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WO2025143095A1 - N-substituted cyclic amide compound - Google Patents

N-substituted cyclic amide compound Download PDF

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Publication number
WO2025143095A1
WO2025143095A1 PCT/JP2024/046100 JP2024046100W WO2025143095A1 WO 2025143095 A1 WO2025143095 A1 WO 2025143095A1 JP 2024046100 W JP2024046100 W JP 2024046100W WO 2025143095 A1 WO2025143095 A1 WO 2025143095A1
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Prior art keywords
alkyl
mixture
alkoxy
added
cycloalkyl
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Pending
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PCT/JP2024/046100
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French (fr)
Japanese (ja)
Inventor
陽輔 務台
聖奈 清澤
昭寛 神谷
文也 棚田
竜弥 伊東
孟 松本
智也 大木
峻輔 松本
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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Publication of WO2025143095A1 publication Critical patent/WO2025143095A1/en
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D513/04—Ortho-condensed systems

Definitions

  • T3 and T4 play important roles in development, growth, and metabolism, and their synthesis and secretion are strictly regulated by thyroid-stimulating hormone (TSH) secreted from the pituitary gland.
  • TSH thyroid-stimulating hormone
  • Thyroid eye disease is also known to accompany Graves' disease. Thyroid eye disease is an autoimmune inflammatory disease that presents a variety of ocular symptoms, and is thought to be primarily caused by the agonistic effect of TRAb on TSHR in the orbital tissue. It often develops at roughly the same time as hyperthyroidism, but may not be accompanied by thyroid dysfunction.
  • TSHR antagonists are thought to have therapeutic effects against Graves' disease and thyroid eye disease caused by the agonistic effect of TRAb on TSHR (Patent Documents 1 and 2).
  • NCGC00242364 is known as a TSHR antagonist, and has been shown to have a blood T4 concentration-reducing effect in mice administered TSH-releasing hormone (TRH) and mice administered the thyroid stimulating antibody M22 (Non-Patent Document 1).
  • the objective of the present invention is to provide a novel compound that has TSHR antagonist activity and is useful for treating thyroid-related diseases.
  • the present invention relates to a compound represented by the following formula (A-I) or a pharmacologically acceptable salt thereof.
  • Ring A is a group represented by the following formula (1), (2) or (3):
  • R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 al
  • Ring A is a group represented by the following formula (1), (2) or (3):
  • R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ; Substitu
  • R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
  • Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C
  • R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
  • Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C
  • R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl);
  • k is an integer from 0 to 3; When k is 2 or 3, each R 1c may be the same or different;
  • Ring Z is C 6-10 aryl, 5- or 6-membered heteroary
  • [A-16] The compound according to any one of [A-1] to [A-11], A compound or a pharmacologically acceptable salt thereof, wherein when ring A is a group represented by formula (2) or formula (3), R 5 is a hydrogen atom, methyl or cyclopropyl.
  • [A-17] The compound according to any one of [A-1] to [A-16], A compound or a pharmacologically acceptable salt thereof, wherein R 5 and R 5' are each independently a hydrogen atom, methyl or cyclopropyl.
  • [A-18] The compound according to any one of [A-1] to [A-17], A compound or a pharmacologically acceptable salt thereof, wherein R2 is -NHR5 .
  • [A-24] The compound according to any one of [A-1] to [A-23], A compound or a pharmacologically acceptable salt thereof, wherein R 1b is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).
  • R 1a is a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
  • n is an integer from 1 to 3; When n is 2 or 3, each R 1a may be the same or different; Two R 1a may be joined together to form a C 3-8 cycloalkyl; Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
  • R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
  • R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
  • R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C
  • [B-30] The compound according to any one of [B-1] to [B-29] above, A compound, or a pharmacologically acceptable salt thereof, wherein R 1a is C 1-6 alkyl, halo C 1-6 alkyl, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).
  • [B-31] The compound according to any one of [B-1] to [B-30], A compound or a pharmacologically acceptable salt thereof, wherein n is 1 or 2.
  • [B-32] The compound according to any one of [B-1] to [B-31] above, A compound or a pharmacologically acceptable salt thereof, wherein k is an integer of 0 to 2.
  • [B-33] The compound according to any one of [B-1] to [B-32] above, A compound or a pharmacologically acceptable salt thereof, wherein k is 1 or 2.
  • R3 and R3 ' are hydrogen atoms or C1-6 alkyl; A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.
  • R3 and R3 ' are hydrogen atoms; A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.
  • [B-39] The compound according to any one of [B-1] to [B-38], A compound or a pharmacologically acceptable salt thereof, wherein R4 is a halogen atom, cyano, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , C6-10 aryloxy, C6-10 arylC1-6 alkoxy, 5- or 6 -membered heteroarylC2-6 alkynyl, C3-8 cycloalkylC2-6 alkynyl, or -SF5.
  • R4 is a halogen atom, cyano, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl
  • [B-40] The compound according to any one of [B-1] to [B-39] above, A compound or a pharmacologically acceptable salt thereof, wherein R4 is a halogen atom, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, haloC1-6 alkoxy, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , 5- or 6-membered heteroarylC2-6 alkynyl, or -SF5 .
  • R4 is a halogen atom, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, haloC1-6 alkoxy, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , 5- or 6-membered heteroarylC2-6 alkynyl, or -SF5 .
  • Reference example E-5 1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-3-nitropyridin-2(1H)-one 6-Methyl-3-nitropyridin-2-ol (0.350 g) and DMF (5.0 mL) were added to a mixture of cesium carbonate (0.805 g) and Reference Example A-8 (0.480 g) at room temperature, and the mixture was stirred at 70° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane and ethyl acetate were added to separate the organic layer.
  • Reference example G-4 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline (0.100 g), Reference Example A-1 (0.111 g) and methanol (2.0 mL) were added to a mixture with decaborane (0.021 g) under ice cooling and stirred at room temperature for 13 hours. APS was added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Reference example G-6 (R)-3-amino-7-methyl-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-methylaniline instead of 2-bromoaniline and 3-(trifluoromethyl)benzaldehyde instead of 3-formylbenzonitrile, Reference Example G-6 was synthesized in the same manner as Reference Example G-2.
  • Reference example G-7 (R)-3-amino-7-methoxy-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-methoxyaniline instead of 2-bromoaniline and 3-(trifluoromethyl)benzaldehyde instead of 3-methylbenzaldehyde, Reference Example G-7 was synthesized in the same manner as Reference Example G-1.
  • Reference example G-9 (R)-3-amino-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline was replaced with 2-bromo-3-fluoroaniline, and Reference Example A-1 was replaced with 2-fluoro-5-(trifluoromethyl)benzaldehyde, and Reference Example G-9 was synthesized in the same manner as Reference Example G-4.
  • Reference example G-10 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one
  • Reference Example G-1 was used instead of 3-amino-4-bromobenzonitrile, and 2-fluoro-5-(trifluoromethyl)benzaldehyde was used instead of 3-(trifluoromethyl)benzaldehyde, and Reference Example G-10 was synthesized in the same manner as Reference Example G-8.
  • Reference example G-11 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-fluoroaniline instead of 2-bromoaniline, Reference Example G-11 was synthesized in the same manner as in Reference Example G-4.
  • Reference example G-12 (R)-3-amino-7-chloro-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-chloroaniline instead of 2-bromoaniline, Reference Example G-12 was synthesized in the same manner as Reference Example G-4.
  • Reference example G-13 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-methylaniline instead of 2-bromoaniline, Reference Example G-13 was synthesized in the same manner as Reference Example G-4.
  • Reference example G-14 (R)-3-amino-7-(difluoromethyl)-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one
  • Reference Example F-1 (0.100 g)
  • Reference Example A-1 0.086 g
  • methanol 2.0 mL
  • decaborane 0.017 g
  • APS was added to the reaction mixture and stirred at room temperature for 10 minutes.
  • the mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Reference example G-15 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one
  • Reference Example G-15 was synthesized in the same manner as in Reference Example G-14, using 2-bromo-5-(trifluoromethyl)aniline instead of Reference Example F-1.
  • Reference example G-16 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one
  • decaborane (0.159 g) was added at room temperature and stirred at the same temperature for 30 minutes.
  • APS was added to the reaction mixture and stirred at room temperature for 10 minutes.
  • the mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Reference example G-17 (R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-3,5-difluoroaniline instead of 2-bromoaniline, Reference Example G-17 was synthesized in the same manner as Reference Example G-4.
  • Reference example G-18 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethoxy)benzyl)-3,4-dihydroquinolin-2(1H)-one
  • Reference Example F-1 (0.118 g), 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.116 g) and methanol (1.0 mL) were added to a mixture, and decaborane (0.020 g) was added at room temperature and stirred at the same temperature for 2 hours. APS was added to the reaction mixture and stirred at room temperature for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Reference example G-19 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(pentafluorosulfur)benzyl)-3,4-dihydroquinolin-2(1H)-one 2-fluoro-5-(trifluoromethoxy)benzaldehyde was replaced with 2-fluoro-5-(pentafluorosulfur)benzaldehyde, and Reference Example G-19 was synthesized in the same manner as Reference Example G-18.
  • Reference example G-20 (R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3,4-dihydroquinolin-2(1H)-one 2-fluoro-5-(trifluoromethoxy)benzaldehyde was used instead of Reference Example A-11, and Reference Example G-20 was synthesized in the same manner as Reference Example G-18.
  • Reference example G-21 (R)-3-amino-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline instead of 2-bromoaniline, 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde instead of Reference Example A-1 was used, and Reference Example G-21 was synthesized in the same manner as Reference Example G-4.
  • a saturated aqueous ammonium chloride solution, water, n-hexane and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • hydrogen chloride (4 mol/L in 1,4-dioxane) (1.35 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours.
  • 5 mol/L aqueous sodium hydroxide solution (1.2 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
  • Reference example G-24 (3R)-3-amino-7-fluoro-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline instead of 2-bromo-5-fluoroaniline, instead of Reference Example A-1, 1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-one was used, and Reference Example G-24 was synthesized in the same manner as Reference Example G-4.
  • Reference example I-2 (S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)piperidin-2-one
  • a mixture of Reference Example I-1 (0.783 g), imidazole (0.825 g), TBDPSCl (1.83 g), DMAP (0.074 g) and DCM (20 mL) was stirred at room temperature for 2 hours.
  • the reaction mixture was poured into water, and the mixture was extracted with DCM.
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Reference example I-4 (2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-formylpyrrolidine-1-carboxylate tert-butyl Reference Example I-3 (0.343 g), 10% Pd/C (0.051 g) and ethanol (3.0 mL) were stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (3.0 mL), BH 3 -THF (0.9 mol/L in THF) (3.89 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours.
  • Reference example J-1 (S)-1-(5-bromo-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Using 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene, Reference Example J-1 was synthesized in the same manner as in Reference Example C-9.
  • Reference example J-5 A mixture of (2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl ester Reference Example J-4 (0.119 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (3.00 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue, TEA (0.140 g) and DCM (3.0 mL), triphosgene (0.033 g) was added at room temperature and stirred at the same temperature for 30 minutes.
  • Reference example J-6 (2S,5S)-2-((Z)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobut-2-en-1-yl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl.
  • Reference Example J-5 (0.059 g) and DCM (3.0 mL) were mixed and DIBAL-H (1.02 mol/L in n-hexane) (0.418 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes.
  • Reference example J-7 (S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one
  • sodium hydride about 60% (0.145 g) was added under ice cooling and stirred at room temperature for 30 minutes.
  • 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.02 g) was added to the reaction mixture and stirred at room temperature for 4 hours.
  • the reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate.
  • Reference example J-14 2-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidin-2-yl)methyl acetate Under an argon atmosphere, DIBAL-H (1.03 mol/L in n-hexane) (34.5 mL) was added to a mixture of Reference Example J-13 (7.73 g) and DCM (100 mL) at -78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Methanol and a saturated Rochelle salt aqueous solution were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and the mixture was extracted with DCM.
  • Reference example L-2 3-Bromo-6-(1,3-dihydroxy-2-(3-(trifluoromethyl)phenyl)propyl)pyridin-2(1H)-one
  • sodium borohydride 0.241 g
  • the reaction mixture was concentrated under reduced pressure.
  • a saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
  • Reference example L-3 6-Bromo-5-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroindolizin-1-yl acetate: DEAD (2.2 mol/L in toluene) (0.654 mL) was added to a mixture of Reference Example L-2 (0.376 g), triphenylphosphine (0.503 g) and THF (6.0 mL) under argon atmosphere, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure.
  • Reference example M-5 tert-Butyl (2-bromothiophen-3-yl)carbamate
  • Reference Example M-5 was synthesized in the same manner as in Reference Example M-2, except that 2-bromothiophene-3-carboxylic acid was used instead of 3-bromothiophene-2-carboxylic acid.
  • Reference example M-6 (R)-6-amino-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one Reference Example M-6 was synthesized in the same manner as in Reference Example M-3, using Reference Example M-5 instead of Reference Example M-2.
  • Reference example M-7 (R)-tert-butyl (5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)carbamate Reference Example M-7 was synthesized in the same manner as in Reference Example M-4, using Reference Example M-6 instead of Reference Example M-3.
  • Reference example M-8 tert-Butyl (2-methylthiazol-5-yl)carbamate
  • Reference Example M-8 was synthesized in the same manner as in Reference Example M-2, except that 2-methylthiazole-5-carboxylic acid was used instead of 3-bromothiophene-2-carboxylic acid.
  • Reference example M-9 (4-Bromo-2-methylthiazol-5-yl)carbamate tert-butyl Reference Example M-8 (0.420 g), NBS (0.349 g) and DMF (20 mL) were stirred at room temperature for 1 hour.
  • the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Reference example M-11 (R)-(2-methyl-5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridin-6-yl)carbamate tert-butyl Reference Example M-10 (0.156 g), 4 mol/L lithium hydroxide aqueous solution (0.282 mL) and THF (3.6 mL) were stirred at room temperature for 2 hours. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Reference example M-13 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate
  • Reference example M-14 (Z)-4-((2-hydroxy-4-nitrophenyl)amino)-4-oxobut-2-enoic acid Reference Example M-14 was synthesized in the same manner as in Reference Example M-12, except that 2-amino-5-nitrophenol was used instead of 2-aminophenol.
  • Reference example M-15 2-(7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate
  • Reference Example M-15 was synthesized in the same manner as in Reference Example M-13, using Reference Example M-14 instead of Reference Example M-12.
  • Reference example N-6 3-Amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)quinoxalin-2(1H)-one Under an argon atmosphere, a mixture of Reference Example N-5 (0.258 g), ammonium cerium nitrate (IV) (0.658 g), trimethylsilyl azide (0.277 g), water (0.029 g) and ethyl acetate (8.0 mL) was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in a mixed solvent of n-hexane/DCM/methanol, and insoluble matter was filtered off. The obtained solid was washed with n-hexane/DCM (1/1) and then dried under reduced pressure to obtain the title compound (0.114 g).
  • Reference example N-7 1-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-7-nitro-3-oxo-3,4-dihydroquinoxalin-2-yl)urea
  • triphosgene 0.044 g
  • TEA 0.045 g
  • Ammonium chloride 0.080 g
  • DIPEA 0.194 g
  • Nitric acid (0.005 g) was added to a mixture of the obtained compound (0.027 g) and sulfuric acid (0.5 mL) under ice cooling, and the mixture was stirred for 1 hour under ice cooling.
  • Nitric acid (0.002 g) was added to the reaction mixture, and the mixture was stirred for 1 hour under ice cooling.
  • Water was added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and then dried under reduced pressure to obtain the title compound (0.023 g).
  • Reference example N-8 1-(7-amino-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)urea
  • Example A-2 1-((3R * ,6R * )-1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea
  • LDA (1.07 mol/L in THF/n-hexane) (0.346 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes.
  • DPPA (0.102 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes.
  • a mixture of Boc 2 O (0.065 g) and THF (0.6 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example A-3 1-((3R * ,6R * )-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Using Reference Example C-3 instead of Reference Example C-2, Example A-3 was synthesized in the same manner as in Example A-2.
  • Example A-4 1-((3R * , 6R * )-1-((4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-6-methyl-2-oxopiperidin-3-yl)urea Using Reference Example C-4 instead of Reference Example C-1, Example A-4 was synthesized in the same manner as in Example A-1.
  • Example A-5 1-((3R * ,6R * )-1-(5-benzyl-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea
  • Example A-5 was synthesized in the same manner as in Example A-1, using Reference Example C-5 instead of Reference Example C-1.
  • Example A-6 1-((3R * ,6R * )-6-methyl-2-oxo-1-(3-phenoxybenzyl)piperidin-3-yl)urea
  • Example A-6 was synthesized in the same manner as in Example A-2, using Reference Example C-6 instead of Reference Example C-2.
  • Example A-7 1-((3R * ,6R * )-1-(2-fluoro-5-(phenylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Under an argon atmosphere, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.003 g) was added to a mixture of Example A-1(0.035 g), phenylacetylene(0.030 g), TEA(0.040 g) and DMF(1.0 mL) at room temperature, and the mixture was stirred at 80 ° C. for 17 hours.
  • Example A-14 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea
  • LDA 1.07 mol/L in THF/n-hexane
  • DPPA 0.209 g
  • Example A-15 1-((3R,6S)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea
  • Reference Example C-10 (0.109 g) and THF (1.7 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.469 mL) at -78°C, and the mixture was stirred at the same temperature for 15 minutes.
  • DPPA (0.138 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes.
  • a mixture of Boc 2 O (0.088 g) and THF (0.85 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 50 minutes. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example A-16 1-((3R,6S)-1-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea
  • Reference Example C-11 (0.165 g) and THF (1.4 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.591 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes.
  • DPPA (0.174 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 50 minutes.
  • a mixture of Boc 2 O (0.110 g) and THF (0.7 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 15 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example A-17 1-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea
  • LDA (1.07 mol/L in THF/n-hexane) (0.656 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes.
  • DPPA 0.193 g was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes.
  • Example A-18 1-((3R,5S)-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea
  • Example A-18 was synthesized in the same manner as in Example A-2, using Reference Example C-13 instead of Reference Example C-2.
  • Example A-19 (2-((3R * ,5S * )-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-3-yl)ethyl)carbamate tert-butyl
  • Example B-3 (0.010 g), platinum oxide (IV) (0.020 g) and methanol (2.0 mL) were stirred under a hydrogen atmosphere at room temperature for 1 hour and at 50 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • Example A-20 1-(5-oxo-4-(3-(trifluoromethyl)benzyl)-4-azaspiro[2.5]octan-6-yl)urea
  • Example A-20 was synthesized in the same manner as in Example A-1, except that Example C-14 was used instead of Example C-1.
  • Example A-21 1-((1R * , 4R * , 6S * )-2-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-2-azabicyclo[4.1.0]heptan-4-yl)urea Using Reference Example C-15 instead of Reference Example C-1, Example A-21 was synthesized in the same manner as in Example A-1.
  • Example A-22 1-((3R,6S)-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea
  • Example A-22 was synthesized in the same manner as in Example A-1, using Reference Example C-16 instead of Reference Example C-1.
  • Example A-24 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)-3-methylurea
  • Reference Example C-9 (0.174 g) and THF (2.5 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.711 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes.
  • DPPA 0.209 g was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes.
  • Example A-25 (S)-N-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)-2-methoxypropanamide
  • Reference Example C-9 (0.174 g) and THF (2.5 mL) were mixed at -78°C with LDA (1.07 mol/L in THF/n-hexane) (0.711 mL) and stirred at the same temperature for 20 minutes.
  • DPPA 0.209 g was added to the reaction mixture at -78°C and stirred at the same temperature for 45 minutes.
  • Example A-26 1-cyclopropyl-3-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea
  • Example A-26 was synthesized in the same manner as in Example A-24, using Reference Example C-12 instead of Reference Example C-9 and cyclopropylamine instead of methylamine.
  • Example A-27 N-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)acetamide
  • Reference Example C-12 (0.152 g) and THF (2.3 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.656 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes.
  • DPPA 0.193 g was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes.
  • Example A-28 N-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)cyclopropanecarboxamide
  • Example A-28 was synthesized in the same manner as in Example A-27, using cyclopropanecarbonyl chloride instead of acetyl chloride.
  • Example A-29 1-((3R * , 4aS * , 8aR * )-(2-oxo-1-(3-(trifluoromethyl)benzyl)decahydroquinolin-3-yl)urea Using Reference Example C-18 instead of Reference Example C-9, Example A-29 was synthesized in the same manner as in Example A-14.
  • Example B-1 1-(5-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea
  • triphosgene (0.114 g) and TEA (0.116 g) were added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling.
  • Ammonium chloride (0.205 g) and DIPEA (0.496 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.130 g).
  • Example B-2 3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)propanoic acid
  • Example B-1 (0.100 g), tri-o-tolylphosphine (0.015 g), TEA (0.099 g), benzyl acrylate (0.079 g) and MeCN (1.0 mL) were added to a mixture, and palladium (II) acetate (0.006 g) was added at room temperature, stirred at 80 ° C. for 1 hour, and then stirred at 140 ° C. for 10 minutes under microwave irradiation.
  • Example B-6 1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea
  • Example B-6 was synthesized in the same manner as in Example B-1, using Reference Example E-8 instead of Reference Example E-2.
  • Example C-2 (R)-1-(1-(3-cyanobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • Reference Example G-2 (0.043 g), water (0.055 mL), potassium cyanate (0.016 g), methanol (0.256 mL) and THF (0.383 mL) were added to a mixture of acetic acid (0.011 g) under ice cooling and stirred at room temperature for 13 hours.
  • THF (0.256 mL), methanol (0.192 mL) and water (1.92 mL) were added to the reaction mixture and stirred at room temperature for 40 minutes. Insoluble matter was filtered off, and the obtained solid was washed with ethanol/n-heptane (1/4) and then dried under reduced pressure to obtain the title compound (0.026 g).
  • Example C-8 (R)-1-(7-cyano-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • Example C-8 was synthesized in the same manner as in Example C-5, using Reference Example G-8 instead of Reference Example G-5.
  • Example C-16 (R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • Reference Example G-16 (0.050 g), water (0.026 mL) and THF (0.5 mL) were added with potassium cyanate (0.015 g) and acetic acid (0.009 g) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water and diethyl ether were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and diethyl ether, and then dried under reduced pressure to obtain the title compound (0.035 g).
  • Example C-19 (R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(pentafluorosulfur)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • water 0.070 mL
  • THF 0.7 mL
  • potassium cyanate 0.023 g
  • acetic acid 0.016 g
  • Example C-20 (R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • Example C-21 (R)-1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • Example C-21 was synthesized in the same manner as in Example C-12, using Reference Example G-21 instead of Reference Example G-12.
  • Example C-22 (R)-1-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydrothieno[3,4-b]pyridin-3-yl)urea
  • Example C-22 was synthesized in the same manner as in Example C-14, using Reference Example G-22 instead of Reference Example G-14.
  • Example C-25 (R)-1-(2-oxo-1-phenethyl-1,2,3,4-tetrahydroquinolin-3-yl)urea
  • Example C-25 was synthesized in the same manner as in Example C-12, using Reference Example G-25 instead of Reference Example G-12.
  • Methylamine (2 mol/L in THF) (0.773 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 10 minutes.
  • a saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM.
  • the extract was concentrated under reduced pressure.
  • the residue was suspended in MTBE, and insoluble matter was collected by filtration. The obtained solid was washed with MTBE and then dried under reduced pressure to obtain the title compound (0.025 g).
  • Example C-29 (R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxylic acid Under an argon atmosphere, zinc powder (0.625 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoic acid methyl (2.15 g) and DMF (7.8 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour.
  • reaction mixture was allowed to cool to room temperature, and then 1 mol/L hydrochloric acid (0.465 mL) and water were added, and the insoluble matter was filtered off. The obtained solid was washed with water and then dried under reduced pressure to obtain the title compound (0.036 g).
  • Example C-30 (R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxamide
  • Example C-29 (0.030 g), ammonium chloride (0.038 g), HATU (0.032 g) and MeCN (2.0 mL) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and MTBE were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.018 g).
  • Example D-1 1-((3R,6S)-1-(5-allyl-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea
  • LDA (1.07 mol/L in THF/n-hexane) (0.565 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes.
  • DPPA (0.166 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 75 minutes.
  • a mixture of Boc 2 O (0.105 g) and THF (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
  • Example D-3 1-((3S,6R,8aR)-5-oxo-3-(2-(trifluoromethyl)benzyl)octahydroindolizin-6-yl)urea
  • Reference Example J-6 0.072 g
  • (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate 0.007 g
  • DCM 2.0 mL
  • the extract was concentrated under reduced pressure.
  • water (0.009 mL) and THF (1.0 mL), potassium cyanate (0.003 g) and acetic acid (0.002 g) were added, and the mixture was stirred at room temperature for 2 hours and at 40°C for 30 minutes.
  • Potassium cyanate (0.001 g) was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour.
  • water was added, and the mixture was extracted with DCM.
  • the extract was concentrated under reduced pressure.
  • Example D-7 1-((3R,6S)-6-(ethoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea
  • TBAF (1 mol/L in THF) (4.85 mL) was added and stirred at room temperature for 20 minutes.
  • a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example D-8 N-(((2S,5R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-2-yl)methyl)acetamide
  • Reference Example J-12 (0.020 g), 10% Pd/C (0.020 g) and ethyl acetate (2.0 mL) were stirred under hydrogen atmosphere for 30 minutes under ice-cooling and at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the insoluble matter was washed with ethyl acetate (2.0 mL).
  • Example E-1 1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)urea
  • Example B-5 (0.143 g) and 1,4-dioxane (5.0 mL) were added to a mixture, and the mixture was stirred at 80 ° C. for 6 hours under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • Example E-4 1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)-1,2-dihydropyridin-3-yl)urea Under an argon atmosphere, phosphorus tribromide (0.083 g) was added to a mixture of Example E-1 (0.081 g) and DCM (3.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours.
  • Example E-5 1-(6-allyl-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea
  • DMF 1.0 mL
  • DME 8.0 mL
  • sodium hydride about 60%
  • Lithium bromide (0.165 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 15 minutes.
  • Reference Example A-3 (0.581 g) was added to the reaction mixture, and the mixture was stirred at 90 ° C.
  • TFA triethylsilane
  • 0.006 g triethylsilane
  • Example E-8 N-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2,2-trifluoroacetamide
  • Reference Example E-6 (0.030 g), DIPEA (0.023 g) and DCM (0.7 mL) were mixed, and trifluoroacetic anhydride (0.017 g) was added under cooling with water, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example E-9 N-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)azetidine-1-carboxamide
  • triphosgene 0.027 g
  • DIPEA 0.027 g
  • Azetidine hydrochloride 0.008 g
  • DIPEA 0.116 g
  • Example F-4 (R)-1-(7-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-5-yl)urea
  • Example F-4 was synthesized in the same manner as in Example F-2, using Reference Example M-4 instead of Reference Example M-1 and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene instead of Reference Example H-3.
  • Example F-8 (2-(2-amino-2-oxoethyl)-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)carbamate tert-butyl Reference Example N-4 (0.105 g), Boc 2 O (0.107 g), TEA (0.075 g) and THF (2.5 mL) were added to a mixture of DMAP (0.015 g) at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
  • Example F-9 1-(tert-butyl)-3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2-dihydroquinoxalin-6-yl)urea
  • Reference Example N-8 (0.013 g), pyridine (0.004 g) and DCM (1.0 mL) were added with 4-nitrophenyl chloroformate (0.007 g) at room temperature and stirred at the same temperature for 45 minutes.
  • tert-Butylamine (0.003 g) and DIPEA (0.010 g) were added to the reaction mixture and stirred at room temperature for 1 hour.
  • the cells were washed twice with 100 ⁇ L of assay buffer (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX) per well. 30 ⁇ L of assay buffer containing the test compound was added to the well and incubated at room temperature for 15 minutes. Then, 30 ⁇ L of assay buffer containing human TSH (R&D Systems, Inc., final concentration 50 ng/mL) was added and incubated at 37 °C for 1 hour. The supernatant was removed, and Lysis and Detection Buffer 2 (Cisbio) was added and incubated at room temperature for 1 hour to prepare cell lysates.
  • assay buffer Hams' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX
  • the cell lysates were reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate labeled antibody (Cisbio) in a 384-well white microplate. Then, the fluorescence intensity ratio (measurement wavelength 665 nm/620 nm) was measured using a multiplate reader (PHERAstarFSX, BMG LABTECH Japan). The fluorescence intensity ratio of each sample was converted to cAMP content using a standard curve. The cAMP content was converted as a percentage of the control value to calculate the cAMP generation rate.
  • the cAMP production rate was plotted against the test compound concentration using Prism (Graph Pad Software Inc.) to calculate IC50 values.
  • the IC50 of each test compound is shown in the above table. In the table, IC50 ⁇ 3.0 ⁇ M is indicated as A, and 3.0 ⁇ M ⁇ IC50 ⁇ 30 ⁇ M is indicated as B. When activity was observed but the IC50 value could not be calculated, it was indicated as C.
  • the compound of the present invention or a pharmacologically acceptable salt thereof has TSHR antagonist activity and is therefore useful as a therapeutic agent for thyroid-related diseases.

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Abstract

The present invention addresses the problem of providing a novel compound that has a thyroid-stimulating hormone receptor antagonistic activity and is useful for the treatment of thyroid-related diseases. The present invention relates to an N-substituted cyclic amide compound represented by the formula or a pharmacologically acceptable salt thereof. The compound or the pharmacologically acceptable salt thereof according to the present invention has a thyroid-stimulating hormone receptor antagonistic activity and is useful as a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer) and others.

Description

Ｎ－置換環状アミド化合物N-substituted cyclic amide compounds

　本発明は、医薬品として有用なN-置換環状アミド化合物に関する。さらに詳しく述べれば、本発明は、甲状腺刺激ホルモン受容体（TSHR）に対するアンタゴニスト活性を有し、甲状腺関連疾患の治療剤として有用なN-置換環状アミド化合物又はその薬理学的に許容される塩に関する。 The present invention relates to an N-substituted cyclic amide compound that is useful as a pharmaceutical. More specifically, the present invention relates to an N-substituted cyclic amide compound or a pharmacologically acceptable salt thereof that has antagonist activity against the thyroid stimulating hormone receptor (TSHR) and is useful as a therapeutic agent for thyroid-related diseases.

　甲状腺ホルモンであるトリヨードサイロニン（T3）やサイロキシン（T4）は発生、成長、代謝において重要な働きを担っており、脳下垂体から分泌される甲状腺刺激ホルモン（TSH）によって、その合成・分泌が厳密に調節されている。 The thyroid hormones triiodothyronine (T3) and thyroxine (T4) play important roles in development, growth, and metabolism, and their synthesis and secretion are strictly regulated by thyroid-stimulating hormone (TSH) secreted from the pituitary gland.

　甲状腺機能亢進症では、何らかの原因でこれらの甲状腺ホルモンが過剰に分泌され、そのホルモン作用を原因として、甲状腺腫、頻脈、高血圧、倦怠感、体重減少、動悸、睡眠障害、月経不順など、様々な好ましくない影響が心身に現れる。 In hyperthyroidism, these thyroid hormones are secreted in excess for some reason, and the hormonal effects of this excess can cause a variety of undesirable physical and mental effects, including goiter, tachycardia, high blood pressure, fatigue, weight loss, palpitations, sleep disorders, and menstrual irregularities.

　甲状腺機能亢進症の原因はさまざま存在するが、その中でも最も割合が高いのがグレーブス病（バセドウ病）である。グレーブス病では、自己免疫機序により自身の甲状腺を異物とみなして、甲状腺濾胞細胞上に存在するTSHRに対する自己抗体、いわゆるTSHR抗体（TRAb）が産生される。このTRAbがTSHRに対してアゴニストとして作用し、TSHRを過剰に刺激することにより、甲状腺ホルモンが必要以上に分泌され、甲状腺機能亢進症を発症すると考えられている。 There are various causes of hyperthyroidism, but the most common is Graves' disease. In Graves' disease, an autoimmune mechanism causes the thyroid gland to be treated as a foreign body, resulting in the production of autoantibodies against the TSHR present on the thyroid follicular cells, known as TSHR antibodies (TRAb). It is believed that this TRAb acts as an agonist against the TSHR, overstimulating it and causing more thyroid hormones to be secreted than necessary, resulting in hyperthyroidism.

　また、グレーブス病に伴う疾患としては、甲状腺眼症も知られている。甲状腺眼症は、多彩な眼症候を呈する自己免疫性炎症性疾患であり、眼窩組織のTSHRに対するTRAbのアゴニスト作用が主な原因であると考えられている。甲状腺機能亢進症とほぼ同時期に発症する場合が多いが、甲状腺機能異常を伴わない場合もある。 Thyroid eye disease is also known to accompany Graves' disease. Thyroid eye disease is an autoimmune inflammatory disease that presents a variety of ocular symptoms, and is thought to be primarily caused by the agonistic effect of TRAb on TSHR in the orbital tissue. It often develops at roughly the same time as hyperthyroidism, but may not be accompanied by thyroid dysfunction.

　現在グレーブス病の薬物療法にはチアマゾールやプロピルチオウラシルといった甲状腺ホルモンの生合成を阻害する抗甲状腺薬が用いられているが、寛解率が低いこと、寛解に至るまでの治療期間が長いこと、副作用の頻度が高いことなどの課題がある。そのため、新たな作用メカニズムを有するグレーブス病の治療薬が現在求められている。 Currently, Graves' disease is treated with antithyroid drugs such as thiamazole and propylthiouracil, which inhibit the biosynthesis of thyroid hormones. However, these drugs have issues such as a low remission rate, a long treatment period until remission is achieved, and a high frequency of side effects. Therefore, there is currently a need for a drug for the treatment of Graves' disease that has a new mechanism of action.

　TSHRを遮断すること、又はTSHRを介して誘発されたシグナル伝達を阻害することは、甲状腺ホルモンの産生、分泌及び甲状腺細胞増殖を阻害する。そのため、TSHRアンタゴニストはTRAbのTSHRに対するアゴニスト作用を原因とするグレーブス病及び甲状腺眼症に対して治療効果を有すると考えられている（特許文献1、2）。TSHRアンタゴニストとしては、NCGC00242364が知られており、TSH放出ホルモン（TRH）投与マウス、及び甲状腺刺激抗体M22投与マウスにおいて、血中T4濃度低下作用を有することが明らかにされている（非特許文献1）。 Blocking TSHR or inhibiting signal transduction induced through TSHR inhibits thyroid hormone production, secretion, and thyroid cell proliferation. Therefore, TSHR antagonists are thought to have therapeutic effects against Graves' disease and thyroid eye disease caused by the agonistic effect of TRAb on TSHR (Patent Documents 1 and 2). NCGC00242364 is known as a TSHR antagonist, and has been shown to have a blood T4 concentration-reducing effect in mice administered TSH-releasing hormone (TRH) and mice administered the thyroid stimulating antibody M22 (Non-Patent Document 1).

　TSHRアンタゴニスト活性を有する化合物が特許文献1から3、及び非特許文献1に記載されている。
　しかしながら、本願発明のN-置換環状アミド化合物は、特許文献1から3及び非特許文献1のいずれにも記載されていない。 Compounds having TSHR antagonist activity are described in Patent Documents 1 to 3 and Non-Patent Document 1.
However, the N-substituted cyclic amide compound of the present invention is not described in any of Patent Documents 1 to 3 and Non-Patent Document 1.

米国特許出願公開第2011/0172267号明細書US Patent Application Publication No. 2011/0172267 米国特許出願公開第2012/0315217号明細書US Patent Application Publication No. 2012/0315217 米国特許出願公開第2019/0134024号明細書US Patent Application Publication No. 2019/0134024

Susanne Neumannら、「Endocrinology」 2014年、第155巻、第1号、p.310-314Susanne Neumann et al., Endocrinology, 2014, Vol. 155, No. 1, pp. 310-314

　本発明は、TSHRアンタゴニスト活性を有し、甲状腺関連疾患の治療に有用な新規化合物を提供することを課題とする。 The objective of the present invention is to provide a novel compound that has TSHR antagonist activity and is useful for treating thyroid-related diseases.

　本発明は、下記式（Ａ-Ｉ）で表される化合物又はその薬理学的に許容される塩に関する。 The present invention relates to a compound represented by the following formula (A-I) or a pharmacologically acceptable salt thereof.

　すなわち、本発明は、下記の〔Ａ-１〕～〔Ａ-５１〕、及び〔Ｂ-１〕～〔Ｂ-５１〕等に関する。
〔Ａ-１〕
式(Ａ-Ｉ)で表される化合物：

Figure JPOXMLDOC01-appb-C000020
〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000021
 W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
Qは、-CRQ1=、-CRQ1RQ1’-、-O-、-N=又は-NRQ2-であり；
RQ1及びRQ1’はそれぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、C1-6アルキル又はハロC1-6アルキルであり；
RQ2は、水素原子、C1-6アルキル又はハロC1-6アルキルであり；
環Bは、5若しくは6員環ヘテロアリール又はベンゼンであり；
R1a及びR1cはそれぞれ独立して、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R1bは、水素原子、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C2-6アルケニル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R7は、水素原子又はC1-6アルキルであり；
R8、R9、R10、R11、R12及びR13はそれぞれ独立して、水素原子又は以下の(i)～(v)からなる群から選択される基であり：
(i)非置換又は置換基群Aから選択される1から6個の基で置換されたC1-6アルキル、
(ii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキル、
(iii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキルC1-6アルキル、
(iv)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリール、及び、
(v)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリールC1-6アルキル、
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R10とR11は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
R12とR13は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
2つのR1aは、一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
Figure JPOXMLDOC01-appb-C000022
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5～10員環ヘテロアリール、又はC3-8シクロアルキルであり；
R2は、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、3～8員環ヘテロシクロアルキル又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2はハロC1-6アルキル、3～8員環ヘテロシクロアルキル、又は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル、ハロC1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、又はシアノC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、C3-8シクロアルキルC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC1-6アルキル、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、ハロヒドロキシC1-6アルキル又は-SF5であり；
R1a、R1b又はR1cは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、0から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 That is, the present invention relates to the following [A-1] to [A-51] and [B-1] to [B-51], etc.
[A-1]
Compound represented by formula (A-I):
Figure JPOXMLDOC01-appb-C000020
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000021
 W, X and Y are each independently -CR 1b = or -N=;
Q is -CR Q1 =, -CR Q1 R Q1' -, -O-, -N= or -NR Q2 -;
R and R are each independently a hydrogen atom, a halogen atom, hydroxy, C alkyl , or haloC alkyl;
R Q2 is a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl;
Ring B is a 5- or 6-membered heteroaryl or benzene;
R 1a and R 1c each independently represent a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy , hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted by 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 1b is a hydrogen atom, a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted by 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 7 is a hydrogen atom or C 1-6 alkyl;
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v):
(i) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(ii) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iii) C 3-8 cycloalkyl C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iv) C 6-10 aryl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and
(v) C 6-10 arylC 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
Figure JPOXMLDOC01-appb-C000022
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5-10 membered heteroaryl, or C 3-8 cycloalkyl;
R2 is C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, 3- to 8-membered heterocycloalkyl or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is haloC1-6alkyl , 3- to 8-membered heterocycloalkyl, or -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, C1-6 alkyl, haloC1-6 alkyl or C3-8 cycloalkyl;
R 3 and R 3' are each independently a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, or cyano C 1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 1-6 alkyl, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, halohydroxy C 1-6 alkyl or -SF5 ;
R 1a , R 1b or R 1c may be joined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 0 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ａ-２〕
前記〔Ａ-１〕に記載の化合物であって、式（Ａ-ＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000023
〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000024
 W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
Qは、-CRQ1=、-CRQ1RQ1’-、-O-、-N=又は-NRQ2-であり；
RQ1及びRQ1’はそれぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、C1-6アルキル又はハロC1-6アルキルであり；
RQ2は、水素原子、C1-6アルキル又はハロC1-6アルキルであり；
環Bは、5若しくは6員環ヘテロアリール又はベンゼンであり；
R1a及びR1cはそれぞれ独立して、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、カルボキシC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R1bは、水素原子、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C2-6アルケニル、C1-6アルコキシ、ハロC1-6アルキル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R7は、水素原子又はC1-6アルキルであり；
R8、R9、R10、R11、R12及びR13は、それぞれ独立して、水素原子又は以下の(i)～(v)からなる群から選択される基であり：
(i)非置換又は置換基群Aから選択される1から6個の基で置換されたC1-6アルキル、
(ii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキル、
(iii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキルC1-6アルキル、
(iv)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリール、及び、
(v)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリールC1-6アルキル、
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R10とR11は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
R12とR13は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
2つのR1aは、一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
Figure JPOXMLDOC01-appb-C000025
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5～10員環ヘテロアリール又はC3-8シクロアルキルであり；
R2は、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、3～8員環ヘテロシクロアルキル、又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2はハロC1-6アルキル、3～8員環ヘテロシクロアルキル、又は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルキルC1-6アルキル、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC1-6アルキル、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル、ハロヒドロキシC1-6アルキル又は-SF5であり；
R1a、R1b又はR1cは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、0から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [A-2]
The compound according to the above [A-1], which is represented by the formula (A-II):
Figure JPOXMLDOC01-appb-C000023
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000024
 W, X and Y are each independently -CR 1b = or -N=;
Q is -CR Q1 =, -CR Q1 R Q1' -, -O-, -N= or -NR Q2 -;
R and R are each independently a hydrogen atom, a halogen atom, hydroxy, C alkyl , or haloC alkyl;
R Q2 is a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl;
Ring B is a 5- or 6-membered heteroaryl or benzene;
R 1a and R 1c each independently represent a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, carboxyC 1-6 alkyl , -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted by 1 to 6 groups selected from substituent group A, -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -( C 1-6 alkylene )-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 1b is a hydrogen atom, a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted by 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 7 is a hydrogen atom or C 1-6 alkyl;
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v):
(i) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(ii) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iii) C 3-8 cycloalkyl C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iv) C 6-10 aryl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and
(v) C 6-10 arylC 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
Figure JPOXMLDOC01-appb-C000025
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5-10 membered heteroaryl or C 3-8 cycloalkyl;
R2 is C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is haloC1-6alkyl , 3- to 8-membered heterocycloalkyl, or -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 1-6 alkyl, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl, halohydroxy C 1-6 alkyl or -SF 5 ;
R 1a , R 1b or R 1c may be joined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 0 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ａ-３〕
前記〔Ａ-１〕又は〔Ａ-２〕に記載の化合物であって、式（Ａ-ＩＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000026
〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000027
 Qは、-CH=、-CH2-、-O-、又は-N=であり；
R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NH-COO-(C1-6アルキル)、-(C1-6アルキレン)-NH-CO-(C1-6アルキル)、又は-(C1-6アルキレン)-CO-N(C1-6アルキル)2であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
R1aは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
R1bは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000028
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000029
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000030
 R2は、C1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。
〔Ａ-４〕
前記〔Ａ-１〕から〔Ａ-３〕の何れかに記載の化合物であって、式（Ａ-ＩＶ）で表される化合物：
Figure JPOXMLDOC01-appb-C000031
 〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000032
 R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NH-COO-(C1-6アルキル)、-(C1-6アルキレン)-NH-CO-(C1-6アルキル)、又は-(C1-6アルキレン)-CO-N(C1-6アルキル)2であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
R1aは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000033
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000034
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000035
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。
〔Ａ-５〕
前記〔Ａ-１〕から〔Ａ-４〕の何れかに記載の化合物であって、R5が水素原子である化合物又はその薬理学的に許容される塩。
〔Ａ-６〕
前記〔Ａ-１〕から〔Ａ-５〕の何れかに記載の化合物であって、L1が-NH-である化合物又はその薬理学的に許容される塩。
〔Ａ-７〕
前記〔Ａ-１〕から〔Ａ-６〕の何れかに記載の化合物であって、
Wが-CR1b=であり；
R1bが、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
S、U及びVがそれぞれ独立して、-CH=又は-CR1c=であり；
R1cが、ハロゲン原子、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。
〔Ａ-８〕
前記〔Ａ-１〕から〔Ａ-７〕の何れかに記載の化合物であって、
X及びYがそれぞれ独立して、-CR1b=であり；
Tが、-CH=又は-CR1c=であり；
pが1又は2である化合物又はその薬理学的に許容される塩。
〔Ａ-９〕
前記〔Ａ-１〕から〔Ａ-８〕の何れかに記載の化合物であって、
nが、1又は2であり；
kが、0から2の整数である化合物又はその薬理学的に許容される塩。
〔Ａ-１０〕
前記〔Ａ-１〕から〔Ａ-９〕の何れかに記載の化合物であって、
R3及びR3’が水素原子であり；
pが1である化合物又はその薬理学的に許容される塩。
〔Ａ-１１〕
前記〔Ａ-１〕から〔Ａ-１０〕の何れかに記載の化合物であって、
mが1から3の整数である化合物又はその薬理学的に許容される塩。 [A-3]
The compound according to the above [A-1] or [A-2], which is represented by the formula (A-III):
Figure JPOXMLDOC01-appb-C000026
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000027
 Q is -CH=, -CH2- , -O-, or -N=;
R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl);
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
two R 1a may join together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
R 1a may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
R 1b may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000028
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000029
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000030
 R2 is C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.
[A-4]
The compound according to any one of [A-1] to [A-3] above, which is represented by formula (A-IV):
Figure JPOXMLDOC01-appb-C000031
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000032
 R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl);
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
two R 1a may join together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
R 1a may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000033
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000034
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000035
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.
[A-5]
A compound according to any one of the above [A-1] to [A-4], wherein R 5 is a hydrogen atom, or a pharmacologically acceptable salt thereof.
[A-6]
The compound according to any one of the above [A-1] to [A-5], wherein L 1 is -NH-, or a pharmacologically acceptable salt thereof.
[A-7]
The compound according to any one of [A-1] to [A-6],
W is -CR 1b =;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
S, U and V are each independently -CH= or -CR 1c =;
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl).
[A-8]
The compound according to any one of [A-1] to [A-7],
X and Y are each independently -CR 1b =;
T is -CH= or -CR 1c =;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.
[A-9]
The compound according to any one of [A-1] to [A-8],
n is 1 or 2;
A compound or a pharmacologically acceptable salt thereof, wherein k is an integer of 0 to 2.
[A-10]
The compound according to any one of [A-1] to [A-9],
R3 and R3 ' are hydrogen atoms;
A compound or a pharmacologically acceptable salt thereof, wherein p is 1.
[A-11]
The compound according to any one of [A-1] to [A-10],
A compound in which m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

〔Ａ-１２〕
前記〔Ａ-１〕から〔Ａ-１１〕の何れかに記載の化合物であって、式（Ａ-Ｖ）で表される化合物：

Figure JPOXMLDOC01-appb-C000036
〔式中、
R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NH-COO-(C1-6アルキル)、-(C1-6アルキレン)-NH-CO-(C1-6アルキル)、又は-(C1-6アルキレン)-CO-N(C1-6アルキル)2であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
R1aは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000037
 R2は、C1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル又は-NR5R5’であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数でり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [A-12]
The compound according to any one of [A-1] to [A-11] above, which is represented by formula (A-V):
Figure JPOXMLDOC01-appb-C000036
 [During the ceremony,
R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
two R 1a may join together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
R 1a may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000037
 R2 is C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl or -NR5R5 ' ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ａ-１３〕
前記〔Ａ-１〕から〔Ａ-１２〕の何れかに記載の化合物であって、式（Ａ-ＶＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000038
〔式中、
R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NH-COO-(C1-6アルキル)、-(C1-6アルキレン)-NH-CO-(C1-6アルキル)、又は-(C1-6アルキレン)-CO-N(C1-6アルキル)2であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
R1aは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000039
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよく；〕
又はその薬理学的に許容される塩。 [A-13]
The compound according to any one of [A-1] to [A-12] above, which is represented by formula (A-VI):
Figure JPOXMLDOC01-appb-C000038
 [During the ceremony,
R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
two R 1a may join together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
R 1a may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000039
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, each R 3 and R 3 ' may be the same or different;
Or a pharmacologically acceptable salt thereof.

〔Ａ-１４〕
前記〔Ａ-１〕から〔Ａ-１１〕の何れかに記載の化合物であって、式（Ａ-ＶＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000040
〔式中、
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000041
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは1から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [A-14]
The compound according to any one of [A-1] to [A-11] above, which is represented by formula (A-VII):
Figure JPOXMLDOC01-appb-C000040
 [During the ceremony,
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000041
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 1 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ａ-１５〕
前記〔Ａ-１〕から〔Ａ-１１〕の何れかに記載の化合物であって、式（Ａ-ＶＩＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000042
〔式中、
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)であり；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000043
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000044
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000045
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [A-15]
The compound according to any one of [A-1] to [A-11] above, which is represented by formula (A-VIII):
Figure JPOXMLDOC01-appb-C000042
 [During the ceremony,
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl);
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000043
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000044
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000045
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, each R 3 and R 3 ' may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ａ-１６〕
前記〔Ａ-１〕から〔Ａ-１１〕の何れかに記載の化合物であって：
環Aが式(２)又は式(３)で表される基である場合、R5が水素原子、メチル又はシクロプロピルである化合物又はその薬理学的に許容される塩。 [A-16]
The compound according to any one of [A-1] to [A-11],
A compound or a pharmacologically acceptable salt thereof, wherein when ring A is a group represented by formula (2) or formula (3), R 5 is a hydrogen atom, methyl or cyclopropyl.

〔Ａ-１７〕
前記〔Ａ-１〕から〔Ａ-１６〕の何れかに記載の化合物であって：
R5及びR5'がそれぞれ独立して、水素原子、メチル又はシクロプロピルである化合物又はその薬理学的に許容される塩。 [A-17]
The compound according to any one of [A-1] to [A-16],
A compound or a pharmacologically acceptable salt thereof, wherein R 5 and R 5' are each independently a hydrogen atom, methyl or cyclopropyl.

〔Ａ-１８〕
前記〔Ａ-１〕から〔Ａ-１７〕の何れかに記載の化合物であって：
R2が-NHR5である化合物又はその薬理学的に許容される塩。 [A-18]
The compound according to any one of [A-1] to [A-17],
A compound or a pharmacologically acceptable salt thereof, wherein R2 is -NHR5 .

〔Ａ-１９〕
前記〔Ａ-１〕から〔Ａ-１８〕の何れかに記載の化合物であって、R5が水素原子である化合物又はその薬理学的に許容される塩。 [A-19]
A compound according to any one of the above [A-1] to [A-18], wherein R 5 is a hydrogen atom, or a pharmacologically acceptable salt thereof.

〔Ａ-２０〕
前記〔Ａ-１〕から〔Ａ-１９〕の何れかに記載の化合物であって、L1が-NH-である化合物又はその薬理学的に許容される塩。 [A-20]
The compound according to any one of the above [A-1] to [A-19], wherein L 1 is -NH-, or a pharmacologically acceptable salt thereof.

〔Ａ-２１〕
前記〔Ａ-１〕から〔Ａ-２０〕の何れかに記載の化合物であって：
Wが-CR1b=である化合物又はその薬理学的に許容される塩。
〔Ａ-２２〕
前記〔Ａ-１〕から〔Ａ-２１〕の何れかに記載の化合物であって：
X及びYがそれぞれ独立して、-CR1b=である化合物又はその薬理学的に許容される塩。 [A-21]
The compound according to any one of [A-1] to [A-20],
A compound wherein W is -CR 1b = or a pharmacologically acceptable salt thereof.
[A-22]
The compound according to any one of [A-1] to [A-21],
A compound, or a pharmacologically acceptable salt thereof, wherein X and Y are each independently -CR 1b =.

〔Ａ-２３〕
前記〔Ａ-１〕から〔Ａ-２２〕の何れかに記載の化合物であって：
R1bが、水素原子、ハロゲン原子、シアノ、C1-6アルキル、カルボキシC1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。 [A-23]
The compound according to any one of [A-1] to [A-22] above,
A compound or a pharmacologically acceptable salt thereof, wherein R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

〔Ａ-２４〕
前記〔Ａ-１〕から〔Ａ-２３〕の何れかに記載の化合物であって：
R1bが、水素原子、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。 [A-24]
The compound according to any one of [A-1] to [A-23],
A compound or a pharmacologically acceptable salt thereof, wherein R 1b is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

〔Ａ-２５〕
前記〔Ａ-１〕から〔Ａ-２４〕の何れかに記載の化合物であって：
S、U及びVがそれぞれ独立して、-CH=又は-CR1c=である化合物又はその薬理学的に許容される塩。 [A-25]
The compound according to any one of [A-1] to [A-24],
A compound, or a pharmacologically acceptable salt thereof, wherein S, U and V are each independently -CH= or -CR 1c =.

〔Ａ-２６〕
前記〔Ａ-１〕から〔Ａ-２５〕の何れかに記載の化合物であって：
Tが、-CH=又は-CR1c=である化合物又はその薬理学的に許容される塩。 [A-26]
The compound according to any one of [A-1] to [A-25] above,
A compound, or a pharmacologically acceptable salt thereof, wherein T is -CH= or -CR 1c =.

