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WO2010137620A1 - Phenoxyethylamine derivative - Google Patents

Phenoxyethylamine derivative Download PDF

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Publication number
WO2010137620A1
WO2010137620A1 PCT/JP2010/058919 JP2010058919W WO2010137620A1 WO 2010137620 A1 WO2010137620 A1 WO 2010137620A1 JP 2010058919 W JP2010058919 W JP 2010058919W WO 2010137620 A1 WO2010137620 A1 WO 2010137620A1
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Prior art keywords
group
substituent
ring
compound
salt
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PCT/JP2010/058919
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French (fr)
Japanese (ja)
Inventor
雅都 吉田
信貴 坂内
歩 佐藤
英紀 古川
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武田薬品工業株式会社
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Publication of WO2010137620A1 publication Critical patent/WO2010137620A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a phenoxyethylamine derivative having an excellent selective ⁇ 1D adrenergic receptor (hereinafter, simply referred to as ⁇ 1D receptor) antagonistic activity and useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like. .
  • ⁇ 1D receptor selective ⁇ 1D adrenergic receptor
  • ⁇ 1 adrenergic receptors (hereinafter sometimes simply referred to as ⁇ 1 receptors) are widely distributed in the cardiovascular system and lower urinary tract, and are involved in sympathetic reaction activity. Furthermore, since it has been suggested to be associated with pathological conditions such as hypertension, cardiac hypertrophy, and dysuria, the ⁇ 1 receptor has been attracting interest for a long time, and many therapeutic drugs have been developed. Recently, it has become clear that ⁇ 1 receptor blockers are effective for dysuria associated with benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the ⁇ 1 receptor gene was cloned, and as a result, it was revealed that there were three subtypes, ⁇ 1A , ⁇ 1B and ⁇ 1D .
  • ⁇ 1D receptors have been confirmed to be expressed in many tissues such as blood vessels, brain, spinal cord, gastrointestinal tract, bladder and kidney.
  • the physiological function of the ⁇ 1D receptor has not been elucidated in detail, it is considered that the ⁇ 1D receptor antagonist may be a therapeutic agent for various diseases due to its wide localization.
  • Non-Patent Documents 2 and 3 ⁇ 1D receptors have been confirmed to be more distributed in bladder and sacral parasympathetic nuclei compared to other subtypes (Non-Patent Documents 2 and 3), suggesting that they are strongly associated with urinary storage symptoms.
  • Non-patent Document 4 the expression level of ⁇ 1D receptor mRNA is increased in the bladder of BPH patients and BPH model animals (Non-patent Documents 5 and 6), and the isolated bladder muscle of BPH patients is mediated by ⁇ 1D receptors.
  • Non-patent Document 7 has been reported, suggesting that the ⁇ 1D receptor expressed in the bladder may be involved in the pathology of BPH. Based on the above, ⁇ 1D receptor antagonists are promising as agents for preventing and treating lower urinary tract symptoms. Examples of the compound exhibiting selective ⁇ 1D receptor antagonistic action include: Non-Patent Document 8 has a formula
  • Patent Document 1 discloses a formula
  • a compound represented by Patent Document 2 has a formula
  • a compound represented by Patent Document 37 has a formula
  • Non-Patent Document 9 has a formula
  • WO8808842 WO9529163 WO9534540 WO9731907 WO9950237 WO2000032568 WO2001047890 WO2001047931 WO2001066520 WO2003002525 WO2003026666 WO2005016862 WO2005037198 WO2006010775 WO2006069807 WO2007070173 WO2007106537 WO2007119984 WO2008011476 WO2008122115 US2946799 US2004214870 US2004167188 US2005245399 EP1676842 EP1953161 JP61055273 JP09221476 JP2006225351 DE19643037 DE3603577 DE3831445 CN1706820 WO2007103996 WO2002023986 WO2006058700 WO08050732
  • An object of the present invention is to provide a compound having an excellent selective ⁇ 1D adrenergic receptor antagonistic activity and useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like.
  • the present inventors have shown that the compound represented by the following formula (I) or a salt thereof has an excellent selective ⁇ 1D adrenergic receptor antagonistic action based on its specific chemical structure, and lower urinary tract symptoms and the like Has been found to have an excellent medicinal effect as a prophylactic / therapeutic agent. Based on this knowledge, the present inventors have conducted intensive research and have completed the present invention.
  • Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent
  • Ring B represents an optionally substituted benzene ring
  • L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group.
  • L 2 represents an ethylene group which may have a substituent other than an oxo group
  • X represents S, SO, or SO 2
  • Y represents a carbon atom
  • Z is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) substituent group Or an amino group which may have a substituent, or (3) a 5- or 6-membered heterocyclic group which may have a substituent, or (4) bonded to Y and further substituted with A ring
  • a condensed bicyclic heterocyclic ring which may have a group may be formed
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, or may be bonded to each other and have a substituent together with Y.
  • Ring A represents an optionally substituted benzene ring or pyridine ring
  • Ring B represents an optionally substituted benzene ring
  • L 1 represents a bond, a methylene group or an ethylene group
  • L 2 represents an ethylene group which may have a substituent other than an oxo group
  • X represents SO 2 Y represents a carbon atom
  • Z represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group, or (5) bonded to Y
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom or a C 1-6 alky
  • Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent
  • Ring B represents an optionally substituted benzene ring
  • L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group.
  • L 2 represents an ethylene group which may have a substituent other than an oxo group
  • X represents S, SO, or SO 2
  • Z ' represents a CR 4, or N
  • R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
  • n represents an integer of 0 to 3.
  • Ring A represents an optionally substituted benzene ring
  • Ring B represents an optionally substituted benzene ring
  • L 1 represents a bond
  • L 2 represents an ethylene group which may have a substituent other than an oxo group
  • X represents SO 2 Z ′ represents CR 4 or N
  • R 2 and R 3 represent a hydrogen atom
  • R 4 represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent
  • n represents 0, 1 or 2
  • Ring A includes (1) halogen atom, (2) hydroxy group, (3) cyano group, (4) phenyl group, (5) C 1-6 alkylthio group, (6) C 1-6 alkoxycarbonyl -C 2-6 alkenyl group, (7) C 1-6 alkylsulfonyl group,
  • a benzene ring substituted with one or two substituents selected from the group L 1 represents a bond
  • L 2 represents an ethylene group which may be substituted with a C 1-6 alkyl group
  • X represents SO 2 Z ′ represents CR 4 or N
  • R 2 and R 3 represent a hydrogen atom
  • R 4 represents a hydrogen atom or a C 1-6 alkyl group
  • Ring A represents a benzene ring which may be substituted with one mono-C 1-6 alkylamino group
  • Ring B represents a benzene ring substituted with two halogen atoms
  • L 1 represents a bond
  • L 2 represents an ethylene group
  • X represents SO 2 Z 'represents a CR 4
  • R 2 , R 3 and R 4 represent a hydrogen atom
  • n represents 1, The compound of
  • Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent
  • Ring B represents an optionally substituted benzene ring
  • L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group.
  • L 2 represents an ethylene group which may have a substituent other than an oxo group
  • X represents S, SO, or SO 2
  • Z ′′ is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) An amino group which may have a substituent, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent, or have a substituent together with an adjacent carbon atom bonded to each other.
  • Ring A represents an optionally substituted benzene ring or pyridine ring
  • Ring B represents an optionally substituted benzene ring
  • L 1 represents a bond, a methylene group, or an ethylene group
  • L 2 represents an ethylene group
  • X represents SO 2 Z ′′ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group
  • R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
  • Ring A represents a benzene ring or a pyridine ring which may be substituted with one substituent selected from a halogen atom, a cyano group, an alkoxy group and a morpholino group
  • Ring B represents a benzene ring substituted with two halogen atoms
  • L 1 represents a bond, a methylene group, or an ethylene group
  • L 2 represents an ethylene group
  • X represents SO 2 Z ′′ is (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group optionally substituted by one or two C 1-6 alkyl groups, or (4) a morpholino group
  • Indicate R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
  • Ring A represents a benzene ring or a pyridine ring
  • Ring B represents a benzene ring substituted with two halogen atoms
  • L 1 represents a bond
  • L 2 represents an ethylene group
  • X represents SO 2 Z ′′ represents a C 1-6 alkyl group or a di-C 1-6 alkylamino group
  • R 1 and R 2 represent a hydrogen atom
  • the compound of the present invention has an excellent selective ⁇ 1D adrenergic receptor antagonistic action and is useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like.
  • the “hydrocarbon group which may have a substituent” includes an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a substituent.
  • the “alkyl group optionally having substituent (s)” (I) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (Ii) a cyano group, (Iii) a hydroxyl group, (Iv) a nitro group, (V) formyl group, (Vi) an amino group, (Vii) mono- or di-C 1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, etc.), (Viii) a C 1-6 alkyl-carbonylamino group (eg, acetylamino, ethylcarbonylamino, etc.), (Ix) a C 1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxy), (eg
  • the “optionally substituted alkenyl group” refers to the substituent that the alkyl group of the above “optionally substituted alkyl group” may have 1 And a C 2-6 alkenyl group (eg, vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.) which may have 4 to, preferably 1 to 3, may be mentioned.
  • a C 2-6 alkenyl group eg, vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.
  • each substituent may be the same or different.
  • the “optionally substituted alkynyl group” refers to the substituent that the alkyl group of the above “optionally substituted alkyl group” may have 1 Or a C 2-6 alkynyl group (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) which may have 4 or preferably 1 to 3 and the like. When there are two or more substituents, each substituent may be the same or different.
  • the “aralkyl group optionally having substituent (s)” may have, (ii) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxyl group, C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.), amino group, mono- or di-C 1 -6 alkylamino groups (eg, methylamino, etc.), C 1-6 alkyl-carbonylamino groups (eg, acetylamino, etc.), C 6-14 arylsulfonyl groups and heterocyclic groups (eg, pyrrolidinyl, morpholinyl, pyridyl, C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobuty
  • C 7-16 aralkyl group eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc.
  • a 5- to 8-membered aromatic heterocyclic-oxy group eg, furyloxy, thienyloxy, pyrrolyloxy, containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms
  • the substituent of the “aralkyl group which may have a substituent” in the present specification may be present in the aryl part and / or the alkylene part of the aralkyl group. When there are two or more substituents, each substituent may be the same or different.
  • the “aryl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have is 1 Or a C 6-14 aryl group (eg, phenyl, naphthyl, etc.) which may have 4 to, preferably 1 to 3, may be mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “cycloalkyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have.
  • Examples thereof include a C 3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) optionally having 1 to 4, preferably 1 to 3.
  • each substituent may be the same or different.
  • substituents of “optionally substituted cycloalkyl group” are bonded to each other to form a ring (cycloalkane ring (C 3-6 cyclohexane ring, cyclopropane ring, cyclopentane ring, cyclopentane ring, etc.
  • the “cycloalkenyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. Examples thereof include C 3-8 cycloalkenyl groups (eg, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.) optionally having 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different.
  • substituents of “optionally substituted cycloalkenyl group” are bonded to each other to form a ring (cycloalkane ring (C 3-6 cyclohexane ring such as cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, Alkane ring) and arene rings (C 6-10 arene rings such as benzene ring and naphthalene ring)).
  • cycloalkane ring C 3-6 cyclohexane ring such as cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, Alkane ring
  • arene rings C 6-10 arene rings such as benzene ring and naphthalene ring
  • the “5-membered or 6-membered heterocyclic group optionally having substituent (s)” (1)
  • the aralkyl group of the above-mentioned “aralkyl group optionally having substituent (s)” may have 1 to 3 substituents which may be present, and is condensed with a benzene ring.
  • each substituent may be the same or different.
  • the “amino group optionally having a substituent” includes an amino group and an amino group having a substituent.
  • the “amino group having a substituent” means the above-mentioned “hydrocarbon group which may have a substituent”, the “acyl group” described later, and the “having a substituent”.
  • the “acyl group” includes “an alkylcarbonyl group which may have a substituent”, “an alkenylcarbonyl group which may have a substituent”, “a substituent which has a substituent”. May be an alkynylcarbonyl group ”,“ aralkylcarbonyl group optionally having substituent (s) ”,“ arylcarbonyl group optionally having substituent (s) ”,“ cycloalkylcarbonyl optionally having substituent (s) ” Group “,” optionally substituted alkoxycarbonyl group ",” optionally substituted alkenyloxycarbonyl group ",” optionally substituted alkynyloxycarbonyl group ", "Aralkyloxycarbonyl group which may have a substituent”, “aryloxycarbonyl group which may have a substituent”, “cycloalkyl which may have a substituent” Oxycarbonyl group "and” carboxyl group ", and the like.
  • alkylcarbonyl group optionally having substituent (s) is the substituent that the alkyl group of the “alkyl group optionally having substituent (s)” may have.
  • C 1-6 alkyl-carbonyl group which may have 1 to 4, preferably 1 to 3 (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl) Tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl, etc.).
  • each substituent may be the same or different.
  • the “optionally substituted alkenylcarbonyl group” refers to the substituent that the alkyl group of the above “optionally substituted alkyl group” may have.
  • C 2-6 alkenyl-carbonyl group which may have 1 to 4, preferably 1 to 3 (eg vinylcarbonyl, 1-propenylcarbonyl, allylcarbonyl, isopropenylcarbonyl, butenylcarbonyl, isobutenyl) Carbonyl etc.).
  • each substituent may be the same or different.
  • the “optionally substituted alkynylcarbonyl group” is the substituent that the alkyl group of the above “optionally substituted alkyl group” may have.
  • examples thereof include a C 2-6 alkynyl-carbonyl group (eg, ethynylcarbonyl, propargylcarbonyl, butynylcarbonyl, 1-hexynylcarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3.
  • each substituent may be the same or different.
  • the “aralkylcarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have.
  • C 7-12 aralkyl-carbonyl group eg, benzylcarbonyl, 2-phenylethylcarbonyl, 1-phenylethylcarbonyl, 3-phenylpropylcarbonyl, etc.
  • each substituent may be the same or different.
  • the “arylcarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have.
  • Examples thereof include a C 6-14 aryl-carbonyl group (eg, phenylcarbonyl, naphthylcarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3.
  • each substituent may be the same or different.
  • the “cycloalkylcarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have.
  • a C 3-8 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl) which may have 1 to 4, preferably 1 to 3.
  • each substituent may be the same or different.
  • alkoxycarbonyl group optionally having substituent (s) is the substituent that the alkyl group of the “alkyl group optionally having substituent (s)” may have.
  • C 1-6 alkoxy-carbonyl group which may have 1 to 4, preferably 1 to 3 (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- Butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, etc.).
  • each substituent may be the same or different.
  • the “optionally substituted alkenyloxycarbonyl group” is the substituent that the alkyl group of the above “optionally substituted alkyl group” may have.
  • a C 2-6 alkenyl-oxycarbonyl group which may have 1 to 4, preferably 1 to 3 (eg, vinyloxycarbonyl, 1-propenyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, Tenenyloxycarbonyl, isobutenyloxycarbonyl and the like).
  • each substituent may be the same or different.
  • the “optionally substituted alkynyloxycarbonyl group” is the substituent that the alkyl group of the above “optionally substituted alkyl group” may have.
  • C 2-6 alkynyl-oxycarbonyl group eg, ethynyloxycarbonyl, propargyloxycarbonyl, butynyloxycarbonyl, 1-hexynyloxycarbonyl, etc.
  • each substituent may be the same or different.
  • the “aralkyloxycarbonyl group optionally having substituent (s)” may be the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have.
  • a C 7-12 aralkyl-oxycarbonyl group eg, benzyloxycarbonyl, 2-phenylethyloxycarbonyl, 1-phenylethyloxycarbonyl, 3-phenyl
  • each substituent may be the same or different.
  • the “aryloxycarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have.
  • C 6-14 aryl-oxycarbonyl group eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.
  • each substituent may be the same or different.
  • the “optionally substituted cycloalkyloxycarbonyl group” is an optionally substituted aralkyl group of the above “optionally substituted aralkyl group”.
  • C 3-8 cycloalkyl-oxycarbonyl group which may have 1 to 4, preferably 1 to 3 groups (eg, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl) Is mentioned.
  • each substituent may be the same or different.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “benzene ring optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have is 1
  • the “6-membered aromatic heterocycle optionally having substituent (s)” may have the aralkyl group of the “aralkyl group optionally having substituent (s)” described above.
  • the “fused bicyclic heterocyclic ring optionally having substituent (s)” may be the aralkyl group of the above “aralkyl group optionally having substituent (s)”.
  • a benzene ring or 6-membered aromatic heterocyclic ring which may have 1 to 4, preferably 1 to 3 good substituents, and a nitrogen atom in addition to the sulfur atom as X Examples thereof include a condensed ring with a 5-membered to 8-membered non-aromatic heterocyclic ring (eg, tetrahydrothiophene ring, tetrahydrothiopyran ring) which may have.
  • each substituent may be the same or different.
  • methylene group which may have a substituent other than oxo group “ethylene group which may have a substituent other than oxo group” and “a substituent other than oxo group”.
  • the “optionally substituted propylene group” is 1 to 4, preferably 1 to 3 substituents that the alkyl group of the above-mentioned “optionally substituted alkyl group” may have.
  • the methylene group, ethylene group, and propylene group which may have are mentioned. When there are two or more substituents, each substituent may be the same or different.
  • a ring shows the benzene ring which may have a substituent, or the 6-membered aromatic heterocyclic ring which may have a substituent.
  • the 6-membered aromatic heterocycle represented by the A ring is preferably a pyridine ring.
  • “Benzene ring” or “6-membered aromatic heterocycle” of “benzene ring which may have a substituent or 6-membered aromatic heterocycle which may have a substituent” represented by ring A is In addition to the “—XZ group” and the “—YR 1 R 2 — group”, they may further have 1 to 4 substituents at substitutable positions.
  • substituent on the A ring examples include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxyl group, halogen atom, hydroxyl group, C 1-6 alkoxy group, amino group, mono- or di-C 1 -6 alkylamino group, C 1-6 alkyl - carbonyl amino group, mono - or di -C 1-6 alkyl - carbamoyl group, and optionally substituted with a substituent selected from the heterocyclic groups C 1-6 Alkyl group (eg, methyl group, isopropyl group, trifluoromethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, acetylaminomethyl group, methylcarbamoylethyl group, pyrrolidinylmethyl group), halogen A substituent selected from an atom, a C 1-6 alkoxy group, a C 1-6 alk
  • Ring B represents a benzene ring which may have a substituent.
  • the “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring B is further 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present.
  • the substituent on the B ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl group optionally substituted with a halogen atom (eg, methyl group, trifluoromethyl).
  • a C 1-6 alkoxy group eg, methoxy group
  • a C 1-6 alkylthio group eg, methylthio group
  • a cyano group e.g., a fluorine atom and a chlorine atom are more preferred.
  • adjacent substituents are bonded to each other to form a 5- to 8-membered aromatic heterocyclic ring (eg, pyrrole ring).
  • L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group.
  • the propylene group which may be sufficient is shown.
  • L 1 is preferably a bond, a methylene group or an ethylene group.
  • L 2 represents an ethylene group which may have a substituent other than an oxo group.
  • L 2 is preferably an ethylene group.
  • X represents S, SO, or SO 2 .
  • X is preferably SO 2 .
  • Y represents a carbon atom.
  • Z is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) substituted An amino group which may have a group, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent, or (4) bonded to Y and further together with A ring A condensed bicyclic heterocyclic ring which may have a substituent may be formed.
  • Z is a C 1-6 alkyl group which may have a substituent (eg, methyl group, ethyl group, isopropyl group), or a C 6-14 aryl group which may have a substituent (eg, phenyl group), 1 to 2 C 1-6 alkyl groups (e.g., non-aromatic methyl group) amino group which may have a, and may have a substituent 5- or 6-membered
  • a heterocyclic group eg, morpholino group
  • Z is preferably bonded to Y to form a dihydrobenzothiophene ring or dihydrothiochromene ring which may further have a substituent together with the A ring.
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent, or may be bonded to each other and have a substituent together with Y. Good cyclopropyl or optionally substituted cyclobutyl may be formed (provided that when Z is bound to Y, R 1 is not present).
  • R 1 and R 2 are the same or different and are preferably a hydrogen atom and a C 1-6 alkyl group (eg, a methyl group), both of which are a hydrogen atom, and one is a hydrogen atom and the other is a methyl group. More preferred.
  • a ring is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group)
  • a benzene ring or a pyridine ring optionally having a substituent selected from an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentoxy group, and a hexoxy group
  • Ring B is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
  • L 1 is a bond, a methylene group or an ethylene group;
  • L 2 is an ethylene group;
  • X is SO 2 ;
  • Y is a carbon atom;
  • the compound (I) includes Ring A represents an optionally substituted benzene ring or pyridine ring; Ring B represents an optionally substituted benzene ring; L 1 represents a bond, a methylene group or an ethylene group; L 2 represents an ethylene group which may have a substituent other than an oxo group; X represents SO 2 ; Y represents a carbon atom; Z represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group, or (5) bonded to Y A dihydrothiochromene ring which may further have a substituent together with the A ring, R 1 represents a hydrogen atom; and R 2 represents a hydrogen atom or a C 1-6 alkyl group (provided that when Z is bonded to Y, R 1 is not present and R 2 represents a hydrogen atom), A compound or a salt thereof is preferred.
  • the compounds of Examples 1-111 are more preferable.
  • the compound (II) when Z is bonded to Y to form a condensed bicyclic heterocyclic ring which may further have a substituent together with the A ring, the compound (II) is preferable.
  • a ring shows the benzene ring which may have a substituent, or the 6-membered aromatic heterocyclic ring which may have a substituent.
  • “Benzene ring” or “6-membered aromatic heterocycle” of “benzene ring which may have a substituent or 6-membered aromatic heterocycle which may have a substituent” represented by ring A is , It may have 1 to 4 substituents at substitutable positions.
  • a benzene ring which may have a substituent is preferable.
  • substituent on the A ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxyl group, halogen atom, hydroxyl group, C 1-6 alkoxy group, amino group, mono- or di-C 1 -6 alkylamino group, C 1-6 alkyl - carbonyl amino group, mono - or di -C 1-6 alkyl - carbamoyl group, and optionally substituted with a substituent selected from the heterocyclic groups C 1-6 Alkyl group (eg, methyl group, isopropyl group, trifluoromethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, acetylaminomethyl group, methylcarbamoylethyl group, pyrrolidinylmethyl group), halogen A substitu
  • Ring B represents a benzene ring which may have a substituent.
  • the “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring B is further 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present.
  • the substituent on the B ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl group optionally substituted with a halogen atom (eg, methyl group, trifluoromethyl).
  • a C 1-6 alkoxy group eg, methoxy group
  • a C 1-6 alkylthio group eg, methylthio group
  • a cyano group e.g., a fluorine atom and a chlorine atom are more preferred.
  • adjacent substituents are bonded to each other to form a 5- to 8-membered aromatic heterocyclic ring (eg, pyrrole ring).
  • L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group.
  • the propylene group which may be sufficient is shown.
  • L 1 is preferably a bond.
  • L 2 represents an ethylene group which may have a substituent other than an oxo group.
  • L 2 is preferably an ethylene group.
  • X represents S, SO, or SO 2 .
  • X is preferably SO 2 .
  • Z ′ represents CR 4 (R 4 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group) or N.
  • Z ′ is preferably CR 4 , and R 4 is preferably a hydrogen atom.
  • R 2 and R 3 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent.
  • R 2 and R 3 are preferably both hydrogen atoms.
  • n represents an integer of 0 to 3. n is preferably 0 or 1.
  • Ring A is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
  • Ring B is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
  • L 1 is a bond;
  • L 2 is an ethylene group;
  • X is SO 2 ;
  • Z ′ is CH;
  • R 2 and R 3 are both hydrogen atoms; and n is 0 or 1.
  • Compounds are preferred.
  • the compound (II) is preferably the following compound (II-a), (II-b), compound (II-c), compound (II-d), or compound (II-e).
  • Compound (II-a) Compound (II), Ring A represents an optionally substituted benzene ring; Ring B represents an optionally substituted benzene ring; L 1 represents a bond; L 2 represents an ethylene group which may have a substituent other than an oxo group; X represents SO 2 ; Z ′ represents CR 4 or N; R 2 and R 3 represent a hydrogen atom; R 4 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group; n represents 0, 1 or 2; Compound or salt thereof.
  • n is preferably 1.
  • Ring A is (1) halogen atom, (2) hydroxy group, (3) cyano group, (4) phenyl group, (5) C 1-6 alkylthio group, (6) C 1-6 alkoxycarbonyl-C 2-6 alkenyl group (7) C 1-6 alkylsulfonyl group, (8) morpholino group, (9) C 1-6 alkyl group, C 2-6 cycloalkyl group, C 1-6 alkylcarbonyl group, and C 1-6 alkyl Selected from an amino group optionally substituted with one or two substituents selected from a sulfonyl group, (10) a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxy-carbonyl group and a carbamoyl group that may be substituted with a substituent C 1-6 alkoxy group, and (11) a halogen atom, hydroxy group, a pyrrolidiny
  • n is preferably 1.
  • Ring A represents a benzene ring optionally substituted by one mono-C 1-6 alkylamino group
  • Ring B represents a benzene ring substituted with two halogen atoms
  • L 1 represents a bond
  • L 2 represents an ethylene group
  • X represents SO 2
  • Z ′ represents CR 4
  • R 2 , R 3 and R 4 represent a hydrogen atom
  • n represents 1, Compound or salt thereof.
  • Ring A represents an optionally substituted benzene ring
  • Ring B represents an optionally substituted benzene ring
  • L 1 represents a bond
  • L 2 represents an ethylene group
  • X represents SO 2
  • Z ′ represents CR 4 or N
  • R 2 , R 3 and R 4 represent a hydrogen atom
  • n represents 0, 1 or 2
  • Compound or salt thereof
  • Ring A represents a benzene ring optionally substituted with a substituent selected from a halogen atom and a mono- or di-C 1-6 alkylamino group
  • Ring B represents a benzene ring substituted with a halogen atom, Compound or salt thereof.
  • ring A is a benzene ring optionally substituted by 1 to 3 (preferably 1) substituents selected from a halogen atom and a mono C 1-6 alkylamino group
  • the B ring is preferably a benzene ring substituted with 1 to 3 (preferably 1) halogen atoms.
  • the compounds of Examples 9, 12, 18, 21 to 26, 31 to 34, 38 to 47, 49 to 56, 59 to 111 are more preferable.
  • compound (III) is preferable when Z and Y do not couple
  • compound (III) is demonstrated.
  • a ring shows the benzene ring which may have a substituent, or the 6-membered aromatic heterocyclic ring which may have a substituent.
  • the 6-membered aromatic heterocycle represented by the A ring is preferably a pyridine ring.
  • Benzene ring or “6-membered aromatic heterocycle” of “benzene ring which may have a substituent or 6-membered aromatic heterocycle which may have a substituent” represented by ring A is In addition to the “—XZ ′′ group” and the “—CR 1 R 2 — group”, they may further have 1 to 4 substituents at substitutable positions.
  • Examples of the substituent on the A ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, hexoxy group), cyano group, and 5- to 8-membered non-aromatic heterocyclic group (eg, morpholinyl group) are preferable.
  • An atom, a chlorine atom and a methoxy group are more preferable.
  • Ring B represents a benzene ring which may have a substituent.
  • the “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring B is further 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present.
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • a fluorine atom and a chlorine atom are more preferable.
  • L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group.
  • the propylene group which may be sufficient is shown.
  • L 1 is preferably a bond, a methylene group or an ethylene group.
  • L 2 represents an ethylene group which may have a substituent other than an oxo group.
  • L 2 is preferably an ethylene group.
  • X represents S, SO, or SO 2 . X is preferably SO 2 .
  • Z ′′ is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group, and methoxyphenyl group are excluded), (2 ) An amino group which may have a substituent, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent.
  • Z ′′ is an optionally substituted C 1-6 alkyl group (eg, a methyl group, ethyl group, isopropyl group), an optionally substituted C 6-14 aryl group ( Eg, phenyl group), an amino group having 1 to 2 C 1-6 alkyl groups (eg, a methyl group), and an optionally substituted 5- or 6-membered non-aromatic heterocyclic group (Eg, morpholino group) is preferable, and methyl group, ethyl group, isopropyl group, methylamino group, dimethylamino group and morpholino group are more preferable.
  • C 1-6 alkyl group eg, a methyl group, ethyl group, isopropyl group
  • Eg, phenyl group an amino group having 1 to 2 C 1-6 alkyl groups
  • an optionally substituted 5- or 6-membered non-aromatic heterocyclic group is preferable
  • R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, or have a substituent together with an adjacent carbon atom bonded to each other. Cyclopropyl which may be substituted or cyclobutyl which may have a substituent may be formed.
  • R 1 and R 2 are the same or different and are preferably a hydrogen atom and a C 1-6 alkyl group (eg, a methyl group), both of which are a hydrogen atom, and one is a hydrogen atom and the other is a methyl group. More preferred.
  • a ring is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group)
  • a benzene ring or a pyridine ring optionally having a substituent selected from an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentoxy group, and a hexoxy group
  • Ring B is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom)
  • L 1 is a bond, a methylene group or an ethylene group
  • L 2 is an ethylene group
  • X is SO 2
  • Z ′′ is an optionally substituted C 1-6 alky
  • compound (III) the following compound (III-a), compound (III-b), compound (III-c) and compound (III-d) are preferred.
  • Ring A represents an optionally substituted benzene ring or pyridine ring
  • Ring B represents an optionally substituted benzene ring
  • L 1 represents a bond, a methylene group, or an ethylene group
  • L 2 represents an ethylene group
  • X represents SO 2
  • Z ′′ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group
  • R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
  • Compound or salt thereof Compound or salt thereof.
  • Ring A is A benzene ring or a pyridine ring optionally substituted with one substituent selected from a halogen atom, a cyano group, an alkoxy group and a morpholino group
  • Ring B represents a benzene ring substituted with two halogen atoms
  • L 1 represents a bond, a methylene group, or an ethylene group
  • L 2 represents an ethylene group
  • X represents SO 2
  • Z ′′ is (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group optionally substituted by one or two C 1-6 alkyl groups, or (4) a morpholino group Indicates
  • R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
  • Compound or salt thereof Compound or salt thereof.
  • Ring A represents an optionally substituted benzene ring
  • Ring B represents an optionally substituted benzene ring
  • L 1 represents a bond
  • L 2 represents an ethylene group
  • X represents SO 2
  • Z '' is (1) may have a substituent group C 1-6 alkyl group, (2) a phenyl group which may have a substituent, may have a (3) substituents
  • R 1 and R 2 represent a hydrogen atom, Compound or salt thereof.
  • Z ′′ is (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group, (4) a mono- or di-C 1-6 alkylamino group, Or (5) preferably a morpholino group.
  • Compound (III-d) Compound (III-c), comprising: Ring A represents a benzene ring which may have a halogen atom; Ring B represents a benzene ring substituted with a halogen atom; Z ′′ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group, (4) a mono- or di-C 1-6 alkylamino group, or (5) a morpholino group. , Compound or salt thereof.
  • ring A is a benzene ring optionally having 1 to 3 (preferably 1) halogen atoms
  • ring B is 1 to 3 (preferably 2).
  • a benzene ring substituted with a halogen atom is preferred.
  • the compounds of Examples 1 to 8, 10, 11, 13 to 17, 19, 20, 27 to 30, 35 to 37, 48, 57, and 58 are more preferable.
  • Compound (I) can be produced by the following method A or a method analogous thereto.
  • the raw material compound may be used as a salt, and examples of such a salt include those described later as examples of the salt of compound (I).
  • Formula (IV) used as a raw material in this method [wherein each symbol is as defined above. Or a salt thereof (hereinafter sometimes referred to as “compound (IV)”) and formula (V) [wherein LG is a leaving group, and other symbols are as defined above. . ] Or a salt thereof (hereinafter sometimes referred to as “compound (V)”) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto.
  • the leaving group represented by LG includes, for example, a halogen atom (eg, chlorine atom, bromine atom, iodine atom), a substituted sulfonyloxy group (eg, C 1-6 alkylsulfonyl such as methanesulfonyloxy, ethanesulfonyloxy, etc.) Oxy groups; C 6-14 arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy; C 7-16 aralkylsulfonyloxy groups such as benzylsulfonyloxy group, etc.), and halogen atoms are particularly preferred.
  • a halogen atom eg, chlorine atom, bromine atom, iodine atom
  • a substituted sulfonyloxy group eg, C 1-6 alkylsulfonyl such as methane
  • Compound (IV) used as a raw material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in Journal of Medicinal Chemistry, 1975, 18, 142-148 or Bioorganic & Medicinal Chemistry, 2003, 11 (20), 4423-4430.
  • the compound (V) used as a raw material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in Journal of the American Chemical Society, 1951, 73 (7), 3159-3162.
  • This reaction is a step for producing compound (I) by reacting compound (IV) with compound (V) in the presence of a base.
  • This reaction can usually be performed in a solvent inert to the reaction in the presence of a base.
  • the base used in this reaction include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.
  • Organic amines such as undec-7-ene (DBU), metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, etc. .
  • the amount of these bases to be used is about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents, relative to compound (IV).
  • the amount of compound (V) to be used is, for example, about 0.1 to 5 molar equivalents, preferably about 0.5 to 3 molar equivalents relative to compound (IV).
  • the solvent is not particularly limited as long as the reaction proceeds.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like.
  • ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like.
  • examples thereof include amides, alcohols such as methanol, ethanol, propanol, tert-butanol and methoxyethanol, sulfoxides such as dimethyl sulfoxide (DMSO), water, and mixed solvents thereof. This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C.
  • the reaction time for this reaction is usually 0.5 to 60 hours.
  • the compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • concentration, concentration under reduced pressure for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • a salt thereof (hereinafter sometimes referred to as “compound (VII)”) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto. You can also.
  • compound (VII) can be produced according to the method described in Journal of Fluorine Chemistry, 2006, 127, 291-295.
  • condensing agent examples include triazoles such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl ) -4-triazines such as methylmorpholinium chloride, azides such as diphenylphosphoric acid azide, N, N′-dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, water-soluble carbodiimide (WSC), 1-ethyl-3- (3- Carbodiimides such as (dimethylaminopropyl) carbodiimide hydrochloride are used, and carbodiimides are particularly preferably used.
  • triazoles such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole
  • 4- (4,6-dimethoxy-1,3,5-triazin-2-yl ) -4-triazines such as methylmorpholinium chlor
  • the amount of these condensing agents to be used is, for example, about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents relative to compound (IV).
  • This reaction can usually be performed in a solvent inert to the reaction, if necessary, in the presence of a base.
  • Examples of the base used as necessary in this reaction include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0]
  • Organic amines such as undec-7-ene (DBU), metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride
  • organic amines are preferably used.
  • the amount of these bases to be used is about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents, relative to compound (IV).
  • the amount of compound (VII) to be used is, for example, about 0.1 to 5 molar equivalents, preferably about 0.5 to 3 molar equivalents relative to compound (IV).
  • the solvent is not particularly limited as long as the reaction proceeds.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like.
  • Examples thereof include amides, sulfoxides such as dimethyl sulfoxide (DMSO), and mixed solvents thereof.
  • This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C.
  • the reaction time for this reaction is usually 0.5 to 60 hours.
  • the compound (VI) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.
  • This step is a step for producing compound (IA) by subjecting compound (VI) to a reduction reaction in an inert solvent.
  • the reducing agent that can be used in this reaction include lithium aluminum hydride, lithium tetrahydroborate, lithium triethylborohydride, diborane, borane complex (borane-THF complex, catecholborane, etc.), diisobutylaluminum hydride, Examples thereof include zinc borohydride, and a borane complex is particularly preferably used.
  • the amount of these reducing agents to be used is about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents, relative to compound (VI).
  • the solvent is not particularly limited as long as the reaction proceeds.
  • the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like.
  • examples thereof include amides, sulfoxides such as dimethyl sulfoxide (DMSO), and mixed solvents thereof.
  • This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C.
  • the reaction time for this reaction is usually 0.5 to 60 hours.
  • the compound (IA) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Formula (VIII) used as a raw material in this method [wherein each symbol is as defined above.
  • a compound represented by formula (IX) [wherein each symbol is as defined above.]
  • a salt thereof (hereinafter sometimes referred to as “compound (IX)”) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto.
  • You can also Compound (VIII) used as a starting material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in Synthesis, 1980, 5, 405-407.
  • compound (IX) or a salt thereof used as a starting material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in the published patent document WO2005035532.
  • This step is a step for producing compound (IB) by subjecting compound (VIII) to reductive alkylation reaction with compound (IX).
  • the reductive alkylation reaction performed in this step can be performed by a method known per se. For example, it can be carried out by reacting compound (VIII) with compound (IX) and subjecting the produced imine or iminium ion to a reduction reaction.
  • the solvent in the imine or iminium ion production reaction is not particularly limited as long as the reaction proceeds.
  • the solvent examples include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as heptane and hexane, halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, Examples thereof include esters such as ethyl acetate and t-butyl acetate, alcohols such as methanol, ethanol and 2-propanol, nitriles such as acetonitrile, dimethylformamide and dimethyl sulfoxide, and a mixed solvent thereof.
  • the reaction can be advantageously advanced by adding a catalyst as necessary.
  • Such catalysts include mineral acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), sulfonic acids (eg, methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids (eg, aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride, etc.), acetates (sodium acetate, potassium acetate, etc.), molecular sieves (molecular sieves 3A) 4A, 5A, etc.).
  • mineral acids eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • carboxylic acids eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.
  • sulfonic acids eg, methanesulfonic
  • the amount of the catalyst to be used is about 0.01 to 50 molar equivalents, particularly preferably about 1 to 10 molar equivalents, relative to compound (VIII).
  • This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C.
  • the reaction time for this reaction is usually 0.5 to 60 hours.
  • the compound (IB) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. [Method D]
  • Step 1 compound (IV) is subjected to a condensation reaction with compound (X) in the presence of a condensing agent to give compound (XI) [wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as “compound (XI)”), and can be carried out by the same method as described in Step 1 of Method B.
  • compound (XII) is subjected to tert-butoxycarbonylation reaction to give compound (XIII) [wherein each symbol is as defined above. Or a salt thereof (hereinafter sometimes referred to as “compound (XIII)”).
  • a reaction is performed according to a known method (for example, according to “Protective Groups in Organic Synthesis, 3rd Ed.” Published by Wiley-Interscience, Theodora W. Greene, Peter G. M. Wuts). I can do it.
  • a tert-butoxycarbonylating agent in a solvent that does not adversely influence the reaction, and if necessary, in the presence of a base.
  • the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), acetates ( Sodium acetate, etc.), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine, etc.), organic amines (pyridine, picoline, N, N-dimethylaniline, etc.) and the like.
  • the amount of the base to be used is generally about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of compound (XII).
  • the tert-butoxycarbonylating agent for example, di-tert-butyl dicarbonate and the like can be mentioned, and the amount thereof to be used is about 1 to 10 mol equivalent, preferably about 1 to 2 mol, per 1 mol of compound (XII). About the molar equivalent.
  • Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, 1-propanol, 2-propanol, butanol, isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.) ), Aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), Nitriles (such as acetonitrile), esters (such as ethyl acetate), carboxylic acids (such as acetic acid), amides (such as N, N-dimethylformamide), sulfoxides (such as dimethyl sulfoxide), water
  • the reaction temperature is, for example, in the range of about ⁇ 50 to 200 ° C., preferably about 0 to 100 ° C., and the reaction time varies depending on the kind of compound (XII) or a salt thereof, the reaction temperature, etc. It is about 5 to 100 hours, preferably about 0.5 to 24 hours.
  • Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine.
  • Examples of the electrophilic agent include diethyl 1,1′-azodicarboxylate, diisopropyl 1,1′-azodicarboxylate, 1,1′-azodicarbonyldipiperazine, and the like.
  • the amount of the organophosphorus compound and electrophilic agent used is 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XIII) and compound (XIV), respectively.
  • solvents that do not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and methylene chloride; aromatic hydrocarbons such as benzene, toluene and xylene; N, N Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide and the like, and mixed solvents thereof.
  • the amount of these solvents to be used is, for example, 1 volume to 100 volumes with respect to compound (XIII).
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 100 ° C.
  • the reaction time is usually about 0.5 hours to about 20 hours.
  • This step is a step for producing compound (IA) by subjecting compound (XV) to a deprotection reaction.
  • a deprotection reaction is carried out according to a known method (for example, according to Theory W. Greene, Peter G. Muts, published by Wiley-Interscience, "Protective Groups in Organic Synthesis, 3rd Ed.”). I can do it.
  • a known method for example, according to Theory W. Greene, Peter G. Muts, published by Wiley-Interscience, "Protective Groups in Organic Synthesis, 3rd Ed.”
  • Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, etc.), carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid, etc.) ), Lewis acids (aluminum chloride, tin chloride, zinc bromide, etc.) and the like may be used, and two or more kinds may be mixed as necessary.
  • the amount of acid used varies depending on the type of solvent and other reaction conditions, but is usually about 0.1 molar equivalents or more per 1 mol of compound (XV), and can also be used as a solvent.
  • Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), Aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles (Such as acetonitrile), esters (such as ethyl acetate), carboxylic acids (such as acetic acid), amides (such as N, N-dimethylformamide), sulfoxides (such as dimethyl sulfoxide), water
  • the reaction temperature is, for example, in the range of about ⁇ 50 to 200 ° C., preferably about 0 to 100 ° C., and the reaction time varies depending on the type of compound (XV), the reaction temperature, etc., for example, about 0.5 to 100 The time is preferably about 0.5 to 24 hours.
  • the compound (I) obtained by the above production method can be further derivatized by subjecting it to a known oxidation reaction.
  • compound (I) may be used after being protected with a protecting group that is usually used in peptide synthesis or the like.
  • the target compound after the reaction, can be obtained by removing the protecting group using a known method, if necessary.
  • inorganic acid for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.
  • organic acid for example, methanesulfonic acid, benzenesulfonic acid
  • Toluenesulfonic acid oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.
  • inorganic bases eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium
  • organic bases for example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.
  • Gain in form If you in a usual manner, it can be converted free compound or into another salt.
  • the compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (examples) , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product.
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • the optical isomer can be produced by a method known per se.
  • an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
  • Racemate and optically active compound eg, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Racemate and optically active compound eg, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column).
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphoric acid)
  • the optical isomers are separated by developing a buffer solution or the like and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution thereof.
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.
  • the separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science).
  • a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science).
  • Diastereomer method A racemic mixture is converted into a diastereomer mixture by a chemical reaction with an optically active reagent, and this mixture is passed through ordinary separation means (eg, fractional recrystallization method, chromatography method, etc.) and the like.
  • a method of obtaining an optical isomer by separating an optically active reagent site by chemical treatment such as hydrolysis after making a single substance.
  • the compound (I) when the compound (I) has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid]) , ( ⁇ )-Menthoxyacetic acid, etc.) and the like are subjected to a condensation reaction, whereby ester or amide diastereomers are obtained, respectively.
  • an amide or ester diastereomer when compound (I) has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and optically active amine or optically active alcohol to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis.
  • Compound (I) may be a crystal. Crystals of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
  • the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane).
  • aromatic hydrocarbons eg, benzene, toluene, xylene, etc.
  • halogenated hydrocarbons eg, dichloromethane, chloroform, etc.
  • saturated hydrocarbons eg, hexane, heptane, cyclohexane.
  • Etc. ethers
  • ethers eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.
  • nitriles eg, acetonitrile, etc.
  • ketones eg, acetone, etc.
  • sulfoxides eg, dimethyl sulfoxide, etc.
  • acid amides Eg, N, N-dimethylformamide, etc.
  • esters eg, ethyl acetate, etc.
  • alcohols eg, methanol, ethanol, isopropyl alcohol, etc.
  • solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).
  • a seed crystal can also be used as needed.
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
  • Examples of the “crystallization from the melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). , Liquid phase epitaxy method) and the like.
  • compound (I) is dissolved in a suitable solvent (eg, alcohols such as methanol and ethanol) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved.
  • a suitable solvent eg, alcohols such as methanol and ethanol
  • Examples thereof include a method of cooling to a temperature below (eg, 0 to 50 ° C., preferably 0 to 20 ° C.).
  • the crystals of compound (I) thus obtained can be isolated, for example, by filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the crystal of compound (I) obtained by the above production method hereinafter abbreviated as “crystal of the present invention”
  • it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), drug effect expression, etc.) and is extremely useful as a medicine.
  • Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).
  • a compound labeled or substituted with an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc. is also encompassed in compound (I).
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds and the like];
  • Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated eg, hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Compound, dimethylaminomethylcarbonylated
  • prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • Compound (I) has an excellent ⁇ 1D adrenergic receptor antagonistic action.
  • compounds having a selective ⁇ 1D adrenergic receptor antagonistic action are preferable.
  • selective ⁇ 1D adrenergic receptor antagonistic activity means that it has at least 10 times or more antagonistic activity against ⁇ 1A adrenergic receptor and 10 times or more against ⁇ 1B adrenergic receptor. Since the compound (I) has a selective ⁇ 1D adrenergic receptor antagonistic action, a blood pressure lowering action or the like that is considered to be based on an antagonistic action on the ⁇ 1A receptor or the ⁇ 1B receptor is reduced. It can be a drug with few side effects.
  • Compound (I) based on alpha 1D adrenergic receptor antagonistic action, a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) all alpha 1D adrenergic receptor for Body related diseases such as (1) Lower urinary tract diseases (including all diseases having lower urinary tract symptoms described below, including overactive bladder, prostatic hypertrophy, interstitial cystitis, chronic prostatitis, etc.), urinary storage symptoms (Daytime frequent urination, nocturia, urgency, urinary incontinence, stress urinary incontinence, urge incontinence, mixed urinary incontinence, enuresis, nocturnal urine, persistent urinary incontinence, other urinary incontinence, increased bladder perception, Urination symptoms (urinary decline, urinary division, urinary scattering, urinary disruption, urination delay, abdominal pressure urination, terminal drop, etc.), post urinary symptoms (resi
  • Metabolic diseases for example, diabetes (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microangiopathy, diabetic neuropathy, etc.), impaired glucose tolerance, obesity, prostatic hypertrophy, sex Dysfunction etc.), (3) CNS diseases [eg, neurodegenerative diseases (eg, Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic spinal sclerosis (ALS), Huntington's chorea, diabetic neuropathy, frequent occurrence] Sclerosis), mental illness (eg, schizophrenia (schizophrenia), depression, mania, anxiety, anxiety, threatening neuropathy, panic disorder, epilepsy, alcoholism, drug dependence, anxiety symptoms, Uncomfortable mental state, emotional abnormalities, emotional circulation, hypersensitivity, autism, syncope, sputum, decreased libido, etc., central and peripheral neuropathy (eg, head trauma, spinal cord injury, brain edema, sensory dysfunction) Sensory dysfunction, autonomic dysfunction, autonom
  • the compound (I) is particularly useful as an agent for improving lower urinary tract symptoms such as overactive bladder and stress urinary incontinence, and a preventive or therapeutic agent for these lower urinary tract symptoms.
  • Preparations containing Compound (I) are tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, Orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion , Patches, suppositories (eg, anal suppositories (e
  • the prophylactic / therapeutic agent of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization treatment, emulsification, etc., depending on the form of the preparation.
  • a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization treatment, emulsification, etc.
  • the preparation of the present invention may be formed into a sustained release agent containing an active ingredient and a biodegradable polymer compound.
  • the sustained-release agent can be prepared according to the method described in JP-A-9-263545.
  • the content of compound (I) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, more preferably based on the whole preparation. Is about 0.5 to 20% by weight.
  • the compound (I) When the compound (I) is used as the above-mentioned pharmaceutical product, it is used as it is or an appropriate pharmacologically acceptable carrier, for example, excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders ( Examples, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (eg, , Carboxymethylcellulose calcium, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), additives (eg, stabilizers, preservatives, colorants, fragrances, solubilizers, emulsifiers, buffers) as necessary.
  • excipients e
  • Powders, fine granules, granules, tablets, caps, etc. It can be administered orally or parenterally in liquid in the form of a solid or injectable agent Le agent.
  • Compound (I) can also be administered directly to the affected area of a joint disease when it is formed into a topical preparation and administered. In this case, an injection is preferable.
  • Parenteral for topical administration eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, lesion And the like, solid preparations such as injections, implants, granules and powders, liquids such as suspensions, ointments and the like.
  • compound (I) is used as a dispersant (eg, surfactants such as Tween 80 and HCO-60, polysaccharides such as carboxymethyl cellulose, sodium alginate, hyaluronic acid, polysorbate, etc.), preservatives ( Examples, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (eg, calcium carbonate, etc.), pH adjusters (eg, sodium phosphate, potassium phosphate)
  • a dispersant eg, surfactants such as Tween 80 and HCO-60, polysaccharides such as carboxymethyl cellulose, sodium alginate, hyaluronic acid, polysorbate, etc.
  • preservatives examples, methylparaben, propylparaben, etc.
  • isotonic agents eg, sodium chloride, mannitol, sorbitol, glucose
  • vegetable oil such as sesame oil, corn oil or the like mixed with phospholipid such as lecithin, or medium chain fatty acid triglyceride (eg, miglyol 812).
  • the prophylactic / therapeutic agent of the present invention can be used together with other drugs.
  • drugs that can be blended or used in combination with compound (I) include the following.
  • Preventive and therapeutic agents for other lower urinary tract diseases include all diseases having symptoms represented by lower urinary tract symptoms
  • adrenergic ⁇ 1 receptor blockers eg, tamsulosin, urapidil, naphthopidyl, silodosin, Doxazosin, alfuzosin, etc.
  • anticholinergic drugs eg, oxybutynin, propiverine, darifenacin, tolterodine, solifenacin, temiverine, trospium chloride or salts thereof
  • NK-1 receptor antagonists eg, aprepitant, casiopitant, LY686017, etc.
  • Adrenergic ⁇ 3 receptor agonists eg, solabegron, YM-178
  • Insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragments Or derivatives (eg, INS-1 etc.)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP) -297, FK-614, CS-011, etc.), ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, Tolbutamide, Rivenclamide, gliclazide, chlorpropamide
  • Aldose reductase inhibitors eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), CT-112 etc.
  • nerve Nutritional factors eg, NGF, NT-3, etc.
  • AGE inhibitors eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.
  • active oxygen elimination Drugs eg, thioctic acid, etc.
  • cerebral vasodilators eg, tiapride, etc.
  • Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt, etc.)), squalene synthase inhibition Agents, fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like.
  • cholesterol synthesis inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt, etc.
  • squalene synthase inhibition Agents eg, fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc
  • Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine and the like.
  • Angiotensin converting enzyme inhibitor eg, captopril, enalapril, delapril, etc.
  • angiotensin II antagonist eg, losartan, candesartan cilexetil, etc.
  • calcium antagonist eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine
  • Anti-obesity agents Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibitor (Eg, orlistat, etc.), ⁇ 3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptidic appetite suppressants (eg, leptin, CNTF (hair-like) Somatic neurotrophic factor)), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.) and the like.
  • ⁇ 3 agonists eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc
  • Diuretics xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.
  • thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetazolamide, etc.
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide, etc.
  • azosemide isosorbide, etacrine Acid, piretanide, bumetanide, furosemide,
  • Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.
  • Alkylating agents eg, cyclophosphamide, ifosfamide, etc.
  • antimetabolites eg, methotrexate, 5-fluorouracil, etc.
  • anticancer antibiotics eg, mitomycin, adriamycin, etc.
  • plants Derived anticancer agents eg, vincristine, vindesine
  • Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among them IL-1, IL-2, IL-12, etc.
  • cytokines obtained by genetic engineering techniques
  • IL Interferon, interleukin (IL), etc.
  • colony stimulating factors eg, granulocyte colony stimulating factor, erythropoietin, etc.
  • Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.) and the like.
  • Steroids eg, dexamethasone, etc.
  • sodium hyaluronate e.g, sodium hyaluronate
  • cyclooxygenase inhibitors eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.
  • Glycation inhibitors eg, ALT-711 etc.
  • nerve regeneration promoters eg, Y-128, VX853, prostide etc.
  • central nervous system drugs eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine
  • Antidepressants such as doxepin
  • antiepileptic drugs eg, lamotrigine, carbamazepine
  • antiarrhythmic drugs eg, mexiletine
  • acetylcholine receptor ligands eg, ABT-594
  • endothelin receptor antagonists eg, ABT) -627
  • monoamine uptake inhibitors eg, tramadol
  • indoleamine uptake inhibitors eg, floxetine, paroxetine
  • narcotic analgesics eg, morphine
  • GABA receptor agonists eg, gabapentin
  • GABA uptake Inhibitor
  • anticholinergic agent examples include atropine, scopolamine, homatropine, tropicamide, cyclopentrate, butylscopolamine bromide, propantheline bromide, methylbenactidium bromide, mepenzolate bromide, flavoxate, pirenzepine, ipratopium bromide, trihepium Xyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospium chloride or its salts (eg, atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide, cyclopentrate hydrochloride, flavoxate hydrochloride, pirenzepine hydrochloride, trihepine Xyphenidyl, oxybutynin hydrochloride, tolterodine tartrate, etc.) are used.
  • oxybutynin, propiverine, darifenacin, tolterodine, temiverine, Supiumu or a salt thereof are preferred.
  • oxybutynin hydrochloride, etc. tolterodine tartrate are preferred.
  • acetylcholinesterase inhibitors eg, distigmine etc.
  • distigmine etc. can also be used.
  • NK-2 receptor antagonists include GR1599897, GR1499861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, pelysin, SCH81373, R132 Perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrolopyrimidine derivatives such as ZM-253270, MEN11420 (nepadutant), SCH217048, L-659877, PD-147714 (CAM-2291), MEN10376, Pseudopeptide derivatives such as S16474, etc. R100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or a salt thereof and the like.
  • the administration timing of the compound (I) and the concomitant drug is not limited, and the compound (I) or a pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof may be simultaneously administered to the administration subject. However, it may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as the compound (I) and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously compounding compound (I) or a pharmaceutical composition thereof and a concomitant drug, and (2) compound (I) or a medicament thereof. Simultaneous administration of the two preparations obtained by separately formulating the composition and the concomitant drug or pharmaceutical composition thereof by the same route of administration, (3) Compound (I) or a pharmaceutical composition thereof and the concomitant drug or pharmaceutical thereof Administration of two types of preparations obtained by separately formulating the composition with a time difference in the same route of administration, (4) Compound (I) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof Simultaneous administration of two types of preparations obtained by separate formulation by different administration routes, (5) obtained by separately formulating Compound (I) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof 2
  • Different administration courses for different types of formulations Administration at an interval via the; include (e.g., Compound (I) or a pharmaceutical composition thereof in combination
  • the compounding ratio of the compound (I) and the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of compound (I) in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
  • the same content may be used when compound (I) and the concomitant drug are formulated separately.
  • the dose varies depending on the type of compound (I) or a pharmaceutically acceptable salt thereof, the route of administration, symptoms, patient age, etc.
  • the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (eg, human, rat, mouse, cat) Mammals such as dogs, rabbits, cows, and pigs), depending on the purpose of administration.
  • the animal to be administered eg, human, rat, mouse, cat
  • Mammals such as dogs, rabbits, cows, and pigs
  • parenteral administration about 0.1 to about 100 mg of compound (I) is administered in a week. May be released from the.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration. Is usually administered in 1 to 4 divided doses per day.
  • the concomitant drug of the present invention When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, compound (I) may be administered, or compound (I) is administered first. Thereafter, the concomitant drug may be administered.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • the method includes administering Compound (I) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day after administration of compound (I), preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour.
  • a method is mentioned.
  • the pharmaceutical composition of the present invention has low toxicity and can be used safely.
  • the Example compounds shown below are excellent in absorbability when administered orally, and can be advantageously used for oral preparations.
  • the ⁇ value was expressed in ppm.
  • the numerical value shown in the mixed solvent is a volume mixing ratio of each solvent unless otherwise specified.
  • % Means weight percent unless otherwise specified.
  • the room temperature (ordinary temperature) in this specification represents a temperature of about 10 ° C. to about 35 ° C.
  • the meanings of the abbreviations in Examples and Reference Examples are as follows.
  • Reference example 1 [5-Chloro-2- (methylsulfonyl) phenyl] methanamine hydrochloride (Step 1) In a DMF (20 mL) solution, 5-chloro-2-fluorobenzonitrile (2.0 g) and sodium methanethiolate (0.99 g) ) was stirred at 60 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid followed by saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 5-chloro-2- (methylsulfanyl) benzonitrile (1.61 g). It was.
  • Step 2 To a solution of 5-chloro-2- (methylsulfanyl) benzonitrile (3.6 g) obtained in Step 1 in THF (150 mL), lithium aluminum hydride (1.12 g) was added at 0 ° C. After stirring at room temperature for 2 hours, sodium sulfate decahydrate was added. Further, after stirring at room temperature for 30 minutes, the inorganic substance was filtered off through celite.
  • Step 3 Dicarbonate was added to a solution of 1- [5-chloro-2- (methylsulfanyl) phenyl] methanamine hydrochloride (10.9 g) obtained in Step 2 and Et 3 N (9.84 g) in THF (200 mL). Di-t-butyl (15.9 g) was added at room temperature. After stirring at the same temperature for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Reference example 2 1- ⁇ 5-Chloro-2-[(1-methylethyl) sulfonyl] phenyl ⁇ methanamine hydrochloride (Step 1) To a suspension of lithium aluminum hydride (1.56 g) in THF (250 mL) was added 5-chloro-2 Of 5-chloro-2-[(1-methylethyl) sulfanyl] benzonitrile (7.25 g) obtained in the same manner as in Step 1 of Reference Example 1 using 2-fluorobenzonitrile and sodium 2-propanethiolate (50 mL) solution was added at 0 ° C. After stirring at room temperature for 3 hours, sodium sulfate decahydrate was added.
  • Step 2 1- ⁇ 5-Chloro-2-[(1-methylethyl) sulfanyl] phenyl ⁇ methanamine hydrochloride (6.3 g) obtained in Step 1 and Et 3 N (5.06 g) in THF (200 mL) ) Di-t-butyl dicarbonate (7.09 g) was added to the solution at room temperature. After stirring at the same temperature for 3 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Reference example 3 [5-Chloro-2- (ethylsulfonyl) phenyl] methanamine hydrochloride (Step 1) In a DMF (50 mL) solution, 5-chloro-2-fluorobenzonitrile (5.83 g) and sodium ethanethiolate (3.47 g) ) At room temperature for 14 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 5-chloro-2- (ethylsulfanyl) benzonitrile (7.4 g).
  • Step 2 To a suspension of lithium aluminum hydride (1.7 g) in THF (300 mL), THF (20 mL) of 5-chloro-2- (ethylsulfanyl) benzonitrile (7.4 g) obtained in Step 1 The solution was added at 0 ° C. After stirring at room temperature for 3 hours, sodium sulfate decahydrate was added.
  • Reference example 4 [5-Methoxy-2- (methylsulfonyl) phenyl] methanamine hydrochloride (Step 1) In DMF (20 mL) solution, 2-fluoro-5-methoxybenzonitrile (10 g) and sodium methanethiolate (5.1 g ) was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, followed by aqueous sodium hydrogen carbonate solution, then saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 To a suspension of lithium aluminum hydride (2.1 g) in THF (200 mL), 5-methoxy-2- (methylsulfanyl) benzonitrile (8.27 g) obtained in Step 1 was added at 0 ° C. . After stirring at room temperature for 3 hours, sodium sulfate decahydrate was added, and the mixture was allowed to reach room temperature and stirred for another 30 minutes. Concentrate the filtrate under reduced pressure, dissolve the residue in methanol, add 4N hydrogen chloride / ethyl acetate solution (15 mL), crystallize with methanol and ethyl acetate, and wash the resulting crystals with ethyl acetate.
  • Gave 1- [5-methoxy-2- (methylsulfanyl) phenyl] methanamine hydrochloride (8.45 g).
  • Step 3 Dicarbonate was added to a solution of 1- [5-methoxy-2- (methylsulfanyl) phenyl] methanamine hydrochloride (6.0 g) obtained in Step 2 and Et 3 N (5.53 g) in THF (150 mL). Di-t-butyl (8.94 g) was added at room temperature. After stirring at the same temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 5-fluoro-2- (methylsulfanyl) benzoic acid obtained in Step 1 (40 g), ammonium chloride (22.9 g), HOBt (58.1 g), WSC (66.7 g) and diisopropylethylamine (150 mL) in DMF (503 mL) was stirred at room temperature for 5 hours, and the solvent was evaporated under reduced pressure.
  • reaction solution was heated to reflux for 6 hours, cooled to 0 ° C., water and 15% aqueous sodium hydroxide solution were added, and the mixture was filtered through celite. The filtrate was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 1- [5-fluoro-2- (methylsulfanyl) phenyl] methanamine (16.2 g). It was.
  • the reaction solution was stirred at room temperature for 12 hours, and then the solvent was distilled off under reduced pressure.
  • the residue was dissolved with water and dichloromethane and extracted twice with dichloromethane.
  • the organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure.
  • Step 5 m-perchlorobenzoic acid (43.9 g) was added to a solution of tert-butyl [5-fluoro-2- (methylsulfanyl) benzyl] carbamate (23 g) obtained in Step 4 in dichloromethane (283 mL). Added at room temperature and stirred for 18 hours. 2N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • Step 6 To a solution of tert-butyl [5-fluoro-2- (methylsulfonyl) benzyl] carbamate (12.6 g) obtained in Step 5 in ethyl acetate (100 mL), 4M hydrogen chloride / dioxane solution (20 mL) was added at 0 ° C. and stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain the title compound (6.5 g).
  • step 1 2-[(acetylamino) in a 2N dimethylamine / methanol solution (7.51 mL) in methanol (15 mL). ) Methyl] -4-chlorobenzenesulfonyl chloride (2.12 g) in THF (5 mL) was added dropwise, and the mixture was warmed to room temperature and stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 2 6N hydrochloric acid (20 mL) was added to a solution of N- [5-chloro-2- (dimethylsulfamoyl) benzyl] acetamide (1.77 g) obtained in Step 1 in ethanol (20 mL) at room temperature.
  • the obtained residue was dissolved in THF (150 mL), and THF-borane complex (200 mL, 1M THF solution) was added at 0 ° C. After stirring the reaction solution at 90 ° C. for 3 hours, ice was added to the reaction solution, and 1N hydrochloric acid (300 mL) was added. After stirring at 90 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 To a solution of 3,4-dihydro-2H-thiochromen-4-amine hydrochloride (5.3 g) obtained in Step 1 and Et 3 N (5.85 g) in THF (200 mL) was added di-t-carbonate. -Butyl (6.88 g) was added at room temperature.
  • reaction solution was poured into water and extracted with ethyl acetate.
  • the organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was dissolved in ethyl acetate (200 mL), and m-chloroperbenzoic acid (18.1 g) was added at room temperature.
  • the reaction solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • the organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the residue was crystallized from ethyl acetate and hexane to give the title compound (880 mg).
  • Step 2 The title compound was obtained in the same manner as in Step 2 of Reference Example 7 using 1- [5-chloro-2- (methylsulfanyl) phenyl] ethanamine obtained in Step 1.
  • Step 2 2- (2-Chloro-5-fluorophenoxy) ethanamine hydrochloride (0.53 g) obtained in Step 1 and 2- (methylsulfanyl) pyridine-3-carbaldehyde (0.36 g) in THF (20 mL) and acetic acid (2 mL) solutions were stirred at room temperature for 30 minutes.
  • NaBH (OAc) 3 (0.75 g) was added at 0 ° C., and the mixture was stirred at room temperature for 24 hours.
  • 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 1- [2- (Methylsulfonyl) phenyl] ethanamine hydrochloride (0.30 g), (2,5-difluorophenoxy) acetic acid (0.24 g), WSC (0.39 g), HOBt obtained in Step 1
  • a solution of (0.30 g) and Et 3 N (0.26 g) in acetonitrile (5 mL) was stirred at room temperature for 2 hours.
  • the reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2-hydroxyacetamide obtained in Step 1 was dissolved in THF (50 mL), and THF- Borane complex (99 mL, 1M in THF) was added at 0 ° C. After stirring the reaction solution at 60 ° C. for 4 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (50 mL) was added to the residue. The mixture was stirred at 70 ° C. for 2 hours, basified with 8N sodium hydroxide solution, and extracted with ethyl acetate.
  • Step 3 tert-butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate (341 mg), 2-methoxyphenol obtained in Step 2 (149 mg) and tributylphosphine (748 mg) were dissolved in THF (4 mL), and 1,1′-azodicarbonylpiperidine (757 mg) was added at 50 ° C. The reaction mixture was stirred at 50 ° C. for 2 hours, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue, the mixture was filtered, and the solvent was distilled off under reduced pressure.
  • Step 3 3,4-dihydro-2H-1,2-benzothiazin-4-amine 1,1-dioxide (500 mg), (2-chloro-5-fluorophenoxy) acetic acid (568) obtained in Step 2 mg), WSC (532 mg), HOBt (425 mg) and Et 3 N (0.39 mL) in THF (30 mL) were stirred at 60 ° C. for 5 hours. After pouring 1N hydrochloric acid into the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 A solution of 2-[(acetylamino) methyl] -4-bromobenzenesulfonyl chloride (4.10 g) obtained in Step 1 and 2N dimethylamine / methanol (15 mL) in THF (10 mL) at room temperature For 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 3 To a solution of N- [5-bromo-2- (dimethylsulfamoyl) benzyl] acetamide (4.40 g) obtained in Step 2 in ethanol (40 mL) was added 6N hydrochloric acid (20 mL) at room temperature. And stirred at 90 ° C. overnight. The solvent was evaporated under reduced pressure, and the residue was filtered and washed with ethyl acetate to give 2- (aminomethyl) -4-bromo-N, N-dimethylbenzenesulfonamide hydrochloride (3.42 g).
  • Step 5 N- [5-Bromo-2- (dimethylsulfamoyl) benzyl] -2- (2-chloro-5-fluorophenoxy) acetamide (2.70 g) obtained in Step 4 in THF (40 mL ) THF-borane complex (17 mL, 1M THF solution) was added to the solution, and the mixture was stirred at 80 ° C. for 3 hours. Ice was added to the reaction mixture, and 1N hydrochloric acid (20 mL) was added. Stir at 80 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, and the separated aqueous layer was made basic with sodium hydroxide solution and extracted with ethyl acetate.
  • Step 6 4-Bromo-2-( ⁇ [2- (2-chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethylbenzenesulfonamide hydrochloride (1.70) obtained in Step 5 g) and tri-ethylamine (1.1 mL) in THF (50 mL) were added di-t-butyl dicarbonate (1.20 g) at room temperature. After stirring at 60 ° C. for 3 hours, saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 2 A solution of 3-[(4-bromophenyl) sulfanyl] propanoic acid (15.3 g) obtained in Step 1 in methanesulfonic acid (150 mL) was stirred at 75 ° C. for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 3 A solution of 6-bromo-2,3-dihydro-4H-thiochromen-4-one (10.8 g) and O-methylhydroxylamine hydrochloride (4.83 g) obtained in Step 2 in pyridine (60 mL) was stirred at room temperature for 20 hours. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 4 (4E) -6-Bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (9.70 g) obtained in Step 3 was dissolved in THF (50 mL). -Borane complex (89 mL, 1M in THF) was added at 0 ° C. After stirring the reaction solution at 65 ° C. for 3 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (45 mL) was added to the residue. After stirring at 75 ° C. for 3 hours, the mixture was basified with 8N sodium hydroxide solution and extracted with ethyl acetate.
  • Step 5 To a solution of tert-butyl (6-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (10.6 g) obtained in Step 4 in ethyl acetate (60 mL) was added m-chloroperoxide. Benzoic acid (15.2 g) was added at 0 ° C. After stirring at the same temperature for 1.5 hours, an aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 6 6-Bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.0 g), (2,5-difluorophenoxy) acetic acid (1.32) obtained in Step 5 g), WSC (1.35 g), HOBt (950 mg) and diisopropylethylamine (1.82 g) in DMF (20 mL) were stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 Using 3- ⁇ [4- (trifluoromethyl) phenyl] sulfanyl ⁇ propanoic acid (3.22 g) obtained in Step 1, in the same manner as in Step 2 of Reference Example 49, 6- (trifluoro Methyl) -2,3-dihydro-4H-thiochromen-4-one (2.42 g) was obtained.
  • Step 3 6- (Trifluoromethyl) -2,3-dihydro-4H-thiochromen-4-one (2.42 g) obtained in Step 2 was used in the same manner as in Step 3 of Reference Example 29 ( 4E) -6- (Trifluoromethyl) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (2.70 g) was obtained.
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ ppm 2.94-3.01 (2H, m), 3.06-3.13 (2H, m), 4.03 (3H, s), 7.28-7.34 (1H, m), 7.37-7.43 ( 1H, m), 8.26 (1H, s).
  • Step 4 Using (4E) -6- (trifluoromethyl) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (2.7 g) obtained in Step 3, In the same manner as in Step 4, tert-butyl [6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (1.93 g) was obtained.
  • Step 5 Step 5 of Reference Example 29 using tert-butyl [6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (1.93 g) obtained in Step 4
  • 6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.14 g) was obtained.
  • Step 6 Step of Reference Example 29 using 6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.14 g) obtained in Step 5
  • the title compound (1.28 g) was obtained by the same method as 6.
  • Step 2 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate of Step 1 ( 1.5 g), benzophenone imine (611 mg), sodium tert-butoxide (378 mg), tris (dibenzylideneacetonato) dipalladium (Pd 2 (dba) 3 ) (51.5 mg) and 4,5-bis (diphenylphosphine)
  • Fino Fino-9,9-dimethylxanthene (65 mg) in toluene (10 mL) was stirred at 100 ° C.
  • Step 2 tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylsulfanyl) -1,1-dioxide-3,4-dihydro-2H-thiochromene-obtained in Step 1
  • 4-yl] carbamate 400 mg
  • ethyl acetate 3 mL
  • m-chloroperbenzoic acid 394 mg
  • Step 2 tert-Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg), dicyclohexyl [2 ', 4', 6'-Tris (1-methylethyl) biphenyl-2-yl] phosphane (13.0 mg), sodium t-butoxide (28.9 mg), morpholine (0.026 mL), Pd 2 (dba) 3 (12.5 mg) in toluene (3 mL) was stirred at 100 ° C. for 3 hours.
  • Step 2 Methyl 4- ⁇ (tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -3,4-dihydro-2H-thiochromene-6-carboxylate obtained in Step 1
  • a solution of 1,1-dioxide (1.27 g) in 1N aqueous sodium hydroxide (5 mL) and THF (10 mL) was stirred at 50 ° C. for 3 hours. The reaction was acidified with 1N hydrochloric acid and extracted with ethyl acetate.
  • Step 3 4- ⁇ (tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -3,4-dihydro-2H-thiochromene-6-carboxylic acid 1 obtained in Step 2 , 1-dioxide (300 mg), 1H-benzotriazol-1-ol ammonium salt (110 mg), WSC (139 mg) and diisopropylethylamine (93.6 mg) in DMF (2 mL) were stirred at room temperature for 19 hours. . The reaction mixture was poured into water and extracted with ethyl acetate.
  • Step 2 Using 3-[(3-bromophenyl) sulfanyl] propanoic acid (15.8 g) obtained in Step 1, in the same manner as in Step 2 of Reference Example 29, 7-bromo-2,3-dihydro -4H-thiochromen-4-one (11.9 g) was obtained.
  • Step 3 (4E) -7 in the same manner as in Step 3 of Reference Example 29 using 7-bromo-2,3-dihydro-4H-thiochromen-4-one (11.9 g) obtained in Step 2 -Bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.1 g) was obtained.
  • Step 4 Similar to Step 4 of Reference Example 29 using (4E) -7-bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.1 g) obtained in Step 3
  • tert-butyl (7-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.9 g) was obtained.
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ ppm 1.47 (9H, s), 2.02-2.14 (1H, m), 2.27-2.40 (1H, m), 2.93-3.12 (2H, m), 4.75 (1H, br), 4.82 (1H, br), 7.15 (2H, s), 7.25 (1H, s).
  • Step 5 The same procedure as in Step 5 of Reference Example 29 using tert-butyl (7-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) obtained in Step 4 Gave 7-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (10.1 g).
  • Step 6 Using 7-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (4 g) obtained in Step 5, the same as Step 6 of Reference Example 29 According to the procedure, N- (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (3.86 g) was obtained.
  • Step 7 N- (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide obtained in Step 6 ( Tert-butyl (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2 , 5-Difluorophenoxy) ethyl] carbamate (2.7 g) was obtained.
  • Step 8 tert-butyl (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl obtained in Step 7 ]
  • the title compound (821 mg) was obtained in the same manner as in Reference Example 37 using carbamate (1 g).
  • Step 2 By using the 3-[(2-bromophenyl) sulfanyl] propanoic acid (21.4 g) obtained in Step 1 in the same manner as in Step 2 of Reference Example 29, 8-bromo-2,3-dihydro -4H-thiochromen-4-one (12.5 g) was obtained.
  • Step 3 (4E) -8 in the same manner as in Step 3 of Reference Example 29 using 8-bromo-2,3-dihydro-4H-thiochromen-4-one (12.5 g) obtained in Step 2 -Bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.7 g) was obtained.
  • Step 4 Similar to Step 4 of Reference Example 29 using (4E) -8-bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.7 g) obtained in Step 3 In this manner, tert-butyl (8-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) was obtained.
  • Step 5 The same procedure as in Step 5 of Reference Example 29 using tert-butyl (8-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) obtained in Step 4 Gave 8-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (9.98 g).
  • Step 6 Similar to Step 6 of Reference Example 29 using 8-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (4 g) obtained in Step 5 According to the procedure, N- (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (5.64 g) was obtained.
  • Step 7 N- (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide obtained in Step 6 ( Tert-Butyl (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2 , 5-Difluorophenoxy) ethyl] carbamate (5.04 g) was obtained.
  • Step 8 tert-butyl (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl obtained in Step 7 ]
  • the title compound (569 mg) was obtained in the same manner as in Reference Example 37 using carbamate (1.0 g).
  • Step 2 Using 2- (2,5-difluorophenoxy) propionic acid (1.5 g) obtained in Step 1 in the same manner as in Step 6 of Reference Example 29, 2- (2,5-difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) propanamide (2.31 g) was obtained.
  • Step 3 2- (2,5-Difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) propanamide obtained in Step 2 (2.31 g) was used to obtain the title compound in the same manner as in Step 7 of Reference Example 29.
  • Step 2 A solution of O- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (3.0 g) obtained in Step 1 in diethylaniline (6 mL) was stirred at 210 to 220 ° C. for 5 hours. The reaction mixture was poured into ice and 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 3 A solution of S- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (3.19 g) obtained in Step 2 and 1N aqueous sodium hydroxide (30.7 mL) in methanol (43 mL) was added at 80 ° C. For 2 hours. 1N Hydrochloric acid (35 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 2-bromo-5-fluorobenzenethiol (2.4 g).
  • Step 5 A solution of 3-[(2-bromo-5-fluorophenyl) sulfanyl] propanoic acid (2.0 g) obtained in Step 4 in concentrated sulfuric acid (20 mL) was stirred at room temperature for 30 minutes.
  • Step 6 m-Chloroperbenzoic acid was added to a solution of 8-bromo-5-fluoro-2,3-dihydro-4H-thiochromen-4-one (0.62 g) obtained in Step 5 in ethyl acetate (20 mL). (1.17 g) was added at room temperature. After stirring at the same temperature for 2 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 7 8-bromo-5-fluoro-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide (0.10 g) and 10% palladium carbon (0.085 g) obtained in Step 6
  • Step 9 The title compound was obtained in the same manner as in Reference Example 13 using 5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Step 8.
  • Step 2 Similar to Step 4 of Reference Example 29 using (4E) -7-fluoro-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (1.06 g) obtained in Step 1.
  • Step 3 The same procedure as in Step 5 of Reference Example 29 using tert-butyl (7-fluoro-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) obtained in Step 2 Gave 7-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (820 mg).
  • Step 4 Similar to Step 6 of Reference Example 29 using 7-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (820 mg) obtained in Step 3.
  • the title compound (1.19 g) was obtained by the procedure.
  • Step 2 The title compound (362 mg) was obtained in the same manner as in Step 3 of Reference Example 22 using 4-chloro-3-hydroxybenzonitrile (154 mg) obtained in Step 1.
  • Step 2 (4E) -3 in the same manner as in Step 3 of Reference Example 29 using 3-methyl-2,3-dihydro-4H-thiochromen-4-one (3.21 g) obtained in Step 1 -Methyl-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.63 g) was obtained.
  • Step 3 Similar to Step 4 of Reference Example 29 using (4E) -3-methyl-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.63 g) obtained in Step 2
  • tert-butyl (3-methyl-3,4-dihydro-2H-thiochromen-4-yl) carbamate was obtained.
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ ppm 1.02-1.16 (3H, m), 1.46 (9H, s), 2.17-2.51 (1H, m), 2.68-3.31 (2H, m), 4.43-4.89 ( 2H, m), 6.99-7.18 (3H, m), 7.23-7.31 (1H, m).
  • Step 4 Using the tert-butyl (3-methyl-3,4-dihydro-2H-thiochromen-4-yl) carbamate obtained in Step 3, according to the same procedure as in Step 5 of Reference Example 29, 3-methyl -3,4-Dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.18 g) was obtained.
  • 1 H-NMR 300 MHz, DMSO-d 6 ) ⁇ ppm 1.22-1.37 (3H, m), 2.77-3.06 (1H, m), 3.58-3.96 (2H, m), 4.47-4.79 (1H, m), 7.63-8.01 (4H, m), 8.96 (3H, br).
  • Step 5 Similar to Step 6 of Reference Example 29 using 3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.18 g) obtained in Step 4
  • the title compound (2.71 g) was obtained by the procedure.
  • Step 2 A solution of 4-[(4-bromophenyl) sulfanyl] butanoic acid (5.27 g) obtained in Step 1 in polyphosphoric acid (40 g) was stirred at 100 ° C. for 3 hours. The reaction mixture was poured into ice and extracted with ethyl acetate.
  • Step 3 7-Bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one (4.06 g) obtained in Step 2 was used in the same manner as in Step 3 of Reference Example 29 (5E ) -7-Bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one O-methyloxime (3.44 g) was obtained.
  • Step 4 Step of Reference Example 29 using (5E) -7-bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one O-methyloxime (3.44 g) obtained in Step 3 4 was used to obtain tert-butyl (7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) carbamate (3.23 g).
  • Step 5 Step 5 of Reference Example 29 using tert-butyl (7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) carbamate (3.23 g) obtained in Step 4
  • 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide hydrochloride (2.31 g) was obtained.
  • 1 H-NMR 300 MHz, DMSO-d 6 ) ⁇ ppm 1.67-1.88 (1H, m), 2.01-2.32 (3H, m), 3.31-3.52 (2H, m), 4.98 (1H, br), 7.81- 7.94 (3H, m), 9.07 (3H, br).
  • Step 6 Step of Reference Example 29 using 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide hydrochloride (2.31 g) obtained in Step 5
  • the title compound (2.56 g) was obtained by the same method as 6.
  • Step 1 (2,5-Difluorophenoxy) -N- (5-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide
  • Step 8 of Reference Example 41 Sodium metal (0.53 g) was added at room temperature to a solution of the obtained 5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (0.50 g) in methanol (15 mL) at 95 ° C. For 14 hours. The reaction solution was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate.
  • Step 2 The title compound was obtained in the same manner as in Reference Example 13 using 5-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Step 1.
  • reaction mixture was stirred with heating under reflux for 30 minutes, and sodium sulfate decahydrate was added at room temperature.
  • the reaction solution was stirred at the same temperature for 3 hours and filtered, and then the solvent was distilled off under reduced pressure.
  • Step 2 A solution of 3-[(4-bromo-2-fluorophenyl) sulfanyl] propanoic acid (15.5 g) obtained in Step 1 in sulfuric acid (25 mL) was stirred at room temperature for 44 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 3 6-Bromo-8-fluoro-2,3-dihydro-4H-thiochromen-4-one (10.3 g) obtained in Step 2 was prepared in the same manner as in Step 3 of Reference Example 29. -Bromo-8-fluoro-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (9.29 g) was obtained.
  • Step 4 Step 5 of Reference Example 29 using tert-butyl (6-bromo-8-fluoro-3,4-dihydro-2H-thiochromen-4-yl) carbamate (7.85 g) obtained in Step 3 6-Bromo-8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (6.03 g) was obtained in the same manner as above.
  • Step 2 Using 3- ⁇ [4- (trifluoromethoxy) phenyl] sulfanyl ⁇ propanoic acid (3.80 g) obtained in Step 1, in the same manner as in Step 2 of Reference Example 49, 6- (trifluoro Methoxy) -2,3-dihydro-4H-thiochromen-4-one (3.39 g) was obtained.
  • Step 3 Using 6- (trifluoromethoxy) -2,3-dihydro-4H-thiochromen-4-one (3.39 g) obtained in Step 2, according to the same procedure as in Step 3 of Reference Example 29 ( 4E) -6- (Trifluoromethoxy) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.58 g) was obtained.
  • Step 4 Using (4E) -6- (trifluoromethoxy) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.58 g) obtained in Step 3, In the same manner as in Step 4, tert-butyl [6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (2.61 g) was obtained.
  • Step 5 Step 5 of Reference Example 29 using tert-butyl [6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (2.61 g) obtained in Step 4
  • 6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.55 g) was obtained.
  • Step 2 (2E) -3- (4- ⁇ (tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3 obtained in Step 1
  • a solution of 4-dihydro-2H-thiochromen-6-yl) prop-2-enoate (3 g) and 10% palladium on carbon (0.4 g) in methanol (10 mL) was stirred at 50 ° C. for 16 hours in a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off under reduced pressure.
  • Step 3 Methyl 3- (4- ⁇ (tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro obtained in Step 2
  • a solution of -2H-thiochromen-6-yl) propanoate (440 mg) and 1N aqueous sodium hydroxide solution (2 mL) in THF (3 mL) was stirred at 60 ° C. for 3 hours.
  • the reaction solution was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (387 mg).
  • Example 1 2- (2-Chloro-5-fluorophenoxy) -N- [5-chloro-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [5-chloro-2- (methylsulfonyl) obtained in Reference Example 1 ) Phenyl] methanamine hydrochloride (500 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (540 mg) and potassium carbonate (670 mg) in ethanol (20 mL) solution at 90 ° C. Stir for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 2 (2-Chloro-5-fluorophenoxy) -N- ⁇ 5-chloro-2-[(1-methylethyl) sulfonyl] benzyl ⁇ ethanamine hydrochloride 1- ⁇ 5-Chloro-- obtained in Reference Example 2 2-[(1-methylethyl) sulfonyl] phenyl ⁇ methanamine hydrochloride (600 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (700 mg) and potassium carbonate (730 mg) The mixture was stirred at 90 ° C. for 16 hours in an ethanol (20 mL) solution. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 3 N- [5-Chloro-2- (ethylsulfonyl) benzyl] -2- (2-chloro-5-fluorophenoxy) ethanamine hydrochloride 1- [5-chloro-2- (ethylsulfonyl) obtained in Reference Example 3 ) Phenyl] methanamine hydrochloride (690 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (840 mg) and potassium carbonate (880 mg) in ethanol (20 mL) solution at 90 ° C. Stir for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 4 2- (2-Chloro-5-fluorophenoxy) -N- [2- (methylsulfonyl) benzyl] ethanamine 1- [2- (methylsulfonyl) phenyl] methanamine hydrochloride (450 mg), 2- (2-bromo Ethoxy) -1-chloro-4-fluorobenzene (670 mg) and potassium carbonate (700 mg) were stirred in an ethanol (15 mL) solution at 90 ° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Example 5 2- (2-Chloro-5-fluorophenoxy) -N- [5-methoxy-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [5-methoxy-2- (methylsulfonyl) obtained in Reference Example 4 ) Phenyl] methanamine hydrochloride (500 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (650 mg) and potassium carbonate (690 mg) in ethanol (15 mL) solution at 90 ° C. Stir for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 6 2- (2-Chloro-5-fluorophenoxy) -N- [4-fluoro-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [4-fluoro-2- (methylsulfonyl) phenyl] methanamine hydrochloride ( 500 mg) (Synthetic Communications, 2007, 37, 1887-1897), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (690 mg) and potassium carbonate (720 mg) in ethanol (15 mL) The solution was stirred at 90 ° C. for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 7 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -4-fluoro-N, N-dimethylbenzenesulfonamide hydrochloride 2- (aminomethyl) -4-fluoro-N , N-dimethylbenzenesulfonamide hydrochloride (300 mg) (Synthetic Communications, 2007, 37, 1887-1897), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (312 mg) and potassium carbonate (300 mg) was stirred in an ethanol (10 mL) solution at 90 ° C. overnight. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure.
  • Example 8 2- (2-Chloro-5-fluorophenoxy) -N- [5-fluoro-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [5-fluoro-2- (methylsulfonyl) obtained in Reference Example 5 ) Phenyl] methanamine hydrochloride (500 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (690 mg) and potassium carbonate (720 mg) in ethanol (15 mL) solution at 90 ° C. Stir for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 9 6-chloro-N- [2- (2-chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 6-chloro-3,4- Dihydro-2H-thiochromen-4-amine-1,1-dioxide hydrochloride (0.34 g) (published patent document US2006025400), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.39 g) and A solution of potassium carbonate (0.53 g) in ethanol (5 mL) was stirred at 70 ° C. overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure.
  • Example 10 4-chloro-2-( ⁇ [2- (2-chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethylbenzenesulfonamide hydrochloride 2- (aminomethyl obtained in Reference Example 6 ) -4-Chloro-N, N-dimethylbenzenesulfonamide hydrochloride (0.47 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.55 g) and potassium carbonate (0.60 g) The mixture was stirred overnight at 90 ° C. in an ethanol (10 mL) solution. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure.
  • Example 11 2- (2-Chloro-5-fluorophenoxy) -N- [2- (phenylsulfonyl) benzyl] ethanamine hydrochloride 1- [2- (phenylsulfonyl) phenyl] methanamine hydrochloride (500 mg) (Journal of Medicinal Chemistry, 1975, 18 (2), 142-146), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (520 mg) and potassium carbonate (610 mg) in ethanol (15 mL) solution at 90 ° C For 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Example 12 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2- Chloro-5-fluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (800 mg) in THF (30 mL) solution in THF-borane complex (10 mL, 1M THF solution) was added at 0 ° C. After stirring at 80 ° C. for 6 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (30 mL) was added. After stirring at 80 ° C.
  • Example 13 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethylbenzenesulfonamide hydrochloride 2- (aminomethyl) -N, obtained in Reference Example 8, N-dimethylbenzenesulfonamide hydrochloride (1.00 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (1.31 g) and potassium carbonate (1.43 g) in ethanol (10 mL) solution in 90 Stir overnight at ° C. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure.
  • Example 14 2- (2-Chloro-5-fluorophenoxy) -N- [2- (morpholin-4-ylsulfonyl) benzyl] ethanamine hydrochloride (Step 1)
  • Step 1 Reference using 2-cyanobenzene-1-sulfonyl chloride and morpholine 1- [2- (morpholin-4-ylsulfonyl) phenyl] methanamine was obtained in the same manner as in Steps 1 and 2 of Example 8 (except for the treatment with a hydrogen chloride / ethyl acetate solution).
  • Step 2 1- [2- (morpholin-4-ylsulfonyl) phenyl] methanamine obtained in Step 1 (1.00 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (1.13 g) and potassium carbonate (1.23 g) were stirred in an ethanol (10 mL) solution at 90 ° C.
  • Example 15 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -1- [5-chloro-2- (methylsulfonyl) phenyl] ethanamine hydrochloride 1- [5-Chloro-] obtained in Reference Example 9 2- (Methylsulfonyl) phenyl] ethanamine hydrochloride (0.23 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.32 g) and potassium carbonate (0.35 g) in ethanol (5 mL) The solution was stirred at 90 ° C. overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure.
  • Example 16 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -N-methylbenzenesulfonamide 2- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (0.30 g) ( Journal of the American Chemical Society, 1960, 82 (7), 1594-1596), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.42 g) and potassium carbonate (0.46 g) with ethanol ( 10 mL) in solution at 90 ° C. overnight. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure.
  • Example 17 (2-Chloro-5-fluorophenoxy) -N- ⁇ [2- (methylsulfonyl) pyridin-3-yl] methyl ⁇ ethanamine hydrochloride 2- (2-chloro-5- To a solution of fluorophenoxy) -N- ⁇ [2- (methylsulfanyl) pyridin-3-yl] methyl ⁇ ethanamine (0.55 g) in THF (30 mL) was added di-t-butyl dicarbonate (0.48 g) at 0 ° C. Added in. After stirring at room temperature for 2 days, the reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate.
  • Example 18 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide hydrochloride 2,3-dihydro-1-benzothiophene- 3-Amine-1,1-dioxide hydrochloride (0.30 g) (published patent document US2666662), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.46 g) and potassium carbonate (0.35 g) Of ethanol (5 mL) was stirred at 80 ° C. overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure.
  • Example 19 2- (2-Chloro-5-fluorophenoxy) -N- ⁇ 2- [2- (methylsulfonyl) phenyl] ethyl ⁇ ethanamine N- [2- (2-chloro-5-fluoro obtained in Reference Example 11]
  • THF-borane complex 9 mL, 1M THF solution
  • Example 20 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3- [2- (methylsulfonyl) phenyl] propan-1-amine N- [2- (2-chloro] obtained in Reference Example 12 -5-Fluorophenoxy) ethyl] -3- [2- (methylsulfonyl) phenyl] propanamide (1.0 g) in THF (30 mL) was added THF-borane complex (10 mL, 1M THF solution) at 0 ° C. added. After stirring at 70 ° C. for 5 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (20 mL) was added. After stirring at 80 ° C.
  • Example 21 N- [2- (2,5-difluorophenoxy) ethyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide hydrochloride 2- (2,5 obtained in Reference Example 13 -Difluorophenoxy) -N- (1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) acetamide (0.19 g) in THF (3 mL) in THF-borane complex (1.6 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added.
  • Example 22 N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2,5- To a solution of difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (0.48 g) in THF (5 mL) was added THF-borane complex (3.9 mL, 1M THF). Solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added.
  • Example 23 6-chloro-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride N- (obtained in Reference Example 15 6-Chloro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (0.51 g) in THF (5 mL) was added THF- Borane complex (3.8 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C.
  • Example 24 N- [2- (2-Fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride N- (1,1-dioxide- obtained in Reference Example 16 Add THF-borane complex (6.1 mL, 1M THF solution) to a solution of 3,4-dihydro-2H-thiochromen-4-yl) -2- (2-fluorophenoxy) acetamide (0.71 g) in THF (5 mL). Added at ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added.
  • Example 25 6-Chloro-N- [2- (2-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride N- (6- Chloro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2-fluorophenoxy) acetamide (0.56 g) in THF (5 mL) solution in THF-borane complex (4.4 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added.
  • Example 26 N- [2- (2-Fluorophenoxy) ethyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide hydrochloride N- (1,1-dioxide obtained in Reference Example 18 -2,3-dihydro-1-benzothiophen-3-yl) -2- (2-fluorophenoxy) acetamide (0.60 g) in THF (5 mL) and THF-borane complex (5.4 mL, 1M in THF) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C.
  • Example 28 N- [2- (2-fluorophenoxy) ethyl] -1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride 2- (2-fluorophenoxy) -N- ⁇ 1- [ To a solution of 2- (methylsulfonyl) phenyl] ethyl ⁇ acetamide (0.35 g) in THF (5 mL) was added THF-borane complex (3 mL, 1M THF solution) at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C.
  • Example 29 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride 2- (2-chloro-5-fluorophenoxy obtained in Reference Example 21 ) -N- ⁇ 1- [2- (methylsulfonyl) phenyl] ethyl ⁇ acetamide (0.44 g) in THF (5 mL) was added THF-borane complex (3.4 mL, 1M THF solution) at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added.
  • Example 30 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) benzenesulfonamide 2- (aminomethyl) benzenesulfonamide (0.30 g), 2- (2-bromoethoxy) -1
  • a solution of -chloro-4-fluorobenzene (0.43 g) in ethanol (5 mL) was stirred at 90 ° C. overnight. The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and partitioned between ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure.
  • Example 31 (Method 1) (4R) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride
  • Compound obtained in Example 12 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (0.45 g) with ethyl acetate and saturated sodium bicarbonate Extract with aqueous solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Example 31 (4R) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1)
  • THF (5 mL ) 2,3-dihydro-4H-thiochromen-4-one (0.82 g)
  • titanium (IV) ethoxide 2.1 mL
  • (R)-(+)-2-methyl-2-propanesulfinamide 0.61 g was stirred at 60 ° C. for 14 hours.
  • reaction solution was cooled to ⁇ 78 ° C.
  • a mixture of sodium hydride (0.38 g) in THF (10 mL) was added.
  • the reaction solution was poured into water.
  • the reaction solution was made alkaline with an aqueous sodium hydroxide solution and then extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 2 N-[(4R) -3,4-dihydro-2H-thiochromen-4-yl] -2-methylpropane-2-sulfinamide (0.34 g) obtained in Step 1 in methanol (5 mL ) 2N hydrogen chloride / 2-propanol solution (10 mL) was added to the solution and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain (4R) -3,4-dihydro-2H-thiochromen-4-amine hydrochloride (0.25 g).
  • Step 3 A solution of (4R) -3,4-dihydro-2H-thiochromen-4-amine hydrochloride (0.20 g) obtained in Step 2 and Et 3 N (0.28 mL) in acetonitrile (10 mL) Di-t-butyl carbonate (0.33 g) was added at room temperature. After stirring for 14 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 4 tert-Butyl (4R) -3,4-dihydro-2H-thiochromen-4-ylcarbamate (2.96 g) obtained in Step 3 was dissolved in ethyl acetate (30 mL), and m-chloro Perbenzoic acid (5.52 g) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was washed with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Step 5 [(4R) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate tert-butyl (2.85 g) obtained in Step 4 was added with 4N hydrogen chloride / acetic acid Ethyl solution (20 mL) was added and stirred at room temperature for 8 hours. The solvent was distilled off under reduced pressure to obtain (4R) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.03 g). [ ⁇ ] D 25 -5.3 ° (c 0.25, MeOH).
  • Step 6 (4R) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (0.60 g), (2-chloro-5-fluorophenoxy) acetic acid obtained in Step 5 (0.63 g), WSC (0.99 g), HOBt (0.59 g), and Et 3 N (0.36 mL) in acetonitrile (15 mL) -N, N′-dimethylacetamide (5 mL) mixed at room temperature for 14 hours. did. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Step 7 2- (2-Chloro-5-fluorophenoxy) -N-[(4R) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] obtained in Step 6
  • a THF-borane complex (4.2 mL, 1M THF solution) was added to a solution of acetamide (0.53 g) in THF (12 mL) at 5 ° C. After stirring at 80 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (8.4 mL) was added. After stirring at 80 ° C. for 2 hours, ethyl acetate was added to the reaction solution.
  • Example 32 (4S) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Optically by Method 1 of Example 31 The fraction having a long retention time was concentrated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the resulting residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.17 g).
  • Example 33 N- [2- (2-methoxyphenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl (1,1) obtained in Step 3 of Reference Example 22
  • 1-dioxide-3,4-dihydro-2H-thiochromen-4-yl [2- (2-methoxyphenoxy) ethyl] carbamate (385 mg) was added 4N hydrogen chloride / ethyl acetate solution (2 mL). The solvent was evaporated under reduced pressure, neutralized with sodium hydrogen carbonate solution, and extracted with ethyl acetate.
  • Example 34 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-1,2-benzothiazin-4-amine 1,1-dioxide 2- (2) obtained in Reference Example 23 2-Chloro-5-fluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-1,2-benzothiazin-4-yl) acetamide (0.80 g) in THF (20 mL) THF-borane complex (6.2 mL, 1M THF solution) was added. After stirring at 90 ° C. for 1.5 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (20 mL) was added. Stir at 90 ° C.
  • Example 35 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethyl-4-morpholin-4-ylbenzenesulfonamide dihydrobromide (Step 1) Tert-Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (150 mg) obtained in Reference Example 24, dicyclohexyl [2 ′ , 4 ', 6'-Tris (1-methylethyl) biphenyl-2-yl] phosphane (12.6 mg), sodium t-butoxide (28.0 mg), morpholine (0.025 mL), Pd 2 (dba) 3 (12.1 mg ) In toluene (3 mL) was stirred at 100 ° C.
  • Step 2 tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-morpholin-4-ylbenzyl] carbamate (110 mg) obtained in Step 1 ) was added 4N hydrogen chloride / ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Example 36 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -4-cyano-N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) tert obtained in Reference Example 24 -Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (150 mg), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 4 ) (30.6 mg) and a solution of zinc cyanide (34.2 mg) in DMF (3 mL) were stirred at 100 ° C.
  • Step 2 To the tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [5-cyano-2- (dimethylsulfamoyl) benzyl] carbamate (120 mg) obtained in Step 1, 4N A hydrogen chloride / ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from methanol and ethyl acetate to obtain the title compound (81.0 mg).
  • Example 37 2-( ⁇ [2- (2-Chloro-5-fluorophenoxy) ethyl] amino ⁇ methyl) -4-methoxy-N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) tert obtained in Reference Example 24 -Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (150 mg), Pd 2 (dba) 3 (4.85 mg), 2 , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (6.60 mg) and sodium methoxide (15.8 mg) in toluene (3 mL) were stirred at 100 ° C.
  • Step 2 To the tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-methoxybenzyl] carbamate (50 mg) obtained in Step 1, 4N A hydrogen chloride / ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the solid was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from methanol and ethyl acetate to give the title compound (45 mg).
  • Example 38 N- ⁇ 2- [2- (methylsulfanyl) phenoxy] ethyl ⁇ -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl (1,1) obtained in Reference Example 25 1-Dioxide-3,4-dihydro-2H-thiochromen-4-yl) ⁇ 2- [2- (methylsulfanyl) phenoxy] ethyl ⁇ carbamate was added with 4N hydrogen chloride / ethyl acetate solution (2 mL). Crystallized with methanol and diethyl ether. The obtained crystals were recrystallized from methanol and diethyl ether to give the title compound (87 mg).
  • Example 39 N- [2- (2-Chlorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl (1,1-dioxide obtained in Reference Example 26 The title compound was obtained in the same manner as in Example 38 using -3,4-dihydro-2H-thiochromen-4-yl) ⁇ 2- [2-chlorophenoxy] ethyl ⁇ carbamate.
  • Example 40 N- [2- (3-Fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert-butyl (2) obtained in Step 2 of Reference Example 22 1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 mL), 0.32 M in triphenylphosphine Toluene-THF (1: 1) (500 ⁇ L) and 3-fluorophenol in 0.2 M toluene-THF (1: 1) (500 ⁇ L) are mixed, and diisopropyl azodicarboxylate (30 ⁇ L) is added at room temperature After that, the mixture was stirred for 16 hours.
