WO2017061534A1 - Dérivés de dihydrothiazine - Google Patents

Dérivés de dihydrothiazine Download PDF

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WO2017061534A1
WO2017061534A1 PCT/JP2016/079767 JP2016079767W WO2017061534A1 WO 2017061534 A1 WO2017061534 A1 WO 2017061534A1 JP 2016079767 W JP2016079767 W JP 2016079767W WO 2017061534 A1 WO2017061534 A1 WO 2017061534A1
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aromatic
substituted
compound
formula
alkyl
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PCT/JP2016/079767
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Yasuyoshi ISOU
Kosuke Anan
Ken-Ichi Kusakabe
Henricus Jacobus Maria Gijsen
Francois Paul Bischoff
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Shionogi & Co., Ltd.
Janssen Pharmaceutica Nv
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Publication of WO2017061534A1 publication Critical patent/WO2017061534A1/fr

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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • 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

Definitions

  • the present invention relates to a compound which has amyloid ⁇ production inhibitory activity, and is useful as an agent for treating or preventing disease induced by production, secretion and/or deposition of amyloid ⁇ proteins.
  • Patent Documents 1 to 30 and Non-Patent Document 1 disclose compounds having a structure similar to those of the compounds of the present invention, but each of substantially disclosed compounds has a structural difference from the compounds of the present invention.
  • the present invention provides compounds which have reducing effects to produce amyloid ⁇ protein, especially BACE1 inhibitory activity, and are useful as an agent for treating disease induced by production, secretion and/or deposition of amyloid ⁇ protein.
  • the present invention for example, provides the inventions described in the following items.
  • a method for treating or preventing Alzheimer dementia, mild cognitive impairment or prodromal Alzheimer's disease, for preventing the progression of Alzheimer dementia, mild cognitive impairment, or prodromal Alzheimer's disease, or for preventing the progression in a patient asymptomatic at risk for Alzheimer dementia comprising administering the compound according to any one of items (1) to (8), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items (1) to (8), or a pharmaceutically acceptable salt thereof for treating or preventing Alzheimer dementia.
  • a method for treating or preventing Alzheimer dementia comprising administering the compound according to any one of items (1) to (8) , or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound of any one of items (1) to (8), or a pharmaceutically acceptable salt thereof, for oral administration.
  • the pharmaceutical composition of (25) which is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction or tincture.
  • the pharmaceutical composition of (26) which is a sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, troche tablet, sublingual tablet, buccal tablet, chewable tablet, orally disintegrated tablet, dry syrup, soft capsule, micro capsule or sustained-release capsule.
  • a pharmaceutical composition comprising the compound of any one of items (1) to (8), or a pharmaceutically acceptable salt thereof, for parenteral administration.
  • a pharmaceutical composition comprising the compound of any one of items (1) to (8), or a pharmaceutically acceptable salt thereof, for a pediatric or geriatric patient.
  • a pharmaceutical composition consisting of a combination of the compound of any one of items (1) to (8) or a pharmaceutically acceptable salt thereof and acetylcholinesterase inhibitor, NMDA antagonist, or other medicament for Alzheimer dementia.
  • a pharmaceutical composition comprising the compound of any one of items (1) to (8), or a pharmaceutically acceptable salt thereof, for a combination therapy with acetylcholinesterase inhibitor, NMDA antagonist, or other medicament for Alzheimer dementia.
  • the compound of the present invention has BACE1 inhibitory activity and is useful as an agent for treating and/or preventing disease induced by production, secretion or deposition of amyloid ⁇ proteins such as Alzheimer dementia.
  • the term of “consisting of” means having only components.
  • the term of “comprising” means not restricting with components and not excluding undescribed factors.
  • the "halogen” includes fluorine, chlorine, bromine, and iodine. Fluorine and chlorine are preferable.
  • the "alkyl” includes linear or branched alkyl of a carbon number of 1 to 15, for example, a carbon number of 1 to 10, for example, a carbon number of 1 to 6, and for example, a carbon number of 1 to 4.
  • Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl.
  • alkyl is methyl, ethyl, n-propyl, isopropyl or tert-butyl.
  • alkenyl includes linear or branched alkenyl of a carbon number or 2 to 15, for example, a carbon number of 2 to 10, for example, a carbon number of 2 to 6, and for example, a carbon number of 2 to 4, having one or more double bonds at any available positions.
  • Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl.
  • Examples are vinyl, allyl, propenyl, isopropenyl and butenyl.
  • alkynyl includes a linear or branched alkynyl of a carbon number of 2 to 15, for example, a carbon number of 2 to 10, for example, a carbon number of 2 to 8, for example, a carbon number of 2 to 6, and for example, a carbon number of 2 to 4 having one or more triple bonds at optionally positions.
  • Specific examples are ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. These may have further a double bond at any available position. Examples are ethynyl, propynyl, butynyl and pentynyl.
  • alkylene include a linear or branched divalent carbon chain of a carbon number of 1 to 15, for example, a carbon number of 1 to 10, for example, a carbon number of 1 to 6, and for example a carbon number of 1 to 4. Examples are methylene, dimethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Alkylene portion in “alkylenedioxy” is the same as the above “alkylene”. Examples are methylenedioxy and dimethylenedioxy.
  • aromatic carbocyclyl includes an aromatic hydrocarbon group which is monocyclic or which consists of two or more rings. Examples are an aromatic hydrocarbon group of a carbon number of 6 to 14, and specific examples are phenyl, naphthyl, anthryl and phenanthryl. In one embodiment, “aromatic carbocyclyl” is phenyl.
  • non-aromatic carbocyclyl also includes a cyclic group having a bridge or a cyclic group to form a spiro ring as follows:
  • non-aromatic monocyclic carbocyclyl includes a group having 3 to 16 carbon atoms, for example, 3 to 12 carbon atoms, for example, 3 to 8 carbon atoms, and for example, 3 to 5 carbon atoms.
  • cycloalkyl includes a carbocyclic group of a carbon number of 3 to 10, for example, a carbon number of 3 to 8, and for example, a carbon number 4 to 8. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Cycloalkyl portion in “cycloalkylalkyl", “cycloalkylamino” and “cycloalkylalkyloxy” are the same as the above "cycloalkyl".
  • aromatic heterocyclyl includes an aromatic group which is monocyclic, or which consists of two or more rings, containing one or more of heteroatoms selected independently from oxygen, sulfur and nitrogen atoms.
  • An “aromatic heterocyclyl” of two or more rings includes a fused cyclic group wherein aromatic monocyclic heterocyclyl or non-aromatic heterocyclyl consisting of two or more rings is fused with a ring of the above “aromatic carbocyclyl”.
  • aromatic monocyclic heterocyclyl includes a 5- to 8-membered group, and for example, 5- to 6- membered group.
  • Examples are pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl.
  • aromatic bicyclic heterocyclyl includes a 9- to 10-membered group, and examples are indolinyl, isoindolinyl, indazolinyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl and thiazolop
  • aromatic heterocyclyl of three or more rings includes a 13 to 14-membered group, and examples are carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl and dibenzofuryl.
  • non-aromatic heterocyclyl includes a non-aromatic group which is monocyclic, or which consists of two or more rings, containing one or more of heteroatoms selected independently from oxygen, sulfur and nitrogen atoms.
  • a “non-aromatic heterocyclyl” of two or more rings includes (i) a fused cyclic group wherein non-aromatic monocyclic heterocyclyl or non-aromatic heterocyclyl of two or more rings is fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”, and (ii) a fused cyclic group wherein aromatic heterocyclyl is fused with non-aromatic carbocyclyl.
  • non-aromatic heterocyclyl also includes a cyclic group having a bridge or a cyclic group to form a spiro ring as follows:
  • non-aromatic monocyclic heterocyclyl includes a 3- to 8-membered ring, and for example, 4-, 5- or 6-membered ring.
  • Examples are dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetra
  • alkyloxy includes a group wherein an oxygen atom is substituted with the above “alkyl”. Examples are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy and hexyloxy. In one embodiment, “alkyloxy” is methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.
  • alkenyloxy includes a group wherein an oxygen atom is substituted with the above “alkenyl”. Examples are vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy and 2-octenyloxy.
  • alkynyloxy includes a group wherein an oxygen atom is substituted with the above “alkynyl”. Examples are ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy and 2-octynyloxy.
  • haloalkyl includes a group wherein one or more hydrogen atoms attached to one or more carbon atoms of the above “alkyl” are replaced with one or more above “halogen”.
  • Examples are monofluoromethyl, monofluoroethyl, monofluoropropyl, difluoromethyl, difluoroethyl, difluoropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, pentafluoropropyl, monochloromethyl, monochloroethyl, monochloropropyl, dichloromethyl, dichloroethyl, dichloropropyl, trichloromethyl, trichloroethyl, trichloropropyl, pentachloropropyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,
  • Examples are monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, and 2,2-difluoroethyl. Examples are monofluoromethyl, difluoromethyl, 1-fluoroehtyl, 1,1-difluoroethyl and 2,2-difluoroethyl.
  • dihalomethyl includes a group wherein the above "alkyl” is substituted with two halogen groups. Examples are difluoromethyl and dichloromethyl.
  • haloalkenyl includes a group wherein one or more hydrogen atoms attached to one or more carbon atoms of the above “alkenyl” are replaced with one or more above "halogen". Examples are monofluorovinyl, monofluoroallyl, monofluoropropenyl, difluorovinyl, difluoroallyl and difluoropropenyl.
  • haloalkynyl includes a group wherein one or more hydrogen atoms attached to one or more carbon atoms of the above "alkynyl” are replaced with one or more above "halogen".
  • Examples are fluoroethynyl, monofluoropropynyl, difluoropropynyl, monofluorobutynyl, chloroethynyl, monochloropropynyl, monochlorobutynyl and dichloropropynyl.
  • haloalkyloxy includes a group wherein an oxygen atom is substituted with the above “haloalkyl”. Examples are monofluoromethyloxy, monofluoroethyloxy, difluoromethyloxy, 1,1-difluoroethyloxy, 2,2-difluoroethyloxy, trifluoromethyloxy, trichloromethyloxy, 2,2,2-trifluoroethyloxy and trichloroethyloxy. In one embodiment, “haloalkyloxy” is difluoromethyloxy, 2,2,2-difluoroethyloxy, trifluoromethyloxy, 2,2,2-trifluoroethyloxy, or trichloromethyloxy.
  • alkyloxyalkyl includes a group wherein the above “alkyl” is substituted with the above “alkyloxy”. Examples are methoxymethyl, methoxyethyl and ethoxymethyl.
  • alkyloxyalkyloxy includes a group wherein the above “alkyloxy” is substituted with the above “alkyloxy”. Examples are methyloxymethyloxy, methyloxyethyloxy, ethyloxymethyloxy and ethyloxyethyloxy.
  • cycloalkylalkyloxy includes a group wherein the above “alkyloxy” is substituted with the above “cycloalkyl”. Examples are cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy and cyclobutylethyloxy.