〔Ａ-２７〕
前記〔Ａ-１〕から〔Ａ-２６〕の何れかに記載の化合物であって：
R1cが、ハロゲン原子、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、C1-6アルコキシ又は-CONH2である化合物又はその薬理学的に許容される塩。 [A-27]
The compound according to any one of [A-1] to [A-26],
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy or -CONH 2 .

〔Ａ-２８〕
前記〔Ａ-１〕から〔Ａ-２７〕の何れかに記載の化合物であって：
R1cが、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又はヒドロキシC1-6アルキルである化合物又はその薬理学的に許容される塩。 [A-28]
The compound according to any one of [A-1] to [A-27],
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or hydroxy C 1-6 alkyl.

〔Ａ-２９〕
前記〔Ａ-１〕から〔Ａ-２８〕の何れかに記載の化合物であって：
R1aが、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
置換基群Aが前記〔Ａ-１〕と同じ意味である化合物又はその薬理学的に許容される塩。 [A-29]
The compound according to any one of [A-1] to [A-28],
R 1a is a halogen atom, a C 1-6 alkyl, a halo C 1-6 alkyl, a C 1-6 alkoxy C 1-6 alkyl, an unsubstituted or substituted -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) with 1 to 6 groups selected from the substituent group A, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
A compound in which the substituent group A has the same meaning as that of the above [A-1] or a pharmacologically acceptable salt thereof.

〔Ａ-３０〕
前記〔Ａ-１〕から〔Ａ-２９〕の何れかに記載の化合物であって：
R1aが、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
置換基群Aが前記〔Ａ-１〕と同じ意味である化合物又はその薬理学的に許容される塩。
〔Ａ-３１〕
前記〔Ａ-１〕から〔Ａ-３０〕の何れかに記載の化合物であって：
nが、1又は2である化合物又はその薬理学的に許容される塩。
〔Ａ-３２〕
前記〔Ａ-１〕から〔Ａ-３１〕の何れかに記載の化合物であって：
kが、0から2の整数である化合物又はその薬理学的に許容される塩。
〔Ａ-３３〕
前記〔Ａ-１〕から〔Ａ-３２〕の何れかに記載の化合物であって：
kが、1又は2である化合物又はその薬理学的に許容される塩。 [A-30]
The compound according to any one of [A-1] to [A-29],
R 1a is C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
A compound in which the substituent group A has the same meaning as that of the above [A-1] or a pharmacologically acceptable salt thereof.
[A-31]
The compound according to any one of [A-1] to [A-30],
A compound or a pharmacologically acceptable salt thereof, wherein n is 1 or 2.
[A-32]
The compound according to any one of [A-1] to [A-31],
A compound or a pharmacologically acceptable salt thereof, wherein k is an integer of 0 to 2.
[A-33]
The compound according to any one of [A-1] to [A-32],
A compound or a pharmacologically acceptable salt thereof, wherein k is 1 or 2.

〔Ａ-３４〕
前記〔Ａ-１〕から〔Ａ-３３〕の何れかに記載の化合物であって：
R3及びR3’が水素原子又はC1-6アルキルであり；
pが1又は2である化合物又はその薬理学的に許容される塩。 [A-34]
The compound according to any one of [A-1] to [A-33],
R3 and R3 ' are hydrogen atoms or C1-6 alkyl;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.

〔Ａ-３５〕
前記〔Ａ-１〕から〔Ａ-３４〕の何れかに記載の化合物であって：
R3及びR3’が水素原子であり；
pが1又は2である化合物又はその薬理学的に許容される塩。 [A-35]
The compound according to any one of [A-1] to [A-34],
R3 and R3 ' are hydrogen atoms;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.

〔Ａ-３６〕
前記〔Ａ-１〕から〔Ａ-３５〕の何れかに記載の化合物であって：
pが1又は2である化合物又はその薬理学的に許容される塩。 [A-36]
The compound according to any one of [A-1] to [A-35],
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.

〔Ａ-３７〕
前記〔Ａ-１〕から〔Ａ-３６〕の何れかに記載の化合物であって：
pが1である化合物又はその薬理学的に許容される塩。 [A-37]
The compound according to any one of [A-1] to [A-36],
A compound or a pharmacologically acceptable salt thereof, wherein p is 1.

〔Ａ-３８〕
前記〔Ａ-１〕から〔Ａ-３７〕の何れかに記載の化合物であって：
環Zが、C6-10アリールである化合物又はその薬理学的に許容される塩。 [A-38]
The compound according to any one of [A-1] to [A-37],
A compound or a pharmacologically acceptable salt thereof, wherein ring Z is C 6-10 aryl.

〔Ａ-３９〕
前記〔Ａ-１〕から〔Ａ-３８〕の何れかに記載の化合物であって：
R4が、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5である化合物又はその薬理学的に許容される塩。 [A-39]
The compound according to any one of [A-1] to [A-38],
A compound or a pharmacologically acceptable salt thereof, wherein R4 is a halogen atom, cyano, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , C6-10 aryloxy, C6-10 arylC1-6 alkoxy, 5- or 6 -membered heteroarylC2-6 alkynyl, C3-8 cycloalkylC2-6 alkynyl, or -SF5.

〔Ａ-４０〕
前記〔Ａ-１〕から〔Ａ-３９〕の何れかに記載の化合物であって：
R4が、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、ハロC1-6アルコキシ、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、5若しくは6員環ヘテロアリールC2-6アルキニル又は-SF5である化合物又はその薬理学的に許容される塩。 [A-40]
The compound according to any one of [A-1] to [A-39],
A compound or a pharmacologically acceptable salt thereof, wherein R4 is a halogen atom, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, haloC1-6 alkoxy, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , 5- or 6-membered heteroarylC2-6 alkynyl, or -SF5 .

〔Ａ-４１〕
前記〔Ａ-１〕から〔Ａ-４０〕の何れかに記載の化合物であって、mが1から3の整数である化合物又はその薬理学的に許容される塩。 [A-41]
The compound according to any one of the above [A-1] to [A-40], wherein m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

〔Ａ-４２〕
以下の化合物からなる群から選択される、前記〔Ａ-１〕から〔Ａ-４１〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000048
 及び
Figure JPOXMLDOC01-appb-C000049
 又はその薬理学的に許容される塩。 [A-42]
A compound according to any one of the above [A-1] to [A-41], which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000048
 and
Figure JPOXMLDOC01-appb-C000049
 Or a pharmacologically acceptable salt thereof.

〔Ａ-４３〕
以下の化合物からなる群から選択される、前記〔Ａ-１〕から〔Ａ-４２〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000050
及び
Figure JPOXMLDOC01-appb-C000051
 又はその薬理学的に許容される塩。 [A-43]
A compound according to any one of the above [A-1] to [A-42], selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000050
 and
Figure JPOXMLDOC01-appb-C000051
 Or a pharmacologically acceptable salt thereof.

〔Ａ-４４〕
以下の化合物からなる群から選択される、前記〔Ａ-１〕から〔Ａ-４２〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000052
及び
Figure JPOXMLDOC01-appb-C000053
 又はその薬理学的に許容される塩。 [A-44]
A compound according to any one of the above [A-1] to [A-42], selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000052
 and
Figure JPOXMLDOC01-appb-C000053
 Or a pharmacologically acceptable salt thereof.

〔Ａ-４５〕
以下の化合物からなる群から選択される、前記〔Ａ-１〕から〔Ａ-４２〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000054
及び
Figure JPOXMLDOC01-appb-C000055
 又はその薬理学的に許容される塩。 [A-45]
A compound according to any one of the above [A-1] to [A-42], selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000054
 and
Figure JPOXMLDOC01-appb-C000055
 Or a pharmacologically acceptable salt thereof.

〔Ａ-４６〕
以下の化合物からなる群から選択される、前記〔Ａ-１〕から〔Ａ-４１〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000056
及び
Figure JPOXMLDOC01-appb-C000057
 又はその薬理学的に許容される塩。 [A-46]
A compound according to any one of the above [A-1] to [A-41], which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000056
 and
Figure JPOXMLDOC01-appb-C000057
 Or a pharmacologically acceptable salt thereof.

〔Ａ-４７〕
前記〔Ａ-１〕から〔Ａ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩、及び医薬品添加物を含む医薬組成物。 [A-47]
A pharmaceutical composition comprising the compound according to any one of the above [A-1] to [A-46] or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

〔Ａ-４８〕
甲状腺関連疾患の治療用医薬組成物である前記〔Ａ-４７〕に記載の医薬組成物。 [A-48]
The pharmaceutical composition described in [A-47] above, which is a pharmaceutical composition for treating a thyroid-related disease.

〔Ａ-４９〕
前記〔Ａ-４８〕に記載の医薬組成物であって、甲状腺関連疾患が甲状腺機能亢進症、グレーブス病、又は甲状腺眼症である医薬組成物。 [A-49]
The pharmaceutical composition according to the above [A-48], wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

〔Ａ-５０〕
前記〔Ａ-１〕から〔Ａ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩を有効成分として含有するTSHR阻害剤。
〔Ａ-５１〕
前記〔Ａ-１〕から〔Ａ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩を有効成分として含有する甲状腺関連疾患治療剤。 [A-50]
A TSHR inhibitor comprising, as an active ingredient, any one of the compounds according to the above [A-1] to [A-46] or a pharmacologically acceptable salt thereof.
[A-51]
A therapeutic agent for thyroid-related diseases, comprising as an active ingredient any one of the compounds according to the above [A-1] to [A-46] or a pharmacologically acceptable salt thereof.

　式（Ａ-Ｉ）～(Ａ-ＶＩ)で表される化合物の一つの実施態様として、例えば、2つのR1aが一緒になって3～8員飽和炭素環を形成する場合、以下の(a)又は(b)の式で表される環：

Figure JPOXMLDOC01-appb-C000058
（式中、qは、1から4の整数である）,
Figure JPOXMLDOC01-appb-C000059
 （式中、rは、1から4の整数である）;
を形成する化合物が挙げられる。 As an embodiment of the compounds represented by formulae (A-I) to (A-VI), for example, when two R 1a are taken together to form a 3- to 8-membered saturated carbocyclic ring, the ring is represented by the following formula (a) or (b):
Figure JPOXMLDOC01-appb-C000058
 (wherein q is an integer from 1 to 4),
Figure JPOXMLDOC01-appb-C000059
 wherein r is an integer from 1 to 4;
Examples of the compound include compounds which form the following formula:

　一つの実施態様として、本発明は、前記〔Ａ-４７〕に記載の医薬組成物を患者に必要量投与することを含む、甲状腺関連疾患の治療方法に関する。 In one embodiment, the present invention relates to a method for treating a thyroid-related disease, comprising administering to a patient a required amount of the pharmaceutical composition described in [A-47] above.

　一つの実施態様として、本発明は、甲状腺関連疾患の治療用医薬組成物を製造するための、前記〔Ａ-１〕から〔Ａ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩の使用に関する。 In one embodiment, the present invention relates to the use of any of the compounds described in [A-1] to [A-46] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating a thyroid-related disease.

〔Ｂ-１〕
式(Ｉ)で表される化合物：

Figure JPOXMLDOC01-appb-C000060
〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000061
 W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
Qは、-CRQ1=、-CRQ1RQ1’-、-O-又は-NRQ2-であり；
RQ1及びRQ1’はそれぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、C1-6アルキル又はハロC1-6アルキルであり；
RQ2は、水素原子、C1-6アルキル又はハロC1-6アルキルであり；
環Bは、5若しくは6員環ヘテロアリール又はベンゼンであり；
R1a及びR1cはそれぞれ独立して、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R1bは、水素原子、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R7は、水素原子又はC1-6アルキルであり；
R8、R9、R10、R11、R12及びR13はそれぞれ独立して、水素原子又は以下の(i)～(v)からなる群から選択される基であり：
(i)非置換又は置換基群Aから選択される1から6個の基で置換されたC1-6アルキル、
(ii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキル、
(iii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキルC1-6アルキル、
(iv)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリール、及び、
(v)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリールC1-6アルキル、
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R10とR11は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
R12とR13は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
2つのR1aは、一緒になってC3-8シクロアルキルを形成してもよく；
Figure JPOXMLDOC01-appb-C000062
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5～10員環ヘテロアリール、C3-8シクロアルキル又は3～8員環ヘテロシクロアルキルであり；
R2は、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、3～8員環ヘテロシクロアルキル又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル、ハロC1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、-NR14COR15、-NR14COOR16、-NR14CONR17R18、-CONR19R20、-(C1-6アルキレン)-NR14COR15、-(C1-6アルキレン)-NR14COOR16、-(C1-6アルキレン)-NR14CONR17R18又は-(C1-6アルキレン)-CONR19R20であり；
R14、R15、R16、R17、R18、R19及びR20はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R3とR3’は、一緒になってオキソ基を形成してもよく；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、C3-8シクロアルキルC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC1-6アルキル、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、シアノC1-6アルキル、-NR21COR22、-NR21COOR23、-NR21CONR24R25、-CONR26R27、-(C1-6アルキレン)-NR21COR22、-(C1-6アルキレン)-NR21COOR23、-(C1-6アルキレン)-NR21CONR24R25、-(C1-6アルキレン)-CONR26R27、ハロヒドロキシC1-6アルキル又は-SF5であり；
R21、R22、R23、R24、R25、R26及びR27はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R1a、R1b又はR1cは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
R4とR3は、一緒になって5～8員環を形成してもよく；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、0から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [B-1]
Compounds represented by formula (I):
Figure JPOXMLDOC01-appb-C000060
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000061
 W, X and Y are each independently -CR 1b = or -N=;
Q is -CR Q1 =, -CR Q1 R Q1 ' -, -O- or -NR Q2 -;
R and R are each independently a hydrogen atom, a halogen atom, hydroxy, C alkyl , or haloC alkyl;
R Q2 is a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl;
Ring B is a 5- or 6-membered heteroaryl or benzene;
R 1a and R 1c each independently represent a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy , hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 1b is a hydrogen atom, a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 7 is a hydrogen atom or C 1-6 alkyl;
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v):
(i) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(ii) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iii) C 3-8 cycloalkyl C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iv) C 6-10 aryl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and
(v) C 6-10 arylC 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Two R 1a may be joined together to form a C 3-8 cycloalkyl;
Figure JPOXMLDOC01-appb-C000062
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;
R2 is C1-6 alkyl, C1-6 alkoxy, haloC1-6 alkyl, haloC1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkoxy, 3- to 8-membered heterocycloalkyl or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, C1-6 alkyl, haloC1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom, a halogen atom, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, hydroxyC1-6 alkyl , aminoC1-6 alkyl, cyanoC1-6 alkyl , -NR14COR15, -NR14COOR16 , -NR14CONR17R18 , -CONR19R20 , - (C1-6 alkylene ) -NR14COR15 , - ( C1-6 alkylene ) -NR14COOR16 , -( C1-6 alkylene ) -NR14CONR17R18 or - ( C1-6 alkylene ) -CONR19R20 ;
R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are each independently a hydrogen atom or a C 1-6 alkyl;
R3 and R3 ' may together form an oxo group;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl , C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 1-6 alkyl, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, -NR 21 COR 22 , -NR 21COOR23 , -NR21CONR24R25 , -CONR26R27 , -(C1-6 alkylene)-NR21COR22 , - ( C1-6 alkylene ) -NR21COOR23 , -( C1-6 alkylene) -NR21CONR24R25 , -( C1-6 alkylene ) -CONR26R27 , halohydroxyC1-6 alkyl or -SF5 ;
R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 are each independently a hydrogen atom or a C 1-6 alkyl;
R 1a , R 1b or R 1c may be joined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
R 4 and R 3 together may form a 5- to 8-membered ring;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 0 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ｂ-２〕
前記〔Ｂ-１〕に記載の化合物であって、式（ＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000063
〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000064
 W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
Qは、-CRQ1=、-CRQ1RQ1’-、-O-又は-NRQ2-であり；
RQ1及びRQ1’はそれぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、C1-6アルキル又はハロC1-6アルキルであり；
RQ2は、水素原子、C1-6アルキル又はハロC1-6アルキルであり；
環Bは、5若しくは6員環ヘテロアリール又はベンゼンであり；
R1a及びR1cはそれぞれ独立して、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R1bは、水素原子、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R7は、水素原子又はC1-6アルキルであり；
R8、R9、R10、R11、R12及びR13は、それぞれ独立して、水素原子又は以下の(i)～(v)からなる群から選択される基であり：
(i)非置換又は置換基群Aから選択される1から6個の基で置換されたC1-6アルキル、
(ii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキル、
(iii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキルC1-6アルキル、
(iv)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリール、及び、
(v)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリールC1-6アルキル、
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R10とR11は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
R12とR13は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
2つのR1aは、一緒になってC3-8シクロアルキルを形成してもよく；
Figure JPOXMLDOC01-appb-C000065
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5～10員環ヘテロアリール又はC3-8シクロアルキルであり；
R2は、C1-6アルキル、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルキルC1-6アルキル、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC1-6アルキル、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル、ハロヒドロキシC1-6アルキル又は-SF5であり；
R1a、R1b又はR1cは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
R4とR3は、一緒になって5～8員環を形成してもよく；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、0から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [B-2]
The compound according to the above [B-1], which is represented by the formula (II):
Figure JPOXMLDOC01-appb-C000063
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000064
 W, X and Y are each independently -CR 1b = or -N=;
Q is -CR Q1 =, -CR Q1 R Q1 ' -, -O- or -NR Q2 -;
R and R are each independently a hydrogen atom, a halogen atom, hydroxy, C alkyl , or haloC alkyl;
R Q2 is a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl;
Ring B is a 5- or 6-membered heteroaryl or benzene;
R 1a and R 1c are each independently a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 1b is a hydrogen atom, a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 7 is a hydrogen atom or C 1-6 alkyl;
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v):
(i) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(ii) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iii) C 3-8 cycloalkyl C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iv) C 6-10 aryl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and
(v) C 6-10 arylC 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Two R 1a may be joined together to form a C 3-8 cycloalkyl;
Figure JPOXMLDOC01-appb-C000065
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5-10 membered heteroaryl or C 3-8 cycloalkyl;
R2 is C1-6 alkyl, C1-6 alkoxyC1-6 alkyl, C3-8 cycloalkyl or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 1-6 alkyl, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl, halohydroxy C 1-6 alkyl or -SF 5 ;
R 1a , R 1b or R 1c may be joined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
R 4 and R 3 together may form a 5- to 8-membered ring;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 0 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ｂ-３〕
前記〔Ｂ-１〕又は〔Ｂ-２〕に記載の化合物であって、式（ＩＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000066
〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000067
 R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、C1-6アルコキシ又は-CONH2であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になってC3-8シクロアルキルを形成してもよく；
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、カルボキシC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000068
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000069
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000070
 R2は、C1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。
〔Ｂ-４〕
前記〔Ｂ-１〕から〔Ｂ-３〕の何れかに記載の化合物であって、式（ＩＶ）で表される化合物：
Figure JPOXMLDOC01-appb-C000071
 〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000072
 R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、C1-6アルコキシ又は-CONH2であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になってC3-8シクロアルキルを形成してもよく；
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、カルボキシC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000073
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000074
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000075
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。
〔Ｂ-５〕
前記〔Ｂ-１〕から〔Ｂ-４〕の何れかに記載の化合物であって、R5が水素原子である化合物又はその薬理学的に許容される塩。
〔Ｂ-６〕
前記〔Ｂ-１〕から〔Ｂ-５〕の何れかに記載の化合物であって、L1が-NH-である化合物又はその薬理学的に許容される塩。
〔Ｂ-７〕
前記〔Ｂ-１〕から〔Ｂ-６〕の何れかに記載の化合物であって、
Wが-CR1b=であり；
R1bが、水素原子、ハロゲン原子、シアノ、C1-6アルキル、カルボキシC1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
S、U及びVがそれぞれ独立して、-CH=又は-CR1c=であり；
R1cが、ハロゲン原子、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、C1-6アルコキシ又は-CONH2である化合物又はその薬理学的に許容される塩。
〔Ｂ-８〕
前記〔Ｂ-１〕から〔Ｂ-７〕の何れかに記載の化合物であって、
X及びYがそれぞれ独立して、-CR1b=であり；
Tが、-CH=又は-CR1c=であり；
pが1又は2である化合物又はその薬理学的に許容される塩。
〔Ｂ-９〕
前記〔Ｂ-１〕から〔Ｂ-８〕の何れかに記載の化合物であって、
nが、1又は2であり；
kが、0から2の整数である化合物又はその薬理学的に許容される塩。
〔Ｂ-１０〕
前記〔Ｂ-１〕から〔Ｂ-９〕の何れかに記載の化合物であって、
R3及びR3’が水素原子であり；
pが1である化合物又はその薬理学的に許容される塩。
〔Ｂ-１１〕
前記〔Ｂ-１〕から〔Ｂ-１０〕の何れかに記載の化合物であって、
mが1から3の整数である化合物又はその薬理学的に許容される塩。 [B-3]
The compound according to the above [B-1] or [B-2], which is represented by formula (III):
Figure JPOXMLDOC01-appb-C000066
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000067
 R 1a is a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy or -CONH 2 ;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
Two R 1a may be joined together to form a C 3-8 cycloalkyl;
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000068
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000069
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000070
 R2 is C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.
[B-4]
The compound according to any one of [B-1] to [B-3] above, which is represented by formula (IV):
Figure JPOXMLDOC01-appb-C000071
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000072
 R 1a is a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy or -CONH 2 ;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
Two R 1a may be joined together to form a C 3-8 cycloalkyl;
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000073
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000074
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000075
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.
[B-5]
A compound according to any one of the above [B-1] to [B-4], wherein R 5 is a hydrogen atom, or a pharmacologically acceptable salt thereof.
[B-6]
The compound according to any one of the above [B-1] to [B-5], wherein L 1 is -NH-, or a pharmacologically acceptable salt thereof.
[B-7]
The compound according to any one of [B-1] to [B-6],
W is -CR 1b =;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
S, U and V are each independently -CH= or -CR 1c =;
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy or -CONH 2 .
[B-8]
The compound according to any one of [B-1] to [B-7],
X and Y are each independently -CR 1b =;
T is -CH= or -CR 1c =;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.
[B-9]
The compound according to any one of [B-1] to [B-8],
n is 1 or 2;
A compound or a pharmacologically acceptable salt thereof, wherein k is an integer of 0 to 2.
[B-10]
The compound according to any one of [B-1] to [B-9],
R3 and R3 ' are hydrogen atoms;
A compound or a pharmacologically acceptable salt thereof, wherein p is 1.
[B-11]
The compound according to any one of [B-1] to [B-10],
A compound in which m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

〔Ｂ-１２〕
前記〔Ｂ-１〕から〔Ｂ-１１〕の何れかに記載の化合物であって、式（Ｖ）で表される化合物：

Figure JPOXMLDOC01-appb-C000076
〔式中、
R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になってC3-8シクロアルキルを形成してもよく；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000077
 R2は、C1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル又は-NR5R5’であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [B-12]
The compound according to any one of [B-1] to [B-11] above, which is represented by formula (V):
Figure JPOXMLDOC01-appb-C000076
 [During the ceremony,
R 1a is a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
Two R 1a may be joined together to form a C 3-8 cycloalkyl;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000077
 R2 is C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl or -NR5R5 ' ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ｂ-１３〕
前記〔Ｂ-１〕から〔Ｂ-１２〕の何れかに記載の化合物であって、式（ＶＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000078
〔式中、
R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になってC3-8シクロアルキルを形成してもよく；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000079
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [B-13]
The compound according to any one of [B-1] to [B-12] above, which is represented by formula (VI):
Figure JPOXMLDOC01-appb-C000078
 [During the ceremony,
R 1a is a halogen atom, C 1-6 alkyl, haloC 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
Two R 1a may be joined together to form a C 3-8 cycloalkyl;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000079
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ｂ-１４〕
前記〔Ｂ-１〕から〔Ｂ-１１〕の何れかに記載の化合物であって、式（ＶＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000080
〔式中、
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、カルボキシC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000081
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは1から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [B-14]
The compound according to any one of [B-1] to [B-11] above, which is represented by formula (VII):
Figure JPOXMLDOC01-appb-C000080
 [During the ceremony,
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000081
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 1 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ｂ-１５〕
前記〔Ｂ-１〕から〔Ｂ-１１〕の何れかに記載の化合物であって、式（ＶＩＩＩ）で表される化合物：

Figure JPOXMLDOC01-appb-C000082
〔式中、
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、C1-6アルコキシ又は-CONH2であり；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000083
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000084
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000085
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 [B-15]
The compound according to any one of [B-1] to [B-11] above, which is represented by formula (VIII):
Figure JPOXMLDOC01-appb-C000082
 [During the ceremony,
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy or -CONH 2 ;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000083
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000084
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000085
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof.

〔Ｂ-１６〕
前記〔Ｂ-１〕から〔Ｂ-１１〕の何れかに記載の化合物であって：
環Aが式(２)又は式(３)で表される基である場合、R5は水素原子、メチル又はシクロプロピルである化合物又はその薬理学的に許容される塩。 [B-16]
The compound according to any one of [B-1] to [B-11] above,
A compound or a pharmacologically acceptable salt thereof, wherein when ring A is a group represented by formula (2) or formula (3), R 5 is a hydrogen atom, methyl or cyclopropyl.

〔Ｂ-１７〕
前記〔Ｂ-１〕から〔Ｂ-１６〕の何れかに記載の化合物であって：
R5及びR5'がそれぞれ独立して、水素原子、メチル又はシクロプロピルである化合物又はその薬理学的に許容される塩。 [B-17]
The compound according to any one of [B-1] to [B-16] above,
A compound or a pharmacologically acceptable salt thereof, wherein R 5 and R 5' are each independently a hydrogen atom, methyl or cyclopropyl.

〔Ｂ-１８〕
前記〔Ｂ-１〕から〔Ｂ-１７〕の何れかに記載の化合物であって：
R2が-NHR5である化合物又はその薬理学的に許容される塩。 [B-18]
The compound according to any one of [B-1] to [B-17] above,
A compound or a pharmacologically acceptable salt thereof, wherein R2 is -NHR5 .

〔Ｂ-１９〕
前記〔Ｂ-１〕から〔Ｂ-１８〕の何れかに記載の化合物であって、R5が水素原子である化合物又はその薬理学的に許容される塩。 [B-19]
A compound according to any one of the above [B-1] to [B-18], wherein R 5 is a hydrogen atom, or a pharmacologically acceptable salt thereof.

〔Ｂ-２０〕
前記〔Ｂ-１〕から〔Ｂ-１９〕の何れかに記載の化合物であって、L1が-NH-である化合物又はその薬理学的に許容される塩。 [B-20]
The compound according to any one of the above [B-1] to [B-19], wherein L 1 is -NH-, or a pharmacologically acceptable salt thereof.

〔Ｂ-２１〕
前記〔Ｂ-１〕から〔Ｂ-２０〕の何れかに記載の化合物であって：
Wが-CR1b=である化合物又はその薬理学的に許容される塩。
〔Ｂ-２２〕
前記〔Ｂ-１〕から〔Ｂ-２１〕の何れかに記載の化合物であって：
X及びYがそれぞれ独立して、-CR1b=である化合物又はその薬理学的に許容される塩。 [B-21]
The compound according to any one of [B-1] to [B-20] above,
A compound wherein W is -CR 1b = or a pharmacologically acceptable salt thereof.
[B-22]
The compound according to any one of [B-1] to [B-21] above,
A compound, or a pharmacologically acceptable salt thereof, wherein X and Y are each independently -CR 1b =.

〔Ｂ-２３〕
前記〔Ｂ-１〕から〔Ｂ-２２〕の何れかに記載の化合物であって：
R1bが、水素原子、ハロゲン原子、シアノ、C1-6アルキル、カルボキシC1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。 [B-23]
The compound according to any one of [B-1] to [B-22] above,
A compound or a pharmacologically acceptable salt thereof, wherein R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, carboxy C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

〔Ｂ-２４〕
前記〔Ｂ-１〕から〔Ｂ-２３〕の何れかに記載の化合物であって：
R1bが、水素原子、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。 [B-24]
The compound according to any one of [B-1] to [B-23] above,
A compound or a pharmacologically acceptable salt thereof, wherein R 1b is a hydrogen atom, a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

〔Ｂ-２５〕
前記〔Ｂ-１〕から〔Ｂ-２４〕の何れかに記載の化合物であって：
S、U及びVがそれぞれ独立して、-CH=又は-CR1c=である化合物又はその薬理学的に許容される塩。 [B-25]
The compound according to any one of [B-1] to [B-24] above,
A compound, or a pharmacologically acceptable salt thereof, wherein S, U and V are each independently -CH= or -CR 1c =.

〔Ｂ-２６〕
前記〔Ｂ-１〕から〔Ｂ-２５〕の何れかに記載の化合物であって：
Tが、-CH=又は-CR1c=である化合物又はその薬理学的に許容される塩。 [B-26]
The compound according to any one of [B-1] to [B-25] above,
A compound, or a pharmacologically acceptable salt thereof, wherein T is -CH= or -CR 1c =.

〔Ｂ-２７〕
前記〔Ｂ-１〕から〔Ｂ-２６〕の何れかに記載の化合物であって：
R1cが、ハロゲン原子、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、C1-6アルコキシ又は-CONH2である化合物又はその薬理学的に許容される塩。 [B-27]
The compound according to any one of [B-1] to [B-26] above,
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy or -CONH 2 .

〔Ｂ-２８〕
前記〔Ｂ-１〕から〔Ｂ-２７〕の何れかに記載の化合物であって：
R1cが、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又はヒドロキシC1-6アルキルである化合物又はその薬理学的に許容される塩。 [B-28]
The compound according to any one of [B-1] to [B-27] above,
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or hydroxy C 1-6 alkyl.

〔Ｂ-２９〕
前記〔Ｂ-１〕から〔Ｂ-２８〕の何れかに記載の化合物であって：
R1aが、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。 [B-29]
The compound according to any one of [B-1] to [B-28] above,
A compound, or a pharmacologically acceptable salt thereof, wherein R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

〔Ｂ-３０〕
前記〔Ｂ-１〕から〔Ｂ-２９〕の何れかに記載の化合物であって：
R1aが、C1-6アルキル、ハロC1-6アルキル又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。
〔Ｂ-３１〕
前記〔Ｂ-１〕から〔Ｂ-３０〕の何れかに記載の化合物であって：
nが、1又は2である化合物又はその薬理学的に許容される塩。
〔Ｂ-３２〕
前記〔Ｂ-１〕から〔Ｂ-３１〕の何れかに記載の化合物であって：
kが、0から2の整数である化合物又はその薬理学的に許容される塩。
〔Ｂ-３３〕
前記〔Ｂ-１〕から〔Ｂ-３２〕の何れかに記載の化合物であって：
kが、1又は2である化合物又はその薬理学的に許容される塩。 [B-30]
The compound according to any one of [B-1] to [B-29] above,
A compound, or a pharmacologically acceptable salt thereof, wherein R 1a is C 1-6 alkyl, halo C 1-6 alkyl, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).
[B-31]
The compound according to any one of [B-1] to [B-30],
A compound or a pharmacologically acceptable salt thereof, wherein n is 1 or 2.
[B-32]
The compound according to any one of [B-1] to [B-31] above,
A compound or a pharmacologically acceptable salt thereof, wherein k is an integer of 0 to 2.
[B-33]
The compound according to any one of [B-1] to [B-32] above,
A compound or a pharmacologically acceptable salt thereof, wherein k is 1 or 2.

〔Ｂ-３４〕
前記〔Ｂ-１〕から〔Ｂ-３３〕の何れかに記載の化合物であって：
R3及びR3’が水素原子又はC1-6アルキルであり；
pが1又は2である化合物又はその薬理学的に許容される塩。 [B-34]
The compound according to any one of [B-1] to [B-33] above,
R3 and R3 ' are hydrogen atoms or C1-6 alkyl;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.

〔Ｂ-３５〕
前記〔Ｂ-１〕から〔Ｂ-３４〕の何れかに記載の化合物であって：
R3及びR3’が水素原子であり；
pが1又は2である化合物又はその薬理学的に許容される塩。 [B-35]
The compound according to any one of [B-1] to [B-34] above,
R3 and R3 ' are hydrogen atoms;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.

〔Ｂ-３６〕
前記〔Ｂ-１〕から〔Ｂ-３５〕の何れかに記載の化合物であって：
pが1又は2である化合物又はその薬理学的に許容される塩。 [B-36]
The compound according to any one of [B-1] to [B-35] above,
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2.

〔Ｂ-３７〕
前記〔Ｂ-１〕から〔Ｂ-３６〕の何れかに記載の化合物であって：
pが1である化合物又はその薬理学的に許容される塩。 [B-37]
The compound according to any one of [B-1] to [B-36] above,
A compound or a pharmacologically acceptable salt thereof, wherein p is 1.

〔Ｂ-３８〕
前記〔Ｂ-１〕から〔Ｂ-３７〕の何れかに記載の化合物であって：
環Zが、C6-10アリールである化合物又はその薬理学的に許容される塩。 [B-38]
The compound according to any one of [B-1] to [B-37] above,
A compound or a pharmacologically acceptable salt thereof, wherein ring Z is C 6-10 aryl.

〔Ｂ-３９〕
前記〔Ｂ-１〕から〔Ｂ-３８〕の何れかに記載の化合物であって：
R4が、ハロゲン原子、シアノ、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5である化合物又はその薬理学的に許容される塩。 [B-39]
The compound according to any one of [B-1] to [B-38],
A compound or a pharmacologically acceptable salt thereof, wherein R4 is a halogen atom, cyano, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , C6-10 aryloxy, C6-10 arylC1-6 alkoxy, 5- or 6 -membered heteroarylC2-6 alkynyl, C3-8 cycloalkylC2-6 alkynyl, or -SF5.

〔Ｂ-４０〕
前記〔Ｂ-１〕から〔Ｂ-３９〕の何れかに記載の化合物であって：
R4が、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、ハロC1-6アルコキシ、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、5若しくは6員環ヘテロアリールC2-6アルキニル又は-SF5である化合物又はその薬理学的に許容される塩。 [B-40]
The compound according to any one of [B-1] to [B-39] above,
A compound or a pharmacologically acceptable salt thereof, wherein R4 is a halogen atom, C1-6 alkyl, haloC1-6 alkyl, halohydroxyC1-6 alkyl, haloC1-6 alkoxy, C6-10 arylC1-6 alkyl, C6-10 arylC2-6 alkynyl , 5- or 6-membered heteroarylC2-6 alkynyl, or -SF5 .

〔Ｂ-４１〕
前記〔Ｂ-１〕から〔Ｂ-４０〕の何れかに記載の化合物であって、mが1から3の整数である化合物又はその薬理学的に許容される塩。 [B-41]
The compound according to any one of the above [B-1] to [B-40], wherein m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

〔Ｂ-４２〕
以下の化合物からなる群から選択される、前記〔Ｂ-１〕から〔Ｂ-４１〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
 及び
Figure JPOXMLDOC01-appb-C000088
 又はその薬理学的に許容される塩。 [B-42]
The compound according to any one of [B-1] to [B-41] above, which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
 and
Figure JPOXMLDOC01-appb-C000088
 Or a pharmacologically acceptable salt thereof.

〔Ｂ-４３〕
以下の化合物からなる群から選択される、前記〔Ｂ-１〕から〔Ｂ-４２〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000089
及び
Figure JPOXMLDOC01-appb-C000090
 又はその薬理学的に許容される塩。 [B-43]
The compound according to any one of [B-1] to [B-42] above, which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000089
 and
Figure JPOXMLDOC01-appb-C000090
 Or a pharmacologically acceptable salt thereof.

〔Ｂ-４４〕
以下の化合物からなる群から選択される、前記〔Ｂ-１〕から〔Ｂ-４２〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000091
及び
Figure JPOXMLDOC01-appb-C000092
 又はその薬理学的に許容される塩。 [B-44]
The compound according to any one of [B-1] to [B-42] above, which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000091
 and
Figure JPOXMLDOC01-appb-C000092
 Or a pharmacologically acceptable salt thereof.

〔Ｂ-４５〕
以下の化合物からなる群から選択される、前記〔Ｂ-１〕から〔Ｂ-４２〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000093
及び
Figure JPOXMLDOC01-appb-C000094
 又はその薬理学的に許容される塩。 [B-45]
The compound according to any one of [B-1] to [B-42] above, which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000093
 and
Figure JPOXMLDOC01-appb-C000094
 Or a pharmacologically acceptable salt thereof.

〔Ｂ-４６〕
以下の化合物からなる群から選択される、前記〔Ｂ-１〕から〔Ｂ-４１〕の何れかに記載の化合物：

Figure JPOXMLDOC01-appb-C000095
及び
Figure JPOXMLDOC01-appb-C000096
 又はその薬理学的に許容される塩。 [B-46]
The compound according to any one of [B-1] to [B-41] above, which is selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000095
 and
Figure JPOXMLDOC01-appb-C000096
 Or a pharmacologically acceptable salt thereof.

〔Ｂ-４７〕
前記〔Ｂ-１〕から〔Ｂ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩、及び医薬品添加物を含む医薬組成物。 [B-47]
A pharmaceutical composition comprising the compound according to any one of the above [B-1] to [B-46] or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

〔Ｂ-４８〕
甲状腺関連疾患の治療用医薬組成物である前記〔Ｂ-４７〕に記載の医薬組成物。 [B-48]
The pharmaceutical composition described in [B-47] above, which is a pharmaceutical composition for treating thyroid-related diseases.

〔Ｂ-４９〕
前記〔Ｂ-４８〕に記載の医薬組成物であって、甲状腺関連疾患が甲状腺機能亢進症、グレーブス病、又は甲状腺眼症である医薬組成物。 [B-49]
The pharmaceutical composition according to the above [B-48], wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

〔Ｂ-５０〕
前記〔Ｂ-１〕から〔Ｂ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩を有効成分として含有するTSHR阻害剤。
〔Ｂ-５１〕
前記〔Ｂ-１〕から〔Ｂ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩を有効成分として含有する甲状腺関連疾患治療剤。 [B-50]
A TSHR inhibitor comprising, as an active ingredient, any one of the compounds according to [B-1] to [B-46] or a pharmacologically acceptable salt thereof.
[B-51]
A therapeutic agent for thyroid-related diseases, comprising as an active ingredient any one of the compounds according to the above [B-1] to [B-46] or a pharmacologically acceptable salt thereof.

　式（Ｉ）～(ＶＩ)で表される化合物の一つの実施態様として、例えば、2つのR1aが一緒になってC3-8シクロアルキルを形成する場合、以下の(a)又は(b)の式で表される環：

Figure JPOXMLDOC01-appb-C000097
（式中、qは、1から4の整数である）,
Figure JPOXMLDOC01-appb-C000098
 （式中、rは、1から4の整数である）;
を形成する化合物が挙げられる。 As an embodiment of the compounds represented by formulae (I) to (VI), for example, when two R 1a are taken together to form a C 3-8 cycloalkyl, the ring is represented by the following formula (a) or (b):
Figure JPOXMLDOC01-appb-C000097
 (wherein q is an integer from 1 to 4),
Figure JPOXMLDOC01-appb-C000098
 wherein r is an integer from 1 to 4;
Examples of the compound include compounds which form the following formula:

　一つの実施態様として、本発明は、前記〔Ｂ-４７〕に記載の医薬組成物を患者に必要量投与することを含む、甲状腺関連疾患の治療方法に関する。 In one embodiment, the present invention relates to a method for treating a thyroid-related disease, comprising administering to a patient a required amount of the pharmaceutical composition described in [B-47] above.

　一つの実施態様として、本発明は、甲状腺関連疾患の治療用医薬組成物を製造するための、前記〔Ｂ-１〕から〔Ｂ-４６〕の何れかに記載の化合物又はその薬理学的に許容される塩の使用に関する。 In one embodiment, the present invention relates to the use of any of the compounds described in [B-1] to [B-46] above or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating a thyroid-related disease.

　本発明の化合物は、優れたTSHRアンタゴニスト活性を有する。したがって、本発明の化合物又はその薬理学的に許容される塩は、甲状腺関連疾患の治療剤として有用である。 The compounds of the present invention have excellent TSHR antagonist activity. Therefore, the compounds of the present invention or their pharmacologically acceptable salts are useful as therapeutic agents for thyroid-related diseases.

　以下、本発明の実施形態についてより詳細に説明する。 The following describes an embodiment of the present invention in more detail.

　本発明において、各用語は、特に断らない限り、以下の意味を有する。 In this invention, each term has the following meaning unless otherwise specified.

　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を意味する。
　「C1-6アルキル」とは、炭素数1～6の直鎖状又は分岐状のアルキル基を意味する。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル等が挙げられる。
　「C1-6アルキレン」とは、炭素数1～6の直鎖状又は分岐状のアルキレン基を意味する。例えば、メチレン、エチレン、1-プロピレン等が挙げられる。
　「C2-6アルケニル」とは、少なくとも1個の二重結合を有する炭素数2～6のアルケニル基を意味する。例えば、エテニル、1-プロペニル、2-プロペニル等が挙げられる。
　「C2-6アルキニル」とは、少なくとも1個の三重結合を有する炭素数2～6のアルキニル基を意味する。例えば、エチニル、1-プロピニル、2-プロピニル、1-ブチニル等が挙げられる。
　「C1-6アルコキシ」とは、炭素数1～6の直鎖状又は分岐状のアルコキシ基を意味する。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ等が挙げられる。 The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.
"C 1-6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like.
"C 1-6 alkylene" means a straight or branched alkylene group having 1 to 6 carbon atoms. Examples include methylene, ethylene, and 1-propylene.
"C 2-6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and at least one double bond, for example, ethenyl, 1-propenyl, 2-propenyl, etc.
"C 2-6 alkynyl" refers to an alkynyl group having from 2 to 6 carbon atoms and at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, etc.
"C 1-6 alkoxy" means a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

　「ヒドロキシC1-6アルキル」とは、1又は2個のヒドロキシで置換されたC1-6アルキルを意味する。例えば、ヒドロキシメチル、2-ヒドロキシエチル、3-ヒドロキシプロピル、2-ヒドロキシプロパン-2-イル等が挙げられる。
　「ハロC1-6アルキル」とは、1～5個の同種又は異種のハロゲン原子で置換されたC1-6アルキルを意味する。例えば、モノフルオロメチル、2-フルオロエチル、ジフルオロメチル、トリフルオロメチル、1,1-ジフルオロエチル、2,2,2-トリフルオロエチル、3,3,3-トリフルオロプロピル、4,4,4-トリフルオロブチル、ペンタフルオロエチル等が挙げられる。
　「ハロC1-6アルコキシ」とは、1～5個の同種又は異種のハロゲン原子で置換されたC1-6アルコキシを意味する。例えば、モノフルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、1,1,2,2-テトラフルオロエトキシ、ペンタフルオロエトキシ等が挙げられる。
　「C1-6アルコキシC1-6アルキル」とは、1個のC1-6アルコキシで置換されたC1-6アルキルを意味する。例えば、メトキシメチル、メトキシエチル、エトキシメチル、エトキシエチル等が挙げられる。
　「カルボキシC1-6アルキル」とは、1個のカルボキシで置換されたC1-6アルキルを意味する。例えば、カルボキシメチル、カルボキシエチル等が挙げられる。
　「アミノC1-6アルキル」とは、1又は2個のC1-6アルキルで置換されてもよい1個のアミノで置換されたC1-6アルキルを意味する。例えば、アミノメチル、N-メチルアミノエチル、N,N-ジメチルアミノエチル等が挙げられる。
　「シアノC1-6アルキル」とは、1個のシアノで置換されたC1-6アルキルを意味する。例えば、シアノメチル、シアノエチル等が挙げられる。
　「ハロヒドロキシC1-6アルキル」とは、1～6個の同種又は異種のハロゲン原子及び1又は2個のヒドロキシで置換されたC1-6アルキルを意味する。例えば、1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イルが挙げられる。 "Hydroxy C 1-6 alkyl" means a C 1-6 alkyl substituted with 1 or 2 hydroxy groups. Examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, and the like.
"Halo C 1-6 alkyl" means a C 1-6 alkyl substituted with 1 to 5 of the same or different halogen atoms, such as monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl, etc.
"Halo C 1-6 alkoxy" means a C 1-6 alkoxy substituted with 1 to 5 of the same or different halogen atoms, for example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, etc.
"C 1-6 alkoxy C 1-6 alkyl" means a C 1-6 alkyl substituted with one C 1-6 alkoxy, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, etc.
"Carboxy C 1-6 alkyl" means a C 1-6 alkyl substituted with one carboxy. Examples include carboxymethyl and carboxyethyl.
"Amino C 1-6 alkyl" means a C 1-6 alkyl substituted with one amino which may be substituted with one or two C 1-6 alkyls. Examples include aminomethyl, N-methylaminoethyl, and N,N-dimethylaminoethyl.
"Cyano C 1-6 alkyl" means a C 1-6 alkyl substituted with one cyano. Examples include cyanomethyl and cyanoethyl.
"HalohydroxyC 1-6 alkyl" refers to a C 1-6 alkyl substituted with 1 to 6 of the same or different halogen atoms and 1 or 2 hydroxy, for example, 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl.

　「C6-10アリール」とは、フェニル基、又はナフチル基を意味する。
　「5若しくは6員環ヘテロアリール」とは、酸素原子、窒素原子及び硫黄原子から選択される1～4個のヘテロ原子を環内に含む5又は6員環の芳香族複素環基を意味する。例えば、ピリジル、フリル、ピロリル、チエニル、イミダゾリル、ピラゾリル、1,2,4-トリアゾリル、イソチアゾリル、イソオキサゾリル、オキサゾリル、チアゾリル、1,3,4-オキサジアゾリル、1,2,4-オキサジアゾリル等が挙げられる。
　「5～10員環ヘテロアリール」とは、酸素原子、窒素原子及び硫黄原子から選択される1～4個のヘテロ原子を環内に含む5から10員環の芳香族複素環基を意味し、環の一部が部分的に飽和されていても良い。例えば、ピリジル、フリル、ピロリル、チエニル、イミダゾリル、ピラゾリル、1,2,4-トリアゾリル、イソチアゾリル、イソオキサゾリル、オキサゾリル、チアゾリル、1,3,4-オキサジアゾリル、1,2,4-オキサジアゾリル、2,3-ジヒドロベンゾフラニル、1,2,3,4-テトラヒドロキノリル、1,2,3,4-テトラヒドロイソキノリル等が挙げられる。
　「C3-8シクロアルキル」とは、3～8員環の飽和炭化水素基を意味し、一部架橋された構造のものも含まれる。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、ビシクロ[1.1.1]ペンチル、ビシクロ[2.2.2]オクチル等が挙げられる。
　「C3-8シクロアルコキシ」とは、(C3-8シクロアルキル)-O-で表される基を意味する。例えば、シクロプロピルオキシが挙げられる。
　「3～8員環ヘテロシクロアルキル」とは、環内の炭素原子が、酸素原子、窒素原子及び硫黄原子から選択される1若しくは2個のヘテロ原子で置換されたシクロアルキル基を意味し、一部架橋された構造のものも含まれる。例えば、アジリジニル、アゼチジニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニル、チオモルホリニル、アゼパニル、アザビシクロ[2.2.2]オクチル、2-オキサ-5-アザビシクロ[2.2.1]ヘプタニル、6-オキサ-3-アザビシクロ[2.2.1]ヘプタニル、8-オキサ-3-アザビシクロ[3.2.1]オクタニル、3-オキサ-8-アザビシクロ[3.2.1]オクタニル、2-アザスピロ[3.3]ヘプタニル、2-オキサ-6-アザスピロ[3.3]ヘプタニル、ピロリドニル、ピペリドニル、オキシラニル、オキセチル、テトラヒドロフラニル、テトラヒドロピラニル等が挙げられる。 " C6-10 aryl" means a phenyl group or a naphthyl group.
The term "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, such as pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl.
The term "5- to 10-membered heteroaryl" refers to an aromatic heterocyclic group having 5 to 10 members and containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms in the ring, and a part of the ring may be partially saturated. Examples of the heterocyclic group include pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, and the like.
"C 3-8 cycloalkyl" refers to a saturated hydrocarbon group having 3 to 8 ring members, including those with a partially bridged structure. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.2.2]octyl.
"C 3-8 cycloalkoxy" refers to a group represented by (C 3-8 cycloalkyl)-O-. For example, cyclopropyloxy is mentioned.
The term "3- to 8-membered heterocycloalkyl" refers to a cycloalkyl group in which carbon atoms in the ring are substituted with 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur atoms, and also includes those having a partially bridged structure. For example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[2.2.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrrolidonyl, piperidonyl, oxiranyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

　「C6-10アリールオキシ」とは、(C6-10アリール)-O-で表される基を意味する。例えば、フェノキシが挙げられる。
　「C6-10アリールC1-6アルコキシ」とは、1個のC6-10アリールで置換されたC1-6アルコキシを意味する。例えば、ベンジルオキシが挙げられる。 " C6-10 aryloxy" refers to a group represented by ( C6-10 aryl)-O-. For example, phenoxy is mentioned.
" C6-10 aryl C1-6 alkoxy" means a C1-6 alkoxy substituted with one C6-10 aryl. For example, benzyloxy is mentioned.

　「C3-8シクロアルキルC1-6アルコキシ」とは、1個のC3-8シクロアルキルで置換されたC1-6アルコキシを意味する。例えば、シクロプロピルメチルオキシが挙げられる。 " C3-8 cycloalkyl C1-6 alkoxy" means a C1-6 alkoxy substituted with one C3-8 cycloalkyl, for example cyclopropylmethyloxy.

　「C6-10アリールC1-6アルキル」とは、1個のC6-10アリールで置換されたC1-6アルキルを意味する。例えば、ベンジルが挙げられる。 " C6-10 aryl C1-6 alkyl" means a C1-6 alkyl substituted with one C6-10 aryl, for example benzyl.

　「5若しくは6員環ヘテロアリールC2-6アルキル」とは、1個の5若しくは6員環ヘテロアリールで置換されたC2-6アルキルを意味する。例えば、ピリジン-4-イルメチル、チオフェン-2-イルエチル、チオフェン-3-イルエチル等が挙げられる。 "5- or 6-membered heteroaryl C2-6 alkyl" means a C2-6 alkyl substituted with one 5- or 6-membered heteroaryl. Examples include pyridin-4-ylmethyl, thiophen-2-ylethyl, and thiophen-3-ylethyl.

　「C3-8シクロアルキルC1-6アルキル」とは、1個のC3-8シクロアルキルで置換されたC1-6アルキルを意味する。例えば、シクロプロピルメチル、シクロプロピルエタン-1-イル、シクロブチルメチル、シクロペンチルメチル、シクロへキシルメチル等が挙げられる。 " C3-8 cycloalkyl C1-6 alkyl" means a C1-6 alkyl substituted with one C3-8 cycloalkyl, for example, cyclopropylmethyl, cyclopropylethan-1-yl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

　「C6-10アリールC2-6アルキニル」とは、1個のC6-10アリールで置換されたC2-6アルキニルを意味する。例えば、フェニルエチニルが挙げられる。 " C6-10 aryl C2-6 alkynyl" means a C2-6 alkynyl substituted with one C6-10 aryl. For example, phenylethynyl is mentioned.

　「5若しくは6員環ヘテロアリールC1-6アルキル」とは、1個の5若しくは6員環ヘテロアリールで置換されたC1-6アルキルを意味する。
　「5若しくは6員環ヘテロアリールC2-6アルキニル」とは、1個の5若しくは6員環ヘテロアリールで置換されたC2-6アルキニルを意味する。例えば、ピリジン-4-イルエチニル、ピリジン-3-イルエチニル等が挙げられる。 "5- or 6-membered heteroaryl C 1-6 alkyl" means a C 1-6 alkyl substituted with one 5- or 6-membered heteroaryl.
"5- or 6-membered heteroaryl C2-6 alkynyl" means a C2-6 alkynyl substituted with one 5- or 6-membered heteroaryl. For example, pyridin-4-ylethynyl, pyridin-3-ylethynyl, etc. are mentioned.

　「C3-8シクロアルキルC2-6アルキニル」とは、1個のC3-8シクロアルキルで置換されたC2-6アルキニルを意味する。例えば、シクロプロピルエチニルが挙げられる。 " C3-8 cycloalkyl C2-6 alkynyl" means a C2-6 alkynyl substituted with one C3-8 cycloalkyl, for example, cyclopropylethynyl.

　「3～8員飽和炭素環」とは、単環式若しくは多環式であり、炭素原子数が3から8である環状の飽和炭化水素を意味する。
　「5～8員飽和炭素環」とは、単環式若しくは多環式であり、炭素原子数が5から8である環状の飽和炭化水素を意味する。 The term "3- to 8-membered saturated carbocyclic ring" refers to a monocyclic or polycyclic saturated hydrocarbon ring having from 3 to 8 carbon atoms.
The term "5- to 8-membered saturated carbocyclic ring" refers to a monocyclic or polycyclic saturated hydrocarbon ring having from 5 to 8 carbon atoms.