  • Example 41 2- ⁇ 2-[(1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) amino] ethoxy ⁇ benzonitrile trifluoroacetate tert-butyl obtained in Step 2 of Reference Example 22
  • the title compound (12.5 mg) was obtained in the same manner as in Example 40 using 0.2 M toluene-THF (1: 1) (500 ⁇ L) solution.
  • Example 42 N- ⁇ 2- [2- (trifluoromethyl) phenoxy] ethyl ⁇ -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate obtained in Step 2 of Reference Example 22
  • the title compound (19.7 mg) was obtained in the same manner as in Example 40 using 0.2 M toluene-THF (1: 1) (500 ⁇ L) solution of trifluoromethylphenol.
  • Example 43 N- [2- (2-methylphenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert-butyl (2) obtained in Step 2 of Reference Example 22 1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 ⁇ L) and 0.2 of o-cresol The title compound (7.3 mg) was obtained in the same manner as in Example 40 using M toluene-THF (1: 1) (500 ⁇ L) solution. MS (ESI +): 332 ( M + H-CF 3 CO 2 H)
  • Example 44 N- ⁇ 2- [2- (benzyloxy) phenoxy] ethyl ⁇ -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert obtained in Step 2 of Reference Example 22 -Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 ⁇ L) and 2- ( The title compound (14.6 mg) was obtained in the same manner as in Example 40 using 0.2 M toluene-THF (1: 1) (500 ⁇ L) solution of (benzyloxy) phenol. MS (ESI +): 424 ( M + H-CF 3 CO 2 H)
  • Example 45 N- [2- (1H-Indol-4-yloxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert obtained in Step 2 of Reference Example 22 -Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 ⁇ L) and 1H-indole The title compound (11 mg) was obtained in the same manner as in Example 40 using 4-ol 4-M toluene-THF (1: 1) solution (500 ⁇ L). MS (ESI +): 357 ( M + H-CF 3 CO 2 H)
  • Example 46 N- [2- (2,4,5-trifluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate salt obtained in Step 2 of Reference Example 22.
  • Tert-butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 ⁇ L) and 2 , 4,5-trifluorophenol in 0.2 M toluene-THF (1: 1) (500 ⁇ L) was used to give the title compound (19.8 mg) in the same manner as in Example 40.
  • Example 47 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2 obtained in Reference Example 27 -(2-Chloro-5-fluorophenoxy) -N- (6-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (0.45 g) in THF (5 mL) To the solution was added THF-borane complex (2.8 mL, 1M THF solution) at 0 ° C. After stirring at 70 ° C.
  • Example 48 2-( ⁇ [2- (2,5-Difluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethylbenzenesulfonamide (Step 1) N- [5-Bromo-2-] obtained in Reference Example 28 To a solution of (dimethylsulfamoyl) benzyl] -2- (2,5-difluorophenoxy) acetamide (2.00 g) in THF (20 mL) was added THF-borane complex (12.9 mL, 1M THF solution) at 80 ° C. After stirring for 3 hours, ice was added to the reaction solution, and 1N hydrochloric acid (20 mL) was added. Stir at 80 ° C. for 1 hour.
  • Step 2 4-Bromo-2-( ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethylbenzenesulfonamide (150 mg) obtained in Step 1 and palladium A suspension of carbon (35.5 mg) in ethanol (10 mL) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain the title compound (22 mg).
  • Example 49 N- [2- (2,5-Difluorophenoxy) ethyl] -6-morpholin-4-yl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1)
  • 6-Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide 300 mg
  • sodium tert -Butoxide 179 mg
  • morpholine 68.7 mg
  • Pd 2 (dba) 3 (10.3 mg)
  • the solution was stirred at 100 ° C.
  • Step 2 N- [2- (2,5-difluorophenoxy) ethyl] -6-morpholin-4-yl-3,4-dihydro-2H-thiochromen-4-amine 1,1 obtained in Step 1 -Dioxide (166 mg) was added 4N hydrogen chloride / ethyl acetate solution (2 mL). Crystallized with ethanol and diethyl ether. The obtained crystals were recrystallized from ethanol and diethyl ether to give the title compound (116 mg).
  • Example 50 Implementation of N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethenyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 108 (178 mg) and 10% palladium carbon (0.05 g) in ethanol (1.5 mL) were stirred at 50 ° C. for 2 hours under a hydrogen atmosphere of 1 atm.
  • Step 2 N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethyl) -3,4-dihydro-2H-thiochromen-4-amine 1, obtained in Step 1
  • the title compound was obtained in the same manner as in Step 2 of Example 49 using 1-dioxide (133 mg).
  • Example 51 4- ⁇ [2- (2,5-Difluorophenoxy) ethyl] amino ⁇ -3,4-dihydro-2H-thiochromene-6-carbonitrile 1,1-dioxide hydrochloride (Step 1) obtained in Example 109 6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (300 mg), zinc cyanide (72.7 mg ) And Pd (PPh 3 ) 4 (32.6 mg) in DMF (3 mL) were stirred at 100 ° C.
  • Step 2 4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -3,4-dihydro-2H-thiochromene-6-carbonitrile 1,1-dioxide (201 mg) was used to obtain the title compound in the same manner as in Step 2 of Example 49.
  • Example 52 N- [2- (2,5-Difluorophenoxy) ethyl] -6- (methylsulfanyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1)
  • Step 109 Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (532 mg), sodium thiomethoxy obtained in Solution (105 mg), Pd 2 (dba) 3 (91.6 mg) and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (63.6 mg) in xylene (5 mL) at 140 ° C.
  • Step 2 N- [2- (2,5-difluorophenoxy) ethyl] -6- (methylsulfanyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1- obtained in Step 1
  • the title compound was obtained in the same manner as in Step 2 of Example 49 using dioxide (120 mg).
  • Example 53 N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) 2 Sodium hydride (45 mg) was added to a toluene (2 mL) solution of -propanol (37.2 mg) at 0 ° C. After stirring at 50 ° C. for 1.5 hours, the reaction mixture was mixed with 6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromene-4-4 obtained in Example 109.
  • Step 2 N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1, obtained in Step 1
  • the title compound (19.1 mg) was obtained in the same manner as in Step 2 of Example 49 using 1-dioxide (36.5 mg).
  • Example 54 N 4 - [2- (2,5- difluorophenoxy) ethyl] -3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride tert- butyl obtained in Reference Example 31 ( Similar to Step 2 of Example 49 using 6-amino-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate The title compound (49.8 mg) was obtained by the procedure.
  • Example 56 N- (4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) acetamide hydrochloride obtained in Reference Example 33 Tert-butyl [6- (acetylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5-difluorophenoxy) ethyl] carbamate (243 mg ) To give the title compound (22.0 mg) in the same manner as in Step 2 of Example 49.
  • the solvent of the reaction solution was distilled off, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained oil was dissolved in ethyl acetate (5 mL), and 2N hydrogen bromide / methanol solution (1 mL) was added.
  • the obtained solid was collected by filtration and recrystallized from methanol and ethyl acetate to give the title compound (41 mg).
  • Example 58 4-cyano-2-( ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ methyl) -N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) obtained in Step 1 of Reference Example 34 tert-Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate (500 mg) and Pd (PPh 3 ) 4 (105 mg), cyanide A solution of zinc halide (118 mg) in DMF (3 mL) was stirred at 100 ° C. for 3 hours.
  • Step 2 tert-Butyl [5-cyano-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate (100 mg) obtained in Step 1 in ethyl acetate ( 5 mL) solution was added 4N hydrogen chloride / ethyl acetate solution (1 mL) and stirred at room temperature overnight. The obtained solid was collected by filtration and recrystallized from methanol and ethyl acetate to give the title compound (85.0 mg).
  • Example 59 N- (4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methanesulfonamide hydrochloride
  • Reference Example 35 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] ⁇ 6-[(methylsulfonyl) amino] -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in ⁇
  • the title compound (116 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate (260 mg).
  • Example 60 4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -3,4-dihydro-2H-thiochromene-6-carboxamide 1,1-dioxide hydrochloride tert-butyl obtained in Reference Example 36 ( The process of example 49 using 6-carbamoyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (200 mg). The title compound (147 mg) was obtained by a method similar to 2.
  • Example 61 N- [2- (2,5-Difluorophenoxy) ethyl] -6-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromene-4-] obtained in Reference Example 37 Yl) carbamate (546 mg), methyl iodide (106 mg), and potassium carbonate (104 mg) in DMF (2 mL) were stirred at room temperature for 3 hours.
  • Step 2 tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 )
  • the title compound (152 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate (253 mg).
  • Example 62 N- [2- (2,5-difluorophenoxy) ethyl] -7-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl obtained in Reference Example 38 Using [2- (2,5-difluorophenoxy) ethyl] (7-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (235 mg) In the same manner as in Step 1, tert-butyl [2- (2,5-difluorophenoxy) ethyl] (7-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate ( 235 mg).
  • Step 2 tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (dimethylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromene-obtained in Step 1
  • the title compound (92.3 mg) was obtained in the same manner as in Step 2 of Example 49 using 4-yl] carbamate (151 mg).
  • Example 64 N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride (Step 1)
  • Reference Example 31 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in step 1 of 31 (300 mg) and 40% methylamine / methanol solution (1.04 mL) in the same manner as in Step 49 of Example 49, tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- ( Methylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (114 mg) was
  • Step 2 tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromene-obtained in Step 1
  • the title compound (80.8 mg) was obtained in the same manner as in Step 2 of Example 49 using 4-yl] carbamate (151 mg).
  • Example 65 N- [2- (2,5-difluorophenoxy) ethyl] -8-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) obtained in Reference Example 39 With tert-butyl [2- (2,5-difluorophenoxy) ethyl] (8-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (235 mg) Tert-butyl [2- (2,5-difluorophenoxy) ethyl] (8-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromene-4- Yl) carbamate (234 mg) was obtained.
  • Step 2 tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (8-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 )
  • the title compound (171 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate (235 mg).
  • Example 66 N- [2- (2,5-Difluorophenoxy) propyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (mixture of four stereoisomers) Tert-Butyl [2- (2,5-difluorophenoxy) propyl] (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (four stereoisomers) obtained in Reference Example 40 Body mixture) (300 mg) was used to give the title compound (185 mg) in the same manner as in Step 2 of Example 49.
  • Example 67 4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -3,4-dihydro-2H-thiochromen-8-ol 1,1-dioxide hydrochloride tert-butyl obtained in Reference Example 39 [ Step of Example 49 using 2- (2,5-difluorophenoxy) ethyl] (8-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (100 mg) The title compound (48.4 mg) was obtained by the same method as 2.
  • Example 68 8-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 7 of Reference Example 39 Performed with tert-butyl (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg) The title compound (47.7 mg) was obtained in the same manner as in Step 2 of Example 49.
  • Example 69 7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 7 of Reference Example 38 Performed with tert-butyl (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg) The title compound (102 mg) was obtained in the same manner as in Step 2 of Example 49.
  • Example 70 6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 1 of Reference Example 31 Performed with tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg) The title compound (78.3 mg) was obtained in the same manner as in Step 2 of Example 49.
  • Example 71 N- [2- (2,5-difluorophenoxy) ethyl] -6-phenyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) Step 1 of Reference Example 31 -Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (300 mg) obtained in And phenylboronic acid (103 mg) in the same manner as in Example 108, tert-butyl [2- (2,5-difluorophenoxy) ethyl] (1,1-dioxide-6-phenyl-3,4- Dihydro-2H-thiochromen-4-yl) carbamate was obtained.
  • Step 2 tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (1,1-dioxide-6-phenyl-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 )
  • the title compound (171 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate.
  • Example 72 N- [2- (2,5-difluorophenoxy) ethyl] -5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2) obtained in Reference Example 41 2,5-Difluorophenoxy) -N- (5-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide was prepared by the same procedure as in Example 12 to give the title compound. Obtained.
  • Example 74 4-chloro-3- ⁇ 2-[(1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) amino] ethoxy ⁇ benzonitrile hydrochloride tert-butyl obtained in Reference Example 43 2- (2-Chloro-5-cyanophenoxy) ethyl] (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (362 mg) and The title compound (221 mg) was obtained by a similar method.
  • Example 75 N- [2- (2,5-Difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (mixture of four stereoisomers) Performed using 2- (2,5-difluorophenoxy) -N- (3-methyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide obtained in Reference Example 44 The title compound (1.82 g) was obtained by a method similar to that in Example 109.
  • Example 77 N- [2- (2,5-difluorophenoxy) ethyl] -5-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2) obtained in Reference Example 46 2,5-Difluorophenoxy) -N- (5-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide was prepared by the same procedure as in Example 12 to give the title compound. Obtained.
  • Example 78 7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide N obtained in Reference Example 45 Performed with-(7-bromo-1,1-dioxide-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) -2- (2,5-difluorophenoxy) acetamide (2.28 g) In a manner similar to Example 109, 7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide ( 1.37 g) was obtained.
  • Step 2 tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (6-formyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 )
  • a mixture of carbamate (262 mg), pyrrolidine (46.5 mg), Et 3 N (66.1 mg) and acetic acid (71.3 mg) in THF (2 mL) was added sodium triacetoxyborohydride (337 mg) at 0 ° C. The mixture was stirred at room temperature for 3 days, and the reaction solution was poured onto ice. The reaction was basified with sodium bicarbonate solution and extracted with ethyl acetate.
  • Example 80 In [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide
  • Example 31 step 1 N 6 - cyclopropyl -N 4
  • the resulting tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (300 mg), Cyclopropylamine (119 mg), sodium tert-butoxide (179 mg), Pd 2 (dba) 3 (10.3 mg) and 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (21.5 mg)
  • a toluene (2 mL) solution of was stirred at 100 ° C.
  • Example 81 N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - ethyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide dihydrochloride Reference Example 31 steps Tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (300 mg) ), Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (ethylamino) -1 , 1-Dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (98.6 mg) was obtained.
  • Example 82 N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - (1- methylethyl) -3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide dihydrochloride Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl obtained in Step 1 of Reference Example 31
  • the title compound (20.5 mg) was obtained in the same manner as in Step 1 and Step 2 of Example 49 using carbamate (300 mg) and isopropylamine (123 mg).
  • Example 83 (4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methanol hydrochloride obtained in Reference Example 48 tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (200 mg) was used to give the title compound (142 mg) in the same manner as in Step 2 of Example 49.
  • Example 84 N- [2- (2,5-Difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide 6-Bromo-N obtained in Example 110 -[2- (2,5-Difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (200 mg) and 10% palladium on carbon (0.05 g) Of methanol (1 mL) was stirred in a hydrogen atmosphere at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure.
  • Example 85 N 4 - [2- (2,5- difluorophenoxy) ethyl] -8-methoxy -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide dihydrochloride salt [ 6-Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 110 (225 mg) and a 40% methanol solution of methylamine (116 mg), and the title compound (76.5 mg) was obtained in the same manner as in Step 1 and Step 2 of Example 49.
  • Example 86 (-) - N 4 - [ 2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride
  • Example 86 (-) - N 4 - [ 2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride
  • Example 102 mg was obtained in the same manner as in Step 2 of Example 49 using the compound (192 mg) having a short retention time obtained in 50.
  • Example 87 (+) - N 4 - [ 2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride
  • the title compound (83.2 mg) was obtained in the same manner as in Step 2 of Example 49 using the compound having a long retention time (192 mg) obtained in 51.
  • Example 88 N- [2- (2,5-difluorophenoxy) ethyl] -6- (methoxymethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 48 tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (200 mg), A solution of potassium hydroxide (57.8 mg) and methyl iodide (118 mg) in DMSO (1.5 mL) was stirred at 80 ° C. for 19 hours.
  • Example 89 N- [2- (2,5-Difluorophenoxy) ethyl] -6- (1H-pyrazol-1-yl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Reference Example 31 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in step 1 of 31 (400 mg), 2-ditert-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl (31.9 mg), sodium tert-butoxide (108 mg), pyrazole (66.5 mg) and Pd 2 (dba ) 3 (17.2 mg) in toluene (2 mL) was stirred at 100 ° C.
  • Example 90 N- [2- (2,5-Difluorophenoxy) ethyl] -6- (1H-imidazol-1-yl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide dihydrochloride
  • Reference Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] obtained in Step 1 of Example 31 Carbamate (400 mg), 2-ditert-butylphosphino-3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropylbiphenyl (36.1 mg), potassium phosphate (239 mg) , A solution of imidazole (66.5 mg) and Pd 2 (dba) 3 (17.2 mg) in toluene (3 mL) was stirred at 100 ° C.
  • Example 91 N- [2- (2,5-difluorophenoxy) ethyl] -6-[(methylamino) methyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Reference Example 48 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (249 mg) , A solution of methanesulfonyl chloride (70.7 mg) and Et 3 N (104 mg) in THF (1.5 mL) was stirred at 0 ° C. for 1 hour.
  • reaction mixture was poured into water and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • a 2 M methylamine / THF (1.03 mL) solution was added to the resulting residue, and the mixture was stirred at 50 ° C. for 20 hours.
  • Example 92 N-[(4- ⁇ [2- (2,5-Difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methyl] acetamide hydrochloride
  • 6- (Aminomethyl) -N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in 111 (121 mg)
  • Acetyl chloride (24.8 mg) was added at 0 ° C. to a solution of Et 3 N (32.1 mg) in THF (1.5 mL).
  • Example 93 (4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methanol obtained in Reference Example 48 4N chloride in butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (160 mg) Hydrogen / isopropyl alcohol solution (1.5 mL) was added. The solvent was distilled off under reduced pressure, neutralized with an aqueous sodium hydroxide solution, and extracted with ethyl acetate.
  • Example 94 3- (4- ⁇ [2- (2,5-Difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) -N-methylpropanamide hydrochloride 3- (4- ⁇ (tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromene obtained in Reference Example 53 -6-yl) propanoic acid (182 mg), 2 M methylamine / THF solution (208 ⁇ L), HOBt (51.3 mg), WSC (72.9 mg) and diisopropylethylamine (98.4 mg) in DMF (1.5 mL) Stir at room temperature for 17 hours.
  • Example 96 2-[(4- ⁇ [2- (2,5-Difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) oxy] acetamide hydrochloride Reference Example Tert-butyl [6- (2-amino-2-oxoethoxy) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5- The title compound (160 mg) was obtained in the same manner as in Step 2 of Example 49 using [difluorophenoxy) ethyl] carbamate (228 mg).
  • Example 97 Methyl [(4- ⁇ [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) oxy] acetate hydrochloride
  • Reference Example 55 [(4- ⁇ (tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino ⁇ -1,1-dioxide-3,4-dihydro-2H-thiochromene-6-
  • the title compound (200 mg) was obtained in the same manner as in Step 2 of Example 49 using (yl) oxy] acetate (274 mg).
  • Example 98 N- [2- (2,5-Difluorophenoxy) ethyl] -6- (2-methoxyethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Obtained in Reference Example 56 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (2-methoxyethoxy) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate ( The title compound (118 mg) was obtained in the same manner as in Step 2 of Example 49 using 267 mg).
  • Example 99 N- [2- (2,5-Difluorophenoxy) ethyl] -6- (2,2,2-trifluoroethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [1,1-dioxide-6- (2,2,2-trifluoroethoxy) -3,4-dihydro- obtained in Reference Example 57
  • the title compound (143 mg) was obtained in the same manner as in Step 2 of Example 49 using [2H-thiochromen-4-yl] carbamate (267 mg).
  • Example 100 N- [2- (2,5-difluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2) obtained in Reference Example 58 2,5-Difluorophenoxy) -N- (6-Fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (741 mg) similar procedure as Example 109 Gave N- [2- (2,5-difluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (268 mg).
  • Example 101 N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 30 2- (2,5-difluorophenoxy) -N- [1,1-dioxide-6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] acetamide (1.28 g) In the same manner as in Example 109, N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1- Dioxide was obtained.
  • Example 102 N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 52 2- (2,5-difluorophenoxy) -N- [1,1-dioxide-6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] acetamide (1.28 g) In the same manner as in Example 109, N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1- Dioxide was obtained.
  • Example 103 N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active form, tR1 (IC))
  • IC optically active form
  • Example 104 N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (optically active form, tR2 (IC)) (Step 1) N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 75 The four isomer mixture (992 mg) was analyzed and optically resolved by chiral column chromatography.
  • Example 105 N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active form, tR3 (IC))
  • IC optically active form
  • Example 106 N- [2- (2,5-Difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active form, tR4 (IC))
  • IC optically active form
  • Example 107 N- [2- (2,5-difluorophenoxy) ethyl] -6-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 1 of Reference Example 31 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (532 mg), methylboronic acid ( 239 mg), potassium phosphate (849 mg) and Pd (PPh 3 ) 4 (116 mg) in 1,2-dimethoxyethane (2 mL) were stirred at 80 ° C for 18 hours under nitrogen atmosphere, Poured into water and extracted with ethyl acetate.
  • tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-methyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate was added with 4N hydrogen chloride / Ethyl acetate solution (2 mL) was added.
  • the solvent was evaporated under reduced pressure, neutralized with sodium hydrogen carbonate solution, and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Example 108 N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethenyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide 6 obtained in Example 109 -Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (300 mg), 4,4,5,5- Tetramethyl-2- (1-methylethenyl) -1,3,2-dioxaborolane (142 mg) and Pd (PPh 3 ) 4 (65.1 mg) in 2N aqueous sodium carbonate (0.84 mL) and 1,2-dimethoxyethane ( 2 mL) was stirred at 80 ° C.
  • Example 109 6-Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide N- (6- Bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (2.70 g) was dissolved in THF (6 mL) and THF- Borane complex (15 mL, 1M in THF) was added at 0 ° C. After stirring the reaction solution at 65 ° C. for 2 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure.
  • Example 110 6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide Obtained in Step 5 of Reference Example 49 Of N- (6-bromo-8-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (2.57 g) was used to give the title compound (1.72 g) in the same manner as in Example 109.
  • the compounds described in Examples 30 to 111 are as follows (Table 4). The free shown in Table 4 is free, Racemate is racemic, (R) -form is (R) -form, (S) -form is (S) -form, (-)-form is (-)-Form, (+)-form is (+)-form, 4 stereoisomers is a mixture of four stereoisomers, Optically active is an optically active form, tR1 (IC), tR2 (IC), tR3 (IC) and tR4 (IC) indicate the order of retention times by chiral chromatography CHIRALPAK IC.
  • Example 1 (1) 10 mg of the compound of Example 1 (2) Lactose 60mg (3) Corn starch 35mg (4) Hydroxypropyl methylcellulose 3mg (5) Magnesium stearate 2mg A mixture of 10 mg of the compound obtained in Example 1, 60 mg of lactose and 35 mg of corn starch was granulated with 0.03 mL of 10 wt% hydroxypropylmethylcellulose aqueous solution (3 mg as hydroxypropylmethylcellulose), and then dried at 40 ° C. Sift through. The obtained granules are mixed with 2 mg of magnesium stearate and compressed. The resulting uncoated tablets are coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablet is polished with beeswax to obtain a coated tablet.
  • Formulation Example 2 (1) 10 mg of the compound of Example 1 (2) Lactose 70mg (3) Corn starch 50mg (4) Soluble starch 7mg (5) Magnesium stearate 3mg 10 mg of the compound obtained in Example 1 and 3 mg of magnesium stearate are granulated with 0.07 mL of an aqueous solution of soluble starch (7 mg as soluble starch), then dried and mixed with 70 mg of lactose and 50 mg of corn starch. The mixture is compressed to obtain tablets.
  • Test example 1 Measurement of ⁇ 1D receptor binding inhibitory activity
  • the gene manipulation method described below is described in the method or reagent attached protocol described in the book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989).
  • (I) from the expression plasmid prepared human liver cDNA for the human alpha 1D receptor was cloned alpha 1D receptor gene by the PCR method.
  • ⁇ 1D receptor gene base sequence reported by DEBRA A. et al. (J. Pharamacol. Exp. Ter., 272, 134-142 (1995)) using 200 ng of human brain hippocampal cDNA library (Takara Shuzo) as a template.
  • the PCR reaction was performed using Gene Amp PCR System 9700 (Applied Biosystems) (reaction conditions: 94 ° C. for 15 seconds, 68 ° C. for 3 minutes 30 seconds for 45 cycles).
  • the PCR fragment obtained above was digested with restriction enzymes NheI (Takara Shuzo) and Kpn I (Takara Shuzo), and then DNA fragments were recovered by agarose gel electrophoresis.
  • the DNA fragment was mixed with animal cell expression plasmid pcDNA3.1 / Zeo (Invitrogen) digested with NheI and KpnI, and DNA Ligation Kit Ver.
  • the plasmid pcDNA3.1 / Zeo-Adre ⁇ 1D was obtained by transforming competent cells of E. coli JM109 after ligation with 2 (Takara Shuzo).
  • a plurality of Zeocin resistant strains thus obtained were selected, and each strain was cultured in a cell culture flask at 150 cm 2 until it became semi-confluent, and a cell membrane fraction was prepared as follows. Semiconfluent cells are detached with D-PBS (-) containing 0.02% EDTA, and the cells are collected by centrifugation and placed in a membrane preparation buffer (10 mM NaHCO 3 pH 7.4, protease inhibitor cocktail (Roche)). The suspension was suspended, and the cells were disrupted by treating with Polytron homogenizer (model PT-3100, KINEMATICA AG) for 3 times at 20000 rpm for 20 seconds.
  • Polytron homogenizer model PT-3100, KINEMATICA AG
  • Membrane fraction (20 ⁇ g / well) diluted with binding assay buffer (50 mM Tris-HCl, 10 mM MgCl 2 , 0.5% BSA, protease inhibitor cocktail pH 7.5) and ligand in 96 well microplate [ 3 H] Prazosin (2.5 nM, Perkin Elmer Life Science) was added and reacted at room temperature for 1 hour. For measurement of non-specific binding, phentolamine (Sigma) was further added to 10 ⁇ M. Next, the membrane fraction was transferred to a unifilter GF / C (Perkin Elmer Life Science) by filtering the reaction solution using a cell harvester (Perkin Elmer Life Science), and ice-cooled 50 mM Tris buffer (pH 7.5).
  • binding assay buffer 50 mM Tris-HCl, 10 mM MgCl 2 , 0.5% BSA, protease inhibitor cocktail pH 7.5
  • Prazosin 2.5 nM, Perkin Elmer Life Science
  • the membrane fraction for compound evaluation shown below was It prepared by the same method and used for the following compound evaluation.
  • Unifilter GF / C Perkin Elmer Life Science
  • the compound of the present invention has an excellent selective ⁇ 1D adrenergic receptor antagonistic action and is useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like.
  • This application is based on Japanese Patent Application No. 2009-128178 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

Disclosed is a phenoxyethylamine derivative having an excellent selective α1D adrenergic receptor antagonistic activity. Specifically disclosed is a compound represented by formula (I) [wherein each symbol is as defined in the description] or a salt thereof.

Description

フェノキシエチルアミン誘導体Phenoxyethylamine derivative
　本発明は、優れた選択的α１Ｄアドレナリン受容体（以下、単にα１Ｄ受容体ということがある。）拮抗作用を有し、下部尿路症状等の予防・治療剤として有用なフェノキシエチルアミン誘導体に関する。 The present invention relates to a phenoxyethylamine derivative having an excellent selective α 1D adrenergic receptor (hereinafter, simply referred to as α 1D receptor) antagonistic activity and useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like. .
（発明の背景）
　α１アドレナリン受容体（以下、単にα1受容体ということがある。）は心臓血管系や下部尿路などに広く分布し、交感神経反応活動に関与している。さらに高血圧、心肥大、排尿障害といった病態との関係も示唆されていることからα1受容体は以前から関心がもたれ、多くの治療薬の開発が試みられてきた。また最近になりα１受容体遮断薬が前立腺肥大（ＢＰＨ）に伴う排尿障害に有効であることが明らかとなり、その市場性とあいまって、再び大きな関心となっている（非特許文献１）。
　１９８０年代後半から１９９０年代前半にかけてα１受容体の遺伝子がクローニングされ、その結果、α１Ａ、α１Ｂおよびα１Ｄの３つのサブタイプが存在することが明らかとなった。なかでもα１Ｄ受容体は、血管、脳、脊髄、消化管、膀胱、腎臓など数多くの組織で発現していることが確認されている。α１Ｄ受容体の生理的機能について詳細には解明されていないものの、その局在の広さからα１Ｄ受容体拮抗薬はさまざまな疾患の治療薬に成り得る可能性が考えられる。
　α１Ｄ受容体は膀胱や仙髄の副交感神経核などで他のサブタイプに比べ多く分布していることが確認されており（非特許文献２、３）、蓄尿症状に強く関わっていると示唆されている。実際、α１Ｄ受容体のノックアウトマウスでは、膀胱容量、１回排尿量が有意に増加すると報告されている（非特許文献４）。また最近になって、ＢＰＨ患者およびＢＰＨモデル動物の膀胱においてα１Ｄ受容体ｍＲＮＡの発現量が増加すること（非特許文献５および６）、ＢＰＨ患者の摘出膀胱筋はα１Ｄ受容体を介した収縮機能が亢進している可能性（非特許文献７）などが報告され、膀胱に発現するα１Ｄ受容体がＢＰＨの病態に関与する可能性が示唆されている。以上のことから、α１Ｄ受容体拮抗薬は下部尿路症状予防・治療剤等として有望である。
　選択的α１Ｄ受容体拮抗作用を示す化合物としては、例えば、
　非特許文献８には式 (Background of the Invention)
α 1 adrenergic receptors (hereinafter sometimes simply referred to as α 1 receptors) are widely distributed in the cardiovascular system and lower urinary tract, and are involved in sympathetic reaction activity. Furthermore, since it has been suggested to be associated with pathological conditions such as hypertension, cardiac hypertrophy, and dysuria, the α 1 receptor has been attracting interest for a long time, and many therapeutic drugs have been developed. Recently, it has become clear that α 1 receptor blockers are effective for dysuria associated with benign prostatic hyperplasia (BPH).
From the late 1980s to the early 1990s, the α 1 receptor gene was cloned, and as a result, it was revealed that there were three subtypes, α 1A , α 1B and α 1D . Among these, α 1D receptors have been confirmed to be expressed in many tissues such as blood vessels, brain, spinal cord, gastrointestinal tract, bladder and kidney. Although the physiological function of the α 1D receptor has not been elucidated in detail, it is considered that the α 1D receptor antagonist may be a therapeutic agent for various diseases due to its wide localization.
α 1D receptors have been confirmed to be more distributed in bladder and sacral parasympathetic nuclei compared to other subtypes (Non-Patent Documents 2 and 3), suggesting that they are strongly associated with urinary storage symptoms. Has been. In fact, it has been reported that in the α 1D receptor knockout mouse, the bladder capacity and the amount of urination once are significantly increased (Non-patent Document 4). Recently, the expression level of α 1D receptor mRNA is increased in the bladder of BPH patients and BPH model animals (Non-patent Documents 5 and 6), and the isolated bladder muscle of BPH patients is mediated by α 1D receptors. The possibility that the contractile function is enhanced (Non-patent Document 7) has been reported, suggesting that the α 1D receptor expressed in the bladder may be involved in the pathology of BPH. Based on the above, α 1D receptor antagonists are promising as agents for preventing and treating lower urinary tract symptoms.
Examples of the compound exhibiting selective α 1D receptor antagonistic action include:
Non-Patent Document 8 has a formula
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
で表される化合物、
　特許文献１には式 A compound represented by
Patent Document 1 discloses a formula
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
で表される化合物、
　特許文献２には式 A compound represented by
Patent Document 2 has a formula
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
で表される化合物、
　特許文献３には式 A compound represented by
In Patent Document 3, there is a formula
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
で表される化合物、
　特許文献３７には式 A compound represented by
Patent Document 37 has a formula
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
で表される化合物が記載されている。
　非特許文献９には式 The compound represented by these is described.
Non-Patent Document 9 has a formula
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
で表される化合物が記載されている。 The compound represented by these is described.
　また、フェノキシエチルアミン誘導体としては、特許文献４～３６および非特許文献１０～１６に記載されているものが知られている。 Further, as phenoxyethylamine derivatives, those described in Patent Documents 4 to 36 and Non-Patent Documents 10 to 16 are known.
WO8808842WO8808842 WO9529163WO9529163 WO9534540WO9534540 WO9731907WO9731907 WO9950237WO9950237 WO2000032568WO2000032568 WO2001047890WO2001047890 WO2001047931WO2001047931 WO2001066520WO2001066520 WO2003002525WO2003002525 WO2003026666WO2003026666 WO2005016862WO2005016862 WO2005037198WO2005037198 WO2006010775WO2006010775 WO2006069807WO2006069807 WO2007070173WO2007070173 WO2007106537WO2007106537 WO2007119984WO2007119984 WO2008011476WO2008011476 WO2008122115WO2008122115 US2946799US2946799 US2004214870US2004214870 US2004167188US2004167188 US2005245399US2005245399 EP1676842EP1676842 EP1953161EP1953161 JP61055273JP61055273 JP09221476JP09221476 JP2006225351JP2006225351 DE19643037DE19643037 DE3603577DE3603577 DE3831445DE3831445 CN1706820CN1706820 WO2007103996WO2007103996 WO2002023986WO2002023986 WO2006058700WO2006058700 WO08050732WO08050732
　本発明は、優れた選択的α１Ｄアドレナリン受容体拮抗作用を有し、下部尿路症状等の予防・治療剤として有用な化合物を提供することを目的とする。 An object of the present invention is to provide a compound having an excellent selective α 1D adrenergic receptor antagonistic activity and useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like.
　本発明者らは、以下の式（Ｉ）で表される化合物またはその塩が、その特異な化学構造に基づいて優れた選択的α１Ｄアドレナリン受容体拮抗作用を有し、下部尿路症状等の予防・治療剤として優れた薬効を有することを見出した。この知見に基づいて、本発明者らは、鋭意研究を行い、本発明を完成するに至った。 The present inventors have shown that the compound represented by the following formula (I) or a salt thereof has an excellent selective α 1D adrenergic receptor antagonistic action based on its specific chemical structure, and lower urinary tract symptoms and the like Has been found to have an excellent medicinal effect as a prophylactic / therapeutic agent. Based on this knowledge, the present inventors have conducted intensive research and have completed the present invention.
　すなわち、本発明は、
[１]　式（Ｉ）： That is, the present invention
[1] Formula (I):
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
〔式中、
Ａ環は置換基を有していても良いベンゼン環、又は置換基を有していても良い６員芳香族複素環を示し、
Ｂ環は置換基を有していても良いベンゼン環を示し、
Ｌ１は結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示し、
Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
ＸはＳ、ＳＯ、又はＳＯ２を示し、
Ｙは炭素原子を示し、
Ｚは（１）置換基を有していても良い炭化水素基（但し、ＸがＳの時は（ヒドロキシメチル)フェニル基、アミノフェニル基、及びメトキシフェニル基を除く）、（２）置換基を有していても良いアミノ基、又は（３）置換基を有していても良い５員または６員複素環基を示すか、あるいは（４）Ｙと結合して、Ａ環と共にさらに置換基を有していても良い縮合二環性複素環を形成してもよく、
Ｒ１及びＲ２は同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示すか、あるいは互いに結合してＹと共に置換基を有していても良いシクロプロピル若しくは置換基を有していても良いシクロブチルを形成しても良い（但し、ＺがＹと結合する時にはＲ１は存在しない）。〕
で表される化合物、又はその塩（以下、化合物（Ｉ）と略記することがある。）；
[２]　Ａ環は置換基を有していても良いベンゼン環、又はピリジン環を示し、
Ｂ環は置換基を有していても良いベンゼン環を示し、
Ｌ１は結合手、メチレン基又はエチレン基を示し、
Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
ＸはＳＯ２を示し、
Ｙは炭素原子を示し、
Ｚは（１）Ｃ１－６アルキル基、(２)フェニル基、（３）置換基を有していても良いアミノ基、又は(４)モルホリノ基を示すか、あるいは（５）Ｙと結合して、Ａ環と共にさらに置換基を有していても良いジヒドロチオクロメン環を形成してもよく、
Ｒ１は水素原子を示し、
Ｒ２は水素原子またはＣ１－６アルキル基を示す（但し、ＺがＹと結合する時にはＲ１は存在せず、かつＲ２は水素原子を示す）、
上記[１]記載の化合物、又はその塩；
[３]　式（ＩＩ）： [Where,
Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent,
Ring B represents an optionally substituted benzene ring,
L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. Also shows a good propylene group,
L 2 represents an ethylene group which may have a substituent other than an oxo group,
X represents S, SO, or SO 2,
Y represents a carbon atom,
Z is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) substituent group Or an amino group which may have a substituent, or (3) a 5- or 6-membered heterocyclic group which may have a substituent, or (4) bonded to Y and further substituted with A ring A condensed bicyclic heterocyclic ring which may have a group may be formed,
R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, or may be bonded to each other and have a substituent together with Y. Cyclopropyl or optionally substituted cyclobutyl may be formed (provided that when Z is bound to Y, R 1 is not present). ]
Or a salt thereof (hereinafter sometimes abbreviated as compound (I));
[2] Ring A represents an optionally substituted benzene ring or pyridine ring,
Ring B represents an optionally substituted benzene ring,
L 1 represents a bond, a methylene group or an ethylene group,
L 2 represents an ethylene group which may have a substituent other than an oxo group,
X represents SO 2
Y represents a carbon atom,
Z represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group, or (5) bonded to Y A dihydrothiochromene ring which may further have a substituent together with the A ring,
R 1 represents a hydrogen atom,
R 2 represents a hydrogen atom or a C 1-6 alkyl group (provided that when Z is bound to Y, R 1 does not exist and R 2 represents a hydrogen atom),
The compound of the above-mentioned [1] or a salt thereof;
[3] Formula (II):
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
〔式中、
Ａ環は置換基を有していても良いベンゼン環、又は置換基を有していても良い６員芳香族複素環を示し、
Ｂ環は置換基を有していても良いベンゼン環を示し、
Ｌ１は結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示し、
Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
ＸはＳ、ＳＯ、又はＳＯ２を示し、
Ｚ’はＣＲ４、又はＮを示し、
Ｒ２、Ｒ３及びＲ４は同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示し、
ｎは０ないし３の整数を示す。〕
で表される上記[１]記載の化合物、又はその塩（以下、化合物（ＩＩ）と略記することがある。）；
[４]　Ａ環は置換基を有していても良いベンゼン環を示し、
Ｂ環は置換基を有していても良いベンゼン環を示し、
Ｌ１は結合手を示し、
Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
ＸはＳＯ２を示し、
Ｚ’はＣＲ４、又はＮを示し、
Ｒ２及びＲ３は水素原子を示し、
Ｒ４は、水素原子または置換基を有していても良いＣ１－６アルキル基を示し、
ｎは０、１または２を示す、
上記[３]記載の化合物、又はその塩；
[４ａ]　Ａ環は、（１）ハロゲン原子、（２）ヒドロキシ基、（３）シアノ基、（４）フェニル基、（５）Ｃ１－６アルキルチオ基、（６）Ｃ１－６アルコキシカルボニル－Ｃ2－６アルケニル基、（７）Ｃ１－６アルキルスルホニル基、（８）モルホリノ基、（９）Ｃ１－６アルキル基、Ｃ２－６シクロアルキル基、Ｃ１－６アルキルカルボニル基、およびＣ１－６アルキルスルホニル基から選択される１または２個の置換基で置換されていてもよいアミノ基、（１０）ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルコキシ－カルボニル基およびカルバモイル基から選択される置換基で置換されていてもよいＣ１－６アルコキシ基、および（１１）ハロゲン原子、ヒドロキシ基、ピロリジニル基、Ｃ１－６アルコキシ基、モノまたはジ－Ｃ１－６アルキル－カルバモイル基、Ｃ１－６アルキルカルボニルアミノ基、アミノ基およびＣ１－６アルケニル基から選択される置換基で置換されていてもよいＣ１－６アルキル基、
から選択される１または２個の置換基で置換されていても良いベンゼン環を示し、
Ｂ環は、（１）ハロゲン原子、（２）シアノ基、（３）ハロゲン原子で置換されていてもよいＣ１－６アルキル基、（４）ベンジルオキシ基および（５）Ｃ１－６アルキルチオ基から選択される１または２個の置換基で置換されたベンゼン環を示し、
Ｌ１は結合手を示し、
Ｌ２はＣ１－６アルキル基で置換されていてもよいエチレン基を示し、
ＸはＳＯ２を示し、
Ｚ’はＣＲ４、又はＮを示し、
Ｒ２及びＲ３は水素原子を示し、
Ｒ４は、水素原子またはＣ１－６アルキル基を示す、
上記[３]化合物またはその塩；
[４ｂ]　ｎは１である、上記[４]または[４ａ]記載の化合物またはその塩；
[５]　Ａ環は１個のモノ－Ｃ１－６アルキルアミノ基で置換されていても良いベンゼン環を示し、
Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し、
Ｌ１は結合手を示し、
Ｌ２はエチレン基を示し、
ＸはＳＯ２を示し、
Ｚ’はＣＲ４を示し、
Ｒ２、Ｒ３及びＲ４は、水素原子を示し、
ｎは１を示す、
上記[３]記載の化合物、又はその塩；
[６]　式（ＩＩＩ）： [Where,
Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent,
Ring B represents an optionally substituted benzene ring,
L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. Also shows a good propylene group,
L 2 represents an ethylene group which may have a substituent other than an oxo group,
X represents S, SO, or SO 2,
Z 'represents a CR 4, or N,
R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group,
n represents an integer of 0 to 3. ]
Or a salt thereof (hereinafter sometimes abbreviated as compound (II)) represented by formula (1);
[4] Ring A represents an optionally substituted benzene ring,
Ring B represents an optionally substituted benzene ring,
L 1 represents a bond,
L 2 represents an ethylene group which may have a substituent other than an oxo group,
X represents SO 2
Z ′ represents CR 4 or N,
R 2 and R 3 represent a hydrogen atom,
R 4 represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent,
n represents 0, 1 or 2;
The compound of the above-mentioned [3], or a salt thereof;
[4a] Ring A includes (1) halogen atom, (2) hydroxy group, (3) cyano group, (4) phenyl group, (5) C 1-6 alkylthio group, (6) C 1-6 alkoxycarbonyl -C 2-6 alkenyl group, (7) C 1-6 alkylsulfonyl group, (8) morpholino group, (9) C 1-6 alkyl group, C 2-6 cycloalkyl group, C 1-6 alkylcarbonyl group , And an amino group optionally substituted with one or two substituents selected from a C 1-6 alkylsulfonyl group, (10) a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxy-carbonyl And a C 1-6 alkoxy group which may be substituted with a substituent selected from a group and a carbamoyl group, and (11) a halogen atom, a hydroxy group, a pyrrolidinyl group, a C 1-6 alkoxy group, Other di -C 1-6 alkyl - carbamoyl group, C 1-6 alkylcarbonylamino group, an amino group and a C 1-6 which may be C 1-6 alkyl group substituted with a substituent selected from an alkenyl group ,
A benzene ring optionally substituted by 1 or 2 substituents selected from:
Ring B includes (1) a halogen atom, (2) a cyano group, (3) an optionally substituted C 1-6 alkyl group, (4) a benzyloxy group, and (5) a C 1-6 alkylthio group. A benzene ring substituted with one or two substituents selected from the group
L 1 represents a bond,
L 2 represents an ethylene group which may be substituted with a C 1-6 alkyl group,
X represents SO 2
Z ′ represents CR 4 or N,
R 2 and R 3 represent a hydrogen atom,
R 4 represents a hydrogen atom or a C 1-6 alkyl group,
[3] Compound or salt thereof;
[4b] The compound according to [4] or [4a] above, wherein n is 1, or a salt thereof;
[5] Ring A represents a benzene ring which may be substituted with one mono-C 1-6 alkylamino group,
Ring B represents a benzene ring substituted with two halogen atoms,
L 1 represents a bond,
L 2 represents an ethylene group,
X represents SO 2
Z 'represents a CR 4,
R 2 , R 3 and R 4 represent a hydrogen atom,
n represents 1,
The compound of the above-mentioned [3], or a salt thereof;
[6] Formula (III):
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
〔式中、
Ａ環は置換基を有していても良いベンゼン環、又は置換基を有していても良い６員芳香族複素環を示し、
Ｂ環は置換基を有していても良いベンゼン環を示し、
Ｌ１は結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示し、
Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
ＸはＳ、ＳＯ、又はＳＯ２を示し、
Ｚ’’は（１）置換基を有していても良い炭化水素基（但し、ＸがＳの時は（ヒドロキシメチル）フェニル基、アミノフェニル基、及びメトキシフェニル基を除く）、（２）置換基を有していても良いアミノ基、又は（３）置換基を有していても良い５員または６員複素環基を示し、
Ｒ１及びＲ２は同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示すか、あるいは互いに結合して隣接する炭素原子と共に置換基を有していても良いシクロプロピル若しくは置換基を有していても良いシクロブチルを形成してもよい。〕
で表される上記[１]記載の化合物、又はその塩（以下、化合物（ＩＩＩ）と略記することがある。）；
[７]　Ａ環は置換基を有していても良いベンゼン環、又はピリジン環を示し、
Ｂ環は置換基を有していても良いベンゼン環を示し、
Ｌ１は結合手、メチレン基、またはエチレン基を示し、
Ｌ２はエチレン基を示し、
ＸはＳＯ２を示し、
Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）置換基を有していても良いアミノ基、又は（４）モルホリノ基を示し、
Ｒ１及びＲ２は、両方とも水素原子、または一方が水素原子で他方がＣ１－６アルキル基を示す、
上記[６]記載の化合物、又はその塩；
[７ａ]　Ａ環は、ハロゲン原子、シアノ基、アルコキシ基およびモルホリノ基から選択される１個の置換基で置換されていても良いベンゼン環、又はピリジン環を示し、
Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し、
Ｌ１は結合手、メチレン基、またはエチレン基を示し、
Ｌ２はエチレン基を示し、
ＸはＳＯ２を示し、
Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）１または２個のＣ１－６アルキル基で置換されていても良いアミノ基、又は（４）モルホリノ基を示し、
Ｒ１及びＲ２は、両方とも水素原子、または一方が水素原子で他方がＣ１－６アルキル基を示す、
上記[６]記載の化合物またはその塩；
[８]　Ａ環はベンゼン環、又はピリジン環を示し、
Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し、
Ｌ１は結合手を示し、
Ｌ２はエチレン基を示し、
ＸはＳＯ２を示し、
Ｚ’’はＣ１－６アルキル基、またはジ－Ｃ１－６アルキルアミノ基を示し、
Ｒ１及びＲ２は、水素原子を示す、
請求項６記載の化合物、又はその塩；
[９]　2-(2-クロロ-5-フルオロフェノキシ)-N-[2-(メチルスルホニル)ベンジル] エタンアミン、又はその塩；
[１０]　2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド、又はその塩；
[１１]　2-(2-クロロ-5-フルオロフェノキシ)-N-{[2-(メチルスルホニル)ピリジン-3-イル]メチル}エタンアミン、又はその塩；
[１２]　(4S)-N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド、又はその塩；
[１３]　（＋）-N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-メチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド、又はその塩；
[１４]　上記[１]記載の化合物又はその塩のプロドラッグ；
[１５]　上記[１]記載の化合物又はその塩、又はそのプロドラッグを含有する医薬；
[１６]　α１Ｄ受容体拮抗剤である上記[１５]記載の医薬；
[１７]　下部尿路症状の予防・治療剤である上記[１５]記載の医薬；
[１８]　上記[１]記載の化合物又はその塩、又はそのプロドラッグの有効量を哺乳動物に投与することを特徴とする下部尿路症状予防・治療方法；
[１９]　下部尿路症状予防・治療剤を製造するための上記[１]記載の化合物又はその塩、又はそのプロドラッグの使用；
[２０]　上記[１]記載の化合物又はその塩、又はそのプロドラッグの下部尿路症状予防・治療剤としての使用；
[２１]　上記[１]記載の化合物、又はそのプロドラッグの有効量を哺乳動物に投与することを特徴とする、当該哺乳動物におけるα１Ｄ受容体拮抗方法；
[２２]　α１Ｄ受容体拮抗薬を製造するための、上記[１]記載の化合物、又はそのプロドラッグの使用；
等に関する。 [Where,
Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent,
Ring B represents an optionally substituted benzene ring,
L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. Also shows a good propylene group,
L 2 represents an ethylene group which may have a substituent other than an oxo group,
X represents S, SO, or SO 2,
Z ″ is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) An amino group which may have a substituent, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent,
R 1 and R 2 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent, or have a substituent together with an adjacent carbon atom bonded to each other. Cyclopropyl which may be substituted or cyclobutyl which may have a substituent may be formed. ]
Or a salt thereof (hereinafter sometimes abbreviated as compound (III)) represented by formula (1);
[7] Ring A represents an optionally substituted benzene ring or pyridine ring,
Ring B represents an optionally substituted benzene ring,
L 1 represents a bond, a methylene group, or an ethylene group,
L 2 represents an ethylene group,
X represents SO 2
Z ″ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group,
R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
The compound according to the above [6], or a salt thereof;
[7a] Ring A represents a benzene ring or a pyridine ring which may be substituted with one substituent selected from a halogen atom, a cyano group, an alkoxy group and a morpholino group,
Ring B represents a benzene ring substituted with two halogen atoms,
L 1 represents a bond, a methylene group, or an ethylene group,
L 2 represents an ethylene group,
X represents SO 2
Z ″ is (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group optionally substituted by one or two C 1-6 alkyl groups, or (4) a morpholino group Indicate
R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
The compound or a salt thereof according to the above [6];
[8] Ring A represents a benzene ring or a pyridine ring,
Ring B represents a benzene ring substituted with two halogen atoms,
L 1 represents a bond,
L 2 represents an ethylene group,
X represents SO 2
Z ″ represents a C 1-6 alkyl group or a di-C 1-6 alkylamino group,
R 1 and R 2 represent a hydrogen atom,
The compound according to claim 6, or a salt thereof;
[9] 2- (2-Chloro-5-fluorophenoxy) -N- [2- (methylsulfonyl) benzyl] ethanamine, or a salt thereof;
[10] 2-({[2- (2-chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide, or a salt thereof;
[11] 2- (2-Chloro-5-fluorophenoxy) -N-{[2- (methylsulfonyl) pyridin-3-yl] methyl} ethanamine, or a salt thereof;
[12] (4S) -N- [2- (2-chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide, or a salt thereof;
[13] (+) - N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide, Or a salt thereof;
[14] A prodrug of the compound according to [1] above or a salt thereof;
[15] A medicament containing the compound according to [1] above or a salt thereof, or a prodrug thereof;
[16] The medicament according to [15] above, which is an α 1D receptor antagonist;
[17] The medicament according to [15] above, which is an agent for preventing / treating lower urinary tract symptoms;
[18] A method for preventing and treating lower urinary tract symptoms, comprising administering to a mammal an effective amount of the compound according to [1] above or a salt thereof, or a prodrug thereof;
[19] Use of the compound of the above-mentioned [1], a salt thereof, or a prodrug thereof for producing an agent for preventing or treating lower urinary tract symptoms;
[20] Use of the compound according to [1] above or a salt thereof, or a prodrug thereof as an agent for preventing or treating lower urinary tract symptoms;
[21] A method for antagonizing an α 1D receptor in a mammal, comprising administering an effective amount of the compound according to [1] above or a prodrug thereof to the mammal;
[22] Use of the compound of the above-mentioned [1] or a prodrug thereof for producing an α 1D receptor antagonist;
Etc.
　本発明の化合物は、優れた選択的α１Ｄアドレナリン受容体拮抗作用を有し、下部尿路症状等の予防・治療剤として有用である。 The compound of the present invention has an excellent selective α 1D adrenergic receptor antagonistic action and is useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like.
（発明の詳細な説明）
　以下に本発明について詳細に説明する。
　本明細書中、「置換基を有していてもよい炭化水素基」としては、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアリール基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよいシクロアルケニル基等が挙げられる。 (Detailed description of the invention)
The present invention is described in detail below.
In the present specification, the “hydrocarbon group which may have a substituent” includes an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a substituent. An alkynyl group which may have a substituent, an aralkyl group which may have a substituent, an aryl group which may have a substituent, a cycloalkyl group which may have a substituent, and a substituent And a cycloalkenyl group which may be present.
　本明細書中、「置換基を有していてもよいアルキル基」としては、
（i）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、
（ii）シアノ基、
（iii）水酸基、
（iv）ニトロ基、
（v）ホルミル基、
（vi）アミノ基、
（vii）モノ－またはジ－Ｃ１－６アルキルアミノ基（例、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ等）、
（viii）Ｃ１－６アルキル－カルボニルアミノ基（例、アセチルアミノ、エチルカルボニルアミノ等）、
（ix）Ｃ１－６アルコキシ－カルボニルアミノ基（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ等）、
（x）ベンゼン環と縮合していてもよいＣ３－８シクロアルキル基（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等）、
（xi）ベンゼン環と縮合していてもよいＣ３－８シクロアルケニル基（例、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル等）、
（xii）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）およびＣ１－６アルコキシ基（例、メトキシ、エトキシ、プロポキシ等）から選ばれる置換基で置換されていてもよいＣ６－１４アリール基（例、フェニル、１－ナフチル、２－ナフチル等）、
（xiii）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、Ｃ１－６アルコキシ基（例、メトキシ等）、Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル等）およびカルバモイル基から選ばれる置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ等）、
（xiv）Ｃ７－１６アラルキルオキシ基（例、ベンジルオキシ等）、
（xv）Ｃ１－６アルコキシ基（例、メトキシ等）、Ｃ１－６アルキル基（例、メチル等）およびハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）から選ばれる置換基で置換されていてもよいＣ６－１４アリールオキシ基（例、フェノキシ等）、
（xvi）カルボキシル基、
（xvii）Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、tert-ブトキシカルボニル等）、
（xviii）Ｃ７－１６アラルキルオキシ－カルボニル基（例、ベンジルオキシカルボニル等）、
（xix）Ｃ６－１４アリールオキシ－カルボニル基（例、フェノキシカルボニル等）、
（xx）Ｃ１－６アルキル－カルボニル基（例、アセチル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、２，２－ジメチルプロピルカルボニル等）、
（xxi）Ｃ３－８シクロアルキル－カルボニル基（例、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等）、
（xxii）Ｃ７－１６アラルキル－カルボニル基（例、ベンジルカルボニル等）、
（xxiii）カルバモイル基、
（xxiv）チオカルバモイル基、
（xxv）モノ－またはジ－Ｃ１－６アルキル－カルバモイル基（例、メチルカルバモイル、エチルカルバモイル、プロピルカルバモイル、イソプロピルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル等）、
（xxvi）モノ－またはジ－Ｃ７－１６アラルキル－カルバモイル基（例、ベンジルカルバモイル、ジベンジルカルバモイル等）、
（xxvii）チオール基、
（xxviii）Ｃ１－６アルキルチオ基（例、メチルチオ、エチルチオ、プロピルチオ等）、
（xxix）Ｃ７－１６アラルキルチオ基（例、ベンジルチオ等）、
（xxx）Ｃ１－６アルキルスルホニル基（例、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル等）、
（xxxi）Ｃ３－８シクロアルキルスルホニル基（例、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等）、
（xxxii）Ｃ６－１４アリールスルホニル基（例、フェニルスルホニル、１－ナフチルスルホニル、２－ナフチルスルホニル等）、
（xxxiii）Ｃ７－１６アラルキルスルホニル基（例、ベンジルスルホニル等）、
（xxxiv）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５ないし８員の非芳香族複素環基（例、ピロリジニル、テトラヒドロフリル、テトラヒドロチエニル、ピペリジル、テトラヒドロピラニル、モルホリニル、チオモルホリニル、ピペラジニル等）、該非芳香族複素環基は、Ｃ１－６アルキル基（例、メチル等）で置換されていてもよい、
（xxxv）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５ないし８員の芳香族複素環基（例、フリル、チエニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、ピラゾリル、１,２,３－オキサジアゾリル、１,２,４－オキサジアゾリル、１,３,４－オキサジアゾリル、フラザニル、１,２,３－チアジアゾリル、１,２,４－チアジアゾリル、１,３,４－チアジアゾリル、１,２,３－トリアゾリル、１,２,４－トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等）、該芳香族複素環基は、ハロゲン原子（例、塩素原子等）またはＣ１－６アルキル基（例、メチル等）で置換されていてもよく、また、ベンゼン環と縮合していてもよい（例、ベンゾチエニル等）、
（xxxvi）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５ないし８員の非芳香族複素環－カルボニル基（例、ピロリジニルカルボニル、テトラヒドロフリルカルボニル、テトラヒドロチエニルカルボニル、ピペリジルカルボニル、テトラヒドロピラニルカルボニル、モルホリニルカルボニル、チオモルホリニルカルボニル、ピペラジニルカルボニル等）、
（xxxvii）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５ないし８員の芳香族複素環－カルボニル基（例、フリルカルボニル、チエニルカルボニル、ピロリルカルボニル、オキサゾリルカルボニル、イソオキサゾリルカルボニル、チアゾリルカルボニル、イソチアゾリルカルボニル、イミダゾリルカルボニル、ピラゾリルカルボニル、１,２,３－オキサジアゾリルカルボニル、１,２,４－オキサジアゾリルカルボニル、１,３,４－オキサジアゾリルカルボニル、フラザニルカルボニル、１,２,３－チアジアゾリルカルボニル、１,２,４－チアジアゾリルカルボニル、１,３,４－チアジアゾリルカルボニル、１,２,３－トリアゾリルカルボニル、１,２,４－トリアゾリルカルボニル、テトラゾリルカルボニル、ピリジルカルボニル、ピリダジニルカルボニル、ピリミジニルカルボニル、ピラジニルカルボニル、トリアジニルカルボニル等）、
（xxxviii）ウレイド基、
（xxxix）Ｃ１－６アルキル－ウレイド基（例、メチルウレイド、エチルウレイド、プロピルウレイド等）、
（xxxx）Ｃ６－１４アリール－ウレイド基（例、フェニルウレイド、１－ナフチルウレイド、２－ナフチルウレイド等）、
（xxxxi）Ｃ１－４アルキレンジオキシ基（例、メチレンジオキシ、エチレンジオキシ、プロピレンジオキシ等）、
（xxxxii）アミノスルホニル基、
（xxxxiii）モノ-Ｎ-Ｃ１－６アルキルアミノスルホニル基（例、メチルアミノスルホニル、エチルアミノスルホニル等）、
（xxxxiv）ジ-N,N-Ｃ１－６アルキルアミノスルホニル基（例、ジメチルアミノスルホニル、ジエチルアミノスルホニル等）、
（xxxxv）Ｃ１－６アルキル基（例、メチル等）で置換されていてもよい橋かけ式のＣ７－１０シクロアルキル基（例、ビシクロ［３．１．１］ヘプチル、アダマンチル等）、
（xxxxvi）Ｃ６－１４アリールチオ基（例、フェニルチオ等）、
（xxxxvii）Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ等）、
（xxxxviii）Ｃ３－８シクロアルキルアミノ基（例、シクロプロピルアミノ等）、
等から選ばれる置換基を有していてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、ネオペンチル、ヘキシル等）が挙げられ、置換基の数は１ないし４個、好ましくは１ないし３個である。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “alkyl group optionally having substituent (s)”
(I) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom),
(Ii) a cyano group,
(Iii) a hydroxyl group,
(Iv) a nitro group,
(V) formyl group,
(Vi) an amino group,
(Vii) mono- or di-C 1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, etc.),
(Viii) a C 1-6 alkyl-carbonylamino group (eg, acetylamino, ethylcarbonylamino, etc.),
(Ix) a C 1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, etc.),
(X) a C 3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) optionally condensed with a benzene ring,
(Xi) a C 3-8 cycloalkenyl group which may be condensed with a benzene ring (eg, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.),
(Xii) C optionally substituted by a substituent selected from a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and a C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.) 6-14 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.),
(Xiii) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkoxy group (e.g., methoxy and the like), C 1-6 alkoxy - carbonyl group (e.g., methoxycarbonyl, etc.) and A C 1-6 alkoxy group optionally substituted with a substituent selected from a carbamoyl group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.),
(Xiv) a C 7-16 aralkyloxy group (eg, benzyloxy etc.),
(Xv) a substitution selected from a C 1-6 alkoxy group (eg, methoxy, etc.), a C 1-6 alkyl group (eg, methyl, etc.) and a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) A C 6-14 aryloxy group (eg, phenoxy etc.) optionally substituted with a group,
(Xvi) a carboxyl group,
(Xvii) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.),
(Xviii) C 7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl etc.),
(Xix) C 6-14 aryloxy-carbonyl group (eg, phenoxycarbonyl etc.),
(Xx) C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, 2,2-dimethylpropylcarbonyl, etc.),
(Xxi) C 3-8 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),
(Xxii) C 7-16 aralkyl - carbonyl groups (e.g., benzylcarbonyl, etc.),
(Xxiii) a carbamoyl group,
(Xxiv) a thiocarbamoyl group,
(Xxv) mono- or di-C 1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, etc.),
(Xxvi) mono- or di-C 7-16 aralkyl-carbamoyl group (eg, benzylcarbamoyl, dibenzylcarbamoyl, etc.),
(Xxvii) a thiol group,
(Xxviii) C 1-6 alkylthio group (eg, methylthio, ethylthio, propylthio etc.),
(Xxix) C 7-16 aralkylthio group (eg, benzylthio etc.),
(Xxx) C 1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, etc.),
(Xxxi) a C 3-8 cycloalkylsulfonyl group (eg, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, etc.),
(Xxxii) a C 6-14 arylsulfonyl group (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.),
(Xxxiii) a C 7-16 aralkylsulfonyl group (eg, benzylsulfonyl),
(Xxxiv) 5- to 8-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom (eg, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl) , Tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.), the non-aromatic heterocyclic group may be substituted with a C 1-6 alkyl group (eg, methyl, etc.),
(Xxxv) a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, Thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.), the aromatic heterocyclic group is a halogen atom (eg , chlorine atom etc.) or a C 1-6 alkyl group (e.g., may be substituted with methyl, etc.), also, Ben Optionally combined emissions ring condensed (eg, benzothienyl, etc.),
(Xxxvi) 5- to 8-membered non-aromatic heterocyclic-carbonyl group containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom (eg, pyrrolidinylcarbonyl, tetrahydrofuryl) Carbonyl, tetrahydrothienylcarbonyl, piperidylcarbonyl, tetrahydropyranylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, piperazinylcarbonyl, etc.),
(Xxxvii) a 5- to 8-membered aromatic heterocyclic-carbonyl group containing 1 to 4 heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms (eg, furylcarbonyl, thienylcarbonyl, pyrrolyl) Carbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl 1,3,4-oxadiazolylcarbonyl, furazanylcarbonyl, 1,2,3-thiadiazolylcarbonyl, 1,2,4-thiadiazolylcarbonyl, 1,3,4-thiadiazolylcarbonyl, 1,2,3-triazolylcarbonyl, 1,2,4-triazolylcarbonyl, tetrazolylcarbonyl Rubonyl, pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, triazinylcarbonyl, etc.),
(Xxxviii) ureido group,
(Xxxix) C 1-6 alkyl-ureido groups (eg, methylureido, ethylureido, propylureido, etc.),
(Xxxx) C 6-14 aryl-ureido group (eg, phenylureido, 1-naphthylureido, 2-naphthylureido, etc.),
(Xxxxi) C 1-4 alkylenedioxy group (eg, methylenedioxy, ethylenedioxy, propylenedioxy, etc.),
(Xxxxii) an aminosulfonyl group,
(Xxxxiii) mono-N—C 1-6 alkylaminosulfonyl group (eg, methylaminosulfonyl, ethylaminosulfonyl, etc.),
(Xxxxiv) di-N, N—C 1-6 alkylaminosulfonyl group (eg, dimethylaminosulfonyl, diethylaminosulfonyl, etc.),
(Xxxxv) a bridged C 7-10 cycloalkyl group (eg, bicyclo [3.1.1] heptyl, adamantyl, etc.) optionally substituted with a C 1-6 alkyl group (eg, methyl, etc.),
(Xxxxvi) a C 6-14 arylthio group (eg, phenylthio etc.),
(Xxxxvii) a C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino),
(Xxxxviii) a C 3-8 cycloalkylamino group (eg, cyclopropylamino),
Optionally substituted C 1-6 alkyl group selected from such (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, neopentyl, hexyl, etc.) The number of substituents is 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアルケニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ２－６アルケニル基（例、ビニル、１－プロペニル、アリル、イソプロペニル、ブテニル、イソブテニル等）等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアルキニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ２－６アルキニル基（例、エチニル、プロパルギル、ブチニル、１－ヘキシニル等）等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “optionally substituted alkenyl group” refers to the substituent that the alkyl group of the above “optionally substituted alkyl group” may have 1 And a C 2-6 alkenyl group (eg, vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.) which may have 4 to, preferably 1 to 3, may be mentioned. When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “optionally substituted alkynyl group” refers to the substituent that the alkyl group of the above “optionally substituted alkyl group” may have 1 Or a C 2-6 alkynyl group (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) which may have 4 or preferably 1 to 3 and the like. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアラルキル基」としては、
(i)上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基、
(ii)ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、水酸基、Ｃ１－６アルコキシ基（例、メトキシ、エトキシ、プロポキシ等）、アミノ基、モノ－またはジ－Ｃ１－６アルキルアミノ基（例、メチルアミノ等）、Ｃ１－６アルキル－カルボニルアミノ基（例、アセチルアミノ等）、Ｃ６－１４アリールスルホニル基および複素環基（例、ピロリジニル、モルホリニル、ピリジル、イミダゾピリジル、ベンゾイミダゾリル等）から選ばれる置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、ネオペンチル、ヘキシル等）、
（iii）Ｃ７－１６アラルキル基（例、ベンジル、２－フェニルエチル、１－フェニルエチル、３－フェニルプロピル、４－フェニルブチル等）、
（iv）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５ないし８員の芳香族複素環－オキシ基（例、フリルオキシ、チエニルオキシ、ピロリルオキシ、オキサゾリルオキシ、イソオキサゾリルオキシ、チアゾリルオキシ、イソチアゾリルオキシ、イミダゾリルオキシ、ピラゾリルオキシ、１,２,３－オキサジアゾリルオキシ、１,２,４－オキサジアゾリルオキシ、１,３,４－オキサジアゾリルオキシ、フラザニルオキシ、１,２,３－チアジアゾリルオキシ、１,２,４－チアジアゾリルオキシ、１,３,４－チアジアゾリルオキシ、１,２,３－トリアゾリルオキシ、１,２,４－トリアゾリルオキシ、テトラゾリルオキシ、ピリジルオキシ、ピリダジニルオキシ、ピリミジニルオキシ、ピラジニルオキシ、トリアジニルオキシ等）、
（v）Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル等）で置換されていてもよいＣ２－６アルケニル基（例、ビニル、イソプロペニル等）、
等を１ないし４個、好ましくは１ないし３個有していてもよいＣ７－１２アラルキル基（例、ベンジル、２－フェニルエチル、１－フェニルエチル、３－フェニルプロピル等）が挙げられる。本明細書中の「置換基を有していてもよいアラルキル基」の置換基は、アラルキル基のアリール部および／またはアルキレン部に有していてもよい。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “aralkyl group optionally having substituent (s)”
(i) the substituent that the alkyl group of the “optionally substituted alkyl group” may have,
(ii) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxyl group, C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.), amino group, mono- or di-C 1 -6 alkylamino groups (eg, methylamino, etc.), C 1-6 alkyl-carbonylamino groups (eg, acetylamino, etc.), C 6-14 arylsulfonyl groups and heterocyclic groups (eg, pyrrolidinyl, morpholinyl, pyridyl, C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl) optionally substituted with a substituent selected from imidazopyridyl, benzimidazolyl, etc. Hexyl),
(Iii) C 7-16 aralkyl group (eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc.),
(Iv) a 5- to 8-membered aromatic heterocyclic-oxy group (eg, furyloxy, thienyloxy, pyrrolyloxy, containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms) Oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy, pyrazolyloxy, 1,2,3-oxadiazolyloxy, 1,2,4-oxadiazolyloxy, 1,3,4 -Oxadiazolyloxy, furazanyloxy, 1,2,3-thiadiazolyloxy, 1,2,4-thiadiazolyloxy, 1,3,4-thiadiazolyloxy, 1,2,3-triazolyl Oxy, 1,2,4-triazolyloxy, tetrazolyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy Triazinyl oxy, etc.),
(V) a C 2-6 alkenyl group (eg, vinyl, isopropenyl, etc.) optionally substituted by a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, etc.),
And a C 7-12 aralkyl group (eg, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, etc.) which may have 1 to 4, preferably 1 to 3 and the like. The substituent of the “aralkyl group which may have a substituent” in the present specification may be present in the aryl part and / or the alkylene part of the aralkyl group. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアリール基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ６－１４アリール基（例、フェニル、ナフチル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいシクロアルキル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ３－８シクロアルキル基（例、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。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。なお、「置換基を有していてもよいシクロアルキル基」の置換基同士が結合して環（シクロアルカン環（シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環等のＣ３－６シクロアルカン環）、アレーン環（ベンゼン環、ナフタレン環等のＣ６－１０アレーン環））を形成していてもよい。
　本明細書中、「置換基を有していてもよいシクロアルケニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ３－８シクロアルケニル基（例、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。なお、「置換基を有していてもよいシクロアルケニル基」の置換基同士が結合して環（シクロアルカン環（シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環等のＣ３－６シクロアルカン環）、アレーン環（ベンゼン環、ナフタレン環等のＣ６－１０アレーン環））を形成していてもよい。 In the present specification, the “aryl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have is 1 Or a C 6-14 aryl group (eg, phenyl, naphthyl, etc.) which may have 4 to, preferably 1 to 3, may be mentioned. When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “cycloalkyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. Examples thereof include a C 3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) optionally having 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different. In addition, substituents of “optionally substituted cycloalkyl group” are bonded to each other to form a ring (cycloalkane ring (C 3-6 cyclohexane ring, cyclopropane ring, cyclopentane ring, cyclopentane ring, etc. Alkane ring) and arene rings (C 6-10 arene rings such as benzene ring and naphthalene ring)).
In the present specification, the “cycloalkenyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. Examples thereof include C 3-8 cycloalkenyl groups (eg, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.) optionally having 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different. In addition, substituents of “optionally substituted cycloalkenyl group” are bonded to each other to form a ring (cycloalkane ring (C 3-6 cyclohexane ring such as cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, Alkane ring) and arene rings (C 6-10 arene rings such as benzene ring and naphthalene ring)).
　本明細書中、「置換基を有していてもよい５員または６員複素環基」としては、
（１）前記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし３個有していてもよく、また、ベンゼン環と縮合していてもよい、炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５員または６員の非芳香族複素環基（例、ピロリジニル、テトラヒドロフリル、テトラヒドロチエニル、ピペリジル、テトラヒドロピラニル、モルホリニル、チオモルホリニル、ピペラジニル、アゼパニル、１，４－ジアゼパニル等）および
（２）前記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし３個有していてもよく、また、ベンゼン環と縮合していてもよい、炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれるヘテロ原子を１ないし４個含有する５員または６員の芳香族複素環基（例、フリル、チエニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、ピラゾリル、１,２,３－オキサジアゾリル、１,２,４－オキサジアゾリル、１,３,４－オキサジアゾリル、フラザニル、１,２,３－チアジアゾリル、１,２,４－チアジアゾリル、１,３,４－チアジアゾリル、１,２,３－トリアゾリル、１,２,４－トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等）が挙げられる。なお、置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “5-membered or 6-membered heterocyclic group optionally having substituent (s)”
(1) The aralkyl group of the above-mentioned “aralkyl group optionally having substituent (s)” may have 1 to 3 substituents which may be present, and is condensed with a benzene ring. A 5- or 6-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl) , Piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, 1,4-diazepanyl, etc.) and (2) the aralkyl group of the above-mentioned “aralkyl group optionally having substituent (s)” It may have 1 to 3 good substituents and may be condensed with a benzene ring, in addition to carbon atoms, nitrogen, sulfur and oxygen atoms. A 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from: (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. In addition, when there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアミノ基」とは、アミノ基および置換基を有するアミノ基が挙げられる。
　本明細書中、「置換基を有するアミノ基」とは、前記の「置換基を有していてもよい炭化水素基」、後述する「アシル基」および前記の「置換基を有していてもよい５員または６員複素環基」から選ばれる置換基を１または２個有するアミノ基が挙げられる。置換基が２個である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “amino group optionally having a substituent” includes an amino group and an amino group having a substituent.
In the present specification, the “amino group having a substituent” means the above-mentioned “hydrocarbon group which may have a substituent”, the “acyl group” described later, and the “having a substituent”. And an amino group having 1 or 2 substituents selected from “an optional 5-membered or 6-membered heterocyclic group”. When there are two substituents, each substituent may be the same or different.
　本明細書中、「アシル基」としては、「置換基を有していてもよいアルキルカルボニル基」、「置換基を有していてもよいアルケニルカルボニル基」、「置換基を有していてもよいアルキニルカルボニル基」、「置換基を有していてもよいアラルキルカルボニル基」、「置換基を有していてもよいアリールカルボニル基」、「置換基を有していてもよいシクロアルキルカルボニル基」、「置換基を有していてもよいアルコキシカルボニル基」、「置換基を有していてもよいアルケニルオキシカルボニル基」、「置換基を有していてもよいアルキニルオキシカルボニル基」、「置換基を有していてもよいアラルキルオキシカルボニル基」、「置換基を有していてもよいアリールオキシカルボニル基」、「置換基を有していてもよいシクロアルキルオキシカルボニル基」および「カルボキシル基」等が挙げられる。
　本明細書中、「置換基を有していてもよいアルキルカルボニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ１－６アルキル－カルボニル基（例、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、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、ペンチルカルボニル、ヘキシルカルボニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアルケニルカルボニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ２－６アルケニル－カルボニル基（例、ビニルカルボニル、１－プロペニルカルボニル、アリルカルボニル、イソプロペニルカルボニル、ブテニルカルボニル、イソブテニルカルボニル等）等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアルキニルカルボニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ２－６アルキニル－カルボニル基（例、エチニルカルボニル、プロパルギルカルボニル、ブチニルカルボニル、１－ヘキシニルカルボニル等）等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “acyl group” includes “an alkylcarbonyl group which may have a substituent”, “an alkenylcarbonyl group which may have a substituent”, “a substituent which has a substituent”. May be an alkynylcarbonyl group ”,“ aralkylcarbonyl group optionally having substituent (s) ”,“ arylcarbonyl group optionally having substituent (s) ”,“ cycloalkylcarbonyl optionally having substituent (s) ” Group "," optionally substituted alkoxycarbonyl group "," optionally substituted alkenyloxycarbonyl group "," optionally substituted alkynyloxycarbonyl group ", "Aralkyloxycarbonyl group which may have a substituent", "aryloxycarbonyl group which may have a substituent", "cycloalkyl which may have a substituent" Oxycarbonyl group "and" carboxyl group ", and the like.
In the present specification, the “alkylcarbonyl group optionally having substituent (s)” is the substituent that the alkyl group of the “alkyl group optionally having substituent (s)” may have. C 1-6 alkyl-carbonyl group which may have 1 to 4, preferably 1 to 3 (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl) Tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl, etc.). When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “optionally substituted alkenylcarbonyl group” refers to the substituent that the alkyl group of the above “optionally substituted alkyl group” may have. C 2-6 alkenyl-carbonyl group which may have 1 to 4, preferably 1 to 3 (eg vinylcarbonyl, 1-propenylcarbonyl, allylcarbonyl, isopropenylcarbonyl, butenylcarbonyl, isobutenyl) Carbonyl etc.). When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “optionally substituted alkynylcarbonyl group” is the substituent that the alkyl group of the above “optionally substituted alkyl group” may have. Examples thereof include a C 2-6 alkynyl-carbonyl group (eg, ethynylcarbonyl, propargylcarbonyl, butynylcarbonyl, 1-hexynylcarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアラルキルカルボニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ７－１２アラルキル－カルボニル基（例、ベンジルカルボニル、２－フェニルエチルカルボニル、１－フェニルエチルカルボニル、３－フェニルプロピルカルボニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアリールカルボニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ６－１４アリール－カルボニル基（例、フェニルカルボニル、ナフチルカルボニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいシクロアルキルカルボニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ３－８シクロアルキル－カルボニル基（例、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。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “aralkylcarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. C 7-12 aralkyl-carbonyl group (eg, benzylcarbonyl, 2-phenylethylcarbonyl, 1-phenylethylcarbonyl, 3-phenylpropylcarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3 Is mentioned. When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “arylcarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. Examples thereof include a C 6-14 aryl-carbonyl group (eg, phenylcarbonyl, naphthylcarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “cycloalkylcarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. A C 3-8 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl) which may have 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアルコキシカルボニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ１－６アルコキシ－カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、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、ペントキシカルボニル、ヘキシロキシカルボニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアルケニルオキシカルボニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ２－６アルケニル－オキシカルボニル基（例、ビニルオキシカルボニル、１－プロペニルオキシカルボニル、アリルオキシカルボニル、イソプロペニルオキシカルボニル、ブテニルオキシカルボニル、イソブテニルオキシカルボニル等）等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアルキニルオキシカルボニル基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ２－６アルキニル－オキシカルボニル基（例、エチニルオキシカルボニル、プロパルギルオキシカルボニル、ブチニルオキシカルボニル、１－ヘキシニルオキシカルボニル等）等が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “alkoxycarbonyl group optionally having substituent (s)” is the substituent that the alkyl group of the “alkyl group optionally having substituent (s)” may have. C 1-6 alkoxy-carbonyl group which may have 1 to 4, preferably 1 to 3 (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- Butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, etc.). When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “optionally substituted alkenyloxycarbonyl group” is the substituent that the alkyl group of the above “optionally substituted alkyl group” may have. A C 2-6 alkenyl-oxycarbonyl group which may have 1 to 4, preferably 1 to 3 (eg, vinyloxycarbonyl, 1-propenyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, Tenenyloxycarbonyl, isobutenyloxycarbonyl and the like). When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “optionally substituted alkynyloxycarbonyl group” is the substituent that the alkyl group of the above “optionally substituted alkyl group” may have. C 2-6 alkynyl-oxycarbonyl group (eg, ethynyloxycarbonyl, propargyloxycarbonyl, butynyloxycarbonyl, 1-hexynyloxycarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3 ) And the like. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「置換基を有していてもよいアラルキルオキシカルボニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ７－１２アラルキル－オキシカルボニル基（例、ベンジルオキシカルボニル、２－フェニルエチルオキシカルボニル、１－フェニルエチルオキシカルボニル、３－フェニルプロピルオキシカルボニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいアリールオキシカルボニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ６－１４アリール－オキシカルボニル基（例、フェニルオキシカルボニル、ナフチルオキシカルボニル等）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。
　本明細書中、「置換基を有していてもよいシクロアルキルオキシカルボニル基」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよいＣ３－８シクロアルキル－オキシカルボニル基（例、シクロプロピルオキシカルボニル、シクロブチルオキシカルボニル、シクロペンチルオキシカルボニル、シクロヘキシルオキシカルボニル）が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “aralkyloxycarbonyl group optionally having substituent (s)” may be the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. A C 7-12 aralkyl-oxycarbonyl group (eg, benzyloxycarbonyl, 2-phenylethyloxycarbonyl, 1-phenylethyloxycarbonyl, 3-phenyl) which may have 1 to 4, preferably 1 to 3 Phenylpropyloxycarbonyl and the like). When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “aryloxycarbonyl group optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have. And C 6-14 aryl-oxycarbonyl group (eg, phenyloxycarbonyl, naphthyloxycarbonyl, etc.) optionally having 1 to 4, preferably 1 to 3. When there are two or more substituents, each substituent may be the same or different.
In the present specification, the “optionally substituted cycloalkyloxycarbonyl group” is an optionally substituted aralkyl group of the above “optionally substituted aralkyl group”. C 3-8 cycloalkyl-oxycarbonyl group which may have 1 to 4, preferably 1 to 3 groups (eg, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl) Is mentioned. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「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。 In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　本明細書中、「置換基を有していてもよいベンゼン環」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし５個、好ましくは１ないし４個、より好ましくは１ないし３個有していてもよいベンゼン環が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。あるいは、隣接する置換基が互いに結合し、５ないし８員の芳香族複素環（例、ピロール環等）を形成してもよい。 In the present specification, the “benzene ring optionally having substituent (s)” is the substituent that the aralkyl group of the “aralkyl group optionally having substituent (s)” may have is 1 The benzene ring which may have 5 thru | or 5, Preferably 1 thru | or 4, More preferably 1 thru | or 3 is mentioned. When there are two or more substituents, each substituent may be the same or different. Alternatively, adjacent substituents may be bonded to each other to form a 5- to 8-membered aromatic heterocyclic ring (eg, pyrrole ring).
　本明細書中、「置換基を有していてもよい６員芳香族複素環」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよい、上記の「置換基を有していてもよい５員または６員複素環基」で例示した「６員の芳香族複素環基」に相当する６員芳香族複素環が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “6-membered aromatic heterocycle optionally having substituent (s)” may have the aralkyl group of the “aralkyl group optionally having substituent (s)” described above. “6-membered fragrance” exemplified in the above-mentioned “optionally substituted 5- or 6-membered heterocyclic group” which may have 1 to 4, preferably 1 to 3 substituents A 6-membered aromatic heterocyclic ring corresponding to “group heterocyclic group”. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「さらに置換基を有していても良い縮合二環性複素環」としては、上記の「置換基を有していてもよいアラルキル基」のアラルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよい、Ａ環であるベンゼン環または６員芳香族複素環と、Ｘとしての硫黄原子以外に１個の窒素原子を有していてもよい５員～８員の非芳香族複素環（例、テトラヒドロチオフェン環、テトラヒドロチオピラン環）との縮合環が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, the “fused bicyclic heterocyclic ring optionally having substituent (s)” may be the aralkyl group of the above “aralkyl group optionally having substituent (s)”. A benzene ring or 6-membered aromatic heterocyclic ring which may have 1 to 4, preferably 1 to 3 good substituents, and a nitrogen atom in addition to the sulfur atom as X Examples thereof include a condensed ring with a 5-membered to 8-membered non-aromatic heterocyclic ring (eg, tetrahydrothiophene ring, tetrahydrothiopyran ring) which may have. When there are two or more substituents, each substituent may be the same or different.
　本明細書中、「オキソ基以外の置換基を有していても良いメチレン基」、「オキソ基以外の置換基を有していても良いエチレン基」および「オキソ基以外の置換基を有していても良いプロピレン基」としては、上記の「置換基を有していてもよいアルキル基」のアルキル基が有していてもよい置換基を１ないし４個、好ましくは１ないし３個有していてもよい、メチレン基、エチレン基およびプロピレン基が挙げられる。置換基が２個以上である場合、各置換基は同一でも異なっていてもよい。 In the present specification, “methylene group which may have a substituent other than oxo group”, “ethylene group which may have a substituent other than oxo group” and “a substituent other than oxo group”. The “optionally substituted propylene group” is 1 to 4, preferably 1 to 3 substituents that the alkyl group of the above-mentioned “optionally substituted alkyl group” may have. The methylene group, ethylene group, and propylene group which may have are mentioned. When there are two or more substituents, each substituent may be the same or different.
　次に、化合物（Ｉ）について説明する。
　Ａ環は、置換基を有していても良いベンゼン環または置換基を有していても良い６員芳香族複素環を示す。
　Ａ環で表される６員芳香族複素環は、好ましくはピリジン環である。
　Ａ環で表される「置換基を有していても良いベンゼン環または置換基を有していても良い６員芳香族複素環」の「ベンゼン環」または「６員芳香族複素環」は、「－Ｘ－Ｚ基」および「－ＹＲ１Ｒ２－基」以外に、置換可能な位置にさらに１ないし４個の置換基を有していてもよい。
　Ａ環の置換基としては、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、水酸基、ハロゲン原子、水酸基、Ｃ１－６アルコキシ基、アミノ基、モノ－またはジ－Ｃ１－６アルキルアミノ基、Ｃ１－６アルキル－カルボニルアミノ基、モノ－またはジ－Ｃ１－６アルキル－カルバモイル基、および複素環基から選ばれる置換基で置換されていてもよいＣ１－６アルキル基（例、メチル基、イソプロピル基、トリフルオロメチル基、ヒロドキシメチル基、メトキシメチル基、アミノメチル基、メチルアミノメチル基、アセチルアミノメチル基、メチルカルバモイルエチル基、ピロリジニルメチル基）、ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルコキシ－カルボニル基およびカルバモイル基から選ばれる置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペントキシ基、ヘキソキシ基、トリフルオロメトキシ基、２，２，２－トリフルオロエトキシ基、メトキシエトキシ基、メトキシカルボニルメトキシ基、カルバモイルメトキシ基）、Ｃ６－１４アリール基（例、フェニル基）、シアノ基、アミノ基、モノ－またはジ－Ｃ１－６アルキルアミノ基（例、メチルアミノ基、エチルアミノ基、イソプロピルアミノ基、ジメチルアミノ基）、Ｃ１－６アルキル－カルボニルアミノ基（例、アセチルアミノ基）、カルバモイル基、Ｃ１－６アルキルチオ基（例、メチルチオ基）、Ｃ１－６アルキルスルホニル基（例、メチルスルホニル基）、５ないし８員の非芳香族複素環基（例、モルホリニル基）、５ないし８員の芳香族複素環基（例、ピラゾリル基、イミダゾリル基）、Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ基）、Ｃ３－８シクロアルキルアミノ基（例、シクロプロピルアミノ基）、Ｃ１－６アルコキシ－カルボニル基で置換されていてもよいＣ２－６アルケニル基（例、イソプロペニル基、メトキシカルボニルビニル基）が好ましく、フッ素原子、塩素原子およびメトキシ基がより好ましい。 Next, compound (I) will be described.
A ring shows the benzene ring which may have a substituent, or the 6-membered aromatic heterocyclic ring which may have a substituent.
The 6-membered aromatic heterocycle represented by the A ring is preferably a pyridine ring.
“Benzene ring” or “6-membered aromatic heterocycle” of “benzene ring which may have a substituent or 6-membered aromatic heterocycle which may have a substituent” represented by ring A is In addition to the “—XZ group” and the “—YR 1 R 2 — group”, they may further have 1 to 4 substituents at substitutable positions.
Examples of the substituent on the A ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxyl group, halogen atom, hydroxyl group, C 1-6 alkoxy group, amino group, mono- or di-C 1 -6 alkylamino group, C 1-6 alkyl - carbonyl amino group, mono - or di -C 1-6 alkyl - carbamoyl group, and optionally substituted with a substituent selected from the heterocyclic groups C 1-6 Alkyl group (eg, methyl group, isopropyl group, trifluoromethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, acetylaminomethyl group, methylcarbamoylethyl group, pyrrolidinylmethyl group), halogen A substituent selected from an atom, a C 1-6 alkoxy group, a C 1-6 alkoxy-carbonyl group and a carbamoyl group C 1-6 alkoxy group optionally substituted by (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group) Group, hexoxy group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, methoxyethoxy group, methoxycarbonylmethoxy group, carbamoylmethoxy group), C 6-14 aryl group (eg, phenyl group), cyano group Amino group, mono- or di-C 1-6 alkylamino group (eg, methylamino group, ethylamino group, isopropylamino group, dimethylamino group), C 1-6 alkyl-carbonylamino group (eg, acetylamino) group), a carbamoyl group, C 1-6 alkylthio group (e.g., methylthio group), C 1-6 alkyl A sulfonyl group (e.g., methylsulfonyl group), a non-aromatic Hajime Tamaki 5- to 8-membered (eg, morpholinyl group), a 5- to 8-membered aromatic Hajime Tamaki (e.g., a pyrazolyl group, an imidazolyl group), C 1 -6 alkylsulfonylamino group (e.g., methylsulfonylamino group), C 3-8 cycloalkylamino group (e.g., cyclopropylamino group), C 1-6 alkoxy - optionally substituted with a carbonyl group C 2- A 6 alkenyl group (eg, isopropenyl group, methoxycarbonylvinyl group) is preferable, and a fluorine atom, a chlorine atom and a methoxy group are more preferable.
　Ｂ環は、置換基を有していても良いベンゼン環を示す。
　Ｂ環で表される「置換基を有していても良いベンゼン環」の「ベンゼン環」は、「－Ｏ－基」以外に、置換可能な位置にさらに１ないし５個（好ましくは１ないし３個）の置換基を有していてもよい。
　Ｂ環の置換基としては、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、ハロゲン原子で置換されていてもよいＣ１－６アルキル基（例、メチル基、トリフルオロメチル基）、Ｃ１－６アルコキシ基（例、メトキシ基）、Ｃ１－６アルキルチオ基（例、メチルチオ基）、シアノ基が好ましく、フッ素原子および塩素原子がより好ましい。
　あるいは、隣接する置換基が互いに結合し、５ないし８員の芳香族複素環（例、ピロール環）を形成する場合も好ましい。 Ring B represents a benzene ring which may have a substituent.
In addition to the “—O— group”, the “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring B is further 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present.
Examples of the substituent on the B ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl group optionally substituted with a halogen atom (eg, methyl group, trifluoromethyl). Group), a C 1-6 alkoxy group (eg, methoxy group), a C 1-6 alkylthio group (eg, methylthio group) and a cyano group are preferred, and a fluorine atom and a chlorine atom are more preferred.
Alternatively, it is also preferable when adjacent substituents are bonded to each other to form a 5- to 8-membered aromatic heterocyclic ring (eg, pyrrole ring).
　Ｌ１は、結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示す。
　Ｌ１としては、結合手、メチレン基およびエチレン基が好ましい。
　Ｌ２は、オキソ基以外の置換基を有していても良いエチレン基を示す。
　Ｌ２としては、エチレン基が好ましい。 L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. The propylene group which may be sufficient is shown.
L 1 is preferably a bond, a methylene group or an ethylene group.
L 2 represents an ethylene group which may have a substituent other than an oxo group.
L 2 is preferably an ethylene group.
　Ｘは、Ｓ、ＳＯ、又はＳＯ２を示す。
　Ｘとしては、ＳＯ２が好ましい。
　Ｙは、炭素原子を示す。 X represents S, SO, or SO 2 .
X is preferably SO 2 .
Y represents a carbon atom.
　Ｚは、（１）置換基を有していても良い炭化水素基（但し、ＸがＳの時は（ヒドロキシメチル)フェニル基、アミノフェニル基、及びメトキシフェニル基を除く）、（２）置換基を有していても良いアミノ基、又は（３）置換基を有していても良い５員または６員複素環基を示すか、あるいは（４）Ｙと結合して、Ａ環と共にさらに置換基を有していても良い縮合二環性複素環を形成してもよい。
　Ｚとしては、置換基を有していても良いＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換基を有していてもよいＣ６－１４アリール基（例、フェニル基）、１ないし２個のＣ１－６アルキル基（例、メチル基）を有していてもよいアミノ基、および置換基を有していても良い５員または６員の非芳香族複素環基（例、モルホリノ基）が好ましく、メチル基、エチル基、イソプロピル基、アミノ基、メチルアミノ基、ジメチルアミノ基およびモルホリノ基がより好ましい。
　また、Ｚとしては、Ｙと結合して、Ａ環と共にさらに置換基を有していても良いジヒドロベンゾチオフェン環またはジヒドロチオクロメン環を形成しているのが好ましい。 Z is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) substituted An amino group which may have a group, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent, or (4) bonded to Y and further together with A ring A condensed bicyclic heterocyclic ring which may have a substituent may be formed.
Z is a C 1-6 alkyl group which may have a substituent (eg, methyl group, ethyl group, isopropyl group), or a C 6-14 aryl group which may have a substituent (eg, phenyl group), 1 to 2 C 1-6 alkyl groups (e.g., non-aromatic methyl group) amino group which may have a, and may have a substituent 5- or 6-membered A heterocyclic group (eg, morpholino group) is preferred, and a methyl group, ethyl group, isopropyl group, amino group, methylamino group, dimethylamino group and morpholino group are more preferred.
Z is preferably bonded to Y to form a dihydrobenzothiophene ring or dihydrothiochromene ring which may further have a substituent together with the A ring.
　Ｒ１及びＲ２は、同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示すか、あるいは互いに結合してＹと共に置換基を有していても良いシクロプロピル若しくは置換基を有していても良いシクロブチルを形成しても良い（但し、ＺがＹと結合する時にはＲ１は存在しない）。
　Ｒ１及びＲ２としては、同一または異なって、水素原子およびＣ１－６アルキル基（例、メチル基）が好ましく、両方とも水素原子、および一方が水素原子で他方がメチル基であるのがより好ましい。 R 1 and R 2 may be the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent, or may be bonded to each other and have a substituent together with Y. Good cyclopropyl or optionally substituted cyclobutyl may be formed (provided that when Z is bound to Y, R 1 is not present).
R 1 and R 2 are the same or different and are preferably a hydrogen atom and a C 1-6 alkyl group (eg, a methyl group), both of which are a hydrogen atom, and one is a hydrogen atom and the other is a methyl group. More preferred.
　化合物（Ｉ）としては、
　Ａ環が、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）およびＣ１－６アルコキシ基（例、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペントキシ基、ヘキソキシ基）から選ばれる置換基を有していてもよいベンゼン環またはピリジン環であり；
　Ｂ環が、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）から選ばれる置換基を有していてもよいベンゼン環であり；
　Ｌ１が、結合手、メチレン基またはエチレン基であり；
　Ｌ２が、エチレン基であり；
　Ｘが、ＳＯ２であり；
　Ｙが、炭素原子であり；
　Ｚが、置換基を有していても良いＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換基を有していてもよいＣ６－１４アリール基（例、フェニル基）、１ないし２個のＣ１－６アルキル基（例、メチル基）を有するアミノ基、または置換基を有していても良い５員または６員の非芳香族複素環基（例、モルホリノ基）であるか、あるいはＹと結合して、Ａ環と共にさらに置換基を有していても良いジヒドロベンゾチオフェン環またはジヒドロチオクロメン環を形成しており；および
　Ｒ１及びＲ２が、同一または異なって、水素原子またはＣ１－６アルキル基（例、メチル基）である、
化合物が好ましい。 As compound (I),
A ring is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group) A benzene ring or a pyridine ring optionally having a substituent selected from an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentoxy group, and a hexoxy group;
Ring B is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
L 1 is a bond, a methylene group or an ethylene group;
L 2 is an ethylene group;
X is SO 2 ;
Y is a carbon atom;
Z is a C 1-6 alkyl group which may have a substituent (eg, methyl group, ethyl group, isopropyl group), a C 6-14 aryl group which may have a substituent (eg, phenyl) Group) an amino group having 1 to 2 C 1-6 alkyl groups (eg, methyl group), or an optionally substituted 5- or 6-membered non-aromatic heterocyclic group (eg, A morpholino group) or a dihydrobenzothiophene ring or a dihydrothiochromene ring which may be further substituted with the A ring by binding to Y; and R 1 and R 2 are The same or different and a hydrogen atom or a C 1-6 alkyl group (eg, methyl group),
Compounds are preferred.
　別の態様において、化合物（Ｉ）としては、
　Ａ環は置換基を有していても良いベンゼン環、又はピリジン環を示し；
　Ｂ環は置換基を有していても良いベンゼン環を示し；
　Ｌ１は結合手、メチレン基又はエチレン基を示し；
　Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｙは炭素原子を示し；
　Ｚは（１）Ｃ１－６アルキル基、(２)フェニル基、（３）置換基を有していても良いアミノ基、または(４)モルホリノ基を示すか、あるいは（５）Ｙと結合して、Ａ環と共にさらに置換基を有していても良いジヒドロチオクロメン環を形成してもよく、
　Ｒ１は水素原子を示し；および
　Ｒ２は水素原子またはＣ１－６アルキル基を示す（但し、ＺがＹと結合する時にはＲ１は存在せず、かつＲ２は水素原子を示す）、
化合物、又はその塩が好ましい。 In another embodiment, the compound (I) includes
Ring A represents an optionally substituted benzene ring or pyridine ring;
Ring B represents an optionally substituted benzene ring;
L 1 represents a bond, a methylene group or an ethylene group;
L 2 represents an ethylene group which may have a substituent other than an oxo group;
X represents SO 2 ;
Y represents a carbon atom;
Z represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group, or (5) bonded to Y A dihydrothiochromene ring which may further have a substituent together with the A ring,
R 1 represents a hydrogen atom; and R 2 represents a hydrogen atom or a C 1-6 alkyl group (provided that when Z is bonded to Y, R 1 is not present and R 2 represents a hydrogen atom),
A compound or a salt thereof is preferred.
　化合物（Ｉ）としては、実施例１～１１１の化合物がより好ましい。 As the compound (I), the compounds of Examples 1-111 are more preferable.
　化合物（Ｉ）のうち、ＺがＹと結合して、Ａ環と共にさらに置換基を有していても良い縮合二環性複素環を形成している場合、化合物（ＩＩ）が好ましい。
　以下、化合物（ＩＩ）について説明する。
　Ａ環は、置換基を有していても良いベンゼン環または置換基を有していても良い６員芳香族複素環を示す。
　Ａ環で表される「置換基を有していても良いベンゼン環または置換基を有していても良い６員芳香族複素環」の「ベンゼン環」または「６員芳香族複素環」は、置換可能な位置に１ないし４個の置換基を有していてもよい。
　Ａ環としては、置換基を有していても良いベンゼン環が好ましい。
　Ａ環の置換基としては、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、水酸基、ハロゲン原子、水酸基、Ｃ１－６アルコキシ基、アミノ基、モノ－またはジ－Ｃ１－６アルキルアミノ基、Ｃ１－６アルキル－カルボニルアミノ基、モノ－またはジ－Ｃ１－６アルキル－カルバモイル基、および複素環基から選ばれる置換基で置換されていてもよいＣ１－６アルキル基（例、メチル基、イソプロピル基、トリフルオロメチル基、ヒロドキシメチル基、メトキシメチル基、アミノメチル基、メチルアミノメチル基、アセチルアミノメチル基、メチルカルバモイルエチル基、ピロリジニルメチル基）、ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルコキシ－カルボニル基およびカルバモイル基から選ばれる置換基で置換されていてもよいＣ１－６アルコキシ基（例、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペントキシ基、ヘキソキシ基、トリフルオロメトキシ基、２，２，２－トリフルオロエトキシ基、メトキシエトキシ基、メトキシカルボニルメトキシ基、カルバモイルメトキシ基）、Ｃ６－１４アリール基（例、フェニル基）、シアノ基、アミノ基、モノ－またはジ－Ｃ１－６アルキルアミノ基（例、メチルアミノ基、エチルアミノ基、イソプロピルアミノ基、ジメチルアミノ基）、Ｃ１－６アルキル－カルボニルアミノ基（例、アセチルアミノ基）、カルバモイル基、Ｃ１－６アルキルチオ基（例、メチルチオ基）、Ｃ１－６アルキルスルホニル基（例、メチルスルホニル基）、５ないし８員の非芳香族複素環基（例、モルホリニル基）、５ないし８員の芳香族複素環基（例、ピラゾリル基、イミダゾリル基）、Ｃ１－６アルキルスルホニルアミノ基（例、メチルスルホニルアミノ基）、Ｃ３－８シクロアルキルアミノ基（例、シクロプロピルアミノ基）、Ｃ１－６アルコキシ－カルボニル基で置換されていてもよいＣ２－６アルケニル基（例、イソプロペニル基、メトキシカルボニルビニル基）が好ましく、塩素原子がより好ましい。 Among the compounds (I), when Z is bonded to Y to form a condensed bicyclic heterocyclic ring which may further have a substituent together with the A ring, the compound (II) is preferable.
