetonitrile

[0948] MeOH: Methanol

[0949] TEA: Triethylamine

[0950] TFA: Trifluoroacetic acid

[0951] THF: Tetrahydrofuran

[0952] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0953] Example 1

[0954] N - {(6S,7aS) - 2 - [4 - (2,6 - Difluorophenyl) - 1,2 - benzoxazol - 3 - yl] - 3 - oxohexahydro - 1H - pyrrolo[1,2 - c]imidazol - 6 - yl}ethanesulfonamide

[0955] A) 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine

[0956] To a mixture of 4-bromo-1,2-benzoxazole-3-amine (7.20g), (2,6-difluorophenyl)boronic acid pinacol ester (24.3g) and potassium fluoride (5.94g) in DMA (60mL) and water (15mL) tri-tert-butylphosphonium tetrafluoroborate (0.986g) and Pd2(dba)3(1.55g). The mixture was stirred for 3 hours at 120°C under an argon atmosphere. After cooling, the mixture was diluted with water and extracted with THF / EtOAc. The extract was washed with water and brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain a crude product. The crude material was wet-ground with cold IPE, and the precipitate was collected by filtration to obtain the title compound (5.01g).

[0957] MS:[M+H] + 247.0.

[0958] B) 2,2,2-Trichloroethyl [4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate

[0959] To a mixture of 4-(2,6-difluorophenyl)-1,2-benzoxazole-3-amine (6.92g) in THF (130mL) was added 1M bis(trimethylsilyl) lithium amide THF solution (60mL) at 0°C. The mixture was stirred for 30 minutes at 0°C. 2,2,2-trichloroethoxycarbonyl chloride (6.60g) was added to the mixture at 0°C. The mixture was stirred for 30 minutes at 0°C. An aqueous ammonium chloride solution and EtOAc were added to the mixture. The water layer was separated and extracted with EtOAc. The organic layers were combined, 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 (8.34g).

[0960] MS:[M+H] + 420.9.

[0961] C) 2-tert-butyl (2S,4S)-4-[(ethylsulfonyl)amino]pyrrolidine-1,2-dicarboxylate

[0962] Ethanesulfonyl chloride (7.54 mL) was added dropwise to a mixture of (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester hydrochloride (15.9 g) and TEA (39.6 mL) in DME (189 mL) at 0 °C. The mixture was stirred overnight at room temperature and then filtered to remove insoluble materials. The filtrate was diluted with EtOAc, washed with 1 M aqueous hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (18.4 g).

[0963] MS: [M+H-Boc] + 237.1。

[0964] D) (2S,4S)-4-[(Ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0965] A solution of (2S,4S)-4-[(ethanesulfonyl)amino]pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (2.65 g) in THF (30.0 mL) was added dropwise to a suspension of lithium aluminum hydride (0.36 g) in THF (30 mL) at 0 °C under an argon atmosphere. The mixture was stirred at 0 °C under an argon atmosphere for 2 h. Aqueous saturated sodium potassium tartrate solution was added to the mixture at 0 °C. The mixture was diluted with EtOAc and 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 (2.18 g).

[0966] MS: [M+H-Boc] + 209.1。

[0967] E) N-[(3S,5S)-5-(Hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride

[0968] A solution of 4 M hydrogen chloride in EtOAc (5 mL) was added to a solution of (2S,4S)-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.18 g) in EtOAc (5 mL) at room temperature. The mixture was stirred overnight at room temperature. A white solid was formed and collected by filtration to give the title compound (1.40 g).

[0969] 11H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.3 Hz), 1.58 - 1.71 (1H, m), 2.23 - 2.36 (1H, m), 2.88 - 3.17 (3H, m), 3.29 - 3.45 (1H, m), 3.51 - 3.71 (3H, m), 3.91 - 4.06 (1H, m), 5.39 (1H, br s), 7.56 (1H, d, J = 7.5 Hz), 8.98 (1H, br s), 9.51 (1H, br s).

[0970] F) (2S,4S)-N-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethylsulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[0971] A mixture of 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate (0.7 g), N-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl]ethylsulfonamide hydrochloride (0.406 g) and N,N-diisopropylethylamine (0.568 mL) in THF (8.30 mL) was stirred at 70 °C for 44 h. After cooling, the mixture was purified by silica gel column chromatography (MeOH / EtOAc) to afford the title compound (0.39 g).

[0972] MS: [M+H] + 481.1.

[0973] G) N-{(6S,7aS)-2-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethylsulfonamide

[0974] To a mixture of (2S,4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethylsulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (260 mg), TEA (0.302 mL), and THF (2.0 mL) at 0 °C was added methanesulfonyl chloride (0.084 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (2.0 mL). To the mixture at 0 °C was added 60% sodium hydride (23.8 mg). The mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride at 0 °C 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). The solid was crystallized from EtOAc - heptane to give the title compound (82 mg).

[0975] 1 H NMR (300 MHz, CDCl3) δ 1.34 (3H, t, J = 7.4 Hz), 1.45 - 1.53 (1H, m), 2.37 - 2.52 (1H, m), 2.95 - 3.13 (3H, m), 3.18 - 3.28 (1H, m), 3.77 - 3.94 (2H, m), 4.04 - 4.23 (3H, m), 6.95 - 7.08 (2H, m), 7.30 - 7.44 (2H, m), 7.58 - 7.70 (2H, m).

[0976] Example 16

[0977] N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[0978] A) 4-(2,4,6-Trifluorophenyl)-1,2-benzoxazol-3-amine

[0979] A mixture of 4-bromo-1,2-benzoxazole-3-amine (10.0 g), (2,4,6-trifluorophenyl)boric acid (33.0 g), Pd2(dba)3 (2.15 g), tri-tert-butylphosphonium tetrafluoroborate (1.36 g) and potassium fluoride (8.18 g) in DME (150 mL) and water (30.0 mL) was heated for 16 hours at 80 ° C under an argon atmosphere. The solid was removed by filtration, and the filtrate was concentrated to half of the original volume under reduced pressure. Water was added to the mixture. 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 preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to obtain the title compound (3.23 g).

[0980] MS:[M+H] + 265.0.

[0981] B) 2,2,2-Trichloroethyl [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate

[0982] To a mixture of 4-(2,4,6-trifluorophenyl)-1,2-benzoxazole-3-amine (5.0g) in THF (95mL) was added 1M bis(trimethylsilyl) lithium amide THF solution (47.3mL) at 0°C. The mixture was stirred for 30 minutes. 2,2,2-trichloroethoxycarbonyl chloride (2.79mL) was added to the mixture. The mixture was stirred for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride solution and 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). The residue was recrystallized from IPE-hexane to obtain the title compound (5.72g).

[0983] MS:[M+H] + 438.9.

[0984] C) 1-(Benzyloxy)-3,3-difluoropent-4-en-2-ol

[0985] A 1 M aqueous hydrochloric acid solution (120 mL) was added to a solution of ((2,2 - diethoxyethoxy)methyl)benzene (31.4 g) in THF (240 mL) and water (120 mL) at room temperature. The mixture was stirred at 70 °C for 2 h. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. Indium powder (16.1 g) was added to a mixture of the residue, 3 - bromo - 3,3 - difluoroprop - 1 - ene (20.0 g) and DMF (240 mL) at room temperature. The mixture was stirred overnight at room temperature under an argon atmosphere. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were 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 (27.2 g).

[0986] 1 H NMR (300 MHz, CDCl3) δ 2.62 (1H, d, J = 4.9 Hz), 3.56 - 3.75 (2H, m), 3.96 - 4.10 (1H, m), 4.58 (2H, s), 5.50 - 5.57 (1H, m), 5.68 - 5.77 (1H, m), 5.91 - 6.09 (1H, m), 7.28 - 7.40 (5H, m).

[0987] D) tert - Butyl [1 - (benzyloxy)-3,3 - difluoropent - 4 - en - 2 - yl]carbamate

[0988] To a mixture of 1-(benzyloxy)-3,3-difluoropent-4-en-2-ol (27.1 g) and pyridine (77 mL) in MeCN (400 mL) at 0 °C was added trifluoromethanesulfonic anhydride (28 mL). The mixture was stirred for 30 minutes at 0 °C under an argon atmosphere. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and the organic layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was diluted with MeCN (400 mL). Tetrabutylammonium azide (66.9 g) was added to the mixture at 0 °C. The mixture was stirred overnight at room temperature under an argon atmosphere. EtOAc - toluene and water were added to the mixture. The aqueous layer was separated, and the organic phase was washed with water and 1 M aqueous hydrochloric acid, filtered through a silica gel pad and concentrated under reduced pressure. Water (40 mL) was added to this residue at room temperature. A mixture of triphenylphosphine (34.3 g) and toluene (40 mL) was added slowly to the mixture. The mixture was stirred at 70 °C for 5 hours. After cooling, di-tert-butyl dicarbonate (41.0 mL) and sodium bicarbonate (11.0 g) were added to the mixture at room temperature. The mixture was stirred overnight at room temperature. Water was added to the mixture at room temperature. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (37.3 g).

[0989] MS: [M + 1 - Boc] + 228.1。

[0990] E) 1 - O - Benzyl - 2 - [(tert - butoxycarbonyl)amino] - 2,3 - dideoxy - 3,3 - difluoropentitol

[0991] To a mixture of tert - butyl [1 - (benzyloxy) - 3,3 - difluoropent - 4 - en - 2 - yl]carbamate (37.3 g) and 4 - methylmorpholine 4 - oxide (26.7 g), acetone (360 mL) and water (36 mL) at room temperature was added water (40 g) containing 4% osmium(VIII) oxide. The mixture was stirred overnight under an argon atmosphere. EtOAc and 10% aqueous sodium thiosulfate were added to the mixture at 0 °C. The aqueous layer was separated and the organic layer was extracted with EtOAc. The combined organic layers were washed with 0.1 M aqueous hydrochloric acid and brine, dried over anhydrous sodium sulfate, then filtered through a silica gel pad and concentrated under reduced pressure to give the title compound (42.1 g).

[0992] MS: [M + 1 - Boc] + 262.1。

[0993] (F) Racemic-(2R,4S)-2-[(Benzyloxy)methyl]-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0994] At room temperature, a solution of tosyl chloride (24.4 g) in MeCN (100 mL) was added to a mixture of 1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-2,3-dideoxy-3,3-difluoropentitol (42.0 g), 2,8-dimethyl-10H-dibenzo[b,e][1,4]oxaborinane-10-ol (1.30 g), and N,N-diisopropylethylamine (30 mL) in MeCN (300 mL). The mixture was stirred for 1 h at room temperature under an argon atmosphere. EtOAc, toluene, and water were added to the mixture at 0 °C. The organic layer was separated, washed with 10% aqueous citric acid and brine, and concentrated under reduced pressure. Toluene (300 mL) and TFA (300 mL) were added to this residue at 0 °C. The mixture was stirred for 30 min at room temperature. The mixture was concentrated under reduced pressure. The residue was diluted with MeOH (400 mL). Sodium carbonate (49.3 g) was added to the mixture at 0 °C. The mixture was stirred overnight at room temperature. 10% aqueous acetic acid (300 mL) was added to the mixture at 0 °C. The mixture was concentrated under reduced pressure and then diluted with toluene and EtOAc. The organic layer was separated and the aqueous layer was extracted with 20% aqueous acetic acid. The combined aqueous layers were quenched with potassium carbonate at 0 °C while adjusting to pH 10. The aqueous layer was extracted with THF-EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Toluene (300 mL), water (300 mL), sodium carbonate (24.6 g), and di-tert-butyl dicarbonate (32.0 mL) were added to the residue at room temperature. The mixture was stirred for 1 h at room temperature. The aqueous layer was separated and the aqueous layer was extracted with toluene. The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (11.9 g).

[0995] MS: [M + 1 - Boc] + 244.0。

[0996] (G) Racemic-(2R,4R)-4-azido-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[0997] To a mixture of racemic -(2R,4S)-2-[(benzyloxy)methyl]-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11.9 g) and pyridine (22.3 mL) in MeCN (120 mL) was added trifluoromethanesulfonic anhydride (11.7 mL) at 0 °C. The mixture was stirred for 30 minutes under a nitrogen atmosphere at 0 °C. EtOAc and water were added to the mixture at 0 °C. The organic layer was separated, washed with 10% aqueous citric acid solution, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with DMF (120 mL). Tetrabutylammonium azide (21.6 g) was added to the mixture at 0 °C. The mixture was stirred for 30 minutes under a nitrogen atmosphere at 0 °C and then stirred overnight at room temperature. EtOAc and water were added to the mixture at 0 °C. The combined organic layers were 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 (5.65 g).

[0998] MS: [M+1-Boc] + 269.1。

[0999] H) Racemic -(2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1000] To a mixture of racemic -(2R,4R)-4-azido-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (5.65 g) and THF (50 mL) was slowly added a solution of triphenylphosphine (4.83 g) in THF (10 mL) at room temperature. The mixture was stirred for 1 hour at room temperature. Water (30 mL) was added to the mixture, and then the mixture was heated to 50 °C. The mixture was stirred overnight at 50 °C. EtOAc and brine were added to the mixture at room temperature. The aqueous layer was separated and 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 / hexane) to give the title compound (4.98 g).

[1001] MS: [M+1-Boc] + 243.1。

[1002] I) (2R,4R)-4-Amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1003] Resolution of racemic-(2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (16.0 g) was carried out by SFC (column: DAICEL CHIRALPAK AY, 250 mm×50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% ammonium hydroxide = 75 / 25 v / v) to give the title compound with a longer retention time (7.12 g).

[1004] MS: [M+1] + 343.2

[1005] J) (2R,4R)-2-[(Benzyloxy)methyl]-3,3-difluoro-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester

[1006] Methanesulfonyl chloride (1.86 mL) was added dropwise to a solution of (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (5.37 g) and TEA (10.9 mL) in DME (52.3 mL) at 0 °C. The mixture was stirred at 0 °C for 15 minutes and then stirred overnight at room temperature. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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 (5.84 g).

[1007] MS: [M-H] + 419.0

[1008] K) (2R,4R)-3,3-Difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester

[1009] A mixture of (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (5.84 g) and 20% palladium hydroxide on carbon (1.18 g) in MeOH (120 mL) was hydrogenated at 20 °C under balloon pressure for 15 h. The catalyst was removed by filtration and the solution was concentrated under reduced pressure to give the title compound (4.45 g).

[1010] MS: [M-H] + 329.0

[1011] L) N-[(3R,5R)-4,4-Difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride

[1012] To a mixture of tert-butyl (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate (4.45 g) and EtOAc (16 mL) was added a CPME solution of 4 M hydrogen chloride (56 mL) at 0 °C. The mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. Volatiles were removed under reduced pressure to afford the title compound (3.40 g).

[1013] 1 H NMR (400 MHz, DMSO-d6) δ 3.01 (3H, s), 3.04 - 3.13 (1H, m), 3.68 - 3.88 (3H, m), 3.96 - 4.12 (1H, m), 4.49 - 4.64 (1H, m), 5.44 - 5.62 (1H, m), 8.07 (1H, d, J = 8.9 Hz), 9.50 - 10.23 (2H, m).

[1014] M) (2R,4R)-3,3-Difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide

[1015] A mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (2.50 g), 2,2,2-trichloroethyl [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (5.60 g), TEA (3.93 mL) and THF (75 mL) was stirred for 2 h at room temperature and then heated overnight at 60 °C under an argon atmosphere. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (3.47 g).

[1016] MS: [M+H] + 521.1。

[1017] N) N-{(6R,7aR)-7,7-Difluoro-1-hydroxy-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1018] At 0 °C, a mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (387 mg), sodium bicarbonate (312 mg) in MeCN (7.5 mL) and water (7.50 mL) was stirred for 5 minutes. At 0 °C, tetrabutylammonium bromide (47.9 mg), 2,2,6,6-tetramethylpiperidin-1-oxyl (23.2 mg) and iodobenzene diacetate (263 mg) were added to the mixture. The mixture was stirred vigorously at 0 °C for 5 minutes and then at room temperature for 15 minutes. At 0 °C, EtOAc and water were added to the mixture. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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 (279 mg).

[1019] MS: [M+H] + 519.1。

[1020] O)N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1021] At room temperature, trifluoroacetic anhydride (0.152 mL) was added to a solution of N-{(6R,7aR)-7,7-difluoro-1-hydroxy-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (279 mg) in TFA (7.5 mL). The mixture was stirred at 40 °C for 16 hours and then at room temperature over the weekend. The mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc. Aqueous saturated sodium bicarbonate solution was added to the mixture. The solution was extracted with EtOAc / THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from EtOAc and two batches of pure precipitate were recovered. The residual oil was purified by silica gel column chromatography (EtOAc / hexane). The pure fractions were combined with the precipitate obtained. The substance was recrystallized from EtOH / heptane to give the title compound (165 mg).

[1022] 11H NMR (400 MHz, CDCl3) δ 3.15 (3H, s), 3.22 (1H, dd, J = 11.1, 8.6 Hz), 4.13 (1H, dd, J = 11.0, 8.7 Hz), 4.63 - 4.76 (1H, m), 4.95 - 5.02 (1H, m), 6.64 - 6.84 (3H, m), 7.37 - 7.43 (1H, m), 7.71 - 7.80 (2H, m).

[1023] Example 24

[1024] N-{ (6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1025] A) (2R,4R)-2-[(Benzyloxy)methyl]-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1026] To a mixture of (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g) and TEA (4.05 mL) in DME (19.5 mL) was added ethanesulfonyl chloride (0.773 mL) at 0 °C. The mixture was stirred at 0 °C for 15 minutes and then stirred overnight at room temperature. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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 (2.56 g).

[1027] MS: [M + H - Boc] + 335.1.

[1028] B) N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride

[1029] At room temperature and under balloon pressure, a mixture of tert-butyl (2R,4R)-2-[(benzyloxy)methyl]-4-[(ethylsulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate (2.56 g) and 20% palladium hydroxide on carbon (663 mg) in MeOH (29.5 mL) was hydrogenated overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give a residue. To a mixture of the residue and EtOAc (4 mL) at 0 °C was added an EtOAc solution of 4 M hydrogen chloride (20 mL). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure. The residue was triturated with EtOAc and the white solid was collected by filtration and washed with EtOAc to give the title compound (1.50 g).

[1030] MS: [M+H] + 245.1.

[1031] C) (2R,4R)-4-[(Ethylsulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide

[1032] To a mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (1.78 g) and TEA (1.93 g) in THF (50 mL) at 0 °C was added 2,2,2-trichloroethyl [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (3.34 g). The mixture was stirred at 60 °C for 15 h. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound (3.14 g).

[1033] MS: [M+H] + 535.1.

[1034] D) N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1035] To a mixture of (2R,4R)-4-[(ethylsulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (3.14 g) and methanesulfonyl chloride (1.35 g) in dichloromethane (30 mL) was added DBU (2.68 g) at 0 °C. The mixture was stirred for 1 h at room temperature. DBU (1.34 g) was added to the mixture at room temperature. The mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. Saturated aqueous ammonium chloride was added to the mixture at room temperature. The 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), followed by NH-silica gel column chromatography (EtOAc / hexane). The residue was recrystallized from EtOAc-heptane to give the title compound (1.58 g).

[1036] 1 H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.3 Hz), 2.96 - 3.14 (3H, m), 3.40 - 3.53 (1H, m), 3.97 - 4.10 (1H, m), 4.15 - 4.26 (1H, m), 4.37 - 4.71 (2H, m), 7.18 - 7.28 (1H, m), 7.29 - 7.38 (1H, m), 7.40 - 7.48 (1H, m), 7.78 - 7.86 (1H, m), 7.88 - 7.94 (1H, m), 7.99 (1H, br s).

[1037] Example 33

[1038] N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1039] A) (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethylsulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[1040] At 0 °C, a toluene solution of 1 M lithium bis(trimethylsilyl)amide (1.63 mL) and trichloroethoxycarbonyl chloride (0.120 mL) were added to a mixture of 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine (200 mg) in THF (4 mL). After stirring for 1 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (4 mL). At 60 °C, N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (228 mg) and DBU (371 mg) were added to the mixture. After stirring for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (252 mg).

[1041] MS: [M+H] + 517.1。

[1042] B) N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1043] At room temperature, DBU (0.22 mL) and methanesulfonyl chloride (0.057 mL) were added to a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide (252 mg) in dichloromethane (2.0 mL). The mixture was stirred for 30 min. DBU (0.22 mL) was added to the reaction mixture. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOH / hexane to give the title compound (72.2 mg).

[1044] 11H NMR (400 MHz, CDCl3) δ 1.41 (3H, t, J = 7.3 Hz), 3.02 - 3.15 (3H, m), 3.66 - 3.79 (1H, m), 4.04 - 4.21 (2H, m), 4.30 - 4.42 (2H, m), 4.50 (1H, br d, J = 9.3 Hz), 6.95 - 7.05 (2H, m), 7.30 - 7.41 (2H, m), 7.61 - 7.70 (2H, m).

[1045] Example 34

[1046] N-{ (6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1047] A) (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1048] A mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (300 mg), 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate (484 mg), DBU (0.504 mL) and THF (10 mL) was heated under microwave irradiation at 70 °C for 2 h. EtOAc and water were added to the mixture. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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 (408 mg).

[1049] MS: [M+H] + 503.1.

[1050] B) N-{ (6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1051] To a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (122 mg) and methanesulfonyl chloride (0.038 mL) in dichloromethane (1.0 mL) was added DBU (0.109 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. DBU (54 μL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 30 minutes. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOAc-hexane to give the title compound (43.6 mg).

[1052] 1 H NMR (400 MHz, CDCl3) δ 3.04 - 3.11 (4H, m), 3.58 (1H, dd, J = 12.2, 8.9 Hz), 4.06 - 4.24 (2H, m), 4.30 - 4.48 (2H, m), 4.51 - 4.60 (1H, m), 6.99 (2H, br d, J = 4.4 Hz), 7.32 - 7.36 (2H, m), 7.61 - 7.71 (2H, m).

[1053] Example 47

[1054] N-{(6R,7aR)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1055] A) 2-Bromo-3,6-difluorobenzaldehyde

[1056] To a mixture of 1-bromo-2,5-difluorobenzene (50.0 g) and THF (250 mL) at -70 °C was added dropwise a THF solution of 2M diisopropylamine lithium (155 mL). After stirring the reaction mixture at the same temperature for 45 minutes, DMF (38.4 g) was added. The reaction solution was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture at 0 °C. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (46.0 g).

[1057] 1 H NMR (400 MHz, CDCl3) δ 7.16 - 7.20 (1H, m), 7.24 - 7.40 (1H, m), 10.33 (1H, s).

[1058] B) 2-Bromo-3,6-difluorobenzonitrile

[1059] A mixture of 2-bromo-3,6-difluorobenzaldehyde (46.0 g), iodobenzene diacetate (100 g), ammonium acetate (80.2 g) and sodium dodecyl sulfate (12.0 g) in water (200 mL) was stirred for 0.5 hours at 70 ° C. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 15 minutes at 25 ° C. The mixture was diluted with water and extracted with dichloromethane. 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 obtain the title compound (36.6 g).

[1060] 1 H NMR (400MHz, CDCl3) δ7.12-7.26(1H,m),7.26-7.45(1H,m).

[1061] C) 4-Bromo-5-fluorobenzo[d]isoxazol-3-amine

[1062] To a solution of acetohydroxamic acid (18.6 g) in DMF (300 mL) and water (60 mL) was added potassium carbonate (34.2 g). After the mixture was stirred at 25 ° C for 2 hours, a solution of 2-bromo-3,6-difluorobenzonitrile (18.0 g) in DMF (60 mL) was added and the resulting mixture was stirred at 60 ° C for 18 hours. The reaction mixture was quenched with water at 0 ° C, and the precipitate was collected to give the title compound (14.1 g).

[1063] 1 H NMR (400MHz, DMSO-d6) δ6.12(2H,s),7.45-7.62(2H,m).

[1064] D) 5-Fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine

[1065] 2,4,6-trifluorophenylboric acid (47.6 g), potassium fluoride (9.43 g), tri-tert-butylphosphonium tetrafluoroborate (3.14 g) and Pd2(dba)3 (4.95 g) were added to a solution of 4-bromo-5-fluorobenzo[d]isoxazole-3-amine (12.5 g) in DME (200 mL) and water (20 mL). The mixture was stirred for 16 hours at 110 ° C under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (9.1 g).

[1066] MS: [M+H] + 283.0

[1067] E) 2,2,2-Trichloroethyl [5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate

[1068] To a solution of 5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (2.85 g) in THF (33.7 mL) at 0 °C was added dropwise a solution of 1 M lithium bis(trimethylsilyl)amide in THF (22.2 mL). The mixture was stirred at the same temperature for 10 minutes. 2,2,2-Trichloroethoxycarbonyl chloride (1.53 mL) was added dropwise to the mixture while maintaining the temperature below 5 °C. The mixture was stirred at 0 °C for 30 minutes. The mixture was quenched with saturated ammonium chloride solution at 0 °C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was triturated with hexane containing 10% EtOAc. The solid was removed by filtration and the filtrate was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.64 g).

[1069] MS: [M+H] + 456.9

[1070] F) (2R,4R)-3,3-Difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1071] To a mixture of 2,2,2-trichloroethyl [5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (6.50 g), N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (3.79 g) in THF (142 mL) was added TEA (5.91 mL). The mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was diluted with EtOAc, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (6.78 g).

[1072] MS: [M+H] + 539.1

[1073] G) N-{(6R,7aR)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1074] To a solution of (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (60 mg) in dichloromethane (1.0 mL) was added DBU (0.05 mL) and methanesulfonyl chloride (0.013 mL) and the mixture was stirred for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (27.2 mg).

[1075] 1 1H NMR (400 MHz, CDCl3) δ 3.07 (3H, s), 3.09 - 3.14 (1H, m), 3.64 (1H, dd, J = 12.2, 9.0 Hz), 4.10 - 4.22 (2H, m), 4.34 - 4.54 (2H, m), 4.61 (1H, br d, J = 9.4 Hz), 6.71 - 6.84 (2H, m), 7.38 - 7.49 (1H, m), 7.63 (1H, dd, J = 9.2, 3.7 Hz).

[1076] Example 50

[1077] N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1078] A) 4-chloro-2-fluoro-6-iodobenzonitrile

[1079] A mixture of 4-chloro-2-fluorobenzonitrile (10 g), N-iodosuccinimide (15.9 g), 4-methylbenzenesulfonic acid monohydrate (6.11 g) and palladium(II) acetate (1.44 g) in DMF (150 mL) was stirred at 70 °C for 6 hours. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with aqueous sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.78 g).

[1080] 1 H NMR (400MHz, DMSO-d6) δ7.82-7.88 (1H, m), 8.08 (1H, s).

[1081] B) 6-Chloro-4-iodo-1,2-benzoxazol-3-amine

[1082] Potassium tert-butoxide (2.98g) was added to a mixture of 2-acetone oxime (1.94g) and DMF (58.5mL) at room temperature. The mixture was stirred for 20 minutes under a nitrogen atmosphere at room temperature. The mixture was added to a mixture of 4-chloro-2-fluoro-6-iodobenzonitrile (7.13g) and DMF (19.5mL) at 0°C. The mixture was stirred for 5 minutes under a nitrogen atmosphere at 0°C. The mixture was quenched with a saturated aqueous ammonium chloride solution at 0°C 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 diluted with EtOH (175mL) and 6M aqueous hydrogen chloride solution (60.8mL). The mixture was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. 8M aqueous sodium hydroxide solution and saturated sodium bicarbonate solution were added to the residue at 0°C. The precipitate was collected by filtration, and the solid was washed with water and IPE to obtain the title compound (4.70g).

[1083] MS:[M+H] + 294.9.

[1084] C) 6-Chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine

[1085] To a mixture of 6-chloro-4-iodo-1,2-benzoxazole-3-amine (5.0 g), (2,6-difluorophenyl)boronic acid pinacol ester (12.2 g) and potassium carbonate (2.96 g) in DMA (34.0 mL) and water (8.50 mL) was added tri-tert-butylphosphonium tetrafluoroborate (0.493 g) and Pd2(dba)3 (0.777 g). The mixture was stirred at 90 ° C under an argon atmosphere for 30 minutes. After cooling, the mixture was diluted with water 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 wet-milled with IPE and the solid was recovered by filtration to obtain the title compound (1.70 g).

[1086] MS:[M+H] + 281.0.

[1087] D) 2,2,2-Trichloroethyl [6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate

[1088] A solution of lithium bis(trimethylsilyl)amide (36.2 mL of 1 M) in THF was added to a solution of 6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine (3.91 g) in THF (69.7 mL) at 0 °C. The mixture was stirred for 30 minutes under an argon atmosphere at 0 °C. 2,2,2-Trichloroethoxycarbonyl chloride (3.16 mL) was added to the mixture at 0 °C. The mixture was stirred for 1 hour under an argon atmosphere at 0 °C. The mixture was quenched with saturated aqueous ammonium chloride at 0 °C and 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 (3.80 g).

[1089] MS: [M+H] + 454.9

[1090] E) (2S,4S)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethylsulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[1091] A mixture of 2,2,2-trichloroethyl [6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate (2.66 g), N-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl]ethylsulfonamide hydrochloride (1.43 g), diisopropylethylamine (2.14 mL) and THF (34.3 mL) was stirred overnight at 70 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.73 g).

[1092] MS: [M+H] + 515.0

[1093] F) N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethylsulfonamide

[1094] A mixture of (2S,4S)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethylsulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2.73 g), TEA (2.96 mL), and methanesulfonyl chloride (0.821 mL) in THF (64 mL) was stirred for 30 minutes at room temperature. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (64 mL). 60% Sodium hydride (0.254 g) was added to the mixture at 0 °C. The mixture was warmed to room temperature and stirred for 1 hour, then quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexanes). The residue was crystallized from EtOH / heptanes to afford the title compound (0.968 g).

[1095] 1 1H NMR (400 MHz, CDCl3) δ 1.33 (3H, t, J = 7.4 Hz), 1.46 - 1.57 (1H, m), 2.40 - 2.50 (1H, m), 2.95 - 3.11 (3H, m), 3.18 - 3.26 (1H, m), 3.81 - 3.94 (2H, m), 4.04 - 4.20 (3H, m), 7.02 (2H, q, J = 9.1 Hz), 7.33 (1H, s), 7.35 - 7.43 (1H, m), 7.64 (1H, d, J = 1.6 Hz).

[1096] Example 71

[1097] N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1098] To a mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (2.71 g) and methanesulfonyl chloride (0.806 mL) in dichloromethane (30 mL) was added DBU (2.33 mL) at 0 °C. The mixture was stirred at room temperature for 30 minutes. DBU (1.18 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and quenched with saturated aqueous ammonium chloride at 0 °C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane), followed by NH silica gel column chromatography (EtOAc / hexane). The residue was crystallized from EtOH - heptane to give the title compound (1.21 g).

[1099] 1 H NMR (400 MHz, CDCl3) δ ppm 3.07 (3H, s), 3.13 (1H, dd, J = 12.0, 8.3 Hz), 3.64 (1H, dd, J = 11.9, 9.0 Hz), 4.11 - 4.22 (2H, m), 4.36 - 4.53 (2H, m), 4.69 (1H, br d, J = 8.9 Hz), 6.72 - 6.82 (2H, m), 7.31 (1H, d, J = 6.2 Hz), 7.58 - 7.71 (2H, m).

[1100] Example 72

[1101] N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1102] A) 2,4-Difluoro-6-iodobenzonitrile

[1103] A mixture of 2,4-difluorobenzonitrile (3 g), N-iodosuccinimide (5.34 g), 4-methylbenzenesulfonic acid hydrate (2.05 g) and palladium(II) acetate (0.242 g) in DMF (45 mL) was heated to 70 °C for 6 hours. After cooling to room temperature, the mixture was poured into water and 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 / hexane) to give the title compound (1.62 g).

[1104] 1H NMR (400MHz, DMSO-d6) δ7.63-7.80(1H,m),7.91-7.98(1H,m).

[1105] B) 6-Fluoro-4-iodo-1,2-benzoxazol-3-amine

[1106] 1M THF solution of potassium tert-butoxide (2.66mL) was added to DMF (26mL) containing 2-acetone oxime (195mg) at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Then this mixture was added dropwise to a solution of 2,4-difluoro-6-iodobenzonitrile (706mg) in DMF (8.67mL) at 0°C. The mixture was stirred under nitrogen for 5 minutes at 0°C. The mixture was quenched with a saturated aqueous ammonium chloride solution at 0°C 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 diluted with EtOH (28.9mL) and 6M aqueous hydrogen chloride solution (14.4mL), and the mixture was stirred under a nitrogen atmosphere for 8 hours at 80°C. The mixture was concentrated under reduced pressure, then neutralized with a saturated sodium bicarbonate aqueous solution at 0°C 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 NH silica gel column chromatography (EtOAc / hexane) to give the title compound (286 mg).

[1107] MS:[M+H] + 278.9.

[1108] C) 4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-amine

[1109] Pd2(dba)3(47.1mg) was added to a mixture of 6-fluoro-4-iodo-1,2-benzoxazole-3-amine (286mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (741mg), potassium fluoride (179mg), tri-tert-butylphosphonium tetrafluoroborate (29.8mg) in water (0.560mL) and DME (2.8mL) at room temperature. The mixture was stirred for 1 hour under microwave irradiation at 120°C. The aqueous phase was removed and the organic phase was concentrated under reduced pressure. The mixture was then filtered through an NH silica gel pad while eluting with EtOAc. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (240mg).

[1110] MS:[M+H] + 265.0.

[1111] D) 2,2,2-Trichloroethyl [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]carbamate

[1112] A solution of 1 M lithium bis(trimethylsilyl)amide in THF (3.47 mL) was added to a solution of 4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-amine (417 mg) in THF (7.89 mL) at 0 °C. The mixture was stirred for 30 minutes at 0 °C under an argon atmosphere. 2,2,2-Trichloroethoxycarbonyl chloride (282 μL) was added to the mixture at 0 °C. The mixture was stirred for 1 hour under an argon atmosphere. The mixture was quenched with saturated aqueous ammonium chloride at 0 °C and 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 (460 mg).

[1113] MS: [M+H] + 438.9。

[1114] E) (2R,4R)-N-[4-(2,6-Difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1115] DBU (0.084 mL) was added to a solution of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (50.0 mg) and 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]carbamate (82.0 mg) in THF (1.25 mL). The mixture was stirred for 1.5 hours at 70 °C under microwave irradiation. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (73.6 mg).

[1116] MS: [M+H] + 521.1。

[1117] F) N-{(6R,7aR)-2-[4-(2,6-Difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1118] To a solution of (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (73 mg) in dichloromethane (1.3 mL) was added DBU (0.126 mL) and methanesulfonyl chloride (0.022 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane), followed by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (18.7 mg).

[1119] 1 H NMR (400 MHz, CDCl3) δ 2.98 - 3.14 (4H, m), 3.58 (1H, dd, J = 12.2, 9.0 Hz), 4.08 - 4.49 (4H, m), 4.61 (1H, br d, J = 9.2 Hz), 7.01 (2H, q, J = 8.2 Hz), 7.14 (1H, dd, J = 9.4, 1.5 Hz), 7.31 - 7.44 (2H, m).

[1120] Example 75

[1121] N-{(6R)-2-[4-(2,6-Difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1122] A) 3,6-Difluoro-2-iodobenzamide

[1123] A mixture of 2,5-difluorobenzonitrile (20 g), N-iodosuccinimide (35.6 g), palladium(II) acetate (1.61 g) and p-toluenesulfonic acid monohydrate (13.7 g) in DMF (500 mL) was stirred at 80 °C for 16 h. The mixture was quenched with water and extracted with IPE. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (8.76 g).

[1124] MS: [M+H] + 283.9。

[1125] B) 3,6-Difluoro-2-iodobenzonitrile

[1126] A mixture of 3,6-difluoro-2-iodobenzamide (8.9 g) and trifluoroacetic anhydride (13.3 mL) in pyridine (100 mL) was stirred at 80 ° C for 16 hours. The mixture was quenched with 1M aqueous hydrogen chloride solution at 0 ° C and extracted with EtOAc. The organic layer was separated, washed with water, 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 (7.83 g).

[1127] 1 H NMR (300MHz, CDCl3) δ7.17-7.34 (2H, m).

[1128] C) 2',3,6,6'-Tetrafluoro[1,1'-biphenyl]-2-carbonitrile

[1129] A mixture of 3,6-difluoro-2-iodobenzonitrile (500 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.53 g), potassium fluoride (329 mg), tri-tert-butylphosphonium tetrafluoroborate (54.7 mg), Pd2(dba)3(86 mg) and DME (0.5 mL) was stirred for 1 hour in a microwave reactor under an argon atmosphere at 120 ° C. The same reaction was repeated 4 more times to obtain five batches of crude material, which were subsequently merged. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was washed with hexane to obtain the title compound (1.98 g).

[1130] 1 H NMR (300MHz, CDCl3) δ7.04-7.16(2H,m),7.27-7.35(1H,m),7.40-7.56(2H,m).

[1131] D) 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine

[1132] A mixture of 2',3,6,6'-tetrafluoro[1,1'-biphenyl]-2-carbonitrile (1.98 g), 2-acetone oxime (1.73 g) and potassium 2-methyl-2-propoxide (1.77 g) in DMF (20 mL) was stirred at room temperature for 1.5 h. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product and 6 M aqueous hydrochloric acid (2 mL) in EtOH (20 mL) were stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.56 g).

[1133] MS: [M+H] + 265.0。

[1134] E) (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1135] To a mixture of 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine (300 mg) in THF (2 mL) at 0 °C was added a THF solution of 1 M lithium bis(trimethylsilyl)amide (2.27 mL) and 2,2,2-trichloroethoxycarbonyl chloride (0.167 mL). The mixture was stirred for 1 h. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue (500 mg). The residue (250 mg), N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (151 mg) and DBU (0.257 mL) in THF (2 mL) were stirred at 60 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (160 mg).

[1136] MS: [M+H] + 521.1。

[1137] F) N-{(6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1138] A mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (50 mg), sodium bicarbonate (40.4 mg) and Dess-Martin periodinane (48.9 mg) in MeCN (1.0 mL) was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue obtained, TFA (0.5 mL) and trifluoroacetic anhydride (0.5 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (12.9 mg).

[1139] 1 H NMR (400 MHz, CDCl3) δ 3.13 - 3.19 (4H, m), 3.97 (1H, dd, J = 11.3, 8.4 Hz), 4.52 - 4.68 (1H, m), 4.95 - 5.05 (1H, m), 6.78 (1H, dd, J = 4.8, 1.8 Hz), 6.95 (2H, tt, J = 8.5, 1.2 Hz), 7.37 - 7.46 (1H, m), 7.50 - 7.55 (1H, m), 7.71 (1H, dd, J = 9.2, 3.5 Hz).

[1140] Example 77

[1141] N-{(6R)-7,7-Difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1142] A) N-{(6R)-7,7-Difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1143] At 0 °C, tetrabutylammonium bromide (0.812 g), iodosobenzene diacetate (4.46 g) and 2,2,6,6-tetramethylpiperidine 1-oxyl (0.394 g) were added to a mixture of (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (6.78 g) and sodium bicarbonate (5.29 g) in MeCN (63 mL) and water (63 mL). The mixture was stirred at 0 °C for 30 minutes. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and 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 (6.10 g).

[1144] MS: [M+Na] + 559.1。

[1145] B) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1146] At room temperature, trifluoroacetic anhydride (3.21 mL) was added to a solution of N-(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (6.10 g) in TFA (0.876 mL). The reaction mixture was stirred at 40 °C overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, neutralized with saturated aqueous sodium bicarbonate and 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). The residue was crystallized from EtOAc-heptane to give the title compound (3.36 g).

[1147] 1 1H NMR (300 MHz, DMSO-d6) δ 3.04 (3H, s), 3.22 - 3.29 (1H, m), 4.08 - 4.19 (1H, m), 4.62 - 4.84 (1H, m), 7.18 - 7.38 (2H, m), 7.41 - 7.46 (1H, m), 7.91 (1H, t, J = 9.6 Hz), 8.13 - 8.20 (1H, m), 8.36 (1H, d, J = 9.4 Hz).

[1148] Example 92

[1149] N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1150] A) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[1151] To a mixture of 2,2,2-trichloroethyl [5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (196 mg) in THF (2 mL) at room temperature was added DBU (0.194 mL) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (121 mg). The mixture was heated at 60 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (111 mg).

[1152] MS: [M+H] + 553.1

[1153] B) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1154] A mixture of (2R,4R)-4-[(ethylsulfonyl)amino]-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (55.2 mg), Dess-Martin periodinane (50.9 mg), and TFA (0.5 mL) in MeCN (1.0 mL) was stirred at 0 °C for 1 h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of this crude product, TFA (0.5 mL), and trifluoroacetic anhydride (0.5 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) to give the title compound (20.9 mg).

[1155] 1H NMR (400 MHz, CDCl3) δ 1.46 (3H, t, J = 7.4 Hz), 3.15 - 3.27 (3H, m), 4.11 (1H, dd, J = 11.1, 8.3 Hz), 4.54 - 4.71 (1H, m), 4.91 (1H, br d, J = 10.0 Hz), 6.62 - 6.92 (3H, m), 7.53 (1H, t, J = 9.1 Hz), 7.72 (1H, dd, J = 9.2, 3.4 Hz).

[1156] Example 102

[1157] N-{(6R)-2-[4-(2,6-Difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1158] To a mixture of (2R, 4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (278 mg), sodium bicarbonate (232 mg) in MeCN (3 mL) was added Dess-Martin periodinane (305 mg) at room temperature. The mixture was stirred for 2 hours. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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). Dichloromethane (4 mL) and trifluoroacetic anhydride (2 mL) were added to the residue at room temperature. The mixture was stirred overnight at room temperature. EtOAc and saturated aqueous sodium bicarbonate solution were added to the mixture at 0°C. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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 (77 mg).

[1159] 1 H NMR(400MHz, CDCl3) δ3.13(3H,s),3.17(1H,dd,J=11.2,8.6Hz),3.97(1H,dd,J=11.2,8.4Hz),4.55-4.6 7(1H,m),5.07-5.15(1H,m),6.76-6.80(1H,m),6.89-6.96(2H,m),7.32-7.43(2H,m),7.68-7.82(2H,m).

[1160] Embodiment 124

[1161] N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1162] A) 6-Fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine

[1163] A mixture of 6-fluoro-4-iodo-1,2-benzoxazol-3-amine (620 mg), (2,4,6-trifluorophenyl)boronic acid (1.57 g), Pd2(dba)3 (102 mg), tri-tert-butylphosphonium tetrafluoroborate (64.7 mg), potassium fluoride (389 mg) in DME (4 mL) and water (0.800 mL) was heated at 120°C under argon atmosphere in a microwave reactor for 1 hour.

[1164] The crude mixture was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (511 mg).

[1165] MS: [M+H] + 283.0.

[1166] B) (2R,4R)-4-[(Ethanesulfonyl)amino]-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[1167] To a mixture of 6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (100 mg) in THF (2 mL) at 0 °C was added a toluene solution of 1 M lithium bis(trimethylsilyl)amide (0.886 mL). The mixture was stirred for 30 minutes. 2,2,2-Trichloroethoxycarbonyl chloride (0.052 mL) was added to the mixture. The mixture was stirred for 1 hour. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This crude product, N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (99 mg) and DBU (162 mg) in THF (2 mL) were stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triant C18, mobile phase: water (containing 10 mM ammonium bicarbonate) / MeCN) to give the title compound (85.1 mg).

[1168] MS: [M+H] + 553.1.

[1169] C) N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1170] At room temperature, DBU (0.049 mL) and methanesulfonyl chloride (0.013 mL) were added to a mixture of (2R,4R)-4-[(ethylsulfonyl)amino]-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (60 mg) in dichloromethane (2.0 mL). The mixture was stirred for 15 minutes. DBU (0.049 mL) was added to the mixture. The mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (16.5 mg).

[1171] 1 1H NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.5 Hz), 2.99 - 3.22 (3H, m), 3.57 - 3.78 (2H, m), 4.15 - 4.19 (1H, m), 4.35 - 4.53 (3H, m), 6.71 - 6.85 (2H, m), 7.11 (1H, d, J = 9.0 Hz), 7.33 (1H, d, J = 7.8 Hz).

[1172] Example 126

[1173] N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1174] A) 4-Bromo-6-methyl-1,2-benzoxazol-3-amine

[1175] Potassium tert-butoxide (7.86 g) was added to a solution of ethanehydroxamic acid (5.26 g) in DMF (60 mL). The mixture was stirred at 20 °C for 30 minutes. A solution of 2-bromo-6-fluoro-4-methylbenzonitrile (5.00 g) in DMF (20 mL) was added to the mixture. The reaction mixture was stirred at 20 °C for 14 hours. The reaction mixture was diluted with water and 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 / petroleum ether) to give the title compound (4.08 g).

[1176] MS: [M + H] + 227.1.

[1177] B) 4-(2,6-Difluorophenyl)-6-methyl-1,2-benzoxazol-3-amine

[1178] A mixture of 4-bromo-6-methyl-1,2-benzoxazole-3-amine (770 mg), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 g), Pd2(dba)3(310 mg), tri-tert-butylphosphonium tetrafluoroborate (197 mg) and potassium fluoride (591 mg) in DME (9 mL) and water (3 mL) was heated for 1 hour at 120 ° C under microwave irradiation. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to obtain the title compound (567 mg).

[1179] MS:[M+H] + 261.0.

[1180] C) 2,2,2-Trichloroethyl [4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]carbamate

[1181] 1M bis(trimethylsilyl)lithium amide THF solution (12.8mL) was added to a solution of 4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazole-3-amine (1.67g) in THF (39mL) at 0°C. The mixture was stirred for 10 minutes at 0°C. 2,2,2-trichloroethoxycarbonyl chloride (0.972mL) was added to the mixture. The mixture was stirred for 30 minutes at 0°C. The mixture was quenched with saturated aqueous ammonium chloride at 0°C and extracted with EtOAc. The organic layer was separated and washed with brine. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to obtain the title compound (1.86g).

[1182] MS:[M+H] + 434.9.

[1183] D) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1184] To a mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (0.162 mL) in THF (2.0 mL) at 0 °C was added 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]carbamate (187 mg). The mixture was stirred at 60 °C for 15 h, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound (190 mg).

[1185] MS: [M+H] + 517.1。

[1186] E) N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1187] To a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (95 mg) in THF (1.84 mL) and 1 M aqueous sodium hydroxide solution (0.920 mL) at -3 °C was added 4-methylbenzenesulfonyl chloride (71.9 mg). The mixture was stirred at -5 °C for 1 h. The mixture was diluted with EtOAc and washed with brine. The separated aqueous layer was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound (45.0 mg).

[1188] 1 H NMR (300 MHz, CDCl3) δ 2.55 (3H, s), 3.01 - 3.12 (4H, m), 3.51 - 3.63 (1H, m), 4.02 - 4.22 (2H, m), 4.24 - 4.50 (2H, m), 4.54 - 4.65 (1H, m), 6.92 - 7.03 (2H m), 7.14 - 7.18 (1H, m), 7.29 - 7.40 (1H, m), 7.41 - 7.44 (1H, m).

[1189] Example 144

[1190] N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}-N'-methylthiourea

[1191] A) tert-Butyl (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methylsulfamoyl)amino]pyrrolidine-1-carboxylate

[1192] To a mixture of tert-butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (210 mg), TEA (0.255 mL), 4-dimethylaminopyridine (13.1 mg) and THF (2 mL) at 0 °C was added a solution of methylsulfamoyl chloride (130 mg) in THF (1 mL). The mixture was stirred overnight at room temperature under an argon atmosphere. The mixture was purified directly by silica gel column chromatography (EtOAc / hexane) to give the title compound (168 mg).

[1193] MS: [M+H - Boc] + 336.1

[1194] B) 2,2,2-Trichloroethyl [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate

[1195] To a mixture of 6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (8.18 g) in THF (120 ml) at -22 °C was added a THF solution of 1 M lithium bis(trimethylsilyl)amide (66.7 ml). After stirring for 10 minutes at -22 °C, a mixture of 2,2,2-trichloroethoxycarbonyl chloride (7.37 g) and THF (5.0 ml) was added to the mixture at the same temperature. The mixture was stirred for 15 minutes at -22 °C under an argon atmosphere. An aqueous ammonium chloride solution and EtOAc were added to the mixture at 0 °C. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, 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 (7.03 g).

[1196] MS: [M+H] + 456.9

[1197] C) (2R,4R)-3,3-Difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfamoyl)amino]pyrrolidine-1-carboxamide

[1198] At room temperature and balloon pressure, a mixture of tert-butyl (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methylsulfamoyl)amino]pyrrolidine-1-carboxylate (168 mg) and 20% palladium hydroxide on carbon (27.2 mg) in MeOH (5 mL) was hydrogenated for 2 h. The mixture was diluted with EtOAc and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue at room temperature was added EtOAc (5 mL) and a CPME solution of 4 M hydrogen chloride (3.0 mL). The mixture was stirred for 3 h under a nitrogen atmosphere at room temperature. The mixture was concentrated under reduced pressure. To the residue at room temperature was added THF (3 mL), TEA (0.160 mL) and 2,2,2-trichloroethyl [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (177 mg). The mixture was stirred overnight under an argon atmosphere at 60 °C. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (178 mg).

[1199] MS: [M+H] + 554.1。

[1200] D) N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}-N'-methylthiodiamide

[1201] At -20 °C, 4-methylbenzenesulfonyl chloride (56.8 mg) was added to a mixture of (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfamoyl)amino]pyrrolidine-1-carboxamide (80.4 mg), 1 M aqueous sodium hydroxide (0.800 mL) and THF (1.6 mL). The mixture was stirred for 2 h at the same temperature. At room temperature, EtOAc and saturated aqueous sodium bicarbonate were added to the mixture. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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), then by NH silica gel column chromatography (EtOAc / hexane) to give the title compound (28.5 mg).

[1202] 11H NMR (300 MHz, CDCl3) δ 2.72 (3H, d, J = 5.3 Hz), 3.17 (1H, dd, J = 12.0, 8.0 Hz), 3.62 (1H, dd, J = 12.1, 8.7 Hz), 4.07 - 4.44 (5H, m), 4.65 (1H, br d, J = 8.0 Hz), 6.69 - 6.86 (2H, m), 7.11 (1H, dd, J = 9.3, 1.4 Hz), 7.33 (1H, dd, J = 7.9, 2.1 Hz).

[1203] Example 149

[1204] N-{ (6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1205] A) (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1206] To a mixture of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (4.20 g), 2,2,2-trichloroethyl [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (7.03 g) and THF (70 mL) at room temperature was added TEA (7.0 mL). The mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was diluted with EtOAc and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.82 g).

[1207] MS: [M+H] + 539.1

[1208] B) N-{ (6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1209] To a mixture of (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (7.82 g), 1 M aqueous sodium hydroxide solution (70 mL), and THF (140 mL) was added 4-methylbenzenesulfonyl chloride (5.76 g) at room temperature. The mixture was stirred for 30 minutes at room temperature. Water and EtOAc were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, 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), followed by NH-silica gel column chromatography (EtOAc / hexane). The residue was recrystallized (EtOAc / heptane) to give the title compound (4.37 g).

[1210] 1 H NMR (300 MHz, DMSO-d6) δ 2.97 (3H, s), 2.99 - 3.09 (1H, m), 3.51 (1H, t, J = 10.2 Hz), 3.99 - 4.10 (1H, m), 4.19 (1H, dd, J = 10.2, 4.1 Hz), 4.37 - 4.75 (2H, m), 7.20 - 7.41 (2H, m), 7.44 - 7.53 (1H, m), 7.88 - 8.00 (2H, m).

[1211] Example 171

[1212] N-{(6R,7aR)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1213] A) 2-Bromo-3,4,6-trifluorobenzaldehyde

[1214] A mixture of 2,4,5-trifluorobenzaldehyde (25.0 g), N-bromosuccinimide (33.4 g), palladium(II) acetate (3.51 g), and 4-amino-3-chlorobenzotrifluoride (4.41 mL) in trifluorotoluene (650 mL) and TFA (130 mL) was stirred at 60 °C for 16 hours. The same reaction was carried out twice to obtain two batches of crude material, which were then combined. The mixture was quenched with 1 M aqueous sodium hydroxide solution at 0 °C and extracted with IPE-hexane. The organic layer was separated, washed with water, 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 (32.5 g).

[1215] 11H NMR (400 MHz, CDCl3) δ 7.08 (1H, td, J = 9.7, 6.0 Hz), 10.27 (1H, s).

[1216] B) N-[(E)-(2-Bromo-3,4,6-trifluorophenyl)methylene]hydroxylamine

[1217] A mixture of 2-bromo-3,4,6-trifluorobenzaldehyde (32.5 g) and 50% aqueous hydroxylamine solution (18.0 g) in EtOH (600 mL) was stirred at 80 °C for 2 h. The mixture was concentrated under reduced pressure. Hexane was added to the resulting solid and the mixture was stirred for 30 min. The solid was collected by filtration to give the title compound (28.8 g).

[1218] MS: [M+H] + 253.9.

[1219] C) 2-Bromo-3,4,6-trifluoro-N'-hydroxybenzene-1-carboximidamide

[1220] N-Chlorosuccinimide (15.5 g) was added to a mixture of N-[(E)-(2-bromo-3,4,6-trifluorophenyl)methylene]hydroxylamine (26.8 g) in DMF (400 mL) at 0 °C. The mixture was heated to 60 °C and stirred for 1 h. The mixture was cooled to 0 °C. The mixture was stirred for 15 min. 27% aqueous ammonia solution (1.78 g) was added to the mixture. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, 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 (15.9 g).

[1221] MS: [M+H] + 268.9.

[1222] D) 4-Bromo-5,6-difluoro-1,2-benzoxazol-3-amine

[1223] A mixture of 2-bromo-3,4,6-trifluoro-N'-hydroxybenzene-1-carboximidamide (560 mg) and cesium carbonate (678 mg) in 1-methyl-2-pyrrolidone (10 mL) was heated in a microwave reactor under an argon atmosphere at 150 °C for 15 min. This process was repeated two more times to give three batches of crude material, which were then combined. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (571 mg).

[1224] MS: [M+H] + 248.9.

[1225] E) 5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine

[1226] Under argon atmosphere, a mixture of 4-bromo-5,6-difluoro-1,2-benzoxazole-3-amine (500 mg), (2,4,6-trifluorophenyl)boric acid (3.53 g), potassium fluoride (350 mg), tri-tert-butylphosphonium tetrafluoroborate (117 mg) and Pd2(dba)3(184 mg) in DME (10 mL) and water (1.00 mL) was heated to 100 ° C. The mixture was stirred at 100 ° C for 2 hours. (2,4,6-trifluorophenyl)boric acid (1.77 g), potassium fluoride (350 mg), tri-tert-butylphosphonium tetrafluoroborate (117 mg) and Pd2(dba)3(184 mg) were added to the reaction mixture. The mixture was stirred at 100 ° C for 16 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, 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 (379 mg).

[1227] MS:[M+H] + 301.0.

[1228] F) 2,2,2-Trichloroethyl [5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate

[1229] To a mixture of 5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazole-3-amine (379 mg) in THF (5 mL) was added 1M THF solution (2.78 mL) of bis(trimethylsilyl) lithium amide. The mixture was stirred at 0 ° C for 30 minutes. 2,2,2-trichloroethoxycarbonyl chloride (0.191 mL) was added to the reaction mixture. The mixture was stirred for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, 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 (378 mg).

[1230] MS:[M+H] + 474.9.

[1231] G) (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1232] At 60 °C, a mixture of 2,2,2-trichloroethyl [5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (185 mg), TEA (0.163 mL), and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (104 mg) in THF (3 mL) was stirred for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (186 mg).

[1233] MS: [M+H] + 557.0.

[1234] H) N-{(6R,7aR)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1235] At 0 °C, 1M aqueous sodium hydroxide solution (0.764 mL) was added to a mixture of (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (85.0 mg) and 4-methylbenzenesulfonyl chloride (58.2 mg) in THF (1 mL). The mixture was stirred for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) and then crystallized from EtOAc-hexane to give the title compound (25.9 mg).

[1236] 1 1H NMR (300 MHz, CDCl3) δ 3.07 (3H, s), 3.08 - 3.14 (1H, m), 3.64 (1H, dd, J = 12.0, 8.7 Hz), 4.11 - 4.24 (2H, m), 4.34 - 4.55 (2H, m), 4.59 - 4.80 (1H, m), 6.80 (2H, d, J = 8.3 Hz), 7.49 (1H, dd, J = 8.5, 5.8 Hz).

[1237] Example 174

[1238] N-{(6R)-7,7-difluoro-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1239] A) 2-Hydroxy-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile

[1240] A solution of 2,4,6-trifluorobenzaldehyde (20.0 g), ethyl 2-cyanoacetate (14.1 g), acetone (9.18 mL) and ammonium acetate (125 g) in n-butanol (400 mL) was stirred at 130 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (11.1 g).

[1241] MS: [M+H] + 265.1

[1242] B) 2-Chloro-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile

[1243] A mixture of 2-hydroxy-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile (11.1 g) in phosphoryl chloride (60 mL) was stirred at 110 °C for 14 h. The reaction mixture was cooled to room temperature and then added dropwise to water with stirring, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (3.85 g).

[1244] MS: [M+H] + 283.1

[1245] C) 6-Methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-amine

[1246] To a solution of 2-acetoxime (597 mg) in THF (20 mL) was added potassium tert-butoxide (785 mg) at 25 °C. The mixture was stirred at 25 °C for 1 h. To the mixture was added a solution of 2-chloro-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile (2.10 g) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 14 h. Water was added to the mixture, and then the mixture was extracted with EtOAc. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was diluted with EtOH (20 mL) and 6 M aqueous hydrochloric acid solution (10 mL). The mixture was stirred at 70 °C under a nitrogen atmosphere for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.20 g).

[1247] MS: [M+H] + 280.1。

[1248] D) 2,2,2-Trichloroethyl [6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]carbamate

[1249] To a solution of 6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-amine (1.28 g) in THF (20 mL) was added a THF solution of 1 M lithium bis(trimethylsilyl)amide (10.1 mL) at 0 °C, and the reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 0.5 h. 2,2,2-Trichloroethoxycarbonyl chloride (1.46 g) was added to the reaction mixture. The mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The mixture was quenched with saturated aqueous ammonium chloride solution at 0 °C, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.10 g).

[1250] MS: [M+H] + 454.0。

[1251] E) (2R,4R)-3,3-Difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]-N-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]pyrrolidine-1-carboxamide

[1252] To a solution of N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (440 mg) and N,N-diisopropylethylamine (569 mg) in THF (10 mL) was added 2,2,2-trichloroethyl [6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]carbamate (500 mg), and the reaction mixture was stirred for 3 h at 60 °C under a nitrogen atmosphere. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (310 mg).

[1253] MS: [M+H] + 536.1。

[1254] F) N-{(6R)-7,7-difluoro-1-hydroxy-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1255] To a solution of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]-N-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]pyrrolidine-1-carboxamide (310 mg) in MeCN (5 mL) and water (5 mL) were added iodobenzene diacetate (224 mg), tetrabutylammonium bromide (47 mg), 2,2,6,6-tetramethylpiperidine 1-oxyl (23 mg) and sodium hydrogen carbonate (268 mg). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (191 mg).

[1256] MS: [M+H] + 534.1。

[1257] G) N-{(6R)-7,7-difluoro-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[1258] To a solution of N-{(6R)-7,7-difluoro-1-hydroxy-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (190 mg) in THF (6 mL) was added methyl N-(triethylammoniumsulfonyl)carbamate (594 mg), and the mixture was then stirred at 50 °C for 1 h. The mixture was quenched with water and 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 preparative HPLC (column: Boston Prime C18, mobile phase: water / MeCN containing ammonium hydroxide) to give the title compound (78.5 mg).

[1259] 1 H NMR (400 MHz, CDCl3) δ 2.80 (3H, s), 3.12 (3H, s), 3.21 - 3.31 (1H, m), 4.04 - 4.14 (1H, m), 4.61 - 4.78 (1H, m), 5.46 (1H, d, J = 9.6 Hz), 6.67 - 6.82 (2H, m), 6.84 - 6.91 (1H, m), 7.29 (1H, s).

[1260] Example 213

[1261] N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide

[1262] A) (2R,4R)-tert-Butyl 3,3-difluoro-2-(hydroxymethyl)-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate

[1263] To a mixture of (2R,4R)-tert-butyl 3,3-difluoro-2-(hydroxymethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate (5.00 g), 1-(chloromethyl)-4-methoxybenzene (5.13 mL) and DMF (101 mL) at room temperature was added potassium carbonate (10.5 g). The mixture was stirred overnight at 60 °C under an argon atmosphere. EtOAc and water were added to the mixture at 0 °C. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were 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 / hexanes) to give the title compound (3.85 g).

[1264] MS: [M+H - Boc] +351.1。

[1265] B) (2R,4R)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}-2-{[(methylsulfonyloxy)methyl]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester

[1266] To a mixture of (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester (2.77 g), N,N-diisopropylethylamine (2.15 mL) and MeCN (12 mL) at 0 °C was added methanesulfonic anhydride (1.61 g), and the mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with EtOAc and water with stirring. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through a NH silica gel pad, eluted with EtOAc simultaneously, and concentrated under reduced pressure to give the title compound (3.11 g).

[1267] MS: [M+Na] + 551.2。

[1268] C) (2R,4R)-2-(cyanomethyl)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester

[1269] A mixture of (2R,4R)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}-2-{[(methylsulfonyloxy)methyl]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester (2.94 g), sodium cyanate (1.78 g) and dimethyl sulfoxide (36 mL) was stirred at 45 - 50 °C for 4.5 h. The mixture was diluted with EtOAc and aqueous ammonium chloride solution while stirring at 0 °C. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.91 g).

[1270] MS: [M+Na] + 482.2。

[1271] D) Methyl [(2R,4R)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidin-2-yl]acetate hydrochloride

[1272] Trimethylsilyl chloride (16.6 mL) was added to a mixture of tert-butyl (2R,4R)-2-(cyanomethyl)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate (1.99 g) and MeOH (60 mL) at room temperature, and the mixture was refluxed for 2.5 h. After addition of trimethylsilyl chloride (8.30 mL), the mixture was refluxed for 1.5 h. After further addition of trimethylsilyl chloride (5.54 mL), the mixture was refluxed for 1 h. The mixture was cooled to 0 °C and a white suspension was formed. IPE (60 mL) was added and the mixture was stirred at 0 °C for 10 min. The precipitate was collected, washed with IPE, and dried under reduced pressure to give the title compound (1.75 g).

[1273] MS: [M+H] + 393.1。

[1274] E) tert-butyl (2R,4R)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[1275] Di-tert-butyl dicarbonate (1.15 mL) was added to a cooled mixture of methyl [(2R,4R)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidin-2-yl]acetate hydrochloride (1.64 g), sodium bicarbonate (0.964 g), THF (30 mL) and water (10 mL) at 0 °C, and the mixture was stirred overnight at room temperature. EtOAc and water were added to the mixture with stirring. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.75 g).

[1276] MS: [M+Na] + 512.2。

[1277] F) tert-butyl (2R,4R)-3,3-difluoro-4-[(methylsulfonyl)amino]-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[1278] To a cooled mixture of tert-butyl (2R,4R)-3,3-difluoro-4-{(methylsulfonyl)[(4-methoxyphenyl)methyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.71 g), MeCN (36 mL), and pH 6.8 phosphate buffer (24 mL) was added ammonium cerium(IV) nitrate (6.28 g), and the mixture was stirred at 0 °C for 10 minutes and then at room temperature for 0.5 hour. The mixture was diluted with EtOAc and 10% aqueous sodium thiosulfate solution was added at 0 °C until the yellow color of the reaction disappeared, and saturated aqueous sodium bicarbonate solution was added with stirring for neutralization. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered 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 (1.20 g).

[1279] 1 H NMR (300 MHz, CDCl3) δ 1.46 (9H, s), 2.76 - 3.02 (2H, m), 3.06 (3H, s), 3.15 - 3.32 (1H, m), 3.72 (3H, s), 4.02 - 4.56 (3H, m), 5.23 (1H, br d, J = 9.6 Hz).

[1280] G) tert-butyl (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate

[1281] To a mixture of tert-butyl (2R,4R)-3,3-difluoro-4-[(methylsulfonyl)amino]-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.16 g) and THF (20 mL) at room temperature was added a THF solution of 4M lithium borohydride (3.89 mL), and the mixture was stirred at 45 - 50 °C for 4.5 hours. Thereafter, the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and aqueous ammonium chloride solution while stirring at 0 °C for 20 minutes and then at room temperature for 20 minutes. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.966 g).

[1282] 1 H NMR (300 MHz, CDCl3) δ 1.48 (9H, s), 1.65 - 1.85 (1H, m), 1.94 - 2.13 (1H, m), 3.02 - 3.21 (4H, m), 3.36 - 3.87 (3H, m), 4.08 - 4.46 (3H, m), 4.91 - 5.24 (1H, m).

[1283] H) N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride

[1284] A mixture of tert-butyl (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxylate (32.7 mg) and a MeOH solution of 2 M hydrogen chloride (2 mL) was refluxed for 0.5 h. After cooling to 0 °C, IPE was added dropwise and the mixture was stirred at 0 °C for 0.5 h. After concentration under reduced pressure, the residue was triturated with EtOAc / heptane to form a white solid, which was collected, washed with EtOAc, and dried under reduced pressure at 50 °C to give the title compound (23.6 mg).

[1285] 1 H NMR (300 MHz, DMSO-d6) δ 1.85 - 1.96 (2H, m), 2.99 - 3.13 (4H, m), 3.51 - 3.64 (2H, m), 3.68 - 3.84 (1H, m), 3.99 - 4.24 (1H, m), 4.52 - 4.76 (1H, m), 4.83 - 5.10 (1H, m), 8.12 (1H, d, J = 9.1 Hz), 9.73 (2H, br s).

[1286] I) (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methylsulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide

[1287] To a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (170 mg), 2,2,2-trichloroethyl [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (280 mg) and THF (3.0 mL) at room temperature was added TEA (0.252 mL). The mixture was stirred overnight at 60 °C under a nitrogen atmosphere. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (318 mg).

[1288] MS: [M+H] + 535.2。

[1289] J) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide

[1290] At room temperature, methanesulfonic anhydride (187 mg) was added to a mixture of (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methylsulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (318 mg), triethylamine (0.412 mL), and MeCN (3.0 mL). The mixture was stirred for 10 minutes at room temperature under a nitrogen atmosphere, then diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The solid was crystallized from EtOAc-heptane to give the title compound (198 mg).

[1291] 1 1H NMR (400 MHz, CDCl3) δ 1.92 - 2.14 (1H, m), 2.15 - 2.30 (1H, m), 2.54 - 2.79 (1H, m), 3.10 (3H, s), 3.35 - 4.15 (4H, m), 4.17 - 4.45 (1H, m), 4.56 - 4.83 (1H, m), 6.60 - 6.88 (2H, m), 7.27 - 7.31 (1H, m), 7.60 - 7.68 (2H, m).

[1292] Example 242

[1293] N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}cyclopropanesulfonamide

[1294] A) (2R,4R)-tert-Butyl 4-amino-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[1295] A mixture of (2R,4R)-tert-butyl 4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (10.2 g) and 10% palladium hydroxide on carbon (500 mg) in EtOH (200 mL) was hydrogenated at room temperature under balloon pressure for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (7.49 g).

[1296] MS: [M + H - Boc] + 153.1

[1297] B) (2R,4R)-tert-Butyl 4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylate

[1298] At room temperature under an argon atmosphere, a mixture of (2R,4R)-4-amino-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (7.52 g), 1H-imidazole (6.08 g) and tert-butyldimethylsilyl chloride (4.94 g) in DMF (50 mL) was stirred for 40 minutes. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (11.4 g).

[1299] MS: [M + H - Boc] + 267.2

[1300] C) (2R,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1301] At 20 °C, cyclopropanesulfonyl chloride (7.86 g) and 4-dimethylaminopyridine (1.37 g) were added to a solution of (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (4.10 g) and TEA (9.34 mL) in anhydrous THF (50 mL), and the mixture was stirred at 70 °C under a nitrogen atmosphere for 14 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were 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 / petroleum ether) to give the title compound (4.15 g).

[1302] 1 H NMR (400 MHz, CDCl3) δ 0.09 - 0.20 (6H, m), 0.92 (9H, s), 0.95 - 1.21 (4H, m), 1.47 (9H, s), 2.35 - 2.48 (1H, m), 3.36 - 3.54 (1H, m), 3.77 - 4.05 (3H, m), 4.09 - 4.27 (2H, m), 6.31 - 6.70 (1H, m).

[1303] D) (2R,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1304] To a solution of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (4.15 g) and 4-methoxybenzyl chloride (3.45 g) in anhydrous DMF (60 mL) at 20 °C was added potassium carbonate (6.09 g), and the mixture was stirred at 60 °C under a nitrogen atmosphere for 7 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were 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 / petroleum ether) to give the title compound (4.80 g).

[1305] MS: [M+H-Boc] + 491.2。

[1306] E) (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1307] To a solution of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (4.80 g) in anhydrous THF (50 mL) at 20 °C was added a THF solution of 1 M tetrabutylammonium fluoride (12.2 mL), and the mixture was stirred at 20 °C under a nitrogen atmosphere for 1 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (4.10 g).

[1308] MS: [M+Na] + 499.3。

[1309] F) (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester

[1310] To a mixture of tert-butyl (2R,4R)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.10 g) and TEA (4.52 mL) in dichloromethane (40 mL) was added methanesulfonic anhydride (2.83 g) at 20 °C, and the mixture was stirred at 20 °C for 0.5 h. The mixture was diluted with EtOAc and water with stirring. 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 / petroleum ether) to give the title compound (4.18 g).

[1311] MS: [M+Na] + 577.1。

[1312] G) (2R,4R)-2-(Cyanomethyl)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate tert-butyl ester

[1313] To a mixture of tert-butyl (2R,4R)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (4.18 g) and dimethyl sulfoxide (50 mL) was added sodium cyanide (1.58 g), and the mixture was stirred at 50 °C under a nitrogen atmosphere for 4 h. The mixture was diluted with EtOAc and water with stirring. 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 / petroleum ether) to give the title compound (2.75 g).

[1314] MS: [M+H-Boc] + 386.2。

[1315] H) Methyl [(2R,4R)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidin-2-yl]acetate hydrochloride

[1316] Trimethylsilyl chloride (9.23 g) was added to a mixture of tert-butyl (2R,4R)-2-(cyanomethyl)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate (2.75 g) and MeOH (40 mL) at 25 °C, and the mixture was stirred for 14 h at 65 °C under a nitrogen atmosphere. Trimethylsilyl chloride (4.62 g) was added and the mixture was stirred for 1 h at 65 °C under a nitrogen atmosphere. Trimethylsilyl chloride (4.62 g) was added and the mixture was stirred for 1 h at 65 °C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give the title compound (2.70 g).

[1317] MS: [M+H] + 419.0。

[1318] I) tert-butyl (2R,4R)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[1319] Di-tert-butyl dicarbonate (2.47 g) and sodium bicarbonate (2.38 g) were added to a mixture of methyl [(2R,4R)-4-{(cyclopropylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidin-2-yl]acetate hydrochloride (2.70 g), THF (30 mL) and water (15 mL) at 25 °C, and the mixture was stirred for 1 h at 25 °C under a nitrogen atmosphere. The mixture was diluted with water and 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 (2.65 g).

[1320] MS: [M+Na] + 541.1。

[1321] J) tert-butyl (2R,4R)-4-[(cyclopropylsulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate

[1322] At 0 °C, cerium(IV) diammonium nitrate (8.40 g) was added to a mixture of tert-butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (2.65 g), MeCN (50 mL), and pH 6.8 phosphate buffer (30 mL), and the mixture was stirred for 2 hours under a nitrogen atmosphere at 20 °C. The mixture was diluted with EtOAc and 10% aqueous sodium thiosulfate solution was added until the yellow color of the reaction disappeared, and saturated aqueous sodium bicarbonate solution was added with stirring for neutralization. The mixture was filtered and the filtrate 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 (1.75 g).

[1323] MS: [M+H - Boc] + 298.9。

[1324] K) (2R,4R)-4-[(Cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate tert-butyl ester

[1325] At 20 °C, a solution of 2M lithium borohydride in THF (13.2 mL) was added dropwise to a mixture of tert-butyl (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.75 g) and THF (20 mL). The mixture was stirred at 60 °C for 2 hours. The mixture was quenched slowly with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layers were separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.60 g).

[1326] MS: [M+H - Boc] + 270.9。

[1327] L) N-[(3R,5R)-4,4-Difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]cyclopropanesulfonamide hydrochloride

[1328] At 20 °C, a solution of tert-butyl (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (1.60 g) in 4M hydrogen chloride in EtOAc solution (25 mL) was stirred for 1 hour. The mixture was filtered and the cake was dried under reduced pressure to give the title compound (1.15 g).

[1329] 11H NMR (400 MHz, DMSO-d6) δ 0.89 - 1.06 (4H, m), 1.83 - 2.22 (2H, m), 2.53 - 2.65 (1H, m), 3.09 - 3.23 (1H, m), 3.50 - 3.73 (3H, m), 4.06 - 4.20 (1H, m), 4.50 - 4.70 (1H, m), 8.08 - 8.20 (1H, m), 10.28 (2H, m).

[1330] M) (2R,4R)-4-[(Cyclopropylsulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide

[1331] At 0 °C, 2,2,2-trichloroethyl [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (107 mg) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]cyclopropanesulfonamide hydrochloride (50.0 mg) and TEA (91.0 μL) in THF (4 mL). The mixture was stirred at 60 °C under a nitrogen atmosphere for 14 h. The reaction mixture was poured into water and 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 preparative TLC (silica gel, EtOAc / petroleum ether) to give the title compound (45 mg).

[1332] MS: [M+H] + 561.0.

[1333] N) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}cyclopropanesulfonamide

[1334] At 0 °C, TEA (65.0 mg) and methanesulfonic anhydride (42.0 mg) were added to a mixture of (2R,4R)-4-[(cyclopropylsulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (45.0 mg) and MeCN (2 mL). The mixture was stirred at 25 °C for 10 h. The reaction mixture was poured into water and 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 preparative HPLC (column: Boston Prime C18, mobile phase: water / MeCN containing ammonia hydroxide), followed by lyophilization to give the title compound (7.2 mg).

[1335] 1 H NMR (400 MHz, CDCl3) δ 1.02 - 1.13 (2H, m), 1.14 - 1.32 (2H, m), 1.97 - 2.29 (2H, m), 2.46 - 2.57 (1H, m), 2.58 - 2.80 (1H, m), 3.40 - 4.42 (5H, m), 4.46 - 4.64 (1H, m), 6.61 - 6.92 (2H, m), 7.27 - 7.31 (1H, m, overlapping with CDCl3 signal), 7.60 - 7.67 (2H, m).

[1336] Example 243

[1337] N-{(4aR,6R)-2-[5,6-Difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide

[1338] A) (2R,4R)-N-[5,6-Difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide

[1339] To a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]methanesulfonamide hydrochloride (39.5 mg), 2,2,2-trichloroethyl [5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (67.0 mg) and THF (1.0 mL) was added TEA (0.059 mL) at room temperature. The mixture was stirred overnight at 60 °C under nitrogen. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (66 mg).

[1340] MS: [M+H] + 571.2。

[1341] B) N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide

[1342] To a mixture of (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (66.0 mg), TEA (0.080 mL) and MeCN (1.0 mL) was added methanesulfonic anhydride (36.3 mg) at room temperature. The mixture was stirred at room temperature under nitrogen for 10 minutes, then diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The solid was crystallized from EtOAc - heptane to give the title compound (53.0 mg).

[1343] 1 1H NMR (400 MHz, CDCl3) δ 1.92 - 2.10 (1H, m), 2.16 - 2.28 (1H, m), 2.49 - 2.81 (1H, m), 3.10 (3H, s), 3.18 - 4.18 (4H, m), 4.22 - 4.43 (1H, m), 4.50 - 4.67 (1H, m), 6.66 - 6.93 (2H, m), 7.43 - 7.55 (1H, m).

[1344] Example 260

[1345] N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide

[1346] A) (2R,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-[(ethylsulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1347] At 0 °C, ethanesulfonyl chloride (4.68 g) was added to a solution of (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (8.90 g) and TEA (7.37 g) in dichloromethane (100 mL), and the reaction mixture was stirred at 20 °C for 1 h. The mixture was diluted with water and extracted with dichloromethane. 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 (10.7 g).

[1348] 1 1H NMR (400 MHz, CDCl3) δ 0.08 - 0.21 (6H, m), 0.90 - 0.96 (9H, m), 1.37 (3H, t, J = 7.6 Hz), 1.47 (9H, s), 2.92 - 3.16 (2H, m), 3.36 - 3.55 (1H, m), 3.74 - 4.12 (4H, m), 4.14 - 4.30 (1H, m), 6.30 - 6.69 (1H, m).

[1349] B) (2R,4R)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

[1350] Potassium carbonate (16.1 g) was added to a mixture of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(ethylsulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (10.7 g) and 1-(chloromethyl)-4-methoxybenzene (9.11 g) in DMF (150 mL). The mixture was stirred at 60 °C for 7 h. The reaction mixture was quenched with water at 0 °C and then extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (10.8 g).

[1351] 11H NMR (400 MHz, CDCl3) δ 0.01 - 0.07 (6H, m), 0.87 (9H, s), 1.36 (3H, t, J = 7.2 Hz), 1.43 (9H, s), 2.82 - 3.37 (3H, m), 3.74 - 4.03 (7H, m), 4.38 - 4.87 (3H, m), 6.79 - 6.91 (2H, m), 7.22 - 7.26 (2H, m).

[1352] C) (2R,4R)-4-{(Ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1353] To a solution of (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (10.8 g) in THF (200 mL) at 20 °C was added a THF solution of 1 M tetrabutylammonium fluoride (28.0 mL), and the mixture was stirred under a nitrogen atmosphere at 20 °C for 16 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were 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 / petroleum ether) to give the title compound (8.05 g).

[1354] 1 1H NMR (400 MHz, CDCl3) δ 1.33 (3H, t, J = 7.2 Hz), 1.43 (9H, s), 2.75 - 3.08 (2H, m), 3.22 - 3.41 (1H, m), 3.60 - 3.74 (1H, m), 3.76 - 3.85 (4H, m), 3.94 - 4.08 (2H, m), 4.34 - 4.54 (2H, m), 4.60 - 4.77 (2H, m), 6.84 - 6.92 (2H, m), 7.27 - 7.36 (2H, m).

[1355] D) (2R,4R)-4-{(Ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylic acid tert-butyl ester

[1356] To a mixture of tert-butyl (2R,4R)-4-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (400 mg) and TEA (349 mg) in dichloromethane (10 mL) was added methanesulfonic anhydride (300 mg) at 25 °C, and the mixture was stirred for 1 h at 25 °C. The mixture was diluted with EtOAc and water with stirring. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (480 mg).

[1357] MS: [M+Na] + 565.2。

[1358] E) tert-butyl (2R,4R)-2-(cyanomethyl)-4-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate

[1359] To a mixture of tert-butyl (2R,4R)-4-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (8.42 g) and dimethyl sulfoxide (120 mL) was added sodium cyanide (3.19 g), and the mixture was stirred for 2 h at 50 °C under a nitrogen atmosphere. The mixture was diluted with EtOAc and water with stirring. 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 / petroleum ether) to give the title compound (5.18 g).

[1360] MS: [M+Na] + 496.2。

[1361] F) Methyl [(2R,4R)-4-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidin-2-yl]acetate hydrochloride

[1362] To a mixture of tert-butyl (2R,4R)-2-(cyanomethyl)-4-{(ethylsulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate (5.18 g) and MeOH (100 mL) was added trimethylsilyl chloride (17.8 g) at 25 °C, and the mixture was stirred for 14 h at 65 °C under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to give the title compound (4.84

[1363] g).

[1364] MS: [M+H] + 407.1。

[1365] (2R,4R)-4-{(Ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1366] At 20 °C, di-tert-butyl dicarbonate (4.77 g) and sodium bicarbonate (4.59 g) were added to a mixture of [(2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidin-2-yl]methyl acetate hydrochloride (4.84 g), THF (80 mL) and water (40 mL), and the mixture was stirred for 1 hour at 20 °C under a nitrogen atmosphere. The mixture was diluted with water and 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 (4.53 g).

[1367] 1 1H NMR (400 MHz, CDCl3) δ 1.35 (3H, t, J = 7.2 Hz), 1.41 (9H, s), 2.63 - 3.10 (4H, m), 3.12 - 3.43 (1H, m), 3.67 - 3.84 (7H, m), 4.34 - 4.52 (2H, m), 4.60 - 4.83 (2H, m), 6.87 (2H, d, J = 8.4 Hz), 7.26 - 7.37 (2H, m).

[1368] (2R,4R)-4-[(Ethanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1369] At 0 °C, ammonium cerium(IV) nitrate (545 mg) was added to a mixture of (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg), MeCN (8 mL) and pH 6.8 phosphate buffer (4 mL), and the mixture was stirred for 1 hour at 25 °C under a nitrogen atmosphere. Ammonium cerium(IV) nitrate (545 mg) was added and the mixture was stirred for 1 hour at 25 °C. The mixture was diluted with EtOAc and 10% aqueous sodium thiosulfate solution was added until the yellow color of the reaction disappeared, and saturated aqueous sodium bicarbonate solution was added with stirring for neutralization. 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 / petroleum ether) to give the title compound (110 mg).

[1370] MS: [M + H - Boc]+ 286.9。

[1371] I) (2R,4R)-4-[(Ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[1372] At 25 °C, a solution of lithium borohydride (4 M in THF, 0.53 mL) was added dropwise to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (162 mg) and THF (5 mL). The mixture was stirred at 60 °C for 2 h. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (146 mg).

[1373] MS: [M + H - Boc] + 258.9。

[1374] J) N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride

[1375] At 25 °C, a solution of hydrogen chloride (4 M in dioxane, 2 mL) was added to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (146 mg) and EtOAc (2 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and co-evaporated with EtOAc to give the title compound (120 mg).

[1376] 1 1H NMR (400 MHz, DMSO-d6) δ 1.22 (3H, t, J = 7.2 Hz), 1.84 - 1.97 (2H, m), 2.99 - 3.17 (3H, m), 3.51 - 3.58 (2H, m, overlapping with dioxane signal), 3.63 - 3.77 (1H, m), 4.06 - 4.16 (1H, m), 4.49 - 4.69 (1H, m), 6.53 (1H, brs), 8.15 (1H, d, J = 8.8 Hz), 10.11 (2H, brs).

[1377] K) (2R,4R)-4-[(Ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide

[1378] At 0 °C, [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamic acid 2,2,2-trichloroethyl ester (45 mg) was added to a mixture of N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (20 mg) and TEA (28 mg) in THF (2 mL). The mixture was stirred at 60 °C under a nitrogen atmosphere for 14 hours. The reaction mixture was poured into water and 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 (22 mg).

[1379] MS: [M+H] + 549.1。

[1380] L) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide

[1381] At 0 °C, TEA (16 mg) and methanesulfonic anhydride (21 mg) were added to a mixture of (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (22 mg) and MeCN (2 mL). The mixture was stirred at 25 °C for 14 hours. The reaction mixture was poured into water and 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 preparative HPLC (column: Boston Prime C18, mobile phase: water containing ammonium hydroxide / MeCN), followed by lyophilization to give the title compound (6.2 mg).

[1382] 1 1H NMR (400 MHz, CDCl3) δ 1.45 (3H, t, J = 7.2 Hz), 1.99 - 2.30 (2H, m), 2.47 - 2.90 (1H, m), 3.17 (2H, q, J = 7.6 Hz), 3.38 - 4.45 (5H, m), 4.48 - 4.84 (1H, m), 6.60 - 6.97 (2H, m), 7.27 - 7.36 (1H, m), 7.61 - 7.70 (2H, m).

[1383] Example 265

[1384] N-{ (4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide

[1385] A) 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]carbamate

[1386] A 1M solution of lithium bis(trimethylsilyl)amide in hexane (37.9 mL) was added dropwise to a solution of 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine (4.00 g) in THF (40 mL) at 0 °C. The mixture was stirred for 0.5 h at 0 °C under a nitrogen atmosphere. 2,2,2-Trichloroethoxycarbonyl chloride (4.81 g) was added. The mixture was stirred for 1 h at 0 °C under a nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were 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 (4.5 g).

[1387] 1 1H NMR (400 MHz, CDCl3) δ 4.40 - 4.57 (2H, m), 6.85 (1H, brs), 7.04 - 7.12 (2H, m), 7.42 - 7.53 (2H, m), 7.61 - 7.68 (1H, m).

[1388] B) (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide

[1389] TEA (288 mg) was added to a solution of 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]carbamate (500 mg) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (335 mg) in THF (8 mL), and then the mixture was stirred at 60 °C under a nitrogen atmosphere for 14 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (551 mg).

[1390] MS: [M+H] + 534.9

[1391] C) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}ethanesulfonamide

[1392] At 0 °C, TEA (121 mg) and methylsulfonyl methanesulfonate (71 mg) were added to a mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methylsulfonyl)amino]pyrrolidine-1-carboxamide (80 mg) and MeCN (3 mL). The mixture was stirred at 28 °C for 2 h. The reaction mixture was poured into water and 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 preparative HPLC (column: Boston Prime C18, mobile phase: water / MeCN containing ammonium hydroxide), followed by lyophilization to give the title compound (48 mg).

[1393] 1 1H NMR (400 MHz, CDCl3) δ 1.94 - 2.25 (2H, m), 2.29 - 3.05 (1H, m), 3.08 (3H, s), 3.13 - 4.40 (5H, m), 4.71 - 4.98 (1H, m), 6.86 - 7.18 (2H, m), 7.37 - 7.52 (2H, m), 7.57 - 7.65 (1H, m).

[1394] Example 282

[1395] N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1396] A) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[1397] To a solution of 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]carbamate (195 mg) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (137 mg) in THF (7 mL) was added TEA (112 mg), and the mixture was then stirred at 60 °C for 14 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were 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 (234 mg).

[1398] MS: [M+H] + 535.0。

[1399] B) N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1400] A mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide (234 mg) and sodium bicarbonate (184 mg) in MeCN (4 mL) and water (2 mL) was stirred at 0 °C. Then, iodobenzene diacetate (170 mg), tetrabutylammonium bromide (28 mg), and 2,2,6,6-tetramethylpiperidin-1-oxyl (14 mg) were added to the mixture at 0 °C. The mixture was stirred at 0 °C for 15 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were 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 (197 mg).

[1401] MS: [M+H] + 533.0。

[1402] C) N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[1403] To a solution of N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide (242 mg) in THF (8 mL) was added methyl N-(triethylammoniumsulfonyl)carbamate (542 mg). The mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: water / MeCN containing ammonium hydroxide), followed by lyophilization to give the title compound (132 mg).

[1404] 1 H NMR (400 MHz, CDCl3) δ 1.44 (3H, t, J = 7.2 Hz), 3.03 - 3.22 (3H, m), 3.88 - 4.05 (1H, m), 4.41 - 4.65 (1H, m), 5.38 - 5.59 (1H, m), 6.72 - 6.78 (1H, m), 6.88 - 6.96 (2H, m), 7.16 - 7.23 (1H, m), 7.32 - 7.45 (2H, m).

[1405] The compounds of the examples are shown in the following table. MS in the table means the measured value. The compounds of Examples 2 - 15, 17 - 23, 25 - 32, 35 - 46, 48, 49, 51 - 70, 73, 74, 76, 78 - 91, 93 - 101, 103 - 123, 125, 127 - 143, 145 - 148, 150 - 170, 172, 173, 175 - 212, 214 - 241, 244 - 259, 261 - 264, 266 - 281 and 283 - 340 in the following table were produced according to the method described in the above examples or a method similar thereto.

[1406] Table 1 - 1

[1407]

[1408]

[1409] Table 1 - 2

[1410]

[1411]

[1412] Table 1 - 3

[1413]

[1414] Table 1-4

[1415]

[1416] Table 1-5

[1417]

[1418] Table 1-6

[1419]

[1420] Table 1-7

[1421]

[1422] Table 1-8

[1423]

[1424] Table 1-9

[1425]

[1426] Table 1-10

[1427]

[1428] Table 1-11

[1429]

[1430]

[1431] Table 1-12

[1432]

[1433]

[1434] Table 1-13

[1435]

[1436]

[1437] Table 1-14

[1438]

[1439]

[1440] Table 1-15

[1441]

[1442]

[1443] Table 1-16

[1444]

[1445] Table 1-17

[1446]

[1447] Table 1-18

[1448]

[1449]

[1450] Table 1-19

[1451]

[1452]

[1453] Table 1-20

[1454]

[1455]

[1456] Table 1-21

[1457]

[1458]

[1459] Table 1-22

[1460]

[1461]

[1462] Table 1-23

[1463]

[1464] Table 1-24

[1465]

[1466] Table 1-25

[1467]

[1468]

[1469] Table 1-26

[1470]

[1471]

[1472] Table 1-27

[1473]

[1474]

[1475] Table 1-28

[1476]

[1477]

[1478] Table 1-29

[1479]

[1480]

[1481] Table 1-30

[1482]

[1483] Table 1-31

[1484]

[1485] Table 1-32

[1486]

[1487]

[1488] Table 1-33

[1489]

[1490] Table 1-34

[1491]

[1492]

[1493] Table 1-35

[1494]

[1495]

[1496]

[1497] Table 1-36

[1498]

[1499]

[1500] Table 1-37

[1501]

[1502]

[1503] Table 1-38

[1504]

[1505]

[1506] Table 1-39

[1507]

[1508]

[1509] Table 1-40

[1510]

[1511]

[1512] Table 1-41

[1513]

[1514]

[1515] Table 1-42

[1516]

[1517]

[1518] Table 1-43

[1519]

[1520]

[1521] Table 1-44

[1522]

[1523]

[1524] Table 1-45

[1525]

[1526]

[1527]

[1528] Table 1-46

[1529]

[1530]

[1531] Table 1-47

[1532]

[1533]

[1534] Table 1-48

[1535]

[1536]

[1537] Table 1-49

[1538]

[1539]

[1540] Table 1-50

[1541]

[1542] Experimental Example 1: Obtaining cells stably expressing human orexin type 2 receptor (hOX2R)

[1543] To obtain cell clones stably expressing the human orexin type 2 receptor, human orexin type 2 (residues 1-444, NCBI reference sequence: AK314279) was constructed in the 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 limited dilution using G418 resistance as a selection marker.

[1544] Experimental Example 2: Measuring orexin type 2 receptor agonist activity

[1545] CHO cells that forcibly express the human OX2 receptor were seeded at 10,000 cells / well into a 384-well black clear bottom plate (BD falcon), and after incubation at room temperature for 30 minutes, they were incubated at 37 °C and 5% CO2 for 1 day. After removing the cell plate medium, a measurement buffer containing calcium indicator A (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4AM (Dojin Kagaku), 0.08% Pluronic F127 (Dojin Kagaku), 1.25 mM probenecid (Dojin Kagaku)) was added at 30 μL / well. After incubation in a 5% CO2 incubator at 37 °C for 30 minutes, they were incubated at room temperature for another 30 minutes. A test compound diluted with measurement buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was added at 10 μL / well, and the fluorescence value was measured once every 1 second for 1 minute using FDSS μCELL (Hamamatsu Photonics), and then once every 2 seconds for 1 minute. The measurement continued for 1 minute and 40 seconds. The amount of the fluorescence value when DMSO was added instead of the test compound was defined as 0%, and the amount of the fluorescence value when orexin A (human) (Peptide Institute) with a final concentration of 10 nM was added was defined as 100%. The activity (%) of the test compound was calculated. Table 2 shows the activity of each compound at a concentration of 3 μM. It is clearly visible from this result that the compounds of the present invention have orexin type 2 receptor activation activity.

[1546] Table 2-1

[1547]

[1548]

[1549] Table 2-2

[1550]

[1551]

[1552] Table 2-3

[1553]

[1554]

[1555] Table 2-4

[1556]

[1557]

[1558] Table 2-5

[1559] Test compound OX2R agonist activity (3 μM, %) 184 101 185 104 186 101 189 103 190 96 191 98 193 103 194 92

[1560] Table 2-6

[1561]

[1562]

[1563] Table 2-7

[1564]

[1565]

[1566] Table 2-8

[1567] Test compound OX2R agonist activity (3 μM, %) 253 101 254 95 255 107 256 103 257 110 258 100 259 96 260 108 261 105 262 114 263 114 264 107 265 107 266 103 267 101 268 104 269 104 270 109 271 107 272 109 273 103 274 102 275 103 276 100 277 106 278 109 279 104 280 101 281 107

[1568] Table 2-9

[1569]

[1570]

[1571] Table 2-10

[1572]

[1573]

[1574] Experimental Example 3: Evaluating the arousal-promoting effect on cynomolgus monkeys

[1575] The arousal-promoting effect was evaluated by measuring the electroencephalogram (EEG), electromyogram (EMG), and motor activity of cynomolgus monkeys. Under isoflurane anesthesia (0.5 - 5%, Pfizer Japan Inc., Tokyo, Japan), a radio-telemetry transmitter (L03-F3, Data Sciences International Inc., MN, USA) was surgically implanted into male cynomolgus monkeys (2 - 3 years old, Hamri Co., Ltd., Ibaraki, Japan). Two EEG electrodes were stereotaxically positioned in the parietal region and fastened to the skull with stainless steel screws in contact with the dura mater. Bilateral EMG electrodes were implanted into...

Claims

1. A compound represented by formula (I): wherein X 1 is NR 8 or CR 9 ; X 2 is O, NR 10 or S; X 3 and X 4 are both C, or one of X 3 and X 4 is N and the other is C; X 5 is CR 11 or N; X 6 is CR 12 ; X 7 is CR 13 or N; X 8 is CR 14 or N; X 9 is CR 2 or N; X 10 is CR 15 or N; R 1 is an optionally substituted C 1-6 alkyl, an optionally substituted C 3-10 cycloalkyl or an optionally substituted mono- or di-C 1-6 alkylamino; R 2 and R 3 each independently is a hydrogen atom or an optionally substituted C 1-6 alkyl group, or When r is 0, then R 2 and R 3 can be joined together to form a bond, or When X 10 is CR 15 then R 3 is capable of combining with R 15 to form a bond; R 4 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; R 5 is an optionally substituted 4-, 5- or 6-membered monocyclic group; R 6 and R 7 each independently is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group; m is 0 or 1; q is 1 or 2; r is 0 or 1; R 9 、R 11 、R 12 and R 13 each independently is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; R 8 and R 10 each independently does not exist, or is selected from a hydrogen atom and an optionally substituted C 1-6 alkyl; and R 14 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group; R 15 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group, or R 15 capable of combining with R 3 to form a bond together; or a salt thereof.

2. The compound according to claim 1, wherein m is 0; q is 1; and r is 0; or a salt thereof.

3. The compound according to claim 1, wherein m is 1; q is 1; and r is 0; or a salt thereof.

4. The compound according to claim 1, wherein m is 0; q is 1; and r is 1; or a salt thereof.

5. The compound according to claim 1, wherein m is 0; q is 2; and r is 0; or a salt thereof.

6. The compound according to claim 1, wherein X 1 is NR 8 where R 8 does not exist; X 2 is O; X 3 and X 4 are both C; X 5 is CR 11 or N, where R 11 is a hydrogen atom; X 6 is CR 12 , where R 12 is a hydrogen atom, C 1-6 alkyl or a halogen atom; and X 7 is CR 13 wherein R 13 is a hydrogen atom or a halogen atom; or a salt thereof.

7. The compound according to claim 1, wherein X 8 is N; X 9 is CR 2 , where R 2 is a hydrogen atom, or when r is 0, then R 2 is capable of combining with R 3 to form a bond; and X 10 is N; or a salt thereof.

8. The compound according to claim 1, wherein R 1 Yes (1) Optionally substituted with 1 to 3 substituents independently selected from the following C 1-6 alkyl groups: (i) a halogen atom, (ii) C 1-6 alkoxy, and (iii)C 3-6 Naphthenyl (2) C 3-10 cycloalkyl, or (3) mono- or di-C 1-6 alkylamino; R 2 and R 3 each independently is a hydrogen atom or a C 1-6 alkyl group, or When r is 0, then R 2 and R 3 can be joined together to form a bond, or When X 10 is CR 15 then R 3 and R 15 together form a bond; R 4 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or hydroxyl; R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl or cyclobutyl, any of which is optionally substituted by one or more substituents independently selected from C 1-6 alkyl, halogen atom, halo(C 1-6 )alkyl and C 1-6 alkoxy; R 6 and R 7 each independently is a hydrogen atom, a halogen atom or a C 1-6 alkyl group; X 1 、 X 2 、 X 3 、 X 4 、 X 5 、 X 6 and X 7 are selected to form a ring system, which is one of the following: (i) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; (ii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ; (iii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is N; (iv) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ; (v)X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; (vi) X 1 is NR 8 and X 2 is NR 10 and, one of R 8 and R 10 is absent and the other of R 8 and R 10 is C 1-6 alkyl, X 3 and X 4 are both C, X 5 is CR 11 X 6 is CR 12 and X 7 is CR 13 ; (vii) X 1 is CR 9 , X 2 is NR 10 and R 10 is absent, X 3 is N, X 4 is C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and (viii) X 1 is CR 9 , X 2 is NR 10 and R 10 is absent, X 3 is C, X 4 is N, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; X 8 , X 9 , X 10 , m, q, and r are selected to form a ring system, which is one of the following: (i) X 8 is N, X 9 is CR 2 , X 10 is N, m is 0, q is 1, and r is 0; (ii) X 8 is N, X 9 is CR 2 , X 10 is N, m is 1, q is 1, and r is 0; (iii) X 8 is N, X 9 is CR 2 , X 10 is N, m is 0, q is 1, and r is 1; (iv) X 8 is N, X 9 is N, X 10 is CR 15 , m is 0, q is 1, and r is 0; (v)X 8 is CR 14 ,X 9 is CR 2 ,X 10 is N, m is 0, q is 1, and r is 0; and (vi) X 8 is N, X 9 is CR 2 , X 10 is N, m is 0, q is 2, and r is 0; R 9 、R 11 、R 12 and R 13 are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a C 3-6 cycloalkyl group, a C 3-6 cycloalkyl(C 1-6 )alkoxy group, a halo(C 1-6 )alkyl group, a halo(C 1-6 )alkoxy group, a C 1-6 alkoxy(C 1-6 )alkyl group, an azetidinyl group, a C 1-6 alkoxy group, a hydroxy group, and a hydroxy(C 1-6 )alkyl group; and R 14 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group; and R 15 Together with R 3 forms a key; or a salt thereof.

9. The compound according to claim 1, wherein the partial structure represented by the formula: wherein each symbol is as defined in claim 1, is one of the partial structures represented by the formula: wherein each symbol is as defined in claim 1.

10. The compound according to claim 1, wherein the compound is represented by formula (Ia): wherein R 1 is C 1-6 alkyl, C 3-10 cycloalkyl or mono-C 1-6 alkylamino; r is 0 or 1; R 2 and R 3 each independently is a hydrogen atom, or When r is 0, then R 2 and R 3 can be joined together to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group optionally substituted with 1 to 3 halogen atoms; R 6 and R 7 each independently is a hydrogen atom or a halogen atom; X 5 is CH or N; and R 12 and R 13 each independently is a hydrogen atom, C 1-6 alkyl or a halogen atom; or a salt thereof.

11. The compound according to claim 10, wherein R 1 is C 1-6 alkyl; r is 0 or 1; R 2 and R 3 each is a hydrogen atom, or When r is 0, then R 2 and R 3 can be joined together to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted by 1 to 3 halogen atoms; R 6 and R 7 each is a halogen atom; X 5 is CH; and R 12 and R 13 each independently is a hydrogen atom or a halogen atom; or a salt thereof.

12. The compound according to claim 1, wherein the compound is represented by formula (Ib): wherein R 1 is an optionally substituted C 1-6 alkyl, an optionally substituted C 3-10 cycloalkyl or an optionally substituted mono- or di-C 1-6 alkylamino; R 2 and R 3 each independently is a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 2 and R 3 form a bond with each other; R 4 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or a hydroxyl group; R 5 is an optionally substituted 5- or 6-membered monocyclic group; R 6 and R 7 each independently is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl group; m is 0 or 1; q is 1 or 2; X 1 is NR 8 or CR 9 ; X 2 is O, NR 10 or S; X 3 and X 4 are both C, or one of X 3 and X 4 is N and the other is C; X 5 is CR 11 or N; X 6 is CR 12 ; X 7 is CR 13 or N; R 9 、R 11 、R 12 and R 13 each independently is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, an optionally substituted C 3-6 cycloalkyl group, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkoxy group or a hydroxy group; and R 8 and R 10 each independently does not exist, or is selected from a hydrogen atom and an optionally substituted C 1-6 alkyl group; or a salt thereof.

13. The compound according to claim 12, wherein R 1 Yes (1) C optionally substituted with 1 to 3 substituents independently selected from the following 1-6 alkyl groups: (i) a halogen atom, (ii)C 1-6 alkoxy, and (iii)C 3-6 Naphthenyl (2)C 3-10 cycloalkyl, or (3) Mono- or di-C 1-6 alkylamino; R 2 and R 3 each independently is a hydrogen atom or a C 1-6 alkyl group, or R 2 and R 3 together with each other form a bond; R 4 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy or hydroxy; R 5 is phenyl, pyrazolyl, furyl, thienyl or thiazolyl, any one of which is optionally substituted with one or more substituents independently selected from C 1-6 alkyl, halogen atom, halo(C 1-6 )alkyl and C 1-6 alkoxy; m is 0 or 1; q is 1 or 2; R 6 and R 7 each independently is a hydrogen atom, a halogen atom or a C 1-6 alkyl group; X 1 、 X 2 、 X 3 、 X 4 、 X 5 、 X 6 and X 7 are selected to form a ring system, which is one of the following: (i) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; (ii) X 1 is NR 8 and R 8 does not exist, X 2 is O, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ; (iii) X 1 is NR 8 and R 8 is absent, X 2 is O, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is N; (iv) X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is N, X 6 is CR 12 , and X 7 is CR 13 ; (v)X 1 is NR 8 and R 8 does not exist, X 2 is S, X 3 and X 4 are both C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; (vi) X 1 is NR 8 and X 2 is NR 10 and either R 8 or R 10 is absent and the other of R 8 and R 10 is C 1-6 alkyl, X 3 and X 4 are both C, X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 ; (vii) X 1 is CR 9 , X 2 is NR 10 and R 10 does not exist, X 3 is N, X 4 is C, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and (viii) X 1 is CR 9 , X 2 is NR 10 and R 10 does not exist, X 3 is C, X 4 is N, X 5 is CR 11 , X 6 is CR 12 , and X 7 is CR 13 ; and R 9 、R 11 、R 12 and R 13 are each independently selected from a hydrogen atom, C 1-6 alkyl, a halogen atom, C 3-6 cycloalkyl, C 3-6 cycloalkyl(C 1-6 )alkoxy, halo(C 1-6 )alkyl, halo(C 1-6 )alkoxy, C 1-6 alkoxy(C 1-6 )alkyl, azetidinyl, C 1-6 alkoxy, hydroxy and hydroxy(C 1-6 )alkyl; or a salt thereof.

14. The compound according to claim 1, wherein the compound is represented by formula (Ic): wherein R 1 is C 1-6 alkyl or mono-C 1-6 alkylamino; R 2 and R 3 each is a hydrogen atom, or R 2 and R 3 combine with each other to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group optionally substituted with 1 to 3 halogen atoms; R 6 and R 7 each independently is a hydrogen atom or a halogen atom; X 5 is CH or N; and R 12 and R 13 each independently is a hydrogen atom, C 1-6 alkyl or a halogen atom; or a salt thereof.

15. The compound according to claim 14, wherein R 1 is C 1-6 alkyl; R 2 and R 3 each is a hydrogen atom, or R 2 and R 3 together with each other form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted by 1 to 3 halogen atoms; R 6 and R 7 each is a halogen atom; X 5 is CH; and R 12 and R 13 each independently is a hydrogen atom or a halogen atom; or a salt thereof.

16. The compound according to claim 1, wherein the compound is selected from the group consisting of: N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(6R,7aR)-7,7-difluoro-2-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide; N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; N-{(4aR,6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonamide; and N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide; or a salt thereof.

17. A medicament, the medicament comprising a compound or a salt thereof as defined in any one of claims 1 to 16.

18. The medicament according to claim 17, the medicament being an orexin type 2 receptor agonist.

19. The medicament according to claim 17, the medicament being 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, disturbance of consciousness, or side effects and complications caused by anesthesia.

20. The medicament according to claim 17, the medicament being an agent for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia or sleep apnea syndrome.

21. The medicament according to claim 17, the medicament being an agent for preventing or treating narcolepsy.

22. A method for preventing or treating a disease or disorder associated with orexin type 2 receptor in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound or a salt thereof as defined in any one of claims 1 to 16.

23. The method according to claim 22, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disturbance of consciousness, and side effects and complications caused by anesthesia.

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

25. The method according to claim 22, wherein the disease or disorder is narcolepsy.

26. A compound or a salt thereof as defined in any one of claims 1 to 16, the compound or the salt thereof being for use in therapy.

27. The compound or the salt according to claim 26, wherein the therapy comprises treating a disease or disorder associated with orexin type 2 receptor.

28. The compound or the salt according to claim 27, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disturbance of consciousness, and side effects and complications caused by anesthesia.

29. The compound or the salt according to claim 27, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

30. The compound or the salt according to claim 27, wherein the disease or disorder is narcolepsy.

31. Use of a compound or a salt thereof as defined in any one of claims 1 to 16 for the manufacture of a medicament for treating a disease or disorder associated with orexin type 2 receptor.

32. The use according to claim 31, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disturbance of consciousness, and side effects and complications caused by anesthesia.

33. The use according to claim 31, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

34. The use according to claim 31, wherein the disease or disorder is narcolepsy.

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