　「5～8員不飽和炭素環」とは、単環式若しくは多環式であり、完全不飽和又は部分不飽和である、炭素原子数が5から8である環状の炭化水素を意味する。 "5- to 8-membered unsaturated carbocyclic ring" means a monocyclic or polycyclic, fully unsaturated or partially unsaturated cyclic hydrocarbon having 5 to 8 carbon atoms.

　「3～8員飽和複素環」とは、窒素原子、酸素原子及び硫黄原子から選択されるヘテロ原子を環内に１個から5個有し、単環式又は多環式である3から8員の飽和複素環を意味する。
　「3～10員飽和複素環」とは、窒素原子、酸素原子及び硫黄原子から選択されるヘテロ原子を環内に１個から5個有し、単環式又は多環式である3から10員の飽和複素環を意味する。
　「5～8員飽和複素環」とは、窒素原子、酸素原子及び硫黄原子から選択されるヘテロ原子を環内に１個から3個有し、単環式又は多環式である5から8員の飽和複素環を意味する。 The term "3- to 8-membered saturated heterocycle" means a monocyclic or polycyclic 3- to 8-membered saturated heterocycle having 1 to 5 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
The term "3- to 10-membered saturated heterocycle" refers to a monocyclic or polycyclic 3- to 10-membered saturated heterocycle having 1 to 5 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
The term "5- to 8-membered saturated heterocycle" means a monocyclic or polycyclic 5- to 8-membered saturated heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.

　「3～10員不飽和複素環」とは、窒素原子、酸素原子及び硫黄原子から選択されるヘテロ原子を環内に１個から5個有する、単環式又は多環式であり、完全不飽和又は部分不飽和である3から10員の複素環を意味する。
　「5～8員不飽和複素環」とは、窒素原子、酸素原子及び硫黄原子から選択されるヘテロ原子を環内に１個から3個有する、単環式又は多環式であり、完全不飽和又は部分不飽和である5から8員の複素環を意味する。 The term "3- to 10-membered unsaturated heterocycle" refers to a monocyclic or polycyclic, fully unsaturated or partially unsaturated 3- to 10-membered heterocycle having 1 to 5 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
The term "5- to 8-membered unsaturated heterocycle" means a monocyclic or polycyclic, fully unsaturated or partially unsaturated 5- to 8-membered heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.

　「5～8員環」とは、5～8員飽和炭素環、5～8員飽和複素環、5～8員不飽和炭素環、又は5～8員不飽和複素環を意味する。 "5- to 8-membered ring" means a 5- to 8-membered saturated carbocyclic ring, a 5- to 8-membered saturated heterocyclic ring, a 5- to 8-membered unsaturated carbocyclic ring, or a 5- to 8-membered unsaturated heterocyclic ring.

　本文中、図中及び表中の以下の略語は、それぞれ以下の意味である。
AIBN：アゾビスイソブチロニトリル
BH3-THF：ボラン-テトラヒドロフラン錯体
Boc：tert-ブトキシカルボニル
Boc2O：二炭酸ジ-tert-ブチル
DBU：ジアザビシクロウンデセン
DCM：ジクロロメタン
DEAD：アゾジカルボン酸ジエチル
DIBAL-H：水素化ジイソブチルアルミニウム
DIPEA：N,N-ジイソプロピルエチルアミン
DMAP：4-ジメチルアミノピリジン
DME：1,2-ジメトキシエタン
DMF：N,N-ジメチルホルムアミド
DMP：デス-マーチンペルヨージナン
DPPA：ジフェニルホスホリルアジド
DMT-MM：4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド
HATU：O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスファート
LDA：リチウムジイソプロピルアミド
MeCN：アセトニトリル
MTBE：メチルtert-ブチルエーテル
NBS：N-ブロモスクシンイミド
NMP：N-メチルピロリドン
PdCl2(dppf)-DCM：[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド DCM付加物
TBAF：テトラブチルアンモニウムフルオリド
TBAI：テトラブチルアンモニウムヨージド
TBDPS：tert-ブチルジフェニルシリル
TBDPSCl：tert-ブチルジフェニルシリルクロリド
TBS：tert-ブチルジメチルシリル
TEA：トリエチルアミン
TFA：トリフルオロ酢酸
THF：テトラヒドロフラン
TMEDA：N,N,N',N'-テトラメチルエチレンジアミン
TMS：トリメチルシリル
TMSCl：トリメチルシリルクロリド
Xphos：2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピルビフェニル
10% Pd/C：10% パラジウム炭素（約55%水湿潤）
APS：アミノプロピル化シリカゲル
Method A：アミノプロピル化シリカゲルカラムの下部にシリカゲルカラムを接続したカラムクロマトグラフィー
Method B：シリカゲルカラムの下部にアミノプロピル化シリカゲルカラムを接続したカラムクロマトグラフィー
ODS：オクタデシルシリル化シリカゲル
PLC：分取薄層クロマトグラフィー
Ref. No.：参考例番号
Str.：構造式
Ex. No.：実施例番号
Phys. data：物性値
IC50：50%阻害濃度
1H-NMR：プロトン核磁気共鳴スペクトル
CD3OD：メタノール-d4
DMSO：ジメチルスルホキシド
DMSO-d6：ジメチルスルホキシド-d6
CDCl3：クロロホルム-d1
MS：質量分析
（表中の測定値は、エレクトロスプレーイオン化法、又はエレクトロスプレーイオン化法－大気圧化学イオン化法のマルチイオン化法により測定した。）
cAMP：アデノシン3',5'-環状一リン酸
CHO：チャイニーズハムスター卵巣
FBS：ウシ胎児血清
HEPES：2-(4-(2-ヒドロキシエチル)-1-ピペラジニル)エタンスルホン酸
IBMX：3-イソブチル-1-メチルキサンチン The following abbreviations used in the text, figures and tables have the following meanings:
AIBN: Azobisisobutyronitrile
BH 3 -THF: Borane-tetrahydrofuran complex
Boc: tert-butoxycarbonyl
Boc2O : di-tert-butyl dicarbonate
DBU: Diazabicycloundecene
DCM: dichloromethane
DEAD: Diethyl azodicarboxylate
DIBAL-H: Diisobutylaluminum hydride
DIPEA: N,N-diisopropylethylamine
DMAP: 4-dimethylaminopyridine
DME: 1,2-dimethoxyethane
DMF: N,N-dimethylformamide
DMP: Dess-Martin periodinane
DPPA: Diphenylphosphoryl azide
DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
LDA: Lithium diisopropylamide
MeCN: Acetonitrile
MTBE: Methyl tert-butyl ether
NBS: N-bromosuccinimide
NMP: N-methylpyrrolidone
PdCl 2 (dppf)-DCM: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM adduct
TBAF: Tetrabutylammonium fluoride
TBAI: Tetrabutylammonium iodide
TBDPS: tert-butyldiphenylsilyl
TBDPSCl: tert-butyldiphenylsilyl chloride
TBS: tert-butyldimethylsilyl
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TMEDA: N,N,N',N'-Tetramethylethylenediamine
TMS: Trimethylsilyl
TMSCl: Trimethylsilyl chloride
Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
10% Pd/C: 10% palladium on carbon (approximately 55% water wet)
APS: Aminopropylated silica gel
Method A: Column chromatography using a silica gel column connected to the bottom of an aminopropylated silica gel column
Method B: Column chromatography using an aminopropylated silica gel column connected to the bottom of a silica gel column
ODS: Octadecylsilylated silica gel
PLC: Preparative thin layer chromatography
Ref. No.: Reference number
Str.: Structural formula
Ex. No.: Example number
Phys. data: Physical properties
IC50 : 50% inhibitory concentration
1H -NMR: Proton nuclear magnetic resonance spectrum
CD3OD :methanol-d4
DMSO: Dimethyl sulfoxide
DMSO-d6: Dimethylsulfoxide-d6
CDCl3 : Chloroform-d1
MS: Mass spectrometry (The values in the table were measured by electrospray ionization or electrospray ionization-atmospheric pressure chemical ionization multi-ionization method.)
cAMP: adenosine 3',5'-cyclic monophosphate
CHO: Chinese hamster ovary
FBS: fetal bovine serum
HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid
IBMX: 3-isobutyl-1-methylxanthine

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物において、１つ又はそれ以上の不斉炭素原子が存在する場合、本発明は、各々の不斉炭素原子がR配置の化合物、S配置の化合物及びそれらの任意の組み合わせの化合物も包含する。また、それらのラセミ化合物、ラセミ混合物、単一のエナンチオマー及びジアステレオマー混合物も本発明の範囲に含まれる。 In the compounds represented by formulae (A-I) to (A-VIII) or formulae (I) to (VIII), when one or more asymmetric carbon atoms are present, the present invention also includes compounds in which each asymmetric carbon atom is in the R configuration, the S configuration, and any combination thereof. In addition, their racemic compounds, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物において、シス－トランス異性体が存在する場合、本発明は、そのシス－トランス異性体のいずれも包含する。 In the compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII), when cis-trans isomers exist, the present invention includes both cis-trans isomers.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物において互変異性体が存在する場合、本発明は、その互変異性体の何れも含む。 When tautomers exist in the compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII), the present invention includes all of those tautomers.

　本発明において、立体化学の決定は、当技術分野で周知の方法で行うこともできる。 In the present invention, the determination of stereochemistry can also be performed by methods well known in the art.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物は、必要に応じて常法に従い、その薬理学的に許容される塩にすることもできる。このような塩としては、酸付加塩又は塩基との塩を挙げることができる。 The compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII) can be converted into their pharmacologically acceptable salts according to conventional methods, if necessary. Examples of such salts include acid addition salts and salts with bases.

　酸付加塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の鉱酸との酸付加塩、ギ酸、酢酸、TFA、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、安息香酸、グルタミン酸、アスパラギン酸等の有機酸との酸付加塩を挙げることができる。 Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, TFA, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

　塩基との塩としては、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩基との塩、N-メチル-D-グルカミン、N,N'-ジベンジルエチレンジアミン、TEA、ピペリジン、モルホリン、ピロリジン、アルギニン、リジン、コリン等の有機塩基との塩を挙げることができる。 Salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, TEA, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

　別段の断りがない限り、例えば「塩酸塩」、又は「HCl」などの塩に関する化学名もしくは構造式への接尾辞は、化学量論的記述ではなく、単に塩形態を意味するものである。 Unless otherwise noted, a suffix to a chemical name or structural formula for a salt, e.g., "hydrochloride" or "HCl," is intended to denote simply the salt form and not a stoichiometric description.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその薬理学的に許容される塩が、例えば結晶として存在する場合、本発明は、何れの結晶形も含む。例えば、薬理学的に許容される塩には、水又はエタノール等の医薬品として許容される溶媒との溶媒和物、適当な共結晶形成剤（Coformer）との共結晶等も含まれる。 When the compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII) or pharmacologically acceptable salts thereof exist, for example, as crystals, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with medicamentously acceptable solvents such as water or ethanol, cocrystals with an appropriate coformer, etc.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物において、各原子の一部は、それぞれ対応する同位体で置き換わっていてもよい。本発明は、これら同位体で置き換わった化合物も含む。同位体の例としては、それぞれ2H、3H、11C、13C、14C、36Cl、18F、123I、125I、13N、15N、15O、17O、18O、及び35Sで表される水素原子、炭素原子、塩素原子、フッ素原子、ヨウ素原子、窒素原子、酸素原子、及び硫黄原子の同位体が挙げられる。一つの実施態様として、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物の一部の水素原子が2H(D:重水素原子）で置き換わった化合物が挙げられる。 In the compounds represented by formulae (A-I) to (A-VIII) or formulae (I) to (VIII), a part of each atom may be replaced by the corresponding isotope. The present invention also includes compounds replaced by these isotopes. Examples of isotopes include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur atoms represented by 2H , 3H , 11C , 13C , 14C , 36Cl , 18F , 123I , 125I , 13N , 15N , 15O , 17O , 18O, and 35S , respectively . One embodiment includes a compound represented by formulae (A-I) to (A-VIII) or formulae (I) to (VIII) in which a part of hydrogen atoms is replaced by 2H (D: deuterium atom).

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物において、一部の原子が同位体で置き換わった化合物は、市販の同位体が導入されたビルディングブロックを用いて、後述の製造方法と同様な方法で製造することができる。また、文献記載の方法（例えば、有機合成化学協会誌、第65巻、12号、1179-1190ページ、2007年参照やRADIOISOTOPES、第56巻、11号、741-750ページ、2007年参照）を用いて、製造することもできる。 Compounds represented by formulae (A-I) to (A-VIII) or formulae (I) to (VIII) in which some atoms are replaced with isotopes can be produced using commercially available building blocks containing isotopes in a similar manner to the production method described below. They can also be produced using methods described in the literature (see, for example, Journal of the Society of Organic Synthesis, Vol. 65, No. 12, pp. 1179-1190, 2007 and RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

　本発明の式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物は、例えばScheme 1～7に示す方法若しくはそれに準じた方法、又は文献記載の方法若しくはそれに準じた方法に従い製造することができる。Scheme中、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物は、式（Ｉ-１）～（Ｉ-５）で表される化合物に対応する。 The compounds of the present invention represented by formulae (A-I) to (A-VIII) or (I) to (VIII) can be produced, for example, by the methods shown in Schemes 1 to 7 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compounds of formulae (A-I) to (A-VIII) or (I) to (VIII) correspond to the compounds of formulae (I-1) to (I-5).

　本発明の式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物は、以下に示す方法によって製造することができるが、下記製造法は一般的製造法を例示するものであり、製造法を限定するものではない。 The compounds of the present invention represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII) can be produced by the methods shown below, but the following production methods are examples of general production methods and are not intended to limit the production methods.

　各工程の反応において、原料物質や試薬が市販されている場合には、市販品を用いることができる。 If the raw materials and reagents for each reaction step are commercially available, they can be used.

　各工程の反応において、反応時間は、使用する原料物質、溶媒、反応温度などにより異なるが、特に記載の無い場合、通常30分～3日間である。 The reaction time for each step varies depending on the raw materials, solvent, reaction temperature, etc. used, but is usually 30 minutes to 3 days unless otherwise specified.

　各工程の反応において、反応温度は、使用する原料物質や溶媒などにより異なるが、特に記載の無い場合、通常-78℃～還流温度である。 The reaction temperature for each step varies depending on the raw materials and solvents used, but unless otherwise specified, it is usually between -78°C and the reflux temperature.

　各工程の反応において、圧力は、使用する原料物質、溶媒、反応温度などにより異なるが、特に記載の無い場合、通常1～20気圧である。 The pressure in each reaction step varies depending on the raw materials, solvent, reaction temperature, etc. used, but is usually 1 to 20 atmospheres unless otherwise specified.

　各工程の反応において、Biotage社製Initiatorなどのマイクロ波反応装置を用いることがある。マイクロ波反応装置を用いて反応を行う場合、使用する原料物質、溶媒及び機種などにより異なるが、圧力範囲：1～30 bar、出力領域：1～400 W、反応温度：室温～300℃、反応時間：1分～1日間の条件下で反応を実施できる。 In the reactions at each step, a microwave reactor such as Biotage's Initiator may be used. When a microwave reactor is used, the reaction can be carried out under the following conditions, which vary depending on the raw materials, solvent, and model used: pressure range: 1-30 bar, power range: 1-400 W, reaction temperature: room temperature to 300°C, reaction time: 1 minute to 1 day.

　各工程の反応は、特に記載の無い場合、無溶媒、又は適当な溶媒を用いて行われる。適当な溶媒の例としては、その反応に対して不活性な溶媒が挙げられる。用いられる溶媒の具体例としては、各工程に対応する参考例若しくは実施例に記載されている溶媒、又は以下の溶媒が挙げられる。以下の溶媒は、二種以上を適当な割合で混合して用いてもよい。
アルコール類：メタノール、エタノール、tert-ブチルアルコール、2-プロパノールなど；
エーテル類：ジエチルエーテル、THF、DME、1,4-ジオキサン、シクロペンチルメチルエーテル、MTBEなど；
芳香族炭化水素類：ベンゼン、クロロベンゼン、1,2-ジクロロベンゼン、トルエン、キシレンなど；
飽和炭化水素類：シクロヘキサン、n-ヘキサン、n-ペンタンなど；
アミド類：DMF、N,N-ジメチルアセトアミド、NMPなど；
ハロゲン化炭化水素類：DCM、1,2-ジクロロエタン、四塩化炭素など；
ニトリル類：MeCNなど；
スルホキシド類：DMSOなど；
芳香族有機塩基類：ピリジンなど；
酸無水物類：無水酢酸など；
有機酸類：ギ酸、酢酸、TFA、メタンスルホン酸など；
エステル類：酢酸エチル、酢酸メチル、酢酸イソプロピルなど；
ケトン類：アセトン、メチルエチルケトンなど；
水。 The reaction in each step is carried out without solvent or using a suitable solvent unless otherwise specified. Examples of suitable solvents include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.;
Ethers: diethyl ether, THF, DME, 1,4-dioxane, cyclopentyl methyl ether, MTBE, etc.;
Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.;
Saturated hydrocarbons: cyclohexane, n-hexane, n-pentane, etc.;
Amides: DMF, N,N-dimethylacetamide, NMP, etc.;
Halogenated hydrocarbons: DCM, 1,2-dichloroethane, carbon tetrachloride, etc.;
Nitriles: MeCN, etc.;
Sulfoxides: DMSO, etc.;
Aromatic organic bases: pyridine, etc.;
Acid anhydrides: acetic anhydride, etc.;
Organic acids: formic acid, acetic acid, TFA, methanesulfonic acid, etc.;
Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.;
Ketones: acetone, methyl ethyl ketone, etc.;
water.

　各工程の反応において、塩基を用いる場合、該反応は、反応に適した塩基を用いて行われる。用いられる塩基の具体例としては、各工程に対応する参考例若しくは実施例に記載されている塩基、又は以下の塩基が挙げられる。
無機塩基類：水酸化ナトリウム、水酸化リチウム、水酸化カリウムなど；
塩基性塩類：炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸セシウムなど；
有機塩基類：TEA、DIPEA、ジエチルアミン、ピリジン、DMAP、2,6-ルチジン、DBU、イミダゾール、ピペリジンなど；
金属アルコキシド類：ナトリウムエトキシド、ナトリウムメトキシド、カリウムtert-ブトキシドなど；
アルカリ金属水素化物類：水素化ナトリウムなど；
金属アミド類：ナトリウムアミド、LDA、リチウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミドなど；
有機マグネシウム類：イソプロピルマグネシウムクロリドなど；
有機リチウム類：メチルリチウム、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウムなど。 When a base is used in the reaction of each step, the reaction is carried out using a base suitable for the reaction. Specific examples of the base to be used include the bases described in the Reference Examples or Examples corresponding to each step, or the following bases.
Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.;
Basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.;
Organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, DBU, imidazole, piperidine, etc.;
Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.;
Alkali metal hydrides: sodium hydride, etc.;
Metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.;
Organomagnesiums: isopropylmagnesium chloride, etc.;
Organolithium compounds: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

　各工程の反応において、酸を用いる場合、該反応は、反応に適した酸を用いて行われる。用いられる酸の具体例としては、各工程に対応する参考例及び実施例に記載されている酸又は以下の酸が挙げられる。
無機酸類：塩酸、硫酸、硝酸、臭化水素酸、リン酸など；
有機酸類：酢酸、TFA、クエン酸、メタンスルホン酸、p-トルエンスルホン酸、10-カンファースルホン酸など；
ルイス酸：三フッ化ホウ素ジエチルエーテルコンプレックス、ヨウ化亜鉛、塩化アルミニウム、塩化亜鉛、チタニウム(IV)クロリドなど。 When an acid is used in the reaction of each step, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid to be used include the acids described in the Reference Examples and Examples corresponding to each step or the following acids.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.;
Organic acids: acetic acid, TFA, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.;
Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

　各工程の反応において、縮合剤を用いる場合、該反応は、反応に適した縮合剤を用いて行われる。用いられる縮合剤の具体例としては、各工程に対応する参考例若しくは実施例に記載されている縮合剤、又は以下の縮合剤が挙げられる。
カルボジイミド類：1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩、N,N'-ジシクロヘキシルカルボジイミドなど；
イミダゾール類：カルボニルジイミダゾールなど；
ウロニウム塩、ホスホニウム塩類：HATU、1H-ベンゾトリアゾール-1-イルオキシトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスファートなど；
トリアジン類：DMT-MMなど；
その他：プロピルホスホン酸無水物(環状トリマー)など。 When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent to be used include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents.
Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, and the like;
Imidazoles: carbonyldiimidazole, etc.;
Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.;
Triazines: DMT-MM, etc.;
Others: Propylphosphonic anhydride (cyclic trimer), etc.

　各工程の反応において、還元剤を用いる場合、該反応は、反応に適した還元剤を用いて行われる。用いられる還元剤の具体例としては、各工程に対応する参考例若しくは実施例に記載されている還元剤、又は以下の還元剤が挙げられる。
金属水素化物類：水素化アルミニウムリチウム、水素化ホウ素リチウム、水素化ホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム、DIBAL-Hなど；
ボラン類：BH3-THF、ピコリンボラン錯体、デカボランなど。 When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, or the following reducing agents.
Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, DIBAL-H, etc.;
Boranes: BH 3 -THF, picoline borane complex, decaborane, etc.

　各工程の反応において、カルボニル基導入試薬を用いる場合、該反応は、反応に適したカルボニル基導入試薬を用いて行われる。用いられるカルボニル基導入試薬の具体例としては、各工程に対応する参考例若しくは実施例に記載されているカルボニル基導入試薬、又は以下のカルボニル基導入試薬が挙げられる。
ホスゲン類：ホスゲン、ジホスゲン、トリホスゲンなど；
クロロギ酸エステル類：クロロギ酸4-ニトロフェニルなど；
イミダゾール類：カルボニルジイミダゾールなど。 When a carbonyl group-introducing reagent is used in the reaction of each step, the reaction is carried out using a carbonyl group-introducing reagent suitable for the reaction. Specific examples of the carbonyl group-introducing reagent to be used include the carbonyl group-introducing reagents described in the Reference Examples or Examples corresponding to each step, or the following carbonyl group-introducing reagents.
Phosgenes: phosgene, diphosgene, triphosgene, etc.;
Chloroformates: 4-nitrophenyl chloroformate, etc.;
Imidazoles: carbonyldiimidazole, etc.

　各工程において、官能基の種類により保護基が必要な場合は、常法に従い適宜導入及び除去の操作を組み合わせて実施をすることもできる。保護基の種類、保護、及び脱保護に関しては、例えば、Peter G. M. Wuts著編、「Greene's Protective Groups in Organic Synthesis」、fifth edition、Wiley-Interscience、2014年に記載の方法を挙げることができる。 In each step, if a protecting group is required due to the type of functional group, it is also possible to combine appropriate introduction and removal operations according to conventional methods. Regarding the types of protecting groups, protection, and deprotection, for example, the methods described in "Greene's Protective Groups in Organic Synthesis", edited by Peter G. M. Wuts, fifth edition, Wiley-Interscience, 2014 can be mentioned.

　各工程において、加水分解反応を行う場合、該反応は、酸又は塩基の存在下で実施できる。用いられる酸及び塩基としては、上述の例が挙げられる。 When a hydrolysis reaction is carried out in each step, the reaction can be carried out in the presence of an acid or a base. The acids and bases that can be used include the examples mentioned above.

　各工程において、接触還元反応を行う場合、該反応は、水素及び触媒の存在下で実施できる。用いられる触媒としては、パラジウム炭素粉末、パールマン触媒、白金炭素粉末、ラネーニッケルなどが挙げられる。なお、必要に応じて、酸を反応に用いてもよい。 When a catalytic reduction reaction is carried out in each step, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. If necessary, an acid may be used in the reaction.

　各工程において、還元反応を行う場合、該反応は、還元剤の存在下で実施できる。用いられる還元剤としては、上述の例が挙げられる。 When a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above.

　各工程において、金属還元反応を行う場合、該反応は、金属等の存在下で実施できる。用いられる金属等としては、鉄粉末、亜鉛粉末、塩化スズ、三塩化チタンなどが挙げられる。なお、必要に応じて、酸を反応に用いてもよい。 When a metal reduction reaction is carried out in each step, the reaction can be carried out in the presence of a metal or the like. Examples of the metal or the like that can be used include iron powder, zinc powder, tin chloride, titanium trichloride, etc. If necessary, an acid may be used in the reaction.

　各工程において、アミド化を行う場合、該反応は、塩基の存在下又は非存在下、縮合剤を用いて実施できる。用いられる縮合剤及び塩基としては、上述の例が挙げられる。なお、縮合剤としてカルボジイミド類を用いる場合は、必要に応じて1-ヒドロキシベンゾトリアゾール、DMAPなどの添加剤を加えて反応を行ってもよい。また、該反応は、塩基の存在下又は非存在下、ハロゲン化アシル又は酸無水物を用いても実施できる。 When amidation is carried out in each step, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base that can be used include those mentioned above. When carbodiimides are used as the condensing agent, the reaction can be carried out by adding an additive such as 1-hydroxybenzotriazole or DMAP, if necessary. The reaction can also be carried out using an acyl halide or an acid anhydride in the presence or absence of a base.

　各工程において、還元的アミノ化を行う場合、該反応は、還元剤の存在下で実施できる。用いられる還元剤としては、上述の例が挙げられる。また、該反応は、水素及び触媒の存在下でも実施できる。用いられる触媒としては、パラジウム炭素粉末、パールマン触媒、白金炭素粉末、ラネーニッケルなどが挙げられる。 When reductive amination is performed in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc.

　各工程において、根岸カップリング反応を行う場合、該反応は、有機亜鉛化合物、パラジウム触媒及びリガンドの存在下で実施できる。用いられるパラジウム触媒としては、酢酸パラジウム(II)、トリス(ジベンジリデンアセトン)パラジウム(0)、などが挙げられる。リガンドとしてはXphos、2-ジシクロヘキシルホスフィノ-2',6'-ジメトキシビフェニル、トリス(2-メチルフェニル)ホスフィンなどが挙げられる。 When the Negishi coupling reaction is carried out in each step, the reaction can be carried out in the presence of an organozinc compound, a palladium catalyst, and a ligand. Examples of the palladium catalyst that can be used include palladium(II) acetate, tris(dibenzylideneacetone)palladium(0), and the like. Examples of the ligand include Xphos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and tris(2-methylphenyl)phosphine.

　各工程において、鈴木-宮浦クロスカップリング反応を行う場合、該反応は、パラジウム触媒及び塩基の存在下で実施できる。用いられるパラジウム触媒としては、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)、テトラキス(トリフェニルホスフィン)パラジウム(0)などが挙げられる。用いられる塩基としては、上述の例が挙げられる。 When the Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst that can be used include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and tetrakis(triphenylphosphine)palladium(0). Examples of the base that can be used include the above-mentioned examples.

　各工程において、ゴールドバーグアミノ化を行う場合、該反応は、銅触媒、リガンド及び塩基の存在下で実施できる。用いられる銅触媒としては、ヨウ化銅(I)、臭化銅(I)、塩化銅(I)、塩化銅(II)、酸化銅(I)、酸化銅(II)、酢酸銅(II)、硫酸銅(II)などが挙げられる。用いられるリガンドとしては、1,10-フェナントロリン、TMEDA、2,2’-ビピリジンなどが挙げられる。用いられる塩基としては、上述の例が挙げられる。 When Goldberg amination is performed in each step, the reaction can be carried out in the presence of a copper catalyst, a ligand, and a base. Examples of the copper catalyst that can be used include copper iodide(I), copper bromide(I), copper chloride(I), copper chloride(II), copper oxide(I), copper oxide(II), copper acetate(II), and copper sulfate(II). Examples of the ligand that can be used include 1,10-phenanthroline, TMEDA, and 2,2'-bipyridine. Examples of the base that can be used include the examples mentioned above.

　各工程において、薗頭カップリング反応を行う場合、該反応は、パラジウム触媒、銅触媒及び塩基の存在下で実施できる。用いられるパラジウム触媒としては、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)、ビス(アセトニトリル)パラジウム(II)塩化物などが挙げられる。用いられる銅触媒としては、ヨウ化銅(I)、臭化銅(I)などが挙げられる。用いられる塩基としては、上述の例が挙げられる。 When the Sonogashira coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst, a copper catalyst, and a base. Examples of the palladium catalyst that can be used include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and bis(acetonitrile)palladium(II) chloride. Examples of the copper catalyst that can be used include copper iodide(I) and copper bromide(I). Examples of the base that can be used include the examples mentioned above.

　各工程において、クルチウス転位反応を行う場合、該反応は、アジド源の存在下で実施できる。用いられるアジド源としては、アジ化ナトリウム、DPPAなどが挙げられる。 When the Curtius rearrangement reaction is carried out in each step, the reaction can be carried out in the presence of an azide source. Examples of the azide source that can be used include sodium azide and DPPA.

　各工程において、カルバメート化又はウレア化を行う場合、該反応は、塩基の存在下又は非存在下、カルボニル基導入試薬を用いて実施できる。用いられるカルボニル基導入試薬及び塩基としては、上述の例が挙げられる。 When carbamate formation or urea formation is carried out in each step, the reaction can be carried out using a carbonyl group-introducing reagent in the presence or absence of a base. Examples of the carbonyl group-introducing reagent and base that can be used include those mentioned above.

　式（Ｉ－１ａ）～（Ｉ－１ｄ）で表される化合物は、例えば、Scheme 1に記載の方法に従い、製造することができる。 The compounds represented by formulae (I-1a) to (I-1d) can be prepared, for example, according to the method described in Scheme 1.

Figure JPOXMLDOC01-appb-C000099
　式中の記号は、前記と同じ意味を持つ。R1Pは、C1-6アルキル、C1-6ハロアルキル、C3-8シクロアルキル、又はC1-6アルコキシC1-6アルキルである。R1P’は、C1-6アルキル、C1-6ハロアルキル又はC3-8シクロアルキルである。
Figure JPOXMLDOC01-appb-C000099
 The symbols in the formula have the same meanings as above. R 1P is C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-6 alkoxyC 1-6 alkyl. R 1P' is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl.

Process 1-1
　化合物(Ｉ－１ａ)は、化合物(１－１)とイソシアン酸トリメチルシリルを反応させることにより製造することもできる。別の方法として、化合物（Ｉ－１ａ）は、酸の存在下、化合物（１－１）とシアン酸カリウム若しくはシアン酸ナトリウムなどを反応させることにより製造することもできる。 Process 1-1
Compound (I-1a) can also be produced by reacting compound (1-1) with trimethylsilyl isocyanate. Alternatively, compound (I-1a) can be produced by reacting compound (1-1) with potassium cyanate or sodium cyanate in the presence of an acid.

Process 1-2
　化合物（Ｉ－１ｂ）は、化合物（１－１）と化合物（１－２）のウレア化により製造することもできる。 Process 1-2
Compound (I-1b) can also be produced by urea reaction of compound (1-1) and compound (1-2).

Process 1-3
　化合物（Ｉ－１ｃ）は、化合物（１－１）と化合物（１－３）のアミド化により製造することもできる。 Process 1-3
Compound (I-1c) can also be produced by amidation of compound (1-1) and compound (1-3).

Process 1-4
　化合物（Ｉ－１ｄ）は、化合物（１－１）と化合物（１－４）のカルバメート化により製造することもできる。 Process 1-4
Compound (I-1d) can also be produced by carbamate reaction of compound (1-1) and compound (1-4).

　式（１－１a）で表される化合物は、例えば、Scheme 2に記載の方法に従い、製造することができる。 The compound represented by formula (1-1a) can be produced, for example, according to the method described in Scheme 2.

Figure JPOXMLDOC01-appb-C000100
　式中の記号は、前記と同じ意味を持つ。
Figure JPOXMLDOC01-appb-C000100
 The symbols in the formula have the same meanings as above.

Process 2-1
　化合物（Ｉ－２）は、塩基の存在下、化合物（２－１）とDPPA及びBoc2Oを反応させることにより製造することもできる。 Process 2-1
Compound (I-2) can also be produced by reacting compound (2-1) with DPPA and Boc 2 O in the presence of a base.

Process 2-2
　化合物（１－１ａ）は、化合物（Ｉ－２）のBoc基を除去することより製造することもできる。 Process 2-2
Compound (1-1a) can also be prepared by removing the Boc group of compound (I-2).

　式（２－１）で表される化合物は、例えば、Scheme 3に記載の方法に従い、製造することができる。 The compound represented by formula (2-1) can be produced, for example, according to the method described in Scheme 3.

Figure JPOXMLDOC01-appb-C000101
　式中の記号は、前記と同じ意味を持つ。LG1は塩素原子、臭素原子、又はヨウ素原子であり、R3PはC1-6アルキル、C6-10アリール、又はC6-10アリールC1-6アルキルであり、LG2は塩素原子、臭素原子、ヨウ素原子、又はメタンスルホニルオキシ基である。
Figure JPOXMLDOC01-appb-C000101
 The symbols in the formula have the same meanings as above, LG1 is a chlorine atom, a bromine atom, or an iodine atom, R3P is a C1-6 alkyl, a C6-10 aryl, or a C6-10 aryl C1-6 alkyl, and LG2 is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.

Process 3-1
　化合物（３－３）は、化合物（３－１）と化合物（３－２）のゴールドバーグアミノ化により製造することもできる。 Process 3-1
Compound (3-3) can also be produced by Goldberg amination of compound (3-1) and compound (3-2).

Process 3-2
　化合物（３－４）は、化合物（３－３）の接触水素還元により製造することもできる。 Process 3-2
The compound (3-4) can also be produced by catalytic hydrogen reduction of the compound (3-3).

Process 3-3
　化合物（２－１）は、塩基の存在下、化合物（３－４）と化合物（３－５）とを反応させることにより製造することもできる。 Process 3-3
Compound (2-1) can also be produced by reacting compound (3-4) with compound (3-5) in the presence of a base.

Process 3-4
　化合物（３－８）は、化合物（３－６）と化合物（３－７）の還元的アミノ化により製造することもできる。 Process 3-4
Compound (3-8) can also be produced by reductive amination of compound (3-6) and compound (3-7).

Process 3-5
　化合物（２－１）は、化合物（３－８）のアミド化により製造することもできる。 Process 3-5
The compound (2-1) can also be produced by amidation of the compound (3-8).

　式（１－４ｂ）で表される化合物は、例えば、Scheme 4に記載の方法に従い、製造することができる。 The compound represented by formula (1-4b) can be produced, for example, according to the method described in Scheme 4.

Figure JPOXMLDOC01-appb-C000102
　式中の記号は、前記と同じ意味を持つ。R4Pは、水素原子、フッ素原子、C1-6アルキル、ハロC1-6アルキル、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)である。
Figure JPOXMLDOC01-appb-C000102
 The symbols in the formula have the same meanings as above. R 4P is a hydrogen atom, a fluorine atom, a C 1-6 alkyl, a haloC 1-6 alkyl, or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl).

Process 4-1
　化合物（Ｉ－４ｂ）は、化合物（Ｉ－４ａ）の接触水素還元により製造することもできる。 Process 4-1
Compound (I-4b) can also be produced by catalytic hydrogen reduction of compound (I-4a).

　式（１－１ｂ）で表される化合物は、例えば、Scheme 5に記載の方法に従い、製造することができる。 The compound represented by formula (1-1b) can be produced, for example, according to the method described in Scheme 5.

Figure JPOXMLDOC01-appb-C000103
　式中の記号は、前記と同じ意味を持つ。
Figure JPOXMLDOC01-appb-C000103
 The symbols in the formula have the same meanings as above.

Process 5-1
　化合物（５－２）は、塩基の存在下、化合物（５－１）と化合物（３－５）を反応させることにより製造することもできる。 Process 5-1
Compound (5-2) can also be produced by reacting compound (5-1) with compound (3-5) in the presence of a base.

Process 5-2
　化合物（１－１ｂ）は、化合物（５－２）のニトロ基を還元することより製造することもできる。 Process 5-2
The compound (1-1b) can also be produced by reducing the nitro group of the compound (5-2).

Process 5-3
　化合物(５－５)は、化合物(５－３)のクルチウス転位反応により製造することもできる。 Process 5-3
The compound (5-5) can also be produced by subjecting the compound (5-3) to Curtius rearrangement reaction.

Process 5-4
　化合物（５－５）は、化合物（５－４）のカルバメート化により製造することもできる。 Process 5-4
The compound (5-5) can also be produced by carbamate conversion of the compound (5-4).

Process 5-5
　化合物（Ｉ－５）は、塩基の存在下、化合物（５－５）と化合物（３－５）を反応させることにより製造することもできる。 Process 5-5
Compound (I-5) can also be produced by reacting compound (5-5) with compound (3-5) in the presence of a base.

Process 5-6
　化合物（１－１ｂ）は、化合物（Ｉ－５）のBoc基を除去することにより製造することもできる。 Process 5-6
Compound (1-1b) can also be produced by removing the Boc group of compound (I-5).

　式（１－１ｃ）で表される化合物は、例えば、Scheme 6に記載の方法に従い、製造することができる。 The compound represented by formula (1-1c) can be produced, for example, according to the method described in Scheme 6.

Figure JPOXMLDOC01-appb-C000104
　式中の記号は、前記と同じ意味を持つ。R6Pは、C1-6アルキルである。
Figure JPOXMLDOC01-appb-C000104
 The symbols in the formula have the same meanings as above. R 6P is C 1-6 alkyl.

Process 6-1
　化合物(６－３)は、化合物(６－１)と化合物（６－２）の根岸カップリング反応により製造することもできる。 Process 6-1
Compound (6-3) can also be produced by subjecting compound (6-1) and compound (6-2) to a Negishi coupling reaction.

Process 6-2
　化合物（１－１ｃ）は、化合物（６－３）と酸を反応させることにより製造することもできる。 Process 6-2
Compound (1-1c) can also be produced by reacting compound (6-3) with an acid.

　式（６－１）及び式（６－１ａ）で表される化合物は、例えば、Scheme 7に記載の方法に従い、製造することができる。 The compounds represented by formula (6-1) and formula (6-1a) can be prepared, for example, according to the method described in Scheme 7.

Figure JPOXMLDOC01-appb-C000105
　式中の記号は、前記と同じ意味を持つ。p’は、0から2の整数である。
Figure JPOXMLDOC01-appb-C000105
 The symbols in the formula have the same meanings as above. p' is an integer of 0 to 2.

Process 7-1
　化合物（６－１）は、塩基の存在下、化合物（７－１）と化合物（３－５）を反応させることにより製造することもできる。 Process 7-1
Compound (6-1) can also be produced by reacting compound (7-1) with compound (3-5) in the presence of a base.

Process 7-2
　化合物（６－１ａ）は、化合物（７－１）と化合物（７－２）の還元的アミノ化により製造することもできる。 Process 7-2
Compound (6-1a) can also be produced by reductive amination of compound (7-1) and compound (7-2).

　上記に示した各Schemeは、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその製造中間体を製造するための方法の例示である。上記に示した各Schemeは、当業者が容易に理解し得るSchemeへ様々な改変が可能である。 Each of the schemes shown above is an example of a method for producing a compound represented by formula (A-I) to (A-VIII) or formula (I) to (VIII) or a production intermediate thereof. Each of the schemes shown above can be modified in various ways to create a scheme that can be easily understood by a person skilled in the art.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物及びその製造中間体は、必要に応じて、当該技術分野の当業者にとって周知の単離及び精製手段である、溶媒抽出、晶析、再結晶、クロマトグラフィー、分取高速液体クロマトグラフィー等により、単離及び精製することもできる。 The compounds represented by formulas (A-I) to (A-VIII) or formulas (I) to (VIII) and their manufacturing intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, and preparative high performance liquid chromatography.

　本発明の化合物は、優れたTSHRアンタゴニスト活性を有するので、甲状腺関連疾患の治療剤として使用できる。本発明において、甲状腺関連疾患には、例えば、甲状腺機能亢進症、グレーブス病、甲状腺眼症及び甲状腺癌が含まれる。好ましくは、本発明の化合物は、甲状腺機能亢進症、グレーブス病、又は甲状腺眼症の治療剤として用いることができる（Endocrinology, 2014, 155 (1), p.310-314参照）。さらに好ましくは、本発明の化合物は、甲状腺機能亢進症又はグレーブス病の治療剤として用いることができる。 The compounds of the present invention have excellent TSHR antagonist activity and can therefore be used as therapeutic agents for thyroid-related diseases. In the present invention, thyroid-related diseases include, for example, hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer. Preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism, Graves' disease, or thyroid eye disease (see Endocrinology, 2014, 155 (1), p. 310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

　また、一つの実施態様として、甲状腺機能亢進症には、例えば、グレーブス病、甲状腺炎、プランマー病、中毒性多結節性甲状腺腫、TSH産生下垂体腺腫、妊娠悪阻、卵巣甲状腺腫、妊娠性絨毛腫瘍、又は胚細胞腫瘍の何れかを原因とする甲状腺機能亢進症が含まれる。好ましくは、本発明の化合物はグレーブス病を原因とする甲状腺機能亢進症の治療剤として用いることができる。 In one embodiment, hyperthyroidism includes hyperthyroidism caused by, for example, Graves' disease, thyroiditis, Plummer's disease, toxic multinodular goiter, TSH-producing pituitary adenoma, hyperemesis gravidarum, ovarian goiter, gestational trophoblastic tumor, or germ cell tumor. Preferably, the compound of the present invention can be used as a therapeutic agent for hyperthyroidism caused by Graves' disease.

　また、一つの実施態様として、甲状腺関連疾患は甲状腺ホルモン値の異常に伴う疾患及び症状である。甲状腺ホルモン値の異常に伴う疾患及び症状には、例えば、TRAbを原因とする疾患及び症状が含まれる。 In one embodiment, the thyroid-related disease is a disease or condition associated with abnormal thyroid hormone levels. Diseases and conditions associated with abnormal thyroid hormone levels include, for example, diseases and conditions caused by TRAb.

　本発明において、「治療」には「予防」の意味が含まれる。例えば、甲状腺機能亢進症、グレーブス病又は甲状腺眼症の治療には、「再燃・再発の予防」及び「寛解維持」の意味が含まれる。また、一つの実施態様として、本発明の化合物はグレーブス病患者における甲状腺眼症の発症の予防のために使用できる。 In the present invention, "treatment" includes the meaning of "prevention." For example, the treatment of hyperthyroidism, Graves' disease, or thyroid eye disease includes the meanings of "prevention of relapse/recurrence" and "maintenance of remission." In addition, in one embodiment, the compounds of the present invention can be used to prevent the onset of thyroid eye disease in patients with Graves' disease.

　本発明において、「アンタゴニスト」は、その結合部位に拘わらず、標的タンパク質の機能を阻害又は遮断する薬物を指す。例えば、「アンタゴニスト」には、「アロステリックアンタゴニスト」、及び「ネガティブアロステリックモジュレーター（NAM）」の意味が含まれる。 In the present invention, "antagonist" refers to a drug that inhibits or blocks the function of a target protein, regardless of its binding site. For example, "antagonist" includes the meanings of "allosteric antagonist" and "negative allosteric modulator (NAM)."

　本発明の化合物の甲状腺関連疾患に対する治療効果は、当該技術分野において周知の方法に従い確認することができる。例えば、甲状腺機能亢進症又はグレーブス病のモデル動物における効果の確認方法としては、Endocrinology 2007, 148(5), p.2335-2344等に記載の方法又はそれに準じた方法が挙げられる。 The therapeutic effect of the compounds of the present invention on thyroid-related diseases can be confirmed according to methods well known in the art. For example, a method for confirming the effect in an animal model of hyperthyroidism or Graves' disease can be the method described in Endocrinology 2007, 148(5), p.2335-2344 or a method similar thereto.

　本発明の医薬組成物は、用法に応じ種々の剤型のものが使用される。このような剤型としては、例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤、軟膏剤、坐剤、貼付剤、点眼剤、及び注腸剤を挙げることができる。 The pharmaceutical composition of the present invention may be used in various dosage forms depending on the method of use. Examples of such dosage forms include powders, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

　本発明の医薬組成物は、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその薬理学的に許容される塩を有効成分として含む。 The pharmaceutical composition of the present invention contains a compound represented by formula (A-I) to (A-VIII) or formula (I) to (VIII) or a pharmacologically acceptable salt thereof as an active ingredient.

　本発明の医薬組成物は、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその薬理学的に許容される塩、及び少なくとも１つの医薬品添加物を用いて調製される。これら医薬組成物は、その剤型に応じ製剤学的に公知の手法により、適切な賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤等の医薬品添加物と適宜混合、希釈又は溶解することにより調製することもできる。 The pharmaceutical compositions of the present invention are prepared using a compound represented by formula (A-I) to (A-VIII) or formula (I) to (VIII) or a pharmacologically acceptable salt thereof, and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, using methods known in pharmaceutical science according to the dosage form.

　本発明の医薬組成物を治療に用いる場合、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその薬理学的に許容される塩の投与量は、患者の年齢、性別、体重、疾患及び治療の程度等により適宜決定される。1日投与量を1回、2回、3回又は4回に分けて投与してもよい。
　経口投与の場合、成人に対する投与量は、例えば、0.1～5000 mg/日の範囲で定めることができる。一つの実施態様として、経口投与量は、1～1500 mg/日の範囲で定めることもでき、好ましくは1～500 mg/日の範囲である。　非経口投与の場合、成人に対する投与量は、例えば、0.01～5000 mg/日で定めることができる。一つの実施態様として、非経口投与量は、0.1～1500 mg/日の範囲で定めることもでき、好ましくは0.1～500 mg/日の範囲である。 When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (A-I) to (A-VIII) or the compound represented by formula (I) to (VIII) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, degree of treatment, etc. of the patient. The daily dosage may be administered once, twice, three times, or four times.
In the case of oral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 5000 mg/day. In one embodiment, the oral dosage can be set in the range of 1 to 1500 mg/day, preferably in the range of 1 to 500 mg/day. In the case of parenteral administration, the dosage for an adult can be set, for example, in the range of 0.01 to 5000 mg/day. In one embodiment, the parenteral dosage can be set in the range of 0.1 to 1500 mg/day, preferably in the range of 0.1 to 500 mg/day.

　一つの実施態様として、本発明の医薬組成物は、TSHRアンタゴニスト以外の他の薬剤と組み合わせて使用することもできる。甲状腺関連疾患の治療において組み合わせて使用することができる他の薬剤としては、例えば、抗甲状腺薬（例えばチアマゾール、プロピルチオウラシル等）、無機ヨウ素、炭酸リチウム、甲状腺ホルモン製剤等が挙げられる。 In one embodiment, the pharmaceutical composition of the present invention can be used in combination with other drugs other than TSHR antagonists. Examples of other drugs that can be used in combination in the treatment of thyroid-related diseases include antithyroid drugs (e.g., thiamazole, propylthiouracil, etc.), inorganic iodine, lithium carbonate, thyroid hormone preparations, etc.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、若しくは式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその薬理学的に許容される塩と他の薬剤とを組み合わせて使用する場合、これらの有効成分を一緒に含有する製剤、又はこれらの有効成分の個々を別々に製剤化した製剤として投与することができる。別々に製剤化した場合、それらの製剤を別々に、又は同時に投与することができる。また、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、若しくは式（Ｉ）～（ＶＩＩＩ）で表される化合物又はその薬理学的に許容される塩の投与量は、組み合わせて使用する他の薬剤の投与量に応じて、適宜減量してもよい。 When the compound represented by formula (A-I) to (A-VIII) or formula (I) to (VIII) or a pharmacologically acceptable salt thereof is used in combination with another drug, it can be administered as a preparation containing these active ingredients together, or as a preparation in which each of these active ingredients is formulated separately. When formulated separately, the preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (A-I) to (A-VIII) or formula (I) to (VIII) or a pharmacologically acceptable salt thereof may be appropriately reduced depending on the dosage of the other drug used in combination.

　式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物は、適宜プロドラッグに変換して使用してもよい。例えば、式（Ａ-Ｉ）～（Ａ-ＶＩＩＩ）、又は式（Ｉ）～（ＶＩＩＩ）で表される化合物のプロドラッグは、相当するハロゲン化物等のプロドラッグ化試薬を用いて、プロドラッグを構成する基を導入し、精製することにより製造することもできる。プロドラッグを構成する基としては、例えば、「医薬品の開発」（廣川書店、1990年）第7巻　p.163-198に記載の基が挙げられる。 The compounds represented by formulae (A-I) to (A-VIII) or (I) to (VIII) may be appropriately converted into prodrugs for use. For example, prodrugs of the compounds represented by formulae (A-I) to (A-VIII) or (I) to (VIII) can be produced by introducing a group constituting a prodrug using a prodrug-forming reagent such as a corresponding halide, followed by purification. Examples of groups constituting prodrugs include those described in "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, p. 163-198.

　以下に、本発明を参考例、実施例及び試験例にもとづいてさらに詳細に説明するが、本発明はその内容に限定されるものではない。 The present invention will be described in more detail below based on reference examples, examples, and test examples, but the present invention is not limited to the contents thereof.

　下記の実施例に記載された化合物名は、市販の試薬を除き、ChemDraw Professional (PerkinElmer)、MarvinSketch (ChemAxon)等を用いて命名した。
　化合物の名称中の「＊」印がついた不斉中心の立体配置は、相対配置であることを意味する。 The names of compounds described in the following examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.
The configuration of the asymmetric center marked with "*" in the compound name means that it is the relative configuration.

参考例A-1
5-(ジフルオロメチル)-2-フルオロベンズアルデヒド
　5-(ジフルオロメチル)-2-フルオロベンゾニトリル(2.30 g)及びDCM(40 mL)の混合物に、DIBAL-H(1.02 mol/L in n-hexane)(27 mL)を氷塩浴下で加え、氷塩浴下で1時間撹拌した。反応混合物に2 mol/L塩酸(40 mL)を加え、室温で1時間撹拌した。混合物をDCMで抽出し、抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、表題化合物(1.62 g)を得た。 Reference example A-1
5-(Difluoromethyl)-2-fluorobenzaldehyde To a mixture of 5-(difluoromethyl)-2-fluorobenzonitrile (2.30 g) and DCM (40 mL), DIBAL-H (1.02 mol/L in n-hexane) (27 mL) was added in an ice-salt bath, and the mixture was stirred for 1 hour in an ice-salt bath. 2 mol/L hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain the title compound (1.62 g).

参考例A-2
メタンスルホン酸5-(ジフルオロメチル)-2-フルオロベンジル
　参考例A-1(0.500 g)及びメタノール(9.6 mL)の混合物に、水素化ホウ素ナトリウム(0.119 g)を氷冷下で加え、氷冷下で1時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～80/20)にて精製し、(5-(ジフルオロメチル)-2-フルオロフェニル)メタノール(0.375 g)を得た。
　得られた化合物(0.374 g)、TEA(0.258 g)及びDCM(7.1 mL)の混合物に、メタンスルホニルクロリド(0.268 g)を氷冷下で加え、氷冷下で10分間、室温で30分間撹拌した。反応混合物に氷冷下、水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=85/15～60/40)にて精製し、表題化合物(0.383 g)を得た。 Reference example A-2
5-(difluoromethyl)-2-fluorobenzyl methanesulfonate Reference Example A-1 (0.500 g) and methanol (9.6 mL) were mixed and sodium borohydride (0.119 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 80/20) to obtain (5-(difluoromethyl)-2-fluorophenyl)methanol (0.375 g).
To a mixture of the obtained compound (0.374 g), TEA (0.258 g) and DCM (7.1 mL), methanesulfonyl chloride (0.268 g) was added under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling and for 30 minutes at room temperature. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 85/15 to 60/40) to obtain the title compound (0.383 g).

参考例A-3
メタンスルホン酸3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル
　参考例A-1の代わりに3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドを用い、参考例A-2と同様の方法により、参考例A-3を合成した。 Reference example A-3
3-Chloro-2-fluoro-5-(trifluoromethyl)benzyl methanesulfonate Reference Example A-3 was synthesized in the same manner as in Reference Example A-2, using 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde instead of Reference Example A-1.

参考例A-4
4-(ベンジルオキシ)-2-(ブロモメチル)-1-フルオロベンゼン
　(5-(ベンジルオキシ)-2-フルオロフェニル)メタノール(0.125 g)及びトルエン(1.3 mL)の混合物に、三臭化リン(0.219 g)を室温で加え、50℃で1時間撹拌した。反応混合物に三臭化リン(0.029 g)を室温で加え、60℃で1時間撹拌した。反応混合物を減圧下濃縮することで、表題化合物(0.159 g)を得た。 Reference example A-4
4-(benzyloxy)-2-(bromomethyl)-1-fluorobenzene To a mixture of (5-(benzyloxy)-2-fluorophenyl)methanol (0.125 g) and toluene (1.3 mL), phosphorus tribromide (0.219 g) was added at room temperature and stirred at 50° C. for 1 hour. To the reaction mixture, phosphorus tribromide (0.029 g) was added at room temperature and stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.159 g).

参考例A-5
2-フルオロ-5-(1,1,2,2-テトラフルオロエトキシ)ベンズアルデヒド
　3-ブロモ-4-フルオロフェノール(1.15 g)、1-ブロモ-1,1,2,2-テトラフルオロ-2-ヨードエタン(3.68 g)及びDMSO(6.0 mL)の混合物に、炭酸セシウム(2.93 g)を室温で加え、60℃で1時間撹拌した。反応混合物を室温まで放冷した後、水を加えた。混合物をn-ヘキサンで2回抽出した。合わせた抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、亜鉛粉末(1.18 g)及び酢酸(1.0 mL)の混合物を50℃で4時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をDCMで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液で洗浄した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～90/10)にて精製し、2-ブロモ-1-フルオロ-4-(1,1,2,2-テトラフルオロエトキシ)ベンゼン(0.618 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.617 g)及びジエチルエーテル(7.1 mL)の混合物に、n-ブチルリチウム(1.57 mol/L in n-hexane)(1.35 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDMF(0.197 mL)を-78℃で加え、同温で1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をジエチルエーテルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮することで、表題化合物(0.559 g)を得た。 Reference example A-5
2-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzaldehyde To a mixture of 3-bromo-4-fluorophenol (1.15 g), 1-bromo-1,1,2,2-tetrafluoro-2-iodoethane (3.68 g) and DMSO (6.0 mL), cesium carbonate (2.93 g) was added at room temperature and stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was extracted twice with n-hexane. The combined extract was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
A mixture of the residue, zinc powder (1.18 g) and acetic acid (1.0 mL) was stirred at 50°C for 4 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. The extract was washed with saturated aqueous sodium bicarbonate solution and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 90/10) to obtain 2-bromo-1-fluoro-4-(1,1,2,2-tetrafluoroethoxy)benzene (0.618 g).
Under an argon atmosphere, n-butyllithium (1.57 mol/L in n-hexane) (1.35 mL) was added to a mixture of the obtained compound (0.617 g) and diethyl ether (7.1 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DMF (0.197 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.559 g).

参考例A-6
メタンスルホン酸2-フルオロ-5-(1,1,2,2-テトラフルオロエトキシ)ベンジル
　参考例A-1の代わりに参考例A-5を用い、参考例A-2と同様の方法により、参考例A-6を合成した。 Reference example A-6
2-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl methanesulfonate Reference Example A-6 was synthesized in the same manner as in Reference Example A-2, except that Reference Example A-5 was used instead of Reference Example A-1.

参考例A-7
メタンスルホン酸2-フルオロ-5-(トリフルオロメチル)ベンジル
　参考例A-1の代わりに2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドを用い、参考例A-2と同様の方法により、参考例A-7を合成した。 Reference example A-7
2-Fluoro-5-(trifluoromethyl)benzyl methanesulfonate Reference Example A-7 was synthesized in the same manner as in Reference Example A-2, except that 2-fluoro-5-(trifluoromethyl)benzaldehyde was used instead of Reference Example A-1.

参考例A-8
1-(ブロモメチル)-3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンゼン
　3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(1.00 g)及びエタノール(10 mL)の混合物に、水素化ホウ素ナトリウム(0.250 g)を氷冷下で加え、室温で20分間撹拌した。反応混合物を飽和塩化アンモニウム水溶液にあけ、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、減圧下濃縮した。
　残渣及び1,2-ジクロロエタン(10 mL)の混合物に、三臭化リン(1.79 g)を室温で加え、同温で40分間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液にあけ、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水及び飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、表題化合物(0.484 g)を得た。 Reference example A-8
1-(Bromomethyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzene To a mixture of 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.00 g) and ethanol (10 mL), sodium borohydride (0.250 g) was added under ice cooling and stirred at room temperature for 20 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then concentrated under reduced pressure.
To a mixture of the residue and 1,2-dichloroethane (10 mL), phosphorus tribromide (1.79 g) was added at room temperature and stirred at the same temperature for 40 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain the title compound (0.484 g).

参考例A-9
2-アミノ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)安息香酸エチル
　2-アミノ安息香酸エチル(2.00 g)、ヘキサフルオロアセトン水和物(2.93 g)及びp-トルエンスルホン酸水和物(0.115 g)の混合物をマイクロ波照射下、140℃で20時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液にあけ、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～80/20)にて精製した。得られた生成物を水に懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、表題化合物(2.30 g)を得た。 Reference example A-9
Ethyl 2-amino-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoate A mixture of ethyl 2-aminobenzoate (2.00 g), hexafluoroacetone hydrate (2.93 g) and p-toluenesulfonic acid hydrate (0.115 g) was stirred at 140°C for 20 hours under microwave irradiation. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 95/5 to 80/20). The obtained product was suspended in water, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (2.30 g).

参考例A-10
2-フルオロ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)安息香酸エチル
　参考例A-9(0.579 g)及びDME(15 mL)の混合物に、三フッ化ホウ素ジエチルエーテルコンプレックス(0.310 g)を氷塩浴下で加え、氷塩浴下で15分間撹拌した。反応混合物に亜硝酸tert-ブチル(0.189 g)及びDME(7.5 mL)の混合物を氷塩浴下で加え、氷冷下で4時間撹拌した。反応混合物を減圧下濃縮した。
　残渣及びクロロベンゼン(15 mL)の混合物を2時間還流した。反応混合物を室温まで放冷した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、表題化合物(0.504 g)を得た。 Reference example A-10
2-Fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid ethyl ester Reference Example A-9 (0.579 g) and DME (15 mL) were added to a mixture of boron trifluoride diethyl ether complex (0.310 g) in an ice-salt bath, and the mixture was stirred for 15 minutes in an ice-salt bath. A mixture of tert-butyl nitrite (0.189 g) and DME (7.5 mL) was added to the reaction mixture in an ice-salt bath, and the mixture was stirred for 4 hours under ice-cooling. The reaction mixture was concentrated under reduced pressure.
A mixture of the residue and chlorobenzene (15 mL) was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain the title compound (0.504 g).

参考例A-11
2-フルオロ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)ベンズアルデヒド
　参考例A-10(0.855 g)、THF(6.4 mL)及びメタノール(0.64 mL)の混合物に、水素化ホウ素リチウム(4 mol/L in THF)(3.20 mL)を氷冷下で加え、室温で19時間撹拌した。反応混合物に水素化ホウ素リチウム(4 mol/L in THF)(1.28 mL)を室温で加え、同温で1.5時間撹拌した。反応混合物にメタノール(0.32 mL)を室温で加え、同温で2.5時間、60℃で45分間撹拌した。反応混合物に氷冷下、水及び飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、1,1,1,3,3,3-ヘキサフルオロ-2-(4-フルオロ-3-(ヒドロキシメチル)フェニル)プロパン-2-オール(0.696 g)を得た。
　得られた化合物(0.696 g)及びDCM(6.2 mL)の混合物に、二酸化マンガン(IV)(1.61 g)を室温で加え、同温で65時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～70/30)にて精製し、表題化合物(0.261 g)を得た。 Reference example A-11
2-Fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzaldehyde Reference Example A-10 (0.855 g), THF (6.4 mL) and methanol (0.64 mL) were added with lithium borohydride (4 mol/L in THF) (3.20 mL) under ice cooling and stirred at room temperature for 19 hours. Lithium borohydride (4 mol/L in THF) (1.28 mL) was added to the reaction mixture at room temperature and stirred at the same temperature for 1.5 hours. Methanol (0.32 mL) was added to the reaction mixture at room temperature and stirred at the same temperature for 2.5 hours and at 60°C for 45 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=90/10-70/30) to give 1,1,1,3,3,3-hexafluoro-2-(4-fluoro-3-(hydroxymethyl)phenyl)propan-2-ol (0.696 g).
To a mixture of the obtained compound (0.696 g) and DCM (6.2 mL), manganese dioxide (IV) (1.61 g) was added at room temperature and stirred at the same temperature for 65 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 70/30) to obtain the title compound (0.261 g).

参考例A-12
2-(1-ブロモエチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン
　3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドの代わりに1-(2-フルオロ-5-(トリフルオロメチル)フェニル)エタン-1-オンを用い、参考例A-8と同様の方法により、参考例A-12を合成した。 Reference example A-12
2-(1-bromoethyl)-1-fluoro-4-(trifluoromethyl)benzene 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde was replaced with 1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-one, and Reference Example A-12 was synthesized in the same manner as Reference Example A-8.

参考例B-1
(S)-6-(トリフルオロメチル)ピペリジン-2-オン
　アルゴン雰囲気下、2-ブロモ-6-(トリフルオロメチル)ピリジン(4.00 g)、(R)-4-ベンジルオキサゾリジン-2-オン(3.76 g)、炭酸カリウム(4.89 g)、ヨウ化銅(I)(0.169 g)、1,10-フェナントロリン(0.319 g)及びトルエン(30 mL)の混合物をマイクロ波照射下、140℃で14時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～85/15)にて精製し、(R)-4-ベンジル-3-(6-(トリフルオロメチル)ピリジン-2-イル)オキサゾリジン-2-オン(5.80 g)を得た。
　得られた化合物(0.872 g)、THF(4.4 mL)、水(4.4 mL)及びメタンスルホン酸(1.04 g)の混合物に、10% Pd/C(0.548 g)を室温で加え、水素雰囲気下、50℃で35時間撹拌した。反応混合物をセライトろ過し、ろ液に飽和炭酸水素ナトリウム水溶液を加えた。混合物を酢酸エチルで抽出し、抽出液を減圧下濃縮した。
　残渣及びトルエン(9.0 mL)の混合物を100℃で2時間撹拌した。反応混合物を減圧下濃縮した。残渣に酢酸エチル(2.7 mL)、n-ヘキサン(16 mL)及び少量の(R)-4-ベンジルオキサゾリジン-2-オンを加え、室温で15分間撹拌した。混合物をろ過した後、不溶物をn-ヘキサン/酢酸エチル(8/1)で洗浄し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/90/10)にて精製し、表題化合物(0.321 g)を得た。 Reference example B-1
(S)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, a mixture of 2-bromo-6-(trifluoromethyl)pyridine (4.00 g), (R)-4-benzyloxazolidin-2-one (3.76 g), potassium carbonate (4.89 g), copper(I) iodide (0.169 g), 1,10-phenanthroline (0.319 g) and toluene (30 mL) was stirred at 140°C for 14 hours under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 85/15) to give (R)-4-benzyl-3-(6-(trifluoromethyl)pyridin-2-yl)oxazolidin-2-one (5.80 g).
To a mixture of the obtained compound (0.872 g), THF (4.4 mL), water (4.4 mL) and methanesulfonic acid (1.04 g), 10% Pd/C (0.548 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere at 50° C. for 35 hours. The reaction mixture was filtered through Celite, and a saturated aqueous solution of sodium bicarbonate was added to the filtrate. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure.
A mixture of the residue and toluene (9.0 mL) was stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (2.7 mL), n-hexane (16 mL) and a small amount of (R)-4-benzyloxazolidin-2-one were added to the residue and stirred at room temperature for 15 minutes. After filtering the mixture, the insoluble matter was washed with n-hexane/ethyl acetate (8/1), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/90/10) to obtain the title compound (0.321 g).

参考例B-2
(S)-6-(ジフルオロメチル)ピペリジン-2-オン
　2-ブロモ-6-(ジフルオロメチル)ピリジン(3.14 g)、(R)-4-ベンジルオキサゾリジン-2-オン(3.21 g)、炭酸カリウム(4.17 g)、ヨウ化銅(I)(0.144 g)、1,10-フェナントロリン(0.272 g)及びトルエン(25 mL)の混合物をマイクロ波照射下、140℃で14時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～75/25)にて精製し、(R)-4-ベンジル-3-(6-(ジフルオロメチル)ピリジン-2-イル)オキサゾリジン-2-オン(4.57 g)を得た。
　得られた化合物(4.57 g)、10% Pd/C(1.29 g)、THF(40 mL)、水(40 mL)及び濃塩酸(1.23 g)の混合物を水素圧下(0.4 MPa)、40℃で90時間撹拌した。反応混合物を室温まで放冷した後、セライトろ過した。ろ液に濃塩酸(1.23 g)を加え、70℃で1.5時間撹拌した。反応混合物を室温まで放冷した後、炭酸ナトリウム(8.95 g)を加えた。混合物をセライトろ過し、ろ液を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/90/10)にて精製し、表題化合物(0.880 g)を得た。 Reference example B-2
A mixture of 2-bromo-6-(difluoromethyl)pyridine (3.14 g), (R)-4-benzyloxazolidin-2-one (3.21 g), potassium carbonate (4.17 g), copper(I) iodide (0.144 g), 1,10-phenanthroline (0.272 g) and toluene (25 mL) was stirred at 140°C for 14 hours under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 75/25) to give (R)-4-benzyl-3-(6-(difluoromethyl)pyridin-2-yl)oxazolidin-2-one (4.57 g).
A mixture of the obtained compound (4.57 g), 10% Pd/C (1.29 g), THF (40 mL), water (40 mL) and concentrated hydrochloric acid (1.23 g) was stirred at 40°C for 90 hours under hydrogen pressure (0.4 MPa). The reaction mixture was allowed to cool to room temperature and then filtered through Celite. Concentrated hydrochloric acid (1.23 g) was added to the filtrate and stirred at 70°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then sodium carbonate (8.95 g) was added. The mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/90/10) to obtain the title compound (0.880 g).

参考例B-3
(S)-5-フルオロピペリジン-2-オン
　2-ブロモ-6-(ジフルオロメチル)ピリジンの代わりに2-ブロモ-5-フルオロピリジンを用い、参考例B-2と同様の方法により、参考例B-3を合成した。 Reference example B-3
(S)-5-fluoropiperidin-2-one Reference Example B-3 was synthesized in the same manner as in Reference Example B-2, except that 2-bromo-5-fluoropyridine was used instead of 2-bromo-6-(difluoromethyl)pyridine.

参考例B-4
(4aS*,8aR*)オクタヒドロキノリン-2(1H)-オン
　3,4,5,6,7,8-ヘキサヒドロキノリン-2(1H)-オン(0.500 g)及びギ酸(2.5 mL)の混合物に、ギ酸ナトリウム(1.40 g)を室温で加え、40時間還流した。反応混合物を室温まで放冷した後、5 mol/L水酸化ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/90/10)にて精製し、表題化合物(0.108 g)を得た。 Reference example B-4
(4aS * ,8aR * ) Octahydroquinolin-2(1H)-one To a mixture of 3,4,5,6,7,8-hexahydroquinolin-2(1H)-one (0.500 g) and formic acid (2.5 mL), sodium formate (1.40 g) was added at room temperature and refluxed for 40 hours. After the reaction mixture was cooled to room temperature, 5 mol/L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/90/10) to obtain the title compound (0.108 g).

参考例C-1
1-(5-ブロモ-2-フルオロベンジル)-6-メチルピペリジン-2-オン
　アルゴン雰囲気下、6-メチルピペリジン-2-オン(0.320 g)及びDMF(6.9 mL)の混合物に、水素化ナトリウム(約60%)(0.170 g)を氷冷下で加え、氷冷下で10分間撹拌した。反応混合物に4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼン(0.833 g)を氷冷下で加え、室温で1.5時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(0.688 g)を得た。 Reference example C-1
1-(5-Bromo-2-fluorobenzyl)-6-methylpiperidin-2-one Under an argon atmosphere, sodium hydride (about 60%) (0.170 g) was added to a mixture of 6-methylpiperidin-2-one (0.320 g) and DMF (6.9 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. 4-Bromo-2-(bromomethyl)-1-fluorobenzene (0.833 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (0.688 g).

参考例C-2
1-(5-(ジフルオロメチル)-2-フルオロベンジル)-6-メチルピペリジン-2-オン
　4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに参考例A-2を用い、参考例C-1と同様の方法により、参考例C-2を合成した。 Reference example C-2
1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methylpiperidin-2-one Reference Example C-2 was synthesized in the same manner as in Reference Example C-1, except that Reference Example A-2 was used instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

参考例C-3
1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチルピペリジン-2-オン
　4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに参考例A-3を用い、参考例C-1と同様の方法により、参考例C-3を合成した。 Reference example C-3
1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpiperidin-2-one Reference Example C-3 was synthesized in the same manner as in Reference Example C-1, using Reference Example A-3 instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

参考例C-4
1-((4-フルオロ-(1,1'-ビフェニル)-3-イル)メチル)-6-メチルピペリジン-2-オン
　参考例C-1(0.210 g)、フェニルボロン酸(0.094 g)、炭酸カリウム(0.145 g)、THF(1.1 mL)及び水(1.1 mL)の混合物に、ビス(トリフェニルホスフィン)パラジウム(II)塩化物(0.049 g)を室温で加え、70℃で30分間撹拌した。反応混合物を室温まで放冷した後、水にあけ、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=100/0/0～0/100/0～0/88/12)にて精製し、表題化合物(0.209 g)を得た。 Reference example C-4
1-((4-fluoro-(1,1'-biphenyl)-3-yl)methyl)-6-methylpiperidin-2-one Reference Example C-1 (0.210 g), phenylboronic acid (0.094 g), potassium carbonate (0.145 g), THF (1.1 mL) and water (1.1 mL) were mixed, and bis(triphenylphosphine)palladium(II) chloride (0.049 g) was added at room temperature and stirred at 70°C for 30 minutes. The reaction mixture was cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 100/0/0 to 0/100/0 to 0/88/12) to obtain the title compound (0.209 g).

参考例C-5
1-(5-ベンジル-2-フルオロベンジル)-6-メチルピペリジン-2-オン
　参考例C-1(0.160 g)、ベンジルトリフルオロホウ酸カリウム(0.211 g)、炭酸セシウム(0.347 g)、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)(0.038 g)、1,4-ジオキサン(1.6 mL)及び水(0.16 mL)の混合物をマイクロ波照射下、120℃で1時間撹拌した。室温下、反応混合物を飽和塩化アンモニウム水溶液にあけ、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.056 g)を得た。 Reference example C-5
1-(5-benzyl-2-fluorobenzyl)-6-methylpiperidin-2-one Reference Example C-1 (0.160 g), potassium benzyl trifluoroborate (0.211 g), cesium carbonate (0.347 g), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.038 g), 1,4-dioxane (1.6 mL) and water (0.16 mL) were stirred at 120°C for 1 hour under microwave irradiation. At room temperature, the reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 60/40) to obtain the title compound (0.056 g).

参考例C-6
6-メチル-1-(3-フェノキシベンジル)ピペリジン-2-オン
　4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに1-(ブロモメチル)-3-フェノキシベンゼンを用い、参考例C-1と同様の方法により、参考例C-6を合成した。 Reference example C-6
6-Methyl-1-(3-phenoxybenzyl)piperidin-2-one Reference Example C-6 was synthesized in the same manner as in Reference Example C-1, except that 1-(bromomethyl)-3-phenoxybenzene was used instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

参考例C-7
1-(5-(ベンジルオキシ)-2-フルオロベンジル)-6-メチルピペリジン-2-オン
　4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに参考例A-4を用い、参考例C-1と同様の方法により、参考例C-7を合成した。 Reference example C-7
1-(5-(benzyloxy)-2-fluorobenzyl)-6-methylpiperidin-2-one Reference Example C-7 was synthesized in the same manner as in Reference Example C-1, except that Reference Example A-4 was used instead of 4-bromo-2-(bromomethyl)-1-fluorobenzene.

参考例C-8
(R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチルピペリジン-2-オン
　(R)-6-メチルピペリジン-2-オン(0.150 g)、2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.409 g)及びDMF(2.0 mL)の混合物に、水素化ナトリウム(約60%)(0.064 g)を水冷下で加え、室温で1時間撹拌した。反応混合物に水冷下、飽和塩化アンモニウム水溶液及び水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水で洗浄した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～15/85)にて精製し、表題化合物(0.352 g)を得た。 Reference example C-8
(R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpiperidin-2-one (R)-6-methylpiperidin-2-one (0.150 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.409 g) and DMF (2.0 mL) were added to a mixture of sodium hydride (about 60%) (0.064 g) under water cooling and stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride and water were added to the reaction mixture under water cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10-15/85) to obtain the title compound (0.352 g).

参考例C-9
(S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(トリフルオロメチル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例B-1(0.113 g)及びDMF(1.8 mL)の混合物に、水素化ナトリウム(約60%)(0.041 g)を氷冷下で加え、氷冷下で10分間撹拌した。反応混合物に2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.226 g)を氷冷下で加え、室温で2時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液及び水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(0.175 g)を得た。 Reference example C-9
(S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, sodium hydride (about 60%) (0.041 g) was added to a mixture of Reference Example B-1 (0.113 g) and DMF (1.8 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.226 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (0.175 g).

参考例C-10
(S)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-6-(トリフルオロメチル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例B-1(0.117 g)及びDMF(1.8 mL)の混合物に、水素化ナトリウム(約60%)(0.040 g)を氷冷下で加え、氷冷下で10分間撹拌した。反応混合物に参考例A-2(0.204 g)を氷冷下で加え、室温で2時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(0.112 g)を得た。 Reference example C-10
(S)-1-(5-(difluoromethyl)-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, sodium hydride (about 60%) (0.040 g) was added to a mixture of Reference Example B-1 (0.117 g) and DMF (1.8 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. Reference Example A-2 (0.204 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (0.112 g).

参考例C-11
(S)-1-(2-フルオロ-5-(1,1,2,2-テトラフルオロエトキシ)ベンジル)-6-(トリフルオロメチル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例B-1(0.100 g)及びDMF(1.6 mL)の混合物に、水素化ナトリウム(約60%)(0.036 g)を氷冷下で加え、氷冷下で15分間撹拌した。反応混合物に参考例A-6(0.220 g)を氷冷下で加え、室温で65時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液及び水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=85/15～50/50)にて精製し、表題化合物(0.166 g)を得た。 Reference example C-11
(S)-1-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, sodium hydride (about 60%) (0.036 g) was added to a mixture of Reference Example B-1 (0.100 g) and DMF (1.6 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 15 minutes. Reference Example A-6 (0.220 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 65 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 85/15 to 50/50) to obtain the title compound (0.166 g).

参考例C-12
(S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例B-2(0.101 g)及びDMF(1.8 mL)の混合物に、水素化ナトリウム(約60%)(0.041 g)を氷冷下で加え、氷冷下で10分間撹拌した。反応混合物に2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.226 g)を氷冷下で加え、室温で2時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液及び水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(0.157 g)を得た。 Reference example C-12
(S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one Under an argon atmosphere, sodium hydride (about 60%) (0.041 g) was added to a mixture of Reference Example B-2 (0.101 g) and DMF (1.8 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 10 minutes. 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.226 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (0.157 g).

参考例C-13
(S)-5-フルオロ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)ピペリジン-2-オン
　参考例B-1の代わりに参考例B-3を用い、参考例C-9と同様の方法により、参考例C-13を合成した。 Reference example C-13
(S)-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one Reference Example C-13 was synthesized in the same manner as in Reference Example C-9, using Reference Example B-3 instead of Reference Example B-1.

参考例C-14
4-(3-(トリフルオロメチル)ベンジル)-4-アザスピロ[2.5]オクタン-5-オン
　6-メチルピペリジン-2-オンの代わりに4-アザスピロ[2.5]オクタン-5-オン、4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに1-(ブロモメチル)-3-(トリフルオロメチル)ベンゼンを用い、参考例C-1と同様の方法により、参考例C-14を合成した。 Reference example C-14
4-(3-(trifluoromethyl)benzyl)-4-azaspiro[2.5]octan-5-one 6-methylpiperidin-2-one instead of 4-azaspiro[2.5]octan-5-one, 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of 1-(bromomethyl)-3-(trifluoromethyl)benzene was used, and Reference Example C-14 was synthesized in the same manner as Reference Example C-1.

参考例C-15
2-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-アザビシクロ[4.1.0]ヘプタン-3-オン
　6-メチルピペリジン-2-オンの代わりに2-アザビシクロ[4.1.0]ヘプタン-3-オン、4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに参考例A-7を用い、参考例C-1と同様の方法により、参考例C-15を合成した。 Reference example C-15
2-(2-fluoro-5-(trifluoromethyl)benzyl)-2-azabicyclo[4.1.0]heptan-3-one 6-methylpiperidin-2-one instead of 2-azabicyclo[4.1.0]heptan-3-one, 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of Reference Example A-7, Reference Example C-15 was synthesized in the same manner as Reference Example C-1.

参考例C-16
(6S)-1-(1-(2-フルオロ-5-(トリフルオロメチル)フェニル)エチル)-6-(トリフルオロメチル)ピペリジン-2-オン
　6-メチルピペリジン-2-オンの代わりに参考例B-1、4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに参考例A-12を用い、参考例C-1と同様の方法により、参考例C-16を合成した。 Reference example C-16
(6S)-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-6-(trifluoromethyl)piperidin-2-one 6-methylpiperidin-2-one was replaced with Reference Example B-1, and 4-bromo-2-(bromomethyl)-1-fluorobenzene was replaced with Reference Example A-12, and Reference Example C-16 was synthesized in the same manner as in Reference Example C-1.

参考例C-17
6-メチル-1-(3-(トリフルオロメチル)フェネチル)ピペリジン-2-オン
　5-オキソヘキサン酸(0.200 g)、2-(3-(トリフルオロメチル)フェニル)エタン-1-アミン(0.291 g)及びメタノール(4.0 mL)の混合物に、デカボラン(0.056 g)を水冷下で加え、室温で30分間撹拌した。反応混合物にAPSを加え、室温で15分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。
　残渣、DIPEA(0.397 g)、HATU(0.701 g)及びMeCN(6.0 mL)の混合物を室温で30分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、混合物を酢酸エチルで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～0/100)にて精製し、表題化合物(0.269 g)を得た。 Reference example C-17
6-Methyl-1-(3-(trifluoromethyl)phenethyl)piperidin-2-one To a mixture of 5-oxohexanoic acid (0.200 g), 2-(3-(trifluoromethyl)phenyl)ethan-1-amine (0.291 g) and methanol (4.0 mL), decaborane (0.056 g) was added under water cooling and stirred at room temperature for 30 minutes. APS was added to the reaction mixture and stirred at room temperature for 15 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure.
A mixture of the residue, DIPEA (0.397 g), HATU (0.701 g) and MeCN (6.0 mL) was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 0/100) to obtain the title compound (0.269 g).

参考例C-18
(4aS*,8aR*)-1-(3-(トリフルオロメチル)ベンジル)オクタヒドロキノリン-2(1H)-オン
　6-メチルピペリジン-2-オンの代わりに参考例B-4、4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンの代わりに1-(ブロモメチル)-3-(トリフルオロメチル)ベンゼンを用い、参考例C-1と同様の方法により、参考例C-18を合成した。 Reference example C-18
(4aS * , 8aR * )-1-(3-(trifluoromethyl)benzyl)octahydroquinolin-2(1H)-one 6-methylpiperidin-2-one instead of Reference Example B-4, 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of 1-(bromomethyl)-3-(trifluoromethyl)benzene, synthesized in the same manner as Reference Example C-1, Reference Example C-18.

参考例D-1
(6-ブロモ-2-ヒドロキシピリジン-3-イル)カルバミン酸tert-ブチル
　3-アミノ-6-ブロモピリジン-2-オール臭化水素酸塩(1.00 g)、Boc2O(0.970 g)、TEA(1.13 g)、DMAP(0.045 g)及びDCM(10 mL)の混合物を室温で2時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～80/20)にて精製し、表題化合物(0.402 g)を得た。 Reference example D-1
(6-Bromo-2-hydroxypyridin-3-yl)carbamate tert-Butyl 3-amino-6-bromopyridin-2-ol hydrobromide (1.00 g), Boc 2 O (0.970 g), TEA (1.13 g), DMAP (0.045 g) and DCM (10 mL) were stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 80/20) to give the title compound (0.402 g).

参考例D-2
(4-ヒドロキシ-2-メチルピリミジン-5-イル)カルバミン酸tert-ブチル
　4-ヒドロキシ-2-メチルピリミジン-5-カルボン酸(0.354 g)、TEA(0.465 g)、tert-ブチルアルコール(0.851 g)及びトルエン(10 mL)の混合物に、DPPA(0.695 g)を室温で加え、3.5時間還流した。反応混合物を室温まで放冷した後、水及び飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=70/30/0～0/100/0～0/85/15)にて精製し、表題化合物(0.068 g)を得た。 Reference example D-2
tert-Butyl (4-hydroxy-2-methylpyrimidin-5-yl)carbamate To a mixture of 4-hydroxy-2-methylpyrimidine-5-carboxylic acid (0.354 g), TEA (0.465 g), tert-butyl alcohol (0.851 g) and toluene (10 mL), DPPA (0.695 g) was added at room temperature and refluxed for 3.5 hours. After cooling to room temperature, water and saturated aqueous ammonium chloride were added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 70/30/0-0/100/0-0/85/15) to give the title compound (0.068 g).

参考例D-3
(3-ヒドロキシ-5-メチルピラジン-2-イル)カルバミン酸tert-ブチル
　4-ヒドロキシ-2-メチルピリミジン-5-カルボン酸の代わりに3-ヒドロキシ-5-メチルピラジン-2-カルボン酸を用い、参考例D-2と同様の方法により、参考例D-3を合成した。 Reference example D-3
tert-Butyl (3-hydroxy-5-methylpyrazine-2-yl)carbamate Reference Example D-3 was synthesized in the same manner as in Reference Example D-2, except that 3-hydroxy-5-methylpyrazine-2-carboxylic acid was used instead of 4-hydroxy-2-methylpyrimidine-5-carboxylic acid.

参考例E-1
5-ブロモ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-ニトロピリジン-2(1H)-オン
　5-ブロモ-3-ニトロピリジン-2-オール(0.222 g)及びDMF(4.0 mL)の混合物に、炭酸セシウム(0.380 g)及び2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.200 g)を室温で加え、70℃で1時間撹拌した。反応混合物を室温まで放冷した後、水、n-ヘキサン及び酢酸エチルを加え、有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(0.180 g)を得た。 Reference example E-1
5-Bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3-nitropyridin-2(1H)-one To a mixture of 5-bromo-3-nitropyridin-2-ol (0.222 g) and DMF (4.0 mL), cesium carbonate (0.380 g) and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.200 g) were added at room temperature and stirred at 70°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane and ethyl acetate were added to separate the organic layer. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (0.180 g).

参考例E-2
3-アミノ-5-ブロモ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)ピリジン-2(1H)-オン
　参考例E-1(0.180 g)及びDMF(2.0 mL)の混合物に、テトラヒドロキシジボロン(0.123 g)及び4,4’-ジピリジル(0.0004 g)を室温で加え、同温で10分間撹拌した。反応混合物に水、n-ヘキサン及び酢酸エチルを加え、有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～60/40)にて精製し、表題化合物(0.140 g)を得た。 Reference example E-2
3-Amino-5-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)pyridin-2(1H)-one To a mixture of Reference Example E-1 (0.180 g) and DMF (2.0 mL), tetrahydroxydiboron (0.123 g) and 4,4'-dipyridyl (0.0004 g) were added at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Water, n-hexane and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 90/10 to 60/40) to obtain the title compound (0.140 g).

参考例E-3
1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-3-ニトロピリジン-2(1H)-オン
　6-メチル-3-ニトロピリジン-2-オール(0.156 g)及びDMF(2.0 mL)の混合物に、炭酸セシウム(0.380 g)及び2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.200 g)を室温で加え、70℃で30分間撹拌した。反応混合物を室温まで放冷した後、水、n-ヘキサン及び酢酸エチルを加え、有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(0.068 g)を得た。 Reference example E-3
1-(2-Fluoro-5-(trifluoromethyl)benzyl)-6-methyl-3-nitropyridin-2(1H)-one To a mixture of 6-methyl-3-nitropyridin-2-ol (0.156 g) and DMF (2.0 mL), cesium carbonate (0.380 g) and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.200 g) were added at room temperature and stirred at 70°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane and ethyl acetate were added to separate the organic layer. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (0.068 g).

参考例E-4
3-アミノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチルピリジン-2(1H)-オン
　参考例E-3(0.065 g)、10% Pd/C(0.050 g)、THF(1.0 mL)及びメタノール(2.0 mL)の混合物を水素雰囲気下、室温で1時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～20/80)にて精製し、表題化合物(0.056 g)を得た。 Reference example E-4
3-Amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpyridin-2(1H)-one Reference Example E-3 (0.065 g), 10% Pd/C (0.050 g), THF (1.0 mL) and methanol (2.0 mL) were stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (0.056 g).

参考例E-5
1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-3-ニトロピリジン-2(1H)-オン
　6-メチル-3-ニトロピリジン-2-オール(0.350 g)及びDMF(5.0 mL)の混合物に、炭酸セシウム(0.805 g)及び参考例A-8(0.480 g)を室温で加え、70℃で30分間撹拌した。反応混合物を室温まで放冷した後、水、n-ヘキサン及び酢酸エチルを加え、有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～30/70)にて精製し、表題化合物(0.170 g)を得た。 Reference example E-5
1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-3-nitropyridin-2(1H)-one 6-Methyl-3-nitropyridin-2-ol (0.350 g) and DMF (5.0 mL) were added to a mixture of cesium carbonate (0.805 g) and Reference Example A-8 (0.480 g) at room temperature, and the mixture was stirred at 70° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then water, n-hexane and ethyl acetate were added to separate the organic layer. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate=90/10-30/70) to obtain the title compound (0.170 g).

参考例E-6
3-アミノ-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチルピリジン-2(1H)-オン
　参考例E-5(0.170 g)、10% Pd/C(0.120 g)、THF(1.0 mL)及びメタノール(5.0 mL)の混合物を水素雰囲気下、室温で2.5時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～20/80)にて精製し、表題化合物(0.113 g)を得た。 Reference example E-6
3-Amino-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpyridin-2(1H)-one Reference Example E-5 (0.170 g), 10% Pd/C (0.120 g), THF (1.0 mL) and methanol (5.0 mL) were stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (0.113 g).

参考例E-7
1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-ニトロ-5-(トリフルオロメチル)ピリジン-2(1H)-オン
　5-ブロモ-3-ニトロピリジン-2-オールの代わりに3-ニトロ-5-(トリフルオロメチル)ピリジン-2-オールを用い、参考例E-1と同様の方法により、参考例E-7を合成した。 Reference example E-7
1-(2-fluoro-5-(trifluoromethyl)benzyl)-3-nitro-5-(trifluoromethyl)pyridin-2(1H)-one Using 3-nitro-5-(trifluoromethyl)pyridin-2-ol instead of 5-bromo-3-nitropyridin-2-ol, Reference Example E-7 was synthesized in the same manner as Reference Example E-1.

参考例E-8
3-アミノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-5-(トリフルオロメチル)ピリジン-2(1H)-オン
　参考例E-7(0.153 g)、10% Pd/C(0.120 g)、THF(1.0 mL)及びメタノール(5.0 mL)の混合物を水素雰囲気下、室温で2時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮することで、表題化合物(0.141 g)を得た。 Reference example E-8
3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one Reference Example E-7 (0.153 g), 10% Pd/C (0.120 g), THF (1.0 mL) and methanol (5.0 mL) were stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.141 g).

参考例F-1
2-ブロモ-5-(ジフルオロメチル)アニリン
　4-ブロモ-3-ニトロベンズアルデヒド(1.00 g)及びトルエン(10 mL)の混合物に、ビス-(2-メトキシエチル)アミノ硫黄三フッ化物(1.92 g)を室温で加え、同温で2時間撹拌した。反応混合物を氷冷下、飽和炭酸水素ナトリウム水溶液(20 mL)にあけ、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及びDMF(10 mL)の混合物に、テトラヒドロキシジボロン(1.17 g)及び4,4'-ジピリジル(0.003 g)を水冷下で加え、水冷下で5分間撹拌した。反応混合物に水を加え、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～80/20)にて精製し、表題化合物(0.840 g)を得た。 Reference example F-1
2-Bromo-5-(difluoromethyl)aniline To a mixture of 4-bromo-3-nitrobenzaldehyde (1.00 g) and toluene (10 mL), bis-(2-methoxyethyl)aminosulfur trifluoride (1.92 g) was added at room temperature and stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL) under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue and DMF (10 mL), tetrahydroxydiboron (1.17 g) and 4,4'-dipyridyl (0.003 g) were added under cooling with water, and the mixture was stirred under cooling with water for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane/ethyl acetate = 98/2 to 80/20) to obtain the title compound (0.840 g).

参考例G-1
(R)-3-アミノ-1-(3-メチルベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリン(0.200 g)、3-メチルベンズアルデヒド(0.140 g)及びメタノール(1.0 mL)の混合物に、デカボラン(0.043 g)を室温で加え、同温で20分間撹拌した。反応混合物にAPSを加え、室温で30分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、2-ブロモ-N-(3-メチルベンジル)アニリン(0.294 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.526 g)及びDMF(1.2 mL)の混合物に、亜鉛粉末(0.153 g)を室温で加え、同温で30分間撹拌した。反応混合物に上記の2-ブロモ-N-(3-メチルベンジル)アニリン(0.294 g)及びDMF(1.2 mL)の混合物、酢酸パラジウム(II)(0.012 g)及びXphos(0.051 g)を室温で加え、45℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液及び酢酸エチルを加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(0.88 mL)及びトルエン(1.5 mL)の混合物に、メタンスルホン酸(0.614 g)を室温で加え、65℃で1時間、室温で終夜撹拌した。反応混合物に酢酸エチル、トルエン及び水を加え、水層を分取した。水層に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を減圧下濃縮することで、表題化合物(0.075 g)を得た。 Reference example G-1
(R)-3-amino-1-(3-methylbenzyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of 2-bromoaniline (0.200 g), 3-methylbenzaldehyde (0.140 g) and methanol (1.0 mL), decaborane (0.043 g) was added at room temperature and stirred at the same temperature for 20 minutes. APS was added to the reaction mixture and stirred at room temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 2-bromo-N-(3-methylbenzyl)aniline (0.294 g).
Under an argon atmosphere, zinc powder (0.153 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.526 g) and DMF (1.2 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The above mixture of 2-bromo-N-(3-methylbenzyl)aniline (0.294 g) and DMF (1.2 mL), palladium(II) acetate (0.012 g) and Xphos (0.051 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 45° C. for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.88 mL) and toluene (1.5 mL), methanesulfonic acid (0.614 g) was added at room temperature, and the mixture was stirred at 65° C. for 1 hour and at room temperature overnight. Ethyl acetate, toluene and water were added to the reaction mixture, and the aqueous layer was separated. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to obtain the title compound (0.075 g).

参考例G-2
(R)-3-((3-アミノ-2-オキソ-3,4-ジヒドロキノリン-1(2H)-イル)メチル)ベンゾニトリル
　2-ブロモアニリン(0.200 g)、3-ホルミルベンゾニトリル(0.198 g)及びメタノール(2.0 mL)の混合物に、デカボラン(0.043 g)を水冷下で加え、室温で30分間撹拌した。反応混合物にAPSを加え、室温で20分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～70/30)にて精製し、3-(((2-ブロモフェニル)アミノ)メチル)ベンゾニトリル(0.242 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.413 g)、THF(0.48 mL)及びDMF(0.96 mL)の混合物に、亜鉛粉末(0.120 g)を水冷下で加え、室温で1時間撹拌した。反応混合物に上記の3-(((2-ブロモフェニル)アミノ)メチル)ベンゾニトリル(0.240 g)及びTHF(0.96 mL)の混合物、酢酸パラジウム(II)(0.009 g)及びXphos(0.040 g)を室温で加え、40℃で2時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液、水及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水で洗浄した後、減圧下濃縮した。
　残渣、エタノール(0.72 mL)及びトルエン(1.2 mL)の混合物に、メタンスルホン酸(0.241 g)を室温で加え、70℃で30分間撹拌した。反応混合物を減圧下濃縮した。残渣に酢酸エチル、トルエン及び水を加え、水層を分取した。水層に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、減圧下濃縮することで、表題化合物(0.043 g)を得た。 Reference example G-2
(R)-3-((3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)benzonitrile To a mixture of 2-bromoaniline (0.200 g), 3-formylbenzonitrile (0.198 g) and methanol (2.0 mL), decaborane (0.043 g) was added under water cooling and stirred at room temperature for 30 minutes. APS was added to the reaction mixture and stirred at room temperature for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0-70/30) to give 3-(((2-bromophenyl)amino)methyl)benzonitrile (0.242 g).
Under an argon atmosphere, zinc powder (0.120 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.413 g), THF (0.48 mL) and DMF (0.96 mL) under water cooling, and the mixture was stirred at room temperature for 1 hour. The above mixture of 3-(((2-bromophenyl)amino)methyl)benzonitrile (0.240 g) and THF (0.96 mL), palladium(II) acetate (0.009 g) and Xphos (0.040 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours. A saturated aqueous solution of ammonium chloride, water and n-hexane/ethyl acetate (1/1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and then concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.72 mL) and toluene (1.2 mL), methanesulfonic acid (0.241 g) was added at room temperature, and the mixture was stirred at 70° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate, toluene and water were added to the residue, and the aqueous layer was separated. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then concentrated under reduced pressure to obtain the title compound (0.043 g).

参考例G-3
(R)-3-アミノ-1-(3-メトキシベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　3-メチルベンズアルデヒドの代わりに3-メトキシベンズアルデヒドを用い、参考例G-1と同様の方法により、参考例G-3を合成した。 Reference example G-3
(R)-3-amino-1-(3-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-3 was synthesized in the same manner as in Reference Example G-1, except that 3-methoxybenzaldehyde was used instead of 3-methylbenzaldehyde.

参考例G-4
(R)-3-アミノ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリン(0.100 g)、参考例A-1(0.111 g)及びメタノール(2.0 mL)の混合物に、デカボラン(0.021 g)を氷冷下で加え、室温で13時間撹拌した。反応混合物にAPSを加え、室温で10分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、2-ブロモ-N-(5-(ジフルオロメチル)-2-フルオロベンジル)アニリン(0.188 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.215 g)及びDMF(2.0 mL)の混合物に、亜鉛粉末(0.078 g)を室温で加え、同温で1時間撹拌した。反応混合物に上記の2-ブロモ-N-(5-(ジフルオロメチル)-2-フルオロベンジル)アニリン(0.180 g)、酢酸パラジウム(II)(0.006 g)及びXphos(0.026 g)を室温で加え、同温で8時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び酢酸エチルを加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及びDCM(3.0 mL)の混合物に、TFA(1.24 g)を氷冷下で加え、室温で37時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(2.2 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=49/49/2～0/98/2～0/86/14)にて精製し、表題化合物(0.120 g)を得た。 Reference example G-4
(R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline (0.100 g), Reference Example A-1 (0.111 g) and methanol (2.0 mL) were added to a mixture with decaborane (0.021 g) under ice cooling and stirred at room temperature for 13 hours. APS was added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 2-bromo-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.188 g).
Under an argon atmosphere, zinc powder (0.078 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.215 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above 2-bromo-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.180 g), palladium(II) acetate (0.006 g) and Xphos (0.026 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 8 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue and DCM (3.0 mL), TFA (1.24 g) was added under ice-cooling, and the mixture was stirred at room temperature for 37 hours. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (2.2 mL) was added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2 to 0/98/2 to 0/86/14) to obtain the title compound (0.120 g).

参考例G-5
(R)-3-アミノ-1-((2,2-ジフルオロベンゾ[d][1,3]ジオキソール-4-イル)メチル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリン(0.104 g)、炭酸カリウム(0.070 g)及びDMF(1.5 mL)の混合物に、4-(ブロモメチル)-2,2-ジフルオロベンゾ[d][1,3]ジオキソール(0.127 g)を室温で加え、80℃で17時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～90/10)にて精製し、2-ブロモ-N-((2,2-ジフルオロベンゾ[d][1,3]ジオキソール-4-イル)メチル)アニリン(0.127 g)を得た。
　アルゴン雰囲気下、亜鉛粉末(0.053 g)及びDMF(0.48 mL)の混合物に、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.183 g)及びDMF(0.24 mL)の混合物を室温で加え、同温で1時間撹拌した。反応混合物に上記の2-ブロモ-N-((2,2-ジフルオロベンゾ[d][1,3]ジオキソール-4-イル)メチル)アニリン(0.127 g)及びDMF(0.48 mL)の混合物、酢酸パラジウム(II)(0.004 g)及びXphos(0.018 g)を室温で加え、80℃で15分間、室温で2時間撹拌した。反応混合物に氷冷下、水、飽和塩化アンモニウム水溶液及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(0.37 mL)及びトルエン(0.55 mL)の混合物に、メタンスルホン酸(0.107 g)を室温で加え、80℃で1時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.223 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/80/20)にて精製し、表題化合物(0.052 g)を得た。 Reference example G-5
(R)-3-amino-1-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-3,4-dihydroquinolin-2(1H)-one 4-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole (0.127 g) was added to a mixture of 2-bromoaniline (0.104 g), potassium carbonate (0.070 g) and DMF (1.5 mL) at room temperature, and the mixture was stirred at 80° C. for 17 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 90/10) to give 2-bromo-N-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)aniline (0.127 g).
Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.183 g) and DMF (0.24 mL) was added to a mixture of zinc powder (0.053 g) and DMF (0.48 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of 2-bromo-N-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)aniline (0.127 g) and DMF (0.48 mL), palladium(II) acetate (0.004 g) and Xphos (0.018 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 80° C. for 15 minutes and at room temperature for 2 hours. Water, a saturated aqueous solution of ammonium chloride, and n-hexane/ethyl acetate (1/1) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.37 mL) and toluene (0.55 mL), methanesulfonic acid (0.107 g) was added at room temperature and stirred at 80°C for 1 hour. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.223 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/80/20) to obtain the title compound (0.052 g).

参考例G-6
(R)-3-アミノ-7-メチル-1-(3-(トリフルオロメチル)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-メチルアニリン、3-ホルミルベンゾニトリルの代わりに3-(トリフルオロメチル)ベンズアルデヒドを用い、参考例G-2と同様の方法により、参考例G-6を合成した。 Reference example G-6
(R)-3-amino-7-methyl-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-methylaniline instead of 2-bromoaniline and 3-(trifluoromethyl)benzaldehyde instead of 3-formylbenzonitrile, Reference Example G-6 was synthesized in the same manner as Reference Example G-2.

参考例G-7
(R)-3-アミノ-7-メトキシ-1-(3-(トリフルオロメチル)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-メトキシアニリン、3-メチルベンズアルデヒドの代わりに3-(トリフルオロメチル)ベンズアルデヒドを用い、参考例G-1と同様の方法により、参考例G-7を合成した。 Reference example G-7
(R)-3-amino-7-methoxy-1-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-methoxyaniline instead of 2-bromoaniline and 3-(trifluoromethyl)benzaldehyde instead of 3-methylbenzaldehyde, Reference Example G-7 was synthesized in the same manner as Reference Example G-1.

参考例G-8
(R)-3-アミノ-2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロキノリン-7-カルボニトリル
　3-アミノ-4-ブロモベンゾニトリル(0.100 g)、3-(トリフルオロメチル)ベンズアルデヒド(0.088 g)及びメタノール(2.0 mL)の混合物に、デカボラン(0.019 g)を室温で加え、同温で30分間撹拌した。反応混合物にAPSを加え、室温で10分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、4-ブロモ-3-((3-(トリフルオロメチル)ベンジル)アミノ)ベンゾニトリル(0.200 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.250 g)及びDMF(1.0 mL)の混合物に、亜鉛粉末(0.073 g)を室温で加え、同温で1時間撹拌した。反応混合物に上記の4-ブロモ-3-((3-(トリフルオロメチル)ベンジル)アミノ)ベンゾニトリル(0.180 g)及びDMF(1.5 mL)の混合物、酢酸パラジウム(II)(0.006 g)及びXphos(0.024 g)を室温で加え、40℃で2時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液及び酢酸エチルを加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(0.5 mL)及びトルエン(1.0 mL)の混合物に、メタンスルホン酸(0.146 g)を室温で加え、70℃で1時間撹拌した。反応混合物に氷冷下、飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=49/49/2～0/98/2～0/86/14)にて精製し、表題化合物(0.110 g)を得た。 Reference example G-8
(R)-3-amino-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoline-7-carbonitrile To a mixture of 3-amino-4-bromobenzonitrile (0.100 g), 3-(trifluoromethyl)benzaldehyde (0.088 g) and methanol (2.0 mL), decaborane (0.019 g) was added at room temperature and stirred at the same temperature for 30 minutes. APS was added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 4-bromo-3-((3-(trifluoromethyl)benzyl)amino)benzonitrile (0.200 g).
Under an argon atmosphere, zinc powder (0.073 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.250 g) and DMF (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of 4-bromo-3-((3-(trifluoromethyl)benzyl)amino)benzonitrile (0.180 g) and DMF (1.5 mL), palladium(II) acetate (0.006 g) and Xphos (0.024 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.5 mL) and toluene (1.0 mL), methanesulfonic acid (0.146 g) was added at room temperature and stirred at 70°C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 49/49/2 to 0/98/2 to 0/86/14) to obtain the title compound (0.110 g).

参考例G-9
(R)-3-アミノ-5-フルオロ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-3-フルオロアニリン、参考例A-1の代わりに2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドを用い、参考例G-4と同様の方法により、参考例G-9を合成した。 Reference example G-9
(R)-3-amino-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline was replaced with 2-bromo-3-fluoroaniline, and Reference Example A-1 was replaced with 2-fluoro-5-(trifluoromethyl)benzaldehyde, and Reference Example G-9 was synthesized in the same manner as Reference Example G-4.

参考例G-10
(R)-3-アミノ-7-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　3-アミノ-4-ブロモベンゾニトリルの代わりに参考例F-1、3-(トリフルオロメチル)ベンズアルデヒドの代わりに2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドを用い、参考例G-8と同様の方法により、参考例G-10を合成した。 Reference example G-10
(R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-1 was used instead of 3-amino-4-bromobenzonitrile, and 2-fluoro-5-(trifluoromethyl)benzaldehyde was used instead of 3-(trifluoromethyl)benzaldehyde, and Reference Example G-10 was synthesized in the same manner as Reference Example G-8.

参考例G-11
(R)-3-アミノ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-フルオロ-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-フルオロアニリンを用い、参考例G-4と同様の方法により、参考例G-11を合成した。 Reference example G-11
(R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-fluoroaniline instead of 2-bromoaniline, Reference Example G-11 was synthesized in the same manner as in Reference Example G-4.

参考例G-12
(R)-3-アミノ-7-クロロ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-クロロアニリンを用い、参考例G-4と同様の方法により、参考例G-12を合成した。 Reference example G-12
(R)-3-amino-7-chloro-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-chloroaniline instead of 2-bromoaniline, Reference Example G-12 was synthesized in the same manner as Reference Example G-4.

参考例G-13
(R)-3-アミノ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-メチル-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-メチルアニリンを用い、参考例G-4と同様の方法により、参考例G-13を合成した。 Reference example G-13
(R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-5-methylaniline instead of 2-bromoaniline, Reference Example G-13 was synthesized in the same manner as Reference Example G-4.

参考例G-14
(R)-3-アミノ-7-(ジフルオロメチル)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　参考例F-1(0.100 g)、参考例A-1(0.086 g)及びメタノール(2.0 mL)の混合物に、デカボラン(0.017 g)を室温で加え、同温で30分間撹拌した。反応混合物にAPSを加え、室温で10分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、2-ブロモ-5-(ジフルオロメチル)-N-(5-(ジフルオロメチル)-2-フルオロベンジル)アニリン(0.210 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.221 g)及びDMF(2.0 mL)の混合物に、亜鉛粉末(0.064 g)を室温で加え、同温で1時間撹拌した。反応混合物に上記の2-ブロモ-5-(ジフルオロメチル)-N-(5-(ジフルオロメチル)-2-フルオロベンジル)アニリン(0.170 g)及びDMF(2.0 mL)の混合物、酢酸パラジウム(II)(0.005 g)及びXphos(0.021 g)を室温で加え、40℃で2時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液及び酢酸エチルを加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(1.0 mL)及びトルエン(2.0 mL)の混合物に、メタンスルホン酸(0.129 g)を室温で加え、70℃で2時間撹拌した。反応混合物に氷冷下、飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=49/49/2～0/98/2～0/86/14)にて精製し、表題化合物(0.065 g)を得た。 Reference example G-14
(R)-3-amino-7-(difluoromethyl)-1-(5-(difluoromethyl)-2-fluorobenzyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of Reference Example F-1 (0.100 g), Reference Example A-1 (0.086 g) and methanol (2.0 mL), decaborane (0.017 g) was added at room temperature and stirred at the same temperature for 30 minutes. APS was added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 2-bromo-5-(difluoromethyl)-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.210 g).
Under an argon atmosphere, zinc powder (0.064 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.221 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of 2-bromo-5-(difluoromethyl)-N-(5-(difluoromethyl)-2-fluorobenzyl)aniline (0.170 g) and DMF (2.0 mL), palladium(II) acetate (0.005 g) and Xphos (0.021 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours. After the reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (1.0 mL) and toluene (2.0 mL), methanesulfonic acid (0.129 g) was added at room temperature and stirred at 70°C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 49/49/2 to 0/98/2 to 0/86/14) to obtain the title compound (0.065 g).

参考例G-15
(R)-3-アミノ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-(トリフルオロメチル)-3,4-ジヒドロキノリン-2(1H)-オン
　参考例F-1の代わりに2-ブロモ-5-(トリフルオロメチル)アニリンを用い、参考例G-14と同様の方法により、参考例G-15を合成した。 Reference example G-15
(R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one Reference Example G-15 was synthesized in the same manner as in Reference Example G-14, using 2-bromo-5-(trifluoromethyl)aniline instead of Reference Example F-1.

参考例G-16
(R)-3-アミノ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-(ヒドロキシメチル)-3,4-ジヒドロキノリン-2(1H)-オン
　3-アミノ-4-ブロモ安息香酸メチル(1.00 g)、参考例A-1(0.917 g)及びメタノール(2.0 mL)の混合物に、デカボラン(0.159 g)を室温で加え、同温で30分間撹拌した。反応混合物にAPSを加え、室温で10分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、4-ブロモ-3-((5-(ジフルオロメチル)-2-フルオロベンジル)アミノ)安息香酸メチル(1.36 g)を得た。
　得られた化合物(1.36 g)及びTHF(12 mL)の混合物に、水素化アルミニウムリチウム(1 mol/L in THF)(4.19 mL)を氷冷下で加え、氷冷下で2時間撹拌した。反応混合物に水(0.16 mL)、5 mol/L水酸化ナトリウム水溶液(0.16 mL)及び水(0.48 mL)を加え、室温でしばらく撹拌した。混合物をセライトろ過し、ろ液を減圧下濃縮することで、(4-ブロモ-3-((5-(ジフルオロメチル)-2-フルオロベンジル)アミノ)フェニル)メタノール(1.28 g)を得た。
　アルゴン雰囲気下、亜鉛粉末(0.160 g)及びDMF(2.0 mL)の混合物に、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.548 g)及びDMF(1.0 mL)の混合物を室温で加え、同温で1時間撹拌した。反応混合物に上記の(4-ブロモ-3-((5-(ジフルオロメチル)-2-フルオロベンジル)アミノ)フェニル)メタノール(0.400 g)及びDMF(2.0 mL)の混合物、酢酸パラジウム(II)(0.012 g)及びXphos(0.053 g)を室温で加え、40℃で16時間撹拌した。反応混合物を室温まで放冷した後、水、飽和塩化アンモニウム水溶液及びn-ヘキサン/酢酸エチル(1/1)を加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(1.0 mL)及びトルエン(1.5 mL)の混合物に、メタンスルホン酸(0.320 g)を室温で加え、70℃で1.5時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.666 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/65/35)にて精製し、表題化合物(0.228 g)を得た。 Reference example G-16
(R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of methyl 3-amino-4-bromobenzoate (1.00 g), Reference Example A-1 (0.917 g) and methanol (2.0 mL), decaborane (0.159 g) was added at room temperature and stirred at the same temperature for 30 minutes. APS was added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain methyl 4-bromo-3-((5-(difluoromethyl)-2-fluorobenzyl)amino)benzoate (1.36 g).
To a mixture of the obtained compound (1.36 g) and THF (12 mL), lithium aluminum hydride (1 mol/L in THF) (4.19 mL) was added under ice cooling, and the mixture was stirred under ice cooling for 2 hours. Water (0.16 mL), 5 mol/L aqueous sodium hydroxide solution (0.16 mL), and water (0.48 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for a while. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain (4-bromo-3-((5-(difluoromethyl)-2-fluorobenzyl)amino)phenyl)methanol (1.28 g).
Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.548 g) and DMF (1.0 mL) was added to a mixture of zinc powder (0.160 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of (4-bromo-3-((5-(difluoromethyl)-2-fluorobenzyl)amino)phenyl)methanol (0.400 g) and DMF (2.0 mL), palladium(II) acetate (0.012 g) and Xphos (0.053 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 16 hours. After the reaction mixture was allowed to cool to room temperature, water, a saturated aqueous solution of ammonium chloride and n-hexane/ethyl acetate (1/1) were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (1.0 mL) and toluene (1.5 mL), methanesulfonic acid (0.320 g) was added at room temperature and stirred at 70°C for 1.5 hours. 5 mol/L aqueous sodium hydroxide solution (0.666 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/65/35) to obtain the title compound (0.228 g).

参考例G-17
(R)-3-アミノ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-5,7-ジフルオロ-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-3,5-ジフルオロアニリンを用い、参考例G-4と同様の方法により、参考例G-17を合成した。 Reference example G-17
(R)-3-amino-1-(5-(difluoromethyl)-2-fluorobenzyl)-5,7-difluoro-3,4-dihydroquinolin-2(1H)-one Using 2-bromo-3,5-difluoroaniline instead of 2-bromoaniline, Reference Example G-17 was synthesized in the same manner as Reference Example G-4.

参考例G-18
(R)-3-アミノ-7-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメトキシ)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　参考例F-1(0.118 g)、2-フルオロ-5-(トリフルオロメトキシ)ベンズアルデヒド(0.116 g)及びメタノール(1.0 mL)の混合物に、デカボラン(0.020 g)を室温で加え、同温で2時間撹拌した。反応混合物にAPSを加え、室温で20分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、2-ブロモ-5-(ジフルオロメチル)-N-(2-フルオロ-5-(トリフルオロメトキシ)ベンジル)アニリン(0.209 g)を得た。
　アルゴン雰囲気下、亜鉛粉末(0.073 g)及びDMF(0.68 mL)の混合物に、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.249 g)及びDMF(0.34 mL)の混合物を室温で加え、同温で1時間撹拌した。反応混合物に上記の2-ブロモ-5-(ジフルオロメチル)-N-(2-フルオロ-5-(トリフルオロメトキシ)ベンジル)アニリン(0.209 g)及びDMF(0.68 mL)の混合物、酢酸パラジウム(II)(0.006 g)及びXphos(0.024 g)を室温で加え、40℃で2時間、室温で16時間撹拌した。反応混合物に氷冷下、水、飽和塩化アンモニウム水溶液及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(0.52 mL)及びトルエン(0.77 mL)の混合物に、メタンスルホン酸(0.145 g)を室温で加え、80℃で1時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.300 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/80/20)にて精製し、表題化合物(0.077 g)を得た。 Reference example G-18
(R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethoxy)benzyl)-3,4-dihydroquinolin-2(1H)-one Reference Example F-1 (0.118 g), 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.116 g) and methanol (1.0 mL) were added to a mixture, and decaborane (0.020 g) was added at room temperature and stirred at the same temperature for 2 hours. APS was added to the reaction mixture and stirred at room temperature for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 2-bromo-5-(difluoromethyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)aniline (0.209 g).
Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.249 g) and DMF (0.34 mL) was added to a mixture of zinc powder (0.073 g) and DMF (0.68 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of 2-bromo-5-(difluoromethyl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)aniline (0.209 g) and DMF (0.68 mL), palladium(II) acetate (0.006 g) and Xphos (0.024 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours and at room temperature for 16 hours. Water, a saturated aqueous solution of ammonium chloride, and n-hexane/ethyl acetate (1/1) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.52 mL) and toluene (0.77 mL), methanesulfonic acid (0.145 g) was added at room temperature and stirred at 80°C for 1 hour. 5 mol/L aqueous sodium hydroxide solution (0.300 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/80/20) to obtain the title compound (0.077 g).

参考例G-19
(R)-3-アミノ-7-(ジフルオロメチル)-1-(2-フルオロ-5-(ペンタフルオロ硫黄)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-フルオロ-5-(トリフルオロメトキシ)ベンズアルデヒドの代わりに2-フルオロ-5-(ペンタフルオロ硫黄)ベンズアルデヒドを用い、参考例G-18と同様の方法により、参考例G-19を合成した。 Reference example G-19
(R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(pentafluorosulfur)benzyl)-3,4-dihydroquinolin-2(1H)-one 2-fluoro-5-(trifluoromethoxy)benzaldehyde was replaced with 2-fluoro-5-(pentafluorosulfur)benzaldehyde, and Reference Example G-19 was synthesized in the same manner as Reference Example G-18.

参考例G-20
(R)-3-アミノ-7-(ジフルオロメチル)-1-(2-フルオロ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)ベンジル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-フルオロ-5-(トリフルオロメトキシ)ベンズアルデヒドの代わりに参考例A-11を用い、参考例G-18と同様の方法により、参考例G-20を合成した。 Reference example G-20
(R)-3-amino-7-(difluoromethyl)-1-(2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3,4-dihydroquinolin-2(1H)-one 2-fluoro-5-(trifluoromethoxy)benzaldehyde was used instead of Reference Example A-11, and Reference Example G-20 was synthesized in the same manner as Reference Example G-18.

参考例G-21
(R)-3-アミノ-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-7-フルオロ-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-フルオロアニリン、参考例A-1の代わりに3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒドを用い、参考例G-4と同様の方法により、参考例G-21を合成した。 Reference example G-21
(R)-3-amino-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline instead of 2-bromoaniline, 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde instead of Reference Example A-1 was used, and Reference Example G-21 was synthesized in the same manner as Reference Example G-4.

参考例G-22
(R)-3-アミノ-1-(3-(トリフルオロメチル)ベンジル)-3,4-ジヒドロチエノ[3,4-b]ピリジン-2(1H)-オン
　(4-ブロモチオフェン-3-イル)カルバミン酸tert-ブチル(0.300 g)及びDMF(3.0 mL)の混合物に、水素化ナトリウム(約60%)(0.047 g)及び1-(ブロモメチル)-3-(トリフルオロメチル)ベンゼン(0.284 g)を氷冷下で加え、室温で1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液、水、n-ヘキサン及び酢酸エチルを加え、有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及びメタノール(3.0 mL)の混合物に、塩化水素(4 mol/L in 1,4-dioxane)(1.35 mL)を室温で加え、同温で4時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(1.2 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～80/20)にて精製し、4-ブロモ-N-(3-(トリフルオロメチル)ベンジル)チオフェン-3-アミン(0.360 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.705 g)及びDMF(2.0 mL)の混合物に、亜鉛粉末(0.154 g)を室温で加え、同温で1時間撹拌した。反応混合物に上記の4-ブロモ-N-(3-(トリフルオロメチル)ベンジル)チオフェン-3-アミン(0.360 g)及びDMF(2.0 mL)の混合物、酢酸パラジウム(II)(0.012 g)及びXphos(0.051 g)を室温で加え、40℃で2時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液、n-ヘキサン及び酢酸エチルを加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(1.0 mL)及びトルエン(2.0 mL)の混合物に、メタンスルホン酸(0.309 g)を室温で加え、70℃で1時間撹拌した。反応混合物を減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=49/49/2～0/98/2～0/86/14)にて精製し、表題化合物(0.260 g)を得た。 Reference example G-22
(R)-3-amino-1-(3-(trifluoromethyl)benzyl)-3,4-dihydrothieno[3,4-b]pyridin-2(1H)-one To a mixture of tert-butyl (4-bromothiophen-3-yl)carbamate (0.300 g) and DMF (3.0 mL), sodium hydride (about 60%) (0.047 g) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.284 g) were added under ice-cooling and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution, water, n-hexane and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous sodium sulfate and concentrated under reduced pressure.
To a mixture of the residue and methanol (3.0 mL), hydrogen chloride (4 mol/L in 1,4-dioxane) (1.35 mL) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (1.2 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2 to 80/20) to give 4-bromo-N-(3-(trifluoromethyl)benzyl)thiophene-3-amine (0.360 g).
Under an argon atmosphere, zinc powder (0.154 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.705 g) and DMF (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of 4-bromo-N-(3-(trifluoromethyl)benzyl)thiophene-3-amine (0.360 g) and DMF (2.0 mL), palladium(II) acetate (0.012 g) and Xphos (0.051 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution, n-hexane and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (1.0 mL) and toluene (2.0 mL), methanesulfonic acid (0.309 g) was added at room temperature and stirred at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 49/49/2 to 0/98/2 to 0/86/14) to obtain the title compound (0.260 g).

参考例G-23
(R)-2-((tert-ブトキシカルボニル)アミノ)-3-(3-((3-(トリフルオロメチル)ベンジル)アミノ)ピリジン-4-イル)プロパン酸メチル
　4-ブロモピリジン-3-アミン(0.300 g)、3-(トリフルオロメチル)ベンズアルデヒド(0.302 g)及びメタノール(3.0 mL)の混合物に、デカボラン(0.064 g)を室温で加え、同温で14時間撹拌した。反応混合物にAPSを加え、室温で10分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～50/50)にて精製し、4-ブロモ-N-(3-(トリフルオロメチル)ベンジル)ピリジン-3-アミン(0.180 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.358 g)及びDMF(1.0 mL)の混合物に、亜鉛粉末(0.078 g)を室温で加え、同温で1時間撹拌した。反応混合物に上記の4-ブロモ-N-(3-(トリフルオロメチル)ベンジル)ピリジン-3-アミン(0.180 g)及びDMF(1.0 mL)の混合物、酢酸パラジウム(II)(0.006 g)及びXphos(0.026 g)を室温で加え、40℃で2時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液及び酢酸エチルを加え、同温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～50/50)にて精製し、表題化合物(0.049 g)を得た。 Reference example G-23
Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-((3-(trifluoromethyl)benzyl)amino)pyridin-4-yl)propanoate 4-Bromopyridin-3-amine (0.300 g), 3-(trifluoromethyl)benzaldehyde (0.302 g) and methanol (3.0 mL) were added with decaborane (0.064 g) at room temperature and stirred at the same temperature for 14 hours. APS was added to the reaction mixture and stirred at room temperature for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 90/10 to 50/50) to give 4-bromo-N-(3-(trifluoromethyl)benzyl)pyridin-3-amine (0.180 g).
Under an argon atmosphere, zinc powder (0.078 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.358 g) and DMF (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The above mixture of 4-bromo-N-(3-(trifluoromethyl)benzyl)pyridin-3-amine (0.180 g) and DMF (1.0 mL), palladium(II) acetate (0.006 g) and Xphos (0.026 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution and ethyl acetate were added, and the mixture was stirred at the same temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane/ethyl acetate=90/10-50/50) to obtain the title compound (0.049 g).

参考例G-24
(3R)-3-アミノ-7-フルオロ-1-(1-(2-フルオロ-5-(トリフルオロメチル)フェニル)エチル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリンの代わりに2-ブロモ-5-フルオロアニリン、参考例A-1の代わりに1-(2-フルオロ-5-(トリフルオロメチル)フェニル)エタン-1-オンを用い、参考例G-4と同様の方法により、参考例G-24を合成した。 Reference example G-24
(3R)-3-amino-7-fluoro-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-3,4-dihydroquinolin-2(1H)-one 2-bromoaniline instead of 2-bromo-5-fluoroaniline, instead of Reference Example A-1, 1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-one was used, and Reference Example G-24 was synthesized in the same manner as Reference Example G-4.

参考例G-25
(R)-3-アミノ-1-フェネチル-3,4-ジヒドロキノリン-2(1H)-オン
　参考例A-1の代わりに2-フェニルアセトアルデヒドを用い、参考例G-4と同様の方法により、参考例G-25を合成した。 Reference example G-25
(R)-3-amino-1-phenethyl-3,4-dihydroquinolin-2(1H)-one Reference Example G-25 was synthesized in the same manner as in Reference Example G-4, except that 2-phenylacetaldehyde was used instead of Reference Example A-1.

参考例G-26
(R)-3-アミノ-1-(3-フェニルプロピル)-3,4-ジヒドロキノリン-2(1H)-オン
　3-フェニルプロパン-1-オール(1.50 g)及びDCM(20 mL)の混合物に、炭酸水素ナトリウム(0.928 g)及びDMP(5.57 g)を氷冷下で加え、室温で1時間撹拌した。反応混合物に氷冷下、飽和炭酸水素ナトリウム水溶液及び1 mol/Lチオ硫酸ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮することで、3-フェニルプロパナール(1.45 g)を得た。
　得られた化合物(0.200 g)及びメタノール(1.0 mL)の混合物に、2-ブロモアニリン(0.200 g)及びデカボラン(0.043 g)を室温で加え、同温で20分間撹拌した。反応混合物にAPSを加え、室温で10分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、2-ブロモ-N-(3-フェニルプロピル)アニリン(0.337 g)を得た。
　アルゴン雰囲気下、亜鉛粉末(0.167 g)及びDMF(2.7 mL)の混合物に、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.573 g)及びTHF(2.0 mL)の混合物を室温で加え、同温で30分間撹拌した。反応混合物に上記の2-ブロモ-N-(3-フェニルプロピル)アニリン(0.337 g)及びTHF(1.0 mL)の混合物、酢酸パラジウム(II)(0.013 g)及びXphos(0.055 g)を室温で加え、同温で30分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び酢酸エチルを加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(1.0 mL)及びトルエン(1.7 mL)の混合物に、メタンスルホン酸(0.335 g)を室温で加え、40℃で30分間、75℃で1時間、室温で終夜撹拌した。反応混合物を減圧下濃縮した。残渣に酢酸エチル、トルエン及び水を加え、水層を分取した。水層に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、表題化合物(0.203 g)を得た。 Reference example G-26
(R)-3-amino-1-(3-phenylpropyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of 3-phenylpropan-1-ol (1.50 g) and DCM (20 mL), sodium hydrogen carbonate (0.928 g) and DMP (5.57 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate and a 1 mol/L aqueous solution of sodium thiosulfate were added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to obtain 3-phenylpropanal (1.45 g).
To a mixture of the obtained compound (0.200 g) and methanol (1.0 mL), 2-bromoaniline (0.200 g) and decaborane (0.043 g) were added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. APS was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain 2-bromo-N-(3-phenylpropyl)aniline (0.337 g).
Under an argon atmosphere, a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.573 g) and THF (2.0 mL) was added to a mixture of zinc powder (0.167 g) and DMF (2.7 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The above mixture of 2-bromo-N-(3-phenylpropyl)aniline (0.337 g) and THF (1.0 mL), palladium(II) acetate (0.013 g) and Xphos (0.055 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (1.0 mL) and toluene (1.7 mL), methanesulfonic acid (0.335 g) was added at room temperature, and the mixture was stirred at 40° C. for 30 minutes, at 75° C. for 1 hour, and at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate, toluene and water were added to the residue, and the aqueous layer was separated. A saturated aqueous solution of sodium bicarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.203 g).

参考例G-27
(R)-3-アミノ-1-(シクロヘキシルメチル)-3,4-ジヒドロキノリン-2(1H)-オン
　2-ブロモアニリン(0.150 g)、シクロヘキサンカルバルデヒド(0.103 g)及びメタノール(1.7 mL)の混合物に、デカボラン(0.032 g)を水冷下で加え、室温で30分間撹拌した。反応混合物にAPSを加え、室温で15分間撹拌した。混合物をろ過し、ろ液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン)にて精製し、2-ブロモ-N-(シクロヘキシルメチル)アニリン(0.196 g)を得た。
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.356 g)及びDMF(1.2 mL)の混合物に、亜鉛粉末(0.104 g)を水冷下で加え、室温で1時間撹拌した。反応混合物に上記の2-ブロモ-N-(シクロヘキシルメチル)アニリン(0.193 g)及びDMF(0.77 mL)の混合物、酢酸パラジウム(II)(0.008 g)及びXphos(0.034 g)を室温で加え、40℃で3時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液、水及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水で洗浄した後、減圧下濃縮した。
　残渣、エタノール(0.58 mL)及びトルエン(0.97 mL)の混合物に、メタンスルホン酸(0.208 g)を室温で加え、70℃で2時間撹拌した。反応混合物を減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～70/30)にて精製し、表題化合物(0.120 g)を得た。 Reference example G-27
(R)-3-amino-1-(cyclohexylmethyl)-3,4-dihydroquinolin-2(1H)-one To a mixture of 2-bromoaniline (0.150 g), cyclohexanecarbaldehyde (0.103 g) and methanol (1.7 mL), decaborane (0.032 g) was added under water cooling and stirred at room temperature for 30 minutes. APS was added to the reaction mixture and stirred at room temperature for 15 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane) to obtain 2-bromo-N-(cyclohexylmethyl)aniline (0.196 g).
Under an argon atmosphere, zinc powder (0.104 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.356 g) and DMF (1.2 mL) under water cooling, and the mixture was stirred at room temperature for 1 hour. The above mixture of 2-bromo-N-(cyclohexylmethyl)aniline (0.193 g) and DMF (0.77 mL), palladium(II) acetate (0.008 g) and Xphos (0.034 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 3 hours. A saturated aqueous solution of ammonium chloride, water and n-hexane/ethyl acetate (1/1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and then concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.58 mL) and toluene (0.97 mL), methanesulfonic acid (0.208 g) was added at room temperature and stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 70/30) to obtain the title compound (0.120 g).

参考例H-1
2-(3-(トリフルオロメチル)フェニル)酢酸メチル
　2-(3-(トリフルオロメチル)フェニル)酢酸(2.02 g)、塩化水素(4 mol/L in 1,4-dioxane)(9.89 mL)及びメタノール(10 mL)の混合物を60℃で1時間撹拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、表題化合物(1.89 g)を得た。 Reference example H-1
Methyl 2-(3-(trifluoromethyl)phenyl)acetate A mixture of 2-(3-(trifluoromethyl)phenyl)acetic acid (2.02 g), hydrogen chloride (4 mol/L in 1,4-dioxane) (9.89 mL) and methanol (10 mL) was stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.89 g).

参考例H-2
2-(ブロモメチル)-4-(トリフルオロメチル)安息香酸メチル
　アルゴン雰囲気下、2-メチル-4-(トリフルオロメチル)安息香酸メチル(0.587 g)及び四塩化炭素(11 mL)の混合物に、NBS(0.575 g)及びAIBN(0.013 g)を室温で加え、70℃で16時間、100℃で1.5時間撹拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。残渣をn-ヘキサンに懸濁し、不溶物をろ去した。ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～97/3)にて精製し、表題化合物(0.674 g)を得た。 Reference example H-2
Methyl 2-(bromomethyl)-4-(trifluoromethyl)benzoate Under an argon atmosphere, NBS (0.575 g) and AIBN (0.013 g) were added to a mixture of methyl 2-methyl-4-(trifluoromethyl)benzoate (0.587 g) and carbon tetrachloride (11 mL) at room temperature, and the mixture was stirred at 70°C for 16 hours and at 100°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was suspended in n-hexane, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0-97/3) to give the title compound (0.674 g).

参考例H-3
メタンスルホン酸(6-(トリフルオロメチル)ピリジン-2-イル)メチル
　(6-(トリフルオロメチル)ピリジン-2-イル)メタノール(0.050 g)、TEA(0.043 g)及びDCM(2.8 mL)の混合物に、メタンスルホニルクロリド(0.039 g)を氷冷下で加え、氷冷下で30分間撹拌した。室温下、反応混合物を水にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、表題化合物(0.065 g)を得た。 Reference example H-3
(6-(trifluoromethyl)pyridin-2-yl)methyl methanesulfonate To a mixture of (6-(trifluoromethyl)pyridin-2-yl)methanol (0.050 g), TEA (0.043 g) and DCM (2.8 mL), methanesulfonyl chloride (0.039 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was poured into water at room temperature, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.065 g).

参考例I-1
(S)-6-(ヒドロキシメチル)ピペリジン-2-オン
　(S)-6-オキソピペリジン-2-カルボン酸(1.00 g)及びメタノール(4.0 mL)の混合物に、塩化チオニル(2.49 g)を氷冷下で加え、60℃で8時間撹拌した。反応混合物を室温まで放冷した後、減圧下濃縮した。残渣に水を加え、混合物を酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及びエタノール(20 mL)の混合物に、水素化ホウ素ナトリウム(1.06 g)を氷冷下で加え、室温で65時間撹拌した。反応混合物に少量の酢酸を加え、混合物を減圧下濃縮した。残渣をDCMに懸濁し、不溶物をろ去した。ろ液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、表題化合物(0.783 g)を得た。 Reference example I-1
(S)-6-(hydroxymethyl)piperidin-2-one To a mixture of (S)-6-oxopiperidine-2-carboxylic acid (1.00 g) and methanol (4.0 mL), thionyl chloride (2.49 g) was added under ice cooling, and the mixture was stirred at 60° C. for 8 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
To a mixture of the residue and ethanol (20 mL), sodium borohydride (1.06 g) was added under ice-cooling, and the mixture was stirred at room temperature for 65 hours. A small amount of acetic acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in DCM, and insoluble matter was removed by filtration. The filtrate was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.783 g).

参考例I-2
(S)-6-(((tert-ブチルジフェニルシリル)オキシ)メチル)ピペリジン-2-オン
　参考例I-1(0.783 g)、イミダゾール(0.825 g)、TBDPSCl(1.83 g)、DMAP(0.074 g)及びDCM(20 mL)の混合物を室温で2時間撹拌した。反応混合物を水にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～0/100)にて精製し、表題化合物(1.21 g)を得た。 Reference example I-2
(S)-6-(((tert-Butyldiphenylsilyl)oxy)methyl)piperidin-2-one A mixture of Reference Example I-1 (0.783 g), imidazole (0.825 g), TBDPSCl (1.83 g), DMAP (0.074 g) and DCM (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 0/100) to obtain the title compound (1.21 g).

参考例I-3
(2S,5S)-5-(2-エトキシ-2-オキソエチル)ピロリジン-1,2-ジカルボン酸1-(tert-ブチル)2-ベンジル
　(S)-5-オキソピロリジン-1,2-ジカルボン酸1-(tert-ブチル)2-ベンジル(1.00 g)及びTHF(20 mL)の混合物に、水素化トリエチルホウ素リチウム(1 mol/L in THF)(4.70 mL)を-78℃で加え、同温で30分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、(2S)-5-ヒドロキシピロリジン-1,2-ジカルボン酸1-(tert-ブチル)2-ベンジル(1.20 g)を得た。
　ジエチルホスホノ酢酸エチル(0.439 g)及びDMF(3.0 mL)の混合物に、水素化ナトリウム(約60%)(0.085 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に上記の(2S)-5-ヒドロキシピロリジン-1,2-ジカルボン酸1-(tert-ブチル)2-ベンジル(0.500 g)及びDMF(2.0 mL)の混合物を加え、室温で30分間撹拌した。反応混合物に水を加え、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、表題化合物(0.343 g)を得た。 Reference example I-3
(2S,5S)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (S)-5-oxopyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (1.00 g) and THF (20 mL) were added to a mixture of lithium triethylborohydride (1 mol/L in THF) (4.70 mL) at -78°C and stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (1.20 g).
Sodium hydride (about 60%) (0.085 g) was added to a mixture of ethyl diethylphosphonoacetate (0.439 g) and DMF (3.0 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The above mixture of (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-benzyl (0.500 g) and DMF (2.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 70/30) to obtain the title compound (0.343 g).

参考例I-4
(2S,5S)-2-(2-エトキシ-2-オキソエチル)-5-ホルミルピロリジン-1-カルボン酸tert-ブチル
　参考例I-3(0.343 g)、10% Pd/C(0.051 g)及びエタノール(3.0 mL)の混合物を水素雰囲気下、室温で2時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。
　残渣及びTHF(3.0 mL)の混合物に、BH3-THF(0.9 mol/L in THF)(3.89 mL)を氷冷下で加え、氷冷下で3時間撹拌した。反応混合物に水及び飽和食塩水を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及びDCM(10 mL)の混合物に、DMP(1.12 g)を室温で加え、同温で2時間撹拌した。反応混合物に1 mol/Lチオ硫酸ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、表題化合物(0.242 g)を得た。 Reference example I-4
(2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-formylpyrrolidine-1-carboxylate tert-butyl Reference Example I-3 (0.343 g), 10% Pd/C (0.051 g) and ethanol (3.0 mL) were stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
To a mixture of the residue and THF (3.0 mL), BH 3 -THF (0.9 mol/L in THF) (3.89 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. Water and saturated saline were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
To a mixture of the residue and DCM (10 mL), DMP (1.12 g) was added at room temperature and stirred at the same temperature for 2 hours. 1 mol/L aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 70/30) to obtain the title compound (0.242 g).

参考例J-1
(S)-1-(5-ブロモ-2-フルオロベンジル)-6-(トリフルオロメチル)ピペリジン-2-オン
　2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼンの代わりに4-ブロモ-2-(ブロモメチル)-1-フルオロベンゼンを用い、参考例C-9と同様の方法により、参考例J-1を合成した。 Reference example J-1
(S)-1-(5-bromo-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Using 4-bromo-2-(bromomethyl)-1-fluorobenzene instead of 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene, Reference Example J-1 was synthesized in the same manner as in Reference Example C-9.

参考例J-2
(S)-1-(5-アリル-2-フルオロベンジル)-6-(トリフルオロメチル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例J-1(0.169 g)、2-アリル-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(0.241 g)、炭酸カリウム(0.330 g)、1,4-ジオキサン(2.0 mL)及び水(0.4 mL)の混合物に、PdCl2(dppf)-DCM(0.117 g)を室温で加え、マイクロ波照射下、80℃で15時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～40/60)にて精製し、表題化合物(0.128 g)を得た。 Reference example J-2
(S)-1-(5-allyl-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, PdCl 2 (dppf)-DCM (0.117 g) was added to a mixture of Reference Example J-1 (0.169 g), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.241 g), potassium carbonate (0.330 g), 1,4-dioxane (2.0 mL) and water (0.4 mL) at room temperature, and the mixture was stirred at 80° C. for 15 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 40/60) to obtain the title compound (0.128 g).

参考例J-3
(S)-1-(5-(シクロプロピルエチニル)-2-フルオロベンジル)-6-(トリフルオロメチル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例J-1(0.169 g)、エチニルシクロプロパン(0.063 g)、炭酸セシウム(0.466 g)及びMeCN(2.4 mL)の混合物に、Xphos(0.034 g)及びビス(アセトニトリル)パラジウム(II)ジクロリド(0.006 g)を室温で加え、マイクロ波照射下、90℃で15時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～40/60)にて精製し、表題化合物(0.138 g)を得た。 Reference example J-3
(S)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-6-(trifluoromethyl)piperidin-2-one Under an argon atmosphere, a mixture of Reference Example J-1 (0.169 g), ethynylcyclopropane (0.063 g), cesium carbonate (0.466 g) and MeCN (2.4 mL) was added with Xphos (0.034 g) and bis(acetonitrile)palladium(II) dichloride (0.006 g) at room temperature, and the mixture was stirred at 90° C. for 15 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 40/60) to obtain the title compound (0.138 g).

参考例J-4
(2S,5S)-2-(2-エトキシ-2-オキソエチル)-5-(ヒドロキシ(2-(トリフルオロメチル)フェニル)メチル)ピロリジン-1-カルボン酸tert-ブチル
　2-ブロモベンゾトリフルオリド(1.13 g)、マグネシウム(0.134 g)、ヨウ素(0.063 g)及びTHF(9.3 mL)の混合物をマイクロ波照射下、60℃で20分間撹拌し、(2-(トリフルオロメチル)フェニル)マグネシウム臭化物(0.5 mol/L in THF)(10 mL)を得た。
　アルゴン雰囲気下、参考例I-4(0.242 g)及びTHF(5.0 mL)の混合物に、上記の(2-(トリフルオロメチル)フェニル)マグネシウム臭化物(0.5 mol/L in THF)(8.5 mL)を-78℃で加え、室温で15分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～60/40)にて精製し、表題化合物(0.119 g)を得た。
1H-NMR（CDCl3）δ ppm：1.24 (3H, t, J=7.2 Hz), 1.52 (9H, s), 1.73-2.52 (4H, m), 2.66-3.31 (1H, m), 3.77-5.14 (6H, m), 5.20-5.88 (1H, m), 7.33-8.09 (4H, m) Reference example J-4
(2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-(hydroxy(2-(trifluoromethyl)phenyl)methyl)pyrrolidine-1-carboxylate tert-butyl 2-bromobenzotrifluoride (1.13 g), magnesium (0.134 g), iodine (0.063 g) and THF (9.3 mL) were stirred under microwave irradiation at 60° C. for 20 minutes to give (2-(trifluoromethyl)phenyl)magnesium bromide (0.5 mol/L in THF) (10 mL).
Under an argon atmosphere, the above (2-(trifluoromethyl)phenyl)magnesium bromide (0.5 mol/L in THF) (8.5 mL) was added to a mixture of Reference Example I-4 (0.242 g) and THF (5.0 mL) at -78°C, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 60/40) to obtain the title compound (0.119 g).
1 H-NMR (CDCl 3 ) δ ppm: 1.24 (3H, t, J=7.2 Hz), 1.52 (9H, s), 1.73-2.52 (4H, m), 2.66-3.31 (1H, m), 3.77-5.14 (6H, m), 5.20-5.88 (1H, m), 7.33-8.09 (4H, m)

参考例J-5
(2S,5S)-2-(2-エトキシ-2-オキソエチル)-5-(2-(トリフルオロメチル)ベンジル)ピロリジン-1-カルボン酸tert-ブチル
　参考例J-4(0.119 g)及び塩化水素(4 mol/L in 1,4-dioxane)(3.00 mL)の混合物を室温で1時間撹拌した。反応混合物を減圧下濃縮した。
　残渣、TEA(0.140 g)及びDCM(3.0 mL)の混合物に、トリホスゲン(0.033 g)を室温で加え、同温で30分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～50/50)にて精製し、2-((1S,5S,7aS)-3-オキソ-1-(2-(トリフルオロメチル)フェニル)テトラヒドロ-1H,3H-ピロロ[1,2-c]オキサゾール-5-イル)酢酸エチル(0.068 g)を得た。
　得られた化合物(0.068 g)、10% Pd/C(0.036 g)及びメタノール(3.0 mL)の混合物を水素雰囲気下、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、Boc2O(0.120 g)を加え、同温で30分間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、表題化合物(0.059 g)を得た。 Reference example J-5
A mixture of (2S,5S)-2-(2-ethoxy-2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl ester Reference Example J-4 (0.119 g) and hydrogen chloride (4 mol/L in 1,4-dioxane) (3.00 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure.
To a mixture of the residue, TEA (0.140 g) and DCM (3.0 mL), triphosgene (0.033 g) was added at room temperature and stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to give ethyl 2-((1S,5S,7aS)-3-oxo-1-(2-(trifluoromethyl)phenyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-5-yl)acetate (0.068 g).
A mixture of the obtained compound (0.068 g), 10% Pd/C (0.036 g) and methanol (3.0 mL) was stirred under a hydrogen atmosphere at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, Boc 2 O (0.120 g) was added and stirred at the same temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 70/30) to obtain the title compound (0.059 g).

参考例J-6
(2S,5S)-2-((Z)-3-(((ベンジルオキシ)カルボニル)アミノ)-4-メトキシ-4-オキソブタ-2-エン-1-イル)-5-(2-(トリフルオロメチル)ベンジル)ピロリジン-1-カルボン酸tert-ブチル
　参考例J-5(0.059 g)及びDCM(3.0 mL)の混合物に、DIBAL-H(1.02 mol/L in n-hexane)(0.418 mL)を-78℃で加え、同温で30分間撹拌した。反応混合物にメタノール及び30%ロッシェル塩水溶液を加え、室温で1時間撹拌し、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、(2S,5S)-2-(2-オキソエチル)-5-(2-(トリフルオロメチル)ベンジル)ピロリジン-1-カルボン酸tert-ブチル(0.053 g)を得た。
　N-ベンジルオキシカルボニル-2-ホスホノグリシントリメチル(0.071 g)及びDCM(1.0 mL)の混合物に、DBU(0.032 g)を室温で加え、同温で10分間撹拌した。反応混合物に上記の(2S,5S)-2-(2-オキソエチル)-5-(2-(トリフルオロメチル)ベンジル)ピロリジン-1-カルボン酸tert-ブチル(0.053 g)及びDCM(1.0 mL)の混合物を加え、室温で30分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～50/50)にて精製し、表題化合物(0.072 g)を得た。 Reference example J-6
(2S,5S)-2-((Z)-3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobut-2-en-1-yl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl. Reference Example J-5 (0.059 g) and DCM (3.0 mL) were mixed and DIBAL-H (1.02 mol/L in n-hexane) (0.418 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methanol and a 30% Rochelle salt solution were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2S,5S)-2-(2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl (0.053 g).
To a mixture of N-benzyloxycarbonyl-2-phosphonoglycine trimethyl (0.071 g) and DCM (1.0 mL), DBU (0.032 g) was added at room temperature and stirred at the same temperature for 10 minutes. To the reaction mixture, the above mixture of (2S,5S)-2-(2-oxoethyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl (0.053 g) and DCM (1.0 mL) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain the title compound (0.072 g).

参考例J-7
(S)-6-(((tert-ブチルジフェニルシリル)オキシ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)ピペリジン-2-オン
　参考例I-2(1.21 g)及びDMF(24 mL)の混合物に、水素化ナトリウム(約60%)(0.145 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(1.02 g)を加え、室温で4時間撹拌した。反応混合物を飽和塩化アンモニウム水溶液にあけ、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～80/20)にて精製し、表題化合物(0.684 g)を得た。 Reference example J-7
(S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one To a mixture of Reference Example I-2 (1.21 g) and DMF (24 mL), sodium hydride (about 60%) (0.145 g) was added under ice cooling and stirred at room temperature for 30 minutes. 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.02 g) was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 80/20) to obtain the title compound (0.684 g).

参考例J-8
(S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソピペリジン-2-カルボン酸2-フルオロ-5-(トリフルオロメチル)ベンジル
　(S)-6-オキソピペリジン-2-カルボン酸(0.500 g)及びDMF(3.0 mL)の混合物に、水素化ナトリウム(約60%)(0.385 g)を氷冷下で加え、氷冷下で20分間撹拌した。反応混合物に2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(1.84 g)を氷冷下で加え、室温で2時間、60℃で4時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.194 g)を得た。 Reference example J-8
(S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidine-2-carboxylate 2-fluoro-5-(trifluoromethyl)benzyl (S)-6-oxopiperidine-2-carboxylic acid (0.500 g) and DMF (3.0 mL) were added to a mixture of sodium hydride (about 60%) (0.385 g) under ice cooling, and the mixture was stirred under ice cooling for 20 minutes. 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.84 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours and at 60° C. for 4 hours. After cooling the reaction mixture to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=100/0-60/40) to obtain the title compound (0.194 g).

参考例J-9
(S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)ピペリジン-2-オン
　参考例J-8(0.194 g)及びエタノール(1.0 mL)の混合物に、水素化ホウ素ナトリウム(0.074 g)を氷冷下で加え、室温で3時間撹拌した。反応混合物に水及び飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～30/70)にて精製し、表題化合物(0.097 g)を得た。 Reference example J-9
(S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)piperidin-2-one Reference Example J-8 (0.194 g) and ethanol (1.0 mL) were mixed, and sodium borohydride (0.074 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 30/70) to obtain the title compound (0.097 g).

参考例J-10
(S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(((トリメチルシリル)オキシ)メチル)ピペリジン-2-オン
　参考例J-9(0.097 g)、TEA(0.096 g)及びTHF(1.0 mL)の混合物に、TMSCl(0.069 g)を氷冷下で加え、室温で1.5時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮することで、表題化合物(0.097 g)を得た。 Reference example J-10
(S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(((trimethylsilyl)oxy)methyl)piperidin-2-one Reference Example J-9 (0.097 g), TEA (0.096 g) and THF (1.0 mL) were added with TMSCl (0.069 g) under ice-cooling and stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to obtain the title compound (0.097 g).

参考例J-11
((3R,6S)-6-(((tert-ブチルジフェニルシリル)オキシ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル
　参考例J-7(1.32 g)及びTHF(20 mL)の混合物に、LDA(1.01 mol/L in THF/n-hexane)(4.80 mL)を-78℃で加え、同温で10分間撹拌した。反応混合物にDPPA(1.33 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.741 g)及びTHF(10 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、表題化合物(0.897 g)を得た。 Reference example J-11
((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-butyl. To a mixture of Reference Example J-7 (1.32 g) and THF (20 mL), LDA (1.01 mol/L in THF/n-hexane) (4.80 mL) was added at -78°C, and the mixture was stirred at the same temperature for 10 minutes. DPPA (1.33 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.741 g) and THF (10 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 95/5 to 70/30) to obtain the title compound (0.897 g).

参考例J-12
((3R,6S)-6-(アジドメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル
　参考例J-11(0.897 g)及びTHF(15 mL)の混合物に、TBAF(1 mol/L in THF)(4.85 mL)を加え、室温で20分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～60/40)、及びシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～30/70)にて順次精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.308 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.020 g)、TEA(0.019 g)及びDCM(1.5 mL)の混合物に、メタンスルホニルクロリド(0.012 g)を氷冷下で加え、室温で15分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣、アジ化ナトリウム(0.012 g)及びDMSO(1.0 mL)の混合物を80℃で2時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～0/100)にて精製し、表題化合物(0.020 g)を得た。 Reference example J-12
((3R,6S)-6-(azidomethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-butyl Reference Example J-11 (0.897 g) and THF (15 mL) were mixed and TBAF (1 mol/L in THF) (4.85 mL) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5-60/40) and silica gel column chromatography (eluent: n-hexane/ethyl acetate=70/30-30/70) in turn to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamic acid tert-butyl (0.308 g).
Under an argon atmosphere, methanesulfonyl chloride (0.012 g) was added to a mixture of the obtained compound (0.020 g), TEA (0.019 g) and DCM (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.012 g) and DMSO (1.0 mL) was stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (0.020 g).

参考例J-13
1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)ピペリジン-2,6-ジオン
　ピペリジン-2,6-ジオン(3.17 g)、2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(7.92 g)、炭酸カリウム(4.65 g)及びアセトン(40 mL)の混合物を14時間還流した。反応混合物を室温まで放冷した後、ろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～75/25)にて精製し、表題化合物(7.73 g)を得た。 Reference example J-13
1-(2-Fluoro-5-(trifluoromethyl)benzyl)piperidine-2,6-dione A mixture of piperidine-2,6-dione (3.17 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (7.92 g), potassium carbonate (4.65 g) and acetone (40 mL) was refluxed for 14 hours. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0-75/25) to give the title compound (7.73 g).

参考例J-14
2-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソピペリジン-2-イル)酢酸メチル
　アルゴン雰囲気下、参考例J-13(7.73 g)及びDCM(100 mL)の混合物に、DIBAL-H(1.03 mol/L in n-hexane)(34.5 mL)を-78℃で加え、同温で1.5時間撹拌した。反応混合物に氷冷下、メタノール及び飽和ロッシェル塩水溶液を加え、室温で30分間撹拌し、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-ヒドロキシピペリジン-2-オン(7.39 g)を得た。
　アルゴン雰囲気下、ホスホノ酢酸トリエチル(10.2 g)及びTHF(80 mL)の混合物に、水素化ナトリウム(約60%)(2.03 g)を氷冷下で加え、氷冷下で50分間撹拌した。反応混合物に上記の1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-ヒドロキシピペリジン-2-オン(7.39 g)及びTHF(20 mL)の混合物を氷冷下で加え、室温で1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～20/80)にて精製し、表題化合物(2.18 g)を得た。 Reference example J-14
2-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidin-2-yl)methyl acetate Under an argon atmosphere, DIBAL-H (1.03 mol/L in n-hexane) (34.5 mL) was added to a mixture of Reference Example J-13 (7.73 g) and DCM (100 mL) at -78 ° C., and the mixture was stirred at the same temperature for 1.5 hours. Methanol and a saturated Rochelle salt aqueous solution were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-hydroxypiperidin-2-one (7.39 g).
Under an argon atmosphere, sodium hydride (about 60%) (2.03 g) was added to a mixture of triethyl phosphonoacetate (10.2 g) and THF (80 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 50 minutes. The above mixture of 1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-hydroxypiperidin-2-one (7.39 g) and THF (20 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (2.18 g).

参考例J-15
6-(2-((tert-ブチルジフェニルシリル)オキシ)エチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)ピペリジン-2-オン
　アルゴン雰囲気下、参考例J-14(2.18 g)、メタノール(10 mL)及びTHF(10 mL)の混合物に、水素化ホウ素ナトリウム(0.685 g)を氷冷下で加え、室温で1時間撹拌した。反応混合物に水素化ホウ素ナトリウム(0.913 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　アルゴン雰囲気下、残渣、イミダゾール(0.821 g)、DMAP(0.074 g)及びDCM(20 mL)の混合物に、TBDPSCl(1.99 g)を室温で加え、同温で15分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～60/40)にて精製し、表題化合物(2.58 g)を得た。 Reference example J-15
6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-2-one Under an argon atmosphere, sodium borohydride (0.685 g) was added to a mixture of Reference Example J-14 (2.18 g), methanol (10 mL) and THF (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Sodium borohydride (0.913 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
Under an argon atmosphere, TBDPSCl (1.99 g) was added to a mixture of the residue, imidazole (0.821 g), DMAP (0.074 g) and DCM (20 mL) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 60/40) to obtain the title compound (2.58 g).

参考例J-16
((3R*,6S*)-6-(2-((tert-ブチルジフェニルシリル)オキシ)エチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル
　アルゴン雰囲気下、参考例J-15(1.50 g)及びTHF(20 mL)の混合物に、LDA(1.01 mol/L in THF/n-hexane)(2.93 mL)を-78℃で加え、同温で25分間撹拌した。反応混合物にDPPA(0.814 g)を-78℃で加え、同温で30分間撹拌した。反応混合物にBoc2O(0.822 g)及びTHF(5.0 mL)の混合物を-78℃で加え、同温で40分間撹拌した。反応混合物に氷冷下、水を加え、50℃で30分間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.539 g)を得た。 Reference example J-16
((3R * ,6S * )-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-butyl Under argon atmosphere, to a mixture of Reference Example J-15 (1.50 g) and THF (20 mL), LDA (1.01 mol / L in THF / n-hexane) (2.93 mL) was added at -78 ° C. and stirred at the same temperature for 25 minutes. DPPA (0.814 g) was added to the reaction mixture at -78 ° C. and stirred at the same temperature for 30 minutes. A mixture of Boc 2 O (0.822 g) and THF (5.0 mL) was added to the reaction mixture at -78 ° C. and stirred at the same temperature for 40 minutes. Water was added to the reaction mixture under ice cooling, and the mixture was stirred at 50 ° C. for 30 minutes. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 60/40) to obtain the title compound (0.539 g).

参考例K-1
5-ブロモ-6-((tert-ブチルジメチルシリル)オキシ)ピコリン酸メチル
　アルゴン雰囲気下、5-ブロモ-6-オキソ-1,6-ジヒドロピリジン-2-カルボン酸メチル(3.04 g)、TEA(5.30 g)及びDCM(60 mL)の混合物に、トリフルオロメタンスルホン酸tert-ブチルジメチルシリル(10.4 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～95/5)にて精製し、表題化合物(1.49 g)を得た。 Reference example K-1
Methyl 5-bromo-6-((tert-butyldimethylsilyl)oxy)picolinate Under argon atmosphere, tert-butyldimethylsilyl trifluoromethanesulfonate (10.4 g) was added to a mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (3.04 g), TEA (5.30 g) and DCM (60 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0-95/5) to give the title compound (1.49 g).

参考例L-1
3-(5-ブロモ-6-((tert-ブチルジメチルシリル)オキシ)ピリジン-2-イル)-3-オキソ-2-(3-(トリフルオロメチル)フェニル)プロパン酸メチル
　アルゴン雰囲気下、参考例K-1(1.49 g)及びTHF(20 mL)の混合物に、リチウムビス(トリメチルシリル)アミド(1 mol/L in THF)(8.61 mL)、次いで参考例H-1(1.31 g)及びTHF(10 mL)の混合物を-78℃で加え、氷冷下で2時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～90/10)にて精製し、表題化合物(0.469 g)を得た。 Reference example L-1
Methyl 3-(5-bromo-6-((tert-butyldimethylsilyl)oxy)pyridin-2-yl)-3-oxo-2-(3-(trifluoromethyl)phenyl)propanoate Under an argon atmosphere, a mixture of Reference Example K-1 (1.49 g) and THF (20 mL) was added with lithium bis(trimethylsilyl)amide (1 mol/L in THF) (8.61 mL), followed by a mixture of Reference Example H-1 (1.31 g) and THF (10 mL) at -78°C, and the mixture was stirred under ice cooling for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 90/10) to obtain the title compound (0.469 g).

参考例L-2
3-ブロモ-6-(1,3-ジヒドロキシ-2-(3-(トリフルオロメチル)フェニル)プロピル)ピリジン-2(1H)-オン
　参考例L-1(0.847 g)及びメタノール(10 mL)の混合物に、水素化ホウ素ナトリウム(0.241 g)を氷冷下で加え、室温で20分間撹拌した。反応混合物を減圧下濃縮した。残渣に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣及びメタノール(10 mL)の混合物に、塩化水素(4 mol/L in 1,4-dioxane)(1.99 mL)を室温で加え、同温で15分間撹拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=50/50～0/100)にて精製し、表題化合物(0.376 g)を得た。 Reference example L-2
3-Bromo-6-(1,3-dihydroxy-2-(3-(trifluoromethyl)phenyl)propyl)pyridin-2(1H)-one To a mixture of Reference Example L-1 (0.847 g) and methanol (10 mL), sodium borohydride (0.241 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue and methanol (10 mL), hydrogen chloride (4 mol/L in 1,4-dioxane) (1.99 mL) was added at room temperature and stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 50/50 to 0/100) to obtain the title compound (0.376 g).

参考例L-3
酢酸6-ブロモ-5-オキソ-2-(3-(トリフルオロメチル)フェニル)-1,2,3,5-テトラヒドロインドリジン-1-イル
　アルゴン雰囲気下、参考例L-2(0.376 g)、トリフェニルホスフィン(0.503 g)及びTHF(6.0 mL)の混合物に、DEAD(2.2 mol/L in toluene)(0.654 mL)を氷冷下で加え、室温で15分間撹拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～0/100)にて精製し、6-ブロモ-1-ヒドロキシ-2-(3-(トリフルオロメチル)フェニル)-2,3-ジヒドロインドリジン-5(1H)-オン(0.359 g)を得た。
　得られた化合物(0.359 g)、無水酢酸(0.147 g)、TEA(0.194 g)、DMAP(0.012 g)及びDCM(5.0 mL)の混合物を室温で20分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～50/50)、シリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～60/40)、及びODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=70/30～10/90)にて順次精製し、表題化合物(0.069 g)を得た。 Reference example L-3
6-Bromo-5-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroindolizin-1-yl acetate: DEAD (2.2 mol/L in toluene) (0.654 mL) was added to a mixture of Reference Example L-2 (0.376 g), triphenylphosphine (0.503 g) and THF (6.0 mL) under argon atmosphere, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 0/100) to give 6-bromo-1-hydroxy-2-(3-(trifluoromethyl)phenyl)-2,3-dihydroindolizin-5(1H)-one (0.359 g).
A mixture of the obtained compound (0.359 g), acetic anhydride (0.147 g), TEA (0.194 g), DMAP (0.012 g) and DCM (5.0 mL) was stirred at room temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 50/50), silica gel column chromatography (eluent: n-hexane/ethyl acetate = 90/10 to 60/40), and ODS column chromatography (eluent: water/MeCN = 70/30 to 10/90) in sequence to obtain the title compound (0.069 g).

参考例M-1
(R)-(7-(ジフルオロメチル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)カルバミン酸tert-ブチル
　アルゴン雰囲気下、亜鉛粉末(0.324 g)及びDMF(4.0 mL)の混合物に、TMSCl(0.049 g)を室温で加え、同温で20分間撹拌した。反応混合物に(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(1.48 g)及びTHF(2.0 mL)の混合物を水冷下で加え、水冷下で30分間撹拌した。反応混合物に酢酸パラジウム(II)(0.025 g)及びXphos(0.107 g)、次いで参考例F-1(0.500 g)及びTHF(4.0 mL)の混合物を水冷下で加え、40℃で2時間撹拌した。反応混合物に酢酸(0.811 g)を加え、60℃で1時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.452 g)を得た。 Reference example M-1
(R)-(7-(difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate tert-butyl Under argon atmosphere, a mixture of zinc powder (0.324 g) and DMF (4.0 mL) was added with TMSCl (0.049 g) at room temperature and stirred at the same temperature for 20 minutes. A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoic acid methyl (1.48 g) and THF (2.0 mL) was added to the reaction mixture under water cooling and stirred for 30 minutes under water cooling. Palladium (II) acetate (0.025 g) and Xphos (0.107 g), then a mixture of Reference Example F-1 (0.500 g) and THF (4.0 mL) was added to the reaction mixture under water cooling and stirred at 40 ° C. for 2 hours. Acetic acid (0.811 g) was added to the reaction mixture, and the mixture was stirred at 60°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 60/40) to obtain the title compound (0.452 g).

参考例M-2
(3-ブロモチオフェン-2-イル)カルバミン酸tert-ブチル
　3-ブロモチオフェン-2-カルボン酸(0.300 g)及びtert-ブタノール(3.0 mL)の混合物に、TEA(0.293 g)及びDPPA(0.598 g)を加え、60℃で4時間撹拌した。反応混合物を室温まで放冷した後、2 mol/L水酸化ナトリウム水溶液(2.5 mL)を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～80/20)にて精製し、表題化合物(0.275 g)を得た。 Reference example M-2
tert-Butyl (3-bromothiophene-2-yl)carbamate To a mixture of 3-bromothiophene-2-carboxylic acid (0.300 g) and tert-butanol (3.0 mL), TEA (0.293 g) and DPPA (0.598 g) were added and stirred at 60°C for 4 hours. After the reaction mixture was cooled to room temperature, 2 mol/L aqueous sodium hydroxide solution (2.5 mL) was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 80/20) to obtain the title compound (0.275 g).

参考例M-3
(R)-5-アミノ-4,7-ジヒドロチエノ[2,3-b]ピリジン-6(5H)-オン
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.089 g)及びDMF(0.65 mL)の混合物に、亜鉛粉末(0.026 g)を室温で加え、同温で1時間撹拌した。反応混合物に参考例M-2 (0.050 g)及びDMF(1.3 mL)の混合物、酢酸パラジウム(II)(0.002 g)及びXphos(0.009 g)を室温で加え、40℃で30分間、室温で15時間撹拌した。反応混合物に水、飽和塩化アンモニウム水溶液及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(1.0 mL)及びトルエン(0.5 mL)の混合物に、メタンスルホン酸(0.052 g)を室温で加え、80℃で45分間撹拌した。反応混合物にメタンスルホン酸(0.294 g)を室温で加え、80℃で4.5時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.720 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=100/0/0～0/100/0～0/80/20)にて精製し、表題化合物(0.008 g)を得た。 Reference example M-3
(R)-5-amino-4,7-dihydrothieno[2,3-b]pyridin-6(5H)-one Under an argon atmosphere, zinc powder (0.026 g) was added to a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (0.089 g) and DMF (0.65 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A mixture of Reference Example M-2 (0.050 g) and DMF (1.3 mL), palladium(II) acetate (0.002 g) and Xphos (0.009 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 30 minutes and at room temperature for 15 hours. Water, a saturated aqueous solution of ammonium chloride and n-hexane/ethyl acetate (1/1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (1.0 mL) and toluene (0.5 mL), methanesulfonic acid (0.052 g) was added at room temperature and stirred at 80°C for 45 minutes. To the reaction mixture, methanesulfonic acid (0.294 g) was added at room temperature and stirred at 80°C for 4.5 hours. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.720 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 100/0/0 to 0/100/0 to 0/80/20) to obtain the title compound (0.008 g).

参考例M-4
(R)-(6-オキソ-4,5,6,7-テトラヒドロチエノ[2,3-b]ピリジン-5-イル)カルバミン酸tert-ブチル
　参考例M-3(0.008 g)及びDCM(0.5 mL)の混合物に、Boc2O(0.016 g)を加え、室温で1.5時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～50/50)にて精製し、表題化合物(0.003 g)を得た。 Reference example M-4
(R)-(6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-5-yl)carbamate tert-butyl Reference Example M-3 (0.008 g) and DCM (0.5 mL) were mixed, and Boc 2 O (0.016 g) was added and stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 100/0 to 50/50) to obtain the title compound (0.003 g).

参考例M-5
(2-ブロモチオフェン-3-イル)カルバミン酸tert-ブチル
　3-ブロモチオフェン-2-カルボン酸の代わりに2-ブロモチオフェン-3-カルボン酸を用い、参考例M-2と同様の方法により、参考例M-5を合成した。 Reference example M-5
tert-Butyl (2-bromothiophen-3-yl)carbamate Reference Example M-5 was synthesized in the same manner as in Reference Example M-2, except that 2-bromothiophene-3-carboxylic acid was used instead of 3-bromothiophene-2-carboxylic acid.

参考例M-6
(R)-6-アミノ-6,7-ジヒドロチエノ[3,2-b]ピリジン-5(4H)-オン
　参考例M-2の代わりに参考例M-5を用い、参考例M-3と同様の方法により、参考例M-6を合成した。 Reference example M-6
(R)-6-amino-6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one Reference Example M-6 was synthesized in the same manner as in Reference Example M-3, using Reference Example M-5 instead of Reference Example M-2.

参考例M-7
(R)-(5-オキソ-4,5,6,7-テトラヒドロチエノ[3,2-b]ピリジン-6-イル)カルバミン酸tert-ブチル
　参考例M-3の代わりに参考例M-6を用い、参考例M-4と同様の方法により、参考例M-7を合成した。 Reference example M-7
(R)-tert-butyl (5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)carbamate Reference Example M-7 was synthesized in the same manner as in Reference Example M-4, using Reference Example M-6 instead of Reference Example M-3.

参考例M-8
(2-メチルチアゾール-5-イル)カルバミン酸tert-ブチル
　3-ブロモチオフェン-2-カルボン酸の代わりに2-メチルチアゾール-5-カルボン酸を用い、参考例M-2と同様の方法により、参考例M-8を合成した。 Reference example M-8
tert-Butyl (2-methylthiazol-5-yl)carbamate Reference Example M-8 was synthesized in the same manner as in Reference Example M-2, except that 2-methylthiazole-5-carboxylic acid was used instead of 3-bromothiophene-2-carboxylic acid.

参考例M-9
(4-ブロモ-2-メチルチアゾール-5-イル)カルバミン酸tert-ブチル
　参考例M-8(0.420 g)、NBS(0.349 g)及びDMF(20 mL)の混合物を室温で1時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液にあけ、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.513 g)を得た。 Reference example M-9
(4-Bromo-2-methylthiazol-5-yl)carbamate tert-butyl Reference Example M-8 (0.420 g), NBS (0.349 g) and DMF (20 mL) were stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 60/40) to obtain the title compound (0.513 g).

参考例M-10
(R)-2-((tert-ブトキシカルボニル)アミノ)-3-(5-((tert-ブトキシカルボニル)アミノ)-2-メチルチアゾール-4-イル)プロパン酸メチル
　アルゴン雰囲気下、亜鉛粉末(0.252 g)及びDMF(4.0 mL)の混合物に、TMSCl(0.038 g)を室温で加え、同温で20分間撹拌した。反応混合物に(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(1.15 g)及びTHF(2.0 mL)の混合物を水冷下で加え、水冷下で30分間撹拌した。反応混合物に酢酸パラジウム(II)(0.020 g)及びXphos(0.083 g)、次いで参考例M-9(0.513 g)及びTHF(4.0 mL)の混合物を水冷下で加え、40℃で12時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.651 g)を得た。 Reference example M-10
(R)-2-((tert-butoxycarbonyl)amino)-3-(5-((tert-butoxycarbonyl)amino)-2-methylthiazol-4-yl)methylpropanoate Under argon atmosphere, TMSCl (0.038 g) was added to a mixture of zinc powder (0.252 g) and DMF (4.0 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1.15 g) and THF (2.0 mL) was added to the reaction mixture under water cooling, and the mixture was stirred for 30 minutes under water cooling. Palladium(II) acetate (0.020 g) and Xphos (0.083 g), followed by a mixture of Reference Example M-9 (0.513 g) and THF (4.0 mL) was added to the reaction mixture under water cooling, and the mixture was stirred at 40° C. for 12 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 60/40) to obtain the title compound (0.651 g).

参考例M-11
(R)-(2-メチル-5-オキソ-4,5,6,7-テトラヒドロチアゾロ[5,4-b]ピリジン-6-イル)カルバミン酸tert-ブチル
　参考例M-10(0.156 g)、4 mol/L水酸化リチウム水溶液(0.282 mL)及びTHF(3.6 mL)の混合物を室温で2時間撹拌した。反応混合物を2 mol/L塩酸にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣、塩化水素(4 mol/L in 1,4-dioxane)(0.470 mL)及び1,4-ジオキサン(3.0 mL)の混合物を50℃で3時間撹拌した。反応混合物を室温まで放冷した後、減圧下濃縮することで、(R)-2-アミノ-3-(5-アミノ-2-メチルチアゾール-4-イル)プロパン酸二塩酸塩(0.103 g)を得た。
　得られた化合物(0.030 g)、TEA(0.055 g)、4-(ジメチルアミノ)ピリジンN-酸化物水和物(0.302 g)及びMeCN(10 mL)の混合物に、Boc2O(0.060 g)を氷冷下で加え、室温で13時間撹拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～25/75)にて精製し、表題化合物(0.017 g)を得た。 Reference example M-11
(R)-(2-methyl-5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridin-6-yl)carbamate tert-butyl Reference Example M-10 (0.156 g), 4 mol/L lithium hydroxide aqueous solution (0.282 mL) and THF (3.6 mL) were stirred at room temperature for 2 hours. The reaction mixture was poured into 2 mol/L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
A mixture of the residue, hydrogen chloride (4 mol/L in 1,4-dioxane) (0.470 mL), and 1,4-dioxane (3.0 mL) was stirred for 3 hours at 50° C. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give (R)-2-amino-3-(5-amino-2-methylthiazol-4-yl)propanoic acid dihydrochloride (0.103 g).
To a mixture of the obtained compound (0.030 g), TEA (0.055 g), 4-(dimethylamino)pyridine N-oxide hydrate (0.302 g) and MeCN (10 mL), Boc 2 O (0.060 g) was added under ice-cooling and stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0-25/75) to obtain the title compound (0.017 g).

参考例M-12
(Z)-4-((2-ヒドロキシフェニル)アミノ)-4-オキソブタ-2-エン酸
　フラン-2,5-ジオン(2.00 g)、2-アミノフェノール(2.23 g)及びトルエン(22 mL)の混合物を室温で12時間撹拌した。不溶物をろ取し、得られた固体をトルエンで洗浄した後、減圧下乾燥することで、表題化合物(6.07 g)を得た。 Reference example M-12
(Z)-4-((2-hydroxyphenyl)amino)-4-oxobut-2-enoic acid A mixture of furan-2,5-dione (2.00 g), 2-aminophenol (2.23 g) and toluene (22 mL) was stirred at room temperature for 12 hours. Insoluble matter was collected by filtration, and the obtained solid was washed with toluene and then dried under reduced pressure to obtain the title compound (6.07 g).

参考例M-13
2-(3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-2-イル)酢酸エチル
　参考例M-12(1.00 g)、TEA(0.910 g)及びエタノール(30 mL)の混合物を3時間還流した。反応混合物を室温まで放冷した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～50/50)にて精製し、表題化合物(0.388 g)を得た。 Reference example M-13
2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate Reference Example M-12 (1.00 g), TEA (0.910 g) and ethanol (30 mL) were refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 50/50) to obtain the title compound (0.388 g).

参考例M-14
(Z)-4-((2-ヒドロキシ-4-ニトロフェニル)アミノ)-4-オキソブタ-2-エン酸
　2-アミノフェノールの代わりに2-アミノ-5-ニトロフェノールを用い、参考例M-12と同様の方法により、参考例M-14を合成した。 Reference example M-14
(Z)-4-((2-hydroxy-4-nitrophenyl)amino)-4-oxobut-2-enoic acid Reference Example M-14 was synthesized in the same manner as in Reference Example M-12, except that 2-amino-5-nitrophenol was used instead of 2-aminophenol.

参考例M-15
2-(7-ニトロ-3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-2-イル)酢酸エチル
　参考例M-12の代わりに参考例M-14を用い、参考例M-13と同様の方法により、参考例M-15を合成した。 Reference example M-15
2-(7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate Reference Example M-15 was synthesized in the same manner as in Reference Example M-13, using Reference Example M-14 instead of Reference Example M-12.

参考例N-1
(3-ブロモ-2-((2-フルオロ-5-(トリフルオロメチル)ベンジル)アミノ)フェニル)メタノール
　2-アミノ-3-ブロモ安息香酸(2.00 g)、2-フルオロ-5-(トリフルオロメチル)ベンズアルデヒド(2.13 g)及びメタノール(19 mL)の混合物に、デカボラン(0.339 g)を水冷下で加え、室温で20時間撹拌した。反応混合物に水及び飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣にn-ヘキサン/DCM(1/1)を加え、混合物をろ過した。ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、3-ブロモ-2-((2-フルオロ-5-(トリフルオロメチル)ベンジル)アミノ)安息香酸(1.70 g)を得た。
　得られた化合物(1.70 g)及びTHF(8.7 mL)の混合物に、BH3-THF(0.9 mol/L in THF)(14.4 mL)を室温で加え、同温で18時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～85/15)にて精製し、表題化合物(0.274 g)を得た。 Reference example N-1
(3-bromo-2-((2-fluoro-5-(trifluoromethyl)benzyl)amino)phenyl)methanol To a mixture of 2-amino-3-bromobenzoic acid (2.00 g), 2-fluoro-5-(trifluoromethyl)benzaldehyde (2.13 g) and methanol (19 mL), decaborane (0.339 g) was added under water cooling and stirred at room temperature for 20 hours. Water and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. n-Hexane/DCM (1/1) was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 95/5 to 70/30) to give 3-bromo-2-((2-fluoro-5-(trifluoromethyl)benzyl)amino)benzoic acid (1.70 g).
To a mixture of the obtained compound (1.70 g) and THF (8.7 mL), BH 3 -THF (0.9 mol/L in THF) (14.4 mL) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 98/2 to 85/15) to obtain the title compound (0.274 g).

参考例N-2
(R)-3-アミノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-8-(ヒドロキシメチル)-3,4-ジヒドロキノリン-2(1H)-オン
　アルゴン雰囲気下、亜鉛粉末(0.104 g)及びDMF(1.3 mL)の混合物に、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(0.358 g)及びDMF(0.65 mL)の混合物を加え、室温で1時間撹拌した。反応混合物に参考例N-1(0.274 g)及びDMF(1.3 mL)の混合物、酢酸パラジウム(II)(0.008 g)及びXphos(0.035 g)を室温で加え、40℃で5時間、室温で14時間撹拌した。反応混合物に水、飽和塩化アンモニウム水溶液及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。混合物をセライトろ過し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、エタノール(0.65 mL)及びトルエン(1.0 mL)の混合物に、メタンスルホン酸(0.209 g)を室温で加え、70℃で1.5時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.435 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/70/30)にて精製し、表題化合物(0.040 g)を得た。 Reference example N-2
(R)-3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-8-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one Under an argon atmosphere, a mixture of zinc powder (0.104 g) and DMF (1.3 mL) was added with a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoic acid methyl (0.358 g) and DMF (0.65 mL), and stirred at room temperature for 1 hour. A mixture of Reference Example N-1 (0.274 g) and DMF (1.3 mL), palladium acetate (II) (0.008 g) and Xphos (0.035 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 40 ° C. for 5 hours and at room temperature for 14 hours. Water, a saturated aqueous ammonium chloride solution, and n-hexane / ethyl acetate (1 / 1) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite, and the organic layer of the filtrate was separated and washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
To a mixture of the residue, ethanol (0.65 mL) and toluene (1.0 mL), methanesulfonic acid (0.209 g) was added at room temperature and stirred at 70°C for 1.5 hours. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.435 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/70/30) to obtain the title compound (0.040 g).

参考例N-3
2-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-7-ニトロ-3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-2-イル)酢酸エチル
　参考例M-15(0.357 g)、炭酸カリウム(0.264 g)、2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.360 g)及びDMF(13 mL)の混合物をマイクロ波照射下、60℃で1.5時間撹拌した。反応混合物を水にあけ、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、表題化合物(0.632 g)を得た。 Reference example N-3
2-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate Reference Example M-15 (0.357 g), potassium carbonate (0.264 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.360 g) and DMF (13 mL) were stirred at 60° C. for 1.5 hours under microwave irradiation. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=100/0-60/40) to obtain the title compound (0.632 g).

参考例N-4
2-(7-アミノ-4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-2-イル)酢酸エチル
　アルゴン雰囲気下、参考例N-3(0.316 g)及びTHF(5.6 mL)の混合物に、10% Pd/C(0.077 g)を加え、水素雰囲気下、50℃で1.5時間撹拌した。反応混合物を室温まで放冷した後、セライトろ過した。ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～40/60)にて精製し、表題化合物(0.211 g)を得た。 Reference example N-4
2-(7-amino-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl acetate Under an argon atmosphere, 10% Pd/C (0.077 g) was added to a mixture of Reference Example N-3 (0.316 g) and THF (5.6 mL), and the mixture was stirred at 50° C. for 1.5 hours under a hydrogen atmosphere. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=100/0-40/60) to obtain the title compound (0.211 g).

参考例N-5
1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)キノキサリン-2(1H)-オン
　キノキサリン-2(1H)-オン(0.731 g)、炭酸カリウム(1.38 g)及びDMF(5.0 mL)の混合物に、2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(1.67 g)を加え、室温で1.5時間撹拌した。反応混合物に水及び飽和塩化アンモニウム水溶液を加えた。不溶物をろ取し、水で洗浄した。得られた固体をDCMに溶解し、混合物を無水硫酸マグネシウムで乾燥した後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～70/30)にて精製し、表題化合物(0.997 g)を得た。
1H-NMR（CDCl3）δ ppm：5.56 (2H, s), 7.19-7.44 (4H, m), 7.48-7.63 (2H, m), 7.94 (1H, dd, J=1.6, 8.0 Hz), 8.43 (1H, s) Reference example N-5
1-(2-Fluoro-5-(trifluoromethyl)benzyl)quinoxalin-2(1H)-one To a mixture of quinoxalin-2(1H)-one (0.731 g), potassium carbonate (1.38 g) and DMF (5.0 mL), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.67 g) was added and stirred at room temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture. Insoluble matter was collected by filtration and washed with water. The obtained solid was dissolved in DCM, and the mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0-70/30) to obtain the title compound (0.997 g).
1 H-NMR (CDCl 3 ) δ ppm: 5.56 (2H, s), 7.19-7.44 (4H, m), 7.48-7.63 (2H, m), 7.94 (1H, dd, J=1.6, 8.0 Hz), 8.43 (1H, s)

参考例N-6
3-アミノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)キノキサリン-2(1H)-オン
　アルゴン雰囲気下、参考例N-5(0.258 g)、硝酸アンモニウムセリウム(IV)(0.658 g)、トリメチルシリルアジド(0.277 g)、水(0.029 g)及び酢酸エチル(8.0 mL)の混合物を室温で16時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をn-ヘキサン/DCM/メタノール混合溶媒に懸濁し、不溶物をろ取した。得られた固体をn-ヘキサン/DCM(1/1)で洗浄した後、減圧下乾燥することで、表題化合物(0.114 g)を得た。 Reference example N-6
3-Amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)quinoxalin-2(1H)-one Under an argon atmosphere, a mixture of Reference Example N-5 (0.258 g), ammonium cerium nitrate (IV) (0.658 g), trimethylsilyl azide (0.277 g), water (0.029 g) and ethyl acetate (8.0 mL) was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in a mixed solvent of n-hexane/DCM/methanol, and insoluble matter was filtered off. The obtained solid was washed with n-hexane/DCM (1/1) and then dried under reduced pressure to obtain the title compound (0.114 g).

参考例N-7
1-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-7-ニトロ-3-オキソ-3,4-ジヒドロキノキサリン-2-イル)尿素
　参考例N-6(0.051 g)及びDCM(0.5 mL)の混合物に、トリホスゲン(0.044 g)及びTEA(0.045 g)を氷冷下で加え、氷冷下で20分間撹拌した。反応混合物に塩化アンモニウム(0.080 g)及びDIPEA(0.194 g)を氷冷下で加え、室温で1.5時間撹拌した。反応混合物にMeCN(0.5 mL)を加え、室温で1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液、MTBE及びn-ヘキサンを加え、不溶物をろ取した。得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、1-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-3,4-ジヒドロキノキサリン-2-イル)尿素(0.039 g)を得た。
　得られた化合物(0.027 g)及び硫酸(0.5 mL)の混合物に、硝酸(0.005 g)を氷冷下で加え、氷冷下で1時間撹拌した。反応混合物に硝酸(0.002 g)を加え、氷冷下で1時間撹拌した。反応混合物に水を加え、不溶物をろ取した。得られた固体を水で洗浄した後、減圧下乾燥することで、表題化合物(0.023 g)を得た。
1H-NMR（DMSO-d6）δ ppm：5.58 (2H, s), 7.40-7.84 (5H, m), 8.17 (1H, dd, J=2.8, 9.2 Hz), 8.60 (1H, br), 8.69 (1H, br), 8.75 (1H, d, J=2.8 Hz) Reference example N-7
1-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-7-nitro-3-oxo-3,4-dihydroquinoxalin-2-yl)urea To a mixture of Reference Example N-6 (0.051 g) and DCM (0.5 mL), triphosgene (0.044 g) and TEA (0.045 g) were added under ice-cooling, and the mixture was stirred for 20 minutes under ice-cooling. Ammonium chloride (0.080 g) and DIPEA (0.194 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. MeCN (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride, MTBE, and n-hexane were added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain 1-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)urea (0.039 g).
Nitric acid (0.005 g) was added to a mixture of the obtained compound (0.027 g) and sulfuric acid (0.5 mL) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Nitric acid (0.002 g) was added to the reaction mixture, and the mixture was stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and then dried under reduced pressure to obtain the title compound (0.023 g).
1 H-NMR (DMSO-d6) δ ppm: 5.58 (2H, s), 7.40-7.84 (5H, m), 8.17 (1H, dd, J=2.8, 9.2 Hz), 8.60 (1H, br), 8.69 (1H, br), 8.75 (1H, d, J=2.8 Hz)

参考例N-8
1-(7-アミノ-4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-3,4-ジヒドロキノキサリン-2-イル)尿素
　参考例N-7(0.022 g)、塩化アンモニウム(0.028 g)、水(0.5 mL)及びエタノール(2.0 mL)の混合物に、鉄粉末(0.029 g)を室温で加え、70℃で2.5時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=50/50～0/100)にて精製し、表題化合物(0.014 g)を得た。 Reference example N-8
1-(7-amino-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)urea Reference Example N-7 (0.022 g), ammonium chloride (0.028 g), water (0.5 mL) and ethanol (2.0 mL) were added with iron powder (0.029 g) at room temperature and stirred at 70° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature, and water was added and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate=50/50-0/100) to obtain the title compound (0.014 g).

　参考例の構造式を以下の表に示す。 The structural formulas of the reference examples are shown in the table below.

　

Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
 　表中の参考例B-4、C-18及びJ-16の立体化学の表記は、相対配置を示す。
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
 The notation of stereochemistry of Reference Examples B-4, C-18 and J-16 in the table indicates the relative configuration.

実施例A-1
1-((3R*,6R*)-1-(5-ブロモ-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-1(0.687 g)及びTHF(11 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(3.21 mL)を-78℃で加え、同温で15分間撹拌した。反応混合物にDPPA(0.945 g)を-78℃で加え、同温で1時間撹拌した。反応混合物にBoc2O(0.599 g)及びTHF(5.5 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R*,6R*)-1-(5-ブロモ-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.446 g)を得た。
　得られた化合物(0.214 g)及びDCM(2.1 mL)の混合物に、TFA(1.17 g)を室温で加え、同温で40分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(2.06 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.210 mL)及びTHF(2.1 mL)の混合物に、シアン酸カリウム(0.055 g)及び酢酸(0.032 g)を氷冷下で加え、室温で2時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)にて精製し、表題化合物(0.113 g)を得た。 Example A-1
1-((3R * ,6R * )-1-(5-bromo-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea To a mixture of Reference Example C-1 (0.687 g) and THF (11 mL), LDA (1.07 mol/L in THF/n-hexane) (3.21 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.945 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 1 hour. A mixture of Boc 2 O (0.599 g) and THF (5.5 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 90/10 to 70/30) to give ((3R * , 6R * )-1-(5-bromo-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)carbamate tert-butyl (0.446 g).
To a mixture of the obtained compound (0.214 g) and DCM (2.1 mL), TFA (1.17 g) was added at room temperature and stirred at the same temperature for 40 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (2.06 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.210 mL) and THF (2.1 mL), potassium cyanate (0.055 g) and acetic acid (0.032 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/95/5) to obtain the title compound (0.113 g).

実施例A-2
1-((3R*,6R*)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-2(0.067 g)及びTHF(1.2 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.346 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.102 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.065 g)及びTHF(0.6 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R*,6R*)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.032 g)を得た。
　得られた化合物(0.031 g)及びDCM(0.5 mL)の混合物に、TFA(0.183 g)を室温で加え、同温で30分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.320 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.050 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.009 g)及び酢酸(0.005 g)を室温で加え、同温で1時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMTBEに懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、表題化合物(0.020 g)を得た。 Example A-2
1-((3R * ,6R * )-1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea To a mixture of Reference Example C-2 (0.067 g) and THF (1.2 mL), LDA (1.07 mol/L in THF/n-hexane) (0.346 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.102 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.065 g) and THF (0.6 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 90/10 to 70/30) to give ((3R * , 6R * )-1-(5-(difluoromethyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)carbamic acid tert-butyl ester (0.032 g).
To a mixture of the obtained compound (0.031 g) and DCM (0.5 mL), TFA (0.183 g) was added at room temperature and stirred at the same temperature for 30 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.320 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.009 g) and acetic acid (0.005 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.020 g).

実施例A-3
1-((3R*,6R*)-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-2の代わりに参考例C-3を用い、実施例A-2と同様の方法により、実施例A-3を合成した。 Example A-3
1-((3R * ,6R * )-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Using Reference Example C-3 instead of Reference Example C-2, Example A-3 was synthesized in the same manner as in Example A-2.

実施例A-4
1-((3R*,6R*)-1-((4-フルオロ-[1,1'-ビフェニル]-3-イル)メチル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-1の代わりに参考例C-4を用い、実施例A-1と同様の方法により、実施例A-4を合成した。 Example A-4
1-((3R * , 6R * )-1-((4-fluoro-[1,1'-biphenyl]-3-yl)methyl)-6-methyl-2-oxopiperidin-3-yl)urea Using Reference Example C-4 instead of Reference Example C-1, Example A-4 was synthesized in the same manner as in Example A-1.

実施例A-5
1-((3R*,6R*)-1-(5-ベンジル-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-1の代わりに参考例C-5を用い、実施例A-1と同様の方法により、実施例A-5を合成した。 Example A-5
1-((3R * ,6R * )-1-(5-benzyl-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-5 was synthesized in the same manner as in Example A-1, using Reference Example C-5 instead of Reference Example C-1.

実施例A-6
1-((3R*,6R*)-6-メチル-2-オキソ-1-(3-フェノキシベンジル)ピペリジン-3-イル)尿素
　参考例C-2の代わりに参考例C-6を用い、実施例A-2と同様の方法により、実施例A-6を合成した。 Example A-6
1-((3R * ,6R * )-6-methyl-2-oxo-1-(3-phenoxybenzyl)piperidin-3-yl)urea Example A-6 was synthesized in the same manner as in Example A-2, using Reference Example C-6 instead of Reference Example C-2.

実施例A-7
1-((3R*,6R*)-1-(2-フルオロ-5-(フェニルエチニル)ベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　アルゴン雰囲気下、実施例A-1(0.035 g)、フェニルアセチレン(0.030 g)、TEA(0.040 g)及びDMF(1.0 mL)の混合物に、ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)(0.003 g)を室温で加え、80℃で17時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液及び水を加え、混合物をジエチルエーテルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)、及びシリカゲルカラムクロマトグラフィー(溶出溶媒：DCM/メタノール=100/0～90/10)にて順次精製し、表題化合物(0.007 g)を得た。 Example A-7
1-((3R * ,6R * )-1-(2-fluoro-5-(phenylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Under an argon atmosphere, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.003 g) was added to a mixture of Example A-1(0.035 g), phenylacetylene(0.030 g), TEA(0.040 g) and DMF(1.0 mL) at room temperature, and the mixture was stirred at 80 ° C. for 17 hours. After cooling the reaction mixture to room temperature, a saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=30/70/0-0/100/0-0/95/5) and silica gel column chromatography (eluent: DCM/methanol=100/0-90/10) to obtain the title compound (0.007 g).

実施例A-8
1-((3R*,6R*)-1-(2-フルオロ-5-(ピリジン-4-イルエチニル)ベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　フェニルアセチレンの代わりに4-エチニルピリジンを用い、実施例A-7と同様の方法により、実施例A-8を合成した。 Example A-8
1-((3R * ,6R * )-1-(2-fluoro-5-(pyridin-4-ylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-8 was synthesized in the same manner as in Example A-7, using 4-ethynylpyridine instead of phenylacetylene.

実施例A-9
1-((3R*,6R*)-1-(2-フルオロ-5-(ピリジン-3-イルエチニル)ベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　フェニルアセチレンの代わりに3-エチニルピリジンを用い、実施例A-7と同様の方法により、実施例A-9を合成した。 Example A-9
1-((3R * ,6R * )-1-(2-fluoro-5-(pyridin-3-ylethynyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-9 was synthesized in the same manner as in Example A-7, using 3-ethynylpyridine instead of phenylacetylene.

実施例A-10
1-((3R*,6R*)-1-(5-(シクロプロピルエチニル)-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　アルゴン雰囲気下、実施例A-1(0.034 g)、エチニルシクロプロパン(0.012 g)、炭酸セシウム(0.091 g)及びMeCN(0.7 mL)の混合物に、Xphos(0.007 g)及びビス(アセトニトリル)パラジウム(II)塩化物(0.001 g)を室温で加え、マイクロ波照射下、90℃で12時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMTBEに懸濁し、不溶物をろ取した。得られた固体をシリカゲルカラムクロマトグラフィー(溶出溶媒：DCM/メタノール=100/0～90/10)にて精製し、表題化合物(0.003 g)を得た。 Example A-10
1-((3R * ,6R * )-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Under an argon atmosphere, to a mixture of Example A-1 (0.034 g), ethynylcyclopropane (0.012 g), cesium carbonate (0.091 g) and MeCN (0.7 mL), Xphos (0.007 g) and bis(acetonitrile)palladium(II) chloride (0.001 g) were added at room temperature, and the mixture was stirred at 90 ° C. for 12 hours under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was collected by filtration. The obtained solid was purified by silica gel column chromatography (elution solvent: DCM / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.003 g).

実施例A-11
1-((3R*,6R*)-1-(5-(ベンジルオキシ)-2-フルオロベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-1の代わりに参考例C-7を用い、実施例A-1と同様の方法により、実施例A-11を合成した。 Example A-11
1-((3R * ,6R * )-1-(5-(benzyloxy)-2-fluorobenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-11 was synthesized in the same manner as in Example A-1, using Reference Example C-7 instead of Reference Example C-1.

実施例A-12
1-((3R*,6R*)-1-(2-フルオロ-5-フェネチルベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　実施例A-7(0.007 g)、10% Pd/C(0.007 g)、THF(0.5 mL)及びメタノール(0.5 mL)の混合物を水素雰囲気下、室温で1時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～80/20)にて精製し、表題化合物(0.004 g)を得た。 Example A-12
1-((3R * ,6R * )-1-(2-fluoro-5-phenethylbenzyl)-6-methyl-2-oxopiperidin-3-yl)urea Example A-7 (0.007 g), 10% Pd/C (0.007 g), THF (0.5 mL) and methanol (0.5 mL) were stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 80/20) to obtain the title compound (0.004 g).

実施例A-13
1-((3R,6R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソピペリジン-3-イル)尿素
　参考例C-8(0.350 g)及びTHF(6.0 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(1.47 mL)を-78℃で加え、同温で30分間撹拌した。反応混合物にDPPA(0.433 g)を-78℃で加え、同温で20分間撹拌した。反応混合物にBoc2O(0.396 g)及びTHF(3.0 mL)の混合物を-78℃で加え、同温で15分間撹拌した。反応混合物に室温で水を加え、同温で1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液、水及び飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.226 g)を得た。
　得られた化合物(0.123 g)及びDCM(2.0 mL)の混合物に、塩化水素(4 mol/L in 1,4-dioxane)(0.685 mL)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=60/40/0～0/100/0～0/70/30)にて精製し、(3R,6R)-3-アミノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチルピペリジン-2-オン(0.050 g)を得た。
　得られた化合物(0.050 g)、水(0.059 mL)、メタノール(0.5 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.017 g)及び酢酸(0.012 g)を室温で加え、同温で2時間撹拌した。反応混合物に水を加え、混合物を酢酸エチルで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=70/30/0～0/100/0～0/32/68)にて精製し、表題化合物(0.027 g)を得た。 Example A-13
1-((3R,6R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)urea To a mixture of Reference Example C-8 (0.350 g) and THF (6.0 mL), LDA (1.07 mol/L in THF/n-hexane) (1.47 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. DPPA (0.433 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 20 minutes. A mixture of Boc 2 O (0.396 g) and THF (3.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution, water, and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 90/10 to 70/30) to give ((3R,6R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxopiperidin-3-yl)carbamic acid tert-butyl ester (0.226 g).
To a mixture of the obtained compound (0.123 g) and DCM (2.0 mL), hydrogen chloride (4 mol/L in 1,4-dioxane) (0.685 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 60/40/0-0/100/0-0/70/30) to obtain (3R,6R)-3-amino-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methylpiperidin-2-one (0.050 g).
To a mixture of the obtained compound (0.050 g), water (0.059 mL), methanol (0.5 mL), and THF (0.5 mL), potassium cyanate (0.017 g) and acetic acid (0.012 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 70/30/0-0/100/0-0/32/68) to obtain the title compound (0.027 g).

実施例A-14
1-((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素
　参考例C-9(0.174 g)及びTHF(2.5 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.711 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.209 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.133 g)及びTHF(1.3 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.144 g)を得た。
　得られた化合物(0.050 g)及びDCM(0.5 mL)の混合物に、TFA(0.249 g)を室温で加え、同温で45分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.435 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.050 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.012 g)及び酢酸(0.007 g)を室温で加え、同温で1.5時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)にて精製し、表題化合物(0.010 g)を得た。 Example A-14
1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example C-9 (0.174 g) and THF (2.5 mL), LDA (1.07 mol/L in THF/n-hexane) (0.711 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.209 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.133 g) and THF (1.3 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.144 g).
To a mixture of the obtained compound (0.050 g) and DCM (0.5 mL), TFA (0.249 g) was added at room temperature and stirred at the same temperature for 45 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.435 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.050 mL) and THF (0.5 mL), potassium cyanate (0.012 g) and acetic acid (0.007 g) were added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/95/5) to obtain the title compound (0.010 g).

実施例A-15
1-((3R,6S)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素
　参考例C-10(0.109 g)及びTHF(1.7 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.469 mL)を-78℃で加え、同温で15分間撹拌した。反応混合物にDPPA(0.138 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.088 g)及びTHF(0.85 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で50分間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.086 g)を得た。
　得られた化合物(0.025 g)及びDCM(0.5 mL)の混合物に、TFA(0.129 g)を室温で加え、同温で40分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.230 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.050 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.006 g)及び酢酸(0.004 g)を氷冷下で加え、室温で2.5時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)にて精製し、表題化合物(0.017 g)を得た。 Example A-15
1-((3R,6S)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea Reference Example C-10 (0.109 g) and THF (1.7 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.469 mL) at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.138 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.088 g) and THF (0.85 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 50 minutes. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.086 g).
To a mixture of the obtained compound (0.025 g) and DCM (0.5 mL), TFA (0.129 g) was added at room temperature and stirred at the same temperature for 40 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.230 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.050 mL) and THF (0.5 mL), potassium cyanate (0.006 g) and acetic acid (0.004 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/95/5) to obtain the title compound (0.017 g).

実施例A-16
1-((3R,6S)-1-(2-フルオロ-5-(1,1,2,2-テトラフルオロエトキシ)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素
　参考例C-11(0.165 g)及びTHF(1.4 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.591 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.174 g)を-78℃で加え、同温で50分間撹拌した。反応混合物にBoc2O(0.110 g)及びTHF(0.7 mL)の混合物を-78℃で加え、同温で15分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で2時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-1-(2-フルオロ-5-(1,1,2,2-テトラフルオロエトキシ)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.098 g)を得た。
　得られた化合物(0.097 g)及びDCM(0.97 mL)の混合物に、TFA(0.437 g)を室温で加え、同温で30分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.765 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.097 mL)及びTHF(0.97 mL)の混合物に、シアン酸カリウム(0.021 g)及び酢酸(0.012 g)を氷冷下で加え、氷冷下で40時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～95/5)にて精製し、表題化合物(0.070 g)を得た。 Example A-16
1-((3R,6S)-1-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea Reference Example C-11 (0.165 g) and THF (1.4 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.591 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.174 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 50 minutes. A mixture of Boc 2 O (0.110 g) and THF (0.7 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 15 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 2 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.098 g).
To a mixture of the obtained compound (0.097 g) and DCM (0.97 mL), TFA (0.437 g) was added at room temperature and stirred at the same temperature for 30 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.765 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.097 mL) and THF (0.97 mL), potassium cyanate (0.021 g) and acetic acid (0.012 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 40 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0-95/5) to obtain the title compound (0.070 g).

実施例A-17
1-((3R,6S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)尿素
　参考例C-12(0.152 g)及びTHF(2.3 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.656 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.193 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.123 g)及びTHF(1.2 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.085 g)を得た。
　得られた化合物(0.027 g)及びDCM(0.5 mL)の混合物に、TFA(0.140 g)を室温で加え、同温で20分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.245 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.050 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.007 g)及び酢酸(0.004 g)を室温で加え、同温で19時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をジエチルエーテルに懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、表題化合物(0.012 g)を得た。 Example A-17
1-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example C-12 (0.152 g) and THF (2.3 mL), LDA (1.07 mol/L in THF/n-hexane) (0.656 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.193 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.123 g) and THF (1.2 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.085 g).
To a mixture of the obtained compound (0.027 g) and DCM (0.5 mL), TFA (0.140 g) was added at room temperature and stirred at the same temperature for 20 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.245 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.050 mL), and THF (0.5 mL), potassium cyanate (0.007 g) and acetic acid (0.004 g) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in diethyl ether, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.012 g).

実施例A-18
1-((3R,5S)-5-フルオロ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)尿素
　参考例C-2の代わりに参考例C-13を用い、実施例A-2と同様の方法により、実施例A-18を合成した。 Example A-18
1-((3R,5S)-5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea Example A-18 was synthesized in the same manner as in Example A-2, using Reference Example C-13 instead of Reference Example C-2.

実施例A-19
(2-((3R*,5S*)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-5-ウレイドピペリジン-3-イル)エチル)カルバミン酸tert-ブチル
　実施例B-3(0.010 g)、酸化白金(IV)(0.020 g)及びメタノール(2.0 mL)の混合物を水素雰囲気下、室温で1時間、50℃で2時間撹拌した。反応混合物を室温まで放冷した後、セライトろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=49/49/2～0/98/2～0/86/14)にて精製し、表題化合物(0.004 g)を得た。 Example A-19
(2-((3R * ,5S * )-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-3-yl)ethyl)carbamate tert-butyl Example B-3 (0.010 g), platinum oxide (IV) (0.020 g) and methanol (2.0 mL) were stirred under a hydrogen atmosphere at room temperature for 1 hour and at 50 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2 to 0 / 98 / 2 to 0 / 86 / 14) to obtain the title compound (0.004 g).

実施例A-20
1-(5-オキソ-4-(3-(トリフルオロメチル)ベンジル)-4-アザスピロ[2.5]オクタン-6-イル)尿素
　参考例C-1の代わりに参考例C-14を用い、実施例A-1と同様の方法により、実施例A-20を合成した。 Example A-20
1-(5-oxo-4-(3-(trifluoromethyl)benzyl)-4-azaspiro[2.5]octan-6-yl)urea Example A-20 was synthesized in the same manner as in Example A-1, except that Example C-14 was used instead of Example C-1.

実施例A-21
1-((1R*,4R*,6S*)-2-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-2-アザビシクロ[4.1.0]ヘプタン-4-イル)尿素
　参考例C-1の代わりに参考例C-15を用い、実施例A-1と同様の方法により、実施例A-21を合成した。 Example A-21
1-((1R * , 4R * , 6S * )-2-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-2-azabicyclo[4.1.0]heptan-4-yl)urea Using Reference Example C-15 instead of Reference Example C-1, Example A-21 was synthesized in the same manner as in Example A-1.

実施例A-22
1-((3R,6S)-1-(1-(2-フルオロ-5-(トリフルオロメチル)フェニル)エチル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素
　参考例C-1の代わりに参考例C-16を用い、実施例A-1と同様の方法により、実施例A-22を合成した。 Example A-22
1-((3R,6S)-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea Example A-22 was synthesized in the same manner as in Example A-1, using Reference Example C-16 instead of Reference Example C-1.

実施例A-23
1-((3R*,6S*)6-メチル-2-オキソ-1-(3-(トリフルオロメチル)フェネチル)ピペリジン-3-イル)尿素
　参考例C-8の代わりに参考例C-17を用い、実施例A-13と同様の方法により、実施例A-23を合成した。 Example A-23
1-((3R * , 6S * ) 6-methyl-2-oxo-1-(3-(trifluoromethyl)phenethyl)piperidin-3-yl)urea Example A-23 was synthesized in the same manner as in Example A-13, using Reference Example C-17 instead of Reference Example C-8.

実施例A-24
1-((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)-3-メチル尿素
　参考例C-9(0.174 g)及びTHF(2.5 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.711 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.209 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.133 g)及びTHF(1.3 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.144 g)を得た。
　得られた化合物(0.046 g)及びDCM(0.5 mL)の混合物に、TFA(0.229 g)を室温で加え、同温で30分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.400 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、TEA(0.030 g)及びDCM(1.0 mL)の混合物に、トリホスゲン(0.030 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物にメチルアミン(2 mol/L in THF)(0.502 mL)を室温で加え、同温で2時間撹拌した。反応混合物にメチルアミン(2 mol/L in THF)(1.00 mL)を室温で加え、同温で30分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)にて精製し、表題化合物(0.006 g)を得た。 Example A-24
1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)-3-methylurea Reference Example C-9 (0.174 g) and THF (2.5 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.711 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.209 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.133 g) and THF (1.3 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.144 g).
To a mixture of the obtained compound (0.046 g) and DCM (0.5 mL), TFA (0.229 g) was added at room temperature and stirred at the same temperature for 30 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.400 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, TEA (0.030 g) and DCM (1.0 mL), triphosgene (0.030 g) was added under ice cooling and stirred at room temperature for 30 minutes. Methylamine (2 mol/L in THF) (0.502 mL) was added to the reaction mixture at room temperature and stirred at the same temperature for 2 hours. Methylamine (2 mol/L in THF) (1.00 mL) was added to the reaction mixture at room temperature and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/95/5) to obtain the title compound (0.006 g).

実施例A-25
(S)-N-((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)-2-メトキシプロパンアミド
　参考例C-9(0.174 g)及びTHF(2.5 mL)の混合物に、-78℃でLDA(1.07 mol/L in THF/n-hexane)(0.711 mL)を加え、同温で20分間撹拌した。反応混合物にDPPA(0.209 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.133 g)及びTHF(1.3 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.144 g)を得た。
　得られた化合物(0.046 g)及びDCM(0.5 mL)の混合物に、TFA(0.228 g)を室温で加え、同温で30分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.400 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、(S)-2-メトキシプロパン酸(0.014 g)、DIPEA(0.019 g)及びMeCN(0.5 mL)の混合物に、HATU(0.046 g)を室温で加え、同温で1時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/95/5)にて精製し、表題化合物(0.034 g)を得た。 Example A-25
(S)-N-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)-2-methoxypropanamide Reference Example C-9 (0.174 g) and THF (2.5 mL) were mixed at -78°C with LDA (1.07 mol/L in THF/n-hexane) (0.711 mL) and stirred at the same temperature for 20 minutes. DPPA (0.209 g) was added to the reaction mixture at -78°C and stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.133 g) and THF (1.3 mL) was added to the reaction mixture at -78°C and stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture and stirred at 50°C for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.144 g).
To a mixture of the obtained compound (0.046 g) and DCM (0.5 mL), TFA (0.228 g) was added at room temperature and stirred at the same temperature for 30 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.400 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, (S)-2-methoxypropanoic acid (0.014 g), DIPEA (0.019 g) and MeCN (0.5 mL), HATU (0.046 g) was added at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/95/5) to obtain the title compound (0.034 g).

実施例A-26
1-シクロプロピル-3-((3R,6S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)尿素
　参考例C-9の代わりに参考例C-12、メチルアミンの代わりにシクロプロピルアミンを用い、実施例A-24と同様の方法により、実施例A-26を合成した。 Example A-26
1-cyclopropyl-3-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea Example A-26 was synthesized in the same manner as in Example A-24, using Reference Example C-12 instead of Reference Example C-9 and cyclopropylamine instead of methylamine.

実施例A-27
N-((3R,6S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)アセトアミド
　参考例C-12(0.152 g)及びTHF(2.3 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.656 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.193 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.123 g)及びTHF(1.2 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～70/30)にて精製し、((3R,6S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.085 g)を得た。
　得られた化合物(0.018 g)及びDCM(0.5 mL)の混合物に、TFA(0.091 g)を室温で加え、同温で1.5時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.160 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、TEA(0.012 g)及びDCM(0.5 mL)の混合物に、塩化アセチル(0.005 g)を室温で加え、同温で45分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)にて精製し、表題化合物(0.011 g)を得た。 Example A-27
N-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)acetamide Reference Example C-12 (0.152 g) and THF (2.3 mL) were added to a mixture of LDA (1.07 mol/L in THF/n-hexane) (0.656 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.193 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.123 g) and THF (1.2 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane/ethyl acetate = 90/10 to 70/30) to give tert-butyl ((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.085 g).
To a mixture of the obtained compound (0.018 g) and DCM (0.5 mL), TFA (0.091 g) was added at room temperature and stirred at the same temperature for 1.5 hours. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.160 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, TEA (0.012 g) and DCM (0.5 mL), acetyl chloride (0.005 g) was added at room temperature and stirred at the same temperature for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/95/5) to give the title compound (0.011 g).

実施例A-28
N-((3R,6S)-6-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)シクロプロパンカルボキサミド
　塩化アセチルの代わりに塩化シクロプロパンカルボニルを用い、実施例A-27と同様の方法により、実施例A-28を合成した。 Example A-28
N-((3R,6S)-6-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)cyclopropanecarboxamide Example A-28 was synthesized in the same manner as in Example A-27, using cyclopropanecarbonyl chloride instead of acetyl chloride.

実施例A-29
1-((3R*,4aS*,8aR*)-(2-オキソ-1-(3-(トリフルオロメチル)ベンジル)デカヒドロキノリン-3-イル)尿素
　参考例C-9の代わりに参考例C-18を用い、実施例A-14と同様の方法により、実施例A-29を合成した。 Example A-29
1-((3R * , 4aS * , 8aR * )-(2-oxo-1-(3-(trifluoromethyl)benzyl)decahydroquinolin-3-yl)urea Using Reference Example C-18 instead of Reference Example C-9, Example A-29 was synthesized in the same manner as in Example A-14.

実施例B-1
1-(5-ブロモ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　参考例E-2(0.140 g)及びDCM(3.0 mL)の混合物に、トリホスゲン(0.114 g)及びTEA(0.116 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.205 g)及びDIPEA(0.496 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.130 g)を得た。 Example B-1
1-(5-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example E-2 (0.140 g) and DCM (3.0 mL), triphosgene (0.114 g) and TEA (0.116 g) were added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. Ammonium chloride (0.205 g) and DIPEA (0.496 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.130 g).

実施例B-2
3-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-5-ウレイド-1,6-ジヒドロピリジン-3-イル)プロパン酸
　実施例B-1(0.100 g)、トリ-o-トリルホスフィン(0.015 g)、TEA(0.099 g)、アクリル酸ベンジル(0.079 g)及びMeCN(1.0 mL)の混合物に、酢酸パラジウム(II)(0.006 g)を室温で加え、80℃で1時間撹拌した後、マイクロ波照射下、140℃で10分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMTBEに懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、(E)-3-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-5-ウレイド-1,6-ジヒドロピリジン-3-イル)アクリル酸ベンジル(0.067 g)を得た。
　得られた化合物(0.065 g)、10% Pd/C(0.030 g)、THF(2.0 mL)及びメタノール(2.0 mL)の混合物を水素雰囲気下、室温で1時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をMTBEに懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、表題化合物(0.044 g)を得た。 Example B-2
3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)propanoic acid Example B-1 (0.100 g), tri-o-tolylphosphine (0.015 g), TEA (0.099 g), benzyl acrylate (0.079 g) and MeCN (1.0 mL) were added to a mixture, and palladium (II) acetate (0.006 g) was added at room temperature, stirred at 80 ° C. for 1 hour, and then stirred at 140 ° C. for 10 minutes under microwave irradiation. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain (E)-3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)benzyl acrylate (0.067 g).
A mixture of the obtained compound (0.065 g), 10% Pd/C (0.030 g), THF (2.0 mL) and methanol (2.0 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was dried under reduced pressure to give the title compound (0.044 g).

実施例B-3
(2-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-5-ウレイド-1,6-ジヒドロピリジン-3-イル)エチル)カルバミン酸tert-ブチル
　実施例B-2(0.042 g)、DMF(0.5 mL)及びtert-ブチルアルコール(1.0 mL)の混合物に、TEA(0.021 g)及びDPPA(0.043 g)を室温で加え、60℃で1時間撹拌した。反応混合物を室温まで放冷した後、1 mol/L水酸化ナトリウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及びTHF(1.0 mL)の混合物に、Boc2O(0.046 g)を室温で加え、同温で30分間撹拌した。反応混合物を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/88/12)にて精製し、表題化合物(0.015 g)を得た。 Example B-3
(2-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureido-1,6-dihydropyridin-3-yl)ethyl)carbamate tert-butyl Example B-2 (0.042 g), DMF (0.5 mL) and tert-butyl alcohol (1.0 mL) were added with TEA (0.021 g) and DPPA (0.043 g) at room temperature and stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and then 1 mol/L aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
To a mixture of the residue and THF (1.0 mL), Boc 2 O (0.046 g) was added at room temperature and stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/88/12) to obtain the title compound (0.015 g).

実施例B-4
1-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　参考例E-4(0.055 g)及びDCM(1.0 mL)の混合物に、トリホスゲン(0.054 g)及びTEA(0.056 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.098 g)及びDIPEA(0.237 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.048 g)を得た。 Example B-4
1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example E-4 (0.055 g) and DCM (1.0 mL), triphosgene (0.054 g) and TEA (0.056 g) were added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. Ammonium chloride (0.098 g) and DIPEA (0.237 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.048 g).

実施例B-5
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　参考例E-6(0.040 g)及びDCM(1.0 mL)の混合物に、トリホスゲン(0.035 g)及びTEA(0.036 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.064 g)及びDIPEA(0.154 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.026 g)を得た。 Example B-5
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example E-6 (0.040 g) and DCM (1.0 mL), triphosgene (0.035 g) and TEA (0.036 g) were added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Ammonium chloride (0.064 g) and DIPEA (0.154 g) were added to the reaction mixture under ice cooling, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the mixture was stirred for 10 minutes at room temperature. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.026 g).

実施例B-6
1-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-5-(トリフルオロメチル)-1,2-ジヒドロピリジン-3-イル)尿素
　参考例E-2の代わりに参考例E-8を用い、実施例B-1と同様の方法により、実施例B-6を合成した。 Example B-6
1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea Example B-6 was synthesized in the same manner as in Example B-1, using Reference Example E-8 instead of Reference Example E-2.

実施例B-7
1-(6-シアノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　参考例D-1(0.402 g)及びMeCN(6.0 mL)の混合物に、炭酸カリウム(0.330 g)及び2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.460 g)を室温で加え、同温で4.5時間撹拌した。反応混合物に水を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をMethod B(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～85/15)にて精製し、(6-ブロモ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)カルバミン酸tert-ブチル(0.035 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.034 g)、シアン化亜鉛(II)(0.017 g)、亜鉛粉末(0.001 g)及びDMF(1.0 mL)の混合物に、ビス(トリ-tert-ブチルホスフィン)パラジウム(0)(0.004 g)を室温で加え、100℃で18時間撹拌した。反応混合物を室温まで放冷した後、セライトろ過した。ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～80/20)にて精製し、(6-シアノ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)カルバミン酸tert-ブチル(0.014 g)を得た。
　得られた化合物(0.013 g)及びDCM(0.5 mL)の混合物に、TFA(0.071 g)を室温で加え、同温で1.5時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.125 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、TEA(0.009 g)及びDCM(0.5 mL)の混合物に、トリホスゲン(0.009 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.017 g)及びDIPEA(0.040 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.005 g)を得た。 Example B-7
1-(6-cyano-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example D-1 (0.402 g) and MeCN (6.0 mL), potassium carbonate (0.330 g) and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.460 g) were added at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method B (eluent: n-hexane/ethyl acetate = 100/0 to 85/15) to give (6-bromo-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamic acid tert-butyl ester (0.035 g).
Under an argon atmosphere, bis(tri-tert-butylphosphine)palladium(0) (0.004 g) was added to a mixture of the obtained compound (0.034 g), zinc cyanide(II) (0.017 g), zinc powder (0.001 g) and DMF (1.0 mL) at room temperature, and the mixture was stirred at 100°C for 18 hours. The reaction mixture was allowed to cool to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 80/20) to give tert-butyl (6-cyano-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (0.014 g).
To a mixture of the obtained compound (0.013 g) and DCM (0.5 mL), TFA (0.071 g) was added at room temperature and stirred at the same temperature for 1.5 hours. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.125 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, TEA (0.009 g) and DCM (0.5 mL), triphosgene (0.009 g) was added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. Ammonium chloride (0.017 g) and DIPEA (0.040 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was collected by filtration, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.005 g).