Hereinafter, compound (II) is demonstrated.
A ring shows the benzene ring which may have a substituent, or the 6-membered aromatic heterocyclic ring which may have a substituent.
“Benzene ring” or “6-membered aromatic heterocycle” of “benzene ring which may have a substituent or 6-membered aromatic heterocycle which may have a substituent” represented by ring A is , It may have 1 to 4 substituents at substitutable positions.
As ring A, a benzene ring which may have a substituent is preferable.
Examples of the substituent on the A ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxyl group, halogen atom, hydroxyl group, C 1-6 alkoxy group, amino group, mono- or di-C 1 -6 alkylamino group, C 1-6 alkyl - carbonyl amino group, mono - or di -C 1-6 alkyl - carbamoyl group, and optionally substituted with a substituent selected from the heterocyclic groups C 1-6 Alkyl group (eg, methyl group, isopropyl group, trifluoromethyl group, hydroxymethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, acetylaminomethyl group, methylcarbamoylethyl group, pyrrolidinylmethyl group), halogen A substituent selected from an atom, a C 1-6 alkoxy group, a C 1-6 alkoxy-carbonyl group and a carbamoyl group C 1-6 alkoxy group optionally substituted by (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group) Group, hexoxy group, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, methoxyethoxy group, methoxycarbonylmethoxy group, carbamoylmethoxy group), C 6-14 aryl group (eg, phenyl group), cyano group Amino group, mono- or di-C 1-6 alkylamino group (eg, methylamino group, ethylamino group, isopropylamino group, dimethylamino group), C 1-6 alkyl-carbonylamino group (eg, acetylamino) group), a carbamoyl group, C 1-6 alkylthio group (e.g., methylthio group), C 1-6 alkyl A sulfonyl group (e.g., methylsulfonyl group), a non-aromatic Hajime Tamaki 5- to 8-membered (eg, morpholinyl group), a 5- to 8-membered aromatic Hajime Tamaki (e.g., a pyrazolyl group, an imidazolyl group), C 1 -6 alkylsulfonylamino group (e.g., methylsulfonylamino group), C 3-8 cycloalkylamino group (e.g., cyclopropylamino group), C 1-6 alkoxy - optionally substituted with a carbonyl group C 2- A 6 alkenyl group (eg, isopropenyl group, methoxycarbonylvinyl group) is preferred, and a chlorine atom is more preferred.
　Ｂ環は、置換基を有していても良いベンゼン環を示す。
　Ｂ環で表される「置換基を有していても良いベンゼン環」の「ベンゼン環」は、「－Ｏ－基」以外に、置換可能な位置にさらに１ないし５個（好ましくは１ないし３個）の置換基を有していてもよい。
　Ｂ環の置換基としては、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、ハロゲン原子で置換されていてもよいＣ１－６アルキル基（例、メチル基、トリフルオロメチル基）、Ｃ１－６アルコキシ基（例、メトキシ基）、Ｃ１－６アルキルチオ基（例、メチルチオ基）、シアノ基が好ましく、フッ素原子および塩素原子がより好ましい。
　あるいは、隣接する置換基が互いに結合し、５ないし８員の芳香族複素環（例、ピロール環）を形成する場合も好ましい。 Ring B represents a benzene ring which may have a substituent.
In addition to the “—O— group”, the “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring B is further 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present.
Examples of the substituent on the B ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl group optionally substituted with a halogen atom (eg, methyl group, trifluoromethyl). Group), a C 1-6 alkoxy group (eg, methoxy group), a C 1-6 alkylthio group (eg, methylthio group) and a cyano group are preferred, and a fluorine atom and a chlorine atom are more preferred.
Alternatively, it is also preferable when adjacent substituents are bonded to each other to form a 5- to 8-membered aromatic heterocyclic ring (eg, pyrrole ring).
　Ｌ１は、結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示す。
　Ｌ１としては、結合手が好ましい。
　Ｌ２は、オキソ基以外の置換基を有していても良いエチレン基を示す。
　Ｌ２としては、エチレン基が好ましい。
　Ｘは、Ｓ、ＳＯ、又はＳＯ２を示す。
　Ｘとしては、ＳＯ２が好ましい。 L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. The propylene group which may be sufficient is shown.
L 1 is preferably a bond.
L 2 represents an ethylene group which may have a substituent other than an oxo group.
L 2 is preferably an ethylene group.
X represents S, SO, or SO 2 .
X is preferably SO 2 .
　Ｚ’は、ＣＲ４（Ｒ４は、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示す。）、又はＮを示す。
　Ｚ’としては、ＣＲ４が好ましく、Ｒ４としては、水素原子が好ましい。 Z ′ represents CR 4 (R 4 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group) or N.
Z ′ is preferably CR 4 , and R 4 is preferably a hydrogen atom.
　Ｒ２及びＲ３は、同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示す。
　Ｒ２及びＲ３としては、両方とも水素原子であるのが好ましい。
　ｎは０ないし３の整数を示す。
　ｎとしては、０または１が好ましい。 R 2 and R 3 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent.
R 2 and R 3 are preferably both hydrogen atoms.
n represents an integer of 0 to 3.
n is preferably 0 or 1.
　化合物（ＩＩ）としては、
　Ａ環が、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）から選ばれる置換基を有していてもよいベンゼン環であり；
　Ｂ環が、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）から選ばれる置換基を有していてもよいベンゼン環であり；
　Ｌ１が、結合手であり；
　Ｌ２が、エチレン基であり；
　Ｘが、ＳＯ２であり；
　Ｚ’が、ＣＨであり；
　Ｒ２及びＲ３が、両方とも水素原子であり；および
　ｎが、０または１である、
化合物が好ましい。
　別の態様において、化合物（ＩＩ）としては、以下の化合物（ＩＩ－ａ）、（ＩＩ－ｂ）、化合物（ＩＩ－ｃ）、化合物（ＩＩ－ｄ）、化合物（ＩＩ－ｅ）が好ましい。
〔化合物（ＩＩ－ａ）〕
　化合物（ＩＩ）であって、
　Ａ環は置換基を有していても良いベンゼン環を示し；
　Ｂ環は置換基を有していても良いベンゼン環を示し；
　Ｌ１は結合手を示し；
　Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’はＣＲ４、又はＮを示し；
　Ｒ２及びＲ３は水素原子を示し；
　Ｒ４は、水素原子または置換基を有していても良いＣ１－６アルキル基を示し；
　ｎは０、１または２を示す、
化合物、又はその塩。
　化合物（ＩＩ－ａ）において、ｎは１であることが好ましい。 As compound (II),
Ring A is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
Ring B is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
L 1 is a bond;
L 2 is an ethylene group;
X is SO 2 ;
Z ′ is CH;
R 2 and R 3 are both hydrogen atoms; and n is 0 or 1.
Compounds are preferred.
In another embodiment, the compound (II) is preferably the following compound (II-a), (II-b), compound (II-c), compound (II-d), or compound (II-e).
[Compound (II-a)]
Compound (II),
Ring A represents an optionally substituted benzene ring;
Ring B represents an optionally substituted benzene ring;
L 1 represents a bond;
L 2 represents an ethylene group which may have a substituent other than an oxo group;
X represents SO 2 ;
Z ′ represents CR 4 or N;
R 2 and R 3 represent a hydrogen atom;
R 4 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
n represents 0, 1 or 2;
Compound or salt thereof.
In the compound (II-a), n is preferably 1.
〔化合物（ＩＩ－ｂ）〕
　化合物（ＩＩ－ａ）であって、
　Ａ環は、
　（１）ハロゲン原子、（２）ヒドロキシ基、（３）シアノ基、（４）フェニル基、（５）Ｃ１－６アルキルチオ基、（６）Ｃ１－６アルコキシカルボニル－Ｃ2－６アルケニル基、（７）Ｃ１－６アルキルスルホニル基、（８）モルホリノ基、（９）Ｃ１－６アルキル基、Ｃ２－６シクロアルキル基、Ｃ１－６アルキルカルボニル基、およびＣ１－６アルキルスルホニル基から選択される１または２個の置換基で置換されていてもよいアミノ基、（１０）ハロゲン原子、Ｃ１－６アルコキシ基、Ｃ１－６アルコキシ－カルボニル基およびカルバモイル基から選択される置換基で置換されていてもよいＣ１－６アルコキシ基、および（１１）ハロゲン原子、ヒドロキシ基、ピロリジニル基、Ｃ１－６アルコキシ基、モノまたはジ－Ｃ１－６アルキル－カルバモイル基、Ｃ１－６アルキルカルボニルアミノ基、アミノ基およびＣ１－６アルケニル基から選択される置換基で置換されていてもよいＣ１－６アルキル基、
から選択される１または２個の置換基で置換されていても良いベンゼン環を示し；
　Ｂ環は、（１）ハロゲン原子、（２）シアノ基、（３）ハロゲン原子で置換されていてもよいＣ１－６アルキル基、（４）ベンジルオキシ基および（５）Ｃ１－６アルキルチオ基から選択される１または２個の置換基で置換されたベンゼン環を示し；
　Ｌ１は結合手を示し；
　Ｌ２はＣ１－６アルキル基で置換されていてもよいエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’はＣＲ４、又はＮを示し；
　Ｒ２及びＲ３は水素原子を示し；
　Ｒ４は、水素原子またはＣ１－６アルキル基を示す；
化合物、またはその塩。
　化合物（ＩＩ－ｂ）において、ｎは１であることが好ましい。 [Compound (II-b)]
Compound (II-a),
Ring A is
(1) halogen atom, (2) hydroxy group, (3) cyano group, (4) phenyl group, (5) C 1-6 alkylthio group, (6) C 1-6 alkoxycarbonyl-C 2-6 alkenyl group (7) C 1-6 alkylsulfonyl group, (8) morpholino group, (9) C 1-6 alkyl group, C 2-6 cycloalkyl group, C 1-6 alkylcarbonyl group, and C 1-6 alkyl Selected from an amino group optionally substituted with one or two substituents selected from a sulfonyl group, (10) a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxy-carbonyl group and a carbamoyl group that may be substituted with a substituent C 1-6 alkoxy group, and (11) a halogen atom, hydroxy group, a pyrrolidinyl group, C 1-6 alkoxy group, a mono- or di -C 1 6 alkyl - carbamoyl group, C 1-6 alkylcarbonylamino group, an amino group and a C 1-6 optionally substituted C 1-6 alkyl group with substituents selected from alkenyl,
A benzene ring optionally substituted by 1 or 2 substituents selected from:
Ring B includes (1) a halogen atom, (2) a cyano group, (3) an optionally substituted C 1-6 alkyl group, (4) a benzyloxy group, and (5) a C 1-6 alkylthio group. Represents a benzene ring substituted with one or two substituents selected from the group;
L 1 represents a bond;
L 2 represents an ethylene group which may be substituted with a C 1-6 alkyl group;
X represents SO 2 ;
Z ′ represents CR 4 or N;
R 2 and R 3 represent a hydrogen atom;
R 4 represents a hydrogen atom or a C 1-6 alkyl group;
Compound or salt thereof.
In the compound (II-b), n is preferably 1.
〔化合物（ＩＩ－ｃ）〕
　化合物（ＩＩ）であって、
　Ａ環は１個のモノ－Ｃ１－６アルキルアミノ基で置換されていても良いベンゼン環を示し；
　Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し；
　Ｌ１は結合手を示し；
　Ｌ２はエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’はＣＲ４を示し；
　Ｒ２、Ｒ３及びＲ４は、水素原子を示し；
　ｎは１を示す、
化合物またはその塩。 [Compound (II-c)]
Compound (II),
Ring A represents a benzene ring optionally substituted by one mono-C 1-6 alkylamino group;
Ring B represents a benzene ring substituted with two halogen atoms;
L 1 represents a bond;
L 2 represents an ethylene group;
X represents SO 2 ;
Z ′ represents CR 4 ;
R 2 , R 3 and R 4 represent a hydrogen atom;
n represents 1,
Compound or salt thereof.
〔化合物（ＩＩ－ｄ）〕
　化合物（ＩＩ）であって、
　Ａ環は置換基を有していても良いベンゼン環を示し；
　Ｂ環は置換基を有していても良いベンゼン環を示し；
　Ｌ１は結合手を示し；
　Ｌ２はエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’はＣＲ４、又はＮを示し；
　Ｒ２、Ｒ３及びＲ４は水素原子を示し；
　ｎは０、１または２を示す、
化合物、又はその塩。 [Compound (II-d)]
Compound (II),
Ring A represents an optionally substituted benzene ring;
Ring B represents an optionally substituted benzene ring;
L 1 represents a bond;
L 2 represents an ethylene group;
X represents SO 2 ;
Z ′ represents CR 4 or N;
R 2 , R 3 and R 4 represent a hydrogen atom;
n represents 0, 1 or 2;
Compound or salt thereof.
〔化合物（ＩＩ－ｅ）〕
　化合物（ＩＩ－ｄ）であって、
　Ａ環はハロゲン原子およびモノ－またはジ－Ｃ１－６アルキルアミノ基から選択される置換基で置換されていても良いベンゼン環を示し；
　Ｂ環はハロゲン原子で置換されたベンゼン環を示す、
化合物、又はその塩。
　化合物（ＩＩ－ｅ）において、Ａ環はハロゲン原子およびモノＣ１－６アルキルアミノ基から選択される１～３個（好ましくは１個）の置換基で置換されていても良いベンゼン環であり、Ｂ環は１～３個（好ましくは１個）のハロゲン原子で置換されたベンゼン環であることが好ましい。 [Compound (II-e)]
Compound (II-d),
Ring A represents a benzene ring optionally substituted with a substituent selected from a halogen atom and a mono- or di-C 1-6 alkylamino group;
Ring B represents a benzene ring substituted with a halogen atom,
Compound or salt thereof.
In compound (II-e), ring A is a benzene ring optionally substituted by 1 to 3 (preferably 1) substituents selected from a halogen atom and a mono C 1-6 alkylamino group The B ring is preferably a benzene ring substituted with 1 to 3 (preferably 1) halogen atoms.
　化合物（ＩＩ）としては、実施例９、１２、１８、２１～２６、３１～３４、３８～４７、４９～５６、５９～１１１の化合物がより好ましい。 As the compound (II), the compounds of Examples 9, 12, 18, 21 to 26, 31 to 34, 38 to 47, 49 to 56, 59 to 111 are more preferable.
　また、化合物（Ｉ）のうち、ＺとＹとが結合していない場合、化合物（ＩＩＩ）が好ましい。
　以下、化合物（ＩＩＩ）について説明する。
　Ａ環は、置換基を有していても良いベンゼン環または置換基を有していても良い６員芳香族複素環を示す。
　Ａ環で表される６員芳香族複素環は、好ましくはピリジン環である。
　Ａ環で表される「置換基を有していても良いベンゼン環または置換基を有していても良い６員芳香族複素環」の「ベンゼン環」または「６員芳香族複素環」は、「－Ｘ－Ｚ’’基」および「－ＣＲ１Ｒ２－基」以外に、置換可能な位置にさらに１ないし４個の置換基を有していてもよい。
　Ａ環の置換基としては、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、Ｃ１－６アルコキシ基（例、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペントキシ基、ヘキソキシ基）、シアノ基、および５ないし８員の非芳香族複素環基（例、モルホリニル基）が好ましく、フッ素原子、塩素原子およびメトキシ基がより好ましい。 Moreover, compound (III) is preferable when Z and Y do not couple | bond among compound (I).
Hereinafter, compound (III) is demonstrated.
A ring shows the benzene ring which may have a substituent, or the 6-membered aromatic heterocyclic ring which may have a substituent.
The 6-membered aromatic heterocycle represented by the A ring is preferably a pyridine ring.
“Benzene ring” or “6-membered aromatic heterocycle” of “benzene ring which may have a substituent or 6-membered aromatic heterocycle which may have a substituent” represented by ring A is In addition to the “—XZ ″ group” and the “—CR 1 R 2 — group”, they may further have 1 to 4 substituents at substitutable positions.
Examples of the substituent on the A ring include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, hexoxy group), cyano group, and 5- to 8-membered non-aromatic heterocyclic group (eg, morpholinyl group) are preferable. An atom, a chlorine atom and a methoxy group are more preferable.
　Ｂ環は、置換基を有していても良いベンゼン環を示す。
　Ｂ環で表される「置換基を有していても良いベンゼン環」の「ベンゼン環」は、「－Ｏ－基」以外に、置換可能な位置にさらに１ないし５個（好ましくは１ないし３個）の置換基を有していてもよい。
　Ｂ環の置換基としては、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）が好ましく、フッ素原子および塩素原子がより好ましい。 Ring B represents a benzene ring which may have a substituent.
In addition to the “—O— group”, the “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring B is further 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present.
As the substituent of the B ring, a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) is preferable, and a fluorine atom and a chlorine atom are more preferable.
　Ｌ１は、結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示す。
　Ｌ１としては、結合手、メチレン基およびエチレン基が好ましい。
　Ｌ２は、オキソ基以外の置換基を有していても良いエチレン基を示す。
　Ｌ２としては、エチレン基が好ましい。
　Ｘは、Ｓ、ＳＯ、又はＳＯ２を示す。
　Ｘとしては、ＳＯ２が好ましい。 L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. The propylene group which may be sufficient is shown.
L 1 is preferably a bond, a methylene group or an ethylene group.
L 2 represents an ethylene group which may have a substituent other than an oxo group.
L 2 is preferably an ethylene group.
X represents S, SO, or SO 2 .
X is preferably SO 2 .
　Ｚ’’は、（１）置換基を有していても良い炭化水素基（但し、ＸがＳの時は（ヒドロキシメチル)フェニル基、アミノフェニル基、及びメトキシフェニル基を除く）、（２）置換基を有していても良いアミノ基、又は（３）置換基を有していても良い５員または６員複素環基を示す。
　Ｚ’’としては、置換基を有していても良いＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換基を有していてもよいＣ６－１４アリール基（例、フェニル基）、１ないし２個のＣ１－６アルキル基（例、メチル基）を有するアミノ基、および置換基を有していても良い５員または６員の非芳香族複素環基（例、モルホリノ基）が好ましく、メチル基、エチル基、イソプロピル基、メチルアミノ基、ジメチルアミノ基およびモルホリノ基がより好ましい。 Z ″ is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group, and methoxyphenyl group are excluded), (2 ) An amino group which may have a substituent, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent.
Z ″ is an optionally substituted C 1-6 alkyl group (eg, a methyl group, ethyl group, isopropyl group), an optionally substituted C 6-14 aryl group ( Eg, phenyl group), an amino group having 1 to 2 C 1-6 alkyl groups (eg, a methyl group), and an optionally substituted 5- or 6-membered non-aromatic heterocyclic group (Eg, morpholino group) is preferable, and methyl group, ethyl group, isopropyl group, methylamino group, dimethylamino group and morpholino group are more preferable.
　Ｒ１及びＲ２は、同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示すか、あるいは互いに結合して隣接する炭素原子と共に置換基を有していても良いシクロプロピル若しくは置換基を有していても良いシクロブチルを形成しても良い。
　Ｒ１及びＲ２としては、同一または異なって、水素原子およびＣ１－６アルキル基（例、メチル基）が好ましく、両方とも水素原子、および一方が水素原子で他方がメチル基であるのがより好ましい。 R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, or have a substituent together with an adjacent carbon atom bonded to each other. Cyclopropyl which may be substituted or cyclobutyl which may have a substituent may be formed.
R 1 and R 2 are the same or different and are preferably a hydrogen atom and a C 1-6 alkyl group (eg, a methyl group), both of which are a hydrogen atom, and one is a hydrogen atom and the other is a methyl group. More preferred.
　化合物（ＩＩＩ）としては、
　Ａ環が、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）およびＣ１－６アルコキシ基（例、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペントキシ基、ヘキソキシ基）から選ばれる置換基を有していてもよいベンゼン環またはピリジン環であり；
　Ｂ環が、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）から選ばれる置換基を有していてもよいベンゼン環であり；
　Ｌ１が、結合手、メチレン基またはエチレン基であり；
　Ｌ２が、エチレン基であり；
　Ｘが、ＳＯ２であり；
　Ｚ’’が、置換基を有していても良いＣ１－６アルキル基（例、メチル基、エチル基、イソプロピル基）、置換基を有していてもよいＣ６－１４アリール基（例、フェニル基）、１ないし２個のＣ１－６アルキル基（例、メチル基）を有するアミノ基、または置換基を有していても良い５員または６員の非芳香族複素環基（例、モルホリノ基）であり；および
　Ｒ１及びＲ２が、同一または異なって、水素原子またはＣ１－６アルキル基（例、メチル基）である、
化合物が好ましい。 As compound (III),
A ring is a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and C 1-6 alkoxy group (eg, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group) A benzene ring or a pyridine ring optionally having a substituent selected from an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentoxy group, and a hexoxy group;
Ring B is a benzene ring which may have a substituent selected from halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom);
L 1 is a bond, a methylene group or an ethylene group;
L 2 is an ethylene group;
X is SO 2 ;
Z ″ is an optionally substituted C 1-6 alkyl group (eg, methyl group, ethyl group, isopropyl group), an optionally substituted C 6-14 aryl group (eg, A phenyl group), an amino group having 1 to 2 C 1-6 alkyl groups (eg, a methyl group), or a 5- or 6-membered non-aromatic heterocyclic group optionally having a substituent ( And R 1 and R 2 are the same or different and are a hydrogen atom or a C 1-6 alkyl group (eg, a methyl group),
Compounds are preferred.
　別の態様において、化合物（ＩＩＩ）としては、以下の化合物（ＩＩＩ－ａ）、化合物（ＩＩＩ－ｂ）、化合物（ＩＩＩ－ｃ）および化合物（ＩＩＩ－ｄ）が好ましい。
〔化合物（ＩＩＩ－ａ）〕
　化合物（ＩＩＩ）であって、
　Ａ環は置換基を有していても良いベンゼン環、又はピリジン環を示し；
　Ｂ環は置換基を有していても良いベンゼン環を示し；
　Ｌ１は結合手、メチレン基、またはエチレン基を示し；
　Ｌ２はエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）置換基を有していても良いアミノ基、又は（４）モルホリノ基を示し；
　Ｒ１及びＲ２は、両方とも水素原子、または一方が水素原子で他方がＣ１－６アルキル基を示す、
化合物、又はその塩。 In another embodiment, as compound (III), the following compound (III-a), compound (III-b), compound (III-c) and compound (III-d) are preferred.
[Compound (III-a)]
Compound (III),
Ring A represents an optionally substituted benzene ring or pyridine ring;
Ring B represents an optionally substituted benzene ring;
L 1 represents a bond, a methylene group, or an ethylene group;
L 2 represents an ethylene group;
X represents SO 2 ;
Z ″ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group;
R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
Compound or salt thereof.
〔化合物（ＩＩＩ－ｂ）〕
　化合物（ＩＩＩ－ａ）であって；
　Ａ環は、
　ハロゲン原子、シアノ基、アルコキシ基およびモルホリノ基から選択される１個の置換基で置換されていても良いベンゼン環、又はピリジン環を示し；
　Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し；
　Ｌ１は結合手、メチレン基、またはエチレン基を示し；
　Ｌ２はエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）１または２個のＣ１－６アルキル基で置換されていても良いアミノ基、又は（４）モルホリノ基を示し；
　Ｒ１及びＲ２は、両方とも水素原子、または一方が水素原子で他方がＣ１－６アルキル基を示す、
化合物またはその塩。 [Compound (III-b)]
Compound (III-a);
Ring A is
A benzene ring or a pyridine ring optionally substituted with one substituent selected from a halogen atom, a cyano group, an alkoxy group and a morpholino group;
Ring B represents a benzene ring substituted with two halogen atoms;
L 1 represents a bond, a methylene group, or an ethylene group;
L 2 represents an ethylene group;
X represents SO 2 ;
Z ″ is (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group optionally substituted by one or two C 1-6 alkyl groups, or (4) a morpholino group Indicates;
R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
Compound or salt thereof.
〔化合物（ＩＩＩ－ｃ）〕
　化合物（ＩＩＩ）であって、
　Ａ環は置換基を有していても良いベンゼン環を示し；
　Ｂ環は置換基を有していても良いベンゼン環を示し；
　Ｌ１は結合手を示し；
　Ｌ２はエチレン基を示し；
　ＸはＳＯ２を示し；
　Ｚ’’は（１）置換基を有していても良いＣ１－６アルキル基、（２）置換基を有していても良いフェニル基、（３）置換基を有していても良いアミノ基、又は（４）置換基を有していても良いモルホリノ基を示し；
　Ｒ１及びＲ２は、水素原子を示す、
化合物、又はその塩。
　化合物（ＩＩＩ－ｃ）において、Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）アミノ基、（４）モノ－またはジ－Ｃ１－６アルキルアミノ基、又は（５）モルホリノ基であることが好ましい。 [Compound (III-c)]
Compound (III),
Ring A represents an optionally substituted benzene ring;
Ring B represents an optionally substituted benzene ring;
L 1 represents a bond;
L 2 represents an ethylene group;
X represents SO 2 ;
Z '' is (1) may have a substituent group C 1-6 alkyl group, (2) a phenyl group which may have a substituent, may have a (3) substituents An amino group or (4) a morpholino group optionally having a substituent;
R 1 and R 2 represent a hydrogen atom,
Compound or salt thereof.
In compound (III-c), Z ″ is (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group, (4) a mono- or di-C 1-6 alkylamino group, Or (5) preferably a morpholino group.
〔化合物（ＩＩＩ－ｄ）〕
　化合物（ＩＩＩ－ｃ）であって、
　Ａ環はハロゲン原子を有していても良いベンゼン環を示し；
　Ｂ環はハロゲン原子で置換されたベンゼン環を示し；
Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）アミノ基、（４）モノ－またはジ－Ｃ１－６アルキルアミノ基、又は（５）モルホリノ基を示す、
化合物、又はその塩。
　化合物（ＩＩＩ－ｄ）において、Ａ環は１から３個（好ましくは１個）のハロゲン原子を有していても良いベンゼン環であり、Ｂ環は１～３個（好ましくは２個）のハロゲン原子で置換されたベンゼン環であることが好ましい。 [Compound (III-d)]
Compound (III-c), comprising:
Ring A represents a benzene ring which may have a halogen atom;
Ring B represents a benzene ring substituted with a halogen atom;
Z ″ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an amino group, (4) a mono- or di-C 1-6 alkylamino group, or (5) a morpholino group. ,
Compound or salt thereof.
In compound (III-d), ring A is a benzene ring optionally having 1 to 3 (preferably 1) halogen atoms, and ring B is 1 to 3 (preferably 2). A benzene ring substituted with a halogen atom is preferred.
　化合物（ＩＩＩ）としては、実施例１～８、１０、１１、１３～１７、１９、２０、２７～３０、３５～３７、４８、５７、５８の化合物がより好ましい。 As the compound (III), the compounds of Examples 1 to 8, 10, 11, 13 to 17, 19, 20, 27 to 30, 35 to 37, 48, 57, and 58 are more preferable.
　次に、本発明の化合物（Ｉ）の製造法について説明する。
　化合物（Ｉ）は、以下に示すＡ法あるいはそれに準ずる方法により製造することができる。なお以下の製造法の各工程において、原料化合物は塩として用いてもよく、このような塩としては、化合物（Ｉ）の塩の例として後述するものなどが用いられる。
［Ａ法］ Next, a method for producing the compound (I) of the present invention will be described.
Compound (I) can be produced by the following method A or a method analogous thereto. In each step of the following production method, the raw material compound may be used as a salt, and examples of such a salt include those described later as examples of the salt of compound (I).
[Method A]
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　本法において原料として用いる式（ＩＶ）［式中、各記号は前記と同意義を示す。］で表される化合物またはその塩（以下、「化合物（ＩＶ）」と称する場合がある）および式（Ｖ）［式中、ＬＧは脱離基を、その他各記号は上記と同意義を示す。］で表される化合物またはその塩（以下、「化合物（Ｖ）」と称する場合がある）は、市販品をそのまま用いてもよく、あるいは、それ自体公知の方法あるいはそれに準じた方法により製造することもできる。
　ＬＧで示される脱離基としては、例えば、ハロゲン原子（例えば、塩素原子、臭素原子、ヨウ素原子など）、置換スルホニルオキシ基（例えば、メタンスルホニルオキシ、エタンスルホニルオキシなどのＣ１－６アルキルスルホニルオキシ基；ベンゼンスルホニルオキシ、ｐ－トルエンスルホニルオキシなどのＣ６－１４アリールスルホニルオキシ基；ベンジルスルホニルオキシ基などのＣ７－１６アラルキルスルホニルオキシ基など）などが用いられ、特にハロゲン原子が好ましく使用される。
　本法において原料として用いる化合物（ＩＶ）は、それ自体公知の方法あるいはそれに準じた方法により製造することができる。例えば、Journal of Medicinal Chemistry, 1975, 18, 142-148またはBioorganic ＆ Medicinal Chemistry, 2003, 11(20), 4423-4430に記載された方法等に準じて製造できる。
　また、本法において原料として用いる化合物（Ｖ）は、それ自体公知の方法あるいはそれに準じた方法により製造することができる。例えばJournal of the American Chemical Society, 1951, 73(7), 3159-3162に記載された方法等に準じて製造できる。 Formula (IV) used as a raw material in this method [wherein each symbol is as defined above. Or a salt thereof (hereinafter sometimes referred to as “compound (IV)”) and formula (V) [wherein LG is a leaving group, and other symbols are as defined above. . ] Or a salt thereof (hereinafter sometimes referred to as “compound (V)”) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto. You can also
The leaving group represented by LG includes, for example, a halogen atom (eg, chlorine atom, bromine atom, iodine atom), a substituted sulfonyloxy group (eg, C 1-6 alkylsulfonyl such as methanesulfonyloxy, ethanesulfonyloxy, etc.) Oxy groups; C 6-14 arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy; C 7-16 aralkylsulfonyloxy groups such as benzylsulfonyloxy group, etc.), and halogen atoms are particularly preferred. Is done.
Compound (IV) used as a raw material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in Journal of Medicinal Chemistry, 1975, 18, 142-148 or Bioorganic & Medicinal Chemistry, 2003, 11 (20), 4423-4430.
The compound (V) used as a raw material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in Journal of the American Chemical Society, 1951, 73 (7), 3159-3162.
（工程１）
　本反応は、化合物（ＩＶ）を塩基存在下、化合物（Ｖ）と反応させることにより化合物（Ｉ）を製造する工程である。
　本反応は、通常、反応に不活性な溶媒中、塩基の存在下で行うことができる。本反応で用いる塩基としては、例えば、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウムなどのアルカリ金属塩、ピリジン、トリエチルアミン、Ｎ，Ｎ－ジメチルアニリン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）等の有機アミン類、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシドなどの金属アルコキシド類、水素化ナトリウム、水素化カリウムなどの金属水素化物などが挙げられる。
　これら塩基の使用量は、化合物（ＩＶ）に対して１～２０モル当量程度であり、特に１～３モル当量程度が好ましい。
　化合物（Ｖ）の使用量は、例えば、化合物（ＩＶ）に対して０．１～５モル当量、好ましくは０．５～３モル当量程度である。
　本反応において溶媒は、反応が進行する限り特に限定されるものではない。該溶媒としては例えば、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類、テトラヒドロフラン、ジメトキシエタン、ジオキサン、ジエチルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルアセトアミド（ＤＭＡ）などのアミド類、メタノール、エタノール、プロパノール、ｔｅｒｔ－ブタノール、メトキシエタノールなどのアルコール類、ジメチルスルホキシド（ＤＭＳＯ）などのスルホキシド類、水およびこれらの混合溶媒が挙げられる。
　本反応は通常－５０℃～２００℃、好ましくは－１０℃～１００℃で行われる。本反応の反応時間は通常、０．５時間～６０時間である。このようにして得られる化合物（Ｉ）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。
　また化合物（Ｉ）のうち式（Ｉ－Ａ） (Process 1)
This reaction is a step for producing compound (I) by reacting compound (IV) with compound (V) in the presence of a base.
This reaction can usually be performed in a solvent inert to the reaction in the presence of a base. Examples of the base used in this reaction include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4. 0] Organic amines such as undec-7-ene (DBU), metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride, etc. .
The amount of these bases to be used is about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents, relative to compound (IV).
The amount of compound (V) to be used is, for example, about 0.1 to 5 molar equivalents, preferably about 0.5 to 3 molar equivalents relative to compound (IV).
In this reaction, the solvent is not particularly limited as long as the reaction proceeds. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like. Examples thereof include amides, alcohols such as methanol, ethanol, propanol, tert-butanol and methoxyethanol, sulfoxides such as dimethyl sulfoxide (DMSO), water, and mixed solvents thereof.
This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C. The reaction time for this reaction is usually 0.5 to 60 hours. The compound (I) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
Of the compounds (I), the compound represented by the formula (IA)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
［式中、Ｌ３はオキソ基以外の置換基を有していてもよいメチレン基を示し、その他各記号は上記と同意義を示す。］で表される化合物またはその塩（以下、「化合物（Ｉ－Ａ）」と称する場合がある）は、以下に示すＢ法あるいはそれに準ずる方法により製造することも出来る。なお以下の製造法の各工程において、原料化合物は塩として用いてもよく、このような塩としては前述の化合物（Ｉ）の塩として例示したものが用いられる。
［Ｂ法］ [Wherein L 3 represents a methylene group which may have a substituent other than an oxo group, and other symbols are as defined above. Or a salt thereof (hereinafter sometimes referred to as “compound (IA)”) can also be produced by Method B shown below or a method analogous thereto. In each step of the following production method, the raw material compound may be used as a salt, and as such a salt, those exemplified as the salt of the aforementioned compound (I) are used.
[Method B]
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　本法において原料として用いる化合物（ＩＶ）および式（ＶＩＩ)［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（以下、「化合物（ＶＩＩ）」と称する場合がある）は、市販品をそのまま用いてもよく、あるいは、それ自体公知の方法あるいはそれに準じた方法により製造することもできる。
　例えば、化合物（ＶＩＩ）は、Journal of Fluorine Chemistry, 2006, 127, 291-295に記載された方法等に準じて製造できる。 Compound (IV) and formula (VII) used as starting materials in this method wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as “compound (VII)”) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto. You can also.
For example, compound (VII) can be produced according to the method described in Journal of Fluorine Chemistry, 2006, 127, 291-295.
（工程１）
　本工程は、化合物（ＩＶ）を縮合剤存在下、化合物（ＶＩＩ）との縮合反応に付すことにより式（ＶＩ）［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（「以下、化合物（ＶＩ）」と称する場合がある）を製造する工程である。
　縮合剤としては、例えば、１－ヒドロキベンゾトリアゾール（ＨＯＢｔ）、１－ヒドロキシ－７－アザベンゾトリアゾールなどのトリアゾール類、４－(４，６－ジメトキシ－１，３，５－トリアジン－２－イル)－４－メチルモルホリニウムクロリドなどのトリアジン類、ジフェニルリン酸アジドなどのアジド類、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、ジシクロヘキシルカルボジイミド、水溶性カルボジイミド（ＷＳＣ)、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などのカルボジイミド類が用いられ、特にカルボジイミド類が好ましく使用される。
　これら縮合剤の使用量としては、例えば、化合物（ＩＶ）に対して１～２０モル当量程度であり、特に１～３モル当量程度が好ましい。
　本反応は、通常、反応に不活性な溶媒中、必要に応じて塩基の存在下で行うことができる。
　本反応で必要に応じて用いる塩基としては、例えば、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウムなどのアルカリ金属塩、ピリジン、トリエチルアミン、Ｎ，Ｎ－ジメチルアニリン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）等の有機アミン類、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシドなどの金属アルコキシド類、水素化ナトリウム、水素化カリウムなどの金属水素化物などが挙げられ、特に有機アミン類が好ましく使用される。
　これら塩基の使用量は、化合物（ＩＶ）に対して１～２０モル当量程度であり、特に１～３モル当量程度が好ましい。
　化合物（ＶＩＩ）の使用量は、例えば、化合物（ＩＶ）に対して０．１～５モル当量、好ましくは０．５～３モル当量程度である。
　本反応において溶媒は、反応が進行する限り特に限定されるものではない。該溶媒としては例えば、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類、テトラヒドロフラン、ジメトキシエタン、ジオキサン、ジエチルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルアセトアミド（ＤＭＡ）などのアミド類、ジメチルスルホキシド（ＤＭＳＯ）などのスルホキシド類およびこれらの混合溶媒が挙げられる。
　本反応は通常－５０℃～２００℃、好ましくは－１０℃～１００℃で行われる。本反応の反応時間は通常、０．５時間～６０時間である。このようにして得られる化合物（ＶＩ）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。 (Process 1)
In this step, compound (IV) is subjected to a condensation reaction with compound (VII) in the presence of a condensing agent to give a compound of formula (VI) [wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as "compound (VI)").
Examples of the condensing agent include triazoles such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl ) -4-triazines such as methylmorpholinium chloride, azides such as diphenylphosphoric acid azide, N, N′-dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, water-soluble carbodiimide (WSC), 1-ethyl-3- (3- Carbodiimides such as (dimethylaminopropyl) carbodiimide hydrochloride are used, and carbodiimides are particularly preferably used.
The amount of these condensing agents to be used is, for example, about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents relative to compound (IV).
This reaction can usually be performed in a solvent inert to the reaction, if necessary, in the presence of a base.
Examples of the base used as necessary in this reaction include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [ 5.4.0] Organic amines such as undec-7-ene (DBU), metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, metal hydrides such as sodium hydride and potassium hydride In particular, organic amines are preferably used.
The amount of these bases to be used is about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents, relative to compound (IV).
The amount of compound (VII) to be used is, for example, about 0.1 to 5 molar equivalents, preferably about 0.5 to 3 molar equivalents relative to compound (IV).
In this reaction, the solvent is not particularly limited as long as the reaction proceeds. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like. Examples thereof include amides, sulfoxides such as dimethyl sulfoxide (DMSO), and mixed solvents thereof.
This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C. The reaction time for this reaction is usually 0.5 to 60 hours. The compound (VI) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, and the like.
（工程２）
　本工程は、化合物（ＶＩ）を不活性な溶媒中、還元反応に付すことにより化合物（Ｉ－Ａ）を製造する工程である。
　本反応で用いることのできる還元剤としては、例えば、水素化アルミニウムリチウム、テトラヒドロホウ酸リチウム、水素化トリエチルホウ素リチウム、ジボラン、ボラン錯体（ボラン－ＴＨＦ錯体、カテコールボランなど）、水素化ジイソブチルアルミニウム、水素化ホウ素亜鉛などが挙げられ、特にボラン錯体が好ましく使用される。
　これらの還元剤の使用量は、化合物（ＶＩ）に対して１～２０モル当量程度であり、とくに１～３モル当量程度が好ましい。
　本反応において溶媒は、反応が進行する限り特に限定されるものではない。該溶媒としては例えば、ベンゼン、トルエン、キシレンなどの芳香族炭化水素類、テトラヒドロフラン、ジメトキシエタン、ジオキサン、ジエチルエーテルなどのエーテル類、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、ジメチルアセトアミド（ＤＭＡ）などのアミド類、ジメチルスルホキシド（ＤＭＳＯ）などのスルホキシド類およびこれらの混合溶媒が挙げられる。
　本反応は通常－５０℃～２００℃、好ましくは－１０℃～１００℃で行われる。本反応の反応時間は通常、０．５時間～６０時間である。このようにして得られる化合物（Ｉ－Ａ）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。
　また化合物（Ｉ）のうち式（Ｉ－Ｂ） (Process 2)
This step is a step for producing compound (IA) by subjecting compound (VI) to a reduction reaction in an inert solvent.
Examples of the reducing agent that can be used in this reaction include lithium aluminum hydride, lithium tetrahydroborate, lithium triethylborohydride, diborane, borane complex (borane-THF complex, catecholborane, etc.), diisobutylaluminum hydride, Examples thereof include zinc borohydride, and a borane complex is particularly preferably used.
The amount of these reducing agents to be used is about 1 to 20 molar equivalents, particularly preferably about 1 to 3 molar equivalents, relative to compound (VI).
In this reaction, the solvent is not particularly limited as long as the reaction proceeds. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether, N, N-dimethylformamide (DMF), dimethylacetamide (DMA) and the like. Examples thereof include amides, sulfoxides such as dimethyl sulfoxide (DMSO), and mixed solvents thereof.
This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C. The reaction time for this reaction is usually 0.5 to 60 hours. The compound (IA) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
Of the compounds (I), the compound represented by formula (IB)
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（以下、「化合物（Ｉ－Ｂ）」と称する場合がある）は、以下に示すＣ法あるいはそれに準ずる方法により製造することも出来る。なお以下の製造法の各工程において、原料化合物は塩として用いてもよく、このような塩としては化合物（Ｉ）の塩として例示したものが用いられる。
［Ｃ法］ [Wherein each symbol is as defined above. Or a salt thereof (hereinafter sometimes referred to as “compound (IB)”) can also be produced by the following method C or a method analogous thereto. In each step of the following production method, the raw material compound may be used as a salt, and as such a salt, those exemplified as the salt of compound (I) are used.
[Method C]
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　本法において原料として用いる式（ＶＩＩＩ）[式中、各記号は前記と同意義を示す。]で表される化合物（以下、「化合物（ＶＩＩＩ）」と称する場合がある）および式（ＩＸ）[式中、各記号は前記と同意義を示す。]で表される化合物またはその塩（以下、「化合物（ＩＸ）」と称する場合がある）は、市販品をそのまま用いてもよく、あるいは、それ自体公知の方法あるいはそれに準じた方法により製造することもできる。
　本法において原料として用いる化合物（ＶＩＩＩ）は、それ自体公知の方法あるいはそれに準じた方法により製造することができる。例えば、Synthesis, 1980, 5, 405-407に記載された方法等に準じて製造できる。
　また、本法において原料として用いる化合物（ＩＸ）またはその塩は、それ自体公知の方法あるいはそれに準じた方法により製造することができる。例えば、公開特許文献ＷＯ２００５０３５５３２に記載された方法等に準じて製造できる。 Formula (VIII) used as a raw material in this method [wherein each symbol is as defined above. And a compound represented by formula (IX) [wherein each symbol is as defined above.] Or a salt thereof (hereinafter sometimes referred to as “compound (IX)”) may be a commercially available product, or can be produced by a method known per se or a method analogous thereto. You can also
Compound (VIII) used as a starting material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in Synthesis, 1980, 5, 405-407.
In addition, compound (IX) or a salt thereof used as a starting material in this method can be produced by a method known per se or a method analogous thereto. For example, it can be produced according to the method described in the published patent document WO2005035532.
（工程１）
　本工程は、化合物（ＶＩＩＩ）を化合物（ＩＸ）と還元的アルキル化反応に付すことにより化合物（Ｉ－Ｂ）を製造する工程である。
　本工程で行う還元的アルキル化反応は、それ自体公知の方法により行うことができる。例えば、化合物（ＶＩＩＩ）を化合物（ＩＸ）と反応させ、生成したイミンあるいはイミニウムイオンを還元反応に付すことによって行うことができる。
　イミンあるいはイミニウムイオンの生成反応における溶媒は、反応が進行する限り特に限定されるものではない。該溶媒としては例えば、トルエン、キシレン等の芳香族炭化水素類、ヘプタン、ヘキサン等の脂肪族炭化水素類、クロロホルム、ジクロロメタン等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類、酢酸エチル、酢酸ｔ－ブチルなどのエステル類、メタノール、エタノール、２－プロパノール等のアルコール類、アセトニトリル等のニトリル類、ジメチルホルムアミド、ジメチルスルホキシド等およびこれらの混合溶媒が挙げられる。
　本工程では必要に応じ、触媒を添加することにより反応を有利に進めることができる。このような触媒としては、鉱酸類（例えば、塩酸、臭化水素酸、硫酸など）、カルボン酸類（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸など）、スルホン酸類（例えば、メタンスルホン酸、ｐ－トルエンスルホン酸など）、ルイス酸類（例えば、塩化アルミニウム、塩化亜鉛、臭化亜鉛、三フッ化ホウ素、塩化チタンなど）、酢酸塩（酢酸ナトリウム、酢酸カリウムなど）、モレキュラーシーブス（モレキュラーシーブス３Ａ、４Ａ、５Ａなど）が挙げられる。触媒の使用量は、化合物（ＶＩＩＩ）に対して０．０１～５０モル当量程度であり、特に１～１０モル当量程度が好ましい。
　本反応は通常－５０℃～２００℃、好ましくは－１０℃～１００℃で行われる。本反応の反応時間は通常、０．５時間～６０時間である。このようにして得られる化合物（Ｉ－Ｂ）は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィーなどにより単離精製することができる。
［Ｄ法］ (Process 1)
This step is a step for producing compound (IB) by subjecting compound (VIII) to reductive alkylation reaction with compound (IX).
The reductive alkylation reaction performed in this step can be performed by a method known per se. For example, it can be carried out by reacting compound (VIII) with compound (IX) and subjecting the produced imine or iminium ion to a reduction reaction.
The solvent in the imine or iminium ion production reaction is not particularly limited as long as the reaction proceeds. Examples of the solvent include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as heptane and hexane, halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether, tetrahydrofuran and dioxane, Examples thereof include esters such as ethyl acetate and t-butyl acetate, alcohols such as methanol, ethanol and 2-propanol, nitriles such as acetonitrile, dimethylformamide and dimethyl sulfoxide, and a mixed solvent thereof.
In this step, the reaction can be advantageously advanced by adding a catalyst as necessary. Such catalysts include mineral acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), sulfonic acids (eg, methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acids (eg, aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride, etc.), acetates (sodium acetate, potassium acetate, etc.), molecular sieves (molecular sieves 3A) 4A, 5A, etc.). The amount of the catalyst to be used is about 0.01 to 50 molar equivalents, particularly preferably about 1 to 10 molar equivalents, relative to compound (VIII).
This reaction is usually carried out at -50 ° C to 200 ° C, preferably -10 ° C to 100 ° C. The reaction time for this reaction is usually 0.5 to 60 hours. The compound (IB) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
[Method D]
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（工程１）
　本工程は化合物（ＩＶ）を縮合剤存在下、化合物（Ｘ）との縮合反応に付すことにより化合物（ＸＩ）［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（「以下、化合物（ＸＩ）」と称する場合がある）を製造する工程であり、Ｂ法の工程１に記載した方法と同様の方法により行うことができる。 (Process 1)
In this step, compound (IV) is subjected to a condensation reaction with compound (X) in the presence of a condensing agent to give compound (XI) [wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as “compound (XI)”), and can be carried out by the same method as described in Step 1 of Method B.
（工程２）
　本工程は化合物（ＸＩ）を不活性な溶媒中、還元反応に付すことにより化合物（ＸＩＩ）［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（「以下、化合物（ＸＩＩ）」と称する場合がある）を製造する工程であり、Ｂ法の工程２に記載した方法と同様の方法により行うことができる。 (Process 2)
In this step, compound (XI) is subjected to a reduction reaction in an inert solvent to give compound (XII) [wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as “compound (XII)”), which can be carried out by the same method as described in Step 2 of Method B.
（工程３）
　本工程は、化合物（ＸＩＩ）をｔｅｒｔ－ブトキシカルボニル化反応に付すことにより化合物（ＸＩＩＩ）［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（「以下、化合物（ＸＩＩＩ）」と称する場合がある）を製造する工程である。
　このような反応は、公知の方法（例えば、Ｗｉｌｅｙ－Ｉｎｔｅｒｓｃｉｅｎｃｅ社１９９９年刊「Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　３ｒｄ　Ｅｄ．」（Ｔｈｅｏｄｏｒａ　Ｗ．　Ｇｒｅｅｎｅ，Ｐｅｔｅｒ　Ｇ．　Ｍ．　Ｗｕｔｓ著））に準じて行うことが出来る。例えば、化合物（ＸＩＩ）の種類によっても異なるが、通常、ｔｅｒｔ－ブトキシカルボニル化剤を用い、反応に悪影響を及ぼさない溶媒中、必要に応じて塩基の存在下で行われる。
　塩基としては、例えば、アルカリ金属水酸化物（水酸化ナトリウム、水酸化カリウムなど）、炭酸水素塩（炭酸水素ナトリウム、炭酸水素カリウムなど）、炭酸塩（炭酸ナトリウム、炭酸カリウムなど）、酢酸塩（酢酸ナトリウムなど）、３級アミン類（トリメチルアミン、トリエチルアミン、Ｎ－メチルモルホリンなど）、有機アミン類（ピリジン、ピコリン、Ｎ，Ｎ－ジメチルアニリンなど）などが挙げられる。塩基の使用量は、通常、化合物（ＸＩＩ）１モルに対して、約１～１０モル当量、好ましくは約１～２モル当量程度である。
　ｔｅｒｔ－ブトキシカルボニル化剤としては、例えば、二炭酸ジ－ｔｅｒｔ－ブチルなどが挙げられ、その使用量は化合物（ＸＩＩ）１モルに対して、約１～１０モル当量、好ましくは約１～２モル当量程度である。
　反応に悪影響を及ぼさない溶媒としては、例えば、アルコール類（メタノール、エタノール、１－プロパノール、２－プロパノール、ブタノール、イソブタノール、ｔ－ブタノールなど）、芳香族炭化水素類（ベンゼン、トルエン、キシレンなど）、脂肪族炭化水素類（ヘキサン、ヘプタンなど）、ハロゲン化炭化水素類（ジクロロメタン、クロロホルムなど）、エーテル類（ジエチルエーテル、ジイソプロピルエーテル、ｔ－ブチルメチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタンなど）、ニトリル類（アセトニトリルなど）、エステル類（酢酸エチルなど）、カルボン酸類（酢酸など）、アミド類（Ｎ，Ｎ－ジメチルホルムアミドなど）、スルホキシド類（ジメチルスルホキシドなど）、水等およびこれらの混合溶媒があげられる。
　反応温度は、例えば、約－５０～２００℃、好ましくは約０～１００℃程度の範囲であり、反応時間は化合物（ＸＩＩ）またはその塩の種類、反応温度などによって異なり、例えば、約０．５～１００時間、好ましくは約０．５～２４時間程度である。 (Process 3)
In this step, compound (XII) is subjected to tert-butoxycarbonylation reaction to give compound (XIII) [wherein each symbol is as defined above. Or a salt thereof (hereinafter sometimes referred to as “compound (XIII)”).
Such a reaction is performed according to a known method (for example, according to “Protective Groups in Organic Synthesis, 3rd Ed.” Published by Wiley-Interscience, Theodora W. Greene, Peter G. M. Wuts). I can do it. For example, although it depends on the type of compound (XII), it is usually carried out using a tert-butoxycarbonylating agent in a solvent that does not adversely influence the reaction, and if necessary, in the presence of a base.
Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), acetates ( Sodium acetate, etc.), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine, etc.), organic amines (pyridine, picoline, N, N-dimethylaniline, etc.) and the like. The amount of the base to be used is generally about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of compound (XII).
As the tert-butoxycarbonylating agent, for example, di-tert-butyl dicarbonate and the like can be mentioned, and the amount thereof to be used is about 1 to 10 mol equivalent, preferably about 1 to 2 mol, per 1 mol of compound (XII). About the molar equivalent.
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, 1-propanol, 2-propanol, butanol, isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.) ), Aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), Nitriles (such as acetonitrile), esters (such as ethyl acetate), carboxylic acids (such as acetic acid), amides (such as N, N-dimethylformamide), sulfoxides (such as dimethyl sulfoxide), water, etc., and mixed solutions thereof And the like.
The reaction temperature is, for example, in the range of about −50 to 200 ° C., preferably about 0 to 100 ° C., and the reaction time varies depending on the kind of compound (XII) or a salt thereof, the reaction temperature, etc. It is about 5 to 100 hours, preferably about 0.5 to 24 hours.
（工程４）
　本工程は化合物（ＸＩＩＩ）と化合物（ＸＩＶ）［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（「以下、化合物（ＸＩＶ）」と称する場合がある）とを、光延反応により化合物（ＸＶ）［式中、各記号は上記と同意義を示す。］で表される化合物またはその塩（「以下、化合物（ＸＶ）」と称する場合がある）を製造する工程である。
　本反応はそれ自体公知の方法、例えばシンセシス（Synthesis）、１頁（１９８１年）等に記載の方法、あるいはそれに準じた方法により行うことができる。すなわち、本反応は有機リン化合物および親電子剤の存在下、反応に悪影響を及ぼさない溶媒中で行われる。
　有機リン化合物としては、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。
　親電子剤としては、例えば１，１’－アゾジカルボン酸ジエチル、１，１’－アゾジカルボン酸ジイソプロピル、１，１’－アゾジカルボニルジピペラジン等が挙げられる。
　有機リン化合物および親電子剤の使用量は、それぞれ化合物（ＸＩＩＩ）および化合物（ＸＩＶ）に対して１モル当量ないし１０モル当量であり、好ましくは１モル当量ないし５モル当量である。
　反応に悪影響を及ぼさない溶媒としては、例えばジエチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル類；クロロホルム、塩化メチレンなどのハロゲン化炭化水素類；ベンゼン、トルエン、キシレンなどの芳香族炭化水素類；Ｎ，Ｎ－ジメチルホルムアミドなどのアミド類；ジメチルスルホキシドなどのスルホキシド類等及びこれらの混合溶媒が挙げられる。これら溶媒の使用量は、例えば化合物（ＸＩＩＩ）に対し、１容量倍ないし１００容量倍である。
　反応温度は、通常約－５０℃ないし約１５０℃、好ましくは約－１０℃ないし約１００℃である。
　反応時間は、通常、約０．５時間ないし約２０時間である。 (Process 4)
In this step, compound (XIII) and compound (XIV) [wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as “compound (XIV)”) by compound Mitsunobu reaction [wherein each symbol is as defined above. ] Or a salt thereof (hereinafter sometimes referred to as "compound (XV)").
This reaction can be carried out by a method known per se, for example, the method described in Synthesis, page 1 (1981), or the like. That is, this reaction is performed in the presence of an organophosphorus compound and an electrophile in a solvent that does not adversely influence the reaction.
Examples of the organic phosphorus compound include triphenylphosphine and tributylphosphine.
Examples of the electrophilic agent include diethyl 1,1′-azodicarboxylate, diisopropyl 1,1′-azodicarboxylate, 1,1′-azodicarbonyldipiperazine, and the like.
The amount of the organophosphorus compound and electrophilic agent used is 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (XIII) and compound (XIV), respectively.
Examples of solvents that do not adversely influence the reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and methylene chloride; aromatic hydrocarbons such as benzene, toluene and xylene; N, N Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide and the like, and mixed solvents thereof. The amount of these solvents to be used is, for example, 1 volume to 100 volumes with respect to compound (XIII).
The reaction temperature is usually about −50 ° C. to about 150 ° C., preferably about −10 ° C. to about 100 ° C.
The reaction time is usually about 0.5 hours to about 20 hours.
（工程５）
　本工程は、化合物（ＸＶ）を脱保護反応に付すことにより化合物（Ｉ－Ａ）を製造する工程である。
　このような脱保護反応は、公知の方法（例えば、Ｗｉｌｅｙ－Ｉｎｔｅｒｓｃｉｅｎｃｅ社１９９９年刊「Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，　３ｒｄ　Ｅｄ．」（Ｔｈｅｏｄｏｒａ　Ｗ．　Ｇｒｅｅｎｅ，Ｐｅｔｅｒ　Ｇ．　Ｍ．　Ｗｕｔｓ著））に準じて行うことが出来る。例えば、化合物（ＸＶ）の種類によっても異なるが、通常、酸の存在下、必要に応じ反応に悪影響を及ぼさない溶媒中で行われる。
　酸としては、例えば、鉱酸類（塩酸、臭化水素酸、硫酸、塩化水素など）、カルボン酸類（酢酸、トリフルオロ酢酸、トリクロロ酢酸など）、スルホン酸類（メタンスルホン酸、ｐ－トルエンスルホン酸など）、ルイス酸類（塩化アルミニウム、塩化スズ、臭化亜鉛など）などが用いられ、必要に応じ２種以上を混合して用いても良い。酸の使用量は、溶媒の種類、その他の反応条件により異なるが、通常、化合物（ＸＶ）１モルに対して約０．１モル当量以上であり、溶媒として用いることもできる。
　反応に悪影響を及ぼさない溶媒としては、例えば、アルコール類（メタノール、エタノール、プロパノール、２－プロパノール、ブタノール、イソブタノール、ｔ－ブタノールなど）、芳香族炭化水素類（ベンゼン、トルエン、キシレンなど）、脂肪族炭化水素類（ヘキサン、ヘプタンなど）、ハロゲン化炭化水素類（ジクロロメタン、クロロホルムなど）、エーテル類（ジエチルエーテル、ジイソプロピルエーテル、ｔ－ブチルメチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタンなど）、ニトリル類（アセトニトリルなど）、エステル類（酢酸エチルなど）、カルボン酸類（酢酸など）、アミド類（Ｎ，Ｎ－ジメチルホルムアミドなど）、スルホキシド類（ジメチルスルホキシドなど）、水等およびこれらの混合溶媒があげられる。
　反応温度は、例えば、約－５０～２００℃、好ましくは約０～１００℃程度の範囲であり、反応時間は化合物（ＸＶ）の種類、反応温度などによって異なり、例えば、約０．５～１００時間、好ましくは約０．５～２４時間程度である。 (Process 5)
This step is a step for producing compound (IA) by subjecting compound (XV) to a deprotection reaction.
Such a deprotection reaction is carried out according to a known method (for example, according to Theory W. Greene, Peter G. Muts, published by Wiley-Interscience, "Protective Groups in Organic Synthesis, 3rd Ed."). I can do it. For example, although it depends on the type of compound (XV), it is usually carried out in the presence of an acid in a solvent that does not adversely influence the reaction as necessary.
Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, etc.), carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid, etc.), sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid, etc.) ), Lewis acids (aluminum chloride, tin chloride, zinc bromide, etc.) and the like may be used, and two or more kinds may be mixed as necessary. The amount of acid used varies depending on the type of solvent and other reaction conditions, but is usually about 0.1 molar equivalents or more per 1 mol of compound (XV), and can also be used as a solvent.
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, t-butanol, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), Aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), nitriles (Such as acetonitrile), esters (such as ethyl acetate), carboxylic acids (such as acetic acid), amides (such as N, N-dimethylformamide), sulfoxides (such as dimethyl sulfoxide), water, etc. It is below.
The reaction temperature is, for example, in the range of about −50 to 200 ° C., preferably about 0 to 100 ° C., and the reaction time varies depending on the type of compound (XV), the reaction temperature, etc., for example, about 0.5 to 100 The time is preferably about 0.5 to 24 hours.
　上記製造法により得られる化合物（Ｉ）を、公知の酸化反応に付すことにより、さらに誘導化することもできる。このような反応では、必要に応じて、化合物（Ｉ）をペプチド合成等で通常用いられるような保護基で保護して使用しても良い。この場合、反応後に、必要に応じて、保護基を公知の方法を用いて除去することにより目的化合物を得ることができる。 The compound (I) obtained by the above production method can be further derivatized by subjecting it to a known oxidation reaction. In such a reaction, if necessary, compound (I) may be used after being protected with a protecting group that is usually used in peptide synthesis or the like. In this case, after the reaction, the target compound can be obtained by removing the protecting group using a known method, if necessary.
　上記の方法において化合物（Ｉ）が遊離化合物として得られる場合、常法に従って、例えば、無機酸（例えば、塩酸、硫酸、臭化水素酸など）、有機酸（例えば、メタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、シュウ酸、フマール酸、マレイン酸、酒石酸など）、無機塩基（例えば、ナトリウム、カリウムなどのアルカリ金属、カルシウム、マグネシウムなどのアルカリ土類金属、アルミニウムまたはアンモニウムなど）または有機塩基（例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミンまたはＮ，Ｎ’－ジベンジルエチレンジアミンなど）などとの塩を生成させることもでき、化合物（Ｉ）が塩の形態で得られる場合は、常法に従って、遊離の化合物または他の塩に変換することもできる。 When compound (I) is obtained as a free compound in the above method, according to a conventional method, for example, inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acid (for example, methanesulfonic acid, benzenesulfonic acid) , Toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium) or organic bases ( For example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) can be formed. Gain in form If you in a usual manner, it can be converted free compound or into another salt.
　このような方法により生成した化合物（Ｉ）は、例えば、再結晶、蒸留、クロマトグラフィー等の通常の分離手段により単離、精製することができる。
　化合物（Ｉ）が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物（Ｉ）として含有されるとともに、自体公知の合成手法、分離手法（例、濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶等）によりそれぞれを単品として得ることができる。例えば、化合物（Ｉ）に光学異性体が存在する場合には、該化合物から分割された光学異性体も化合物（Ｉ）に包含される。
　光学異性体は自体公知の方法により製造することができる。具体的には、光学活性な合成中間体を用いる、または、最終物のラセミ体を常法に従って光学分割することにより光学異性体を得る。
　光学分割法としては、自体公知の方法、例えば、分別再結晶法、キラルカラム法、ジアステレオマー法等が用いられる。 The compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and synthetic methods and separation methods known per se (examples) , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.
　１）分別再結晶法
　ラセミ体と光学活性な化合物（例、（＋）－マンデル酸、（－）－マンデル酸、（＋）－酒石酸、（－）－酒石酸、（＋）－１－フェネチルアミン、（－）－１－フェネチルアミン、シンコニン、（－）－シンコニジン、ブルシン等）との塩を形成させ、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学異性体を得る方法。
　２）キラルカラム法
　ラセミ体またはその塩を光学異性体分離用カラム（キラルカラム）にかけて分離する方法。例えば液体クロマトグラフィーの場合、ＥＮＡＮＴＩＯ－ＯＶＭ（東ソー社製）あるいは、ＣＨＩＲＡＬシリーズ（ダイセル化学工業社製）等のキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液（例、リン酸緩衝液等）、有機溶媒（例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン等）を単独であるいはこれらを混合した溶液として展開させることにより、光学異性体を分離する。また、例えばガスクロマトグラフィーの場合、ＣＰ－Ｃｈｉｒａｓｉｌ－ＤｅＸ　ＣＢ（ジーエルサイエンス社製）等のキラルカラムを使用して分離する。
　３）ジアステレオマー法
　ラセミ体の混合物を光学活性な試薬との化学反応によってジアステレオマーの混合物とし、これを通常の分離手段（例、分別再結晶法、クロマトグラフィー法等）等を経て単一物質とした後、加水分解反応等の化学的な処理により光学活性な試薬部位を切り離すことにより光学異性体を得る方法。例えば、化合物（Ｉ）が分子内に水酸基または１級、２級アミノ基を有する場合、該化合物と光学活性な有機酸（例、ＭＴＰＡ〔α－メトキシ－α－（トリフルオロメチル）フェニル酢酸〕、（－）－メントキシ酢酸等）等とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、化合物（Ｉ）がカルボキシル基を有する場合、該化合物と光学活性アミンまたは光学活性アルコールとを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。分離されたジアステレオマーは、酸加水分解あるいは塩基性加水分解に付すことにより、元の化合物の光学異性体に変換される。 1) Fractional recrystallization method Racemate and optically active compound (eg, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), and this is separated by fractional recrystallization. If desired, a free optical isomer is obtained through a neutralization step. How to get.
2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphoric acid) The optical isomers are separated by developing a buffer solution or the like and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) alone or as a mixed solution thereof. Further, for example, in the case of gas chromatography, the separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science).
3) Diastereomer method A racemic mixture is converted into a diastereomer mixture by a chemical reaction with an optically active reagent, and this mixture is passed through ordinary separation means (eg, fractional recrystallization method, chromatography method, etc.) and the like. A method of obtaining an optical isomer by separating an optically active reagent site by chemical treatment such as hydrolysis after making a single substance. For example, when the compound (I) has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid]) , (−)-Menthoxyacetic acid, etc.) and the like are subjected to a condensation reaction, whereby ester or amide diastereomers are obtained, respectively. On the other hand, when compound (I) has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and optically active amine or optically active alcohol to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis.
　化合物（Ｉ）は、結晶であってもよい。
　化合物（Ｉ）の結晶は、化合物（Ｉ）に自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　ここで、結晶化法としては、例えば、溶液からの結晶化法、蒸気からの結晶化法、溶融体からの結晶化法等が挙げられる。 Compound (I) may be a crystal.
Crystals of compound (I) can be produced by crystallization by applying a crystallization method known per se to compound (I).
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like.
　該「溶液からの結晶化法」としては、化合物の溶解度に関係する因子（溶媒組成、ｐＨ、温度、イオン強度、酸化還元状態等）または溶媒の量を変化させることによって、飽和していない状態から過飽和状態に移行させる方法が一般的であり、具体的には、例えば濃縮法、徐冷法、反応法（拡散法、電解法）、水熱育成法、融剤法等が挙げられる。用いられる溶媒としては、例えば、芳香族炭化水素類（例、ベンゼン、トルエン、キシレン等）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム等）、飽和炭化水素類（例、ヘキサン、ヘプタン、シクロヘキサン等）、エーテル類（例、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等）、ニトリル類（例、アセトニトリル等）、ケトン類（例、アセトン等）、スルホキシド類（例、ジメチルスルホキシド等）、酸アミド類（例、Ｎ，Ｎ－ジメチルホルムアミド等）、エステル類（例、酢酸エチル等）、アルコール類（例、メタノール、エタノール、イソプロピルアルコール等）、水等が挙げられる。これらの溶媒は単独あるいは二種以上を適当な割合（例、１：１ないし１：１００（容積比））で混合して用いられる。必要に応じて種晶を使用することもできる。
　該「蒸気からの結晶化法」としては、例えば気化法（封管法、気流法）、気相反応法、化学輸送法等が挙げられる。
　該「溶融体からの結晶化法」としては、例えば、ノルマルフリージング法（引上げ法、温度傾斜法、ブリッジマン法）、帯溶融法（ゾーンレベリング法、フロートゾーン法）、特殊成長法（ＶＬＳ法、液相エピタキシー法）等が挙げられる。 The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), acid amides (Eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). A seed crystal can also be used as needed.
Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like.
Examples of the “crystallization from the melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method). , Liquid phase epitaxy method) and the like.
　結晶化法の好適な例としては、化合物（Ｉ）を２０～１２０℃の温度下に、適当な溶媒（例、メタノール、エタノール等のアルコール類等）に溶解し、得られる溶液を溶解時の温度以下（例、０～５０℃、好ましくは０～２０℃）に冷却する方法等が挙げられる。
　このようにして得られる化合物（Ｉ）の結晶は、例えばろ過等によって単離することができる。
　得られた結晶の解析方法としては、粉末Ｘ線回折による結晶解析の方法が一般的である。さらに、結晶の方位を決定する方法としては、機械的な方法または光学的な方法等も挙げられる。 As a suitable example of the crystallization method, compound (I) is dissolved in a suitable solvent (eg, alcohols such as methanol and ethanol) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. Examples thereof include a method of cooling to a temperature below (eg, 0 to 50 ° C., preferably 0 to 20 ° C.).
The crystals of compound (I) thus obtained can be isolated, for example, by filtration.
As a method for analyzing the obtained crystal, a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
　化合物（Ｉ）は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。
　上記の製造法で得られる化合物（Ｉ）の結晶（以下、「本発明の結晶」と略記する）は、高純度、高品質であり、吸湿性が低く、通常条件下で長期間保存しても変質せず、安定性に極めて優れている。また、生物学的性質（例、体内動態（吸収性、分布、代謝、排泄）、薬効発現等）にも優れ、医薬として極めて有用である。 Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
The crystal of compound (I) obtained by the above production method (hereinafter abbreviated as “crystal of the present invention”) has high purity and high quality, low hygroscopicity, and is stored for a long time under normal conditions. Is very stable. In addition, it has excellent biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), drug effect expression, etc.) and is extremely useful as a medicine.
　化合物（Ｉ）は、溶媒和物（例えば、水和物など）であっても、無溶媒和物であってもよく、いずれも化合物（Ｉ）に包含される。また、同位元素（例、２Ｈ、３Ｈ、１１Ｃ、１４Ｃ、１８Ｆ、３５Ｓ、１２５Ｉなど）などで標識または置換された化合物も、化合物（Ｉ）に包含される。 Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I). A compound labeled or substituted with an isotope (eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.) is also encompassed in compound (I).
　化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）に変化する化合物、胃酸等により加水分解等を起こして化合物（Ｉ）に変化する化合物をいう。化合物（Ｉ）のプロドラッグとしては、化合物（Ｉ）のアミノ基がアシル化、アルキル化、リン酸化された化合物［例、化合物（Ｉ）のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、tert-ブチル化された化合物等］；化合物（Ｉ）の水酸基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物（例、化合物（Ｉ）の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等）；化合物（Ｉ）のカルボキシル基がエステル化、アミド化された化合物［例、化合物（Ｉ）のカルボキシル基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等］等が挙げられる。これらの化合物は自体公知の方法によって化合物（Ｉ）から製造することができる。
　また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような、生理的条件で化合物（Ｉ）に変化するものであってもよい。 A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like. As a prodrug of compound (I), a compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated [eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds and the like]; Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (eg, hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Compound, dimethylaminomethylcarbonylated compound, etc.); carboxyl group of compound (I) is esterified, amide [Example, Compound (I) carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl Esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compound, etc.]. These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
　化合物（Ｉ）は優れたα１Ｄアドレナリン受容体拮抗作用を有する。また、化合物（Ｉ）のなかでも、選択的なα１Ｄアドレナリン受容体拮抗作用を有する化合物が好ましい。ここで選択的なα１Ｄアドレナリン受容体拮抗作用とは、少なくとも、α１Ａアドレナリン受容体に対して１０倍以上、α１Ｂアドレナリン受容体に対して１０倍以上の拮抗活性を有することを意味する。化合物（Ｉ）は、選択的なα１Ｄアドレナリン受容体拮抗作用を有することによって、α１Ａ受容体あるいはα１Ｂ受容体への拮抗作用に基づくと考えられる血圧低下作用等が低減されることから、副作用の少ない薬剤になりうると考えられる。 Compound (I) has an excellent α 1D adrenergic receptor antagonistic action. Of the compounds (I), compounds having a selective α 1D adrenergic receptor antagonistic action are preferable. Here, selective α 1D adrenergic receptor antagonistic activity means that it has at least 10 times or more antagonistic activity against α 1A adrenergic receptor and 10 times or more against α 1B adrenergic receptor. Since the compound (I) has a selective α 1D adrenergic receptor antagonistic action, a blood pressure lowering action or the like that is considered to be based on an antagonistic action on the α 1A receptor or the α 1B receptor is reduced. It can be a drug with few side effects.
　化合物（Ｉ）は、α１Ｄアドレナリン受容体拮抗作用に基づき、哺乳動物（例、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト等）に対する総てのα１Ｄアドレナリン受容体関連疾患、例えば、
（１）下部尿路疾患（下記に記載する下部尿路症状を有するすべての疾患を含み、例えば、過活動膀胱、前立腺肥大症、間質性膀胱炎、慢性前立腺炎等を含む）、蓄尿症状（昼間頻尿、夜間頻尿、尿意切迫感、尿失禁、腹圧性尿失禁、切迫性尿失禁、混合性尿失禁、遺尿、夜間遺尿、持続性尿失禁、その他の尿失禁、膀胱知覚亢進、低下及び欠如等）、排尿症状（尿勢低下、尿線分割、尿線散乱、尿線途絶、排尿遅延、腹圧排尿、終末滴下等）、排尿後症状（残尿感、排尿後尿滴下等）、性交に伴う症状（性交痛、膣乾燥、尿失禁等）、骨盤臓器脱に伴う症状（異物感、腰痛等）、生殖器痛・下部尿路痛（膀胱痛、尿道痛、外陰部痛、膣痛、陰嚢痛、会陰痛、骨盤痛等）、生殖器・尿路痛症候群（膀胱痛症候群、尿道痛症候群、外陰痛症候群、膣症候群、陰嚢痛症候群、会陰痛症候群、骨盤痛症候群等）、下部尿路機能障害を示唆する症状症候群（過活動膀胱症候群、膀胱出口部閉塞を示唆する下部尿路症状等）、多尿、尿路結石（尿管、尿道）等、
（２）代謝性疾患〔例えば、糖尿病（インスリン依存性糖尿病、糖尿病性合併症、糖尿病性網膜症、糖尿病性細小血管症、糖尿病性神経障害等）、耐糖能異常、肥満、前立腺肥大症、性的機能不全等〕、
（３）中枢神経疾患〔例えば、神経変性疾患（例、アルツハイマー病、ダウン症、パーキンソン病、クロイツフェルト・ヤコブ病、筋萎縮性脊髄側索硬化症（ＡＬＳ）、ハンチントン舞踏病、糖尿病性ニューロパシー、多発性硬化症等）、精神疾患（例、統合失調症（精神分裂病）、うつ病、躁病、不安神経症、脅迫神経症、恐慌性障害、てんかん、アルコール依存症、薬物依存症、不安症状、不快精神状態、情緒異常、感情循環気質、神経過敏症、自閉症、失神、耽溺、性欲低下等）、中枢および末梢神経障害（例、頭部外傷、脊髄損傷、脳浮腫、知覚機能障害、知覚機能異常、自律神経機能障害、自律神経機能異常、むち打ち症等）、記憶障害（例、老年期認知症、健忘症、脳血管認知症等）、脳血管障害（例、脳出血、脳梗塞等の障害及びその後遺症・合併症、無症候性脳血管障害、一過性脳虚血発作、高血圧性脳症、脳血液関門の障害等）、脳血管障害の再発および後遺症（例、神経症候、精神症候、自覚症状、日常生活動作障害等）、脳血管閉塞後の中枢機能低下症、脳循環・腎循環自動調節能の障害または異常等〕、睡眠障害、
（４）性機能不全疾患〔例えば、男性勃起不全、射精障害、女性性機能不全等〕、
（５）消化器疾患〔例えば、過敏性腸症候群、炎症性腸疾患、潰瘍性大腸炎、クローン病、ウレアーゼ陽性のラセン状グラム陰性菌（例、ヘリコバクター・ピロリ等）に起因する異常（例、胃炎、胃潰瘍等）、胃癌、胃手術後障害、消化不良、食道潰瘍、膵炎、大腸ポリープ、胆石症、痔疾患、消化性潰瘍、時局性回腸炎、大食、便秘、下痢、腹鳴等〕、
（６）炎症性もしくはアレルギー性疾患〔例えば、アレルギー性鼻炎、結膜炎、消化管アレルギー、花粉症、アナフィラキシー、皮膚炎、ヘルペス、乾癬、気管支炎、喀痰、網膜症、手術・外傷後の炎症、腫脹の緩解、咽頭炎、膀胱炎、髄膜炎、炎症性眼疾患等〕、
（７）骨・関節疾患〔例えば、関節リウマチ（慢性関節リウマチ）、変形性関節炎、リウマチ様脊髄炎、骨粗鬆症、細胞等の異常増殖、骨折、再骨折、骨軟化症、骨減少症、骨ページェット病、硬直性脊髄炎、変形性膝関節炎及びそれらの類似疾患における関節組織の破壊等〕、
（８）呼吸器疾患〔例えば、かぜ症候群、肺炎、喘息、肺高血圧症、肺血栓・肺塞栓、肺サルコイドーシス、肺結核、間質性肺炎、珪肺、成人呼吸促迫症候群、慢性閉塞性肺疾患、咳等〕、
（９）感染症〔ＨＩＶ感染症、サイトメガロウイルス、インフルエンザウイルス、ヘルペスウイルス等のウイルス感染症、リケッチア感染症、細菌感染症、性感染症、カリニ肺炎、ヘリコバクターピロリ感染症、全身性真菌感染症、結核、侵襲性ブドウ状球菌感染症、急性ウイルス脳炎、急性バクテリア髄膜炎、エイズ脳症、敗血症、セプシス、重症セプシス、敗血症性ショック、内毒素性ショック、トキシンショック症候群等〕、
（１０）癌〔例えば、原発性、転移性または再発性の、乳癌、前立腺癌、膵癌、胃癌、肺癌、大腸癌（結腸癌、直腸癌、肛門癌）、食道癌、十二指腸癌、頭頚部癌（舌癌、咽頭癌、喉頭癌）、脳腫瘍、神経鞘腫、非小細胞肺癌、肺小細胞癌、肝臓癌、腎臓癌、胆管癌、子宮癌（子宮体癌、子宮頸癌）、卵巣癌、膀胱癌、皮膚癌、血管腫、悪性リンパ腫、悪性黒色腫、甲状腺癌、骨腫瘍、血管腫、血管線維腫、網膜肉腫、陰茎癌、小児固形癌、カポジ肉腫、ＡＩＤＳに起因するカポジ肉腫、上顎洞腫瘍、線維性組織球腫、平滑筋肉腫、横紋筋肉腫、脂肪肉腫、子宮筋腫、骨芽細胞腫、骨肉腫、軟骨肉腫、癌性の中皮腫瘍、白血病等の腫瘍、ホジキン病等〕、
（１１）循環器疾患〔例えば、急性冠動脈症候群（例、急性心筋梗塞、不安定狭心症等）、末梢動脈閉塞症、レイノー病、バージャー病、冠動脈インターベンション（経皮的冠動脈形成術（ＰＴＣＡ）、アテレクトミー（ＤＣＡ）、ステント留置等）後の再狭窄、冠動脈バイパス手術後の再狭窄、その他の末梢動脈におけるインターベンション（血管形成術、アテレクトミー、ステント留置等）及びバイパス手術後の再狭窄、虚血性心疾患（例、心筋梗塞、狭心症等）、心筋炎、間歇性跛行、ラクネ梗塞、動脈硬化症（例、アテローム性動脈硬化症等）、心不全（急性心不全、うっ血性を含む慢性心不全）、不整脈、動脈硬化巣の進展、血栓症、高血圧症、高血圧性耳鳴り、低血圧症等〕、
（１２）疼痛〔例えば、頭痛、偏頭痛、神経痛、膀胱痛を含む骨盤内臓痛等〕、
（１３）自己免疫疾患〔例えば、膠原病、全身性エリテマトーデス、強皮症、多発動脈炎、重症筋無力症、多発性硬化症、シェーグレン症候群、ベーチェット病等〕、
（１４）肝疾患〔例えば、慢性を含む肝炎、肝硬変、間質性肝疾患等〕、
（１５）膵疾患〔例えば、慢性を含む膵炎等〕、
（１６）腎疾患〔例えば、腎炎、糸球体腎炎、糸球体硬化症、腎不全、血栓性微小血管症、透析の合併症、放射線照射による腎症を含む臓器障害、糖尿病性腎症等〕、
（１７）内分泌疾患〔例えば、アジソン病、クッシング症候群、褐色細胞腫、原発性アルドステロン症等〕、
（１８）その他の疾患
（ａ）移植片拒絶反応〔例えば、移植後の拒絶反応、移植後の赤血球増加症・高血圧・臓器障害・血管肥厚、移植片対宿主疾患等〕、
（ｂ）血液・血球成分の性状異常〔例えば、血小板凝集能亢進、赤血球変形能の異常、白血球粘着能の亢進、血液粘度上昇、赤血球増加症、血管性紫斑病、自己免疫性溶血性貧血、播種性血管内凝固症候群（ＤＩＣ）、多発性骨髄症等〕、
（ｃ）婦人科疾患〔例えば、更年期障害、妊娠中毒、子宮内膜症、子宮筋腫、卵巣疾患、乳腺疾患、月経前期症候群、骨盤臓器脱（Pelvic Organ Prolapse）（例、膣前壁脱、膣尖端の脱、膣後壁脱、子宮脱等）、骨盤底筋群の脆弱化により臓器が正常位置から脱出する他の疾患（例、直腸脱等）等〕、
（ｄ）皮膚疾患〔例えば、ケロイド、血管腫、乾癬、掻痒等〕、
（ｅ）眼疾患〔例えば、緑内障、高眼圧症等〕、
（ｆ）耳鼻咽喉疾患〔例えば、メヌエル症候群、耳鳴り、味覚障害、めまい、平衡障害、嚥下障害等〕、
（ｇ）環境・職業性因子による疾患〔例えば、放射線障害、紫外線・赤外線・レーザー光線による障害、高山病等〕、
（ｈ）運動失調、硬直、振せん、運動障害、無動症、
（ｉ）慢性疲労症候群、
（ｊ）乳児突然死症候群、
（ｋ）吃逆（しゃっくり）、
（ｌ）動悸、眩暈、胸やけ等を起こす疾患の予防、治療薬として有用である。 Compound (I), based on alpha 1D adrenergic receptor antagonistic action, a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.) all alpha 1D adrenergic receptor for Body related diseases such as
(1) Lower urinary tract diseases (including all diseases having lower urinary tract symptoms described below, including overactive bladder, prostatic hypertrophy, interstitial cystitis, chronic prostatitis, etc.), urinary storage symptoms (Daytime frequent urination, nocturia, urgency, urinary incontinence, stress urinary incontinence, urge incontinence, mixed urinary incontinence, enuresis, nocturnal urine, persistent urinary incontinence, other urinary incontinence, increased bladder perception, Urination symptoms (urinary decline, urinary division, urinary scattering, urinary disruption, urination delay, abdominal pressure urination, terminal drop, etc.), post urinary symptoms (residual urine sensation, post-urine urine drop, etc.) ), Symptoms associated with intercourse (sexual pain, vaginal dryness, urinary incontinence, etc.), symptoms associated with pelvic organ prolapse (foreign body sensation, low back pain, etc.), genital pain / lower urinary tract pain (bladder pain, urethral pain, vulva pain, Vaginal pain, scrotal pain, perineal pain, pelvic pain, etc.), genital / urinary tract pain syndrome (bladder pain syndrome, urethral pain syndrome, vulvodynia syndrome) Vaginal syndrome, scrotal pain syndrome, perineal pain syndrome, pelvic pain syndrome, etc.), symptom syndrome suggesting lower urinary tract dysfunction (overactive bladder syndrome, lower urinary tract symptom suggesting bladder outlet obstruction, etc.), many Urine, urolithiasis (ureter, urethra), etc.
(2) Metabolic diseases [for example, diabetes (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microangiopathy, diabetic neuropathy, etc.), impaired glucose tolerance, obesity, prostatic hypertrophy, sex Dysfunction etc.),
(3) CNS diseases [eg, neurodegenerative diseases (eg, Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic spinal sclerosis (ALS), Huntington's chorea, diabetic neuropathy, frequent occurrence] Sclerosis), mental illness (eg, schizophrenia (schizophrenia), depression, mania, anxiety, anxiety, threatening neuropathy, panic disorder, epilepsy, alcoholism, drug dependence, anxiety symptoms, Uncomfortable mental state, emotional abnormalities, emotional circulation, hypersensitivity, autism, syncope, sputum, decreased libido, etc., central and peripheral neuropathy (eg, head trauma, spinal cord injury, brain edema, sensory dysfunction) Sensory dysfunction, autonomic dysfunction, autonomic dysfunction, whiplash, etc.), memory impairment (eg, senile dementia, amnesia, cerebral vascular dementia, etc.), cerebrovascular disorder (eg, cerebral hemorrhage, cerebral infarction, etc.) Failure And subsequent sequelae / complications, asymptomatic cerebrovascular disorder, transient ischemic attack, hypertensive encephalopathy, cerebral blood barrier disorder, etc., recurrence of cerebrovascular disorder and sequelae (eg, neurological symptoms, psychiatric symptoms, awareness) Symptoms, movements of daily living, etc.), hypofunction of central function after cerebrovascular occlusion, disorder or abnormality of cerebral circulation / autonomous regulation of renal circulation, etc.), sleep disorder,
(4) Sexual dysfunction diseases (for example, male erectile dysfunction, ejaculation disorder, female sexual dysfunction, etc.),
(5) Gastrointestinal diseases [eg, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, urease-positive spiral gram-negative bacteria (eg, Helicobacter pylori, etc.) (eg, Gastritis, gastric ulcer, etc.), gastric cancer, postoperative gastric surgery, indigestion, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoid disease, peptic ulcer, local ileitis, large meal, constipation, diarrhea, belly ],
(6) Inflammatory or allergic diseases [eg, allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, dermatitis, herpes, psoriasis, bronchitis, epilepsy, retinopathy, inflammation after surgery / trauma, swelling Remission, sore throat, cystitis, meningitis, inflammatory eye disease, etc.)
(7) Bone / joint diseases [eg rheumatoid arthritis (chronic rheumatoid arthritis), osteoarthritis, rheumatoid myelitis, osteoporosis, abnormal proliferation of cells, fracture, re-fracture, osteomalacia, osteopenia, bone page Etto's disease, ankylosing myelitis, osteoarthritis of the knee and joint tissue destruction in similar diseases, etc.]
(8) Respiratory diseases [eg, cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus / pulmonary embolism, pulmonary sarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, cough etc〕,
(9) Infectious diseases [HIV infection, cytomegalovirus, influenza virus, herpes virus and other viral infections, rickettsia infection, bacterial infection, sexually transmitted disease, carini pneumonia, Helicobacter pylori infection, systemic fungal infection Tuberculosis, invasive staphylococcal infection, acute viral encephalitis, acute bacterial meningitis, AIDS encephalopathy, sepsis, sepsis, severe sepsis, septic shock, endotoxic shock, toxin shock syndrome, etc.),
(10) Cancer [for example, primary, metastatic or recurrent breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer (colon cancer, rectal cancer, anal cancer), esophageal cancer, duodenal cancer, head and neck cancer (Tongue cancer, pharyngeal cancer, laryngeal cancer), brain tumor, schwannoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, uterine cancer (uterine body cancer, cervical cancer), ovarian cancer , Bladder cancer, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, hemangioma, hemangiofibroma, retinal sarcoma, penile cancer, childhood solid cancer, Kaposi sarcoma, Kaposi sarcoma caused by AIDS, Maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, uterine fibroid, osteoblastoma, osteosarcoma, chondrosarcoma, cancerous mesothelioma, leukemia tumor, Hodgkin disease etc〕,
(11) Cardiovascular diseases [for example, acute coronary syndrome (eg, acute myocardial infarction, unstable angina pectoris), peripheral arterial occlusion, Raynaud's disease, Buerger's disease, coronary intervention (percutaneous coronary angioplasty (PTCA) ), Restenosis after atherectomy (DCA), stent placement, etc., restenosis after coronary artery bypass surgery, other peripheral arterial interventions (angioplasty, atherectomy, stent placement, etc.) and restenosis after bypass surgery, Ischemic heart disease (eg, myocardial infarction, angina pectoris), myocarditis, intermittent claudication, lacunar infarction, arteriosclerosis (eg, atherosclerosis, etc.), heart failure (acute heart failure, chronic including congestive disease) Heart failure), arrhythmia, arteriosclerotic lesion development, thrombosis, hypertension, hypertensive tinnitus, hypotension etc.),
(12) pain (for example, pelvic visceral pain including headache, migraine, neuralgia, bladder pain, etc.),
(13) Autoimmune diseases (eg, collagen disease, systemic lupus erythematosus, scleroderma, polyarteritis, myasthenia gravis, multiple sclerosis, Sjogren's syndrome, Behcet's disease, etc.),
(14) Liver diseases [eg, chronic hepatitis, cirrhosis, interstitial liver disease, etc.]
(15) Pancreatic diseases [for example, chronic pancreatitis, etc.]
(16) Renal diseases (eg, nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, organ damage including nephropathy due to radiation, diabetic nephropathy, etc.),
(17) Endocrine diseases [eg Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.]
(18) Other diseases (a) Graft rejection (for example, rejection after transplantation, post-transplantation erythrocytosis / hypertension / organ damage / vascular thickening, graft-versus-host disease, etc.),
(B) abnormal properties of blood and blood cell components [for example, increased platelet aggregation ability, abnormal red blood cell deformability, increased white blood cell adhesion ability, increased blood viscosity, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, Disseminated intravascular coagulation syndrome (DIC), multiple myelopathy, etc.]
(C) gynecological diseases [eg climacteric disorder, pregnancy intoxication, endometriosis, uterine fibroids, ovarian disease, breast disease, premenstrual syndrome, pelvic organ prolapse (eg, anterior vaginal prolapse, vagina] (Prolapse of the apex, posterior wall of the vagina, prolapse of the uterus, etc.), other diseases in which the organ escapes from the normal position due to weakening of the pelvic floor muscles (eg rectal prolapse etc.)
(D) skin diseases [eg, keloids, hemangiomas, psoriasis, pruritus, etc.]
(E) eye diseases [eg glaucoma, ocular hypertension, etc.]
(F) Otolaryngology diseases (for example, Menuel syndrome, tinnitus, taste disorder, dizziness, balance disorder, swallowing disorder, etc.),
(G) Diseases caused by environmental / occupational factors (for example, radiation damage, ultraviolet / infrared / laser light damage, altitude sickness, etc.),
(H) ataxia, stiffness, tremor, movement disorder, ataxia,
(I) chronic fatigue syndrome,
(J) sudden infant death syndrome,
(K) Rebellion (hiccup),
(L) Useful as a preventive or therapeutic agent for diseases that cause palpitations, dizziness, heartburn, etc.
　これらの疾患のうち、特に、化合物（Ｉ）は、過活動膀胱、腹圧性尿失禁等の下部尿路症状改善剤やこれらの下部尿路症状の予防、治療薬として有用である。
　化合物（Ｉ）を含む製剤は、錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（吸入剤）、点眼剤のいずれであってもよい。
　本発明の予防・治療剤は、製剤の形態に応じて、例えば、混和、混練、造粒、打錠、コーティング、滅菌処理、乳化等の慣用の方法で製造できる。なお、製剤の製造に関して、例えば日本薬局方製剤総則の各項等を参照できる。また本発明の製剤は、有効成分と生体内分解性高分子化合物とを含む徐放剤に成形してもよい。該徐放剤の調製は、特開平９－２６３５４５号公報に記載の方法に準ずることができる。 Among these diseases, the compound (I) is particularly useful as an agent for improving lower urinary tract symptoms such as overactive bladder and stress urinary incontinence, and a preventive or therapeutic agent for these lower urinary tract symptoms.
Preparations containing Compound (I) are tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (eg, Orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion , Patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal agents, pulmonary agents (inhalants), and eye drops.
The prophylactic / therapeutic agent of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization treatment, emulsification, etc., depending on the form of the preparation. In addition, regarding manufacture of a formulation, each item etc. of the Japanese Pharmacopoeia general rules for preparation can be referred, for example. The preparation of the present invention may be formed into a sustained release agent containing an active ingredient and a biodegradable polymer compound. The sustained-release agent can be prepared according to the method described in JP-A-9-263545.
　本発明の製剤において、化合物（Ｉ）の含有量は、製剤の形態によって相違するが、通常、製剤全体に対して０．０１～１００重量％、好ましくは０．１～５０重量％、さらに好ましくは０．５～２０重量％程度である。
　化合物（Ｉ）を前記の医薬品として用いる場合、そのまま、或いは適宜の薬理学的に許容され得る担体、例えば、賦形剤（例、デンプン、乳糖、白糖、炭酸カルシウム、リン酸カルシウム等）、結合剤（例、デンプン、アラビアゴム、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、結晶セルロース、アルギン酸、ゼラチン、ポリビニルピロリドン等）、滑沢剤（例、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク等）、崩壊剤（例、カルボキシメチルセルロースカルシウム、タルク等）、希釈剤（例、注射用水、生理食塩水等）、必要に応じて添加剤（例、安定剤、保存剤、着色剤、香料、溶解助剤、乳化剤、緩衝剤、等張化剤等）等と常法により混合し、散剤、細粒剤、顆粒剤、錠剤、カプセル剤等の固形剤または注射剤等の液剤の形態で経口的または非経口的に投与することができる。また、化合物（Ｉ）は局所投与製剤に成形して投与すると関節疾患の患部に直接投与することもできる。この場合は、注射剤とするのが好ましい。局所投与用の非経口剤（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位、病巣等への注射剤、埋め込み剤、顆粒剤、散剤等の固形製剤、懸濁剤等の液剤、軟膏剤等）等として投与することもできる。 In the preparation of the present invention, the content of compound (I) varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 50% by weight, more preferably based on the whole preparation. Is about 0.5 to 20% by weight.
When the compound (I) is used as the above-mentioned pharmaceutical product, it is used as it is or an appropriate pharmacologically acceptable carrier, for example, excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders ( Examples, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (eg, , Carboxymethylcellulose calcium, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), additives (eg, stabilizers, preservatives, colorants, fragrances, solubilizers, emulsifiers, buffers) as necessary. Powders, fine granules, granules, tablets, caps, etc. It can be administered orally or parenterally in liquid in the form of a solid or injectable agent Le agent. Compound (I) can also be administered directly to the affected area of a joint disease when it is formed into a topical preparation and administered. In this case, an injection is preferable. Parenteral for topical administration (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, lesion And the like, solid preparations such as injections, implants, granules and powders, liquids such as suspensions, ointments and the like.
　例えば、注射剤とするには、化合物（Ｉ）を分散剤（例、Ｔｗｅｅｎ８０、ＨＣＯ－６０等の界面活性剤、カルボキシメチルセルロース、アルギン酸ナトリウム、ヒアルロン酸等の多糖類、ポリソルベート等）、保存剤（例、メチルパラベン、プロピルパラベン等）、等張化剤（例、塩化ナトリウム、マンニトール、ソルビトール、ブドウ糖等）、緩衝剤（例、炭酸カルシウム等）、ｐＨ調整剤（例、リン酸ナトリウム、リン酸カリウム等）等と共に水性懸濁剤とすることにより、実用的な注射用製剤が得られる。また、ゴマ油、コーン油等の植物油あるいはこれにレシチン等のリン脂質を混合したもの、あるいは中鎖脂肪酸トリグリセリド（例、ミグリオール８１２等）と共に分散して油性懸濁剤として実際に使用できる注射剤とする。 For example, for injection, compound (I) is used as a dispersant (eg, surfactants such as Tween 80 and HCO-60, polysaccharides such as carboxymethyl cellulose, sodium alginate, hyaluronic acid, polysorbate, etc.), preservatives ( Examples, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffers (eg, calcium carbonate, etc.), pH adjusters (eg, sodium phosphate, potassium phosphate) A practical injectable preparation can be obtained by using an aqueous suspension together with the like. In addition, an injection that can be used as an oily suspension by being dispersed together with vegetable oil such as sesame oil, corn oil or the like mixed with phospholipid such as lecithin, or medium chain fatty acid triglyceride (eg, miglyol 812). To do.
