WO2011071109A1 - Composé hétérocyclique fusionné comportant un groupement amino - Google Patents

Composé hétérocyclique fusionné comportant un groupement amino Download PDF

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WO2011071109A1
WO2011071109A1 PCT/JP2010/072121 JP2010072121W WO2011071109A1 WO 2011071109 A1 WO2011071109 A1 WO 2011071109A1 JP 2010072121 W JP2010072121 W JP 2010072121W WO 2011071109 A1 WO2011071109 A1 WO 2011071109A1
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substituted
unsubstituted
carbocyclic
heterocyclic
ring
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PCT/JP2010/072121
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English (en)
Japanese (ja)
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周平 吉田
一生 加藤
光記 渕野
雄二 郡山
良泰 馬場
谷本　憲彦
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塩野義製薬株式会社
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Application filed by 塩野義製薬株式会社 filed Critical 塩野義製薬株式会社
Priority to US13/514,907 priority Critical patent/US20120245155A1/en
Priority to EP10836029.8A priority patent/EP2511269A4/fr
Priority to JP2011545241A priority patent/JPWO2011071109A1/ja
Publication of WO2011071109A1 publication Critical patent/WO2011071109A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having an amyloid ⁇ production inhibitory effect and useful as a therapeutic or prophylactic agent for diseases induced by production, secretion and / or deposition of amyloid ⁇ protein.
  • Alzheimer's disease In the brain of Alzheimer's disease patients, insoluble spots (senile plaques) in which a peptide consisting of about 40 amino acids called amyloid ⁇ protein accumulates outside the nerve cells are widely observed. It is thought that Alzheimer's disease develops when this senile plaque kills nerve cells, and amyloid ⁇ protein degradation accelerators, amyloid ⁇ vaccines, and the like have been studied as therapeutic agents for Alzheimer's disease.
  • Secretase is an enzyme that cleaves a protein called amyloid ⁇ precursor protein (APP) in cells to produce amyloid ⁇ protein.
  • the enzyme that controls the N-terminal generation of amyloid ⁇ protein is called ⁇ -secretase (beta-site APP-cleaving enzyme 1, BACE1). By inhibiting this enzyme, the production of amyloid ⁇ protein is suppressed, and Alzheimer's disease is treated. Or it could be a prophylactic agent.
  • Patent Documents 1 to 15 and the like are known as BACE1 inhibitors, but all have structures different from the compounds of the present invention.
  • a compound having an inhibitory action on amyloid ⁇ production particularly a BACE1 inhibitory action, and useful as a therapeutic or preventive agent for diseases induced by production, secretion or deposition of amyloid ⁇ protein.
  • the present invention provides the following items, for example.
  • —X— is —O—, —S— or —N (R 1 ) —
  • R 1 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted Substituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thi
  • —Y— represents a single bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, —N (R 7 ) —, —O—, —S—, —SO— or —SO 2.
  • -And -Z- is a single bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, -N (R 7 ) Ak-, -OAk-, -SAk-, -SOAk- or -SO 2
  • Ak- Ak is a single bond, substituted or unsubstituted C1-C3 alkylene or substituted or unsubstituted C2-C3 alkenylene, However, when —Y— is —N (R 7 ) —, —O—, —S—, —SO— or —SO 2 —, Ak is not a single bond, R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstitute
  • R 1 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted Substituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted
  • —Y— represents a single bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, —N (R 7 ) —, —O—, —S—, —SO— or —SO 2.
  • -And -Z- is a single bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, -N (R 7 ) Ak-, -OAk-, -SAk-, -SOAk- or -SO 2
  • Ak- Ak is a single bond, substituted or unsubstituted C1-C3 alkylene or substituted or unsubstituted C2-C3 alkenylene, However, when —Y— is —N (R 7 ) —, —O—, —S—, —SO— or —SO 2 —, Ak is not a single bond, R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstitute
  • R za and R zb are each independently hydrogen, halogen or substituted or unsubstituted alkyl, and R 4a , R 5a , R 5b , R 6a and R 6b are each independently hydrogen or substituted or The compound according to item (1), (1-1) or (2), or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is unsubstituted alkyl.
  • ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring
  • —W— is a single bond, —L 1 —C ( ⁇ O) N (R 8 ) —L 2 —, —L 1 —N (R 8 ) C ( ⁇ O) —L 2 — or —L 1 —N (R 8 ) —L 2 —, wherein L 1 is attached to ring B, L 2 is attached to ring A ′, L 1 and L 2 are each independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or un
  • the active ingredient is the compound according to any one of items (1), (1-1), (2) to (7), or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a pharmaceutical composition having BACE1 inhibitory activity (10) The pharmaceutical composition according to item (8) or (9), which is a medicament for treating or preventing a disease induced by production, secretion or deposition of amyloid ⁇ protein. (11) The pharmaceutical composition according to item (8) or (9), which is a medicament for treating or preventing Alzheimer's disease. (12) A compound according to any one of items (1), (1-1), (2) to (7), or a pharmaceutically acceptable salt thereof or a solvate thereof, A method of inhibiting BACE1 activity.
  • a compound according to any one of items (1), (1-1), (2) to (7) or a pharmaceutically acceptable salt thereof or a solvate thereof is administered.
  • a method of treating or preventing Alzheimer's disease is administered.
  • the compound according to any one of items (1), (1-1), (2) to (7), or a pharmaceutically acceptable salt thereof, or those used for the treatment or prevention of Alzheimer's disease Solvates.
  • a pharmaceutical composition comprising the compound according to any one of items (1), (1-1), (2) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof. Preparation methods, systems, devices, kits, etc.
  • the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases (such as Alzheimer's disease) induced by production, secretion or deposition of amyloid ⁇ protein.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl refers to a linear or branched alkyl having 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 3 carbon atoms.
  • alkoxy “halogenoalkyl”, “hydroxyalkyl”, “halogenoalkoxy”, “hydroxyalkoxy”, “alkoxycarbonyl”, “halogenoalkoxycarbonyl”, “alkylamino”, “aminoalkyl”, “alkoxyalkoxy”, “Alkoxyalkenyloxy”, “alkoxyalkynyl”, “alkoxyalkynyloxy”, “alkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “alkoxyimino”, “alkylcarbonyl", “alkylthio", “alkylsulfonyl", “alkylsulfonyl” Oxy, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylal “Luamino”, “alkylsulfin
  • the substituted or unsubstituted alkyl may be substituted with one or more groups selected from the substituent group ⁇ .
  • the substituent group ⁇ is halogen, hydroxy, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, Carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, carbon Cyclic and heterocyclic groups (where each carbo,
  • Substituents of “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted alkylsulfinyl” and “substituted or unsubstituted alkylsulfonyl” Includes one or more groups selected from the substituent group ⁇ .
  • halogenoalkyl examples include trifluoromethyl, fluoromethyl, trichloromethyl and the like.
  • halogenoalkoxy examples include trifluoromethoxy, fluoromethoxy, trichloromethoxy and the like.
  • Alkylidene includes the above-mentioned divalent group of “alkyl” and includes, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene and the like.
  • Alkenyl is a straight chain having 2 to 15 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more double bonds at any position. Or includes branched alkenyl.
  • alkenyl part of “alkenyloxy”, “alkenyloxycarbonyl”, “alkenylcarbonyl”, “alkoxyalkenyloxy”, “alkenylthio”, “alkenylamino”, “alkenylsulfonyl” and “alkenylsulfinyl” is the above “alkenyl”. It is the same.
  • Alkynyl includes straight-chain or branched alkynyl having 2 to 10 carbon atoms, for example, 2 to 8 carbon atoms, for example 3 to 6 carbon atoms, having one or more triple bonds at any position. . Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included. These may further have a double bond at an arbitrary position.
  • alkynyl part of “alkoxyalkynyl”, “alkynyloxy”, “alkynyloxycarbonyl”, “alkynylcarbonyl”, “alkoxyalkynyloxy”, “alkynylthio”, “alkynylsulfinyl”, “alkynylsulfonyl” and “alkynylamino” The same as the above “alkynyl”.
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted thiocarbamoyl” and “substituted or unsubstituted sulfamoyl” include alkyl, acyl, hydroxy, alkoxy, Examples thereof include 1 to 2 groups selected from alkoxycarbonyl, carbocyclic group, heterocyclic group and the like.
  • “Acyl” includes formyl, alkylcarbonyl having 1 to 10 carbon atoms, alkenylcarbonyl having 2 to 10 carbon atoms, alkynylcarbonyl having 2 to 10 carbon atoms, carbocyclic carbonyl and heterocyclic carbonyl.
  • acyl part of “acyloxy” and “acylamino” is the same as the above “acyl”.
  • the substituent of “substituted or unsubstituted acyl” and “substituted or unsubstituted acyloxy” includes one or more groups selected from substituent group ⁇ .
  • the ring portion of carbocyclic carbonyl and heterocyclic carbonyl is substituted with one or more groups selected from alkyl, substituent group ⁇ , and alkyl substituted with one or more groups selected from substituent group ⁇ . It may be.
  • Carbocyclic group includes cycloalkyl, cycloalkenyl, aryl, non-aromatic fused carbocyclic group, and the like.
  • Cycloalkyl is a carbocyclic group having 3 to 10, for example, 3 to 8, for example, 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. , Cyclononyl, cyclodecyl and the like.
  • Cycloalkylalkyl “Cycloalkylalkyl”, “cycloalkyloxy”, “cycloalkylalkoxy”, “cycloalkylthio”, “cycloalkylamino”, “cycloalkylalkylamino”, “cycloalkylsulfamoyl”, “cycloalkylsulfonyl”,
  • the cycloalkyl part of “cycloalkylcarbamoyl”, “cycloalkylalkylcarbamoyl”, “cycloalkylalkoxycarbonyl” and “cycloalkyloxycarbonyl” is the same as the above “cycloalkyl”.
  • Cycloalkenyl includes those having one or more double bonds at any position in the ring of the cycloalkyl, specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclo Examples include heptynyl, cyclooctynyl and cyclohexadienyl.
  • Aryl includes phenyl, naphthyl, anthryl, phenanthryl, and the like, and particularly includes phenyl.
  • non-aromatic fused carbocyclic group includes a non-aromatic group in which two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl” are condensed, and specifically Includes indanyl, indenyl, tetrahydronaphthyl, fluorenyl and the like.
  • the carbocyclic portion of the “non-aromatic carbocycle” is the same as the above “cycloalkyl”, “cycloalkenyl”, and “non-aromatic fused carbocyclic group”, and more specifically, cyclopropane, cyclobutane, cyclo Including pentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like.
  • Carbocycle “carbocycle oxy”, “carbocycle alkyl”, “carbocycle alkoxy”, “carbocycle alkoxycarbonyl”, “carbocycle thio”, “carbocycle amino”, “carbocycle alkylamino”, “ Carbon of carbocyclic carbonyl, carbocyclic sulfamoyl, carbocyclic sulfinyl, carbocyclic sulfonyl, carbocyclic carbamoyl, carbocyclic alkylcarbamoyl, carbocyclic oxycarbonyl, carbocyclic sulfonyl
  • the ring portion is the same as the “carbocyclic group”.
  • Arylalkyl “aryloxy”, “aryloxycarbonyl”, “arylalkoxycarbonyl”, “arylthio”, “arylamino”, “arylalkoxy”, “arylalkylamino”, “arylsulfonyl”, “arylsulfur”
  • aryl moiety of “famoyl”, “arylcarbamoyl” and “arylalkylcarbamoyl” is the same as the above “aryl”.
  • Heterocyclic group includes a heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl.
  • 5- to 6-membered heteroaryl such as, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc .; Dioxanyl, thilanyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholinoyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl,
  • Heterocycle “heterocycle alkyl”, “heterocycle oxy”, “heterocycle thio”, “heterocycle carbonyl”, “heterocycle alkoxy”, “heterocycle amino”, “heterocycle sulfamoyl”, “heterocycle”
  • the heterocyclic moieties of “sulfonyl”, “heterocyclic sulfinyl”, “heterocyclic carbamoyl”, “heterocyclic oxycarbonyl”, “heterocyclic alkylamino”, “heterocyclic alkoxycarbonyl” and “heterocyclic alkylcarbamoyl” are also referred to as “heterocyclic”.
  • heterocyclic portion of the “non-aromatic heterocyclic ring” is the same as the heterocyclic portion of the above “non-aromatic heterocyclic group”, and more specifically, dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane.
  • the bond of the above “heterocyclic group” may be located on any ring.
  • Heteroaryl includes an aromatic cyclic group among the above “heterocyclic groups”.
  • examples of the ring A include groups represented by the following formulae.
  • ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring
  • W 2 is O, S or N (R 8 )
  • R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl;
  • R 9 is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted
  • L is each independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, and ring T is substituted with a group selected from substituent group ⁇
  • the substituents of “unsubstituted pyridine”, “substituted or unsubstituted pyrimidine” and “substituted or unsubstituted pyrazine” include A group selected from the substituent group ⁇ (for example, halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl, amino, cyano, alkylamino and / or alkylthio, etc.), Substituent group ⁇ , alkyl substituted with one or more groups selected from the group consisting of hydroxyimino and alkoxyimino (wherein the substituents include, for example, halogen, hydroxy, alkoxy and / or alkoxycarbonyl, etc.), or non- Substituted alkyl, An aminoalkyl substituted with one or more groups selected from the substituent group ⁇ (wherein the substituents include, for example, acyl, al
  • substituent other than “—W-ring B” of “substituted or unsubstituted carbocycle” or “substituted or unsubstituted heterocycle” in ring A include, for example, halogen, alkyl, alkenyl, alkynyl, alkoxy Alkenyloxy, alkynyloxy or cyano.
  • substituent of “substituted or unsubstituted carbocycle”, “substituted or unsubstituted heterocycle”, or “substituted or unsubstituted benzene” in ring A ′ is, for example, halogen.
  • substituents of “substituted or unsubstituted pyridine”, “substituted or unsubstituted pyrimidine”, and “substituted or unsubstituted pyrazine” in ring B include, for example, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, Alkynyloxy or cyano.
  • Alkylene includes linear or branched divalent carbon chains having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 3 carbon atoms. Specific examples include methylene, dimethylene, trimethylene, tetramethylene, methyltrimethylene and the like.
  • alkylene part of “alkylenedioxy” is the same as the above “alkylene”.
  • Alkenylene refers to a straight or branched divalent carbon chain having a double bond at any position and having 2 to 10, for example, 2 to 6, for example, 2 to 4 carbon atoms. Include. Specific examples include vinylene, propenylene, butenylene, butadienylene, methylpropenylene, pentenylene and hexenylene.
  • Alkynylene is a linear or branched carbon having 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, which has a triple bond at an arbitrary position and may further have a double bond, for example, And a divalent carbon chain having 2 to 4 carbon atoms. Specific examples include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
  • Substituted or unsubstituted alkylene “Substituted or unsubstituted C1-C3 alkylene”, “Substituted or unsubstituted alkenylene”, “Substituted or unsubstituted C2-C3 alkenylene”, “Substituted or unsubstituted alkynylene”
  • substituent include a substituent selected from the substituent group ⁇ , and examples thereof include halogen and hydroxy.
  • R za and R zb together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle
  • R 3a and R 3b together with the carbon atom to which they are attached form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • R 5a and R 5b are In combination with the carbon atom to which it is attached to form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • R 6a and R 6b are substituted together with the carbon atom to which they are attached.
  • the “solvate” includes, for example, solvates and hydrates with an organic solvent, and can be converted into solvates and hydrates by a known method.
  • Suitable solvates include solvates with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether and the like.
  • non-toxic and water-soluble hydrates or solvates for example, ethanol and the like
  • it may be coordinated with any number of solvent molecules or water molecules.
  • the compound represented by the formula (I) includes a pharmaceutically acceptable salt.
  • alkali metals such as lithium, sodium or potassium
  • alkaline earth metals such as calcium
  • magnesium transition metals (such as zinc and iron), ammonium
  • salts with organic bases and amino acids or inorganic acids (such as hydrochloric acid and sulfuric acid) , Nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid) and organic acids (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, And malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like.
  • the compound represented by the formula (I) is not limited to a specific isomer, and all possible isomers (keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) And rotational isomers) and racemates.
  • the compound represented by the formula (I) in which R 2a is hydrogen includes the following tautomers.
  • one or more hydrogen, carbon or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms.
  • Compounds of formula (I) include all radiolabeled forms of compounds of formula (I). Such “radiolabeled”, “radiolabeled” and the like of the compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. . It is also useful as a pharmaceutical product.
  • Examples of isotopes that can be incorporated into the compounds of formula (I) of the present invention are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, respectively.
  • 35 S, 18 F, 123 I and 36 Cl include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • This method comprises reacting a compound of formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base.
  • a suitable catalyst for example Pd / C
  • Suitable methods for preparing other tritium labeled compounds include the documents Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14C-labeled compounds can be prepared by using raw materials having 14C carbon.
  • the compounds of the present invention represented by the formulas (I), (I-a1) to (I-a3), (I-b1) to (I-b6), (I-c1) and (I-c2) It can be produced according to the method described in Document 4 or by the following method.
  • the compound of the present invention represented by the formula (I) can be produced by the following method.
  • a substituent for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.
  • the protecting group may be removed at a desired stage.
  • a crossed bond means that the double bond may be either E-form, Z-form, or a mixture.
  • Compound (a-1) can be produced from a commercially available product by Preparation Method D described later. Moreover, it can also manufacture by a well-known method from a commercial item, and also can synthesize
  • Compound (a-1) and hydroxylamine or hydroxylamine salt (for example, hydroxylamine hydrochloride or hydroxylamine sulfate) in the presence or absence of a base, for example, ethanol, methanol, tetrahydrofuran, Compound (a-2) can be obtained by reaction in an organic solvent such as 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, or a mixed solvent of these solvents and water.
  • the base to be used include sodium acetate, pyridine, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, 2,6-lutidine and the like.
  • the reaction time is not particularly limited, but is usually 5 minutes to 30 hours, preferably 5 minutes to 12 hours.
  • the reaction temperature is usually from ⁇ 20 ° C. to the reflux temperature of the solvent, preferably from 0 ° C. to the reflux temperature of the solvent.
  • the oxime compound (a-2) is converted into, for example, dichloromethane, chloroform, benzene, toluene, xylene, N, N-dimethylformamide, tetrahydrofuran, 1,4- Conversion to nitrile oxide by reaction for 30 minutes to 48 hours, preferably 0.5 to 24 hours, in ice-cold to solvent reflux temperature in a solvent such as dioxane, followed by addition of 1,3-dipole Compound (a-3) can be obtained by cyclization reaction.
  • this reaction is more preferably carried out in the presence of sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, or an aqueous solution thereof, and a base such as triethylamine or pyridine, thereby suppressing side reactions and improving yield. May get results.
  • compound (a-2) is converted into a nitrile oxide derivative, and then compound (a-3) is obtained by 1,3-dipolar cycloaddition reaction with an olefin moiety in the same molecule.
  • the reaction in this step is carried out under conditions usually used for 1,3 monodipolar cycloaddition reaction, for example, Org. Lett. , 9 (2007) 5, 753-6, Tetrahedron 54 (1998) 22, 5868-82, Tetrahedron: Asymmetry 5 (1994) 6, 1018-28, and the like. Also good.
  • Step 3 Compound (a-3) can be prepared by methods known to those skilled in the art.
  • Aryllithium reagents including heterocyclic rings
  • Grignard reagents including Grignard reagents, including heterocyclic rings
  • aryls including heterocyclic rings
  • an organic metal reagent such as a magnesium reagent and a solvent that does not interfere with reagent preparation and reaction
  • an organic solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, or Compound (a-4) can be obtained by reacting in the mixed solvent.
  • the reaction time is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours.
  • the reaction temperature may be appropriately selected depending on the starting material, the reagent to be used, the solubility, and the like. In general, it is preferable to keep the reaction temperature at a temperature that minimizes the formation of by-products (eg, ⁇ 78 ° C.).
  • Additives such as tetramethylethylenediamine, hexamethylphosphoramide or boron trifluoride / diethyl ether complex as additives can give good results in improving yield and shortening reaction time. Sometimes.
  • reaction in this step is described in, for example, SYNLETT, 2004, 8, 1408-13, J.M. Am. Chem. Soc. 2005, 127, 5376-83, Bull. Chem. Soc. Jpn. , 1993, 66, 2730-7, etc., may be used.
  • the acid examples include acetic acid, formic acid, hydrochloric acid and the like, and the solvent used for the reaction can be appropriately selected from the aforementioned solvents, or the aforementioned acids can be used as the solvent.
  • the reaction temperature is usually from ⁇ 20 ° C. to the reflux temperature of the solvent, preferably from 0 ° C. to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.
  • the reaction may be carried out under the same conditions.
  • platinum oxide or the like is used as the metal catalyst.
  • Tetrahedron Asymmetry, 5 (1994) 6, 1018-28, Tetrahedron, Vol. 53, no. 16, pp 5752-46, 1997, and the like.
  • compound (a-5) can be obtained by hydrogenating compound (a-4) using platinum oxide as a catalyst in a solvent such as methanol in a hydrogen atmosphere.
  • compound (a-5) can be obtained by reducing compound (a-4) with lithium aluminum hydride in a solvent such as ether.
  • Fifth Step (a-6) can be obtained by subjecting compound (a-5) to functional group protecting conditions known to those skilled in the art.
  • the protecting group is a t-butoxycarbonyl group (hereinafter referred to as a BOC group) or a 9-fluorenylmethoxycarbonyl group (hereinafter referred to as Fmoc group)
  • conditions generally used for protecting amine compounds for example, T.I.
  • the compound can be obtained under the same conditions as those described in W. Green and PGM Wuts, “Protective Groups in Organic Chemistry, Third Edition”, John Wiley & Sons et al.
  • the compound (a-6) is added with an oxidizing agent such as 2-iodoxybenzoic acid in a solvent such as dimethyl sulfoxide or dichloromethane, and 0 ° C. to 80 ° C., preferably 10 ° C. to 40 ° C., 0.5%
  • Compound (a-7) can be obtained by reacting for a period of time to 48 hours, preferably 1 hour to 12 hours.
  • the oxidation conditions used are known to those skilled in the art, for example, Swan oxidation (Swern oxidation), Cory-Kim oxidation (Corey-Kim oxidation), Moffat oxidation (Moffatt oxidation), Pyridinium chlorochromate oxidation (PCC oxidation), Pyridinium dichromate oxidation (PDC oxidation), Dess-Martin oxidation (Dess-Martin oxidation), SO 3 -pyridine oxidation, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical oxidation (TEMPO oxidation), etc.
  • the reaction conditions described in Comprehensive Organic Transformations, Rchard C. Larock; VCH ", etc. may be used.
  • Seventh step R 3a R 3b CHPPh 3 L, etc. (for example, methyltriphenylphosphonium iodide, etc.) that can be synthesized in a solvent such as ether, tetrahydrofuran, dioxane, etc.
  • a strong base such as an alkyl metal reagent such as n-butyllithium was added to prepare a Wittig reagent (Wittig reagent) corresponding to the target compound, and the compound (a-7) dissolved in a solvent such as ether, tetrahydrofuran or dioxane Is added at ⁇ 40 ° C. to 60 ° C., preferably ⁇ 20 ° C. to 30 ° C., and reacted for 0.1 hours to 24 hours, preferably 0.3 hours to 6 hours to obtain compound (a-8). be able to.
  • the compound (a-8) is subjected to deprotection conditions known to those skilled in the art (for example, when the protecting group is a BOC group or Fmoc group, conditions generally used for deprotecting the protecting group of the amine compound, such as TW Green and PGM Wuts, “Protective Groups in Organic Chemistry, Third Edition”, conditions described in John Wiley & Sons et al.
  • deprotection conditions known to those skilled in the art (for example, when the protecting group is a BOC group or Fmoc group, conditions generally used for deprotecting the protecting group of the amine compound, such as TW Green and PGM Wuts, “Protective Groups in Organic Chemistry, Third Edition”, conditions described in John Wiley & Sons et al.
  • an isocyanate having a protective group isothiocyanate (for example, benzoyl isocyanate, benzoyl isothiocyanate) prepared by a commercially available method is added, and -30 °C ⁇ 50 °C, preferred Ku is -10 ° C. - 25 ° C., 0.5 hour to 24 hours, preferably, may be obtained compound by reacting 0.5 hour to 12 hours (a-9).
  • a compound (a-9) is added with a halogenium cation source such as iodine, bromine, N-bromosuccinimide (hereinafter referred to as NBS), N-chlorosuccinimide (hereinafter referred to as NCS), and ⁇ 20 Compound (a-10) can be obtained by reacting at 0 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 6 hours.
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • Tenth Step Compound (a-10) is mixed with pyrrolidine, piperidine, piperazine, morpholine, 1,8-diazabicyclo [5.4.0] undeca-7 in a solvent such as dioxane, tetrahydrofuran, toluene or a mixed solvent thereof.
  • a base such as -ene (hereinafter referred to as DBU) is added and reacted at 20 ° C. to 100 ° C., preferably 40 ° C. to 80 ° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • DBU -ene
  • Eleventh Step Amino group can be deprotected by subjecting compound (a-11) to deprotection conditions known to those skilled in the art.
  • the protecting group is a BOC group or an Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PGM Wuts, “Protective Groups in Organic”.
  • Compound (I-a1) can be prepared by deprotection under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • R ′ is a group that does not interfere with the reaction, such as an amino protecting group
  • LG is a leaving group such as halogen, alkylsulfonyloxy, etc., and other symbols are as defined above
  • Deprotection conditions known to those skilled in the art for the first step compound (a-8) for example, when the protecting group is a BOC group or Fmoc group, conditions generally used for deprotecting the protecting group of the amine compound (for example, , TW Green and PGM Wuts, “Protective Groups in Organic Chemistry, Third Edition”, conditions described in John Wiley & Sons et al.
  • the free form is mixed with 3,5-dimethylpyrazole-1-carboxyamidine or S-methylthiourea in a solvent such as acetonitrile, tetrahydrofuran, dimethylformamide and the like at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.5 hours to Compound by reacting for 120 hours, preferably 1 to 24 hours A product (a-12) can be obtained.
  • a solvent such as acetonitrile, tetrahydrofuran, dimethylformamide and the like
  • a halogenium cation source such as iodine, bromine, NBS, or NCS is added in a solvent such as dichloromethane, and the mixture is added at ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C.
  • Compound (a-13) can be obtained by reacting for 1 to 12 hours, preferably 0.1 to 6 hours.
  • the third step compound (a-13) is added with a base such as pyrrolidine, piperidine, piperazine, morpholine, DBU in a solvent such as dioxane, tetrahydrofuran, toluene or the like, or a mixed solvent thereof.
  • Compound (a-14) can be obtained by reacting at 40 to 80 ° C. for 0.1 to 24 hours, preferably 1 to 12 hours.
  • R ′ is a protecting group
  • the amino group can be deprotected by subjecting compound (a-14) to deprotection conditions known to those skilled in the art.
  • the protecting group is a BOC group or Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PMGM Wuts, “Protective Groups in Organic”.
  • Compound (I-a2) can be prepared by deprotection under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • R ′ and R ′′ are groups that do not interfere with the reaction, such as an amino protecting group, and other symbols are as defined above.
  • the compound (a-8) is subjected to deprotection conditions known to those skilled in the art (for example, when the protecting group is a BOC group or Fmoc group, conditions generally used for deprotecting the protecting group of the amine compound [Example As described in TW Green and PGM Wuts, “Protective Groups in Organic Chemistry, Third Edition”, John Wiley & Sons et al.]].
  • An isocyanate-free compound having a protective group (for example, benzoyl isocyanate) prepared by a commercially available method or a known method is added to the amine-free compound in a solvent such as dichloromethane, dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof.
  • a solvent such as dichloromethane, dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof.
  • a halogenium cation source such as iodine, bromine, NBS, or NCS is added in a solvent such as dichloromethane, and the mixture is added at ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C.
  • Compound (a-16) can be obtained by reacting for 1 to 12 hours, preferably 0.1 to 6 hours.
  • a base such as pyrrolidine, piperidine, piperazine, morpholine, DBU or the like is added in a solvent such as dioxane, tetrahydrofuran, toluene or the like, or a mixed solvent thereof.
  • Compound (a-17) can be obtained by reacting at 40 to 80 ° C. for 0.1 to 24 hours, preferably 1 to 12 hours.
  • the amino group can be deprotected by subjecting compound (a-17) to deprotection conditions known to those skilled in the art.
  • the protecting group is a BOC group or an Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PGM Wuts, “Protective Groups in Organic”.
  • Compound (I-a3) can be prepared by deprotecting under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • the amino group can be deprotected by subjecting the prepared compound (a-7) to deprotection conditions known to those skilled in the art.
  • the protecting group is a BOC group or an Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PGM Wuts, “Protective Groups in Organic”.
  • Compound (b-8) can be prepared by deprotection under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • the amino group can be deprotected by subjecting compound (b-9) to deprotection conditions known to those skilled in the art.
  • the protecting group is a BOC group or Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PMGM Wuts, “Protective Groups in Organic”.
  • Compound (I-b1) can be prepared by performing deprotection under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • First step Compound (b-8) is mixed with 3,5-dimethylpyrazole-1-carboxyamidine or S-methylthiourea in a solvent such as acetonitrile, tetrahydrofuran, dimethylformamide and the like at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • Compound (b-10) can be obtained by reacting at 0 ° C. for 0.5 hour to 120 hours, preferably 1 hour to 24 hours.
  • the second step compound (b-10) is reacted with concentrated sulfuric acid, concentrated nitric acid, etc. at ⁇ 30 ° C. to 70 ° C., preferably ⁇ 20 ° C. to 50 ° C. for 1 hour to 12 hours, preferably 1 hour to 6 hours. To give compound (b-11).
  • R ' is a protecting group
  • the amino group can be deprotected by subjecting compound (a-14) to deprotection conditions known to those skilled in the art.
  • the protecting group is a BOC group or Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PMGM Wuts, “Protective Groups in Organic”.
  • Compound (I-b2) can be prepared by performing deprotection under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • An isocyanate having a protective group (for example, benzoyl isocyanate) prepared by a commercially available or known method in the first step compound (b-8) in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or a mixed solvent thereof.
  • the compound (b-12) can be obtained by reacting at ⁇ 30 ° C. to 50 ° C., preferably ⁇ 10 ° C. to 25 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours. it can.
  • the amino group can be deprotected.
  • the protecting group is a BOC group or Fmoc group
  • the conditions generally used for deprotecting the protecting group of the amine compound for example, TW Green and PMGM Wuts, “Protective Groups in Organic”.
  • Compound (Ib3) can be prepared by deprotecting under the same conditions as those described in the literature such as Chemistry, Third Edition ", John Wiley & Sons.
  • Compound (a-1 ′) can be produced from a commercially available product in the same manner as in Preparation Method D described later. Moreover, it can also manufacture by a well-known method from a commercial item, and also can synthesize
  • Compound (a-7 ′) can be synthesized by reacting compound (a-7) with a Grignard reagent according to a conventional method known to those skilled in the art and oxidizing the resulting alcohol.
  • compound (a-7 ′) is synthesized by oxidizing compound (a-7) to carboxylic acid according to a conventional method, reacting with Grignard reagent via Weinreb amide, and oxidizing the resulting alcohol. I can do it.
  • the reaction conditions described in “Comprehensive Organic Transformations, Rchard C. Larock; VCH” and the like can also be used for the conversion of these functional groups.
  • LG is a leaving group such as halogen or alkylsulfonyloxy
  • R ′ is alkyl, arylalkyl or the like
  • Tf is a trifluoromethanesulfonyl group
  • a broken line indicates the presence of a bond.
  • other symbols are as defined above
  • the compound (c-1) a commercially available product can be used as it is. Moreover, it can also manufacture with a method well-known to those skilled in the art from a commercial item. Furthermore, it can also manufacture using the method of the description of the manufacture example in an Example.
  • N-phenyltrifluoromethane Compound (c-2) can be obtained by reacting with sulfonimide or trifluoromethanesulfonic anhydride.
  • the solvent used include ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene, toluene, and the reaction time is usually 5 minutes to 24 hours. Preferably 5 minutes to 12 hours.
  • the reaction temperature is usually ⁇ 100 ° C. to 40 ° C., more preferably ⁇ 78 ° C. to room temperature.
  • the reaction in this step is carried out under conditions usually used for the trifluoromethanesulfonylation reaction of a carbonyl compound (for example, J. Org. Chem., 57, 6972-5 (1992), Tetrahedron, 61, 4128-40 (2005)). , Tetrahedron Letters, 40, 8133-6 (1999), and the like.
  • Second Step Compound (c-3) can be obtained by subjecting compound (c-2) to a coupling reaction using a transition metal.
  • the coupling reaction for example, the reaction can be carried out under conditions usually used for Suzuki-Miyaura reaction, Stil reaction, and the like. Examples of the reaction conditions include Chem. Rev. , 2007, 107, 133-73, Tetrahedron, 58 (2002), 9633-95, and the like.
  • the organometallic catalyst used in this reaction is not particularly limited.
  • the amount of the organometallic catalyst used is a catalytic amount (about 0.001 to 0.1 equivalent) with respect to the raw material.
  • the organometallic compound is not particularly limited, but preferred examples include organotin reagents such as aryltri-n-butyltin and organoboron reagents such as arylboronic acid.
  • the amount of the organometallic compound used is equivalent to excess with respect to the raw material. Any solvent may be used as long as it does not interfere with the reaction. For example, benzene, toluene, xylene, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, 1,4-dioxane, propionitrile and the like can be used.
  • the reaction temperature is usually from ice cooling to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • this reaction is carried out in the presence of a base, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate or an aqueous solution thereof, and a base such as triethylamine, thereby suppressing side reactions and improving the yield. More favorable results may be obtained.
  • a base for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate or an aqueous solution thereof, and a base such as triethylamine
  • Third Step Compound (c-3) is subjected to a reduction reaction by adding diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride, etc. in a solvent such as dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof.
  • the compound (c-4) is obtained by reacting at ⁇ 80 ° C. to 0 ° C., preferably ⁇ 80 ° C. to ⁇ 20 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours. Can do.
  • Fourth Step Compound (c-4) is thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, carbon tetrachloride-triphenylphosphine, etc. in the presence or absence of a solvent such as toluene or dichloromethane. Reaction with a halogenating agent at ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • a sulfonylating agent such as methanesulfonyl chloride or p-toluenesulfonyl chloride is added at ⁇ 80 ° C. to 50 ° C., preferably at ⁇ 20 ° C. to 20 ° C. for 0.1 hour in the presence of a base such as triethylamine.
  • Compound (c-5) can be obtained by reacting for 24 hours, preferably 0.5 to 12 hours.
  • Compound (c-6) can be obtained from compound (c-5) by a method known to those skilled in the art. Specifically, for example, (c-5) and thiourea are reacted in an organic solvent such as ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and the like. Compound (c-6) can be obtained.
  • the reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
  • the reaction temperature is usually 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • Compound (c-6) is added with a halogenium cation source such as iodine, bromine, NBS, NCS or the like in a solvent such as dichloromethane, and at ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C.
  • Compound (Ic1) can be obtained by reacting for 1 to 12 hours, preferably 0.1 to 6 hours.
  • the target substituent R 4b can be introduced into the compound thus obtained by methods known to those skilled in the art.
  • Compound (I-c1) is added to a base such as pyrrolidine, piperidine, piperazine, morpholine, DBU in a solvent such as dioxane, tetrahydrofuran, toluene or the like, or a mixed solvent thereof.
  • Compound (Ic2) can be obtained by reacting at 40 to 80 ° C. for 0.1 to 24 hours, preferably 1 to 12 hours.
  • Second step In a solvent such as ether, tetrahydrofuran, or a mixed solvent such as ether-tetrahydrofuran, compound (c-3) is converted to methyl magnesium chloride, ethyl magnesium at ⁇ 100 ° C. to 50 ° C., preferably ⁇ 80 ° C. to 30 ° C.
  • a Grignard reagent having a substituent corresponding to the target compound such as bromide is added, or after hydrolysis from the compound (c-3), the target such as R 3a MgBr, R 3b MgBr and the like is passed through Weinreb Amide.
  • the compound (c-4 ′) is obtained by reacting a Grignard reagent having a substituent corresponding to the compound to be reacted sequentially as necessary and reacting for 0.2 to 24 hours, preferably 0.2 to 5 hours. Can be obtained.
  • Compound I-c1 'and Compound I-c2' can be synthesized according to Preparation Method CI.
  • Conversion of Leaving Group R 4 can be introduced into compound (Ic1) or (Ic1 ′) by appropriately selecting reaction conditions according to the methods described in the following documents known to those skilled in the art. .
  • First Step A base such as sodium hydride, potassium hydride, potassium t-butoxy and the like is added to a solution of compound (d-1) in THF, DMF, dimethylsulfoxide, etc. to give an alkoxide, and then compound (d-2) Compound (d-3) can be obtained by reacting with.
  • the base and compound (d-2) can be reacted with an equivalent to excess amount of compound (d-1).
  • the reaction time is usually 5 minutes to 90 hours, preferably 30 minutes to 24 hours.
  • the reaction temperature is usually ⁇ 20 ° C. to 80 ° C.
  • a salt such as tetrabutylammonium iodide
  • This reaction is carried out under the same conditions as those usually used for the O-alkylation reaction of alcohol compounds (for example, the conditions described in Tetrahedron Lett., 46 (2005) 45, 7751-5, etc.). Also good.
  • Second Step The compound (d-3) is added with an oxidant such as 2-iodoxybenzoic acid in a solvent such as dimethyl sulfoxide or dichloromethane, and 0 to 80 ° C., preferably 10 to 40 ° C.
  • oxidation conditions to be used include Swan oxidation (Swern oxidation), Corey-Kim oxidation (Corey-Kim oxidation), Moffat oxidation (Moffatt oxidation), Pyridinium chlorochromate oxidation (PCC oxidation), Pyridinium dichromate oxidation (PDC oxidation), Dess-Martin oxidation (Dess-Martin oxidation), SO 3 -pyridine oxidation, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical oxidation (TEMPO oxidation) and the like may be used.
  • the acetal group of the compound (d-5) is converted into, for example, T.I. W. Greenand P.M. G. M.M.
  • First Step (d-7) can be obtained by subjecting compound (d-6) to functional group protecting conditions known to those skilled in the art.
  • the protecting group is a BOC group or an Fmoc group
  • conditions generally used for protecting amine compounds for example, TW Green and PGM Wuts, “Protective Groups in Organic Chemistry, Third Edition.
  • the compound (d-7) can be obtained under the same conditions as those described in the literature “John Wiley & Sons”.
  • Compound (d-8) can be obtained by reacting compound (d-2) at ⁇ 20 ° C. to 100 ° C. for 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • the base and compound (d-2) can be reacted with an equivalent to excess amount of compound (d-7).
  • a salt such as tetrabutylammonium iodide
  • This reaction is performed under the same conditions as those usually used for the N-alkylation reaction of compound (d-7) (for example, the conditions described in J. Med. Chem., 2007, 50, 5493-508, etc.).
  • the reaction can be carried out with
  • the PG group of the compound (d-8) is prepared, for example, according to T.M. W. Greenand P.M. G. M.M.
  • the compound (a-1) in which Y is NH can be obtained by deprotection under the same conditions as those described in the literature such as Wuts, “Protective Groups in Organic Chemistry, Third Edition”, John Wiley & Sons.
  • the optically active compound (I) is an optically active raw material, an asymmetric synthesis is carried out at an appropriate stage to obtain an optically active intermediate, or an intermediate or final product of each racemate is processed at an appropriate stage. It can be manufactured by optically dividing with Optical resolution methods include separation of optical isomers using an optically active column, kinetic optical resolution using enzymatic reactions, etc., diastereomers by salt formation using chiral acids and chiral bases. There are crystallization division, preferential crystallization method and the like.
  • —X— is, for example, —O—, —S— or —N (R 1 ) —.
  • -X- is, for example, -O- or -S-.
  • —X— is, for example, —O—.
  • -X- is, for example, -S-.
  • R 1 is, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl
  • R 1 is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group.
  • R 2a and R 2b are each independently, for example, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted carbamoyl.
  • R 2a and R 2b are, for example, both hydrogen.
  • Ring A is, for example, a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring.
  • Ring A is, for example,
  • Ring A ′ and Ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring;
  • W 2 is O, S or N (R 8 )
  • R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl;
  • R 9 is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or
  • Ring A is, for example,
  • L is each independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, and ring T is substituted with a group selected from substituent group ⁇
  • Ring A is, for example,
  • Ring A is, for example,
  • L 1 and L 2 are each independently, for example, a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl.
  • Ring A is, for example,
  • Ring A ′ is, for example, a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring.
  • Ring A ′ is, for example, substituted or unsubstituted benzene (wherein the substituent is halogen or the like).
  • Ring B is, for example, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine (the substituent is, for example, halogen, alkyl, alkoxy, halogenoalkoxy, alkynyloxy, alkylcarbamoyl or cyano) ).
  • R 8 is, for example, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl.
  • R 8 is, for example, hydrogen.
  • —Y— represents, for example, a single bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, —N (R 7 ) —, —O—, —S—, — SO— or —SO 2 —.
  • —Y— is, for example, substituted or unsubstituted C1-C3 alkylene or —O—.
  • -Z- is, for example, a single bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C2-C3 alkenylene, -N (R 7 ) Ak-, -OAk-, -SAk-, -SOAk -, - SO 2 Ak- or -SO 2 AK-.
  • -Z- is, for example, a single bond.
  • Ak is, for example, a single bond, substituted or unsubstituted C1-C3 alkylene, or substituted or unsubstituted C2-C3 alkenylene.
  • —Y— is —N (R 7 ) —, —O—, —S—, —SO— or —SO 2 —
  • Ak is not a single bond
  • —ZY— is, for example, substituted or unsubstituted C1-C3 alkylene, —O— or —O— (substituted or unsubstituted C1-C3 alkylene)-.
  • R 7 represents, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy Substituted, unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substitute
  • R 7 is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted carbamoyl.
  • R za and R zb are, for example, each independently hydrogen, halogen, a substituent or unsubstituted alkyl, or R za and R zb are substituted with the carbon atom to which they are attached, or An unsubstituted carbocycle is formed.
  • R za and R zb are, for example, each independently hydrogen, halogen, or substituted or unsubstituted alkyl.
  • R 3a and R 3b are, for example, independently of each other hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted Or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sul
  • R 3a and R 3b are, for example, both hydrogen.
  • R 4a and R 4b are each independently, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic oxy It is.
  • R 4a and R 4b are each independently, for example, hydrogen or substituted or unsubstituted alkyl.
  • R 4b is not hydrogen.
  • R 5a , R 5b , R 6a and R 6b are each independently, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted Or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbon
  • R 5a , R 5b , R 6a and R 6b are each independently, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted Or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbon
  • R 5a , R 5b , R 6a and R 6b are each independently, for example, hydrogen or substituted or unsubstituted alkyl.
  • R 5a , R 5b , R 6a and R 6b are, for example, both hydrogen.
  • Ring A ′ is a substituted or unsubstituted carbocycle (substituent is, for example, halogen);
  • Ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine (the substituent is, for example, halogen, alkyl, alkoxy, halogenoalkoxy, alkynyloxy, alkylcarbamoyl or cyano).
  • R 8 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl (more specifically, R 8 is hydrogen); R za and R zb are each independently hydrogen, halogen or substituted or unsubstituted alkyl; R 3a ′ is hydrogen or substituted or unsubstituted alkyl).
  • Ring A is A compound, Ring B is Wherein R b1 and R b2 are each independently hydrogen, chloro, fluoro, methoxy, butynyloxy, cyano, amino or carbamoyl.
  • R b1 and R b2 are each independently hydrogen, chloro, fluoro, methoxy, butynyloxy, cyano, amino or carbamoyl.
  • a compound, A compound in which the combination of ring B, R b1 and R b2 (B, R b1 , R b2 ) is as follows.
  • ring B (B1, hydrogen, hydrogen) (hereinafter, ring B is b1), (B1, hydrogen, chloro) (hereinafter, ring B is b2), (B1, hydrogen, fluoro) (hereinafter, ring B is b3), (B1, hydrogen, methoxy) (hereinafter, ring B is b4), (B1, hydrogen, butynyloxy) (hereinafter, ring B is b5), (B1, hydrogen, cyano) (hereinafter, ring B is b6), (B1, hydrogen, amino) (hereinafter, ring B is b7), (B1, hydrogen, carbamoyl) (hereinafter, ring B is b8), (B1, chloro, hydrogen) (hereinafter, ring B is b9), (B1, chloro, chloro) (hereinafter, ring B is b10), (B1, chloro, fluoro) (hereinafter, ring B is b11), (B1, chloro, methoxy
  • ring B (B3, hydrogen, hydrogen) (hereinafter, ring B is b60), (B3, hydrogen, chloro) (hereinafter, ring B is b61), (B3, hydrogen, fluoro) (hereinafter, ring B is b62), (B3, hydrogen, methoxy) (hereinafter, ring B is b63), (B3, hydrogen, butynyloxy) (hereinafter, ring B is b64), (B3, hydrogen, cyano) (hereinafter, ring B is b65), (B3, hydrogen, amino) (hereinafter, ring B is b66), (B3, hydrogen, carbamoyl) (hereinafter, ring B is assumed to be b67), (B3, chloro, hydrogen) (hereinafter, ring B is b68), (B3, chloro, chloro) (hereinafter, ring B is b69), (B3, chloro, fluoro) (hereinafter, ring B is b70), (B3, chloro,
  • a compound in which the combination of ring B and R b1 (B, R b1 ) is as follows.
  • a combination of ring A and ring B (r, A, b) is as follows. (r1, A1, b1), (r1, A1, b2), (r1, A1, b3), (r1, A1, b4), (r1, A1, b5), (r1, A1, b6), (r1 , A1, b7), (r1, A1, b8), (r1, A1, b9), (r1, A1, b10), (r1, A1, b11), (r1, A1, b12), (r1, A1 , b13), (r1, A1, b14), (r1, A1, b15), (r1, A1, b16), (r1, A1, b17), (r1, A1, b18), (r1, A1, b19 ), (r1, A1, b20), (r1, A1, b21), (r1, A1, b22), (r1, A1, b23), (r1, A1, b24), (r1, A1, A1, b9
  • the compound of the present invention is useful for diseases induced by production, secretion or deposition of amyloid ⁇ protein.
  • diseases induced by production, secretion or deposition of amyloid ⁇ protein For example, Alzheimer type dementia (Alzheimer's disease, Alzheimer type senile dementia etc.), Down's syndrome, memory disorder, prion disease (Kreuz's disease) Felt-Jakob disease, etc.), mild cognitive impairment (MCI), Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy, other degenerative dementia, mixed vascular degenerative dementia, dementia associated with Parkinson's disease, progression Treatment and / or prevention of dementia associated with supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy body Alzheimer's disease, age-related macular degeneration, Parkinson's disease, amyloid angiopathy, etc.
  • treatment of Alzheimer's disease includes prevention of MCI severity and prevention of familial Alzheimer's disease.
  • pharmaceutical composition for treating Alzheimer's disease includes a pharmaceutical composition for preventing MCI from becoming severe, a pharmaceutical composition for preventing the onset of familial Alzheimer's disease, and the like.
  • the compound of the present invention has high inhibitory activity against BACE1 and / or high selectivity to other enzymes, and therefore can be a pharmaceutical with reduced side effects. Furthermore, since it has a high inhibitory effect on amyloid ⁇ production in cell systems, and particularly has a high inhibitory effect on amyloid ⁇ production in the brain, it can be an excellent pharmaceutical product. Moreover, it can become a pharmaceutical with a wider safety margin with respect to a side effect by setting it as the optically active substance which has appropriate stereochemistry.
  • the compound of the present invention has high metabolic stability, high solubility, high oral absorption, good bioavailability, good clearance, high brain transferability, long half-life, non-protein binding rate It has also advantages such as low HERG channel inhibition, low CYP inhibition, low CYP MBI (Mechanism-based inhibition) and / or negative Ames test.
  • the compound of the present invention When the compound of the present invention is administered, it may be used in combination with other drugs (for example, other Alzheimer's disease treatment or prevention agents such as acetylcholinesterase).
  • other drugs for example, other Alzheimer's disease treatment or prevention agents such as acetylcholinesterase.
  • antidementia drugs such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine, and vinpocetine.
  • the compound of the present invention When the compound of the present invention is administered to humans, it can be administered orally as powders, granules, tablets, capsules, pills, liquids, etc. or parenterally as injections, suppositories, transdermal absorption agents, inhalants, etc. Can be administered.
  • excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives suitable for the dosage form may be mixed with an effective amount of the present compound as necessary to obtain a pharmaceutical preparation. it can.
  • the dose varies depending on the disease state, administration route, patient age, or body weight, but when administered orally to an adult, it is usually 0.1 ⁇ g to 1 g / day, preferably 0.01 to 200 mg / day. In the case of parenteral administration, it is usually 1 ⁇ g to 10 g / day, preferably 0.1 to 2 g / day.
  • the broken line bond in the chemical formula represents a relative configuration, and all the compounds are racemic.
  • the crude product (43 mg) containing the obtained compound (20) was dissolved in THF (0.75 mL), and methanol (0.75 mL) and water (0.45 mL) were added.
  • potassium carbonate (61 mg) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours.
  • the reaction solution was heated to 45 ° C. and stirred for 150 minutes, and then cooled to room temperature.
  • potassium carbonate (61 mg) was added to the reaction solution was stirred at the same temperature for 1 hour.
  • the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • Example 3 Synthesis of Compound (I-17)
  • the first step compound (22) (1.50 g) was dissolved in ethyl acetate (15 ml), 2-iodoxybenzoic acid (4.78 g) was added at room temperature, and the mixture was stirred at reflux for 3 hours.
  • the reaction solution was returned to room temperature, filtered, and concentrated under reduced pressure at room temperature.
  • the residue was dissolved in 50% aqueous ethanol (40 ml), hydroxylamine hydrochloride (1.37 g) and sodium acetate (1.94 g) were added at room temperature, and the mixture was stirred for 90 min.
  • the second step compound (23) (1.26 g) was dissolved in methylene chloride (44 ml), 5% aqueous sodium hypochlorite solution (14.7 ml) was added at room temperature, and the mixture was stirred at the same temperature for 30 min. The distributed organic layer was dried over magnesium sulfate, the extract was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by chromatography to give compound (24) (1.07 g).
  • the fourth step compound (25) (1.17 g) was dissolved in concentrated sulfuric acid (7 ml), fuming nitric acid (0.24 ml) was added dropwise at ice temperature, and the mixture was further stirred at the same temperature for 1 hour. After quenching by adding an aqueous sodium carbonate solution, the mixture was extracted with chloroform. The obtained organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was precipitated with an ethyl acetate-diethyl ether-hexane solution, and this was filtered to obtain Compound (26) (1.29 g).
  • the sixth step compound (27) (1.08 g) was dissolved in methanol (10 ml), ethyl trifluoroacetate (1.14 ml) and triethylamine (0.63 ml) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After the extract was filtered, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography to obtain compound (28) (1.41 g).
  • the seventh step compound (28) (1.41 g) was dissolved in ethanol (14 ml), 5% rhodium / carbon was added at room temperature, and the mixture was stirred at the same temperature for 23 hours in a hydrogen atmosphere.
  • the reaction solution was filtered through celite, and the resulting filtrate was concentrated under reduced pressure.
  • the obtained residue was dissolved in tetrahydrofuran (10 ml), di-tert-butyl dicarbonate (1.97 ml) was added at room temperature, and the mixture was stirred at 70 ° C. for 14 hr.
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain compound (29) (1.23 g).
  • the tenth step compound (31) (1.02 g) was dissolved in ethyl acetate (10 ml), 2-iodoxybenzoic acid (761 mg) was added at room temperature, and the mixture was stirred for 6 hours under reflux.
  • the reaction solution was returned to room temperature and filtered, and then concentrated under reduced pressure at room temperature.
  • a 2 mol / L hydrochloric acid methanol solution (9.70 ml) was added at room temperature, stirred at the same temperature for 2 hours, and further allowed to stand overnight.
  • a sodium carbonate aqueous solution and ethyl acetate were added to the reaction solution, and the organic layer was partitioned, washed with brine, and dried over magnesium sulfate.
  • the thirteenth step compound (34) (365 mg) was dissolved in N, N-dimethylacetamide, triethylamine (1.09 ml) and 4-chlorobenzenethiol (571 mg) were added at room temperature, and the mixture was stirred at 60 ° C. for 2 hours.
  • a 1 mol / L aqueous hydrochloric acid solution was added to make an acidic solution, and the mixture was washed with ethyl acetate.
  • the aqueous layer was made basic by adding an aqueous sodium carbonate solution, extracted with a chloroform-methanol (9: 1) solution, and the partitioned organic layer was dried over magnesium sulfate. After the extract was filtered, the solvent was distilled off under reduced pressure.
  • the mixture was made basic by adding aqueous sodium hydroxide solution (2 mol / L, 76 ⁇ l) and 50% aqueous potassium carbonate solution at ice temperature, and then extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. After filtering the extract, the solvent was distilled off under reduced pressure. The resulting residue was roughly purified by chromatography, and then a solid was precipitated with diethyl ether, and this was filtered to obtain Compound (I-17) (34 mg).
  • the second step compound (37) (6.07 g) was dissolved in dichloromethane (60 ml), metachloroperbenzoic acid (7.09 g) was added little by little while stirring in an ice bath, and the mixture was warmed to room temperature and stirred for 3 hours. Thereafter, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography to give compound (38) (3.61 g).
  • the fifth step compound (40) (1.28 g) was dissolved in tetrahydrofuran (15 ml), di-tert-butyl dicarbonate (0.89 ml) and dimethylaminopyridine (402 mg) were added, and the mixture was stirred at room temperature for 5 hours. Thereafter, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give compound (41) (1.74 g) as a crude product. Got as.
  • Example 5 Synthesis of Compound (I-35)
  • the first step compound (43) (1.80 g) was dissolved in concentrated acid (1 ml) and stirred at 60 ° C. for 1.5 hours.
  • the reaction mixture was poured into ice water, neutralized with 2 mol / L aqueous sodium hydroxide solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure.
  • the compound (44) (1.39 g) was obtained by leaving.
  • the second step compound (44) (1.39 g) was dissolved in methanol (15 ml), tetrahydrofuran (5 ml) and water (5 ml), potassium carbonate (1.57 g) was added, and the mixture was stirred at 40 ° C. for 17 hours. Saturated aqueous sodium hydrogen carbonate was then added, and the mixture was extracted with a chloroform-methanol (9: 1) solution. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give compound (45 ) (923 g) was obtained.
  • the third step compound (45) (50 mg) was dissolved in methanol (1 ml), 2 mol / L hydrochloric acid (0.099 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Thereafter, carboxylic acid (34 mg) and WSCD hydrochloride were added, and the mixture was stirred at the same temperature for 1.5 hours. Thereafter, 10% aqueous sodium bicarbonate was added, and the precipitated solid was collected by filtration, washed with water, and then dried by heating to obtain compound (I-35) (34 mg).
  • RT represents the retention time (minutes).
  • the substrate peptide was synthesized by reacting biotin-XSEVNLDAEFRHDSGC (manufactured by Peptide Institute) with cryptate TBPCOOH mono SMP (manufactured by CIS bio international).
  • the final concentration of substrate peptide was 18 nmol / L
  • the final concentration of recombinant human BACE1 was 7.4 nmol / L
  • the reaction buffer was sodium acetate buffer (50 mmol / L sodium acetate pH 5.0, 0.008%). Triton X-100) is used.
  • Enzyme activity was determined from the count rate (10000 x count 665 / count 620) of each measurement wavelength, and the dose (IC 50 ) that inhibits enzyme activity by 50% was calculated.
  • Resulting compound I-3 0.029 ⁇ M
  • Compound I-37 0.027 ⁇ M
  • Compound I-33, 35, 36, 38, etc. had an IC 50 of 1 ⁇ M or less.
  • Neuroblastoma SH-SY5Y cells (SH / APPwt) overexpressing human wild-type ⁇ APP were adjusted to 8 ⁇ 10 5 cells / mL and plated on a 96-well culture plate (Falcon) at 150 ⁇ l per well.
  • the cells were cultured at 37 ° C. in a 5% carbon dioxide incubator for 2 hours. Thereafter, a solution in which a test compound (DMSO: dimethyl sulfoxide solution) was added and suspended in advance to be a 2 ⁇ l / 50 ⁇ l medium was added to the cell solution. That is, the final DMSO concentration was 1% and the cell culture solution was 200 ⁇ l. After 24 hours of incubation from the addition of the test compound, 100 ⁇ l of the culture supernatant was collected and the amount of A ⁇ contained therein was measured.
  • DMSO dimethyl sulfoxide solution
  • the method for measuring the amount of A ⁇ was 384-well half area plate (black plate; manufactured by Coaster), 10 ⁇ l of homogeneous time-resolved fluorescence (HTRF) measurement reagent (Amyloid ⁇ 40 peptide; IBA Molecular Holding, SA), 10 ⁇ l of the culture supernatant was added, mixed, and left at 4 ° C. overnight protected from light. Thereafter, fluorescence intensity (excitation wavelength: 337 nm, measurement wavelengths: 620 nm and 665 nm) was measured using a Wallac 1420 multilabel counter (manufactured by Perkin Elmer life sciences).
  • HTRF time-resolved fluorescence
  • the amount of A ⁇ was determined from the count rate of each measurement wavelength (10000 ⁇ count 665 / count 620), and the dose that inhibits A ⁇ production by 50% (IC 50 ) was calculated from at least 6 different doses.
  • Resulting compound I-37 0.001 ⁇ M
  • Compounds I-3, 33 to 36, and 38 to 46 had an IC 50 of 1 ⁇ M or less.
  • Test Example 3 Rat brain ⁇ -amyloid reducing action
  • the test compound is suspended in 0.5% methylcellulose, prepared to a final concentration of 2 mg / mL, and orally administered to male Crj: SD rats (7-9 weeks old) to 10 mg / kg. .
  • the base control group is administered with 0.5% methylcellulose alone, and 3 to 8 animals are administered in each group.
  • the brain is removed, the cerebral hemisphere is isolated, weighed, and then immediately frozen in liquid nitrogen and stored at ⁇ 80 ° C. until the date of extraction.
  • the frozen cerebral hemisphere was transferred to a Teflon (registered trademark) homogenizer under ice-cooling, and an extraction buffer (1% CHAPS ( ⁇ 3-[(3-chloroamidopropyl) dimethylammonio] -1-propane) having a volume 5 times its weight was used. Sulfonate ⁇ ), 20 mmol / L Tris-HCl (pH 8.0), 150 mmol / L NaCl and Complete (Roche) protease inhibitor) are added, and the mixture is repeatedly homogenized for 2 minutes to solubilize. The suspension is transferred to a centrifuge tube and left on ice for 3 hours or more, and then centrifuged at 100,000 ⁇ g, 4 ° C.
  • ⁇ -amyloid 40 manufactured by Wako Pure Chemical Industries, Ltd., product number 294-62501.
  • the ELISA measurement is performed according to the attached instructions.
  • the decreasing effect is calculated as the ratio of the base control group of each test to ⁇ -amyloid 40 in the brain.
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme using E. coli-expressed CYP3A4 as an enzyme.
  • the reaction for producing a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) was performed as an indicator.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • Test Example 5 CYP inhibition test
  • CYP1A2 7-ethoxyresorufin O-deethylation
  • CYP2C9, 2C19, 2D6, 3A4 7-ethoxyresorufin O-deethylation
  • CYP2C9, 2C19, 2D6, 3A4 -Hydroxylation
  • CYP2C19 mephenytoin 4'-hydroxylation
  • CYP2D6 dextromethorphan O-demethylation
  • CYP3A4 terfenadine hydroxylation
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6) 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L ( 4 points).
  • each of 5 types of substrate, human liver microsomes, and test drug is added in 50 mmol / L Hepes buffer with the above composition, and NADPH as a coenzyme is added as an indicator for metabolic reaction.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin (CYP1A2 metabolite) in the centrifugal supernatant was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. Results Compound I-33: IC 50 > 20 (5 types)
  • Test Example 6 FAT test Inoculate 20 mL of cryopreserved Salmonella typhimurium TA98 and TA100 strains into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and incubate at 37 ° C for 10 hours before shaking. .
  • 9 mL of the bacterial solution was centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1).
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, and 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, TA98 strain under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution for TA100 strain, respectively, and 588 ⁇ L of test bacterial solution (498 ⁇ L of test bacterial solution under metabolic activation conditions) And S9 mix (90 ⁇ L) are mixed and incubated at 37 ° C.
  • Test Example 7 Solubility test
  • 10 mM DMSO solution of the test compound to the media (JP-I, JP-II). From the turbidity (crystallization information) after 4 hours, Three-stage evaluation (High;> 40 ⁇ M, Medium; 3 to 40 ⁇ M, Low; ⁇ 3 ⁇ M).
  • Test Example 8 Metabolic stability test
  • the target compound was allowed to react for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • Test Example 10 Powder solubility test
  • JP-1 solution 2.0 g of sodium chloride, 7.0 mL of hydrochloric acid to 1000 mL
  • JP-2 solution 500 mL of pH 6.8 phosphate buffer. 200 mL of water
  • 20 mmol / L TCA (sodium taurocholate) / JP-2 solution water is added to 1.08 g of TCA to make 100 mL.
  • Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • Evaluation items Blood is collected over time, and the drug concentration in plasma is measured using LC / MS / MS.
  • Rats are intravenously administered at a dose of 0.5 mg / mL / kg, and after 30 minutes, they are exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia. The brain is then removed and 20-25% homogenate is prepared with distilled water. On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma is added to the brain sample and control brain is added to the plasma sample at a ratio of 1: 1, and each sample is measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement is defined as the brain Kp value.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • Formulation Example 4 The following ingredients are heated and mixed and then sterilized to give an injection.
  • the compound of the present invention can be a useful drug as a therapeutic or prophylactic agent for diseases induced by production, secretion and / or deposition of amyloid ⁇ protein.

Abstract

La présente invention concerne un composé, ou similaire, servant d'agent prophylactique ou thérapeutique contre des pathologies induites par la production, la sécrétion et/ou le dépôt de la protéine β-amyloïde. La présente invention concerne spécifiquement un composé de formule (I), l'un de ses sels de qualité pharmaceutique ou un solvate du composé ou du sel. (Dans la formule, R1, R2a, R2b, R3, R4, R5a, R5b, R6a, R6b, X, Y, Z, le cycle A et le segment interrompu sont tels que définis dans la description.)
PCT/JP2010/072121 2009-12-11 2010-12-09 Composé hétérocyclique fusionné comportant un groupement amino WO2011071109A1 (fr)

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US13/514,907 US20120245155A1 (en) 2009-12-11 2010-12-09 Fused heterocyclic compound having amino group
EP10836029.8A EP2511269A4 (fr) 2009-12-11 2010-12-09 Composé hétérocyclique fusionné comportant un groupement amino
JP2011545241A JPWO2011071109A1 (ja) 2009-12-11 2010-12-09 アミノ基を有する縮合ヘテロ環化合物

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JP2009-282193 2009-12-11
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168630B2 (en) 2007-04-24 2012-05-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
WO2012057247A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé d'aminodihydropyrimidine fusionnée
WO2012057248A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé de naphtyridine
US8173642B2 (en) 2005-10-25 2012-05-08 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
WO2013030713A1 (fr) * 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazine-2-amines
JP2013513563A (ja) * 2009-12-11 2013-04-22 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての２−アミノ−５，５−ジフルオロ−５，６−ジヒドロ−４ｈ−オキサジン
JP2013513568A (ja) * 2009-12-10 2013-04-22 エフ．ホフマン−ラ ロシュ アーゲー アミノオキサジン誘導体
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
WO2013164730A1 (fr) * 2012-05-04 2013-11-07 Pfizer Inc. Composés d'hexahydropyrano[3,4-d][1,3]thiazin-2-amine substitués par des hétérocycliques à titre d'inhibiteurs d'app, bace1 et bace2
WO2014013076A1 (fr) * 2012-07-20 2014-01-23 Eisai R&D Management Co., Ltd. Composés d'hexahydropyrrolothiazine
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
JP2014510120A (ja) * 2011-04-04 2014-04-24 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての１，４−オキサゼピン
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
JP2014520777A (ja) * 2011-07-06 2014-08-25 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としてのシクロプロピル−縮合−１，３−チアゼピン
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WO2014138484A1 (fr) 2013-03-08 2014-09-12 Amgen Inc. Composés à base de 1,3-oxazin-2-amine fusionnée avec du cyclopropyle perfluoré utilisables en tant qu'inhibiteurs de la bêta-sécrétase et leurs procédés d'utilisation
US8865706B2 (en) 2013-02-13 2014-10-21 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
JP2015504906A (ja) * 2012-01-26 2015-02-16 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ フルオロメチル−５，６−ジヒドロ−４ｈ−［１，３］オキサジン
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9233981B1 (en) 2013-02-15 2016-01-12 Pfizer Inc. Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2016503785A (ja) * 2012-12-19 2016-02-08 ファイザー・インク 炭素環式および複素環式置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9315520B2 (en) 2014-04-10 2016-04-19 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
JP2016522254A (ja) * 2013-06-18 2016-07-28 イーライ リリー アンド カンパニー Ｂａｃｅ阻害剤
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2017051276A1 (fr) 2015-09-24 2017-03-30 Pfizer Inc. N-[2-(2-amino-6,6-disubstitués-4,4a,5,6-tétrahydropyrano[3,4-d][1,3]thiazin-8a(8h)-yl)-1,3-thiazol-4-yl]amides
WO2017051294A1 (fr) 2015-09-24 2017-03-30 Pfizer Inc. N-[2-(3-amino-2,5-diméthyl-1,1-dioxido-5,6-dihydro-2h-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides utiles comme inhibiteurs de bace
WO2017051303A1 (fr) 2015-09-24 2017-03-30 Pfizer Inc. Dérivés de tétrahydropyrano[3,4-d] [1,3]oxazine et leur utilisation en tant qu'inhibiteurs de bace
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
CN109121412A (zh) * 2016-05-20 2019-01-01 伊莱利利公司 N-[3-[2-氨基-5-(1,1-二氟乙基)-4,4a,5,7-四氢呋喃并[3,4-d][1,3]噁嗪-7a-基]-4-氟-苯基]-5-(三氟甲基)吡啶-2-甲酰胺及其(4aR,5S,7aS)异构体作为选择性BACE1抑制剂用于治疗如阿尔茨海默病的用途
US10889595B2 (en) 2016-12-26 2021-01-12 Tetranov Pharmaceutical Co., Ltd. [1,3]thiazin-2-amine compound, application, and pharmaceutical composition
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO3143B1 (ar) 2012-04-03 2017-09-20 Lilly Co Eli مركبات تتراهيدرو بيرولو ثيازين
JP6243921B2 (ja) 2012-10-26 2017-12-06 イーライ リリー アンド カンパニー Ｂａｃｅ阻害剤
TWI593692B (zh) 2013-03-12 2017-08-01 美國禮來大藥廠 四氫吡咯并噻嗪化合物
AR103680A1 (es) 2015-02-23 2017-05-24 Lilly Co Eli Inhibidores selectivos de bace1
MX2019010659A (es) * 2017-03-07 2019-10-21 Janssen Pharmaceutica Nv Inhibidores de beta secretasa.
WO2018162443A1 (fr) * 2017-03-07 2018-09-13 Janssen Pharmaceutica Nv Inhibiteurs de bêta-sécrétase
US20200010482A1 (en) * 2017-03-07 2020-01-09 Janssen Pharmaceutica Nv Inhibitors of beta secretase

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058311A1 (fr) 2003-12-15 2005-06-30 Schering Corporation Inhibiteurs de protease aspartyle heterocyclique
WO2006138264A2 (fr) 2005-06-14 2006-12-28 Schering Corporation Inhibiteurs d'aspartyl protease
WO2007049532A1 (fr) 2005-10-25 2007-05-03 Shionogi & Co., Ltd. Derive aminodihydrothiazine
WO2008073365A1 (fr) 2006-12-12 2008-06-19 Schering Corporation Inhibiteurs de la protéase d'aspartyle
WO2008073370A1 (fr) 2006-12-12 2008-06-19 Schering Corporation Inhibiteurs de la protéase aspartyle contenant un système de noyau tricyclique
WO2008133273A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Composition pharmaceutique pour le traitement de la maladie d'alzheimer
WO2008133274A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Dérivés d'aminodihydrothiazine substitués par des groupes cycliques
WO2009091016A1 (fr) 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. Dérivé d'aminodihydrothiazine condensée
WO2009131974A1 (fr) 2008-04-22 2009-10-29 Schering Corporation Composes de 2-imino-3-methyl-pyrrolo pyrimidinone substitues par thiophenyle utilises en tant qu’inhibiteurs bace-1, compositions et utilisation associees
WO2009151098A1 (fr) 2008-06-13 2009-12-17 塩野義製薬株式会社 DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DU SOUFRE AYANT UNE ACTIVITÉ INHIBANT LA β-SÉCRÉTASE
WO2010013794A1 (fr) 2008-07-28 2010-02-04 Eisai R&D Management Co., Ltd. Dérivés de spiroaminodihydrothiazine
WO2010013302A1 (fr) 2008-07-28 2010-02-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de spiroaminodihydrothiazine
WO2010038686A1 (fr) 2008-09-30 2010-04-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé d'aminodihydrothiazine fusionné inédit
WO2011009898A1 (fr) * 2009-07-22 2011-01-27 Eisai R&D Management Co., Ltd Dérivés condensés d'aminodihydro-oxazine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR077277A1 (es) * 2009-07-09 2011-08-17 Lilly Co Eli Compuestos de biciclo (1,3)tiazin-2-amina formulacion farmaceutica que lo comprende y su uso para la manufactura de un medicamento util para el tratamiento de la enfermedad de alzheimer
US7964594B1 (en) * 2009-12-10 2011-06-21 Hoffmann-La Roche Inc. Amino oxazine derivatives

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005058311A1 (fr) 2003-12-15 2005-06-30 Schering Corporation Inhibiteurs de protease aspartyle heterocyclique
WO2006138264A2 (fr) 2005-06-14 2006-12-28 Schering Corporation Inhibiteurs d'aspartyl protease
JP2008543849A (ja) * 2005-06-14 2008-12-04 シェーリング コーポレイション アスパルチルプロテアーゼ阻害剤
WO2007049532A1 (fr) 2005-10-25 2007-05-03 Shionogi & Co., Ltd. Derive aminodihydrothiazine
WO2008073365A1 (fr) 2006-12-12 2008-06-19 Schering Corporation Inhibiteurs de la protéase d'aspartyle
WO2008073370A1 (fr) 2006-12-12 2008-06-19 Schering Corporation Inhibiteurs de la protéase aspartyle contenant un système de noyau tricyclique
WO2008133273A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Composition pharmaceutique pour le traitement de la maladie d'alzheimer
WO2008133274A1 (fr) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Dérivés d'aminodihydrothiazine substitués par des groupes cycliques
WO2009091016A1 (fr) 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. Dérivé d'aminodihydrothiazine condensée
WO2009131974A1 (fr) 2008-04-22 2009-10-29 Schering Corporation Composes de 2-imino-3-methyl-pyrrolo pyrimidinone substitues par thiophenyle utilises en tant qu’inhibiteurs bace-1, compositions et utilisation associees
WO2009131975A1 (fr) 2008-04-22 2009-10-29 Schering Corporation Composes de 2-imino-3-methyl-pyrrolo pyrimidinone substitues par phenyle utilises en tant qu’inhibiteurs bace-1, compositions et utilisation associees
WO2009151098A1 (fr) 2008-06-13 2009-12-17 塩野義製薬株式会社 DÉRIVÉ HÉTÉROCYCLIQUE CONTENANT DU SOUFRE AYANT UNE ACTIVITÉ INHIBANT LA β-SÉCRÉTASE
WO2010013794A1 (fr) 2008-07-28 2010-02-04 Eisai R&D Management Co., Ltd. Dérivés de spiroaminodihydrothiazine
WO2010013302A1 (fr) 2008-07-28 2010-02-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé de spiroaminodihydrothiazine
WO2010038686A1 (fr) 2008-09-30 2010-04-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 Dérivé d'aminodihydrothiazine fusionné inédit
WO2011009898A1 (fr) * 2009-07-22 2011-01-27 Eisai R&D Management Co., Ltd Dérivés condensés d'aminodihydro-oxazine

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Isotopes in the Physical and Biomedical Sciences", vol. 1, 1987
BULL. CHEM. SOC. JPN., vol. 66, 1993, pages 2730 - 2737
BULL. CHEM. SOC. JPN., vol. 66, 1993, pages 2730 - 7
CAO, Y.-Q.; WU,G.-Q.; LI,Y.-B.; DAI,Z.; CHEN,B.-H., SYNTH. COMMUN., vol. 36, no. 22, 2006, pages 3353 - 3358
CHEM.REV., vol. 107, 2007, pages 133 - 73
J. AM. CHEM. SOC., vol. 127, 2005, pages 5376 - 83
J. MED. CHEM., vol. 50, 2007, pages 5493 - 508
J. ORG. CHEM., vol. 200, no. 68, pages 1207 - 1215
J. ORG. CHEM., vol. 57, 1992, pages 6972 - 6975
KISS, L.; MANGELINCKX, S.; FUELOEP, F.; DE KIMPE, N., ORG. LETT., vol. 9, no. 21, 2007, pages 4399 - 4402
MAHAMMED, K. A.; MURTHY, P. S. K.; RAJU, K. M., INDIAN J. CHEM. SECT. B: ORG. CHEM. INCL. MED. CHEM., vol. 47, no. 4, 2008, pages 575 - 578
ORG. LETT., vol. 7, no. 25, 2005, pages 5741 - 5742
ORG. LETT., vol. 9, no. 5, 2007, pages 753 - 6
See also references of EP2511269A4 *
SYNLETT, vol. 8, 2004, pages 1408 - 13
T. W GREEN; P. G M. WUTS: "Protective Groups in Organic Chemistry", JOHN WILEY & SONS
TETRAHEDRON LETT., vol. 46, no. 45, 2005, pages 7751 - 5
TETRAHEDRON LETTERS, vol. 40, 1999, pages 8133 - 8136
TETRAHEDRON, vol. 53, no. 16, 1997, pages 5752 - 5746
TETRAHEDRON, vol. 54, no. 22, 1998, pages 5808 - 82
TETRAHEDRON, vol. 54, no. 22, 1998, pages 5868 - 82
TETRAHEDRON, vol. 58, 2002, pages 9633 - 35
TETRAHEDRON, vol. 61, 2005, pages 4129 - 4140
TETRAHEDRON: ASYMMETRY, vol. 5, no. 6, 1994, pages 1018 - 28
TETRAHEDRON: ASYMMETRY, vol. 5, no. 6, 1994, pages 1019 - 1028
THEODORA W GREENE: "Protective Groups in organic Synthesis", JOHN WILEY & SONS
VACHAL,P.; FLETCHER, J.M.; HAGMANN, W. K., TETRAHEDRON LETT., vol. 48, no. 33, 2007, pages 5761 - 5765

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US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8815851B2 (en) 2005-10-25 2014-08-26 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8173642B2 (en) 2005-10-25 2012-05-08 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US9029358B2 (en) 2005-10-25 2015-05-12 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8546380B2 (en) 2005-10-25 2013-10-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8633188B2 (en) 2005-10-25 2014-01-21 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8884062B2 (en) 2007-04-24 2014-11-11 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8168630B2 (en) 2007-04-24 2012-05-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8895548B2 (en) 2007-04-24 2014-11-25 Shionogi & Co., Ltd. Pharmaceutical composition for treating alzheimer's disease
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US9273053B2 (en) 2008-06-13 2016-03-01 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having Beta secretase inhibitory activity
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US8940748B2 (en) 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US9687494B2 (en) 2009-10-08 2017-06-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9428475B2 (en) 2009-10-08 2016-08-30 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
JP2013513568A (ja) * 2009-12-10 2013-04-22 エフ．ホフマン−ラ ロシュ アーゲー アミノオキサジン誘導体
US9290466B2 (en) 2009-12-11 2016-03-22 Shionogi & Co., Ltd. Oxazine derivatives
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9656974B2 (en) 2009-12-11 2017-05-23 Shionogi & Co., Ltd. Oxazine derivatives
JP2013513563A (ja) * 2009-12-11 2013-04-22 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての２−アミノ−５，５−ジフルオロ−５，６−ジヒドロ−４ｈ−オキサジン
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
WO2012057247A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé d'aminodihydropyrimidine fusionnée
WO2012057248A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé de naphtyridine
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
JP2014510120A (ja) * 2011-04-04 2014-04-24 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての１，４−オキサゼピン
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
JP2014520777A (ja) * 2011-07-06 2014-08-25 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としてのシクロプロピル−縮合−１，３−チアゼピン
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9550795B2 (en) 2011-08-31 2017-01-24 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2014525432A (ja) * 2011-08-31 2014-09-29 ファイザー・インク ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
WO2013030713A1 (fr) * 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazine-2-amines
US8933221B2 (en) 2011-08-31 2015-01-13 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2015504906A (ja) * 2012-01-26 2015-02-16 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ フルオロメチル−５，６−ジヒドロ−４ｈ−［１，３］オキサジン
WO2013164730A1 (fr) * 2012-05-04 2013-11-07 Pfizer Inc. Composés d'hexahydropyrano[3,4-d][1,3]thiazin-2-amine substitués par des hétérocycliques à titre d'inhibiteurs d'app, bace1 et bace2
US8962616B2 (en) 2012-05-04 2015-02-24 Pfizer Inc. Heterocyclic substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2015520140A (ja) * 2012-05-04 2015-07-16 ファイザー・インク ＡＰＰ、ＢＡＣＥ１、およびＢＡＣＥ２の阻害剤としての複素環式置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
WO2014013076A1 (fr) * 2012-07-20 2014-01-23 Eisai R&D Management Co., Ltd. Composés d'hexahydropyrrolothiazine
US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9198917B2 (en) 2012-12-11 2015-12-01 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9045498B2 (en) 2012-12-11 2015-06-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8822456B2 (en) 2012-12-11 2014-09-02 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2016503785A (ja) * 2012-12-19 2016-02-08 ファイザー・インク 炭素環式および複素環式置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
US9403846B2 (en) 2012-12-19 2016-08-02 Pfizer Inc. Carbocyclic- and heterocyclic-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9192612B2 (en) 2013-02-13 2015-11-24 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2016507551A (ja) * 2013-02-13 2016-03-10 ファイザー・インク ヘテロアリール置換ヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
US9045499B2 (en) 2013-02-13 2015-06-02 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US8865706B2 (en) 2013-02-13 2014-10-21 Pfizer Inc. Heteroaryl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
JP2016507580A (ja) * 2013-02-15 2016-03-10 ファイザー・インク 置換フェニルヘキサヒドロピラノ［３，４−ｄ］［１，３］チアジン−２−アミン化合物
US9233981B1 (en) 2013-02-15 2016-01-12 Pfizer Inc. Substituted phenyl hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9085576B2 (en) 2013-03-08 2015-07-21 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2014138484A1 (fr) 2013-03-08 2014-09-12 Amgen Inc. Composés à base de 1,3-oxazin-2-amine fusionnée avec du cyclopropyle perfluoré utilisables en tant qu'inhibiteurs de la bêta-sécrétase et leurs procédés d'utilisation
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
JP2016522254A (ja) * 2013-06-18 2016-07-28 イーライ リリー アンド カンパニー Ｂａｃｅ阻害剤
US9315520B2 (en) 2014-04-10 2016-04-19 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9428523B2 (en) 2014-04-10 2016-08-30 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9605007B2 (en) 2014-04-10 2017-03-28 Pfizer Inc. 2-amino-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US10028962B2 (en) 2014-04-10 2018-07-24 Pfizer Inc. 2-amino-6-methy1-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
US9744173B2 (en) 2014-04-10 2017-08-29 Pfizer Inc. 2-amino 6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
KR20160141849A (ko) 2014-04-11 2016-12-09 시오노기세이야쿠가부시키가이샤 Bace1 저해 작용을 갖는 디하이드로티아진 및 디하이드로옥사진 유도체
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2017051303A1 (fr) 2015-09-24 2017-03-30 Pfizer Inc. Dérivés de tétrahydropyrano[3,4-d] [1,3]oxazine et leur utilisation en tant qu'inhibiteurs de bace
US9611264B1 (en) 2015-09-24 2017-04-04 Pfizer Inc. N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides
US9751895B2 (en) 2015-09-24 2017-09-05 Pfizer Inc. N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)-1,3-thiazol-4-yl]amides
WO2017051294A1 (fr) 2015-09-24 2017-03-30 Pfizer Inc. N-[2-(3-amino-2,5-diméthyl-1,1-dioxido-5,6-dihydro-2h-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides utiles comme inhibiteurs de bace
US9771379B2 (en) 2015-09-24 2017-09-26 Pfizer Inc. N-(2-(2-amino-6-substituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]OXAZIN-8a(8H)-yl)-thiazol-4-yl) amides
WO2017051276A1 (fr) 2015-09-24 2017-03-30 Pfizer Inc. N-[2-(2-amino-6,6-disubstitués-4,4a,5,6-tétrahydropyrano[3,4-d][1,3]thiazin-8a(8h)-yl)-1,3-thiazol-4-yl]amides
US10112958B2 (en) 2015-09-24 2018-10-30 Pfizer Inc. N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-YL)-1,3-thiazol-4-YL] amides
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
CN109121412A (zh) * 2016-05-20 2019-01-01 伊莱利利公司 N-[3-[2-氨基-5-(1,1-二氟乙基)-4,4a,5,7-四氢呋喃并[3,4-d][1,3]噁嗪-7a-基]-4-氟-苯基]-5-(三氟甲基)吡啶-2-甲酰胺及其(4aR,5S,7aS)异构体作为选择性BACE1抑制剂用于治疗如阿尔茨海默病的用途
US10889595B2 (en) 2016-12-26 2021-01-12 Tetranov Pharmaceutical Co., Ltd. [1,3]thiazin-2-amine compound, application, and pharmaceutical composition
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11629154B2 (en) 2018-04-27 2023-04-18 Shionogi & Co., Ltd. Tetrahydropyranooxazine derivatives having selective BACE1 inhibitory activity
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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