WO2012173174A1 - Azaspiroalkane compound - Google Patents

Azaspiroalkane compound Download PDF

Info

Publication number
WO2012173174A1
WO2012173174A1 PCT/JP2012/065201 JP2012065201W WO2012173174A1 WO 2012173174 A1 WO2012173174 A1 WO 2012173174A1 JP 2012065201 W JP2012065201 W JP 2012065201W WO 2012173174 A1 WO2012173174 A1 WO 2012173174A1
Authority
WO
WIPO (PCT)
Prior art keywords
azaspiro
nonane
propyl
carboxylate
phenoxy
Prior art date
Application number
PCT/JP2012/065201
Other languages
French (fr)
Japanese (ja)
Inventor
円 川村
陽平 小橋
大輔 松田
史康 塩澤
洋一郎 須賀
啓子 伏木
浩行 柿沼
憲一 大嶽
Original Assignee
大正製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大正製薬株式会社 filed Critical 大正製薬株式会社
Publication of WO2012173174A1 publication Critical patent/WO2012173174A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • A61P3/04—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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a GPR119 agonist.
  • GPR119 is a G protein-coupled receptor (GPCR) having an endogenous ligand such as oleylethanolamide, which is a natural long chain fatty acid amide. It is known that this receptor is highly expressed in pancreatic ⁇ cells, which are insulin-producing cells of the pancreas, and small intestinal endocrine cells involved in incretin secretion. It has been reported that the pancreas is activated by stimulation with a GPR119 agonist and the like and enhances insulin secretion in a hyperglycemic-dependent manner.
  • GPCR G protein-coupled receptor
  • GLP-1 Glucagon-like peptide 1
  • pancreatic ⁇ cells has been reported to be enhanced.
  • the hypoglycemia risk is assumed to be extremely low because it exerts hyperglycemic-dependent insulin secretion and, in turn, a hypoglycemic action from both the direct action on the pancreas and the indirect action through incretin secretion from the small intestine.
  • GPR119 agonist can be a novel anti-diabetic drug having both pancreatic protective action and anti-obesity action (see Non-Patent Documents 1 to 3).
  • oleylethanolamide As the GPR119 agonist, oleylethanolamide (OEA), which is the aforementioned endogenous ligand, is known.
  • some compounds such as certain bipiperidinyl derivatives (see Patent Document 1), pyrimidinyl derivatives (see Patent Document 2 and Non-Patent Document 4), oxadiazolyl derivatives (see Patent Document 3), thiazolyl derivatives (see Patent Document 4), etc.
  • certain types of cyclopropane derivatives see Patent Documents 5 to 6 and Non-Patent Document 5
  • certain diazaspiroalkane derivatives see Patent Documents 7 to 8) have been reported. There is no disclosure.
  • combination of a certain kind of azaspiroalkane derivative (refer patent document 9) is suggested, there is no indication of the compound of this invention.
  • An object of the present invention is to provide an excellent GPR119 agonist.
  • m1 represents an integer of 0 to 2
  • m2 represents an integer of 1 to 2
  • the ring represented by A represents a benzene ring or a 6-membered heteroaromatic ring
  • R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z1;
  • Substituent group Z1 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C
  • a saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of hydroxy, halogen atom, carbamoyl, cyano and oxo, the same or different) Monosaturated heterocyclylaminocarbonyl, C 1-6 alkylsulfinyl (wherein the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) and C 1-6 Represents a group consisting of alkylsulfonyl groups, wherein the C 1-6 alkylsulfonyl is unsubstituted or substituted with one hydroxy;
  • X represents —O— or —NR 3 —;
  • R 3 represents a hydrogen atom or C 1-4 alkyl, Y represents C 1-6 alkanediyl;
  • R 2 is (A) C 1-6 alkyl [wherein the C 1-6 alkyl
  • Halo C 1-6 alkyl or C 3-8 cycloalkyl, (B) —COOR 21 ⁇ R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). ⁇ , (C) 5- or 6-membered heteroaryl represented by the following formula ( ⁇ )
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1.
  • R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z2;
  • Substituent group Z2 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl are unsubstituted or hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the
  • R 2 is (A) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or single C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or trifluoro Substituted with one group selected from the group consisting of methyl and C 1-6 alkyl.
  • Halo C 1-6 alkyl or C 3-8 cycloalkyl, (B) —COOR 21 ⁇ R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). ⁇ Or (c) 5- or 6-membered heteroaryl represented by the following formula ( ⁇ )
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different. Or a pharmaceutically acceptable salt thereof according to (1).
  • R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted) Or is substituted with 1 trifluoromethyl). ] Or a pharmaceutically acceptable salt thereof according to any one of (1) to (2), which represents halo C 1-6 alkyl.
  • R 2 is (b) -COOR 21 ⁇ R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 Cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups).
  • the compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
  • R 2 is (b) -COOR 21 ⁇ R 21 is methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl Is replaced by ], Isopropyl, isobutyl, tert-butyl (the tert-butyl is unsubstituted or substituted with 1 to 2 fluorine atoms), neopentyl, cyclopropyl (the cyclopropyl is not substituted) Or substituted with 1 methyl) or cyclopentyl.
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ )
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
  • the compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
  • R 2 represents (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ),
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted, fluorine atom, chlorine atom, methyl, ethyl , Substituted with one group selected from the group consisting of isopropyl and cyclopropyl.) (1) to (2) or (6), or a pharmaceutically acceptable salt thereof.
  • R 2 is (e) a C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl is unsubstituted or substituted with one C 3-8 cycloalkyl) or C 3-8 Cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with 1 C 1-6 alkyl)
  • the compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
  • m1 represents 1, m2 represents 1, X represents —O—, Y is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein C 3-4 alkanediyl.
  • the ring represented by A is to provide the compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9), wherein the ring represented by A represents a benzene ring or a pyridine ring.
  • R 11 is carbamoyl, mono C 1-6 alkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl is unsubstituted or is hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy Is unsubstituted or substituted with 1 hydroxy) and is substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino.
  • the ring represented by A represents a benzene ring;
  • R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [the ethylamino Carbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (wherein the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with 1 group.
  • N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), Shows an hydroxy
  • the ring represented by A represents a pyridine ring;
  • R 11 represents ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl;
  • R 12 represents a hydrogen atom,
  • R 13 is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (11), in which R 13 represents a hydrogen atom.
  • hypoglycemic agent containing the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a compound of the general formula (I) having an excellent GPR119 agonist activity or a pharmaceutically acceptable salt thereof.
  • n is normal, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” is ortho, “m” “Represents meta, and” p "represents para.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-4 alkyl refers to a linear or branched alkyl having 1 to 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl are shown.
  • C 3-6 alkyl refers to a linear or branched alkyl having 3 to 6 carbon atoms.
  • n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
  • C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
  • Halo C 1-4 alkyl refers to a linear or branched alkyl having 1 to 4 carbon atoms substituted with a halogen atom.
  • a preferred number of substitution of halogen atoms is 1 to 3.
  • Halo C 3-6 alkyl refers to a linear or branched alkyl having 3 to 6 carbon atoms substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 3. Examples include 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl and the like.
  • Halo C 1-6 alkyl refers to a linear or branched alkyl having 1 to 6 carbon atoms substituted with a halogen atom.
  • a preferred number of substitution of halogen atoms is 1 to 3.
  • C 3-6 cycloalkyl refers to a cyclic alkyl having 3 to 6 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • C 3-8 cycloalkyl refers to cyclic alkyl having 3 to 8 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Aryl refers to a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples thereof include phenyl, naphthyl, anthryl and the like.
  • Heteroaryl is a 5- to 7-membered monocyclic fragrance consisting of one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or the same or different, and 1 to 6 carbon atoms.
  • a polycyclic aromatic heterocyclic group is shown.
  • Examples include imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, quinolyl and the like.
  • a group partially saturated in heteroaryl is also included in “heteroaryl”.
  • the “partially saturated group in heteroaryl” refers to one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1 to 6 carbon atoms.
  • oxazolidinyl, thiazolinyl and the like can be mentioned.
  • 6-membered heteroaromatic ring refers to a 6-membered monocyclic aromatic heterocycle composed of one or more nitrogen atoms and 1 to 5 carbon atoms. Examples include pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
  • “Saturated heterocyclyl” is a 3 to 8 membered monocyclic group consisting of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 7 carbon atoms.
  • a saturated heterocyclic group is shown. Examples include azetidinyl, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, piperazinyl, pyrazolidinyl, quinuclidinyl, morpholinyl, oxetanyl, oxolanyl, oxanyl and the like.
  • C 1-4 alkoxy refers to linear or branched alkoxy having 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 1-6 alkoxy represents linear or branched alkoxy having 1 to 6 carbon atoms.
  • Halo C 1-6 alkoxy refers to a straight or branched alkoxy having 1 to 6 carbon atoms substituted with a halogen atom.
  • a preferred number of substitution of halogen atoms is 1 to 3.
  • “Mono C 1-4 alkylamino” means amino having one “C 1-4 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino and the like can be mentioned.
  • “Mono C 1-6 alkylamino” refers to amino having one “C 1-6 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, neopentylamino, n-hexylamino , Isohexylamino and the like.
  • “DiC 1-4 alkylamino” refers to amino having two “C 1-4 alkyl” as the same or different as a substituent. For example, N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn- And propylamino, N-isopropyl-N-methylamino and the like.
  • “DiC 1-6 alkylamino” refers to an amino having the same or different two “C 1-6 alkyl” as the substituent. For example, N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn- And propylamino, N-isopropyl-N-methylamino and the like.
  • C 3-6 alkylcarbonyl refers to a group in which the above “C 3-6 alkyl” and carbonyl are bonded.
  • n-propylcarbonyl isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 2-methylbutylcarbonyl, n-hexylcarbonyl And isohexylcarbonyl.
  • C 1-6 alkylcarbonyl refers to a group in which the above “C 1-6 alkyl” is bonded to carbonyl.
  • Examples include carbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like.
  • C 3-6 cycloalkylcarbonyl refers to a group in which the above “C 3-6 cycloalkyl” is bonded to carbonyl. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.
  • C 3-8 cycloalkylcarbonyl refers to a group in which the above “C 3-8 cycloalkyl” is bonded to carbonyl. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, and cyclooctylcarbonyl.
  • C 1-6 alkoxycarbonyl refers to a group in which the above “C 1-6 alkoxy” is bonded to carbonyl.
  • C 1-6 alkylcarbonylamino refers to a group in which amino is bonded to a group in which the above “C 1-6 alkyl” is bonded to carbonyl.
  • “Mono C 1-4 alkylaminocarbonyl” refers to a group in which amino and carbonyl having one “mono C 1-4 alkyl” as a substituent is bonded. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl and the like.
  • “Mono C 1-6 alkylaminocarbonyl” refers to a group in which the above “mono C 1-6 alkylamino” is bonded to carbonyl.
  • Examples include carbonyl, neopentylaminocarbonyl, n-hexylaminocarbonyl, isohexylaminocarbonyl and the like.
  • “Mono C 3-6 cycloalkylaminocarbonyl” refers to a group in which amino having one “C 3-6 cycloalkyl” as a substituent and carbonyl are bonded. Examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, and cyclohexylaminocarbonyl.
  • “Mono C 3-8 cycloalkylaminocarbonyl” refers to a group in which amino having one “C 3-8 cycloalkyl” as a substituent and carbonyl are bonded. Examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, and cyclooctylaminocarbonyl.
  • “DiC 1-4 alkylaminocarbonyl” refers to a group in which the above “diC 1-4 alkylamino” and carbonyl are bonded.
  • “DiC 1-6 alkylaminocarbonyl” refers to a group in which the above “diC 1-6 alkylamino” is bonded to carbonyl.
  • C 1-4 alkyl C 3-6 cycloalkylaminocarbonyl is a combination of amino and carbonyl having one each of the above “C 1-4 alkyl” and “C 3-6 cycloalkyl” as substituents. Indicates a group. For example, N-cyclopropyl-N-methylaminocarbonyl, N-cyclopropyl-N-ethylaminocarbonyl, N-cyclobutyl-N-methylaminocarbonyl, N-cyclobutyl-N-ethylaminocarbonyl, N-cyclopentyl-N-methyl Aminocarbonyl, N-cyclohexyl-N-methylaminocarbonyl and the like can be mentioned.
  • C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl is a combination of amino and carbonyl having one each of the above “C 1-6 alkyl” and “C 3-8 cycloalkyl” as substituents. Indicates a group.
  • N-cyclopropyl-N-methylaminocarbonyl N-cyclopropyl-N-ethylaminocarbonyl, N-cyclobutyl-N-methylaminocarbonyl, N-cyclobutyl-N-ethylaminocarbonyl, N-cyclopentyl-N-methyl
  • Examples include aminocarbonyl, N-cyclohexyl-N-methylaminocarbonyl, N-cycloheptyl-N-methylaminocarbonyl, N-cyclooctyl-N-methylaminocarbonyl and the like.
  • “Saturated heterocyclylcarbonyl” refers to a group in which the above “saturated heterocyclylcarbonyl” and carbonyl are bonded. Examples include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-hexamethyleneiminylcarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl and the like.
  • “Mono-saturated heterocyclylaminocarbonyl” refers to a group in which amino and carbonyl having one “saturated heterocyclyl” as a substituent is bonded. Examples include oxetanylaminocarbonyl, oxolanylaminocarbonyl, oxanylaminocarbonyl, tetrahydrothiopyranylaminocarbonyl, pyrrolidinylaminocarbonyl, piperidinylaminocarbonyl and the like.
  • C 1-4 alkylsulfinyl refers to a group in which the above “C 1-4 alkyl” and sulfinyl are bonded. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, isobutylsulfinyl and the like.
  • C 1-6 alkylsulfinyl refers to a group in which the above “C 1-6 alkyl” and sulfinyl are bonded. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, n-hexylsulfinyl and the like.
  • C 1-4 alkylsulfonyl refers to a group in which the above “C 1-4 alkyl” and sulfonyl are bonded.
  • methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl and the like can be mentioned.
  • C 1-6 alkylsulfonyl refers to a group in which the above “C 1-6 alkyl” and sulfonyl are bonded. Examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, n-hexylsulfonyl and the like.
  • C 3-8 cycloalkylsulfonyl refers to a group in which the above “C 3-8 cycloalkyl” is bonded to sulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl.
  • C 1-6 alkylsulfonylamino refers to a group in which the above “C 1-6 alkylsulfonyl” is linked to amino.
  • “Mono C 1-6 alkylaminosulfonyl” refers to a group in which the above “mono C 1-6 alkylamino” is bonded to sulfonyl.
  • Oxo refers to a substituent ( ⁇ O) in which an oxygen atom is substituted via a double bond. Therefore, when oxo is substituted with a carbon atom, it forms a carbonyl together with the carbon atom, and when one oxo is substituted with one sulfur atom, it forms a sulfinyl together with the sulfur atom, When two oxos are substituted with one sulfur atom, they are combined with the sulfur atom to form a sulfonyl.
  • saturated heterocyclyl substituted with oxo when oxo is substituted with saturated heterocyclyl include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 3 -Oxopiperazinyl, 1,1-dioxidetetrahydrothiophenyl, 1-oxidetetrahydro-2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2- Examples thereof include oxo-1,3-oxazolidinyl, 6-oxo-1,1-dihydropyridazinyl and the like.
  • C 3-4 alkanediyl refers to a divalent saturated hydrocarbon group having 3 to 4 carbon atoms. Examples thereof include propane-1,3-diyl, butane-1,4-diyl and the like.
  • C 1-6 alkanediyl refers to a divalent hydrocarbon group having 1 to 6 carbon atoms.
  • methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl and the like can be mentioned.
  • a 5- or 6-membered monocyclic aromatic heterocyclic group composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 5 carbon atoms.
  • Examples include oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like.
  • Preferred embodiments of the compound of the present invention are as follows. That is, Of the azaspiro ring structure represented by the following formula ( ⁇ 1),
  • Preferred azaspiro ring structures are the following structures:
  • More preferred azaspiro ring structures are the following structures:
  • More preferred azaspiro ring structures are the following structures
  • a preferred ring represented by A is a benzene ring or a 6-membered heteroaromatic ring
  • a more preferable ring represented by A is a benzene ring, a pyridine ring, a pyrazine ring or a pyrimidine ring
  • a more preferable ring represented by A is a benzene ring, a pyridine ring or a pyrazine ring
  • a particularly preferred ring represented by A is a benzene ring;
  • R 11 , R 12 and R 13 are hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl may be unsubstituted, hydroxy, carbamoyl, cyano, C 1-6 alkoxy (wherein the C 1-6 alkoxy is unsubstituted or And substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino.
  • R 11 , R 12 and R 13 are more preferably hydrogen atom, halogen atom, carbamoyl, C 1-4 alkyl, mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, diC.
  • Saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 hydroxy), monosaturated heterocyclylaminocarbonyl or C 1-4 alkylsulfonyl;
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
  • R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylamino.
  • Carbonyl the ethylaminocarbonyl consists of unsubstituted, hydroxy, methoxy, ethoxy (the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino Substituted with one group selected from the group.
  • N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), It is o
  • R 11 is ethylaminocarbonyl [wherein the ethylaminocarbonyl is one group selected from the group consisting of hydroxy, methoxy and ethoxy (the ethoxy is substituted with one hydroxy).
  • R 11 , R 12 and R 13 are mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8.
  • Cycloalkylaminocarbonyl (the mono-C 1-6 alkylaminocarbonyl, mono-C 3-8 cycloalkylaminocarbonyl, di-C 1-6 alkylaminocarbonyl and C 1-6 alkyl-C 3-8 cycloalkylaminocarbonyl are mono- C 1-6 substituted with one group identical to or different selected from alkyl aminocarbonyl and the group consisting of di-C 1-6 alkylaminocarbonyl.), heterocyclylcarbonyl in heterocyclylcarbonyl (saturated saturated Substituted with 1 to 2 groups selected from the group consisting of halogen atom, carbamoyl, cyano and oxo, the same or different C 1-6 alkylsulfinyl (the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) or C 1-6 alkylsulfonyl (the C 1- 6 alkylsulfonyl is
  • R 11 , R 12 and R 13 are more preferably mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, di C 1-4 alkylaminocarbonyl, C 1-4 alkyl C 3. -6 cycloalkylaminocarbonyl (the mono-C 1-4 alkylaminocarbonyl, mono-C 3-6 cycloalkylaminocarbonyl, di-C 1-4 alkylaminocarbonyl and C 1-4 alkylC 3-6 cycloalkylaminocarbonyl are Substituted with one or two groups selected from the same or different from the group consisting of mono C 1-4 alkylaminocarbonyl and diC 1-4 alkylaminocarbonyl), saturated heterocyclylcarbonyl (the saturated The heterocyclylcarbonyl is substituted with 1 to 2 groups selected from the group consisting of a halogen atom, carbamoyl and oxo).
  • C 1-4 alkylsulfinyl (wherein the C 1-4 alkylsulfinyl is unsubstituted or substituted with one hydroxy) or C 1-4 alkylsulfonyl (wherein the C 1-4 alkylsulfonyl is Substituted with one hydroxy).
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of methylaminocarbonyl and N, N-dimethylaminocarbonyl), N, N-dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), azetidin-1-yl-carbonyl (The azetidin-1-yl-carbonyl is substituted with 2 fluorine atoms), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is either unsubstituted or 1 Substituted with oxo).
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl
  • R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of carbamoyl and cyano), N, N-dimethylaminocarbonyl (the N , N-dimethylaminocarbonyl is substituted with 1 cyano), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is substituted with oxo),
  • R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring
  • particularly preferred R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl, Wherein R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
  • Preferred X is —O— or —NH—, More preferred X is —O—;
  • Preferred Y is ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl; More preferred Y is propane-1,3-diyl or butane-1,4-diyl, More preferred Y is propane-1,3-diyl;
  • R 2 is (a) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted) Or is substituted with 1 trifluoromethyl).
  • R 2 is (a) methyl (the methyl is substituted with one C 3-6 cycloalkyl), C 3-6 alkyl or haloC 3-6 alkyl, In this case, more preferable R 2 is (a) methyl (the methyl is substituted with one cyclopentyl), neopentyl or isopropyl (the isopropyl is substituted with one fluorine atom). Is;
  • R 21 is C 1-6 alkyl [the C 1-6 alkyl is not substituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is substituted). Or is substituted with one C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is unsubstituted or substituted with one C 1-6 alkyl. In this case, more preferable R 21 is C 1-6 alkyl (the C 1-6 alkyl is not substituted or one C 3-6 cycloalkyl (the C 3-6 cycloalkyl is substituted).
  • R 21 is more preferably methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl). Has been replaced.
  • R 21 is methyl [the methyl is substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl).
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is not substituted. Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1-6 alkoxy Is)
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted or halogenated) Substituted with one group selected from the group consisting of an atom, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 alkoxy.
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) is oxadiazolyl (the oxadiazolyl is not substituted or substituted with one isopropyl) ), Pyridyl or pyrimidinyl (the pyridyl and pyrimidinyl are unsubstituted or substituted with one group selected from the group consisting of fluorine atom, chlorine atom, methyl, ethyl, isopropyl and cyclopropyl).
  • R 2 is (c) 5-oxadiazolyl of 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) (the 5-oxadiazolyl is substituted with one isopropyl). Or 2-pyrimidinyl (the 2-pyrimidinyl is substituted with 1 ethyl);
  • R 2 is (e) C 1-6 alkylcarbonyl or C 3-8 cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with one C 1-6 Substituted with alkyl).
  • R 2 is (e) C 3-6 alkylcarbonyl or C 3-6 cycloalkylcarbonyl (the C 3-6 cycloalkylcarbonyl is either unsubstituted or substituted with one C 1-4). Substituted with alkyl).
  • R 2 is (e) tert-butylcarbonyl, neopentylcarbonyl or cyclopropylcarbonyl (the cyclopropylcarbonyl is unsubstituted or substituted with one methyl).
  • particularly preferred R 2 is (e) tert-butylcarbonyl or neopentylcarbonyl.
  • One preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (II).
  • Preferred embodiments of the ring represented by A, R 11 , R 12 , R 13 , Y and R 2 are as described above.
  • Another preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (III).
  • Preferred embodiments of the ring represented by A, R 11 , R 12 , R 13 , Y and R 2 are as described above.
  • a preferred ring represented by A is a benzene ring
  • R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [ The ethylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with one selected group.
  • N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), It is o
  • R 11 is more preferably ethylaminocarbonyl [wherein the ethylaminocarbonyl is a group selected from the group consisting of hydroxy, methoxy and ethoxy (wherein the ethoxy is substituted with one hydroxy).
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of methylaminocarbonyl and N, N-dimethylaminocarbonyl), N, N— Dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), azetidin-1-yl-carbonyl (the Azetidin-1-yl-carbonyl is substituted with 2 fluorine atoms), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is either unsubstituted or Substituted with oxo).
  • R 11 is substituted at the para-position of the benzene ring
  • preferable R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
  • R 12 and R 13 are independently substituted at the ortho-position or meta-position of the benzene ring,
  • R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of carbamoyl and cyano), N, N-dimethylaminocarbonyl (the N , N-dimethylaminocarbonyl is substituted with one cyano), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is substituted with oxo),
  • R 11 is substituted at the para-position of the benzene ring
  • R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
  • R 12 and R 13 are independently substituted at the ortho or meta position of the benzene ring.
  • a preferred ring represented by A is a pyridine ring
  • Preferred R 11 is ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl; In this case, more preferred R 11 is cyclopropylaminocarbonyl or methylsulfonyl; Preferred R 12 is a hydrogen atom; Preferred R 13 is a hydrogen atom.
  • a preferred ring represented by A is a pyrazine ring
  • R 11 is ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with one hydroxy), cyclopropylaminocarbonyl, N, N-dimethylaminocarbonyl (the N, N -Dimethylaminocarbonyl is unsubstituted or substituted with 1 cyano), pyrrolidin-1-yl-carbonyl (wherein the pyrrolidin-1-yl-carbonyl is unsubstituted or 1 Substituted with hydroxy)), morpholinocarbonyl or methylsulfonyl, In this case, more preferable R 11 is cyclopropylaminocarbonyl, N, N-dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is substituted with one cyano), morpholinocarbonyl or methylsulfonyl.
  • Preferred R 12 is a hydrogen atom or
  • Preferred azaspiro ring structures are the following structures:
  • More preferred azaspiro ring structures are the following structures
  • a preferred ring represented by A is a benzene ring or a 6-membered heteroaromatic ring, A more preferable ring represented by A is a benzene ring, a pyridine ring or a pyrimidine ring;
  • R 11 , R 12 and R 13 are hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl And C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl is unsubstituted, hydroxy, carbamoyl, cyano, C 1-6 alkoxy (wherein the C 1-6 alkoxy is unsubstituted or substituted with hydroxy.) and optionally substituted with one to two groups the same or different and selected from the group consisting of di-C 1-6 alkylamino .
  • Preferred X is -O-
  • Preferred Y is ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl; More preferred Y is propane-1,3-diyl;
  • R 21 is preferably C 1-6 alkyl (the C 1-6 alkyl is not substituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted) Substituted with 1 C 1-6 alkyl.)), Halo C 1-6 alkyl or C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted) Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, the same or different from each other);
  • R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) (the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is not substituted) And substituted with one group selected from the group consisting of a halogen atom, C 1-6 alkyl and C 3-8 cycloalkyl).
  • R 2 is 5-oxadiazolyl (the 5-oxadiazolyl is unsubstituted or substituted with one C 1-6 alkyl), 2-pyridyl or 2-pyrimidinyl 2-pyridyl and 2-pyrimidinyl are unsubstituted or substituted with one group selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-8 cycloalkyl.
  • the compound of the present invention is an azaspiroalkane compound and may be a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention” as appropriate).
  • Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, mineral salts such as methanesulfonate, ethanesulfone, and the like.
  • Acid addition salts such as acid salts, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartic acid
  • Amino acid salts such as salts, or inorganic or ammonium salts such as lithium, sodium, potassium, calcium, and magnesium salts, triethylamine salts, Isopropylamine salt, salts with organic bases such as cyclohexylamine salts.
  • the salt includes a hydrated salt.
  • the compound of the present invention may have an asymmetric center, in which case various optical isomers exist.
  • the compounds of the present invention may exist as separate optically active forms of (R) and (S) and as racemates or (RS) mixtures.
  • 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 of the present invention may have geometric isomers such as cis isomer and trans isomer.
  • the compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.
  • the compound of the present invention has GPR119 agonist activity. Therefore, the compound of the present invention causes pancreatic ⁇ cell GLP-1 receptor activation through direct activation of pancreatic ⁇ cell GPR119 or small intestine GLP-1 secretion, and increases insulin secretion from pancreatic ⁇ cells in a hyperglycemic manner Can correct hyperglycemia.
  • pancreatic ⁇ -cell dysfunction and exhaustion are alleviated or improved by pancreatic ⁇ -cell protective action through activation of pancreatic ⁇ -cell GPR119. Therefore, it can be used as a new drug therapy having a different mechanism of action from existing anti-diabetic drugs. Diabetes includes type I diabetes, type II diabetes, and other diabetes due to specific causes.
  • the compound of the present invention can also be used for the treatment or prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout. Since the compound of the present invention has a pancreatic ⁇ -cell protective action, it can be used to improve the prognosis at the time of islet transplantation. Furthermore, the compound of the present invention can be used for ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, peripheral artery occlusion, etc.), neuropathy (sensory nerve, motor Nerves, autonomic nerves, etc.), foot gangrene, infections and other diabetic complications.
  • diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout. Since the compound of the present invention has a pancreatic ⁇ -cell protective action, it can be used to improve the progno
  • the compound of the present invention can also be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension and the like having a different mechanism of action other than the GPR119 agonistic action.
  • a therapeutic agent for diabetes a therapeutic agent for diabetic complications
  • a therapeutic agent for hyperlipidemia a therapeutic agent for hypertension and the like having a different mechanism of action other than the GPR119 agonistic action.
  • Examples of antidiabetic drugs and diabetic complications that can be used in combination include insulin preparations, insulin fragments or derivatives (INS-1), oral insulin preparations, insulin resistance improving drugs (PPAR ⁇ agonists, PPAR ⁇ / ⁇ agonists, PPAR ⁇ ). Agonists, PPAR ⁇ / ⁇ / ⁇ agonists, etc.
  • ⁇ -glucosidase inhibitors eg, voglibose, acarbose, Miglitol
  • biguanide drugs eg, metformin, buformin, phenformin
  • insulin secretagogues eg, glibenclamide, glimepiride, repaglinide, nateglinide, mitiglinide
  • glucagon receptor antagonist Insulin receptor kinase promoter, dipeptidyl peptidase IV inhibitor (eg, vildagliptin, alogliptin, sitagliptin, linagliptin, saxagliptin), SGLT inhibitor (eg, sagliflozin, canagliflozin, dapagliflozin, TS-071,
  • drugs for diabetes-related diseases examples include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid adsorbents, IBAT inhibitors, CETP inhibitors, CPT inhibitors, fibrate drugs, ACAT Inhibitor, MGAT inhibitor, DGAT inhibitor, cholesterol absorption inhibitor, pancreatic lipase inhibitor, MTP inhibitor, nicotinic acid derivative, LXR agonist, LDL receptor promoter, angiotensin converting enzyme inhibitor, angiotensin II antagonist, diuretic , Calcium antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, appetite suppressants, uric acid production inhibitors, uric acid excretion promoters, and the like.
  • the compound of the present invention can be administered alone or together with a pharmaceutically or pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically or pharmaceutically acceptable carrier or diluent When the compound of the present invention is used as a GPR119 agonist or the like, the compound of the present invention may be orally or parenterally administered as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient.
  • Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. It is desirable to administer this amount once to three times a day.
  • the agonistic effect of GPR119 of the compound of the present invention can be evaluated according to a known method such as the method described in the test method.
  • the compound of the present invention represented by the general formula (I) has desirable properties as a pharmaceutical product. For example, it is advantageous in terms of effectiveness because it has good water solubility, and is advantageous in terms of safety because it exhibits no inhibitory activity against liver metabolic enzymes. .
  • the method for producing the compound according to the present compound will be described in detail, it is not particularly limited to those exemplified. Moreover, the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction.
  • Compound (I) can be produced by a method known per se, for example, the production methods 1 to 19 shown below or a method analogous thereto.
  • the raw material compound may be used as a salt, and examples thereof include the above-mentioned “pharmaceutically acceptable salts”.
  • the compound (I-2) in which X is —O— can be produced, for example, by the following production method 1 or a method analogous thereto.
  • Step 1-1 This step is a method for producing compound (I-2) using compound (I-1). This method can be performed using a known method, the so-called Mitsunobu reaction (Synthesis, 1981, 1-28).
  • the amount of compound (I-3) used in this step is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
  • Examples of the azo compound to be used include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide) and the like.
  • the amount of the azo compound used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
  • Examples of the phosphine compound used usually include triphenylphosphine and tributylphosphine.
  • the amount of the phosphine compound used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
  • Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, diethyl ether, chloroform, dichloromethane, toluene, N, N-dimethylformamide, dimethyl sulfoxide and the like, which are not involved in the reaction. You may mix and use by the ratio. These reactions can usually be performed at room temperature to reflux temperature for 1 to 4 hours.
  • this step can be performed using methods described in the literature (Tetrahedron Letters, 1995, 36, 2531-2534, Tetrahedron Letters, 1996, 37, 2463-2466).
  • the reagent used in this step include (cyanomethylene) trimethylphosphorane, (cyanomethylene) tributylphosphorane, and the like.
  • the amount of the reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-1).
  • the solvent used for the reaction include the same solvents as described above. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • the compound (I-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (II-2) in which the ring represented by A is a 6-membered heteroaromatic ring can be produced, for example, by the following production method 2 or a method analogous thereto. .
  • Ua represents a leaving group
  • a ′ represents a 6-membered heteroaromatic ring
  • m1, m2, R 11 , R 12 , R 13 , X, Y, and R 2 have the same meaning as described above.
  • Examples of the “leaving group” represented by Ua include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • the “6-membered heteroaromatic ring” represented by A ′ has the same meaning as described above.
  • Step 2-1 This step is a method for producing compound (II-2) by reacting compound (II-1) with compound (II-3) in the presence of a base.
  • a base examples include sodium hydride, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. Is equivalent.
  • the solvent used include N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and N-methyl-2-pyrrolidone. These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
  • the compound (II-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (III-3) in which R 11 is R 14 R 15 NCO— can be produced, for example, by the following production method 3 or a method analogous thereto.
  • the starting compound (III-1) in which R 11 is a carboxylic acid precursor (for example, ethoxycarbonyl, methoxycarbonyl, cyano, etc.) can be obtained by, for example, the production method 1 or a method analogous thereto. Can be manufactured.
  • R 14 and R 15 are the same or different and each represents a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl or saturated heterocyclyl, or R 14 and R 15 are bonded nitrogen atoms. Together with m 1, m 2, A, R 12 , R 13 , X, Y and R 2 are as defined above. ]
  • Step 3-1 This step is a method for producing compound (III-2) from compound (III-1) by hydrolysis with a base.
  • the base used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • the amount of the base used is 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (III-1).
  • the solvent used in the reaction include solvents such as methanol, ethanol, tetrahydrofuran, and water, and these solvents may be mixed and used at an appropriate ratio. These reactions can usually be performed at room temperature to reflux temperature.
  • Step 3-2 This step is a method for producing compound (III-3) by condensing compound (III-2) and compound (III-4).
  • This reaction can be performed by a known method, for example, using a condensing agent in the presence or absence of a base and an activator in a solvent that does not participate in the reaction.
  • the amount of compound (III-4) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the condensing agent used in the reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, diethyl cyanophosphonate and the like.
  • the amount of the condensing agent to be used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the activator used in the reaction include 1-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide and the like.
  • the amount of the activator used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, and pyridine.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (III-2).
  • Examples of the solvent used for the reaction include N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, water and the like, which are not involved in the reaction. May be mixed and used at an appropriate ratio. These reactions can usually be performed at 0 to 100 ° C.
  • the compound (III-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • R 2 is (c) a compound (IV-3) which is a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) or a compound (IV-5) which is a substituted oxadiazolyl )
  • IV-3 which is a 5- or 6-membered heteroaryl represented by the following formula ( ⁇ ) or a compound (IV-5) which is a substituted oxadiazolyl
  • the 5- or 6-membered heteroaryl represented by the formula ( ⁇ ) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different. Production method 4:
  • compound (IV-6) represents a 5- or 6-membered heteroaryl represented by the above formula ( ⁇ ) having the leaving group Ub as a substituent
  • R 22 represents C 1 -6 alkyl or C 3-8 cycloalkyl, m1, m2, A, R 11 , R 12 , R 13 , X and Y are as defined above.
  • Examples of the “leaving group” represented by Ub include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • “C 1-6 alkyl” for R 22 is as defined above.
  • “C 3-8 cycloalkyl” represented by R 22 is as defined above.
  • Step 4-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
  • the acid used for the reaction usually include 4M hydrogen chloride / ethyl acetate solution, 4M hydrogen chloride / 1,4-dioxane solution, trifluoroacetic acid and the like.
  • the amount of the acid used is 5 to 50 equivalents, preferably 10 to 30 equivalents, relative to 1 equivalent of compound (IV-1).
  • Examples of the solvent used for the reaction include ethyl acetate, tetrahydrofuran, 1,4- Examples include solvents that do not participate in the reaction, such as dioxane, methanol, ethanol, water, chloroform, and dichloromethane, and these solvents may be mixed and used at an appropriate ratio. These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • Step 4-2 This step is a method for producing compound (IV-3) from compound (IV-2) and compound (IV-6).
  • Compound (IV-3) can be produced by reacting compound (IV-2) with compound (IV-6) in the presence or absence of a base.
  • Examples of the compound (IV-6) used in this reaction include 2-chloro-5-isopropylpyridine, 2-chloro-5-methylpyridine, 2,5-dichloropyridine and the like.
  • the amount of compound (IV-6) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate and potassium carbonate, and pyridine.
  • the amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
  • Examples of the solvent used in the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, tetrahydrofuran, 2-propanol and the like, which are not involved in the reaction. You may mix and use. These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
  • Compound (IV-3) can be produced by reacting compound (IV-2) with compound (IV-6) in the presence of a metal catalyst and a base. This reaction can be carried out in an inert gas atmosphere such as argon or nitrogen in a solvent that does not participate in the reaction in the presence of a palladium catalyst, a base, and in the presence or absence of a phosphine compound.
  • the amount of compound (IV-6) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the palladium catalyst used in the reaction include (1,3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] palladium.
  • the amount of the palladium catalyst to be used is generally 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IV-2).
  • Examples of the phosphine compound used in the reaction include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 1,1′-bis (diphenylphosphino) ferrocene, and 4,5′-bis (diphenyl). Phosphino) -9,9'-dimethylxanthene and the like.
  • the amount of the phosphine compound used is usually 0.02 to 2 equivalents, preferably 0.2 to 1 equivalent.
  • Examples of the base used in the reaction include alkali metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide and sodium phenoxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, potassium phosphate and the like And alkali metal phosphates.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used for the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like, which are not involved in the reaction.
  • Step 4-3 This step is a method for producing compound (IV-4) by reacting compound (IV-2) with cyanogen bromide in the presence of a base.
  • the amount of cyanogen bromide used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used in the reaction usually include sodium acetate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine and the like.
  • the amount of the base used is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, water, ethanol, methanol, and the like, and these solvents may be mixed and used at an appropriate ratio. These reactions are usually performed at 0 ° C. to reflux temperature, and can be performed in 1 to 24 hours.
  • Step 4-4 is a method for producing compound (IV-5) by reacting compound (IV-4) with compound (IV-7) in the presence of zinc chloride and then treating with hydrochloric acid.
  • This step can be performed by a known method, for example, the method described in WO200808204 or a method analogous thereto.
  • Examples of the compound (IV-7) used in this reaction include N′-hydroxy-2-methylpropanimidamide and the like.
  • the amount of compound (IV-7) to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-4).
  • the amount of zinc chloride to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-4).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, and ethyl acetate. These solvents may be mixed and used at an appropriate ratio. This reaction is usually carried out at 0 ° C. to 50 ° C. for 15 minutes to 24 hours.
  • Examples of the solvent used in the treatment with hydrochloric acid include solvents that do not participate in the reaction, such as ethanol, methanol, diethyl ether, tetrahydrofuran, and 1,4-dioxane. These solvents may be used by mixing at an appropriate ratio. good. This reaction is usually carried out at room temperature to reflux temperature for 1 to 24 hours.
  • the compound (IV-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • R 2 is (b) -COOR 21 ⁇ R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3- Substituted with 8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups).
  • ⁇ (V-1) can be produced, for example, by the following production method 5 or a method analogous thereto. Production method 5:
  • Uc is a leaving group, and m1, m2, A, R 11 , R 12 , R 13 , X, Y and R 21 are as defined above].
  • Examples of the “leaving group” represented by Uc include leaving groups such as chlorine atom, bromine atom, iodine atom, methylimidazolium and 4-nitrophenoxy.
  • Step 5-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 5-2 This step is a method for producing compound (V-1) from compound (IV-2).
  • Compound (V-1) can be produced by reacting compound (IV-2) with compound (V-2) in the presence of a base.
  • the amount of compound (V-2) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the compound (V-2) used in the reaction include isopropyl chloroformate, isobutyl chloroformate, 1-methylcyclopropyl chloroformate, 1- ⁇ [(1-fluoro-2-methylpropan-2-yl) oxy] Carbonyl ⁇ -3-methyl-4,5-dihydro-1H-imidazol-3-ium iodide, 1- ⁇ [(1,1-difluoro-2-methylpropan-2-yl) oxy] carbonyl ⁇ -3-methyl
  • Examples include -4,5-dihydro-1H-imidazol-3-ium iodide, 1-methylcyclopropyl 4-nitrophenyl carbonate, and N- (methylcyclopropyloxycarbonyloxy) succinimide.
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, sodium hydroxide and pyridine. N, N-dimethyl-4-aminopyridine and the like.
  • the amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
  • Examples of the solvent used in the reaction include chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, methanol, ethanol, water, ethyl acetate, acetonitrile, acetone, toluene, and other solvents that do not participate in the reaction. These solvents may be mixed and used at an appropriate ratio. These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • Compound (V-1) can be produced by reacting compound (IV-2) with compound (V-3) in the presence of triphosgene.
  • the amount of compound (V-3) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the compound (V-3) used in the reaction include cyclopropanemethanol, 1-methylcyclopropanemethanol, cyclopentanol, neopentyl alcohol and the like.
  • Examples of the base used in the reaction include tertiary aliphatic amines such as triethylamine, aromatic heterocyclic amines such as pyridine, and the like.
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as dichloromethane, chloroform, and tetrahydrofuran, and these solvents may be mixed and used at an appropriate ratio. These reactions can be usually performed at 0 ° C. to room temperature for 5 minutes to 24 hours.
  • the thus obtained compound (V-1) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-6 8 cycloalkyl is unsubstituted or substituted with 1 group selected from the group consisting of trifluoromethyl and C 1-6 alkyl. ]
  • Compounds (VI-1), (VI-2), (VI-4) and (VI-6) which are halo C 1-6 alkyl or C 3-8 cycloalkyl can be produced, for example, by the following production method 6 or It can manufacture by the method according to this. Production method 6:
  • Ud represents a leaving group
  • Ue represents a hydroxy or halogen atom
  • R 23 and R 24 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 3-8 cycloalkyl, or R 23 and R 24 together with the carbon atoms to which they are attached form C 3-8 cycloalkyl
  • R 25 represents a hydrogen atom, C 1-5 alkyl or C 3-8 cycloalkyl
  • R 26 and R 27 may be the same or different and represents a hydrogen atom, C 1-5 alkyl or C 3-8 cycloalkyl, or R 26 and R 27 together with the carbon atom to which they are attached represent C 3-8 cycloalkyl.
  • Examples of the “leaving group” represented by Ud include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • Examples of the “halogen atom” represented by Ue include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1-5 alkyl represented by R 23 , R 24 and R 25 represents linear or branched alkyl having 1 to 5 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl and the like.
  • C 1-4 alkyl represented by R 26 and R 27 are as defined above.
  • Step 6-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 6-2 This reaction is a method for producing compound (VI-1) by reacting compound (IV-2) with compound (VI-7) in the presence or absence of a base.
  • Examples of the compound (VI-7) used in this reaction include 2,2-difluoropropyl 4-methylbenzenesulfonate.
  • the amount of compound (VI-7) to be used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, sodium hydroxide and pyridine. N, N-dimethyl-4-aminopyridine and the like.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used for the reaction include acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, ethanol and the like which do not participate in the reaction, and these solvents are mixed in an appropriate ratio. May be used. These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
  • the compound (VI-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 6-3 This reaction is a method for producing compound (VI-2) by carrying out reductive amination reaction from compound (IV-2) and compound (VI-8).
  • the reducing agent used in the reaction include sodium triacetoxyborohydride, sodium cyanoborohydride, borane-2-picoline complex, and the like.
  • the amount of the reducing agent used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • the solvent used for the reaction include N, N-dimethylformamide, chloroform, dichloromethane, methanol and the like. These reactions can usually be carried out at 0 ° C. to reflux temperature.
  • the compound (VI-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 6-4 This step is a method for producing compound (VI-3) by reacting compound (IV-2) with compound (VI-9).
  • Step 6-5 This step is a method for producing compound (VI-4) by reducing compound (VI-3).
  • the reducing agent used in this reaction include lithium aluminum hydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, and borane-dimethyl sulfide complex.
  • the amount of the reducing agent used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (VI-3).
  • the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, and these solvents may be used by mixing at an appropriate ratio.
  • the reaction can usually be carried out at 0 ° C. to reflux temperature.
  • the compound (VI-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 6-6 This reaction is a method for producing compound (VI-5) by reacting compound (IV-2) with compound (VI-10) in the presence or absence of a base.
  • the compound (VI-10) used in this reaction include isobutylene oxide.
  • the amount of compound (VI-10) used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, sodium hydroxide and pyridine.
  • the amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • the solvent used in the reaction include N, N-dimethylformamide, acetonitrile, ethanol, methanol, 2-propanol, water, and other solvents that do not participate in the reaction, and these solvents are used by mixing at an appropriate ratio. Also good. These reactions can usually be performed at 0 to 100 ° C.
  • This reaction is a method for producing compound (VI-6) by reacting compound ((VI-5) with a fluorinating agent.
  • a fluorinating agent examples include bis (2-methoxyethyl) aminosulfur trifluoride, (diethylamino) sulfur trifluoride, and Ishikawa reagent.
  • the amount of the fluorinating agent to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (VI-5).
  • Examples of the solvent used in the reaction include dichloroethane, chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, and the like, which are not involved in the reaction. It may be used. These reactions can usually be performed at ⁇ 78 ° C. to 100 ° C.
  • the compound (VI-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (VII-1) in which R 2 is (d) C 1-6 alkylsulfonyl or C 3-8 cycloalkylsulfonyl is, for example, in accordance with the following production method 7 or the same. It can be manufactured by a method. Production method 7:
  • Uf represents a halogen atom
  • R 28 represents C 1-6 alkyl or C 3-8 cycloalkyl
  • m1, m2 A, R 11 , R 12 , R 13 , X and Y are as defined above. Indicates.
  • Examples of the “halogen atom” represented by Uf include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Step 7-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 7-2 This step is a method for producing compound (VII-1) by reacting compound (IV-2) with compound (VII-2) in the presence or absence of a base.
  • This step can be performed by a known method, for example, a method described in the literature (Journal of Medicinal Chemistry, 2008, 51, 2170-2177) or a method analogous thereto.
  • Examples of the compound (VII-2) used in the reaction include cyclopropanesulfonyl chloride.
  • the amount of compound (VII-2) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the base used usually include N, N-diisopropylethylamine, triethylamine, potassium carbonate and the like.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, water, and the like. These solvents may be mixed and used at an appropriate ratio. These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • the compound (VII-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Compound (I-1) which is a starting material in Production Method 1 Compound (II-1) which is a starting material in Production Method 2 (wherein Compound (II-1) wherein X is —O— is compound (I) -1) and X is —NR 3 — (II-1) is Compound (VIII-3)) and Compound (IV-1) which is the starting material in Production Methods 4 to 7 is
  • it can be produced by the following production method 8 or a method analogous thereto.
  • Ug represents hydroxy or a leaving group
  • Ua, A ′, m1, m2, A, R 11 , R 12 , R 13 , X, Y, and R 2 have the same meaning as described above.
  • Examples of the “leaving group” represented by Ug include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • Step 8-1 This step is a method for producing compound (VIII-2) by treating compound (VIII-1) under acidic conditions. This reaction can be carried out according to the method described in Process 4-1, Step 4-1.
  • Step 8-2 This step is a method for producing compound (I-1) from compound (VIII-2). This reaction can be carried out according to the methods described in Production Methods 4 to 7.
  • the compound (I-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 8-3 This step is a method for producing compound (VIII-3) from compound (I-1). This method can be performed using a known method, for example, a method described in WO2011 / 019538.
  • the thus obtained compound (VIII-3) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 8-4 This step is a method for producing compound (IV-1) from compound (VIII-1).
  • Method A When Ug of compound (VIII-4) is hydroxy, this reaction is carried out by reacting compound (VIII-1) with compound (VIII-4) using a so-called Mitsunobu reaction to give compound (IV-1) Can be manufactured. This reaction can be carried out according to the method described in Production Method 1.
  • Method B When Ug of compound (VIII-4) is a leaving group and the ring represented by A is a 6-membered heteroaryl, this reaction is carried out by reacting compound (VIII-1) with compound (VIII-) in the presence of a base. Compound (IV-1) can be produced by reacting with 4).
  • This reaction can be carried out according to the method described in Production Method 2.
  • the thus obtained compound (IV-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 8-5 This step is a method for producing compound (VIII-5) from compound (VIII-1). This can be carried out according to the method described in Step 8-3 of Production Method 8.
  • Step 8-6 This step is a method for producing compound (IV-1) from compound (VIII-5).
  • This step is a method for producing compound (IV-1) by reacting compound (VIII-5) with compound (II-3) in the presence of a base.
  • This reaction can be carried out according to the method described in Production Method 2.
  • the thus obtained compound (IV-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is the starting material in production method 8
  • compound (IX-6) wherein Y is propane-1,3-diyl is obtained, for example, from compound (IX-1) by the following production method 9 or It can manufacture by the method according to this.
  • Step 9-1 This step is a method for producing compound (IX-2) by reacting compound (IX-1) with (methoxymethyl) triphenylphosphonium chloride in the presence of a base.
  • the amount of (methoxymethyl) triphenylphosphonium chloride used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-1).
  • Examples of the base used in the reaction usually include n-butyl lithium, sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide and the like.
  • the amount of the base used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-1).
  • solvent used in the reaction examples include solvents that do not participate in the reaction, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, and benzene. These solvents are mixed in an appropriate ratio. It may be used. These reactions can be usually performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • Step 9-2 This step is a method for producing compound (IX-3) by treating compound (IX-2) under acidic conditions.
  • the acid used for the reaction usually include p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid and the like.
  • the amount of the acid used is 1 to 10 equivalents relative to 1 equivalent of compound (IX-2).
  • the solvent used for the reaction include acetonitrile, tetrahydrofuran, 1,4-dioxane, diethyl ether, water, chloroform, dichloromethane and the like, which are not involved in the reaction. These solvents are used in a mixture at an appropriate ratio. Also good.
  • These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • Step 9-3 This step is a method for producing compound (IX-4) by reacting compound (IX-3) with triethyl phosphonoacetate in the presence of a base.
  • the amount of triethyl phosphonoacetate used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-3).
  • Examples of the base used usually include n-butyllithium, sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide and the like.
  • the amount of the base used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-3).
  • solvent used in the reaction examples include solvents that do not participate in the reaction, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, and benzene. These solvents are mixed in an appropriate ratio. It may be used. These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
  • Step 9-4 This step is a method for producing compound (IX-5) by reducing compound (IX-4).
  • This reaction can be performed in the presence of a metal and hydrogen gas in a solvent that does not participate in the reaction.
  • the metal used include palladium, nickel, platinum and the like.
  • the amount of the metal used is 0.1 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IX-4).
  • the hydrogen pressure used in the reaction is from normal pressure to 10 atm, preferably from normal pressure to 4 atm.
  • Examples of the solvent used for the reaction include methanol, ethanol, water, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, and the like, which are not involved in the reaction, and these solvents may be used by mixing at an appropriate ratio. These reactions can usually be performed at room temperature to reflux temperature.
  • Step 9-5 This step is a method for producing compound (IX-6) by reducing compound (IX-5).
  • the reducing agent used in this reaction include lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, lithium aluminum hydride, diisobutylaluminum hydride and the like.
  • the amount of the reducing agent used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IX-5).
  • Examples of the solvent used in this reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, diethyl ether, 1,4-dioxane, ethanol, methanol, and the like, and these solvents may be used in an appropriate ratio. These reactions can be usually performed at 0 ° C. to reflux temperature for 30 minutes to 24 hours.
  • the thus obtained compound (IX-6) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (IX-1) which is the starting material in production method 9
  • compound (X-4) wherein m1 is 1 and m2 is 1 is obtained, for example, from compound (X-1) by the following production method 10 or Can be produced by a method according to the above.
  • the starting compound (X-1) can be produced by a method known per se. Production method 10:
  • Steps 10-1 to 10-3 This step is a method for producing compound (X-4) from compound (X-1).
  • This method can be carried out using a known method, for example, the method described in Chemical & Pharmaceutical Bulletin, 2004, 675-687.
  • the compound (X-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (IX-1) which is the starting material in production method 9
  • compound (XI-4) in which m1 is 1 and m2 is 2 is obtained, for example, from compound (XI-1) by the following production method 11 or Can be produced by a method according to the above.
  • the starting compound (XI-1) can be produced by a method known per se. Production method 11:
  • This step is a method for producing compound (XI-4) from compound (XI-1).
  • This step can be performed by a known method, for example, the method described in Chemistry-a European Journal, 2009, 9773-9784, or a method analogous thereto.
  • the compound (XI-4) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (IX-1) which is the starting material in production method 9
  • compound (XII-3) wherein m1 is 2 and m2 is 2 is obtained, for example, from compound (XII-1) by the following production method 12 or It can be manufactured by a method according to the above.
  • the starting compound (XII-1) can be produced by a method known per se. Production method 12:
  • Steps 12-1 to 12-2 This step is a method for producing compound (XII-3) from compound (XII-1).
  • This method can be performed using a known method, for example, a method described in WO2010 / 049146.
  • the thus obtained compound (XII-3) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (XIII-7) wherein Y is propane-1,3-diyl, m1 is 0 and m2 is 1, for example, the compound (XIII From 1) it can be produced by the following production method 13 or a method analogous thereto.
  • the starting compound (XIII-1) can be produced by a method known per se. Production method 13:
  • Step 13-1 This step is a method for producing compound (XIII-2) by reacting compound (XIII-1) with phosphonoacetic acid triethyl in the presence of a base. This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
  • Step 13-2 This step is a method for producing compound (XIII-3) by reacting compound (XIII-2) with trimethylsulfoxonium salt in the presence of a base. Examples of the trimethylsulfoxonium salt used in the reaction include trimethylsulfoxonium iodide, trimethylsulfoxonium bromide, trimethylsulfoxonium chloride, and the like.
  • the amount of the trimethylsulfoxonium salt to be used is generally 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (XIII-2).
  • the base used in the reaction include sodium hydride and potassium tert-butoxide.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (XIII-2).
  • the solvent used for the reaction include solvents that do not participate in the reaction, such as dimethyl sulfoxide, and these solvents may be mixed and used at an appropriate ratio. These reactions are usually carried out at room temperature to 100 ° C. for 5 to 72 hours. [Step 13-3] This step is a method for producing compound (XIII-4) by reducing compound (XIII-3).
  • This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
  • This step is a method for producing compound (XIII-5) by reacting compound (XIII-4) with triphenylphosphine and iodine in the presence of imidazole.
  • the amount of imidazole used in this reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (XIII-5).
  • the amount of triphenylphosphine used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (XIII-5).
  • the amount of iodine used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (XIII-5).
  • Step 13-5 This step is a method for producing compound (XIII-6) by reacting compound (XIII-5) with tert-butyl acetate and lithium diisopropylamide in the presence of N, N′-dimethylpropyleneurea.
  • the amount of tert-butyl acetate used in this reaction is usually 1 to 5 equivalents, preferably 1.5 to 4 equivalents, relative to 1 equivalent of compound (XIII-5).
  • the amount of lithium diisopropylamide used in this reaction is usually 1 to 5 equivalents, preferably 1.5 to 4 equivalents, per 1 equivalent of tert-butyl acetate.
  • substitute compounds for N, N′-dimethylpropyleneurea used in the reaction include hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, and tetramethylurea.
  • Step 13-6 This step is a method for producing compound (XIII-7) by reducing compound (XIII-6). This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
  • the thus obtained compound (VIII-7) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is the starting material in production method 8 compound (XIV-3) wherein Y is ethane-1,2-diyl is obtained, for example, from compound (IX-1) by the following production method 14 or It can manufacture by the method according to this.
  • Compound (IX-1) as a starting material can be produced by the method described in Production methods 10 to 12 or a method analogous thereto. Production method 14:
  • Step 14-1 This step is a method for producing compound (XIV-1) by reacting compound (IX-1) with triethyl phosphonoacetate in the presence of a base. This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
  • Step 14-2 This step is a method for producing compound (XIV-2) by reducing compound (XIV-1). This can be carried out according to the method described in Step 9-4 of Production Method 9.
  • Step 14-3 This step is a method for producing compound (XIV-3) from compound (XIV-2).
  • This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
  • the thus obtained compound (XIV-3) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is the starting material in production method 8
  • the starting compound (XIII-4) can be produced by the method described in Production Method 13 or a method analogous thereto.
  • This step is a method for producing compound (XV-1) by oxidizing compound (XIII-4).
  • This reaction can be performed using Dess-Martin oxidation or the like.
  • the oxidizing agent used in the reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (XIII-4).
  • Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform and dichloromethane, and these solvents may be used by mixing at an appropriate ratio.
  • These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
  • this reaction can be performed using a so-called Swan oxidation reaction (J. Org. Chem. 1976, 41, 3329.), 2-iodoxybenzoic acid (IBX) oxidation or the like.
  • Step 15-2 This step is a method for producing compound (XV-2) by reacting compound (XV-1) with (methoxymethyl) triphenylphosphonium chloride in the presence of a base. This can be carried out according to the method described in Step 9-1 of Production Method 9.
  • Step 15-3 This step is a method for producing compound (XV-3) by treating compound (XV-2) under acidic conditions. This can be carried out according to the method described in Step 9-2 of Production Method 9.
  • Step 15-4 This step is a method for producing compound (XV-4) by reducing compound (XV-3). This can be carried out according to the method described in Step 9-5 of Production Method 9.
  • the thus obtained compound (XV-4) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • compound (VIII-1) which is a starting material in production method 8
  • compound (XVI-5) wherein Y is butane-1,4-diyl is synthesized, for example, from compound (XVI-1) by the following production method 16 or It can manufacture by the method according to this.
  • the starting compound (XVI-1) can be produced by the method described in Production Methods 14 to 15 or a method analogous thereto.
  • Step 16-1 This step is a method for producing compound (XVI-2) by oxidizing compound (XVI-1). This can be carried out according to the method described in Step 15-1 of Production Method 15.
  • Step 16-2 This step is a method for producing compound (XVI-3) by reacting compound (XVI-2) with triethyl phosphonoacetate in the presence of a base. This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
  • Step 16-3 This step is a method for producing compound (XVI-4) by reducing compound (XVI-3). This can be carried out according to the method described in Step 9-4 of Production Method 9.
  • Step 16-4 This step is a method for producing compound (XVI-5) by reducing compound (XVI-4). This can be carried out according to the method described in Step 9-5 of Production Method 9.
  • the compound (XVI-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (XVII-1) in which R 2 is (e) C 1-6 alkylcarbonyl or C 3-8 cycloalkylcarbonyl is, for example, in accordance with the following Production method 17 or the like. It can be manufactured by a method. Production method 17:
  • Step 17-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 17-2 This step is a method for producing compound (XVII-1) by reacting compound (IV-2) with compound (XVII-2). This reaction can be carried out using the method described in Step 6-4 of Production Method 6.
  • R 2 is di-C 1-6 alkylamino carbonyl
  • compound (XVIII-1) and C 1-6 compound alkylaminocarbonyl (XVIII-2) is, for example, the following It can be produced by production method 18 or a method analogous thereto.
  • Step 18-1 This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 18-2 This step is a reaction for obtaining compound (XVIII-1) by reacting compound (IV-2) with compound (XVIII-3) in the presence of a carbonylating reagent.
  • the carbonylation reagent used here is 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, triphosgene, etc.
  • the amount of reagent used is usually 1 to 3 equivalents, preferably 1 Is equivalent.
  • a base such as triethylamine, pyridine or N-methylmorpholine may coexist.
  • the solvent used in the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these solvents may be used by mixing at an appropriate ratio. These reactions are usually carried out at room temperature to 80 ° C. for 30 minutes to 48 hours.
  • Step 18-3 This step is a reaction for obtaining the compound (XVIII-2) by reacting the compound (IV-2) with the compound (XVIII-4).
  • a base such as triethylamine, pyridine or N-methylmorpholine may coexist.
  • the solvent used in the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these solvents may be used by mixing at an appropriate ratio. These reactions are usually carried out at room temperature to 80 ° C. for 30 minutes to 24 hours.
  • Ud is a leaving group
  • Z is a single bond or C 1-3 alkanediyl
  • R 32 is C 1-3 alkyl
  • A, R 11 , R 12 , R 13 , R 2 and R 3 are as defined above.
  • Examples of the “leaving group” represented by Ud include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
  • C 1-3 alkyl represented by R 32 is linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl and isopropyl.
  • C 1-3 alkanediyl represented by Z represents a divalent hydrocarbon group having 1 to 3 carbon atoms, and examples thereof include methanediyl, ethane-1,2-diyl, and propane-1,3-diyl. Can be mentioned.
  • Step 19-1 This step is a reaction in which the compound (XIX-9) is obtained from the compound (XIX-10) by hydrolysis with a base. This reaction can be carried out using the method described in Process 3-1, Step 3-1.
  • Step 19-2 This step is a method for producing compound (XIX-7) by condensing compound (XIX-9) and compound (XIX-8). This reaction can be carried out using the method described in Step 3-2 of Production Method 3.
  • Step 19-3 This step is a method for producing compound (XIX-2) by reacting compound (XIX-7) with a reducing agent. This reaction can be carried out using the method described in Process 9-5 of Production Method 9.
  • Step 19-4 This step is a method for producing compound (XIX-1) by reacting compound (XIX-2) with R 32 —CHO or R 3 —Ud. This reaction can be carried out using the method described in Step 6-2 or 6-3 of Production Method 6.
  • Step 19-5 This step is a method for producing compound (XIX-6) by treating compound (XIX-7) under acidic conditions. This reaction can be carried out using the method described in Process 4-1, Production Method 4.
  • Step 19-6 This step is a method for producing compound (XIX-5) from compound (XIX-6). This reaction can be carried out according to the methods described in Production Methods 4 to 7.
  • the compound (XIX-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • Step 19-7 This step is a method for producing compound (XIX-4) by allowing a reducing agent to act on compound (XIX-5).
  • This reaction can be carried out using the method described in Process 9-5 of Production Method 9.
  • Step 19-8 This step is a method for producing compound (XIX-3) by allowing R 32 —CHO or R 3 —Ud to act on compound (XIX-4). This reaction can be carried out using the method described in Step 6-2 or 6-3 of Production Method 6.
  • NH silica gel column chromatography refers to column chromatography separation and purification using NH 2 type silica gel (Chromatolex NH 2 type, Fuji Silysia Chemical Ltd.). The ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • MS mass spectrum
  • PlatformMLC Waters
  • LCMS-2010EV Shiadzu
  • LCMS-IT-TOF Shiadzu
  • ESI Electron-ray Ionization
  • APCI Admospheric Pressure Chemical Ionization
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (—Boc), a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated is observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment peak. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
  • Compound name is ACD / Name ver. It was named using 12.01 (trade name) or the like.
  • Dess-Martin periodinane (1.1 g) was added to a chloroform (10 ml) solution of the compound (526 mg) obtained in Reference Example 3-3 under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature.
  • the reaction mixture was diluted with chloroform, washed with a mixed solution of saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate.
  • n-butyllithium (2.76 M hexane solution, 3.9 mL) was added dropwise to a tetrahydrofuran (27 ml) solution of diisopropylamine (1.5 ml) under ice cooling, and the mixture was stirred for 30 minutes.
  • the reaction mixture was cooled at ⁇ 78 ° C., tert-butyl acetate (1.5 ml) was added, and the mixture was stirred for 30 min.
  • Dess-Martin periodinane (1.3 g) was added to a chloroform solution of the compound (600 mg) obtained in Reference Example 5-3 under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature.
  • the reaction mixture was diluted with chloroform, washed with a mixed solution of saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 1-formyl-6-azaspiro [2.5] octane-6-carboxylate.
  • tert-butyl 1- (2-oxoethyl) -6-azaspiro [2.5] octane-6-carboxylate was obtained.
  • the obtained tert-butyl 1- (2-oxoethyl) -6-azaspiro [2.5] octane-6-carboxylate was dissolved in methanol (5 ml). The reaction mixture was ice-cooled, sodium borohydride (38 mg) was added, and the mixture was stirred for 2 hr while warming to room temperature.
  • Lithium borohydride (87 mg) was added to a toluene-tetrahydrofuran (1: 1, 14 ml) solution of the compound (470 mg) obtained in Reference Example 8-4, and the mixture was stirred at 60 ° C. for 16 hours.
  • the reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off.
  • Triethylamine (4.9 ml) was added to a chloroform (90 ml) solution of ethyl 3- (7-azaspiro [3.5] non-2-yl) propanoate obtained, and isopropyl chloroformate (2. 4 ml) in chloroform (24 ml) was added dropwise. The reaction was stirred for 4 hours while warming to room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off.
  • 2-Fluoro-4-hydroxybenzoic acid 1.0 g is dissolved in N, N-dimethylformamide (32 ml), and azetidine (560 ⁇ l), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 1.6 g) and 1-hydroxybenzotriazole monohydrate (1.28 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off.
  • Methyl 5-chloropyrazine-2-carboxylate (2.4 g) was dissolved in methanol (140 mL), and 28% sodium methoxide methanol solution (2.7 mL) was added under ice cooling. The ice bath was removed and the mixture was stirred for 1 hour, and the reaction solution was evaporated under reduced pressure. Saturated aqueous ammonium chloride was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and then evaporated under reduced pressure to obtain the title compound (2.1 g).
  • Examples 2-2 to 2-6 also show the compounds obtained in Reference Examples 2-4 and 11-2 and the compounds obtained in Reference Examples 36-1, 37-1, 38-1, and 39-1.
  • synthesis was performed according to the method described in Example 2-1 using 2-bromo-5- (1H-1,2,3-triazol-1-yl) pyridine.
  • the structures, NMR data, and MS data of these compounds are shown in Tables 2-1 and 2-2.
  • Examples 3-2 to 3-96 below also refer to Reference Examples 10-2, 11-4, 12-4, 13-2, 14-2, 15-2, 16-2, 18-3, 19-3. 20-2, 21-2, 22-3, 23-2, 24-2, 25-3, 26-2, 27-2, 28-2, 29-2, 30-2, 31-2, 32 -3, 40-8, 41-2, 42-2, 43-1, 44-2, 45-2, 50-4, 51-2 and the corresponding amine compound Synthesized according to the method described in Example 3-1. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 to 3-17.
  • Examples 4-2 to 4-19 below are also the same as Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9. 1-11, 2-1 and 2-2 and the corresponding chloropyrimidine compound were synthesized according to the method described in Example 4-1.
  • the structures, NMR data, and MS data of these compounds are shown in Tables 4-1 to 4-3.
  • Examples 5-2 to 5-3 were also synthesized according to the method described in Example 5-1 using the compound obtained in Example 1-3 and the corresponding pyridine compound. .
  • the structure, NMR data and MS data of these compounds are shown in Table 5-1.
  • Example 6-1 1-methylcyclopropyl 2- ⁇ 3- [4- (methylsulfonyl) phenoxy] propyl ⁇ -7-azaspiro [3.5] nonane-7-carboxylate
  • Examples 6-2 to 6-17 below also correspond to the compounds obtained in Examples 1-1, 1-3, 1-9, 1-11, 1-12, 1-18, and 12-1. This was synthesized according to the method described in Example 6-1 using the carbamate reagent or sulfonyl chloride. The structures, NMR data, and MS data of these compounds are shown in Tables 6-1 to 6-3.
  • Example 7-2 to 7-14 below are also described in Example 7-1 using the compounds obtained in Examples 1-1, 1-3, 1-9 and the corresponding alcohol compounds. Synthesized according to the method. The structures, NMR data, and MS data of these compounds are shown in Tables 7-1 and 7-2.
  • reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure.
  • Example 1-11 The compound (515 mg) obtained in Example 1-11 was used for reaction and purification in the same manner as in Reference Example 12-2 to give 2- (3- ⁇ [6- (methylsulfonyl) pyridin-3-yl]. Oxy ⁇ propyl) -7-azaspiro [3.5] nonane (485 mg) was obtained.
  • Examples 15-2 to 15-3 below were also synthesized according to the method described in Example 15-1 using the compound obtained in Reference Example 33-1 and the corresponding amine compound. .
  • Table 8-1 shows the structures, NMR data, and MS data of these compounds.
  • the compound (500 mg) obtained above was dissolved in a mixed solution of tetrahydrofuran and N, N-dimethylformamide (1: 1) (20 mL), and sodium hydride (60%, dispersed in liquid paraffin) under ice-cooling. (102 mg) was added. After stirring for 10 minutes, 2- (2-chloroethoxy) tetrahydro-2H-pyran (375 ⁇ L) was added, the ice bath was removed, and the mixture was stirred for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off.
  • the compound (54 mg) obtained above was dissolved in ethanol (1 mL), p-toluenesulfonic acid monohydrate (4 mg) was added, and the mixture was stirred overnight at room temperature.
  • Example 18-1 The compound (37 mg) obtained in Example 18-1 was dissolved in N, N-dimethylformamide (850 ⁇ L), sodium hydride (60% w / w) (5.1 mg) was added, and the mixture was stirred for 20 minutes. To this was added iodomethane (11 ⁇ L) and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and the aqueous layer was extracted with a mixed solvent of ethyl acetate and normal hexane. Combined with the previous organic layer, the solvent was distilled off under reduced pressure through a phase separator, and the resulting residue was purified by preparative HPLC to obtain the title compound (18 mg).
  • Example 3-1 The compound (80 mg) obtained in Example 3-1 was used for reaction and purification in the same manner as in Reference Example 12-2 to give 4- [3- (7-azaspiro [3.5] non-2- Yl) propoxy] -2-fluoro-N- (2-hydroxyethyl) benzamide (74 mg). Further, sodium triacetoxyborohydride (75 mg) was added to a dimethyl sulfoxide-tetrahydrofuran solution (1: 1, 2 mL) of the compound obtained above (50 mg), pivalaldehyde (25 mg), and acetic acid (25 ⁇ L) for 3 hours. Stir.
  • the compound (88 mg) obtained above was dissolved in dimethyl sulfoxide (1 mL), sodium methanesulfinate (45 mg), N, N′-dimethylethylenediamine (9 ⁇ L) and copper trifluoromethanesulfonate (I) benzene complex ( 12 mg) was added and the mixture was stirred at 110 ° C. for 5 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the aqueous layer was extracted with a mixed solvent of ethyl acetate and normal hexane.
  • Test example 1 The compound of the present invention was added to human GPR119-expressing cells, and GPR119 agonist activity was evaluated using the amount of cAMP produced by the cells as an index.
  • Human GPR119 (NM — 178471) was amplified by polymerase chain reaction (PCR) using KOD-plus polymerase using human MTC multi-tissue cDNA panel (Clontech) as a template.
  • PCR polymerase chain reaction
  • a human GPR119 amplification product was inserted into pcDNA5 / FRT / TO (Invitrogen) as an insert, and a cell line capable of inducing expression of the human GPR119 gene in a tetracycline dose-dependent manner using the Flp-In T-Rex system was prepared.
  • Tetracycline having a final concentration of 10 ng / ml was added to the cell line to induce expression of human GPR119.
  • Cells were collected 24 hours after the expression-inducing stimulation and suspended in assay buffer (D-MEM (Invitrogen), 1 mM 3-Isobutyl-1-methylxantine (Sigma), 0.01% bovine serum albumin (Sigma)). Later, it was seeded on a 96-well half area plate (Corning) at 5000 cells / 15 ⁇ l. 15 ⁇ l of a test compound solution dissolved in assay buffer was added to each well, incubated at 37 ° C.
  • the compound concentration that activates 50% of the maximum activated GPR119 activity as 100% from the value obtained by subtracting the cAMP concentration in the presence of DMSO from the maximum cAMP concentration (Emax) under the high dose of the test compound (EC 50 ) was calculated.
  • Emax maximum activation rate of the test compound
  • cAMP concentration increase rate (% stimulation) in the presence of the test compound was calculated with the cAMP concentration in the presence of DMSO as 100%.
  • Results Tables 10-1 to 10-3 show the GPR119 agonist activities calculated based on the measurement results obtained by conducting the above tests on the compounds of the present invention.
  • Formulation examples of the compound of the present invention are shown below.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Component Compound represented by formula (I) 10mg Lactose 700mg Corn starch 274mg HPC-L 16mg 1000mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulated pore diameter: 0.5 to 1 mm), and then dried.
  • the obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.
  • HPC-L low-viscosity hydroxypropylcellulose
  • Formulation Example 2 A powder for capsule filling containing the following components is produced.
  • Component Compound represented by formula (I) 10mg Lactose 79mg Corn starch 10mg Magnesium stearate 1mg 100mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.
  • Formulation Example 3 A capsule filling granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 15mg Lactose 90mg Cornstarch 42mg HPC-L 3mg 150mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried.
  • the obtained dried granule is sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.
  • HPC-L low-viscosity hydroxypropylcellulose
  • Formulation Example 4 A tablet containing the following ingredients is produced.
  • a compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.
  • Formulation Example 5 The intravenous formulation is produced as follows. 100 mg of the compound represented by formula (I) Saturated fatty acid glyceride 1000ml Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
  • the compound of the present invention has an excellent GPR119 agonist activity, and according to the present invention, it is possible to provide a pharmaceutical effective for the prevention or treatment of diseases derived from diabetes, thereby reducing the burden on the patient and contributing to the development of the pharmaceutical industry. Is expected to do.

Abstract

Provided is a compound represented by general formula (I) and having an excellent GPR119 agonistic activity, or a pharmaceutically acceptable salt thereof. [In general formula (I), m1 represents an integer of 0-2; m2 represents an integer of 1-2; the ring represented by A represents a benzene ring or a 6-membered heteroaromatic ring; X represents -O- or -NR3-; and Y represents a C1-6 alkanediyl.]

Description

アザスピロアルカン化合物Azaspiroalkane compounds
　本発明は、ＧＰＲ１１９アゴニストに関する。 The present invention relates to a GPR119 agonist.
　ＧＰＲ１１９は天然の長鎖脂肪酸アミドであるオレイルエタノールアミド等を内因性リガンドとするＧ蛋白結合型受容体（ＧＰＣＲ）である。本受容体は膵臓のインスリン産生細胞である膵β細胞およびインクレチン分泌に関わる小腸内分泌細胞に高度に発現していることが知られている。膵臓ではＧＰＲ１１９アゴニストなどの刺激により活性化され、高血糖依存的にインスリン分泌を亢進することが報告されている。加えて小腸内分泌細胞で活性化されることにより抗糖尿病ホルモンであるＧｌｕｃａｇｏｎ－ｌｉｋｅ　ｐｅｐｔｉｄｅ　１（ＧＬＰ－１）等に代表されるインクレチン類の分泌を促し、膵臓β細胞からのインスリン分泌を間接的に亢進することが報告されている。膵臓への直接作用、小腸からのインクレチン分泌を介した間接作用の両面から高血糖依存的なインスリン分泌、ひいては血糖低下作用を発揮するため、低血糖リスクは極めて低いと想定される。また、ｄｂ／ｄｂ糖尿病モデルマウスでは膵臓β細胞におけるＧＰＲ１１９の持続的な活性化によって膵保護を主体とした糖尿病発症遅延作用が報告されている。一方、高脂肪食負荷ラットにおいてはＧＰＲ１１９アゴニストを用いた検討により摂食抑制、胃排出遅延等を介した体重増加抑制作用が報告されており、抗肥満効果を併せ持つことも期待される。以上のような知見から、ＧＰＲ１１９アゴニストは膵保護作用、抗肥満作用を併せ持つ新規抗糖尿病薬となりうることが期待される（非特許文献１～３参照）。 GPR119 is a G protein-coupled receptor (GPCR) having an endogenous ligand such as oleylethanolamide, which is a natural long chain fatty acid amide. It is known that this receptor is highly expressed in pancreatic β cells, which are insulin-producing cells of the pancreas, and small intestinal endocrine cells involved in incretin secretion. It has been reported that the pancreas is activated by stimulation with a GPR119 agonist and the like and enhances insulin secretion in a hyperglycemic-dependent manner. In addition, it is activated by small intestinal endocrine cells to promote the secretion of incretins such as Glucagon-like peptide 1 (GLP-1), which is an anti-diabetic hormone, and indirectly secretes insulin secretion from pancreatic β cells Has been reported to be enhanced. The hypoglycemia risk is assumed to be extremely low because it exerts hyperglycemic-dependent insulin secretion and, in turn, a hypoglycemic action from both the direct action on the pancreas and the indirect action through incretin secretion from the small intestine. In addition, in the db / db diabetic model mouse, a diabetes onset delay action mainly composed of pancreatic protection has been reported by continuous activation of GPR119 in pancreatic β cells. On the other hand, in high fat diet-fed rats, studies using a GPR119 agonist have been reported to inhibit body weight gain through suppression of feeding, delayed gastric emptying, and the like, and are also expected to have an anti-obesity effect. From the above findings, it is expected that GPR119 agonist can be a novel anti-diabetic drug having both pancreatic protective action and anti-obesity action (see Non-Patent Documents 1 to 3).
　ＧＰＲ１１９アゴニストとしては、前述の内因性リガンドであるオレイルエタノールアミド（ＯＥＡ）が知られている。またある種のビピペリジニル誘導体（特許文献１参照）やピリミジニル誘導体（特許文献２及び非特許文献４参照）、オキサジアゾリル誘導体（特許文献３参照）、チアゾリル誘導体（特許文献４参照）など、いくつかの化合物の報告があるが、本発明の化合物の開示はない。さらに、ある種のシクロプロパン誘導体（特許文献５～６及び非特許文献５参照）やある種のジアザスピロアルカン誘導体（特許文献７～８参照）も報告されているが、本発明の化合物の開示はない。また、ある種のアザスピロアルカン誘導体（特許文献９参照）の合成が示唆されているが、本発明の化合物の開示はない。 As the GPR119 agonist, oleylethanolamide (OEA), which is the aforementioned endogenous ligand, is known. In addition, some compounds such as certain bipiperidinyl derivatives (see Patent Document 1), pyrimidinyl derivatives (see Patent Document 2 and Non-Patent Document 4), oxadiazolyl derivatives (see Patent Document 3), thiazolyl derivatives (see Patent Document 4), etc. However, there is no disclosure of the compound of the present invention. Furthermore, certain types of cyclopropane derivatives (see Patent Documents 5 to 6 and Non-Patent Document 5) and certain diazaspiroalkane derivatives (see Patent Documents 7 to 8) have been reported. There is no disclosure. Moreover, although the synthesis | combination of a certain kind of azaspiroalkane derivative (refer patent document 9) is suggested, there is no indication of the compound of this invention.
ＷＯ２００８／０７６２４３号WO2008 / 076243 ＷＯ２００７／０３５３５５号WO2007 / 035355 ＷＯ２００７／１１６２２９号WO2007 / 116229 ＷＯ２００８／０８３２３８号WO2008 / 083238 ＷＯ２００９／１２９０３６号WO2009 / 129036 ＷＯ２０１１／０１９５３８号WO2011 / 019538 ＷＯ２００８／０３３４６０号WO2008 / 033460 ＷＯ２０１０／１２３０１８号WO2010 / 123018 ＷＯ２０１０／００９１９５号WO2010 / 009195
　本発明の目的は、優れたＧＰＲ１１９アゴニストを提供することである。 An object of the present invention is to provide an excellent GPR119 agonist.
　本発明者らは、上記課題を達成すべく鋭意検討を重ねた結果、下記一般式（Ｉ）で表される化合物が、優れたＧＰＲ１１９アゴニスト作用を有することを見出した。 As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that a compound represented by the following general formula (I) has an excellent GPR119 agonistic action.
　すなわち、本発明は、
（１）下記一般式（Ｉ） That is, the present invention
(1) The following general formula (I)
Figure JPOXMLDOC01-appb-C000006
 （式（Ｉ）中、
　ｍ１は、０～２の整数を示し、
　ｍ２は、１～２の整数を示し、
　Ａで表される環は、ベンゼン環又は６員のヘテロ芳香環を示し、
　Ｒ11、Ｒ12及びＲ13は、同一に又は異なって置換基群Ｚ１から選ばれる基を示し、
　置換基群Ｚ１は、水素原子、ハロゲン原子、カルバモイル、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、アリール、ヘテロアリール、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）、ジＣ1-6アルキルアミノ、モノＣ1-6アルキルアミノカルボニル及びジＣ1-6アルキルアミノカルボニルからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、ヒドロキシ、ハロゲン原子、カルバモイル、シアノ及びオキソからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル、Ｃ1-6アルキルスルフィニル（該Ｃ1-6アルキルスルフィニルは、置換されていないか、１個のヒドロキシで置換されている。）及びＣ1-6アルキルスルホニル（該Ｃ1-6アルキルスルホニルは、置換されていないか、１個のヒドロキシで置換されている。）の基からなる群を示し、
　Ｘは、-Ｏ-又は-ＮＲ3-を示し、
　　Ｒ3は、水素原子又はＣ1-4アルキルを示し、
　Ｙは、Ｃ1-6アルカンジイルを示し、
　Ｒ2は、
　（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、Ｃ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、トリフルオロメチル及びＣ1-6アルキルからなる群より選ばれる１個の基で置換されている。）及びアリールからなる群より選ばれる１個の基で置換されている。］、ハロＣ1-6アルキル若しくはＣ3-8シクロアルキル、
　（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝、
　（ｃ）下記式（β）で表される５又は６員のヘテロアリール
Figure JPOXMLDOC01-appb-C000006
 (In the formula (I),
m1 represents an integer of 0 to 2,
m2 represents an integer of 1 to 2,
The ring represented by A represents a benzene ring or a 6-membered heteroaromatic ring,
R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z1;
Substituent group Z1 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl are unsubstituted or hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy is not substituted) or is substituted by one hydroxy.), di-C 1-6 alkylamino, mono-C 1-6 alkylaminocarbonyl and di-C 1-6 alkyl The same from the group consisting of amino carbonyl or different substituted with 1 to 2 groups selected. A saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of hydroxy, halogen atom, carbamoyl, cyano and oxo, the same or different) Monosaturated heterocyclylaminocarbonyl, C 1-6 alkylsulfinyl (wherein the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) and C 1-6 Represents a group consisting of alkylsulfonyl groups, wherein the C 1-6 alkylsulfonyl is unsubstituted or substituted with one hydroxy;
X represents —O— or —NR 3 —;
R 3 represents a hydrogen atom or C 1-4 alkyl,
Y represents C 1-6 alkanediyl;
R 2 is
(A) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted, trifluoromethyl and C Substituted with one group selected from the group consisting of 1-6 alkyl) and one group selected from the group consisting of aryl. ] Halo C 1-6 alkyl or C 3-8 cycloalkyl,
(B) —COOR 21 {R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). },
(C) 5- or 6-membered heteroaryl represented by the following formula (β)
Figure JPOXMLDOC01-appb-C000007
 （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）、
　（ｄ）Ｃ1-6アルキルスルホニル若しくはＣ3-8シクロアルキルスルホニル、
　（ｅ）Ｃ1-6アルキルカルボニル（該Ｃ1-6アルキルカルボニルは、置換されていないか、１個のＣ3-8シクロアルキルで置換されている。）若しくはＣ3-8シクロアルキルカルボニル（該Ｃ3-8シクロアルキルカルボニルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）又は
　（ｆ）Ｃ1-6アルキルアミノカルボニル
を示す。）
で表される化合物又はその製薬学的に許容される塩であるを提供することである。
Figure JPOXMLDOC01-appb-C000007
 (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected identically or differently from the group consisting of -6 alkoxy),
(D) C 1-6 alkylsulfonyl or C 3-8 cycloalkylsulfonyl,
(E) C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl is unsubstituted or substituted with one C 3-8 cycloalkyl) or C 3-8 cycloalkylcarbonyl ( The C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with one C 1-6 alkyl.) Or (f) C 1-6 alkylaminocarbonyl. )
Or a pharmaceutically acceptable salt thereof.
（２）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ11、Ｒ12及びＲ13は、同一に又は異なって置換基群Ｚ２から選ばれる基を示し、
　置換基群Ｚ２は、水素原子、ハロゲン原子、カルバモイル、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、アリール、ヘテロアリール、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-6アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル及びＣ1-6アルキルスルホニルの基からなる群を示し、
　Ｒ2が、
　（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、トリフルオロメチル及びＣ1-6アルキルからなる群より選ばれる１個の基で置換されている。）で置換されている。］、ハロＣ1-6アルキル若しくはＣ3-8シクロアルキル、
　（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝又は
　（ｃ）下記式（β）で表される５又は６員のヘテロアリール (2) As another aspect of the present invention,
In the general formula (I),
R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z2;
Substituent group Z2 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl are unsubstituted or hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy is not substituted) or, one hydroxy substituted with.) and di C 1-6 1 ~ 2 groups that are identical to or different selected from the group consisting of alkylamino It has been replaced. ], Saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 hydroxy), monosaturated heterocyclylaminocarbonyl and C 1-6 alkylsulfonyl groups Indicate
R 2 is
(A) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or single C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or trifluoro Substituted with one group selected from the group consisting of methyl and C 1-6 alkyl. ] Halo C 1-6 alkyl or C 3-8 cycloalkyl,
(B) —COOR 21 {R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). } Or (c) 5- or 6-membered heteroaryl represented by the following formula (β)
Figure JPOXMLDOC01-appb-C000008
 （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）
を示す（１）に記載の化合物又はその製薬学的に許容される塩を提供することである。
Figure JPOXMLDOC01-appb-C000008
 (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
Or a pharmaceutically acceptable salt thereof according to (1).
（３）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ2が、（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のトリフルオロメチルで置換されている。）で置換されている。］又はハロＣ1-6アルキル
を示す（１）～（２）のいずれかに記載の化合物又はその製薬学的に許容される塩を提供することである。 (3) As another aspect of the present invention,
In the general formula (I),
R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted) Or is substituted with 1 trifluoromethyl). ] Or a pharmaceutically acceptable salt thereof according to any one of (1) to (2), which represents halo C 1-6 alkyl.
（４）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ2が、（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝
を示す（１）～（２）のいずれかに記載の化合物又はその製薬学的に許容される塩を提供することである。 (4) As another aspect of the present invention,
In the general formula (I),
R 2 is (b) -COOR 21 {R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 Cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). }
The compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
（５）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ2が、（ｂ）－ＣＯＯＲ21｛Ｒ21は、メチル［該メチルは、置換されていないか、１個のシクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）で置換されている。］、イソプロピル、イソブチル、tert-ブチル（該tert-ブチルは、置換されていないか、１～２個のフッ素原子で置換されている。）、ネオペンチル、シクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）又はシクロペンチルを示す。｝
を示す（１）～（２）又は（４）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。 (5) As another aspect of the present invention,
In the general formula (I),
R 2 is (b) -COOR 21 {R 21 is methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl Is replaced by ], Isopropyl, isobutyl, tert-butyl (the tert-butyl is unsubstituted or substituted with 1 to 2 fluorine atoms), neopentyl, cyclopropyl (the cyclopropyl is not substituted) Or substituted with 1 methyl) or cyclopentyl. }
(1) to (2) or (4), or a pharmaceutically acceptable salt thereof.
（６）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ2が、（ｃ）下記式（β）で表される５又は６員のヘテロアリール (6) As another aspect of the present invention,
In the general formula (I),
R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula (β)
Figure JPOXMLDOC01-appb-C000009
 （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）
を示す（１）～（２）のいずれかに記載の化合物又はその製薬学的に許容される塩を提供することである。
Figure JPOXMLDOC01-appb-C000009
 (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
The compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
（７）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ2が、（ｃ）下記式（β）で表される５又は６員のヘテロアリールを示し、 (7) As another aspect of the present invention,
In the general formula (I),
R 2 represents (c) a 5- or 6-membered heteroaryl represented by the following formula (β),
Figure JPOXMLDOC01-appb-C000010
 　ここで、該式（β）で表される５又は６員のヘテロアリールが、オキサジアゾリル、ピリジル又はピリミジニル（該オキサジアゾリル、ピリジル及びピリミジニルは、置換されていないか、フッ素原子、塩素原子、メチル、エチル、イソプロピル及びシクロプロピルからなる群より選ばれる１個の基で置換されている。）
を示す（１）～（２）又は（６）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。
Figure JPOXMLDOC01-appb-C000010
 Here, the 5- or 6-membered heteroaryl represented by the formula (β) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted, fluorine atom, chlorine atom, methyl, ethyl , Substituted with one group selected from the group consisting of isopropyl and cyclopropyl.)
(1) to (2) or (6), or a pharmaceutically acceptable salt thereof.
（８）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ2が、（ｅ）Ｃ1-6アルキルカルボニル（該Ｃ1-6アルキルカルボニルは、置換されていないか、１個のＣ3-8シクロアルキルで置換されている。）又はＣ3-8シクロアルキルカルボニル（該Ｃ3-8シクロアルキルカルボニルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）
を示す（１）～（２）のいずれかに記載の化合物又はその製薬学的に許容される塩を提供することである。 (8) As another aspect of the present invention,
In the general formula (I),
R 2 is (e) a C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl is unsubstituted or substituted with one C 3-8 cycloalkyl) or C 3-8 Cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with 1 C 1-6 alkyl)
The compound according to any one of (1) to (2) or a pharmaceutically acceptable salt thereof is provided.
（９）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　ｍ１が、１を示し、
　ｍ２が、１を示し、
　Ｘが、-Ｏ-を示し、
　Ｙが、Ｃ3-4アルカンジイル
を示す（１）～（８）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。 (9) As another aspect of the present invention,
In the general formula (I),
m1 represents 1,
m2 represents 1,
X represents —O—,
Y is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (8), wherein C 3-4 alkanediyl.
（１０）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ａで表される環が、ベンゼン環又はピリジン環
を示す（１）～（９）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。 (10) As another aspect of the present invention,
In the general formula (I),
The ring represented by A is to provide the compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9), wherein the ring represented by A represents a benzene ring or a pyridine ring.
（１１）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ｒ11が、カルバモイル、モノＣ1-6アルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-6アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル（該ジＣ1-6アルキルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル又はＣ1-6アルキルスルホニルを示し、
　Ｒ12及びＲ13が、同一に又は異なって水素原子、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる基
を示す（１）～（１０）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。 (11) As another aspect of the present invention,
In the general formula (I),
R 11 is carbamoyl, mono C 1-6 alkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl is unsubstituted or is hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy Is unsubstituted or substituted with 1 hydroxy) and is substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino. ], Mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is unsubstituted or substituted with one hydroxy). C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl, saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy), monosaturated heterocyclylaminocarbonyl Or C 1-6 alkylsulfonyl,
The compound according to any one of (1) to (10), wherein R 12 and R 13 are the same or different and each represents a group selected from the group consisting of a hydrogen atom, a halogen atom and C 1-6 alkyl, or a compound thereof It is to provide a pharmaceutically acceptable salt.
（１２）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ａで表される環が、ベンゼン環を示し、
　Ｒ11が、カルバモイル、メチルアミノカルボニル（該メチルアミノカルボニルは、置換されていないか、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、エチルアミノカルボニル［該エチルアミノカルボニルは、置換されていないか、ヒドロキシ、メトキシ、エトキシ（該エトキシは、置換されていないか、１個のヒドロキシで置換されている。）及びＮ，Ｎ－ジメチルアミノからなる群より選ばれる１個の基で置換されている。］、ｎ－プロピルアミノカルボニル（該ｎ－プロピルアミノカルボニル、置換されていないか、１～２個のヒドロキシで置換されている。）、イソプロピルアミノカルボニル（該イソプロピルアミノカルボニルは、置換されていないか、１～２個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル（該Ｎ－エチル－Ｎ－メチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｎ－シクロプロピル－Ｎ－メチルアミノカルボニル、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、オキセタン-３-イルアミノカルボニル又はメチルスルホニルを示し、
　ここで、該Ｒ11は、上記ベンゼン環のパラ位に置換し、
　Ｒ12及びＲ13が、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基を示し、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環のオルト位又はメタ位に置換する
（１）～（１１）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。 (12) As another aspect of the present invention,
In the general formula (I),
The ring represented by A represents a benzene ring;
R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [the ethylamino Carbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (wherein the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with 1 group. ], N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), Shows an oxetane-3-yl-aminocarbonyl or methylsulfonyl,
Here, R 11 is substituted at the para-position of the benzene ring,
R 12 and R 13 are the same or different and each represents a group selected from the group consisting of a hydrogen atom, a fluorine atom and methyl;
Wherein R 12 and R 13 are independently substituted at the ortho-position or meta-position of the benzene ring, or a pharmaceutically acceptable compound thereof according to any one of (1) to (11) Providing salt.
（１３）本発明の他の態様としては、
　前記一般式（Ｉ）において、
　Ａで表される環が、ピリジン環を示し、
　Ｒ11が、エチルアミノカルボニル（該エチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル又はメチルスルホニルを示し、
　Ｒ12が、水素原子を示し、
　Ｒ13が、水素原子
を示す（１）～（１１）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を提供することである。 (13) As another aspect of the present invention,
In the general formula (I),
The ring represented by A represents a pyridine ring;
R 11 represents ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl;
R 12 represents a hydrogen atom,
R 13 is to provide a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (11), in which R 13 represents a hydrogen atom.
（１４）本発明の他の態様としては、
　以下に示す、（１）に記載の化合物又はその製薬学的に許容される塩を提供することである：
ｔｅｒｔ－ブチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　９－｛２－［４－（メチルスルホニル）フェノキシ］エチル｝－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート、
ｔｅｒｔ－ブチル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－｛３－［４－（アゼチジン－１－イルカルボニル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－（３－｛３－フルオロ－４－［（２－メトキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－（３－｛［５－（メチルスルホニル）ピリジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－｛３－［４－（シクロプロピルカルバモイル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－［３－（４－カルバモイル－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛［６－（シクロプロピルカルバモイル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（３－フルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（３－フルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（シアノメチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（１，３－ジヒドロキシプロパン－２－イル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（４－｛［（２Ｒ）－２，３－ジヒドロキシプロピル］カルバモイル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［３－フルオロ－４－（オキセタン－３－イルカルバモイル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（４－カルバモイル－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）（メチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［３－フルオロ－４－（ピロリジン－１－イルカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛［６－（シクロプロピルカルバモイル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（｛６－［（２－ヒドロキシエチル）カルバモイル］ピリジン－３－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛［５－（シクロプロピルカルバモイル）ピリジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（３－フルオロ－４－｛［２－（２－ヒドロキシエトキシ）エチル］カルバモイル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（４－｛［２－（ジメチルアミノ）エチル］カルバモイル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－メトキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［４－（アゼチジン－１－イルカルボニル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３－フルオロ－４－［（３－ヒドロキシアゼチジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）－２－メチルフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）－２－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛３，５－ジフルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
４－｛３－［７－（３，３－ジメチルブタノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
Ｎ－ｔｅｒｔ－ブチル－２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキサミド、
１，１－ジフルオロ－２－メチルプロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
４－｛３－［７－（シクロペンチルメチル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
２－フルオロ－Ｎ－（２－ヒドロキシエチル）－４－（３－｛７－［３－（プロパン－２－イル）－１，２，４－オキサジアゾール－５－イル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンズアミド、
４－｛３－［７－（２，２－ジメチルプロパノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
１－フルオロ－２－メチルプロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（３－フルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（３－フルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン-2-イル　2-(3-{2,5-ジフルオロ-4-[(2-ヒドロキシエチル)カルバモイル]フェノキシ}プロピル)-7-アザスピロ[3.5]ノナン-7-カルボキシラート、
プロパン－２－イル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（シアノメチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（３，３－ジフルオロアゼチジン－１－イル）カルボニル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２－フルオロ－Ｎ－（２－ヒドロキシエチル）－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンズアミド、
１－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）（メチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［３－フルオロ－４－（モルホリン－４－イルカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［３－フルオロ－４－（モルホリン－４－イルカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３－フルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３，５－ジフルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛２，５－ジフルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）（メチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（４－｛［（２Ｓ）－２－カルバモイルピロリジン－１－イル］カルボニル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
Ｎ－シクロプロピル－２，５－ジフルオロ－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンズアミド、
プロパン－２－イル　２－（３－｛２，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛２，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛３，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛３，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（シアノメチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［（３，３－ジフルオロアゼチジン－１－イル）カルボニル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（３－フルオロ－４－｛［２－（メチルアミノ）－２－オキソエチル］カルバモイル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（４－｛［２－（ジメチルアミノ）－２－オキソエチル］カルバモイル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛［５－（モルホリン－４－イルカルボニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（｛５－［（２－ヒドロキシエチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（｛５－［（２－アミノ－２－オキソエチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［（５－カルバモイルピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（｛５－［（シアノメチル）（メチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（｛５－［（２－ヒドロキシエチル）（メチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［（５－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝ピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［（５－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝ピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－［３－（｛５－［（３－オキソピペラジン－１－イル）カルボニル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
Ｎ－シクロプロピル－４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンズアミド、
７－（５－エチルピリミジン－２－イル）－２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン、
７－（５－エチルピリミジン－２－イル）－２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン、
１－メチルシクロプロピル ２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－フルオロ－２－メチルプロパン－２－イル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－フルオロ－２－メチルプロパン－２－イル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－｛３－［４－（アゼチジン－１－イルカルボニル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－メトキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
シクロプロピルメチル　２－｛３－［４－メチルスルホニル］フェノキシ｝プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
シクロペンチル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
（１－メチルシクロプロピル）メチル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２－メチルプロピル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２－メチルプロピル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
シクロプロピルメチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
（１－メチルシクロプロピル）メチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
シクロペンチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２，２－ジメチルプロピル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２－メチルプロピル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
シクロプロピルメチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
（１－メチルシクロプロピル）メチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
シクロペンチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２，２－ジメチルプロピル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－［３－（プロパン－２－イル）－１，２，４－オキサジアゾール－５－イル］－７－アザスピロ［３．５］ノナン、
ｔｅｒｔ－ブチル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
３，３－ジメチル－１－［２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナ－７－イル］ブタン－１－オン、
プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）カルバモイル］－３－メチルフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（１，３－ジヒドロキシプロパン－２－イル）カルバモイル］－３－メチルフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）スルフィニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）スルホニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
ｔｅｒｔ－ブチル　２－（３－｛［４－（メチルスルホニル）フェニル］アミノ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
４－｛３－［７－（２，２－ジメチルプロピル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
プロパン－２－イル　２－（３－｛［５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛［５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
１－メチルシクロプロピル　２－（３－｛［３－メチル－５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
プロパン－２－イル　２－（３－｛［３－メチル－５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート。 (14) As another aspect of the present invention,
It is to provide the compound according to (1) or a pharmaceutically acceptable salt thereof shown below:
tert-butyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 9- {2- [4- (methylsulfonyl) phenoxy] ethyl} -3-azaspiro [5.5] undecane-3-carboxylate,
tert-butyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- {3- [4- (azetidin-1-ylcarbonyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
tert-butyl 2- (3- {3-fluoro-4-[(2-methoxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- (3-{[5- (methylsulfonyl) pyridin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- (3-{[5- (cyclopropylcarbamoyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
tert-butyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- {3- [4- (cyclopropylcarbamoyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- [3- (4-carbamoyl-3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3-{[6- (cyclopropylcarbamoyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- [3- (3-fluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
Propan-2-yl 2- [3- (3-fluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4-[(cyanomethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4-[(1,3-dihydroxypropan-2-yl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
Propan-2-yl 2- [3- (4-{[(2R) -2,3-dihydroxypropyl] carbamoyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
Propan-2-yl 2- {3- [3-fluoro-4- (oxetan-3-ylcarbamoyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- [3- (4-carbamoyl-3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) (methyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- {3- [3-fluoro-4- (pyrrolidin-1-ylcarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3-{[6- (cyclopropylcarbamoyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- [3-({6-[(2-hydroxyethyl) carbamoyl] pyridin-3-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3-{[5- (cyclopropylcarbamoyl) pyridin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- [3- (3-fluoro-4-{[2- (2-hydroxyethoxy) ethyl] carbamoyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate ,
Propan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- [3- (4-{[2- (dimethylamino) ethyl] carbamoyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {3-fluoro-4-[(2-methoxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- {3- [4- (azetidin-1-ylcarbonyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {3-fluoro-4-[(3-hydroxyazetidin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) -2-methylphenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) -2-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
1-methylcyclopropyl 2- (3- {3,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
4- {3- [7- (3,3-dimethylbutanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide;
N-tert-butyl-2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxamide;
1,1-difluoro-2-methylpropan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane 7-carboxylate,
4- {3- [7- (5-ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
4- {3- [7- (cyclopentylmethyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
2-Fluoro-N- (2-hydroxyethyl) -4- (3- {7- [3- (propan-2-yl) -1,2,4-oxadiazol-5-yl] -7-azaspiro [3.5] non-2-yl} propoxy) benzamide,
4- {3- [7- (2,2-dimethylpropanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
1-Fluoro-2-methylpropan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7- Carboxylate,
1-methylcyclopropyl 2- [3- (3-fluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
1-methylcyclopropyl 2- [3- (3-fluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
Propan-2-yl 2- (3- {2,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- [3- (2,5-difluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
Propan-2-yl 2- [3- (2,5-difluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
Propan-2-yl 2- (3- {4-[(cyanomethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4-[(3,3-difluoroazetidin-1-yl) carbonyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7- Carboxylate,
2-fluoro-N- (2-hydroxyethyl) -4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzamide,
1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) (methyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- {3- [3-fluoro-4- (morpholin-4-ylcarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- {3- [3-fluoro-4- (morpholin-4-ylcarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {3-fluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
Propan-2-yl 2- (3- {3,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {3-fluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
1-methylcyclopropyl 2- (3- {2,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- [3- (2,5-difluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
1-methylcyclopropyl 2- [3- (2,5-difluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) (methyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
1-methylcyclopropyl 2- [3- (4-{[(2S) -2-carbamoylpyrrolidin-1-yl] carbonyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
N-cyclopropyl-2,5-difluoro-4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzamide,
Propan-2-yl 2- (3- {2,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- (3- {2,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
Propan-2-yl 2- (3- {3,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- (3- {3,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- (3- {4-[(cyanomethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {4-[(3,3-difluoroazetidin-1-yl) carbonyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7- Carboxylate,
1-methylcyclopropyl 2- [3- (3-fluoro-4-{[2- (methylamino) -2-oxoethyl] carbamoyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- [3- (4-{[2- (dimethylamino) -2-oxoethyl] carbamoyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- (3-{[5- (cyclopropylcarbamoyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3-{[5- (morpholin-4-ylcarbonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- [3-({5-[(2-hydroxyethyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- [3-({5-[(2-amino-2-oxoethyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- {3-[(5-carbamoylpyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- [3-({5-[(cyanomethyl) (methyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- [3-({5-[(2-hydroxyethyl) (methyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
1-methylcyclopropyl 2- {3-[(5-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] Nonane-7-carboxylate,
1-methylcyclopropyl 2- {3-[(5-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] Nonane-7-carboxylate,
1-methylcyclopropyl 2- [3-({5-[(3-oxopiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7- Carboxylate,
N-cyclopropyl-4- {3- [7- (5-ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzamide,
7- (5-ethylpyrimidin-2-yl) -2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane,
7- (5-ethylpyrimidin-2-yl) -2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane,
1-methylcyclopropyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1,1-difluoro-2-methylpropan-2-yl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1-fluoro-2-methylpropan-2-yl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1-fluoro-2-methylpropan-2-yl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1,1-difluoro-2-methylpropan-2-yl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
1,1-difluoro-2-methylpropan-2-yl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- {3- [4- (azetidin-1-ylcarbonyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
1-methylcyclopropyl 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-methoxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
Cyclopropylmethyl 2- {3- [4-methylsulfonyl] phenoxy} propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Cyclopentyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
(1-methylcyclopropyl) methyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
2-methylpropyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
2-methylpropyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Cyclopropylmethyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
(1-methylcyclopropyl) methyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Cyclopentyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
2,2-dimethylpropyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
2-methylpropyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
Cyclopropylmethyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
(1-methylcyclopropyl) methyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
Cyclopentyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
2,2-dimethylpropyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7- [3- (propan-2-yl) -1,2,4-oxadiazol-5-yl] -7-azaspiro [3 .5] Nonane,
tert-butyl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
3,3-Dimethyl-1- [2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] non-7-yl] butane-1 -on,
Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) carbamoyl] -3-methylphenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4-[(1,3-dihydroxypropan-2-yl) carbamoyl] -3-methylphenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) sulfinyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) sulfonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
tert-butyl 2- (3-{[4- (methylsulfonyl) phenyl] amino} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
4- {3- [7- (2,2-dimethylpropyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
Propan-2-yl 2- (3-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
1-methylcyclopropyl 2- (3-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
1-methylcyclopropyl 2- (3-{[3-methyl-5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
Propan-2-yl 2- (3-{[3-methyl-5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate.
（１５）本発明の他の態様としては、
　（１）～（１４）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する医薬を提供することである。 (15) As another aspect of the present invention,
(1) It is intended to provide a medicament containing the compound according to any one of (14) or (14) or a pharmaceutically acceptable salt thereof as an active ingredient.
（１６）本発明の他の態様としては、
　（１）～（１４）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を有効成分として含有するＧＰＲ１１９アゴニストを提供することである。 (16) As another aspect of the present invention,
(1) It is to provide a GPR119 agonist containing the compound according to any one of (14) or a pharmaceutically acceptable salt thereof as an active ingredient.
（１７）本発明の他の態様としては、
　（１）～（１４）のいずれか１つに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する血糖低下作用薬を提供することである。 (17) As another aspect of the present invention,
It is to provide a hypoglycemic agent containing the compound according to any one of (1) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient.
（１８）本発明の他の態様としては、
　（１）～（１４）ののいずれか１つに記載の化合物又はその製薬学的に許容される塩を有効成分として含有する糖尿病の予防薬又は治療薬を提供することである。 (18) As another aspect of the present invention,
(1) It is intended to provide a prophylactic or therapeutic agent for diabetes comprising the compound according to any one of (14) or a pharmaceutically acceptable salt thereof as an active ingredient.
　本発明により、優れたＧＰＲ１１９アゴニスト作用を有する化合物を提供することが可能となった。 According to the present invention, it is possible to provide a compound having an excellent GPR119 agonistic action.
　本発明は、優れたＧＰＲ１１９アゴニスト作用を有する一般式（Ｉ）の化合物又はその製薬学的に許容される塩を提供する。 The present invention provides a compound of the general formula (I) having an excellent GPR119 agonist activity or a pharmaceutically acceptable salt thereof.
　以下に、本発明の化合物についてさらに詳細に説明するが、例示されたものに特に限定されない。 Hereinafter, the compound of the present invention will be described in more detail, but it is not particularly limited to those exemplified.
　本発明において、「ｎ」はノルマルを、「ｓ」及び「ｓｅｃ」はセカンダリーを、「ｔ」及び「ｔｅｒｔ」はターシャリーを、「ｃ」はシクロを、「ｏ」はオルトを、「ｍ」はメタを、「ｐ」はパラを示す。 In the present invention, “n” is normal, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” is ortho, “m” "Represents meta, and" p "represents para.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　「Ｃ1-4アルキル」とは、炭素原子を１～４個有する直鎖状又は分岐状のアルキルを示す。メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチルを示す。 “C 1-4 alkyl” refers to a linear or branched alkyl having 1 to 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl are shown.
　「Ｃ3-6アルキル」とは、炭素原子を３～６個有する直鎖状又は分岐状のアルキルを示す。例えばｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、２－メチルブチル、ｎ－ヘキシル、イソヘキシル等が挙げられる。 “C 3-6 alkyl” refers to a linear or branched alkyl having 3 to 6 carbon atoms. For example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
　「Ｃ1-6アルキル」とは、炭素原子を１～６個有する直鎖状又は分岐状のアルキルを示す。例えばメチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、２－メチルブチル、ｎ－ヘキシル、イソヘキシル等が挙げられる。 “C 1-6 alkyl” refers to a linear or branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl and the like can be mentioned.
　「ハロＣ1-4アルキル」とは、ハロゲン原子で置換された炭素原子を１～４個有する直鎖状又は分岐状のアルキルを示す。ハロゲン原子の好ましい置換数は１～３個である。例えばモノフルオロメチル、ジフルオロメチル、トリフルオロメチル、１－フルオロエチル、１，１－ジフルオロエチル、２－フルオロエチル、２－フルオロ－２－メチルプロピル、２，２－ジフルオロプロピル、１－フルオロ－２－メチルプロパン－２－イル、１，１－ジフルオロ－２－メチルプロパン－２－イル等が挙げられる。 “Halo C 1-4 alkyl” refers to a linear or branched alkyl having 1 to 4 carbon atoms substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 3. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2 -Methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl and the like.
　「ハロＣ3-6アルキル」とは、ハロゲン原子で置換された炭素原子を３～６個有する直鎖状又は分岐状のアルキルを示す。ハロゲン原子の好ましい置換数は１～３個である。例えば２－フルオロ－２－メチルプロピル、２，２－ジフルオロプロピル、１－フルオロ－２－メチルプロパン－２－イル、１，１－ジフルオロ－２－メチルプロパン－２－イル等が挙げられる。 “Halo C 3-6 alkyl” refers to a linear or branched alkyl having 3 to 6 carbon atoms substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 3. Examples include 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl and the like.
　「ハロＣ1-6アルキル」とは、ハロゲン原子で置換された炭素原子を１～６個有する直鎖状又は分岐状のアルキルを示す。ハロゲン原子の好ましい置換数は１～３個である。例えばモノフルオロメチル、ジフルオロメチル、トリフルオロメチル、１－フルオロエチル、１，１－ジフルオロエチル、２－フルオロエチル、２－フルオロ－２－メチルプロピル、２，２－ジフルオロプロピル、１－フルオロ－２－メチルプロパン－２－イル、１，１－ジフルオロ－２－メチルプロパン－２－イル等が挙げられる。 “Halo C 1-6 alkyl” refers to a linear or branched alkyl having 1 to 6 carbon atoms substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 3. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2 -Methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl and the like.
　「Ｃ3-6シクロアルキル」とは、炭素原子を３～６個有する環状のアルキルを示す。シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルが挙げられる。 “C 3-6 cycloalkyl” refers to a cyclic alkyl having 3 to 6 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
　「Ｃ3-8シクロアルキル」とは、炭素原子を３～８個有する環状のアルキルを示す。シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルが挙げられる。 “C 3-8 cycloalkyl” refers to cyclic alkyl having 3 to 8 carbon atoms. And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
　「アリール」とは、炭素原子を６～１４個有する単環式芳香族炭化水素基又は縮合多環式芳香族炭化水素基を示す。例えばフェニル、ナフチル、アントリル等が挙げられる。 “Aryl” refers to a monocyclic aromatic hydrocarbon group or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Examples thereof include phenyl, naphthyl, anthryl and the like.
　「ヘテロアリール」とは、酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～６個の炭素原子からなる５～７員の単環式芳香族複素環基又は酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～１３個の炭素原子からなる９～１４個の原子から構成される縮合多環式芳香族複素環基を示す。例えばイミダゾリル、ピラゾリル、チアゾリル、チアジアゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、ピロリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、トリアジニル、インドリル、ベンゾピラゾリル、ベンゾトリアゾリル、キノリル等が挙げられる。
　また、ヘテロアリールにおいて部分的に飽和された基も「ヘテロアリール」に含まれる。「ヘテロアリールにおける部分的に飽和された基」とは、酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～６個の炭素原子からなる５～７員の部分的に飽和された単環式複素環基又は酸素原子、硫黄原子及び窒素原子からなる群より同一に若しくは異なって選ばれる１個以上の原子と１～１３個の炭素原子からなる９～１４個の原子から構成される部分的に飽和された縮合多環式複素環基を示す。例えばオキサゾリジニル、チアゾリニル等が挙げられる。 “Heteroaryl” is a 5- to 7-membered monocyclic fragrance consisting of one or more atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or the same or different, and 1 to 6 carbon atoms. A group consisting of one or more atoms selected from the group consisting of a heterocyclic group or an oxygen atom, a sulfur atom and a nitrogen atom, or 9 to 14 atoms consisting of 1 to 13 carbon atoms. A polycyclic aromatic heterocyclic group is shown. Examples include imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzopyrazolyl, benzotriazolyl, quinolyl and the like.
A group partially saturated in heteroaryl is also included in “heteroaryl”. The “partially saturated group in heteroaryl” refers to one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1 to 6 carbon atoms. A 7-membered partially saturated monocyclic heterocyclic group or one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or 1-13 carbon atoms, which are the same or different And a partially saturated condensed polycyclic heterocyclic group composed of 9 to 14 atoms. For example, oxazolidinyl, thiazolinyl and the like can be mentioned.
　「６員のヘテロ芳香環」とは、１個以上の窒素原子と１～５個の炭素原子からなる６員の単環式芳香族複素環を示す。例えばピリジン、ピリミジン、ピラジン、ピリダジン、トリアジン等が挙げられる。 “6-membered heteroaromatic ring” refers to a 6-membered monocyclic aromatic heterocycle composed of one or more nitrogen atoms and 1 to 5 carbon atoms. Examples include pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
　「飽和のヘテロシクリル」とは、酸素原子、硫黄原子及び窒素原子からなる群より同一に又は異なって選ばれる１個以上の原子と１～７個の炭素原子からなる３～８員の単環式飽和複素環基を示す。例えばアゼチジニル、ピロリジニル、ピペリジニル、ヘキサメチレンイミニル、ピペラジニル、ピラゾリジニル、キヌクリジニル、モルホリニル、オキセタニル、オキソラニル、オキサニル等が挙げられる。 "Saturated heterocyclyl" is a 3 to 8 membered monocyclic group consisting of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 7 carbon atoms. A saturated heterocyclic group is shown. Examples include azetidinyl, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, piperazinyl, pyrazolidinyl, quinuclidinyl, morpholinyl, oxetanyl, oxolanyl, oxanyl and the like.
　「Ｃ1-4アルコキシ」とは、炭素原子を１～４個有する直鎖状又は分岐状のアルコキシを示す。例えばメトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ等が挙げられる。 “C 1-4 alkoxy” refers to linear or branched alkoxy having 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
　「Ｃ1-6アルコキシ」とは、炭素原子を１～６個有する直鎖状又は分岐状のアルコキシを示す。例えばメトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、２－メチルブトキシ、ｎ－ヘキシルオキシ、イソヘキシルオキシ等が挙げられる。 “C 1-6 alkoxy” represents linear or branched alkoxy having 1 to 6 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, n-hexyloxy, iso And hexyloxy.
　「ハロＣ1-6アルコキシ」とは、ハロゲン原子で置換された炭素原子を１～６個有する直鎖状又は分岐状のアルコキシを示す。ハロゲン原子の好ましい置換数は１～３個である。例えばモノフルオロメトキシ、ジフルオロメトキシ、トリフルオロメトキシ、１－フルオロエトキシ、１，１－ジフルオロエトキシ、２－フルオロエトキシ、２－フルオロ－２－メチルプロポキシ、２，２－ジフルオロプロポキシ、１－フルオロ－２－メチルプロパン－２－イルオキシ、１，１－ジフルオロ－２－メチルプロパン－２－イルオキシ等が挙げられる。 “Halo C 1-6 alkoxy” refers to a straight or branched alkoxy having 1 to 6 carbon atoms substituted with a halogen atom. A preferred number of substitution of halogen atoms is 1 to 3. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2-fluoroethoxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2 -Methylpropan-2-yloxy, 1,1-difluoro-2-methylpropan-2-yloxy and the like.
　「モノＣ1-4アルキルアミノ」とは、前記の「Ｃ1-4アルキル」を置換基として１個有するアミノを示す。例えばメチルアミノ、エチルアミノ、ｎ－プロピルアミノ、イソプロピルアミノ、ｎ－ブチルアミノ、イソブチルアミノ、ｓｅｃ－ブチルアミノ、ｔｅｒｔ－ブチルアミノ等が挙げられる。 “Mono C 1-4 alkylamino” means amino having one “C 1-4 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino and the like can be mentioned.
　「モノＣ1-6アルキルアミノ」とは、前記の「Ｃ1-6アルキル」を置換基として１個有するアミノを示す。例えばメチルアミノ、エチルアミノ、ｎ－プロピルアミノ、イソプロピルアミノ、ｎ－ブチルアミノ、イソブチルアミノ、ｓｅｃ－ブチルアミノ、ｔｅｒｔ－ブチルアミノ、ｎ－ペンチルアミノ、イソペンチルアミノ、ネオペンチルアミノ、ｎ－ヘキシルアミノ、イソヘキシルアミノ等が挙げられる。 “Mono C 1-6 alkylamino” refers to amino having one “C 1-6 alkyl” as a substituent. For example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, neopentylamino, n-hexylamino , Isohexylamino and the like.
　「ジＣ1-4アルキルアミノ」とは、前記の「Ｃ1-4アルキル」を置換基として同一に又は異なって２個有するアミノを示す。例えばＮ，Ｎ－ジメチルアミノ、Ｎ，Ｎ－ジエチルアミノ、Ｎ，Ｎ－ジ（ｎ－プロピル）アミノ、Ｎ，Ｎ－ジイソプロピルアミノ、Ｎ－エチル－Ｎ－メチルアミノ、Ｎ－メチル－Ｎ－ｎ－プロピルアミノ、Ｎ－イソプロピル－Ｎ－メチルアミノ等が挙げられる。 “DiC 1-4 alkylamino” refers to amino having two “C 1-4 alkyl” as the same or different as a substituent. For example, N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn- And propylamino, N-isopropyl-N-methylamino and the like.
　「ジＣ1-6アルキルアミノ」とは、前記の「Ｃ1-6アルキル」を置換基として同一に又は異なって２個有するアミノを示す。例えばＮ，Ｎ－ジメチルアミノ、Ｎ，Ｎ－ジエチルアミノ、Ｎ，Ｎ－ジ（ｎ－プロピル）アミノ、Ｎ，Ｎ－ジイソプロピルアミノ、Ｎ－エチル－Ｎ－メチルアミノ、Ｎ－メチル－Ｎ－ｎ－プロピルアミノ、Ｎ－イソプロピル－Ｎ－メチルアミノ等が挙げられる。 “DiC 1-6 alkylamino” refers to an amino having the same or different two “C 1-6 alkyl” as the substituent. For example, N, N-dimethylamino, N, N-diethylamino, N, N-di (n-propyl) amino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn- And propylamino, N-isopropyl-N-methylamino and the like.
　「Ｃ3-6アルキルカルボニル」とは、前記の「Ｃ3-6アルキル」とカルボニルが結合した基を示す。例えばｎ－プロピルカルボニル、イソプロピルカルボニル、ｎ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ｔｅｒｔ－ブチルカルボニル、ｎ－ペンチルカルボニル、イソペンチルカルボニル、ネオペンチルカルボニル、２－メチルブチルカルボニル、ｎ－ヘキシルカルボニル、イソヘキシルカルボニル等が挙げられる。 “C 3-6 alkylcarbonyl” refers to a group in which the above “C 3-6 alkyl” and carbonyl are bonded. For example, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 2-methylbutylcarbonyl, n-hexylcarbonyl And isohexylcarbonyl.
　「Ｃ1-6アルキルカルボニル」とは、前記の「Ｃ1-6アルキル」とカルボニルが結合した基を示す。例えばメチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニル、イソプロピルカルボニル、ｎ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ｔｅｒｔ－ブチルカルボニル、ｎ－ペンチルカルボニル、イソペンチルカルボニル、ネオペンチルカルボニル、２－メチルブチルカルボニル、ｎ－ヘキシルカルボニル、イソヘキシルカルボニル等が挙げられる。 “C 1-6 alkylcarbonyl” refers to a group in which the above “C 1-6 alkyl” is bonded to carbonyl. For example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 2-methylbutyl Examples include carbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like.
　「Ｃ3-6シクロアルキルカルボニル」とは、前記の「Ｃ3-6シクロアルキル」とカルボニルが結合した基を示す。例えばシクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニルが挙げられる。 “C 3-6 cycloalkylcarbonyl” refers to a group in which the above “C 3-6 cycloalkyl” is bonded to carbonyl. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl.
　「Ｃ3-8シクロアルキルカルボニル」とは、前記の「Ｃ3-8シクロアルキル」とカルボニルが結合した基を示す。例えばシクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル、シクロヘプチルカルボニル、シクロオクチルカルボニルが挙げられる。 “C 3-8 cycloalkylcarbonyl” refers to a group in which the above “C 3-8 cycloalkyl” is bonded to carbonyl. Examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, and cyclooctylcarbonyl.
　「Ｃ1-6アルコキシカルボニル」とは、前記の「Ｃ1-6アルコキシ」とカルボニルが結合した基を示す。例えばメトキシカルボニル、エトキシカルボニル、ｎ－プロポキシカルボニル、イソプロポキシカルボニル、ｎ－ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、ｎ－ペンチルオキシカルボニル、イソペンチルオキシカルボニル、ネオペンチルオキシカルボニル、２－メチルブトキシカルボニル、ｎ－ヘキシルオキシカルボニル、イソヘキシルオキシカルボニル等が挙げられる。 “C 1-6 alkoxycarbonyl” refers to a group in which the above “C 1-6 alkoxy” is bonded to carbonyl. For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl 2-methylbutoxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl and the like.
　「Ｃ1-6アルキルカルボニルアミノ」とは、前記の「Ｃ1-6アルキル」とカルボニルが結合した基にアミノが結合した基を示す。例えばアセチルアミノ、プロピオニルアミノ、ｎ－プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ｎ－ブチルカルボニルアミノ、イソブチルカルボニルアミノ、ｓｅｃ－ブチルカルボニルアミノ、ｔｅｒｔ－ブチルカルボニルアミノ、ｎ－ペンチルカルボニルアミノ、イソペンチルカルボニルアミノ、ネオペンチルカルボニルアミノ、２－メチルブチルカルボニルアミノ、ｎ－ヘキシルカルボニルアミノ、イソヘキシルカルボニルアミノ等が挙げられる。 “C 1-6 alkylcarbonylamino” refers to a group in which amino is bonded to a group in which the above “C 1-6 alkyl” is bonded to carbonyl. For example, acetylamino, propionylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino, isopentylcarbonylamino, Neopentylcarbonylamino, 2-methylbutylcarbonylamino, n-hexylcarbonylamino, isohexylcarbonylamino and the like can be mentioned.
　「モノＣ1-4アルキルアミノカルボニル」とは、前記の「モノＣ1-4アルキル」を置換基として１個有するアミノとカルボニルが結合した基を示す。例えばメチルアミノカルボニル、エチルアミノカルボニル、ｎ－プロピルアミノカルボニル、イソプロピルアミノカルボニル、ｎ－ブチルアミノカルボニル、イソブチルアミノカルボニル、ｓｅｃ－ブチルアミノカルボニル、ｔｅｒｔ－ブチルアミノカルボニル等が挙げられる。 “Mono C 1-4 alkylaminocarbonyl” refers to a group in which amino and carbonyl having one “mono C 1-4 alkyl” as a substituent is bonded. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl and the like.
　「モノＣ1-6アルキルアミノカルボニル」とは、前記の「モノＣ1-6アルキルアミノ」とカルボニルが結合した基を示す。例えばメチルアミノカルボニル、エチルアミノカルボニル、ｎ－プロピルアミノカルボニル、イソプロピルアミノカルボニル、ｎ－ブチルアミノカルボニル、イソブチルアミノカルボニル、ｓｅｃ－ブチルアミノカルボニル、ｔｅｒｔ－ブチルアミノカルボニル、ｎ－ペンチルアミノカルボニル、イソペンチルアミノカルボニル、ネオペンチルアミノカルボニル、ｎ－ヘキシルアミノカルボニル、イソヘキシルアミノカルボニル等が挙げられる。 “Mono C 1-6 alkylaminocarbonyl” refers to a group in which the above “mono C 1-6 alkylamino” is bonded to carbonyl. For example, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylamino Examples include carbonyl, neopentylaminocarbonyl, n-hexylaminocarbonyl, isohexylaminocarbonyl and the like.
　「モノＣ3-6シクロアルキルアミノカルボニル」とは、前記の「Ｃ3-6シクロアルキル」を置換基として１個有するアミノとカルボニルが結合した基を示す。シクロプロピルアミノカルボニル、シクロブチルアミノカルボニル、シクロペンチルアミノカルボニル、シクロヘキシルアミノカルボニルが挙げられる。 “Mono C 3-6 cycloalkylaminocarbonyl” refers to a group in which amino having one “C 3-6 cycloalkyl” as a substituent and carbonyl are bonded. Examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, and cyclohexylaminocarbonyl.
　「モノＣ3-8シクロアルキルアミノカルボニル」とは、前記の「Ｃ3-8シクロアルキル」を置換基として１個有するアミノとカルボニルが結合した基を示す。シクロプロピルアミノカルボニル、シクロブチルアミノカルボニル、シクロペンチルアミノカルボニル、シクロヘキシルアミノカルボニル、シクロヘプチルアミノカルボニル、シクロオクチルアミノカルボニルが挙げられる。 “Mono C 3-8 cycloalkylaminocarbonyl” refers to a group in which amino having one “C 3-8 cycloalkyl” as a substituent and carbonyl are bonded. Examples include cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, and cyclooctylaminocarbonyl.
　「ジＣ1-4アルキルアミノカルボニル」とは、前記の「ジＣ1-4アルキルアミノ」とカルボニルが結合した基を示す。例えばＮ，Ｎ－ジメチルアミノカルボニル、Ｎ，Ｎ－ジエチルアミノカルボニル、Ｎ，Ｎ－ジ（ｎ－プロピル）アミノカルボニル、Ｎ，Ｎ－ジイソプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル、Ｎ－メチル－Ｎ－ｎ－プロピルアミノカルボニル、Ｎ－メチル－Ｎ－イソプロピルアミノカルボニル等が挙げられる。 “DiC 1-4 alkylaminocarbonyl” refers to a group in which the above “diC 1-4 alkylamino” and carbonyl are bonded. For example, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N, N-di (n-propyl) aminocarbonyl, N, N-diisopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl -Nn-propylaminocarbonyl, N-methyl-N-isopropylaminocarbonyl and the like.
　「ジＣ1-6アルキルアミノカルボニル」とは、前記の「ジＣ1-6アルキルアミノ」とカルボニルが結合した基を示す。例えばＮ，Ｎ－ジメチルアミノカルボニル、Ｎ，Ｎ－ジエチルアミノカルボニル、Ｎ，Ｎ－ジ（ｎ－プロピル）アミノカルボニル、Ｎ，Ｎ－ジイソプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル、Ｎ－メチル－Ｎ－ｎ－プロピルアミノカルボニル、Ｎ－メチル－Ｎ－イソプロピルアミノカルボニル等が挙げられる。 “DiC 1-6 alkylaminocarbonyl” refers to a group in which the above “diC 1-6 alkylamino” is bonded to carbonyl. For example, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N, N-di (n-propyl) aminocarbonyl, N, N-diisopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl -Nn-propylaminocarbonyl, N-methyl-N-isopropylaminocarbonyl and the like.
　「Ｃ1-4アルキルＣ3-6シクロアルキルアミノカルボニル」とは、前記の「Ｃ1-4アルキル」及び「Ｃ3-6シクロアルキル」を置換基として１個ずつ有するアミノとカルボニルが結合した基を示す。例えばＮ－シクロプロピル－Ｎ－メチルアミノカルボニル、Ｎ－シクロプロピル－Ｎ－エチルアミノカルボニル、Ｎ－シクロブチル－Ｎ－メチルアミノカルボニル、Ｎ－シクロブチル－Ｎ－エチルアミノカルボニル、Ｎ－シクロペンチル－Ｎ－メチルアミノカルボニル、Ｎ－シクロヘキシル－Ｎ－メチルアミノカルボニル等が挙げられる。 “C 1-4 alkyl C 3-6 cycloalkylaminocarbonyl” is a combination of amino and carbonyl having one each of the above “C 1-4 alkyl” and “C 3-6 cycloalkyl” as substituents. Indicates a group. For example, N-cyclopropyl-N-methylaminocarbonyl, N-cyclopropyl-N-ethylaminocarbonyl, N-cyclobutyl-N-methylaminocarbonyl, N-cyclobutyl-N-ethylaminocarbonyl, N-cyclopentyl-N-methyl Aminocarbonyl, N-cyclohexyl-N-methylaminocarbonyl and the like can be mentioned.
　「Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル」とは、前記の「Ｃ1-6アルキル」及び「Ｃ3-8シクロアルキル」を置換基として１個ずつ有するアミノとカルボニルが結合した基を示す。例えばＮ－シクロプロピル－Ｎ－メチルアミノカルボニル、Ｎ－シクロプロピル－Ｎ－エチルアミノカルボニル、Ｎ－シクロブチル－Ｎ－メチルアミノカルボニル、Ｎ－シクロブチル－Ｎ－エチルアミノカルボニル、Ｎ－シクロペンチル－Ｎ－メチルアミノカルボニル、Ｎ－シクロヘキシル－Ｎ－メチルアミノカルボニル、Ｎ－シクロヘプチル－Ｎ－メチルアミノカルボニル、Ｎ－シクロオクチル－Ｎ－メチルアミノカルボニル等が挙げられる。 “C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl” is a combination of amino and carbonyl having one each of the above “C 1-6 alkyl” and “C 3-8 cycloalkyl” as substituents. Indicates a group. For example, N-cyclopropyl-N-methylaminocarbonyl, N-cyclopropyl-N-ethylaminocarbonyl, N-cyclobutyl-N-methylaminocarbonyl, N-cyclobutyl-N-ethylaminocarbonyl, N-cyclopentyl-N-methyl Examples include aminocarbonyl, N-cyclohexyl-N-methylaminocarbonyl, N-cycloheptyl-N-methylaminocarbonyl, N-cyclooctyl-N-methylaminocarbonyl and the like.
　「飽和のヘテロシクリルカルボニル」とは、前記の「飽和のヘテロシクリル」とカルボニルが結合した基を示す。例えば１－アゼチジニルカルボニル、１－ピロリジニルカルボニル、１－ピペリジニルカルボニル、１－ヘキサメチレンイミニルカルボニル、１－ピペラジニルカルボニル、モルホリノカルボニル等が挙げられる。 “Saturated heterocyclylcarbonyl” refers to a group in which the above “saturated heterocyclylcarbonyl” and carbonyl are bonded. Examples include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-hexamethyleneiminylcarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl and the like.
　「モノ飽和のヘテロシクリルアミノカルボニル」とは、前記の「飽和のヘテロシクリル」を置換基として１個有するアミノとカルボニルが結合した基を示す。オキセタニルアミノカルボニル、オキソラニルアミノカルボニル、オキサニルアミノカルボニル、テトラヒドロチオピラニルアミノカルボニル、ピロリジニルアミノカルボニル、ピペリジニルアミノカルボニル等が挙げられる。 “Mono-saturated heterocyclylaminocarbonyl” refers to a group in which amino and carbonyl having one “saturated heterocyclyl” as a substituent is bonded. Examples include oxetanylaminocarbonyl, oxolanylaminocarbonyl, oxanylaminocarbonyl, tetrahydrothiopyranylaminocarbonyl, pyrrolidinylaminocarbonyl, piperidinylaminocarbonyl and the like.
　「Ｃ1-4アルキルスルフィニル」とは、前記の「Ｃ1-4アルキル」とスルフィニルが結合した基を示す。例えばメチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル、イソブチルスルフィニル等が挙げられる。 “C 1-4 alkylsulfinyl” refers to a group in which the above “C 1-4 alkyl” and sulfinyl are bonded. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, isobutylsulfinyl and the like.
　「Ｃ1-6アルキルスルフィニル」とは、前記の「Ｃ1-6アルキル」とスルフィニルが結合した基を示す。例えばメチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル、イソブチルスルフィニル、ｎ－ヘキシルスルフィニル等が挙げられる。 “C 1-6 alkylsulfinyl” refers to a group in which the above “C 1-6 alkyl” and sulfinyl are bonded. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, isobutylsulfinyl, n-hexylsulfinyl and the like.
　「Ｃ1-4アルキルスルホニル」とは、前記の「Ｃ1-4アルキル」とスルホニルが結合した基を示す。例えばメチルスルホニル、エチルスルホニル、ｎ－プロピルスルホニル、イソプロピルスルホニル、イソブチルスルホニル等が挙げられる。 “C 1-4 alkylsulfonyl” refers to a group in which the above “C 1-4 alkyl” and sulfonyl are bonded. For example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl and the like can be mentioned.
　「Ｃ1-6アルキルスルホニル」とは、前記の「Ｃ1-6アルキル」とスルホニルが結合した基を示す。例えばメチルスルホニル、エチルスルホニル、ｎ－プロピルスルホニル、イソプロピルスルホニル、イソブチルスルホニル、ｎ－ヘキシルスルホニル等が挙げられる。 “C 1-6 alkylsulfonyl” refers to a group in which the above “C 1-6 alkyl” and sulfonyl are bonded. Examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, n-hexylsulfonyl and the like.
　「Ｃ3-8シクロアルキルスルホニル」とは、前記の「Ｃ3-8シクロアルキル」とスルホニルが結合した基を示す。例えばシクロプロピルスルホニル、シクロブチルスルホニル、シクロペンチルスルホニル、シクロヘキシルスルホニル、シクロヘプチルスルホニル、シクロオクチルスルホニルが挙げられる。 “C 3-8 cycloalkylsulfonyl” refers to a group in which the above “C 3-8 cycloalkyl” is bonded to sulfonyl. Examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, and cyclooctylsulfonyl.
　「Ｃ1-6アルキルスルホニルアミノ」とは、前記の「Ｃ1-6アルキルスルホニル」とアミノが結合した基を示す。例えばメチルスルホニルアミノ、エチルスルホニルアミノ、ｎ－プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ｎ－ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｓｅｃ－ブチルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、ｎ－ペンチルスルホニルアミノ、イソペンチルスルホニルアミノ、ネオペンチルスルホニルアミノ、ｎ－ヘキシルスルホニルアミノ、イソヘキシルスルホニルアミノ等が挙げられる。 “C 1-6 alkylsulfonylamino” refers to a group in which the above “C 1-6 alkylsulfonyl” is linked to amino. For example, methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino, isopentylsulfonyl Amino, neopentylsulfonylamino, n-hexylsulfonylamino, isohexylsulfonylamino and the like can be mentioned.
　「モノＣ1-6アルキルアミノスルホニル」とは、前記の「モノＣ1-6アルキルアミノ」とスルホニルが結合した基を示す。例えばメチルアミノスルホニル、エチルアミノスルホニル、ｎ－プロピルアミノスルホニル、イソプロピルアミノスルホニル、ｎ－ブチルアミノスルホニル、イソブチルアミノスルホニル、ｓｅｃ－ブチルアミノスルホニル、ｔｅｒｔ－ブチルアミノスルホニル、ｎ－ペンチルアミノスルホニル、イソペンチルアミノスルホニル、ネオペンチルアミノスルホニル、ｎ－ヘキシルアミノスルホニル、イソヘキシルアミノスルホニル等が挙げられる。 “Mono C 1-6 alkylaminosulfonyl” refers to a group in which the above “mono C 1-6 alkylamino” is bonded to sulfonyl. For example, methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, isobutylaminosulfonyl, sec-butylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, isopentylamino Examples include sulfonyl, neopentylaminosulfonyl, n-hexylaminosulfonyl, isohexylaminosulfonyl and the like.
　「オキソ」とは、酸素原子が二重結合を介して置換する置換基（＝Ｏ）を示す。従って、オキソが炭素原子に置換した場合は当該炭素原子と一緒となってカルボニルを形成し、１つのオキソが１つの硫黄原子に置換した場合は当該硫黄原子と一緒となってスルフィニルを形成し、２つのオキソが１つの硫黄原子に置換した場合は当該硫黄原子と一緒になってスルホニルを形成する。本発明においてオキソが飽和のヘテロシクリルに置換した場合のオキソが置換した飽和のヘテロシクリルの具体的な例としては、２－オキソピロリジニル、２－オキソピペリジニル、２－オキソピペラジニル、３－オキソピペラジニル、１，１－ジオキシドテトラヒドロチオフェニル、１－オキシドテトラヒドロ－２Ｈ－チオピラニル、１，１－ジオキシドテトラヒドロ－２Ｈ－チオピラニル、１，１－ジオキシドイソチアゾリジニル、２－オキソ－１，３－オキサゾリジニル、６－オキソ－１，１－ジヒドロピリダジニルなどが挙げられる。 “Oxo” refers to a substituent (═O) in which an oxygen atom is substituted via a double bond. Therefore, when oxo is substituted with a carbon atom, it forms a carbonyl together with the carbon atom, and when one oxo is substituted with one sulfur atom, it forms a sulfinyl together with the sulfur atom, When two oxos are substituted with one sulfur atom, they are combined with the sulfur atom to form a sulfonyl. In the present invention, specific examples of the saturated heterocyclyl substituted with oxo when oxo is substituted with saturated heterocyclyl include 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 3 -Oxopiperazinyl, 1,1-dioxidetetrahydrothiophenyl, 1-oxidetetrahydro-2H-thiopyranyl, 1,1-dioxidetetrahydro-2H-thiopyranyl, 1,1-dioxideisothiazolidinyl, 2- Examples thereof include oxo-1,3-oxazolidinyl, 6-oxo-1,1-dihydropyridazinyl and the like.
　「Ｃ3-4アルカンジイル」とは、炭素原子を３～４個有する２価の飽和炭化水素基を示す。例えば、プロパン－１，３－ジイル、ブタン－１，４－ジイル等が挙げられる。 “C 3-4 alkanediyl” refers to a divalent saturated hydrocarbon group having 3 to 4 carbon atoms. Examples thereof include propane-1,3-diyl, butane-1,4-diyl and the like.
　「Ｃ1-6アルカンジイル」とは、炭素原子を１～６個有する２価の炭化水素基を示す。例えば、メタンジイル、エタン－１，２－ジイル、プロパン－１，３－ジイル、ブタン－１，４－ジイル、ペンタン－１，５－ジイル、ヘキサン－１，６－ジイル等が挙げられる。 “C 1-6 alkanediyl” refers to a divalent hydrocarbon group having 1 to 6 carbon atoms. For example, methanediyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl and the like can be mentioned.
　「式（β）で表される５又は６員のヘテロアリール」とは、 “The 5- or 6-membered heteroaryl represented by the formula (β)”
Figure JPOXMLDOC01-appb-C000011
 酸素原子、硫黄原子及び窒素原子からなる群より同一に又は異なって選ばれる１個以上の原子と１～５個の炭素原子からなる５又は６員の単環式芳香族複素環基を示す。例えば、オキサジアゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル等が挙げられる。
Figure JPOXMLDOC01-appb-C000011
 A 5- or 6-membered monocyclic aromatic heterocyclic group composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 5 carbon atoms. Examples include oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like.
　本発明化合物の好ましい態様は以下の通りである。
　すなわち、
　下記式（α１）で表されるアザスピロ環構造のうち、 Preferred embodiments of the compound of the present invention are as follows.
That is,
Of the azaspiro ring structure represented by the following formula (α1),
Figure JPOXMLDOC01-appb-C000012
 　好ましいアザスピロ環構造は、以下の構造であり、
Figure JPOXMLDOC01-appb-C000012
 Preferred azaspiro ring structures are the following structures:
Figure JPOXMLDOC01-appb-C000013
 　より好ましいアザスピロ環構造は、以下の構造であり、
Figure JPOXMLDOC01-appb-C000013
 More preferred azaspiro ring structures are the following structures:
Figure JPOXMLDOC01-appb-C000014
 　さらに好ましいアザスピロ環構造は、以下の構造であり；
Figure JPOXMLDOC01-appb-C000014
 More preferred azaspiro ring structures are the following structures;
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　Ａで表される好ましい環は、ベンゼン環又は６員のヘテロ芳香環であり、
　Ａで表されるより好ましい環は、ベンゼン環、ピリジン環、ピラジン環又はピリミジン環であり、
　Ａで表されるさらに好ましい環は、ベンゼン環、ピリジン環又はピラジン環であり、
　Ａで表される特に好ましい環は、ベンゼン環であり； A preferred ring represented by A is a benzene ring or a 6-membered heteroaromatic ring,
A more preferable ring represented by A is a benzene ring, a pyridine ring, a pyrazine ring or a pyrimidine ring,
A more preferable ring represented by A is a benzene ring, a pyridine ring or a pyrazine ring,
A particularly preferred ring represented by A is a benzene ring;
　ひとつの好ましいＲ11、Ｒ12及びＲ13は、水素原子、ハロゲン原子、カルバモイル、シアノ、Ｃ1-6アルキル、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-6アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル又はＣ1-6アルキルスルホニルであり、 One preferred R 11 , R 12 and R 13 are hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl may be unsubstituted, hydroxy, carbamoyl, cyano, C 1-6 alkoxy (wherein the C 1-6 alkoxy is unsubstituted or And substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino. ], Saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 hydroxy), monosaturated heterocyclylaminocarbonyl or C 1-6 alkylsulfonyl;
　このとき、より好ましいＲ11、Ｒ12及びＲ13は、水素原子、ハロゲン原子、カルバモイル、Ｃ1-4アルキル、モノＣ1-4アルキルアミノカルボニル、モノＣ3-6シクロアルキルアミノカルボニル、ジＣ1-4アルキルアミノカルボニル、Ｃ1-4アルキルＣ3-6シクロアルキルアミノカルボニル［該モノＣ1-4アルキルアミノカルボニル、モノＣ3-6シクロアルキルアミノカルボニル、ジＣ1-4アルキルアミノカルボニル及びＣ1-4アルキルＣ3-6シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-4アルコキシ（該Ｃ1-4アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-4アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル又はＣ1-4アルキルスルホニルであり、
　ここで、該Ｒ11は、上記ベンゼン環又は６員のヘテロ芳香環の４位に置換し、
　また、該Ｒ12及びＲ13は、独立して上記ベンゼン環又は６員のヘテロ芳香環の２位又は３位に置換し、 In this case, R 11 , R 12 and R 13 are more preferably hydrogen atom, halogen atom, carbamoyl, C 1-4 alkyl, mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, diC. 1-4 alkylaminocarbonyl, C 1-4 alkylC 3-6 cycloalkylaminocarbonyl [the mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, diC 1-4 alkylaminocarbonyl and C 1-4 alkyl C 3-6 cycloalkylaminocarbonyl can be unsubstituted, hydroxy, carbamoyl, cyano, C 1-4 alkoxy (wherein the C 1-4 alkoxy is unsubstituted or And substituted with 1 to 2 groups selected identically or differently from the group consisting of di-C 1-4 alkylamino. ], Saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 hydroxy), monosaturated heterocyclylaminocarbonyl or C 1-4 alkylsulfonyl;
Here, R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring,
R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
　このとき、さらに好ましいＲ11は、カルバモイル、メチルアミノカルボニル（該メチルアミノカルボニルは、置換されていないか、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、エチルアミノカルボニル［該エチルアミノカルボニルは、置換されていないか、ヒドロキシ、メトキシ、エトキシ（該エトキシは、置換されていないか、１個のヒドロキシで置換されている。）及びＮ，Ｎ－ジメチルアミノからなる群より選ばれる１個の基で置換されている。］、ｎ－プロピルアミノカルボニル（該ｎ－プロピルアミノカルボニル、置換されていないか、１～２個のヒドロキシで置換されている。）、イソプロピルアミノカルボニル（該イソプロピルアミノカルボニルは、置換されていないか、１～２個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル（該Ｎ－エチル－Ｎ－メチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｎ－シクロプロピル－Ｎ－メチルアミノカルボニル、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、オキセタン-３-イルアミノカルボニル又はメチルスルホニルであり、
　ここで、該Ｒ11は、上記ベンゼン環又は６員のヘテロ芳香環の４位に置換し、
　このとき、さらに好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環又は６員のヘテロ芳香環の２位又は３位に置換し、 In this case, more preferred R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylamino. Carbonyl [the ethylaminocarbonyl consists of unsubstituted, hydroxy, methoxy, ethoxy (the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino Substituted with one group selected from the group. ], N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), It is oxetane-3-yl-aminocarbonyl or methylsulfonyl,
Here, R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring,
At this time, more preferred R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Here, R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring,
　このとき、特に好ましいＲ11は、エチルアミノカルボニル［該エチルアミノカルボニルは、ヒドロキシ、メトキシ及びエトキシ（該エトキシは、１個のヒドロキシで置換されている。）からなる群より選ばれる１個の基で置換されている。］、イソプロピルアミノカルボニル（該イソプロピルアミノカルボニルは、１～２個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル（該Ｎ－エチル－Ｎ－メチルアミノカルボニルは、１個のヒドロキシで置換されている。）、Ｎ－シクロプロピル－Ｎ－メチルアミノカルボニル、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、１個のヒドロキシで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、１個のヒドロキシで置換されている。）又はオキセタン-３-イルアミノカルボニル又はメチルスルホニルであり、
　ここで、該Ｒ11は、上記ベンゼン環又は６員のヘテロ芳香環の４位に置換し、
　このとき、特に好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環又は６員のヘテロ芳香環の２位又は３位に置換し； In this case, particularly preferred R 11 is ethylaminocarbonyl [wherein the ethylaminocarbonyl is one group selected from the group consisting of hydroxy, methoxy and ethoxy (the ethoxy is substituted with one hydroxy). Has been replaced by ], Isopropylaminocarbonyl (the isopropylaminocarbonyl is substituted with 1 to 2 hydroxys), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylamino Carbonyl is substituted with 1 hydroxy), N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is substituted with 1 hydroxy) ), Pyrrolidin-1-yl-carbonyl (wherein the pyrrolidin-1-yl-carbonyl is substituted with 1 hydroxy) or oxetan-3-ylaminocarbonyl or methylsulfonyl;
Here, R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring,
At this time, particularly preferred R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Wherein R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
　他の好ましいＲ11、Ｒ12及びＲ13は、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル（該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、モノＣ1-6アルキルアミノカルボニル及びジＣ1-6アルキルアミノカルボニルからなる群より同一に又は異なって選ばれる１個の基で置換されている。）、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、ハロゲン原子、カルバモイル、シアノ及びオキソからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。）、Ｃ1-6アルキルスルフィニル（該Ｃ1-6アルキルスルフィニルは、置換されていないか、１個のヒドロキシで置換されている。）又はＣ1-6アルキルスルホニル（該Ｃ1-6アルキルスルホニルは、１個のヒドロキシで置換されている。）であり、 Other preferred R 11 , R 12 and R 13 are mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8. Cycloalkylaminocarbonyl (the mono-C 1-6 alkylaminocarbonyl, mono-C 3-8 cycloalkylaminocarbonyl, di-C 1-6 alkylaminocarbonyl and C 1-6 alkyl-C 3-8 cycloalkylaminocarbonyl are mono- C 1-6 substituted with one group identical to or different selected from alkyl aminocarbonyl and the group consisting of di-C 1-6 alkylaminocarbonyl.), heterocyclylcarbonyl in heterocyclylcarbonyl (saturated saturated Substituted with 1 to 2 groups selected from the group consisting of halogen atom, carbamoyl, cyano and oxo, the same or different C 1-6 alkylsulfinyl (the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) or C 1-6 alkylsulfonyl (the C 1- 6 alkylsulfonyl is substituted with 1 hydroxy)),
　このとき、より好ましいＲ11、Ｒ12及びＲ13は、モノＣ1-4アルキルアミノカルボニル、モノＣ3-6シクロアルキルアミノカルボニル、ジＣ1-4アルキルアミノカルボニル、Ｃ1-4アルキルＣ3-6シクロアルキルアミノカルボニル（該モノＣ1-4アルキルアミノカルボニル、モノＣ3-6シクロアルキルアミノカルボニル、ジＣ1-4アルキルアミノカルボニル及びＣ1-4アルキルＣ3-6シクロアルキルアミノカルボニルは、モノＣ1-4アルキルアミノカルボニル及びジＣ1-4アルキルアミノカルボニルからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。）、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、ハロゲン原子、カルバモイル及びオキソからなる群より選ばれる１～２個の基で置換されている。）、Ｃ1-4アルキルスルフィニル（該Ｃ1-4アルキルスルフィニルは、置換されていないか、１個のヒドロキシで置換されている。）又はＣ1-4アルキルスルホニル（該Ｃ1-4アルキルスルホニルは、１個のヒドロキシで置換されている。）であり、
　ここで、該Ｒ11は、上記ベンゼン環又は６員のヘテロ芳香環の４位に置換し、
　また、該Ｒ12及びＲ13は、独立して上記ベンゼン環又は６員のヘテロ芳香環の２位又は３位に置換し、 R 11 , R 12 and R 13 are more preferably mono C 1-4 alkylaminocarbonyl, mono C 3-6 cycloalkylaminocarbonyl, di C 1-4 alkylaminocarbonyl, C 1-4 alkyl C 3. -6 cycloalkylaminocarbonyl (the mono-C 1-4 alkylaminocarbonyl, mono-C 3-6 cycloalkylaminocarbonyl, di-C 1-4 alkylaminocarbonyl and C 1-4 alkylC 3-6 cycloalkylaminocarbonyl are Substituted with one or two groups selected from the same or different from the group consisting of mono C 1-4 alkylaminocarbonyl and diC 1-4 alkylaminocarbonyl), saturated heterocyclylcarbonyl (the saturated The heterocyclylcarbonyl is substituted with 1 to 2 groups selected from the group consisting of a halogen atom, carbamoyl and oxo). C 1-4 alkylsulfinyl (wherein the C 1-4 alkylsulfinyl is unsubstituted or substituted with one hydroxy) or C 1-4 alkylsulfonyl (wherein the C 1-4 alkylsulfonyl is Substituted with one hydroxy).
Here, R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring,
R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
　このとき、さらに好ましいＲ11は、メチルアミノカルボニル（該メチルアミノカルボニルは、メチルアミノカルボニル及びＮ，Ｎ－ジメチルアミノカルボニルからなる群より選ばれる１個の基で置換されている。）、Ｎ，Ｎ－ジメチルアミノカルボニル（該Ｎ，Ｎ－ジメチルアミノカルボニルは、置換されていないか、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、２個のフッ素原子で置換されている。）、モルホリノカルボニル又は１－ピペラジニルカルボニル（該１－ピペラジニルカルボニルは、置換されていないか、１個のオキソで置換されている。）であり、
　ここで、該Ｒ11は、上記ベンゼン環又は６員のヘテロ芳香環の４位に置換し、
　このとき、さらに好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環又は６員のヘテロ芳香環の２位又は３位に置換し、 In this case, more preferred R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of methylaminocarbonyl and N, N-dimethylaminocarbonyl), N, N-dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), azetidin-1-yl-carbonyl (The azetidin-1-yl-carbonyl is substituted with 2 fluorine atoms), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is either unsubstituted or 1 Substituted with oxo).
Here, R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring,
At this time, more preferred R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Here, R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring,
　このとき、特に好ましいＲ11は、メチルアミノカルボニル（該メチルアミノカルボニルは、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、Ｎ，Ｎ－ジメチルアミノカルボニル（該Ｎ，Ｎ－ジメチルアミノカルボニルは、１個のシアノで置換されている。）、モルホリノカルボニル又は１－ピペラジニルカルボニル（該１－ピペラジニルカルボニルは、オキソで置換されている。）であり、
　ここで、該Ｒ11は、上記ベンゼン環又は６員のヘテロ芳香環の４位に置換し、
　このとき、特に好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環又は６員のヘテロ芳香環の２位又は３位に置換し； Particularly preferred R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of carbamoyl and cyano), N, N-dimethylaminocarbonyl (the N , N-dimethylaminocarbonyl is substituted with 1 cyano), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is substituted with oxo),
Here, R 11 is substituted at the 4-position of the benzene ring or 6-membered heteroaromatic ring,
At this time, particularly preferred R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Wherein R 12 and R 13 are independently substituted at the 2-position or 3-position of the benzene ring or 6-membered heteroaromatic ring;
　好ましいＸは、－Ｏ－又は－ＮＨ－であり、
　より好ましいＸは、－Ｏ－であり； Preferred X is —O— or —NH—,
More preferred X is —O—;
　好ましいＹは、エタン－１,２－ジイル、プロパン－１,３－ジイル又はブタン－１,４－ジイルであり、
　より好ましいＹは、プロパン－１,３－ジイル又はブタン－１,４－ジイルであり、
　さらに好ましいＹは、プロパン－１,３－ジイルであり； Preferred Y is ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl;
More preferred Y is propane-1,3-diyl or butane-1,4-diyl,
More preferred Y is propane-1,3-diyl;
　ひとつの好ましいＲ2は、（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のトリフルオロメチルで置換されている。）で置換されている。］又はハロＣ1-6アルキルであり、
　このとき、より好ましいＲ2は、（ａ）メチル（該メチルは、１個のＣ3-6シクロアルキルで置換されている。）、Ｃ3-6アルキル又はハロＣ3-6アルキルであり、
　このとき、さらに好ましいＲ2は、（ａ）メチル（該メチルは、１個のシクロペンチルで置換されている。）、ネオペンチル又はイソプロピル（該イソプロピルは、１個のフッ素原子で置換されている。）であり； One preferred R 2 is (a) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted) Or is substituted with 1 trifluoromethyl). Or haloC 1-6 alkyl;
In this case, more preferable R 2 is (a) methyl (the methyl is substituted with one C 3-6 cycloalkyl), C 3-6 alkyl or haloC 3-6 alkyl,
In this case, more preferable R 2 is (a) methyl (the methyl is substituted with one cyclopentyl), neopentyl or isopropyl (the isopropyl is substituted with one fluorine atom). Is;
　他の好ましいＲ2は、（ｂ）－ＣＯＯＲ21であり、
　このとき、好ましいＲ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）であり、
　このとき、より好ましいＲ21は、Ｃ1-6アルキル（該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-6シクロアルキル（該Ｃ3-6シクロアルキルは、置換されていないか、１個のＣ1-4アルキルで置換されている。）で置換されている。）、ハロＣ3-6アルキル又はＣ3-6シクロアルキル（該Ｃ3-6シクロアルキルは、置換されていないか、１個のＣ1-4アルキルで置換されている。）であり、
　このとき、さらに好ましいＲ21は、メチル［該メチルは、置換されていないか、１個のシクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）で置換されている。］、イソプロピル、イソブチル、tert-ブチル（該tert-ブチルは、置換されていないか、１～２個のフッ素原子で置換されている。）、ネオペンチル、シクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）又はシクロペンチルであり、
　このとき、特に好ましいＲ21は、メチル［該メチルは、１個のシクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）で置換されている。］、イソプロピル、イソブチル、tert-ブチル（該tert-ブチルは、置換されていないか、１～２個のフッ素原子で置換されている。）、シクロプロピル（該シクロプロピルは、１個のメチルで置換されている。）又はシクロペンチルであり； Another preferred R 2 is (b) -COOR 21
In this case, preferable R 21 is C 1-6 alkyl [the C 1-6 alkyl is not substituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is substituted). Or is substituted with one C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl, wherein the C 3-8 cycloalkyl is unsubstituted or substituted with one C 1-6 alkyl.
In this case, more preferable R 21 is C 1-6 alkyl (the C 1-6 alkyl is not substituted or one C 3-6 cycloalkyl (the C 3-6 cycloalkyl is substituted). Or substituted with 1 C 1-4 alkyl.)), Halo C 3-6 alkyl or C 3-6 cycloalkyl (wherein the C 3-6 cycloalkyl is Unsubstituted or substituted with one C 1-4 alkyl).
At this time, R 21 is more preferably methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl). Has been replaced. ], Isopropyl, isobutyl, tert-butyl (the tert-butyl is unsubstituted or substituted with 1 to 2 fluorine atoms), neopentyl, cyclopropyl (the cyclopropyl is substituted Or substituted with one methyl) or cyclopentyl,
In this case, particularly preferred R 21 is methyl [the methyl is substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl). ], Isopropyl, isobutyl, tert-butyl (the tert-butyl is unsubstituted or substituted with 1 to 2 fluorine atoms), cyclopropyl (the cyclopropyl is 1 methyl Substituted) or cyclopentyl;
　また、他の好ましいＲ2は、（ｃ）下記式（β）で表される５又は６員のヘテロアリール（該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）であり、 Another preferable R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula (β) (the 5- or 6-membered heteroaryl represented by the formula (β) is not substituted. Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1-6 alkoxy Is)
Figure JPOXMLDOC01-appb-C000016
 　このとき、より好ましいＲ2は、（ｃ）上記式（β）で表される５又は６員のヘテロアリールがオキサジアゾリル、ピリジル又はピリミジニル（該オキサジアゾリル、ピリジル及びピリミジニルは、置換されていないか、ハロゲン原子、Ｃ1-4アルキル、ハロＣ1-4アルキル、Ｃ3-6シクロアルキル及びＣ1-4アルコキシからなる群より選ばれる１個の基で置換されている。）であり、
　このとき、さらに好ましいＲ2は、（ｃ）上記式（β）で表される５又は６員のヘテロアリールがオキサジアゾリル（該オキサジアゾリルは、置換されていないか、１個のイソプロピルで置換されている。）、ピリジル又はピリミジニル（該ピリジル及びピリミジニルは、置換されていないか、フッ素原子、塩素原子、メチル、エチル、イソプロピル及びシクロプロピルからなる群より選ばれる１個の基で置換されている。）であり、
　このとき、特に好ましいＲ2は、（ｃ）上記式（β）で表される５又は６員のヘテロアリールが５－オキサジアゾリル（該５－オキサジアゾリルは、１個のイソプロピルで置換されている。）又は２－ピリミジニル（該２－ピリミジニルは、１個のエチルで置換されている。）であり；
Figure JPOXMLDOC01-appb-C000016
 In this case, more preferable R 2 is (c) a 5- or 6-membered heteroaryl represented by the above formula (β) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted or halogenated) Substituted with one group selected from the group consisting of an atom, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl and C 1-4 alkoxy.
At this time, more preferable R 2 is (c) a 5- or 6-membered heteroaryl represented by the above formula (β) is oxadiazolyl (the oxadiazolyl is not substituted or substituted with one isopropyl) ), Pyridyl or pyrimidinyl (the pyridyl and pyrimidinyl are unsubstituted or substituted with one group selected from the group consisting of fluorine atom, chlorine atom, methyl, ethyl, isopropyl and cyclopropyl). And
In this case, particularly preferred R 2 is (c) 5-oxadiazolyl of 5- or 6-membered heteroaryl represented by the above formula (β) (the 5-oxadiazolyl is substituted with one isopropyl). Or 2-pyrimidinyl (the 2-pyrimidinyl is substituted with 1 ethyl);
　また、他の好ましいＲ2は、（ｅ）Ｃ1-6アルキルカルボニル又はＣ3-8シクロアルキルカルボニル（該Ｃ3-8シクロアルキルカルボニルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）であり、
　このとき、より好ましいＲ2は、（ｅ）Ｃ3-6アルキルカルボニル又はＣ3-6シクロアルキルカルボニル（該Ｃ3-6シクロアルキルカルボニルは、置換されていないか、１個のＣ1-4アルキルで置換されている。）であり、
　このとき、さらに好ましいＲ2は、（ｅ）tert-ブチルカルボニル、ネオペンチルカルボニル又はシクロプロピルカルボニル（該シクロプロピルカルボニルは、置換されていないか、１個のメチルで置換されている。）であり、
　このとき、特に好ましいＲ2は、（ｅ）tert-ブチルカルボニル又はネオペンチルカルボニルである。 Further, other preferable R 2 is (e) C 1-6 alkylcarbonyl or C 3-8 cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with one C 1-6 Substituted with alkyl).
In this case, more preferable R 2 is (e) C 3-6 alkylcarbonyl or C 3-6 cycloalkylcarbonyl (the C 3-6 cycloalkylcarbonyl is either unsubstituted or substituted with one C 1-4). Substituted with alkyl).
In this case, more preferable R 2 is (e) tert-butylcarbonyl, neopentylcarbonyl or cyclopropylcarbonyl (the cyclopropylcarbonyl is unsubstituted or substituted with one methyl). ,
In this case, particularly preferred R 2 is (e) tert-butylcarbonyl or neopentylcarbonyl.
　本発明のひとつの好ましい態様は、下記式（II）において、以下に示される化合物又はその製薬学的に許容される塩である。 One preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (II).
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　ここで、
　Ａで表される環、Ｒ11、Ｒ12、Ｒ13、Ｙ及びＲ2の好ましい態様は、上記に記載した通りである。 here,
Preferred embodiments of the ring represented by A, R 11 , R 12 , R 13 , Y and R 2 are as described above.
　本発明の他の好ましい態様は、下記式（III）において、以下に示される化合物又はその製薬学的に許容される塩である。 Another preferred embodiment of the present invention is a compound shown below or a pharmaceutically acceptable salt thereof in the following formula (III).
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　ここで、
　Ａで表される環、Ｒ11、Ｒ12、Ｒ13、Ｙ及びＲ2の好ましい態様は、上記に記載した通りである。 here,
Preferred embodiments of the ring represented by A, R 11 , R 12 , R 13 , Y and R 2 are as described above.
　また、本発明化合物の他の態様は下記の通りである（この態様は、上記式（II）及び（III）にも適用される）。 Further, other embodiments of the compound of the present invention are as follows (this embodiment is also applied to the above formulas (II) and (III)).
　ここで、
　Ｙ及びＲ2の好ましい態様は、上記に記載した通りであり；
　Ａで表される好ましい環は、ベンゼン環であり； here,
Preferred embodiments of Y and R 2 are as described above;
A preferred ring represented by A is a benzene ring;
　ひとつの好ましいＲ11は、カルバモイル、メチルアミノカルボニル（該メチルアミノカルボニルは、置換されていないか、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、エチルアミノカルボニル［該エチルアミノカルボニルは、置換されていないか、ヒドロキシ、メトキシ、エトキシ（該エトキシは、置換されていないか、１個のヒドロキシで置換されている。）及びＮ，Ｎ－ジメチルアミノからなる群より選ばれる１個の基で置換されている。］、ｎ－プロピルアミノカルボニル（該ｎ－プロピルアミノカルボニル、置換されていないか、１～２個のヒドロキシで置換されている。）、イソプロピルアミノカルボニル（該イソプロピルアミノカルボニルは、置換されていないか、１～２個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル（該Ｎ－エチル－Ｎ－メチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｎ－シクロプロピル－Ｎ－メチルアミノカルボニル、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、オキセタン-３-イルアミノカルボニル又はメチルスルホニルであり、
　ここで、該Ｒ11は、上記ベンゼン環のパラ位に置換し、
　このとき、好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環のオルト位又はメタ位に置換し、 One preferred R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [ The ethylaminocarbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with one selected group. ], N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), It is oxetane-3-yl-aminocarbonyl or methylsulfonyl,
Here, R 11 is substituted at the para-position of the benzene ring,
In this case, preferable R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Here, R 12 and R 13 are independently substituted at the ortho-position or meta-position of the benzene ring,
　このとき、より好ましいＲ11は、エチルアミノカルボニル［該エチルアミノカルボニルは、ヒドロキシ、メトキシ及びエトキシ（該エトキシは、１個のヒドロキシで置換されている。）からなる群より選ばれる１個の基で置換されている。］、イソプロピルアミノカルボニル（該イソプロピルアミノカルボニルは、１～２個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル（該Ｎ－エチル－Ｎ－メチルアミノカルボニルは、１個のヒドロキシで置換されている。）、Ｎ－シクロプロピル－Ｎ－メチルアミノカルボニル、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、１個のヒドロキシで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、１個のヒドロキシで置換されている。）、オキセタン-３-イルアミノカルボニル又はメチルスルホニルであり、
　ここで、該Ｒ11は、上記ベンゼン環のパラ位に置換し、
　このとき、より好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環のオルト位又はメタ位に置換し； In this case, R 11 is more preferably ethylaminocarbonyl [wherein the ethylaminocarbonyl is a group selected from the group consisting of hydroxy, methoxy and ethoxy (wherein the ethoxy is substituted with one hydroxy). Has been replaced by ], Isopropylaminocarbonyl (the isopropylaminocarbonyl is substituted with 1-2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylamino) Carbonyl is substituted with 1 hydroxy), N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is substituted with 1 hydroxy) Pyrrolidin-1-yl-carbonyl (wherein the pyrrolidin-1-yl-carbonyl is substituted with one hydroxy), oxetane-3-ylaminocarbonyl or methylsulfonyl;
Here, R 11 is substituted at the para-position of the benzene ring,
At this time, more preferable R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Wherein R 12 and R 13 are independently substituted at the ortho or meta position of the benzene ring;
　他の好ましいＲ11は、メチルアミノカルボニル（該メチルアミノカルボニルは、メチルアミノカルボニル及びＮ，Ｎ－ジメチルアミノカルボニルからなる群より選ばれる１個の基で置換されている。）、Ｎ，Ｎ－ジメチルアミノカルボニル（該Ｎ，Ｎ－ジメチルアミノカルボニルは、置換されていないか、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、２個のフッ素原子で置換されている。）、モルホリノカルボニル又は１－ピペラジニルカルボニル（該１－ピペラジニルカルボニルは、置換されていないか、１個のオキソで置換されている。）であり、
　ここで、該Ｒ11は、上記ベンゼン環のパラ位に置換し、
　このとき、好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環のオルト位又はメタ位に置換し、 Other preferable R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of methylaminocarbonyl and N, N-dimethylaminocarbonyl), N, N— Dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), azetidin-1-yl-carbonyl (the Azetidin-1-yl-carbonyl is substituted with 2 fluorine atoms), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is either unsubstituted or Substituted with oxo).
Here, R 11 is substituted at the para-position of the benzene ring,
In this case, preferable R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Here, R 12 and R 13 are independently substituted at the ortho-position or meta-position of the benzene ring,
　このとき、より好ましいＲ11は、メチルアミノカルボニル（該メチルアミノカルボニルは、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、Ｎ，Ｎ－ジメチルアミノカルボニル（該Ｎ，Ｎ－ジメチルアミノカルボニルは、１個のシアノで置換されている。）、モルホリノカルボニル又は１－ピペラジニルカルボニル（該１－ピペラジニルカルボニルは、オキソで置換されている。）であり、
　ここで、該Ｒ11は、上記ベンゼン環のパラ位に置換し、
　このとき、より好ましいＲ12及びＲ13は、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基であり、
　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環のオルト位又はメタ位に置換する。 In this case, more preferred R 11 is methylaminocarbonyl (the methylaminocarbonyl is substituted with one group selected from the group consisting of carbamoyl and cyano), N, N-dimethylaminocarbonyl (the N , N-dimethylaminocarbonyl is substituted with one cyano), morpholinocarbonyl or 1-piperazinylcarbonyl (the 1-piperazinylcarbonyl is substituted with oxo),
Here, R 11 is substituted at the para-position of the benzene ring,
At this time, more preferable R 12 and R 13 are the same or different groups selected from the group consisting of a hydrogen atom, a fluorine atom and methyl,
Here, R 12 and R 13 are independently substituted at the ortho or meta position of the benzene ring.
　また、本発明化合物の他の態様は下記の通りである（この態様は、上記式（II）及び（III）にも適用される）。 Further, other embodiments of the compound of the present invention are as follows (this embodiment is also applied to the above formulas (II) and (III)).
　ここで、
　Ｙ及びＲ2の好ましい態様は、上記に記載した通りであり；
　Ａで表される好ましい環は、ピリジン環であり； here,
Preferred embodiments of Y and R 2 are as described above;
A preferred ring represented by A is a pyridine ring;
　好ましいＲ11は、エチルアミノカルボニル（該エチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル又はメチルスルホニルであり；
　このとき、より好ましいＲ11は、シクロプロピルアミノカルボニル又はメチルスルホニルであり；
　好ましいＲ12は、水素原子であり；
　好ましいＲ13は、水素原子である。 Preferred R 11 is ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl;
In this case, more preferred R 11 is cyclopropylaminocarbonyl or methylsulfonyl;
Preferred R 12 is a hydrogen atom;
Preferred R 13 is a hydrogen atom.
　また、本発明化合物の他の態様は下記の通りである（この態様は、上記式（II）及び（III）にも適用される）。 Further, other embodiments of the compound of the present invention are as follows (this embodiment is also applied to the above formulas (II) and (III)).
　ここで、
　Ｙ及びＲ2の好ましい態様は、上記に記載した通りであり；
　Ａで表される好ましい環は、ピラジン環であり； here,
Preferred embodiments of Y and R 2 are as described above;
A preferred ring represented by A is a pyrazine ring;
　好ましいＲ11は、エチルアミノカルボニル（該エチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ，Ｎ－ジメチルアミノカルボニル（該Ｎ，Ｎ－ジメチルアミノカルボニルは、置換されていないか、１個のシアノで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モルホリノカルボニル又はメチルスルホニルであり、
　このとき、より好ましいＲ11は、シクロプロピルアミノカルボニル、Ｎ，Ｎ－ジメチルアミノカルボニル（該Ｎ，Ｎ－ジメチルアミノカルボニルは、１個のシアノで置換されている。）、モルホリノカルボニル又はメチルスルホニルであり；
　好ましいＲ12は、水素原子又はメチルであり；
　好ましいＲ13は、水素原子である。 Preferred R 11 is ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with one hydroxy), cyclopropylaminocarbonyl, N, N-dimethylaminocarbonyl (the N, N -Dimethylaminocarbonyl is unsubstituted or substituted with 1 cyano), pyrrolidin-1-yl-carbonyl (wherein the pyrrolidin-1-yl-carbonyl is unsubstituted or 1 Substituted with hydroxy)), morpholinocarbonyl or methylsulfonyl,
In this case, more preferable R 11 is cyclopropylaminocarbonyl, N, N-dimethylaminocarbonyl (the N, N-dimethylaminocarbonyl is substituted with one cyano), morpholinocarbonyl or methylsulfonyl. Yes;
Preferred R 12 is a hydrogen atom or methyl;
Preferred R 13 is a hydrogen atom.
　また、本発明化合物の他の態様は下記の通りである（この態様は、上記式（II）及び（III）にも適用される）。 Further, other embodiments of the compound of the present invention are as follows (this embodiment is also applied to the above formulas (II) and (III)).
　下記式（α１）で表されるアザスピロ環構造のうち、 Of the azaspiro ring structure represented by the following formula (α1),
Figure JPOXMLDOC01-appb-C000019
 　好ましいアザスピロ環構造は、以下の構造であり、
Figure JPOXMLDOC01-appb-C000019
 Preferred azaspiro ring structures are the following structures:
Figure JPOXMLDOC01-appb-C000020
 　より好ましいアザスピロ環構造は、以下の構造であり；
Figure JPOXMLDOC01-appb-C000020
 More preferred azaspiro ring structures are the following structures;
Figure JPOXMLDOC01-appb-C000021
 　Ａで表される好ましい環は、ベンゼン環又は６員のヘテロ芳香環であり、
　Ａで表されるより好ましい環は、ベンゼン環、ピリジン環又はピリミジン環であり；
Figure JPOXMLDOC01-appb-C000021
 A preferred ring represented by A is a benzene ring or a 6-membered heteroaromatic ring,
A more preferable ring represented by A is a benzene ring, a pyridine ring or a pyrimidine ring;
　好ましいＲ11、Ｒ12及びＲ13は、水素原子、ハロゲン原子、カルバモイル、シアノ、Ｃ1-6アルキル、ヘテロアリール、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル（該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-6アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。）、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｃ1-6アルキルスルホニルであり； Preferred R 11 , R 12 and R 13 are hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl (the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl And C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl is unsubstituted, hydroxy, carbamoyl, cyano, C 1-6 alkoxy (wherein the C 1-6 alkoxy is unsubstituted or substituted with hydroxy.) and optionally substituted with one to two groups the same or different and selected from the group consisting of di-C 1-6 alkylamino ..), Heterocyclylcarbonyl in heterocyclylcarbonyl (saturated in saturation, which is unsubstituted or substituted, is substituted with one hydroxy), it is a C 1-6 alkylsulfonyl;
　好ましいＸは、－Ｏ－であり； Preferred X is -O-;
　好ましいＹは、エタン－１,２－ジイル、プロパン－１,３－ジイル又はブタン－１,４－ジイルであり、
　より好ましいＹは、プロパン－１,３－ジイルであり； Preferred Y is ethane-1,2-diyl, propane-1,3-diyl or butane-1,4-diyl;
More preferred Y is propane-1,3-diyl;
　ひとつの好ましいＲ2は、（ｂ）－ＣＯＯＲ21であり、
　このとき好ましいＲ21はＣ1-6アルキル（該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。）、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）であり； One preferred R 2 is (b) -COOR 21
R 21 is preferably C 1-6 alkyl (the C 1-6 alkyl is not substituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is not substituted) Substituted with 1 C 1-6 alkyl.)), Halo C 1-6 alkyl or C 3-8 cycloalkyl (wherein the C 3-8 cycloalkyl is substituted) Or substituted with 1 to 3 groups selected from the group consisting of a halogen atom and C 1-6 alkyl, the same or different from each other);
　他の好ましいＲ2は、（ｃ）下記式（β）で表される５又は６員のヘテロアリール（該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル及びＣ3-8シクロアルキルからなる群より選ばれる１個の基で置換されている。）であり、 Another preferable R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula (β) (the 5- or 6-membered heteroaryl represented by the formula (β) is not substituted) And substituted with one group selected from the group consisting of a halogen atom, C 1-6 alkyl and C 3-8 cycloalkyl).
Figure JPOXMLDOC01-appb-C000022
 　このとき、より好ましいＲ2は、５－オキサジアゾリル（該５－オキサジアゾリルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）、２－ピリジル又は２－ピリミジニル（該２－ピリジル及び２－ピリミジニルは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル及びＣ3-8シクロアルキルからなる群より選ばれる１個の基で置換されている。）である。
Figure JPOXMLDOC01-appb-C000022
 In this case, more preferred R 2 is 5-oxadiazolyl (the 5-oxadiazolyl is unsubstituted or substituted with one C 1-6 alkyl), 2-pyridyl or 2-pyrimidinyl 2-pyridyl and 2-pyrimidinyl are unsubstituted or substituted with one group selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-8 cycloalkyl.
　本発明の化合物は、アザスピロアルカン化合物であり、その製薬学的に許容される塩でも良い（以下、適宜「本発明の化合物」という。）。 The compound of the present invention is an azaspiroalkane compound and may be a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compound of the present invention” as appropriate).
　製薬学的に許容される塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩、硫酸塩、硝酸塩のような鉱酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩のようなスルホン酸塩、シュウ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、コハク酸塩、酢酸塩、安息香酸塩、マンデル酸塩、アスコルビン酸塩、乳酸塩、グルコン酸塩、リンゴ酸塩のような有機酸塩等の酸付加塩、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩、又は、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩のような無機塩若しくはアンモニウム塩、トリエチルアミン塩、ジイソプロピルアミン塩、シクロヘキシルアミン塩のような有機塩基との塩が挙げられる。なお、塩には、含水塩が含まれる。 Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, hydroiodides, phosphates, sulfates, nitrates, mineral salts such as methanesulfonate, ethanesulfone, and the like. Sulfonate, benzenesulfonate, p-toluenesulfonate, sulfonate such as trifluoromethanesulfonate, oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate Acid addition salts such as acid salts, mandelate, ascorbate, lactate, gluconate, malate, glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartic acid Amino acid salts such as salts, or inorganic or ammonium salts such as lithium, sodium, potassium, calcium, and magnesium salts, triethylamine salts, Isopropylamine salt, salts with organic bases such as cyclohexylamine salts. The salt includes a hydrated salt.
　本発明の化合物は、不斉中心を持つことがあり、その場合種々の光学異性体が存在する。したがって、本発明の化合物は、（Ｒ）および（Ｓ）の別々の光学活性体として、およびラセミ体又は（ＲＳ）混合物として存在し得る。また、不斉中心を２個以上持つ化合物の場合には、さらにそれぞれの光学異性によるジアステレオマーも存在する。本発明の化合物は、これらすべての型を、任意の割合で含むものも含む。たとえば、ジアステレオマーは当業者によく知られた方法、たとえば分別結晶法等によって分離することができ、また、光学活性体はこの目的のためによく知られた有機化学的手法によって得ることができる。また、本発明の化合物には、シス体、トランス体などの幾何異性体が存在することがある。本発明の化合物は、それらの異性体、及びそれらの異性体を任意の割合で含んだものも含む。 The compound of the present invention may have an asymmetric center, in which case various optical isomers exist. Thus, the compounds of the present invention may exist as separate optically active forms of (R) and (S) and as racemates or (RS) mixtures. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, 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 of the present invention may have geometric isomers such as cis isomer and trans isomer. The compound of the present invention includes those isomers and those containing these isomers in an arbitrary ratio.
　本発明化合物は、ＧＰＲ１１９アゴニスト活性を有する。よって、本発明化合物は膵β細胞ＧＰＲ１１９の直接活性化あるいは小腸ＧＬＰ－１分泌を介した膵β細胞ＧＬＰ－１受容体活性化を引き起こし、高血糖依存的に膵β細胞からのインスリン分泌を増大させることで高血糖を是正することができる。また、膵β細胞ＧＰＲ１１９活性化を介する膵β細胞保護作用により、膵β細胞の機能不全、疲弊を緩和あるいは改善する。従って、既存の糖尿病治療薬とは作用機序の異なる新たな薬物療法として利用できる。糖尿病とは、I型糖尿病、II型糖尿病、特定の原因によるその他の糖尿病を包含する。
本発明化合物は肥満症、高脂血症、高血圧症、メタボリックシンドローム、浮腫、高尿酸血症、痛風などの糖尿病関連疾患の治療或いは予防薬にも利用可能である。
本発明化合物は膵β細胞保護作用を有することから、膵島移植時の予後改善に使用可能である。
　さらに、本発明化合物は、ケトアシドーシス、細小血管症（網膜症、腎症）、動脈硬化症（アテローム性動脈硬化症、心筋梗塞、脳梗塞、抹消動脈閉塞など）、神経障害（感覚神経、運動神経、自律神経など）、足壊疽、感染症などの糖尿病性合併症の治療薬或いは予防薬として利用できる。
　また、本発明化合物はＧＰＲ１１９アゴニスト作用以外の異なる作用機序の糖尿病治療薬、糖尿病合併症治療薬、高脂血症治療薬、高血圧治療薬などと併用して使用することもできる。本発明の化合物とその他の薬剤を組み合わせることによって、上記疾患においてそれぞれ単剤で得られる効果よりも併用した場合に相加的な効果が期待できる。 The compound of the present invention has GPR119 agonist activity. Therefore, the compound of the present invention causes pancreatic β cell GLP-1 receptor activation through direct activation of pancreatic β cell GPR119 or small intestine GLP-1 secretion, and increases insulin secretion from pancreatic β cells in a hyperglycemic manner Can correct hyperglycemia. In addition, pancreatic β-cell dysfunction and exhaustion are alleviated or improved by pancreatic β-cell protective action through activation of pancreatic β-cell GPR119. Therefore, it can be used as a new drug therapy having a different mechanism of action from existing anti-diabetic drugs. Diabetes includes type I diabetes, type II diabetes, and other diabetes due to specific causes.
The compound of the present invention can also be used for the treatment or prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension, metabolic syndrome, edema, hyperuricemia, and gout.
Since the compound of the present invention has a pancreatic β-cell protective action, it can be used to improve the prognosis at the time of islet transplantation.
Furthermore, the compound of the present invention can be used for ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, peripheral artery occlusion, etc.), neuropathy (sensory nerve, motor Nerves, autonomic nerves, etc.), foot gangrene, infections and other diabetic complications.
The compound of the present invention can also be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a therapeutic agent for hypertension and the like having a different mechanism of action other than the GPR119 agonistic action. By combining the compound of the present invention with other drugs, an additive effect can be expected when used in combination with the above diseases, rather than the effect obtained with a single agent.
　併用可能な糖尿病治療薬、糖尿病合併症治療薬としては、例えば、インスリン製剤、インスリンのフラグメントまたは誘導体（ＩＮＳ－１）、経口インスリン製剤、インスリン抵抗性改善薬（ＰＰＡＲγアゴニスト、ＰＰＡＲα／γアゴニスト、ＰＰＡＲδアゴニスト、ＰＰＡＲα／γ／δアゴニスト等）（例、ピオグリタゾン、ロシグリタゾン、ＧＷ－５０１５１６、ＧＷ－５９０７３５、ＡＢＴ－３３５、ＡＺＤ－６６１０、ＡＶＥ－８１３３）、αグルコシダーゼ阻害薬（例、ボグリボース、アカルボース、ミグリトール）、ビグアナイド薬（例、メトホルミン、ブホルミン、フェンホルミン）、インスリン分泌促進薬（例、グリベンクラミド、グリメピリド、レパグリニド、ナテグリニド、ミチグリニド）、グルカゴン受容体アンタゴニスト、インスリン受容体キナーゼ促進薬、ジペプチジルペプチダーゼＩＶ阻害薬（例、ビルダグリプチン、アログリプチン、シタグリプチン、リナグリプチン、サクサグリプチン）、ＳＧＬＴ阻害薬（例、サーグリフロジン、カナグリフロジン、ダパグリフロジン、ＴＳ－０７１、ＡＳＰ－１９４１）、ＰＴＰ１ｂ阻害薬（例、バナジン酸ナトリウム）、グルコース６ホスファターゼ阻害薬、グリコーゲンホスホリラーゼ阻害薬（例、ＰＳＮ－３５７、ＦＲ－２５８９００）、ＦＢＰａｓｅ阻害薬（例、ＭＢ－０７８０３）、ＰＥＰＣＫ阻害薬、ピルビン酸デヒドロゲナーゼキナーゼ阻害薬、Ｄ－カイロイノシトール、ＧＳＫ３阻害薬、ＧＬＰ－１アゴニスト（例、リラグルチド、エクセナチド）、ＧＩＰアゴニスト、アミリンアゴニスト（例、プラムリンチド）、ソマトスタチン受容体アゴニスト、グルココルチコイド受容体アンタゴニスト、１１ベータＨＳＤ１阻害薬（例、ＡＭＧ－２２１、ＩＮＣＢ－１３７３９）、プロテインキナーゼＣ阻害薬（例、ルボキシスタウリン）、ＩＫＫβ阻害薬、ベータ３アドレナリン受容体アゴニスト（例、ＡＪ－９６７７）、フォスファチジルイノシトールキナーゼ阻害薬、フォスファチジルイノシトールホスファターゼ阻害薬、ＡＣＣ阻害薬、ＧＰＲ４０受容体アゴニスト、ＧＰＲ１２０受容体アゴニスト、ＴＧＲ５受容体アゴニスト、ＡＭＰＫ活性化薬（例、ＤＲＬ－１６５３６）、グルコキナーゼ活性化薬、ＦＧＦ２１、ＦＧＦアナログ、アルドース還元酵素阻害薬、ＡＧＥ阻害薬などが挙げられる。
　また併用可能な糖尿病関連疾患の薬剤としては、例えば、ＨＭＧ－ＣｏＡ還元酵素阻害薬、スクアレン合成酵素阻害薬、胆汁酸吸着剤、ＩＢＡＴ阻害薬、ＣＥＴＰ阻害薬、ＣＰＴ阻害薬、フィブラート系薬剤、ＡＣＡＴ阻害薬、ＭＧＡＴ阻害薬、ＤＧＡＴ阻害薬、コレステロール吸収阻害薬、膵リパーゼ阻害薬、ＭＴＰ阻害薬、ニコチン酸誘導体、ＬＸＲアゴニスト、ＬＤＬ受容体促進薬、アンジオテンシン変換酵素阻害薬、アンジオテンシンＩＩアンタゴニスト、利尿薬、カルシウム拮抗薬、エンドセリン変換酵素阻害薬、エンドセリン受容体アンタゴニスト、食欲抑制薬、尿酸生成阻害薬、尿酸排泄促進薬などが挙げられる。 Examples of antidiabetic drugs and diabetic complications that can be used in combination include insulin preparations, insulin fragments or derivatives (INS-1), oral insulin preparations, insulin resistance improving drugs (PPARγ agonists, PPARα / γ agonists, PPARδ). Agonists, PPARα / γ / δ agonists, etc. (eg, pioglitazone, rosiglitazone, GW-501516, GW-590735, ABT-335, AZD-6610, AVE-8133), α-glucosidase inhibitors (eg, voglibose, acarbose, Miglitol), biguanide drugs (eg, metformin, buformin, phenformin), insulin secretagogues (eg, glibenclamide, glimepiride, repaglinide, nateglinide, mitiglinide), glucagon receptor antagonist Insulin receptor kinase promoter, dipeptidyl peptidase IV inhibitor (eg, vildagliptin, alogliptin, sitagliptin, linagliptin, saxagliptin), SGLT inhibitor (eg, sagliflozin, canagliflozin, dapagliflozin, TS-071, ASP -1941), PTP1b inhibitors (eg, sodium vanadate), glucose 6 phosphatase inhibitors, glycogen phosphorylase inhibitors (eg, PSN-357, FR-258900), FBPase inhibitors (eg, MB-07803), PEPCK inhibition Drug, pyruvate dehydrogenase kinase inhibitor, D-kaileunositol, GSK3 inhibitor, GLP-1 agonist (eg, liraglutide, exenatide), GIP agonist, amylin agonist (eg, Plumlintide), somatostatin receptor agonist, glucocorticoid receptor antagonist, 11 beta HSD1 inhibitor (eg, AMG-221, INCB-13739), protein kinase C inhibitor (eg, ruboxistaurin), IKKβ inhibitor, beta 3-adrenergic receptor agonist (eg, AJ-9679), phosphatidylinositol kinase inhibitor, phosphatidylinositol phosphatase inhibitor, ACC inhibitor, GPR40 receptor agonist, GPR120 receptor agonist, TGR5 receptor agonist, AMPK activity And glucokinase activators, FGF21, FGF analogs, aldose reductase inhibitors, AGE inhibitors and the like.
Examples of drugs for diabetes-related diseases that can be used in combination include HMG-CoA reductase inhibitors, squalene synthetase inhibitors, bile acid adsorbents, IBAT inhibitors, CETP inhibitors, CPT inhibitors, fibrate drugs, ACAT Inhibitor, MGAT inhibitor, DGAT inhibitor, cholesterol absorption inhibitor, pancreatic lipase inhibitor, MTP inhibitor, nicotinic acid derivative, LXR agonist, LDL receptor promoter, angiotensin converting enzyme inhibitor, angiotensin II antagonist, diuretic , Calcium antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, appetite suppressants, uric acid production inhibitors, uric acid excretion promoters, and the like.
　本発明化合物は、単独又は薬学的あるいは薬剤学的に許容される担体又は希釈剤と共に投与することができる。本発明化合物をＧＰＲ１１９アゴニストなどとして使用する場合は、本発明化合物をそのまま経口投与、又は非経口投与してもよい。また、本発明化合物を有効成分として含む剤として経口投与、又は非経口投与してもよい。非経口投与としては、静脈内投与、経鼻投与、経皮投与、皮下投与、筋肉内投与、舌下投与があげられる。 The compound of the present invention can be administered alone or together with a pharmaceutically or pharmaceutically acceptable carrier or diluent. When the compound of the present invention is used as a GPR119 agonist or the like, the compound of the present invention may be orally or parenterally administered as it is. Moreover, you may administer orally or parenterally as an agent which contains this invention compound as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.
　本発明化合物の投与量は、投与対象、投与ルート、対象疾患、症状などによっても異なるが、例えば、成人の糖尿病患者に経口投与する場合、通常１回量として０．１ｍｇ～１０００ｍｇ、好ましくは１ｍｇ～２００ｍｇであり、この量を１日１回～３回投与するのが望ましい。 The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. It is desirable to administer this amount once to three times a day.
　本発明の化合物のＧＰＲ１１９のアゴニスト作用を評価するには、例えば、試験方法に記載した方法など、公知の手法に従って行うことができる。 The agonistic effect of GPR119 of the compound of the present invention can be evaluated according to a known method such as the method described in the test method.
　なお、一般式（Ｉ）で示される本発明化合物は、医薬品として望ましい性質を有している。例えば、良好な水溶性を有していることで有効性の面で有利であったり、肝代謝酵素に対して阻害活性を示さないことで安全性の面で有利である等の性質が挙げられる。 The compound of the present invention represented by the general formula (I) has desirable properties as a pharmaceutical product. For example, it is advantageous in terms of effectiveness because it has good water solubility, and is advantageous in terms of safety because it exhibits no inhibitory activity against liver metabolic enzymes. .
　本化合物に係る化合物の製造方法を詳細に説明するが、例示されたものに特に限定されない。また、反応に使用する溶媒においても、各反応を阻害しないものであればよく、特に下記の記載に限定されない。 Although the method for producing the compound according to the present compound will be described in detail, it is not particularly limited to those exemplified. Moreover, the solvent used for the reaction is not particularly limited as long as it does not inhibit each reaction.
　以下、化合物（Ｉ）の製造法について説明する。 Hereinafter, the production method of compound (I) will be described.
　化合物（Ｉ）は、自体公知の方法、例えば、以下に示す製造法１～１９又はこれらに準ずる方法により製造することができる。なお、以下の各製造方法において、原料化合物は塩として用いてもよく、例えば、前記の「製薬学的に許容される塩」が挙げられる。 Compound (I) can be produced by a method known per se, for example, the production methods 1 to 19 shown below or a method analogous thereto. In each of the following production methods, the raw material compound may be used as a salt, and examples thereof include the above-mentioned “pharmaceutically acceptable salts”.
　本発明の化合物（Ｉ）のうち、Ｘが－Ｏ－である化合物（Ｉ－２）は、例えば、下記製造法１又はこれに準ずる方法により製造することができる。
　製造法１： Among the compounds (I) of the present invention, the compound (I-2) in which X is —O— can be produced, for example, by the following production method 1 or a method analogous thereto.
Production method 1:
Figure JPOXMLDOC01-appb-C000023
 [式中、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｙ及びＲ2は前記と同意義を示す。]
Figure JPOXMLDOC01-appb-C000023
 [Wherein, m1, m2, A, R 11 , R 12 , R 13 , Y and R 2 are as defined above] ]
[工程１－１]
　本工程は、化合物（Ｉ－１）を用いて化合物（Ｉ－２）を製造する方法である。
　本方法は、公知の方法、いわゆる光延反応（Ｓｙｎｔｈｅｓｉｓ，１９８１，１－２８）を用いて行うことができる。
　本工程において用いられる化合物（Ｉ－３）の量は、化合物（Ｉ－１）１当量に対して０．５から５当量であり、好ましくは１から３当量である。
　用いられるアゾ化合物としては、通常例えばアゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル、１，１’－アゾビス（Ｎ，Ｎ－ジメチルホルムアミド）等が挙げられる。用いられるアゾ化合物の量は、化合物（Ｉ－１）１当量に対して０．５から５当量であり、好ましくは１から３当量である。
　用いられるホスフィン化合物としては、通常例えばトリフェニルホスフィン、トリブチルホスフィン等が挙げられる。用いられるホスフィン化合物の量は、化合物（Ｉ－１）１当量に対して０．５から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジエチルエーテル、クロロホルム、ジクロロメタン、トルエン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常室温から還流温度で、１から４時間で行うことができる。
　また、本工程は、文献記載の方法（Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔｅｒｓ，１９９５，３６，２５３１－２５３４、Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔｅｒｓ，１９９６，３７，２４６３－２４６６）を用いて行うことができる。
　本工程に用いられる試薬としては、例えば、（シアノメチレン）トリメチルホスホラン、又は（シアノメチレン）トリブチルホスホラン等が挙げられる。用いられる試薬の量は、化合物（１－１）１当量に対して、１から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としては、前記と同様なものが挙げられる。
　これらの反応は、通常室温から還流温度で、１から２４時間で行うことができる。
　このようにして得られる化合物（Ｉ－２）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 1-1]
This step is a method for producing compound (I-2) using compound (I-1).
This method can be performed using a known method, the so-called Mitsunobu reaction (Synthesis, 1981, 1-28).
The amount of compound (I-3) used in this step is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
Examples of the azo compound to be used include diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1′-azobis (N, N-dimethylformamide) and the like. The amount of the azo compound used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
Examples of the phosphine compound used usually include triphenylphosphine and tributylphosphine. The amount of the phosphine compound used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (I-1).
Examples of the solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, diethyl ether, chloroform, dichloromethane, toluene, N, N-dimethylformamide, dimethyl sulfoxide and the like, which are not involved in the reaction. You may mix and use by the ratio.
These reactions can usually be performed at room temperature to reflux temperature for 1 to 4 hours.
In addition, this step can be performed using methods described in the literature (Tetrahedron Letters, 1995, 36, 2531-2534, Tetrahedron Letters, 1996, 37, 2463-2466).
Examples of the reagent used in this step include (cyanomethylene) trimethylphosphorane, (cyanomethylene) tributylphosphorane, and the like. The amount of the reagent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1-1).
Examples of the solvent used for the reaction include the same solvents as described above.
These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
The compound (I-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ａで表される環が６員のヘテロ芳香環である化合物（II－２）は、例えば、下記製造法２又はこれに準ずる方法により製造することができる。
　製造法２： Among the compounds (I) of the present invention, the compound (II-2) in which the ring represented by A is a 6-membered heteroaromatic ring can be produced, for example, by the following production method 2 or a method analogous thereto. .
Production method 2:
Figure JPOXMLDOC01-appb-C000024
 [式中、Ｕａは脱離基を、Ａ’は６員のヘテロ芳香環を、ｍ１、ｍ２、Ｒ11、Ｒ12、Ｒ13、Ｘ、Ｙ及びＲ2は前記と同意義を示す。]
　Ｕａで示される「脱離基」としては、例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、ベンゼンスルホニルオキシ等が挙げられる。
　Ａ’で表される「６員のヘテロ芳香環」は、前記と同意義を示す。
Figure JPOXMLDOC01-appb-C000024
 [Wherein Ua represents a leaving group, A ′ represents a 6-membered heteroaromatic ring, and m1, m2, R 11 , R 12 , R 13 , X, Y, and R 2 have the same meaning as described above. ]
Examples of the “leaving group” represented by Ua include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
The “6-membered heteroaromatic ring” represented by A ′ has the same meaning as described above.
[工程２－１]
　本工程は、塩基の存在下、化合物（II－１）を化合物（II－３）と反応させることにより化合物（II－２）を製造する方法である。
　用いられる塩基としては、水素化ナトリウム、炭酸セシウム、カリウム　ｔｅｒｔ－ブトキシド、ナトリウム　ｔｅｒｔ－ブトキシド等が挙げられ、化合物（II－１）１当量に対して１から５当量であり、好ましくは１から３当量である。
　用いられる溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、テトラヒドロフラン、Ｎ－メチル－２－ピロリドン等が挙げられる。
　これらの反応は、通常室温から還流温度で、１から２４時間で行うことができる。
　このようにして得られる化合物（II－２）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 2-1]
This step is a method for producing compound (II-2) by reacting compound (II-1) with compound (II-3) in the presence of a base.
Examples of the base to be used include sodium hydride, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. Is equivalent.
Examples of the solvent used include N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and N-methyl-2-pyrrolidone.
These reactions can be usually performed at room temperature to reflux temperature for 1 to 24 hours.
The compound (II-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ｒ11がＲ14Ｒ15ＮＣＯ－である化合物（III－３）は、例えば、下記製造法３又はこれに準ずる方法により製造することができる。
　なお、Ｒ11がカルボン酸前駆体（例えば、エトキシカルボニル、メトキシカルボニル、シアノ等が挙げられる）である、出発物質である化合物（III－１）は、例えば、前記製造法１又はこれに準ずる方法により製造することができる。
　製造法３： Among the compounds (I) of the present invention, the compound (III-3) in which R 11 is R 14 R 15 NCO— can be produced, for example, by the following production method 3 or a method analogous thereto.
The starting compound (III-1) in which R 11 is a carboxylic acid precursor (for example, ethoxycarbonyl, methoxycarbonyl, cyano, etc.) can be obtained by, for example, the production method 1 or a method analogous thereto. Can be manufactured.
Production method 3:
Figure JPOXMLDOC01-appb-C000025
 [式中、Ｒ14及びＲ15は、同一に若しくは異なって水素原子、Ｃ1-6アルキル、Ｃ3-8シクロアルキル若しくは飽和のヘテロシクリルを示し又はＲ14及びＲ15は結合している窒素原子と一緒になって飽和のヘテロシクリル形成し、ｍ１、ｍ２、Ａ、Ｒ12、Ｒ13、Ｘ、Ｙ及びＲ2は前記と同意義を示す。]
Figure JPOXMLDOC01-appb-C000025
 [Wherein R 14 and R 15 are the same or different and each represents a hydrogen atom, C 1-6 alkyl, C 3-8 cycloalkyl or saturated heterocyclyl, or R 14 and R 15 are bonded nitrogen atoms. Together with m 1, m 2, A, R 12 , R 13 , X, Y and R 2 are as defined above. ]
［工程３－１］
　本工程は、塩基により加水分解を行い、化合物（III－１）より化合物（III－２）を製造する方法である。
　反応に用いられる塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等が挙げられる。用いられる塩基の量は、化合物（III－１）１当量に対して、１から２０当量であり、好ましくは１から５当量である。
　反応に用いられる溶媒としては、メタノール、エタノール、テトラヒドロフラン、水等の溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常室温から還流温度で行うことができる。 [Step 3-1]
This step is a method for producing compound (III-2) from compound (III-1) by hydrolysis with a base.
Examples of the base used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The amount of the base used is 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (III-1).
Examples of the solvent used in the reaction include solvents such as methanol, ethanol, tetrahydrofuran, and water, and these solvents may be mixed and used at an appropriate ratio.
These reactions can usually be performed at room temperature to reflux temperature.
［工程３－２］
　本工程は、化合物（III－２）と化合物（III－４）を縮合し、化合物（III－３）を製造する方法である。
　本反応は、公知の方法、例えば縮合剤を用いて、塩基及び活性化剤の存在下又は非存在下、反応に関与しない溶媒中で行うことができる。
　本反応に用いられる化合物（III－４）の量は、化合物（III－２）１当量に対して１から５当量であり、好ましくは１から３当量である。
　反応に用いられる縮合剤としては、例えば１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、シアノホスホン酸ジエチル等が挙げられる。用いられる縮合剤の量は、化合物（III－２）１当量に対して、１から５当量であり、好ましくは１から３当量である。
　反応に用いられる活性化剤としては、例えば、１－ヒドロキシベンゾトリアゾール一水和物、Ｎ－ヒドロキシスクシンイミド等が挙げられる。用いられる活性化剤の量は、化合物（III－２）１当量に対して、１から５当量であり、好ましくは１から２当量である。
　反応に用いられる塩基としては、例えば、Ｎ，Ｎ－ジイソプロピルエチルアミン、トリエチルアミン等の第３級脂肪族アミン、ピリジン等が挙げられる。用いられる塩基の量は、化合物（III－２）１当量に対して、１から５当量であり、好ましくは１から２当量である。
　反応に用いられる溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、トルエン、テトラヒドロフラン、１，４－ジオキサン、水等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から１００℃で行うことができる。
　このようにして得られる化合物（III－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 3-2]
This step is a method for producing compound (III-3) by condensing compound (III-2) and compound (III-4).
This reaction can be performed by a known method, for example, using a condensing agent in the presence or absence of a base and an activator in a solvent that does not participate in the reaction.
The amount of compound (III-4) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (III-2).
Examples of the condensing agent used in the reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, diethyl cyanophosphonate and the like. The amount of the condensing agent to be used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (III-2).
Examples of the activator used in the reaction include 1-hydroxybenzotriazole monohydrate, N-hydroxysuccinimide and the like. The amount of the activator used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (III-2).
Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, and pyridine. The amount of the base used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (III-2).
Examples of the solvent used for the reaction include N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane, toluene, tetrahydrofuran, 1,4-dioxane, water and the like, which are not involved in the reaction. May be mixed and used at an appropriate ratio.
These reactions can usually be performed at 0 to 100 ° C.
The compound (III-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ｒ2が（ｃ）下記式（β）で表される５若しくは６員のヘテロアリールである化合物（IV－３）又は置換オキサジアゾリルである化合物（IV－５）は、例えば、下記製造法４又はこれに準ずる方法により製造することができる。 Among the compounds (I) of the present invention, R 2 is (c) a compound (IV-3) which is a 5- or 6-membered heteroaryl represented by the following formula (β) or a compound (IV-5) which is a substituted oxadiazolyl ) Can be produced, for example, by the following production method 4 or a method analogous thereto.
Figure JPOXMLDOC01-appb-C000026
 （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）
　製造法４：
Figure JPOXMLDOC01-appb-C000026
 (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
Production method 4:
Figure JPOXMLDOC01-appb-C000027
 [式中、Ｕｂは脱離基を、化合物（IV－６）は脱離基Ｕｂを置換基として有する前記式（β）で表される５又は６員のヘテロアリールを、Ｒ22はＣ1-6アルキル又はＣ3-8シクロアルキルを、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ及びＹは前記と同意義を示す。]
　Ｕｂで示される「脱離基」としては、例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、ベンゼンスルホニルオキシ等が挙げられる。
　Ｒ22で示される「Ｃ1-6アルキル」は、前記と同意義を示す。
　Ｒ22で示される「Ｃ3-8シクロアルキル」は、前記と同意義を示す。
Figure JPOXMLDOC01-appb-C000027
 [Wherein Ub represents a leaving group, compound (IV-6) represents a 5- or 6-membered heteroaryl represented by the above formula (β) having the leaving group Ub as a substituent, and R 22 represents C 1 -6 alkyl or C 3-8 cycloalkyl, m1, m2, A, R 11 , R 12 , R 13 , X and Y are as defined above. ]
Examples of the “leaving group” represented by Ub include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
“C 1-6 alkyl” for R 22 is as defined above.
“C 3-8 cycloalkyl” represented by R 22 is as defined above.
［工程４－１］
　本工程は、化合物（IV－１）を酸性条件下で処理することにより、化合物（IV－２）を製造する方法である。
　反応に用いられる酸としては、通常例えば、４Ｍ塩化水素・酢酸エチル溶液、４Ｍ塩化水素・１，４－ジオキサン溶液、トリフルオロ酢酸等が挙げられる。用いられる酸の量は、化合物（IV－１）１当量に対して５から５０当量であり、好ましくは１０から３０当量である
　反応に用いられる溶媒としては、酢酸エチル、テトラヒドロフラン、１，４－ジオキサン、メタノール、エタノール、水、クロロホルム、ジクロロメタン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から室温で、１から２４時間で行うことができる。 [Step 4-1]
This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
Examples of the acid used for the reaction usually include 4M hydrogen chloride / ethyl acetate solution, 4M hydrogen chloride / 1,4-dioxane solution, trifluoroacetic acid and the like. The amount of the acid used is 5 to 50 equivalents, preferably 10 to 30 equivalents, relative to 1 equivalent of compound (IV-1). Examples of the solvent used for the reaction include ethyl acetate, tetrahydrofuran, 1,4- Examples include solvents that do not participate in the reaction, such as dioxane, methanol, ethanol, water, chloroform, and dichloromethane, and these solvents may be mixed and used at an appropriate ratio.
These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
［工程４－２］
　本工程は、化合物（IV－２）と化合物（IV－６）より化合物（IV－３）を製造する方法である。 [Step 4-2]
This step is a method for producing compound (IV-3) from compound (IV-2) and compound (IV-6).
（Ａ法）
　塩基の存在下又は非存在下で、化合物（IV－２）と化合物（IV－６）を反応させることにより化合物（IV－３）を製造することができる。
　本反応で用いられる化合物（IV－６）としては、２－クロロ－５－イソプロピルピリジン、２－クロロ－５－メチルピリジン、２,５－ジクロロピリジン等が挙げられる。本反応に用いられる化合物（IV－６）の量は、化合物（IV－２）１当量に対して１から５当量で好ましくは１から３当量である。
　反応に用いられる塩基としては、Ｎ，Ｎ－ジイソプロピルエチルアミン、トリエチルアミン等の第３級脂肪族アミン、炭酸セシウム、炭酸カリウム等のアルカリ金属炭酸塩、ピリジン等が挙げられる。用いられる塩基の量は、１から５当量で好ましくは１から３当量である。
　反応に用いられる溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、トルエン、１，４－ジオキサン、テトラヒドロフラン、２－プロパノール等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常室温から１８０℃で、１から２４時間で行うことができ、またマイクロ波照射下でも行うことができる。 (Method A)
Compound (IV-3) can be produced by reacting compound (IV-2) with compound (IV-6) in the presence or absence of a base.
Examples of the compound (IV-6) used in this reaction include 2-chloro-5-isopropylpyridine, 2-chloro-5-methylpyridine, 2,5-dichloropyridine and the like. The amount of compound (IV-6) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate and potassium carbonate, and pyridine. The amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
Examples of the solvent used in the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, tetrahydrofuran, 2-propanol and the like, which are not involved in the reaction. You may mix and use.
These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
（Ｂ法）
　金属触媒及び塩基の存在下で、化合物（IV－２）と化合物（IV－６）を反応させることにより化合物（IV－３）を製造することができる。
　本反応は、アルゴン、窒素等の不活性ガス雰囲気において、パラジウム触媒、塩基の存在下及びホスフィン化合物の存在下又は非存在下で反応に関与しない溶媒中で行うことができる。
　本反応で用いられる化合物（IV－６）の量は、化合物（IV－２）１当量に対して１から５当量で好ましくは１から３当量である。
　反応に用いられるパラジウム触媒としては、例えば、（１，３－ジイソプロピルイミダゾール－２－イリデン）（３－クロロピリジル）パラジウム（II）ジクロリド、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（II）ジクロリド　ジクロロメタン錯体、酢酸パラジウム（II）、トリス（ジベンジリデンアセトン）ジパラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム（II）、テトラキス（トリフェニルホスフィン）パラジウム（０）等が挙げられる。用いられるパラジウム触媒の量は、化合物（IV－２）１当量に対して、通常０．０１から１当量で好ましくは０．１から０．５当量である。
　反応に用いられるホスフィン化合物としては、例えば２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル、１，１’－ビス（ジフェニルホスフィノ）フェロセン、４，５’－ビス（ジフェニルホスフィノ）－９，９’－ジメチルキサンテン等が挙げられる。用いられるホスフィン化合物の量は、通常０．０２から２等量で好ましくは０．２から1当量である。
　反応に用いられる塩基としては、例えばカリウム　ｔｅｒｔ－ブトキシド、ナトリウム　ｔｅｒｔ－ブトキシド、ナトリウムフェノキシド等のアルカリ金属アルコキシド、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のアルカリ金属炭酸塩、リン酸カリウム等のアルカリ金属リン酸塩等が挙げられる。用いられる塩基の量は、化合物（IV－２）１当量に対して１から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としてはＮ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、トルエン、１，４－ジオキサン、１，２－ジメトキシエタン、テトラヒドロフラン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常室温から１８０度で、１から２４時間で行うことができ、またマイクロ波照射下でも行うことができる。
　このようにして得られる化合物（IV－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 (Method B)
Compound (IV-3) can be produced by reacting compound (IV-2) with compound (IV-6) in the presence of a metal catalyst and a base.
This reaction can be carried out in an inert gas atmosphere such as argon or nitrogen in a solvent that does not participate in the reaction in the presence of a palladium catalyst, a base, and in the presence or absence of a phosphine compound.
The amount of compound (IV-6) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the palladium catalyst used in the reaction include (1,3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] palladium. (II) Dichloride Dichloromethane complex, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0) and the like. The amount of the palladium catalyst to be used is generally 0.01 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IV-2).
Examples of the phosphine compound used in the reaction include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 1,1′-bis (diphenylphosphino) ferrocene, and 4,5′-bis (diphenyl). Phosphino) -9,9'-dimethylxanthene and the like. The amount of the phosphine compound used is usually 0.02 to 2 equivalents, preferably 0.2 to 1 equivalent.
Examples of the base used in the reaction include alkali metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide and sodium phenoxide, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, potassium phosphate and the like And alkali metal phosphates. The amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the solvent used for the reaction include N, N-dimethylformamide, dimethyl sulfoxide, toluene, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like, which are not involved in the reaction. You may mix and use by a ratio.
These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
The compound (IV-3) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
[工程４－３]
　本工程は、化合物（IV－２）と臭化シアンを塩基の存在下反応させることにより、化合物（IV－４）を製造する方法である。
　本反応で用いられる臭化シアンの量は、化合物（IV－２）１当量に対して通常１から３当量であり、好ましくは１から１．５当量である。
　反応に用いられる塩基としては、通常例えば、酢酸ナトリウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、トリエチルアミン等が挙げられる。用いられる塩基の量は、化合物（IV－２）１当量に対して、通常１から３当量であり、好ましくは1から２当量である。
　反応に用いられる溶媒としては、クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン、水、エタノール、メタノール等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常０℃から還流温度であり、１から２４時間で行うことができる。 [Step 4-3]
This step is a method for producing compound (IV-4) by reacting compound (IV-2) with cyanogen bromide in the presence of a base.
The amount of cyanogen bromide used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the base used in the reaction usually include sodium acetate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine and the like. The amount of the base used is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, diethyl ether, tetrahydrofuran, water, ethanol, methanol, and the like, and these solvents may be mixed and used at an appropriate ratio.
These reactions are usually performed at 0 ° C. to reflux temperature, and can be performed in 1 to 24 hours.
[工程４－４]
　本工程は、化合物（IV－４）と化合物（IV－７）を塩化亜鉛存在下で反応させた後に塩酸で処理することにより、化合物（IV－５）を製造する方法である。
　本工程は、公知の方法、例えば、ＷＯ２００８０８１２０４に記載の方法又はそれに準じた方法により行うことができる。
　本反応で用いられる化合物（IV－７）としては、例えばＮ’－ヒドロキシ－２－メチルプロパンイミドアミド等が挙げられる。用いられる化合物（IV－７）の量は、化合物（IV－４）１当量に対して、通常１から３当量であり、好ましくは１から2当量である。
　用いられる塩化亜鉛の量は、化合物（IV－４）１当量に対して、通常１から３当量であり、好ましくは１から2当量である。
　反応に用いられる溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジエチルエーテル、酢酸エチル等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　この反応は通常０℃から５０℃で、１５分間から２４時間で行うことができる。
　塩酸で処理する際に用いられる溶媒は、エタノール、メタノール、ジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いても良い。
　この反応は通常室温から還流温度で、１から２４時間で行うことができる。
　このようにして得られる化合物（IV－５）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 4-4]
This step is a method for producing compound (IV-5) by reacting compound (IV-4) with compound (IV-7) in the presence of zinc chloride and then treating with hydrochloric acid.
This step can be performed by a known method, for example, the method described in WO200808204 or a method analogous thereto.
Examples of the compound (IV-7) used in this reaction include N′-hydroxy-2-methylpropanimidamide and the like. The amount of compound (IV-7) to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-4).
The amount of zinc chloride to be used is generally 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-4).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, and ethyl acetate. These solvents may be mixed and used at an appropriate ratio.
This reaction is usually carried out at 0 ° C. to 50 ° C. for 15 minutes to 24 hours.
Examples of the solvent used in the treatment with hydrochloric acid include solvents that do not participate in the reaction, such as ethanol, methanol, diethyl ether, tetrahydrofuran, and 1,4-dioxane. These solvents may be used by mixing at an appropriate ratio. good.
This reaction is usually carried out at room temperature to reflux temperature for 1 to 24 hours.
The compound (IV-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ｒ2が（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝である化合物（Ｖ－１）は、例えば、下記製造法５又はこれに準ずる方法により製造することができる。
　製造法５： In the compound (I) of the present invention, R 2 is (b) -COOR 21 {R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3- Substituted with 8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). } (V-1) can be produced, for example, by the following production method 5 or a method analogous thereto.
Production method 5:
Figure JPOXMLDOC01-appb-C000028
 [式中、Ｕｃは脱離基を、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ、Ｙ及びＲ21は前記と同意義を示す。]
　Ｕｃで示される「脱離基」としては、例えば、塩素原子、臭素原子、ヨウ素原子、メチルイミダゾリウム及び４－ニトロフェノキシ等の脱離基が挙げられる。
Figure JPOXMLDOC01-appb-C000028
 [Wherein Uc is a leaving group, and m1, m2, A, R 11 , R 12 , R 13 , X, Y and R 21 are as defined above]. ]
Examples of the “leaving group” represented by Uc include leaving groups such as chlorine atom, bromine atom, iodine atom, methylimidazolium and 4-nitrophenoxy.
[工程５－１]
　本工程は、化合物（IV－１）を酸性条件下で処理することにより、化合物（IV－２）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法を用いて行うことができる。 [Step 5-1]
This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
This reaction can be carried out using the method described in Process 4-1, Production Method 4.
[工程５－２]
　本工程は、化合物（IV－２）より化合物（Ｖ－１）を製造する方法である。 [Step 5-2]
This step is a method for producing compound (V-1) from compound (IV-2).
　（Ａ法）
　塩基の存在下、化合物（IV－２）と化合物（Ｖ－２）を反応させることにより、化合物（Ｖ－１）を製造することができる。
　本反応に用いられる化合物（Ｖ－２）の量は、化合物（IV－２）１当量に対して１から５当量であり、好ましくは１から３当量である。
　反応に用いられる化合物（Ｖ－２）としては、例えばクロロギ酸イソプロピル、クロロギ酸イソブチル、クロロギ酸１－メチルシクロプロピル、１－｛［（１－フルオロ－２－メチルプロパン－２－イル）オキシ］カルボニル｝－３－メチル－４，５－ジヒドロ－１Ｈ－イミダゾル－３－イウム　ヨージド、１－｛［（１，１－ジフルオロ－２－メチルプロパン－２－イル）オキシ］カルボニル｝－３－メチル－４，５－ジヒドロ－１Ｈ－イミダゾル－３－イウム　ヨージド、１－メチルシクロプロピル　４－ニトロフェニルカーボネート、Ｎ－（メチルシクロプロピルオキシカルボニルオキシ）スクシンイミド等が挙げられる。
　反応に用いられる塩基としては、例えばＮ，Ｎ－ジイソプロピルエチルアミン、トリエチルアミン等の第３級脂肪族アミン、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のアルカリ金属炭酸塩、水酸化ナトリウム、ピリジン、Ｎ，Ｎ－ジメチル－４－アミノピリジン等が挙げられる。用いられる塩基の量は、１から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としてはクロロホルム、ジクロロメタン、１，４－ジオキサン、１，２－ジメトキシエタン、テトラヒドロフラン、メタノール、エタノール、水、酢酸エチル、アセトニトリル、アセトン、トルエン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から還流温度で、１から２４時間で行うことができる。 (Method A)
Compound (V-1) can be produced by reacting compound (IV-2) with compound (V-2) in the presence of a base.
The amount of compound (V-2) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the compound (V-2) used in the reaction include isopropyl chloroformate, isobutyl chloroformate, 1-methylcyclopropyl chloroformate, 1-{[(1-fluoro-2-methylpropan-2-yl) oxy] Carbonyl} -3-methyl-4,5-dihydro-1H-imidazol-3-ium iodide, 1-{[(1,1-difluoro-2-methylpropan-2-yl) oxy] carbonyl} -3-methyl Examples include -4,5-dihydro-1H-imidazol-3-ium iodide, 1-methylcyclopropyl 4-nitrophenyl carbonate, and N- (methylcyclopropyloxycarbonyloxy) succinimide.
Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, sodium hydroxide and pyridine. N, N-dimethyl-4-aminopyridine and the like. The amount of base used is 1 to 5 equivalents, preferably 1 to 3 equivalents.
Examples of the solvent used in the reaction include chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, methanol, ethanol, water, ethyl acetate, acetonitrile, acetone, toluene, and other solvents that do not participate in the reaction. These solvents may be mixed and used at an appropriate ratio.
These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
（Ｂ法）
　トリホスゲン存在下、化合物（IV－２）と化合物（Ｖ－３）を反応させることにより、化合物（Ｖ－１）を製造することができる。
本反応に用いられる化合物（Ｖ－３）の量は、化合物（IV－２）１当量に対して１から５当量であり、好ましくは１から３当量である。
　反応に用いられる化合物（Ｖ－３）としては、例えばシクロプロパンメタノール、１－メチルシクロプロパンメタノール、シクロペンタノール、ネオペンチルアルコール等が挙げられる。
　反応に用いられる塩基としては、トリエチルアミン等の第３級脂肪族アミン、ピリジン等の芳香族ヘテロ環アミン等が挙げられる。
　反応に用いられる溶媒としては、ジクロロメタン、クロロホルム、テトラヒドロフラン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から室温で、５分間から２４時間で行うことができる。
　このようにして得られる化合物（Ｖ－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 (Method B)
Compound (V-1) can be produced by reacting compound (IV-2) with compound (V-3) in the presence of triphosgene.
The amount of compound (V-3) used in this reaction is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the compound (V-3) used in the reaction include cyclopropanemethanol, 1-methylcyclopropanemethanol, cyclopentanol, neopentyl alcohol and the like.
Examples of the base used in the reaction include tertiary aliphatic amines such as triethylamine, aromatic heterocyclic amines such as pyridine, and the like.
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as dichloromethane, chloroform, and tetrahydrofuran, and these solvents may be mixed and used at an appropriate ratio.
These reactions can be usually performed at 0 ° C. to room temperature for 5 minutes to 24 hours.
The thus obtained compound (V-1) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ｒ2が（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、トリフルオロメチル及びＣ1-6アルキルからなる群より選ばれる１個の基で置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキルである化合物（VI－１）、（VI－２）、（VI－４）及び（VI－６）は、例えば、下記製造法６又はこれに準ずる方法により製造することができる。
　製造法６： Among the compounds (I) of the present invention, R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-6 8 cycloalkyl is unsubstituted or substituted with 1 group selected from the group consisting of trifluoromethyl and C 1-6 alkyl. ] Compounds (VI-1), (VI-2), (VI-4) and (VI-6) which are halo C 1-6 alkyl or C 3-8 cycloalkyl can be produced, for example, by the following production method 6 or It can manufacture by the method according to this.
Production method 6:
Figure JPOXMLDOC01-appb-C000029
 [式中、Ｕｄは脱離基を、Ｕｅはヒドロキシ又はハロゲン原子を示し、Ｒ23及びＲ24は同一に若しくは異なって水素原子、Ｃ1-4アルキル若しくはＣ3-8シクロアルキルを示し又はＲ23及びＲ24は結合している炭素原子と一緒になってＣ3-8シクロアルキルを形成し、Ｒ25は水素原子、Ｃ1-5アルキル若しくはＣ3-8シクロアルキルを示し、Ｒ26及びＲ27は同一に若しくは異なって水素原子、Ｃ1-5アルキル若しくはＣ3-8シクロアルキルを示し又はＲ26及びＲ27は結合している炭素原子と一緒になってＣ3-8シクロアルキルを形成し、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ、Ｙ及びＲ2は前記と同意義を示す。]
　Ｕｄで示される「脱離基」としては、例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、ベンゼンスルホニルオキシ等が挙げられる。
　Ｕｅで示される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
　Ｒ23、Ｒ24及びＲ25で示される「Ｃ1-5アルキル」とは、炭素原子を１～５個有する直鎖状又は分岐状のアルキルを示し、例えばメチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、２－メチルブチル等が挙げられる。
　Ｒ26及びＲ27で示される「Ｃ1-4アルキル」は、前記と同意義を示す。
Figure JPOXMLDOC01-appb-C000029
 [Wherein Ud represents a leaving group, Ue represents a hydroxy or halogen atom, and R 23 and R 24 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 3-8 cycloalkyl, or R 23 and R 24 together with the carbon atoms to which they are attached form C 3-8 cycloalkyl, R 25 represents a hydrogen atom, C 1-5 alkyl or C 3-8 cycloalkyl, R 26 and R 27 may be the same or different and represents a hydrogen atom, C 1-5 alkyl or C 3-8 cycloalkyl, or R 26 and R 27 together with the carbon atom to which they are attached represent C 3-8 cycloalkyl. And m1, m2, A, R 11 , R 12 , R 13 , X, Y and R 2 are as defined above. ]
Examples of the “leaving group” represented by Ud include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
Examples of the “halogen atom” represented by Ue include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
“C 1-5 alkyl” represented by R 23 , R 24 and R 25 represents linear or branched alkyl having 1 to 5 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl and the like.
"C 1-4 alkyl" represented by R 26 and R 27 are as defined above.
[工程６－１]
　本工程は、化合物（IV－１）を酸性条件下で処理することにより、化合物（IV－２）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法を用いて行うことができる。 [Step 6-1]
This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
This reaction can be carried out using the method described in Process 4-1, Production Method 4.
［工程６－２］
　本反応は、塩基の存在下又は非存在下で、化合物（IV－２）と化合物（VI－７）を反応させることにより、化合物（VI－１）を製造する方法である。
　本反応に用いられる化合物（VI－７）としては、例えば２，２－ジフルオロプロピル ４－メチルベンゼンスルホナート等が挙げられる。用いられる化合物（VI－７）の量は、化合物（IV－２）１当量に対して１から５当量であり、好ましくは１から３当量である。
　反応に用いられる塩基としては、例えばＮ，Ｎ－ジイソプロピルエチルアミン、トリエチルアミン等の第３級脂肪族アミン、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のアルカリ金属炭酸塩、水酸化ナトリウム、ピリジン、Ｎ，Ｎ－ジメチル－４－アミノピリジン等が挙げられる。用いられる塩基の量は、化合物（IV－２）１当量に対して、１から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としては、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、１，４－ジオキサン、テトラヒドロフラン、エタノール等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常室温から１８０℃で、１から２４時間で行うことができ、またマイクロ波照射下でも行うことができる。
　このようにして得られる化合物（VI－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 6-2]
This reaction is a method for producing compound (VI-1) by reacting compound (IV-2) with compound (VI-7) in the presence or absence of a base.
Examples of the compound (VI-7) used in this reaction include 2,2-difluoropropyl 4-methylbenzenesulfonate. The amount of compound (VI-7) to be used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium bicarbonate, sodium hydroxide and pyridine. N, N-dimethyl-4-aminopyridine and the like. The amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the solvent used for the reaction include acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, ethanol and the like which do not participate in the reaction, and these solvents are mixed in an appropriate ratio. May be used.
These reactions can usually be performed at room temperature to 180 ° C. for 1 to 24 hours, and can also be performed under microwave irradiation.
The compound (VI-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程６－３］
　本反応は、化合物（IV－２）と化合物（VI－８）から還元的アミノ化反応を行うことにより、化合物（VI－２）を製造する方法である。
　反応に用いられる還元剤としては、ナトリウムトリアセトキシボロヒドリド、ナトリウムシアノボロヒドリド、ボラン－２－ピコリン錯体等が挙げられる。用いられる還元剤の量は、化合物（IV－２）１当量に対して、１から３当量であり、好ましくは１から２当量である。
　反応に用いられる溶媒は、Ｎ，Ｎ－ジメチルホルムアミド、クロロホルム、ジクロロメタン、メタノール等が挙げられる。
　これらの反応は、通常０℃から還流温度で行うことができる。
　このようにして得られる化合物（VI－２）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 6-3]
This reaction is a method for producing compound (VI-2) by carrying out reductive amination reaction from compound (IV-2) and compound (VI-8).
Examples of the reducing agent used in the reaction include sodium triacetoxyborohydride, sodium cyanoborohydride, borane-2-picoline complex, and the like. The amount of the reducing agent used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the solvent used for the reaction include N, N-dimethylformamide, chloroform, dichloromethane, methanol and the like.
These reactions can usually be carried out at 0 ° C. to reflux temperature.
The compound (VI-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程６－４］
　本工程は、化合物（IV－２）と化合物（VI－９）を反応させることにより、化合物（VI－３）を製造する方法である。 [Step 6-4]
This step is a method for producing compound (VI-3) by reacting compound (IV-2) with compound (VI-9).
（Ａ法）
　化合物（VI－９）のＵｅがヒドロキシである場合、化合物（IV－２）と化合物（VI－９）を縮合し、化合物（VI－３）を製造することができる。
　本反応は、公知の方法、例えば縮合剤を用いて、塩基及び活性化剤の存在下又は非存在下、反応に関与しない溶媒中で行うことができる。
　本反応は、製造法３の工程３－２に記載した方法に準じて行うことができる。 (Method A)
When Ue of compound (VI-9) is hydroxy, compound (IV-2) and compound (VI-9) can be condensed to produce compound (VI-3).
This reaction can be performed by a known method, for example, using a condensing agent in the presence or absence of a base and an activator in a solvent that does not participate in the reaction.
This reaction can be carried out according to the method described in Process 3-2 of Production Method 3.
（Ｂ法）
　化合物（VI－９）のＵｅがハロゲン原子である場合、塩基の存在下又は非存在下、化合物（IV－２）と化合物（VI－９）を反応させることにより、化合物（VI－３）を製造することができる。
　本工程は、公知の方法、例えば、文献（Ｃｈｅｍｉｃａｌ＆Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ，２００１，４９，９８８－９９８．）に記載の方法又はそれに準じた方法で行うことができる。 (Method B)
When Ue of compound (VI-9) is a halogen atom, compound (VI-3) is reacted with compound (VI-2) in the presence or absence of a base to react with compound (VI-9). Can be manufactured.
This step can be performed by a known method, for example, a method described in the literature (Chemical & Pharmaceutical Bulletin, 2001, 49, 988-998.) Or a method analogous thereto.
［工程６－５］
　本工程は、化合物（VI－３）を還元することにより、化合物（VI－４）を製造する方法である。
　本反応に用いられる還元剤は、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム、ボラン－テトラヒドロフラン錯体、ボラン－ジメチルスルフィド錯体等が挙げられる。用いられる還元剤の量は、化合物（VI－３）１当量に対して、１から３当量であり、好ましくは１から２当量である。
　反応に用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から還流温度で行うことができる。
　このようにして得られる化合物（VI－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 6-5]
This step is a method for producing compound (VI-4) by reducing compound (VI-3).
Examples of the reducing agent used in this reaction include lithium aluminum hydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, and borane-dimethyl sulfide complex. The amount of the reducing agent used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (VI-3).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, and these solvents may be used by mixing at an appropriate ratio.
These reactions can usually be carried out at 0 ° C. to reflux temperature.
The compound (VI-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
［工程６－６］
　本反応は、塩基の存在下又は非存在下、化合物（IV－２）と化合物（VI－１０）を反応させて化合物（VI－５）を製造する方法である。
　本反応に用いられる化合物（VI－１０）としては、例えばイソブチレンオキシド等が挙げられる。用いられる化合物（VI－１０）の量は、化合物（IV－２）１当量に対して１から３当量であり、好ましくは１から２当量である。
　反応に用いられる塩基としては、例えばＮ，Ｎ－ジイソプロピルエチルアミン、トリエチルアミン等の第３級脂肪族アミン、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のアルカリ金属炭酸塩、水酸化ナトリウム、ピリジン、ナトリウムメトキシド、ナトリウムエトキシド等が挙げられる。用いられる塩基の量は、化合物（IV－２）１当量に対して、１から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、アセトニトリル、エタノール、メタノール、２－プロパノール、水等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から１００℃で行うことができる。 [Step 6-6]
This reaction is a method for producing compound (VI-5) by reacting compound (IV-2) with compound (VI-10) in the presence or absence of a base.
Examples of the compound (VI-10) used in this reaction include isobutylene oxide. The amount of compound (VI-10) used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the base used in the reaction include tertiary aliphatic amines such as N, N-diisopropylethylamine and triethylamine, alkali metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, sodium hydroxide and pyridine. Sodium methoxide, sodium ethoxide and the like. The amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the solvent used in the reaction include N, N-dimethylformamide, acetonitrile, ethanol, methanol, 2-propanol, water, and other solvents that do not participate in the reaction, and these solvents are used by mixing at an appropriate ratio. Also good.
These reactions can usually be performed at 0 to 100 ° C.
［工程６－７］
　本反応は、化合物（（VI－５）とフッ素化剤を反応させることにより、化合物（VI－６）を製造する方法である。
　反応に用いられるフッ素化剤としては、ビス（2－メトキシエチル）アミノサルファートリフルオリド、（ジエチルアミノ）サルファートリフルオリド、石川試薬等が挙げられる。用いられるフッ素化剤の量は、化合物（VI－５）１当量に対して、１から３当量であり、好ましくは１から２当量である。
　反応に用いられる溶媒としては、ジクロロエタン、クロロホルム、ジクロロメタン、１，４－ジオキサン、１，２－ジメトキシエタン、テトラヒドロフラン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常－７８℃から１００℃で行うことができる。
　このようにして得られる化合物（VI－６）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 6-7]
This reaction is a method for producing compound (VI-6) by reacting compound ((VI-5) with a fluorinating agent.
Examples of the fluorinating agent used in the reaction include bis (2-methoxyethyl) aminosulfur trifluoride, (diethylamino) sulfur trifluoride, and Ishikawa reagent. The amount of the fluorinating agent to be used is 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (VI-5).
Examples of the solvent used in the reaction include dichloroethane, chloroform, dichloromethane, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, and the like, which are not involved in the reaction. It may be used.
These reactions can usually be performed at −78 ° C. to 100 ° C.
The compound (VI-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ｒ2が（ｄ）Ｃ1-6アルキルスルホニル又はＣ3-8シクロアルキルスルホニルである化合物（VII－１）は、例えば、下記製造法７又はこれに準ずる方法により製造することができる。
　製造法７： Among the compounds (I) of the present invention, the compound (VII-1) in which R 2 is (d) C 1-6 alkylsulfonyl or C 3-8 cycloalkylsulfonyl is, for example, in accordance with the following production method 7 or the same. It can be manufactured by a method.
Production method 7:
Figure JPOXMLDOC01-appb-C000030
 [式中、Ｕｆはハロゲン原子を、Ｒ28はＣ1-6アルキル又はＣ3-8シクロアルキルを、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ及びＹは前記と同意義を示す。]
　Ｕｆで示される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。
Figure JPOXMLDOC01-appb-C000030
 [Wherein Uf represents a halogen atom, R 28 represents C 1-6 alkyl or C 3-8 cycloalkyl, m1, m2, A, R 11 , R 12 , R 13 , X and Y are as defined above. Indicates. ]
Examples of the “halogen atom” represented by Uf include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
[工程７－１]
　本工程は、化合物（IV－１）を酸性条件下で処理することにより、化合物（IV－２）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法を用いて行うことができる。 [Step 7-1]
This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
This reaction can be carried out using the method described in Process 4-1, Production Method 4.
[工程７－２]
　本工程は、塩基の存在下又は非存在下、化合物（IV－２）と化合物（VII－２）を反応させ、化合物（VII－１）を製造する方法である。
　本工程は、公知の方法、例えば、文献（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２００８，５１，２１７０－２１７７）に記載の方法又はそれに準じた方法で行うことができる。
　反応で用いられる化合物（VII－２）としては、例えば、シクロプロパンスルホニルクロリド等が挙げられる。用いられる化合物（VII－２）の量は、化合物（IV－２）１当量に対して通常１から５当量であり、好ましくは１から２当量である。
　用いられる塩基としては、通常例えば、Ｎ，Ｎ－ジイソプロピルエチルアミン、トリエチルアミン、炭酸カリウム等が挙げられる。用いられる塩基の量は、化合物（IV－２）１当量に対して、通常１から５当量であり、好ましくは１から３当量である。
　反応に用いられる溶媒としては、クロロホルム、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、アセトニトリル、水等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から室温で、１から２４時間で行うことができる。
　このようにして得られる化合物（VII－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 7-2]
This step is a method for producing compound (VII-1) by reacting compound (IV-2) with compound (VII-2) in the presence or absence of a base.
This step can be performed by a known method, for example, a method described in the literature (Journal of Medicinal Chemistry, 2008, 51, 2170-2177) or a method analogous thereto.
Examples of the compound (VII-2) used in the reaction include cyclopropanesulfonyl chloride. The amount of compound (VII-2) to be used is generally 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the base used usually include N, N-diisopropylethylamine, triethylamine, potassium carbonate and the like. The amount of the base used is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IV-2).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, 1,4-dioxane, tetrahydrofuran, acetonitrile, water, and the like. These solvents may be mixed and used at an appropriate ratio.
These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
The compound (VII-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法１における出発物質である化合物（Ｉ－１）、製造法２における出発物質である化合物（II－１）（ここで、Ｘが－Ｏ－である化合物（II－１）は化合物（Ｉ－１）であり、Ｘが－ＮＲ3－である化合物（II－１）は化合物（VIII－３）である。）及び製造法４～７における出発物質である化合物（IV－１）は、例えば、下記製造法８又はこれに準ずる方法により製造することができる。
　製造法８： Compound (I-1) which is a starting material in Production Method 1, Compound (II-1) which is a starting material in Production Method 2 (wherein Compound (II-1) wherein X is —O— is compound (I) -1) and X is —NR 3 — (II-1) is Compound (VIII-3)) and Compound (IV-1) which is the starting material in Production Methods 4 to 7 is For example, it can be produced by the following production method 8 or a method analogous thereto.
Production method 8:
Figure JPOXMLDOC01-appb-C000031
 [式中、Ｕｇはヒドロキシ又は脱離基を、Ｕａ、Ａ’、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ、Ｙ及びＲ2は前記と同意義を示す。]
　Ｕｇで示される「脱離基」としては、例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、ベンゼンスルホニルオキシ等が挙げられる。
Figure JPOXMLDOC01-appb-C000031
 [Wherein Ug represents hydroxy or a leaving group, and Ua, A ′, m1, m2, A, R 11 , R 12 , R 13 , X, Y, and R 2 have the same meaning as described above. ]
Examples of the “leaving group” represented by Ug include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
[工程８－１]
　本工程は、化合物（VIII－１）を酸性条件下で処理することにより、化合物（VIII－２）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法に準じて行うことができる。 [Step 8-1]
This step is a method for producing compound (VIII-2) by treating compound (VIII-1) under acidic conditions.
This reaction can be carried out according to the method described in Process 4-1, Step 4-1.
[工程８－２]
　本工程は、化合物（VIII－２）より化合物（Ｉ－１）を製造する方法である。
　本反応は、製造法４～７に記載した方法に準じて行うことができる。
　このようにして得られる化合物（Ｉ－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。
[工程８－３]
　本工程は、化合物（Ｉ－１）より化合物（VIII－３）を製造する方法である。
　本方法は、公知の方法、例えばＷＯ２０１１／０１９５３８に記載されている方法を用いて行うことができる。
　このようにして得られる化合物（VIII－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 8-2]
This step is a method for producing compound (I-1) from compound (VIII-2).
This reaction can be carried out according to the methods described in Production Methods 4 to 7.
The compound (I-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
[Step 8-3]
This step is a method for producing compound (VIII-3) from compound (I-1).
This method can be performed using a known method, for example, a method described in WO2011 / 019538.
The thus obtained compound (VIII-3) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
[工程８－４]
　本工程は、化合物（VIII－１）より化合物（IV－１）を製造する方法である。
（Ａ法）
　化合物（VIII－４）のＵｇがヒドロキシである場合、本反応は、いわゆる光延反応を用いて、化合物（VIII－１）と化合物（VIII－４）を反応させることにより、化合物（IV－１）を製造することができる。
　本反応は、製造法１に記載した方法に準じて行うことができる。
（Ｂ法）
　化合物（VIII－４）のＵｇが脱離基でありＡで表される環が６員のヘテロアリールである場合、本反応は、塩基の存在下、化合物（VIII－１）を化合物（VIII－４）と反応させることにより化合物（IV－１）を製造することができる。
　本反応は、製造法２に記載した方法に準じて行うことができる。
　このようにして得られる化合物（IV－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。
[工程８－５]
　本工程は、化合物（VIII－１）より化合物（VIII－５）を製造する方法である。
　製造法８の工程８－３に記載した方法に準じて行うことができる。
[工程８－６]
　本工程は、化合物（VIII－５）より化合物（IV－１）を製造する方法である。
　本工程は、塩基の存在下、化合物（VIII－５）を化合物（II－３）と反応させることにより化合物（IV－１）を製造する方法である。
　本反応は、製造法２に記載した方法に準じて行うことができる。
　このようにして得られる化合物（IV－１）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 8-4]
This step is a method for producing compound (IV-1) from compound (VIII-1).
(Method A)
When Ug of compound (VIII-4) is hydroxy, this reaction is carried out by reacting compound (VIII-1) with compound (VIII-4) using a so-called Mitsunobu reaction to give compound (IV-1) Can be manufactured.
This reaction can be carried out according to the method described in Production Method 1.
(Method B)
When Ug of compound (VIII-4) is a leaving group and the ring represented by A is a 6-membered heteroaryl, this reaction is carried out by reacting compound (VIII-1) with compound (VIII-) in the presence of a base. Compound (IV-1) can be produced by reacting with 4).
This reaction can be carried out according to the method described in Production Method 2.
The thus obtained compound (IV-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
[Step 8-5]
This step is a method for producing compound (VIII-5) from compound (VIII-1).
This can be carried out according to the method described in Step 8-3 of Production Method 8.
[Step 8-6]
This step is a method for producing compound (IV-1) from compound (VIII-5).
This step is a method for producing compound (IV-1) by reacting compound (VIII-5) with compound (II-3) in the presence of a base.
This reaction can be carried out according to the method described in Production Method 2.
The thus obtained compound (IV-1) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法８における出発物質である化合物（VIII－１）において、Ｙがプロパン－１,３－ジイルである化合物（IX－６）は、例えば、化合物（IX－１）より、下記製造法９又はこれに準ずる方法により製造することができる。
　製造法９： In compound (VIII-1) which is the starting material in production method 8, compound (IX-6) wherein Y is propane-1,3-diyl is obtained, for example, from compound (IX-1) by the following production method 9 or It can manufacture by the method according to this.
Production method 9:
Figure JPOXMLDOC01-appb-C000032
 [式中、ｍ１及びｍ２は前記と同意義を示す。]
Figure JPOXMLDOC01-appb-C000032
 [Wherein, m1 and m2 are as defined above. ]
[工程９－１]
　本工程は、化合物（IX－１）と（メトキシメチル）トリフェニルホスホニウムクロリドを塩基の存在下反応させることにより、化合物（IX－２）を製造する方法である。
　本反応で用いられる（メトキシメチル）トリフェニルホスホニウムクロリドの量は、化合物（IX－１）１当量に対して通常１から３当量であり、好ましくは１から１．５当量である。
　反応に用いられる塩基としては、通常例えば、ｎ－ブチルリチウム、水素化ナトリウム、カリウム　ｔｅｒｔ－ブトキシド、ナトリウムビス（トリメチルシリル）アミド等が挙げられる。用いられる塩基の量は、化合物（IX－１）１当量に対して、通常１から３当量であり、好ましくは１から１．５当量である。
　反応に用いられる溶媒としては、ジエチルエーテル、テトラヒドロフラン、１，２－ジメトキシエタン、メチルｔｅｒｔ－ブチルエーテル、トルエン、ベンゼン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常０℃から還流温度で、１から２４時間で行うことができる。 [Step 9-1]
This step is a method for producing compound (IX-2) by reacting compound (IX-1) with (methoxymethyl) triphenylphosphonium chloride in the presence of a base.
The amount of (methoxymethyl) triphenylphosphonium chloride used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-1).
Examples of the base used in the reaction usually include n-butyl lithium, sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide and the like. The amount of the base used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-1).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, and benzene. These solvents are mixed in an appropriate ratio. It may be used.
These reactions can be usually performed at 0 ° C. to reflux temperature for 1 to 24 hours.
[工程９－２]
　本工程は、化合物（IX－２）を酸性条件下で処理することにより、化合物（IX－３）を製造する方法である。
　反応に用いられる酸としては、通常例えば、ｐ－トルエンスルホン酸、トリフルオロ酢酸、塩酸等が挙げられる。用いられる酸の量は、化合物（IX－２）１当量に対して１から１０当量である。
　反応に用いられる溶媒としては、アセトニトリル、テトラヒドロフラン、１，４－ジオキサン、ジエチルエーテル、水、クロロホルム、ジクロロメタン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から室温で、１から２４時間で行うことができる。 [Step 9-2]
This step is a method for producing compound (IX-3) by treating compound (IX-2) under acidic conditions.
Examples of the acid used for the reaction usually include p-toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid and the like. The amount of the acid used is 1 to 10 equivalents relative to 1 equivalent of compound (IX-2).
Examples of the solvent used for the reaction include acetonitrile, tetrahydrofuran, 1,4-dioxane, diethyl ether, water, chloroform, dichloromethane and the like, which are not involved in the reaction. These solvents are used in a mixture at an appropriate ratio. Also good.
These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
[工程９－３]
　本工程は、塩基の存在下、化合物（IX－３）とホスホノ酢酸トリエチルを反応させることにより、化合物（IX－４）を製造する方法である。
　本反応で用いられるホスホノ酢酸トリエチルの量は、化合物（IX－３）１当量に対して通常１から３当量であり、好ましくは１から１．５当量である。
　用いられる塩基としては、通常例えば、ｎ－ブチルリチウム、水素化ナトリウム、カリウム　ｔｅｒｔ－ブトキシド、ナトリウムビス（トリメチルシリル）アミド等が挙げられる。用いられる塩基の量は、化合物（IX－３）１当量に対して、通常１から３当量であり、好ましくは１から１．５当量である。
　反応に用いられる溶媒としては、ジエチルエーテル、テトラヒドロフラン、１，２－ジメトキシエタン、メチルｔｅｒｔ－ブチルエーテル、トルエン、ベンゼン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から還流温度で、１から２４時間で行うことができる。 [Step 9-3]
This step is a method for producing compound (IX-4) by reacting compound (IX-3) with triethyl phosphonoacetate in the presence of a base.
The amount of triethyl phosphonoacetate used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-3).
Examples of the base used usually include n-butyllithium, sodium hydride, potassium tert-butoxide, sodium bis (trimethylsilyl) amide and the like. The amount of the base used is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (IX-3).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, methyl tert-butyl ether, toluene, and benzene. These solvents are mixed in an appropriate ratio. It may be used.
These reactions can usually be performed at 0 ° C. to reflux temperature for 1 to 24 hours.
[工程９－４]
　本工程は、化合物（IX－４）を還元することにより、化合物（IX－５）を製造する方法である。
　本反応は、金属及び水素ガスの存在下、反応に関与しない溶媒中で行う方法を用いることができる。
　用いられる金属としては、パラジウム、ニッケル、白金などが挙げられる。用いられる金属の量は化合物（IX－４）１当量に対して０．１から１当量で好ましくは０．１から０．５当量である。
　反応に用いられる水素圧は、常圧から１０気圧で好ましくは常圧から４気圧である。
　反応に用いられる溶媒としては、メタノール、エタノール、水、テトラヒドロフラン、クロロホルム、ジクロロメタン、酢酸エチル等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常室温から還流温度で行うことができる。 [Step 9-4]
This step is a method for producing compound (IX-5) by reducing compound (IX-4).
This reaction can be performed in the presence of a metal and hydrogen gas in a solvent that does not participate in the reaction.
Examples of the metal used include palladium, nickel, platinum and the like. The amount of the metal used is 0.1 to 1 equivalent, preferably 0.1 to 0.5 equivalent, relative to 1 equivalent of compound (IX-4).
The hydrogen pressure used in the reaction is from normal pressure to 10 atm, preferably from normal pressure to 4 atm.
Examples of the solvent used for the reaction include methanol, ethanol, water, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, and the like, which are not involved in the reaction, and these solvents may be used by mixing at an appropriate ratio.
These reactions can usually be performed at room temperature to reflux temperature.
[工程９－５]
　本工程は、化合物（IX－５）を還元することにより、化合物（IX－６）を製造する方法である。
　本反応に用いられる還元剤としては、例えば水素化ホウ素リチウム、水素化ホウ素ナトリウム、ボラン－テトラヒドロフラン錯体、ボラン－ジメチルスルフィド錯体、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム等が挙げられる。用いられる還元剤の量は、化合物（IX－５）１当量に対して０．５から５当量であり好ましくは１から３当量である。
　本反応に用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサン、エタノール、メタノール等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常０℃から還流温度で、３０分間から２４時間で行うことができる。
　このようにして得られる化合物（IX－６）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 9-5]
This step is a method for producing compound (IX-6) by reducing compound (IX-5).
Examples of the reducing agent used in this reaction include lithium borohydride, sodium borohydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, lithium aluminum hydride, diisobutylaluminum hydride and the like. The amount of the reducing agent used is 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (IX-5).
Examples of the solvent used in this reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, diethyl ether, 1,4-dioxane, ethanol, methanol, and the like, and these solvents may be used in an appropriate ratio.
These reactions can be usually performed at 0 ° C. to reflux temperature for 30 minutes to 24 hours.
The thus obtained compound (IX-6) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法９における出発物質である化合物（IX－１）において、ｍ１が１でありｍ２が１である化合物（Ｘ－４）は、例えば、化合物（Ｘ－１）より、下記製造法１０又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（Ｘ－１）は、自体公知の方法で製造することができる。
　製造法１０： In compound (IX-1) which is the starting material in production method 9, compound (X-4) wherein m1 is 1 and m2 is 1 is obtained, for example, from compound (X-1) by the following production method 10 or Can be produced by a method according to the above.
The starting compound (X-1) can be produced by a method known per se.
Production method 10:
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　[工程１０－１～１０－３]
　本工程は、化合物（Ｘ－１）より化合物（Ｘ－４）を製造する方法である。
　本方法は、公知の方法、例えばＣｈｅｍｉｃａｌ ＆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ，２００４，６７５－６８７に記載されている方法を用いて行うことができる。
　このようにして得られる化合物（Ｘ－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Steps 10-1 to 10-3]
This step is a method for producing compound (X-4) from compound (X-1).
This method can be carried out using a known method, for example, the method described in Chemical & Pharmaceutical Bulletin, 2004, 675-687.
The compound (X-4) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法９における出発物質である化合物（IX－１）において、ｍ１が１でありｍ２が２である化合物（XI－４）は、例えば、化合物（XI－１）より、下記製造法１１又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（XI－１）は、自体公知の方法で製造することができる。
　製造法１１： In compound (IX-1) which is the starting material in production method 9, compound (XI-4) in which m1 is 1 and m2 is 2 is obtained, for example, from compound (XI-1) by the following production method 11 or Can be produced by a method according to the above.
The starting compound (XI-1) can be produced by a method known per se.
Production method 11:
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
[工程１１－１～１１－３]
　本工程は、化合物（XI－１）より化合物（XI－４）を製造する方法である。
　本工程は、公知の方法、例えば、Ｃｈｅｍｉｓｔｒｙ－ａ Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ，２００９，９７７３－９７８４に記載の方法又はそれに準じた方法で行うことができる。
　このようにして得られる化合物（XI－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Steps 11-1 to 11-3]
This step is a method for producing compound (XI-4) from compound (XI-1).
This step can be performed by a known method, for example, the method described in Chemistry-a European Journal, 2009, 9773-9784, or a method analogous thereto.
The compound (XI-4) thus obtained can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法９における出発物質である化合物（IX－１）において、ｍ１が２でありｍ２が２である化合物（XII－３）は、例えば、化合物（XII－１）より、下記製造法１２又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（XII－１）は、自体公知の方法で製造することができる。
　製造法１２： In compound (IX-1) which is the starting material in production method 9, compound (XII-3) wherein m1 is 2 and m2 is 2 is obtained, for example, from compound (XII-1) by the following production method 12 or It can be manufactured by a method according to the above.
The starting compound (XII-1) can be produced by a method known per se.
Production method 12:
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　[工程１２－１～１２－２]
　本工程は、化合物（XII－１）より化合物（XII－３）を製造する方法である。
　本方法は、公知の方法、例えばＷＯ２０１０／０４９１４６に記載されている方法を用いて行うことができる。
　このようにして得られる化合物（XII－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Steps 12-1 to 12-2]
This step is a method for producing compound (XII-3) from compound (XII-1).
This method can be performed using a known method, for example, a method described in WO2010 / 049146.
The thus obtained compound (XII-3) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法８における出発物質である化合物（VIII－１）において、Ｙがプロパン－１,３－ジイルでありｍ１が０でありｍ２が１である化合物（XIII－７）は、例えば、化合物（XIII－１）より、下記製造法１３又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（XIII－１）は、自体公知の方法で製造することができる。
　製造法１３： In the compound (VIII-1) which is the starting material in the production method 8, the compound (XIII-7) wherein Y is propane-1,3-diyl, m1 is 0 and m2 is 1, for example, the compound (XIII From 1), it can be produced by the following production method 13 or a method analogous thereto.
The starting compound (XIII-1) can be produced by a method known per se.
Production method 13:
Figure JPOXMLDOC01-appb-C000036
 ［工程１３－１］
　本工程は、化合物（XIII－１）とホスホノ酢酸トリエチルを塩基の存在下反応させることにより、化合物（XIII－２）を製造する方法である。
　本反応は、製造法９の工程９－３に記載した方法に準じて行うことができる。
［工程１３－２］
　本工程は、化合物（XIII－２）とトリメチルスルホキソニウム塩を、塩基の存在下反応させることにより、化合物（XIII－３）を製造する方法である。
　反応に用いるトリメチルスルホキソニウム塩としては、トリメチルスルホキソニウムヨージド、トリメチルスルホキソニウムブロミド、トリメチルスルホキソニウムクロリド等が挙げられる。用いられるトリメチルスルホキソニウム塩の量は、化合物（XIII－２）１当量に対して通常１から５当量であり、好ましくは１．５から３当量である。
　反応に用いる塩基としては、水素化ナトリウム、カリウム　ｔｅｒｔ－ブトキシド等が挙げられる。用いられる塩基の量は、化合物（XIII－２）１当量に対して通常１から５当量であり、好ましくは１．５から３当量である。
　反応に用いる溶媒としては、ジメチルスルホキシド等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常室温から１００℃で、５から７２時間で行うことができる。
［工程１３－３］
　本工程は、化合物（XIII－３）を還元することにより、化合物（XIII－４）を製造する方法である。
　本反応は、製造法９の工程９－５に記載した方法に準じて行うことができる。
［工程１３－４］
　本工程は、イミダゾールの存在下、化合物（XIII－４）にトリフェニルホスフィン及びヨウ素を反応させることにより、化合物（XIII－５）を製造する方法である。
　本反応で用いられるイミダゾールの量は、化合物（XIII－５）１当量に対して通常１から３当量であり、好ましくは１から２当量である。
　本反応で用いられるトリフェニルホスフィンの量は、化合物（XIII－５）１当量に対して通常１から３当量であり、好ましくは１から１．５当量である。
　本反応で用いられるヨウ素の量は、化合物（XIII－５）１当量に対して通常１から３当量であり、好ましくは１から１．５当量である。
　反応に用いる溶媒としては、クロロホルム、ジクロロメタン、アセトニトリル、１，４－ジオキサン、ジエチルエーテル等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常０℃から還流温度で、３０分間から２４時間で行うことができる。
［工程１３－５］
　本工程は、Ｎ，Ｎ’－ジメチルプロピレン尿素の存在下、化合物（XIII－５）に酢酸ｔｅｒｔ－ブチル及びリチウムジイソプロピルアミドを反応させることにより、化合物（XIII－６）を製造する方法である。
　本反応で用いられる酢酸ｔｅｒｔ－ブチルの量は、化合物（XIII－５）１当量に対して通常１から５当量であり、好ましくは１．５から４当量である。
　本反応で用いられるリチウムジイソプロピルアミドの量は、酢酸ｔｅｒｔ－ブチル１当量に対して通常１から５当量であり、好ましくは１．５から４当量である。
　反応に用いるＮ，Ｎ’－ジメチルプロピレン尿素の代替化合物としては、ヘキサメチルリン酸トリアミド、１，３－ジメチル－２－イミダゾリジノン、テトラメチル尿素等が挙げられる。
　反応に用いる溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジエチルエーテル等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常－７８℃から室温で、１から２４時間で行うことができる。
［工程１３－６］
　本工程は、化合物（XIII－６）を還元することにより、化合物（XIII－７）を製造する方法である。
　本反応は、製造法９の工程９－５に記載した方法に準じて行うことができる。
　このようにして得られる化合物（VIII－７）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。
Figure JPOXMLDOC01-appb-C000036
 [Step 13-1]
This step is a method for producing compound (XIII-2) by reacting compound (XIII-1) with phosphonoacetic acid triethyl in the presence of a base.
This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
[Step 13-2]
This step is a method for producing compound (XIII-3) by reacting compound (XIII-2) with trimethylsulfoxonium salt in the presence of a base.
Examples of the trimethylsulfoxonium salt used in the reaction include trimethylsulfoxonium iodide, trimethylsulfoxonium bromide, trimethylsulfoxonium chloride, and the like. The amount of the trimethylsulfoxonium salt to be used is generally 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (XIII-2).
Examples of the base used in the reaction include sodium hydride and potassium tert-butoxide. The amount of the base used is usually 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of compound (XIII-2).
Examples of the solvent used for the reaction include solvents that do not participate in the reaction, such as dimethyl sulfoxide, and these solvents may be mixed and used at an appropriate ratio.
These reactions are usually carried out at room temperature to 100 ° C. for 5 to 72 hours.
[Step 13-3]
This step is a method for producing compound (XIII-4) by reducing compound (XIII-3).
This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
[Step 13-4]
This step is a method for producing compound (XIII-5) by reacting compound (XIII-4) with triphenylphosphine and iodine in the presence of imidazole.
The amount of imidazole used in this reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (XIII-5).
The amount of triphenylphosphine used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (XIII-5).
The amount of iodine used in this reaction is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (XIII-5).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform, dichloromethane, acetonitrile, 1,4-dioxane, diethyl ether, and the like, and these solvents may be mixed and used at an appropriate ratio.
These reactions can be usually performed at 0 ° C. to reflux temperature for 30 minutes to 24 hours.
[Step 13-5]
This step is a method for producing compound (XIII-6) by reacting compound (XIII-5) with tert-butyl acetate and lithium diisopropylamide in the presence of N, N′-dimethylpropyleneurea.
The amount of tert-butyl acetate used in this reaction is usually 1 to 5 equivalents, preferably 1.5 to 4 equivalents, relative to 1 equivalent of compound (XIII-5).
The amount of lithium diisopropylamide used in this reaction is usually 1 to 5 equivalents, preferably 1.5 to 4 equivalents, per 1 equivalent of tert-butyl acetate.
Examples of substitute compounds for N, N′-dimethylpropyleneurea used in the reaction include hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, and tetramethylurea.
Examples of the solvent used for the reaction include solvents that do not participate in the reaction, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, and the like. These solvents may be mixed and used at an appropriate ratio.
These reactions are usually carried out at −78 ° C. to room temperature for 1 to 24 hours.
[Step 13-6]
This step is a method for producing compound (XIII-7) by reducing compound (XIII-6).
This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
The thus obtained compound (VIII-7) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法８における出発物質である化合物（VIII－１）において、Ｙがエタン－１,２－ジイルである化合物（XIV－３）は、例えば、化合物（IX－１）より、下記製造法１４又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（IX－１）は、製造法１０～１２に記載の方法又はこれらに準ずる方法により製造することができる。
　製造法１４： In compound (VIII-1) which is the starting material in production method 8, compound (XIV-3) wherein Y is ethane-1,2-diyl is obtained, for example, from compound (IX-1) by the following production method 14 or It can manufacture by the method according to this.
Compound (IX-1) as a starting material can be produced by the method described in Production methods 10 to 12 or a method analogous thereto.
Production method 14:
Figure JPOXMLDOC01-appb-C000037
 [式中、ｍ１及びｍ２は前記と同意義を示す。]
Figure JPOXMLDOC01-appb-C000037
 [Wherein, m1 and m2 are as defined above. ]
［工程１４－１］
　本工程は、塩基の存在下、化合物（IX－１）にホスホノ酢酸トリエチルを反応させることにより、化合物（XIV－１）を製造する方法である。
　本反応は、製造法９の工程９－３に記載した方法に準じて行うことができる。 [Step 14-1]
This step is a method for producing compound (XIV-1) by reacting compound (IX-1) with triethyl phosphonoacetate in the presence of a base.
This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
［工程１４－２］
　本工程は、化合物（XIV－１）を還元することにより、化合物（XIV－２）を製造する方法である。
　製造法９の工程９－４に記載した方法に準じて行うことができる。 [Step 14-2]
This step is a method for producing compound (XIV-2) by reducing compound (XIV-1).
This can be carried out according to the method described in Step 9-4 of Production Method 9.
［工程１４－３］
　本工程は、化合物（XIV－２）より化合物（XIV－３）を製造する方法である。
　本反応は、製造法９の工程９－５に記載した方法に準じて行うことができる。
　このようにして得られる化合物（XIV－３）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 14-3]
This step is a method for producing compound (XIV-3) from compound (XIV-2).
This reaction can be carried out according to the method described in Process 9-5 of Production Method 9.
The thus obtained compound (XIV-3) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法８における出発物質である化合物（VIII－１）において、Ｙがエタン－１,２－ジイルでありｍ１が０でありｍ２が１である化合物（XV－４）は、例えば、化合物（XIII－４）より、下記製造法１５又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（XIII－４）は、製造法１３に記載の方法又はこれに準ずる方法により製造することができる。
　製造法１５： In the compound (VIII-1) which is the starting material in production method 8, compound (XV-4) wherein Y is ethane-1,2-diyl, m1 is 0 and m2 is 1, for example, compound (XIII -4), it can be produced by the following production method 15 or a method analogous thereto.
The starting compound (XIII-4) can be produced by the method described in Production Method 13 or a method analogous thereto.
Production method 15:
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
［工程１５－１］
　本工程は、化合物（XIII－４）を酸化することにより、化合物（XV－１）を製造する方法である。
　本反応は、デス・マーチン酸化等を用いて行うことができる。
反応で用いられる酸化剤は、化合物（XIII－４）１当量に対して通常１から３当量であり、好ましくは１から２当量である。
　反応に用いられる溶媒としては、クロロホルム、ジクロロメタン等の反応に関与しない溶媒が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は、通常０℃から室温で、１から２４時間で行うことができる。
また本反応は、いわゆるスワン酸化反応（Ｊ． Ｏｒｇ． Ｃｈｅｍ． １９７６， ４１， ３３２９．）、２－ヨードキシ安息香酸（ＩＢＸ）酸化等を用いて行うことができる。 [Step 15-1]
This step is a method for producing compound (XV-1) by oxidizing compound (XIII-4).
This reaction can be performed using Dess-Martin oxidation or the like.
The oxidizing agent used in the reaction is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (XIII-4).
Examples of the solvent used in the reaction include solvents that do not participate in the reaction, such as chloroform and dichloromethane, and these solvents may be used by mixing at an appropriate ratio.
These reactions can be carried out usually at 0 ° C. to room temperature for 1 to 24 hours.
In addition, this reaction can be performed using a so-called Swan oxidation reaction (J. Org. Chem. 1976, 41, 3329.), 2-iodoxybenzoic acid (IBX) oxidation or the like.
［工程１５－２］
　本工程は、塩基の存在下、化合物（XV－１）と（メトキシメチル）トリフェニルホスホニウムクロリドを反応させることにより、化合物（XV－２）を製造する方法である。
　製造法９の工程９－１に記載した方法に準じて行うことができる。 [Step 15-2]
This step is a method for producing compound (XV-2) by reacting compound (XV-1) with (methoxymethyl) triphenylphosphonium chloride in the presence of a base.
This can be carried out according to the method described in Step 9-1 of Production Method 9.
［工程１５－３］
　本工程は、化合物（XV－２）を酸性条件下で処理することにより、化合物（XV－３）を製造する方法である。
　製造法９の工程９－２に記載した方法に準じて行うことができる。 [Step 15-3]
This step is a method for producing compound (XV-3) by treating compound (XV-2) under acidic conditions.
This can be carried out according to the method described in Step 9-2 of Production Method 9.
［工程１５－４］
　本工程は、化合物（XV－３）を還元することにより、化合物（XV－４）を製造する方法である。
　製造法９の工程９－５に記載した方法に準じて行うことができる。
　このようにして得られる化合物（XV－４）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 15-4]
This step is a method for producing compound (XV-4) by reducing compound (XV-3).
This can be carried out according to the method described in Step 9-5 of Production Method 9.
The thus obtained compound (XV-4) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　製造法８における出発物質である化合物（VIII－１）において、Ｙがブタン－１,４－ジイルである化合物（XVI－５）は、例えば、化合物（XVI－１）より、下記製造法１６又はこれに準ずる方法により製造することができる。
　なお、出発物質である化合物（XVI－１）は、製造法１４～１５に記載の方法又はこれらに準ずる方法により製造することができる。
　製造法１６： In compound (VIII-1) which is a starting material in production method 8, compound (XVI-5) wherein Y is butane-1,4-diyl is synthesized, for example, from compound (XVI-1) by the following production method 16 or It can manufacture by the method according to this.
The starting compound (XVI-1) can be produced by the method described in Production Methods 14 to 15 or a method analogous thereto.
Production method 16:
Figure JPOXMLDOC01-appb-C000039
 [式中、ｍ１及びｍ２は前記と同意義を示す。]
Figure JPOXMLDOC01-appb-C000039
 [Wherein, m1 and m2 are as defined above. ]
［工程１６－１］
　本工程は、化合物（XVI－１）を酸化することにより、化合物（XVI－２）を製造する方法である。
　製造法１５の工程１５－１に記載した方法に準じて行うことができる。 [Step 16-1]
This step is a method for producing compound (XVI-2) by oxidizing compound (XVI-1).
This can be carried out according to the method described in Step 15-1 of Production Method 15.
［工程１６－２］
　本工程は、塩基の存在下、化合物（XVI－２）とホスホノ酢酸トリエチルを反応させることにより、化合物（XVI－３）を製造する方法である。
　本反応は、製造法９の工程９－３に記載した方法に準じて行うことができる。 [Step 16-2]
This step is a method for producing compound (XVI-3) by reacting compound (XVI-2) with triethyl phosphonoacetate in the presence of a base.
This reaction can be carried out according to the method described in Step 9-3 of Production Method 9.
［工程１６－３］
　本工程は、化合物（XVI－３）を還元することにより、化合物（XVI－４）を製造する方法である。
　製造法９の工程９－４に記載した方法に準じて行うことができる。 [Step 16-3]
This step is a method for producing compound (XVI-4) by reducing compound (XVI-3).
This can be carried out according to the method described in Step 9-4 of Production Method 9.
［工程１６－４］
　本工程は、化合物（XVI－４）を還元することにより、化合物（XVI－５）を製造する方法である。
　製造法９の工程９－５に記載した方法に準じて行うことができる。
　このようにして得られる化合物（XVI－５）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。 [Step 16-4]
This step is a method for producing compound (XVI-5) by reducing compound (XVI-4).
This can be carried out according to the method described in Step 9-5 of Production Method 9.
The compound (XVI-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
　本発明の化合物（Ｉ）のうち、Ｒ2が（ｅ）Ｃ1-6アルキルカルボニル又はＣ3-8シクロアルキルカルボニルである化合物（XVII－１）は、例えば、下記製造法１７又はこれに準ずる方法により製造することができる。
製造法１７： Among the compounds (I) of the present invention, the compound (XVII-1) in which R 2 is (e) C 1-6 alkylcarbonyl or C 3-8 cycloalkylcarbonyl is, for example, in accordance with the following Production method 17 or the like. It can be manufactured by a method.
Production method 17:
Figure JPOXMLDOC01-appb-C000040
 　[式中、Ｕｅはハロゲン原子を、Ｒ29はＣ1-6アルキル又はＣ3-8シクロアルキルを、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ及びＹは前記と同意義を示す。]
Ｕｅで示される「ハロゲン原子」としては、塩素原子、臭素原子及びヨウ素原子が挙げられる。
[工程１７－１]
　本工程は、化合物（IV－１）を酸性条件下で処理することにより、化合物（IV－２）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法を用いて行うことができる。
[工程１７－２]
　本工程は、化合物（IV－２）と化合物（XVII－２）を反応させることにより、化合物（XVII－１）を製造する方法である。
　本反応は製造法６の工程６－４に記載した方法を用いて行うことができる。
Figure JPOXMLDOC01-appb-C000040
 [Wherein Ue is a halogen atom, R 29 is C 1-6 alkyl or C 3-8 cycloalkyl, m1, m2, A, R 11 , R 12 , R 13 , X and Y are as defined above] Indicates. ]
Examples of the “halogen atom” represented by Ue include a chlorine atom, a bromine atom, and an iodine atom.
[Step 17-1]
This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
This reaction can be carried out using the method described in Process 4-1, Production Method 4.
[Step 17-2]
This step is a method for producing compound (XVII-1) by reacting compound (IV-2) with compound (XVII-2).
This reaction can be carried out using the method described in Step 6-4 of Production Method 6.
　本発明の化合物（Ｉ）のうち、Ｒ2がジＣ1-6アルキルアミノカルボニルである化合物（XVIII－１）およびＣ1-6アルキルアミノカルボニルである化合物（XVIII－２）は、例えば、下記製造法１８又はこれに準ずる方法により製造することができる。
製造法１８： Among the compounds of the present invention (I), R 2 is di-C 1-6 alkylamino carbonyl, compound (XVIII-1) and C 1-6 compound alkylaminocarbonyl (XVIII-2) is, for example, the following It can be produced by production method 18 or a method analogous thereto.
Production method 18:
Figure JPOXMLDOC01-appb-C000041
 [式中、Ｒ30及びＲ31はＣ1-6アルキルを、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｘ及びＹは前記と同意義を示す。]
[工程１８－１]
　本工程は、化合物（IV－１）を酸性条件下で処理することにより、化合物（IV－２）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法を用いて行うことができる。
[工程１８－２]
　本工程は化合物（IV－２）と化合物（XVIII－３）をカルボニル化試薬の存在下で反応させることにより化合物（XVIII－１）を得る反応である。
　ここで用いるカルボニル化試薬としては、１，１′－カルボニルジイミダゾール、ｐ－ニトロフェニルクロロフォルメート、トリホスゲン等であり、用いる試薬量は化合物に対して通常１から３当量であり、好ましくは１当量である。
　本反応には、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン等の塩基を共存させても良い。
　反応に用いる溶媒としては、クロロホルム、ジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド等が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常室温～８０℃で、３０分間から４８時間で行うことが出来る。
[工程１８－３]
　本工程は化合物（IV－２）と化合物（XVIII－４）を反応させることにより化合物（XVIII－２）を得る反応である。
　本反応には、トリエチルアミン、ピリジン、Ｎ－メチルモルホリン等の塩基を共存させても良い。
　反応に用いる溶媒としては、クロロホルム、ジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド等が挙げられ、これらの溶媒は適宜の割合で混合して用いてもよい。
　これらの反応は通常室温～８０℃で、３０分間から２４時間で行うことが出来る。
Figure JPOXMLDOC01-appb-C000041
 Wherein the R 30 and R 31 are C 1-6 alkyl, m1, m2, A, R 11, R 12, R 13, X and Y are as defined above. ]
[Step 18-1]
This step is a method for producing compound (IV-2) by treating compound (IV-1) under acidic conditions.
This reaction can be carried out using the method described in Process 4-1, Production Method 4.
[Step 18-2]
This step is a reaction for obtaining compound (XVIII-1) by reacting compound (IV-2) with compound (XVIII-3) in the presence of a carbonylating reagent.
The carbonylation reagent used here is 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, triphosgene, etc. The amount of reagent used is usually 1 to 3 equivalents, preferably 1 Is equivalent.
In this reaction, a base such as triethylamine, pyridine or N-methylmorpholine may coexist.
Examples of the solvent used in the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these solvents may be used by mixing at an appropriate ratio.
These reactions are usually carried out at room temperature to 80 ° C. for 30 minutes to 48 hours.
[Step 18-3]
This step is a reaction for obtaining the compound (XVIII-2) by reacting the compound (IV-2) with the compound (XVIII-4).
In this reaction, a base such as triethylamine, pyridine or N-methylmorpholine may coexist.
Examples of the solvent used in the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and these solvents may be used by mixing at an appropriate ratio.
These reactions are usually carried out at room temperature to 80 ° C. for 30 minutes to 24 hours.
　本発明の化合物（Ｉ）のうち、Ｘが－ＮＲ3－である化合物（XIX－１）、（XIX－２）、（XIX－３）および（XIX－４）は、例えば、下記製造法１９又はこれに準ずる方法により製造することができる。
製造法１９： Among the compounds (I) of the present invention, compounds (XIX-1), (XIX-2), (XIX-3) and (XIX-4) in which X is —NR 3 — are prepared, for example, by the following production method 19 Or it can manufacture by the method according to this.
Production method 19:
Figure JPOXMLDOC01-appb-C000042
 [式中、Ｕｄは脱離基を、Ｚは単結合又はＣ1-3アルカンジイルを、Ｒ32はＣ1-3アルキルを、ｍ１、ｍ２、Ａ、Ｒ11、Ｒ12、Ｒ13、Ｒ2、Ｒ3は前記と同意義を示す。]
Ｕｄで示される「脱離基」としては、例えば、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ、ｐ－トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ、ベンゼンスルホニルオキシ等が挙げられる。
Ｒ32で示される「Ｃ1-3アルキル」とは、炭素原子を１～３個有する直鎖状又は分岐状のアルキルであり、例えばメチル、エチル、ｎ－プロピル、イソプロピルが挙げられる。
Ｚで示されるＣ1-3アルカンジイルとは、炭素原子を１～３個有する２価の炭化水素基を示し、例えば、メタンジイル、エタン－１，２－ジイル、プロパン－１，３－ジイルが挙げられる。
[工程１９－１]
　本工程は塩基により加水分解を行い、化合物（XIX－１０）より化合物（XIX－９）を得る反応である。
　本反応は製造法３の工程３－１に記載した方法を用いて行うことができる。
[工程１９－２]
　本工程は、化合物（XIX－９）と化合物（XIX－８）を縮合し、化合物（XIX－７）を製造する方法である。
　本反応は製造法３の工程３－２に記載した方法を用いて行うことができる。
[工程１９－３]
　本工程は、化合物（XIX－７）に還元剤を作用させることにより、化合物（XIX－２）を製造する方法である。
　本反応は製造法９の工程９－５に記載した方法を用いて行うことができる。
[工程１９－４]
　本工程は、化合物（XIX－２）にＲ32－ＣＨＯ又はＲ3-Ｕｄを作用させることにより、化合物（XIX－１）を製造する方法である。
　本反応は製造法６の工程６－２又は６－３に記載した方法を用いて行うことができる。
[工程１９－５]
　本工程は、化合物（XIX－７）を酸性条件下で処理することにより、化合物（XIX－６）を製造する方法である。
　本反応は製造法４の工程４－１に記載した方法を用いて行うことができる。
[工程１９－６]
　本工程は、化合物（XIX－６）より化合物（XIX－５）を製造する方法である。
　本反応は、製造法４～７に記載した方法に準じて行うことができる。
　このようにして得られる化合物（XIX－５）は、公知の分離精製手段、例えば濃縮、減圧濃縮、再沈殿、溶媒抽出、結晶化、クロマトグラフィー等により単離精製することができる。
[工程１９－７]
　本工程は、化合物（XIX－５）に還元剤を作用させることにより、化合物（XIX－４）を製造する方法である。
　本反応は製造法９の工程９－５に記載した方法を用いて行うことができる。
[工程１９－８]
　本工程は、化合物（XIX－４）にＲ32－ＣＨＯ又はＲ3-Ｕｄを作用させることにより、化合物（XIX－３）を製造する方法である。
　本反応は製造法６の工程６－２又は６－３に記載した方法を用いて行うことができる。
Figure JPOXMLDOC01-appb-C000042
 [In the formula, Ud is a leaving group, Z is a single bond or C 1-3 alkanediyl, R 32 is C 1-3 alkyl, m1, m2, A, R 11 , R 12 , R 13 , R 2 and R 3 are as defined above. ]
Examples of the “leaving group” represented by Ud include a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and the like.
“C 1-3 alkyl” represented by R 32 is linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl and isopropyl.
C 1-3 alkanediyl represented by Z represents a divalent hydrocarbon group having 1 to 3 carbon atoms, and examples thereof include methanediyl, ethane-1,2-diyl, and propane-1,3-diyl. Can be mentioned.
[Step 19-1]
This step is a reaction in which the compound (XIX-9) is obtained from the compound (XIX-10) by hydrolysis with a base.
This reaction can be carried out using the method described in Process 3-1, Step 3-1.
[Step 19-2]
This step is a method for producing compound (XIX-7) by condensing compound (XIX-9) and compound (XIX-8).
This reaction can be carried out using the method described in Step 3-2 of Production Method 3.
[Step 19-3]
This step is a method for producing compound (XIX-2) by reacting compound (XIX-7) with a reducing agent.
This reaction can be carried out using the method described in Process 9-5 of Production Method 9.
[Step 19-4]
This step is a method for producing compound (XIX-1) by reacting compound (XIX-2) with R 32 —CHO or R 3 —Ud.
This reaction can be carried out using the method described in Step 6-2 or 6-3 of Production Method 6.
[Step 19-5]
This step is a method for producing compound (XIX-6) by treating compound (XIX-7) under acidic conditions.
This reaction can be carried out using the method described in Process 4-1, Production Method 4.
[Step 19-6]
This step is a method for producing compound (XIX-5) from compound (XIX-6).
This reaction can be carried out according to the methods described in Production Methods 4 to 7.
The compound (XIX-5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
[Step 19-7]
This step is a method for producing compound (XIX-4) by allowing a reducing agent to act on compound (XIX-5).
This reaction can be carried out using the method described in Process 9-5 of Production Method 9.
[Step 19-8]
This step is a method for producing compound (XIX-3) by allowing R 32 —CHO or R 3 —Ud to act on compound (XIX-4).
This reaction can be carried out using the method described in Step 6-2 or 6-3 of Production Method 6.
　本発明は、以下の参考例、実施例、試験例および製剤例によってさらに詳しく説明されるが、これらは本発明を限定するものではなく、また、本発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention will be described in more detail with reference to the following Reference Examples, Examples, Test Examples and Formulation Examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention. Also good.
　以下の参考例および実施例において、ＮＨシリカゲルカラムクロマトグラフィーとは、ＮＨ２タイプシリカゲル（クロマトレックスＮＨ２タイプ、富士シリシア化学株式会社）を用いたカラムクロマトグラフィー分離精製を示す。溶出溶媒の比は特に断らない限り容量比を示す。 In the following Reference Examples and Examples, NH silica gel column chromatography refers to column chromatography separation and purification using NH 2 type silica gel (Chromatolex NH 2 type, Fuji Silysia Chemical Ltd.). The ratio of elution solvent indicates a volume ratio unless otherwise specified.
　本明細書中で用いられている略語は下記の意味を示す。
ｓ　　：　シングレット（ｓｉｎｇｌｅｔ）
ｄ　　：　ダブレット（ｄｏｕｂｌｅｔ）
ｔ　　：　トリプレット（ｔｒｉｐｌｅｔ）
ｑ　　：　クァルテット（ｑｕａｒｔｅｔ）
ｄｄ　：　ダブルダブレット（ｄｏｕｂｌｅ　ｄｏｕｂｌｅｔ）
ｄｔ　：　ダブルトリプレット（ｄｏｕｂｌｅ　ｔｒｉｐｌｅｔ）
ｍ　　：　マルチプレット（ｍｕｌｔｉｐｌｅｔ）
ｂｒ　：　ブロード（ｂｒｏａｄ）
Ｊ　　：　カップリング定数（ｃｏｕｐｌｉｎｇ　ｃｏｎｓｔａｎｔ）
Ｈｚ　：　ヘルツ（Ｈｅｒｔｚ）
ＣＤＣｌ3、ＣＨＬＯＲＯＦＯＲＭ－ｄ　:　重クロロホルム
ＤＭＳＯ－ｄ6：　重ジメチルスルホキシド Abbreviations used in this specification have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
dd: double doublet (double doublet)
dt: double triplet
m: multiplet
br: broad
J: Coupling constant
Hz: Hertz
CDCl 3 , CHLOROFORM-d: deuterated chloroform DMSO-d 6 : deuterated dimethyl sulfoxide
　1Ｈ－ＮＭＲ（プロトン核磁気共鳴スペクトル）は下記のフーリエ変換型ＮＭＲで測定した。
２００ＭＨｚ：　Ｇｅｍｉｎｉ２０００　（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）
３００ＭＨｚ：　Ｉｎｏｖａ３００　（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）
６００ＭＨｚ：　ＪＮＭ－ＥＣＡ６００　（ＪＥＯＬ）
　解析にはＡＣＤ／ＳｐｅｃＭａｎａｇｅｒ　ｖｅｒ．１２．０１（商品名）などを用いた。水酸基やアミノ基などのプロトンが非常に緩やかなピークについては記載していない。 1 H-NMR (proton nuclear magnetic resonance spectrum) was measured by the following Fourier transform NMR.
200 MHz: Gemini 2000 (Agilent Technologies)
300 MHz: Inova300 (Agilent Technologies)
600MHz: JNM-ECA600 (JEOL)
For analysis, ACD / SpecManager ver. 12.01 (trade name) or the like was used. Peaks with very gentle protons such as hydroxyl groups and amino groups are not described.
　ＭＳ（マススペクトル）は以下の装置にて測定した。
ＰｌａｔｆｏｒｍＬＣ　（Ｗａｔｅｒｓ）
ＬＣＭＳ－２０１０ＥＶ　（Ｓｈｉｍａｄｚｕ）
ＬＣＭＳ－ＩＴ－ＴＯＦ　（Ｓｈｉｍａｄｚｕ）
　イオン化法としては、ＥＳＩ（Ｅｌｅｃｔｒｏｓｐｒａｙ　Ｉｏｎｉｚａｔｉｏｎ、エレクトロスプレーイオン化）法または、ＥＳＩとＡＰＣＩ（Ａｔｍｏｓｐｈｅｒｉｃ　Ｐｒｅｓｓｕｒｅ　Ｃｈｅｍｉｃａｌ　Ｉｏｎｉｚａｔｉｏｎ、大気圧化学イオン化）法とのデュアルイオン化法を用いた。データは実測値（ｆｏｕｎｄ）を記載した。通常、分子イオンピークが観測されるが、ｔｅｒｔ－ブトキシカルボニル基（－Ｂｏｃ）を有する化合物の場合、フラグメントイオンとして、ｔｅｒｔ－ブトキシカルボニル基あるいはｔｅｒｔ－ブチル基が脱離したピークが観測されることもある。また、水酸基（－ＯＨ）を有する化合物の場合、フラグメントピークとしてＨ2Ｏが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピークもしくはフラグメントイオンピークが観測される。 MS (mass spectrum) was measured with the following apparatus.
PlatformMLC (Waters)
LCMS-2010EV (Shimadzu)
LCMS-IT-TOF (Shimadzu)
As the ionization method, an ESI (Electrospray Ionization) method or a dual ionization method of ESI and APCI (Atmospheric Pressure Chemical Ionization) method was used. The data described the actual value (found). Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (—Boc), a peak from which a tert-butoxycarbonyl group or a tert-butyl group is eliminated is observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment peak. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
　化合物名はＡＣＤ／Ｎａｍｅ　ｖｅｒ．１２．０１（商品名）などを用いて命名した。 Compound name is ACD / Name ver. It was named using 12.01 (trade name) or the like.
参考例１
ｔｅｒｔ－ブチル ２－オキソ－７－アザスピロ［３．５］ノナン－７－カルボキシラート Reference example 1
tert-Butyl 2-oxo-7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000043
 ｔｅｒｔ－ブチル　４－オキソピペリジン－１－カルボキシラート（５０ｇ）を用い、文献（Ｃｈｅｍｉｃａｌ ＆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｂｕｌｌｅｔｉｎ， ２００４，６７５－６８７）に従って実験を行い、表題化合物（１７．２ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H) 1.64 - 1.76 (m, 4 H) 2.82 (s, 4 H) 3.35 - 3.46 (m, 4 H)．
MS ESI/APCI Dual posi: 262[M+Na]+.
参考例２－１
ｔｅｒｔ－ブチル ２－（メトキシメチリデン）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000043
 An experiment was performed using tert-butyl 4-oxopiperidine-1-carboxylate (50 g) according to the literature (Chemical & Pharmaceutical Bulletin, 2004, 675-687) to obtain the title compound (17.2 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H) 1.64-1.76 (m, 4 H) 2.82 (s, 4 H) 3.35-3.46 (m, 4 H).
MS ESI / APCI Dual posi: 262 [M + Na] + .
Reference Example 2-1
tert-Butyl 2- (methoxymethylidene) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000044
 アルゴン雰囲気下、（メトキシメチル)トリフェニルホスホニウムクロリド（３２ｇ）をトルエン（２００ｍｌ）に懸濁し、カリウム　ｔｅｒｔ－ブトキシド（１０．５ｇ）を加え、室温にて２０分撹拌した。ここへ参考例１で得られた化合物（１７．２ｇ）のトルエン（１６０ｍｌ）溶液を滴下した後、７０℃で４時間撹拌した。氷冷下、反応液に飽和塩化アンモニウム水を加えて酢酸エチルにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９５：５～８０：２０）にて精製し、表題化合物（１２．８ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 1.52 - 1.59 (m, 4 H) 2.29 - 2.47 (m, 4 H) 3.26 - 3.37 (m, 4 H) 3.53 - 3.57 (m, 3 H) 5.80 - 5.87 (m, 1 H).
MS ESI/APCI Dual posi: 290[M+Na]+.
参考例２－２
ｔｅｒｔ－ブチル ２－（３－エトキシ－３－オキソプロパ－１－エン－１－イル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000044
 Under an argon atmosphere, (methoxymethyl) triphenylphosphonium chloride (32 g) was suspended in toluene (200 ml), potassium tert-butoxide (10.5 g) was added, and the mixture was stirred at room temperature for 20 minutes. A solution of the compound (17.2 g) obtained in Reference Example 1 in toluene (160 ml) was added dropwise thereto, followed by stirring at 70 ° C. for 4 hours. Under ice-cooling, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 95: 5 to 80:20) to obtain the title compound (12.8 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 1.52-1.59 (m, 4 H) 2.29-2.47 (m, 4 H) 3.26-3.37 (m, 4 H) 3.53-3.57 (m, 3 H) 5.80-5.87 (m, 1 H).
MS ESI / APCI Dual posi: 290 [M + Na] + .
Reference Example 2-2
tert-Butyl 2- (3-Ethoxy-3-oxoprop-1-en-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000045
 参考例２－１で得られた化合物（１２．８ｇ）をアセトニトリル（４６０ｍｌ）に溶解し、水（１１４ｍＬ）、次いでトリフルオロ酢酸（４．０ｍｌ）を加え、室温で１時間撹拌した。反応液を氷冷し、飽和重曹水を加えて減圧下濃縮した。得られた水層を酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、ｔｅｒｔ－ブチル ２－ホルミル－７－アザスピロ［３．５］ノナン－７－カルボキシラートを得た。ホスホノ酢酸トリエチル（１１ｍｌ）のＮ，Ｎ－ジメチルホルムアミド（６０ｍｌ）とテトラヒドロフラン（６０ｍｌ）の溶液に、氷冷下、水素化ナトリウム（６０％オイル懸濁、２．３ｇ）を加えて２０分撹拌後、得られたｔｅｒｔ－ブチル ２－ホルミル－７－アザスピロ［３．５］ノナン－７－カルボキシラートのＮ，Ｎ－ジメチルホルムアミド（６０ｍｌ）とテトラヒドロフラン（６０ｍｌ）の溶液を滴下した。反応液を室温まで昇温しながら３時間撹拌した。氷冷下、反応液に飽和塩化アンモニウム水を加え、水層を酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄後、水層をノルマルヘキサンと酢酸エチルの混合溶液で抽出し、有機層を合わせ、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９５：５～８０：２０）にて精製し、表題化合物（１３．６ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3 H) 1.45 (s, 9 H) 1.53 - 1.78 (m, 4 H) 2.01 - 2.16 (m, 4 H) 2.98 - 3.14 (m, 1 H) 3.23 - 3.40 (m, 4 H) 4.19 (q, J=7.1 Hz, 2 H) 5.74 (dd, J=15.5, 1.6 Hz, 1 H) 7.05 (dd, J=15.5, 6.7 Hz, 1 H).
MS ESI/APCI Dual posi: 346[M+Na]+.
参考例２－３
ｔｅｒｔ－ブチル ２－（３－エトキシ－３－オキソプロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000045
 The compound (12.8 g) obtained in Reference Example 2-1 was dissolved in acetonitrile (460 ml), water (114 mL) and then trifluoroacetic acid (4.0 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate was added, and the mixture was concentrated under reduced pressure. The obtained aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate. Sodium hydride (60% oil suspension, 2.3 g) was added to a solution of triethyl phosphonoacetate (11 ml) in N, N-dimethylformamide (60 ml) and tetrahydrofuran (60 ml) under ice cooling, and the mixture was stirred for 20 minutes. Then, a solution of the obtained tert-butyl 2-formyl-7-azaspiro [3.5] nonane-7-carboxylate in N, N-dimethylformamide (60 ml) and tetrahydrofuran (60 ml) was added dropwise. The reaction was stirred for 3 hours while warming to room temperature. Under ice-cooling, saturated aqueous ammonium chloride was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the aqueous layer was extracted with a mixed solution of normal hexane and ethyl acetate. The bottom was concentrated. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 95: 5 to 80:20) to obtain the title compound (13.6 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.1 Hz, 3 H) 1.45 (s, 9 H) 1.53-1.78 (m, 4 H) 2.01-2.16 (m, 4 H) 2.98-3.14 (m, 1 H) 3.23-3.40 (m, 4 H) 4.19 (q, J = 7.1 Hz, 2 H) 5.74 (dd, J = 15.5, 1.6 Hz, 1 H) 7.05 (dd, J = (15.5, 6.7 Hz, 1 H).
MS ESI / APCI Dual posi: 346 [M + Na] + .
Reference Example 2-3
tert-Butyl 2- (3-Ethoxy-3-oxopropyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000046
 参考例２－２で得られた化合物（１３．６ｇ）をエタノール（４２０ｍｌ）に溶解し、２０％水酸化パラジウム ／ 炭素（２．７ｇ）を加え、水素雰囲気下、室温で一晩撹拌した。反応液をセライト（登録商標）濾過し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９５：５～７０：３０）にて精製し、表題化合物（１３．３ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.1 Hz, 3 H) 1.32 - 1.61 (m, 15 H) 1.67 - 1.78 (m, 2 H) 1.88 - 2.00 (m, 2 H) 2.13 - 2.28 (m, 3 H) 3.19 - 3.38 (m, 4 H) 4.12 (q, J=7.1 Hz, 2 H).
MS ESI/APCI Dual posi: 348[M+Na]+.
参考例２－４
ｔｅｒｔ－ブチル ２－（３－ヒドロキシプロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000046
 The compound (13.6 g) obtained in Reference Example 2-2 was dissolved in ethanol (420 ml), 20% palladium hydroxide / carbon (2.7 g) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 95: 5 to 70:30) to obtain the title compound (13.3 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.32-1.61 (m, 15 H) 1.67-1.78 (m, 2 H) 1.88-2.00 (m, 2 H) 2.13-2.28 (m, 3 H) 3.19-3.38 (m, 4 H) 4.12 (q, J = 7.1 Hz, 2 H).
MS ESI / APCI Dual posi: 348 [M + Na] + .
Reference Example 2-4
tert-Butyl 2- (3-hydroxypropyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000047
 参考例２－３で得られた化合物（１０．４ｇ）のテトラヒドロフラン（１６０ｍｌ）溶液に、氷冷下、水素化ジイソブチルアルミニウム(１．０Ｍトルエン溶液、８０ｍｌ）を滴下し、室温まで昇温しながら３時間撹拌した。反応液を氷冷し、１Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝６０：４０～３０：７０）にて精製し、表題化合物（６．６ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31 - 1.60 (m, 19 H) 1.89 - 2.00 (m, 2 H) 2.10 - 2.31 (m, 1 H) 3.19 - 3.39 (m, 4 H) 3.56 - 3.68 (m, 2 H).
MS ESI/APCI Dual posi: 306[M+Na]+.
参考例３－１
ｔｅｒｔ－ブチル ２－（２－エトキシ－２－オキソエチリデン）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000047
 To a solution of the compound (10.4 g) obtained in Reference Example 2-3 in tetrahydrofuran (160 ml), diisobutylaluminum hydride (1.0 M toluene solution, 80 ml) was added dropwise under ice cooling, and the temperature was raised to room temperature. Stir for 3 hours. The reaction mixture was ice-cooled, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 60: 40-30: 70) to obtain the title compound (6.6 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.60 (m, 19 H) 1.89-2.00 (m, 2 H) 2.10-2.31 (m, 1 H) 3.19-3.39 (m, 4 H) 3.56 -3.68 (m, 2 H).
MS ESI / APCI Dual posi: 306 [M + Na] + .
Reference Example 3-1
tert-Butyl 2- (2-Ethoxy-2-oxoethylidene) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000048
 ホスホノ酢酸トリエチル（８２２μｌ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍｌ）溶液に、氷冷下、水素化ナトリウム（６０％オイル懸濁、１６４ｍｇ）を加えて３０分撹拌し、次いで参考例１で得られた化合物（６５５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４ｍｌ）溶液を滴下した。反応液を室温まで昇温しながら３時間撹拌した。反応液に飽和塩化アンモニウム水を加えて酢酸エチルにて抽出し、有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９１：９～８５：１５）にて精製し、表題化合物（８００ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.0 Hz, 3 H) 1.46 (s, 9 H) 1.52 - 1.62 (m, 4 H) 2.55 - 2.61 (m, 2 H) 2.85 - 2.92 (m, 2 H) 3.25 - 3.44 (m, 4 H) 4.15 (q, J=7.0 Hz, 2 H) 5.67 - 5.73 (m, 1 H).
MS ESI/APCI Dual posi: 332[M+Na]+.
参考例３－２
ｔｅｒｔ－ブチル ２－（２－エトキシ－２－オキソエチル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000048
 Sodium hydride (60% oil suspension, 164 mg) was added to a solution of triethyl phosphonoacetate (822 μl) in N, N-dimethylformamide (10 ml) under ice cooling, and the mixture was stirred for 30 minutes, and then obtained in Reference Example 1. A solution of the compound (655 mg) in N, N-dimethylformamide (4 ml) was added dropwise. The reaction was stirred for 3 hours while warming to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 91: 9 to 85:15) to obtain the title compound (800 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.0 Hz, 3 H) 1.46 (s, 9 H) 1.52-1.62 (m, 4 H) 2.55-2.61 (m, 2 H) 2.85-2.92 (m, 2 H) 3.25-3.44 (m, 4 H) 4.15 (q, J = 7.0 Hz, 2 H) 5.67-5.73 (m, 1 H).
MS ESI / APCI Dual posi: 332 [M + Na] + .
Reference Example 3-2
tert-Butyl 2- (2-Ethoxy-2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000049
 参考例３－１で得られた化合物（７９７ｍｇ）を用い、参考例２－３と同様にして反応及び精製を行い、表題化合物（７３０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.0 Hz, 3 H) 1.37 - 1.68 (m, 15 H) 1.98 - 2.09 (m, 2 H) 2.41 (d, J=7.6 Hz, 2 H) 2.57 - 2.72 (m, 1 H) 3.19 - 3.39 (m, 4 H) 4.11 (q, J=7.0 Hz, 2 H).
MS ESI/APCI Dual posi: 334[M+Na]+.
参考例３－３
ｔｅｒｔ－ブチル ２－（２－ヒドロキシエチル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000049
 Using the compound (797 mg) obtained in Reference Example 3-1, reaction and purification were carried out in the same manner as in Reference Example 2-3 to obtain the title compound (730 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.0 Hz, 3 H) 1.37-1.68 (m, 15 H) 1.98-2.09 (m, 2 H) 2.41 (d, J = 7.6 (Hz, 2 H) 2.57-2.72 (m, 1 H) 3.19-3.39 (m, 4 H) 4.11 (q, J = 7.0 Hz, 2 H).
MS ESI / APCI Dual posi: 334 [M + Na] + .
Reference Example 3-3
tert-Butyl 2- (2-hydroxyethyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000050
 参考例３－２で得られた化合物（７３２ｍｇ）をテトラヒドロフラン（１２ｍｌ）に溶解し、水素化ホウ素リチウム（１７４ｍｇ）を加え、加熱還流下で５時間撹拌した。反応液を氷冷し、氷水を加えて酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、表題化合物（５８０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35 - 1.49 (m, 13 H) 1.51 - 1.62 (m, 2 H) 1.63 - 1.74 (m, 2 H) 1.94 - 2.03 (m, 2 H) 2.25 - 2.43 (m, 1 H) 3.20 - 3.38 (m, 4 H) 3.52 - 3.64 (m, 2 H).
MS ESI/APCI Dual posi: 292[M+Na]+.
参考例４－１
ｔｅｒｔ－ブチル ２－［（２Ｅ）－４－エトキシ－４－オキソブタ－２－エン－１－イル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000050
 The compound (732 mg) obtained in Reference Example 3-2 was dissolved in tetrahydrofuran (12 ml), lithium borohydride (174 mg) was added, and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was ice-cooled, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (580 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35-1.49 (m, 13 H) 1.51-1.62 (m, 2 H) 1.63-1.74 (m, 2 H) 1.94-2.03 (m, 2 H) 2.25 -2.43 (m, 1 H) 3.20-3.38 (m, 4 H) 3.52-3.64 (m, 2 H).
MS ESI / APCI Dual posi: 292 [M + Na] + .
Reference Example 4-1
tert-Butyl 2-[(2E) -4-Ethoxy-4-oxobut-2-en-1-yl] -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000051
 参考例３－３で得られた化合物（５２６ｍｇ）のクロロホルム（１０ｍｌ）溶液に、氷冷下、デス－マーチンペルヨージナン（１．１ｇ）を加え、室温まで昇温しながら２時間撹拌した。反応液をクロロホルムで希釈し、飽和亜硫酸ナトリウム水溶液及び飽和重曹水の混合溶液で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、ｔｅｒｔ－ブチル ２－（２－オキソエチル）－７－アザスピロ［３．５］ノナン－７－カルボキシラートを得た。得られたｔｅｒｔ－ブチル ２－（２－オキソエチル）－７－アザスピロ［３．５］ノナン－７－カルボキシラートを用い、参考例３－１と同様にして反応及び精製を行い、表題化合物（３６０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3 H) 1.36 - 1.49 (m, 13 H) 1.50 - 1.60 (m, 2 H) 1.93 - 2.06 (m, 2 H) 2.23 - 2.46 (m, 3 H) 3.21 - 3.37 (m, 4 H) 4.18 (q, J=7.1 Hz, 2 H) 5.73 - 5.83 (m, 1 H) 6.78 - 6.94 (m, 1 H).
MS ESI/APCI Dual posi: 360[M+Na]+.
参考例４－２
ｔｅｒｔ－ブチル ２－（４－エトキシ－４－オキソブチル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000051
 Dess-Martin periodinane (1.1 g) was added to a chloroform (10 ml) solution of the compound (526 mg) obtained in Reference Example 3-3 under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature. The reaction mixture was diluted with chloroform, washed with a mixed solution of saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate. The obtained tert-butyl 2- (2-oxoethyl) -7-azaspiro [3.5] nonane-7-carboxylate was subjected to reaction and purification in the same manner as in Reference Example 3-1, to give the title compound (360 mg )
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J = 7.1 Hz, 3 H) 1.36-1.49 (m, 13 H) 1.50-1.60 (m, 2 H) 1.93-2.06 (m, 2 H) 2.23-2.46 (m, 3 H) 3.21-3.37 (m, 4 H) 4.18 (q, J = 7.1 Hz, 2 H) 5.73-5.83 (m, 1 H) 6.78-6.94 (m, 1 H) .
MS ESI / APCI Dual posi: 360 [M + Na] + .
Reference Example 4-2
tert-Butyl 2- (4-Ethoxy-4-oxobutyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000052
 参考例４－１で得られた化合物（３６１ｍｇ）を用い、参考例２－３と同様にして反応及び精製を行い、表題化合物（３５０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.0 Hz, 3 H) 1.30 - 1.61 (m, 19 H) 1.89 - 2.00 (m, 2 H) 2.12 - 2.31 (m, 3 H) 3.19 - 3.39 (m, 4 H) 4.12 (q, J=7.0 Hz, 2 H).
MS ESI/APCI Dual posi: 362[M+Na]+.
参考例４－３
ｔｅｒｔ－ブチル ２－（４－ヒドロキシブチル）－７－アザスピロ［３．５］ノナン－７－カルボキシレート
Figure JPOXMLDOC01-appb-C000052
 Using the compound (361 mg) obtained in Reference Example 4-1, reaction and purification were carried out in the same manner as in Reference Example 2-3 to obtain the title compound (350 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.0 Hz, 3 H) 1.30-1.61 (m, 19 H) 1.89-2.00 (m, 2 H) 2.12-2.31 (m, 3 H) 3.19-3.39 (m, 4 H) 4.12 (q, J = 7.0 Hz, 2 H).
MS ESI / APCI Dual posi: 362 [M + Na] + .
Reference Example 4-3
tert-Butyl 2- (4-hydroxybutyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000053
 参考例４－２で得られた化合物（３４５ｍｇ）をテトラヒドロフラン（１０ｍｌ）に溶解し、水素化ホウ素リチウム（７４ｍｇ）を加え、６０℃で８時間撹拌した。反応液を氷冷し、氷水を加えて酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝６０：４０～３０：７０）にて精製し、表題化合物（２７７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 - 1.61 (m, 21H) 1.87 - 1.99 (m, 2 H) 2.10 - 2.30 (m, 1 H) 3.20 - 3.38 (m, 4 H) 3.58 - 3.70 (m, 2 H).
MS ESI/APCI Dual posi: 320[M+Na]+.
参考例５－１
ｔｅｒｔ－ブチル ４－（２－エトキシ－２－オキソエチリデン）ピペリジン－１－カルボキシラート
Figure JPOXMLDOC01-appb-C000053
 The compound (345 mg) obtained in Reference Example 4-2 was dissolved in tetrahydrofuran (10 ml), lithium borohydride (74 mg) was added, and the mixture was stirred at 60 ° C. for 8 hours. The reaction mixture was ice-cooled, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 60: 40-30: 70) to give the title compound (277 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16-1.61 (m, 21H) 1.87-1.99 (m, 2 H) 2.10-2.30 (m, 1 H) 3.20-3.38 (m, 4 H) 3.58- 3.70 (m, 2 H).
MS ESI / APCI Dual posi: 320 [M + Na] + .
Reference Example 5-1
tert-Butyl 4- (2-ethoxy-2-oxoethylidene) piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000054
 ホスホノ酢酸トリエチル（１２ｍｌ）のＮ，Ｎ－ジメチルホルムアミド（６０ｍｌ）及びテトラヒドロフラン（６０ｍｌ）溶液に、氷冷下、水素化ナトリウム（６０％オイル懸濁、２．４ｇ）を加えて３０分撹拌後、ｔｅｒｔ－ブチル　４－オキソピペリジン－１－カルボキシラート（１０ｇ）のＮ，Ｎ－ジメチルホルムアミド（６０ｍｌ）／テトラヒドロフラン（６０ｍｌ）溶液を滴下した。反応液を室温まで昇温しながら３時間撹拌した。反応液に飽和塩化アンモニウム水を加えて酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥して濾過した。濾液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９５：５～８５：１５）にて精製し、表題化合物（１３ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H) 1.48 (s, 9 H) 2.23 - 2.33 (m, 2 H) 2.89 - 2.98 (m, 2 H) 3.43 - 3.55 (m, 4 H) 4.16 (q, J=7.1 Hz, 2 H) 5.71 (t, J=1.2 Hz, 1 H).
MS ESI/APCI Dual posi: 292[M+Na]+.
参考例５－２
６－ｔｅｒｔ－ブチル １－エチル ６－アザスピロ［２．５］オクタン－１，６－ジカルボキシラート
Figure JPOXMLDOC01-appb-C000054
 Sodium hydride (60% oil suspension, 2.4 g) was added to a solution of triethyl phosphonoacetate (12 ml) in N, N-dimethylformamide (60 ml) and tetrahydrofuran (60 ml) under ice cooling, and the mixture was stirred for 30 minutes. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g) in N, N-dimethylformamide (60 ml) / tetrahydrofuran (60 ml) was added dropwise. The reaction was stirred for 3 hours while warming to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (normal hexane: ethyl acetate = 95: 5 to 85:15) to obtain the title compound (13 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J = 7.1 Hz, 3 H) 1.48 (s, 9 H) 2.23-2.33 (m, 2 H) 2.89-2.98 (m, 2 H) 3.43-3.55 (m, 4 H) 4.16 (q, J = 7.1 Hz, 2 H) 5.71 (t, J = 1.2 Hz, 1 H).
MS ESI / APCI Dual posi: 292 [M + Na] + .
Reference Example 5-2
6-tert-butyl 1-ethyl 6-azaspiro [2.5] octane-1,6-dicarboxylate
Figure JPOXMLDOC01-appb-C000055
 トリメチルスルホキソニウムヨージド（２０ｇ）のジメチルスルホキシド（１９０ｍｌ）溶液に、カリウム　ｔｅｒｔ－ブトキシド（１０ｇ）を加えて、室温で１時間撹拌した後、参考例５－１で得られた化合物（１３ｇ）のジメチルスルホキシド（６０ｍｌ）溶液を滴下し、室温で３日間撹拌した。反応液に飽和食塩水、飽和塩化アンモニウム水を加え、ジエチルエーテルにて抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９２：８～８５：１５）にて精製し、表題化合物（８．９ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85 - 0.97 (m, 1 H) 1.13 - 1.21 (m, 1 H) 1.21 - 1.32 (m, 3 H) 1.34 - 1.75 (m, 5 H) 1.46 (s, 9 H) 3.20 - 3.57 (m, 4 H) 4.05 - 4.21 (m, 2 H).
MS ESI/APCI Dual posi: 306[M+Na]+.
参考例５－３
ｔｅｒｔ－ブチル １－（ヒドロキシメチル）－６－アザスピロ［２．５］オクタン－６－カルボキシラート
Figure JPOXMLDOC01-appb-C000055
 To a solution of trimethylsulfoxonium iodide (20 g) in dimethylsulfoxide (190 ml) was added potassium tert-butoxide (10 g), and the mixture was stirred at room temperature for 1 hour, and then the compound (13 g) obtained in Reference Example 5-1 Of dimethyl sulfoxide (60 ml) was added dropwise and stirred at room temperature for 3 days. To the reaction solution were added saturated brine and saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 92: 8 to 85:15) to obtain the title compound (8.9 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85-0.97 (m, 1 H) 1.13-1.21 (m, 1 H) 1.21-1.32 (m, 3 H) 1.34-1.75 (m, 5 H) 1.46 (s, 9 H) 3.20-3.57 (m, 4 H) 4.05-4.21 (m, 2 H).
MS ESI / APCI Dual posi: 306 [M + Na] + .
Reference Example 5-3
tert-Butyl 1- (hydroxymethyl) -6-azaspiro [2.5] octane-6-carboxylate
Figure JPOXMLDOC01-appb-C000056
 参考例５－２で得られた化合物（８．９ｇ）を用い、参考例４－３と同様にして反応及び精製を行い、表題化合物（７５０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.25 (t, J=4.7 Hz, 1 H) 0.58 (dd, J=8.6, 4.7 Hz, 1 H) 0.92 - 1.05 (m, 1 H) 1.12 - 1.73 (m, 13 H) 3.21 - 3.37 (m, 2 H) 3.49 - 3.80 (m, 4 H).
MS ESI/APCI Dual posi: 264[M+Na]+.
参考例５－４
ｔｅｒｔ－ブチル １－（ヨードメチル）－６－アザスピロ［２．５］オクタン－６－カルボキシラート
Figure JPOXMLDOC01-appb-C000056
 The compound (8.9 g) obtained in Reference Example 5-2 was used for reaction and purification in the same manner as in Reference Example 4-3 to obtain the title compound (750 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.25 (t, J = 4.7 Hz, 1 H) 0.58 (dd, J = 8.6, 4.7 Hz, 1 H) 0.92-1.05 (m, 1 H) 1.12- 1.73 (m, 13 H) 3.21-3.37 (m, 2 H) 3.49-3.80 (m, 4 H).
MS ESI / APCI Dual posi: 264 [M + Na] + .
Reference Example 5-4
tert-Butyl 1- (iodomethyl) -6-azaspiro [2.5] octane-6-carboxylate
Figure JPOXMLDOC01-appb-C000057
 アルゴン雰囲気下、トリフェニルホスフィン（９３６ｍｇ）のクロロホルム（２７ｍｌ）溶液に、イミダゾール（４２３ｍｇ）を加え、氷冷下、ヨウ素（８６７ｍｇ）を加えて２０分撹拌した。反応液に参考例５－３で得られた化合物（７４９ｍｇ）のクロロホルム（９ｍｌ）溶液を滴下し、反応液を室温まで昇温しながら３時間撹拌した。反応液をクロロホルムで希釈し、飽和チオ硫酸ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９５：５～９０：１０）にて精製し、表題化合物（９５０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.23 (t, J=4.8 Hz, 1 H), 0.74 (dd, J=8.4, 4.8 Hz, 1 H), 1.12 - 1.41 (m, 3 H), 1.43 - 1.59 (m, 10 H), 1.64 - 1.79 (m, 1 H), 3.07 - 3.43 (m, 4 H), 3.51 - 3.81 (m, 2 H).
MS ESI/APCI Dual posi: 374[M+Na]+.
参考例５－５
ｔｅｒｔ－ブチル １－（３－ｔｅｒｔ－ブトキシ－３－オキソプロピル）－６－アザスピロ［２．５］オクタン－６－カルボキシラート
Figure JPOXMLDOC01-appb-C000057
 Under an argon atmosphere, imidazole (423 mg) was added to a chloroform (27 ml) solution of triphenylphosphine (936 mg), and iodine (867 mg) was added under ice cooling, followed by stirring for 20 minutes. A chloroform (9 ml) solution of the compound (749 mg) obtained in Reference Example 5-3 was added dropwise to the reaction solution, and the reaction solution was stirred for 3 hours while warming to room temperature. The reaction solution was diluted with chloroform, washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 95: 5 to 90:10) to obtain the title compound (950 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.23 (t, J = 4.8 Hz, 1 H), 0.74 (dd, J = 8.4, 4.8 Hz, 1 H), 1.12-1.41 (m, 3 H) , 1.43-1.59 (m, 10 H), 1.64-1.79 (m, 1 H), 3.07-3.43 (m, 4 H), 3.51-3.81 (m, 2 H).
MS ESI / APCI Dual posi: 374 [M + Na] + .
Reference Example 5-5
tert-Butyl 1- (3-tert-Butoxy-3-oxopropyl) -6-azaspiro [2.5] octane-6-carboxylate
Figure JPOXMLDOC01-appb-C000058
 アルゴン雰囲気下、ジイソプロピルアミン（１．５ｍｌ）のテトラヒドロフラン（２７ｍｌ）溶液に、氷冷下、ｎ－ブチルリチウム（２．７６Ｍヘキサン溶液、３．９ｍＬ）を滴下して３０分撹拌した。反応液を－７８℃にて冷却し、酢酸　ｔｅｒｔ－ブチル（１．５ｍｌ）を加え、３０分撹拌した。ここへ、参考例５－４で得られた化合物（９５０ｍｇ）のテトラヒドロフラン（１４ｍｌ）溶液を滴下し、次いでＮ，Ｎ’－ジメチルプロピレン尿素（１．３ｍｌ）を加えて１時間撹拌した。飽和塩化アンモニウム水を加え、反応液を室温まで昇温させた後、酢酸エチルにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９６：４～９０：１０）にて精製し、表題化合物（７７０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.01 - 0.07 (m, 1 H) 0.44 - 0.51 (m, 1 H) 0.53 - 0.67 (m, 1 H) 1.05 - 1.85 (m, 24 H) 2.23 - 2.37 (m, 2 H) 3.18 - 3.30 (m, 2 H) 3.49 - 3.70 (m, 2 H).
MS ESI/APCI Dual posi: 340[M+H]+, 362[M+Na]+.
参考例５－６
ｔｅｒｔ－ブチル １－（３－ヒドロキシプロピル）－６－アザスピロ［２．５］オクタン－６－カルボキシラート
Figure JPOXMLDOC01-appb-C000058
 Under an argon atmosphere, n-butyllithium (2.76 M hexane solution, 3.9 mL) was added dropwise to a tetrahydrofuran (27 ml) solution of diisopropylamine (1.5 ml) under ice cooling, and the mixture was stirred for 30 minutes. The reaction mixture was cooled at −78 ° C., tert-butyl acetate (1.5 ml) was added, and the mixture was stirred for 30 min. To this was added dropwise a tetrahydrofuran (14 ml) solution of the compound (950 mg) obtained in Reference Example 5-4, then N, N′-dimethylpropyleneurea (1.3 ml) was added and stirred for 1 hour. Saturated aqueous ammonium chloride was added and the reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 96: 4 to 90:10) to obtain the title compound (770 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.01-0.07 (m, 1 H) 0.44-0.51 (m, 1 H) 0.53-0.67 (m, 1 H) 1.05-1.85 (m, 24 H) 2.23 -2.37 (m, 2 H) 3.18-3.30 (m, 2 H) 3.49-3.70 (m, 2 H).
MS ESI / APCI Dual posi: 340 [M + H] + , 362 [M + Na] + .
Reference Example 5-6
tert-Butyl 1- (3-hydroxypropyl) -6-azaspiro [2.5] octane-6-carboxylate
Figure JPOXMLDOC01-appb-C000059
 参考例５－５で得られた化合物（７７０ｍｇ）を用い、参考例４－３と同様にして反応及び精製を行い、表題化合物（２０３ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.02 - 0.04 (m, 1 H) 0.43 - 0.52 (m, 1 H) 0.53 - 0.64 (m, 1 H) 1.04 - 1.17 (m, 1 H) 1.18 - 1.36 (m, 3 H) 1.39 - 1.77 (m, 13 H) 3.14 - 3.31 (m, 2 H) 3.48 - 3.76 (m, 4 H).
MS ESI/APCI Dual posi: 292[M+Na]+.
参考例６－１
ｔｅｒｔ－ブチル １－（２－メトキシエテニル）－６－アザスピロ［２．５］オクタン－６－カルボキシラート
Figure JPOXMLDOC01-appb-C000059
 The compound (770 mg) obtained in Reference Example 5-5 was used for reaction and purification in the same manner as in Reference Example 4-3 to obtain the title compound (203 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.02-0.04 (m, 1 H) 0.43-0.52 (m, 1 H) 0.53-0.64 (m, 1 H) 1.04-1.17 (m, 1 H) 1.18-1.36 (m, 3 H) 1.39-1.77 (m, 13 H) 3.14-3.31 (m, 2 H) 3.48-3.76 (m, 4 H).
MS ESI / APCI Dual posi: 292 [M + Na] + .
Reference Example 6-1
tert-Butyl 1- (2-methoxyethenyl) -6-azaspiro [2.5] octane-6-carboxylate
Figure JPOXMLDOC01-appb-C000060
 参考例５－３で得られた化合物（６００ｍｇ）のクロロホルム溶液に、氷冷下、デス－マーチンペルヨージナン（１．３ｇ）を加え、室温まで昇温しながら２時間撹拌した。反応液をクロロホルムで希釈し、飽和亜硫酸ナトリウム水溶液及び飽和重曹水の混合溶液で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、ｔｅｒｔ－ブチル １－ホルミル－６－アザスピロ［２．５］オクタン－６－カルボキシラートを得た。得られたｔｅｒｔ－ブチル １－ホルミル－６－アザスピロ［２．５］オクタン－６－カルボキシラートを用い、参考例２－１と同様にして反応及び精製を行い、表題化合物（１５０ｍｇ、Ｅ／Ｚ体混合物）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28 - 0.36 (m, 1 H) 0.59 - 0.68 (m, 0.5 H) 0.71 - 0.78 (m, 0.5 H) 1.15 - 1.62 (m, 14 H) 3.31 - 3.48 (m, 4 H) 3.50 (s, 1.5 H) 3.62 (s, 1.5 H) 4.03 - 4.11 (m, 0.5 H) 4.58 - 4.68 (m, 0.5 H) 5.95 - 6.00 (m, 0.5 H) 6.31 - 6.39 (m, 0.5 H).
MS ESI/APCI Dual posi: 290[M+Na]+.
参考例６－２
ｔｅｒｔ－ブチル １－（２－ヒドロキシエチル）－６－アザスピロ［２．５］オクタン－６－カルボキシラート
Figure JPOXMLDOC01-appb-C000060
 Dess-Martin periodinane (1.3 g) was added to a chloroform solution of the compound (600 mg) obtained in Reference Example 5-3 under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature. The reaction mixture was diluted with chloroform, washed with a mixed solution of saturated aqueous sodium sulfite and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 1-formyl-6-azaspiro [2.5] octane-6-carboxylate. The obtained tert-butyl 1-formyl-6-azaspiro [2.5] octane-6-carboxylate was subjected to reaction and purification in the same manner as in Reference Example 2-1, and the title compound (150 mg, E / Z Body mixture).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28-0.36 (m, 1 H) 0.59-0.68 (m, 0.5 H) 0.71-0.78 (m, 0.5 H) 1.15-1.62 (m, 14 H) 3.31 -3.48 (m, 4 H) 3.50 (s, 1.5 H) 3.62 (s, 1.5 H) 4.03-4.11 (m, 0.5 H) 4.58-4.68 (m, 0.5 H) 5.95-6.00 (m, 0.5 H) 6.31 -6.39 (m, 0.5 H).
MS ESI / APCI Dual posi: 290 [M + Na] + .
Reference Example 6-2
tert-Butyl 1- (2-hydroxyethyl) -6-azaspiro [2.5] octane-6-carboxylate
Figure JPOXMLDOC01-appb-C000061
 参考例６－１で得られた化合物（１５０ｍｇ）をアセトニトリル（５．６ｍｌ）に溶解し、水（１．３ｍｌ）、次いでトリフルオロ酢酸（５０μｌ）を加え、室温で２時間撹拌した。トリフルオロ酢酸（５０μｌ）を加え、さらに２時間撹拌した。さらにトリフルオロ酢酸（５０μｌ）を加え、室温で一晩撹拌した。反応液を氷冷し、飽和重曹水を加えた後、減圧下濃縮した。得られた水層を酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、ｔｅｒｔ－ブチル １－（２－オキソエチル）－６－アザスピロ［２．５］オクタン－６－カルボキシラートを得た。得られたｔｅｒｔ－ブチル １－（２－オキソエチル）－６－アザスピロ［２．５］オクタン－６－カルボキシラートをメタノール（５ｍｌ）に溶解した。反応液を氷冷し、水素化ホウ素ナトリウム（３８ｍｇ）を加え、室温まで昇温しながら２時間撹拌した。反応液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝６０：４０～４０：６０）にて精製し、表題化合物（８０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.04 - 0.12 (m, 1 H) 0.47 - 0.56 (m, 1 H) 0.57 - 0.71 (m, 1 H) 1.06 - 1.18 (m, 1 H) 1.20 - 1.66 (m, 13 H) 1.70 - 1.87 (m, 1 H) 3.16 - 3.30 (m, 2 H) 3.51 - 3.79 (m, 4 H).
MS ESI/APCI Dual posi: 278[M+Na]+.
参考例７－１
ｔｅｒｔ－ブチル ９－オキソ－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000061
 The compound (150 mg) obtained in Reference Example 6-1 was dissolved in acetonitrile (5.6 ml), water (1.3 ml) and then trifluoroacetic acid (50 μl) were added, and the mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (50 μl) was added and stirred for another 2 hours. Further, trifluoroacetic acid (50 μl) was added and stirred overnight at room temperature. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate was added, and the mixture was concentrated under reduced pressure. The obtained aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain tert-butyl 1- (2-oxoethyl) -6-azaspiro [2.5] octane-6-carboxylate. The obtained tert-butyl 1- (2-oxoethyl) -6-azaspiro [2.5] octane-6-carboxylate was dissolved in methanol (5 ml). The reaction mixture was ice-cooled, sodium borohydride (38 mg) was added, and the mixture was stirred for 2 hr while warming to room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (normal hexane: ethyl acetate = 60: 40 to 40:60) to obtain the title compound (80 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.04-0.12 (m, 1 H) 0.47-0.56 (m, 1 H) 0.57-0.71 (m, 1 H) 1.06-1.18 (m, 1 H) 1.20 -1.66 (m, 13 H) 1.70-1.87 (m, 1 H) 3.16-3.30 (m, 2 H) 3.51-3.79 (m, 4 H).
MS ESI / APCI Dual posi: 278 [M + Na] + .
Reference Example 7-1
tert-Butyl 9-oxo-3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000062
 ｔｅｒｔ－ブチル ４－ホルミルピペリジン－１－カルボキシラート（１．８ｇ）を用い、ＷＯ２０１０／０４９１４６に従って実験を行い、表題化合物（８８ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H) 1.52 - 1.61 (m, 4 H) 1.71 - 1.82 (m, 4 H) 2.30 - 2.39 (m, 4 H) 3.40 - 3.47 (m, 4 H).
参考例８－１
ｔｅｒｔ－ブチル　９－（メトキシメチリデン）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000062
 Experiments were performed according to WO2010 / 049146 using tert-butyl 4-formylpiperidine-1-carboxylate (1.8 g) to obtain the title compound (88 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H) 1.52-1.61 (m, 4 H) 1.71-1.82 (m, 4 H) 2.30-2.39 (m, 4 H) 3.40-3.47 (m, 4 H).
Reference Example 8-1
tert-Butyl 9- (methoxymethylidene) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000063
 参考例７－１で得られた化合物（１．１ｇ）を用いて参考例２－１と同様にして反応及び精製を行い、表題化合物（５３６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 - 1.44 (m, 8 H) 1.45 (s, 9 H) 1.90 - 1.99 (m, 2 H) 2.12 - 2.23 (m, 2 H) 3.34 - 3.42 (m, 4 H) 3.53 (s, 3 H) 5.77 (t, J=1.2 Hz, 1 H).
MS ESI/APCI Dual posi: 318[M+Na]+.
参考例８－２
ｔｅｒｔ－ブチル　９－ホルミル－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000063
 The compound (1.1 g) obtained in Reference Example 7-1 was used for reaction and purification in the same manner as in Reference Example 2-1, to give the title compound (536 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.44 (m, 8 H) 1.45 (s, 9 H) 1.90-1.99 (m, 2 H) 2.12-2.23 (m, 2 H) 3.34-3.42 (m, 4 H) 3.53 (s, 3 H) 5.77 (t, J = 1.2 Hz, 1 H).
MS ESI / APCI Dual posi: 318 [M + Na] + .
Reference Example 8-2
tert-Butyl 9-formyl-3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000064
 参考例８－１で得られた化合物（５３０ｍｇ）をアセトニトリル（１８ｍｌ）に溶解し、水（１４ｍｌ）、次いでトリフルオロ酢酸（４５２μｌ）を加え、室温で９時間撹拌した。反応溶液に飽和重曹水を加えた後、水層をクロロホルムにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、表題化合物（４６３ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 - 1.85 (m, 21 H) 2.18 - 2.31 (m, 1 H) 3.31 - 3.43 (m, 4 H) 9.65 (ｓ, 1 H).
MS ESI/APCI Dual posi: 304[M+Na]+.
参考例８－３
ｔｅｒｔ－ブチル　９－（３－エトキシ－３－オキソプロパ－１－エン－１－イル）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000064
 The compound (530 mg) obtained in Reference Example 8-1 was dissolved in acetonitrile (18 ml), water (14 ml) and then trifluoroacetic acid (452 μl) were added, and the mixture was stirred at room temperature for 9 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (463 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16-1.85 (m, 21 H) 2.18-2.31 (m, 1 H) 3.31-3.43 (m, 4 H) 9.65 (s, 1 H).
MS ESI / APCI Dual posi: 304 [M + Na] + .
Reference Example 8-3
tert-Butyl 9- (3-Ethoxy-3-oxoprop-1-en-1-yl) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000065
 水素化ナトリウム（６０％オイル懸濁、９８ｍｇ）のテトラヒドロフラン／Ｎ，Ｎ－ジメチルホルムアミド（１：１，６ｍｌ）懸濁液にホスホノ酢酸トリエチル（５５０ｍｇ）、次いで参考例８－２で得られた化合物（４６０ｍｇ）を加え、室温で２時間攪拌した。反応溶液に水を加えた後、水層を酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（５２１ｍｇ、Ｅ／Ｚ体混合物）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 - 1.80 (m, 24 H) 2.06 - 2.23 (m, 1 H) 3.28 - 3.44 (m, 4 H) 4.19 (q, J=7.2 Hz, 2 H) 5.74 - 5.82 (m, 1 H) 6.86 - 6.98 (m, 1 H).
MS ESI/APCI Dual posi: 374[M+Na]+.
参考例８－４
ｔｅｒｔ－ブチル　９－（３－エトキシ－３－オキソプロピル）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000065
 Sodium hydride (60% oil suspension, 98 mg) in tetrahydrofuran / N, N-dimethylformamide (1: 1, 6 ml) suspension in triethyl phosphonoacetate (550 mg), then compound obtained in Reference Example 8-2 (460 mg) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50) to obtain the title compound (521 mg, E / Z mixture). .
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.80 (m, 24 H) 2.06-2.23 (m, 1 H) 3.28-3.44 (m, 4 H) 4.19 (q, J = 7.2 Hz, 2 H) 5.74-5.82 (m, 1 H) 6.86-6.98 (m, 1 H).
MS ESI / APCI Dual posi: 374 [M + Na] + .
Reference Example 8-4
tert-Butyl 9- (3-Ethoxy-3-oxopropyl) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000066
 参考例８－３で得られた化合物（５１５ｍｇ）を用いて参考例２－３と同様にして反応及び精製を行い、表題化合物（４７１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99 - 1.82 (m, 27 H) 2.23 - 2.38 (m, 2 H) 3.27 - 3.42 (m, 4 H) 4.12 (q, J=7.2 Hz, 2 H).
MS ESI/APCI Dual posi: 376[M+Na]+.
参考例８－５
ｔｅｒｔ－ブチル　９－（３－ヒドロキシプロピル）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000066
 Using the compound (515 mg) obtained in Reference Example 8-3, the reaction and purification were carried out in the same manner as in Reference Example 2-3 to obtain the title compound (471 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-1.82 (m, 27 H) 2.23-2.38 (m, 2 H) 3.27-3.42 (m, 4 H) 4.12 (q, J = 7.2 Hz, 2 H).
MS ESI / APCI Dual posi: 376 [M + Na] + .
Reference Example 8-5
tert-Butyl 9- (3-hydroxypropyl) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000067
 参考例８－４で得られた化合物（４７０ｍｇ）のトルエン－テトラヒドロフラン（１：１，１４ｍｌ）溶液に水素化ホウ素リチウム（８７ｍｇ）を加え、６０℃で１６時間攪拌した。反応溶液を室温に戻した後、飽和塩化アンモニウム水溶液を加え、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～８０：２０）にて精製し、表題化合物（３７０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.98 - 1.73 (m, 26 H) 3.28 - 3.40 (m, 4 H) 3.57 - 3.67 (m, 2 H).
MS ESI/APCI Dual posi: 334[M+Na]+.
参考例９－１
ｔｅｒｔ－ブチル ９－（２－エトキシ－２－オキソエチリデン）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000067
 Lithium borohydride (87 mg) was added to a toluene-tetrahydrofuran (1: 1, 14 ml) solution of the compound (470 mg) obtained in Reference Example 8-4, and the mixture was stirred at 60 ° C. for 16 hours. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 80:20) to obtain the title compound (370 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.98-1.73 (m, 26 H) 3.28-3.40 (m, 4 H) 3.57-3.67 (m, 2 H).
MS ESI / APCI Dual posi: 334 [M + Na] + .
Reference Example 9-1
tert-Butyl 9- (2-ethoxy-2-oxoethylidene) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000068
 参考例７－１で得られた化合物（８５ｍｇ）を用い、参考例３－１と同様にして反応及び精製を行い、表題化合物（８０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.1 Hz, 3 H) 1.41 - 1.59 (m, 17 H) 2.17 - 2.27 (m, 2 H) 2.79 - 2.90 (m, 2 H) 3.34 - 3.45 (m, 4 H) 4.14 (q, J=7.1 Hz, 2 H) 5.63 (s, 1 H).
MS ESI/APCI Dual posi: 360[M+Na]+.
参考例９－２
ｔｅｒｔ－ブチル ９－（２－エトキシ－２－オキソエチル）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000068
 The compound (85 mg) obtained in Reference Example 7-1 was used for reaction and purification in the same manner as in Reference Example 3-1, to give the title compound (80 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 1.41-1.59 (m, 17 H) 2.17-2.27 (m, 2 H) 2.79-2.90 (m, 2 H) 3.34-3.45 (m, 4 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.63 (s, 1 H).
MS ESI / APCI Dual posi: 360 [M + Na] + .
Reference Example 9-2
tert-Butyl 9- (2-Ethoxy-2-oxoethyl) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000069
 参考例９－１で得られた化合物（７６ｍｇ）をエタノール（２．２ｍｌ）に溶解し、２０％水酸化パラジウム ／ 炭素（１５ｍｇ）を加え、水素雰囲気下、室温で一晩撹拌した。反応液をセライト（登録商標）濾過し、濾液を減圧下濃縮し、表題化合物（７０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 - 1.74 (m, 25 H), 2.20 (d, J=7.0 Hz, 2 H), 3.30 - 3.41 (m, 4 H), 4.12 (q, J=7.0 Hz, 2 H).
MS ESI/APCI Dual posi: 362[M+Na]+.
参考例９－３
ｔｅｒｔ－ブチル ９－（２－ヒドロキシエチル）－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート
Figure JPOXMLDOC01-appb-C000069
 The compound (76 mg) obtained in Reference Example 9-1 was dissolved in ethanol (2.2 ml), 20% palladium hydroxide / carbon (15 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give the title compound (70 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.74 (m, 25 H), 2.20 (d, J = 7.0 Hz, 2 H), 3.30-3.41 (m, 4 H), 4.12 (q, J = 7.0 Hz, 2 H).
MS ESI / APCI Dual posi: 362 [M + Na] + .
Reference Example 9-3
tert-Butyl 9- (2-hydroxyethyl) -3-azaspiro [5.5] undecane-3-carboxylate
Figure JPOXMLDOC01-appb-C000070
 参考例９－２で得られた化合物（７０ｍｇ）を用い、参考例３－３と同様にして反応及び精製を行い、表題化合物（６０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.77 - 1.72 (m, 24 H) 3.29 - 3.39 (m, 4 H) 3.69 (t, J=6.7 Hz, 2 H).
MS ESI/APCI Dual posi: 320[M+Na]+.
参考例１０－１
ｔｅｒｔ－ブチル　２－［３－（４－シアノ－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000070
 The compound (70 mg) obtained in Reference Example 9-2 was used for reaction and purification in the same manner as in Reference Example 3-3 to obtain the title compound (60 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.77-1.72 (m, 24 H) 3.29-3.39 (m, 4 H) 3.69 (t, J = 6.7 Hz, 2 H).
MS ESI / APCI Dual posi: 320 [M + Na] + .
Reference Example 10-1
tert-Butyl 2- [3- (4-Cyano-3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000071
 参考例２で得られた化合物（２１０ｍｇ）のテトラヒドロフラン（３．０ｍl）溶液に４－シアノ－３－フルオロフェノール（１５４ｍｇ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルバミド（１９４ｍｇ）、トリブチルホスフィン（２２８ｍｇ）を加え、６０℃で１．５時間攪拌した。反応溶液を室温まで冷却し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（２９０ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.31 - 1.49 (m, 13 H) 1.51 - 1.62 (m, 4 H) 1.63 - 1.79 (m, 2 H) 1.90 - 2.04 (m, 2 H) 2.16 - 2.37 (m, 1 H) 3.18 - 3.42 (m, 4 H) 3.96 (t, J=6.4 Hz, 2 H) 6.61 - 6.79 (m, 2 H) 7.39 - 7.57 (m, 1 H).
MS ESI/APCI Dual posi: 425[M+Na]+.
参考例１０－２
４－｛３－［７－（ｔｅｒｔ－ブトキシカルボニル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000071
 To a solution of the compound (210 mg) obtained in Reference Example 2 in tetrahydrofuran (3.0 ml) was added 4-cyano-3-fluorophenol (154 mg), N, N, N ′, N′-tetramethylazodicarbamide (194 mg). , Tributylphosphine (228 mg) was added, and the mixture was stirred at 60 ° C. for 1.5 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50) to obtain the title compound (290 mg).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.31-1.49 (m, 13 H) 1.51-1.62 (m, 4 H) 1.63-1.79 (m, 2 H) 1.90-2.04 (m, 2 H) 2.16 -2.37 (m, 1 H) 3.18-3.42 (m, 4 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.61-6.79 (m, 2 H) 7.39-7.57 (m, 1 H).
MS ESI / APCI Dual posi: 425 [M + Na] + .
Reference Example 10-2
4- {3- [7- (tert-Butoxycarbonyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000072
 参考例１０－１で得られた化合物（２７０ｍｇ）の２Ｍ水酸化ナトリウム水溶液（１．０ｍｌ）／エタノール（２．０ｍｌ）溶液を、加熱還流下にて５日間攪拌した。反応溶液を室温へ冷却後、１Ｍ塩酸を加え、水層をクロロホルムにて抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０～９０：１０）にて精製し、表題化合物（１３８ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 - 1.50 (m, 13 H) 1.52 - 1.63 (m, 4 H) 1.66 - 1.79 (m, 2 H) 1.92 - 2.03 (m, 2 H) 2.15 - 2.35 (m, 1 H) 3.20 - 3.40 (m, 4 H) 3.98 (t, J=6.5 Hz, 2 H) 6.58 - 6.78 (m, 2 H) 7.90 - 8.01 (m, 1 H).
MS ESI/APCI Dual posi: 444[M+Na]+.
参考例１１－１
プロパン－２－イル ２－（３－エトキシ－３－オキソプロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000072
 A 2M sodium hydroxide aqueous solution (1.0 ml) / ethanol (2.0 ml) solution of the compound (270 mg) obtained in Reference Example 10-1 was stirred for 5 days under heating to reflux. The reaction solution was cooled to room temperature, 1M hydrochloric acid was added, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 90:10) to obtain the title compound (138 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.50 (m, 13 H) 1.52-1.63 (m, 4 H) 1.66-1.79 (m, 2 H) 1.92-2.03 (m, 2 H) 2.15 -2.35 (m, 1 H) 3.20-3.40 (m, 4 H) 3.98 (t, J = 6.5 Hz, 2 H) 6.58-6.78 (m, 2 H) 7.90-8.01 (m, 1 H).
MS ESI / APCI Dual posi: 444 [M + Na] + .
Reference Example 11-1
Propan-2-yl 2- (3-ethoxy-3-oxopropyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000073
 参考例２－３で得られた化合物（５．７ｇ）の酢酸エチル（８８ｍｌ）溶液に、４Ｍ塩化水素・酢酸エチル溶液（８８ｍｌ）を加え、室温で１．５時間撹拌した。反応液を減圧下濃縮し、得られた残渣に飽和重曹水を加え、酢酸エチル、クロロホルムにて順次抽出し、有機層を無水硫酸ナトリウムで乾燥して濾過した。濾液を減圧下濃縮して、エチル３－（７－アザスピロ［３．５］ノナ－２－イル）プロパノアートを得た。得られたエチル３－（７－アザスピロ［３．５］ノナ－２－イル）プロパノアートのクロロホルム（９０ｍｌ）溶液に、トリエチルアミン（４．９ｍｌ）を加え、氷冷下、クロロぎ酸イソプロピル（２．４ｍｌ）のクロロホルム（２４ｍｌ）溶液を滴下した。反応液を室温まで昇温しながら４時間撹拌した。反応液に水を加えてクロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝８５：１５～７５：２５）にて精製し、表題化合物（５．５ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 - 1.30 (m, 9 H) 1.31 - 1.61 (m, 8 H) 1.66 - 1.78 (m, 2 H) 1.89 - 2.01 (m, 2 H) 2.16 - 2.28 (m, 3 H) 3.23 - 3.41 (m, 4 H) 4.12 (q, J=7.1 Hz, 2 H) 4.82 - 4.96 (m, 1 H).
MS ESI/APCI Dual posi: 312[M+H]+, 334[M+Na]+.
参考例１１－２
プロパン－２－イル ２－（３－ヒドロキシプロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000073
 To a solution of the compound (5.7 g) obtained in Reference Example 2-3 in ethyl acetate (88 ml) was added 4M hydrogen chloride / ethyl acetate solution (88 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting residue, and the mixture was extracted successively with ethyl acetate and chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl 3- (7-azaspiro [3.5] non-2-yl) propanoate. Triethylamine (4.9 ml) was added to a chloroform (90 ml) solution of ethyl 3- (7-azaspiro [3.5] non-2-yl) propanoate obtained, and isopropyl chloroformate (2. 4 ml) in chloroform (24 ml) was added dropwise. The reaction was stirred for 4 hours while warming to room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 85: 15 to 75:25) to obtain the title compound (5.5 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.30 (m, 9 H) 1.31-1.61 (m, 8 H) 1.66-1.78 (m, 2 H) 1.89-2.01 (m, 2 H) 2.16 -2.28 (m, 3 H) 3.23-3.41 (m, 4 H) 4.12 (q, J = 7.1 Hz, 2 H) 4.82-4.96 (m, 1 H).
MS ESI / APCI Dual posi: 312 [M + H] + , 334 [M + Na] + .
Reference Example 11-2
Propan-2-yl 2- (3-hydroxypropyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000074
 参考例１１－１で得られた化合物（５．４６ｇ）を用い、参考例２－４と同様にして反応及び精製を行い、表題化合物（４．２６ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ　ppm 1.23 (d, J=6.4 Hz, 6 H) 1.31 - 1.62 (m, 10 H) 1.88 - 2.02 (m, 2 H) 2.12 - 2.31 (m, 1 H) 3.15 - 3.43 (m, 4 H) 3.55 - 3.68 (m, 2 H) 4.80 - 4.97 (m, 1 H).
MS ESI/APCI Dual posi: 270[M+H]+, 292[M+Na]+.
参考例１１－３
プロパン－２－イル　２－｛３－［３－フルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000074
 The compound (5.46 g) obtained in Reference Example 11-1 was used for reaction and purification in the same manner as in Reference Example 2-4 to obtain the title compound (4.26 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.4 Hz, 6 H) 1.31-1.62 (m, 10 H) 1.88-2.02 (m, 2 H) 2.12-2.31 (m, 1 H) 3.15-3.43 (m, 4 H) 3.55-3.68 (m, 2 H) 4.80-4.97 (m, 1 H).
MS ESI / APCI Dual posi: 270 [M + H] + , 292 [M + Na] + .
Reference Example 11-3
Propan-2-yl 2- {3- [3-fluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000075
 参考例１１－２で得られた化合物（２．００ｇ）のテトラヒドロフラン（３７．１ｍｌ）溶液にメチル　２－フルオロ－４－ヒドロキシベンゾエート（１．８９ｇ）、Ｎ，Ｎ，Ｎ，Ｎ－テトラメチルアゾジカルバミド（１．９１ｇ）、トリブチルホスフィン（２．２５ｇ）を加え、６０℃で２時間攪拌した。反応溶液を減圧下濃縮し、得られた残渣に飽和食塩水を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）、続いてＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）にて精製し、表題化合物（３．１０ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.31 - 1.51 (m, 4 H) 1.51 - 1.63 (m, 4 H) 1.63 - 1.81 (m, 2 H) 1.90 - 2.04 (m, 2 H) 2.12 - 2.36 (m, 1 H) 3.23 - 3.44 (m, 4 H) 3.89 (s, 3 H) 3.96 (t, J=6.2 Hz, 2 H) 4.79 - 5.00 (m, 1 H) 6.55 - 6.75 (m, 2 H) 7.88 (t, J=8.6 Hz, 1 H).
MS ESI/APCI Dual posi: 422[M+H]+, 444[M+Na]+.
参考例１１－４
2－フルオロ－４－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000075
 To a solution of the compound obtained in Reference Example 11-2 (2.00 g) in tetrahydrofuran (37.1 ml) was added methyl 2-fluoro-4-hydroxybenzoate (1.89 g), N, N, N, N-tetramethylazo. Dicarbamide (1.91 g) and tributylphosphine (2.25 g) were added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, saturated brine was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), followed by NH silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (3.10 g). Obtained.
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.31-1.51 (m, 4 H) 1.51-1.63 (m, 4 H) 1.63-1.81 (m, 2 H) 1.90-2.04 (m, 2 H) 2.12-2.36 (m, 1 H) 3.23-3.44 (m, 4 H) 3.89 (s, 3 H) 3.96 (t, J = 6.2 Hz, 2 H) 4.79- 5.00 (m, 1 H) 6.55-6.75 (m, 2 H) 7.88 (t, J = 8.6 Hz, 1 H).
MS ESI / APCI Dual posi: 422 [M + H] + , 444 [M + Na] + .
Reference Example 11-4
2-Fluoro-4- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000076
 参考例１１－３で得られた化合物（３．１０ｇ）のメタノール（３６．８ｍｌ）溶液に２Ｍ水酸化ナトリウム水溶液（３６．８ｍｌ）を加え、６０℃で３時間攪拌した。反応溶液のメタノールを減圧留去し、残渣の水層をジエチルエーテルで洗浄した。水層に１Ｍ塩酸を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、溶媒を減圧留去し、表題化合物（２．９６ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.31 - 1.51 (m, 4 H) 1.52 - 1.64 (m, 4 H) 1.64 - 1.84 (m, 2 H) 1.90 - 2.07 (m, 2 H) 2.11 - 2.42 (m, 1 H) 3.24 - 3.44 (m, 4 H) 3.92 - 4.05 (m, 2 H) 4.82 - 4.99 (m, 1 H) 6.58 - 6.78 (m, 2 H) 7.96 (t, J=8.8 Hz, 1 H).
MS ESI/APCI Dual posi: 408[M+H]+.
MS ESI/APCI Dual nega: 406[M-H]-.
参考例１２－１
ｔｅｒｔ－ブチル　２－｛３－［（６－シアノピリジン－３－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000076
 To a solution of the compound (3.10 g) obtained in Reference Example 11-3 in methanol (36.8 ml) was added 2M aqueous sodium hydroxide solution (36.8 ml), and the mixture was stirred at 60 ° C. for 3 hours. The methanol in the reaction solution was distilled off under reduced pressure, and the aqueous layer of the residue was washed with diethyl ether. 1M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (2.96 g).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.31-1.51 (m, 4 H) 1.52-1.64 (m, 4 H) 1.64-1.84 (m, 2 H) 1.90-2.07 (m, 2 H) 2.11-2.42 (m, 1 H) 3.24-3.44 (m, 4 H) 3.92-4.05 (m, 2 H) 4.82-4.99 (m, 1 H) 6.58-6.78 (m, 2 H) 7.96 (t, J = 8.8 Hz, 1 H).
MS ESI / APCI Dual posi: 408 [M + H] + .
MS ESI / APCI Dual nega: 406 [MH] - .
Reference Example 12-1
tert-Butyl 2- {3-[(6-Cyanopyridin-3-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000077
 参考例２－４で得られた化合物（７０ｍｇ）と５－ヒドロキシピコリンニトリル（４５ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（７０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30 - 1.82 (m, 19 H) 1.90 - 2.04 (m, 2 H) 2.18 - 2.34 (m, 1 H) 3.22 - 3.39 (m, 4 H) 4.04 (t, J=6.4 Hz, 2 H) 7.17 - 7.24 (m, 1 H) 7.59 - 7.66 (m, 1 H) 8.32 - 8.38 (m, 1 H).
MS ESI/APCI Dual posi: 408[M+Na]+.
参考例１２－２
５－［３－（７－アザスピロ［３．５］ノナ－2－イル］プロポキシ］ピリジン－２－カルボニトリル
Figure JPOXMLDOC01-appb-C000077
 Reaction and purification were conducted in the same manner as in Reference Example 10-1 using the compound (70 mg) obtained in Reference Example 2-4 and 5-hydroxypicolinonitrile (45 mg) to obtain the title compound (70 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30-1.82 (m, 19 H) 1.90-2.04 (m, 2 H) 2.18-2.34 (m, 1 H) 3.22-3.39 (m, 4 H) 4.04 (t, J = 6.4 Hz, 2 H) 7.17-7.24 (m, 1 H) 7.59-7.66 (m, 1 H) 8.32-8.38 (m, 1 H).
MS ESI / APCI Dual posi: 408 [M + Na] + .
Reference Example 12-2
5- [3- (7-Azaspiro [3.5] non-2-yl] propoxy] pyridine-2-carbonitrile
Figure JPOXMLDOC01-appb-C000078
 参考例１２－１で得られた化合物（７０ｍｇ）の酢酸エチル（１．０ｍl）に４Ｍ塩化水素・酢酸エチル溶液（１．０ｍｌ）を加え、室温で一晩攪拌した。反応溶液に２Ｍ水酸化ナトリウム水溶液を加えた後、水層をクロロホルムにて抽出した。有機層を減圧下濃縮し、表題化合物（５０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 - 1.64 (m, 6 H) 1.67 - 1.82 (m, 2 H) 1.89 - 2.03 (m, 2 H) 2.09 - 2.32 (m, 3 H) 2.58 - 2.85 (m, 4 H) 3.93 - 4.10 (m, 2 H) 5.70 (br. s, 1 H) 7.16 - 7.25 (m, 1 H) 7.55 - 7.68 (m, 1 H) 8.30 - 8.40 (m, 1 H).
MS ESI/APCI Dual posi: 286[M+H]+.
参考例１２－３
1－メチルシクロプロピル　２－｛３－［（６－シアノピジジン－３－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000078
 A 4M hydrogen chloride / ethyl acetate solution (1.0 ml) was added to ethyl acetate (1.0 ml) of the compound (70 mg) obtained in Reference Example 12-1, and the mixture was stirred overnight at room temperature. A 2M aqueous sodium hydroxide solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure to obtain the title compound (50 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.64 (m, 6 H) 1.67-1.82 (m, 2 H) 1.89-2.03 (m, 2 H) 2.09-2.32 (m, 3 H) 2.58 -2.85 (m, 4 H) 3.93-4.10 (m, 2 H) 5.70 (br. S, 1 H) 7.16-7.25 (m, 1 H) 7.55-7.68 (m, 1 H) 8.30-8.40 (m, 1 H).
MS ESI / APCI Dual posi: 286 [M + H] + .
Reference Example 12-3
1-methylcyclopropyl 2- {3-[(6-cyanopyridin-3-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000079
 参考例１２－２で得られた化合物（５０ｍｇ）のクロロホルム（１．０ｍｌ）溶液に１－メチルシクロプロピル（４－ニトロフェニル）カルボナート（５０ｍｇ）、トリエチルアミン（４９μｌ）を加え、室温で５時間攪拌した。反応溶液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（５４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.55 - 0.66 (m, 2 H) 0.82 - 0.89 (m, 2 H) 1.31 - 1.49 (m, 4 H) 1.51 - 1.67 (m, 7 H) 1.69 - 1.80 (m, 2 H) 1.92 - 2.03 (m, 2 H) 2.15 - 2.36 (m, 1 H) 3.12 - 3.43 (m, 4 H) 4.03 (t, J=6.5 Hz, 2 H) 7.16 - 7.24 (m, 1 H) 7.60 - 7.68 (m, 1 H) 8.28 - 8.40 (m, 1 H).
MS ESI/APCI Dual posi: 384[M+H]+, 406[M+Na]+.
参考例１２－４
５－［３－（７｛［（１－メチルシクロプロピル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］ピリジン－２－カルボン酸
Figure JPOXMLDOC01-appb-C000079
 To a solution of the compound obtained in Reference Example 12-2 (50 mg) in chloroform (1.0 ml), 1-methylcyclopropyl (4-nitrophenyl) carbonate (50 mg) and triethylamine (49 μl) were added and stirred at room temperature for 5 hours. did. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (54 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.55-0.66 (m, 2 H) 0.82-0.89 (m, 2 H) 1.31-1.49 (m, 4 H) 1.51-1.67 (m, 7 H) 1.69 -1.80 (m, 2 H) 1.92-2.03 (m, 2 H) 2.15-2.36 (m, 1 H) 3.12-3.43 (m, 4 H) 4.03 (t, J = 6.5 Hz, 2 H) 7.16-7.24 (m, 1 H) 7.60-7.68 (m, 1 H) 8.28-8.40 (m, 1 H).
MS ESI / APCI Dual posi: 384 [M + H] + , 406 [M + Na] + .
Reference Example 12-4
5- [3- (7 {[(1-Methylcyclopropyl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] pyridine-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000080
 参考例１２－３で得られた化合物（５０ｍｇ）を用いて参考例１０－２と同様にして反応及び精製を行い、表題化合物（３６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57 - 0.66 (m, 2 H) 0.82 - 0.89 (m, 2 H) 1.34 - 1.65 (m, 11 H) 1.70 - 1.84 (m, 2 H) 1.93 - 2.05 (m, 2 H) 2.15 - 2.35 (m, 1 H) 3.18 - 3.47 (m, 4 H) 4.07 (t, J=6.3 Hz, 2 H) 6.95 - 7.03 (m, 1 H) 7.34 - 7.40 (m, 1 H) 8.16 - 8.22 (m, 1 H).
MS ESI/APCI Dual posi: 403[M+H]+, 425[M+Na]+.
MS ESI/APCI Dual nega: 401[M-H]-.
参考例１３－１
プロパン－２－イル　２－｛３－［（５－シアノピリジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000080
 The compound (50 mg) obtained in Reference Example 12-3 was used for reaction and purification in the same manner as in Reference Example 10-2 to obtain the title compound (36 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57-0.66 (m, 2 H) 0.82-0.89 (m, 2 H) 1.34-1.65 (m, 11 H) 1.70-1.84 (m, 2 H) 1.93 -2.05 (m, 2 H) 2.15-2.35 (m, 1 H) 3.18-3.47 (m, 4 H) 4.07 (t, J = 6.3 Hz, 2 H) 6.95-7.03 (m, 1 H) 7.34-7.40 (m, 1 H) 8.16-8.22 (m, 1 H).
MS ESI / APCI Dual posi: 403 [M + H] + , 425 [M + Na] + .
MS ESI / APCI Dual nega: 401 [MH] - .
Reference Example 13-1
Propan-2-yl 2- {3-[(5-cyanopyridin-2-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000081
 参考例１１－２で得られた化合物（２００ｍｇ）と６－ヒドロキシニコチンニトリル（１０７ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（１５０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.4 Hz, 6 H) 1.33 - 1.61 (m, 8 H) 1.63 - 1.76 (m, 2 H) 1.91 - 2.02 (m, 2 H) 2.18 - 2.33 (m, 1 H) 3.25 - 3.43 (m, 4 H) 4.32 (t, J=6.7 Hz, 2 H) 4.84 - 4.95 (m, 1 H) 6.76 - 6.82 (m, 1 H) 7.73 - 7.79 (m, 1 H) 8.45 - 8.48 (m, 1 H).
MS ESI/APCI Dual posi: 372[M+H]+, 394[M+Na]+.
参考例１３－２ 
６－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３.５］ノナ－２－イル｝プロポキシ）ピリジン－３－カルボン酸
Figure JPOXMLDOC01-appb-C000081
 Reaction and purification were conducted in the same manner as in Reference Example 10-1 using the compound (200 mg) obtained in Reference Example 11-2 and 6-hydroxynicotine nitrile (107 mg) to obtain the title compound (150 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.4 Hz, 6 H) 1.33-1.61 (m, 8 H) 1.63-1.76 (m, 2 H) 1.91-2.02 (m, 2 H) 2.18-2.33 (m, 1 H) 3.25-3.43 (m, 4 H) 4.32 (t, J = 6.7 Hz, 2 H) 4.84-4.95 (m, 1 H) 6.76-6.82 (m, 1 H) 7.73-7.79 (m, 1 H) 8.45-8.48 (m, 1 H).
MS ESI / APCI Dual posi: 372 [M + H] + , 394 [M + Na] + .
Reference Example 13-2
6- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) pyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000082
 参考例１３－１で得られた化合物（１５０ｍｇ）を用いて参考例１０－２と同様にして反応及び精製を行い、表題化合物（１４９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 - 1.27 (m, 6 H) 1.32 - 1.61 (m, 8 H) 1.64 - 1.79 (m, 2 H) 1.88 - 2.05 (m, 2 H) 2.16 - 2.37 (m, 1 H) 3.24 - 3.45 (m, 4 H) 4.35 (t, J=6.6 Hz, 2 H) 4.85 - 4.96 (m, 1 H) 6.71 - 6.80 (m, 1 H) 8.13 - 8.24 (m, 1 H) 8.86 - 8.92 (m, 1 H).
参考例１４－１
プロパン－２－イル　２－｛３－［（６－シアノピリジン－３－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000082
 Using the compound (150 mg) obtained in Reference Example 13-1, the reaction and purification were carried out in the same manner as in Reference Example 10-2 to obtain the title compound (149 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.27 (m, 6 H) 1.32-1.61 (m, 8 H) 1.64-1.79 (m, 2 H) 1.88-2.05 (m, 2 H) 2.16 -2.37 (m, 1 H) 3.24-3.45 (m, 4 H) 4.35 (t, J = 6.6 Hz, 2 H) 4.85-4.96 (m, 1 H) 6.71-6.80 (m, 1 H) 8.13-8.24 (m, 1 H) 8.86-8.92 (m, 1 H).
Reference Example 14-1
Propan-2-yl 2- {3-[(6-cyanopyridin-3-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000083
 参考例１１－２で得られた化合物（２００ｍｇ）と５－ヒドロキシピコリンニトリル（１０７ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（２０３ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.33 - 1.64 (m, 8 H) 1.67 - 1.82 (m, 2 H) 1.93 - 2.05 (m, 2 H) 2.17 - 2.35 (m, 1 H) 3.24 - 3.44 (m, 4 H) 4.04 (t, J=6.4 Hz, 2 H) 4.83 - 4.97 (m, 1 H) 7.17 - 7.23 (m, 1 H) 7.59 - 7.66 (m, 1 H) 8.32 - 8.37 (m, 1 H).
MS ESI/APCI Dual posi: 372[M+H]+, 394[M+Na]+.
参考例１４－２
５－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ピリジン－２－カルボン酸
Figure JPOXMLDOC01-appb-C000083
 The reaction and purification were carried out in the same manner as in Reference Example 10-1 using the compound (200 mg) obtained in Reference Example 11-2 and 5-hydroxypicolinonitrile (107 mg) to obtain the title compound (203 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.33-1.64 (m, 8 H) 1.67-1.82 (m, 2 H) 1.93-2.05 (m, 2 H) 2.17-2.35 (m, 1 H) 3.24-3.44 (m, 4 H) 4.04 (t, J = 6.4 Hz, 2 H) 4.83-4.97 (m, 1 H) 7.17-7.23 (m, 1 H) 7.59-7.66 (m, 1 H) 8.32-8.37 (m, 1 H).
MS ESI / APCI Dual posi: 372 [M + H] + , 394 [M + Na] + .
Reference Example 14-2
5- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) pyridine-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000084
 参考例１４－１で得られた化合物（２００ｍｇ）を用いて参考例１０－２と同様の操作にて反応及び精製を行い、表題化合物（１６９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.34 - 1.66 (m, 8 H) 1.67 - 1.84 (m, 2 H) 1.93 - 2.06 (m, 2 H) 2.19 - 2.38 (m, 1 H) 3.26 - 3.42 (m, 4 H) 4.06 (t, J=6.5 Hz, 2 H) 4.84 - 4.96 (m, 1 H) 7.30 - 7.36 (m, 1 H) 8.14 - 8.19 (m, 1 H) 8.23 - 8.25 (m, 1 H).
参考例１５－１
プロパン－２－イル　２－｛３［４－（メトキシカルボニル）－２－メチルフェノキシ]プロピル］－７－アザスピロ［３．５］ノナン－7－カルボキシラート
Figure JPOXMLDOC01-appb-C000084
 Using the compound (200 mg) obtained in Reference Example 14-1, the reaction and purification were carried out in the same manner as in Reference Example 10-2 to obtain the title compound (169 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.34-1.66 (m, 8 H) 1.67-1.84 (m, 2 H) 1.93-2.06 (m, 2 H) 2.19-2.38 (m, 1 H) 3.26-3.42 (m, 4 H) 4.06 (t, J = 6.5 Hz, 2 H) 4.84-4.96 (m, 1 H) 7.30-7.36 (m, 1 H) 8.14-8.19 (m, 1 H) 8.23-8.25 (m, 1 H).
Reference Example 15-1
Propan-2-yl 2- {3 [4- (methoxycarbonyl) -2-methylphenoxy] propyl] -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000085
 参考例１１－２で得られた化合物（１００ｍｇ）と４－ヒドロキシ－３－メチル安息香酸メチル（７４ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（１３９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 - 1.25 (m, 6 H) 1.33 - 1.65 (m, 8 H) 1.67 - 1.81 (m, 2 H) 1.92 - 2.03 (m, 2 H) 2.19 - 2.31 (m, 4 H) 3.25 - 3.43 (m, 4 H) 3.88 (s, 3 H) 3.94 - 4.04 (m, 2 H) 4.84 - 4.97 (m, 1 H) 6.76 - 6.83 (m, 1 H) 7.73 - 7.91 (m, 2 H).
MS ESI/APCI Dual posi: 418[M+H]+, 440[M+Na]+.
参考例１５－２
３－メチル－４－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000085
 Using the compound (100 mg) obtained in Reference Example 11-2 and methyl 4-hydroxy-3-methylbenzoate (74 mg), the reaction and purification were carried out in the same manner as in Reference Example 10-1, and the title compound (139 mg) Got.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.25 (m, 6 H) 1.33-1.65 (m, 8 H) 1.67-1.81 (m, 2 H) 1.92-2.03 (m, 2 H) 2.19 -2.31 (m, 4 H) 3.25-3.43 (m, 4 H) 3.88 (s, 3 H) 3.94-4.04 (m, 2 H) 4.84-4.97 (m, 1 H) 6.76-6.83 (m, 1 H ) 7.73-7.91 (m, 2 H).
MS ESI / APCI Dual posi: 418 [M + H] + , 440 [M + Na] + .
Reference Example 15-2
3-methyl-4- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000086
 参考例１５－１で得られた化合物（１３９ｍｇ）を用いて参考例１１－４と同様の操作にて反応及び精製を行い、表題化合物（１３４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.31 - 1.64 (m, 8 H) 1.66 - 1.83 (m, 2 H) 1.89 - 2.06 (m, 2 H) 2.17 - 2.35 (m, 4 H) 3.24 - 3.45 (m, 4 H) 4.00 (t, J=6.2 Hz, 2 H) 4.82 - 5.00 (m, 1 H) 6.77 - 6.85 (m, 1 H) 7.86 - 7.99 (m, 2 H).
MS ESI/APCI Dual posi: 404[M+H]+, 426[M+Na]+.
MS ESI/APCI Dual nega: 402[M-H]-.
参考例１６－１
プロパン－２－イル　２－｛３［２－フルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000086
 The compound (139 mg) obtained in Reference Example 15-1 was subjected to reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (134 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.31-1.64 (m, 8 H) 1.66-1.83 (m, 2 H) 1.89-2.06 (m, 2 H) 2.17-2.35 (m, 4 H) 3.24-3.45 (m, 4 H) 4.00 (t, J = 6.2 Hz, 2 H) 4.82-5.00 (m, 1 H) 6.77-6.85 (m, 1 H) 7.86-7.99 (m, 2 H).
MS ESI / APCI Dual posi: 404 [M + H] + , 426 [M + Na] + .
MS ESI / APCI Dual nega: 402 [MH] - .
Reference Example 16-1
Propan-2-yl 2- {3 [2-fluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000087
 参考例１１－２で得られた化合物（１００ｍｇ）と３－フルオロ－４－ヒドロキシ安息香酸メチル（７６ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（１５９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.32 - 1.64 (m, 8 H) 1.70 - 1.83 (m, 2 H) 1.92 - 2.02 (m, 2 H) 2.20 - 2.34 (m, 1 H) 3.23 - 3.45 (m, 4 H) 3.89 (s, 3 H) 4.06 (t, J=6.5 Hz, 2 H) 4.84 - 4.95 (m, 1 H) 6.90 - 6.99 (m, 1 H) 7.69 - 7.82 (m, 2 H).
MS ESI/APCI Dual posi: 422[M+H]+, 444[M+Na]+.
参考例１６－２
３－フルオロ－４－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000087
 Using the compound (100 mg) obtained in Reference Example 11-2 and methyl 3-fluoro-4-hydroxybenzoate (76 mg), the reaction and purification were carried out in the same manner as in Reference Example 10-1, and the title compound (159 mg) Got.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.32-1.64 (m, 8 H) 1.70-1.83 (m, 2 H) 1.92-2.02 (m, 2 H) 2.20-2.34 (m, 1 H) 3.23-3.45 (m, 4 H) 3.89 (s, 3 H) 4.06 (t, J = 6.5 Hz, 2 H) 4.84-4.95 (m, 1 H) 6.90- 6.99 (m, 1 H) 7.69-7.82 (m, 2 H).
MS ESI / APCI Dual posi: 422 [M + H] + , 444 [M + Na] + .
Reference Example 16-2
3-Fluoro-4- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000088
 参考例１６－１で得られた化合物（１５０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（１３７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J=6.4 Hz, 6 H) 1.31 - 1.63 (m, 8 H) 1.67 - 1.83 (m, 2 H) 1.87 - 2.06 (m, 2 H) 2.17 - 2.37 (m, 1 H) 3.22 - 3.43 (m, 4 H) 3.93 - 4.10 (m, 2 H) 4.80 - 4.98 (m, 1 H) 6.79 - 6.97 (m, 1 H) 7.63 - 7.85 (m, 2 H).
MS ESI/APCI Dual posi: 408[M+H]+, 430[M+Na]+.
MS ESI/APCI Dual nega: 406[M-H]-.
参考例１７－１
アゼチジン－１－イル（２－フルオロ－４－ヒドロキシフェニル）メタノン
Figure JPOXMLDOC01-appb-C000088
 The compound (150 mg) obtained in Reference Example 16-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (137 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.4 Hz, 6 H) 1.31-1.63 (m, 8 H) 1.67-1.83 (m, 2 H) 1.87-2.06 (m, 2 H) 2.17-2.37 (m, 1 H) 3.22-3.43 (m, 4 H) 3.93-4.10 (m, 2 H) 4.80-4.98 (m, 1 H) 6.79-6.97 (m, 1 H) 7.63-7.85 (m, 2 H).
MS ESI / APCI Dual posi: 408 [M + H] + , 430 [M + Na] + .
MS ESI / APCI Dual nega: 406 [MH] - .
Reference Example 17-1
Azetidin-1-yl (2-fluoro-4-hydroxyphenyl) methanone
Figure JPOXMLDOC01-appb-C000089
 ２－フルオロ－４－ヒドロキシ安息香酸（１．０ｇ）をＮ，Ｎ－ジメチルホルムアミド（３２ｍｌ）に溶解し、アゼチジン（５６０μｌ）、１－エチル－３－(３－ジメチルアミノプロピル)カルボジイミド塩酸塩（１．６ｇ）、１－ヒドロキシベンゾトリアゾール一水和物（１．２８ｇ）を加え、室温で一晩攪拌した。反応溶液に水を加え、水層を酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝５５：４５～３０：７０）にて精製し、表題化合物（８８７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.21 - 2.44 (m, 2 H) 4.04 - 4.31 (m, 4 H) 6.42 - 6.63 (m, 2 H) 7.26 - 7.33 (m, 1 H) 9.18 (br. s., 1 H).
MS ESI/APCI Dual posi: 196[M+H]+.
参考例１８－１
４－ヒドロキシ－２－メチル安息香酸メチル
Figure JPOXMLDOC01-appb-C000089
 2-Fluoro-4-hydroxybenzoic acid (1.0 g) is dissolved in N, N-dimethylformamide (32 ml), and azetidine (560 μl), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 1.6 g) and 1-hydroxybenzotriazole monohydrate (1.28 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 55: 45-30: 70) to obtain the title compound (887 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.21-2.44 (m, 2 H) 4.04-4.31 (m, 4 H) 6.42-6.63 (m, 2 H) 7.26-7.33 (m, 1 H) 9.18 (br. s., 1 H).
MS ESI / APCI Dual posi: 196 [M + H] + .
Reference Example 18-1
Methyl 4-hydroxy-2-methylbenzoate
Figure JPOXMLDOC01-appb-C000090
 ４－ヒドロキシ－２－メチル安息香酸（１．０ｇ）および濃硫酸（３００μＭ）のメタノール（２０ｍＬ）溶液を３日間加熱還流した。室温に冷却後、２Ｎ水酸化ナトリウム水溶液を用いてｐＨ＝７～８に調節後、クロロホルムで抽出した。有機層を減圧濃縮し表題化合物（０．５９ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.58 (s, 3 H) 3.86 (s, 3 H) 6.60 - 6.75 (m, 2 H) 7.90 (d, J=9.0 Hz, 1 H).
MS ESI/APCI Dual posi: 167[M+H]+.
MS ESI/APCI Dual nega: 165[M-H]-.
参考例１８－２
プロパン－２－イル　２－｛３－［４－（メトキシカルボニル）－３－メチルフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000090
 A solution of 4-hydroxy-2-methylbenzoic acid (1.0 g) and concentrated sulfuric acid (300 μM) in methanol (20 mL) was heated to reflux for 3 days. After cooling to room temperature, the mixture was adjusted to pH = 7-8 with 2N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was concentrated under reduced pressure to obtain the title compound (0.59 g).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 2.58 (s, 3 H) 3.86 (s, 3 H) 6.60-6.75 (m, 2 H) 7.90 (d, J = 9.0 Hz, 1 H).
MS ESI / APCI Dual posi: 167 [M + H] + .
MS ESI / APCI Dual nega: 165 [MH] - .
Reference Example 18-2
Propan-2-yl 2- {3- [4- (methoxycarbonyl) -3-methylphenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000091
 参考例１１－２で得られた化合物（１００ｍｇ）と参考例１８－１で得られた化合物（７４ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（１６０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.23 (d, J=6.2 Hz, 6 H) 1.32 - 1.62 (m, 8 H) 1.64 - 1.77 (m, 2 H) 1.91 - 2.03 (m, 2 H) 2.17 - 2.35 (m, 1 H) 2.53 - 2.63 (m, 3 H) 3.23 - 3.43 (m, 4 H) 3.85 (s, 3 H) 3.96 (t, J=6.5 Hz, 2 H) 4.83 - 4.97 (m, 1 H) 6.66 - 6.77 (m, 2 H) 7.84 - 7.97 (m, 1 H).
MS ESI/APCI Dual posi: 440[M+Na]+.
MS ESI/APCI Dual nega: 416[M-H]-.
参考例１８－３
２－メチル－４－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000091
 The reaction and purification were conducted in the same manner as in Reference Example 10-1 using the compound (100 mg) obtained in Reference Example 11-2 and the compound (74 mg) obtained in Reference Example 18-1, and the title compound (160 mg) Got.
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.32-1.62 (m, 8 H) 1.64-1.77 (m, 2 H) 1.91-2.03 (m, 2 H) 2.17-2.35 (m, 1 H) 2.53-2.63 (m, 3 H) 3.23-3.43 (m, 4 H) 3.85 (s, 3 H) 3.96 (t, J = 6.5 Hz, 2 H) 4.83- 4.97 (m, 1 H) 6.66-6.77 (m, 2 H) 7.84-7.97 (m, 1 H).
MS ESI / APCI Dual posi: 440 [M + Na] + .
MS ESI / APCI Dual nega: 416 [MH] - .
Reference Example 18-3
2-Methyl-4- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000092
 参考例１８－２で得られた化合物（１６０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（１５１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.23 (d, J=6.2 Hz, 6 H) 1.32 - 1.82 (m, 10 H) 1.90 - 2.04 (m, 2 H) 2.18 - 2.34 (m, 1 H) 2.63 (s, 3 H) 3.26 - 3.42 (m, 4 H) 3.98 (t, J=6.5 Hz, 2 H) 4.84 - 4.96 (m, 1 H) 6.71 - 6.79 (m, 2 H) 7.98 - 8.09 (m, 1 H).
MS ESI/APCI Dual posi: 426[M+Na]+.
MS ESI/APCI Dual nega: 402[M-H]-.
参考例１９－１
ｔｅｒｔ－ブチル　２－｛３－［３－フルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000092
 The reaction and purification were carried out in the same manner as in Reference Example 11-4 using the compound (160 mg) obtained in Reference Example 18-2 to obtain the title compound (151 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.32-1.82 (m, 10 H) 1.90-2.04 (m, 2 H) 2.18-2.34 (m, 1 H) 2.63 (s, 3 H) 3.26-3.42 (m, 4 H) 3.98 (t, J = 6.5 Hz, 2 H) 4.84-4.96 (m, 1 H) 6.71-6.79 (m, 2 H) 7.98- 8.09 (m, 1 H).
MS ESI / APCI Dual posi: 426 [M + Na] + .
MS ESI / APCI Dual nega: 402 [MH] - .
Reference Example 19-1
tert-Butyl 2- {3- [3-Fluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000093
 参考例２－４で得られた化合物（０．８０ｇ）と２－フルオロ－４－ヒドロキシ安息香酸メチル（０．７２ｇ）を用いて参考例１０‐１と同様にして反応及び精製を行い、表題化合物（１．２ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.31 - 1.62 (m, 17 H) 1.63 - 1.79 (m, 2 H) 1.88 - 2.05 (m, 2 H) 2.17 - 2.33 (m, 1 H) 3.20 - 3.39 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 6.55 - 6.73 (m, 2 H) 7.88 (t, J=8.7 Hz, 1 H).
参考例１９－２
メチル　４－［３－（７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000093
 The reaction and purification were conducted in the same manner as in Reference Example 10-1 using the compound (0.80 g) obtained in Reference Example 2-4 and methyl 2-fluoro-4-hydroxybenzoate (0.72 g). Compound (1.2 g) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.31-1.62 (m, 17 H) 1.63-1.79 (m, 2 H) 1.88-2.05 (m, 2 H) 2.17-2.33 (m, 1 H) 3.20 -3.39 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.55-6.73 (m, 2 H) 7.88 (t, J = 8.7 Hz, 1 H).
Reference Example 19-2
Methyl 4- [3- (7-azaspiro [3.5] non-2-yl) propoxy] -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000094
 参考例１９－１で得られた化合物（１．２ｇ）を用いて参考例１２－２と同様にして反応及び精製を行い、表題化合物（０．９１ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.29 - 1.44 (m, 2 H) 1.48 - 1.78 (m, 8 H) 1.90 - 2.04 (m, 2 H) 2.14 - 2.32 (m, 1 H) 2.67 - 2.92 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 6.54 - 6.74 (m, 2 H) 7.88 (t, J=8.6 Hz, 1 H).
MS ESI/APCI Dual posi: 336[M+H]+.
参考例１９－３
２－フルオロ－４－［３－（７－｛［（１－メチルシクロプロピル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］安息香酸
Figure JPOXMLDOC01-appb-C000094
 Using the compound (1.2 g) obtained in Reference Example 19-1, the reaction and purification were carried out in the same manner as in Reference Example 12-2 to obtain the title compound (0.91 g).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.29-1.44 (m, 2 H) 1.48-1.78 (m, 8 H) 1.90-2.04 (m, 2 H) 2.14-2.32 (m, 1 H) 2.67 -2.92 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.54-6.74 (m, 2 H) 7.88 (t, J = 8.6 Hz, 1 H).
MS ESI / APCI Dual posi: 336 [M + H] + .
Reference Example 19-3
2-Fluoro-4- [3- (7-{[(1-methylcyclopropyl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] benzoic acid
Figure JPOXMLDOC01-appb-C000095
 参考例１９－２で得られた化合物（８０ｍｇ）を用いて参考例１２－３と同様にして反応及び精製を行い、１－メチルシクロプロピル ２－｛３－［３－フルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラートと不純物の混合物（１２７ｍｇ）を得た。さらに、この混合物を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（７１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.56 - 0.66 (m, 2 H) 0.80 - 0.88 (m, 2 H) 1.23 - 1.82 (m, 13 H) 1.90 - 2.05 (m, 2 H) 2.16 - 2.37 (m, 1 H) 3.17 - 3.44 (m, 4 H) 3.97 (t, J=6.5 Hz, 2 H) 6.57 - 6.76 (m, 2 H) 7.95 (t, J=8.9 Hz, 1 H).
参考例２０－１
メチル　４－｛３－［７－（３，３－ジメチルブタノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000095
 The compound (80 mg) obtained in Reference Example 19-2 was used for reaction and purification in the same manner as in Reference Example 12-3 to give 1-methylcyclopropyl 2- {3- [3-fluoro-4- (methoxy). Carbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate and impurity mixture (127 mg) were obtained. Furthermore, this mixture was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (71 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.56-0.66 (m, 2 H) 0.80-0.88 (m, 2 H) 1.23-1.82 (m, 13 H) 1.90-2.05 (m, 2 H) 2.16 -2.37 (m, 1 H) 3.17-3.44 (m, 4 H) 3.97 (t, J = 6.5 Hz, 2 H) 6.57-6.76 (m, 2 H) 7.95 (t, J = 8.9 Hz, 1 H) .
Reference Example 20-1
Methyl 4- {3- [7- (3,3-dimethylbutanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000096
 参考例１９－２で得られた化合物（５０ｍｇ）、ｔｅｒｔ－ブチルアセチルクロリド（２４ｍｇ）およびトリエチルアミン（３１μＬ）のクロロホルム溶液（１ｍＬ）を室温で一晩撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ノルマルヘキサンのみ～ノルマルヘキサン：酢酸エチル＝７５：２５）にて精製し、表題化合物（５７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.97 - 1.07 (m, 9 H) 1.32 - 1.81 (m, 10 H) 1.91 - 2.07 (m, 2 H) 2.14 - 2.35 (m, 3 H) 3.26 - 3.62 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 6.53 - 6.74 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 456[M+Na]+.
MS ESI/APCI Dual nega: 468[M+Cl]-.
参考例２０－２
４－｛３－［７－（３，３－ジメチルブタノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000096
 A chloroform solution (1 mL) of the compound obtained in Reference Example 19-2 (50 mg), tert-butylacetyl chloride (24 mg) and triethylamine (31 μL) was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography (normal hexane only to normal hexane: ethyl acetate = 75: 25) to obtain the title compound (57 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.97-1.07 (m, 9 H) 1.32-1.81 (m, 10 H) 1.91-2.07 (m, 2 H) 2.14-2.35 (m, 3 H) 3.26 -3.62 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.53-6.74 (m, 2 H) 7.89 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 456 [M + Na] + .
MS ESI / APCI Dual nega: 468 [M + Cl] - .
Reference Example 20-2
4- {3- [7- (3,3-Dimethylbutanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000097
 参考例２０－１で得られた化合物（５５ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（５０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.99 - 1.06 (m, 9 H) 1.33 - 1.78 (m, 10 H) 1.92 - 2.07 (m, 2 H) 2.19 - 2.33 (m, 2 H) 3.28 - 3.62 (m, 4 H) 3.96 (t, J=6.3 Hz, 2 H) 6.56 - 6.73 (m, 2 H) 7.83 - 7.99 (m, 1 H).
参考例２１－１
メチル　４－｛３－［７－（ｔｅｒｔ－ブチルカルバモイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000097
 Using the compound (55 mg) obtained in Reference Example 20-1, the reaction and purification were conducted in the same manner as in Reference Example 11-4 to obtain the title compound (50 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.99-1.06 (m, 9 H) 1.33-1.78 (m, 10 H) 1.92-2.07 (m, 2 H) 2.19-2.33 (m, 2 H) 3.28 -3.62 (m, 4 H) 3.96 (t, J = 6.3 Hz, 2 H) 6.56-6.73 (m, 2 H) 7.83-7.99 (m, 1 H).
Reference Example 21-1
Methyl 4- {3- [7- (tert-butylcarbamoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000098
 参考例１９－２で得られた化合物（５０ｍｇ）、ｔｅｒｔ－ブチルイソシアナート（１８ｍｇ）およびトリエチルアミン（３１μＬ）のクロロホルム溶液（１ｍＬ）を室温で一晩撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ノルマルヘキサンのみ～ノルマルヘキサン：酢酸エチル＝７５：２５）にて精製し、表題化合物（７０ｍｇ）を得た
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28 - 1.63 (m, 17 H) 1.65 - 1.78 (m, 2 H) 1.90 - 2.03 (m, 2 H) 2.16 - 2.32 (m, 1 H) 3.10 - 3.29 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 6.56 - 6.73 (m, 2 H) 7.88 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 457[M+Na]+.
MS ESI/APCI Dual nega: 469[M+Cl]-.
参考例２１－２
４－｛３－［７－（ｔｅｒｔ－ブチルカルバモイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000098
 A chloroform solution (1 mL) of the compound obtained in Reference Example 19-2 (50 mg), tert-butyl isocyanate (18 mg) and triethylamine (31 μL) was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography (normal hexane only to normal hexane: ethyl acetate = 75: 25) to obtain the title compound (70 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28-1.63 (m, 17 H) 1.65-1.78 (m, 2 H) 1.90-2.03 (m, 2 H) 2.16-2.32 (m, 1 H) 3.10 -3.29 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.56-6.73 (m, 2 H) 7.88 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 457 [M + Na] + .
MS ESI / APCI Dual nega: 469 [M + Cl] - .
Reference Example 21-2
4- {3- [7- (tert-Butylcarbamoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000099
 参考例２１－１で得られた化合物（７０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（５２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.25 - 1.63 (m, 17 H) 1.65 - 1.80 (m, 2 H) 1.89 - 2.05 (m, 2 H) 2.16 - 2.33 (m, 1 H) 3.08 - 3.32 (m, 4 H) 3.91 - 4.02 (m, 2 H) 6.53 - 6.77 (m, 2 H) 7.95 (t, J=8.7 Hz, 1 H).
参考例２２－１
１－｛［（１，１－ジフルオロ－２－メチルプロパン－２－イル）オキシ］カルボニル｝－３－メチル－１Ｈ－イミダゾル－３－イウム　ヨージド
Figure JPOXMLDOC01-appb-C000099
 The compound (70 mg) obtained in Reference Example 21-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (52 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.25-1.63 (m, 17 H) 1.65-1.80 (m, 2 H) 1.89-2.05 (m, 2 H) 2.16-2.33 (m, 1 H) 3.08 -3.32 (m, 4 H) 3.91-4.02 (m, 2 H) 6.53-6.77 (m, 2 H) 7.95 (t, J = 8.7 Hz, 1 H).
Reference Example 22-1
1-{[(1,1-Difluoro-2-methylpropan-2-yl) oxy] carbonyl} -3-methyl-1H-imidazol-3-ium iodide
Figure JPOXMLDOC01-appb-C000100
 ジフルオロ酢酸エチルを用いて文献記載の方法（Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２０１１，１９，１５８０－１５９３）と同様の方法で反応を行い、表題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 - 1.70 (m, 6 H) 3.94 (s, 3 H) 6.09 - 6.52 (m, 1 H) 7.86 (t, J=1.9 Hz, 1 H) 8.09 (t, J=1.9 Hz, 1 H) 9.80 - 9.85 (m, 1 H).
MS ESI/APCI Dual nega: 381[M+Cl]-.
参考例２２－２
１，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［３－フルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000100
 The title compound was obtained using ethyl difluoroacetate in the same manner as described in the literature (Bioorganic & Medicinal Chemistry, 2011, 19, 1580-1593).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.64-1.70 (m, 6 H) 3.94 (s, 3 H) 6.09-6.52 (m, 1 H) 7.86 (t, J = 1.9 Hz, 1 H ) 8.09 (t, J = 1.9 Hz, 1 H) 9.80-9.85 (m, 1 H).
MS ESI / APCI Dual nega: 381 [M + Cl] - .
Reference Example 22-2
1,1-difluoro-2-methylpropan-2-yl 2- {3- [3-fluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000101
 参考例１９－２で得られた化合物（８０ｍｇ）、参考例２２－１で得られた化合物（１１６ｍｇ）およびトリエチルアミン（５０μＬ）のクロロホルム溶液（１．６ｍＬ）を室温で一晩撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ノルマルヘキサンのみ～ノルマルヘキサン：酢酸エチル＝７５：２５）にて精製し、表題化合物（１０１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.32 - 1.63 (m, 14 H) 1.65 - 1.77 (m, 2 H) 1.92 - 2.03 (m, 2 H) 2.17 - 2.34 (m, 1 H) 3.22 - 3.39 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 5.94 - 6.39 (m, 1 H) 6.53 - 6.74 (m, 2 H) 7.88 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 494[M+Na]+.
MS ESI/APCI Dual nega: 506[M+Cl]-.
参考例２２－３
４－［３－（７－｛［（１，１－ジフルオロ－２－メチルプロパン－２－イル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000101
 A chloroform solution (1.6 mL) of the compound obtained in Reference Example 19-2 (80 mg), the compound obtained in Reference Example 22-1 (116 mg) and triethylamine (50 μL) was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography (normal hexane only to normal hexane: ethyl acetate = 75: 25) to obtain the title compound (101 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.32-1.63 (m, 14 H) 1.65-1.77 (m, 2 H) 1.92-2.03 (m, 2 H) 2.17-2.34 (m, 1 H) 3.22 -3.39 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 5.94-6.39 (m, 1 H) 6.53-6.74 (m, 2 H) 7.88 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 494 [M + Na] + .
MS ESI / APCI Dual nega: 506 [M + Cl] - .
Reference Example 22-3
4- [3- (7-{[(1,1-Difluoro-2-methylpropan-2-yl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] -2- Fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000102
 参考例２２－２で得られた化合物（１０１ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（９５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.30 - 1.80 (m, 16 H) 1.91 - 2.04 (m, 2 H) 2.18 - 2.34 (m, 1 H) 3.21 - 3.43 (m, 4 H) 3.98 (t, J=6.4 Hz, 2 H) 5.91 - 6.39 (m, 1 H) 6.58 - 6.76 (m, 2 H) 7.96 (t, J=8.8 Hz, 2 H).
MS ESI/APCI Dual posi: 480[M+H]+.
MS ESI/APCI Dual nega: 456[M-H]-.
参考例２３－１
メチル　４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000102
 Using the compound (101 mg) obtained in Reference Example 22-2, the reaction and purification were conducted in the same manner as in Reference Example 11-4 to obtain the title compound (95 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.30-1.80 (m, 16 H) 1.91-2.04 (m, 2 H) 2.18-2.34 (m, 1 H) 3.21-3.43 (m, 4 H) 3.98 (t, J = 6.4 Hz, 2 H) 5.91-6.39 (m, 1 H) 6.58-6.76 (m, 2 H) 7.96 (t, J = 8.8 Hz, 2 H).
MS ESI / APCI Dual posi: 480 [M + H] + .
MS ESI / APCI Dual nega: 456 [MH] - .
Reference Example 23-1
Methyl 4- {3- [7- (5-ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000103
 参考例１９－２で得られた化合物（８０ｍｇ）、２－クロロ－５－エチルピリミジン（４１ｍｇ）及び炭酸セシウム（１１７ｍｇ）のジメチルスルホキシド（１．０ｍｌ）懸濁液を、マイクロ波照射下、１８０℃で２０分攪拌した。不溶物を濾別した後、濾液を減圧下濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（４９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.17 (t, J=7.6 Hz, 3 H) 1.36 - 1.79 (m, 10 H) 1.94 - 2.09 (m, 2 H) 2.19 - 2.36 (m, 1 H) 2.44 (q, J=7.6 Hz, 2 H) 3.60 - 3.76 (m, 4 H) 3.90 (s, 3 H) 3.97 (t, J=6.4 Hz, 2 H) 6.55 - 6.74 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H) 8.15 (s, 2 H).
MS ESI/APCI Dual posi: 464[M+Na]+.
MS ESI/APCI Dual nega: 440[M-H]-.
参考例２３－２
４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000103
 A suspension of the compound obtained in Reference Example 19-2 (80 mg), 2-chloro-5-ethylpyrimidine (41 mg) and cesium carbonate (117 mg) in dimethyl sulfoxide (1.0 ml) was subjected to 180 ° irradiation under microwave irradiation. Stir at 20 ° C. for 20 minutes. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (49 mg) Got.
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.17 (t, J = 7.6 Hz, 3 H) 1.36-1.79 (m, 10 H) 1.94-2.09 (m, 2 H) 2.19-2.36 (m, 1 H) 2.44 (q, J = 7.6 Hz, 2 H) 3.60-3.76 (m, 4 H) 3.90 (s, 3 H) 3.97 (t, J = 6.4 Hz, 2 H) 6.55-6.74 (m, 2 H ) 7.89 (t, J = 8.7 Hz, 1 H) 8.15 (s, 2 H).
MS ESI / APCI Dual posi: 464 [M + Na] + .
MS ESI / APCI Dual nega: 440 [MH] - .
Reference Example 23-2
4- {3- [7- (5-Ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000104
 参考例２３－１で得られた化合物（４９ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（４２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.18 (t, J=7.6 Hz, 3 H) 1.37 - 1.80 (m, 10 H) 1.95 - 2.11 (m, 2 H) 2.21 - 2.36 (m, 1 H) 2.45 (q, J=7.6 Hz, 2 H) 3.61 - 3.79 (m, 4 H) 3.91 - 4.03 (m, 2 H) 6.53 - 6.80 (m, 2 H) 7.97 (t, J=8.8 Hz, 1 H) 8.19 (s, 2 H).
MS ESI/APCI Dual posi: 428[M+H]+.
MS ESI/APCI Dual nega: 426[M-H]-.
参考例２４－１
メチル　４－｛３－［７－（シクロペンチルメチル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000104
 The compound (49 mg) obtained in Reference Example 23-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (42 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.18 (t, J = 7.6 Hz, 3 H) 1.37-1.80 (m, 10 H) 1.95-2.11 (m, 2 H) 2.21-2.36 (m, 1 H) 2.45 (q, J = 7.6 Hz, 2 H) 3.61-3.79 (m, 4 H) 3.91-4.03 (m, 2 H) 6.53-6.80 (m, 2 H) 7.97 (t, J = 8.8 Hz, 1 H) 8.19 (s, 2 H).
MS ESI / APCI Dual posi: 428 [M + H] + .
MS ESI / APCI Dual nega: 426 [MH] - .
Reference Example 24-1
Methyl 4- {3- [7- (cyclopentylmethyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000105
 ヨードメチルシクロペンタン（７５ｍｇ）、参考例１９－２で得られた化合物（８０ｍｇ）、および炭酸カリウム（６６ｍｇ）のアセトニトリル懸濁液（１．０ｍＬ）を７０℃で１０時間撹拌した。不溶物を濾別した後、濾液を減圧下濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（９０ｍｇ）を得た。
MS ESI/APCI Dual posi: 418[M+H]+.
参考例２４－２
４－｛３－［７－（シクロペンチルメチル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000105
 A suspension of iodomethylcyclopentane (75 mg), the compound obtained in Reference Example 19-2 (80 mg), and potassium carbonate (66 mg) in acetonitrile (1.0 mL) was stirred at 70 ° C. for 10 hours. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (90 mg). Got.
MS ESI / APCI Dual posi: 418 [M + H] + .
Reference Example 24-2
4- {3- [7- (Cyclopentylmethyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000106
 参考例２４－１で得られた化合物（９０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（８５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.77 - 2.83 (m, 24 H) 2.97 (d, J=6.8 Hz, 2 H) 3.31 - 3.61 (m, 2 H) 3.96 (t, J=6.2 Hz, 2 H) 6.52 - 6.76 (m, 2 H) 7.95 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 404[M+H]+.
MS ESI/APCI Dual nega: 402[M-H]-.
参考例２５－１
メチル　３－フルオロ－５－ヒドロキシピリジン－２－カルボキシラート
Figure JPOXMLDOC01-appb-C000106
 The compound (90 mg) obtained in Reference Example 24-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (85 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.77-2.83 (m, 24 H) 2.97 (d, J = 6.8 Hz, 2 H) 3.31-3.61 (m, 2 H) 3.96 (t, J = 6.2 (Hz, 2 H) 6.52-6.76 (m, 2 H) 7.95 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 404 [M + H] + .
MS ESI / APCI Dual nega: 402 [MH] - .
Reference Example 25-1
Methyl 3-fluoro-5-hydroxypyridine-2-carboxylate
Figure JPOXMLDOC01-appb-C000107
 ３，５－ジフルオロピリジン－２－安息香酸（２．０ｇ）のテトラヒドロフラン（２０ｍＬ）、水（２０ｍＬ）混合溶液へ、水酸化リチウム水和物（１．７ｇ）を加えて１００℃で一晩撹拌した。室温に冷却後、４Ｎ塩化水素　酢酸エチル溶液を加えて溶媒を減圧留去し、残渣を得た（１．８ｇ）。この残渣をメタノール（２０ｍＬ）に溶解させた後、塩化チオニル（２．０ｍＬ）を加え、７０℃で２０時間撹拌した。室温に冷却後、反応液を減圧濃縮し残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０～８０：２０）にて精製し、表題化合物（８０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 4.06 (s, 3 H) 7.09 (dd, J=9.3, 2.5 Hz, 1 H) 8.12 - 8.17 (m, 1 H) 10.88 (s, 1 H).
参考例２５－２
プロパン－２－イル　２－（３－｛［５－フルオロ－６－（メトキシカルボニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000107
 To a mixed solution of 3,5-difluoropyridine-2-benzoic acid (2.0 g) in tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide hydrate (1.7 g), and the mixture was stirred at 100 ° C. overnight. did. After cooling to room temperature, 4N hydrogen chloride ethyl acetate solution was added and the solvent was distilled off under reduced pressure to obtain a residue (1.8 g). This residue was dissolved in methanol (20 mL), thionyl chloride (2.0 mL) was added, and the mixture was stirred at 70 ° C. for 20 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 80:20) to give the title compound (80 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 4.06 (s, 3 H) 7.09 (dd, J = 9.3, 2.5 Hz, 1 H) 8.12-8.17 (m, 1 H) 10.88 (s, 1 H) .
Reference Example 25-2
Propan-2-yl 2- (3-{[5-fluoro-6- (methoxycarbonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000108
 参考例１１－２で得られた化合物（８０ｍｇ）と参考例２５－１で得られた化合物（６１ｍｇ）を用いて参考例１０－１と同様にして反応及び精製を行い、表題化合物（８５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.23 (d, J=6.2 Hz, 6 H) 1.33 - 1.67 (m, 8 H) 1.71 - 1.87 (m, 2 H) 1.90 - 2.06 (m, 2 H) 2.16 - 2.37 (m, 1 H) 3.24 - 3.43 (m, 4 H) 3.92 - 3.98 (m, 3 H) 4.02 (t, J=6.5 Hz, 2 H) 4.82 - 4.97 (m, 1 H) 7.02 - 7.14 (m, 1 H) 8.08 - 8.19 (m, 1 H).
参考例２５－３
３－フルオロ－５－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ピリジン－２－カルボン酸
Figure JPOXMLDOC01-appb-C000108
 Using the compound obtained in Reference Example 11-2 (80 mg) and the compound obtained in Reference Example 25-1 (61 mg), the reaction and purification were carried out in the same manner as in Reference Example 10-1, and the title compound (85 mg) Got.
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.33-1.67 (m, 8 H) 1.71-1.87 (m, 2 H) 1.90-2.06 (m, 2 H) 2.16-2.37 (m, 1 H) 3.24-3.43 (m, 4 H) 3.92-3.98 (m, 3 H) 4.02 (t, J = 6.5 Hz, 2 H) 4.82-4.97 (m, 1 H) 7.02-7.14 (m, 1 H) 8.08-8.19 (m, 1 H).
Reference Example 25-3
3-Fluoro-5- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) pyridine-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000109
 参考例２５－２で得られた化合物（８５ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（６１ｍｇ）を得た。
MS ESI/APCI Dual posi: 431[M+Na]+.
MS ESI/APCI Dual nega: 407[M-H]-.
参考例２６－１
メチル　２－フルオロ－４－（３－｛７－［３－（プロパン－２－イル）－１，２，４－オキサジアゾル－５－イル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンゾアート
Figure JPOXMLDOC01-appb-C000109
 The compound (85 mg) obtained in Reference Example 25-2 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (61 mg).
MS ESI / APCI Dual posi: 431 [M + Na] + .
MS ESI / APCI Dual nega: 407 [MH] - .
Reference Example 26-1
Methyl 2-fluoro-4- (3- {7- [3- (propan-2-yl) -1,2,4-oxadiazol-5-yl] -7-azaspiro [3.5] non-2-yl } Propoxy) benzoate
Figure JPOXMLDOC01-appb-C000110
 参考例１９－２で得られた化合物（２４０ｍｇ）をクロロホルム（９ｍｌ）に溶解し、水（３ｍｌ）及び重曹（１５０ｍｇ）を加えた。反応液を氷冷し、臭化シアン（１０８ｍｇ）を加え、反応液を室温へ昇温させながら１時間激しく撹拌した。反応液の有機層をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～７０：３０）にて精製し、メチル　４－［３－（７－シアノ－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２－フルオロベンゾアート（７０ｍｇ）を得た。この化合物（１２８ｍｇ）の酢酸エチル溶液（２．５ｍＬ）へ、塩化亜鉛（１．０Ｍジエチルエーテル溶液、７０９μｌ）、およびＮ－ヒドロキシイソブチリミダミド（７３ｍｇ）を加え、室温にて一晩撹拌した。反応液を濾過し、得られた固体をジエチルエーテルで洗浄後、濃塩酸（３２０μＬ）及びメタノール（４．６ｍＬ）に溶解させ、６０℃で一晩撹拌した。反応液を飽和重曹水で中和後、クロロホルムで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０～９０：１０）にて精製し、表題化合物（１２５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.8 Hz, 6 H) 1.37 - 1.51 (m, 2 H) 1.51 - 1.63 (m, 4 H) 1.65 - 1.79 (m, 4 H) 1.96 - 2.08 (m, 2 H) 2.20 - 2.37 (m, 1 H) 2.79 - 2.94 (m, 1 H) 3.41 - 3.58 (m, 4 H) 3.90 (s, 3 H) 3.93 - 4.01 (m, 2 H) 6.56 - 6.74 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 468[M+H]+.
参考例２６－２
２－フルオロ－４－（３－｛７－［３－（プロパン－２－イル）－１，２，４－オキサジアゾル－５－イル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000110
 The compound (240 mg) obtained in Reference Example 19-2 was dissolved in chloroform (9 ml), and water (3 ml) and sodium bicarbonate (150 mg) were added. The reaction mixture was ice-cooled, cyanogen bromide (108 mg) was added, and the reaction mixture was vigorously stirred for 1 hour while warming to room temperature. The organic layer of the reaction solution was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 70:30) to obtain methyl 4- [3- (7-cyano-7-azaspiro [3.5] nona. -2-yl) propoxy] -2-fluorobenzoate (70 mg) was obtained. To a solution of this compound (128 mg) in ethyl acetate (2.5 mL) were added zinc chloride (1.0 M diethyl ether solution, 709 μl) and N-hydroxyisobutyrimamide (73 mg), and the mixture was stirred overnight at room temperature. . The reaction mixture was filtered, and the resulting solid was washed with diethyl ether, dissolved in concentrated hydrochloric acid (320 μL) and methanol (4.6 mL), and stirred at 60 ° C. overnight. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 90:10) to obtain the title compound (125 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.28 (d, J = 6.8 Hz, 6 H) 1.37-1.51 (m, 2 H) 1.51-1.63 (m, 4 H) 1.65-1.79 (m, 4 H) 1.96-2.08 (m, 2 H) 2.20-2.37 (m, 1 H) 2.79-2.94 (m, 1 H) 3.41-3.58 (m, 4 H) 3.90 (s, 3 H) 3.93-4.01 (m , 2 H) 6.56-6.74 (m, 2 H) 7.89 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 468 [M + H] + .
Reference Example 26-2
2-Fluoro-4- (3- {7- [3- (propan-2-yl) -1,2,4-oxadiazol-5-yl] -7-azaspiro [3.5] non-2-yl} Propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000111
 参考例２６－１で得られた化合物（１２５ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（１１０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.26 (d, J=6.8 Hz, 6 H) 1.35 - 1.84 (m, 10 H) 1.91 - 2.13 (m, 2 H) 2.15 - 2.39 (m, 1 H) 2.71 - 2.97 (m, 1 H) 3.31 - 3.65 (m, 4 H) 3.67 - 3.95 (m, 2 H) 6.03 - 6.60 (m, 2 H) 7.46 - 7.81 (m, 1 H)
MS ESI/APCI Dual posi: 454[M+Na]+.
MS ESI/APCI Dual nega: 430[M-H]-.
参考例２７－１
メチル　４－｛３－［７－（２，２－ジメチルプロパノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000111
 Using the compound (125 mg) obtained in Reference Example 26-1, the reaction and purification were carried out in the same manner as in Reference Example 11-4 to obtain the title compound (110 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.26 (d, J = 6.8 Hz, 6 H) 1.35-1.84 (m, 10 H) 1.91-2.13 (m, 2 H) 2.15-2.39 (m, 1 H) 2.71-2.97 (m, 1 H) 3.31-3.65 (m, 4 H) 3.67-3.95 (m, 2 H) 6.03-6.60 (m, 2 H) 7.46-7.81 (m, 1 H)
MS ESI / APCI Dual posi: 454 [M + Na] + .
MS ESI / APCI Dual nega: 430 [MH] - .
Reference Example 27-1
Methyl 4- {3- [7- (2,2-dimethylpropanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000112
 参考例１９－２で得られた化合物（８０ｍｇ）、ピバロイルクロリド（４４μＬ）およびトリエチルアミン（６７μＬ）のクロロホルム溶液（１ｍＬ）を室温で一晩撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ノルマルヘキサンのみ～ノルマルヘキサン：酢酸エチル＝７５：２５）にて精製し、表題化合物（３９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.27 (s, 9 H) 1.35 - 1.65 (m, 8 H) 1.66 - 1.79 (m, 2 H) 1.91 - 2.07 (m, 2 H) 2.17 - 2.34 (m, 1 H) 3.39 - 3.58 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 6.54 - 6.76 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 442[M+Na]+.
参考例２７－２
４－｛３－［７－（２，２－ジメチルプロパノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000112
 A chloroform solution (1 mL) of the compound obtained in Reference Example 19-2 (80 mg), pivaloyl chloride (44 μL) and triethylamine (67 μL) was stirred overnight at room temperature. The reaction solution was purified by silica gel column chromatography (normal hexane only to normal hexane: ethyl acetate = 75: 25) to obtain the title compound (39 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.27 (s, 9 H) 1.35-1.65 (m, 8 H) 1.66-1.79 (m, 2 H) 1.91-2.07 (m, 2 H) 2.17-2.34 (m, 1 H) 3.39-3.58 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.54-6.76 (m, 2 H) 7.89 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 442 [M + Na] + .
Reference Example 27-2
4- {3- [7- (2,2-dimethylpropanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000113
 参考例２７－１で得られた化合物（３９ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（２５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.27 (s, 9 H) 1.35 - 1.64 (m, 8 H) 1.66 - 1.80 (m, 2 H) 1.93 - 2.06 (m, 2 H) 2.18 - 2.36 (m, 1 H) 3.40 - 3.61 (m, 4 H) 3.98 (t, J=6.3 Hz, 2 H) 6.57 - 6.79 (m, 2 H) 7.96 (t, J=8.6 Hz, 1 H)
MS ESI/APCI Dual posi: 428[M+Na]+.
MS ESI/APCI Dual nega: 404[M-H]-.
参考例２８－１
メチル　２－フルオロ－４－［３－（７－プロパノイル－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］ベンゾアート
Figure JPOXMLDOC01-appb-C000113
 The compound (39 mg) obtained in Reference Example 27-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (25 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.27 (s, 9 H) 1.35-1.64 (m, 8 H) 1.66-1.80 (m, 2 H) 1.93-2.06 (m, 2 H) 2.18-2.36 (m, 1 H) 3.40-3.61 (m, 4 H) 3.98 (t, J = 6.3 Hz, 2 H) 6.57-6.79 (m, 2 H) 7.96 (t, J = 8.6 Hz, 1 H)
MS ESI / APCI Dual posi: 428 [M + Na] + .
MS ESI / APCI Dual nega: 404 [MH] - .
Reference Example 28-1
Methyl 2-fluoro-4- [3- (7-propanoyl-7-azaspiro [3.5] non-2-yl) propoxy] benzoate
Figure JPOXMLDOC01-appb-C000114
 参考例１９－２で得られた化合物（１２０ｍｇ）、およびプロピオン酸クロリド（５０ｍｇ）を用いて参考例２７－１と同様にして反応及び精製を行い表題化合物（１３０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.13 (t, J=7.4 Hz, 3 H) 1.31 - 1.64 (m, 8 H) 1.65 - 1.79 (m, 2 H) 1.91 - 2.07 (m, 2 H) 2.18 - 2.41 (m, 3 H) 3.23 - 3.58 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.3 Hz, 2 H) 6.55 - 6.75 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 414[M+Na]+.
MS ESI/APCI Dual nega: 426[M+Cl]-.
参考例２８－２
２－フルオロ－４－［３－（７－プロパノイル－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］安息香酸
Figure JPOXMLDOC01-appb-C000114
 The title compound (130 mg) was obtained by reacting and purifying in the same manner as in Reference Example 27-1 using the compound (120 mg) obtained in Reference Example 19-2 and propionic acid chloride (50 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.13 (t, J = 7.4 Hz, 3 H) 1.31-1.64 (m, 8 H) 1.65-1.79 (m, 2 H) 1.91-2.07 (m, 2 H) 2.18-2.41 (m, 3 H) 3.23-3.58 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.3 Hz, 2 H) 6.55-6.75 (m, 2 H) 7.89 ( t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 414 [M + Na] + .
MS ESI / APCI Dual nega: 426 [M + Cl] - .
Reference Example 28-2
2-Fluoro-4- [3- (7-propanoyl-7-azaspiro [3.5] non-2-yl) propoxy] benzoic acid
Figure JPOXMLDOC01-appb-C000115
 参考例２８－１で得られた化合物（１３０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（１２０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.05 - 1.20 (m, 3 H) 1.31 - 1.82 (m, 10 H) 1.92 - 2.08 (m, 2 H) 2.18 - 2.43 (m, 3 H) 3.21 - 3.60 (m, 4 H) 3.98 (t, J=6.3 Hz, 2 H) 6.58 - 6.77 (m, 2 H) 7.96 (t, J=8.8 Hz, 1 H).
MS ESI/APCI Dual posi: 400[M+Na]+.
MS ESI/APCI Dual nega: 376[M-H]-.
参考例２９－１
メチル　２－フルオロ－４－｛３－［７－（３－メチルブタノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝ベンゾアート
Figure JPOXMLDOC01-appb-C000115
 Using the compound (130 mg) obtained in Reference Example 28-1, the reaction and purification were conducted in the same manner as in Reference Example 11-4 to obtain the title compound (120 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.05-1.20 (m, 3 H) 1.31-1.82 (m, 10 H) 1.92-2.08 (m, 2 H) 2.18-2.43 (m, 3 H) 3.21 -3.60 (m, 4 H) 3.98 (t, J = 6.3 Hz, 2 H) 6.58-6.77 (m, 2 H) 7.96 (t, J = 8.8 Hz, 1 H).
MS ESI / APCI Dual posi: 400 [M + Na] + .
MS ESI / APCI Dual nega: 376 [MH] - .
Reference Example 29-1
Methyl 2-fluoro-4- {3- [7- (3-methylbutanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} benzoate
Figure JPOXMLDOC01-appb-C000116
 参考例１９－２で得られた化合物（１２０ｍｇ）、およびイソバレリルクロリド（６５ｍｇ）を用いて参考例２７－１と同様にして反応及び精製を行い、表題化合物（１４０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.90 - 1.02 (m, 6 H) 1.35 - 1.80 (m, 1１ H) 1.89 - 2.38 (m, 5 H) 3.23 - 3.60 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 6.55 - 6.75 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 442[M+Na]+.
MS ESI/APCI Dual nega: 454[M+Cl]-.
参考例２９－２
２－フルオロ－４－｛３－［７－（３－メチルブタノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝安息香酸
Figure JPOXMLDOC01-appb-C000116
 Reaction and purification were carried out in the same manner as in Reference Example 27-1 using the compound (120 mg) obtained in Reference Example 19-2 and isovaleryl chloride (65 mg) to obtain the title compound (140 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.90-1.02 (m, 6 H) 1.35-1.80 (m, 11 H) 1.89-2.38 (m, 5 H) 3.23-3.60 (m, 4 H) 3.90 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 6.55-6.75 (m, 2 H) 7.89 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 442 [M + Na] + .
MS ESI / APCI Dual nega: 454 [M + Cl] - .
Reference Example 29-2
2-Fluoro-4- {3- [7- (3-methylbutanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} benzoic acid
Figure JPOXMLDOC01-appb-C000117
 参考例２９－１で得られた化合物（１４０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（１３０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.95 (d, J=6.5 Hz, 6 H) 1.33 - 1.81 (m, 11 H) 1.89 - 2.37 (m, 5 H) 3.22 - 3.62 (m, 4 H) 3.79 - 4.08 (m, 2 H) 6.42 - 6.75 (m, 2 H) 7.74 - 8.01 (m, 1 H).
MS ESI/APCI Dual posi: 428[M+Na]+.
MS ESI/APCI Dual nega: 404[M-H]-.
参考例３０－１
メチル　４－｛３－［７－（シクロプロピルアセチル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000117
 The compound (140 mg) obtained in Reference Example 29-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (130 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.95 (d, J = 6.5 Hz, 6 H) 1.33-1.81 (m, 11 H) 1.89-2.37 (m, 5 H) 3.22-3.62 (m, 4 H) 3.79-4.08 (m, 2 H) 6.42-6.75 (m, 2 H) 7.74-8.01 (m, 1 H).
MS ESI / APCI Dual posi: 428 [M + Na] + .
MS ESI / APCI Dual nega: 404 [MH] - .
Reference Example 30-1
Methyl 4- {3- [7- (cyclopropylacetyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000118
 参考例１９－２で得られた化合物（８０ｍｇ）、シクロプロピル酢酸（２９ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（６９ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（５５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０ｍＬ）、テトラヒドロフラン（２．０ｍＬ）混合溶液を室温で一晩攪拌した。反応液に水を加え、水層を酢酸エチルにて抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝５０：５０）で精製し、表題化合物（８１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.09 - 0.25 (m, 2 H) 0.47 - 0.63 (m, 2 H) 0.95 - 1.15 (m, 1 H) 1.31 - 1.82 (m, 10 H) 1.92 - 2.07 (m, 2 H) 2.18 - 2.33 (m, 3 H) 3.17 - 3.64 (m, 4 H) 3.90 (s, 3 H) 3.93 - 4.02 (m, 2 H) 6.54 - 6.75 (m, 2 H) 7.89 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 440[M+Na]+.
MS ESI/APCI Dual nega： 452[M+Cl]-.
参考例３０－２
４－｛３－［７－（シクロプロピルアセチル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000118
 Compound obtained in Reference Example 19-2 (80 mg), cyclopropylacetic acid (29 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (69 mg), 1-hydroxybenzotriazole monohydrate A mixed solution of (55 mg) of N, N-dimethylformamide (1.0 mL) and tetrahydrofuran (2.0 mL) was stirred overnight at room temperature. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 50: 50) to obtain the title compound (81 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.09-0.25 (m, 2 H) 0.47-0.63 (m, 2 H) 0.95-1.15 (m, 1 H) 1.31-1.82 (m, 10 H) 1.92 -2.07 (m, 2 H) 2.18-2.33 (m, 3 H) 3.17-3.64 (m, 4 H) 3.90 (s, 3 H) 3.93-4.02 (m, 2 H) 6.54-6.75 (m, 2 H ) 7.89 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 440 [M + Na] + .
MS ESI / APCI Dual nega: 452 [M + Cl] - .
Reference Example 30-2
4- {3- [7- (Cyclopropylacetyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000119
 参考例３０－１で得られた化合物（８１ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（７５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 0.13 - 0.22 (m, 2 H) 0.48 - 0.61 (m, 2 H) 0.94 - 1.12 (m, 1 H) 1.33 - 1.80 (m, 10 H) 1.92 - 2.07 (m, 2 H) 2.18 - 2.37 (m, 3 H) 3.22 - 3.62 (m, 4 H) 3.97 (t, J=6.4 Hz, 2 H) 6.55 - 6.79 (m, 2 H) 7.96 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 426[M+H]+.
MS ESI/APCI Dual nega: 402[M-H]-.
参考例３１－１
メチル　４－［３－（７－ベンジル－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２－フルオロベンゾアート
Figure JPOXMLDOC01-appb-C000119
 Using the compound (81 mg) obtained in Reference Example 30-1, the reaction and purification were carried out in the same manner as in Reference Example 11-4 to obtain the title compound (75 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 0.13-0.22 (m, 2 H) 0.48-0.61 (m, 2 H) 0.94-1.12 (m, 1 H) 1.33-1.80 (m, 10 H) 1.92 -2.07 (m, 2 H) 2.18-2.37 (m, 3 H) 3.22-3.62 (m, 4 H) 3.97 (t, J = 6.4 Hz, 2 H) 6.55-6.79 (m, 2 H) 7.96 (t , J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 426 [M + H] + .
MS ESI / APCI Dual nega: 402 [MH] - .
Reference Example 31-1
Methyl 4- [3- (7-benzyl-7-azaspiro [3.5] non-2-yl) propoxy] -2-fluorobenzoate
Figure JPOXMLDOC01-appb-C000120
 ベンジルブロミド（２５μＬ）、および参考例１９－２で得られた化合物（５８ｍｇ）のクロロホルム溶液（１．０ｍＬ）を室温で２．５時間撹拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～８０：２０）にて精製し、表題化合物（２９ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.27 - 1.40 (m, 2 H) 1.46 - 1.78 (m, 8 H) 1.86 - 1.98 (m, 2 H) 2.10 - 2.42 (m, 5 H) 3.45 (s, 2 H) 3.89 (s, 3 H) 3.95 (t, J=6.5 Hz, 2 H) 6.56 - 6.73 (m, 2 H) 7.18 - 7.34 (m, 5 H) 7.88 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 426[M+H]+.
参考例３１－２
４－［３－（７－ベンジル－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２－フルオロ安息香酸
Figure JPOXMLDOC01-appb-C000120
 A solution (1.0 mL) of benzyl bromide (25 μL) and the compound obtained in Reference Example 19-2 (58 mg) in chloroform (1.0 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 80:20) to give the title compound (29 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.27-1.40 (m, 2 H) 1.46-1.78 (m, 8 H) 1.86-1.98 (m, 2 H) 2.10-2.42 (m, 5 H) 3.45 (s, 2 H) 3.89 (s, 3 H) 3.95 (t, J = 6.5 Hz, 2 H) 6.56-6.73 (m, 2 H) 7.18-7.34 (m, 5 H) 7.88 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 426 [M + H] + .
Reference Example 31-2
4- [3- (7-Benzyl-7-azaspiro [3.5] non-2-yl) propoxy] -2-fluorobenzoic acid
Figure JPOXMLDOC01-appb-C000121
 参考例３１－１で得られた化合物（２５ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（２１ｍｇ）を得た。
MS ESI/APCI Dual posi: 412[M+H]+.
MS ESI/APCI Dual nega: 410[M-H]-.
参考例３２－１
１－｛［（１－フルオロ－２－メチルプロパン－２－イル）オキシ］カルボニル｝－３－メチル－１Ｈ－イミダゾル－３－イウム　ヨージド
Figure JPOXMLDOC01-appb-C000121
 The compound (25 mg) obtained in Reference Example 31-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (21 mg).
MS ESI / APCI Dual posi: 412 [M + H] + .
MS ESI / APCI Dual nega: 410 [MH] - .
Reference Example 32-1
1-{[(1-Fluoro-2-methylpropan-2-yl) oxy] carbonyl} -3-methyl-1H-imidazol-3-ium iodide
Figure JPOXMLDOC01-appb-C000122
 フルオロ酢酸エチルを用いて、文献記載の方法（Ｂｉｏｏｒｇａｎｉｃ ＆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２０１１，１９，１５８０－１５９３）と同様の方法で反応を行い、表題化合物を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (s, 1 H) 1.63 (s, 3 H) 3.94 (s, 3 H) 4.57 - 4.77 (m, 2 H) 7.84 - 7.89 (m, 1 H) 8.07 - 8.13 (m, 1 H) 9.81 - 9.88 (m, 1 H).
MS ESI/APCI Dual nega: 381[M+Cl]-.
参考例３２－２
１－フルオロ－２－メチルプロパン－２－イル　２－｛３－［３－フルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000122
 The title compound was obtained using ethyl fluoroacetate in the same manner as described in the literature (Bioorganic & Medicinal Chemistry, 2011, 19, 1580-1593).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.62 (s, 1 H) 1.63 (s, 3 H) 3.94 (s, 3 H) 4.57-4.77 (m, 2 H) 7.84-7.89 (m, 1 H) 8.07-8.13 (m, 1 H) 9.81-9.88 (m, 1 H).
MS ESI / APCI Dual nega: 381 [M + Cl] - .
Reference Example 32-2
1-fluoro-2-methylpropan-2-yl 2- {3- [3-fluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000123
 参考例１９－２で得られた化合物（７０ｍｇ）、および参考例３２－１で得られた化合物（１０３ｍｇ）を用いて参考例２２－２と同様にして反応及び精製を行い、表題化合物（８２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.30 - 1.62 (m, 14 H) 1.65 - 1.78 (m, 2 H) 1.91 - 2.03 (m, 2 H) 2.15 - 2.34 (m, 1 H) 3.23 - 3.41 (m, 4 H) 3.89 (s, 3 H) 3.96 (t, J=6.4 Hz, 2 H) 4.33 - 4.59 (m, 2 H) 6.55 - 6.74 (m, 2 H) 7.88 (t, J=8.6 Hz, 1 H).
MS ESI/APCI Dual posi: 476[M+Na]+.
参考例３２－３
２－フルオロ－４－［３－（７－｛［（１－フルオロ－２－メチルプロパン－２－イル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］安息香酸
Figure JPOXMLDOC01-appb-C000123
 The reaction and purification were carried out in the same manner as in Reference Example 22-2 using the compound obtained in Reference Example 19-2 (70 mg) and the compound obtained in Reference Example 32-1 (103 mg), and the title compound (82 mg )
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.30-1.62 (m, 14 H) 1.65-1.78 (m, 2 H) 1.91-2.03 (m, 2 H) 2.15-2.34 (m, 1 H) 3.23 -3.41 (m, 4 H) 3.89 (s, 3 H) 3.96 (t, J = 6.4 Hz, 2 H) 4.33-4.59 (m, 2 H) 6.55-6.74 (m, 2 H) 7.88 (t, J = 8.6 Hz, 1 H).
MS ESI / APCI Dual posi: 476 [M + Na] + .
Reference Example 32-3
2-Fluoro-4- [3- (7-{[(1-fluoro-2-methylpropan-2-yl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] benzoic acid acid
Figure JPOXMLDOC01-appb-C000124
 参考例３２－２で得られた化合物（８０ｍｇ）を用いて参考例１１－４と同様にして反応及び精製を行い、表題化合物（６２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.29 - 1.81 (m, 16 H) 1.90 - 2.05 (m, 2 H) 2.15 - 2.35 (m, 1 H) 3.22 - 3.41 (m, 4 H) 3.98 (t, J=6.5 Hz, 2 H) 4.35 - 4.62 (m, 2 H) 6.58 - 6.77 (m, 2 H) 7.95 (t, J=8.8 Hz, 1 H).
参考例３３－１
プロパン－２－イル　２－（３－｛４－［（１Ｈ－ベンゾトリアゾル－１－イルオキシ）カルボニル］－３－メチルフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000124
 Using the compound (80 mg) obtained in Reference Example 32-2, the reaction and purification were carried out in the same manner as in Reference Example 11-4 to obtain the title compound (62 mg).
1 H NMR (300 MHz, CHLOROFORM-d) d ppm 1.29-1.81 (m, 16 H) 1.90-2.05 (m, 2 H) 2.15-2.35 (m, 1 H) 3.22-3.41 (m, 4 H) 3.98 (t, J = 6.5 Hz, 2 H) 4.35-4.62 (m, 2 H) 6.58-6.77 (m, 2 H) 7.95 (t, J = 8.8 Hz, 1 H).
Reference Example 33-1
Propan-2-yl 2- (3- {4-[(1H-benzotriazol-1-yloxy) carbonyl] -3-methylphenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000125
 参考例１８－３で得られた化合物（１００ｍｇ）をクロロホルム（３２ｍｌ）に溶解し、エタノールアミン（１９μｌ）、１－エチル－３－(３－ジメチルアミノプロピル)カルボジイミド塩酸塩（６２ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（４９ｍｇ）を加え、室温で一晩攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、水層をクロロホルムにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウム乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝７０：３０～６０：４０）にて精製し、表題化合物（５１ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J=6.6 Hz, 6 H) 1.35 - 1.63 (m, 8 H) 1.70 - 1.78 (m, 2 H) 1.94 - 2.03 (m, 2 H) 2.22 - 2.32 (m, 1 H) 2.63 (s, 3 H) 3.24 - 3.43 (m, 4 H) 4.04 (t, J=6.4 Hz, 2 H) 4.85 - 4.93 (m, 1 H) 6.83 - 6.90 (m, 2 H) 7.40 - 7.49 (m, 2 H) 7.51 - 7.57 (m, 1 H) 8.09 (d, J=8.7 Hz, 1 H) 8.34 (d, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 521[M+H]+.
参考例３４－１
Ｎ－シクロプロピル－４－ヒドロキシベンズアミド
Figure JPOXMLDOC01-appb-C000125
 The compound (100 mg) obtained in Reference Example 18-3 was dissolved in chloroform (32 ml), and ethanolamine (19 μl), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (62 mg), 1- Hydroxybenzotriazole monohydrate (49 mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 70: 30-60: 40) to give the title compound (51 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.6 Hz, 6 H) 1.35-1.63 (m, 8 H) 1.70-1.78 (m, 2 H) 1.94-2.03 (m, 2 H) 2.22-2.32 (m, 1 H) 2.63 (s, 3 H) 3.24-3.43 (m, 4 H) 4.04 (t, J = 6.4 Hz, 2 H) 4.85-4.93 (m, 1 H) 6.83- 6.90 (m, 2 H) 7.40-7.49 (m, 2 H) 7.51-7.57 (m, 1 H) 8.09 (d, J = 8.7 Hz, 1 H) 8.34 (d, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 521 [M + H] + .
Reference Example 34-1
N-cyclopropyl-4-hydroxybenzamide
Figure JPOXMLDOC01-appb-C000126
 シクロプロピルアミン（６５５μＬ）、および４－ヒドロキシ安息香酸（１．０ｇ）を用いて、参考例１７－１と同様にして反応および精製を行い、表題化合物（５４０ｍｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 0.47 - 0.58 (m, 2 H) 0.60 - 0.71 (m, 2 H) 2.68 - 2.86 (m, 1 H) 6.76 (d, J=8.2 Hz, 2 H) 7.68 (d, J=8.2 Hz, 2 H) 8.15 (d, J=3.4 Hz, 1 H) 9.93 (br. s., 1 H).
MS ESI/APCI Dual posi: 200[M+Na]+.
参考例３５－１
Ｎ－シクロプロピル－３－ヒドロキシベンズアミド
Figure JPOXMLDOC01-appb-C000126
 Reaction and purification were carried out in the same manner as in Reference Example 17-1 using cyclopropylamine (655 μL) and 4-hydroxybenzoic acid (1.0 g) to obtain the title compound (540 mg).
1 H NMR (300 MHz, DMSO-d6) δ ppm 0.47-0.58 (m, 2 H) 0.60-0.71 (m, 2 H) 2.68-2.86 (m, 1 H) 6.76 (d, J = 8.2 Hz, 2 H) 7.68 (d, J = 8.2 Hz, 2 H) 8.15 (d, J = 3.4 Hz, 1 H) 9.93 (br.s., 1 H).
MS ESI / APCI Dual posi: 200 [M + Na] + .
Reference Example 35-1
N-cyclopropyl-3-hydroxybenzamide
Figure JPOXMLDOC01-appb-C000127
 シクロプロピルアミン（６５５μＬ）、および３－ヒドロキシ安息香酸（１．０ｇ）を用いて、参考例１７－１と同様にして反応および精製を行い、表題化合物（８９２ｍｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 0.50 - 0.60 (m, 2 H) 0.60 - 0.72 (m, 2 H) 2.75 - 2.88 (m, 1 H) 6.81 - 6.95 (m, 1 H) 7.13 - 7.28 (m, 3 H) 8.24 - 8.38 (m, 1 H) 9.60 (s, 1 H) .
MS ESI/APCI Dual posi: 200[M+Na]+.
参考例３６－１
６－クロロ－Ｎ－シクロプロピルピリダジン－３－カルボキサミド
Figure JPOXMLDOC01-appb-C000127
 Reaction and purification were carried out in the same manner as in Reference Example 17-1 using cyclopropylamine (655 μL) and 3-hydroxybenzoic acid (1.0 g) to obtain the title compound (892 mg).
1 H NMR (300 MHz, DMSO-d6) δ ppm 0.50-0.60 (m, 2 H) 0.60-0.72 (m, 2 H) 2.75-2.88 (m, 1 H) 6.81-6.95 (m, 1 H) 7.13 -7.28 (m, 3 H) 8.24-8.38 (m, 1 H) 9.60 (s, 1 H).
MS ESI / APCI Dual posi: 200 [M + Na] + .
Reference Example 36-1
6-Chloro-N-cyclopropylpyridazine-3-carboxamide
Figure JPOXMLDOC01-appb-C000128
 シクロプロピルアミン（２８５μＬ）、および６－クロロピリダジン－３－カルボン酸（５００ｍｇ）を用いて、参考例１７－１と同様にして反応および精製を行い、表題化合物（２２３ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.65 - 0.76 (m, 2 H) 0.87 - 0.99 (m, 2 H) 2.91 - 3.07 (m, 1 H) 7.68 (d, J=8.7 Hz, 1 H) 8.06 (br. s., 1 H) 8.28 (d, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 198[M+H]+, 220[M+Na]+.
参考例３７－１
２－クロロ－Ｎ－シクロプロピルピリミジン－５－カルボキサミド
Figure JPOXMLDOC01-appb-C000128
 Reaction and purification were carried out in the same manner as in Reference Example 17-1 using cyclopropylamine (285 μL) and 6-chloropyridazine-3-carboxylic acid (500 mg) to obtain the title compound (223 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.65-0.76 (m, 2 H) 0.87-0.99 (m, 2 H) 2.91-3.07 (m, 1 H) 7.68 (d, J = 8.7 Hz, 1 H) 8.06 (br.s., 1 H) 8.28 (d, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 198 [M + H] + , 220 [M + Na] + .
Reference Example 37-1
2-Chloro-N-cyclopropylpyrimidine-5-carboxamide
Figure JPOXMLDOC01-appb-C000129
 シクロプロピルアミン（２８５μＬ）、および２－クロロピリミジン－５－カルボン酸（５００ｍｇ）を用いて、参考例１７－１と同様にして反応および精製を行い、表題化合物（３０８ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 0.61 - 0.74 (m, 2 H) 0.85 - 1.02 (m, 2 H) 2.84 - 3.01 (m, 1 H) 6.31 (br. s., 1 H) 8.96 (s, 2 H). 
MS ESI/APCI Dual posi: 198[M+H]+.
参考例３８－１
６－クロロ－２－メチルピリミジン－４－カルボニトリル
Figure JPOXMLDOC01-appb-C000129
 Reaction and purification were carried out in the same manner as in Reference Example 17-1 using cyclopropylamine (285 μL) and 2-chloropyrimidine-5-carboxylic acid (500 mg) to obtain the title compound (308 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δppm 0.61-0.74 (m, 2 H) 0.85-1.02 (m, 2 H) 2.84-3.01 (m, 1 H) 6.31 (br. S., 1 H) 8.96 (s, 2 H).
MS ESI / APCI Dual posi: 198 [M + H] + .
Reference Example 38-1
6-Chloro-2-methylpyrimidine-4-carbonitrile
Figure JPOXMLDOC01-appb-C000130
 ４，６－ジクロロ－２－メチル－ピリミジン（３．０ｇ）、シアン化亜鉛（II）（５．４ｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（２．２ｇ）のテトラヒドロフラン溶液を、マイクロ波照射下、１５０℃で１時間撹拌した。反応液に酢酸エチル、水を加えた後、濾過した。ろ液に飽和食塩水を加えた後、酢酸エチルで抽出を行い、有機層を分離後、硫酸マグネシウムで乾燥した。乾燥剤をろ別後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９９：２～８５：１５）にて精製し、表題化合物（３２４ｍｇ）を得た。
1H NMR (300 MHz, METHANOL-d4) δ ppm 2.76 - 2.85 (m, 3 H) 8.18 - 8.26 (m, 1 H).
参考例３９－１
５－クロロ－Ｎ－シクロプロピルピラジン－２－カルボキサミド
Figure JPOXMLDOC01-appb-C000130
 A tetrahydrofuran solution of 4,6-dichloro-2-methyl-pyrimidine (3.0 g), zinc (II) cyanide (5.4 g), tetrakis (triphenylphosphine) palladium (0) (2.2 g) The mixture was stirred at 150 ° C. for 1 hour under wave irradiation. Ethyl acetate and water were added to the reaction solution, followed by filtration. Saturated saline was added to the filtrate, followed by extraction with ethyl acetate, and the organic layer was separated and dried over magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 99: 2 to 85:15) to give the title compound (324 mg).
1 H NMR (300 MHz, METHANOL-d 4 ) δ ppm 2.76-2.85 (m, 3 H) 8.18-8.26 (m, 1 H).
Reference Example 39-1
5-Chloro-N-cyclopropylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000131
 シクロプロピルアミン（２９０ｍｇ）、および５－クロロピラジン－２－カルボン酸（５００ｍｇ）を用いて、参考例１７－１と同様にして反応および精製を行い、表題化合物（２９２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.62 - 0.73 (m, 2 H) 0.86 - 0.97 (m, 2 H) 2.89 - 3.01 (m, 1 H) 7.68 (br. s., 1 H) 8.48 (d, J=1.4 Hz, 1 H) 9.17 (d, J=1.4 Hz, 1 H).
MS ESI/APCI Dual posi: 220[M+Na]+.
参考例４０－１
１－（ベンジルオキシ）－４－ブロモ－２，５－ジフルオロベンゼン
Figure JPOXMLDOC01-appb-C000131
 Reaction and purification were carried out in the same manner as in Reference Example 17-1 using cyclopropylamine (290 mg) and 5-chloropyrazine-2-carboxylic acid (500 mg) to obtain the title compound (292 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.62-0.73 (m, 2 H) 0.86-0.97 (m, 2 H) 2.89-3.01 (m, 1 H) 7.68 (br. S., 1 H) 8.48 (d, J = 1.4 Hz, 1 H) 9.17 (d, J = 1.4 Hz, 1 H).
MS ESI / APCI Dual posi: 220 [M + Na] + .
Reference Example 40-1
1- (Benzyloxy) -4-bromo-2,5-difluorobenzene
Figure JPOXMLDOC01-appb-C000132
 ４－ブロモ－２，５－ジフルオロフェノール（３．０ｇ）のＮ，Ｎ－ジメチルホルムアミド（１５ｍＬ）溶液に炭酸カリウム（３．０ｇ）、ベンジルブロミド（２ｍＬ）を加え、室温で３時間攪拌した。反応液にメタノール（１０ｍＬ）を加えてしばらく攪拌したのち、水を加えて酢酸エチルで３回抽出した。有機層を水で３回、飽和食塩水で１回洗浄し、硫酸マグネシウムで乾燥した。乾燥剤をろ別後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（４．５ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2 H) 6.77 - 6.85 (m, 1 H) 7.24 - 7.31 (m, 1 H) 7.34 - 7.44 (m, 5 H).
参考例４０－２
４－（ベンジルオキシ）－２，５－ジフルオロ安息香酸
Figure JPOXMLDOC01-appb-C000132
 To a solution of 4-bromo-2,5-difluorophenol (3.0 g) in N, N-dimethylformamide (15 mL) were added potassium carbonate (3.0 g) and benzyl bromide (2 mL), and the mixture was stirred at room temperature for 3 hours. Methanol (10 mL) was added to the reaction solution and stirred for a while, then water was added and extracted three times with ethyl acetate. The organic layer was washed 3 times with water and once with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50) to give the title compound (4.5 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2 H) 6.77-6.85 (m, 1 H) 7.24-7.31 (m, 1 H) 7.34-7.44 (m, 5 H).
Reference Example 40-2
4- (Benzyloxy) -2,5-difluorobenzoic acid
Figure JPOXMLDOC01-appb-C000133
 窒素雰囲気下、参考例４０－１で得られた化合物（２．０ｇ）のジエチルエーテル（１４ｍＬ）溶液を外温－７８度で攪拌しているところに、２．６Ｍノルマルブチルリチウム　ノルマルヘキサン溶液（２．９ｍＬ）を滴下し、同温で３０分攪拌した。ここに、ドライアイスを加え、室温に昇温して２時間攪拌した。反応液に水を加え、２Ｍ塩酸を加えてｐＨ＜２とし、クロロホルムで３回抽出した。有機層を減圧濃縮し、粗精製物として表題化合物（１．９ｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 5.27 (s, 2 H) 7.29 - 7.52 (m, 6 H) 7.59 - 7.72 (m, 1 H).
MS ESI/APCI Dual posi: 265[M+H]+.
MS ESI/APCI Dual nega: 263[M-H]-.
参考例４０－３
メチル　４－（ベンジルオキシ）－２，５－ジフルオロベンゾアート
Figure JPOXMLDOC01-appb-C000133
 In a nitrogen atmosphere, a solution of the compound (2.0 g) obtained in Reference Example 40-1 in diethyl ether (14 mL) was stirred at an external temperature of −78 ° C., and a 2.6 M normal butyl lithium normal hexane solution ( 2.9 mL) was added dropwise and stirred at the same temperature for 30 minutes. Dry ice was added here, and it heated up to room temperature and stirred for 2 hours. Water was added to the reaction solution, and 2M hydrochloric acid was added to adjust the pH to <2. The organic layer was concentrated under reduced pressure to obtain the title compound (1.9 g) as a crude product.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 5.27 (s, 2 H) 7.29-7.52 (m, 6 H) 7.59-7.72 (m, 1 H).
MS ESI / APCI Dual posi: 265 [M + H] + .
MS ESI / APCI Dual nega: 263 [MH] - .
Reference Example 40-3
Methyl 4- (benzyloxy) -2,5-difluorobenzoate
Figure JPOXMLDOC01-appb-C000134
 参考例４０－２で得られた化合物（１．９ｇ）のメタノール（３０ｍＬ）溶液に濃硫酸（５ｍＬ）を加えて、室温で１８時間攪拌した。反応液に水を加えて減圧下溶媒を半分程度留去し、クロロホルムで３回抽出した。有機層を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（１．４ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 5.16 (s, 2 H) 6.70 - 6.82 (m, 1 H) 7.32 - 7.46 (m, 5 H) 7.63 - 7.72 (m, 1 H).
MS ESI/APCI Dual posi: 278[M+H]+.
参考例４０－４
メチル　２，５－ジフルオロ－４－ヒドロキシベンゾアート
Figure JPOXMLDOC01-appb-C000134
 Concentrated sulfuric acid (5 mL) was added to a solution of the compound (1.9 g) obtained in Reference Example 40-2 in methanol (30 mL), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the solvent was distilled off about half under reduced pressure, followed by extraction with chloroform three times. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50) to obtain the title compound (1.4 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 5.16 (s, 2 H) 6.70-6.82 (m, 1 H) 7.32-7.46 (m, 5 H) 7.63-7.72 (m , 1 H).
MS ESI / APCI Dual posi: 278 [M + H] + .
Reference Example 40-4
Methyl 2,5-difluoro-4-hydroxybenzoate
Figure JPOXMLDOC01-appb-C000135
 参考例４０－３で得られた化合物（１．４ｇ）のメタノール（５０ｍＬ）溶液に、１０％パラジウム炭素（２８９ｍｇ）を加えて、水素雰囲気下室温で２時間攪拌した。反応液をクロロホルムで希釈してセライトろ過し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９０：１０～５０：５０）にて精製し、表題化合物（８５６ｍｇ）を得た。
1H NMR (300 MHz, METHANOL-d4) δ ppm 3.86 (s, 3 H) 6.65 - 6.76 (m, 1 H) 7.55 - 7.65 (m, 1 H).
MS ESI/APCI Dual nega: 187[M-H]-.
参考例４０－５
ｔｅｒｔ－ブチル　２－｛３－［２，５－ジフルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000135
 To a solution of the compound obtained in Reference Example 40-3 (1.4 g) in methanol (50 mL) was added 10% palladium carbon (289 mg), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction mixture was diluted with chloroform, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 90: 10-50: 50) to obtain the title compound (856 mg).
1 H NMR (300 MHz, METHANOL-d 4 ) δ ppm 3.86 (s, 3 H) 6.65-6.76 (m, 1 H) 7.55-7.65 (m, 1 H).
MS ESI / APCI Dual nega: 187 [MH] - .
Reference Example 40-5
tert-Butyl 2- {3- [2,5-difluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000136
 参考例４０－４で得られた化合物（３４５ｍｇ）、および参考例２－４で得られた化合物（４００ｍｇ）を用いて、参考例１０－１と同様にして反応および精製を行い、表題化合物（６２５ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 - 1.41 (m, 2 H) 1.41 - 1.47 (m, 11 H) 1.51 - 1.61 (m, 4 H) 1.72 - 1.80 (m, 2 H) 1.93 - 2.01 (m, 2 H) 2.21 - 2.31 (m, 1 H) 3.22 - 3.29 (m, 2 H) 3.31 - 3.38 (m, 2 H) 3.90 (s, 3 H) 4.02 (t, J=6.6 Hz, 2 H) 6.65 - 6.70 (m, 1 H) 7.63 - 7.68 (m, 1 H).
MS ESI posi: 476[M+Na]+.
参考例４０－６
メチル　４－［３－（７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２，５－ジフルオロベンゾアート
Figure JPOXMLDOC01-appb-C000136
 Using the compound (345 mg) obtained in Reference Example 40-4 and the compound (400 mg) obtained in Reference Example 2-4, the reaction and purification were carried out in the same manner as in Reference Example 10-1, and the title compound ( 625 mg) was obtained.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35-1.41 (m, 2 H) 1.41-1.47 (m, 11 H) 1.51-1.61 (m, 4 H) 1.72-1.80 (m, 2 H) 1.93 -2.01 (m, 2 H) 2.21-2.31 (m, 1 H) 3.22-3.29 (m, 2 H) 3.31-3.38 (m, 2 H) 3.90 (s, 3 H) 4.02 (t, J = 6.6 Hz , 2 H) 6.65-6.70 (m, 1 H) 7.63-7.68 (m, 1 H).
MS ESI posi: 476 [M + Na] + .
Reference Example 40-6
Methyl 4- [3- (7-azaspiro [3.5] non-2-yl) propoxy] -2,5-difluorobenzoate
Figure JPOXMLDOC01-appb-C000137
 参考例４０－５で得られた化合物（６２５ｍｇ）を用いて、参考例１２－２と同様にして反応および精製を行い、表題化合物（５９０ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.36 - 1.44 (m, 2 H) 1.53 - 1.65 (m, 4 H) 1.68 - 1.80 (m, 4 H) 1.95 - 2.03 (m, 2 H) 2.20 - 2.31 (m, 1 H) 2.79 - 2.87 (m, 2 H) 2.87 - 2.96 (m, 2 H) 3.90 (s, 3 H) 4.01 (t, J=6.4 Hz, 2 H) 6.64 - 6.70 (m, 1 H) 7.62 - 7.69 (m, 1 H).
MS ESI posi: 354[M+H]+.
参考例４０－７
プロパン－２－イル　２－｛３－［２，５－ジフルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000137
 Using the compound (625 mg) obtained in Reference Example 40-5, the reaction and purification were conducted in the same manner as in Reference Example 12-2 to obtain the title compound (590 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.36-1.44 (m, 2 H) 1.53-1.65 (m, 4 H) 1.68-1.80 (m, 4 H) 1.95-2.03 (m, 2 H) 2.20 -2.31 (m, 1 H) 2.79-2.87 (m, 2 H) 2.87-2.96 (m, 2 H) 3.90 (s, 3 H) 4.01 (t, J = 6.4 Hz, 2 H) 6.64-6.70 (m , 1 H) 7.62-7.69 (m, 1 H).
MS ESI posi: 354 [M + H] + .
Reference Example 40-7
Propan-2-yl 2- {3- [2,5-difluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000138
 参考例４０－６で得られた化合物（２９０ｍｇ）、およびトリエチルアミン（２４９ｍｇ）のクロロホルム（８．２ｍｌ）溶液に、クロロぎ酸イソプロピル（１２１ｍｇ）を加え、室温にて１時間撹拌した。反応液に水を加えてクロロホルムにて抽出後、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝４：１）にて精製し、表題化合物（２８５ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.36 - 1.42 (m, 2 H) 1.42 - 1.49 (m, 2 H) 1.51 - 1.63 (m, 4 H) 1.72 - 1.81 (m, 2 H) 1.93 - 2.02 (m, 2 H) 2.21 - 2.31 (m, 1 H) 3.25 - 3.33 (m, 2 H) 3.34 - 3.43 (m, 2 H) 3.90 (s, 3 H) 4.02 (t, J=6.6 Hz, 2 H) 4.86 - 4.94 (m, 1 H) 6.64 - 6.71 (m, 1 H) 7.63 - 7.68 (m, 1 H).
MS ESI posi: 440[M+H]+, 462[M+Na]+.
参考例４０－８
２，５－ジフルオロ－４－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000138
 To a solution of the compound obtained in Reference Example 40-6 (290 mg) and triethylamine (249 mg) in chloroform (8.2 ml) was added isopropyl chloroformate (121 mg), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 4: 1) to obtain the title compound (285 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.36-1.42 (m, 2 H) 1.42-1.49 (m, 2 H) 1.51-1.63 (m, 4 H) 1.72-1.81 (m, 2 H) 1.93-2.02 (m, 2 H) 2.21-2.31 (m, 1 H) 3.25-3.33 (m, 2 H) 3.34-3.43 (m, 2 H) 3.90 (s , 3 H) 4.02 (t, J = 6.6 Hz, 2 H) 4.86-4.94 (m, 1 H) 6.64-6.71 (m, 1 H) 7.63-7.68 (m, 1 H).
MS ESI posi: 440 [M + H] + , 462 [M + Na] + .
Reference Example 40-8
2,5-difluoro-4- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
参考例４０－７で得られた化合物（２８５ｍｇ）を用いて、参考例１１－４と同様にして反応および精製を行い、表題化合物（２８０ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.36 - 1.42 (m, 2 H) 1.43 - 1.49 (m, 2 H) 1.53 - 1.62 (m, 4 H) 1.74 - 1.82 (m, 2 H) 1.94 - 2.01 (m, 2 H) 2.22 - 2.32 (m, 1 H) 3.26 - 3.34 (m, 2 H) 3.35 - 3.44 (m, 2 H) 4.04 (t, J=6.4 Hz, 2 H) 4.87 - 4.94 (m, 1 H) 6.67 - 6.73 (m, 1 H) 7.68 - 7.74 (m, 1 H).
MS ESI posi: 426[M+H]+, 448[M+Na]+.
MS ESI nega: 424[M-H]-.
参考例４１－１
メチル　２，６－ジフルオロ－４－ヒドロキシベンゾアート Using the compound (285 mg) obtained in Reference Example 40-7, the reaction and purification were conducted in the same manner as in Reference Example 11-4 to obtain the title compound (280 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.36-1.42 (m, 2 H) 1.43-1.49 (m, 2 H) 1.53-1.62 (m, 4 H) 1.74-1.82 (m, 2 H) 1.94-2.01 (m, 2 H) 2.22-2.32 (m, 1 H) 3.26-3.34 (m, 2 H) 3.35-3.44 (m, 2 H) 4.04 (t , J = 6.4 Hz, 2 H) 4.87-4.94 (m, 1 H) 6.67-6.73 (m, 1 H) 7.68-7.74 (m, 1 H).
MS ESI posi: 426 [M + H] + , 448 [M + Na] + .
MS ESI nega: 424 [MH] - .
Reference Example 41-1
Methyl 2,6-difluoro-4-hydroxybenzoate
Figure JPOXMLDOC01-appb-C000140
 ２，６－ジフルオロ－４－ヒドロキシ安息香酸（３００ｍｇ）、およびメタノール（５５１ｍｇ）のクロロホルム溶液（５．７４ｍＬ）に、１－エチル－３－(３－ジメチルアミノプロピル)カルボジイミド塩酸塩（３９６ｍｇ）、Ｎ，Ｎ－ジメチル－４－アミノピリジン（２１．０ｍｇ）を加え、室温にて３時間攪拌した。反応溶液に水を加え、水層をクロロホルムにて抽出後、有機層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝２：１～１：１）にて精製し、表題化合物（２７５ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 5.76 (s, 1 H) 6.41 - 6.47 (m, 2 H).
MS ESI posi: 189[M+H]+.
MS ESI nega: 187[M-H]-.
参考例４１－２
２，６－ジフルオロ－４－（３－｛７－［（プロパン－２－イルオキシ）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000140
 To a chloroform solution (5.74 mL) of 2,6-difluoro-4-hydroxybenzoic acid (300 mg) and methanol (551 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (396 mg), N, N-dimethyl-4-aminopyridine (21.0 mg) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, the aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 2: 1 to 1: 1) to give the title compound (275 mg). It was.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3 H) 5.76 (s, 1 H) 6.41-6.47 (m, 2 H).
MS ESI posi: 189 [M + H] + .
MS ESI nega: 187 [MH] - .
Reference Example 41-2
2,6-Difluoro-4- (3- {7-[(propan-2-yloxy) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000141
 参考例４１－１で得られた化合物（２７４ｍｇ）、および参考例２－４で得られた化合物（３１８ｍｇ）を用いて、参考例４０－５～参考例４０－８と同様にして反応および精製を行い、表題化合物（１６６ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.36 - 1.42 (m, 2 H) 1.42 - 1.49 (m, 2 H) 1.52 - 1.61 (m, 4 H) 1.68 - 1.74 (m, 2 H) 1.94 - 2.01 (m, 2 H) 2.20 - 2.30 (m, 1 H) 3.26 - 3.34 (m, 2 H) 3.35 - 3.43 (m, 2 H) 3.95 (t, J=6.4 Hz, 2 H) 4.86 - 4.95 (m, 1 H) 6.48 (d, J=10.3 Hz, 2 H).
MS ESI posi: 426[M+H]+, 448[M+Na]+.
参考例４２－１
１－メチルシクロプロピル　２－｛３－［２，５－ジフルオロ－４－（メトキシカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000141
 Using the compound (274 mg) obtained in Reference Example 41-1 and the compound (318 mg) obtained in Reference Example 2-4, the reaction and purification were carried out in the same manner as in Reference Example 40-5 to Reference Example 40-8. To give the title compound (166 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.36-1.42 (m, 2 H) 1.42-1.49 (m, 2 H) 1.52-1.61 (m, 4 H) 1.68-1.74 (m, 2 H) 1.94-2.01 (m, 2 H) 2.20-2.30 (m, 1 H) 3.26-3.34 (m, 2 H) 3.35-3.43 (m, 2 H) 3.95 (t , J = 6.4 Hz, 2 H) 4.86-4.95 (m, 1 H) 6.48 (d, J = 10.3 Hz, 2 H).
MS ESI posi: 426 [M + H] + , 448 [M + Na] + .
Reference Example 42-1
1-methylcyclopropyl 2- {3- [2,5-difluoro-4- (methoxycarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000142
 参考例４０－５で得られた化合物（６２５ｍｇ）を用いて、実施例６－１と同様にして反応および精製を行い、表題化合物（３０９ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.58 - 0.63 (m, 2 H) 0.82 - 0.88 (m, 2 H) 1.35 - 1.49 (m, 4 H) 1.50 - 1.62 (m, 7 H) 1.72 - 1.79 (m, 2 H) 1.93 - 2.01 (m, 2 H) 2.21 - 2.31 (m, 1 H) 3.16 - 3.44 (m, 4 H) 3.90 (s, 3 H) 4.01 (t, J=6.6 Hz, 2 H) 6.64 - 6.70 (m, 1 H) 7.62 - 7.68 (m, 1 H).
MS ESI posi: 474[M+Na]+.
参考例４２－２
２，５－ジフルオロ－４－［３－（７－｛［（１－メチルシクロプロピル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］安息香酸
Figure JPOXMLDOC01-appb-C000142
 The compound (625 mg) obtained in Reference Example 40-5 was subjected to reaction and purification in the same manner as in Example 6-1 to obtain the title compound (309 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.58-0.63 (m, 2 H) 0.82-0.88 (m, 2 H) 1.35-1.49 (m, 4 H) 1.50-1.62 (m, 7 H) 1.72 -1.79 (m, 2 H) 1.93-2.01 (m, 2 H) 2.21-2.31 (m, 1 H) 3.16-3.44 (m, 4 H) 3.90 (s, 3 H) 4.01 (t, J = 6.6 Hz , 2 H) 6.64-6.70 (m, 1 H) 7.62-7.68 (m, 1 H).
MS ESI posi: 474 [M + Na] + .
Reference Example 42-2
2,5-difluoro-4- [3- (7-{[(1-methylcyclopropyl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] benzoic acid
参考例４２－１で得られた化合物（３０９ｍｇ）を用いて、参考例１１－４と同様にして反応および精製を行い、表題化合物（２６９ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.58 - 0.64 (m, 2 H) 0.82 - 0.88 (m, 2 H) 1.35 - 1.49 (m, 4 H) 1.51 - 1.62 (m, 7 H) 1.73 - 1.81 (m, 2 H) 1.93 - 2.01 (m, 2 H) 2.21 - 2.31 (m, 1 H) 3.16 - 3.44 (m, 4 H) 4.03 (t, J=6.4 Hz, 2 H) 6.67 - 6.73 (m, 1 H) 7.68 - 7.74 (m, 1 H).
MS ESI posi: 460[M+Na]+.
MS ESI nega: 436[M-H]-.
参考例４３－１
２，６－ジフルオロ－４－［３－（７－｛［（１－メチルシクロプロピル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］安息香酸 The compound (309 mg) obtained in Reference Example 42-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the title compound (269 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.58-0.64 (m, 2 H) 0.82-0.88 (m, 2 H) 1.35-1.49 (m, 4 H) 1.51-1.62 (m, 7 H) 1.73 -1.81 (m, 2 H) 1.93-2.01 (m, 2 H) 2.21-2.31 (m, 1 H) 3.16-3.44 (m, 4 H) 4.03 (t, J = 6.4 Hz, 2 H) 6.67-6.73 (m, 1 H) 7.68-7.74 (m, 1 H).
MS ESI posi: 460 [M + Na] + .
MS ESI nega: 436 [MH] - .
Reference Example 43-1
2,6-Difluoro-4- [3- (7-{[(1-methylcyclopropyl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] benzoic acid
Figure JPOXMLDOC01-appb-C000144
 参考例４１－１で得られた化合物（２７４ｍｇ）、および参考例２－４で得られた化合物（３１８ｍｇ）を用いて、参考例４０－５、および、参考例４２－１～参考例４２－２と同様にして反応および精製を行い、表題化合物（６０ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.59 - 0.63 (m, 2 H) 0.83 - 0.87 (m, 2 H) 1.35 - 1.48 (m, 4 H) 1.51 - 1.58 (m, 7 H) 1.67 - 1.74 (m, 2 H) 1.94 - 2.00 (m, 2 H) 2.20 - 2.28 (m, 1 H) 3.19 - 3.42 (m, 4 H) 3.94 (t, J=6.4 Hz, 2 H) 6.48 (d, J=10.3 Hz, 2 H).
MS ESI posi: 460[M+Na]+.
参考例４４－１
メチル　２－フルオロ－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンゾアート
Figure JPOXMLDOC01-appb-C000144
 Using the compound (274 mg) obtained in Reference Example 41-1 and the compound (318 mg) obtained in Reference Example 2-4, Reference Example 40-5 and Reference Examples 42-1 to 42- Reaction and purification were carried out in the same manner as in 2 to obtain the title compound (60 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.59-0.63 (m, 2 H) 0.83-0.87 (m, 2 H) 1.35-1.48 (m, 4 H) 1.51-1.58 (m, 7 H) 1.67 -1.74 (m, 2 H) 1.94-2.00 (m, 2 H) 2.20-2.28 (m, 1 H) 3.19-3.42 (m, 4 H) 3.94 (t, J = 6.4 Hz, 2 H) 6.48 (d , J = 10.3 Hz, 2 H).
MS ESI posi: 460 [M + Na] + .
Reference Example 44-1
Methyl 2-fluoro-4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoate
Figure JPOXMLDOC01-appb-C000145
 参考例１９－２で得られた化合物（１１１ｍｇ）、１－メチルシクロプロパン－１－カルボン酸（５０ｍｇ）、およびトリエチルアミン（１３８μＬ）のＮ，Ｎ－ジメチルホルムアミド溶液に５０％無水プロピル燐酸　Ｎ，Ｎ－ジメチルホルムアミド溶液（１３８μＬ）を加え、室温で１４時間撹拌した。反応液を酢酸エチルで希釈後、有機層を水で３回、飽和食塩水で１回洗浄し、硫酸マグネシウムで乾燥した。乾燥剤をろ別後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝８５：１５～０：１００）にて精製し、表題化合物（１９６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm  0.52 - 0.58 (m, 2 H) 0.88 - 0.94 (m, 2 H) 1.29 (s, 3 H) 1.38 - 1.52 (m, 4 H) 1.55 - 1.65 (m, 4 H) 1.66 - 1.78 (m, 2 H) 1.96 - 2.07 (m, 2 H) 2.21 - 2.36 (m, 1 H) 3.43 - 3.60 (m, 4 H) 3.90 (s, 3 H) 3.97 (t, J=6.3 Hz, 2 H) 6.57 - 6.65 (m, 1 H) 6.67 - 6.73 (m, 1 H) 7.84 - 7.92 (m, 1 H).
MS ESI/APCI Dual posi: 418[M+H]+.
参考例４４－２
２－フルオロ－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000145
 To a solution of the compound obtained in Reference Example 19-2 (111 mg), 1-methylcyclopropane-1-carboxylic acid (50 mg), and triethylamine (138 μL) in N, N-dimethylformamide, 50% propylphosphoric anhydride N, N -Dimethylformamide solution (138 μL) was added and stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed 3 times with water and once with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 85: 15 to 0: 100) to give the title compound (196 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.52-0.58 (m, 2 H) 0.88-0.94 (m, 2 H) 1.29 (s, 3 H) 1.38-1.52 (m, 4 H) 1.55-1.65 (m, 4 H) 1.66-1.78 (m, 2 H) 1.96-2.07 (m, 2 H) 2.21-2.36 (m, 1 H) 3.43-3.60 (m, 4 H) 3.90 (s, 3 H) 3.97 (t, J = 6.3 Hz, 2 H) 6.57-6.65 (m, 1 H) 6.67-6.73 (m, 1 H) 7.84-7.92 (m, 1 H).
MS ESI / APCI Dual posi: 418 [M + H] + .
Reference Example 44-2
2-Fluoro-4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000146
 参考例４４－１で得られた化合物（９６ｍｇ）を用いて、参考例１１－４と同様にして反応および精製を行い、粗表題化合物（１０１ｍｇ）を得た。
1H NMR (300 MHz, METHANOL-d4) δ ppm 0.84 - 0.90 (m, 2 H) 1.28 (s, 3 H) 1.41 - 1.80 (m, 10 H) 1.98 - 2.10 (m, 2 H) 2.24 - 2.38 (m, 1 H) 3.43 - 3.67 (m, 4 H) 4.03 (t, J=6.3 Hz, 2 H) 6.69 - 6.76 (m, 1 H) 6.76 - 6.82 (m, 1 H) 7.83 - 7.92 (m, 1 H).
MS ESI/APCI Dual posi: 404[M+H]+.
MS ESI/APCI Dual nega: 402[M-H]-.
参考例４５－１
メチル　２，５－ジフルオロ－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンゾアート
Figure JPOXMLDOC01-appb-C000146
 The compound (96 mg) obtained in Reference Example 44-1 was used for reaction and purification in the same manner as in Reference Example 11-4 to obtain the crude title compound (101 mg).
1 H NMR (300 MHz, METHANOL-d 4 ) δ ppm 0.84-0.90 (m, 2 H) 1.28 (s, 3 H) 1.41-1.80 (m, 10 H) 1.98-2.10 (m, 2 H) 2.24- 2.38 (m, 1 H) 3.43-3.67 (m, 4 H) 4.03 (t, J = 6.3 Hz, 2 H) 6.69-6.76 (m, 1 H) 6.76-6.82 (m, 1 H) 7.83-7.92 ( m, 1 H).
MS ESI / APCI Dual posi: 404 [M + H] + .
MS ESI / APCI Dual nega: 402 [MH] - .
Reference Example 45-1
Methyl 2,5-difluoro-4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoate
Figure JPOXMLDOC01-appb-C000147
 参考例４０－５で得られた化合物（１５７ｍｇ）を用いて、参考例１２－２、および参考例４４－１と同様にして反応および精製を行い、表題化合物（２３４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.53 - 0.59 (m, 2 H) 0.87 - 0.94 (m, 2 H) 1.29 (s, 3 H) 1.38 - 1.52 (m, 4 H) 1.55 - 1.63 (m, 4 H) 1.72 - 1.83 (m, 2 H) 1.96 - 2.06 (m, 2 H) 2.22 - 2.36 (m, 1 H) 3.45 - 3.61 (m, 4 H) 3.90 (s, 3 H) 4.02 (t, J=6.4 Hz, 2 H) 6.63 - 6.72 (m, 1 H) 7.62 - 7.70 (m, 1 H).
MS ESI/APCI Dual posi: 436[M+H]+.
参考例４５－２
２，５－ジフルオロ－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）安息香酸
Figure JPOXMLDOC01-appb-C000147
 Using the compound (157 mg) obtained in Reference Example 40-5, the reaction and purification were carried out in the same manner as in Reference Example 12-2 and Reference Example 44-1 to obtain the title compound (234 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.53-0.59 (m, 2 H) 0.87-0.94 (m, 2 H) 1.29 (s, 3 H) 1.38-1.52 (m, 4 H) 1.55-1.63 (m, 4 H) 1.72-1.83 (m, 2 H) 1.96-2.06 (m, 2 H) 2.22-2.36 (m, 1 H) 3.45-3.61 (m, 4 H) 3.90 (s, 3 H) 4.02 (t, J = 6.4 Hz, 2 H) 6.63-6.72 (m, 1 H) 7.62-7.70 (m, 1 H).
MS ESI / APCI Dual posi: 436 [M + H] + .
Reference Example 45-2
2,5-difluoro-4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzoic acid
Figure JPOXMLDOC01-appb-C000148
 参考例４５－１で得られた化合物（１６９ｍｇ）を用いて、参考例１１－４と同様にして反応および精製を行い、表題化合物（１７９ｍｇ）を得た。
1H NMR (300 MHz, METHANOL-d4) δ ppm 0.56 - 0.64 (m, 2 H) 0.82 - 0.90 (m, 2 H) 1.28 (s, 3 H) 1.40 - 1.54 (m, 4 H) 1.55 - 1.68 (m, 4 H) 1.70 - 1.83 (m, 2 H) 1.98 - 2.11 (m, 2 H) 2.24 - 2.41 (m, 1 H) 3.40 - 3.72 (m, 4 H) 4.03 - 4.15 (m, 2 H) 6.88 - 7.02 (m, 1 H) 7.55 - 7.70 (m, 1 H).
MS ESI/APCI Dual posi: 422[M+H]+.
MS ESI/APCI Dual nega: 420[M-H]-.
参考例４６－１
２－フルオロ－４－ヒドロキシ－Ｎ－（２－メトキシエチル）ベンズアミド
Figure JPOXMLDOC01-appb-C000148
 Using the compound (169 mg) obtained in Reference Example 45-1, the reaction and purification were conducted in the same manner as in Reference Example 11-4 to obtain the title compound (179 mg).
1 H NMR (300 MHz, METHANOL-d 4 ) δ ppm 0.56-0.64 (m, 2 H) 0.82-0.90 (m, 2 H) 1.28 (s, 3 H) 1.40-1.54 (m, 4 H) 1.55- 1.68 (m, 4 H) 1.70-1.83 (m, 2 H) 1.98-2.11 (m, 2 H) 2.24-2.41 (m, 1 H) 3.40-3.72 (m, 4 H) 4.03-4.15 (m, 2 H) 6.88-7.02 (m, 1 H) 7.55-7.70 (m, 1 H).
MS ESI / APCI Dual posi: 422 [M + H] + .
MS ESI / APCI Dual nega: 420 [MH] - .
Reference Example 46-1
2-Fluoro-4-hydroxy-N- (2-methoxyethyl) benzamide
Figure JPOXMLDOC01-appb-C000149
 ２－フルオロ－４－ヒドロキシ安息香酸（２３４ｍｇ）、および２－メトキシエチルアミン（１５６μＬ）を用いて、参考例４４－１と同様にして反応および精製を行い、表題化合物（９６ｍｇ）を得た。
1H NMR (300 MHz, METHANOL-d4) δ ppm 3.38 (s, 3 H) 3.49 - 3.58 (m, 4 H) 6.51 - 6.60 (m, 1 H) 6.63 - 6.72 (m, 1 H) 7.62 - 7.74 (m, 1 H).
MS ESI/APCI Dual posi: 214[M+H]+.
MS ESI/APCI Dual nega: 212[M-H]-.
参考例４８－１
ｔｅｒｔ－ブチル　２－｛３－［（５－ブロモピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000149
 Reaction and purification were carried out in the same manner as in Reference Example 44-1 using 2-fluoro-4-hydroxybenzoic acid (234 mg) and 2-methoxyethylamine (156 μL) to obtain the title compound (96 mg).
1 H NMR (300 MHz, METHANOL-d 4 ) δ ppm 3.38 (s, 3 H) 3.49-3.58 (m, 4 H) 6.51-6.60 (m, 1 H) 6.63-6.72 (m, 1 H) 7.62- 7.74 (m, 1 H).
MS ESI / APCI Dual posi: 214 [M + H] + .
MS ESI / APCI Dual nega: 212 [MH] - .
Reference Example 48-1
tert-Butyl 2- {3-[(5-Bromopyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000150
 参考例２－４で得られた化合物（２００ｍｇ）、および２－ブロモ－５－ヒドロキシピラジン（１８５ｍｇ）を用いて、参考例１０－１と同様にして反応および精製を行い、表題化合物（２２４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ 1.32 - 1.59 (m, 8 H) 1.45 (s, 9 H) 1.63 - 1.77 (m, 2 H) 1.89 - 2.03 (m, 2 H) 2.14 - 2.32 (m, 1 H) 3.19 - 3.39 (m, 4 H) 4.26 (t, J=6.5 Hz, 2 H) 7.97 - 8.01 (m, 1 H) 8.14 - 8.19 (m, 1 H).
MS ESI/APCI Dual posi: 462[M+Na]+.
参考例４９－１
５－ブロモ－３－メチルピラジン－２－オール
Figure JPOXMLDOC01-appb-C000150
 Using the compound (200 mg) obtained in Reference Example 2-4 and 2-bromo-5-hydroxypyrazine (185 mg), the reaction and purification were carried out in the same manner as in Reference Example 10-1, and the title compound (224 mg) Got.
1 H NMR (300 MHz, CHLOROFORM-d) δ 1.32-1.59 (m, 8 H) 1.45 (s, 9 H) 1.63-1.77 (m, 2 H) 1.89-2.03 (m, 2 H) 2.14-2.32 ( m, 1 H) 3.19-3.39 (m, 4 H) 4.26 (t, J = 6.5 Hz, 2 H) 7.97-8.01 (m, 1 H) 8.14-8.19 (m, 1 H).
MS ESI / APCI Dual posi: 462 [M + Na] + .
Reference Example 49-1
5-Bromo-3-methylpyrazin-2-ol
Figure JPOXMLDOC01-appb-C000151
 ２－ヒドロキシ－３－メチルピラジン（１．５ｇ）をＮ，Ｎ－ジメチルホルムアミド
（２７ｍＬ）に溶解し、氷冷下にてＮ－ブロモスクシンイミド（２．６７ｇ）を加えた後、徐々に室温へと昇温させ、一晩撹拌した。反応液に水を加え、クロロホルム／イソプロパノールの混合溶液で抽出し、硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝５０：５０～２５：７５）にて精製し、表題化合物（２．４ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.45 - 2.51 (m, 3 H) 7.36 - 7.40 (m, 1 H).
MS ESI/APCI Dual posi: 189[M+H]+.
MS ESI/APCI Dual nega: 187[M-H]-.
参考例４９－２
ｔｅｒｔ－ブチル　２－｛３－［（５－ブロモ－３－メチルピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000151
 2-Hydroxy-3-methylpyrazine (1.5 g) was dissolved in N, N-dimethylformamide (27 mL), N-bromosuccinimide (2.67 g) was added under ice-cooling, and then gradually brought to room temperature. And the mixture was stirred overnight. Water was added to the reaction solution, extracted with a mixed solution of chloroform / isopropanol, and dried over magnesium sulfate. After the desiccant was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 50: 50 to 25:75) to give the title compound (2.4 g). Obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.45-2.51 (m, 3 H) 7.36-7.40 (m, 1 H).
MS ESI / APCI Dual posi: 189 [M + H] + .
MS ESI / APCI Dual nega: 187 [MH] - .
Reference Example 49-2
tert-Butyl 2- {3-[(5-Bromo-3-methylpyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000152
 参考例２－４で得られた化合物（１００ｍｇ）、および参考例４９－１で得られた化合物（２００ｍｇ）を用いて、参考例１０－１と同様にして反応および精製を行い、表題化合物（１３７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.21 - 1.61 (m, 8 H) 1.44 (s, 9 H) 1.63 - 1.78 (m, 2 H) 1.90 - 2.03 (m, 2 H) 2.16 - 2.34 (m, 1 H) 2.41 - 2.47 (m, 3 H) 3.21 - 3.39 (m, 4 H) 4.26 (t, J=6.6 Hz, 2 H) 7.96 - 8.02 (m, 1 H) 
MS ESI/APCI Dual posi: 476[M+Na]+.
参考例５０－１
メチル　５－メトキシピラジン－２－カルボキシラート
Figure JPOXMLDOC01-appb-C000152
 Using the compound (100 mg) obtained in Reference Example 2-4 and the compound (200 mg) obtained in Reference Example 49-1, the reaction and purification were carried out in the same manner as in Reference Example 10-1, and the title compound ( 137 mg) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δppm 1.21-1.61 (m, 8 H) 1.44 (s, 9 H) 1.63-1.78 (m, 2 H) 1.90-2.03 (m, 2 H) 2.16-2.34 ( m, 1 H) 2.41-2.47 (m, 3 H) 3.21-3.39 (m, 4 H) 4.26 (t, J = 6.6 Hz, 2 H) 7.96-8.02 (m, 1 H)
MS ESI / APCI Dual posi: 476 [M + Na] + .
Reference Example 50-1
Methyl 5-methoxypyrazine-2-carboxylate
Figure JPOXMLDOC01-appb-C000153
 メチル　５－クロロピラジン－２－カルボキシラート（２．４ｇ）をメタノール（１４０ｍＬ）に溶解し、氷冷下にて２８％ナトリウムメトキシド　メタノール溶液（２．７ｍＬ）を加えた。氷浴をはずして１時間撹拌し、反応液を減圧下留去した。残渣に飽和塩化アンモニウム水を加え、酢酸エチルで抽出し、有機層をフェーズセパレーターに通した後、減圧下留去し、表題化合物（２．１ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.0 - 4.0 (m, 3 H) 4.0 - 4.1 (m, 3 H) 8.3 - 8.3 (m, 1 H) 8.9 - 8.9 (m, 1 H).
MS ESI/APCI Dual posi: 191[M+Na]+.
参考例５０－２
メチル　５－ヒドロキシピラジン－２－カルボキシラート
Figure JPOXMLDOC01-appb-C000153
 Methyl 5-chloropyrazine-2-carboxylate (2.4 g) was dissolved in methanol (140 mL), and 28% sodium methoxide methanol solution (2.7 mL) was added under ice cooling. The ice bath was removed and the mixture was stirred for 1 hour, and the reaction solution was evaporated under reduced pressure. Saturated aqueous ammonium chloride was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was passed through a phase separator and then evaporated under reduced pressure to obtain the title compound (2.1 g).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.0-4.0 (m, 3 H) 4.0-4.1 (m, 3 H) 8.3-8.3 (m, 1 H) 8.9-8.9 (m, 1 H).
MS ESI / APCI Dual posi: 191 [M + Na] + .
Reference Example 50-2
Methyl 5-hydroxypyrazine-2-carboxylate
Figure JPOXMLDOC01-appb-C000154
 参考例５０－１で得られた化合物（２．１ｇ）をアセトニトリル（１４０ｍＬ）に溶解し、クロロトリメチルシラン（６ｍＬ）およびよう化カリウム（１１．５ｇ）を加え、６０℃で一晩撹拌した。飽和チオ硫酸ナトリウム水溶液を加え、減圧下留去後、水層をクロロホルム／メタノールの混合溶液で抽出し、有機層を硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９７：３～９０：１０）にて精製し、表題化合物（１．７ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.98 - 4.02 (m, 3 H) 4.04 - 4.08 (m, 3 H) 8.26 - 8.30 (m, 1 H) 8.87 - 8.91 (m, 1 H).
MS ESI/APCI Dual posi: 177[M+Na]+.
MS ESI/APCI Dual nega: 153[M-H]-.
参考例５０－３
１－メチルシクロプロピル　２－（３－｛［５－（メトキシカルボニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000154
 The compound (2.1 g) obtained in Reference Example 50-1 was dissolved in acetonitrile (140 mL), chlorotrimethylsilane (6 mL) and potassium iodide (11.5 g) were added, and the mixture was stirred at 60 ° C. overnight. A saturated aqueous sodium thiosulfate solution was added, and after distilling off under reduced pressure, the aqueous layer was extracted with a mixed solution of chloroform / methanol, and the organic layer was dried over magnesium sulfate. After the desiccant was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3-90: 10) to obtain the title compound (1.7 g). .
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.98-4.02 (m, 3 H) 4.04-4.08 (m, 3 H) 8.26-8.30 (m, 1 H) 8.87-8.91 (m, 1 H).
MS ESI / APCI Dual posi: 177 [M + Na] + .
MS ESI / APCI Dual nega: 153 [MH] - .
Reference Example 50-3
1-methylcyclopropyl 2- (3-{[5- (methoxycarbonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000155
 参考例２－４で得られた化合物（３４０ｍｇ）、および参考例５０－２で得られた化合物（７６０ｍｇ）を用いて、参考例１０－１、参考例１２－２および参考例１２－３と同様にして反応および精製を行い、表題化合物（２７０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.56 - 0.65 (m, 2 H) 0.80 - 0.89 (m, 2 H) 1.32 - 1.61 (m, 8 H) 1.53 (s, 3 H) 1.65 - 1.79 (m, 2 H) 1.91 - 2.03 (m, 2 H) 2.16 - 2.35 (m, 1 H) 3.16 - 3.43 (m, 4 H) 3.97 - 4.01 (m, 3 H) 4.37 (t, J=6.6 Hz, 2 H) 8.24 - 8.27 (m, 1 H) 8.83 - 8.88 (m, 1 H).
MS ESI/APCI Dual posi: 440[M+Na]+.
参考例５０－４
５－［３－（７－｛［（１－メチルシクロプロピル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］ピラジン－２－カルボン酸
Figure JPOXMLDOC01-appb-C000155
 Using the compound obtained in Reference Example 2-4 (340 mg) and the compound obtained in Reference Example 50-2 (760 mg), Reference Example 10-1, Reference Example 12-2 and Reference Example 12-3 The reaction and purification were conducted in the same manner to obtain the title compound (270 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.56-0.65 (m, 2 H) 0.80-0.89 (m, 2 H) 1.32-1.61 (m, 8 H) 1.53 (s, 3 H) 1.65-1.79 (m, 2 H) 1.91-2.03 (m, 2 H) 2.16-2.35 (m, 1 H) 3.16-3.43 (m, 4 H) 3.97-4.01 (m, 3 H) 4.37 (t, J = 6.6 Hz , 2 H) 8.24-8.27 (m, 1 H) 8.83-8.88 (m, 1 H).
MS ESI / APCI Dual posi: 440 [M + Na] + .
Reference Example 50-4
5- [3- (7-{[(1-Methylcyclopropyl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] pyrazine-2-carboxylic acid
Figure JPOXMLDOC01-appb-C000156
 参考例５０－３で得られた化合物（２７０ｍｇ）を用い、参考例１１－４と同様の方法で反応、精製を行い、表題化合物（２２６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57 - 0.65 (m, 2 H) 0.81 - 0.89 (m, 2 H) 1.33 - 1.61 (m, 8 H) 1.54 (s, 3 H) 1.67 - 1.80 (m, 2 H) 1.91 - 2.03 (m, 2 H) 2.16 - 2.35 (m, 1 H) 3.14 - 3.44 (m, 4 H) 4.41 (t, J=6.6 Hz, 2 H) 8.13 - 8.17 (m, 1 H) 8.94 - 8.97 (m, 1 H).
MS ESI/APCI Dual posi: 402[M-H]-.
参考例５１－１
２－（３－｛４－［（２－ｔｅｒｔ－ブトキシ-2-オキソエチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン-7-カルボン酸 １－メチルシクロプロピル
Figure JPOXMLDOC01-appb-C000156
 Using the compound (270 mg) obtained in Reference Example 50-3, the reaction and purification were conducted in the same manner as in Reference Example 11-4 to obtain the title compound (226 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57-0.65 (m, 2 H) 0.81-0.89 (m, 2 H) 1.33-1.61 (m, 8 H) 1.54 (s, 3 H) 1.67-1.80 (m, 2 H) 1.91-2.03 (m, 2 H) 2.16-2.35 (m, 1 H) 3.14-3.44 (m, 4 H) 4.41 (t, J = 6.6 Hz, 2 H) 8.13-8.17 (m , 1 H) 8.94-8.97 (m, 1 H).
MS ESI / APCI Dual posi: 402 [MH]-.
Reference Example 51-1
2- (3- {4-[(2-tert-Butoxy-2-oxoethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylic acid 1-methylcyclopropyl
Figure JPOXMLDOC01-appb-C000157
 参考例１９－３で得られた化合物（２９５ｍｇ）およびｔｅｒｔ－ブチルグリシナート塩酸塩（１６８ｍｇ）を用いて、参考例４４－１と同様にして反応および精製を行い、表題化合物（２７４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.56 - 0.65 (m, 2 H) 0.80 - 0.90 (m, 2 H) 1.30 - 1.62 (m, 20 H) 1.63 - 1.77 (m, 2 H) 1.89 - 2.03 (m, 2 H) 2.18 - 2.32 (m, 1 H) 3.16 - 3.43 (m, 4 H) 3.95 (t, J=6.5 Hz, 2 H) 4.11 - 4.18 (m, 2 H) 6.61 (dd, J=14.1, 2.3 Hz, 1 H) 6.75 (dd, J=8.8, 2.4 Hz, 1 H) 7.11 - 7.24 (m, 1 H) 8.03 (t, J=9.0 Hz, 1 H).
参考例５１－２
Ｎ－｛２－フルオロ－４－［３－（７－｛［（１－メチルシクロプロピル）オキシ］カルボニル｝－７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］ベンゾイル｝グリシン
Figure JPOXMLDOC01-appb-C000157
 Using the compound (295 mg) obtained in Reference Example 19-3 and tert-butylglycinate hydrochloride (168 mg), the reaction and purification were carried out in the same manner as in Reference Example 44-1 to obtain the title compound (274 mg). It was.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.56-0.65 (m, 2 H) 0.80-0.90 (m, 2 H) 1.30-1.62 (m, 20 H) 1.63-1.77 (m, 2 H) 1.89 -2.03 (m, 2 H) 2.18-2.32 (m, 1 H) 3.16-3.43 (m, 4 H) 3.95 (t, J = 6.5 Hz, 2 H) 4.11-4.18 (m, 2 H) 6.61 (dd , J = 14.1, 2.3 Hz, 1 H) 6.75 (dd, J = 8.8, 2.4 Hz, 1 H) 7.11-7.24 (m, 1 H) 8.03 (t, J = 9.0 Hz, 1 H).
Reference Example 51-2
N- {2-Fluoro-4- [3- (7-{[(1-methylcyclopropyl) oxy] carbonyl} -7-azaspiro [3.5] non-2-yl) propoxy] benzoyl} glycine
Figure JPOXMLDOC01-appb-C000158
 参考例５１－１で得られた化合物（２７４ｍｇ）の酢酸エチル溶液（３．０ｍL）に４Ｍ塩化水素－酢酸エチル溶液（３．０ｍL）を加え室温で１８時間撹拌した。反応液に水を加え抽出し、有機層を飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後、濾過し溶媒を留去した。残渣にジイソプロピルエーテルを加え粉末にして濾取し、表題化合物（１８７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.56 - 0.66 (m, 2 H) 0.80 - 0.90 (m, 2 H) 1.30 - 1.48 (m, 4 H) 1.49 - 1.62 (m, 7 H) 1.63 - 1.78 (m, 2 H) 1.89 - 2.04 (m, 2 H) 2.15 - 2.34 (m, 1 H) 3.15 - 3.46 (m, 4 H) 3.96 (t, J=6.4 Hz, 2 H) 4.23 - 4.35 (m, 2 H) 6.61 (dd, J=14.2, 2.4 Hz, 1 H) 6.77 (dd, J=8.9, 2.3 Hz, 1 H) 7.17 - 7.30 (m, 1 H) 8.03 (t, J=9.1 Hz, 1 H).
MS ESI/APCI Dual posi: 477[M+H]+.
MS ESI/APCI Dual nega: 475[M-H]-.
実施例１－１
ｔｅｒｔ－ブチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000158
 A 4M hydrogen chloride-ethyl acetate solution (3.0 mL) was added to an ethyl acetate solution (3.0 mL) of the compound (274 mg) obtained in Reference Example 51-1, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution for extraction, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered to remove the solvent. Diisopropyl ether was added to the residue and the mixture was powdered and collected by filtration to obtain the title compound (187 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.56-0.66 (m, 2 H) 0.80-0.90 (m, 2 H) 1.30-1.48 (m, 4 H) 1.49-1.62 (m, 7 H) 1.63 -1.78 (m, 2 H) 1.89-2.04 (m, 2 H) 2.15-2.34 (m, 1 H) 3.15-3.46 (m, 4 H) 3.96 (t, J = 6.4 Hz, 2 H) 4.23-4.35 (m, 2 H) 6.61 (dd, J = 14.2, 2.4 Hz, 1 H) 6.77 (dd, J = 8.9, 2.3 Hz, 1 H) 7.17-7.30 (m, 1 H) 8.03 (t, J = 9.1 Hz, 1 H).
MS ESI / APCI Dual posi: 477 [M + H] + .
MS ESI / APCI Dual nega: 475 [MH] - .
Example 1-1
tert-Butyl 2- {3- [2-Fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000159
 参考例２－４で得られた化合物（７０ｍｇ）及び２－フルオロ－４－（メチルスルホニル）フェノ－ル（７１ｍｇ）を用いて参考例１０－１と同様にして、表題化合物（５８ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm  1.24 - 1.67 (m, 17 H) 1.69 - 1.86 (m, 2 H) 1.90 - 2.07 (m, 2 H) 2.14 - 2.38 (m, 1 H) 3.04 (s, 3 H) 3.20 - 3.41 (m, 4 H) 4.08 (t, J=6.4 Hz, 2 H) 6.98 - 7.13 (m, 1 H) 7.57 - 7.74 (m, 2 H).
MS ESI/APCI Dual posi: 478[M+Na]+.
Figure JPOXMLDOC01-appb-C000159
 The title compound (58 mg) was obtained in the same manner as in Reference Example 10-1 using the compound (70 mg) obtained in Reference Example 2-4 and 2-fluoro-4- (methylsulfonyl) phenol (71 mg). It was.
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.24-1.67 (m, 17 H) 1.69-1.86 (m, 2 H) 1.90-2.07 (m, 2 H) 2.14-2.38 (m, 1 H) 3.04 (s, 3 H) 3.20-3.41 (m, 4 H) 4.08 (t, J = 6.4 Hz, 2 H) 6.98-7.13 (m, 1 H) 7.57-7.74 (m, 2 H).
MS ESI / APCI Dual posi: 478 [M + Na] + .
以下の実施例１－２～１－１８も、参考例２－４、３－３、４－３、５－６、６－２、８－５、９－３、１１－２で得られた化合物と、参考例１７－１、３４－１、３５－１、４６－１で得られた化合物又は対応するフェノール化合物を用いて、実施例１－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１－１～１－３に示す。 The following Examples 1-2 to 1-18 were also obtained in Reference Examples 2-4, 3-3, 4-3, 5-6, 6-2, 8-5, 9-3, and 11-2. Using the compound and the compound obtained in Reference Examples 17-1, 34-1, 35-1, and 46-1 or the corresponding phenol compound, synthesis was performed according to the method described in Example 1-1. did. The structures, NMR data and MS data of these compounds are shown in Tables 1-1 to 1-3.
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
 実施例２－１
ｔｅｒｔ－ブチル　２－（３－｛［５－（メチルスルホニル）ピリジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-T000162
 Example 2-1
tert-Butyl 2- (3-{[5- (methylsulfonyl) pyridin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000163
 水素化ナトリウム（６０％オイル懸濁、１５ｍｇ）のテトラヒドロフラン（１．０ｍＬ）懸濁液に、参考例２－４で得られた化合物（７０ｍｇ）、２－ブロモ－５－（メタンスルホニル）ピリジン （８８ｍｇ）を加え、８０℃で１０時間攪拌した。反応溶液に水を加え、水層を酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～８０：２０）にて精製し、表題化合物（６１ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.24 - 1.62 (m, 17 H) 1.62 - 1.81 (m, 2 H) 1.89 - 2.03 (m, 2 H) 2.15 - 2.38 (m, 1 H) 3.07 (s, 3 H) 3.20 - 3.38 (m, 4 H) 4.36 (t, J=6.4 Hz, 2 H) 6.79 - 6.88 (m, 1 H) 7.98 - 8.07 (m, 1 H) 8.69 - 8.73 (m, 1 H).
MS ESI/APCI Dual posi: 461[M+Na]+.
Figure JPOXMLDOC01-appb-C000163
 To a suspension of sodium hydride (60% oil suspension, 15 mg) in tetrahydrofuran (1.0 mL) was added the compound (70 mg) obtained in Reference Example 2-4, 2-bromo-5- (methanesulfonyl) pyridine ( 88 mg) was added, and the mixture was stirred at 80 ° C. for 10 hours. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 80:20) to obtain the title compound (61 mg).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.24-1.62 (m, 17 H) 1.62-1.81 (m, 2 H) 1.89-2.03 (m, 2 H) 2.15-2.38 (m, 1 H) 3.07 (s, 3 H) 3.20-3.38 (m, 4 H) 4.36 (t, J = 6.4 Hz, 2 H) 6.79-6.88 (m, 1 H) 7.98-8.07 (m, 1 H) 8.69-8.73 (m , 1 H).
MS ESI / APCI Dual posi: 461 [M + Na] + .
以下の実施例２－２～２－６も、参考例２－４、１１－２で得られた化合物と参考例３６－１、３７－１、３８－１、３９－１で得られた化合物又は２－ブロモ－５－（１Ｈ－１，２，３－トリアゾー１－イル）ピリジンを用いて、実施例２－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表２－１～２－２に示す。 The following Examples 2-2 to 2-6 also show the compounds obtained in Reference Examples 2-4 and 11-2 and the compounds obtained in Reference Examples 36-1, 37-1, 38-1, and 39-1. Alternatively, synthesis was performed according to the method described in Example 2-1 using 2-bromo-5- (1H-1,2,3-triazol-1-yl) pyridine. The structures, NMR data, and MS data of these compounds are shown in Tables 2-1 and 2-2.
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
 実施例３－１
ｔｅｒｔ－ブチル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-T000165
 Example 3-1
tert-Butyl 2- (3- {3-Fluoro-4-[(2-hydroxyethyl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000166
 参考例１０－２で得られた化合物（１００ｍｇ）、２－アミノエタノール（１７ｍｇ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（５５ｍｇ）、１－ヒドロキシベンゾトリアゾール一水和物（４４ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０ｍｌ）溶液を室温で一晩攪拌した。反応溶液に水を加え、水層を酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）で精製し、表題化合物（８２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31 - 1.49 (m, 13 H) 1.50 - 1.62 (m, 4 H) 1.64 - 1.79 (m, 2 H) 1.90 - 2.03 (m, 2 H) 2.16 - 2.33 (m, 1 H) 3.21 - 3.38 (m, 4 H) 3.60 - 3.69 (m, 2 H) 3.80 - 3.87 (m, 2 H) 3.92 - 4.00 (m, 2 H) 6.56 - 6.65 (m, 1 H) 6.73 - 6.80 (m, 1 H) 7.08 (br. s, 1 H) 7.99 - 8.09 (m, 1 H).
MS ESI/APCI Dual posi: 465[M+H]+, 487[M+Na]+.
Figure JPOXMLDOC01-appb-C000166
 Compound (100 mg) obtained in Reference Example 10-2, 2-aminoethanol (17 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (55 mg), 1-hydroxybenzotriazole monohydrate A solution of the product (44 mg) in N, N-dimethylformamide (1.0 ml) was stirred at room temperature overnight. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50) to obtain the title compound (82 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.49 (m, 13 H) 1.50-1.62 (m, 4 H) 1.64-1.79 (m, 2 H) 1.90-2.03 (m, 2 H) 2.16 -2.33 (m, 1 H) 3.21-3.38 (m, 4 H) 3.60-3.69 (m, 2 H) 3.80-3.87 (m, 2 H) 3.92-4.00 (m, 2 H) 6.56-6.65 (m, 1 H) 6.73-6.80 (m, 1 H) 7.08 (br.s, 1 H) 7.99-8.09 (m, 1 H).
MS ESI / APCI Dual posi: 465 [M + H] + , 487 [M + Na] + .
以下の実施例３－２～３－９６も、参考例１０－２、１１－４、１２－４、１３－２、１４－２、１５－２、１６－２、１８－３、１９－３、２０－２、２１－２、２２－３、２３－２、２４－２、２５－３、２６－２、２７－２、２８－２、２９－２、３０－２、３１－２、３２－３、４０－８、４１－２、４２－２、４３－１、４４－２、４５－２、５０－４、５１－２で得られた化合物と、対応するアミン化合物を用いて、実施例３－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表３－１～３－１７に示す。 Examples 3-2 to 3-96 below also refer to Reference Examples 10-2, 11-4, 12-4, 13-2, 14-2, 15-2, 16-2, 18-3, 19-3. 20-2, 21-2, 22-3, 23-2, 24-2, 25-3, 26-2, 27-2, 28-2, 29-2, 30-2, 31-2, 32 -3, 40-8, 41-2, 42-2, 43-1, 44-2, 45-2, 50-4, 51-2 and the corresponding amine compound Synthesized according to the method described in Example 3-1. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 to 3-17.
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
 実施例４－１
Ｎ－シクロプロピル－４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンズアミド
Figure JPOXMLDOC01-appb-T000183
 Example 4-1
N-cyclopropyl-4- {3- [7- (5-ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzamide
Figure JPOXMLDOC01-appb-C000184
 実施例３－２で得られた化合物（２０ｍｇ）の酢酸エチル（１．０ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（１．０ｍｌ）を加え、室温で一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸マグネシウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して４－｛３－（７－アザスピロ［３．５］ノナ－２－イル）プロピルオキシ］－Ｎ－シクロプロピル－２－フルオロベンズアミド（１４ｍｇ）を得た。得られた４－［３－（７－アザスピロ［３．５］ノナ－２－イル）プロピルオキシ］－Ｎ－シクロプロピル－２－フルオロベンズアミド（１４ｍｇ）、２－クロロ－５－エチルピリミジン（６ｍｇ）及び炭酸セシウム（１８ｍｇ）のジメチルスルホキシド（１．０ｍｌ）懸濁液を封管中、マイクロ波照射下、１８０℃で２０分攪拌した。不溶物を濾別した後、濾液を減圧下濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.55 - 0.67 (m, 2 H) 0.80 - 0.92 (m, 2 H) 1.18 (t, J=7.5 Hz, 3 H) 1.37 - 1.49 (m, 2 H) 1.50 - 1.79 (m, 8 H) 1.95 - 2.08 (m, 2 H) 2.20 - 2.37 (m, 1 H) 2.39 - 2.52 (m, 2 H) 2.84 - 2.98 (m, 1 H) 3.59 - 3.79 (m, 4 H) 3.96 (t, J=6.5 Hz, 2 H) 6.52 - 6.63 (m, 1 H) 6.66 - 6.80 (m, 2 H) 7.99 - 8.10 (m, 1 H) 8.15 (s, 2 H).
MS ESI/APCI Dual posi: 467[M+H]+, 489[M+Na]+.
Figure JPOXMLDOC01-appb-C000184
 To a suspension of the compound (20 mg) obtained in Example 3-2 in ethyl acetate (1.0 ml) was added 4M hydrogen chloride / ethyl acetate solution (1.0 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give 4- {3- (7-azaspiro [3.5] non-2-yl) propyloxy] -N-cyclopropyl-2-fluorobenzamide (14 mg). The obtained 4- [3- (7-azaspiro [3.5] non-2-yl) propyloxy] -N-cyclopropyl-2-fluorobenzamide (14 mg), 2-chloro-5-ethylpyrimidine (6 mg ) And cesium carbonate (18 mg) in dimethyl sulfoxide (1.0 ml) were stirred in a sealed tube at 180 ° C. for 20 minutes under microwave irradiation. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0-50: 50) to give the title compound (4 mg). Got.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.55-0.67 (m, 2 H) 0.80-0.92 (m, 2 H) 1.18 (t, J = 7.5 Hz, 3 H) 1.37-1.49 (m, 2 H) 1.50-1.79 (m, 8 H) 1.95-2.08 (m, 2 H) 2.20-2.37 (m, 1 H) 2.39-2.52 (m, 2 H) 2.84-2.98 (m, 1 H) 3.59-3.79 (m, 4 H) 3.96 (t, J = 6.5 Hz, 2 H) 6.52-6.63 (m, 1 H) 6.66-6.80 (m, 2 H) 7.99-8.10 (m, 1 H) 8.15 (s, 2 H).
MS ESI / APCI Dual posi: 467 [M + H] + , 489 [M + Na] + .
以下の実施例４－２～４－１９も、実施例１－１、１－２、１－３、１－４、１－５、１－６、１－７、１－８、１－９、１－１１、２－１、２－２で得られた化合物と、対応するクロロピリミジン化合物を用いて、実施例４－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表４－１～４－３に示す。 Examples 4-2 to 4-19 below are also the same as Examples 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9. 1-11, 2-1 and 2-2 and the corresponding chloropyrimidine compound were synthesized according to the method described in Example 4-1. The structures, NMR data, and MS data of these compounds are shown in Tables 4-1 to 4-3.
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
 実施例５‐１
７－（５－クロロ－２－ピリジル）－２－［３－（４－メチルスルホニルフェノキシプロピル）－７－アザスピロ［３．５］ノナン
Figure JPOXMLDOC01-appb-T000187
 Example 5-1
7- (5-Chloro-2-pyridyl) -2- [3- (4-methylsulfonylphenoxypropyl) -7-azaspiro [3.5] nonane
Figure JPOXMLDOC01-appb-C000188
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（８０ｍｇ）、２，５－ジクロロピリジン（４２ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（１１ｍｇ）、（±）－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（１５ｍｇ）、ナトリウム　ｔｅｒｔ－ブトキシド（６８ｍｇ）を１，２－ジメトキシエタン（３ｍｌ）に懸濁し、８０℃にて２時間攪拌後、室温にて１４時間撹拌した。反応液を濾過し、濾液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９：１～３：２）にて精製し、表題化合物（２１ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.39 - 1.46 (m, 2 H) 1.48 - 1.61 (m, 4 H) 1.65 - 1.69 (m, 2 H) 1.70 - 1.77 (m, 2 H) 1.97 - 2.05 (m, 2 H) 2.23 - 2.32 (m, 1 H) 3.02 (s, 3 H) 3.35 - 3.41 (m, 2 H) 3.43 - 3.49 (m, 2 H) 4.00 (t, J=6.4 Hz, 2 H) 6.55 - 6.59 (m, 1 H) 6.95 - 7.02 (m, 2 H) 7.33 - 7.39 (m, 1 H) 7.81 - 7.87 (m, 2 H) 8.04 - 8.10 (m, 1 H). 
MS ESI posi: 449[M+H]+.
Figure JPOXMLDOC01-appb-C000188
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane. (2.0 g) was obtained. The resulting 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (80 mg), 2,5-dichloropyridine (42 mg), tris (dibenzylideneacetone) di Palladium (11 mg), (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (15 mg), sodium tert-butoxide (68 mg) was suspended in 1,2-dimethoxyethane (3 ml). It became cloudy and stirred at 80 ° C. for 2 hours and then at room temperature for 14 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (normal hexane: ethyl acetate = 9: 1 to 3: 2) to obtain the title compound (21 mg). .
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.39-1.46 (m, 2 H) 1.48-1.61 (m, 4 H) 1.65-1.69 (m, 2 H) 1.70-1.77 (m, 2 H) 1.97 -2.05 (m, 2 H) 2.23-2.32 (m, 1 H) 3.02 (s, 3 H) 3.35-3.41 (m, 2 H) 3.43-3.49 (m, 2 H) 4.00 (t, J = 6.4 Hz , 2 H) 6.55-6.59 (m, 1 H) 6.95-7.02 (m, 2 H) 7.33-7.39 (m, 1 H) 7.81-7.87 (m, 2 H) 8.04-8.10 (m, 1 H).
MS ESI posi: 449 [M + H] + .
以下の実施例５－２～５－３も、実施例１－３で得られた化合物と、対応するピリジン化合物を用いて、実施例５－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表５－１に示す。 The following Examples 5-2 to 5-3 were also synthesized according to the method described in Example 5-1 using the compound obtained in Example 1-3 and the corresponding pyridine compound. . The structure, NMR data and MS data of these compounds are shown in Table 5-1.
Figure JPOXMLDOC01-appb-T000189
 実施例６－１
１－メチルシクロプロピル ２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-T000189
 Example 6-1
1-methylcyclopropyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000190
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（６０ｍｇ）、トリエチルアミン（５０μｌ）をクロロホルム（２．０ｍｌ）に溶解し、氷冷下にて１－メチルシクロプロピル ４－ニトロフェニル カルボナート（５１ｍｇ）を加え、反応液を室温まで昇温しながら６時間撹拌した。反応液に水を加えてクロロホルムにて抽出を行い、有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧留去して得られた残渣を、シリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝７：３～２：３）にて精製し、ノルマルヘキサン／酢酸エチルから再結晶することにより表題化合物（５３ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.58 - 0.63 (m, 2 H) 0.83 - 0.87 (m, 2 H) 1.35 - 1.47 (m, 4 H) 1.50 - 1.60 (m, 7 H) 1.69 - 1.76 (m, 2 H) 1.94 - 2.01 (m, 2 H) 2.21 - 2.30 (m, 1 H) 3.03 (s, 3 H) 3.18 - 3.45 (m, 4 H) 4.00 (t, J=6.4 Hz, 2 H) 6.98 - 7.01 (m, 2 H) 7.84 - 7.87 (m, 2 H).
MS ESI/APCI Dual posi: 436[M+H]+, 458[M+Na]+.
Figure JPOXMLDOC01-appb-C000190
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane. (2.0 g) was obtained. The obtained 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (60 mg) and triethylamine (50 μl) were dissolved in chloroform (2.0 ml) and ice-cooled. Below, 1-methylcyclopropyl 4-nitrophenyl carbonate (51 mg) was added, and the reaction mixture was stirred for 6 hours while warming to room temperature. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the desiccant was filtered off. The residue obtained by evaporating the filtrate under reduced pressure was purified by silica gel column chromatography (normal hexane: ethyl acetate = 7: 3 to 2: 3) and recrystallized from normal hexane / ethyl acetate to give the title compound. (53 mg) was obtained.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.58-0.63 (m, 2 H) 0.83-0.87 (m, 2 H) 1.35-1.47 (m, 4 H) 1.50-1.60 (m, 7 H) 1.69 -1.76 (m, 2 H) 1.94-2.01 (m, 2 H) 2.21-2.30 (m, 1 H) 3.03 (s, 3 H) 3.18-3.45 (m, 4 H) 4.00 (t, J = 6.4 Hz , 2 H) 6.98-7.01 (m, 2 H) 7.84-7.87 (m, 2 H).
MS ESI / APCI Dual posi: 436 [M + H] + , 458 [M + Na] + .
以下の実施例６－２～６－１７も、実施例１－１、１－３、１－９、１－１１、１－１２、１－１８、１２－１で得られた化合物と、対応するカルバマート化試薬、もしくはスルホニルクロリドを用いて、実施例６－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表６－１～６－３に示す。 Examples 6-2 to 6-17 below also correspond to the compounds obtained in Examples 1-1, 1-3, 1-9, 1-11, 1-12, 1-18, and 12-1. This was synthesized according to the method described in Example 6-1 using the carbamate reagent or sulfonyl chloride. The structures, NMR data, and MS data of these compounds are shown in Tables 6-1 to 6-3.
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
 実施例７－１
シクロプロピルメチル　２－｛３－［４－メチルスルホニル］フェノキシ｝プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-T000193
 Example 7-1
Cyclopropylmethyl 2- {3- [4-methylsulfonyl] phenoxy} propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000194
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別し、濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。シクロプロパンメタノール（５０μｌ）をテトラヒドロフラン（２．１ｍｌ）に溶解し、トリホスゲン（６２ｍｇ）を加えた。反応液を氷冷し、トリエチルアミン（１７５μｌ）を加えて１０分撹拌した。反応液に上記で得た２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（７０ｍｇ）を加え、反応液を室温へ昇温しながら３０分撹拌した。反応液に水を加え、クロロホルムにて抽出し、有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝３：１～３：２）にて精製し、ノルマルヘキサン／酢酸エチルから再結晶することにより表題化合物（１８ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.24 - 0.28 (m, 2 H) 0.51 - 0.56 (m, 2 H) 1.08 - 1.16 (m, 1 H) 1.38 - 1.43 (m, 2 H) 1.46 - 1.49 (m, 2 H) 1.55 - 1.61 (m, 4 H) 1.71 - 1.77 (m, 2 H) 1.96 - 2.02 (m, 2 H) 2.21 - 2.31 (m, 1 H) 3.03 (s, 3 H) 3.29 - 3.46 (m, 4 H) 3.89 (d, J=7.0 Hz, 2 H) 4.00 (t, J=6.4 Hz, 2 H) 6.97 - 7.02 (m, 2 H) 7.83 - 7.87 (m, 2 H).
MS ESI/APCI Dual posi: 436[M+H]+, 458[M+Na]+.
Figure JPOXMLDOC01-appb-C000194
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane. (2.0 g) was obtained. Cyclopropanemethanol (50 μl) was dissolved in tetrahydrofuran (2.1 ml), and triphosgene (62 mg) was added. The reaction mixture was ice-cooled, triethylamine (175 μl) was added, and the mixture was stirred for 10 min. 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (70 mg) obtained above was added to the reaction solution, and the reaction solution was warmed to room temperature for 30 minutes. Stir. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 3: 1 to 3: 2) and recrystallized from normal hexane / ethyl acetate to give the title compound ( 18 mg) was obtained.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.24-0.28 (m, 2 H) 0.51-0.56 (m, 2 H) 1.08-1.16 (m, 1 H) 1.38-1.43 (m, 2 H) 1.46 -1.49 (m, 2 H) 1.55-1.61 (m, 4 H) 1.71-1.77 (m, 2 H) 1.96-2.02 (m, 2 H) 2.21-2.31 (m, 1 H) 3.03 (s, 3 H ) 3.29-3.46 (m, 4 H) 3.89 (d, J = 7.0 Hz, 2 H) 4.00 (t, J = 6.4 Hz, 2 H) 6.97-7.02 (m, 2 H) 7.83-7.87 (m, 2 H).
MS ESI / APCI Dual posi: 436 [M + H] + , 458 [M + Na] + .
以下の実施例７－２～７－１４も、実施例１－１、１－３、１－９で得られた化合物と、対応するアルコール化合物を用いて、実施例７－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表７－１～７－２に示す。 Examples 7-2 to 7-14 below are also described in Example 7-1 using the compounds obtained in Examples 1-1, 1-3, 1-9 and the corresponding alcohol compounds. Synthesized according to the method. The structures, NMR data, and MS data of these compounds are shown in Tables 7-1 and 7-2.
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
 実施例８－１
２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－［３－（プロパン－２－イル）－１，２，４－オキサゾール－５－イル］－７－アザスピロ［３．５］ノナン
Figure JPOXMLDOC01-appb-T000196
 Example 8-1
2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7- [3- (propan-2-yl) -1,2,4-oxazol-5-yl] -7-azaspiro [3.5 ] Nonane
Figure JPOXMLDOC01-appb-C000197
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（１００ｍｇ）をクロロホルム（３ｍｌ）に溶解し、水（１ｍｌ）及び重曹（５０ｍｇ）を加えた。反応液を氷冷し、臭化シアン（３６ｍｇ）を加え、反応液を室温へ昇温させながら一晩撹拌した。反応液に水を加え、クロロホルムにて抽出した。有機層を飽和重曹水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝３：２～３：７）にて精製し、２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボニトリル（１１１ｍｇ）を得た。得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボニトリル（１０７ｍｇ）、Ｎ’－ヒドロキシ－２－メチルプロパンイミドアミド（３９ｍｇ）のテトラヒドロフラン（１．０ｍＬ）溶液へ、塩化亜鉛（１．０Ｍジエチルエーテル溶液、３８０μｌ）を加え、室温にて３０分撹拌した。反応液を濾過し、得られた固体を濃塩酸（２ｍｌ）及びエタノール（２ｍｌ）に溶解させ、加熱還流下３時間撹拌した。反応液を氷冷し、飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１３：７～１：１）にて精製後、ノルマルヘキサン／酢酸エチルで再結晶することにより、表題化合物（５３ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J=7.0 Hz, 6 H) 1.41 - 1.48 (m, 2 H) 1.54 - 1.63 (m, 4 H) 1.68 - 1.78 (m, 4 H) 2.00 - 2.06 (m, 2 H) 2.23 - 2.36 (m, 1 H) 2.83 - 2.92 (m, 1 H) 3.03 (s, 3 H) 3.44 - 3.48 (m, 2 H) 3.51 - 3.57 (m, 2 H) 4.01 (t, J=6.4 Hz, 2 H) 6.97 - 7.02 (m, 2 H) 7.83 - 7.88 (m, 2 H).
MS ESI/APCI Dual posi: 448[M+H]+, 470[M+Na]+.
実施例９－１
７－（２，２－ジフルオロプロピル）－２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン
Figure JPOXMLDOC01-appb-C000197
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (2.0 g). The obtained 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (100 mg) was dissolved in chloroform (3 ml), water (1 ml) and sodium bicarbonate (50 mg). Was added. The reaction mixture was ice-cooled, cyanogen bromide (36 mg) was added, and the reaction mixture was stirred overnight while warming to room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 3: 2 to 3: 7) to give 2- {3- [4- (methylsulfonyl) phenoxy]. Propyl} -7-azaspiro [3.5] nonane-7-carbonitrile (111 mg) was obtained. The obtained 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carbonitrile (107 mg), N′-hydroxy-2-methylpropanimidamide ( Zinc chloride (1.0 M diethyl ether solution, 380 μl) was added to a solution of 39 mg) in tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the resulting solid was dissolved in concentrated hydrochloric acid (2 ml) and ethanol (2 ml), and the mixture was stirred for 3 hours with heating under reflux. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 13: 7 to 1: 1) and then recrystallized with normal hexane / ethyl acetate to give the title compound. (53 mg) was obtained.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J = 7.0 Hz, 6 H) 1.41-1.48 (m, 2 H) 1.54-1.63 (m, 4 H) 1.68-1.78 (m, 4 H) 2.00-2.06 (m, 2 H) 2.23-2.36 (m, 1 H) 2.83-2.92 (m, 1 H) 3.03 (s, 3 H) 3.44-3.48 (m, 2 H) 3.51-3.57 (m , 2 H) 4.01 (t, J = 6.4 Hz, 2 H) 6.97-7.02 (m, 2 H) 7.83-7.88 (m, 2 H).
MS ESI / APCI Dual posi: 448 [M + H] + , 470 [M + Na] + .
Example 9-1
7- (2,2-Difluoropropyl) -2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane
Figure JPOXMLDOC01-appb-C000198
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（１００ｍｇ）、ＷＯ２０１１／００８６６３に記載の２，２－ジフルオロプロピル ４－メチルベンゼンスルホナート（７４ｍｇ）をジメチルスルホキシド（３．０ｍｌ）に溶解し、マイクロ波照射下、１８０℃にて１時間撹拌した。反応液に水を加え、酢酸エチルにて抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝４：１～１３：７）にて精製し、ノルマルヘキサン／酢酸エチルで再結晶することにより、表題化合物（６ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 - 1.37 (m, 2 H) 1.48 - 1.66 (m, 9 H) 1.69 - 1.76 (m, 2 H) 1.90 - 1.99 (m, 2 H) 2.18 - 2.26 (m, 1 H) 2.37 - 2.52 (m, 4 H) 2.56 - 2.64 (m, 2 H) 3.03 (s, 3 H) 4.00 (t, J=6.6 Hz, 2 H) 6.98 - 7.01 (m, 2 H) 7.83 - 7.88 (m, 2 H).
MS ESI/APCI Dual posi: 416[M+H]+, 438[M+Na]+.
実施例１０－１
７－（２－フルオロ－２－メチル－プロピル）－２－［３－（４－メチルスルホニルフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン
Figure JPOXMLDOC01-appb-C000198
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (2.0 g). The obtained 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (100 mg), 2,2-difluoropropyl 4-methylbenzenesulfone described in WO2011 / 008663 Nart (74 mg) was dissolved in dimethyl sulfoxide (3.0 ml) and stirred at 180 ° C. for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 4: 1 to 13: 7) and recrystallized with normal hexane / ethyl acetate to give the title compound. (6 mg) was obtained.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32-1.37 (m, 2 H) 1.48-1.66 (m, 9 H) 1.69-1.76 (m, 2 H) 1.90-1.99 (m, 2 H) 2.18 -2.26 (m, 1 H) 2.37-2.52 (m, 4 H) 2.56-2.64 (m, 2 H) 3.03 (s, 3 H) 4.00 (t, J = 6.6 Hz, 2 H) 6.98-7.01 (m , 2 H) 7.83-7.88 (m, 2 H).
MS ESI / APCI Dual posi: 416 [M + H] + , 438 [M + Na] + .
Example 10-1
7- (2-Fluoro-2-methyl-propyl) -2- [3- (4-methylsulfonylphenoxy) propyl] -7-azaspiro [3.5] nonane
Figure JPOXMLDOC01-appb-C000199
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（１００ｍｇ）をメタノール（１．０ｍｌ）に溶解し、イソブチレンオキシド（４０μｌ）を加え、室温で一晩撹拌した。反応液に水を加えて酢酸エチルにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝７：３～１：１）で精製し、２－メチル－１－（２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナ－７－イル）プロパン－２－オール（９５ｍｇ）を得た。得られた２－メチル－１－（２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナ－７－イル）プロパン－２－オール（９５ｍｇ）をクロロホルム（１．２ｍｌ）に溶解し、ビス（２－メトキシエチル）アミノサルファートリフルオリド（５０μｌ）を加え、室温で一晩撹拌した。反応液に飽和重曹水を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝４：１～１３：７）にて精製し、表題化合物（４７ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.29 - 1.38 (m, 8 H) 1.46 - 1.64 (m, 6 H) 1.68 - 1.77 (m, 2 H) 1.88 - 1.97 (m, 2 H) 2.15 - 2.26 (m, 1 H) 2.32 - 2.48 (m, 6 H) 3.03 (s, 3 H) 4.00 (t, J=6.1 Hz, 2 H) 6.98 - 7.02 (m, 2 H) 7.83 - 7.87 (m, 2 H).
MS ESI/APCI Dual posi: 412[M+H]+.
実施例１１－１
２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－｛［１－（トリフルオロメチル）シクロプロピル］メチル｝－７－アザスピロ［３．５］ノナン
Figure JPOXMLDOC01-appb-C000199
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (2.0 g). The obtained 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (100 mg) was dissolved in methanol (1.0 ml), and isobutylene oxide (40 μl) was added. Stir at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (normal hexane: ethyl acetate = 7: 3 to 1: 1) to give 2-methyl-1- (2- {3- [4 -(Methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] non-7-yl) propan-2-ol (95 mg) was obtained. The resulting 2-methyl-1- (2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] non-7-yl) propan-2-ol (95 mg) Dissolved in chloroform (1.2 ml), bis (2-methoxyethyl) aminosulfur trifluoride (50 μl) was added and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 4: 1 to 13: 7) to obtain the title compound (47 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.29-1.38 (m, 8 H) 1.46-1.64 (m, 6 H) 1.68-1.77 (m, 2 H) 1.88-1.97 (m, 2 H) 2.15 -2.26 (m, 1 H) 2.32-2.48 (m, 6 H) 3.03 (s, 3 H) 4.00 (t, J = 6.1 Hz, 2 H) 6.98-7.02 (m, 2 H) 7.83-7.87 (m , 2 H).
MS ESI / APCI Dual posi: 412 [M + H] + .
Example 11-1
2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-{[1- (trifluoromethyl) cyclopropyl] methyl} -7-azaspiro [3.5] nonane
Figure JPOXMLDOC01-appb-C000200
 実施例１－３で得られた化合物（２．７ｇ）の酢酸エチル（３１ｍｌ）懸濁液へ、４Ｍ塩化水素・酢酸エチル溶液（３１ｍｌ）を加え、室温にて一晩攪拌した。反応液を減圧下濃縮し、得られた残渣に１Ｍ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（２．０ｇ）を得た。１－（トリフルオロメチル）シクロプロパン－１－カルボン酸（６８ｍｇ）のテトラヒドロフラン（１．５ｍｌ）溶液に、１，１’－カルボニルジイミダゾール（７２ｍｇ）、上記で得られた２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン（１００ｍｇ）を順次加え、室温で一晩撹拌した。反応液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤を濾別した。濾液を減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１：１～１：３）にて精製し、（２－｛３－［４－（メチルスルホニル）フェノキシ）プロピル］－７－アザスピロ［３．５］ノナ－７－イル｝［１－（トリフルオロメチル）シクロプロピル］メタノン（９８ｍｇ）を得た。得られた（２－｛３－［４－（メチルスルホニル）フェノキシ）プロピル］－７－アザスピロ［３．５］ノナ－７－イル｝［１－（トリフルオロメチル）シクロプロピル］メタノン（９８ｍｇ）をテトラヒドロフラン（２．０ｍｌ）に溶解し、氷冷下で水素化リチウムアルミニウム（１０ｍｇ）を加え、反応液を室温まで昇温しながら３時間撹拌した。氷冷下にて反応液に水（１０μｌ）、２．５Ｍ水酸化ナトリウム水溶液（１０μｌ）及び水（３０μｌ）を順次加え室温で８時間撹拌した。反応液をセライト（登録商標）濾過し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝４：１～１３：７）にて精製し、表題化合物（２２ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.59 - 0.66 (m, 2 H) 0.91 - 0.97 (m, 2 H) 1.29 - 1.38 (m, 2 H) 1.44 - 1.64 (m, 6 H) 1.67 - 1.77 (m, 2 H) 1.87 - 1.96 (m, 2 H) 2.14 - 2.40 (m, 5 H) 2.47 (s, 2 H) 2.99 - 3.06 (m, 3 H) 3.99 (t, J=6.1 Hz, 2 H) 6.96 - 7.02 (m, 2 H) 7.81 - 7.88 (m, 2 H).
MS ESI/APCI Dual posi: 460[M+H]+, 482[M+Na]+.
実施例１２－１
ｔｅｒｔ－ブチル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000200
 To a suspension of the compound obtained in Example 1-3 (2.7 g) in ethyl acetate (31 ml) was added 4M hydrogen chloride / ethyl acetate solution (31 ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 1M aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the desiccant was filtered off. The filtrate was concentrated under reduced pressure to give 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (2.0 g). To a solution of 1- (trifluoromethyl) cyclopropane-1-carboxylic acid (68 mg) in tetrahydrofuran (1.5 ml) was added 1,1′-carbonyldiimidazole (72 mg) and 2- {3- [ 4- (Methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane (100 mg) was sequentially added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (normal hexane: ethyl acetate = 1: 1 to 1: 3) to give (2- {3- [4- (methylsulfonyl) phenoxy ) Propyl] -7-azaspiro [3.5] non-7-yl} [1- (trifluoromethyl) cyclopropyl] methanone (98 mg). Obtained (2- {3- [4- (methylsulfonyl) phenoxy) propyl] -7-azaspiro [3.5] non-7-yl} [1- (trifluoromethyl) cyclopropyl] methanone (98 mg) Was dissolved in tetrahydrofuran (2.0 ml), lithium aluminum hydride (10 mg) was added under ice cooling, and the reaction mixture was stirred for 3 hours while warming to room temperature. Under ice-cooling, water (10 μl), 2.5 M aqueous sodium hydroxide solution (10 μl) and water (30 μl) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 4: 1 to 13: 7) to obtain the title compound (22 mg).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.59-0.66 (m, 2 H) 0.91-0.97 (m, 2 H) 1.29-1.38 (m, 2 H) 1.44-1.64 (m, 6 H) 1.67 -1.77 (m, 2 H) 1.87-1.96 (m, 2 H) 2.14-2.40 (m, 5 H) 2.47 (s, 2 H) 2.99-3.06 (m, 3 H) 3.99 (t, J = 6.1 Hz , 2 H) 6.96-7.02 (m, 2 H) 7.81-7.88 (m, 2 H).
MS ESI / APCI Dual posi: 460 [M + H] + , 482 [M + Na] + .
Example 12-1
tert-Butyl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000201
 実施例３－２で得られた化合物（２６ｍｇ）のテトラヒドロフラン（１．０ｍｌ）溶液に水素化ナトリウム（６０％オイル懸濁、３ｍｇ）を加えて３０分攪拌後、ヨウ化メチル（５μｌ）を加え室温で一晩攪拌した。反応溶液に水を加えた後、水層を酢酸エチルで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.33 - 0.63 (m, 4 H) 1.33 - 1.49 (m, 12 H) 1.51 - 1.62 (m, 6 H) 1.65 - 1.79 (m, 2 H) 1.88 - 2.03 (m, 2 H) 2.16 - 2.34 (m, 1 H) 2.74 - 2.90 (m, 1 H) 3.10 (br. s., 2 H) 3.20 - 3.42 (m, 4 H) 3.93 (t, J=6.4 Hz, 2 H) 6.48 - 6.62 (m, 1 H) 6.66 - 6.74 (m, 1 H) 7.23 - 7.35 (m, 1 H).
MS ESI/APCI Dual posi: 475[M+H]+, 497[M+Na]+.
実施例１３－１
Ｎ－ｔｅｒｔ－ブチル－２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキサミド
Figure JPOXMLDOC01-appb-C000201
 Sodium hydride (60% oil suspension, 3 mg) was added to a solution of the compound obtained in Example 3-2 (26 mg) in tetrahydrofuran (1.0 ml) and stirred for 30 minutes, and then methyl iodide (5 μl) was added. Stir overnight at room temperature. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50) to obtain the title compound (5 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.33-0.63 (m, 4 H) 1.33-1.49 (m, 12 H) 1.51-1.62 (m, 6 H) 1.65-1.79 (m, 2 H) 1.88 -2.03 (m, 2 H) 2.16-2.34 (m, 1 H) 2.74-2.90 (m, 1 H) 3.10 (br. S., 2 H) 3.20-3.42 (m, 4 H) 3.93 (t, J = 6.4 Hz, 2 H) 6.48-6.62 (m, 1 H) 6.66-6.74 (m, 1 H) 7.23-7.35 (m, 1 H).
MS ESI / APCI Dual posi: 475 [M + H] + , 497 [M + Na] + .
Example 13-1
N-tert-butyl-2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxamide
Figure JPOXMLDOC01-appb-C000202
 実施例１－１１で得られた化合物（５１５ｍｇ）を用いて参考例１２－２と同様にして反応及び精製を行い、２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン（４８５ｍｇ）を得た。
上記で得られた化合物（５０ｍｇ）、およびトリエチルアミン（３１μＬ）のクロロホルム溶液（１．０ｍＬ）にｔｅｒｔ－ブチルイソシアナート（１８ｍｇ）を加えて２時間撹拌後、反応液をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（３４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 9 H) 1.35 - 1.44 (m, 2 H) 1.45 - 1.51 (m, 2 H) 1.53 - 1.62 (m, 4 H) 1.70 - 1.82 (m, 2 H) 1.93 - 2.03 (m, 2 H) 2.19 - 2.32 (m, 1 H) 3.11 - 3.29 (m, 7 H) 4.06 (t, J=6.4 Hz, 2 H) 4.29 (br. s, 1 H) 7.31 (dd, J=8.7, 2.8 Hz, 1 H) 8.03 (dd, J=8.7, 0.6 Hz, 1 H) 8.36 (dd, J=2.9, 0.5 Hz, 1 H).
MS ESI/APCI Dual posi: 438[M+H]+, 460[M+Na]+.
MS ESI/APCI Dual nega: 436[M-H]-, 472[M+Cl]-.
実施例１４－１
３，３－ジメチル－１－［２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナ－７－イル］ブタン－１－オン
Figure JPOXMLDOC01-appb-C000202
 The compound (515 mg) obtained in Example 1-11 was used for reaction and purification in the same manner as in Reference Example 12-2 to give 2- (3-{[6- (methylsulfonyl) pyridin-3-yl]. Oxy} propyl) -7-azaspiro [3.5] nonane (485 mg) was obtained.
To a chloroform solution (1.0 mL) of the compound (50 mg) obtained above and triethylamine (31 μL) was added tert-butyl isocyanate (18 mg), and the mixture was stirred for 2 hours, and then the reaction mixture was subjected to silica gel column chromatography (normal hexane : Ethyl acetate = 100: 0 to 50:50) to obtain the title compound (34 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 9 H) 1.35-1.44 (m, 2 H) 1.45-1.51 (m, 2 H) 1.53-1.62 (m, 4 H) 1.70-1.82 (m, 2 H) 1.93-2.03 (m, 2 H) 2.19-2.32 (m, 1 H) 3.11-3.29 (m, 7 H) 4.06 (t, J = 6.4 Hz, 2 H) 4.29 (br. s , 1 H) 7.31 (dd, J = 8.7, 2.8 Hz, 1 H) 8.03 (dd, J = 8.7, 0.6 Hz, 1 H) 8.36 (dd, J = 2.9, 0.5 Hz, 1 H).
MS ESI / APCI Dual posi: 438 [M + H] + , 460 [M + Na] + .
MS ESI / APCI Dual nega: 436 [MH] - , 472 [M + Cl] - .
Example 14-1
3,3-Dimethyl-1- [2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] non-7-yl] butane-1 -on
Figure JPOXMLDOC01-appb-C000203
 参考例１３－１の中間体として得られた２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン（５０ｍｇ）、およびトリエチルアミン（３１μＬ）のクロロホルム溶液（１．０ｍＬ）にｔｅｒｔ－ブチルアセチルクロリド（２４ｍｇ）を加えて２時間撹拌後、反応液をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～５０：５０）にて精製し、表題化合物（５２ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (s, 9 H) 1.34 - 1.53 (m, 4 H) 1.53 - 1.63 (m, 4 H) 1.68 - 1.83 (m, 2 H) 1.92 - 2.07 (m, 2 H) 2.21 - 2.36 (m, 3 H) 3.19 (s, 3 H) 3.28 - 3.62 (m, 4 H) 4.06 (t, J=6.4 Hz, 2 H) 7.31 (dd, J=8.7, 2.8 Hz, 1 H) 8.01 - 8.06 (m, 1 H) 8.36 (d, J=2.8 Hz, 1 H).
MS ESI/APCI Dual posi: 437[M+H]+, 459[M+Na]+.
MS ESI/APCI Dual nega: 471[M+Cl]-.
実施例１５－１
プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３－メチルフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000203
 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane (50 mg) obtained as an intermediate of Reference Example 13-1, and After adding tert-butylacetyl chloride (24 mg) to a chloroform solution (1.0 mL) of triethylamine (31 μL) and stirring for 2 hours, the reaction solution was subjected to silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 50:50). ) To give the title compound (52 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (s, 9 H) 1.34-1.53 (m, 4 H) 1.53-1.63 (m, 4 H) 1.68-1.83 (m, 2 H) 1.92-2.07 (m, 2 H) 2.21-2.36 (m, 3 H) 3.19 (s, 3 H) 3.28-3.62 (m, 4 H) 4.06 (t, J = 6.4 Hz, 2 H) 7.31 (dd, J = 8.7 , 2.8 Hz, 1 H) 8.01-8.06 (m, 1 H) 8.36 (d, J = 2.8 Hz, 1 H).
MS ESI / APCI Dual posi: 437 [M + H] + , 459 [M + Na] + .
MS ESI / APCI Dual nega: 471 [M + Cl] - .
Example 15-1
Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3-methylphenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000204
 参考例３３－１で得られた化合物（５４ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）に溶解し、グリシンアミド塩酸塩（１５ｍｇ）、トリエチルアミン（２０μＬ）を加え、室温で一晩撹拌した。反応液を酢酸エチルで希釈後、有機層を水で洗浄し、水層を酢酸エチルおよびノルマルヘキサンの混合溶液で抽出した。先の有機層と合わせて、硫酸マグネシウムで乾燥し、乾燥剤をろ別後、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９８：２～９３：７）にて精製後、得られた固体を酢酸エチルおよびノルマルへキサンを用いて再結晶化し、表題化合物（４３ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.33 - 1.78 (m, 10 H) 1.90 - 2.04 (m, 2 H) 2.16 - 2.33 (m, 1 H) 2.47 (s, 3 H) 3.25 - 3.43 (m, 4 H) 3.94 (t, J=6.4 Hz, 2 H) 4.14 (d, J=5.1 Hz, 2 H) 4.84 - 4.96 (m, 1 H) 5.38 - 5.52 (m, 1 H) 6.00 - 6.15 (m, 1 H) 6.45 - 6.54 (m, 1 H) 6.65 - 6.78 (m, 2 H) 7.41 (d, J=8.2 Hz, 1 H).
MS ESI/APCI Dual posi: 460[M+H]+.
Figure JPOXMLDOC01-appb-C000204
 The compound (54 mg) obtained in Reference Example 33-1 was dissolved in N, N-dimethylformamide (1 mL), glycinamide hydrochloride (15 mg) and triethylamine (20 μL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, the organic layer was washed with water, and the aqueous layer was extracted with a mixed solution of ethyl acetate and normal hexane. The organic layer was combined and dried over magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2-93: 7), and the obtained solid was recrystallized from ethyl acetate and normal hexane to give the title compound (43 mg). Got.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.33-1.78 (m, 10 H) 1.90-2.04 (m, 2 H) 2.16-2.33 (m, 1 H) 2.47 (s, 3 H) 3.25-3.43 (m, 4 H) 3.94 (t, J = 6.4 Hz, 2 H) 4.14 (d, J = 5.1 Hz, 2 H) 4.84-4.96 (m, 1 H ) 5.38-5.52 (m, 1 H) 6.00-6.15 (m, 1 H) 6.45-6.54 (m, 1 H) 6.65-6.78 (m, 2 H) 7.41 (d, J = 8.2 Hz, 1 H).
MS ESI / APCI Dual posi: 460 [M + H] + .
　以下の実施例１５－２～１５－３も、参考例３３－１で得られた化合物と、対応するアミン化合物を用いて、実施例１５－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表８－１に示す。 Examples 15-2 to 15-3 below were also synthesized according to the method described in Example 15-1 using the compound obtained in Reference Example 33-1 and the corresponding amine compound. . Table 8-1 shows the structures, NMR data, and MS data of these compounds.
Figure JPOXMLDOC01-appb-T000205
 実施例１６－１
プロパン－２－イル　２－｛３－［３－フルオロ－４－（１Ｈ－テトラゾル－５－イル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-T000205
 Example 16-1
Propan-2-yl 2- {3- [3-fluoro-4- (1H-tetrazol-5-yl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000206
 参考例１１－２で得られた化合物（１００ｍｇ）および２－フルオロ－４－ヒドロキシベンゾニトリル（７６ｍｇ）を用いて、参考例１０－１と同様にして反応および精製を行い、プロパン－２－イル　２－［３－（４－シアノ－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート（１１６ｍｇ）を得た。
上記で得られた化合物（１１２ｍｇ）をトルエン（１ｍＬ）に溶解し、アジ化ナトリウム（５６ｍｇ）、トリエチルアミン塩酸塩（１５９ｍｇ）を加え、マイクロウェーブ照射下１３０℃で３０分、１４０℃で３０分、１５０℃で３０分、１６０℃で３０分撹拌後、１７０℃で一晩撹拌した。反応液を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液を加え、セライトろ過し、ろ液を酢酸エチルで抽出した。有機層を無水硫酸ナトリウム乾燥後、乾燥剤をろ別し、ろ液を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９１：９～８５：１５）にて精製し、得られた固体を酢酸エチルおよびノルマルヘキサンを用いて再結晶し、表題化合物（４６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.4 Hz, 6 H) 1.34 - 1.50 (m, 4 H) 1.52 - 1.64 (m, 4 H) 1.67 - 1.80 (m, 2 H) 1.91 - 2.04 (m, 2 H) 2.19 - 2.34 (m, 1 H) 3.26 - 3.44 (m, 4 H) 4.00 (t, J=6.4 Hz, 2 H) 4.84 - 4.99 (m, 1 H) 6.71 - 6.81 (m, 1 H) 6.84 - 6.93 (m, 1 H) 8.26 (t, J=8.7 Hz, 1 H).
MS ESI/APCI Dual posi: 432[M+H]+.
実施例１７－１
プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）スルフィニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000206
 Using the compound (100 mg) obtained in Reference Example 11-2 and 2-fluoro-4-hydroxybenzonitrile (76 mg), the reaction and purification were carried out in the same manner as in Reference Example 10-1, and propan-2-yl 2- [3- (4-Cyano-3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate (116 mg) was obtained.
The compound (112 mg) obtained above was dissolved in toluene (1 mL), sodium azide (56 mg) and triethylamine hydrochloride (159 mg) were added, and 30 minutes at 130 ° C. and 30 minutes at 140 ° C. under microwave irradiation. The mixture was stirred at 150 ° C. for 30 minutes and 160 ° C. for 30 minutes, and then stirred at 170 ° C. overnight. The reaction mixture was diluted with ethyl acetate, saturated aqueous ammonium chloride solution was added, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 91: 9 to 85:15), and the obtained solid was recrystallized from ethyl acetate and normal hexane to obtain the title compound (46 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.4 Hz, 6 H) 1.34-1.50 (m, 4 H) 1.52-1.64 (m, 4 H) 1.67-1.80 (m, 2 H) 1.91-2.04 (m, 2 H) 2.19-2.34 (m, 1 H) 3.26-3.44 (m, 4 H) 4.00 (t, J = 6.4 Hz, 2 H) 4.84-4.99 (m, 1 H) 6.71-6.81 (m, 1 H) 6.84-6.93 (m, 1 H) 8.26 (t, J = 8.7 Hz, 1 H).
MS ESI / APCI Dual posi: 432 [M + H] + .
Example 17-1
Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) sulfinyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000207
 ４－メルカプトフェニルボロン酸（２．０ｇ）、ピナコール（１．５５ｇ）、硫酸マグネシウム（３．２６ｇ）のクロロホルム懸濁液を室温で一晩撹拌した。反応液をろ過後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝８５：１５）にて精製し、４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）ベンゼンチオール（３．３６ｇ）を得た。
上記で得られた化合物（５００ｍｇ）をテトラヒドロフランおよびＮ，Ｎ－ジメチルホルムアミドの混合溶液（１：１）（２０ｍＬ）に溶解し、氷冷下にて水素化ナトリウム (６０％、流動パラフィンに分散)（１０２ｍｇ）を加えた。１０分間撹拌後、２－(２－クロロエトキシ)テトラヒドロ－２Ｈ－ピラン（３７５μＬ）を加え、氷浴をはずして３時間撹拌した。反応液へ水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、乾燥剤をろ別した。ろ液を減圧下留去し、２－（２－｛［４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）フェニル］スルファニル｝エトキシ）テトラヒドロ－２Ｈ－ピラン（８３０ｍｇ）を得た。
さらに、上記で得られた化合物（８３０ｍｇ）をテトラヒドロフランおよびメタノールの混合溶媒（１：１）（２０ｍＬ）に溶解し、氷冷下にて３０％過酸化水素水（９６０μＬ）を加え、氷浴をはずして一晩撹拌した。反応液へ飽和チオ硫酸ナトリウム水溶液を加えて３０分間撹拌後、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥後、乾燥剤をろ別し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝７５：２５～６０：４０）にて精製し、４－｛［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］スルファニル｝フェノール
（２７５ｍｇ）を得た。
参考例１１－２で得られた化合物（８０ｍｇ）および上記で得られた化合物（１２８ｍｇ）を用い、参考例１０－１と同様にして反応および精製を行い、プロパン－２－イル　２－［３－（４－｛［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］スルファニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート（１６６ｍｇ）を得た。
上記で得られた化合物（６３ｍｇ）をテトラヒドロフランおよびメタノールの混合溶媒（１：１）（１．２ｍＬ）に溶解し、氷冷下にて３０％過酸化水素水（７８０μＬ）を加え、氷浴をはずして一晩撹拌した。反応液へ飽和チオ硫酸ナトリウム水溶液を加えて３０分間撹拌後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウム乾燥後、乾燥剤をろ別し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝５０：５０～２０：８０）にて精製し、プロパン－２－イル　２－［３－（４－｛［２－（テトラヒドロ－２Ｈ－ピラン－２－イルオキシ）エチル］スルフィニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート（５４ｍｇ）を得た。
上記で得られた化合物（５４ｍｇ）をエタノール（１ｍＬ）に溶解し、ｐ－トルエンスルホン酸一水和物（４ｍｇ）を加え、室温で一晩撹拌した。溶媒を減圧下留去し、飽和重曹水を加えてクロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、乾燥剤をろ別し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝２５：７５～０：１００）にて精製し、表題化合物（４６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.34 - 1.49 (m, 4 H) 1.50 - 1.63 (m, 4 H) 1.66 - 1.79 (m, 2 H) 1.92 - 2.03 (m, 2 H) 2.19 - 2.33 (m, 1 H) 2.79 - 2.90 (m, 1 H) 3.02 - 3.21 (m, 2 H) 3.25 - 3.42 (m, 4 H) 3.92 - 4.22 (m, 4 H) 4.84 - 4.95 (m, 1 H) 6.99 - 7.07 (m, 2 H) 7.53 - 7.61 (m, 2 H).
MS ESI/APCI Dual posi: 438[M+H]+.
実施例１７－２
プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）スルフォニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000207
 A chloroform suspension of 4-mercaptophenylboronic acid (2.0 g), pinacol (1.55 g), and magnesium sulfate (3.26 g) was stirred at room temperature overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 85: 15) to give 4- (4, 4, 5, 5- Tetramethyl-1,3,2-dioxaborolan-2-yl) benzenethiol (3.36 g) was obtained.
The compound (500 mg) obtained above was dissolved in a mixed solution of tetrahydrofuran and N, N-dimethylformamide (1: 1) (20 mL), and sodium hydride (60%, dispersed in liquid paraffin) under ice-cooling. (102 mg) was added. After stirring for 10 minutes, 2- (2-chloroethoxy) tetrahydro-2H-pyran (375 μL) was added, the ice bath was removed, and the mixture was stirred for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The filtrate was evaporated under reduced pressure to give 2- (2-{[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfanyl} ethoxy) tetrahydro- 2H-pyran (830 mg) was obtained.
Further, the compound (830 mg) obtained above was dissolved in a mixed solvent of tetrahydrofuran and methanol (1: 1) (20 mL), 30% hydrogen peroxide (960 μL) was added under ice cooling, and the ice bath was added. Removed and stirred overnight. A saturated aqueous sodium thiosulfate solution was added to the reaction solution and stirred for 30 minutes, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 75: 25-60: 40), and 4-{[2- (tetrahydro-2H-pyran-2-yloxy) ethyl] sulfanyl} Phenol (275 mg) was obtained.
Using the compound obtained in Reference Example 11-2 (80 mg) and the compound obtained above (128 mg), the reaction and purification were carried out in the same manner as in Reference Example 10-1, and propan-2-yl 2- [3 -(4-{[2- (Tetrahydro-2H-pyran-2-yloxy) ethyl] sulfanyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate (166 mg) was obtained.
The compound (63 mg) obtained above was dissolved in a mixed solvent of tetrahydrofuran and methanol (1: 1) (1.2 mL), 30% hydrogen peroxide (780 μL) was added under ice cooling, and the ice bath was added. Removed and stirred overnight. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 50: 50 to 20:80), and propan-2-yl 2- [3- (4-{[2- (tetrahydro-2H -Pyran-2-yloxy) ethyl] sulfinyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate (54 mg) was obtained.
The compound (54 mg) obtained above was dissolved in ethanol (1 mL), p-toluenesulfonic acid monohydrate (4 mg) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 25: 75-0: 100) to give the title compound (46 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.34-1.49 (m, 4 H) 1.50-1.63 (m, 4 H) 1.66-1.79 (m, 2 H) 1.92-2.03 (m, 2 H) 2.19-2.33 (m, 1 H) 2.79-2.90 (m, 1 H) 3.02-3.21 (m, 2 H) 3.25-3.42 (m, 4 H) 3.92-4.22 (m, 4 H) 4.84-4.95 (m, 1 H) 6.99-7.07 (m, 2 H) 7.53-7.61 (m, 2 H).
MS ESI / APCI Dual posi: 438 [M + H] + .
Example 17-2
Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) sulfonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000208
 実施例１７－１で得られた化合物（３３ｍｇ）をクロロホルム（１．０ｍＬ）に溶解し、３－クロロ過安息香酸 (７０％ｗ／ｗ)（２６ｍｇ）を加え、室温で一晩撹拌した。反応液へ飽和重曹水を加えた後、クロロホルムで抽出した。有機層を無水硫酸ナトリウム乾燥後、乾燥剤をろ別し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝７５：２５～６０：４０）にて精製し、表題化合物（１５ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.32 - 1.63 (m, 8 H) 1.66 - 1.81 (m, 2 H) 1.93 - 2.04 (m, 2 H) 2.19 - 2.34 (m, 1 H) 2.71 - 2.82 (m, 1 H) 3.22 - 3.44 (m, 6 H) 3.93 - 4.06 (m, 4 H) 4.84 - 4.96 (m, 1 H) 6.96 - 7.05 (m, 2 H) 7.80 - 7.88 (m, 2 H).
MS ESI/APCI Dual posi: 454[M+H]+.
実施例１８－１
ｔｅｒｔ－ブチル　２－（３－｛［４－（メチルスルホニル）フェニル］アミノ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000208
 The compound (33 mg) obtained in Example 17-1 was dissolved in chloroform (1.0 mL), 3-chloroperbenzoic acid (70% w / w) (26 mg) was added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 75: 25-60: 40) to obtain the title compound (15 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.32-1.63 (m, 8 H) 1.66-1.81 (m, 2 H) 1.93-2.04 (m, 2 H) 2.19-2.34 (m, 1 H) 2.71-2.82 (m, 1 H) 3.22-3.44 (m, 6 H) 3.93-4.06 (m, 4 H) 4.84-4.96 (m, 1 H) 6.96-7.05 (m, 2 H) 7.80-7.88 (m, 2 H).
MS ESI / APCI Dual posi: 454 [M + H] + .
Example 18-1
tert-Butyl 2- (3-{[4- (methylsulfonyl) phenyl] amino} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000209
 参考例２－３で得られた化合物（３００ｍｇ）をエタノール（６ｍＬ）に溶解し、２．５Ｍ水酸化ナトリウム水溶液（３ｍＬ）を加え、室温で一晩撹拌した。溶媒を減圧下留去し、残渣に１Ｍ塩酸水溶液を加え、クロロホルムで抽出した。有機層をフェーズセパレーターに通した後、減圧濃縮し、３－［７－（ｔｅｒｔ－ブトキシカルボニル）－７－アザスピロ［３．５］ノナ－２－イル］プロパン酸（３１０ｍｇ）を得た。
上記で得られた化合物（２４０ｍｇ）をクロロホルム（８ｍＬ）に溶解し、Ｎ－メチルモルホリン（１１５μＬ）を加え、氷冷下にてクロロぎ酸イソブチル（１３０μＬ）を加えた。室温に昇温後、２時間撹拌し、４－（メチルチオ）アニリン（１５５μＬ）を加え、１．５時間撹拌した。反応液へ水を加え、クロロホルムで抽出し、有機層をフェーズセパレーターに通した後、減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝８５：１５～７０：３０）にて精製し、ｔｅｒｔ－ブチル ２－（３－｛［４－（メチルスルファニル)フェニル）アミノ］－３－オキソプロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート（２８０ｍｇ）を得た。
上記で得られた化合物（２７６ｍｇ）を用い、実施例１７－２と同様にして反応および精製を行い、ｔｅｒｔ－ブチル ２－（３－｛［４－（メチルスルホニル）フェニル］アミノ｝－３－オキソプロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート（１１０ｍｇ）を得た。
上記で得られた化合物（９０ｍｇ）をテトラヒドロフラン（２ｍＬ）に溶解し、氷冷下にて水素化リチウムアルミニウム（１０ｍｇ）を加え、室温で５時間撹拌後、さらに氷冷下で水素化リチウムアルミニウム（２０ｍｇ）を加え、室温で３時間撹拌した。その後、反応温度を５０℃に昇温して一晩撹拌した。反応容器を氷冷で冷却後、硫酸ナトリウム１０水和物を適量加え、氷浴をはずして一晩撹拌し、反応液をセライトろ過した。ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝６５：３５～５０：５０）にて精製し、表題化合物（５１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32 - 1.58 (m, 10 H) 1.43 (s, 9 H) 1.91 - 1.98 (m, 2 H) 2.17 - 2.26 (m, 1 H) 2.98 (s, 3 H) 3.09 - 3.16 (m, 2 H) 3.21 - 3.27 (m, 2 H) 3.30 - 3.35 (m, 2 H) 4.16 - 4.22 (m, 1 H) 6.55 - 6.62 (m, 2 H) 7.64 - 7.71 (m, 2 H).
MS ESI/APCI Dual posi: 459[M+Na]+.
MS ESI/APCI Dual posi: 435[M-H]-.
実施例１８－２
ｔｅｒｔ－ブチル　２－（３－｛メチル［４－（メチルスルホニル）フェニル］アミノ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000209
 The compound (300 mg) obtained in Reference Example 2-3 was dissolved in ethanol (6 mL), 2.5 M aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, 1M aqueous hydrochloric acid solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was passed through a phase separator and then concentrated under reduced pressure to obtain 3- [7- (tert-butoxycarbonyl) -7-azaspiro [3.5] non-2-yl] propanoic acid (310 mg).
The compound (240 mg) obtained above was dissolved in chloroform (8 mL), N-methylmorpholine (115 μL) was added, and isobutyl chloroformate (130 μL) was added under ice cooling. After warming to room temperature, the mixture was stirred for 2 hours, 4- (methylthio) aniline (155 μL) was added, and the mixture was stirred for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was passed through a phase separator and then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 85: 15 to 70:30), and tert-butyl 2- (3-{[4- (methylsulfanyl) phenyl) amino]- 3-Oxopropyl} -7-azaspiro [3.5] nonane-7-carboxylate (280 mg) was obtained.
The compound (276 mg) obtained above was used for reaction and purification in the same manner as in Example 17-2, and tert-butyl 2- (3-{[4- (methylsulfonyl) phenyl] amino} -3- Oxopropyl) -7-azaspiro [3.5] nonane-7-carboxylate (110 mg) was obtained.
The compound (90 mg) obtained above was dissolved in tetrahydrofuran (2 mL), lithium aluminum hydride (10 mg) was added under ice cooling, the mixture was stirred at room temperature for 5 hours, and further lithium aluminum hydride (10 mg) under ice cooling. 20 mg) was added and stirred at room temperature for 3 hours. Thereafter, the reaction temperature was raised to 50 ° C. and stirred overnight. After cooling the reaction vessel with ice cooling, an appropriate amount of sodium sulfate decahydrate was added, the ice bath was removed and the mixture was stirred overnight, and the reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 65: 35-50: 50) to obtain the title compound (51 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32-1.58 (m, 10 H) 1.43 (s, 9 H) 1.91-1.98 (m, 2 H) 2.17-2.26 (m, 1 H) 2.98 (s , 3 H) 3.09-3.16 (m, 2 H) 3.21-3.27 (m, 2 H) 3.30-3.35 (m, 2 H) 4.16-4.22 (m, 1 H) 6.55-6.62 (m, 2 H) 7.64 -7.71 (m, 2 H).
MS ESI / APCI Dual posi: 459 [M + Na] + .
MS ESI / APCI Dual posi: 435 [MH] - .
Example 18-2
tert-Butyl 2- (3- {methyl [4- (methylsulfonyl) phenyl] amino} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000210
 実施例１８－１で得られた化合物（３７ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（８５０μＬ）に溶解し、水素化ナトリウム (６０％ｗ／ｗ)（５．１ｍｇ）を加え、２０分間撹拌した。ここへヨードメタン（１１μＬ）を加え、一晩撹拌した。反応液を酢酸エチルで希釈後、水および飽和食塩水で順次洗浄し、水層を酢酸エチルおよびノルマルヘキサンの混合溶媒で抽出した。先の有機層と合わせて、フェーズセパレーターに通して減圧下溶媒を留去し、得られた残渣を分取用ＨＰＬＣで精製し、表題化合物（１８ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31 - 1.59 (m, 10 H) 1.43 (s, 9 H) 1.91 - 1.97 (m, 2 H) 2.15 - 2.24 (m, 1 H) 2.99 (s, 3 H) 3.00 (s, 3 H) 3.20 - 3.27 (m, 2 H) 3.29 - 3.38 (m, 4 H) 6.62 - 6.69 (m, 2 H) 7.67 - 7.74 (m, 2 H).
MS ESI/APCI Dual posi: 473[M+Na]+.
実施例１９－１
４－｛３－［７－（２，２－ジメチルプロピル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド
Figure JPOXMLDOC01-appb-C000210
 The compound (37 mg) obtained in Example 18-1 was dissolved in N, N-dimethylformamide (850 μL), sodium hydride (60% w / w) (5.1 mg) was added, and the mixture was stirred for 20 minutes. To this was added iodomethane (11 μL) and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and the aqueous layer was extracted with a mixed solvent of ethyl acetate and normal hexane. Combined with the previous organic layer, the solvent was distilled off under reduced pressure through a phase separator, and the resulting residue was purified by preparative HPLC to obtain the title compound (18 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.59 (m, 10 H) 1.43 (s, 9 H) 1.91-1.97 (m, 2 H) 2.15-2.24 (m, 1 H) 2.99 (s , 3 H) 3.00 (s, 3 H) 3.20-3.27 (m, 2 H) 3.29-3.38 (m, 4 H) 6.62-6.69 (m, 2 H) 7.67-7.74 (m, 2 H).
MS ESI / APCI Dual posi: 473 [M + Na] + .
Example 19-1
4- {3- [7- (2,2-dimethylpropyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide
Figure JPOXMLDOC01-appb-C000211
 実施例３－１で得られた化合物（８０ｍｇ）を用いて、参考例１２－２と同様にして反応及び精製を行い、４－［３－（７－アザスピロ［３．５］ノナ－２－イル）プロポキシ］－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド（７４ｍｇ）を得た。
さらに上記で得られた化合物（５０ｍｇ）、ピバルアルデヒド（２５ｍｇ）、および酢酸（２５μＬ）のジメチルスルホキシド－テトラヒドロフラン溶液（１：１、２ｍＬ）にナトリウムトリアセトキシボロヒドリド（７５ｍｇ）を加え、３時間撹拌した。反応液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０～８０：２０）、およびＮＨ型シリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝１００：０～０：１００）にて精製し、表題化合物（６ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84 (s, 9 H) 1.25 - 1.36 (m, 2 H) 1.43 - 1.64 (m, 6 H) 1.65 - 1.77 (m, 2 H) 1.87 - 2.00 (m, 4 H) 2.12 - 2.27 (m, 1 H) 2.28 - 2.44 (m, 4 H) 3.59 - 3.68 (m, 2 H) 3.78 - 3.88 (m, 2 H) 3.96 (t, J=6.5 Hz, 2 H) 6.61 (dd, J=14.2, 2.4 Hz, 1 H) 6.77 (dd, J=9.0, 2.3 Hz, 1 H) 6.99 - 7.15 (m, 1 H) 8.04 (t, J=9.0 Hz, 1 H).
MS ESI/APCI Dual posi: 435[M+H]+, 457[M+Na]+.
MS ESI/APCI Dual nega: 433[M-H]-, 469[M+Cl]-.
実施例２０－１
プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－オキソピロリジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000211
 The compound (80 mg) obtained in Example 3-1 was used for reaction and purification in the same manner as in Reference Example 12-2 to give 4- [3- (7-azaspiro [3.5] non-2- Yl) propoxy] -2-fluoro-N- (2-hydroxyethyl) benzamide (74 mg).
Further, sodium triacetoxyborohydride (75 mg) was added to a dimethyl sulfoxide-tetrahydrofuran solution (1: 1, 2 mL) of the compound obtained above (50 mg), pivalaldehyde (25 mg), and acetic acid (25 μL) for 3 hours. Stir. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 0 to 80:20) and NH type silica gel column chromatography (normal hexane: ethyl acetate = 100: 0 to 0: 100). Purification gave the title compound (6 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84 (s, 9 H) 1.25-1.36 (m, 2 H) 1.43-1.64 (m, 6 H) 1.65-1.77 (m, 2 H) 1.87-2.00 (m, 4 H) 2.12-2.27 (m, 1 H) 2.28-2.44 (m, 4 H) 3.59-3.68 (m, 2 H) 3.78-3.88 (m, 2 H) 3.96 (t, J = 6.5 Hz , 2 H) 6.61 (dd, J = 14.2, 2.4 Hz, 1 H) 6.77 (dd, J = 9.0, 2.3 Hz, 1 H) 6.99-7.15 (m, 1 H) 8.04 (t, J = 9.0 Hz, 1 H).
MS ESI / APCI Dual posi: 435 [M + H] + , 457 [M + Na] + .
MS ESI / APCI Dual nega: 433 [MH] - , 469 [M + Cl] - .
Example 20-1
Propan-2-yl 2- (3- {3-fluoro-4-[(2-oxopyrrolidin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000212
 参考例１１－４で得られた化合物（７０ｍｇ）のトルエン（２ｍＬ）溶液に塩化チオニル（５０μＬ）、Ｎ，Ｎ－ジメチルホルムアミド（２０μＬ）を加え、室温で２時間攪拌した後、反応液を減圧濃縮した。残渣のテトラヒドロフラン（１ｍＬ）溶液を、氷冷下攪拌している２－ピロリドン（３０ｍｇ）、トリエチルアミン（６０μＬ）のテトラヒドロフラン（１ｍＬ）溶液に加えて、室温で２時間攪拌した。反応液に水を加え、酢酸エチルで３回抽出した。有機層を水で１回、飽和食塩水で１回洗浄し、硫酸マグネシウムで乾燥した。乾燥剤をろ別後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ノルマルヘキサン：酢酸エチル＝９０：１０～０：１００）、次いでＮHシリカゲルクロマトグラフィー（９０：１０～０：１００）にて精製し、表題化合物（２１ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.4 Hz, 6 H) 1.33 - 1.49 (m, 4 H) 1.50 - 1.60 (m, 4 H) 1.64 - 1.77 (m, 2 H) 1.92 - 2.02 (m, 2 H) 2.06 - 2.18 (m, 2 H) 2.19 - 2.32 (m, 1 H) 2.55 - 2.64 (m, 2 H) 3.26 - 3.43 (m, 4 H) 3.91 - 4.01 (m, 4 H) 4.83 - 4.96 (m, 1 H) 6.51 - 6.62 (m, 1 H) 6.67 - 6.76 (m, 1 H) 7.38 - 7.47 (m, 1 H).
MS ESI/APCI Dual posi: 475[M+H]+.
実施例２１－１
プロパン－２－イル　２－（３－｛［５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート
Figure JPOXMLDOC01-appb-C000212
 Thionyl chloride (50 μL) and N, N-dimethylformamide (20 μL) were added to a toluene (2 mL) solution of the compound (70 mg) obtained in Reference Example 11-4, and the mixture was stirred at room temperature for 2 hours. Concentrated. A solution of the residue in tetrahydrofuran (1 mL) was added to a solution of 2-pyrrolidone (30 mg) and triethylamine (60 μL) in tetrahydrofuran (1 mL) stirred under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed once with water and once with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane: ethyl acetate = 90: 10 to 0: 100) and then NH silica gel chromatography (90:10 to 0: 100). To give the title compound (21 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.4 Hz, 6 H) 1.33-1.49 (m, 4 H) 1.50-1.60 (m, 4 H) 1.64-1.77 (m, 2 H) 1.92-2.02 (m, 2 H) 2.06-2.18 (m, 2 H) 2.19-2.32 (m, 1 H) 2.55-2.64 (m, 2 H) 3.26-3.43 (m, 4 H) 3.91-4.01 (m, 4 H) 4.83-4.96 (m, 1 H) 6.51-6.62 (m, 1 H) 6.67-6.76 (m, 1 H) 7.38-7.47 (m, 1 H).
MS ESI / APCI Dual posi: 475 [M + H] + .
Example 21-1
Propan-2-yl 2- (3-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate
Figure JPOXMLDOC01-appb-C000213
 参考例４８－１で得られた化合物（２２４ｍｇ）を用いて参考例１２－２と同様に反応、精製を行い、２－｛３－［（５－ブロモピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン（１６０ｍｇ）を得た。
つぎに上記で得られた化合物（７７ｍｇ）を用いて、参考例４０－７と同様に反応、精製を行い、プロパン－２－イル　２－｛３－［（５－ブロモピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート（８８ｍｇ）を得た。
さらに上記で得られた化合物（８８ｍｇ）をジメチルスルホキシド（１ｍＬ）に溶解し、メタンスルフィン酸ナトリウム（４５ｍｇ）、Ｎ，Ｎ’－ジメチルエチレンジアミン（９μＬ）およびトリフルオロメタンスルホン酸銅（Ｉ) ベンゼン コンプレックス（１２ｍｇ）を加え、１１０℃で５時間撹拌した。反応液を酢酸エチルで希釈し、水および飽和食塩水で洗浄後、水層を酢酸エチルおよびノルマルヘキサンの混合溶媒で抽出した。先の有機層と合わせて、フェーズセパレーターに通して減圧下溶媒を留去し、得られた残渣をＨＰＬＣで精製し、表題化合物（３８ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.2 Hz, 6 H) 1.33 - 1.62 (m, 8 H) 1.68 - 1.80 (m, 2 H) 1.93 - 2.03 (m, 2 H) 2.19 - 2.33 (m, 1 H) 3.19 (s, 3 H) 3.26 - 3.34 (m, 2 H) 3.35 - 3.42 (m, 2 H) 4.41 (t, J=6.6 Hz, 2 H) 4.85 - 4.95 (m, 1 H) 8.22 - 8.25 (m, 1 H) 8.78 - 8.81 (m, 1 H).
MS ESI/APCI Dual posi: 426[M+H]+.
Figure JPOXMLDOC01-appb-C000213
 Using the compound (224 mg) obtained in Reference Example 48-1, reaction and purification were carried out in the same manner as in Reference Example 12-2 to give 2- {3-[(5-bromopyrazin-2-yl) oxy] propyl}. -7-azaspiro [3.5] nonane (160 mg) was obtained.
Next, using the compound (77 mg) obtained above, the reaction and purification were carried out in the same manner as in Reference Example 40-7 to produce propan-2-yl 2- {3-[(5-bromopyrazin-2-yl). Oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate (88 mg) was obtained.
Further, the compound (88 mg) obtained above was dissolved in dimethyl sulfoxide (1 mL), sodium methanesulfinate (45 mg), N, N′-dimethylethylenediamine (9 μL) and copper trifluoromethanesulfonate (I) benzene complex ( 12 mg) was added and the mixture was stirred at 110 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and the aqueous layer was extracted with a mixed solvent of ethyl acetate and normal hexane. The combined organic layer was passed through a phase separator, the solvent was distilled off under reduced pressure, and the resulting residue was purified by HPLC to obtain the title compound (38 mg).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.2 Hz, 6 H) 1.33-1.62 (m, 8 H) 1.68-1.80 (m, 2 H) 1.93-2.03 (m, 2 H) 2.19-2.33 (m, 1 H) 3.19 (s, 3 H) 3.26-3.34 (m, 2 H) 3.35-3.42 (m, 2 H) 4.41 (t, J = 6.6 Hz, 2 H) 4.85- 4.95 (m, 1 H) 8.22-8.25 (m, 1 H) 8.78-8.81 (m, 1 H).
MS ESI / APCI Dual posi: 426 [M + H] + .
以下の実施例２１－２～２１－４も、参考例４８－１、または参考例４９－２で得られた化合物と対応するカーバメート化試薬を用いて、参考例２１－１に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表９－１に示す。 Examples 21-2 to 21-4 below are also described in Reference Example 21-1, using the carbamate reagent corresponding to the compound obtained in Reference Example 48-1 or Reference Example 49-2. Synthesized according to the method. The structures, NMR data, and MS data of these compounds are shown in Table 9-1.
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000214
　試験例１
　本発明化合物をヒトＧＰＲ１１９発現細胞に添加し、同細胞のｃＡＭＰ産生量を指標としてＧＰＲ１１９アゴニスト活性の評価を行った。 Test example 1
The compound of the present invention was added to human GPR119-expressing cells, and GPR119 agonist activity was evaluated using the amount of cAMP produced by the cells as an index.
（１）ヒトＧＰＲ１１９発現細胞の構築
　ヒトＧＰＲ１１９（ＮＭ_１７８４７１）はヒトＭＴＣ多組織ｃＤＮＡパネル（Ｃｌｏｎｔｅｃｈ）を鋳型とし、ＫＯＤ－ｐｌｕｓ　ｐｏｌｙｍｅｒａｓｅを用いたポリメラーゼ連鎖反応（ＰＣＲ）により増幅した。ヒトＧＰＲ１１９増幅産物をインサートとしてｐｃＤＮＡ５／ＦＲＴ／ＴＯ（Ｉｎｖｉｔｒｏｇｅｎ）に組込み、Ｆｌｐ－Ｉｎ　Ｔ－Ｒｅｘシステムを用いてテトラサイクリン用量依存的にヒトＧＰＲ１１９遺伝子を発現誘導可能な細胞株を作製した。 (1) Construction of human GPR119-expressing cells Human GPR119 (NM — 178471) was amplified by polymerase chain reaction (PCR) using KOD-plus polymerase using human MTC multi-tissue cDNA panel (Clontech) as a template. A human GPR119 amplification product was inserted into pcDNA5 / FRT / TO (Invitrogen) as an insert, and a cell line capable of inducing expression of the human GPR119 gene in a tetracycline dose-dependent manner using the Flp-In T-Rex system was prepared.
（２）細胞内ｃＡＭＰ産生亢進の測定法
　当該細胞株に最終濃度１０ｎｇ／ｍｌのテトラサイクリンを添加し、ヒトＧＰＲ１１９を発現誘導した。発現誘導刺激２４時間後に細胞を回収し、アッセイ用緩衝液（Ｄ－ＭＥＭ（Ｉｎｖｉｔｒｏｇｅｎ）、１ｍＭ　３－Ｉｓｏｂｕｔｙｌ－１－Ｍｅｔｈｙｌｘａｎｔｉｎｅ（Ｓｉｇｍａ）、０．０１％ウシ血清アルブミン（Ｓｉｇｍａ））に懸濁した後に５０００ｃｅｌｌｓ／１５μｌで９６穴ハーフエリアプレート（コーニング）に播種した。アッセイバッファーに溶解した被検化合物溶液１５μｌを各ウェルに添加し、３７℃で３０分間インキュベートした後にｃＡＭＰ　ＨｉＲａｎｇｅキット（Ｃｉｓｂｉｏ）のプロトコールに従いＥｎＶｉｓｉｏｎにて時間分解蛍光（Ｅｘ：３２０ｎｍ、Ｅｍ：６６５ｎｍ、６２０ｎｍ）を測定した。測定された蛍光強度からａｎｔｉ－ｃＡＭＰ－ＣｒｙｐｔａｔｅとｃＡＭＰ－ｄ２のＲａｔｉｏ値を算出した。Ｒａｔｉｏ値の解析にはＸＬｆｉｔを使用し、ｃＡＭＰ標準曲線を作成した後に被検化合物存在下における各ウェルのｃＡＭＰ濃度を算出した。被検化合物高用量下の最大ｃＡＭＰ濃度（Ｅｍａｘ）からＤＭＳＯ存在下のｃＡＭＰ濃度を差し引いた値より、最大に活性化されたＧＰＲ１１９活性を１００％として、５０％活性化する化合物濃度（ＥＣ50）を算出した。なお、被検化合物の最大活性化率（Ｅｍａｘ）を算出できない場合、ＤＭＳＯ存在下のｃＡＭＰ濃度を１００％として、被検化合物存在下のｃＡＭＰ濃度上昇率（％ｓｔｉｍｕｌａｔｉｏｎ）を算出した。 (2) Measurement method for enhancement of intracellular cAMP production Tetracycline having a final concentration of 10 ng / ml was added to the cell line to induce expression of human GPR119. Cells were collected 24 hours after the expression-inducing stimulation and suspended in assay buffer (D-MEM (Invitrogen), 1 mM 3-Isobutyl-1-methylxantine (Sigma), 0.01% bovine serum albumin (Sigma)). Later, it was seeded on a 96-well half area plate (Corning) at 5000 cells / 15 μl. 15 μl of a test compound solution dissolved in assay buffer was added to each well, incubated at 37 ° C. for 30 minutes, and then time-resolved fluorescence (Ex: 320 nm, Em: 665 nm, 620 nm) with EnVision according to the protocol of cAMP HiRange kit (Cisbio). ) Was measured. The ratio values of anti-cAMP-Cryptate and cAMP-d2 were calculated from the measured fluorescence intensity. For analysis of the ratio value, XLfit was used, and after preparing a cAMP standard curve, the cAMP concentration in each well in the presence of the test compound was calculated. The compound concentration that activates 50% of the maximum activated GPR119 activity as 100% from the value obtained by subtracting the cAMP concentration in the presence of DMSO from the maximum cAMP concentration (Emax) under the high dose of the test compound (EC 50 ) Was calculated. When the maximum activation rate (Emax) of the test compound could not be calculated, the cAMP concentration increase rate (% stimulation) in the presence of the test compound was calculated with the cAMP concentration in the presence of DMSO as 100%.
（３）結果
　本発明の化合物について上記試験を行った測定結果をもとに算出したＧＰＲ１１９アゴニスト活性を表１０－１～１０－３に示す。 (3) Results Tables 10-1 to 10-3 show the GPR119 agonist activities calculated based on the measurement results obtained by conducting the above tests on the compounds of the present invention.
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000217
　本発明化合物の製剤例を以下に示す。
製剤例１
　以下の成分を含有する顆粒剤を製造する。
成分　式（Ｉ）で表される化合物　　　　　10mg
　　　乳糖　　　　　　　　　　　　　　　700mg
　　　コーンスターチ　　　　　　　　　　274mg
　　　ＨＰＣ－Ｌ　　　　　　　　　　　　 16mg
　　　　　　　　　　　　　　　　　　　 1000mg
式（Ｉ）で表される化合物と乳糖を６０メッシュのふるいに通す。コーンスターチを１２０メッシュのふるいに通す。これらをＶ型混合機にて混合する。混合末に低粘度ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ）水溶液を添加し、練合、造粒（押し出し造粒　孔径０．５～１ｍｍ）した後、乾燥する。得られた乾燥顆粒を振動ふるい（１２／６０メッシュ）で篩過し顆粒剤を得る。 Formulation examples of the compound of the present invention are shown below.
Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (I) 10mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulated pore diameter: 0.5 to 1 mm), and then dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.
製剤例２
　以下の成分を含有するカプセル充填用散剤を製造する。
成分　式（Ｉ）で表される化合物　　　　　10mg
　　　乳糖　　　　　　　　　　　　　　　79mg
　　　コーンスターチ　　　　　　　　　　10mg
　　　ステアリン酸マグネシウム　　　　　 1mg
　　　　　　　　　　　　　　　　　　　 100mg
式（Ｉ）で表される化合物と乳糖を６０メッシュのふるいに通す。コーンスターチを１２０メッシュのふるいに通す。これらとステアリン酸マグネシウムをＶ型混合機にて混合する。１０倍散１００ｍｇを５号硬ゼラチンカプセルに充填する。 Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (I) 10mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
100mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.
製剤例３
　以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分　式（Ｉ）で表される化合物　　　　　15mg
　　　乳糖　　　　　　　　　　　　　　　90mg
　　　コーンスターチ　　　　　　　　　　42mg
　　　ＨＰＣ－Ｌ　　　　　　　　　　　　 3mg
　　　　　　　　　　　　　　　　　　　 150mg
式（Ｉ）で表される化合物と乳糖を６０メッシュのふるいに通す。コーンスターチを１２０メッシュのふるいに通す。これらをＶ型混合機にて混合する。混合末に低粘度ヒドロキシプロピルセルロース（ＨＰＣ－Ｌ）水溶液を添加し、練合、造粒した後、乾燥する。得られた乾燥顆粒を振動ふるい（１２／６０メッシュ）で篩過し整粒し、その１５０ｍｇを４号硬ゼラチンカプセルに充填する。 Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Ingredient Compound represented by formula (I) 15mg
Lactose 90mg
Cornstarch 42mg
HPC-L 3mg
150mg
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granule is sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.
製剤例４
　以下の成分を含有する錠剤を製造する。
成分　式（Ｉ）で表される化合物　　　　　10mg
　　　乳糖　　　　　　　　　　　　　　　90mg
　　　微結晶セルロース　　　　　　　　　30mg
　　　ステアリン酸マグネシウム　　　　　 5mg
　　　CMC-Na　　　　　　　　　　　　　　15mg
　　　　　　　　　　　　　　　　　　　　150mg
式（Ｉ）で表される化合物と乳糖と微結晶セルロース、ＣＭＣ－Ｎａ（カルボキシメチルセルロース　ナトリウム塩）を６０メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウムを添加し、製剤用混合末を得る。本混合末を直打し１５０ｍｇの錠剤を得る。 Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
150mg
A compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.
製剤例５
　静脈用製剤は次のように製造する。
式（Ｉ）で表される化合物　　　　　　　 100mg
飽和脂肪酸グリセリド　　　　　　　　　1000ml
上記成分の溶液は通常、１分間に１ｍｌの速度で患者に静脈内投与される。 Formulation Example 5
The intravenous formulation is produced as follows.
100 mg of the compound represented by formula (I)
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.
　本発明化合物は優れたＧＰＲ１１９アゴニスト作用を有し、本発明により糖尿病に由来する疾病等の予防又は治療に有効な医薬品を提供するが可能となり、患者の負担を軽減し、医薬品産業の発達に寄与することが期待される。 The compound of the present invention has an excellent GPR119 agonist activity, and according to the present invention, it is possible to provide a pharmaceutical effective for the prevention or treatment of diseases derived from diabetes, thereby reducing the burden on the patient and contributing to the development of the pharmaceutical industry. Is expected to do.

Claims (18)

  1. 　下記一般式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
     （式（Ｉ）中、
    　ｍ１は、０～２の整数を示し、
    　ｍ２は、１～２の整数を示し、
    　Ａで表される環は、ベンゼン環又は６員のヘテロ芳香環を示し、
    　Ｒ11、Ｒ12及びＲ13は、同一に又は異なって置換基群Ｚ１から選ばれる基を示し、
    　置換基群Ｚ１は、水素原子、ハロゲン原子、カルバモイル、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、アリール、ヘテロアリール、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）、ジＣ1-6アルキルアミノ、モノＣ1-6アルキルアミノカルボニル及びジＣ1-6アルキルアミノカルボニルからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、ヒドロキシ、ハロゲン原子、カルバモイル、シアノ及びオキソからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル、Ｃ1-6アルキルスルフィニル（該Ｃ1-6アルキルスルフィニルは、置換されていないか、１個のヒドロキシで置換されている。）及びＣ1-6アルキルスルホニル（該Ｃ1-6アルキルスルホニルは、置換されていないか、１個のヒドロキシで置換されている。）の基からなる群を示し、
    　Ｘは、-Ｏ-又は-ＮＲ3-を示し、
    　　Ｒ3は、水素原子又はＣ1-4アルキルを示し、
    　Ｙは、Ｃ1-6アルカンジイルを示し、
    　Ｒ2は、
    　（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、Ｃ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、トリフルオロメチル及びＣ1-6アルキルからなる群より選ばれる１個の基で置換されている。）及びアリールからなる群より選ばれる１個の基で置換されている。］、ハロＣ1-6アルキル若しくはＣ3-8シクロアルキル、
    　（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝、
    　（ｃ）下記式（β）で表される５又は６員のヘテロアリール
    Figure JPOXMLDOC01-appb-C000002
     （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）、
    　（ｄ）Ｃ1-6アルキルスルホニル若しくはＣ3-8シクロアルキルスルホニル、
    　（ｅ）Ｃ1-6アルキルカルボニル（該Ｃ1-6アルキルカルボニルは、置換されていないか、１個のＣ3-8シクロアルキルで置換されている。）若しくはＣ3-8シクロアルキルカルボニル（該Ｃ3-8シクロアルキルカルボニルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）又は
    　（ｆ）Ｃ1-6アルキルアミノカルボニル
    を示す。）
    で表される化合物又はその製薬学的に許容される塩。     The following general formula (I)
    Figure JPOXMLDOC01-appb-C000001
     (In the formula (I),
    m1 represents an integer of 0 to 2,
    m2 represents an integer of 1 to 2,
    The ring represented by A represents a benzene ring or a 6-membered heteroaromatic ring,
    R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z1;
    Substituent group Z1 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl are unsubstituted or hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy is not substituted) or is substituted by one hydroxy.), di-C 1-6 alkylamino, mono-C 1-6 alkylaminocarbonyl and di-C 1-6 alkyl The same from the group consisting of amino carbonyl or different substituted with 1 to 2 groups selected. A saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of hydroxy, halogen atom, carbamoyl, cyano and oxo, the same or different) Monosaturated heterocyclylaminocarbonyl, C 1-6 alkylsulfinyl (wherein the C 1-6 alkylsulfinyl is unsubstituted or substituted with one hydroxy) and C 1-6 Represents a group consisting of alkylsulfonyl groups, wherein the C 1-6 alkylsulfonyl is unsubstituted or substituted with one hydroxy;
    X represents —O— or —NR 3 —;
    R 3 represents a hydrogen atom or C 1-4 alkyl,
    Y represents C 1-6 alkanediyl;
    R 2 is
    (A) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted, trifluoromethyl and C Substituted with one group selected from the group consisting of 1-6 alkyl) and one group selected from the group consisting of aryl. ] Halo C 1-6 alkyl or C 3-8 cycloalkyl,
    (B) —COOR 21 {R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). },
    (C) 5- or 6-membered heteroaryl represented by the following formula (β)
    Figure JPOXMLDOC01-appb-C000002
     (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected identically or differently from the group consisting of -6 alkoxy),
    (D) C 1-6 alkylsulfonyl or C 3-8 cycloalkylsulfonyl,
    (E) C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl is unsubstituted or substituted with one C 3-8 cycloalkyl) or C 3-8 cycloalkylcarbonyl ( The C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with one C 1-6 alkyl.) Or (f) C 1-6 alkylaminocarbonyl. )
    Or a pharmaceutically acceptable salt thereof.
  2. 　前記一般式（Ｉ）において、
    　Ｒ11、Ｒ12及びＲ13は、同一に又は異なって置換基群Ｚ２から選ばれる基を示し、
    　置換基群Ｚ２は、水素原子、ハロゲン原子、カルバモイル、シアノ、Ｃ1-6アルキル、ハロＣ1-6アルキル、アリール、ヘテロアリール、モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニル、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル及びＣ1-6アルキルＣ3-8シクロアルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-6アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル及びＣ1-6アルキルスルホニルの基からなる群を示し、
    　Ｒ2が、
    　（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、トリフルオロメチル及びＣ1-6アルキルからなる群より選ばれる１個の基で置換されている。）で置換されている。］、ハロＣ1-6アルキル若しくはＣ3-8シクロアルキル、
    　（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝又は
    　（ｃ）下記式（β）で表される５又は６員のヘテロアリール
    Figure JPOXMLDOC01-appb-C000003
     （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）
    を示す請求項１に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 11 , R 12 and R 13 are the same or different and each represents a group selected from the substituent group Z2;
    Substituent group Z2 is hydrogen atom, halogen atom, carbamoyl, cyano, C 1-6 alkyl, halo C 1-6 alkyl, aryl, heteroaryl, mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkyl Aminocarbonyl, di C 1-6 alkylaminocarbonyl, C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl, mono C 3-8 cycloalkylaminocarbonyl, diC 1- 6 alkylaminocarbonyl and C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl are unsubstituted or hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy is not substituted) or, one hydroxy substituted with.) and di C 1-6 1 ~ 2 groups that are identical to or different selected from the group consisting of alkylamino It has been replaced. ], Saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with 1 hydroxy), monosaturated heterocyclylaminocarbonyl and C 1-6 alkylsulfonyl groups Indicate
    R 2 is
    (A) C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or single C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or trifluoro Substituted with one group selected from the group consisting of methyl and C 1-6 alkyl. ] Halo C 1-6 alkyl or C 3-8 cycloalkyl,
    (B) —COOR 21 {R 21 is C 1-6 alkyl [wherein the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is Unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). } Or (c) 5- or 6-membered heteroaryl represented by the following formula (β)
    Figure JPOXMLDOC01-appb-C000003
     (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
    The compound of Claim 1 which shows or its pharmaceutically acceptable salt.
  3. 　前記一般式（Ｉ）において、
    　Ｒ2が、（ａ）Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のトリフルオロメチルで置換されている。）で置換されている。］又はハロＣ1-6アルキル
    を示す請求項１～２のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 2 is (a) C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or one C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted) Or is substituted with 1 trifluoromethyl). Or a pharmaceutically acceptable salt thereof. 3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, which represents halo C 1-6 alkyl.
  4. 　前記一般式（Ｉ）において、
    　Ｒ2が、（ｂ）－ＣＯＯＲ21｛Ｒ21は、Ｃ1-6アルキル［該Ｃ1-6アルキルは、置換されていないか、１個のＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）で置換されている。］、ハロＣ1-6アルキル又はＣ3-8シクロアルキル（該Ｃ3-8シクロアルキルは、置換されていないか、ハロゲン原子及びＣ1-6アルキルからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）を示す。｝
    を示す請求項１～２のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 2 is (b) -COOR 21 {R 21 is C 1-6 alkyl [the C 1-6 alkyl is unsubstituted or substituted with one C 3-8 cycloalkyl (the C 3-8 Cycloalkyl is unsubstituted or substituted with 1 C 1-6 alkyl). ] Halo C 1-6 alkyl or C 3-8 cycloalkyl (the C 3-8 cycloalkyl is unsubstituted or selected from the group consisting of halogen atoms and C 1-6 alkyl, the same or different) Substituted with 1 to 3 groups). }
    The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein
  5. 　前記一般式（Ｉ）において、
    　Ｒ2が、（ｂ）－ＣＯＯＲ21｛Ｒ21は、メチル［該メチルは、置換されていないか、１個のシクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）で置換されている。］、イソプロピル、イソブチル、tert-ブチル（該tert-ブチルは、置換されていないか、１～２個のフッ素原子で置換されている。）、ネオペンチル、シクロプロピル（該シクロプロピルは、置換されていないか、１個のメチルで置換されている。）又はシクロペンチルを示す。｝
    を示す請求項１～２又は４のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 2 is (b) -COOR 21 {R 21 is methyl [the methyl is unsubstituted or substituted with one cyclopropyl (the cyclopropyl is unsubstituted or substituted with one methyl Is replaced by ], Isopropyl, isobutyl, tert-butyl (the tert-butyl is unsubstituted or substituted with 1 to 2 fluorine atoms), neopentyl, cyclopropyl (the cyclopropyl is not substituted) Or substituted with 1 methyl) or cyclopentyl. }
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 4, wherein
  6. 　前記一般式（Ｉ）において、
    　Ｒ2が、（ｃ）下記式（β）で表される５又は６員のヘテロアリール
    Figure JPOXMLDOC01-appb-C000004
     （該式（β）で表される５又は６員のヘテロアリールは、置換されていないか、ハロゲン原子、Ｃ1-6アルキル、ハロＣ1-6アルキル、Ｃ3-8シクロアルキル及びＣ1-6アルコキシからなる群より同一に又は異なって選ばれる１～３個の基で置換されている。）
    を示す請求項１～２のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 2 is (c) a 5- or 6-membered heteroaryl represented by the following formula (β)
    Figure JPOXMLDOC01-appb-C000004
     (The 5- or 6-membered heteroaryl represented by the formula (β) is unsubstituted or substituted with a halogen atom, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl and C 1. Substituted with 1 to 3 groups selected from the group consisting of -6 alkoxy, the same or different.
    The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein
  7. 　前記一般式（Ｉ）において、
    　Ｒ2が、（ｃ）下記式（β）で表される５又は６員のヘテロアリールを示し、
    Figure JPOXMLDOC01-appb-C000005
     　ここで、該式（β）で表される５又は６員のヘテロアリールが、オキサジアゾリル、ピリジル又はピリミジニル（該オキサジアゾリル、ピリジル及びピリミジニルは、置換されていないか、フッ素原子、塩素原子、メチル、エチル、イソプロピル及びシクロプロピルからなる群より選ばれる１個の基で置換されている。）
    を示す請求項１～２又は６のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 2 represents (c) a 5- or 6-membered heteroaryl represented by the following formula (β),
    Figure JPOXMLDOC01-appb-C000005
     Here, the 5- or 6-membered heteroaryl represented by the formula (β) is oxadiazolyl, pyridyl or pyrimidinyl (the oxadiazolyl, pyridyl and pyrimidinyl are not substituted, fluorine atom, chlorine atom, methyl, ethyl , Substituted with one group selected from the group consisting of isopropyl and cyclopropyl.)
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 6, wherein
  8. 　前記一般式（Ｉ）において、
    　Ｒ2が、（ｅ）Ｃ1-6アルキルカルボニル（該Ｃ1-6アルキルカルボニルは、置換されていないか、１個のＣ3-8シクロアルキルで置換されている。）又はＣ3-8シクロアルキルカルボニル（該Ｃ3-8シクロアルキルカルボニルは、置換されていないか、１個のＣ1-6アルキルで置換されている。）
    を示す請求項１～２のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 2 is (e) a C 1-6 alkylcarbonyl (the C 1-6 alkylcarbonyl is unsubstituted or substituted with one C 3-8 cycloalkyl) or C 3-8 Cycloalkylcarbonyl (the C 3-8 cycloalkylcarbonyl is unsubstituted or substituted with 1 C 1-6 alkyl)
    The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein
  9. 　前記一般式（Ｉ）において、
    　ｍ１が、１を示し、
    　ｍ２が、１を示し、
    　Ｘが、-Ｏ-を示し、
    　Ｙが、Ｃ3-4アルカンジイル
    を示す請求項１～８のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    m1 represents 1,
    m2 represents 1,
    X represents —O—,
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein Y represents C 3-4 alkanediyl.
  10. 　前記一般式（Ｉ）において、
    　Ａで表される環が、ベンゼン環又はピリジン環
    を示す請求項１～９のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the ring represented by A represents a benzene ring or a pyridine ring.
  11. 　前記一般式（Ｉ）において、
    　Ｒ11が、カルバモイル、モノＣ1-6アルキルアミノカルボニル［該モノＣ1-6アルキルアミノカルボニルは、置換されていないか、ヒドロキシ、カルバモイル、シアノ、Ｃ1-6アルコキシ（該Ｃ1-6アルコキシは、置換されていないか、１個のヒドロキシで置換されている。）及びジＣ1-6アルキルアミノからなる群より同一に又は異なって選ばれる１～２個の基で置換されている。］、モノＣ3-8シクロアルキルアミノカルボニル、ジＣ1-6アルキルアミノカルボニル（該ジＣ1-6アルキルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｃ1-6アルキルＣ3-8シクロアルキルアミノカルボニル、飽和のヘテロシクリルカルボニル（該飽和のヘテロシクリルカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、モノ飽和のヘテロシクリルアミノカルボニル又はＣ1-6アルキルスルホニルを示し、
    　Ｒ12及びＲ13が、同一に又は異なって水素原子、ハロゲン原子及びＣ1-6アルキルからなる群より選ばれる基
    を示す請求項１～１０のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    R 11 is carbamoyl, mono C 1-6 alkylaminocarbonyl [the mono C 1-6 alkylaminocarbonyl is unsubstituted or is hydroxy, carbamoyl, cyano, C 1-6 alkoxy (the C 1-6 alkoxy Is unsubstituted or substituted with 1 hydroxy) and is substituted with 1 to 2 groups selected identically or differently from the group consisting of diC 1-6 alkylamino. ], Mono C 3-8 cycloalkylaminocarbonyl, diC 1-6 alkylaminocarbonyl (the diC 1-6 alkylaminocarbonyl is unsubstituted or substituted with one hydroxy). C 1-6 alkyl C 3-8 cycloalkylaminocarbonyl, saturated heterocyclylcarbonyl (the saturated heterocyclylcarbonyl is unsubstituted or substituted with one hydroxy), monosaturated heterocyclylaminocarbonyl Or C 1-6 alkylsulfonyl,
    The compound according to any one of claims 1 to 10, wherein R 12 and R 13 are the same or different and each represents a group selected from the group consisting of a hydrogen atom, a halogen atom, and C 1-6 alkyl, or a pharmaceutical preparation thereof Acceptable salt.
  12. 　前記一般式（Ｉ）において、
    　Ａで表される環が、ベンゼン環を示し、
    　Ｒ11が、カルバモイル、メチルアミノカルボニル（該メチルアミノカルボニルは、置換されていないか、カルバモイル及びシアノからなる群より選ばれる１個の基で置換されている。）、エチルアミノカルボニル［該エチルアミノカルボニルは、置換されていないか、ヒドロキシ、メトキシ、エトキシ（該エトキシは、置換されていないか、１個のヒドロキシで置換されている。）及びＮ，Ｎ－ジメチルアミノからなる群より選ばれる１個の基で置換されている。］、ｎ－プロピルアミノカルボニル（該ｎ－プロピルアミノカルボニル、置換されていないか、１～２個のヒドロキシで置換されている。）、イソプロピルアミノカルボニル（該イソプロピルアミノカルボニルは、置換されていないか、１～２個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル、Ｎ－エチル－Ｎ－メチルアミノカルボニル（該Ｎ－エチル－Ｎ－メチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、Ｎ－シクロプロピル－Ｎ－メチルアミノカルボニル、アゼチジン-１-イル-カルボニル（該アゼチジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、ピロリジン-１-イル-カルボニル（該ピロリジン-１-イル-カルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、オキセタン-３-イルアミノカルボニル又はメチルスルホニル
    を示し、
    　ここで、該Ｒ11は、上記ベンゼン環のパラ位に置換し、
    　Ｒ12及びＲ13が、同一に又は異なって水素原子、フッ素原子及びメチルからなる群より選ばれる基を示し、
    　ここで、該Ｒ12及びＲ13は、独立して上記ベンゼン環のオルト位又はメタ位に置換する
    請求項１～１１のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    The ring represented by A represents a benzene ring;
    R 11 is carbamoyl, methylaminocarbonyl (the methylaminocarbonyl is unsubstituted or substituted with one group selected from the group consisting of carbamoyl and cyano), ethylaminocarbonyl [the ethylamino Carbonyl is unsubstituted or selected from the group consisting of hydroxy, methoxy, ethoxy (wherein the ethoxy is unsubstituted or substituted with one hydroxy) and N, N-dimethylamino. Substituted with 1 group. ], N-propylaminocarbonyl (the n-propylaminocarbonyl, unsubstituted or substituted with 1 to 2 hydroxys), isopropylaminocarbonyl (whether the isopropylaminocarbonyl is not substituted) Substituted with 1 to 2 hydroxy), cyclopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl (the N-ethyl-N-methylaminocarbonyl is either unsubstituted or N-cyclopropyl-N-methylaminocarbonyl, azetidin-1-yl-carbonyl (the azetidin-1-yl-carbonyl is unsubstituted or substituted with one hydroxy) Substituted), pyrrolidin-1-yl-carbonyl (the pyrrolidin-1-yl-carbonyl is substituted) Do not, is substituted with one hydroxy.), Shows an oxetane-3-yl-aminocarbonyl or methylsulfonyl,
    Here, R 11 is substituted at the para-position of the benzene ring,
    R 12 and R 13 are the same or different and each represents a group selected from the group consisting of a hydrogen atom, a fluorine atom and methyl;
    The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 12 and R 13 are independently substituted at the ortho-position or meta-position of the benzene ring. .
  13. 　前記一般式（Ｉ）において、
    　Ａで表される環が、ピリジン環を示し、
    　Ｒ11が、エチルアミノカルボニル（該エチルアミノカルボニルは、置換されていないか、１個のヒドロキシで置換されている。）、シクロプロピルアミノカルボニル又はメチルスルホニルを示し、
    　Ｒ12が、水素原子を示し、
    　Ｒ13が、水素原子
    を示す請求項１～１１のいずれか１項に記載の化合物又はその製薬学的に許容される塩。     In the general formula (I),
    The ring represented by A represents a pyridine ring;
    R 11 represents ethylaminocarbonyl (the ethylaminocarbonyl is unsubstituted or substituted with 1 hydroxy), cyclopropylaminocarbonyl or methylsulfonyl;
    R 12 represents a hydrogen atom,
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 13 represents a hydrogen atom.
  14. 　以下に示す、請求項１に記載の化合物又はその製薬学的に許容される塩：
    ｔｅｒｔ－ブチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　９－｛２－［４－（メチルスルホニル）フェノキシ］エチル｝－３－アザスピロ［５．５］ウンデカン－３－カルボキシラート、
    ｔｅｒｔ－ブチル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－｛３－［４－（アゼチジン－１－イルカルボニル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－（３－｛３－フルオロ－４－［（２－メトキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－（３－｛［５－（メチルスルホニル）ピリジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－｛３－［４－（シクロプロピルカルバモイル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－［３－（４－カルバモイル－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛［６－（シクロプロピルカルバモイル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（３－フルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（３－フルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（シアノメチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（１，３－ジヒドロキシプロパン－２－イル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（４－｛［（２Ｒ）－２，３－ジヒドロキシプロピル］カルバモイル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［３－フルオロ－４－（オキセタン－３－イルカルバモイル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（４－カルバモイル－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）（メチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［３－フルオロ－４－（ピロリジン－１－イルカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛［６－（シクロプロピルカルバモイル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（｛６－［（２－ヒドロキシエチル）カルバモイル］ピリジン－３－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛［５－（シクロプロピルカルバモイル）ピリジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（３－フルオロ－４－｛［２－（２－ヒドロキシエトキシ）エチル］カルバモイル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（４－｛［２－（ジメチルアミノ）エチル］カルバモイル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－メトキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［４－（アゼチジン－１－イルカルボニル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３－フルオロ－４－［（３－ヒドロキシアゼチジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）－２－メチルフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［４－（シクロプロピルカルバモイル）－２－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛３，５－ジフルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ４－｛３－［７－（３，３－ジメチルブタノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
    Ｎ－ｔｅｒｔ－ブチル－２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキサミド、
    １，１－ジフルオロ－２－メチルプロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
    ４－｛３－［７－（シクロペンチルメチル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
    ２－フルオロ－Ｎ－（２－ヒドロキシエチル）－４－（３－｛７－［３－（プロパン－２－イル）－１，２，４－オキサジアゾール－５－イル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンズアミド、
    ４－｛３－［７－（２，２－ジメチルプロパノイル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
    １－フルオロ－２－メチルプロパン－２－イル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（３－フルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（３－フルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン-2-イル　2-(3-{2,5-ジフルオロ-4-[(2-ヒドロキシエチル)カルバモイル]フェノキシ}プロピル)-7-アザスピロ[3.5]ノナン-7-カルボキシラート、
    プロパン－２－イル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（シアノメチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（３，３－ジフルオロアゼチジン－１－イル）カルボニル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２－フルオロ－Ｎ－（２－ヒドロキシエチル）－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンズアミド、
    １－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）（メチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［３－フルオロ－４－（モルホリン－４－イルカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［３－フルオロ－４－（モルホリン－４－イルカルボニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３－フルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３，５－ジフルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛２，５－ジフルオロ－４－［（２－ヒドロキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（２，５－ジフルオロ－４－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－ヒドロキシエチル）（メチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－２，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３，５－ジフルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（４－｛［（２Ｓ）－２－カルバモイルピロリジン－１－イル］カルボニル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（２－アミノ－２－オキソエチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    Ｎ－シクロプロピル－２，５－ジフルオロ－４－（３－｛７－［（１－メチルシクロプロピル）カルボニル］－７－アザスピロ［３．５］ノナ－２－イル｝プロポキシ）ベンズアミド、
    プロパン－２－イル　２－（３－｛２，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛２，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛３，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛３，５－ジフルオロ－４－［（３－オキソピペラジン－１－イル）カルボニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（シアノメチル）（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［（３，３－ジフルオロアゼチジン－１－イル）カルボニル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（３－フルオロ－４－｛［２－（メチルアミノ）－２－オキソエチル］カルバモイル｝フェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（４－｛［２－（ジメチルアミノ）－２－オキソエチル］カルバモイル｝－３－フルオロフェノキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛［５－（モルホリン－４－イルカルボニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（｛５－［（２－ヒドロキシエチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（｛５－［（２－アミノ－２－オキソエチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［（５－カルバモイルピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（｛５－［（シアノメチル）（メチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（｛５－［（２－ヒドロキシエチル）（メチル）カルバモイル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［（５－｛［（３Ｒ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝ピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［（５－｛［（３Ｓ）－３－ヒドロキシピロリジン－１－イル］カルボニル｝ピラジン－２－イル）オキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－［３－（｛５－［（３－オキソピペラジン－１－イル）カルボニル］ピラジン－２－イル｝オキシ）プロピル］－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    Ｎ－シクロプロピル－４－｛３－［７－（５－エチルピリミジン－２－イル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロベンズアミド、
    ７－（５－エチルピリミジン－２－イル）－２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン、
    ７－（５－エチルピリミジン－２－イル）－２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン、
    １－メチルシクロプロピル ２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－フルオロ－２－メチルプロパン－２－イル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－フルオロ－２－メチルプロパン－２－イル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １，１－ジフルオロ－２－メチルプロパン－２－イル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－｛３－［４－（アゼチジン－１－イルカルボニル）－３－フルオロフェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛３－フルオロ－４－［（２－メトキシエチル）カルバモイル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    シクロプロピルメチル　２－｛３－［４－メチルスルホニル］フェノキシ｝プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    シクロペンチル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    （１－メチルシクロプロピル）メチル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２－メチルプロピル　２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２－メチルプロピル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    シクロプロピルメチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    （１－メチルシクロプロピル）メチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    シクロペンチル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２，２－ジメチルプロピル　２－｛３－［２－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２－メチルプロピル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    シクロプロピルメチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    （１－メチルシクロプロピル）メチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    シクロペンチル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２，２－ジメチルプロピル　２－｛３－［３－フルオロ－４－（メチルスルホニル）フェノキシ］プロピル｝－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ２－｛３－［４－（メチルスルホニル）フェノキシ］プロピル｝－７－［３－（プロパン－２－イル）－１，２，４－オキサジアゾール－５－イル］－７－アザスピロ［３．５］ノナン、
    ｔｅｒｔ－ブチル　２－（３－｛４－［シクロプロピル（メチル）カルバモイル］－３－フルオロフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ３，３－ジメチル－１－［２－（３－｛［６－（メチルスルホニル）ピリジン－３－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナ－７－イル］ブタン－１－オン、
    プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）カルバモイル］－３－メチルフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（１，３－ジヒドロキシプロパン－２－イル）カルバモイル］－３－メチルフェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）スルフィニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛４－［（２－ヒドロキシエチル）スルホニル］フェノキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ｔｅｒｔ－ブチル　２－（３－｛［４－（メチルスルホニル）フェニル］アミノ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    ４－｛３－［７－（２，２－ジメチルプロピル）－７－アザスピロ［３．５］ノナ－２－イル］プロポキシ｝－２－フルオロ－Ｎ－（２－ヒドロキシエチル）ベンズアミド、
    プロパン－２－イル　２－（３－｛［５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛［５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    １－メチルシクロプロピル　２－（３－｛［３－メチル－５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート、
    プロパン－２－イル　２－（３－｛［３－メチル－５－（メチルスルホニル）ピラジン－２－イル］オキシ｝プロピル）－７－アザスピロ［３．５］ノナン－７－カルボキシラート。     The compound according to claim 1 or a pharmaceutically acceptable salt thereof shown below:
    tert-butyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 9- {2- [4- (methylsulfonyl) phenoxy] ethyl} -3-azaspiro [5.5] undecane-3-carboxylate,
    tert-butyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- {3- [4- (azetidin-1-ylcarbonyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    tert-butyl 2- (3- {3-fluoro-4-[(2-methoxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- (3-{[5- (methylsulfonyl) pyridin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- (3-{[5- (cyclopropylcarbamoyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    tert-butyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- {3- [4- (cyclopropylcarbamoyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- [3- (4-carbamoyl-3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3-{[6- (cyclopropylcarbamoyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- [3- (3-fluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
    Propan-2-yl 2- [3- (3-fluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
    Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4-[(cyanomethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4-[(1,3-dihydroxypropan-2-yl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    Propan-2-yl 2- [3- (4-{[(2R) -2,3-dihydroxypropyl] carbamoyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
    Propan-2-yl 2- {3- [3-fluoro-4- (oxetan-3-ylcarbamoyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- [3- (4-carbamoyl-3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) (methyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- {3- [3-fluoro-4- (pyrrolidin-1-ylcarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3-{[6- (cyclopropylcarbamoyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- [3-({6-[(2-hydroxyethyl) carbamoyl] pyridin-3-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3-{[5- (cyclopropylcarbamoyl) pyridin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- [3- (3-fluoro-4-{[2- (2-hydroxyethoxy) ethyl] carbamoyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate ,
    Propan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- [3- (4-{[2- (dimethylamino) ethyl] carbamoyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {3-fluoro-4-[(2-methoxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- {3- [4- (azetidin-1-ylcarbonyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {3-fluoro-4-[(3-hydroxyazetidin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
    Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) -2-methylphenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- {3- [4- (cyclopropylcarbamoyl) -2-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    1-methylcyclopropyl 2- (3- {3,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    4- {3- [7- (3,3-dimethylbutanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide;
    N-tert-butyl-2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxamide;
    1,1-difluoro-2-methylpropan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane 7-carboxylate,
    4- {3- [7- (5-ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
    4- {3- [7- (cyclopentylmethyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
    2-Fluoro-N- (2-hydroxyethyl) -4- (3- {7- [3- (propan-2-yl) -1,2,4-oxadiazol-5-yl] -7-azaspiro [3.5] non-2-yl} propoxy) benzamide,
    4- {3- [7- (2,2-dimethylpropanoyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
    1-Fluoro-2-methylpropan-2-yl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7- Carboxylate,
    1-methylcyclopropyl 2- [3- (3-fluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
    1-methylcyclopropyl 2- [3- (3-fluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
    Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
    Propan-2-yl 2- (3- {2,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- [3- (2,5-difluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
    Propan-2-yl 2- [3- (2,5-difluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
    Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    Propan-2-yl 2- (3- {4-[(cyanomethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4-[(3,3-difluoroazetidin-1-yl) carbonyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7- Carboxylate,
    2-fluoro-N- (2-hydroxyethyl) -4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzamide,
    1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) (methyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- {3- [3-fluoro-4- (morpholin-4-ylcarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- {3- [3-fluoro-4- (morpholin-4-ylcarbonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {3-fluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
    Propan-2-yl 2- (3- {3,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {3-fluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
    1-methylcyclopropyl 2- (3- {2,5-difluoro-4-[(2-hydroxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- [3- (2,5-difluoro-4-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
    1-methylcyclopropyl 2- [3- (2,5-difluoro-4-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} phenoxy) propyl] -7-azaspiro [3.5] nonane -7-carboxylate,
    1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate ,
    1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-hydroxyethyl) (methyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
    Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
    1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -2,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
    Propan-2-yl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3,5-difluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7 -Carboxylates,
    1-methylcyclopropyl 2- [3- (4-{[(2S) -2-carbamoylpyrrolidin-1-yl] carbonyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7 -Carboxylates,
    1-methylcyclopropyl 2- (3- {4-[(2-amino-2-oxoethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    N-cyclopropyl-2,5-difluoro-4- (3- {7-[(1-methylcyclopropyl) carbonyl] -7-azaspiro [3.5] non-2-yl} propoxy) benzamide,
    Propan-2-yl 2- (3- {2,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- (3- {2,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    Propan-2-yl 2- (3- {3,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- (3- {3,5-difluoro-4-[(3-oxopiperazin-1-yl) carbonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- (3- {4-[(cyanomethyl) (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {4-[(3,3-difluoroazetidin-1-yl) carbonyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7- Carboxylate,
    1-methylcyclopropyl 2- [3- (3-fluoro-4-{[2- (methylamino) -2-oxoethyl] carbamoyl} phenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- [3- (4-{[2- (dimethylamino) -2-oxoethyl] carbamoyl} -3-fluorophenoxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- (3-{[5- (cyclopropylcarbamoyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3-{[5- (morpholin-4-ylcarbonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- [3-({5-[(2-hydroxyethyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- [3-({5-[(2-amino-2-oxoethyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- {3-[(5-carbamoylpyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- [3-({5-[(cyanomethyl) (methyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- [3-({5-[(2-hydroxyethyl) (methyl) carbamoyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7-carboxy Lat,
    1-methylcyclopropyl 2- {3-[(5-{[(3R) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] Nonane-7-carboxylate,
    1-methylcyclopropyl 2- {3-[(5-{[(3S) -3-hydroxypyrrolidin-1-yl] carbonyl} pyrazin-2-yl) oxy] propyl} -7-azaspiro [3.5] Nonane-7-carboxylate,
    1-methylcyclopropyl 2- [3-({5-[(3-oxopiperazin-1-yl) carbonyl] pyrazin-2-yl} oxy) propyl] -7-azaspiro [3.5] nonane-7- Carboxylate,
    N-cyclopropyl-4- {3- [7- (5-ethylpyrimidin-2-yl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluorobenzamide,
    7- (5-ethylpyrimidin-2-yl) -2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane,
    7- (5-ethylpyrimidin-2-yl) -2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane,
    1-methylcyclopropyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1,1-difluoro-2-methylpropan-2-yl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1-fluoro-2-methylpropan-2-yl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1-fluoro-2-methylpropan-2-yl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1,1-difluoro-2-methylpropan-2-yl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    1,1-difluoro-2-methylpropan-2-yl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- {3- [4- (azetidin-1-ylcarbonyl) -3-fluorophenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    1-methylcyclopropyl 2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {3-fluoro-4-[(2-methoxyethyl) carbamoyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    Cyclopropylmethyl 2- {3- [4-methylsulfonyl] phenoxy} propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Cyclopentyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    (1-methylcyclopropyl) methyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    2-methylpropyl 2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    2-methylpropyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Cyclopropylmethyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    (1-methylcyclopropyl) methyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Cyclopentyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    2,2-dimethylpropyl 2- {3- [2-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    2-methylpropyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    Cyclopropylmethyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    (1-methylcyclopropyl) methyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate;
    Cyclopentyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    2,2-dimethylpropyl 2- {3- [3-fluoro-4- (methylsulfonyl) phenoxy] propyl} -7-azaspiro [3.5] nonane-7-carboxylate,
    2- {3- [4- (methylsulfonyl) phenoxy] propyl} -7- [3- (propan-2-yl) -1,2,4-oxadiazol-5-yl] -7-azaspiro [3 .5] Nonane,
    tert-butyl 2- (3- {4- [cyclopropyl (methyl) carbamoyl] -3-fluorophenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    3,3-Dimethyl-1- [2- (3-{[6- (methylsulfonyl) pyridin-3-yl] oxy} propyl) -7-azaspiro [3.5] non-7-yl] butane-1 -on,
    Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) carbamoyl] -3-methylphenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4-[(1,3-dihydroxypropan-2-yl) carbamoyl] -3-methylphenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxy Lat,
    Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) sulfinyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    Propan-2-yl 2- (3- {4-[(2-hydroxyethyl) sulfonyl] phenoxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    tert-butyl 2- (3-{[4- (methylsulfonyl) phenyl] amino} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    4- {3- [7- (2,2-dimethylpropyl) -7-azaspiro [3.5] non-2-yl] propoxy} -2-fluoro-N- (2-hydroxyethyl) benzamide,
    Propan-2-yl 2- (3-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate;
    1-methylcyclopropyl 2- (3-{[5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    1-methylcyclopropyl 2- (3-{[3-methyl-5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate,
    Propan-2-yl 2- (3-{[3-methyl-5- (methylsulfonyl) pyrazin-2-yl] oxy} propyl) -7-azaspiro [3.5] nonane-7-carboxylate.
  15. 　請求項１～１４のいずれか１項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
  16. 　請求項１～１４のいずれか１項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有するＧＰＲ１１９アゴニスト。 A GPR119 agonist comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
  17. 　請求項１～１４のいずれか１項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有する血糖低下作用薬。 15. A hypoglycemic agent comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
  18. 　請求項１～１４のいずれか１項に記載の化合物又はその製薬学的に許容される塩を有効成分として含有する糖尿病の予防薬又は治療薬。 A prophylactic or therapeutic agent for diabetes comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
PCT/JP2012/065201 2011-06-17 2012-06-14 Azaspiroalkane compound WO2012173174A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-134927 2011-06-17
JP2011134927A JP2014159376A (en) 2011-06-17 2011-06-17 Azaspiroalkane compound

Publications (1)

Publication Number Publication Date
WO2012173174A1 true WO2012173174A1 (en) 2012-12-20

Family

ID=47357156

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/065201 WO2012173174A1 (en) 2011-06-17 2012-06-14 Azaspiroalkane compound

Country Status (3)

Country Link
JP (1) JP2014159376A (en)
TW (1) TW201313684A (en)
WO (1) WO2012173174A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
CN103787839A (en) * 2014-01-21 2014-05-14 苏州昊帆生物科技有限公司 Method for synthesizing 2,3,4,5,6-pentafluorophenol
JP2016538296A (en) * 2013-11-26 2016-12-08 チョン クン ダン ファーマシューティカル コーポレーション Amide derivatives as GPR119 agonists
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
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
US10329308B2 (en) 2017-01-20 2019-06-25 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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008033460A2 (en) * 2006-09-15 2008-03-20 Schering Corporation Treating pain, diabetes, and lipid metabolism disorders
WO2010009195A1 (en) * 2008-07-16 2010-01-21 Schering Corporation Bicyclic heterocycle derivatives and use thereof as gpr119 modulators
WO2010123018A1 (en) * 2009-04-24 2010-10-28 日本ケミファ株式会社 Diazaspiroalkane derivative
WO2012041158A1 (en) * 2010-09-29 2012-04-05 上海恒瑞医药有限公司 Tricyclic compound, preparation method and pharmaceutical use thereof
WO2012047703A2 (en) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-piperidines useful as sodium channel blockers

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008033460A2 (en) * 2006-09-15 2008-03-20 Schering Corporation Treating pain, diabetes, and lipid metabolism disorders
WO2010009195A1 (en) * 2008-07-16 2010-01-21 Schering Corporation Bicyclic heterocycle derivatives and use thereof as gpr119 modulators
WO2010123018A1 (en) * 2009-04-24 2010-10-28 日本ケミファ株式会社 Diazaspiroalkane derivative
WO2012041158A1 (en) * 2010-09-29 2012-04-05 上海恒瑞医药有限公司 Tricyclic compound, preparation method and pharmaceutical use thereof
WO2012047703A2 (en) * 2010-10-04 2012-04-12 Schering Corporation Cyclopropyl-spiro-piperidines useful as sodium channel blockers

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9944600B2 (en) 2012-06-12 2018-04-17 Chong Kun Dang Pharmaceutical Corp. Piperidine derivatives for GPR119 agonist
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
JP2016538296A (en) * 2013-11-26 2016-12-08 チョン クン ダン ファーマシューティカル コーポレーション Amide derivatives as GPR119 agonists
US9776987B2 (en) 2013-11-26 2017-10-03 Chong Kun Dang Pharmaceutical Corp Amide derivatives for GPR119 agonist
CN103787839A (en) * 2014-01-21 2014-05-14 苏州昊帆生物科技有限公司 Method for synthesizing 2,3,4,5,6-pentafluorophenol
CN103787839B (en) * 2014-01-21 2015-12-02 苏州昊帆生物科技有限公司 The method of synthesis 2,3,4,5,6-Pentafluorophenol
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
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
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
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

Also Published As

Publication number Publication date
TW201313684A (en) 2013-04-01
JP2014159376A (en) 2014-09-04

Similar Documents

Publication Publication Date Title
TWI606039B (en) Triazole agonists of the apj receptor
WO2012173174A1 (en) Azaspiroalkane compound
JP2022545359A (en) cystic fibrosis transmembrane conductance regulator
JP2011529483A (en) Fluorinated heteroaryl
WO2007037534A1 (en) 2-heteroaryl-substituted indole derivative
US11548871B2 (en) Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
JP2010138073A (en) Picolinic acid amide compound
JP2021526123A (en) Autotaxin inhibitors and their use
WO2017001812A1 (en) Compounds and their use as inhibitors of n-myristoyl transferase
CN115942972A (en) LPA receptor antagonists and uses thereof
WO2012086735A1 (en) Condensed heterocyclic compound
CN109153664B (en) Pyridyl derivatives, pharmaceutical compositions and their use as copper-containing amine oxidase 3 inhibitors
KR20240007233A (en) LPA receptor antagonists and uses thereof
KR20240005892A (en) LPA receptor antagonists and uses thereof
JP2014118368A (en) Hypoglycemic agent containing aza spiro alkane compound as active ingredient
TWI591064B (en) 2-pyridone compound
KR20190036550A (en) Composition for treating pulmonary fibrosis
TW201625545A (en) Substituted azole compound and antidiabetes agent
JP2014024838A (en) Hypoglycemic agonist containing condensed heterocyclic compound as active ingredient
JP6048533B2 (en) Medicament containing 2-pyridone compound
WO2024054840A1 (en) Macrocyclic compounds, compositions, and methods of using thereof
CN113015736A (en) 6-hydroxy-8-oxatricyclo [3.2.1.02,4] octane-2-carboxamide derivatives for inducing chondrogenesis to treat joint damage

Legal Events

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

Ref document number: 12800302

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12800302

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP