WO2011142359A1 - Composé spiro et médicament pour activer le récepteur d'adiponectine - Google Patents

Composé spiro et médicament pour activer le récepteur d'adiponectine Download PDF

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WO2011142359A1
WO2011142359A1 PCT/JP2011/060769 JP2011060769W WO2011142359A1 WO 2011142359 A1 WO2011142359 A1 WO 2011142359A1 JP 2011060769 W JP2011060769 W JP 2011060769W WO 2011142359 A1 WO2011142359 A1 WO 2011142359A1
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substituted
unsubstituted
alkyl
alkyl group
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Japanese (ja)
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智 中野
啓治 ▲高▼橋
純子 ▲高▼田
寿公 岩元
慧 永榮
佑司 丸山
友輔 新谷
拓也 岡田
祐介 伊藤
孝 門脇
敏正 山内
真人 岩部
美紀 岩部
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日産化学工業株式会社
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Priority to JP2012514807A priority Critical patent/JPWO2011142359A1/ja
Publication of WO2011142359A1 publication Critical patent/WO2011142359A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a preventive / therapeutic / ameliorating agent for diseases in which an adiponectin receptor activation action is effective, characterized by having affinity for an adiponectin receptor and / or an agonistic action. Furthermore, the present invention relates to a metabolic syndrome containing a drug having an adiponectin receptor agonistic action as an active ingredient, particularly a metabolic syndrome associated with obesity or diabetes, and a prophylactic or therapeutic agent for arteriosclerosis.
  • Adiponectin is a kind of adipocytokine that is a physiologically active substance secreted from adipocytes.
  • adiponectin a physiologically active substance secreted from adipocytes.
  • Various possibilities have been suggested for the role of adiponectin, but the most important role is to prevent tissues from acquiring insulin resistance and to act as a protective factor for diabetes. It has been reported that the resistance index is inversely correlated with the blood adiponectin concentration (see, for example, Non-Patent Document 1).
  • adiponectin may improve obesity through improvement of insulin resistance, and it has been reported that the degree of obesity actually decreases in inverse proportion to the blood adiponectin concentration (for example, Non-patent document 5). Furthermore, adiponectin may be effective in treating metabolic syndrome, which is a complex pathological condition involving them, by improving diabetes and obesity.
  • AdipoR adiponectin receptor
  • AdipoR1 is distributed in systemic tissues, and its stimulation mainly shows AMP kinase activation (gluconeogenesis suppression) action, while AdipoR2 is the main It is reported that the stimulation is mainly exerted on the action of enhancing ⁇ -oxidation of fatty acids through the activation of PPAR ⁇ .
  • AMP kinase is a kinase whose substrate is an enzyme important for glycolipid metabolism such as ACC and HMG-CoA, and regulates various metabolic pathways such as sugar transport, glycolysis, and lipid metabolism.
  • ⁇ -oxidation of activated AMP kinase and activated fatty acid enhances metabolic pathways such as fatty acid degradation and glycolysis, and exerts an insulin resistance improving action by suppressing lipid biosynthesis and the like.
  • adiponectin has been reported to reduce glycogen content by reducing liver glycogen synthase activity.
  • Non-Patent Documents 6 and 7, and 8 Non-Patent Documents 6 and 7, and 8
  • a compound having an affinity for an adiponectin receptor and / or an agonistic action exhibits an adiponectin-like action, whereby a disease in which the adiponectin receptor activating action is effective, such as diabetes, obesity, metabolic It may be effective in the prevention, treatment and improvement of syndrome, arteriosclerosis, coronary artery disease, nonalcoholic steatohepatitis, liver fibrosis or malignant tumors, especially diabetes.
  • Adiponectin as a biomarker of the metabolic syndrome. Nat. Med. 2002, 8 (11), 1288-1295. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Proc. Natl. Acad. Sci. USA. 2002, 99 (25), 16309-16313. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Diabetes.
  • Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Proc. Natl. Acad. Sci. USA. 2004, 101 (8), 2476-2481. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis.
  • E means an oxygen atom or a sulfur atom
  • L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
  • L 2 represents a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
  • X represents a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted
  • R 1 and R 3 are R 1 is a hydrogen atom, OR 11 , NR 11 R 12 , C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or one selected independently from substituent group A 3 ) Substituted with the above substituents), a C 3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6 -10 aryl or 5-10 membered heteroaryl (wherein the C 6-10 aryl and 5-10 membered heteroaryl are unsubstituted or independently of the group consisting of substituent groups A 2 and C 4-6 alkyl groups)
  • the C 3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be un
  • R 3 means a hydrogen atom or a C 1-3 alkyl group Or Or R 1 and R 3 together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) Substituted with one or more substituents independently selected from the group consisting of group A 1 and a C 4-6 alkyl group; R 2 represents a C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A 3 ).
  • a C 3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6-10 aryl or 5-10 membered heteroaryl ( The C 6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent groups A 2 and C 4-6 alkyl groups.
  • the C 3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent groups A 1 and C 4-6 alkyl.
  • R 4 and R 5 each independently represents a hydrogen atom or a C 1-3 alkyl group.
  • Each R 7 independently represents a C 1-3 alkyl group; T represents the formulas (VI-1) to (VI-3)
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond, an oxygen atom, a sulfur atom, S ( ⁇ O), S ( ⁇ O) 2 , C ⁇ O or C ⁇ NOR 12
  • R 8 represents a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted with the substituent groups A 2 and C 4. Substituted with one or more substituents independently selected from the group consisting of -6 alkyl groups).
  • J 2 means an oxygen atom or a sulfur atom
  • G 2 means an oxygen atom
  • R 9 represents a C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A 4 ).
  • a C 6-10 aryl group (the C 6-10 aryl group is one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A 2 and C 4-6 alkyl groups)
  • a C 3-11 cycloalkyl group (wherein the C 3-11 cycloalkyl group is a C 6-10 aryl or 5-10 membered heteroaryl (the C 6-10 aryl and 5-10 membered) Heteroaryl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A 2 and C 4-6 alkyl groups.
  • the C 3-11 cycloalkyl Group is substituted by one or more substituents selected as or independently from Substituent group A 2 unsubstituted.
  • a C 1-3 alkyl group (the C 1-3 alkyl group Is a C 6-10 aryl group or a C 3-11 cycloalkyl group (the C 6-10 aryl group and the C 3-11 cycloalkyl group are unsubstituted or substituted with the substituent groups A 2 and C 4-6.
  • R 10 represents a C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A 4 ).
  • Substituted with one or more independently selected substituents Means either Substituent group A 1 is a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A 3 ).
  • Substituent group A 3 is A C 3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6-10 aryl or 5-10 membered heteroaryl (the C 6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A 2 and C 4-6 alkyl groups The C 3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent group A 2 and the C 4-6 alkyl group.
  • C 6-10 aryl group, 5-10-membered heteroaryl group (the C 6-10 aryl group and 5 to 1 Membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl cycloalkane is substituted by one or more substituents selected as or independently from Substituent group A 2 unsubstituted
  • the C 6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or a group consisting of the substituent group A 2 and the C 4-6 alkyl group.
  • E means an oxygen atom or a sulfur atom
  • L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
  • L 2 represents a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
  • X represents a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted
  • R 1 each independently represents an oxygen atom or a sulfur atom; G 1 means a single bond, an oxygen atom or a sulfur atom, R 1 and R 3 are R 1 is a hydrogen atom, OR 11 , NR 11 R 12 , C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or one selected independently from substituent group A 3 ) Substituted with the above substituents), a C 3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6 -10 aryl or 5- to 10-membered heteroaryl (the C 6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 The C 3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstitute
  • a C 3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6-10 aryl or 5-10 membered heteroaryl ( The C 6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 ).
  • R 4 and R 5 each independently represents a hydrogen atom or a C 1-3 alkyl group.
  • n means an integer of 0 to 4,
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond, an oxygen atom, a sulfur atom, S ( ⁇ O), S ( ⁇ O) 2 , C ⁇ O or C ⁇ NOR 12
  • R 8 represents a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently of the substituent group A 2
  • Substituted with one or more substituents selected from J 2 means an oxygen atom or a sulfur atom
  • G 2 means an oxygen atom, a sulfur atom or NR 11
  • R 9 represents a C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A 4 ).
  • a C 6-10 aryl group (the C 6-10 aryl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 ), C 3 -11 cycloalkyl group (wherein the C 3-11 cycloalkyl group is C 6-10 aryl or 5- to 10-membered heteroaryl (the C 6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted) Substituted with one or more substituents independently selected from group A 2 ) and the C 3-11 cycloalkyl group may be unsubstituted or substituted.
  • R 10 represents a C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A 4 ).
  • C 6-10 aryl group, 5- to 10-membered heteroaryl group (the C 6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or independently selected from substituent group A 2 Substituted with one or more substituents), a C 3-11 cycloalkyl group (wherein the C 3-11 cycloalkyl group is C 6-10 aryl or 5- to 10-membered heteroaryl (the C 6-10 Aryl and 5- to 10-membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A 2 ) and The C 3-11 cycloalkyl group is , Unsubstituted or substituted with one or more substituents independently selected from substituent group A 2 ), or a C 1-3 alkyl group (the C 1-3 alkyl group is C 3 Substituted with an -11 cycloalkyl group (the C 3-11 cycloalkyl group is unsubstituted
  • Substituent group A 1 is a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A 3 ). .) and means a substituent group consisting of substituent group a 3, Substituent group A 3 is A C 3-11 cycloalkyl group, a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6-10 aryl or 5-10 membered heteroaryl (the C 6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 .
  • C 3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 .
  • C 6-10 aryl group, 5-10-membered heteroaryl group (the C 6-10 aryl and 5-10 membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 Heterocycloalkane may be condensed with unsubstituted or substituted with or independently from the substituent group A 2 is substituted by one or more substituents selected.
  • (3) X is a C 3-11 cycloalkylene group or a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C 2 , C 2-3 alkenyl groups, —OR 16 and cyano groups.) The spiro compound according to the above (2), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
  • X is a C 6-10 arylene group or a 5- to 10-membered heteroarylene group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted, halogen atoms, nitro groups, cyano groups, A C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a halogen atom and —OR 16 ).
  • L 1 is a C 1-3 alkylene group, C 2-3 alkenylene group or C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are unsubstituted) Or substituted by a cyclopropyl group.)
  • Z 1 is represented by formulas (II-1) to (II-8)
  • J 1 each independently represents an oxygen atom or a sulfur atom; G 1 means a single bond, an oxygen atom or a sulfur atom, R 1 and R 3 are R 1 is a hydrogen atom, OR 11 , NR 11 R 12 , C 1-5 alkyl group (wherein the C 1-5 alkyl group is unsubstituted or independently selected from Substituent Group A 3 Substituted by the above substituents, provided that when m is 1 and both R 6 are hydrogen atoms, the C 1-5 alkyl group is independently selected from the substituent group A 3 A C 6-9 alkyl group (wherein the C 6-9 alkyl group is unsubstituted or independently selected from Substituent Group A 3 ).
  • a C 3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group are C 6 -10 aryl or 5-10 membered hetero ants (Wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 ) and fused rings
  • the C 3-11 cycloalkyl group and the 4-11 membered heterocycloalkyl group may be unsubstituted or substituted by one or more substituents independently selected from the substituent group A 1
  • R 3 represents a hydrogen atom or a C 1-3 alkyl group, Or R 1 and R 3 together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocyclo
  • a C 6-9 alkyl group (the C 6-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A 3 ).
  • a C 3-11 cycloalkyl group or a 4-11 membered heterocycloalkyl group (the C 3-11 cycloalkyl group and 4-11 membered heterocycloalkyl group are C 6-10 aryl or 5-10 membered heteroaryl (the C 6-10 aryl and 5-10 Heteroaryl may be condensed one or more are replaced by a substituent.)
  • the C 3-11 cycloalkyl groups and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a 1 unsubstituted.
  • R 4 and R 5 each independently represents a hydrogen atom or a C 1-3 alkyl group.
  • L 1 is a C 1-3 alkylene group
  • L 2 is a single bond
  • Z 1 represents the formula (II-1), (II-4) or (II-7)
  • L 1 is a C 1-3 alkylene group
  • L 2 is a single bond
  • Z 1 represents the formula (II-1), (II-4) or (II-7)
  • Z 1 is Formula (II-1), (II-4) or (II-7)
  • R 1 and R 3 are R 1 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl))
  • R 3 represents a hydrogen atom
  • R 1 is a C 1-6 alkyl group
  • the C 1-6 alkyl group is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group
  • the C 6-10 aryl group and a 5- to 10-membered heteroaryl group is 4-11 membered heterocycloalkyl alkanes (the 4-11 membered heterocycloalkyl alkanes are substituted by one or more substituents selected as or independently from substituent group a 2 unsubstituted.
  • the C 6-10 aryl group and the 5- to 10-membered heteroaryl group may be condensed or substituted with one or more substituents independently selected from substituent group A
  • R 3 Means a hydrogen atom
  • R 1 is a 4- to 11-membered nitrogen-containing heterocycloalkyl group
  • the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C 1-3 alkyl group
  • the C 1-3 alkyl group is a phenyl group
  • the phenyl group is Unsubstituted or independently from the group consisting of —C ( ⁇ O) OCH 3 , cyano group, nitro group, —SCH 3 , —OCF 3 , —OCH 3 , chlorine atom, —CF 3 and —CH 3
  • Substituted with one or more selected substituents or substituted with either a cyano group) or substituted with either —C ( ⁇ O) O (C 1-6 alkyl).