　本発明の予防・治療剤は、他の薬剤と共に用いることもできる。
　化合物（Ｉ）と配合又は併用し得る薬物（以下、併用薬物と略記する）としては、例えば、以下のようなものが用いられる。
（１）その他の下部尿路疾患（下部尿路症状に代表される症状を有するすべての疾患を含む）の予防・治療剤、アドレナリンα１受容体遮断薬（例、タムスロシン、ウラピジル、ナフトピジル、シロドシン、ドキサゾシン、アルフゾシン等）、抗コリン薬（例、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、ソリフェナシン、テミベリン、塩化トロスピウムまたはこれらの塩等）、ＮＫ－１受容体拮抗薬（例、アプレピタント、カソピタント、ＬＹ６８６０１７等）、アドレナリンβ３受容体作動薬（例、ソラベグロン、ＹＭ－１７８、ＫＲＰ－２０４、ＫＵＣ－７４８３、ＭＮ－２４６、ＣＬ－３１６２４３等）、ＴＲＰＶ１受容体作動薬（例、レジニフェラトキシン、カプサイシン製剤等）、ＴＲＰＶ１受容体拮抗薬（例、ＳＢ－７０５４９８、ＮＧＤ－８２４３等）、ボツリヌストキシン製剤（例、ＢＴＸ－Ａ等）、アドレナリンα１受容体作動薬（例、塩酸エフェドリン、塩酸ミトドリン等）、アドレナリンβ２受容体作動薬（例、クレンブテロール等）、ノルアドレナリン取り込み阻害物質、ノルアドレナリンおよびセロトニン取り込み阻害物質（例、デュロキセチン等）、３環性抗うつ薬（例、塩酸イミプラミン等）、平滑筋刺激薬（例、塩酸セリメベリン等）、女性ホルモン薬（例、結合型エストロゲン（プレマリン）、エストリオール等）等。
（２）糖尿病治療剤
　インスリン製剤〔例、ウシ、ブタの膵臓から抽出された動物インスリン製剤；大腸菌、イーストを用い、遺伝子工学的に合成したヒトインスリン製剤；インスリン亜鉛；プロタミンインスリン亜鉛；インスリンのフラグメント又は誘導体（例、ＩＮＳ－１等）等〕、インスリン感受性増強剤（例、塩酸ピオグリタゾン、トログリタゾン、ロシグリタゾン又はそのマレイン酸塩、ＪＴＴ－５０１、ＭＣＣ－５５５、ＹＭ－４４０、ＧＩ－２６２５７０、ＫＲＰ－２９７、ＦＫ－６１４、ＣＳ－０１１等）、α－グルコシダーゼ阻害剤（例、ボグリボース、アカルボース、ミグリトール、エミグリテート等）、ビグアナイド剤（例、フェンホルミン、メトホルミン、ブホルミン等）、スルホニルウレア剤（例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド等）やその他のインスリン分泌促進剤（例、レパグリニド、セナグリニド、ミチグリニド又はそのカルシウム塩水和物、ＧＬＰ－１、ナテグリニド等）、ジペプチジルペプチダーゼＩＶ阻害剤（例、ＮＶＰ－ＤＰＰ－２７８、ＰＴ－１００、Ｐ３２／９８等）、β３アゴニスト（例、ＣＬ－３１６２４３、ＳＲ－５８６１１－Ａ、ＵＬ－ＴＧ－３０７、ＡＪ－９６７７、ＡＺ４０１４０等）、アミリンアゴニスト（例、プラムリンチド等）、ホスホチロシンホスファターゼ阻害剤（例、バナジン酸等）、糖新生阻害剤（例、グリコーゲンホスホリラーゼ阻害剤、グルコース－６－ホスファターゼ阻害剤、グルカゴン拮抗剤等）、ＳＧＬＴ（ｓｏｄｉｕｍ－ｇｌｕｃｏｓｅ　ｃｏｔｒａｎｓｐｏｒｔｅｒ）阻害剤（例、Ｔ－１０９５等）等。
（３）糖尿病性合併症治療剤
　アルドース還元酵素阻害剤（例、トルレスタット、エパルレスタット、ゼナレスタット、ゾポルレスタット、フィダレスタット（ＳＮＫ－８６０）、ミナルレスタット（ＡＲＩ－５０９）、ＣＴ－１１２等）、神経栄養因子（例、ＮＧＦ、ＮＴ－３等）、ＡＧＥ阻害剤（例、ＡＬＴ－９４５、ピマゲジン、ピラトキサチン、Ｎ－フェナシルチアゾリウムブロミド（ＡＬＴ－７６６）、ＥＸＯ－２２６等）、活性酸素消去薬（例、チオクト酸等）、脳血管拡張剤（例、チアプリド等）等。
（４）抗高脂血剤
　コレステロール合成阻害剤であるスタチン系化合物（例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、セリバスタチン又はそれらの塩（例、ナトリウム塩等）等）、スクアレン合成酵素阻害剤、トリグリセリド低下作用を有するフィブラート系化合物（例、ベザフィブラート、クロフィブラート、シムフィブラート、クリノフィブラート等）等。
（５）降圧剤
　アンジオテンシン変換酵素阻害剤（例、カプトプリル、エナラプリル、デラプリル等）、アンジオテンシンＩＩ拮抗剤（例、ロサルタン、カンデサルタン　シレキセチル等）、カルシウム拮抗剤（例、マニジピン、ニフェジピン、アムロジピン、エホニジピン、ニカルジピン等）、クロニジン等。
（６）抗肥満剤
　中枢性抗肥満薬（例、デキスフェンフルラミン、フェンフルラミン、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン、クロベンゾレックス等）、膵リパーゼ阻害薬（例、オルリスタット等）、β３アゴニスト（例、ＣＬ－３１６２４３、ＳＲ－５８６１１－Ａ、ＵＬ－ＴＧ－３０７、ＡＪ－９６７７、ＡＺ４０１４０等）、ペプチド性食欲抑制薬（例、レプチン、ＣＮＴＦ（毛様体神経栄養因子）等）、コレシストキニンアゴニスト（例、リンチトリプト、ＦＰＬ－１５８４９等）等。
（７）利尿剤
　キサンチン誘導体（例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン等）、チアジド系製剤（例、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンジルヒドロクロロチアジド、ペンフルチジド、ポリチアジド、メチクロチアジド等）、抗アルドステロン製剤（例、スピロノラクトン、トリアムテレン等）、炭酸脱水酵素阻害剤（例、アセタゾラミド等）、クロルベンゼンスルホンアミド系製剤（例、クロルタリドン、メフルシド、インダパミド等）、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミド等。
（８）化学療法剤
　アルキル化剤（例、サイクロフォスファミド、イフォスファミド等）、代謝拮抗剤（例、メソトレキセート、５－フルオロウラシル等）、抗癌性抗生物質（例、マイトマイシン、アドリアマイシン等）、植物由来抗癌剤（例、ビンクリスチン、ビンデシン、タキソール等）、シスプラチン、カルボプラチン、エトポシド等、なかでも５－フルオロウラシル誘導体であるフルツロンあるいはネオフルツロン等。
（９）免疫療法剤
　微生物又は細菌成分（例、ムラミルジペプチド誘導体、ピシバニール等）、免疫増強活性のある多糖類（例、レンチナン、シゾフィラン、クレスチン等）、遺伝子工学的手法で得られるサイトカイン（例、インターフェロン、インターロイキン（ＩＬ）等）、コロニー刺激因子（例、顆粒球コロニー刺激因子、エリスロポエチン等）等、なかでもＩＬ－１、ＩＬ－２、ＩＬ－１２等。
（１０）動物モデルや臨床で悪液質改善作用が認められている薬剤
　プロゲステロン誘導体（例、メゲステロールアセテート）〔ジャーナル・オブ・クリニカル・オンコロジー（Ｊｏｕｒｎａｌ　ｏｆ　Ｃｌｉｎｉｃａｌ　Ｏｎｃｏｌｏｇｙ）、第１２巻、２１３～２２５頁、１９９４年〕、メトクロプラミド系薬剤、テトラヒドロカンナビノール系薬剤（文献はいずれも上記と同様）、脂肪代謝改善剤（例、エイコサペンタエン酸等）〔ブリティシュ・ジャーナル・オブ・キャンサー（Ｂｒｉｔｉｓｈ　Ｊｏｕｒｎａｌ　ｏｆ　Ｃａｎｃｅｒ）、第６８巻、３１４～３１８頁、１９９３年〕、成長ホルモン、ＩＧＦ－１、あるいは悪液質を誘導する因子であるＴＮＦ－α、ＬＩＦ、ＩＬ－６、オンコスタチンＭに対する抗体等。
（１１）消炎剤
　ステロイド剤（例、デキサメサゾン等）、ヒアルロン酸ナトリウム、シクロオキシゲナーゼ阻害剤（例、インドメタシン、ケトプロフェン、ロキソプロフェン、メロキシカム、アムピロキシカム、セレコキシブ、ロフェコキシブ等）等。
（１２）その他
　糖化阻害剤（例、ＡＬＴ－７１１等）、神経再生促進薬（例、Ｙ－１２８、ＶＸ８５３、ｐｒｏｓａｐｔｉｄｅ等）、中枢神経系作用薬（例、デシプラミン、アミトリプチリン、イミプラミン、フロキセチン、パロキセチン、ドキセピン等の抗うつ薬）、抗てんかん薬（例、ラモトリジン、カルバマゼピン）、抗不整脈薬（例、メキシレチン）、アセチルコリン受容体リガンド（例、ＡＢＴ－５９４）、エンドセリン受容体拮抗薬（例、ＡＢＴ－６２７）、モノアミン取り込み阻害薬（例、トラマドル）、インドールアミン取り込み阻害薬（例、フロキセチン、パロキセチン）、麻薬性鎮痛薬（例、モルヒネ）、ＧＡＢＡ受容体作動薬（例、ギャバペンチン）、ＧＡＢＡ取り込み阻害薬（例、チアガビン）、α２受容体作動薬（例、クロニジン）、局所鎮痛薬（例、カプサイシン）、プロテインキナーゼＣ阻害剤（例、ＬＹ－３３３５３１）、抗不安薬（例、ベンゾジアゼピン類）、ホスホジエステラーゼ阻害薬（例、シルデナフィル）、ドーパミン受容体作動薬（例、アポモルフィン）、ドーパミン受容体拮抗薬（例、ハロペリドール）、セロトニン受容体作動薬（例、クエン酸タンドスピロン、スマトリプタン）、セロトニン受容体拮抗薬（例、塩酸シプロヘプタジン、オンダンセトロン）、セロトニン取り込み阻害薬（例、マレイン酸フルボキサミン、フロキセチン、パロキセチン）、睡眠導入剤（例、トリアゾラム、ゾルピデム）、抗コリン剤、α１受容体遮断薬（例、タムスロシン）、筋弛緩薬（例、バクロフェン等）、カリウムチャンネル開口薬（例、ニコランジル）、カルシウムチャンネル遮断薬（例、ニフェジピン）、アルツハイマー病予防・治療薬（例、ドネペジル、リバスチグミン、ガランタミン）、パーキンソン病治療薬（例、Ｌ－ドーパ）、多発性硬化症予防・治療薬（例、インターフェロンβ－１ａ）、ヒスタミンＨ１受容体阻害薬（例、塩酸プロメタジン）、プロトンポンプ阻害薬（例、ランソプラゾール、オメプラゾール）、抗血栓薬（例、アスピリン、シロスタゾール）、ＮＫ－２受容体アンタゴニスト、ＨＩＶ感染症治療薬（サキナビル、ジドブジン、ラミブジン、ネビラピン）、慢性閉塞性肺疾患治療薬（サルメテロール、チオトロピウムブロミド、シロミラスト）等。 The prophylactic / therapeutic agent of the present invention can be used together with other drugs.
Examples of drugs that can be blended or used in combination with compound (I) (hereinafter abbreviated as concomitant drugs) include the following.
(1) Preventive and therapeutic agents for other lower urinary tract diseases (including all diseases having symptoms represented by lower urinary tract symptoms), adrenergic α1 receptor blockers (eg, tamsulosin, urapidil, naphthopidyl, silodosin, Doxazosin, alfuzosin, etc.), anticholinergic drugs (eg, oxybutynin, propiverine, darifenacin, tolterodine, solifenacin, temiverine, trospium chloride or salts thereof), NK-1 receptor antagonists (eg, aprepitant, casiopitant, LY686017, etc.) , Adrenergic β3 receptor agonists (eg, solabegron, YM-178, KRP-204, KUC-7484, MN-246, CL-316243, etc.), TRPV1 receptor agonists (eg, resiniferatoxin, capsaicin preparations, etc.) ), TRPV1 receptor antagonist ( Examples, SB-705498, NGD-8243, etc.), botulinum toxin preparations (eg, BTX-A, etc.), adrenergic α1 receptor agonists (eg, ephedrine hydrochloride, mitodrine hydrochloride, etc.), adrenergic β2 receptor agonists (eg, Clenbuterol, etc.), noradrenaline uptake inhibitors, noradrenaline and serotonin uptake inhibitors (eg, duloxetine, etc.), tricyclic antidepressants (eg, imipramine hydrochloride, etc.), smooth muscle stimulants (eg, selimevelin hydrochloride, etc.), female hormones Drugs (eg, conjugated estrogens (premarin), estriol, etc.) etc.
(2) Diabetes therapeutic agent Insulin preparations [eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin fragments Or derivatives (eg, INS-1 etc.)], insulin sensitivity enhancers (eg, pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP) -297, FK-614, CS-011, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), sulfonylurea agents (eg, Tolbutamide, Rivenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.) and other insulin secretagogues (eg, repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, GLP-1, nateglinide, etc.) Dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT-100, P32 / 98, etc.), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9777) , AZ40140, etc.), amylin agonist (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitor (eg, vanadic acid, etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist) Etc.), SGLT (sodium-glucose transporter) inhibitors (eg, T-1095 etc.) and the like.
(3) Treatment for diabetic complications Aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), CT-112 etc.), nerve Nutritional factors (eg, NGF, NT-3, etc.), AGE inhibitors (eg, ALT-945, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT-766), EXO-226, etc.), active oxygen elimination Drugs (eg, thioctic acid, etc.), cerebral vasodilators (eg, tiapride, etc.), etc.
(4) Antihyperlipidemic agents Statin compounds that are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin or salts thereof (eg, sodium salt, etc.)), squalene synthase inhibition Agents, fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.) and the like.
(5) Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonist (eg, losartan, candesartan cilexetil, etc.), calcium antagonist (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine) Etc.), clonidine and the like.
(6) Anti-obesity agents Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex, etc.), pancreatic lipase inhibitor (Eg, orlistat, etc.), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140, etc.), peptidic appetite suppressants (eg, leptin, CNTF (hair-like) Somatic neurotrophic factor)), cholecystokinin agonists (eg, Lynchtripto, FPL-15849, etc.) and the like.
(7) Diuretics xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, etacrine Acid, piretanide, bumetanide, furosemide, etc.
(8) Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), plants Derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide, etc., among others, 5-fluorouracil derivatives such as furtulon or neoflutulon.
(9) Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among them IL-1, IL-2, IL-12, etc.
(10) Drugs that have been shown to improve cachexia in animal models and clinically Progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225 P., 1994], metoclopramide drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer (British Journal of Cancer) , 68, 314-318, 1993], growth hormone, IGF-1, or antibodies to TNF-α, LIF, IL-6, oncostatin M, which are factors that induce cachexia, and the like.
(11) Anti-inflammatory agents Steroids (eg, dexamethasone, etc.), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib, etc.) and the like.
(12) Others Glycation inhibitors (eg, ALT-711 etc.), nerve regeneration promoters (eg, Y-128, VX853, prostide etc.), central nervous system drugs (eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine) , Antidepressants such as doxepin), antiepileptic drugs (eg, lamotrigine, carbamazepine), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT-594), endothelin receptor antagonists (eg, ABT) -627), monoamine uptake inhibitors (eg, tramadol), indoleamine uptake inhibitors (eg, floxetine, paroxetine), narcotic analgesics (eg, morphine), GABA receptor agonists (eg, gabapentin), GABA uptake Inhibitor (eg, tiagabin), α 2 receptor agonist (Eg, clonidine), topical analgesics (eg, capsaicin), protein kinase C inhibitors (eg, LY-333531), anxiolytics (eg, benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptors Agonist (eg, apomorphine), dopamine receptor antagonist (eg, haloperidol), serotonin receptor agonist (eg, tandospirone citrate, sumatriptan), serotonin receptor antagonist (eg, cyproheptadine hydrochloride, ondansetron) , Serotonin uptake inhibitors (eg, fluvoxamine maleate, floxetine, paroxetine), sleep inducers (eg, triazolam, zolpidem), anticholinergic agents, α 1 receptor blockers (eg, tamsulosin), muscle relaxants (eg, Baclofen, etc.), potassium channel openers (eg, Corandil), calcium channel blockers (eg, nifedipine), Alzheimer's disease preventive / therapeutic (eg, donepezil, rivastigmine, galantamine), Parkinson's disease (eg, L-dopa), multiple sclerosis preventive / therapeutic ( Examples, interferon β-1a), histamine H 1 receptor inhibitors (eg, promethazine hydrochloride), proton pump inhibitors (eg, lansoprazole, omeprazole), antithrombotic agents (eg, aspirin, cilostazol), NK-2 receptor Antagonists, drugs for treating HIV infection (saquinavir, zidovudine, lamivudine, nevirapine), drugs for treating chronic obstructive pulmonary disease (salmeterol, tiotropium bromide, silomilast) and the like.
　抗コリン剤としては、例えば、アトロピン、スコポラミン、ホマトロピン、トロピカミド、シクロペントラート、臭化ブチルスコポラミン、臭化プロパンテリン、臭化メチルベナクチジウム、臭化メペンゾラート、フラボキサート、ピレンゼピン、臭化イプラトピウム、トリヘキシフェニジル、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、テミベリン、塩化トロスピウム又はその塩（例、硫酸アトロピン、臭化水素酸スコポラミン、臭化水素酸ホマトロピン、塩酸シクロペントラート、塩酸フラボキサート、塩酸ピレンゼピン、塩酸トリヘキシフェニジル、塩酸オキシブチニン、酒石酸トルテロジン等）等が用いられ、なかでも、オキシブチニン、プロピベリン、ダリフェナシン、トルテロジン、テミベリン、塩化トロスピウム又はその塩（例、塩酸オキシブチニン、酒石酸トルテロジン等）が好適である。また、アセチルコリンエステラーゼ阻害薬（例、ジスチグミン等）等も使用することができる。 Examples of the anticholinergic agent include atropine, scopolamine, homatropine, tropicamide, cyclopentrate, butylscopolamine bromide, propantheline bromide, methylbenactidium bromide, mepenzolate bromide, flavoxate, pirenzepine, ipratopium bromide, trihepium Xyphenidyl, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospium chloride or its salts (eg, atropine sulfate, scopolamine hydrobromide, homatropine hydrobromide, cyclopentrate hydrochloride, flavoxate hydrochloride, pirenzepine hydrochloride, trihepine Xyphenidyl, oxybutynin hydrochloride, tolterodine tartrate, etc.) are used. Among them, oxybutynin, propiverine, darifenacin, tolterodine, temiverine, Supiumu or a salt thereof (e.g., oxybutynin hydrochloride, etc. tolterodine tartrate) are preferred. In addition, acetylcholinesterase inhibitors (eg, distigmine etc.) and the like can also be used.
　ＮＫ－２受容体アンタゴニストとしては、例えば、ＧＲ１５９８９７、ＧＲ１４９８６１、ＳＲ４８９６８（ｓａｒｅｄｕｔａｎｔ）、ＳＲ１４４１９０、ＹＭ３５３７５、ＹＭ３８３３６、ＺＤ７９４４、Ｌ－７４３９８６、ＭＤＬ１０５２１２Ａ、ＺＤ６０２１、ＭＤＬ１０５１７２Ａ、ＳＣＨ２０５５２８、ＳＣＨ６２３７３、Ｒ－１１３２８１等のピペリジン誘導体、ＲＰＲ－１０６１４５等のペルヒドロイソインドール誘導体、ＳＢ－４１４２４０等のキノリン誘導体、ＺＭ－２５３２７０等のピロロピリミジン誘導体、ＭＥＮ１１４２０（ｎｅｐａｄｕｔａｎｔ）、ＳＣＨ２１７０４８、Ｌ－６５９８７７、ＰＤ－１４７７１４（ＣＡＭ－２２９１）、ＭＥＮ１０３７６、Ｓ１６４７４等のプソイドペプチド誘導体、その他、ＧＲ１００６７９、ＤＮＫ３３３、ＧＲ９４８００、ＵＫ－２２４６７１、ＭＥＮ１０３７６、ＭＥＮ１０６２７、又はそれらの塩等が挙げられる。 Examples of NK-2 receptor antagonists include GR1599897, GR1499861, SR48968 (saredutant), SR144190, YM35375, YM38336, ZD7944, L-743986, MDL105212A, ZD6021, MDL105172A, SCH205528, pelysin, SCH81373, R132 Perhydroisoindole derivatives such as RPR-106145, quinoline derivatives such as SB-414240, pyrrolopyrimidine derivatives such as ZM-253270, MEN11420 (nepadutant), SCH217048, L-659877, PD-147714 (CAM-2291), MEN10376, Pseudopeptide derivatives such as S16474, etc. R100679, DNK333, GR94800, UK-224671, MEN10376, MEN10627, or a salt thereof and the like.
　併用に際しては、化合物（Ｉ）と併用薬物の投与時期は限定されず、化合物（Ｉ）またはその医薬組成物と併用薬物またはその医薬組成物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。
　併用の投与形態は、特に限定されず、投与時に、化合物（Ｉ）と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、（１）化合物（Ｉ）またはその医薬組成物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、（２）化合物（Ｉ）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、（３）化合物（Ｉ）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、（４）化合物（Ｉ）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、（５）化合物（Ｉ）またはその医薬組成物と併用薬物またはその医薬組成物とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例、化合物（Ｉ）またはその医薬組成物；併用薬物またはその医薬組成物の順序での投与、あるいは逆の順序での投与）等が挙げられる。
　本発明の併用剤における化合物（Ｉ）と併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。
　例えば、本発明の併用剤における化合物（Ｉ）の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし１００重量％、好ましくは約０．１ないし５０重量％、さらに好ましくは約０．５ないし２０重量％程度である。 In the combined use, the administration timing of the compound (I) and the concomitant drug is not limited, and the compound (I) or a pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof may be simultaneously administered to the administration subject. However, it may be administered with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
The administration form of the combination is not particularly limited as long as the compound (I) and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously compounding compound (I) or a pharmaceutical composition thereof and a concomitant drug, and (2) compound (I) or a medicament thereof. Simultaneous administration of the two preparations obtained by separately formulating the composition and the concomitant drug or pharmaceutical composition thereof by the same route of administration, (3) Compound (I) or a pharmaceutical composition thereof and the concomitant drug or pharmaceutical thereof Administration of two types of preparations obtained by separately formulating the composition with a time difference in the same route of administration, (4) Compound (I) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof Simultaneous administration of two types of preparations obtained by separate formulation by different administration routes, (5) obtained by separately formulating Compound (I) or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof 2 Different administration courses for different types of formulations Administration at an interval via the; include (e.g., Compound (I) or a pharmaceutical composition thereof in combination administration in the order of the drug or a pharmaceutical composition thereof, or in the reverse order) and the like.
The compounding ratio of the compound (I) and the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of compound (I) in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
　本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし１００重量％、好ましくは約０．１ないし５０重量％、さらに好ましくは約０．５ないし２０重量％程度である。
　本発明の併用剤における担体等の添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１ないし９９．９９重量％、好ましくは約１０ないし９０重量％程度である。
　また、化合物（Ｉ）および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。
　投与量は、化合物（Ｉ）または薬学上許容可能なその塩の種類、投与ルート、症状、患者の年令等によっても異なるが、例えば、過活動膀胱成人患者に経口的に投与する場合、１日当たり体重１ｋｇあたり化合物（Ｉ）として約０．００５～５０ｍｇ、好ましくは約０．０５～１０ｍｇ、さらに好ましくは約０．０５～１ｍｇを１～３回程度に分割投与できる。
　本発明の医薬組成物が徐放性製剤である場合の投与量は、化合物（Ｉ）の種類と含量、剤形、薬物放出の持続時間、投与対象動物（例、ヒト、ラット、マウス、ネコ、イヌ、ウサギ、牛、豚等の哺乳動物）、投与目的により種々異なるが、例えば非経口投与により適用する場合には、1週間に約０．１から約１００ｍｇの化合物（Ｉ）が投与製剤から放出されるようにすればよい。
　併用薬物は、副作用が問題とならない範囲でどのような量を設定することも可能である。併用薬物としての一日投与量は、症状の程度、投与対象の年齢、性別、体重、感受性差、投与の時期、間隔、医薬製剤の性質、調剤、種類、有効成分の種類等によって異なり、特に限定されないが、薬物の量として通常、たとえば経口投与で哺乳動物１ｋｇ体重あたり約０．００１～２０００ｍｇ、好ましくは約０．０１～５００ｍｇ、さらに好ましくは、約０．１～１００ｍｇ程度であり、これを通常１日１～４回に分けて投与する。 The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation About 0.5 to 20% by weight.
The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
The same content may be used when compound (I) and the concomitant drug are formulated separately.
The dose varies depending on the type of compound (I) or a pharmaceutically acceptable salt thereof, the route of administration, symptoms, patient age, etc. For example, when administered orally to an overactive bladder adult patient, 1 About 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.05 to 1 mg as compound (I) per kg body weight per day can be divided and administered in about 1 to 3 times.
When the pharmaceutical composition of the present invention is a sustained-release preparation, the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (eg, human, rat, mouse, cat) Mammals such as dogs, rabbits, cows, and pigs), depending on the purpose of administration. For example, when applied by parenteral administration, about 0.1 to about 100 mg of compound (I) is administered in a week. May be released from the.
The amount of the concomitant drug can be set as long as side effects do not become a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, weight, sensitivity difference, timing of administration, interval, nature of the pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration. Is usually administered in 1 to 4 divided doses per day.
　本発明の併用剤を投与するに際しては、同時期に投与してもよいが、併用薬物を先に投与した後、化合物（Ｉ）を投与してもよいし、化合物（Ｉ）を先に投与し、その後で併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後１分～３日以内、好ましくは１０分～１日以内、より好ましくは１５分～１時間以内に化合物（Ｉ）を投与する方法が挙げられる。化合物（Ｉ）を先に投与する場合、化合物（Ｉ）を投与した後、１分～１日以内、好ましくは１０分～６時間以内、より好ましくは１５分から１時間以内に併用薬物を投与する方法が挙げられる。
　本発明の医薬組成物は、低毒性で安全に使用することができる。特に以下に示す実施例化合物は、経口投与されたときの吸収性において優れているので、経口用製剤のために有利に使用できる。 When administering the concomitant drug of the present invention, it may be administered at the same time, but after administering the concomitant drug first, compound (I) may be administered, or compound (I) is administered first. Thereafter, the concomitant drug may be administered. In the case of administration with a time difference, the time difference varies depending on the active ingredient, dosage form, and administration method to be administered. The method includes administering Compound (I) within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When compound (I) is administered first, the concomitant drug is administered within 1 minute to 1 day after administration of compound (I), preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
The pharmaceutical composition of the present invention has low toxicity and can be used safely. In particular, the Example compounds shown below are excellent in absorbability when administered orally, and can be advantageously used for oral preparations.
　以下に、参考例、実施例および試験例に基づいて本発明をより詳細に説明するが、本発明は実施例により限定されるものではなく、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。
（分取ＨＰＬＣ条件）
　下記の実施例において、分取ＨＰＬＣによる精製は以下の条件により行った。
機器：ギルソン社ハイスループット精製システム
カラム：資生堂　Capcelpak C18 UG-120, S-5 μM, 20 x 50 mm、あるいはYMC　CombiPrep Hydrosphere C18 HS-340-CC, S-5 μM, 20 x 50 mm
溶媒：Ａ液；0.1%トリフルオロ酢酸含有水、Ｂ液；0.1%トリフルオロ酢酸含有アセトニトリル
グラジエントサイクル：0.00分（A液/B液＝95/5）, 1.10分（A液/B液＝95/5）, 5.00分（A液/B液＝0/100）, 6.40分（A液/B液＝0/100）, 6.50分（A液/B液＝95/5）
流速：20 mL/min
検出法：UV 220nm
（その他の条件）
　1H-NMRスペクトルは、内部標準としてテトラメチルシランを用いてブルカー社製AV-400M（400MHz）、AVANCE300（300MHz）、AVANCEII300（300MHz）、Varian社製 VNMRS-400（400MHz）で測定し、全δ値をppmで示した。混合溶媒において示した数値は、特に断らない限り各溶媒の容積混合比である。%は特に断らない限り重量パーセントを意味する。本明細書中における室温（常温）とは、約10℃から約35℃の温度を表す。
　実施例および参考例における略号の意味は以下の通りである。
　ＮＭＲ：核磁気共鳴スペクトル
　ＬＣ－ＭＳ：液体クロマトグラフィー－質量分析スペクトル
　ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
　ＴＨＦ：テトラヒドロフラン
　ＤＭＳＯ：ジメチルスルホキシド
　ＩＰＥ：ジイソプロピルエーテル
　ＮａＢＨ（ＯＡｃ）３：トリアセトキシ水素化ホウ素ナトリウム
　ＨＯＢｔ：１－ヒドロキシベンゾトリアゾール
　ＷＳＣ：１－エチル－３－（ジメチルアミノプロピル）カルボジイミド塩酸塩
　Ｅｔ３Ｎ：トリエチルアミン
　Ｈz：ヘルツ
　Ｊ：カップリング定数
　ｍ：マルチプレット
　ｑ：クワルテット
　ｑｕｉｎ：クインテット
　ｔｄ：トリプルダブレット
　ｔ：トリプレット
　ｄｄ：ダブルダブレット
　ｄｄｄ：ダブルダブルダブレット
　ｄ：ダブレット
　ｓ：シングレット
　ｂｒ：ブロード
　Ｎ：規定濃度
　Ｍ：モル濃度
　Ｂｏｃ：ｔｅｒｔ－ブチルオキシカルボニル Hereinafter, the present invention will be described in more detail based on reference examples, examples, and test examples. However, the present invention is not limited to the examples, and may be changed without departing from the scope of the present invention. Also good.
(Preparative HPLC conditions)
In the following examples, purification by preparative HPLC was performed under the following conditions.
Equipment: Gilson High Throughput Purification System Column: Shiseido Capcelpak C18 UG-120, S-5 μM, 20 x 50 mm, or YMC CombiPrep Hydrosphere C18 HS-340-CC, S-5 μM, 20 x 50 mm
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (A solution / B solution = 95/5), 1.10 minutes (A solution / B solution = 95 / 5), 5.00 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B liquid = 95/5)
Flow rate: 20 mL / min
Detection method: UV 220nm
(Other conditions)
1 H-NMR spectrum was measured with Bruker AV-400M (400MHz), AVANCE300 (300MHz), AVANCEII300 (300MHz), Varian VNMRS-400 (400MHz) using tetramethylsilane as an internal standard. The δ value was expressed in ppm. The numerical value shown in the mixed solvent is a volume mixing ratio of each solvent unless otherwise specified. % Means weight percent unless otherwise specified. The room temperature (ordinary temperature) in this specification represents a temperature of about 10 ° C. to about 35 ° C.
The meanings of the abbreviations in Examples and Reference Examples are as follows.
NMR: Nuclear magnetic resonance spectrum LC-MS: Liquid chromatography-mass spectrometry spectrum DMF: N, N-dimethylformamide THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide IPE: Diisopropyl ether NaBH (OAc) 3 : Sodium triacetoxyborohydride HOBt: 1-hydroxybenzotriazole WSC: 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride Et 3 N: triethylamine Hz: Hertz J: coupling constant m: multiplet q: quartet quin: quintet td: triplet t: Triplet dd: Double doublet ddd: Double double doublet d: Doublet s: Singlet br: Broad N: Normal concentration M: Molar concentration oc: tert- butyloxycarbonyl
参考例１
1-[5-クロロ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩
（工程１）ＤＭＦ（20 mL）溶液中、5-クロロ-2-フルオロベンゾニトリル（2.0 g）とナトリウム メタンチオラート（0.99 g）を60℃で1時間攪拌した。反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ塩酸、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去し、5-クロロ-2-(メチルスルファニル)ベンゾニトリル（1.61 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.55 (3H, s), 7.20-7.28 (1H, m), 7.49 (1H, dd, J= 8.3, 2.3 Hz), 7.57 (1H, d, J= 2.3 Hz).
（工程２）工程１で得られた5-クロロ-2-(メチルスルファニル)ベンゾニトリル（3.6 g）のＴＨＦ（150 mL）溶液に水素化リチウムアルミニウム（1.12 g）を0℃で加えた。室温で2時間攪拌後、硫酸ナトリウム10水和物を加えた。さらに室温で30分攪拌後、無機物をセライトでろ別した。ろ液を減圧濃縮後、残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。得られた固体をろ取することにより、1-[5-クロロ-2-(メチルスルファニル)フェニル]メタンアミン塩酸塩（3.43 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.52 (3H, s), 4.06 (2H, s), 7.37-7.52 (2H, m), 7.56 (1H, d, J= 2.1 Hz), 8.43 (3H, s).
（工程３）工程２で得られた1-[5-クロロ-2-(メチルスルファニル)フェニル]メタンアミン塩酸塩（10.9 g）とＥｔ３Ｎ（9.84 g）のＴＨＦ（200 mL）溶液に二炭酸ジ-t-ブチル（15.9 g）を室温で加えた。同温で3時間攪拌後、反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ塩酸、続いて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチル（250 mL）に溶解後、m-クロロ過安息香酸（28.9 g）を室温で加えた。同温で2時間攪拌後、反応液を炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:1）で精製した。得られた残渣をメタノール（30 mL）に溶解させ、4Ｎ塩化水素／酢酸エチル溶液（20 mL）を加え、60℃で30分間攪拌した。溶媒を減圧下留去し、得られた固体をろ取した後、酢酸エチルで洗浄して、標題化合物（7.85 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.36 (3H, s), 4.44 (2H, s), 7.79 (1H, dd, J= 8.5, 2.1 Hz), 7.91-8.09 (2H, m), 8.58 (3H, s). Reference example 1
1- [5-Chloro-2- (methylsulfonyl) phenyl] methanamine hydrochloride (Step 1) In a DMF (20 mL) solution, 5-chloro-2-fluorobenzonitrile (2.0 g) and sodium methanethiolate (0.99 g) ) Was stirred at 60 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid followed by saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 5-chloro-2- (methylsulfanyl) benzonitrile (1.61 g). It was. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.55 (3H, s), 7.20-7.28 (1H, m), 7.49 (1H, dd, J = 8.3, 2.3 Hz), 7.57 (1H, d, J = 2.3 Hz).
(Step 2) To a solution of 5-chloro-2- (methylsulfanyl) benzonitrile (3.6 g) obtained in Step 1 in THF (150 mL), lithium aluminum hydride (1.12 g) was added at 0 ° C. After stirring at room temperature for 2 hours, sodium sulfate decahydrate was added. Further, after stirring at room temperature for 30 minutes, the inorganic substance was filtered off through celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in methanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The obtained solid was collected by filtration to obtain 1- [5-chloro-2- (methylsulfanyl) phenyl] methanamine hydrochloride (3.43 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.52 (3H, s), 4.06 (2H, s), 7.37-7.52 (2H, m), 7.56 (1H, d, J = 2.1 Hz), 8.43 (3H, s).
(Step 3) Dicarbonate was added to a solution of 1- [5-chloro-2- (methylsulfanyl) phenyl] methanamine hydrochloride (10.9 g) obtained in Step 2 and Et 3 N (9.84 g) in THF (200 mL). Di-t-butyl (15.9 g) was added at room temperature. After stirring at the same temperature for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (250 mL), and m-chloroperbenzoic acid (28.9 g) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 1). The obtained residue was dissolved in methanol (30 mL), 4N hydrogen chloride / ethyl acetate solution (20 mL) was added, and the mixture was stirred at 60 ° C. for 30 min. The solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (7.85 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.36 (3H, s), 4.44 (2H, s), 7.79 (1H, dd, J = 8.5, 2.1 Hz), 7.91-8.09 (2H, m) , 8.58 (3H, s).
参考例２
1-{5-クロロ-2-[(1-メチルエチル)スルホニル]フェニル}メタンアミン塩酸塩
（工程１）水素化リチウムアルミニウム（1.56 g）のＴＨＦ（250 mL）懸濁液に5-クロロ-2-フルオロベンゾニトリルとナトリウム 2-プロパンチオラートを用いて参考例１の工程１と同様の手法で得られた5-クロロ-2-[(1-メチルエチル)スルファニル]ベンゾニトリル（7.25 g）のＴＨＦ（50 mL）溶液を0℃で加えた。室温で3時間攪拌後、硫酸ナトリウム10水和物を加えた。さらに室温で30分攪拌後、無機物をセライトでろ別した。ろ液を減圧濃縮後、残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加えたのち、溶媒を減圧下留去した。得られた固体をＩＰＥと酢酸エチルで洗浄し、1-{5-クロロ-2-[(1-メチルエチル)スルファニル]フェニル}メタンアミン塩酸塩（6.57 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.23 (6H, d, J= 6.6 Hz), 3.38-3.52 (1H, m), 4.16 (2H, s), 7.42-7.50 (1H, m), 7.54-7.60 (1H, m), 7.68-7.75 (1H, m), 8.62 (3H, s).
（工程２）工程１で得られた1-{5-クロロ-2-[(1-メチルエチル)スルファニル]フェニル}メタンアミン塩酸塩（6.3 g）とＥｔ３Ｎ（5.06 g）のＴＨＦ（200 mL）溶液に二炭酸ジ-t-ブチル（7.09 g）を室温で加えた。同温で3時間攪拌後、反応溶液に1Ｎ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチル（250 mL）に溶解後、m-クロロ過安息香酸（14.2 g）を室温で加えた。同温で14時間攪拌後、反応液に炭酸水素ナトリウム水溶液を加えた。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝2:3）で精製した。得られた残渣をメタノール（50 mL）に溶解後、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加え、60℃で1時間攪拌した。溶媒を減圧下留去し、メタノールとＩＰＥで結晶化し、標題化合物（5.0 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.19 (6H, d, J= 6.78 Hz), 3.51-3.63 (1H, m), 4.40 (2H, s), 7.78 (1H, dd, J= 8.6, 2.2 Hz), 7.93 (1H, d, J= 8.7 Hz), 7.97-8.02 (1H, m), 8.59 (3H, s). Reference example 2
1- {5-Chloro-2-[(1-methylethyl) sulfonyl] phenyl} methanamine hydrochloride (Step 1) To a suspension of lithium aluminum hydride (1.56 g) in THF (250 mL) was added 5-chloro-2 Of 5-chloro-2-[(1-methylethyl) sulfanyl] benzonitrile (7.25 g) obtained in the same manner as in Step 1 of Reference Example 1 using 2-fluorobenzonitrile and sodium 2-propanethiolate (50 mL) solution was added at 0 ° C. After stirring at room temperature for 3 hours, sodium sulfate decahydrate was added. Further, after stirring at room temperature for 30 minutes, the inorganic substance was filtered off through celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in methanol, 4N hydrogen chloride / ethyl acetate solution (15 mL) was added, and the solvent was evaporated under reduced pressure. The obtained solid was washed with IPE and ethyl acetate to obtain 1- {5-chloro-2-[(1-methylethyl) sulfanyl] phenyl} methanamine hydrochloride (6.57 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.23 (6H, d, J = 6.6 Hz), 3.38-3.52 (1H, m), 4.16 (2H, s), 7.42-7.50 (1H, m) , 7.54-7.60 (1H, m), 7.68-7.75 (1H, m), 8.62 (3H, s).
(Step 2) 1- {5-Chloro-2-[(1-methylethyl) sulfanyl] phenyl} methanamine hydrochloride (6.3 g) obtained in Step 1 and Et 3 N (5.06 g) in THF (200 mL) ) Di-t-butyl dicarbonate (7.09 g) was added to the solution at room temperature. After stirring at the same temperature for 3 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (250 mL), and m-chloroperbenzoic acid (14.2 g) was added at room temperature. After stirring at the same temperature for 14 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 2: 3). The obtained residue was dissolved in methanol (50 mL), 4N hydrogen chloride / ethyl acetate solution (15 mL) was added, and the mixture was stirred at 60 ° C. for 1 hr. The solvent was distilled off under reduced pressure and crystallized from methanol and IPE to obtain the title compound (5.0 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.19 (6H, d, J = 6.78 Hz), 3.51-3.63 (1H, m), 4.40 (2H, s), 7.78 (1H, dd, J = 8.6, 2.2 Hz), 7.93 (1H, d, J = 8.7 Hz), 7.97-8.02 (1H, m), 8.59 (3H, s).
参考例３
1-[5-クロロ-2-(エチルスルホニル)フェニル]メタンアミン塩酸塩
（工程１）ＤＭＦ（50 mL）溶液中、5-クロロ-2-フルオロベンゾニトリル（5.83 g）とナトリウム エタンチオラート（3.47 g）を室温で14時間攪拌した。反応溶液に1Ｎ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去し、5-クロロ-2-(エチルスルファニル)ベンゾニトリル（7.4 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.36 (3H, t, J= 7.4 Hz), 3.04 (2H, q, J= 7.4 Hz), 7.32-7.38 (1H, m), 7.44-7.50 (1H, m), 7.59 (1H, d, J= 2.3 Hz).
（工程２）水素化リチウムアルミニウム（1.7 g）のＴＨＦ（300 mL）懸濁液に工程１で得られた5-クロロ-2-(エチルスルファニル)ベンゾニトリル（7.4 g）のＴＨＦ（20 mL）溶液を0℃で加えた。室温で3時間攪拌後、硫酸ナトリウム10水和物を加えた。さらに室温で30分攪拌後、無機物をセライトでろ別した。ろ液を減圧濃縮後、残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加えた後、メタノールと酢酸エチルで結晶化し、1-[5-クロロ-2-(エチルスルファニル)フェニル]メタンアミン塩酸塩（5.89 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.22 (3H, t, J= 7.2 Hz), 3.00 (2H, q, J= 7.2 Hz), 4.10 (2H, s), 7.39-7.56 (2H, m), 7.62 (1H, d, J= 1.9 Hz), 8.50 (3H, s).
（工程３）工程２で得られた1-[5-クロロ-2-(エチルスルファニル)フェニル]メタンアミン塩酸塩（5.0 g）とＥｔ３Ｎ（4.25 g）のＴＨＦ（150 mL）溶液に二炭酸ジ-t-ブチル（5.5 g）を室温で加えた。同温で14時間攪拌後、反応溶液に1Ｎ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチル（200 mL）に溶解後、m-クロロ過安息香酸（12.9 g）を室温で加えた。同温で2時間攪拌後、反応液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:1）で精製した。得られた残渣をメタノール（100 mL）に溶解させ、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加え、60℃で1時間攪拌した。溶媒を減圧下留去することで、標題化合物（3.81 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.14 (3H, t, J= 7.2 Hz), 3.43 (2H, q, J= 7.2 Hz), 4.41 (2H, s), 7.78 (1H, d, J= 8.7 Hz), 7.95 (2H, d, J= 8.7 Hz), 8.58 (3H, s). Reference example 3
1- [5-Chloro-2- (ethylsulfonyl) phenyl] methanamine hydrochloride (Step 1) In a DMF (50 mL) solution, 5-chloro-2-fluorobenzonitrile (5.83 g) and sodium ethanethiolate (3.47 g) ) At room temperature for 14 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 5-chloro-2- (ethylsulfanyl) benzonitrile (7.4 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.36 (3H, t, J = 7.4 Hz), 3.04 (2H, q, J = 7.4 Hz), 7.32-7.38 (1H, m), 7.44-7.50 (1H , m), 7.59 (1H, d, J = 2.3 Hz).
(Step 2) To a suspension of lithium aluminum hydride (1.7 g) in THF (300 mL), THF (20 mL) of 5-chloro-2- (ethylsulfanyl) benzonitrile (7.4 g) obtained in Step 1 The solution was added at 0 ° C. After stirring at room temperature for 3 hours, sodium sulfate decahydrate was added. Further, after stirring at room temperature for 30 minutes, the inorganic substance was filtered off through celite. The filtrate was concentrated under reduced pressure, the residue was dissolved in methanol, 4N hydrogen chloride / ethyl acetate solution (15 mL) was added, and the mixture was crystallized from methanol and ethyl acetate to give 1- [5-chloro-2- (ethylsulfanyl). ) Phenyl] methanamine hydrochloride (5.89 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.22 (3H, t, J = 7.2 Hz), 3.00 (2H, q, J = 7.2 Hz), 4.10 (2H, s), 7.39-7.56 (2H , m), 7.62 (1H, d, J = 1.9 Hz), 8.50 (3H, s).
(Step 3) Dicarbonate was added to a solution of 1- [5-chloro-2- (ethylsulfanyl) phenyl] methanamine hydrochloride (5.0 g) and Et 3 N (4.25 g) obtained in Step 2 in THF (150 mL). Di-t-butyl (5.5 g) was added at room temperature. After stirring at the same temperature for 14 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 mL), and m-chloroperbenzoic acid (12.9 g) was added at room temperature. After stirring at the same temperature for 2 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 1). The obtained residue was dissolved in methanol (100 mL), 4N hydrogen chloride / ethyl acetate solution (15 mL) was added, and the mixture was stirred at 60 ° C. for 1 hr. The solvent was distilled off under reduced pressure to obtain the title compound (3.81 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.14 (3H, t, J = 7.2 Hz), 3.43 (2H, q, J = 7.2 Hz), 4.41 (2H, s), 7.78 (1H, d , J = 8.7 Hz), 7.95 (2H, d, J = 8.7 Hz), 8.58 (3H, s).
参考例４
1-[5-メトキシ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩
（工程１）ＤＭＦ（20 mL）溶液中、2-フルオロ-5-メトキシベンゾニトリル（10 g）とナトリウム メタンチオラート（5.1 g）を60℃で3時間攪拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を1Ｎ塩酸、続いて炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチルとヘキサンで結晶化することで、5-メトキシ-2-(メチルスルファニル)ベンゾニトリル（8.3 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.52 (3H, s), 3.82 (3H, s), 7.02-7.11 (1H, m), 7.13 (1H, d, J= 3.0 Hz), 7.37 (1H, d, J= 8.7 Hz).
（工程２）水素化リチウムアルミニウム（2.1 g）のＴＨＦ（200 mL）懸濁液に工程１で得られた5-メトキシ-2-(メチルスルファニル)ベンゾニトリル（8.27 g）を0℃で加えた。室温で3時間攪拌後、硫酸ナトリウム10水和物を加え、室温にしてさらに30分攪拌後、無機物をセライトでろ別した。ろ液を減圧濃縮後、残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加えた後、メタノールと酢酸エチルで結晶化させ、得られた結晶を酢酸エチルで洗浄することで、1-[5-メトキシ-2-(メチルスルファニル)フェニル]メタンアミン塩酸塩（8.45 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.40 (3H, s), 3.77 (3H, s), 4.12 (2H, s), 6.86-7.03 (1H, m), 7.13-7.27 (1H, m), 7.43 (1H, d, J= 8.7 Hz), 8.51 (3H, s).
（工程３）工程２で得られた1-[5-メトキシ-2-(メチルスルファニル)フェニル]メタンアミン塩酸塩（6.0 g）とＥｔ３Ｎ（5.53 g）のＴＨＦ（150 mL）溶液に二炭酸ジ-t-ブチル（8.94 g）を室温で加えた。同温で4時間攪拌後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を1Ｎ塩酸、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチル（200 mL）に溶解後、m-クロロ過安息香酸（16.83 g）を室温で加えた。同温で20時間攪拌後、反応液に炭酸水素ナトリウム水溶液を加えた。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:1）で精製した。得られた残渣をメタノール（100 mL）に溶解させ、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加え、60℃で1時間攪拌した。溶媒を減圧下留去し、得られた結晶を酢酸エチルで洗浄することで、標題化合物（5.5 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.27 (3H, s), 3.90 (3H, s), 4.40 (2H, s), 7.19 (1H, dd, J= 8.9, 2.5 Hz), 7.41 (1H, s), 7.92 (1H, d, J= 8.7 Hz), 8.56 (3H, s). Reference example 4
1- [5-Methoxy-2- (methylsulfonyl) phenyl] methanamine hydrochloride (Step 1) In DMF (20 mL) solution, 2-fluoro-5-methoxybenzonitrile (10 g) and sodium methanethiolate (5.1 g ) Was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, followed by aqueous sodium hydrogen carbonate solution, then saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate and hexane to obtain 5-methoxy-2- (methylsulfanyl) benzonitrile (8.3 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.52 (3H, s), 3.82 (3H, s), 7.02-7.11 (1H, m), 7.13 (1H, d, J = 3.0 Hz), 7.37 (1H , d, J = 8.7 Hz).
(Step 2) To a suspension of lithium aluminum hydride (2.1 g) in THF (200 mL), 5-methoxy-2- (methylsulfanyl) benzonitrile (8.27 g) obtained in Step 1 was added at 0 ° C. . After stirring at room temperature for 3 hours, sodium sulfate decahydrate was added, and the mixture was allowed to reach room temperature and stirred for another 30 minutes. Concentrate the filtrate under reduced pressure, dissolve the residue in methanol, add 4N hydrogen chloride / ethyl acetate solution (15 mL), crystallize with methanol and ethyl acetate, and wash the resulting crystals with ethyl acetate. Gave 1- [5-methoxy-2- (methylsulfanyl) phenyl] methanamine hydrochloride (8.45 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.40 (3H, s), 3.77 (3H, s), 4.12 (2H, s), 6.86-7.03 (1H, m), 7.13-7.27 (1H, m), 7.43 (1H, d, J = 8.7 Hz), 8.51 (3H, s).
(Step 3) Dicarbonate was added to a solution of 1- [5-methoxy-2- (methylsulfanyl) phenyl] methanamine hydrochloride (6.0 g) obtained in Step 2 and Et 3 N (5.53 g) in THF (150 mL). Di-t-butyl (8.94 g) was added at room temperature. After stirring at the same temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 mL), and m-chloroperbenzoic acid (16.83 g) was added at room temperature. After stirring at the same temperature for 20 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 1). The obtained residue was dissolved in methanol (100 mL), 4N hydrogen chloride / ethyl acetate solution (15 mL) was added, and the mixture was stirred at 60 ° C. for 1 hr. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (5.5 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.27 (3H, s), 3.90 (3H, s), 4.40 (2H, s), 7.19 (1H, dd, J = 8.9, 2.5 Hz), 7.41 (1H, s), 7.92 (1H, d, J = 8.7 Hz), 8.56 (3H, s).
参考例５
1-[5-フルオロ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩
（工程１）２－ブロモ－５－フルオロ安息香酸（80 g）のＴＨＦ（1.6 L）溶液にメチルマグネシウムクロリド（134 mL, 3Ｍ ＴＨＦ溶液）を0℃で加え、15分撹拌した。反応液を‐78℃に冷却し、n-ブチルリチウム（321 mL, 2.5Ｍ ヘキサン溶液）を10分かけて加えた後、１時間撹拌した。さらに、ジメチルスルフィド（197 mL）を‐78℃で加え10分間撹拌し、室温に昇温後、2時間撹拌した。反応液に12Ｎ塩酸を0℃で加え、酢酸エチルで5回抽出した。有機層を硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をジクロロメタンで再結晶することで、5-フルオロ-2-(メチルスルファニル)安息香酸（40 g）を得た。1H-NMR (400 MHz, DMSO-d6) δppm 3.36 (3H, s), 7.34-7.40 (1H, m), 7.46 (1H, td, J= 8.5, 3.2 Hz), 7.66 (1H, dd, J= 9.4, 3.0 Hz), 13.35 (1H, br).
（工程２）工程１で得られた5-フルオロ-2-(メチルスルファニル)安息香酸（40 g）、塩化アンモニウム（22.9 g）、ＨＯＢｔ（58.1 g）、ＷＳＣ（66.7 g）及びジイソプロピルエチルアミン（150 mL）のＤＭＦ（503 mL）溶液を室温で５時間撹拌した後、溶媒を減圧下留去した。残渣をジクロロメタンと２Ｎ塩酸で溶解させ、ジクロロメタンで３回抽出した。有機層を硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をジクロロメタンで再結晶することにより、5-フルオロ-2-(メチルスルファニル)ベンズアミド（33 g）を得た。1H-NMR (400 MHz, CDCl3) δppm 2.49 (3H, s), 5.82 (1H, br), 6.93 (1H, br), 7.14 (1H, td, J= 8.2, 2.8 Hz), 7.39 (1H, dd, J= 8.6, 5.0 Hz), 7.52 (1H, dd, J= 9.0, 3.0 Hz).
（工程３）工程２で得られた5-フルオロ-2-(メチルスルファニル)ベンズアミド（23 g）のＴＨＦ（500 mL）溶液に水素化リチウムアルミニウム（7.1 g）を0℃で加えた。反応液を6時間加熱還流し、0℃に冷却した後、水と15％水酸化ナトリウム水溶液を加え、セライトを用いてろ過した。ろ液を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去することで1-[5-フルオロ-2-(メチルスルファニル)フェニル]メタンアミン（16.2 g）を得た。1H-NMR (400 MHz, CDCl3) δppm 2.46 (3H, s), 3.91 (2H, s), 6.95 (1H, td, J= 8.4, 2.8 Hz), 7.10 (1H, dd, J= 9.6, 3.2 Hz), 7.22 (1H, dd, J= 8.4, 5.6 Hz).
（工程４）工程３で得られた1-[5-フルオロ-2-(メチルスルファニル)フェニル]メタンアミン（16.2 g）のジクロロメタン（237 mL）溶液に二炭酸ジ-t-ブチル（31 g）とＥｔ３Ｎ（13.1 mL）を0℃で加えた。反応液を室温で12時間攪拌した後、溶媒を減圧下留去した。残渣を水とジクロロメタンで溶解させ、ジクロロメタンで2回抽出した。有機層を硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝5:1）で精製することで、tert-ブチル [5-フルオロ-2-(メチルスルファニル)ベンジル]カルバマート（23 g）を得た。1H-NMR (400 MHz, CDCl3) δppm 1.46 (9H, s), 2.44 (3H, s), 4.39 (2H, d, J= 6.4 Hz), 5.02 (1H, br), 6.96 (1H, td, J= 8.4, 2.8 Hz), 7.06 (1H, dd, J= 9.2, 2.8 Hz), 7.25 (1H, dd, J= 8.6, 5.4 Hz).
（工程５）工程４で得られたtert-ブチル [5-フルオロ-2-(メチルスルファニル)ベンジル]カルバマート（23 g）のジクロロメタン（283 mL）溶液にm-過クロロ安息香酸（43.9 g）を室温で加え、１８時間撹拌した。反応液に２Ｎ水酸化ナトリウム溶液を加え、ジクロロメタンで抽出した。有機層を２Ｎ水酸化ナトリウムで洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去することにより、tert-ブチル [5-フルオロ-2-(メチルスルホニル)ベンジル]カルバマート（13 g）を得た。1H-NMR (400 MHz, CDCl3) δppm 1.43 (9H, s), 3.15 (3H, s), 4.61 (2H, d, J= 11.6 Hz), 5.42 (1H, br), 7.15 (1H, td, J= 8.1, 2.6 Hz), 7.34 (1H, dd, J= 9.0, 1.8 Hz), 8.04 (1H, dd, J= 8.8, 5.6 Hz).
（工程６）工程５で得られたtert-ブチル [5-フルオロ-2-(メチルスルホニル)ベンジル]カルバマート（12.6 g）の酢酸エチル（100 mL）溶液に４Ｍ塩化水素／ジオキサン溶液（20 mL）を0℃で加え、12時間室温で撹拌した。析出した結晶をろ取し、酢酸エチルで洗浄することにより標題化合物（6.5 g）を得た。1H-NMR (400 MHz, DMSO-d6) δppm 3.13 (3H, s), 4.42 (2H, br), 7.53 (1H, td, J= 8.5, 2.6 Hz), 7.70 (1H, dd, J= 10.0, 2.8 Hz), 8.04 (1H, dd, J= 8.8, 5.6 Hz), 8.57 (3H, br). Reference Example 5
1- [5-Fluoro-2- (methylsulfonyl) phenyl] methanamine hydrochloride (Step 1) To a solution of 2-bromo-5-fluorobenzoic acid (80 g) in THF (1.6 L) was added methylmagnesium chloride (134 mL, 3M THF solution) was added at 0 ° C. and stirred for 15 minutes. The reaction solution was cooled to −78 ° C., n-butyllithium (321 mL, 2.5 M hexane solution) was added over 10 minutes, and the mixture was stirred for 1 hour. Furthermore, dimethyl sulfide (197 mL) was added at −78 ° C., and the mixture was stirred for 10 minutes. 12N hydrochloric acid was added to the reaction solution at 0 ° C., and the mixture was extracted 5 times with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from dichloromethane to obtain 5-fluoro-2- (methylsulfanyl) benzoic acid (40 g). 1 H-NMR (400 MHz, DMSO-d 6 ) δppm 3.36 (3H, s), 7.34-7.40 (1H, m), 7.46 (1H, td, J = 8.5, 3.2 Hz), 7.66 (1H, dd, J = 9.4, 3.0 Hz), 13.35 (1H, br).
(Step 2) 5-fluoro-2- (methylsulfanyl) benzoic acid obtained in Step 1 (40 g), ammonium chloride (22.9 g), HOBt (58.1 g), WSC (66.7 g) and diisopropylethylamine (150 mL) in DMF (503 mL) was stirred at room temperature for 5 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved with dichloromethane and 2N hydrochloric acid and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from dichloromethane to obtain 5-fluoro-2- (methylsulfanyl) benzamide (33 g). 1 H-NMR (400 MHz, CDCl 3 ) δppm 2.49 (3H, s), 5.82 (1H, br), 6.93 (1H, br), 7.14 (1H, td, J = 8.2, 2.8 Hz), 7.39 (1H , dd, J = 8.6, 5.0 Hz), 7.52 (1H, dd, J = 9.0, 3.0 Hz).
(Step 3) To a solution of 5-fluoro-2- (methylsulfanyl) benzamide (23 g) obtained in Step 2 in THF (500 mL) was added lithium aluminum hydride (7.1 g) at 0 ° C. The reaction solution was heated to reflux for 6 hours, cooled to 0 ° C., water and 15% aqueous sodium hydroxide solution were added, and the mixture was filtered through celite. The filtrate was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 1- [5-fluoro-2- (methylsulfanyl) phenyl] methanamine (16.2 g). It was. 1 H-NMR (400 MHz, CDCl 3 ) δppm 2.46 (3H, s), 3.91 (2H, s), 6.95 (1H, td, J = 8.4, 2.8 Hz), 7.10 (1H, dd, J = 9.6, 3.2 Hz), 7.22 (1H, dd, J = 8.4, 5.6 Hz).
(Step 4) Di-t-butyl dicarbonate (31 g) was added to a solution of 1- [5-fluoro-2- (methylsulfanyl) phenyl] methanamine (16.2 g) obtained in Step 3 in dichloromethane (237 mL). Et 3 N (13.1 mL) was added at 0 ° C. The reaction solution was stirred at room temperature for 12 hours, and then the solvent was distilled off under reduced pressure. The residue was dissolved with water and dichloromethane and extracted twice with dichloromethane. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 1) to obtain tert-butyl [5-fluoro-2- (methylsulfanyl) benzyl] carbamate (23 g). 1 H-NMR (400 MHz, CDCl 3 ) δppm 1.46 (9H, s), 2.44 (3H, s), 4.39 (2H, d, J = 6.4 Hz), 5.02 (1H, br), 6.96 (1H, td , J = 8.4, 2.8 Hz), 7.06 (1H, dd, J = 9.2, 2.8 Hz), 7.25 (1H, dd, J = 8.6, 5.4 Hz).
(Step 5) m-perchlorobenzoic acid (43.9 g) was added to a solution of tert-butyl [5-fluoro-2- (methylsulfanyl) benzyl] carbamate (23 g) obtained in Step 4 in dichloromethane (283 mL). Added at room temperature and stirred for 18 hours. 2N sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with 2N sodium hydroxide, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give tert-butyl [5-fluoro-2- (methylsulfonyl) benzyl] carbamate (13 g ) 1 H-NMR (400 MHz, CDCl 3 ) δppm 1.43 (9H, s), 3.15 (3H, s), 4.61 (2H, d, J = 11.6 Hz), 5.42 (1H, br), 7.15 (1H, td , J = 8.1, 2.6 Hz), 7.34 (1H, dd, J = 9.0, 1.8 Hz), 8.04 (1H, dd, J = 8.8, 5.6 Hz).
(Step 6) To a solution of tert-butyl [5-fluoro-2- (methylsulfonyl) benzyl] carbamate (12.6 g) obtained in Step 5 in ethyl acetate (100 mL), 4M hydrogen chloride / dioxane solution (20 mL) Was added at 0 ° C. and stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain the title compound (6.5 g). 1 H-NMR (400 MHz, DMSO-d 6 ) δppm 3.13 (3H, s), 4.42 (2H, br), 7.53 (1H, td, J = 8.5, 2.6 Hz), 7.70 (1H, dd, J = 10.0, 2.8 Hz), 8.04 (1H, dd, J = 8.8, 5.6 Hz), 8.57 (3H, br).
参考例６
2-(アミノメチル)-4-クロロ-N,N-ジメチルベンゼンスルホンアミド塩酸塩
（工程１）2Ｎジメチルアミン／メタノール溶液（7.51 mL）のメタノール（15 mL）溶液中に2-[(アセチルアミノ)メチル]-4-クロロベンゼンスルホニルクロリド（2.12 g）のＴＨＦ（5 mL）懸濁液を滴下し、室温に昇温後3時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、N-[5-クロロ-2-(ジメチルスルファモイル)ベンジル]アセトアミド（1.77 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.98 (3H, s), 2.82 (6H, s), 4.66 (2H, d, J= 6.4 Hz), 6.45 (1H, br), 7.40 (1H, dd, J= 8.3, 2.3 Hz), 7.66 (1H, d, J= 2.3 Hz), 7.77 (1H, d, J= 8.7 Hz).
（工程２）工程１で得られたN-[5-クロロ-2-(ジメチルスルファモイル)ベンジル]アセトアミド（1.77 g）のエタノール（20 mL）溶液に6Ｎ塩酸（20 mL）を室温で加え、加熱還流下3時間攪拌した後、80℃で終夜攪拌した。溶媒を減圧下留去し、残渣をろ過後、ジエチルエーテルで洗浄することにより標題化合物（1.61 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.75 (6H, s), 4.36 (2H, br), 7.72 (1H, dd, J= 8.6, 2.0 Hz), 7.82-7.90 (1H, m), 7.91-8.05 (1H, m), 8.67 (3H, br). Reference Example 6
2- (Aminomethyl) -4-chloro-N, N-dimethylbenzenesulfonamide hydrochloride (step 1) 2-[(acetylamino) in a 2N dimethylamine / methanol solution (7.51 mL) in methanol (15 mL). ) Methyl] -4-chlorobenzenesulfonyl chloride (2.12 g) in THF (5 mL) was added dropwise, and the mixture was warmed to room temperature and stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain N- [5-chloro-2- (dimethylsulfamoyl) benzyl] acetamide (1.77 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.98 (3H, s), 2.82 (6H, s), 4.66 (2H, d, J = 6.4 Hz), 6.45 (1H, br), 7.40 (1H, dd , J = 8.3, 2.3 Hz), 7.66 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 8.7 Hz).
(Step 2) 6N hydrochloric acid (20 mL) was added to a solution of N- [5-chloro-2- (dimethylsulfamoyl) benzyl] acetamide (1.77 g) obtained in Step 1 in ethanol (20 mL) at room temperature. The mixture was stirred for 3 hours under reflux with heating, and then stirred at 80 ° C. overnight. The solvent was evaporated under reduced pressure, and the residue was filtered and washed with diethyl ether to give the title compound (1.61 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.75 (6H, s), 4.36 (2H, br), 7.72 (1H, dd, J = 8.6, 2.0 Hz), 7.82-7.90 (1H, m) , 7.91-8.05 (1H, m), 8.67 (3H, br).
参考例７
2-(2-クロロ-5-フルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
（工程１）ピリジン（30 mL）溶媒中、2,3-ジヒドロ-4H-チオクロメン-4-オン（13.0 g）と塩酸Ｏ-メチルヒドロキシルアミン（7.93 g）を室温で4時間攪拌した。反応溶液を水に注いだ後、酢酸エチルで抽出した。有機層を1Ｎ塩酸、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をＴＨＦ（150 mL）に溶解させ、ＴＨＦ-ボラン錯体（200 mL, １Ｍ ＴＨＦ溶液）を0℃にて加えた。反応液を90℃で3時間攪拌後、反応液に氷を加え、1Ｎ塩酸（300 mL）を加えた。90℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を、8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（20 mL）を加え、得られた析出物をろ過し、酢酸エチルで洗浄することにより、3,4-ジヒドロ-2H-チオクロメン-4-アミン塩酸塩（6.16 g）を得た。1H-NMR (300 M Hz, DMSO-d6) δppm 2.12-2.27 (1H, m), 2.36-2.48 (1H, m), 2.96-3.29 (2H, m), 4.52 (1H, d, J= 3.4 Hz), 7.09-7.31 (3H, m), 7.53 (1H, d, J= 8.0 Hz), 8.66 (3H, s).
（工程２）工程１で得られた3,4-ジヒドロ-2H-チオクロメン-4-アミン塩酸塩（5.3 g）とＥｔ３Ｎ（5.85 g）のＴＨＦ（200 mL）溶液に二炭酸ジ-t-ブチル（6.88 g）を室温で加えた。3時間攪拌後、反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ塩酸と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチル（200 mL）に溶解させ、m-クロロ過安息香酸（18.1 g）を室温で加えた。同温で6時間攪拌後、反応液を炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝2:1）で精製した。得られた残渣をメタノール（30 mL）に溶解後、4Ｎ塩化水素／酢酸エチル溶液（15 mL）を加え、50℃で1時間攪拌した。溶媒を減圧下留去した後、得られた析出物をろ過後、酢酸エチルで洗浄することにより、3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（5.3 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.60-2.80 (2H, m), 3.66-3.86 (2H, m), 4.79 (1H, s), 7.64-7.90 (4H, m), 8.98 (3H, s).
（工程３）工程２で得られた3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（600 mg）、(2-クロロ-5-フルオロフェノキシ)酢酸（525 mg）、ＷＳＣ（640 mg）、ＨＯＢｔ（511 mg）及びＥｔ３Ｎ（520 mg）のＤＭＦ（20 mL）溶液を室温で2日間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を1Ｎ塩酸、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。残渣を酢酸エチルとヘキサンで結晶化させ、標題化合物（880 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.59-2.87 (2H, m), 3.39-3.57 (2H, m), 4.61 (2H, s), 5.49 (1H, td, J= 8.4, 5.1 Hz), 6.65-6.80 (2H, m), 7.18 (1H, d, J= 8.3 Hz), 7.34 (1H, dd, J= 8.9, 5.8 Hz), 7.39-7.46 (1H, m), 7.51-7.62 (2H, m), 7.90-8.02 (1H, m). Reference Example 7
2- (2-Chloro-5-fluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (step 1) pyridine (30 mL) in solvent, 2 , 3-Dihydro-4H-thiochromen-4-one (13.0 g) and O-methylhydroxylamine hydrochloride (7.93 g) were stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in THF (150 mL), and THF-borane complex (200 mL, 1M THF solution) was added at 0 ° C. After stirring the reaction solution at 90 ° C. for 3 hours, ice was added to the reaction solution, and 1N hydrochloric acid (300 mL) was added. After stirring at 90 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol, 4N hydrogen chloride / ethyl acetate solution (20 mL) was added, and the resulting precipitate was filtered and washed with ethyl acetate to give 3,4-dihydro-2H-thiochromene. 4-Amine hydrochloride (6.16 g) was obtained. 1 H-NMR (300 M Hz, DMSO-d 6 ) δppm 2.12-2.27 (1H, m), 2.36-2.48 (1H, m), 2.96-3.29 (2H, m), 4.52 (1H, d, J = 3.4 Hz), 7.09-7.31 (3H, m), 7.53 (1H, d, J = 8.0 Hz), 8.66 (3H, s).
(Step 2) To a solution of 3,4-dihydro-2H-thiochromen-4-amine hydrochloride (5.3 g) obtained in Step 1 and Et 3 N (5.85 g) in THF (200 mL) was added di-t-carbonate. -Butyl (6.88 g) was added at room temperature. After stirring for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 mL), and m-chloroperbenzoic acid (18.1 g) was added at room temperature. After stirring at the same temperature for 6 hours, the reaction solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 2: 1). The obtained residue was dissolved in methanol (30 mL), 4N hydrogen chloride / ethyl acetate solution (15 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. After the solvent was distilled off under reduced pressure, the resulting precipitate was filtered and washed with ethyl acetate to give 3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (5.3 g) Got. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.60-2.80 (2H, m), 3.66-3.86 (2H, m), 4.79 (1H, s), 7.64-7.90 (4H, m), 8.98 ( 3H, s).
(Step 3) 3,4-Dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (600 mg), (2-chloro-5-fluorophenoxy) acetic acid (525 mg) obtained in Step 2 , WSC (640 mg), HOBt (511 mg) and Et 3 N (520 mg) in DMF (20 mL) were stirred at room temperature for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (880 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.59-2.87 (2H, m), 3.39-3.57 (2H, m), 4.61 (2H, s), 5.49 (1H, td, J = 8.4, 5.1 Hz) , 6.65-6.80 (2H, m), 7.18 (1H, d, J = 8.3 Hz), 7.34 (1H, dd, J = 8.9, 5.8 Hz), 7.39-7.46 (1H, m), 7.51-7.62 (2H , m), 7.90-8.02 (1H, m).
参考例８
2-(アミノメチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩
（工程１）ジメチルアミン（49.6 mL、2Ｍ ＴＨＦ溶液）、Ｅｔ３Ｎ（3.46 mL）の混合物に、2-シアノベンゼン-1-スルホニルクロリド（5.0 g）のＴＨＦ（20 mL）溶液を室温で加えた。2時間攪拌した後、溶媒を減圧下留去した。残渣に水を加え、固体をろ取した。得られた固体をジクロロメタンに溶解させ、水で洗浄後、有機層を硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製することで、2-シアノ-N,N-ジメチルベンゼンスルホンアミド（5.1 g）を得た。1H-NMR (400 MHz, CDCl3) δppm 2.89 (6H, s), 7.71 (1H, td, J= 7.6, 1.6 Hz), 7.77 (1H, td, J= 7.8, 1.6 Hz), 7.89-7.91 (1H, m), 8.06 (1H, dd, J= 8.0, 1.2 Hz).
（工程２）工程１で得られた2-シアノ-N,N-ジメチルベンゼンスルホンアミド（9.25 g）及びラネーニッケル（0.52 g）のメタノール（220 mL）溶液を水素雰囲気下（50 psi）、室温で17時間攪拌した。反応液をセライトを用いてろ過し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:メタノール＝1:0～5:1）で精製した。得られた残渣を酢酸エチル（67 mL）に溶解させ、4Ｎ塩化水素／1,4-ジオキサン溶液（33.6 mL）を0℃で加えた。室温で1時間攪拌後、析出した結晶をろ取し、酢酸エチルで洗浄することで、標題化合物（7.3 g）を得た。1H-NMR (400 MHz, DMSO-d6) δppm 2.75 (6H, s), 4.36 (2H, s), 7.64 (1H, td, J= 7.6, 1.6 Hz), 7.78 (1H, td, J= 7.5, 1.2 Hz), 7.85 (2H, dd, J= 8.0, 1.2 Hz), 8.66 (3H, br). Reference Example 8
To a mixture of 2- (aminomethyl) -N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) dimethylamine (49.6 mL, 2M THF solution), Et 3 N (3.46 mL) was added 2-cyanobenzene-1- A solution of sulfonyl chloride (5.0 g) in THF (20 mL) was added at room temperature. After stirring for 2 hours, the solvent was distilled off under reduced pressure. Water was added to the residue, and the solid was collected by filtration. The obtained solid was dissolved in dichloromethane, washed with water, the organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 2-cyano-N, N-dimethylbenzenesulfonamide (5.1 g). 1 H-NMR (400 MHz, CDCl 3 ) δppm 2.89 (6H, s), 7.71 (1H, td, J = 7.6, 1.6 Hz), 7.77 (1H, td, J = 7.8, 1.6 Hz), 7.89-7.91 (1H, m), 8.06 (1H, dd, J = 8.0, 1.2 Hz).
(Step 2) A solution of 2-cyano-N, N-dimethylbenzenesulfonamide (9.25 g) and Raney nickel (0.52 g) obtained in Step 1 in methanol (220 mL) was placed under a hydrogen atmosphere (50 psi) at room temperature. Stir for 17 hours. The reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1: 0-5: 1). The obtained residue was dissolved in ethyl acetate (67 mL), and 4N hydrogen chloride / 1,4-dioxane solution (33.6 mL) was added at 0 ° C. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration and washed with ethyl acetate to obtain the title compound (7.3 g). 1 H-NMR (400 MHz, DMSO-d 6 ) δppm 2.75 (6H, s), 4.36 (2H, s), 7.64 (1H, td, J = 7.6, 1.6 Hz), 7.78 (1H, td, J = 7.5, 1.2 Hz), 7.85 (2H, dd, J = 8.0, 1.2 Hz), 8.66 (3H, br).
参考例９
1-[5-クロロ-2-(メチルスルホニル)フェニル]エタンアミン塩酸塩
（工程１）5-クロロ-2-(メチルスルファニル)ベンゾニトリル（1 g）（Journal fuer Praktische Chime, 1924, 108(2), 12）のＴＨＦ（10 mL）溶液にヨウ化メチルマグネシウム（8.2 mL）を0℃で加え、室温で１時間撹拌した。さらに水素化ホウ素ナトリウム（2.1 g）を0℃で加え、２時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝1:4）で精製し、1-[5-クロロ-2-(メチルスルファニル)フェニル]エタンアミン（0.31 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.36 (3H, d, J= 6.4 Hz), 1.54 (2H, br), 2.46 (3H, s), 4.52 (1H, d, J= 6.4 Hz), 7.01-7.26 (1H, m), 7.15 (1H, q, J= 8.3 Hz), 7.49 (1H, d, J= 2.3 Hz).
（工程２）工程１で得られた1-[5-クロロ-2-(メチルスルファニル)フェニル]エタンアミンを用いて参考例７の工程２と同様の手法に準じて、標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.56 (3H, d, J= 6.8 Hz), 3.38 (3H, s), 5.19 (1H, br), 7.76 (1H, dd, J= 8.5, 2.1 Hz), 8.00 (1H, d, J= 8.3 Hz), 8.17 (1H, s), 8.71 (3H, br). Reference Example 9
1- [5-Chloro-2- (methylsulfonyl) phenyl] ethanamine hydrochloride (Step 1) 5-chloro-2- (methylsulfanyl) benzonitrile (1 g) (Journal fuer Praktische Chime, 1924, 108 (2) , 12) in THF (10 mL) was added methylmagnesium iodide (8.2 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Further, sodium borohydride (2.1 g) was added at 0 ° C. and stirred for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain 1- [5-chloro-2- (methylsulfanyl) phenyl] ethanamine (0.31 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.36 (3H, d, J = 6.4 Hz), 1.54 (2H, br), 2.46 (3H, s), 4.52 (1H, d, J = 6.4 Hz), 7.01-7.26 (1H, m), 7.15 (1H, q, J = 8.3 Hz), 7.49 (1H, d, J = 2.3 Hz).
(Step 2) The title compound was obtained in the same manner as in Step 2 of Reference Example 7 using 1- [5-chloro-2- (methylsulfanyl) phenyl] ethanamine obtained in Step 1. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.56 (3H, d, J = 6.8 Hz), 3.38 (3H, s), 5.19 (1H, br), 7.76 (1H, dd, J = 8.5, 2.1 Hz), 8.00 (1H, d, J = 8.3 Hz), 8.17 (1H, s), 8.71 (3H, br).
参考例１０
2-(2-クロロ-5-フルオロフェノキシ)-N-{[2-(メチルスルファニル)ピリジン-3-イル]メチル}エタンアミン
（工程１）2-クロロ-5-フルオロフェノール（20.0 g）、tert-ブチル(2-ブロモエチル)カルバマート（36.7 g）及び炭酸カリウム（28.2 g）のＴＨＦ（250 mL）及びＤＭＦ（25 mL）の混合溶液を65℃で15時間攪拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を水、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製し、油状物を得た。得られた油状物と4Ｎ塩化水素／酢酸エチル溶液（50 mL）をメタノール（300 mL）溶媒中60℃で2時間攪拌した。溶媒を減圧下留去し、得られた固体をろ過後、ジエチルエーテルで洗浄し、2-(2-クロロ-5-フルオロフェノキシ)エタンアミン塩酸塩（25.0 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.24 (2H, t, J= 5.3 Hz), 4.29 (2H, t, J= 5.3 Hz), 6.89 (1H, td, J= 8.5, 2.6 Hz), 7.21 (1H, dd, J=10.7, 2.8 Hz), 7.50 (1H, dd, J= 8.9, 6.2 Hz), 8.13 (3 H, br).
（工程２）工程１で得られた2-(2-クロロ-5-フルオロフェノキシ)エタンアミン塩酸塩（0.53 g）と2-(メチルスルファニル)ピリジン-3-カルバルデヒド（0.36 g）のＴＨＦ（20 mL）及び酢酸（2 mL）溶液を室温で30分間攪拌した。ＮａＢＨ（ＯＡｃ）３（0.75 g）を0℃で加え、室温で24時間攪拌した。反応液に1Ｎ水酸化ナトリウムを加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:6）で精製し、標題化合物（0.15 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.59 (3H, s), 3.08 (2H, t, J= 5.1 Hz), 3.89 (2H, s), 4.06-4.20 (2H, m), 6.56-6.73 (2H, m), 7.00 (1H, dd, J= 7.4, 4.7 Hz), 7.2-7.4 (1H, m), 7.60 (1H, d, J= 7.6 Hz), 8.37 (1H, d, J=4.9 Hz). Reference Example 10
2- (2-Chloro-5-fluorophenoxy) -N-{[2- (methylsulfanyl) pyridin-3-yl] methyl} ethanamine (Step 1) 2-chloro-5-fluorophenol (20.0 g), tert A mixed solution of -butyl (2-bromoethyl) carbamate (36.7 g) and potassium carbonate (28.2 g) in THF (250 mL) and DMF (25 mL) was stirred at 65 ° C. for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give an oil. The obtained oil and 4N hydrogen chloride / ethyl acetate solution (50 mL) were stirred in methanol (300 mL) solvent at 60 ° C. for 2 hours. The solvent was evaporated under reduced pressure, and the resulting solid was filtered and washed with diethyl ether to give 2- (2-chloro-5-fluorophenoxy) ethanamine hydrochloride (25.0 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.24 (2H, t, J = 5.3 Hz), 4.29 (2H, t, J = 5.3 Hz), 6.89 (1H, td, J = 8.5, 2.6 Hz ), 7.21 (1H, dd, J = 10.7, 2.8 Hz), 7.50 (1H, dd, J = 8.9, 6.2 Hz), 8.13 (3 H, br).
(Step 2) 2- (2-Chloro-5-fluorophenoxy) ethanamine hydrochloride (0.53 g) obtained in Step 1 and 2- (methylsulfanyl) pyridine-3-carbaldehyde (0.36 g) in THF (20 mL) and acetic acid (2 mL) solutions were stirred at room temperature for 30 minutes. NaBH (OAc) 3 (0.75 g) was added at 0 ° C., and the mixture was stirred at room temperature for 24 hours. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain the title compound (0.15 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.59 (3H, s), 3.08 (2H, t, J = 5.1 Hz), 3.89 (2H, s), 4.06-4.20 (2H, m), 6.56-6.73 (2H, m), 7.00 (1H, dd, J = 7.4, 4.7 Hz), 7.2-7.4 (1H, m), 7.60 (1H, d, J = 7.6 Hz), 8.37 (1H, d, J = 4.9 Hz).
参考例１１
Ｎ-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-2-[2-(メチルスルホニル)フェニル]アセトアミド
（工程１）2-(2-クロロ-5-フルオロフェノキシ)エタンアミン塩酸塩（1.24 g）、[2-(メチルスルファニル)フェニル]酢酸（1.0 g）（Journal of the American Chemical Society, 1967, 89(10), 2411-2416）、ＷＳＣ（1.26 g）、ＨＯＢｔ（1.01 g）及びＥｔ３Ｎ（0.83 g）のＤＭＦ（20 mL）溶液を60℃で14時間攪拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を1Ｎ塩酸、炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去し、N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-2-[2-(メチルスルファニル)フェニル]アセトアミド（1.92 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.36 (3H, s), 3.63-3.69 (2H, m), 3.71 (2H, s), 4.02 (2H, t, J= 5.1 Hz), 6.09 (1H, br), 6.57-6.69 (2H, m), 7.11-7.35 (5H, m).
（工程２）工程１で得たＮ-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-2-[2-(メチルスルファニル)フェニル]アセトアミド（1.92 g）の酢酸エチル（20 mL）溶液に、m-クロロ過安息香酸（2.91 g）を室温で加えた。同温で2時間攪拌後、反応液にチオ硫酸ナトリウム水溶液を加えた。有機層を炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して、標題化合物（1.28 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.12 (3H, s) 3.67 (2H, q, J= 5.3 Hz), 4.00-4.07 (4H, m), 6.58-6.75 (3H, m), 7.27-7.33 (1H, m), 7.43-7.63 (3H, m), 8.05 (1H, d, J= 7.9 Hz). Reference Example 11
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -2- [2- (methylsulfonyl) phenyl] acetamide (Step 1) 2- (2-Chloro-5-fluorophenoxy) ethanamine hydrochloride ( 1.24 g), [2- (methylsulfanyl) phenyl] acetic acid (1.0 g) (Journal of the American Chemical Society, 1967, 89 (10), 2411-2416), WSC (1.26 g), HOBt (1.01 g) and A solution of Et 3 N (0.83 g) in DMF (20 mL) was stirred at 60 ° C. for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate solution and then saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give N- [2- (2-chloro-5-fluoro Phenoxy) ethyl] -2- [2- (methylsulfanyl) phenyl] acetamide (1.92 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.36 (3H, s), 3.63-3.69 (2H, m), 3.71 (2H, s), 4.02 (2H, t, J = 5.1 Hz), 6.09 (1H , br), 6.57-6.69 (2H, m), 7.11-7.35 (5H, m).
(Step 2) N- [2- (2-chloro-5-fluorophenoxy) ethyl] -2- [2- (methylsulfanyl) phenyl] acetamide (1.92 g) obtained in Step 1 in ethyl acetate (20 mL) To the solution, m-chloroperbenzoic acid (2.91 g) was added at room temperature. After stirring at the same temperature for 2 hours, an aqueous sodium thiosulfate solution was added to the reaction solution. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (1.28 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.12 (3H, s) 3.67 (2H, q, J = 5.3 Hz), 4.00-4.07 (4H, m), 6.58-6.75 (3H, m), 7.27- 7.33 (1H, m), 7.43-7.63 (3H, m), 8.05 (1H, d, J = 7.9 Hz).
参考例１２
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3-[2-(メチルスルホニル)フェニル]プロパンアミド
　2-(2-クロロ-5-フルオロフェノキシ)エタンアミン塩酸塩（0.99 g）、3-[2-(メチルスルホニル)フェニル]プロパン酸（1.0 g）、ＷＳＣ（1.09 g）、ＨＯＢｔ（0.87 g）及びＥｔ３Ｎ（0.89 g）のＤＭＦ（20 mL）溶液を50℃で3日間攪拌した。反応液を1Ｎ塩酸に注いだ後、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去し、標題化合物（1.35 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.59-2.68 (2H, m), 3.10 (3H, s), 3.26-3.36 (2H, m), 3.69 (2H, q, J= 5.3 Hz), 4.03 (2H, t, J= 5.1 Hz), 6.19 (1H, br), 6.60-6.70 (2H, m), 7.27-7.43 (3H, m), 7.47-7.55 (1H, m), 8.00 (1H, d, J= 7.9 Hz). Reference Example 12
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3- [2- (methylsulfonyl) phenyl] propanamide 2- (2-Chloro-5-fluorophenoxy) ethanamine hydrochloride (0.99 g) , 3- [2- (methylsulfonyl) phenyl] propanoic acid (1.0 g), WSC (1.09 g), HOBt (0.87 g) and Et 3 N (0.89 g) in DMF (20 mL) at 50 ° C. Stir for days. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and then saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (1.35 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.59-2.68 (2H, m), 3.10 (3H, s), 3.26-3.36 (2H, m), 3.69 (2H, q, J = 5.3 Hz), 4.03 (2H, t, J = 5.1 Hz), 6.19 (1H, br), 6.60-6.70 (2H, m), 7.27-7.43 (3H, m), 7.47-7.55 (1H, m), 8.00 (1H, d , J = 7.9 Hz).
参考例１３
2-(2,5-ジフルオロフェノキシ)-N-(1,1-ジオキシド-2,3-ジヒドロ-1-ベンゾチオフェン-3-イル)アセトアミド
　2,3-ジヒドロ-1-ベンゾチオフェン-3-アミン-1,1-ジオキシド塩酸塩（0.31 g）（公開特許文献ＵＳ２６６６７６２）、(2,5-ジフルオロフェノキシ)酢酸（0.27 g）、ＷＳＣ（0.41 g）、ＨＯＢｔ（0.33 g）及びＥｔ３Ｎ（0.29 g）のアセトニトリル（7 mL）溶液を室温で４時間攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝3:7～7:3）で精製し、標題化合物（0.19 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.43 (1H, dd, J= 13.6, 3.8 Hz), 3.90 (1H, dd, J= 13.6, 7.6 Hz), 4.59 (2H, s), 5.95 (1H, td, J= 8.0, 4.0 Hz), 6.64-6.78 (2H, m), 6.97-7.12 (1H, m), 7.16-7.25 (1H, m), 7.50-7.74 (3H, m), 7.77-7.85 (1H, m). Reference Example 13
2- (2,5-Difluorophenoxy) -N- (1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) acetamide 2,3-dihydro-1-benzothiophen-3-amine -1,1-dioxide hydrochloride (0.31 g) (published patent document US 2666762), (2,5-difluorophenoxy) acetic acid (0.27 g), WSC (0.41 g), HOBt (0.33 g) and Et 3 N (0.29) A solution of g) in acetonitrile (7 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-7: 3) to give the title compound (0.19 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.43 (1H, dd, J = 13.6, 3.8 Hz), 3.90 (1H, dd, J = 13.6, 7.6 Hz), 4.59 (2H, s), 5.95 (1H , td, J = 8.0, 4.0 Hz), 6.64-6.78 (2H, m), 6.97-7.12 (1H, m), 7.16-7.25 (1H, m), 7.50-7.74 (3H, m), 7.77-7.85 (1H, m).
参考例１４
2-(2,5-ジフルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
　3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（0.36 g）、(2,5-ジフルオロフェノキシ)酢酸（0.29 g）、ＷＳＣ（0.45 g）、ＨＯＢｔ（0.36 g）及びＥｔ３Ｎ（0.31 g）のアセトニトリル（7 mL）溶液を室温で４時間攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～7:3）で精製し、標題化合物（0.48 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.57-2.84 (2H, m), 3.36-3.57 (2H, m), 4.54-4.68 (2H, m), 5.50 (1H, td, J= 8.3, 5.3 Hz), 6.65-6.78 (2H, m), 7.00-7.14 (2H, m), 7.34-7.43 (1H, m), 7.48-7.64 (2H, m), 7.91-8.01 (1H, m). Reference Example 14
2- (2,5-Difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide 3,4-dihydro-2H-thiochromen-4-amine 1, 1-dioxide hydrochloride (0.36 g), (2,5-difluorophenoxy) acetic acid (0.29 g), WSC (0.45 g), HOBt (0.36 g) and Et 3 N (0.31 g) in acetonitrile (7 mL) Was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-7: 3) to give the title compound (0.48 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.57-2.84 (2H, m), 3.36-3.57 (2H, m), 4.54-4.68 (2H, m), 5.50 (1H, td, J = 8.3, 5.3 Hz), 6.65-6.78 (2H, m), 7.00-7.14 (2H, m), 7.34-7.43 (1H, m), 7.48-7.64 (2H, m), 7.91-8.01 (1H, m).
参考例１５
N-(6-クロロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド
　6-クロロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（0.41 g）、(2,5-ジフルオロフェノキシ)酢酸（0.29 g）、ＷＳＣ（0.44 g）、ＨＯＢｔ（0.35 g）及びＥｔ３Ｎ（0.31 g）のアセトニトリル（7 mL）溶液を室温で４時間攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:1～7:3）で精製し、標題化合物（0.51 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.56-2.81 (2H, m), 3.36-3.56 (2H, m), 4.56-4.74 (2H, m), 5.48 (1H, td, J= 8.6, 5.5 Hz), 6.67-6.80 (2H, m), 7.02-7.16 (2H, m), 7.35 (1H, dd, J= 1.9, 0.8 Hz), 7.50 (1H, dd, J= 8.1, 1.7 Hz), 7.89 (1H, d, J= 8.7 Hz). Reference Example 15
N- (6-Chloro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide 6-chloro-3,4-dihydro-2H -Thiochromen-4-amine 1,1-dioxide hydrochloride (0.41 g), (2,5-difluorophenoxy) acetic acid (0.29 g), WSC (0.44 g), HOBt (0.35 g) and Et 3 N (0.31 g) ) In acetonitrile (7 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1-7: 3) to give the title compound (0.51 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.56-2.81 (2H, m), 3.36-3.56 (2H, m), 4.56-4.74 (2H, m), 5.48 (1H, td, J = 8.6, 5.5 Hz), 6.67-6.80 (2H, m), 7.02-7.16 (2H, m), 7.35 (1H, dd, J = 1.9, 0.8 Hz), 7.50 (1H, dd, J = 8.1, 1.7 Hz), 7.89 (1H, d, J = 8.7 Hz).
参考例１６
N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2-フルオロフェノキシ)アセトアミド
　3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（0.46 g）、(2-フルオロフェノキシ)酢酸（0.33 g）、ＷＳＣ（0.56 g）、ＨＯＢｔ（0.45 g）及びＥｔ３Ｎ（0.40 g）のアセトニトリル（7 mL）溶液を室温で終夜攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝3:7～3:2）で精製し、標題化合物（0.73 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.60-2.85 (2H, m), 3.35-3.57 (2H, m), 4.57-4.72 (2H, m), 5.49 (1H, td, J= 8.3, 5.3 Hz), 6.92-7.20 (4H, m), 7.33-7.86 (4H, m), 7.91-8.00 (1H, m). Reference Example 16
N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2-fluorophenoxy) acetamide 3,4-dihydro-2H-thiochromen-4-amine 1,1- A solution of dioxide hydrochloride (0.46 g), (2-fluorophenoxy) acetic acid (0.33 g), WSC (0.56 g), HOBt (0.45 g) and Et 3 N (0.40 g) in acetonitrile (7 mL) at room temperature overnight. Stir. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-3: 2) to give the title compound (0.73 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.60-2.85 (2H, m), 3.35-3.57 (2H, m), 4.57-4.72 (2H, m), 5.49 (1H, td, J = 8.3, 5.3 Hz), 6.92-7.20 (4H, m), 7.33-7.86 (4H, m), 7.91-8.00 (1H, m).
参考例１７
N-(6-クロロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2-フルオロフェノキシ)アセトアミド
　6-クロロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（0.50 g）、（2-フルオロフェノキシ)酢酸（0.32 g）、ＷＳＣ（0.54 g）、ＨＯＢｔ（0.43 g）及びＥｔ３Ｎ（0.38 g）のアセトニトリル（7 mL）溶液を室温で終夜攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝2:3～3:2）で精製し、標題化合物（0.56 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.55-2.83 (2H, m), 3.34-3.56 (2H, m), 4.57-4.75 (2H, m), 5.47 (1H, td, J= 8.6, 5.5 Hz), 6.94-7.22 (5H, m), 7.31-7.39 (1H, m), 7.43-7.58 (1H, m), 7.88 (1H, d, J= 8.7 Hz). Reference Example 17
N- (6-Chloro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2-fluorophenoxy) acetamide 6-chloro-3,4-dihydro-2H-thiochromene 4-Amine 1,1-dioxide (0.50 g), (2-fluorophenoxy) acetic acid (0.32 g), WSC (0.54 g), HOBt (0.43 g) and Et 3 N (0.38 g) in acetonitrile (7 mL) ) The solution was stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3-3: 2) to give the title compound (0.56 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.55-2.83 (2H, m), 3.34-3.56 (2H, m), 4.57-4.75 (2H, m), 5.47 (1H, td, J = 8.6, 5.5 Hz), 6.94-7.22 (5H, m), 7.31-7.39 (1H, m), 7.43-7.58 (1H, m), 7.88 (1H, d, J = 8.7 Hz).
参考例１８
N-(1,1-ジオキシド-2,3-ジヒドロ-1-ベンゾチオフェン-3-イル)-2-(2-フルオロフェノキシ)アセトアミド
　2,3-ジヒドロ-１-ベンゾチオフェン-３-アミン-１,１-ジオキシド塩酸塩（0.40 g）、(2-フルオロフェノキシ)酢酸（0.31 g）、ＷＳＣ（0.53 g）、ＨＯＢｔ（0.42 g）及びＥｔ３Ｎ（0.37 g）のアセトニトリル（7 mL）溶液を室温で終夜攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝2:3～3:2）で精製し、標題化合物（0.62 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.35 (1H, dd, J= 13.8, 4.3 Hz), 3.84 (1H, dd, J= 13.6, 7.5 Hz), 4.55 (2H, s), 5.87 (1H, td, J= 8.0, 4.3 Hz), 6.82-7.10 (4H, m), 7.24 (1H, d, J= 8.7 Hz), 7.41-7.67 (3H, m), 7.68-7.77 (1H, m). Reference Example 18
N- (1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) -2- (2-fluorophenoxy) acetamide 2,3-dihydro-1-benzothiophen-3-amine-1 , 1-dioxide hydrochloride (0.40 g), (2-fluorophenoxy) acetic acid (0.31 g), WSC (0.53 g), HOBt (0.42 g) and Et 3 N (0.37 g) in acetonitrile (7 mL) Stir at room temperature overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3-3: 2) to give the title compound (0.62 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.35 (1H, dd, J = 13.8, 4.3 Hz), 3.84 (1H, dd, J = 13.6, 7.5 Hz), 4.55 (2H, s), 5.87 (1H , td, J = 8.0, 4.3 Hz), 6.82-7.10 (4H, m), 7.24 (1H, d, J = 8.7 Hz), 7.41-7.67 (3H, m), 7.68-7.77 (1H, m).
参考例１９
2-(2,5-ジフルオロフェノキシ)-N-{1-[2-(メチルスルホニル)フェニル]エチル}アセトアミド
（工程１）1-[2-(メチルスルホニル)フェニル]エタノン（5.11 g）（Journal of Medicinal Chemistry, 1965, 8(3), 305-312）と(アミノオキシ)メタン塩酸塩（2.80 g）のピリジン（30 mL）溶液を室温下、終夜攪拌した。反応混合物を水に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ塩酸、続いて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥して、溶媒を減圧下留去した。得られた残渣のＴＨＦ（100mL）溶液に、ＴＨＦ-ボラン錯体（75 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。反応液を80℃で4時間攪拌後、反応液に氷を加え、1Ｎ塩酸（120 mL）を加えた。80℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を、8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（20 mL）を加えた。溶媒を減圧下留去し、メタノールと酢酸エチルで結晶化させ、1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩（1.35 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.55 (3H, d, J= 6.8 Hz), 3.36 (3H, s), 5.21 (1H, br), 7.63-7.72 (1H, m), 7.83-7.91 (1H, m), 7.97-8.06 (2H, m), 8.68 (3H, br).
（工程２）工程１で得られた1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩（0.30 g）、(2,5-ジフルオロフェノキシ)酢酸（0.24 g）、ＷＳＣ（0.39 g）、ＨＯＢｔ（0.30 g）及びＥｔ３Ｎ（0.26 g）のアセトニトリル（5 mL）溶液を室温で２時間攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝3:7～1:1）で精製し、標題化合物（0.37 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.58 (3H, d, J= 6.3 Hz), 3.44 (3H, s), 4.37-4.58 (2H, m), 5.74-5.86 (1H, m), 6.65-6.80 (2H, m), 7.08-7.25 (2H, m), 7.39-7.49 (2H, m), 7.56-7.65 (1H, m), 8.01-8.08 (1H, m). Reference Example 19
2- (2,5-Difluorophenoxy) -N- {1- [2- (methylsulfonyl) phenyl] ethyl} acetamide (Step 1) 1- [2- (methylsulfonyl) phenyl] ethanone (5.11 g) (Journal of Medicinal Chemistry, 1965, 8 (3), 305-312) and (aminooxy) methane hydrochloride (2.80 g) in pyridine (30 mL) were stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To a THF (100 mL) solution of the obtained residue, a THF-borane complex (75 mL, 1M THF solution) was added at 0 ° C. After stirring the reaction solution at 80 ° C. for 4 hours, ice was added to the reaction solution, and 1N hydrochloric acid (120 mL) was added. After stirring at 80 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol, and 4N hydrogen chloride / ethyl acetate solution (20 mL) was added. The solvent was distilled off under reduced pressure and crystallized with methanol and ethyl acetate to obtain 1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride (1.35 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.55 (3H, d, J = 6.8 Hz), 3.36 (3H, s), 5.21 (1H, br), 7.63-7.72 (1H, m), 7.83 -7.91 (1H, m), 7.97-8.06 (2H, m), 8.68 (3H, br).
(Step 2) 1- [2- (Methylsulfonyl) phenyl] ethanamine hydrochloride (0.30 g), (2,5-difluorophenoxy) acetic acid (0.24 g), WSC (0.39 g), HOBt obtained in Step 1 A solution of (0.30 g) and Et 3 N (0.26 g) in acetonitrile (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) to obtain the title compound (0.37 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.58 (3H, d, J = 6.3 Hz), 3.44 (3H, s), 4.37-4.58 (2H, m), 5.74-5.86 (1H, m), 6.65 -6.80 (2H, m), 7.08-7.25 (2H, m), 7.39-7.49 (2H, m), 7.56-7.65 (1H, m), 8.01-8.08 (1H, m).
参考例２０
2-(2-フルオロフェノキシ)-N-{1-[2-(メチルスルホニル)フェニル]エチル}アセトアミド
　参考例１９の工程１で得られた1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩（0.30 g）、（2-フルオロフェノキシ)酢酸（0.22 g）、ＷＳＣ（0.37 g）、ＨＯＢｔ（0.30 g）及びＥｔ３Ｎ（0.26 g）のアセトニトリル（5 mL）溶液を室温で終夜攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝2:3～1:1）で精製し、標題化合物（0.37 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.58 (3H, d, J= 6.6 Hz), 3.45 (3H, s), 4.41-4.60 (2H, m), 5.73-5.87 (1H, m), 6.89-7.23 (4H, m), 7.27-7.34 (1H, m), 7.39-7.48 (2H, m), 7.55-7.63 (1H, m), 8.00-8.07 (1H, m). Reference Example 20
2- (2-Fluorophenoxy) -N- {1- [2- (methylsulfonyl) phenyl] ethyl} acetamide 1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride obtained in Step 1 of Reference Example 19 A solution of (0.30 g), (2-fluorophenoxy) acetic acid (0.22 g), WSC (0.37 g), HOBt (0.30 g) and Et 3 N (0.26 g) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 1: 1) to obtain the title compound (0.37 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.58 (3H, d, J = 6.6 Hz), 3.45 (3H, s), 4.41-4.60 (2H, m), 5.73-5.87 (1H, m), 6.89 -7.23 (4H, m), 7.27-7.34 (1H, m), 7.39-7.48 (2H, m), 7.55-7.63 (1H, m), 8.00-8.07 (1H, m).
参考例２１
2-(2-クロロ-5-フルオロフェノキシ)-N-{1-[2-(メチルスルホニル)フェニル]エチル}アセトアミド
　参考例１９の工程１で得られた1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩（0.31 g）、(2-クロロ-5-フルオロフェノキシ)酢酸（0.27 g）、ＷＳＣ（0.37 g）、ＨＯＢｔ（0.30 g）及びＥｔ３Ｎ（0.26 g）のアセトニトリル（5 mL）溶液を室温で２時間攪拌した。反応液を水に注ぎ、酢酸エチルで二回抽出した。有機層を合わせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝3:7～1:1）で精製し、標題化合物（0.46 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.59 (3H, d, J= 6.6 Hz), 3.44 (3H, s), 4.35-4.60 (2H, m), 5.75-5.88 (1H, m), 6.65 (1H, dd, J= 9.6, 2.8 Hz), 6.73-6.82 (1H, m), 7.37-7.49 (4H, m), 7.56-7.65 (1H, m), 8.01-8.08 (1H, m). Reference Example 21
2- (2-Chloro-5-fluorophenoxy) -N- {1- [2- (methylsulfonyl) phenyl] ethyl} acetamide 1- [2- (methylsulfonyl) phenyl obtained in Step 1 of Reference Example 19 ] Ethanamine hydrochloride (0.31 g), (2-chloro-5-fluorophenoxy) acetic acid (0.27 g), WSC (0.37 g), HOBt (0.30 g) and Et 3 N (0.26 g) in acetonitrile (5 mL) The solution was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) to obtain the title compound (0.46 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.59 (3H, d, J = 6.6 Hz), 3.44 (3H, s), 4.35-4.60 (2H, m), 5.75-5.88 (1H, m), 6.65 (1H, dd, J = 9.6, 2.8 Hz), 6.73-6.82 (1H, m), 7.37-7.49 (4H, m), 7.56-7.65 (1H, m), 8.01-8.08 (1H, m).
　参考例１～２１に記載される化合物は以下の通りである（表１）。表１に示されたfreeはフリー体を示し、Racemateはラセミ体を示す。 The compounds described in Reference Examples 1 to 21 are as follows (Table 1). Free shown in Table 1 indicates a free form, and Racemate indicates a racemic form.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
参考例２２
tert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2-メトキシフェノキシ)エチル]カルバマート
（工程１）参考例７の工程１で得られた3,4-ジヒドロ-2H-チオクロメン-4-アミン塩酸塩（10.95 g）、グリコール酸 (3.92 g)、ＷＳＣ(9.88 g)、ＨＯＢｔ(6.96 g)及びジイソプロピルエチルアミン(13.32 g)のＤＭＦ(50 mL)溶液を室温で20時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 2:3～1:0）で精製してN-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-ヒドロキシアセトアミド（8.41 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.57-2.81 (2H, m), 3.36-3.56 (2H, m), 4.24 (2H, s), 5.45 (1H, td, J= 8.1, 5.3Hz), 7.01 (1H, br), 7.36-7.44 (1H, m), 7.49-7.63 (2H, m), 7.91-7.98 (1H, m)(An OH peak was not observed).
（工程２）工程１で得られたN-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-ヒドロキシアセトアミドをＴＨＦ（50 mL）に溶解させ、ＴＨＦ-ボラン錯体（99 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。反応液を60℃で4時間撹拌後、反応液にメタノールを加え、溶媒を減圧下留去した。残渣に6Ｎ塩酸（50 mL）を加えた。70℃で2時間撹拌後、8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を酢酸エチルに溶解させ、二炭酸ジ-tert-ブチル（7.90 g）を0℃で加えた。反応液を室温で18時間撹拌後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:1～3:1）で精製してtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマート（8.50 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.08-1.62 (9H, m), 2.49-2.62 (1H, m), 2.78-3.13 (2H, m), 3.23-3.51 (3H, m), 3.52-3.91 (3H, m), 4.60-5.72 (1H, m), 7.40 (1H, br), 7.44-7.51 (1H, m), 7.52-7.59 (1H, m), 7.93 (1H, dd, J= 8.0, 1.5 Hz).
（工程３）工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマート（341 mg）、２－メトキシフェノール（149 mg）及びトリブチルホスフィン（748 mg）をＴＨＦ（4 mL）に溶解させ、1,1'-アゾジカルボニルピペリジン（757 mg）を50℃で加えた。反応液を50℃で2時間撹拌後、溶媒を減圧下留去した。残渣にジイソプロピルエーテルを加え、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～3:7）で精製して標題化合物（385 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.17 (6H, br), 1.48 (3H, br), 2.54-2.76 (1H, m), 2.97-3.21 (1H, m), 3.28-3.52 (3H, m), 3.73 (3H, s), 3.77-3.83 (1H, m), 3.94-4.17 (1H, m), 4.19-4.30 (1H, m), 4.87-5.59 (1H, m), 6.76-6.98 (4H, m), 7.18-7.38 (1H, m), 7.39-7.55 (2H, m), 7.87-7.97 (1H, m). Reference Example 22
tert-Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2-methoxyphenoxy) ethyl] carbamate (Step 1) Obtained in Step 1 of Reference Example 7. 3,4-dihydro-2H-thiochromen-4-amine hydrochloride (10.95 g), glycolic acid (3.92 g), WSC (9.88 g), HOBt (6.96 g) and diisopropylethylamine (13.32 g) in DMF (50 mL) The solution was stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 1: 0) to give N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2-Hydroxyacetamide (8.41 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.57-2.81 (2H, m), 3.36-3.56 (2H, m), 4.24 (2H, s), 5.45 (1H, td, J = 8.1, 5.3Hz) , 7.01 (1H, br), 7.36-7.44 (1H, m), 7.49-7.63 (2H, m), 7.91-7.98 (1H, m) (An OH peak was not observed).
(Step 2) N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2-hydroxyacetamide obtained in Step 1 was dissolved in THF (50 mL), and THF- Borane complex (99 mL, 1M in THF) was added at 0 ° C. After stirring the reaction solution at 60 ° C. for 4 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (50 mL) was added to the residue. The mixture was stirred at 70 ° C. for 2 hours, basified with 8N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and di-tert-butyl dicarbonate (7.90 g) was added at 0 ° C. The reaction mixture was stirred at room temperature for 18 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1-3: 1) to give tert-butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl). ) (2-hydroxyethyl) carbamate (8.50 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.08-1.62 (9H, m), 2.49-2.62 (1H, m), 2.78-3.13 (2H, m), 3.23-3.51 (3H, m), 3.52- 3.91 (3H, m), 4.60-5.72 (1H, m), 7.40 (1H, br), 7.44-7.51 (1H, m), 7.52-7.59 (1H, m), 7.93 (1H, dd, J = 8.0 , 1.5 Hz).
(Step 3) tert-butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate (341 mg), 2-methoxyphenol obtained in Step 2 (149 mg) and tributylphosphine (748 mg) were dissolved in THF (4 mL), and 1,1′-azodicarbonylpiperidine (757 mg) was added at 50 ° C. The reaction mixture was stirred at 50 ° C. for 2 hours, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue, the mixture was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-3: 7) to give the title compound (385 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.17 (6H, br), 1.48 (3H, br), 2.54-2.76 (1H, m), 2.97-3.21 (1H, m), 3.28-3.52 (3H, m), 3.73 (3H, s), 3.77-3.83 (1H, m), 3.94-4.17 (1H, m), 4.19-4.30 (1H, m), 4.87-5.59 (1H, m), 6.76-6.98 ( 4H, m), 7.18-7.38 (1H, m), 7.39-7.55 (2H, m), 7.87-7.97 (1H, m).
参考例２３
2-(2-クロロ-5-フルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-1,2-ベンゾチアジン-4-イル)アセトアミド
（工程１）2,3-ジヒドロ-4H-1,2-ベンゾチアジン-4-オン 1,1-ジオキシド（6.60 g）（公開特許文献ＵＳ５８７４４２９）のピリジン（67 mL）溶液に塩酸Ｏ-メチルヒドロキシルアミン（8.39 g）を室温で加えた。40℃で2時間撹拌し、室温まで冷却、溶媒を減圧下留去した後、残渣に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、2,3-ジヒドロ-4H-1,2-ベンゾチアジン-4-オン Ｏ-メチルオキシム 1,1-ジオキシド（5.30 g）を白色固体として得た。1H-NMR (400 MHz, DMSO-d6) δppm 4.01 (3H, s), 4.37 (2H, d, J= 7.2 Hz), 7.63-7.71 (2H, m), 7.80-7.12 (1H, m), 7.93 (1H, br), 7.95-7.99 (1H, m). 
（工程２）工程１で得られた2,3-ジヒドロ-4H-1,2-ベンゾチアジン-4-オン Ｏ-メチルオキシム 1,1-ジオキシド（5.30 g）と5%パラジウム－炭素（0.75 g）のメタノール（234 mL）懸濁液を水素雰囲気下室温で2時間撹拌した。反応液をセライトでろ過し、ろ液を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、3,4-ジヒドロ-2H-1,2-ベンゾチアジン-4-アミン 1,1-ジオキシド（3.60 g）を得た。1H-NMR (400 MHz, DMSO-d6)δppm 2.18 (2H, br), 3.37 (1H, dd, J= 14.4, 8.0 Hz), 3.60 (1H, dd, J= 12.4, 6.8 Hz), 3.88 (1H, dd, J = 7.6, 4.4 Hz), 7.43 (1H, t, J= 7.8 Hz), 7.56-7.60 (1H, m), 7.64 (1H, dd, J= 8.0, 1.2 Hz), 7.72 (1H, d, J= 7.6 Hz) （A SO2NH peak was not observed）. 
（工程３）工程２で得られた3,4-ジヒドロ-2H-1,2-ベンゾチアジン-4-アミン 1,1-ジオキシド（500 mg）、(2-クロロ-5-フルオロフェノキシ)酢酸（568 mg）、ＷＳＣ（532 mg）、ＨＯＢｔ（425 mg）及びＥｔ３Ｎ（0.39 mL）のＴＨＦ（30 mL）溶液を60℃で5時間撹拌した。反応液に1Ｎ塩酸を注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。残渣にエタノールを加え、ろ取し、標題化合物（803 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.51-3.69 (2H, m), 4.64-4.92 (2H, m), 5.13-5.36 (1H, m), 6.72-6.94 (1H, m), 6.94-7.13 (1H, m), 7.30-7.41 (1H, m), 7.41-7.65 (3H, m), 7.65-7.79 (1H, m), 7.79-7.94 (1H, m), 8.66 (1H, d, J= 9.0 Hz). Reference Example 23
2- (2-Chloro-5-fluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-1,2-benzothiazin-4-yl) acetamide (Step 1) 2,3-dihydro O-methylhydroxylamine hydrochloride (8.39 g) was added to a pyridine (67 mL) solution of -4H-1,2-benzothiazin-4-one 1,1-dioxide (6.60 g) (published patent document US5874429) at room temperature. . The mixture was stirred at 40 ° C. for 2 hours, cooled to room temperature, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give 2,3-dihydro-4H-1,2-benzothiazin-4-one O-methyloxime 1,1-dioxide (5.30 g) as a white solid Got as. 1 H-NMR (400 MHz, DMSO-d 6 ) δppm 4.01 (3H, s), 4.37 (2H, d, J = 7.2 Hz), 7.63-7.71 (2H, m), 7.80-7.12 (1H, m) , 7.93 (1H, br), 7.95-7.99 (1H, m).
(Step 2) 2,3-Dihydro-4H-1,2-benzothiazin-4-one O-methyloxime 1,1-dioxide (5.30 g) obtained in Step 1 and 5% palladium-carbon (0.75 g) Of methanol (234 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 3,4-dihydro-2H-1,2-benzothiazin-4-amine 1,1-dioxide (3.60 g). 1 H-NMR (400 MHz, DMSO-d 6 ) δppm 2.18 (2H, br), 3.37 (1H, dd, J = 14.4, 8.0 Hz), 3.60 (1H, dd, J = 12.4, 6.8 Hz), 3.88 (1H, dd, J = 7.6, 4.4 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.56-7.60 (1H, m), 7.64 (1H, dd, J = 8.0, 1.2 Hz), 7.72 ( 1H, d, J = 7.6 Hz) (A SO 2 NH peak was not observed).
(Step 3) 3,4-dihydro-2H-1,2-benzothiazin-4-amine 1,1-dioxide (500 mg), (2-chloro-5-fluorophenoxy) acetic acid (568) obtained in Step 2 mg), WSC (532 mg), HOBt (425 mg) and Et 3 N (0.39 mL) in THF (30 mL) were stirred at 60 ° C. for 5 hours. After pouring 1N hydrochloric acid into the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Ethanol was added to the residue and collected by filtration to give the title compound (803 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.51-3.69 (2H, m), 4.64-4.92 (2H, m), 5.13-5.36 (1H, m), 6.72-6.94 (1H, m), 6.94-7.13 (1H, m), 7.30-7.41 (1H, m), 7.41-7.65 (3H, m), 7.65-7.79 (1H, m), 7.79-7.94 (1H, m), 8.66 (1H, d , J = 9.0 Hz).
参考例２４
tert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2-クロロ-5-フルオロフェノキシ)エチル]カルバマート
（工程１）氷冷したクロロスルホン酸（20 mL）にN-(3-ブロモベンジル)アセトアミド（8.5 g）を加え、70℃に昇温後、3時間撹拌した。氷に反応液をゆっくり加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、ろ過後、溶媒を減圧下留去した。得られた固体を酢酸エチルで洗浄し、2-[(アセチルアミノ)メチル]-4-ブロモベンゼンスルホニルクロリド（8.6 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.02 (3H, s), 4.81 (2H, d, J= 6.8 Hz), 6.25 (1H, br), 7.67 (1H, dd, J= 8.7, 2.3 Hz), 7.87-8.02 (2H, m).
（工程２）工程１で得られた2-[(アセチルアミノ)メチル]-4-ブロモベンゼンスルホニルクロリド（4.10 g）と2Ｎジメチルアミン／メタノール (15 mL) 溶液のＴＨＦ(10 mL)溶液を室温で3時間撹拌した。反応液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、N-[5-ブロモ-2-(ジメチルスルファモイル)ベンジル]アセトアミド（4.35 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.98 (3H, s), 2.83 (6H, s), 4.65 (2H, d, J= 6.4 Hz), 6.45 (1H, br), 7.54-7.60 (1H, m), 7.66-7.72 (1H, m), 7.82 (1H, d, J= 1.9 Hz).
（工程３）工程２で得られたN-[5-ブロモ-2-(ジメチルスルファモイル)ベンジル]アセトアミド（4.40 g）のエタノール（40 mL）溶液に6Ｎ塩酸（20 mL）を室温で加え、90℃で終夜撹拌した。溶媒を減圧下留去し、残渣をろ過後、酢酸エチルで洗浄して2-(アミノメチル)-4-ブロモ-N,N-ジメチルベンゼンスルホンアミド塩酸塩（3.42 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.74 (6H, s), 4.35 (2H, br), 7.71-7.83 (1H, m), 7.83-7.92 (1H, m), 8.03 (1H, br), 8.44 (3H, br).
（工程４）工程３で得られた2-(アミノメチル)-4-ブロモ-N,N-ジメチルベンゼンスルホンアミド塩酸塩（2.00 g）、(2-クロロ-5-フルオロフェノキシ)酢酸（1.31 g）、ＷＳＣ(1.28 g)、ＨＯＢｔ(1.02 g)及びＥｔ３Ｎ(1.35 g)のＴＨＦ(40 mL)溶液を50℃で3時間撹拌した。反応液に1Ｎ塩酸を注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、N-[5-ブロモ-2-(ジメチルスルファモイル)ベンジル]-2-(2-クロロ-5-フルオロフェノキシ)アセトアミド(2.70 g)を得た。1H-NMR (300 MHz, CDCl3) δppm 2.84 (6H, s), 4.52 (2H, s), 4.82 (2H, d, J= 6.4 Hz), 6.61 (1H, dd, J= 9.4, 2.6 Hz), 6.70 (1H, td, J= 8.3, 2.6 Hz), 7.34 (1H, dd, J= 8.7, 6.0 Hz), 7.48-7.78 (3H, m), 7.78-7.90 (1H, m).
（工程５）工程４で得られたN-[5-ブロモ-2-(ジメチルスルファモイル)ベンジル]-2-(2-クロロ-5-フルオロフェノキシ)アセトアミド（2.70 g）のＴＨＦ（40 mL）溶液にＴＨＦ-ボラン錯体（17 mL, 1Ｍ ＴＨＦ溶液）を加え、80℃で3時間撹拌後、反応液に氷を加え、1Ｎ塩酸（20 mL）を加えた。80℃で1時間撹拌した。反応液に酢酸エチルを加え、分離した水層を水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製した。得られた油状物質を少量のメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた固体を酢酸エチルとヘキサンで再結晶して4-ブロモ-2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩（1.70 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.73 (6H, s), 3.42-3.63 (2H, m), 4.44 (2H, t, J= 4.7 Hz), 4.52-4.66 (2H, m), 6.90 (1H, td, J= 8.5, 2.6 Hz), 7.22 (1H, dd, J= 10.7, 2.8 Hz), 7.51 (1H, dd, J= 9.0, 6.0 Hz), 7.72-7.85 (1H, m), 7.92 (1H, dd, J= 8.5, 2.1 Hz), 8.15 (1H, d, J= 1.9 Hz), 9.40 (2H, br).
（工程６）工程５で得られた4-ブロモ-2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩（1.70 g）と、トリエチルアミン（1.1 mL）のＴＨＦ（50 mL）溶液に二炭酸ジ-t-ブチル(1.20 g)を室温で加えた。60℃で3時間撹拌後、反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を1Ｎ塩酸、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をメタノールと水で再結晶して、標題化合物（1.78 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.23 (5H, s), 1.39 (4H, s), 2.73 (6H, d, J= 5.3 Hz), 3.62-3.84 (2H, m), 4.12-4.28 (2H, m), 4.84 (2H, s), 6.67-6.90 (1H, m), 7.12 (1H, dd, J= 10.8, 2.8 Hz), 7.34-7.50 (2H, m), 7.63-7.76 (2H, m). Reference Example 24
tert-butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (Step 1) N in ice-cooled chlorosulfonic acid (20 mL) -(3-Bromobenzyl) acetamide (8.5 g) was added, and the temperature was raised to 70 ° C., followed by stirring for 3 hours. The reaction solution was slowly added to ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain 2-[(acetylamino) methyl] -4-bromobenzenesulfonyl chloride (8.6 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.02 (3H, s), 4.81 (2H, d, J = 6.8 Hz), 6.25 (1H, br), 7.67 (1H, dd, J = 8.7, 2.3 Hz ), 7.87-8.02 (2H, m).
(Step 2) A solution of 2-[(acetylamino) methyl] -4-bromobenzenesulfonyl chloride (4.10 g) obtained in Step 1 and 2N dimethylamine / methanol (15 mL) in THF (10 mL) at room temperature For 3 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain N- [5-bromo-2- (dimethylsulfamoyl) benzyl] acetamide (4.35 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.98 (3H, s), 2.83 (6H, s), 4.65 (2H, d, J = 6.4 Hz), 6.45 (1H, br), 7.54-7.60 (1H , m), 7.66-7.72 (1H, m), 7.82 (1H, d, J = 1.9 Hz).
(Step 3) To a solution of N- [5-bromo-2- (dimethylsulfamoyl) benzyl] acetamide (4.40 g) obtained in Step 2 in ethanol (40 mL) was added 6N hydrochloric acid (20 mL) at room temperature. And stirred at 90 ° C. overnight. The solvent was evaporated under reduced pressure, and the residue was filtered and washed with ethyl acetate to give 2- (aminomethyl) -4-bromo-N, N-dimethylbenzenesulfonamide hydrochloride (3.42 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.74 (6H, s), 4.35 (2H, br), 7.71-7.83 (1H, m), 7.83-7.92 (1H, m), 8.03 (1H, br), 8.44 (3H, br).
(Step 4) 2- (Aminomethyl) -4-bromo-N, N-dimethylbenzenesulfonamide hydrochloride (2.00 g) obtained in Step 3 and (2-chloro-5-fluorophenoxy) acetic acid (1.31 g) ), WSC (1.28 g), HOBt (1.02 g) and Et 3 N (1.35 g) in THF (40 mL) were stirred at 50 ° C. for 3 hours. After pouring 1N hydrochloric acid into the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and N- [5-bromo-2- (dimethylsulfamoyl) benzyl] -2- (2-chloro-5-fluorophenoxy) acetamide (2.70 g) was purified. Obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.84 (6H, s), 4.52 (2H, s), 4.82 (2H, d, J = 6.4 Hz), 6.61 (1H, dd, J = 9.4, 2.6 Hz ), 6.70 (1H, td, J = 8.3, 2.6 Hz), 7.34 (1H, dd, J = 8.7, 6.0 Hz), 7.48-7.78 (3H, m), 7.78-7.90 (1H, m).
(Step 5) N- [5-Bromo-2- (dimethylsulfamoyl) benzyl] -2- (2-chloro-5-fluorophenoxy) acetamide (2.70 g) obtained in Step 4 in THF (40 mL ) THF-borane complex (17 mL, 1M THF solution) was added to the solution, and the mixture was stirred at 80 ° C. for 3 hours. Ice was added to the reaction mixture, and 1N hydrochloric acid (20 mL) was added. Stir at 80 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, and the separated aqueous layer was made basic with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography. The obtained oil was dissolved in a small amount of methanol, 4N hydrogen chloride / ethyl acetate solution (1 mL) was added, and the obtained solid was recrystallized from ethyl acetate and hexane to give 4-bromo-2-({[ 2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide hydrochloride (1.70 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.73 (6H, s), 3.42-3.63 (2H, m), 4.44 (2H, t, J = 4.7 Hz), 4.52-4.66 (2H, m) , 6.90 (1H, td, J = 8.5, 2.6 Hz), 7.22 (1H, dd, J = 10.7, 2.8 Hz), 7.51 (1H, dd, J = 9.0, 6.0 Hz), 7.72-7.85 (1H, m ), 7.92 (1H, dd, J = 8.5, 2.1 Hz), 8.15 (1H, d, J = 1.9 Hz), 9.40 (2H, br).
(Step 6) 4-Bromo-2-({[2- (2-chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide hydrochloride (1.70) obtained in Step 5 g) and tri-ethylamine (1.1 mL) in THF (50 mL) were added di-t-butyl dicarbonate (1.20 g) at room temperature. After stirring at 60 ° C. for 3 hours, saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from methanol and water to give the title compound (1.78 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.23 (5H, s), 1.39 (4H, s), 2.73 (6H, d, J = 5.3 Hz), 3.62-3.84 (2H, m), 4.12 -4.28 (2H, m), 4.84 (2H, s), 6.67-6.90 (1H, m), 7.12 (1H, dd, J = 10.8, 2.8 Hz), 7.34-7.50 (2H, m), 7.63-7.76 (2H, m).
参考例２５
tert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル){2-[2-(メチルスルファニル)フェノキシ]エチル}カルバマート
　2-(メチルスルファニル)フェノールを用いて参考例２２の工程３と同様の手法により標題化合物を得た。1H-NMR (300 MHz, CDCl3) δppm 1.09-1.55 (9H, m), 2.37 (3H, s), 2.58-2.74 (1H, m), 3.02-3.24 (1H, m), 3.32 (1H, d, J= 5.7 Hz), 3.36-3.61 (2H, m), 3.68-3.80 (1H, m), 4.16-4.37 (2H, m), 4.84-5.56 (1H, m), 6.84 (1H, d, J= 7.9 Hz), 6.94-7.04 (1H, m), 7.07-7.18 (2H, m), 7.33 (1H, d, J= 7.5 Hz), 7.46 (2H, s), 7.88-7.96 (1H, m). Reference Example 25
tert-Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) {2- [2- (methylsulfanyl) phenoxy] ethyl} carbamate Reference using 2- (methylsulfanyl) phenol The title compound was obtained in the same manner as in Step 3 of Example 22. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.09-1.55 (9H, m), 2.37 (3H, s), 2.58-2.74 (1H, m), 3.02-3.24 (1H, m), 3.32 (1H, d, J = 5.7 Hz), 3.36-3.61 (2H, m), 3.68-3.80 (1H, m), 4.16-4.37 (2H, m), 4.84-5.56 (1H, m), 6.84 (1H, d, J = 7.9 Hz), 6.94-7.04 (1H, m), 7.07-7.18 (2H, m), 7.33 (1H, d, J = 7.5 Hz), 7.46 (2H, s), 7.88-7.96 (1H, m ).
参考例２６
tert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル){2-[2-クロロフェノキシ]エチル}カルバマート
　2-クロロフェノールを用いて参考例２２の工程３と同様の手法により標題化合物を得た。1H-NMR (300 MHz, CDCl3) δppm 1.12-1.54 (9H, m), 2.58-2.74 (1H, m), 3.00-3.27 (1H, m), 3.34-3.51 (2H, m), 3.55-3.84 (1H, m), 3.98-4.33 (3H, m), 4.80-5.62 (1H, m), 6.80-6.98 (2H, m), 7.23 (1H, d, J= 7.5 Hz), 7.30-7.39 (2H, m), 7.40-7.53 (2H, m), 7.92 (1H, d, J= 6.8 Hz). Reference Example 26
tert-Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) {2- [2-chlorophenoxy] ethyl} carbamate Step 2 of Reference Example 22 using 2-chlorophenol and The title compound was obtained in a similar manner. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.12-1.54 (9H, m), 2.58-2.74 (1H, m), 3.00-3.27 (1H, m), 3.34-3.51 (2H, m), 3.55- 3.84 (1H, m), 3.98-4.33 (3H, m), 4.80-5.62 (1H, m), 6.80-6.98 (2H, m), 7.23 (1H, d, J = 7.5 Hz), 7.30-7.39 ( 2H, m), 7.40-7.53 (2H, m), 7.92 (1H, d, J = 6.8 Hz).
参考例２７
2-(2-クロロ-5-フルオロフェノキシ)-N-(6-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
　6-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オンを用いて参考例７の工程１から工程３と同様の手法を用いて標題化合物を得た。
1H-NMR (300 MHz, CDCl3) δppm 2.57-2.85 (2H, m), 3.40-3.56 (2H, m), 4.56-4.70 (2H, m), 5.48 (1H, td, J= 8.8, 5.1 Hz), 6.65-6.81 (2H, m), 7.08-7.15 (1H, m), 7.17-7.25 (2H, m), 7.36 (1H, dd, J= 8.9, 5.8 Hz), 7.99 (1H, dd, J= 8.9, 5.5 Hz). Reference Example 27
2- (2-Chloro-5-fluorophenoxy) -N- (6-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide 6-fluoro-2,3-dihydro The title compound was obtained in the same manner as in Step 1 to Step 3 of Reference Example 7 using -4H-thiochromen-4-one.
1 H-NMR (300 MHz, CDCl 3 ) δppm 2.57-2.85 (2H, m), 3.40-3.56 (2H, m), 4.56-4.70 (2H, m), 5.48 (1H, td, J = 8.8, 5.1 Hz), 6.65-6.81 (2H, m), 7.08-7.15 (1H, m), 7.17-7.25 (2H, m), 7.36 (1H, dd, J = 8.9, 5.8 Hz), 7.99 (1H, dd, J = 8.9, 5.5 Hz).
参考例２８
N-[5-ブロモ-2-(ジメチルスルファモイル)ベンジル]-2-(2,5-ジフルオロフェノキシ)アセトアミド
　参考例２４の工程３で得られた2-(アミノメチル)-4-ブロモ-N,N-ジメチルベンゼンスルホンアミド塩酸塩（2.00 g）、(2,5-ジフルオロフェノキシ)酢酸（1.42 g）、ＷＳＣ(0.89 g)、ＨＯＢｔ(0.73 g)及びＥｔ３Ｎ(1.32 mL)のＴＨＦ(40 mL)溶液を50℃で3時間撹拌した。反応液に1Ｎ塩酸を注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、標題化合物 (2.0 g)を得た。1H-NMR (300 MHz, CDCl3) δppm 2.83 (6H, s), 4.53 (2H, s), 4.80 (2H, d, J= 6.8 Hz), 6.54-6.75 (2H, m), 6.96-7.15 (1H, m), 7.48-7.62 (2H, m), 7.71 (1H, d, J= 8.3 Hz), 7.80 (1H, d, J= 2.3 Hz). Reference Example 28
N- [5-Bromo-2- (dimethylsulfamoyl) benzyl] -2- (2,5-difluorophenoxy) acetamide 2- (aminomethyl) -4-bromo- obtained in Step 3 of Reference Example 24 N, N-dimethylbenzenesulfonamide hydrochloride (2.00 g), (2,5-difluorophenoxy) acetic acid (1.42 g), WSC (0.89 g), HOBt (0.73 g) and Et 3 N (1.32 mL) in THF The solution (40 mL) was stirred at 50 ° C. for 3 hours. After pouring 1N hydrochloric acid into the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (2.0 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.83 (6H, s), 4.53 (2H, s), 4.80 (2H, d, J = 6.8 Hz), 6.54-6.75 (2H, m), 6.96-7.15 (1H, m), 7.48-7.62 (2H, m), 7.71 (1H, d, J = 8.3 Hz), 7.80 (1H, d, J = 2.3 Hz).
参考例２９
N-(6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド
（工程１）4-ブロモベンゼンチオール（15.9 g）の2Ｎ水酸化ナトリウム水溶液（40 mL）溶液に3-ブロモプロピオン酸（11.7 g）および炭酸カリウム（5.29 g）の水溶液を加え、室温で2日間撹拌した。反応液をろ過し、トルエンで洗浄し、1Ｎ塩酸で酸性とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して3-[(4-ブロモフェニル)スルファニル]プロパン酸（15.9 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.66 (2H, t, J= 7.2 Hz), 3.13 (2H, t, J= 7.2 Hz), 7.18-7.27 (2H, m), 7.38-7.45 (2H, m), 7.53-8.66 (1H, m).
（工程２）工程１で得られた3-[(4-ブロモフェニル)スルファニル]プロパン酸（15.3 g）のメタンスルホン酸（150 mL）溶液を75℃で6時間撹拌した。反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ水酸化ナトリウムと飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:1）で精製して6-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン（10.8 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.92-3.01 (2H, m), 3.21-3.27 (2H, m), 7.16 (1H, d, J= 8.7 Hz), 7.48 (1H, dd, J= 8.7, 2.3 Hz), 8.22 (1H, d, J= 2.3 Hz).
（工程３）工程２で得られた6-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン（10.8 g）および塩酸Ｏ-メチルヒドロキシルアミン（4.83 g）のピリジン（60 mL）の溶液を室温で20時間撹拌した。反応液を濃縮し、水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～9:1）で精製して(4E)-6-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（9.70 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.89-2.97 (2H, m), 3.01-3.09 (2H, m), 4.01 (3H, s), 7.09 (1H, d, J= 8.3 Hz), 7.30 (1H, dd, J= 8.3, 2.3 Hz), 8.13 (1H, d, J= 2.3 Hz).
（工程４）工程３で得られた(4E)-6-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（9.70 g）をＴＨＦ（50 mL）に溶解させ、ＴＨＦ-ボラン錯体（89 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。反応液を65℃で3時間撹拌後、反応液にメタノールを加え、溶媒を減圧下留去した。残渣に6Ｎ塩酸（45 mL）を加えた。75℃で3時間撹拌後、8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を酢酸エチルに溶解させ、二炭酸ジ-tert-ブチル（7.78 g）を0℃で加えた。反応液を室温で17時間撹拌後、溶媒を減圧下留去し、ジイソプロピルエーテルで結晶化し、tert-ブチル (6-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（10.6 g ）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.48 (9H, s), 2.03-2.16 (1H, m), 2.24-2.39 (1H, m), 2.93-3.12 (2H, m), 4.80 (2H, d, J= 13.3 Hz), 6.97 (1H, d, J= 8.3 Hz), 7.23 (1H, dd, J= 8.3, 2.3 Hz), 7.43 (1H, d, J= 2.3 Hz).
（工程５）工程４で得られたtert-ブチル (6-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（10.6 g ）の酢酸エチル（60 mL）溶液にm-クロロ過安息香酸(15.2 g)を0℃で加えた。同温で1.5時間撹拌後、反応液にチオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に４Ｎ塩化水素／酢酸エチル溶液（15 mL）を0℃で加え、ろ過して6-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（8.77 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.54-2.67 (1H, m), 2.68-2.81 (1H, m), 3.64-3.77 (1H, m), 3.79-3.91 (1H, m), 4.81 (1H, br), 7.80-7.92 (1H, m), 8.18 (1H, d, J= 1.5 Hz), 9.00 (3H, br)（HCl peak was not obserbed）.
（工程６）工程５で得られた6-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（2.0 g）、(2,5-ジフルオロフェノキシ)酢酸 （1.32g)、ＷＳＣ(1.35 g)、ＨＯＢｔ(950 mg)及びジイソプロピルエチルアミン(1.82 g)のＤＭＦ(20 mL)溶液を室温で2時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を水、続いて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製してN-(6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（2.74 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.57-2.80 (2H, m), 3.36-3.54 (2H, m), 4.64 (2H, d, J= 4.1 Hz), 5.48 (1H, td, J= 8.6, 5.5 Hz), 6.67-6.78 (2H, m), 7.03-7.14 (2H, m), 7.52 (1H, s), 7.66 (1H, dd, J= 9.0, 1.9 Hz), 7.81 (1H, d, J= 8.3 Hz). Reference Example 29
N- (6-Bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (Step 1) 4-bromobenzenethiol (15.9 To a solution of g) in 2N aqueous sodium hydroxide solution (40 mL) was added an aqueous solution of 3-bromopropionic acid (11.7 g) and potassium carbonate (5.29 g), and the mixture was stirred at room temperature for 2 days. The reaction solution was filtered, washed with toluene, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 3-[(4-bromophenyl) sulfanyl] propanoic acid (15.9 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.66 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.2 Hz), 7.18-7.27 (2H, m), 7.38-7.45 (2H , m), 7.53-8.66 (1H, m).
(Step 2) A solution of 3-[(4-bromophenyl) sulfanyl] propanoic acid (15.3 g) obtained in Step 1 in methanesulfonic acid (150 mL) was stirred at 75 ° C. for 6 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1) to give 6-bromo-2,3-dihydro-4H-thiochromen-4-one (10.8 g). It was. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.92-3.01 (2H, m), 3.21-3.27 (2H, m), 7.16 (1H, d, J = 8.7 Hz), 7.48 (1H, dd, J = 8.7, 2.3 Hz), 8.22 (1H, d, J = 2.3 Hz).
(Step 3) A solution of 6-bromo-2,3-dihydro-4H-thiochromen-4-one (10.8 g) and O-methylhydroxylamine hydrochloride (4.83 g) obtained in Step 2 in pyridine (60 mL) Was stirred at room temperature for 20 hours. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-9: 1) to give (4E) -6-bromo-2,3-dihydro-4H-thiochromen-4-one O- Methyl oxime (9.70 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.89-2.97 (2H, m), 3.01-3.09 (2H, m), 4.01 (3H, s), 7.09 (1H, d, J = 8.3 Hz), 7.30 (1H, dd, J = 8.3, 2.3 Hz), 8.13 (1H, d, J = 2.3 Hz).
(Step 4) (4E) -6-Bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (9.70 g) obtained in Step 3 was dissolved in THF (50 mL). -Borane complex (89 mL, 1M in THF) was added at 0 ° C. After stirring the reaction solution at 65 ° C. for 3 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (45 mL) was added to the residue. After stirring at 75 ° C. for 3 hours, the mixture was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and di-tert-butyl dicarbonate (7.78 g) was added at 0 ° C. After stirring the reaction solution at room temperature for 17 hours, the solvent was distilled off under reduced pressure, crystallized with diisopropyl ether, and tert-butyl (6-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (10.6 g ) 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.48 (9H, s), 2.03-2.16 (1H, m), 2.24-2.39 (1H, m), 2.93-3.12 (2H, m), 4.80 (2H, d, J = 13.3 Hz), 6.97 (1H, d, J = 8.3 Hz), 7.23 (1H, dd, J = 8.3, 2.3 Hz), 7.43 (1H, d, J = 2.3 Hz).
(Step 5) To a solution of tert-butyl (6-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (10.6 g) obtained in Step 4 in ethyl acetate (60 mL) was added m-chloroperoxide. Benzoic acid (15.2 g) was added at 0 ° C. After stirring at the same temperature for 1.5 hours, an aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. To the obtained residue was added a 4N hydrogen chloride / ethyl acetate solution (15 mL) at 0 ° C., filtered, and 6-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride ( 8.77 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.54-2.67 (1H, m), 2.68-2.81 (1H, m), 3.64-3.77 (1H, m), 3.79-3.91 (1H, m), 4.81 (1H, br), 7.80-7.92 (1H, m), 8.18 (1H, d, J = 1.5 Hz), 9.00 (3H, br) (HCl peak was not obserbed).
(Step 6) 6-Bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.0 g), (2,5-difluorophenoxy) acetic acid (1.32) obtained in Step 5 g), WSC (1.35 g), HOBt (950 mg) and diisopropylethylamine (1.82 g) in DMF (20 mL) were stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to give N- (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromene- 4-yl) -2- (2,5-difluorophenoxy) acetamide (2.74 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.57-2.80 (2H, m), 3.36-3.54 (2H, m), 4.64 (2H, d, J = 4.1 Hz), 5.48 (1H, td, J = 8.6, 5.5 Hz), 6.67-6.78 (2H, m), 7.03-7.14 (2H, m), 7.52 (1H, s), 7.66 (1H, dd, J = 9.0, 1.9 Hz), 7.81 (1H, d , J = 8.3 Hz).
参考例３０
2-(2,5-ジフルオロフェノキシ)-N-[1,1-ジオキシド-6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-イル]アセトアミド
（工程１）4-トリフルオロベンゼンチオール（4.41 g）を用いて参考例２９の工程１と同様の手法により3-{[4-(トリフルオロメチル)フェニル]スルファニル}プロパン酸（3.47 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.73 (2H, t, J= 7.2 Hz), 3.24 (2H, t, J= 7.4 Hz), 7.41 (2H, d, J= 7.9 Hz), 7.54 (2H, d, J= 8.3 Hz) (A CO2H peak was not observed).
（工程２）工程１で得られた3-{[4-(トリフルオロメチル)フェニル]スルファニル}プロパン酸（3.22 g）を用いて参考例４９の工程２と同様の手法により6-(トリフルオロメチル)-2,3-ジヒドロ-4H-チオクロメン-4-オン（2.42 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.98-3.07 (2H, m), 3.25-3.34 (2H, m), 7.40 (1H, d, J= 8.3 Hz), 7.59 (1H, dd, J= 8.7, 1.9 Hz), 8.37 (1H, d, J= 1.5 Hz).
（工程３）工程２で得られた6-(トリフルオロメチル)-2,3-ジヒドロ-4H-チオクロメン-4-オン（2.42 g）を用いて参考例２９の工程３と同様の手法により(4E)-6-(トリフルオロメチル)-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（2.70 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.94-3.01 (2H, m), 3.06-3.13 (2H, m), 4.03 (3H, s), 7.28-7.34 (1H, m), 7.37-7.43 (1H, m), 8.26 (1H, s).
（工程４）工程３で得られた(4E)-6-(トリフルオロメチル)-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（2.7 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル [6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（1.93 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.48 (9H, s), 2.03-2.20 (1H, m), 2.30-2.44 (1H, m), 2.98-3.17 (2H, m), 4.69-4.95 (2H, m), 7.20 (1H, d, J= 8.3 Hz), 7.35 (1H, d, J= 8.3 Hz), 7.54 (1H, s).
（工程５）工程４で得られたtert-ブチル [6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（1.93 g）を用いて参考例２９の工程５と同様の手法により6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（1.14 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.57-2.72 (1H, m), 2.72-2.85 (1H, m), 3.70-3.85 (1H, m), 3.86-4.00 (1H, m), 4.89 (1H, t, J= 5.7 Hz), 7.98-8.07 (1H, m), 8.08-8.17 (1H, m), 8.38 (1H, s), 9.11 (3H, br).
（工程６）工程５で得られた6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（1.14 g）を用いて参考例２９の工程６と同様の手法により標題化合物（1.28 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.60-2.83 (2H, m), 3.41-3.59 (2H, m), 4.57-4.70 (2H, m), 5.54 (1H, td, J= 8.5, 5.7 Hz), 6.68-6.78 (2H, m), 7.01-7.12 (1H, m), 7.19 (1H, d, J= 9.1 Hz), 7.63 (1H, s), 7.77 (1H, d, J= 8.3 Hz), 8.06 (1H, d, J= 8.3 Hz). Reference Example 30
2- (2,5-Difluorophenoxy) -N- [1,1-dioxide-6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] acetamide (Step 1) 4-tri 3-{[4- (trifluoromethyl) phenyl] sulfanyl} propanoic acid (3.47 g) was obtained in the same manner as in Step 1 of Reference Example 29 using fluorobenzenethiol (4.41 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.73 (2H, t, J = 7.2 Hz), 3.24 (2H, t, J = 7.4 Hz), 7.41 (2H, d, J = 7.9 Hz), 7.54 ( (2H, d, J = 8.3 Hz) (A CO 2 H peak was not observed).
(Step 2) Using 3-{[4- (trifluoromethyl) phenyl] sulfanyl} propanoic acid (3.22 g) obtained in Step 1, in the same manner as in Step 2 of Reference Example 49, 6- (trifluoro Methyl) -2,3-dihydro-4H-thiochromen-4-one (2.42 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.98-3.07 (2H, m), 3.25-3.34 (2H, m), 7.40 (1H, d, J = 8.3 Hz), 7.59 (1H, dd, J = 8.7, 1.9 Hz), 8.37 (1H, d, J = 1.5 Hz).
(Step 3) 6- (Trifluoromethyl) -2,3-dihydro-4H-thiochromen-4-one (2.42 g) obtained in Step 2 was used in the same manner as in Step 3 of Reference Example 29 ( 4E) -6- (Trifluoromethyl) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (2.70 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.94-3.01 (2H, m), 3.06-3.13 (2H, m), 4.03 (3H, s), 7.28-7.34 (1H, m), 7.37-7.43 ( 1H, m), 8.26 (1H, s).
(Step 4) Using (4E) -6- (trifluoromethyl) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (2.7 g) obtained in Step 3, In the same manner as in Step 4, tert-butyl [6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (1.93 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.48 (9H, s), 2.03-2.20 (1H, m), 2.30-2.44 (1H, m), 2.98-3.17 (2H, m), 4.69-4.95 ( 2H, m), 7.20 (1H, d, J = 8.3 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.54 (1H, s).
(Step 5) Step 5 of Reference Example 29 using tert-butyl [6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (1.93 g) obtained in Step 4 In the same manner as above, 6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.14 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.57-2.72 (1H, m), 2.72-2.85 (1H, m), 3.70-3.85 (1H, m), 3.86-4.00 (1H, m), 4.89 (1H, t, J = 5.7 Hz), 7.98-8.07 (1H, m), 8.08-8.17 (1H, m), 8.38 (1H, s), 9.11 (3H, br).
(Step 6) Step of Reference Example 29 using 6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.14 g) obtained in Step 5 The title compound (1.28 g) was obtained by the same method as 6. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.60-2.83 (2H, m), 3.41-3.59 (2H, m), 4.57-4.70 (2H, m), 5.54 (1H, td, J = 8.5, 5.7 Hz), 6.68-6.78 (2H, m), 7.01-7.12 (1H, m), 7.19 (1H, d, J = 9.1 Hz), 7.63 (1H, s), 7.77 (1H, d, J = 8.3 Hz) ), 8.06 (1H, d, J = 8.3 Hz).
参考例３１
tert-ブチル (6-アミノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート
（工程１）参考例２９の工程６で得られたN-(6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（8.19 g）をＴＨＦ（20 mL）に溶解させ、ＴＨＦ-ボラン錯体（45.9 mL, １Ｍ ＴＨＦ溶液）を０℃にて加えた。反応液を65℃で2時間撹拌後、反応液にメタノールを加え、溶媒を減圧下留去した。残渣に6Ｎ塩酸（25 mL）を加えた。75℃で2時間撹拌後、8Ｎ水酸化ナトリウム溶液で塩基性とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を酢酸エチルに溶解させ、二炭酸ジ-tert-ブチル（4.00 g）を室温で加えた。反応液を50℃で2時間撹拌後、溶媒を減圧下留去し、ジイソプロピルエーテルとヘキサンで結晶化し、tert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（8.50 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.14-1.56 (9H, m), 2.53-2.70 (1H, m), 2.94-3.21 (1H, m), 3.34-3.54 (2H, m), 3.57-3.81 (1H, m), 3.91-4.35 (3H, m), 4.67-5.56 (1H, m), 6.56-6.77 (2H, m), 7.02 (1H, ddd, J= 10.5, 9.0, 5.3 Hz), 7.32-7.51 (1H, m), 7.59 (1H, d, J= 8.3 Hz), 7.78 (1H, d, J= 8.3 Hz).
（工程２）工程１のtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1.5 g）、ベンゾフェノンイミン（611 mg）、ナトリウムtert－ブトキシド（378 mg）、トリス（ジベンジリデンアセトナト）ジパラジウム（Pd2(dba)3）（51.5 mg）及び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（65 mg）のトルエン（10 mL）溶液を 100℃で 20時間、窒素雰囲気下撹拌し、反応液をろ過後、溶媒を減圧下留去した。得られた残渣をメタノール（6 mL）に溶解させ、酢酸ナトリウム（346 mg）及び塩酸ヒドロキシルアミン（234 mg）を加えた。反応液を室温で 4時間撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～3:2）で精製して標題化合物（950 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.19-1.58 (9H, m), 2.46-2.67 (1H, m), 2.82-3.20 (1H, m), 3.27-3.88 (4H, m), 3.97-4.35 (4H, m), 4.62-5.64 (1H, m), 6.46 (1H, br), 6.55-6.79 (3H, m), 7.02 (1H, td, J= 9.8, 5.3 Hz), 7.69 (1H, d, J= 8.7 Hz). Reference Example 31
tert-Butyl (6-amino-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (Step 1) of Reference Example 29 N- (6-Bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (8.19 g) obtained in Step 6 was It was dissolved in THF (20 mL), and THF-borane complex (45.9 mL, 1M THF solution) was added at 0 ° C. After stirring the reaction solution at 65 ° C. for 2 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (25 mL) was added to the residue. After stirring at 75 ° C. for 2 hours, the mixture was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and di-tert-butyl dicarbonate (4.00 g) was added at room temperature. After stirring the reaction solution at 50 ° C. for 2 hours, the solvent was distilled off under reduced pressure, crystallized with diisopropyl ether and hexane, and tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromene). -4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (8.50 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.14-1.56 (9H, m), 2.53-2.70 (1H, m), 2.94-3.21 (1H, m), 3.34-3.54 (2H, m), 3.57- 3.81 (1H, m), 3.91-4.35 (3H, m), 4.67-5.56 (1H, m), 6.56-6.77 (2H, m), 7.02 (1H, ddd, J = 10.5, 9.0, 5.3 Hz), 7.32-7.51 (1H, m), 7.59 (1H, d, J = 8.3 Hz), 7.78 (1H, d, J = 8.3 Hz).
(Step 2) tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate of Step 1 ( 1.5 g), benzophenone imine (611 mg), sodium tert-butoxide (378 mg), tris (dibenzylideneacetonato) dipalladium (Pd 2 (dba) 3 ) (51.5 mg) and 4,5-bis (diphenylphosphine) A solution of Fino) -9,9-dimethylxanthene (65 mg) in toluene (10 mL) was stirred at 100 ° C. for 20 hours under a nitrogen atmosphere, the reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (6 mL), and sodium acetate (346 mg) and hydroxylamine hydrochloride (234 mg) were added. The reaction solution was stirred at room temperature for 4 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-3: 2) to give the title compound (950 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.19-1.58 (9H, m), 2.46-2.67 (1H, m), 2.82-3.20 (1H, m), 3.27-3.88 (4H, m), 3.97- 4.35 (4H, m), 4.62-5.64 (1H, m), 6.46 (1H, br), 6.55-6.79 (3H, m), 7.02 (1H, td, J = 9.8, 5.3 Hz), 7.69 (1H, d, J = 8.7 Hz).
参考例３２
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルスルホニル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート
（工程１）参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（532 mg）を用いて実施例５２の工程１と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルスルファニル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（419 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.15-1.54 (9H, m), 2.36-2.49 (3H, m), 2.52-2.67 (1H, m), 2.90-3.20 (1H, m), 3.26-3.50 (2H, m), 3.52-4.07 (2H, m), 4.10-4.36 (2H, m), 4.68-5.68 (1H, m), 6.54-6.76 (2H, m), 6.95-7.09 (2H, m), 7.23-7.29 (1H, m), 7.81 (1H, d, J= 8.7 Hz).
（工程２）工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルスルファニル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（400 mg）の酢酸エチル（3 mL）溶液にm-クロロ過安息香酸(394 mg)を室温で加えた。同温で3時間撹拌後、反応液にチオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製して標題化合物（400 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.09-1.53 (9H, m), 2.72 (1H, d, J= 6.8 Hz), 2.96 (3H, s), 3.06-3.25 (1H, m, J= 5.3 Hz), 3.40-3.74 (3H, m), 3.78-4.04 (1H, m), 4.17-4.41 (2H, m), 4.72-5.44 (1H, m), 6.57-6.80 (2H, m), 6.94-7.07 (1H, m), 7.80-8.04 (2H, m), 8.13 (1H, d, J= 7.9 Hz). Reference Example 32
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylsulfonyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (Step 1) Reference Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] obtained in Step 1 of Example 31 Tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylsulfanyl) -1,1-dioxide-3 was prepared in the same manner as in Step 1 of Example 52 using carbamate (532 mg). , 4-Dihydro-2H-thiochromen-4-yl] carbamate (419 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.15-1.54 (9H, m), 2.36-2.49 (3H, m), 2.52-2.67 (1H, m), 2.90-3.20 (1H, m), 3.26- 3.50 (2H, m), 3.52-4.07 (2H, m), 4.10-4.36 (2H, m), 4.68-5.68 (1H, m), 6.54-6.76 (2H, m), 6.95-7.09 (2H, m ), 7.23-7.29 (1H, m), 7.81 (1H, d, J = 8.7 Hz).
(Step 2) tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylsulfanyl) -1,1-dioxide-3,4-dihydro-2H-thiochromene-obtained in Step 1 To a solution of 4-yl] carbamate (400 mg) in ethyl acetate (3 mL) was added m-chloroperbenzoic acid (394 mg) at room temperature. After stirring at the same temperature for 3 hours, an aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to give the title compound (400 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.09-1.53 (9H, m), 2.72 (1H, d, J = 6.8 Hz), 2.96 (3H, s), 3.06-3.25 (1H, m, J = 5.3 Hz), 3.40-3.74 (3H, m), 3.78-4.04 (1H, m), 4.17-4.41 (2H, m), 4.72-5.44 (1H, m), 6.57-6.80 (2H, m), 6.94 -7.07 (1H, m), 7.80-8.04 (2H, m), 8.13 (1H, d, J = 7.9 Hz).
参考例３３
tert-ブチル [6-(アセチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート
　参考例３１の工程２で得られたtert-ブチル (6-アミノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（234 mg）及びＥｔ３Ｎ（75.9 mg）のＴＨＦ（2 mL）溶液に、塩化アセチル（47.1 mg）を0℃で加えた。反応液を室温で24時間撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝2:3～4:1）で精製して標題化合物（243 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.14-1.59 (9H, m), 2.16 (3H, s), 2.62 (1H, br), 3.09 (1H, br), 3.44 (2H, br), 3.53-3.93 (1H, m), 4.07-4.37 (3H, m), 4.57-5.71 (1H, m), 6.54-6.80 (2H, m), 6.95-7.07 (1H, m), 7.28-7.88 (4H, m). Reference Example 33
tert-Butyl [6- (acetylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5-difluorophenoxy) ethyl] carbamate Reference Example 31 Tert-butyl (6-amino-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (234 mg) ) And Et 3 N (75.9 mg) in THF (2 mL) were added acetyl chloride (47.1 mg) at 0 ° C. The reaction solution was stirred at room temperature for 24 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3-4: 1) to give the title compound (243 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.14-1.59 (9H, m), 2.16 (3H, s), 2.62 (1H, br), 3.09 (1H, br), 3.44 (2H, br), 3.53 -3.93 (1H, m), 4.07-4.37 (3H, m), 4.57-5.71 (1H, m), 6.54-6.80 (2H, m), 6.95-7.07 (1H, m), 7.28-7.88 (4H, m).
参考例３４
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][2-(ジメチルスルファモイル)-5-モルホリン-4-イルベンジル]カルバマート
（工程１）実施例４８の工程１で得られた4-ブロモ-2-({[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド（1.33 g）と二炭酸ジ-t-ブチル(0.722 mL)のアセトニトリル（10 mL）溶液に、N,N-ジメチル-4-アミノピリジン（3.62 mg）を室温で加えた。反応液を3時間撹拌後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、tert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1.21 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.37 (5H, s), 1.53 (4H, br), 2.79 (6H, s), 3.63-3.82 (2H, m), 4.05-4.28 (2H, m), 4.90-5.05 (2H, m), 6.53-6.75 (2H, m), 6.89-7.06 (1H, m), 7.40-7.66 (2H, m), 7.76 (1H, d, J= 8.3 Hz).
（工程２）工程１で得られたtert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（150 mg）、ジシクロヘキシル[2',4',6'-トリス(1-メチルエチル)ビフェニル-2-イル]ホスファン（13.0 mg）、ナトリウム t-ブトキシド（28.9 mg）、モルホリン（0.026 mL）、Pd2(dba)3（12.5 mg）のトルエン溶液（3 mL）を100℃で3時間撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して標題化合物（115 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.38 (5H, s), 1.51 (4H, s), 2.73 (6H, s), 3.07-3.29 (4H, m), 3.63-3.86 (6H, m), 3.92-4.24 (2H, m), 4.94 (2H, s), 6.37-6.99 (4H, m), 7.27 (1H, s), 7.65-7.94 (1H, m). Reference Example 34
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-morpholin-4-ylbenzyl] carbamate (Step 1) 4 obtained in Step 1 of Example 48 -Bromo-2-({[2- (2,5-difluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide (1.33 g) and di-t-butyl dicarbonate (0.722 mL) N, N-dimethyl-4-aminopyridine (3.62 mg) was added to an acetonitrile (10 mL) solution at room temperature. After stirring the reaction solution for 3 hours, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), and tert-butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate ( 1.21 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.37 (5H, s), 1.53 (4H, br), 2.79 (6H, s), 3.63-3.82 (2H, m), 4.05-4.28 (2H, m) , 4.90-5.05 (2H, m), 6.53-6.75 (2H, m), 6.89-7.06 (1H, m), 7.40-7.66 (2H, m), 7.76 (1H, d, J = 8.3 Hz).
(Step 2) tert-Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg), dicyclohexyl [2 ', 4', 6'-Tris (1-methylethyl) biphenyl-2-yl] phosphane (13.0 mg), sodium t-butoxide (28.9 mg), morpholine (0.026 mL), Pd 2 (dba) 3 (12.5 mg) in toluene (3 mL) was stirred at 100 ° C. for 3 hours. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (115 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.38 (5H, s), 1.51 (4H, s), 2.73 (6H, s), 3.07-3.29 (4H, m), 3.63-3.86 (6H, m) , 3.92-4.24 (2H, m), 4.94 (2H, s), 6.37-6.99 (4H, m), 7.27 (1H, s), 7.65-7.94 (1H, m).
参考例３５
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル]{6-[(メチルスルホニル)アミノ]-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル}カルバマート
　参考例３１の工程２で得られたtert-ブチル (6-アミノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（234 mg）及びＥｔ３Ｎ（228 mg）のＴＨＦ（2 mL）溶液に、塩化メタンスルホニル（206 mg）を0℃で加えた。反応液を室温で二日間撹拌し、反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:17～1:1）で精製して標題化合物（260 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.16-1.54 (9H, m), 2.54-2.68 (1H, m, J= 1.9 Hz), 2.99 (3H, br), 3.04-3.71 (4H, m), 3.83 (1H, br), 4.17-4.40 (2H, m), 4.63-5.58 (1H, m), 6.56-6.79 (3H, m), 7.03 (1H, ddd, J= 10.7, 9.0, 5.3 Hz), 7.17 (1H, s), 7.28-7.37 (1H, m), 7.91 (1H, d, J= 8.7 Hz). Reference Example 35
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] {6-[(methylsulfonyl) amino] -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl} carbamate Reference Example 31 tert-butyl (6-amino-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in step 2 of 31 Methanesulfonyl chloride (206 mg) was added to a solution of (234 mg) and Et 3 N (228 mg) in THF (2 mL) at 0 ° C. The reaction was stirred at room temperature for 2 days, poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 17-1: 1) to give the title compound (260 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.16-1.54 (9H, m), 2.54-2.68 (1H, m, J = 1.9 Hz), 2.99 (3H, br), 3.04-3.71 (4H, m) , 3.83 (1H, br), 4.17-4.40 (2H, m), 4.63-5.58 (1H, m), 6.56-6.79 (3H, m), 7.03 (1H, ddd, J = 10.7, 9.0, 5.3 Hz) , 7.17 (1H, s), 7.28-7.37 (1H, m), 7.91 (1H, d, J = 8.7 Hz).
参考例３６
tert-ブチル (6-カルバモイル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート
（工程１）参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1.5 g）、Ｅｔ３Ｎ（314 mg）、ジフェニルホスフィノフェロセン（78.2 mg）及び酢酸パラジウム（31.6 mg）のメタノール（6 mL）及びＴＨＦ（6 mL）溶液を 100℃で 6時間、一酸化炭素雰囲気下、撹拌した。反応液を濃縮し、水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製してメチル 4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボキシラート 1,1-ジオキシド（1.43 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.11-1.56 (9H, m), 2.68 (1H, d, J= 6.4 Hz), 3.14 (1H, d, J= 15.5 Hz), 3.32-3.67 (3H, m), 3.73-4.38 (6H, m), 4.74-5.67 (1H, m), 6.54-6.79 (2H, m), 6.94-7.06 (1H, m), 7.86-8.13 (3H, m).
（工程２）工程１で得られたメチル 4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボキシラート 1,1-ジオキシド（1.27 g）の1Ｎ水酸化ナトリウム水溶液（5 mL）及びＴＨＦ（10 mL）の溶液を50℃で3時間撹拌した。反応液を1Ｎ塩酸で酸性にし、酢酸エチルで抽出した。有機層を水、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボン酸1,1-ジオキシド（1 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.01-1.68 (9H, m), 2.58-2.76 (1H, m), 2.99-3.25 (1H, m), 3.37-3.69 (3H, m), 3.71-3.89 (1H, m), 3.92-4.42 (2H, m), 4.76-5.64 (1H, m), 6.53-6.66 (1H, m), 6.68-6.79 (1H, m), 6.99 (1H, td, J= 9.8, 5.3 Hz), 7.89-8.10 (2H, m), 8.10-8.18 (1H, m)(A CO2H peak was not observed).
（工程３）工程２で得られた4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボン酸1,1-ジオキシド（300 mg）、1H-ベンゾトリアゾール-1-オール アンモニウム塩　(110 mg)、ＷＳＣ(139 mg)及びジイソプロピルエチルアミン(93.6 mg)のＤＭＦ(2 mL)溶液を室温で19時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～3:2）で精製して標題化合物（200 mg）を得た。ＭＳ（ＥＳＩ＋）：397（Ｍ＋２Ｈ－Ｂｏｃ） Reference Example 36
tert-Butyl (6-carbamoyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (Step 1) of Reference Example 31 Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in Step 1 (1.5 g) A solution of Et 3 N (314 mg), diphenylphosphinoferrocene (78.2 mg) and palladium acetate (31.6 mg) in methanol (6 mL) and THF (6 mL) at 100 ° C. for 6 hours in a carbon monoxide atmosphere Under stirring. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to obtain methyl 4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] Amino} -3,4-dihydro-2H-thiochromene-6-carboxylate 1,1-dioxide (1.43 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.11-1.56 (9H, m), 2.68 (1H, d, J = 6.4 Hz), 3.14 (1H, d, J = 15.5 Hz), 3.32-3.67 (3H , m), 3.73-4.38 (6H, m), 4.74-5.67 (1H, m), 6.54-6.79 (2H, m), 6.94-7.06 (1H, m), 7.86-8.13 (3H, m).
(Step 2) Methyl 4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -3,4-dihydro-2H-thiochromene-6-carboxylate obtained in Step 1 A solution of 1,1-dioxide (1.27 g) in 1N aqueous sodium hydroxide (5 mL) and THF (10 mL) was stirred at 50 ° C. for 3 hours. The reaction was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to remove 4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy). ) Ethyl] amino} -3,4-dihydro-2H-thiochromene-6-carboxylic acid 1,1-dioxide (1 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.01-1.68 (9H, m), 2.58-2.76 (1H, m), 2.99-3.25 (1H, m), 3.37-3.69 (3H, m), 3.71- 3.89 (1H, m), 3.92-4.42 (2H, m), 4.76-5.64 (1H, m), 6.53-6.66 (1H, m), 6.68-6.79 (1H, m), 6.99 (1H, td, J = 9.8, 5.3 Hz), 7.89-8.10 (2H, m), 8.10-8.18 (1H, m) (A CO 2 H peak was not observed).
(Step 3) 4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -3,4-dihydro-2H-thiochromene-6-carboxylic acid 1 obtained in Step 2 , 1-dioxide (300 mg), 1H-benzotriazol-1-ol ammonium salt (110 mg), WSC (139 mg) and diisopropylethylamine (93.6 mg) in DMF (2 mL) were stirred at room temperature for 19 hours. . The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-3: 2) to give the title compound (200 mg). MS (ESI +): 397 (M + 2H-Boc)
参考例３７
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1 g）、2-ジtert-ブチルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル（159 mg）、水酸化カリウム（316 mg）、及びPd2(dba)3（86.0 mg）の水（2.5 mL）及び1,2-ジメトキシエタン（6 mL）溶液を 80℃で 17時間、窒素雰囲気下撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:17～1:1）で精製して標題化合物（546 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.18-1.54 (9H, m), 2.48-2.70 (1H, m), 3.13 (1H, br), 3.28-3.79 (4H, m), 4.03-4.36 (2H, m), 4.69-6.05 (2H, m), 6.54-6.81 (3H, m), 6.85-6.95 (1H, m), 6.97-7.10 (1H, m), 7.82 (1H, d, J= 8.7 Hz). Reference Example 37
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate Obtained in Step 1 of Reference Example 31 Tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (1 g), 2 -Di-tert-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl (159 mg), potassium hydroxide (316 mg), and Pd 2 (dba) 3 (86.0 mg) in water (2.5 mL) The 1,2-dimethoxyethane (6 mL) solution was stirred at 80 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 17-1: 1) to give the title compound (546 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.18-1.54 (9H, m), 2.48-2.70 (1H, m), 3.13 (1H, br), 3.28-3.79 (4H, m), 4.03-4.36 ( 2H, m), 4.69-6.05 (2H, m), 6.54-6.81 (3H, m), 6.85-6.95 (1H, m), 6.97-7.10 (1H, m), 7.82 (1H, d, J = 8.7 Hz).
参考例３８
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](7-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート
（工程１）3-ブロモベンゼンチオール（13.4 g）を用いて参考例２９の工程１と同様の手法により3-[(3-ブロモフェニル)スルファニル]プロパン酸（15.8 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.70 (2H, t, J= 7.2 Hz), 3.17 (2H, t, J= 7.2 Hz), 7.12-7.20 (1H, m), 7.26-7.30 (1H, m), 7.32-7.37 (1H, m), 7.50 (1H, t, J= 1.9 Hz) (A CO2H peak was not observed).
（工程２）工程１で得られた3-[(3-ブロモフェニル)スルファニル]プロパン酸（15.8 g）を用いて参考例２９の工程２と同様の手法により7-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン（11.9 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.93-3.03 (2H, m), 3.21-3.30 (2H, m), 7.30 (1H, dd, J= 8.3, 1.9 Hz), 7.46 (1H, d, J= 1.9 Hz), 7.95 (1H, d, J= 8.3 Hz).
（工程３）工程２で得られた7-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン（11.9 g）を用いて参考例２９の工程３と同様の手法により(4E)-7-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（12.1 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.89-2.96 (2H, m), 3.03-3.09 (2H, m), 3.99 (3H, s), 7.18-7.24 (1H, m), 7.38 (1H, d, J= 1.9 Hz), 7.84 (1H, d, J= 8.3 Hz).
（工程４）工程３で得られた(4E)-7-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（12.1 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル (7-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（12.9 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.47 (9H, s), 2.02-2.14 (1H, m), 2.27-2.40 (1H, m), 2.93-3.12 (2H, m), 4.75 (1H, br), 4.82 (1H, br), 7.15 (2H, s), 7.25 (1H, s).
（工程５）工程４で得られたtert-ブチル (7-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（12.3 g）を用いて参考例２９の工程５と同様の手法により７-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（10.1 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.56-2.69 (1H, m), 2.69-2.83 (1H, m), 3.67-3.80 (1H, m), 3.83-3.96 (1H, m), 4.77 (1H, t, J= 5.5 Hz), 7.85-7.91 (1H, m), 7.97-8.02 (2H, m), 9.09 (3H, br).
（工程６）工程５で得られた7-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（4 g）を用いて参考例２９の工程６と同様の手法によりN-(7-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（3.86 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.57-2.80 (2H, m), 3.36-3.54 (2H, m), 4.60 (2H, s), 5.44 (1H, td, J= 8.4, 5.5 Hz), 6.68-6.77 (2H, m), 7.02-7.13 (2H, m), 7.22-7.29 (1H, m), 7.66 (1H, dd, J= 8.5, 2.1 Hz), 8.05 (1H, d, J= 2.3 Hz).
（工程７）工程６で得られたN-(7-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（3.86 g）を用いて参考例２９の工程７と同様の手法によりtert-ブチル (7-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（2.7 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.15-1.53 (9H, m), 2.66 (1H, br), 3.12 (1H, br), 3.27-3.63 (3H, m), 3.64-4.00 (1H, m), 4.00-4.37 (2H, m), 4.64-5.54 (1H, m), 6.55-6.76 (2H, m), 7.02 (1H, td, J= 9.9, 5.1 Hz), 7.20 (1H, br), 7.61 (1H, d, J= 7.5 Hz), 8.05 (1H, s).
（工程８）工程７で得られたtert-ブチル (7-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1 g）を用いて参考例３７と同様の手法により標題化合物（821 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.08-1.62 (9H, m), 1.88 (1H, br), 2.46-2.70 (1H, m), 2.80-3.19 (1H, m), 3.19-4.35 (6H, m), 4.62-5.62 (1H, m), 6.52-6.76 (2H, m), 6.93-7.09 (2H, m), 7.16 (1H, d, J= 8.7 Hz), 7.39 (1H, br). Reference Example 38
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (7-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (Step 1) 3-bromobenzene 3-[(3-Bromophenyl) sulfanyl] propanoic acid (15.8 g) was obtained in the same manner as in Step 1 of Reference Example 29 using thiol (13.4 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.70 (2H, t, J = 7.2 Hz), 3.17 (2H, t, J = 7.2 Hz), 7.12-7.20 (1H, m), 7.26-7.30 (1H , m), 7.32-7.37 (1H, m), 7.50 (1H, t, J = 1.9 Hz) (A CO 2 H peak was not observed).
(Step 2) Using 3-[(3-bromophenyl) sulfanyl] propanoic acid (15.8 g) obtained in Step 1, in the same manner as in Step 2 of Reference Example 29, 7-bromo-2,3-dihydro -4H-thiochromen-4-one (11.9 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.93-3.03 (2H, m), 3.21-3.30 (2H, m), 7.30 (1H, dd, J = 8.3, 1.9 Hz), 7.46 (1H, d, J = 1.9 Hz), 7.95 (1H, d, J = 8.3 Hz).
(Step 3) (4E) -7 in the same manner as in Step 3 of Reference Example 29 using 7-bromo-2,3-dihydro-4H-thiochromen-4-one (11.9 g) obtained in Step 2 -Bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.1 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.89-2.96 (2H, m), 3.03-3.09 (2H, m), 3.99 (3H, s), 7.18-7.24 (1H, m), 7.38 (1H, d, J = 1.9 Hz), 7.84 (1H, d, J = 8.3 Hz).
(Step 4) Similar to Step 4 of Reference Example 29 using (4E) -7-bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.1 g) obtained in Step 3 In this manner, tert-butyl (7-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.9 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.47 (9H, s), 2.02-2.14 (1H, m), 2.27-2.40 (1H, m), 2.93-3.12 (2H, m), 4.75 (1H, br), 4.82 (1H, br), 7.15 (2H, s), 7.25 (1H, s).
(Step 5) The same procedure as in Step 5 of Reference Example 29 using tert-butyl (7-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) obtained in Step 4 Gave 7-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (10.1 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.56-2.69 (1H, m), 2.69-2.83 (1H, m), 3.67-3.80 (1H, m), 3.83-3.96 (1H, m), 4.77 (1H, t, J = 5.5 Hz), 7.85-7.91 (1H, m), 7.97-8.02 (2H, m), 9.09 (3H, br).
(Step 6) Using 7-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (4 g) obtained in Step 5, the same as Step 6 of Reference Example 29 According to the procedure, N- (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (3.86 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.57-2.80 (2H, m), 3.36-3.54 (2H, m), 4.60 (2H, s), 5.44 (1H, td, J = 8.4, 5.5 Hz) , 6.68-6.77 (2H, m), 7.02-7.13 (2H, m), 7.22-7.29 (1H, m), 7.66 (1H, dd, J = 8.5, 2.1 Hz), 8.05 (1H, d, J = 2.3 Hz).
(Step 7) N- (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide obtained in Step 6 ( Tert-butyl (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2 , 5-Difluorophenoxy) ethyl] carbamate (2.7 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.15-1.53 (9H, m), 2.66 (1H, br), 3.12 (1H, br), 3.27-3.63 (3H, m), 3.64-4.00 (1H, m), 4.00-4.37 (2H, m), 4.64-5.54 (1H, m), 6.55-6.76 (2H, m), 7.02 (1H, td, J = 9.9, 5.1 Hz), 7.20 (1H, br) , 7.61 (1H, d, J = 7.5 Hz), 8.05 (1H, s).
(Step 8) tert-butyl (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl obtained in Step 7 ] The title compound (821 mg) was obtained in the same manner as in Reference Example 37 using carbamate (1 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.08-1.62 (9H, m), 1.88 (1H, br), 2.46-2.70 (1H, m), 2.80-3.19 (1H, m), 3.19-4.35 ( 6H, m), 4.62-5.62 (1H, m), 6.52-6.76 (2H, m), 6.93-7.09 (2H, m), 7.16 (1H, d, J = 8.7 Hz), 7.39 (1H, br) .
参考例３９
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](8-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート
（工程１）2-ブロモベンゼンチオール（25 g）を用いて参考例２９の工程１と同様の手法により3-[(2-ブロモフェニル)スルファニル]プロパン酸（26.4 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.72 (2H, t, J= 7.3 Hz), 3.19 (2H, t, J= 7.3 Hz), 6.99-7.09 (1H, m, J= 8.1, 6.0, 2.4 Hz), 7.27-7.33 (2H, m), 7.56 (1H, d, J= 8.7 Hz) (A CO2H peak was not observed).
（工程２）工程１で得られた3-[(2-ブロモフェニル)スルファニル]プロパン酸（21.4 g）を用いて参考例２９の工程２と同様の手法により8-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン（12.5 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.92-3.00 (2H, m), 3.22-3.30 (2H, m), 7.07 (1H, t, J= 7.9 Hz), 7.63-7.69 (1H, m), 8.11 (1H, dd, J= 7.9, 1.5 Hz).
（工程３）工程２で得られた8-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン（12.5 g）を用いて参考例２９の工程３と同様の手法により(4E)-8-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（12.7 g）を得た。
（工程４）工程３で得られた(4E)-8-ブロモ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（12.7 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル (8-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（12.3 g ）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.47 (9H, s), 1.97-2.11 (1H, m, J= 14.0, 10.5, 3.8, 3.8 Hz), 2.30-2.43 (1H, m), 2.98-3.17 (2H, m), 4.77 (1H, br), 4.89 (1H, br), 6.90-6.97 (1H, m), 7.29 (1H, s), 7.43 (1H, d, J= 7.9 Hz).
（工程５）工程４で得られたtert-ブチル (8-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（12.3 g）を用いて参考例２９の工程５と同様の手法により8-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（9.98 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.53-2.64 (1H, m), 2.65-2.78 (1H, m), 3.68-3.79 (1H, m), 3.81-3.93 (1H, m), 4.81 (1H, t, J= 5.5 Hz), 7.56-7.65 (1H, m), 7.85-7.95 (2H, m), 9.07 (3H, br).
（工程６）工程５で得られた8-ブロモ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（4 g）を用いて参考例２９の工程６と同様の手法によりN-(8-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（5.64 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.54-2.75 (2H, m), 3.42-3.63 (2H, m), 4.61 (2H, s), 5.47 (1H, td, J= 8.1, 4.9 Hz), 6.67-6.78 (2H, m), 6.99-7.12 (2H, m), 7.33-7.39 (2H, m), 7.68-7.75 (1H, m).
（工程７）工程６で得られたN-(8-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（5.64 g）を用いて参考例２９の工程７と同様の手法によりtert-ブチル (8-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（5.04 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.07-1.56 (9H, m), 2.58 (1H,d, J= 13.6 Hz), 3.07 (1H, br), 3.36-4.38 (6H, m), 4.50-5.70 (1H, m), 6.55-6.75 (2H, m), 7.02 (1H, ddd, J= 10.6, 9.1, 5.1 Hz), 7.13-7.39 (2H, m), 7.66 (1H, d, J= 8.7 Hz).
（工程８）工程７で得られたtert-ブチル (8-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1.0 g）を用いて参考例３７と同様の手法により標題化合物（569 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.22-1.54 (9H, m), 2.69 (1H, dd, J= 9.4, 5.3 Hz), 3.11 (1H, br), 3.30-4.33 (6H, m), 4.78-5.59 (1H, m), 6.51-6.86 (3H, m), 6.89-7.07 (2H, m), 7.38 (1H, t, J= 8.1 Hz), 8.06-8.30 (1H, m). Reference Example 39
tert-butyl [2- (2,5-difluorophenoxy) ethyl] (8-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (Step 1) 2-bromobenzene 3-[(2-Bromophenyl) sulfanyl] propanoic acid (26.4 g) was obtained in the same manner as in Step 1 of Reference Example 29 using thiol (25 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.72 (2H, t, J = 7.3 Hz), 3.19 (2H, t, J = 7.3 Hz), 6.99-7.09 (1H, m, J = 8.1, 6.0, 2.4 Hz), 7.27-7.33 (2H, m), 7.56 (1H, d, J = 8.7 Hz) (A CO 2 H peak was not observed).
(Step 2) By using the 3-[(2-bromophenyl) sulfanyl] propanoic acid (21.4 g) obtained in Step 1 in the same manner as in Step 2 of Reference Example 29, 8-bromo-2,3-dihydro -4H-thiochromen-4-one (12.5 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.92-3.00 (2H, m), 3.22-3.30 (2H, m), 7.07 (1H, t, J = 7.9 Hz), 7.63-7.69 (1H, m) , 8.11 (1H, dd, J = 7.9, 1.5 Hz).
(Step 3) (4E) -8 in the same manner as in Step 3 of Reference Example 29 using 8-bromo-2,3-dihydro-4H-thiochromen-4-one (12.5 g) obtained in Step 2 -Bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.7 g) was obtained.
(Step 4) Similar to Step 4 of Reference Example 29 using (4E) -8-bromo-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (12.7 g) obtained in Step 3 In this manner, tert-butyl (8-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.47 (9H, s), 1.97-2.11 (1H, m, J = 14.0, 10.5, 3.8, 3.8 Hz), 2.30-2.43 (1H, m), 2.98- 3.17 (2H, m), 4.77 (1H, br), 4.89 (1H, br), 6.90-6.97 (1H, m), 7.29 (1H, s), 7.43 (1H, d, J = 7.9 Hz).
(Step 5) The same procedure as in Step 5 of Reference Example 29 using tert-butyl (8-bromo-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) obtained in Step 4 Gave 8-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (9.98 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.53-2.64 (1H, m), 2.65-2.78 (1H, m), 3.68-3.79 (1H, m), 3.81-3.93 (1H, m), 4.81 (1H, t, J = 5.5 Hz), 7.56-7.65 (1H, m), 7.85-7.95 (2H, m), 9.07 (3H, br).
(Step 6) Similar to Step 6 of Reference Example 29 using 8-bromo-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (4 g) obtained in Step 5 According to the procedure, N- (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (5.64 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.54-2.75 (2H, m), 3.42-3.63 (2H, m), 4.61 (2H, s), 5.47 (1H, td, J = 8.1, 4.9 Hz) , 6.67-6.78 (2H, m), 6.99-7.12 (2H, m), 7.33-7.39 (2H, m), 7.68-7.75 (1H, m).
(Step 7) N- (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide obtained in Step 6 ( Tert-Butyl (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2 , 5-Difluorophenoxy) ethyl] carbamate (5.04 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.07-1.56 (9H, m), 2.58 (1H, d, J = 13.6 Hz), 3.07 (1H, br), 3.36-4.38 (6H, m), 4.50 -5.70 (1H, m), 6.55-6.75 (2H, m), 7.02 (1H, ddd, J = 10.6, 9.1, 5.1 Hz), 7.13-7.39 (2H, m), 7.66 (1H, d, J = 8.7 Hz).
(Step 8) tert-butyl (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl obtained in Step 7 ] The title compound (569 mg) was obtained in the same manner as in Reference Example 37 using carbamate (1.0 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.22-1.54 (9H, m), 2.69 (1H, dd, J = 9.4, 5.3 Hz), 3.11 (1H, br), 3.30-4.33 (6H, m) , 4.78-5.59 (1H, m), 6.51-6.86 (3H, m), 6.89-7.07 (2H, m), 7.38 (1H, t, J = 8.1 Hz), 8.06-8.30 (1H, m).
参考例４０
tert-ブチル [2-(2,5-ジフルオロフェノキシ)プロピル](1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（４つの立体異性体混合物）
（工程１）2-ブロモプロピオン酸エチル（7.95 g）、2,5-ジフルオロフェノール（5.71 g）及び炭酸セシウム（29.4 g）のＤＭＦ（130 mL）溶液を90℃で22時間撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をＴＨＦ（100 mL）に溶解し、1Ｎ水酸化ナトリウム（50 mL）を加えた。反応液を50℃で3時間撹拌し、反応液を1Ｎ塩酸で酸性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去し、2-(2,5-ジフルオロフェノキシ)プロピオン酸（2.92 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.70 (3H, d, J= 6.8 Hz), 4.80 (1H, q, J= 6.8 Hz), 6.62-6.74 (2H, m), 7.05 (1H, ddd, J= 10.7, 8.8, 5.5 Hz) (A CO2H peak was not observed).
（工程２）工程１で得られた2-(2,5-ジフルオロフェノキシ)プロピオン酸（1.5 g）を用いて参考例２９の工程６と同様の手法により2-(2,5-ジフルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)プロパンアミド（2.31 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.62-1.70 (3H, m), 2.47-2.82 (2H, m), 3.33-3.56 (2H, m), 4.66-4.80 (1H, m), 5.34-5.46 (1H, m), 6.66-6.78 (2H, m), 6.94-7.13 (2H, m), 7.14-7.41 (1H, m), 7.41-7.64 (2H, m), 7.89-7.98 (1H, m).
（工程３）工程２で得られた2-(2,5-ジフルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)プロパンアミド（2.31 g）を用いて参考例２９の工程７と同様の手法により標題化合物を得た。1H-NMR (300 MHz, CDCl3) δppm 1.01-1.56 (12H, m), 2.34-2.72 (1H, m), 2.90-4.76 (6H, m), 4.76-5.67 (1H, m), 6.52-6.79 (2H, m), 6.91-7.15 (1H, m), 7.15-7.34 (1H, m), 7.34-7.56 (2H, m), 7.91 (1H, d, J= 7.9 Hz). Reference Example 40
tert-Butyl [2- (2,5-difluorophenoxy) propyl] (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (mixture of four stereoisomers)
(Step 1) A solution of ethyl 2-bromopropionate (7.95 g), 2,5-difluorophenol (5.71 g) and cesium carbonate (29.4 g) in DMF (130 mL) is stirred at 90 ° C. for 22 hours. Was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in THF (100 mL), and 1N sodium hydroxide (50 mL) was added. The reaction was stirred at 50 ° C. for 3 hours, the reaction was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 2- (2,5-difluorophenoxy) propionic acid (2.92 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.70 (3H, d, J = 6.8 Hz), 4.80 (1H, q, J = 6.8 Hz), 6.62-6.74 (2H, m), 7.05 (1H, ddd , J = 10.7, 8.8, 5.5 Hz) (A CO 2 H peak was not observed).
(Step 2) Using 2- (2,5-difluorophenoxy) propionic acid (1.5 g) obtained in Step 1 in the same manner as in Step 6 of Reference Example 29, 2- (2,5-difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) propanamide (2.31 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.62-1.70 (3H, m), 2.47-2.82 (2H, m), 3.33-3.56 (2H, m), 4.66-4.80 (1H, m), 5.34- 5.46 (1H, m), 6.66-6.78 (2H, m), 6.94-7.13 (2H, m), 7.14-7.41 (1H, m), 7.41-7.64 (2H, m), 7.89-7.98 (1H, m ).
(Step 3) 2- (2,5-Difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) propanamide obtained in Step 2 (2.31 g) Was used to obtain the title compound in the same manner as in Step 7 of Reference Example 29. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.01-1.56 (12H, m), 2.34-2.72 (1H, m), 2.90-4.76 (6H, m), 4.76-5.67 (1H, m), 6.52- 6.79 (2H, m), 6.91-7.15 (1H, m), 7.15-7.34 (1H, m), 7.34-7.56 (2H, m), 7.91 (1H, d, J = 7.9 Hz).
参考例４１
2-(2,5-ジフルオロフェノキシ)-N-(5-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
（工程１）2-ブロモ-5-フルオロフェノール（10 g）およびジアザビシクロウンデセン（11.9 g）のN，N-ジメチルアセトアミド（60 mL）溶液にジメチルチオカルバモイル クロリド（9.6 g）を5℃で加え、室温で14時間撹拌した。反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を0.5Ｎ塩酸、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:19～1:4）で精製してＯ-(2-ブロモ-5-フルオロフェニル) ジメチルチオカルバマート(12.6 g)を得た。1H-NMR (300 MHz, CDCl3) δppm 3.39 (3H, s), 3.47 (3H, s), 6.86-6.95 (2H, m), 7.54 (1H, dd, J= 9.0, 5.7 Hz).
（工程２）工程１で得られたＯ-(2-ブロモ-5-フルオロフェニル) ジメチルチオカルバマート(3.0 g)のジエチルアニリン（6 mL）溶液を210～220℃で5時間撹拌した。反応液を氷と6N塩酸に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ塩酸と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:19～1:4）で精製してS-(2-ブロモ-5-フルオロフェニル) ジメチルチオカルバマート（2.73 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.05 (3H, s), 3.12 (3H, s), 6.98 (1H, ddd, J= 8.7, 7.5, 3.0 Hz), 7.39 (1H, dd, J= 8.4, 3.0 Hz), 7.62 (1H, dd, J= 9.0, 5.4 Hz).
（工程３）工程２で得られたS-(2-ブロモ-5-フルオロフェニル) ジメチルチオカルバマート（3.19 g）および1Ｎ水酸化ナトリウム水溶液（30.7 mL）のメタノール（43 mL）溶液を80℃で2時間撹拌した。1Ｎ塩酸（35 mL）を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して2-ブロモ-5-フルオロベンゼンチオール（2.4 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 4.08 (1H, s), 6.73 (1H, ddd, J= 9.0, 8.1, 3.0 Hz), 7.09 (1H, dd, J= 9.0, 2.7 Hz), 7.47 (1H, dd, J= 9.0, 5.4 Hz).
（工程４）工程３で得られた2-ブロモ-5-フルオロベンゼンチオール（2.4 g）の8N水酸化ナトリウム水溶液（1.8 mL）および水（5.8 mL）溶液に3-ブロモプロピオン酸（1.76 g）および炭酸カリウム（0.8 g）の水溶液を加え、室温で5日間撹拌した。反応液を1Ｎ塩酸で酸性とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して3-[(2-ブロモ-5-フルオロフェニル)スルファニル]プロパン酸（3.2 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.77 (2H, t, J= 7.2 Hz), 3.20 (2H, t, J= 7.2Hz), 6.74-6.81 (1H, m), 6.98 (1H, dd, J= 9.0, 2.7 Hz), 7.49 (1H, dd, J= 8.4, 5.1 Hz) (A CO2H peak was not observed).
（工程５）工程４で得られた3-[(2-ブロモ-5-フルオロフェニル)スルファニル]プロパン酸（2.0 g）の濃硫酸（20 mL）溶液を室温で30分間撹拌した。反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ塩酸と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して8-ブロモ-5-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン（0.69 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.95-3.00 (2H, m), 3.23-3.28 (2H, m), 6.78 (1H, dd, J= 10.8, 8.7 Hz), 7.60 (1H, dd, J= 9.0, 4.8 Hz).
（工程６）工程５で得られた8-ブロモ-5-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン（0.62 g）の酢酸エチル（20 mL）溶液にm-クロロ過安息香酸(1.17 g)を室温で加えた。同温で2時間撹拌後、反応液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去して8-ブロモ-5-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン 1,1-ジオキシド（0.63 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.35-3.39 (2H, m), 3.74-3.79 (2H, m), 7.27 (1H, dd, J= 10.2, 8.7 Hz), 7.94 (1H, dd, J= 9.0, 4.5 Hz).
（工程７）工程６で得られた8-ブロモ-5-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン 1,1-ジオキシド（0.10 g）および10%パラジウム炭素（0.085 g）のエタノール（12 mL）溶液を1気圧の水素雰囲気下、室温で14時間撹拌した。触媒をろ別した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:2）で精製して5-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン 1,1-ジオキシド(0.070 g)を得た。1H-NMR (300 MHz, CDCl3) δppm 3.37-3.42 (2H, m), 3.67-3.71 (2H, m), 7.44 (1H, ddd, J= 9.6, 8.1, 1.8 Hz), 7.76-7.87 (2H, m).
（工程８）工程７で得られた5-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン 1,1-ジオキシド(3.6 g)および塩酸Ｏ-メチルヒドロキシルアミン（1.92 g）のピリジン（20 mL）溶液を室温で14時間撹拌した。反応溶液を水に注いだ後、酢酸エチルで抽出した。有機層を1Ｎ塩酸、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をＴＨＦ（150 mL）に溶解させ、ＴＨＦ-ボラン錯体（200 mL, １Ｍ ＴＨＦ溶液）を5℃で加えた。反応液を90℃で2時間撹拌後、反応液に氷を加え、6Ｎ塩酸（60 mL）を加えた。90℃で1時間撹拌後、反応液に酢酸エチルを加えた。分離した水層を、8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:1～1:0）で精製して5-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（3.45 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.35-2.42 (1H, m), 2.74-2.88 (1H, m), 3.24 (1H, ddd, J= 8.7, 6.3, 2.4 Hz), 3.80-3.92 (1H, m), 4.55 (1H, t, J= 3.9 Hz), 7.23-7.30 (1H, m), 7.48 (1H, dt, J= 5.1, 8.1 Hz), 7.74 (1H, d, J= 8.1 Hz) (A NH2 peak was not observed).
（工程９）工程８で得られた5-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドを用いて参考例１３と同様の手法により標題化合物を得た。1H-NMR (300 MHz, CDCl3) δppm 2.68-2.90 (2H, m), 3.30-3.40 (1H, m), 3.50-3.60 (1H, m), 4.57 (2H, s), 5.61-5.66 (1H, m), 6.66-6.75 (2H, m), 6.92-7.10 (2H, m), 7.25-7.35 (1H, m), 7.58 (1H, dt, J= 8.1, 5.1 Hz), 7.79 (1H, d, J= 8.1 Hz). Reference Example 41
2- (2,5-difluorophenoxy) -N- (5-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (Step 1) 2-bromo-5-fluoro Dimethylthiocarbamoyl chloride (9.6 g) was added to a solution of phenol (10 g) and diazabicycloundecene (11.9 g) in N, N-dimethylacetamide (60 mL) at 5 ° C., and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19 to 1: 4) to obtain O- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (12.6 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.39 (3H, s), 3.47 (3H, s), 6.86-6.95 (2H, m), 7.54 (1H, dd, J = 9.0, 5.7 Hz).
(Step 2) A solution of O- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (3.0 g) obtained in Step 1 in diethylaniline (6 mL) was stirred at 210 to 220 ° C. for 5 hours. The reaction mixture was poured into ice and 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19 to 1: 4) to obtain S- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (2.73 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.05 (3H, s), 3.12 (3H, s), 6.98 (1H, ddd, J = 8.7, 7.5, 3.0 Hz), 7.39 (1H, dd, J = 8.4, 3.0 Hz), 7.62 (1H, dd, J = 9.0, 5.4 Hz).
(Step 3) A solution of S- (2-bromo-5-fluorophenyl) dimethylthiocarbamate (3.19 g) obtained in Step 2 and 1N aqueous sodium hydroxide (30.7 mL) in methanol (43 mL) was added at 80 ° C. For 2 hours. 1N Hydrochloric acid (35 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 2-bromo-5-fluorobenzenethiol (2.4 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 4.08 (1H, s), 6.73 (1H, ddd, J = 9.0, 8.1, 3.0 Hz), 7.09 (1H, dd, J = 9.0, 2.7 Hz), 7.47 (1H, dd, J = 9.0, 5.4 Hz).
(Step 4) 3-Bromopropionic acid (1.76 g) was added to a solution of 2-bromo-5-fluorobenzenethiol (2.4 g) obtained in Step 3 in 8N aqueous sodium hydroxide (1.8 mL) and water (5.8 mL). And an aqueous solution of potassium carbonate (0.8 g) was added and stirred at room temperature for 5 days. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 3-[(2-bromo-5-fluorophenyl) sulfanyl] propanoic acid (3.2 g). It was. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.77 (2H, t, J = 7.2 Hz), 3.20 (2H, t, J = 7.2 Hz), 6.74-6.81 (1H, m), 6.98 (1H, dd , J = 9.0, 2.7 Hz), 7.49 (1H, dd, J = 8.4, 5.1 Hz) (A CO 2 H peak was not observed).
(Step 5) A solution of 3-[(2-bromo-5-fluorophenyl) sulfanyl] propanoic acid (2.0 g) obtained in Step 4 in concentrated sulfuric acid (20 mL) was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to remove 8-bromo-5-fluoro-2,3-dihydro-4H-thiochromene-4- On (0.69 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.95-3.00 (2H, m), 3.23-3.28 (2H, m), 6.78 (1H, dd, J = 10.8, 8.7 Hz), 7.60 (1H, dd, J = 9.0, 4.8 Hz).
(Step 6) m-Chloroperbenzoic acid was added to a solution of 8-bromo-5-fluoro-2,3-dihydro-4H-thiochromen-4-one (0.62 g) obtained in Step 5 in ethyl acetate (20 mL). (1.17 g) was added at room temperature. After stirring at the same temperature for 2 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to remove 8-bromo-5-fluoro-2,3-dihydro-4H-thiochromen-4-one 1, 1-dioxide (0.63 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.35-3.39 (2H, m), 3.74-3.79 (2H, m), 7.27 (1H, dd, J = 10.2, 8.7 Hz), 7.94 (1H, dd, J = 9.0, 4.5 Hz).
(Step 7) of 8-bromo-5-fluoro-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide (0.10 g) and 10% palladium carbon (0.085 g) obtained in Step 6 The ethanol (12 mL) solution was stirred at room temperature for 14 hours under 1 atmosphere of hydrogen. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 2) to give 5-fluoro-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide (0.070 g) Got. 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.37-3.42 (2H, m), 3.67-3.71 (2H, m), 7.44 (1H, ddd, J = 9.6, 8.1, 1.8 Hz), 7.76-7.87 ( 2H, m).
(Step 8) Pyridine of 5-fluoro-2,3-dihydro-4H-thiochromen-4-one 1,1-dioxide (3.6 g) obtained in Step 7 and O-methylhydroxylamine hydrochloride (1.92 g) ( The solution was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in THF (150 mL), and THF-borane complex (200 mL, 1M THF solution) was added at 5 ° C. After stirring the reaction solution at 90 ° C. for 2 hours, ice was added to the reaction solution, and 6N hydrochloric acid (60 mL) was added. After stirring at 90 ° C. for 1 hour, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 1: 0) to give 5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide ( 3.45 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.35-2.42 (1H, m), 2.74-2.88 (1H, m), 3.24 (1H, ddd, J = 8.7, 6.3, 2.4 Hz), 3.80-3.92 ( 1H, m), 4.55 (1H, t, J = 3.9 Hz), 7.23-7.30 (1H, m), 7.48 (1H, dt, J = 5.1, 8.1 Hz), 7.74 (1H, d, J = 8.1 Hz ) (A NH 2 peak was not observed).
(Step 9) The title compound was obtained in the same manner as in Reference Example 13 using 5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Step 8. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.68-2.90 (2H, m), 3.30-3.40 (1H, m), 3.50-3.60 (1H, m), 4.57 (2H, s), 5.61-5.66 ( 1H, m), 6.66-6.75 (2H, m), 6.92-7.10 (2H, m), 7.25-7.35 (1H, m), 7.58 (1H, dt, J = 8.1, 5.1 Hz), 7.79 (1H, d, J = 8.1 Hz).
参考例４２
N-(7-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド
（工程１）7-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン（1.0 g）を用いて参考例２９の工程３と同様の手法により(4E)-7-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（1.06 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.91-2.99 (2H, m), 3.03-3.11 (2H, m), 3.98 (3H, s), 6.81 (1H, td, J= 8.5, 2.6 Hz), 6.93 (1H, dd, J= 9.0, 2.6 Hz), 7.98 (1H, dd, J= 9.0, 6.0 Hz).
（工程２）工程１で得られた(4E)-7-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（1.06 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル (7-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（1.06 g）を得た。
（工程３）工程２で得られたtert-ブチル (7-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（12.3 g）を用いて参考例２９の工程５と同様の手法により7-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（820 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.54-2.69 (1H, m), 2.69-2.82 (1H, m), 3.67-3.79 (1H, m), 3.80-3.92 (1H, m), 4.78 (1H, t, J= 5.5 Hz), 7.68 (1H, td, J= 8.7, 2.6 Hz), 7.75 (1H, dd, J= 8.3, 2.6 Hz), 7.98 (1H, dd, J= 8.9, 5.1 Hz), 8.98 (3H, br).
（工程４）工程３で得られた7-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（820 mg）を用いて参考例２９の工程６と同様の手法により標題化合物（1.19 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.58-2.86 (2H, m), 3.37-3.56 (2H, m), 4.61 (2H, s), 5.40-5.59 (1H, m), 6.67-6.80 (2H, m), 7.01-7.18 (2H, m), 7.21-7.33 (1H, m), 7.40 (1H, dd, J= 8.7, 4.9 Hz), 7.62 (1H, dd, J= 7.6, 2.7 Hz). Reference Example 42
N- (7-Fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (Step 1) 7-Fluoro-2,3 (4E) -7-Fluoro-2,3-dihydro-4H-thiochromen-4-one O using 4-dihydro-4H-thiochromen-4-one (1.0 g) in the same manner as in Step 3 of Reference Example 29 -Methyl oxime (1.06 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.91-2.99 (2H, m), 3.03-3.11 (2H, m), 3.98 (3H, s), 6.81 (1H, td, J = 8.5, 2.6 Hz) , 6.93 (1H, dd, J = 9.0, 2.6 Hz), 7.98 (1H, dd, J = 9.0, 6.0 Hz).
(Step 2) Similar to Step 4 of Reference Example 29 using (4E) -7-fluoro-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (1.06 g) obtained in Step 1. In this manner, tert-butyl (7-fluoro-3,4-dihydro-2H-thiochromen-4-yl) carbamate (1.06 g) was obtained.
(Step 3) The same procedure as in Step 5 of Reference Example 29 using tert-butyl (7-fluoro-3,4-dihydro-2H-thiochromen-4-yl) carbamate (12.3 g) obtained in Step 2 Gave 7-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (820 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.54-2.69 (1H, m), 2.69-2.82 (1H, m), 3.67-3.79 (1H, m), 3.80-3.92 (1H, m), 4.78 (1H, t, J = 5.5 Hz), 7.68 (1H, td, J = 8.7, 2.6 Hz), 7.75 (1H, dd, J = 8.3, 2.6 Hz), 7.98 (1H, dd, J = 8.9, 5.1 Hz), 8.98 (3H, br).
(Step 4) Similar to Step 6 of Reference Example 29 using 7-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (820 mg) obtained in Step 3. The title compound (1.19 g) was obtained by the procedure. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.58-2.86 (2H, m), 3.37-3.56 (2H, m), 4.61 (2H, s), 5.40-5.59 (1H, m), 6.67-6.80 ( 2H, m), 7.01-7.18 (2H, m), 7.21-7.33 (1H, m), 7.40 (1H, dd, J = 8.7, 4.9 Hz), 7.62 (1H, dd, J = 7.6, 2.7 Hz) .
参考例４３
tert-ブチル [2-(2-クロロ-5-シアノフェノキシ)エチル](1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート
（工程１）5-ブロモ-2-クロロフェノール（2.07 g）を用いて実施例５１の工程１と同様の手法により4-クロロ-3-ヒドロキシベンゾニトリル（1.01 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 5.90 (1H, br), 7.18 (1H, dd, J= 8.3, 1.9 Hz), 7.30 (1H, d, J= 1.9 Hz), 7.44 (1H, d, J= 8.3 Hz).
（工程２）工程１で得られた4-クロロ-3-ヒドロキシベンゾニトリル（154 mg）を用いて参考例２２の工程３と同様の手法により標題化合物（362 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.14-1.57 (9H, m), 2.50-2.72 (1H, m), 3.17 (1H, br), 3.29-3.57 (2H, m), 3.59-4.47 (4H, m), 4.82-5.70 (1H, m), 7.15-7.37 (3H, m), 7.41-7.58 (3H, m), 7.94 (1H, d, J= 6.8 Hz). Reference Example 43
tert-butyl [2- (2-chloro-5-cyanophenoxy) ethyl] (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (Step 1) 5-bromo-2- 4-Chloro-3-hydroxybenzonitrile (1.01 g) was obtained in the same manner as in Step 1 of Example 51 using chlorophenol (2.07 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 5.90 (1H, br), 7.18 (1H, dd, J = 8.3, 1.9 Hz), 7.30 (1H, d, J = 1.9 Hz), 7.44 (1H, d , J = 8.3 Hz).
(Step 2) The title compound (362 mg) was obtained in the same manner as in Step 3 of Reference Example 22 using 4-chloro-3-hydroxybenzonitrile (154 mg) obtained in Step 1. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.14-1.57 (9H, m), 2.50-2.72 (1H, m), 3.17 (1H, br), 3.29-3.57 (2H, m), 3.59-4.47 ( 4H, m), 4.82-5.70 (1H, m), 7.15-7.37 (3H, m), 7.41-7.58 (3H, m), 7.94 (1H, d, J = 6.8 Hz).
参考例４４
2-(2,5-ジフルオロフェノキシ)-N-(3-メチル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
（工程１）ジイソプロピルアミン（7.64 g）のＴＨＦ（100 mL）溶液に1.6 Ｍｎ-ブチルリチウム（43.3 mL）を-78℃で加えた。反応液に2,3-ジヒドロ-4H-チオクロメン-4-オン（10.34 g）のＴＨＦ（20 mL）溶液を-78℃で加えた。反応液を同温で30分撹拌し、-30℃まで昇温した。反応液に-78℃でヨウ化メチル（9.83 g）のＴＨＦ（10 mL）溶液を加え、同温で30分間撹拌し、室温で1.5時間撹拌し、塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:19～3:17）で精製して3-メチル-2,3-ジヒドロ-4H-チオクロメン-4-オン（3.21 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.35 (3H, d, J= 6.8 Hz), 2.87-3.00 (1H, m), 3.13 (1H, d, J= 1.9 Hz), 3.15 (1H, s), 7.12-7.20 (1H, m), 7.23 (1H, s), 7.32-7.40 (1H, m), 8.10 (1H, dd, J= 8.3, 1.5 Hz).
（工程２）工程１で得られた3-メチル-2,3-ジヒドロ-4H-チオクロメン-4-オン（3.21 g）を用いて参考例２９の工程３と同様の手法により(4E)-3-メチル-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（3.63 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.28 (3H, d, J= 6.8 Hz), 2.67 (1H, dd, J= 13.3, 3.8 Hz), 3.28 (1H, dd, J= 13.3, 3.8 Hz), 3.79-3.91 (1H, m), 3.99 (3H, s), 7.02-7.11 (1H, m), 7.14-7.21 (2H, m), 8.01 (1H, d, J= 8.0 Hz).
（工程３）工程２で得られた(4E)-3-メチル-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（3.63 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル (3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートを得た。1H-NMR (300 MHz, CDCl3) δppm 1.02-1.16 (3H, m), 1.46 (9H, s), 2.17-2.51 (1H, m), 2.68-3.31 (2H, m), 4.43-4.89 (2H, m), 6.99-7.18 (3H, m), 7.23-7.31 (1H, m).
（工程４）工程３で得られたtert-ブチル (3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートを用いて参考例２９の工程５と同様の手法により3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（2.18 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.22-1.37 (3H, m), 2.77-3.06 (1H, m), 3.58-3.96 (2H, m), 4.47-4.79 (1H, m), 7.63-8.01 (4H, m), 8.96 (3H, br).
（工程５）工程４で得られた3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（2.18 g）を用いて参考例２９の工程６と同様の手法により標題化合物（2.71 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.24 (3H, dd, J= 15.5, 6.8 Hz), 2.75-3.12 (1H, m), 3.22-3.46 (2H, m), 4.56-4.71 (2H, m), 5.21-5.57 (1H, m), 6.64-6.81 (2H, m), 6.97-7.20 (2H, m), 7.32-7.59 (3H, m), 7.88-7.96 (1H, m). Reference Example 44
2- (2,5-Difluorophenoxy) -N- (3-methyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (Step 1) diisopropylamine (7.64 g) 1.6 Mn-butyllithium (43.3 mL) was added to a THF (100 mL) solution at -78 ° C. A solution of 2,3-dihydro-4H-thiochromen-4-one (10.34 g) in THF (20 mL) was added to the reaction solution at -78 ° C. The reaction solution was stirred at the same temperature for 30 minutes and heated to -30 ° C. To the reaction solution was added a solution of methyl iodide (9.83 g) in THF (10 mL) at −78 ° C., stirred at the same temperature for 30 minutes, stirred at room temperature for 1.5 hours, added with aqueous ammonium chloride, Extracted. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19 to 3:17) to give 3-methyl-2,3-dihydro-4H-thiochromen-4-one (3.21 g). It was. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.35 (3H, d, J = 6.8 Hz), 2.87-3.00 (1H, m), 3.13 (1H, d, J = 1.9 Hz), 3.15 (1H, s ), 7.12-7.20 (1H, m), 7.23 (1H, s), 7.32-7.40 (1H, m), 8.10 (1H, dd, J = 8.3, 1.5 Hz).