実施例B-8
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル)尿素
　参考例D-2(0.067 g)及びDMF(1.3 mL)の混合物に、水素化ナトリウム(約60%)(0.018 g)を氷冷下で加え、室温で20分間撹拌した。反応混合物に参考例A-3(0.100 g)を氷冷下で加え、室温で1時間、50℃で1.5時間撹拌した。反応混合物に参考例A-3(0.046 g)を室温で加え、50℃で1時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～30/70)にて精製し、(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル)カルバミン酸tert-ブチル(0.053 g)を得た。
　得られた化合物(0.050 g)及びDCM(0.5 mL)の混合物に、TFA(0.261 g)を室温で加え、同温で1時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.460 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、TEA(0.035 g)及びDCM(0.5 mL)の混合物に、トリホスゲン(0.034 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.061 g)、DIPEA(0.148 g)及びDCM(0.5 mL)を氷冷下で加え、室温で1.5時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMTBEに懸濁し、不溶物をろ取した。得られた固体をMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.005 g)を得た。 Example B-8
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)urea To a mixture of Reference Example D-2 (0.067 g) and DMF (1.3 mL), sodium hydride (about 60%) (0.018 g) was added under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Reference Example A-3 (0.100 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour and at 50° C. for 1.5 hours. Reference Example A-3 (0.046 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 50° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 90/10 to 30/70) to give (1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)carbamate tert-butyl (0.053 g).
To a mixture of the obtained compound (0.050 g) and DCM (0.5 mL), TFA (0.261 g) was added at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.460 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, TEA (0.035 g) and DCM (0.5 mL), triphosgene (0.034 g) was added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, ammonium chloride (0.061 g), DIPEA (0.148 g) and DCM (0.5 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and the insoluble matter was filtered off. The obtained solid was washed with MTBE and then dried under reduced pressure to obtain the title compound (0.005 g).

実施例B-9
1-(4-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-5-メチル-3-オキソ-3,4-ジヒドロピラジン-2-イル)尿素
　参考例D-2の代わりに参考例D-3を用い、実施例B-8と同様の方法により、実施例B-9を合成した。 Example B-9
1-(4-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-3-oxo-3,4-dihydropyrazin-2-yl)urea Example B-9 was synthesized in the same manner as in Example B-8, using Reference Example D-3 instead of Reference Example D-2.

実施例B-10
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-イル)-3-メチル尿素
　参考例E-6(0.033 g)及びDCM(1.0 mL)の混合物に、トリホスゲン(0.032 g)及びTEA(0.030 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物にメチルアミン(2 mol/L in THF)(0.986 mL)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=98/2～45/55)にて精製し、表題化合物(0.008 g)を得た。 Example B-10
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-methylurea To a mixture of Reference Example E-6 (0.033 g) and DCM (1.0 mL), triphosgene (0.032 g) and TEA (0.030 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Methylamine (2 mol/L in THF) (0.986 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 98/2 to 45/55) to obtain the title compound (0.008 g).

実施例B-11
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-イル)-3-シクロプロピル尿素
　メチルアミンの代わりにシクロプロパンアミンを用い、実施例B-10と同様の方法により、実施例B-11を合成した。 Example B-11
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-3-cyclopropylurea Example B-11 was synthesized in the same manner as in Example B-10, except that cyclopropanamine was used instead of methylamine.

実施例C-1
(R)-1-(1-(3-メチルベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-1(0.050 g)、酢酸(0.012 g)及びメタノール(0.15 mL)の混合物に、シアン酸カリウム(0.018 g)及び水(0.068 mL)の混合物を室温で加え、同温で1時間撹拌した。反応混合物に水を加え、室温で20分間撹拌した。不溶物をろ取し、得られた固体を水/THF/メタノール(10/1/1)混合溶媒で洗浄した後、減圧下乾燥することで、表題化合物(0.010 g)を得た。 Example C-1
(R)-1-(1-(3-methylbenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-1 (0.050 g), acetic acid (0.012 g) and methanol (0.15 mL) were added to a mixture of potassium cyanate (0.018 g) and water (0.068 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. Insoluble matter was collected by filtration, and the obtained solid was washed with a mixed solvent of water/THF/methanol (10/1/1), and then dried under reduced pressure to obtain the title compound (0.010 g).

実施例C-2
(R)-1-(1-(3-シアノベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-2(0.043 g)、水(0.055 mL)、シアン酸カリウム(0.016 g)、メタノール(0.256 mL)及びTHF(0.383 mL)の混合物に、酢酸(0.011 g)を氷冷下で加え、室温で13時間撹拌した。反応混合物にTHF(0.256 mL)、メタノール(0.192 mL)及び水(1.92 mL)を加え、室温で40分間撹拌した。不溶物をろ取し、得られた固体をエタノール/n-ヘプタン(1/4)で洗浄した後、減圧下乾燥することで、表題化合物(0.026 g)を得た。 Example C-2
(R)-1-(1-(3-cyanobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-2 (0.043 g), water (0.055 mL), potassium cyanate (0.016 g), methanol (0.256 mL) and THF (0.383 mL) were added to a mixture of acetic acid (0.011 g) under ice cooling and stirred at room temperature for 13 hours. THF (0.256 mL), methanol (0.192 mL) and water (1.92 mL) were added to the reaction mixture and stirred at room temperature for 40 minutes. Insoluble matter was filtered off, and the obtained solid was washed with ethanol/n-heptane (1/4) and then dried under reduced pressure to obtain the title compound (0.026 g).

実施例C-3
(R)-1-(1-(3-メトキシベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-1の代わりに参考例G-3を用い、実施例C-1と同様の方法により、実施例C-3を合成した。 Example C-3
(R)-1-(1-(3-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-3 was synthesized in the same manner as in Example C-1, using Reference Example G-3 instead of Reference Example G-1.

実施例C-4
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-4(0.120 g)、水(0.067 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.040 g)及びメタンスルホン酸(0.038 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液、メタノール及び水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣を酢酸エチルに懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、表題化合物(0.058 g)を得た。 Example C-4
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-4 (0.120 g), water (0.067 mL) and THF (1.0 mL), potassium cyanate (0.040 g) and methanesulfonic acid (0.038 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate, methanol and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.058 g).

実施例C-5
(R)-1-(1-((2,2-ジフルオロベンゾ[d][1,3]ジオキソール-4-イル)メチル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-5(0.052 g)、水(0.071 mL)及びTHF(0.71 mL)の混合物に、シアン酸カリウム(0.023 g)、酢酸(0.016 g)及びTHF(0.5 mL)を室温で加え、同温で17時間撹拌した。反応混合物に水、飽和炭酸水素ナトリウム水溶液及びMTBEを加え、不溶物をろ取した。得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.037 g)を得た。 Example C-5
(R)-1-(1-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-5 (0.052 g), water (0.071 mL) and THF (0.71 mL) were added to a mixture of potassium cyanate (0.023 g), acetic acid (0.016 g) and THF (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 17 hours. Water, a saturated aqueous sodium bicarbonate solution and MTBE were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.037 g).

実施例C-6
(R)-1-(7-メチル-2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-2の代わりに参考例G-6を用い、実施例C-2と同様の方法により、実施例C-6を合成した。 Example C-6
(R)-1-(7-methyl-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-6 was synthesized in the same manner as in Example C-2, using Reference Example G-6 instead of Reference Example G-2.

実施例C-7
(R)-1-(7-メトキシ-2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-1の代わりに参考例G-7を用い、実施例C-1と同様の方法により、実施例C-7を合成した。 Example C-7
(R)-1-(7-methoxy-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-7 was synthesized in the same manner as in Example C-1, using Reference Example G-7 instead of Reference Example G-1.

実施例C-8
(R)-1-(7-シアノ-2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-5の代わりに参考例G-8を用い、実施例C-5と同様の方法により、実施例C-8を合成した。 Example C-8
(R)-1-(7-cyano-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-8 was synthesized in the same manner as in Example C-5, using Reference Example G-8 instead of Reference Example G-5.

実施例C-9
(R)-1-(5-フルオロ-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-9(0.085 g)、水(0.043 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.025 g)及びメタンスルホン酸(0.024 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及び酢酸エチルで洗浄した後、減圧下乾燥することで、表題化合物(0.064 g)を得た。 Example C-9
(R)-1-(5-fluoro-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-9 (0.085 g), water (0.043 mL) and THF (1.0 mL) were added to a mixture of potassium cyanate (0.025 g) and methanesulfonic acid (0.024 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and ethyl acetate, and then dried under reduced pressure to obtain the title compound (0.064 g).

実施例C-10
(R)-1-(7-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-10(0.079 g)、水(0.037 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.021 g)及び酢酸(0.013 g)を室温で加え、同温で14時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.052 g)を得た。 Example C-10
(R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-10 (0.079 g), water (0.037 mL) and THF (0.5 mL) were added to a mixture of potassium cyanate (0.021 g) and acetic acid (0.013 g) at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.052 g).

実施例C-11
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-フルオロ-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-11(0.110 g)、水(0.059 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.034 g)及びメタンスルホン酸(0.033 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.100 g)を得た。 Example C-11
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-11 (0.110 g), water (0.059 mL) and a mixture of THF (1.0 mL) were added with potassium cyanate (0.034 g) and methanesulfonic acid (0.033 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.100 g).

実施例C-12
(R)-1-(7-クロロ-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-12(0.150 g)、水(0.076 mL)及びTHF(1.5 mL)の混合物に、シアン酸カリウム(0.045 g)及びメタンスルホン酸(0.043 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣を酢酸エチルに懸濁し、不溶物をろ取した。得られた固体を減圧下乾燥することで、表題化合物(0.090 g)を得た。 Example C-12
(R)-1-(7-chloro-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-12 (0.150 g), water (0.076 mL) and THF (1.5 mL) were added to a mixture of potassium cyanate (0.045 g) and methanesulfonic acid (0.043 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble matter was filtered off. The obtained solid was dried under reduced pressure to obtain the title compound (0.090 g).

実施例C-13
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-メチル-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-13(0.099 g)、水(0.053 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.031 g)及びメタンスルホン酸(0.030 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.083 g)を得た。 Example C-13
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-13 (0.099 g), water (0.053 mL) and a mixture of THF (1.0 mL) were added with potassium cyanate (0.031 g) and methanesulfonic acid (0.030 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.083 g).

実施例C-14
(R)-1-(7-(ジフルオロメチル)-1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-14(0.065 g)、水(0.032 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.019 g)及び酢酸(0.011 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.045 g)を得た。 Example C-14
(R)-1-(7-(difluoromethyl)-1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-14 (0.065 g), water (0.032 mL) and a mixture of THF (0.5 mL) were added with potassium cyanate (0.019 g) and acetic acid (0.011 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.045 g).

実施例C-15
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-7-(トリフルオロメチル)-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-15(0.039 g)、水(0.018 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.011 g)及び酢酸(0.006 g)を室温で加え、同温で14時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.033 g)を得た。 Example C-15
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-15 (0.039 g), water (0.018 mL) and a mixture of THF (0.5 mL) were added with potassium cyanate (0.011 g) and acetic acid (0.006 g) at room temperature, and the mixture was stirred at the same temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.033 g).

実施例C-16
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-7-(ヒドロキシメチル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-16(0.050 g)、水(0.026 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.015 g)及び酢酸(0.009 g)を氷冷下で加え、氷冷下で1時間撹拌した。反応混合物に水及びジエチルエーテルを加え、不溶物をろ取した。得られた固体を水及びジエチルエーテルで洗浄した後、減圧下乾燥することで、表題化合物(0.035 g)を得た。 Example C-16
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-7-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-16 (0.050 g), water (0.026 mL) and THF (0.5 mL) were added with potassium cyanate (0.015 g) and acetic acid (0.009 g) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water and diethyl ether were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and diethyl ether, and then dried under reduced pressure to obtain the title compound (0.035 g).

実施例C-17
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-5,7-ジフルオロ-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-17(0.150 g)、水(0.076 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.044 g)及びメタンスルホン酸(0.042 g)を室温で加え、同温で2時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.040
g)を得た。 Example C-17
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-5,7-difluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-17 (0.150 g), water (0.076 mL) and THF (1.0 mL), potassium cyanate (0.044 g) and methanesulfonic acid (0.042 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was filtered off, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.040
g).

実施例C-18
(R)-1-(7-(ジフルオロメチル)-1-(2-フルオロ-5-(トリフルオロメトキシ)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-18(0.077 g)、水(0.084 mL)及びTHF(0.84 mL)の混合物に、シアン酸カリウム(0.028 g)及び酢酸(0.019 g)を室温で加え、同温で1時間撹拌した。反応混合物に水及びMTBEを加え、不溶物をろ取した。得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.030 g)を得た。 Example C-18
(R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(trifluoromethoxy)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-18 (0.077 g), water (0.084 mL) and a mixture of THF (0.84 mL) were added with potassium cyanate (0.028 g) and acetic acid (0.019 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and MTBE were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.030 g).

実施例C-19
(R)-1-(7-(ジフルオロメチル)-1-(2-フルオロ-5-(ペンタフルオロ硫黄)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-19(0.063 g)、水(0.070 mL)及びTHF(0.7 mL)の混合物に、シアン酸カリウム(0.023 g)及び酢酸(0.016 g)を室温で加え、同温で2時間撹拌した。反応混合物に水を加え、不溶物をろ取した。得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.026 g)を得た。 Example C-19
(R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(pentafluorosulfur)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a mixture of Reference Example G-19 (0.063 g), water (0.070 mL) and THF (0.7 mL), potassium cyanate (0.023 g) and acetic acid (0.016 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and insoluble matter was filtered off. The obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.026 g).

実施例C-20
(R)-1-(7-(ジフルオロメチル)-1-(2-フルオロ-5-(1,1,1,3,3,3-ヘキサフルオロ-2-ヒドロキシプロパン-2-イル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-20(0.036 g)、水(0.050 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.012 g)及び酢酸(0.008 g)を室温で加え、同温で19時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=40/60/0～0/100/0～0/90/10)にて精製し、表題化合物(0.032 g)を得た。 Example C-20
(R)-1-(7-(difluoromethyl)-1-(2-fluoro-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example G-20 (0.036 g), water (0.050 mL) and a mixture of THF (0.5 mL) were added with potassium cyanate (0.012 g) and acetic acid (0.008 g) at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 40/60/0-0/100/0-0/90/10) to obtain the title compound (0.032 g).

実施例C-21
(R)-1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-7-フルオロ-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-12の代わりに参考例G-21を用い、実施例C-12と同様の方法により、実施例C-21を合成した。 Example C-21
(R)-1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-21 was synthesized in the same manner as in Example C-12, using Reference Example G-21 instead of Reference Example G-12.

実施例C-22
(R)-1-(2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロチエノ[3,4-b]ピリジン-3-イル)尿素
　参考例G-14の代わりに参考例G-22を用い、実施例C-14と同様の方法により、実施例C-22を合成した。 Example C-22
(R)-1-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydrothieno[3,4-b]pyridin-3-yl)urea Example C-22 was synthesized in the same manner as in Example C-14, using Reference Example G-22 instead of Reference Example G-14.

実施例C-23
(R)-1-(2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロ-1,7-ナフチリジン-3-イル)尿素
　参考例G-23(0.049 g)、メタノール(0.5 mL)及びTHF(0.5 mL)の混合物に、4 mol/L水酸化リチウム水溶液(0.081 mL)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に1 mol/L塩酸(0.4 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣及びTHF(1.0 mL)の混合物に、HATU(0.062 g)及びTEA(0.022 g)を室温で加え、同温で1時間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～0/100)にて精製し、(R)-(2-オキソ-1-(3-(トリフルオロメチル)ベンジル)-1,2,3,4-テトラヒドロ-1,7-ナフチリジン-3-イル)カルバミン酸tert-ブチル(0.028 g)を得た。
　得られた化合物(0.028 g)及びDCM(1.0 mL)の混合物に、TFA(0.152 g)を氷冷下で加え、室温で2時間撹拌した。反応混合物を減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.012 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.007 g)及び酢酸(0.004 g)を室温で加え、同温で2時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、室温で10分間撹拌した。不溶物をろ取し、得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.010 g)を得た。 Example C-23
(R)-1-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)urea Reference Example G-23 (0.049 g), methanol (0.5 mL) and THF (0.5 mL) were added with 4 mol/L lithium hydroxide aqueous solution (0.081 mL) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. 1 mol/L hydrochloric acid (0.4 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue and THF (1.0 mL), HATU (0.062 g) and TEA (0.022 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate = 70/30 to 0/100) to give (R)-(2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-3-yl)carbamate tert-butyl (0.028 g).
To a mixture of the obtained compound (0.028 g) and DCM (1.0 mL), TFA (0.152 g) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.012 mL) and THF (1.0 mL), potassium cyanate (0.007 g) and acetic acid (0.004 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was collected by filtration, and the obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.010 g).

実施例C-24
1-((3R)-7-フルオロ-1-(1-(2-フルオロ-5-(トリフルオロメチル)フェニル)エチル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-20の代わりに参考例G-24を用い、実施例C-20と同様の方法により、実施例C-24を合成した。 Example C-24
1-((3R)-7-fluoro-1-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-24 was synthesized in the same manner as in Example C-20, using Reference Example G-24 instead of Reference Example G-20.

実施例C-25
(R)-1-(2-オキソ-1-フェネチル-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-12の代わりに参考例G-25を用い、実施例C-12と同様の方法により、実施例C-25を合成した。 Example C-25
(R)-1-(2-oxo-1-phenethyl-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-25 was synthesized in the same manner as in Example C-12, using Reference Example G-25 instead of Reference Example G-12.

実施例C-26
(R)-1-(2-オキソ-1-(3-フェニルプロピル)-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-2の代わりに参考例G-26を用い、実施例C-2と同様の方法により、実施例C-26を合成した。 Example C-26
(R)-1-(2-oxo-1-(3-phenylpropyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-26 was synthesized in the same manner as in Example C-2, except that Reference Example G-26 was used instead of Reference Example G-2.

実施例C-27
(R)-1-(1-(シクロヘキシルメチル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例G-2の代わりに参考例G-27を用い、実施例C-2と同様の方法により、実施例C-27を合成した。 Example C-27
(R)-1-(1-(cyclohexylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Example C-27 was synthesized in the same manner as in Example C-2, except that Reference Example G-27 was used instead of Reference Example G-2.

実施例C-28
(R)-1-(1-(5-(ジフルオロメチル)-2-フルオロベンジル)-2-オキソ-7-(トリフルオロメチル)-1,2,3,4-テトラヒドロキノリン-3-イル)-3-メチル尿素
　参考例G-15(0.030 g)及びDCM(1.0 mL)の混合物に、トリホスゲン(0.023 g)及びTEA(0.023 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物にメチルアミン(2 mol/L in THF)(0.058 mL)を氷冷下で加え、室温で1時間撹拌した。反応混合物にメチルアミン(2 mol/L in THF)(0.773 mL)を室温で加え、同温で10分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及び水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMTBEに懸濁し、不溶物をろ取した。得られた固体をMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.025 g)を得た。 Example C-28
(R)-1-(1-(5-(difluoromethyl)-2-fluorobenzyl)-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)-3-methylurea To a mixture of Reference Example G-15 (0.030 g) and DCM (1.0 mL), triphosgene (0.023 g) and TEA (0.023 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Methylamine (2 mol/L in THF) (0.058 mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Methylamine (2 mol/L in THF) (0.773 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was suspended in MTBE, and insoluble matter was collected by filtration. The obtained solid was washed with MTBE and then dried under reduced pressure to obtain the title compound (0.025 g).

実施例C-29
(R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-3-ウレイド-1,2,3,4-テトラヒドロキノリン-7-カルボン酸
　アルゴン雰囲気下、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-ヨードプロパン酸メチル(2.15 g)及びDMF(7.8 mL)の混合物に、亜鉛粉末(0.625 g)を室温で加え、同温で1時間撹拌した。反応混合物に3-アミノ-4-ブロモ安息香酸メチル(1.00 g)及びDMF(3.9 mL)の混合物、酢酸パラジウム(II)(0.049 g)及びXphos(0.207 g)を室温で加え、40℃で5時間撹拌した。反応混合物に酢酸(0.783 g)を加え、70℃で1時間撹拌した。反応混合物を室温まで放冷した後、水及びn-ヘキサン/酢酸エチル(1/1)を加え、室温で10分間撹拌した。不溶物をろ去し、ろ液の有機層を分取した。有機層を水及び飽和食塩水で洗浄した後、減圧下濃縮した。残渣をn-ヘキサン/酢酸エチル(2/1)に懸濁し、不溶物をろ取した。得られた固体を水及びn-ヘキサンで洗浄した後、減圧下乾燥することで、(R)-3-((tert-ブトキシカルボニル)アミノ)-2-オキソ-1,2,3,4-テトラヒドロキノリン-7-カルボン酸メチル(0.619 g)を得た。
　得られた化合物(0.300 g)及びDMF(3.0 mL)の混合物に、2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.265 g)及び炭酸カリウム(0.194 g)を氷冷下で加え、氷冷下で30分間、室温で6時間撹拌した。反応混合物に氷冷下、飽和塩化アンモニウム水溶液及び水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をn-ヘキサンに懸濁し、不溶物をろ取した。得られた固体をn-ヘキサンで洗浄した後、減圧下乾燥することで、(R)-3-((tert-ブトキシカルボニル)アミノ)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-7-カルボン酸メチル(0.390 g)を得た。
　得られた化合物(0.206 g)及びDCM(2.0 mL)の混合物に、TFA(0.946 g)を室温で加え、同温で45分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(1.66 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.2 mL)及びTHF(2.0 mL)の混合物に、シアン酸カリウム(0.037 g)及び酢酸(0.026 g)を氷冷下で加え、氷冷下で45分間撹拌した。反応混合物にTHF(2.0 mL)を加え、氷冷下で2時間、室温で65時間撹拌した。反応混合物に水を加え、不溶物をろ取した。得られた固体を水で洗浄した後、減圧下乾燥することで、(R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-3-ウレイド-1,2,3,4-テトラヒドロキノリン-7-カルボン酸メチル(0.173 g)を得た。
　得られた化合物(0.051 g)、メタノール(0.5 mL)及びTHF(0.5 mL)の混合物に、4 mol/L水酸化リチウム水溶液(0.116 mL)を氷冷下で加え、室温で50分間、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、1 mol/L塩酸(0.465 mL)及び水を加え、不溶物をろ取した。得られた固体を水で洗浄した後、減圧下乾燥することで、表題化合物(0.036 g)を得た。 Example C-29
(R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxylic acid Under an argon atmosphere, zinc powder (0.625 g) was added to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoic acid methyl (2.15 g) and DMF (7.8 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A mixture of 3-amino-4-bromobenzoic acid methyl (1.00 g) and DMF (3.9 mL), palladium (II) acetate (0.049 g) and Xphos (0.207 g) was added to the reaction mixture at room temperature, and the mixture was stirred at 40° C. for 5 hours. Acetic acid (0.783 g) was added to the reaction mixture, and the mixture was stirred at 70° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, water and n-hexane/ethyl acetate (1/1) were added and the mixture was stirred at room temperature for 10 minutes. The insoluble matter was removed by filtration, and the organic layer of the filtrate was separated. The organic layer was washed with water and saturated saline, and then concentrated under reduced pressure. The residue was suspended in n-hexane/ethyl acetate (2/1), and the insoluble matter was removed by filtration. The obtained solid was washed with water and n-hexane, and then dried under reduced pressure to obtain methyl (R)-3-((tert-butoxycarbonyl)amino)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (0.619 g).
To a mixture of the obtained compound (0.300 g) and DMF (3.0 mL), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.265 g) and potassium carbonate (0.194 g) were added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 6 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in n-hexane, and insoluble matter was filtered out. The obtained solid was washed with n-hexane and dried under reduced pressure to obtain (R)-3-((tert-butoxycarbonyl)amino)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate methyl (0.390 g).
To a mixture of the obtained compound (0.206 g) and DCM (2.0 mL), TFA (0.946 g) was added at room temperature and stirred at the same temperature for 45 minutes. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (1.66 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.2 mL) and THF (2.0 mL), potassium cyanate (0.037 g) and acetic acid (0.026 g) were added under ice cooling, and the mixture was stirred for 45 minutes under ice cooling. THF (2.0 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours under ice cooling and at room temperature for 65 hours. Water was added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and then dried under reduced pressure to obtain (R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxylate methyl (0.173 g).
A mixture of the obtained compound (0.051 g), methanol (0.5 mL) and THF (0.5 mL) was added with 4 mol/L lithium hydroxide aqueous solution (0.116 mL) under ice cooling, and stirred at room temperature for 50 minutes and at 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and then 1 mol/L hydrochloric acid (0.465 mL) and water were added, and the insoluble matter was filtered off. The obtained solid was washed with water and then dried under reduced pressure to obtain the title compound (0.036 g).

実施例C-30
(R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-3-ウレイド-1,2,3,4-テトラヒドロキノリン-7-カルボキサミド
　実施例C-29(0.030 g)、塩化アンモニウム(0.038 g)、HATU(0.032 g)及びMeCN(2.0 mL)の混合物に、TEA(0.093 g)を加え、室温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液及びMTBEを加え、不溶物をろ取した。得られた固体を水及びMTBEで洗浄した後、減圧下乾燥することで、表題化合物(0.018 g)を得た。 Example C-30
(R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2,3,4-tetrahydroquinoline-7-carboxamide Example C-29 (0.030 g), ammonium chloride (0.038 g), HATU (0.032 g) and MeCN (2.0 mL) were added to the mixture, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and MTBE were added to the reaction mixture, and the insoluble matter was filtered off. The obtained solid was washed with water and MTBE, and then dried under reduced pressure to obtain the title compound (0.018 g).

実施例D-1
1-((3R,6S)-1-(5-アリル-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素
　参考例J-2(0.127 g)及びTHF(2.0 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.565 mL)を-78℃で加え、同温で15分間撹拌した。反応混合物にDPPA(0.166 g)を-78℃で加え、同温で75分間撹拌した。反応混合物にBoc2O(0.105 g)及びTHF(1.0 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、((3R,6S)-1-(5-アリル-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.129 g)を得た。
　得られた化合物(0.128 g)及びDCM(1.3 mL)の混合物に、TFA(0.678 g)を室温で加え、同温で1時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(1.19 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.130 mL)及びTHF(1.3 mL)の混合物に、シアン酸カリウム(0.032 g)及び酢酸(0.019 g)を氷冷下で加え、室温で21時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=40/60/0～0/100/0～0/95/5)にて精製し、表題化合物(0.082 g)を得た。 Example D-1
1-((3R,6S)-1-(5-allyl-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example J-2 (0.127 g) and THF (2.0 mL), LDA (1.07 mol/L in THF/n-hexane) (0.565 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.166 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 75 minutes. A mixture of Boc 2 O (0.105 g) and THF (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 95/5 to 70/30) to give ((3R,6S)-1-(5-allyl-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamic acid tert-butyl ester (0.129 g).
To a mixture of the obtained compound (0.128 g) and DCM (1.3 mL), TFA (0.678 g) was added at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (1.19 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.130 mL) and THF (1.3 mL), potassium cyanate (0.032 g) and acetic acid (0.019 g) were added under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 40/60/0-0/100/0-0/95/5) to obtain the title compound (0.082 g).

実施例D-2
1-((3R,6S)-1-(5-(2-シクロプロピルエチル)-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素
　参考例J-3(0.137 g)及びTHF(2.0 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.566 mL)を-78℃で加え、同温で15分間撹拌した。反応混合物にDPPA(0.167 g)を-78℃で加え、同温で75分間撹拌した。反応混合物にBoc2O(0.106 g)及びTHF(1.0 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～70/30)にて精製し、((3R,6S)-1-(5-(シクロプロピルエチニル)-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.098 g)を得た。
　得られた化合物(0.097 g)及びDCM(0.97 mL)の混合物に、TFA(0.487 g)を室温で加え、同温で1時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(0.854 mL)を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.097 mL)及びTHF(0.97 mL)の混合物に、シアン酸カリウム(0.023 g)及び酢酸(0.013 g)を氷冷下で加え、室温で21時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=40/60/0～0/100/0～0/95/5)、及びMethod A(溶出溶媒：DCM/メタノール=100/0～90/10)にて順次精製し、1-((3R,6S)-1-(5-(シクロプロピルエチニル)-2-フルオロベンジル)-2-オキソ-6-(トリフルオロメチル)ピペリジン-3-イル)尿素(0.008 g)を得た。
　得られた化合物(0.007 g)、10% Pd/C(0.002 g)、THF(0.5 mL)及びメタノール(0.5 mL)の混合物を水素雰囲気下、室温で2時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をMethod A(溶出溶媒：酢酸エチル/メタノール=100/0～90/10)にて精製し、表題化合物(0.004 g)を得た。 Example D-2
1-((3R,6S)-1-(5-(2-cyclopropylethyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea To a mixture of Reference Example J-3 (0.137 g) and THF (2.0 mL), LDA (1.07 mol/L in THF/n-hexane) (0.566 mL) was added at -78°C, and the mixture was stirred at the same temperature for 15 minutes. DPPA (0.167 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 75 minutes. A mixture of Boc 2 O (0.106 g) and THF (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5-70/30) to give tert-butyl ((3R,6S)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)carbamate (0.098 g).
To a mixture of the obtained compound (0.097 g) and DCM (0.97 mL), TFA (0.487 g) was added at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture, 5 mol/L aqueous sodium hydroxide solution (0.854 mL) was added under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.097 mL), and THF (0.97 mL), potassium cyanate (0.023 g) and acetic acid (0.013 g) were added under ice-cooling, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 40/60/0-0/100/0-0/95/5) and Method A (eluent: DCM/methanol = 100/0-90/10) to give 1-((3R,6S)-1-(5-(cyclopropylethynyl)-2-fluorobenzyl)-2-oxo-6-(trifluoromethyl)piperidin-3-yl)urea (0.008 g).
A mixture of the obtained compound (0.007 g), 10% Pd/C (0.002 g), THF (0.5 mL) and methanol (0.5 mL) was stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate/methanol = 100/0 to 90/10) to obtain the title compound (0.004 g).

実施例D-3
1-((3S,6R,8aR)-5-オキソ-3-(2-(トリフルオロメチル)ベンジル)オクタヒドロインドリジン-6-イル)尿素
　参考例J-6(0.072 g)、(1,5-シクロオクタジエン)(ピリジン)(トリシクロヘキシルホスフィン)イリジウム(I)ヘキサフルオロホスファート(0.007 g)及びDCM(2.0 mL)の混合物を水素圧下(0.4 MPa)、室温で3時間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～50/50)にて精製し、(2R,5S)-2-(3-(((ベンジルオキシ)カルボニル)アミノ)-4-メトキシ-4-オキソブチル)-5-(2-(トリフルオロメチル)ベンジル)ピロリジン-1-カルボン酸tert-ブチル(0.072 g)を得た。
　得られた化合物(0.072 g)、4 mol/L水酸化リチウム水溶液(0.156 mL)、水(0.156 mL)及びメタノール(2.0 mL)の混合物を室温で1時間撹拌した。反応混合物に2 mol/L塩酸を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　残渣及び塩化水素(4 mol/L in 1,4-dioxane)(2.00 mL)の混合物を室温で30分間撹拌した。反応混合物を減圧下濃縮した。
　残渣、DIEPA(0.065 g)及びDMF(2.0 mL)の混合物に、HATU(0.052 g)を室温で加え、同温で15分間撹拌した。反応混合物に水を加え、混合物を酢酸エチルで抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～60/40)にて精製し、((3S,6R,8aR)-5-オキソ-3-(2-(トリフルオロメチル)ベンジル)オクタヒドロインドリジン-6-イル)カルバミン酸ベンジル(0.020 g)を得た。
　得られた化合物(0.020 g)、10% Pd/C(0.006 g)及びTHF(2.0 mL)の混合物を水素雰囲気下、室温で1時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。
　アルゴン雰囲気下、残渣、水(0.016 g)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.005 g)及び酢酸(0.005 g)を室温で加え、同温で3時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=98/2～80/20)にて精製し、表題化合物(0.013 g)を得た。 Example D-3
1-((3S,6R,8aR)-5-oxo-3-(2-(trifluoromethyl)benzyl)octahydroindolizin-6-yl)urea Reference Example J-6 (0.072 g), (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluorophosphate (0.007 g) and DCM (2.0 mL) were stirred at room temperature under hydrogen pressure (0.4 MPa) for 3 hours. The reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 50/50) to obtain (2R,5S)-2-(3-(((benzyloxy)carbonyl)amino)-4-methoxy-4-oxobutyl)-5-(2-(trifluoromethyl)benzyl)pyrrolidine-1-carboxylate tert-butyl (0.072 g).
A mixture of the obtained compound (0.072 g), 4 mol/L lithium hydroxide aqueous solution (0.156 mL), water (0.156 mL) and methanol (2.0 mL) was stirred at room temperature for 1 hour. 2 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The mixture of the residue and hydrogen chloride (4 mol/L in 1,4-dioxane) (2.00 mL) was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure.
To a mixture of the residue, DIEPA (0.065 g) and DMF (2.0 mL), HATU (0.052 g) was added at room temperature and stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 60/40) to give ((3S,6R,8aR)-5-oxo-3-(2-(trifluoromethyl)benzyl)octahydroindolizin-6-yl)benzyl carbamate (0.020 g).
The mixture of the obtained compound (0.020 g), 10% Pd/C (0.006 g) and THF (2.0 mL) was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
Under an argon atmosphere, potassium cyanate (0.005 g) and acetic acid (0.005 g) were added to a mixture of the residue, water (0.016 g) and THF (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 98/2 to 80/20) to obtain the title compound (0.013 g).

実施例D-4
1-((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)尿素
　参考例J-7(0.150 g)及びTHF(2.5 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.387 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.114 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.072 g)及びTHF(1.3 mL)の混合物を-78℃で加え、同温で10分間、室温で3時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～80/20)にて精製し、((3R,6S)-6-(((tert-ブチルジフェニルシリル)オキシ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.076 g)を得た。
　得られた化合物(0.074 g)及びDCM(1.0 mL)の混合物に、TFA(0.256 g)を室温で加え、同温で20分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.050 mL)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.010 g)及び酢酸(0.007 g)を室温で加え、同温で19時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、TBAF(1 mol/L in THF)(0.135 mL)及びTHF(1.0 mL)の混合物を室温で2時間撹拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=100/0/0～0/100/0～0/70/30)、及びPLC(展開溶媒：酢酸エチル/メタノール=90/10)にて順次精製し、表題化合物(0.001 g)を得た。 Example D-4
1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-7 (0.150 g) and THF (2.5 mL), LDA (1.07 mol/L in THF/n-hexane) (0.387 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.114 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.072 g) and THF (1.3 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 80/20) to give tert-butyl ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.076 g).
To a mixture of the obtained compound (0.074 g) and DCM (1.0 mL), TFA (0.256 g) was added at room temperature and stirred at the same temperature for 20 minutes. A 5 mol/L aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.050 mL) and THF (0.5 mL), potassium cyanate (0.010 g) and acetic acid (0.007 g) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
A mixture of the residue, TBAF (1 mol/L in THF) (0.135 mL), and THF (1.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 100/0/0 to 0/100/0 to 0/70/30) and PLC (development solvent: ethyl acetate/methanol = 90/10) to give the title compound (0.001 g).

実施例D-5
1-((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(ピロリジン-1-イルメチル)ピペリジン-3-イル)尿素
　参考例J-7(0.189 g)及びTHF(1.5 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.650 mL)を-78℃で加え、同温で20分間撹拌した。反応混合物にDPPA(0.191 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.091 g)及びTHF(1.0 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～60/40)にて精製し、((3R,6S)-6-(((tert-ブチルジフェニルシリル)オキシ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.184 g)を得た。
　得られた化合物(0.184 g)及びTHF(3.0 mL)の混合物に、TBAF(1 mol/L in THF)(0.559 mL)を室温で加え、同温で30分間撹拌した。反応混合物に水及び飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～50/50)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.081 g)を得た。
　得られた化合物(0.033 g)、TEA(0.028 g)及びDCM(1.0 mL)の混合物に、メタンスルホニルクロリド(0.018 g)を氷冷下で加え、室温で20分間撹拌した。反応混合物に水及び飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、ピロリジン(0.140 g)、TBAI(0.029 g)及びDMF(1.0 mL)の混合物に、炭酸カリウム(0.054 g)を加え、75℃で2.5時間撹拌した。反応混合物を室温まで放冷した後、水及び飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=88/12～0/100)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(ピロリジン-1-イルメチル)ピペリジン-3-イル)カルバミン酸tert-ブチル(0.012 g)を得た。
　得られた化合物(0.012 g)及びDCM(1.0 mL)の混合物に、TFA(0.296 g)を加え、室温で20分間撹拌した。反応混合物に水及び飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.009 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.003 g)及び酢酸(0.002 g)を加え、室温で2時間、40℃で30分間撹拌した。反応混合物にシアン酸カリウム(0.001 g)を加え、50℃で1時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～80/20)にて精製し、表題化合物(0.003 g)を得た。 Example D-5
1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)piperidin-3-yl)urea To a mixture of Reference Example J-7 (0.189 g) and THF (1.5 mL), LDA (1.07 mol/L in THF/n-hexane) (0.650 mL) was added at -78°C, and the mixture was stirred at the same temperature for 20 minutes. DPPA (0.191 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.091 g) and THF (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 95/5 to 60/40) to give tert-butyl ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate (0.184 g).
To a mixture of the obtained compound (0.184 g) and THF (3.0 mL), TBAF (1 mol/L in THF) (0.559 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 50/50) to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.081 g).
To a mixture of the obtained compound (0.033 g), TEA (0.028 g) and DCM (1.0 mL), methanesulfonyl chloride (0.018 g) was added under ice-cooling and stirred at room temperature for 20 minutes. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, pyrrolidine (0.140 g), TBAI (0.029 g) and DMF (1.0 mL), potassium carbonate (0.054 g) was added and stirred at 75° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 88/12 to 0/100) to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)piperidin-3-yl)carbamate tert-butyl (0.012 g).
To a mixture of the obtained compound (0.012 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 20 minutes. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.009 mL) and THF (1.0 mL), potassium cyanate (0.003 g) and acetic acid (0.002 g) were added, and the mixture was stirred at room temperature for 2 hours and at 40°C for 30 minutes. Potassium cyanate (0.001 g) was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 80/20) to obtain the title compound (0.003 g).

実施例D-6
1-((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(メトキシメチル)-2-オキソピペリジン-3-イル)尿素
　参考例J-10(0.097 g)及びTHF(1.0 mL)の混合物に、LDA(1.07 mol/L in THF/n-hexane)(0.408 mL)を-78℃で加え、同温で10分間撹拌した。反応混合物にDPPA(0.120 g)を-78℃で加え、同温で45分間撹拌した。反応混合物にBoc2O(0.067 g)及びTHF(0.5 mL)の混合物を-78℃で加え、同温で10分間、氷冷下で1時間撹拌した。反応混合物に水を加え、50℃で1時間撹拌した。反応混合物に酢酸(0.25 mL)及び2 mol/L塩酸(0.321 mL)を室温で加え、同温で30分間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=18/82～0/100)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.021 g)を得た。
　得られた化合物(0.021 g)、ヨウ化メチル(0.014 g)及びDMF(0.5 mL)の混合物に、水素化ナトリウム(約60%)(0.003 g)を室温で加え、同温で1時間撹拌した。反応混合物に水及び飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=88/12～0/100)にて精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(メトキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.009 g)を得た。
　得られた化合物(0.009 g)及びDCM(1.0 mL)の混合物に、TFA(0.296 g)を加え、室温で30分間撹拌した。反応混合物を減圧下濃縮した。
　残渣、水(0.008 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.002 g)及び酢酸(0.003 g)を加え、室温で1.5時間撹拌した。反応混合物に水及び飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～80/20)にて精製し、表題化合物(0.001 g)を得た。 Example D-6
1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(methoxymethyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-10 (0.097 g) and THF (1.0 mL), LDA (1.07 mol/L in THF/n-hexane) (0.408 mL) was added at -78°C, and the mixture was stirred at the same temperature for 10 minutes. DPPA (0.120 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 45 minutes. A mixture of Boc 2 O (0.067 g) and THF (0.5 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 10 minutes and under ice cooling for 1 hour. Water was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. Acetic acid (0.25 mL) and 2 mol/L hydrochloric acid (0.321 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 18/82 to 0/100) to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.021 g).
To a mixture of the obtained compound (0.021 g), methyl iodide (0.014 g) and DMF (0.5 mL), sodium hydride (about 60%) (0.003 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 88/12 to 0/100) to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(methoxymethyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.009 g).
To a mixture of the obtained compound (0.009 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure.
To a mixture of the residue, water (0.008 mL) and THF (1.0 mL), potassium cyanate (0.002 g) and acetic acid (0.003 g) were added and stirred at room temperature for 1.5 hours. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 80/20) to obtain the title compound (0.001 g).

実施例D-7
1-((3R,6S)-6-(エトキシメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)尿素
　参考例J-11(0.897 g)及びTHF(15 mL)の混合物に、TBAF(1 mol/L in THF)(4.85 mL)を加え、室温で20分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～60/40)、及びシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～30/70)にて順次精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.308 g)を得た。
　得られた化合物(0.025 g)、ヨウ化エチル(0.012 g)及びDMF(0.5 mL)の混合物に、水素化ナトリウム(約60%)(0.003 g)を室温で加え、同温で30分間撹拌した。反応混合物にヨウ化エチル(0.005 g)を加え、室温で30分間撹拌した。反応混合物に水素化ナトリウム(約60%)(0.003 g)を加え、室温で30分間撹拌した。反応混合物に水及び飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=88/12～0/100)にて精製し、((6S)-6-(エトキシメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.008 g)を得た。
　得られた化合物(0.008 g)及びDCM(1.0 mL)の混合物に、TFA(0.296 g)を加え、室温で20分間撹拌した。反応混合物を減圧下濃縮した。
　残渣、水(0.006 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.002 g)及び酢酸(0.002 g)を加え、室温で1.5時間、50℃で2時間撹拌した。反応混合物を室温まで放冷した後、水及び飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～80/20)にて精製し、表題化合物(0.001 g)を得た。 Example D-7
1-((3R,6S)-6-(ethoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-11 (0.897 g) and THF (15 mL), TBAF (1 mol/L in THF) (4.85 mL) was added and stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5-60/40) and silica gel column chromatography (eluent: n-hexane/ethyl acetate=70/30-30/70) in turn to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamic acid tert-butyl (0.308 g).
To a mixture of the obtained compound (0.025 g), ethyl iodide (0.012 g) and DMF (0.5 mL), sodium hydride (about 60%) (0.003 g) was added at room temperature and stirred at the same temperature for 30 minutes. Ethyl iodide (0.005 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Sodium hydride (about 60%) (0.003 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Water and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 88/12 to 0/100) to give ((6S)-6-(ethoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamic acid tert-butyl ester (0.008 g).
To a mixture of the obtained compound (0.008 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure.
To a mixture of the residue, water (0.006 mL) and THF (1.0 mL), potassium cyanate (0.002 g) and acetic acid (0.002 g) were added, and the mixture was stirred at room temperature for 1.5 hours and at 50°C for 2 hours. After the reaction mixture was allowed to cool to room temperature, water and a saturated aqueous solution of sodium bicarbonate were added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 80/20) to obtain the title compound (0.001 g).

実施例D-8
N-(((2S,5R)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-5-ウレイドピペリジン-2-イル)メチル)アセトアミド
　参考例J-12(0.020 g)、10% Pd/C(0.020 g)及び酢酸エチル(2.0 mL)の混合物を水素雰囲気下、氷冷下で30分間、室温で2時間撹拌した。反応混合物をセライトろ過し、不溶物を酢酸エチル(2.0 mL)で洗浄した。ろ液にDIPEA(0.035 g)及び塩化アセチル(0.017 g)を氷冷下で加え、室温で15分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=70/30/0～0/100/0～0/80/20)にて精製し、((3R,6S)-6-(アセトアミドメチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.019 g)を得た。
　得られた化合物(0.019 g)、塩化水素(4 mol/L in 1,4-dioxane)(1.5 mL)及びメタノール(1.5 mL)の混合物を室温で40分間撹拌した。反応混合物を減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。
　残渣、水(0.015 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.005 g)及び酢酸(0.005 g)を室温で加え、同温で3時間撹拌した。反応混合物に水を加え、混合物をDCMで10回抽出した。合わせた抽出液を減圧下濃縮した。残渣をODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=90/10～10/90)にて精製し、表題化合物(0.005 g)を得た。 Example D-8
N-(((2S,5R)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-2-yl)methyl)acetamide Reference Example J-12 (0.020 g), 10% Pd/C (0.020 g) and ethyl acetate (2.0 mL) were stirred under hydrogen atmosphere for 30 minutes under ice-cooling and at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the insoluble matter was washed with ethyl acetate (2.0 mL). DIPEA (0.035 g) and acetyl chloride (0.017 g) were added to the filtrate under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 70/30/0 to 0/100/0 to 0/80/20) to give ((3R,6S)-6-(acetamidomethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.019 g).
A mixture of the obtained compound (0.019 g), hydrogen chloride (4 mol/L in 1,4-dioxane) (1.5 mL) and methanol (1.5 mL) was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
To a mixture of the residue, water (0.015 mL) and THF (1.0 mL), potassium cyanate (0.005 g) and acetic acid (0.005 g) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted 10 times with DCM. The combined extracts were concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water/MeCN=90/10-10/90) to obtain the title compound (0.005 g).

実施例D-9
1-((3R,6S)-6-((ジメチルアミノ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)尿素
　参考例J-11(0.897 g)及びTHF(15 mL)の混合物に、TBAF(1 mol/L in THF)(4.85 mL)を加え、室温で20分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=95/5～60/40)、及びシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～30/70)にて順次精製し、((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.308 g)を得た。
　アルゴン雰囲気下、塩化オキサリル(0.023 g)及びDCM(1.0 mL)の混合物に、DMSO(0.028 g)を-78℃で加え、同温で1時間撹拌した。反応混合物に上記の((3R,6S)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.050 g)及びDCM(0.3 mL)の混合物を-78℃で加え、同温で30分間撹拌した。反応混合物にTEA(0.060 g)を-78℃で加え、室温で30分間撹拌した。反応混合物を減圧下濃縮した。
　残渣、ジメチルアミン(2 mol/L in THF)(0.178 mL)及びDCM(2.0 mL)の混合物に、トリアセトキシ水素化ホウ素ナトリウム(0.076 g)を加え、室温で1時間撹拌した。反応混合物に水及び飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=88/12～0/100)にて精製し、((3R,6S)-6-((ジメチルアミノ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.024 g)を得た。
　得られた化合物(0.024 g)及びDCM(1.0 mL)の混合物に、TFA(0.296 g)を加え、室温で20分間撹拌した。反応混合物を減圧下濃縮した。
　残渣、水(0.019 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.009 g)及び酢酸(0.006 g)を加え、室温で2.5時間撹拌した。反応混合物に水及び飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～90/10)にて精製し、表題化合物(0.007 g)を得た。 Example D-9
1-((3R,6S)-6-((dimethylamino)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)urea To a mixture of Reference Example J-11 (0.897 g) and THF (15 mL), TBAF (1 mol/L in THF) (4.85 mL) was added and stirred at room temperature for 20 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5-60/40) and silica gel column chromatography (eluent: n-hexane/ethyl acetate=70/30-30/70) in turn to give ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamic acid tert-butyl (0.308 g).
Under an argon atmosphere, DMSO (0.028 g) was added to a mixture of oxalyl chloride (0.023 g) and DCM (1.0 mL) at -78°C, and the mixture was stirred at the same temperature for 1 hour. The above mixture of ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.050 g) and DCM (0.3 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 30 minutes. TEA (0.060 g) was added to the reaction mixture at -78°C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure.
To a mixture of the residue, dimethylamine (2 mol/L in THF) (0.178 mL) and DCM (2.0 mL), sodium triacetoxyborohydride (0.076 g) was added and stirred at room temperature for 1 hour. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 88/12 to 0/100) to give ((3R,6S)-6-((dimethylamino)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.024 g).
To a mixture of the obtained compound (0.024 g) and DCM (1.0 mL), TFA (0.296 g) was added and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure.
To a mixture of the residue, water (0.019 mL) and THF (1.0 mL), potassium cyanate (0.009 g) and acetic acid (0.006 g) were added and stirred at room temperature for 2.5 hours. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate/methanol = 100/0 to 90/10) to obtain the title compound (0.007 g).

実施例D-10
2-((2S*,5R*)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-5-ウレイドピペリジン-2-イル)-N,N-ジメチルアセトアミド
　アルゴン雰囲気下、参考例J-16(0.384 g)及びTHF(4.5 mL)の混合物に、TBAF(1 mol/L in THF)(1.14 mL)を氷冷下で加え、室温で20分間撹拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/20～30/70)にて精製し、((3R*,6S*)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(2-ヒドロキシエチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.153 g)を得た。
　アルゴン雰囲気下、塩化オキサリル(0.043 g)及びDCM(1.0 mL)の混合物に、DMSO(0.053 g)を-78℃で加え、同温で20分間撹拌した。反応混合物に上記の((3R*,6S*)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(2-ヒドロキシエチル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.098 g)及びDCM(1.0 mL)の混合物を-78℃で加え、同温で30分間撹拌した。反応混合物にTEA(0.114 g)を-78℃で加え、室温で40分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　アルゴン雰囲気下、残渣、2-メチル-2-ブテン(0.15 mL)及びtert-ブタノール(1.5 mL)の混合物に、亜塩素酸ナトリウム(0.127 g)、リン酸二水素ナトリウム(0.135 g)及び水(0.375 mL)の混合物を室温で加え、同温で30分間撹拌した。反応混合物に2 mol/L塩酸を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、2-((2S*,5R*)-5-((tert-ブトキシカルボニル)アミノ)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソピペリジン-2-イル)酢酸(0.101 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.034 g)、ジメチルアミン塩酸塩(0.018 g)、DIEPA(0.048 g)及びMeCN(1.0 mL)の混合物に、HATU(0.031 g)を室温で加え、同温で45分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=60/40～20/80)にて精製し、((3R*,6S*)-6-(2-(ジメチルアミノ)-2-オキソエチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソピペリジン-3-イル)カルバミン酸tert-ブチル(0.028 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.028 g)及びDCM(1.0 mL)の混合物に、TFA(0.198 g)を室温で加え、同温で30分間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、水(0.021 mL)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.006 g)及び酢酸(0.004 g)を室温で加え、同温で12時間撹拌した。反応混合物に水を加え、混合物をDCM/2-プロパノール(1/1)で抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～85/15)にて精製し、表題化合物(0.011 g)を得た。 Example D-10
2-((2S * ,5R * )-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-5-ureidopiperidin-2-yl)-N,N-dimethylacetamide Under an argon atmosphere, TBAF (1 mol/L in THF) (1.14 mL) was added to a mixture of Reference Example J-16 (0.384 g) and THF (4.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/20 to 30/70) to obtain ((3R * ,6S * )-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(2-hydroxyethyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.153 g).
Under an argon atmosphere, DMSO (0.053 g) was added to a mixture of oxalyl chloride (0.043 g) and DCM (1.0 mL) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. The above mixture of ((3R * , 6S * )-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(2-hydroxyethyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.098 g) and DCM (1.0 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 30 minutes. TEA (0.114 g) was added to the reaction mixture at -78°C, and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
Under an argon atmosphere, a mixture of the residue, 2-methyl-2-butene (0.15 mL) and tert-butanol (1.5 mL) was added with a mixture of sodium chlorite (0.127 g), sodium dihydrogen phosphate (0.135 g) and water (0.375 mL) at room temperature, and stirred at the same temperature for 30 minutes. 2 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-((2S * ,5R * )-5-((tert-butoxycarbonyl)amino)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidin-2-yl)acetic acid (0.101 g).
Under an argon atmosphere, HATU (0.031 g) was added to a mixture of the obtained compound (0.034 g), dimethylamine hydrochloride (0.018 g), DIEPA (0.048 g) and MeCN (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 60/40 to 20/80) to obtain ((3R * ,6S * )-6-(2-(dimethylamino)-2-oxoethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidin-3-yl)carbamate tert-butyl (0.028 g).
Under an argon atmosphere, TFA (0.198 g) was added to a mixture of the obtained compound (0.028 g) and DCM (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. A 5 mol/L aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, water (0.021 mL) and THF (1.0 mL), potassium cyanate (0.006 g) and acetic acid (0.004 g) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM/2-propanol (1/1). The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-85/15) to obtain the title compound (0.011 g).

実施例E-1
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　実施例B-5(0.143 g)及び1,4-ジオキサン(5.0 mL)の混合物に、二酸化セレン(IV)(0.168 g)を加え、マイクロ波照射下、80℃で6時間撹拌した。反応混合物をセライトろ過し、ろ液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=100/0/0～0/100/0～0/90/10)、及びODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=90/10～10/90)にて順次精製し、表題化合物(0.025 g)を得た。 Example E-1
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)urea Example B-5 (0.143 g) and 1,4-dioxane (5.0 mL) were added to a mixture, and the mixture was stirred at 80 ° C. for 6 hours under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 90 / 10) and ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 10 / 90) in sequence to obtain the title compound (0.025 g).

実施例E-2
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(メトキシメチル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　アルゴン雰囲気下、実施例E-1(0.023 g)及びDCM(1.0 mL)の混合物に、三臭化リン(0.019 g)を氷冷下で加え、氷冷下で2.5時間、室温で2時間撹拌した。反応混合物に三臭化リン(0.006 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物に氷冷下、メタノールを加え、混合物を減圧下濃縮した。
　アルゴン雰囲気下、残渣及びメタノール(1.0 mL)の混合物に、ナトリウムメトキシド(0.010 g)を室温で加え、同温で30分間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル/メタノール=100/0～95/5)にて精製し、表題化合物(0.014 g)を得た。 Example E-2
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)urea Under argon atmosphere, phosphorus tribromide (0.019 g) was added to a mixture of Example E-1 (0.023 g) and DCM (1.0 mL) under ice-cooling, and the mixture was stirred for 2.5 hours under ice-cooling and 2 hours at room temperature. Phosphorus tribromide (0.006 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Methanol was added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure.
Under an argon atmosphere, sodium methoxide (0.010 g) was added to a mixture of the residue and methanol (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol = 100/0-95/5) to obtain the title compound (0.014 g).

実施例E-3
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-((ジメチルアミノ)メチル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　アルゴン雰囲気下、実施例E-1(0.110 g)及びDCM(3.0 mL)の混合物に、三臭化リン(0.121 g)を氷冷下で加え、氷冷下で12時間撹拌した。反応混合物にメタノールを加え、混合物を減圧下濃縮することで、1-(6-(ブロモメチル)-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素(0.128 g)を得た。
　得られた化合物(0.026 g)、ジメチルアミン塩酸塩(0.014 g)、DIPEA(0.036 g)及びDMF(1.0 mL)の混合物を室温で2時間撹拌した。反応混合物を水にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～30/70)にて精製し、表題化合物(0.003 g)を得た。 Example E-3
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((dimethylamino)methyl)-2-oxo-1,2-dihydropyridin-3-yl)urea Under an argon atmosphere, phosphorus tribromide (0.121 g) was added to a mixture of Example E-1 (0.110 g) and DCM (3.0 mL) under ice-cooling, and the mixture was stirred for 12 hours under ice-cooling. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain 1-(6-(bromomethyl)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea (0.128 g).
A mixture of the obtained compound (0.026 g), dimethylamine hydrochloride (0.014 g), DIPEA (0.036 g) and DMF (1.0 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane/ethyl acetate = 100/0-30/70) to obtain the title compound (0.003 g).

実施例E-4
1-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(ピロリジン-1-イルメチル)-1,2-ジヒドロピリジン-3-イル)尿素
　アルゴン雰囲気下、実施例E-1(0.081 g)及びDCM(3.0 mL)の混合物に、三臭化リン(0.083 g)を氷冷下で加え、室温で2時間撹拌した。反応混合物に氷冷下、メタノールを加え、混合物を減圧下濃縮することで、1-(6-(ブロモメチル)-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素(0.093 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.023 g)、ピロリジン(0.011 g)及びDMF(1.0 mL)の混合物に、DIPEA(0.033 g)を氷冷下で加え、室温で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～30/70)にて精製した。得られた生成物を1 mol/L塩酸に懸濁し、不溶物をろ去した。ろ液に2 mol/L水酸化ナトリウム水溶液を加えて塩基性とし、混合物をDCMで抽出した。抽出液を減圧下濃縮することで、表題化合物(0.005 g)を得た。 Example E-4
1-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)-1,2-dihydropyridin-3-yl)urea Under an argon atmosphere, phosphorus tribromide (0.083 g) was added to a mixture of Example E-1 (0.081 g) and DCM (3.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure to obtain 1-(6-(bromomethyl)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea (0.093 g).
Under an argon atmosphere, DIPEA (0.033 g) was added to a mixture of the obtained compound (0.023 g), pyrrolidine (0.011 g) and DMF (1.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 30/70). The obtained product was suspended in 1 mol/L hydrochloric acid, and insoluble matter was removed by filtration. The filtrate was made basic by adding a 2 mol/L aqueous solution of sodium hydroxide, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to obtain the title compound (0.005 g).

実施例E-5
1-(6-アリル-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素
　参考例D-1(0.712 g)、DMF(1.0 mL)及びDME(8.0 mL)の混合物に、水素化ナトリウム(約60%)(0.099 g)を氷冷下で加え、氷冷下で10分間撹拌した。反応混合物に臭素化リチウム(0.165 g)を氷冷下で加え、室温で15分間撹拌した。反応混合物に参考例A-3(0.581 g)を加え、90℃で3時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～90/10)にて精製し、(6-ブロモ-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)カルバミン酸tert-ブチル(0.516 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.446 g)、アリルトリブチルスタンナン(0.342 g)及びDMF(10 mL)の混合物に、テトラキス(トリフェニルホスフィン)パラジウム(0)(0.052 g)を室温で加え、100℃で30分間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～90/10)にて精製し、(6-アリル-1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)カルバミン酸tert-ブチル(0.269 g)を得た。
　得られた化合物(0.070 g)、塩化水素(4 mol/L in 1,4-dioxane)(0.759 mL)及びDCM(0.5 mL)の混合物を室温で5時間撹拌した。反応混合物を減圧下濃縮した。
　残渣及びDCM(1.0 mL)の混合物に、トリホスゲン(0.045 g)及びTEA(0.092 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.081 g)及びDIPEA(0.196 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物を水にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～0/100)にて精製し、表題化合物(0.038 g)を得た。 Example E-5
1-(6-allyl-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)urea To a mixture of Reference Example D-1 (0.712 g), DMF (1.0 mL) and DME (8.0 mL), sodium hydride (about 60%) (0.099 g) was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes. Lithium bromide (0.165 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Reference Example A-3 (0.581 g) was added to the reaction mixture, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, and then water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 90/10) to give tert-butyl (6-bromo-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (0.516 g).
Under an argon atmosphere, tetrakis(triphenylphosphine)palladium(0) (0.052 g) was added to a mixture of the obtained compound (0.446 g), allyltributylstannane (0.342 g) and DMF (10 mL) at room temperature, and the mixture was stirred at 100°C for 30 minutes. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 90/10) to obtain tert-butyl (6-allyl-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate (0.269 g).
A mixture of the obtained compound (0.070 g), hydrogen chloride (4 mol/L in 1,4-dioxane) (0.759 mL) and DCM (0.5 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure.
To a mixture of the residue and DCM (1.0 mL), triphosgene (0.045 g) and TEA (0.092 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, ammonium chloride (0.081 g) and DIPEA (0.196 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 0/100) to obtain the title compound (0.038 g).

実施例E-6
1-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-6-(ピロリジン-1-イルメチル)-1,2-ジヒドロピリジン-3-イル)尿素
　実施例B-4(0.406 g)及び1,4-ジオキサン(12 mL)の混合物に、二酸化セレン(IV)(0.443 g)を加え、80℃で13時間撹拌した。反応混合物を室温まで放冷した後、セライトろ過し、ろ液を減圧下濃縮した。残渣をMethod B(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=70/30/0～0/100/0～0/90/10)にて精製し、1-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-(ヒドロキシメチル)-2-オキソ-1,2-ジヒドロピリジン-3-イル)尿素(0.148 g)を得た。
　得られた化合物(0.036 g)及びDCM(1.5 mL)の混合物に、三臭化リン(0.041 g)を氷冷下で加え、室温で1時間撹拌した。反応混合物に氷冷下、メタノールを加え、混合物を減圧下濃縮した。
　アルゴン雰囲気下、残渣、ピロリジン(0.021 g)及びDMF(1.0 mL)の混合物に、DIPEA(0.064 g)を加え、室温で30分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を水及び飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=70/30～30/70)にて精製し、表題化合物(0.016 g)を得た。 Example E-6
1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(pyrrolidin-1-ylmethyl)-1,2-dihydropyridin-3-yl)urea Example B-4 (0.406 g) and 1,4-dioxane (12 mL) were mixed, and selenium dioxide (IV) (0.443 g) was added and stirred at 80 ° C. for 13 hours. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method B (elution solvent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0-0 / 100 / 0-0 / 90 / 10) to obtain 1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-3-yl)urea (0.148 g).
To a mixture of the obtained compound (0.036 g) and DCM (1.5 mL), phosphorus tribromide (0.041 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture under ice-cooling, and the mixture was concentrated under reduced pressure.
Under an argon atmosphere, DIPEA (0.064 g) was added to a mixture of the residue, pyrrolidine (0.021 g) and DMF (1.0 mL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 30/70) to obtain the title compound (0.016 g).

実施例E-7
1-(5-オキソ-2-(3-(トリフルオロメチル)フェニル)-1,2,3,5-テトラヒドロインドリジン-6-イル)尿素
　参考例L-3(0.069 g)、カルバミン酸tert-ブチル(0.059 g)、炭酸セシウム(0.244 g)、クロロ(2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピル-1,1'-ビフェニル)[2-(2'-アミノ-1,1'-ビフェニル)]パラジウム(II)(0.039 g)及び1,4-ジオキサン(1.5 mL)の混合物をマイクロ波照射下、90℃で30分間撹拌した。反応混合物に1,4-ジオキサン(0.5 mL)を加え、マイクロ波照射下、110℃で30分間撹拌した。反応混合物に水及びDCMを加え、混合物をセライトろ過した。ろ液の有機層を分取し、有機層を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～50/50)にて精製し、酢酸6-((tert-ブトキシカルボニル)アミノ)-5-オキソ-2-(3-(トリフルオロメチル)フェニル)-1,2,3,5-テトラヒドロインドリジン-1-イル(0.049 g)を得た。
　得られた化合物(0.083 g)、炭酸カリウム(0.076 g)及びメタノール(1.0 mL)の混合物を室温で30分間撹拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=80/20～40/60)にて精製し、(1-ヒドロキシ-5-オキソ-2-(3-(トリフルオロメチル)フェニル)-1,2,3,5-テトラヒドロインドリジン-6-イル)カルバミン酸tert-ブチル(0.011 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.011 g)及びDCM(1.0 mL)の混合物に、TFA(0.031 g)及びトリエチルシラン(0.006 g)を室温で加え、同温で14時間撹拌した。反応混合物にTFA(0.031 g)を室温で加え、同温で3時間撹拌した。反応混合物に氷冷下、5 mol/L水酸化ナトリウム水溶液(1.0 mL)を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。
　アルゴン雰囲気下、残渣及びDCM(1.0 mL)の混合物に、トリホスゲン(0.008 g)及びTEA(0.008 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物に塩化アンモニウム(0.015 g)及びDIPEA(0.036 g)を氷冷下で加え、室温で1時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=30/70/0～0/100/0～0/95/5)にて精製し、表題化合物(0.001 g)を得た。 Example E-7
1-(5-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroindolizin-6-yl)urea Reference Example L-3 (0.069 g), tert-butyl carbamate (0.059 g), cesium carbonate (0.244 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.039 g) and 1,4-dioxane (1.5 mL) were stirred at 90°C for 30 minutes under microwave irradiation. 1,4-dioxane (0.5 mL) was added to the reaction mixture and stirred at 110°C for 30 minutes under microwave irradiation. Water and DCM were added to the reaction mixture, and the mixture was filtered through Celite. The organic layer of the filtrate was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 50/50) to give 6-((tert-butoxycarbonyl)amino)-5-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroindolizin-1-yl acetate (0.049 g).
A mixture of the obtained compound (0.083 g), potassium carbonate (0.076 g) and methanol (1.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 80/20 to 40/60) to give tert-butyl (1-hydroxy-5-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroindolizin-6-yl)carbamate (0.011 g).
Under an argon atmosphere, TFA (0.031 g) and triethylsilane (0.006 g) were added to a mixture of the obtained compound (0.011 g) and DCM (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 14 hours. TFA (0.031 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 3 hours. A 5 mol/L aqueous sodium hydroxide solution (1.0 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
Under argon atmosphere, triphosgene (0.008 g) and TEA (0.008 g) were added to a mixture of the residue and DCM (1.0 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. Ammonium chloride (0.015 g) and DIPEA (0.036 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol = 30/70/0-0/100/0-0/95/5) to give the title compound (0.001 g).

実施例E-8
N-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-イル)-2,2,2-トリフルオロアセトアミド
　参考例E-6(0.030 g)、DIPEA(0.023 g)及びDCM(0.7 mL)の混合物に、無水トリフルオロ酢酸 (0.017 g)を水冷下で加え、室温で1時間撹拌した。反応混合物を水にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～0/100)、及びODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=70/30～10/90)にて順次精製し、表題化合物(0.028 g)を得た。 Example E-8
N-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2,2,2-trifluoroacetamide Reference Example E-6 (0.030 g), DIPEA (0.023 g) and DCM (0.7 mL) were mixed, and trifluoroacetic anhydride (0.017 g) was added under cooling with water, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 100/0 to 0/100) and ODS column chromatography (elution solvent: water/MeCN = 70/30 to 10/90) in sequence to obtain the title compound (0.028 g).

実施例E-9
N-(1-(3-クロロ-2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-イル)アゼチジン-1-カルボキサミド
　参考例E-6(0.030 g)及びDCM(1.0 mL)の混合物に、トリホスゲン(0.027 g)及びDIPEA(0.027 g)を氷冷下で加え、氷冷下で30分間撹拌した。反応混合物にアゼチジン塩酸塩(0.008 g)及びDIPEA(0.116 g)を氷冷下で加え、室温で30分間撹拌した。反応混合物を水にあけ、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～0/100)、及びODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=70/30～10/90)にて順次精製し、表題化合物(0.008 g)を得た。 Example E-9
N-(1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)azetidine-1-carboxamide To a mixture of Reference Example E-6 (0.030 g) and DCM (1.0 mL), triphosgene (0.027 g) and DIPEA (0.027 g) were added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. Azetidine hydrochloride (0.008 g) and DIPEA (0.116 g) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=100/0-0/100) and ODS column chromatography (eluent: water/MeCN=70/30-10/90) to obtain the title compound (0.008 g).

実施例F-1
(R)-1-(7-(ジフルオロメチル)-1-(2-(ヒドロキシメチル)-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　アルゴン雰囲気下、参考例M-1(0.151 g)及びDMF(2.0 mL)の混合物に、参考例H-2(0.172 g)及び炭酸カリウム(0.100 g)を氷冷下で加え、氷冷下で30分間、室温で62時間撹拌した。反応混合物に氷冷下、水及び飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～80/20)にて精製し、(R)-2-((3-((tert-ブトキシカルボニル)アミノ)-7-(ジフルオロメチル)-2-オキソ-3,4-ジヒドロキノリン-1(2H)-イル)メチル)-4-(トリフルオロメチル)安息香酸メチル(0.217 g)を得た。
　得られた化合物(0.101 g)、4 mol/L水酸化リチウム水溶液(0.191 mL)、THF(0.5 mL)及びメタノール(0.5 mL)の混合物をマイクロ波照射下、60℃で30分間撹拌した。反応混合物に2 mol/L塩酸(0.420 mL)を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮することで、(R)-2-((3-((tert-ブトキシカルボニル)アミノ)-7-(ジフルオロメチル)-2-オキソ-3,4-ジヒドロキノリン-1(2H)-イル)メチル)-4-(トリフルオロメチル)安息香酸(0.084 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.053 g)及びTHF(0.75 mL)の混合物に、BH3-THF(0.93 mol/L in THF)(0.133 mL)を氷冷下で加え、室温で3時間撹拌した。反応混合物にメタノールを加え、室温で30分間撹拌した。混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=90/10～50/50)にて精製し、(R)-(7-(ジフルオロメチル)-1-(2-(ヒドロキシメチル)-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)カルバミン酸tert-ブチル(0.038 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.038 g)及びDCM(0.75 mL)の混合物に、TFA(0.174 g)を室温で加え、同温で1時間撹拌した。反応混合物に氷冷下、2 mol/L水酸化ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　アルゴン雰囲気下、残渣、水(0.027 g)及びTHF(0.75 mL)の混合物に、シアン酸カリウム(0.008 g)及び酢酸(0.005 g)を氷冷下で加え、室温で64時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=0/100/0～0/100/0～0/95/5)にて精製し、表題化合物(0.007 g)を得た。 Example F-1
(R)-1-(7-(difluoromethyl)-1-(2-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Under an argon atmosphere, Reference Example H-2 (0.172 g) and potassium carbonate (0.100 g) were added to a mixture of Reference Example M-1 (0.151 g) and DMF (2.0 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling and at room temperature for 62 hours. Water and a saturated aqueous ammonium chloride solution were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 80/20) to give (R)-2-((3-((tert-butoxycarbonyl)amino)-7-(difluoromethyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)-4-(trifluoromethyl)benzoate methyl (0.217 g).
A mixture of the obtained compound (0.101 g), 4 mol/L lithium hydroxide aqueous solution (0.191 mL), THF (0.5 mL) and methanol (0.5 mL) was stirred at 60° C. for 30 minutes under microwave irradiation. 2 mol/L hydrochloric acid (0.420 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-2-((3-((tert-butoxycarbonyl)amino)-7-(difluoromethyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyl)-4-(trifluoromethyl)benzoic acid (0.084 g).
Under an argon atmosphere, BH 3 -THF (0.93 mol/L in THF) (0.133 mL) was added to a mixture of the obtained compound (0.053 g) and THF (0.75 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 50/50) to give (R)-(7-(difluoromethyl)-1-(2-(hydroxymethyl)-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate tert-butyl (0.038 g).
Under an argon atmosphere, TFA (0.174 g) was added to a mixture of the obtained compound (0.038 g) and DCM (0.75 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A 2 mol/L aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
Under an argon atmosphere, potassium cyanate (0.008 g) and acetic acid (0.005 g) were added to a mixture of the residue, water (0.027 g) and THF (0.75 mL) under ice-cooling, and the mixture was stirred at room temperature for 64 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 0/100/0 to 0/100/0 to 0/95/5) to obtain the title compound (0.007 g).

実施例F-2
(R)-1-(7-(ジフルオロメチル)-2-オキソ-1-((6-(トリフルオロメチル)ピリジン-2-イル)メチル)-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　アルゴン雰囲気下、参考例M-1(0.030 g)及びDMF(2.0 mL)の混合物に、参考例H-3(0.025 g)及び炭酸カリウム(0.020 g)を氷冷下で加え、氷冷下で30分間、室温で20時間撹拌した。反応混合物に氷冷下、水及び飽和塩化アンモニウム水溶液を加え、混合物をn-ヘキサン/酢酸エチル(1/1)で抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～70/30)にて精製し、(R)-(7-(ジフルオロメチル)-2-オキソ-1-((6-(トリフルオロメチル)ピリジン-2-イル)メチル)-1,2,3,4-テトラヒドロキノリン-3-イル)カルバミン酸tert-ブチル(0.024 g)を得た。
　アルゴン雰囲気下、得られた化合物(0.024 g)及びDCM(1.0 mL)の混合物に、TFA(0.117 g)を室温で加え、同温で1時間撹拌した。反応混合物に氷冷下、2 mol/L水酸化ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　アルゴン雰囲気下、残渣、水(0.019 g)及びTHF(1.0 mL)の混合物に、シアン酸カリウム(0.005 g)及び酢酸(0.003 g)を氷冷下で加え、室温で2.5時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=100/0/0～0/100/0～0/95/5)にて精製し、表題化合物(0.012 g)を得た。 Example F-2
(R)-1-(7-(difluoromethyl)-2-oxo-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Under an argon atmosphere, Reference Example H-3 (0.025 g) and potassium carbonate (0.020 g) were added to a mixture of Reference Example M-1 (0.030 g) and DMF (2.0 mL) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling and for 20 hours at room temperature. Water and a saturated aqueous ammonium chloride solution were added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane/ethyl acetate (1/1). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 70/30) to give (R)-(7-(difluoromethyl)-2-oxo-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl (0.024 g).
Under an argon atmosphere, TFA (0.117 g) was added to a mixture of the obtained compound (0.024 g) and DCM (1.0 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A 2 mol/L aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
Under an argon atmosphere, potassium cyanate (0.005 g) and acetic acid (0.003 g) were added to a mixture of the residue, water (0.019 g) and THF (1.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 100/0/0 to 0/100/0 to 0/95/5) to obtain the title compound (0.012 g).

実施例F-3
(R)-1-(8-((ジメチルアミノ)メチル)-1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素
　参考例N-2(0.039 g)、水(0.019 g)及びTHF(0.5 mL)の混合物に、シアン酸カリウム(0.011 g)及び酢酸(0.007 g)を氷冷下で加え、室温で18時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。残渣をn-ヘキサン/MBTE(1/1)に懸濁し、不溶物をろ取した。得られた固体をMTBEで洗浄した後、減圧下乾燥することで、(R)-1-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-8-(ヒドロキシメチル)-2-オキソ-1,2,3,4-テトラヒドロキノリン-3-イル)尿素(0.037 g)を得た。
　得られた化合物(0.015 g)及びDCM(1.0 mL)の混合物に、三臭化リン(0.015 g)を氷冷下で加え、氷冷下で1時間撹拌した。反応混合物にメタノールを加え、混合物を減圧下濃縮した。
　残渣、ジメチルアミン塩酸塩(0.009 g)、DIPEA(0.023 g)及びDMF(1.0 mL)の混合物を室温で20時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をAPSカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル/メタノール=50/50/0～0/100/0～0/90/10)にて精製し、表題化合物(0.012 g)を得た。 Example F-3
(R)-1-(8-((dimethylamino)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Reference Example N-2 (0.039 g), water (0.019 g) and THF (0.5 mL) were added to a mixture of potassium cyanate (0.011 g) and acetic acid (0.007 g) under ice cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The residue was suspended in n-hexane/MBTE (1/1), and insoluble matter was collected by filtration. The obtained solid was washed with MTBE and then dried under reduced pressure to obtain (R)-1-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-8-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (0.037 g).
To a mixture of the obtained compound (0.015 g) and DCM (1.0 mL), phosphorus tribromide (0.015 g) was added under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
A mixture of the residue, dimethylamine hydrochloride (0.009 g), DIPEA (0.023 g) and DMF (1.0 mL) was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane/ethyl acetate/methanol = 50/50/0-0/100/0-0/90/10) to obtain the title compound (0.012 g).

実施例F-4
(R)-1-(7-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-6-オキソ-4,5,6,7-テトラヒドロチエノ[2,3-b]ピリジン-5-イル)尿素
　参考例M-1の代わりに参考例M-4、参考例H-3の代わりに2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼンを用い、実施例F-2と同様の方法により、実施例F-4を合成した。 Example F-4
(R)-1-(7-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridin-5-yl)urea Example F-4 was synthesized in the same manner as in Example F-2, using Reference Example M-4 instead of Reference Example M-1 and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene instead of Reference Example H-3.

実施例F-5
(R)-1-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-5-オキソ-4,5,6,7-テトラヒドロチエノ[3,2-b]ピリジン-6-イル)尿素
　参考例M-1の代わりに参考例M-7、参考例H-3の代わりに2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼンを用い、実施例F-2と同様の方法により、実施例F-5を合成した。 Example F-5
(R)-1-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-5-oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridin-6-yl)urea Example F-5 was synthesized in the same manner as in Example F-2, using Reference Example M-7 instead of Reference Example M-1 and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene instead of Reference Example H-3.

実施例F-6
(R)-1-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-メチル-5-オキソ-4,5,6,7-テトラヒドロチアゾロ[5,4-b]ピリジン-6-イル)尿素
　参考例M-1の代わりに参考例M-11、参考例H-3の代わりに2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼンを用い、実施例F-2と同様の方法により、実施例F-6を合成した。 Example F-6
(R)-1-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-2-methyl-5-oxo-4,5,6,7-tetrahydrothiazolo[5,4-b]pyridin-6-yl)urea Example F-6 was synthesized in the same manner as in Example F-2, using Reference Example M-11 instead of Reference Example M-1 and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene instead of Reference Example H-3.

実施例F-7
2-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-2-イル)アセトアミド
　参考例M-13(0.100 g)、2-(ブロモメチル)-1-フルオロ-4-(トリフルオロメチル)ベンゼン(0.120 g)、炭酸カリウム(0.088 g)及びDMF(4.3 mL)の混合物をマイクロ波照射下、60℃で1.5時間撹拌した。反応混合物を水にあけ、混合物を酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=100/0～60/40)にて精製し、2-(4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-2-イル)酢酸エチル(0.109 g)を得た。
　得られた化合物(0.098 g)、THF(0.5 mL)及びメタノール(0.5 mL)の混合物に、4 mol/L水酸化リチウム水溶液(0.179 mL)を氷冷下で加え、氷冷下で1時間、室温で1時間撹拌した。反応混合物に氷冷下、1 mol/L塩酸及び水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣及びMeCN(2.4 mL)の混合物に、DMT-MM(0.099 g)及び15 mol/Lアンモニア水(0.024 mL)を室温で加え、同温で30分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：n-ヘキサン/酢酸エチル=0/100～100/0)、及びODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=90/10～10/90)にて順次精製し、表題化合物(0.018 g)を得た。 Example F-7
2-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamide Reference Example M-13 (0.100 g), 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (0.120 g), potassium carbonate (0.088 g) and DMF (4.3 mL) were stirred at 60° C. for 1.5 hours under microwave irradiation. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 100/0 to 60/40) to give ethyl 2-(4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (0.109 g).
To a mixture of the obtained compound (0.098 g), THF (0.5 mL) and methanol (0.5 mL), 4 mol/L lithium hydroxide aqueous solution (0.179 mL) was added under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling and at room temperature for 1 hour. 1 mol/L hydrochloric acid and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue and MeCN (2.4 mL), DMT-MM (0.099 g) and 15 mol/L aqueous ammonia (0.024 mL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 0/100-100/0) and ODS column chromatography (eluent: water/MeCN = 90/10-10/90) in turn to obtain the title compound (0.018 g).

実施例F-8
(2-(2-アミノ-2-オキソエチル)-4-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-3-オキソ-3,4-ジヒドロ-2H-ベンゾ[b][1,4]オキサジン-7-イル)カルバミン酸tert-ブチル
　参考例N-4(0.105 g)、Boc2O(0.107 g)、TEA(0.075 g)及びTHF(2.5 mL)の混合物に、DMAP(0.015 g)を室温で加え、同温で1時間撹拌した。反応混合物に水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、炭酸カリウム(0.085 g)及びメタノール(2.5 mL)の混合物を60℃で1時間撹拌した。反応混合物を室温まで放冷した後、水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣、THF(0.5 mL)及びメタノール(0.5 mL)の混合物に、4 mol/L水酸化リチウム水溶液(0.185 mL)を室温で加え、同温で1時間撹拌した。反応混合物に氷冷下、1 mol/L塩酸(1.00 mL)及び水を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。
　残渣及びMeCN(2.4 mL)の混合物に、DMT-MM(0.102 g)及び15 mol/Lアンモニア水 (0.025 mL)を室温で加え、同温で30分間撹拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒：酢酸エチル)、及びODSカラムクロマトグラフィー(溶出溶媒：水/MeCN=70/30～10/90)にてし、表題化合物(0.011 g)を得た。 Example F-8
(2-(2-amino-2-oxoethyl)-4-(2-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)carbamate tert-butyl Reference Example N-4 (0.105 g), Boc 2 O (0.107 g), TEA (0.075 g) and THF (2.5 mL) were added to a mixture of DMAP (0.015 g) at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
A mixture of the residue, potassium carbonate (0.085 g) and methanol (2.5 mL) was stirred at 60° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue, THF (0.5 mL) and methanol (0.5 mL), 4 mol/L lithium hydroxide aqueous solution (0.185 mL) was added at room temperature and stirred at the same temperature for 1 hour. To the reaction mixture, 1 mol/L hydrochloric acid (1.00 mL) and water were added under ice-cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure.
To a mixture of the residue and MeCN (2.4 mL), DMT-MM (0.102 g) and 15 mol/L aqueous ammonia (0.025 mL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) and ODS column chromatography (elution solvent: water/MeCN=70/30-10/90) to obtain the title compound (0.011 g).

実施例F-9
1-(tert-ブチル)-3-(1-(2-フルオロ-5-(トリフルオロメチル)ベンジル)-2-オキソ-3-ウレイド-1,2-ジヒドロキノキサリン-6-イル)尿素
　参考例N-8(0.013 g)、ピリジン(0.004 g)及びDCM(1.0 mL)の混合物に、クロロギ酸4-ニトロフェニル(0.007 g)を室温で加え、同温で45分間撹拌した。反応混合物にtert-ブチルアミン(0.003 g)及びDIPEA(0.010 g)を加え、室温で1時間撹拌した。反応混合物にtert-ブチルアミン(0.002 g)を加え、室温で1.5時間撹拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、混合物をDCMで抽出した。抽出液を減圧下濃縮した。残渣をMethod A(溶出溶媒：n-ヘキサン/酢酸エチル=50/50～100/0)にて精製し、表題化合物(0.002 g)を得た。 Example F-9
1-(tert-butyl)-3-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-3-ureido-1,2-dihydroquinoxalin-6-yl)urea Reference Example N-8 (0.013 g), pyridine (0.004 g) and DCM (1.0 mL) were added with 4-nitrophenyl chloroformate (0.007 g) at room temperature and stirred at the same temperature for 45 minutes. tert-Butylamine (0.003 g) and DIPEA (0.010 g) were added to the reaction mixture and stirred at room temperature for 1 hour. tert-Butylamine (0.002 g) was added to the reaction mixture and stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane/ethyl acetate=50/50-100/0) to obtain the title compound (0.002 g).

　実施例の構造式、物性値、及びTSHRアンタゴニスト活性（試験例1参照）を以下の表に示す。 The structural formulas, physical properties, and TSHR antagonist activity (see Test Example 1) of the examples are shown in the table below.

Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128

Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000133

Figure JPOXMLDOC01-appb-T000134
 　表中の実施例A-1からA-12、A-19、A-21、A-23、A-29及びD-10の立体化学の表記は、相対配置を示す。
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128

Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000133

Figure JPOXMLDOC01-appb-T000134
 The stereochemical designations in the table for Examples A-1 to A-12, A-19, A-21, A-23, A-29 and D-10 indicate the relative configuration.

試験例1
ヒトTSHR安定発現CHO細胞におけるTSH誘発cAMP生成を指標としたアンタゴニスト活性の測定 Test Example 1
Measurement of antagonist activity using TSH-induced cAMP production in human TSHR-stably expressing CHO cells

　ヒトTSHRの遺伝子配列（参照番号NM_000369.2）をpcDNA3.1(+)のマルチクローニング部位に挿入した。作製したプラスミドベクターをリポフェクション法を用いてCHO細胞へ導入し、ヒトTSHR安定発現CHO細胞を樹立した。得られた細胞を96ウェルのポリ-D-リジンコートプレートに5 x 104個/ウェルで播種し、10%FBS、400 μg/mLのG418、50 U/mLのペニシリン及び50 μg/mLのストレプトマイシンを含有するF12培地中、37 ℃、5%CO2の条件下で1日間培養した。培地を除去した後、1ウェルあたり100 μLのアッセイ用緩衝液（20 mM HEPES及び1 mM IBMXを含有するHanks' Balanced Salt Solution）で細胞を2回洗浄した。ウェルに30 μLの試験化合物含有アッセイ用緩衝液を添加し、室温で15分間インキュベートした。次いで、30 μLのヒトTSH（R&D Systems, Inc.、最終濃度50 ng/mL）を含むアッセイ用緩衝液を添加し、37 ℃で1時間インキュベートした。上清を除去し、Lysis and Detection Buffer 2（Cisbio）を添加して、室温で1時間インキュベートすることにより細胞溶解液を調製した。cAMP Gs HiRangeキット（Cisbio）の使用説明書に従って、384ウェル白色マイクロプレート内で細胞溶解液とd2-labeled cAMP及び抗cAMP Europium Cryptate labeled抗体（Cisbio）を反応させた。次いで、マルチプレートリーダー（PHERAstarFSX、BMG LABTECH ジャパン）を用いて蛍光強度比（測定波長665 nm/620 nm）を測定した。標準曲線を用いて各サンプルの蛍光強度比をcAMP含量に変換した。cAMP含量を対照値の百分率として換算し、cAMP生成率を算出した。Prism（Graph Pad Software Inc.）を用いて試験化合物濃度に対してcAMP生成率をプロットし、IC50値を算出した。各被験化合物のIC50を上述の表に示した。表中、IC50＜3.0 μM：A、3.0 μM≦IC50＜30 μM：Bとして表記した。活性が認められたもののIC50値が算出されない場合には、Cとして表記した。 The gene sequence of human TSHR (reference number NM_000369.2) was inserted into the multicloning site of pcDNA3.1(+). The constructed plasmid vector was introduced into CHO cells using the lipofection method to establish human TSHR stably expressing CHO cells. The obtained cells were seeded at 5 x 104 cells/well on a 96-well poly-D-lysine coated plate and cultured for 1 day under the conditions of 37 °C and 5% CO2 in F12 medium containing 10% FBS, 400 μg/mL G418, 50 U/mL penicillin and 50 μg/mL streptomycin. After removing the medium, the cells were washed twice with 100 μL of assay buffer (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX) per well. 30 μL of assay buffer containing the test compound was added to the well and incubated at room temperature for 15 minutes. Then, 30 μL of assay buffer containing human TSH (R&D Systems, Inc., final concentration 50 ng/mL) was added and incubated at 37 °C for 1 hour. The supernatant was removed, and Lysis and Detection Buffer 2 (Cisbio) was added and incubated at room temperature for 1 hour to prepare cell lysates. According to the instruction manual of the cAMP Gs HiRange kit (Cisbio), the cell lysates were reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate labeled antibody (Cisbio) in a 384-well white microplate. Then, the fluorescence intensity ratio (measurement wavelength 665 nm/620 nm) was measured using a multiplate reader (PHERAstarFSX, BMG LABTECH Japan). The fluorescence intensity ratio of each sample was converted to cAMP content using a standard curve. The cAMP content was converted as a percentage of the control value to calculate the cAMP generation rate. The cAMP production rate was plotted against the test compound concentration using Prism (Graph Pad Software Inc.) to calculate IC50 values. The IC50 of each test compound is shown in the above table. In the table, IC50 < 3.0 μM is indicated as A, and 3.0 μM ≦ IC50 < 30 μM is indicated as B. When activity was observed but the IC50 value could not be calculated, it was indicated as C.

　上記表に示したように、本発明の化合物は、ヒトTSHRアンタゴニスト活性を有することが明らかとなった。 As shown in the table above, it has been revealed that the compounds of the present invention have human TSHR antagonist activity.

　本発明の化合物又はその薬理学的に許容される塩は、TSHRアンタゴニスト活性を有するので、甲状腺関連疾患の治療剤として有用である。 The compound of the present invention or a pharmacologically acceptable salt thereof has TSHR antagonist activity and is therefore useful as a therapeutic agent for thyroid-related diseases.

Claims (15)

式（Ａ-ＩＩＩ）で表される化合物：
Figure JPOXMLDOC01-appb-C000001
 〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000002
 Qは、-CH=、-CH2-、-O-、又は-N=であり；
R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NH-COO-(C1-6アルキル)、-(C1-6アルキレン)-NH-CO-(C1-6アルキル)、又は-(C1-6アルキレン)-CO-N(C1-6アルキル)2であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
R1aは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
R1bは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000003
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000004
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000005
 R2は、C1-6アルキル、C3-8シクロアルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 Compound represented by formula (A-III):
Figure JPOXMLDOC01-appb-C000001
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000002
 Q is -CH=, -CH2- , -O-, or -N=;
R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl);
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
two R 1a may join together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
R 1a may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
R 1b may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000003
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000004
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000005
 R2 is C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof. 請求項１に記載の化合物であって、式（Ａ-ＩＶ）で表される化合物：
Figure JPOXMLDOC01-appb-C000006
 〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000007
 R1aは、ハロゲン原子、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NH-COO-(C1-6アルキル)、-(C1-6アルキレン)-NH-CO-(C1-6アルキル)、又は-(C1-6アルキレン)-CO-N(C1-6アルキル)2であり；
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R1cは、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)であり；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
2つのR1aは一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
R1aは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
R1bは、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシ、C1-6アルコキシC1-6アルキル、-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
少なくとも1つのR1bは水素原子以外であり；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
環Bは、下記式で表される基：
Figure JPOXMLDOC01-appb-C000008
 チアゾール又はチオフェンであり；
S、T、U及びVはそれぞれ独立して、-CH=、-CR1c=又は-N=であり；
Figure JPOXMLDOC01-appb-C000009
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5若しくは6員環ヘテロアリール、C3-8シクロアルキル又は下記式で表される環であり：
Figure JPOXMLDOC01-appb-C000010
 R5は、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ハロC1-6アルキル、ハロヒドロキシC1-6アルキル、C1-6アルコキシ、ハロC1-6アルコキシ、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル又は-SF5であり；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、1から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩。 The compound according to claim 1, which is represented by formula (A-IV):
Figure JPOXMLDOC01-appb-C000006
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000007
 R 1a is a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-NH-CO-(C 1-6 alkyl ) , or -(C 1-6 alkylene)-CO-N(C 1-6 alkyl) 2 ;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 1c is a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl);
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
two R 1a may join together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
R 1a may be combined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
W, X and Y are each independently -CR 1b = or -N=;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
at least one R 1b is other than a hydrogen atom;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
Ring B is a group represented by the following formula:
Figure JPOXMLDOC01-appb-C000008
 is a thiazole or a thiophene;
S, T, U and V are each independently -CH=, -CR 1c =, or -N=;
Figure JPOXMLDOC01-appb-C000009
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or a ring represented by the formula:
Figure JPOXMLDOC01-appb-C000010
 R5 is a hydrogen atom, C1-6 alkyl or C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, halo C 1-6 alkyl, halohydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl or -SF 5 ;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 1 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
Or a pharmacologically acceptable salt thereof. 請求項２に記載の化合物であって、R5が水素原子である化合物又はその薬理学的に許容される塩。 The compound according to claim 2, wherein R5 is a hydrogen atom, or a pharmacologically acceptable salt thereof. 請求項３に記載の化合物であって、L1が-NH-である化合物又はその薬理学的に許容される塩。 The compound according to claim 3, wherein L 1 is -NH-, or a pharmacologically acceptable salt thereof. 請求項４に記載の化合物であって、
Wが-CR1b=であり；
R1bが、水素原子、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、又は-(C1-6アルキレン)-NH-COO-(C1-6アルキル)であり；
S、U及びVがそれぞれ独立して、-CH=又は-CR1c=であり；
R1cが、ハロゲン原子、カルボキシ、シアノ、C1-6アルキル、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、C1-6アルコキシ、-CONH2、-NH-COO-(C1-6アルキル)、又は-NH-CO-NH-(C1-6アルキル)である化合物又はその薬理学的に許容される塩。 5. The compound according to claim 4,
W is -CR 1b =;
R 1b is a hydrogen atom, a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl), or -(C 1-6 alkylene)-NH-COO-(C 1-6 alkyl);
S, U and V are each independently -CH= or -CR 1c =;
A compound or a pharmacologically acceptable salt thereof, wherein R 1c is a halogen atom, carboxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CONH 2 , -NH-COO-(C 1-6 alkyl), or -NH-CO-NH-(C 1-6 alkyl). 請求項５に記載の化合物であって、
X及びYがそれぞれ独立して、-CR1b=であり；
Tが、-CH=又は-CR1c=であり；
pが1又は2である化合物又はその薬理学的に許容される塩。 6. The compound according to claim 5,
X and Y are each independently -CR 1b =;
T is -CH= or -CR 1c =;
A compound, or a pharmacologically acceptable salt thereof, wherein p is 1 or 2. 請求項６に記載の化合物であって、
nが、1又は2であり；
kが、0から2の整数である化合物又はその薬理学的に許容される塩。 7. The compound according to claim 6,
n is 1 or 2;
A compound or a pharmacologically acceptable salt thereof, wherein k is an integer of 0 to 2. 請求項７に記載の化合物であって、
R3及びR3’が水素原子であり；
pが1である化合物又はその薬理学的に許容される塩。 8. The compound according to claim 7,
R3 and R3 ' are hydrogen atoms;
A compound or a pharmacologically acceptable salt thereof, wherein p is 1. 請求項８に記載の化合物であって、
mが1から3の整数である化合物又はその薬理学的に許容される塩。 9. The compound according to claim 8,
A compound in which m is an integer of 1 to 3, or a pharmacologically acceptable salt thereof. 以下の化合物からなる群から選択される化合物：
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000013
 及び
Figure JPOXMLDOC01-appb-C000014
 又はその薬理学的に許容される塩。 A compound selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000013
 and
Figure JPOXMLDOC01-appb-C000014
 Or a pharmacologically acceptable salt thereof. 以下の化合物からなる群から選択される化合物：
Figure JPOXMLDOC01-appb-C000015
 及び
Figure JPOXMLDOC01-appb-C000016
 又はその薬理学的に許容される塩。 A compound selected from the group consisting of the following compounds:
Figure JPOXMLDOC01-appb-C000015
 and
Figure JPOXMLDOC01-appb-C000016
 Or a pharmacologically acceptable salt thereof. 請求項１～１１の何れか一項に記載の化合物又はその薬理学的に許容される塩、及び医薬品添加物を含む医薬組成物。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof, and a pharmaceutical additive. 甲状腺関連疾患の治療用医薬組成物である請求項１２に記載の医薬組成物。 The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for treating a thyroid-related disease. 請求項１３に記載の医薬組成物であって、甲状腺関連疾患が甲状腺機能亢進症、グレーブス病、又は甲状腺眼症である医薬組成物。 The pharmaceutical composition according to claim 13, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease. 式（Ａ-ＩＩ）で表される化合物：
Figure JPOXMLDOC01-appb-C000017
 〔式中、
環Aは、下記式(１)、(２)又は(３)で表される基であり：
Figure JPOXMLDOC01-appb-C000018
 W、X及びYはそれぞれ独立して、-CR1b=又は-N=であり；
Qは、-CRQ1=、-CRQ1RQ1’-、-O-、-N=又は-NRQ2-であり；
RQ1及びRQ1’はそれぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、C1-6アルキル又はハロC1-6アルキルであり；
RQ2は、水素原子、C1-6アルキル又はハロC1-6アルキルであり；
環Bは、5若しくは6員環ヘテロアリール又はベンゼンであり；
R1a及びR1cはそれぞれ独立して、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、ヒドロキシC1-6アルキル、カルボキシC1-6アルキル、アミノC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R1bは、水素原子、ハロゲン原子、ヒドロキシ、カルボキシ、シアノ、C1-6アルキル、C2-6アルケニル、C1-6アルコキシ、ハロC1-6アルキル、ヒドロキシC1-6アルキル、アミノC1-6アルキル、カルボキシC1-6アルキル、-NR7COR8、-NR7COOR9、-NR7CONR10R11、-CONR12R13、非置換又は置換基群Aから選択される1から6個の基で置換された-(C1-6アルキレン)-(3～8員環ヘテロシクロアルキル)、-(C1-6アルキレン)-NR7COR8、-(C1-6アルキレン)-NR7COOR9、-(C1-6アルキレン)-NR7CONR10R11又は-(C1-6アルキレン)-CONR12R13であり；
R7は、水素原子又はC1-6アルキルであり；
R8、R9、R10、R11、R12及びR13は、それぞれ独立して、水素原子又は以下の(i)～(v)からなる群から選択される基であり：
(i)非置換又は置換基群Aから選択される1から6個の基で置換されたC1-6アルキル、
(ii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキル、
(iii)非置換又は置換基群Aから選択される1から6個の基で置換されたC3-8シクロアルキルC1-6アルキル、
(iv)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリール、及び、
(v)非置換又は置換基群Aから選択される1から6個の基で置換されたC6-10アリールC1-6アルキル、
置換基群Aは、ハロゲン原子、シアノ、C1-6アルキル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルコキシ、C3-8シクロアルキルC1-6アルキル、及びC3-8シクロアルキルC1-6アルコキシからなる群であり；
置換基群Aから選択される2以上の基で置換される場合、それぞれの基は同一でも異なっていてもよく；
R10とR11は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
R12とR13は、一緒になって3～10員飽和複素環又は3～10員不飽和複素環を形成してもよく；
nは、1から3の整数であり；
nが2又は3である場合は、それぞれのR1aは互いに同一でも異なっていてもよく；
R1bが2つ以上存在する場合、それぞれのR1bは互いに同一でも異なっていてもよく；
kは、0から3の整数であり；
kが2又は3である場合は、それぞれのR1cは互いに同一でも異なっていてもよく；
2つのR1aは、一緒になって3～8員飽和炭素環、又は3～8員飽和複素環を形成してもよく；
Figure JPOXMLDOC01-appb-C000019
 は、単結合又は二重結合を表し；
環Zは、C6-10アリール、5～10員環ヘテロアリール又はC3-8シクロアルキルであり；
R2は、C1-6アルキル、ハロC1-6アルキル、C1-6アルコキシC1-6アルキル、C3-8シクロアルキル、3～8員環ヘテロシクロアルキル、又は-NR5R5’であり；
ただし、環Aが式(２)又は式(３)で表される基である場合、R2はハロC1-6アルキル、3～8員環ヘテロシクロアルキル、又は-NHR5であり；
R5及びR5'はそれぞれ独立して、水素原子、C1-6アルキル又はC3-8シクロアルキルであり；
R3及びR3'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
R4は、ハロゲン原子、シアノ、C1-6アルキル、C2-6アルケニル、C1-6アルコキシ、ハロC1-6アルキル、ハロC1-6アルコキシ、C3-8シクロアルキル、C3-8シクロアルキルC1-6アルキル、C6-10アリール、C6-10アリールC1-6アルキル、C6-10アリールC2-6アルキニル、C6-10アリールオキシ、C6-10アリールC1-6アルコキシ、5若しくは6員環ヘテロアリールC1-6アルキル、5若しくは6員環ヘテロアリールC2-6アルキニル、C3-8シクロアルキルC2-6アルキニル、ハロヒドロキシC1-6アルキル又は-SF5であり；
R1a、R1b又はR1cは、R3と一緒になって5～8員飽和複素環又は5～8員不飽和複素環を形成してもよく；
L1は、-CR6R6'-、-O-又は-NR6-であり；
R6及びR6'はそれぞれ独立して、水素原子又はC1-6アルキルであり；
mは、0から3の整数であり；
mが2又は3である場合は、それぞれのR4は互いに同一でも異なっていてもよく；
ただし、環Aが式(２)で表される基である場合、mは1から3の整数であり；
pは、0から3の整数であり；
pが2又は3である場合は、それぞれのR3及びR3'は互いに同一でも異なっていてもよい〕
又はその薬理学的に許容される塩を有効成分として含有するTSHR阻害剤。 Compound represented by formula (A-II):
Figure JPOXMLDOC01-appb-C000017
 [During the ceremony,
Ring A is a group represented by the following formula (1), (2) or (3):
Figure JPOXMLDOC01-appb-C000018
 W, X and Y are each independently -CR 1b = or -N=;
Q is -CR Q1 =, -CR Q1 R Q1' -, -O-, -N= or -NR Q2 -;
R and R are each independently a hydrogen atom, a halogen atom, hydroxy, C alkyl , or haloC alkyl;
R Q2 is a hydrogen atom, C 1-6 alkyl or haloC 1-6 alkyl;
Ring B is a 5- or 6-membered heteroaryl or benzene;
R 1a and R 1c each independently represent a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxyC 1-6 alkyl, aminoC 1-6 alkyl , -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted by 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -( C 1-6 alkylene )-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 1b is a hydrogen atom, a halogen atom, hydroxy, carboxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl, -NR 7 COR 8 , -NR 7 COOR 9 , -NR 7 CONR 10 R 11 , -CONR 12 R 13 , -(C 1-6 alkylene)-(3- to 8-membered heterocycloalkyl) unsubstituted or substituted by 1 to 6 groups selected from the substituent group A, -(C 1-6 alkylene)-NR 7 COR 8 , -(C 1-6 alkylene)-NR 7 COOR 9 , -(C 1-6 alkylene)-NR 7 CONR 10 R 11 or -(C 1-6 alkylene)-CONR 12 R 13 ;
R 7 is a hydrogen atom or C 1-6 alkyl;
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently a hydrogen atom or a group selected from the group consisting of the following (i) to (v):
(i) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(ii) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iii) C 3-8 cycloalkyl C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
(iv) C 6-10 aryl, unsubstituted or substituted with 1 to 6 groups selected from the substituent group A, and
(v) C 6-10 arylC 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from the substituent group A;
Substituent group A is the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 3-8 cycloalkyl C 1-6 alkyl, and C 3-8 cycloalkyl C 1-6 alkoxy;
When substituted with two or more groups selected from the substituent group A, each group may be the same or different;
R 10 and R 11 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
R 12 and R 13 may be joined together to form a 3- to 10-membered saturated heterocycle or a 3- to 10-membered unsaturated heterocycle;
n is an integer from 1 to 3;
When n is 2 or 3, each R 1a may be the same or different;
When two or more R 1b are present, each R 1b may be the same or different;
k is an integer from 0 to 3;
When k is 2 or 3, each R 1c may be the same or different;
two R 1a may be joined together to form a 3- to 8-membered saturated carbocyclic ring or a 3- to 8-membered saturated heterocyclic ring;
Figure JPOXMLDOC01-appb-C000019
 represents a single bond or a double bond;
Ring Z is C 6-10 aryl, 5-10 membered heteroaryl or C 3-8 cycloalkyl;
R2 is C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxyC1-6 alkyl, C3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, or -NR5R5 ' ;
However, when ring A is a group represented by formula (2) or formula (3), R2 is haloC1-6alkyl , 3- to 8-membered heterocycloalkyl, or -NHR5 ;
R5 and R5 ' are each independently a hydrogen atom, a C1-6 alkyl or a C3-8 cycloalkyl;
R3 and R3 ' are each independently a hydrogen atom or a C1-6 alkyl;
R 4 is a halogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 6-10 aryl C 2-6 alkynyl, C 6-10 aryloxy, C 6-10 aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl C 1-6 alkyl, 5- or 6-membered heteroaryl C 2-6 alkynyl, C 3-8 cycloalkyl C 2-6 alkynyl, halohydroxy C 1-6 alkyl or -SF 5 ;
R 1a , R 1b or R 1c may be joined with R 3 to form a 5- to 8-membered saturated heterocycle or a 5- to 8-membered unsaturated heterocycle;
L1 is -CR6R6'- , -O- or -NR6- ;
R 6 and R 6' are each independently a hydrogen atom or a C 1-6 alkyl;
m is an integer from 0 to 3;
When m is 2 or 3, each R 4 may be the same or different;
However, when ring A is a group represented by formula (2), m is an integer of 1 to 3;
p is an integer from 0 to 3;
When p is 2 or 3, R 3 and R 3′ may be the same or different.
or a pharmacologically acceptable salt thereof as an active ingredient.
PCT/JP2024/046100 2023-12-29 2024-12-26 N-substituted cyclic amide compound Pending WO2025143095A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010536934A (en) * 2007-08-31 2010-12-02 ナームローゼ・フエンノートチヤツプ・オルガノン TSH receptor antagonistic tetrahydroquinoline compound
WO2024005113A1 (en) * 2022-06-30 2024-01-04 キッセイ薬品工業株式会社 3,4-dihydroquinolin-2(1h)-one compound

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JP2010536934A (en) * 2007-08-31 2010-12-02 ナームローゼ・フエンノートチヤツプ・オルガノン TSH receptor antagonistic tetrahydroquinoline compound
WO2024005113A1 (en) * 2022-06-30 2024-01-04 キッセイ薬品工業株式会社 3,4-dihydroquinolin-2(1h)-one compound

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