Heterocyclic compound

Abstract

To provide a heterocyclic compound with orexin-2 receptor agonistic activity.SOLUTION: A compound represented by formula (I) in the figure or a salt thereof is useful as a preventive or therapeutic agent for narcolepsy.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] BACKGROUND OF THEINVENTION Orexin is a neuropeptide that is specifically produced by certain neurons scattered in the lateral hypothalamus and its surrounding areas, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptor, a G protein-coupled receptor that exists mainly in the brain, and two subtypes of the orexin receptor, type 1 and type 2, are known (Non-Patent Document 1).

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

[0004] From studies using transgenic mice with degenerated orexin neurons and double transgenic mice crossed with transgenic mice with orexin overexpression, it was observed that narcolepsy-like symptoms caused by degeneration of orexin neurons disappeared by sustained expression of orexin. Similarly, when orexin peptide was administered intracerebroventricularly to transgenic mice with degenerated orexin neurons, narcolepsy-like symptoms were improved (Non-Patent Document 3). In addition, studies on orexin type 2 receptor knockout mice suggest that the orexin type 2 receptor is important for maintaining wakefulness (Non-Patent Document 4, Non-Patent Document 5). In light of this background, it has been suggested that orexin type 2 receptor agonists could be used as a treatment for narcolepsy and other sleep disorders that exhibit hypersomnia (Non-Patent Document 6).

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

[0006] Therefore, a compound having orexin type 2 receptor agonist activity is expected to be useful as a therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, consciousness disorders such as coma, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barre syndrome, and Kleine-Levin syndrome), Alzheimer's, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, etc. Furthermore, an orexin type 2 receptor agonist may be useful as an anesthetic antagonist, or as a preventive or therapeutic agent for side effects and complications caused by anesthesia.

[0007] On the other hand, as sulfonamide derivatives, formula

[0008] [ka]

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

[0010] In addition, the following compounds have been reported as having orexin type 2 receptor agonist activity. formula

[0011] [ka]

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

[0013] [ka]

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

[0015] [ka]

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

[0017] [ka]

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

[0019] [ka]

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

[0021] [ka]

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

[0023] [ka]

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

[0025] [ka]

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

[0027] [ka]

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

[0029] [ka]

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

[0031] [ka]

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

[0033] [ka]

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

[0035] [ka]

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

[0037] However, these compounds are considered to be insufficient in terms of activity, pharmacokinetics, or safety, and there is still a need for the development of compounds having orexin type 2 receptor agonist activity. [Prior art documents] [Patent documents]

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

Patent document 10

Patent document 11

Patent document 12

Patent document 13

Patent document 14

Patent document 15

Patent document 16

Patent document 17

Non-licensed literature

[0039] [Non-licensed document 1] Cell, Vol.92, 573-585, 1998)

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

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

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

[0042] That is, the present invention relates to the following.

[0043] [1] Formula (I):

[0044] [ka]

[0045] [In the formula, X 1 is NR 8 , or CR 9 and; X 2 , O, NR 10 , or S; X 3 and X 4 are both C or X 3 and X 4 one is N and the other is C; X 5 CR 11 or N; X 6 CR 12 and; X 7 CR 13 or N; X 8 CR 14 or N; X 9 CR 2 or N; X 10 CR 15 or N; R 1 is optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-10 Cycloalkyl groups or optionally substituted mono- or di-C 1-6 is an alkylamino group; R 2 and R 3 each independently represents a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, or When r is 0, R 2 and R 3 may join together to form a bond, or X 10 CR 15 Then, R 3 is R 15 together with may form a bond; R 4 is a hydrogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group; R5 is an optionally substituted 4-, 5- or 6-membered monocyclic group; R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 is an 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 represents a hydrogen atom or an optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group; R 8 and R 10 each independently represents either zero, a hydrogen atom or an optionally substituted C 1-6 alkyl groups; and R 14 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 is an alkyl group; R 15 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 is an alkyl group, or R 15 is R 3 may be joined together to form a bond; A compound represented by the formula:

[0046] [2] m is 0; q is 1; and r is 0; The compound according to the above [1] or a salt thereof. [3] m is 1; q is 1; and r is 0; The compound according to the above [1] or a salt thereof. [4] m is 0; q is 1; and r is 1; The compound according to the above [1] or a salt thereof. [5] m is 0; q is 2; and r is 0; The compound according to the above [1] or a salt thereof.

[0047] [6] X 1 But NR 8 (In the formula, R 8 does not exist.) and; X 2 is O; X 3 and X 4 But both are C; X 5 But, CR 11 or N (wherein R 11 is a hydrogen atom; X 6 But, CR 12 (In the formula, R 12 is a hydrogen atom, C 1-6 an alkyl group, or a halogen atom; and X 7 But, CR 13 (In the formula, R 13 is a hydrogen atom or a halogen atom; the compound according to the above [1], or a salt thereof.

[0048] [7] X 8 is N; X 9 But, CR 2 (In the formula, R 2 is a hydrogen atom, or when r is 0, R 2 is R 3 may form a bond together with; and X 10 is N; The compound according to the above [1] or a salt thereof.

[0049] [8] R 1 but, (1)(i) a halogen atom, (ii) C1-6 alkoxy groups, and (iii) C 3-6 Cycloalkyl group C optionally substituted with 1 to 3 substituents independently selected from 1-6 Alkyl groups, (2) C 3-10 a cycloalkyl group, or (3) Mono- or di-C 1-6 Alkylamino group and; R 2 and R 3 are each independently a hydrogen atom or C 1-6 is an alkyl group, or When r is 0, R 2 and R 3 may be taken together to form a bond, or X 10 CR 15 Then, R 3 But R 15 together to form a bond; R 4 is a hydrogen atom, C 1-6 Alkyl group, C 1-6 an alkoxy group, or a hydroxy group; R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl, or cyclobutyl, any of which is C 1-6 Alkyl group, halogen atom, halo(C 1-6 ) alkyl groups, and C 1-6 may be substituted with one or more substituents independently selected from alkoxy groups; R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or C 1-6 is an alkyl group; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 But the following: (i) X 1 NR 8 And R 8 does not exist and X 2 is O;X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is; (ii) X 1 NR 8 And R 8 does not exist and X 2 is O and X 3 and X 4 Both are C Yes, X 5 is N and X 6 CR 12 and X 7 CR 13 is; (iii) X 1 NR 8 And R 8 does not exist and X 2 is O and X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 is N; (iv) X 1 NR 8 And R 8 does not exist and X 2 is S and X 3 and X 4 Both are C Yes, X 5 is N and X 6 CR 12 and X 7 CR 13 is; (v) X 1 NR 8 And R 8 does not exist and X 2is S;X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is; (vi) X 1 NR 8 And X 2 NR 10 and R 8 and R 10 If one of the two exists, ZR 8 and R 10 The other is C 1-6 is an alkyl group, and X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is; (vii) X 1 CR 9 and X 2 NR 10 And R 10 does not exist and X 3 is N and X 4 is C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 and (viii) X 1 CR 9 and X 2 NR 10 And R 10 does not exist and X 3 is C , X 4 is N and X 5 CR 11 and X 6 CR 12 and X 7 CR 13is is selected to form a ring system which is one of: X 8 , X 9 , X 10 , m, q, and r are as follows: (i) X 8 is N and X 9 CR 2 and X 10 is N, m is 0, q is 1, and r is 0; (ii) X 8 is N and X 9 CR 2 and X 10 is N, m is 1, and q is 1 and r is 0; (iii) X 8 is N and X 9 CR 2 and X 10 is N, m is 0, q is 1, and r is 1; (iv) X 8 is N and X 9 is N and X 10 CR 15 where m is 0 and q is 1 and r is 0; (v) X 8 CR 14 and X 9 CR 2 and X 10 is N, m is 0, q is 1, and r is 0; and (vi) X 8 is N and X 9 CR 2 and X 10 is N, m is 0, and q is 2 and r is 0 is selected to form a ring system which is one of: R 9 , R 11 , R 12 , and R 13 are each independently a hydrogen atom, C 1-6Alkyl group, halogen atom, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl(C 1-6 ) alkoxy group, halo(C 1-6 ) alkyl group, halo(C 1-6 ) alkoxy group, C 1-6 Alkoxy(C 1-6 ) Alkyl group, azetidinyl group, C 1-6 Alkoxy groups, hydroxy groups, and hydroxy (C 1-6 ) alkyl groups; and R 14 is a hydrogen atom, a halogen atom, or C 1-6 is an alkyl group; and R 15 But R 3 together to form a bond; The compound according to the above [1] or a salt thereof.

[0050] [9] The formula:

[0051] [ka]

[0052] (The symbols in the formula are the same as those in [1] above.) The partial structure represented by the following formula:

[0053] [ka]

[0054] (The symbols in the formula are the same as those in [1] above.) The compound according to the above [1], which is one of the partial structures represented by the following formula:

[0055]

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

[0056] [ka]

[0057] [In the formula, R 1 is C 1-6 Alkyl group, C 3-10 Cycloalkyl group, or mono-C 1-6 is an alkylamino group; r is 0 or 1; R 2 and R 3 are each independently a hydrogen atom, or When r is 0, R 2 and R 3 may combine with one another to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group optionally substituted by 1 to 3 halogen atoms; R 6 and R 7 are each independently a hydrogen atom or a halogen atom; X 5 is CH or N; and R 12 and R 13 are each independently a hydrogen atom, C 1-6 an alkyl group, or a halogen atom; The compound according to the above [1], or a salt thereof,

[0058]

[11] R 1 But, C 1-6 is an alkyl group; r is 0 or 1; R 2 and R 3 are each a hydrogen atom, or When r is 0, R 2 and R 3 may combine with one another to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted by 1 to 3 halogen atoms; R6 and R 7 are each a halogen atom; X 5 is CH; and R 12 and R 13 are each independently a hydrogen atom or a halogen atom; The compound according to the above

[10] , or a salt thereof.

[0059]

[12] The compound has formula (Ib):

[0060] [ka]

[0061] [In the formula, R 1 is an optionally substituted C 1-6 Alkyl group, optionally substituted C 3-10 Cycloalkyl groups or optionally substituted mono- or di-C 1-6 is an alkylamino group; R 2 and R 3 each independently represents a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, or R 2 and R 3 come together and form a bond; R 4 is a hydrogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group; R 5 is an optionally substituted 5- or 6-membered monocyclic group; R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 is an alkyl group; m is 0 or 1; q is 1 or 2; X 1 is NR 8 , or CR 9 and; X 2 , O, NR 10 , or S; X 3 and X 4 are both C or X 3 and X 4 one is N and the other is C; X 5 CR 11 or N; X 6 CR 12 and; X 7 CR 13 or N; R 9 , R 11 , R 12 , and R 13 each independently represents a hydrogen atom or an optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group; and R 8 and R 10 each independently represents either zero, a hydrogen atom or an optionally substituted C 1-6 alkyl groups; The compound according to the above [1], or a salt thereof,

[0062] [12a] R 2 and R 3 and each of them is a hydrogen atom; the compound according to the above

[12] , or a salt thereof. [12b] R 2 and R 3 are combined with each other to form a bond; the compound according to the above

[12] , or a salt thereof. [12c] The compound according to the above

[12] , or a salt thereof, wherein m is 0; and q is 1. [12d] m is 1; and q is 1; the compound according to the above

[12] , or a salt thereof. [12e] R 1 But, C 1-6 The compound according to the above

[12] , or a salt thereof. [12f] X 1 NR 8 and R 8 does not exist; X 2 is O; X 3 and X 4 But both are C; X 5 is CH or N; X 6 But, CR 12 and R 12 is a hydrogen atom, C 1-6 alkyl, or halogen atom; and X 7 But, CR 13 and R 13 is a hydrogen atom or a halogen atom; The compound according to the above

[12] , or a salt thereof.

[0063]

[13] R 1 but, (1)(i) a halogen atom, (ii) C 1-6 alkoxy groups, and (iii) C 3-6 Cycloalkyl group C optionally substituted with 1 to 3 substituents independently selected from 1-6 Alkyl groups, (2) C 3-10 a cycloalkyl group, or (3) Mono- or di-C 1-6 Alkylamino group and; R 2 and R 3are each independently a hydrogen atom or C 1-6 is an alkyl group or R 2 and R 3 but come together and form a bond; R 4 is a hydrogen atom, C 1-6 Alkyl group, C 1-6 an alkoxy group, or a hydroxy group; R 5 is phenyl, pyrazolyl, furyl, thienyl or thiazolyl, any of which is C 1-6 Alkyl group, halogen atom, halo(C 1-6 ) alkyl groups, and C 1-6 may be substituted with one or more substituents independently selected from alkoxy groups; m is 0 or 1; q is 1 or 2; R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or C 1-6 is an alkyl group; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 But the following: (i) X 1 NR 8 And R 8 does not exist and X 2 is O;X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is; (ii) X 1 NR 8 And R 8 does not exist and X 2 is O and X 3 and X 4 Both are C Yes, X 5 is N and X 6 CR 12 and X 7 CR 13 is; (iii) X 1 NR 8 And R 8 does not exist and X 2 is O and X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 is N; (iv) X 1 NR 8 And R 8 does not exist and X 2 is S and X 3 and X 4 Both are C Yes, X 5 is N and X 6 CR 12 and X 7 CR 13 is; (v) X 1 NR 8 And R 8 does not exist and X 2 is S;X 3 and X 4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is; (vi) X 1 NR 8 And X 2 NR 10 and R 8 and R 10 If one of the two exists, ZR 8 and R 10 The other is C 1-6 is an alkyl group, and X 3 and X4 are both C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is; (vii) X 1 CR 9 and X 2 NR 10 And R 10 does not exist and X 3 is N and X 4 is C and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 and (viii) X 1 CR 9 and X 2 NR 10 And R 10 does not exist and X 3 is C , X 4 is N and X 5 CR 11 and X 6 CR 12 and X 7 CR 13 is is selected to form a ring system which is one of R 9 , R 11 , R 12 , and R 13 are each independently a hydrogen atom, C 1-6 Alkyl group, halogen atom, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyl(C 1-6 ) alkoxy group, halo(C 1-6 ) alkyl group, halo(C 1-6 ) alkoxy group, C 1-6 Alkoxy(C 1-6 ) Alkyl group, azetidinyl group, C 1-6 Alkoxy groups, hydroxy groups, and hydroxy (C1-6 ) alkyl groups; The compound according to the above

[12] , or a salt thereof.

[0064]

[14] The compound has formula (Ic):

[0065] [ka]

[0066] [In the formula, R 1 is C 1-6 Alkyl group, or mono-C 1-6 is an alkylamino group; R 2 and R 3 are each a hydrogen atom or R 2 and R 3 come together and form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group optionally substituted by 1 to 3 halogen atoms; R 6 and R 7 are each independently a hydrogen atom or a halogen atom; X 5 is CH or N; and R 12 and R 13 are each independently a hydrogen atom, C 1-6 an alkyl group, or a halogen atom; The compound according to the above [1], or a salt thereof,

[0067]

[15] R 1 But, C 1-6 is an alkyl group; R 2 and R 3 are each a hydrogen atom or R 2 and R 3 but come together and 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 are each a halogen atom; X 5 is CH; and R 12 and R 13 are each independently a hydrogen atom or a halogen atom; The compound according to the above

[14] , or a salt thereof.

[0068]

[16] A compound comprising: 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; The compound according to the above [1], or a salt thereof, selected from the group consisting of:

[0069]

[17] A medicine comprising the compound or a salt thereof according to any one of [1] to

[16] above.

[18] The pharmaceutical agent described in

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

[19] The pharmaceutical described in

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

[20] The pharmaceutical agent according to

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

[21] The pharmaceutical agent described in

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

[0070]

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

[16] above.

[23] The method according to

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

[24] The method according to

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

[25] The method according to

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

[0071]

[26] A compound or salt thereof according to any one of the above [1] to

[16] for use in therapy.

[27] Therapeutic methods include treating a disease or disorder associated with the orexin type 2 receptor. The compound or salt according to

[26] .

[28] The compound or salt according to

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

[29] The compound or salt according to

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

[30] The compound or salt according to

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

[0072]

[31] Use of the compound or salt thereof according to any one of [1] to

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

[32] 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 accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects or complications due to anesthesia.

[33] 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.

[34] The use according to

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

[0073] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for certain diseases such as narcolepsy.

[0074] [Detailed Description of the Invention] The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. In the present specification, "optionally halogenated C 1-6 The alkyl group may, for example, be a C alkyl group optionally having 1 to 7, preferably 1 to 5, and more preferably 1 to 3 halogen atoms. 1-6 Examples of the alkyl group 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. As used herein, "haloC 1-6 Examples of the alkyl group include the above-mentioned "optionally halogenated C 1-6 Among the "alkyl groups", "halogenated C 1-6 "Alkyl group". In this specification, "C 2-6 Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, and the like. Examples of aryl include 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl. In this specification, "C 2-6Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 2-methyl-1-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butenyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-3-pentenyl, 1-hexynyl, 3-hexynyl, and 5-hexynyl. In this specification, "C 2-6 Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. In this specification, "C 3-10 Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In the present specification, "optionally halogenated C 3-10 The "cycloalkyl group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples of cycloalkyl groups include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 7-16 The "aralkyl group" includes, for example, benzyl, phenethyl, naphthylmethyl and phenylpropyl.

[0075] In this specification, "C1-6 The "alkoxy group" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. In the present specification, "optionally halogenated C 1-6 The "alkoxy group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, and more preferably 1 to 3 halogen atoms. 1-6 Specific examples of alkoxy groups include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. As used herein, "HaloC 1-6 Examples of the "alkoxy group" include the above-mentioned "optionally halogenated C 1-6 Among the "alkoxy groups," "halogenated C 1-6 Alkoxy groups are examples of such alkyl groups. In this specification, "C 3-10 The "cycloalkyloxy group" includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. In this specification, "C 1-6 The "alkylthio group" includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. In the present specification, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, C alkylthio groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylthio, difluoromethylthio, and trimethylthio. Examples include trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[0076] In this specification, "C 1-6 The "alkyl-carbonyl group" includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl and heptanoyl. In the present specification, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, C alkyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of the alkyl-carbonyl group include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl. In this specification, "C 1-6 The "alkoxy-carbonyl group" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl. In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl and 2-naphthoyl. In this specification, "C 7-16 The "aralkyl-carbonyl group" includes, for example, phenylacetyl and phenylpropionyl.

[0033] In the present specification, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0043] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0077] As used herein, "mono- or di-C 1-6 The "alkyl-carbamoyl group" includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl. As used herein, "optionally substituted mono- or di-C 1-6 The "alkylamino group" is, for example, an alkylamino group having one or two C 1-6 An example of the amino group is an amino group having an alkyl group. 1-6 The alkyl portion may have 1 to 3 substituents selected from the substituent group A. 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 It may have one or two substituents selected from arylsulfonyl groups.

[0078] As used herein, the term "optionally substituted amino group" refers to, for example, "amino group optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsul phenyl group and C 6-14 and an arylsulfonyl group, optionally having 1 or 2 substituents selected from the group consisting of arylsulfonyl groups. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0079] As used herein, a "hydroxy group" refers to -OH. As used herein, "hydroxyl" and "hydroxy" are the same. In the present specification, examples of the "4-, 5- or 6-membered monocyclic group" include, for example, 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Among aryl groups and heterocyclic groups (eg aromatic or non-aromatic heterocyclic groups), mention may be made of 4-, 5- or 6-membered monocyclic groups. In this specification, "C 6-14 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

[0080] In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, and a combination thereof.

[0081] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered, more preferably 5- to 6-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof. Examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; and benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benziso ... and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0082] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered, more preferably 5- or 6-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, an oxygen atom, and a combination thereof. Examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane. Also, dihydrobenzofuran and dihydrobenzimidazole. and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. As used herein, examples of the "3- to 7-membered nitrogen-containing heterocyclic ring" include the 3- to 7-membered "heterocyclic group" described herein containing at least one nitrogen atom (e.g., 1, 2, 3, etc.) as a ring-constituting atom.

