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WO2014010748A1 - Cyclopropane derivative having bace1 inhibiting activity - Google Patents

Cyclopropane derivative having bace1 inhibiting activity Download PDF

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Publication number
WO2014010748A1
WO2014010748A1 PCT/JP2013/069231 JP2013069231W WO2014010748A1 WO 2014010748 A1 WO2014010748 A1 WO 2014010748A1 JP 2013069231 W JP2013069231 W JP 2013069231W WO 2014010748 A1 WO2014010748 A1 WO 2014010748A1
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substituted
unsubstituted
compound
alkyl
ring
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French (fr)
Inventor
Satoshi Shuto
Shuji Yonezawa
Kazunari Hattori
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Hokkaido University NUC
Shionogi and Co Ltd
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Hokkaido University NUC
Shionogi and Co Ltd
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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    • 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
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    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61K9/4841—Filling excipients; Inactive ingredients
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    • 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
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a compound which has an effect of inhibiting amyloid- production and is useful as a ⁇ therapeutic or preventing agent for diseases induced by production, secretion and/or deposition of amyloid- ⁇ proteins.
  • amyloid- ⁇ proteins which widely accumulate outside neurons to form insoluble plaques (senile plaques) are observed. These senile plaques are thought to kill neurons and cause the onset of Alzheimer's disease.
  • agents promoting degradation of amyloid- ⁇ proteins and amyloid- ⁇ vaccines have been studied.
  • Secretases are enzymes which cleave a protein called amyloid- ⁇ precursor protein (APP) within a cell and generate an amyloid- ⁇ protein.
  • An enzyme involving production of the N-terminal of amyloid- ⁇ proteins is called as ⁇ -secretase (beta-site APP-cleaving enzyme 1, BACE1) . It is considered that production of amyloid- ⁇ proteins may be suppressed by inhibiting this enzyme, and thus a substance with such an effect can serve as a therapeutic or preventing agent for Alzheimer's disease.
  • Patent Document 1 discloses compounds having a similar structure, to that of the compound of the ' present invention and these compounds can be a therapeutic agent for Alzheimer's disease or Alzheimer-related symptoms. However, the document specifically discloses different structures in its basic skeleton from that of the present invention.
  • Non-Patent Document 1 Compounds having a similar structure to that of the compounds of the present invention are disclosed in Patent Document 2 and Non-Patent Document 1 as an inhibitor of Na/H exchanger (NHE) , in Non-Patent Document 2 as an inhibitor of the receptor tyrosine kinases Tie-2, in Non-Patent Document 3 as a positive allosteric modulator of the metabotropic glutamate receptor subtype 4, and in Patent Document 3 and Patent Document 4 as a modulator of histamine H4 receptor.
  • Non-Patent Document 4 discloses a process for the production of a compound having similar structure to that of the compound of the invention. However, BACEl inhibitor activity is not suggested in any way.
  • the present invention provides a compound which has an effect of inhibiting amyloid- ⁇ production, in particular a BACE1 inhibitory effect, and is useful as a therapeutic or preventing agent for diseases induced by production, secretion or deposition of amyloid- ⁇ proteins.
  • the present invention provides for examples as follows: [0010]
  • a compound of the Formula (II), or a- pharmaceutically acceptable salt thereof : .
  • Ring A is aromatic carbocycle or aromatic heterocycle;
  • -X- is -N ( R 4 ) - , -0- or -S-;
  • R 4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio, carboxy or substituted or unsubstituted amino;
  • r is 1 or 2;
  • R 15 is hydrogen, or substituted or unsubstituted alkyl; each R 16 is independently hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
  • each R 17 is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl ;
  • either two R 16 and/or two R 17 on the different carbon atoms are optionally taken together to form a single bond when r is 2;
  • R 11 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
  • R 12 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio; R and R are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio;
  • R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; [Chemical Formula 2]
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
  • R za and R z are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclylalkoxy or substituted or unsubstituted
  • heterocyclyloxycarbonyl or R za and R zb , taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle ;
  • R 3 , R 3b , R 3c , R 3d , R 3e and R 3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
  • substituted or unsubstituted alkynylthio substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
  • alkynyloxycarbonyl substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubsti
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 3a and R 3b taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
  • R 3c and R 3d taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle;
  • Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle
  • Y 3 and Y 4 are each independently -C (R 5 ) (R 6 )-, -N(R 7 )-, -S-, -SO-, -SO 2 - or -0-;
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted a kyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
  • alkoxycarbonyl substituted or unsubstituted .
  • alkylsulfinyl substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl, or substituted or unsubstituted heterocyclylsulfonyl ;
  • n 1, 2 or 3;
  • each R 8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
  • Ph is phenyl
  • Ring A is aromatic carbocycle or aromatic heterocycle;
  • -X- is -N ( R 4 ) - , -0- or -S-;
  • R 4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio,. carboxy, or substituted or unsubstituted amino;
  • a dashed line indicates the presence or absence of a bond
  • R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; [Chemical Formula 5]
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
  • R za and R zb are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclylalkoxy or substituted or unsubstituted
  • heterocyclyloxycarbonyl or R za and R zb , taken together with the carbon atom to which, they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle;
  • R 3 , R 3b , R 3c , R 3d , R 3e and R 3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
  • substituted or unsubstituted alkynylthio substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
  • alkynyloxycarbonyl substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, " substituted or unsub
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heter.ocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 3 and R 3b taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
  • R 0 and R taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
  • Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle
  • Y 3 and Y 4 are each independently -C (R 5 ) (R 6 ) -, -N (R 7 ) -, -S-, -SO-, -S0 2 - or -0-;
  • R 5 and R 6 are each independently hydrogen,, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
  • heterocyclylalkyl substituted or unsubstituted
  • heterocyclyloxycarbonyl substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
  • n 1, 2 or 3 ;
  • each R 8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
  • unsubstituted alkoxycarbonyl a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclylalkyl , substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkenyl , substituted or
  • R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
  • R 3a , R 3b , R 3c and R 3d are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted
  • heterocyclylalkoxy substituted or unsubstituted alkylthio, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted amino, substituted or
  • R 3a and R 3b taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle.
  • Ring A is benzene ring or pyridine ring.
  • R 8 is a group of the formula:
  • Ring B is aromatic carbocycle or aromatic heterocycle; m is 0 , 1 or 2 ;
  • R 9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl ; and
  • Ak is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, and each of the other R , when n is 2 or 3, is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclylalkyl , or
  • ring-constituting atom at any one of ⁇ -, ⁇ -, ⁇ - or ⁇ -position is nitrogen atom when Ring A is pyridine ring.
  • Ring B is benzene ring, or 5- or 6-membered aromatic heterocycle .
  • a pharmaceutical composition comprising a compound according to any one of the above (1) to (12) or a
  • a method for treatment and/or prevention of disease caused by BACEl comprising administering the compound according to any one of the above ( 1 ) to (12) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the compounds of the invention are useful as an agent for treating or preventing disease induced by production, secretion or deposition of amyloid ⁇ protein such as Alzheimer's disease.
  • aromatic carbocycle refers to monocyclic or condensed aromatic carbocycle, and examples include benzene ring, napthalene ring, anthracene ring, preferably benzene ring.
  • aromatic heterocycle refers to include tomonocyclic or condensed aromatic heterocycle, and examples include pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, isothiazole ring, isoxazol ring, oxazole ring, thiazole ring, pyrazine ring, pyrimidine ring, pyridazine ring, tetrazole ring, oxadiazole ring, thiadiazol ring, indolizine ring, isoindole ring, indole ring, indazole ring, purine ring, quinolizine ring, isoquinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinolone ring, quinazoline ring, cinnoline ring, pteridin ring, carba
  • ring acridine ring, dibenzofuran ring, benzoxazolone ring, benzoxazinone ring, benzimidazole ring, benzisoxazole ring, benzoxazole ring, benzoxadiazole ring, benzisothiazole ring, benzothiazol ring, benzofuran ring, benzothiophene ring, Dibenzothiophene ring, benzodioxolan ring etc ., preferably pyridinium ring, furan ring, thiophene ring.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl includes C1-C15, preferably C1-C10, more, preferably C1-C6, and further, preferably C1-C3 straight or branched alkyl. 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 .
  • alkylsulfonylamino , “alkylsulfonyl alkylamino”
  • alkylsulfonylimino "alkylsulfinyl amino", “alkylsulfinyl alkylamino", “alkylsulfinylimino” , “alkyl sulfamoyl”, “alkylsulfinyl” , “carbocyclylalkyl “ , “carbocyclylalkoxy” , “carbocyclylalkoxycarbonyl” , “carbocyclylalkylamino” , v"carbocyclylalkyl carbamoyl", “heterocyclyalkyl",
  • heterocyclylalkoxycarbonyl and “heterocyclyalkyl carbamoyl” is defined above for “alkyl”.
  • substituted or unsubstituted alkyl refers to the above “alkyl” substituted or unsubstituted with one or more groups selected from the substituent group a.
  • the substituent group a herein consists of halogens, hydroxy, alkoxy, halogeno alkyl , halogeno alkoxy, hydroxy alkoxy, alkoxy alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkyl carbamoyl, hydroxyalkyl carbamoyl, sulfamoyl, alkyl sulfamoyl, alkylsulfinyl , alkylsulfonylamino, alkylsulfonyl alkylamino, alkylsulfonylimino, alkylsulfinyl amino, alkylsulfinyl alkylamino, alkylsulfinylimino, cyano, nitro, carbocycl
  • substituent group in "substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl” , “substituted or unsubstituted alkylthio", “substituted or unsubstituted alkylsulfonyl” and “substituted or unsubstituted alkylsulfinyl" may be one or more groups selected from the . substituent group ex.
  • halogeno alkyl includes trifluoromethyl, fluoro methyl , trichloro methyl , and the like.
  • halogeno alkoxy includes trifuoro methoxy, fluoro methoxy, . trichloro methoxy, and the like.
  • alkenyl refers to include C2-C15, preferably C2-C10, more, preferably C2-C6, and further, preferably C2-C4 straight or branched alkenyl having one or more double bonds at any position. Specific examples thereof include vinyl, allyl, propenyl, isopropenyl, butenyl, .
  • alkenyl moiety in “alkenyloxy” , “alkenyl oxycarbonyl” , “alkenyl- carbonyl”, “alkoxy alkenyloxy”, “alkenylthio” , “alkenylamino” , “alkenyl sulphonyl” and “alkenyl sulfinyl” is defined above for “alkenyl”.
  • alkynyl refers to include C2-C10, preferably C2-C8, and more, preferably C3-C6 straight or branched alkynyl having one or more triple bonds at any position Specific examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl . These groups may further have a double bond at any position. [0040]
  • alkynyl moiety in “alkoxy alkynyl”, “alkynyloxy”, “alkynyl oxycarbonyl " , “alkynyl carbonyl”, “alkoxy alkynyloxy”, “alkynylthio” , “alkynyl sulfinyl”, “alkynyl sulphonyl” and “alkynyl amino” is defined above for “alkynyl”.
  • acyl refers to include formyl, C1-C10 alkylcarbonyl, C2-C10 alkenyl carbonyl, C2-C10 alkynyl carbonyl, carbocyclylcarbonyl and heterocyclic carbonyl. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,.
  • hexanoyl acryloyl, propioloyl, methacryloyl , crotonoyl, benzoyl, cyclohexanecarbonyl , pyridinium carbonyl, furan carbonyl , thiophene carbonyl, benzothiazol carbonyl, pyrazine carbonyl, piperidine carbonyl and thiomorpholino .
  • carbocyclic group includes cycloalkyl, cycloalkenyl , aryl and fused non-aromatic carbocyclic groups . [0044] .
  • cycloalkyl includes C3-C10, preferably C3-C8 , and more, preferably C4-C8 carbocyclic groups . Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl . [0045]
  • cycloalkenyl includes those having one or more double bonds at any position in the ring of the cycloalkyl. Specific examples thereof include cyclopropenyl, cyclobutenyl , cyclopentenyl , cyclohexenyl , cycloheptynyl , cyclooctynyl and cyclohexadienyl .
  • aryl includes phenyl, naphthyl, anthryl and phenanthryl . Phenyl is particularly preferable among these.
  • fused non-aromatic carbocyclic group includes non-aromatic groups formed by fusion of two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl”. Specific examples thereof include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
  • non-aromatic carbocycle is the same as that of the "cycloalkyl” , “cycloalkenyl” and “fused non-aromatic carbocyclic group". Specific examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane , cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
  • Carbocyclylsulfinyl is defined above for “carbocyclic group” .
  • heterocyclic group includes heterocyclic groups having one or more hetero atoms arbitrarily selected from oxygen atom, sulphur atom and nitrogen atom in the ring. Specific examples thereof include .5- or 6-membered heteroaryls such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl , thiazolyl, and thiadiazolyl ;
  • non-aromatic heterocyclic groups such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathioranyl , azetidinyl, thianyl, thiazolidinyl , pyrrolidinyl , pyrrolinyl, imidazolidinyl , imidazolinyl , pyrazolidinyl , pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl , thiomorpholino, dihydropyridyl , tetrahydropyridyl , tetrahydrofuryl , tetrahydropyranyl , dihydrothiazolyl , tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl , hexahydro
  • bicyclic heterocyclic groups such as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl , quinolyl, isoquinolyl, cinnolinyl, phthalazinyl , quinazolinyl , naphthyridinyl , quinoxalinyl , purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl , benzoxadiazolyl , benzoisothiazolyl , benzothiazolyl , benzothiadiazolyl , benzofuryl, isobenzofuryl , benzothienyl , benzotriazolyl, thienopyridyl , thienopyrrolyl , thienopyrazolyl , thi
  • chromanyl chromenyl, octahydrochromenyl , dihydrobenzodioxinyl , dihydrobenzooxedinyl , dihydrobenzodioxepinyl and dihydrothienodioxinyl ; and fused tricyclic heterocyclic groups such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl , phenoxathiinyl , phenoxazinyl , dibenzofuryl , imidazoquinolyl and tetrahydrocarbazolyl .
  • Preferable among these are 5- or 6-membered heteroaryls or non-aromatic heterocyclic groups.
  • heterocyclylsulphonyl , “heterocyclylcarbamoyl” , “heterocyclyloxycarbonyl “ , “heterocyclylalkylamino” , “heterocyclylalkoxycarbonyl” and “heterocyclyalkyl carbamoyl” is defined above for “heterocyclic group”.
  • heterocycle moiety in "non-aromatic heterocycle” is the same as that in the above “non-aromatic heterocyclic group” .
  • Specific examples thereof include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidin, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine , pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydro pyridinium, tetrahydro pyridinium, tetrahydrofuran, tetrahydro pyran, dihydro thiazole, tetrahydro thiazole, tetrahydro isothiazole, dihydro oxazine, hexahydro azepine, tetrahydro diazepine, te
  • the bond (s) in the above “heterocyclic group” may be positioned in any ring.
  • heteroaryl includes aromatic heterocyclic groups which are included in the “heterocyclic group”.
  • alkylene includes C1-C10, preferably C1-C6, and more, preferably C1-C3 straight or branched divalent carbon chains. Specific examples thereof include methylene, dimethylene, .trimethylene, tetramethylene and methyl trimethylene.
  • alkenylene includes C2-C10, preferably C2-C6, and more, preferably C2-C4 straight or branched divalent carbon chains having a double bond at any position. Specific examples thereof include vinylene, propenylene, butenylene, butadienylene , methyl propenylene, pentenylene and hexenylene.
  • alkynylene includes C2-C10, more, preferably C2-C6, and more, preferably C2-C4 straight or branched divalent carbon chains having a triple bond at any position and optionally further having a double bond. Specific examples thereof include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
  • the compound of formula (I) includes pharmaceutically acceptable salts thereof.
  • examples thereof include salts with alkaline metals (e.g. lithium, sodium and potassium) , alkaline earth metals (e.g. magnesium and calcium), transition metals (e.g., zinc), ammonium, organic bases and amino acids, and salts with inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and hydroiodic acid) and organic acids (e.g.
  • acetic acid trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and ethanesulfonic acid) .
  • Specifically preferable are hydrochloric acid, phosphoric acid, tartaric acid and methanesulfonic acid. These salts may be formed by a conventional method.
  • the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate) and/or crystal polymorphism. Such solvates and crystal polymorphism is encompassed by the present invention.
  • any number of solvent (e.g., water) molecules may be conjugated with one molecule of the compound of formula (I) and (II) .
  • the compound of formula (I) and (II) or a pharmaceutically acceptable salt thereof by allowing it to stand in the atmosphere, may absorb moisture leading to attachment of adsorbed water or formation of a hydrate.
  • the compound of formula (I) and (II) of a pharmaceutically acceptable salt thereof may form crystal polymorphism by recrystallization thereof.
  • the compounds of formula (I) and (II) are not limited to a specific isomer, and include any possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers , optical isomers and rotamers ) and racemic mixtures .
  • compounds of formula (I) wherein R 2a is hydrogen include the following tautomers .
  • a compound of formula (I), wherein -X- is -N(H)-, and R 3a and R 3b are taken together with the carbon atom to which they are attached to form a carbonyl group includes the following tautomers.
  • the compound of formula (I) and (II) has an asymmetric carbon atom(s), and thus, includes the following optical isomers. [Chemical Formula 20]
  • An optical isomer of the compound of formula (I) and (II) may be obtained by conventional technique known in the art, such as chiral chromatography, and formation of diastereomer salt using an optical active acid or base.
  • one or more hydrogen, carbon or other atoms of acompound of formula (I) and (II) may be replaced by an isotope of the hydrogen, carbon or other atoms.
  • Compounds of formula (I) and (II) include all radiolabeled forms of compounds of formula (I) and (II) .
  • Such "radiolabeled, " “radiolabeled form” , and the like of a compound of formula (I) and (II) is useful as a research and/or diagnostic to ol in metabolism pharmacokinetic studies and in binding assays, and also as a medicament.
  • isotopes that can be incorporated into a compound of formula (I) and (II) of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 123 I and 36 C1.
  • Radiolabeled compounds of the invention can be prepared by methods well known in the art.
  • tritiated compounds of. formula (I) or (II) can be prepared by introducing tritium into the particular compound of formula (I) or (II) , for example, by catalytic dehalogenation with tritium.
  • This method may include reacting a suitably halogen-substituted precursor of a compound of formula (I) or (II) with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base.
  • a suitable catalyst such as Pd/C
  • Other suitable methods for preparing tritiated compounds can be found in Isotopes in the Physical and Biomedical Sciences , Vol. 1, Labeled Compounds (Part A) Chapter 6 (1987) .
  • 14 C-labeled compounds can be prepared by employing starting materials having a. 14 C carbon.
  • ring A in formula (I) or (II) includes benzene ring or pyridine ring.
  • R 2a and R 2b in formula (I) or (II) include respectively hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl--, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl .
  • R 2a and R 2 may be both hydrogen.
  • R za and R zb are taken together with the carbon atom to which they are attached to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle.
  • R 3a and R 3b in formula (I) or (II) can be taken together with the carbon atom to which they are attached to form a carbonyl group.
  • R 3a and R 3b are taken together with the carbon atom to which they are attached to form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • R 3c and R 3d are taken together with the carbon atom to which they are attached to form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle
  • R 8 can be represented by the formula:
  • each variable is as defined above, and R 9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring.
  • R 9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring.
  • m 1 is 0 or 1
  • the other variables are as defined above.
  • R 8 can be represented by the formula
  • each variable is as defined above, and R 9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring, and
  • R 8 can be halogens, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl .
  • R 8 can be represented by the formula [Chemical Formula 37]
  • Ring B is aromatic carbocycle or aromatic heterocycle
  • n is an integer of 0 to 2;
  • R 9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C1- .
  • R 8 can be represented by the formula [Chemical Formula 38]
  • ring B, m, R 9 are as defined above, Ak is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C3 alkenylene or substituted or unsubstituted C1-C3 alkynylene.
  • Ak can be G2 alkylene, C2 alkenylene or C2 alkynylene .
  • ring B can be benzene ring, napthalene ring, or 5 or .6-membered aromatic heterocycle.
  • R 1 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • R 1 is specifically, for example, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • R 1 is more particularly, for example, C1-C3 unsubstituted alkyl.
  • Me is methyl; ) in formula (I) or (II), [Chemical Formula 64]
  • each R 9 in the above 5) is independently [Chemical Formula 71]
  • n in the above 5) is 0, 1 or 2.
  • the present compound of the formula (I) or (II) can be prepared by the following method .
  • any substituent group that interferes with the reaction e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy
  • wedge-shaped solid or dashed lines are used to denote absolute configuration, and bold solid or dashed lines are used to denote relative configuration.
  • Lactone 3 can be prepared according to the procedure as described in Journal of Organic Chemistry (J. Org. Chem. ) 1996, 61, 915-923, using epichlorohydrin 1 as a starting material.
  • a base e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide
  • the mixture is reacted at a temperature from-10 to 50°C, preferably 0 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs .
  • An acid such as hydrochloric acid is added to neutralize, and the solvent is removed.
  • An alkylsilyl halide is added to react at a temperature from-10 to 50°C, preferably 0 to 2°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs.
  • a base e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide
  • a solvent e.g., methanol, ethanol, water
  • the solution is neutralized with an acid such as hydrochloric acid to obtain compound 4.
  • Compound 5 can be prepared by isomerizing compound 4 according to the procedure as described in Journal of Organic Chemistry (J. Org. Chem.) 2003, 68, 9255-9262. [0105]
  • Compound 6 can be prepared by oxidation of compound 5 using sodium periodate and ruthenium chloride, using potassium permaganate under alkaline condition, by Jones oxidation, under condition using PCC, PDC, ruthenium tetroxide and TEMPO, or using sodium hypochlorite, sodium chlorite and TEMPO.
  • An optically active compound 6 can be prepared using an optically active epichlorohydrin 1.
  • Carboxylic acid 6, 10a (1R,2R) or 10b (1S,2S) obtained above can be reacted with CDI to convert to an active ester. Then, salt of malonic acid halfester, magnesium chloride and triethylamine are added, and the mixture is reacted at 0 to 100°C, preferably 25 to 80°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, to obtain compound 11.
  • compound la can be prepared by treating compound 11 with guanidine to form amino pyrimidone ring.
  • compounds of the present invention may be prepared by forming aminooxazine ring or aminothiazine ring according to the procedure described below.
  • An ester compound such as ethyl propionate is reacted in the presence of a. base, such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof to obtain an enolate.
  • a. base such as lithium diisopropylamide
  • a solvent e.g., toluene, dichloromethane, THF
  • a titanium agent such as chlorotitanium triisopropoxide, and compound a, which can be prepared by known method, are added to the enolate, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound b.
  • Compound b is reacted with a Grignard reagent commercially available or prepared by known method such as methylmagnesium bromide, or an reducing agent such as borane,. sodium borohydride, and lithium aluminum hydride, in a solvent (e.g., dioxane, THF, ether, toluene) or a mixed solvent thereof at -80 to 80°G, preferably -20 to 30°C, for 0.5 to 48 hrs, preferably 1 to 12 hrs, to obtain compound c.
  • a Grignard reagent commercially available or prepared by known method such as methylmagnesium bromide, or an reducing agent such as borane,. sodium borohydride, and lithium aluminum hydride
  • Compound c is reacted in a solvent (e.g., dioxane, methanol, dichl-o omethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound d.
  • a solvent e.g., dioxane, methanol, dichl-o omethane
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound d is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) , in a solvent (e . g . , ⁇ dioxane , THF, toluene, acetone) or a mixed solvent thereof at -30 to 50 °C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound e.
  • a solvent e . g . , ⁇ dioxane , THF, toluene, acetone
  • Compound e is reacted with an alkylating agent (e.g., methyl iodide, diethyl sulfate, benzyl bromide) in a solvent (e.g., methanol, ethanol, dimethylformamide, THF) , in the presence or absence of an base (e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide), at 0 to 200°C, preferably 40 to 150°C for 1 to 48 hrs, preferably 0.5 to 24 hrs, to obtain compound lb.
  • an alkylating agent e.g., methyl iodide, diethyl sulfate, benzyl bromide
  • a solvent e.g., methanol, ethanol, dimethylformamide, THF
  • an base e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydrox
  • Compound a which can be prepared by known method, is added to a Grignard reagent such as allylmagnesium bromide, in a solvent (e.g., toluene, dichloromethane , THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound f .
  • a solvent e.g., toluene, dichloromethane , THF
  • Step 2 Compound f is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound g.
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound g is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate ) , in a solvent (e.g., dichloromethane, dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30to50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound h.
  • a solvent e.g., dichloromethane, dioxane, THF, toluene, acetone
  • Compound h is reacted with a hologenium ion source (e.g. , iodine, bromine, N-bromo succinimide (NBS)), in a solvent such as dichloromethane, at -20 to 40°C, preferably 0 to 20°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by the reaction with a base (e.g., pyrrolidine, piperidine, piperazine, morpholine) at 20 to 100°C, preferably 40 to 80°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Ic.
  • a hologenium ion source e.g. , iodine, bromine, N-bromo succinimide (NBS)
  • a solvent such as dichloromethane
  • a base e.g., pyrrolidine, piperidine, piperazine, morpholine
  • a carbonyl compound such as diethyl ketone is reacted in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof to obtain an enolate.
  • a titanium agent such as chlorotitanium triisopropoxide, and compound a, which. can be prepared by known method, are added to the enolate, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound i.
  • Compound i is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound j ⁇ .
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound j is reacted with an isocyanate having .
  • a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate), in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound k.
  • Compound k is reacted with an acid such as cone, sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound [0130]
  • an acid such as cone, sulfuric acid and cone, nitric acid
  • Y a is Y 1 or Y 3
  • Y b is Y 2 or Y 4
  • a dashed line indicates the presence or absence of a bond
  • Compound a which can be prepared by known method, is reacted with an enolate obtained by the reaction with a desired carbonyl compound such as cyclopentanone, in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound 1.
  • a solvent e.g., toluene, dichloromethane, THF
  • a mixed solvent thereof e.g., toluene, dichloromethane, THF
  • Compound 1 is reacted in a solvent (e.g., dioxane, methanol, dichloromethane) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound m.
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound m is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound le.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone .
  • sulfuric acid and cone, nitric acid at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12
  • Compound le wherein a dashed line indicates the absence of a bond can be prepared from compound le wherein either dashed line indicates the presence of a bond, using conventional method such as a method of hydrogenation .
  • Compound a which can be prepared by known method, is reacted with an enolate which was obtained by the reaction with a desired carbonyl compound such as cyclopentanone, in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof at -80 to 30 °C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound n.
  • a solvent e.g., toluene, dichloromethane, THF
  • a mixed solvent thereof e.g., toluene, dichloromethane, THF
  • Compound n is reacted with a Grignard reagent commercially available or prepared by known method (e.g., methylmagnesium bromide) in a solvent (e.g., dioxane, THF, ether, toluene) or a mixed solvent thereof, at -80 to 80°C, preferably -20 to 30°C, for 0.5 to 48 hrs, preferably 1 to 12 hrs, followed by the reaction in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound o.
  • a solvent e.g., dioxane, THF, ether, toluene
  • an acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • Compound o is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e . g ., benzoyl isocyanate) in a solvent (e . g ., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound p.
  • a solvent e . g ., dioxane, THF, toluene, acetone
  • an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to
  • Step 4 To compound p in a solvent (e . g . , dichloromethane, THF, toluene) are added oxalyl chloride or thionyl chloride and a catalytic quantity of N, N-dimethylformamide, or is added a chlorinating agent such as l-chloro-2-trimethylpropenylamine, and the mixture is reacted at 0 to 100°C, preferably 10 to 50°C, for 0.5 to 72 hrs, preferably 0.5 to 6 hrs, to obtain compound If.
  • a solvent e . g . , dichloromethane, THF, toluene
  • Compound a is added to a Grignard reagent (e.g., phenylmagnesium bromide having optionally protected hydroxy group at ortho position) or a lithium agent (e.g., pyridyl lithium having optionally protected hydroxy group at ortho position) in a solvent (e.g., toluene, diethylether, THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, and the protecting group is removed by known method to obtain compound q. .
  • a Grignard reagent e.g., phenylmagnesium bromide having optionally protected hydroxy group at ortho position
  • a lithium agent e.g., pyridyl lithium having optionally protected hydroxy group at ortho position
  • solvent e.g., toluene, diethylether, THF
  • Compound q is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic.acid, sulfuric acid, trifluoroacetic acid) at 0 to 80°C, preferably 0 to 30°C for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound r .
  • a solvent e.g., dioxane, methanol, dichloromethane
  • an acid e.g., hydrochloric acid, hydrobromic.acid, sulfuric acid, trifluoroacetic acid
  • Compound r is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound s.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • Compound s is reacted with an alkylating agent (e.g., methyl iodide, diethyl sulfate, benzyl bromide) in a solvent (e.g., methanol, ethanol, dimethylformamide, THF) , in the presence or absence of an base (e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide) at 0. to 200°C, preferably 40 to 150°C, for 1 to 48 hrs, preferably 0.5 to 24 hrs, to obtain compound Ig.
  • an alkylating agent e.g., methyl iodide, diethyl sulfate, benzyl bromide
  • a solvent e.g., methanol, ethanol, dimethylformamide, THF
  • an base e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide
  • compounds of the invention can be prepared by forming amino thiazine ring according to the procedure as described in Journal of Hetero cyclic Chemistry, 14, 717-723 (1977) .
  • a solvent e.g. , ' dichloromethane, THF, toluene
  • a chlorinating agent such as l-chloro-2-trimethylpropenylamine
  • Compound a which can be prepared by known method, is added to an enolate obtained by the reaction with corresponding alkyl ketone (e.g., 3-methyl -2-butanone) , in the presence of a base, such as lithium diisopropylamide , potassium hexamethyldisilazide, ' in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound i.
  • a base such as lithium diisopropylamide , potassium hexamethyldisilazide
  • a solvent e.g., toluene, dichloromethane, THF
  • Compound i is reacted with an acid such as hydrochloric acid, hydrobromic acid, and trifluoroacetic acid, at 0 to 60°C, preferably 0 to 30°C, for 0.1 to 24 hrs, preferably 0.5 to 12 hrs, to obtain compound ii.
  • an acid such as hydrochloric acid, hydrobromic acid, and trifluoroacetic acid
  • Compound ii is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 70°C, preferably -20 to 50°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by removing the solvent and addition of an acid such as cone, sulfuric acid and cone, nitric acid to react at -30 to 70°C, preferably -20 to 50°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, to obtain compound Ii.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone, sulfuric acid and cone, nitric acid
  • Compound j is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 70°C, preferably -20 to 50°C for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by removing the solvent and addition of an acid such as cone, sulfuric acid and cone, nitric acid to react at -30 to 70°C, preferably -20 to 50°C, for 1 to 12 hrs, preferably 1 to 6 hrs, to obtain compound Ij..
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone, sulfuric acid and cone, nitric acid
  • Compound m is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid to react at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Ik.
  • a solvent e.g., dioxane, THF, toluene, acetone
  • an acid such as cone .
  • sulfuric acid and cone nitric acid to react at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24
  • Compound o is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate ) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone, sulfuric acid and cone .
  • nitric acid at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound p .
  • a solvent e.g., dichloromethane, THF, toluene
  • Compound II wherein a dashed line indicates the absence of a bond can be prepared from compound II wherein either dashed line indicates the presence of a bond, using a conventional method such as a method of hydrogenation .
  • R is a group such as optionally substituted alkyl, optionally substituted hydrocarbon ring, and optionally substituted heterocyclic group, and the other variables are as defined above.
  • Compound I wherein R is hydrogen is reacted with an acylating agent having a substituent group corresponding to the desired compound, such as benzoyl chloride, 2-furoyl chloride, and acetic anhydride, in the presence or absence of a solvent such as THF and dichloromethane, in the presence or absence of a base such as pyridine and triethylamine, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs reactions, or the above compound I is reacted with a carboxylic acid having a substituent group corresponding to the desired compound, such as amino acid, and -glycol acid, in a solvent such .
  • NHR U is optionally substituted amino
  • NR 20 COR ,2 ' 1 L is optionally substituted acylamino, optionally substituted ureido, or carboxy amino having a substitutent group on oxygen atom, and the other variables are as defined above.
  • Compound I wherein Ring A is optionally substituted with amino is reacted with a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoylchloride,.
  • a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoylchloride,.
  • NHR is optionally substituted amino
  • R z 22 is alkyl
  • R is a group, such as optionally substituted alkyl, optionally substituted carbocyclic group, and optionally substituted heterocyclic group, and the other variables are as defined above.
  • G is a group such as optionally substituted alkenyl, optionally substituted alkynyl, . optionally substituted alkoxycarbonyl, optionally substituted carbocyclic group, and optionally substituted heterocyclic group, and the other variables are as defined above.
  • R 24 is hydrogen or optionally substituted alkyl
  • R 25 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted carbocyclic group or optionally substituted heterocyclic group, and the other variables are as defined above.
  • Compound I is reacted with a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, and isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chlorocarbonate, di-tert-butyl dicarbonate, phenyl isocyanate, etc.
  • a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, and isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chlorocarbonate, di-tert-butyl dicarbonate, phenyl isocyanate, etc.
  • the substituent group may be protected in advance for coupling reaction, and the protective group may be removed at a desirable step.
  • the compound is reacted at -30 to 100 °C, preferably 0 to 90°G for 0.5 to 12 hrs in a solvent such as methanol, ethanol, ether, THF, 1,4-dioxane, dichloromethane , ethyl acetate, containing hydrogen chloride, trifluoroacetic acid etc., or trifluoroacetic acid in the absence of a solvent, or according to the method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) to obtain compound Is.
  • a solvent such as methanol, ethanol, ether, THF, 1,4-dioxane, dichloromethane , ethyl acetate, containing hydrogen chloride, trifluoroacetic acid etc., or trifluoroacetic acid in the absence of a solvent, or according to the method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) to
  • LI is methanesulfonyl or toluenesulfonyl , etc. , and the other variables are as defined above.
  • a solvent such as ether, and THF
  • Compound 15 is reacted with sodium borohydride, lithium triethylborohydride or lithium aluminum hydride, etc. in a solvent such as ether, and THF, at -30 to 50°C, preferably 0 to 25°C, for 0.5 to 5 hrs, to obtain compound 16.
  • Compound 12 is reacted with compound 17 in a solvent such as THF, and toluene, at -80 to 150°C, preferably -30 to 100°C, for 0.5 to 24 hrs, to obtain compound 18.
  • a solvent such as THF, and toluene
  • Compound 18 is reacted with hydrogen gas in a solvent such as methanol, ethanol, ether, THF, ethyl acetate, acetic acid, and a mixed solvent thereof, in the presence of a metal catalyst at 0 to reflux temperature, preferably 0 to 40°C, for 0.5 to 72 hrs, preferably 1 to 12 hrs, . to obtain compound 19.
  • a solvent such as methanol, ethanol, ether, THF, ethyl acetate, acetic acid, and a mixed solvent thereof
  • Compound 12 is reacted with compound 20 in a solvent such as dichloromethane, in the presence of a reducing agent such as sodium cyanoborohydride , sodium triacetoxyborohydride, at -30 to 100°C, preferably 0 to 25°C, for 0.5 to 24 hrs to obtain compound 21.
  • a reducing agent such as sodium cyanoborohydride , sodium triacetoxyborohydride
  • Cyclopropane intermediate 24 and 25 are prepared according to the method as described in J. Med. Chem. , 2006, 49, 5587-5596.
  • Compound 26 is reacted with compound 27 in a solvent such as THF, DMF, and D SO, in the presence of sodium hydride, potassium carbonate, cesium carbonate, etc. at 0 to 120°C, preferably 0 to 50 °C, for 0.5 to 24 hrs to obtain compound 28.
  • a solvent such as THF, DMF, and D SO
  • PI is a carboxy protecting group and the other variables are as defined above.
  • An optically active from of compound (I) or (II) can be prepared by using an optical activate starting material, obtaining an optical activate intermediate by asymmetric synthesis in appropriate step, or optically resoluting. an intermediate of each racemate and a final product in an appropriate step.
  • Procedures of the optical resolution include a method of separating an optical isomer using an optically active column; kinetic optical resolution utilizing an enzymatic reaction and the like; crystallization resolution of a diastereomer by salt formation using a chiral acid or a chiral base; preferential crystallization method and the like.
  • compound 4 obtained in Step 2 can be subjected to cyclization reaction to form amino pyrimidone ring, followed by isomerization reaction by Barton decarboxylation to obtain cis-form stereoselectively .
  • the compound of the invention is useful in disease induced by the production / secretion or deposition of amyloid ⁇ protein, and are effective in treatment and/or .
  • prevention and symptom improvement of diseases such as dementia of the Alzheimer' s type (e.g. , Alzheimer ' s disease, senile dementia of Alzheimer type ) , Down's syndrome, memory impairment, prion disease (e.g., Creutzfeldt-Jakob disease) , mild cognitive impairment (MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other type of degenerative dementia, mixed dementia with Alzheimer's and vascular type, 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.
  • dementia of the Alzheimer' s type e.g. , Alzheimer
  • treating Alzheimer's disease includes prevention of aggravation of MCI and prevention of familial Alzheimer's disease.
  • a pharmaceutical composition for treating Alzheimer's disease includes a pharmaceutical composition for prevention of aggravation of MCI and prevention of familial Alzheimer's disease.
  • the present compound Since the present compound has high inhibitory activity on BACEl, and/or has high selectivity on other enzymes, it can be a medicament with reduced side effect. Further, since the compound has high effect of reducing amyloid ⁇ production in a cell system, particularly, has high effect of reducing amyloid ⁇ production in .brain, it can be an excellent medicament. In addition, by converting the compound into aft optically active compound having suitable stereochemistry, the compound can be a medicament having a wider safety margin on the side effect.
  • the present compound also has advantages that metabolism stability is high, solubility is high, oral absorbability is high, good bioavailability is exhibited, clearance is good, brain transference is high, a half-life is long, non-protein binding rate is high, hERGchannel inhibition is low, CYP inhibition is low, CYP MBI (mechanism-based inhibition) is low, and/or an Ames test is negative. [0181]
  • the compound of the invention can be administrated in combination with other pharmaceutical agents such as other therapeutic drugs for .
  • Alzheimer's disease e.g., acetylcholinesterase and the like.
  • the compound of the invention can be administered in combination with anti-dementia agents such as Donepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinpocetine.
  • anti-dementia agents such as Donepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinpocetine.
  • the compound of the invention When the compound of the invention is administered to a human, it can be administered orally as powders, granules, tablets, capsules, pills, solutions, or the like, or parenterally as injectables, suppositories, transdermal absorbable agents, inhalations, or the like.
  • the compound of the invention can be formulated into pharmaceutical, preparations by adding pharmaceutical additives such as excipients, binders, wetting agents , disintegrating agents , lubricants and the like, which are suitable for mulations and an effective amount of the compound.
  • the dose is varied depending on state of disease, an administration route, and an age and a weight of a patient, and is usually 0.1 pg to 1 g/day, preferably 0.01 to 200 mg/day when orally administered to an adult, and is usually 1 ]iq to 10 g/day, preferably 0.1 to 2 g/day when parenterally administered.
  • RT in the tables means retention time (minute) in LC/MS: liguid chromatography / Mass spectroscopy measured under the following condition.
  • UV detection wavelength 254 nm
  • ethanol 120ml
  • lOmol/L aqueous potassium hydroxide 40ml
  • the solvent was removed to half its original volume under reduced pressure, and the solution was poured into a mixture of cooled cone, hydrochloric acid (60ml) and water (60ml).
  • the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over sodium sulfate. Sodium sulfate was removed, and the solution was concentrated under reduced pressure.
  • the aqueous layer was acidified with 6mol/L hydrochloric acid, and the solution was extracted with ethyl acetate.
  • the organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residual solid was washed with hexane to yield compound all (16.2g, 56.8mmol, 87%) as a greyish brown solid.
  • Triisopropoxy titanium (IV) chloride (3.72ml, 15.6mmol) in THF (6ml) was added over 10 min, and the mixture was stirred at - 70°C for 20 min.
  • Compound a21 (977mg, 3.71mmol) in THF (4ml) was. added over 5 min, and the reaction mixture was stirred at - 70°C for 1 hr and added dropwise to ammonium chloride (1.19g) in water (4ml) under ice-cooling.
  • ethyl acetate (10ml) and celite (2g) To the reaction mixture were added ethyl acetate (10ml) and celite (2g) , the mixture was stirred at room.temperature for 10 min. The resultant insoluble solids were filtered off over celite, and water was added to the filtrate.
  • compound a28 was obtained as a colorless liquid.

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Description

[DESCRIPTION]
[Title of Invention]
CYCLOPROPANE DERIVATIVE HAVING BACE1 INHIBITING ACTIVITY
[Technical field]
[0001]
The present invention relates to a compound which has an effect of inhibiting amyloid- production and is useful as a ^therapeutic or preventing agent for diseases induced by production, secretion and/or deposition of amyloid-β proteins.
[Background Art]
[0002]
In the brains of patients with Alzheimer's disease, peptides each consisting of approximately 40 amino acids, called amyloid-β proteins, which widely accumulate outside neurons to form insoluble plaques (senile plaques) are observed. These senile plaques are thought to kill neurons and cause the onset of Alzheimer's disease. As therapeutic agents for Alzheimer's disease, agents promoting degradation of amyloid-β proteins and amyloid-β vaccines have been studied.
[0003]
Secretases are enzymes which cleave a protein called amyloid-β precursor protein (APP) within a cell and generate an amyloid-β protein. An enzyme involving production of the N-terminal of amyloid-β proteins is called as β-secretase (beta-site APP-cleaving enzyme 1, BACE1) . It is considered that production of amyloid-β proteins may be suppressed by inhibiting this enzyme, and thus a substance with such an effect can serve as a therapeutic or preventing agent for Alzheimer's disease.
[0004]
Patent Document 1 discloses compounds having a similar structure, to that of the compound of the' present invention and these compounds can be a therapeutic agent for Alzheimer's disease or Alzheimer-related symptoms. However, the document specifically discloses different structures in its basic skeleton from that of the present invention.
[0005]
Compounds having a similar structure to that of the compounds of the present invention are disclosed in Patent Document 2 and Non-Patent Document 1 as an inhibitor of Na/H exchanger (NHE) , in Non-Patent Document 2 as an inhibitor of the receptor tyrosine kinases Tie-2, in Non-Patent Document 3 as a positive allosteric modulator of the metabotropic glutamate receptor subtype 4, and in Patent Document 3 and Patent Document 4 as a modulator of histamine H4 receptor. Non-Patent Document 4 discloses a process for the production of a compound having similar structure to that of the compound of the invention. However, BACEl inhibitor activity is not suggested in any way.
[Citation List]
[Patent Literature]
[0006]
[PTL 1]
WO 2006/041404
[PTL 2]
WO 2001/027107
[PTL 3]
US Published Patent Application 2008/0194577
[PTL 4]
WO 2009/068512 [Non Patent Literature]
.[0007]
[NPL 1]
Bioorganic & Medicinal. Chemistry Letters 14 (2004) 177-180 [NPL 2]
Bioorganic & Medicinal Chemistry Letters 18 (2008) 4723-4726 [NPL 3]
Bioorganic & Medicinal Chemistry Letters 20 (2010) 4901-4905 [NPL 4]
Indian Journal of Chemistry, Section B: Organic Chemistry In eluding Medicinal Chemistry (1997), 36B (12), 1123-1125
[Summary of Invention]
[Technical Problem]
[0008]
The present invention provides a compound which has an effect of inhibiting amyloid-β production, in particular a BACE1 inhibitory effect, and is useful as a therapeutic or preventing agent for diseases induced by production, secretion or deposition of amyloid-β proteins.
[Solution to Problem]
[0009]
The present invention provides for examples as follows: [0010]
(1) A compound of the Formula (II), or a- pharmaceutically acceptable salt thereof : .
[Chemical Formula 1]
Figure imgf000006_0001
wherein
Ring A is aromatic carbocycle or aromatic heterocycle; -X- is -N ( R4 ) - , -0- or -S-;
R4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio, carboxy or substituted or unsubstituted amino;
-W- is a single bond, - (C (R16) (R17) ) r-, -C(=0)-,
-N (R15) -C (=0) -, -N (R15) -C (R16) (R17) -, or -0-C (R16 ) ( R17 ) - ;
r is 1 or 2;
R15 is hydrogen, or substituted or unsubstituted alkyl; each R16 is independently hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
each R17 is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl ;
either two R16 and/or two R17 on the different carbon atoms are optionally taken together to form a single bond when r is 2;
R11 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
R12 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio; R and R are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio;
a dashed line indicates the presence or absence of a bond; R2a and R2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; [Chemical Formula 2]
Figure imgf000008_0001
R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; Rza and Rz are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthid, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , a substituted or unsubstituted heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, or substituted or unsubstituted
heterocyclyloxycarbonyl ; or Rza and Rzb, taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle ;
R3 , R3b, R3c, R3d, R3e and R3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio,
substituted or unsubstituted alkynylthio, . substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbohyl , substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , substituted or unsubstituted carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
R3a and R3b, taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
R3c and R3d, taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle;
Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
Y1 and Y2 are each independently -C(R5) (R6)-, -C(R5)=, -N(R7)-, -N=, -S-, -SO-, -SO2- or -0-;
Y3 and Y4 are each independently -C (R5) (R6)-, -N(R7)-, -S-, -SO-, -SO2- or -0-; R5 and R6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted a kyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl , substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl , substituted or
unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or . unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl , substituted or unsubstituted carbocyclylsulfinyl , substituted or unsubstituted carbocyclylsulfonyl, a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
R7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl , substituted or unsubstituted .
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted
alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or
unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted .
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl, substituted or unsubstituted
carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl, or substituted or unsubstituted heterocyclylsulfonyl ;
n is 1, 2 or 3;
each R8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, . substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkenyl , substituted or
unsubstituted heterocyclylalkenyl, substituted or
unsubstituted carbocyclylalkynyl , or substituted or
unsubstituted heterocyclylalkynyl ,
provided that the following compounds are excluded: [Chemical Formula 3]
Figure imgf000015_0001
wherein Ph is phenyl.
[0011]
(2) A compound of the Formula (I), or a pharmaceutically acceptable salt thereof:
[Chemical Formula 4]
Figure imgf000016_0001
wherein
Ring A is aromatic carbocycle or aromatic heterocycle; -X- is -N ( R4 ) - , -0- or -S-;
R4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio,. carboxy, or substituted or unsubstituted amino;
a dashed line indicates the presence or absence of a bond;
R2a and R2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl; [Chemical Formula 5]
Figure imgf000016_0002
R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic . group, or a substituted or unsubstituted heterocyclic group;
Rza and Rzb are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, or substituted or unsubstituted
heterocyclyloxycarbonyl, or Rza and Rzb, taken together with the carbon atom to which, they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle;
R3 , R3b, R3c, R3d, R3e and R3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio,
substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl , substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, "substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , substituted or unsubstituted carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted.
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heter.ocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
R3 and R3b, taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle; R 0 and R , taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
. Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
Y1 and Y2 are each independently -C(R5) (R6)-, -C(R5)=, -N(R7)-, -N=, -S-, -SO-, -S02- or -0-;
Y3 and Y4 are each independently -C (R5) (R6) -, -N (R7) -, -S-, -SO-, -S02- or -0-;
R5 and R6 are each independently hydrogen,, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl , substituted or
unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted . carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl , substituted or unsubstituted
' carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
R7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl , substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted
alkylsulfi.nyl , substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or
unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl , substituted or unsubstituted
carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
n is 1, 2 or 3 ; and
each R8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkoxycarbonyl , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclylalkyl , substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkenyl , substituted or
unsubstituted heterocyclylalkenyl , substituted or
unsubstituted carbocyclylalkynyl , or substituted or
unsubstituted heterocyclylalkynyl ,
provided that the following compounds are excluded: [Chemical Formula 6]
Figure imgf000024_0001
wherein Ph is phenyl. [0012]
(3) The compound according to the above (1) or
pharmaceutically acceptable salt thereof, wherein
[Chemical Formula 7]
Figure imgf000024_0002
wherein
R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted alkylthio, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted amino, substituted or
unsubstituted carbamoyl, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; and
R3a and R3b, taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle.
[0013]
(4) The compound according to any one of the above (1) to (3), or a pharmaceutically acceptable salt thereof, wherein [Chemical Formula 8]
Figure imgf000025_0001
is [Chemical Formula 9]
Figure imgf000026_0001
R3b' R3a , and
[Chemical Formula 10]
Figure imgf000026_0002
[Chemical Formula
Figure imgf000026_0003
[0014]
(5). The compound according to any one of the above (1) to (3), or a pharmaceutically acceptable salt thereof, wherein [Chemical Formula 12]
Figure imgf000026_0004
s
[Chemical Formula 13]
Figure imgf000027_0001
[Chemical Formula 14]
Figure imgf000027_0002
i s
[Chemical Formula 15]
Figure imgf000027_0003
[0015]
(6) The compound according to any one of the above (1) to (5) , or a pharmaceutically acceptable salt thereof, wherein -X- is -N(R4)-, and R3a and R3b, taken together with the carbon atom to which they are attached, form carbonyl group.
[0016]
(7) The compound according to any one of the above (1) to (6) , or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are both hydrogen. [0017]
(8) The compound according to any one of the above (1) to
(7) , or a pharmaceutically acceptable salt thereof, wherein Ring A is benzene ring or pyridine ring.
[0018]
(9)■ . The compound according to any one of the above (1) to
(8) , or a pharmaceutically acceptable salt thereof, wherein one of R8 is a group of the formula:
[Chemical Formula 16]
Figure imgf000028_0001
wherein
Ring B is aromatic carbocycle or aromatic heterocycle; m is 0 , 1 or 2 ;
R9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl ; and
Ak is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, and each of the other R , when n is 2 or 3, is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclylalkyl , or substituted or unsubstituted non-aromatic heterocyclylalkyl .
[0019]
(10) The compound according to the above (9), or a pharmaceutically acceptable salt thereof, wherein Ring A is benzene ring or pyridine ring, and
[Chemical Formula 17]
Figure imgf000029_0001
wherein the ring-constituting atom at any one of α-, β-, γ- or δ-position is nitrogen atom when Ring A is pyridine ring.
[0020] (11) The compound according to the above (9) or (10), or a pharmaceutically acceptable salt thereof, wherein Ak is C2 alkylene, C2 alkenylene, or C2 alkynylene. [0021]
(12) The compound according to any one of the above (9) to (11), or a pharmaceutically acceptable salt thereof, wherein
Ring B is benzene ring, or 5- or 6-membered aromatic heterocycle .
[0022]
(13) A pharmaceutical composition comprising a compound according to any one of the above (1) to (12) or a
pharmaceutically acceptable salt thereof.
[0023]
(14) The pharmaceutical composition according to the above (13) having BACEl inhibitory activity. [0024]
(15) A method for treatment and/or prevention of disease caused by BACEl comprising administering the compound according to any one of the above ( 1 ) to (12) or a pharmaceutically acceptable salt thereof to a subject in need thereof. [0025]
(16) The compound according to any one of the above (1) to (12) or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of disease caused by BACEl.
[Advantageous Effects of Invention]
[0026].
The compounds of the invention are useful as an agent for treating or preventing disease induced by production, secretion or deposition of amyloid β protein such as Alzheimer's disease.
[Description of Embodiments]
[0027]
As used herein, the term "aromatic carbocycle" refers to monocyclic or condensed aromatic carbocycle, and examples include benzene ring, napthalene ring, anthracene ring, preferably benzene ring.
[0028]
As used herein, the term "aromatic heterocycle" refers to include tomonocyclic or condensed aromatic heterocycle, and examples include pyrrole ring, furan ring, thiophene ring, pyrazole ring, imidazole ring, isothiazole ring, isoxazol ring, oxazole ring, thiazole ring, pyrazine ring, pyrimidine ring, pyridazine ring, tetrazole ring, oxadiazole ring, thiadiazol ring, indolizine ring, isoindole ring, indole ring, indazole ring, purine ring, quinolizine ring, isoquinoline ring, quinoline ring, phthalazine ring, naphthyridine ring, quinolone ring, quinazoline ring, cinnoline ring, pteridin ring, carbazol ring, phenanthridine . ring, acridine ring, dibenzofuran ring, benzoxazolone ring, benzoxazinone ring, benzimidazole ring, benzisoxazole ring, benzoxazole ring, benzoxadiazole ring, benzisothiazole ring, benzothiazol ring, benzofuran ring, benzothiophene ring, Dibenzothiophene ring, benzodioxolan ring etc ., preferably pyridinium ring, furan ring, thiophene ring.
[0029]
As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.
[0030]
As used herein, the term "alkyl" includes C1-C15, preferably C1-C10, more, preferably C1-C6, and further, preferably C1-C3 straight or branched alkyl. 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 . The alkyl moiety in "alkoxy" , "halogeno alkyl" , "hydroxyalkyl " , "halogeno alkoxy", "hydroxy alkoxy", "alkoxycarbonyl" , "halogeno alkoxycarbonyl", "alkylamino" , "aminoalkyl" , "alkoxy alkoxy", "alkoxy alkenyloxy", "alkoxy alkynyl", "alkylcarbonyl" , "alkyl carbamoyl " , "hydroxyalkyl carbamoyl " , "alkoxyimino" , "alkylthio", "alkylsulfonyl" ,
"alkylsulfonylamino" , "alkylsulfonyl alkylamino",
"alkylsulfonylimino" , "alkylsulfinyl amino", "alkylsulfinyl alkylamino", "alkylsulfinylimino" , "alkyl sulfamoyl", "alkylsulfinyl" , "carbocyclylalkyl " , "carbocyclylalkoxy" , "carbocyclylalkoxycarbonyl" , "carbocyclylalkylamino" , v"carbocyclylalkyl carbamoyl", "heterocyclyalkyl",
"heterocyclylalkoxy" , "heterocyclylalkylamino" ,
"heterocyclylalkoxycarbonyl" , and "heterocyclyalkyl carbamoyl" is defined above for "alkyl".
[0032]
As used herein, the term "substituted or unsubstituted alkyl" refers to the above "alkyl" substituted or unsubstituted with one or more groups selected from the substituent group a.
[0033]
The substituent group a herein consists of halogens, hydroxy, alkoxy, halogeno alkyl , halogeno alkoxy, hydroxy alkoxy, alkoxy alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkyl carbamoyl, hydroxyalkyl carbamoyl, sulfamoyl, alkyl sulfamoyl, alkylsulfinyl , alkylsulfonylamino, alkylsulfonyl alkylamino, alkylsulfonylimino, alkylsulfinyl amino, alkylsulfinyl alkylamino, alkylsulfinylimino, cyano, nitro, carbocyclic groups and heterocyclic groups wherein said carbocyclic groups and heterocyclic groups are optionally substituted with one or more groups selected from the group consisting of halogens, alkyl, hydroxy and alkoxy.
[0034]
The substituent group in "substituted or unsubstituted alkoxy", "substituted or unsubstituted alkoxycarbonyl" , "substituted or unsubstituted alkylthio", "substituted or unsubstituted alkylsulfonyl" and "substituted or unsubstituted alkylsulfinyl " may be one or more groups selected from the. substituent group ex.
[0035]
As used herein, the term "halogeno alkyl" includes trifluoromethyl, fluoro methyl , trichloro methyl , and the like.
[0036]
As used herein, the term "halogeno alkoxy" includes trifuoro methoxy, fluoro methoxy, . trichloro methoxy, and the like. [0037]
As used herein, the term "alkenyl" refers to include C2-C15, preferably C2-C10, more, preferably C2-C6, and further, preferably C2-C4 straight or branched alkenyl having one or more double bonds at any position. Specific examples thereof include vinyl, allyl, propenyl, isopropenyl, butenyl, . isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, penta dienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl .
[0038]
The alkenyl moiety in "alkenyloxy" , "alkenyl oxycarbonyl" , "alkenyl- carbonyl", "alkoxy alkenyloxy", "alkenylthio" , "alkenylamino" , "alkenyl sulphonyl" and "alkenyl sulfinyl" is defined above for "alkenyl".
[0039]
As used herein, the term "alkynyl" refers to include C2-C10, preferably C2-C8, and more, preferably C3-C6 straight or branched alkynyl having one or more triple bonds at any position Specific examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl . These groups may further have a double bond at any position. [0040]
The alkynyl moiety in "alkoxy alkynyl", "alkynyloxy", "alkynyl oxycarbonyl " , "alkynyl carbonyl", "alkoxy alkynyloxy", "alkynylthio" , "alkynyl sulfinyl", "alkynyl sulphonyl" and "alkynyl amino" is defined above for "alkynyl".
[0041]
As used herein, the term "acyl" refers to include formyl, C1-C10 alkylcarbonyl, C2-C10 alkenyl carbonyl, C2-C10 alkynyl carbonyl, carbocyclylcarbonyl and heterocyclic carbonyl. Specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl,. hexanoyl, acryloyl, propioloyl, methacryloyl , crotonoyl, benzoyl, cyclohexanecarbonyl , pyridinium carbonyl, furan carbonyl , thiophene carbonyl, benzothiazol carbonyl, pyrazine carbonyl, piperidine carbonyl and thiomorpholino .
[0042]
The acyl moiety in "acyloxy", "acylamino" is defined above for "acyl".
[0043]
As used herein, the term "carbocyclic group" includes cycloalkyl, cycloalkenyl , aryl and fused non-aromatic carbocyclic groups . [0044] .
As used herein, the term "cycloalkyl" includes C3-C10, preferably C3-C8 , and more, preferably C4-C8 carbocyclic groups . Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl . [0045]
As used herein, the term "cycloalkenyl" includes those having one or more double bonds at any position in the ring of the cycloalkyl. Specific examples thereof include cyclopropenyl, cyclobutenyl , cyclopentenyl , cyclohexenyl , cycloheptynyl , cyclooctynyl and cyclohexadienyl .
[0046]
As used herein, the term "aryl" includes phenyl, naphthyl, anthryl and phenanthryl . Phenyl is particularly preferable among these.
[0047] .
As used herein, the term "fused non-aromatic carbocyclic group" includes non-aromatic groups formed by fusion of two or more cyclic groups selected from the above "cycloalkyl", "cycloalkenyl" and "aryl". Specific examples thereof include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
[0048]
The carbocyclic moiety in "non-aromatic carbocycle" is the same as that of the "cycloalkyl" , "cycloalkenyl" and "fused non-aromatic carbocyclic group". Specific examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane , cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
[0049]
The carbocycle moiety in "carbocycle", "carbocyclyloxy" , "carbocyclylalkyl" , "carbocyclylalkoxy" ,
"carbocyclylalkoxycarbonyl " , "carbocyclylthio" ,
"carbocyclylamino" , "carbocyclylalkylamino" ,
"carbocyclylcarbonyl" , "carbocyclylsulfamoyl" ,
"carbocyclylsulfinyl " , "carbocyclylsulphonyl " , "carbocyclylcarbamoyl" , "carbocyclylalkyl carbamoyl" and "carbocyclyloxycarbonyl" is defined above for "carbocyclic group" .
[0050]
As used herein, the term "heterocyclic group" includes heterocyclic groups having one or more hetero atoms arbitrarily selected from oxygen atom, sulphur atom and nitrogen atom in the ring. Specific examples thereof include .5- or 6-membered heteroaryls such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl , thiazolyl, and thiadiazolyl ;
non-aromatic heterocyclic groups such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathioranyl , 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 and tetrahydropyridazinyl ;
fused bicyclic heterocyclic groups such as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl , quinolyl, isoquinolyl, cinnolinyl, phthalazinyl , quinazolinyl , naphthyridinyl , quinoxalinyl , purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl , benzoxadiazolyl , benzoisothiazolyl , benzothiazolyl , benzothiadiazolyl , benzofuryl, isobenzofuryl , benzothienyl , benzotriazolyl, thienopyridyl , thienopyrrolyl , thienopyrazolyl , thienopyrazinyl , furopyrrolyl , thienothienyl , imidazopyrazyl , imidazopyrazolyl , imidazopyridyl , pyrazolopyridyl , pyrazolopyrazinyl , thiazolopyridyl , pyrazolopyrimidinyl , pyrazolotriazinyl , pyridazolo pyridyl, triazolo pyridyl,. imidazo thiazolyl, - pyrazino pyridazinyl, dihydro thiazolo pyrimidinyl, tetrahydro quinolyl, tetrahydro isoquinolyl, dihydro benzo furyl, dihydro benzoxazinyl , dihydro benzimidazolyl , tetrahydro benzthienyl , tetrahydro benzofuryl, benzo dioxolyl, benzodioxonyl , . chromanyl, chromenyl, octahydrochromenyl , dihydrobenzodioxinyl , dihydrobenzooxedinyl , dihydrobenzodioxepinyl and dihydrothienodioxinyl ; and fused tricyclic heterocyclic groups such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl , phenoxathiinyl , phenoxazinyl , dibenzofuryl , imidazoquinolyl and tetrahydrocarbazolyl . Preferable among these are 5- or 6-membered heteroaryls or non-aromatic heterocyclic groups.
[0051]
The heterocyclic moiety in "heterocycle", "heterocyclyloxy" , "heterocyclylthio" , "heterocyclyalkyl " , "heterocyclic carbonyl", "heterocyclylalkoxy" , "heterocyclylamino" , "heterocyclylsulfamoyl" , "heterocyclylsulfinyl" ,
"heterocyclylsulphonyl" , "heterocyclylcarbamoyl" , "heterocyclyloxycarbonyl " , "heterocyclylalkylamino" , "heterocyclylalkoxycarbonyl" and "heterocyclyalkyl carbamoyl" is defined above for "heterocyclic group".
[0052]
The heterocycle moiety in "non-aromatic heterocycle" is the same as that in the above "non-aromatic heterocyclic group" . Specific examples thereof include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidin, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine , pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydro pyridinium, tetrahydro pyridinium, tetrahydrofuran, tetrahydro pyran, dihydro thiazole, tetrahydro thiazole, tetrahydro isothiazole, dihydro oxazine, hexahydro azepine, tetrahydro diazepine, tetrahydro pyridazine.
[0053]
The bond (s) in the above "heterocyclic group" may be positioned in any ring.
[0054]
As used herein, the term "heteroaryl" includes aromatic heterocyclic groups which are included in the "heterocyclic group". [0055]
As used herein, the term "alkylene" includes C1-C10, preferably C1-C6, and more, preferably C1-C3 straight or branched divalent carbon chains. Specific examples thereof include methylene, dimethylene, .trimethylene, tetramethylene and methyl trimethylene.
[0056]
As used herein, the term "alkenylene" includes C2-C10, preferably C2-C6, and more, preferably C2-C4 straight or branched divalent carbon chains having a double bond at any position. Specific examples thereof include vinylene, propenylene, butenylene, butadienylene , methyl propenylene, pentenylene and hexenylene.
.[0057]
As used herein, the term "alkynylene" includes C2-C10, more, preferably C2-C6, and more, preferably C2-C4 straight or branched divalent carbon chains having a triple bond at any position and optionally further having a double bond. Specific examples thereof include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
[0058]
The substituent group for "substituted or unsubstituted acyl", "substituted or unsubstituted acyloxy", "substituted or unsubstituted amino", "substituted or unsubstituted alkynyl", "substituted or unsubstituted alkynyloxy", "substituted or unsubstituted alkynyl oxycarbonyl", "substituted or unsubstituted alkynyl sulfinyl", "substituted or unsubstituted alkynyl sulphonyl", "substituted or unsubstituted alkynylthio" , "substituted or unsubstituted alkenyl", "substituted or unsubstituted alkenyloxy", "substituted or unsubstituted alkenyl oxycarbonyl", "substituted or unsubstituted alkenyl sulfinyl", "substituted or unsubstituted alkenyl sulphonyl", "substituted or unsubstituted alkenylthio" , "substituted or unsubstituted carbamoyl", "substituted or unsubstituted sulfamoyl", "substituted or unsubstitutedthiocarbamoyl", "substituted or unsubstituted carbocycle", "substituted or unsubstituted carbocyclylalkyl " , "substituted or unsubstituted carbocyclylalkoxy" , "substituted or unsubstituted carbocyclyloxy" , "substituted or unsubstituted carbocyclyloxycarbonyl" , "substituted or unsubstituted ' carbocyclylsulfinyl " , "substituted or unsubstituted carbocyclylsulphonyl" , "substituted or unsubstituted carbocyclylthio" , "substituted or unsubstituted carbocyclic group", "substituted or unsubstituted carbocycle alkenyl", "substituted or unsubstituted carbocycle alkynyl", "substituted or unsubstituted alkynylene", "substituted or unsubstituted alkylene", "substituted or unsubstituted alkenylene", "substituted or unsubstituted non-aromatic carbocycle", "substituted or unsubstituted non-aromatic carbocyclic group", "substituted or unsubstituted non-aromatic carbocyclylalkyl " , "substituted or unsubstituted non-aromatic heterocycle" , . "substituted or unsubstituted non-aromatic heterocyclic group", "substituted or unsubstituted non-aromatic heterocyclyalkyl", "substituted or unsubstituted heterocycle", "substituted or unsubstituted heterocyclyalkyl", "substituted or unsubstituted heterocyclylalkoxy'V, "substituted or unsubstituted heterocyclyloxy" , "substituted or unsubstituted heterocyclyloxycarbonyl " , "substituted or unsubstituted heterocyclylsulfinyl" , "substituted or unsubstituted heterocyclylsulphonyl " , "substituted or unsubstituted heterocyclylthio" , "substituted or unsubstituted heterocyclic group", "substituted or unsubstituted heterocyclylalkenyl", "substituted or unsubstituted heterocyclylalkynyl" may be one or more groups selected from the substituent group a.
[0059]
The compound of formula (I) includes pharmaceutically acceptable salts thereof. Examples thereof include salts with alkaline metals (e.g. lithium, sodium and potassium) , alkaline earth metals (e.g. magnesium and calcium), transition metals (e.g., zinc), ammonium, organic bases and amino acids, and salts with inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and hydroiodic acid) and organic acids (e.g. acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and ethanesulfonic acid) . Specifically preferable are hydrochloric acid, phosphoric acid, tartaric acid and methanesulfonic acid. These salts may be formed by a conventional method.
[0060]
The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof may form a solvate (e.g., hydrate) and/or crystal polymorphism. Such solvates and crystal polymorphism is encompassed by the present invention. In the "solvate", any number of solvent (e.g., water) molecules may be conjugated with one molecule of the compound of formula (I) and (II) . The compound of formula (I) and (II) or a pharmaceutically acceptable salt thereof, by allowing it to stand in the atmosphere, may absorb moisture leading to attachment of adsorbed water or formation of a hydrate. Furthermore, The compound of formula (I) and (II) of a pharmaceutically acceptable salt thereof may form crystal polymorphism by recrystallization thereof.
[0061]
The compounds of formula (I) and (II) are not limited to a specific isomer, and include any possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers , optical isomers and rotamers ) and racemic mixtures . For example, compounds of formula (I) wherein R2a is hydrogen include the following tautomers .
[Chemical Formula 18]
Figure imgf000046_0001
[0062]
Furthermore, a compound of formula (I), wherein -X- is -N(H)-, and R3a and R3b are taken together with the carbon atom to which they are attached to form a carbonyl group, includes the following tautomers.
[Chemical Formula 19]
Figure imgf000047_0001
[0063]
The compound of formula (I) and (II) has an asymmetric carbon atom(s), and thus, includes the following optical isomers. [Chemical Formula 20]
Figure imgf000047_0002
[0064]
An optical isomer of the compound of formula (I) and (II) may be obtained by conventional technique known in the art, such as chiral chromatography, and formation of diastereomer salt using an optical active acid or base. [0065]
In addition, one or more hydrogen, carbon or other atoms of acompound of formula (I) and (II) may be replaced by an isotope of the hydrogen, carbon or other atoms. Compounds of formula (I) and (II) include all radiolabeled forms of compounds of formula (I) and (II) . Such "radiolabeled, " "radiolabeled form" , and the like of a compound of formula (I) and (II) , each of which is encompassed by the invention, is useful as a research and/or diagnostic to ol in metabolism pharmacokinetic studies and in binding assays, and also as a medicament.
[0066]
Examples of isotopes that can be incorporated into a compound of formula (I) and (II) of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, nC, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, 123I and 36C1. Radiolabeled compounds of the invention can be prepared by methods well known in the art. For example, tritiated compounds of. formula (I) or (II) can be prepared by introducing tritium into the particular compound of formula (I) or (II) , for example, by catalytic dehalogenation with tritium. This method may include reacting a suitably halogen-substituted precursor of a compound of formula (I) or (II) with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Isotopes in the Physical and Biomedical Sciences , Vol. 1, Labeled Compounds (Part A) Chapter 6 (1987) . 14C-labeled compounds can be prepared by employing starting materials having a. 14C carbon.
[0067]
Examples of particular embodiments of the invention wherein each variable is as described above are described below..
[0068]
In one embodiment, ring A in formula (I) or (II) includes benzene ring or pyridine ring.
[0069]
In one embodiment, -X- in formula (I) or (II) includes =N-, -NH-, -N (CH3) -, -0- or -S- . [0070]
In one embodiment, -W- in formula (I) or (II) includes a single bond, -CH2-, -C(=0)-, -N (H.) -C (=0) -, -N(H)-CH2-, or -0-CH2-.
[0071]
In, one embodiment, R2a and R2b in formula (I) or (II) include respectively hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl--, substituted or unsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl .
[0072]
In further embodiment, R2a and R2 may be both hydrogen. [0073]
In the embodiment, "Rza and Rzb are taken together with the carbon atom to which they are attached to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle" includes
[Chemical Formula 21]
Figure imgf000051_0001
, which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group a, or one or more substituent groups selected from Substituent Group a.
[0074]
In one embodiment, R3a and R3b in formula (I) or (II) can be taken together with the carbon atom to which they are attached to form a carbonyl group.
[0075] -
In the embodiment/- "R3a and R3b are taken together with the carbon atom to which they are attached to form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle" and "R3c and R3dare taken together with the carbon atom to which they are attached to form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle" includes
[Chemical Formula 22]
Figure imgf000052_0001
which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group a, or one or more substituent groups selected from Substituent Group a.
[0076]
In one embodiment of the invention, [Chemical Formula 23]
Figure imgf000053_0001
in formula (I) or (II) is
[Chemical Formula 24]
Figure imgf000053_0002
wherein each variable is as defined above
[0077]
In another embodiment
[Chemical Formula 25]
Figure imgf000053_0003
in formula (I) or (II)
[Chemical Formula 26]
Figure imgf000054_0001
wherein each variable is as defined above.
[0078]
In further embodiment,
[Chemical Formula 27]
Figure imgf000054_0002
in formula (I) or (II) is
[Chemical Formula 28]
Figure imgf000054_0003
wherein each variable is as defined above
[0079]
In one embodiment, examples of
[Chemical Formula 29]
Figure imgf000055_0001
in formula (I) or (II) include [Chemical Formula 30]
Figure imgf000056_0001
wherein R is as defined above.
[0080] In another embodiment, exampl [Chemical Formula 31]
Figure imgf000057_0001
in formula (I) or (II) include [Chemical Formula 32]
Figure imgf000057_0002
wherein R is as defined above. [0081]
In one embodiment of the invention, R8 can be represented by the formula:
[Chemical Formula 33]
Figure imgf000058_0001
wherein each variable is as defined above, and R9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring.
The phrase "R9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring" means [Chemical Formula 34]
Figure imgf000059_0001
wherein m1 is 0 or 1, and the other variables are as defined above.
[0082]
In another embodiment of the invention, R8 can be represented by the formula
[Chemical Formula 35]
Figure imgf000059_0002
wherein each variable is as defined above, and R9 is optionally attached to the nitrogen atom in the ring when the ring is pyrrole ring or pyrazole ring, and
[Chemical Formula 36]
Figure imgf000060_0001
may be methylene, ethylene, vinylene, ethynylene, propylene or propenylene. [0083]
In yet another embodiment of the invention, R8 can be halogens, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl .
[0084]
In further embodiment, R8 can be represented by the formula [Chemical Formula 37]
Figure imgf000060_0002
wherein
Ring B is aromatic carbocycle or aromatic heterocycle;
m is an integer of 0 to 2;
R9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C1-.C6 alkoxy or substituted or unsubstituted C1-C6 alkoxycarbonyl .
[0085]
In further embodiment, R8 can be represented by the formula [Chemical Formula 38]
Figure imgf000061_0001
wherein
ring B, m, R9 are as defined above, Ak is substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted C1-C3 alkenylene or substituted or unsubstituted C1-C3 alkynylene.
[0086]
In one embodiment, Ak can be G2 alkylene, C2 alkenylene or C2 alkynylene . [0087]
In one embodiment, ring B can be benzene ring, napthalene ring, or 5 or .6-membered aromatic heterocycle.
[0088] In one embodiment, R1 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
[0089]
In one embodiment, R1 is specifically, for example, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group.
[0090]
In one embodiment, R1 is more particularly, for example, C1-C3 unsubstituted alkyl.
[0091]
In one specific embodiment of the invention,
[Chemical Formula 39]
Figure imgf000063_0001
in formula (I), or (II) is represented by the formula [Chemical Formula 40]
Figure imgf000063_0002
and examples include
[Chemical Formula 41]
Figure imgf000064_0001
, which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group a, or one or more substituent groups selected from Substituent Group a.
[0092]
In another specific embodiment of the invention,
[Chemical Formula 42]
Figure imgf000065_0001
in formula (I) or (II) is represented by the formula [Chemical Formula 43]
Figure imgf000065_0002
and examples include
[Chemical Formula 44]
Figure imgf000066_0001
which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group a, or one or more substituent groups selected from Substituent Group a.
[0093]
In further embodiment of the invention,
[Chemical Formula 45]
Figure imgf000067_0001
in formula (I) or (II) is represented by the formula Chemical Formula 46]
Figure imgf000067_0002
and examples include
[Chemical Formula 47]
Figure imgf000068_0001
which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group a, or one or more substituent groups selected from Substituent Group a.
[0094]
In further embodiment of the invention,
[Chemical Formula 48]
Figure imgf000069_0001
in formula (I) or (II) is represented by the formula
[Chemical Formula 49]
Figure imgf000069_0002
and examples include
[Chemical Formula 50]
Figure imgf000069_0003
which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group CK, or one or more substituent groups selected from Substituent Group a.
[0095]
In further embodiment of the invention, [Chemical Formula 51]
Figure imgf000070_0001
in formula (I) or (II) is represented by the formula
[Chemical Formula 52]
Figure imgf000070_0002
and examples include
[Chemical Formula 53]
Figure imgf000071_0001
which are optionally substituted at any position with alkyl substituted or unsubstituted with one or more substituent groups selected from Substituent Group a, or one or more substituent groups selected from Substituent Group a.
[0096]
In one embodiment of the invention, when
[Chemical Formula 54]
Figure imgf000072_0001
in formula (I) or (II)
[Chemical Formula 55]
Figure imgf000072_0002
wherein Me is methyl,
[Chemical Formula 56]
Figure imgf000072_0003
is
[Chemical Formula 57]
Figure imgf000072_0004
[0097]
In another embodiment of the invention, when [Chemical Formula 58]
Figure imgf000073_0001
in" formula (I) or (II) is
[Chemical Formula 59]
Figure imgf000073_0002
wherein Me is methyl,
[Chemical Formula 60]
Figure imgf000073_0003
is
[Chemical Formula 61]
Figure imgf000073_0004
[0098]
Specific examples of the compounds of formula (I) or (II) includes those having any combination of the following particular embodiments 1) to 8) : ) in formula (I) or (II), [Chemical Formula 62]
Figure imgf000074_0001
herein Me is methyl; ) in formula (I) or (II), [Chemical Formula 64]
Figure imgf000074_0002
s
[Chemical Formula
Figure imgf000075_0001
4) each R in the above 3) . is independently [Chemical Formula 68]
y , v, v, >■ or y
r
5) the group
[Chemical Formula 69]
Figure imgf000076_0001
in the above 3) is
[Chemical Formula 70]
Figure imgf000077_0001
) each R9 in the above 5) is independently [Chemical Formula 71]
Figure imgf000078_0001
and
7 ) m in the above 5) is 0, 1 or 2.
[0099]
The present compound of the formula (I) or (II) can be prepared by the following method . In the following steps , any substituent group that interferes with the reaction, e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy, may be protected by the method well known to one of ordinary skill in the art such as those described in Protective Groups in organic Synthesis, and Theodora W Greene (John Wiley & Sons) in advance, and the protective group may be removed at a desirable stage. [0100]
The following abbreviations have the following meanings.
Me: methyl
Et: ethyl
n-Pr: normal propyl
. i-Pr: isopropyl
t-Bu: tert- butyl
Ac: acetyl
. THF: tetrahydrofuran
RT: retention time in LC/MS
In the chemical formula, wedge-shaped solid or dashed lines are used to denote absolute configuration, and bold solid or dashed lines are used to denote relative configuration.
[0101]
1) Preparation of amino pyrimidone la
1-1) Preparation of cyclopropane-containing carboxylic acid 6 [Chemical Formula. 72]
Figure imgf000080_0001
Figure imgf000080_0002
wherein P is a protecting group of hydroxy group and the other variables are as defined above. [0102]
Step 1
Lactone 3 can be prepared according to the procedure as described in Journal of Organic Chemistry (J. Org. Chem. ) 1996, 61, 915-923, using epichlorohydrin 1 as a starting material.
[0103]
Step 2
To compound 3 in a solvent such as methanol, ethanol, water, and a mixture thereof, is added a base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide) , and the mixture is reacted at a temperature from-10 to 50°C, preferably 0 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs . An acid such as hydrochloric acid is added to neutralize, and the solvent is removed. An alkylsilyl halide is added to react at a temperature from-10 to 50°C, preferably 0 to 2°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs. To the residue is added a base (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide) to react at a temperature from-10 to 50 °C, preferably 0 to 25 °C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, in a solvent (e.g., methanol, ethanol, water) or a mixture thereof. The solution is neutralized with an acid such as hydrochloric acid to obtain compound 4.
[0104]
Step 3
Compound 5 can be prepared by isomerizing compound 4 according to the procedure as described in Journal of Organic Chemistry (J. Org. Chem.) 2003, 68, 9255-9262. [0105]
Step 4
Compound 6 can be prepared by oxidation of compound 5 using sodium periodate and ruthenium chloride, using potassium permaganate under alkaline condition, by Jones oxidation, under condition using PCC, PDC, ruthenium tetroxide and TEMPO, or using sodium hypochlorite, sodium chlorite and TEMPO. An optically active compound 6 can be prepared using an optically active epichlorohydrin 1.
[0106]
1-2) Preparation of cyclopropane-containing carboxylic acid 10a, 10b
[Chemical Formula 73]
Figure imgf000082_0001
10a (1 R, -2R)
10b (1 S. 2S)
wherein each variable is as defined above,
[0107]
Step 1
To styrene compound 8 in dichloromethane solvent is added copper (I) trifluoromethane sulfonate toluene complex and
2, 2' -isopropylidene bis- [ ( 4S ) -4 - t-butyl-2 - oxazoline] . The mixture is reacted at -10 to 50°C, preferably 0 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs . Then, t-butyl diazoacetate 7 is added, and the mixture is reacted at -10 to 50°C, preferably 0 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound 9a (1R,2R). Alternatively, 9b (1S,2S) can be obtained by using 2 , 2 ' -isopropylidene bis- [ (4R) -4 - t-butyl-2 - oxazoline] . [0108]
Step 2
To compound 9a (1R,2R) or 9b (1S,2S) in a solvent such as dichloromethane, is added an acid such as trifluoroacetic acid, and the mixture is reacted at -10 to 50°C, preferably 0 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs. Then, the mixture is neutralized with a base such as sodium hydroxide to obtain compound 10a (1R,2R) or 10b (1S,2S).
[0109]
1-4) Formation of amino pyrimidone ring
[Chemical Formula 74]
Figure imgf000083_0001
wherein each variable is as defined above. [0110]
Step 1
Carboxylic acid 6, 10a (1R,2R) or 10b (1S,2S) obtained above can be reacted with CDI to convert to an active ester. Then, salt of malonic acid halfester, magnesium chloride and triethylamine are added, and the mixture is reacted at 0 to 100°C, preferably 25 to 80°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, to obtain compound 11.
[0111] ■
Step 2
According to the procedure as described in Journal of Organic Chemistry (J. Org. Chem. ) 2007, 50, 5912-5925, compound la can be prepared by treating compound 11 with guanidine to form amino pyrimidone ring.
[0112]
In all steps described above, the order of steps to be implemented may be appropriately changed, and each intermediate may be isolated and used in the next step.
[0113]
In another embodiment, compounds of the present invention may be prepared by forming aminooxazine ring or aminothiazine ring according to the procedure described below.
[0114]
2) Preparation of amino oxazine
[Chemical Formula 75]
Figure imgf000085_0001
wherein each variable is as defined above.
[0115]
Step 1
An ester compound such as ethyl propionate is reacted in the presence of a. base, such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof to obtain an enolate. A titanium agent such as chlorotitanium triisopropoxide, and compound a, which can be prepared by known method, are added to the enolate, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound b.
[0116]
Step 2
Compound b is reacted with a Grignard reagent commercially available or prepared by known method such as methylmagnesium bromide, or an reducing agent such as borane,. sodium borohydride, and lithium aluminum hydride, in a solvent (e.g., dioxane, THF, ether, toluene) or a mixed solvent thereof at -80 to 80°G, preferably -20 to 30°C, for 0.5 to 48 hrs, preferably 1 to 12 hrs, to obtain compound c.
[0117]
Step 3
Compound c is reacted in a solvent (e.g., dioxane, methanol, dichl-o omethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound d. [0118] Ste 4
Compound d is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) , in a solvent (e . g . , · dioxane , THF, toluene, acetone) or a mixed solvent thereof at -30 to 50 °C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound e.
[0119]
Step 5
Compound e is reacted with an alkylating agent (e.g., methyl iodide, diethyl sulfate, benzyl bromide) in a solvent (e.g., methanol, ethanol, dimethylformamide, THF) , in the presence or absence of an base (e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide), at 0 to 200°C, preferably 40 to 150°C for 1 to 48 hrs, preferably 0.5 to 24 hrs, to obtain compound lb.
[0120]
3) Preparation of amino oxazine Ic
[Chemical Formula 76]
Figure imgf000088_0001
wherein each variable is as defined above,
[0121]
Step 1
Compound a, which can be prepared by known method, is added to a Grignard reagent such as allylmagnesium bromide, in a solvent (e.g., toluene, dichloromethane , THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound f .
[0122]
Step 2 Compound f is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g. , hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound g.
[0123]
Step 3
Compound g is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate ) , in a solvent (e.g., dichloromethane, dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30to50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound h.
[0124]
Step 4
Compound h is reacted with a hologenium ion source (e.g. , iodine, bromine, N-bromo succinimide (NBS)), in a solvent such as dichloromethane, at -20 to 40°C, preferably 0 to 20°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by the reaction with a base (e.g., pyrrolidine, piperidine, piperazine, morpholine) at 20 to 100°C, preferably 40 to 80°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Ic. [0125]
4) Preparation of amino oxazine
[Chemical Formula 77]
Figure imgf000090_0001
wherein each variable is as defined above.
[0126]
Step 1
A carbonyl compound such as diethyl ketone is reacted in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof to obtain an enolate. A titanium agent such as chlorotitanium triisopropoxide, and compound a, which. can be prepared by known method, are added to the enolate, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound i.
[0127]
Step 2
Compound i is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound j · .
[0128]
Step 3
Compound j is reacted with an isocyanate having . a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate), in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound k.
[0129]
Step 4
Compound k is reacted with an acid such as cone, sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound [0130]
Compounds le to Ig wherein
[Chemical Formula 78]
Figure imgf000092_0001
can be prepared according to the following scheme. [0131]
5) Preparation of compound le
[Chemical Formula 79]
Figure imgf000093_0001
wherein Ya is Y1 or Y3, Yb is Y2 or Y4, and a dashed line indicates the presence or absence of a bond, and the other variables are as defined above.
[0132]
Step 1
Compound a, which can be prepared by known method, is reacted with an enolate obtained by the reaction with a desired carbonyl compound such as cyclopentanone, in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound 1.
[0133]
Step 2
Compound 1 is reacted in a solvent (e.g., dioxane, methanol, dichloromethane) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound m.
[0134]
Step 3
Compound m is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound le.
[0135]
Compound le wherein a dashed line indicates the absence of a bond can be prepared from compound le wherein either dashed line indicates the presence of a bond, using conventional method such as a method of hydrogenation .
[0136]
6) Preparation of compound If [Chemical Formula 80]
Figure imgf000095_0001
wherein each variable is as defined above. [0137]
Step 1
Compound a, which can be prepared by known method, is reacted with an enolate which was obtained by the reaction with a desired carbonyl compound such as cyclopentanone, in the presence of a base such as lithium diisopropylamide, in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof at -80 to 30 °C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound n.
[0138] Step 2
Compound n is reacted with a Grignard reagent commercially available or prepared by known method (e.g., methylmagnesium bromide) in a solvent (e.g., dioxane, THF, ether, toluene) or a mixed solvent thereof, at -80 to 80°C, preferably -20 to 30°C, for 0.5 to 48 hrs, preferably 1 to 12 hrs, followed by the reaction in the presence of an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid) , at 0 to 80°C, preferably 0 to 30°C, for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound o.
[0139]
Step 3
Compound o. is reacted with an isocyanate having a protecting group as commercially available or prepared by known method (e . g ., benzoyl isocyanate) in a solvent ( e . g ., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound p.
[0140]
Step 4 To compound p in a solvent (e . g . , dichloromethane, THF, toluene) are added oxalyl chloride or thionyl chloride and a catalytic quantity of N, N-dimethylformamide, or is added a chlorinating agent such as l-chloro-2-trimethylpropenylamine, and the mixture is reacted at 0 to 100°C, preferably 10 to 50°C, for 0.5 to 72 hrs, preferably 0.5 to 6 hrs, to obtain compound If.
[0141]
7) Preparation of compound Ig
[Chemical Formula 81]
Figure imgf000097_0001
wherein each variable is as defined above.
[0142] Step 1
Compound a is added to a Grignard reagent (e.g., phenylmagnesium bromide having optionally protected hydroxy group at ortho position) or a lithium agent (e.g., pyridyl lithium having optionally protected hydroxy group at ortho position) in a solvent (e.g., toluene, diethylether, THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, and the protecting group is removed by known method to obtain compound q. .
[0143]
Step 2
Compound q is reacted in a solvent (e.g., dioxane, methanol, dichloromethane ) or a mixed solvent thereof, in the presence of an acid (e.g., hydrochloric acid, hydrobromic.acid, sulfuric acid, trifluoroacetic acid) at 0 to 80°C, preferably 0 to 30°C for 0.5 to 48 hrs, preferably 1 to 24 hrs, to obtain compound r .
[0144]
Step 3
Compound r is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, to obtain compound s. [0145]
Step 4 .
Compound s is reacted with an alkylating agent (e.g., methyl iodide, diethyl sulfate, benzyl bromide) in a solvent (e.g., methanol, ethanol, dimethylformamide, THF) , in the presence or absence of an base (e.g., diisopropylethylamine, triethylamine , pyridine, sodium hydroxide) at 0. to 200°C, preferably 40 to 150°C, for 1 to 48 hrs, preferably 0.5 to 24 hrs, to obtain compound Ig. [0146]
In another embodiment, compounds of the invention can be prepared by forming amino thiazine ring according to the procedure as described in Journal of Hetero cyclic Chemistry, 14, 717-723 (1977) .
[0147]
8) Preparation of amino thiazine Ih
[Chemical Formula 82]
Figure imgf000100_0001
wherein each variable is as defined above.
To compound e in a solvent (e.g. , 'dichloromethane, THF, toluene) are added oxalyl chloride or thionyl chloride and a catalytic quantity of N, -dimethylformamide, or is. added a chlorinating agent such as l-chloro-2-trimethylpropenylamine , and the mixture is reacted at -20 to 100°C, preferably 10 to 50°C, for 0.5 to 72 hrs, preferably 1 to 72 hrs, to obtain compound Ih.
[0148]
9) Preparation of amino thiazine Ii
[Chemical Formula 83]
Figure imgf000100_0002
wherein each variable is as defined above. [0149]
Step 1
Compound a, which can be prepared by known method, is added to an enolate obtained by the reaction with corresponding alkyl ketone (e.g., 3-methyl -2-butanone) , in the presence of a base, such as lithium diisopropylamide , potassium hexamethyldisilazide, ' in a solvent (e.g., toluene, dichloromethane, THF) or a mixed solvent thereof, and the mixture is reacted at -80 to 30°C, preferably -80 to 0°C, for 0.1 to 24 hrs, preferably 0.1 to 12 hrs, to obtain compound i.
[0150]
Step 2
Compound i is reacted with an acid such as hydrochloric acid, hydrobromic acid, and trifluoroacetic acid, at 0 to 60°C, preferably 0 to 30°C, for 0.1 to 24 hrs, preferably 0.5 to 12 hrs, to obtain compound ii. [0151]
Step 3
Compound ii is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof at -30 to 70°C, preferably -20 to 50°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by removing the solvent and addition of an acid such as cone, sulfuric acid and cone, nitric acid to react at -30 to 70°C, preferably -20 to 50°C, for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, to obtain compound Ii.
[0152]
10) Preparation of amino dihydro thiazine
[Chemical Formula 84]
Figure imgf000102_0001
wherein each variable is as defined above.
[0153]
Compound j is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 70°C, preferably -20 to 50°C for 0.1 to 12 hrs, preferably 0.1 to 6 hrs, followed by removing the solvent and addition of an acid such as cone, sulfuric acid and cone, nitric acid to react at -30 to 70°C, preferably -20 to 50°C, for 1 to 12 hrs, preferably 1 to 6 hrs, to obtain compound Ij.. [0154]
11) Preparation of amino thiazine
Chemical Formula 85]
Figure imgf000103_0001
wherein each variable is as defined above. [0155]
Compound m is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably-10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone . sulfuric acid and cone, nitric acid to react at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Ik.
[0156]
Compound Ik wherein a dashed line indicates the absence of a bond can be prepared from compound Ik wherein either dashed line indicates the presence of a bond, using a conventional method such as a method of hydrogenation . [0157]
12) Preparation of amino thiazinell
[Chemical Formula 86]
Figure imgf000104_0001
wherein each variable is as defined above.
[0158]
Step 1
Compound o is reacted with an isothiocyanate having a protecting group as commercially available or prepared by known method (e.g., benzoyl isothiocyanate ) in a solvent (e.g., dioxane, THF, toluene, acetone) or a mixed solvent thereof, at -30 to 50°C, preferably -10 to 25°C, for 0.1 to 12 hrs, preferably 0.1 to 3 hrs, followed by the reaction with an acid such as cone, sulfuric acid and cone . nitric acid, at 0 to 100°C, preferably 0 to 60°C, for 0.5 to 24 hrs, preferably 1 to 12 hrs, to obtain compound p .
[0159]
Step 2
To compound iii in a solvent (e.g., dichloromethane, THF, toluene) are added oxalyl chloride or thionyl chloride and a catalytic quantity of N, N-dimethylformamide, or is added a chlorinating agent such as l-chloro-2-trimethylpropenylamine, and the mixture is reacted at 0 to 100°C, preferably 10 to 50°C, for 0.5 to 72 hrs, preferably 0.5 to 6 hrs, to obtain compound II. .
[0160]
Compound II wherein a dashed line indicates the absence of a bond can be prepared from compound II wherein either dashed line indicates the presence of a bond, using a conventional method such as a method of hydrogenation .
[0161]
13) Converting substituent groups
Compounds having various substituent groups on the above compounds la to II may be prepared according to the methods as described above or known in the art (e.g., O2007/049532, WO2008/133273, WO2008/133274 ) . [0162]
Preparation of acylamino derivative
Chemical Formula 87]
Figure imgf000106_0001
wherein R is a group such as optionally substituted alkyl, optionally substituted hydrocarbon ring, and optionally substituted heterocyclic group, and the other variables are as defined above. Compound I wherein R is hydrogen is reacted with an acylating agent having a substituent group corresponding to the desired compound, such as benzoyl chloride, 2-furoyl chloride, and acetic anhydride, in the presence or absence of a solvent such as THF and dichloromethane, in the presence or absence of a base such as pyridine and triethylamine, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs reactions, or the above compound I is reacted with a carboxylic acid having a substituent group corresponding to the desired compound, such as amino acid, and -glycol acid, in a solvent such . as dimethylformamide, THF, and dichloromethane, in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, and carbonyl diimidazole, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, to obtain compound Im.
[0163]
Preparation of acylamino derivative
[Chemical Formula 88]
Figure imgf000107_0001
wherein NHRU is optionally substituted amino, NR20COR ,2'1L is optionally substituted acylamino, optionally substituted ureido, or carboxy amino having a substitutent group on oxygen atom, and the other variables are as defined above.
Compound I wherein Ring A is optionally substituted with amino is reacted with a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoylchloride,. 2-furoyl chloride, acetic anhydride, benzyl chlorocarbonate, di-tert-butyl dicarbonate, phenyl isocyanate, etc.) in the presence or absence of a solvent such as THF and dichloromethane, in the presence or absence of a base such as pyridine, and triethylamine, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, or the above compound I is reacted with a carboxylic acid having a substituent group corresponding to the desired compound, such as benzoic acid, and 2-pyridinium carboxylic acid, in a solvent such as dimethylformamide, THF, and dichloromethane, in the presence of dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyl diimidazole , and dicyclohexylcarbodiimide-N-hydroxybenztriazole, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, to obtain compound In.
[0164]
Preparation of alkylamino derivative Io
[Chemical . Formula 89]
Figure imgf000108_0001
wherein NHR is optionally substituted amino, Rz 22 is alkyl.
Compound I wherein Ring A is substituted with amino is reacted with an aldehydes such as benzaldehyde , and pyridin-2-carboaldehyde, having a substituent group corresponding to the desired compound and a reducing agent such as sodium cyanotrihydroborate, and sodium triacetoxyborohydride , in a solvent such as dichloromethane and THF, in the presence or absence of an acid such as acetic acid, at -80 to 100°C, preferably 0 to 40°C, for 0.5 to 150 hrs, preferably 1 to 24 hrs, to obtain compound Io.
[0165]
Preparation of alkoxy derivative Ip
Chemical Formula 90]
Figure imgf000109_0001
I
wherein R is a group, such as optionally substituted alkyl, optionally substituted carbocyclic group, and optionally substituted heterocyclic group, and the other variables are as defined above.
Compound I wherein ring A is. substituted with hydroxy group is reacted with an alkylating agent such as benzyl chloride, and methyl iodide, having a substituent group corresponding to the desired compound, in a solvent such as dimethylformamide, and THF, in the presence of a base such as potassium carbonate, sodium hydroxide, and sodium hydride, at -80 to 100°C, preferably 0 to 40°C, for 0.5 to 150 hrs, preferably 1 to 24 hrs, or compound I is reacted with an alcohol such as 2-amino ethanol in a solvent such as dimethylformamide, THF, in the presence of a Mitsunobu reagent such as triphenylphosphine-diethyl azodicarboxylate, at -80 to 100 °C, preferably 0 to 40°C, for 0.5 to 72 hrs, preferably 1 to 24 hrs, to obtain compound Ip.
[0166]
Introduction of substituent group by palladium coupling
[Chemical Formula 91]
Figure imgf000110_0001
wherein G is a group such as optionally substituted alkenyl, optionally substituted alkynyl, . optionally substituted alkoxycarbonyl, optionally substituted carbocyclic group, and optionally substituted heterocyclic group, and the other variables are as defined above.
Compound I wherein ring A is substituted with halogen is reacted with a compound corresponding to substituent group in the desired compound (styrene, propargyl alcohols, aryl boronic acid, carbon monoxide, etc.) in a solvent such as THF, dimethylformamide, 1 , 2-dimethoxyethane, and methanol, in the presence of a base such as triethylamine, sodium carbonate, and a palladium catalyst, such as palladium acetate, palladium chloride, and a ligand such as triphenylphosphine, under microwave irradiation or not, at -80 to 150°C, preferably 0 to 100°C, for 0.5 to 72 hrs, preferably 1 to 24 hrs, to obtain compound Ig.
[0167]
Preparation of oxime derivative Ir
[Chemical Formula 92]
Figure imgf000111_0001
I Ir
wherein R24 is hydrogen or optionally substituted alkyl, R25 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted carbocyclic group or optionally substituted heterocyclic group, and the other variables are as defined above. .
Compound I wherein ring A is substituted with acyl is reacted with a hydroxylamine having a substituent group corresponding to the desired compound (hydroxylamine, methoxyl amine, 0- benzyl hydroxylamine, etc. ) or a salt thereof in a solvent such as methanol, and ethanol, in the presence or absence of an agent such as potassium acetate at -80 to 100°C, preferably 0 to 40°C, for 0.5 to 150 hrs, preferably 1 to 72 hrs, to obtain compound Ir. [0168]
Introduction of substituent group by coupling reaction
[Chemical Formula 93]
Figure imgf000112_0001
compound.
Compound I is reacted with a reagent such as acid chlorides, acid anhydrides, chlorocarbonate esters, and isocyanates, having a substituent group corresponding to the desired compound (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chlorocarbonate, di-tert-butyl dicarbonate, phenyl isocyanate, etc. ) in the presence or absence of a solvent such as THF, dichloromethane, and dimethylformamide, in the presence or absence of a base such as pyridine, and triethylamine, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, or the above compound I is reacted with a carboxylic acid such as benzoic acid, and 2-pyridinium carboxylic acid, having a substituent group corresponding to the desired compound, in a solvent such as dimethylformamide , THF, dichloromethane, and methanol, in the presence of a hehydration-condensationagent such as dicyclohexylcarbodiimide, carbonyl diimidazole, dicyclohexylcarbodiimide-N-hydroxy benztriazole, . and 4- (4, 6-dimethoxy-l , 3, 5-triazine-2-yl ) -4-methylmorpholinium chloride,
2- ( 7-Aza-lH-benzotriazole-l-yl ) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate, at -80 to 100°C, preferably -20 to 40°C, for 0.1 to 24 hrs, preferably 1 to 12 hrs, to obtain amide compound .
In case where R has a substituent that would interfere in the reaction, the substituent group may be protected in advance for coupling reaction, and the protective group may be removed at a desirable step.
Then, the compound is reacted at -30 to 100 °C, preferably 0 to 90°G for 0.5 to 12 hrs in a solvent such as methanol, ethanol, ether, THF, 1,4-dioxane, dichloromethane , ethyl acetate, containing hydrogen chloride, trifluoroacetic acid etc., or trifluoroacetic acid in the absence of a solvent, or according to the method as described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) to obtain compound Is.
[0169]
14) Preparation of cyclopropane intermediate 1-1)
[Chemical Formula 94]
Figure imgf000114_0001
wherein LI is methanesulfonyl or toluenesulfonyl , etc. , and the other variables are as defined above.
Step 1
Each optically active form of compound 12, which can be prepared according to the method described in J. Med. Chem. , 2006, 49, 5587-5596, is reacted with compound 13 in a solvent such as ether, and THF, at -80 to 25°C, preferably -30 to 25°C, for 0.5 to 5 hrs, to obtain compound 14.
Step 2
Compound 14 is reacted with methanesulfonyl halide or toluenesulfonyl halide, etc. in a solvent such as THF, and dichloromethane, at -30 to 50°C, preferably 0 to 25°C, for 0.5 to 5 hrs, to obtain compound 15. Step 3
Compound 15 is reacted with sodium borohydride, lithium triethylborohydride or lithium aluminum hydride, etc. in a solvent such as ether, and THF, at -30 to 50°C, preferably 0 to 25°C, for 0.5 to 5 hrs, to obtain compound 16.
[0170]
1-2)
Figure imgf000115_0001
wherein each variable is as defined above. Step 1
Compound 12 is reacted with compound 17 in a solvent such as THF, and toluene, at -80 to 150°C, preferably -30 to 100°C, for 0.5 to 24 hrs, to obtain compound 18.
Step 2
Compound 18 is reacted with hydrogen gas in a solvent such as methanol, ethanol, ether, THF, ethyl acetate, acetic acid, and a mixed solvent thereof, in the presence of a metal catalyst at 0 to reflux temperature, preferably 0 to 40°C, for 0.5 to 72 hrs, preferably 1 to 12 hrs,. to obtain compound 19.
[0171]
1-3)
[Chemical Formula
Figure imgf000116_0001
20 21
wherein each variable is as defined above.
Compound 12 is reacted with compound 20 in a solvent such as dichloromethane, in the presence of a reducing agent such as sodium cyanoborohydride , sodium triacetoxyborohydride, at -30 to 100°C, preferably 0 to 25°C, for 0.5 to 24 hrs to obtain compound 21.
[0172]
1-4)
[Chemical Formula 97]
Figure imgf000117_0001
25
wherein each variable is as defined above.
Cyclopropane intermediate 24 and 25 are prepared according to the method as described in J. Med. Chem. , 2006, 49, 5587-5596.
[0173]
1-5)
[Chemical Formula 98]
Figure imgf000117_0002
wherein each variable is as defined above.
Step 1
Compound 12 is reacted in a solvent such as THF, in the presence of a reducing agent such as lithium borohydride, at -30 to 50°C, preferably 0 to 25°C, for 0.5 to 24 hrs to obtain compound 26. Step 2
Compound 26 is reacted with compound 27 in a solvent such as THF, DMF, and D SO, in the presence of sodium hydride, potassium carbonate, cesium carbonate, etc. at 0 to 120°C, preferably 0 to 50 °C, for 0.5 to 24 hrs to obtain compound 28.
[0174]
Preparation of substituted cyclopropane intermediate
1-6)
[Chemical Formula 99]
Figure imgf000118_0001
wherein PI is a carboxy protecting group and the other variables are as defined above.
Compound 29, which is commercially available or can be prepared by standard procedures, is subjected to cyclopropanation according to the method as described in WO2001/027107 or WO1999/033460 to obtain compound 30.
[0175]
1-7) Using the compound 16, 19, 21, 24, 25, 28 or 30 as obtained in the above steps in 14) 1-1) to 1-6) , a compound of formula (II) corresponding to the above compound la to Is can be prepared according to the procedures described above in 1) to 13) .
[0176]
Preparation of optically active compound
An optically active from of compound (I) or (II) can be prepared by using an optical activate starting material, obtaining an optical activate intermediate by asymmetric synthesis in appropriate step, or optically resoluting. an intermediate of each racemate and a final product in an appropriate step. Procedures of the optical resolution include a method of separating an optical isomer using an optically active column; kinetic optical resolution utilizing an enzymatic reaction and the like; crystallization resolution of a diastereomer by salt formation using a chiral acid or a chiral base; preferential crystallization method and the like. [0177]
Alternatively, for example, in the preparation in 1) 1-1), compound 4 obtained in Step 2 can be subjected to cyclization reaction to form amino pyrimidone ring, followed by isomerization reaction by Barton decarboxylation to obtain cis-form stereoselectively . [0178]
The compound of the invention is useful in disease induced by the production/ secretion or deposition of amyloid β protein, and are effective in treatment and/or . prevention and symptom improvement of diseases such as dementia of the Alzheimer' s type (e.g. , Alzheimer ' s disease, senile dementia of Alzheimer type ) , Down's syndrome, memory impairment, prion disease (e.g., Creutzfeldt-Jakob disease) , mild cognitive impairment (MCI), Dutch type of hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other type of degenerative dementia, mixed dementia with Alzheimer's and vascular type, 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.
[0179]
As used herein, "treating Alzheimer's disease" includes prevention of aggravation of MCI and prevention of familial Alzheimer's disease. As used herein, "a pharmaceutical composition for treating Alzheimer's disease" includes a pharmaceutical composition for prevention of aggravation of MCI and prevention of familial Alzheimer's disease. [0180]
Since the present compound has high inhibitory activity on BACEl, and/or has high selectivity on other enzymes, it can be a medicament with reduced side effect. Further, since the compound has high effect of reducing amyloid β production in a cell system, particularly, has high effect of reducing amyloid β production in .brain, it can be an excellent medicament. In addition, by converting the compound into aft optically active compound having suitable stereochemistry, the compound can be a medicament having a wider safety margin on the side effect. In addition, the present compound also has advantages that metabolism stability is high, solubility is high, oral absorbability is high, good bioavailability is exhibited, clearance is good, brain transference is high, a half-life is long, non-protein binding rate is high, hERGchannel inhibition is low, CYP inhibition is low, CYP MBI (mechanism-based inhibition) is low, and/or an Ames test is negative. [0181]
The compound of the invention can be administrated in combination with other pharmaceutical agents such as other therapeutic drugs for . Alzheimer's disease, e.g., acetylcholinesterase and the like. For example, the compound of the invention can be administered in combination with anti-dementia agents such as Donepezil Hydrochloride, Tacrine, Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinpocetine. [0182]-
When the compound of the invention is administered to a human, it can be administered orally as powders, granules, tablets, capsules, pills, solutions, or the like, or parenterally as injectables, suppositories, transdermal absorbable agents, inhalations, or the like. In addition, the compound of the invention can be formulated into pharmaceutical, preparations by adding pharmaceutical additives such as excipients, binders, wetting agents , disintegrating agents , lubricants and the like, which are suitable for mulations and an effective amount of the compound.
[0183]
The dose is varied depending on state of disease, an administration route, and an age and a weight of a patient, and is usually 0.1 pg to 1 g/day, preferably 0.01 to 200 mg/day when orally administered to an adult, and is usually 1 ]iq to 10 g/day, preferably 0.1 to 2 g/day when parenterally administered.
[Examples]
[0184] Following examples and test examples illustrate the present invention in more detail, but the present invention is not limited by these examples.
[0185]
1H-NMR . was measured in deuterium chloroform (CDC13) using tetramethylsilane as an internal standard. Alternatively, the measurement was conducted in deuterium dimethylsulphoxide (DMSO-de) . δ values were shown as ppm. Coupling constant (J) was shown as Hz. In the data, s means singlet, d means doublet, t means triplet, m means multiplet, br means broad-line and brs means broad-singlet.
[0186] .
NMR data as shown in each Example were obtained at 500MHz or 600MHzusing DMSO-d6 or CDC13.
RT in the tables means retention time (minute) in LC/MS: liguid chromatography / Mass spectroscopy measured under the following condition.
Column: intakt Unison U-18 (3pm, i.d. 4.6 x 75mm)
Flow rate: 2 mL/min
UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing agueous solution, [B] is 0.1% formic acid-containing acetonitrile solution
Gradient: Linear gradient of 10% to 95% solvent [B] for 6 minutes was performed, and 95% solvent [B] was maintained for 2 minutes.
[0187]
Example 1: compound 1-1
[Chemical Formula 100]
Figure imgf000124_0001
[0188]
Step 1
To a suspension of sodium amide (7.54g, 193mmol) in benzene (40ml) was added dropwise a solution of phenyl acetonitrile (10. Og, 85.1mmol) in benzene (20ml) over 7 min under ice-cooling, and the reaction mixture was stirred for 1 hr at room temperature . Under ice-cooling, a solution of (S) - (+) -epichlorohydrin al (7.16g, 77.3mmol) in benzene (20ml) was added to the reaction mixture over 20 min, and the mixture was stirred for 20 min. After removing the solvent, ethanol (120ml) and lOmol/L aqueous potassium hydroxide (40ml) were added, and the mixture was refluxed for 19 hrs . The solvent was removed to half its original volume under reduced pressure, and the solution was poured into a mixture of cooled cone, hydrochloric acid (60ml) and water (60ml). The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine, and dried over sodium sulfate. Sodium sulfate was removed, and the solution was concentrated under reduced pressure. The residue was purified by chromatography (hexane : ethyl acetate = 3:1) to yield compound a2 (7.49g, 43.0mmol, 56%) as a light brown solid . NMR data was consistent with the literature values.
[0189]
Step 2
To a solution of compound a2 (7.34g, 42.1mmol) in ethanol (59ml) was added lOmol/L aqueous potassium hydroxide (6.3ml) , and the solution was stirred for 1 hr at room temperature. Under ice-cooling, the reaction mixture was added to the mixture of ethyl acetate (50ml), cone, hydrochloric acid (8ml) and water (30ml) with stirring. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. Dimethylformamide (59ml) was added, and sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure. Under ice-cooling and argon atmosphere, imidazole (14.3g, 211mmol) and t-butyl ( chloro) diphenyl silane (32.9ml, 126.4mmol) were added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (chloro) diphenylsilane (16.48ml, 63.4mmol) and dimethylformamide (30ml) were added, and the mixture was stirred for 1 hr at room temperature. Ethyl acetate and water were added to the reaction mixture, aqueous layer was adjusted to pH=2 with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol ( 80ml ) , lOmol/L aqueous potassium hydroxide (25ml) was added, and the mixture was stirred for 1 hr at room temperature. After concentration to half its volume, ethyl acetate and water were added, and extracted with water. The aqueous layer was adjusted to pH=l with hydrochloric acid, and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (hexane : ethyl acetate =5:1) to yield compound a3 (8.69g, 20.2mmol, 48%) as a light brown liquid.
NMR data was consistent with the literature values.
[0190]
Step .3
To a solution of compound a3 (9.87g, 22.9mmol) in benzene (197ml) were added sequentially 2 , 2 ' -disulfanediyldipyridine 1- oxide (6.94g, 27.5mmol), tris ( trimethylsilyl ) silane (21.2ml, 68.8mmol), azobisisobutyronitrile (752mg, 4.58mmol), tri-n--butylphosphine (8.59ml, 34.38mmol) while the light was shielded under argon atmosphere, and the mixture was stirred at room temperature for 1 hour, and at 80°C for 6 hrs and 40 minutes . Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over, sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexarie: diethylether =50:1) to yield colorless liquid (4.56g). This was dissolved in THF (36ml), and a solution of lmol/L tetrabutylammonium fluoride in THF (17.7ml) was added under argon atmosphere, and the solution was stirred at room temperature for 3 hrs. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (hexane : ethyl acetate =2 : 1 ) to yield compound a4 (1.52g, 19.3mmol, 45%) as a colorless liquid.
NMR data was consistent with the literature values.
[0191]
Step 4
To a solution of compound a4 (1.50g, lO.lmmol) . in dichloromethane ( 20ml ) were added sequencially molecular sieve 4A (5.0g), N-methylmorpholine oxide (2.95g, 25.3mmol) and tetrapropylammonium perruthenate (354mg, l.Olmmol) under argon atmosphere, and the mixture was stirred at room temperature for 3 hrs . The reaction mixture was filtered over celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =5:1) to yield compound a5 (l.llg, 7.61mmol, 75% ) as a colorless liquid.
NMR data was consistent with the literature values.
[0192]
Step 5
To a solution of compound a5 (569mg, 3.90mmol) in methanol (11.4ml) and water (5.7ml) were added sulfamidic acid (567mg, 5.84mmol) and sodium chlorite (528mg, 5.84mmol) under ice-cooling, and the mixture was stirred at 0°C for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroformrmethanol =20:1) to yield compound a6 (571mg, 3.52mmol, 90%) as a light brown solid . NMR data was consistent with the literature values.
[0193]
Step 6
To a solution of compound a6 (201mg, 1.24mmol) in acetonitrile (2ml) was added carbonyl diimidazole (221mg, 1.36mmol) at room temperature, and the solution was stirred for 45 min to obtain a solution of imidazolide of compound 16. Separately, a mixture of magnesium chloride (294mg, 3.09mmol), ethyl malonate potassium salt (442mg, 2.60mmol) and triethylamine (0.552ml, 3.96mmol) in acetonitrile (6ml) was stirred for 40 min, and the solution of imidazolide of compound a6 as prepared was added at room temperature, and the solution was stirred at 80 °C for 2 hrs . The reaction mixture was filtered, and the filtrate was concentrated, and ethyl acetate and lmol/L hydrochloric acid, were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =5:1) to yield compound a7 (220mg, 0.947mmol, 77%) as a colorless oil.
1H-NMR (CDCI3, 400MHz) : δ 1.22 (3H, t, J = 7.3 Hz), 1.39-1.43 (1H, m) , 1.88-1.94 (1H, m) , 2.55-2.61 (1H, m) , 2.74-2.83 (1H, m) , 3.31 (1H, ABq, J = 15.1 Hz), 3.36 (1H, ABq, J = 15.1 Hz), 4.05-4.19 (2H, m) , 7.17-7.30 (5H, m)
[0194]
Step 7
To a solution of compound a7 (171mg, 0.734mmol) in ethanol (3.4ml) were added guanidine carbonate (132mg, 0.735mmol) and then 20% sodium ethoxide in ethanol (0.576ml, 1.47mmol) at room temperature, and the mixture was stirred at 80°C for 5 hrs. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was adjusted to pH=6 and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by chromatography ( chloroform:methanol =5:1, amino silica gel ) to yield compound a8 (123mg, 0.543mmol, 74%) as a colorless foam.
1H-NMR (DMSO-d6, 400MHz) : cis-isomer δ 1.23-1.29 (1H, m) , 1.61-1.67 (1H, m) , 2.11-2.19 (1H, m) , 2.44-2.50 (1H, m) , 5.20 (1H, s), 6.26 (2H, br s), 7.05-7.29 (5H, m) , 10.4 (1H, br s).
[0195] -■ Step 8
To a solution of compound a8 (105mg, 0.460mmol) in dimethylformamide (3.1ml) was added potassium carbonate (63.6mg, 0.460mmol) and then methyl iodide (0.0287ml, 0.460mmol) and stirred for 1 hr at room temperature. Methyl iodide (0.0086ml, 0.138mmol) was added to the reaction mixture, and the mixture was stirred for 15 hours. Potassium carbonate (63.6mg, 0.460mmol) and then methyl iodide (0.0287ml, 0.460mmol) were added to the reaction mixture, and the mixture was stirred for 3 hrs . Eethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by chromatography ( chloroformrmethanol ='30:1, amino silica gel) to yield a mixture of compound I-l and its isomer (52.6mg, 0.218mmol, 47%) as a colorless foam.
The mixture was dissolved in a mixture of water (2ml) and acetonitrile (6ml) and purified by reverse phase HPLC (column : GL Science Inertsil ODS-3 10x250mm, eluent:A 0.1% TFA in H20, B 0.1% TFA in MeCN, gradient conditionrB 10% to 60% for 40min, flow rate : 3ml/min) to yield compound 1-1 (21.2mg, 0.0879mmol, 23%) as a colorless solid.
LC/MS RT = 2.90, [M+H]+ = 242
"""H-NMR (CDCI3, 400MHz) δ 1.34-1.41 (1H, m) , 1.57-1.65 (1H, m) , 2.15-2.23 (1H, m) , 2.52-2.62 (1H, m) , 4.79 (2H, br s) 5.64 (1H, s), 7.07-7.20 (5H, m)
[0196]
Example 2: compound 1-2
[Chemical Formula 101]
Figure imgf000132_0001
[0197]
Step 1
To a suspension of sodium amide (10.5g, .270mmol) in benzene (60ml) was added dropwise a solution of m-bromophenyl acetonitrile (23.29g, 119mmol) in benzene (30ml) over 15 minute under ice-cooling, and the mixture was stirred at room temperature for 30 min. A solution of ( S ) - ( + ) -epichlorohydrin al (10. Og, 108mmol) in benzene (30ml) was then added to the reaction mixture over 25 min under ice-cooling, and the mixture was stirred for 30 min. The solvent was removed, and ethanol (150ml) and lOmol/L aqueous potassium hydroxide (50ml) were added, and the mixture was refluxed for 8 hrs . The solvent was removed to half its original volume under reduced pressure, and the solution was poured into cooled cone, hydrochloric acid (90ml) and water (90ml.) solution. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by chromatography (hexane : ethyl acetate =2:1) to yield compound a9 (16. g, 66.1mmol, 61%) as a brown liquid.
''"H-NMR (CDCls, 400MHz) δ 1.38-1.42 (1H, m) , 1.62-1.67 (1H, m) , 2.56-2.62 (1H, m), 4.31 (1H, d, J = 9.2 Hz), 4.47 (1H, dd, J = 9.2, 4.2 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.44 (1H, d, J = 7.8 Hz), 7.56 (1H, s)
[0198]
Step 2
To a solution of compound a9 (16.13g, 63.7mmol) in ethanol (81ml) and water (9.6ml) was added dropwise lOmol/L aqueous potassium hydroxide (9.6ml, 96mmol) at room temperature, and the solution was stirred for 1 hr at room temperature. The reaction mixture was added to a cooled solution of diethyl ether .(130ml) and 2mol/L hydrochloric acid (64ml) with stirring . The reaction mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried with magnesium sulfate. Magnesium sulphate was filtered off, and 28% sodium methoxide in methanol (13.0ml) was added to the filtrate. The resultant solid was collected by filtration, and washed with diethyl ether to yield compound alO (16.3g, 55.5mmol, 87%) as a colorless solid.
1H-NMR (DMSO-d6, 600MHz) δ 0.90-0.93 (1H, m) , 1.17-1.20 (1H, m) , 1.23-1.30 (1H, m) , 3.34-3.36 (1H, m) , 3.77-3.82 (1H, m) , 6.01 (1H, br s) , 7.15 (lH, t, J = 7.8 Hz) , 7.20 (1H, d, J = 7.8 Hz) , 7.27 (1H, d, J = 7.8Hz), 7.46 (1H, s) .
[0199]
Step 3
To a solution of compound alO (19.25g, 65.7mmol) in acetonitrile (97ml) and water (193ml) were added sodium periodate (28. lg, 131mmol ) and ruthenium chloride (III) (409mg, 1.97mmol) at room temperature, and the mixture was stirred at room temperature for 5 hrs . Under ice-cooling, the reaction mixture was added to ethyl acetate (200ml) and 2mol/L hydrochloric acid (100ml) solution with stirring. The mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated sodium bicarbonate and water. The aqueous layer was acidified with 6mol/L hydrochloric acid, and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residual solid was washed with hexane to yield compound all (16.2g, 56.8mmol, 87%) as a greyish brown solid. 1H-NMR (CDCI3, 500MHz) δ 1.62-1.65 (1H, m) , 2.20-2.24 (1H, m) , 2.35-2.39 (1H, m), 7.22 (1H, t, J = 7.8 Hz), 7.37 (1H, dt, J = 7.8, 1.8 Hz) , 7.46 (1H, dt, J = 7.8, 1.8 Hz), 7.58 (1H, t, J = 1.8 Hz) [0200]
Step 4
Using compound all (6.56g, 23.0mmol) and the procedure as described in the preparation of compound a7, a mixture of compound al2 and mono-ethyl malonate (6.63g) was obtained as a light brown liquid, which was used in the next step without purification.
1H-NMR ( CDCI3, 600MHz) 51.18-1.30 (IH, m) , 1.32 (3H, t, J = 7.3 Hz), 1.56-1.58 (1H, m) , 2.59-2.63 (IH, m) , 2.95 (2H, br s), 4.24-4.30 (2H, m), 7.23 (IH, t, J = 7.8 Hz), 7.39 (IH, d, J = 7.8 Hz), 7.45 (IH, d, J = 7.8 Hz), 7.57 (IH, s)
[0201]
Step 5
To a solution of the mixture of compound al2 and mono-ethyl malonate (6.55g) in ethanol ( 98ml ) was added 20% sodium ethoxide in ethanol (7.23ml, 18.4mmol), and the mixture was stirred for 10 min. Guanidine carbonate (1.66g, 9.22mmol) was added to the reaction mixture, and the mixture was stirred at 95 °C for 14 hrs . The solvent was removed to concentrate the mixture under reduced pressure. The residue was dissolved in dimethylformamide (52ml), and potassium carbonate (2.55g, 18.4mmol) and methyl iodide (2.31ml, 36.9mmol) were added, and the mixture was stirred at room temperature for 5 hrs . Potassium carbonate (1.27g, .9.22mmol) and methyl iodide (1.15ml, 18.4mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 16 hrs. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (chloroform: (chloroform:methanol : ammonia water=32 : 6 : 0.5 ) =2:1) to yield compound al3 (2.94g, 7.77mmol, 34% in two steps) as a colorless foam.
1H-NMR (CDC13, 600MHz) 51.51-1.55 (1H, m) , 2.19-2.22 (1H, m) , 2.40-2.44 (lH, m), 3.39 (3H, s), 3.54 (3H, s), 5.16 (2H, s),. 5.98 (1H, s), 7.21 (1H, t , J = 7.8 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.61 (1H, s) [0202]
Step 6
To a solution of compound al3 (2.87g, 7.59mmol) in dichloromethane (29ml) were added dimethylamino pyridine (278mg, 2.28mmol) and di-tert-butyl dicarbonate (4.40ml, 19. Ommol ) , and the mixture was stirred at room temperature for 2 hrs . The reaction mixture was concentrated under reduced pressure, and the residue was .purified by silica gel chromatography (hexane: ethyl acetate =1:1) to yield compound al4 (3.92g, 6.78mmol, 89%) as a colorless foam.
1H-NMR (CDCI3, 600MHz) 51.47. (9H, s), 1.50 (9H, s), 1.63-1.67 (1H, m) , 2.17-2.20 (1H, m) , 2.47-2.50 (1H, m) , 3.43 (3H, s), 3.53 (3H, s), 6.42 (1H, s), 7.21 (1H, t, J = 7.8 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.42 (lH, d, J = 7.8 Hz), 7.60 (1H, s) [0203] Step 7
To a solution of compound al4 (3.85g, 6.66mmol) in ethanol (39ml) were added water (3.3ml) and lOmol/L aqueous potassium hydroxide (3.3ml), and the mixture was stirred at 60°C for 3 hrs . The reaction mixture was added to a mixed solution of ethyl acetate (150ml), 2N hydrochloric acid (33ml) and water (50ml) with stirring, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with hexane to yield compound al5 (2.88g) as a colorless solid.
[0204]
" ' Step 8
To a solution of compound al5 (2.85g, 6.14mmol) in dichloromethane (57ml) was added
N, O-Bis (trimethylsilyl) acetamide (4.50ml, 18.4mmol), and the mixture was stirred at room temperature for 10 minutes. Dimethylaminopyridine (150mg, 1.23mmol) and di-tert-butyl dicarbonate (2.14ml, 9.21mmol) were added, and the mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (chloroformrmethanol =10:1) to yield compound al6 (2.99g, 5.30mmol, 80% in two steps) as a brownish orange foam.
1H-NMR (CDCI3, 600MHz) δ 1.42 (9H, s), 1.48 (9H, s), 1.71-1.75 (1H, m) , 2.22-2.25 (1H, m) , 2.60-2.64 (lH, m) , 3.42 (3H, s), 6.47 (1H, s), 7.21 (1H, t, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.60 (1H, s)
[0205]
Step 9
To a suspension of compound al6 (l.OOg, 1.77mmol), 2 , 2 ' -disulfanediyldipyridine 1- oxide (536mg, 2.13mmol) in toluene (40ml) was added tri-n-butyltin (1.42ml, 5.32mmol), azobisisobutyronitrile (58.2mg, 0.354mmol) and tri-n-butyl phosphine (1.33ml, 5.32mmol), under nitrogen atmosphere, and the mixture was stirred at room temperature for 15 minutes and then at 80 °C for 4 hrs and 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane : ethyl acetate =1:1) to yield compound al7 (442mg, 0.850mmol, 48%) as a light gray' solid .
1H-NMR (CDCI3, 500MHz) δ 1.38 (9H, s), 1.40 (9H, s), 1.45-1.51 (1H, m) , 1.60-1.65 (1H, m) , 2.32-2.38 (1H, m) , 2.60-2.66 (1H, m) , 3.31 (3H, s), 6.06 (1H, s), 7.00-7.06 (2H, m) , 7.23 (1H, d, J = 7.9 Hz) , 7.36 (1H, s) [0206] Step 10
To a solution of compound al7 (55.9mg, 0.107mmol) and m-trifluoromethylphenylboronic acid (21.9mg, 0.161mmol) in dioxane (1.1ml) and water (0.5ml) were added sodium carbonate (44.5mg, 0.322mmol), dicholorobis ( triphenylphosphine ) palladium (3.8mg, 0.00537mmol ) , and the mixture was stirred at 150°C for 30 minutes under microwave irradiation. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and. dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: methanol =10:1) to yield free form of the desired compound. This was dissolved in dioxane (0.5ml) to obtain a solution, which was then added with 4mol/L hydrochloric acid in dioxane (0.081ml, 0.322mmol), and concentrated under reduced pressure. Ethyl acetate was added, and resultant solid was collected by filtration and washed with ethyl acetate to yield compound 1-2 (21.5mg, 0.0584mmol, 54%) as. a colorless solid.
LC/MS RT = 4.36, [M+H]+ = 332
^-NMR (CD30D, 600MHz) δ 1.58-1.63 (1H, m) , 1.82-1.87 (1H, m). , 2.33-2.38 (1H, m) , 2.39 (3H, s), 2.88-2.93 (1H, m) , 5.70 (1H, s), 7.13-7.22 (2H, m) , 7.26-7.35 (4H, m) , 7.38-7.43 (2H, m) [0207]
Example 3: compound 1-3
[Chemical Formula 102]
Figure imgf000141_0001
To a solution of compound al7 (54.9mg, 0.105mmol), potassium phenylethyl trifluoroborate (44.6mg, 0.21mmol), dicholoro
(diphenylphosphinoferrocene) palladium (15.6mg, 0.019mmol), cesium carbonate (103mg, 0.316mmol) in THF (1ml) and water
(0.1ml) was stirred at 80°C for 14 hrs . Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane
(lml), and trifluoroacetic acid (1ml) was added, and the solution was stirred at room temperature for l.hr and 30 minutes . The reaction mixture was concentrated, and ethyl acetate and 5% potassium carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (ethyl acetate: methanol =20:1, amino silica gel) to yield compound 1-3 (22.7mg, 0.0657mmol, 63%) as a colorless solid.
LC/MS RT = 4.41, [M+H]+ = 345
^-NMR (CDC13, 600MHz) δ 1.34-1.38 (1H, m) , 1.58-1.62 (1H, m) , 2.15-2.20 (1H, m) , 2.52-2.58 (1H, m) , 2.81 (4H, s), 3.24 (3H, s) , 5.65 (1H, s) , 6.88 (1H, d, J = 7.6 Hz), 6.98 (1H, d, J = 7.6 Hz), 7.01 (1H, s), 7.07 (1H, t, J = 7.6 Hz), 7.12 (2H, d, J = 7.7 Hz), 7.18 (1H, t, J = 7.7 Hz), 7.24-7.28 (2H, m)
[0208]
Example 4: compound 1-4
Chemical Form la 103]
Figure imgf000142_0001
A solution of compound al7 (54.5mg, 0.105mmol), phenylacetylene (11.8mg, 0.115mmol), dicholorobis ( triphenylphosphine ) palladium . (6.0mg,
0.0084mmol), copper iodide .(I) (1.6mg, 0.0084mmol), triethylamine (0.5ml) in acetonitrile (1ml) was stirred at 80 °C for 3 hrs . Additionally, phenylacetylene (11.8mg, 0.115mmol), copper iodide (I) (1.2mg, 0.0063mmol), dicholorobis ( triphenylphosphine ) palladium ( 4.5mg,
0.0063mmol) were added, and the mixture was stirred at 120 °C for 1 hr under microwave irradiation. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane
(0.7ml), and trifluoroacetic acid (0.7ml) was added to the solution, and the solution was stirred for 1 hr at room temperature. The reaction mixture was concentrated, ethyl acetate and 5% aqueous potassium carbonate were added,, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica, gel chromatography (ethyl acetate: methanol =50:1) and followed by ODS column (0.1% TFA in water: 0.1% TFA in acetonitrile =50:50). The obtained residue was dissolved in dioxane (0.3ml), and 4mol/L hydrochloric acid in dioxane
(0.026ml) was added, and the solution was concentrated under reduced pressure. Ethyl acetate was added, and the resultant solid was collected by filtration and washed to yield compound 1-4 (6.9 mg, 0.018mmol, 17%) as a colorless solid.
LC/MS RT = 4.58, [M+H]+ = 342 ^"H-NMR (CD30D, 500MHz) 51.57-1.62 (1H, m) , 1.79-1.84 (1H, m), 2.30-2.36 (1H, m) , 2.81-2.87 (lH, m) , 3.28 (3H, s), 5.65 (1H, s), 7.20 (1H, d, J = 7.8 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.32-7.40 (5H, m) , 7.47-7.50 (2H, m)
[0209]
Example 5: compound 1-5
[Chemical Formula 104],
Figure imgf000144_0001
[0210]
Step 1
To a solution of compound al8 (5.48g, 33.8mmol) in dichloromethane (55ml) was added oxalyl chloride (3.55ml, 40.5mmol) and then trace amount of dimethylformamide, and the mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (55ml), and N,0-dimethyl hydroxylamine hydrochloride (4.94g, 50.7mmol) and pyridine (10.9ml, 1.35mmol) were added, and the mixture was stirred at room temperature for 1 hr and 30 min. To the reaction mixture ethyl acetate was added 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, saturated sodium bicarbonate and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =2:1) to yield compound al9 (5.81g, 28.3mmol, 84%) as a colorless liquid.
"""H-NMR (CDCI3, 500MHz) δ 1.28-1.33 (1H, m) , 1.61-1.66 (1H, m) , 2.41 (1H, br s) , 2.48-2.53 (1H, m) , 3.28 (3H, s) , 3.69 (3H, s) , 7.12-7.15 (2H, m) , 7.17-7.22 (1H, m) , 7.26-7.30 (2H, m)
[0211]
Step 2
To a solution of compound al9 (5.75g, 28.0mmol) in THF (86ml) was added 1.12mol/L methylmagnesium bromide in THF (45ml, 50.4mmol) under ice-cooling, and the mixture was stirred for 1 hr at room temperature. Under ice-cooling, saturated amonium chloride in water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =5:1) to yield compound a20 (4.27g, 26.7mmol, 95%) as a colorless liquid.
XH-NMR (CDCI3, 500MHz) δ 1.35-1.40 (1H, m) , 1.65-1.70 (1H, m) , 2.19-2.24 (1H, m) , 2.30 (3H, s), 2.50-2.55 (1H, m) , 7.08-7.11 (2H, m) , 7.18-7.23 (1H, m) , 7.26-7.31 (2H, m)
[0212]
Step 3
To a solution of titanium (IV) ethoxide (2.14g, 9.36mmol) in THF (5mi) were added compound a20 (l.OOg, 6.24mmol) in THF (2ml) and (R) -2-methylpropane-2-sulfinamide (832mg, 9.36mmol), and the mixture was stirred at 85°C for 5 hrs . After cooling the reaction mixture to room temperature, ethyl acetate (20ml) and brine (2ml) were added, and the solution was stirred at room temperature for 30 min. The insoluble solids were filtered off, and water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =2:1) to yield compound a21 (l.OOg, 3.8 Ommol , 61% ) as a colorless liquid. Compound a2Q (269mg, 27%) was recovered.
1H-NMR (CDCI3, 500MHz) δ 1.24 (9H, s), 1.39-1.43 (1H, m) , 1.70-1.74 (1H, m) , 1.90-1.95 (1H, m) , 2.46 (3H, s), 2.51-2.57 (1H, m) , 7.09-7.12 (2H, m) , 7.18-7.23 (1H, m) , 7.26-7.31 (2H, m) [0213]
Step 4
To a solution of diisopropylamine (1.72ml, 12.2mmol) in THF (6ml) was added dropwise 1.63mol/L n-butyllithium in hexane (7.87ml, 12.8mmol) over 15 minutes at -70°C under cooling on dry ice-acetone bath. The reaction mixture was warmed to 0°C and then cooled to - 70 °C .' Methyl acetate (0.886ml, ll.lmmol) in THF (2ml) was added over 5 min, and the reaction mixture was stirred at -70°C for 15 minutes. Triisopropoxy titanium (IV) chloride (3.72ml, 15.6mmol) in THF (6ml) was added over 10 min, and the mixture was stirred at - 70°C for 20 min. Compound a21 (977mg, 3.71mmol) in THF (4ml) was. added over 5 min, and the reaction mixture was stirred at - 70°C for 1 hr and added dropwise to ammonium chloride (1.19g) in water (4ml) under ice-cooling. To the reaction mixture were added ethyl acetate (10ml) and celite (2g) , the mixture was stirred at room.temperature for 10 min. The resultant insoluble solids were filtered off over celite, and water was added to the filtrate. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =1:2) to yield compound a22 (990mg, 2.93mmol, 79%) as a colorless liquid . 1H-NMR (CDCI3, 500MHz) δ 0.84-0.92 (2H, m) , 1.13-1.18 (1H, m), 1.20 (9H, s), 1.44 (3H, s), 1.98-2.03 (1H, m) , 1.90-1.95 (1H, m) , 2.56, 2.82 (2H, ABq, J = 14.9 Hz) , 3.53 (3H, s) , 5.05 (1H, s), 7.04-7.07 (2H, m) , 7.12-7.16 ( 1H, m) , 7.22-7.26 (2H, m)
[0214]
Step 5
To a solution of compound a22 (954mg, 2.83mmol) in methanol (9.5ml) was added 4mol/L hydrochloric acid in dioxane (2.12ml) . The mixture was stirred at room temperature for 2 hrs . Saturated sodium bicarbonate and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure.. The residue was purified by silica gel chromatography (chloroformtmethanol =10:1) to yield compound a23. (620mg, 2.66mmol, 94%) as a colorless liquid.
^H-NMR (CDCI3, 500MHz) δ 0.78-0.82 (1H, m) , 0.95-1.00 (1H, m)., 1.20 (3H, s), 1.21-1.26 (1H, m) , 1.89-1.93 (1H, m) , 2.47, 2.52 (2H, ABq, J = 9.2 Hz) , 3.52 (3H, s) , 7.05-7.07 ( 2H, m) , .7.11-7.15 (1H, m) , 7.22-7.26 (2H, m) [0215]
Step 6
To a solution of compound a23 (306mg, 1.31mmol) and N-(t-butyl carbonyl ) -N' -methylthiourea (308mg, 1.31mmol) in dimethylformamide (3.1ml) were added diisopropylethylamine (0.916ml, 5.24mmol) and l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (352mg, 1..84mmol), and the mixture was stirred at room temperature for 17 hrs . Ethyl acetate and water were added to the reaction, mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =2:1) to yield compound a24 (460mg, 1.29mmol, 98%) as a colorless liquid.
1H-NMR (CDC13, 500MHz) δ 0.96-1.05 ( 2H, m) , 1.15-1.18 (1H, m) ,1.39 (3H, s), 1.53 (9H, s), 1.81-1.86 (1H, m) , 2.70, 2.76 (2H, ABq, J = 15.8 Hz), 3.32 (3H, s), 7.02-7.04 (2H, m) , 7.14-7.18 (1H, m) , 7.23-7.27 (2H, m)
[0216]
Step 7 .
To a solution of compound a24 (520mg, 1.46mmol) in dichloromethane (5.2ml) was added trifluoroacetic acid (5.2ml) , and the mixture was stirred at room temperature for 1 hr and 30 minutes. The reaction mixture was concentrated. Ethyl acetate and 5% aqueous potassium carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (chloroform: methanol =50:1, amino silica gel) to yield free form of compound 1-5 (352mg, 1.37mmol, 94%) as a colorless solid. The free form of compound 1-5 (164mg) was solidified in hexane (2ml) and ethyl acetate (1.4ml). The obtained solid was dissolved in dichloromethane (0.2ml) and trifluoroacetate (0.2ml), and the solution was concentrated under reduced pressure. The residual solid was washed with hexane-ethyl acetate (10:1) to yield compound 1-5 (105.2mg). LC/ S RT = 3.44, [M+H]+ = 258
1H-NMR (CD30D, 500MHz) δ 1.00-1.04 (2H, m) , 1.30-1.35 (1H, m) , 1.41 (3H, s), 1.53 (9H, s), 1.86-1.90 (1H, m) , 2.92 (2H, s), 3.31 (3H, s), 7.05-7.08 (2H, m) , 7.12-7.16 (1H, m) , 7.21-7.25
(2H, m)
[0217]
Example 6: compound 1-6
[Chemical Formula 105]
Figure imgf000151_0001
[0218]
Step 1
To a solution of copper (I) trifluoromethane sulfonate toluene complex (99mg, 0.19mmol), 2 , 2 ' -isopropylidene bis-[(4S)-4 - t-butyl-2 - oxazoline] (113mg, 0.382mmol) in dichloromethane (14ml) was added m-bromostyrene (4.98ml, 3.82mmol), and the mixture was stirred at room temperature for 1 hr and 20 minutes. Under ice-cooling, tert-Butyl diazoacetate a25 (2.07ml, 12.8mmol) in dichloromethane (7ml) was added dropwise over 2 hrs. The mixture was stirred for additional 3 hrs and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate =20:1) to yield a mixture of compound a26 and its cis-isomer (4:1) (2.95g, 9.93mmol, 77%) as a colorless liquid.
1H-NMR (CDCI3, 500MHz) trans-isomer δ 1.19-1.24 (1H, m) , 1.52-1.56 (1H, m) , 1.55 (9H, s), 1.80-1.84 (1H, m) , 2.37-2.42 (1H, m) , 7.01-7.03 (1H, m) , 7.13 (1H, t, J = 7.7 Hz) , 7.22 (1H, t, J = 2.0 Hz), 7.32 (1H, ddd, J = 7.7, 2.0, 1.1 Hz)
[0219]
Step 2
To the mixture of compound a26 and cis-isomer (2.24g, 7.54mmol) in dichloromethane (14ml) was added trifluoroacetate (2.2ml), and the mixture was stirred for 1 hr at room temp.erature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol =10:1) to yield a mixture of compound a27 and its cis-isomer (1.79g, 7.42mmol, 98%) as a colorless liquid . 1H-NMR (CDCI3, 500MHz) trans-isomer δ 1.33-1.38 (1H, m) , 1.60-1.68 (1H, m) , 1.84-1.88 (1H, m) , 2.50-2.55 (1H, m.) , 6.99-7.02 (1H, m) , 7.12 (1H, t, J = 7.8 Hz), 7.22 (1H, t, J = 2.0 Hz), 7.32 (1H, ddd, J = 7.8, 2.0, 1.0 Hz)
[0220]
Step 3
Using the mixture of compound a27 and its cis-isomer and the procedure as described in the preparation of compound a24, compound a28 was obtained as a colorless liquid.
^-NMR (CDCI3, 500MHz) δ 1.00-1.04 (2H, m) , 1.15-1.20 (1H, m) , 1.38 (3H, s), 1.53 (9H, s), 1.78-1.83 (1H, m) , 2.70, 2.75 (2H, ABq, J = 16.1 Hz), 3.32 (3H, s), 6.95-6.98 (1H, m) , 7.11 (1H, t, J = 7.9 Hz), 7.15 (1H, t, J = 2.0 Hz), 7.30 (1H, ddd, J = 7.9, 2.0, 1.0 Hz) , 9.86 (1H, s)
[0221]
Step 4
To a solution of compound a28 (51.5mg, 0.118mmol ) , m-phenyl boronic acid (26.9mg, 0.127mmol) in dioxane (1ml) and water (0.5ml) were added potassium carbonate (48.9mg, 0.354mmol) and dicholorobis (triphenylphosphine) palladium (4.1mg, 0.0059mmol), and the mixture was stirred at 100°C for 2 hrs . Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolvedin dichloromethane (0.6ml), and the solution was added with trifluoroacetic acid (0.6ml) and stirred at room temperature for. 1 hr. The reaction mixture was concentrated, and ethyl acetate and 5% aqueous potassium carbonate were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (ethyl acetate rmethanol =10:1, amino silica gel) to yield free form of compound 1-6. The free form was dissolved in dichloromethane (0.6ml), and the solution was added with trifluoroacetic acid (0.6ml) and concentrated under reduced pressure. The residue was solidified in hexane-diethyl ether to yield compound 1-6 (47.8mg, O.lOOmmol, 84.8%) as a colorless powder.
LC/MS RT = 4.27, [M+H]+ = 364
^H- MR (CD30D, 500MHz) δ 1.02-1.07 (1H, m) , 1.09-1.14 (1H, m), 1.35-1.40 (1H, m) , 1.43 (3H, s), 1.93-2.01 (1H, m) , 2.93, 2.97 (2H, ABq, J = 16.1 Hz), 3.33 (3H, s), 3.85 (3H, s), 6.91 (1H, dd, J = 8.3, 2.5 Hz), 7.04 (1H, d, J = 7.8 Hz), 7.10-7.12 (1H, m) , 7.15 (1H, d, J = 7.6 Hz), 7.29-7.35 (3H, m) , 7.40 (1H, d, J = 7.8 Hz)
[0222]
Example 7: compounds 1-7 and 1-8
[Chemical Formula 106]
Figure imgf000155_0001
[0223]
Step 1
To a. solution of compound a29 (304mg, 0.729mmol), which was obtained in Step 3 of Example 6, in THF (6ml) was added lithium borohydride (47.7mg, 2.19mmol), and the mixture was stirred at room temperature for 4 hrs .
Water was added to . the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol =30:1) to yield compound a30 (175mg, 0.450mmol, 62%) as a colorless liquid.
1H-NMR (CDCI3, 500MHz) δ 0.86-0.91 (1H, m) , 0.92-0.96 (1H, m), 1.04-1.09 (1H, m) , 1.18 (9H, s), 1.41 (3H, s), 1.75-1.80 (1H, m) , 1.93-1.96 (1H, m) , 2.01-2.07 (1H, m) , 3.35-3.38 (1H, m) , 3.80-3.88 (1H, m) , 3.91-3.97 (1H, m) , 4.46 (1H, s), 7.01-7.04 (1H, m) , 7.12 (1H, t, J = 7.9 Hz) , 7.19-7.21 (1H, m) , 7.28 (lH, ddd, J = 7.9, 2.0, 1.1 Hz) [0224]
Step 2
Using compound a30 (160mg, 0.412mmol) and the procedure as described in Example 5 , Step 5, compound a31 (95.8mg, 0.337 mmol, 82%) was obtained as a colorless liquid.
1H-NMR (CDCI3, 500MHz) δ 0.86-0.95 (2H, m) , 1.04-1.09 (1H, m) , 1.16 (3H, s ) , 1.16-1.21 (1Ή, m) , 1.57-1.62 (lH, m) , 1.68-1.74 (1H, m) , 1.86-1.91. (1H, m), 3.82-3.91 (1H, m) , 7.00-7.03 ( 1H, m) , 7.12 (1H, t, J = 8.0 Hz), 7.19-7.21 (1H, m) , 7.28 (1H, ddd, J = 8.0, 2.0, 1.1 Hz)
[0225]
Step 3
To a solution of compound a31 (86.9mg, 0.306mmol) in toluene (0.9ml) and water (0.5ml) were added potassium carbonate (85mg, 0.612mmol) and thiophosgene (35μ1, 0.459mmol), and the mixture was stirred for 1 hr at room temperature. The reaction mixture was extracted with toluene, and the organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the solution was concentrated under reduced pressure. The residue was dissolved in toluene (2ml), and the solution was added with thionyl chloride ( 67μ1, 0.918mmol) and catalytic guantity of DMF and stirred at 80°C for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. The residue was purified by silica gel chromatography (hexane: ethyl acetate =20:1) to yield compound a32 (79.5mg, 0.231mmol, 75%) as a colorless liquid.
1H-NMR (CDC13, 500MHz) δ 0.97-1.02 (1H, m) , 1.11-1.16 (1H, m) , 1.18-1.22 (1H, m) , 1.54 (3H, s), 1.98-2.03 (1H, m) , 2.24 (2H, t, J = 7.9 Hz), 3.58-3.68 (2H, m) , 7.02 (lH,d, J = 7.8 Hz) , 7.14 (1H, t, J = 7.8 Hz), 7.16-7.18 (1H, m) , 7.30-7.33 (1H, m) [0226]
Step 4
A solution of compound a32 (75.0mg, 0.2l8mmol) in THF (1.0ml), ammonia water (1.0ml) and methanol (0.8ml) was stirred at room temperature for 46 hrs . Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. The residue was purified by silica gel chromatography
(hexane : ethyl acetate =1 : 1 , amino silica gel ) to yield compound 1-7 (61.8-mg, 0.190mmol, 87%) as a colorless liquid.
^H-NMR (CDC13, 500MHz) δ 0.74-0.79 (1H, m) , 0.99-1.04 (1H, m) , 1.19-1.24 (lH, m) , 1.26 (3H, s), 1.69-1.80 (3H, m) , 2.96-3.02
(1H, m) , 3.05-3.10 (1H, m) , 6.97-7.01 (1H, m) , 7.09 (1H, t, J = 7.8 Hz), 7.16-7.18 (1H, m) , 7.25 (1H, d, J = 7.8, 2.0, 1.0 Hz)
[0227]
Step 5
Using compound 1-7 (58.3mg, 0.179mmol) and the procedure as described in Example 2 , Step 6, compound a33 (85.4mg, 0.163mmol, 91%) 'was obtained as a colorless liquid.
1H-NMR (CDCI3, 500MHz) δ 0.79-0.84 (1H, m) , 1.10-1.15 (1H, m) , 1.28-1.33 (1H, m) , 1.29 (3H, s), 1.50 (18H, s), 1.72-1.83 (2H, m), 1.84-1.89 (1H, m) , 3.13 (2H, t, J = 6 . 2 Hz) , 6.99-7.02 (1H, m) , 7.10 (1H, t, J = 7.8 Hz)-, 7.15 (lH, t, J = 1.7 Hz) , 7.24-7.28 (1H, m)
[0228]
Step 6
Using compound a33 (20.5mg, 0.0390mmol) and phenylboronic acid (7.1mg, 0.059mmol), and the procedure as described in Example 2, Step 10, compound 1-8 (10.6mg, 0.0329mmol , 84%) was obtained as a colorless powder.
""■H-NMR (CDC13, 500MHz) δ 0.82-0.87 (1H, m) , 1.05-1.10 (1H, m) , 1.19-1.24 (1H, m) , 1.29 (3H, s), 1.69-1.76 (1H, m) , 1.78-1.85
(2H, m) , 2.96-3.00 (1H, m) , 3.11-3.17 (1H, m) , 7.04 (1H, d, J = 7.6 Hz), 7.25-7.37 (4H, m) , 7.43 (2H, t, J = 7.6 Hz), 7.57
(2H, d, J = 7.6 Hz)
[0229]
Example 8: compound 11^3
[Chemical Formula 107]
Figure imgf000160_0001
[0230]
Step 1
To a solution of compound a34 (4.00g, 15.8mmol) in toluene (40ml) was added lmol/L diisobutylaluminumhydride in hexane (19.0ml) over 25 minutes at -70°C under cooling and nitrogen atmosphere, and the mixture was stirred at -70°C for 2 hrs. Methanol (10ml) and then 20% Rochelle salt (40ml) were added, and the mixture was stirred at room temperature for 2 hrs. Ethyl acetate and water were added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. 4.03g of the residue obtained was . dissolved in dimethylformamide (32ml) , and the solution was added with imidazole (2.15g, 31.6mmol) and cooled to 0°C. t-Butyl chlorodiphenylsilane (4.87ml, 19.0mmol) was added, and the solution was stirred at room temperature for 4 hrs. Ethyl acetate and water were added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The residue was purified by silica gel chromatography (hexane : ethyl acetate =15:1) to yield compound a35 (7.32g, 14.8mmol, 93.9%) as a colorless oil.
1H-NMR (CDC13, 500MHz) 51.07 (9H, s), 1.51-1.54 (1H, m) , 1.74-1.78 (1H, m) , 1.93-2.00 (1H, m) , 3.68 (1H, dd, J = 11.5, 9.3 Hz) , 4.08 (1H, dd, J =.11.5, 5.4 Hz) , 7.24 (1H, t, J = 7.7 Hz), 7.29 (1H, dt, J = 7.7, 1.5 Hz), 7.38-7.47 (7H, m) , 7.53 (1H, t, J = 1.8 Hz) , 7.62-7.66 (2H, m) , 7.67-7.71 (2H, m) , 9.57 (1H, s)
[0231]
Step 2
To a solution of compound a35 (5.87g, 11.9mmol) in methanol (47ml) and THF (6ml) was added sodium borohydride (900mg, 23.8mmol) at 0°C under cooling and nitrogen atmosphere, and the mixture was stirred at 0°C for 1 hr and 30 minutes. Water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =5:1) to yield compound a36 (3.99g, 8.05mmol, 67.7%) as a light brown oil.
1H-NMR (CDC13, 500MHz) 50.70-0.74 (1H, m), 1.00-1.04 (1H, m) , 1.10 (9H, s), 1.42-1.50 (1H, m) , 3.49-3.55 (2H, m) , 3.66-3.71 (1H, m) , 4.08 (1H, t, 12.2 Hz), 4.19 (1H, dd, J = 12.2 Hz, 5.4 Hz) , 7.21 (1H, t, J = 7.9 Hz) , 7.35-7.49 (8H, m) , 7.55 (1H, t, J = 1.8. Hz), 7.68-7.71 (2H, m) , 7.71-7.75 (2H, m) [0232] Step 3
To a solution of compound a36 (3.52g, 7.10mmol) in THF (35ml) was added triethylamine (3.94ml, 28.4mmol), and under cooling and nitrogen atmosphere, methanesulfonyl chloride (2.28ml, 28.4mmol) was added a t 0°C. The mixture was stirred at 0°C for l.hr and 20 minutes, ethyl acetate and water were added and extracted twice with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure . The residue was dissolved in THF (50ml) , and 1.02mol/L lithium triethylborohydride in THF (41.7ml, 42.6mmol) was added at 0°C, under cooling and nitrogen atmosphere. The mixture was stirred at room temperature for 19 hrs and 40 minutes, ethyl acetate and water were added and extracted twice with ethyl acetate. The organic layer was dissolved in 2mol/L hydrochloric acid, and washed with saturated agueous sodium bicarbonate and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (47ml), and lmol/L tetrabutylammonium fluoride in THF (42.6ml) was added at room temperature. The. mixture was stirred at room temperature for 18 hrs and 40 minutes . Ethyl acetate and water were added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane : ethyl acetate =2:1) to yield compound a37 (1.47g, 6.10mmol, 86.0%) as a colorless oil.
^-NMR (CDCI3, 500MHz) δ 0.60-0.63 (1H, m) , 1.11-1.15 (1H, m) , 1.37-1.42 (1H, m) , 1.44 (3H, s), 3.68 (1H, t, 11.5 Hz), 3.91 (1H, dd, J = 11.5 Hz, 6.4 Hz), 7.15 (1H, t, J = 7.7 Hz), 7.19 (1H, dt, J = 7.7, 1.4 Hz) , 7.30 (1H, ddd, J = 7.7, 2.0, 1.4 Hz), 7.40-7.42 (1H, m)
[0233]
Step 4
Using compound a37 (1.43g, 5.92mmol) and the procedure as described above in the preparation of compound a5, compound a38 (l.llg, 4.64mmol, 78.4%) was obtained as a colorless liquid. ^-NMR (CDCI3, 500MHz) 51.57 (3H, s), 1.60-1.64 (1H, m) , 1.68-1.72 (1H, m) , 2.14-2.18 (1H, m) , 7.18-7.24 (2H, m) , 7.35-7.37 (1H, m) , 7.45 (1H, dt, J = 8.8, 1.7 Hz), 7.40-7.42 (1H, m) , 9.61 (1H, d, J = 4.7 Hz)
[0234]
Step 5
Using compound a38 (1.09g, 4.58mmol) and the procedure as described above in the preparation of compound a6, compound a39 (1.14g) was obtained as a colorless liquid, which was used in the next step without purification.
[0235]
Step 6
Using compound a39 (1.14g) and the procedure as described above in the preparation .... of compound al9, compound a40 (985mg, 3.30mmol, 72.1% from a38) was obtained as a colorless liquid. """H-NMR . (CDCI3, 500MHz) δ 1.32-1.35 (IH, m) , 1.44 (3H, s), 1.54-1.57 (1H, m) , 2.32-2.42 (IH, m) , 3.27 (3H, s), 3.57 (3H, s) , 7.18 (1H, t, J = 7.8 Hz) , 7.23-7.26 (lH, m), 7.34 (1H, ddd, J = 7.8, 2.0, 1.2 Hz), 7.47-7.48 (1H, m)
[0236]
Step 7
Using compound a40 (956mg, 3.21mmol) and the procedure as described above in the preparation of compound a20, compound a41 ( 609mg, 2.4 lmmol , 75.0%) was obtained as a colorless liquid. ^-NMR (CDCI3, 500MHz) δ 1.38-1.40 (1H, m) , 1.40 (3H, s), 1.58-1.61 (1H, m) , 2.25-2.29 (1H, m) , 2.35 (3H, s), 7.19 (1H, t, J = 7.7 Hz), 7.21 ( IH, dt , J = 7.7 , 1.7 Hz) , 7.36 (IH, dt, J = 7.7, 1.7. Hz), 7.42 (IH, t, J = 1.7 Hz)
[0237]
Step 8
Using compound a41 (591mg, 2.33mmol) and (R) -2-methylpropane-2-sulfinamide (424mg, 3.50mmol) and the procedure as described above in the preparation of compound a21, compound a42 (503mg, 1.41mmol, 60.5%) was obtained as a colorless liquid.
1H-NMR (CDC13, 500MHz) 6 1.26 (9H, s), 1.32-1.36 (1H, m), 1.45 '(3H, s), 1.61-1.65 (1H, m) , 1.97-2.02 (lH, m) , 2.53 (3H, s), 7.19 (1H, t, J = 7.7 Hz), 7.20-7.25 (1H, m) , 7.36 (1H, dt, J = 7.7, 2.0 Hz), 7.40-7.43 (1H, m) [0238]
Step 9
Using compound a42 (470mg, 1.32mmol) and the procedure as described above in the preparation of compound a22, compound a43 (210mg, 0.489mmol, 37.0%) was obtained as a colorless liquid.
1H-NMR (CDCI3, 500MHz) δ 0.73-0.77 (1H, m) , 1.08-1.18 (2H, m) , 1.25 (9H, s), 1.52 (3H, s), 1.59 (3H, s), 2.65, 2.92, (2H, ABq, J = 15.4 Hz), 3.72 (3H, s), 5.03 (1H, ,s), 7.13 (1H, t, J = 7.6 Hz) , 7.15-7.18 (1H, m) , 7.29 (1H, dt, J = 7.6, 1.7 Hz) , 7.39-7.42 (1H, m)
[0239]
Step 10
Using compound a43 (196mg, 0.455mmol) and the procedure as described above in the preparation of compound a23, compound a44 (121mg, 0.372mmol, 81.6%) was obtained as a colorless liquid .
1H-NMR (CDCI3, 500MHz) δ 0.86-0.90 (1H, m) , 1.01-1.09 (2H, m) , 1.33 (3H, s), 1.61 (3H, s), 2.64, (2H, s), 3.68 (3H, s), 5.03 (1H, s) , 7.13 (1H, t, J = 7.8 Hz) , 7.16-7.19 (1H, m) , 7.28 (1H, ddd, J = 7.8, 1.7, 1.5 Hz), 7.37-7.40 (1H, m)
[0240]
Step 11.
Using compound a44. (109mg, 0.333mmol) and the procedure as described above in the preparation of compound a24, compound a45 (144mg, 0.319mmol, 95.7%) was obtained as a colorless liquid .
"""H-NMR (CDCI3, 500MHz) 50.89-0.92 (1H, m) , 1.15-1.19 (1H, m) , 1.25-1.28 (1H, m), 1.47 (3H, s), 1.47 (3H, s), 1.53 (9H, s), 2.79, 2.87, (2H, ABq, J = 16.1 Hz) , 3.32 (3H, s) , 7.12-7.15 (1H, m), 7.16 (1H, t, J = 7.9 Hz), 7.30-7.34 (1H, m) , 7.34-7.36 (1H, m) , 10.06 (1H, s) [0241]
Step 12
Using compound a45 (28.7mg, 0.0637mmol) and phenylboronic acid (11.7mg, 0.0960mmol) and the procedure as described above in the preparation of compound 1-6, II-3 (25.2mg, 0.0546mmol, 85.7%) was obtained as a colorless solid. 1H-NMR (CD3OD, 500MHz) δ 0.91-0.94 (1H, m) , 1.27-1.35 (2H, m) , 1.50 (3H, s) , 1.57 (3H, s) , 3.02, 3.07, (2H, ABq, J = 16.4 Hz) , 3.30 (3H, s), 7.20-7.24 (1H, m) , 7.31-7.38 (2H, m) , 7.41-7.45 (4H, m) , 7.56-7.60 (2H, m)
[0242]
Compounds 1-9 to 1-141 and II-l to II-5 as shown in the following tables were prepared according to the procedures as described in the above Examples and General procedure for preparation. The optical purity of the compound was determined from the absorbance at 205nm, 210 nm, 215nm, 220nm, 254nm, 270nm, 298nm by HPLC.
[Table 1]
Figure imgf000169_0001
[0243] [Table
Figure imgf000170_0001
[0244]
[Table 3]
Figure imgf000171_0001
[0245] [Table
Figure imgf000172_0001
[0246] [Table 5]
Figure imgf000173_0001
[0247] [Table
Figure imgf000174_0001
[0248]
[Table 7]
Figure imgf000175_0001
[0249] [Table
Figure imgf000176_0001
[0250] [Table
Figure imgf000177_0001
[0251] [Table
Figure imgf000178_0001
[0252] [Table
Figure imgf000179_0001
[0253] [Table
Figure imgf000180_0001
[0254] [Table 13]
Figure imgf000181_0001
[0255]
[Table 14]
Figure imgf000182_0001
[0256] [Table
Figure imgf000183_0001
[0257] [Table
Figure imgf000184_0001
[0258] [Table
Figure imgf000185_0001
[0259] [Table
Figure imgf000186_0001
[0260] [Table
Figure imgf000187_0001
[0261] [Table
Figure imgf000188_0001
[0262] [Table
Figure imgf000189_0001
[0263] [Table
Figure imgf000190_0001
[0264] [Table
Figure imgf000191_0001
[0265]
The effect of the compound was confirmed in the following test Examples .
Test Example 1: BACEl inhibiting activity
48.5 pL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu: X=e-amino-n-capronic acid, Eu=Europium cryptate) was added to each well of 96-well half-area plate (a black plate: Corning Incorporated), and after addition of 0.5 μΐ of the test compound (dissolved in N, N ' -dimethylformaldehyde ) and 1 μΐ of Recombinant human BACE-1 (R&D Systems ) , the reaction mixture was incubated at 30 °C for 3 hours. The substrate peptide was synthesized by reacting Cryptate TBPCOOH mono SMP (CIS bio international) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.). The final concentrations of the substrate peptide and Recombinant human BACE1 were adjusted to 18 nM and 7.4 nM respectively, and the reaction was performed in sodium acetate buffer (50 mM sodium acetate, pH 5.0, 0.008% Triton X-100).
After the incubation for reaction, 50 μΐ of 8.0 g/ml Streptavidin-XL665 (CIS bio international) dissolved in phosphate buffer (150 mM K2HPO4-KH2PO4, pH 7.0, 0.008 % Triton X-100, 0.8 M KF) was added to each well and left stand at 30°C for an hour. After then, fluorescence intensity was measured (excitation wavelength: 320 nm, measuring wavelength: 620 nm and 665 nm) using Wallac 1420 multilabel counter (Perkin Elmer life sciences) . Enzymatic activity was determined from counting ratio of each wavelength (10, 000 x Count 665/Count 620) and the 50% inhibitory concentration against the enzymatic activity (IC50) was calculated. The IC50 values of the compounds of the invention are shown below. [Table 24]
Figure imgf000193_0001
[0266]
Test Example 2: Enzyme Assay (ELISA)
The human BACEl was prepared as follows and used as an enzyme. As a substrate, SEVNLDAEFRHDSGYEK-biotin (American Peptide Company, Inc.) was used.
Preparation of human BACEl
The cDNA fragment encoding the amino acids 43-454 of human BACEl was cloned into pET28a and transformed into E.coli BL21 (DE3) . Human BACEl protein was expressed in inclusion body and refolded by the improved method using iFOLD protein Refolding system3 (Novagen) . The protein was purified on Q-Sepharose FF column. The fractions containing BACE activity were corrected and purified sequencially on His Trap HP column, HiLoad Q Sepharose HP column, and Superdex200 column. After thrombin digestion, it was applied on HisTrap Benzamine FF column and then His Trap column to obtain human BACEl (> 98% purity by SDS-PAGE) . The buffer was exchanged to 20 mM Tris-HCl (pH 8.0), 150 mM NaCl, 2 mM DTT.
The substrate was diluted to 25 nM with PBS. 100 pL of the solution was placed in each well of streptavidin 96well-format plate (Nunc) and stand for 2 hours at room temperature to imobilize the substrate. 70 ]i of the reaction solution (50mM sodium acetate, pH4.5, 0.25 mg/ mL bovine serum albumin (BSA) ) , 10 iL of the test compund solution or DMSO, and 20 μΐ of BACE 1 (final concentration: 0.45 nM) were added to each well to initiate enzymatic reaction.
After incubation at 25°C for 3 hours, each, well was washed with TBST (Tris-buffered. saline containing 0.1% of tween-20) . The cleavage fragment on the plate was detected using horseradish peroxidase (HRP) -conj ugated 82E1 (IBL Co., Ltd.) . HRP enzyme activity was determined by measuring the absorbance using TMB substrate (Thermo Scientific, Inc.), and the 50% inhibitory concentration against the enzymatic activity (IC50) was calculated. The IC50 values of the compounds of the invention are shown below.
[Table 25]
Figure imgf000195_0001
[0267]
The biological tests of the compound were conducted in the following test Examples.
Test Example 3: CYP inhibition test
Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4 ' -hydroxylation (CYP2C19) , dextromethorphan O-demethylation (CYP2D6) , and terfenedine hydroxylation (CYP3A4) as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4 ) , an inhibitory degree of each metabolite production amount by a test compound was assessed. [0268]
The reaction conditions were as follows: substrate, 0.5 μιηοΙ/L ethoxyresorufin (CYP1A2 ), 100 μπιοΙ/L tolbutamide (CYP2C9 ) , 50 μΓηοΙ/L S-mephenitoin (CYP2C19) , 5 mol/L dextromethorphan (CYP2D6), 1 mol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; test compound concentration, 1, 5, 10, 20 mol/L (four points) .
[0269]
Each of the five substrates, human hepatic microsome, or a test compound in 50 mM Hepes buffer as a reaction solution was added to a 96-well plate at the composition as described above, NADPH as a cofactor was added to initiate metabolism reactions. After the incubation at 37°C for 15 minutes, a methanol/acetonitrile = 1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter, and tributamide hydroxide (CYP2CP metabolite), mephenytoin 4' hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite) , and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
[0270]
In the reaction, only the solvent DMSO without test compound was added to serve as a control. The percentage of remaining activity (%) of the CYP enzyme was calculated as 100% of the control. IC5o was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate. [0271]
Test Example 4: BA Test
Materials and methods for studies on oral absorption.
(1) Animal: mouse or SD rat
(2) Breeding conditions: animals were allowed to freely take solid feed and sterilized tap water
(3) . Dose and grouping: orally or intravenously administered at a predetermined dose; grouping was as follows (Dose depends on the compound)
Oral administration: 1 to 30 mg/kg (n=2 to 3)
Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)
(4) Preparation of dosing solution: for oral administration, in a solution or a suspension, state; for intravenous administration, in a solubilized state
(5) Administration method: in oral administration, forcedly administer into ventriculus with oral probe; in intravenous administration, administer from caudal vein with a needle-equipped syringe
(6) Measurement: blood was collected over time, and the plasma concentration of drug was measured by LC/MS/MS
(7) Statistical analysis: regarding the transition of the plasma concentration, the area under the plasma concentration-time curve (AUC) was calculated by non-linear least squares program WinNonlin™. The bioavailability (BA) was calculated from the AUCs of the oral administration group and intravenous administration group.
[0272]
Test Example 5: Metabolism Stability Test
Using a commercially available pooled human hepatic microsomes, a test compound, 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. [0273]
The 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. After the reaction, 50 L of the reaction solution was added to 100 L of a methanol/acetonitrile = 1/1 (v/v) , and the mixture was centrifuged at 3000 rpm for 15 minutes. The test compound in the supernatant was quantified by LC/MS/MS, and a remaining amount of the test compound after the reaction was calculated as 100% of the compound amount at 0 minute. The hydrolysis reaction was conducted in the absence of NADPH, and the glucuronidation reaction was conducted in the presence of 5mmol/L UDP-glucuronic acid instead of NADPH.
[0274]
Test Example 6: CYP3A4 Fluorescent MBI Test
The CYP3A4 fluorescent MBI test was a test of investigating enhancement of CYP3A4 inhibition of a compound by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylchmarin (7-BFC) was debenzylated by the CYP3A4 enzyme to produce a metabolite emitting fluorescent light, 7-hydroxytrifluoromethylchmarin (HFC) .
[0275]
The reaction conditions were as follows: substrate, 5.6 μιηοΙ/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25°C ( room temperature ) ; CYP3A4 content (expressed in Escherichia coli), at pre-reaction 62.5 pmol/mL, at reaction 6.25 pmol/mL (at 10-fold dilution); test compound concentration, 0.625, 1.25, 2.5, 5, 10, 20 pmol/L (six points ) .
[0276] As a pre-reaction solution, the enzyme in a K-Pi buffer (pH 7.4) and the test compound solution were added to 96-well plate at the composition in the pre-reaction. A part of the solution was transferred to another 96-well plate and 10-fold diluted with the substrate in K-Pi buffer. NADPH as a co-factor was added to initiate the reaction (without pre-reaction) for predetermined time. Acetonitrile/0.5mol/L Tris
(trishydroxyaminomethane) = 4/1 was added to stop the reaction. Separately, NADPH was added to the remaining pre-reaction solution to initiate pre-reaction for predetermined time. A part of the solution was transferred to another plate and 10-fold diluted with the substrate and K-Pi buffer to initiate the reaction. Acetonitrile/0.5mol/L Tris
(trishydroxyaminomethane) = 4/1 was added to stop the reaction. The fluorescent value of 7-HFC was measured for each plate as reacted using a fluorescent plate reader. (Ex = 420 nm, Em = 535 nm) .
[0277]
In the reaction, only the solvent DMSO without test compound was added to serve as control. The percentage of remaining activity (%) of the enzyme was calculated as 100% of the control. IC50 was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate. The difference of IC50 between with and without pre-reaction was obtained . The result is expressed as follows:
(+) , difference of IC50 values ≥ 5 μΜ;
(±) , 5 μΜ > difference of IC50 values > 3 μΜ;
(-) , 3 μΜ ≥ difference of IC50 values
(Result)
Compound 1-10 : (±) [0278]
Test Example 7 : Fluctuation Ames Test
The compound of the invention was assessed for mutagenic property .
Each 20 μL of freeze-stored Salmonella typhimurium (Strain: TA98, TA100) was inoculated in 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No .2 ) , and the cultures were incubated at 37 °C under shaking for 10 hours . 9 mL of TA98 culture was centrifuged (2000 χ g, 10 minutes) to remove medium, and the bacteria was suspended in 9 mL of Micro F buffer. (K2HP04: 3.5 g/L, KH2P0 : 1 g/L, (NH4)2S04: 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgS04 · 7H20: 0.1 g/L), and the suspension was added to 110 mL of Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL) . 3.16 mL.of TA100 culture was added to 120 mL of Exposure medium to prepare test bacterial solution. 588 μL of the test bacterial solution (or mixed solution of 498 μΐ of the test bacterial solution and 90 μΐ, of the S9, in the case with metabolic activation system) were mixed with each 12 μϋ of. the following solutions: the test substance in DMSO (several doses 2- to 3-fold diluted from the maximum dose 50 mg/mL) ;
DMSO as negative control;
50 pg/mL of 4-nitroquinoline-l-oxide in DMSO as positive control for TA98 without metabolic activation system;
0.25 μg/mL of 2- ( 2-furyl ) -3- ( 5-nitro-2-furyl ) acrylamide in DMSO as positive control for TA100 without.metabolic activation system;
40 μg/mL of 2-aminoanthracene in DMSO as positive control for TA98 with metabolic activation system; and .20 μg/mL of 2-aminoanthracene in DMSO as positive control for TA100 with metabolic activation system,
and each mixed solution was incubated at 37 °C under shaking for 90 minutes.
460 'pL of the bacterial solution exposed to the test compound was mixed with 2300 μΐι of Indicator medium (Micro F buffer containing biotin: 8 pg/mL, histidine: 0.2 pg/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 pg/inL) , and each 50 μΙ> was dispensed into 48 wells of the microwell plates per dose, and was subjected to stationary cultivation at 37°C for 3 days. The well containing the bacteria that has acquired proliferating ability by mutation of the gene encoding 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 was counted, and the mutagenicity was evaluated by comparing with the negative control group. (-) means that mutagenicity was negative and (+) means positive.
[0279]
Test Example 8: hERG Test
For the purpose of assessing risk of an electrocardiogram QT interval prolongation, effects on delayed rectifier K+ current (IKr) , which plays an important role in the ventricular repolarization process, was studied using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel. After the cell was retained at a membrane potential of -80 mV by whole.cell patch clamp method using an automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc. ) , IKr induced by depolarization pulse stimulation at +40 mV for 2 seconds and, further, repolarization pulse stimulation at -50 mV for 2 seconds was recorded. After the generated current was stabilized, an extracellular solution wherein the test compound has been dissolved at an objective concentration (NaCl:1.35 mmol/L, KC1 : 5.4 mmol/L, NaH2PO4:0.3 mmol/L, CaCl2 · 2H20 : 1.8 mmol/L, MgCl2 ' 6H20:1 mmol/L, glucose: 10 mmol/L, HEPES ( 4- (2-hydroxyethyl ) -1-piperazineethanesulfonic acid, 4- ( 2-hydroxyethyl ) -l--piperazineethanesulfonic acid): 10 mmol/L, pH=7.4 ) was applied to the cell under the room temperature condition for 10 minutes. From the recording IKr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (DataXpress ver.l, Molecular Devices Corporation) . Further, the percentage of inhibition relative to the tail peak current before application of the test compoud was calculated, and compared with the vehicle-applied group (0.1% dimethyl sulfoxide solution) to assess the effect of the test compound on IKr.
(Result)
The % inhibition at 5 μιηοΙ/L of the compound is shown.
Compound 1-10:18.7%
[0280]
Test Example 9: Solubility Test
The solubility of the compound was determined under the condition with 1% DMSO. A 10 mM solution of the compound was prepared in DMSO, and 6 μΐ, of the compound solution was added to 594 pL of an artificial intestinal juice (118 mL of 0.2 mol/L NaOH, 250 mL of 0.2 mol/L potassium dihydrogen phosphate, and water to 1000 mL; pH 6.8). The mixture was left standing for 16 hours at 25°C, and the mixture was vacuum-filtered. The filtrate was two-fold diluted with methanol/water = 1/1 (V/V) . The concentration in the filtrate was determined by HPLC or LC/MS/MS with an absolute calibration method. (Result)
Compound 1-10: > 50pmol/L
[0281]
Test Example 10: Powder solubility test
Appropriate amounts of the test compound was put into appropriate containers . To the respective containers were added 200 μΐ. of JP-1 fluid (sodium chloride 2.0 g, hydrochloric acid 7.0 mL and water to 1.000 mL) , 200 of JP-2 fluid (phosphate buffer (pH 6.8) 500 mL and water 500 mL) , and 200 L of 20 mmol/L TCA (sodium taurocholate) /JP-2 fluid (TCA 1.08 g and water to reach 100 mL) . In the case that the test compound was dissolved after the addition of the test fluid, the bulk powder was added as appropriate. The containers were sealed, and shaken for 1 hour at 37 °C. The mixtures were filtered, and 100 L of methanol was added to each of the filtrate (100 pL) so that the filtrates were two-fold diluted. The dilution ratio may be changed if necessary. The dilutions were observed for bubbles and precipitates, and then the containers were sealed and shaken. Quantification was performed by HPLC with an absolute calibration method. [0282]
Formulation 1
A granule containing the following ingredients is prepared.
Compound of formula (I) or (II) 10 mg
Lactose 700 mg
Corn starch 274 mg
HPC-L 16 mg
.Total 1000 mg
The compound of formula (I) or (II), and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed with a V-type mixer. To the mixed powder is added a HPC-L (low viscosity hydroxypropylcellulose) aqueous solution, this is kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm), and dried. The resulting dry granule is passed through a vibration sieve (12/60 mesh) to obtain a granule.
[0283]
Formulation 2
A granule for filling a capsule containing the following ingredients is produced. Compound of formula (I) or (II) 15 mg
Lactose 90 mg
Corn starch 42 mg
HPC-L 3 mg
Total 150 mg
The compound of formula (I) or (II), and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed, a HPC-L solution is added to the mixed powder, this is kneaded, granulated, and dried. The resulting dry granule is adjusted in a size, and 150 mg of it is filled into a No .4 hard gelatin capsule..
[0284]
Formulation 3
A tablet containing the following ingredients is prepared.
Compound of formula (I) or (II) 10 mg
Lactose 90 mg
Microcrystalline cellulose 30 mg
CMC-Na 15 mg
Magnesium stearate 5 mg
Total 150 mg The compound of formula (I) or (II), lactose, microcrystalline cellulose, and CMC-Na ( carboxymethylcellulose sodium salt ) are passed through a 60 mesh sieve, and mixed. Magnesium stearate is mixed into the mixed powder to obtain a mixed powder for tabletting. The present mixed powder is directly compressed to obtain a 150 mg of a tablet.
[0285]
Formulation 4
The following ingredients are warmed, mixed, and sterilized to obtain an injectable.
Compound of formula (I) or (II) 3 mg
Nonionic surfactant 15 mg
Purified water for injection 1 ml
[Industrial Applicability]
[0286]
The compound of the invention can be a medicament useful as an agent for treating a disease induced by production, secretion and/or deposition of amyloid β protein.

Claims

[CLAIMS]
[Claim 1]
A compound of the Formula (II) , or a pharmaceutically acceptable salt thereof:
Figure imgf000209_0001
wherein
Ring A is aromatic carbocycle or aromatic heterocycle; -X- is -N(R4)-, -0- or -S-;
R4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio, carboxy or substituted or unsubstituted amino;
-W- is a single bond, - (C (R16) (R17) ) r-, -C(=0)-,
-N (R15) -C (=0) -, -N (R15) -C (R16) (R17)-, or -0-C (R16) (R17) -;
r is 1 or 2;
R15 is hydrogen, or substituted or unsubstituted alkyl; each R16 is independently hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
each R17 is independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; either two R and/or two R on the different carbon atoms are optionally taken together to form a single bond when r is 2;
R11 is. hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy;
R12 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio;
R13 and R14 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted alkylthio;
a dashed line indicates the presence or absence of a bond;
R2a and R2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;
Figure imgf000210_0001
R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or.
unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group;
Rza and Rz are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted . or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , a substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, or substituted or unsubstituted
heterocyclyloxycarbonyl; or Rza and Rzb, taken together with the carbon atom to which they are attached,, optionally form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
R3a, R3b, R3c, R3d, R3e and R3f are. each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio,
substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl , substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted of unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , substituted or unsubstituted carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy , substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
R3a and R3b, taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
R3c and R3d, taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle; Ring Q is substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
Y1 and Y2 are each independently -C(R5) (R6)-, -C(R5)=, -N(R7)-, -N=, -S-, -SO-, -SO2- or -0-;
Y3 and Y4 are each independently -C (R5) (R6) -, -N (R7) -, -S-,
-SO-, -SO2- or -0-;
R5 and R6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl , substituted or
unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl , substituted or unsubstituted
carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy , substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
R7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or
unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl , substituted or unsubstituted
carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
: heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy , substituted or unsubstituted
heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl, or substituted or unsubstituted heterocyclylsulfonyl ;
n is 1, 2 or 3; each R is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio substituted or unsubstituted alkoxy, substituted or
unsubstituted alkoxycarbonyl , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclylalkyl , substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkenyl , substituted or
unsubstituted heterocyclylalkenyl , substituted or
unsubstituted carbocyclylalkynyl , or substituted or
unsubstituted heterocyclylalkynyl ,
provided that the following compounds are excluded:
Figure imgf000217_0001
wherein Ph is phenyl. [Claim 2]
A compound of the Formula (I) , or a pharmaceutically acceptable salt thereof:
Figure imgf000218_0001
wherein
Ring A is aromatic carbocycle or aromatic heterocycle; -X- is -N(R4)-, -0- or -S-;
R4 is hydrogen, halogen, hydroxy, cyano, alkyl, alkenyl, alkynyl, acyl, alkoxy, alkylthio, carboxy, or substituted or unsubstituted amino;
a dashed line indicates the presence or absence of a bond;
R2a and R2b are each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;
Figure imgf000219_0001
R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group;
Rza and Rz are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or. unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy , substituted or unsubstituted carbocyclyloxycarbonyl , a subst tuted or unsubstituted heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, or substituted or unsubstituted
heterocyclyloxycarbonyl , or Rza and Rzb, taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle;
R3a, R3b, R3c, R3d, R3e and R3f are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl , substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl ,. a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl , substituted or unsubstituted carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted heterocyclylalkyl , substituted or unsubstituted heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl, substituted or unsubstituted heterocyclylsulfinyl, or substituted or unsubstituted , heterocyclylsulfonyl ;
R3a and R3b, taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
R3c and R3d, taken together with the carbon atom to which they are attached, optionally form substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
Ring Q is substituted. or unsubstituted carbocycle, or substituted or unsubstituted heterocycle;
Y1 and Y2 are each independently -C(R5) (R6)-, -C(R5)=,
-N(R7)-, -N=, -S-, -SO-, -S02- or -0-;
Y3 and Y4 are each independently -C (R5) (R6) -, -N(R7)-, -S-, -SO-, -S02- or -0-;
R5 and R6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl , substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted alkenyloxycarbonyl , substituted or
unsubstituted alkynyloxycarbonyl , substituted or
unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , a substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy, substituted or unsubstituted
carbocyclyloxycarbonyl , substituted or unsubstituted
carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl;
R7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted
alkoxycarbonyl , substituted or unsubstituted
alkenyloxycarbonyl , substituted or unsubstituted
alkynyloxycarbonyl , substituted or unsubstituted
alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl , substituted or unsubstituted alkynylsulfinyl , substituted or unsubstituted alkylsulfonyl , substituted or unsubstituted alkenylsulfonyl , substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, a substituted or unsubstituted carbocyclic group, substituted or
unsubstituted carbocyclyloxy, substituted or unsubstituted carbocyclylthio, substituted or unsubstituted
carbocyclylalkyl , substituted or unsubstituted
carbocyclylalkoxy , substituted or unsubstituted carbocyclyloxycarbonyl , substituted or unsubstituted
carbocyclylsulfinyl , substituted or unsubstituted
carbocyclylsulfonyl , a substituted or unsubstituted
heterocyclic group, substituted or unsubstituted
heterocyclyloxy, substituted or unsubstituted
heterocyclylthio, substituted or unsubstituted
heterocyclylalkyl , substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted
heterocyclyloxycarbonyl , substituted or unsubstituted heterocyclylsulfinyl , or substituted or unsubstituted heterocyclylsulfonyl ;
n is 1,
2 or 3; and
each R8 is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or
unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or
unsubstituted alkoxycarbonyl , a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted carbocyclylalkyl , substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkenyl, substituted or
unsubstituted heterocyclylalkenyl , substituted or unsubstituted carbocyclylalkynyl , or substituted or unsubstituted heterocyclylalkynyl,
provided that the following compounds are excluded:
Figure imgf000226_0001
wherein Ph is phenyl.
[Claim 3]
The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein
wherein R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R3a, R3b, R3c and R3d are each independently hydrogen, halogen,' hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carbocyclylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted carbocyclylalkoxy, substituted or unsubstituted
heterocyclylalkoxy, substituted or unsubstituted alkylthio, carboxy, substituted or unsubstituted alkoxycarbonyl , substituted or unsubstituted amino, substituted or
unsubstituted carbamoyl , a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; and
R3a and R3b, taken together with the carbon atom to which they are attached, optionally form a carbonyl group, substituted or unsubstituted carbocycle, or substituted or unsubstituted heterocycle.
[Claim 4]
The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein -X- is -N(R4)-, and R3a and R3b, taken together with the carbon atom to which they are attached, form carbonyl group.
[Claim 5]
The compound according to any one of claims 2 to 4 , or a pharmaceutically acceptable salt thereof, wherein R2a and R: are both hydrogen.
[Claim 6]
The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring. A is benzene ring or pyridine ring.
[Claim 7]
The compound according to any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein
one of R8 is a group of the formula:
Figure imgf000228_0001
wherein
Ring B is aromatic carbocycle or aromatic heterocycle; m is 0, 1 or 2;
R9 are each independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkoxycarbonyl; and
Ak is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, and
each of the other R8, when n is 2 or 3, is independently halogen, hydroxy, cyano, carboxy, substituted or unsubstituted acyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclylalkyl , or substituted or unsubstituted non-aromatic heterocyclylalkyl .
[Claim 8]
The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is benzene ring or pyridine ring, and
Figure imgf000230_0001
wherein the ring-constituting atom at any one of α-, β-, γ- or δ-position is nitrogen atom when Ring A is pyridine ring.
[Claim 9]
The compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is benzene ring, or 5- or 6-membered aromatic heterocycle.
[Claim 10]
A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
[Claim 11]
The pharmaceutical composition according to claim 10 having BACEl inhibitory activity.
[Claim 12]
A method for treatment and/or prevention of disease caused by BACEl comprising administering the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
[Claim 13]
The compound according to any one of claims 1 to 9 or a ' pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of disease caused by BACE1.
PCT/JP2013/069231 2012-07-10 2013-07-09 Cyclopropane derivative having bace1 inhibiting activity Ceased WO2014010748A1 (en)

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