WO2010137620A1 - Dérivé de phénoxyéthylamine - Google Patents

Dérivé de phénoxyéthylamine Download PDF

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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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group
substituent
ring
compound
salt
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Japanese (ja)
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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/fr

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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
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • 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
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    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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

L'invention porte sur un dérivé de phénoxyéthylamine ayant une excellente activité antagoniste sélective du récepteur adrénergique α1D. De façon spécifique, l'invention porte sur un composé représenté par la formule (I) [dans laquelle chaque symbole est tel que défini dans la description] ou un sel de celui-ci.
PCT/JP2010/058919 2009-05-27 2010-05-26 Dérivé de phénoxyéthylamine WO2010137620A1 (fr)

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US9796697B2 (en) 2015-06-12 2017-10-24 Peloton Therapeutics, Inc. Tricyclic inhibitors of HIF-2-alpha and uses thereof
US9884843B2 (en) * 2013-12-16 2018-02-06 Peloton Therapeutics, Inc. Cyclic sulfone and sulfoximine analogs and uses thereof
US9896418B2 (en) 2013-09-09 2018-02-20 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US10155726B2 (en) 2015-03-11 2018-12-18 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
US10278942B2 (en) 2015-03-11 2019-05-07 Peloton Therapeutics, Inc. Compositions for use in treating pulmonary arterial hypertension
US10335388B2 (en) 2015-04-17 2019-07-02 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof
US10512626B2 (en) 2015-03-11 2019-12-24 Peloton Therapeautics, Inc. Compositions for use in treating glioblastoma
US10807948B2 (en) 2015-03-11 2020-10-20 Peloton Therapeutics, Inc. Aromatic compounds and uses thereof

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JP2003505375A (ja) * 1999-07-15 2003-02-12 レコルダチ エッセ．ア．，ケミカル アンド ファーマシューティカル カンパニー アルファ−１ｄアドレナリン作動性レセプターで選択的アンタゴニスト活性を有する環状アミドおよびイミド
CN1706820A (zh) * 2005-05-25 2005-12-14 天津大学 N－[2－(芳氧基）乙基]－2－（芳硫基）苄胺衍生物及制备方法和应用
WO2008050732A1 (fr) * 2006-10-23 2008-05-02 Takeda Pharmaceutical Company Limited Dérivé de l'iminopyridine et son utilisation

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JP2003505375A (ja) * 1999-07-15 2003-02-12 レコルダチ エッセ．ア．，ケミカル アンド ファーマシューティカル カンパニー アルファ−１ｄアドレナリン作動性レセプターで選択的アンタゴニスト活性を有する環状アミドおよびイミド
CN1706820A (zh) * 2005-05-25 2005-12-14 天津大学 N－[2－(芳氧基）乙基]－2－（芳硫基）苄胺衍生物及制备方法和应用
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US10597366B2 (en) 2013-09-09 2020-03-24 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US9896418B2 (en) 2013-09-09 2018-02-20 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US9908845B2 (en) 2013-09-09 2018-03-06 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US9969689B2 (en) 2013-09-09 2018-05-15 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US10144711B2 (en) 2013-09-09 2018-12-04 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
USRE49948E1 (en) 2013-09-09 2024-04-30 Peloton Therapeutics, Inc. Aryl ethers and uses thereof
US9884843B2 (en) * 2013-12-16 2018-02-06 Peloton Therapeutics, Inc. Cyclic sulfone and sulfoximine analogs and uses thereof
US10155726B2 (en) 2015-03-11 2018-12-18 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
US10512626B2 (en) 2015-03-11 2019-12-24 Peloton Therapeautics, Inc. Compositions for use in treating glioblastoma
US10278942B2 (en) 2015-03-11 2019-05-07 Peloton Therapeutics, Inc. Compositions for use in treating pulmonary arterial hypertension
US10807948B2 (en) 2015-03-11 2020-10-20 Peloton Therapeutics, Inc. Aromatic compounds and uses thereof
US10335388B2 (en) 2015-04-17 2019-07-02 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof
US10786480B2 (en) 2015-04-17 2020-09-29 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-α inhibitor and an immunotherapeutic agent and uses thereof
US9796697B2 (en) 2015-06-12 2017-10-24 Peloton Therapeutics, Inc. Tricyclic inhibitors of HIF-2-alpha and uses thereof

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