  • alkylcarbonyl includes a group wherein a carbonyl group is substituted with the above “alkyl”. Examples are methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl and hexylcarbonyl. Examples are methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.
  • alkenylcarbonyl includes a group wherein a carbonyl group is substituted with the above “alkenyl”. Examples are ethylenylcarbonyl, propenylcarbonyl and butenylcarbonyl.
  • alkynylcarbonyl includes a group wherein a carbonyl group is substituted with the above “alkynyl”. Examples are ethynylcarbonyl, propynylcarbonyl and butynylcarbonyl.
  • monoalkylamino includes a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with the above “alkyl”. Examples are methylamino, ethylamino and isopropylamino. In one embodiment, "monoalkylamino" is methylamino or ethylamino.
  • dialkylamino includes a group wherein two hydrogen atoms attached to a nitrogen atom of an amino group are replaced with two above “alkyl”. These two alkyl groups may be the same or different. Examples are dimethylamino, diethylamino, N,N-diisopropylamino, N-methyl-N-ethylamino and N-isopropyl-N-ethylamino. In one embodiment, "dialkylamino” is dimethylamino or diethylamino.
  • alkylsulfonyl includes a group wherein a sulfonyl group is substituted with the above “alkyl”. Examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl and sec-butylsulfonyl. In one embodiment, "alkylsulfonyl” is methylsulfonyl or ethylsulfonyl.
  • alkyloxyimino includes a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkyloxy”. Examples are methyloxyimino, ethyloxyimino, n-propyloxyimino and isopropyloxyimino.
  • alkylcarbonyloxy includes a group wherein an oxygen atom is substituted with the above “alkylcarbonyl”. Examples are methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy and sec-butylcarbonyloxy. In one embodiment, “alkylcarbonyloxy” is methylcarbonyloxy or ethylcarbonyloxy.
  • alkynylcarbonyloxy includes a group wherein an oxygen atom is substituted with the above “alkynylcarbonyl”. Examples are ethynylcarbonyloxy and propynylcarbonyloxy.
  • alkyloxycarbonyl includes a group wherein a carbonyl group is substituted with the above “alkyloxy”. Examples are methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl and hexyloxycarbonyl. In one embodiment, "alkyloxycarbonyl” is methyloxycarbonyl, ethyloxycarbonyl or propyloxycarbonyl.
  • alkylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkyl”. Examples are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, tert-butylsulfanyl and isobutylsulfanyl.
  • cyanoalkylsulfanyl includes a group wherein the above "alkylsulfanyl” is substituted with a cyano group. Examples are cyanomethylsulfanyl, cyanoethylsulfanyl and cyanopropylsulfanyl.
  • alkylsulfinyl includes a group wherein a sulfinyl group is substituted with the above “alkyl”. Examples are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and isopropylsulfinyl.
  • monoalkylcarbamoyl includes a group wherein a hydrogen atom attached to a nitrogen atom of a carbamoyl group is replaced with the above “alkyl”. Examples are methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl and isopropylcarbamoyl.
  • dialkylcarbamoyl includes a group wherein two hydrogen atom attached to a nitrogen atom of a carbamoyl group are replaced with two above “alkyl”. These two alkyl groups may be the same or different. Examples are dimethylcarbamoyl, diethylcarbamoyl and N-methyl-N-ethylcarbamoyl.
  • dialkylsulfamoyl includes a group wherein two hydrogen atoms attached to a nitrogen atom of a sulfamoyl group are replaced with two above “alkyl”. These two alkyl groups may be the same or different. Examples are dimethylsulfamoyl, diethylsulfamoyl and N-methyl-N-ethylsulfamoyl.
  • alkylidene includes a divalent group derived from alkane by removing two hydrogen atoms from the same carbon atom. Examples are methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene.
  • aromatic carbocyclylalkyl includes alkyl substituted with one or more above “aromatic carbocyclyl”. Examples are benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl and a group of the formula of In one embodiment, “aromatic carbocyclylalkyl” is benzyl, phenethyl or benzhydryl.
  • aromatic heterocyclylalkyl includes alkyl substituted with one or more above “aromatic heterocyclyl”. Also, “aromatic heterocyclylalkyl” includes “aromatic heterocyclylalkyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”, and/or “non-aromatic carbocyclyl”.
  • Examples are pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl and groups of the formula of
  • non-aromatic heterocyclylalkyl includes alkyl substituted with one or more above “non-aromatic heterocyclyl”. Also, “non-aromatic heterocyclylalkyl” includes a “non-aromatic heterocyclylalkyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. Examples are tetrahydropyranylmethyl, morpholinylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl and groups of the formula of
  • aromatic carbocyclylalkyloxy includes alkyloxy substituted with one or more above “aromatic carbocyclyl”. Examples are benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy and a group of the formula of
  • non-aromatic carbocyclylalkyloxy includes alkyloxy substituted with one or more above “non-aromatic carbocyclyl”. Also, “non-aromatic carbocyclylalkyloxy” includes a “non-aromatic carbocyclylalkyloxy” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”. Examples are cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy and a group of the formula of
  • aromatic heterocyclylalkyloxy includes alkyloxy substituted with one or more above “aromatic heterocyclyl”. Also, “aromatic heterocyclylalkyloxy” includes “aromatic heterocyclylalkyloxy” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”, and/or “non-aromatic carbocyclyl”.
  • Examples are pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy and groups of the formula of
  • non-aromatic heterocyclylalkyloxy includes alkyloxy substituted with one or more above “non-aromatic heterocyclyl”. Also, “non-aromatic heterocyclylalkyloxy” includes a “non-aromatic heterocyclylalkyloxy” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”. Examples are tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy and groups of the formula of
  • aromatic carbocyclyl alkyloxycarbonyl includes alkyloxycarbonyl substituted with one or more above “aromatic carbocyclyl”. Examples are benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl and a group of the formula of
  • non-aromatic carbocyclylalkyloxycarbonyl includes alkyloxycarbonyl substituted with one or more above “non-aromatic carbocyclyl”. Also, “non-aromatic carbocyclylalkyloxycarbonyl” includes “non-aromatic carbocyclylalkyloxycarbonyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”. Examples are cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl and a group of the formula of
  • non-aromatic heterocyclyl alkyloxycarbonyl includes alkyloxycarbonyl substituted with one or more above “non-aromatic heterocyclyl”. Also, “non-aromatic heterocyclyl alkyloxycarbonyl” includes “non-aromatic heterocyclyl alkyloxycarbonyl” wherein the alkyl portion thereof is substituted with one or more above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.
  • Examples are tetrahydropyranylmethyloxycarbonyl, morpholinylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl and groups of the formula of
  • aromatic carbocyclylalkylamino includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced with the above “aromatic carbocyclylalkyl”. Examples are benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino and dibenzylamino.
  • non-aromatic carbocyclylalkylamino includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced with the above “non-aromatic carbocyclylalkyl”. Examples are cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino and cyclohexylmethylamino.
  • non-aromatic heterocyclylalkylamino includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced with the above “non-aromatic heterocyclylalkyl”. Examples are tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino and piperazinylmethyamino.
  • aromatic carbocyclylalkylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “aromatic carbocyclylalkyl”.
  • Examples are benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl, benzhydrylcarbamoyl, tritylcarbamoyl, naphthylmethylcarbamoyl and dibenzylcarbamoyl.
  • non-aromatic carbocyclylalkylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “non-aromatic carbocyclylalkyl”. Examples are cyclopropylmethylcarbamoyl, cyclobutylmethylcarbamoyl, cyclopentylmethylcarbamoyl and cyclohexylmethylcarbamoyl.
  • Examples are pyridylmethylcarbamoyl, furanylmethylcarbamoyl, imidazolylmethylcarbamoyl, indolylmethylcarbamoyl, benzothiophenylmethylcarbamoyl, oxazolylmethylcarbamoyl, isoxazolylmethylcarbamoyl, thiazolylmethylcarbamoyl, isothiazolylmethylcarbamoyl, pyrazolylmethylcarbamoyl, isopyrazolylmethylcarbamoyl, pyrrolidinylmethylcarbamoyl and benzoxazolylmethylcarbamoyl.
  • non-aromatic heterocyclylalkylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “non-aromatic heterocyclyl alkyl”. Examples are tetrahydropyranylmethylcarbamoyl, morpholinylethylcarbamoyl, piperidinylmethylcarbamoyl and piperazinylmethycarbamoyl.
  • aromatic carbocycle portion of “aromatic carbocycle”, “aromatic carbocyclyloxy”, “aromatic carbocyclylcarbonyl”, “aromatic carbocyclylcarbonyloxy”, “aromatic carbocyclyloxycarbonyl”, “aromatic carbocyclylamino”, “aromatic carbocyclylsulfanyl”, “aromatic carbocyclyl sulfonyl”, “aromatic carbocyclylsulfamoyl” and “aromatic carbocyclylcarbamoyl” means the above “aromatic carbocyclyl”.
  • aromatic carbocyclyloxycarbonyl includes a group wherein a carbonyl group is substituted with the above “aromatic carbocyclyloxy”. Examples are phenyloxycarbonyl and naphthyloxycarbonyl.
  • aromatic carbocyclylamino includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced with the above “aromatic carbocyclyl”. Examples are phenylamino and naphthylamino.
  • aromatic carbocyclylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of sulfanyl is replaced with the above “aromatic carbocyclyl”. Examples are phenylsulfanyl and naphthylsulfanyl.
  • aromatic carbocyclylsulfonyl includes a group wherein a sulfonyl group is substituted with the above “aromatic carbocyclyl”. Examples are phenylsulfonyl and naphthylsulfonyl.
  • aromatic carbocyclylsulfamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a sulfamoyl group is replaced with the above “aromatic carbocyclyl”. Examples are phenylsulfamoyl and naphthylsulfamoyl.
  • aromatic carbocyclylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “aromatic carbocyclyl”. Examples are phenylcarbamoyl and naphthylcarbamoyl.
  • non-aromatic carbocycle portion of "non-aromatic carbocycle”, “non-aromatic carbocyclyloxy”, “non-aromatic carbocyclylcarbonyloxy”, “non-aromatic carbocyclylcarbonyl”, “non-aromatic carbocyclyloxycarbonyl”, “non-aromatic carbocyclylamino”, “non-aromatic carbocyclylsulfanyl”, “non-aromatic carbocyclylsulfonyl”, “non-aromatic carbocyclylsulfamoyl” and “non-aromatic carbocyclylcarbamoyl” means the above “non-aromatic carbocyclyl”.
  • non-aromatic carbocyclyloxy includes a group wherein an oxygen atom is substituted with the above “non-aromatic carbocyclyl”. Examples are cyclopropyloxy, cyclohexyloxy and cyclohexenyloxy.
  • non-aromatic carbocyclylcarbonyl includes a group wherein a carbonyl group is substituted with the above “non-aromatic carbocyclyl”. Examples are cyclopropylcarbonyl, cyclohexylcarbonyl and cyclohexenylcarbonyl.
  • non-aromatic carbocyclylcarbonyloxy includes a group wherein a carbonyloxy group is substituted with the above “non-aromatic carbocyclyl”. Examples are cyclopropylcarbonyloxy, cyclohexylcarbonyloxy and cyclohexenylcarbonyloxy.
  • non-aromatic carbocyclyloxycarbonyl includes a group wherein a carbonyl group is substituted with the above “non-aromatic carbocyclyloxy”. Examples are cyclopropyloxycarbonyl, cyclohexyloxycarbonyl and cyclohexenyloxycarbonyl.
  • non-aromatic carbocyclylamino includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced with the above “non-aromatic carbocyclyl”. Examples are cyclopropylamino, cyclohexylamino and cyclohexenylamino.
  • non-aromatic carbocyclylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl is replaced with the above “non-aromatic carbocyclyl”. Examples are cyclopropylsulfanyl, cyclohexylsulfanyl and cyclohexenylsulfanyl.
  • non-aromatic carbocyclylsulfonyl includes a group wherein a sulfonyl group is substituted with the above “non-aromatic carbocyclyl”.
  • non-aromatic carbocyclylsulfamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a sulfamoyl group is replaced with the above “non-aromatic carbocyclyl”.
  • Examples are cyclopropylsulfamoyl, cyclohexylsulfamoyl and cyclohexenylsulfamoyl.
  • non-aromatic carbocyclylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “non-aromatic carbocyclyl”. Examples are cyclopropylcarbamoyl, cyclohexylcarbamoyl and cyclohexenylcarbamoyl.
  • aromatic heterocycle in ring B are pyridine, pyrazine, pyrimidine, pyridazine, oxazole and pyrazole.
  • aromatic heterocyclyloxy includes a group wherein an oxygen atom is substituted with the above “aromatic heterocyclyl”. Examples are pyridyloxy and oxazolyloxy.
  • aromatic heterocyclylcarbonyl includes a group wherein a carbonyl group is substituted with the above “aromatic heterocyclyl”. Examples are pyridylcarbonyl and oxazolylcarbonyl.
  • aromatic heterocyclylcarbonyloxy includes a group wherein a carbonyloxy group is substituted with the above “aromatic heterocyclyl”. Examples are pyridylcarbonyloxy and oxazolylcarbonyloxy.
  • aromatic heterocyclyloxycarbonyl includes a group wherein a carbonyl group is substituted with the above “aromatic heterocyclyloxy”. Examples are pyridyloxycarbonyl and oxazolyloxycarbonyl.
  • aromatic heterocyclylamino includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of an amino group is replaced with the above “aromatic heterocyclyl”. Examples are pyridylamino and oxazolylamino.
  • aromatic heterocyclylsulfanyl includes a group wherein a hydrogen atom attached to a sulfur atom of sulfanyl is replaced with the above “aromatic heterocyclyl”. Examples are pyridylsulfanyl and oxazolylsulfanyl.
  • aromatic heterocyclylsulfonyl includes a group wherein a sulfonyl group is substituted with the above “aromatic heterocyclyl”. Examples are pyridylsulfonyl and oxazolylsulfonyl.
  • aromatic heterocyclylsulfamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a sulfamoyl group is replaced with the above “aromatic heterocyclyl”. Examples are pyridylsulfamoyl and oxazolylsulfamoyl.
  • aromatic heterocyclylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “aromatic heterocyclyl”. Examples are pyridylcarbamoyl and oxazolylcarbamoyl.
  • non-aromatic heterocycle portion of "non-aromatic heterocycle”, “non-aromatic heterocyclyloxy”, “non-aromatic heterocyclylcarbonyl”, “non-aromatic heterocyclylcarbonyloxy”, “non-aromatic heterocyclyloxycarbonyl”, “non-aromatic heterocyclylamino”, “non-aromatic heterocyclylsulfanyl”, “non-aromatic heterocyclylsulfonyl”, “non-aromatic heterocyclylsulfamoyl” and “non-aromatic heterocyclylcarbamoyl” means the above “non-aromatic heterocyclyl”.
  • non-aromatic heterocyclyloxy includes a group wherein an oxygen atom is substituted with the above “non-aromatic heterocyclyl”. Examples are piperidinyloxy and tetrahydrofuryloxy.
  • non-aromatic heterocyclylcarbonyl includes a group wherein a carbonyl group is substituted with the above “non-aromatic heterocyclyl”. Examples are piperidinylcarbonyl and tetrahydrofurylcarbonyl.
  • non-aromatic heterocyclylcarbonyloxy includes a group wherein a carbonyloxy group is substituted with the above “non-aromatic heterocyclyl”.
  • non-aromatic heterocyclyloxycarbonyl includes a group wherein a carbonyl group is substituted with the above “non-aromatic heterocyclyloxy”.
  • Examples are piperidinyloxycarbonyl and tetrahydrofuryloxycarbonyl.
  • non-aromatic heterocyclylsulfonyl includes a group wherein a sulfonyl group is substituted with the above “non-aromatic heterocyclyl”.
  • Examples are piperidinylsulfonyl and tetrahydrofurylsulfonyl.
  • non-aromatic heterocyclylsulfamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a sulfamoyl group is replaced with the above “non-aromatic heterocyclyl”. Examples are piperidinylsulfamoyl and tetrahydrofurylsulfamoyl.
  • non-aromatic heterocyclylcarbamoyl includes a group wherein one or two hydrogen atoms attached to a nitrogen atom of a carbamoyl group is replaced with the above “non-aromatic heterocyclyl”. Examples are piperidinylcarbamoyl and tetrahydrofurylcarbamoyl.
  • substituents of "substituted or unsubstituted aromatic carbocycle”, “substituted or unsubstituted non-aromatic carbocycle”, “substituted or unsubstituted aromatic heterocycle”, “substituted or unsubstituted non-aromatic heterocycle”, “substituted or unsubstituted pyridine”, “ substituted or unsubstituted pyrazine”, “substituted or unsubstituted pyrimidine” or “substituted or unsubstituted pyridazine” in ring B include (a) a group selected from the substituent group ⁇ , for example, halogen, hydroxy, alkyloxy, formyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aromatic carbocyclylcarbonyl, non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, non-
  • substituents of "substituted or unsubstituted aromatic carbocycle”, “substituted or unsubstituted non-aromatic carbocycle”, “substituted or unsubstituted aromatic heterocycle", “substituted or unsubstituted non-aromatic heterocycle”, “substituted or unsubstituted pyridine”, “ substituted or unsubstituted pyrazine”, “substituted or unsubstituted pyrimidine” or “substituted or unsubstituted pyridazine” in ring B are one or more selected from halogen; cyano; hydroxy; nitro; carboxy; alkyl substituted with one or more substituents selected from the substituent group ⁇ ; unsubstituted alkyl; alkenyl substituted with one or more substituents selected from the substituent group ⁇ ; unsubstituted alkenyl; alkynyl substituted
  • substituents of ring B are one or more selected from halogen, cyano, hydroxy, alkyl, haloalkyl, cycloalkylalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, cyanoalkyloxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkenyloxy, alkynyloxy, alkylsulfanyl, cyanoalkylsulfanyl, amino, monoalkylamino, dialkylamino, cycloalkylamino and cycloalkyl.
  • R 1 is alkyl, R 1 is methyl, R 1 is haloalkyl, R 1 is -CH 2 F, R 2 is H, R 2 is halogen, R 2 is F, R 3 is H, R 3 is alkyl, R 3 is Me, R 3 is alkyloxyalkyl, R 3 is -CH 2 OMe, R 3 is haloalkyl, R 3 is -CH 2 F, R 3 is -CHF 2 , R 3 is -CF 2 CH 3 , R 3 is -CF 3 , R 3 is haloalkyl substituted with cycloalkyl, R 3 is -CF 2 -cyclopropyl, R 4 is H, R 4 is halogen, R 4 is H, R 4 is halogen, R 4
  • R 1 is alkyl and ring B is B1 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ). In one embodiment, R 1 is alkyl and ring B is B2 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ). In one embodiment, R 1 is alkyl and ring B is B3 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is alkyl and ring B is B4 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is alkyl and ring B is B5 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II), (IJ) or (IK).
  • R 1 is alkyl and ring B is B6 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II), (IJ) or (IK).
  • R 1 is alkyl and ring B is B7 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is haloalkyl and ring B is B1 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is haloalkyl and ring B is B2 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is haloalkyl and ring B is B3 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is haloalkyl and ring B is B4 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is haloalkyl and ring B is B5 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II), (IJ) or (IK).
  • R 1 is haloalkyl and ring B is B6 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II), (IJ) or (IK).
  • R 1 is haloalkyl and ring B is B7 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is -CH 2 F and ring B is B1 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is -CH 2 F and ring B is B2 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is -CH 2 F and ring B is B3 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is -CH 2 F and ring B is B4 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is -CH 2 F and ring B is B5 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II), (IJ) or (IK).
  • R 1 is -CH 2 F and ring B is B6 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II), (IJ) or (IK).
  • R 1 is -CH 2 F and ring B is B7 in the formula (I), (IA), (IB), (IC), (IE), (IH), (II) or (IJ).
  • R 1 is haloalkyl
  • R 1 is haloalkyl
  • R 1 is haloalkyl
  • R 1 is haloalkyl
  • R 1 is haloalkyl
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is alkyl
  • R 1 is alkyl
  • R 1 is alkyl
  • R 1 is haloalkyl
  • R 1 is haloalkyl
  • R 1 is haloalkyl
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • R 1 is -CH 2 F
  • Hal is F in the formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) or (IK).
  • R 4 is F in the formula (I).
  • the compound of formula (I) is not limited to a specific isomer, and includes all possible isomers such as keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers and rotation isomers, racemate and the mixture thereof.
  • the compound of formula (I) includes the following tautomers.
  • the compound of formula (I) has an asymmetric carbon atom and the compound includes the following optical isomers.
  • Optically active compounds of formula (I) can be produced by employing an optically active starting material, by obtaining an optically active intermediate in asymmetry synthesis at a suitable stage, or by performing optical resolution of an intermediate or an objective compound, each of which is a racemate, at a suitable stage.
  • Examples of a method for optical resolution are separation of an optical isomer using an optically active column; kinetic optical resolution utilizing an enzymatic reaction; crystallization resolution of a diastereomer by salt formation using a chiral acid or a chiral base; and preferential crystallization method.
  • One or more hydrogen, carbon and/or other atoms of a compound of formula (I) can be replaced with an isotope of hydrogen, carbon and/or other atoms, respectively.
  • isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl, respectively.
  • the compound of formula (I) also includes the compound replaced with such isotopes.
  • the compound replaced with such isotopes is useful also as a medicament, and includes all the radiolabeled compounds of the compound of formula (I).
  • the invention includes "radiolabelling method" for manufacturing the "radiolabeled compound” and the method is useful as a tool of metabolic pharmacokinetic research, the research in binding assay and/or diagnosis.
  • a radiolabeled compound of the compound of formula (I) can be prepared by methods known in the art.
  • tritiated compounds of formula (I) can be prepared by introducing tritium into the particular compound of formula (I) such as by catalytic dehalogenation with tritium. This method may include reacting a suitably halogenated precursor of a compound of formula (I) with tritium gas in the presence of a suitable catalyst such as Pd/C, in the presence or absence of a base.
  • examples include salts with alkaline metals (e.g. lithium, sodium and potassium), alkaline earth metals (e.g. calcium and barium), magnesium, transition metal (e.g. zinc and iron), ammonia, organic bases (e.g. trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline), and amino acids, and salts with inorganic acids (e.g.
  • crystal means that a compound of formula (I) or a salt thereof and a counter-molecule exists in the same crystal lattice, and it can be formed with any number of counter-molecules.
  • the compounds of the present invention represented by formula (I) or pharmaceutically acceptable salts thereof may form prodrugs.
  • the present invention also encompasses such various prodrugs.
  • Prodrugs are derivatives of the compounds of the present invention that have chemically or metabolically degradable groups and are compounds that are converted to the pharmaceutically active compounds of the present invention through solvolysis or under physiological conditions in vivo.
  • Prodrugs include compounds that are converted to the compounds represented by formula (I) through enzymatic oxidation, reduction, hydrolysis and the like under physiological conditions in vivo and compounds that are converted to the compounds represented by formula (I) through hydrolysis by gastric acid and the like. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in the Design of Prodrugs, Elsevier, Amsterdam 1985.
  • prodrugs themselves may be active compounds.
  • prodrugs include acyloxy derivatives and sulfonyloxy derivatives which can be prepared by reacting a compound having a hydroxy group with a suitable acid halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonylanhydride and mixed anhydride or with a condensing agent.
  • Examples are CH 3 COO-, C 2 H 5 COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 ) COO-, CH 2 N(CH 3 ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p-CH 3 -O-PhSO 3 -, PhSO 3 - and p-CH 3 PhSO 3 -.
  • the compounds of formula (I) may be prepared by the methods described below, together with synthetic methods known to a person skilled in the art.
  • the starting materials are commercially available or may be prepared in accordance with known methods.
  • P 1 is alkyl
  • each of P 2 is hydrogen or a protective group such as alkyl, benzoyl, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzylre
  • Y is halogen (e.g., Br, I), nitro, or trifluoroacetylamino (-NHCOCF 3 ), and other symbols are the same as defined above.
  • General Procedure A is a method for preparing compounds of formula (I) from compounds of formula (A1) through multiple steps of Step 1 to Step 6.
  • protective groups P 1 and P 2 can be chosen depending on the reaction conditions used in later steps.
  • the starting material of formula (A1) can be prepared in a manner similar to the conditions described in Chem. Rev. 2010, 110, 3600-3740.
  • Step1 Compounds of formula (A2) can be prepared by Mannich reaction of sulfinyl imine (A1) with enolates derived from the corresponding esters. This type of reactions can be conducted using the conditions described in Chem. Rev. 2010, 110, 3600-3740.
  • the enolates can be prepared from the corresponding esters, lithium diisopropylamide (LDA), and TiCl(Oi-Pr)3, which can be then reacted with compounds of formula (A1) to give compounds of formula (A2).
  • LDA lithium diisopropylamide
  • TiCl(Oi-Pr)3 titanium chloride
  • Examples of the solvent include tetrahydrofuran, 1,4-dioxanne, 1,2-dimethoxyethane, diethyl ether, toluene, and benzene.
  • the reaction temperature is preferably -78 °C to -30 °C.
  • the reaction time is not particularly limited and is usually 5 minutes to 24 hours, preferably 30 minutes to 24 hours.
  • compounds of formula (A2) can be obtained by reacting compounds of formula (A1) with the corresponding ester in the presence of zinc powder (the Reformatsky reaction). The reaction can be done in ether solvents such as tetrahydrofuran, 1,4-dioxane, and dimethoxyethane in the presence of an excess amount of zinc powder.
  • the zinc powder is activated by treatment with an aqueous HCl solution prior to the reaction.
  • the activation can be achieved according to the method described in Organic Process Res. Dev. 2009, 13, 1094-1099.
  • the reaction temperature is usually ice-cold temperature to solvent reflux temperature.
  • the reaction time changes depending on the starting material, it is generally 0.5 to 6 hours.
  • Step 2 Compounds of formula (A3) can be prepared by deprotection of compounds of formula (A2).
  • This deprotection reaction is known to a person skilled in the art and can be performed under the conditions described in Chem. Rev. 2010, 110, 3600-3740.
  • the reaction can be conducted under acidic conditions using e.g. hydrochloric acid at room temperature to 60 °C.
  • the solvent include methanol, 1,4-dioxane, and ethyl acetate.
  • the reaction time is not particularly limited and is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.
  • Step 3 Compounds of formula (A4) can be prepared by reaction of compounds of formula (A3) with reagents such as benzoyl isothiocyanate and benzyl isothiocyanate.
  • reagents such as benzoyl isothiocyanate and benzyl isothiocyanate.
  • the solvent used in this step is not particularly limited in so far as it does not interfere with the reaction. Examples of the solvent include dichloromethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and toluene.
  • Step 4 Compounds of formula (A5) can be prepared by reaction of compounds of formula (A4) with Grignard reagents such as methyl magnesium bromide and ethyl magnesium bromide and alkyl lithium reagents such as methyllithium, butyllithium, and phenyllithium. Stepwise addition of these nucleophiles can provide compounds of formula (A5) with various substituents of R 3 .
  • the solvent used is not particularly limited in so far as it does not interfere with the reaction.
  • Preferable examples of the solvent include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, toluene, and benzene.
  • the reaction time is not particularly limited and is usually 5 minutes to 24 hours, preferably 5 minutes to 6 hours.
  • the reaction temperature is usually -100 °C to room temperature, preferably -78 °C to 0 °C.
  • Step 5 Compounds of formula (A6) can be prepared by cyclization reaction of compounds of formula (A5) by converting the hydroxyl group into leaving groups such as Cl, Br, and triflate.
  • the reaction conditions are known to those skilled in the art. For example, chlorination followed by cyclization may be achieved using reagents such as 1-chloro-N,N,2-trimethylpropenylamine. Alternatively, triflic anhydride may be used in the presence of bases such as N,N-dimethyl-4-aminopyridine and pyridine.
  • P 2 is benzoyl
  • the deprotection can be conducted with bases such as hydrazine hydrate or potassium carbonate using the solvent such as methanol and ethanol at room temperature to 80 °C.
  • Nitration of the deprotected compounds can be conducted by methods known to a person skilled in the art.
  • the nitrated compounds can be obtained by use of nitric acid or nitrate in solvents such as sulfuric acid or mixed solvent of sulfuric and trifluoroacetic acid.
  • the reaction temperature is usually -20 °C to 0 °C.
  • the reaction time is usually 1 minute to 1 hour.
  • the amidine group in the deprotected compounds can be protected by Boc under the conditions described in Greene's Protective Groups in Organic Synthesis.
  • the Boc protection can be conducted using Boc 2 O and a catalytic amount of N,N-dimethyl-4-aminopyridine in solvents such as dichloromethane and tetrahydrofuran at room temperature to 50 °C.
  • Amide coupling reaction of the aniline with carboxylic acids can be conducted by a method known to a person skilled in the art, and suitable coupling conditions can be found in Chem. Rev. 2011, 111, 6557-6602, which includes: a) reactions using condensation reagents; b) reactions using acid chlorides or fluorides.
  • Reaction a) can be conducted by use of condensation reagents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), and 1H-Benzotriazol-1-yloxy-tri(pyrrolidino) phosphonium hexafluorophosphate (PyBOP).
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • EDC hydrochloride 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • HATU O-(7
  • the reaction can be performed in the presence of bases such as triethylamine and diisopropylethylamine.
  • bases such as triethylamine and diisopropylethylamine.
  • the reaction may be accelerated by use of catalysts such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt).
  • the solvent used in the reaction is not particularly limited in so far as it does not interfere with the reaction. Examples of the solvent include dichloromethane, N,N-dimethylformamide(DMF), N-methylpyrrolidone(NMP), and tetrahydrofuran.
  • the reaction temperature is usually 0 °C to 50 °C and is preferably room temperature.
  • Reaction b) can be performed by use of commercially available acid chlorides or those synthesized by known methods to a person skilled in the art in solvents such as dichloromethane, tetrahydrofuran, and ethyl acetate in the presence of bases such as triethylamine, diisopropylethylamine, pyridine, and N,N-dimethyl-4-aminopyridine.
  • the reaction temperature is usually 0 °C to 60 °C and is preferably 0 °C to room temperature.
  • the reaction time is not particularly limited and is usually 5 minutes to 24 hours, preferably 20 minutes to 6 hours.
  • Y Br or I: Buchwald-Hartwig reaction of compounds of formula (A6) with amide derivatives can be conducted by a methods described in Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.
  • this reaction can be performed by use of transition metal catalysts such as tris(dibenzylideneacetone) dipalladium and palladium acetate and ligands such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) in the presence of bases such as sodium tert-butoxide, cesium carbonate, and potassium phosphate.
  • bases such as sodium tert-butoxide, cesium carbonate, and
  • the reaction temperature is usually 40 °C to 150 °C and is preferably 60 °C to 100 °C. This reaction may be accelerated by microwave irradiation.
  • the solvent include toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane.
  • Y trifluoroacetylamino:
  • Deprotection of the trifluoroacetylamino group in compounds of formula (A6) can be conducted by a methods known to a person skilled in the art. Suitable conditions can be found in Greene's Protective Groups in Organic Synthesis. For example, use of potassium carbonate in methanol at room temperature may be a usual method, but not limited to. The following amide coupling reaction and deprotection of P 2 can be conducted under the same conditions described above.
  • General Procedure B is a method for preparing compounds of formula (Ib) from compounds of formula (A3) through multiple steps.
  • compounds of formula (B5) can be prepared according to the methods described in General procedure A.
  • Step 1 Compounds of formula (B1) can be prepared by thiourea formation of compounds of formula (A3). This type of reaction is known to those skilled in the art and is usually performed by treatment of compounds of formula (A3) with reagents such as triphosgene, 4-nitrophenyl chloroformate, and carbonyl diimidazole followed by addition of amines such as bis(2,4-dimethoxybenzyl)amine.
  • reagents such as triphosgene, 4-nitrophenyl chloroformate, and carbonyl diimidazole followed by addition of amines such as bis(2,4-dimethoxybenzyl)amine.
  • Preferable combinations of these reagents may be 4-nitrophenyl chloroformate and bis(2,4-dimethoxybenzyl)amine.
  • the reaction can be performed in the presence of bases such as sodium bicarbonate in solvents such as water, tetrahydrofuran, ethyl acetate, and mixture of these solvents.
  • bases such as sodium bicarbonate
  • solvents such as water, tetrahydrofuran, ethyl acetate, and mixture of these solvents.
  • the reaction temperature is usually 0 °C to room temperature.
  • the reaction time is not particularly limited and is usually 1 to 12 hours.
  • Step 2 Compounds of formula (B2) can be prepared by reduction of compounds of formula (B1).
  • This reaction is known to those skilled in the art and is usually preformed using diisobutylaluminium hydride (DIBAL-H).
  • the solvents include dichloromethane, tetrahydrofuran, and toluene.
  • the reaction temperature is usually below -60 °C and preferably below -70 °C.
  • the reaction time is not particularly limited and is usually 1 to 12 hours.
  • Step 3 Compounds of formula (B3) can be prepared by Wittig reaction of compounds of formula (B2) with the corresponding phosphonium ylides.
  • Peterson olefination, Horner-Wadsworth-Emmons reaction, Julia coupling, and Knoevenagel condensation may be considered. These reactions are known to those skilled in the art.
  • Wittig reaction can be generally conducted by treatment of the corresponding alkyl halide with triphenylphosphine followed by bases such as n-butyl lithium, which can be then added to compounds of formula (B3) in solvents such as tetrahydrofuran.
  • the reaction time is not particularly limited and is usually 1 to 12 hours.
  • Step 4 Compounds of formula (B4) can be prepared by cyclization of compounds of formula (B3) using iodine.
  • the solvent include acetonitrile, tetrahydrofuran, and dichloromethane.
  • the reaction temperature is usually 0 °C to 50 °C and preferably room temperature.
  • the reaction time is not particularly limited and is usually 1 to 12 hours.
  • Compounds of formula (B5) can be prepared by 1) halogenation of compounds of formula (B4); 2) hydroxylation of compounds of formula (B4) followed by deoxohalogenation of the corresponding alcohol.
  • halogenation e.g., fluorination
  • reagents such as tetrabutylammonium fluoride (TBAF).
  • the solvent include acetonitrile and tetrahydrofuran.
  • the reaction temperature is usually 0 °C to 50 °C and preferably room temperature.
  • the reaction time is not particularly limited and is usually 1 to 12 hours.
  • hydroxylation of compounds of formula (B4) can be conducted with reagents such as potassium superoxide (KO 2 ), silver trifluoroacetate, and silver tetrafluoroborate.
  • deoxohalogenation e.g., deoxofluorination
  • reagents such as N,N-diethylaminosulfur trifluoride (DAST), and bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor; Registered trademark).
  • DAST N,N-diethylaminosulfur trifluoride
  • Deoxo-Fluor bis(2-methoxyethyl)aminosulfur trifluoride
  • the solvent include dichloromethane, acetonitrile, and tetrahydrofuran.
  • the reaction temperature is usually -78 °C to room temperature and is preferably -78 °C to 0 °C. Alternative conditions can be found in Synthesis 2002, 2561-2578.
  • General procedure C In the above formulas, the symbols are the same as defined in General Procedure A.
  • General Procedure C is a method for preparing compounds of formula (I) from compounds of formula (C1) through multiple steps. Using compounds of formula (A5), compounds of formula (I) can be prepared according to the methods described in General procedure A. The starting material of formula (C1) can be prepared in a manner similar to the conditions described in Chem. Rev. 2010, 110, 3600-3740.
  • Step 1 Compounds of formula (C2) can be prepared by addition of compound of formula (C1) to ketones of formula (R 3 CHO). This reaction can be performed under conditions similar to those described in Chem. Rev. 2010, 110, 3600-3740.
  • the ketimines derived from compounds of formula (C1) can be prepared using lithium diisopropylamide followed by addition of ketones (R 3 CHO) to afford compounds of formula (C2).
  • the solvent include tetrahydrofuran and toluene.
  • the reaction temperature is usually below -60 °C and preferably below -70 °C.
  • the reaction time is not particularly limited and is usually 1 to 12 hours.
  • Step 2 Compounds of formula (C3) can be prepared by reaction of compounds of formula (C2) with Grignard reagents such as methyl magnesium bromide and ethyl magnesium bromide and alkyl lithium reagents such as methyllithium, butyllithium, and phenyllithium.
  • the solvent is not particularly limited in so far as it does not interfere with the reaction.
  • Preferable examples of the solvent include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, toluene, and benzene.
  • the reaction time is not particularly limited and is usually 5 minutes to 24 hours, preferably 5 minutes to 6 hours.
  • Step 3 Compounds of formula (C4) can be prepared according to the method described in Step 2 of General Procedure A.
  • Step 4 Compounds of formula (A5) can be prepared according to the method described in Step 3 of General Procedure A.
  • Step 1 Compounds of formula (D1) can be prepared by reaction of compounds of formula (A1) with allylmagnesium bromide.
  • the solvent used is not particularly limited in so far as it does not interfere with the reaction.
  • Preferable examples of the solvent include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, toluene, and benzene.
  • the reaction time is not particularly limited and is usually 5 minutes to 24 hours, preferably 5 minutes to 6 hours.
  • the reaction temperature is usually -78 °C to 0 °C.
  • Step 2 Compounds of formula (D2) can be prepared by ozonolysis of compounds of formula (D1). The reaction is well known to those skilled in the art.
  • the reaction can be done in dichloromethane under a bubbling condition of ozone at -78 °C followed by a quenching reagent such as dimethyl sulfide, triethylamine, and triphenylphosphine to afford compounds of formula (D2).
  • a quenching reagent such as dimethyl sulfide, triethylamine, and triphenylphosphine to afford compounds of formula (D2).
  • Step 3 Compounds of formula (D3) can be prepared by addition of TMSCF 3 (Ruppert reagent) with compounds of formula (D2).
  • the reaction is generally conducted in a solvent such as tetrahydrofuran, 1,4-dioxane, DMF, and toluene.
  • the reaction temperature is usually -78 °C to 0 °C and is preferably -20 °C to 0 °C.
  • the reaction time is not particularly limited and is usually 0.5 to 6 hours.
  • Step 4 Compounds of formula (D4) can be prepared according to the method described in Step 2 of General Procedure A.
  • Step 5 Compounds of formula (D5) can be prepared according to the method described in Step 3 of General Procedure A.
  • Step 6 Compounds of formula (D6) can be prepared by cyclization reaction of compounds of formula (D5) with a reagent such as N,N-diethylaminosulfur trifluoride (DAST) and Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor, Registered trademark).
  • DAST N,N-diethylaminosulfur trifluoride
  • Deoxo-Fluor Registered trademark
  • General procedure E In the above formulas, the symbols are the same as defined in General Procedure A.
  • General procedure E is a method for preparing compounds of formula (Ie) from compounds of formula (A1).
  • the formula (Ie) is a derivative of compounds of formula (I) when R 2 and R 3 are H and CF 2 H, respectively.
  • compounds of formula (Ie) can be prepared according to the methods described in General procedure D.
  • Step1 Compounds of formula (E1) can be prepared according to the method described in Step 1 of General Procedure A.
  • Step 2 Compounds of formula (E2) can be prepared by reaction of compounds of formula (E1) with diethyl (difluoromethyl) phosphonate in the presence of a base such as LDA at -78 °C.
  • a preferable solvent includes tetrahydrofuran. The reaction time is usually 0.5 h to 6 hours.
  • Step 3 Compounds of formula (E3) can be prepared by reduction of compounds of formula (E2) with a reagent such as NaBH 4 and LiBH 4 .
  • the reaction is well known to those skilled in the art; the reducing reagents in the reaction are not limited to those described above.
  • Typical examples of solvents include tetrahydrofuran, 1,4-dioxane, methanol, and ethanol.
  • the reaction temperature is generally -20 °C to room temperature and is preferably 0 °C to room temperature.
  • the reaction time is generally 0.5 to 6 hours.
  • Step 4 Compounds of formula (E4) can be prepared according to the method described in Step 2 of General Procedure A.
  • General procedure F In the above formulas, the symbols are the same as defined in General Procedure A.
  • General procedure F is a method for preparing compounds of formula (If) from compounds of formula (D2).
  • the formula (If) is a derivative of compounds of formula (I) when R 2 and R 3 are H and CF 2 Me, respectively.
  • compounds of formula (If) can be prepared according to the methods described in General procedure A.
  • Step 4 Compounds of formula (F4) can be prepared according to the methods described in Step 3 of General Procedure E.
  • Step 5 Compounds of formula (F5) can be prepared by converting the hydroxyl to the I by a method known to a person skilled in the art.
  • Preferable examples of solvents includes tetrahydrofuran, 1,4-dioxane, MeCN, toluene, and Et2O.
  • the reaction temperature changes depending on the staring material, it is generally room temperature to 100 °C and is preferably room temperature to 80 °C.
  • the reaction time also changes depending on the starting material and is generally 1 hour to 12 hours.
  • Step 6 Compounds of formula (F6) can be prepared by converting the I to the hydrogen.
  • reaction is well known to a person skilled in the art, preferable example of reagents would be n-Bu 3 SnH in the presence of a catalytic amount of AIBN.
  • the solvent used in this reaction is generally toluene, and the reaction temperature is preferably 60 to 110 °C.
  • Step 1 Compounds of formula (B4) can be prepared according to the methods described in Step 5 of General Procedure B.
  • Step 2 Compounds of formula (G1) can be prepared by alkylating the hydroxyl with alkyl halides by a method known to a person skilled in the art. The reaction is generally conducted in a solvent such as tetrahydrofuran and DMF in the presence of a base such as NaH. The reaction temperature varies depending on the starting material and is generally 0 to 60 °C. The reaction time is generally 0.5 to 12 hours and is preferably 0 °C to room temperature.
  • the compounds of the present invention have BACE1 inhibitory activity and are effective in treatment and/or prevention, symptom improvement, and prevention of the progression of disease induced by the production, secretion or deposition of-amyloid ⁇ protein, such as Alzheimer’s disease, Alzheimer dementia, senile dementia of Alzheimer type, mild cognitive impairment (MCI), prodromal Alzheimer's disease (e.g., MCI due to Alzheimer’s disease), Down's syndrome, memory impairment, prion disease (Creutzfeldt-Jakob disease), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other type of degenerative dementia, mixed dementia such as coexist Alzheimer's disease with vascular type dementia, dementia with Parkinson's Disease, dementia with progressive supranuclear palsy, dementia with Cortico-basal degeneration, Alzheimer’s disease with diffuse Lewy body disease, age-related macular degeneration, Parkinson's Disease, amyloid angiopathy or the like.
  • MCI mild cognitive impairment
  • the compounds of the present invention are effective in preventing the progression in a patient asymptomatic at risk for Alzheimer dementia (preclinical Alzheimer’s disease).
  • a patient asymptomatic at risk for Alzheimer dementia includes a subject who is cognitively and functionally normal but has potential very early signs of Alzheimer’s disease or typical age related changes (e.g., mild white matter hyper intensity on MRI), and/or has evidence of amyloid deposition as demonstrated by low cerebrospinal fluid A ⁇ 1-42 levels.
  • a patient asymptomatic at risk for Alzheimer dementia includes a subject whose score of the Clinical Dementia Rating (CDR) or Clinical Dementia Rating-Japanese version (CDR-J) is 0, and/or whose stage of the Functional Assessment Staging (FAST) is stage 1 or stage 2.
  • CDR Clinical Dementia Rating
  • CDR-J Clinical Dementia Rating-Japanese version
  • FAST Functional Assessment Staging
  • the compound of the present invention has not only BACE1 inhibitory activity but the beneficialness as a medicament.
  • the compound has any or all of the following superior properties. a) The compound has weak inhibitory activity for CYP enzymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4. b) The compound show excellent pharmacokinetics profiles such as high bioavailability or low clearance. c) The compound has a high metabolic stability. d) The compound does not show irreversible inhibitions to CYP enzymes such as CYP3A4 in the range of the concentrations of the measurement conditions described in this description. e) The compound does not show a mutagenesis.
  • compositions of the present invention When a pharmaceutical composition of the present invention is administered, it can be administered orally or parenterally.
  • the composition for oral administration can be administered in usual dosage forms such as oral solid formulations (e.g., tablets, powders, granules, capsules, pills, films or the like), oral liquid formulations (e.g., suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction, tincture or the like) and the like which may be prepared according to the usual method and administered.
  • the tablets can be sugar-coated tablets, film-coated tablets, enteric-coating tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrated tablets.
  • Powders and granules can be dry syrups.
  • Capsules can be soft capsules, micro capsules or sustained-release capsules.
  • the composition for parenteral administration can be administered suitably in usual parenteral dosage forms such as dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear or vaginal administration and the like.
  • any forms which are usually used, such as injections, drips, external preparations (e.g., ophthalmic drops, nasal drops, ear drops, aerosols, inhalations, lotion, infusion, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder, suppository or the like) and the like can be preferably administered.
  • Injections can be emulsions whose type is O/W, W/O, O/W/O, W/O/W or the like.
  • the compounds of the present invention can be preferably administered in an oral dosage form because of their high oral absorbability.
  • a pharmaceutical composition can be formulated by mixing various additive agents for medicaments, if needed, such as excipients, binders, disintegrating agents, and lubricants which are suitable for the formulations with an effective amount of the compound of the present invention.
  • the pharmaceutical composition can be for pediatric patients, geriatric patients, serious cases or operations by appropriately changing the effective amount of the compound of the present invention, formulation and/or various pharmaceutical additives.
  • the pediatric pharmaceutical compositions are preferably administered to patients under 12 or 15 years old.
  • the pediatric pharmaceutical compositions can be administered to patients who are under 27 days old after the birth, 28 days to 23 months old after the birth, 2 to 11 years old, 12 to 16 years old, or 18 years old.
  • the geriatric pharmaceutical compositions are preferably administered to patients who are 65 years old or over.
  • the mix ratio of the compound of the present invention and a concomitant medicament can be suitably selected in consideration of the subject of administration, administration route, target diseases, symptoms, combinations, etc.
  • the concomitant medicament can be used in the range of 0.01 to 100 parts by weight relative to 1 part by weight of the compounds of the present invention.
  • Examples of a concomitant medicament are Donepezil hydrochloride, Tacrine, Galanthamine, Rivastigmine, Zanapezil, Memantine and Vinpocetine.
  • Step 3 Synthesis of compound 1-4
  • hydrazine hydrate (0.316 ml, 6.51 mmol) at room temperature.
  • the mixture was stirred overnight at the same temperature and was treated with 3% aqueous sodium hydrogen carbonate.
  • the mixture was extracted with ethyl acetate, and the combined organic layer was dried over MgSO 4 and filtered.
  • the filtrate was concentrated in vacuo.
  • the crude product was added to an amino silica gel column and eluted with hexane/EtOAc 30%. Collected fractions were evaporated to afford compound 1-4 (539 mg, 1.84 mmol, 85 %) as a colorless oil.
  • Step 4 Synthesis of compound 1-5
  • nitric acid (0.13 mL, 2.95 mmol
  • the mixture was extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was evaporated to give compound 1-5 (581 mg, 1.72 mmol, 93.4 %) as a yellow solid.
  • Step 6 Synthesis of compound (I-5) To a stirred solution of 1-6 (25 mg, 0.081 mmol) in MeOH (1.0 ml) and hydrogen chloride (0.041 mL, 0.081 mmol, 2 mol/L in water) were added 5-(fluoromethoxy)pyrazine-2-carboxylic acid (14 mg, 0.081 mmol) and EDC hydrochloride (17 mg, 0.089 mmol) at 0°C. After being stirred for 1 hr at room temperature, the reaction was quenched with a saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 , and filtered.
  • Step 3 Synthesis of compound 2-4
  • a solution of compound 2-3 (127 mg, 0.376 mmol) in dioxane (2 ml) was added 4 mol/L of HCl in dioxane (0.376 ml, 1.506 mmol) at room temperature. After stirring for 1 h at the same temperature, the reaction mixture was evaporated. The residue was diluted with water then washed with isopropyl ether. The aqueous layer was basified with 5% aqueous sodium hydrogen carbonate then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and filtered.
  • Step 7 Synthesis of compound 2-8 To a stirred suspension of compound 2-7 (72 mg, 0.27 mmol) and sulfuric acid (0.175 mL, 3.28 mmol) in trifluoroacetic acid (0.708 mL) was added nitric acid (0.023 mL, 0.525 mmol) at -10 °C. After being stirred for 1 hr at 0 °C, the reaction was quenched with 30% aqueous potassium carbonate. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water. The solvent was evaporated to give compound 2-8 (78 mg, 0.244 mmol, 93.1 %) as a yellow solid.
  • Step 8 Synthesis of compound 2-9 A suspension of 2-8 (75 mg, 0.235 mmol), iron (105 mg, 1.879 mmol), and ammonium chloride (151 mg, 2.82 mmol) in toluene (2 mL) and water (2 mL) was stirred for 2 h at 80 to 90°C. After being cooled to room temperature, the reaction was quenched with potassium carbonate. The mixture was filtered through Celite (Registered trademark) pad. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and filtered. The solvent was evaporated to give compound 2-9 (68 mg, 0.235 mmol, 100 %) as a yellow solid.
  • Step 9 Synthesis of compound (I-7) To a stirred solution of 2-9 (34 mg, 0.118 mmol) in MeOH ( 1.0 ml ) and hydrogen chloride (0.059 mL, 0.118 mmol, 2 mol/L in water) were added 5-(fluoromethoxy)pyrazine-2-carboxylic acid (20 mg, 0.118 mmol) and EDC hydrochloride (25 mg, 0.129 mmol) at 0°C. After being stirred for 1 h at room temperature, the reaction was quenched with a saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 , and filtered.
  • Step 2 Synthesis of compound 3-3 To a solution of compound 3-2 (338 mg, 0.83 mmol) in dioxane (3 ml) was added 4 mol/L of HCl in dioxane (0.83 ml, 3.30 mmol) at room temperature. After stirring for 1 h at the same temperature, the reaction mixture was evaporated. The residue was diluted with water then washed with isopropyl ether. The aqueous layer was basified with 5% aqueous sodium hydrogen carbonate then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum to give a crude product, which was used for the next step without further purification.
  • Step 3 Synthesis of compound 3-4
  • DAST 0.057 ml, 0.43 mmol
  • the mixture was stirred for 1 h at the same temperature and was treated with 0.5 mol/L aqueous potassium carbonate.
  • the mixture was extracted with CH 2 Cl 2 , and the organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo.
  • the crude product was added to a silica gel column and eluted with hexane/EtOAc 20%. Collected fractions were evaporated to afford compound 3-4 (38 mg, 0.08 mmol, 59 %) as a colorless oil.
  • Step 4 Synthesis of compound 3-5
  • a solution of compound 3-4 35 mg, 0.078 mmol
  • EtOH 1 ml
  • NaBH 4 2.94 mg, 0.078 mmol
  • the mixture was treated with saturated aqueous ammonium chloride.
  • the mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over MgSO 4 and filtered.
  • the filtrate was concentrated under vacuum to give compound 3-5 ( 32 mg, 0.078 mmol, 100%) as a colorless oil, which was used for the next step without further purification.
  • Step 5 Synthesis of compound 3-6 To a solution of compound 3-5 (20 mg, 0.049 mmol) in THF (1 ml) were added triphenylphosphine (51 mg, 0.196 mmol), imidazole (13 mg, 0.196 mmol) and iodine (50 mg, 0.196 mmol) at room temperature. After stirring for 3 hr at 80 °C, the mixture was treated with 10% aqueous sodium hydrogen sulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo.
  • Step 6 Synthesis of compound 3-7 To a solution of compound 3-6 (22 mg, 0.042 mmol) in toluene (2 ml) were added Bu 3 SnH (0.027 ml, 0.102 mmol) and AIBN (2.8 mg, 0.017 mmol) at room temperature. After stirring for 1 h at 80 °C, the reaction mixture was concentrated. The resulting residue was added to an amino silica gel column and eluted with Hexane/EtOAc 20%. Collected fractions were evaporated to afford compound 3-7 (17 mg, 0.042 mmol, 100 %) as a colorless oil.
  • Step 8 Synthesis of compound 3-9
  • nitric acid 0.002 mL, 0.055 mmol
  • the mixture was extracted with ethyl acetate and the combined organic layers were washed with water. The solvent was evaporated to give compound 3-9 (5 mg, 0.015 mmol, 54 %) as a yellow amorphous, which was used for the next step without further purification.
  • Step 9 Synthesis of compound 3-10 A suspension of compound 3-9 (5 mg, 0.015 mmol), iron (7 mg, 0.12 mmol), and ammonium chloride (48 mg, 0.9 mmol) in toluene (1 mL) and water (1 mL) was stirred for 5 h at 80 to 90 °C. After being cooled to room temperature, the reaction was quenched with potassium carbonate. The mixture was filtered through Celite (Registered trademark) pad. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and filtered.
  • Step 10 Synthesis of compound (I-13) To a stirred solution of compound 3-10 (5 mg, 0.016 mmol) in MeOH (1.0 ml) and hydrogen chloride (0.008 mL, 0.016 mmol, 2 mol/L in water) were added 5-(fluoromethoxy)pyrazine-2-carboxylic acid (2.8 mg, 0.016 mmol) and EDC hydrochloride (3.5 mg, 0.018 mmol) at 0 °C.
  • Step 2 Synthesis of compound 4-4 To a solution of Iodine (559 mg, 2.20 mmol) in MeCN (30 ml) was added compound 4-3 (397 mg, 1.10 mmol) in MeCN (10 ml) at 0 °C. After stirring for 20 min at the same temperature, the reaction mixture was treated with aqueous NaHCO 3 and Na 2 S 2 O 3 . The aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The crude product was added to a silica gel column and eluted with hexane/EtOAc 0% to 20%.
  • Step 3 Synthesis of compound 4-5
  • Step 4 Synthesis of compound 4-6 To a solution of compound 4-5 (336 mg, 0.932 mmol) in EtOH (3 ml) was added hydrazine hydrate (0.226 ml, 4.66 mmol) at room temperature. After stirring for 14 h at the same temperature, the reaction mixture was concentrated. The resulting residue was added to a amino silica gel column and eluted with Hexane/EtOAc 10% to 50%. Collected fractions were evaporated to afford compound 4-6 (195 mg, 0.761 mmol, 82%) as a white solid.
  • Step 6 Synthesis of compound 4-8 To a solution of compound 4-7 (514 mg, 1.71 mmol) in toluene (5 ml) and H 2 O (5 ml) were added NH 4 Cl (1.10 g, 20.5 mmol) and Fe (762 mg, 13.7 mmol) at room temperature. After stirring for 90 min at 80 °C, the mixture was treated with H 2 O and filtrated through Celite (Registered trademark) pad. The aqueous layer was extracted with AcOEt, and the organic layer was dried over Na 2 SO 4 , filtered and concentrated to afford compound 4-8 (422 mg, 1.56 mmol, 91%) as a yellow solid.
  • Step 7 Synthesis of compound (I-64) To a solution of compound 4-8 (100 mg, 0.369 mmol) in MeOH (2 ml) were added 5-chloropyrimidine-2-carboxylic acid (58.4 mg, 0.369 mmol) and 2 mol/L HCl (0.184 ml, 0.369 mmol) at room temperature. The reaction mixture was added to WSCD HCl (108 mg, 0.405 mmol) at 0 °C. After stirring for 30 min at room temperature, the reaction mixture was treated with aqueous NaHCO 3 .
  • Step 2 Synthesis of compound 5-3
  • 5-2 (1.15 g, 2.09 mmol) in ethanol (12 mL)
  • sodium borohydride (79 mg, 2.09 mmol) at 0 °C.
  • the reaction was quenched with a saturated solution of ammonium chloride.
  • the mixture was extracted with ethyl acetate, and the combined organic layers were washed with water.
  • the solvent was evaporated, and the crude product was purified by flash column chromatography (silica gel, 3:1 hexane:ethyl acetate) to give 5-3 (741 mg, 88%) as a colorless amorphous.
  • Step 4 Synthesis of compound 5-5
  • a solution of methyltriphenylphosphonium bromide (778 mg, 2.18 mmol) and potassium tert-butoxide (2.04 mL, 2.04 mmol, 1 mol/L in toluene) in THF (3 ml) was stirred at room temperature for 20 min.
  • To the mixture was added 5-4 in THF (3 ml) at 0 °C, and the resulting mixture was stirred for 2 h at room temperature.
  • the reaction was quenched with water.
  • the mixture was extracted with ethyl acetate, and the combined organic layers were washed with water.
  • Step 5 Synthesis of compound 5-6 A solution of 5-5 (190 mg, 0.47 mmol), Boc 2 O (0.22 mL, 0.95 mmol), and DMAP (11.6 mg, 0.095 mmol) in THF (2 mL) was stirred at room temperature for 1 h. The mixture was evaporated, and the crude product was purified by flash column chromatography (silica gel, 8:1 hexane:ethyl acetate) to give 5-6 (215 mg, 91%) as a white solid.
  • tR means LC/MS retention time (minute).
  • Test Examples for the compounds of the present invention are mentioned below.
  • Test Example 1 Assay of BACE1 inhibitory activity: 384-well
  • DMSO solution 0.1 ⁇ l of the compound of the present invention
  • Recombinant human BACE1(R&D Systems) 5 ⁇ l of Recombinant human BACE1(R&D Systems
  • Test Example 1-2 Assay of BACE2 inhibitory activity
  • substrate peptide solution SEVNLDAEFRHDSGYEK-biotin
  • DMSO solution 1 ⁇ l of the compound of the present invention
  • 10 ⁇ l of the human BACE2 which purified FreeStyle TM293-F cells condition medium that express human BACE2 ectodomain
  • the final concentrations of the substrate peptide and human BACE2 are adjusted to 1000 nmol/L and 20 ng/mL, respectively, and the reaction is performed in sodium acetate buffer (50 mmol/L sodium acetate, pH 4.5, 0.25 mg/mL bovine serum albumin). After the incubation for reaction, 30 ⁇ l of 1 M Tris-HCL (pH 7.6) is added to reaction mixtures. The reaction mixtures are added to each well coated with 82E1 (anti-amyloid ⁇ antibody; Immuno-Biological Loboratories) and incubated overnight at 4 °C.
  • the A ⁇ amount was measured as follows. 5 ⁇ l of a homogeneous time resolved fluorescence (HTRF) measurement reagent (Amyloid ⁇ 1-40 peptide; CIS bio international) and 5 ⁇ l of the culture supernatant were put into a 384-well plate (a black plate: Corning) and mixed with each other, and then left standing overnight at 4 °C while the light was shielded. Then, the fluorescence intensity (620 nm and 665 nm) was measured with EnVision (Perkin Elmer life sciences). The A ⁇ amount was determined from the count rate at each measurement wavelength (Count 665/Count 620), and the amount needed to inhibit A ⁇ production by 50 % (IC 50 ) was calculated from at least six different dosages.
  • HTRF time resolved fluorescence
  • Test Example 3-1 Lowering effect on the brain ⁇ amyloid in mice
  • Compound of the present invention is dissolved in 20% hydroxyl-beta-cyclodextrin, the final concentration is adjusted to 2 mg/mL, and this is orally administered to male Crl:CD1 (ICR) mouse (6 to 8 weeks old) at 1 to 10 mg/kg.
  • ICR ICR
  • a vehicle control group only 20% hydroxyl-beta-cyclodextrin is administered, and an administration test is performed at 3 to 6 animals per group.
  • a brain is isolated 1 to 6 hours after administration, a cerebral hemisphere is isolated, a weight thereof is measured, the hemisphere is rapidly frozen in liquid nitrogen, and stored at -80 °C until extraction date.
  • the frozen cerebral hemisphere is transferred to a homogenize tube containing ceramic beads in a 8-fold volume of a weight of an extraction buffer (containing 0.4% DEA (diethylamine), 50 mmol/L NaCl, Complete protease inhibitor (Roche)) and incubated on an ice for 20 minutes. Thereafter, the homogenization is done using MP BIO FastPrep(Registered trademark)-24 with Lysing matrix D 1.4 mm ceramic beads (20 seconds at 6 m/s). Then, the tube spins down for 1 minute, the supernatant is transferred to a centrifugation tube, and centrifuged at 221,000 x g, 4 °C for 50 minutes.
  • an extraction buffer containing 0.4% DEA (diethylamine), 50 mmol/L NaCl, Complete protease inhibitor (Roche)
  • the supernatant is transferred to Nunc Maxisorp (Registered trademark) plate (Thermo Fisher Scientific) coating with antibody against N-terminal of ⁇ amyloid for measuring total ⁇ amyloid, and the plate is incubated overnight at 4°C.
  • the plate is washed with TBS-T (Tris buffered saline containing 0.05% Triton X-100), and HRP-conjugated 4G8 dissolved in PBS (pH 7.4) containing 0.1% casein is added in the plate and incubated at 4°C for 1 hour.
  • TBS-T Tris buffered saline containing 0.05% Triton X-100
  • CYP3A4 (MDZ) MBI test is a test of investigating mechanism based inhibition (MBI) potential on CYP3A4 inhibition of a compound. CYP3A4 inhibition is evaluated using 1-hydroxylation reaction of midazolam (MDZ) by pooled human liver microsomes as a marker reaction.
  • the reaction conditions were as follows: substrate, 10 ⁇ mol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate reaction time, 2 minutes; reaction temperature, 37 °C; protein content of pooled human liver microsomes, at pre-reaction time 0.5 mg/mL, at reaction time 0.05 mg/mL (at 10-fold dilution); concentrations of the compound of the present invention, 1, 5, 10, 20 ⁇ mol/L (four points).
  • Pooled human liver microsomes and a compound of the present invention solution in a K-Pi buffer (pH 7.4) as a pre-reaction solution were added to a 96-well plate at the composition of the pre-reaction.
  • a part of pre-reaction solution was transferred to another 96-well plate, and 1/10 diluted by a K-Pi buffer containing a substrate.
  • NADPH as a co-factor was added to initiate a marker reaction (without preincubation).
  • NADPH was also added to a remaining pre-reaction solution in order to initiate a preincubation (with preincubation).
  • a part was transferred to another 96-well plate, and 1/10 diluted by K-Pi buffer containing a substrate in order to initiate a marker reaction.
  • Shifted IC value was calculated as “IC of preincubation at 0 min/ IC of preincubation at 30min”. When a shifted IC was 1.5 or more, this was defined as positive. When a shifted IC was 1.0 or less, this was defined as negative. The following compounds were defined as negative. I-4, 10, 14, 25 to 31, 39, 41, 42, 44, 55, 57, 59 to 64 and 73
  • the CYP inhibition test is a test to assess the inhibitory effect of a compound of the present invention towards typical substrate metabolism reactions on CYP enzymes in human liver microsomes.
  • the marker reactions on human main five CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) are used as follows; 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4’-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4).
  • the commercially available pooled human liver microsomes are used as an enzyme resource.
  • the reaction conditions were 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 microsomes 0.2 mg protein/mL; concentrations of the compound of the present invention, 1, 5, 10, 20 ⁇ mol/L (four points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant
  • hydroxytolbutamide CYP2C9 metabolite
  • 4'-hydroxymephenytoin CYP2C19 metabolite
  • dextrorphan CYP2D6 metabolite
  • terfenadine alcohol metabolite CYP3A4 metabolite
  • the sample adding DMSO to a reaction system instead of the compound of the present invention solution was adopted as a control (100 %) because DMSO was used as a solvent to dissolve a compound of the present invention.
  • Remaining activity (%) was calculated at each concentration of a compound of the present invention, and IC 50 value was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.
  • DMSO solution of the compound of the present invention (several stage dilution from maximum dose 50 mg/mL at 2 to 3-fold ratio); DMSO as negative control; 50 ⁇ g/mL of 4-nitroquinoline-1-oxide DMSO solution as positive control for TA98 without metabolic activation system; 0.25 ⁇ g/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution as positive control for TA100 without metabolic activation system; 40 ⁇ g/mL of 2-aminoanthracene DMSO solution as positive control for TA98 with metabolic activation system; or 20 ⁇ g/mL of 2-a
  • a mixed solution is incubated at 37 °C under shaking for 90 minutes.
  • 460 ⁇ L of the bacterial solution exposed to the compound of the present invention is mixed with 2300 ⁇ L of Indicator medium (Micro F buffer containing biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 ⁇ g/mL), each 50 ⁇ L is dispensed into 48 wells/dose in the microwell plates, and is subjected to stationary cultivation at 37 °C for 3 days.
  • a well containing the bacteria which has obtained the ability of proliferation by mutation in the gene coding amino acid (histidine) synthetase, turns the color from purple to yellow due to pH change. The number of the yellow wells among the 48 total wells per dose is counted, and evaluate the mutagenicity by comparing with the negative control group.
  • (-) means that mutagenicity is negative and (+) means positive.
  • the mixture was shaken for 1 hour at room temperature, and the mixture was vacuum-filtered.
  • Test Example 8 Metabolic stability test
  • a compound of the present invention was reacted for a constant time, a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
  • a reaction was performed (oxidative reaction) at 37 °C for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes.
  • a buffer 50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride
  • the compound of the present invention in the supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.
  • SPE solid phase extraction
  • Test Example 12 Brain distribution studies
  • Compound of the present invention was intravenously administered to a rat at 0.5 mg/mL/kg. 30 minutes later, whole blood was collected from the abdominal aorta under isoflurane anesthesia to sacrifice the rat.
  • the brain was enucleated and 25% brain homogenate was prepared with distilled water.
  • the obtained blood was centrifuged to obtain plasma.
  • the control plasma was added to the brain homogenate sample at 1:1.
  • the control brain homogenate was added to the plasma sample at 1:1.
  • Each sample was subjected to the measurement using LC/MS/MS.
  • the obtained area ratio (a brain/plasma) was calculated as the brain Kp value.
  • Ames test is performed by using Salmonellas (Salmonella typhimurium) TA 98, TA100, TA1535 and TA1537 and Escherichia coli WP2uvrA as test strains to evaluate gene mutagenicity of the compound of the present invention.
  • 0.1 mL of the compound of the present invention (DMSO solution) is mixed with 0.5 mL of S9 mix in the presence of metabolic activation or 0.5 mL of phosphate buffer in the absence of metabolic activation, and 0.1 mL of test strain suspension. As needed, the mixture is preincubated at 37°C in the water bath for 20 minutes under shaking.
  • these cells were seeded on Transwell (Registered trademark) insert (96-well, pore size: 0.4 ⁇ m, Coaster) at a density of 1.4 ⁇ 10 4 cells/insert and added Medium B (Medium 199 supplemented with 10 % FBS and gentamycin at 0.05 mg/mL) to the feeder tray. These cells were incubated in a CO 2 incubator (5% CO 2 /95% O 2 gasses, 37°C) and replace apical and basolateral culture medium every 48-72 hr after seeding. These cells were used between 4 and 6 days after seeding. 2. The medium in the culture insert seeded with MDR1 expressing cells or parent cells were removed by aspiration and rinsed by HBSS.
  • Transwell Registered trademark
  • the apical side (140 ⁇ L) or basolateral side (175 ⁇ L) was replaced with transport buffer containing reference substrates and the present invention and then an aliquot (50 ⁇ L) of transport buffer in the donor side was collected to estimate initial concentration of reference substrate and the present invention. After incubation for designed time at 37°C, an aliquot (50 ⁇ L) of transport buffer in the donor and receiver side were collected. Assay was performed by duplicate or triplicate. 3. Reference substrate and the compound of the present invention in the aliquot was quantified by LC/MS/MS.
  • Pe (cm/sec) Permeated amount (pmol) / area of cell membrane (cm 2 ) / initial concentration (nM) / incubation time (sec) Where, permeated amount was calculated from permeation concentration (nM, concentration of the receiver side) of the substance after incubation for the defined time (sec) multiplied by volume (mL) and area of cell membrane was used 0.1433 (cm 2 ).
  • MDR1 expressing LLC-PK1 cells and its parent cells are routinely cultured in Medium A (Medium 199 (Invitrogen) supplemented with 10 % FBS (Invitrogen), gentamycin (0.05 mg/mL, Invitrogen) and hygromycin B (100 ⁇ g/mL, Invitrogen)) at 37 °C under 5% CO 2 /95% O 2 gasses.
  • Medium A Medium 199 (Invitrogen) supplemented with 10 % FBS (Invitrogen), gentamycin (0.05 mg/mL, Invitrogen) and hygromycin B (100 ⁇ g/mL, Invitrogen)
  • these cells are seeded on Transwell (Registered trademark) insert (24-well, pore size: 0.4 ⁇ m, Coaster) at a density of 4 ⁇ 10 4 cells/insert and added Medium B (Medium 199 supplemented with 10 % FBS and gentamycin at 0.05 mg/mL) to the feeder tray. These cells are incubated in a CO 2 incubator (5% CO 2 /95% O 2 gasses, 37°C) and replace apical and basolateral culture medium every 48-72 hr after seeding. These cells are used between 6 and 9 days after seeding. 2. The medium in the culture insert seeded with MDR1 expressing cells or parent cells are removed by aspiration and rinsed by HBSS.
  • Transwell Registered trademark
  • Pe (cm/sec) Permeated amount (pmol) / area of cell membrane (cm 2 ) / initial concentration (nM) / incubation time (sec) Where, permeated amount is calculated from permeation concentration (nM, concentration of the receiver side) of the substance after incubation for the defined time (sec) multiplied by volume.(mL) and area of cell membrane is used 0.33 (cm 2 ).
  • mice Materials Animal: mdr1a (-/-) B6 mice (KO mouse) or C57BL/6J mice (Wild mouse) Methods and Procedures 1. Animals may be fed prior to dosing of the compounds of the present invention. 2. The compounds of the present invention are dosed to three animals for each time point and blood and brain samples are removed at selected time points (e.g. 15 min, 30min, 1hr, 2hr, 4hr, 6hr, 8hr, or 24hr) after dosing.
  • time points e.g. 15 min, 30min, 1hr, 2hr, 4hr, 6hr, 8hr, or 24hr
  • Blood (0.3-0.7 mL) is collected via trunk blood collection with syringe containing anticoagulants (EDTA and heparin).
  • Blood and tissue (e.g. brain) samples are immediately placed on melting ice. 3. Blood samples are centrifuged (1780 x g for 10 minutes) for cell removal to obtain plasma. Then, plasma samples are transferred to a clean tube and stored in a -70 °C freezer until analysis. 4. Tissue (e.g. brain) samples are homogenized at a 1:3 ratio of tissue weight to ml of distilled water and transferred to a clean tube and stored in a -70 °C freezer until analysis. 5. Plasma and tissue (e.g. brain) samples are prepared using protein precipitation and analyzed by LC/MS/MS.
  • the analytical method is calibrated by including a standard curve constructed with blank plasma or brain samples and known quantities of analyte. Quality control samples are included to monitor the accuracy and precision of the methodology. 6.
  • Group composition Vehicle group and the compound of the present invention group (4 guinea pigs per group).
  • Evaluation method Evaluation items: Mean blood pressure [mmHg], Heart rate (derived from blood pressure waveform [beats/min]), QTc (ms), and Toxicokinetics.
  • Guinea pigs are anesthetized by urethane (1.4 g/kg, i.p.), and inserted polyethylene tubes into carotid artery (for measuring blood pressure and sampling blood) and jugular vein (for infusion test compounds). Electrodes are attached subcutaneously (Lead 2).
  • Plasma samples are obtained by centrifugation (4°C, 10000 rpm, 9300 xg, 2 minutes). The procedure for separation of plasma is conducted on ice or at 4°C. The obtained plasma (TK samples) is stored in a deep freezer (set temperature: -80°C). Analysis methods: Mean blood pressure and heart rate are averaged a 30-second period at each evaluation time point.
  • ECG parameters (QT interval [ms] and QTc are derived as the average waveform of a 10-second consecutive beats in the evaluation time points.
  • Data analysis of QTc Percentage changes (%) in QTc from the pre-dose value are calculated (the pre-dose value is regarded as 100%). Relative QTc is compared with vehicle value at the same evaluation point.
  • Test Example 18-1 Single dose toxicity test
  • the compounds of the present invention are administered by gavage at 100, 300 and 1000 mg/kg in a 0.5% methylcellulose solution (vehicle) to Crl:CD(SD) rats (3/sex/dose).
  • the dosing volume is 10 mL/kg.
  • Clinical observation is monitored for 4 days. On the first day of dosing, observation is conducted continuously from just after dosing to 4 hours after dosing, and intermittently until 8 hours after dosing. On the other days, clinical observation is checked once daily.
  • Test Example 18-2 Single dose toxicity test
  • the compounds of the present invention were administered by gavage at 50, 100 and 300 mg/kg in a 0.5% methylcellulose solution (vehicle) to Marshal beagle dogs (2/sex/dose).
  • the dosing volume is 5 mL/kg.
  • Clinical observation was monitored for 4 days. On the first day of dosing, observation was conducted continuously from just after dosing to 4 hours after dosing, and intermittently until 8 hours after dosing. On the other days, clinical observation was checked once daily. No central nervous system adverse events such as convulsion, tremor or the like were not caused at 300 mg/kg of compound I-5.
  • Formulation Examples The following Formulation Examples are only exemplified and not intended to limit the scope of the present invention.
  • Formulation Example 1 Tablet Compound of the present invention 15 mg Lactose 15 mg Calcium stearate 3 mg All of the above ingredients except for calcium stearate are uniformly mixed. Then the mixture is crushed, granulated and dried to obtain a suitable size of granules. Then, calcium stearate is added to the granules. Finally, tableting is performed under a compression force.
  • Formulation Example 2 Capsules Compound of the present invention 10 mg Magnesium stearate 10 mg Lactose 80 mg The above ingredients are mixed uniformly to obtain powders or fine granules, and then the obtained mixture is filled in capsules.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265 g Magnesium stearate 5 g After the above ingredients are mixed uniformly, the mixture is compressed. The compressed matters are crushed, granulated and sieved to obtain suitable size of granules.
  • Formulation Example 4 Orally disintegrated tablets The compounds of the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrated tablets.
  • Formulation Example 5 Dry syrups The compounds of the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.
  • Formulation Example 6 Injections The compounds of the present invention and phosphate buffer are mixed to give injection.
  • Formulation Example 7 Infusions The compounds of the present invention and phosphate buffer are mixed to give infusion.
  • Formulation Example 9 Ointments The compounds of the present invention and petrolatum are mixed to give ointments.
  • Formulation Example 10 Patches The compounds of the present invention and base such as adhesive plaster or the like are mixed to give patches.
  • the compounds of the present invention can be a medicament useful as an agent for treating or preventing a disease induced by production, secretion and/or deposition of amyloid ⁇ proteins.

Abstract

La présente invention concerne un composé ayant un effet d'inhibition de la production de bêta-amyloïde, notamment un effet d'inhibition de BACE1, et qui est utile à titre d'agent thérapeutique ou prophylactique pour les maladies induites par la production, la sécrétion et/ou le dépôt de protéines bêta-amyloïdes. Le composé selon l'invention est un composé de formule (I) où R1 est un alkyle ou haloalkyle, R2 est H ou un halogène, R3 est H, un alkyle, alkyloxyalkyle ou haloalkyle éventuellement substitué par un cycloalkyle, R4 est H ou un halogène, -X = est -CH= ou -N=, le cycle B est un carbocycle aromatique substitué ou non, un hétérocycle aromatique substitué ou non, ou autre, ou un sel pharmaceutiquement acceptable de celui-ci.
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