  • R 3 represents a hydrogen atom, or R 1 and R 3 together with the nitrogen atom to which they are bonded are 4- to 11-membered nitrogen-containing heterocycloalkyl groups (the 4- to 11-membered nitrogen-containing heterocycloalkyl groups are represented by substituent group A 1 Substituted with one or more independently selected substituents), R 2 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is substituted with a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl)). .) R 4 represents a hydrogen atom, J 1 means an oxygen atom, G 1 means a single bond or an oxygen atom. ) The spiro compound according to any one of (2) to (11) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. (13) Z 1 is Formula (II-1), (II-4) or (II-7)
  • R 1 and R 3 are R 1 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl))
  • R 3 represents a hydrogen atom
  • R 1 is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C ( ⁇ O) OCH 3 , a cyano group, a nitro group, —SCH 3 , —OCF 3 , —OCH 3 , a chlorine atom, —CF 3 and —CH 3 Substituted with one or more selected substituents)), substituted with), and R 3 represents
  • R 2 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is substituted with a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl)).
  • R 4 represents a hydrogen atom
  • J 1 means an oxygen atom
  • G 1 means a single bond or an oxygen atom.
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and a 5- to 10-membered heteroaryl group) Is a 4- to 7-membered oxygenated heterocycloalkane (the 4- to 7-membered oxygenated heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from substituent group A 2) And the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently selected from substituent group A 2
  • the C 1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group.
  • R 3 means a hydrogen atom
  • R 1 represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C ( ⁇ O) O (C 1-6 alkyl)).
  • R 3 represents a hydrogen atom, or R 1 and R 3 together with the nitrogen atom to which they are bonded are an azetidinyl group (the azetidinyl group is independently of the substituent group A 1 Substituted with one or more selected substituents), R 4 represents a hydrogen atom, J 1 is, means an oxygen atom.
  • T is the formula (VI-1) or (VI-2)
  • T is the formula (VI-1) or (VI-2)
  • R 8 and R 10 are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C 1-3 alkyl group (the C 1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group
  • T is the formula (VI-1) or (VI-2)
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond
  • R 8 and R 10 are each independently a phenyl group (the phenyl group represents one or two Or a C 1-3 alkyl group (the C 1-3 alkyl group is substituted with one or more fluorine atoms) or a cyano group).
  • T is the formula (VI-1) or (VI-2)
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond
  • R 8 and R 10 each independently represents a phenyl group (the phenyl group represents one or more fluorine atoms) Substituted by an atom, and the phenyl group is substituted by either a C 1-3 alkyl group (the C 1-3 alkyl group is substituted by one or more fluorine atoms) or a cyano group
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are 5- to 7-membered nitrogen-containing heterocycloalkyl group
  • the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, 5-10 A member heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or one or more Substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups), —C ( ⁇ O) OR 13 , —C ( ⁇ O) substituted with one or more substituents independently selected from the group consisting of R 13 , —OR 13 , —NR 12 R 13 , a halogen atom and a cyano group.
  • R 12 represents a hydrogen atom
  • R 13 represents a C 1-6 alkyl group (the C 1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a C 6-10 aryl group, or 5 to 10 members.
  • a heteroaryl group (the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or Substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —OR 14 ), R 14 represents a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms); R 4 represents a hydrogen atom, J 1 is, means an oxygen atom.
  • the spiro compound according to any one of (2) to (13) or (15) to (18), a tautomer of the compound, or a pharmaceutically acceptable salt thereof .
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group and the isoxazolyl group are 4 to 7-membered).
  • phenyl group, pyridyl group, furyl group and isoxazolyl group may be unsubstituted, halogen atom, cyano group, C 1-3 alkyl group (the C 1-3 1-3 alkyl groups are substituted by one or more fluorine atoms.) And one or more substituents independently selected from the group consisting of —O (C 1-3 alkyl).
  • R 3 is a hydrogen atom, or R 1 is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group).
  • Pyridyl group or furyl group (the phenyl group, pyridyl group and furyl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group and furyl group are unsubstituted. Or one or more independently selected from the group consisting of a halogen atom, a cyano group and a C 1-3 alkyl group (wherein the C 1-3 alkyl group is substituted by one or more fluorine atoms) And the C 1-3 alkyl group is one or more independently selected from the group consisting of a hydroxyl group, a halogen atom, and a cyano group.
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • J 1 is, means an oxygen atom.
  • (21) Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are -C ( ⁇ O) OR 13 , —C ( ⁇ O) R 13 , —OR 13 , —NR 12 R 13 , substituted by one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Means)
  • R 12 represents a hydrogen atom
  • R 13 is a C 1-6 alkyl group (the C 1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group).
  • the group may be unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C 1-3 alkyl).
  • R 4 represents a hydrogen atom
  • J 1 is, means an oxygen atom.
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are phenyl groups , Pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group or quinolyl group (the phenyl group, pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group and quinolyl group are unsubstituted) Or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), independently selected from the group consisting of a halogen atom and a cyano group Substituted with one or more substituents).
  • R 4 represents a hydrogen atom
  • J 1 is, means an oxygen atom.
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are azetidinyl groups (the azetidinyl group is unsubstituted or —C ( ⁇ O) OR 13 , —C ( ⁇ O) Substituted with one or more substituents independently selected from the group consisting of R 13 , —OR 13 , —NR 12 R 13 , a halogen atom and a cyano group.
  • R 12 represents a hydrogen atom
  • R 13 represents a C 1-6 alkyl group, a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted). Or substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —O (C 1-3 alkyl).
  • R 4 represents a hydrogen atom
  • J 1 is, means an oxygen atom.
  • L 1 is a C 1-3 alkylene group
  • L 2 is a single bond
  • E is an oxygen atom
  • m is an integer of 1 or 2
  • R 6 is a hydrogen atom
  • n is 0,
  • T is the formula (VI-1) or (VI-2)
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 is either a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are substituted with a C 4-6 alkyl group)).
  • R 3 represents a hydrogen atom, or R 1 represents a piperidyl group (the piperidyl group is substituted by a C 4-6 alkyl group), R 3 represents a hydrogen atom, or R 1 and R 3 are bonded to each other.
  • R 12 represents a hydrogen atom
  • R 13 represents either a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or substituted by a C 4-6 alkyl group)
  • R 4 represents a hydrogen atom
  • J 1 is, means an oxygen atom.
  • Z 1 is Formula (II-1) or (II-4)
  • R 1 and R 3 are R 1 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl))
  • R 3 represents a hydrogen atom
  • R 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a halogen atom, a cyano group, C 1-3 alkyl groups (the C 1-3 alkyl groups are unsubstituted or substituted by one or more fluorine atoms),
  • R 3 represents a hydrogen atom, or R 1 and R 3 together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group).
  • a 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C 1-3 alkyl group)
  • the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replaced
  • R 13 is a C 1-6 alkyl group (the C 1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group).
  • the group may be unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C 1-3 alkyl).
  • R 4 represents a hydrogen atom
  • J 1 is, means an oxygen atom.
  • (27) T is the formula (VI-1) or (VI-2)
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond
  • R 8 and R 10 are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C 1-3 alkyl group (wherein the C 1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group
  • T is the formula (VI-1) or (VI-2)
  • An adiponectin receptor activator comprising the spiro compound according to any one of (1) to (31) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a preventive or therapeutic agent for metabolic syndrome and arteriosclerosis comprising the adiponectin receptor activator according to (32) above as an active ingredient.
  • the pharmaceutical which contains the spiro compound of any one of said (1) thru
  • n- is normal, “s-” and “sec-” are secondary, “t-” and “tert-” are tertiary, “o-” is ortho, “m-” Means meta, “p-” means para, “rac-” means racemate, “Ph” means phenyl, “Py” means pyridyl, “Me” means methyl, “Et” means ethyl, “Pr” means propyl , “Bu” means butyl, “Boc” means tert-butoxycarbonyl, “Ms” means methanesulfonyl, “Ts” means p-toluenesulfonyl, and “Tf” means trifluoromethanesulfonyl.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • “4 to 11-membered heterocycloalkane” means 1) 4 to 11 atoms constituting the ring, 2) The atoms constituting the ring contain at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, 3) the ring is saturated or partially unsaturated, 4) The ring may contain 1 to 3 carbonyl groups or thiocarbonyl groups, 5) When a sulfur atom is contained in the atoms constituting the ring, the sulfur atom may be a sulfinyl group or a sulfone group. 6) An aromatic heterocyclic ring is meant. Specific examples of this “4 to 11-membered heterocycloalkane” include, for example:
  • the 4-11 membered heterocycloalkyl group means a monovalent substituent obtained by removing one hydrogen atom from the “4-11 membered heterocycloalkane”.
  • “4- to 11-membered oxygen-containing heterocycloalkyl group” refers to the above-mentioned definition of “4- to 11-membered heterocycloalkyl group” in which the hetero atom contained in the atoms constituting the ring is one kind of oxygen atom. Means. Specific examples of the group include, for example,
  • the 4 to 7-membered oxygen-containing heterocycloalkyl group means the above-mentioned definition “4 to 11-membered oxygen-containing heterocycloalkyl group” having 4 to 7 atoms constituting the ring.
  • “4- to 11-membered nitrogen-containing heterocycloalkyl group” is defined as “4- to 11-membered heterocycloalkyl group” in which a hetero atom contained in a ring atom is one kind of nitrogen atom Means.
  • Specific examples of the group include, for example,
  • the 5- to 7-membered nitrogen-containing heterocycloalkyl group means the above-mentioned definition “the 4- to 11-membered nitrogen-containing heterocycloalkyl group” having 5 to 7 atoms constituting the ring.
  • the “4 to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group” means that the hetero atoms contained in the atoms constituting the ring in the above-mentioned definition “4 to 11-membered heterocycloalkyl group” are oxygen atoms and nitrogen atoms. Means two types. Specific examples of the group include, for example,
  • the “4- to 11-membered sulfur-containing nitrogen-containing heterocycloalkyl group” means that the hetero atom contained in the atoms constituting the ring in the above-mentioned definition “the 4- to 11-membered heterocycloalkyl group” is a sulfur atom and a nitrogen atom. Means two types.
  • the “4- to 11-membered sulfur-containing nitrogen-containing heterocycloalkyl group” also includes a monooxide and a dioxide of a sulfur atom. Specific examples of the group include, for example,
  • “5-10 membered heteroaryl” 1) There are 5 to 10 atoms constituting the ring, 2) The atoms constituting the ring contain at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, 3) A monocyclic or bicyclic aromatic heterocycle.
  • this “5- to 10-membered heteroaryl” include, for example, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, benzotriazole, pyrazole, imidazole, benzimidazole, indole, isoindole, and India.
  • C 6-10 aryl means 1) There are 6 to 10 atoms constituting the ring, 2) It means a monocyclic or bicyclic aromatic hydrocarbon ring in which all atoms constituting the ring are carbon atoms. Specific examples of “C 6-10 aryl” include benzene, pentalene, naphthalene, azulene and the like.
  • the “C 6-10 aryl group” means a monovalent substituent obtained by removing one hydrogen atom from the above-defined “C 6-10 aryl”.
  • C 1-3 alkyl group means a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • C 1-6 alkyl group means A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 6 carbon atoms.
  • Specific examples of the group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-
  • C 1-9 alkyl group means A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 9 carbon atoms.
  • C 1-5 alkyl group means A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 5 carbon atoms.
  • C 4-6 alkyl group means A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 4 to 6 carbon atoms.
  • C 6-9 alkyl group means A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 6 to 9 carbon atoms.
  • C 3-6 cycloalkane means 1) 3-6 atoms constituting the ring, 2) An aromatic hydrocarbon ring of “monocyclic system” or “bridged ring system” in which all atoms constituting the ring are carbon atoms.
  • Specific examples of the “C 3-6 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
  • C 3-11 cycloalkane means 1) 3 to 11 atoms constituting the ring, 2) The atoms constituting the ring are all carbon atoms. 3) “Monocyclic system”, “fused ring system”, “bridged ring system” or “spiro ring system” aliphatic hydrocarbon ring. Specific examples of this “C 3-11 cycloalkane” include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, bicyclo [3.1.0] octane, bicyclo [2.2. 1] heptane, spiro [5.5] undecane, etc.
  • C 3-11 cycloalkyl group means a monovalent substituent obtained by removing one hydrogen atom from the above-mentioned definition “C 3-11 cycloalkane”.
  • the “C 3-4 cycloalkyl group” means the above-defined “C 3-11 cycloalkyl group” having 3 to 4 atoms constituting the ring.
  • C 2-3 alkenyl group refers to an ethenyl group, a prop-1-en-1-yl group, a prop-2-en-1-yl group, or a prop-1-en-2-yl group.
  • C 2-6 alkenyl group means 1) 2 to 6 carbon atoms, 2) A monovalent substituent obtained by removing one hydrogen atom from a linear or branched unsaturated hydrocarbon having one or more double bonds.