[0083] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of the heterocyclic group include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has "1 or 2 substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group." The term "acyl group" also includes hydrocarbyl-sulfonyl groups, heterocyclic sulfonyl groups, hydrocarbyl-sulfinyl groups, and heterocyclic sulfinyl groups. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocyclic sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocyclic sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Examples of "acyl groups" include formyl groups, carboxy groups, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3-10 Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, and mono- or di-C 1-6 Examples of the alkylphosphono group include dimethylphosphono, diethylphosphono, diisopropylphosphono, and dibutylphosphono groups.

[0084]

[0033] In the present specification, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0043] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0085] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and aralkyl-carbamoyl groups, which may have 1 or 2 substituents selected from the group consisting of carbamoyl groups. Suitable examples of the optionally substituted carbamoyl group include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples of such groups include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl), and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0086] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and thiocarbamoyl groups which may have 1 or 2 substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Examples of such thiocarbamoyl groups include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl), and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0087] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which may optionally have 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and an aralkyl-carbamoyl group, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted sulfamoyl group include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples of such groups include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl), and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0088] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups, each of which may have a substituent selected from the group consisting of arylsulfonyl groups and arylsulfonyl groups. Preferable examples of the optionally substituted hydroxy group include a hydroxy group, C 1-6 Alkoxy group, C 2-6Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), and C 6-14 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) are included.

[0089] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14a sulfanyl group which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, and a halogenated sulfanyl group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples of such thio groups include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0090] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples of the silyl groups include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0091] In the present specification, examples of the "hydrocarbon ring" include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes, and C 3-10 Cycloalkenes are mentioned. As used herein, "mono- or di-C 7-16 The "aralkyl-carbamoyl group" includes, for example, benzylcarbamoyl and phenethylcarbamoyl.

[0092] In this specification, "C 1-6 The "alkylsulfonyl group" includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl. In the present specification, "optionally halogenated C 1-6 The "alkylsulfonyl group" includes, for example, C alkylsulfonyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0093] In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups, and C 7-16 Examples of such groups include aralkyl groups.

[0094] In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0095] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; and benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridyl, and the like. nyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phen and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups such as noxazinyl.

[0096] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydro 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; and Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0097] In the present specification, suitable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom. In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0098] In this specification, "C 6-14 The "aromatic hydrocarbon ring" includes, for example, benzene and naphthalene. In this specification, "C 3-10 "Cycloalkanes" include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10"Cycloalkenes" include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom. In the present specification, the term "4- to 6-membered heterocyclic group" includes aromatic or non-aromatic 4- to 6-membered heterocyclic groups. Specific examples thereof include oxetanyl, furyl, pyrazolyl, pyridyl, and and pyrimidinyl. In the present specification, examples of the "ring" include a "hydrocarbon ring" and a "heterocycle".

[0099] As used herein, a particular moiety may be "optionally substituted", which means that the group may have a substituent selected from the following Substituent Group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 Alkoxy groups, (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., tetrahydropyranyloxy, morpholinyloxy, piperidinyloxy), (11) C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (12) C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15) C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) Optionally halogenated C 1-6 Alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 Alkyl-carbonyl groups, (26)C 6-14 Aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl groups, (30)C 6-14Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl groups, (35)C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 Alkylsulfonyl groups, (39)C 6-14 Arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 Alkylsulfinyl groups, (42)C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14Arylamino groups (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) a formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino); (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino); (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 Alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) Optionally halogenated C 1-6 Alkyl groups, (58)C 2-6 Alkenyl groups, (59)C 2-6 Alkynyl groups, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0100] In some embodiments, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted Examples of the alkyl group include an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. The number of the above-mentioned substituents is, for example, 1 to 5 (e.g., 1, 2, 3, 4 or 5), preferably 1 to 3 (e.g., 1, 2 or 3). When the number of the substituents is 2 or more, each substituent may be the same or different.

[0101] The definition of each symbol in Compound (I) will be explained in detail below. R 1 is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-10 Cycloalkyl groups or optionally substituted mono- or di-C 1-6 It is an alkylamino group. In some embodiments, R 1 teeth, (1)(i) a halogen atom (e.g., a fluorine atom), (ii) C 1-6 Alkoxy groups (e.g., methoxy), and (iii) C 3-6 Cycloalkyl groups (e.g., cyclopropyl) C optionally substituted with 1 to 3 substituents independently selected from 1-6 Alkyl groups (e.g., methyl, ethyl), (2) C 3-10 a cycloalkyl group (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, dimethylamino). In some embodiments, R 1 is C 1-6Alkyl groups (e.g., methyl, ethyl), C 3-10 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups, e.g., cyclopropyl, or mono-C 1-6 An alkylamino group (e.g., methylamino). In some embodiments, R 1 is C 1-6 Alkyl groups (e.g., methyl, ethyl), or mono-C 1-6 An alkylamino group (e.g., methylamino). In some embodiments, R 1 is C 1-6 It is an alkyl group (e.g., methyl, ethyl).

[0102] R 2 and R 3 each independently represents a hydrogen atom or an optionally substituted C 1-6 is an alkyl group. Alternatively, when r is 0, R 2 and R 3 may be taken together to form a bond; or X 10 R 15 Then, R 3 is R 15 may be taken together to form a bond. In some embodiments, R 2 and R 3 are each independently a hydrogen atom or C 1-6 an alkyl group (e.g., methyl), or When r is 0, R 2 and R 3 may join together to form a bond, or X 10 R 15 Then, R 3 is R 15 together to form a bond. In some embodiments, R 2 and R 3 are each a hydrogen atom, or When r is 0, R 2 and R 3may join together to form a bond, or X 10 R 15 Then, R 3 is R 15 together to form a bond. In some embodiments, X 10 If N, R 2 and R 3 are each independently a hydrogen atom, or When r is 0, R 2 and R 3 may join together to form a bond. In some embodiments, X 10 If N, R 2 and R 3 are each a hydrogen atom, or When r is 0, R 2 and R 3 may join together to form a bond. R 2 and R 3 When they join together to form a bond, X 8 , X 9 and X 10 The ring containing R 2 and R 3 It contains a double bond between the carbons to which it is attached.

[0103] R 4 is a hydrogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 It is an alkoxy group or a hydroxy group. In some embodiments, R 4 is a hydrogen atom, C 1-6 Alkyl group (e.g., methyl), C 1-6 It is an alkoxy group (eg, ethoxy), or a hydroxy group. In some embodiments, R 4 is a hydrogen atom.

[0104] R5 is an optionally substituted 4-, 5- or 6-membered monocyclic group. In some embodiments, R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl, or cyclobutyl, any of which is C 1-6 Alkyl group (e.g., methyl), halogen atom (e.g., fluorine atom, chlorine atom), halo(C 1-6 ) alkyl groups (e.g., trifluoromethyl), and C 1-6 It may be substituted with one or more (eg, 1, 2, 3, etc.) substituents independently selected from alkoxy groups (eg, methoxy). In some embodiments, R 5 is a phenyl group optionally substituted by 1 to 3 (eg, 1, 2, 3, etc.) halogen atoms (eg, fluorine atoms). In some embodiments, R 5 is a phenyl group substituted with 1 to 3 (eg, 1, 2, 3, etc.) halogen atoms (eg, fluorine atoms). In some embodiments, R 5 is a phenyl group substituted with 2 or 3 fluorine atoms (eg, 2,6-substituted or 2,4,6-substituted). In some embodiments, R 5 is a phenyl group substituted with three fluorine atoms (e.g., 2,4,6-substituted).

[0105] R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 It is an alkyl group. In some embodiments, R 6 and R 7 are each independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or C 1-6 It is an alkyl group (e.g., methyl). In some embodiments, R 6 and R 7 are each independently a hydrogen atom or a halogen atom (e.g., a fluorine atom). In some embodiments, R6 and R 7 are each a hydrogen atom or a halogen atom (e.g., a fluorine atom). In some embodiments, R 6 and R 7 are each a halogen atom (e.g., a fluorine atom).

[0106] The subscript "m" together with "q" is either 0 (forming a 5- or 6-membered ring) or 1 (forming a 6- or 7-membered ring). The subscript "q" together with "m" is either 1 (forming a 5- or 6-membered ring) or 2 (forming a 6- or 7-membered ring). In some embodiments, m is 0; and q is 1, forming a 5-membered ring. In some embodiments, m is 1; and q is 1, forming a 6-membered ring. The subscript "r" is either 0 (forming a 5-membered ring) or 1 (forming a 6-membered ring). In some embodiments, the combination of m, q and r is such that m is 0; q is 1; and r is 0. In some embodiments, the combination of m, q and r is such that m is 1; q is 1; and r is 0. In some embodiments, the combination of m, q and r is such that m is 0; q is 1; and r is 1. In some embodiments, the combination of m, q and r is such that m is 0; q is 2; and r is 0.

[0107] X 1 is NR 8 or CR 9 (In the formula, R 8 does not exist (i.e., =N-), or Hydrogen atom and optionally substituted C 1-6 alkyl groups, R 9 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group. In some embodiments, X 1 is NR 8 (In the formula, R 8 does not exist (i.e., =N-) or C 1-6 It is an alkyl group (e.g., methyl). In some embodiments, X 1 is NR 8 (In the formula, R 8 does not exist (i.e., =N-). In some embodiments, X 1 CR 9 (In the formula, R 9 is a hydrogen atom or C 1-6 It is an alkyl group (e.g., methyl).

[0108] X 2 , O, NR 10 or S (wherein R 10 is absent (i.e., =N-) or is a hydrogen atom and optionally substituted C 1-6 The alkyl group is selected from the group consisting of aryl, aryl, aryl and alkyl groups. In some embodiments, X 2 is O. In some embodiments, X 2 is NR 10 (In the formula, R 10 does not exist or is C 1-6 It is an alkyl group (e.g., methyl). In some embodiments, X 2 is S.

[0109] X 3 and X 4 are (i) both C, or (ii) X 3 and X 4 One of them is N and the other is C , or In some embodiments, X 3 and X 4are both C. In some embodiments, X 3 is N and X 4 is C. In some embodiments, X 3 is C and X 4 is N.

[0110] X 5 CR 11 or N (wherein R 11 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group. In some embodiments, X 5 is N. In some embodiments, X 5 CR 11 (In the formula, R 11 is a hydrogen atom, a halogen atom (e.g., a fluorine atom), or C 1-6 It is an alkyl group (e.g., methyl). In some embodiments, X 5 CR 11 or N (wherein R 11 is a hydrogen atom.

[0111] X 6 CR 12 (In the formula, R 12 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group. In some embodiments, R 12 is a hydrogen atom, C 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6Cycloalkyl groups (e.g., cyclopropyl), C 3-6 Cycloalkyl(C 1-6 ) alkoxy groups (e.g., cyclopropylmethoxy), halo (C 1-6 ) alkyl group (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 ) alkoxy group (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy(C 1-6 ) alkyl group (e.g., methoxymethyl), azetidinyl group, C 1-6 Alkoxy groups (e.g., methoxy, ethoxy), hydroxy groups, or hydroxy (C 1-6 ) alkyl groups (e.g., hydroxymethyl, 2-hydroxyethyl); In some embodiments, R 12 is a hydrogen atom, C 1-6 It is an alkyl group (eg, methyl) or a halogen atom (eg, a chlorine atom or a fluorine atom). In some embodiments, R 12 is a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0112] X 7 CR 13 or N (wherein R 13 is a hydrogen atom, optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group. In some embodiments, X 7 is N. In some embodiments, X 7 CR 13 (In the formula, R 13 is a hydrogen atom or a halogen atom (e.g., a fluorine atom, a chlorine atom).

[0113] In some embodiments, X 1 , X 2 , X 3 , X 4, X 5 , X 6 , and X 7 is selected to form a ring system which is a pyrazolopyridine, 1,2-benzoxazole, indazole, imidazolopyridine, 1,2-benzothiazole, [1,2]oxazolo[4,5-c]pyridine, isoxazolo[5,4-b]pyridine, or isothiazolo[5,4-b]pyridine. In these embodiments, R 9 , R 11 , R 12 , and R 13 are each independently a hydrogen atom, C 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), C 3-6 Cycloalkyl(C 1-6 ) alkoxy groups (e.g., cyclopropylmethoxy), halo (C 1-6 ) alkyl group (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 ) alkoxy group (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy(C 1-6 ) alkyl group (e.g., methoxymethyl), azetidinyl group, C 1-6 Alkoxy groups (e.g., methoxy, ethoxy), hydroxy groups, and hydroxy (C 1-6 ) alkyl groups (e.g., hydroxymethyl, 2-hydroxyethyl); and R 8 and R 10 are each independently absent (i.e., =N-) or a hydrogen atom and C 1-6 It is selected from alkyl groups (e.g., methyl).

[0114] In some embodiments, X 1 is NR 8 (In the formula, R 8 does not exist (i.e., =N-). X 2 is O; X 3 and X4 are both C; X 5 CR 11 or N (wherein R 11 is a hydrogen atom; X 6 CR 12 (In the formula, R 12 is a hydrogen atom, C 1-6 an alkyl group (e.g., methyl), or a halogen atom (e.g., a chlorine atom or a fluorine atom); and X 7 CR 13 (In the formula, R 13 is a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0115] In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is the following: (i) X 1 is NR 8 And R 8 does not exist, and X 2 is O;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (ii) X 1 is NR 8 And R 8 does not exist, and X 2 is O and X 3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is; (iii) X 1 is NR8 And R 8 does not exist, and X 2 is O and X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is N; (iv) X 1 is NR 8 And R 8 does not exist, and X 2 is S and X 3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is; (v) X 1 is NR 8 And R 8 does not exist, and X 2 is S;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (vi) X 1 is NR 8 And X 2 is NR 10 and R 8 and R 10 One of them does not exist ZR 8 and R 10 The other is C 1-6 is an alkyl group (e.g., methyl), and X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (vii) X 1 is CR 9 and X 2 is NR 10 And R 10 does not exist, and X 3 is N and X 4 is C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 and (viii) X 1 is CR 9 and X 2 is NR 10 And R 10 does not exist, and X 3 is C , X 4 is N and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is The ring system is selected to form one of the ring systems: In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is the following: (i) X 1 is NR 8 And R 8 does not exist, and X 2 is O;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 and (ii) X 1 is NR 8 And R 8 does not exist, and X 2 is O and X3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is The ring system is selected to form one of the ring systems: In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 (i) X 1 is NR 8 And R 8 does not exist, and X 2 is O;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is The ring system is selected to form In some embodiments, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 (i) X 1 is NR 8 And R 8 does not exist, and X 2 is O;X 3 and X 4 are both C and X 5 , CH, X 6 is CR 12 and X 7 is CR 13 is The ring system is selected to form

[0116] In these embodiments, R 9 , R 11 , R12 , and R 13 are each independently a hydrogen atom, C 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), C 3-6 Cycloalkyl(C 1-6 ) alkoxy groups (e.g., cyclopropylmethoxy), halo (C 1-6 ) alkyl group (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 ) alkoxy group (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy(C 1-6 ) alkyl group (e.g., methoxymethyl), azetidinyl group, C 1-6 Alkoxy groups (e.g., methoxy, ethoxy), hydroxy groups, and hydroxy (C 1-6 ) alkyl groups (e.g., hydroxymethyl, 2-hydroxyethyl).

[0117] X 8 CR 14 or N (wherein R 14 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 It is an alkyl group. In some embodiments, X 8 is N. In some embodiments, X 8 CR 14 (In the formula, R 14 is a hydrogen atom.

[0118] X 9 CR 2 or N (wherein R 2 is a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, or when r is 0, R 2 is R 3 may form a bond together with In some embodiments, X 9 CR 2 (In the formula, R 2is a hydrogen atom or C 1-6 An alkyl group (e.g., methyl) or when r is 0, R 2 is R 3 may form a bond together with In some embodiments, X 9 CR 2 (In the formula, R 2 is a hydrogen atom, or when r is 0, R 2 is R 3 may form a bond together with In some embodiments, X 9 CR 2 (In the formula, R 2 is a hydrogen atom. In some embodiments, X 9 CR 2 , r is 0, and R 2 is R 3 together to form a bond. In some embodiments, X 9 is N.

[0119] X 10 CR 15 or N (wherein R 15 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 is an alkyl group or R 15 is R 3 may form a bond together with In some embodiments, X 10 is N. In some embodiments, X 10 CR 15 (In the formula, R 15 is R 3 Together with, they form a bond.

[0120] In some embodiments, X 8 is N; X 9 CR 2 (In the formula, R 2is a hydrogen atom, or when r is 0, R 2 is R 3 may form a bond together with; and X 10 is N. In some embodiments, X 8 is N; X 9 CR 2 (In the formula, R 2 is a hydrogen atom; and X 10 is N. In some embodiments, X 8 is N; X 9 CR 2 (wherein r is 0 and R2 is R 3 ) together with the bond; and X 10 is N.

[0121] In some embodiments, X 8 , X 9 , X 10 , m, q, and r are as follows: (i) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 0; (ii) X 8 is N and X 9 is CR 2 and X 10 is N, m is 1, and q is 1 and r is 0; (iii) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 1; (iv) X 8 is N and X 9 is N and X10 is CR 15 where m is 0 and q is 1 and r is 0; (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 (vi) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, and q is 2 and r is 0 The ring system is selected to form one of the ring systems: In some embodiments, X 8 , X 9 , X 10 , m, q, and r are as follows: (i) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 0; and (iii) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 1 The ring system is selected to form one of the ring systems:

[0122] In these aspects, R 2 is a hydrogen atom or C 1-6 An alkyl group (e.g., methyl) or when r is 0, R 2 is R 3 together with may form a bond; R 14 is a hydrogen atom, a halogen atom, or C 1-6 is an alkyl group; and R 15 is R 3together to form a bond;

[0123] In some embodiments, the compound of the formula:

[0124] [ka]

[0125] (The symbols in the formula are as defined above.) The partial structure represented by the formula:

[0126] [ka]

[0127] (The symbols in the formula are as defined above.) It is one of the partial structures represented by:

[0128] In some embodiments of compound (I), R 1 teeth, (1)(i) a halogen atom (e.g., a fluorine atom), (ii) C 1-6 Alkoxy groups (e.g., methoxy), and (iii) C 3-6 Cycloalkyl groups (e.g., cyclopropyl) C optionally substituted with 1 to 3 substituents independently selected from 1-6 Alkyl groups (e.g., methyl, ethyl), (2) C 3-10 a cycloalkyl group (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 an alkylamino group (e.g., methylamino, dimethylamino); R 2 and R 3 are each independently a hydrogen atom or C 1-6 an alkyl group (e.g., methyl) or When r is 0, R 2 and R 3may be taken together to form a bond, or X 10 CR 15 Then, R 3 is R 15 together to form a bond; R 4 is a hydrogen atom, C 1-6 Alkyl group (e.g., methyl), C 1-6 an alkoxy group (e.g., ethoxy), or a hydroxy group; R 5 is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl, or cyclobutyl, any of which is C 1-6 Alkyl group (e.g., methyl), halogen atom (e.g., fluorine atom, chlorine atom), halo(C 1-6 ) alkyl groups (e.g., trifluoromethyl), and C 1-6 optionally substituted with one or more (e.g., 1, 2, 3, etc.) substituents independently selected from alkoxy groups (e.g., methoxy); R 6 and R 7 are each independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or C 1-6 is an alkyl group (e.g., methyl); X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is the following: (i) X 1 is NR 8 And R 8 does not exist, and X 2 is O;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (ii) X 1 is NR 8 And R 8 does not exist, and X2 is O and X 3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is; (iii) X 1 is NR 8 And R 8 does not exist, and X 2 is O and X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is N; (iv) X 1 is NR 8 And R 8 does not exist, and X 2 is S and X 3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is; (v) X 1 is NR 8 And R 8 does not exist, and X 2 is S;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (vi) X 1 is NR 8 And X 2 is NR 10 and R 8 and R 10 One of them does not exist ZR 8and R 10 The other is C 1-6 is an alkyl group (e.g., methyl), and X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (vii) X 1 is CR 9 and X 2 is NR 10 And R 10 does not exist, and X 3 is N and X 4 is C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 and (viii) X 1 is CR 9 and X 2 is NR 10 And R 10 does not exist, and X 3 is C , X 4 is N and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is is selected to form a ring system which is one of: X 8 , X 9 , X 10 , m, q, and r are as follows: (i) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 0; (ii) X 8 is N and X 9 is CR 2and X 10 is N, m is 1, and q is 1 and r is 0; (iii) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, q is 1, and r is 1; (iv) X 8 is N and X 9 is N and X 10 is CR 15 where m is 0 and q is 1 and r is 0; (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 (vi) X 8 is N and X 9 is CR 2 and X 10 is N, m is 0, and q is 2 and r is 0 is selected to form a ring system which is one of: R 9 , R 11 , R 12 , and R 13 are each independently a hydrogen atom, C 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), C 3-6 Cycloalkyl(C 1-6 ) alkoxy groups (e.g., cyclopropylmethoxy), halo (C 1-6 ) alkyl group (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 ) alkoxy group (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy(C 1-6 ) alkyl group (e.g., methoxymethyl), azetidinyl group, C1-6 Alkoxy groups (e.g., methoxy, ethoxy), hydroxy groups, and hydroxy (C 1-6 ) alkyl groups (e.g., hydroxymethyl, 2-hydroxyethyl); and R 14 is a hydrogen atom; and R 15 is R 3 together to form a bond.