(Step 2) (4E) -3 in the same manner as in Step 3 of Reference Example 29 using 3-methyl-2,3-dihydro-4H-thiochromen-4-one (3.21 g) obtained in Step 1 -Methyl-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.63 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.28 (3H, d, J = 6.8 Hz), 2.67 (1H, dd, J = 13.3, 3.8 Hz), 3.28 (1H, dd, J = 13.3, 3.8 Hz) ), 3.79-3.91 (1H, m), 3.99 (3H, s), 7.02-7.11 (1H, m), 7.14-7.21 (2H, m), 8.01 (1H, d, J = 8.0 Hz).
(Step 3) Similar to Step 4 of Reference Example 29 using (4E) -3-methyl-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.63 g) obtained in Step 2 In this manner, tert-butyl (3-methyl-3,4-dihydro-2H-thiochromen-4-yl) carbamate was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.02-1.16 (3H, m), 1.46 (9H, s), 2.17-2.51 (1H, m), 2.68-3.31 (2H, m), 4.43-4.89 ( 2H, m), 6.99-7.18 (3H, m), 7.23-7.31 (1H, m).
(Step 4) Using the tert-butyl (3-methyl-3,4-dihydro-2H-thiochromen-4-yl) carbamate obtained in Step 3, according to the same procedure as in Step 5 of Reference Example 29, 3-methyl -3,4-Dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.18 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.22-1.37 (3H, m), 2.77-3.06 (1H, m), 3.58-3.96 (2H, m), 4.47-4.79 (1H, m), 7.63-8.01 (4H, m), 8.96 (3H, br).
(Step 5) Similar to Step 6 of Reference Example 29 using 3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.18 g) obtained in Step 4 The title compound (2.71 g) was obtained by the procedure. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.24 (3H, dd, J = 15.5, 6.8 Hz), 2.75-3.12 (1H, m), 3.22-3.46 (2H, m), 4.56-4.71 (2H, m), 5.21-5.57 (1H, m), 6.64-6.81 (2H, m), 6.97-7.20 (2H, m), 7.32-7.59 (3H, m), 7.88-7.96 (1H, m).
参考例４５
N-(7-ブロモ-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド
（工程１）水素化ナトリウム（2.33 g）のＴＨＦ（180 mL）溶液に4-ブロモチオフェノール（10 g）を室温で加えた。反応液を室温で1時間撹拌し、γ-ブチロラクトン（5 g）を加えた。反応液を加熱還流し、6時間撹拌した。反応液を１Ｎ水酸化ナトリウム（30 mL）と水（30 mL）に注ぎ、ジエチルエーテルで洗浄した。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し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～1:1）で精製して4-[(4-ブロモフェニル)スルファニル]ブタン酸（6.27 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.95 (2H, quin, J= 7.2 Hz), 2.52 (2H, t, J= 7.2 Hz), 2.96 (2H, t, J= 7.2 Hz), 7.16-7.23 (2H, m), 7.36-7.44 (2H, m).
（工程２）工程１で得られた4-[(4-ブロモフェニル)スルファニル]ブタン酸（5.27 g）のポリリン酸（40 g）溶液を100℃で3時間撹拌した。反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を1Ｎ水酸化ナトリウムと飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 0:1～1:19）で精製して7-ブロモ-3,4-ジヒドロ-1-ベンゾチエピン-5(2H)-オン（3.29 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.22-2.34 (2H, m), 2.97 (2H, t, J= 6.8 Hz), 3.04 (2H, t, J= 6.6 Hz), 7.30-7.37 (1H, m), 7.39-7.46 (1H, m), 7.96 (1H, d, J= 1.9 Hz).
（工程３）工程２で得られた7-ブロモ-3,4-ジヒドロ-1-ベンゾチエピン-5(2H)-オン（4.06 g）を用いて参考例２９の工程３と同様の手法により(5E)-7-ブロモ-3,4-ジヒドロ-1-ベンゾチエピン-5(2H)-オン Ｏ-メチルオキシム（3.44 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.03-2.15 (2H, m), 2.93 (4H, dt, J= 15.4, 6.4 Hz), 3.99 (3H, s), 7.18-7.23 (1H, m), 7.28-7.34 (1H, m), 7.67 (1H, d, J= 2.3 Hz).
（工程４）工程３で得られた (5E)-7-ブロモ-3,4-ジヒドロ-1-ベンゾチエピン-5(2H)-オン Ｏ-メチルオキシム（3.44 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル (7-ブロモ-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-イル)カルバマート（3.23 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.44 (9H, br), 1.86 (2H, br), 1.99-2.21 (2H, m), 2.67-2.84 (2H, m), 4.90-5.42 (1H, m), 5.47-5.95 (1H, m), 7.23-7.31 (1H, m), 7.31-7.40 (1H, m), 7.43 (1H, s).
（工程５）工程４で得られたtert-ブチル (7-ブロモ-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-イル)カルバマート（3.23 g）を用いて参考例２９の工程５と同様の手法により7-ブロモ-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-アミン 1,1-ジオキシド塩酸塩（2.31 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.67-1.88 (1H, m), 2.01-2.32 (3H, m), 3.31-3.52 (2H, m), 4.98 (1H, br), 7.81-7.94 (3H, m), 9.07 (3H, br).
（工程６）工程５で得られた7-ブロモ-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-アミン 1,1-ジオキシド塩酸塩（2.31 g）を用いて参考例２９の工程６と同様の手法により標題化合物（2.56 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.59-1.68 (2H, m), 1.76-1.97 (1H, m), 2.04-2.25 (1H, m), 2.29-2.59 (2H, m), 3.19 (1H, ddd, J= 15.1, 12.4, 2.8 Hz), 3.32-3.54 (1H, m), 4.45-4.70 (2H, m), 5.72 (1H, dd, J= 9.1, 7.2 Hz), 6.58-6.81 (2H, m), 6.96-7.13 (1H, m), 7.59-7.79 (2H, m), 7.97 (1H, d, J= 8.3 Hz), 8.59 (1H, br). Reference Example 45
N- (7-bromo-1,1-dioxide-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) -2- (2,5-difluorophenoxy) acetamide (step 1) sodium hydride 4-Bromothiophenol (10 g) was added to a solution of (2.33 g) in THF (180 mL) at room temperature. The reaction solution was stirred at room temperature for 1 hour, and γ-butyrolactone (5 g) was added. The reaction was heated to reflux and stirred for 6 hours. The reaction mixture was poured into 1N sodium hydroxide (30 mL) and water (30 mL), and washed with diethyl ether. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1) to obtain 4-[(4-bromophenyl) sulfanyl] butanoic acid (6.27 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.95 (2H, quin, J = 7.2 Hz), 2.52 (2H, t, J = 7.2 Hz), 2.96 (2H, t, J = 7.2 Hz), 7.16- 7.23 (2H, m), 7.36-7.44 (2H, m).
(Step 2) A solution of 4-[(4-bromophenyl) sulfanyl] butanoic acid (5.27 g) obtained in Step 1 in polyphosphoric acid (40 g) was stirred at 100 ° C. for 3 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 1 to 1:19) to give 7-bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one (3.29 g). ) 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.22-2.34 (2H, m), 2.97 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 6.6 Hz), 7.30-7.37 (1H , m), 7.39-7.46 (1H, m), 7.96 (1H, d, J = 1.9 Hz).
(Step 3) 7-Bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one (4.06 g) obtained in Step 2 was used in the same manner as in Step 3 of Reference Example 29 (5E ) -7-Bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one O-methyloxime (3.44 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.03-2.15 (2H, m), 2.93 (4H, dt, J = 15.4, 6.4 Hz), 3.99 (3H, s), 7.18-7.23 (1H, m) , 7.28-7.34 (1H, m), 7.67 (1H, d, J = 2.3 Hz).
(Step 4) Step of Reference Example 29 using (5E) -7-bromo-3,4-dihydro-1-benzothiepin-5 (2H) -one O-methyloxime (3.44 g) obtained in Step 3 4 was used to obtain tert-butyl (7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) carbamate (3.23 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.44 (9H, br), 1.86 (2H, br), 1.99-2.21 (2H, m), 2.67-2.84 (2H, m), 4.90-5.42 (1H, m), 5.47-5.95 (1H, m), 7.23-7.31 (1H, m), 7.31-7.40 (1H, m), 7.43 (1H, s).
(Step 5) Step 5 of Reference Example 29 using tert-butyl (7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) carbamate (3.23 g) obtained in Step 4 In the same manner, 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide hydrochloride (2.31 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.67-1.88 (1H, m), 2.01-2.32 (3H, m), 3.31-3.52 (2H, m), 4.98 (1H, br), 7.81- 7.94 (3H, m), 9.07 (3H, br).
(Step 6) Step of Reference Example 29 using 7-bromo-2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide hydrochloride (2.31 g) obtained in Step 5 The title compound (2.56 g) was obtained by the same method as 6. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.59-1.68 (2H, m), 1.76-1.97 (1H, m), 2.04-2.25 (1H, m), 2.29-2.59 (2H, m), 3.19 ( 1H, ddd, J = 15.1, 12.4, 2.8 Hz), 3.32-3.54 (1H, m), 4.45-4.70 (2H, m), 5.72 (1H, dd, J = 9.1, 7.2 Hz), 6.58-6.81 ( 2H, m), 6.96-7.13 (1H, m), 7.59-7.79 (2H, m), 7.97 (1H, d, J = 8.3 Hz), 8.59 (1H, br).
参考例４６
2-(2,5-ジフルオロフェノキシ)-N-(5-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
（工程１）参考例４１の工程８で得られた5-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（0.50 g）のメタノール（15 mL）溶液にナトリウム金属（0.53 g）を室温で加え、95℃で14時間撹拌した。反応溶液を塩化アンモニウム水溶液に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:19～1:9）で精製して5-メトキシ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（0.22 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.30-2.40 (1H, m), 2.70-2.85 (1H, m), 3.21 (1H, ddd, J= 8.7, 6.0, 2.7 Hz), 3.77 (1H, dt, J= 3.0, 13.5 Hz), 3.91 (3H, s), 4.47 (1H, t, J= 4.1 Hz), 7.04 (1H, dd, J= 7.8, 0.9 Hz), 7.74 (1H, t, J= 8.1 Hz), 7.52 (1H, dd, J= 8.1, 1.2 Hz)(An NH2 peak was not observed).
（工程２）工程１で得られた5-メトキシ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドを用いて参考例１３と同様の手法により標題化合物を得た。1H-NMR (300 MHz, CDCl3) δppm 2.70-2.80 (2H, m), 3.25-3.35 (1H, m), 3.45-3.60 (1H, m), 3.83 (3H, s), 4.50 (1H, d, J= 14.7 Hz), 4.58 (1H, d, J= 14.7 Hz), 5.54 (1H, quin, J= 3.5 Hz), 6.64-6.76 (3H, m), 6.96-7.10 (2H, m), 7.49-7.56 (2H, m). Reference Example 46
2- (2,5-Difluorophenoxy) -N- (5-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (Step 1) In Step 8 of Reference Example 41 Sodium metal (0.53 g) was added at room temperature to a solution of the obtained 5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (0.50 g) in methanol (15 mL) at 95 ° C. For 14 hours. The reaction solution was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 19 to 1: 9) to give 5-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide ( 0.22 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.30-2.40 (1H, m), 2.70-2.85 (1H, m), 3.21 (1H, ddd, J = 8.7, 6.0, 2.7 Hz), 3.77 (1H, dt, J = 3.0, 13.5 Hz), 3.91 (3H, s), 4.47 (1H, t, J = 4.1 Hz), 7.04 (1H, dd, J = 7.8, 0.9 Hz), 7.74 (1H, t, J = 8.1 Hz), 7.52 (1H, dd, J = 8.1, 1.2 Hz) (An NH 2 peak was not observed).
(Step 2) The title compound was obtained in the same manner as in Reference Example 13 using 5-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Step 1. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.70-2.80 (2H, m), 3.25-3.35 (1H, m), 3.45-3.60 (1H, m), 3.83 (3H, s), 4.50 (1H, d, J = 14.7 Hz), 4.58 (1H, d, J = 14.7 Hz), 5.54 (1H, quin, J = 3.5 Hz), 6.64-6.76 (3H, m), 6.96-7.10 (2H, m), 7.49-7.56 (2H, m).
参考例４７
tert-ブチル (6-シアノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート
　参考例３１の工程１で得られた、tert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（4 g）を用いて実施例５１と同様の手法によりtert-ブチル (6-シアノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（3.28 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.05-1.57 (9H, m), 2.57-2.76 (1H, m), 3.01-3.24 (1H, m), 3.38-4.39 (6H, m), 4.65-5.47 (1H, m), 6.57-6.78 (2H, m), 6.96-7.11 (1H, m), 7.51-7.77 (2H, m), 8.03 (1H, d, J= 8.3 Hz). Reference Example 47
tert-Butyl (6-cyano-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate Obtained in Step 1 of Reference Example 31 Tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (4 g) Tert-butyl (6-cyano-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl by a method similar to that in Example 51. Carbamate (3.28 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.05-1.57 (9H, m), 2.57-2.76 (1H, m), 3.01-3.24 (1H, m), 3.38-4.39 (6H, m), 4.65- 5.47 (1H, m), 6.57-6.78 (2H, m), 6.96-7.11 (1H, m), 7.51-7.77 (2H, m), 8.03 (1H, d, J = 8.3 Hz).
参考例４８
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ヒドロキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート
　水素化アルミニウムリチウム（185 mg）のジエチルエーテル溶液（20 mL）に参考例３６の工程１で得られたメチル　4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボキシラート 1,1-ジオキシド（2.5 g）のジエチルエーテル（10 mL）溶液を0℃で加えた。反応液を加熱還流下30分撹拌し、室温で硫酸ナトリウム十水和物を加えた。反応液を同温で3時間撹拌し、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～4:1）で精製して標題化合物（1.36 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.04-1.57 (9H, m), 1.90 (1H, br), 2.52-2.69 (1H, m), 2.88-3.22 (1H, m), 3.27-4.36 (6H, m), 4.68 (2H, br), 4.78-5.65 (1H, m), 6.55-6.77 (2H, m), 7.01 (1H, ddd, J= 10.8, 9.3, 5.3 Hz), 7.20-7.35 (1H, m), 7.43 (1H, d, J= 8.3 Hz), 7.90 (1H, d, J= 8.3 Hz). Reference Example 48
tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate lithium aluminum hydride ( 185 mg) in diethyl ether solution (20 mL), methyl 4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -3, obtained in Step 1 of Reference Example 36, 4-Dihydro-2H-thiochromene-6-carboxylate 1,1-dioxide (2.5 g) in diethyl ether (10 mL) was added at 0 ° C. The reaction mixture was stirred with heating under reflux for 30 minutes, and sodium sulfate decahydrate was added at room temperature. The reaction solution was stirred at the same temperature for 3 hours and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-4: 1) to give the title compound (1.36 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.04-1.57 (9H, m), 1.90 (1H, br), 2.52-2.69 (1H, m), 2.88-3.22 (1H, m), 3.27-4.36 ( 6H, m), 4.68 (2H, br), 4.78-5.65 (1H, m), 6.55-6.77 (2H, m), 7.01 (1H, ddd, J = 10.8, 9.3, 5.3 Hz), 7.20-7.35 ( 1H, m), 7.43 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 8.3 Hz).
参考例４９
N-(6-ブロモ-8-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド
（工程１）4-ブロモ-2-フルオロベンゼンチオール（1 g）を用いて参考例２９の工程１と同様の手法により3-[(4-ブロモ-2-フルオロフェニル)スルファニル]プロパン酸（615 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.65 (2H, t, J= 7.2 Hz), 3.13 (2H, t, J= 7.2 Hz), 7.22-7.35 (3H, m)(A CO2H peak was not observed).
（工程２）工程１で得られた3-[(4-ブロモ-2-フルオロフェニル)スルファニル]プロパン酸（15.5 g）の硫酸（25 mL）溶液を室温で44時間撹拌した。反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 0:1～1:9）で精製して6-ブロモ-8-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン（10.3 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.94-3.10 (2H, m), 3.20-3.34 (2H, m), 7.35 (1H, dd, J= 8.7, 1.9 Hz), 8.01-8.15 (1H, m).
(工程３) 工程２で得られた6-ブロモ-8-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン（10.3 g）を用いて参考例２９の工程３と同様の手法により6-ブロモ-8-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（9.29 g）を得た。得られた6-ブロモ-8-フルオロ-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（9.29 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル (6-ブロモ-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（7.85 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.48 (9H, s), 2.03-2.18 (1H, m), 2.24-2.39 (1H, m), 2.97-3.08 (2H, m), 4.64-4.94 (2H, m), 7.10 (1H, dd, J= 9.1, 1.9 Hz), 7.29 (1H, s).
（工程４）工程３で得られたtert-ブチル (6-ブロモ-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（7.85 g）を用いて参考例２９の工程５と同様の手法により6-ブロモ-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（6.03 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.53-2.64 (1H, m), 2.64-2.78 (1H, m), 3.70-3.96 (2H, m), 4.80 (1H, br), 7.93-8.01 (1H, m), 8.05 (1H, s), 9.07 (3H, br).
（工程５）工程４で得られた6-ブロモ-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（2.0 g）を用いて参考例２９の工程６と同様の手法により標題化合物（2.57 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.58-2.71 (2H, m), 3.41-3.58 (2H, m), 4.57-4.71 (2H, m), 5.38-5.49 (1H, m), 6.69-6.81 (2H, m), 7.04-7.19 (2H, m), 7.32 (1H, s), 7.39 (1H, dd, J= 9.2, 1.7 Hz). Reference Example 49
N- (6-Bromo-8-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (Step 1) 4-Bromo 3-[(4-Bromo-2-fluorophenyl) sulfanyl] propanoic acid (615 mg) was obtained in the same manner as in Step 1 of Reference Example 29 using 2-fluorobenzenethiol (1 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.65 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.2 Hz), 7.22-7.35 (3H, m) (A CO 2 H peak was not observed).
(Step 2) A solution of 3-[(4-bromo-2-fluorophenyl) sulfanyl] propanoic acid (15.5 g) obtained in Step 1 in sulfuric acid (25 mL) was stirred at room temperature for 44 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 1 to 1: 9) to give 6-bromo-8-fluoro-2,3-dihydro-4H-thiochromen-4-one (10.3 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.94-3.10 (2H, m), 3.20-3.34 (2H, m), 7.35 (1H, dd, J = 8.7, 1.9 Hz), 8.01-8.15 (1H, m).
(Step 3) 6-Bromo-8-fluoro-2,3-dihydro-4H-thiochromen-4-one (10.3 g) obtained in Step 2 was prepared in the same manner as in Step 3 of Reference Example 29. -Bromo-8-fluoro-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (9.29 g) was obtained. The obtained 6-bromo-8-fluoro-2,3-dihydro-4H-thiochromen-4-one O-methyloxime (9.29 g) was used in the same manner as in Step 4 of Reference Example 29 to prepare tert-butyl ( 6-Bromo-8-fluoro-3,4-dihydro-2H-thiochromen-4-yl) carbamate (7.85 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.48 (9H, s), 2.03-2.18 (1H, m), 2.24-2.39 (1H, m), 2.97-3.08 (2H, m), 4.64-4.94 ( 2H, m), 7.10 (1H, dd, J = 9.1, 1.9 Hz), 7.29 (1H, s).
(Step 4) Step 5 of Reference Example 29 using tert-butyl (6-bromo-8-fluoro-3,4-dihydro-2H-thiochromen-4-yl) carbamate (7.85 g) obtained in Step 3 6-Bromo-8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (6.03 g) was obtained in the same manner as above. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.53-2.64 (1H, m), 2.64-2.78 (1H, m), 3.70-3.96 (2H, m), 4.80 (1H, br), 7.93- 8.01 (1H, m), 8.05 (1H, s), 9.07 (3H, br).
(Step 5) Step of Reference Example 29 using 6-bromo-8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.0 g) obtained in Step 4 The title compound (2.57 g) was obtained by the same method as 6. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.58-2.71 (2H, m), 3.41-3.58 (2H, m), 4.57-4.71 (2H, m), 5.38-5.49 (1H, m), 6.69- 6.81 (2H, m), 7.04-7.19 (2H, m), 7.32 (1H, s), 7.39 (1H, dd, J = 9.2, 1.7 Hz).
参考例５０
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（保持時間小）
　実施例６４の工程１で得られた化合物（400 mg）をキラルカラムクロマトグラフィーによって光学分割した。保持時間小の分取画分を濃縮して標題化合物（192 mg）を得た。ＭＳ（ＥＳＩ＋）：４８３（Ｍ＋Ｈ）
キラルクロマトグラフィーによる精製条件
カラム：ＣＨＩＲＡＬＰＡＫ　ＡＳＨ（ＬＡ００５）２０ｍｍＩＤ×２５０ｍｍＬ
溶媒：ＣＯ２／ＭｅＯＨ＝７００／３００
流速：６０ ｍＬ／ｍｉｎ
温度：３５℃
検出法：ＵＶ２２０ｎｍ Reference Example 50
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (low retention time)
The compound (400 mg) obtained in Step 1 of Example 64 was optically resolved by chiral column chromatography. The fraction with a short retention time was concentrated to obtain the title compound (192 mg). MS (ESI +): 483 (M + H)
Purification condition column by chiral chromatography: CHIRALPAK ASH (LA005) 20 mm ID × 250 mm L
Solvent: CO 2 / MeOH = 700/300
Flow rate: 60 mL / min
Temperature: 35 ° C
Detection method: UV 220 nm
参考例５１
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（保持時間大）
　実施例６４の工程１で得られた化合物（400 mg）を用い、参考例５０と同様の手法により保持時間大の分取画分を濃縮して標題化合物（192 mg）を得た。ＭＳ（ＥＳＩ＋）：４８３（Ｍ＋Ｈ） Reference Example 51
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (large retention time)
Using the compound (400 mg) obtained in Step 1 of Example 64, the fraction with a long retention time was concentrated in the same manner as in Reference Example 50 to obtain the title compound (192 mg). MS (ESI +): 483 (M + H)
参考例５２
2-(2,5-ジフルオロフェノキシ)-N-[1,1-ジオキシド-6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-イル]アセトアミド
（工程１）4-(トリフルオロメトキシ)ベンゼンチオール（6.81 g）を用いて参考例２９の工程１と同様の手法により3-{[4-(トリフルオロメトキシ)フェニル]スルファニル}プロパン酸（4.04 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.68 (2H, t, J= 7.2 Hz), 3.16 (2H, t, J= 7.2 Hz), 7.16 (2H, d, J= 7.9 Hz), 7.36-7.44 (2H, m)(A CO2H peak was not observed).
（工程２）工程１で得られた3-{[4-(トリフルオロメトキシ)フェニル]スルファニル}プロパン酸（3.80 g）を用いて参考例４９の工程２と同様の手法により6-(トリフルオロメトキシ)-2,3-ジヒドロ-4H-チオクロメン-4-オン（3.39 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.94-3.04 (2H, m), 3.21-3.30 (2H, m), 7.20-7.26 (1H, m), 7.29-7.36 (1H, m), 7.97 (1H, s).
（工程３）工程２で得られた6-(トリフルオロメトキシ)-2,3-ジヒドロ-4H-チオクロメン-4-オン（3.39 g）を用いて参考例２９の工程３と同様の手法により(4E)-6-(トリフルオロメトキシ)-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（3.58 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.90-2.98 (2H, m), 3.02-3.10 (2H, m), 4.01 (3H, s), 7.03-7.09 (1H, m), 7.23 (1H, d, J= 8.7 Hz), 7.87 (1H, d, J= 1.9 Hz).
（工程４）工程３で得られた(4E)-6-(トリフルオロメトキシ)-2,3-ジヒドロ-4H-チオクロメン-4-オン Ｏ-メチルオキシム（3.58 g）を用いて参考例２９の工程４と同様の手法によりtert-ブチル [6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（2.61 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.48 (9H, s), 2.07-2.20 (1H, m), 2.24-2.37 (1H, m), 2.96-3.12 (2H, m), 4.73-4.92 (2H, m), 6.97-7.04 (1H, m), 7.07-7.13 (1H, m), 7.19 (1H, d, J= 2.3 Hz).
（工程５）工程４で得られたtert-ブチル [6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（2.61 g）を用いて参考例２９の工程５と同様の手法により6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（1.55 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.54-2.69 (1H, m), 2.69-2.85 (1H, m), 3.68-3.91 (2H, m), 4.84 (1H, t, J= 5.8 Hz), 7.70 (1H, d, J= 8.7 Hz), 7.97 (1H, s), 8.06 (1H, d, J= 9.0 Hz), 9.00 (3H, br).
（工程６）工程５で得られた6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（1.55 g）を用いて参考例２９の工程６と同様の手法により標題化合物（1.92 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.59-2.81 (2H, m), 3.39-3.56 (2H, m), 4.57-4.69 (2H, m), 5.50 (1H, td, J= 8.7, 5.7 Hz), 6.67-6.78 (2H, m), 7.02-7.12 (1H, m), 7.12-7.23 (2H, m), 7.36 (1H, d, J= 8.7 Hz), 7.99 (1H, d, J= 8.7 Hz). Reference Example 52
2- (2,5-Difluorophenoxy) -N- [1,1-dioxide-6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] acetamide (Step 1) 4- ( 3-{[4- (Trifluoromethoxy) phenyl] sulfanyl} propanoic acid (4.04 g) was obtained in the same manner as in Step 1 of Reference Example 29 using (trifluoromethoxy) benzenethiol (6.81 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.68 (2H, t, J = 7.2 Hz), 3.16 (2H, t, J = 7.2 Hz), 7.16 (2H, d, J = 7.9 Hz), 7.36- 7.44 (2H, m) (A CO 2 H peak was not observed).
(Step 2) Using 3-{[4- (trifluoromethoxy) phenyl] sulfanyl} propanoic acid (3.80 g) obtained in Step 1, in the same manner as in Step 2 of Reference Example 49, 6- (trifluoro Methoxy) -2,3-dihydro-4H-thiochromen-4-one (3.39 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.94-3.04 (2H, m), 3.21-3.30 (2H, m), 7.20-7.26 (1H, m), 7.29-7.36 (1H, m), 7.97 ( 1H, s).
(Step 3) Using 6- (trifluoromethoxy) -2,3-dihydro-4H-thiochromen-4-one (3.39 g) obtained in Step 2, according to the same procedure as in Step 3 of Reference Example 29 ( 4E) -6- (Trifluoromethoxy) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.58 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.90-2.98 (2H, m), 3.02-3.10 (2H, m), 4.01 (3H, s), 7.03-7.09 (1H, m), 7.23 (1H, d, J = 8.7 Hz), 7.87 (1H, d, J = 1.9 Hz).
(Step 4) Using (4E) -6- (trifluoromethoxy) -2,3-dihydro-4H-thiochromen-4-one O-methyloxime (3.58 g) obtained in Step 3, In the same manner as in Step 4, tert-butyl [6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (2.61 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.48 (9H, s), 2.07-2.20 (1H, m), 2.24-2.37 (1H, m), 2.96-3.12 (2H, m), 4.73-4.92 ( 2H, m), 6.97-7.04 (1H, m), 7.07-7.13 (1H, m), 7.19 (1H, d, J = 2.3 Hz).
(Step 5) Step 5 of Reference Example 29 using tert-butyl [6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (2.61 g) obtained in Step 4 In the same manner, 6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.55 g) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.54-2.69 (1H, m), 2.69-2.85 (1H, m), 3.68-3.91 (2H, m), 4.84 (1H, t, J = 5.8 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.97 (1H, s), 8.06 (1H, d, J = 9.0 Hz), 9.00 (3H, br).
(Step 6) Step of Reference Example 29 using 6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (1.55 g) obtained in Step 5 The title compound (1.92 g) was obtained by the same method as 6. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.59-2.81 (2H, m), 3.39-3.56 (2H, m), 4.57-4.69 (2H, m), 5.50 (1H, td, J = 8.7, 5.7 Hz), 6.67-6.78 (2H, m), 7.02-7.12 (1H, m), 7.12-7.23 (2H, m), 7.36 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 8.7 Hz).
参考例５３
3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパン酸
（工程１）参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（4 g）、アクリル酸メチル（1.92 g）、Ｅｔ３Ｎ（1.67 g）、テトラブチルアンモニウムブロミド（2.9 g）、酢酸パラジウム（169 mg）及びジフェニルホスフィノフェロセン（416 mg）のＤＭＦ（15 mL）溶液を 100℃で 14時間、窒素雰囲気下撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:10～1:3）で精製してメチル (2E)-3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパ-2-エノアート（3.27 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.17 (6H, br), 1.55 (3H, br) 2.55-2.70 (1H, m), 2.94-3.25 (1H, m), 3.35-3.59 (3H, m), 3.69-4.41 (6H, m), 4.65-5.65 (1H, m), 6.29-6.51 (1H, m), 6.54-6.78 (2H, m), 7.00 (1H, ddd, J= 10.7, 9.2, 5.3 Hz), 7.28-7.66 (3H, m), 7.93 (1H, d, J= 8.3 Hz).
（工程２）工程１で得られた(2E)-3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパ-2-エノアート（3 g）および10%パラジウム炭素（0.4 g）のメタノール（10 mL）溶液を水素雰囲気下、50℃で16時間撹拌した。触媒をろ別した後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:10～1:3）で精製してメチル 3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパノアート (440 mg)を得た。1H-NMR (300 MHz, CDCl3) δppm 1.06-1.59 (9H, m), 2.45-2.68 (3H, m), 2.84-3.21 (3H, m), 3.23-3.61 (3H, m), 3.66 (3H, s), 3.79 (1H, d, J= 13.2 Hz), 3.95-4.37 (2H, m), 4.59-5.66 (1H, m), 6.54-6.78 (2H, m), 6.95-7.16 (2H, m), 7.23-7.35 (1H, m), 7.80-7.90 (1H, m).
（工程３）工程２で得られたメチル 3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパノアート (440 mg)及び１Ｎ水酸化ナトリウム水溶液（2 mL）のＴＨＦ（3 mL）溶液を60℃で3時間撹拌した。反応液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去して標題化合物（387 mg）を得た。ＭＳ（ＥＳＩ＋）：４２６（Ｍ-Ｂｏｃ＋２Ｈ） Reference Example 53
3- (4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) propanoic acid (Step 1) tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5- Difluorophenoxy) ethyl] carbamate (4 g), methyl acrylate (1.92 g), Et 3 N (1.67 g), tetrabutylammonium bromide (2.9 g), palladium acetate (169 mg) and diphenylphosphinoferrocene (416 mg) ) In DMF (15 mL) at 100 ° C. for 14 hours under a nitrogen atmosphere, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 3) to give methyl (2E) -3- (4-{(tert-butoxycarbonyl) [2- (2, 5-Difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) prop-2-enoate (3.27 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.17 (6H, br), 1.55 (3H, br) 2.55-2.70 (1H, m), 2.94-3.25 (1H, m), 3.35-3.59 (3H, m ), 3.69-4.41 (6H, m), 4.65-5.65 (1H, m), 6.29-6.51 (1H, m), 6.54-6.78 (2H, m), 7.00 (1H, ddd, J = 10.7, 9.2, 5.3 Hz), 7.28-7.66 (3H, m), 7.93 (1H, d, J = 8.3 Hz).
(Step 2) (2E) -3- (4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3 obtained in Step 1 A solution of 4-dihydro-2H-thiochromen-6-yl) prop-2-enoate (3 g) and 10% palladium on carbon (0.4 g) in methanol (10 mL) was stirred at 50 ° C. for 16 hours in a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10-1: 3) and methyl 3- (4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] Amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) propanoate (440 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.06-1.59 (9H, m), 2.45-2.68 (3H, m), 2.84-3.21 (3H, m), 3.23-3.61 (3H, m), 3.66 ( 3H, s), 3.79 (1H, d, J = 13.2 Hz), 3.95-4.37 (2H, m), 4.59-5.66 (1H, m), 6.54-6.78 (2H, m), 6.95-7.16 (2H, m), 7.23-7.35 (1H, m), 7.80-7.90 (1H, m).
(Step 3) Methyl 3- (4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro obtained in Step 2 A solution of -2H-thiochromen-6-yl) propanoate (440 mg) and 1N aqueous sodium hydroxide solution (2 mL) in THF (3 mL) was stirred at 60 ° C. for 3 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (387 mg). MS (ESI +): 426 (M-Boc + 2H)
参考例５４
tert-ブチル [6-(2-アミノ-2-オキソエトキシ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート
　参考例３７の工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（250 mg）と2-ブロモアセトアミド（77.0 mg）を用いて実施例６１の工程１と同様の手法によって標題化合物（228 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.10-1.59 (9H, m), 2.64 (1H, br), 3.11 (1H, br), 3.33-3.83 (4H, m), 4.03-4.38 (2H, m), 4.44 (2H, br), 5.48 (1H, br), 5.71 (1H, br), 6.39 (1H, br), 6.55-6.90 (3H, m), 6.94-7.07 (2H, m), 7.91 (1H, d, J= 8.7 Hz). Reference Example 54
tert-butyl [6- (2-amino-2-oxoethoxy) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5-difluorophenoxy) ethyl] Carbamate tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromene-4-] obtained in Step 1 of Reference Example 37 Yl) carbamate (250 mg) and 2-bromoacetamide (77.0 mg) were used to give the title compound (228 mg) in the same manner as in Step 1 of Example 61. 1 H-NMR (300 MHz, CDCl 3) δppm 1.10-1.59 (9H, m), 2.64 (1H, br), 3.11 (1H, br), 3.33-3.83 (4H, m), 4.03-4.38 (2H, m), 4.44 (2H, br), 5.48 (1H, br), 5.71 (1H, br), 6.39 (1H, br), 6.55-6.90 (3H, m), 6.94-7.07 (2H, m), 7.91 (1H, d, J = 8.7 Hz).
参考例５５
メチル [(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)オキシ]アセタート
　参考例３７で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（250 mg）とブロモ酢酸メチル（85.3 mg）を用いて実施例６１の工程１と同様の手法によって標題化合物（274 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.16-1.56 (9H, m), 2.53-2.68 (1H, m), 3.10 (1H, br), 3.25-3.76 (4H, m), 3.79 (3H, s), 3.98-4.35 (2H, m), 4.53-4.68 (2H, m), 4.74-5.63 (1H, m), 6.55-6.85 (3H, m), 6.91-7.07 (2H, m), 7.82-7.93 (1H, m). Reference Example 55
Methyl [(4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) oxy] Acetate tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate obtained in Reference Example 37 (250 mg) and methyl bromoacetate (85.3 mg) were used to give the title compound (274 mg) in the same manner as in Step 1 of Example 61. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.16-1.56 (9H, m), 2.53-2.68 (1H, m), 3.10 (1H, br), 3.25-3.76 (4H, m), 3.79 (3H, s), 3.98-4.35 (2H, m), 4.53-4.68 (2H, m), 4.74-5.63 (1H, m), 6.55-6.85 (3H, m), 6.91-7.07 (2H, m), 7.82- 7.93 (1H, m).
参考例５６
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(2-メトキシエトキシ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート
　参考例３７で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（250 mg）と1-ブロモ-2-メトキシエタン（77.6 mg）を用いて実施例６１の工程１と同様の手法によって標題化合物（267 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.07-1.56 (9H, m), 2.50-2.67 (1H, m), 2.88-3.22 (1H, m), 3.24-3.83 (9H, m), 3.97-4.35 (4H, m), 5.54 (1H, br), 6.55-6.86 (3H, m), 6.95-7.06 (2H, m), 7.81-7.91 (1H, m). Reference Example 56
tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (2-methoxyethoxy) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate Reference Example 37 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (250 mg) And 1-bromo-2-methoxyethane (77.6 mg) were used to give the title compound (267 mg) in the same manner as in Step 1 of Example 61. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.07-1.56 (9H, m), 2.50-2.67 (1H, m), 2.88-3.22 (1H, m), 3.24-3.83 (9H, m), 3.97- 4.35 (4H, m), 5.54 (1H, br), 6.55-6.86 (3H, m), 6.95-7.06 (2H, m), 7.81-7.91 (1H, m).
参考例５７
tert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][1,1-ジオキシド-6-(2,2,2-トリフルオロエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート
　参考例３７で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（250 mg）及び炭酸セシウム（182 mg）のＤＭＦ（2 mL）溶液に2,2,2-トリフルオロエチル トリフルオロメタンスルホナート（130 mg）を0℃で加え、反応液を室温で2時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～9:11）で精製して標題化合物（278 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.12-1.56 (9H, m), 2.51-2.70 (1H, m), 2.92-3.21 (1H, m), 3.31-3.52 (2H, m), 3.55-4.40 (6H, m), 4.63-5.61 (1H, m), 6.53-6.67 (1H, m), 6.68-6.81 (1H, m), 6.88 (1H, br), 6.95-7.07 (2H, m), 7.90 (1H, d, J= 8.7 Hz). Reference Example 57
tert-butyl [2- (2,5-difluorophenoxy) ethyl] [1,1-dioxide-6- (2,2,2-trifluoroethoxy) -3,4-dihydro-2H-thiochromen-4-yl Carbamate tert-butyl [2- (2,5-difluorophenoxy) ethyl] obtained in Reference Example 37 (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) To a solution of carbamate (250 mg) and cesium carbonate (182 mg) in DMF (2 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (130 mg) at 0 ° C, and the reaction solution was stirred at room temperature for 2 hours. Stir. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 9:11) to give the title compound (278 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.12-1.56 (9H, m), 2.51-2.70 (1H, m), 2.92-3.21 (1H, m), 3.31-3.52 (2H, m), 3.55- 4.40 (6H, m), 4.63-5.61 (1H, m), 6.53-6.67 (1H, m), 6.68-6.81 (1H, m), 6.88 (1H, br), 6.95-7.07 (2H, m), 7.90 (1H, d, J = 8.7 Hz).
参考例５８
2-(2,5-ジフルオロフェノキシ)-N-(6-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド
　6-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミンを用いて参考例７の工程1から工程２と同様の手法を用いて6-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩を得た後、参考例２９の工程６と同様の手法により標題化合物を得た。1H-NMR (300 MHz, CDCl3) δppm 2.58-2.81 (2H, m), 3.38-3.54 (2H, m), 4.56-4.70 (2H, m), 5.49 (1H, td, J= 8.6, 5.5 Hz), 6.68-6.78 (2H, m), 7.03-7.14 (3H, m), 7.17-7.25 (1H, m), 7.98 (1H, dd, J= 8.9, 5.5 Hz). Reference Example 58
2- (2,5-Difluorophenoxy) -N- (6-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide 6-fluoro-3,4-dihydro-2H Using 6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride in the same manner as in Step 1 to Step 2 of Reference Example 7 using -thiochromen-4-amine Then, the title compound was obtained in the same manner as in Step 6 of Reference Example 29. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.58-2.81 (2H, m), 3.38-3.54 (2H, m), 4.56-4.70 (2H, m), 5.49 (1H, td, J = 8.6, 5.5 Hz), 6.68-6.78 (2H, m), 7.03-7.14 (3H, m), 7.17-7.25 (1H, m), 7.98 (1H, dd, J = 8.9, 5.5 Hz).
　参考例２２～５８に記載される化合物は以下の通りである（表２）。表２に示されたfreeはフリー体を示し、Racemateはラセミ体を示す。 The compounds described in Reference Examples 22 to 58 are as follows (Table 2). Free shown in Table 2 indicates a free form, and Racemate indicates a racemate.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
実施例１
2-(2-クロロ-5-フルオロフェノキシ)-N-[5-クロロ-2-(メチルスルホニル)ベンジル]エタンアミン塩酸塩
　参考例１で得られた1-[5-クロロ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩（500 mg）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（540 mg）及び炭酸カリウム（670 mg）をエタノール（20 mL）溶液中90℃で24時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（70 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.33 (3H, s), 3.52 (2H, br), 4.45 (2H, t, J= 4.7 Hz), 4.67 (2H, br), 6.90 (1H, td, J= 8.4, 2.8 Hz), 7.22 (1H, dd, J= 10.6, 2.7 Hz), 7.51 (1H, dd, J= 8.7, 6.1 Hz), 7.76-7.90 (1H, m), 7.96-8.11 (2H, m), 9.45 (2H, br). Example 1
2- (2-Chloro-5-fluorophenoxy) -N- [5-chloro-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [5-chloro-2- (methylsulfonyl) obtained in Reference Example 1 ) Phenyl] methanamine hydrochloride (500 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (540 mg) and potassium carbonate (670 mg) in ethanol (20 mL) solution at 90 ° C. Stir for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from ethanol and diethyl ether to give the title compound (70 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.33 (3H, s), 3.52 (2H, br), 4.45 (2H, t, J = 4.7 Hz), 4.67 (2H, br), 6.90 (1H , td, J = 8.4, 2.8 Hz), 7.22 (1H, dd, J = 10.6, 2.7 Hz), 7.51 (1H, dd, J = 8.7, 6.1 Hz), 7.76-7.90 (1H, m), 7.96- 8.11 (2H, m), 9.45 (2H, br).
実施例２
2-(2-クロロ-5-フルオロフェノキシ)-N-{5-クロロ-2-[(1-メチルエチル)スルホニル] ベンジル}エタンアミン塩酸塩
　参考例２で得られた1-{5-クロロ-2-[(1-メチルエチル)スルホニル]フェニル}メタンアミン塩酸塩（600 mg）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（700 mg）及び炭酸カリウム（730 mg）をエタノール（20 mL）溶液中90℃で16時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（110 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.16 (6H, d, J= 6.8 Hz), 3.25-3.60 (3H, m), 4.46 (2H, br), 4.62 (2H, br), 6.90 (1H, td, J= 8.5, 3.0 Hz), 7.22 (1H, dd, J= 10.7, 2.8 Hz), 7.51 (1H, dd, J= 8.9, 6.2 Hz), 7.78-7.87 (1H, m), 7.91-7.98 (1H, m), 8.00-8.11 (1H, m), 9.54 (2H, br). Example 2
2- (2-Chloro-5-fluorophenoxy) -N- {5-chloro-2-[(1-methylethyl) sulfonyl] benzyl} ethanamine hydrochloride 1- {5-Chloro-- obtained in Reference Example 2 2-[(1-methylethyl) sulfonyl] phenyl} methanamine hydrochloride (600 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (700 mg) and potassium carbonate (730 mg) The mixture was stirred at 90 ° C. for 16 hours in an ethanol (20 mL) solution. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure and crystallized from ethanol and diethyl ether to obtain the title compound (110 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.16 (6H, d, J = 6.8 Hz), 3.25-3.60 (3H, m), 4.46 (2H, br), 4.62 (2H, br), 6.90 (1H, td, J = 8.5, 3.0 Hz), 7.22 (1H, dd, J = 10.7, 2.8 Hz), 7.51 (1H, dd, J = 8.9, 6.2 Hz), 7.78-7.87 (1H, m), 7.91-7.98 (1H, m), 8.00-8.11 (1H, m), 9.54 (2H, br).
実施例３
N-[5-クロロ-2-(エチルスルホニル)ベンジル]-2-(2-クロロ-5-フルオロフェノキシ) エタンアミン塩酸塩
　参考例３で得られた1-[5-クロロ-2-(エチルスルホニル)フェニル]メタンアミン塩酸塩（690 mg）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（840 mg）及び炭酸カリウム（880 mg）をエタノール（20 mL）溶液中90℃で16時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（210 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.13 (3H, t, J= 7.4 Hz), 3.35-3.47 (4H, m), 4.45 (2H, t, J= 4.73 Hz), 4.64 (2H, br), 6.90 (1H, td, J= 8.4, 2.8 Hz), 7.22 (1H, dd, J= 10.8, 2.8 Hz), 7.51 (1H, dd, J= 8.7, 6.1 Hz), 7.83 (1H, dd, J= 8.5, 2.1 Hz), 7.98 (1H, d, J= 8.3 Hz), 8.06 (1H, s), 9.51 (2H, br). Example 3
N- [5-Chloro-2- (ethylsulfonyl) benzyl] -2- (2-chloro-5-fluorophenoxy) ethanamine hydrochloride 1- [5-chloro-2- (ethylsulfonyl) obtained in Reference Example 3 ) Phenyl] methanamine hydrochloride (690 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (840 mg) and potassium carbonate (880 mg) in ethanol (20 mL) solution at 90 ° C. Stir for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from ethanol and diethyl ether to obtain the title compound (210 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.13 (3H, t, J = 7.4 Hz), 3.35-3.47 (4H, m), 4.45 (2H, t, J = 4.73 Hz), 4.64 (2H , br), 6.90 (1H, td, J = 8.4, 2.8 Hz), 7.22 (1H, dd, J = 10.8, 2.8 Hz), 7.51 (1H, dd, J = 8.7, 6.1 Hz), 7.83 (1H, dd, J = 8.5, 2.1 Hz), 7.98 (1H, d, J = 8.3 Hz), 8.06 (1H, s), 9.51 (2H, br).
実施例４
2-(2-クロロ-5-フルオロフェノキシ)-N-[2-(メチルスルホニル)ベンジル] エタンアミン
　1-[2-(メチルスルホニル)フェニル]メタンアミン塩酸塩（450 mg）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（670 mg）及び炭酸カリウム（700 mg）をエタノール（15 mL）溶液中90℃で16時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製し、標題化合物（150 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.14 (2H, t, J= 5.1 Hz), 3.29 (3H, s), 4.06-4.18 (2H, m), 4.31 (2H, s), 6.59-6.71 (2H, m), 7.29 (1H, dd, J= 8.5, 5.9 Hz), 7.43-7.52 (1H, m), 7.54-7.66 (2H, m), 8.09 (1H, d, J= 7.6 Hz). Example 4
2- (2-Chloro-5-fluorophenoxy) -N- [2- (methylsulfonyl) benzyl] ethanamine 1- [2- (methylsulfonyl) phenyl] methanamine hydrochloride (450 mg), 2- (2-bromo Ethoxy) -1-chloro-4-fluorobenzene (670 mg) and potassium carbonate (700 mg) were stirred in an ethanol (15 mL) solution at 90 ° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (150 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.14 (2H, t, J = 5.1 Hz), 3.29 (3H, s), 4.06-4.18 (2H, m), 4.31 (2H, s), 6.59-6.71 (2H, m), 7.29 (1H, dd, J = 8.5, 5.9 Hz), 7.43-7.52 (1H, m), 7.54-7.66 (2H, m), 8.09 (1H, d, J = 7.6 Hz).
実施例５
2-(2-クロロ-5-フルオロフェノキシ)-N-[5-メトキシ-2-(メチルスルホニル)ベンジル] エタンアミン塩酸塩
　参考例４で得られた1-[5-メトキシ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩（500 mg）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（650 mg）及び炭酸カリウム（690 mg）をエタノール（15 mL）溶液中90℃で18時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:3）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（180 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.28 (3H, s), 3.48 (2H, br), 3.90 (3H, s), 4.45 (2H, d, J=4.1 Hz), 4.63 (2 H, br), 6.89 (1H, td, J= 8.5, 3.0 Hz), 7.23 (2H, td, J= 10.7, 2.6 Hz), 7.51 (2H, dd, J= 8.7, 6.0 Hz), 7.96 (1H, d, J= 9.0 Hz), 9.46 (2H, br). Example 5
2- (2-Chloro-5-fluorophenoxy) -N- [5-methoxy-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [5-methoxy-2- (methylsulfonyl) obtained in Reference Example 4 ) Phenyl] methanamine hydrochloride (500 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (650 mg) and potassium carbonate (690 mg) in ethanol (15 mL) solution at 90 ° C. Stir for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 3). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from ethanol and diethyl ether to give the title compound (180 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.28 (3H, s), 3.48 (2H, br), 3.90 (3H, s), 4.45 (2H, d, J = 4.1 Hz), 4.63 (2 H, br), 6.89 (1H, td, J = 8.5, 3.0 Hz), 7.23 (2H, td, J = 10.7, 2.6 Hz), 7.51 (2H, dd, J = 8.7, 6.0 Hz), 7.96 (1H , d, J = 9.0 Hz), 9.46 (2H, br).
実施例６
2-(2-クロロ-5-フルオロフェノキシ)-N-[4-フルオロ-2-(メチルスルホニル)ベンジル] エタンアミン塩酸塩
　1-[4-フルオロ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩（500 mg）（Synthetic Communications, 2007, 37, 1887-1897）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（690 mg）及び炭酸カリウム（720 mg）をエタノール（15 mL）溶液中90℃で14時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:3）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（160 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.41 (3H, s), 3.48 (2H, br), 4.45 (2H, t, J= 4.9 Hz), 4.64 (2H, br), 6.89 (1H, td, J= 8.4, 2.8 Hz), 7.21 (1H, dd, J= 10.8, 2.8 Hz), 7.51 (1H, dd, J= 8.9, 6.3 Hz), 7.70-7.81 (1H, m), 7.84 (1H, dd, J= 8.7, 2.7 Hz), 7.97 (1H, dd, J=8.7, 5.3 Hz), 9.45 (2H, br). Example 6
2- (2-Chloro-5-fluorophenoxy) -N- [4-fluoro-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [4-fluoro-2- (methylsulfonyl) phenyl] methanamine hydrochloride ( 500 mg) (Synthetic Communications, 2007, 37, 1887-1897), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (690 mg) and potassium carbonate (720 mg) in ethanol (15 mL) The solution was stirred at 90 ° C. for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 3). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from ethanol and diethyl ether to give the title compound (160 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.41 (3H, s), 3.48 (2H, br), 4.45 (2H, t, J = 4.9 Hz), 4.64 (2H, br), 6.89 (1H , td, J = 8.4, 2.8 Hz), 7.21 (1H, dd, J = 10.8, 2.8 Hz), 7.51 (1H, dd, J = 8.9, 6.3 Hz), 7.70-7.81 (1H, m), 7.84 ( 1H, dd, J = 8.7, 2.7 Hz), 7.97 (1H, dd, J = 8.7, 5.3 Hz), 9.45 (2H, br).
実施例７
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-4-フルオロ-N,N-ジメチルベンゼンスルホンアミド塩酸塩
　2-(アミノメチル)-4-フルオロ-N,N-ジメチルベンゼンスルホンアミド塩酸塩（300 mg）（Synthetic Communications, 2007, 37, 1887-1897）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（312 mg）及び炭酸カリウム（300 mg）をエタノール（10 mL）溶液中90℃で終夜撹拌した。反応液をセライトを用いてろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9→1:1）で精製した。得られた残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、メタノールと酢酸エチルで結晶化させ、標題化合物（30 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.72 (6H, s), 3.46 (2H, br), 4.39 (2H, br), 4.56 (2H, br), 6.89 (1H, td, J= 8.5, 3.0 Hz), 7.20 (1H, dd, J= 10.6, 3.0 Hz), 7.50 (2H, dd, J= 8.9, 6.2 Hz), 7.75 (1H, dd, J= 9.8, 2.7 Hz), 7.95 (1H, dd, J= 8.7, 5.7 Hz), 9.24 (2H, br). Example 7
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -4-fluoro-N, N-dimethylbenzenesulfonamide hydrochloride 2- (aminomethyl) -4-fluoro-N , N-dimethylbenzenesulfonamide hydrochloride (300 mg) (Synthetic Communications, 2007, 37, 1887-1897), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (312 mg) and potassium carbonate (300 mg) was stirred in an ethanol (10 mL) solution at 90 ° C. overnight. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 → 1: 1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from methanol and ethyl acetate to give the title compound (30 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.72 (6H, s), 3.46 (2H, br), 4.39 (2H, br), 4.56 (2H, br), 6.89 (1H, td, J = 8.5, 3.0 Hz), 7.20 (1H, dd, J = 10.6, 3.0 Hz), 7.50 (2H, dd, J = 8.9, 6.2 Hz), 7.75 (1H, dd, J = 9.8, 2.7 Hz), 7.95 ( 1H, dd, J = 8.7, 5.7 Hz), 9.24 (2H, br).
実施例８
2-(2-クロロ-5-フルオロフェノキシ)-N-[5-フルオロ-2-(メチルスルホニル)ベンジル] エタンアミン塩酸塩
　参考例５で得られた1-[5-フルオロ-2-(メチルスルホニル)フェニル]メタンアミン塩酸塩（500 mg）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（690 mg）及び炭酸カリウム（720 mg）をエタノール（15 mL）溶液中90℃で16時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:3）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（140 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.36 (3H, s), 3.51 (2H, br), 4.44 (2H, t, J= 4.9 Hz), 4.67 (2H, br), 6.90 (1H, td, J= 8.5, 2.7 Hz), 7.21 (1H, dd, J= 10.8, 2.8 Hz), 7.51 (1H, dd, J= 9.1, 6.1 Hz), 7.61 (1H, td, J= 8.5, 2.7 Hz), 7.80 (1H, dd, J= 9.8, 2.7 Hz), 8.11 (1H, dd, J= 9.1, 5.7 Hz), 9.41 (2H, br). Example 8
2- (2-Chloro-5-fluorophenoxy) -N- [5-fluoro-2- (methylsulfonyl) benzyl] ethanamine hydrochloride 1- [5-fluoro-2- (methylsulfonyl) obtained in Reference Example 5 ) Phenyl] methanamine hydrochloride (500 mg), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (690 mg) and potassium carbonate (720 mg) in ethanol (15 mL) solution at 90 ° C. Stir for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 3). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from ethanol and diethyl ether to obtain the title compound (140 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.36 (3H, s), 3.51 (2H, br), 4.44 (2H, t, J = 4.9 Hz), 4.67 (2H, br), 6.90 (1H , td, J = 8.5, 2.7 Hz), 7.21 (1H, dd, J = 10.8, 2.8 Hz), 7.51 (1H, dd, J = 9.1, 6.1 Hz), 7.61 (1H, td, J = 8.5, 2.7 Hz), 7.80 (1H, dd, J = 9.8, 2.7 Hz), 8.11 (1H, dd, J = 9.1, 5.7 Hz), 9.41 (2H, br).
実施例９
6-クロロ-N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
　6-クロロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン-1,1-ジオキシド塩酸塩（0.34 g）（公開特許文献ＵＳ2006025400）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（0.39 g）と炭酸カリウム（0.53 g）のエタノール（5 mL）溶液を70℃で終夜撹拌した。反応液をろ過した後、溶媒を減圧下留去した。残渣を酢酸エチルと飽和炭酸水素ナトリウム溶液で溶解させ、酢酸エチルで二回抽出した。有機層をあわせ、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥して、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～2:3）で精製し、油状物を得た。得られた油状物をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去し、酢酸エチルとＩＰＥで再結晶して、標題化合物（12 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.64-2.97 (2H, m), 3.57-4.06 (4H, m), 4.29-4.56 (2H, m), 4.76-5.10 (1H, m), 6.89 (1H, td, J= 8.4, 2.8 Hz), 7.21 (1H, dd, J= 11.0, 2.8 Hz), 7.51 (1H, dd, J= 8.7, 6.1 Hz), 7.71-7.85 (1H, m), 7.88-7.99 (1H, m), 8.10 (1H, br), 9.44-10.02 (2H, m). Example 9
6-chloro-N- [2- (2-chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 6-chloro-3,4- Dihydro-2H-thiochromen-4-amine-1,1-dioxide hydrochloride (0.34 g) (published patent document US2006025400), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.39 g) and A solution of potassium carbonate (0.53 g) in ethanol (5 mL) was stirred at 70 ° C. overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was dissolved with ethyl acetate and saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 2: 3) to give an oil. The obtained oil was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and recrystallized from ethyl acetate and IPE to obtain the title compound (12 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.64-2.97 (2H, m), 3.57-4.06 (4H, m), 4.29-4.56 (2H, m), 4.76-5.10 (1H, m), 6.89 (1H, td, J = 8.4, 2.8 Hz), 7.21 (1H, dd, J = 11.0, 2.8 Hz), 7.51 (1H, dd, J = 8.7, 6.1 Hz), 7.71-7.85 (1H, m) , 7.88-7.99 (1H, m), 8.10 (1H, br), 9.44-10.02 (2H, m).
実施例１０
4-クロロ-2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩
　参考例６で得られた2-(アミノメチル)-4-クロロ-N,N-ジメチルベンゼンスルホンアミド塩酸塩（0.47 g）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（0.55 g）及び炭酸カリウム（0.60 g）をエタノール（10 mL）溶液中90℃で終夜撹拌した。反応液をセライトを用いてろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～1:1）で精製した。得られた残渣をメタノールに溶解後、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、メタノールと酢酸エチルで結晶化させ、標題化合物（0.20 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.73 (6H, s), 3.50 (2H, t), 4.45 (2H, t, J= 4.9 Hz), 4.60 (2H, br), 6.90 (1H, td, J= 8.5, 2.7 Hz), 7.21 (1H, dd, J= 10.6, 2.7 Hz), 7.51 (1H, dd, J= 8.9, 6.2 Hz), 7.73-7.81 (1H, m), 7.84-7.93 (1H, m), 8.05 (1H, d, J= 2.3 Hz), 9.50 (2H, br). Example 10
4-chloro-2-({[2- (2-chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide hydrochloride 2- (aminomethyl obtained in Reference Example 6 ) -4-Chloro-N, N-dimethylbenzenesulfonamide hydrochloride (0.47 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.55 g) and potassium carbonate (0.60 g) The mixture was stirred overnight at 90 ° C. in an ethanol (10 mL) solution. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from methanol and ethyl acetate to give the title compound (0.20 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.73 (6H, s), 3.50 (2H, t), 4.45 (2H, t, J = 4.9 Hz), 4.60 (2H, br), 6.90 (1H , td, J = 8.5, 2.7 Hz), 7.21 (1H, dd, J = 10.6, 2.7 Hz), 7.51 (1H, dd, J = 8.9, 6.2 Hz), 7.73-7.81 (1H, m), 7.84- 7.93 (1H, m), 8.05 (1H, d, J = 2.3 Hz), 9.50 (2H, br).
実施例１１
2-(2-クロロ-5-フルオロフェノキシ)-N-[2-(フェニルスルホニル)ベンジル]エタンアミン塩酸塩
　1-[2-(フェニルスルホニル)フェニル]メタンアミン塩酸塩（500mg）（Journal of Medicinal Chemistry, 1975, 18(2), 142-146）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（520 mg）及び炭酸カリウム（610 mg）をエタノール（15 mL）溶液中90℃で14時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させ、標題化合物（140 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.52 (2H, br), 4.47 (2H, br), 4.54 (2H, br), 6.91 (1H, td, J= 8.5, 3.0 Hz), 7.23 (1H, dd, J= 10.7, 2.8 Hz), 7.52 (1H, dd, J= 8.7, 6.0 Hz), 7.58-7.66 (2H, m), 7.70-7.85 (4H, m), 7.95 (2H, d, J= 7.2 Hz), 8.19 (1 H, d, J= 7.5 Hz), 9.44 (2H, br). Example 11
2- (2-Chloro-5-fluorophenoxy) -N- [2- (phenylsulfonyl) benzyl] ethanamine hydrochloride 1- [2- (phenylsulfonyl) phenyl] methanamine hydrochloride (500 mg) (Journal of Medicinal Chemistry, 1975, 18 (2), 142-146), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (520 mg) and potassium carbonate (610 mg) in ethanol (15 mL) solution at 90 ° C For 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 2). The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from ethanol and diethyl ether to obtain the title compound (140 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.52 (2H, br), 4.47 (2H, br), 4.54 (2H, br), 6.91 (1H, td, J = 8.5, 3.0 Hz), 7.23 (1H, dd, J = 10.7, 2.8 Hz), 7.52 (1H, dd, J = 8.7, 6.0 Hz), 7.58-7.66 (2H, m), 7.70-7.85 (4H, m), 7.95 (2H, d , J = 7.2 Hz), 8.19 (1 H, d, J = 7.5 Hz), 9.44 (2H, br).
実施例１２
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例７で得られた2-(2-クロロ-5-フルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド（800 mg）のＴＨＦ（30 mL）溶液にＴＨＦ-ボラン錯体（10 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。80℃で6時間攪拌後、反応液に氷を加え、1Ｎ塩酸（30 mL）を加えた。80℃で16時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、エタノールとジエチルエーテルで結晶化させた。得られた結晶をエタノールとジエチルエーテルで再結晶して、標題化合物（80 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.84 (2H, br), 3.48-3.96 (4H, m), 4.43 (2H, br), 4.95 (1H, br), 6.81-6.95 (1H, m), 7.22 (1H, dd, J= 10.4, 2.5 Hz), 7.52 (1H, dd, J= 8.7, 6.1 Hz), 7.76 (2H, br), 7.93 (2H, br), 9.60 (2H, br). Example 12
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2- Chloro-5-fluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (800 mg) in THF (30 mL) solution in THF-borane complex (10 mL, 1M THF solution) was added at 0 ° C. After stirring at 80 ° C. for 6 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (30 mL) was added. After stirring at 80 ° C. for 16 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was distilled off under reduced pressure and then crystallized with ethanol and diethyl ether. The obtained crystals were recrystallized from ethanol and diethyl ether to give the title compound (80 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.84 (2H, br), 3.48-3.96 (4H, m), 4.43 (2H, br), 4.95 (1H, br), 6.81-6.95 (1H, m), 7.22 (1H, dd, J = 10.4, 2.5 Hz), 7.52 (1H, dd, J = 8.7, 6.1 Hz), 7.76 (2H, br), 7.93 (2H, br), 9.60 (2H, br ).
実施例１３
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩
　参考例８で得られた2-(アミノメチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩（1.00 g）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（1.31 g）及び炭酸カリウム（1.43 g）をエタノール（10 mL）溶液中90℃で終夜撹拌した。反応液をセライトを用いてろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～1:1）で精製した。得られた残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、メタノールと酢酸エチルで結晶化させ、標題化合物（0.50 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.72 (6H, s), 3.48 (2H, t, J= 4.5 Hz), 4.46 (2H, t, J= 4.9 Hz), 4.60 (2H, s), 6.89 (1H, td, J= 8.5, 2.7 Hz), 7.22 (1H, dd, J= 10.8, 2.8 Hz), 7.51 (1 H, dd, J= 8.9, 6.2 Hz), 7.67-7.75 (1H, m), 7.77-8.01 (3H, m), 9.46 (2H, br). Example 13
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide hydrochloride 2- (aminomethyl) -N, obtained in Reference Example 8, N-dimethylbenzenesulfonamide hydrochloride (1.00 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (1.31 g) and potassium carbonate (1.43 g) in ethanol (10 mL) solution in 90 Stir overnight at ° C. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure, and crystallized from methanol and ethyl acetate to obtain the title compound (0.50 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.72 (6H, s), 3.48 (2H, t, J = 4.5 Hz), 4.46 (2H, t, J = 4.9 Hz), 4.60 (2H, s ), 6.89 (1H, td, J = 8.5, 2.7 Hz), 7.22 (1H, dd, J = 10.8, 2.8 Hz), 7.51 (1 H, dd, J = 8.9, 6.2 Hz), 7.67-7.75 (1H , m), 7.77-8.01 (3H, m), 9.46 (2H, br).
実施例１４
2-(2-クロロ-5-フルオロフェノキシ)-N-[2-(モルホリン-4-イルスルホニル)ベンジル]エタンアミン塩酸塩
（工程１）2-シアノベンゼン-1-スルホニルクロリドとモルホリンを用いて参考例８の工程１、２と同様の手法（ただし、塩化水素／酢酸エチル溶液での処理は省く）で1-[2-(モルホリン-4-イルスルホニル)フェニル]メタンアミンを得た。1H-NMR (400 MHz, CDCl3) δppm 2.05 (2H, s), 3.14-3.16 (4H, m), 3.72-3.75(4H, m), 4.14 (2H, s), 7.41-7.45 (1H, m), 7.58-7.63 (2H, m), 7.88 (1H, d, J= 8.8 Hz).
（工程２）工程１で得られた1-[2-(モルホリン-4-イルスルホニル)フェニル]メタンアミン （1.00 g）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（1.13 g）及び炭酸カリウム（1.23 g）をエタノール（10 mL）溶液中90℃で終夜撹拌した。反応液をセライトを用いてろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:1）で精製した。得られた残渣をメタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去した後、メタノールと酢酸エチルで結晶化させ、標題化合物（0.22 g）を得た。1H NMR (300 MHz, DMSO-d6) δppm 2.99 (4H, t, J= 4.9 Hz), 3.40-3.56 (2H, m), 3.61 (4H, t, J= 4.5 Hz), 4.33-4.49 (2H, m), 4.50-4.68 (2H, m), 6.90 (1H, td, J= 8.5, 2.7 Hz), 7.22 (1H, dd, J= 10.6, 2.7 Hz), 7.52 (1 H, dd, J= 8.7, 6.1 Hz), 7.65-7.81 (1H, m), 7.81-7.94 (3H, m), 9.23 (2H, br). Example 14
2- (2-Chloro-5-fluorophenoxy) -N- [2- (morpholin-4-ylsulfonyl) benzyl] ethanamine hydrochloride (Step 1) Reference using 2-cyanobenzene-1-sulfonyl chloride and morpholine 1- [2- (morpholin-4-ylsulfonyl) phenyl] methanamine was obtained in the same manner as in Steps 1 and 2 of Example 8 (except for the treatment with a hydrogen chloride / ethyl acetate solution). 1 H-NMR (400 MHz, CDCl 3 ) δppm 2.05 (2H, s), 3.14-3.16 (4H, m), 3.72-3.75 (4H, m), 4.14 (2H, s), 7.41-7.45 (1H, m), 7.58-7.63 (2H, m), 7.88 (1H, d, J = 8.8 Hz).
(Step 2) 1- [2- (morpholin-4-ylsulfonyl) phenyl] methanamine obtained in Step 1 (1.00 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (1.13 g) and potassium carbonate (1.23 g) were stirred in an ethanol (10 mL) solution at 90 ° C. overnight. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was distilled off under reduced pressure, and then crystallized from methanol and ethyl acetate to obtain the title compound (0.22 g). 1 H NMR (300 MHz, DMSO-d 6 ) δppm 2.99 (4H, t, J = 4.9 Hz), 3.40-3.56 (2H, m), 3.61 (4H, t, J = 4.5 Hz), 4.33-4.49 ( 2H, m), 4.50-4.68 (2H, m), 6.90 (1H, td, J = 8.5, 2.7 Hz), 7.22 (1H, dd, J = 10.6, 2.7 Hz), 7.52 (1 H, dd, J = 8.7, 6.1 Hz), 7.65-7.81 (1H, m), 7.81-7.94 (3H, m), 9.23 (2H, br).
実施例１５
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-1-[5-クロロ-2-(メチルスルホニル)フェニル]エタンアミン塩酸塩
　参考例９で得られた1-[5-クロロ-2-(メチルスルホニル)フェニル]エタンアミン塩酸塩（0.23 g）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（0.32 g）と炭酸カリウム（0.35 g）のエタノール（5 mL）溶液を90℃で終夜撹拌した。反応液をろ過した後、溶媒を減圧下留去した。残渣を酢酸エチルと飽和炭酸水素ナトリウム溶液で溶解させ、酢酸エチルで二回抽出した。有機層をあわせ、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥して、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:5～1:1）で精製し、油状物を得た。得られた油状物をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去し、エタノールとＩＰＥより再結晶させ、標題化合物（61 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.69 (3H, d, J= 6.8 Hz), 3.10-3.69 (5H, m), 4.23-4.48 (2H, m), 5.20-5.37 (1H, m), 6.81-6.96 (1H, m), 7.19 (1H, dd, J= 10.5, 2.6 Hz), 7.51 (1H, dd, J= 8.9, 6.2 Hz), 7.81 (1H, dd, J= 8.5, 1.3 Hz), 8.04 (1H, d, J= 8.7 Hz), 8.28 (1H, br), 9.33-9.69 (1H, m), 10.06-10.38 (1H, m). Example 15
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -1- [5-chloro-2- (methylsulfonyl) phenyl] ethanamine hydrochloride 1- [5-Chloro-] obtained in Reference Example 9 2- (Methylsulfonyl) phenyl] ethanamine hydrochloride (0.23 g), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.32 g) and potassium carbonate (0.35 g) in ethanol (5 mL) The solution was stirred at 90 ° C. overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was dissolved with ethyl acetate and saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 5 to 1: 1) to give an oil. The obtained oil was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was distilled off under reduced pressure and recrystallized from ethanol and IPE to obtain the title compound (61 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.69 (3H, d, J = 6.8 Hz), 3.10-3.69 (5H, m), 4.23-4.48 (2H, m), 5.20-5.37 (1H, m), 6.81-6.96 (1H, m), 7.19 (1H, dd, J = 10.5, 2.6 Hz), 7.51 (1H, dd, J = 8.9, 6.2 Hz), 7.81 (1H, dd, J = 8.5, 1.3 Hz), 8.04 (1H, d, J = 8.7 Hz), 8.28 (1H, br), 9.33-9.69 (1H, m), 10.06-10.38 (1H, m).
実施例１６
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N-メチルベンゼンスルホンアミド
　2-(アミノメチル)-N-メチルベンゼンスルホンアミド塩酸塩（0.30 g）（Journal of the American Chemical Society, 1960, 82(7), 1594-1596）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（0.42 g）及び炭酸カリウム（0.46 g）をエタノール（10 mL）溶液中90℃で終夜撹拌した。反応液をセライトを用いてろ過後、溶媒を減圧下留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:0）で精製した。得られた残渣をジエチルエーテルとヘキサンで結晶化させ、標題化合物（0.05 g）を得た。1H-NMR (300 MHz, CDCl3) δ ppm 2.45 (3H, s), 3.14 (2H, t), 4.10 (2H, d, J= 5.3 Hz), 4.30 (2H, s), 6.59-6.72 (2H, m), 7.29 (1H, d, J= 6.8 Hz), 7.40 (1H, d, J= 1.9 Hz), 7.49 (2H, ddd, J= 11.2, 7.4, 1.7 Hz), 8.01 (1H, dd, J= 7.5, 1.5 Hz). Example 16
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -N-methylbenzenesulfonamide 2- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (0.30 g) ( Journal of the American Chemical Society, 1960, 82 (7), 1594-1596), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.42 g) and potassium carbonate (0.46 g) with ethanol ( 10 mL) in solution at 90 ° C. overnight. The reaction mixture was filtered using celite, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 0). The obtained residue was crystallized from diethyl ether and hexane to give the title compound (0.05 g). 1 H-NMR (300 MHz, CDCl 3 ) δ ppm 2.45 (3H, s), 3.14 (2H, t), 4.10 (2H, d, J = 5.3 Hz), 4.30 (2H, s), 6.59-6.72 ( 2H, m), 7.29 (1H, d, J = 6.8 Hz), 7.40 (1H, d, J = 1.9 Hz), 7.49 (2H, ddd, J = 11.2, 7.4, 1.7 Hz), 8.01 (1H, dd , J = 7.5, 1.5 Hz).
実施例１７
2-(2-クロロ-5-フルオロフェノキシ)-N-{[2-(メチルスルホニル)ピリジン-3-イル]メチル}エタンアミン塩酸塩
　参考例１０で得られた2-(2-クロロ-5-フルオロフェノキシ)-N-{[2-(メチルスルファニル)ピリジン-3-イル]メチル}エタンアミン（0.55 g）のＴＨＦ（30 mL）溶液に、二炭酸ジ-t-ブチル（0.48 g）を0℃で加えた。室温で2日間攪拌後、反応溶液を1Ｎ塩酸に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣とオキソン（2.07 g）をＴＨＦ（10 mL）、アセトニトリル（20 mL）及び水（20 mL）の混合溶液中、室温で2日間攪拌した。反応液を炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:2）で精製し、白色固体を得た。得られた固体と4Ｎ塩化水素／酢酸エチル溶液（2 mL）をメタノール（5 mL）中、60℃で1.5時間攪拌した。溶媒を減圧下留去し得られた固体をメタノールと酢酸エチルで再結晶し、標題化合物（0.40 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.47 (3H, s), 3.50 (2H, br), 4.47 (2H, t, J= 5.1 Hz), 4.72 (2H, s), 6.89 (1H, td, J= 8.5, 3.0 Hz), 7.22 (1H, dd, J= 10.7, 2.8 Hz), 7.50 (1H, dd, J= 8.9, 6.2 Hz), 7.86 (1H, dd, J= 7.9, 4.5 Hz), 8.39 (1H, d, J=7.91 Hz) 8.78 (1H, dd, J= 4.9, 1.5 Hz) 9.79 (2H, br). Example 17
2- (2-Chloro-5-fluorophenoxy) -N-{[2- (methylsulfonyl) pyridin-3-yl] methyl} ethanamine hydrochloride 2- (2-chloro-5- To a solution of fluorophenoxy) -N-{[2- (methylsulfanyl) pyridin-3-yl] methyl} ethanamine (0.55 g) in THF (30 mL) was added di-t-butyl dicarbonate (0.48 g) at 0 ° C. Added in. After stirring at room temperature for 2 days, the reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue and oxone (2.07 g) were stirred in a mixed solution of THF (10 mL), acetonitrile (20 mL) and water (20 mL) at room temperature for 2 days. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give a white solid. The obtained solid and 4N hydrogen chloride / ethyl acetate solution (2 mL) were stirred in methanol (5 mL) at 60 ° C. for 1.5 hours. The solvent was distilled off under reduced pressure, and the resulting solid was recrystallized from methanol and ethyl acetate to obtain the title compound (0.40 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.47 (3H, s), 3.50 (2H, br), 4.47 (2H, t, J = 5.1 Hz), 4.72 (2H, s), 6.89 (1H , td, J = 8.5, 3.0 Hz), 7.22 (1H, dd, J = 10.7, 2.8 Hz), 7.50 (1H, dd, J = 8.9, 6.2 Hz), 7.86 (1H, dd, J = 7.9, 4.5 Hz), 8.39 (1H, d, J = 7.91 Hz) 8.78 (1H, dd, J = 4.9, 1.5 Hz) 9.79 (2H, br).
実施例１８
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-2,3-ジヒドロ-1-ベンゾチオフェン-3-アミン 1,1-ジオキシド塩酸塩
　2,3-ジヒドロ-１-ベンゾチオフェン-３-アミン-１,１-ジオキシド塩酸塩（0.30 g）（公開特許文献ＵＳ２６６６７６２）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン（0.46 g）と炭酸カリウム（0.35 g）のエタノール（5 mL）溶液を80℃で終夜撹拌した。反応液をろ過後、溶媒を減圧下留去した。残渣を酢酸エチルと飽和炭酸水素ナトリウム溶液で溶解させ、酢酸エチルで二回抽出した。有機層をあわせ、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥して、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～3:7）で精製し、油状物を得た。得られた油状物をエタノールに溶解させ、4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。溶媒を減圧下留去し、エタノールとＩＰＥで再結晶して、標題化合物（23 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.29-3.45 (1H, m), 3.46-3.62 (1H, m), 3.89-4.10 (1H, m), 4.17-4.34 (1H, m), 4.47 (2H, br), 5.33-5.62 (1H, m), 6.89 (1H, td, J= 8.5, 2.6 Hz), 7.22 (1H, dd, J= 10.9, 2.6 Hz), 7.50 (1H, dd, J= 8.7, 6.0 Hz), 7.69-8.05 (3H, m), 8.09-8.32 (1H, m), 9.60-11.17 (2H, m). Example 18
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide hydrochloride 2,3-dihydro-1-benzothiophene- 3-Amine-1,1-dioxide hydrochloride (0.30 g) (published patent document US2666662), 2- (2-bromoethoxy) -1-chloro-4-fluorobenzene (0.46 g) and potassium carbonate (0.35 g) Of ethanol (5 mL) was stirred at 80 ° C. overnight. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was dissolved with ethyl acetate and saturated sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 3: 7) to give an oil. The obtained oil was dissolved in ethanol, and 4N hydrogen chloride / ethyl acetate solution (1 mL) was added. The solvent was evaporated under reduced pressure and recrystallized from ethanol and IPE to obtain the title compound (23 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.29-3.45 (1H, m), 3.46-3.62 (1H, m), 3.89-4.10 (1H, m), 4.17-4.34 (1H, m), 4.47 (2H, br), 5.33-5.62 (1H, m), 6.89 (1H, td, J = 8.5, 2.6 Hz), 7.22 (1H, dd, J = 10.9, 2.6 Hz), 7.50 (1H, dd, J = 8.7, 6.0 Hz), 7.69-8.05 (3H, m), 8.09-8.32 (1H, m), 9.60-11.17 (2H, m).
実施例１９
2-(2-クロロ-5-フルオロフェノキシ)-N-{2-[2-(メチルスルホニル)フェニル]エチル}エタンアミン
　参考例１１で得られたN-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-2-[2-(メチルスルホニル)フェニル]アセトアミド（1.0 g）のＴＨＦ（50 mL）溶液にＴＨＦ-ボラン錯体（9 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。80℃で4時間攪拌後、反応液に氷を加え、1Ｎ塩酸（30 mL）を加えた。80℃で14時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去し、標題化合物 （80 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 3.03-3.16 (7H, m), 3.21-3.30 (2H, m), 4.10 (2H, t, J= 5.1 Hz), 6.58-6.71 (2H, m), 7.24-7.32 (1H, m), 7.36-7.47 (2H, m), 7.53-7.63 (1H, m), 8.05 (1H, d, J= 7.9 Hz). Example 19
2- (2-Chloro-5-fluorophenoxy) -N- {2- [2- (methylsulfonyl) phenyl] ethyl} ethanamine N- [2- (2-chloro-5-fluoro obtained in Reference Example 11] To a solution of phenoxy) ethyl] -2- [2- (methylsulfonyl) phenyl] acetamide (1.0 g) in THF (50 mL) was added THF-borane complex (9 mL, 1M THF solution) at 0 ° C. After stirring at 80 ° C. for 4 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (30 mL) was added. After stirring at 80 ° C. for 14 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (80 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 3.03-3.16 (7H, m), 3.21-3.30 (2H, m), 4.10 (2H, t, J = 5.1 Hz), 6.58-6.71 (2H, m) , 7.24-7.32 (1H, m), 7.36-7.47 (2H, m), 7.53-7.63 (1H, m), 8.05 (1H, d, J = 7.9 Hz).
実施例２０
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3-[2-(メチルスルホニル)フェニル]プロパン-1-アミン
　参考例１２で得られたN-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3-[2-(メチルスルホニル)フェニル]プロパンアミド（1.0 g）のＴＨＦ（30 mL）溶液にＴＨＦ-ボラン錯体（10 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で5時間攪拌後、反応液に氷を加え、1Ｎ塩酸（20 mL）を加えた。80℃で終夜攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:4）で精製し、標題化合物（50 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.87-2.02 (2H, m), 2.82 (2H, t, J= 6.8 Hz), 3.03-3.16 (7H, m), 4.11 (2H, t, J= 5.1 Hz), 6.57-6.73 (2H, m), 7.27-7.32 (1H, m), 7.34-7.45 (2H, m), 7.51-7.60 (1H, m), 7.99-8.08 (1H, m). Example 20
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3- [2- (methylsulfonyl) phenyl] propan-1-amine N- [2- (2-chloro] obtained in Reference Example 12 -5-Fluorophenoxy) ethyl] -3- [2- (methylsulfonyl) phenyl] propanamide (1.0 g) in THF (30 mL) was added THF-borane complex (10 mL, 1M THF solution) at 0 ° C. added. After stirring at 70 ° C. for 5 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (20 mL) was added. After stirring at 80 ° C. overnight, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (50 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.87-2.02 (2H, m), 2.82 (2H, t, J = 6.8 Hz), 3.03-3.16 (7H, m), 4.11 (2H, t, J = 5.1 Hz), 6.57-6.73 (2H, m), 7.27-7.32 (1H, m), 7.34-7.45 (2H, m), 7.51-7.60 (1H, m), 7.99-8.08 (1H, m).
実施例２１
N-[2-(2,5-ジフルオロフェノキシ)エチル]-2,3-ジヒドロ-1-ベンゾチオフェン-3-アミン 1,1-ジオキシド塩酸塩
　参考例１３で得られた2-(2,5-ジフルオロフェノキシ)-N-(1,1-ジオキシド-2,3-ジヒドロ-1-ベンゾチオフェン-3-イル)アセトアミド（0.19 g）のＴＨＦ（3 mL）溶液にＴＨＦ-ボラン錯体（1.6 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.15 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.24-3.41 (1H, m), 3.43-3.58 (1H, m), 3.85-4.05 (1H, m), 4.12-4.26 (1H, m), 4.30-4.54 (2H, m), 5.29-5.63 (1H, m), 6.75-6.91 (1H, m), 7.12-7.37 (2H, m), 7.64-7.99 (3H, m), 8.04-8.28 (1H, m), 9.60-10.68 (2H, m). Example 21
N- [2- (2,5-difluorophenoxy) ethyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide hydrochloride 2- (2,5 obtained in Reference Example 13 -Difluorophenoxy) -N- (1,1-dioxide-2,3-dihydro-1-benzothiophen-3-yl) acetamide (0.19 g) in THF (3 mL) in THF-borane complex (1.6 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the resulting residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.15 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.24-3.41 (1H, m), 3.43-3.58 (1H, m), 3.85-4.05 (1H, m), 4.12-4.26 (1H, m), 4.30-4.54 (2H, m), 5.29-5.63 (1H, m), 6.75-6.91 (1H, m), 7.12-7.37 (2H, m), 7.64-7.99 (3H, m), 8.04-8.28 (1H , m), 9.60-10.68 (2H, m).
実施例２２
N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例１４で得られた2-(2,5-ジフルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド（0.48 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（3.9 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.38 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.67-2.95 (2H, m), 3.46-3.58 (2H, m), 3.59-3.74 (1H, m), 3.82-4.01 (1H, m), 4.32-4.51 (2H, m), 4.83-5.01 (1H, m), 6.76-6.91 (1H, m), 7.15-7.38 (2H, m), 7.65-7.82 (2H, m), 7.84-8.03 (2H, m), 9.47-9.95 (2H, m). Example 22
N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2,5- To a solution of difluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (0.48 g) in THF (5 mL) was added THF-borane complex (3.9 mL, 1M THF). Solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.38 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.67-2.95 (2H, m), 3.46-3.58 (2H, m), 3.59-3.74 (1H, m), 3.82-4.01 (1H, m), 4.32-4.51 (2H, m), 4.83-5.01 (1H, m), 6.76-6.91 (1H, m), 7.15-7.38 (2H, m), 7.65-7.82 (2H, m), 7.84-8.03 (2H , m), 9.47-9.95 (2H, m).
実施例２３
6-クロロ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例１５で得られたN-(6-クロロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（0.51 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（3.8 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.44 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.66-2.94 (2H, m), 3.49-3.60 (2H, m), 3.61-3.75 (1H, m), 3.86-4.03 (1H, m), 4.35-4.53 (2H, m), 4.83-5.00 (1H, m), 6.84 (1H, tt, J= 8.5, 3.2 Hz), 7.16-7.38 (2H, m), 7.75-7.85 (1H, m), 7.95 (1H, d, J= 8.3 Hz), 8.05-8.20 (1H, m), 9.62-10.08 (2H, m). Example 23
6-chloro-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride N- (obtained in Reference Example 15 6-Chloro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (0.51 g) in THF (5 mL) was added THF- Borane complex (3.8 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.44 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.66-2.94 (2H, m), 3.49-3.60 (2H, m), 3.61-3.75 (1H, m), 3.86-4.03 (1H, m), 4.35-4.53 (2H, m), 4.83-5.00 (1H, m), 6.84 (1H, tt, J = 8.5, 3.2 Hz), 7.16-7.38 (2H, m), 7.75-7.85 (1H, m), 7.95 (1H, d, J = 8.3 Hz), 8.05-8.20 (1H, m), 9.62-10.08 (2H, m).
実施例２４
N-[2-(2-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例１６で得られたN-(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2-フルオロフェノキシ)アセトアミド（0.71 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（6.1 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.46 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.67-2.98 (2H, m), 3.39-3.57 (2H, m), 3.59-3.76 (1H, m), 3.84-4.03 (1H, m), 4.33-4.51 (2H, m), 4.84-5.03 (1H, m), 6.93-7.06 (1H, m), 7.11-7.32 (3H, m), 7.66-7.83 (2H, m), 7.88-8.07 (2H, m), 9.70-10.15 (2H, m). Example 24
N- [2- (2-Fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride N- (1,1-dioxide- obtained in Reference Example 16 Add THF-borane complex (6.1 mL, 1M THF solution) to a solution of 3,4-dihydro-2H-thiochromen-4-yl) -2- (2-fluorophenoxy) acetamide (0.71 g) in THF (5 mL). Added at ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the obtained crystal was collected by filtration and recrystallized from ethanol and IPE to obtain the title compound (0.46 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.67-2.98 (2H, m), 3.39-3.57 (2H, m), 3.59-3.76 (1H, m), 3.84-4.03 (1H, m), 4.33-4.51 (2H, m), 4.84-5.03 (1H, m), 6.93-7.06 (1H, m), 7.11-7.32 (3H, m), 7.66-7.83 (2H, m), 7.88-8.07 (2H , m), 9.70-10.15 (2H, m).
実施例２５
6-クロロ-N-[2-(2-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例１７で得られたN-(6-クロロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2-フルオロフェノキシ)アセトアミド（0.56 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（4.4 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.46 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.67-2.96 (2H, m), 3.47-3.75 (3H, m), 3.85-4.01 (1H, m), 4.30-4.48 (2H, m), 4.80-5.00 (1H, m), 6.94-7.06 (1H, m), 7.12-7.32 (3H, m), 7.73-7.85 (1H, m), 7.89-8.00 (1H, m), 8.03-8.17 (1H, m), 9.44-9.98 (2H, m). Example 25
6-Chloro-N- [2- (2-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride N- (6- Chloro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2-fluorophenoxy) acetamide (0.56 g) in THF (5 mL) solution in THF-borane complex (4.4 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the obtained crystal was collected by filtration and recrystallized from ethanol and IPE to obtain the title compound (0.46 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.67-2.96 (2H, m), 3.47-3.75 (3H, m), 3.85-4.01 (1H, m), 4.30-4.48 (2H, m), 4.80-5.00 (1H, m), 6.94-7.06 (1H, m), 7.12-7.32 (3H, m), 7.73-7.85 (1H, m), 7.89-8.00 (1H, m), 8.03-8.17 (1H , m), 9.44-9.98 (2H, m).
実施例２６
N-[2-(2-フルオロフェノキシ)エチル]-2,3-ジヒドロ-1-ベンゾチオフェン-3-アミン 1,1-ジオキシド塩酸塩
　参考例１８で得られたN-(1,1-ジオキシド-2,3-ジヒドロ-1-ベンゾチオフェン-3-イル)-2-(2-フルオロフェノキシ)アセトアミド（0.60 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（5.4 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.42 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 3.25-3.42 (1H, m), 3.52 (1H, dd, J= 9.2, 4.0 Hz), 3.90-4.09 (1H, m), 4.12-4.30 (1H, m), 4.34-4.56 (2H, m), 5.31-5.60 (1H, m), 6.94-7.07 (1H, m), 7.10-7.33 (3H, m), 7.72-7.82 (1H, m), 7.83-7.99 (2H, m), 8.14-8.37 (1H, m), 9.80-10.98 (2H, m). Example 26
N- [2- (2-Fluorophenoxy) ethyl] -2,3-dihydro-1-benzothiophen-3-amine 1,1-dioxide hydrochloride N- (1,1-dioxide obtained in Reference Example 18 -2,3-dihydro-1-benzothiophen-3-yl) -2- (2-fluorophenoxy) acetamide (0.60 g) in THF (5 mL) and THF-borane complex (5.4 mL, 1M in THF) Was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the obtained crystal was collected by filtration and recrystallized from ethanol and IPE to obtain the title compound (0.42 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 3.25-3.42 (1H, m), 3.52 (1H, dd, J = 9.2, 4.0 Hz), 3.90-4.09 (1H, m), 4.12-4.30 ( 1H, m), 4.34-4.56 (2H, m), 5.31-5.60 (1H, m), 6.94-7.07 (1H, m), 7.10-7.33 (3H, m), 7.72-7.82 (1H, m), 7.83-7.99 (2H, m), 8.14-8.37 (1H, m), 9.80-10.98 (2H, m).
実施例２７
N-[2-(2,5-ジフルオロフェノキシ)エチル]-1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩
　参考例１９で得られた2-(2,5-ジフルオロフェノキシ)-N-{1-[2-(メチルスルホニル)フェニル]エチル}アセトアミド（0.35 g）のＴＨＦ溶液（5 mL）にＴＨＦ-ボラン錯体（2.9 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.38 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.96 (3H, d, J= 6.9 Hz), 3.14-3.19 (3H, m), 3.19-3.32 (1H, m), 3.35-3.54 (1H, m), 4.33-4.58 (2H, m), 5.49-5.68 (1H, m), 6.52-6.83 (2H, m), 6.90-7.09 (1H, m), 7.53-7.68 (1H, m), 7.82 (1H, td, J= 7.7, 1.1 Hz), 8.02-8.18 (1H, m), 8.44 (1H, d, J= 7.5 Hz), 9.85-10.11 (1H, m), 10.80-11.03 (1H, m). Example 27
N- [2- (2,5-difluorophenoxy) ethyl] -1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride 2- (2,5-difluorophenoxy) -N— obtained in Reference Example 19 To a THF solution (5 mL) of {1- [2- (methylsulfonyl) phenyl] ethyl} acetamide (0.35 g), a THF-borane complex (2.9 mL, 1M THF solution) was added at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.38 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.96 (3H, d, J = 6.9 Hz), 3.14-3.19 (3H, m), 3.19-3.32 (1H, m), 3.35-3.54 (1H, m), 4.33-4.58 (2H, m), 5.49-5.68 (1H, m), 6.52-6.83 (2H, m), 6.90-7.09 (1H, m), 7.53-7.68 (1H, m), 7.82 ( 1H, td, J = 7.7, 1.1 Hz), 8.02-8.18 (1H, m), 8.44 (1H, d, J = 7.5 Hz), 9.85-10.11 (1H, m), 10.80-11.03 (1H, m) .
実施例２８
N-[2-(2-フルオロフェノキシ)エチル]-1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩
　参考例２０で得られた2-(2-フルオロフェノキシ)-N-{1-[2-(メチルスルホニル)フェニル]エチル}アセトアミド（0.35 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（3 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.39 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.95 (3H, d, J= 6.8 Hz), 3.11-3.33 (4H, m), 3.36-3.53 (1H, m), 4.37-4.57 (2H, m), 5.49-5.71 (1H, m), 6.84-7.15 (4H, m), 7.53-7.67 (1H, m), 7.74-7.87 (1H, m), 8.01-8.15 (1H, m), 8.36-8.52 (1H, m), 9.83-10.09 (1H, m), 10.68-10.89 (1H, m). Example 28
N- [2- (2-fluorophenoxy) ethyl] -1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride 2- (2-fluorophenoxy) -N- {1- [ To a solution of 2- (methylsulfonyl) phenyl] ethyl} acetamide (0.35 g) in THF (5 mL) was added THF-borane complex (3 mL, 1M THF solution) at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the resulting residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.39 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.95 (3H, d, J = 6.8 Hz), 3.11-3.33 (4H, m), 3.36-3.53 (1H, m), 4.37-4.57 (2H, m), 5.49-5.71 (1H, m), 6.84-7.15 (4H, m), 7.53-7.67 (1H, m), 7.74-7.87 (1H, m), 8.01-8.15 (1H, m), 8.36- 8.52 (1H, m), 9.83-10.09 (1H, m), 10.68-10.89 (1H, m).
実施例２９
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-1-[2-(メチルスルホニル)フェニル]エタンアミン塩酸塩
　参考例２１で得られた2-(2-クロロ-5-フルオロフェノキシ)-N-{1-[2-(メチルスルホニル)フェニル]エチル}アセトアミド（0.44 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（3.4 mL, １M ＴＨＦ溶液）を0℃で加えた。70℃で2時間攪拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間攪拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.48 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.97 (3H, d, J= 6.8 Hz), 3.12-3.20 (3H, m), 3.25-3.60 (2H, m), 4.32-4.62 (2H, m), 5.52-5.70 (1H, m), 6.58-6.76 (2H, m), 7.22-7.36 (1H, m), 7.54-7.67 (1H, m), 7.75-7.89 (1H, m), 8.00-8.17 (1H, m), 8.33-8.47 (1H, m), 9.67-9.94 (1H, m), 10.80-11.05 (1H, m). Example 29
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -1- [2- (methylsulfonyl) phenyl] ethanamine hydrochloride 2- (2-chloro-5-fluorophenoxy obtained in Reference Example 21 ) -N- {1- [2- (methylsulfonyl) phenyl] ethyl} acetamide (0.44 g) in THF (5 mL) was added THF-borane complex (3.4 mL, 1M THF solution) at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the obtained crystal was collected by filtration and recrystallized from ethanol and IPE to obtain the title compound (0.48 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.97 (3H, d, J = 6.8 Hz), 3.12-3.20 (3H, m), 3.25-3.60 (2H, m), 4.32-4.62 (2H, m), 5.52-5.70 (1H, m), 6.58-6.76 (2H, m), 7.22-7.36 (1H, m), 7.54-7.67 (1H, m), 7.75-7.89 (1H, m), 8.00- 8.17 (1H, m), 8.33-8.47 (1H, m), 9.67-9.94 (1H, m), 10.80-11.05 (1H, m).
　実施例１～２９に記載される化合物は以下の通りである（表３）。表３に示されたfreeはフリー体を示し、Racemateはラセミ体を示す。 The compounds described in Examples 1 to 29 are as follows (Table 3). Free shown in Table 3 indicates a free form, and Racemate indicates a racemate.
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
実施例３０
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)ベンゼンスルホンアミド
　2-(アミノメチル)ベンゼンスルホンアミド（0.30 g）、2-(2-ブロモエトキシ)-1-クロロ-4-フルオロベンゼン(0.43 g)のエタノール（5 mL）溶液を90℃で終夜撹拌した。溶媒を減圧下留去した。残渣を酢酸エチルに溶解させ、酢酸エチルと飽和食塩水で分液した。有機層を硫酸マグネシウムで乾燥して、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～1:0）で精製した。得られた固体を酢酸エチルとヘキサンより結晶化し標題化合物（0.14 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.04 (1H, br), 3.15 (2H, t, J= 4.7 Hz), 3.98-4.10 (2H, m), 4.33 (2H, s), 6.43-6.77 (4H, m), 7.27-7.59 (3H, m), 7.90-8.18 (1H, m)(A NH peak was not observed). Example 30
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) benzenesulfonamide 2- (aminomethyl) benzenesulfonamide (0.30 g), 2- (2-bromoethoxy) -1 A solution of -chloro-4-fluorobenzene (0.43 g) in ethanol (5 mL) was stirred at 90 ° C. overnight. The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and partitioned between ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 0). The obtained solid was crystallized from ethyl acetate and hexane to obtain the title compound (0.14 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.04 (1H, br), 3.15 (2H, t, J = 4.7 Hz), 3.98-4.10 (2H, m), 4.33 (2H, s), 6.43-6.77 (4H, m), 7.27-7.59 (3H, m), 7.90-8.18 (1H, m) (A NH peak was not observed).
実施例３１（工法１）
(４R)-N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
　実施例１２で得られた化合物N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（0.45 ｇ）を酢酸エチルと飽和炭酸水素ナトリウム水溶液で抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をキラルHPLCで光学分割した。保持時間小の画分を減圧下濃縮した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.18 g）を得た。
　キラルHPLC条件
　　カラム：CHIRALCEL　OJ-H　（LA001）　20 mmID × 250 mmL
　　移動相：二酸化炭素／メタノール／アセトニトリル＝ 850／ 75／ 75
　　流速：45 mL／min
　　圧力：100 bar
　　温度：30℃
　　検出法：UV220 nm
　　濃度：2.5 mg／ mL (メタノール／アセトニトリル)
1H-NMR (300 MHz, DMSO-d6) δppm 2.69-2.96 (2H, m), 3.62-3.76 (2H, m), 3.80-4.00 (2H, m), 4.35-4.53 (2H, m), 4.85-5.05 (1H, m), 6.89 (1H, td, J= 8.5, 2.7 Hz), 7.22 (1H, dd, J= 10.6, 2.7 Hz), 7.52 (1H, dd, J= 8.7, 6.1 Hz), 7.66-7.83 (2H, m), 7.87-8.03 (2H, m), 9.44-10.04 (2H, m).
［α］Ｄ ２５　＋６．４°（ｃ　0.38，ＭｅＯＨ）． Example 31 (Method 1)
(4R) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Compound obtained in Example 12 N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (0.45 g) with ethyl acetate and saturated sodium bicarbonate Extract with aqueous solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was optically resolved by chiral HPLC. The fraction with a short retention time was concentrated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the resulting residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.18 g).
Chiral HPLC conditions Column: CHIRALCEL OJ-H (LA001) 20 mmID × 250 mmL
Mobile phase: carbon dioxide / methanol / acetonitrile = 850/75/75
Flow rate: 45 mL / min
Pressure: 100 bar
Temperature: 30 ° C
Detection method: UV220 nm
Concentration: 2.5 mg / mL (methanol / acetonitrile)
1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.69-2.96 (2H, m), 3.62-3.76 (2H, m), 3.80-4.00 (2H, m), 4.35-4.53 (2H, m), 4.85-5.05 (1H, m), 6.89 (1H, td, J = 8.5, 2.7 Hz), 7.22 (1H, dd, J = 10.6, 2.7 Hz), 7.52 (1H, dd, J = 8.7, 6.1 Hz) , 7.66-7.83 (2H, m), 7.87-8.03 (2H, m), 9.44-10.04 (2H, m).
[Α] D 25 + 6.4 ° (c 0.38, MeOH).
実施例３１（工法２）
(４R)-N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
（工程１）ＴＨＦ（5 mL）溶媒中、2,3-ジヒドロ-4H-チオクロメン-4-オン（0.82 g）、チタン(IV) エトキシド（2.1 mL）および(R)-(+)-2-メチル-2-プロパンスルフィンアミド（0.61 g）を60℃で14時間撹拌した。反応溶液を-78℃に冷却した後、水素化ナトリウム（0.38 g）のＴＨＦ（10 mL）混合物を加えた。室温で24時間撹拌した後、反応溶液を水に注いだ。反応溶液を水酸化ナトリウム水溶液でアルカリ性とした後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:3）で精製して、N-[(4R)-3,4-ジヒドロ-2H-チオクロメン-4-イル]-2-メチルプロパン-2-スルフィンアミド（0.68 g）を針状結晶として得た。1H-NMR (300 M Hz, CDCl3) δppm 1.22 (9H, s), 1.97-2.09 (1H, m), 2.40-2.50 (1H, m), 2.78-2.85 (1H, m), 3.16 (1H, br), 3.28 (1H, dt, J= 12.6, 2.7 Hz), 4.64 (1H, q, J= 3.1 Hz), 7.03-7.18 (3H, m), 7.25-7.34 (1H, m). 
（工程２）工程１で得られたN-[(4R)-3,4-ジヒドロ-2H-チオクロメン-4-イル]-2-メチルプロパン-2-スルフィンアミド（0.34 g）のメタノール（5 mL）溶液に2Ｎ塩化水素／2-プロパノール溶液（10 mL）を加え、室温で2時間撹拌した。反応溶液を減圧下濃縮して、(4R)-3,4-ジヒドロ-2H-チオクロメン-4-アミン塩酸塩（0.25 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.12-2.30 (1H, m), 2.40-2.60 (1H, m), 3.00-3.10 (1H, m), 3.15-3.30 (1H, m), 4.52 (1H, t, J= 4.5 Hz), 7.09-7.27 (3H, m), 7.50 (1H, d, J= 6.9 Hz), 8.59 (3H, br).
（工程３）工程２で得られた(4R)-3,4-ジヒドロ-2H-チオクロメン-4-アミン塩酸塩（0.20 g)とＥｔ３Ｎ(0.28 mL)のアセトニトリル（10 mL）溶液に二炭酸ジ-t-ブチル(0.33 g)を室温で加えた。14時間撹拌後、反応溶液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:3）で精製して(4R)-3,4-ジヒドロ-2H-チオクロメン-4-イルカルバミン酸 tert-ブチル（0.26 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.47 (9H, s), 2.04-2.15 (1H, m)、2.30-2.45 (1H, m), 2.90-3.01 (1H, m), 3.05-3.14 (1H, m), 4.75-4.90 (2H, m), 7.00-7.15 (3H, m), 7.25-7.30 (1H, m).
（工程４）工程３で得られた(4R)-3,4-ジヒドロ-2H-チオクロメン-4-イルカルバミン酸 tert-ブチル（2.96 g）を酢酸エチル（30 mL）に溶解させ、m-クロロ過安息香酸(5.52 g)を室温で加えた。同温で2時間撹拌後、反応液をチオ硫酸ナトリウム水溶液、炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:9～1:3）で精製して、[(4R)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバミン酸 tert-ブチル（2.91 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.50 (9H, s), 2.55-2.80 (2H, m), 3.34-3.45 (1H, m), 3.45-3.60 (1H, m), 4.85-5.00 (1H, m), 5.00-5.10 (1H, m)，7.44-7.60 (3H, m), 7.89-7.92 (1H, m). 
（工程５）工程４で得られた[(4R)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバミン酸 tert-ブチル（2.85 g）に4Ｎ塩化水素／酢酸エチル溶液（20 mL）を加え、室温で8時間撹拌した。溶媒を減圧下留去して、(4R)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩（2.03 g）を得た。
［α］Ｄ ２５　－５．３°（ｃ　0.25，ＭｅＯＨ）．
（工程６）工程５で得られた(4R)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩(0.60 g)、(2-クロロ-5-フルオロフェノキシ)酢酸(0.63 g)、ＷＳＣ(0.99 g)、ＨＯＢｔ(0.59 g)及びＥｔ３Ｎ(0.36 mL)のアセトニトリル(15 mL)－N,N’-ジメチルアセトアミド（5 mL）混合溶液を室温で14時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～1:1）で精製して、2-(2-クロロ-5-フルオロフェノキシ)-N-[(4R)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]アセトアミド (0.88 g)を得た。
［α］Ｄ ２５　＋３８．９°（ｃ　0.27，ＭｅＯＨ）．
（工程７）工程６で得られた2-(2-クロロ-5-フルオロフェノキシ)-N-[(4R)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]アセトアミド(0.53 g)のＴＨＦ（12 mL）溶液にＴＨＦ-ボラン錯体（4.2 mL, １Ｍ ＴＨＦ溶液）を5℃で加えた。80℃で2時間撹拌後、反応液に氷を加え、1Ｎ塩酸（8.4 mL）を加えた。80℃で2時間撹拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～1:1）で精製した。得られた生成物に4Ｎ塩化水素／酢酸エチル溶液（0.35 mL）を加え、溶媒を減圧下留去して標題化合物(0.48 g)を得た。各種物性スペクトルを比較して、実施例３１（工法１）と同一物質であることを確認した。 Example 31 (Method 2)
(4R) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) THF (5 mL ) 2,3-dihydro-4H-thiochromen-4-one (0.82 g), titanium (IV) ethoxide (2.1 mL) and (R)-(+)-2-methyl-2-propanesulfinamide ( 0.61 g) was stirred at 60 ° C. for 14 hours. After the reaction solution was cooled to −78 ° C., a mixture of sodium hydride (0.38 g) in THF (10 mL) was added. After stirring at room temperature for 24 hours, the reaction solution was poured into water. The reaction solution was made alkaline with an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 3) to give N-[(4R) -3,4-dihydro-2H-thiochromen-4-yl]- 2-Methylpropane-2-sulfinamide (0.68 g) was obtained as needle crystals. 1 H-NMR (300 M Hz, CDCl 3 ) δppm 1.22 (9H, s), 1.97-2.09 (1H, m), 2.40-2.50 (1H, m), 2.78-2.85 (1H, m), 3.16 (1H , br), 3.28 (1H, dt, J = 12.6, 2.7 Hz), 4.64 (1H, q, J = 3.1 Hz), 7.03-7.18 (3H, m), 7.25-7.34 (1H, m).
(Step 2) N-[(4R) -3,4-dihydro-2H-thiochromen-4-yl] -2-methylpropane-2-sulfinamide (0.34 g) obtained in Step 1 in methanol (5 mL ) 2N hydrogen chloride / 2-propanol solution (10 mL) was added to the solution and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain (4R) -3,4-dihydro-2H-thiochromen-4-amine hydrochloride (0.25 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.12-2.30 (1H, m), 2.40-2.60 (1H, m), 3.00-3.10 (1H, m), 3.15-3.30 (1H, m), 4.52 (1H, t, J = 4.5 Hz), 7.09-7.27 (3H, m), 7.50 (1H, d, J = 6.9 Hz), 8.59 (3H, br).
(Step 3) A solution of (4R) -3,4-dihydro-2H-thiochromen-4-amine hydrochloride (0.20 g) obtained in Step 2 and Et 3 N (0.28 mL) in acetonitrile (10 mL) Di-t-butyl carbonate (0.33 g) was added at room temperature. After stirring for 14 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 3) to give tert-butyl (4R) -3,4-dihydro-2H-thiochromen-4-ylcarbamate ( 0.26 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.47 (9H, s), 2.04-2.15 (1H, m), 2.30-2.45 (1H, m), 2.90-3.01 (1H, m), 3.05-3.14 ( 1H, m), 4.75-4.90 (2H, m), 7.00-7.15 (3H, m), 7.25-7.30 (1H, m).
(Step 4) tert-Butyl (4R) -3,4-dihydro-2H-thiochromen-4-ylcarbamate (2.96 g) obtained in Step 3 was dissolved in ethyl acetate (30 mL), and m-chloro Perbenzoic acid (5.52 g) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was washed with an aqueous sodium thiosulfate solution, an aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 3) to give [(4R) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] Tert-butyl carbamate (2.91 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.50 (9H, s), 2.55-2.80 (2H, m), 3.34-3.45 (1H, m), 3.45-3.60 (1H, m), 4.85-5.00 ( 1H, m), 5.00-5.10 (1H, m), 7.44-7.60 (3H, m), 7.89-7.92 (1H, m).
(Step 5) [(4R) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate tert-butyl (2.85 g) obtained in Step 4 was added with 4N hydrogen chloride / acetic acid Ethyl solution (20 mL) was added and stirred at room temperature for 8 hours. The solvent was distilled off under reduced pressure to obtain (4R) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (2.03 g).
[Α] D 25 -5.3 ° (c 0.25, MeOH).
(Step 6) (4R) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (0.60 g), (2-chloro-5-fluorophenoxy) acetic acid obtained in Step 5 (0.63 g), WSC (0.99 g), HOBt (0.59 g), and Et 3 N (0.36 mL) in acetonitrile (15 mL) -N, N′-dimethylacetamide (5 mL) mixed at room temperature for 14 hours. did. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1) to give 2- (2-chloro-5-fluorophenoxy) -N-[(4R) -1,1-dioxide -3,4-Dihydro-2H-thiochromen-4-yl] acetamide (0.88 g) was obtained.
[Α] D 25 + 38.9 ° (c 0.27, MeOH).
(Step 7) 2- (2-Chloro-5-fluorophenoxy) -N-[(4R) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] obtained in Step 6 A THF-borane complex (4.2 mL, 1M THF solution) was added to a solution of acetamide (0.53 g) in THF (12 mL) at 5 ° C. After stirring at 80 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (8.4 mL) was added. After stirring at 80 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7 to 1: 1). A 4N hydrogen chloride / ethyl acetate solution (0.35 mL) was added to the obtained product, and the solvent was evaporated under reduced pressure to obtain the title compound (0.48 g). By comparing various physical property spectra, it was confirmed that it was the same substance as Example 31 (Method 1).
実施例３２
(4S)-N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　実施例３１の工法１で光学分割した保持時間大の画分を減圧下濃縮した。得られた残渣に４Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.17 g）を得た。
1H-NMR (300 MHz, DMSO-d6) δppm 2.67-2.97 (2H, m), 3.34-3.77 (3H, m), 3.83-3.99 (1H, m), 4.35-4.54 (2H, m), 4.86-5.05 (1H, m), 6.90 (1H, td, J= 8.5, 2.7 Hz), 7.22 (1H, dd, J= 10.6, 2.7 Hz), 7.52 (1H, dd, J= 8.7, 6.1 Hz), 7.67-7.83 (2H, m), 7.89-8.02 (2H, m), 9.63-10.02 (2H, m).
［α］Ｄ ２５　－６．４°（ｃ　0.38，ＭｅＯＨ）． Example 32
(4S) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Optically by Method 1 of Example 31 The fraction having a long retention time was concentrated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the resulting residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.17 g).
1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.67-2.97 (2H, m), 3.34-3.77 (3H, m), 3.83-3.99 (1H, m), 4.35-4.54 (2H, m), 4.86-5.05 (1H, m), 6.90 (1H, td, J = 8.5, 2.7 Hz), 7.22 (1H, dd, J = 10.6, 2.7 Hz), 7.52 (1H, dd, J = 8.7, 6.1 Hz) , 7.67-7.83 (2H, m), 7.89-8.02 (2H, m), 9.63-10.02 (2H, m).
[Α] D 25 -6.4 ° (c 0.38, MeOH).
実施例３３
N-[2-(2-メトキシフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例２２の工程３で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2-メトキシフェノキシ)エチル]カルバマート（385 mg）に４Ｎ塩化水素／酢酸エチル溶液（2 mL）を加えた。溶媒を減圧下留去した後、炭酸水素ナトリウム溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:1～3:1）で精製してN-[2-(2-メトキシフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドを得た。N-[2-(2-メトキシフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドに４Ｎ塩化水素／酢酸エチル溶液（1 mL）を加えた。メタノールと酢酸エチルで結晶化させた。得られた結晶をメタノールと酢酸エチルで再結晶して、標題化合物(166 mg)を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.83 (2H, br), 3.42-3.55 (2H, m), 3.61-3.73 (1H, m), 3.78 (3H, s), 3.84-3.98 (1H, m), 4.29 (2H, br), 4.93 (1H, br), 6.87-7.07 (4H, m), 7.67-7.82 (2H, m), 7.92 (2H, br), 9.60 (2H, br). Example 33
N- [2- (2-methoxyphenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl (1,1) obtained in Step 3 of Reference Example 22 To 1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2-methoxyphenoxy) ethyl] carbamate (385 mg) was added 4N hydrogen chloride / ethyl acetate solution (2 mL). The solvent was evaporated under reduced pressure, neutralized with sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1-3: 1) to give N- [2- (2-methoxyphenoxy) ethyl] -3,4-dihydro-2H-thiochromene. 4-Amine 1,1-dioxide was obtained. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to N- [2- (2-methoxyphenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide. Crystallized with methanol and ethyl acetate. The obtained crystals were recrystallized from methanol and ethyl acetate to give the title compound (166 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.83 (2H, br), 3.42-3.55 (2H, m), 3.61-3.73 (1H, m), 3.78 (3H, s), 3.84-3.98 ( 1H, m), 4.29 (2H, br), 4.93 (1H, br), 6.87-7.07 (4H, m), 7.67-7.82 (2H, m), 7.92 (2H, br), 9.60 (2H, br) .
実施例３４
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-1,2-ベンゾチアジン-4-アミン 1,1-ジオキシド
　参考例２３で得られた2-(2-クロロ-5-フルオロフェノキシ)-N-(1,1-ジオキシド-3,4-ジヒドロ-2H-1,2-ベンゾチアジン-4-イル)アセトアミド（0.80 g）のＴＨＦ（20 mL）溶液にＴＨＦ-ボラン錯体（6.2 mL, １Ｍ ＴＨＦ溶液）を加えた。90℃で1.5時間撹拌後、反応液に氷を加え、1Ｎ塩酸（20 mL）を加えた。90℃で2時間撹拌した。反応液に酢酸エチルを加え、分離した水層を水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製した。得られた固体を酢酸エチルとヘキサンで再結晶して標題化合物（0.56 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.54-2.65 (1H, m), 2.85-3.11 (2H, m), 3.51-3.77 (2H, m), 3.85-3.98 (1H, m), 4.14 (2H, t, J= 5.7 Hz), 6.82 (1H, td, J= 8.5, 3.0 Hz), 7.14 (1H, dd, J= 11.0, 2.7 Hz), 7.46 (2H, dd, J= 8.7, 6.4 Hz), 7.51-7.64 (2H, m), 7.64-7.75 (2H, m). Example 34
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-1,2-benzothiazin-4-amine 1,1-dioxide 2- (2) obtained in Reference Example 23 2-Chloro-5-fluorophenoxy) -N- (1,1-dioxide-3,4-dihydro-2H-1,2-benzothiazin-4-yl) acetamide (0.80 g) in THF (20 mL) THF-borane complex (6.2 mL, 1M THF solution) was added. After stirring at 90 ° C. for 1.5 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (20 mL) was added. Stir at 90 ° C. for 2 hours. Ethyl acetate was added to the reaction solution, and the separated aqueous layer was made basic with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography. The obtained solid was recrystallized from ethyl acetate and hexane to obtain the title compound (0.56 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.54-2.65 (1H, m), 2.85-3.11 (2H, m), 3.51-3.77 (2H, m), 3.85-3.98 (1H, m), 4.14 (2H, t, J = 5.7 Hz), 6.82 (1H, td, J = 8.5, 3.0 Hz), 7.14 (1H, dd, J = 11.0, 2.7 Hz), 7.46 (2H, dd, J = 8.7, 6.4 Hz), 7.51-7.64 (2H, m), 7.64-7.75 (2H, m).
実施例３５
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチル-4-モルホリン-4-イルベンゼンスルホンアミド二臭化水素酸塩
（工程１）参考例２４で得られたtert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2-クロロ-5-フルオロフェノキシ)エチル]カルバマート（150 mg）、ジシクロヘキシル[2',4',6'-トリス(1-メチルエチル)ビフェニル-2-イル]ホスファン（12.6 mg）、ナトリウム t-ブトキシド（28.0 mg）、モルホリン（0.025 mL）、Pd2(dba)3（12.1 mg）のトルエン（3 mL）溶液を100℃で3時間撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製してtert-ブチル [2-(2-クロロ-5-フルオロフェノキシ)エチル][2-(ジメチルスルファモイル)-5-モルホリン-4-イルベンジル]カルバマート（115 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.38 (5H, s), 1.51 (4H, s), 2.73 (6H, s), 3.07-3.29 (4H, m), 3.63-3.86 (6H, m), 3.92-4.24 (2H, m), 4.94 (2H, s), 6.37-6.99 (4H, m), 7.27 (1H, s), 7.65-7.94 (1H, m).
（工程２）工程１で得られたtert-ブチル [2-(2-クロロ-5-フルオロフェノキシ)エチル][2-(ジメチルスルファモイル)-5-モルホリン-4-イルベンジル]カルバマート（110 mg）に4Ｎ塩化水素／酢酸エチル溶液（3 mL）を加え、室温で3時間撹拌した。反応溶液に1Ｎ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた油状物をメタノールに溶解させ、２Ｎ臭化水素／メタノール溶液（1 mL）を加えた。溶媒を減圧下留去し、得られた固体をろ取、メタノール－酢酸エチルで再結晶して、標題化合物（32 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.62 (6H, s), 3.31-3.38 (4H, m), 3.41-3.59 (2H, m), 3.69-3.79 (4H, m), 4.41 (2H, t, J= 4.3 Hz), 4.47-4.64 (2H, m), 6.90 (1H, td, J= 8.5, 2.6 Hz), 7.06-7.33 (3H, m), 7.51 (1H, dd, J= 8.7, 6.0 Hz), 7.69 (1H, d, J= 9.0 Hz), 8.95 (2H, br). Example 35
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethyl-4-morpholin-4-ylbenzenesulfonamide dihydrobromide (Step 1) Tert-Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (150 mg) obtained in Reference Example 24, dicyclohexyl [2 ′ , 4 ', 6'-Tris (1-methylethyl) biphenyl-2-yl] phosphane (12.6 mg), sodium t-butoxide (28.0 mg), morpholine (0.025 mL), Pd 2 (dba) 3 (12.1 mg ) In toluene (3 mL) was stirred at 100 ° C. for 3 hours. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-morpholine-4 -Ilbenzyl] carbamate (115 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.38 (5H, s), 1.51 (4H, s), 2.73 (6H, s), 3.07-3.29 (4H, m), 3.63-3.86 (6H, m) , 3.92-4.24 (2H, m), 4.94 (2H, s), 6.37-6.99 (4H, m), 7.27 (1H, s), 7.65-7.94 (1H, m).
(Step 2) tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-morpholin-4-ylbenzyl] carbamate (110 mg) obtained in Step 1 ) Was added 4N hydrogen chloride / ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained oil was dissolved in methanol, and 2N hydrogen bromide / methanol solution (1 mL) was added. The solvent was evaporated under reduced pressure, and the resulting solid was collected by filtration and recrystallized from methanol-ethyl acetate to give the title compound (32 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.62 (6H, s), 3.31-3.38 (4H, m), 3.41-3.59 (2H, m), 3.69-3.79 (4H, m), 4.41 ( 2H, t, J = 4.3 Hz), 4.47-4.64 (2H, m), 6.90 (1H, td, J = 8.5, 2.6 Hz), 7.06-7.33 (3H, m), 7.51 (1H, dd, J = 8.7, 6.0 Hz), 7.69 (1H, d, J = 9.0 Hz), 8.95 (2H, br).
実施例３６
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-4-シアノ-N,N-ジメチルベンゼンスルホンアミド塩酸塩
（工程１）参考例２４で得られたtert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2-クロロ-5-フルオロフェノキシ)エチル]カルバマート（150 mg）、テトラキス（トリフェニルホスフィン）パラジウム（Pd(PPh3)4）（30.6 mg）、シアン化亜鉛（34.2 mg）のＤＭＦ（3 mL）溶液を100℃で3時間撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、tert-ブチル [2-(2-クロロ-5-フルオロフェノキシ)エチル][5-シアノ-2-(ジメチルスルファモイル)ベンジル]カルバマート（125 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.29 (5H, s), 1.52 (4H, s), 2.85 (6H, s), 3.65-3.88 (2H, m), 4.03-4.30 (2H, m), 5.03 (2H, s), 6.60-6.72 (2H, m), 7.20-7.38 (1H, m), 7.56-7.77 (2H, m), 7.97 (1H, d, J= 8.3 Hz).
（工程２）工程１で得られたtert-ブチル [2-(2-クロロ-5-フルオロフェノキシ)エチル][5-シアノ-2-(ジメチルスルファモイル)ベンジル]カルバマート（120 mg）に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、室温で5時間撹拌した。溶媒を減圧下留去し、得られた固体をメタノールと酢酸エチルで再結晶して標題化合物（81.0 mg）を得た。
1H-NMR (300 MHz, DMSO-d6) δppm 2.78 (6H, s), 3.43-3.60 (2H, m), 4.33-4.50 (2H, m), 4.55-4.71 (2H, m), 6.90 (1H, td, J= 8.5, 3.0 Hz), 7.22 (1H, dd, J= 10.7, 2.8 Hz), 7.51 (1H, dd, J= 8.7, 6.0 Hz), 8.03 (1H, d, J= 7.9 Hz), 8.12-8.26 (1H, m), 8.34 (1H, s), 9.34 (2H, br). Example 36
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -4-cyano-N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) tert obtained in Reference Example 24 -Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (150 mg), tetrakis (triphenylphosphine) palladium (Pd (PPh 3 4 ) (30.6 mg) and a solution of zinc cyanide (34.2 mg) in DMF (3 mL) were stirred at 100 ° C. for 3 hours. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [5-cyano-2- (dimethylsulfamoyl) benzyl]. Carbamate (125 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.29 (5H, s), 1.52 (4H, s), 2.85 (6H, s), 3.65-3.88 (2H, m), 4.03-4.30 (2H, m) , 5.03 (2H, s), 6.60-6.72 (2H, m), 7.20-7.38 (1H, m), 7.56-7.77 (2H, m), 7.97 (1H, d, J = 8.3 Hz).
(Step 2) To the tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [5-cyano-2- (dimethylsulfamoyl) benzyl] carbamate (120 mg) obtained in Step 1, 4N A hydrogen chloride / ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from methanol and ethyl acetate to obtain the title compound (81.0 mg).
1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.78 (6H, s), 3.43-3.60 (2H, m), 4.33-4.50 (2H, m), 4.55-4.71 (2H, m), 6.90 ( 1H, td, J = 8.5, 3.0 Hz), 7.22 (1H, dd, J = 10.7, 2.8 Hz), 7.51 (1H, dd, J = 8.7, 6.0 Hz), 8.03 (1H, d, J = 7.9 Hz) ), 8.12-8.26 (1H, m), 8.34 (1H, s), 9.34 (2H, br).
実施例３７
2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-4-メトキシ-N,N-ジメチルベンゼンスルホンアミド塩酸塩
（工程１）参考例２４で得られたtert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2-クロロ-5-フルオロフェノキシ)エチル]カルバマート（150 mg）、Pd2(dba)3（4.85 mg）、2,2'-ビス（ジフェニルホスフィノ）-1,1'-ビナフチル（6.60 mg）、ナトリウムメトキシド（15.8 mg）のトルエン（3 mL）溶液を100℃で3時間撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、tert-ブチル [2-(2-クロロ-5-フルオロフェノキシ)エチル][2-(ジメチルスルファモイル)-5-メトキシベンジル]カルバマート（50.0 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.38 (5H, s), 1.51 (4H, s), 2.75 (6H, s), 3.60-3.77 (2H, m), 3.80 (3H, s), 3.96-4.28 (2H, m), 4.87-5.05 (2H, m), 6.50-6.73 (2H, m), 6.74-6.98 (2H, m), 7.11-7.39 (1H, m), 7.75-7.96 (1H, m).
（工程２）工程１で得られたtert-ブチル [2-(2-クロロ-5-フルオロフェノキシ)エチル][2-(ジメチルスルファモイル)-5-メトキシベンジル]カルバマート（50 mg）に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、室温で5時間撹拌した。溶媒を減圧下留去し、固体をろ取、酢酸エチルで洗浄した。得られた固体をメタノールと酢酸エチルで再結晶して標題化合物（45 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.66 (6H, s), 3.42-3.63 (2H, m), 3.90 (3H, s), 4.34-4.51 (2H, m), 4.51-4.67 (2H, m), 6.76-7.00 (1H, m), 7.13-7.32 (2H, m), 7.38-7.62 (2H, m), 7.83 (1H, d, J= 8.7 Hz), 9.35 (2H, br). Example 37
2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -4-methoxy-N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) tert obtained in Reference Example 24 -Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2-chloro-5-fluorophenoxy) ethyl] carbamate (150 mg), Pd 2 (dba) 3 (4.85 mg), 2 , 2′-bis (diphenylphosphino) -1,1′-binaphthyl (6.60 mg) and sodium methoxide (15.8 mg) in toluene (3 mL) were stirred at 100 ° C. for 3 hours. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), and tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-methoxybenzyl] Carbamate (50.0 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.38 (5H, s), 1.51 (4H, s), 2.75 (6H, s), 3.60-3.77 (2H, m), 3.80 (3H, s), 3.96 -4.28 (2H, m), 4.87-5.05 (2H, m), 6.50-6.73 (2H, m), 6.74-6.98 (2H, m), 7.11-7.39 (1H, m), 7.75-7.96 (1H, m).
(Step 2) To the tert-butyl [2- (2-chloro-5-fluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-methoxybenzyl] carbamate (50 mg) obtained in Step 1, 4N A hydrogen chloride / ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the solid was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from methanol and ethyl acetate to give the title compound (45 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.66 (6H, s), 3.42-3.63 (2H, m), 3.90 (3H, s), 4.34-4.51 (2H, m), 4.51-4.67 ( 2H, m), 6.76-7.00 (1H, m), 7.13-7.32 (2H, m), 7.38-7.62 (2H, m), 7.83 (1H, d, J = 8.7 Hz), 9.35 (2H, br) .
実施例３８
N-{2-[2-(メチルスルファニル)フェノキシ]エチル}-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例２５で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル){2-[2-(メチルスルファニル)フェノキシ]エチル}カルバマートに４Ｎ塩化水素／酢酸エチル溶液（2 mL）を加えた。メタノールとジエチルエーテルで結晶化させた。得られた結晶をメタノールとジエチルエーテルで再結晶して、標題化合物（87 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.41 (3H, s), 2.85 (2H, br), 3.54 (2H, br), 3.63-3.75 (1H, m), 3.88-4.00 (1H, m), 4.40 (2H, br), 4.97 (1H, br), 7.04 (2H, dd, J= 7.0, 4.3 Hz), 7.12-7.23 (2H, m), 7.68-7.82 (2H, m), 7.90-8.01 (2H, m), 9.83 (2H, br). Example 38
N- {2- [2- (methylsulfanyl) phenoxy] ethyl} -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl (1,1) obtained in Reference Example 25 1-Dioxide-3,4-dihydro-2H-thiochromen-4-yl) {2- [2- (methylsulfanyl) phenoxy] ethyl} carbamate was added with 4N hydrogen chloride / ethyl acetate solution (2 mL). Crystallized with methanol and diethyl ether. The obtained crystals were recrystallized from methanol and diethyl ether to give the title compound (87 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.41 (3H, s), 2.85 (2H, br), 3.54 (2H, br), 3.63-3.75 (1H, m), 3.88-4.00 (1H, m), 4.40 (2H, br), 4.97 (1H, br), 7.04 (2H, dd, J = 7.0, 4.3 Hz), 7.12-7.23 (2H, m), 7.68-7.82 (2H, m), 7.90 -8.01 (2H, m), 9.83 (2H, br).
実施例３９
N-[2-(2-クロロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例２６で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル){2-[2-クロロフェノキシ]エチル}カルバマートを用いて実施例３８と同様の手法により標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.85 (2H, br), 3.47-3.60 (2H, m), 3.71 (1H, d, J= 7.6 Hz), 3.84-3.99 (1H, m), 4.43 (2H, br), 4.97 (1H, br), 7.02 (1H, t, J= 7.2 Hz), 7.21 (1H, d, J= 7.2 Hz), 7.28-7.42 (1H, m), 7.47 (1H, dd, J= 8.0, 1.5 Hz), 7.75 (2H, quin, J= 7.5 Hz), 7.86-8.05 (2H, m), 9.86 (2H, br). Example 39
N- [2- (2-Chlorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl (1,1-dioxide obtained in Reference Example 26 The title compound was obtained in the same manner as in Example 38 using -3,4-dihydro-2H-thiochromen-4-yl) {2- [2-chlorophenoxy] ethyl} carbamate. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.85 (2H, br), 3.47-3.60 (2H, m), 3.71 (1H, d, J = 7.6 Hz), 3.84-3.99 (1H, m) , 4.43 (2H, br), 4.97 (1H, br), 7.02 (1H, t, J = 7.2 Hz), 7.21 (1H, d, J = 7.2 Hz), 7.28-7.42 (1H, m), 7.47 ( 1H, dd, J = 8.0, 1.5 Hz), 7.75 (2H, quin, J = 7.5 Hz), 7.86-8.05 (2H, m), 9.86 (2H, br).
実施例４０
N-[2-(3-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの0.16 Ｍトルエン－ＴＨＦ（1：1）（500 mL）溶液、トリフェニルホスフィンの0.32 Ｍトルエン－ＴＨＦ（1：1）（500 μL）溶液及び3-フルオロフェノールの0.2 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液を混合し、室温でアゾジカルボン酸ジイソプロピル（30 μL）を添加したのち16時間撹拌した。反応液に、酢酸エチル（3.5 mL）－２％炭酸水素ナトリウム水溶液（1.0 mL）を加えて抽出し、有機層を上層フェーズセップチューブ（和光純薬製）により採取した。溶媒を濃縮して、残渣をＤＭＳＯとメタノール（１：１）（1 mL）に溶かし、中性条件下＊１）分取ＨＰＬＣで精製した。目的分画を集めて濃縮し、残渣に1Ｍ メタンスルホン酸／アセトニトリル（0.5 mL）溶液を加え、室温で16時間撹拌した。反応終了後、1 Ｍジイソプロピルエチルアミン／アセトニトリル（0.5 mL）溶液を加え、酸性条件下＊２）分取ＨＰＬＣで精製して標題化合物（12.2 mg）を得た。ＭＳ（ＥＳＩ＋）：336（Ｍ＋Ｈ－CF3CO2H） Example 40
N- [2- (3-Fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert-butyl (2) obtained in Step 2 of Reference Example 22 1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 mL), 0.32 M in triphenylphosphine Toluene-THF (1: 1) (500 μL) and 3-fluorophenol in 0.2 M toluene-THF (1: 1) (500 μL) are mixed, and diisopropyl azodicarboxylate (30 μL) is added at room temperature After that, the mixture was stirred for 16 hours. Ethyl acetate (3.5 mL) -2% aqueous sodium hydrogen carbonate solution (1.0 mL) was added to the reaction solution for extraction, and the organic layer was collected with an upper phase sep tube (manufactured by Wako Pure Chemical Industries). The solvent was concentrated and the residue was dissolved in DMSO and methanol (1: 1) (1 mL) and purified by preparative HPLC under neutral conditions * 1) . The target fractions were collected and concentrated, and a 1M methanesulfonic acid / acetonitrile (0.5 mL) solution was added to the residue, followed by stirring at room temperature for 16 hours. After completion of the reaction, a 1 M diisopropylethylamine / acetonitrile (0.5 mL) solution was added, and purified by preparative HPLC under acidic conditions * 2 ) to obtain the title compound (12.2 mg). MS (ESI +): 336 ( M + H-CF 3 CO 2 H)
中性条件＊１）
溶媒：Ａ液；１０ｍＭ 重炭酸アンモニウム水溶液、Ｂ液；アセトニトリル
グラジェントサイクル：０．００分（Ａ液/Ｂ液＝９５/５）、１．００分（Ａ液/Ｂ液＝９５/５）、５．２０分（Ａ液/Ｂ液＝０/１００）、６．４０分（Ａ液/Ｂ液＝０/１００）、６．５０分（Ａ液/Ｂ液＝９５/５）、６．６０分（Ａ液/Ｂ液＝９５/５）
流速：２０ｍＬ/ｍｉｎ、検出法：ＵＶ２２０ｎｍ Neutral condition * 1)
Solvent: A solution; 10 mM ammonium bicarbonate aqueous solution, B solution; acetonitrile gradient cycle: 0.00 minutes (A solution / B solution = 95/5), 1.00 minutes (A solution / B solution = 95/5) 5.20 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B liquid = 95/5), 6 60 minutes (A liquid / B liquid = 95/5)
Flow rate: 20 mL / min, detection method: UV 220 nm
酸性条件＊２）
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジェントサイクル：０．００分（Ａ液/Ｂ液＝９５/５）、１．００分（Ａ液/Ｂ液＝９５/５）、５．２０分（Ａ液/Ｂ液＝０/１００）、６．４０分（Ａ液/Ｂ液＝０/１００）、６．５０分（Ａ液/Ｂ液＝９５/５）、６．６０分（Ａ液/Ｂ液＝９５/５）
流速：２０ｍＬ/ｍｉｎ、検出法：ＵＶ２２０ｎｍ Acid condition * 2)
Solvent: A liquid; 0.1% trifluoroacetic acid-containing water, B liquid; 0.1% trifluoroacetic acid-containing acetonitrile gradient cycle: 0.00 minutes (A liquid / B liquid = 95/5), 1.00 Minute (A liquid / B liquid = 95/5), 5.20 minutes (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes ( A liquid / B liquid = 95/5), 6.60 minutes (A liquid / B liquid = 95/5)
Flow rate: 20 mL / min, detection method: UV 220 nm
実施例４１
2-{2-[(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アミノ]エトキシ}ベンゾニトリル　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの0.16 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液及び2-シアノフェノールの0.2 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液を用いて実施例４０と同様の手法により標題化合物（12.5 mg）を得た。ＭＳ（ＥＳＩ＋）：343（Ｍ＋Ｈ－CF3CO2H） Example 41
2- {2-[(1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) amino] ethoxy} benzonitrile trifluoroacetate tert-butyl obtained in Step 2 of Reference Example 22 A solution of (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 μL) and 2-cyanophenol. The title compound (12.5 mg) was obtained in the same manner as in Example 40 using 0.2 M toluene-THF (1: 1) (500 μL) solution. MS (ESI +): 343 ( M + H-CF 3 CO 2 H)
実施例４２
N-{2-[2-(トリフルオロメチル)フェノキシ]エチル}-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの0.16 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液及び2-トリフルオロメチルフェノールの0.2 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液を用いて実施例４０と同様の手法により標題化合物（19.7 mg）を得た。ＭＳ（ＥＳＩ＋）:386（Ｍ＋Ｈ－CF3CO2H） Example 42
N- {2- [2- (trifluoromethyl) phenoxy] ethyl} -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate obtained in Step 2 of Reference Example 22 A solution of tert-butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 μL) and 2- The title compound (19.7 mg) was obtained in the same manner as in Example 40 using 0.2 M toluene-THF (1: 1) (500 μL) solution of trifluoromethylphenol. MS (ESI +): 386 ( M + H-CF 3 CO 2 H)
実施例４３
N-[2-(2-メチルフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの０．１６Mトルエン－THF（１：１）（500 μL）溶液及びo-クレゾールの0.2 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液を用いて実施例４０と同様の手法により標題化合物（7.3 mg）を得た。ＭＳ（ＥＳＩ＋）：332（Ｍ＋Ｈ－CF3CO2H） Example 43
N- [2- (2-methylphenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert-butyl (2) obtained in Step 2 of Reference Example 22 1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 μL) and 0.2 of o-cresol The title compound (7.3 mg) was obtained in the same manner as in Example 40 using M toluene-THF (1: 1) (500 μL) solution. MS (ESI +): 332 ( M + H-CF 3 CO 2 H)
実施例４４
N-{2-[2-(ベンジルオキシ)フェノキシ]エチル}-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの0.16 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液及び2-(ベンジルオキシ)フェノールの0.2 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液を用いて実施例４０と同様の手法により標題化合物（14.6 mg）を得た。ＭＳ（ＥＳＩ＋）：424（Ｍ＋Ｈ－CF3CO2H） Example 44
N- {2- [2- (benzyloxy) phenoxy] ethyl} -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert obtained in Step 2 of Reference Example 22 -Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 μL) and 2- ( The title compound (14.6 mg) was obtained in the same manner as in Example 40 using 0.2 M toluene-THF (1: 1) (500 μL) solution of (benzyloxy) phenol. MS (ESI +): 424 ( M + H-CF 3 CO 2 H)
実施例４５
N-[2-(1H-インドール-4-イルオキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの0.16 Ｍトルエン－ＴＨＦ（１：１）溶液（500 μL）及び1H-インドール-4-オールの0.2 Ｍトルエン－ＴＨＦ（１：１）溶液（500 μL）を用いて実施例４０と同様の手法により標題化合物（11 mg）を得た。ＭＳ（ＥＳＩ＋）：357（Ｍ＋Ｈ－CF3CO2H） Example 45
N- [2- (1H-Indol-4-yloxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate tert obtained in Step 2 of Reference Example 22 -Butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 μL) and 1H-indole The title compound (11 mg) was obtained in the same manner as in Example 40 using 4-ol 4-M toluene-THF (1: 1) solution (500 μL). MS (ESI +): 357 ( M + H-CF 3 CO 2 H)
実施例４６
N-[2-(2,4,5-トリフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド　トリフルオロ酢酸塩
　参考例２２の工程２で得られたtert-ブチル (1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)(2-ヒドロキシエチル)カルバマートの0.16 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液及び2,4,5-トリフルオロフェノールの0.2 Ｍトルエン－ＴＨＦ（１：１）（500 μL）溶液を用いて実施例４０と同様の手法により標題化合物（19.8 mg）を得た。ＭＳ（ＥＳＩ＋）：372（Ｍ＋Ｈ－CF3CO2H） Example 46
N- [2- (2,4,5-trifluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide trifluoroacetate salt obtained in Step 2 of Reference Example 22. Tert-butyl (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) (2-hydroxyethyl) carbamate in 0.16 M toluene-THF (1: 1) (500 μL) and 2 , 4,5-trifluorophenol in 0.2 M toluene-THF (1: 1) (500 μL) was used to give the title compound (19.8 mg) in the same manner as in Example 40. MS (ESI +): 372 ( M + H-CF 3 CO 2 H)
実施例４７
N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-6-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
　参考例２７で得られた2-(2-クロロ-5-フルオロフェノキシ)-N-(6-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド（0.45 g）のＴＨＦ（5 mL）溶液にＴＨＦ-ボラン錯体（2.8 mL, １Ｍ ＴＨＦ溶液）を0℃で加えた。70℃で2時間撹拌後、反応液に氷を加え、1Ｎ塩酸（5 mL）を加えた。70℃で2時間撹拌後、反応液に酢酸エチルを加えた。分離した水層を8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルとＴＨＦで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、得られた結晶をろ取し、エタノールとＩＰＥで再結晶して標題化合物（0.31 g）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.69-2.97 (2H, m), 3.61-4.03 (4H, m), 4.35-4.54 (2H, m), 4.84-5.08 (1H, m), 6.89 (1H, td, J= 8.5, 2.6 Hz), 7.22 (1H, dd, J= 10.7, 2.8 Hz), 7.44-7.66 (2H, m), 7.83-8.09 (2H, m), 9.71-10.17 (2H, m). Example 47
N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2 obtained in Reference Example 27 -(2-Chloro-5-fluorophenoxy) -N- (6-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (0.45 g) in THF (5 mL) To the solution was added THF-borane complex (2.8 mL, 1M THF solution) at 0 ° C. After stirring at 70 ° C. for 2 hours, ice was added to the reaction mixture, and 1N hydrochloric acid (5 mL) was added. After stirring at 70 ° C. for 2 hours, ethyl acetate was added to the reaction solution. The separated aqueous layer was basified with 8N sodium hydroxide solution and extracted with ethyl acetate and THF. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 4N hydrogen chloride / ethyl acetate solution (1 mL) was added to the obtained residue, and the resulting crystals were collected by filtration and recrystallized from ethanol and IPE to give the title compound (0.31 g). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.69-2.97 (2H, m), 3.61-4.03 (4H, m), 4.35-4.54 (2H, m), 4.84-5.08 (1H, m), 6.89 (1H, td, J = 8.5, 2.6 Hz), 7.22 (1H, dd, J = 10.7, 2.8 Hz), 7.44-7.66 (2H, m), 7.83-8.09 (2H, m), 9.71-10.17 ( 2H, m).
実施例４８
2-({[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド
（工程１）参考例２８で得られたN-[5-ブロモ-2-(ジメチルスルファモイル)ベンジル]-2-(2,5-ジフルオロフェノキシ)アセトアミド(2.00 g)のＴＨＦ（20 mL）溶液にＴＨＦ-ボラン錯体（12.9 mL, １Ｍ ＴＨＦ溶液）を加え、80℃で3時間撹拌後、反応液に氷を加え、1Ｎ塩酸（20 mL）を加えた。80℃で1時間撹拌した。反応液に1Ｎ水酸化ナトリウム溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製し、4-ブロモ-2-({[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド（1.67 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.81 (6H, s), 2.96-3.16 (2H, m), 3.94-4.22 (4H, m), 6.53-6.65 (1H, m), 6.65-6.77 (1H, m), 6.91-7.10 (1H, m), 7.53 (1H, dd, J= 8.5, 2.1 Hz), 7.75 (1H, d, J= 8.3 Hz), 7.90 (1H, d, J= 1.9 Hz) (A NH peak was not observed).
（工程２）工程１で得られた4-ブロモ-2-({[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド（150 mg）とパラジウム－炭素（35.5 mg）のエタノール（10 mL）懸濁液を水素雰囲気下2時間撹拌した。反応液をセライトろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィーで精製し、標題化合物（22 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.86 (6H, s), 3.21-3.36 (2H, m), 4.23 (2H, t, J= 5.1 Hz), 4.39 (2H, s), 5.31 (1H, br), 6.53-6.66 (1H, m), 6.66-6.78 (1H, m), 6.93-7.09 (1H, m), 7.44-7.54 (1H, m), 7.55-7.67 (1H, m), 7.67-7.77 (1H, m), 7.86 (1H, dd, J= 8.0, 1.5 Hz). Example 48
2-({[2- (2,5-Difluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide (Step 1) N- [5-Bromo-2-] obtained in Reference Example 28 To a solution of (dimethylsulfamoyl) benzyl] -2- (2,5-difluorophenoxy) acetamide (2.00 g) in THF (20 mL) was added THF-borane complex (12.9 mL, 1M THF solution) at 80 ° C. After stirring for 3 hours, ice was added to the reaction solution, and 1N hydrochloric acid (20 mL) was added. Stir at 80 ° C. for 1 hour. To the reaction solution was added 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography, and 4-bromo-2-({[2- (2,5-difluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide ( 1.67 g) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.81 (6H, s), 2.96-3.16 (2H, m), 3.94-4.22 (4H, m), 6.53-6.65 (1H, m), 6.65-6.77 ( 1H, m), 6.91-7.10 (1H, m), 7.53 (1H, dd, J = 8.5, 2.1 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.90 (1H, d, J = 1.9 Hz (A NH peak was not observed).
(Step 2) 4-Bromo-2-({[2- (2,5-difluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide (150 mg) obtained in Step 1 and palladium A suspension of carbon (35.5 mg) in ethanol (10 mL) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain the title compound (22 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.86 (6H, s), 3.21-3.36 (2H, m), 4.23 (2H, t, J = 5.1 Hz), 4.39 (2H, s), 5.31 (1H , br), 6.53-6.66 (1H, m), 6.66-6.78 (1H, m), 6.93-7.09 (1H, m), 7.44-7.54 (1H, m), 7.55-7.67 (1H, m), 7.67 -7.77 (1H, m), 7.86 (1H, dd, J = 8.0, 1.5 Hz).
実施例４９
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-モルホリン-4-イル-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
（工程１）実施例１０９で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（300 mg）、ナトリウムtert－ブトキシド（179 mg）、モルホリン（68.7 mg）、Pd2(dba)3（10.3 mg）及び2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル（21.5 mg）のトルエン（2 mL）溶液を 100℃で 6時間、窒素雰囲気下撹拌し、反応液をセライト濾過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:1～3:1）で精製してN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-モルホリン-4-イル-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（166 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.40-2.53 (1H, m), 2.57-2.70 (1H, m), 3.12 (2H, t, J= 5.1 Hz), 3.17-3.22 (1H, m), 3.22-3.28 (4H, m), 3.75 (1H, ddd, J= 13.7, 10.5, 3.4 Hz), 3.80-3.87 (3H, m), 3.99 (1H, dd, J= 6.0, 3.8 Hz), 4.04-4.23 (3H, m), 6.56-6.66 (1H, m), 6.70 (1H, ddd, J= 9.5, 6.7, 3.0 Hz), 6.88-6.95 (2H, m), 7.02 (1H, ddd, J= 10.9, 9.0, 5.3 Hz), 7.78 (1H, d, J= 9.4 Hz) (A NH peak was not observed).
（工程２）工程１で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-モルホリン-4-イル-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（166 mg）に４Ｎ塩化水素／酢酸エチル溶液（2 mL）を加えた。エタノールとジエチルエーテルで結晶化させた。得られた結晶をエタノールとジエチルエーテルで再結晶して標題化合物（116 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.74 (2H, m), 3.31 (4H, br), 3.44-3.61 (3H, m), 3.74 (4H, t, J= 4.7 Hz), 3.77-3.83 (1H, m), 4.43 (2H, br), 4.82 (1H, br), 6.76-6.92 (1H, m), 7.15-7.44 (4H, m), 7.70 (1H, d, J= 9.0 Hz), 9.71 (2H, br). Example 49
N- [2- (2,5-Difluorophenoxy) ethyl] -6-morpholin-4-yl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) Examples 6-Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (300 mg), sodium tert -Butoxide (179 mg), morpholine (68.7 mg), Pd 2 (dba) 3 (10.3 mg) and 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (21.5 mg) in toluene (2 mL) The solution was stirred at 100 ° C. for 6 hours under a nitrogen atmosphere, the reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1-3: 1) to give N- [2- (2,5-difluorophenoxy) ethyl] -6-morpholin-4-yl -3,4-Dihydro-2H-thiochromen-4-amine 1,1-dioxide (166 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.40-2.53 (1H, m), 2.57-2.70 (1H, m), 3.12 (2H, t, J = 5.1 Hz), 3.17-3.22 (1H, m) , 3.22-3.28 (4H, m), 3.75 (1H, ddd, J = 13.7, 10.5, 3.4 Hz), 3.80-3.87 (3H, m), 3.99 (1H, dd, J = 6.0, 3.8 Hz), 4.04 -4.23 (3H, m), 6.56-6.66 (1H, m), 6.70 (1H, ddd, J = 9.5, 6.7, 3.0 Hz), 6.88-6.95 (2H, m), 7.02 (1H, ddd, J = 10.9, 9.0, 5.3 Hz), 7.78 (1H, d, J = 9.4 Hz) (A NH peak was not observed).
(Step 2) N- [2- (2,5-difluorophenoxy) ethyl] -6-morpholin-4-yl-3,4-dihydro-2H-thiochromen-4-amine 1,1 obtained in Step 1 -Dioxide (166 mg) was added 4N hydrogen chloride / ethyl acetate solution (2 mL). Crystallized with ethanol and diethyl ether. The obtained crystals were recrystallized from ethanol and diethyl ether to give the title compound (116 mg). 1 H-NMR (300 MHz, DMSO-d 6) δppm 2.74 (2H, m), 3.31 (4H, br), 3.44-3.61 (3H, m), 3.74 (4H, t, J = 4.7 Hz), 3.77 -3.83 (1H, m), 4.43 (2H, br), 4.82 (1H, br), 6.76-6.92 (1H, m), 7.15-7.44 (4H, m), 7.70 (1H, d, J = 9.0 Hz ), 9.71 (2H, br).
実施例５０
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
（工程１）実施例１０８で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエテニル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（178 mg）および10%パラジウム炭素（0.05 g）のエタノール（1.5 mL）溶液を1気圧の水素雰囲気下、50℃で2時間撹拌した。触媒をろ別した後、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（酢酸エチル:ヘキサン＝ 1:4～2:3）で精製してN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド (133 mg)を得た。1H-NMR (300 MHz, CDCl3) δppm 1.20-1.29 (6H, m), 2.43-2.55 (1H, m), 2.59-2.72 (1H, m), 2.86-3.01 (1H, m), 3.11 (2H, t, J = 4.9 Hz), 3.19-3.29 (1H, m), 3.85 (1H, ddd, J= 13.8, 11.0, 3.0 Hz), 4.00-4.06 (1H, m), 4.07-4.14 (1H, m), 4.15-4.23 (1H, m), 6.56-6.65 (1H, m), 6.70 (1H, ddd, J= 9.7, 6.7, 2.8 Hz), 6.97-7.08 (1H, m), 7.30-7.37 (2H, m), 7.84 (1H, d, J= 8.3 Hz) (A NH peak was not observed).
（工程２）工程１で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド (133 mg)を用いて実施例４９の工程２と同様の手法により標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.24 (6H, dd, J= 7.0, 2.1 Hz), 2.68-2.86 (2H, m), 2.99 (1H, dt, J= 13.8, 7.1 Hz), 3.45-3.70 (3H, m), 3.85 (1H, br), 4.45 (2H, br), 4.89 (1H, br), 6.78-6.90 (1H, m), 7.17-7.39 (2H, m), 7.60 (1H, d, J= 8.3 Hz), 7.85 (2H, d, J= 8.7 Hz), 9.74 (2H, br). Example 50
Implementation of N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethenyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 108 (178 mg) and 10% palladium carbon (0.05 g) in ethanol (1.5 mL) were stirred at 50 ° C. for 2 hours under a hydrogen atmosphere of 1 atm. After the catalyst was filtered off, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 2: 3) to give N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethyl) -3 , 4-Dihydro-2H-thiochromen-4-amine 1,1-dioxide (133 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.20-1.29 (6H, m), 2.43-2.55 (1H, m), 2.59-2.72 (1H, m), 2.86-3.01 (1H, m), 3.11 ( 2H, t, J = 4.9 Hz), 3.19-3.29 (1H, m), 3.85 (1H, ddd, J = 13.8, 11.0, 3.0 Hz), 4.00-4.06 (1H, m), 4.07-4.14 (1H, m), 4.15-4.23 (1H, m), 6.56-6.65 (1H, m), 6.70 (1H, ddd, J = 9.7, 6.7, 2.8 Hz), 6.97-7.08 (1H, m), 7.30-7.37 ( 2H, m), 7.84 (1H, d, J = 8.3 Hz) (A NH peak was not observed).
(Step 2) N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethyl) -3,4-dihydro-2H-thiochromen-4-amine 1, obtained in Step 1 The title compound was obtained in the same manner as in Step 2 of Example 49 using 1-dioxide (133 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.24 (6H, dd, J = 7.0, 2.1 Hz), 2.68-2.86 (2H, m), 2.99 (1H, dt, J = 13.8, 7.1 Hz) , 3.45-3.70 (3H, m), 3.85 (1H, br), 4.45 (2H, br), 4.89 (1H, br), 6.78-6.90 (1H, m), 7.17-7.39 (2H, m), 7.60 (1H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.7 Hz), 9.74 (2H, br).
実施例５１
4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボニトリル 1,1-ジオキシド塩酸塩
（工程１）実施例１０９で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（300 mg）、シアン化亜鉛（72.7 mg）及びPd(PPh3)4（32.6 mg）のＤＭＦ（3 mL）溶液を 100℃で 5時間、窒素雰囲気下撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製して4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボニトリル 1,1-ジオキシド（201 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.47-2.61 (1H, m), 2.65-2.78 (1H, m), 3.05-3.21 (2H, m), 3.36 (1H, ddd, J= 13.9, 8.3, 3.0 Hz), 3.81 (1H, ddd, J= 13.8, 10.2, 3.0 Hz), 4.07-4.23 (3H, m), 6.58-6.75 (2H, m), 7.05 (1H, ddd, J= 10.5, 9.0, 5.3 Hz), 7.76 (1H, d, J= 8.3 Hz), 7.94-8.05 (2H, m) (A NH peak was not observed).
（工程２）工程１で得られた4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボニトリル 1,1-ジオキシド(201 mg)を用いて実施例４９の工程２と同様の手法により標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.81 (2H, br.), 3.50-3.64 (2H, m), 3.77 (1H, d, J = 6.8 Hz), 4.03 (1H, q, J= 7.2 Hz), 4.44 (2H, br), 4.95 (1H, d, J= 9.8 Hz), 6.83 (1H, tt, J= 8.5, 3.2 Hz), 7.22 (1H, ddd, J= 10.3, 7.1, 3.2 Hz), 7.26-7.35 (1H, m), 8.04-8.22 (2H, m), 8.50 (1H, br), 9.91 (2H, br). Example 51
4-{[2- (2,5-Difluorophenoxy) ethyl] amino} -3,4-dihydro-2H-thiochromene-6-carbonitrile 1,1-dioxide hydrochloride (Step 1) obtained in Example 109 6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (300 mg), zinc cyanide (72.7 mg ) And Pd (PPh 3 ) 4 (32.6 mg) in DMF (3 mL) were stirred at 100 ° C. for 5 hours under a nitrogen atmosphere, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to give 4-{[2- (2,5-difluorophenoxy) ethyl] amino} -3,4- Dihydro-2H-thiochromene-6-carbonitrile 1,1-dioxide (201 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.47-2.61 (1H, m), 2.65-2.78 (1H, m), 3.05-3.21 (2H, m), 3.36 (1H, ddd, J = 13.9, 8.3 , 3.0 Hz), 3.81 (1H, ddd, J = 13.8, 10.2, 3.0 Hz), 4.07-4.23 (3H, m), 6.58-6.75 (2H, m), 7.05 (1H, ddd, J = 10.5, 9.0 , 5.3 Hz), 7.76 (1H, d, J = 8.3 Hz), 7.94-8.05 (2H, m) (A NH peak was not observed).
(Step 2) 4-{[2- (2,5-difluorophenoxy) ethyl] amino} -3,4-dihydro-2H-thiochromene-6-carbonitrile 1,1-dioxide (201 mg) was used to obtain the title compound in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.81 (2H, br.), 3.50-3.64 (2H, m), 3.77 (1H, d, J = 6.8 Hz), 4.03 (1H, q, J = 7.2 Hz), 4.44 (2H, br), 4.95 (1H, d, J = 9.8 Hz), 6.83 (1H, tt, J = 8.5, 3.2 Hz), 7.22 (1H, ddd, J = 10.3, 7.1, 3.2 Hz), 7.26-7.35 (1H, m), 8.04-8.22 (2H, m), 8.50 (1H, br), 9.91 (2H, br).
実施例５２
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(メチルスルファニル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
（工程１）実施例１０９で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（532 mg）、ナトリウムチオメトキシド（105 mg）、Pd2(dba)3（91.6 mg）及び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（63.6 mg）のキシレン（5 mL）溶液を 140℃で 5時間、窒素雰囲気下撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製してN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(メチルスルファニル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（321 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.43-2.56 (1H, m), 2.50 (3H, s), 2.59-2.74 (1H, m, J= 14.6, 7.1, 7.1, 3.2 Hz), 3.11 (2H, t, J= 4.9 Hz), 3.26 (1H, ddd, J= 13.8, 7.6, 3.0 Hz), 3.80 (1H, ddd, J= 13.8, 10.5, 3.0 Hz), 4.02 (1H, dd, J= 5.7, 3.8 Hz), 4.06-4.21 (2H, m), 6.56-6.66 (1H, m), 6.70 (1H, ddd, J= 9.5, 6.7, 3.0 Hz), 7.03 (1H, ddd, J= 10.7, 8.9, 5.3 Hz), 7.27-7.35 (2H, m), 7.80 (1H, d, J= 8.3 Hz)(A NH peak was not observed).
（工程２）工程１で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(メチルスルファニル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド(120 mg)を用いて実施例４９の工程２と同様の手法により標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.59 (3H, s), 2.79 (2H, br), 3.50-3.66 (3H, m), 3.80-3.95 (1H, m), 4.44 (2H, br), 4.88 (1H, br), 6.78-6.88 (1H, m), 7.22 (1H, ddd, J= 10.3, 7.1, 3.0 Hz), 7.26-7.36 (1H, m), 7.55 (1H, d, J= 8.7 Hz), 7.73-7.84 (2H, m), 9.79 (2H, br). Example 52
N- [2- (2,5-Difluorophenoxy) ethyl] -6- (methylsulfanyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) Example 109 -Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (532 mg), sodium thiomethoxy obtained in Solution (105 mg), Pd 2 (dba) 3 (91.6 mg) and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (63.6 mg) in xylene (5 mL) at 140 ° C. The mixture was stirred for an hour under a nitrogen atmosphere, and the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to give N- [2- (2,5-difluorophenoxy) ethyl] -6- (methylsulfanyl)- 3,4-Dihydro-2H-thiochromen-4-amine 1,1-dioxide (321 mg) was obtained. 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.43-2.56 (1H, m), 2.50 (3H, s), 2.59-2.74 (1H, m, J = 14.6, 7.1, 7.1, 3.2 Hz), 3.11 ( 2H, t, J = 4.9 Hz), 3.26 (1H, ddd, J = 13.8, 7.6, 3.0 Hz), 3.80 (1H, ddd, J = 13.8, 10.5, 3.0 Hz), 4.02 (1H, dd, J = 5.7, 3.8 Hz), 4.06-4.21 (2H, m), 6.56-6.66 (1H, m), 6.70 (1H, ddd, J = 9.5, 6.7, 3.0 Hz), 7.03 (1H, ddd, J = 10.7, 8.9, 5.3 Hz), 7.27-7.35 (2H, m), 7.80 (1H, d, J = 8.3 Hz) (A NH peak was not observed).
(Step 2) N- [2- (2,5-difluorophenoxy) ethyl] -6- (methylsulfanyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1- obtained in Step 1 The title compound was obtained in the same manner as in Step 2 of Example 49 using dioxide (120 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.59 (3H, s), 2.79 (2H, br), 3.50-3.66 (3H, m), 3.80-3.95 (1H, m), 4.44 (2H, br), 4.88 (1H, br), 6.78-6.88 (1H, m), 7.22 (1H, ddd, J = 10.3, 7.1, 3.0 Hz), 7.26-7.36 (1H, m), 7.55 (1H, d, J = 8.7 Hz), 7.73-7.84 (2H, m), 9.79 (2H, br).
実施例５３
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
（工程１）2-プロパノール（37.2 mg）のトルエン（2 mL）溶液に水素化ナトリウム(45 mg)を0℃で加えた。50℃で1.5時間撹拌後、反応液に実施例１０９で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（300 mg）、2,2’-ビス（ジフェニルホスフィノ）-1,1’-ビナフチル （11.6 mg）、及びPd2(dba)3（15.5 mg）を加え、溶液を 100℃で 20時間、窒素雰囲気下撹拌し、反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～1:1）で精製してN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（36.5 mg）を得た。
（工程２）工程１で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（36.5 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（19.1 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.30 (6H, d, J= 5.7 Hz), 2.78 (2H, br), 3.46-3.64 (3H, m), 3.81 (1H, br), 4.43 (2H, br), 4.70-4.94 (2H, m), 6.84 (1H, br), 7.15-7.38 (3H, m), 7.46 (1H, br), 7.80 (1H, br), 9.49-9.85 (2H, m). Example 53
N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) 2 Sodium hydride (45 mg) was added to a toluene (2 mL) solution of -propanol (37.2 mg) at 0 ° C. After stirring at 50 ° C. for 1.5 hours, the reaction mixture was mixed with 6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromene-4-4 obtained in Example 109. Add amine 1,1-dioxide (300 mg), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (11.6 mg), and Pd 2 (dba) 3 (15.5 mg), and add the solution. The mixture was stirred at 100 ° C. for 20 hours under a nitrogen atmosphere, and the reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1) to give N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethoxy ) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (36.5 mg) was obtained.
(Step 2) N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1, obtained in Step 1 The title compound (19.1 mg) was obtained in the same manner as in Step 2 of Example 49 using 1-dioxide (36.5 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.30 (6H, d, J = 5.7 Hz), 2.78 (2H, br), 3.46-3.64 (3H, m), 3.81 (1H, br), 4.43 (2H, br), 4.70-4.94 (2H, m), 6.84 (1H, br), 7.15-7.38 (3H, m), 7.46 (1H, br), 7.80 (1H, br), 9.49-9.85 (2H , m).
実施例５４
N4-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン 1,1-ジオキシド塩酸塩
　参考例３１で得られたtert-ブチル (6-アミノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマートを用いて実施例４９の工程２と同様の手法により標題化合物（49.8 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.60-2.85 (2H, m), 3.35-3.55 (3H, m), 3.69-3.83 (1H, m), 4.43 (2H, t, J= 5.1 Hz), 4.69 (1H, d, J= 1.5 Hz), 6.73-6.90 (3H, m), 7.21 (1H, ddd, J= 10.3, 7.1, 3.0 Hz), 7.27-7.37 (1H, m), 7.54 (1H, d, J= 8.3 Hz), 9.47 (1H, br), 9.70 (1H, br)(Two NH peaks were not observed). Example 54
N 4 - [2- (2,5- difluorophenoxy) ethyl] -3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride tert- butyl obtained in Reference Example 31 ( Similar to Step 2 of Example 49 using 6-amino-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate The title compound (49.8 mg) was obtained by the procedure. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.60-2.85 (2H, m), 3.35-3.55 (3H, m), 3.69-3.83 (1H, m), 4.43 (2H, t, J = 5.1 Hz), 4.69 (1H, d, J = 1.5 Hz), 6.73-6.90 (3H, m), 7.21 (1H, ddd, J = 10.3, 7.1, 3.0 Hz), 7.27-7.37 (1H, m), 7.54 (1H, d, J = 8.3 Hz), 9.47 (1H, br), 9.70 (1H, br) (Two NH peaks were not observed).
実施例５５
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(メチルスルホニル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
　参考例３２で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルスルホニル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（400 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（172 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.68-3.01 (2H, m), 3.37 (3H, s), 3.59-3.84 (3H, m), 4.03 (1H, q, J= 7.2 Hz), 4.47 (2H, br), 5.04 (1H, br), 6.77-6.89 (1H, m), 7.17-7.37 (2H, m), 8.21 (2H, s), 8.60 (1H, br), 9.85 (1H, br), 10.10 (1H, br). Example 55
N- [2- (2,5-difluorophenoxy) ethyl] -6- (methylsulfonyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 32 tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylsulfonyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (400 mg) Was used to give the title compound (172 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.68-3.01 (2H, m), 3.37 (3H, s), 3.59-3.84 (3H, m), 4.03 (1H, q, J = 7.2 Hz) , 4.47 (2H, br), 5.04 (1H, br), 6.77-6.89 (1H, m), 7.17-7.37 (2H, m), 8.21 (2H, s), 8.60 (1H, br), 9.85 (1H , br), 10.10 (1H, br).
実施例５６
N-(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)アセトアミド塩酸塩
　参考例３３で得られたtert-ブチル [6-(アセチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（243 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（22.0 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.11 (3H, s), 2.73 (2H, br), 3.46-3.68 (3H, m), 3.86 (1H, br), 4.40 (2H, br), 4.85 (1H, br), 6.76-6.89 (1H, m), 7.15-7.25 (1H, m), 7.30 (1H, ddd, J= 11.0, 8.9, 5.7 Hz), 7.75 (1H, dd, J= 8.7, 1.9 Hz), 7.83-7.91 (1H, m), 8.10 (1H, br), 9.49 (1H, br), 9.65 (1H, br), 10.52 (1H, br). Example 56
N- (4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) acetamide hydrochloride obtained in Reference Example 33 Tert-butyl [6- (acetylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5-difluorophenoxy) ethyl] carbamate (243 mg ) To give the title compound (22.0 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.11 (3H, s), 2.73 (2H, br), 3.46-3.68 (3H, m), 3.86 (1H, br), 4.40 (2H, br) , 4.85 (1H, br), 6.76-6.89 (1H, m), 7.15-7.25 (1H, m), 7.30 (1H, ddd, J = 11.0, 8.9, 5.7 Hz), 7.75 (1H, dd, J = 8.7, 1.9 Hz), 7.83-7.91 (1H, m), 8.10 (1H, br), 9.49 (1H, br), 9.65 (1H, br), 10.52 (1H, br).
実施例５７
2-({[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチル-4-モルホリン-4-イルベンゼンスルホンアミド二臭素酸塩
　参考例３４で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][2-(ジメチルスルファモイル)-5-モルホリン-4-イルベンジル]カルバマート（110 mg）の酢酸エチル（3 mL）溶液に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、室温で3時間撹拌した。反応溶液の溶媒を留去後、1Ｎ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた油状物を酢酸エチル（5 mL）に溶解させ、２Ｎ臭化水素／メタノール溶液（1 mL）を加えた。得られた固体をろ取し、メタノールと酢酸エチルで再結晶して標題化合物（41 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.62 (6H, s), 3.27-3.39 (4H, m), 3.40-3.84 (6H, m), 4.24-4.62 (4H, m), 6.69-6.94 (1H, m, J= 8.6, 8.6, 3.2, 3.0 Hz), 7.04-7.37 (4H, m), 7.59-7.81 (1H, m), 8.95 (2H, br)（A NH peak was not observed）. Example 57
2-({[2- (2,5-difluorophenoxy) ethyl] amino} methyl) -N, N-dimethyl-4-morpholin-4-ylbenzenesulfonamide dibromate tert obtained in Reference Example 34 -Butyl [2- (2,5-difluorophenoxy) ethyl] [2- (dimethylsulfamoyl) -5-morpholin-4-ylbenzyl] carbamate (110 mg) in ethyl acetate (3 mL) in 4N hydrogen chloride / Ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 3 hours. The solvent of the reaction solution was distilled off, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained oil was dissolved in ethyl acetate (5 mL), and 2N hydrogen bromide / methanol solution (1 mL) was added. The obtained solid was collected by filtration and recrystallized from methanol and ethyl acetate to give the title compound (41 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.62 (6H, s), 3.27-3.39 (4H, m), 3.40-3.84 (6H, m), 4.24-4.62 (4H, m), 6.69- 6.94 (1H, m, J = 8.6, 8.6, 3.2, 3.0 Hz), 7.04-7.37 (4H, m), 7.59-7.81 (1H, m), 8.95 (2H, br) (A NH peak was not observed) .
実施例５８
4-シアノ-2-({[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド塩酸塩
（工程１）参考例３４の工程１で得られたtert-ブチル [5-ブロモ-2-(ジメチルスルファモイル)ベンジル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（500 mg）と、Pd(PPh3)4（105 mg）、シアン化亜鉛（118 mg）のＤＭＦ（3 mL）溶液を100℃で3時間撹拌した。反応溶液に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、tert-ブチル [5-シアノ-2-(ジメチルスルファモイル)ベンジル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（413 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.36 (4H, s), 1.53 (5H, s), 2.85 (6H, s), 3.60-3.84 (2H, m), 4.05-4.25 (2H, m), 5.01 (2H, br), 6.46-6.78 (2H, m), 6.85-7.14 (1H, m), 7.53-7.76 (2H, m), 7.99 (1H, d, J= 8.7 Hz).
（工程２）工程１で得られたtert-ブチル [5-シアノ-2-(ジメチルスルファモイル)ベンジル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（100 mg）の酢酸エチル（5 mL）溶液に4Ｎ塩化水素／酢酸エチル溶液（1 mL）を加え、室温で終夜撹拌した。得られた固体をろ取し、メタノールと酢酸エチルで再結晶して標題化合物（85.0 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.78 (6H, s), 3.44-3.61 (2H, m), 4.34-4.52 (2H, m), 4.52-4.69 (2H, m), 6.75-6.90 (1H, m, J= 8.6, 8.6, 3.2, 3.0 Hz), 7.12-7.38 (2H, m), 8.02 (1H, d, J= 8.3 Hz), 8.15-8.22 (1H, m), 8.30-8.46 (1H, m), 9.44 (2H, br). Example 58
4-cyano-2-({[2- (2,5-difluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide hydrochloride (Step 1) obtained in Step 1 of Reference Example 34 tert-Butyl [5-bromo-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate (500 mg) and Pd (PPh 3 ) 4 (105 mg), cyanide A solution of zinc halide (118 mg) in DMF (3 mL) was stirred at 100 ° C. for 3 hours. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), and tert-butyl [5-cyano-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate ( 413 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.36 (4H, s), 1.53 (5H, s), 2.85 (6H, s), 3.60-3.84 (2H, m), 4.05-4.25 (2H, m) , 5.01 (2H, br), 6.46-6.78 (2H, m), 6.85-7.14 (1H, m), 7.53-7.76 (2H, m), 7.99 (1H, d, J = 8.7 Hz).
(Step 2) tert-Butyl [5-cyano-2- (dimethylsulfamoyl) benzyl] [2- (2,5-difluorophenoxy) ethyl] carbamate (100 mg) obtained in Step 1 in ethyl acetate ( 5 mL) solution was added 4N hydrogen chloride / ethyl acetate solution (1 mL) and stirred at room temperature overnight. The obtained solid was collected by filtration and recrystallized from methanol and ethyl acetate to give the title compound (85.0 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.78 (6H, s), 3.44-3.61 (2H, m), 4.34-4.52 (2H, m), 4.52-4.69 (2H, m), 6.75- 6.90 (1H, m, J = 8.6, 8.6, 3.2, 3.0 Hz), 7.12-7.38 (2H, m), 8.02 (1H, d, J = 8.3 Hz), 8.15-8.22 (1H, m), 8.30- 8.46 (1H, m), 9.44 (2H, br).
実施例５９
N-(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)メタンスルホンアミド塩酸塩
　参考例３５で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル]{6-[(メチルスルホニル)アミノ]-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル}カルバマート（260 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（116 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.73 (2H, br), 3.21 (3H, s), 3.39-3.67 (3H, m), 3.80-3.95 (1H, m), 4.43 (2H, br), 4.86 (1H, br), 6.78-6.89 (1H, m), 7.15-7.25 (1H, m), 7.30 (1H, ddd, J= 10.9, 9.0, 5.3 Hz), 7.44 (1H, d, J= 8.7 Hz), 7.58 (1H, s), 7.90 (1H, d, J= 8.3 Hz), 9.76 (2H, br), 10.54 (1H, br). Example 59
N- (4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methanesulfonamide hydrochloride Reference Example 35 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] {6-[(methylsulfonyl) amino] -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in } The title compound (116 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate (260 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.73 (2H, br), 3.21 (3H, s), 3.39-3.67 (3H, m), 3.80-3.95 (1H, m), 4.43 (2H, br), 4.86 (1H, br), 6.78-6.89 (1H, m), 7.15-7.25 (1H, m), 7.30 (1H, ddd, J = 10.9, 9.0, 5.3 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.58 (1H, s), 7.90 (1H, d, J = 8.3 Hz), 9.76 (2H, br), 10.54 (1H, br).
実施例６０
4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-6-カルボキサミド 1,1-ジオキシド塩酸塩
　参考例３６で得られたtert-ブチル (6-カルバモイル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（200 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（147 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.69-2.97 (2H, m), 3.53-3.77 (3H, m), 3.95 (1H, br), 4.45 (2H, br), 4.95 (1H, br), 6.78-6.88 (1H, m), 7.16-7.35 (2H, m), 7.76 (1H, br), 7.96-8.07 (1H, m), 8.12 (1H, d, J= 8.7 Hz), 8.24 (1H, br), 8.45 (1H, br), 9.71 (2H, br). Example 60
4-{[2- (2,5-difluorophenoxy) ethyl] amino} -3,4-dihydro-2H-thiochromene-6-carboxamide 1,1-dioxide hydrochloride tert-butyl obtained in Reference Example 36 ( The process of example 49 using 6-carbamoyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (200 mg). The title compound (147 mg) was obtained by a method similar to 2. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.69-2.97 (2H, m), 3.53-3.77 (3H, m), 3.95 (1H, br), 4.45 (2H, br), 4.95 (1H, br), 6.78-6.88 (1H, m), 7.16-7.35 (2H, m), 7.76 (1H, br), 7.96-8.07 (1H, m), 8.12 (1H, d, J = 8.7 Hz), 8.24 (1H, br), 8.45 (1H, br), 9.71 (2H, br).
実施例６１
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-メトキシ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
(工程１)参考例３７で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（546 mg）、ヨウ化メチル（106 mg）、及び炭酸カリウム（104 mg）のＤＭＦ（2 mL）溶液を室温で3時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～3:2）で精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（253 mg）を得た。
（工程２）工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（253 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（152 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.79 (2H, br), 3.60 (3H, d, J= 7.5 Hz), 3.76-3.86 (1H, m), 3.89 (3H, s), 4.45 (2H, br), 4.89 (1H, br), 6.83 (1H, tt, J= 8.5, 3.2 Hz), 7.16-7.36 (3H, m), 7.57 (1H, br), 7.84 (1H, d, J= 8.7 Hz), 9.86 (2H, br). Example 61
N- [2- (2,5-Difluorophenoxy) ethyl] -6-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride
(Step 1) tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromene-4-] obtained in Reference Example 37 Yl) carbamate (546 mg), methyl iodide (106 mg), and potassium carbonate (104 mg) in DMF (2 mL) were stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-3: 2) to give tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-methoxy-1, 1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (253 mg) was obtained.
(Step 2) tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 ) The title compound (152 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate (253 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.79 (2H, br), 3.60 (3H, d, J = 7.5 Hz), 3.76-3.86 (1H, m), 3.89 (3H, s), 4.45 (2H, br), 4.89 (1H, br), 6.83 (1H, tt, J = 8.5, 3.2 Hz), 7.16-7.36 (3H, m), 7.57 (1H, br), 7.84 (1H, d, J = 8.7 Hz), 9.86 (2H, br).
実施例６２
N-[2-(2,5-ジフルオロフェノキシ)エチル]-7-メトキシ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３８で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](7-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（235 mg）を用いて実施例６１の工程１と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](7-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（235 mg）を得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](7-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（235 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（149 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.68-2.90 (2H, m), 3.33-3.55 (3H, m), 3.64 (1H, br), 3.87 (3H, s), 4.40 (2H, br), 4.84 (1H, br), 6.78-6.89 (1H, m), 7.15-7.25 (1H, m), 7.25-7.39 (3H, m), 7.83 (1H, br), 9.51 (2H, br). Example 62
N- [2- (2,5-difluorophenoxy) ethyl] -7-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride tert-butyl obtained in Reference Example 38 Using [2- (2,5-difluorophenoxy) ethyl] (7-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (235 mg) In the same manner as in Step 1, tert-butyl [2- (2,5-difluorophenoxy) ethyl] (7-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate ( 235 mg). Obtained tert-butyl [2- (2,5-difluorophenoxy) ethyl] (7-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (235 mg) Was used to give the title compound (149 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.68-2.90 (2H, m), 3.33-3.55 (3H, m), 3.64 (1H, br), 3.87 (3H, s), 4.40 (2H, br), 4.84 (1H, br), 6.78-6.89 (1H, m), 7.15-7.25 (1H, m), 7.25-7.39 (3H, m), 7.83 (1H, br), 9.51 (2H, br) .
実施例６３
N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6,N6-ジメチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド塩酸塩
（工程１）参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（300 mg）及びジメチルアミンの２Ｍ ＴＨＦ溶液（1 mL）を用いて実施例４９の工程１と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ジメチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（151 mg）を得た。
(工程２)工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ジメチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（151 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（92.3 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.62-2.86 (2H, m), 3.03 (6H, s), 3.43-3.60 (3H, m), 3.67-3.82 (1H, m), 4.44 (2H, br), 4.82 (1H, br), 6.77-6.88 (1H, m), 6.92 (1H, dd, J= 8.9, 2.1 Hz), 7.11 (1H, br), 7.16-7.37 (2H, m), 7.64 (1H, d, J= 9.0 Hz), 9.78 (2H, br). Example 63
N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6, N 6 - dimethyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride (Step 1 ) Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) obtained in Step 1 of Reference Example 31 Ethyl] carbamate (300 mg) and 2M THF solution of dimethylamine (1 mL) were used in the same manner as in Step 1 of Example 49 to obtain tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6 -(Dimethylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (151 mg) was obtained.
(Step 2) tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (dimethylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromene-obtained in Step 1 The title compound (92.3 mg) was obtained in the same manner as in Step 2 of Example 49 using 4-yl] carbamate (151 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.62-2.86 (2H, m), 3.03 (6H, s), 3.43-3.60 (3H, m), 3.67-3.82 (1H, m), 4.44 ( 2H, br), 4.82 (1H, br), 6.77-6.88 (1H, m), 6.92 (1H, dd, J = 8.9, 2.1 Hz), 7.11 (1H, br), 7.16-7.37 (2H, m) , 7.64 (1H, d, J = 9.0 Hz), 9.78 (2H, br).
実施例６４
N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-メチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド塩酸塩
（工程１）参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（300 mg）及び40％メチルアミン／メタノール溶液（1.04 mL）を用いて実施例４９の工程１と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（114 mg）を得た。
(工程２)工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（151 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（80.8 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.62-2.86 (5H, m), 3.40-3.59 (3H, m), 3.68-3.82 (1H, m), 4.46 (2H, t, J= 5.1 Hz), 4.77 (1H, br), 6.73-6.88 (2H, m), 6.91 (1H, d, J= 2.3 Hz), 7.16-7.37 (2H, m), 7.55 (1H, d, J= 8.7 Hz), 9.82 (2H, br)(A NH peak was not observed). Example 64
N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride (Step 1) Reference Example 31 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in step 1 of 31 (300 mg) and 40% methylamine / methanol solution (1.04 mL) in the same manner as in Step 49 of Example 49, tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- ( Methylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (114 mg) was obtained.
(Step 2) tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromene-obtained in Step 1 The title compound (80.8 mg) was obtained in the same manner as in Step 2 of Example 49 using 4-yl] carbamate (151 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.62-2.86 (5H, m), 3.40-3.59 (3H, m), 3.68-3.82 (1H, m), 4.46 (2H, t, J = 5.1 Hz), 4.77 (1H, br), 6.73-6.88 (2H, m), 6.91 (1H, d, J = 2.3 Hz), 7.16-7.37 (2H, m), 7.55 (1H, d, J = 8.7 Hz ), 9.82 (2H, br) (A NH peak was not observed).
実施例６５
N-[2-(2,5-ジフルオロフェノキシ)エチル]-8-メトキシ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
（工程１）参考例３９で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](8-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（235 mg）を用いて実施例６１の工程１と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](8-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（234 mg）を得た。
（工程２）工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](8-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（235 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（171 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.57-2.82 (2H, m), 3.33-3.70 (3H, m), 3.74-3.87 (1H, m), 3.90 (3H, s), 4.44 (2H, br), 4.85 (1H, br), 6.83 (1H, tt, J= 8.6, 3.1 Hz), 7.21 (1H, ddd, J= 10.3, 7.1, 3.0 Hz), 7.26-7.38 (2H, m), 7.48 (1H, d, J= 7.5 Hz), 7.61-7.71 (1H, m), 9.90 (2H, br). Example 65
N- [2- (2,5-difluorophenoxy) ethyl] -8-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) obtained in Reference Example 39 With tert-butyl [2- (2,5-difluorophenoxy) ethyl] (8-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (235 mg) Tert-butyl [2- (2,5-difluorophenoxy) ethyl] (8-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromene-4- Yl) carbamate (234 mg) was obtained.
(Step 2) tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (8-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 ) The title compound (171 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate (235 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.57-2.82 (2H, m), 3.33-3.70 (3H, m), 3.74-3.87 (1H, m), 3.90 (3H, s), 4.44 ( 2H, br), 4.85 (1H, br), 6.83 (1H, tt, J = 8.6, 3.1 Hz), 7.21 (1H, ddd, J = 10.3, 7.1, 3.0 Hz), 7.26-7.38 (2H, m) , 7.48 (1H, d, J = 7.5 Hz), 7.61-7.71 (1H, m), 9.90 (2H, br).
実施例６６
N-[2-(2,5-ジフルオロフェノキシ)プロピル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（４つの立体異性体混合物）
　参考例４０で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)プロピル](1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（４つの立体異性体混合物）（300 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（185 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.24-1.34 (3H, m), 2.82 (2H, br), 3.21-3.44 (2H, m), 3.60-3.74 (1H, m), 3.88 (1H, dd, J= 10.0, 5.8 Hz), 4.82-5.10 (2H, m), 6.77-6.90 (1H, m), 7.23-7.40 (2H, m), 7.64-7.79 (2H, m), 7.92 (1H, d, J= 7.2 Hz), 8.00 (1H, d, J= 7.2 Hz), 9.29-10.46 (2H, m). Example 66
N- [2- (2,5-Difluorophenoxy) propyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (mixture of four stereoisomers)
Tert-Butyl [2- (2,5-difluorophenoxy) propyl] (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (four stereoisomers) obtained in Reference Example 40 Body mixture) (300 mg) was used to give the title compound (185 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.24-1.34 (3H, m), 2.82 (2H, br), 3.21-3.44 (2H, m), 3.60-3.74 (1H, m), 3.88 ( 1H, dd, J = 10.0, 5.8 Hz), 4.82-5.10 (2H, m), 6.77-6.90 (1H, m), 7.23-7.40 (2H, m), 7.64-7.79 (2H, m), 7.92 ( 1H, d, J = 7.2 Hz), 8.00 (1H, d, J = 7.2 Hz), 9.29-10.46 (2H, m).
実施例６７
4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-3,4-ジヒドロ-2H-チオクロメン-8-オール 1,1-ジオキシド塩酸塩
　参考例３９で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](8-ヒドロキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（100 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（48.4 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.57-2.79 (2H, m), 3.43-3.56 (3H, m), 3.66-3.81 (1H, m), 4.40 (2H, br), 4.78 (1H, br), 6.76-6.89 (1H, m), 7.09 (1H, d, J= 8.3 Hz), 7.15-7.25 (2H, m), 7.25-7.37 (1H, m), 7.43-7.53 (1H, m), 9.56 (2H, br), 10.96 (1H, br). Example 67
4-{[2- (2,5-difluorophenoxy) ethyl] amino} -3,4-dihydro-2H-thiochromen-8-ol 1,1-dioxide hydrochloride tert-butyl obtained in Reference Example 39 [ Step of Example 49 using 2- (2,5-difluorophenoxy) ethyl] (8-hydroxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (100 mg) The title compound (48.4 mg) was obtained by the same method as 2. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.57-2.79 (2H, m), 3.43-3.56 (3H, m), 3.66-3.81 (1H, m), 4.40 (2H, br), 4.78 ( 1H, br), 6.76-6.89 (1H, m), 7.09 (1H, d, J = 8.3 Hz), 7.15-7.25 (2H, m), 7.25-7.37 (1H, m), 7.43-7.53 (1H, m), 9.56 (2H, br), 10.96 (1H, br).
実施例６８
8-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３９の工程７で得られたtert-ブチル (8-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（150 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（47.7 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.77 (2H, br), 3.49 (1H, br), 3.59-4.07 (3H, m), 4.44 (2H, br), 4.91 (1H, br), 6.78-6.90 (1H, m), 7.17-7.37 (2H, m), 7.56-7.67 (1H, m), 7.89-8.04 (2H, m), 9.93 (2H, br). Example 68
8-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 7 of Reference Example 39 Performed with tert-butyl (8-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg) The title compound (47.7 mg) was obtained in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.77 (2H, br), 3.49 (1H, br), 3.59-4.07 (3H, m), 4.44 (2H, br), 4.91 (1H, br) , 6.78-6.90 (1H, m), 7.17-7.37 (2H, m), 7.56-7.67 (1H, m), 7.89-8.04 (2H, m), 9.93 (2H, br).
実施例６９
7-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３８の工程７で得られたtert-ブチル (7-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（150 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（102 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.65-2.93 (2H, m), 3.33-3.46 (1H, m), 3.57-3.82 (2H, m), 3.94 (1H, d, J= 10.5 Hz), 4.43 (2H, br), 4.89 (1H, d, J= 4.1 Hz), 6.76-6.89 (1H, m), 7.16-7.36 (2H, m), 7.87-8.11 (3H, m), 9.92 (2H, br). Example 69
7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 7 of Reference Example 38 Performed with tert-butyl (7-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg) The title compound (102 mg) was obtained in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.65-2.93 (2H, m), 3.33-3.46 (1H, m), 3.57-3.82 (2H, m), 3.94 (1H, d, J = 10.5 Hz), 4.43 (2H, br), 4.89 (1H, d, J = 4.1 Hz), 6.76-6.89 (1H, m), 7.16-7.36 (2H, m), 7.87-8.11 (3H, m), 9.92 (2H, br).
実施例７０
6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（150 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（78.3 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.63-2.93 (2H, m), 3.69 (3H, d, J= 4.5 Hz), 3.95 (1H, br), 4.44 (2H, br), 4.90 (1H, br), 6.76-6.89 (1H, m), 7.14-7.37 (2H, m), 7.79-8.00 (2H, m), 8.25 (1H, br), 9.80 (2H, br). Example 70
6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 1 of Reference Example 31 Performed with tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (150 mg) The title compound (78.3 mg) was obtained in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.63-2.93 (2H, m), 3.69 (3H, d, J = 4.5 Hz), 3.95 (1H, br), 4.44 (2H, br), 4.90 (1H, br), 6.76-6.89 (1H, m), 7.14-7.37 (2H, m), 7.79-8.00 (2H, m), 8.25 (1H, br), 9.80 (2H, br).
実施例７１
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-フェニル-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド塩酸塩
（工程１）参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（300 mg）及びフェニルボロン酸（103 mg）を用いて実施例１０８と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](1,1-ジオキシド-6-フェニル-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートを得た。
（工程２）工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](1,1-ジオキシド-6-フェニル-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートを用いて実施例４９の工程２と同様の手法により標題化合物（171 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.85 (2H, br), 3.52-3.75 (3H, m), 3.86-4.05 (1H, m), 4.47 (2H, br), 4.99 (1H, br), 6.74-6.91 (1H, m), 7.15-7.36 (2H, m), 7.42-7.62 (3H, m), 7.84 (2H, d, J= 7.6 Hz), 7.93-8.08 (2H, m), 8.28 (1H, br), 9.87 (2H, br). Example 71
N- [2- (2,5-difluorophenoxy) ethyl] -6-phenyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (Step 1) Step 1 of Reference Example 31 -Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (300 mg) obtained in And phenylboronic acid (103 mg) in the same manner as in Example 108, tert-butyl [2- (2,5-difluorophenoxy) ethyl] (1,1-dioxide-6-phenyl-3,4- Dihydro-2H-thiochromen-4-yl) carbamate was obtained.
(Step 2) tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (1,1-dioxide-6-phenyl-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 ) The title compound (171 mg) was obtained in the same manner as in Step 2 of Example 49 using carbamate. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.85 (2H, br), 3.52-3.75 (3H, m), 3.86-4.05 (1H, m), 4.47 (2H, br), 4.99 (1H, br), 6.74-6.91 (1H, m), 7.15-7.36 (2H, m), 7.42-7.62 (3H, m), 7.84 (2H, d, J = 7.6 Hz), 7.93-8.08 (2H, m) , 8.28 (1H, br), 9.87 (2H, br).
実施例７２
N-[2-(2,5-ジフルオロフェノキシ)エチル]-5-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例４１で得られた2-(2,5-ジフルオロフェノキシ)-N-(5-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミドを用いて実施例１２と同様の手法により標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.60-2.80 (1H, m), 2.90-3.10 (1H, m), 3.40-3.75 (3H, m), 4.20-4.35 (1H, m), 4.38-4.54 (2H, m), 4.97 (1H, br), 6.80-6.90 (1H, m), 7.20-7.40 (2H, m), 7.60-7.80 (1H, m), 7.80-7.90 (2H, m), 9.30-9.60 (1H, br), 10.0-10.4 (1H, br). Example 72
N- [2- (2,5-difluorophenoxy) ethyl] -5-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2) obtained in Reference Example 41 2,5-Difluorophenoxy) -N- (5-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide was prepared by the same procedure as in Example 12 to give the title compound. Obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.60-2.80 (1H, m), 2.90-3.10 (1H, m), 3.40-3.75 (3H, m), 4.20-4.35 (1H, m), 4.38-4.54 (2H, m), 4.97 (1H, br), 6.80-6.90 (1H, m), 7.20-7.40 (2H, m), 7.60-7.80 (1H, m), 7.80-7.90 (2H, m ), 9.30-9.60 (1H, br), 10.0-10.4 (1H, br).
実施例７３
N-[2-(2,5-ジフルオロフェノキシ)エチル]-7-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド
　参考例４２で得られたN-(7-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（1.19 g）をＴＨＦ（30 mL）に溶解させ、ＴＨＦ-ボラン錯体（7.72 mL, １Ｍ ＴＨＦ溶液）を０℃で加えた。反応液を60℃で3時間撹拌後、反応液にメタノールを加え、溶媒を減圧下留去した。残渣に6Ｎ塩酸（40 mL）を加えた。70℃で2時間撹拌後、8Ｎ水酸化ナトリウム溶液で塩基性とし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～1:1）で精製して標題化合物（939 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.45-2.58 (1H, m), 2.59-2.73 (1H, m), 3.10 (2H, t, J= 4.9 Hz), 3.28 (1H, ddd, J= 13.7, 7.5, 2.7 Hz), 3.83 (1H, ddd, J= 13.7, 10.7, 3.2 Hz), 4.02-4.20 (3H, m), 6.56-6.75 (2H, m), 7.03 (1H, ddd, J= 10.6, 9.1, 5.3 Hz), 7.19-7.29 (1H, m), 7.51-7.63 (2H, m) (A NH peak was not observed). Example 73
N- [2- (2,5-difluorophenoxy) ethyl] -7-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide N- (7- Fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (1.19 g) was dissolved in THF (30 mL) and THF- Borane complex (7.72 mL, 1M THF solution) was added at 0 ° C. After stirring the reaction solution at 60 ° C. for 3 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (40 mL) was added to the residue. The mixture was stirred at 70 ° C. for 2 hours, basified with 8N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1) to give the title compound (939 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.45-2.58 (1H, m), 2.59-2.73 (1H, m), 3.10 (2H, t, J = 4.9 Hz), 3.28 (1H, ddd, J = 13.7, 7.5, 2.7 Hz), 3.83 (1H, ddd, J = 13.7, 10.7, 3.2 Hz), 4.02-4.20 (3H, m), 6.56-6.75 (2H, m), 7.03 (1H, ddd, J = 10.6, 9.1, 5.3 Hz), 7.19-7.29 (1H, m), 7.51-7.63 (2H, m) (A NH peak was not observed).
実施例７４
4-クロロ-3-{2-[(1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アミノ]エトキシ}ベンゾニトリル塩酸塩
　参考例４３で得られたtert-ブチル [2-(2-クロロ-5-シアノフェノキシ)エチル](1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマート（362 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（221 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.69-2.95 (2H, m), 3.71 (3H, br), 3.84-4.00 (1H, m), 4.52 (2H, br), 4.95 (1H, br), 7.52 (1H, dd, J= 8.1, 1.7 Hz), 7.67-7.82 (4H, m), 7.89-8.02 (2H, m), 9.88 (2H, br). Example 74
4-chloro-3- {2-[(1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) amino] ethoxy} benzonitrile hydrochloride tert-butyl obtained in Reference Example 43 2- (2-Chloro-5-cyanophenoxy) ethyl] (1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate (362 mg) and The title compound (221 mg) was obtained by a similar method. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.69-2.95 (2H, m), 3.71 (3H, br), 3.84-4.00 (1H, m), 4.52 (2H, br), 4.95 (1H, br), 7.52 (1H, dd, J = 8.1, 1.7 Hz), 7.67-7.82 (4H, m), 7.89-8.02 (2H, m), 9.88 (2H, br).
実施例７５
N-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（４つの立体異性体混合物）
　参考例４４で得られた2-(2,5-ジフルオロフェノキシ)-N-(3-メチル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミドを用いて実施例１０９と同様の手法により標題化合物（1.82 g）を得た。（NMRよりジアステレオマー混合比は78：22）1H-NMR (300 MHz, CDCl3) δppm 1.23-1.38 (3H, m), 2.77-2.93 (2H, m), 2.96-3.12 (1H, m), 3.18 (1H, dd, J= 13.8, 9.6 Hz), 3.63 (1H, dd, J= 13.8, 3.6 Hz), 3.76-3.85 (1H, m), 4.01-4.15 (2H, m), 6.55-6.72 (2H, m), 6.96-7.08 (1H, m), 7.37-7.73 (3H, m), 7.90-7.96 (1H, m) (A NH peak was not observed). Example 75
N- [2- (2,5-Difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (mixture of four stereoisomers)
Performed using 2- (2,5-difluorophenoxy) -N- (3-methyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide obtained in Reference Example 44 The title compound (1.82 g) was obtained by a method similar to that in Example 109. (The diastereomeric mixing ratio is 78:22 from NMR) 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.23-1.38 (3H, m), 2.77-2.93 (2H, m), 2.96-3.12 (1H, m ), 3.18 (1H, dd, J = 13.8, 9.6 Hz), 3.63 (1H, dd, J = 13.8, 3.6 Hz), 3.76-3.85 (1H, m), 4.01-4.15 (2H, m), 6.55- 6.72 (2H, m), 6.96-7.08 (1H, m), 7.37-7.73 (3H, m), 7.90-7.96 (1H, m) (A NH peak was not observed).
実施例７６
N-[2-(2,5-ジフルオロフェノキシ)エチル]-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-アミン 1,1-ジオキシド
　参考例４５で得られたN-(7-ブロモ-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（200 mg）および10%パラジウム炭素（0.1 g）のメタノール（2 mL）溶液を水素雰囲気下、室温で2時間撹拌した。触媒をろ別した後、溶媒を減圧下留去した。残渣を分取液体クロマトグラフィーで精製して標題化合物（45 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.99 (2H, br), 2.31 (2H, br), 2.88-3.08 (2H, m), 3.12-3.35 (2H, m), 4.13 (2H, t, J= 5.3 Hz), 4.52 (1H, br), 6.59 (1H, tt, J= 8.3, 3.2 Hz), 6.71 (1H, ddd, J= 9.6, 6.8, 2.8 Hz), 7.02 (1H, ddd, J= 10.6, 8.9, 5.3 Hz), 7.39-7.49 (1H, m), 7.62 (1H, t, J= 7.5 Hz), 7.66-7.80 (1H, m), 8.12 (1H, d, J= 7.9 Hz)(A NH peak was not observed). Example 76
N- [2- (2,5-difluorophenoxy) ethyl] -2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide N- (7- Bromo-1,1-dioxide-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) -2- (2,5-difluorophenoxy) acetamide (200 mg) and 10% palladium on carbon (0.1 g ) In methanol (2 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by preparative liquid chromatography to give the title compound (45 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.99 (2H, br), 2.31 (2H, br), 2.88-3.08 (2H, m), 3.12-3.35 (2H, m), 4.13 (2H, t, J = 5.3 Hz), 4.52 (1H, br), 6.59 (1H, tt, J = 8.3, 3.2 Hz), 6.71 (1H, ddd, J = 9.6, 6.8, 2.8 Hz), 7.02 (1H, ddd, J = 10.6, 8.9, 5.3 Hz), 7.39-7.49 (1H, m), 7.62 (1H, t, J = 7.5 Hz), 7.66-7.80 (1H, m), 8.12 (1H, d, J = 7.9 Hz) (A NH peak was not observed).
実施例７７
N-[2-(2,5-ジフルオロフェノキシ)エチル]-5-メトキシ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例４６で得られた2-(2,5-ジフルオロフェノキシ)-N-(5-メトキシ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミドを用いて実施例１２と同様の手法により標題化合物を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.60-2.80 (1H, m), 2.85-3.00 (1H, m), 3.50-3.70 (3H, m), 3.86 (3H, s), 4.18-4.36 (1H, m), 4.36-4.60 (2H, m), 4.80-4.95 (1H, m), 6.80-6.90 (1H, m), 7.20-7.38 (2H, m), 7.41 (1H, d, J= 8.4 Hz), 7.49 (1H, d, J= 8.4 Hz), 7.72 (1H, t, J= 8.3 Hz), 8.64 (1H, br), 9.92 (1H, br). Example 77
N- [2- (2,5-difluorophenoxy) ethyl] -5-methoxy-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2) obtained in Reference Example 46 2,5-Difluorophenoxy) -N- (5-methoxy-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide was prepared by the same procedure as in Example 12 to give the title compound. Obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.60-2.80 (1H, m), 2.85-3.00 (1H, m), 3.50-3.70 (3H, m), 3.86 (3H, s), 4.18- 4.36 (1H, m), 4.36-4.60 (2H, m), 4.80-4.95 (1H, m), 6.80-6.90 (1H, m), 7.20-7.38 (2H, m), 7.41 (1H, d, J = 8.4 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.72 (1H, t, J = 8.3 Hz), 8.64 (1H, br), 9.92 (1H, br).
実施例７８
7-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-アミン 1,1-ジオキシド
　参考例４５で得られたN-(7-ブロモ-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（2.28 g）を用いて実施例１０９と同様の手法により7-ブロモ-Ｎ-[2-(2,5-ジフルオロフェノキシ)エチル]-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-アミン 1,1-ジオキシド（1.37 g）を得た。得られた7-ブロモ-Ｎ-[2-(2,5-ジフルオロフェノキシ)エチル]-2,3,4,5-テトラヒドロ-1-ベンゾチエピン-5-アミン 1,1-ジオキシド（200 mg）に４Ｎ塩化水素／酢酸エチル溶液（2 mL）を加えた。溶媒を減圧下留去した後、炭酸水素ナトリウム溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を分取液体クロマトグラフィーで精製して標題化合物（56.8 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.69-2.49 (5H, m), 2.88-3.35 (4H, m), 4.07-4.20 (2H, m), 4.51 (1H, br), 6.56-6.66 (1H, m), 6.73 (1H, ddd, J= 9.7, 6.7, 2.8 Hz), 7.03 (1H, ddd, J= 10.8, 8.9, 5.3 Hz), 7.58 (1H, dd, J= 8.3, 1.9 Hz), 7.95 (2H, d, J= 8.3 Hz). Example 78
7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide N obtained in Reference Example 45 Performed with-(7-bromo-1,1-dioxide-2,3,4,5-tetrahydro-1-benzothiepin-5-yl) -2- (2,5-difluorophenoxy) acetamide (2.28 g) In a manner similar to Example 109, 7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide ( 1.37 g) was obtained. To the obtained 7-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -2,3,4,5-tetrahydro-1-benzothiepin-5-amine 1,1-dioxide (200 mg) A 4N hydrogen chloride / ethyl acetate solution (2 mL) was added. The solvent was evaporated under reduced pressure, neutralized with sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative liquid chromatography to give the title compound (56.8 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.69-2.49 (5H, m), 2.88-3.35 (4H, m), 4.07-4.20 (2H, m), 4.51 (1H, br), 6.56-6.66 ( 1H, m), 6.73 (1H, ddd, J = 9.7, 6.7, 2.8 Hz), 7.03 (1H, ddd, J = 10.8, 8.9, 5.3 Hz), 7.58 (1H, dd, J = 8.3, 1.9 Hz) , 7.95 (2H, d, J = 8.3 Hz).
実施例７９
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(ピロリジン-1-イルメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド二塩酸塩
（工程１）参考例４７で得られたtert-ブチル (6-シアノ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（1 g）のトルエン（1 mL）溶液に1.5 Ｍ水素化ジイソブチルアルミニウムのトルエン溶液（1.46 mL）を-78℃で加え、反応液を室温で4.5時間撹拌し、反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製して原料とtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ホルミル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートの混合物(262 mg)を得た。
（工程２）工程１で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-ホルミル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートの混合物(262 mg)、ピロリジン（46.5 mg）、Ｅｔ３Ｎ（66.1 mg）及び酢酸（71.3 mg）のＴＨＦ（2 mL）溶液にトリアセトキシ水素化ホウ素ナトリウム（337 mg）を0℃で加え、室温で三日間撹拌し、反応液を氷に注いだ。反応液を炭酸水素ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を分取液体クロマトグラフィーで精製してN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(ピロリジン-1-イルメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシドを得た。得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(ピロリジン-1-イルメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドを用いて実施例４９の工程２と同様の手法により標題化合物（27.5 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.79-2.11 (4H, m), 2.67-3.35 (5H, m), 3.63 (4H, br), 3.96 (1H, br), 4.33-4.60 (4H, m), 4.92 (1H, br), 6.76-6.91 (1H, m), 7.17-7.37 (2H, m), 7.87-8.08 (2H, m), 8.23 (1H, br), 9.94 (2H, br), 11.10 (1H, br). Example 79
N- [2- (2,5-difluorophenoxy) ethyl] -6- (pyrrolidin-1-ylmethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide dihydrochloride (Step 1) ) Tert-butyl (6-cyano-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in Reference Example 47 To a solution of (1 g) in toluene (1 mL) was added 1.5 M diisobutylaluminum hydride in toluene (1.46 mL) at −78 ° C., and the reaction was stirred at room temperature for 4.5 hours. Extracted with ethyl. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1), and the starting material and tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-formyl- A mixture (262 mg) of 1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate was obtained.
(Step 2) tert-Butyl [2- (2,5-difluorophenoxy) ethyl] (6-formyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl obtained in Step 1 ) A mixture of carbamate (262 mg), pyrrolidine (46.5 mg), Et 3 N (66.1 mg) and acetic acid (71.3 mg) in THF (2 mL) was added sodium triacetoxyborohydride (337 mg) at 0 ° C. The mixture was stirred at room temperature for 3 days, and the reaction solution was poured onto ice. The reaction was basified with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative liquid chromatography to give N- [2- (2,5-difluorophenoxy) ethyl] -6- (pyrrolidin-1-ylmethyl) -3,4-dihydro-2H-thiochromene- 4-Amine 1,1-dioxide was obtained. Using the obtained N- [2- (2,5-difluorophenoxy) ethyl] -6- (pyrrolidin-1-ylmethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide The title compound (27.5 mg) was obtained in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.79-2.11 (4H, m), 2.67-3.35 (5H, m), 3.63 (4H, br), 3.96 (1H, br), 4.33-4.60 ( 4H, m), 4.92 (1H, br), 6.76-6.91 (1H, m), 7.17-7.37 (2H, m), 7.87-8.08 (2H, m), 8.23 (1H, br), 9.94 (2H, br), 11.10 (1H, br).
実施例８０
N6-シクロプロピル-N4-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン 1,1-ジオキシド
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（300 mg）、シクロプロピルアミン（119 mg）、ナトリウムtert－ブトキシド （179 mg）、Pd2(dba)3（10.3 mg）及び2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル （21.5 mg）のトルエン（2 mL）溶液を 100℃で 17時間、窒素雰囲気下撹拌し、反応液をセライト濾過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～1:1）で精製してtert-ブチル [6-(シクロプロピルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマートを得た。得られたtert-ブチル [6-(シクロプロピルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマートに４Ｎ塩化水素／酢酸エチル溶液（2 mL）を加えた。溶媒を減圧下留去した後、炭酸水素ナトリウム溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を分取液体クロマトグラフィーで精製して標題化合物（17 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 0.48-0.57 (2H, m), 0.72-0.84 (2H, m), 2.39-2.68 (3H, m), 3.05-3.29 (3H, m), 3.73 (1H, ddd, J= 13.5, 10.4, 3.3 Hz), 3.93-4.03 (1H, m), 4.04-4.23 (2H, m), 4.55 (1H, br), 6.50-6.64 (1H, m), 6.70 (1H, ddd, J= 9.7, 6.8, 3.0 Hz), 6.75-6.83 (2H, m), 7.01 (1H, ddd, J= 10.7, 8.9, 5.4 Hz), 7.71 (1H, d, J= 9.1 Hz)(A NH peak was not observed).  Example 80
In [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide Example 31 step 1 - N 6 - cyclopropyl -N 4 The resulting tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (300 mg), Cyclopropylamine (119 mg), sodium tert-butoxide (179 mg), Pd 2 (dba) 3 (10.3 mg) and 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (21.5 mg) A toluene (2 mL) solution of was stirred at 100 ° C. for 17 hours under a nitrogen atmosphere, the reaction mixture was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1) to give tert-butyl [6- (cyclopropylamino) -1,1-dioxide-3,4-dihydro -2H-thiochromen-4-yl] [2- (2,5-difluorophenoxy) ethyl] carbamate was obtained. To the resulting tert-butyl [6- (cyclopropylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5-difluorophenoxy) ethyl] carbamate A 4N hydrogen chloride / ethyl acetate solution (2 mL) was added. The solvent was evaporated under reduced pressure, neutralized with sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative liquid chromatography to give the title compound (17 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 0.48-0.57 (2H, m), 0.72-0.84 (2H, m), 2.39-2.68 (3H, m), 3.05-3.29 (3H, m), 3.73 ( 1H, ddd, J = 13.5, 10.4, 3.3 Hz), 3.93-4.03 (1H, m), 4.04-4.23 (2H, m), 4.55 (1H, br), 6.50-6.64 (1H, m), 6.70 ( 1H, ddd, J = 9.7, 6.8, 3.0 Hz), 6.75-6.83 (2H, m), 7.01 (1H, ddd, J = 10.7, 8.9, 5.4 Hz), 7.71 (1H, d, J = 9.1 Hz) (A NH peak was not observed).
実施例８１
N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-エチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド二塩酸塩
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（300 mg）、エチルアミンの２Ｍ ＴＨＦ溶液（1.04 mL）を用いて実施例４９の工程１と同様の手法によりtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(エチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（98.6 mg）を得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(エチルアミノ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（98.6 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（20.5 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.16 (3H, t, J= 7.2 Hz), 2.73 (2H, d, J= 4.2 Hz), 3.02-3.22 (2H, m), 3.36-3.57 (3H, m), 3.62-3.80 (2H, m), 4.44 (2H, t, J= 4.9 Hz), 4.76 (1H, br), 6.66 (1H, br), 6.75-6.91 (3H, m), 7.15-7.37 (2H, m), 7.54 (1H, d, J= 8.7 Hz), 9.75 (2H, br). Example 81
N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - ethyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide dihydrochloride Reference Example 31 steps Tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (300 mg) ), Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (ethylamino) -1 , 1-Dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (98.6 mg) was obtained. The resulting tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (ethylamino) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (98.6 mg) was used to obtain the title compound (20.5 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.16 (3H, t, J = 7.2 Hz), 2.73 (2H, d, J = 4.2 Hz), 3.02-3.22 (2H, m), 3.36-3.57 (3H, m), 3.62-3.80 (2H, m), 4.44 (2H, t, J = 4.9 Hz), 4.76 (1H, br), 6.66 (1H, br), 6.75-6.91 (3H, m), 7.15-7.37 (2H, m), 7.54 (1H, d, J = 8.7 Hz), 9.75 (2H, br).
実施例８２
N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-(1-メチルエチル)-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド二塩酸塩
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（300 mg）、イソプロピルアミン（123 mg）を用いて実施例４９の工程１及び工程２と同様の手法により標題化合物（20.5 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.14 (6H, dd, J= 6.1, 4.5 Hz), 2.74 (2H, br), 3.34-3.56 (3H, m), 3.58-3.70 (2H, m), 4.44 (2H, t, J= 4.9 Hz), 4.75 (1H, br), 6.51 (1H, br), 6.72-6.91 (3H, m), 7.15-7.37 (2H, m), 7.53 (1H, d, J= 9.1 Hz), 9.63 (2H, br)（A HCl peak was not observed）. Example 82
N 4 - [2- (2,5- difluorophenoxy) ethyl] -N 6 - (1- methylethyl) -3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide dihydrochloride Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl obtained in Step 1 of Reference Example 31 The title compound (20.5 mg) was obtained in the same manner as in Step 1 and Step 2 of Example 49 using carbamate (300 mg) and isopropylamine (123 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.14 (6H, dd, J = 6.1, 4.5 Hz), 2.74 (2H, br), 3.34-3.56 (3H, m), 3.58-3.70 (2H, m), 4.44 (2H, t, J = 4.9 Hz), 4.75 (1H, br), 6.51 (1H, br), 6.72-6.91 (3H, m), 7.15-7.37 (2H, m), 7.53 (1H , d, J = 9.1 Hz), 9.63 (2H, br) (A HCl peak was not observed).
実施例８３
(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)メタノール塩酸塩
　参考例４８で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ヒドロキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（200 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（142 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.81 (2H, br), 3.22-3.45 (3H, m), 3.57-3.74 (1H, m), 3.85-4.00 (1H, m), 4.45 (2H, br), 4.61 (1H, s), 4.90 (1H, br), 5.17 (1H, s), 6.76-6.90 (1H, m), 7.14-7.36 (2H, m), 7.68 (1H, t, J= 7.9 Hz), 7.79-8.02 (2H, m), 9.93 (2H, br). Example 83
(4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methanol hydrochloride obtained in Reference Example 48 tert-Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (200 mg) Was used to give the title compound (142 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.81 (2H, br), 3.22-3.45 (3H, m), 3.57-3.74 (1H, m), 3.85-4.00 (1H, m), 4.45 ( 2H, br), 4.61 (1H, s), 4.90 (1H, br), 5.17 (1H, s), 6.76-6.90 (1H, m), 7.14-7.36 (2H, m), 7.68 (1H, t, J = 7.9 Hz), 7.79-8.02 (2H, m), 9.93 (2H, br).
実施例８４
N-[2-(2,5-ジフルオロフェノキシ)エチル]-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド
　実施例１１０で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（200 mg）および10%パラジウム炭素（0.05 g）のメタノール（1 mL）溶液を水素雰囲気下、室温で3時間撹拌した。触媒をろ別した後、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:7～4:1）で精製して標題化合物（88.1 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.32-2.45 (2H, m), 2.95 (2H, d, J= 3.8 Hz), 3.43-3.55 (1H, m), 3.76-3.90 (1H, m), 3.97-4.08 (1H, m), 4.13 (2H, t, J= 5.7 Hz),6.75 (1H, tt, J= 8.5, 3.2 Hz), 7.14 (1H, ddd, J= 10.5, 7.3, 3.0 Hz), 7.25 (1H, ddd, J= 11.1, 9.1, 5.5 Hz), 7.31-7.41 (1H, m), 7.50 (1H, d, J= 7.9 Hz), 7.57-7.68 (1H, m) Example 84
N- [2- (2,5-Difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide 6-Bromo-N obtained in Example 110 -[2- (2,5-Difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (200 mg) and 10% palladium on carbon (0.05 g) Of methanol (1 mL) was stirred in a hydrogen atmosphere at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 7-4: 1) to give the title compound (88.1 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.32-2.45 (2H, m), 2.95 (2H, d, J = 3.8 Hz), 3.43-3.55 (1H, m), 3.76-3.90 (1H, m), 3.97-4.08 (1H, m), 4.13 (2H, t, J = 5.7 Hz), 6.75 (1H, tt, J = 8.5, 3.2 Hz), 7.14 (1H, ddd, J = 10.5, 7.3, 3.0 Hz), 7.25 (1H, ddd, J = 11.1, 9.1, 5.5 Hz), 7.31-7.41 (1H, m), 7.50 (1H, d, J = 7.9 Hz), 7.57-7.68 (1H, m)
実施例８５
N4-[2-(2,5-ジフルオロフェノキシ)エチル]-8-メトキシ-N6-メチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン 1,1-ジオキシド二塩酸塩
　実施例１１０で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド（225 mg）及びメチルアミンの40％メタノール溶液（116 mｇ）を用いて実施例４９の工程１及び工程２と同様の手法により標題化合物（76.5 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.57-2.71 (2H, m), 2.76 (3H, br), 3.26-3.42 (2H, m), 3.57-3.73 (1H, m), 3.80 (3H, s), 4.43 (2H, br), 4.67 (1H, br), 6.32 (1H, s), 6.46 (1H, br), 6.63 (1H, br), 6.76-6.93 (1H, m), 7.13-7.39 (2H, m), 9.39-9.96 (2H, m)（A HCl peak and a NH peak were not observed）. Example 85
N 4 - [2- (2,5- difluorophenoxy) ethyl] -8-methoxy -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide dihydrochloride salt [ 6-Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 110 (225 mg) and a 40% methanol solution of methylamine (116 mg), and the title compound (76.5 mg) was obtained in the same manner as in Step 1 and Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.57-2.71 (2H, m), 2.76 (3H, br), 3.26-3.42 (2H, m), 3.57-3.73 (1H, m), 3.80 ( 3H, s), 4.43 (2H, br), 4.67 (1H, br), 6.32 (1H, s), 6.46 (1H, br), 6.63 (1H, br), 6.76-6.93 (1H, m), 7.13 -7.39 (2H, m), 9.39-9.96 (2H, m) (A HCl peak and a NH peak were not observed).
実施例８６
(-)-N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-メチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド塩酸塩
　参考例５０で得られた保持時間小の化合物（192 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（102 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.59-2.87 (5H, m), 3.38-3.60 (3H, m), 3.72 (1H, br), 4.42 (2H, br), 4.77 (1H, br), 6.64-6.92 (4H, m), 7.16-7.37 (2H, m), 7.56 (1H, d, J= 8.7 Hz), 9.38-9.77 (2H, m).[α]Ｄ 25 -58.4°（ｃ 0.229、ＭｅＯＨ）. Example 86
(-) - N 4 - [ 2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride Example The title compound (102 mg) was obtained in the same manner as in Step 2 of Example 49 using the compound (192 mg) having a short retention time obtained in 50. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.59-2.87 (5H, m), 3.38-3.60 (3H, m), 3.72 (1H, br), 4.42 (2H, br), 4.77 (1H, br), 6.64-6.92 (4H, m), 7.16-7.37 (2H, m), 7.56 (1H, d, J = 8.7 Hz), 9.38-9.77 (2H, m). [α] D 25 -58.4 ° (C 0.229, MeOH).
実施例８７
(+)-N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-メチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド塩酸塩
　参考例５１で得られた保持時間大の化合物（192 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（83.2 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.57-2.84 (5H, m), 3.40-3.57 (3H, m), 3.72 (1H, br), 4.42 (2H, br), 4.76 (1H, br), 6.63-6.89 (4H, m), 7.15-7.37 (2H, m), 7.56 (1H, d, J= 8.3 Hz), 9.35-9.79 (2H, m).[α]Ｄ 25 +57.4°（ｃ 0.226、ＭｅＯＨ）. Example 87
(+) - N 4 - [ 2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide hydrochloride Example The title compound (83.2 mg) was obtained in the same manner as in Step 2 of Example 49 using the compound having a long retention time (192 mg) obtained in 51. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.57-2.84 (5H, m), 3.40-3.57 (3H, m), 3.72 (1H, br), 4.42 (2H, br), 4.76 (1H, br), 6.63-6.89 (4H, m), 7.15-7.37 (2H, m), 7.56 (1H, d, J = 8.3 Hz), 9.35-9.79 (2H, m). [α] D 25 + 57.4 ° (C 0.226, MeOH).
実施例８８
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(メトキシメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例４８で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ヒドロキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（200 mg）、水酸化カリウム（57.8 mg）及びヨウ化メチル（118 mg）のＤＭＳＯ（1.5 mL）溶液を80℃で19時間撹拌した。反応液を氷に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝1:9～1:1）で精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メトキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（122 mg）を得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(メトキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマートを用いて実施例４９の工程２と同様の手法により標題化合物（59.6 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.67-2.93 (2H, m), 3.35 (3H, s), 3.50-3.70 (3H, m), 3.88 (1H, br), 4.41 (2H, br), 4.52 (2H, s), 4.91 (1H, br), 6.75-6.91 (1H, m), 7.14-7.39 (2H, m), 7.66 (1H, br), 7.90 (2H, br), 9.24-9.87 (2H, m). Example 88
N- [2- (2,5-difluorophenoxy) ethyl] -6- (methoxymethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 48 tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (200 mg), A solution of potassium hydroxide (57.8 mg) and methyl iodide (118 mg) in DMSO (1.5 mL) was stirred at 80 ° C. for 19 hours. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 1) to give tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methoxymethyl) -1,1-Dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (122 mg) was obtained. Using the obtained tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (methoxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate In the same manner as in Step 2 of Example 49, the title compound (59.6 mg) was obtained. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.67-2.93 (2H, m), 3.35 (3H, s), 3.50-3.70 (3H, m), 3.88 (1H, br), 4.41 (2H, br), 4.52 (2H, s), 4.91 (1H, br), 6.75-6.91 (1H, m), 7.14-7.39 (2H, m), 7.66 (1H, br), 7.90 (2H, br), 9.24 -9.87 (2H, m).
実施例８９
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1H-ピラゾール-1-イル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（400 mg）、2-ジtert-ブチルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル（31.9 mg）、ナトリウムtert-ブトキシド（108 mg）、ピラゾール（66.5 mg）及びPd2(dba)3（17.2 mg）のトルエン（2 mL）溶液を 100℃で 17時間、窒素雰囲気下撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～1:1）で精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][1,1-ジオキシド-6-(1H-ピラゾール-1-イル)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（369 mg）を得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][1,1-ジオキシド-6-(1H-ピラゾール-1-イル)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（369 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（224 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.84 (2H, br), 3.57-3.74 (3H, m), 3.92 (1H, br), 4.45 (2H, br), 4.98 (1H, br), 6.67 (1H, d, J= 2.3 Hz), 6.76-6.89 (1H, m), 7.14-7.35 (2H, m), 7.88 (1H, d, J= 1.5 Hz), 8.05 (1H, d, J= 8.7 Hz), 8.17 (1H, br), 8.52 (1H, br), 8.69 (1H, br), 9.79 (2H, br). Example 89
N- [2- (2,5-Difluorophenoxy) ethyl] -6- (1H-pyrazol-1-yl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Reference Example 31 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate obtained in step 1 of 31 (400 mg), 2-ditert-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl (31.9 mg), sodium tert-butoxide (108 mg), pyrazole (66.5 mg) and Pd 2 (dba ) 3 (17.2 mg) in toluene (2 mL) was stirred at 100 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 1: 1) to give tert-butyl [2- (2,5-difluorophenoxy) ethyl] [1,1-dioxide- 6- (1H-pyrazol-1-yl) -3,4-dihydro-2H-thiochromen-4-yl] carbamate (369 mg) was obtained. The resulting tert-butyl [2- (2,5-difluorophenoxy) ethyl] [1,1-dioxide-6- (1H-pyrazol-1-yl) -3,4-dihydro-2H-thiochromene-4- The title compound (224 mg) was obtained in the same manner as in Step 2 of Example 49 using [Il] carbamate (369 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.84 (2H, br), 3.57-3.74 (3H, m), 3.92 (1H, br), 4.45 (2H, br), 4.98 (1H, br) , 6.67 (1H, d, J = 2.3 Hz), 6.76-6.89 (1H, m), 7.14-7.35 (2H, m), 7.88 (1H, d, J = 1.5 Hz), 8.05 (1H, d, J = 8.7 Hz), 8.17 (1H, br), 8.52 (1H, br), 8.69 (1H, br), 9.79 (2H, br).
実施例９０
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1H-イミダゾール-1-イル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド二塩酸塩
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（400 mg）、2-ジtert-ブチルホスフィノ-3,4,5,6-テトラメチル-2’,4’,6’-トリイソプロピルビフェニル（36.1 mg）、リン酸カリウム（239 mg）、イミダゾール（66.5 mg）及びPd2(dba)3（17.2 mg）のトルエン（3 mL）溶液を 100℃で 17時間、窒素雰囲気下撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水、続いて飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 2:3～17:3）で精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(1H-イミダゾール-1-イル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（53.4 mg）を得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(1H-イミダゾール-1-イル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（53.4 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（31.9 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.69-3.02 (2H, m), 3.61 (2H, br), 3.73 (1H, d, J= 7.9 Hz), 4.01 (1H, d, J= 11.3 Hz), 4.47-4.62 (2H, m), 5.02 (1H, br), 6.76-6.88 (1H, m), 7.17-7.34 (2H, m), 7.84 (1H, s), 8.10-8.22 (2H, m), 8.48 (1H, s), 8.71 (1H, s), 9.70 (1H, s), 10.52 (1H, s) （A HCl peak was not observed）. Example 90
N- [2- (2,5-Difluorophenoxy) ethyl] -6- (1H-imidazol-1-yl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide dihydrochloride Reference Tert-Butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] obtained in Step 1 of Example 31 Carbamate (400 mg), 2-ditert-butylphosphino-3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropylbiphenyl (36.1 mg), potassium phosphate (239 mg) , A solution of imidazole (66.5 mg) and Pd 2 (dba) 3 (17.2 mg) in toluene (3 mL) was stirred at 100 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3 to 17: 3) to give tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (1H-imidazole). -1-yl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (53.4 mg) was obtained. The resulting tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (1H-imidazol-1-yl) -1,1-dioxide-3,4-dihydro-2H-thiochromene-4- The title compound (31.9 mg) was obtained in the same manner as in Step 2 of Example 49 using [Il] carbamate (53.4 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.69-3.02 (2H, m), 3.61 (2H, br), 3.73 (1H, d, J = 7.9 Hz), 4.01 (1H, d, J = 11.3 Hz), 4.47-4.62 (2H, m), 5.02 (1H, br), 6.76-6.88 (1H, m), 7.17-7.34 (2H, m), 7.84 (1H, s), 8.10-8.22 (2H , m), 8.48 (1H, s), 8.71 (1H, s), 9.70 (1H, s), 10.52 (1H, s) (A HCl peak was not observed).
実施例９１
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-[(メチルアミノ)メチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド
　参考例４８で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ヒドロキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（249 mg）、塩化メタンスルホニル（70.7 mg）及びＥｔ3Ｎ（104 mg）のＴＨＦ（1.5 mL）溶液を0℃で1時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣に2 Ｍメチルアミン／ＴＨＦ（1.03 mL）溶液を加え、50℃で20時間撹拌した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:1～1:0）で精製して標題化合物（13.5 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.39-2.57 (4H, m), 2.59-2.73 (1H, m, J= 14.6, 11.3, 3.2, 3.2 Hz), 3.12 (2H, t, J= 4.9 Hz), 3.26 (1H, ddd, J= 13.6, 7.3, 2.7 Hz), 3.76-3.91 (3H, m), 4.01-4.21 (3H, m), 6.55-6.64 (1H, m), 6.70 (1H, ddd, J= 9.7, 6.7, 2.9 Hz), 7.02 (1H, ddd, J= 10.7, 9.1, 5.2 Hz), 7.39-7.51 (2H, m), 7.87 (1H, d, J= 8.2 Hz).  Example 91
N- [2- (2,5-difluorophenoxy) ethyl] -6-[(methylamino) methyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Reference Example 48 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (249 mg) , A solution of methanesulfonyl chloride (70.7 mg) and Et 3 N (104 mg) in THF (1.5 mL) was stirred at 0 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. A 2 M methylamine / THF (1.03 mL) solution was added to the resulting residue, and the mixture was stirred at 50 ° C. for 20 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 1: 0) to give the title compound (13.5 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.39-2.57 (4H, m), 2.59-2.73 (1H, m, J = 14.6, 11.3, 3.2, 3.2 Hz), 3.12 (2H, t, J = 4.9 Hz), 3.26 (1H, ddd, J = 13.6, 7.3, 2.7 Hz), 3.76-3.91 (3H, m), 4.01-4.21 (3H, m), 6.55-6.64 (1H, m), 6.70 (1H, ddd, J = 9.7, 6.7, 2.9 Hz), 7.02 (1H, ddd, J = 10.7, 9.1, 5.2 Hz), 7.39-7.51 (2H, m), 7.87 (1H, d, J = 8.2 Hz).
実施例９２
N-[(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)メチル]アセトアミド塩酸塩
　実施例１１１で得られた6-(アミノメチル)-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（121 mg）及びＥｔ3Ｎ（32.1 mg）のＴＨＦ（1.5 mL）溶液に塩化アセチル（24.8 mg）を0℃で加えた。反応液を同温で2時間撹拌し、反応液を水に注いだ後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:1～1:0）で精製してN-[(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)メチル]アセトアミド（108 mg）を得た。得られたN-[(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)メチル]アセトアミド（108 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（77.7 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.90 (3H, s), 2.81 (2H, br), 3.47-3.72 (3H, m), 3.90 (1H, br), 4.23-4.53 (4H, m), 4.89 (1H, br), 6.84 (1H, br), 7.22 (2H, br, 7.58 (1H, br), 7.75-7.98 (2H, m), 8.51 (1H, br), 9.78 (2H, br). Example 92
N-[(4-{[2- (2,5-Difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methyl] acetamide hydrochloride Examples 6- (Aminomethyl) -N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in 111 (121 mg) Acetyl chloride (24.8 mg) was added at 0 ° C. to a solution of Et 3 N (32.1 mg) in THF (1.5 mL). The reaction solution was stirred at the same temperature for 2 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1 to 1: 0) to give N-[(4-{[2- (2,5-difluorophenoxy) ethyl] amino}- 1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methyl] acetamide (108 mg) was obtained. N-[(4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methyl] acetamide ( 108 mg) was used to give the title compound (77.7 mg) in the same manner as in Step 2 of Example 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.90 (3H, s), 2.81 (2H, br), 3.47-3.72 (3H, m), 3.90 (1H, br), 4.23-4.53 (4H, m), 4.89 (1H, br), 6.84 (1H, br), 7.22 (2H, br, 7.58 (1H, br), 7.75-7.98 (2H, m), 8.51 (1H, br), 9.78 (2H, br).
実施例９３
(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)メタノール
　参考例４８で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ヒドロキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（160 mg）に４Ｎ塩化水素／イソプロピルアルコール溶液（1.5 mL）を加えた。溶媒を減圧下留去した後、水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 2:3～3:1）で精製して標題化合物（74.2 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.44-2.58 (1H, ｍ), 2.60-2.73 (1H, m), 3.12（2H, t, J= 4.9 Hz）, 3.22-3.32 (1H, m), 3.84(1H, ddd, J= 13.8, 10.8, 3.0 Hz), 4.02-4.21 (3H, m), 4.76 (2H, s), 6.61 (1H, tt, J= 8.4, 3.2 Hz), 6.70 (1H, ddd, J=9.5, 6.7, 3.0 Hz), 7.03 (1H, ddd, J= 11.0, 9.1, 5.3 Hz), 7.47 (1H, d, J= 8.3 Hz), 7.53 (1H, s), 7.90 (1H, d, J= 7.9 Hz) (A NH peak and an OH peak were not observed). Example 93
(4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) methanol obtained in Reference Example 48 4N chloride in butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (160 mg) Hydrogen / isopropyl alcohol solution (1.5 mL) was added. The solvent was distilled off under reduced pressure, neutralized with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3-3: 1) to give the title compound (74.2 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.44-2.58 (1H, m), 2.60-2.73 (1H, m), 3.12 (2H, t, J = 4.9 Hz), 3.22-3.32 (1H, m) , 3.84 (1H, ddd, J = 13.8, 10.8, 3.0 Hz), 4.02-4.21 (3H, m), 4.76 (2H, s), 6.61 (1H, tt, J = 8.4, 3.2 Hz), 6.70 (1H , ddd, J = 9.5, 6.7, 3.0 Hz), 7.03 (1H, ddd, J = 11.0, 9.1, 5.3 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.53 (1H, s), 7.90 ( (1H, d, J = 7.9 Hz) (A NH peak and an OH peak were not observed).
実施例９４
3-(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)-N-メチルプロパンアミド塩酸塩
　参考例５３で得られた3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパン酸（182 mg）、2 Ｍメチルアミン／ＴＨＦ溶液（208 μL）、ＨＯＢｔ(51.3 mg)、ＷＳＣ(72.9 mg)及びジイソプロピルエチルアミン(98.4 mg)のＤＭＦ(1.5 mL)溶液を室温で17時間撹拌した。反応液を水に注いだ後、酢酸エチルで抽出した。有機層を水、続いて飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:1～1:0）で精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル]{6-[3-(メチルアミノ)-3-オキソプロピル]-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル}カルバマートを得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル]{6-[3-(メチルアミノ)-3-オキソプロピル]-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル}カルバマートを用いて実施例４９の工程２と同様の手法により標題化合物（18.5 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.38-2.49 (3H, m), 2.54 (3H, d, J= 4.5 Hz), 2.67-2.86 (2H, m), 2.91 (2H, t, J= 7.6 Hz), 3.58-3.69 (2H, m), 3.86 (1H, d, J= 10.2 Hz), 4.45 (2H, br), 4.87 (1H, br), 6.74-6.90 (1H, m), 7.17-7.39 (2H, m), 7.54 (1H, d, J= 7.6 Hz), 7.74-7.91 (3H, m), 9.76 (2H, br). Example 94
3- (4-{[2- (2,5-Difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) -N-methylpropanamide hydrochloride 3- (4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromene obtained in Reference Example 53 -6-yl) propanoic acid (182 mg), 2 M methylamine / THF solution (208 μL), HOBt (51.3 mg), WSC (72.9 mg) and diisopropylethylamine (98.4 mg) in DMF (1.5 mL) Stir at room temperature for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1 to 1: 0) to give tert-butyl [2- (2,5-difluorophenoxy) ethyl] {6- [3- ( Methylamino) -3-oxopropyl] -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl} carbamate was obtained. The resulting tert-butyl [2- (2,5-difluorophenoxy) ethyl] {6- [3- (methylamino) -3-oxopropyl] -1,1-dioxide-3,4-dihydro-2H- The title compound (18.5 mg) was obtained in the same manner as in Step 2 of Example 49 using thiochromen-4-yl} carbamate. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.38-2.49 (3H, m), 2.54 (3H, d, J = 4.5 Hz), 2.67-2.86 (2H, m), 2.91 (2H, t, J = 7.6 Hz), 3.58-3.69 (2H, m), 3.86 (1H, d, J = 10.2 Hz), 4.45 (2H, br), 4.87 (1H, br), 6.74-6.90 (1H, m), 7.17-7.39 (2H, m), 7.54 (1H, d, J = 7.6 Hz), 7.74-7.91 (3H, m), 9.76 (2H, br).
実施例９５
メチル (2E)-3-(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパ-2-エノアート塩酸塩
　参考例５３の工程１で得られたメチル (2E)-3-(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)プロパ-2-エノアート（200 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（113 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.66-2.94 (2H, m), 3.47-3.73 (3H, m), 3.76 (3H, s), 3.93 (1H, br), 4.46 (2H, br), 4.91 (1H, d, J= 6.0 Hz), 6.77-6.95 (2H, m), 7.14-7.36 (2H, m), 7.70 (1H, d, J= 15.9 Hz), 7.88-7.98 (1H, m), 7.98-8.07 (1H, m), 8.35 (1H, br), 9.88 (2H, br). Example 95
Methyl (2E) -3- (4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) propa-2 -Enoate hydrochloride Methyl (2E) -3- (4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1 obtained in Step 1 of Reference Example 53 The title compound (113 mg) was obtained in the same manner as in Step 2 of Example 49 using -dioxide-3,4-dihydro-2H-thiochromen-6-yl) prop-2-enoate (200 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.66-2.94 (2H, m), 3.47-3.73 (3H, m), 3.76 (3H, s), 3.93 (1H, br), 4.46 (2H, br), 4.91 (1H, d, J = 6.0 Hz), 6.77-6.95 (2H, m), 7.14-7.36 (2H, m), 7.70 (1H, d, J = 15.9 Hz), 7.88-7.98 (1H , m), 7.98-8.07 (1H, m), 8.35 (1H, br), 9.88 (2H, br).
実施例９６
2-[(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)オキシ]アセトアミド塩酸塩
　参考例５４で得られたtert-ブチル [6-(2-アミノ-2-オキソエトキシ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル][2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（228 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（160 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.66-2.93 (2H, m), 3.43-3.66 (3H, m), 3.78-3.94 (1H, m), 4.37-4.51 (2H, m), 4.57-4.71 (2H, m), 4.87 (1H, br), 6.83 (1H, tt, J= 8.5, 3.2 Hz), 7.17-7.36 (3H, m), 7.45 (1H, br), 7.60 (2H, d, J= 7.2 Hz), 7.86 (1H, d, J= 8.7 Hz), 9.94 (2H, br). Example 96
2-[(4-{[2- (2,5-Difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) oxy] acetamide hydrochloride Reference Example Tert-butyl [6- (2-amino-2-oxoethoxy) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] [2- (2,5- The title compound (160 mg) was obtained in the same manner as in Step 2 of Example 49 using [difluorophenoxy) ethyl] carbamate (228 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.66-2.93 (2H, m), 3.43-3.66 (3H, m), 3.78-3.94 (1H, m), 4.37-4.51 (2H, m), 4.57-4.71 (2H, m), 4.87 (1H, br), 6.83 (1H, tt, J = 8.5, 3.2 Hz), 7.17-7.36 (3H, m), 7.45 (1H, br), 7.60 (2H, d, J = 7.2 Hz), 7.86 (1H, d, J = 8.7 Hz), 9.94 (2H, br).
実施例９７
メチル [(4-{[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)オキシ]アセタート塩酸塩
　参考例５５で得られたメチル [(4-{(tert-ブトキシカルボニル)[2-(2,5-ジフルオロフェノキシ)エチル]アミノ}-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-6-イル)オキシ]アセタート（274 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（200 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.68-2.92 (2H, m), 3.49-3.66 (3H, m), 3.70 (3H, s), 3.79-3.98 (1H, m), 4.48 (2H, t, J= 4.9 Hz), 4.89 (1H, br), 5.01 (2H, s), 6.83 (1H, tt, J= 8.6, 3.2 Hz), 7.16-7.38 (3H, m), 7.68 (1H, d, J= 1.9 Hz), 7.84 (1H, d, J= 9.1 Hz), 10.07 (2H, br). Example 97
Methyl [(4-{[2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromen-6-yl) oxy] acetate hydrochloride Reference Example 55 [(4-{(tert-butoxycarbonyl) [2- (2,5-difluorophenoxy) ethyl] amino} -1,1-dioxide-3,4-dihydro-2H-thiochromene-6- The title compound (200 mg) was obtained in the same manner as in Step 2 of Example 49 using (yl) oxy] acetate (274 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.68-2.92 (2H, m), 3.49-3.66 (3H, m), 3.70 (3H, s), 3.79-3.98 (1H, m), 4.48 ( 2H, t, J = 4.9 Hz), 4.89 (1H, br), 5.01 (2H, s), 6.83 (1H, tt, J = 8.6, 3.2 Hz), 7.16-7.38 (3H, m), 7.68 (1H , d, J = 1.9 Hz), 7.84 (1H, d, J = 9.1 Hz), 10.07 (2H, br).
実施例９８
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(2-メトキシエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例５６で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(2-メトキシエトキシ)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（267 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（118 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.79 (2H, br), 3.31 (3H, s), 3.44-3.65 (3H, m), 3.69 (2H, t, J= 4.4 Hz), 3.76-3.93 (1H, m), 4.16-4.35 (2H, m), 4.45 (2H, br), 4.88 (1H, d, J= 5.3 Hz), 6.83 (1H, tt, J= 8.6, 3.1 Hz), 7.17-7.37 (3H, m), 7.58 (1H, br), 7.83 (1H, d, J= 8.7 Hz), 9.85 (2H, br). Example 98
N- [2- (2,5-Difluorophenoxy) ethyl] -6- (2-methoxyethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Obtained in Reference Example 56 Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [6- (2-methoxyethoxy) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate ( The title compound (118 mg) was obtained in the same manner as in Step 2 of Example 49 using 267 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.79 (2H, br), 3.31 (3H, s), 3.44-3.65 (3H, m), 3.69 (2H, t, J = 4.4 Hz), 3.76 -3.93 (1H, m), 4.16-4.35 (2H, m), 4.45 (2H, br), 4.88 (1H, d, J = 5.3 Hz), 6.83 (1H, tt, J = 8.6, 3.1 Hz), 7.17-7.37 (3H, m), 7.58 (1H, br), 7.83 (1H, d, J = 8.7 Hz), 9.85 (2H, br).
実施例９９
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(2,2,2-トリフルオロエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例５７で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][1,1-ジオキシド-6-(2,2,2-トリフルオロエトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（267 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（143 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.80 (2H, br), 3.33-3.72 (3H, m), 3.80-3.98 (1H, m, J= 10.5 Hz), 4.47 (2H, br), 4.78-5.09 (3H, m), 6.83 (1H, tt, J= 8.5, 3.2 Hz), 7.15-7.45 (3H, m), 7.77 (1H, br), 7.90 (1H, d, J= 9.0 Hz), 9.95 (2H, br). Example 99
N- [2- (2,5-Difluorophenoxy) ethyl] -6- (2,2,2-trifluoroethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride Tert-butyl [2- (2,5-difluorophenoxy) ethyl] [1,1-dioxide-6- (2,2,2-trifluoroethoxy) -3,4-dihydro- obtained in Reference Example 57 The title compound (143 mg) was obtained in the same manner as in Step 2 of Example 49 using [2H-thiochromen-4-yl] carbamate (267 mg). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.80 (2H, br), 3.33-3.72 (3H, m), 3.80-3.98 (1H, m, J = 10.5 Hz), 4.47 (2H, br) , 4.78-5.09 (3H, m), 6.83 (1H, tt, J = 8.5, 3.2 Hz), 7.15-7.45 (3H, m), 7.77 (1H, br), 7.90 (1H, d, J = 9.0 Hz ), 9.95 (2H, br).
実施例１００
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例５８で得られた2-(2,5-ジフルオロフェノキシ)-N-(6-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)アセトアミド（741 mg）を用いて実施例１０９と同様の手法によりN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（268 mg）を得た。得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（268 mg）を用いて実施例４９の工程２と同様の手法により標題化合物（252 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.80 (2H, br), 3.50 (2H, br), 3.61-3.75 (1H, m), 3.85-4.00 (1H, m), 4.45 (2H, br), 4.93 (1H, br), 6.75-6.93 (1H, m), 7.14-7.39 (2H, m), 7.49-7.67 (1H, m), 7.86-8.12 (2H, m, J= 8.9, 5.5 Hz), 10.03 (2H, br). Example 100
N- [2- (2,5-difluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride 2- (2) obtained in Reference Example 58 2,5-Difluorophenoxy) -N- (6-Fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) acetamide (741 mg) similar procedure as Example 109 Gave N- [2- (2,5-difluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (268 mg). Example using the obtained N- [2- (2,5-difluorophenoxy) ethyl] -6-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (268 mg) The title compound (252 mg) was obtained by a method similar to that in Step 2 of 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.80 (2H, br), 3.50 (2H, br), 3.61-3.75 (1H, m), 3.85-4.00 (1H, m), 4.45 (2H, br), 4.93 (1H, br), 6.75-6.93 (1H, m), 7.14-7.39 (2H, m), 7.49-7.67 (1H, m), 7.86-8.12 (2H, m, J = 8.9, 5.5 Hz), 10.03 (2H, br).
実施例１０１
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３０で得られた2-(2,5-ジフルオロフェノキシ)-N-[1,1-ジオキシド-6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-イル]アセトアミド（1.28 g）を用いて実施例１０９と同様の手法によりN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシドを得た。得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(トリフルオロメチル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシドを用いて実施例４９の工程２と同様の手法により標題化合物（686 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.84 (2H, br), 3.54 (2H, br), 3.67-3.81 (1H, m, J= 8.7 Hz), 3.94-4.11 (1H, m), 4.44 (2H, br), 5.00 (1H, br), 6.78-6.90 (1H, m), 7.17-7.36 (2H, m), 8.03-8.20 (2H, m), 8.41 (1H, br), 9.86 (2H, br). Example 101
N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 30 2- (2,5-difluorophenoxy) -N- [1,1-dioxide-6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-yl] acetamide (1.28 g) In the same manner as in Example 109, N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1- Dioxide was obtained. Examples using the obtained N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide The title compound (686 mg) was obtained in the same manner as in Step 2 of 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.84 (2H, br), 3.54 (2H, br), 3.67-3.81 (1H, m, J = 8.7 Hz), 3.94-4.11 (1H, m) , 4.44 (2H, br), 5.00 (1H, br), 6.78-6.90 (1H, m), 7.17-7.36 (2H, m), 8.03-8.20 (2H, m), 8.41 (1H, br), 9.86 (2H, br).
実施例１０２
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例５２で得られた2-(2,5-ジフルオロフェノキシ)-N-[1,1-ジオキシド-6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-イル]アセトアミド（1.28 g）を用いて実施例１０９と同様の手法によりN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシドを得た。得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(トリフルオロメトキシ)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシドを用いて実施例４９の工程２と同様の手法により標題化合物（600 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.83 (2H, br), 3.37-3.60 (2H, m), 3.68-3.75 (1H, m), 3.95 (1H, d, J= 9.8 Hz), 4.45 (2H, br), 4.96 (1H, br), 6.75-6.88 (1H, m), 7.15-7.37 (2H, m), 7.73 (1H, d, J= 8.7 Hz), 8.08 (2H, d, J= 8.7 Hz), 10.05 (2H, br). Example 102
N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Reference Example 52 2- (2,5-difluorophenoxy) -N- [1,1-dioxide-6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-yl] acetamide (1.28 g) In the same manner as in Example 109, N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1- Dioxide was obtained. Example using the obtained N- [2- (2,5-difluorophenoxy) ethyl] -6- (trifluoromethoxy) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide The title compound (600 mg) was obtained by a method similar to that in Step 2 of 49. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.83 (2H, br), 3.37-3.60 (2H, m), 3.68-3.75 (1H, m), 3.95 (1H, d, J = 9.8 Hz) , 4.45 (2H, br), 4.96 (1H, br), 6.75-6.88 (1H, m), 7.15-7.37 (2H, m), 7.73 (1H, d, J = 8.7 Hz), 8.08 (2H, d , J = 8.7 Hz), 10.05 (2H, br).
実施例１０３
N-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（光学活性体、tR1（IC））
　実施例７５で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドの４つの異性体混合物（992 mg）をキラルカラムクロマトグラフィーによって分析及び光学分割した。
　ＣＨＩＲＡＬＰＡＫ　ＡＤにより分取して取得した保持時間大の分取画分を濃縮し、続いてＣＨＩＲＡＬＰＡＫ　ＩＣにより分取して取得した保持時間小の分取画分を濃縮し、標題化合物（470 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.32 (3H, d, J= 7.2 Hz), 1.88-2.43 (1H, m), 2.77-2.94 (2H, m), 2.97-3.07 (1H, m), 3.18 (1H, dd, J= 13.8, 9.6 Hz), 3.63 (1H, dd, J= 13.6, 3.4 Hz), 3.80 (1H, d, J= 7.9 Hz), 4.02-4.15 (2H, m), 6.55-6.72 (2H, m), 7.03 (1H, ddd, J= 10.6, 9.1, 5.3 Hz), 7.43-7.52 (1H, m), 7.57 (1H, td, J= 7.6, 1.5 Hz), 7.70 (1H, d, J= 7.9 Hz), 7.89-7.96 (1H, m).
キラルクロマトグラフィーによる分析条件
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ（ＭＤ027）4.6 ｍｍＩＤ×250 ｍｍＬ
溶媒：ｈｅｘａｎｅ／ＥｔＯＨ＝500／500
流速：0.5 ｍＬ／ｍｉｎ
温度：40℃
検出法：ＵＶ220 ｎｍ
キラルクロマトグラフィーによる精製条件（１）
カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（ＮＦ001）50 ｍｍＩＤ×500 ｍｍＬ
溶媒：ｈｅｘａｎｅ／ＥｔＯＨ＝500／500
流速：60 ｍＬ／ｍｉｎ
温度：30℃
検出法：ＵＶ220 ｎｍ
キラルクロマトグラフィーによる精製条件（２）
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ（ＭＥ001）50 ｍｍＩＤ×500 ｍｍＬ
溶媒：ｈｅｘａｎｅ／ＥｔＯＨ＝400／600
流速：60 ｍＬ／ｍｉｎ
温度：30℃
検出法：ＵＶ220 ｎｍ Example 103
N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active form, tR1 (IC))
Four isomers of N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 75 The mixture (992 mg) was analyzed and optically resolved by chiral column chromatography.
Concentrate the fraction with a long retention time obtained by fractionation with CHIRALPAK AD, and then concentrate the fraction with a short retention time obtained by fractionation with CHIRALPAK IC to give the title compound (470 mg) Got. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.32 (3H, d, J = 7.2 Hz), 1.88-2.43 (1H, m), 2.77-2.94 (2H, m), 2.97-3.07 (1H, m) , 3.18 (1H, dd, J = 13.8, 9.6 Hz), 3.63 (1H, dd, J = 13.6, 3.4 Hz), 3.80 (1H, d, J = 7.9 Hz), 4.02-4.15 (2H, m), 6.55-6.72 (2H, m), 7.03 (1H, ddd, J = 10.6, 9.1, 5.3 Hz), 7.43-7.52 (1H, m), 7.57 (1H, td, J = 7.6, 1.5 Hz), 7.70 ( 1H, d, J = 7.9 Hz), 7.89-7.96 (1H, m).
Analytical condition column by chiral chromatography: CHIRALPAK IC (MD027) 4.6 mmID × 250 mmL
Solvent: hexane / EtOH = 500/500
Flow rate: 0.5 mL / min
Temperature: 40 ° C
Detection method: UV220 nm
Purification conditions by chiral chromatography (1)
Column: CHIRALPAK AD (NF001) 50 mmID x 500 mmL
Solvent: hexane / EtOH = 500/500
Flow rate: 60 mL / min
Temperature: 30 ° C
Detection method: UV220 nm
Purification conditions by chiral chromatography (2)
Column: CHIRALPAK IC (ME001) 50 mmID x 500 mmL
Solvent: hexane / EtOH = 400/600
Flow rate: 60 mL / min
Temperature: 30 ° C
Detection method: UV220 nm
実施例１０４
N-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩（光学活性体、tR2（IC））
（工程１）実施例７５で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドの４つの異性体混合物（992 mg）をキラルカラムクロマトグラフィーによって分析及び光学分割した。
　ＣＨＩＲＡＬＰＡＫ　ＡＤにより分取して取得した保持時間小の分取画分を濃縮し、続いてＣＨＩＲＡＬＰＡＫ　ＡＳＨにより分取して取得した保持時間大の分取画分を濃縮し、N-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（光学活性体、tR２（IC））（140 mg）を得た。
キラルクロマトグラフィーによる分析条件
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＣ（ＭＤ027）4.6 ｍｍＩＤ×250 ｍｍＬ
溶媒：ｈｅｘａｎｅ／ＥｔＯＨ＝500／500
流速：0.5 ｍＬ／ｍｉｎ
温度：40℃
検出法：ＵＶ220 ｎｍ
キラルクロマトグラフィーによる精製条件（１）
カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ（ＮＦ００１）50 ｍｍＩＤ×500 ｍｍＬ
溶媒：ｈｅｘａｎｅ／ＥｔＯＨ＝500／500
流速：60 ｍＬ／ｍｉｎ
温度：30℃
検出法：ＵＶ220 ｎｍ
キラルクロマトグラフィーによる精製条件（２）
カラム：ＣＨＩＲＡＬＰＡＫ　ＡＳＨ（ＬＡ００５）20 ｍｍＩＤ×250 ｍｍＬ
溶媒：ＣＯ２／２－ＰｒＯＨ＝７００／３００
流速：50 ｍＬ／ｍｉｎ
温度：35℃
検出法：ＵＶ220 ｎｍ
（工程２）得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（光学活性体、tR２（IC））を用いて実施例４９の工程２と同様の手法により標題化合物（51.7 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 1.34 (3H, d, J= 6.4 Hz), 3.08 (1H, br), 3.61-4.16 (4H, m), 4.47 (2H, br), 4.80 (1H, br), 6.74-6.92 (1H, m), 7.14-7.37 (2H, m), 7.75 (3H, br), 7.92 (1H, d, J= 4.5 Hz), 9.05-10.10 (2H, m). Example 104
N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride (optically active form, tR2 (IC))
(Step 1) N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 75 The four isomer mixture (992 mg) was analyzed and optically resolved by chiral column chromatography.
Fraction fractions collected with CHIRALPAK AD and obtained with a short retention time were concentrated, and fractions obtained with fractionation using CHIRALPAK ASH and obtained with a large retention time were concentrated, and N- [2- ( 2,5-Difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active substance, tR2 (IC)) (140 mg) was obtained.
Analytical condition column by chiral chromatography: CHIRALPAK IC (MD027) 4.6 mmID × 250 mmL
Solvent: hexane / EtOH = 500/500
Flow rate: 0.5 mL / min
Temperature: 40 ° C
Detection method: UV220 nm
Purification conditions by chiral chromatography (1)
Column: CHIRALPAK AD (NF001) 50 mmID × 500 mmL
Solvent: hexane / EtOH = 500/500
Flow rate: 60 mL / min
Temperature: 30 ° C
Detection method: UV220 nm
Purification conditions by chiral chromatography (2)
Column: CHIRALPAK ASH (LA005) 20 mmID × 250 mmL
Solvent: CO 2 / 2-PrOH = 700/300
Flow rate: 50 mL / min
Temperature: 35 ° C
Detection method: UV220 nm
(Step 2) N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained (optically active substance, The title compound (51.7 mg) was obtained in the same manner as in Step 2 of Example 49 using tR2 (IC)). 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 1.34 (3H, d, J = 6.4 Hz), 3.08 (1H, br), 3.61-4.16 (4H, m), 4.47 (2H, br), 4.80 (1H, br), 6.74-6.92 (1H, m), 7.14-7.37 (2H, m), 7.75 (3H, br), 7.92 (1H, d, J = 4.5 Hz), 9.05-10.10 (2H, m ).
実施例１０５
N-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（光学活性体、tR3（IC））
　実施例７５で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドの４つの異性体混合物（992 mg）を実施例１０４と同様の手法により光学分割した。
　ＣＨＩＲＡＬＰＡＫ　ＡＤにより分取して取得した保持時間小の分取画分を濃縮し、続いてＣＨＩＲＡＬＰＡＫ　ＡＳＨにより分取して取得した保持時間小の分取画分を濃縮し、標題化合物（120 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.30 (3H, d, J= 6.8 Hz), 2.79-2.97 (1H, m), 3.12 (2H, br), 3.23 (1H, dd, J= 13.6, 3.4 Hz), 3.78 (1H, dd, J= 13.6, 11.7 Hz), 3.92 (1H, br), 4.05-4.19 (2H, m), 6.55-6.73 (2H, m), 7.02 (1H, ddd, J= 10.6, 9.1, 5.3 Hz), 7.37-7.46 (1H, m), 7.49-7.58 (2H, m), 7.91-7.99 (1H, m) (A NH peak was not observed).  Example 105
N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active form, tR3 (IC))
Four isomers of N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 75 The mixture (992 mg) was optically resolved in the same manner as in Example 104.
Concentrate the fraction with a small retention time obtained by fractionation with CHIRALPAK AD, and then concentrate the fraction with a small retention time obtained by fractionation with CHIRALPAK ASH to give the title compound (120 mg) Got. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.30 (3H, d, J = 6.8 Hz), 2.79-2.97 (1H, m), 3.12 (2H, br), 3.23 (1H, dd, J = 13.6, 3.4 Hz), 3.78 (1H, dd, J = 13.6, 11.7 Hz), 3.92 (1H, br), 4.05-4.19 (2H, m), 6.55-6.73 (2H, m), 7.02 (1H, ddd, J = 10.6, 9.1, 5.3 Hz), 7.37-7.46 (1H, m), 7.49-7.58 (2H, m), 7.91-7.99 (1H, m) (A NH peak was not observed).
実施例１０６
N-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（光学活性体、tR4（IC））
　実施例７５で得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-3-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドの４つの異性体混合物（992 mg）を実施例１０３と同様の手法により光学分割した。
　ＣＨＩＲＡＬＰＡＫ　ＡＤにより分取して取得した保持時間大の分取画分を濃縮し、続いてＣＨＩＲＡＬＰＡＫ　ＩＣにより分取して取得した保持時間大の分取画分を濃縮し、標題化合物（450 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.32 (3H, d, J= 6.8 Hz), 2.78-2.94 (2H, m), 2.97-3.07 (1H, m), 3.18 (1H, dd, J= 14.0, 9.4 Hz), 3.63 (1H, dd, J= 14.0, 3.6 Hz), 3.81 (1H, d, J= 7.9 Hz), 4.02-4.15 (2H, m), 6.56-6.72 (2H, m), 7.03 (1H, ddd, J= 10.8, 8.9, 5.3 Hz), 7.44-7.52 (1H, m), 7.53-7.61 (1H, m), 7.67-7.73 (1H, m), 7.90-7.97 (1H, m) (A NH peak was not observed). Example 106
N- [2- (2,5-Difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (optically active form, tR4 (IC))
Four isomers of N- [2- (2,5-difluorophenoxy) ethyl] -3-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide obtained in Example 75 The mixture (992 mg) was optically resolved in the same manner as in Example 103.
Concentrate the fraction with a long retention time obtained by fractionation with CHIRALPAK AD, and then concentrate the fraction with a long retention time obtained by fractionation with CHIRALPAK IC to give the title compound (450 mg) Got. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.32 (3H, d, J = 6.8 Hz), 2.78-2.94 (2H, m), 2.97-3.07 (1H, m), 3.18 (1H, dd, J = 14.0, 9.4 Hz), 3.63 (1H, dd, J = 14.0, 3.6 Hz), 3.81 (1H, d, J = 7.9 Hz), 4.02-4.15 (2H, m), 6.56-6.72 (2H, m), 7.03 (1H, ddd, J = 10.8, 8.9, 5.3 Hz), 7.44-7.52 (1H, m), 7.53-7.61 (1H, m), 7.67-7.73 (1H, m), 7.90-7.97 (1H, m (A NH peak was not observed).
実施例１０７
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド塩酸塩
　参考例３１の工程１で得られたtert-ブチル (6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)[2-(2,5-ジフルオロフェノキシ)エチル]カルバマート（532 mg）、メチルボロン酸（239 mg）、リン酸カリウム（849 mg）及びPd(PPh3)4（116 mg）の1,2-ジメトキシエタン（2 mL）溶液を 80℃で 18時間、窒素雰囲気下撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～2:3）及び分取クロマトグラフィーで精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-メチル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートを得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル](6-メチル-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)カルバマートに４Ｎ塩化水素／酢酸エチル溶液（2 mL）を加えた。溶媒を減圧下留去した後、炭酸水素ナトリウム溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣を分取液体クロマトグラフィーで精製してN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドを得た。得られたN-[2-(2,5-ジフルオロフェノキシ)エチル]-6-メチル-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシドを用いて実施例４９の工程２と同様の手法により標題化合物（19.4 mg）を得た。1H-NMR (300 MHz, DMSO-d6) δppm 2.41 (3H, s), 2.65-2.93 (2H, m), 3.48-3.69 (3H, m), 3.80-3.96 (1H, m), 4.44 (2H, br), 4.86 (1H, br), 6.76-6.90 (1H, m), 7.16-7.38 (2H, m), 7.53 (1H, d, J= 7.6 Hz), 7.70-7.86 (2H, m), 9.76 (2H, br). Example 107
N- [2- (2,5-difluorophenoxy) ethyl] -6-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide hydrochloride obtained in Step 1 of Reference Example 31 tert-butyl (6-bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) [2- (2,5-difluorophenoxy) ethyl] carbamate (532 mg), methylboronic acid ( 239 mg), potassium phosphate (849 mg) and Pd (PPh 3 ) 4 (116 mg) in 1,2-dimethoxyethane (2 mL) were stirred at 80 ° C for 18 hours under nitrogen atmosphere, Poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 2: 3) and preparative chromatography to obtain tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6 -Methyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate was obtained. The resulting tert-butyl [2- (2,5-difluorophenoxy) ethyl] (6-methyl-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) carbamate was added with 4N hydrogen chloride / Ethyl acetate solution (2 mL) was added. The solvent was evaporated under reduced pressure, neutralized with sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative liquid chromatography to give N- [2- (2,5-difluorophenoxy) ethyl] -6-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1 -Dioxide was obtained. Step 2 of Example 49 using the resulting N- [2- (2,5-difluorophenoxy) ethyl] -6-methyl-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide The title compound (19.4 mg) was obtained by a method similar to that described above. 1 H-NMR (300 MHz, DMSO-d 6 ) δppm 2.41 (3H, s), 2.65-2.93 (2H, m), 3.48-3.69 (3H, m), 3.80-3.96 (1H, m), 4.44 ( 2H, br), 4.86 (1H, br), 6.76-6.90 (1H, m), 7.16-7.38 (2H, m), 7.53 (1H, d, J = 7.6 Hz), 7.70-7.86 (2H, m) , 9.76 (2H, br).
実施例１０８
N-[2-(2,5-ジフルオロフェノキシ)エチル]-6-(1-メチルエテニル)-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド
　実施例１０９で得られた6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド（300 mg）、4,4,5,5-テトラメチル-2-(1-メチルエテニル)-1,3,2-ジオキサボロラン（142 mg）及びPd(PPh3)4（65.1 mg）の2Ｎ炭酸ナトリウム水溶液（0.84 mL）と1,2-ジメトキシエタン（2 mL）の溶液を 80℃で 6時間、窒素雰囲気下撹拌し、反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:4～2:3）で精製して標題化合物（178 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.14 (3H, s), 2.45-2.58 (1H, m), 2.61-2.73 (1H, m), 3.12 (2H, t, J= 4.9 Hz), 3.21-3.31 (1H, m), 3.86 (1H, ddd, J= 13.8, 11.0, 3.0 Hz), 4.03-4.22 (3H, m), 5.21 (1H, s), 5.43 (1H, s), 6.55-6.65 (1H, m), 6.70 (1H, ddd, J= 9.7, 6.7, 2.8 Hz), 7.02 (1H, ddd, J= 10.5, 9.0, 5.3 Hz), 7.51-7.61 (2H, m), 7.87 (1H, d, J= 8.3 Hz) (A NH peak was not observed). Example 108
N- [2- (2,5-difluorophenoxy) ethyl] -6- (1-methylethenyl) -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide 6 obtained in Example 109 -Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide (300 mg), 4,4,5,5- Tetramethyl-2- (1-methylethenyl) -1,3,2-dioxaborolane (142 mg) and Pd (PPh 3 ) 4 (65.1 mg) in 2N aqueous sodium carbonate (0.84 mL) and 1,2-dimethoxyethane ( 2 mL) was stirred at 80 ° C. for 6 hours under a nitrogen atmosphere, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to 2: 3) to give the title compound (178 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.14 (3H, s), 2.45-2.58 (1H, m), 2.61-2.73 (1H, m), 3.12 (2H, t, J = 4.9 Hz), 3.21 -3.31 (1H, m), 3.86 (1H, ddd, J = 13.8, 11.0, 3.0 Hz), 4.03-4.22 (3H, m), 5.21 (1H, s), 5.43 (1H, s), 6.55-6.65 (1H, m), 6.70 (1H, ddd, J = 9.7, 6.7, 2.8 Hz), 7.02 (1H, ddd, J = 10.5, 9.0, 5.3 Hz), 7.51-7.61 (2H, m), 7.87 (1H , d, J = 8.3 Hz) (A NH peak was not observed).
実施例１０９
6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド
　参考例２９で得られたN-(6-ブロモ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（2.70 g）をＴＨＦ（6 mL）に溶解させ、ＴＨＦ-ボラン錯体（15 mL, 1Ｍ ＴＨＦ溶液）を0℃で加えた。反応液を65℃で2時間撹拌後、反応液にメタノールを加え、溶媒を減圧下留去した。残渣に6Ｎ塩酸（8 mL）を加えた。75℃で2時間撹拌後、8Ｎ水酸化ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させ、ろ過後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 3:17～3:7）で精製して標題化合物（2.0 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.44-2.58 (1H, m), 2.61-2.73 (1H, m), 3.12 (2H, t, J= 4.7 Hz), 3.24-3.34 (1H, m), 3.78 (1H, ddd, J= 13.7, 10.3, 3.2 Hz), 4.00-4.07 (1H, m), 4.08-4.22 (2H, m), 6.57-6.67 (1H, m), 6.67-6.75 (1H, m), 7.04 (1H, ddd, J= 10.7, 9.0, 5.3 Hz), 7.59-7.66 (1H, m), 7.73-7.83 (2H, m). Example 109
6-Bromo-N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide N- (6- Bromo-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (2.70 g) was dissolved in THF (6 mL) and THF- Borane complex (15 mL, 1M in THF) was added at 0 ° C. After stirring the reaction solution at 65 ° C. for 2 hours, methanol was added to the reaction solution, and the solvent was distilled off under reduced pressure. 6N hydrochloric acid (8 mL) was added to the residue. After stirring at 75 ° C. for 2 hours, the mixture was basified with 8N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 17-3: 7) to give the title compound (2.0 g). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.44-2.58 (1H, m), 2.61-2.73 (1H, m), 3.12 (2H, t, J = 4.7 Hz), 3.24-3.34 (1H, m) , 3.78 (1H, ddd, J = 13.7, 10.3, 3.2 Hz), 4.00-4.07 (1H, m), 4.08-4.22 (2H, m), 6.57-6.67 (1H, m), 6.67-6.75 (1H, m), 7.04 (1H, ddd, J = 10.7, 9.0, 5.3 Hz), 7.59-7.66 (1H, m), 7.73-7.83 (2H, m).
実施例１１０
6-ブロモ-N-[2-(2,5-ジフルオロフェノキシ)エチル]-8-フルオロ-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド
　参考例４９の工程５で得られたN-(6-ブロモ-8-フルオロ-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル)-2-(2,5-ジフルオロフェノキシ)アセトアミド（2.57 g）を用いて実施例１０９と同様の手法により標題化合物（1.72 g）を得た。1H-NMR (300 MHz, CDCl3) δppm 1.68 (1H, br), 2.40-2.54 (1H, m), 2.55-2.69 (1H, m), 3.10 (2H, d, J= 4.9 Hz), 3.29 (1H, ddd, J= 13.9, 7.9, 2.6 Hz), 3.91 (1H, ddd, J= 13.8, 10.8, 2.8 Hz), 3.97-4.06 (1H, m), 4.06-4.22 (2H, m), 6.58-6.76 (2H, m), 7.04 (1H, ddd, J= 10.7, 8.9, 5.3 Hz), 7.36 (1H, dd, J= 9.2, 1.7 Hz), 7.54 (1H, s). Example 110
6-bromo-N- [2- (2,5-difluorophenoxy) ethyl] -8-fluoro-3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide Obtained in Step 5 of Reference Example 49 Of N- (6-bromo-8-fluoro-1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl) -2- (2,5-difluorophenoxy) acetamide (2.57 g) Was used to give the title compound (1.72 g) in the same manner as in Example 109. 1 H-NMR (300 MHz, CDCl 3 ) δppm 1.68 (1H, br), 2.40-2.54 (1H, m), 2.55-2.69 (1H, m), 3.10 (2H, d, J = 4.9 Hz), 3.29 (1H, ddd, J = 13.9, 7.9, 2.6 Hz), 3.91 (1H, ddd, J = 13.8, 10.8, 2.8 Hz), 3.97-4.06 (1H, m), 4.06-4.22 (2H, m), 6.58 -6.76 (2H, m), 7.04 (1H, ddd, J = 10.7, 8.9, 5.3 Hz), 7.36 (1H, dd, J = 9.2, 1.7 Hz), 7.54 (1H, s).
実施例１１１
6-(アミノメチル)-N-[2-(2,5-ジフルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン 1,1-ジオキシド
　参考例４８で得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル][6-(ヒドロキシメチル)-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル]カルバマート（560 mg）、1,1'-アゾジカルボニルピペリジン（878 mg）、トリブチルホスフィン（704 mg）及びフタルイミド（170 mg）のＴＨＦ（6 mL）溶液を60℃で3時間撹拌後、溶媒を減圧下留去した。残渣にジイソプロピルエーテルを加え、ろ過し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～3:2）で精製してtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル]{6-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル}カルバマート（513 mg）を得た。得られたtert-ブチル [2-(2,5-ジフルオロフェノキシ)エチル]{6-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)メチル]-1,1-ジオキシド-3,4-ジヒドロ-2H-チオクロメン-4-イル}カルバマート（513 mg）、ヒドラジン一水和物（126 mg）のメタノール（3 mL）溶液を室温で3時間撹拌し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル:ヘキサン＝ 1:3～1:1）で精製して標題化合物（259 mg）を得た。1H-NMR (300 MHz, CDCl3) δppm 2.42-2.58 (1H, m), 2.60-2.74 (1H, m), 3.12 (2H, t, J= 5.1 Hz), 3.26 (1H, ddd, J= 13.8, 7.4, 3.0 Hz), 3.84 (1H, ddd, J= 13.8, 10.8, 3.0 Hz), 3.93 (2H, s), 4.03-4.24 (4H, m), 6.61 (1H, tt, J= 8.3, 3.2 Hz), 6.70 (1H, ddd, J= 9.7, 6.7, 2.8 Hz), 7.03 (1H, ddd, J= 10.8, 8.9, 5.3 Hz), 7.40-7.53 (2H, m), 7.88 (1H, d, J= 8.3 Hz)(An NH2peak was not observed).   Example 111
6- (Aminomethyl) -N- [2- (2,5-difluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide tert-- obtained in Reference Example 48 Butyl [2- (2,5-difluorophenoxy) ethyl] [6- (hydroxymethyl) -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl] carbamate (560 mg), 1, A solution of 1′-azodicarbonylpiperidine (878 mg), tributylphosphine (704 mg) and phthalimide (170 mg) in THF (6 mL) was stirred at 60 ° C. for 3 hours, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue, the mixture was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 3: 2) to give tert-butyl [2- (2,5-difluorophenoxy) ethyl] {6-[(1, 3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -1,1-dioxide-3,4-dihydro-2H-thiochromen-4-yl} carbamate (513 mg) was obtained. . The resulting tert-butyl [2- (2,5-difluorophenoxy) ethyl] {6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -1, Stir a solution of 1-dioxide-3,4-dihydro-2H-thiochromen-4-yl} carbamate (513 mg) and hydrazine monohydrate (126 mg) in methanol (3 mL) at room temperature for 3 hours. Distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to 1: 1) to give the title compound (259 mg). 1 H-NMR (300 MHz, CDCl 3 ) δppm 2.42-2.58 (1H, m), 2.60-2.74 (1H, m), 3.12 (2H, t, J = 5.1 Hz), 3.26 (1H, ddd, J = 13.8, 7.4, 3.0 Hz), 3.84 (1H, ddd, J = 13.8, 10.8, 3.0 Hz), 3.93 (2H, s), 4.03-4.24 (4H, m), 6.61 (1H, tt, J = 8.3, 3.2 Hz), 6.70 (1H, ddd, J = 9.7, 6.7, 2.8 Hz), 7.03 (1H, ddd, J = 10.8, 8.9, 5.3 Hz), 7.40-7.53 (2H, m), 7.88 (1H, d , J = 8.3 Hz) (An NH 2 peak was not observed).
　実施例３０～１１１に記載される化合物は以下の通りである（表４）。表４に示されたfreeはフリー体を、Racemateはラセミ体を、(R)-formは(R)-体を、(S)-formは(S)-体を、(-)-formは(-)-体を、(+)-formは(+)-体を、4 stereoisomersは４つの立体異性体混合物を、Optically activeは光学活性体を、tR1(IC)、tR2(IC)、tR3(IC)、tR4(IC)はそれぞれキラルクロマトグラフィーＣＨＩＲＡＬＰＡＫ　ＩＣによる保持時間の順番を示す。 The compounds described in Examples 30 to 111 are as follows (Table 4). The free shown in Table 4 is free, Racemate is racemic, (R) -form is (R) -form, (S) -form is (S) -form, (-)-form is (-)-Form, (+)-form is (+)-form, 4 stereoisomers is a mixture of four stereoisomers, Optically active is an optically active form, tR1 (IC), tR2 (IC), tR3 (IC) and tR4 (IC) indicate the order of retention times by chiral chromatography CHIRALPAK IC.
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
製剤例１
（１）実施例１の化合物　　　　　　　　　　　　１０ｍｇ
（２）乳糖　　　　　　　　　　　　　　　　　　６０ｍｇ
（３）コーンスターチ　　　　　　　　　　　　　３５ｍｇ
（４）ヒドロキシプロピルメチルセルロース　　　　３ｍｇ
（５）ステアリン酸マグネシウム　　　　　　　　　２ｍｇ
　実施例１で得られた化合物１０ｍｇ、乳糖６０ｍｇおよびコーンスターチ３５ｍｇの混合物を、１０重量％ヒドロキシプロピルメチルセルロース水溶液０．０３ｍＬ（ヒドロキシプロピルメチルセルロースとして３ｍｇ）を用いて顆粒化した後、４０℃で乾燥し、篩過する。得られた顆粒をステアリン酸マグネシウム２ｍｇと混合し、圧縮する。得られる素錠を、蔗糖、二酸化チタン、タルクおよびアラビアゴムの水懸濁液による糖衣でコーティングする。コーティングが施された錠剤をミツロウで艶出してコート錠を得る。 Formulation Example 1
(1) 10 mg of the compound of Example 1
(2) Lactose 60mg
(3) Corn starch 35mg
(4) Hydroxypropyl methylcellulose 3mg
(5) Magnesium stearate 2mg
A mixture of 10 mg of the compound obtained in Example 1, 60 mg of lactose and 35 mg of corn starch was granulated with 0.03 mL of 10 wt% hydroxypropylmethylcellulose aqueous solution (3 mg as hydroxypropylmethylcellulose), and then dried at 40 ° C. Sift through. The obtained granules are mixed with 2 mg of magnesium stearate and compressed. The resulting uncoated tablets are coated with a sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablet is polished with beeswax to obtain a coated tablet.
製剤例２
（１）実施例１の化合物　　　　　　　　１０ｍｇ
（２）乳糖　　　　　　　　　　　　　　７０ｍｇ
（３）コーンスターチ　　　　　　　　　５０ｍｇ
（４）可溶性デンプン　　　　　　　　　　７ｍｇ
（５）ステアリン酸マグネシウム　　　　　３ｍｇ
　実施例１で得られた化合物１０ｍｇおよびステアリン酸マグネシウム３ｍｇを可溶性デンプンの水溶液０．０７ｍＬ（可溶性デンプンとして７ｍｇ）で顆粒化した後、乾燥し、乳糖７０ｍｇおよびコーンスターチ５０ｍｇと混合する。混合物を圧縮して錠剤を得る。 Formulation Example 2
(1) 10 mg of the compound of Example 1
(2) Lactose 70mg
(3) Corn starch 50mg
(4) Soluble starch 7mg
(5) Magnesium stearate 3mg
10 mg of the compound obtained in Example 1 and 3 mg of magnesium stearate are granulated with 0.07 mL of an aqueous solution of soluble starch (7 mg as soluble starch), then dried and mixed with 70 mg of lactose and 50 mg of corn starch. The mixture is compressed to obtain tablets.
試験例１
α１Ｄ受容体結合阻害活性の測定
　以下に記載の遺伝子操作法は、成書（Maniatisら、モレキュラー・クローニング、Cold Spring Harbor Laboratory、１９８９年）に記載されている方法もしくは試薬の添付プロトコールに記載されている方法などに従った。
（ｉ）ヒトα１Ｄ受容体の発現プラスミド作製
　ヒト肝臓ｃＤＮＡから、ＰＣＲ法でα１Ｄ受容体遺伝子のクローニングを行った。２００ｎｇのヒト脳海馬ｃＤＮＡライブラリー（宝酒造）を鋳型とし、DEBRA A.ら（J.Pharamacol.Exp.Ter., 272, 134-142 (1995)）が報告しているα１Ｄ受容体遺伝子塩基配列を参考に作製したプライマーセット　５’－ＣＣＧＡＣＧＧＣＣＧＣＴＡＧＣＧＡＧＡＴＧＡＣＴＴＴＣＣＧＣＧＡＴＣＴＣＣＴＧＡＧＣＧＴＣ－３’〔配列番号１〕と５’－ＧＣＴＣＴＧＧＧＴＡＣＣＴＴＡＡＡＴＡＴＣＧＧＴＣＴＣＣＣＧＴＡＧＧＴＴＧＣ－３’〔配列番号２〕を各５０ｐｍｏｌずつ添加し、ＴａＫａＲａ　ＬＡ－ＴａｑＤＮＡ　Ｐｏｌｙｍｅｒａｓｅ（宝酒造）を使用して、ＰＣＲ反応をＧｅｎｅ　Ａｍｐ　ＰＣＲ　Ｓｙｓｔｅｍ　９７００（Applied Biosystems）にて行った（反応条件：９４℃で１５秒間、６８℃で３分３０秒間を４５サイクル）。
　上記で得られたＰＣＲ断片を制限酵素ＮｈｅＩ（宝酒造）とＫｐｎ　Ｉ（宝酒造）で消化した後、アガロースゲル電気泳動してＤＮＡ断片を回収した。そのＤＮＡ断片とＮｈｅＩとＫｐｎ　Ｉで消化した動物細胞用発現プラスミドｐｃＤＮＡ３．１／Ｚｅｏ（Invitrogen）を混合し、ＤＮＡ　Ｌｉｇａｔｉｏｎ　Ｋｉｔ　Ｖｅｒ．２（宝酒造）で連結して、大腸菌ＪＭ１０９のコンピテントセルを形質転換することでプラスミドｐｃＤＮＡ３．１／Ｚｅｏ－Ａｄｒｅα１Ｄを得た。 Test example 1
Measurement of α 1D receptor binding inhibitory activity The gene manipulation method described below is described in the method or reagent attached protocol described in the book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989). Followed the method and so on.
(I) from the expression plasmid prepared human liver cDNA for the human alpha 1D receptor, was cloned alpha 1D receptor gene by the PCR method. Α 1D receptor gene base sequence reported by DEBRA A. et al. (J. Pharamacol. Exp. Ter., 272, 134-142 (1995)) using 200 ng of human brain hippocampal cDNA library (Takara Shuzo) as a template. The primer set 5'-CCGACGGCCCGCTAGCGGAGATGACTTCCCGCATCCTCGAGGCGTC-3 '[SEQ ID NO: 1] and 5'-GCTCTGGGTACCTTAAATATCGGTCTCCCGTTAGGTGC-3' [SEQ ID NO: 2] The PCR reaction was performed using Gene Amp PCR System 9700 (Applied Biosystems) (reaction conditions: 94 ° C. for 15 seconds, 68 ° C. for 3 minutes 30 seconds for 45 cycles).
The PCR fragment obtained above was digested with restriction enzymes NheI (Takara Shuzo) and Kpn I (Takara Shuzo), and then DNA fragments were recovered by agarose gel electrophoresis. The DNA fragment was mixed with animal cell expression plasmid pcDNA3.1 / Zeo (Invitrogen) digested with NheI and KpnI, and DNA Ligation Kit Ver. The plasmid pcDNA3.1 / Zeo-Adreα 1D was obtained by transforming competent cells of E. coli JM109 after ligation with 2 (Takara Shuzo).
（ｉｉ）ヒトα１Ｄ受容体発現用プラスミドのＣＨＯ－Ｋ１細胞への導入と膜画分の調製
　１０％ウシ胎児血清（TRACE SCIENCETIFIC）を含むハムＦ１２培地（Invitrogen）を用いて１５０ｃｍ２培養フラスコ（Corning Coaster）で継代培養しておいたＣＨＯ－Ｋ１細胞を０．５ｇ／Ｌ　トリプシン－０．２ｇ／Ｌ　ＥＤＴＡ（Invitrogen）で剥がした後、細胞をＤ－ＰＢＳ（－）（Invitrogen）で洗浄して遠心（１０００ｒｐｍ，５分）した。次に、ジーンパルサーII（BioRad）を用いて、下記の条件に従って、ＤＮＡを細胞に導入した。即ち、０．４ｃｍギャップのキュベット（BioRad）にＤ－ＰＢＳ（－）７００μｌで懸濁した１ｘ１０７個の細胞と１０μｇのｐｃＤＮＡ３．１／Ｚｅｏ－Ａｄｒｅα１Ｄを加え、電圧０．２５ｋＶ、キャパシタンス９６０μＦ下でエレクトロポレーションを実施した。１０％ウシ胎児血清および２５０μｇ／ｍＬ　Ｚｅｏｃｉｎ（Invitrogen）を含むハムＦ１２培地で培養することにより、Ｚｅｏｃｉｎ耐性株を選択した。
　このようにして得られたＺｅｏｃｉｎ耐性株を複数株選択し、各株をセルカルチャーフラスコ１５０ｃｍ２にセミコンフルエントになるまで培養し、細胞膜画分を次の要領で調製した。
　セミコンフルエントになった細胞を０．０２％ＥＤＴＡ含有Ｄ－ＰＢＳ（－）で剥がし、遠心分離で細胞を回収し、膜調製用バッファー（10 mM NaHCO3 pH 7.4、プロテアーゼインヒビターカクテル(ロシュ)）に懸濁し、ポリトロンホモジナイザー（モデルＰＴ－３１００，KINEMATICA AG）にて２００００ｒｐｍで２０秒間を３回処理することで細胞を破砕した。細胞破砕後、２０００ｒｐｍで１０分間遠心分離して、膜画分を含む上清を得た。その上清を超遠心機（モデルＬ８－７０Ｍ，ローター７０Ｔｉ，ベックマン）にて３００００ｒｐｍで１時間遠心分離して、膜画分を含む沈殿物を得た。得られた各クローンの膜画分を次に示す結合実験に供した。
　９６ウェルマイクロプレートに結合アッセイバッファー(50 mM Tris-HCl, 10 mM MgCl2, 0.5% BSA, プロテアーゼインヒビターカクテル pH7.5)で希釈した膜画分（２０μｇ／ウェル）およびリガンドである［３Ｈ］プラゾシン（２．５ｎＭ，パーキンエルマーライフサイエンス）を添加し、室温で１時間反応させた。非特異的な結合の測定には、さらにフェントールアミン（Sigma）を１０μＭになるように添加した。次に、セルハーベスター（パーキンエルマーライフサイエンス）を使用して反応液を濾過することで膜画分をユニフィルターＧＦ／Ｃ（パーキンエルマーライフサイエンス）に移し、氷冷した５０ｍＭ　Ｔｒｉｓバッファー（ｐＨ７．５）で３回洗浄した。フィルターを乾燥後、マイクロシンチ０（パーキンエルマーライフサイエンス）をフィルターに加え、トップカウント（パーキンエルマーライフサイエンス）で放射活性を計測した。膜画分を用いた結合測定で最も優れたＳ／Ｂ値（全結合放射活性／非特異的結合放射活性）を示した株を用いて、次に示す化合物評価用の膜画分を上記と同様の方法にて調製し、以下の化合物評価に用いた。 (Ii) Introduction of plasmid for human α 1D receptor expression into CHO-K1 cells and preparation of membrane fraction 150 cm 2 culture flask using Ham's F12 medium (Invitrogen) containing 10% fetal calf serum (TRACE SCIENCETIFIC) ( CHO-K1 cells subcultured in Corning Coaster) were peeled off with 0.5 g / L trypsin-0.2 g / L EDTA (Invitrogen), and the cells were washed with D-PBS (-) (Invitrogen). And then centrifuged (1000 rpm, 5 minutes). Next, DNA was introduced into the cells using Gene Pulser II (BioRad) according to the following conditions. Specifically, 1 × 10 7 cells suspended in 700 μl of D-PBS (−) and 10 μg of pcDNA3.1 / Zeo-Adreα 1D were added to a 0.4 cm gap cuvette (BioRad), and the voltage was 0.25 kV and the capacitance was 960 μF. The electroporation was performed. Zeocin resistant strains were selected by culturing in Ham's F12 medium containing 10% fetal bovine serum and 250 μg / mL Zeocin (Invitrogen).
A plurality of Zeocin resistant strains thus obtained were selected, and each strain was cultured in a cell culture flask at 150 cm 2 until it became semi-confluent, and a cell membrane fraction was prepared as follows.
Semiconfluent cells are detached with D-PBS (-) containing 0.02% EDTA, and the cells are collected by centrifugation and placed in a membrane preparation buffer (10 mM NaHCO 3 pH 7.4, protease inhibitor cocktail (Roche)). The suspension was suspended, and the cells were disrupted by treating with Polytron homogenizer (model PT-3100, KINEMATICA AG) for 3 times at 20000 rpm for 20 seconds. After cell disruption, centrifugation was performed at 2000 rpm for 10 minutes to obtain a supernatant containing a membrane fraction. The supernatant was centrifuged at 30000 rpm for 1 hour in an ultracentrifuge (model L8-70M, rotor 70Ti, Beckman) to obtain a precipitate containing a membrane fraction. The obtained membrane fraction of each clone was subjected to the following binding experiment.
Membrane fraction (20 μg / well) diluted with binding assay buffer (50 mM Tris-HCl, 10 mM MgCl 2 , 0.5% BSA, protease inhibitor cocktail pH 7.5) and ligand in 96 well microplate [ 3 H] Prazosin (2.5 nM, Perkin Elmer Life Science) was added and reacted at room temperature for 1 hour. For measurement of non-specific binding, phentolamine (Sigma) was further added to 10 μM. Next, the membrane fraction was transferred to a unifilter GF / C (Perkin Elmer Life Science) by filtering the reaction solution using a cell harvester (Perkin Elmer Life Science), and ice-cooled 50 mM Tris buffer (pH 7.5). ) 3 times. After drying the filter, microcinch 0 (Perkin Elmer Life Science) was added to the filter, and the radioactivity was measured with a top count (Perkin Elmer Life Science). Using the strain that showed the most excellent S / B value (total bound radioactivity / non-specific bound radioactivity) in the binding measurement using the membrane fraction, the membrane fraction for compound evaluation shown below was It prepared by the same method and used for the following compound evaluation.
（ｉｉｉ）実施例化合物の評価
　９６ウェルマイクロプレートに結合アッセイバッファーで希釈した膜画分（２０μｇ／well）、化合物および［３Ｈ］－プラゾシン（２．５ｎＭ，パーキンエルマーライフサイエンス）を添加し、室温で１時間反応させた。非特異的な結合の測定には、さらにｃｏｌｄのリガンドであるフェントールアミン（Sigma）を1０μＭになるように添加した。次に、セルハーベスター（パーキンエルマーライフサイエンス）を使用して反応液を濾過することで膜画分をユニフィルターＧＦ／Ｃ（パーキンエルマーライフサイエンス）に移し、冷却した５０ｍＭ　Ｔｒｉｓバッファー（ｐＨ７．５）で３回洗浄した。フィルターを乾燥後、マイクロシンチ０（パーキンエルマーライフサイエンス）をフィルターに加え、トップカウント（パーキンエルマーライフサイエンス）で放射活性を計測した。
　［３Ｈ］－プラゾシンの膜画分への結合量を５０％にまで減少させるのに必要な化合物の濃度（ＩＣ５０）をＧｌａｐｈＰａｄＰｒｉｓｍ　Ｖｅｒ３．２（GlaphPad Software）にて算出した。
　上記の方法で測定した結果（１μＭにおけるα１Ｄ受容体結合阻害率）を表５に示す。 (Iii) Evaluation of Example Compound A membrane fraction (20 μg / well) diluted with a binding assay buffer, a compound and [ 3 H] -prazosin (2.5 nM, Perkin Elmer Life Sciences) were added to a 96-well microplate, The reaction was allowed to proceed for 1 hour at room temperature. For measurement of non-specific binding, phentolamine (Sigma), which is a cold ligand, was further added to 10 μM. Next, the membrane fraction was transferred to Unifilter GF / C (Perkin Elmer Life Science) by filtering the reaction solution using Cell Harvester (Perkin Elmer Life Science), and cooled 50 mM Tris buffer (pH 7.5). And washed 3 times. After drying the filter, microcinch 0 (Perkin Elmer Life Science) was added to the filter, and the radioactivity was measured with a top count (Perkin Elmer Life Science).
The concentration of compound (IC 50 ) required to reduce the amount of [ 3 H] -prazosin bound to the membrane fraction to 50% was calculated using GraphPad Prism Ver 3.2 (GlaphPad Software).
Table 5 shows the results (α 1D receptor binding inhibition rate at 1 μM) measured by the above method.
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
　本発明の化合物は、優れた選択的α１Ｄアドレナリン受容体拮抗作用を有し、下部尿路症状等の予防・治療剤として有用である。
　本出願は日本で出願された特願２００９－１２８１７８を基礎としており、その内容は本明細書に全て包含される。 The compound of the present invention has an excellent selective α 1D adrenergic receptor antagonistic action and is useful as a preventive / therapeutic agent for lower urinary tract symptoms and the like.
This application is based on Japanese Patent Application No. 2009-128178 filed in Japan, the contents of which are incorporated in full herein.

Claims (20)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     〔式中、
    Ａ環は置換基を有していても良いベンゼン環、又は置換基を有していても良い６員芳香族複素環を示し、
    Ｂ環は置換基を有していても良いベンゼン環を示し、
    Ｌ１は結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示し、
    Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
    ＸはＳ、ＳＯ、又はＳＯ２を示し、
    Ｙは炭素原子を示し、
    Ｚは（１）置換基を有していても良い炭化水素基（但し、ＸがＳの時は（ヒドロキシメチル)フェニル基、アミノフェニル基、及びメトキシフェニル基を除く）、（２）置換基を有していても良いアミノ基、又は（３）置換基を有していても良い５員または６員複素環基を示すか、あるいは（４）Ｙと結合して、Ａ環と共にさらに置換基を有していても良い縮合二環性複素環を形成してもよく、
    Ｒ１及びＲ２は同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示すか、あるいは互いに結合してＹと共に置換基を有していても良いシクロプロピル若しくは置換基を有していても良いシクロブチルを形成しても良い（但し、ＺがＹと結合する時にはＲ１は存在しない）。〕
    で表される化合物、又はその塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Where,
    Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent,
    Ring B represents an optionally substituted benzene ring,
    L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. Also shows a good propylene group,
    L 2 represents an ethylene group which may have a substituent other than an oxo group,
    X represents S, SO, or SO 2,
    Y represents a carbon atom,
    Z is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) substituent group Or an amino group which may have a substituent, or (3) a 5- or 6-membered heterocyclic group which may have a substituent, or (4) bonded to Y and further substituted with A ring A condensed bicyclic heterocyclic ring which may have a group may be formed,
    R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group, or may be bonded to each other and have a substituent together with Y. Cyclopropyl or optionally substituted cyclobutyl may be formed (provided that when Z is bound to Y, R 1 is not present). ]
    Or a salt thereof.
  2. 　Ａ環は置換基を有していても良いベンゼン環、又はピリジン環を示し、
    　Ｂ環は置換基を有していても良いベンゼン環を示し、
    　Ｌ１は結合手、メチレン基又はエチレン基を示し、
    　Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
    　ＸはＳＯ２を示し、
    　Ｙは炭素原子を示し、
    　Ｚは（１）Ｃ１－６アルキル基、(２)フェニル基、（３）置換基を有していても良いアミノ基、または(４)モルホリノ基を示すか、あるいは（５）Ｙと結合して、Ａ環と共にさらに置換基を有していても良いジヒドロチオクロメン環を形成してもよく、
    　Ｒ１は水素原子を示し、
    　Ｒ２は水素原子またはＣ１－６アルキル基を示す（但し、ＺがＹと結合する時にはＲ１は存在せず、かつＲ２は水素原子を示す）、
    請求項１記載の化合物、又はその塩。     Ring A represents an optionally substituted benzene ring or pyridine ring,
    Ring B represents an optionally substituted benzene ring,
    L 1 represents a bond, a methylene group or an ethylene group,
    L 2 represents an ethylene group which may have a substituent other than an oxo group,
    X represents SO 2
    Y represents a carbon atom,
    Z represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group, or (5) bonded to Y A dihydrothiochromene ring which may further have a substituent together with the A ring,
    R 1 represents a hydrogen atom,
    R 2 represents a hydrogen atom or a C 1-6 alkyl group (provided that when Z is bound to Y, R 1 does not exist and R 2 represents a hydrogen atom),
    The compound according to claim 1, or a salt thereof.
  3. 　式（ＩＩ）：
    Figure JPOXMLDOC01-appb-C000002
     〔式中、
    Ａ環は置換基を有していても良いベンゼン環、又は置換基を有していても良い６員芳香族複素環を示し、
    Ｂ環は置換基を有していても良いベンゼン環を示し、
    Ｌ１は結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示し、
    Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
    ＸはＳ、ＳＯ、又はＳＯ２を示し、
    Ｚ’はＣＲ４、又はＮを示し、
    Ｒ２、Ｒ３及びＲ４は同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示し、
    ｎは０ないし３の整数を示す。〕
    で表される請求項１記載の化合物、又はその塩。     Formula (II):
    Figure JPOXMLDOC01-appb-C000002
     [Where,
    Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent,
    Ring B represents an optionally substituted benzene ring,
    L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. Also shows a good propylene group,
    L 2 represents an ethylene group which may have a substituent other than an oxo group,
    X represents S, SO, or SO 2,
    Z ′ represents CR 4 or N,
    R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group,
    n represents an integer of 0 to 3. ]
    The compound of Claim 1 represented by these, or its salt.
  4. 　Ａ環は置換基を有していても良いベンゼン環を示し、
    　Ｂ環は置換基を有していても良いベンゼン環を示し、
    　Ｌ１は結合手を示し、
    　Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
    　ＸはＳＯ２を示し、
    　Ｚ’はＣＲ４、又はＮを示し、
    　Ｒ２及びＲ３は水素原子を示し、
    　Ｒ４は、水素原子または置換基を有していても良いＣ１－６アルキル基を示し、
    　ｎは０、１または２を示す、
    請求項３記載の化合物、又はその塩。     Ring A represents an optionally substituted benzene ring,
    Ring B represents an optionally substituted benzene ring,
    L 1 represents a bond,
    L 2 represents an ethylene group which may have a substituent other than an oxo group,
    X represents SO 2
    Z ′ represents CR 4 or N,
    R 2 and R 3 represent a hydrogen atom,
    R 4 represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent,
    n represents 0, 1 or 2;
    The compound according to claim 3, or a salt thereof.
  5. 　Ａ環は１個のモノ－Ｃ１－６アルキルアミノ基で置換されていても良いベンゼン環を示し、
    　Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し、
    　Ｌ１は結合手を示し、
    　Ｌ２はエチレン基を示し、
    　ＸはＳＯ２を示し、
    　Ｚ’はＣＲ４を示し、
    　Ｒ２、Ｒ３及びＲ４は、水素原子を示し、
    　ｎは１を示す、
    請求項３記載の化合物、又はその塩。     Ring A represents a benzene ring which may be substituted with one mono-C 1-6 alkylamino group,
    Ring B represents a benzene ring substituted with two halogen atoms,
    L 1 represents a bond,
    L 2 represents an ethylene group,
    X represents SO 2
    Z 'represents a CR 4,
    R 2 , R 3 and R 4 represent a hydrogen atom,
    n represents 1,
    The compound according to claim 3, or a salt thereof.
  6. 　式（ＩＩＩ）：
    Figure JPOXMLDOC01-appb-C000003
     〔式中、
    Ａ環は置換基を有していても良いベンゼン環、又は置換基を有していても良い６員芳香族複素環を示し、
    Ｂ環は置換基を有していても良いベンゼン環を示し、
    Ｌ１は結合手、オキソ基以外の置換基を有していても良いメチレン基、オキソ基以外の置換基を有していても良いエチレン基、又はオキソ基以外の置換基を有していても良いプロピレン基を示し、
    Ｌ２はオキソ基以外の置換基を有していても良いエチレン基を示し、
    ＸはＳ、ＳＯ、又はＳＯ２を示し、
    Ｚ’’は（１）置換基を有していても良い炭化水素基（但し、ＸがＳの時は（ヒドロキシメチル）フェニル基、アミノフェニル基、及びメトキシフェニル基を除く）、（２）置換基を有していても良いアミノ基、又は（３）置換基を有していても良い５員または６員複素環基を示し、
    Ｒ１及びＲ２は同一または異なって、水素原子、又は置換基を有していても良いＣ１－６アルキル基を示すか、あるいは互いに結合して隣接する炭素原子と共に置換基を有していても良いシクロプロピル若しくは置換基を有していても良いシクロブチルを形成してもよい。〕
    で表される請求項１記載の化合物、又はその塩。     Formula (III):
    Figure JPOXMLDOC01-appb-C000003
     [Where,
    Ring A represents a benzene ring which may have a substituent, or a 6-membered aromatic heterocyclic ring which may have a substituent,
    Ring B represents an optionally substituted benzene ring,
    L 1 has a bond, a methylene group which may have a substituent other than an oxo group, an ethylene group which may have a substituent other than an oxo group, or a substituent other than an oxo group. Also shows a good propylene group,
    L 2 represents an ethylene group which may have a substituent other than an oxo group,
    X represents S, SO, or SO 2,
    Z ″ is (1) a hydrocarbon group which may have a substituent (however, when X is S, (hydroxymethyl) phenyl group, aminophenyl group and methoxyphenyl group are excluded), (2) An amino group which may have a substituent, or (3) a 5-membered or 6-membered heterocyclic group which may have a substituent,
    R 1 and R 2 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group which may have a substituent, or have a substituent together with an adjacent carbon atom bonded to each other. Cyclopropyl which may be substituted or cyclobutyl which may have a substituent may be formed. ]
    The compound of Claim 1 represented by these, or its salt.
  7. 　Ａ環は置換基を有していても良いベンゼン環、又はピリジン環を示し、
    　Ｂ環は置換基を有していても良いベンゼン環を示し、
    　Ｌ１は結合手、メチレン基、またはエチレン基を示し、
    　Ｌ２はエチレン基を示し、
    　ＸはＳＯ２を示し、
    　Ｚ’’は（１）Ｃ１－６アルキル基、（２）フェニル基、（３）置換基を有していても良いアミノ基、又は（４）モルホリノ基を示し、
    　Ｒ１及びＲ２は、両方とも水素原子、または一方が水素原子で他方がＣ１－６アルキル基を示す、
    請求項６記載の化合物、又はその塩。     Ring A represents an optionally substituted benzene ring or pyridine ring,
    Ring B represents an optionally substituted benzene ring,
    L 1 represents a bond, a methylene group, or an ethylene group,
    L 2 represents an ethylene group,
    X represents SO 2
    Z ″ represents (1) a C 1-6 alkyl group, (2) a phenyl group, (3) an optionally substituted amino group, or (4) a morpholino group,
    R 1 and R 2 both represent a hydrogen atom, or one represents a hydrogen atom and the other represents a C 1-6 alkyl group.
    The compound according to claim 6, or a salt thereof.
  8. 　Ａ環はベンゼン環、又はピリジン環を示し、
    　Ｂ環は２個のハロゲン原子で置換されたベンゼン環を示し、
    　Ｌ１は結合手を示し、
    　Ｌ２はエチレン基を示し、
    　ＸはＳＯ２を示し、
    　Ｚ’’はＣ１－６アルキル基、又はジ－Ｃ１－６アルキルアミノ基を示し、
    　Ｒ１及びＲ２は、水素原子を示す、
    請求項６記載の化合物、又はその塩。     Ring A represents a benzene ring or a pyridine ring,
    Ring B represents a benzene ring substituted with two halogen atoms,
    L 1 represents a bond,
    L 2 represents an ethylene group,
    X represents SO 2
    Z ″ represents a C 1-6 alkyl group or a di-C 1-6 alkylamino group,
    R 1 and R 2 represent a hydrogen atom,
    The compound according to claim 6, or a salt thereof.
  9. 　2-(2-クロロ-5-フルオロフェノキシ)-N-[2-(メチルスルホニル)ベンジル] エタンアミン、又はその塩。 2- (2-Chloro-5-fluorophenoxy) -N- [2- (methylsulfonyl) benzyl] ethanamine or a salt thereof.
  10. 　2-({[2-(2-クロロ-5-フルオロフェノキシ)エチル]アミノ}メチル)-N,N-ジメチルベンゼンスルホンアミド、又はその塩。 2-({[2- (2-Chloro-5-fluorophenoxy) ethyl] amino} methyl) -N, N-dimethylbenzenesulfonamide or a salt thereof.
  11. 　2-(2-クロロ-5-フルオロフェノキシ)-N-{[2-(メチルスルホニル)ピリジン-3-イル]メチル}エタンアミン、又はその塩。 2- (2-chloro-5-fluorophenoxy) -N-{[2- (methylsulfonyl) pyridin-3-yl] methyl} ethanamine, or a salt thereof.
  12. 　(4S)-N-[2-(2-クロロ-5-フルオロフェノキシ)エチル]-3,4-ジヒドロ-2H-チオクロメン-4-アミン1,1-ジオキシド、又はその塩。 (4S) -N- [2- (2-Chloro-5-fluorophenoxy) ethyl] -3,4-dihydro-2H-thiochromen-4-amine 1,1-dioxide, or a salt thereof.
  13. 　（＋）－N4-[2-(2,5-ジフルオロフェノキシ)エチル]-N6-メチル-3,4-ジヒドロ-2H-チオクロメン-4,6-ジアミン1,1-ジオキシド、又はその塩。 (+) - N 4 - [ 2- (2,5- difluorophenoxy) ethyl] -N 6 - methyl-3,4-dihydro -2H- thiochromen 4,6-diamine 1,1-dioxide, or a salt thereof .
  14. 　請求項１記載の化合物又はその塩のプロドラッグ。 A prodrug of the compound according to claim 1 or a salt thereof.
  15. 　請求項１記載の化合物又はその塩、又はそのプロドラッグを含有する医薬。 A pharmaceutical comprising the compound according to claim 1 or a salt thereof, or a prodrug thereof.
  16. 　α１Ｄ受容体拮抗剤である請求項１５記載の医薬。 The medicament according to claim 15, which is an α 1D receptor antagonist.
  17. 　下部尿路症状の予防・治療剤である請求項１５記載の医薬。 The medicine according to claim 15, which is a preventive / therapeutic agent for lower urinary tract symptoms.
  18. 　請求項１記載の化合物又はその塩、又はそのプロドラッグの有効量を哺乳動物に投与することを特徴とする下部尿路症状予防・治療方法。 A method for preventing and treating lower urinary tract symptoms, comprising administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to a mammal.
  19. 　下部尿路症状予防・治療剤を製造するための請求項１記載の化合物又はその塩、又はそのプロドラッグの使用。 Use of the compound according to claim 1 or a salt thereof, or a prodrug thereof for producing an agent for preventing or treating lower urinary tract symptoms.
  20. 　請求項１記載の化合物又はその塩、又はそのプロドラッグの下部尿路症状予防・治療剤としての使用。 Use of the compound according to claim 1 or a salt thereof, or a prodrug thereof as a preventive or therapeutic agent for lower urinary tract symptoms.
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