  • Specific examples of the group include, for example, ethenyl group, prop-1-en-1-yl group, prop-2-en-1-yl group, prop-1-en-2-yl group, butane -1-en-1-yl group, but-2-en-1-yl group, but-3-en-1-yl group, penta-1-en-1-yl group, penta-4-en-1 -Yl group, hexa-1-en-1-yl group, hexa-5-en-1-yl group, 4-methylpent-3-en-1-yl group penta-2,4-dien-1-yl group Etc.
  • C 3-11 cycloalkene means 1) 3 to 11 atoms constituting the ring, 2) The atoms constituting the ring are all carbon atoms, 3) means a “monocyclic”, “fused ring”, “bridged ring” or “spiro ring” aliphatic hydrocarbon ring having one or more double bonds.
  • C 3-11 cycloalkene include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptene, cyclooctene, 1 , 4-cyclooctadiene, 1,2,3,3a, 4,6a-hexahydropentalene, (1R, 4S) -bicyclo [2.2.1] hept-2-ene, spiro [5.5] undec-2- En.
  • the “C 3-11 cycloalkenyl group” means a monovalent substituent obtained by removing one hydrogen atom from the above definition “C 3-11 cycloalkene”.
  • C 2-3 alkynyl group means an ethynyl group, a prop-1-in-1-yl group, or a prop-2-in-1-yl group.
  • the “C 1-3 alkylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the definition “C 1-3 alkyl group”. Specific examples of the group include methylene group, ethylene group, propane-1,3-diyl group, propane-2,2-diyl group and the like.
  • the “C 1-6 alkylene group” means a divalent substituent in which one hydrogen atom at any position is removed from the above-defined “C 1-6 alkyl group”.
  • Specific examples of the group include methylene group, ethylene group, propane-1,3-diyl group, propane-2,2-diyl group, 2,2-dimethyl-propane-1,3-diyl group, Hexane-1,6-diyl group, 3-methylbutane-1,2-diyl group and the like can be mentioned.
  • the “C 3-11 cycloalkylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-defined “C 3-11 cycloalkyl group”.
  • Specific examples of the group include cyclopropane-1,1-diyl group, cyclopropane-1,2-diyl group, cyclopentane-1,3-diyl group, cyclohexane-1,4-diyl group, Cyclohexane-1,1-diyl group, bicyclo [2.2.1] heptane-2,5-diyl group, bicyclo [3.3.0] octane-2,5-diyl group, spiro [5.5] undecane-3,9-diyl Groups and the like.
  • the “C 3-11 cycloalkenylene group” means a divalent substituent obtained by further removing one hydrogen atom at any position from the above-defined “C 3-11 cycloalkenyl group”.
  • the “C 6-10 arylene group” means a divalent substituent in which one hydrogen atom at an arbitrary position is removed from the above-defined “C 6-10 aryl group”.
  • Specific examples of the group include a phenylene group and a naphthalene-2,6-diyl group.
  • the “5- to 10-membered heteroarylene group” means a divalent substituent obtained by further removing one hydrogen atom at any position from the above-defined “5- to 10-membered heteroaryl group”.
  • Specific examples of the group include a pyridine-2,5-diyl group, a pyrimidine-2,4-diyl group, and a pyridazine-3,6-diyl group.
  • the “C 2-3 alkenylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the definition “C 2-3 alkenyl group”.
  • the “C 2-3 alkynylene group” means a divalent substituent obtained by removing one hydrogen atom at any position from the above-defined “C 2-3 alkynyl group”.
  • E is preferably an oxygen atom.
  • L 1 is preferably a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are It is unsubstituted or substituted by a cyclopropyl group.), More preferably a C 1-3 alkylene group, and still more preferably a methylene group.
  • L 2 is preferably a single bond or a C 1-3 alkylene group, more preferably a single bond or a methylene group, and still more preferably a single bond.
  • Preferable examples of X include a C 3-11 cycloalkylene group, more preferably a cyclohexanediyl group, and still more preferably a cyclohexane-1,4-diyl group.
  • Other preferable examples of X include a C 6-10 arylene group (the C 6-10 arylene group is unsubstituted or substituted with a methoxy group) or a 5- to 10-membered heteroarylene group. More preferably, it is a phenylene group, a thiophenediyl group or a pyridinediyl group, and more preferably a phenylene group.
  • R 4 is preferably a hydrogen atom.
  • R 6 is preferably each independently a hydrogen atom or a C 1-3 alkyl group, more preferably a hydrogen atom or a methyl group, and still more preferably a hydrogen atom.
  • R 7 is preferably each independently a methyl group.
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond
  • R 8 represents a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or C 1 independently selected from the group consisting of a 1-6 alkyl group, a fluorine atom, a C 1-3 alkyl group (the C 1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group.
  • R 10 is a phenyl group, a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C 1-6 alkyl group, a fluorine atom, a C atom).
  • 1-3 alkyl group (the C 1-3 alkyl group is substituted with one or more fluorine atoms) and one or more substituents independently selected from the group consisting of cyano groups .) or C 6-10 It means a C 3-11 cycloalkyl group which is fused with the reel.) Is either.
  • Z 1 examples include those of formula (III-1), (III-2) or (III-3)
  • R 1 and R 3 are R 1 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is a 4- to 11-membered heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl)).
  • R 3 represents a hydrogen atom
  • G 1 represents a single bond or an oxygen atom.
  • R 1 and R 3 are R 1 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl)) .
  • R 3 represents a hydrogen atom
  • G 1 represents a single bond or an oxygen atom.
  • Z 1 examples include compounds of the formula (III-1), (III-2) or (III-3)
  • R 1 and R 3 are R 1 is a 4- to 11-membered heterocycloalkyl group (the 4- to 11-membered heterocycloalkyl group is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group (the phenyl group is unsubstituted) Or independently selected from the group consisting of —C ( ⁇ O) OCH 3 , a cyano group, a nitro group, —SCH 3 , —OCF 3 , —OCH 3 , a chlorine atom, —CF 3 and —CH 3.
  • R 1 and R 3 are R 1 is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C ( ⁇ O) OCH 3 , cyano group, nitro group, —SCH 3 , —OCF 3 , —OCH 3 , chlorine atom, —CF 3 and —CH 3 Substituted with one or more selected substituents)), substituted with), R 3 represents a hydrogen atom, and G 1 represents a single bond or an oxygen atom.
  • More specific examples of the 5- to 7-membered nitrogen-containing heterocycloalkyl group include a piperidyl group, a piperazinyl group, a homopiperidyl group, and a homopiperazinyl group.
  • Z 1 examples include compounds of the formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups
  • the 4- to 11-membered heterocycloalkyl group is a C 1-6 alkyl group
  • phenyl A 5- to 10-membered heteroaryl group (the phenyl group and 5- to 10-membered heteroaryl group are unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted); Or substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.)
  • —C ( ⁇ O) OR 13 —C ( ⁇ O) R 13 , —OR 13 , —NR 12 R 13 , substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.
  • R 12 represents a hydrogen atom
  • R 13 is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or C 1-3 alkyl)
  • substituents independently selected from the group consisting of a group (the C 1-3 alkyl group is substituted by one or more fluorine atoms), a C 1-6 alkyl group, a halogen atom and a cyano group; Substituted by a group).
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are an azetidinyl group, a 5- to 7-membered nitrogen-containing heterocycloalkyl group, or a 4- to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group
  • the azetidinyl A 5- to 7-membered nitrogen-containing heterocycloalkyl group and a 4- to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group include a C 1-6 alkyl group, a phenyl group, and a 5-10-membered heteroaryl group (the phenyl group and A 5-10 membered heteroaryl group is unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms).
  • a -10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C 1-3 alkyl group (the C 1-3 alkyl group Is substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of C 1-6 alkyl groups, halogen atoms and cyano groups. It means either. ) More preferably, the formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group
  • the azetidinyl group and a 5- to 7-membered nitrogen-containing heterocycloalkyl group are A C 1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C 1-3 alkyl group (the C 1-3
  • the alkyl group is unsubstituted or substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups.
  • R 12 is, represents a hydrogen atom
  • R 13 is C 1-3 alkyl group (the C 1-3 alkyl group is either unsubstituted or one or more fluorine atoms
  • One or more selected from the group consisting of an alkyl group wherein the C 1-3 alkyl group is substituted by one or more fluorine atoms
  • a C 1-6 alkyl group a halogen atom and a cyano group
  • It is substituted by a substituent.
  • Z 1 examples include compounds of the formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C 4-6 alkyl group, A halogen atom, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C 1-3 alkyl) Substituted with one or more substituents independently selected from the group consisting of: and the C 1-6 alkyl group is independent of the group consisting of a hydroxyl group, a halogen
  • R 1 and R 3 are R 1 is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group, or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group, and the isoxazolyl group are 4 to 7 members) It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group are unsubstituted or a C 4-6 alkyl group, a halogen atom, a cyano group, C 1- Independently selected from the group consisting of 3 alkyl groups (wherein the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C 1-3 alkyl) which is substituted by one or more substituents.
  • R 3 means a hydrogen atom.
  • Z 1 examples include compounds of the formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 represents a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is substituted by —C ( ⁇ O) O (C 1-6 alkyl)); R 3 represents a hydrogen atom.
  • R 1 and R 3 are R 1 represents a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is substituted by —C ( ⁇ O) O (C 1-6 alkyl)); R 3 represents a hydrogen atom.
  • R 1 and R 3 are R 1 represents a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is substituted by —C ( ⁇ O) O (C 1-6 alkyl)); R 3 represents a hydrogen atom.
  • R 1 and R 3 are R 1 represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C ( ⁇ O) O (C 1-6 alkyl)).
  • R 3 means a hydrogen atom.
  • More specific examples of the 4-11 membered nitrogen-containing heterocycloalkyl group include azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, homopiperidyl group and homopiperazinyl group.
  • E means an oxygen atom
  • L 1 means a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group
  • L 2 represents a single bond or a C 1-3 alkylene group
  • X represents a C 3-11 cycloalkylene group
  • a C 6-10 arylene group (the C 6-10 arylene group is unsubstituted or substituted with a methoxy group) or a 5- to 10-membered heteroarylene group.
  • Means Z 1 is Formula (III-1), (III-2) or (III-3)
  • R 1 and R 3 are R 1 is a C 1-6 alkyl group
  • the C 1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group, a C 6-10 aryl group, a 5- to 10-membered heteroaryl group
  • the C 6- The 10 aryl group and the 5- to 10-membered heteroaryl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted.
  • a C 4-6 alkyl group, a halogen atom, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms).
  • —O (C 1-3 alkyl) is substituted by one or more substituents independently selected from the group consisting of :) or —NHC ( ⁇ O) O (C 1-6 alkyl) It is substituted with one, and the C 1- Alkyl group means a hydroxyl group, with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group may be substituted.
  • R 3 means a hydrogen atom or
  • R 1 is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C ( ⁇ O) OCH 3 , cyano group, nitro group, —SCH 3 , —OCF 3 , —OCH 3 , chlorine atom
  • R 3 represents a hydrogen atom, or R 1 and R 3 together with the nitrogen atom to which they are attached are a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogenated heterocycloalkyl group is a C 1-6 alkyl group).
  • R 12 is Represents a hydrogen atom
  • R 13 represents a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or C 1-3 alkyl group (wherein the C 1-3 alkyl group is substituted by one or more fluorine atoms), a C 1-6 alkyl group, a halogen atom and a cyano group independently selected from the group Substituted with one or more substituents)
  • G 1 means a single bond or an oxygen atom.
  • m means 1
  • R 6 represents a hydrogen atom
  • n means 0,
  • T represents the formula (VI-1) or (VI-2)
  • L 4 represents a C 1-3 alkylene group
  • L 5 represents a single bond
  • R 8 represents a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or C 1 independently selected from the group consisting of a 1-6 alkyl group, a fluorine atom, a C 1-3 alkyl group (the C 1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group.
  • R 10 is a phenyl group, a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C 1-6 alkyl group, a fluorine atom, a C atom).
  • 1-3 alkyl group (the C 1-3 alkyl group is substituted with one or more fluorine atoms) and one or more substituents independently selected from the group consisting of cyano groups .) or C 6-10 Means a C 3-11 cycloalkyl group which is fused with the reel.) Means.
  • Z 1 is represented by the formula (III-1), (III-2) or (III-3)
  • R 1 and R 3 are R 1 is substituted with a C 1-6 alkyl group (the C 1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC ( ⁇ O) O (C 1-6 alkyl)) .
  • R 3 represents a hydrogen atom
  • G 1 represents a single bond or an oxygen atom.
  • Z 1 is represented by the formula (III-1), (III-2) or (III-3)
  • R 1 and R 3 are R 1 is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C 1-3 alkyl group (the C 1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C ( ⁇ O) OCH 3 , cyano group, nitro group, —SCH 3 , —OCF 3 , —OCH 3 , chlorine atom, —CF 3 and —CH 3 Substituted with one or more selected substituents)), substituted with), R 3 represents a hydrogen atom, and G 1 represents a single bond or an oxygen atom.
  • Z 1 is represented by formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 and R 3 together with the nitrogen atom to which they are attached are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group
  • the azetidinyl group and a 5- to 7-membered nitrogen-containing heterocycloalkyl group are A C 1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C 1-3 alkyl group (the C 1-3
  • the alkyl group is unsubstituted or substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups.
  • R 12 is, represents a hydrogen atom
  • R 13 is C 1-3 alkyl group (the C 1-3 alkyl group is either unsubstituted or one or more fluorine atoms
  • One or more selected from the group consisting of an alkyl group wherein the C 1-3 alkyl group is substituted by one or more fluorine atoms
  • a C 1-6 alkyl group a halogen atom and a cyano group
  • It is substituted by a substituent.
  • (21) The spiro compound according to (19), wherein Z 1 is any one of the structures shown below.
  • Z 1 is represented by formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is a C 6-10 aryl group or a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C 4-6 alkyl group, A halogen atom, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C 1-3 alkyl) Substituted with one or more substituents independently selected from the group consisting of: and the C 1-6 alkyl group is independent of the group consisting of a hydroxyl group, a halogen
  • R 3 means a hydrogen atom.
  • Z 1 is represented by the formula (III-1) or (III-2)
  • R 1 and R 3 are R 1 represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C ( ⁇ O) O (C 1-6 alkyl)).
  • R 3 means a hydrogen atom.
  • the spiro compound according to any one of (1) to (13), wherein (26) The spiro compound according to the above (25), wherein the 4-11 membered nitrogen-containing heterocycloalkyl group is an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a homopiperidyl group or a homopiperazinyl group.
  • Z 1 is any one of the structures shown below.
  • the compound represented by the formula (I) of the present invention exists, for example, via the tautomerism and geometric isomerism, both inside and outside the ring, in addition to a mixture thereof, It also exists as a mixture of isomers.
  • an asymmetric center is present, or when an asymmetric center is formed as a result of isomerization, it includes the presence of each optical isomer and a mixture in an arbitrary ratio.
  • diastereomers by respective optical isomerism also exist.
  • the compounds of the present invention also include those containing all these types in any proportion.
  • diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can exist as any crystal form depending on the production conditions, and can exist as any hydrate. Forms and hydrates and mixtures thereof are also included within the scope of the present invention. Moreover, although it may exist as a solvate containing organic solvents, such as acetone, ethanol, and tetrahydrofuran, all of these forms are contained in the scope of the present invention.
  • the compound represented by the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt as needed, or can be liberated from the produced salt.
  • the pharmaceutically acceptable salt of the present invention include salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases and amino acids. It is done.
  • inorganic acids hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.
  • organic acids acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.
  • Other salts are also possible.
  • the prophylactic / therapeutic / ameliorating agent for “disease with an effective adiponectin receptor activation effect” containing the “adiponectin receptor activator” of the present invention as an active ingredient is usually a tablet, capsule, powder, granule, It can be administered as an oral preparation such as a pill or syrup, a rectal administration agent, a transdermal absorption agent or an injection.
  • the agent can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives.
  • additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents can be used for oral preparations.
  • Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or provided as dry syrups prepared with water or other suitable solvent prior to use.
  • the liquid preparation may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository.
  • Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, preservatives, etc. as necessary Can be added.
  • Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used.
  • the dosage is determined depending on the age, condition, etc. of the patient. In general, in the case of adults, injection is about 0.1 to 1000 mg / human / day for oral administration or rectal administration. The dosage is about 0.05 mg to 500 mg / human / day. These numerical values are merely examples, and the dosage is determined according to the symptoms of the patient.
  • a compound having an adiponectin receptor activating action As a scene where the present invention is used, there is a scene where improvement of a disease state can be expected by using a compound having an adiponectin receptor activating action.
  • metabolic syndrome particularly metabolic syndrome with obesity, diabetes, hypertension, etc., and arteriosclerosis
  • cardiovascular diseases such as myocardial infarction and myocardial hypertrophy
  • non-alcoholic fatty Prevention and treatment of liver diseases such as hepatitis and liver fibrosis
  • prevention and treatment of malignant tumors such as gastric cancer, rectal cancer, breast cancer and myeloblastic leukemia
  • other systemic lupus erythematosus due to anti-inflammatory action, renal failure
  • a scene of performing prevention / treatment of acute lung injury is assumed, but is not limited thereto.
  • the compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.
  • the compound of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), etc., and if necessary, it has a high purity by recrystallization or washing with a solvent. Can be obtained.
  • Examples of the base in the description of the general production method of the compound of the present invention include sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium t-butoxide, Alkali metal salts such as sodium t-butoxide, sodium amide, sodium hydride, lithium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, n-butyllithium, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, And amines such as N-methylpiperidine and bis (trimethylsilyl) amine.
  • the solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not hinder the reaction.
  • a sulfoxide solvent represented by dimethyl sulfoxide; an amide solvent represented by N, N-dimethylformamide or N, N-dimethylacetamide; diethyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether Ether solvents represented by: halogen solvents represented by dichloromethane, chloroform or 1,2-dichloroethane; nitrile solvents represented by acetonitrile or propionitrile; aromatic hydrocarbon systems represented by benzene or toluene Solvent; hydrocarbon solvent represented by n-hexane, n-heptane or cyclohexane; ester solvent represented by ethyl acetate or n-but
  • the reaction temperature in the general production method of the compound of the present invention can be selected from ⁇ 78 ° C. within the range of the boiling point of the solvent used for the reaction. It can be carried out under irradiation or the like.
  • a precursor means a compound that can be derived into a target product by performing deprotection, hydrolysis, reduction, oxidation, alkylation, etc., if necessary.
  • the compound represented by the formula (I-1) can be produced, for example, by the following method.
  • Step 1 This step is a so-called Corey-Chaykovsky reaction in which the compound (2) is produced by converting the carbonyl group of the compound (1) into an epoxide by reaction with sulfur ylide.
  • the compound (1) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the reaction in this step is performed by reacting a sulfur ylide generated by reacting a base with a sulfonium ion such as trimethylsulfonium iodide or a sulfoxonium ion such as trimethylsulfoxonium iodide and the compound (1). Can be done.
  • the amount of trimethylsulfonium iodide, trimethylsulfoxonium iodide, etc. used in this step is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1).
  • Examples of the base used in this step include sodium hydroxide, potassium hydroxide, sodium hydride, lithium hexamethyldisilazide and the like, preferably sodium hydroxide.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (1).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol, water, dimethyl sulfoxide, N, N-dimethylformamide, and the like. Methanol, acetonitrile, water.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 120 hours.
  • Step 2 This step is a method for producing an amino alcohol compound (4) by reacting the epoxide moiety of the compound (2) obtained in the step 1 with the amino group of the compound (3).
  • the compound (3) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water, and the like, preferably methanol and water.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 120 hours.
  • Step 3 compound (6) is produced by reacting compound (4) obtained in step 2 above with the carbonylating agent or thiocarbonylating agent represented by compound (5). It is a method to do.
  • the compound (5) used include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole, triphosgene, thiophosgene, and preferably 1,1′-carbonyl.
  • the amount of the compound (5) is usually 1 to 20 equivalents, preferably 1 to 6 equivalents, relative to 1 equivalent of the compound (4).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and the like, and preferably 1,4-dioxane and chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 120 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 72 hours.
  • Step 4 is a method for producing the compound (7) by hydrolyzing the ester group of the compound (6) obtained in the step 3 with a base.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (6).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 5 compound (9) is produced by reacting the carboxyl group of compound (7) obtained in step 4 with the amine moiety of compound (8) to produce an amide bond.
  • the compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (7) or a reactive derivative thereof.
  • Examples of the reactive derivative of the compound (7) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds). ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (7) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7).
  • the amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • Step 6 This step is a method for producing the compound (10) by removing the amino-protecting group of the compound (9) obtained in the step 5.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and is a method described in the literature [for example, Protective Groups In Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.], a method according to it, or a combination of these and ordinary methods Can do.
  • Step 7 is a method for producing compound (I-1) or a precursor thereof by reacting compound (10) obtained in step 6 with compound (11) in the presence of a base.
  • the compound (11) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
  • Examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.
  • the compound represented by the formula (I-2) can be produced, for example, by the following method.
  • V 3 represents a leaving group, and other symbols are the same as defined above.
  • Step 8 In this step, compound (I-2) or a precursor thereof is reacted with the amine moiety of compound (10) obtained in step 6 above and compound (12) or compound (13). It is a method of manufacturing.
  • the compound (12) or compound (13) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the compound represented by the formula (I-3) can be produced, for example, by the following method.
  • V 4a represents a halogen atom or a halogen atom equivalent
  • R 10a represents a C 6-10 aryl group, a 5- to 10-membered heteroaryl group (the C 6-10 aryl group and a 5- to 10-membered heteroaryl group Is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A 2.
  • the other symbols are the same as defined above.
  • Step 9 compound (I-3) or a precursor thereof is produced by reacting compound (10) obtained in step 6 with compound (14) in the presence of a transition metal catalyst.
  • This is the so-called Buchwald-Hartwig reaction.
  • the compound (14) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the reaction in this step is carried out according to a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, 37, 2046-2067, Accounts of Chemical Research ( Acc. Chem. Res.), 1998, Vol. 31, pp. 805-818).
  • transition metal catalyst combination used in this step examples include palladium acetate and tris (dibenzylideneacetone) palladium as the transition metal complex, and 2,2′-bis (diphenylphosphino) as the ligand. ) -1,1'-binaphthalene and the like.
  • base examples include cesium carbonate, potassium phosphate, sodium tert-butoxide and the like. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably toluene, 1,4-dioxane.
  • the reaction temperature is usually 20 ° C. to the reflux temperature of the reaction solvent, preferably 50 to 180 ° C.
  • the reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.
  • compound (I-3) can also be produced without using a transition metal catalyst.
  • examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • the compound represented by the formula (I-4) can be produced, for example, by the following method.
  • V 4b represents a leaving group
  • R 10b represents a C 1-9 alkyl group (the C 1-9 alkyl group is unsubstituted or independently selected from substituent group A 4 ) Substituted with one or more substituents), a C 3-11 cycloalkyl group (wherein the C 3-11 cycloalkyl group is C 6-10 aryl or 5- to 10-membered heteroaryl (the C 6-10 Aryl and 5- to 10-membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A 2 ) and A C 3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A 2 ), or a C 1-3 alkyl group C 1-3 alkyl group is C 3-11 cycloalkyl A group (the C 3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituents
  • Step 10 This step is a method for producing compound (I-4) or a precursor thereof by reacting compound (10) obtained in step 6 with compound (15) in the presence of a base.
  • a base examples include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • V 4b and one hydrogen atom are combined to form carbonyl.
  • Compound (I-4) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
  • the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and the like, preferably sodium triacetoxyborohydride.
  • the amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.
  • the compound represented by the formula (I-1) can also be produced from the compound (6) by the following method.
  • Step 11 This step is a method for producing the compound (16) by removing the amino-protecting group of the compound (6) obtained in the step 3.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • Step 12 This step is a method for producing the compound (17) by reacting the compound (16) obtained in the step 11 with the compound (11) in the presence of a base.
  • the compound (11) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
  • Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • compound (11) used in this step when the carbon atom to which V 2 is bonded is substituted with 1 to 2 hydrogen atoms, V 2 and one hydrogen atom are combined to form carbonyl Compound (17) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
  • the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and the like, preferably sodium triacetoxyborohydride.
  • the amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.
  • Step 13 This step is a method for producing the compound (18) by hydrolyzing the ester group of the compound (17) obtained in the step 12 with a base.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (17).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 14 an amide bond is formed by reacting the carboxyl group of compound (18) obtained in step 13 with the amine moiety of compound (8) to produce compound (I-1) or It is a method for producing these precursors.
  • the compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (18) or a reactive derivative thereof.
  • Examples of the reactive derivative of the compound (18) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds). ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (18) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • the compound represented by the formula (I-2) can also be produced from the compound (16) by the following method.
  • Step 15 This step is a method for producing a compound (19) by reacting the amine moiety of the compound (16) obtained in the step 11 with the compound (12) or the compound (13).
  • the compound (12) or compound (13) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • Step 16 This step is a method for producing the compound (20) by hydrolyzing the ester group of the compound (19) obtained in the step 15 with a base.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (19).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 17 an amide bond is produced by reacting the carboxyl group of the compound (20) obtained in the above step 16 with the amine moiety of the compound (8) to produce the compound (I-2) or It is a method for producing these precursors.
  • the compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (20) or a reactive derivative thereof.
  • Examples of the reactive derivative of the compound (20) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organics). ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (20) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (20).
  • the amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (20).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • the compound represented by the formula (I-3) can also be produced from the compound (16) by the following method.
  • Step 18 This step is a method for producing the compound (21) by reacting the compound (16) obtained in the step 11 with the compound (14) in the presence of a transition metal catalyst, so-called Buchwald- It is a Buchwald-Hartwig reaction.
  • the compound (14) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the reaction in this step is carried out according to a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, 37, 2046-2067, Accounts of Chemical Research ( Acc. Chem. Res.), 1998, Vol. 31, pp. 805-818).
  • transition metal catalyst combination used in this step examples include palladium acetate and tris (dibenzylideneacetone) palladium as the transition metal complex, and 2,2′-bis (diphenylphosphino) as the ligand. ) -1,1'-binaphthalene and the like.
  • base examples include cesium carbonate, potassium phosphate, sodium tert-butoxide and the like. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably toluene, 1,4-dioxane.
  • the reaction temperature is usually 20 ° C to the reflux temperature of the reaction solvent, preferably 50 ° C to 180 ° C.
  • the reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.
  • compound (21) can also be produced without using a transition metal catalyst.
  • examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • Step 19 This step is a method for producing the compound (22) by hydrolyzing the ester group of the compound (21) obtained in the step 18.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (21).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 20 an amide bond is produced by reacting the carboxyl group of compound (22) obtained in step 15 with the amine moiety of compound (8) to produce compound (I-3) or It is a method for producing these precursors.
  • the compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (22) or a reactive derivative thereof.
  • Examples of the reactive derivative of the compound (22) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds). ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (22) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (22).
  • the amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (22).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • the compound represented by the formula (I-4) can also be produced from the compound (16) by the following method.
  • Step 21 This step is a method for producing a compound (23) by reacting the compound (16) obtained in the step 11 with a compound (15) in the presence of a base.
  • a base examples include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • V 4b and one hydrogen atom are combined to form carbonyl.
  • Compound (23) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
  • the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and the like, preferably sodium triacetoxyborohydride.
  • the amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.
  • Step 22 This step is a method for producing the compound (24) by hydrolyzing the ester group of the compound (23) obtained in the step 21.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (23).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 23 an amide bond is formed by reacting the carboxyl group of the compound (24) obtained in the above step 22 with the amine moiety of the compound (8) to produce the compound (I-4) or It is a method for producing these precursors.
  • the compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (24) or a reactive derivative thereof.
  • Examples of the reactive derivative of the compound (24) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds). ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (24) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • the compound represented by the formula (I-5) can be produced, for example, by the following method.
  • Step 24 This step is a step wherein the compound (I-1), compound (I-2), compound (I-3) or compound (I-3) obtained in the step 7, 8, 9, 10, 14, 17, 20, or 23 is used.
  • compound (I-5) is produced by converting a carbonyl group of compound (I-4) into a thiocarbonyl group.
  • the reaction in this step can be carried out by using a Lawesson reagent or diphosphorus pentasulfide.
  • the amount of Lawesson's reagent or diphosphorus pentasulfide used in this step is 1 to 100 equivalents, preferably 1 to 1 with respect to 1 equivalent of any of compounds (I-1) to (I-4). 10 equivalents.
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
  • the reaction temperature is usually 20 to 200 ° C., preferably 50 ° C. to the reflux temperature of the reaction solvent.
  • the reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.
  • the compound represented by the formula (I-6) can be produced, for example, by the following method.
  • V 5 represents a leaving group, and other symbols are the same as defined above.
  • Step 25 an anion is generated at the ⁇ -position of the ester group of the compound (25) in the presence of a base, and this is allowed to act on the carbonyl group of the compound (1), whereby the compound (26) is produced.
  • a base used in this step
  • Examples of the base used in this step include lithium diisopropylamide and lithium hexamethyldisilazide.
  • the amount of the base used in this step is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (25).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
  • the reaction temperature is usually ⁇ 78 to 100 ° C., preferably ⁇ 78 to 30 ° C.
  • the reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.
  • Step 26 This step is a method for producing the compound (27) by hydrolyzing the ester group of the compound (26) obtained in the step 25.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (26).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 27 This step is a method for producing the compound (28) by converting the carboxyl group of the compound (27) obtained in the step 26 into an isocyanate by a rearrangement reaction and cyclizing it as it is in the molecule. is there.
  • the reaction in this step is performed according to a method described in the literature (for example, Comprehensive Organic Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard ⁇ C. Larock, John Wiley & Sands Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), a method according to them, or a combination of these and conventional methods.
  • Step 28 This step is a method for producing a compound (30) by reacting the compound (28) obtained in the step 27 with a compound part (29) in the presence of a base.
  • the compound (29) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • Examples of the base used in this step include sodium hydride, potassium hydride, potassium t-butoxide, cesium fluoride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like. Is sodium hydride, potassium t-butoxide.
  • the amount of the base is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (28).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tert -Butanol and the like, and tetrahydrofuran, N, N-dimethylformamide are preferable.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • the conversion from the compound (30) to the compound represented by the formula (I-6) is performed by the above steps 4 to 7, 8, 9, 10, 11 to 14, 15 to 17, 18 to 20, 21 to 23, And 24 can be carried out by a method combining any of the methods similar to those described above, a method according to this, or a method combining these with conventional methods.
  • the compound represented by the formula (I-7) can be produced, for example, by the following method.
  • Step 29 an anion is generated at the ⁇ -position of the cyano group of the compound (31) in the presence of a base, and this is allowed to act on the carbonyl group of the compound (1), whereby the compound (32) It is a manufacturing method.
  • Compound (1) and compound (31) used in this step can be obtained as commercially available compounds, known compounds, or compounds synthesized from readily available compounds using various organic synthesis methods known to those skilled in the art.
  • Examples of the base used in this step include lithium diisopropylamide and lithium hexamethyldisilazide.
  • the amount of the base used in this step is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (31).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
  • the reaction temperature is usually ⁇ 78 to 100 ° C., preferably ⁇ 78 to 30 ° C.
  • the reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.
  • Step 30 This step is a method for producing a compound (33) by reducing the cyano group of the compound (32) obtained in the step 29 and converting it to an aminomethyl group in the presence of a base.
  • the reaction in this step is performed according to a method described in the literature (for example, Comprehensive Organic Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard ⁇ C. Larock, John Wiley & Sands Incorporated (John Wiley & Sons Inc. (1999) pp. 875-878, etc.), a method based thereon, or a combination of these and conventional methods.
  • Step 31 compound (34) is produced by reacting compound (33) obtained in step 30 with the carbonylating agent or thiocarbonylating agent represented by compound (5). It is a method to do.
  • the compound (5) used include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole, triphosgene, thiophosgene and the like.
  • the amount of the compound (5) is usually 1 to 20 equivalents, preferably 1 to 6 equivalents, relative to 1 equivalent of the compound (33).
  • the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and the like, and preferably 1,4-dioxane and chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 120 ° C.
  • the reaction time is usually 0.1 to 100 hours, preferably 0.1 to 72 hours.
  • Step 32 This step is a method for producing a compound (35) by reacting the compound (34) obtained in the step 31 with a compound part (29) in the presence of a base.
  • the compound (29) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • Examples of the base used in this step include sodium hydride and potassium t-butoxide.
  • Examples of the base used in this step include sodium hydride, potassium hydride, potassium t-butoxide, cesium fluoride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like.
  • the amount of the base is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (34).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tert -Butanol and the like, and tetrahydrofuran, N, N-dimethylformamide are preferable.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
  • the conversion from the compound (35) to the compound represented by the formula (I-7) is performed by the above steps 4 to 7, 8, 9, 10, 11 to 14, 15 to 17, 18 to 20, 21 to 23, And 24 can be carried out by a method combining any of the methods similar to those described above, a method according to this, or a method combining these with conventional methods.
  • the compound represented by the formula (I-8) can be produced, for example, by the following method.
  • P 1 and P 3 is an amino-protecting group
  • P 2 represents a protecting group of carboxyl group
  • V 6 represents a leaving group
  • other symbols are as defined above.
  • Step 33 This step is a method for producing a compound (37) by hydrolyzing the ester group of the compound (36) obtained in the step 3, 28 or 32.
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (36).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 34 a hydrazide bond is generated by reacting the carboxyl group of the compound (37) obtained in Step 33 with the amine moiety of the compound (38) to produce the compound (39).
  • the compound (37) used in this step can be obtained as a compound synthesized using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the hydrazide bond forming reaction in this step is performed using a carboxylic acid represented by compound (37) or a reactive derivative thereof.
  • Examples of the reactive derivative of compound (37) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in literature (for example, comprehensive organic ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (37) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (37).
  • the amount of compound (38) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (37).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • Step 35 compound (40) is obtained by selectively removing the group (P 3 : amino-protecting group) protecting the hydrazide group of compound (39) obtained in Step 34. It is a method of manufacturing.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method based thereon or a combination of these with conventional methods it can.
  • Step 36 This step is a method for producing the compound (42) by reacting the hydrazide moiety of the compound (40) obtained in the step 35 with the compound (41).
  • the compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • Step 37 This step is a method for producing the compound (43) by removing the amino-protecting group of the compound (42) obtained in the step 36.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • the compound represented by the formula (I-8) can also be produced, for example, by the following method.
  • P 1 and P 3 is an amino-protecting group
  • P 2 represents a protecting group of carboxyl group
  • V 6 represents a leaving group
  • other symbols are as defined above.
  • Step 38 This step is a method for producing the compound (44) by removing the amino-protecting group (P 1 ) of the compound (36) obtained in the step 3, 28 or 32.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method based thereon or a combination of these with conventional methods it can.
  • the conversion from the compound (44) to the compound (45) can be carried out by the same method as in the above-mentioned step 12, 15, 18 or 23, a method according to this, or a method combining these with conventional methods.
  • Step 39 This step is a method for producing a compound (46) by hydrolyzing the ester group of the compound (45).
  • the base used in this step include sodium hydroxide and potassium hydroxide.
  • the amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (45).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.
  • Step 40 a hydrazide bond is generated by reacting the carboxyl group of compound (46) obtained in Step 39 with the amine moiety of compound (38) to produce compound (47).
  • the compound (38) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the hydrazide bond forming reaction in this step is performed using a carboxylic acid represented by compound (46) or a reactive derivative thereof.
  • Examples of the reactive derivative of the compound (46) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds). ⁇ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949).
  • the carboxylic acid represented by the compound (46) for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate,
  • a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
  • the reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
  • the reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.
  • Step 41 compound (48) is produced by removing the group (P 3 : protecting group for amino group) protecting the hydrazide group of compound (47) obtained in Step 40.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method based thereon or a combination of these with conventional methods it can.
  • Step 42 This step is a method for producing compound (I-8) or a precursor thereof by reacting the hydrazide moiety of compound (48) obtained in step 41 with compound (41). is there.
  • the compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • the compound represented by the formula (I-9) can be produced, for example, by the following method.
  • Step 43 This step is a method for producing compound (51) by reacting the hydrazide moiety of compound (40) obtained in step 35 with compound (49) or compound (50).
  • the compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
  • Step 44 This step is a method for producing the compound (52) by removing the amino-protecting group of the compound (51) obtained in the step 43.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • the compound represented by the above formula (I-9) can also be produced, for example, by the following method.
  • V 7 represents a leaving group, and other symbols are the same as defined above.
  • Step 45 This step comprises reacting the hydrazide moiety of compound (48) obtained in step 41 with compound (49) or compound (50) to give compound (I-9) or a precursor thereof. It is a method of manufacturing.
  • the compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
  • compounds represented by the formula (I-10), the formula (I-11), the formula (I-12) and the formula (I-13) can be produced, for example, by the following method.
  • V 8 and V 9 represent a leaving group, and other symbols are the same as defined above.
  • Step 46 This step is a method for producing a compound (53) by converting the carboxyl group of the compound (46) obtained in the step 39 into an amino group by a rearrangement reaction.
  • Rearrangement reactions that can be used in this process include rearrangement reactions via acyl azides (so-called Curtius rearrangement and Schmidt rearrangement), rearrangement reactions via primary amides (so-called Hofmann rearrangement) and hydroxams. Examples include a rearrangement reaction via an acid (so-called Lossen rearrangement). These reactions are described in literature (eg Comprehensive Organic Transformations, Second Edition, Richard C. Larock, John Wiley and Sons). Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), a method according to it, or a combination of these and conventional methods.
  • Step 47 This step is a method for producing compound (I-10) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (41). is there.
  • the compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • Step 48 In this step, compound (I-11) or a precursor thereof is reacted with the amine moiety of compound (53) obtained in step 46 and compound (49) or compound (50). It is a method of manufacturing.
  • the compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
  • Step 49 This step is a method for producing compound (I-12) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (54). is there.
  • the compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized by various organic synthesis methods known to those skilled in the art from a readily available compound.
  • Step 50 This step is a method for producing compound (I-13) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (55). is there.
  • the compound (55) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized from various readily available organic synthesis methods known to those skilled in the art.
  • the compound represented by the above formula (I-10) can also be produced, for example, by the following method.
  • Step 51 This step is a method for producing a compound (56) by converting the carboxyl group of the compound (37) obtained in the step 33 to an amino group by a rearrangement reaction.
  • Rearrangement reactions that can be used in this process include rearrangement reactions via acyl azides (so-called Curtius rearrangement and Schmidt rearrangement), rearrangement reactions via primary amides (so-called Hofmann rearrangement) and hydroxams. Examples include a rearrangement reaction via an acid (so-called Lossen rearrangement). These reactions are described in literature (eg Comprehensive Organic Transformations, Second Edition, Richard C. Larock, John Wiley and Sons). Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), a method according to it, or a combination of these and conventional methods.
  • Step 52 This step is a method for producing a compound (57) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (41).
  • the compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
  • Step 53 This step is a method for producing the compound (58) by removing the amino-protecting group of the compound (57) obtained in the step 52.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • the compound represented by the formula (I-11) can also be produced, for example, by the following method.
  • Step 54 This step is a method for producing the compound (59) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (49) or the compound (50).
  • the compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
  • Step 55 This step is a method for producing the compound (60) by removing the amino-protecting group of the compound (59) obtained in the step 54.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • the compound represented by the formula (I-12) can also be produced, for example, by the following method.
  • Step 56 This step is a method for producing the compound (61) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (54).
  • the compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized by various organic synthesis methods known to those skilled in the art from a readily available compound.
  • Step 57 This step is a method for producing the compound (62) by removing the amino-protecting group of the compound (61) obtained in the step 56.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • the compound represented by the formula (I-13) can also be produced, for example, by the following method.
  • Step 58 This step is a method for producing a compound (63) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (55).
  • the compound (55) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized from various readily available organic synthesis methods known to those skilled in the art.
  • Step 59 This step is a method for producing the compound (64) by removing the amino-protecting group of the compound (63) obtained in the step 58.
  • the reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.
  • the present invention will be described in more detail with reference synthesis examples, synthesis examples, test examples, and formulation examples below, but the present invention is not limited to these examples.
  • the NMR (nuclear magnetic resonance) spectrum was measured at room temperature using a 300 MHz (JNM-ECP300; manufactured by JEOL or JNM-ECX300; manufactured by JEOL) type spectrometer.
  • the chemical shift value in this specification uses tetramethylsilane as an internal standard substance when any of deuterated chloroform (CDCl 3 ), deuterated dimethyl sulfoxide (DMSO-d 6 ), and deuterated methanol (CD 3 OD) is used. All ⁇ values are shown in ppm (parts per million).
  • s is a singlet
  • d is a doublet
  • dd is a doublet of doublet
  • dt is a doublet of triplet
  • dq is a doublet of quartet
  • ddd is a doublet of doublet of Doublet
  • t is triplet
  • tt is triplet of triplet
  • q is quartet
  • sep septet
  • quint is quintet
  • m multiplet
  • br is broad
  • J is coupling constant
  • Hz hertz.
  • the LC-MS (liquid chromatograph-mass spectrometry) spectrum was measured using the following conditions and apparatus.
  • Condition 1 Device: Waters micromass ZQ Column: Waters SunFire C18 (3.5 ⁇ m, 4.6 ⁇ 30 mm) Column temperature: 40 ° C Eluent composition: acetonitrile / 0.1 mass% formic acid aqueous solution (volume ratio: 10/90 ⁇ 85/15)
  • Condition 2 Device: Waters micromass ZQ Column: Waters SunFire C18 (3.5 ⁇ m, 2.1 ⁇ 20 mm) Column temperature: 40 ° C Eluent composition: acetonitrile / 0.1 mass% formic acid aqueous solution (volume ratio: 15/85 ⁇ 85/15) When purified by HPLC, the following conditions and equipment were used.
  • a mixing ratio means a volume ratio.
  • Reference Example 1-2 Production of t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Obtained in Reference Example 1-1 1-oxa-6-azaspiro [2.5] octane-6-carboxylate t-butyl (17 g, 80 mmol) and methyl 4-aminomethylbenzoate (purchased from Aldrich) (17 g, 86 mmol) 340 mL), water (30 mL) and 1M aqueous sodium hydroxide solution (86 mL, 86 mol) were added, and the mixture was stirred at room temperature for 3 days, and methanol was evaporated under reduced pressure.
  • Example 5 (1r, 4r) -4-( ⁇ 8- [2- (ethylthio) ethyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N— Preparation of [(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 5) Substantially Examples except that 2-bromoethylethyl sulfide was used instead of 3- (bromomethyl) pyridine hydrobromide The reaction was performed in the same manner as in 4 to obtain the title compound (3.1 mg, yield 7%) as a colorless powder.
  • Example 6 4-[(1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ (Methyl) cyclohexanecarboxamido] piperidine-1-carboxylate t-butyl (Compound No.
  • Example 11 (1r, 4r) -N- (1-methoxybutan-2-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl ⁇ methyl) cyclohexane carboxamide (Compound No. 11) Substantially Example 10 except that 2-amino-1-methoxybutane was used instead of tetrahydrofurfurylamine. The title compound (20 mg, yield 78%) was obtained as a white powder.
  • Example 12 2-[(1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ Preparation of t-butyl methyl) cyclohexanecarbonyl] hydrazinecarboxylate (Compound No. 12) The compound (140 mg, yield 95%) was obtained as a white powder.
  • reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer.
  • the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
  • Example 19 (1r, 4r) -4- ⁇ [8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl ⁇ -N- [1 Preparation of — (cyanomethyl) piperidin-4-yl] cyclohexanecarboxamide (Compound No. 19) The reaction was conducted in substantially the same manner as in Example 18 except that bromoacetonitrile was used instead of methyl chloroformate to give the title compound ( 2.4 mg, 13% yield) was obtained as a white solid.
  • Example 20 (1r, 4r) -4- ⁇ [8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl ⁇ -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 20) Substantially the same as Example 17 except that tetrahydrofurfurylamine was used in place of t-butyl 4-aminopiperidine-1-carboxylate Reaction was performed to obtain the title compound (13 mg, yield 32%) as a white solid.
  • Example 23 N- [1- (cyanomethyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 23) The reaction was conducted in substantially the same manner as in Example 22 except that bromoacetonitrile was used instead of methyl chloroformate to give the title compound (30 mg, yield). 80%) was obtained as a white solid.
  • Example 24 N- (1-acetylpiperidin-4-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl ⁇ methyl) benzamide (Compound No. 24)
  • the reaction was conducted in substantially the same manner as in Example 22 except that acetyl chloride was used in place of methyl chloroformate to give the title compound (31 mg, yield 82 %) As a white solid.
  • Example 25 N- [1- (methylsulfonyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 25) The reaction was conducted in substantially the same manner as in Example 22 except that methanesulfonyl chloride was used in place of methyl chloroformate to give the title compound (30 mg Yield 75%) as a white solid.
  • Example 26 N- [1- (4-Chlorobenzyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 26) The reaction was carried out in substantially the same manner as in Example 22 except that 4-chlorobenzyl bromide was used instead of methyl chloroformate. The title compound (18 mg, 41% yield) was obtained as a white solid.
  • Example 27 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N- ⁇ 1- [ Preparation of 4- (trifluoromethyl) benzyl] piperidin-4-yl ⁇ benzamide (Compound No. 27) Substantially Example 22 except that 4- (trifluoromethyl) benzyl bromide was used instead of methyl chloroformate. The title compound (27 mg, yield 60%) was obtained as a white solid.
  • Example 28 N- [1- (3-Methylbenzyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 28) The reaction was carried out in substantially the same manner as in Example 22 except that ⁇ -bromo-m-xylene was used instead of methyl chloroformate. To give the title compound (22 mg, 51% yield) as a white solid.
  • Example 30 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N- ⁇ 1- [ Preparation of 4- (trifluoromethoxy) benzyl] piperidin-4-yl ⁇ benzamide (Compound No. 30) Substantially the same as in Example 22 except that 4- (trifluoromethoxy) benzyl bromide was used instead of methyl chloroformate. The reaction was performed in the same manner to obtain the title compound (30 mg, yield 66%) as a white solid.
  • Example 32 N- ⁇ 1- [4- (methylthio) benzyl] piperidin-4-yl ⁇ -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-3-yl ⁇ methyl) benzamide (Compound No. 32) Substantially the same as in Example 31 except that 4- (methylthio) benzyl bromide was used instead of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (13 mg, yield 30%) as a yellow solid.
  • Example 33 N- [1- (Naphthalen-2-ylmethyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 33) Substantially the same as Example 31 except that 2- (bromomethyl) naphthalene was used instead of N, N-diethylchloroacetamide. Reaction was performed to obtain the title compound (16 mg, yield 36%) as a yellow solid.
  • Example 34 N- [1- (3-nitrobenzyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 34) The reaction was carried out in substantially the same manner as in Example 31 except that 3-nitrobenzyl bromide was used instead of N, N-diethylchloroacetamide Performed to give the title compound (14 mg, 32% yield) as a yellow solid.
  • Example 35 N- [1- (3-Chlorobenzyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 35) The reaction was carried out in substantially the same manner as in Example 31 except that 3-chlorobenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (13 mg, 30% yield) as a yellow solid.
  • Example 36 N- [1- (3-methoxybenzyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 36) The reaction was carried out in substantially the same manner as in Example 31 except that 3-methoxybenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (14 mg, 33% yield) as a yellow solid.
  • Example 37 N- [1- (3-cyanobenzyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 37) Reaction was substantially the same as Example 31 except that 3-bromomethylbenzonitrile was used instead of N, N-diethylchloroacetamide. To give the title compound (12 mg, 28% yield) as a yellow solid.
  • Example 38 4- (4- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide
  • ethyl 4-bromobutyrate was used in place of N, N-diethylchloroacetamide.
  • the title compound (63 mg, 61% yield) was obtained as a white solid.
  • Example 39 3-( ⁇ 4- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Preparation of benzamido] piperidin-1-yl ⁇ methyl) methyl benzoate (Compound No. 39) Essentially the same as Example 31 except that methyl 3- (bromomethyl) benzoate was used in place of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (73 mg, yield 67%) as a white solid.
  • Example 40 4-( ⁇ 4- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Benzamido] piperidin-1-yl ⁇ methyl) Preparation of Methyl Benzoate (Compound No. 40) Substantially as in Example 31 except that methyl 4- (bromomethyl) benzoate is used in place of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (84 mg, yield 77%) as a yellow solid.
  • Example 43 N- [1- (cyclohexylmethyl) piperidin-4-yl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl ⁇ methyl) benzamide (Compound No. 43)
  • the reaction was conducted in substantially the same manner as in Example 42 except that cyclohexanecarboxaldehyde was used instead of 2-ethylbutyraldehyde to give the title compound ( 2.8 mg, 11% yield) was obtained as a yellow solid.
  • Example 45 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N- [3- ( Preparation of 2-oxopyrrolidin-1-yl) propyl] benzamide (Compound No. 45) Substantially except that 1- (3-aminopropyl) -2-pyrrolidone is used instead of 4- (2-aminoethyl) morpholine was reacted in the same manner as in Example 44 to give the title compound (41 mg, quantitative) as a brown oil.
  • Example 46 N- (1-methoxybutan-2-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl ⁇ methyl) benzamide (Compound No. 46)
  • the reaction was carried out in substantially the same manner as in Example 44, except that 2-amino-1-methoxybutane was used instead of 4- (2-aminoethyl) morpholine. Performed to give the title compound (35 mg, quantitative) as a yellow solid.
  • Example 47 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 47)
  • the reaction was conducted in substantially the same manner as in Example 44 except that tetrahydrofurfurylamine was used in place of 4- (2-aminoethyl) morpholine. (35 mg, quantitative) was obtained as a white solid.
  • Example 48 N-cyclooctyl-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide ( Preparation of Compound No. 48) The reaction was conducted in substantially the same manner as in Example 44 except that cyclooctylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (37 mg, quantitative) as yellow Obtained as a solid.
  • Example 49 (S) -N- (1-hydroxy-4-methylpentan-2-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide (Compound No. 49) Substantially carried out except that L-(+)-leucinol was used instead of 4- (2-aminoethyl) morpholine The reaction was carried out in the same manner as in Example 44 to obtain the title compound (33 mg, yield 94%) as a white solid.
  • Example 50 N- (1-adamantylmethyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ Preparation of methyl) benzamide (Compound No. 50)
  • the reaction was conducted in substantially the same manner as in Example 44 except that 1-adamantanemethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (39 mg , Quantitative) was obtained as a yellow solid.
  • Example 51 t-butyl 5- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide
  • pentylcarbamate Compound No. 51
  • N- (t-butoxycarbonyl) -1,5-diaminopentane was used instead of 4- (2-aminoethyl) morpholine.
  • the title compound (41 mg, quantitative) was obtained as a brown oil.
  • Example 52 t-butyl 6- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide
  • hexyl carbamate Compound No. 52
  • N- (t-butoxycarbonyl) -1,6-diaminohexane was used instead of 4- (2-aminoethyl) morpholine.
  • the title compound (43 mg, quantitative) was obtained as a white solid.
  • Example 53 3- [4- (Thiomorpholine-4-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (compound Preparation of No. 53)
  • the reaction was carried out in substantially the same manner as in Example 44 except that thiomorpholine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (35 mg, quantitative) as a white solid. Obtained.
  • Example 54 3- ⁇ 4- [4- (Pyrrolidin-1-yl) piperidin-1-carbonyl] benzyl ⁇ -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5
  • decan-2-one Compound No. 54
  • 4- (pyrrolidin-1-yl) piperidine was used instead of 4- (2-aminoethyl) morpholine
  • Example 55 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one
  • the reaction was conducted in substantially the same manner as in Example 44 except that 4-benzoylpiperidine hydrochloride and triethylamine were used instead of 4- (2-aminoethyl) morpholine to give the title compound (41 mg , Quantitative) was obtained as a white solid.
  • Example 56 N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 56) The reaction was carried out in substantially the same manner as in Example 44, except that piperonylamine was used instead of 4- (2-aminoethyl) morpholine. To give the title compound (38 mg, quantitative) as a yellow solid.
  • Example 57 N- (2,3-dihydro-1H-inden-1-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 57) Reaction substantially in the same manner as in Example 44 except that 1-aminoindane was used instead of 4- (2-aminoethyl) morpholine To give the title compound (37 mg, quantitative) as a yellow solid.
  • Example 58 N- (Naphthalen-1-ylmethyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇
  • the reaction was conducted in substantially the same manner as in Example 44 except that 1-naphthylmethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound ( 38 mg, quantitative) was obtained as a yellow solid.
  • Example 59 N- (2,3-dihydro-1H-inden-2-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl ⁇ methyl) benzamide (Compound No. 59) Reaction substantially in the same manner as in Example 44 except that 2-aminoindane was used instead of 4- (2-aminoethyl) morpholine To give the title compound (10 mg, 27% yield) as a yellow solid.
  • Example 60 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N-phenethylbenzamide (compound Preparation of No. 60) The reaction was conducted in substantially the same manner as in Example 44 except that phenethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (30 mg, yield 81%) as a white solid Got as.
  • Example 61 N-isopropyl-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide (compound Preparation of No. 61)
  • the reaction was conducted in substantially the same manner as in Example 44 except that isopropylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (39 mg, yield 88%) as white Obtained as a solid.
  • Example 62 N-cyclohexyl-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide (compound Preparation of No. 62) The reaction was carried out in substantially the same manner as in Example 44 except that cyclohexylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (47 mg, quantitative) as a white solid. Obtained.
  • Example 63 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N- [1- ( Preparation of Pyridin-4-yl) piperidin-4-yl] benzamide (Compound No. 63) Essentially except that 4- (4-aminopiperidino) pyridine was used in place of 4- (2-aminoethyl) morpholine The reaction was conducted in the same manner as for 44 to give the title compound (51 mg, yield 79%) as a white solid.
  • Example 65 N- [3- (dimethylamino) propyl] -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il ⁇ methyl)
  • benzamidoformate Compound No. 65
  • N, N-dimethylpropanediamine purchased from Tokyo Chemical Industry Co., Ltd.
  • 4- (2-aminoethyl) morpholine The reaction was carried out as in Example 44 to give the title compound (43 mg, 79% yield) as a pale yellow oil.
  • Example 66 3- [4- (morpholine-4-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-oneformate ( Preparation of Compound No. 66)
  • the reaction was conducted in substantially the same manner as in Example 44 except that morpholine (purchased from Junsei Kagaku) was used instead of 4- (2-aminoethyl) morpholine to give the title compound ( 38 mg, yield 76%) was obtained as a pale yellow oil.
  • Example 68 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) -N- (pyridine-3 -Preparation of ylmethyl) benzamide (Compound No. 68) Except for using 4-picolylamine (purchased from Tokyo Chemical Industry Co., Ltd.) instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to obtain the title compound (17 mg, yield 70%) as a white solid.
  • 4-picolylamine purchased from Tokyo Chemical Industry Co., Ltd.
  • Example 69 4-([4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamido] methyl )
  • methyl benzoate Compound No. 69
  • the reaction was carried out substantially in the same manner as in Example 64 except that was used to obtain the title compound (140 mg, quantitative) as a white solid.
  • Example 70 t-butyl 2- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide
  • ethyl carbamate Compound No. 70
  • 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, t-butyl 2-aminoethylcarbamate (purchased from Tokyo Chemical Industry Co., Ltd.) The reaction was carried out substantially in the same manner as in Example 64 except for using, and the title compound (11 mg, yield 43%) was obtained as a white solid.
  • Example 72 N-butyl-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide (compound Preparation of No. 72) Substantially the same as Example 64 except that butylamine (purchased from Wako Pure Chemical Industries, Ltd.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The title compound (17 mg, 76% yield) was obtained as a white solid.
  • Example 73 N- (2-methoxyethyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇
  • 2-methoxyethylamine purchased from Wako Pure Chemical Industries, Ltd.
  • 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to obtain the title compound (15 mg, yield 64%) as a white solid.
  • the reaction was carried out in substantially the same manner as in Example 64 except that piperidine (purchased from Junsei Kagaku) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride.
  • the title compound (12 mg, 52% yield) was obtained as a white solid.
  • Example 75 (1r, 4r) -4- ⁇ [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ Methyl) benzamido] methyl ⁇ methyl cyclohexanecarboxylate (Compound No. 75) Trans-4 obtained in Reference Example 2-1 instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride Reaction was carried out in substantially the same manner as in Example 64 except that methyl aminomethylcyclohexanecarboxylate hydrochloride was used to obtain the title compound as a white solid (20 mg, yield 75%).
  • Example 76 1- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzoyl] piperidine- Preparation of methyl 4-carboxylate (Compound No. 76) Instead of using 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, methyl isonipecotate (purchased from Tokyo Chemical Industry Co., Ltd.) was used. The reaction was carried out substantially in the same manner as in Example 64 to give the title compound (20 mg, yield 75%) as a colorless oil.
  • Example 77 2- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamido] acetic acid ethyl
  • (Compound No. 77) Substantially except that glycine ethyl ester hydrochloride (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out in the same manner as in Example 64 to obtain the title compound as a white solid (20 mg, yield 75%).
  • Example 78 (1r, 4r) -N- (2-Isopropoxyethyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Decan-3-yl ⁇ methyl) cyclohexanecarboxamide (Compound No. 78)
  • the reaction was carried out in substantially the same manner as in Example 10 except that 2-aminoethylisopropyl ether was used instead of tetrahydrofurfurylamine.
  • the compound 32 mg, 88% yield) was obtained as a white solid.
  • Example 79 (1r, 4r) -N- (furan-2-ylmethyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl ⁇ methyl) cyclohexanecarboxamide (Compound No. 79)
  • the reaction was conducted in substantially the same manner as in Example 10 except that furfurylamine was used instead of tetrahydrofurfurylamine to give the title compound (35 mg, (96% yield) was obtained as a white solid.
  • Example 80 (1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl)- Preparation of N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarboxamide (Compound No. 80) Substantially Example 10 except that 4-amino-tetrahydro-2H-pyran hydrochloride was used instead of tetrahydrofurfurylamine The title compound (31 mg, yield 84%) was obtained as a pale yellow solid.
  • Example 81 (1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl)- Preparation of N-[(tetrahydro-2H-pyran-4-yl) methyl] cyclohexanecarboxamide (Compound No. 81) Substantially Example 10 except that 4- (aminomethyl) tetrahydropyran was used in place of tetrahydrofurfurylamine. The title compound (31 mg, 84% yield) was obtained as a pale yellow solid.
  • the reaction mixture was cooled to room temperature, ethyl acetate (5.0 mL) and water (5.0 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • N- (t-butoxycarbonyl) -1,3-diaminopropane (purchased from Tokyo Chemical Industry Co., Ltd.) (33 mg, 0.19 mmol) was added as it was, and the mixture was stirred at 80 ° C. for 4 hours.
  • the reaction mixture was cooled to room temperature, ethyl acetate (3.0) mL and water (3.0) mL were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3.0) mL.
  • the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Example 84 1- (1-Benzylpiperidin-4-yl) -3- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl ⁇ methyl) phenyl] urea (Compound No. 84) N- (t-butoxycarbonyl) -1,3-diaminopropane instead of 4-amino-1-benzylpiperidine (Tokyo Chemical Industry ( The title compound (7.0 mg, yield 11%) was obtained as a white solid in substantially the same manner as in Example 83, except that the product purchased from KK was used.
  • Example 85 1-Benzylpiperidin-4-yl 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl )
  • phenyl carbamate Compound No. 85
  • 4-hydroxy-1-benzylpiperidine purchased from Tokyo Chemical Industry Co., Ltd.
  • N- (t-butoxycarbonyl) -1,3-diaminopropane was reacted in substantially the same manner as in Example 83 to give the title compound (4.9 mg, yield 8%) as a colorless oil.
  • Example 86 3- (t-Butoxycarbonylamino) propyl 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ Methyl) Phenylcarbamate (Compound No. 86) Preparation of t-butyl N- (3-hydroxypropyl) carbamate instead of N- (t-butoxycarbonyl) -1,3-diaminopropane (Tokyo Chemical Industry Co., Ltd.) The title compound (16 mg, 27% yield) was obtained as a colorless oil substantially in the same manner as in Example 83 except that the above compound was used.
  • Example 87 1-cyclohexyl-3- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Preparation of phenyl] urea (Compound No. 87) Substantially Examples except that cyclohexylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was conducted in the same manner as in 83 to give the title compound (17 mg, yield 34%) as a white solid.
  • Example 88 Cyclohexyl 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) phenylcarbamate (Compound No. 88 )Manufacturing of The title compound was reacted in substantially the same manner as in Example 83 except that cyclohexanol (purchased from Kanto Chemical Co., Inc.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane. (3.0 mg, 6% yield) was obtained as a colorless oil.
  • cyclohexanol purchasedd from Kanto Chemical Co., Inc.
  • Example 89 1- [4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) phenyl] -3 -Preparation of [(tetrahydrofuran-2-yl) methyl] urea (Compound No. 89) Tetrahydrofurfurylamine instead of N- (t-butoxycarbonyl) -1,3-diaminopropane (purchased from Tokyo Chemical Industry Co., Ltd.) The title compound (20 mg, 38% yield) was obtained as a colorless oil by substantially reacting in the same manner as in Example 83 except that was used.
  • Example 90 Tetrahydrofuran-2-yl methyl 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl )
  • phenyl carbamate Compound No. 90
  • tetrahydrofurfuryl alcohol purchased from Tokyo Chemical Industry Co., Ltd.
  • N- (t-butoxycarbonyl) -1,3-diaminopropane was carried out in the same manner as in Example 83 to obtain the title compound (30 mg, yield 96%) as a colorless oil.
  • Example 91 1-[(1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ Preparation of methyl) cyclohexyl] -3-[(tetrahydrofuran-2-yl) methyl] urea (Compound No.
  • Example 100 (1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4- ⁇ [8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl ⁇ cyclohexanecarboxamide (Compound No. 100)
  • the reaction was conducted in substantially the same manner as in Example 98 except that 4-cyanobenzyl bromide was used instead of benzyl bromide to give the title compound (11 mg Yield 51%) as a white solid.
  • Example 101 (1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-( ⁇ 8-[(3,5-dimethylisoxazol-4-yl) methyl] -2-oxo-1-oxa Preparation of —3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) cyclohexanecarboxamide (Compound No. 101) 4- (chloromethyl) -3,5-dimethylisoxazole (Aldrich) instead of benzyl bromide The title compound (18 mg, yield 85%) was obtained as a white solid in substantially the same manner as in Example 98 except that the product (purchased from KK) was used.
  • Example 102 (1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4- ⁇ [8- (3-methoxybenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl ⁇ cyclohexanecarboxamide (Compound No. 102)
  • the reaction was conducted in substantially the same manner as in Example 98 except that 3-methoxybenzyl bromide was used instead of benzyl bromide to give the title compound (13 mg Yield 61%) as a white solid.
  • Example 103 4-[(3- ⁇ [(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl ⁇ -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-8-yl) methyl] Preparation of methylbenzoate (Compound No. 103) The title compound (30 mg, 65% yield) was obtained as a white solid.
  • Example 104 4-[(3- ⁇ [(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl ⁇ -2-oxo-1-oxa-3,8-diazaspiro [4.5] Preparation of decan-8-yl) methyl] benzoic acid (Compound No.
  • Decan-3-yl ⁇ methyl) methyl cyclohexanecarboxylate (110 mg, 0.25 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 5 M aqueous sodium hydroxide solution (0. 60 mL) was added and stirred at room temperature for 9 hours. After cooling to 0 ° C., the pH was adjusted to 4 by adding 5M hydrochloric acid. The precipitated white solid was collected by filtration and dried under reduced pressure at 50 ° C. for 1 hour to obtain the tetrahydrofuran-methanol hydrate (110 mg) of the title compound.
  • Example 106 (1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl)- Production of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No.
  • Triethylamine (2.7 mg, 0.027 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate 100%] to give the title compound (8.4 mg, yield 63%). Was obtained as a colorless oil.
  • Triethylamine (2.7 mg, 0.027 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate 100%], and the title compound (14 mg, yield 82%) was colorless. Obtained as an oil.
  • Ethanol (0.20 mL) was added to the reaction suspension, and the mixture was stirred at room temperature overnight.
  • the reaction mixture was concentrated to dryness under reduced pressure and further azeotroped with methanol three times to give 6-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] nicotine.
  • Ethyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (1.0 mL), 4- (trifluoromethyl) benzyl bromide (62 mg, 0.26 mmol) and triethylamine (52 mg, 0.52 mmol) were added, and then room temperature was added. Stir for 24 hours.
  • the reaction mixture was cooled to 0 ° C., and 5 M hydrochloric acid was added to adjust the pH to 5. After adding water, the white solid was collected by filtration and dried under reduced pressure at 50 ° C. for 1 hour to obtain the title compound (12 mg, 27%).
  • a mixed solvent of chloroform / isopropyl alcohol (5/1) was added to the filtrate, the organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform / isopropyl alcohol (5/1). After adding sodium chloride to the aqueous layer, the mixture was further extracted once with a mixed solvent of chloroform / isopropyl alcohol (5/1). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (24 mg, 52%).
  • the organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography [Polipack SI 60 ⁇ m, developed by Moritex, developing solvent: hexane / ethyl acetate] to obtain the title compound (300 mg, yield 36%).
  • Reference Example 112-3 Reference example for production of methyl 6-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) picolinate 3- ⁇ [6- (Methoxycarbonyl) pyridin-2-yl] methyl ⁇ -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid obtained in 112-2 t-Butyl (93 mg) was dissolved in methanol (0.20 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was cooled to 0 ° C., and 5 M hydrochloric acid was added to adjust the pH to 5.
  • a mixed solvent of water and chloroform / 2-propanol (5/1) the organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform / 2-propanol (5/1).
  • Sodium chloride was added to the aqueous layer, and the mixture was further extracted once with a mixed solvent of chloroform / 2-propanol (5/1).
  • the combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (42 mg, 91%).
  • Decan-3-yl ⁇ methyl) benzoic acid (10 mg, 0.022 mmol), N- (t-butoxycarbonyl) -1,3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (5.1 mg, 0.027 mmol) was added and stirred at room temperature for 3 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.
  • Example 114 N- (1-Benzylpiperidin-4-yl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl ⁇ methyl) benzamide (Compound No. 114) 4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl ⁇ methyl) benzoic acid (10 mg, 0.022 mmol), 4-amino-1-benzylpiperidine (5.1 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.
  • Furyl amine (purchased from Tokyo Chemical Industry (Ltd.)) (0.013 mL, 0.13 mmol) and added triethylamine (0.018 mL, 0.13 mmol) and was stirred at room temperature for 20 hours. After stopping the reaction, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). did. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained solid was washed with hexane, dried at 50 ° C.
  • Example 116 4- [3-methoxy-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Benzamide] Preparation of t-butyl piperidine-1-carboxylate (Compound No. 116) Instead of using tetrahydrofurfurylamine, t-butyl 4-aminopiperidine-1-carboxylate (purchased from Aldrich Corporation) The reaction was carried out substantially as in Example 115 to give the title compound as a white solid (100 mg, 84% yield).
  • a saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). .
  • the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure.
  • the obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate], and N- [1- (cyanomethyl) piperidin-4-yl] -3-methoxy-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzamide ( 18 mg, 60% yield) was obtained as a white solid.
  • Example 118 4- [3-methoxy-4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 118) In substantially the same manner as in Example 117, except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. To give the title compound as a white solid (20 mg, 64% yield).
  • the resulting aqueous layer was adjusted to pH 4 by adding 1 M hydrochloric acid, extracted three times with ethyl acetate (20 mL), and the combined organic layer was washed with saturated brine (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 2- [1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid as a yellow oil (790 mg). ). The crude product was used in the next reaction without purification.
  • Reference Example 119-5 Preparation of t-butyl 3- [4- (methoxycarbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate
  • Reference Example 119-3 4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (200 mg, 0.74 mmol) obtained in 1 above was added to N, N-dimethylformamide ( 4.0 ml), sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (39 mg, 0.89 mmol) was added and stirred for 30 minutes, and then obtained in Reference Example 119-4.
  • Reference Example 119-6 Preparation of 4-[(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 119-5 3- [4- (Methoxycarbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (280 mg, 0.67 mmol) To the solution was added 4M hydrogen chloride-dioxane solution (3 mL), and the mixture was stirred at room temperature for 3 hours.
  • Reference Example 119-7 4-( ⁇ 4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) methyl benzoate 4 obtained in reference example 119-6 of - [(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride To (200 mg, 0.56 mmol) was added N, N-dimethylformamide (2.0 mL).
  • Reference Example 119-8 4-( ⁇ 4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) benzoic acid 4-( ⁇ 4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 119-7 -3-yl ⁇ methyl) methyl benzoate (240 mg, 0.49 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3.0 mL) and methanol (2.0 mL), and then a 1 M aqueous sodium hydroxide solution (3 0.0 mL) was added and stirred at room temperature.
  • Example 120 4- [4-( ⁇ 4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Benzamide] Production of t-butyl piperidine-1-carboxylate (Compound No. 120) The reaction was carried out substantially as in Example 119 to give the title compound as a white solid (150 mg, 89% yield).
  • Example 122 4- [4-( ⁇ 4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) Benzamide] Production of methyl piperidine-1-carboxylate (Compound No. 122) In substantially the same manner as in Example 121 except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. To give the title compound as a white powder (46 mg, 87% yield).
  • Example 125 t-butyl 3-[(1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il ⁇ methyl) cyclohexanecarboxamido] propyl carbamate (Compound No. 125) Substantially except that N- (t-butoxycarbonyl) -1,3-diaminopropane is used instead of 4-amino-1-benzylpiperidine was reacted in the same manner as in Example 124 to obtain the title compound (0.23 g, yield 84%) as a white solid.
  • Example 128 (1r, 4r) -N- (3-aminopropyl) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl ⁇ methyl) cyclohexanecarboxamide hydrochloride (Compound No.
  • Benzoyl (0.024 mL, 0.16 mmol) was added and stirred at room temperature for 20 minutes. After adding water (1 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure to give (1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl). ) Benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) methyl cyclohexanecarboxylate (71 mg, quantitative yield) was obtained as a white solid.
  • Reference Example 133-2 Production of t-butyl 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 1) Obtained in Reference Example 133-1 4-aminocyclohexanecarboxylic acid methyl hydrochloride (0.25 g, 1.3 mmol), 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid t obtained in Reference Example 1-1 -Butyl (0.25 g, 1.2 mmol) was suspended in water (2.5 mL), methanol (4.0 mL) and 1 M aqueous sodium hydroxide solution (1.2 mL, 1.2 mmol) were added, and 3 days at room temperature.
  • Reference Example 133-4 Preparation of 4- ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ cyclohexanecarboxylic acid
  • Reference Example 133-3 4- ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ cyclohexanecarboxylate ( 60 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3.0 mL), water (0.50 mL) and 1M aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 10 minutes.
  • Example 134 t-butyl 3- (4- ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ cyclohexanecarboxamido) propyl Preparation of carbamate (Compound No. 134)
  • the reaction was carried out in substantially the same manner as in Example 133, except that N- (t-butoxycarbonyl) -1,3-diaminopropane was used instead of 4-amino-1-benzylpiperidine. Performed to give the title compound (22 mg, 92% yield) as a white solid.
  • Example 135 4- [6-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) nicotinamide] piperidine Preparation of methyl-1-carboxylate (Compound No. 135) Substantially in Examples, except that methyl 4-aminopiperidine-1-carboxylate hydrochloride obtained in Reference Example 135 and triethylamine were used instead of tetrahydrofurfurylamine. The reaction was carried out in the same manner as 111 to give the title compound (14 mg, quantitative) as an amorphous solid.
  • Example 136 4-[(1r, 4r) -4-( ⁇ 2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ Methyl) cyclohexanecarboxamide] Production of methyl piperidine-1-carboxylate (Compound No. 136) Except for using 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine obtained in Reference Example 135 instead of cyclohexylamine The reaction was carried out substantially in the same manner as in Example 107 to obtain the title compound (11 mg, yield 83%) as a colorless solid.
  • Example 137 3- ⁇ [5- (4-Benzoylpiperidin-1-carbonyl) pyridin-2-yl] methyl ⁇ -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Production of decan-2-one (Compound No. 137) The reaction was conducted in substantially the same manner as in Example 111 except that 4-benzoylpiperidine hydrochloride and triethylamine were used instead of tetrahydrofurfurylamine to give the title compound ( 14 mg, 80% yield) was obtained as a white solid.
  • Example 138 1- [6-( ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ methyl) pyridine-3- Yl] -3-[(tetrahydrofuran-2-yl) methyl] urea (Compound No.
  • Example 140 4- (1- ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ ethyl) -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 140)
  • the reaction was conducted in substantially the same manner as in Example 139, except that 4-benzoylpiperidine hydrochloride and tetrahydrofurfurylamine were used in place of triethylamine.
  • the compound (6.8 mg, yield 73%) was obtained as a colorless oil.
  • Example 141 4- [4- (1- ⁇ 2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl ⁇ ethyl) benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 141) Substantially except that 4-aminopiperidine-1-carboxylate methyl hydrochloride obtained in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 139 to obtain the title compound (8.6 mg, yield 82%) as a colorless solid.
  • reaction mixture was concentrated under reduced pressure, diluted with chloroform and water, the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a mixture (2.5 g) containing mainly the title compound as a yellow oil.

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Abstract

La présente invention concerne un nouveau médicament qui présente une affinité pour récepteur d'adiponectine et des effets agonistes, et qui est utile dans la prévention ou le traitement du syndrome métabolique, en particulier le syndrome métabolique accompagné par l'obésité et le diabète, et l'artériosclérose entre autres. L'invention concerne également un nouveau composé spiro représenté par la formule (I) dans laquelle Z1, X, L1, L2, E, R6, R7, m, n, et T sont tels que définis dans la description, les tautomères du composé, ou des sels pharmaceutiquement acceptables de celui-ci.
PCT/JP2011/060769 2010-05-10 2011-05-10 Composé spiro et médicament pour activer le récepteur d'adiponectine WO2011142359A1 (fr)

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US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US9845301B2 (en) 2015-07-31 2017-12-19 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
CN107663151A (zh) * 2016-07-28 2018-02-06 江苏豪森药业集团有限公司 甲磺酸氟马替尼的中间体合成方法
US10329308B2 (en) 2017-01-20 2019-06-25 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors
US20190270744A1 (en) * 2018-03-01 2019-09-05 Reaction Biology Corp. Histone Deacetylase Inhibitors and Methods of Use Thereof
CN110357797A (zh) * 2018-04-11 2019-10-22 江西天宇化工有限公司 一种2-(2-氯-3-氯甲基-4-甲磺酰基苯甲酰基)-1,3-环己二酮的制备方法
US10858373B2 (en) 2017-01-23 2020-12-08 Pfizer Inc. Heterocyclic spiro compounds as MAGL inhibitors
CN112305100A (zh) * 2020-10-16 2021-02-02 中国辐射防护研究院 一种药物中基因毒性杂质溴化苄含量的检测方法
WO2021113368A1 (fr) * 2019-12-03 2021-06-10 Kallyope, Inc. Antagonistes de sstr5
WO2022130352A1 (fr) * 2020-12-19 2022-06-23 Cadila Healthcare Limited Nouveaux composés appropriés pour le traitement de la dyslipidémie

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US8710043B2 (en) 2011-06-24 2014-04-29 Amgen Inc. TRPM8 antagonists and their use in treatments
US8778941B2 (en) 2011-06-24 2014-07-15 Amgen Inc. TRPM8 antagonists and their use in treatments
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US10428034B2 (en) 2015-07-31 2019-10-01 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
US9845301B2 (en) 2015-07-31 2017-12-19 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
US10723711B2 (en) 2015-07-31 2020-07-28 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
CN107663151A (zh) * 2016-07-28 2018-02-06 江苏豪森药业集团有限公司 甲磺酸氟马替尼的中间体合成方法
CN107663151B (zh) * 2016-07-28 2021-11-26 江苏豪森药业集团有限公司 甲磺酸氟马替尼的中间体合成方法
US10329308B2 (en) 2017-01-20 2019-06-25 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors
US10626125B2 (en) 2017-01-20 2020-04-21 Pfizer Inc. 1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors
US10858373B2 (en) 2017-01-23 2020-12-08 Pfizer Inc. Heterocyclic spiro compounds as MAGL inhibitors
US20190270744A1 (en) * 2018-03-01 2019-09-05 Reaction Biology Corp. Histone Deacetylase Inhibitors and Methods of Use Thereof
WO2019169257A1 (fr) * 2018-03-01 2019-09-06 Reaction Biology Corp. Inhibiteurs de l'histone désacétylase et leurs méthodes d'utilisation
US11155550B2 (en) 2018-03-01 2021-10-26 Reaction Biology Corporation Histone deacetylase inhibitors and methods of use thereof
CN110357797A (zh) * 2018-04-11 2019-10-22 江西天宇化工有限公司 一种2-(2-氯-3-氯甲基-4-甲磺酰基苯甲酰基)-1,3-环己二酮的制备方法
WO2021113368A1 (fr) * 2019-12-03 2021-06-10 Kallyope, Inc. Antagonistes de sstr5
EP4069702A4 (fr) * 2019-12-03 2023-12-27 Kallyope, Inc. Antagonistes de sstr5
CN112305100A (zh) * 2020-10-16 2021-02-02 中国辐射防护研究院 一种药物中基因毒性杂质溴化苄含量的检测方法
WO2022130352A1 (fr) * 2020-12-19 2022-06-23 Cadila Healthcare Limited Nouveaux composés appropriés pour le traitement de la dyslipidémie

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