WO2021201126A1 - Amide compound or salt thereof, pharmaceutical composition and histone deacetylase inhibitor - Google Patents

Amide compound or salt thereof, pharmaceutical composition and histone deacetylase inhibitor Download PDF

Info

Publication number
WO2021201126A1
WO2021201126A1 PCT/JP2021/013923 JP2021013923W WO2021201126A1 WO 2021201126 A1 WO2021201126 A1 WO 2021201126A1 JP 2021013923 W JP2021013923 W JP 2021013923W WO 2021201126 A1 WO2021201126 A1 WO 2021201126A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituent
group
alkyl group
aryl
heteroaryl
Prior art date
Application number
PCT/JP2021/013923
Other languages
French (fr)
Japanese (ja)
Inventor
上田　聡
田村　崇
大介 寺田
啓太 田中
Original Assignee
富士フイルム株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 富士フイルム株式会社 filed Critical 富士フイルム株式会社
Publication of WO2021201126A1 publication Critical patent/WO2021201126A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to an amide compound or a salt thereof having an HDAC (histone deacetylase) inhibitory action, a pharmaceutical composition containing the above amide compound or a salt thereof, and a histone deacetylase inhibitor.
  • HDAC histone deacetylase
  • HDAC is an enzyme that catalyzes the deacetylation of acetylated lysine residues in the N-terminal region of histones.
  • HDACs 1 to 11 Eleven types of isozymes (HDACs 1 to 11) are known for HDACs.
  • inhibition of HDAC is known to be involved in the development and progression of cancer (see Non-Patent Document 1).
  • isozyme-selective HDAC inhibitors are expected as therapeutic agents for various diseases (see Non-Patent Documents 2 and 3). From the above, HDAC inhibitors are expected as therapeutic agents for various diseases. Further, the compounds described in Patent Documents 1 to 4 are known.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2016-528226
  • Patent Document 2 US Patent Application Publication No. 2014/0350002
  • Patent Document 3 Japanese Patent Application Laid-Open No. 2018-515494
  • Patent Document 4 Japanese Patent Application Laid-Open No. 2006-522791
  • Non-Patent Document 1 Tatsuya Abe, Akita J. Med., Vol.36, p9-18, 2009
  • Non-Patent Document 2 Takayoshi Suzuki, Kyoto Prefectural University of Medicine Magazine, Vol.121, No.9, p461-467 , 2012
  • Non-Patent Document 3 Kyle V. Butler et al., J. Am. Chem. Soc., Vol.132, p10842-10846, 2010
  • An object to be solved by one embodiment of the present invention is to provide an amide compound having an HDAC inhibitory action or a salt thereof.
  • Another object to be solved by another embodiment of the present invention is to provide a pharmaceutical composition containing the amide compound or a salt thereof, or a histone deacetylase inhibitor.
  • an amide compound having a specific structure or a salt thereof has an HDAC inhibitory action, and have completed the present disclosure.
  • Means for solving the above problems include the following aspects. ⁇ 1> An amide compound represented by the following formula (I-1) or a salt thereof.
  • R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent.
  • All R 1 ⁇ R 4 are not hydrogen atoms at the same time, R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
  • R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
  • R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 5 is a fluorine atom, Two R 5 may be combined with each other to form a ring, R 6 represents a hydrogen atom or a C 1-10 alkyl group.
  • L1 represents 0 or 1.
  • R 1 ⁇ R 4 is an aromatic hetero ring which may have an aromatic hydrocarbon ring or a substituted group which may have a substituent which forms together is, it may have a substituent
  • R 1 ⁇ R 4 are the aromatic hydrocarbon ring or a substituent which may have on the aromatic hetero ring formed together is, Halogen atom, hydroxy group, a carboxy group, an optionally substituted C 1-10 alkyl group, an optionally substituted C 2-10 alkenyl group, an optionally substituted C 2- 10 Alkinyl group, C 3-8 cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent which may have a substituent.
  • C 3-8 cycloalkyl C 1-10 alkyl group, an optionally substituted aryl C 1-10 alkyl group, an optionally substituted heteroaryl C 1-10 alkyl group, a substituent a may be C 3-8 cycloalkyl C 2-10 alkenyl group, an optionally substituted aryl C 2-10 alkenyl group, an optionally substituted heteroaryl C 2-10 alkenyl group , an optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, a C 1-6 alkoxycarbonyl which may have a substituent Group, aryloxycarbonyl group which may have a substituent, -L 2- NR 51 R 52 , -L 2- NR 51 C (O) R 54 , -L 2- NR 51 C (O) NR 53 R At least one group selected from the group consisting of 54, -L 2- NR 51 SO 2 R 54 , -L 2- C (O)
  • R 51 , R 52 , R 53 and R 54 independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl which may have a substituent. It may have a group, a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a substituent.
  • the amide compound represented by the above formula (I-1) or a salt thereof is an amide compound represented by any of the following formulas (II-1) to (II-4) or a salt thereof.
  • R 11 is independently a halogen atom, a hydroxy group, a carboxy group, It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent.
  • L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
  • m1 represents an integer of 1 to 4.
  • R 12 is independently a halogen atom, a hydroxy group, a carboxy group, It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent.
  • L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
  • m2 represents 1 or 2.
  • X independently represents N, NH or NR 13.
  • R 13 is independently a halogen atom, a hydroxy group, a carboxy group, It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent.
  • C 3-8 cycloalkyl group an aryl group which may have a substituent, a heteroaryl group which may have a substituent, C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent.
  • L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
  • m3 represents an integer of 0 to 2.
  • R 14 to R 17 each independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent.
  • R 14 to R 17 become hydrogen atoms at the same time.
  • ⁇ 7> A pharmaceutical composition containing the amide compound according to any one of ⁇ 1> to ⁇ 6> or a salt thereof.
  • the pharmaceutical composition according to ⁇ 7> which is a therapeutic agent for a disease involving histone deacetylase.
  • ⁇ 9> A histone deacetylase inhibitor containing an amide compound represented by the following formula (I) or a salt thereof.
  • R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent.
  • R 02 is a C 1-10 alkyl group which may have a substituent
  • a C 2-6 alkenyl group which may have a substituent
  • a C 2-6 alkynyl group which may have a substituent and a substituent.
  • R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
  • R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 03 is a fluorine atom Two R 03s may be combined to form a ring.
  • R 04 represents a hydrogen atom or a C 1-10 alkyl group.
  • R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent.
  • All R 1 ⁇ R 4 are not hydrogen atoms at the same time, R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
  • R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
  • R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 5 is a fluorine atom, Two R 5 may be combined with each other to form a ring, R 6 represents a hydrogen atom or a C 1-10 alkyl group.
  • L1 represents an integer of 0 to 2.
  • R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent.
  • R 02 is a C 1-10 alkyl group which may have a substituent
  • a C 2-6 alkenyl group which may have a substituent
  • a C 2-6 alkynyl group which may have a substituent and a substituent.
  • R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
  • R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 03 is a fluorine atom Two R 03s may be combined to form a ring.
  • R 04 represents a hydrogen atom or a C 1-10 alkyl group.
  • R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent.
  • All R 1 ⁇ R 4 are not hydrogen atoms at the same time, R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
  • R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
  • R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 5 is a fluorine atom, Two R 5 may be combined with each other to form a ring, R 6 represents a hydrogen atom or a C 1-10 alkyl group.
  • L1 represents an integer of 0 to 2.
  • a disease comprising the step of administering the amide compound according to any one of ⁇ 1> to ⁇ 6> or a salt thereof to a subject (mammal including human, preferably human).
  • Treatment method for inflammatory bowel disease e.g., cancer, etc.
  • the histone deacetylase inhibitor according to ⁇ 9> or ⁇ 10>, or the metalloprotease inhibitor having Zn according to ⁇ 11> or ⁇ 12>, is a subject (mammalian including human,
  • a method for treating a disease eg, cancer, inflammatory bowel disease
  • comprising the step of administering to preferably a human.
  • ⁇ A-1> The amide compound according to any one of ⁇ 1> to ⁇ 6> or a salt thereof for producing a pharmaceutical composition.
  • ⁇ A-2> The amide compound according to any one of ⁇ 1> to ⁇ 6> for producing a therapeutic agent for a disease involving histone deacetylase (for example, cancer, inflammatory bowel disease). Or its salt.
  • ⁇ A-3> Use of the amide compound according to any one of ⁇ 1> to ⁇ 6> or a salt thereof for producing a therapeutic agent for a disease involving a metalloprotease having Zn.
  • ⁇ B-1> The amide compound according to any one of ⁇ 1> to ⁇ 6> or a salt thereof for use in a pharmaceutical composition.
  • ⁇ B-2> The amide compound according to any one of ⁇ 1> to ⁇ 6> for use in the treatment of diseases involving histone deacetylase (for example, cancer, inflammatory bowel disease). That salt.
  • ⁇ B-3> The amide compound according to any one of ⁇ 1> to ⁇ 6> or a salt thereof for treating a disease involving a metalloprotease having Zn.
  • an amide compound having an HDAD inhibitory effect or a salt thereof can be provided.
  • a pharmaceutical composition containing the amide compound or a salt thereof, or a histone deacetylase inhibitor can be provided.
  • the numerical range represented by using "-" in the present specification means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
  • the upper limit value or the lower limit value described in one numerical range may be replaced with the upper limit value or the lower limit value of another numerical range described stepwise. good.
  • the upper limit value or the lower limit value of the numerical range may be replaced with the value shown in the examples.
  • the term "process” is included in this term not only as an independent process but also as long as the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes.
  • the notation that does not describe substitution and non-substitution includes those having no substituent as well as those having a substituent.
  • the "alkyl group” includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group).
  • the chemical structural formula in the present specification may be described by a simplified structural formula in which a hydrogen atom is omitted.
  • “% by mass” and “% by weight” are synonymous, and “parts by mass” and “parts by weight” are synonymous.
  • a combination of two or more preferred embodiments is a more preferred embodiment.
  • C xy means that the number of carbon atoms (also referred to as “the number of carbon atoms”) is xy, and for example, the C 1-6 alkyl group has 1 to 1 carbon atoms. Represents an alkyl group of 6.
  • the "alkyl group” in the present disclosure may be a linear alkyl group or a branched alkyl group unless otherwise specified.
  • the alkenyl group and the alkynyl group are the same as those of the alkyl group.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl groups are direct groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3-pentyl and hexyl groups. It means a chain or branched C 1-6 alkyl group.
  • the C 1-8 alkyl group is a linear or branched C 1-8 alkyl such as the above C 1-6 alkyl group, heptyl, 2-methylheptyl, 2-methyl-4-heptyl and octyl group. Means a group.
  • the C 1-10 alkyl group means a linear or branched C 1-10 alkyl group such as the above C 1-8 alkyl group, 2-ethylhexyl, nonyl and decyl group.
  • the C 2-6 alkenyl group is a linear or branched C 2-6 alkenyl group such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. Means a group.
  • the C 2-10 alkenyl group means a linear or branched C 2-10 alkenyl group such as the C 2-6 alkenyl group, peptenyl, octenyl, nonenyl, and decenyl group.
  • the C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.
  • the C 2-10 alkynyl group means a linear or branched C 2-10 alkynyl group such as the above-mentioned C 2-6 alkynyl group, pentynyl, octynyl, noninyl, decynyl group.
  • the C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
  • the C 3-8 cycloalkenyl group means a C 3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl groups.
  • C 3-8 Cycloalkyl C 1-10 Alkyl groups are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclohexylethyl, 1-cyclohexylethyl, 3-cyclohexyl.
  • C 1-10 alkyl group to which a C 3-8 cycloalkyl group such as propyl and 10-cyclohexyldecyl group is bonded.
  • C 3-8 Cycloalkyl C 2-10 Alkyl groups are 2-cyclopropyl ethenyl, 2-cyclobutyl ethenyl, 2-cyclopentyl ethenyl, 2-cyclohexyl ethenyl, 2-cycloheptyl ethenyl, 2- It means a C 2-10 alkenyl group to which a C 3-8 cycloalkyl group such as cyclooctyl ethenyl, 1-cyclohexyl ethenyl, 3-cyclohexyl allyl and 10-cyclohexyl-9-decenyl group is attached.
  • the crosslinked hydrocarbon ring groups include adamantyl groups, bicyclo [2.1.0] pentyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.1] octyl and bicyclo [5.2.0].
  • Nonyl group and the like can be mentioned.
  • Examples of the spiro-type hydrocarbon ring group include a spiro [3.3] heptyl group and a spiro [3.4] octyl group.
  • the C 1-6 alkylene groups are methylene, ethylene, 1,2-propylene, 1,3-propylene, dimethylmethylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, dimethylethylene, 1 , 5-Pentylene, 2,2-dimethyl-1,3-pentylene, 1,6-hexylene group and other linear or branched C 1-6 alkylene groups.
  • the aryl group means an aromatic hydrocarbon group, and may be a fused aromatic hydrocarbon group, preferably a phenyl group or a naphthyl group. Further, the aromatic hydrocarbon ring may be a fused aromatic hydrocarbon ring, and is preferably a benzene ring or a naphthalene ring.
  • the aryl C 1-6 alkyl group means a benzyl, diphenylmethyl, trityl, phenethyl, aryl C 1-6 alkyl group such as 2-phenylpropyl, 3-phenylpropyl and naphthylmethyl groups.
  • Aryl C 1-10 alkyl groups are aryl C 1-6 alkyl groups such as benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl, 6-phenylhexyl, 10phenyldecyl and naphthylmethyl groups. Means.
  • the aryl C 2-6 alkenyl group is 2-phenylvinyl, 1-phenylvinyl, 3-phenylallyl, 3-phenyl-1-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6 -Phenyl-5 means an aryl C 2-6 alkenyl group such as hexenyl and 2-naphthylvinyl groups.
  • the aryl C 2-10 alkenyl group is 2-phenylvinyl, 1-phenylvinyl, 3-phenylallyl, 3-phenyl-1-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6 It means an aryl C 2-10 alkenyl group such as -phenyl-5-hexenyl, 10-phenyl-9-decenyl and 2-naphthylvinyl group.
  • the heteroaryl C 2-6 alkenyl group is 2- (2-thienyl) vinyl, 2- (2-furanyl) vinyl, 2- (2-pyridyl) vinyl, 2- (2-thiazolyl) vinyl, 3-( 2-thienyl) allyl, 3- (2-thienyl) -1-propenyl, 4- (2-thienyl) -3-butenyl, 5- (2-thienyl) -4-pentenyl and 6- (2-thienyl)- It means an aryl C 2-6 alkenyl group such as a 5-hexenyl group.
  • the heteroaryl C 2-6 alkenyl group is 2- (2-thienyl) vinyl, 2- (2-furanyl) vinyl, 2- (2-pyridyl) vinyl, 2- (2-thiazolyl) vinyl, 3-( 2-thienyl) allyl, 3- (2-thienyl) -1-propenyl, 4- (2-thienyl) -3-butenyl, 5- (2-thienyl) -4-pentenyl, 6- (2-thienyl)- It means an aryl C 2-10 alkenyl group such as 5-hexenyl, 10- (2-thienyl) -9-decenyl group.
  • the C 1-6 alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy, cyclohexyloxy, hexyloxy and cyclohexyloxy groups. It means a linear, cyclic or branched C 1-6 alkyloxy group.
  • the C 1-6 alkoxy C 1-10 alkyl group means a C 1-6 alkyloxy C 1-10 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
  • the aryl C 1-6 alkoxy C 1-6 alkyl group means an aryl C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyl oxymethyl group.
  • the aryloxy group is preferably a phenoxy group or a naphthyloxy group.
  • the acyl group is preferably a formyl group, a succinyl group, a glutalyl group, a maleoil group, a phthaloyl group, a C 2-6 alkanoyl group, an aroyl group, a heterocyclic carbonyl group or a ( ⁇ -substituted) aminoacetyl group.
  • the C 2-6 alkanoyl group means a linear or branched C 2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
  • the aloyl group means an aromatic acyl group, and is preferably a benzoyl group or a naphthoyl group.
  • the heterocyclic carbonyl group means a fluoroyl, tenoyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl or pyridinylcarbonyl group.
  • the ( ⁇ -substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, aspartic acid, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine.
  • Amino acids such as tyrosine, tryptophan, proline and hydroxyproline
  • the acyl C 1-6 alkyl group means an acyl C 1-6 alkyl group such as acetylmethyl, benzoylmethyl and 1-benzoylethyl group.
  • acyloxy C 1-6 alkyl group means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, an acyloxy C 1-6 alkyl group such as benzoyloxymethyl and 1 (benzoyloxy) ethyl.
  • the C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl group.
  • the aryl C 1-6 alkoxycarbonyl group means an aryl C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
  • the aryloxycarbonyl group is preferably a phenyloxycarbonyl group or a naphthyloxycarbonyl group.
  • C 1-6 alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, sec-butylamino, tert-butylamino, cyclobutylamino, pentylamino, cyclopentylamino, hexyl. It means a linear, branched or cyclic C 1-6 alkylamino group such as amino and cyclohexylamino groups.
  • the di (C 1-6 alkyl) amino groups are dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino, Linear, branched or cyclic di (C 1 ) such as (methyl) (propyl) amino, (cyclopropyl) (methyl) amino, (cyclobutyl) (methyl) amino and (cyclohexyl) (methyl) amino groups.
  • -6 alkyl means an amino group.
  • the C 2-7 alkylamide group means a linear or branched C 2-7 alkylamide group such as an acetylamide, a propionylamide, a valerylamide, an isovalerylamide and a pivaloylamide group.
  • the C 7-11 arylamide group means a C 7-11 arylamide group such as a phenylamide and a naphthylamide group.
  • the C 1-6 alkyl sulfonyl group means a linear, branched or cyclic C 1-6 alkane sulfonyl group such as methanesulfonyl, ethanesulfonyl, hexanesulfonyl and cyclohexanesulfonyl groups.
  • the heteroaryl group means an aromatic heterocyclic group, and may be an aromatic heterocyclic group in which an aromatic heterocycle, an aromatic hydrocarbon ring, a heteroaliphatic ring, or an aliphatic hydrocarbon ring is fused.
  • the aromatic hetero ring means an aromatic ring having a hetero atom as a ring member, and even if the aromatic hetero ring, the aromatic hydrocarbon ring, the heteroaromatic ring or the aliphatic hydrocarbon ring is fused.
  • the monocyclic nitrogen-containing heteroaryl group has an aromatic ring containing at least one nitrogen atom such as pyrrolinyl, pyrrolyl, tetrahydropyridyl, pyridyl, imidazolinyl, imidazolyl, pyrazolinyl, pyrazolyl, pyrazinyl, pyridadinyl, pyrimidinyl, triazolyl and tetrazolyl groups. It means a heteroaryl group having a group property (this heteroaryl group may be partially saturated). This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
  • the monocyclic oxygen-containing heteroaryl group is a heteroaryl group in which the ring containing at least one oxygen atom such as a furanyl or pyranyl group has aromaticity (this heteroaryl group may be partially saturated. ) Means.
  • This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
  • the monocyclic sulfur-containing heteroaryl group is a heteroaryl group having an aromatic ring containing at least one sulfur atom such as a thienyl group (this heteroaryl group may be partially saturated). means.
  • This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
  • the monocyclic nitrogen-containing oxygen-containing heteroaryl group means an oxazolyl, an isooxazolyl, an oxadiazolyl group, or the like. This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
  • the monocyclic nitrogen-containing sulfur-containing heteroaryl group means a thiazolyl, isothiazolyl, thiadiazolyl group or the like. This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
  • Bicyclic nitrogen-containing heteroaryl groups include indolyl, isoindrill, benzimidazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthylidineyl.
  • the bicyclic oxygen-containing heteroaryl group is a bicyclic heteroaryl group in which the ring containing at least one oxygen atom such as benzofuranyl, isobenzofuranyl and chromenyl group has aromaticity (this heteroaryl group is , May be partially saturated.)
  • a bicyclic sulfur-containing heteroaryl group is a bicyclic heteroaryl group in which a ring containing at least one sulfur atom such as a benzothienyl group has aromaticity (this heteroaryl group is partially saturated. May be.) Means.
  • the bicyclic nitrogen-containing oxygen-containing heteroaryl groups are benzoxazolyl, benzoisooxazolyl, benzoxadiazolyl, dihydropyranopyridyl, dihydrodioxynopyridyl, dihydropyridoxazienyl, 3,4.
  • bicyclic heteroaryl group having an aromatic ring containing an oxygen atom (this heteroaryl group may be partially saturated).
  • the bicyclic nitrogen-containing sulfur-containing heteroaryl group has an aromatic ring containing at least one nitrogen atom and at least one sulfur atom such as benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl and thiazolopyridyl group. It means a dicyclic heteroaryl group having a property (this heteroaryl group may be partially saturated).
  • the heteroaliphatic ring group is a nitrogen-containing heteroaliphatic ring group, an oxygen-containing heteroaliphatic ring group, a sulfur-containing heteroaliphatic ring group, a nitrogen-containing oxygen-containing heteroaliphatic ring group, and a nitrogen-containing sulfur-containing heteroaliphatic ring. It means a group, a heterobridged ring group or a heterospiro ring group.
  • the heteroaliphatic ring means an aliphatic ring having a heteroatom as a ring member, and is a nitrogen-containing heteroaliphatic ring, an oxygen-containing heteroaliphatic ring, a sulfur-containing heteroaliphatic ring, and a nitrogen-containing oxygen-containing heterofat.
  • Preferred examples thereof include a group ring, a nitrogen-containing sulfur-containing heteroaliphatic ring, a heterobridged ring, and a heterospiro ring.
  • the nitrogen-containing heteroaliphatic ring group is a hetero whose ring containing at least one nitrogen atom such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, pyrazolydinyl, piperazinyl and homopiperazinyl group has no aromaticity. It means an aliphatic ring group.
  • This nitrogen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.
  • the oxygen-containing heteroaliphatic ring group means a tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, 1,3-dioxanyl group or the like. This oxygen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.
  • the sulfur-containing heteroaliphatic ring group means a tetrahydrothienyl group, a tetrahydrothiopyranyl group, or the like. This sulfur-containing heteroaliphatic ring group contains a group in which a sulfur atom is oxidized, and may be further condensed with another aromatic ring or an aliphatic ring.
  • the nitrogen-containing oxygen-containing heteroaliphatic ring group means a morpholinyl group, a 1,4-oxazepanyl group, or the like. This nitrogen-containing oxygen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.
  • the nitrogen-containing sulfur-containing heteroaliphatic ring group means a thiomorpholinyl group or the like. This nitrogen-containing sulfur-containing heteroaliphatic ring group contains a group in which a sulfur atom is oxidized, and may be further condensed with another aromatic ring or an aliphatic ring.
  • Heterobridged ring groups are 3-aza-6-oxabicyclo [3.1.1] heptyl, 3-aza-8-oxabicyclo [3.2.1] octyl and 8-aza-3-oxabicyclo [ 3.2.1] Means a heterocrosslinked ring group containing at least one heteroatom (eg, oxygen atom, nitrogen atom, sulfur atom) such as an octyl group.
  • the heterobridged ring means a ring in which two or more heteroaliphatic rings are fused, or a ring in which one or more heteroaliphatic rings and one or more aliphatic hydrocarbon rings are fused.
  • Heterospiro ring groups include 2-azaspiro [3.3] heptyl, 2-oxaspiro [3.3] heptyl, 6-aza-2-oxaspiro [3.3] heptyl, 1-azaspiro [4.5] decyl and 1-Oxaspiro [4.5] means a heterospirocyclic group containing at least one heteroatom (eg, oxygen atom, nitrogen atom, sulfur atom) such as a decyl group.
  • heteroatom eg, oxygen atom, nitrogen atom, sulfur atom
  • the heteroaliphatic ring C 1-8 alkyl group is a hetero such as pyrrolidinyl methyl group, pyrrolidinyl ethyl group, pyrrolidinyl propyl group, pyrrolidinyl octyl group, piperidinyl methyl group and tetrahydrofuranyl methyl group. It means a linear, branched or cyclic C 1-8 alkyl group to which an aliphatic ring group is bonded.
  • Hydroxy group protecting groups include all groups that can be used as conventional hydroxy group protecting groups, such as T.I. W. TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, The groups described in INC.) Can be mentioned. Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy C 1-6.
  • Examples thereof include an alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an aryl C 1-6 alkoxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group.
  • the monosubstituted or unsubstituted amino group protecting groups include all groups that can be used as ordinary amino group protecting groups, for example, T.I. W. TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons , INC.). Specifically, for example, an aryl C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an aryl C 1-6 alkoxycarbonyl group, and an aryloxycarbonyl group. , C 1-6 alkylsulfonyl group, arylsulfonyl group or silyl group.
  • Carboxy-protecting groups include all groups that can be used as conventional carboxy-protecting groups, such as T.I. W. TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007, John Wiley & Sons , INC.). Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy C. Examples thereof include 1-6 alkyl groups, acyl C 1-6 alkyl groups, acyloxy C 1-6 alkyl groups and silyl groups.
  • prevention means inhibition of onset, reduction of onset risk, delay on onset, and the like.
  • treatment means improvement or suppression of progression of a disease or condition of interest.
  • treatment means prevention or treatment for various diseases.
  • the therapeutic agent means a substance provided for the purpose of prevention or treatment for various diseases.
  • a disease involving histone deacetylase means any disease that can be prevented or treated by inhibiting HDAC.
  • the amide compound or a salt thereof is an amide compound represented by the following formula (I-1) or a salt thereof.
  • R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent.
  • All R 1 ⁇ R 4 are not hydrogen atoms at the same time, R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
  • R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
  • R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 5 is a fluorine atom, Two R 5 may be combined with each other to form a ring, R 6 represents a hydrogen atom or a C 1-10 alkyl group.
  • L1 represents 0 or 1.
  • the present inventors have found that the amide compound represented by the formula (I-1) or a salt thereof has an HDAC inhibitory effect.
  • the amide compound or a salt thereof according to the present disclosure can be suitably used as a therapeutic agent for diseases involving histone deacetylase. Further, the amide compound or a salt thereof according to the present disclosure can be suitably used as a histone deacetylase inhibitor or a metalloprotease inhibitor having Zn.
  • R 5 in the formula (I-1) is preferably a hydrogen atom or a fluorine atom, and more preferably all R 5s are fluorine atoms.
  • R 6 in the formula (I-1) from the viewpoint of HDAC inhibitory, hydrogen atom, or, preferably a methyl group, and more preferably a hydrogen atom.
  • L1 in the formula (I-1) is preferably 1 from the viewpoint of HDAC inhibitory property.
  • R 1 and R 2 are integrated to form an alkylidene group which may have a substituent
  • R 3 and R are R.
  • 4 is a hydrogen atom
  • R 1 to R 4 are united to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
  • R 1 to R 4 are integrally formed to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent. More preferably, R 1 to R 4 are integrated to form an aromatic hydrocarbon ring which may have a substituent.
  • aromatic hydrocarbon ring which may have a substituent or the aromatic heterocycle which may have a substituent formed by integrating R 1 to R 4 is from the viewpoint of HDAC inhibitory property.
  • R 1 to R 4 of the formula (I-1) may have are not particularly limited, but are a heavy hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl.
  • R st independently represents a hydrogen atom, an alkyl group or an aryl group.
  • two or more substituents may be bonded to form a ring structure.
  • the carbon number of the substituent is preferably 0 to 50, more preferably 1 to 30, further preferably 1 to 25, and particularly preferably 1 to 20.
  • R 1 ⁇ R 4 is R 11 also may be a substituent (described later have on the aromatic hydrocarbon ring or the aromatic hetero ring formed together of the formula (I-1), R 12 , R The same applies to substituents on aromatic hydrocarbon rings or aromatic heterocycles such as 13.) From the viewpoint of HDAC inhibitory property.
  • Halogen atom, hydroxy group, carboxy group It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent.
  • Examples of the aromatic hydrocarbon ring or the substituent which may have on the aromatic heterocycle R 1 ⁇ R 4 form together, It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May be C 3-8 cycloalkyl group, -L 2- NR 51 R 52 , -L 2- NR 51 C (O) R 54 , -L 2- NR 51 C (O) NR 53 R 54 , -L 2- NR 51 SO 2 R 54 , -L 2- C (O) NR 51 R 52 , or -L 2- SO 2 NR 51 R 52 is preferable. -L 2- NR 51 C (O) R 54 is particularly preferable.
  • R 51 , R 52 , R 53 and R 54 may each independently have a hydrogen atom and one or more substituents selected from the substituent group A 1.
  • R 51 in view of the HDAC inhibitory, hydrogen atom, or is preferably one or more may have a substituent group C 1-10 alkyl group selected from Substituent Group A 1, a hydrogen atom Is more preferable.
  • R 52 and R 54 are independently from the C 1-10 alkyl group, substituent group A 1 , which may have one or more substituents selected from the substituent group A 1 from the viewpoint of HDAC inhibitory property.
  • substituent group A 1 which may have one or more substituents selected from the substituent group A 1 from the viewpoint of HDAC inhibitory property.
  • one or more optionally substituted aryl group selected, or is preferably one or more may have a substituent group heteroaryl group selected from substituent group a 1,
  • One or more optionally substituted aryl group selected from Substituent Group A 1, or, is a heteroaryl group which may have one or more substituents selected from Substituent Group A 1 Is more preferable.
  • the aryl group a phenyl group and a naphthyl group are preferable.
  • R 53 is preferably a hydrogen atom or a C 1-10 alkyl group which may have one or more substituents selected from the substituent group A 1, and is preferably a substituent. and more preferably have one or more substituents selected from the group a 1 is optionally C 1-10 alkyl group.
  • a C 1-10 alkylene group which may have a substituent is preferable, a C 1-6 alkylene group which may have a substituent is preferable, and C 1 which may have a substituent is preferable.
  • the alkylene group is more preferable, and the methylene group is particularly preferable from the viewpoint of HDAC inhibitory property.
  • Preferred substituents in L 2 are halogen atom, hydroxy group, carboxy group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-6 alkoxy group, C 1-6.
  • Examples thereof include an alkoxy C 1-10 alkyl group and a C 1-6 alkoxycarbonyl group, which may have a plurality of substituents.
  • a halogen atom, a hydroxy group, a carboxy group, and a C 1-10 alkyl group are preferable.
  • Substituent group A 1 Halogen atom, hydroxy group, carboxy group, an amino group, one or more may have a substituent group C 1-6 alkylamino group selected from substituent group B 1, one selected from substituent group B 1 Di (C 1-6 alkyl) amino group which may have the above-mentioned substituents, C 1-10 alkyl groups which may have one or more substituents selected from the substituent group B 1 , and substituents.
  • one or more may have a substituent group C 2-10 alkenyl group selected from the group B 1, which may have one or more substituents selected from substituent group B 1 C 2-10 alkynyl group, which may have one or more substituents selected from substituent group B 1 C 3-8 cycloalkyl group,
  • substituent group B 1 may have substituent group B 1 C 2-10 alkynyl group, which may have one or more substituents selected from substituent group B 1 C 3-8 cycloalkyl group
  • Have one or more may have a substituent C 3-8 cycloalkyl C 1-10 alkyl group, one or more substituents selected from substituent group B 1 selected from substituent group B 1 May have an aryl C 1-10 alkyl group, a heteroaryl C 1-10 alkyl group which may have one or more
  • One or more may have a substituent group C 1-6 alkoxy group selected from substituent group B 1, which may have one or more substituents selected from substituent group B 1 C 1- 6 alkoxy C 1-10 alkyl group which may have one or more substituents selected from substituent group B 1 C 1-6 alkoxycarbonyl group, one or more substituents selected from substituent group B 1 an aryloxy group which may have a group, one or more may have a substituent group C 2-7 alkyl amide group selected from substituent group B 1, one selected from substituent group B 1 A C 7-11 arylamide group which may have the above substituents.
  • the substituent group A 1 includes a C 1-10 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 cycloalkyl C 1-10 alkyl group, an aryl C 1-10 alkyl group, and a heteroaryl C 1-10. Alkyl groups are preferred.
  • Substituent group B 1 Halogen atom, hydroxy group, carboxy group, amino group, C 1-6 alkyl amino group, di (C 1-6 alkyl) amino group, C 1-10 alkyl group, C 3-8 cycloalkyl group, aryl group, hetero Aryl group, C 1-6 alkoxy group, C 2-7 alkylamide group, C 7-11 arylamide group.
  • Examples of the salt of the amide compound represented by the formula (I-1) include commonly known salts of basic groups such as amino groups, salts of acidic groups such as hydroxy groups and carboxy groups, and the like. can. Preferred salts include pharmacologically acceptable salts. Hereinafter, the same applies to compounds having other structures.
  • the amide compound represented by the above formula (I-1) or a salt thereof is an amide compound represented by any of the following formulas (II-1) to (II-4) or a salt thereof from the viewpoint of HDAC inhibitory property. It is preferably a salt, more preferably an amide compound represented by any of the following formulas (II-1) to (II-3) or a salt thereof, and the following formula (II-1) or formula (II-1). It is more preferably an amide compound represented by II-2) or a salt thereof.
  • R 11 is independently a halogen atom, a hydroxy group, a carboxy group, It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent.
  • It may have a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, or a substituent.
  • a heteroaryl group L 2 represents an alkylene group (preferably a straight chain) which may have a single bond or a substituent.
  • m1 represents an integer of 1 to 4.
  • R 11 in the above formula (II-1) is on the above aromatic hydrocarbon ring or the above aromatic heterocycle formed by integrally forming R 1 to R 4 in the above formula (I-1). This is the same as the preferred embodiment of the substituent which may be used.
  • the substituents represented by R 11 have the same meaning and the same suitable range unless otherwise specified.
  • m1 in the above formula (II-1) is preferably 1 or 2, and more preferably 1.
  • the substitution position of R 11 in the above formula (II-1) is preferably the position represented by the following formula (II-1A) from the viewpoint of HDAC inhibitory property. That is, the compound represented by the above formula (II-1) is preferably a compound represented by the following formula (II-1A) from the viewpoint of HDAC inhibitory property.
  • R 12 has the same meaning as R 11 described above, and the preferred embodiment is also the same.
  • R 51 , R 52 , R 53 and R 54 are synonymous with the above-mentioned R 51 , R 52 , R 53 and R 54 , and the preferred embodiments are also the same.
  • L 2 has the same meaning as L 2 described above, and the preferred embodiment is also the same.
  • m2 represents 1 or 2.
  • R 12 in the above formula (II-2) is on the above aromatic hydrocarbon ring or the above aromatic hetero ring formed by integrally forming R 1 to R 4 in the above formula (I-1). This is the same as the preferred embodiment of the substituent which may be used.
  • the substituents represented by R 11 have the same meaning and the same suitable range unless otherwise specified.
  • the m2 in the above formula (II-2) is preferably 1 from the viewpoint of HDAC inhibitory property.
  • the substitution position of R 12 in the above formula (II-2) is preferably the position shown in the following formula (II-2A) from the viewpoint of HDAC inhibitory property. That is, the compound represented by the above formula (II-2) is preferably a compound represented by the following formula (II-2A) from the viewpoint of HDAC inhibitory property.
  • X independently represents N, NH or NR 13.
  • R 13 has the same meaning as R 11 described above, and the preferred embodiment is also the same.
  • R 51 , R 52 , R 53 and R 54 are synonymous with the above-mentioned R 51 , R 52 , R 53 and R 54 , and the preferred embodiments are also the same.
  • L 2 has the same meaning as L 2 described above, and the preferred embodiment is also the same.
  • m3 represents an integer of 0 to 2.
  • X in the above formula (II-3) it is preferable that one X is N and the other X is NH.
  • m3 in the above formula (II-3) is preferably 0 or 1, and more preferably 0.
  • the compound represented by the above formula (II-3) is preferably a compound represented by the following formula (II-3A) from the viewpoint of HDAC inhibitory property.
  • R 13 in the above formula (II-3) is the same as the preferred embodiment of R 11 in the above formula (II-1). Further, among them, R 13 in the above Formula (II-3), from the viewpoint of HDAC inhibitory, one or more substituents which may C 1-10 optionally alkyl substituted by selected from substituent group A 3 group, substituted with one or more optionally substituted with a substituent C 2-6 alkenyl group, one or more substituents selected from the substituent group a 3 is selected from the substituent group a 3 which may be C 2-6 alkynyl group, or is preferably one or more substituents which may be an amide group substituted in selected from substituent group a 3.
  • R 14 to R 17 are independent halogen atoms, hydroxy groups, carboxy groups, It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent.
  • It may have a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, or a substituent.
  • L 2 represents an alkylene group which may have a single bond or a substituent.
  • R 14 and R 15 may be integrated, or R 16 and R 17 may be integrated to form a C 1-6 alkylidene group which may have a substituent. However, not all of R 14 to R 17 become hydrogen atoms at the same time.
  • ⁇ Substituent group A 4 An aryl group which may have a substituent and a heteroaryl group which may have a substituent.
  • R 14 and R 15 in view of the HDAC inhibitory, by bonding with R 14 and R 15, have one or more substituents selected from Substituent Group A 1 described above It is also a phenylmethylidene group, or a 2-thienylmethylidene group which may have one or more substituents selected from the above-mentioned substituent group A 1 , and R 16 and R 17 are hydrogens. It is particularly preferred to be an atom.
  • the method for synthesizing the amide compound represented by the formula (I-1) is not particularly limited, but for example, an isoindoline compound or a pyrrolidine compound is reacted with 3,3,3-trifluoro-2-hydroxypropanoic acid. , A method for obtaining an amide compound represented by the formula (I-1) is preferably mentioned. Further, the isoindoline compound or the pyrrolidine compound may be synthesized by converting a substituent or the like by a known method, or a cross-coupling reaction of an aromatic compound such as Suzuki-Miyaura coupling may be carried out, if necessary.
  • each raw material compound can be synthesized by using a known method or by referring to a known method.
  • the amide compound represented by the formula (I-1) can be used as a salt of the amide compound represented by the formula (1) by a known salt forming method.
  • the amide compound represented by the formula (1) can also be purified by a known purification method such as column chromatography, thin layer chromatography, recrystallization and reprecipitation.
  • amide compounds and their salts represented by formula (I-1) has the formula (I-1) and hydroxy groups of the carbonyl group in (R 5) 3-position ⁇ on the side where C- is attached is It is preferably a (S) body.
  • a known solvent is used for the method for synthesizing the amide compound represented by the above formula (I-1) and its salt, and the method for purifying the amide compound represented by the above formula (I-1) and its salt. Can be done. Moreover, you may use a known solvent as a poor solvent in recrystallization, reprecipitation and the like.
  • the solvent is not particularly limited, and water and an organic solvent can be used. Examples of the organic solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, sulfoxides, carboxylic acids, aromatic hydrocarbons and the like.
  • Pentane, hexane, cyclohexane and the like are preferably used as the aliphatic hydrocarbons.
  • the halogenated hydrocarbons include methylene chloride, chloroform, dichloroethane and the like.
  • Preferable examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol, ethylene glycol, diethylene glycol, triethylene glycol, and propylene glycol.
  • ethers include diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and the like.
  • ketones include acetone, 2-butanone, 4-methyl-2-pentanone and the like.
  • esters include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, cyclohexyl acetate, and amyl acetate.
  • amides include N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone.
  • sulfoxides include dimethyl sulfoxide and the like.
  • carboxylic acids include formic acid, acetic acid, and trifluoroacetic acid.
  • aromatic hydrocarbons include benzene, toluene, and xylene.
  • the histone deacetylase inhibitor according to the present disclosure or the metalloprotease inhibitor having Zn according to the present disclosure contains an amide compound represented by the following formula (I) or a salt thereof.
  • the metalloprotease having Zn is a peptide bond hydrolase having a zinc ion in the catalytic mechanism. Many metalloproteinases have zinc ions.
  • R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent.
  • R 02 is a C 1-10 alkyl group which may have a substituent
  • a C 2-6 alkenyl group which may have a substituent
  • a C 2-6 alkynyl group which may have a substituent and a substituent.
  • R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
  • R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 03 is a fluorine atom Two R 03s may be combined to form a ring.
  • R 04 represents a hydrogen atom or a C 1-10 alkyl group.
  • the amide compound represented by the above formula (I) or a salt thereof is represented by the following formula (I-01). It is preferably an amide compound represented by or a salt thereof.
  • R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent.
  • All R 1 ⁇ R 4 are not hydrogen atoms at the same time, R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
  • R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
  • R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom. At least one of R 5 is a fluorine atom, Two R 5 may be combined with each other to form a ring, R 6 represents a hydrogen atom or a C 1-10 alkyl group.
  • L1 represents an integer of 0 to 2.
  • a preferred embodiment of the amide compound represented by the above formula (I-01) or a salt thereof in the histone deacetylase inhibitor according to the present disclosure or the metalloprotease inhibitor having Zn according to the present disclosure is preferably L1.
  • L1 in the amide compound represented by the above formula (I-01) or a salt thereof is preferably 0 or 1, and more preferably 1.
  • the pharmaceutical composition according to the present disclosure includes an amide compound or a salt thereof according to the present disclosure, a histone deacetylase inhibitor, or a metalloprotease inhibitor having Zn.
  • the pharmaceutical composition according to the present disclosure can be suitably used as a therapeutic agent for diseases, particularly as a therapeutic agent for diseases associated with HDAC.
  • 18 types of HDAC are known and are classified into Class I, Class II, Class III, or Class IV.
  • Human class IHDACs include HDACs 1, 2, 3 and 8.
  • Human Class II HDAC includes HDAC 4, 5, 6, 7, 9 and 10.
  • the activity of human class IHDAC and human class IIHDAC is Zn 2+ dependent, and Zn 2+ is present in the enzyme active site.
  • the amide compound or a salt thereof according to the present disclosure is highly safe because it has a high inhibitory ability on human class IIHDAC and a low inhibitory ability on human class IIHDAC.
  • Conventional hydroxamic acid inhibitors inhibited all human class IHDAC and human class II HDAC, and were highly toxic. It is presumed that the amide compound or a salt thereof according to the present disclosure forms a chelate with Zn 2+ at the HDAC catalyst site and antagonizes the acetylated lysine of the substrate to inhibit its activity. Therefore, the amide compound or a salt thereof according to the present disclosure can be said to be a metalloprotease inhibitor having Zn.
  • the amide compound or a salt thereof according to the present disclosure has a high inhibitory ability of at least one of HDACs 6, 7 and 9, and a low inhibitory ability of at least one of HDACs 1 and 2. More specifically, the amide compound or a salt thereof according to the present disclosure has a high inhibitory ability of HDAC6 and a low inhibitory ability of HDAC1.
  • a disease involving HDAC a disease involving human class II HDAC is preferable, and a disease involving HDAC6 is particularly preferable. Since the amide compound or its salt and histone deacetylase inhibitor according to the present disclosure are excellent in the selective inhibitory ability of HDAC6, it is possible to create a drug having few side effects.
  • HDAC inflammatory bowel disease
  • the pharmaceutical composition according to the present disclosure is preferably a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis. It is presumed that the pharmaceutical composition according to the present disclosure can reduce the cells that cause inflammation and can reduce the production of inflammatory cytokines.
  • the subject of using the pharmaceutical composition according to the present disclosure includes, but is not limited to, animals such as mammals, for example, primates (eg, humans, monkeys, etc.).
  • the subject is preferably human.
  • the pharmaceutical composition according to the present disclosure can be formulated in various dosage forms.
  • the pharmaceutical composition according to the present disclosure may be appropriately mixed with pharmacologically acceptable additives.
  • the additive include known additives such as excipients, disintegrants, binders, lubricants, flavoring agents, colorants, flavoring agents, surfactants, coating agents, and plasticizers. These additives may be used alone or in combination of two or more.
  • silica gel column chromatography purification by silica gel column chromatography was performed using an automatic purification device ISOLERA (Biotage) or a medium pressure liquid chromatograph YFLC-Wprep2XY.N (Yamazen Corporation).
  • the carrier in silica gel column chromatography is SNAP KP-Sil Cartridge (Biotage), high flash columns W001, W002, W003, W004 or W005 (Yamazen Co., Ltd.) in basic silica gel column chromatography.
  • SNAP KP-NH Cartridge Biotage
  • HPLC High Performance Liquid Chromatography
  • H-Cube manufactured by Thales Nano
  • Initiator + or Initiator Sixty both manufactured by Biotage
  • the MS spectrum was measured using an ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization) method).
  • the NMR spectrum was measured using Bruker AV300 (manufactured by Bruker) or JNM-AL400 (manufactured by JEOL Ltd.) using tetramethylsilane as an internal reference, and the total ⁇ value was shown in ppm.
  • Phenylisocyanate (0.016 mL) was added to a solution of tert-butyl 5-aminoisoindoline-2-carboxylate (23 mg) in tetrahydrofuran (1.0 mL), and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature and hexane (5.0 mL) was added. After the solid matter was collected by filtration, trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes.
  • tert-butyl 5-bromoisoindoline-2-carboxylate 596 mg
  • phenyl formate 488 mg
  • palladium acetate 14 mg
  • tri-tert-butylphosphonium tetrafluoroborate 94 mg
  • triethylamine 0.584 mL
  • the toluene (2.0 mL) suspension was stirred in a sealed tube under a nitrogen atmosphere at 100 ° C. for 8 hours.
  • the reaction mixture was cooled to room temperature and ethyl acetate and water were added.
  • the organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 0010 the colorless oily (S) -N-((2- (3,3) 3) was used in the same manner as in Example 0010 except that acetic acid was used instead of 1H-indole-6-carboxylic acid. , 3-Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) acetamide (Am-11) was obtained.
  • Example 0010 a colorless oily (S) -2-methoxy-N- was used in the same manner as in Example 0010 except that 2-methoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-12) was obtained.
  • Example 0010 the colorless oily (S) -3,5- was carried out in the same manner as in Example 0010 except that 3,5-dimethoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. Dimethoxy-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-13) was obtained.
  • Example 0010 the colorless oily (S) -4-acetamide-N- was used in the same manner as in Example 0010 except that 4-acetamidobenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-14) was obtained.
  • Example 0010 the colorless oily (S) -3-methoxy-N- was used in the same manner as in Example 0010 except that 3-methoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-15) was obtained.
  • a 60% sodium hydride liquid paraffin dispersion (80 mg) was added to a solution of 1H-indole-3-carboxylic acid (161 mg) in N, N-dimethylformamide (1.5 mL) under ice-cooling, and the temperature was the same for 10 minutes. Stirred. 1-Bromo-2-methoxyethane (0.095 mL) was added, and the mixture was stirred at room temperature for 6 hours. A 10% (w / v) aqueous citric acid solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 0010 white was formed in the same manner as in Example 0010 except that 1- (2-methoxyethyl) -1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 in the same manner as in Example 0010, except that 2- (4- (dimethylamino) phenyl) cyclopropan-1-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • White solid 2- (4- (dimethylamino) phenyl) -N-((2-((S) -3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) Cyclopropan-1-carboxamide (Am-17) was obtained.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 1-propyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • 1-propyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 2-methyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • 2-methyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 1-isopropyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • 1-isopropyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 a colorless oily (S) -4-(in the same manner as in Example 0010 except that 4- (dimethylamino) benzoic acid was used instead of 1H-indole-6-carboxylic acid.
  • Dimethylamino) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-22) was obtained.
  • Example 0010 a colorless oily (S) -3-(in the same manner as in Example 0010 except that 3- (dimethylamino) benzoic acid was used instead of 1H-indole-6-carboxylic acid.
  • Dimethylamino) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-23) was obtained.
  • Example 0010 a white solid (S) -N- (S) -N- (in the same manner as in Example 0010, except that 1H-indole-2-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-2-carboxamide (Am-24) was obtained.
  • Example 0010 a white solid (S) -N-((2- (2-() was used in the same manner as in Example 0010 except that 1-naphthoic acid was used instead of 1H-indole-6-carboxylic acid. 3,3,3-Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1-naphthamide (Am-25) was obtained.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 1-benzyl-1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • 1-benzyl-1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 a white solid (S) -N- (S) -N- (in the same manner as in Example 0010 except that 1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-3-carboxamide (Am-27) was obtained.
  • Example 0010 a white solid (S) -N- (S) -N- (in the same manner as in Example 0010 except that 1H-indole-4-carboxylic acid was used instead of 1H-indole-6-carboxylic acid (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-4-carboxamide (Am-28) was obtained.
  • Example 0010 white was formed in the same manner as in Example 0010 except that 1- (2-hydroxyethyl) -1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Solid (S) -1- (2-Hydroxyethyl) -N-((2- (3,3,3-trifluoro-2-hydroxypropanol) isoindoline-5-yl) methyl) -1H-indole -3-Carboxamide (Am-29) was obtained.
  • Example 0010 the same method as in Example 0010 except that 1- (2-amino-2-oxoethyl) -1H-indole-3-carboxylic acid is used instead of 1H-indole-6-carboxylic acid. Then, the white solid (S) -1- (2-amino-2-oxoethyl) -N- ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl)) Methyl) -1H-indole-3-carboxyxamide (Am-30) was obtained.
  • Example 0010 the white solid (S) -N-((2- (3, 3,)) was used in the same manner as in Example 0010 except that benzoic acid was used instead of 1H-indole-6-carboxylic acid. 3,3-Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-31) was obtained.
  • Example 0010 a white solid (S) -N- (S) -N- (in the same manner as in Example 0010 except that 1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrrole-3-carboxamide (Am-32) was obtained.
  • Example 0010 a white solid (S) -4-methoxy-N- was used in the same manner as in Example 0010 except that 4-methoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-33) was obtained.
  • Example 0010 the colorless oily (S) -3-acetamide-N- was used in the same manner as in Example 0010 except that 3-acetamidobenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-34) was obtained.
  • a 60% sodium hydride liquid paraffin dispersion (95 mg) was added to a solution of 1H-pyrrole-3-carboxylic acid (106 mg) in N, N-dimethylformamide (5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. .. After adding bromocyclobutane (0.074 mL), the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 1-cyclobutyl-1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0036 In the N-cyclobutylation reaction of Example 0036, a white solid was used in the same manner as the N-cyclobutylation reaction of Example 0036 except that 1- (bromomethyl) -2-fluorobenzene was used instead of bromocyclobutane. 1- (2-Fluorobenzyl) -1H-pyrrole-3-carboxylic acid was obtained. MS (m / z): 220.2 (M + H) +
  • Example 0010 white in the same manner as in Example 0010 except that 1- (2-fluorobenzyl) -1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Solid (S) -1- (2-fluorobenzyl) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrrole -3-Carboxamide (Am-37) was obtained.
  • Example 0010 in the same manner as in Example 0010, except that 1- (pyridin-2-ylmethyl) -1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 1-benzyl-1H-pyrazole-4-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • 1-benzyl-1H-pyrazole-4-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • Example 0010 a white solid (S) -N- (1) was used in the same manner as in Example 0010 except that 1-benzamide cyclopropanecarboxylic acid was used instead of 1H-indole-6-carboxylic acid. -(((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) carbamoyl) cyclopropyl) benzamide (Am-40) was obtained. MS (m / z): 462.2 (M + H) +
  • a 60% sodium hydride liquid paraffin dispersion (143 mg) was added to a solution of diethyl benzylphosphonate (1.25 mL) in tetrahydrofuran (10 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes.
  • tert-Butyl 3-oxopyrrolidine-1-carboxylate (1.0 g) was added, and the mixture was stirred at 70 ° C. for 3.5 hours.
  • the reaction mixture was cooled in an ice bath, 5 mL of saturated aqueous ammonium chloride solution was added, and then ethyl acetate and water were added.
  • Example 0002 In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindoline-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. , 3 of Example 0002, except that tert-butyl 3-benzylidenepyrrolidin-1-carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropanoic acid are used instead of using tert-butyl 3-benzylidenepyrrolidin-1-carboxylate, respectively.
  • Example 0010 a white solid (S) was prepared in the same manner as in Example 0010 except that 1-methyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • 1-methyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid.
  • tert-Butyl 5-bromoisoindoline-2-carboxylate (1.30 g), methyl acrylate (0.41 g), palladium acetate (25 mg), tris (2-methylphenyl) phosphine (66 mg) and triethylamine (1. 8 mL) of a solution of N, N-dimethylformamide (5.0 mL) was stirred in a sealed tube under a nitrogen atmosphere at 130 ° C. for 10 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • a 1 mol / L lithium aluminum hydride / tetrahydrofuran solution (3.3 mL) was added to a solution of the obtained residue (0.75 g) in tetrahydrofuran (5.0 mL) at 0 ° C., and the mixture was stirred at the same temperature for 15 minutes.
  • Methanol (1 mL) was added to the reaction mixture at 0 ° C. over 3 minutes, followed by 5% (w / v) aqueous Rochelle salt solution and ethyl acetate.
  • Example 0010 instead of using tert-butyl 5- (aminomethyl) isoindoline-2-carboxylate and 1H-indole-6-carboxylic acid, tert-butyl 5- (3-aminopropyl) iso, respectively.
  • the white solid (S) -1-benzyl-N- (3-( 2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) propyl) -1H-pyrazol-4-carboxamide (Am-50) was obtained.
  • HDAC6 a.a. full length, 161 kDa, glutathione S-transferase (GST) tag
  • GST glutathione S-transferase
  • Enzyme evaluation was performed on 25 mM Tris hydrochloride buffer (Tris / HCl buffer, pH 7.5), 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , 0.1 mg / mL bovine serum albumin (BSA, fatty acid free), 0. Each well so as to have a final concentration of 0.0001 ⁇ M to 1 ⁇ M (10-step dilution concentration) using a 1% DMSO solution (DMSO diluted compound) of the test compound in a solution of 5 ⁇ M buffer (peptide substrate) and 63 nM enzyme (HDAC6).
  • Tris hydrochloride buffer Tris / HCl buffer, pH 7.5
  • 137 mM NaCl 1 mM MgCl 2
  • BSA bovine serum albumin
  • a well to which DMSO was added was also prepared as a control, and the reaction was carried out in a well of a 384-well plate at 25 ° C. for 20 minutes.
  • the rate of Accification was detected using a Caliper EZ reader device.
  • Exact Mass in Tables 1 to 7 is a calculated precision mass, and represents an isotope mass (monoisotopic mass) having the maximum natural abundance ratio in each element.
  • the amide compounds or salts thereof used in Examples 101 to 145 and 147 to 150 according to the present disclosure have an HDAC inhibitory effect.
  • the amide compounds used in Examples 101 to 145 and 147 to 150, which are the amide compounds or salts thereof according to the present disclosure are useful as pharmaceutical compositions for the treatment of diseases associated with HDAC.
  • the efficacy of the amide compound or a salt thereof according to the present disclosure will be evaluated for colitis model mice with inflammatory bowel disease. In the model mouse, the weight loss associated with colitis is suppressed, the decrease in cells causing inflammation is suppressed, and the decrease in inflammatory cytokines is confirmed.
  • HDAC1 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that all the compounds had low HDAC1 inhibitory ability.
  • HDAC2 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that the HDAC2 inhibitory ability was low.
  • HDAC7 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that the HDAC7 inhibitory ability was high.
  • HDAC9 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that all the compounds have high HDAC9 inhibitory ability. It was confirmed that Examples 127, 136 and 139 had higher HDAC9 inhibitory ability than Example 101.
  • a permeation test via an artificial phospholipid membrane was performed at 25 ° C. for 4 hours.
  • the concentration of the compound in the solution on the donor plate and the acceptor plate was measured by LC / MS / MS, and the membrane permeation rate ( Pe ) of the compound was calculated from the following formula.
  • the membrane permeability (Pe ( 10-6 cm / sec)) obtained by the above method is shown in Table 8 below.
  • the amide compound or a salt thereof according to the present disclosure is also excellent in membrane permeability.
  • Cell culture Human breast cancer cell MCF-7 obtained from Japanese Collection of Research Bioresources; JCRB0134, Japan was obtained from 10% fetal bovine serum albumin (FBS; Sigma-Aldrich, # 173012-500ML), 1% antibiotic- antimycotic mixed stock solution (Nacalai Tesque, Inc., # 09366-44), 1% L-glutamine stock solution (Nacalai, # 16948-04), 1% sodium pyruvate solution (Nacalai Tesque, Inc., # 06977) In Dulbecco's modified Eagle's medium (DMEM; manufactured by Nacalai Tesque Co., Ltd., # 08489-45) containing -34), a CO 2 incubator (manufactured by PHC Co., Ltd., MCO) set at 37 ° C.
  • DMEM Dulbecco's modified Eagle's medium
  • Electrophoresis and transfer to the PVDF membrane were performed using a mini slab electrophoresis device (Ato Co., Ltd., AE-6530P). Electrophoresis is performed by applying 5 ⁇ g of protein to a 5-20% SDS-polyacrylamide gel (e-PAGEL, manufactured by Atto Co., Ltd., E-R520L), and after the electrophoresis is completed, the protein is transferred from the gel to a PVDF membrane (Merck). Transferred to IPVH00010) manufactured by the company.
  • a mini slab electrophoresis device Ato Co., Ltd., AE-6530P. Electrophoresis is performed by applying 5 ⁇ g of protein to a 5-20% SDS-polyacrylamide gel (e-PAGEL, manufactured by Atto Co., Ltd., E-R520L), and after the electrophoresis is completed, the protein is transferred from the gel to a PVDF membrane (Merck). Transferred to IPVH00010) manufactured by the company.
  • ECL mouse IgG, HRP-linked whole antibody (GE Healthcare Life Sciences, # NA931) (1: 2500 dilution) Can Get Signal (Toyo Boseki Co., Ltd.) ), NKB-101) solution, or ECL rabbit IgG, HRP-linked whole antibody (GE Healthcare Life Sciences, # NA934) (1: 2500 dilution) TBS containing 5% skimmed milk solution at room temperature 1 Reacted for time. After the reaction, the membrane was washed again with TBS solution for washing three times. (5) The stained band was detected by chemiluminescence.
  • Immobilon TM Western Chemiluminescent HRP Substrate (Merck, WBKLS0050) was used as a detection agent and detected with ImageQuant LAS 500 (Cytiva).
  • SAHA the following compound
  • acetylated not only ⁇ -tubulin which is a substrate of HDAC6, but also H3 in a dose-dependent manner.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An amide compound represented by formula (I-1) or a salt thereof, a pharmaceutical composition that comprises the amide compound or a salt thereof, and a histone deacetylase inhibitor. In the formula: R1 to R4 independently represent a hydrogen atom or a substituent, provided that all of R1 to R4 are not hydrogen atoms at the same time, or R1 to R4 may be bonded together to form an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic heterocycle; and at least one of R5s is a fluorine atom.

Description

アミド化合物又はその塩、医薬組成物、及び、ヒストン脱アセチル化酵素阻害剤Amide compounds or salts thereof, pharmaceutical compositions, and histone deacetylase inhibitors
　本開示は、ＨＤＡＣ（ヒストン脱アセチル化酵素（Histone Deacetylase））阻害作用を有するアミド化合物又はその塩、上記アミド化合物又はその塩を含む医薬組成物、及び、ヒストン脱アセチル化酵素阻害剤に関する。 The present disclosure relates to an amide compound or a salt thereof having an HDAC (histone deacetylase) inhibitory action, a pharmaceutical composition containing the above amide compound or a salt thereof, and a histone deacetylase inhibitor.
　ＨＤＡＣはヒストンのＮ末端領域のアセチル化されたリジン残基の脱アセチルを触媒する酵素である。しかしながら、ＨＤＡＣは、単なる脱アセチル化酵素としてだけでなく、細胞内で転写調節に関わるタンパク質と複合体を形成することにより、真核生物の遺伝子発現調節に深く関わることが明らかになってきた。
　ＨＤＡＣには、１１種類のアイソザイム（ＨＤＡＣ１～１１）が知られている。
　例えば、ＨＤＡＣの阻害が、癌の発生や進行に関与することが知られている（非特許文献１参照）。
　また、アイソザイム選択的なＨＤＡＣ阻害剤が、種々の疾患に対する治療薬として期待されている（非特許文献２及び３参照）。
　以上のことから、ＨＤＡＣ阻害剤は、様々な疾患に対する治療薬として期待される。
　また、特許文献１～４に記載された化合物が知られている。 HDAC is an enzyme that catalyzes the deacetylation of acetylated lysine residues in the N-terminal region of histones. However, it has become clear that HDAC is deeply involved in the regulation of gene expression in eukaryotes by forming a complex with a protein involved in transcriptional regulation in the cell, not only as a mere deacetylase.
Eleven types of isozymes (HDACs 1 to 11) are known for HDACs.
For example, inhibition of HDAC is known to be involved in the development and progression of cancer (see Non-Patent Document 1).
In addition, isozyme-selective HDAC inhibitors are expected as therapeutic agents for various diseases (see Non-Patent Documents 2 and 3).
From the above, HDAC inhibitors are expected as therapeutic agents for various diseases.
Further, the compounds described in Patent Documents 1 to 4 are known.
　　特許文献１：特表２０１６－５２８２２６号公報
　　特許文献２：米国特許出願公開第２０１４／０３５０００２号明細書
　　特許文献３：特表２０１８－５１５４９４号公報
　　特許文献４：特表２００６－５２２７９１号公報 Patent Document 1: Japanese Patent Application Laid-Open No. 2016-528226 Patent Document 2: US Patent Application Publication No. 2014/0350002 Patent Document 3: Japanese Patent Application Laid-Open No. 2018-515494 Patent Document 4: Japanese Patent Application Laid-Open No. 2006-522791
　　非特許文献１：阿部達也, Akita J. Med., Vol.36, p9-18, 2009年
　　非特許文献２：鈴木孝禎, 京都府立医科大学雑誌, Vol.121, No.9, p461～467, 2012年
　　非特許文献３：Kyle V. Butler et al., J. Am. Chem. Soc., Vol.132, p10842～10846, 2010年 Non-Patent Document 1: Tatsuya Abe, Akita J. Med., Vol.36, p9-18, 2009 Non-Patent Document 2: Takayoshi Suzuki, Kyoto Prefectural University of Medicine Magazine, Vol.121, No.9, p461-467 , 2012 Non-Patent Document 3: Kyle V. Butler et al., J. Am. Chem. Soc., Vol.132, p10842-10846, 2010
　本発明の一実施形態が解決しようとする課題は、ＨＤＡＣ阻害作用を有するアミド化合物又はその塩を提供することである。
　また、本発明の他の一実施形態が解決しようとする課題は、上記アミド化合物又はその塩を含む医薬組成物、又は、ヒストン脱アセチル化酵素阻害剤を提供することである。 An object to be solved by one embodiment of the present invention is to provide an amide compound having an HDAC inhibitory action or a salt thereof.
Another object to be solved by another embodiment of the present invention is to provide a pharmaceutical composition containing the amide compound or a salt thereof, or a histone deacetylase inhibitor.
　本発明者らは、上記課題に対し鋭意検討を重ねた結果、特定の構造を有するアミド化合物又はその塩が、ＨＤＡＣ阻害作用を有することを見出し、本開示を完成するに至った。　上記課題を解決するための手段には、以下の態様が含まれる。
＜１＞　下記式（Ｉ－１）で表されるアミド化合物又はその塩。 As a result of diligent studies on the above problems, the present inventors have found that an amide compound having a specific structure or a salt thereof has an HDAC inhibitory action, and have completed the present disclosure. Means for solving the above problems include the following aspects.
<1> An amide compound represented by the following formula (I-1) or a salt thereof.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　式（Ｉ－１）において、
　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ５のうち少なくとも１つはフッ素原子であり、
　２個のＲ５が結合して環を形成してもよく、
　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
　Ｌ１は、０又は１を表す。 In formula (I-1)
R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
All R 1 ~ R 4 are not hydrogen atoms at the same time,
R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 5 is a fluorine atom,
Two R 5 may be combined with each other to form a ring,
R 6 represents a hydrogen atom or a C 1-10 alkyl group.
L1 represents 0 or 1.
＜２＞　全てのＲ５が、フッ素原子である、＜１＞に記載のアミド化合物又はその塩。
＜３＞　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成している、＜１＞又は＜２＞に記載のアミド化合物又はその塩。
＜４＞　Ｒ１～Ｒ４が一体となって形成する置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環が、置換基を有してもよいベンゼン環、置換基を有してもよいチオフェン環又は置換基を有してもよいピラゾール環である、＜３＞に記載のアミド化合物又はその塩。
＜５＞　Ｒ１～Ｒ４が一体となって形成する上記芳香族炭化水素環又は上記芳香族ヘテロ環上に有していてもよい置換基が、
ハロゲン原子、ヒドロキシ基、カルボキシ基、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルケニル基、置換基を有してもよいアリールＣ２－１０アルケニル基、置換基を有してもよいヘテロアリールＣ２－１０アルケニル基、置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、－Ｌ２－ＮＲ５１Ｒ５２、－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、及び、－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２よりなる群から選ばれた少なくとも１種の基である、＜３＞又は＜４＞に記載のアミド化合物又はその塩。
　なお、Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
　Ｌ２は、単結合、又は、置換基を有してもよいアルキレン基を表す。
＜６＞　上記式（Ｉ－１）で表されるアミド化合物又はその塩が、下記式（ＩＩ－１）～式（ＩＩ－４）のいずれかで表されるアミド化合物又はその塩である、＜１＞～＜５＞のいずれか１つに記載のアミド化合物又はその塩。 <2> The amide compound according to <1> or a salt thereof, wherein all R 5s are fluorine atoms.
<3> R 1 to R 4 are integrally formed to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent, <1> or. The amide compound according to <2> or a salt thereof.
<4> R 1 ~ R 4 is an aromatic hetero ring which may have an aromatic hydrocarbon ring or a substituted group which may have a substituent which forms together is, it may have a substituent The amide compound according to <3> or a salt thereof, which is a good benzene ring, a thiophene ring which may have a substituent, or a pyrazole ring which may have a substituent.
<5> R 1 ~ R 4 are the aromatic hydrocarbon ring or a substituent which may have on the aromatic hetero ring formed together is,
Halogen atom, hydroxy group, a carboxy group, an optionally substituted C 1-10 alkyl group, an optionally substituted C 2-10 alkenyl group, an optionally substituted C 2- 10 Alkinyl group, C 3-8 cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent which may have a substituent. good C 3-8 cycloalkyl C 1-10 alkyl group, an optionally substituted aryl C 1-10 alkyl group, an optionally substituted heteroaryl C 1-10 alkyl group, a substituent a may be C 3-8 cycloalkyl C 2-10 alkenyl group, an optionally substituted aryl C 2-10 alkenyl group, an optionally substituted heteroaryl C 2-10 alkenyl group , an optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, a C 1-6 alkoxycarbonyl which may have a substituent Group, aryloxycarbonyl group which may have a substituent, -L 2- NR 51 R 52 , -L 2- NR 51 C (O) R 54 , -L 2- NR 51 C (O) NR 53 R At least one group selected from the group consisting of 54, -L 2- NR 51 SO 2 R 54 , -L 2- C (O) NR 51 R 52 , and -L 2- SO 2 NR 51 R 52. The amide compound according to <3> or <4> or a salt thereof.
In addition, R 51 , R 52 , R 53 and R 54 independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl which may have a substituent. It may have a group, a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a substituent. It may have a heteroaryl group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a substituent. Represents a good heteroaryl C 1-10 alkyl group,
L 2 represents an alkylene group which may have a single bond or a substituent.
<6> The amide compound represented by the above formula (I-1) or a salt thereof is an amide compound represented by any of the following formulas (II-1) to (II-4) or a salt thereof. The amide compound according to any one of <1> to <5> or a salt thereof.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　式（ＩＩ－１）中、
　Ｒ１１はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
　Ｌ２は、単結合、又は、置換基を有してもよいＣ１－１０アルキレン基を表し、
　ｍ１は、１～４の整数を表す。 In formula (II-1),
R 11 is independently a halogen atom, a hydroxy group, a carboxy group,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 , representing
R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. A crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl which may have a substituent. A group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a hetero which may have a substituent. Represents an aryl C 1-10 alkyl group
L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
m1 represents an integer of 1 to 4.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　式（ＩＩ－２）中、
　Ｒ１２はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
　Ｌ２は、単結合、又は、置換基を有してもよいＣ１－１０アルキレン基を表し、
　ｍ２は、１又は２を表す。 In formula (II-2),
R 12 is independently a halogen atom, a hydroxy group, a carboxy group,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 , representing
R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. A crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl which may have a substituent. A group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a hetero which may have a substituent. Represents an aryl C 1-10 alkyl group
L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
m2 represents 1 or 2.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　式（ＩＩ－３）中、
　Ｘはそれぞれ独立に、Ｎ、ＮＨ又はＮＲ１３を表し、
　Ｒ１３はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
　Ｌ２は、単結合、又は、置換基を有してもよいＣ１－１０アルキレン基を表し、
　ｍ３は、０～２の整数を表す。 In formula (II-3),
X independently represents N, NH or NR 13.
R 13 is independently a halogen atom, a hydroxy group, a carboxy group,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 , representing
R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. A crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl which may have a substituent. A group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a hetero which may have a substituent. Represents an aryl C 1-10 alkyl group
L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
m3 represents an integer of 0 to 2.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　式（ＩＩ－４）中、
　Ｒ１４～Ｒ１７はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、又は、置換基を有してもよいＣ２－６アルキニル基を表し、
　Ｒ１４とＲ１５とが、又は、Ｒ１６とＲ１７とが結合して、置換基を有してもよいＣ１－６アルキリデン基を形成してもよい。ただし、Ｒ１４～Ｒ１７の全てが同時に水素原子となることはない。 In formula (II-4),
R 14 to R 17 each independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. Represents a optionally C 2-6 alkynyl group and represents
R 14 and R 15 may be combined, or R 16 and R 17 may be combined to form a C 1-6 alkylidene group which may have a substituent. However, not all of R 14 to R 17 become hydrogen atoms at the same time.
＜７＞　＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩を含有する医薬組成物。
＜８＞　ヒストン脱アセチル化酵素が関与する疾患の処置剤である、＜７＞に記載の医薬組成物。
＜９＞　下記式（Ｉ）で表されるアミド化合物又はその塩を含有するヒストン脱アセチル化酵素阻害剤。 <7> A pharmaceutical composition containing the amide compound according to any one of <1> to <6> or a salt thereof.
<8> The pharmaceutical composition according to <7>, which is a therapeutic agent for a disease involving histone deacetylase.
<9> A histone deacetylase inhibitor containing an amide compound represented by the following formula (I) or a salt thereof.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　式（Ｉ）において、
　Ｒ０１は、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、又は、置換基を有してもよい炭化水素環基を表し、
　Ｒ０２は、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、又は、置換基を有してもよいヘテロ環基を表し、
　Ｒ０１とＲ０２とは一体となって、置換基を有してもよい含窒素ヘテロ環を形成してもよく、
　Ｒ０３はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ０３のうち少なくとも１つはフッ素原子であり、
　２個のＲ０３が結合して環を形成してもよく、
　Ｒ０４は、水素原子又はＣ１－１０アルキル基を表す。 In formula (I)
R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent. Represents a hydrocarbon ring group which may have a group or a substituent,
R 02 is a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, a C 2-6 alkynyl group which may have a substituent, and a substituent. Represents a hydrocarbon ring group which may have a group or a heterocyclic group which may have a substituent.
R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 03 is a fluorine atom
Two R 03s may be combined to form a ring.
R 04 represents a hydrogen atom or a C 1-10 alkyl group.
＜１０＞　上記式（Ｉ）で表されるアミド化合物又はその塩が、下記式（Ｉ－０１）で表されるアミド化合物又はその塩である、＜９＞に記載のヒストン脱アセチル化酵素阻害剤。 <10> Histone deacetylase inhibition according to <9>, wherein the amide compound represented by the above formula (I) or a salt thereof is an amide compound represented by the following formula (I-01) or a salt thereof. Agent.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　式（Ｉ－０１）において、
　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ５のうち少なくとも１つはフッ素原子であり、
　２個のＲ５が結合して環を形成してもよく、
　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
　Ｌ１は、０～２の整数を表す。 In formula (I-01)
R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
All R 1 ~ R 4 are not hydrogen atoms at the same time,
R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 5 is a fluorine atom,
Two R 5 may be combined with each other to form a ring,
R 6 represents a hydrogen atom or a C 1-10 alkyl group.
L1 represents an integer of 0 to 2.
＜１１＞　下記式（Ｉ）で表されるアミド化合物又はその塩を含有するＺｎを有するメタロプロテアーゼ阻害剤。 <11> A metalloprotease inhibitor having Zn containing an amide compound represented by the following formula (I) or a salt thereof.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　式（Ｉ）において、
　Ｒ０１は、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、又は、置換基を有してもよい炭化水素環基を表し、
　Ｒ０２は、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、又は、置換基を有してもよいヘテロ環基を表し、
　Ｒ０１とＲ０２とは一体となって、置換基を有してもよい含窒素ヘテロ環を形成してもよく、
　Ｒ０３はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ０３のうち少なくとも１つはフッ素原子であり、
　２個のＲ０３が結合して環を形成してもよく、
　Ｒ０４は、水素原子又はＣ１－１０アルキル基を表す。 In formula (I)
R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent. Represents a hydrocarbon ring group which may have a group or a substituent,
R 02 is a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, a C 2-6 alkynyl group which may have a substituent, and a substituent. Represents a hydrocarbon ring group which may have a group or a heterocyclic group which may have a substituent.
R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 03 is a fluorine atom
Two R 03s may be combined to form a ring.
R 04 represents a hydrogen atom or a C 1-10 alkyl group.
＜１２＞　上記式（Ｉ）で表されるアミド化合物又はその塩が、下記式（Ｉ－０１）で表されるアミド化合物又はその塩である、＜１１＞に記載のＺｎを有するメタロプロテアーゼ阻害剤。 <12> Inhibition of a metalloproteinase having Zn according to <11>, wherein the amide compound represented by the above formula (I) or a salt thereof is the amide compound represented by the following formula (I-01) or a salt thereof. Agent.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　式（Ｉ－０１）において、
　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ５のうち少なくとも１つはフッ素原子であり、
　２個のＲ５が結合して環を形成してもよく、
　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
　Ｌ１は、０～２の整数を表す。 In formula (I-01)
R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
All R 1 ~ R 4 are not hydrogen atoms at the same time,
R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 5 is a fluorine atom,
Two R 5 may be combined with each other to form a ring,
R 6 represents a hydrogen atom or a C 1-10 alkyl group.
L1 represents an integer of 0 to 2.
＜１３＞　＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩を、対象（ヒトを含む哺乳動物、好ましくはヒト）に投与する工程を含む、疾患（例えば、癌、炎症性腸疾患）の処置方法。
＜１４＞　＜９＞若しくは＜１０＞に記載のヒストン脱アセチル化酵素阻害剤、又は、＜１１＞若しくは＜１２＞に記載のＺｎを有するメタロプロテアーゼ阻害剤を、対象（ヒトを含む哺乳動物、好ましくはヒト）に投与する工程を含む、疾患（例えば、癌、炎症性腸疾患）の処置方法。
＜Ａ－１＞　医薬組成物の製造のための、＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩。
＜Ａ－２＞　ヒストン脱アセチル化酵素が関与する疾患（例えば、癌、炎症性腸疾患）の処置剤の製造のための、＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩。
＜Ａ－３＞　Ｚｎを有するメタロプロテアーゼが関与する疾患の処置剤の製造のための、＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩の使用。
＜Ｂ－１＞　医薬組成物に使用するための、＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩。
＜Ｂ－２＞　ヒストン脱アセチル化酵素が関与する疾患（例えば、癌、炎症性腸疾患）の処置に使用するための、＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩。
＜Ｂ－３＞　Ｚｎを有するメタロプロテアーゼが関与する疾患の処置のための、＜１＞～＜６＞のいずれか１つに記載のアミド化合物又はその塩。 <13> A disease (eg, cancer, etc.) comprising the step of administering the amide compound according to any one of <1> to <6> or a salt thereof to a subject (mammal including human, preferably human). Treatment method for inflammatory bowel disease).
<14> The histone deacetylase inhibitor according to <9> or <10>, or the metalloprotease inhibitor having Zn according to <11> or <12>, is a subject (mammalian including human, A method for treating a disease (eg, cancer, inflammatory bowel disease), comprising the step of administering to (preferably a human).
<A-1> The amide compound according to any one of <1> to <6> or a salt thereof for producing a pharmaceutical composition.
<A-2> The amide compound according to any one of <1> to <6> for producing a therapeutic agent for a disease involving histone deacetylase (for example, cancer, inflammatory bowel disease). Or its salt.
<A-3> Use of the amide compound according to any one of <1> to <6> or a salt thereof for producing a therapeutic agent for a disease involving a metalloprotease having Zn.
<B-1> The amide compound according to any one of <1> to <6> or a salt thereof for use in a pharmaceutical composition.
<B-2> The amide compound according to any one of <1> to <6> for use in the treatment of diseases involving histone deacetylase (for example, cancer, inflammatory bowel disease). That salt.
<B-3> The amide compound according to any one of <1> to <6> or a salt thereof for treating a disease involving a metalloprotease having Zn.
　本発明の一実施形態によれば、ＨＤＡＤ阻害作用を有するアミド化合物又はその塩を提供することができる。
　また、本発明の他の一実施形態によれば、上記アミド化合物又はその塩を含む医薬組成物、又は、ヒストン脱アセチル化酵素阻害剤を提供することができる。 According to one embodiment of the present invention, an amide compound having an HDAD inhibitory effect or a salt thereof can be provided.
Further, according to another embodiment of the present invention, a pharmaceutical composition containing the amide compound or a salt thereof, or a histone deacetylase inhibitor can be provided.
　以下において、本開示の内容について詳細に説明する。以下に記載する構成要件の説明は、本開示の代表的な実施態様に基づいてなされることがあるが、本開示はそのような実施態様に限定されるものではない。
　また、本明細書において「～」を用いて表される数値範囲は、「～」の前後に記載される数値を下限値及び上限値として含む範囲を意味する。
　本明細書中に段階的に記載されている数値範囲において、一つの数値範囲で記載された上限値又は下限値は、他の段階的な記載の数値範囲の上限値又は下限値に置き換えてもよい。また、本明細書中に記載されている数値範囲において、その数値範囲の上限値又は下限値は、実施例に示されている値に置き換えてもよい。
　本明細書において「工程」との語は、独立した工程だけでなく、他の工程と明確に区別できない場合であっても工程の所期の目的が達成されれば、本用語に含まれる。
　本明細書における基（原子団）の表記において、置換及び無置換を記していない表記は、置換基を有さないものと共に置換基を有するものをも包含するものである。例えば「アルキル基」とは、置換基を有さないアルキル基（無置換アルキル基）のみならず、置換基を有するアルキル基（置換アルキル基）をも包含するものである。
　また、本明細書における化学構造式は、水素原子を省略した簡略構造式で記載する場合もある。
　本開示において、「質量％」と「重量％」とは同義であり、「質量部」と「重量部」とは同義である。
　また、本開示において、２以上の好ましい態様の組み合わせは、より好ましい態様である。 The contents of the present disclosure will be described in detail below. The description of the constituent elements described below may be based on the representative embodiments of the present disclosure, but the present disclosure is not limited to such embodiments.
In addition, the numerical range represented by using "-" in the present specification means a range including the numerical values before and after "-" as the lower limit value and the upper limit value.
In the numerical range described stepwise in the present specification, the upper limit value or the lower limit value described in one numerical range may be replaced with the upper limit value or the lower limit value of another numerical range described stepwise. good. Further, in the numerical range described in the present specification, the upper limit value or the lower limit value of the numerical range may be replaced with the value shown in the examples.
In the present specification, the term "process" is included in this term not only as an independent process but also as long as the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes.
In the notation of a group (atomic group) in the present specification, the notation that does not describe substitution and non-substitution includes those having no substituent as well as those having a substituent. For example, the "alkyl group" includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group).
Further, the chemical structural formula in the present specification may be described by a simplified structural formula in which a hydrogen atom is omitted.
In the present disclosure, "% by mass" and "% by weight" are synonymous, and "parts by mass" and "parts by weight" are synonymous.
Further, in the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.
　更に、本開示において、「Ｃｘ－ｙ」は、炭素数（「炭素原子数」ともいう。）がｘ～ｙであることを表し、例えば、Ｃ１－６アルキル基は、炭素数１～６のアルキル基を表す。
　また、本開示における「アルキル基」は、特に言及していない場合、直鎖アルキル基であっても、分岐アルキル基であってもよい。また、アルケニル基、及び、アルキニル基についても、アルキル基と同様である。
　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。 Further, in the present disclosure, "C xy " means that the number of carbon atoms (also referred to as "the number of carbon atoms") is xy, and for example, the C 1-6 alkyl group has 1 to 1 carbon atoms. Represents an alkyl group of 6.
Further, the "alkyl group" in the present disclosure may be a linear alkyl group or a branched alkyl group unless otherwise specified. Further, the alkenyl group and the alkynyl group are the same as those of the alkyl group.
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　Ｃ１－６アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、ｓｅｃ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、２－メチルブチル、２－ペンチル、３－ペンチル及びヘキシル基などの直鎖状又は分枝鎖状のＣ１－６アルキル基を意味する。
　Ｃ１－８アルキル基とは、上記Ｃ１－６アルキル基、ヘプチル、２－メチルヘプチル、２－メチル－４－ヘプチル及びオクチル基などの直鎖状又は分枝鎖状のＣ１－８アルキル基を意味する。
　Ｃ１－１０アルキル基とは、上記Ｃ１－８アルキル基、２－エチルヘキシル、ノニル及びデシル基などの直鎖状又は分枝鎖状のＣ１－１０アルキル基を意味する。
　Ｃ２－６アルケニル基とは、ビニル、アリル、１－プロペニル、イソプロペニル、ブテニル、イソブテニル、１，３－ブタジエニル、ペンテニル及びヘキセニル基などの直鎖状又は分枝鎖状のＣ２－６アルケニル基を意味する。
　Ｃ２－１０アルケニル基とは、上記Ｃ２－６アルケニル基、ペプテニル、オクテニル、ノネニル、デセニル基などの直鎖状又は分枝鎖状のＣ２－１０アルケニル基を意味する。
　Ｃ２－６アルキニル基とは、エチニル、プロピニル、ブチニル、ペンチニル及びヘキシニル基などの直鎖状又は分枝鎖状のＣ２－６アルキニル基を意味する。
　Ｃ２－１０アルキニル基とは、上記Ｃ２－６アルキニル基、ペンチニル、オクチニル、ノニニル、デシニル基などの直鎖状又は分枝鎖状のＣ２－１０アルキニル基を意味する。
　Ｃ３－８シクロアルキル基とは、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、シクロヘプチル及びシクロオクチル基などのＣ３－８シクロアルキル基を意味する。
　Ｃ３－８シクロアルケニル基とは、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル及びシクロオクテニル基などのＣ３－８シクロアルケニル基を意味する。
　Ｃ３－８シクロアルキルＣ１－１０アルキル基とは、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、シクロヘプチルメチル、シクロオクチルメチル、２－シクロヘキシルエチル、１－シクロヘキシルエチル、３－シクロヘキシルプロピル及び１０－シクロヘキシルデシル基などのＣ３－８シクロアルキル基が結合したＣ１－１０アルキル基を意味する。
　Ｃ３－８シクロアルキルＣ２－１０アルケニル基とは、２－シクロプロピルエテニル、２－シクロブチルエテニル、２－シクロペンチルエテニル、２－シクロヘキシルエテニル、２－シクロヘプチルエテニル、２－シクロオクチルエテニル、１－シクロヘキシルエテニル、３－シクロヘキシルアリル及び１０－シクロヘキシル－９－デセニル基などのＣ３－８シクロアルキル基が結合したＣ２－１０アルケニル基を意味する。
　架橋式炭化水素環基としては、アダマンチル基、ビシクロ［２．１．０］ペンチル、ビシクロ［２．２．０］ヘキシル、ビシクロ［３．２．１］オクチル及びビシクロ［５．２．０］ノニル基などが挙げられる。
　スピロ式炭化水素環基としては、スピロ［３．３］ヘプチル及びスピロ［３．４］オクチル基などが挙げられる。 C 1-6 alkyl groups are direct groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3-pentyl and hexyl groups. It means a chain or branched C 1-6 alkyl group.
The C 1-8 alkyl group is a linear or branched C 1-8 alkyl such as the above C 1-6 alkyl group, heptyl, 2-methylheptyl, 2-methyl-4-heptyl and octyl group. Means a group.
The C 1-10 alkyl group means a linear or branched C 1-10 alkyl group such as the above C 1-8 alkyl group, 2-ethylhexyl, nonyl and decyl group.
The C 2-6 alkenyl group is a linear or branched C 2-6 alkenyl group such as vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups. Means a group.
The C 2-10 alkenyl group means a linear or branched C 2-10 alkenyl group such as the C 2-6 alkenyl group, peptenyl, octenyl, nonenyl, and decenyl group.
The C 2-6 alkynyl group means a linear or branched C 2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.
The C 2-10 alkynyl group means a linear or branched C 2-10 alkynyl group such as the above-mentioned C 2-6 alkynyl group, pentynyl, octynyl, noninyl, decynyl group.
The C 3-8 cycloalkyl group means a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The C 3-8 cycloalkenyl group means a C 3-8 cycloalkenyl group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl groups.
C 3-8 Cycloalkyl C 1-10 Alkyl groups are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclohexylethyl, 1-cyclohexylethyl, 3-cyclohexyl. It means a C 1-10 alkyl group to which a C 3-8 cycloalkyl group such as propyl and 10-cyclohexyldecyl group is bonded.
C 3-8 Cycloalkyl C 2-10 Alkyl groups are 2-cyclopropyl ethenyl, 2-cyclobutyl ethenyl, 2-cyclopentyl ethenyl, 2-cyclohexyl ethenyl, 2-cycloheptyl ethenyl, 2- It means a C 2-10 alkenyl group to which a C 3-8 cycloalkyl group such as cyclooctyl ethenyl, 1-cyclohexyl ethenyl, 3-cyclohexyl allyl and 10-cyclohexyl-9-decenyl group is attached.
The crosslinked hydrocarbon ring groups include adamantyl groups, bicyclo [2.1.0] pentyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.1] octyl and bicyclo [5.2.0]. Nonyl group and the like can be mentioned.
Examples of the spiro-type hydrocarbon ring group include a spiro [3.3] heptyl group and a spiro [3.4] octyl group.
　Ｃ１－６アルキレン基とは、メチレン、エチレン、１，２－プロピレン、１，３－プロピレン、ジメチルメチレン、１，２－ブチレン、１，３－ブチレン、１，４－ブチレン、ジメチルエチレン、１，５－ペンチレン、２，２－ジメチル－１，３－ペンチレン、１，６－ヘキシレン基などの直鎖状又は分枝鎖状のＣ１－６アルキレン基を意味する。
　Ｃ１－６アルキリデン基とは、メチリデン、メチルメチリデン、エチルメチリデン、ジメチルメチリデン、プロピルメチリデン、ブチルメチリデン及びペンチルメチリデン基などの直鎖状又は分岐鎖状のＣ１－６アルキリデン基（２価の基、無置換又は１個若しくは２個のアルキル基が置換したメチリデン基（Ｈ２Ｃ＝））を意味する。 The C 1-6 alkylene groups are methylene, ethylene, 1,2-propylene, 1,3-propylene, dimethylmethylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, dimethylethylene, 1 , 5-Pentylene, 2,2-dimethyl-1,3-pentylene, 1,6-hexylene group and other linear or branched C 1-6 alkylene groups.
The C 1-6 alkylidene group is a linear or branched C 1-6 alkylidene group (divalent group) such as methylidene, methylmethylidene, ethylmethylidene, dimethylmethylidene, propylmethylidene, butylmethylidene and pentylmethylidene group. , Unsubstituted or substituted with one or two alkyl groups (H 2 C =)).
　アリール基とは、芳香族炭化水素基を意味し、また、縮環した芳香族炭化水素基であってもよく、フェニル基又はナフチル基であることが好ましい。
　また、芳香族炭化水素環は、縮環した芳香族炭化水素環であってもよく、ベンゼン環又はナフタレン環であることが好ましい。
　アリールＣ１－６アルキル基とは、ベンジル、ジフェニルメチル、トリチル、フェネチル、２－フェニルプロピル、３－フェニルプロピル及びナフチルメチル基などのアリールＣ１－６アルキル基を意味する。
　アリールＣ１－１０アルキル基とは、ベンジル、ジフェニルメチル、トリチル、フェネチル、２－フェニルプロピル、３－フェニルプロピル、６－フェニルヘキシル、１０フェニルデシル及びナフチルメチル基などのアリールＣ１－６アルキル基を意味する。
　アリールＣ２－６アルケニル基とは、２－フェニルビニル、１－フェニルビニル、３－フェニルアリル、３－フェニル－１－プロペニル、４－フェニル－３－ブテニル、５－フェニル－４－ペンテニル、６－フェニル－５－ヘキセニル及び２－ナフチルビニル基などのアリールＣ２－６アルケニル基を意味する。
　アリールＣ２－１０アルケニル基とは、２－フェニルビニル、１－フェニルビニル、３－フェニルアリル、３－フェニル－１－プロペニル、４－フェニル－３－ブテニル、５－フェニル－４－ペンテニル、６－フェニル－５－ヘキセニル、１０－フェニル－９－デセニル及び２－ナフチルビニル基などのアリールＣ２－１０アルケニル基を意味する。
　ヘテロアリールＣ２－６アルケニル基とは、２－（２－チエニル）ビニル、２－（２－フラニル）ビニル、２－（２－ピリジル）ビニル、２－（２－チアゾリル）ビニル、３－（２－チエニル）アリル、３－（２－チエニル）－１－プロペニル、４－（２－チエニル）－３－ブテニル、５－（２－チエニル）－４－ペンテニル及び６－（２－チエニル）－５－ヘキセニル基などのアリールＣ２－６アルケニル基を意味する。
　ヘテロアリールＣ２－６アルケニル基とは、２－（２－チエニル）ビニル、２－（２－フラニル）ビニル、２－（２－ピリジル）ビニル、２－（２－チアゾリル）ビニル、３－（２－チエニル）アリル、３－（２－チエニル）－１－プロペニル、４－（２－チエニル）－３－ブテニル、５－（２－チエニル）－４－ペンテニル、６－（２－チエニル）－５－ヘキセニル、１０－（２－チエニル）－９－デセニル基などのアリールＣ２－１０アルケニル基を意味する。 The aryl group means an aromatic hydrocarbon group, and may be a fused aromatic hydrocarbon group, preferably a phenyl group or a naphthyl group.
Further, the aromatic hydrocarbon ring may be a fused aromatic hydrocarbon ring, and is preferably a benzene ring or a naphthalene ring.
The aryl C 1-6 alkyl group means a benzyl, diphenylmethyl, trityl, phenethyl, aryl C 1-6 alkyl group such as 2-phenylpropyl, 3-phenylpropyl and naphthylmethyl groups.
Aryl C 1-10 alkyl groups are aryl C 1-6 alkyl groups such as benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl, 6-phenylhexyl, 10phenyldecyl and naphthylmethyl groups. Means.
The aryl C 2-6 alkenyl group is 2-phenylvinyl, 1-phenylvinyl, 3-phenylallyl, 3-phenyl-1-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6 -Phenyl-5 means an aryl C 2-6 alkenyl group such as hexenyl and 2-naphthylvinyl groups.
The aryl C 2-10 alkenyl group is 2-phenylvinyl, 1-phenylvinyl, 3-phenylallyl, 3-phenyl-1-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6 It means an aryl C 2-10 alkenyl group such as -phenyl-5-hexenyl, 10-phenyl-9-decenyl and 2-naphthylvinyl group.
The heteroaryl C 2-6 alkenyl group is 2- (2-thienyl) vinyl, 2- (2-furanyl) vinyl, 2- (2-pyridyl) vinyl, 2- (2-thiazolyl) vinyl, 3-( 2-thienyl) allyl, 3- (2-thienyl) -1-propenyl, 4- (2-thienyl) -3-butenyl, 5- (2-thienyl) -4-pentenyl and 6- (2-thienyl)- It means an aryl C 2-6 alkenyl group such as a 5-hexenyl group.
The heteroaryl C 2-6 alkenyl group is 2- (2-thienyl) vinyl, 2- (2-furanyl) vinyl, 2- (2-pyridyl) vinyl, 2- (2-thiazolyl) vinyl, 3-( 2-thienyl) allyl, 3- (2-thienyl) -1-propenyl, 4- (2-thienyl) -3-butenyl, 5- (2-thienyl) -4-pentenyl, 6- (2-thienyl)- It means an aryl C 2-10 alkenyl group such as 5-hexenyl, 10- (2-thienyl) -9-decenyl group.
　Ｃ１－６アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、シクロプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、シクロブトキシ、ペンチルオキシ、シクロヘキシルオキシ、ヘキシルオキシ及びシクロヘキシルオキシ基などの直鎖状、環状又は分枝鎖状のＣ１－６アルキルオキシ基を意味する。
　Ｃ１－６アルコキシＣ１－１０アルキル基とは、メトキシメチル及び１－エトキシエチル基などのＣ１－６アルキルオキシＣ１－１０アルキル基を意味する。
　アリールＣ１－６アルコキシＣ１－６アルキル基とは、ベンジルオキシメチル及びフェネチルオキシメチル基などのアリールＣ１－６アルキルオキシＣ１－６アルキル基を意味する。
　アリールオキシ基としては、フェノキシ基又はナフチルオキシ基であることが好ましい。 The C 1-6 alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy, cyclohexyloxy, hexyloxy and cyclohexyloxy groups. It means a linear, cyclic or branched C 1-6 alkyloxy group.
The C 1-6 alkoxy C 1-10 alkyl group means a C 1-6 alkyloxy C 1-10 alkyl group such as methoxymethyl and 1-ethoxyethyl group.
The aryl C 1-6 alkoxy C 1-6 alkyl group means an aryl C 1-6 alkyloxy C 1-6 alkyl group such as benzyloxymethyl and phenethyl oxymethyl group.
The aryloxy group is preferably a phenoxy group or a naphthyloxy group.
　アシル基は、ホルミル基、スクシニル基、グルタリル基、マレオイル基、フタロイル基、Ｃ２－６アルカノイル基、アロイル基、複素環式カルボニル基又は（α－置換）アミノアセチル基であることが好ましい。
　Ｃ２－６アルカノイル基とは、アセチル、プロピオニル、バレリル、イソバレリル及びピバロイル基などの直鎖状又は分枝鎖状のＣ２－６アルカノイル基を意味する。
　アロイル基とは、芳香族アシル基を意味し、ベンゾイル基又はナフトイル基であることが好ましい。
　複素環式カルボニル基とは、フロイル、テノイル、ピロリジニルカルボニル、ピペリジニルカルボニル、ピペラジニルカルボニル、モルホリニルカルボニル又はピリジニルカルボニル基を意味する。
　（α－置換）アミノアセチル基とは、アミノ酸（グリシン、アラニン、バリン、ロイシン、イソロイシン、セリン、トレオニン、システイン、メチオニン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、アルギニン、リジン、ヒスチジン、ヒドロキシリジン、フェニルアラニン、チロシン、トリプトファン、プロリン及びヒドロキシプロリンなどのアミノ酸が挙げられる。）から誘導されるＮ末端が保護されてもよい（α－置換）アミノアセチル基を意味する。 The acyl group is preferably a formyl group, a succinyl group, a glutalyl group, a maleoil group, a phthaloyl group, a C 2-6 alkanoyl group, an aroyl group, a heterocyclic carbonyl group or a (α-substituted) aminoacetyl group.
The C 2-6 alkanoyl group means a linear or branched C 2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
The aloyl group means an aromatic acyl group, and is preferably a benzoyl group or a naphthoyl group.
The heterocyclic carbonyl group means a fluoroyl, tenoyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl or pyridinylcarbonyl group.
The (α-substituted) aminoacetyl group is an amino acid (glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, aspartic acid, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine. , Amino acids such as tyrosine, tryptophan, proline and hydroxyproline) may be protected at the N-terminal (α-substituted) aminoacetyl group.
　アシルＣ１－６アルキル基とは、アセチルメチル、ベンゾイルメチル及び１－ベンゾイルエチル基などのアシルＣ１－６アルキル基を意味する。
　アシルオキシＣ１－６アルキル基とは、アセトキシメチル、プロピオニルオキシメチル、ピバロイルオキシメチル、ベンゾイルオキシメチル及び１－（ベンゾイルオキシ）エチル基などのアシルオキシＣ１－６アルキル基を意味する。
　Ｃ１－６アルコキシカルボニル基とは、メトキシカルボニル、エトキシカルボニル、イソプロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニル及び１，１－ジメチルプロポキシカルボニル基などの直鎖状又は分枝鎖状のＣ１－６アルキルオキシカルボニル基を意味する。
　アリールＣ１－６アルコキシカルボニル基とは、ベンジルオキシカルボニル及びフェネチルオキシカルボニル基などのアリールＣ１－６アルキルオキシカルボニル基を意味する。
　アリールオキシカルボニル基は、フェニルオキシカルボニル基又はナフチルオキシカルボニル基であることが好ましい。 The acyl C 1-6 alkyl group means an acyl C 1-6 alkyl group such as acetylmethyl, benzoylmethyl and 1-benzoylethyl group.
And acyloxy C 1-6 alkyl group means acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, an acyloxy C 1-6 alkyl group such as benzoyloxymethyl and 1 (benzoyloxy) ethyl.
The C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 alkyloxy such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl group. It means a carbonyl group.
The aryl C 1-6 alkoxycarbonyl group means an aryl C 1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.
The aryloxycarbonyl group is preferably a phenyloxycarbonyl group or a naphthyloxycarbonyl group.
　Ｃ１－６アルキルアミノ基とは、メチルアミノ、エチルアミノ、プロピルアミノ、イソプロピルアミノ、シクロプロピルアミノ、ブチルアミノ、ｓｅｃ－ブチルアミノ、ｔｅｒｔ－ブチルアミノ、シクロブチルアミノ、ペンチルアミノ、シクロペンチルアミノ、ヘキシルアミノ及びシクロヘキシルアミノ基などの直鎖状、分枝鎖状又は環状のＣ１－６アルキルアミノ基を意味する。
　ジ（Ｃ１－６アルキル）アミノ基とは、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、ジイソプロピルアミノ、ジブチルアミノ、ジ（ｔｅｒｔ－ブチル）アミノ、ジペンチルアミノ、ジヘキシルアミノ、（エチル）（メチル）アミノ、（メチル）（プロピル）アミノ、（シクロプロピル）（メチル）アミノ、（シクロブチル）（メチル）アミノ及び（シクロヘキシル）（メチル）アミノ基などの直鎖状、分枝鎖状又は環状のジ（Ｃ１－６アルキル）アミノ基を意味する。 C 1-6 alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, sec-butylamino, tert-butylamino, cyclobutylamino, pentylamino, cyclopentylamino, hexyl. It means a linear, branched or cyclic C 1-6 alkylamino group such as amino and cyclohexylamino groups.
The di (C 1-6 alkyl) amino groups are dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino, Linear, branched or cyclic di (C 1 ) such as (methyl) (propyl) amino, (cyclopropyl) (methyl) amino, (cyclobutyl) (methyl) amino and (cyclohexyl) (methyl) amino groups. -6 alkyl) means an amino group.
　Ｃ２－７アルキルアミド基とは、アセチルアミド、プロピオニルアミド、バレリルアミド、イソバレリルアミド及びピバロイルアミド基などの直鎖状又は分枝鎖状のＣ２－７アルキルアミド基を意味する。
　Ｃ７－１１アリールアミド基とは、フェニルアミド及びナフチルアミド基などのＣ７－１１アリールアミド基を意味する。 The C 2-7 alkylamide group means a linear or branched C 2-7 alkylamide group such as an acetylamide, a propionylamide, a valerylamide, an isovalerylamide and a pivaloylamide group.
The C 7-11 arylamide group means a C 7-11 arylamide group such as a phenylamide and a naphthylamide group.
　Ｃ１－６アルキルスルホニル基とは、メタンスルホニル、エタンスルホニル、ヘキサンスルホニル及びシクロヘキサンスルホニル基などの直鎖状、分枝鎖状又は環状のＣ１－６アルカンスルホニル基を意味する。 The C 1-6 alkyl sulfonyl group means a linear, branched or cyclic C 1-6 alkane sulfonyl group such as methanesulfonyl, ethanesulfonyl, hexanesulfonyl and cyclohexanesulfonyl groups.
　ヘテロアリール基とは、芳香族ヘテロ環基を意味し、芳香族ヘテロ環、芳香族炭化水素環、ヘテロ脂肪族環又は脂肪族炭化水素環が縮環した芳香族ヘテロ環基であってもよく、単環の含窒素ヘテロアリール基、単環の含酸素ヘテロアリール基、単環の含硫黄ヘテロアリール基、単環の含窒素含酸素ヘテロアリール基、単環の含窒素含硫黄ヘテロアリール基、二環式の含窒素ヘテロアリール基、二環式の含酸素ヘテロアリール基、二環式の含硫黄ヘテロアリール基、二環式の含窒素含酸素ヘテロアリール基又は二環式の含窒素含硫黄ヘテロアリール基であることが好ましい。
　また、芳香族ヘテロ環とは、環員にヘテロ原子を有する芳香環を意味し、芳香族ヘテロ環、芳香族炭化水素環、ヘテロ脂肪族環又は脂肪族炭化水素環が縮環していてもよく、単環の含窒素芳香族ヘテロ環、単環の含酸素芳香族ヘテロ環、単環の含硫黄芳香族ヘテロ環、単環の含窒素含酸素芳香族ヘテロ環、単環の含窒素含硫黄芳香族ヘテロ環、二環式の含窒素芳香族ヘテロ環、二環式の含酸素芳香族ヘテロ環、二環式の含硫黄芳香族ヘテロ環、二環式の含窒素含酸素芳香族ヘテロ環又は二環式の含窒素含硫黄芳香族ヘテロ環であることが好ましい。
　単環の含窒素ヘテロアリール基とは、ピロリニル、ピロリル、テトラヒドロピリジル、ピリジル、イミダゾリニル、イミダゾリル、ピラゾリニル、ピラゾリル、ピラジニル、ピリダジニル、ピリミジニル、トリアゾリル及びテトラゾリル基などの少なくとも１つの窒素原子を含む環が芳香族性を有するヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。このヘテロアリール基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　単環の含酸素ヘテロアリール基とは、フラニル又はピラニル基などの少なくとも１つの酸素原子を含む環が芳香族性を有するヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。このヘテロアリール基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　単環の含硫黄ヘテロアリール基とは、チエニル基などの少なくとも１つの硫黄原子を含む環が芳香族性を有するヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。このヘテロアリール基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　単環の含窒素含酸素ヘテロアリール基とは、オキサゾリル、イソオキサゾリル又はオキサジアゾリル基などを意味する。このヘテロアリール基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　単環の含窒素含硫黄ヘテロアリール基とは、チアゾリル、イソチアゾリル又はチアジアゾリル基などを意味する。このヘテロアリール基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　二環式の含窒素ヘテロアリール基とは、インドリル、イソインドリル、ベンズイミダゾリル、インダゾリル、ベンゾトリアゾリル、キノリル、イソキノリル、テトラヒドロキノリル、テトラヒドロイソキノリル、キノリジニル、シンノリニル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル、ピロロピリジル、イミダゾピリジル、ピラゾロピリジル、ピリドピラジル、プリニル、プテリジニル、５，６，７，８－テトラヒドロフタラジニル、５，６，７，８－テトラヒドロシンノリニル、１，２，３，４－テトラヒドロピリド［２，３－ｄ］ピリダジニル、５，６，７，８－テトラヒドロ－［１，２，４］トリアゾロ［４，３－ａ］ピラジニル、５，６，７，８－テトラヒドロピリド［３，４－ｄ］ピリダジニル、５，６，７，８－テトラヒドロピリド［３，２－ｃ］ピリダジニル、５，６，７，８－テトラヒドロピリド［４，３－ｃ］ピリダジニル、６，７－ジヒドロ－５Ｈ－シクロペンタ［ｄ］ピリダジニル、６，７－ジヒドロ－５Ｈ－シクロペンタ［ｃ］ピリダジニル、２，３－ジヒドロ－１Ｈ－ピロロ［２，３－ｄ］ピリダジニル、６，７－ジヒドロ－５Ｈ－ピロロ［３，４－ｄ］ピリダジニル、６，７－ジヒドロ－５Ｈ－ピロロ［３，２－ｃ］ピリダジニル、６，７－ジヒドロ－５Ｈ－ピロロ［３，４－ｃ］ピリダジニル及び６，７－ジヒドロ－５Ｈ－ピロロ［２，３－ｃ］ピリダジニル基などの少なくとも１つの窒素原子を含む環が芳香族性を有する二環式のヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。
　二環式の含酸素ヘテロアリール基とは、ベンゾフラニル、イソベンゾフラニル及びクロメニル基などの少なくとも１つの酸素原子を含む環が芳香族性を有する二環式のヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。
　二環式の含硫黄ヘテロアリール基とは、ベンゾチエニル基などの少なくとも１つの硫黄原子を含む環が芳香族性を有する二環式のヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。
　二環式の含窒素含酸素ヘテロアリール基とは、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾオキサジアゾリル、ジヒドロピラノピリジル、ジヒドロジオキシノピリジル、ジヒドロピリドオキサジエニル、３，４－ジヒドロ－２Ｈ－ピラノ［２，３－ｄ］ピリダジニル、７，８－ジヒドロ－５Ｈ－ピラノ［３，４－ｄ］ピリダジニル、７，８－ジヒドロ－６Ｈ－ピラノ［３，２－ｃ］ピリダジニル、７，８－ジヒドロ－５Ｈ－ピラノ［４，３－ｃ］ピリダジニル、２，３－ジヒドロフロ［２，３－ｄ］ピリダジニル、５，７－ジヒドロフロ［３，４－ｄ］ピリダジニル、６，７－ジヒドロフロ［３，２－ｃ］ピリダジニル、５，７－ジヒドロフロ［３，４－ｃ］ピリダジニル及び５，６－ジヒドロフロ［２，３－ｃ］ピリダジニル基などの少なくとも１つの窒素原子と少なくとも１つの酸素原子とを含む環が芳香族性を有する二環式のヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。
　二環式の含窒素含硫黄ヘテロアリール基とは、ベンゾチアゾリル、ベンゾイソチアゾリル、ベンゾチアジアゾリル及びチアゾロピリジル基などの少なくとも１つの窒素原子と少なくとも１つの硫黄原子とを含む環が芳香族性を有する二環式のヘテロアリール基（このヘテロアリール基は、一部飽和されていてもよい。）を意味する。 The heteroaryl group means an aromatic heterocyclic group, and may be an aromatic heterocyclic group in which an aromatic heterocycle, an aromatic hydrocarbon ring, a heteroaliphatic ring, or an aliphatic hydrocarbon ring is fused. , Monocyclic nitrogen-containing heteroaryl group, monocyclic oxygen-containing heteroaryl group, monocyclic sulfur-containing heteroaryl group, monocyclic nitrogen-containing oxygen-containing heteroaryl group, monocyclic nitrogen-containing sulfur-containing heteroaryl group, Bicyclic nitrogen-containing heteroaryl group, bicyclic oxygen-containing heteroaryl group, bicyclic sulfur-containing heteroaryl group, bicyclic nitrogen-containing oxygen-containing heteroaryl group or bicyclic nitrogen-containing heteroaryl group It is preferably a heteroaryl group.
Further, the aromatic hetero ring means an aromatic ring having a hetero atom as a ring member, and even if the aromatic hetero ring, the aromatic hydrocarbon ring, the heteroaromatic ring or the aliphatic hydrocarbon ring is fused. Often, monocyclic nitrogen-containing aromatic heterocycles, monocyclic oxygen-containing aromatic heterocycles, monocyclic sulfur-containing aromatic heterocycles, monocyclic nitrogen-containing oxygen-containing aromatic heterocycles, monocyclic nitrogen-containing heterocycles Sulfur aromatic hetero rings, bicyclic nitrogen-containing aromatic hetero rings, bicyclic oxygen-containing aromatic hetero rings, bicyclic sulfur-containing aromatic hetero rings, bicyclic nitrogen-containing oxygen-containing aromatic hetero rings It is preferably a ring- or bicyclic nitrogen-containing sulfur-containing aromatic hetero ring.
The monocyclic nitrogen-containing heteroaryl group has an aromatic ring containing at least one nitrogen atom such as pyrrolinyl, pyrrolyl, tetrahydropyridyl, pyridyl, imidazolinyl, imidazolyl, pyrazolinyl, pyrazolyl, pyrazinyl, pyridadinyl, pyrimidinyl, triazolyl and tetrazolyl groups. It means a heteroaryl group having a group property (this heteroaryl group may be partially saturated). This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
The monocyclic oxygen-containing heteroaryl group is a heteroaryl group in which the ring containing at least one oxygen atom such as a furanyl or pyranyl group has aromaticity (this heteroaryl group may be partially saturated. ) Means. This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
The monocyclic sulfur-containing heteroaryl group is a heteroaryl group having an aromatic ring containing at least one sulfur atom such as a thienyl group (this heteroaryl group may be partially saturated). means. This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
The monocyclic nitrogen-containing oxygen-containing heteroaryl group means an oxazolyl, an isooxazolyl, an oxadiazolyl group, or the like. This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
The monocyclic nitrogen-containing sulfur-containing heteroaryl group means a thiazolyl, isothiazolyl, thiadiazolyl group or the like. This heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.
Bicyclic nitrogen-containing heteroaryl groups include indolyl, isoindrill, benzimidazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthylidineyl. , Pyrrolopyridyl, imidazolepyridyl, pyrazolopyridyl, pyridopyrazil, prynyl, pteridinyl, 5,6,7,8-tetrahydrophthalazinyl, 5,6,7,8-tetrahydrocinnolinyl, 1,2,3,4- Tetrahydropyrido [2,3-d] pyridadinyl, 5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazinyl, 5,6,7,8-tetrahydropyrido [3,4-d] pyridadinyl, 5,6,7,8-tetrahydropyrido [3,2-c] pyridadinyl, 5,6,7,8-tetrahydropyrido [4,3-c] pyridadinyl, 6 , 7-Dihydro-5H-cyclopenta [d] pyridadinyl, 6,7-dihydro-5H-cyclopenta [c] pyridadinyl, 2,3-dihydro-1H-pyrrolo [2,3-d] pyridadinyl, 6,7-dihydro -5H-pyrrolo [3,4-d] pyridadinyl, 6,7-dihydro-5H-pyrrolo [3,2-c] pyridadinyl, 6,7-dihydro-5H-pyrrolo [3,4-c] pyridadinyl and 6 , 7-Dihydro-5H-pyrrolo [2,3-c] Bicyclic heteroaryl group in which the ring containing at least one nitrogen atom such as pyridazinyl group is aromatic (this heteroaryl group is partially saturated. It may be).
The bicyclic oxygen-containing heteroaryl group is a bicyclic heteroaryl group in which the ring containing at least one oxygen atom such as benzofuranyl, isobenzofuranyl and chromenyl group has aromaticity (this heteroaryl group is , May be partially saturated.)
A bicyclic sulfur-containing heteroaryl group is a bicyclic heteroaryl group in which a ring containing at least one sulfur atom such as a benzothienyl group has aromaticity (this heteroaryl group is partially saturated. May be.) Means.
The bicyclic nitrogen-containing oxygen-containing heteroaryl groups are benzoxazolyl, benzoisooxazolyl, benzoxadiazolyl, dihydropyranopyridyl, dihydrodioxynopyridyl, dihydropyridoxazienyl, 3,4. -Dihydro-2H-pyrano [2,3-d] pyridadinyl, 7,8-dihydro-5H-pyrano [3,4-d] pyridadinyl, 7,8-dihydro-6H-pyridazinyl [3,2-c] pyridadinyl , 7,8-Dihydro-5H-pyrano [4,3-c] pyridadinyl, 2,3-dihydroflo [2,3-d] pyridadinyl, 5,7-dihydroflo [3,4-d] pyridadinyl, 6,7 At least one nitrogen atom and at least one nitrogen atom, such as -dihydroflo [3,2-c] pyridadinyl, 5,7-dihydroflo [3,4-c] pyridadinyl and 5,6-dihydroflo [2,3-c] pyridadinyl groups. It means a bicyclic heteroaryl group having an aromatic ring containing an oxygen atom (this heteroaryl group may be partially saturated).
The bicyclic nitrogen-containing sulfur-containing heteroaryl group has an aromatic ring containing at least one nitrogen atom and at least one sulfur atom such as benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl and thiazolopyridyl group. It means a dicyclic heteroaryl group having a property (this heteroaryl group may be partially saturated).
　ヘテロ脂肪族環基とは、含窒素ヘテロ脂肪族環基、含酸素ヘテロ脂肪族環基、含硫黄ヘテロ脂肪族環基、含窒素含酸素ヘテロ脂肪族環基、含窒素含硫黄ヘテロ脂肪族環基、ヘテロ架橋環基又はヘテロスピロ環基を意味する。
　また、ヘテロ脂肪族環とは、環員にヘテロ原子を有する脂肪族環を意味し、含窒素ヘテロ脂肪族環、含酸素ヘテロ脂肪族環、含硫黄ヘテロ脂肪族環、含窒素含酸素ヘテロ脂肪族環、含窒素含硫黄ヘテロ脂肪族環、ヘテロ架橋環、及び、ヘテロスピロ環が好ましく挙げられる。
　含窒素ヘテロ脂肪族環基とは、アゼチジニル、ピロリジニル、ピペリジニル、ホモピペリジニル、オクタヒドロアゾシニル、イミダゾリジニル、ピラゾリジニル、ピペラジニル及びホモピペラジニル基などの少なくとも１つの窒素原子を含む環が芳香族性を有さないヘテロ脂肪族環基を意味する。この含窒素ヘテロ脂肪族環基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　含酸素ヘテロ脂肪族環基とは、テトラヒドロフラニル、テトラヒドロピラニル、オキセタニル又は１，３－ジオキサニル基などを意味する。この含酸素ヘテロ脂肪族環基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　含硫黄ヘテロ脂肪族環基とは、テトラヒドロチエニル又はテトラヒドロチオピラニル基などを意味する。この含硫黄ヘテロ脂肪族環基は、硫黄原子が酸化された基を含み、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　含窒素含酸素ヘテロ脂肪族環基とは、モルホリニル又は１，４－オキサゼパニル基などを意味する。この含窒素含酸素ヘテロ脂肪族環基は、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　含窒素含硫黄ヘテロ脂肪族環基とは、チオモルホリニル基などを意味する。この含窒素含硫黄ヘテロ脂肪族環基は、硫黄原子が酸化された基を含み、更に他の芳香族環又は脂肪族環と縮合していてもよい。
　ヘテロ架橋環基とは、３－アザ－６－オキサビシクロ［３．１．１］ヘプチル、３－アザ－８－オキサビシクロ［３．２．１］オクチル及び８－アザ－３－オキサビシクロ［３．２．１］オクチル基などの少なくとも１つのヘテロ原子（例えば、酸素原子、窒素原子、硫黄原子）を含むヘテロ架橋環基を意味する。
　また、ヘテロ架橋環とは、２以上のヘテロ脂肪族環が縮環した環、又は、１以上のヘテロ脂肪族環と１以上の脂肪族炭化水素環とが縮環した環を意味し、３－アザ－６－オキサビシクロ［３．１．１］ヘプタン環、３－アザ－８－オキサビシクロ［３．２．１］オクタン環及び８－アザ－３－オキサビシクロ［３．２．１］オクタン環が好ましく挙げられる。
　ヘテロスピロ環基とは、２－アザスピロ［３．３］ヘプチル、２－オキサスピロ［３．３］ヘプチル、６－アザ－２－オキサスピロ［３．３］ヘプチル、１－アザスピロ［４．５］デシル及び１－オキサスピロ［４．５］デシル基などの少なくとも１つのヘテロ原子（例えば、酸素原子、窒素原子、硫黄原子）を含むヘテロスピロ環基を意味する。
　ヘテロ脂肪族環Ｃ１－８アルキル基とは、ピロリジニルメチル基、ピロリジニルエチル基、ピロリジニルプロピル基、ピロリジニルオクチル基、ピペリジニルメチル基、テトラヒドロフラニルメチル基などのヘテロ脂肪族環基が結合した直鎖状、分枝鎖状又は環状のＣ１－８アルキル基を意味する。 The heteroaliphatic ring group is a nitrogen-containing heteroaliphatic ring group, an oxygen-containing heteroaliphatic ring group, a sulfur-containing heteroaliphatic ring group, a nitrogen-containing oxygen-containing heteroaliphatic ring group, and a nitrogen-containing sulfur-containing heteroaliphatic ring. It means a group, a heterobridged ring group or a heterospiro ring group.
The heteroaliphatic ring means an aliphatic ring having a heteroatom as a ring member, and is a nitrogen-containing heteroaliphatic ring, an oxygen-containing heteroaliphatic ring, a sulfur-containing heteroaliphatic ring, and a nitrogen-containing oxygen-containing heterofat. Preferred examples thereof include a group ring, a nitrogen-containing sulfur-containing heteroaliphatic ring, a heterobridged ring, and a heterospiro ring.
The nitrogen-containing heteroaliphatic ring group is a hetero whose ring containing at least one nitrogen atom such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, pyrazolydinyl, piperazinyl and homopiperazinyl group has no aromaticity. It means an aliphatic ring group. This nitrogen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.
The oxygen-containing heteroaliphatic ring group means a tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, 1,3-dioxanyl group or the like. This oxygen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.
The sulfur-containing heteroaliphatic ring group means a tetrahydrothienyl group, a tetrahydrothiopyranyl group, or the like. This sulfur-containing heteroaliphatic ring group contains a group in which a sulfur atom is oxidized, and may be further condensed with another aromatic ring or an aliphatic ring.
The nitrogen-containing oxygen-containing heteroaliphatic ring group means a morpholinyl group, a 1,4-oxazepanyl group, or the like. This nitrogen-containing oxygen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.
The nitrogen-containing sulfur-containing heteroaliphatic ring group means a thiomorpholinyl group or the like. This nitrogen-containing sulfur-containing heteroaliphatic ring group contains a group in which a sulfur atom is oxidized, and may be further condensed with another aromatic ring or an aliphatic ring.
Heterobridged ring groups are 3-aza-6-oxabicyclo [3.1.1] heptyl, 3-aza-8-oxabicyclo [3.2.1] octyl and 8-aza-3-oxabicyclo [ 3.2.1] Means a heterocrosslinked ring group containing at least one heteroatom (eg, oxygen atom, nitrogen atom, sulfur atom) such as an octyl group.
The heterobridged ring means a ring in which two or more heteroaliphatic rings are fused, or a ring in which one or more heteroaliphatic rings and one or more aliphatic hydrocarbon rings are fused. -Aza-6-oxabicyclo [3.1.1] heptane ring, 3-aza-8-oxabicyclo [3.2.1] octane ring and 8-aza-3-oxabicyclo [3.2.1] An octane ring is preferred.
Heterospiro ring groups include 2-azaspiro [3.3] heptyl, 2-oxaspiro [3.3] heptyl, 6-aza-2-oxaspiro [3.3] heptyl, 1-azaspiro [4.5] decyl and 1-Oxaspiro [4.5] means a heterospirocyclic group containing at least one heteroatom (eg, oxygen atom, nitrogen atom, sulfur atom) such as a decyl group.
The heteroaliphatic ring C 1-8 alkyl group is a hetero such as pyrrolidinyl methyl group, pyrrolidinyl ethyl group, pyrrolidinyl propyl group, pyrrolidinyl octyl group, piperidinyl methyl group and tetrahydrofuranyl methyl group. It means a linear, branched or cyclic C 1-8 alkyl group to which an aliphatic ring group is bonded.
　また、本開示におけるヒドロキシ基、一置換又は無置換アミノ基、及び、カルボキシ基は、保護されていてもよい。
　ヒドロキシ基の保護基としては、通常のヒドロキシ基の保護基として使用し得るすべての基が挙げられ、例えば、Ｔ．Ｗ．グリーン（T. W. Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第16～299頁、2007年、ジョン・ワイリー・アンド・サンズ社（JohnWiley & Sons,INC.）に記載されている基が挙げられる。具体的には例えば、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、アリールＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アリールＣ１－６アルコキシＣ１－６アルキル基、アシル基、Ｃ１－６アルコキシカルボニル基、アリールＣ１－６アルコキシカルボニル基、Ｃ１－６アルキルスルホニル基、アリールスルホニル基、シリル基、テトラヒドロフラニル基又はテトラヒドロピラニル基が挙げられる。 In addition, the hydroxy group, monosubstituted or unsubstituted amino group, and carboxy group in the present disclosure may be protected.
Hydroxy group protecting groups include all groups that can be used as conventional hydroxy group protecting groups, such as T.I. W. TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, The groups described in INC.) Can be mentioned. Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy C 1-6. Examples thereof include an alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an aryl C 1-6 alkoxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group.
　一置換又は無置換アミノ基の保護基としては、通常のアミノ基の保護基として使用し得るすべての基を含み、例えば、Ｔ．Ｗ．グリーン（T. W. Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第696～926頁、2007年、ジョン・ワイリー・アンド・サンズ社（John Wiley & Sons, INC.）に記載されている基が挙げられる。具体的には例えば、アリールＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アシル基、Ｃ１－６アルコキシカルボニル基、アリールＣ１－６アルコキシカルボニル基、アリールオキシカルボニル基、Ｃ１－６アルキルスルホニル基、アリールスルホニル基又はシリル基が挙げられる。 The monosubstituted or unsubstituted amino group protecting groups include all groups that can be used as ordinary amino group protecting groups, for example, T.I. W. TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons , INC.). Specifically, for example, an aryl C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an aryl C 1-6 alkoxycarbonyl group, and an aryloxycarbonyl group. , C 1-6 alkylsulfonyl group, arylsulfonyl group or silyl group.
　カルボキシ基の保護基としては、通常のカルボキシ基の保護基として使用し得るすべての基を含み、例えば、Ｔ．Ｗ．グリーン（T. W. Greene）ら、プロテクティブ・グループス・イン・オーガニック・シンセシス（Protective Groups in Organic Synthesis）第4版、第533～643頁、2007年、ジョン・ワイリー・アンド・サンズ社（John Wiley & Sons, INC.）に記載されている基が挙げられる。具体的には例えば、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、アリール基、アリールＣ１－６アルキル基、Ｃ１－６アルコキシＣ１－６アルキル基、アリールＣ１－６アルコキシＣ１－６アルキル基、アシルＣ１－６アルキル基、アシルオキシＣ１－６アルキル基又はシリル基が挙げられる。 Carboxy-protecting groups include all groups that can be used as conventional carboxy-protecting groups, such as T.I. W. TW Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 533-643, 2007, John Wiley & Sons , INC.). Specifically, for example, C 1-6 alkyl group, C 2-6 alkenyl group, aryl group, aryl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, aryl C 1-6 alkoxy C. Examples thereof include 1-6 alkyl groups, acyl C 1-6 alkyl groups, acyloxy C 1-6 alkyl groups and silyl groups.
　本開示において、予防とは、発症の阻害、発症リスクの低減又は発症の遅延などを意味する。
　本開示において、治療とは、対象となる疾患又は状態の改善又は進行の抑制などを意味する。
　本開示において、処置とは、各種疾患に対する予防又は治療などを意味する。
　本開示において、処置剤とは、各種疾患に対して予防又は治療などの目的で供せられる物質を意味する。 In the present disclosure, prevention means inhibition of onset, reduction of onset risk, delay on onset, and the like.
In the present disclosure, treatment means improvement or suppression of progression of a disease or condition of interest.
In the present disclosure, treatment means prevention or treatment for various diseases.
In the present disclosure, the therapeutic agent means a substance provided for the purpose of prevention or treatment for various diseases.
　本開示において、ヒストン脱アセチル化酵素（ＨＤＡＣ）が関与する疾患とは、ＨＤＡＣを阻害することにより予防又は治療が可能なあらゆる疾患を意味する。 In the present disclosure, a disease involving histone deacetylase (HDAC) means any disease that can be prevented or treated by inhibiting HDAC.
（アミド化合物又はその塩）
　本開示に係るアミド化合物又はその塩は、下記式（Ｉ－１）で表されるアミド化合物又はその塩である。 (Amid compound or salt thereof)
The amide compound or a salt thereof according to the present disclosure is an amide compound represented by the following formula (I-1) or a salt thereof.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　式（Ｉ－１）において、
　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ５のうち少なくとも１つはフッ素原子であり、
　２個のＲ５が結合して環を形成してもよく、
　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
　Ｌ１は、０又は１を表す。 In formula (I-1)
R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
All R 1 ~ R 4 are not hydrogen atoms at the same time,
R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 5 is a fluorine atom,
Two R 5 may be combined with each other to form a ring,
R 6 represents a hydrogen atom or a C 1-10 alkyl group.
L1 represents 0 or 1.
　本発明者らは、上記課題に対し鋭意検討を重ねた結果、式（Ｉ－１）で表されるアミド化合物又はその塩が、ＨＤＡＣ阻害作用を有することを見出した。
　本開示に係るアミド化合物又はその塩は、ヒストン脱アセチル化酵素が関与する疾患の処置剤として好適に用いることができる。
　また、本開示に係るアミド化合物又はその塩は、ヒストン脱アセチル化酵素阻害剤、又は、Ｚｎを有するメタロプロテアーゼ阻害剤として好適に用いることができる。 As a result of diligent studies on the above problems, the present inventors have found that the amide compound represented by the formula (I-1) or a salt thereof has an HDAC inhibitory effect.
The amide compound or a salt thereof according to the present disclosure can be suitably used as a therapeutic agent for diseases involving histone deacetylase.
Further, the amide compound or a salt thereof according to the present disclosure can be suitably used as a histone deacetylase inhibitor or a metalloprotease inhibitor having Zn.
　式（Ｉ－１）におけるＲ５、Ｒ６及びＬ１を説明した後、Ｒ１～Ｒ４について説明する。
　式（Ｉ－１）におけるＲ５はそれぞれ独立に、ＨＤＡＣ阻害性の観点から、水素原子、又は、フッ素原子であることが好ましく、全てのＲ５がフッ素原子であることがより好ましい。
　式（Ｉ－１）におけるＲ６は、ＨＤＡＣ阻害性の観点から、水素原子、又は、メチル基であることが好ましく、水素原子であることがより好ましい。
　式（Ｉ－１）におけるＬ１は、ＨＤＡＣ阻害性の観点から、１であることが好ましい。 After explaining R 5 , R 6 and L 1 in the formula (I-1) , R 1 to R 4 will be described.
From the viewpoint of HDAC inhibition, R 5 in the formula (I-1) is preferably a hydrogen atom or a fluorine atom, and more preferably all R 5s are fluorine atoms.
R 6 in the formula (I-1), from the viewpoint of HDAC inhibitory, hydrogen atom, or, preferably a methyl group, and more preferably a hydrogen atom.
L1 in the formula (I-1) is preferably 1 from the viewpoint of HDAC inhibitory property.
　式（１）におけるＲ１～Ｒ４は、ＨＤＡＣ阻害性の観点から、Ｒ１とＲ２とが一体となって、置換基を有してもよいアルキリデン基を形成し、かつＲ３及びＲ４が水素原子であるか、又は、Ｒ１～Ｒ４は一体となって、置換基を有してもよい芳香族炭化水素環若しくは置換基を有してもよい芳香族ヘテロ環を形成していることが好ましく、Ｒ１～Ｒ４は一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成していることがより好ましく、Ｒ１～Ｒ４は一体となって、置換基を有してもよい芳香族炭化水素環を形成していることが特に好ましい。
　また、Ｒ１～Ｒ４が一体となって形成する「置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環」は、ＨＤＡＣ阻害性の観点から、置換基を有してもよいベンゼン環、置換基を有してもよいチオフェン環又は置換基を有してもよいピラゾール環であることが好ましく、置換基を有してもよいベンゼン環であることがより好ましい。 In R 1 to R 4 in the formula (1), from the viewpoint of HDAC inhibitory property, R 1 and R 2 are integrated to form an alkylidene group which may have a substituent, and R 3 and R are R. 4 is a hydrogen atom, or R 1 to R 4 are united to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent. R 1 to R 4 are integrally formed to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent. More preferably, R 1 to R 4 are integrated to form an aromatic hydrocarbon ring which may have a substituent.
Further, the "aromatic hydrocarbon ring which may have a substituent or the aromatic heterocycle which may have a substituent" formed by integrating R 1 to R 4 is from the viewpoint of HDAC inhibitory property. , A benzene ring which may have a substituent, a thiophene ring which may have a substituent, or a pyrazole ring which may have a substituent, preferably a benzene ring which may have a substituent. More preferably.
　式（Ｉ－１）のＲ１～Ｒ４が有してもよい置換基としては、特に制限はないが、重水素原子、ハロゲン原子、アルキル基、アルケニル基、アルキニル基、アリール基、ヘテロアリール基、ヘテロ脂肪族環基、ヒドロキシ基、アルコキシ基、アリーロキシ基、アシル基、アシルオキシ基、カルボキシ基、アルコキシカルボニル基、アリーロキシカルボニル基、アルキルチオ基、アリールチオ基、－Ｎ（Ｒｓｔ）－ＣＯ－Ｒｓｔ、－ＣＯＮ（Ｒｓｔ）２、アミノ基、アルキルアミノ基、アリールアミノ基、ジアルキルアミノ基、アルキルアリールアミノ基、ジアリールアミノ基、ウレア基、ウレタン基、シアノ基、ニトロ基、アルキルスルフィニル基、アリールスルフィニル基、アルキルスルホンアミド基、アリールスルホンアミド基、アルキルスルホニル基、アリールスルホニル基、オキソ基、並びに、これらの基及びこれらの基から水素原子を１つ以上除いた基よりなる群から選ばれた少なくとも１種の基を２以上組み合わせた基等が挙げられる。なお、Ｒｓｔはそれぞれ独立に、水素原子、アルキル基又はアリール基を表す。また、２以上の置換基が結合して、環構造を形成していてもよい。
　また、上記置換基の炭素数は、０～５０であることが好ましく、１～３０であることがより好ましく、１～２５であることが更に好ましく、１～２０であることが特に好ましい。
　式（Ｉ－１）のＲ１～Ｒ４が一体となって形成する上記芳香族炭化水素環又は上記芳香族ヘテロ環上に有してもよい置換基（後述するＲ１１、Ｒ１２、Ｒ１３などの芳香族炭化水素環又は芳香族ヘテロ環上の置換基も同様である。）は、ＨＤＡＣ阻害性の観点から、
ハロゲン原子、ヒドロキシ基、カルボキシ基、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２であることが好ましい。
　Ｒ１～Ｒ４が一体となって形成する上記芳香族炭化水素環又は上記芳香族ヘテロ環上に有してもよい置換基としては、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２であることが好ましく、
　－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４であることが特に好ましい。 The substituents that R 1 to R 4 of the formula (I-1) may have are not particularly limited, but are a heavy hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl. Group, heteroaliphatic ring group, hydroxy group, alkoxy group, allyloxy group, acyl group, acyloxy group, carboxy group, alkoxycarbonyl group, allyloxycarbonyl group, alkylthio group, arylthio group, -N (R st ) -CO- R st , -CON (R st ) 2 , amino group, alkylamino group, arylamino group, dialkylamino group, alkylarylamino group, diarylamino group, urea group, urethane group, cyano group, nitro group, alkylsulfinyl group , Arylsulfonyl group, alkylsulfonamide group, arylsulfonamide group, alkylsulfonyl group, arylsulfonyl group, oxo group, and a group consisting of these groups and a group obtained by removing one or more hydrogen atoms from these groups. Examples thereof include a group in which two or more groups of at least one of the above are combined. In addition, R st independently represents a hydrogen atom, an alkyl group or an aryl group. Further, two or more substituents may be bonded to form a ring structure.
The carbon number of the substituent is preferably 0 to 50, more preferably 1 to 30, further preferably 1 to 25, and particularly preferably 1 to 20.
R 1 ~ R 4 is R 11 also may be a substituent (described later have on the aromatic hydrocarbon ring or the aromatic hetero ring formed together of the formula (I-1), R 12 , R The same applies to substituents on aromatic hydrocarbon rings or aromatic heterocycles such as 13.) From the viewpoint of HDAC inhibitory property.
Halogen atom, hydroxy group, carboxy group,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 is preferable.
Examples of the aromatic hydrocarbon ring or the substituent which may have on the aromatic heterocycle R 1 ~ R 4 form together,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May be C 3-8 cycloalkyl group,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 is preferable.
-L 2- NR 51 C (O) R 54 is particularly preferable.
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいＣ１－１０アルキル基、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいＣ３－８シクロアルキル基、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよい架橋式炭化水素環基、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいヘテロ脂肪族環基、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいアリール基、又は、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいヘテロアリール基を表し、
　Ｌ２は、単結合、又は、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいアルキレン基を表す。以下、他の構造式により表されるもの（式（ＩＩ－１）、（ＩＩ－２）、（ＩＩ－３）、（ＩＩ－４）など）でも、Ｒ５１、Ｒ５２、Ｒ５３、Ｒ５４、Ｌ２で示される原子、置換基又は連結基などは、特に説明しない限り、同じ意味であり、好適な範囲も同じである。
　Ｒ５１は、ＨＤＡＣ阻害性の観点から、水素原子、又は、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいＣ１－１０アルキル基であることが好ましく、水素原子であることがより好ましい。
　Ｒ５２及びＲ５４はそれぞれ独立に、ＨＤＡＣ阻害性の観点から、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいＣ１－１０アルキル基、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいアリール基、又は、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいヘテロアリール基であることが好ましく、
置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいアリール基、又は、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいヘテロアリール基であることがより好ましい。上記アリール基としては、フェニル基、ナフチル基が好ましい。上記ヘテロアリール基としては、単環の含窒素ヘテロアリール基が好ましく、ピロリル、ピロゾリルがより好ましい。
　Ｒ５３は、ＨＤＡＣ阻害性の観点から、水素原子、又は、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいＣ１－１０アルキル基であることが好ましく、置換基群Ａ１から選ばれる１つ以上の置換基を有してもよいＣ１－１０アルキル基であることがより好ましい。 R 51 , R 52 , R 53 and R 54 may each independently have a hydrogen atom and one or more substituents selected from the substituent group A 1. C 1-10 alkyl group, substituent group A. one or more may have a substituent C 3-8 cycloalkyl group selected from 1, may have one or more substituents selected from substituent group a 1 crosslinked hydrocarbon ring group , one or more may have a substituent heteroaliphatic ring group, one or more aryl group which may have a substituent selected from substituent group a 1 selected from substituent group a 1, or represents a heteroaryl group which may have one or more substituents selected from substituent group a 1,
L 2 represents a single bond, or represents one or more alkylene group which may have a substituent selected from Substituent Group A 1. Hereinafter, even those represented by other structural formulas (formulas (II-1), (II-2), (II-3), (II-4), etc.) are also R 51 , R 52 , R 53 , R. 54, atoms represented by L 2, etc. substituent or linking group, unless otherwise noted, have the same meaning, the preferred range is also the same.
R 51, in view of the HDAC inhibitory, hydrogen atom, or is preferably one or more may have a substituent group C 1-10 alkyl group selected from Substituent Group A 1, a hydrogen atom Is more preferable.
R 52 and R 54 are independently from the C 1-10 alkyl group, substituent group A 1 , which may have one or more substituents selected from the substituent group A 1 from the viewpoint of HDAC inhibitory property. one or more optionally substituted aryl group selected, or is preferably one or more may have a substituent group heteroaryl group selected from substituent group a 1,
One or more optionally substituted aryl group selected from Substituent Group A 1, or, is a heteroaryl group which may have one or more substituents selected from Substituent Group A 1 Is more preferable. As the aryl group, a phenyl group and a naphthyl group are preferable. As the heteroaryl group, a monocyclic nitrogen-containing heteroaryl group is preferable, and pyrrolyl and pyrozolyl are more preferable.
From the viewpoint of HDAC inhibitory property, R 53 is preferably a hydrogen atom or a C 1-10 alkyl group which may have one or more substituents selected from the substituent group A 1, and is preferably a substituent. and more preferably have one or more substituents selected from the group a 1 is optionally C 1-10 alkyl group.
　上記Ｌ２としては、置換基を有してもよいＣ１－１０アルキレン基が好ましく、置換基を有してもよいＣ１－６アルキレン基が好ましく、置換基を有してもよいＣ１－３アルキレン基がより好ましく、ＨＤＡＣ阻害性の観点から、メチレン基が特に好ましい。
　Ｌ２における好ましい置換基としては、ハロゲン原子、ヒドロキシ基、カルボキシ基、Ｃ１－１０アルキル基、Ｃ２－１０アルケニル基、Ｃ２－１０アルキニル基、Ｃ１－６アルコキシ基、Ｃ１－６アルコキシＣ１－１０アルキル基、Ｃ１－６アルコキシカルボニル基が挙げられ、複数の置換基を有してもよい。中でも、ハロゲン原子、ヒドロキシ基、カルボキシ基、Ｃ１－１０アルキル基が好ましい。 As the above L 2 , a C 1-10 alkylene group which may have a substituent is preferable, a C 1-6 alkylene group which may have a substituent is preferable, and C 1 which may have a substituent is preferable. -3 The alkylene group is more preferable, and the methylene group is particularly preferable from the viewpoint of HDAC inhibitory property.
Preferred substituents in L 2 are halogen atom, hydroxy group, carboxy group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 1-6 alkoxy group, C 1-6. Examples thereof include an alkoxy C 1-10 alkyl group and a C 1-6 alkoxycarbonyl group, which may have a plurality of substituents. Of these, a halogen atom, a hydroxy group, a carboxy group, and a C 1-10 alkyl group are preferable.
＜置換基群Ａ１＞
　ハロゲン原子、ヒドロキシ基、カルボキシ基、アミノ基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ１－６アルキルアミノ基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいジ（Ｃ１－６アルキル）アミノ基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ１－１０アルキル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ２－１０アルケニル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ２－１０アルキニル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ３－８シクロアルキル基、
置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいアリール基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいヘテロアリール基、
置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいアリールＣ１－１０アルキル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ１－６アルコキシ基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいアリールオキシカルボニル基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ２－７アルキルアミド基、置換基群Ｂ１から選ばれる１つ以上の置換基を有してもよいＣ７－１１アリールアミド基。
　置換基群Ａ１としては、Ｃ１－１０アルキル基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルＣ１－１０アルキル基、アリールＣ１－１０アルキル基、ヘテロアリールＣ１－１０アルキル基が好ましい。 <Substituent group A 1 >
Halogen atom, hydroxy group, carboxy group, an amino group, one or more may have a substituent group C 1-6 alkylamino group selected from substituent group B 1, one selected from substituent group B 1 Di (C 1-6 alkyl) amino group which may have the above-mentioned substituents, C 1-10 alkyl groups which may have one or more substituents selected from the substituent group B 1 , and substituents. one or more may have a substituent group C 2-10 alkenyl group selected from the group B 1, which may have one or more substituents selected from substituent group B 1 C 2-10 alkynyl group, which may have one or more substituents selected from substituent group B 1 C 3-8 cycloalkyl group,
One or more aryl group which may have a substituent selected from Substituent Group B 1, one or more may have a substituent group heteroaryl group selected from substituent group B 1,
Have one or more may have a substituent C 3-8 cycloalkyl C 1-10 alkyl group, one or more substituents selected from substituent group B 1 selected from substituent group B 1 May have an aryl C 1-10 alkyl group, a heteroaryl C 1-10 alkyl group which may have one or more substituents selected from the substituent group B 1.
One or more may have a substituent group C 1-6 alkoxy group selected from substituent group B 1, which may have one or more substituents selected from substituent group B 1 C 1- 6 alkoxy C 1-10 alkyl group which may have one or more substituents selected from substituent group B 1 C 1-6 alkoxycarbonyl group, one or more substituents selected from substituent group B 1 an aryloxy group which may have a group, one or more may have a substituent group C 2-7 alkyl amide group selected from substituent group B 1, one selected from substituent group B 1 A C 7-11 arylamide group which may have the above substituents.
The substituent group A 1 includes a C 1-10 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 cycloalkyl C 1-10 alkyl group, an aryl C 1-10 alkyl group, and a heteroaryl C 1-10. Alkyl groups are preferred.
＜置換基群Ｂ１＞
　ハロゲン原子、ヒドロキシ基、カルボキシ基、アミノ基、Ｃ１－６アルキルアミノ基、ジ（Ｃ１－６アルキル）アミノ基、Ｃ１－１０アルキル基、Ｃ３－８シクロアルキル基、アリール基、ヘテロアリール基、Ｃ１－６アルコキシ基、Ｃ２－７アルキルアミド基、Ｃ７－１１アリールアミド基。 <Substituent group B 1 >
Halogen atom, hydroxy group, carboxy group, amino group, C 1-6 alkyl amino group, di (C 1-6 alkyl) amino group, C 1-10 alkyl group, C 3-8 cycloalkyl group, aryl group, hetero Aryl group, C 1-6 alkoxy group, C 2-7 alkylamide group, C 7-11 arylamide group.
　式（Ｉ－１）で表されるアミド化合物の塩としては、通常知られているアミノ基などの塩基性基における塩、及び、ヒドロキシ基又はカルボキシ基などの酸性基における塩等を挙げることができる。好ましい塩としては、薬理学的に許容される塩が挙げられる。以下、他の構造の化合物でも同様である。 Examples of the salt of the amide compound represented by the formula (I-1) include commonly known salts of basic groups such as amino groups, salts of acidic groups such as hydroxy groups and carboxy groups, and the like. can. Preferred salts include pharmacologically acceptable salts. Hereinafter, the same applies to compounds having other structures.
　上記式（Ｉ－１）で表されるアミド化合物又はその塩は、ＨＤＡＣ阻害性の観点から、下記式（ＩＩ－１）～式（ＩＩ－４）のいずれかで表されるアミド化合物又はその塩であることが好ましく、下記式（ＩＩ－１）～式（ＩＩ－３）のいずれかで表されるアミド化合物又はその塩であることがより好ましく、下記式（ＩＩ－１）又は式（ＩＩ－２）で表されるアミド化合物又はその塩であることが更に好ましい。 The amide compound represented by the above formula (I-1) or a salt thereof is an amide compound represented by any of the following formulas (II-1) to (II-4) or a salt thereof from the viewpoint of HDAC inhibitory property. It is preferably a salt, more preferably an amide compound represented by any of the following formulas (II-1) to (II-3) or a salt thereof, and the following formula (II-1) or formula (II-1). It is more preferably an amide compound represented by II-2) or a salt thereof.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　式（ＩＩ－１）中、
　Ｒ１１はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルケニル基、置換基を有してもよいアリールＣ２－１０アルケニル基、置換基を有してもよいヘテロアリールＣ２－１０アルケニル基、
置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、又は、置換基を有してもよいヘテロアリール基を表し、
　Ｌ２は、単結合、又は、置換基を有してもよいアルキレン基（直鎖が好ましい）を表し、
　ｍ１は、１～４の整数を表す。 In formula (II-1),
R 11 is independently a halogen atom, a hydroxy group, a carboxy group,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
C 3-8 cycloalkyl C 2-10 alkenyl group which may have a substituent, aryl C 2-10 alkenyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkenyl groups,
An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 , representing
R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. It may have a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, or a substituent. Represents a heteroaryl group
L 2 represents an alkylene group (preferably a straight chain) which may have a single bond or a substituent.
m1 represents an integer of 1 to 4.
　上記式（ＩＩ－１）におけるＲ１１の好ましい態様は、上記式（Ｉ－１）におけるＲ１～Ｒ４が一体となって形成する上記芳香族炭化水素環又は上記芳香族ヘテロ環上に有してもよい置換基の好ましい態様と同様である。以下、構造式が異なるもの（式（ＩＩ－１Ａ））でも、Ｒ１１で示される置換基は、特に説明しない限り、同じ意味であり、好適な範囲も同じである。 A preferred embodiment of R 11 in the above formula (II-1) is on the above aromatic hydrocarbon ring or the above aromatic heterocycle formed by integrally forming R 1 to R 4 in the above formula (I-1). This is the same as the preferred embodiment of the substituent which may be used. Hereinafter, even if the structural formulas are different (formula (II-1A)), the substituents represented by R 11 have the same meaning and the same suitable range unless otherwise specified.
　上記式（ＩＩ－１）におけるｍ１は、ＨＤＡＣ阻害性の観点から、１又は２であることが好ましく、１であることがより好ましい。
　また、ｍ１が１である場合、上記式（ＩＩ－１）におけるＲ１１の置換位置は、ＨＤＡＣ阻害性の観点から、下記式（ＩＩ－１Ａ）に示す位置であることが好ましい。すなわち、上記式（ＩＩ－１）で表される化合物は、ＨＤＡＣ阻害性の観点から、下記式（ＩＩ－１Ａ）で表される化合物であることが好ましい。 From the viewpoint of HDAC inhibitory property, m1 in the above formula (II-1) is preferably 1 or 2, and more preferably 1.
When m1 is 1, the substitution position of R 11 in the above formula (II-1) is preferably the position represented by the following formula (II-1A) from the viewpoint of HDAC inhibitory property. That is, the compound represented by the above formula (II-1) is preferably a compound represented by the following formula (II-1A) from the viewpoint of HDAC inhibitory property.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　式（ＩＩ－２）中、
　Ｒ１２は、上述したＲ１１と同義であり、好ましい態様も同様であり、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４は、上述したＲ５１、Ｒ５２、Ｒ５３及びＲ５４と同義であり、好ましい態様も同様であり、
　Ｌ２は、上述したＬ２と同義であり、好ましい態様も同様であり、
　ｍ２は、１又は２を表す。 In formula (II-2),
R 12 has the same meaning as R 11 described above, and the preferred embodiment is also the same.
R 51 , R 52 , R 53 and R 54 are synonymous with the above-mentioned R 51 , R 52 , R 53 and R 54 , and the preferred embodiments are also the same.
L 2 has the same meaning as L 2 described above, and the preferred embodiment is also the same.
m2 represents 1 or 2.
　上記式（ＩＩ－２）におけるＲ１２の好ましい態様は、上記式（Ｉ－１）におけるＲ１～Ｒ４が一体となって形成する上記芳香族炭化水素環又は上記芳香族ヘテロ環上に有してもよい置換基の好ましい態様と同様である。以下、構造式が異なるもの（式（ＩＩ－２Ａ））でも、Ｒ１１で示される置換基は、特に説明しない限り、同じ意味であり、好適な範囲も同じである。 A preferred embodiment of R 12 in the above formula (II-2) is on the above aromatic hydrocarbon ring or the above aromatic hetero ring formed by integrally forming R 1 to R 4 in the above formula (I-1). This is the same as the preferred embodiment of the substituent which may be used. Hereinafter, even if the structural formulas are different (formula (II-2A)), the substituents represented by R 11 have the same meaning and the same suitable range unless otherwise specified.
　上記式（ＩＩ－２）におけるｍ２は、ＨＤＡＣ阻害性の観点から、１であることが好ましい。
　また、ｍ２が１である場合、上記式（ＩＩ－２）におけるＲ１２の置換位置は、ＨＤＡＣ阻害性の観点から、下記式（ＩＩ－２Ａ）に示す位置であることが好ましい。すなわち、上記式（ＩＩ－２）で表される化合物は、ＨＤＡＣ阻害性の観点から、下記式（ＩＩ－２Ａ）で表される化合物であることが好ましい。 The m2 in the above formula (II-2) is preferably 1 from the viewpoint of HDAC inhibitory property.
When m2 is 1, the substitution position of R 12 in the above formula (II-2) is preferably the position shown in the following formula (II-2A) from the viewpoint of HDAC inhibitory property. That is, the compound represented by the above formula (II-2) is preferably a compound represented by the following formula (II-2A) from the viewpoint of HDAC inhibitory property.
Figure JPOXMLDOC01-appb-C000021
 
Figure JPOXMLDOC01-appb-C000021
 
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　式（ＩＩ－３）中、
　Ｘはそれぞれ独立に、Ｎ、ＮＨ又はＮＲ１３を表し、
　Ｒ１３は、上述したＲ１１と同義であり、好ましい態様も同様であり、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４は、上述したＲ５１、Ｒ５２、Ｒ５３及びＲ５４と同義であり、好ましい態様も同様であり、
　Ｌ２は、上述したＬ２と同義であり、好ましい態様も同様であり、
　ｍ３は、０～２の整数を表す。 In formula (II-3),
X independently represents N, NH or NR 13.
R 13 has the same meaning as R 11 described above, and the preferred embodiment is also the same.
R 51 , R 52 , R 53 and R 54 are synonymous with the above-mentioned R 51 , R 52 , R 53 and R 54 , and the preferred embodiments are also the same.
L 2 has the same meaning as L 2 described above, and the preferred embodiment is also the same.
m3 represents an integer of 0 to 2.
　上記式（ＩＩ－３）におけるＸは、１つのＸがＮであり、かつもう１つのＸがＮＨであることが好ましい。
　上記式（ＩＩ－３）におけるｍ３は、ＨＤＡＣ阻害性の観点から、０又は１であることが好ましく、０であることがより好ましい。
　また、ｍ３が０である場合、上記式（ＩＩ－３）で表される化合物は、ＨＤＡＣ阻害性の観点から、下記式（ＩＩ－３Ａ）で表される化合物であることが好ましい。 As for X in the above formula (II-3), it is preferable that one X is N and the other X is NH.
From the viewpoint of HDAC inhibitory property, m3 in the above formula (II-3) is preferably 0 or 1, and more preferably 0.
When m3 is 0, the compound represented by the above formula (II-3) is preferably a compound represented by the following formula (II-3A) from the viewpoint of HDAC inhibitory property.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　上記式（ＩＩ－３）におけるＲ１３の好ましい態様は、上記式（ＩＩ－１）におけるＲ１１の好ましい態様と同様である。
　また、中でも、上記式（ＩＩ－３）におけるＲ１３は、ＨＤＡＣ阻害性の観点から、置換基群Ａ３から選択される１つ以上の置換基で置換されていてもよいＣ１－１０アルキル基、置換基群Ａ３から選択される１つ以上の置換基で置換されていてもよいＣ２－６アルケニル基、置換基群Ａ３から選択される１つ以上の置換基で置換されていてもよいＣ２－６アルキニル基、又は、置換基群Ａ３から選択される１つ以上の置換基で置換されていてもよいアミド基であることが好ましい。
＜置換基群Ａ３＞
　置換基を有してもよいカルバモイル基、置換基を有してもよいアリール基、及び、置換基を有してもよいヘテロアリール基 The preferred embodiment of R 13 in the above formula (II-3) is the same as the preferred embodiment of R 11 in the above formula (II-1).
Further, among them, R 13 in the above Formula (II-3), from the viewpoint of HDAC inhibitory, one or more substituents which may C 1-10 optionally alkyl substituted by selected from substituent group A 3 group, substituted with one or more optionally substituted with a substituent C 2-6 alkenyl group, one or more substituents selected from the substituent group a 3 is selected from the substituent group a 3 which may be C 2-6 alkynyl group, or is preferably one or more substituents which may be an amide group substituted in selected from substituent group a 3.
<Substituent group A 3 >
A carbamoyl group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　式（ＩＩ－４）中、
　Ｒ１４～Ｒ１７はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルケニル基、置換基を有してもよいアリールＣ２－１０アルケニル基、置換基を有してもよいヘテロアリールＣ２－１０アルケニル基、
置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
－Ｌ２－ＮＲ５１Ｒ５２、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
－Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
－Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
－Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
－Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、又は、置換基を有してもよいヘテロアリール基を表し、
　Ｌ２は、単結合、又は、置換基を有してもよいアルキレン基を表し、
　Ｒ１４とＲ１５とが、又は、Ｒ１６とＲ１７とが一体となって、置換基を有してもよいＣ１－６アルキリデン基を形成してもよい。
　ただし、Ｒ１４～Ｒ１７の全てが同時に水素原子となることはない。 In formula (II-4),
R 14 to R 17 are independent halogen atoms, hydroxy groups, carboxy groups,
It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
C 3-8 cycloalkyl C 2-10 alkenyl group which may have a substituent, aryl C 2-10 alkenyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkenyl groups,
An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
-L 2- NR 51 R 52 ,
-L 2- NR 51 C (O) R 54 ,
-L 2- NR 51 C (O) NR 53 R 54 ,
-L 2- NR 51 SO 2 R 54 ,
-L 2- C (O) NR 51 R 52 , or
-L 2- SO 2 NR 51 R 52 , representing
R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. It may have a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, or a substituent. Represents a heteroaryl group
L 2 represents an alkylene group which may have a single bond or a substituent.
R 14 and R 15 may be integrated, or R 16 and R 17 may be integrated to form a C 1-6 alkylidene group which may have a substituent.
However, not all of R 14 to R 17 become hydrogen atoms at the same time.
　上記式（ＩＩ－４）におけるＲ１４～Ｒ１７はそれぞれ独立に、ＨＤＡＣ阻害性の観点から、水素原子、置換基群Ａ４から選択される１つ以上の置換基で置換されていてもよいＣ１－１０アルキル基、置換基群Ａ４から選択される１つ以上の置換基で置換されていてもよいＣ２－６アルケニル基、置換基群Ａ４から選択される１つ以上の置換基で置換されていてもよいＣ２－６アルキニル基、又は、Ｒ１４とＲ１５とが若しくはＲ１６とＲ１７とが結合して、置換基群Ａ４から選択される１つ以上の置換基で置換されていてもよいＣ１－６アルキリデン基であることが好ましい。
＜置換基群Ａ４＞
　置換基を有してもよいアリール基、及び、置換基を有してもよいヘテロアリール基。 Each independently R 14 ~ R 17 in formula (II-4), in view of the HDAC inhibitory, hydrogen atom, it may be substituted with one or more substituents selected from substituent group A 4 C 1-10 alkyl group, one or more optionally substituted with a substituent C 2-6 alkenyl group selected from substituent group a 4, one or more substituents selected from substituent group a 4 good C 2-6 alkynyl group optionally substituted with a group, or by bonding the R 14 and R 15 guilt or R 16 and R 17, 1 or more substituents selected from substituent group a 4 It is preferably a C 1-6 alkylidene group which may be substituted with a group.
<Substituent group A 4 >
An aryl group which may have a substituent and a heteroaryl group which may have a substituent.
　上記式（ＩＩ－４）において、ＨＤＡＣ阻害性の観点から、少なくとも、Ｒ１４とＲ１５とが又はＲ１６とＲ１７とが結合して、置換基群Ａ４から選択される１つ以上の置換基で置換されていてもよいＣ１－６アルキリデン基であることがより好ましく、Ｒ１４とＲ１５とが結合して、置換基群Ａ４から選択される１つ以上の置換基で置換されていてもよいＣ１－６アルキリデン基であることが更に好ましい。
　更に、上記式（ＩＩ－４）において、ＨＤＡＣ阻害性の観点から、Ｒ１４とＲ１５とが結合して、上述した置換基群Ａ１から選択される１つ以上の置換基を有してもよいフェニルメチリデン基、又は、上述した置換基群Ａ１から選択される１つ以上の置換基を有してもよい２－チエニルメチリデン基であり、かつ、Ｒ１６及びＲ１７が水素原子であることが特に好ましい。 In the above formula (II-4), in view of the HDAC inhibitory, at least, by bonding with R 14 and R 15 guilt or R 16 and R 17, 1 or more selected from the substituent group A 4 more preferably it is an optionally substituted C 1-6 alkylidene group substituents, by bonding with R 14 and R 15, substituted with one or more substituents selected from substituent group a 4 It is more preferably a C 1-6 alkylidene group which may be used.
Further, in the above formula (II-4), in view of the HDAC inhibitory, by bonding with R 14 and R 15, have one or more substituents selected from Substituent Group A 1 described above It is also a phenylmethylidene group, or a 2-thienylmethylidene group which may have one or more substituents selected from the above-mentioned substituent group A 1 , and R 16 and R 17 are hydrogens. It is particularly preferred to be an atom.
　式（Ｉ－１）で表されるアミド化合物又はその塩の好ましい具体例を以下に示すが、これらに限定されないことは、言うまでもない。 Preferred specific examples of the amide compound represented by the formula (I-1) or a salt thereof are shown below, but it goes without saying that the amide compound is not limited thereto.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
＜式（Ｉ－１）で表されるアミド化合物又はその塩の合成方法＞
　式（Ｉ－１）で表されるアミド化合物の合成方法は、特に制限はないが、例えば、イソインドリン化合物又はピロリジン化合物に、３，３，３－トリフルオロ－２－ヒドロキシプロパン酸を反応させ、式（Ｉ－１）で表されるアミド化合物を得る方法が好適に挙げられる。
　また、イソインドリン化合物又はピロリジン化合物については、公知の方法により置換基等を変換して合成してもよいし、鈴木－宮浦カップリング等の芳香族化合物のクロスカップリング反応を行い、必要に応じて置換基等を変換して合成してもよい。
　また、各原料化合物については、公知の方法を用いて、又は、公知の方法を参照して合成することができる。
　また、式（Ｉ－１）で表されるアミド化合物を、公知の塩形成方法により、式（１）で表されるアミド化合物の塩とすることができる。
　また、式（１）で表されるアミド化合物は、カラムクロマトグラフィー、薄層クロマトグラフィー、再結晶、再沈殿等の公知の精製方法により精製することもできる。 <Method for synthesizing an amide compound represented by the formula (I-1) or a salt thereof>
The method for synthesizing the amide compound represented by the formula (I-1) is not particularly limited, but for example, an isoindoline compound or a pyrrolidine compound is reacted with 3,3,3-trifluoro-2-hydroxypropanoic acid. , A method for obtaining an amide compound represented by the formula (I-1) is preferably mentioned.
Further, the isoindoline compound or the pyrrolidine compound may be synthesized by converting a substituent or the like by a known method, or a cross-coupling reaction of an aromatic compound such as Suzuki-Miyaura coupling may be carried out, if necessary. The substituents and the like may be converted and synthesized.
Further, each raw material compound can be synthesized by using a known method or by referring to a known method.
Further, the amide compound represented by the formula (I-1) can be used as a salt of the amide compound represented by the formula (1) by a known salt forming method.
The amide compound represented by the formula (1) can also be purified by a known purification method such as column chromatography, thin layer chromatography, recrystallization and reprecipitation.
　また、式（Ｉ－１）で表されるアミド化合物及びその塩において、異性体（例えば、光学異性体、幾何異性体及び互変異性体など）が存在する場合、これらの異性体も使用することができる。また、溶媒和物、水和物及び種々の形状の結晶が存在する場合、これらの溶媒和物、水和物及び種々の形状の結晶も使用することができる。
　中でも、式（Ｉ－１）で表されるアミド化合物及びその塩は、式（Ｉ－１）におけるカルボニル基のヒドロキシ基及び（Ｒ５）３Ｃ－が結合している側のα位が、（Ｓ）体であることが好ましい。 Further, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present in the amide compound represented by the formula (I-1) and its salt, these isomers are also used. be able to. Further, when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used.
Of these, amide compounds and their salts represented by formula (I-1) has the formula (I-1) and hydroxy groups of the carbonyl group in (R 5) 3-position α on the side where C- is attached is It is preferably a (S) body.
　上記式（Ｉ－１）で表されるアミド化合物及びその塩の合成方法、並びに、上記式（Ｉ－１）で表されるアミド化合物及びその塩の精製方法には、公知の溶媒を用いることができる。また、公知の溶媒を、再結晶、再沈殿等における貧溶媒として用いてもよい。
　溶媒としては、特に制限はなく、水、及び、有機溶媒を用いることができる。
　有機溶媒としては、脂肪族炭化水素類、ハロゲン化炭化水素類、アルコール類、エーテル類、ケトン類、エステル類、アミド類、スルホキシド類、カルボン酸類、芳香族炭化水素類等が挙げられる。 A known solvent is used for the method for synthesizing the amide compound represented by the above formula (I-1) and its salt, and the method for purifying the amide compound represented by the above formula (I-1) and its salt. Can be done. Moreover, you may use a known solvent as a poor solvent in recrystallization, reprecipitation and the like.
The solvent is not particularly limited, and water and an organic solvent can be used.
Examples of the organic solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones, esters, amides, sulfoxides, carboxylic acids, aromatic hydrocarbons and the like.
　脂肪族炭化水素類としては、ペンタン、ヘキサン、及び、シクロヘキサンなどが好適に挙げられる。
　ハロゲン化炭化水素類としては、塩化メチレン、クロロホルム、及び、ジクロロエタンなどが好適に挙げられる。
　アルコール類としては、メタノール、エタノール、プロパノール、２－プロパノール、ブタノール、２－メチル－２－プロパノール、エチレングリコール、ジエチレングリコール、トリエチレングリコール、及び、プロピレングリコールなどが好適に挙げられる。
　エーテル類としては、ジエチルエーテル、ジイソプロピルエーテル、１，４－ジオキサン、テトラヒドロフラン、アニソール、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル、及び、ジエチレングリコールジエチルエーテルなど等が好適に挙げられる。
　ケトン類としては、アセトン、２－ブタノン、及び、４－メチル－２－ペンタノンなど等が好適に挙げられる。
　エステル類としては、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ブチル、酢酸シクロヘキシル、及び、酢酸アミルなどが好適に挙げられる。
　アミド類としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、及び、Ｎ－メチルピロリドンなどが好適に挙げられる。
　スルホキシド類としては、ジメチルスルホキシドなどが好適に挙げられる。
　カルボン酸類としては、ギ酸、酢酸、及び、トリフルオロ酢酸などが好適に挙げられる。
　芳香族炭化水素類としては、ベンゼン、トルエン、及び、キシレンなど好適に挙げられる。 Pentane, hexane, cyclohexane and the like are preferably used as the aliphatic hydrocarbons.
Preferable examples of the halogenated hydrocarbons include methylene chloride, chloroform, dichloroethane and the like.
Preferable examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol, 2-methyl-2-propanol, ethylene glycol, diethylene glycol, triethylene glycol, and propylene glycol.
Preferable examples of the ethers include diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and the like.
Preferable examples of the ketones include acetone, 2-butanone, 4-methyl-2-pentanone and the like.
Preferable examples of the esters include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, cyclohexyl acetate, and amyl acetate.
Preferable examples of the amides include N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone.
Preferable examples of sulfoxides include dimethyl sulfoxide and the like.
Preferred examples of the carboxylic acids include formic acid, acetic acid, and trifluoroacetic acid.
Preferred examples of aromatic hydrocarbons include benzene, toluene, and xylene.
（ヒストン脱アセチル化酵素阻害剤、又は、Ｚｎを有するメタロプロテアーゼ阻害剤）
　本開示に係るヒストン脱アセチル化酵素阻害剤、又は、本開示に係るＺｎを有するメタロプロテアーゼ阻害剤は、下記式（Ｉ）で表されるアミド化合物又はその塩を含有する。
　また、Ｚｎを有するメタロプロテアーゼは、触媒機構に亜鉛イオンを有するペプチド結合加水分解酵素である。金属プロテアーゼの多くが亜鉛イオンを有している。 (Histone deacetylase inhibitor or metalloprotease inhibitor having Zn)
The histone deacetylase inhibitor according to the present disclosure or the metalloprotease inhibitor having Zn according to the present disclosure contains an amide compound represented by the following formula (I) or a salt thereof.
Further, the metalloprotease having Zn is a peptide bond hydrolase having a zinc ion in the catalytic mechanism. Many metalloproteinases have zinc ions.
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　式（Ｉ）において、
　Ｒ０１は、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、又は、置換基を有してもよい炭化水素環基を表し、
　Ｒ０２は、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、又は、置換基を有してもよいヘテロ環基を表し、
　Ｒ０１とＲ０２とは一体となって、置換基を有してもよい含窒素ヘテロ環を形成していてもよく、
　Ｒ０３はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ０３のうち少なくとも１つはフッ素原子であり、
　２個のＲ０３が結合して環を形成してもよく、
　Ｒ０４は、水素原子又はＣ１－１０アルキル基を表す。 In formula (I)
R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent. Represents a hydrocarbon ring group which may have a group or a substituent,
R 02 is a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, a C 2-6 alkynyl group which may have a substituent, and a substituent. Represents a hydrocarbon ring group which may have a group or a heterocyclic group which may have a substituent.
R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 03 is a fluorine atom
Two R 03s may be combined to form a ring.
R 04 represents a hydrogen atom or a C 1-10 alkyl group.
　本開示に係るヒストン脱アセチル化酵素阻害剤、又は、本開示に係るＺｎを有するメタロプロテアーゼ阻害剤において、上記式（Ｉ）で表されるアミド化合物又はその塩は、下記式（Ｉ－０１）で表されるアミド化合物又はその塩であることが好ましい。 In the histone deacetylase inhibitor according to the present disclosure or the metalloprotease inhibitor having Zn according to the present disclosure, the amide compound represented by the above formula (I) or a salt thereof is represented by the following formula (I-01). It is preferably an amide compound represented by or a salt thereof.
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　式（Ｉ－０１）において、
　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
　Ｒ５のうち少なくとも１つはフッ素原子であり、
　２個のＲ５が結合して環を形成してもよく、
　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
　Ｌ１は、０～２の整数を表す。 In formula (I-01)
R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
All R 1 ~ R 4 are not hydrogen atoms at the same time,
R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
At least one of R 5 is a fluorine atom,
Two R 5 may be combined with each other to form a ring,
R 6 represents a hydrogen atom or a C 1-10 alkyl group.
L1 represents an integer of 0 to 2.
　本開示に係るヒストン脱アセチル化酵素阻害剤、又は、本開示に係るＺｎを有するメタロプロテアーゼ阻害剤における上記式（Ｉ－０１）で表されるアミド化合物又はその塩の好ましい態様は、Ｌ１の好ましい態様以外、本開示に係るアミド化合物又はその塩における上記式（Ｉ－１）で表されるアミド化合物又はその塩の好ましい態様と同様である。
　上記式（Ｉ－０１）で表されるアミド化合物又はその塩におけるＬ１は、ＨＤＡＣ阻害性の観点から、０又は１であることが好ましく、１であることがより好ましい。 A preferred embodiment of the amide compound represented by the above formula (I-01) or a salt thereof in the histone deacetylase inhibitor according to the present disclosure or the metalloprotease inhibitor having Zn according to the present disclosure is preferably L1. Other than the embodiment, it is the same as the preferred embodiment of the amide compound represented by the above formula (I-1) or the salt thereof in the amide compound or the salt thereof according to the present disclosure.
From the viewpoint of HDAC inhibitory property, L1 in the amide compound represented by the above formula (I-01) or a salt thereof is preferably 0 or 1, and more preferably 1.
（医薬組成物）
　本開示に係る医薬組成物は、本開示に係るアミド化合物又はその塩、ヒストン脱アセチル化酵素阻害剤、又は、Ｚｎを有するメタロプロテアーゼ阻害剤を含む。
　本開示に係る医薬組成物は、疾患の処置剤として、特にＨＤＡＣが関与する疾患の処置剤として好適に用いることができる。
　ヒトでは、１８種類のＨＤＡＣが知られており、クラスI、クラスII、クラスIII、又は、クラスIVに分類される。ヒトクラスIＨＤＡＣには、ＨＤＡＣ１，２，３及び８が含まれる。ヒトクラスIIＨＤＡＣには、ＨＤＡＣ４，５，６，７，９及び１０が含まれる。ヒトクラスIＨＤＡＣ及びヒトクラスIIＨＤＡＣの活性はＺｎ２＋依存性があり、酵素活性部位にはＺｎ２＋が存在する。
　本開示に係るアミド化合物又はその塩は、ヒトクラスIIＨＤＡＣの阻害能が高く、ヒトクラスIＨＤＡＣの阻害能が低いことから、安全性が高い。従来のヒドロキサム酸阻害剤は、ヒトクラスIＨＤＡＣ及びヒトクラスIIＨＤＡＣの全てを阻害し、強い毒性が見られた。本開示に係るアミド化合物又はその塩は、ＨＤＡＣ触媒部位のＺｎ２＋とキレートを形成し、基質のアセチル化リジンに拮抗して活性を阻害すると推定される。そのため、本開示に係るアミド化合物又はその塩は、Ｚｎを有するメタロプロテアーゼ阻害剤ともいえる。
　本開示に係るアミド化合物又はその塩は、ＨＤＡＣ６、７及び９の少なくとも１つの阻害能が高く、ＨＤＡＣ１及び２の少なくとも１つの阻害能が低い。より具体的には、本開示に係るアミド化合物又はその塩は、ＨＤＡＣ６の阻害能が高く、ＨＤＡＣ１の阻害能が低い。
　ＨＤＡＣが関与する疾患としては、ヒトクラスIIＨＤＡＣが関与する疾患が好ましく、ＨＤＡＣ６が関与する疾患が特に好ましい。本開示に係るアミド化合物又はその塩、ヒストン脱アセチル化酵素阻害剤は、ＨＤＡＣ６の選択的阻害能に優れることから、副作用の少ない医薬の創製が可能である。ＨＤＡＣが関与する疾患としては、クローン病又は潰瘍性大腸炎などの炎症性腸疾患（ＩＢＤ）が挙げられる。
　本開示に係る医薬組成物は、クローン病又は潰瘍性大腸炎などの炎症性腸疾患（ＩＢＤ）の予防又は治療用医薬組成物であることが好ましい。本開示に係る医薬組成物は、炎症の原因となる細胞を減少させることができ、炎症性サイトカインの産生を減少させることができると推定される。 (Pharmaceutical composition)
The pharmaceutical composition according to the present disclosure includes an amide compound or a salt thereof according to the present disclosure, a histone deacetylase inhibitor, or a metalloprotease inhibitor having Zn.
The pharmaceutical composition according to the present disclosure can be suitably used as a therapeutic agent for diseases, particularly as a therapeutic agent for diseases associated with HDAC.
In humans, 18 types of HDAC are known and are classified into Class I, Class II, Class III, or Class IV. Human class IHDACs include HDACs 1, 2, 3 and 8. Human Class II HDAC includes HDAC 4, 5, 6, 7, 9 and 10. The activity of human class IHDAC and human class IIHDAC is Zn 2+ dependent, and Zn 2+ is present in the enzyme active site.
The amide compound or a salt thereof according to the present disclosure is highly safe because it has a high inhibitory ability on human class IIHDAC and a low inhibitory ability on human class IIHDAC. Conventional hydroxamic acid inhibitors inhibited all human class IHDAC and human class II HDAC, and were highly toxic. It is presumed that the amide compound or a salt thereof according to the present disclosure forms a chelate with Zn 2+ at the HDAC catalyst site and antagonizes the acetylated lysine of the substrate to inhibit its activity. Therefore, the amide compound or a salt thereof according to the present disclosure can be said to be a metalloprotease inhibitor having Zn.
The amide compound or a salt thereof according to the present disclosure has a high inhibitory ability of at least one of HDACs 6, 7 and 9, and a low inhibitory ability of at least one of HDACs 1 and 2. More specifically, the amide compound or a salt thereof according to the present disclosure has a high inhibitory ability of HDAC6 and a low inhibitory ability of HDAC1.
As the disease involving HDAC, a disease involving human class II HDAC is preferable, and a disease involving HDAC6 is particularly preferable. Since the amide compound or its salt and histone deacetylase inhibitor according to the present disclosure are excellent in the selective inhibitory ability of HDAC6, it is possible to create a drug having few side effects. Diseases associated with HDAC include inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis.
The pharmaceutical composition according to the present disclosure is preferably a pharmaceutical composition for the prevention or treatment of inflammatory bowel disease (IBD) such as Crohn's disease or ulcerative colitis. It is presumed that the pharmaceutical composition according to the present disclosure can reduce the cells that cause inflammation and can reduce the production of inflammatory cytokines.
　本開示に係る医薬組成物を用いる対象は、哺乳動物等の動物、例えば、霊長類（例、ヒト、サル等）が挙げられるが、これらに限定されない。上記対象は、ヒトであることが好ましい。
　本開示に係る医薬組成物は、種々の剤形により処方することができる。
　本開示に係る医薬組成物は、薬理学的に許容される添加物を適宜混合してもよい。
　添加物としては、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、矯味剤、着色剤、着香剤、界面活性剤、コーティング剤、可塑剤等の公知の添加物が挙げられる。
　これらの添加物は、いずれか一種又は二種以上を組み合わせて用いてもよい。 The subject of using the pharmaceutical composition according to the present disclosure includes, but is not limited to, animals such as mammals, for example, primates (eg, humans, monkeys, etc.). The subject is preferably human.
The pharmaceutical composition according to the present disclosure can be formulated in various dosage forms.
The pharmaceutical composition according to the present disclosure may be appropriately mixed with pharmacologically acceptable additives.
Examples of the additive include known additives such as excipients, disintegrants, binders, lubricants, flavoring agents, colorants, flavoring agents, surfactants, coating agents, and plasticizers.
These additives may be used alone or in combination of two or more.
　以下に実施例を挙げて本発明の実施形態を更に具体的に説明する。以下の実施例に示す材料、使用量、割合、処理内容、及び、処理手順等は、本発明の実施形態の趣旨を逸脱しない限り、適宜、変更することができる。したがって、本発明の実施形態の範囲は以下に示す具体例に限定されない。なお、特に断りのない限り、「部」、「％」は質量基準である。
　また、実施例で使用したＡｍ－１～Ａｍ－４５、及び、Ａｍ－４７～Ａｍ－５０は、上述したＡｍ－１～Ａｍ－４５、及び、Ａｍ－４７～Ａｍ－５０とそれぞれ同じ化合物である。 Hereinafter, embodiments of the present invention will be described in more detail with reference to examples. The materials, amounts used, proportions, treatment contents, treatment procedures, etc. shown in the following examples can be appropriately changed as long as they do not deviate from the gist of the embodiment of the present invention. Therefore, the scope of the embodiment of the present invention is not limited to the specific examples shown below. Unless otherwise specified, "parts" and "%" are based on mass.
Further, Am-1 to Am-45 and Am-47 to Am-50 used in the examples are the same compounds as Am-1 to Am-45 and Am-47 to Am-50 described above, respectively. be.
　特に記載のない場合、シリカゲルカラムクロマトグラフィーによる精製は、自動精製装置ISOLERA（Biotage社）又は中圧液体クロマトグラフYFLC-Wprep2XY.N（山善株式会社）を使用した。
　特に記載のない場合、シリカゲルカラムクロマトグラフィーにおける担体は、SNAP KP-Sil Cartridge（Biotage社）、ハイフラッシュカラムW001、W002、W003、W004又はW005（山善株式会社）を、塩基性シリカゲルカラムクロマトグラフィーにおける担体は、SNAP KP-NH Cartridge（Biotage社）を使用した。
　特に記載のない場合、ＨＰＬＣ（高速液体クロマトグラフィー）は、Waters 600Eシステム（Waters社）を使用した。
　特に記載のない場合、ＨＰＬＣにおける担体は、SunFire C18 OBDカラム（Waters社）を使用した。
　溶離液における混合比は、容量比である。例えば、「ヘキサン：酢酸エチル＝１００：０→５０：５０」は、１００％ヘキサン／０％酢酸エチルの溶離液を最終的に５０％ヘキサン／５０％酢酸エチルの溶離液へ変化させたことを意味する。 Unless otherwise specified, purification by silica gel column chromatography was performed using an automatic purification device ISOLERA (Biotage) or a medium pressure liquid chromatograph YFLC-Wprep2XY.N (Yamazen Corporation).
Unless otherwise specified, the carrier in silica gel column chromatography is SNAP KP-Sil Cartridge (Biotage), high flash columns W001, W002, W003, W004 or W005 (Yamazen Co., Ltd.) in basic silica gel column chromatography. As a carrier, SNAP KP-NH Cartridge (Biotage) was used.
Unless otherwise stated, HPLC (High Performance Liquid Chromatography) used the Waters 600E system (Waters).
Unless otherwise stated, a SunFire C18 OBD column (Waters) was used as the carrier for HPLC.
The mixing ratio in the eluent is the volume ratio. For example, "Hexane: Ethyl Acetate = 100: 0 → 50:50" indicates that the eluate of 100% hexane / ethyl acetate was finally changed to the eluent of 50% hexane / 50% ethyl acetate. means.
　フロー式水素化反応装置は、H-Cube（ThalesNano社製）を使用した。
　マイクロウェーブ装置は、Initiator+又はInitiator Sixty（いずれもBiotage社製）を使用した。
　ＭＳスペクトルは、ACQUITY SQD LC/MS System（Waters社製、イオン化法：ESI（ElectroSpray Ionization、エレクトロスプレーイオン化）法）を用いて測定した。
　ＮＭＲスペクトルは、内部基準としてテトラメチルシランを用い、Bruker AV300（Bruker社製）又はJNM-AL400型（日本電子（株）製）を用いて測定し、全δ値をｐｐｍで示した。 As the flow type hydrogenation reactor, H-Cube (manufactured by Thales Nano) was used.
As the microwave device, Initiator + or Initiator Sixty (both manufactured by Biotage) was used.
The MS spectrum was measured using an ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization) method).
The NMR spectrum was measured using Bruker AV300 (manufactured by Bruker) or JNM-AL400 (manufactured by JEOL Ltd.) using tetramethylsilane as an internal reference, and the total δ value was shown in ppm.
　ＮＭＲ測定における略号は、以下の意味を有する。
　　ｓ：シングレット
　　ｂｒ：ブロードシングレット
　　ｄ：ダブレット
　　ｄｄ：ダブルダブレット
　　ｔ：トリプレット
　　ｍ：マルチプレット
　　ＤＭＳＯ－ｄ６：重ジメチルスルホキシド Abbreviations in NMR measurement have the following meanings.
s: Singlet br: Broad singlet d: Doublet dd: Double doublet t: Triplet m: Multiplet DMSO-d 6 : Deuterated dimethyl sulfoxide
　実施例における略号は、以下の意味を有する。
　Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
　Ｃｂｚ：ベンジルオキシカルボニル
　Ｍｅ：メチル The abbreviations in the examples have the following meanings.
Boc: tert-butoxycarbonyl Cbz: benzyloxycarbonyl Me: methyl
＜比較用化合物ＣＡｍ－１の合成＞
Figure JPOXMLDOC01-appb-C000036
 <Synthesis of comparative compound CAm-1>
Figure JPOXMLDOC01-appb-C000036
　２－フェニルエタン－１－アミン（３６ｍｇ）、３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（４３ｍｇ）、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（５８ｍｇ）及び１－ヒドロキシベンゾトリアゾール１水和物（４６ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）溶液を室温（２５℃±２℃、以下同様）で３時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１→１：１）で精製し、白色固体の３，３，３－トリフルオロ－２－ヒドロキシ－Ｎ－フェネチルプロパンアミド（ＣＡｍ－１、２２ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.30 (t, J = 5.4 Hz, 1H), 7.32-7.26 (m, 2H), 7.23-7.15 (m, 4H), 4.55-4.43 (m, 1H), 3.37-3.30 (m, 2H), 2.75 (t, J = 8.1 Hz, 2H).
　ＭＳ（ｍ／ｚ）：２４８．２（Ｍ＋Ｈ）＋ 2-Phenylethane-1-amine (36 mg), 3,3,3-trifluoro-2-hydroxypropanoic acid (43 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg) and A solution of 1-hydroxybenzotriazole monohydrate (46 mg) in N, N-dimethylformamide (0.5 mL) was stirred at room temperature (25 ° C ± 2 ° C, and so on) for 3 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to form a white solid 3,3,3-trifluoro-2-hydroxy-N-phenethylpropanamide (). CAm-1, 22 mg) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.30 (t, J = 5.4 Hz, 1H), 7.32-7.26 (m, 2H), 7.23-7.15 (m, 4H), 4.55-4.43 (m, 1H), 3.37-3.30 (m, 2H), 2.75 (t, J = 8.1 Hz, 2H).
MS (m / z): 248.2 (M + H) +
＜比較用化合物ＣＡｍ－２の合成＞
Figure JPOXMLDOC01-appb-C000037
 <Synthesis of comparative compound CAm-2>
Figure JPOXMLDOC01-appb-C000037
　比較用化合物ＣＡｍ－１の合成において、２－フェニルエタン－１－アミンを用いた代わりに、４－テトフェニルピペリジンを用いる以外は比較用化合物ＣＡｍ－１の合成と同様の方法で、白色固体の３，３，３－トリフルオロ－２－ヒドロキシ－１－（４－フェニルピペリジン－１－イル）プロパン－１－オン（ＣＡｍ－２）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=7.34-7.19 (m, 5H), 6.69-6.63 (m, 1H), 5.21-5.09 (m, 1H), 4.56-4.49 (m, 1H), 4.20-4.10 (m, 1H), 3.20-3.07 (m, 1H), 2.88-2.66 (m, 2H), 1.89-1.75 (m, 2H), 1.70-1.40 (m, 2H).
　ＭＳ（ｍ／ｚ）：２８８．２（Ｍ＋Ｈ）＋ In the synthesis of the comparative compound CAm-1, a white solid was prepared in the same manner as in the synthesis of the comparative compound CAm-1 except that 4-tetophenylpiperidine was used instead of 2-phenylethane-1-amine. 3,3,3-Trifluoro-2-hydroxy-1- (4-phenylpiperidine-1-yl) propan-1-one (CAm-2) was obtained.
1 1 H-NMR (300MHz, DMSO-d 6 ) δ = 7.34-7.19 (m, 5H), 6.69-6.63 (m, 1H), 5.21-5.09 (m, 1H), 4.56-4.49 (m, 1H), 4.20-4.10 (m, 1H), 3.20-3.07 (m, 1H), 2.88-2.66 (m, 2H), 1.89-1.75 (m, 2H), 1.70-1.40 (m, 2H).
MS (m / z): 288.2 (M + H) +
＜実施例０００１：Ａｍ－１の合成＞
Figure JPOXMLDOC01-appb-C000038
 <Example 0001: Synthesis of Am-1>
Figure JPOXMLDOC01-appb-C000038
　比較用化合物ＣＡｍ－１の合成において、２－フェニルエタン－１－アミンと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれイソインドリンと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は比較例０００１と同様の方法で、淡黄色油状の（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシ－１－（イソインドリン－２－イル）プロパン－１－オン（Ａｍ－１）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=7.41-7.29 (4H, m), 6.99 (1H, d, J = 8.1 Hz), 5.08-4.91 (3H, m), 4.72 (2H, s).
　ＭＳ（ｍ／ｚ）：２４６．２（Ｍ＋Ｈ）＋ In the synthesis of the comparative compound CAm-1, instead of using 2-phenylethane-1-amine and 3,3,3-trifluoro-2-hydroxypropanoic acid, isoindoline and (S) -3, respectively. In the same manner as in Comparative Example 0001 except that 3,3-trifluoro-2-hydroxypropanoic acid was used, the pale yellow oily (S) -3,3,3-trifluoro-2-hydroxy-1-( Isoindoline-2-yl) propan-1-one (Am-1) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 7.41-7.29 (4H, m), 6.99 (1H, d, J = 8.1 Hz), 5.08-4.91 (3H, m), 4.72 (2H, s) ..
MS (m / z): 246.2 (M + H) +
＜実施例０００２：Ａｍ－２の合成＞
－フェニル化反応－
Figure JPOXMLDOC01-appb-C000039
 <Example 0002: Synthesis of Am-2>
-Phenylation reaction-
Figure JPOXMLDOC01-appb-C000039
　ｔｅｒｔ－ブチル　５－ブロモイソインドリン－２－カルボキシラート（４５ｍｇ）、フェニルボロン酸（２７ｍｇ）、（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）メタンスルホナート（４．２ｍｇ）、リン酸カリウム（４８ｍｇ）及び水（０．２ｍＬ）の１，４－ジオキサン（０．８ｍＬ）懸濁液を、封管中、窒素雰囲気下、１００℃で１時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→７０：３０）で精製し、無色油状のｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラート（３６ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２９６．２（Ｍ＋Ｈ）＋ tert-butyl 5-bromoisoindoline-2-carboxylate (45 mg), phenylboronic acid (27 mg), (2-dicyclohexylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-Amino-1,1'-biphenyl)] Palladium (II) methanesulfonate (4.2 mg), potassium phosphate (48 mg) and water (0.2 mL) 1,4-dioxane ( 0.8 mL) The suspension was stirred in a sealed tube under a nitrogen atmosphere at 100 ° C. for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 70: 30) to obtain colorless and oily tert-butyl 5-phenylisoindoline-2-carboxylate (36 mg). ..
MS (m / z): 296.2 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000040
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000040
　ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラート（３０ｍｇ）に４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（０．５ｍＬ）を加え、室温で１時間撹拌した。減圧下で溶媒を留去し、白色固体を得た。３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（２２ｍｇ）、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（２９ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（２３ｍｇ）、トリエチルアミン（０．０４ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（１．０ｍＬ）を加え、室温で１時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：５０→３５：６５）で精製し、白色固体の３，３，３－トリフルオロ－２－ヒドロキシ－１－（５－フェニルイソインドリン－２－イル）プロパン－１－オン（Ａｍ－２、１７ｍｇ）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=7.61-7.51 (4H, m), 7.42-7.34 (3H, m), 7.32-7.27 (1H, m), 7.01-6.95 (1H, m), 5.05-4.88 (3H, m), 4.72-4.66 (2H, m).
　ＭＳ（ｍ／ｚ）：３２２．２（Ｍ＋Ｈ）＋ A 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.5 mL) was added to tert-butyl 5-phenylisoindoline-2-carboxylate (30 mg), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a white solid. 3,3,3-Trifluoro-2-hydroxypropanoic acid (22 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (29 mg), 1-hydroxybenzotriazole monohydrate (23 mg) , Triethylamine (0.04 mL) and N, N-dimethylformamide (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 → 35:65) to form a white solid 3,3,3-trifluoro-2-hydroxy-1- (5-phenyl). Isoindoline-2-yl) propane-1-one (Am-2, 17 mg) was obtained.
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ = 7.61-7.51 (4H, m), 7.42-7.34 (3H, m), 7.32-7.27 (1H, m), 7.01-6.95 (1H, m), 5.05-4.88 (3H, m), 4.72-4.66 (2H, m).
MS (m / z): 322.2 (M + H) +
＜実施例０００３：Ａｍ－３の合成＞
Figure JPOXMLDOC01-appb-C000041
 <Example 0003: Synthesis of Am-3>
Figure JPOXMLDOC01-appb-C000041
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　２，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（４Ｈ）－カルボキシラートと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体の（Ｓ）－１－（２，６－ジヒドロピロロ［３，４－ｃ］ピラゾール－５（４Ｈ）－イル）－３，３，３－トリフルオロ－２－ヒドロキシプロパン－１－オン（Ａｍ－３）を得た。
　ＭＳ（ｍ／ｚ）：２３６．２（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindrin-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. Instead of using tert-butyl 2,6-dihydropyrrolo [3,4-c] pyrazole-5 (4H) -carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropane, respectively. In the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002 except that an acid is used, the white solid (S) -1- (2,6-dihydropyrrolo [3,] 4-c] Pyrazole-5 (4H) -yl) -3,3,3-trifluoro-2-hydroxypropan-1-one (Am-3) was obtained.
MS (m / z): 236.2 (M + H) +
＜実施例０００４：Ａｍ－４の合成＞
－アミド化反応－
Figure JPOXMLDOC01-appb-C000042
 <Example 0004: Synthesis of Am-4>
-Amidation reaction-
Figure JPOXMLDOC01-appb-C000042
　ｔｅｒｔ－ブチル　５－ブロモイソインドリン－２－カルボキシラート（４５ｍｇ）、ベンズアミド（２７ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（４．５ｍｇ）、２－ジ－ｔｅｒｔ－ブチルホスフィノ－３，４，５，６－テトラメチル－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル（９．６ｍｇ）及びリン酸カリウム（６４ｍｇ）の２－メチル－２－ブタノール（０．５ｍＬ）懸濁液を、封管中、窒素雰囲気下、１１０℃で３．５時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０→５０：５０）で精製し、白色固体のｔｅｒｔ－ブチル　５－ベンズアミドイソインドリン－２－カルボキシラート（３５ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３３９．２（Ｍ＋Ｈ）＋ tert-Butyl 5-bromoisoindoline-2-carboxylate (45 mg), benzamide (27 mg), tris (dibenzylideneacetone) dipalladium (0) (4.5 mg), 2-di-tert-butylphosphino-3 , 4,5,6-tetramethyl-2', 4', 6'-triisopropyl-1,1'-biphenyl (9.6 mg) and potassium phosphate (64 mg) 2-methyl-2-butanol (0) .5 mL) The suspension was stirred in a sealed tube under a nitrogen atmosphere at 110 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20 → 50:50) to obtain a white solid tert-butyl 5-benzamide isoindoline-2-carboxylate (35 mg). ..
MS (m / z): 339.2 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000043
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000043
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートを用いた代わりに、ｔｅｒｔ－ブチル　５－ベンズアミドイソインドリン－２－カルボキシラートを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体のＮ－（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）ベンズアミド（Ａｍ－４）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=10.34 (1H, s), 7.97-7.93 (2H, m), 7.86-7.80 (1H, m), 7.68-7.57 (2H, m), 7.56-7.50 (2H, m), 7.38-7.31 (1H, m), 7.05 (1H, br), 5.08-4.90 (3H, m), 4.74-4.68 (2H, m).
　ＭＳ（ｍ／ｚ）：３６５．１（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, instead of using tert-butyl 5-phenylisoindoline-2-carboxylate, tert-butyl 5-benzamide isoindoline-2 N- (2- (3,3,3-trifluoro-) in a white solid was carried out in the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002 except that -carboxylate was used. 2-Hydroxypropanoyl) isoindoline-5-yl) benzamide (Am-4) was obtained.
1 1 H-NMR (400MHz, DMSO-d 6 ) δ = 10.34 (1H, s), 7.97-7.93 (2H, m), 7.86-7.80 (1H, m), 7.68-7.57 (2H, m), 7.56- 7.50 (2H, m), 7.38-7.31 (1H, m), 7.05 (1H, br), 5.08-4.90 (3H, m), 4.74-4.68 (2H, m).
MS (m / z): 365.1 (M + H) +
＜実施例０００５：Ａｍ－５の合成＞
Figure JPOXMLDOC01-appb-C000044
 <Example 0005: Synthesis of Am-5>
Figure JPOXMLDOC01-appb-C000044
　ｔｅｒｔ－ブチル　５－ブロモイソインドリン－２－カルボキシラート（４５ｍｇ）、アクリル酸エチル（０．０２４ｍＬ）、アリルパラジウム（II）クロリドダイマー（２．７ｍｇ）、トリ－ｔｅｒｔ－ブチルホスホニウムテトラフルオロボラート（８．７ｍｇ）及びトリエチルアミン（０．０４２ｍＬ）の１，４－ジオキサン溶液（１．０ｍＬ）を、封管中、窒素雰囲気下、１１０℃で１．５時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物に４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（１．０ｍＬ）を加え、室温で１時間撹拌した。減圧下で溶媒を留去し、褐色個体を得た。３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（３２ｍｇ）、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（４３ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（３４ｍｇ）、トリエチルアミン（０．０４ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８３：１７→５０：５０）で精製し、白色固体のエチル　３－（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）アクリラート（Ａｍ－５、２２ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３４４．１（Ｍ＋Ｈ）＋ tert-Butyl 5-bromoisoindoline-2-carboxylate (45 mg), ethyl acrylate (0.024 mL), allylpalladium (II) chloride dimer (2.7 mg), tri-tert-butylphosphonium tetrafluoroborate ( A 1,4-dioxane solution (1.0 mL) of 8.7 mg) and triethylamine (0.042 mL) was stirred in a sealed tube under a nitrogen atmosphere at 110 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a brown solid. 3,3,3-Trifluoro-2-hydroxypropanoic acid (32 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg), 1-hydroxybenzotriazole monohydrate (34 mg) , Triethylamine (0.04 mL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 83: 17 → 50:50) to form a white solid ethyl 3- (2- (3,3,3-trifluoro-2-hydroxy). Propanoyl) isoindoline-5-yl) acrylate (Am-5, 22 mg) was obtained.
MS (m / z): 344.1 (M + H) +
＜実施例０００６：Ａｍ－６の合成＞
－スルホンアミド化反応－
Figure JPOXMLDOC01-appb-C000045
 <Example 0006: Synthesis of Am-6>
-Sulfonamide reaction-
Figure JPOXMLDOC01-appb-C000045
　実施例０００４のアミド化反応において、ベンズアミドを用いた代わりに、ベンゼンスルホンアミドを用いる以外は実施例０００４のアミド化反応と同様の方法で、無色油状のｔｅｒｔ－ブチル　５－（フェニルスルホンアミド）イソインドリン－２－カルボキシラートを得た。
　ＭＳ（ｍ／ｚ）：３７３．２（Ｍ－Ｈ）－ In the amidation reaction of Example 0004, a colorless oily tert-butyl 5- (phenylsulfonamide) iso was used in the same manner as in the amidation reaction of Example 0004 except that benzenesulfonamide was used instead of benzamide. Indoline-2-carboxylate was obtained.
MS (m / z): 373.2 (MH) -
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000046
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000046
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートを用いた代わりに、ｔｅｒｔ－ブチル　５－（フェニルスルホンアミド）イソインドリン－２－カルボキシラートを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体のＮ－（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）ベンゼンスルホンアミド（Ａｍ－６）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=10.36 (1H, s), 7.78-7.74 (2H, m), 7.64-7.50 (3H, m), 7.23-7.16 (1H, m), 7.12-6.99 (2H, m), 6.95-6.90 (1H, m), 4.98-4.79 (3H, m), 4.63-4.57 (2H, m).
　ＭＳ（ｍ／ｚ）：３９９．１（Ｍ－Ｈ）－ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, instead of using tert-butyl 5-phenylisoindoline-2-carboxylate, tert-butyl 5- (phenyl sulfone amide) N- (2- (3,3,3)) of a white solid was carried out in the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002 except that isoindoline-2-carboxylate was used. -Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) benzenesulfonamide (Am-6) was obtained.
1 1 H-NMR (400MHz, DMSO-d 6 ) δ = 10.36 (1H, s), 7.78-7.74 (2H, m), 7.64-7.50 (3H, m), 7.23-7.16 (1H, m), 7.12- 6.99 (2H, m), 6.95-6.90 (1H, m), 4.98-4.79 (3H, m), 4.63-4.57 (2H, m).
MS (m / z): 399.1 (MH) -
＜実施例０００７：Ａｍ－７の合成＞
Figure JPOXMLDOC01-appb-C000047
 <Example 0007: Synthesis of Am-7>
Figure JPOXMLDOC01-appb-C000047
　ｔｅｒｔ－ブチル　５－アミノイソインドリン－２－カルボキシラート（２３ｍｇ）のテトラヒドロフラン（１．０ｍＬ）溶液にフェニルイソシアナート（０．０１６ｍＬ）を加え、６０℃で１時間撹拌した。反応混合物を室温まで冷却し、ヘキサン（５．０ｍＬ）を加えた。固形物を濾取した後、トリフルオロ酢酸（１．０ｍＬ）を加え、室温で３０分間撹拌した。減圧下で溶媒を留去し、得られた残留物に３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（２２ｍｇ）、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（２９ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（２３ｍｇ）、トリエチルアミン（０．０４ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→９０：１０）で精製し、白色固体の１－フェニル－３－（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）ウレア（Ａｍ－７、９ｍｇ）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.76 (1H, s), 8.70-8.67 (1H, m), 7.56-7.52 (1H, m), 7.47-7.43 (2H, m), 7.35-7.23 (4H, m), 7.02-6.94 (2H, m), 5.05-4.85 (3H, m), 4.71-4.64 (2H, m).
　ＭＳ（ｍ／ｚ）：３８０．２（Ｍ＋Ｈ）＋ Phenylisocyanate (0.016 mL) was added to a solution of tert-butyl 5-aminoisoindoline-2-carboxylate (23 mg) in tetrahydrofuran (1.0 mL), and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature and hexane (5.0 mL) was added. After the solid matter was collected by filtration, trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and 3,3,3-trifluoro-2-hydroxypropanoic acid (22 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added to the obtained residue. 29 mg), 1-hydroxybenzotriazole monohydrate (23 mg), triethylamine (0.04 mL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 90: 10) to form a white solid 1-phenyl-3- (2- (3,3,3-tri). Fluoro-2-hydroxypropanoyl) isoindoline-5-yl) urea (Am-7, 9 mg) was obtained.
1 1 H-NMR (400MHz, DMSO-d 6 ) δ = 8.76 (1H, s), 8.70-8.67 (1H, m), 7.56-7.52 (1H, m), 7.47-7.43 (2H, m), 7.35- 7.23 (4H, m), 7.02-6.94 (2H, m), 5.05-4.85 (3H, m), 4.71-4.64 (2H, m).
MS (m / z): 380.2 (M + H) +
＜実施例０００８：Ａｍ－８の合成＞
－フェノキシカルボニル化反応－
Figure JPOXMLDOC01-appb-C000048
 <Example 0008: Synthesis of Am-8>
-Phenoxycarbonylation reaction-
Figure JPOXMLDOC01-appb-C000048
　ｔｅｒｔ－ブチル　５－ブロモイソインドリン－２－カルボキシラート（５９６ｍｇ）、ギ酸フェニル（４８８ｍｇ）、酢酸パラジウム（１４ｍｇ）、トリ－ｔｅｒｔ－ブチルホスホニウムテトラフルオロボラート（９４ｍｇ）及びトリエチルアミン（０．５８４ｍＬ）のトルエン（２．０ｍＬ）懸濁液を、封管中、窒素雰囲気下、１００℃で８時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９０：１０→８０：２０）で精製し、淡黄色油状の２－ｔｅｒｔ－ブチル　５－フェニル　イソインドリン－２，５－ジカルボキシラート（６１７ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=8.16-8.05 (2H, m), 7.47-7.34 (3H, m), 7.31-7.18 (3H, m), 4.80-4.71 (4H, m), 1.54 (9H, s). Of tert-butyl 5-bromoisoindoline-2-carboxylate (596 mg), phenyl formate (488 mg), palladium acetate (14 mg), tri-tert-butylphosphonium tetrafluoroborate (94 mg) and triethylamine (0.584 mL) The toluene (2.0 mL) suspension was stirred in a sealed tube under a nitrogen atmosphere at 100 ° C. for 8 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 → 80:20), and the pale yellow oil 2-tert-butyl 5-phenyl isoindoline-2,5-dicarboxylate was purified. (617 mg) was obtained.
1 1 H-NMR (300MHz, CDCl 3 ) δ = 8.16-8.05 (2H, m), 7.47-7.34 (3H, m), 7.31-7.18 (3H, m), 4.80-4.71 (4H, m), 1.54 ( 9H, s).
－フェニルエステル構造の選択的還元反応－
Figure JPOXMLDOC01-appb-C000049
 -Selective reduction reaction of phenyl ester structure-
Figure JPOXMLDOC01-appb-C000049
　２－ｔｅｒｔ－ブチル　５－フェニル　イソインドリン－２，５－ジカルボキシラート（４００ｍｇ）のテトラヒドロフラン（５．０ｍＬ）溶液に、０℃で１ｍｏｌ／Ｌ水素化アルミニウムリチウム／テトラヒドロフラン溶液（１．７７ｍＬ）を加え、同温度で３０分間撹拌した。反応混合物に０℃でメタノール（１ｍＬ）を３分間かけて加えた後、５％（ｗ／ｖ）ロッシェル塩水溶液及び酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝６０：４０→４０：６０）で精製し、白色固体のｔｅｒｔ－ブチル　５－（ヒドロキシメチル）イソインドリン－２－カルボキシラート（２５４ｍｇ）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ=7.29-7.18 (3H, m), 4.70 (2H, s), 4.66-4.61 (4H, m), 2.01 (1H, br), 1.52 (9H, s). 2-tert-Butyl 5-phenyl isoindoline-2,5-dicarboxylate (400 mg) in tetrahydrofuran (5.0 mL) with 1 mol / L lithium aluminum hydride / tetrahydrofuran solution (1.77 mL) at 0 ° C. In addition, the mixture was stirred at the same temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture at 0 ° C. over 3 minutes, followed by 5% (w / v) aqueous Rochelle salt solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 60:40 → 40:60), and a white solid tert-butyl 5- (hydroxymethyl) isoindoline-2-carboxylate (254 mg) was purified. Got
1 1 H-NMR (400MHz, CDCl 3 ) δ = 7.29-7.18 (3H, m), 4.70 (2H, s), 4.66-4.61 (4H, m), 2.01 (1H, br), 1.52 (9H, s) ..
－フタルイミド化反応－
Figure JPOXMLDOC01-appb-C000050
 -Phthalimideization reaction-
Figure JPOXMLDOC01-appb-C000050
　ｔｅｒｔ－ブチル　５－（ヒドロキシメチル）イソインドリン－２－カルボキシラート（１２５ｍｇ）、トリフェニルホスフィン（２６２ｍｇ）及びフタルイミド（１６６ｍｇ）のテトラヒドロフラン（３．０ｍＬ）溶液に、０℃で１．９ｍｏｌ／Ｌアゾジカルボン酸ジイソプロピル／トルエン溶液（０．５２６ｍＬ）を加えた後、室温で１時間撹拌した。減圧下で溶媒を留去し、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝６７：３３→５０：５０）で精製し、黄色油状のｔｅｒｔ－ブチル　５－（（１，３－ジオキソイソインドリン－２－イル）メチル）イソインドリン－２－カルボキシラート（１７４ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３７９．２（Ｍ＋Ｈ）＋ tert-Butyl 5- (hydroxymethyl) isoindoline-2-carboxylate (125 mg), triphenylphosphine (262 mg) and phthalimide (166 mg) in tetrahydrofuran (3.0 mL) at 0 ° C. at 1.9 mol / L azo After adding a diisopropyl / toluene solution of dicarboxylate (0.526 mL), the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 67: 33 → 50:50) to obtain a yellow oily tert-butyl 5-((1). , 3-Dioxoisoindoline-2-yl) methyl) Isoindoline-2-carboxylate (174 mg) was obtained.
MS (m / z): 379.2 (M + H) +
－フタルイミド基のアミノ化反応－
Figure JPOXMLDOC01-appb-C000051
 -Amino acid reaction of phthalimide group-
Figure JPOXMLDOC01-appb-C000051
　ｔｅｒｔ－ブチル　５－（（１，３－ジオキソイソインドリン－２－イル）メチル）イソインドリン－２－カルボキシラート（１７４ｍｇ）のエタノール（２．０ｍＬ）溶液に、ヒドラジン１水和物（０．２ｍＬ）を加え、還流下、１．５時間撹拌した。反応混合物を室温まで冷却し、不溶物を濾去した。減圧下で溶媒を留去し、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、無色油状のｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラート（１１１ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=7.26-7.16 (3H, m), 4.69-4.62 (4H, m), 3.88 (2H, s), 1.51 (9H, s), 1.46 (2H, br).
　ＭＳ（ｍ／ｚ）：２４９．３（Ｍ＋Ｈ）＋ Hydrazine monohydrate (0.) In a solution of tert-butyl 5-((1,3-dioxoisoindoline-2-yl) methyl) isoindoline-2-carboxylate (174 mg) in ethanol (2.0 mL). 2 mL) was added, and the mixture was stirred under reflux for 1.5 hours. The reaction mixture was cooled to room temperature and the insoluble material was filtered off. The solvent was distilled off under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to obtain a colorless oily tert-butyl 5- (aminomethyl). ) Isoindoline-2-carboxylate (111 mg) was obtained.
1 1 H-NMR (300MHz, CDCl 3 ) δ = 7.26-7.16 (3H, m), 4.69-4.62 (4H, m), 3.88 (2H, s), 1.51 (9H, s), 1.46 (2H, br) ..
MS (m / z): 249.3 (M + H) +
－スルホンアミド化反応－
Figure JPOXMLDOC01-appb-C000052
 -Sulfonamide reaction-
Figure JPOXMLDOC01-appb-C000052
　ｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラート（２０ｍｇ）及びトリエチルアミン（０．０２７ｍＬ）のテトラヒドロフラン（１．０ｍＬ）溶液に、氷冷下、ベンゼンスルホニルクロリド（０．０１３ｍＬ）を加え、３０分間撹拌した。反応混合物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：５０→０：１００）で精製した。得られた残留物に４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（１．０ｍＬ）を加え、室温で１時間撹拌した。減圧下で溶媒を留去し、白色固体を得た。（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（１４ｍｇ）、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（１８ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（１５ｍｇ）、トリエチルアミン（０．０２７ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→８０：２０）で精製し、無色油状の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンゼンスルホンアミド（Ａｍ－８、３．３ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.19 (1H, br), 7.81-7.76 (2H, m), 7.62-7.55 (3H, m), 7.30-7.14 (3H, m), 7.01 (1H, br), 5.02-4.52 (5H, m), 4.00 (2H, s).
　ＭＳ（ｍ／ｚ）：４１５．３（Ｍ＋Ｈ）＋ To a solution of tert-butyl 5- (aminomethyl) isoindoline-2-carboxylate (20 mg) and triethylamine (0.027 mL) in tetrahydrofuran (1.0 mL) under ice cooling, add benzenesulfonyl chloride (0.013 mL). , Stirred for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 → 0: 100). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a white solid. (S) -3,3,3-trifluoro-2-hydroxypropanoic acid (14 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18 mg), 1-hydroxybenzotriazole monohydration The product (15 mg), triethylamine (0.027 mL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 80: 20) and was colorless and oily (S) -N- ((2- (3,3,3-)). Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzenesulfonamide (Am-8, 3.3 mg) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.19 (1H, br), 7.81-7.76 (2H, m), 7.62-7.55 (3H, m), 7.30-7.14 (3H, m), 7.01 ( 1H, br), 5.02-4.52 (5H, m), 4.00 (2H, s).
MS (m / z): 415.3 (M + H) +
＜実施例０００９：Ａｍ－９の合成＞
Figure JPOXMLDOC01-appb-C000053
 <Example 0009: Synthesis of Am-9>
Figure JPOXMLDOC01-appb-C000053
　実施例０００８のスルホンアミド化反応において、ベンゼンスルホニルクロリドを用いた代わりに、２－フェニルアセチルクロリドを用いる以外は実施例０００８のスルホンアミド化反応と同様の方法で、白色固体の（Ｓ）－２－フェニル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）アセトアミド（Ａｍ－９）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.62-8.51 (1H, m), 7.32-7.16 (8H, m), 6.99 (1H, d, J = 8.7 Hz), 5.02-4.87 (3H, m), 4.67 (2H, s), 4.27 (2H, d, J = 6.0 Hz), 3.47 (2H, s).
　ＭＳ（ｍ／ｚ）：３９３．３（Ｍ＋Ｈ）＋ In the sulfonamide reaction of Example 0008, a white solid (S) -2 was prepared in the same manner as the sulfonamide reaction of Example 0008 except that 2-phenylacetyl chloride was used instead of benzenesulfonyl chloride. -Phenyl-N- ((2- (3,3,3-trifluoro-2-hydroxypropanol) isoindrin-5-yl) methyl) acetamide (Am-9) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.62-8.51 (1H, m), 7.32-7.16 (8H, m), 6.99 (1H, d, J = 8.7 Hz), 5.02-4.87 (3H, m) m), 4.67 (2H, s), 4.27 (2H, d, J = 6.0 Hz), 3.47 (2H, s).
MS (m / z): 393.3 (M + H) +
＜実施例００１０：Ａｍ－１０の合成＞
Figure JPOXMLDOC01-appb-C000054
 <Example 0010: Synthesis of Am-10>
Figure JPOXMLDOC01-appb-C000054
　ｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラート（２０ｍｇ）、１Ｈ－インドール－６－カルボン酸（１５ｍｇ）、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（１８ｍｇ）及び１－ヒドロキシベンゾトリアゾール１水和物（１５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）溶液を室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：５０→０：１００）で精製した。得られた残留物に４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（１．０ｍＬ）を加え、室温で１時間撹拌した。減圧下で溶媒を留去し、白色固体を得た。（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（１４ｍｇ）、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（１８ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（１５ｍｇ）、トリエチルアミン（０．０２７ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→９０：１０）で精製し、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－６－カルボキサミド（Ａｍ－１０）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=11.40 (1H, s), 9.00-8.95 (1H, m), 8.00 (1H, s), 7.61-7.54 (2H, m), 7.52-7.48 (1H, m), 7.36-7.28 (3H, m), 7.00-6.94 (1H, m), 6.50-6.47 (1H, m), 5.06-4.88 (3H, m), 4.72-4.67 (2H, m), 4.50 (2H, d, J = 5.7 Hz).
　ＭＳ（ｍ／ｚ）：４１８．３（Ｍ＋Ｈ）＋ tert-butyl 5- (aminomethyl) isoindolin-2-carboxylate (20 mg), 1H-indole-6-carboxylic acid (15 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18 mg) ) And 1-hydroxybenzotriazole monohydrate (15 mg) in N, N-dimethylformamide (0.5 mL) were stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 → 0: 100). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a white solid. (S) -3,3,3-trifluoro-2-hydroxypropanoic acid (14 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18 mg), 1-hydroxybenzotriazole monohydration The product (15 mg), triethylamine (0.027 mL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 90: 10) to form a white solid (S) -N- ((2- (3,3,3-)). Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-6-carboxamide (Am-10) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 11.40 (1H, s), 9.00-8.95 (1H, m), 8.00 (1H, s), 7.61-7.54 (2H, m), 7.52-7.48 ( 1H, m), 7.36-7.28 (3H, m), 7.00-6.94 (1H, m), 6.50-6.47 (1H, m), 5.06-4.88 (3H, m), 4.72-4.67 (2H, m), 4.50 (2H, d, J = 5.7 Hz).
MS (m / z): 418.3 (M + H) +
＜実施例００１１：Ａｍ－１１の合成＞
Figure JPOXMLDOC01-appb-C000055
 <Example 0011: Synthesis of Am-11>
Figure JPOXMLDOC01-appb-C000055
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、酢酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）アセトアミド（Ａｍ－１１）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.36 (1H, t, J = 5.6 Hz), 7.34-7.18 (3H, m), 6.98 (1H, d, J = 8.4 Hz), 5.05-4.88 (3H, m), 4.71-4.68 (2H, m), 4.25 (2H, d, J = 6.0 Hz), 1.87 (3H, s).
　ＭＳ（ｍ／ｚ）：３１７．３（Ｍ＋Ｈ）＋ In Example 0010, the colorless oily (S) -N-((2- (3,3) 3) was used in the same manner as in Example 0010 except that acetic acid was used instead of 1H-indole-6-carboxylic acid. , 3-Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) acetamide (Am-11) was obtained.
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ = 8.36 (1H, t, J = 5.6 Hz), 7.34-7.18 (3H, m), 6.98 (1H, d, J = 8.4 Hz), 5.05-4.88 (3H, m), 4.71-4.68 (2H, m), 4.25 (2H, d, J = 6.0 Hz), 1.87 (3H, s).
MS (m / z): 317.3 (M + H) +
＜実施例００１２：Ａｍ－１２の合成＞
Figure JPOXMLDOC01-appb-C000056
 <Example 0012: Synthesis of Am-12>
Figure JPOXMLDOC01-appb-C000056
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、２－メトキシ安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－２－メトキシ－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－１２）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.72 (1H, t, J = 6.0 Hz), 7.75-7.71 (1H, m), 7.51-7.44 (1H, m), 7.36-7.26 (3H, m), 7.15 (1H, d, J = 7.8 Hz), 7.07-6.95 (2H, m), 5.06-4.80 (3H, m), 4.72-4.66 (2H, m), 4.50 (2H, d, J = 6.0 Hz), 3.89 (3H, s).
　ＭＳ（ｍ／ｚ）：４０９．４（Ｍ＋Ｈ）＋ In Example 0010, a colorless oily (S) -2-methoxy-N- was used in the same manner as in Example 0010 except that 2-methoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-12) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.72 (1H, t, J = 6.0 Hz), 7.75-7.71 (1H, m), 7.51-7.44 (1H, m), 7.36-7.26 (3H, m) m), 7.15 (1H, d, J = 7.8 Hz), 7.07-6.95 (2H, m), 5.06-4.80 (3H, m), 4.72-4.66 (2H, m), 4.50 (2H, d, J = 6.0 Hz), 3.89 (3H, s).
MS (m / z): 409.4 (M + H) +
＜実施例００１３：Ａｍ－１３の合成＞
Figure JPOXMLDOC01-appb-C000057
 <Example 0013: Synthesis of Am-13>
Figure JPOXMLDOC01-appb-C000057
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、３，５－ジメトキシ安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－３，５－ジメトキシ－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－１３）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=9.39 (1H, t, J = 6.0 Hz), 7.35-7.24 (3H, m), 7.06 (2H, d, J = 2.4 Hz), 7.00-6.94 (1H, m), 6.66-6.63 (1H, m), 5.05-4.87 (3H, m), 4.71-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 3.78 (6H, s).
　ＭＳ（ｍ／ｚ）：４３９．４（Ｍ＋Ｈ）＋ In Example 0010, the colorless oily (S) -3,5- was carried out in the same manner as in Example 0010 except that 3,5-dimethoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. Dimethoxy-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-13) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 9.39 (1H, t, J = 6.0 Hz), 7.35-7.24 (3H, m), 7.06 (2H, d, J = 2.4 Hz), 7.00-6.94 (1H, m), 6.66-6.63 (1H, m), 5.05-4.87 (3H, m), 4.71-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 3.78 (6H, s) ).
MS (m / z): 439.4 (M + H) +
＜実施例００１４：Ａｍ－１４の合成＞
Figure JPOXMLDOC01-appb-C000058
 <Example 0014: Synthesis of Am-14>
Figure JPOXMLDOC01-appb-C000058
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、４－アセトアミド安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－４－アセトアミド－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－１４）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=10.17 (1H, s), 8.98-8.90 (1H, m), 7.84 (2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.35-7.24 (3H, m), 7.00-6.94 (1H, m), 5.05-4.87 (3H, m), 4.72-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 2.07 (3H, s).
　ＭＳ（ｍ／ｚ）：４３６．４（Ｍ＋Ｈ）＋ In Example 0010, the colorless oily (S) -4-acetamide-N- was used in the same manner as in Example 0010 except that 4-acetamidobenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-14) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 10.17 (1H, s), 8.98-8.90 (1H, m), 7.84 (2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.35-7.24 (3H, m), 7.00-6.94 (1H, m), 5.05-4.87 (3H, m), 4.72-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz) ), 2.07 (3H, s).
MS (m / z): 436.4 (M + H) +
＜実施例００１５：Ａｍ－１５の合成＞
Figure JPOXMLDOC01-appb-C000059
 <Example 0015: Synthesis of Am-15>
Figure JPOXMLDOC01-appb-C000059
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、３－メトキシ安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－３－メトキシ－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－１５）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=9.06 (1H, t, J = 5.4 Hz), 7.50-7.24 (6H, m), 7.13-7.07 (1H, m), 7.00-6.94 (1H, m), 5.06-4.88 (3H, m), 4.72-4.66 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 3.80 (3H, s).
　ＭＳ（ｍ／ｚ）：４０９．３（Ｍ＋Ｈ）＋ In Example 0010, the colorless oily (S) -3-methoxy-N- was used in the same manner as in Example 0010 except that 3-methoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-15) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 9.06 (1H, t, J = 5.4 Hz), 7.50-7.24 (6H, m), 7.13-7.07 (1H, m), 7.00-6.94 (1H, m) m), 5.06-4.88 (3H, m), 4.72-4.66 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 3.80 (3H, s).
MS (m / z): 409.3 (M + H) +
＜実施例００１６：Ａｍ－１６の合成＞
－Ｎ－（メトキシエチル）化反応－
Figure JPOXMLDOC01-appb-C000060
 <Example 0016: Synthesis of Am-16>
-N- (methoxyethyl) conversion reaction-
Figure JPOXMLDOC01-appb-C000060
　１Ｈ－インドール－３－カルボン酸（１６１ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．５ｍＬ）溶液に、氷冷下、６０％水素化ナトリウム流動パラフィン分散物（８０ｍｇ）を加え、同温度で１０分間撹拌した。１－ブロモ－２－メトキシエタン（０．０９５ｍＬ）を加え、室温で６時間撹拌した。反応混合物に１０％（ｗ／ｖ）クエン酸水溶液及び酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、白色固体の１－（２－メトキシエチル）－１Ｈ－インドール－３－カルボン酸（９９ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２２０．２（Ｍ＋Ｈ）＋ A 60% sodium hydride liquid paraffin dispersion (80 mg) was added to a solution of 1H-indole-3-carboxylic acid (161 mg) in N, N-dimethylformamide (1.5 mL) under ice-cooling, and the temperature was the same for 10 minutes. Stirred. 1-Bromo-2-methoxyethane (0.095 mL) was added, and the mixture was stirred at room temperature for 6 hours. A 10% (w / v) aqueous citric acid solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100), and a white solid 1- (2-methoxyethyl) -1H-indole-3-carboxylic acid (99 mg) was purified. ) Was obtained.
MS (m / z): 220.2 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000061
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000061
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－（２－メトキシエチル）－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－（２－メトキシエチル）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－１６）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.52-8.46 (1H, m), 8.18 (1H, d, J = 7.2 Hz), 8.07 (1H, s), 7.55 (1H, d, J = 7.8 Hz), 7.35-7.28 (3H, m), 7.23-7.12 (2H, m), 7.00-6.95 (1H, m), 5.05-4.88 (3H, m), 4.71-4.66 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 4.37 (2H, t, J = 4.8 Hz), 3.68 (2H, t, J = 4.8 Hz), 3.23 (3H, s).
　ＭＳ（ｍ／ｚ）：４７６．４（Ｍ＋Ｈ）＋ In Example 0010, white was formed in the same manner as in Example 0010 except that 1- (2-methoxyethyl) -1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. Solid (S) -1- (2-Methoxyethyl) -N-((2- (3,3,3-trifluoro-2-hydroxypropanol) isoindoline-5-yl) methyl) -1H-indole -3-Carboxamide (Am-16) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.52-8.46 (1H, m), 8.18 (1H, d, J = 7.2 Hz), 8.07 (1H, s), 7.55 (1H, d, J = 7.8 Hz), 7.35-7.28 (3H, m), 7.23-7.12 (2H, m), 7.00-6.95 (1H, m), 5.05-4.88 (3H, m), 4.71-4.66 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 4.37 (2H, t, J = 4.8 Hz), 3.68 (2H, t, J = 4.8 Hz), 3.23 (3H, s).
MS (m / z): 476.4 (M + H) +
＜実施例００１７：Ａｍ－１７の合成＞
Figure JPOXMLDOC01-appb-C000062
 <Example 0017: Synthesis of Am-17>
Figure JPOXMLDOC01-appb-C000062
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、２－（４－（ジメチルアミノ）フェニル）シクロプロパン－１－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の２－（４－（ジメチルアミノ）フェニル）－Ｎ－（（２－（（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）シクロプロパン－１－カルボキサミド（Ａｍ－１７）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.60 (1H, t, J = 5.7 Hz), 7.35-7.18 (3H, m), 7.00-6.01 (3H, m), 6.66(2H, d, J = 8.1 Hz), 5.06-4.87 (3H, m), 4.71-4.66 (2H, m), 4.39-4.22 (2H, m), 2.83 (6H, s), 2.20-2.12 (1H, m), 1.82-1.74 (1H, m), 1.32-1.25 (1H, m), 1.14-1.06 (1H, m).
　ＭＳ（ｍ／ｚ）：４６２．４（Ｍ＋Ｈ）＋ In Example 0010, in the same manner as in Example 0010, except that 2- (4- (dimethylamino) phenyl) cyclopropan-1-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. White solid 2- (4- (dimethylamino) phenyl) -N-((2-((S) -3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) Cyclopropan-1-carboxamide (Am-17) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.60 (1H, t, J = 5.7 Hz), 7.35-7.18 (3H, m), 7.00-6.01 (3H, m), 6.66 (2H, d, J = 8.1 Hz), 5.06-4.87 (3H, m), 4.71-4.66 (2H, m), 4.39-4.22 (2H, m), 2.83 (6H, s), 2.20-2.12 (1H, m), 1.82 -1.74 (1H, m), 1.32-1.25 (1H, m), 1.14-1.06 (1H, m).
MS (m / z): 462.4 (M + H) +
＜実施例００１８：Ａｍ－１８の合成＞
－ニトロフェノキシカルボニル化反応－
Figure JPOXMLDOC01-appb-C000063
 <Example 0018: Synthesis of Am-18>
-Nitrophenoxycarbonylation reaction-
Figure JPOXMLDOC01-appb-C000063
　クロロギ酸４－ニトロフェニル（１００ｍｇ）及びトリエチルアミン（０．０７６ｍＬ）のテトラヒドロフラン（２．０ｍＬ）溶液にインドリン（６０ｍｇ）を加え、室温で３０分間撹拌した。反応混合物を酢酸エチルで希釈した後、不溶物を濾去した。減圧下で溶媒を留去し、ヘキサン（１．５ｍＬ）及び酢酸エチル（１．５ｍＬ）を加えた。固形物を濾取し、黄色固体の４－ニトロフェニル　インドリン－１－カルボキシラート（１１４ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２８５．２（Ｍ＋Ｈ）＋ Indoline (60 mg) was added to a solution of 4-nitrophenyl chloroformate (100 mg) and triethylamine (0.076 mL) in tetrahydrofuran (2.0 mL), and the mixture was stirred at room temperature for 30 minutes. After diluting the reaction mixture with ethyl acetate, the insoluble material was removed by filtration. The solvent was distilled off under reduced pressure, and hexane (1.5 mL) and ethyl acetate (1.5 mL) were added. The solid was collected by filtration to give 4-nitrophenyl indoline-1-carboxylate (114 mg) as a yellow solid.
MS (m / z): 285.2 (M + H) +
－ニトロフェニルカーバメート構造の置換反応－
Figure JPOXMLDOC01-appb-C000064
 -Substitution reaction of nitrophenyl carbamate structure-
Figure JPOXMLDOC01-appb-C000064
　４－ニトロフェニル　インドリン－１－カルボキシラート（２８ｍｇ）、ｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラート（２０ｍｇ）及び炭酸ナトリウム（１７ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．２ｍＬ）溶液を１００℃で３時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７０：３０→０：１００）で精製し、無色油状のｔｅｒｔ－ブチル　５－（（インドリン－１－カルボキサミド）メチル）イソインドリン－２－カルボキシラート（２６ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３９４．４（Ｍ＋Ｈ）＋ N, N-dimethylformamide (0.2 mL) of 4-nitrophenyl indoline-1-carboxylate (28 mg), tert-butyl 5- (aminomethyl) isoindoline-2-carboxylate (20 mg) and sodium carbonate (17 mg) ) The solution was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 → 0: 100), and the colorless oily tert-butyl 5-((indolin-1-carboxamide) methyl) isoindoline-2. -Carboxamide (26 mg) was obtained.
MS (m / z): 394.4 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000065
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000065
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　５－（（インドリン－１－カルボキサミド）メチル）イソインドリン－２－カルボキシラートと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）インドリン－１－カルボキサミド（Ａｍ－１８）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=7.84 (1H, d, J = 7.8 Hz), 7.40-7.24 (4H, m), 7.15 (1H, d, J = 7.8 Hz), 7.09-7.02 (1H, m), 6.99-6.94 (1H, m), 6.87-6.79 (1H, m), 5.06-4.75 (3H, m), 4.69 (2H, d, J = 6.0 Hz), 4.34 (2H, d, J = 6.0 Hz), 3.94 (2H, t, J = 8.7 Hz), 3.13 (2H, t, J = 8.7 Hz).
　ＭＳ（ｍ／ｚ）：４２０．３（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindoline-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. Instead of using tert-butyl 5-((indrin-1-carboxamide) methyl) isoindoline-2-carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropanoic acid, respectively. (S) -N- ((2- (3,3,3-trifluoro)) of the white solid was carried out in the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002 except that it was used. -2-Hydroxypropanoyl) isoindoline-5-yl) methyl) indolin-1-carboxamide (Am-18) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 7.84 (1H, d, J = 7.8 Hz), 7.40-7.24 (4H, m), 7.15 (1H, d, J = 7.8 Hz), 7.09-7.02 (1H, m), 6.99-6.94 (1H, m), 6.87-6.79 (1H, m), 5.06-4.75 (3H, m), 4.69 (2H, d, J = 6.0 Hz), 4.34 (2H, d) , J = 6.0 Hz), 3.94 (2H, t, J = 8.7 Hz), 3.13 (2H, t, J = 8.7 Hz).
MS (m / z): 420.3 (M + H) +
＜実施例００１９：Ａｍ－１９の合成＞
－Ｎ－プロピル化反応－
Figure JPOXMLDOC01-appb-C000066
 <Example 0019: Synthesis of Am-19>
-N-propylation reaction-
Figure JPOXMLDOC01-appb-C000066
　実施例００１６のＮ－（メトキシエチル）化反応において、１－ブロモ－２－メトキシエタンを用いた代わりに、１－ヨードプロパンを用いる以外は実施例００１６のＮ－（メトキシエチル）化反応と同様の方法で、白色固体の１－プロピル－１Ｈ－インドール－３－カルボン酸を得た。
　ＭＳ（ｍ／ｚ）：２０４．３（Ｍ＋Ｈ）＋ In the N- (methoxyethyl) conversion reaction of Example 0016, the same as the N- (methoxyethyl) conversion reaction of Example 0016 except that 1-iodopropane was used instead of 1-bromo-2-methoxyethane. 1-propyl-1H-indole-3-carboxylic acid as a white solid was obtained by the above method.
MS (m / z): 204.3 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000067
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000067
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－プロピル－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－プロピル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－１９）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.49-8.42 (1H, m), 8.16 (1H, d, J = 7.2 Hz), 8.09 (1H, s), 7.54 (1H, d, J = 8.4 Hz), 7.35-7.28 (3H, m), 7.23-7.12 (2H, m), 7.00-6.94 (1H, m), 5.05-4.88 (3H, m), 4.71-4.66 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 4.17 (2H, t, J = 7.5 Hz), 1.86-1.76 (2H, m), 0.86 (3H, t, J = 7.2 Hz).
　ＭＳ（ｍ／ｚ）：４６０．４（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 1-propyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -1-propyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-3-carboxyxamide (Am-19) Obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.49-8.42 (1H, m), 8.16 (1H, d, J = 7.2 Hz), 8.09 (1H, s), 7.54 (1H, d, J = 8.4 Hz), 7.35-7.28 (3H, m), 7.23-7.12 (2H, m), 7.00-6.94 (1H, m), 5.05-4.88 (3H, m), 4.71-4.66 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 4.17 (2H, t, J = 7.5 Hz), 1.86-1.76 (2H, m), 0.86 (3H, t, J = 7.2 Hz).
MS (m / z): 460.4 (M + H) +
＜実施例００２０：Ａｍ－２０の合成＞
Figure JPOXMLDOC01-appb-C000068
 <Example 0020: Synthesis of Am-20>
Figure JPOXMLDOC01-appb-C000068
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、２－メチル－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－２－メチル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－２０）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=11.45 (1H, s), 8.01-7.94 (1H, m), 7.82-7.76 (1H, m), 7.38-7.28 (4H, m), 7.11-6.60 (3H, m), 5.07-4.88 (3H, m), 4.71-4.66 (2H, m), 4.50 (2H, d, J = 6.0 Hz), 2.59 (3H, s).
　ＭＳ（ｍ／ｚ）：４３２．４（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 2-methyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -2-Methyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-3-carboxyxamide (Am-20) Obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 11.45 (1H, s), 8.01-7.94 (1H, m), 7.82-7.76 (1H, m), 7.38-7.28 (4H, m), 7.11- 6.60 (3H, m), 5.07-4.88 (3H, m), 4.71-4.66 (2H, m), 4.50 (2H, d, J = 6.0 Hz), 2.59 (3H, s).
MS (m / z): 432.4 (M + H) +
＜実施例００２１：Ａｍ－２１の合成＞
－Ｎ－イソプロピル化反応－
Figure JPOXMLDOC01-appb-C000069
 <Example 0021: Synthesis of Am-21>
-N-isopropylization reaction-
Figure JPOXMLDOC01-appb-C000069
　実施例００１６のＮ－（メトキシエチル）化反応において、１－ブロモ－２－メトキシエタンを用いた代わりに、２－ヨードプロパンを用いる以外は実施例００１６のＮ－（メトキシエチル）化反応と同様の方法で、白色固体の１－イソプロピル－１Ｈ－インドール－３－カルボン酸を得た。
　ＭＳ（ｍ／ｚ）：２０４．３（Ｍ＋Ｈ）＋ In the N- (methoxyethyl) conversion reaction of Example 0016, the same as the N- (methoxyethyl) conversion reaction of Example 0016 except that 2-iodopropane was used instead of 1-bromo-2-methoxyethane. 1-Isopropyl-1H-indole-3-carboxylic acid as a white solid was obtained by the above method.
MS (m / z): 204.3 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000070
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000070
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－イソプロピル－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－イソプロピル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－２１）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.48-8.40 (1H, m), 8.25 (1H, s), 8.18 (1H, d, J = 7.2 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.36-7.28 (3H, m), 7.23-7.10 (2H, m), 7.00-6.94 (1H, m), 5.05-4.88 (3H, m), 4.84-4.76 (1H, m), 4.72-4.66 (2H, m), 4.49 (2H, d, J = 6.3 Hz), 1.48 (6H, d, J = 6.6 Hz).
　ＭＳ（ｍ／ｚ）：４６０．４（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 1-isopropyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -1-Isopropyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-3-carboxamide (Am-21) Obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.48-8.40 (1H, m), 8.25 (1H, s), 8.18 (1H, d, J = 7.2 Hz), 7.57 (1H, d, J = 8.1 Hz), 7.36-7.28 (3H, m), 7.23-7.10 (2H, m), 7.00-6.94 (1H, m), 5.05-4.88 (3H, m), 4.84-4.76 (1H, m), 4.72 -4.66 (2H, m), 4.49 (2H, d, J = 6.3 Hz), 1.48 (6H, d, J = 6.6 Hz).
MS (m / z): 460.4 (M + H) +
＜実施例００２２：Ａｍ－２２の合成＞
Figure JPOXMLDOC01-appb-C000071
 <Example 0022: Synthesis of Am-22>
Figure JPOXMLDOC01-appb-C000071
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、４－（ジメチルアミノ）安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－４－（ジメチルアミノ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－２２）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.71 (1H, t, J = 6.0 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.34-7.26 (3H, m), 6.99-6.93 (1H, m), 6.71 (2H, d, J = 9.0 Hz), 5.05-4.87 (3H, m), 4.71-4.65 (2H, m), 4.45 (2H, d, J = 6.0 Hz), 2.97 (6H, s).
　ＭＳ（ｍ／ｚ）：４２２．４（Ｍ＋Ｈ）＋ In Example 0010, a colorless oily (S) -4-(in the same manner as in Example 0010 except that 4- (dimethylamino) benzoic acid was used instead of 1H-indole-6-carboxylic acid. Dimethylamino) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-22) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.71 (1H, t, J = 6.0 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.34-7.26 (3H, m), 6.99-6.93 (1H, m), 6.71 (2H, d, J = 9.0 Hz), 5.05-4.87 (3H, m), 4.71-4.65 (2H, m), 4.45 (2H, d, J = 6.0 Hz), 2.97 ( 6H, s).
MS (m / z): 422.4 (M + H) +
＜実施例００２３：Ａｍ－２３の合成＞
Figure JPOXMLDOC01-appb-C000072
 <Example 0023: Synthesis of Am-23>
Figure JPOXMLDOC01-appb-C000072
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、３－（ジメチルアミノ）安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－３－（ジメチルアミノ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－２３）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.96 (1H, t, J = 5.1 Hz), 7.34-7.10 (6H, m), 7.00-6.94 (1H, m), 6.90-6.84 (1H, m), 5.06-4.88 (3H, m), 4.72-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 2.93 (6H, s).
　ＭＳ（ｍ／ｚ）：４２２．４（Ｍ＋Ｈ）＋ In Example 0010, a colorless oily (S) -3-(in the same manner as in Example 0010 except that 3- (dimethylamino) benzoic acid was used instead of 1H-indole-6-carboxylic acid. Dimethylamino) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-23) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.96 (1H, t, J = 5.1 Hz), 7.34-7.10 (6H, m), 7.00-6.94 (1H, m), 6.90-6.84 (1H, m) m), 5.06-4.88 (3H, m), 4.72-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 2.93 (6H, s).
MS (m / z): 422.4 (M + H) +
＜実施例００２４：Ａｍ－２４の合成＞
Figure JPOXMLDOC01-appb-C000073
 <Example 0024: Synthesis of Am-24>
Figure JPOXMLDOC01-appb-C000073
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１Ｈ－インドール－２－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－２－カルボキサミド（Ａｍ－２４）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=11.61 (1H, s), 9.10-9.02 (1H, m), 7.62 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 8.1 Hz), 7.38-7.28 (3H, m), 7.22-7.14 (2H, m), 7.08-6.94 (2H, m), 5.07-4.88 (3H, m), 4.72-4.67 (2H, m), 4.53 (2H, d, J = 5.7 Hz).
　ＭＳ（ｍ／ｚ）：４１８．４（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -N- (S) -N- (in the same manner as in Example 0010, except that 1H-indole-2-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-2-carboxamide (Am-24) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 11.61 (1H, s), 9.10-9.02 (1H, m), 7.62 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 8.1 Hz), 7.38-7.28 (3H, m), 7.22-7.14 (2H, m), 7.08-6.94 (2H, m), 5.07-4.88 (3H, m), 4.72-4.67 (2H, m), 4.53 (2H, d, J = 5.7 Hz).
MS (m / z): 418.4 (M + H) +
＜実施例００２５：Ａｍ－２５の合成＞
Figure JPOXMLDOC01-appb-C000074
 <Example 0025: Synthesis of Am-25>
Figure JPOXMLDOC01-appb-C000074
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－ナフトエ酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１－ナフトアミド（Ａｍ－２５）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=9.13 (1H, t, J = 6.0 Hz), 8.24-8.16 (1H, m), 8.05-7.95 (2H, m), 7.68-7.62 (1H, m), 7.60-7.52 (3H, m), 7.42-7.34 (3H, m), 6.99 (1H, d, J = 8.7 Hz), 5.10-4.90 (3H, m), 4.75-4.70 (2H, m), 4.56 (2H, d, J = 6.0 Hz).
　ＭＳ（ｍ／ｚ）：４２９．４（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -N-((2- (2-() was used in the same manner as in Example 0010 except that 1-naphthoic acid was used instead of 1H-indole-6-carboxylic acid. 3,3,3-Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1-naphthamide (Am-25) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 9.13 (1H, t, J = 6.0 Hz), 8.24-8.16 (1H, m), 8.05-7.95 (2H, m), 7.68-7.62 (1H, m) m), 7.60-7.52 (3H, m), 7.42-7.34 (3H, m), 6.99 (1H, d, J = 8.7 Hz), 5.10-4.90 (3H, m), 4.75-4.70 (2H, m) , 4.56 (2H, d, J = 6.0 Hz).
MS (m / z): 429.4 (M + H) +
＜実施例００２６：Ａｍ－２６の合成＞
－Ｎ－ベンジル化反応－
Figure JPOXMLDOC01-appb-C000075
 <Example 0026: Synthesis of Am-26>
-N-benzylation reaction-
Figure JPOXMLDOC01-appb-C000075
　メチル　１Ｈ－ピロール－３－カルボキシラート（６３ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）溶液に、氷冷下で６０％水素化ナトリウム流動パラフィン分散物（２０ｍｇ）を加え、同温度で５分間撹拌した。ベンジルブロミド（０．０６ｍＬ）を加え、室温で３０分間撹拌した後、反応混合物に水及び酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→６０：４０）で精製し、無色油状のメチル　１－ベンジル－１Ｈ－ピロール－３－カルボキシラート（８４ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２１６．３（Ｍ＋Ｈ）＋ To a solution of methyl 1H-pyrrole-3-carboxylate (63 mg) in N, N-dimethylformamide (0.5 mL), add 60% sodium hydride liquid paraffin dispersion (20 mg) under ice-cooling, and add 5 at the same temperature. Stirred for minutes. Benzyl bromide (0.06 mL) was added, and the mixture was stirred at room temperature for 30 minutes, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 60: 40) to obtain a colorless oily methyl 1-benzyl-1H-pyrrole-3-carboxylate (84 mg). ..
MS (m / z): 216.3 (M + H) +
－エステル構造の加水分解反応－
Figure JPOXMLDOC01-appb-C000076
 -Ester structure hydrolysis reaction-
Figure JPOXMLDOC01-appb-C000076
　メチル　１－ベンジル－１Ｈ－ピロール－３－カルボキシラート（８４ｍｇ）のメタノール（１．０ｍＬ）及びテトラヒドロフラン（１．０ｍＬ）溶液に、４ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．５ｍＬ）を加え、６０℃で２時間撹拌した。反応混合物を室温まで冷却し、酢酸エチルと１ｍｏｌ／Ｌ塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、白色固体の１－ベンジル－１Ｈ－ピロール－３－カルボン酸（７７ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２０２．１（Ｍ＋Ｈ）＋ A 4 mol / L sodium hydroxide aqueous solution (0.5 mL) was added to a solution of methyl 1-benzyl-1H-pyrrole-3-carboxylate (84 mg) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL), and the temperature was 60 ° C. Was stirred for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and 1 mol / L hydrochloric acid were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid 1-benzyl-1H-pyrrole-3-carboxylic acid (77 mg).
MS (m / z): 202.1 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000077
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000077
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－ベンジル－１Ｈ－ピロール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－ベンジル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－ピロール－３－カルボキサミド（Ａｍ－２６）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.35 (1H, t, J = 5.7 Hz), 7.40-7.20 (9H, m), 6.99 (1H, s), 6.86-6.83 (1H, m), 6.52-6.49 (1H, m), 5.11 (2H, s), 5.04-4.86 (3H, m), 4.70-4.66 (2H, m), 4.38 (2H, d, J = 5.7 Hz).
　ＭＳ（ｍ／ｚ）：４５８．５（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 1-benzyl-1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -1-Benzyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrrole-3-carboxamide (Am-26) Obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.35 (1H, t, J = 5.7 Hz), 7.40-7.20 (9H, m), 6.99 (1H, s), 6.86-6.83 (1H, m) , 6.52-6.49 (1H, m), 5.11 (2H, s), 5.04-4.86 (3H, m), 4.70-4.66 (2H, m), 4.38 (2H, d, J = 5.7 Hz).
MS (m / z): 458.5 (M + H) +
＜実施例００２７：Ａｍ－２７の合成＞
Figure JPOXMLDOC01-appb-C000078
 <Example 0027: Synthesis of Am-27>
Figure JPOXMLDOC01-appb-C000078
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－２７）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=11.57 (1H, s), 8.50-8.45 (1H, m), 8.15 (1H, d, J = 7.2 Hz), 8.06 (1H, d, J = 2.4 Hz), 7.43 (1H, d, J = 7.2 Hz), 7.35-7.26 (3H, m), 7.18-7.07 (2H, m), 7.01-6.95 (1H, m), 5.05-4.88 (3H, m), 4.71-4.68 (2H, m), 4.49 (2H, d, J = 6.0 Hz).
　ＭＳ（ｍ／ｚ）：４１８．３（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -N- (S) -N- (in the same manner as in Example 0010 except that 1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-3-carboxamide (Am-27) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 11.57 (1H, s), 8.50-8.45 (1H, m), 8.15 (1H, d, J = 7.2 Hz), 8.06 (1H, d, J = 2.4 Hz), 7.43 (1H, d, J = 7.2 Hz), 7.35-7.26 (3H, m), 7.18-7.07 (2H, m), 7.01-6.95 (1H, m), 5.05-4.88 (3H, m) ), 4.71-4.68 (2H, m), 4.49 (2H, d, J = 6.0 Hz).
MS (m / z): 418.3 (M + H) +
＜実施例００２８：Ａｍ－２８の合成＞
Figure JPOXMLDOC01-appb-C000079
 <Example 0028: Synthesis of Am-28>
Figure JPOXMLDOC01-appb-C000079
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１Ｈ－インドール－４－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－４－カルボキサミド（Ａｍ－２８）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=11.30 (1H, s), 8.85-8.79 (1H, m), 7.55 (1H, d, J = 8.0 Hz), 7.50-7.43 (2H, m), 7.38-7.20 (3H, m), 7.16 (1H, t, J = 8.0 Hz), 7.00-6.96 (1H, m), 6.88-6.85 (1H, m), 5.06-4.90 (3H, m), 4.73-4.68 (2H, m), 4.53 (2H, d, J = 6.0 Hz).
　ＭＳ（ｍ／ｚ）：４１８．４（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -N- (S) -N- (in the same manner as in Example 0010 except that 1H-indole-4-carboxylic acid was used instead of 1H-indole-6-carboxylic acid (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-4-carboxamide (Am-28) was obtained.
1 1 H-NMR (400 MHz, DMSO-d 6 ) δ = 11.30 (1H, s), 8.85-8.79 (1H, m), 7.55 (1H, d, J = 8.0 Hz), 7.50-7.43 (2H, m) , 7.38-7.20 (3H, m), 7.16 (1H, t, J = 8.0 Hz), 7.00-6.96 (1H, m), 6.88-6.85 (1H, m), 5.06-4.90 (3H, m), 4.73 -4.68 (2H, m), 4.53 (2H, d, J = 6.0 Hz).
MS (m / z): 418.4 (M + H) +
＜実施例００２９：Ａｍ－２９の合成＞
－Ｎ－ヒドロキシエチル化反応－
Figure JPOXMLDOC01-appb-C000080
 <Example 0029: Synthesis of Am-29>
-N-Hydroxyethylation reaction-
Figure JPOXMLDOC01-appb-C000080
　メチル　１Ｈ－インドール－３－カルボキシラート（１７５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、氷冷下で６０％水素化ナトリウム流動パラフィン分散物（４０ｍｇ）を加え、同温度で５分間撹拌した。（２－ブロモエトキシ）（ｔｅｒｔ－ブチル）ジメチルシラン（２３９ｍｇ）を加えた後、室温で２時間撹拌した。反応混合物にメタノール（２ｍＬ）及び４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（０．２ｍＬ）を加え、室温で１時間撹拌した。反応混合物に水及び酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７０：３０→０：１００）で精製し、無色油状のメチル　１－（２－ヒドロキシエチル）－１Ｈ－インドール－３－カルボキシラート（１４７ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２２０．２（Ｍ＋Ｈ）＋ 60% sodium hydride liquid paraffin dispersion (40 mg) was added to a solution of methyl 1H-indole-3-carboxylate (175 mg) in N, N-dimethylformamide (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. bottom. After adding (2-bromoethoxy) (tert-butyl) dimethylsilane (239 mg), the mixture was stirred at room temperature for 2 hours. Methanol (2 mL) and a 4 mol / L hydrogen chloride / 1,4-dioxane solution (0.2 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70: 30 → 0: 100), and the colorless oily methyl 1- (2-hydroxyethyl) -1H-indol-3-carboxylate ( 147 mg) was obtained.
MS (m / z): 220.2 (M + H) +
－エステル構造の加水分解反応－
Figure JPOXMLDOC01-appb-C000081
 -Ester structure hydrolysis reaction-
Figure JPOXMLDOC01-appb-C000081
　実施例００２６のエステル構造の加水分解反応において、メチル　１－ベンジル－１Ｈ－ピロール－３－カルボキシラートを用いた代わりに、メチル　１－（２－ヒドロキシエチル）－１Ｈ－インドール－３－カルボキシラートを用いる以外は実施例００２６のエステル構造の加水分解反応と同様の方法で、白色固体の１－（２－ヒドロキシエチル）－１Ｈ－インドール－３－カルボン酸を得た。
　ＭＳ（ｍ／ｚ）：２０６．２（Ｍ＋Ｈ）＋ In the hydrolysis reaction of the ester structure of Example 0026, instead of using methyl 1-benzyl-1H-pyrrole-3-carboxylate, methyl 1- (2-hydroxyethyl) -1H-indole-3-carboxylate was used. A white solid 1- (2-hydroxyethyl) -1H-indole-3-carboxylic acid was obtained in the same manner as in the hydrolysis reaction of the ester structure of Example 0026 except that it was used.
MS (m / z): 206.2 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000082
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000082
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－（２－ヒドロキシエチル）－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－（２－ヒドロキシエチル）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－２９）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.52-8.44 (1H, m), 8.18 (1H, d, J = 7.5 Hz), 8.01 (1H, s), 7.53 (1H, d, J = 8.1 Hz), 7.35-7.28 (3H, m), 7.23-7.10 (2H, m), 7.00-6.94 (1H, m), 5.05-4.88 (4H, m), 4.71-4.65 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 4.22 (2H, t, J = 5.1 Hz), 3.77-3.71 (2H, m).
　ＭＳ（ｍ／ｚ）：４６２．４（Ｍ＋Ｈ）＋ In Example 0010, white was formed in the same manner as in Example 0010 except that 1- (2-hydroxyethyl) -1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. Solid (S) -1- (2-Hydroxyethyl) -N-((2- (3,3,3-trifluoro-2-hydroxypropanol) isoindoline-5-yl) methyl) -1H-indole -3-Carboxamide (Am-29) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.52-8.44 (1H, m), 8.18 (1H, d, J = 7.5 Hz), 8.01 (1H, s), 7.53 (1H, d, J = 8.1 Hz), 7.35-7.28 (3H, m), 7.23-7.10 (2H, m), 7.00-6.94 (1H, m), 5.05-4.88 (4H, m), 4.71-4.65 (2H, m), 4.48 (2H, d, J = 6.0 Hz), 4.22 (2H, t, J = 5.1 Hz), 3.77-3.71 (2H, m).
MS (m / z): 462.4 (M + H) +
＜実施例００３０：Ａｍ－３０の合成＞
－Ｎ－（アミノカルボニルメチル）化反応－
Figure JPOXMLDOC01-appb-C000083
 <Example 0030: Synthesis of Am-30>
-N- (aminocarbonylmethyl) conversion reaction-
Figure JPOXMLDOC01-appb-C000083
　１Ｈ－インドール－３－カルボン酸（１６１ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．５ｍＬ）溶液に、氷冷下で６０％水素化ナトリウム（８０ｍｇ）を加え、同温度で５分間撹拌した。２－クロロアセタミド（９４ｍｇ）を加え、室温で６時間撹拌した。反応混合物に１０％（ｗ／ｖ）クエン酸水溶液及び酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→７０：３０）で精製し、白色固体の１－（２－アミノ－２－オキソエチル）－１Ｈ－インドール－３－カルボン酸（６０ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２１９．２（Ｍ＋Ｈ）＋ To a solution of 1H-indole-3-carboxylic acid (161 mg) in N, N-dimethylformamide (1.5 mL) was added 60% sodium hydride (80 mg) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. 2-Chloroacetamide (94 mg) was added, and the mixture was stirred at room temperature for 6 hours. A 10% (w / v) aqueous citric acid solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 70: 30) to form a white solid 1- (2-amino-2-oxoethyl) -1H-indole-3-carboxylate. Acid (60 mg) was obtained.
MS (m / z): 219.2 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000084
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000084
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－（２－アミノ－２－オキソエチル）－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－（２－アミノ－２－オキソエチル）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－３０）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.55-8.48 (1H, m), 8.18 (1H, d, J = 7.2 Hz), 8.02 (1H, s), 7.71 (1H, s), 7.42-7.28 (5H, m), 7.23-7.10 (2H, m), 7.00-6.94 (1H, m), 5.05-4.83 (5H, m), 4.71-4.65 (2H, m), 4.48 (2H, d, J = 5.7 Hz).
　ＭＳ（ｍ／ｚ）：４７５．４（Ｍ＋Ｈ）＋ In Example 0010, the same method as in Example 0010 except that 1- (2-amino-2-oxoethyl) -1H-indole-3-carboxylic acid is used instead of 1H-indole-6-carboxylic acid. Then, the white solid (S) -1- (2-amino-2-oxoethyl) -N- ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl)) Methyl) -1H-indole-3-carboxyxamide (Am-30) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.55-8.48 (1H, m), 8.18 (1H, d, J = 7.2 Hz), 8.02 (1H, s), 7.71 (1H, s), 7.42 -7.28 (5H, m), 7.23-7.10 (2H, m), 7.00-6.94 (1H, m), 5.05-4.83 (5H, m), 4.71-4.65 (2H, m), 4.48 (2H, d, J = 5.7 Hz).
MS (m / z): 475.4 (M + H) +
＜実施例００３１：Ａｍ－３１の合成＞
Figure JPOXMLDOC01-appb-C000085
 <Example 0031: Synthesis of Am-31>
Figure JPOXMLDOC01-appb-C000085
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、安息香酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－３１）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=9.08 (1H, t, J = 5.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 7.57-7.44 (3H, m), 7.35-7.26 (3H, m), 7.00-6.94 (1H, m), 5.06-4.89 (3H, m), 4.70-4.68 (2H, m), 4.59 (2H, d, J = 6.0 Hz).
　ＭＳ（ｍ／ｚ）：３７９．３（Ｍ＋Ｈ）＋ In Example 0010, the white solid (S) -N-((2- (3, 3,)) was used in the same manner as in Example 0010 except that benzoic acid was used instead of 1H-indole-6-carboxylic acid. 3,3-Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-31) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 9.08 (1H, t, J = 5.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 7.57-7.44 (3H, m), 7.35-7.26 (3H, m), 7.00-6.94 (1H, m), 5.06-4.89 (3H, m), 4.70-4.68 (2H, m), 4.59 (2H, d, J = 6.0 Hz).
MS (m / z): 379.3 (M + H) +
＜実施例００３２：Ａｍ－３２の合成＞
Figure JPOXMLDOC01-appb-C000086
 <Example 0032: Synthesis of Am-32>
Figure JPOXMLDOC01-appb-C000086
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１Ｈ－ピロール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－ピロール－３－カルボキサミド（Ａｍ－３２）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=11.14 (1H, s), 8.36-8.30 (1H, m), 7.35-7.26 (4H, m), 7.00-6.94 (1H, m), 6.77-6.72 (1H, m), 6.52-6.47 (1H, m), 5.05-4.86 (3H, m), 4.71-4.65 (2H, m), 4.40 (2H, d, J = 6.0 Hz).
　ＭＳ（ｍ／ｚ）：３６８．３（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -N- (S) -N- (in the same manner as in Example 0010 except that 1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. (2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrrole-3-carboxamide (Am-32) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 11.14 (1H, s), 8.36-8.30 (1H, m), 7.35-7.26 (4H, m), 7.00-6.94 (1H, m), 6.77- 6.72 (1H, m), 6.52-6.47 (1H, m), 5.05-4.86 (3H, m), 4.71-4.65 (2H, m), 4.40 (2H, d, J = 6.0 Hz).
MS (m / z): 368.3 (M + H) +
＜実施例００３３：Ａｍ－３３の合成＞
Figure JPOXMLDOC01-appb-C000087
 <Example 0033: Synthesis of Am-33>
Figure JPOXMLDOC01-appb-C000087
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、４－メトキシ安息香酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－４－メトキシ－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－３３）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.92 (1H, t, J = 6.0 Hz), 7.87 (2H, d, J = 8.4 Hz), 7.34-7.24 (3H, m), 7.03-6.94 (3H, m), 5.05-4.87 (3H, m), 4.71-4.65 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 3.81 (3H, s).
　ＭＳ（ｍ／ｚ）：４０９．３（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -4-methoxy-N- was used in the same manner as in Example 0010 except that 4-methoxybenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-33) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.92 (1H, t, J = 6.0 Hz), 7.87 (2H, d, J = 8.4 Hz), 7.34-7.24 (3H, m), 7.03-6.94 (3H, m), 5.05-4.87 (3H, m), 4.71-4.65 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 3.81 (3H, s).
MS (m / z): 409.3 (M + H) +
＜実施例００３４：Ａｍ－３４の合成＞
Figure JPOXMLDOC01-appb-C000088
 <Example 0034: Synthesis of Am-34>
Figure JPOXMLDOC01-appb-C000088
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、３－アセトアミド安息香酸を用いる以外は実施例００１０と同様の方法で、無色油状の（Ｓ）－３－アセトアミド－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ベンズアミド（Ａｍ－３４）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=10.09 (1H, s), 9.06-8.99 (1H, m), 8.06-8.02 (1H, m), 7.79-7.73 (1H, m), 7.56-7.51 (1H, m), 7.42-7.24 (4H, m), 7.00-6.94 (1H, m), 5.08-4.88 (3H, m), 4.72-4.66 (2H, m), 4.47 (2H, d, J = 6.0 Hz), 2.05 (3H, s).
　ＭＳ（ｍ／ｚ）：４３６．４（Ｍ＋Ｈ）＋ In Example 0010, the colorless oily (S) -3-acetamide-N- was used in the same manner as in Example 0010 except that 3-acetamidobenzoic acid was used instead of 1H-indole-6-carboxylic acid. ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) benzamide (Am-34) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 10.09 (1H, s), 9.06-8.99 (1H, m), 8.06-8.02 (1H, m), 7.79-7.73 (1H, m), 7.56- 7.51 (1H, m), 7.42-7.24 (4H, m), 7.00-6.94 (1H, m), 5.08-4.88 (3H, m), 4.72-4.66 (2H, m), 4.47 (2H, d, J) = 6.0 Hz), 2.05 (3H, s).
MS (m / z): 436.4 (M + H) +
＜実施例００３５：Ａｍ－３５の合成＞
Figure JPOXMLDOC01-appb-C000089
 <Example 0035: Synthesis of Am-35>
Figure JPOXMLDOC01-appb-C000089
　ｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラート（２０ｍｇ）のテトラヒドロフラン（０．５ｍＬ）溶液に４－メトキシフェニルイソシアナート（０．０１３ｍＬ）を加え、５０℃で２時間撹拌した。反応混合物を室温まで冷却し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７０：３０→０：１００）で精製した。得られた残留物に４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（１ｍＬ）を加え、室温で３０分間撹拌した後、減圧下で溶媒を留去し、白色固体を得た。（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（１７ｍｇ）、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（２３ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（１８ｍｇ）、トリエチルアミン（０．０３３ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→９０：１０）で精製し、白色固体の（Ｓ）－１－（４－メトキシフェニル）－３－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ウレア（Ａｍ－３５、３．９ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.36 (1H, s), 7.35-7.21 (5H, m), 7.00-6.95 (1H, m), 6.81 (2H, d, J = 8.4 Hz), 6.52 (1H, t, J = 5.7 Hz), 5.07-4.87 (3H, m), 4.72-4.66 (2H, m), 4.29 (2H, d, J = 6.0 Hz), 3.81 (3H, s).
　ＭＳ（ｍ／ｚ）：４２４．３（Ｍ＋Ｈ）＋ 4-Methoxyphenyl isocyanate (0.013 mL) was added to a solution of tert-butyl 5- (aminomethyl) isoindoline-2-carboxylate (20 mg) in tetrahydrofuran (0.5 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 → 0: 100). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (1 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain a white solid. (S) -3,3,3-trifluoro-2-hydroxypropanoic acid (17 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (23 mg), 1-hydroxybenzotriazole monohydration The product (18 mg), triethylamine (0.033 mL) and N, N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 90: 10) to form a white solid (S) -1- (4-methoxyphenyl) -3-(((). 2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) urea (Am-35, 3.9 mg) was obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.36 (1H, s), 7.35-7.21 (5H, m), 7.00-6.95 (1H, m), 6.81 (2H, d, J = 8.4 Hz) , 6.52 (1H, t, J = 5.7 Hz), 5.07-4.87 (3H, m), 4.72-4.66 (2H, m), 4.29 (2H, d, J = 6.0 Hz), 3.81 (3H, s).
MS (m / z): 424.3 (M + H) +
＜実施例００３６：Ａｍ－３６の合成＞
－Ｎ－シクロブチル化反応－
Figure JPOXMLDOC01-appb-C000090
 <Example 0036: Synthesis of Am-36>
-N-cyclobutylation reaction-
Figure JPOXMLDOC01-appb-C000090
　１Ｈ－ピロール－３－カルボン酸（１０６ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）溶液に、氷冷下で６０％水素化ナトリウム流動パラフィン分散物（９５ｍｇ）を加え、同温度で５分間撹拌した。ブロモシクロブタン（０．０７４ｍＬ）を加えた後、７０℃で３時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、白色固体の１－シクロブチル－１Ｈ－ピロール－３－カルボン酸（２８ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：１６６．１（Ｍ＋Ｈ）＋ A 60% sodium hydride liquid paraffin dispersion (95 mg) was added to a solution of 1H-pyrrole-3-carboxylic acid (106 mg) in N, N-dimethylformamide (5 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. .. After adding bromocyclobutane (0.074 mL), the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to obtain 1-cyclobutyl-1H-pyrrole-3-carboxylic acid (28 mg) as a white solid.
MS (m / z): 166.1 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000091
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000091
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－シクロブチル－１Ｈ－ピロール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－シクロブチル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－ピロール－３－カルボキサミド（Ａｍ－３６）を得た。
　ＭＳ（ｍ／ｚ）：４２２．３（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 1-cyclobutyl-1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -1-Cyclobutyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrrole-3-carboxamide (Am-36) Obtained.
MS (m / z): 422.3 (M + H) +
＜実施例００３７：Ａｍ－３７の合成＞
－Ｎ－（フルオロフェニルメチル）化反応－
Figure JPOXMLDOC01-appb-C000092
 <Example 0037: Synthesis of Am-37>
-N- (fluorophenylmethyl) conversion reaction-
Figure JPOXMLDOC01-appb-C000092
　実施例００３６のＮ－シクロブチル化反応において、ブロモシクロブタンを用いた代わりに、１－（ブロモメチル）－２－フルオロベンゼンを用いる以外は実施例００３６のＮ－シクロブチル化反応と同様の方法で、白色固体の１－（２－フルオロベンジル）－１Ｈ－ピロール－３－カルボン酸を得た。
　ＭＳ（ｍ／ｚ）：２２０．２（Ｍ＋Ｈ）＋ In the N-cyclobutylation reaction of Example 0036, a white solid was used in the same manner as the N-cyclobutylation reaction of Example 0036 except that 1- (bromomethyl) -2-fluorobenzene was used instead of bromocyclobutane. 1- (2-Fluorobenzyl) -1H-pyrrole-3-carboxylic acid was obtained.
MS (m / z): 220.2 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000093
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000093
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－（２－フルオロベンジル）－１Ｈ－ピロール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－（２－フルオロベンジル）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－ピロール－３－カルボキサミド（Ａｍ－３７）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=7.34-7.20 (6H, m), 7.14-7.02 (3H, m), 6.70-6.66 (1H, m), 6.38-6.35 (1H, m), 6.10-6.02 (1H, m), 5.10 (2H, s), 5.02-4.58 (7H, m).
　ＭＳ（ｍ／ｚ）：４７６．２（Ｍ＋Ｈ）＋ In Example 0010, white in the same manner as in Example 0010 except that 1- (2-fluorobenzyl) -1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. Solid (S) -1- (2-fluorobenzyl) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrrole -3-Carboxamide (Am-37) was obtained.
1 1 H-NMR (300MHz, CDCl 3 ) δ = 7.34-7.20 (6H, m), 7.14-7.02 (3H, m), 6.70-6.66 (1H, m), 6.38-6.35 (1H, m), 6.10- 6.02 (1H, m), 5.10 (2H, s), 5.02-4.58 (7H, m).
MS (m / z): 476.2 (M + H) +
＜実施例００３８：Ａｍ－３８の合成＞
－Ｎ－（ピリジルメチル）化反応－
Figure JPOXMLDOC01-appb-C000094
 <Example 0038: Synthesis of Am-38>
-N- (pyridylmethyl) reaction-
Figure JPOXMLDOC01-appb-C000094
　１Ｈ－ピロール－３－カルボン酸（５１ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、氷冷下で６０％水素化ナトリウム流動パラフィン分散物（５５ｍｇ）を加え、同温度で５分間撹拌した。２－（クロロメチル）ピリジン塩酸塩（７５ｍｇ）を加えた後、室温で１時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、白色固体の１－（ピリジン－２－イルメチル）－１Ｈ－ピロール－３－カルボン酸（１４ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２０３．１（Ｍ＋Ｈ）＋ A 60% sodium hydride liquid paraffin dispersion (55 mg) was added to a solution of 1H-pyrrole-3-carboxylic acid (51 mg) in N, N-dimethylformamide (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. .. After adding 2- (chloromethyl) pyridine hydrochloride (75 mg), the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a white solid 1- (pyridin-2-ylmethyl) -1H-pyrrole-3-carboxylic acid (14 mg).
MS (m / z): 203.1 (M + H) +
－アミド化反応－
Figure JPOXMLDOC01-appb-C000095
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000095
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－（ピリジン－２－イルメチル）－１Ｈ－ピロール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－（ピリジン－２－イルメチル）－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－ピロール－３－カルボキサミド（Ａｍ－３８）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=8.58 (1H, d, J = 4.5 Hz), 7.67-7.60 (1H, m), 7.36-7.20 (6H, m), 6.94 (1H, d, J = 7.8 Hz), 6.74-6.70 (1H, m), 6.43-6.40 (1H, m), 6.16-6.03 (1H, m), 5.19 (2H, s), 5.03-4.57 (7H, m).
　ＭＳ（ｍ／ｚ）：４５９．２（Ｍ＋Ｈ）＋ In Example 0010, in the same manner as in Example 0010, except that 1- (pyridin-2-ylmethyl) -1H-pyrrole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. White solid (S) -1- (pyridin-2-ylmethyl) -N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H -Pyrrole-3-carboxamide (Am-38) was obtained.
1 1 H-NMR (300 MHz, CDCl 3 ) δ = 8.58 (1H, d, J = 4.5 Hz), 7.67-7.60 (1H, m), 7.36-7.20 (6H, m), 6.94 (1H, d, J = 7.8 Hz), 6.74-6.70 (1H, m), 6.43-6.40 (1H, m), 6.16-6.03 (1H, m), 5.19 (2H, s), 5.03-4.57 (7H, m).
MS (m / z): 459.2 (M + H) +
＜実施例００３９：Ａｍ－３９の合成＞
Figure JPOXMLDOC01-appb-C000096
 <Example 0039: Synthesis of Am-39>
Figure JPOXMLDOC01-appb-C000096
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－ベンジル－１Ｈ－ピラゾール－４－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－ベンジル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－ピラゾール－４－カルボキサミド（Ａｍ－３９）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＤＭＳＯ－ｄ６）δ=8.67-8.61 (1H, m), 8.26 (1H, s), 7.91 (1H, s), 7.38-7.23 (8H, m), 7.00-6.95 (1H, m), 5.35 (2H, s), 5.04-4.86 (3H, m), 4.80-4.56 (2H, m), 4.40 (2H, d, J = 6.0 Hz).
　ＭＳ（ｍ／ｚ）：４５９．２（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 1-benzyl-1H-pyrazole-4-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -1-Benzyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-pyrazole-4-carboxamide (Am-39) Obtained.
1 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 8.67-8.61 (1H, m), 8.26 (1H, s), 7.91 (1H, s), 7.38-7.23 (8H, m), 7.00-6.95 ( 1H, m), 5.35 (2H, s), 5.04-4.86 (3H, m), 4.80-4.56 (2H, m), 4.40 (2H, d, J = 6.0 Hz).
MS (m / z): 459.2 (M + H) +
＜実施例００４０：Ａｍ－４０の合成＞
Figure JPOXMLDOC01-appb-C000097
 <Example 0040: Synthesis of Am-40>
Figure JPOXMLDOC01-appb-C000097
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－ベンズアミドシクロプロパンカルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－Ｎ－（１－（（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）カルバモイル）シクロプロピル）ベンズアミド（Ａｍ－４０）を得た。
　ＭＳ（ｍ／ｚ）：４６２．２（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) -N- (1) was used in the same manner as in Example 0010 except that 1-benzamide cyclopropanecarboxylic acid was used instead of 1H-indole-6-carboxylic acid. -(((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) carbamoyl) cyclopropyl) benzamide (Am-40) was obtained.
MS (m / z): 462.2 (M + H) +
＜実施例００４１：Ａｍ－４１の合成＞
－ホーナー－ワズワース－エモンズ反応－
Figure JPOXMLDOC01-appb-C000098
 <Example 0041: Synthesis of Am-41>
-Horner-Wadsworth-Emmons Reaction-
Figure JPOXMLDOC01-appb-C000098
　ベンジルホスホン酸ジエチル（１．２５ｍＬ）のテトラヒドロフラン（１０ｍＬ）溶液に、氷冷下で６０％水素化ナトリウム流動パラフィン分散物（１４３ｍｇ）を加え、同温度で５分間撹拌した。ｔｅｒｔ－ブチル　３－オキソピロリジン－１－カルボキシラート（１．０ｇ）を加え、７０℃で３．５時間撹拌した。反応混合物を氷浴で冷却し、飽和塩化アンモニウム水溶液５ｍＬを加えた後、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、無色油状のｔｅｒｔ－ブチル　３－ベンジリデンピロリジン－１－カルボキシラート（７ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２６０．２（Ｍ＋Ｈ）＋ A 60% sodium hydride liquid paraffin dispersion (143 mg) was added to a solution of diethyl benzylphosphonate (1.25 mL) in tetrahydrofuran (10 mL) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. tert-Butyl 3-oxopyrrolidine-1-carboxylate (1.0 g) was added, and the mixture was stirred at 70 ° C. for 3.5 hours. The reaction mixture was cooled in an ice bath, 5 mL of saturated aqueous ammonium chloride solution was added, and then ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to obtain a colorless oily tert-butyl 3-benzylidenepyrrolidine-1-carboxylate (7 mg).
MS (m / z): 260.2 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000099
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000099
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　３－ベンジリデンピロリジン－１－カルボキシラートと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体の（Ｓ）－１－（３－ベンジリデンピロリジン－１－イル）－３，３，３－トリフルオロ－２－ヒドロキシプロパン－１－オン（Ａｍ－４１）を得た。
　ＭＳ（ｍ／ｚ）：２８６．２（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindoline-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. , 3 of Example 0002, except that tert-butyl 3-benzylidenepyrrolidin-1-carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropanoic acid are used instead of using tert-butyl 3-benzylidenepyrrolidin-1-carboxylate, respectively. , 3-Trifluoro-2-hydroxypropionylation reaction, white solid (S) -1- (3-benzylidenepyrrolidin-1-yl) -3,3,3-trifluoro-2-hydroxy Propane-1-one (Am-41) was obtained.
MS (m / z): 286.2 (M + H) +
＜実施例００４２：Ａｍ－４２の合成＞
－グリニャール反応－
Figure JPOXMLDOC01-appb-C000100
 <Example 0042: Synthesis of Am-42>
-Grignard reaction-
Figure JPOXMLDOC01-appb-C000100
　ｔｅｒｔ－ブチル　３－ホルミルピロリジン－１－カルボキシラート（２２８ｍｇ）のテトラヒドロフラン（３ｍＬ）溶液に０℃で２－チエニルマグネシウムブロミドのテトラヒドロフラン溶液（１ｍｏｌ／Ｌ、１．２５ｍＬ）を加え、窒素雰囲気下、同温度で１時間撹拌した。反応混合物に飽和クエン酸水溶液と酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、無色油状のｔｅｒｔ－ブチル　３－（ヒドロキシ（チオフェン－２－イル）メチル）ピロリジン－１－カルボキシラート（１５０ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２８４．２（Ｍ＋Ｈ）＋ To a solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (228 mg) in tetrahydrofuran (3 mL) at 0 ° C., a solution of 2-thienyl magnesium bromide in tetrahydrofuran (1 mol / L, 1.25 mL) was added, and the same was added under a nitrogen atmosphere. The mixture was stirred at temperature for 1 hour. Saturated aqueous citric acid solution and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100), and the colorless oily tert-butyl 3- (hydroxy (thiophen-2-yl) methyl) pyrrolidine-1 was purified. -Carboxylate (150 mg) was obtained.
MS (m / z): 284.2 (M + H) +
－脱水反応－
Figure JPOXMLDOC01-appb-C000101
 -Dehydration reaction-
Figure JPOXMLDOC01-appb-C000101
　ｔｅｒｔ－ブチル　３－（ヒドロキシ（チオフェン－２－イル）メチル）ピロリジン－１－カルボキシラート（１５０ｍｇ）のテトラヒドロフラン（５ｍＬ）溶液に、室温でカルバミン酸メチル－Ｎ－（トリエチルアンモニウムスルホニル）（１４３ｍｇ）を加え、７５℃で１時間撹拌した。反応混合物を室温まで冷却した後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、無色油状のｔｅｒｔ－ブチル　３－（チオフェン－２－イルメチレン）ピロリジン－１－カルボキシラート（７ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２６５．２（Ｍ＋Ｈ）＋ Methyl carbamate-N- (triethylammoniumsulfonyl) (143 mg) in a solution of tert-butyl 3- (hydroxy (thiophen-2-yl) methyl) pyrrolidine-1-carboxylate (150 mg) in tetrahydrofuran (5 mL) at room temperature. In addition, it was stirred at 75 ° C. for 1 hour. The reaction mixture is cooled to room temperature and then purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to obtain a colorless oily tert-butyl 3- (thiophene-2-ylmethylene) pyrrolidine-1-. Carboxylate (7 mg) was obtained.
MS (m / z): 265.2 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000102
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000102
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　３－（チオフェン－２－イルメチレン）ピロリジン－１－カルボキシラートと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体の（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシ－１－（３－（チオフェン－２－イルメチレン）ピロリジン－１－イル）プロパン－１－オン（Ａｍ－４２）を得た。
　ＭＳ（ｍ／ｚ）：２９２．１（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindrin-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. Instead of using tert-butyl 3- (thiophene-2-ylmethylene) pyrrolidine-1-carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropanoic acid, respectively. In the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, the white solid (S) -3,3,3-trifluoro-2-hydroxy-1- (3-( Thiophene-2-ylmethylene) pyrrolidine-1-yl) propan-1-one (Am-42) was obtained.
MS (m / z): 292.1 (M + H) +
＜実施例００４３：Ａｍ－４３の合成＞
－イミド基の還元反応－
Figure JPOXMLDOC01-appb-C000103
 <Example 0043: Synthesis of Am-43>
-Reduction reaction of imide group-
Figure JPOXMLDOC01-appb-C000103
　５，６－ジブロモイソインドリン－１，３－ジオン（３５０ｍｇ）のテトラヒドロフラン（１０ｍＬ）溶液に水素化ホウ素ナトリウム（４３４ｍｇ）と三フッ化ホウ素ジエチルエーテル錯体（１．４６ｍｌ）とを加え、６０℃で３時間撹拌した。反応混合物を室温まで冷却し、メタノール（５０ｍＬ）を５分間かけて滴下した後、減圧下で溶媒を留去した。酢酸エチルを加え、不溶物を濾去した後、減圧下で溶媒を留去した。得られた残留物にテトラヒドロフラン（５ｍＬ）とジ－ｔｅｒｔ－ブチル　ジカルボナート（４００ｍｇ）を加え、室温で１時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和塩化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、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、白色固体のｔｅｒｔ－ブチル　５，６－ジブロモイソインドリン－２－カルボキシラート（１３０ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３７７．９（Ｍ＋Ｈ）＋ Sodium borohydride (434 mg) and boron trifluoride diethyl ether complex (1.46 ml) were added to a solution of 5,6-dibromoisoindoline-1,3-dione (350 mg) in tetrahydrofuran (10 mL) at 60 ° C. The mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature, methanol (50 mL) was added dropwise over 5 minutes, and then the solvent was evaporated under reduced pressure. Ethyl acetate was added and the insoluble material was filtered off, and then the solvent was distilled off under reduced pressure. Tetrahydrofuran (5 mL) and di-tert-butyl dicarbonate (400 mg) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to obtain a white solid tert-butyl 5,6-dibromoisoindoline-2-carboxylate (130 mg). Obtained.
MS (m / z): 377.9 (M + H) +
－モノピリジルアミノ化及び３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000104
 -Monopyridyl amination and 3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000104
　ｔｅｒｔ－ブチル　５，６－ジブロモイソインドリン－２－カルボキシラート（２０ｍｇ）、２－アミノピリジン（１１ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（４ｍｇ）、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（５ｍｇ）及び炭酸セシウム（１６３ｍｇ）の１，４－ジオキサン（１ｍＬ）懸濁液を封管中、窒素雰囲気下、１１０℃で２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（ヘキサン：酢酸エチル＝１００：０→７０：３０）で精製した。得られた残留物にトリフルオロ酢酸（１ｍＬ）を加え、室温で３０分間撹拌した後、減圧下で溶媒を留去した。得られた残留物に（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（２２ｍｇ）、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（２９ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（２３ｍｇ）、トリエチルアミン（０．０５ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液及び飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→７０：３０）で精製し、白色固体の（Ｓ）－１－（５－ブロモ－６－（ピリジン－２－イルアミノ）イソインドリン－２－イル）－３，３，３－トリフルオロ－２－ヒドロキシプロパン－１－オン（Ａｍ－４３、０．８ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：４１６．０（Ｍ＋Ｈ）＋ tert-butyl 5,6-dibromoisoindoline-2-carboxylate (20 mg), 2-aminopyridine (11 mg), tris (dibenzylideneacetone) dipalladium (0) (4 mg), 4,5-bis (diphenylphos) A suspension of 1,4-dioxane (1 mL) of fino) -9,9-dimethylxanthene (5 mg) and cesium carbonate (163 mg) was stirred in a sealed tube at 110 ° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 70: 30). Trifluoroacetic acid (1 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. The residue obtained was (S) -3,3,3-trifluoro-2-hydroxypropanoic acid (22 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (29 mg), 1-. Hydroxybenzotriazole monohydrate (23 mg), triethylamine (0.05 mL) and N, N-dimethylformamide (1 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 70: 30) to form a white solid (S) -1- (5-bromo-6- (pyridin-2)). -Ilamino) isoindoline-2-yl) -3,3,3-trifluoro-2-hydroxypropan-1-one (Am-43, 0.8 mg) was obtained.
MS (m / z): 416.0 (M + H) +
＜実施例００４４：Ａｍ－４４の合成＞
－ヒドロキシ基の酸化反応－
Figure JPOXMLDOC01-appb-C000105
 <Example 0044: Synthesis of Am-44>
-Hydroxy group oxidation reaction-
Figure JPOXMLDOC01-appb-C000105
　ｔｅｒｔ－ブチル　５－（ヒドロキシメチル）イソインドリン－２－カルボキシラート（８２８ｍｇ）のジクロロメタン（２０ｍＬ）溶液に二酸化マンガン（４００ｍｇ）を加え、室温で２４時間撹拌した。不溶物を濾去した後、減圧下で溶媒を留去し、褐色個体のｔｅｒｔ－ブチル　５－ホルミルイソインドリン－２－カルボキシラート（７５０ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：２４８．３（Ｍ＋Ｈ）＋ Manganese dioxide (400 mg) was added to a solution of tert-butyl 5- (hydroxymethyl) isoindoline-2-carboxylate (828 mg) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 24 hours. After removing the insoluble material by filtration, the solvent was distilled off under reduced pressure to obtain a brown solid tert-butyl 5-formylisoindoline-2-carboxylate (750 mg).
MS (m / z): 248.3 (M + H) +
－還元的アミノ化反応－
Figure JPOXMLDOC01-appb-C000106
 -Reductive amination reaction-
Figure JPOXMLDOC01-appb-C000106
　ｔｅｒｔ－ブチル　５－ホルミルイソインドリン－２－カルボキシラート（４０ｍｇ）、２－アミノピラジン（１９ｍｇ）、ナトリウムトリアセトキシボロヒドリド（６４ｍｇ）及び酢酸（０．４ｍＬ）のクロロホルム（２ｍＬ）溶液を封管中、７０℃で５時間撹拌した。反応混合物を室温まで冷却した後、酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：５０→０：１００）で精製し、無色油状のｔｅｒｔ－ブチル　５－（（ピラジン－２－イルアミノ）メチル）イソインドリン－２－カルボキシラート（１０ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３２７．２（Ｍ＋Ｈ）＋ A solution of tert-butyl 5-formylisoindoline-2-carboxylate (40 mg), 2-aminopyrazine (19 mg), sodium triacetoxyborohydride (64 mg) and acetic acid (0.4 mL) in chloroform (2 mL) is in a sealed tube. , 70 ° C. for 5 hours. After cooling the reaction mixture to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 → 0: 100), and the colorless oil of tert-butyl 5-((pyrazine-2-ylamino) methyl) isoindoline-2. -Carboxylate (10 mg) was obtained.
MS (m / z): 327.2 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000107
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000107
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　５－（（ピラジン－２－イルアミノ）メチル）イソインドリン－２－カルボキシラートと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体の（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシ－１－（５－（（ピラジン－２－イルアミノ）メチル）イソインドリン－２－イル）プロパン－１－オン（Ａｍ－４４）を得た。
　ＭＳ（ｍ／ｚ）：３５３．１（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindoline-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. Instead of using tert-butyl 5-((pyrazine-2-ylamino) methyl) isoindoline-2-carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropanoic acid, respectively. A white solid (S) -3,3,3-trifluoro-2-hydroxy-1-in the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002 except that it is used. (5-((Pyrazine-2-ylamino) methyl) isoindoline-2-yl) propan-1-one (Am-44) was obtained.
MS (m / z): 353.1 (M + H) +
＜実施例００４５：Ａｍ－４５の合成＞
－ウレア化反応－
Figure JPOXMLDOC01-appb-C000108
 <Example 0045: Synthesis of Am-45>
-Ureaization reaction-
Figure JPOXMLDOC01-appb-C000108
　ｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラート（３０ｍｇ）及びピリジン（０．０３２ｍＬ）のジクロロメタン（１ｍＬ）溶液に、ビス（トリクロロメチル）カーボナート（１９ｍｇ）を加え、室温で１時間撹拌した。反応混合物にＮ－ブチルアニリン（２６ｍｇ）及びＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）を加え、８０℃で２時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、白色固体のｔｅｒｔ－ブチル　５－（（３－ブチル－３－フェニルウレイド）メチル）イソインドリン－２－カルボキシラート（５ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：４２４．２（Ｍ＋Ｈ）＋ Add bis (trichloromethyl) carbonate (19 mg) to a solution of tert-butyl 5- (aminomethyl) isoindoline-2-carboxylate (30 mg) and pyridine (0.032 mL) in dichloromethane (1 mL) for 1 hour at room temperature. Stirred. N-Butylaniline (26 mg) and N, N-dimethylformamide (1 mL) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to form a white solid tert-butyl 5-((3-butyl-3-phenylureido) methyl) iso. Indoline-2-carboxylate (5 mg) was obtained.
MS (m / z): 424.2 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000109
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000109
　実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応において、ｔｅｒｔ－ブチル　５－フェニルイソインドリン－２－カルボキシラートと３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　５－（（３－ブチル－３－フェニルウレイド）メチル）イソインドリン－２－カルボキシラートと（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸とを用いる以外は実施例０００２の３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応と同様の方法で、白色固体の（Ｓ）－１－ブチル－１－フェニル－３－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）ウレア（Ａｍ－４５）を得た。
　ＭＳ（ｍ／ｚ）：４５０．２（Ｍ＋Ｈ）＋ In the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002, tert-butyl 5-phenylisoindrin-2-carboxylate and 3,3,3-trifluoro-2-hydroxypropanoic acid were used. Instead of using tert-butyl 5-((3-butyl-3-phenylureido) methyl) isoindrin-2-carboxylate and (S) -3,3,3-trifluoro-2-hydroxypropane, respectively. In the same manner as in the 3,3,3-trifluoro-2-hydroxypropionylation reaction of Example 0002 except that an acid is used, the white solid (S) -1-butyl-1-phenyl-3-((() 2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindrin-5-yl) methyl) urea (Am-45) was obtained.
MS (m / z): 450.2 (M + H) +
＜実施例００４７：Ａｍ－４７の合成＞
－Ｂｏｃ保護、アミド基の還元反応及びブロモ化反応－
Figure JPOXMLDOC01-appb-C000110
 <Example 0047: Synthesis of Am-47>
-Boc protection, amide group reduction reaction and bromoization reaction-
Figure JPOXMLDOC01-appb-C000110
　４，５－ジヒドロ－６Ｈ－チエノ［２，３－ｃ］ピロール－６－オン（１．７ｇ）のアセトニトリル（１７ｍＬ）溶液にジ－ｔｅｒｔ－ブチル　ジカルボナート（４．０ｇ）とＮ，Ｎ－ジメチルピリジン－４－アミン（０．７４５ｇ）を加え、室温で１時間撹拌した。反応混合物に酢酸エチル及び水を加えた。有機層を分取し、５％（ｗ／ｖ）クエン酸水溶液及び飽和塩化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、減圧下で溶媒を留去した。得られた残留物に１ｍｏｌ／Ｌボラン－テトラヒドロフラン錯体（２４ｍＬ）を加え、６０℃で３時間撹拌した。反応混合物を室温まで冷却した後、１ｍｏｌ／Ｌボラン－テトラヒドロフラン錯体（１２ｍＬ）を追加し、６０℃で１時間撹拌した。反応混合物を室温まで冷却し、メタノール（２０ｍＬ）を５分間かけて滴下した後、減圧下で溶媒を留去した。得られた残留物にジクロロメタン（５０ｍＬ）及びＮ－ブロモスクシンイミド（３．３ｇ）を加え、室温で１時間撹拌した。反応混合物に水（５０ｍＬ）、チオ硫酸ナトリウム（３．０ｇ）及び酢酸エチル（５０ｍＬ）を加え、不溶物をセライトで濾去した。有機層を分取し、飽和塩化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、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８０：２０）で精製し、薄紫色固体のｔｅｒｔ－ブチル　２－ブロモ－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（０．８７０ｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=6.86 (1H, d, J = 15.0 Hz), 4.62-4.42 (4H, m), 1.50 (9H, s). Di-tert-butyl dicarbonate (4.0 g) and N, N-dimethyl in a solution of 4,5-dihydro-6H-thieno [2,3-c] pyrrole-6-one (1.7 g) in acetonitrile (17 mL). Pyridine-4-amine (0.745 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a 5% (w / v) aqueous citric acid solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A 1 mol / L borane-tetrahydrofuran complex (24 mL) was added to the obtained residue, and the mixture was stirred at 60 ° C. for 3 hours. After cooling the reaction mixture to room temperature, 1 mol / L borane-tetrahydrofuran complex (12 mL) was added, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature, methanol (20 mL) was added dropwise over 5 minutes, and then the solvent was distilled off under reduced pressure. Dichloromethane (50 mL) and N-bromosuccinimide (3.3 g) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Water (50 mL), sodium thiosulfate (3.0 g) and ethyl acetate (50 mL) were added to the reaction mixture, and the insoluble material was filtered off with Celite. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20) and tert-butyl 2-bromo-4,6-dihydro-5H-thieno [2,3-c] as a lilac solid. ] Pyrrole-5-carboxylate (0.870 g) was obtained.
1 1 H-NMR (300 MHz, CDCl 3 ) δ = 6.86 (1H, d, J = 15.0 Hz), 4.62-4.42 (4H, m), 1.50 (9H, s).
－根岸カップリング反応－
Figure JPOXMLDOC01-appb-C000111
 -Negishi coupling reaction-
Figure JPOXMLDOC01-appb-C000111
　ｔｅｒｔ－ブチル　２－ブロモ－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（３１５ｍｇ）、シアン化亜鉛（II）（１４９ｍｇ）及びテトラキス（トリフェニルホスフィン）パラジウム（0）（１０２ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．５ｍＬ）溶液を、マイクロウェーブ装置を使用して、１２０℃で１時間撹拌した。反応混合物を室温まで冷却した後、１０％（ｗ／ｖ）アンモニア水及び酢酸エチルを加えた。有機層を分取し、飽和塩化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、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→８２：１８）で精製し、白色固体のｔｅｒｔ－ブチル　２－シアノ－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（２０２ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=8.39 (1H, d, J = 13.8 Hz), 4.73-4.65 (2H, m), 4.57-4.49 (2H, m), 1.51 (9H, s). tert-Butyl 2-bromo-4,6-dihydro-5H-thieno [2,3-c] pyrrole-5-carboxylate (315 mg), zinc cyanide (II) (149 mg) and tetrakis (triphenylphosphine) palladium (0) A solution of (102 mg) N, N-dimethylformamide (1.5 mL) was stirred at 120 ° C. for 1 hour using a microwave device. After cooling the reaction mixture to room temperature, 10% (w / v) aqueous ammonia and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 82: 18) and tert-butyl 2-cyano-4,6-dihydro-5H-thieno [2] as a white solid. 3-c] Pyrrole-5-carboxylate (202 mg) was obtained.
1 1 H-NMR (300 MHz, CDCl 3 ) δ = 8.39 (1H, d, J = 13.8 Hz), 4.73-4.65 (2H, m), 4.57-4.49 (2H, m), 1.51 (9H, s).
－シアノ基への水素添加反応－
Figure JPOXMLDOC01-appb-C000112
 -Hydrogenation reaction to cyano group-
Figure JPOXMLDOC01-appb-C000112
　ｔｅｒｔ－ブチル　２－シアノ－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（５４ｍｇ）のメタノール（２００ｍＬ）溶液を、フロー式水素化反応装置を用いて水素添加反応（ラネーニッケル、５０℃、４０ｂａｒ、１．５時間）を行った。減圧下で溶媒を留去した後、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、白色固体のｔｅｒｔ－ブチル　２－（アミノメチル）－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（５８ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=6.68 (1H, d, J = 13.2 Hz), 4.65-4.55 (2H, m), 4.49-4.40 (2H, m), 4.01 (2H, s), 1.56 (2H, br), 1.51 (9H, s). A solution of tert-butyl 2-cyano-4,6-dihydro-5H-thieno [2,3-c] pyrrole-5-carboxylate (54 mg) in methanol (200 mL) was hydrogenated using a flow hydrogenation reactor. The addition reaction (Raney nickel, 50 ° C., 40 bar, 1.5 hours) was carried out. After distilling off the solvent under reduced pressure, the obtained residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) to form a white solid tert-butyl 2- (amino). Methyl) -4,6-dihydro-5H-thieno [2,3-c] pyrrole-5-carboxylate (58 mg) was obtained.
1 1 H-NMR (300 MHz, CDCl 3 ) δ = 6.68 (1H, d, J = 13.2 Hz), 4.65-4.55 (2H, m), 4.49-4.40 (2H, m), 4.01 (2H, s), 1.56 (2H, br), 1.51 (9H, s).
－アミド化反応－
Figure JPOXMLDOC01-appb-C000113
 -Amidation reaction-
Figure JPOXMLDOC01-appb-C000113
　ｔｅｒｔ－ブチル　２－（アミノメチル）－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（１２５ｍｇ）、１－ベンジル－１Ｈ－ピラゾール－４－カルボン酸（１０９ｍｇ）、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（２９３ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（６０ｍｇ）及びＮ，Ｎ－ジイソプロピルエチルアミン（０．６５ｍＬ）のジクロロメタン（６．５ｍＬ）溶液を室温で３時間撹拌した。反応混合物に酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、有機層を分取し、無水硫酸マグネシウムで乾燥した後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製し、白色固体のｔｅｒｔ－ブチル　２－（（１－ベンジル－１Ｈ－ピラゾール－４－カルボキサミド）メチル）－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（１８６ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ３）δ=7.90-7.84 (2H, m), 7.39-7.20 (5H, m), 6.84-6.60 (2H, m), 5.28 (2H, s), 4.64 (2H, d, J = 5.4 Hz), 4.54-4.26 (4H, m), 1.50 (9H, s).
　ＭＳ（ｍ／ｚ）：４３９．０（Ｍ＋Ｈ）＋ tert-butyl 2- (aminomethyl) -4,6-dihydro-5H-thieno [2,3-c] pyrrole-5-carboxylate (125 mg), 1-benzyl-1H-pyrazole-4-carboxylic acid (109 mg) ), 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (293 mg), 1-hydroxybenzotriazole monohydrate (60 mg) and N, N-diisopropylethylamine (0.65 mL) in dichloromethane (6). .5 mL) The solution was stirred at room temperature for 3 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100) and tert-butyl 2-((1-benzyl-1H-pyrazole-4-carboxamide)) as a white solid. Methyl) -4,6-dihydro-5H-thieno [2,3-c] pyrrole-5-carboxylate (186 mg) was obtained.
1 1 H-NMR (300MHz, CDCl 3 ) δ = 7.90-7.84 (2H, m), 7.39-7.20 (5H, m), 6.84-6.60 (2H, m), 5.28 (2H, s), 4.64 (2H, d, J = 5.4 Hz), 4.54-4.26 (4H, m), 1.50 (9H, s).
MS (m / z): 439.0 (M + H) +
－３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000114
 -3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000114
　ｔｅｒｔ－ブチル　２－（（１－ベンジル－１Ｈ－ピラゾール－４－カルボキサミド）メチル）－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－５－カルボキシラート（１８６ｍｇ）のジクロロメタン（３．０ｍＬ）溶液に、氷冷下、トリフルオロ酢酸（２．０ｍＬ）を加え、同温度で１時間撹拌した。減圧下で溶媒を留去した後、得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→０：１００）で精製した。得られた残留物にジクロロメタン（５．０ｍＬ）とＮ，Ｎ－ジイソプロピルエチルアミン（１．０ｍＬ）を加えた後、氷冷下で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（２８６ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（１２０ｍｇ）及び（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロピオン酸（８９ｍｇ）を加えた。反応混合物を４０℃で５時間撹拌した後、酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、無水硫酸ナトリウムで乾燥した後、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→７０：３０）で精製し、白色固体の（Ｓ）－１－ベンジル－Ｎ－（（５－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）－４，６－ジヒドロ－５Ｈ－チエノ［２，３－ｃ］ピロール－２－イル）メチル）－１Ｈ－ピラゾール－４－カルボキサミド（Ａｍ－４７、１０２ｍｇ）を得た。
　１Ｈ－ＮＭＲ（３００ＭＨｚ，ＣＤ３ＯＤ）δ=8.11 (1H, s), 7.91 (1H, s), 7.38-7.23 (5H, m), 6.84 (1H, d, J = 6.0 Hz), 5.34 (2H, s), 5.04-4.46 (7H, m).
　ＭＳ（ｍ／ｚ）：４６５．９（Ｍ＋Ｈ）＋ tert-Butyl 2-((1-benzyl-1H-pyrazole-4-carboxamide) methyl) -4,6-dihydro-5H-thieno [2,3-c] pyrrole-5-carboxylate (186 mg) dichloromethane ( To the 3.0 mL) solution, trifluoroacetic acid (2.0 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After distilling off the solvent under reduced pressure, the obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 0: 100). Dichloromethane (5.0 mL) and N, N-diisopropylethylamine (1.0 mL) were added to the obtained residue, and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1-ethylaminopropyl) carbodiimide hydrochloride (under ice-cooling). 286 mg), 1-hydroxybenzotriazole monohydrate (120 mg) and (S) -3,3,3-trifluoro-2-hydroxypropionic acid (89 mg) were added. After stirring the reaction mixture at 40 ° C. for 5 hours, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 70: 30) to form a white solid (S) -1-benzyl-N-((5- (3, 3,)). 3,3-Trifluoro-2-hydroxypropanoyl) -4,6-dihydro-5H-thieno [2,3-c] pyrrole-2-yl) methyl) -1H-pyrazole-4-carboxamide (Am-47) , 102 mg) was obtained.
1 1 H-NMR (300 MHz, CD 3 OD) δ = 8.11 (1H, s), 7.91 (1H, s), 7.38-7.23 (5H, m), 6.84 (1H, d, J = 6.0 Hz), 5.34 ( 2H, s), 5.04-4.46 (7H, m).
MS (m / z): 465.9 (M + H) +
＜実施例００４８：Ａｍ－４８の合成＞
Figure JPOXMLDOC01-appb-C000115
 <Example 0048: Synthesis of Am-48>
Figure JPOXMLDOC01-appb-C000115
　実施例００１０において、１Ｈ－インドール－６－カルボン酸を用いた代わりに、１－メチル－１Ｈ－インドール－３－カルボン酸を用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－メチル－Ｎ－（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）－１Ｈ－インドール－３－カルボキサミド（Ａｍ－４８）を得た。
　ＭＳ（ｍ／ｚ）：４３２．２（Ｍ＋Ｈ）＋ In Example 0010, a white solid (S) was prepared in the same manner as in Example 0010 except that 1-methyl-1H-indole-3-carboxylic acid was used instead of 1H-indole-6-carboxylic acid. -1-Methyl-N-((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) -1H-indole-3-carboxyxamide (Am-48) Obtained.
MS (m / z): 432.2 (M + H) +
＜実施例００４９：Ａｍ－４９の合成＞
－還元的アミノ化及び３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000116
 <Example 0049: Synthesis of Am-49>
-Reductive amination and 3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000116
　ｔｅｒｔ－ブチル　５－ホルミルイソインドリン－２－カルボキシラート（３１ｍｇ）、ベンジルアミン（０．０１６ｍＬ）、ナトリウムトリアセトキシボロヒドリド（５５ｍｇ）及び酢酸（０．１ｍＬ）のクロロホルム（２ｍＬ）溶液を封管中、５０℃で３時間撹拌した。反応混合物を室温まで冷却した後、酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物のＮ，Ｎ－ジメチルホルムアミド（１．０ｍＬ）溶液にトリエチルアミン（０．０３５ｍＬ）及びクロロギ酸ベンジル（０．０１８ｍＬ）を加え、室温で１時間撹拌した。反応混合物に水及び酢酸エチルを加え、有機層を分取し、無水硫酸マグネシウムで乾燥した後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→０：１００）で精製した。得られた残留物に、４ｍｏｌ／Ｌ塩化水素／１，４－ジオキサン溶液（１．０ｍＬ）を加え、室温で３０分間撹拌した。減圧下で溶媒を留去し、白色固体を得た。（Ｓ）－３，３，３－トリフルオロ－２－ヒドロキシプロパン酸（２０ｍｇ）、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（５０ｍｇ）、１－ヒドロキシベンゾトリアゾール１水和物（５ｍｇ）、トリエチルアミン（０．０５ｍＬ）及びＮ，Ｎ－ジメチルホルムアミド（１．０ｍＬ）を加え、室温で２時間撹拌した。反応混合物に酢酸エチル及び水を加え、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１００：０→８０：２０）で精製し、白色固体のベンジル　（Ｓ）－ベンジル（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）カルバマート（１．５ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：４９９．３（Ｍ＋Ｈ）＋ A solution of tert-butyl 5-formylisoindoline-2-carboxylate (31 mg), benzylamine (0.016 mL), sodium triacetoxyborohydride (55 mg) and acetic acid (0.1 mL) in chloroform (2 mL) is in a sealed tube. , Stirred at 50 ° C. for 3 hours. After cooling the reaction mixture to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Triethylamine (0.035 mL) and benzyl chloroformate (0.018 mL) were added to a solution of the obtained residue in N, N-dimethylformamide (1.0 mL), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 0: 100). A 4 mol / L hydrogen chloride / 1,4-dioxane solution (1.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain a white solid. (S) -3,3,3-trifluoro-2-hydroxypropanoic acid (20 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (50 mg), 1-hydroxybenzotriazole monohydration The product (5 mg), triethylamine (0.05 mL) and N, N-dimethylformamide (1.0 mL) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 80: 20) and benzyl (S) -benzyl ((2- (3,3,3-)) as a white solid. Trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) carbamate (1.5 mg) was obtained.
MS (m / z): 499.3 (M + H) +
－Ｃｂｚ基の脱保護反応－
Figure JPOXMLDOC01-appb-C000117
 -Cbz group deprotection reaction-
Figure JPOXMLDOC01-appb-C000117
　ベンジル　（Ｓ）－ベンジル（（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）メチル）カルバマート（１．５ｍｇ）に５．１ｍｏｌ／Ｌ臭化水素／酢酸（０．２ｍＬ）を加え、室温で３０分間撹拌した。減圧下で溶媒を留去し、白色固体の（Ｓ）－１－（５－（（ベンジルアミノ）メチル）イソインドリン－２－イル）－３，３，３－トリフルオロ－２－ヒドロキシプロパン－１－オンの臭化水素塩（Ａｍ－４９、１．４ｍｇ）を得た。
　ＭＳ（ｍ／ｚ）：３６５．２（Ｍ＋Ｈ）＋ Benzyl (S) -benzyl ((2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) methyl) carbamate (1.5 mg) with 5.1 mol / L hydrogen bromide / Acetic acid (0.2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the white solid (S) -1-(5-((benzylamino) methyl) isoindoline-2-yl) -3,3,3-trifluoro-2-hydroxypropane- A 1-one hydrogen bromide salt (Am-49, 1.4 mg) was obtained.
MS (m / z): 365.2 (M + H) +
＜実施例００５０：Ａｍ－５０の合成＞
－３－ヒドロキシプロピル化反応－
Figure JPOXMLDOC01-appb-C000118
 <Example 0050: Synthesis of Am-50>
-3-Hydroxypropylation reaction-
Figure JPOXMLDOC01-appb-C000118
　ｔｅｒｔ－ブチル　５－ブロモイソインドリン－２－カルボキシラート（１．３０ｇ）、アクリル酸メチル（０．４１ｇ）、酢酸パラジウム（２５ｍｇ）、トリス（２－メチルフェニル）ホスフィン（６６ｍｇ）及びトリエチルアミン（１．８ｍＬ）のＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）溶液を、封管中、窒素雰囲気下、１３０℃で１０時間撹拌した。反応混合物を室温まで冷却し、酢酸エチル及び水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→７０：３０）で精製した。得られた残留物（０．７５ｇ）のテトラヒドロフラン（５．０ｍＬ）溶液に、０℃で１ｍｏｌ／Ｌ水素化アルミニウムリチウム／テトラヒドロフラン溶液（３．３ｍＬ）を加え、同温度で１５分間撹拌した。反応混合物に０℃でメタノール（１ｍＬ）を３分間かけて加えた後、５％（ｗ／ｖ）ロッシェル塩水溶液及び酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０→５０：５０）で精製し、黄色油状のｔｅｒｔ－ブチル　５－（３－ヒドロキシプロピル）イソインドリン－２－カルボキシラート（０．１４ｇ）を得た。
　ＭＳ（ｍ／ｚ）：２７７．２（Ｍ＋Ｈ）＋ tert-Butyl 5-bromoisoindoline-2-carboxylate (1.30 g), methyl acrylate (0.41 g), palladium acetate (25 mg), tris (2-methylphenyl) phosphine (66 mg) and triethylamine (1. 8 mL) of a solution of N, N-dimethylformamide (5.0 mL) was stirred in a sealed tube under a nitrogen atmosphere at 130 ° C. for 10 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 70: 30). A 1 mol / L lithium aluminum hydride / tetrahydrofuran solution (3.3 mL) was added to a solution of the obtained residue (0.75 g) in tetrahydrofuran (5.0 mL) at 0 ° C., and the mixture was stirred at the same temperature for 15 minutes. Methanol (1 mL) was added to the reaction mixture at 0 ° C. over 3 minutes, followed by 5% (w / v) aqueous Rochelle salt solution and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 → 50: 50), and the yellow oily tert-butyl 5- (3-hydroxypropyl) isoindoline-2-carboxylate (" 0.14 g) was obtained.
MS (m / z): 277.2 (M + H) +
－フタルイミド化反応－
Figure JPOXMLDOC01-appb-C000119
 -Phthalimideization reaction-
Figure JPOXMLDOC01-appb-C000119
　実施例０００８のフタルイミド化反応において、ｔｅｒｔ－ブチル　５－（ヒドロキシメチル）イソインドリン－２－カルボキシラートを用いた代わりに、ｔｅｒｔ－ブチル　５－（３－ヒドロキシプロピル）イソインドリン－２－カルボキシラートを用いる以外は実施例０００８のフタルイミド化反応と同様の方法で、無色油状のｔｅｒｔ－ブチル　５－（３－（１，３－ジオキソイソインドリン－２－イル）プロピル）イソインドリン－２－カルボキシラートを得た。
　ＭＳ（ｍ／ｚ）：４０７．１（Ｍ＋Ｈ）＋ In the phthalimidization reaction of Example 0008, instead of using tert-butyl 5- (hydroxymethyl) isoindoline-2-carboxylate, tert-butyl 5- (3-hydroxypropyl) isoindoline-2-carboxylate was used. The colorless oily tert-butyl 5- (3- (1,3-dioxoisoindoline-2-yl) propyl) isoindoline-2-carboxylate is used in the same manner as in the phthalimidization reaction of Example 0008 except that it is used. Got
MS (m / z): 407.1 (M + H) +
－フタルイミド基のアミノ化反応－
Figure JPOXMLDOC01-appb-C000120
 -Amino acid reaction of phthalimide group-
Figure JPOXMLDOC01-appb-C000120
　実施例０００８のフタルイミド基のアミノ化反応において、ｔｅｒｔ－ブチル　５－（（１，３－ジオキソイソインドリン－２－イル）メチル）イソインドリン－２－カルボキシラートを用いた代わりに、ｔｅｒｔ－ブチル　５－（３－（１，３－ジオキソイソインドリン－２－イル）プロピル）イソインドリン－２－カルボキシラートを用いる以外は実施例０００８のフタルイミド基のアミノ化反応と同様の方法で、無色油状のｔｅｒｔ－ブチル　５－（３－アミノプロピル）イソインドリン－２－カルボキシラートを得た。
　ＭＳ（ｍ／ｚ）：２７７．２（Ｍ＋Ｈ）＋ In the phthalimide group amination reaction of Example 0008, instead of using tert-butyl 5-((1,3-dioxoisoindoline-2-yl) methyl) isoindoline-2-carboxylate, tert-butyl 5- (3- (1,3-Dioxoisoindoline-2-yl) propyl) Isoindoline-2-carboxylate is a colorless oil in the same manner as the phthalimide group amination reaction of Example 0008 except that it is used. Tart-butyl 5- (3-aminopropyl) isoindoline-2-carboxylate was obtained.
MS (m / z): 277.2 (M + H) +
－アミド化及び３，３，３－トリフルオロ－２－ヒドロキシプロピオニル化反応－
Figure JPOXMLDOC01-appb-C000121
 -Amidation and 3,3,3-trifluoro-2-hydroxypropionylation reaction-
Figure JPOXMLDOC01-appb-C000121
　実施例００１０において、ｔｅｒｔ－ブチル　５－（アミノメチル）イソインドリン－２－カルボキシラートと１Ｈ－インドール－６－カルボン酸とを用いた代わりに、それぞれｔｅｒｔ－ブチル　５－（３－アミノプロピル）イソインドリン－２－カルボキシラートと１－ベンジル－１Ｈ－ピラゾール－４－カルボン酸とを用いる以外は実施例００１０と同様の方法で、白色固体の（Ｓ）－１－ベンジル－Ｎ－（３－（２－（３，３，３－トリフルオロ－２－ヒドロキシプロパノイル）イソインドリン－５－イル）プロピル）－１Ｈ－ピラゾール－４－カルボキサミド（Ａｍ－５０）を得た。
　ＭＳ（ｍ／ｚ）：４８６．４（Ｍ＋Ｈ）＋ In Example 0010, instead of using tert-butyl 5- (aminomethyl) isoindoline-2-carboxylate and 1H-indole-6-carboxylic acid, tert-butyl 5- (3-aminopropyl) iso, respectively. In the same manner as in Example 0010 except that indoline-2-carboxylate and 1-benzyl-1H-pyrazole-4-carboxylic acid were used, the white solid (S) -1-benzyl-N- (3-( 2- (3,3,3-trifluoro-2-hydroxypropanoyl) isoindoline-5-yl) propyl) -1H-pyrazol-4-carboxamide (Am-50) was obtained.
MS (m / z): 486.4 (M + H) +
（実施例１０１～１４５、１４７～１５０、並びに、比較例１０１及び１０２）
＜ＨＤＡＣ６酵素反応阻害評価＞
－酵素反応阻害試験－
　ＨＤＡＣ６酵素の活性は、ペプチド基質の脱アセチル化による帯電状態の変化を検出する酵素評価系を用いて評価した。精製された組換えヒトＨＤＡＣ６（ＨＤＡＣ６，ａ．ａ．　ｆｕｌｌ　ｌｅｎｇｔｈ，１６１ｋＤａ，グルタチオン　Ｓ－トランスフェラーゼ（ＧＳＴ）　ｔａｇ）をＢＰＳ社から購入した。ペプチド基質としてＡｃ化されたペプチド（５－ＦＩＴＣ－ＡＨＡ－ＬＧＫＧＧＡＫ（Ａｃ）－ＣＯＮＨ２）を用いた。酵素評価は、２５ｍＭトリス塩酸緩衝液（Ｔｒｉｓ／ＨＣｌバッファー、ｐＨ７．５），１３７ｍＭ ＮａＣｌ，２．７ｍＭ ＫＣｌ，１ｍＭ ＭｇＣｌ２，０．１ｍｇ／ｍＬウシ血清アルブミン（ＢＳＡ、ｆａｔｔｙ　ａｃｉｄ　ｆｒｅｅ），０．５μＭ ｓｕｂｓｔｒａｔｅ（ペプチド基質），６３ｎＭ ｅｎｚｙｍｅ（ＨＤＡＣ６）である液に、試験化合物の１％ＤＭＳＯ溶液（ＤＭＳＯ希釈化合物）を用いて終濃度０．０００１μＭ～１μＭ（１０段階希釈濃度）となるよう各ウェルに添加し、また、対照としてＤＭＳＯを添加したウェルも用意し、２５℃２０分、３８４ウェルプレートのウェル内で反応させ、エチレンジアミン四酢酸（ＥＤＴＡ）を含む反応停止液を加え、基質ペプチドの脱Ａｃ化の割合をＣａｌｉｐｅｒ社のＥＺ　ｒｅａｄｅｒ機器を用いて検出した。 (Examples 101 to 145, 147 to 150, and Comparative Examples 101 and 102)
<Evaluation of HDAC6 enzyme reaction inhibition>
-Enzyme reaction inhibition test-
The activity of the HDAC6 enzyme was evaluated using an enzyme evaluation system that detects changes in the charged state due to deacetylation of the peptide substrate. Purified recombinant human HDAC6 (HDAC6, a.a. full length, 161 kDa, glutathione S-transferase (GST) tag) was purchased from BPS. An Ac-ized peptide (5-FITC-AHA-LGKGGAK (Ac) -CONH 2 ) was used as the peptide substrate. Enzyme evaluation was performed on 25 mM Tris hydrochloride buffer (Tris / HCl buffer, pH 7.5), 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , 0.1 mg / mL bovine serum albumin (BSA, fatty acid free), 0. Each well so as to have a final concentration of 0.0001 μM to 1 μM (10-step dilution concentration) using a 1% DMSO solution (DMSO diluted compound) of the test compound in a solution of 5 μM buffer (peptide substrate) and 63 nM enzyme (HDAC6). In addition, a well to which DMSO was added was also prepared as a control, and the reaction was carried out in a well of a 384-well plate at 25 ° C. for 20 minutes. The rate of Accification was detected using a Caliper EZ reader device.
－ＩＣ５０（μＭ（＝μｍｏｌ／Ｌ））の算出－
　上記酵素反応阻害試験を１０段階の試験化合物濃度で行い、各試験化合物濃度における下記式で表される酵素反応阻害率を求め、ＸＬｆｉｔソフトウエア（ＩＤ　Ｂｕｓｉｎｅｓｓ　Ｓｏｌｕｔｉｏｎｓ社製）を用いて５０％酵素反応阻害濃度［ＩＣ５０（μｍｏｌ／Ｌ）］を算出した。
　　酵素反応阻害率（％）＝（試験化合物添加ウェルｐｒｏｄｕｃｔ変換率）÷（ＤＭＳＯのみ添加ウェルｐｒｏｄｕｃｔ変換率）×１００ -Calculation of IC50 (μM (= μmol / L))-
The above enzyme reaction inhibition test was carried out at 10 levels of test compound concentration, the enzyme reaction inhibition rate represented by the following formula was determined at each test compound concentration, and 50% enzyme reaction was performed using XLfit software (manufactured by ID Business Solutions). The inhibition concentration [IC50 (μmol / L)] was calculated.
Enzyme reaction inhibition rate (%) = (well product conversion rate with test compound added) ÷ (well product conversion rate with DMSO only) x 100
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
　なお、表１～表７における「Ｅｘａｃｔ　Ｍａｓｓ」は、計算精密質量であり、各元素における天然存在比が最大の同位体質量（モノアイソトピック質量）を表す。
　表１～表７に示すように、本開示に係るアミド化合物又はその塩である実施例１０１～１４５及び１４７～１５０で使用したアミド化合物又はその塩は、ＨＤＡＣ阻害作用を有する。
　また、本開示に係るアミド化合物又はその塩である実施例１０１～１４５及び１４７～１５０で使用したアミド化合物は、ＨＤＡＣが関与する疾患の治療のための医薬組成物として有用である。
　また、本開示に係るアミド化合物又はその塩を用いて炎症性腸疾患の大腸炎モデルマウスに対し、薬効評価を行う。モデルマウスでは、大腸炎に伴う体重減少が抑制され、炎症の原因となる細胞の減少が抑制され、炎症性サイトカインの減少が確認される。 In addition, "Exact Mass" in Tables 1 to 7 is a calculated precision mass, and represents an isotope mass (monoisotopic mass) having the maximum natural abundance ratio in each element.
As shown in Tables 1 to 7, the amide compounds or salts thereof used in Examples 101 to 145 and 147 to 150 according to the present disclosure have an HDAC inhibitory effect.
In addition, the amide compounds used in Examples 101 to 145 and 147 to 150, which are the amide compounds or salts thereof according to the present disclosure, are useful as pharmaceutical compositions for the treatment of diseases associated with HDAC.
In addition, the efficacy of the amide compound or a salt thereof according to the present disclosure will be evaluated for colitis model mice with inflammatory bowel disease. In the model mouse, the weight loss associated with colitis is suppressed, the decrease in cells causing inflammation is suppressed, and the decrease in inflammatory cytokines is confirmed.
　実施例１０１、１２７、１３６及び１３９については、ＨＤＡＣ１酵素反応阻害評価も行った。評価は、Reaction Biology Corporationに委託して行った。その結果、いずれの化合物もＨＤＡＣ１阻害能が低いことが確認された。
　実施例１０１については、ＨＤＡＣ２酵素反応阻害評価も行った。評価は、Reaction Biology Corporationに委託して行った。その結果、ＨＤＡＣ２阻害能が低いことが確認された。
　実施例１０１については、ＨＤＡＣ７酵素反応阻害評価も行った。評価は、Reaction Biology Corporationに委託して行った。その結果、ＨＤＡＣ７阻害能が高いことが確認された。
　実施例１０１、１２７、１３６及び１３９については、ＨＤＡＣ９酵素反応阻害評価も行った。評価は、Reaction Biology Corporationに委託して行った。その結果、いずれの化合物もＨＤＡＣ９阻害能が高いことが確認された。なお、実施例１２７、１３６及び１３９は、実施例１０１よりＨＤＡＣ９阻害能が高いことが確認された。 For Examples 101, 127, 136 and 139, HDAC1 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that all the compounds had low HDAC1 inhibitory ability.
For Example 101, HDAC2 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that the HDAC2 inhibitory ability was low.
For Example 101, HDAC7 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that the HDAC7 inhibitory ability was high.
For Examples 101, 127, 136 and 139, HDAC9 enzyme reaction inhibition evaluation was also performed. The evaluation was outsourced to Reaction Biology Corporation. As a result, it was confirmed that all the compounds have high HDAC9 inhibitory ability. It was confirmed that Examples 127, 136 and 139 had higher HDAC9 inhibitory ability than Example 101.
（実施例２０１～２０５、及び、比較例２０１）
＜ＰＡＭＰＡ法による化合物の膜透過性評価＞
　合成した化合物の膜透過性を比較検討するために、ＰＡＭＰＡ（Parallel Artificial Membrane Permeability Assay）を実施した。
　Filter Plate（Merck Millipore社製, Cat.MAIPN4550）に、L-α-phosphatidylcholine（Avanti, Cat.840051P, 1.67%）、1,2-dioleoyl-sn-glycero-3-phospho-L-serine（Avanti Polar Lipids社製, Cat.840035P, 0.33%）、ｎ－ドデカン特級（富士フイルム和光純薬（株）製，０４７－２１６１２）／１－オクタノール試薬特級（関東化学（株）製，Ｃａｔ．３１０１３－０８）＝１０：１からなる、リン脂質有機溶媒溶液を５μＬ添加することで、人工リン脂質膜を作製した。 (Examples 201 to 205 and Comparative Example 201)
<Evaluation of Membrane Permeability of Compounds by PAMPA Method>
In order to compare and examine the membrane permeability of the synthesized compound, PAMPA (Parallel Artificial Membrane Permeability Assay) was carried out.
Filter Plate (Merck Millipore, Cat.MAIPN4550), L-α-phosphatidylcholine (Avanti, Cat.840051P, 1.67%), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (Avanti Polar) Lipids, Cat.840035P, 0.33%), n-dodecane special grade (Fujifilm Wako Junyaku Co., Ltd., 047-21612) / 1-octanol reagent special grade (Kanto Chemical Co., Ltd., Cat.31013-08) ) = 10: 1 An artificial phospholipid membrane was prepared by adding 5 μL of a phospholipid organic solvent solution.
　合成した化合物を２０μｍｏｌ／Ｌの濃度で含むＤＭＳＯ溶液２５μＬに５０ｍｍｏｌ／Ｌ　ＫＰＢ（カリウムリン酸緩衝液、ｐＨ７．４あるいはｐＨ６．５）を４７５μＬ加えて最終濃度１μｍｏｌ／Ｌまで希釈した。その化合物溶液を上記ＰＡＭＰＡ９６ウェルプレート（Ｆｉｌｔｅｒ　Ｐｌａｔｅ（Ｍｅｒｃｋ　Ｍｉｌｌｉｐｏｒｅ社製，Ｃａｔ．ＭＡＩＰＮ４５５０））の人工リン脂質膜を挟んで下側（ドナー側）に３００μＬずつ添加した。人工リン脂質膜を挟んで上側（アクセプター側）に２００μＬずつ５％ＤＭＳＯ　ＫＰＢ（ｐＨ７．４）を添加した。人工リン脂質膜を介した透過試験を２５℃、４時間行った。ドナープレート及びアクセプタープレートにおける溶液中化合物濃度をＬＣ／ＭＳ／ＭＳにより測定し、下記式より化合物の膜透過速度（Ｐｅ）を算出した。
　ただし、Ｃ０をドナー液中の化合物初期濃度、ｔを試験時間、Ａをメンブレンフィルター面積＝０．３ｃｍ２、ＶＤをドナー液量＝３００μＬ、ＶＡをアクセプター液量＝２００μＬ、ＣＤ（ｔ）を時間ｔにおけるドナー液中化合物濃度、ＣＡ（ｔ）を時間ｔにおけるアクセプター液中化合物濃度Ｃｅｑｕｉｌｉｂｒｉｕｍ＝［ＣＤ（ｔ）×ＶＤ＋ＣＡ（ｔ）×ＶＡ］／ＶＤ＋ＶＡ）とする。 475 μL of 50 mmol / L KPB (potassium phosphate buffer, pH 7.4 or pH 6.5) was added to 25 μL of a DMSO solution containing the synthesized compound at a concentration of 20 μmol / L to dilute to a final concentration of 1 μmol / L. 300 μL of the compound solution was added to the lower side (donor side) of the PAMPA 96-well plate (Fitter Plate (manufactured by Merck Millipore, Cat. MAIPN4550)) with an artificial phospholipid membrane sandwiched between them. 200 μL of 5% DMSO KPB (pH 7.4) was added to the upper side (acceptor side) with the artificial phospholipid membrane in between. A permeation test via an artificial phospholipid membrane was performed at 25 ° C. for 4 hours. The concentration of the compound in the solution on the donor plate and the acceptor plate was measured by LC / MS / MS, and the membrane permeation rate ( Pe ) of the compound was calculated from the following formula.
However, compounds initial concentration of donor liquid in C 0, the time test t, A membrane filter area = 0.3 cm 2, V D donor solution volume = 300 [mu] L, acceptor solution amount V A = 200μL, C D ( concentration donor fluid compound in t) of time t, C a (acceptor liquid compound in t) of time t concentration C equilibrium = [C D (t ) × V D + C a (t) × V a] / V D + VA ).
Figure JPOXMLDOC01-appb-M000129
Figure JPOXMLDOC01-appb-M000129
　上記方法により得られた膜透過性（Ｐｅ（１０－６ｃｍ／ｓｅｃ））を、以下の表８に記載した。 The membrane permeability (Pe ( 10-6 cm / sec)) obtained by the above method is shown in Table 8 below.
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
　表８に示すように、本開示に係るアミド化合物又はその塩は、膜透過性にも優れる。 As shown in Table 8, the amide compound or a salt thereof according to the present disclosure is also excellent in membrane permeability.
＜ウエスタンブロット解析＞
（１）細胞培養
　ヒト乳がん細胞MCF-7（Japanese Collection of Research Bioresourcesから入手; JCRB0134, Japan）を10％ウシ胎児血清アルブミン(FBS; Sigma-Aldrich社製, #173012-500ML)、1％ antibiotic- antimycotic mixed stock solution (ナカライテスク（株）製, #09366-44), 1% L-glutamine stock solution (Nacalai, #16948-04), 1% ピルビン酸ナトリウム溶液(ナカライテスク（株）製, #06977-34)を含む、Dulbecco’s modified Eagle’s medium (DMEM;ナカライテスク（株）製, #08489-45)中、5%ＣＯ２雰囲気下、37℃に設定したＣＯ２インキュベーター（ＰＨＣ（株）製, MCO-170AIC-PJ）で培養した。
（２）タンパク質濃度定量
　上記（１）細胞培養の項に記載した培地を用い、6ウェルプレート（IWAKI 3810-006, ＡＧＣテクノグラス（株）製）にMCF-7細胞（25 x 104cells/2 mL/well）を播種し、5%ＣＯ２雰囲気下、37℃で24時間培養した。各濃度の試験化合物-DMSO溶液（2μL）を加え、更に5%ＣＯ２雰囲気下、37℃で8時間培養した。培地を除去した後、Dulbecco's Phosphate Buffered Saline(D-PBS)（-）緩衝液（0.5 mL/well）で洗浄し、生着している細胞を2％ドデシル硫酸ナトリウム(SDS)バッファー（150μL）で抽出し、細胞ライセートのタンパク質濃度をBCA protein assayを用いて測定した。
（３）電気泳動とポリフッ化ビニリデン（ＰＶＤＦ）膜への転写
　抽出した細胞タンパク質に、1％メルカプトエタノール・ブロモフェノールブルー含有SDSバッファーを加え95℃で5分間加熱処理し、電気泳動サンプルとして用いた。電気泳動及びＰＶＤＦ膜への転写は、ミニスラブ電気泳動装置（アトー（株）製, AE-6530P）を用いて行った。電気泳動は、5μgのタンパク質を5-20% SDS-polyacrylamideゲル（e-PAGEL,アトー（株）製, E-R520L）にアプライして行い、電気泳動終了後、タンパク質をゲルからPVDFメンブレン(Merck社製, IPVH00010)に転写した。
（４）ウエスタンブロット
　タンパク質を転写したメンブレンを、5%スキムミルクTris Buffered Saline(TBS)溶液を用いて室温で1時間ブロッキングした後、一次抗体としてそれぞれ、mouse monoclonal acetyl-α-tubulin antibody (Sigma-Aldrich社製, #T6793) (1:3000 希釈) Can Get Signal (東洋紡（株）製, NKB-101)溶液、mouse monoclonal α-tubulin antibody (Sigma-Aldrich社製, #T8203) (1:1000 希釈) Can Get Signal (東洋紡（株）製, NKB-101)溶液、rabbit polyclonal acetyl H3 (K9, K14, K18 K23 and K27) antibody (Abcam社製, #ab47915) (1:6000 希釈) TBS containing 5% skimmed milk溶液、rabbit polyclonal H3 antibody (Abcam社製, #ab1791) (1:2000 希釈)TBS containing 5% skimmed milk溶液を用い、4℃で終夜反応させた。メンブレンを洗浄用TBS溶液で3回洗浄後、二次抗体として、ECL mouse IgG, HRP- linked whole antibody (GE Healthcare Life Sciences社製, #NA931) (1:2500 希釈) Can Get Signal (東洋紡（株）製, NKB-101) 溶液、又は、ECL rabbit IgG, HRP-linked whole antibody (GE Healthcare Life Sciences社製, #NA934) (1:2500 希釈) TBS containing 5% skimmed milk溶液を用い、室温で1時間反応させた。反応後、メンブレンを再度洗浄用TBS溶液で3回洗浄した。
（５）染色
　バンドは化学発光により検出した。ImmobilonTMWestern Chemiluminescent HRP Substrate (Merck社製, WBKLS0050)を検出薬として使用し、ImageQuant LAS 500（Cytiva社製）で検出した。
　結果、市販の非選択的HDAC阻害剤であるSAHA（下記化合物）は、HDAC6の基質であるα-tubulinだけでなく、H3も用量依存的にアセチル化した。一方、Am-36及びAm-47はα-tubulinを用量依存的にアセチル化し、H3のアセチル化に対する影響はSAHAよりも著しく小さかった。以上の結果は、細胞評価系において、Am-36及びAm-47のHDAC6選択性がSAHAより高いことを支持する。 <Western blot analysis>
(1) Cell culture Human breast cancer cell MCF-7 (obtained from Japanese Collection of Research Bioresources; JCRB0134, Japan) was obtained from 10% fetal bovine serum albumin (FBS; Sigma-Aldrich, # 173012-500ML), 1% antibiotic- antimycotic mixed stock solution (Nacalai Tesque, Inc., # 09366-44), 1% L-glutamine stock solution (Nacalai, # 16948-04), 1% sodium pyruvate solution (Nacalai Tesque, Inc., # 06977) In Dulbecco's modified Eagle's medium (DMEM; manufactured by Nacalai Tesque Co., Ltd., # 08489-45) containing -34), a CO 2 incubator (manufactured by PHC Co., Ltd., MCO) set at 37 ° C. under a 5% CO 2 atmosphere. -170AIC-PJ) was cultured.
(2) Quantification of protein concentration Using the medium described in (1) Cell culture above, MCF-7 cells (25 x 10 4 cells /) were placed on a 6-well plate (IWAKI 3810-006, manufactured by AGC Technograss Co., Ltd.). 2 mL / well) was seeded and cultured at 37 ° C. for 24 hours in a 5% CO 2 atmosphere. A test compound-DMSO solution (2 μL) at each concentration was added, and the cells were further cultured in a 5% CO 2 atmosphere at 37 ° C. for 8 hours. After removing the medium, wash with Dulbecco's Phosphate Buffered Saline (D-PBS) (-) buffer (0.5 mL / well) and engraft cells with 2% sodium dodecyl sulfate (SDS) buffer (150 μL). The protein was extracted and the protein concentration of cell lysate was measured using the BCA protein assay.
(3) Electrophoresis and transfer to polyvinylidene fluoride (PVDF) membrane To the extracted cell protein, SDS buffer containing 1% mercaptoethanol / bromophenol blue was added and heat-treated at 95 ° C. for 5 minutes, and used as an electrophoresis sample. .. Electrophoresis and transfer to the PVDF membrane were performed using a mini slab electrophoresis device (Ato Co., Ltd., AE-6530P). Electrophoresis is performed by applying 5 μg of protein to a 5-20% SDS-polyacrylamide gel (e-PAGEL, manufactured by Atto Co., Ltd., E-R520L), and after the electrophoresis is completed, the protein is transferred from the gel to a PVDF membrane (Merck). Transferred to IPVH00010) manufactured by the company.
(4) Western blot The membrane on which the protein was transferred was blocked with a 5% skim milk Tris Buffered Saline (TBS) solution at room temperature for 1 hour, and then mouse monoclonal acetyl-α-tubulin antibody (Sigma-Aldrich) was used as the primary antibody. Can Get Signal (Toyo Boseki Co., Ltd., NKB-101) solution, mouse monoclonal α-tubulin antibody (Sigma-Aldrich, # T8203) (1: 1000 dilution) Can Get Signal (Toyo Boseki Co., Ltd., NKB-101) solution, rabbit polyclonal acetyl H3 (K9, K14, K18 K23 and K27) antibody (Abcam, # ab47915) (1: 6000 diluted) TBS containing 5% skimmed Milk solution, rabbit polyclonal H3 antibody (Abcam, # ab1791) (1: 2000 dilution) TBS containing 5% skimmed milk solution was used and reacted overnight at 4 ° C. After washing the membrane 3 times with a TBS solution for washing, as a secondary antibody, ECL mouse IgG, HRP-linked whole antibody (GE Healthcare Life Sciences, # NA931) (1: 2500 dilution) Can Get Signal (Toyo Boseki Co., Ltd.) ), NKB-101) solution, or ECL rabbit IgG, HRP-linked whole antibody (GE Healthcare Life Sciences, # NA934) (1: 2500 dilution) TBS containing 5% skimmed milk solution at room temperature 1 Reacted for time. After the reaction, the membrane was washed again with TBS solution for washing three times.
(5) The stained band was detected by chemiluminescence. Immobilon TM Western Chemiluminescent HRP Substrate (Merck, WBKLS0050) was used as a detection agent and detected with ImageQuant LAS 500 (Cytiva).
As a result, SAHA (the following compound), which is a commercially available non-selective HDAC inhibitor, acetylated not only α-tubulin, which is a substrate of HDAC6, but also H3 in a dose-dependent manner. On the other hand, Am-36 and Am-47 acetylated α-tubulin in a dose-dependent manner, and the effect of H3 on acetylation was significantly smaller than that of SAHA. These results support that Am-36 and Am-47 have higher HDAC6 selectivity than SAHA in the cell evaluation system.
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　２０２０年３月３１日に出願された日本国特許出願第２０２０－０６４６１６号の開示は、その全体が参照により本明細書に取り込まれる。
　本明細書に記載された全ての文献、特許出願、及び、技術規格は、個々の文献、特許出願、及び、技術規格が参照により取り込まれることが具体的かつ個々に記された場合と同程度に、本明細書中に参照により取り込まれる。 The disclosure of Japanese Patent Application No. 2020-064616 filed on March 31, 2020 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards described herein are to the same extent as if the individual documents, patent applications, and technical standards were specifically and individually stated to be incorporated by reference. Is incorporated herein by reference.