[0129] In some embodiments, compound (I) has formula (Ia):

[0130] [ka]

[0131] [In the formula, R 1 is C 1-6 Alkyl groups (e.g., methyl, ethyl), C 3-10 Cycloalkyl groups (preferably C 3-6 Cycloalkyl groups, e.g., cyclopropyl, or mono-C 1-6 an alkylamino group (e.g., methylamino); r is 0 or 1; R 2 and R 3 are each independently a hydrogen atom, or When r is 0, R 2 and R 3 may combine with one another to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group optionally substituted by 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 are each independently a hydrogen atom or a halogen atom (e.g., a fluorine atom); X 5 is CH or N; and R 12 and R13 are each independently a hydrogen atom, C 1-6 an alkyl group (e.g., methyl), or a halogen atom (e.g., fluorine atom, chlorine atom); or a salt thereof (also referred to as compound (Ia)).

[0132] In some embodiments of compound (Ia), R 1 is C 1-6 an alkyl group (e.g., methyl, ethyl); r is 0 or 1; R 2 and R 3 are each a hydrogen atom, or When r is 0, R 2 and R 3 may combine with one another to form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 are each a halogen atom (e.g., a fluorine atom); X 5 is CH; and R 12 and R 13 are each independently a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0133] In some embodiments, compound (I) has formula (Ib):

[0134] [ka]

[0135] [In the formula, R 1 is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-10Cycloalkyl groups or optionally substituted mono- or di-C 1-6 is an alkylamino group; R 2 and R 3 each independently represents a hydrogen atom or an optionally substituted C 1-6 is an alkyl group, or R 2 and R 3 come together and form a bond; R 4 is a hydrogen atom, optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group; R 5 is an optionally substituted 5- or 6-membered monocyclic group; R 6 and R 7 each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 is an alkyl group; m is 0 or 1; q is 1 or 2; X 1 is NR 8 , or CR 9 and; X 2 , O, NR 10 , or S; X 3 and X 4 are both C or X 3 and X 4 one is N and the other is C; X 5 CR 11 or N; X 6 CR 12 and; X 7 CR 13 or N; R 9 , R 11 , R 12 , and R 13each independently represents a hydrogen atom or an optionally substituted C 1-6 Alkyl group, halogen atom, optionally substituted C 3-6 Cycloalkyl groups, optionally substituted 3- to 7-membered nitrogen-containing heterocyclic groups, optionally substituted C 1-6 an alkoxy group, or a hydroxy group; and R 8 and R 10 each independently represents either zero, a hydrogen atom or an optionally substituted C 1-6 alkyl groups; or a salt thereof (also referred to as compound (Ib)).

[0136] In some embodiments of compound (Ib), R 1 teeth, (1)(i) a halogen atom (e.g., a fluorine atom), (ii) C 1-6 Alkoxy groups (e.g., methoxy), and (iii) C 3-6 Cycloalkyl groups (e.g., cyclopropyl) C optionally substituted with 1 to 3 substituents independently selected from 1-6 Alkyl groups (e.g., methyl, ethyl), (2) C 3-10 a cycloalkyl group (e.g., cyclopropyl), or (3) Mono- or di-C 1-6 an alkylamino group (e.g., methylamino, dimethylamino); R 2 and R 3 are each independently a hydrogen atom or C 1-6 An alkyl group (e.g., methyl) or R 2 and R 3 come together and form a bond; R 4 is a hydrogen atom, C 1-6 Alkyl group (e.g., methyl), C 1-6 an alkoxy group (e.g., ethoxy), or a hydroxy group; R5 is phenyl, pyrazolyl, furyl, thienyl or thiazolyl, any of which is 1-6 Alkyl group (e.g., methyl), halogen atom (e.g., fluorine atom, chlorine atom), halo(C 1-6 ) alkyl groups (e.g., trifluoromethyl), and C 1-6 may be substituted with one or more substituents independently selected from alkoxy groups (e.g., methoxy); m is 0 or 1; q is 1 or 2; R 6 and R 7 are each independently a hydrogen atom, a halogen atom (e.g., a fluorine atom), or C 1-6 is an alkyl group (e.g., methyl); X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is the following: (i) X 1 is NR 8 And R 8 does not exist, and X 2 is O;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (ii) X 1 is NR 8 And R 8 does not exist, and X 2 is O and X 3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is; (iii) X 1 is NR 8 And R 8does not exist, and X 2 is O and X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is N; (iv) X 1 is NR 8 And R 8 does not exist, and X 2 is S and X 3 and X 4 are both in C Yes, X 5 is N and X 6 is CR 12 and X 7 is CR 13 is; (v) X 1 is NR 8 And R 8 does not exist, and X 2 is S;X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (vi) X 1 is NR 8 And X 2 is NR 10 and R 8 and R 10 One of them does not exist ZR 8 and R 10 The other is C 1-6 is an alkyl group (e.g., methyl), and X 3 and X 4 are both C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is; (vii) X 1is CR 9 and X 2 is NR 10 And R 10 does not exist, and X 3 is N and X 4 is C and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 and (viii) X 1 is CR 9 and X 2 is NR 10 And R 10 does not exist, and X 3 is C , X 4 is N and X 5 is CR 11 and X 6 is CR 12 and X 7 is CR 13 is is selected to form a ring system which is one of R 9 , R 11 , R 12 , and R 13 are each independently a hydrogen atom, C 1-6 Alkyl groups (e.g., methyl, ethyl), halogen atoms (e.g., fluorine, chlorine, bromine), C 3-6 Cycloalkyl groups (e.g., cyclopropyl), C 3-6 Cycloalkyl(C 1-6 ) alkoxy groups (e.g., cyclopropylmethoxy), halo (C 1-6 ) alkyl group (e.g., difluoromethyl, trifluoromethyl), halo(C 1-6 ) alkoxy group (e.g., difluoromethoxy, trifluoromethoxy), C 1-6 Alkoxy(C 1-6 ) alkyl group (e.g., methoxymethyl), azetidinyl group, C 1-6 Alkoxy groups (e.g., methoxy, ethoxy ), hydroxyl groups, and hydroxyl (C 1-6) alkyl groups (e.g., hydroxymethyl, 2-hydroxyethyl).

[0137] In some embodiments, compound (I) has formula (Ic):

[0138] [ka]

[0139] [In the formula, R 1 is C 1-6 Alkyl groups (e.g., methyl, ethyl), or mono-C 1-6 an alkylamino group (e.g., methylamino); R 2 and R 3 are each a hydrogen atom or R 2 and R 3 come together and form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group optionally substituted by 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 are each independently a hydrogen atom or a halogen atom (e.g., a fluorine atom); X 5 is CH or N; and R 12 and R 13 are each independently a hydrogen atom, C 1-6 an alkyl group (e.g., methyl), or a halogen atom (e.g., fluorine atom, chlorine atom); or a salt thereof (also referred to as compound (Ic)).

[0140] In some embodiments of compound (Ic), R 1 is C 1-6 an alkyl group (e.g., methyl, ethyl); R 2and R 3 are each a hydrogen atom or R 2 and R 3 come together and form a bond; R 4 is a hydrogen atom; R 5 is a phenyl group substituted with 1 to 3 (e.g., 1, 2, 3, etc.) halogen atoms (e.g., fluorine atoms); R 6 and R 7 are each a halogen atom (e.g., a fluorine atom); X 5 is CH; and R 12 and R 13 are each independently a hydrogen atom or a halogen atom (e.g., a fluorine atom).

[0141] Representative examples of compound (I), including compounds (Ia), (Ib) and (Ic), include the compounds shown in the Examples and Table 1. In some aspects, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: 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; The present invention provides a compound selected from the group consisting of:

[0142] In some aspects, the 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. In some aspects, the 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. In some aspects, the 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. In some aspects, the present disclosure provides a method for the preparation of a compound comprising administering to a subject a compound comprising administering to a subject a compound comprising administering to a subject a compound comprising administering to a subject a compound comprising administering to a subject a compound comprising administering to a subject a compound comprising administering to a subject a compound comprising administering to a subject a compound The present invention provides a compound which is a cyclic amide, or a salt thereof. In some aspects, the 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. In some aspects, the 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. In some aspects, the 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. In some aspects, the 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. In some aspects, the 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. In some aspects, the 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. In some aspects, the 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.

[0143] As the salt of the compound represented by formula (I), a pharmacologically acceptable salt is preferable. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts, and the like. Examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. 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, and p-toluenesulfonic acid. 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.

[0144] The process for producing the compound of the present invention is explained below.

[0145] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt, such as the salt of the compound represented by formula (I).

[0146] When the compound obtained in each step is a free compound, it can be converted to the desired salt by a known method. When the compound obtained in each step is a salt, it can be converted to the desired free form or other types of salt by a known method.

[0147] The compound obtained in each step can be used in the next reaction directly as a reaction liquid or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture according to a known method, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc.

[0148] When the raw material compounds and / or reagent compounds in each step are commercially available, the commercially available products can be used as they are.

[0149] In the reaction of each step, the reaction time may vary depending on the reagent and solvent used. Unless otherwise specified, the reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0150] In the reaction of each step, the reaction temperature may vary depending on the reagents and solvent used. Unless otherwise specified, the reaction temperature is usually −78° C. to 300° C., preferably −78° C. to 150° C.

[0151] In the reaction of each step, the pressure may vary depending on the reagents and solvents used. Unless otherwise specified, the pressure is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0152] In the reactions of each step, for example, a microwave synthesis device such as Biotage's Initiator+ can be used. The reaction temperature may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually room temperature to 300° C., preferably 50° C. to 250° C. The reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0153] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in an amount equal to the solvent amount.

[0154] Unless otherwise specified, the reaction in each step is carried out without a solvent or by dissolving or suspending the raw material in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; and water. The above solvents may be used alone or in combination of two or more in an appropriate ratio.

[0155] When a base is used in the reaction of each step, for example, the following base or the base described in the Examples can be used: Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; and Organolithium compounds: n-butyllithium, etc.

[0156] When an acid or an acid catalyst is used in the reaction of each step, for example, the following acids or acid catalysts or the acids or acid catalysts described in the Examples can be used: Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0157] Unless otherwise specified, the reactions in each step are carried out according to known methods, for example, those described in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Name Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC This can be carried out in accordance with the methods described in SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (written by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Tomioka Kiyoshi, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.) 1989, or the methods described in the Examples.

[0158] In each step, the protection or deprotection reaction of a functional group can be carried out by a known method, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W . Greene, Peter GM Wuts); Thieme Press, 2004, "Protecting Groups, 3rd Ed." (PJ Kocienski), or in accordance with the method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a known method, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or the like, or a reduction method.

[0159] In each step, when a reduction reaction is carried out, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon or Lindlar catalyst can be used.

[0160] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0161] In each step, when a radical cyclization reaction is carried out, the radical initiator to be used is, Examples of the radical initiator include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction agent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0162] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes, etc. The alkylidene phosphoranes can be prepared by a known method, for example, by reacting a phosphonium salt with a strong base.

[0163] When the Horner-Emmons reaction is carried out in each step, examples of the reagent used include phosphonoacetates such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0164] In each step, when the Friedel-Crafts reaction is carried out, a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.) is used as a reagent. Alternatively, an organic acid or inorganic acid described in this specification can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0165] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0166] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0167] In the case where a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[0168] In each step, when a Knoevenagel condensation reaction is carried out, a compound having an active methylene group sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases, each of which is described in this specification) are used as reagents.

[0169] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0170] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, for the azidation reaction of alcohols, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a method using trimethylsilyl azide and a Lewis acid is adopted.

[0171] In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include aldehydes such as paraformaldehyde and acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include primary amines such as ammonia, methylamine, etc.; secondary amines such as dimethylamine, etc.

[0172] In each step, when Mitsunobu reaction is carried out, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0173] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is performed, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, activated esters, and sulfates. Examples of activators for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); Examples of suitable condensing agents include 2-chloro-1-methyl-pyridinium iodide (Mukaiyama's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; and combinations of these. When using a carbodiimide-based condensing agent, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) can be added to the reaction system.

[0174] In each step, when a coupling reaction is carried out, examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases described herein.

[0175] In each step, when a thiocarbonylation reaction is carried out, diphosphorus pentasulfide is typically used as the thiocarbonylation agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) and the like) may be used in addition to diphosphorus pentasulfide.

[0176] In each step, when the Wohl-Ziegler reaction is carried out, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile is provided to the reaction system. This can accelerate the reaction.

[0177] In each step, when a halogenation reaction of a hydroxy group is carried out, examples of the halogenating agent used include hydrohalic acid and acid halides of inorganic acids. Specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc., may be used. A method of producing alkyl halides by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. may also be used. Alternatively, a method of producing alkyl halides through a two-step reaction including converting an alcohol to a corresponding sulfonic acid ester and then reacting it with lithium bromide, lithium chloride, or sodium iodide may also be used.

[0178] In each step, when the Arbuzov reaction is carried out, examples of the reagent used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0179] When a sulfonyl esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0180] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. In addition, for the acid hydrolysis reaction of tert-butyl ester, formic acid, triethylsilane, etc. can be added to reductively trap the by-product tert-butyl cation.

[0181] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0182] Compound (7) used in Scheme 2 described later can be produced from compound (1) according to the method shown in Scheme 1 below. 1 and P2 are a protecting group or a hydrogen atom, and LG 1 is a leaving group, and R 16 is optionally substituted C 1-6 Alkyl group or optionally substituted C 6-14 The other symbols are as defined above.

[0183] [ka]

[0184] P 1 Examples of the "protecting group" include those exemplified above as the "protecting group for amino group, and aromatic heterocycles such as imidazole, pyrrole, and indole." P 2 Examples of the "protecting group" include those exemplified above as the "protecting group for the hydroxyl group of alcohol, etc." LG 1 The "leaving group" in the formula (I) is, for example, a halogen atom, an optionally halogenated C 1-6 Alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with alkyl 6-14 Examples thereof include arylsulfonyloxy (eg, benzenesulfonyloxy, toluenesulfonyloxy), and the like. Compound (1) is a commercially available product that is readily available, or can be produced according to a method known per se. Compound (3) can be produced by subjecting compound (1) to a sulfonamidation reaction with compound (2). Examples of compound (2) used include sulfonyl chloride, sulfamoyl chloride, etc. Compound (2) is a commercially available product that is easily available, or can be produced according to a method known per se. Compound (7) can be, for example, X 8Compound (5), in which is a nitrogen atom, can be produced by subjecting the compound (5) to a condensation reaction with compound (6)-1 or compound (6)-2. Compound (6)-1 and compound (6)-2 are either readily available commercial products or can be produced according to a method known per se.

[0185] Compound (I) can be prepared from compound (7) according to the method shown in Scheme 2 below. 17 is an optionally substituted C 1-6 Alkyl group or optionally substituted C 6-14 The other symbols are as defined above.

[0186] [ka]

[0187] Compound (8) can be produced by subjecting compound (7) to a sulfonyl esterification reaction. Examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and trifluoromethanesulfonic anhydride. Compound (9) can be, for example, R 4 The compound (7), in which is a hydrogen atom, can be produced by subjecting the compound (7) to an oxidation reaction. 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, and alkali metal hydrides. X 9 CR 2 , r is 0, and R 2 and R 3 Compound (I) in which the above are combined to form a bond can be produced, for example, by subjecting compound (9) to a dehydration reaction. X 10 CR 15 , and R 3 and R 15Compound (I) in which can be produced, for example, by subjecting compound (9) to a dehydration reaction.

[0188] In compound (I), the functional groups in the molecule can be converted to the desired functional groups by combining known chemical reactions, such as oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0189] In the above-mentioned production methods, 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 or the like can be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0190] Compound (I) can be isolated and purified by known means, such as solvent extraction, liquid conversion, dissolution transfer, crystallization, recrystallization, chromatography, and the like. When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or a separation method. For example, when compound (I) contains optical isomers, optical isomers separated from the compound are also included in compound (I). The optical isomers can be produced by known methods. Compound (I) may be in a crystalline form. The crystals of compound (I) (hereinafter sometimes abbreviated as the crystals of the present invention) can be produced by crystallizing compound (I) using a known crystallization method.

[0191] In this specification, the melting point means a melting point measured, for example, by a micro melting point analyzer (Yanaco, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1). In general, the melting point may vary depending on the measuring instrument, the measuring conditions, etc. The crystals in this specification may have a melting point different from that described in this specification within the normal error range. The crystals of the present invention have excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), efficacy) and can be extremely useful as pharmaceuticals.

[0192] Compound (I) can be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body. For example, a prodrug of compound (I) is a compound that is converted to compound (I) by oxidation, reduction, hydrolysis, or the like in the presence of an enzyme, or a compound that is converted to compound (I) by hydrolysis, or the like, with gastric acid, or the like. Prodrugs of Compound (I) include: A compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., a compound in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated); A compound in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); or Compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compounds in which the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxylated, (cyclohexyloxycarbonylethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated compounds) It could be. All of these compounds can be produced from compound (I) by known methods.

[0193] The prodrug of compound (I) may also be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Publishing in 1990. In the present specification, the prodrug may form a salt, and such salts include those exemplified as the salts of the compound represented by the above formula (I). Compound (I) may contain isotopes (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, 125 I), etc. Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) for use in positron emission tomography (PET), and is useful in fields such as medical diagnosis. Further, Compound (I) may be hydrated or non-hydrated, non-solvated (eg, anhydrous), or solvated (eg, hydrated). Compound (I) may also be 1 H 2 Deuterium converted to H(D) is also included. Furthermore, compound (I) may be a pharma- ceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or co-crystal salt refers to a crystalline substance that is composed of two or more distinct solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A co-crystal or co-crystal salt can be prepared according to known co-crystallization methods.

[0194] Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) can be used as it is or as a pharmaceutical composition (also referred to as a medicine) by mixing it with a pharmacologically acceptable carrier or the like, as an agent for preventing or treating various diseases described later in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys). Here, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used as pharmacologically acceptable carriers. These are blended as excipients, lubricants, binders, disintegrants in solid preparations, or as solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and preparation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used as necessary.

[0195] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. Examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylsta Examples of suitable antioxidants include sodium silicic acid, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose. Examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate. Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Examples of isotonicity agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. An example of a soothing agent is benzyl alcohol. Examples of preservatives include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Examples of antioxidants include sulfites and ascorbates. Examples of coloring agents include water-soluble edible coal-tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble edible coal-tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide). Examples of sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0196] Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, and buccal tablets), capsules (including soft capsules and microcapsules), pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films and oral mucosa patch films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drips), topical preparations (e.g., transdermal preparations, ointments, lotions, and patches), suppositories (e.g., rectal suppositories and vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. The compound of the present invention and the medicament of the present invention can be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorgan, intranasally, intradermally, by eye drop, intracerebrally, intravaginally, intraperitoneally, intratumorally, administration near a tumor, and administration to a lesion). These formulations may be immediate release formulations or controlled release formulations such as sustained release formulations (eg, sustained release microcapsules).

[0197] The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical preparations, for example, a method described in the Japanese Pharmacopoeia. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight. When preparing oral preparations, coating may be carried out, if necessary, for the purposes of taste masking, enteric properties or durability.

[0198] Examples of coating bases used for coating include sugar-coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. As the sugar-coating base, white sugar can be used, and one or more selected from the group consisting of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. can be used in combination. Examples of water-soluble film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)]; and natural products such as shellac. Examples of sustained-release film coating bases include cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS (trade name)) and ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE (trade name)). The above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. In addition, a light-shielding agent such as titanium oxide or ferric oxide may be used during coating.

[0199] The compound of the present invention has low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as a preventive or therapeutic agent, or a diagnostic agent for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0200] The compound of the present invention has excellent orexin type 2 receptor agonist activity and can treat, prevent, and ameliorate the risk of various neurological and psychiatric disorders associated with the orexin type 2 receptor. The compound of the present invention is effective in treating, for example, narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by daytime excessive sleepiness (e.g., Kleine-Lewin syndrome, major depression accompanied by hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemia obesity, hyperplasma obesity, pituitary obesity, hypoplasma obesity, hypothyroidism obesity, hypothalamic obesity, symptomatic obesity, smallpox, etc.), and childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, coma and other disorders of consciousness, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM sleep interruptions, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight syndrome, disorders related to circadian rhythm, fibromyalgia, conditions resulting from poor quality sleep, overeating, compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, heart abnormal heartbeat, arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormonal abnormalities, sexual and reproductive disorders such as reduced fertility, infertility, hypogonadism in men, and hirsutism in women, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (HHS) Pickwickian syndrome), respiratory disorders such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of secondary consequences of obesity such as reducing the risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, disorders of the genital / urinary system, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia disorder, acute stress disorder, wide Acute neurological and psychiatric disorders such as ophthalmopathy, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, cerebral defects following cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neurological damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injuries, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, integration It is useful as a preventive or therapeutic drug for various diseases such as schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, medication-induced Parkinson's syndrome, Gilles de la Tourette's syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury.

[0201] In particular, the compound of the present invention is useful as a therapeutic or preventive agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disorders of consciousness such as coma, side effects and complications due to anesthesia, and the like, or as an anesthetic antagonist.

[0202] In some embodiments, the compounds of the present invention are useful as prophylactic or therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects or complications due to anesthesia. In some embodiments, the compounds of the present invention are useful as agents for the prevention or treatment of narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome. In some embodiments, the compounds of the present invention are useful as agents for the prevention or treatment of narcolepsy.

[0203] Central hypersomnia (CDH) is characterized by excessive daytime sleepiness in the absence of other sleep disorders and in the presence of adequate and regular sleep habits. CDH includes narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. Kleine-Levin syndrome and insufficient sleep syndromes or hypersomnia caused by medical conditions, drugs or substances, or psychiatric conditions are also considered central hypersomnia. Evaluation of CDH includes sleep testing in a sleep laboratory (polysomnography, PSG) followed by multiple sleep latency testing (MSLT). Symptoms associated with narcolepsy include abnormal intrusions characteristic of REM sleep into wakefulness, such as sleep-related hallucinations, sleep paralysis, or vivid dreams and confusion between dreams and reality. These symptoms can occur even in people who don't have a sleep disorder. Some people with narcolepsy experience cataplexy (narcolepsy type 1), a loss of muscle tone that is triggered by emotion, typically laughter or anticipation. Cataplexy can be generalized or partial and does not involve loss of consciousness. This muscle weakness usually improves within seconds to minutes. Patients with idiopathic hypersomnia (IDH) often complain of excessive daytime sleepiness, long periods of sleep (more than 10-11 hours of sleep each night), and severe difficulty waking up in the morning (sleep inertia). In contrast to narcolepsy, patients with IDH often take long, unrefreshing naps. Another common symptom of IDH is "brain fog," a feeling of cognitive clouding during the day. Kleine-Levin syndrome is a rare disorder of periodic hypersomnia.

[0204] One aspect of the disclosure is a method of treating a subject having one or more central hypersomnias (CDH), comprising administering to the subject a compound of the invention. Another aspect of the present disclosure is the use of a compound of the present invention for the manufacture of a medicament for the treatment of one or more central hypersomnias (CDH) in a subject. Another aspect of the disclosure is a compound of the invention for use in treating one or more central hypersomnias (CDH) in a subject. Another embodiment is the method or use of the above embodiment, wherein the subject has narcolepsy.In one embodiment, the subject is diagnosed with narcolepsy type 1.In another embodiment, the subject is diagnosed with narcolepsy type 2.In yet another embodiment, the subject is diagnosed with idiopathic hypersomnia.

[0205] Another embodiment is the method or use of the previous embodiment, wherein administering a compound of the invention reduces daytime sleepiness, reduces instances of loss of muscle control, and / or reduces instances of sleep disruption in a subject. Another embodiment is the method or use, wherein a compound of the invention is administered in an amount effective to reduce excessive daytime sleepiness in adults with narcolepsy. Another aspect is the method or use, wherein a compound of the invention is administered in an amount effective to increase mean sleep latency. Another aspect is the method or use, wherein a compound of the invention is administered in an amount effective to reduce cataplexy events. Another aspect is the method or use, wherein a compound of the invention is administered in an amount effective to reduce nocturnal sleep disturbances in a subject.

[0206] The dosage of the compound of the present invention varies depending on the subject, route of administration, target disease, symptoms, etc., but for example, when orally or parenterally administered to an adult patient, the dosage is, for example, about 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight, more preferably 0.5 to 20 mg / kg body weight per administration. It is desirable to administer this amount in one to three divided doses per day.

[0207] The compound of the present invention can be used in combination with other drugs (hereinafter, abbreviated as concomitant drugs). By combining the compound of the present invention with a concomitant drug, for example, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to the case where the compound is administered alone. (2) Drugs to be used in combination with the compound of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug with a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. It is possible to achieve (5) A synergistic effect can be obtained by combining the compound of the present invention with a concomitant drug. The above-mentioned excellent effects can be obtained.

[0208] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as "the combined drug of the present invention." When using the combination drug of the present invention, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag. The dosage of the combination drug may be in accordance with the dosage used in clinical practice, and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes with a time lag (for example, administration in the order of the compound of the present invention; the combination drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the target disease, symptoms, combination, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total preparation. In addition, when the compound of the present invention and the concomitant drug are separately formulated, the contents may be similar.

[0209] Examples of concomitant drugs include the following: narcolepsy treatment drugs (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drugs (amphetamine, benzphetamine, bromoclopridine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia drugs (e.g., memantine), β-amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors, β-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin , 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2- [2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, optically active substances thereof, salts thereof and hydrates thereof, OM99-2 (International Publication No. 01 / 00663)), gamma secretase inhibitors, beta amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHE MED (NC-531), PPI-368 (JP Patent Publication No. 11-514333), PPI-558 (JP Patent Publication No. 2001-500852), SKF-74652 (Biochem.J.(1999),340(1),283-289)), β-amyloid vaccine, β-amyloid decomposing enzyme, etc., brain function activators (e.g., aniracetam, nicergoline), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine MAO inhibitors (e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], drugs for treating amyotrophic lateral sclerosis (e.g., riluzole, neurotrophic factors), drugs for treating abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation and regeneration promoters (e.g., leteprinim, xaliproden;SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active forms, salts, and hydrates), non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (dexamethasone, 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, ... xazone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), urinary incontinence and frequent urination treatments (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil citrate), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or derivatives thereof (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatments (e.g., alphacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, insomnia treatments (e.g., benzodiazepines, non-benzodiazepines; antipsychotics (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs acting on metabotropic or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines Antidepressants (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, amine, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1A agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT2A antagonists, 5-HT2A inverse agonists, 5-HT3 antagonists (cyamemazine, etc.), non-cardioselective β-blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3-adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type Calcium channel blockers, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), bipolar disorder medications (lithium carbonate, sodium valproate drugs for treating alcoholism, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for smoking cessation, drugs for treating myasthenia gravis, drugs for treating cerebral infarction, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating dysthymia, drugs for treating autonomic nervous system disorders, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling,Drugs for treating restless leg syndrome, drugs for treating substance dependence, drugs for treating alcohol-related diseases, drugs for treating irritable bowel syndrome, drugs for treating dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for treating abnormal behavior or drugs to suppress wandering caused by dementia (sedatives, anti-anxiety drugs, etc.), drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating high blood pressure, drugs for treating low blood pressure, diuretics, chemotherapy drugs, immunotherapy drugs, antithrombotic drugs, anticancer drugs, etc.

[0210] The above-mentioned concomitant drugs may be used in combination of two or more kinds in an appropriate ratio. Furthermore, when the compound of the present invention is used for the treatment of each of the above-mentioned diseases, it can be used in combination with a biological preparation (e.g., an antibody drug, a nucleic acid or a nucleic acid derivative, an aptamer drug, or a vaccine preparation), and can also be used in combination with a gene therapy method or the like, or in combination with a drug-free psychiatric therapy. Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibodies and other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., DIAPEP-277 by Peptor), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in blood coagulation and fibrinolysis systems, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, etc. In addition, they can be used in combination with biological preparations related to growth factors such as GH and IGF. Examples of gene therapy include therapy using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes, therapy using DNA decoys such as NFκB decoys, therapy using antisense, and genes related to enzymes and proteins involved in blood lipid metabolism (e.g., cholesterol, Examples of such therapies include therapies using genes related to the metabolism, excretion, and absorption of HDL-cholesterol or triglycerides, or HDL-cholesterol, or blood phospholipids; therapies using genes related to enzymes and proteins (e.g., growth factors such as HGF and VEGF) involved in angiogenesis therapy targeting peripheral vascular occlusion, etc.; therapies using genes related to proteins involved in glucose metabolism and insulin resistance; and antisense therapy against cytokines such as TNF. Non-drug psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy including cognitive behavioral therapy. In addition, the compound of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (e.g., artificial blood vessels, cardiomyocyte sheets). EXAMPLES

[0211] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. The ratio of mixed solvents is indicated by volume ratio unless otherwise specified. % is indicated by weight % unless otherwise specified.

[0212] In the examples, elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, a 60 F chromatographic plate manufactured by Merck was used as a saturated LC plate. 254The solvent used in column chromatography was used as the eluent. A UV detector was used for detection. In silica gel column chromatography, the NH symbol indicates the use of aminopropylsilane-bonded silica gel, and the DIOL symbol indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. Preparative HPLC (high performance liquid chromatography) was performed under the following conditions; Column: Boston Prime C18 (150mm x 30mm, 5μm), Xtimate C18 (100mm x 30mm, 3μm), Gemini NX C18 (150mm x 30mm, 5μm), YMC Triart C18 (250mm x 50mm, 7μm), Exsil plus C18 (150mm x 50mm, 5μm), or Water Xbridge C18 (150mm x 30mm, 5μm), Mobile phase: Ammonia water / MeCN, water / MeCN (both containing 0.1% TFA), ammonia hydroxide water / MeCN. C18 indicates the use of octadecyl-bonded silica gel. The ratio of elution solvents is by volume unless otherwise specified. 1 H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Peaks with very gentle proton peaks such as hydroxyl and amino groups may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shows actual measurements (found values). Molecular ion peaks are usually observed, but fragment ions may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0213] The following abbreviations are used in the following examples: MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization Boc: tert-butoxycarbonyl CPME: Cyclopentyl methyl ether DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene Dess-Martin Periodinane: 3-Oxo-1l5-benzo[d][1,2]iodoxol-1,1,1(3H)-triyl triacetate DMA: N,N-Dimethylacetamide DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide EtOAc: ethyl acetate EtOH: Ethanol IPE: Diisopropyl ether MeCN: Acetonitrile MeOH: Methanol TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0214] Example 1 N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo Hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[0215] A) 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine To a mixture of 4-bromo-1,2-benzoxazol-3-amine (7.20 g), (2,6-difluorophenyl)boronic acid pinacol ester (24.3 g) and potassium fluoride (5.94 g) in DMA (60 mL) and water (15 mL) was added tri-tert-butylphosphonium tetrafluoroborate (0.986 g) and Pd2(dba)3 (1.55 g). The mixture was heated at 120 °C for 3 h under argon atmosphere. After cooling, the mixture was diluted with water and extracted with THF / EtOAc. The extract was diluted with water and sodium chloride. The mixture was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the crude product. The crude product was triturated with cold IPE, and the precipitate was collected by filtration to give the title compound (5.01 g). MS: [M+H] + 247.0.

[0216] B) 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-1,2-benzoxazole-3- Il]carbamate To a mixture of 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine (6.92 g) in THF (130 mL) was added 1M lithium bis(trimethylsilyl)amide THF solution (60 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. To the mixture was added 2,2,2-trichloroethoxycarbonyl chloride (6.60 g) at 0° C. The mixture was stirred at 0° C. for 30 minutes. To the mixture was added aryl chloride (1.0 mL). Aqueous ammonium solution and EtOAc were added. 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 (8.34 g). MS: [M+H] + 420.9.

[0217] C) 1-tert-butyl 2-methyl (2S,4S)-4-[(ethanesulfonyl)amino]pyrrolidine-1,2-di Carboxylate Ethanesulfonyl chloride (7.54 mL) was dissolved in 1-(tert-butyl) 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (15.9 g) and TEA (39.6 mL) in DME at 0 °C. (189 mL). The mixture was stirred at room temperature overnight and then filtered to remove insoluble matter. The filtrate was diluted with EtOAc, washed with 1M aqueous hydrogen chloride 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 (18.4 g). MS: [M+H-Boc] + 237.1.

[0218] D) tert-Butyl (2S,4S)-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxylate A suspension of lithium aluminum hydride (0.36 g) in THF (30 mL) was added to 0 1-tert-Butyl 2-methyl(2S,4S)-4-[(ethanesulfonyl)amino]pyrrolidine-1,2-diamine at ℃ A solution of carboxylate (2.65 g) in THF (30.0 mL) was added dropwise. The mixture was stirred under argon atmosphere at 0° C. for 2 hours. A saturated aqueous solution of potassium sodium tartrate was added to the mixture at 0° C. The mixture was diluted with EtOAc, the organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The mixture was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (2.18 g). MS: [M+H-Boc] + 209.1.

[0219] E) N-[(3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride A 4M solution of hydrogen chloride in EtOAc (5 mL) was added to a solution of tert-butyl (2S,4S)-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.18 g) in EtOAc (5 mL) at room temperature. The mixture was stirred at room temperature overnight. A white solid formed and was collected by filtration to give the title compound. The product (1.40 g) was obtained. 1 H 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)

[0220] F) (2S,4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide 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]ethanesulfonamide hydrochloride (0.406 g) and N,N-diisopropylethylamine (0.568 mL) in THF (8.30 mL) was stirred at 70° C. for 44 hours. After cooling, the mixture was purified by silica gel column chromatography. Purification by chromatography (MeOH / EtOAc) gave the title compound (0.39 g). MS: [M+H] + 481.1.

[0221] G) N-{(6S,7aS)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide (2S,4S)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethoxy) A mixture of [2-(hydroxymethyl)pyrrolidine-1-carboxamide (260 mg), TEA (0.302 mL) and THF (2.0 mL) was added with methanesulfonyl chloride (0.084 mL) at 0°C. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was concentrated at 0° C. The residue was dissolved in THF (2.0 mL). To the mixture was added 60% sodium hydride (23.8 mg) at 0° C. 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, and extracted with anhydrous magnesium sulfate. The mixture was dried over NaCl 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). obtained. 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).

[0222] Example 16 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

[0223] A) 4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine 4-Bromo-1,2-benzoxazol-3-amine (10.0 g), (2,4,6-trifluorophenyl)boronic acid (33.0 g), Pd2(dba)3 (2.15 g), tri-tert-butylphosphonium tetrafluoroborate (TTBPA) A mixture of roborate (1.36 g) and potassium fluoride (8.18 g) in DME (150 mL) and water (30.0 mL) was heated at 80° C. for 16 h under an argon atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to half of its original volume. Water was added to the mixture. The mixture was extracted with EtOAc. The organic phase was The layers were 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 give the title compound (3.23 g). MS: [M+H] + 265.0.

[0224] B) 2,2,2-trichloroethyl [4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate To a mixture of 4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (5.0 g) in THF (95 mL) was added 1M lithium bis(trimethylsilyl)amide THF solution (47.3 mL) at 0° C. The mixture was stirred for 30 minutes. The mixture was added with 2,2,2-trichloroethoxycarbonyl Chloride (2.79 mL) was added. 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, washed with brine, and diluted with anhydrous sodium sulfate. The mixture was dried over sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was recrystallized from IPE-hexane to give the title compound (5.72 g). MS: [M+H] + 438.9.

[0225] C) 1-(benzyloxy)-3,3-difluoropent-4-en-2-ol To a solution of ((2,2-diethoxyethoxy)methyl)benzene (31.4 g) in THF (240 mL) and water (120 mL) was added 1M aqueous hydrogen chloride solution (120 mL) at room temperature. The mixture was stirred at 70° C. for 2 hours. EtOAc and water were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. A mixture of the residue, 3-bromo-3,3-difluoroprop-1-ene (20.0 g) and DMF (240 mL) was added. Indium powder (16.1 g) was added at room temperature. The mixture was heated at room temperature under an argon atmosphere until completion. The mixture was stirred overnight. EtOAc and water were added 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. The title compound (27.2 g) was obtained. 1H 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).

[0226] D) tert-Butyl [1-(benzyloxy)-3,3-difluoropent-4-en-2-yl]carbamate 1-(benzyloxy)-3,3-difluoropent-4-en-2-ol (27.1 g) and pyridine (77 mL) in MeCN (400 mL) was added trifluoromethanesulfonic anhydride (28 The mixture was stirred at 0° C. for 30 min under 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 layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was extracted with MeCN (400 mL) The mixture was diluted with tetra-n-butylammonium azide (66.9 g) at 0° C. The mixture was stirred at room temperature overnight 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 1M aqueous hydrogen chloride solution, and the mixture was poured into a silica gel pad. The mixture was filtered through a filtration membrane and concentrated under reduced pressure. Water (40 mL) was added to the residue at room temperature. A mixture of triphenylphosphine (34.3 g) and toluene (40 mL) was slowly added to the mixture. The mixture was stirred at 70° C. for 5 hours. After cooling, di-tert-butyl dicarbonate (41.0 mL) and sodium hydrogen carbonate (11.0 g) were added to the mixture at room temperature. The mixture was stirred at room temperature overnight. 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 / hexanes) to give the title compound (37.3 g). MS: [M+1-Boc] + 228.1

[0227] E) 1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-2,3-dideoxy-3,3-difluoro Ropentitol tert-Butyl [1-(benzyloxy)-3,3-difluoropent-4-en-2-yl]carbamate To a mixture of morpholine (37.3 g), 4-methylmorpholine 4-oxide (26.7 g), acetone (360 mL) and water (36 mL) was added 4% osmium(VIII) oxide in water (40 g) at room temperature. The mixture was stirred overnight under an argon atmosphere. The mixture was diluted with EtOAc and 10% sodium thiosulfate at 0 °C. Aqueous thorium solution was added. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with 0.1M aqueous hydrogen chloride solution and brine, dried over anhydrous sodium sulfate, then filtered through a pad of silica gel and concentrated under reduced pressure to give the title compound (42.1 g). MS: [M+1-Boc] + 262.1

[0228] F) rac-tert-butyl (2R,4S)-2-[(benzyloxy)methyl]-3,3-difluoro-4-hydroxy Cypyrrolidine-1-carboxylate 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]oxaborin-10-ol (1.30 g) and N,N-diisopropylethylamine (30 mL) in MeCN (300 mL) was added a solution of toluenesulfonyl chloride (24.4 g) in MeCN (100 mL) at room temperature. The mixture was stirred at room temperature for 1 hour under argon atmosphere. Water was added. The organic layer was separated, washed with 10% aqueous citric acid and brine, and concentrated under reduced pressure. To the residue was added toluene (300 mL) and TFA (300 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was diluted with MeOH (400 mL). Mixture To the mixture was added sodium carbonate (49.3 g) at 0° C. The mixture was stirred at room temperature overnight. To the mixture was added 10% aqueous acetic acid (300 mL) at 0° C. The mixture was concentrated under reduced pressure and then extracted with toluene. and diluted with EtOAc. The organic layer was separated and extracted with 20% aqueous acetic acid. The combined aqueous layers were The mixture was quenched with potassium carbonate at 37° C. and adjusted 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. The residue was diluted with toluene at room temperature. (300 mL), water (300 mL), sodium carbonate (24.6 g) and di-tert-butyl dicarbonate (32.0 mL) were added. The mixture was stirred at room temperature for 1 hour. The aqueous layer was separated and extracted with toluene. The combined organic layer was 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). MS: [M+1-Boc] + 244.0

[0229] G) rac-tert-butyl (2R,4R)-4-azido-2-[(benzyloxy)methyl]-3,3-difluoropyridine Rolidin-1-carboxylate rac-tert-Butyl (2R,4S)-2-[(benzyloxy)methyl]-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (11.9 g) and pyridine (22.3 mL) in MeCN (120 mL) To the mixture was added trifluoromethanesulfonic anhydride (11.7 mL) at 0°C. The mixture was stirred under nitrogen atmosphere at 0° C. for 30 minutes. EtOAc and water were added to the mixture at 0° C. The organic layer The extract was separated, washed with 10% aqueous citric acid, water, and brine, and dried over anhydrous sodium sulfate. The mixture was stirred at 0° C. for 30 minutes under nitrogen atmosphere, then concentrated under reduced pressure. The residue was diluted with DMF (120 mL). To the mixture was added tetra-n-butylammonium azide (21.6 g) at 0° C. The mixture was stirred at 0° C. for 30 minutes under nitrogen atmosphere, then concentrated under reduced pressure. The mixture was stirred at room temperature overnight. EtOAc and water were added to the mixture at 0° C. The combined 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 (5.65 g). MS: [M+1-Boc] + 269.1

[0230] H) rac-tert-butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyridine Rolidin-1-carboxylate A mixture of rac-tert-butyl (2R,4R)-4-azido-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (5.65 g) and THF (50 mL) was added to triphenylphosphine at room temperature. A solution of arylphosphine (4.83 g) in THF (10 mL) was slowly added. The mixture was stirred at room temperature for 1 h. The mixture was stirred. Water (30 mL) was added to the mixture, and then the mixture was heated to 50° C. The mixture was stirred at 50° C. overnight. EtOAc and brine were added to the mixture at room temperature. 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. The compound (4.98 g) was obtained. MS: [M+1-Boc] + 243.1

[0231] I) tert-Butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidone Zin-1-carboxylate rac-tert-Butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (16.0 g) was separated by SFC (column: DAICEL Chiral PAK AY, 250 mmx50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% ammonium hydroxide = 75 / 25 v / v). The title compound (7.12 g) was obtained with the longer retention time. MS: [M+1] + 343.2

[0232] J) tert-Butyl (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methanesulfonyl) (phenyl)amino]pyrrolidine-1-carboxylate A solution of tert-butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (5.37 g) and TEA (10.9 mL) in DME (52.3 mL) was added at 0° C. Tanesulfonyl chloride (1.86 mL) was added dropwise. The mixture was stirred at 0° C. for 15 min, then at room temperature overnight. 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 / hexanes) to give The title compound (5.84 g) was obtained. MS: [MH] + 419.0.

[0233] K) tert-Butyl (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate A mixture of tert-butyl (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (5.84 g) and 20% palladium hydroxide on carbon (1.18 g) in MeOH (120 mL) was hydrogenated under balloon pressure at 20° C. for 15 h. After filtration, the solution was concentrated under reduced pressure to give the title compound (4.45 g). MS: [MH] + 329.0.

[0234] L) N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]methanesulfonate Namide hydrochloride tert-Butyl (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl) To a mixture of 1,2-diaminopyrrolidine-1-carboxylate (4.45 g) and EtOAc (16 mL), 4M hydrogen chloride in CPME (56 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. The volatiles were removed under reduced pressure to give the title compound (3.40 g). 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).

[0235] M) (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carbo Kisamide 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 at room temperature for 2 hours and then heated at 60° C. under an argon atmosphere overnight. The mixture was filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Purification by chromatography (EtOAc / hexanes) gave the title compound (3.47 g). MS: [M+H] + 521.1.

[0236] 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 (2R,4R)-3,3-Difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)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). The mixture was stirred at 0° C. for 5 minutes. The mixture was added with tetra-n-butylammonium bromide at 0° C. amide (47.9 mg), 2,2,6,6-tetramethylpiperidine 1-oxyl (23.2 mg) and iodine Soybean I,I-diacetate (263 mg) was added. The mixture was vigorously stirred at 0° C. for 5 min and then at room temperature for 15 min. To the mixture was added EtOAc and water 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. The residue was purified by silica gel column chromatography (EtOAc / hexane). Purification gave the title compound (279 mg). MS: [M+H] + 519.1.

[0237] O) N-{(6R)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzo oxazol-3-yl]-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide N-{(6R,7aR)-7,7-difluoro-1-hydroxy-3-oxo-2-[4-(2,4,6-trifluorophenyl To a solution of 1H-pyrrolo[1,2-c]imidazol-6-yl)-1,2-benzoxazol-3-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (279 mg) in TFA (7.5 mL) was added trifluoroacetic anhydride (0.152 mL) at room temperature. 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 then the residue was diluted with EtOAc. The mixture was diluted with saturated bicarbonate. Aqueous sodium solution was added. The solution was extracted with EtOAc / THF. The combined organic layers were washed with anhydrous sodium sulfate. The mixture was dried over sodium chloride, filtered and concentrated under reduced pressure. The residue was crystallized from EtOAc and two pure precipitates were collected. The residual oil was purified by silica gel column chromatography (EtOAc / Hexane The material was recrystallized from EtOH / heptane to give the title compound (165 mg). 1H 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).

[0238] Example 24 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}ethanesulfonyl Honamide

[0239] A) tert-Butyl (2R,4R)-2-[(benzyloxy)methyl]-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate To a mixture of tert-butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (2.00 g) and TEA (4.05 mL) in DME (19.5 mL), Ethanesulfonyl chloride (0.773 mL) was added at 0°C. The mixture was stirred at 0°C for 15 minutes, then The mixture was stirred at room temperature overnight. 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). MS: [M+H-Boc] + 335.1.

[0240] B) N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonate Namide hydrochloride A mixture of tert-butyl (2R,4R)-2-[(benzyloxy)methyl]-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate (2.56 g) and 20% palladium hydroxide on carbon (663 mg) in MeOH (29.5 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give a residue. A mixture of the residue and EtOAc (4 mL) was added at 0° C. A 4M solution of hydrogen chloride in EtOAc (20 mL) was added. The mixture was stirred at room temperature for 5 hours. 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). MS: [M+H] + 245.1.

[0241] C) (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carbo Kisamide 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) was added 2,2,2-trichloroethyl[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (3.34 g) at 0° C. The mixture was stirred at 60° C. for 15 hours. 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. Purification by column chromatography (EtOAc / hexane) gave the title compound (3.14 g). MS: [M+H] + 535.1.

[0242] D) N-{(6R,7aR)-7,7-difluoro-3-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzyl] 1H-pyrrolo[1,2-c]imidazol-6-yl]hexahydro-1H-pyrrolo[1,2-c]imidazol-3-yl}ethane Sulfonamides (2R,4R)-4-[(ethanesulfonyl)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). To the mixture in was added DBU (2.68 g) at 0° C. The mixture was stirred at room temperature for 1 hour. To the mixture was added DBU (1.34 g) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. To the mixture was added saturated aqueous ammonium chloride solution 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 purified by EtOAc-hepta The title compound (1.58 g) was obtained by recrystallization from ethyl acetate. 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).

[0243] Example 33 N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-di Fluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide

[0244] A) (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide Mid To a mixture of 4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine (200 mg) in THF (4 mL) was added 1M lithium bis(trimethylsilyl)amide in toluene (1.63 mL) and 2,2,2-trichloroethoxycarbonyl chloride (0.120 mL) at 0° C. After stirring for 1 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The layers were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (4 mL). To the mixture was added N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (228 mg) and DBU (371 mg) at 60° C. 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). MS: [M+H] + 517.1.

[0245] 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 (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethoxy) (phenylsulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide To a mixture of the mide (252 mg) in dichloromethane (2.0 mL) was added DBU (0.22 mL) and methanesulfonyl chloride (0.057 mL) at room temperature. The mixture was stirred for 30 minutes. To the reaction mixture was added DBU (0.22 mL). The mixture was quenched with saturated aqueous ammonium chloride solution 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). 1 H 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).

[0246] Example 34 N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-di Fluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[0247] A) (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide Mid 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- A mixture of benzoxazol-3-yl]carbamate (484 mg), DBU (0.504 mL) and THF (10 mL) was heated at 70° C. for 2 hours under microwave irradiation. 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 and diluted with anhydrous sulfuric acid. The mixture was dried over sodium and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (408 mg). MS: [M+H] + 503.1.

[0248] 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 (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro Fluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide To a mixture of 1,2-dichloromethane (1.0 mL) and methanesulfonyl chloride (0.038 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. This was converted to the title compound (43.6 mg). 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)

[0249] Example 47 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

[0250] A) 2-Bromo-3,6-difluorobenzaldehyde A mixture of 1-bromo-2,5-difluorobenzene (50.0 g) and THF (250 mL) was added at -70 °C for 2 M Lithium diisopropylamide in THF (155 mL) was added dropwise. The reaction mixture was stirred at the same temperature for 1 h. After stirring at 40° C. for 45 min, DMF (38.4 g) was added, and the reaction solution was stirred at the same temperature for 2 h. To the reaction mixture was added saturated aqueous ammonium chloride solution 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). The title compound (46.0 g) was obtained. 1H NMR (400 MHz, CDCl3) δ 7.16-7.20 (1H, m), 7.24-7.40 (1H, m), 10.33 (1H, s).

[0251] B) 2-Bromo-3,6-difluorobenzonitrile 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 The mixture in 1 mL of sodium thiosulfate was stirred at 70° C. for 0.5 hours. The mixture was stirred at 25° C. for 15 min. 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 give the title compound. The mixture (36.6 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.12-7.26 (1H, m), 7.26-7.45 (1H, m).

[0252] C) 4-Bromo-5-fluorobenzo[d]isoxazol-3-amine A solution of acetohydroxamic acid (18.6 g) in DMF (300 mL) and water (60 mL) was The mixture was stirred at 25°C for 2 hours, and then 2-bromo-3,6-difluorobenzene (34.2 g) was added. A solution of benzonitrile (18.0 g) in DMF (60 mL) was added and the resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was quenched with water at 0° C., and the precipitate was collected to give the title compound (14.1 g). 1 H NMR (400 MHz, DMSO-d6) δ 6.12 (2H, s), 7.45-7.62 (2H, m).

[0253] D) 5-Fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine A solution of 4-bromo-5-fluorobenzo[d]isoxazol-3-amine (12.5 g) in DME (200 mL) and water (20 mL) was added with 2,4,6-trifluorophenylboronic acid (47.6 g), potassium fluoride, (9.43 g), tri-tert-butylphosphonium tetrafluoroborate (3.14 g) and and Pd2(dba)3 (4.95 g) were added. The mixture was stirred at 110 °C under nitrogen atmosphere for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (9.1 g). MS: [M+H] + 283.0.

[0254] E) 2,2,2-trichloroethyl [5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzo Oxazol-3-yl]carbamate A solution of 5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (2.85 g) in THF (33.7 mL) was added to 1M lithium bis(trimethylsilyl)amide THF solution at 0°C. (22.2 mL) was added dropwise. The mixture was stirred at the same temperature for 10 min. The temperature was kept below 5°C. Then, 2,2,2-trichloroethoxycarbonyl chloride (1.53 mL) was added dropwise to the mixture. The mixture was stirred at 0° C. for 30 min. 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 Concentrate under reduced pressure. Triturate the resulting solid with 10% EtOAc-hexane. Remove the solid by filtration. The filtrate was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound. The mixture (3.64 g) was obtained. MS: [M+H] + 456.9.

[0255] F) (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzo[ 2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide 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) To the mixture was added TEA (5.91 mL) at room temperature. 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. Purification by column chromatography (EtOAc / hexane) gave the title compound (6.78 g). MS: [M+H] + 539.1.

[0256] 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]imidazole-6- yl}methanesulfonamide (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine A solution of 1-carboxamide (60 mg) in dichloromethane (1.0 mL) was added with DBU (0.05 mL) and and methanesulfonyl chloride (0.013 mL) were added 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 obtain the title compound (27.2 mg). 1 H 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).

[0257] Example 50 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

[0258] A) 4-chloro-2-fluoro-6-iodobenzonitrile 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 The mixture in (150 mL) was stirred at 70° C. for 6 h. 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 and brine. The mixture was concentrated under reduced pressure, dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.78 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.82-7.88 (1H, m), 8.08 (1H, s).

[0259] B) 6-chloro-4-iodo-1,2-benzoxazol-3-amine To a mixture of 2-propanone oxime (1.94 g) and DMF (58.5 mL) was added potassium tert-butoxide (2.98 g) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 20 minutes. The mixture was added to a mixture of 4-chloro-2-fluoro-6-iodobenzonitrile (7.13 g) and DMF (19.5 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes under nitrogen atmosphere. The mixture was added to a mixture of saturated salt solution at 0° C. The mixture was quenched with aqueous ammonium chloride and extracted with EtOAc. The organic layer was separated and washed with brine. The residue was dissolved in EtOH (175 mL) and 6 M The mixture was diluted with aqueous hydrogen chloride (60.8 mL) and stirred at 80° C. overnight under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was diluted with 8 M aqueous sodium hydroxide and saturated carbonate at 0° C. Aqueous sodium bicarbonate solution was added. The precipitate was collected by filtration, and the solid was washed with water and IPE to give the title compound. The compound (4.70 g) was obtained. MS: [M+H] + 294.9.

[0260] C) 6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-amine To a mixture of 6-chloro-4-iodo-1,2-benzoxazol-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. for 30 min under argon atmosphere. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was separated and It was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure The residue was triturated with IPE and the solid was collected by filtration to give the title compound (1.70 g). MS: [M+H] + 281.0.

[0261] D) 2,2,2-trichloroethyl [6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxa 3-[3-yl]carbamate 1M Lithium bis(trimethylsilyl)amide THF solution (36.2 mL) 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 at 0° C. for 30 minutes under an argon atmosphere. The mixture was added with 2,2, 2-Trichloroethoxycarbonyl chloride (3.16 mL) was added and the mixture was placed under an argon atmosphere. The mixture was stirred at 0° C. for 1 hour under atmospheric pressure. The mixture was quenched with saturated aqueous ammonium chloride solution at 0° C. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane). This gave the title compound (3.80 g). MS: [M+H] + 454.9.

[0262] E) (2S,4S)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide 2,2,2-Trichloroethyl [6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]carbamate (2.66 g), N-[(3S,5S)-5-(hydroxymethyl)pyrrolidine-3- 1.43 g), diisopropylethylamine (2.14 mL) A mixture of ethyl acetate and THF (34.3 mL) was stirred at 70° C. overnight. 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). MS: [M+H] + 515.0.

[0263] F) N-{(6S,7aS)-2-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazole-3- yl]-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonate Mid (2S,4S)-N-[6-chloro-4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2.73 g), TEA (2.96 mL), and methanesulfonyl chloride (0.821 mL) in THF (64 mL) The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride solution 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 allowed to warm to room temperature, stirred for 1 hour, and then washed with saturated aqueous ammonium chloride. The mixture was quenched 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 / heptane to give the title compound (0.968 g). 1 H 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).

[0264] Example 71 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}methanesulfonate Honamide (2R,4R)-3,3-Difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (2.71 g), methanesulfonyl chloride (0.806 mL) in dichloromethane (30 mL). To the mixture was added DBU (2.33 mL) at 0° C. The mixture was stirred at room temperature for 30 min. To the mixture was added DBU (1.18 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, 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). 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).

[0265] Example 72 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

[0266] A) 2,4-Difluoro-6-iodobenzonitrile 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 h. After cooling to room temperature, the mixture was poured into 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 / hexane) to give the title compound. The title compound (1.62 g) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 7.63-7.80 (1H, m), 7.91-7.98 (1H, m).

[0267] B) 6-Fluoro-4-iodo-1,2-benzoxazol-3-amine 1M potassium tert-butoxide in THF (2.66 mL) was added to 2-propanediol in DMF (26 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was then added to 2,4-difluoro-6-iodobenzonitrile (706 mg) in DMF (8.67 g) at 0° C. The mixture was stirred under nitrogen at 0° C. for 5 minutes. The mixture was then added dropwise to a saturated aqueous solution of ammonium chloride at 0° C. The mixture was quenched with aqueous ammonium hydroxide and extracted with EtOAc. The organic layer was separated, washed with brine, and The mixture was concentrated under reduced pressure. The residue was diluted with EtOH (28.9 mL) and 6 M aqueous hydrogen chloride solution (14.4 mL), and the mixture was stirred at 80° C. for 8 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure, then neutralized with saturated aqueous sodium bicarbonate 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). MS: [M+H]+ 278.9.

[0268] C) 4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-amine 6-Fluoro-4-iodo-1,2-benzoxazol-3-amine (286 mg), 2-(2,6-difluoro (triphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (741 mg), potassium fluoride To a mixture of (179 mg), tri-tert-butylphosphonium tetrafluoroborate (29.8 mg) in water (0.560 mL) and DME (2.8 mL) was added Pd2(dba)3 (47.1 mg) at room temperature. The mixture was stirred at 120 °C for 1 h under microwave irradiation. The aqueous phase was removed and the organic phase was concentrated under reduced pressure. The mixture was then filtered through a NH silica gel pad, eluting with EtOAc. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc / hexane) Purification gave the title compound (240 mg). MS: [M+H] + 265.0.

[0269] D) 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazole Sazolyl-3-yl]carbamate 1M Lithium bis(trimethylsilyl)amide THF solution (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 at 0° C. for 30 minutes under an argon atmosphere. 2,2,2-Trichloroethoxycarbonyl chloride (282 μl) was added to the mixture at 0° C. The mixture was stirred at 0° C. for 30 minutes under an argon atmosphere. The mixture was stirred under atmosphere for 1 hour. The mixture was quenched with saturated aqueous ammonium chloride at 0° C. and diluted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). To obtain the title compound (460 mg). MS: [M+H] + 438.9.

[0270] E) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazole-3-yl [3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide 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) To the solution was added DBU (0.084 mL), and the mixture was stirred under microwave irradiation at 70° C. for 1.5 hours. The reaction mixture was quenched with water and then it was extracted with EtOAc. The layer was 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). MS: [M+H] + 521.1.

[0271] 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 (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1- A solution of the carboxamide (73 mg) in dichloromethane (1.3 mL) was added with DBU (0.126 mL) and Sulfonyl chloride (0.022 mL) was added. The mixture was stirred at 25° C. for 1 h. The reaction mixture The mixture was quenched with water and then extracted with dichloromethane. The combined organic layer was 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). 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).

[0272] Example 75 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

[0273] A) 3,6-difluoro-2-iodobenzamide 2,5-Difluorobenzonitrile (20 g), N-iodosuccinimide (35.6 g), paraacetate Dinium(II) (1.61 g), and p-toluenesulfonic acid monohydrate (13.7 g) in DMF (500 mL) The mixture was stirred at 80° C. for 16 h. The mixture was quenched with water and extracted with IPE. The layers were 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. The compound (8.76 g) was obtained. MS: [M+H] + 283.9.

[0274] B) 3,6-difluoro-2-iodobenzonitrile 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 diluted with 1M aqueous chloride at 0° C. The mixture was quenched with aqueous sodium chloride and extracted with EtOAc. The organic layer was separated, washed with water and diluted with anhydrous sodium sulfate. The mixture was dried over sodium and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (7.83 g). 1 H NMR (300 MHz, CDCl3) δ 7.17-7.34 (2H, m)

[0275] C) 2',3,6,6'-Tetrafluoro[1,1'-biphenyl]-2-carbonitrile 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 A mixture of 1,200 mL of dimethyl ether (DMSO) and DME (0.5 mL) was heated at 120 The reaction was repeated four more times to obtain five batches of crude material, which were then mixed at 100° C. for 1 hour. The mixture was then quenched with water and extracted with EtOAc. The organic layer was separated and washed with anhydrous sodium sulfate. The mixture was dried over sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). The residue was washed with hexane to give the title compound (1.98 g). 1 H NMR (300 MHz, CDCl3) δ 7.04-7.16 (2H, m), 7.27-7.35 (1H, m), 7.40-7.56 (2H, m).

[0276] D) 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine 2',3,6,6'-Tetrafluoro[1,1'-biphenyl]-2-carbonitrile (1.98 g), 2-propanediol Non-oxime (1.73 g), and potassium 2-methylpropan-2-olate (1.77 g) in DMF The mixture was stirred at room temperature for 1.5 hours in (20 mL). The mixture was quenched with ethyl acetate and extracted with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture of this crude product and 6 M aqueous hydrogen chloride (2 mL) in EtOH (20 mL) was The mixture was stirred for 16 h at 80° C. 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). MS: [M+H] + 265.0.

[0277] E) (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazole-3-yl [3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide To a mixture of 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine (300 mg) in THF (2 mL) was added 1M lithium bis(trimethylsilyl)amide THF solution (2.27 mL) and 2,2,2-trichloroethoxycarbonyl chloride (0.167 mL) at 0°C. 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, 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)pyrrolidine A mixture of 1,3-dimethyl-3-yl]methanesulfonamide hydrochloride (151 mg) and DBU (0.257 mL) in THF (2 mL) was 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). MS: [M+H] + 521.1.

[0278] F) N-{(6R)-2-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazole-3-yl 3H-pyrrolo[1,2-c]imidazol-6-yl]-7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1- Carboxamide (50 mg), sodium bicarbonate (40.4 mg), and Dess-Martin peroxidase A mixture of phenylenediamine (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 and diluted with anhydrous sulfuric acid. The mixture was dried over sodium and concentrated under reduced pressure. The resulting residue, TFA (0.5 mL), and trifluoroacetic anhydride (0.5 mL) were stirred at room temperature 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 obtain the title compound (12.9 mg). 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).

[0279] Example 77 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

[0280] A) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzene 1-Hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazoxazol-3-yl 6-(2-phenyl)methanesulfonamide Tetra-n-butylammonium bromide (0.812 g), iodosobenzene I,I-diacetate (2R,4R)-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzo[3,4-difluorophenyl]-1,2- benzo[3,4-difluorophenyl] ... A mixture of 1,3-dioxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (6.78 g) and sodium bicarbonate (5.29 g) in MeCN (63 mL) and water (63 mL) was added. The mixture was stirred at 0° C. for 30 min. 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, and then extracted with anhydrous ethyl acetate. The mixture was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (6.10 g). MS: [M+Na] + 559.1.

[0281] B) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzene 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazo[3-yl] {6-yl}methanesulfonamide 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) at room temperature. 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). 1 H 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).

[0282] Example 92 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

[0283] 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 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) was added with DBU (0.194 mL) and N-[(3R,5R)-4,4-difluoro-5-(hydroxymethyl)pyrrolidin-3-yl]ethoxyacetone (0.194 mL) at room temperature. To the mixture was added phenylsulfonamide 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). MS: [M+H] + 553.1.

[0284] B) N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzene 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazo[3-yl] {6-yl}ethanesulfonamide (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[5-fluoro-4-(2,4,6-trifluorophenyl) [0.3-trifluorophenyl]-1,2-benzoxazol-3-yl-2-(hydroxymethyl)pyrrolidine A mixture of 1-methyl-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 separated. Purification by preparative HPLC (YMC-Actus Triant C18, mobile phase: water / MeCN (both containing 0.1% TFA)) gave the title compound (20.9 mg). 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).

[0285] Example 102 N-{(6R)-2-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-7,7-difluoro Oro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methane Sulfonamide (2R,4R)-N-[4-(2,6-difluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro Fluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide To a mixture of amide (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). The residue was diluted with dichloromethane (4 C. The mixture was stirred at room temperature overnight. To the mixture was added EtOAc and saturated aqueous sodium bicarbonate at 0° C. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined, washed with water and brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EtOAc / hexane). Purification gave the title compound (77 mg). 1 H NMR (400 MHz, CDCl3) δ 3.13 (3H, s), 3.17 (1H, dd, J = 11.2, 8.6 Hz), 3.97 (1H, dd, J = 11.2, 8.4 Hz), 4.55-4.67 (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).

[0286] Example 124 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

[0287] A) 6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine 6-Fluoro-4-iodo-1,2-benzoxazol-3-amine (620 mg), (2,4,6-trifluoro A mixture of (1.57 g)(phenyl)boronic acid, 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 for 1 h in a microwave reactor under an argon atmosphere. 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). MS: [M+H] + 283.0.

[0288] 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 6-Fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (100 To a mixture of 1 mg of 1,2,3-trichloroethoxycarbonyl chloride (0.052 mL) in THF (2 mL) was added 1M lithium bis(trimethylsilyl)amide in toluene (0.886 mL) at 0° C. The mixture was stirred for 30 minutes. To the mixture was added 2,2,2-trichloroethoxycarbonyl chloride (0.052 mL). The mixture was stirred for 1 hour. The mixture was saturated It was quenched with ammonium chloride solution and extracted with EtOAc. The organic layer was separated and washed with anhydrous sodium sulfate. The crude product, N-[(3R,5R)-4,4-difluoro-5-(phenylenediamine)-2,4-difluoro-5-(phenylenediamine)-2,5-difluoro-4 ... A mixture of hydroxymethyl)pyrrolidin-3-yl]ethanesulfonamide hydrochloride (99 mg) and DBU (162 mg) in THF (2 mL) was stirred at 60° C. 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 (85.1 mg). MS: [M+H] + 553.1.

[0289] 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]imidazole-6- yl}ethanesulfonamide (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl) [0.3-trifluorophenyl]-1,2-benzoxazol-3-yl-2-(hydroxymethyl)pyrrolidine To a mixture of 1-methyl-1-carboxamide (60 mg) in dichloromethane (2.0 mL) was added DBU (0.049 mL) and methanesulfonyl chloride (0.013 mL) at room temperature. The mixture was stirred for 15 min. To the mixture was added DBU (0.049 mL). The mixture was stirred for 30 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (16.5 mg). 1 H 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).

[0290] Example 126 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

[0291] A) 4-Bromo-6-methyl-1,2-benzoxazol-3-amine To a solution of ethanehydroxamic acid (5.26 g) in DMF (60 mL) was added potassium tert-butoxide (7.86 g). The mixture was stirred at 20° C. for 30 minutes. The mixture was added with 2-bromo-6-fluoro-4-methyl A solution of benzonitrile (5.00 g) in DMF (20 mL) was added. 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 and diluted with anhydrous sulfuric acid. The mixture was dried over sodium and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Purification with EtOAc / petroleum ether) gave the title compound (4.08 g). MS: [M+H] + 227.1.

[0292] B) 4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-amine 4-Bromo-6-methyl-1,2-benzoxazol-3-amine (770 mg), 2-(2,6-difluoro (phenyl)-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 A mixture of ethanol (591 mg) in DME (9 mL) and water (3 mL) was heated at 120° C. for 1 h under microwave irradiation. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers The extract 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 (567 mg). MS: [M+H] + 261.0.

[0293] C) 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxa 3-[3-yl]carbamate 1M Lithium bis(trimethylsilyl)amide THF solution (12.8 mL) was added to a solution of 4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-amine (1.67 g) in THF (39 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes. 2,2,2-Trichloroethoxycarbonyl chloride (0.972 mL) was added to the mixture. The mixture was stirred at 0° C. for 30 minutes. The mixture was saturated at 0° C. The mixture was quenched with aqueous ammonium chloride 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 give the title compound (1.86 g). MS: [M+H] + 434.9.

[0294] D) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide 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) was added 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]carbamate (187 mg) at 0° C. The mixture was stirred at 60° C. for 15 hours, then it was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound. The compound (190 mg) was obtained. MS: [M+H] + 517.1

[0295] E) N-{(6R,7aR)-2-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazole-3- yl]-7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide (2R,4R)-N-[4-(2,6-difluorophenyl)-6-methyl-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate Ruboxamide (95 mg) in THF (1.84 mL) and 1M aqueous sodium hydroxide (0.920 mL) To the mixture was added 4-methylbenzenesulfonyl chloride (71.9 mg) at -3°C. 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. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound. The product (45.0 mg) was obtained. 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).

[0296] Example 144 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'-methylsulfuric acid diamide

[0297] A) tert-Butyl (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methylsulfonyl) Famoyl)amino]pyrrolidine-1-carboxylate 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) was added a solution of methylsulfamoyl chloride (130 mg) in THF (1 mL) at 0° C. The mixture was stirred at room temperature under an argon atmosphere overnight. The mixture was directly purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (168 mg). MS: [M+H-Boc] + 336.1.

[0298] B) 2,2,2-trichloroethyl [6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzo Oxazol-3-yl]carbamate To a mixture of 6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (8.18 g) in THF (120 ml) was added 1M lithium bis(trimethylsilyl)amide THF solution (66.7 ml) at -22°C. After stirring for 10 min 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 min at -22°C under an argon atmosphere. To the mixture was added aqueous ammonium chloride solution and EtOAc at 0°C. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined and The mixture 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 (7.03 g). MS: [M+H] + 456.9.

[0299] C) (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzo[ 2-(hydroxymethyl)-4-[(methylsulfamoyl)amino]pyrrolidine-1-carboxamide tert-Butyl (2R,4R)-2-[(benzyloxy)methyl]-3,3-difluoro-4-[(methylsulfamoyl)amino]pyrrolidine-1-carboxylate (168 mg) and 20% palladium hydroxide A mixture of carbon (27.2 mg) in MeOH (5 mL) was hydrogenated under balloon pressure at room temperature for 2 hours. The mixture was diluted with EtOAc and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue was added EtOAc (5 mL) and 4M hydrogen chloride in CPME (3.0 mL) at room temperature. The mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure. To the residue, 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) were added at room temperature. The mixture was stirred under an argon atmosphere. The mixture was stirred at 60° C. overnight. The mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was concentrated on silica gel. Purification by column chromatography (EtOAc / hexanes) gave the title compound (178 mg). MS: [M+H] + 554.1.

[0300] 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]imidazole-6- {yl}-N'-methylsulfuric acid diamide (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), 1M aqueous sodium hydroxide (0.800 mL) and THF ( 1.6 mL) was added 4-methylbenzenesulfonyl chloride (56.8 mg) at -20°C. The mixture was stirred at the same temperature for 2 hours. EtOAc and saturated aqueous sodium bicarbonate solution were added to the mixture at room temperature. The aqueous layer was separated and extracted with EtOAc. The organic layers were combined and washed with water and sodium chloride. 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 (28.5 mg). 1 H 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).

[0301] Example 149 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

[0302] A) (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzo[ 2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide 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) was added TEA (7.0 mL) at room temperature. 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. Purification by chromatography (EtOAc / hexanes) gave the title compound (7.82 g). MS: [M+H] + 539.1.

[0303] 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]imidazole-6- yl}methanesulfonamide (2R,4R)-3,3-difluoro-N-[6-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (7.82 g), 1M aqueous sodium hydroxide (70 mL) and THF (140 mL). To the mixture was added 4-methylbenzenesulfonyl chloride (5.76 g) at room temperature. The mixture was stirred at room temperature for 30 minutes. 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 The residue was recrystallized (EtOAc / heptane) to give the title compound (4.37 g). 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).

[0304] Example 171 N-{(6R,7aR)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazo 7,7-difluoro-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide

[0305] A) 2-Bromo-3,4,6-trifluorobenzaldehyde 2,4,5-trifluorobenzaldehyde (25.0 g), N-bromosuccinimide (33.4 g), A mixture of 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 h. The mixture was quenched with 1M aqueous sodium hydroxide 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). 1 H NMR (400 MHz, CDCl3) δ 7.08 (1H, td, J = 9.7, 6.0 Hz), 10.27 (1H, s).

[0306] B) N-[(E)-(2-bromo-3,4,6-trifluorophenyl)methylidene]hydroxyamine 2-Bromo-3,4,6-trifluorobenzaldehyde (32.5 g), and 50% hydroxyamine A mixture of aqueous dimethylformamide (18.0 g) in EtOH (600 mL) was stirred at 80° C. for 2 h. The mixture was then cooled to 50° 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 minutes. The solid was collected by filtration to give the title compound (28.8 g). MS: [M+H] + 253.9.

[0307] C) 2-Bromo-3,4,6-trifluoro-N'-hydroxybenzene-1-carboximidamide To a mixture of N-[(E)-(2-bromo-3,4,6-trifluorophenyl)methylidene]hydroxyamine (26.8 g) in DMF (400 mL) was added N-chlorosuccinimide (15.5 g) 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. To the mixture was added 27% aqueous ammonia solution (1.78 g). The mixture was quenched with water and washed 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). MS: [M+H] + 268.9.

[0308] D) 4-Bromo-5,6-difluoro-1,2-benzoxazol-3-amine 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 The mixture was heated in a microwave reactor at 150° C. for 15 minutes under a nitrogen atmosphere. The procedure was repeated two more times to give three batches of crude material, which were combined in sequence, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (571 mg). MS: [M+H] + 248.9.

[0309] E) 5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine 4-Bromo-5,6-difluoro-1,2-benzoxazol-3-amine (500 mg), (2,4,6-trifluoro fluorophenyl)boronic acid (3.53 g), potassium fluoride (350 mg), tri-tert-butyl boronic acid A mixture of phosphonium tetrafluoroborate (117 mg) and Pd2(dba)3 (184 mg) in DME (10 mL) and water (1.00 mL) was heated to 100° C. under an argon atmosphere. The mixture was stirred at 100° C. for 2 h. To the reaction mixture were added (2,4,6-trifluorophenyl)boronic acid (1.77 g), potassium fluoride (350 mg), tri-tert-butylphosphonium tetrafluoroborate (117 mg) and Pd2(dba)3 (184 mg). The mixture was stirred at 100° C. for 16 h. The mixture was washed with water and cooled to 100° C. 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) was obtained. MS: [M+H] + 301.0.

[0310] F) 2,2,2-trichloroethyl [5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-phenyl Benzooxazol-3-yl carbamate A mixture of 5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-amine (379 mg) in THF (5 mL) was diluted with 1M lithium bis(trimethylsilyl)amide at 0 °C. A THF solution (2.78 mL) was added. The mixture was stirred at 0° C. for 30 minutes. To the reaction mixture, 2,2,2-trichloroethoxycarbonyl chloride (0.191 mL) was added. 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 and The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to afford the title compound (378 mg). MS: [M+H] + 474.9.

[0311] G) (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidone Lysine-1-carboxamide 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 at 60° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (186 mg). MS: [M+H] + 557.0.

[0312] 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 (2R,4R)-N-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol- [(3-yl)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]pyrrolidone Lysine-1-carboxamide (85.0 mg) and 4-methylbenzenesulfonyl chloride (58.2 To a mixture of 1 mg of 1M sodium hydroxide solution (0.764 mL) in THF (1 mL) was added at 0°C. The mixture was stirred for 2 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. The residue was purified by silica gel column chromatography (EtOAc / hexane), then purified by EtOAc-hexane. Crystallization from silica gel gave the title compound (25.9 mg). 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).

[0313] Example 174 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

[0314] A) 2-Hydroxy-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile 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 The mixture was stirred at 130° C. for 3 hours. 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). MS: [M+H] + 265.1.

[0315] B) 2-chloro-6-methyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile 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 hours. The reaction mixture Cool to room temperature, then add it dropwise to water with stirring, then add it to EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (3.85 g). MS: [M+H] + 283.1.

[0316] C) 6-Methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridine-3-amine hmm A solution of 2-propanone oxime (597 mg) in THF (20 mL) was added with potassium tert-butoxide at 25°C. C. The mixture was stirred at 25.degree. C. for 1 h. 2-Chloro-6-methyl-2-phenylpropanediol (10 mL) was added. Cetyl-4-(2,4,6-trifluorophenyl)pyridine-3-carbonitrile (2.10 g) was added to the mixture at 0° C. The reaction mixture was stirred at 25° C. for 14 h. Water was added to the mixture, which was then 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 hydrogen chloride solution (10 mL). The mixture was stirred at 70° C. under nitrogen atmosphere for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and concentrated in water. The mixture was dried over aqueous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.20 g). MS: [M+H] + 280.1.

[0317] D) 2,2,2-trichloroethyl [6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazo 4,5-di[5,4-b]pyridin-3-yl]carbamate 6-Methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-amine A solution of (1.28 g) in THF (20 mL) was added to 1M lithium bis(trimethylsilyl)amide (THF) at 0°C. Solution (10.1 mL) was added and the reaction mixture was stirred at 0° C. under 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 nitrogen atmosphere for 1 h. The mixture was quenched with saturated aqueous ammonium chloride solution at 0° C. It was then extracted with EtOAc. The combined organic layers were washed with brine and anhydrous sodium sulfate. The mixture was dried over ice and then concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.10 g). MS: [M+H] + 454.0.

[0318] E) (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]pyrrolidine-1-carboxamide 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) The solution was added with 2,2,2-trichloroethyl [6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxy Xazolo[5,4-b]pyridin-3-yl]carbamate (500 mg) was added and the reaction mixture was stirred at 60° C. for 3 hours under nitrogen atmosphere. The reaction mixture was quenched with water, and then it was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give 1H2O, 2H3O, and 2H4O. Purification gave the title compound (310 mg). MS: [M+H] + 536.1.

[0319] 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]i Midazol-6-yl}methanesulfonamide (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl)amino]-N-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxazolo[5,4-b]pyridin-3-yl]pyrrolid A solution of lysine-1-carboxamide (310 mg) in MeCN (5 mL) and water (5 mL) was added with iodosobenzene diacetate (224 mg), tetrabutylammonium bromide (47 mg), 2,2,6,6 -Tetramethylpiperidine 1-oxyl (23 mg) and sodium bicarbonate (268 mg) were added. 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 obtain the title compound (191 mg). MS: [M+H] + 534.1.

[0320] G) N-{(6R)-7,7-difluoro-2-[6-methyl-4-(2,4,6-trifluorophenyl)[1,2]oxa 3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide 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), methyl N-(trifluorophenyl) Ethylammoniumsulfonyl)carbamate (594 mg) was added, 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: ammonia hydroxide-containing water / MeCN) to give the title compound (78.5 mg) was obtained. 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).

[0321] Example 213 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}methanesulfonyl Mid

[0322] A) tert-Butyl (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-[(methanesulfonyl) To a mixture of 1-(amino)pyrrolidine-1-carboxylate (5.00 g), 1-(chloromethyl)-4-methoxybenzene (5.13 mL), and DMF (101 mL), potassium carbonate (10.5 g) was added at room temperature. The mixture was stirred at 60° C. overnight under argon atmosphere. EtOAc and water 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, and concentrated. The mixture was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (3.85 g). MS: [M+H-Boc] + 351.1.

[0323] B) tert-Butyl (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate A mixture of tert-butyl (2R,4R)-3,3-difluoro-2-(hydroxymethyl)-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate (2.77 g), N,N-diisopropylethylamine (2.15 mL), and MeCN (12 mL) was added to methanesulfonate at 0° C. Sulfonic anhydride (1.61 g) was added and the mixture was stirred at 0° C. for 0.5 hours. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through a pad of NH silica gel eluting with EtOAc, and concentrated under reduced pressure to give the title compound. (3.11 g) was obtained. MS: [M+Na] + 551.2.

[0324] C) tert-Butyl (2R,4R)-2-(cyanomethyl)-3,3-difluoro-4-{(methanesulfonyl)[(4- Methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl) A mixture of 2-{[(methyl)amino}-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (2.94 g), sodium cyanide (1.78 g), and dimethyl sulfoxide (36 mL) The mixture was stirred at 45-50° C. for 4.5 h. The mixture was diluted with EtOAc and aqueous ammonium chloride solution with 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). MS: [M+Na] + 482.2.

[0325] D) Methyl [(2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}pyrrolidin-2-yl]acetate hydrochloride tert-Butyl (2R,4R)-2-(cyanomethyl)-3,3-difluoro-4-{(methanesulfonyl)[(4- To a mixture of methoxyphenyl)methyl]amino}pyrrolidine-1-carboxylate (1.99 g) and MeOH (60 mL), trimethylsilyl chloride (16.6 mL) was added at room temperature, and the mixture was refluxed for 2.5 hours. After the addition of trimethylsilyl chloride (8.30 mL), the mixture was refluxed for 1.5 hours. After the addition of further 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 h. The precipitate was collected, washed with IPE, and dried under vacuum to give the title compound (1.75 g). MS: [M+H] + 393.1.

[0326] E) tert-Butyl (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate Methyl [(2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl)methyl 1.64 g), sodium bicarbonate (0.964 To a cooled mixture of 1.2g of ethyl acetate, THF (30 mL), and water (10 mL) was added di-tert-butyl dicarbonate (1.15 mL) at 0° C., and the mixture was stirred at room temperature overnight. To the mixture was added EtOAc and water with stirring. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated with silica gel. The mixture was filtered through a pad of ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (1.75 g). MS: [M+Na] + 512.2.

[0327] F) tert-Butyl (2R,4R)-3,3-difluoro-4-[(methanesulfonyl)amino]-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-3,3-difluoro-4-{(methanesulfonyl)[(4-methoxyphenyl) To a cooled mixture of 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.71 g), MeCN (36 mL), and pH 6.8 phosphate buffer (24 mL) was added dichloromethane. Ce(IV) ammonium (6.28 g) was added and the mixture was stirred at 0° C. for 10 min and then at room temperature for 0.5 h. The mixture was diluted with EtOAc and diluted with 10% sodium thiosulfate at 0° C. until the yellow color of the reaction disappeared. The organic layer was washed with saline, dried over anhydrous sodium sulfate, filtered through a NH silica gel pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane). Purification gave the title compound (1.20 g). 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).

[0328] G) tert-Butyl (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl) (amino)pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-3,3-difluoro-4-[(methanesulfonyl)amino]-2-(2-methoxy- To a mixture of 2-oxoethyl)pyrrolidine-1-carboxylate (1.16 g) and THF (20 mL) At room temperature, 4M lithium borohydride in THF (3.89 mL) was added, and the mixture was heated at 45-50° C. for 4.5 hours. The mixture was then stirred at room temperature for 16 hours. The reaction was stirred at 0° C. for 20 minutes. The mixture was then diluted with EtOAc and aqueous ammonium chloride, and then stirred at room temperature for 20 minutes. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered through a pad of silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.966 g). 1H 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).

[0329] H) N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]methanesulfur Fonamide hydrochloride A mixture of tert-butyl (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxylate (32.7 mg) and 2 M hydrogen chloride solution in MeOH (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). obtained. 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).

[0330] I) (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide Voxamide 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) was added TEA (0.252 mL) at room temperature. 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). MS: [M+H] + 535.2.

[0331] J) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzyl] benzoxazol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}methanesulfonate Amido To a mixture of (2R,4R)-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)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), Methanesulfonic anhydride (187 mg) was added at room temperature, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. The mixture was then diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by column chromatography (EtOAc / hexanes). The solid was crystallized from EtOAc-heptane to give the title compound (198 mg). 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).

[0332] Example 242 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}cyclopropane Sulfonamide

[0333] A) tert-Butyl (2R,4R)-4-amino-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-amino-2-[(benzyloxy)methyl]-3,3-difluoropyrrolidine-1-carboxylate (10.2 g) and 10% palladium hydroxide on carbon (500 mg) in EtOH (200 The mixture in 1 mL of ethyl acetate was hydrogenated under balloon pressure at room temperature for 16 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (7.49 g). MS: [M+H-Boc] + 153.1.

[0334] B) tert-Butyl (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-amino-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1- Carboxylate (7.52 g), 1H-imidazole (6.08 g), and tert-butyldimethylsilyl A mixture of aryl chloride (4.94 g) in DMF (50 mL) was stirred at room temperature for 40 min under an argon atmosphere. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The layers were 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). MS: [M+H-Boc] + 267.2.

[0335] C) tert-Butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(cyclohexyl) (propyl)amino)-3,3-difluoropyrrolidine-1-carboxylate A solution of tert-butyl (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,3-difluoropyrrolidine-1-carboxylate (4.10 g) and TEA (9.34 mL) in anhydrous THF (50 mL) was added with cyclopropanesulfonyl chloride (7.86 g) and 4-dimethylsilyloxymethyl at 20°C. Aminopyridine (1.37 g) was added and the mixture was stirred under a nitrogen atmosphere at 70° C. for 14 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated and washed with water and sodium chloride. The mixture was washed with water, 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). 1H 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).

[0336] D) tert-Butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(cyclohexyl) {(4-methoxyphenyl)methyl)amino}-3,3-difluoropyrrolidine 1-carboxylate tert-Butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate (4.15 g) A solution of 4-methoxybenzyl chloride (3.45 g) in anhydrous DMF (60 mL) was added to carbonate at 20°C. Lithium (6.09 g) was added and the mixture was stirred at 60° C. under nitrogen atmosphere for 7 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was separated and washed with water and brine. The mixture was 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). MS: [M+H-Boc] + 491.2.

[0337] E) tert-Butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate A solution of tert-butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate (4.80 g) in anhydrous THF (50 mL) was added to 1M tetrabutyl fluoride at 20 °C. A solution of ammonium in THF (12.2 mL) was added, and the mixture was stirred under a nitrogen atmosphere at 20° C. for 1 hour. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were separated and washed with water and The mixture was washed with sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (4.10 g). MS: [M+Na] + 499.3.

[0338] F) tert-Butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl] To a mixture of {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 evaporated. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether). Purification gave the title compound (4.18 g). MS: [M+Na] + 577.1.

[0339] G) tert-Butyl (2R,4R)-2-(cyanomethyl)-4-{(cyclopropanesulfonyl)[(4-methoxy (phenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl] A mixture of {amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (4.18 g) and dimethyl sulfoxide (50 mL) was added with sodium cyanide. C. (1.58 g) was added and the mixture was stirred at 50.degree. C. for 4 h under nitrogen atmosphere. The mixture was diluted with EtOAc and water with stirring. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (2.75 g). MS: [M+H-Boc] + 386.2.

[0340] H) Methyl [(2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidin-2-yl]acetate hydrochloride To a mixture of tert-butyl (2R,4R)-2-(cyanomethyl)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate (2.75 g) and MeOH (40 mL), trimethylsilyl chloride (9.23 g) was added at 25°C, and the mixture was stirred at 65°C under nitrogen atmosphere for 14 hours. Trimethylsilyl chloride (4.62 g) was added, and the mixture was stirred at 65°C under nitrogen atmosphere for 1 hour. Trimethylsilyl chloride (4.62 g) was added. The mixture was stirred at 65° C. for 1 hour under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give the title compound. The compound (2.70 g) was obtained. MS: [M+H]+ 419.0.

[0341] I) tert-Butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate to Methyl [(2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl]amine 3,3-difluoropyrrolidin-2-yl]acetate hydrochloride (2.70 g), THF (30 mL) and To a mixture of water (15 mL) and di-tert-butyl dicarbonate (2.47 g) and sodium hydrogen carbonate (2.38 g) were added at 25° C., and the mixture was stirred at 25° C. for 1 hour under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine and anhydrous sodium sulfate. The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (2.65 g). MS: [M+Na] + 541.1.

[0342] J) tert-Butyl (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-{(cyclopropanesulfonyl)[(4-methoxyphenyl)methyl] Amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate A mixture of 2.65 g of nitric acid, MeCN (50 mL) and pH 6.8 phosphate buffer (30 mL) was added to nitric acid at 0°C. Diammonium cerium(IV) (8.40 g) was added and the mixture was stirred at 20° C. for 2 hours under nitrogen atmosphere. The mixture was diluted with EtOAc, and 10% aqueous sodium thiosulfate was added until the yellow color of the reaction disappeared, and then saturated aqueous sodium bicarbonate was added with stirring to neutralize. The mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (1.75 g). MS: [M+H-Boc] + 298.9.

[0343] K) tert-Butyl (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate 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) To the mixture was added dropwise 2 M lithium borohydride in THF (13.2 mL) at 20° C. The mixture was stirred at 60° C. for 2 h. The mixture was slowly quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.60 g). MS: [M+H-Boc] + 270.9.

[0344] L) N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]cyclopropane Pansulfonamide hydrochloride tert-Butyl (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2- A solution of hydroxyethyl)pyrrolidine-1-carboxylate (1.60 g) in hydrogen chloride EtOAc (25 mL) was stirred at 20° C. for 1 hour. The mixture was filtered and the filter cake was dried under reduced pressure to give The title compound (1.15 g) was obtained. 1 H 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).

[0345] M) (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)-N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide 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) was added 2,2,2-trichloroethyl[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (107 mg) at 0° C. The mixture was stirred at 60° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was poured into water, which was extracted with EtOAc. The combined organic layers were washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by preparative TLC (silica gel, EtOAc / petroleum ether) to give the title compound (45 mg). MS: [M+H] + 561.0.

[0346] N) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzyl] cyclopropanediol-3-yl]octahydropyrrolo[1,2-c]pyrimidin-6-yl}cyclopropane Sulfonamides (2R,4R)-4-[(cyclopropanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl) To a mixture of N-[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]pyrrolidine-1-carboxamide (45.0 mg) and MeCN (2 mL) was added TEA (65.0 mg) and methanesulfonic anhydride (42.0 mg) at 0° C. The mixture was stirred at 25° C. for 10 hours. The reaction mixture was poured into water, which was extracted with EtOAc. The combined organic layer was washed with brine and diluted with anhydrous sodium sulfate. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: ammonia hydroxide-containing water / MeCN) and then lyophilized to give the title compound (7.2 mg). 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 signals), 7.60-7.67 (2H, m).

[0347] Example 243 N-{(4aR,6R)-2-[5,6-difluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazo pyrrolo[1,2-c]pyrimidin-6-yl]-5,5-difluoro-1-oxooctahydropyrrolo[1,2-c]pyrimidin-6-yl} Methanesulfonamide

[0348] 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]pi Roridin-1-carboxamide 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), TEA (0.059 mL) was added 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. Purification by column chromatography (EtOAc / hexanes) afforded the title compound (66 mg). MS: [M+H] + 571.2.

[0349] 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 (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]pi To a mixture of loridine-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, and then the mixture was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The solid was crystallized from EtOAc-heptane to give the title compound (53.0 mg). 1 H 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).

[0350] Example 260 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}ethanesulfonate Mid

[0351] A) tert-Butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(ethoxy)methyl] (phenylsulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3 ,3-Difluoropyrrolidine-1-carboxylate (8.90 g) and TEA (7.37 g) To the methane (100 mL) solution was added ethanesulfonyl chloride (4.68 g) at 0° C., and the reaction mixture was stirred at 20° C. for 1 hour. The mixture was diluted with water, and it was 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). 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).

[0352] B) tert-Butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(ethoxymethyl) (4-Methoxyphenyl)methyl)amino}-3,3-difluoropyrrolidine-1-carboxylate A mixture of tert-butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[(ethanesulfonyl)amino]-3,3-difluoropyrrolidine-1-carboxylate (10.7 g) and 1-(chloromethyl)-4-methoxybenzene (9.11 g) in DMF (150 mL) was added to potassium carbonate. The mixture was stirred at 60° C. for 7 hours. The reaction mixture was quenched with water at 0° C. It was then extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was Purification by column chromatography (EtOAc / petroleum ether) gave the title compound (10.8 g). 1 H 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).

[0353] C) tert-Butyl (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate A solution of tert-butyl (2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidine-1-carboxylate (10.8 g) in THF (200 mL) was added to 1 M tetrabutylammonium fluoride at 20 °C. A THF solution (28.0 mL) was added and the mixture was stirred under nitrogen atmosphere at 20° C. for 16 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was separated and washed with water and brine. The mixture was washed, 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). 1 H 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).

[0354] D) tert-Butyl (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (400 mg) and TEA To a mixture of (349 mg) in dichloromethane (10 mL) was added methanesulfonic anhydride (300 mg) at 25° C. and the mixture was stirred at 25° C. for 1 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 to give the title compound (480 mg). MS: [M+Na] + 565.2.

[0355] E) tert-Butyl (2R,4R)-2-(cyanomethyl)-4-{(ethanesulfonyl)[(4-methoxyphenyl (methyl)amino)-3,3-difluoropyrrolidine-1-carboxylate tert-Butyl (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3 To a mixture of 3-difluoro-2-{[(methanesulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (8.42 g) and dimethylsulfoxide (120 mL), sodium cyanide (3.19 g) was added, and the mixture was stirred at 50° C. for 2 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc and The mixture was diluted with water, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether). To obtain the title compound (5.18 g). MS: [M+Na] + 496.2.

[0356] F) Methyl [(2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoropyrrolidin-2-yl]acetate hydrochloride To a mixture of tert-butyl (2R,4R)-2-(cyanomethyl)-4-{(ethanesulfonyl)[(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 heated under nitrogen The mixture was stirred at 65° C. under atmospheric pressure for 14 hours. The mixture was concentrated under reduced pressure to give the title compound (4.84 g). Got it. MS: [M+H] + 407.1.

[0357] G) tert-Butyl (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate Methyl [(2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3- To a mixture of difluoropyrrolidin-2-yl]acetate hydrochloride (4.84 g), THF (80 mL) and water (40 mL) was added di-tert-butyl dicarbonate (4.77 g) and sodium bicarbonate (4.59 g) at 20° C., and the mixture was stirred at 20° C. for 1 hour under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether). Purification by ethyl acetate gave the title compound (4.53 g). 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).

[0358] H) tert-Butyl (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate A mixture of tert-butyl (2R,4R)-4-{(ethanesulfonyl)[(4-methoxyphenyl)methyl]amino}-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (180 mg), MeCN (8 mL) and pH 6.8 phosphate buffer (4 mL) was added with diammonium nitrate at 0 °C. Cerium(IV) (545 mg) was added and the mixture was stirred at 25° C. for 1 h under nitrogen atmosphere. Diammonium cerium(IV) nitrate (545 mg) was added and the mixture was stirred at 25° C. for 1 h. The mixture was diluted with EtOAc, 10% aqueous sodium thiosulfate was added until the yellow color of the reaction disappeared, and saturated aqueous sodium bicarbonate was added with stirring to neutralize. 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). MS: [M+H-Boc] + 286.9.

[0359] I) tert-Butyl (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate To a mixture of tert-butyl (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (162 mg) and THF (5 mL), At 25° C., 4M lithium borohydride in THF (0.53 mL) was added dropwise. The mixture was stirred at 60° C. for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution, which was then extracted with EtOAc. The combined organic layers were separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Concentration gave the title compound (146 mg). MS: [M+H-Boc] + 258.9.

[0360] J) N-[(3R,5R)-4,4-difluoro-5-(2-hydroxyethyl)pyrrolidin-3-yl]ethanesulfonyl Fonamide hydrochloride tert-Butyl (2R,4R)-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(2-hydroxy To a mixture of diethyl)pyrrolidine-1-carboxylate (146 mg) and EtOAc (2 mL) was added 4M hydrogen chloride in dioxane (2 mL) at 25° C. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure and co-evaporated with EtOAc to give the title compound (120 mg). 1 H 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 signals), 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).

[0361] 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 Voxamide 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) was added 2,2,2-trichloroethyl[4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]carbamate (45 mg) at 0° C. The mixture was stirred at 60° C. for 14 hours under nitrogen atmosphere. The reaction mixture was poured into water, which was extracted with EtOAc. The combined organic layer was washed with brine and diluted with anhydrous sodium sulfate. The mixture was dried over silica gel and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (22 mg). MS: [M+H] + 549.1.

[0362] L) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzyl] 1,2-C-Pyrrolo[1,2-C]pyrimidin-6-yl}ethanesulfonate Amido 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) was added with TEA (16 mg) and methanesulfonyl chloride at 0 °C. To the mixture was added carboxylic anhydride (21 mg). The mixture was stirred at 25° C. for 14 hours. The reaction mixture was poured into water, which was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: ammonia hydroxide-containing water / MeCN) and then lyophilized to give the title compound (6.2 mg). 1 H 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).

[0363] Example 265 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}ethanesulfonate Mid

[0364] A) 2,2,2-trichloroethyl [4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazole Sazolyl-3-yl]carbamate 1M Lithium bis(trimethylsilyl)amide in hexane (37.9 mL) was added to 4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-amine (4.00 g) in THF (40 The mixture was stirred at 0°C for 0.5 hours under nitrogen atmosphere. Ethoxycarbonyl chloride (4.81 g) was added. The mixture was stirred at 0° C. for 1 hour under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with anhydrous sodium sulfate. The mixture was dried at 40° C. and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (4.5 g). 1 H 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).

[0365] B) (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazole-3-yl [3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide 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) Then, TEA (288 mg) was added, and the mixture was stirred at 60° C. for 14 hours under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine and diluted with anhydrous sodium sulfate. The mixture was dried over sodium and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound (551 mg). MS: [M+H] + 534.9.

[0366] C) N-{(4aR,6R)-5,5-difluoro-1-oxo-2-[4-(2,4,6-trifluorophenyl)-1,2-benzyl] 1,2-C-Pyrrolo[1,2-C]pyrimidin-6-yl}ethanesulfonate Amido A mixture of (2R,4R)-N-[4-(2,6-difluorophenyl)-5-fluoro-1,2-benzoxazol-3-yl]-3,3-difluoro-2-(2-hydroxyethyl)-4-[(methanesulfonyl)amino]pyrrolidine-1-carboxamide (80 mg) and MeCN (3 mL) was added with TEA (121 mg) and methyl Then, sulfonyl methanesulfonate (71 mg) was added. The mixture was stirred at 28° C. for 2 hours. The reaction mixture was poured into water, which was extracted with EtOAc. The combined organic layers were washed with brine and diluted with anhydrous The residue was purified by preparative HPLC (column: Boston Prime C18, mobile phase: ammonia hydroxide-containing water / MeCN) and then lyophilized to give the title compound. (48 mg) was obtained. 1 H 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).

[0367] Example 282 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

[0368] A) (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazole-3-yl [(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxamide 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) TEA (112 mg) was added, and the mixture was then stirred at 60° C. for 14 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was 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 target compound. The title compound (234 mg) was obtained. MS: [M+H] + 535.0.

[0369] B) N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazole-3-yl [1,2-c]-7,7-difluoro-1-hydroxy-3-oxohexahydro-1H-pyrrolo[1,2-c]imidazo[3,4-difluoro ... {6-yl}ethanesulfonamide (2R,4R)-N-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazol-3-yl]-4-[(ethanesulfonyl)amino]-3,3-difluoro-2-(hydroxymethyl)pyrrolidine-1- A mixture of carboxamide (234 mg) and sodium bicarbonate (184 mg) in MeCN (4 mL) and water (2 mL) was stirred at 0° C. Then, the mixture was added iodosobenzene diacetate (170 mg), tetra-N-butylammonium bromide (28 mg) and 2,2,6,6-tetramethylammonium bromide (28 mg) at 0° C. Methylpiperidine 1-oxyl (14 mg) was added. The mixture was stirred at 0° C. for 15 minutes. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether). Purification by ethyl acetate gave the title compound (197 mg). MS: [M+H] + 533.0.

[0370] C) N-{(6R)-2-[4-(2,6-difluorophenyl)-6-fluoro-1,2-benzoxazole-3-yl 7,7-difluoro-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}ethanesulfonamide 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) and THF (8 mL) was added methyl N-(triethylammoniumsulfonyl)carbamate (542 mg). The mixture was stirred at 50° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with anhydrous sodium sulfate. The residue was purified by preparative HPLC (column: Welch Xtimate C18, mobile phase: The product was purified using ammonium hydroxide / MeCN) followed by lyophilization to give the title compound (132 mg). Got it. 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).

[0371] The example compounds are shown in the following table. MS in the table indicates the measured value. According to the method shown in the above example or a method similar thereto, 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 prepared.

[0372] [Table 1-1]

[0373] [Table 1-2]

[0374] [Table 1-3]

[0375] [Table 1-4]

[0376] [Table 1-5]

[0377] [Table 1-6]

[0378] [Table 1-7]

[0379] [Table 1-8]

[0380]

Table 1-9

[0381]

Table 1-10

[0382]

Table 1-11

[0383]

Table 1-12

[0384]

Table 1-13

[0385]

Table 1-14

[0386]

Table 1-15

[0387]

Table 1-16

[0388]

Table 1-17

[0389]

Table 1-18

[0390]

Table 1-19

[0391]

Table 1-20

[0392]

Table 1-21

[0393]

Table 1-22

[0394]

Table 1-23

[0395]

Table 1-24

[0396]

Table 1-25

[0397]

Table 1-26

[0398]

Table 1-27

[0399]

Table 1-28

[0400]

Table 1-29

[0401]

Table 1-30

[0402]

Table 1-31

[0403]

Table 1-32

[0404]

Table 1-33

[0405]

Table 1-34

[0406]

Table 1-35

[0407]

Table 1-36

[0408]

Table 1-37

[0409]

Table 1-38

[0410]

Table 1-39

[0411]

Table 1-40

[0412]

Table 1-41

[0413]

Table 1-42

[0414]

Table 1-43

[0415]

Table 1-44

[0416]

Table 1-45

[0417]

Table 1-46

[0418]

Table 1-47

[0419]

Table 1-48

[0420] [Table 1-49]

[0421] [Table 1-50]

[0422] Test Example 1: Acquisition of human orexin type 2 receptor (hOX2R) stably expressing cells To obtain cell clones stably expressing human orexin type 2 receptor, human orexin type 2 (residues 1-444, NCBI reference sequence: AK314279) was constructed in the pcDNA3.1(+) vector (Invitrogen) and expressed in mammalian cells. This plasmid DNA was transfected into CHO-K1 cells by electroporation, and stable clones were obtained by limiting dilution using G418 resistance as a selection marker.

[0423] Test Example 2: Measurement of orexin type 2 receptor agonist activity CHO cells expressing human OX2 receptor were seeded at 10,000 cells / well in a 384-well black clear-bottom plate (BD Falcon) and incubated at room temperature for 30 min, followed by incubation at 37°C and 5% CO2 for 1 day. After removing the cell plate medium, 30 μL / well of assay buffer containing calcium indicator A (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4AM (Dojindo Chemical), 0.08% Pluronic F127 (Dojindo Chemical), 1.25 mM probenecid (Dojindo Chemical)) was added. The plates were incubated at 37°C for 30 min in a 5% CO2 incubator, followed by another 30 min at room temperatur...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, X １ is N.R. ８ , or C.R. ９ and X ２ , O, NR １０ or S; X ３ and X ４ are both C or X ３ and X ４ one of which is N and the other is C; X ５ is CR １１ or N; X ６ is CR １２ and 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 group, optionally substituted C ３－１０ Cycloalkyl group or optionally substituted mono- or di-C １－６ an alkylamino group; R ２ and R ３ each independently represents a hydrogen atom or an optionally substituted C １－６ is an alkyl group, or When r is 0, R ２ and R ３ may join together to form a bond, or X １０ is CR １５ When R ３ is R １５ together with may form a bond; R ４ is a hydrogen atom, an optionally substituted C １－６ Alkyl group, optionally substituted C １－６ an alkoxy group, or a hydroxy group; R ５ is an optionally substituted 4-, 5- or 6-membered monocyclic group; R ６ and R ７ each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C １－６ is an 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 represents a hydrogen atom or an optionally substituted C １－６ An alkyl group, a halogen atom, an optionally substituted C ３－６ a cycloalkyl group, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C １－６ an alkoxy group, or a hydroxy group; R ８ and R １０ are each independently absent, a hydrogen atom, or an optionally substituted C １－６ alkyl groups; and R １４ is a hydrogen atom, a halogen atom, or an optionally substituted C １－６ is an alkyl group; R １５ is a hydrogen atom, a halogen atom, or an optionally substituted C １－６ Alkyl group Yes or no R １５ is R ３ may form a bond; A compound represented by the formula:

2. m is 0; q is 1; and r is 0; 2. The compound according to claim 1, or a salt thereof.

3. m is 1; q is 1; and r is 0; 2. The compound according to claim 1, or a salt thereof.

4. m is 0; q is 1; and r is 1; 2. The compound according to claim 1, or a salt thereof.

5. m is 0; q is 2; and r is 0; 2. The compound according to claim 1, or a salt thereof.

6. X １ But, N.R. ８ (In the formula, R ８ does not exist; X ２ is O; X ３ and X ４ are both C; X ５ But, CR １１ or N (wherein R １１ is a hydrogen atom; X ６ But, CR １２ (In the formula, R １２ is a hydrogen atom, C １－６ an alkyl group, or a halogen atom; and X ７ But, CR １３ (In the formula, R １３ is a hydrogen atom or a halogen atom; or a salt thereof.

7. X ８ is N; X ９ But, CR ２ (In the formula, R ２ is a hydrogen atom, or when r is 0, R ２ is R ３ may form a bond; and X １０ is N; 2. The compound according to claim 1, or a salt thereof.

8. R １ but, (1)(i) a halogen atom, (ii) C １－６ alkoxy groups, and (iii) C ３－６ Cycloalkyl group C optionally substituted by 1 to 3 substituents independently selected from １－６ Alkyl groups, (2) C ３－１０ a cycloalkyl group, or (3) Mono- or di-C １－６ Alkylamino group and R ２ and R ３ are each independently a hydrogen atom or C １－６ is an alkyl group, or When r is 0, R ２ and R ３ may be taken together to form a bond, or X １０ is CR １５ When R ３ But, R １５ together to form a bond; R ４ is a hydrogen atom, C １－６ Alkyl group, C １－６ an alkoxy group, or a hydroxy group; R ５ is phenyl, pyrazolyl, furyl, thienyl, thiazolyl, pyridyl, piperidyl, or cyclobutyl, any of which is １－６ Alkyl group, halogen atom, halo(C １－６ ) alkyl group, and C １－６ One or more independently selected alkoxy groups may be substituted with the above substituents; R ６ and R ７ are each independently a hydrogen atom, a halogen atom, or C １－６ is an alkyl group; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ but the following: (i) X １ is NR ８ And R ８ does not exist, and X ２ is O; X ３ and X ４ Both are C and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is; (ii) X １ is NR ８ And R ８ does not exist, and X ２ is O and X ３ and X ４ Both are C Yes, X ５ is N and X ６ is CR １２ And X ７ is CR １３ is; (iii) X １ is NR ８ And R ８ does not exist, and X ２ is O and X ３ and X ４ Both are C, and X ５ is CR １１ And X ６ is CR １２ And X ７ is N; (iv) X １ is NR ８ And R ８ does not exist, and X ２ is S and X ３ and X ４ Both are C Yes, X ５ is N and X ６ is CR １２ And X ７ is CR １３ is; (v) X １ is NR ８ And R ８ does not exist, and X ２ is S; X ３ and X ４ Both are C, and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is; (vi) X １ is NR ８ And X ２ is NR １０ and R ８ and R １０ If one of the two exists, ZR ８ and R １０ The other is C １－６ is an alkyl group, and X ３ and X ４ Both are C and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is; (vii) X １ is CR ９ And X ２ is NR １０ And R １０ does not exist, and X ３ is N and X ４ is C and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ and (viii) X １ is CR ９ And X ２ is NR １０ And R １０ does not exist, and X ３ is C , X ４ is N and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is is selected to form a ring system which is one of: X ８ , X ９ , X １０ , m, q, and r are as follows: (i) X ８ is N and X ９ is CR ２ And X １０ is N, m is 0, q is 1, and r is 0; (ii) X ８ is N and X ９ is CR ２ And X １０ is N, m is 1, and q is 1 and r is 0; (iii) X ８ is N and X ９ is CR ２ And X １０ is N, m is 0, q is 1, and r is 1; (iv) X ８ is N and X ９ is N and X １０ is CR １５ m is 0 and q is 1 and r is 0; (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 (vi) X ８ is N and X ９ is CR ２ And X １０ is N, m is 0, and q is 2 and r is 0 is selected to form a ring system which is one of: R ９ , R １１ , R １２ , and R １３ each independently represents a hydrogen atom, C １－６ Alkyl group, halogen atom, C ３－６ Cycloalkyl group, C ３－６ Cycloalkyl (C １－６ ) alkoxy group, halo(C １－６ ) alkyl group, halo(C １－６ ) an alkoxy group, C １－６ Alkoxy (C １－６ ) an alkyl group, an azetidinyl group, C １－６ Alkoxy groups, hydroxy groups, and hydroxy(C １－６ ) alkyl groups; and R １４ is a hydrogen atom, a halogen atom, or C １－６ is an alkyl group; and R １５ But, R ３ together to form a bond; 2. The compound according to claim 1, or a salt thereof.

9. The following formula: 【Chemistry 2】 (The symbols in the formula have the same meanings as in claim 1.) The partial structure represented by the following formula: 【Chemistry 3】 (The symbols in the formula have the same meanings as in claim 1.) One of the partial structures represented by The compound of claim 1.

10. The compound has the formula (Ia): 【Chemistry 4】 [In the formula, R １ is C １－６ Alkyl group, C ３－１０ Cycloalkyl group, or mono-C １－６ an alkylamino group; r is 0 or 1; R ２ and R ３ are each independently a hydrogen atom, or When r is 0, R ２ and R ３ may combine with each other to form a bond; R ４ is a hydrogen atom; R ５ is a phenyl group optionally substituted by 1 to 3 halogen atoms; R ６ and R ７ are each independently a hydrogen atom or a halogen atom; X ５ is CH or N; and R １２ and R １３ are each independently a hydrogen atom, C １－６ an alkyl group, or a halogen atom; The compound according to claim 1 , or a salt thereof,

11. R １ But, C １－６ is an alkyl group; r is 0 or 1; R ２ and R ３ are each a hydrogen atom, or When r is 0, R ２ and R ３ may combine with each other 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 are each a halogen atom; X ５ is CH; and R １２ and R １３ are each independently a hydrogen atom or a halogen atom; 11. The compound according to claim 10, or a salt thereof.

12. The compound has the formula (Ib): 【Chemistry 5】 [In the formula, R １ is an optionally substituted C １－６ Alkyl group, optionally substituted C ３－１０ Cycloalkyl group or optionally substituted mono- or di-C １－６ an alkylamino group; R ２ and R ３ each independently represents a hydrogen atom or an optionally substituted C １－６ is an alkyl group, or R ２ and R ３ come together to form a bond; R ４ is a hydrogen atom, an optionally substituted C １－６ Alkyl group, optionally substituted C １－６ an alkoxy group, or a hydroxy group; R ５ is an optionally substituted 5- or 6-membered monocyclic group; R ６ and R ７ each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C １－６ is an alkyl group; m is 0 or 1; q is 1 or 2; X １ is N.R. ８ , or C.R. ９ and X ２ , O, NR １０ or S; X ３ and X ４ are both C or X ３ and X ４ one of which is N and the other is C; X ５ is CR １１ or N; X ６ is CR １２ and X ７ is CR １３ or N; R ９ , R １１ , R １２ , and R １３ each independently represents a hydrogen atom or an optionally substituted C １－６ Alkyl group, halogen atom, optionally substituted C ３－６ a cycloalkyl group, an optionally substituted 3- to 7-membered nitrogen-containing heterocyclic group, an optionally substituted C １－６ an alkoxy group, or a hydroxy group; and R ８ and R １０ are each independently absent, a hydrogen atom, or an optionally substituted C １－６ alkyl groups; The compound according to claim 1 , or a salt thereof,

13. R １ but, (1)(i) a halogen atom, (ii) C １－６ alkoxy groups, and (iii) C ３－６ Cycloalkyl group C optionally substituted by 1 to 3 substituents independently selected from １－６ Alkyl groups, (2) C ３－１０ a cycloalkyl group, or (3) Mono- or di-C １－６ Alkylamino group and R ２ and R ３ are each independently a hydrogen atom or C １－６ is an alkyl group or R ２ and R ３ come together to form a bond; R ４ is a hydrogen atom, C １－６ Alkyl group, C １－６ an alkoxy group, or a hydroxy group; R ５ is phenyl, pyrazolyl, furyl, thienyl or thiazolyl, any of which is １－６ Alkyl group, halogen atom, halo(C １－６ ) alkyl group, and C １－６ may be substituted with one or more substituents independently selected from alkoxy groups; m is 0 or 1; q is 1 or 2; R ６ and R ７ are each independently a hydrogen atom, a halogen atom, or C １－６ is an alkyl group; X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ but the following: (i) X １ is NR ８ And R ８ does not exist, and X ２ is O; X ３ and X ４ Both are C, and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is; (ii) X １ is NR ８ And R ８ does not exist, and X ２ is O and X ３ and X ４ Both are C Yes, X ５ is N and X ６ is CR １２ And X ７ is CR １３ is; (iii) X １ is NR ８ And R ８ does not exist, and X ２ is O and X ３ and X ４ Both are C, and X ５ is CR １１ And X ６ is CR １２ And X ７ is N; (iv) X １ is NR ８ And R ８ does not exist, and X ２ is S and X ３ and X ４ Both are C Yes, X ５ is N and X ６ is CR １２ And X ７ is CR １３ is; (v) X １ is NR ８ And R ８ does not exist, and X ２ is S; X ３ and X ４ Both are C, and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is; (vi) X １ is NR ８ And X ２ is NR １０ and R ８ and R １０ If one of the two exists, ZR ８ and R １０ The other is C １－６ is an alkyl group, and X ３ and X ４ Both are C and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is; (vii) X １ is CR ９ And X ２ is NR １０ And R １０ does not exist, and X ３ is N and X ４ is C and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ and (viii) X １ is CR ９ And X ２ is NR １０ And R １０ does not exist, and X ３ is C , X ４ is N and X ５ is CR １１ And X ６ is CR １２ And X ７ is CR １３ is and R ９ , R １１ , R １２ , and R １３ each independently represents a hydrogen atom, C １－６ Alkyl group, halogen atom, C ３－６ Cycloalkyl group, C ３－６ Cycloalkyl (C １－６ ) alkoxy group, halo(C １－６ ) alkyl group, halo(C １－６ ) an alkoxy group, C １－６ Alkoxy (C １－６ ) an alkyl group, an azetidinyl group, C １－６ Alkoxy groups, hydroxy groups, and hydroxy(C １－６ ) alkyl groups; 13. The compound according to claim 12, or a salt thereof.

14. The compound has the formula (Ic): 【Chemistry 6】 [In the formula, R １ is C １－６ Alkyl group, or mono-C １－６ an alkylamino group; R ２ and R ３ are each a hydrogen atom or R ２ and R ３ come together to form a bond; R ４ is a hydrogen atom; R ５ is a phenyl group optionally substituted by 1 to 3 halogen atoms; R ６ and R ７ are each independently a hydrogen atom or a halogen atom; X ５ is CH or N; and R １２ and R １３ are each independently a hydrogen atom, C １－６ an alkyl group, or a halogen atom; The compound according to claim 1 , or a salt thereof,

15. R １ But, C １－６ is an alkyl group; R ２ and R ３ are each a hydrogen atom or R ２ and R ３ come 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 are each a halogen atom; X ５ is CH; and R １２ and R １３ are each independently a hydrogen atom or a halogen atom; 15. The compound of claim 14, or a salt thereof.

16. The compound 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; 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; 2. The compound according to claim 1, selected from the group consisting of:

17. A medicament comprising a compound according to any one of claims 1 to 16 or a salt thereof.

18. The pharmaceutical agent according to claim 17, which is an orexin type 2 receptor agonist.

19. The pharmaceutical according to claim 17, which is a preventive or therapeutic agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, or side effects or complications due to anesthesia.

20. The pharmaceutical composition according to claim 17, which is an agent for preventing or treating narcolepsy, idiopathic hypersomnia, hypersomnia, or sleep apnea syndrome.

21. The pharmaceutical agent according to claim 17, which is a preventive or therapeutic agent for narcolepsy.

22. 20. A method for preventing or treating a disease or disorder associated with the orexin type 2 receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a salt thereof.

23. The method according to claim 22, wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects or complications due to anesthesia.

24. 23. The method of claim 22, wherein the disease or disorder is selected from narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea.

25. 23. The method of claim 22, wherein the disease or disorder is narcolepsy.

26. 17. A compound or salt thereof according to any one of claims 1 to 16 for use in therapy.

27. 27. The compound or salt of claim 26, wherein the therapeutic method comprises treatment of a disease or disorder associated with the orexin type 2 receptor.

28. 28. The compound or 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 accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, disturbance of consciousness, and side effects or complications due to anesthesia.

29. 28. The compound or salt of claim 27, wherein the disease or disorder is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.

30. 28. The compound or salt of claim 27, wherein the disease or disorder is narcolepsy.

31. 20. Use of a compound according to any one of claims 1 to 16, or a salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with the orexin type 2 receptor.

32. The disease or disorder is narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea, The use according to claim 31, wherein the symptom is selected from the group consisting of narcolepsy syndrome accompanied by lucolepsy-like symptoms, hypersomnia syndrome accompanied by excessive daytime sleepiness, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, impaired consciousness, and side effects and complications due to anesthesia.

33. 32. 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. 32. The use according to claim 31 , wherein the disease or disorder is narcolepsy.

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