Claims (10)

  1. 　下記式（Ｉ－１）で表されるアミド化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000001
    　式（Ｉ－１）において、
    　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
    　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
    　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
    　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
    　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
    　Ｒ５のうち少なくとも１つはフッ素原子であり、
    　２個のＲ５が結合して環を形成してもよく、
    　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
    　Ｌ１は、０又は１を表す。     An amide compound represented by the following formula (I-1) or a salt thereof.
    Figure JPOXMLDOC01-appb-C000001
    In formula (I-1)
    R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
    All R 1 ~ R 4 are not hydrogen atoms at the same time,
    R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
    R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
    R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
    At least one of R 5 is a fluorine atom,
    Two R 5 may be combined with each other to form a ring,
    R 6 represents a hydrogen atom or a C 1-10 alkyl group.
    L1 represents 0 or 1.
  2. 　全てのＲ５が、フッ素原子である、請求項１に記載のアミド化合物又はその塩。 The amide compound according to claim 1, or a salt thereof, wherein all R 5s are fluorine atoms.
  3. 　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成している、請求項１又は請求項２に記載のアミド化合物又はその塩。 Claim 1 or claim 2 in which R 1 to R 4 are integrally formed to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent. The amide compound or a salt thereof according to.
  4. 　Ｒ１～Ｒ４が一体となって形成する置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環が、置換基を有してもよいベンゼン環、置換基を有してもよいチオフェン環又は置換基を有してもよいピラゾール環である、請求項３に記載のアミド化合物又はその塩。 An aromatic hydrocarbon ring which may have a substituent which is formed by integrating R 1 to R 4 or an aromatic hetero ring which may have a substituent may have a substituent. The amide compound according to claim 3, or a salt thereof, which is a thiophene ring which may have a substituent or a pyrazole ring which may have a substituent.
  5. 　Ｒ１～Ｒ４が一体となって形成する前記芳香族炭化水素環又は前記芳香族ヘテロ環上に有していてもよい置換基が、
    ハロゲン原子、ヒドロキシ基、カルボキシ基、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルケニル基、置換基を有してもよいアリールＣ２－１０アルケニル基、置換基を有してもよいヘテロアリールＣ２－１０アルケニル基、置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
    －Ｌ２－ＮＲ５１Ｒ５２、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
    －Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
    －Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、及び、
    －Ｌ２－ＳＯ２ＮＲ５１Ｒ５２よりなる群から選ばれた少なくとも１種の基である、請求項３又は請求項４に記載のアミド化合物又はその塩。
    　なお、Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
    　Ｌ２は、単結合、又は、置換基を有してもよいアルキレン基を表す。     R 1 ~ R 4 are the aromatic hydrocarbon ring or the substituent which may have on the aromatic heterocycle formed together is,
    Halogen atom, hydroxy group, a carboxy group, an optionally substituted C 1-10 alkyl group, an optionally substituted C 2-10 alkenyl group, an optionally substituted C 2- 10 Alkinyl group, C 3-8 cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent which may have a substituent. good C 3-8 cycloalkyl C 1-10 alkyl group, an optionally substituted aryl C 1-10 alkyl group, an optionally substituted heteroaryl C 1-10 alkyl group, a substituent a may be C 3-8 cycloalkyl C 2-10 alkenyl group, an optionally substituted aryl C 2-10 alkenyl group, an optionally substituted heteroaryl C 2-10 alkenyl group , an optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, a C 1-6 alkoxycarbonyl which may have a substituent A group, an aryloxycarbonyl group which may have a substituent,
    -L 2- NR 51 R 52 ,
    -L 2- NR 51 C (O) R 54 ,
    -L 2- NR 51 C (O) NR 53 R 54 ,
    -L 2- NR 51 SO 2 R 54 ,
    -L 2- C (O) NR 51 R 52 , and
    The amide compound or salt thereof according to claim 3 or 4, which is at least one group selected from the group consisting of -L 2- SO 2 NR 51 R 52.
    In addition, R 51 , R 52 , R 53 and R 54 independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl which may have a substituent. It may have a group, a crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a substituent. It may have a heteroaryl group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a substituent. Represents a good heteroaryl C 1-10 alkyl group,
    L 2 represents an alkylene group which may have a single bond or a substituent.
  6. 　前記式（Ｉ－１）で表されるアミド化合物又はその塩が、下記式（ＩＩ－１）～式（ＩＩ－４）のいずれかで表されるアミド化合物又はその塩である、請求項１～請求項５のいずれか１項に記載のアミド化合物又はその塩。
    Figure JPOXMLDOC01-appb-C000002
    　式（ＩＩ－１）中、
    　Ｒ１１はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
    置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
    置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
    置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
    置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
    －Ｌ２－ＮＲ５１Ｒ５２、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
    －Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
    －Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
    －Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
    　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
    　Ｌ２は、単結合、又は、置換基を有してもよいＣ１－１０アルキレン基を表し、
    　ｍ１は、１～４の整数を表す。
    Figure JPOXMLDOC01-appb-C000003
    　式（ＩＩ－２）中、
    　Ｒ１２はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
    置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
    置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
    置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
    置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
    －Ｌ２－ＮＲ５１Ｒ５２、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
    －Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
    －Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
    －Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
    　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
    　Ｌ２は、単結合、又は、置換基を有してもよいＣ１－１０アルキレン基を表し、
    　ｍ２は、１又は２を表す。
    Figure JPOXMLDOC01-appb-C000004
    　式（ＩＩ－３）中、
    　Ｘはそれぞれ独立に、Ｎ、ＮＨ又はＮＲ１３を表し、
    　Ｒ１３はそれぞれ独立に、ハロゲン原子、ヒドロキシ基、カルボキシ基、
    置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－１０アルケニル基、置換基を有してもよいＣ２－１０アルキニル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、
    置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、置換基を有してもよいヘテロアリールＣ１－１０アルキル基、
    置換基を有してもよいＣ３－８シクロアルキルＣ２－１０アルキニル基、置換基を有してもよいアリールＣ２－１０アルキニル基、置換基を有してもよいヘテロアリールＣ２－１０アルキニル基、
    置換基を有してもよいＣ１－６アルコキシ基、置換基を有してもよいＣ１－６アルコキシＣ１－１０アルキル基、置換基を有してもよいＣ１－６アルコキシカルボニル基、置換基を有してもよいアリールオキシカルボニル基、
    －Ｌ２－ＮＲ５１Ｒ５２、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）Ｒ５４、
    －Ｌ２－ＮＲ５１Ｃ（Ｏ）ＮＲ５３Ｒ５４、
    －Ｌ２－ＮＲ５１ＳＯ２Ｒ５４、
    －Ｌ２－Ｃ（Ｏ）ＮＲ５１Ｒ５２、又は、
    －Ｌ２－ＳＯ２ＮＲ５１Ｒ５２を表し、
    　Ｒ５１、Ｒ５２、Ｒ５３及びＲ５４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ３－８シクロアルキル基、置換基を有してもよい架橋式炭化水素環基、置換基を有してもよいヘテロ脂肪族環基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよいＣ３－８シクロアルキルＣ１－１０アルキル基、置換基を有してもよいアリールＣ１－１０アルキル基、又は、置換基を有してもよいヘテロアリールＣ１－１０アルキル基を表し、
    　Ｌ２は、単結合、又は、置換基を有してもよいＣ１－１０アルキレン基を表し、
    　ｍ３は、０～２の整数を表す。
    Figure JPOXMLDOC01-appb-C000005
    　式（ＩＩ－４）中、
    　Ｒ１４～Ｒ１７はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、又は、置換基を有してもよいＣ２－６アルキニル基を表し、
    　Ｒ１４とＲ１５とが、又は、Ｒ１６とＲ１７とが結合して、置換基を有してもよいＣ１－６アルキリデン基を形成してもよい。ただし、Ｒ１４～Ｒ１７の全てが同時に水素原子となることはない。     Claim 1 The amide compound represented by the formula (I-1) or a salt thereof is an amide compound represented by any of the following formulas (II-1) to (II-4) or a salt thereof. The amide compound according to any one of claim 5 or a salt thereof.
    Figure JPOXMLDOC01-appb-C000002
    In formula (II-1),
    R 11 is independently a halogen atom, a hydroxy group, a carboxy group,
    It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
    C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
    C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
    An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
    -L 2- NR 51 R 52 ,
    -L 2- NR 51 C (O) R 54 ,
    -L 2- NR 51 C (O) NR 53 R 54 ,
    -L 2- NR 51 SO 2 R 54 ,
    -L 2- C (O) NR 51 R 52 , or
    -L 2- SO 2 NR 51 R 52 , representing
    R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. A crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl which may have a substituent. A group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a hetero which may have a substituent. Represents an aryl C 1-10 alkyl group
    L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
    m1 represents an integer of 1 to 4.
    Figure JPOXMLDOC01-appb-C000003
    In formula (II-2),
    R 12 is independently a halogen atom, a hydroxy group, a carboxy group,
    It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
    C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
    C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
    An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
    -L 2- NR 51 R 52 ,
    -L 2- NR 51 C (O) R 54 ,
    -L 2- NR 51 C (O) NR 53 R 54 ,
    -L 2- NR 51 SO 2 R 54 ,
    -L 2- C (O) NR 51 R 52 , or
    -L 2- SO 2 NR 51 R 52 , representing
    R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. A crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl which may have a substituent. A group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a hetero which may have a substituent. Represents an aryl C 1-10 alkyl group
    L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
    m2 represents 1 or 2.
    Figure JPOXMLDOC01-appb-C000004
    In formula (II-3),
    X independently represents N, NH or NR 13.
    R 13 is independently a halogen atom, a hydroxy group, a carboxy group,
    It has a C 1-10 alkyl group that may have a substituent, a C 2-10 alkenyl group that may have a substituent, a C 2-10 alkynyl group that may have a substituent, and a substituent. May have a C 3-8 cycloalkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
    C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, aryl C 1-10 alkyl group which may have a substituent, heteroaryl C 1- which may have a substituent. 10 alkyl groups,
    C 3-8 cycloalkyl C 2-10 alkynyl group which may have a substituent, aryl C 2-10 alkynyl group which may have a substituent, heteroaryl C 2 which may have a substituent. 10 alkynyl groups,
    An optionally substituted C 1-6 alkoxy group, an optionally substituted C 1-6 alkoxy C 1-10 alkyl group, an optionally substituted C 1-6 alkoxycarbonyl group , Aryloxycarbonyl group which may have a substituent,
    -L 2- NR 51 R 52 ,
    -L 2- NR 51 C (O) R 54 ,
    -L 2- NR 51 C (O) NR 53 R 54 ,
    -L 2- NR 51 SO 2 R 54 ,
    -L 2- C (O) NR 51 R 52 , or
    -L 2- SO 2 NR 51 R 52 , representing
    R 51 , R 52 , R 53 and R 54 are independently hydrogen atoms, a C 1-10 alkyl group which may have a substituent, and a C 3-8 cycloalkyl group which may have a substituent, respectively. A crosslinked hydrocarbon ring group which may have a substituent, a heteroaliphatic ring group which may have a substituent, an aryl group which may have a substituent, and a heteroaryl which may have a substituent. A group, a C 3-8 cycloalkyl C 1-10 alkyl group which may have a substituent, an aryl C 1-10 alkyl group which may have a substituent, or a hetero which may have a substituent. Represents an aryl C 1-10 alkyl group
    L 2 represents a C 1-10 alkylene group which may have a single bond or a substituent.
    m3 represents an integer of 0 to 2.
    Figure JPOXMLDOC01-appb-C000005
    In formula (II-4),
    R 14 to R 17 each independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, or a substituent. Represents a optionally C 2-6 alkynyl group and represents
    R 14 and R 15 may be combined, or R 16 and R 17 may be combined to form a C 1-6 alkylidene group which may have a substituent. However, not all of R 14 to R 17 become hydrogen atoms at the same time.
  7. 　請求項１～請求項６のいずれか１項に記載のアミド化合物又はその塩を含有する医薬組成物。 A pharmaceutical composition containing the amide compound according to any one of claims 1 to 6 or a salt thereof.
  8. 　ヒストン脱アセチル化酵素が関与する疾患の処置剤である、請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, which is a therapeutic agent for a disease involving histone deacetylase.
  9. 　下記式（Ｉ）で表されるアミド化合物又はその塩を含有するヒストン脱アセチル化酵素阻害剤。
    Figure JPOXMLDOC01-appb-C000006
    　式（Ｉ）において、
    　Ｒ０１は、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、又は、置換基を有してもよい炭化水素環基を表し、
    　Ｒ０２は、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、又は、置換基を有してもよいヘテロ環基を表し、
    　Ｒ０１とＲ０２とは一体となって、置換基を有してもよい含窒素ヘテロ環を形成してもよく、
    　Ｒ０３はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
    　Ｒ０３のうち少なくとも１つはフッ素原子であり、
    　２個のＲ０３が結合して環を形成してもよく、
    　Ｒ０４は、水素原子又はＣ１－１０アルキル基を表す。     A histone deacetylase inhibitor containing an amide compound represented by the following formula (I) or a salt thereof.
    Figure JPOXMLDOC01-appb-C000006
    In formula (I)
    R 01 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a C 2-6 alkynyl which may have a substituent. Represents a hydrocarbon ring group which may have a group or a substituent,
    R 02 is a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, a C 2-6 alkynyl group which may have a substituent, and a substituent. Represents a hydrocarbon ring group which may have a group or a heterocyclic group which may have a substituent.
    R 01 and R 02 may be integrated to form a nitrogen-containing heterocycle which may have a substituent.
    R 03 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
    At least one of R 03 is a fluorine atom
    Two R 03s may be combined to form a ring.
    R 04 represents a hydrogen atom or a C 1-10 alkyl group.
  10. 　前記式（Ｉ）で表されるアミド化合物又はその塩が、下記式（Ｉ－０１）で表されるアミド化合物又はその塩である、請求項９に記載のヒストン脱アセチル化酵素阻害剤。
    Figure JPOXMLDOC01-appb-C000007
    　式（Ｉ－０１）において、
    　Ｒ１～Ｒ４はそれぞれ独立に、水素原子、置換基を有してもよいＣ１－１０アルキル基、置換基を有してもよいＣ２－６アルケニル基、置換基を有してもよいＣ２－６アルキニル基、置換基を有してもよい炭化水素環基、置換基を有してもよいアリールＣ２－６アルケニル基、又は、置換基を有してもよいヘテロアリールＣ２－６アルケニル基を表し、
    　Ｒ１～Ｒ４の全てが同時に水素原子となることはなく、
    　Ｒ１とＲ２と、又は、Ｒ３とＲ４とが一体となって、置換基を有してもよいアルキリデン基を形成してもよく、
    　Ｒ１～Ｒ４が一体となって、置換基を有してもよい芳香族炭化水素環又は置換基を有してもよい芳香族ヘテロ環を形成してもよく、
    　Ｒ５はそれぞれ独立に、水素原子、Ｃ１－１０アルキル基、又は、フッ素原子を表し、
    　Ｒ５のうち少なくとも１つはフッ素原子であり、
    　２個のＲ５が結合して環を形成してもよく、
    　Ｒ６は、水素原子又はＣ１－１０アルキル基を表し、
    　Ｌ１は、０～２の整数を表す。     The histone deacetylase inhibitor according to claim 9, wherein the amide compound represented by the formula (I) or a salt thereof is an amide compound represented by the following formula (I-01) or a salt thereof.
    Figure JPOXMLDOC01-appb-C000007
    In formula (I-01)
    R 1 to R 4 may independently have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 2-6 alkenyl group which may have a substituent, and a substituent. A good C 2-6 alkynyl group, a hydrocarbon ring group which may have a substituent, an aryl C which may have a substituent 2-6 alkenyl group, or a heteroaryl C which may have a substituent. Represents a 2-6 alkenyl group
    All R 1 ~ R 4 are not hydrogen atoms at the same time,
    R 1 and R 2 or R 3 and R 4 may be integrated to form an alkylidene group which may have a substituent.
    R 1 to R 4 may be integrated to form an aromatic hydrocarbon ring which may have a substituent or an aromatic hetero ring which may have a substituent.
    R 5 independently represents a hydrogen atom, a C 1-10 alkyl group, or a fluorine atom.
    At least one of R 5 is a fluorine atom,
    Two R 5 may be combined with each other to form a ring,
    R 6 represents a hydrogen atom or a C 1-10 alkyl group.
    L1 represents an integer of 0 to 2.
PCT/JP2021/013923 2020-03-31 2021-03-31 Amide compound or salt thereof, pharmaceutical composition and histone deacetylase inhibitor WO2021201126A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-064616 2020-03-31
JP2020064616 2020-03-31

Publications (1)

Publication Number Publication Date
WO2021201126A1 true WO2021201126A1 (en) 2021-10-07

Family

ID=77929117

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/013923 WO2021201126A1 (en) 2020-03-31 2021-03-31 Amide compound or salt thereof, pharmaceutical composition and histone deacetylase inhibitor

Country Status (1)

Country Link
WO (1) WO2021201126A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114656363A (en) * 2022-03-28 2022-06-24 南京林业大学 Synthetic method of palladium-catalyzed aromatic ester compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010038465A1 (en) * 2008-10-02 2010-04-08 旭化成ファーマ株式会社 8-substituted isoquinoline derivative and use thereof
WO2012174199A1 (en) * 2011-06-16 2012-12-20 Merck Sharp & Dohme Corp. Imidazopyridin-2-one derivatives
JP2015500845A (en) * 2011-12-21 2015-01-08 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． Pyrrole-6-membered heteroaryl ring derivative, synthesis method thereof and pharmaceutical use thereof
WO2017095758A1 (en) * 2015-12-01 2017-06-08 Merck Sharp & Dohme Corp. Homobispiperidinyl derivatives as liver x receptor beta agonists, compositions, and their use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010038465A1 (en) * 2008-10-02 2010-04-08 旭化成ファーマ株式会社 8-substituted isoquinoline derivative and use thereof
WO2012174199A1 (en) * 2011-06-16 2012-12-20 Merck Sharp & Dohme Corp. Imidazopyridin-2-one derivatives
JP2015500845A (en) * 2011-12-21 2015-01-08 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． Pyrrole-6-membered heteroaryl ring derivative, synthesis method thereof and pharmaceutical use thereof
WO2017095758A1 (en) * 2015-12-01 2017-06-08 Merck Sharp & Dohme Corp. Homobispiperidinyl derivatives as liver x receptor beta agonists, compositions, and their use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114656363A (en) * 2022-03-28 2022-06-24 南京林业大学 Synthetic method of palladium-catalyzed aromatic ester compound

Similar Documents

Publication Publication Date Title
CN111278815B (en) Glutarimide
ES2528730T3 (en) 2-aminobenzoimidazol-5-carboxamides as anti-inflammatory agents
DK2887943T3 (en) HIS UNKNOWN 4,6-DISUBSTITUTED AMINOPYRIMIDINE DERIVATIVES
ES2679521T3 (en) FGFR4 pyrimidine inhibitors
RU2560153C2 (en) Jak-inhibiting triazolopyridine compounds and methods
TWI820276B (en) Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
JP5820882B2 (en) Quinolines and quinoxaline derivatives as kinase inhibitors
ES2575215T3 (en) Imidazolidinedione derivatives
KR102525375B1 (en) Selective HDAC6 inhibitor
BR112014021189B1 (en) COMPOUND, ITS USE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
KR20080087070A (en) Pyrimidine or triazine fused bicyclic metalloprotease inhibitors
KR20050074571A (en) Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist
KR20170095964A (en) Piperidine derivatives as hdac1/2 inhibitors
US9000183B2 (en) Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors
BR112021012186A2 (en) SUBSTITUTED 3-((3-AMINOPHENYL)AMINO)PIPERIDINE-2,6-DIONE COMPOUNDS, COMPOSITIONS THEREOF AND TREATMENT METHODS THEREOF
ES2566373T3 (en) Monofluoro beta-secretase inhibitors
WO2021201126A1 (en) Amide compound or salt thereof, pharmaceutical composition and histone deacetylase inhibitor
US11858919B2 (en) HDAC1,2 inhibitors
WO2021201120A1 (en) Agent for treating inflammatory bowel disease, and amide compound or salt thereof
ES2928919T3 (en) Heteroaromatics as vanin inhibitors
EP3568391B1 (en) Benzene disulfonamide for the treatment of cancer
WO2002070467A1 (en) Derivatives of diphenylurea, diphenyloxalic acid diamide and diphenylsulfuric acid diamide and their use as medicaments
EP2671885A1 (en) Imidazo-oxadiazole and Imidazo-thiadiazole derivatives
EP3089974B1 (en) Novel imidazolidine-2,4-dione derivatives
AU2014308182B2 (en) 3-substituted cyclopentylamine derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21779547

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21779547

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP