WO2011111880A1 - Pharmaceutical composition for treating or preventing diseases caused by the nuclear export of gsk3, including a compound for inhibiting the nuclear export of gsk3 - Google Patents

Pharmaceutical composition for treating or preventing diseases caused by the nuclear export of gsk3, including a compound for inhibiting the nuclear export of gsk3 Download PDF

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WO2011111880A1
WO2011111880A1 PCT/KR2010/001445 KR2010001445W WO2011111880A1 WO 2011111880 A1 WO2011111880 A1 WO 2011111880A1 KR 2010001445 W KR2010001445 W KR 2010001445W WO 2011111880 A1 WO2011111880 A1 WO 2011111880A1
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substituted
unsubstituted
tetrahydropyrido
pyrimidin
bond
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PCT/KR2010/001445
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French (fr)
Korean (ko)
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WO2011111880A9 (en
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육종인
김현실
김남희
노경태
김수연
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주식회사 메디젠텍
사단법인 분자설계연구소
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Priority to PCT/KR2010/001445 priority Critical patent/WO2011111880A1/en
Publication of WO2011111880A1 publication Critical patent/WO2011111880A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition for treating or preventing a disease caused by GSK3 migration from a cell nucleus to a cytoplasm containing a compound that inhibits the migration of GSK3 from the nucleus to the cytoplasm, and more particularly, to the cytoplasm in the nucleus.
  • the present invention relates to a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells and a pharmaceutical composition for treating immunological diseases, which contain a novel compound that inhibits the migration of GSK3 to the stratum.
  • Glycogen synthase kinase-3 (GSK3) is a serine / threonine kinase and has a molecular weight of about 47 kD and phosphorylates 50 proteins.
  • GSK3 has two isoforms, GSK3 ⁇ and GSK3 ⁇ , and these genes are known to be very similar and very similar in function (Double BW & Woodgett. JR, J. Cell Sci., 116: 1175, 2003). .
  • GSK3 has numerous proteins, especially ⁇ -catenin or (1) in the course of (1) onset, (2) cancer development and progression, and (3) development of immune and chronic inflammatory diseases such as rheumatoid arthritis or It regulates the phosphorylation of proteins such as snail.
  • abnormality in signaling systems such as Wnt signaling promotes the development and progression of various diseases by increasing the half-life by inhibiting the phosphorylation of cancer-causing and metastatic activators such as ⁇ -catenin and snail by GSK3.
  • substances that promote the activity of GSK3 in cells or in the nucleus may be helpful in suppressing disease occurrence and progression by Wnt signaling.
  • increasing the activity of GSK3 can reduce the inhibition of GSK3 in the nucleus by Wnt signaling and effectively inhibit the onset and progression of many diseases caused by Wnt signaling.
  • the Axin gene has two isoforms, Axin1 and Axin2 (conductin).
  • the Axin1 and Axin2 genes are known to regulate protein phosphorylation through different transcriptional regulation processes.
  • the Axin gene acts as a negative regulator of Wnt signaling by promoting the phosphorylation of ⁇ -catenin by GSK3 and reducing its half-life (US Patent 2001 / 0052137A1).
  • FRAT-1 and FRAT-2 genes that bind to GSK3 to perform the nuclear export function of GSK3.
  • FRAT was found to be a GSK3 inhibitor, unlike Axin, which is known to promote ⁇ -catenin phosphorylation (Ciani, L. et al. , J. Cell Biol. , 164: 243, 2004; Yost, C. et al. ., Cell, 93: 1031, 1998), as well as GSK3 is different from the binding point and a binding form.
  • it is not related to Wnt at all, but knock-out of either Axin-1 or Axin-2 genes does not normally occur (Chia, IV & Costatini, F., Mol.
  • FRAT-1, -2, -3 can be knocked out in the normal occurrence (van Amerongen, R. et al. , Genes De., 19: 425, 2005) FRAT It is not yet clear what role genes play in Wnt signaling.
  • the present inventors have made diligent efforts to develop new compounds for treating diseases caused by a decrease in GSK3 concentration in the nucleus, resulting in novel compounds that inhibit GSK3 migration from the nucleus to the cytoplasm, and the compounds in the nucleus.
  • the present invention has been found to be useful in treating various diseases caused by decreasing GSK3 concentration.
  • Another object of the present invention is to provide a pharmaceutical composition for treating or preventing GSK3 migration-related diseases from the cell nucleus to the cytoplasm containing the compound as an active ingredient.
  • Another object of the present invention to provide a pharmaceutical composition for inhibiting growth and metastasis of cancer cells containing the compound as an active ingredient.
  • Still another object of the present invention is to provide a pharmaceutical composition for treating an immunological disease containing the compound as an active ingredient.
  • the bond between A and D is a single bond or a double bond
  • A is C ⁇ O, C ⁇ S, SO 2 , CHR a , O, S or NR a, or when the bond between A and D is a double bond, A Is CR a or N;
  • D When the bond between A and D is a single bond, D is CHR d or NR d, or when the bond between A and D is a double bond, D is CR d or N;
  • R a and R d are each independently hydrogen, halogen, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or-(CR 1 R 2 ) n- T 1- (CH 2 ) n T 2- (CH 2 ) n -T 3 ;
  • R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 , substituted or unsubstituted alkyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
  • N 0, 1, 2, 3, 4, 5 or 6;
  • T 1 is a covalent bond, -C (O)-(CR 1 R 2 ) n- , -N (R 1 )-(CR 1 R 2 ) n- , -O- (CR 1 R 2 ) n- , -C (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O)-(CR 1 R 2 ) n- , -S (O) p- (CR 1 R 2 ) n- , -S (O) p N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) S (O) p- (CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -OC (O) N (R 1 )-(
  • P is 1 or 2;
  • T 2 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, Substitute
  • T 3 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -Arylalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heter
  • the bond between G and J is a single bond or a double bond
  • G When the bond between G and J is a single bond, G is CHR g or NR g , or when the bond between G and J is a double bond, G is CR g or N;
  • R g is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic mono- or bicyclic Ring, or-(CR 1 R 2 ) n -T 4- (CR 1 R 2 ) n -T 1- (CH 2 ) n -T 3 ;
  • T 4 is a covalent bond, phenyl, hydroxyphenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxa Substituted or unsubstituted aryl or heteroaryl single, including diazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Or substituted or unsubstituted non-aromatic mono- or bicyclic, including bicyclic rings or piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazolidinyl ring
  • J When the bond between G and J is a double bond, J is CHR j or NR j , or when J and G is a double bond, J is CR j or N;
  • R j is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
  • Y is Y 1 ( ) Or Y 2 ( );
  • W is CHR w or NR w or when Y is Y 2 , W is CR w or N;
  • R w is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or Unsubstituted
  • M is CHR m or NR m or when Y is Y 2 , M is CR m or N;
  • R m is independently hydrogen, halogen,-(CR 1 R 2 ) n -O-alkyl, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 2- (CH 2 ) n- T 3 ;
  • R q is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
  • Z is CHR z or NR z or when Y is Y 2 , Z is CR z or N;
  • R z is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or Unsubstituted
  • the present invention also provides a pharmaceutical composition for inhibiting growth and metastasis of cancer cells containing the compound represented by Formula 2, a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient.
  • FIG. 1 is a schematic diagram showing the activation of ⁇ -catenin, increased Axin2 expression, and GSK3 regulation in the nucleus by Wnt signaling.
  • Figure 2 is a schematic diagram of the process of concentration control of nuclear GSK3 by nuclear signaling by Wnt signaling.
  • FIG. 3 is a schematic diagram of the binding structure of Axin and GSK3.
  • alkyl refers to a saturated straight or branched ratio having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, most preferably 1 to 4 carbon atoms.
  • -Means a cyclic hydrocarbon.
  • saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, and saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2 -Methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl,
  • Alkyl groups may be unsubstituted or substituted. Alkyl groups can be specified as having a certain number of carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms may be specified as a C1-C8 alkyl group, while an alkyl group having 1 to 6 carbon atoms may be specified as a C1-C6 alkyl group.
  • the symbol "-" denotes the point of attachment to the rest of the molecule, wherein one of the hydrogens of the alkyl group is associated with an aryl group. It is substituted with a bond.
  • — (C 1 -C 2 alkyl) aryl includes groups such as —CH 2 Ph, —CH 2 CH 2 Ph and —CH (Ph) CH 3 .
  • alkenyl refers to an unsaturated straight or branched non-cyclic hydrocarbon having 2 to 20 carbon atoms and one or more carbon-carbon double bonds. Preferably alkenyl has 2 to 10 carbon atoms.
  • Exemplary straight-chain alkenyls include, but are not limited to, -but-3-ene, -hex-4-ene and -oct-1-ene.
  • Exemplary branched alkenyls include, but are not limited to, 2-methyl-but-2-ene, -1-methyl-hex-4-ene and -4-ethyl-oct-1-ene Can be.
  • Alkenyl groups may be substituted or unsubstituted.
  • Alkenyl groups can be specified as having a certain number of carbon atoms. For example, alkenyl groups having 2 to 8 carbon atoms can be specified as C 2 -C 8 alkenyl groups, while alkenyl groups with 2 to 6 carbon atoms can be specified as C 2 -C 6 alkenyl groups.
  • alkynyl means an alkyl group wherein one or more carbon-carbon single bonds are replaced with the same number of carbon-carbon triple bonds. Alkynyl groups must contain two or more carbon atoms and can be substituted or unsubstituted. Alkynyl groups can be specified as having a certain number of carbon atoms. For example, an alkynyl group having 2 to 8 carbon atoms may be specified as a C 2 -C 8 alkynyl group, while an alkynyl group having 2 to 6 carbon atoms may be specified as a C 2 -C 6 alkynyl group.
  • oxo means a ⁇ O group.
  • hydroxy and hydroxyl refer to an -OH group.
  • hydroxyalkyl as used herein, means an alkyl group wherein at least one hydrogen is substituted with a hydroxyl group.
  • hydroxyalkenyl as used herein refers to an alkenyl group in which one or more hydrogens are substituted with hydroxyl groups.
  • hydroxyalkynyl as used herein, means an alkynyl group in which one or more hydrogens are substituted with a hydroxyl group.
  • Alkoxy means the structure of formula -O-alkyl, wherein alkyl has the meanings described above.
  • Haloalkoxy means an alkoxy group wherein at least one hydrogen has been replaced with a halogen atom.
  • Hydroxyalkoxy means an alkoxy key in which at least one hydrogen is substituted with a hydroxy group.
  • Alkylsulfonyl means the structure of the formula -S (O) 2 -alkyl.
  • Amino refers to the -NH 2 group.
  • Alkylamino and dialkylamino refer to the structures of the formula -NH-alkyl and -N (alkyl) alkyl, respectively, wherein alkyl is as defined above.
  • the alkyl groups in the dialkylamino groups can be the same or different.
  • Alkylsulfonyl amino refers to the structure of the formula -NHS (O) 2 -alkyl.
  • Carbocyclic ring system and “carbocyclic” refer to ring systems in which all ring members are carbon atoms. Carbocyclic ring systems typically contain 3 to 14 ring atoms. Carbocyclic ring systems may be aromatic or non-aromatic. Carbocyclic ring systems include cycloalkyl rings and may also include fused ring systems. Examples of fused ring carbocyclic ring systems include, but are not limited to, decalin, norbornane, tetrahydronaphthalene, naphthalene, indene and adamantane. Ring atoms in the carbocyclic ring system may be substituted or unsubstituted.
  • heterocyclic ring refers to a carbocyclic ring system in which one or more ring atoms is a hetero atom such as N, O, S or Si.
  • the heterocyclic ring system includes 1 to 4 hetero atoms.
  • the hetero atom is selected from N, O or S.
  • Heterocyclic ring systems can include one ring or a fused ring system.
  • the heterocyclic ring system may comprise two six membered rings fused to each other, or may comprise one five membered ring and one six membered ring fused to each other.
  • Heterocyclic ring systems can be aromatic or non-aromatic, and can be unsaturated, partially unsaturated or saturated. Ring atoms in the heterocyclic ring system may be substituted or unsubstituted.
  • aryl refers to a carbocyclic ring or ring system containing 6 to 14 ring atoms wherein at least one ring is aromatic.
  • the ring atoms of the carbocyclic aryl group are all carbon atoms.
  • Aryl groups include mono-, bi- and tricyclic groups, as well as benzo-fused carbocyclic moieties such as, but not limited to, 5,6,7,8-tetrahydronaphthyl and the like.
  • the aryl group is a monocyclic ring or bicyclic ring.
  • aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and naphthyl.
  • the aryl group can be unsubstituted or substituted.
  • heteroaryl means an aryl group in which one or more, but not all, ring carbon atoms in any ring that is aromatic or non-aromatic is substituted with a hetero atom.
  • pyridine is a heteroaryl group, such as a compound in which benzene is fused to a non-aromatic ring containing one or more hetero atoms.
  • exemplary hetero atoms are N, O, S and Si.
  • the hetero atom is N, O or S.
  • Heteroaryl groups can be unsubstituted or substituted.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3- Pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-iso Sazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, dibenzofuryl, 2-thienyl (2 -Thiophenyl), 3-thienyl (3-thiophenyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidiny
  • Non-limiting examples of other heteroaryl groups include pyridyl, indazolyl, isoquinolinyl, thiazolopyridinyl, benzothiazolonyl, dihydroquinolinonyl, benzoisoxazolyl, benzooxazoloyl, indolinonyl, Benzoimidazolonyl, phthalazinyl, naphthyridinyl, thienopyridinyl, benzodioxolyl, isoindolinonyl, quinazolinyl or cinnaolinyl.
  • cycloalkyl refers to an unsaturated or saturated hydrocarbon that forms one or more rings having 3 to 20 ring carbon atoms, and in some embodiments 3 to 10, 3 to 8 or 3 to 6 ring carbon atoms do.
  • the ring in the cycloalkyl group is non-aromatic. Cycloalkyl groups can be unsubstituted or substituted.
  • a compound of the present invention may be optionally substituted with one or more substituents, such as those generally exemplified above or exemplified by certain classes, subclasses and species of the present invention.
  • substituents such as those generally exemplified above or exemplified by certain classes, subclasses and species of the present invention.
  • substituted refers to the substitution of a hydrogen radical in a given structure with a radical of a specified substituent, whether or not preceded by "optionally”.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from the specified group, such substituents May be the same or different at all positions.
  • Combinations of substituents contemplated in the present invention are preferably combinations which lead to the formation of stable or chemically suitable compounds.
  • inhibiting of growth and metastasis of cancer cells means “anticancer”. That is, it means the action of inhibiting or killing the proliferation of cancer cells and the action of inhibiting or blocking the metastasis of cancer cells, and means both prevention and treatment of cancer.
  • prevention refers to any action that inhibits cancer formation or delays the onset of administration of the composition
  • treatment refers to any action that improves or advantageously changes the symptoms of the disease by administration of the composition. It means.
  • treatment includes (i) preventing the disease, disorder or symptom in a mammal that may be susceptible to disease, disorder and / or symptom but cannot yet be diagnosed with it; (ii) inhibiting a disease, disorder or symptom, ie, arresting their onset; And (iii) alleviating a disease, disorder or symptom, ie, causing regression of one or more of the disease, disorder and / or symptoms, or signs thereof.
  • prevention also specifically refers to the ability of a compound or composition of the invention to prevent such a disease in a mammal diagnosed with or at risk of developing the disease identified herein. The term also includes preventing further progression of the disease in a mammal already suffering from or having signs of the disease.
  • containing as an active ingredient is meant to contain a “therapeutically effective amount” or “prophylactically effective amount” of the compound represented by formula (2) according to the present invention, a pharmaceutically acceptable salt, prodrug or isomer thereof.
  • a “therapeutically effective amount” is a compound of the invention sufficient to provide an advantage in the treatment or prevention of a symptom or disease, such as cancer, to delay or minimize a symptom associated with the symptom or disease, or to treat or ameliorate a disease or cause thereof. Or the amount of a prodrug thereof.
  • a therapeutically effective amount means an amount sufficient to provide a therapeutic benefit in vivo.
  • prophylactically effective amount refers to an amount of a compound of the present invention or other active ingredient sufficient to prevent a symptom or disease, such as cancer, or recurrence or metastasis of the cancer.
  • a prophylactically effective amount refers to an amount sufficient to prevent the initial disease, or recurrence or spread of the disease.
  • the term “preferably” includes non-toxic amounts that improve overall prophylaxis or enhance or synergize with the prophylactic efficacy of another prophylactic or therapeutic agent.
  • the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic and organic acids and bases.
  • the compound of formula (2) is a base, any suitable method available in the art, for example, treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, or organic acids such as acetic acid, male Acids, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acids such as aspartic acid Or by treating with glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic
  • any suitable method is preferred, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline earth metal hydroxide and the like.
  • Phase acceptable salts can be prepared.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and sodium, calcium, Inorganic salts derived from potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the salt can be contacted with a base or acid in a conventional manner and the parent compound can be isolated to regenerate the neutral form of the compound from the salt.
  • the parent form of the compound differs from some physical properties, such as various salt forms, solubility in polar solvents, for the purposes of the present invention, the salt is equivalent to the parent form of the compound.
  • prodrug means any chemical that is converted to various therapeutically effective chemicals after administration.
  • Prodrugs of the compounds described herein are compounds that readily change chemically under physiological conditions to provide the compounds of the present invention.
  • Prodrugs may also be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is present with a suitable enzyme or chemical reagent in a transdermal package reservoir, it may be slowly converted to a compound of the present invention.
  • Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, prodrugs are available in vivo by oral administration, while parent drugs are not.
  • Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug.
  • Various prodrug derivatives such as derivatives based on hydrolytic or oxidative activation of prodrugs, are known in the art.
  • Non-limiting examples of prodrugs will be compounds of the invention that are administered as esters ("prodrugs"), but then metabolically hydrolyzed with an active substance called carboxylic acid. Further examples include peptidyl derivatives of the compounds.
  • the compounds of the present invention may contain one or more asymmetric centers and may therefore exist in racemic and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. have. All such isomeric forms of these compounds are expressly included in the present invention.
  • optically pure or “stereoisomericly pure” means a composition comprising one stereoisomer of a compound and substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomers of the compound.
  • a typical stereoisomerically pure compound is greater than about 80 weight percent of one isomer of the compound, less than about 20 weight percent of the other stereoisomer of the compound, more preferably greater than about 90 weight percent of one stereoisomer of the compound, Less than about 10 weight percent of stereoisomers, even more preferably more than about 95 weight percent of one stereoisomer of the compound, less than about 5 weight percent of the other stereoisomers of the compound, most preferably about 97 weight of one stereoisomer of the compound Greater than weight percent and less than about 3 weight percent of other stereoisomers of the compound.
  • the present invention encompasses the use of stereoisomericly pure forms of such compounds as well as the use of mixtures of these forms.
  • mixtures comprising the same or non-equivalent amounts of enantiomers of certain compounds of the invention can be used in the methods and compositions of the invention.
  • isomers can be synthesized asymmetrically or cleaved using standard techniques such as chiral columns or chiral splitting agents (see, eg, Jacques, J., et al, Enantiomers, Racemates and Resolution (Wiley-lnterscience). , New York, 1981); Wilen, SH, et al.
  • Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present invention.
  • GSK3 tau protein kinase (TPK I), FA factor (Factor A) kinase, kinase FA and ATP-citrate lyase kinase (ACLK).
  • Glycogen synthase kinase 3 present in two isotypes, GSK3 ⁇ and GSK3 ⁇ , is a proline-associated serine / threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase.
  • GSK3 is a glycogen synthase, phosphatase inhibitor I-2, type II subunit of cAMP-dependent protein kinase, G-subunit of phosphatase-1, acetyl coenzyme A carboxylase, myelin basic protein, microtubule- Related protein, neurofibrillary protein, M-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous It has been demonstrated to phosphorylate many proteins in vitro, such as polyposis tumor suppressor protein, tau protein and ⁇ -catenin.
  • the various proteins described above that can be phosphorylated by GSK3 mean that GSK3 is involved in a number of metabolic and regulatory processes in the cell.
  • GSK3 migration-related diseases from the nucleus to the cytoplasm include diseases mediated through GSK3, such as cancer, diabetes mellitus, Niemann Pick's disease type C, bipolar disorder ( Especially manic depression), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, peak Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, postencephalic Parkinsonism ), Frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dyst rophy), subacute sclerotizing panencephalitis, prion disease, Down's syndrome, allergic or asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, Skin diseases such as baldness, pain
  • the signaling mechanism proposed by the present invention suggests a new therapeutic effect and concept of the ⁇ -catenin targeted therapeutic agent that has been developed or developed in the future.
  • As a method of inhibiting the activity of ⁇ -catenin it is known to inhibit the ⁇ -catenin transcriptional regulation by competitively binding to ⁇ -catenin transcription complexes, that is, LEF / TCF, CBP300 and the like. In this case, most of the drugs developed so far have been expected to induce apoptosis of cells by targeting ⁇ -catenin.
  • Wnt signaling reduces the expression of E-cadherin, increases the expression of ⁇ -catenin and Snail, and invades growth and metastasis of cancer cells.
  • Snail phosphorylation control process by ⁇ -catenin is as shown in FIG. Briefly, the expression of Axin is increased by ⁇ -catenin, and Axin binds to GSK3 in the nucleus and transfers GSK3 into the cytoplasm. This increases the expression of Snail and metastasis of cancer cells occurs.
  • 2 is a schematic diagram illustrating the GSK3 concentration control process in the nucleus by Wnt signaling.
  • the activation of ⁇ -catenin gene induces Axin2 gene expression, and the Axin2 gene binds to GSK3 present in the cell nucleus to perform the nuclear export function of GSK3, thereby reducing the concentration of GSK3 in the nucleus.
  • the expression of the Snail gene which is phosphorylated and degraded by GSK3, is increased.
  • increased expression of the Snail gene by Wnt signaling leads to invasive growth and metastasis of cancer cells and clinically leads to continuous recurrence and distant metastasis.
  • FIG. 3 shows the binding structure of Axin and GSK3, it can be seen that Axin binds to GSK3 by Axin-derived peptide fragment (370-390 amino acid sequence of hAxin2) (Dajani et al. , EMBO J. , 22: 494, 2003).
  • Axin and FRAT proteins have ⁇ -helix structure, and the intermediate hydrophobic residues bind to the groove structure of GSK3, and the compound that can competitively bind to inhibit the nuclear export function of GSK3 by Axin or FRAT.
  • Axin1 and Axin2 have very similar structures and similar functions to transfer GSK3 into the cytoplasm inside the nucleus.
  • Axin1 and Axin2 appear to have the same function, ie, very similar structure, by replacing Axin1 and Axin2 during development (Chia, IV & Cos tantini, F., Mol. Cell Biol). ., 25: 4371, 2005).
  • the present inventors have confirmed that the induction of Axin1 or Axin2 expression in cells after numerous trials and errors rapidly decreases the expression of GSK3 in the cell nucleus and consequently strongly increases the expression of the Snail protein, which is phosphorylated and degraded by GSK3.
  • the present invention has a fundamentally different concept from the development of various compounds for inhibiting existing phosphatase. That is, the compound described in the present invention is fundamentally different from the conventional phosphatase inhibition in that it increases the GSK3 kinase activity inside the cell nucleus by inhibiting the nuclear export function of GSK3 by Axin, rather than inhibiting the kinase domain. The concept is different.
  • the present inventors first analyzed the X-ray structure of GSK3-Axin2 to develop a new inhibitor that inhibits the binding of GSK3 and Axin2, and through this, the structural and functional pharmacophore of Axin2 binding to GSK3 Obtained new information on On the basis of this, 39 compounds of the final product obtained through several stages of organic chemical reaction were obtained, and their structure was confirmed through NMR and Mass experiment equipment. The pharmacological activity is for pharmacophore fitness score is ranked higher compound, expected for the selected compounds have been predicted through the docking studies, the actual pharmacological activity of the compound was confirmed by in vitro experiments screeening.
  • the present invention provides a composition for inhibiting GSK3 migration from the nucleus to the cytoplasm comprising a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt, a prodrug, or an isomer thereof, in other words, from the nucleus to the cytoplasm.
  • the bond between A and D is a single bond or a double bond
  • A is C ⁇ O, C ⁇ S, SO 2 , CHR a , O, S or NR a, or when the bond between A and D is a double bond, A Is CR a or N;
  • D When the bond between A and D is a single bond, D is CHR d or NR d, or when the bond between A and D is a double bond, D is CR d or N;
  • R a and R d are each independently hydrogen, halogen, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or-(CR 1 R 2 ) n- T 1- (CH 2 ) n T 2- (CH 2 ) n -T 3 ;
  • R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 , substituted or unsubstituted alkyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
  • N 0, 1, 2, 3, 4, 5 or 6;
  • T 1 is a covalent bond, -C (O)-(CR 1 R 2 ) n- , -N (R 1 )-(CR 1 R 2 ) n- , -O- (CR 1 R 2 ) n- , -C (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O)-(CR 1 R 2 ) n- , -S (O) p- (CR 1 R 2 ) n- , -S (O) p N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) S (O) p- (CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -OC (O) N (R 1 )-(
  • P is 1 or 2;
  • T 2 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, Substitute
  • T 3 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -Arylalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heter
  • the bond between G and J is a single bond or a double bond
  • G When the bond between G and J is a single bond, G is CHR g or NR g , or when the bond between G and J is a double bond, G is CR g or N;
  • R g is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic mono- or bicyclic Ring, or-(CR 1 R 2 ) n -T 4- (CR 1 R 2 ) n -T 1- (CH 2 ) n -T 3 ;
  • T 4 is a covalent bond, phenyl, hydroxyphenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxa Substituted or unsubstituted aryl or heteroaryl single, including diazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Or substituted or unsubstituted non-aromatic mono- or bicyclic, including bicyclic rings or piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazolidinyl ring
  • J When the bond between G and J is a double bond, J is CHR j or NR j , or when J and G is a double bond, J is CR j or N;
  • R j is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
  • Y is Y 1 ( ) Or Y 2 ( );
  • W is CHR w or NR w or when Y is Y 2 , W is CR w or N;
  • R w is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or Unsubstituted
  • M is CHR m or NR m or when Y is Y 2 , M is CR m or N;
  • R m is independently hydrogen, halogen,-(CR 1 R 2 ) n -O-alkyl, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 2- (CH 2 ) n- T 3 ;
  • R q is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
  • Z is CHR z or NR z or when Y is Y 2 , Z is CR z or N;
  • R z is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or Unsubstituted
  • D is NH
  • G is CR g
  • J is N
  • Y may be Y 1 .
  • W when Y is Y 1 , W is CHR w , M is NR m , and Q may be CHR q .
  • W when Y is Y 1 , W may be CHR w , M may be CHR m , and Q may be NR q .
  • A is CHR a
  • D is CR d
  • G is CR g
  • J is N
  • Y may be Y 2 .
  • the compound may be a compound according to the following examples.
  • Example 8 (Compound 73): 1-allyl-3- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) urea
  • Example 22 (Compound 117): 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (1- (blood
  • Example 27 (Compound 146): 4- (1- (4-nicotinoylpiperidin-1-yl) -1-oxopropan-2-yl)
  • Example 38 (Compound 166): 2- (3-Methylpiperidin-1-yl) -6- (quinolin-6-ylmethyl) -5,6,7,8-
  • Example 39 7-isobutyryl-2-morpholino-5,6,7,8-tetrahydropyrido
  • the compound is N1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) piperidine-1,4-dicarboxamide, 1- (4-hydroxy -6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2-methylbenzyl) -2-morpholino-5,6,7,8 Tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl)- 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 7- (2-hydroxy-4-methoxybenzyl) -2-methyl-5, 6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7
  • the compounds according to the present invention are available from commercial compound library vendors such as LeadQuest, Asinex, or can be synthesized through known synthetic methods.
  • the compounds inhibit the nuclear export function of GSK3 by binding to GSK3 competitively with Axin. That is, the compounds according to the present invention inhibit GSK3 migration from the cell nucleus to the cytoplasm by binding to Axin, thereby promoting intracellular activity of GSK, or inhibiting or maintaining and increasing GSK3 concentration or activity decrease in the cell nucleus. It is useful for the treatment of diseases caused by decreasing GSK3 concentration.
  • the above-mentioned diseases related to the movement of GSK3 from the nucleus to the cytoplasm may include diseases mediated through GSK3, such as cancer, diabetes, Niemann Pick's disease type C, bipolar disorder (especially manic depression). ), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, and peak disease ( Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, postencephalic Parkinsonism, Frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dystrophy, Subacute sclerotizing panencephalitis, prion disease, Down syndrome, allergic or asthma, multiple sclerosis, inflammatory diseases such as rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, baldness, etc.
  • the compound according to the present invention inhibits the movement of GSK3 from the nucleus of the cell to the cytoplasm, thereby inhibiting the function of GSK, preventing and It can be useful for treatment. It can also be used to inhibit sperm movement and thus can be used as a male contraceptive.
  • the compounds of the present invention are useful for the prevention or treatment of cancer.
  • the compound of formula (2) or a pharmaceutically acceptable salt, prodrug, or isomer thereof can be used as a medicament.
  • the compounds can be used to prepare a medicament for treating or preventing GSK3 migration-related diseases from the nucleus to the cytoplasm. More particularly, the compounds can be used to prepare a medicament for treating or preventing immune diseases, including arthritis, and cancer.
  • the pharmaceutical composition for inhibiting the growth and metastasis of cancer cells containing the compound represented by the formula (2), a pharmaceutically acceptable salt, prodrug or isomer thereof as an active ingredient and the treatment of immune diseases It relates to a pharmaceutical composition.
  • the composition is a compound 18, 30, 35, 46, 61, 65, 70, 73 to 77, 79, 88 to 93, 115 to 119, 136, 144, 146, 150, 155, 158 to 167 It may contain.
  • the compounds according to the present invention can be usefully used to inhibit the development and progression of autoimmune and degenerative diseases such as rheumatoid arthritis as well as metastasis of cancer cells promoted by Wnt signal transduction.
  • the compounds according to the invention can be used by themselves or in the form of pharmaceutically acceptable acid addition salts or salts of metal complexes such as zinc, iron and the like.
  • the acid addition salt may be selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfate, phosphate, maleate, acetate, citralate, benzoate, succinate, dried salt, ascorbate and tartalate. It is preferable.
  • compositions containing a compound according to the invention as an active ingredient may contain a pharmaceutically acceptable excipient or matrix according to conventional administration methods, dosage forms and therapeutic purposes. Mixing and dilution with a phosphorus carrier or encapsulation in a carrier in the form of a container is preferred. It can also be used in combination with other medicines that are beneficial for the treatment of other bone defects. At this time, the preparation of a physiologically acceptable protein composition having a desired pH, isotonicity, stability and the like can be used within the conventional technical scope in the field of the present invention.
  • the matrix is a biodegradable and chemical substance such as calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, or polyanhydride, depending on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and contact properties; Biodegradable and biological substances such as bone or skin collagen, other pure proteins or matrix components of cells; Non-biodegradable and chemical materials such as sintered hydroxyapatite, bioglass, aluminate or other ceramics; Preference is given to using combinations of the foregoing materials such as polylactic acid, hydroxyapatite, collagen and tricalcium phosphate.
  • the present invention is not limited to the carrier.
  • Excipients in the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stanrate, water, methylhydroxy Benzoate (methylhydroxybenzoate), propylhydroxybenzoate (propylhydroxybenzoate), talc (talc), mineral oil and the like can be used.
  • the compounds of formula (2) may be used in other conventional drugs used to treat cancer, such as platinum coordination compounds such as cisplatin or carboplatin; Taxane compounds such as paclitaxel or docetaxel; Camptothecin compounds such as irinotecan or topotecan; Anti-tumor vinca alkaloids such as vinblastine, vincristine or vinorelbine; Anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine; Nitrogen mustard or nitrosourea alkylating agents such as cyclophosphamide, chlorambucil, carmustine or romustine; Anti-tumor anthracycline derivatives such as daunorubicin, doxorubicin or idarubicin; HER2 antibodies such as trastuzumab; And anti-tumor grapephytotoxin derivatives such as etoposide or ten
  • the present invention also relates to a combination of a compound of formula 2 and another agent capable of preventing or treating cancer.
  • the combination can be used as a medicament.
  • the present invention also relates to a product containing (a) Formula (2) and (b) another agent capable of preventing or treating cancer as a combination formulation for simultaneous, separate or continuous use in the prevention or treatment of cancer.
  • Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.
  • the compounds of formula (2) may be used in other conventional drugs used to treat inflammatory diseases such as steroids, cyclooxygenase-2 inhibitors, nonsteroidal-anti-inflammatory drugs, TNF - ⁇ antibodies, for example acetyl salicylic acid, bufexamac, diclofenac potassium, schlindax, diclofenac sodium, ketorolac tromethamol, tolmethine, ibuprofen, naproxen, naproxen sodium, triaprofenic acid, flubiprofen, mefenamic acid , Niflumic acid, meclofenamate, indomethacin, proglumetacin, ketoprofen, nabumethone, paracetamol, pyroxhamm, tenoxycam, nimesulide, phenylbutazone, tramadol, beclomethasone Dipropionate, betamethasone, beclomethasone Dipropionate, betamethasone, beclomethas
  • the present invention also relates to a combination of a compound of formula (2), a pharmaceutically acceptable salt, prodrug, or isomer and another agent capable of preventing or treating an inflammatory disease.
  • the combination can be used as a medicament.
  • the invention also provides a combination formulation for use simultaneously, separately or continuously in the prevention or treatment of an inflammatory disease, comprising: (a) a compound of formula (2), a pharmaceutically acceptable salt, a prodrug, or an isomer thereof; and (b
  • the present invention relates to a product containing another agent capable of preventing or treating an inflammatory disease.
  • Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.
  • the present invention provides methods for treating or preventing mammals, including humans suffering from GSK3 migration-related diseases from the nucleus to the cytoplasm, more particularly immune diseases including cancer, arthritis, Alzheimer's disease, diabetes, in particular Methods of treating or preventing type 2 diabetes, or bipolar disorder, are provided.
  • the method comprises administering to a mammal, including a human, an effective amount of a compound of Formula 2 or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
  • the pharmaceutical composition containing the compound according to the present invention can be prepared in a variety of formulations, it is preferable to use injectable or capsulated in a viscous form for injection into the site where the therapeutic effect is expected.
  • the dosage of the composition according to the present invention can be adjusted in consideration of the type of carrier such as the excipient or matrix used, the treatment site of the patient, the age, sex and diet of the patient, the severity of the infection, the time of administration and other clinical factors.
  • a conventionally known effective amount can be administered continuously or dividedly, in consideration of weight, to observe the therapeutic effect and to determine further administration.
  • Axin2-His cDNA was obtained by PCR amplification in A549 cells and amplified at the HindIII and BamHI sites of the pcDNA3.1-hyg (+) (invitrogen) vector.
  • Axin2-His cDNA was prepared and amplified in E. coli DH5 ⁇ to obtain pcDNA3.1-Axin2-His expression vector.
  • pcDNA3.1-Axin2-His expression vector After transfection of the episomal Axin2-His expression vector, pcDNA3.1-Axin2-His expression vector, to MCF7 cells (ATCC HTB-26), 200 ⁇ g / ml of hygromycin (hygromycin) ) was treated to obtain Axin2-His overexpressing cells.
  • Triton X-100 lysis buffer was added to the obtained Axin2-His overexpressing cells to obtain cell lysate.
  • 1000 ⁇ l of Triton X-100 lysis buffer was added to 20 ⁇ l of beads, and the procedure of precipitation for 1 minute at 2000 rpm was repeated three times.
  • 10 ⁇ M of the cell lysate and the compounds represented by the compounds 70, 75, 76, 77, 79, 93, 159, 160, and 163 of the compound according to the present invention were added to the neutralized bead, and Triton X-100 lysis buffer was added. The total volume was adjusted to 1000 ⁇ l.
  • a nitrocellulose membrane Pall Corp., NY
  • the primary antibodies were anti-conductin (Sigma) and anti-GSK3 ⁇ (BD Bioscience), and protein expression level was horseradish peroxidase (HRP) -conjugated secondary antibody and enhanced chemiluminescence (ECL) detection kit ( Intron, Korea) was used to sensitize the x-ray film.
  • HRP horseradish peroxidase
  • ECL enhanced chemiluminescence
  • the present invention has an effect of providing a composition for inhibiting the development and progression of a disease caused by the GSK3 migration from the cell nucleus to the cytoplasm, which occurs due to a decrease in the concentration of GSK3 in the nucleus.
  • the compounds according to the present invention are useful for the treatment or prevention of various diseases caused by a decrease in the GSK3 concentration in the nucleus by inhibiting the nuclear export function of GSK3 by Axin and increasing the GSK3 concentration in the nucleus.

Abstract

The present invention relates to a pharmaceutical composition for treating or preventing disease caused by the nuclear export of GSK3, including a compound for inhibiting the nuclear export of GSK3, and more specifically, to a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells and including a novel compound for inhibiting the nuclear export of GSK3, and to a pharmaceutical composition for treating autoimmune diseases. According to the present invention, a composition for inhibiting the onset and progression of a disease caused by a decrease in GSK3 concentration in a cell nucleus through the nuclear export of GSK3 is provided. The compound according to the present invention is useful for treating or preventing various diseases by inhibiting the nuclear export function of GSK3 by Axin and increasing the concentration of GSK3 in the nucleus.

Description

세포핵에서 세포질로의 ＧＳＫ３의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 GSK3 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물 Pharmaceutical compositions for the treatment or prophylaxis of diseases caused by GSK3 migration from the nucleus to the cytoplasm containing a compound that inhibits the transfer of UsX3 from the nucleus to the cytoplasm
본 발명은 세포핵에서 세포질로의 GSK3의 이동을 억제하는 화합물을 함유하는 세포핵에서 세포질로의 GSK3 이동에 의해 발생되는 질환의 치료 또는 예방용 약학적 조성물에 관한 것으로, 보다 상세하게는, 세포핵에서 세포질로의 GSK3의 이동을 억제하는 신규 화합물을 함유하는 암 세포의 성장 또는 전이 억제용 약학적 조성물 및 면역질환 치료용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for treating or preventing a disease caused by GSK3 migration from a cell nucleus to a cytoplasm containing a compound that inhibits the migration of GSK3 from the nucleus to the cytoplasm, and more particularly, to the cytoplasm in the nucleus. The present invention relates to a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells and a pharmaceutical composition for treating immunological diseases, which contain a novel compound that inhibits the migration of GSK3 to the stratum.
글리코겐 신타아제 카이네이즈-3 (glycogen synthase kinase-3, GSK3)은 세린/트레오닌 카이네이즈 (serine/threonine kinase)로서, 약 47kD의 분자량을 가지며, 50여개의 단백질을 인산화시킨다. GSK3은 두 개의 아이소폼 (isoform), 즉 GSK3α 및 GSK3β가 있으며, 이들 유전자는 매우 유사하고 기능도 매우 유사한 것으로 알려져 있다 (Double B.W. & Woodgett. J. R., J. Cell Sci., 116:1175, 2003). Glycogen synthase kinase-3 (GSK3) is a serine / threonine kinase and has a molecular weight of about 47 kD and phosphorylates 50 proteins. GSK3 has two isoforms, GSK3α and GSK3β, and these genes are known to be very similar and very similar in function (Double BW & Woodgett. JR, J. Cell Sci., 116: 1175, 2003). .
GSK3은 (1) 개체 발생, (2) 암 발생 및 진행 과정, (3) 류마티스 관절염 (rheumatic arthritis)과 같은 면역 및 만성 염증성 질환의 발병 과정에서 수많은 단백질, 특히 β-카테닌 (β-catenin) 또는 Snail과 같은 단백질의 인산화를 조절하는 기능을 수행한다. 즉, Wnt signaling과 같은 신호체계의 이상은 GSK3에 의한 β-catenin 및 Snail과 같은 암 발생 및 전이 활성 인자의 인산화를 억제하여 반감기를 증가시킴으로써 다양한 질병의 발생과 진행을 촉진한다. GSK3 has numerous proteins, especially β-catenin or (1) in the course of (1) onset, (2) cancer development and progression, and (3) development of immune and chronic inflammatory diseases such as rheumatoid arthritis or It regulates the phosphorylation of proteins such as snail. In other words, abnormality in signaling systems such as Wnt signaling promotes the development and progression of various diseases by increasing the half-life by inhibiting the phosphorylation of cancer-causing and metastatic activators such as β-catenin and snail by GSK3.
따라서, GSK3의 세포 내 또는 핵 내부의 활성을 촉진하는 물질은 Wnt signaling에 의한 질병 발생 및 진행을 억제하는데 도움이 될 수 있을 것이다. 특히, GSK3의 활성을 증가시킨다면 Wnt signaling 등에 의한 핵 내부의 GSK3 억제를 경감시킬 수 있고, Wnt signaling에 의해 발생하는 많은 질환의 발병 및 진행을 효과적으로 억제할 수 있을 것이다. Thus, substances that promote the activity of GSK3 in cells or in the nucleus may be helpful in suppressing disease occurrence and progression by Wnt signaling. In particular, increasing the activity of GSK3 can reduce the inhibition of GSK3 in the nucleus by Wnt signaling and effectively inhibit the onset and progression of many diseases caused by Wnt signaling.
그러나, GSK3에 의한 기질 단백질의 정확한 인산화 조절과정은 거의 알려져 있지 않고, 핵 내부의 GSK3 활성을 억제하여 발생하는 질환에 대한 치료물질도 거의 알려져 있지 않다. 이는 Wnt signaling에 의한 GSK3에 이르는 기전들이 명확히 밝혀지지 않은 것에 기인한다. However, little is known about the precise phosphorylation process of substrate proteins by GSK3, and little is known about the diseases caused by inhibition of GSK3 activity in the nucleus. This is because the mechanisms leading to GSK3 by Wnt signaling are not clear.
아울러, Axin 유전자는 Axin1 및 Axin2 (conductin)의 두 개의 아이소폼 (isoform)을 가지고 있다. 상기 Axin1 및 Axin2 유전자는 서로 다른 전사 조절 과정을 통해 단백질 인산화를 조절하는 것으로 알려져 있다. Axin 유전자는 GSK3에 의한 β-catenin의 인산화를 촉진하여 반감기를 감소시킴으로써 Wnt signaling의 음성 조절자 (negative regulator)로서의 역할을 한다 (미국특허 2001/0052137A1). In addition, the Axin gene has two isoforms, Axin1 and Axin2 (conductin). The Axin1 and Axin2 genes are known to regulate protein phosphorylation through different transcriptional regulation processes. The Axin gene acts as a negative regulator of Wnt signaling by promoting the phosphorylation of β-catenin by GSK3 and reducing its half-life (US Patent 2001 / 0052137A1).
그 외에 GSK3과 결합하여 GSK3의 nuclear export function을 하는 FRAT-1 및 FRAT-2 유전자가 있다. 그러나, FRAT는 β-catenin의 인산화를 촉진한다고 알려진 Axin과는 달리 GSK3 억제 인자임이 밝혀졌고 (Ciani, L. et al., J. Cell Biol., 164:243, 2004; Yost, C. et al., Cell, 93:1031, 1998), 아울러 GSK3과는 binding point 및 결합 형태가 다르다. 특히, Wnt와 전혀 관련이 없다고 할 수는 없으나, Axin-1이나 Axin-2 유전자 중 하나를 knock-out하면 정상적인 발생이 이루어지지 않지만 (Chia, IV & Costatini, F., Mol. Cell Biol., 25:4371, 2005), FRAT-1, -2, -3을 모두 knock-out시켜도 정상적인 발생이 가능하다는 점에서 (van Amerongen, R. et al., Genes De., 19:425, 2005) FRAT 유전자가 Wnt 신호 전달에서 어떤 역할을 하는지 아직 명확하지 않다.In addition, there are FRAT-1 and FRAT-2 genes that bind to GSK3 to perform the nuclear export function of GSK3. However, FRAT was found to be a GSK3 inhibitor, unlike Axin, which is known to promote β-catenin phosphorylation (Ciani, L. et al. , J. Cell Biol. , 164: 243, 2004; Yost, C. et al. ., Cell, 93: 1031, 1998), as well as GSK3 is different from the binding point and a binding form. In particular, it is not related to Wnt at all, but knock-out of either Axin-1 or Axin-2 genes does not normally occur (Chia, IV & Costatini, F., Mol. Cell Biol. , 25: 4371, 2005), FRAT-1, -2, -3 can be knocked out in the normal occurrence (van Amerongen, R. et al. , Genes De., 19: 425, 2005) FRAT It is not yet clear what role genes play in Wnt signaling.
지금까지 GSK3 활성을 억제하는 약물에 대한 개발이 많이 이루어져 왔으나, GSK3 활성을 증가시켜 Wnt signaling에 의한 질환의 발병 및 진행을 억제하는 개념과 물질은 알려져 있지 않은 실정이다. 본 발명자들은 새롭게 규명한 Axin에 의한 GSK3의 nuclear export function을 근거로 Wnt signaling에 의한 질환의 발병 및 진행을 억제하는 폴리펩티드를 개발한 바 있으며, 구체적으로, 글리코겐 신타아제 카이네이즈 3 (glycogen synthase kinase 3, GSK3)과 결합하는 GBD (GSK3 binding domain) 또는 Axin과 결합하는 ABD (Axin binding domain) 및 세포막 수용체의 도움 없이 세포막을 투과할 수 있게 하는 PTD를 포함하는 폴리펩티드를 개발하였고, 상기 폴리펩티드가 핵 내부의 GSK3 농도 감소에 의해 발생되는 다양한 질환을 치료하는데 유용하다는 것을 확인한 바 있다 (WO 2008/051048).Until now, many drugs have been developed to inhibit GSK3 activity, but concepts and substances that inhibit the onset and progression of diseases caused by Wnt signaling by increasing GSK3 activity are not known. The inventors have developed a polypeptide that inhibits the onset and progression of diseases caused by Wnt signaling based on the newly identified nuclear export function of GSK3 by Axin, and specifically, glycogen synthase kinase 3 (glycogen synthase kinase 3, Polypeptides have been developed that include a GD3 binding domain (GSK3) or ABD (Axin binding domain) that binds Axin and a PTD that can permeate cell membranes without the help of cell membrane receptors. It has been shown to be useful for treating various diseases caused by decreasing GSK3 concentrations (WO 2008/051048).
본 발명자들은, 핵 내부의 GSK3 농도 감소로 인해 발생하는 질환을 치료하기 위한 새로운 화합물을 개발하고자 예의 노력한 결과, 세포핵에서 세포질로의 GSK3 이동을 억제하는 신규 화합물들을 수득하고, 상기 화합물들이 핵 내부의 GSK3 농도 감소에 의해 발생되는 다양한 질환을 치료하는데 유용하다는 것을 확인하고 본 발명을 완성하게 되었다.The present inventors have made diligent efforts to develop new compounds for treating diseases caused by a decrease in GSK3 concentration in the nucleus, resulting in novel compounds that inhibit GSK3 migration from the nucleus to the cytoplasm, and the compounds in the nucleus. The present invention has been found to be useful in treating various diseases caused by decreasing GSK3 concentration.
발명의 요약Summary of the Invention
본 발명의 주된 목적은 Axin과의 결합에 의해 세포핵에서 세포질로의 GSK3 이동을 억제하는 화학식 II의 신규 화합물을 제공하는데 있다.It is a primary object of the present invention to provide novel compounds of formula (II) which inhibit GSK3 migration from the nucleus to the cytoplasm by binding to Axin.
본 발명의 다른 목적은 상기 화합물을 유효성분으로 함유하는 세포핵에서 세포질로의 GSK3 이동 관련 질환의 치료 또는 예방용 약학적 조성물을 제공하는데 있다.Another object of the present invention is to provide a pharmaceutical composition for treating or preventing GSK3 migration-related diseases from the cell nucleus to the cytoplasm containing the compound as an active ingredient.
본 발명의 또 다른 목적은, 상기 화합물을 유효성분으로 함유하는 암 세포의 성장 및 전이 억제용 약학적 조성물을 제공하는데 있다.Another object of the present invention to provide a pharmaceutical composition for inhibiting growth and metastasis of cancer cells containing the compound as an active ingredient.
본 발명의 또 다른 목적은, 상기 화합물을 유효성분으로 함유하는 면역 질환 치료용 약학적 조성물을 제공하는데 있다.Still another object of the present invention is to provide a pharmaceutical composition for treating an immunological disease containing the compound as an active ingredient.
화학식 2
Figure PCTKR2010001445-appb-C000001
 Formula 2
Figure PCTKR2010001445-appb-C000001
상기 식에서, Where
상기 A와 D 사이의 결합은 단일 결합 또는 이중결합; The bond between A and D is a single bond or a double bond;
상기 A와 D 사이의 결합이 단일 결합일 때, A는 C=O, C=S, SO2, CHRa, O, S 또는 NRa이거나, A와 D 사이의 결합이 이중 결합일 때, A는 CRa 또는 N;When the bond between A and D is a single bond, A is C═O, C═S, SO 2 , CHR a , O, S or NR a, or when the bond between A and D is a double bond, A Is CR a or N;
상기 A와 D 사이의 결합이 단일 결합일 때, D는 CHRd 또는 NRd이거나, A와 D 사이의 결합이 이중 결합일 때, D는 CRd 또는 N;When the bond between A and D is a single bond, D is CHR d or NR d, or when the bond between A and D is a double bond, D is CR d or N;
상기 Ra와 Rd는 각각 독립적으로 수소, 할로겐, -OH, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 -(CR1R2)n-T1-(CH2)nT2-(CH2)n-T3;R a and R d are each independently hydrogen, halogen, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or-(CR 1 R 2 ) n- T 1- (CH 2 ) n T 2- (CH 2 ) n -T 3 ;
상기 R1과 R2는 각각 독립적으로 수소, 할로겐, -(CH2)n-CN, -(CH2)n-NO2, -(CH2)n-C(O)OH, -(CH2)n-C(O)H, -(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-C(O)NH2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 치환된 또는 비치환된 아미노; R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 , substituted or unsubstituted alkyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
상기 n은 0, 1, 2, 3, 4, 5 또는 6;N is 0, 1, 2, 3, 4, 5 or 6;
상기 T1 은 공유결합,-C(O)-(CR1R2)n-, -N(R1)-(CR1R2)n-, -O-(CR1R2)n-, -C(O)N(R1)-(CR1R2)n-, -N(R1)C(O)-(CR1R2)n-, -S(O)p-(CR1R2)n-, -S(O)pN(R1)-(CR1R2)n-, -N(R1)S(O)p-(CR1R2)n-, -OC(O)N(R1)-(CR1R2)n-, -N(R1)C(O)O-(CR1R2)n-, -N(R1)C(O)N(R1)-(CR1R2)n-, 또는 -N(R1)C(S)N(R1)-(CR1R2)n-; T 1 is a covalent bond, -C (O)-(CR 1 R 2 ) n- , -N (R 1 )-(CR 1 R 2 ) n- , -O- (CR 1 R 2 ) n- , -C (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O)-(CR 1 R 2 ) n- , -S (O) p- (CR 1 R 2 ) n- , -S (O) p N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) S (O) p- (CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O) O- (CR 1 R 2 ) n- , -N (R 1 ) C (O) N (R 1 )-(CR 1 R 2 ) n- , or -N (R 1 ) C (S) N (R 1 )-(CR 1 R 2 ) n- ;
상기 p는 1 또는 2;P is 1 or 2;
상기 T2 는 공유결합, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 아릴알킬, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤지미다졸릴, 이미다졸릴, 인도릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 헤테로아릴알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 시클로알킬알킬,
Figure PCTKR2010001445-appb-I000001
, 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일 또는 바이시클릭 고리, 퀴놀리닐, 퀴녹사리닐, 퀴나졸리닐, 이소퀴놀리닐 및 프탈라지닐을 포함하는, 각각의 고리에 6개의 원자를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로시클, 또는 이미다조피리미디닐, 이미다조이미다졸릴, 이미다조티아졸릴, 나프틸, 테트라히드로나프틸, 벤조티에닐, 벤족사졸릴, 벤즈이미다졸릴, 벤조이속사졸릴 또는 벤조티아졸릴을 포함하는 하나의 방향족 고리가 다섯 개의 원자를 가지고 다른 하나의 방향족 고리가 6개의 고리를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로시클;T 2 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
Figure PCTKR2010001445-appb-I000001
Substituted or unsubstituted non-aromatic single or bicyclic rings, quinolinyl, quinoxari, including, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl Substituted or unsubstituted bicyclic aromatic heterocycles having 6 atoms in each ring, or imidazopyrimidinyl, imidazoy, including nil, quinazolinyl, isoquinolinyl and phthalazinyl One aromatic ring comprising midazolyl, imidazothiazolyl, naphthyl, tetrahydronaphthyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoisoxazolyl or benzothiazolyl has five atoms and the other Substituted or unsubstituted bicyclic aromatic heterocycle in which one aromatic ring has six rings;
상기 T3는 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 알케닐, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는, 디플루오로페닐, 디메톡시페닐, 메톡시히드록시페닐, 디메틸피라졸릴, 디메틸몰포리닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 옥사졸릴, 옥사디아졸릴, 이속사졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴, 벤조퓨라닐, 벤조트리아졸릴, 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐, 또는
Figure PCTKR2010001445-appb-I000002
를 포함하는 단일- 또는 다중치환된 또는 비치환된 방향족 또는 비-방향족 고리;T 3 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -Arylalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or difluorophenyl, dimethoxyphenyl, methoxyhydroxyphenyl, dimethylpyrazolyl, dimethylmorpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, oxazolyl, oxdiazolyl, isoxazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzo Furanyl, benzotriazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, or
Figure PCTKR2010001445-appb-I000002
Mono- or polysubstituted or unsubstituted aromatic or non-aromatic rings comprising;
상기 G와 J사이의 결합은 단일 결합 또는 이중결합; The bond between G and J is a single bond or a double bond;
G와 J 사이 결합이 단일 결합일 경우, G는 CHRg 또는 NRg, 또는, G와 J 사이 결합이 이중 결합일 경우, G는 CRg 또는 N; When the bond between G and J is a single bond, G is CHR g or NR g , or when the bond between G and J is a double bond, G is CR g or N;
상기 Rg는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 비-방향족 단일- 또는 바이 시클릭 고리, 또는 -(CR1R2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R g is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic mono- or bicyclic Ring, or-(CR 1 R 2 ) n -T 4- (CR 1 R 2 ) n -T 1- (CH 2 ) n -T 3 ;
상기 T4는 공유결합, 페닐, 히드록시페닐, 플루오로페닐, 피리디닐, 피리미디닐, 피라지닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 아릴 또는 헤테로아릴 단일- 또는 바이시클릭 고리, 또는 피페리디닐, 피페라지닐, 몰포리닐, 테트라히드로퓨라닐, 피롤리디닐 또는 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일- 또는 바이시클릭 고리;T 4 is a covalent bond, phenyl, hydroxyphenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxa Substituted or unsubstituted aryl or heteroaryl single, including diazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Or substituted or unsubstituted non-aromatic mono- or bicyclic, including bicyclic rings or piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazolidinyl ring;
상기 G와 J 사이의 결합이 이중 결합인 경우 상기 J는 CHRj 또는 NRj , 또는 J와 G가 이중 결합인 경우, 상기 J 는 CRj 또는 N;When the bond between G and J is a double bond, J is CHR j or NR j , or when J and G is a double bond, J is CR j or N;
상기 Rj는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R j is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
상기 Y 는 Y1 (
Figure PCTKR2010001445-appb-I000003
) 또는 Y2 (
Figure PCTKR2010001445-appb-I000004
);Y is Y 1 (
Figure PCTKR2010001445-appb-I000003
) Or Y 2 (
Figure PCTKR2010001445-appb-I000004
);
Y가 Y1인 경우, 상기 W는 CHRw 또는 NRw 또는 Y가 Y2인 경우, 상기 W는 CRw 또는 N; When Y is Y 1 , W is CHR w or NR w or when Y is Y 2 , W is CR w or N;
상기 Rw는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리;R w is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings;
상기 Y가 Y1인 경우, 상기 M은 CHRm 또는 NRm 또는 상기 Y가 Y2인 경우, 상기 M은 CRm 또는 N;When Y is Y 1 , M is CHR m or NR m or when Y is Y 2 , M is CR m or N;
상기 Rm은 독립적으로 수소, 할로겐, -(CR1R2)n-O-알킬, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T2-(CH2)n-T3;R m is independently hydrogen, halogen,-(CR 1 R 2 ) n -O-alkyl, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 2- (CH 2 ) n- T 3 ;
상기 Y가 Y1인 경우, 상기 Q는 CHRq 또는 NRq, 또는 상기 Y가 Y2인 경우, 상기 Q는 CRq 또는 N;When Y is Y 1 , Q is CHR q or NR q , or when Y is Y 2 , Q is CR q or N;
상기 Rq는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R q is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
상기 Y가 Y1인 경우, 상기 Z는 CHRz 또는 NRz 또는 상기 Y가 Y2인 경우, 상기 Z 는 CRz 또는 N; 및When Y is Y 1 , Z is CHR z or NR z or when Y is Y 2 , Z is CR z or N; And
상기 Rz는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리.R z is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings.
본 발명은 또한 상기 화학식 2로 표시되는 화합물, 그의 약학적으로 허용가능한 염, 전구약물, 또는 이성질체를 유효성분으로 함유하는 암 세포의 성장 및 전이 억제용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for inhibiting growth and metastasis of cancer cells containing the compound represented by Formula 2, a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient.
본 발명의 다른 특징 및 구현예는 다음의 상세한 설명 및 첨부된 특허청구범위로부터 더욱 명백해 질 것이다.Other features and embodiments of the present invention will become more apparent from the following detailed description and the appended claims.
도 1은 Wnt 신호전달에 의한 β-catenin의 활성화, Axin2 발현 증가 및 핵 내부의 GSK3 조절을 나타낸 모식도이다.1 is a schematic diagram showing the activation of β-catenin, increased Axin2 expression, and GSK3 regulation in the nucleus by Wnt signaling.
도 2는 Wnt 신호전달에 의한 핵 내부 GSK3의 농도 조절과정에 대한 모식도이다. Figure 2 is a schematic diagram of the process of concentration control of nuclear GSK3 by nuclear signaling by Wnt signaling.
도 3은 Axin과 GSK3의 결합 구조에 대한 모식도이다.3 is a schematic diagram of the binding structure of Axin and GSK3.
도 4는 본 발명에 따른 화합물 70, 75 내지 77, 79, 93, 159, 160, 163의 Axin2에 대한 활성을 GSK3β 발현량을 통해 분석한 결과이다.4 is a result of analyzing the activity of Axin2 of the compounds 70, 75 to 77, 79, 93, 159, 160, 163 according to the present invention through the expression of GSK3β.
발명의 상세한 설명 및 구체적인 구현예Detailed Description of the Invention and Specific Embodiments
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로, 본 명세서에서 사용된 명명법 및 이하에 기술하는 실험 방법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
1. 용어의 정의1. Definition of terms
본 발명에서 "함유하는", "포함하는" 및 "비롯한"은 열린, 비제한적인 의미로 본원에서 사용된다. In the present invention, "containing", "comprising" and "including" are used herein in an open, non-limiting sense.
달리 명시하지 않는 한, 본원에서 사용된 용어 "알킬"은 1 내지 20개의 탄소 원자, 바람직하게는 1 내지 10개의 탄소 원자, 가장 바람직하게는 1 내지 4개의 탄소 원자를 갖는 포화 직쇄 또는 분지된 비-시클릭 탄화수소를 의미한다. 대표적인 포화 직쇄 알킬로는, 이들로 한정되지는 않지만, -메틸, -에틸, -n-프로필, -n-부틸, -n-펜틸, -n-헥실, -n-헵틸, -n-옥틸, -n-노닐 및 -n-데실을 들 수 있고, 포화 분지 알킬로는, 이들로 한정되지는 않지만, -이소프로필, -sec-부틸, -이소부틸, -tert-부틸, -이소펜틸, 2-메틸부틸, 3-메틸부틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 4-메틸헥실, 5-메틸헥실, 2,3-디메틸부틸, 2,3-디메틸펜틸, 2,4-디메틸펜틸, 2,3-디메틸헥실, 2,4-디메틸헥실, 2,5-디메틸헥실, 2,2-디메틸펜틸, 2,2-디메틸헥실, 3,3-디메틸펜틸, 3,3-디메틸헥실, 4,4-디메틸헥실, 2-에틸펜틸, 3-에틸펜틸, 2-에틸헥실, 3-에틸헥실, 4-에틸헥실, 2-메틸-2-에틸펜틸, 2-메틸-3-에틸펜틸, 2-메틸-4-에틸펜틸, 2-메틸-2-에틸헥실, 2-메틸-3-에틸헥실, 2-메틸-4-에틸헥실, 2,2-디에틸펜틸, 3,3-디에틸헥실, 2,2-디에틸헥실, 3,3-디에틸헥실 등을 들 수 있다. 알킬기는 비치환되거나 또는 치환될 수 있다. 알킬기는 특정 수의 탄소 원자를 갖는 것으로 명시될 수 있다. 예를 들어, 1 내지 8개의 탄소 원자를 갖는 알킬기는 C1-C8 알킬기로 명시될 수 있는 반면, 1 내지 6개의 탄소 원자를 갖는 알킬기는 C1-C6 알킬기로 명시될 수 있다. 이러한 용어가 기타 용어와 함께, 예컨대 용어 "-(C1-C6 알킬)아릴"에서 사용시, 기호 "-"는 분자의 나머지에 대한 부착 지점을 나타내며, 상기 용어는 알킬기의 수소 중 하나가 아릴기와의 결합으로 치환되었음을 나타낸다. 예를 들어, -(C1-C2 알킬)아릴은 -CH2Ph, -CH2CH2Ph 및 -CH(Ph)CH3과 같은 기를 포함한다. Unless otherwise specified, the term "alkyl" as used herein refers to a saturated straight or branched ratio having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, most preferably 1 to 4 carbon atoms. -Means a cyclic hydrocarbon. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, and saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2 -Methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl- 2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2- And the like-ethylhexyl, 3,3-diethylhexyl. Alkyl groups may be unsubstituted or substituted. Alkyl groups can be specified as having a certain number of carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms may be specified as a C1-C8 alkyl group, while an alkyl group having 1 to 6 carbon atoms may be specified as a C1-C6 alkyl group. When used in conjunction with other terms, such as in the term "-(C1-C6 alkyl) aryl", the symbol "-" denotes the point of attachment to the rest of the molecule, wherein one of the hydrogens of the alkyl group is associated with an aryl group. It is substituted with a bond. For example, — (C 1 -C 2 alkyl) aryl includes groups such as —CH 2 Ph, —CH 2 CH 2 Ph and —CH (Ph) CH 3 .
달리 명시하지 않는 한, 본원에서 사용된 용어 "알케닐"은 2 내지 20개의 탄소 원자 및 하나 이상의 탄소-탄소 이중 결합을 갖는 불포화 직쇄 또는 분지된 비-시클릭 탄화수소를 의미한다. 바람직하게는 알케닐은 2 내지 10개의 탄소 원자를 갖는다. 예시적인 직쇄 알케닐로는, 이들로 한정되지는 않지만, -부트-3-엔, -헥스-4-엔 및 -옥트-1-엔을 들 수 있다. 예시적인 분지쇄 알케닐로는, 이들로 한정되지는 않지만, -2-메틸-부트-2-엔, -1-메틸-헥스-4-엔 및 -4-에틸-옥트-1-엔을 들 수 있다. 알케닐기는 치환되거나 또는 비치환될 수 있다. 알케닐기는 특정 수의 탄소 원자를 갖는 것으로 명시될 수 있다. 예를 들어, 2 내지 8개의 탄소 원자를 갖는 알케닐기는 C2-C8 알케닐기로 명시될 수 있는 반면, 2 내지 6개의 탄소 원자를 갖는 알케닐기는 C2-C6 알케닐기로 명시될 수 있다.Unless otherwise specified, the term "alkenyl" as used herein refers to an unsaturated straight or branched non-cyclic hydrocarbon having 2 to 20 carbon atoms and one or more carbon-carbon double bonds. Preferably alkenyl has 2 to 10 carbon atoms. Exemplary straight-chain alkenyls include, but are not limited to, -but-3-ene, -hex-4-ene and -oct-1-ene. Exemplary branched alkenyls include, but are not limited to, 2-methyl-but-2-ene, -1-methyl-hex-4-ene and -4-ethyl-oct-1-ene Can be. Alkenyl groups may be substituted or unsubstituted. Alkenyl groups can be specified as having a certain number of carbon atoms. For example, alkenyl groups having 2 to 8 carbon atoms can be specified as C 2 -C 8 alkenyl groups, while alkenyl groups with 2 to 6 carbon atoms can be specified as C 2 -C 6 alkenyl groups.
달리 명시하지 않는 한, 본원에서 사용된 용어 "알키닐"은 하나 이상의 탄소-탄소 단일 결합이 동일한 수의 탄소-탄소 삼중 결합으로 치환된 알킬기를 의미한다. 알키닐기는 2개 이상의 탄소 원자를 포함해야 하며, 치환되거나 또는 비치환될 수 있다. 알키닐기는 특정 수의 탄소 원자를 갖는 것으로 명시될 수 있다. 예를 들어, 2 내지 8개의 탄소 원자를 갖는 알키닐기는 C2-C8 알키닐기로 명시될 수 있는 반면, 2 내지 6개의 탄소 원자를 갖는 알키닐기는 C2-C6 알키닐기로 명시될 수 있다. Unless otherwise specified, the term "alkynyl" as used herein, means an alkyl group wherein one or more carbon-carbon single bonds are replaced with the same number of carbon-carbon triple bonds. Alkynyl groups must contain two or more carbon atoms and can be substituted or unsubstituted. Alkynyl groups can be specified as having a certain number of carbon atoms. For example, an alkynyl group having 2 to 8 carbon atoms may be specified as a C 2 -C 8 alkynyl group, while an alkynyl group having 2 to 6 carbon atoms may be specified as a C 2 -C 6 alkynyl group.
본원에서 사용된 용어 "옥소"는 =O기를 의미한다. 본원에서 사용된 용어 "히드록시" 및 "히드록실"은 -OH기를 의미한다. 달리 명시하지 않는 한, 본원에서 사용된 용어 "히드록시알킬"은 하나 이상의 수소가 히드록실기로 치환된 알킬기를 의미한다. 달리 명시하지 않는 한, 본원에서 사용된 용어 "히드록시알케닐"은 하나 이상의 수소가 히드록실기로 치환된 알케닐기를 의미한다. 달리 명시하지 않는 한, 본원에서 사용된 용어 "히드록시알키닐"은 하나 이상의 수소가 히드록실기로 치환된 알키닐기를 의미한다.As used herein, the term “oxo” means a ═O group. As used herein, the terms "hydroxy" and "hydroxyl" refer to an -OH group. Unless otherwise specified, the term "hydroxyalkyl" as used herein, means an alkyl group wherein at least one hydrogen is substituted with a hydroxyl group. Unless otherwise specified, the term "hydroxyalkenyl" as used herein refers to an alkenyl group in which one or more hydrogens are substituted with hydroxyl groups. Unless otherwise specified, the term "hydroxyalkynyl" as used herein, means an alkynyl group in which one or more hydrogens are substituted with a hydroxyl group.
"알콕시"는 화학식 -O-알킬의 구조를 의미하며, 여기서 알킬은 상기에서 설명된 의미를 갖는다. "할로알콕시"는 하나 이상의 수소가 할로겐 원자로 치환된 알콕시기를 의미한다. "히드록시알콕시"는 하나 이상의 수소가 히드록시기로 치환된 알콕시키를 의미한다. "알킬설포닐"은 화학식 -S(O)2-알킬의 구조를 의미한다. "아미노"는 -NH2기를 의미한다. "알킬아미노" 및 "디알킬아미노"는 각각 화학식 -NH-알킬 및 -N(알킬)알킬의 구조를 의미하며, 여기서 알킬은 상기에서 정의된 바와 같다. 디알킬아미노기에서 알킬기는 동일하거나 상이할 수 있다. "알킬설포닐 아미노"는 화학식 -NHS(O)2-알킬의 구조를 의미한다."Alkoxy" means the structure of formula -O-alkyl, wherein alkyl has the meanings described above. "Haloalkoxy" means an alkoxy group wherein at least one hydrogen has been replaced with a halogen atom. "Hydroxyalkoxy" means an alkoxy key in which at least one hydrogen is substituted with a hydroxy group. "Alkylsulfonyl" means the structure of the formula -S (O) 2 -alkyl. "Amino" refers to the -NH 2 group. "Alkylamino" and "dialkylamino" refer to the structures of the formula -NH-alkyl and -N (alkyl) alkyl, respectively, wherein alkyl is as defined above. The alkyl groups in the dialkylamino groups can be the same or different. "Alkylsulfonyl amino" refers to the structure of the formula -NHS (O) 2 -alkyl.
"카르보시클릭 고리계" 및 "카르보시클릭"은 모든 고리원이 탄소 원자인 고리계를 의미한다. 카르보시클릭 고리계는 전형적으로는 3 내지 14개의 고리 원자를 포함한다. 카르보시클릭 고리계는 방향족이거나 또는 비-방향족일 수 있다. 카르보시클릭 고리계는 시클로알킬 고리를 포함하고, 또한 융합된 고리계를 포함할 수 있다. 융합된 고리 카르보시클릭 고리계의 예로는, 이들로 한정되지는 않지만, 데칼린, 노르보르난, 테트라히드로나프탈렌, 나프탈렌, 인덴 및 아다만탄을 들 수 있다. 카르보시클릭 고리계에서 고리 원자는 치환되거나 또는 비치환될 수 있다."Carbocyclic ring system" and "carbocyclic" refer to ring systems in which all ring members are carbon atoms. Carbocyclic ring systems typically contain 3 to 14 ring atoms. Carbocyclic ring systems may be aromatic or non-aromatic. Carbocyclic ring systems include cycloalkyl rings and may also include fused ring systems. Examples of fused ring carbocyclic ring systems include, but are not limited to, decalin, norbornane, tetrahydronaphthalene, naphthalene, indene and adamantane. Ring atoms in the carbocyclic ring system may be substituted or unsubstituted.
본원에서 사용된 용어 "헤테로시클릭 고리", "헤테로시클릭" 및 "헤테로시클릴"은 하나 이상의 고리 원자가 헤테로 원자, 예컨대 N, O, S 또는 Si인 카르보시클릭 고리계를 의미한다. 몇몇 실시양태에서, 헤테로시클릭 고리계는 1 내지 4개의 헤테로 원자를 포함한다. 몇몇 실시양태에서, 헤테로 원자는 N, O 또는 S로부터 선택된다. 헤테로시클릭 고리계는 하나의 고리 또는 융합된 고리계를 포함할 수 있다. 비제한적인 예로, 헤테로시클릭 고리계는 서로 융합된 2개의 6원 고리를 포함할 수 있거나, 또는 서로 융합된 1개의 5원 고리 및 1개의 6원 고리를 포함할 수 있다. 헤테로시클릭 고리계는 방향족 또는 비-방향족일 수 있고, 불포화, 부분적으로 불포화 또는 포화될 수 있다. 헤테로시클릭 고리계에서 고리 원자는 치환되거나 또는 비치환될 수 있다.As used herein, the terms “heterocyclic ring”, “heterocyclic” and “heterocyclyl” refer to a carbocyclic ring system in which one or more ring atoms is a hetero atom such as N, O, S or Si. In some embodiments, the heterocyclic ring system includes 1 to 4 hetero atoms. In some embodiments, the hetero atom is selected from N, O or S. Heterocyclic ring systems can include one ring or a fused ring system. By way of non-limiting example, the heterocyclic ring system may comprise two six membered rings fused to each other, or may comprise one five membered ring and one six membered ring fused to each other. Heterocyclic ring systems can be aromatic or non-aromatic, and can be unsaturated, partially unsaturated or saturated. Ring atoms in the heterocyclic ring system may be substituted or unsubstituted.
달리 명시하지 않는 한, 본원에서 사용된 용어 "아릴"은 하나 이상의 고리가 방향족인, 6 내지 14개의 고리 원자를 함유하는 카르보시클릭 고리 또는 고리계를 의미한다. 카르보시클릭 아릴기의 고리 원자는 모두 탄소 원자이다. 아릴기로는 모노-, 바이- 및 트리시클릭기, 뿐만 아니라 벤조-융합된 카르보시클릭 잔기, 예컨대, 이들로 한정되지는 않지만, 5,6,7,8-테트라히드로나프틸 등을 들 수 있다. 몇몇 실시양태에서, 아릴기는 모노시클릭 고리 또는 바이시클릭 고리이다. 대표적인 아릴기로는, 이들로 한정되지는 않지만, 페닐, 톨릴, 안트라세닐, 플루오레닐, 인데닐, 아줄레닐, 페난트레닐 및 나프틸을 들 수 있다. 아릴기는 비치환되거나 또는 치환될 수 있다.Unless otherwise specified, the term "aryl" as used herein refers to a carbocyclic ring or ring system containing 6 to 14 ring atoms wherein at least one ring is aromatic. The ring atoms of the carbocyclic aryl group are all carbon atoms. Aryl groups include mono-, bi- and tricyclic groups, as well as benzo-fused carbocyclic moieties such as, but not limited to, 5,6,7,8-tetrahydronaphthyl and the like. . In some embodiments, the aryl group is a monocyclic ring or bicyclic ring. Representative aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and naphthyl. The aryl group can be unsubstituted or substituted.
용어 "헤테로아릴"은 방향족이거나 또는 비-방향족인 임의의 고리에서 하나 이상의, 그러나 전부는 아닌 고리 탄소 원자가 헤테로 원자로 치환된 아릴기를 의미한다. 예를 들어, 피리딘은, 벤젠이 하나 이상의 헤테로 원자를 포함하는 비-방향족 고리에 융합된 화합물과 같은 헤테로아릴기이다. 예시적인 헤테로 원자는 N, O, S 및 Si이다. 몇몇 실시양태에서, 헤테로 원자는 N, O 또는 S이다. 헤테로아릴기는 비치환되거나 또는 치환될 수 있다. 아릴 및 헤테로아릴기의 비제한적인 예로는 페닐, 1-나프틸, 2-나프틸, 4-바이페닐, 1-피롤릴, 2-피롤릴, 3-피롤릴, 1-피라졸릴, 3-피라졸릴, 5-피라졸릴, 2-이미다졸릴, 4-이미다졸릴, 피라지닐, 2-옥사졸릴, 4-옥사졸릴, 2-페닐-4-옥사졸릴, 5-옥사졸릴, 3-이속사졸릴, 4-이속사졸릴, 5-이속사졸릴, 2-티아졸릴, 4-티아졸릴, 5-티아졸릴, 2-푸라닐, 3-푸라닐, 디벤조푸릴, 2-티에닐 (2-티오페닐), 3-티에닐 (3-티오페닐), 2-피리딜, 3-피리딜, 4-피리딜, 2-피리미디닐, 4-피리미디닐, 5-피리미디닐, 3-피리다지닐, 4-피리다지닐, 5-벤조티아졸릴, 2-벤즈옥사졸릴, 5-벤즈옥사졸릴, 벤조[c][1,2,5]옥사디아졸릴, 푸리닐, 2-벤즈이미다졸릴, 5-인돌릴, 1H-인다졸릴, 카르바졸릴, α-카르볼리닐, β-카르볼리닐, γ-카르볼리닐, 1-이소퀴놀릴, 5-이소퀴놀릴, 2-퀴녹살리닐, 5-퀴녹살리닐, 2-퀴놀릴, 3-퀴놀릴, 4-퀴놀릴, 5-퀴놀릴, 6-퀴놀릴, 7-퀴놀릴 및 8-퀴놀릴을 들 수 있다. 다른 헤테로아릴기의 비제한적인 예로는 피리딜, 인다졸릴, 이소퀴놀리닐, 티아졸로피리디닐, 벤조티아졸로닐, 디히드로퀴놀리노닐, 벤조이속사졸릴, 벤조옥사졸로닐, 인돌리노닐, 벤조이미다졸로닐, 프탈라지닐, 나프티리디닐, 티에노피리디닐, 벤조디옥솔릴, 이소인돌리노닐, 퀴나졸리닐 또는 신놀리닐을 들 수 있다. 비-방향족 고리를 포함하는 아릴 및 헤테로아릴기에서 비-방향족 고리는, 예를 들어, 이들로 한정되지는 않지만, 벤조[d]티아졸-2(3H)-오닐기와 같은 기에서 옥소 (=O) 기를 포함한 본원에 기재된 다양한 기로 치환될 수 있다.The term "heteroaryl" means an aryl group in which one or more, but not all, ring carbon atoms in any ring that is aromatic or non-aromatic is substituted with a hetero atom. For example, pyridine is a heteroaryl group, such as a compound in which benzene is fused to a non-aromatic ring containing one or more hetero atoms. Exemplary hetero atoms are N, O, S and Si. In some embodiments, the hetero atom is N, O or S. Heteroaryl groups can be unsubstituted or substituted. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3- Pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-iso Sazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, dibenzofuryl, 2-thienyl (2 -Thiophenyl), 3-thienyl (3-thiophenyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3 -Pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzo [c] [1,2,5] oxadiazolyl, furinyl, 2-benz Imidazolyl, 5-indolyl, 1H-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2- Quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3- Quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, there may be mentioned 7-quinolyl and 8-quinolyl. Non-limiting examples of other heteroaryl groups include pyridyl, indazolyl, isoquinolinyl, thiazolopyridinyl, benzothiazolonyl, dihydroquinolinonyl, benzoisoxazolyl, benzooxazoloyl, indolinonyl, Benzoimidazolonyl, phthalazinyl, naphthyridinyl, thienopyridinyl, benzodioxolyl, isoindolinonyl, quinazolinyl or cinnaolinyl. Non-aromatic rings in aryl and heteroaryl groups comprising non-aromatic rings are, for example, but not limited to, oxo (=) in groups such as benzo [d] thiazole-2 (3H) -onyl groups. O) can be substituted with a variety of groups described herein, including groups.
용어 "시클로알킬"은 3 내지 20개의 고리 탄소 원자, 몇몇 실시양태에서는 3 내지 10개, 3 내지 8개 또는 3 내지 6개의 고리 탄소 원자를 갖는, 하나 이상의 고리를 형성하는 불포화 또는 포화 탄화수소를 의미한다. 시클로알킬기에서 고리는 비-방향족이다. 시클로알킬기는 비치환되거나 또는 치환될 수 있다.The term "cycloalkyl" refers to an unsaturated or saturated hydrocarbon that forms one or more rings having 3 to 20 ring carbon atoms, and in some embodiments 3 to 10, 3 to 8 or 3 to 6 ring carbon atoms do. The ring in the cycloalkyl group is non-aromatic. Cycloalkyl groups can be unsubstituted or substituted.
본원에 기재된 바와 같이, 본 발명의 화합물은, 상기에서 일반적으로 예시되거나 또는 본 발명의 특정 부류, 하위 부류 및 종으로 예시된 것과 같은 하나 이상의 치환기로 임의 치환될 수 있다. 일반적으로, "치환된"이라는 용어는 "임의로"가 선행하는지 여부에 관계없이, 주어진 구조에서 수소 라디칼이 명시된 치환기의 라디칼로 치환되는 것을 지칭한다. 달리 나타내지 않는 한, 임의 치환된 기는 기의 각각의 치환가능한 위치에서 치환기를 가질 수 있고, 임의의 주어진 구조에서 하나 초과의 위치가 명시된 기로부터 선택된 하나 초과의 치환기로 치환될 수 있는 경우, 상기 치환기는 모든 위치에서 동일하거나 상이할 수 있다. 본 발명에서 고려되는 치환기의 조합은 바람직하게는, 안정하거나 또는 화학적으로 적합한 화합물의 형성을 유발하는 조합이다. As described herein, a compound of the present invention may be optionally substituted with one or more substituents, such as those generally exemplified above or exemplified by certain classes, subclasses and species of the present invention. In general, the term "substituted" refers to the substitution of a hydrogen radical in a given structure with a radical of a specified substituent, whether or not preceded by "optionally". Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from the specified group, such substituents May be the same or different at all positions. Combinations of substituents contemplated in the present invention are preferably combinations which lead to the formation of stable or chemically suitable compounds.
본 발명에서 "암 세포의 성장 및 전이 억제용"은 "항암"을 의미한다. 즉, 암세포의 증식을 억제하거나 사멸하는 작용 및 암세포의 전이를 억제하거나 차단하는 작용을 의미하는 것으로, 암의 예방 및 치료 모두를 의미한다. 본원에 있어서, "예방"이란 조성물의 투여로 암 형성을 억제시키거나 발병을 지연시키는 모든 행위를 의미하는 것이며, "치료"란 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미하는 것이다.In the present invention, "inhibition of growth and metastasis of cancer cells" means "anticancer". That is, it means the action of inhibiting or killing the proliferation of cancer cells and the action of inhibiting or blocking the metastasis of cancer cells, and means both prevention and treatment of cancer. As used herein, "prevention" refers to any action that inhibits cancer formation or delays the onset of administration of the composition, and "treatment" refers to any action that improves or advantageously changes the symptoms of the disease by administration of the composition. It means.
구체적으로, "치료"는, (i) 질환, 장애 및/또는 증상에 걸리기 쉬울 수 있지만, 아직 이를 갖는 것으로는 진단될 수 없는 포유동물에서 상기 질환, 장애 또는 증상을 미연에 예방하는 것; (ii) 질환, 장애 또는 증상을 억제, 즉 이들의 발병을 저지시키는 것; 및 (iii) 질환, 장애 또는 증상을 경감시키는 것, 즉, 질환, 장애 및/또는 증상, 또는 이들의 징후 중 하나 이상의 퇴행을 유발하는 것을 지칭한다. 또한, "예방"은 구체적으로, 본원에서 확인된 질환을 갖는 것으로 진단되거나 이러한 질환이 발병할 위험성이 있는 포유동물에서 상기 질환을 예방하는 본 발명의 화합물 또는 조성물의 능력을 지칭한다. 상기 용어는 또한 이미 상기 질환을 앓고 있거나 그의 징후를 갖는 포유동물에서 질환의 추가 진행을 예방하는 것을 포함한다.In particular, “treatment” includes (i) preventing the disease, disorder or symptom in a mammal that may be susceptible to disease, disorder and / or symptom but cannot yet be diagnosed with it; (ii) inhibiting a disease, disorder or symptom, ie, arresting their onset; And (iii) alleviating a disease, disorder or symptom, ie, causing regression of one or more of the disease, disorder and / or symptoms, or signs thereof. "Prevention" also specifically refers to the ability of a compound or composition of the invention to prevent such a disease in a mammal diagnosed with or at risk of developing the disease identified herein. The term also includes preventing further progression of the disease in a mammal already suffering from or having signs of the disease.
본 발명에서 "유효성분으로 함유하는"은 본 발명에 따른 화학식 2로 표시되는 화합물, 그의 약학적으로 허용가능한 염, 전구약물 또는 이성질체를 "치료유효량" 또는 "예방유효량" 함유하는 것을 의미한다. In the present invention, "containing as an active ingredient" is meant to contain a "therapeutically effective amount" or "prophylactically effective amount" of the compound represented by formula (2) according to the present invention, a pharmaceutically acceptable salt, prodrug or isomer thereof.
"치료 유효량"은 증상 또는 질환, 예컨대 암의 치료 또는 예방에 이점을 제공하거나, 증상 또는 질환과 관련된 징후를 지연 또는 최소화하거나, 또는 질환 또는 그 원인을 치료 또는 개선하기에 충분한, 본 발명의 화합물 또는 그의 전구약물의 양을 지칭한다. 특히, 치료 유효량은 생체내에서 치료 이점을 제공하기에 충분한 양을 의미한다. 본 발명의 화합물의 양과 함께 사용되는 용어 "바람직하게는"은 전반적인 요법을 개선시키거나, 질환의 징후 또는 원인을 감소 또는 피하거나, 또는 또다른 치료제의 치료 효능을 향상시키거나 이와 상승작용을 하는 비독성 양을 포함한다.A "therapeutically effective amount" is a compound of the invention sufficient to provide an advantage in the treatment or prevention of a symptom or disease, such as cancer, to delay or minimize a symptom associated with the symptom or disease, or to treat or ameliorate a disease or cause thereof. Or the amount of a prodrug thereof. In particular, a therapeutically effective amount means an amount sufficient to provide a therapeutic benefit in vivo. The term “preferably” when used in conjunction with the amount of a compound of the present invention, improves the overall therapy, reduces or avoids the signs or causes of the disease, or enhances or synergizes with the therapeutic efficacy of another therapeutic agent. Contains non-toxic amounts.
본원에서 사용된 "예방 유효량"은 증상 또는 질환, 예컨대 암, 또는 암의 재발 또는 전이를 예방하기에 충분한,본 발명의 화합물 또는 다른 활성 성분의 양을 지칭한다. 예방 유효량은 초기 질환, 또는 질환의 재발 또는 확산을 예방하기에 충분한 양을 지칭한다. 용어 "바람직하게는"는 전반적인 예방법을 개선시키거나, 또는 또다른 예방제 또는 치료제의 예방 효능을 향상시키거나 이와 상승작용을 하는 비독성 양을 포함한다.As used herein, “prophylactically effective amount” refers to an amount of a compound of the present invention or other active ingredient sufficient to prevent a symptom or disease, such as cancer, or recurrence or metastasis of the cancer. A prophylactically effective amount refers to an amount sufficient to prevent the initial disease, or recurrence or spread of the disease. The term “preferably” includes non-toxic amounts that improve overall prophylaxis or enhance or synergize with the prophylactic efficacy of another prophylactic or therapeutic agent.
본원에서 사용된 용어 "약학적으로 허용가능한 염"은 무기산 및 유기산 및 염기를 포함한 제약상 허용가능한 비독성산 또는 염기로부터 제조된 염을 지칭한다. 화학식 2의 화합물이 염기인 경우, 당업계에서 이용가능한 임의의 적합한 방법, 예를 들어 유리 염기를 무기산, 예컨대 염산, 브롬화수소산, 황산, 질산, 인산 등으로 처리하거나, 또는 유기산, 예컨대 아세트산, 말레산, 숙신산, 만델산, 푸마르산, 말론산, 피루브산, 옥살산, 글리콜산, 살리실산, 피라노시딜산, 예컨대 글루쿠론산 또는 갈락투론산, 알파-히드록시산, 예컨대 시트르산 또는 타르타르산, 아미노산, 예컨대 아스파르트산 또는 글루탐산, 방향족 산, 예컨대 벤조산 또는 신남산, 술폰산, 예컨대 p-톨루엔술폰산 또는 에탄술폰산 등으로 처리하여 바람직한 제약상 허용가능한 염을 제조할 수 있다. 화학식 2의 화합물이 산인 경우, 임의의 적합한 방법, 예를 들어 유리산을 무기 또는 유기 염기, 예컨대 아민 (1급, 2급 또는 3급), 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 등으로 처리하여 바람직한 제약상 허용가능한 염을 제조할 수 있다. 적합한 염의 실례로는 아미노산, 예컨대 글리신 및 아르기닌으로부터 유도된 유기염, 암모니아, 1급, 2급 및 3급 아민, 및 시클릭 아민, 예컨대 피페리딘, 모르폴린 및 피페라진, 및 나트륨, 칼슘, 칼륨, 마그네슘, 망간, 철, 구리, 아연, 알루미늄 및 리튬으로부터 유도된 무기염을 들 수 있다.As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic and organic acids and bases. If the compound of formula (2) is a base, any suitable method available in the art, for example, treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, or organic acids such as acetic acid, male Acids, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acids such as aspartic acid Or by treating with glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid and the like to produce the desired pharmaceutically acceptable salts. When the compound of formula (2) is an acid, any suitable method is preferred, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline earth metal hydroxide and the like. Phase acceptable salts can be prepared. Examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and sodium, calcium, Inorganic salts derived from potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
통상의 방식으로 염을 염기 또는 산과 접촉시키고, 모 화합물을 단리하여 화합물의 중성 형태를 염으로부터 재생시킬 수 있다. 화합물의 모 형태는 일부 물리적 특성, 예컨대 극성 용매 내 용해도가 다양한 염 형태와 상이하지만, 본 발명의 목적을 위해 염은 화합물의 모 형태와 동등하다.The salt can be contacted with a base or acid in a conventional manner and the parent compound can be isolated to regenerate the neutral form of the compound from the salt. Although the parent form of the compound differs from some physical properties, such as various salt forms, solubility in polar solvents, for the purposes of the present invention, the salt is equivalent to the parent form of the compound.
염 형태 뿐만 아니라 본 발명은 전구약물 형태인 화합물을 제공한다. 용어 "전구약물"은 투여 후 다양한 치료 유효 화학 물질로 전환되는 임의의 화학 물질을 의미한다. 본원에 기재된 화합물의 전구약물은 생리 조건하에 용이하게 화학적으로 변화하여 본 발명의 화합물을 제공하는 화합물이다. 또한, 전구약물은 생체외 환경에서 화학적 또는 생화학적 방법에 의해 본 발명의 화합물로 전환될 수 있다. 예를 들어, 전구약물이 경피 패지 저장소에서 적합한 효소 또는 화학적 시약과 함께 존재하는 경우, 이는 서서히 본 발명의 화합물로 전환될 수 있다. 전구약물은 몇몇 경우에 모 약물보다 용이하게 투여될 수 있으므로 종종 유용하다. 예를 들어, 전구약물은 경구 투여에 의해 생체내에서 이용가능한 반면, 모 약물은 그렇지 않다. 전구약물은 또한 모 약물에 비해 제약 조성물에서 개선된 용해도를 가질 수 있다. 다양한 전구약물 유도체, 예컨대 전구약물의 가수분해 또는 산화 활성화에 기초한 유도체가 당업계에 공지되어 있다. 전구약물의 비제한적인 예는, 에스테르 ("전구약물")로 투여되지만, 이어서 카르복실산이라는 활성 물질로 대사성 가수분해되는 본 발명의 화합물일 것이다. 추가 예로는 화합물의 펩티딜 유도체를 들 수 있다.In addition to salt forms, the present invention provides compounds in prodrug form. The term “prodrug” means any chemical that is converted to various therapeutically effective chemicals after administration. Prodrugs of the compounds described herein are compounds that readily change chemically under physiological conditions to provide the compounds of the present invention. Prodrugs may also be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when a prodrug is present with a suitable enzyme or chemical reagent in a transdermal package reservoir, it may be slowly converted to a compound of the present invention. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, prodrugs are available in vivo by oral administration, while parent drugs are not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Various prodrug derivatives, such as derivatives based on hydrolytic or oxidative activation of prodrugs, are known in the art. Non-limiting examples of prodrugs will be compounds of the invention that are administered as esters ("prodrugs"), but then metabolically hydrolyzed with an active substance called carboxylic acid. Further examples include peptidyl derivatives of the compounds.
본 발명의 화합물은 하나 이상의 비대칭 중심을 함유할 수 있고, 이에 따라 라세미체 및 라세미체 혼합물, 스칼레믹(scalemic) 혼합물, 단일 거울상이성질체, 개별 부분입체이성질체 및 부분입체이성질체 혼합물로 존재할 수 있다. 이들 화합물의 이러한 모든 이성질체 형태가 본 발명에 명백히 포함된다.The compounds of the present invention may contain one or more asymmetric centers and may therefore exist in racemic and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. have. All such isomeric forms of these compounds are expressly included in the present invention.
달리 나타내지 않는 한, 본원에서 사용된 용어 "광학적으로 순수한" 또는 "입체이성질체적으로 순수한"은 화합물의 한 입체이성질체를 포함하고, 상기 화합물의 다른 입체이성질체가 실질적으로 없는 조성물을 의미한다.Unless indicated otherwise, as used herein, the term “optically pure” or “stereoisomericly pure” means a composition comprising one stereoisomer of a compound and substantially free of other stereoisomers of that compound.
예를 들어, 하나의 키랄 중심을 갖는 입체이성질체적으로 순수한 화합물은 화합물의 반대 거울상이성질체가 실질적으로 없을 것이다. 전형적인 입체이성질체적으로 순수한 화합물은 화합물의 한 이성질체를 약 80중량％ 초과, 화합물의 다른 입체이성질체를 약 20 중량％ 미만, 보다 바람직하게는 화합물의 한 입체이성질체를 약 90중량％ 초과, 화합물의 다른 입체이성질체를 약 10 중량％ 미만, 보다 더 바람직하게는 화합물의 한 입체이성질체를 약 95 중량％ 초과, 화합물의 다른 입체이성질체를 약 5 중량％ 미만, 가장 바람직하게는 화합물의 한 입체이성질체를 약 97 중량％ 초과, 화합물의 다른 입체이성질체를 약 3 중량％ 미만 포함한다. 본 발명은 이러한 화합물의 입체이성질체적으로 순수한 형태의 용도 뿐만 아니라 이들 형태의 혼합물의 용도도 포함한다. 예를 들어, 본 발명의 특정 화합물의 거울상이성질체를 동량으로 또는 비-동량으로 포함하는 혼합물이 본 발명의 방법 및 조성물에서 사용될 수 있다. 이들 이성질체는 비대칭적으로 합성되거나 또는 표준 기술, 예컨대 키랄 컬럼 또는 키랄 분할제를 사용하여 분할될 수 있다 (예를 들어, 문헌 [Jacques, J., et al, Enantiomers,Racemates and Resolution (Wiley-lnterscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H.,Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press,Notre Dame, IN, 1972)] 참조).For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomers of the compound. A typical stereoisomerically pure compound is greater than about 80 weight percent of one isomer of the compound, less than about 20 weight percent of the other stereoisomer of the compound, more preferably greater than about 90 weight percent of one stereoisomer of the compound, Less than about 10 weight percent of stereoisomers, even more preferably more than about 95 weight percent of one stereoisomer of the compound, less than about 5 weight percent of the other stereoisomers of the compound, most preferably about 97 weight of one stereoisomer of the compound Greater than weight percent and less than about 3 weight percent of other stereoisomers of the compound. The present invention encompasses the use of stereoisomericly pure forms of such compounds as well as the use of mixtures of these forms. For example, mixtures comprising the same or non-equivalent amounts of enantiomers of certain compounds of the invention can be used in the methods and compositions of the invention. These isomers can be synthesized asymmetrically or cleaved using standard techniques such as chiral columns or chiral splitting agents (see, eg, Jacques, J., et al, Enantiomers, Racemates and Resolution (Wiley-lnterscience). , New York, 1981); Wilen, SH, et al. (1997) Tetrahedron 33: 2725; Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN, 1972)).
본 발명의 화합물은 호변이성질체화(tautomerization) 현상을 나타낼 수 있다. 본원에서 설명된 화학식 2이 모든 가능한 호변이성질체 형태를 명백히 묘사할 수 없지만, 이들 구조가 묘사된 화합물의 모든 호변이성질체 형태를 나타내며, 화학식으로 묘사된 특정 화합물 형태로만 제한되지 않는다는 것을 알 것이다.Compounds of the present invention may exhibit tautomerization. Although Formula 2 described herein does not explicitly depict all possible tautomeric forms, it will be understood that these structures represent all tautomeric forms of the depicted compounds and are not limited to the specific compound forms depicted in the formulas.
본 발명의 일부 화합물은 다중 결정성 또는 비결정성 형태로 존재할 수 있다. 일반적으로, 모든 물리적 형태가 본 발명에 의해 고려되는 용도에 대해 동등하며, 본 발명의 범주에 속한다.Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present invention.
본 발명에서, GSK3의 동의어는 타우 프로테인 키나제 (TPK I), FA 인자 (Factor A) 키나제, 키나제 FA 및ATP-시트레이트 리사제 키나제 (ACLK)이다.In the present invention, synonyms of GSK3 are tau protein kinase (TPK I), FA factor (Factor A) kinase, kinase FA and ATP-citrate lyase kinase (ACLK).
두 개의 이소형, 즉 GSK3α 및 GSK3β로 존재하는 글리코겐 신타제 키나제 3(GSK3)는 원래 글리코겐 신타제를 인산화하는 효소로서 동정된 프롤린-관련 세린/트레오닌 키나제이다. 그러나, GSK3가 글리코겐 신타제, 포스파타제 억제제 I-2, cAMP-의존 프로테인 키나제의 II-형 서브유닛, 포스파타제-1의 G-서브유닛, 아세틸 보조효소 A 카복실라제, 마이엘린 기본 프로테인, 미세관-관련 프로테인, 신경미세섬유 프로테인, M-CAM 세포부착분자, 신경성장인자 수용체, c-Jun 전사인자, JunD 전사인자, c-Myb 전사인자, c-Myc 전사인자, L-Myc 전사인자, 선종성 폴립증 종양 억제 프로테인, 타우 프로테인 및 β-카테닌과 같이 시험관내에서 다수의 프로테인을 인산화하는 것이 입증되었다. GSK3에 의해 인산화될 수 있는 상기한 다양한 프로테인은 GSK3가 세포내에서 다수의 대사 및 조절 과정과 관련이 있음을 의미한다.Glycogen synthase kinase 3 (GSK3), present in two isotypes, GSK3α and GSK3β, is a proline-associated serine / threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase. However, GSK3 is a glycogen synthase, phosphatase inhibitor I-2, type II subunit of cAMP-dependent protein kinase, G-subunit of phosphatase-1, acetyl coenzyme A carboxylase, myelin basic protein, microtubule- Related protein, neurofibrillary protein, M-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous It has been demonstrated to phosphorylate many proteins in vitro, such as polyposis tumor suppressor protein, tau protein and β-catenin. The various proteins described above that can be phosphorylated by GSK3 mean that GSK3 is involved in a number of metabolic and regulatory processes in the cell.
따라서, 본 발명에서, "세포핵에서 세포질로의 GSK3 이동 관련 질환"은, GSK3를 통해 매개된 질병, 예를 들어 암, 당뇨병, C형 니이만-픽병(Niemann Pick's disease type C), 양극성 장애(특히 조울증), 알츠하이머병, FTDP-17(파킨슨병과 관련된 전두측두성 치매), 피질-기저 퇴행(cortico-basal degeneration), 진행성 핵상 마비(progressive supranuclear palsy), 다발성전신위축증(Multiple system atrophy), 피크병(Pick's disease), 권투선수치매(dementia Pugilistica), 에이즈관련 치매 (AIDS associated dementia), 치매, 뇌졸중(stroke), 괌형 파킨슨-치매 증후군 (Guam parkinsonism-dementia complex), 뇌염후 파킨슨 증후군(postencephalic Parkinsonism), 전두엽 퇴행(frontal lobe degeneration), 은친화성 입자 질환(argyrophilic grains disease), 우울장애(depression), 정신분열증(Schizophrenia), 헌팅턴병(Huntington's disease), 근육긴장성 이영양증(myotonic dystrophy), 아급성경화범뇌염(subacute sclerotizing panencephalitis), 프리온 질병(prion disease), 다운증후군, 알러지나 천식, 다발성 경화증, 류마티스 관절염, 동맥경화증, 염증성 장질환(inflammatory bowel disease)과 같은 염증성 질환, 대머리 등의 피부질환, 동통 중 특히 신경병증성 동통, 골관절염, 백혈구감소증 등이 있다. Thus, in the present invention, "GSK3 migration-related diseases from the nucleus to the cytoplasm" include diseases mediated through GSK3, such as cancer, diabetes mellitus, Niemann Pick's disease type C, bipolar disorder ( Especially manic depression), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, peak Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, postencephalic Parkinsonism ), Frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dyst rophy), subacute sclerotizing panencephalitis, prion disease, Down's syndrome, allergic or asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, Skin diseases such as baldness, pain, especially neuropathic pain, osteoarthritis, leukopenia and the like.
2. 본 발명의 구체적 내용2. Specific contents of the present invention
지금까지의 대부분의 항암제나 β-catenin 표적 치료제는 암세포의 사멸 (apoptosis)을 유도하는 물질로 개발되고 있다. 그러므로, 본 발명에서 제시하는 신호전달 기전은 지금까지 개발되었거나 향후 개발되는 β-catenin 표적 치료제의 새로운 치료 효과와 개념을 제시하는 것이다. β-catenin의 활성을 억제하는 방법으로는 β-catenin 전사복합체, 즉 LEF/TCF, CBP300등과 경쟁적으로 결합하여 β-catenin에 의한 전사조절을 억제하는 것이 많이 알려져 있다. 이 경우, 지금까지 개발된 약물의 대부분은 β-catenin을 표적화하여 세포의 apoptosis를 유도하는 효과를 기대하였다.Most anticancer drugs and β-catenin-targeted therapeutic agents to date have been developed as substances that induce apoptosis of cancer cells. Therefore, the signaling mechanism proposed by the present invention suggests a new therapeutic effect and concept of the β-catenin targeted therapeutic agent that has been developed or developed in the future. As a method of inhibiting the activity of β-catenin, it is known to inhibit the β-catenin transcriptional regulation by competitively binding to β-catenin transcription complexes, that is, LEF / TCF, CBP300 and the like. In this case, most of the drugs developed so far have been expected to induce apoptosis of cells by targeting β-catenin.
그러나, 본 발명자들은 암 발생 과정에서 가장 중요한 인자로 알려진 β-catenin (Giles, R.H. et al., Biochim. Biophys. Acta, 1653:1, 2003)의 새로운 기능과 조절 기전을 제시함으로써, β-catenin이 암 발생뿐만 아니라 암세포의 침윤성 성장과 전이를 유도하는 역할을 한다는 것을 규명한 바 있다 (WO 2008/051048). 일반적으로 사람에서 발생하는 암의 90% 이상에서 Wnt 신호전달체계의 유전적 돌연변이나 다른 이상이 관찰되는 바, 암 발생에 있어 Wnt 신호전달 체계가 매우 중요한 것으로 고려되나, Wnt 신호 전달에 대한 구체적인 조절 기전은 잘 알려져 있지 않다. 다만, Wnt 신호전달의 유전적 이상이 공통적으로 β-catenin 유전자를 활성화하고 이를 통해 암 발생과정이 진행된다는 것이다. However, by presenting new functions and regulatory mechanisms of β-catenin (Giles, RH et al. , Biochim. Biophys. Acta , 1653: 1, 2003), which are known to be the most important factors in the development of cancer, In addition to this cancer development, it has been shown to play a role in inducing invasive growth and metastasis of cancer cells (WO 2008/051048). Genetic mutations or other abnormalities of the Wnt signaling system are generally observed in more than 90% of cancers in humans. Therefore, the Wnt signaling system is considered to be very important in the development of cancer. The mechanism is not well known. However, the genetic abnormalities of Wnt signaling activate the β-catenin gene in common and the cancer development process proceeds.
Wnt 신호전달에 의해 E-cadherin의 발현이 감소하고, β-catenin 및 Snail의 발현이 증가하며, 암 세포의 침윤성 성장 및 전이가 발생한다. β-catenin에 의한 Snail 인산화 조절과정을 모식화하면 도 1과 같다. 간략하게 설명하자면, β-catenin에 의해 Axin의 발현이 증가되고, Axin은 핵 내부의 GSK3과 결합하여 GSK3을 세포질로 이동시킨다. 이로 인해 Snail 발현이 증가하고 암 세포의 전이가 발생하게 된다. Wnt 신호전달에 의한 핵 내부의 GSK3 농도 조절 과정을 모식화하면 도 2와 같다. 즉, β-catenin 유전자의 활성화가 Axin2 유전자 발현을 유도하고, Axin2 유전자는 세포핵에 존재하는 GSK3과 결합하여 GSK3의 nuclear export function을 수행하여, 핵 내부의 GSK3 농도를 감소시킨다. 이로 인해, 결과적으로 GSK3에 의해 인산화 및 분해되는 Snail 유전자 발현이 증가하게 되는 것이다. 결국 Wnt 신호 전달에 의한 Snail 유전자의 발현 증가는 암세포의 침윤성 성장과 전이를 유도하고, 임상적으로는 지속적인 재발과 원격전이를 유발하게 된다.Wnt signaling reduces the expression of E-cadherin, increases the expression of β-catenin and Snail, and invades growth and metastasis of cancer cells. Snail phosphorylation control process by β-catenin is as shown in FIG. Briefly, the expression of Axin is increased by β-catenin, and Axin binds to GSK3 in the nucleus and transfers GSK3 into the cytoplasm. This increases the expression of Snail and metastasis of cancer cells occurs. 2 is a schematic diagram illustrating the GSK3 concentration control process in the nucleus by Wnt signaling. That is, the activation of β-catenin gene induces Axin2 gene expression, and the Axin2 gene binds to GSK3 present in the cell nucleus to perform the nuclear export function of GSK3, thereby reducing the concentration of GSK3 in the nucleus. As a result, the expression of the Snail gene, which is phosphorylated and degraded by GSK3, is increased. Eventually, increased expression of the Snail gene by Wnt signaling leads to invasive growth and metastasis of cancer cells and clinically leads to continuous recurrence and distant metastasis.
따라서, Axin의 GSK3과의 결합 부위와 동일하거나 유사한 구조를 가지는 화합물을 이용할 경우, Axin 등에 의한 GSK3의 nuclear export function을 억제함으로써 Wnt 신호전달 및 β-catenin 활성화에 의해 발생하는 다양한 질환의 발생 및 진행을 억제할 수 있다. 특히, 암 환자의 치료에 있어 기존의 β-catenin 표적 치료제나 본 발명에서 제시하는 화합물을 이용하여 지속적인 재발과 원격전이를 억제하거나 조절한다면 암환자의 생존율과 생존기간을 최소 2배 이상 증가시킬 수 있을 것으로 판단되며, 나아가 기존 30년 이상 지속되었던 암 치료 개념을 획기적으로 바꿀 수 있을 것이다.Therefore, when a compound having the same or similar structure as the binding site of Axin to GSK3 is used, the development and progression of various diseases caused by Wnt signaling and β-catenin activation by inhibiting the nuclear export function of GSK3 by Axin, etc. Can be suppressed. In particular, in the treatment of cancer patients, if the existing β-catenin-targeted therapeutic agent or the compound of the present invention is inhibited or controlled, the recurrence and distant metastasis of cancer can be increased by at least 2 times. It is expected to change the concept of cancer treatment that has lasted for more than 30 years.
도 3은 Axin과 GSK3의 결합구조를 나타낸 것으로, Axin 유래 펩티드 단편 (hAxin2의 370~390 아미노산 서열)에 의해 Axin이 GSK3과 결합하는 것을 알 수 있다 (Dajani et al., EMBO J., 22:494, 2003). 이때 Axin 및 FRAT 단백질은 α-helix 구조를 가지고, 그 중간의 hydrophobic residue가 GSK3의 groove 구조에 결합하게 되어, 이와 경쟁적으로 결합할 수 있는 화합물은 Axin이나 FRAT에 의한 GSK3의 nuclear export function을 억제할 수 있다는 사실은 본 발명자들에 의해 처음으로 규명되었고, 지금까지 GSK3과 결합하는 부위로 알려져 있는 Axin1의 아미노산 383~401 부위가 GSK3β의 helix (아미노산 262~273) 및 extended loop (아미노산 285~299)로 형성된 홈 (groove)에 결합하는 것으로 밝혀졌다. 특히, 페닐알라닌388 (Phe388), 루신392 (Leu392), 루신396 (Leu396), 발린399 (Val399)의 잔기로 구성된 hydrophobic ridge가 GSK3β와의 결합에 결정적인 역할을 한다. Axin1과 Axin2는 매우 유사한 구조를 가지고 있으며, 핵 내부의 GSK3을 세포질로 이동시키는 기능도 유사하다. 나아가 발생과정에서 Axin1과 Axin2를 치환하여도 정상적인 발생이 진행되는 것으로 보아 Axin1과 Axin2는 동일한 기능, 즉 매우 유사한 구조를 가지고 있는 것으로 추정된다 (Chia, I.V. & Cos tantini, F., Mol. Cell Biol., 25:4371, 2005). 본 발명자들은 수많은 시행착오 끝에 세포에서 Axin1이나 Axin2 발현을 유도하면 세포 핵 내부의 GSK3 발현이 급격히 감소하고 결과적으로 GSK3에 의해 인산화되어 분해되는 Snail 단백질의 발현이 강력하게 증가하는 것을 확인한 바 있다. Figure 3 shows the binding structure of Axin and GSK3, it can be seen that Axin binds to GSK3 by Axin-derived peptide fragment (370-390 amino acid sequence of hAxin2) (Dajani et al. , EMBO J. , 22: 494, 2003). At this time, the Axin and FRAT proteins have α-helix structure, and the intermediate hydrophobic residues bind to the groove structure of GSK3, and the compound that can competitively bind to inhibit the nuclear export function of GSK3 by Axin or FRAT. The fact that it can be identified for the first time by the present inventors, and the amino acid 383 ~ 401 site of Axin1 so far known as the binding site of GSK3 is the helix (amino acids 262-273) and extended loop (amino acids 285-299) of GSK3β It has been found to bind to grooves formed by. In particular, hydrophobic ridges consisting of residues of phenylalanine 388 (Phe388), leucine 392 (Leu392), leucine 396 (Leu396) and valine 399 (Val399) play a crucial role in binding to GSK3β. Axin1 and Axin2 have very similar structures and similar functions to transfer GSK3 into the cytoplasm inside the nucleus. In addition, Axin1 and Axin2 appear to have the same function, ie, very similar structure, by replacing Axin1 and Axin2 during development (Chia, IV & Cos tantini, F., Mol. Cell Biol). ., 25: 4371, 2005). The present inventors have confirmed that the induction of Axin1 or Axin2 expression in cells after numerous trials and errors rapidly decreases the expression of GSK3 in the cell nucleus and consequently strongly increases the expression of the Snail protein, which is phosphorylated and degraded by GSK3.
지금까지 인산화 효소를 억제하는 화합물은 ATP (Adenosin triphosphate)가 결합하는 kinase domain에 특이적으로 결합하는 약물의 개발이 대부분이었다. 하지만, 본 발명은 기존의 인산화 효소를 억제하고자 하는 다양한 화합물 개발과는 근본적으로 다른 개념을 갖는다. 즉, 본 발명에 기술된 화합물은 kinase domain을 억제하는 것이 아니라, 오히려 Axin에 의한 GSK3의 nuclear export function을 억제함으로서 세포 핵 내부의 GSK3 kinase 활성도를 높인다는 점에서 기존의 인산화 효소 억제와는 근본적으로 개념이 다르다. Until now, the development of drugs that specifically bind to the kinase domain to which ATP (Adenosin triphosphate) binds has been mostly developed. However, the present invention has a fundamentally different concept from the development of various compounds for inhibiting existing phosphatase. That is, the compound described in the present invention is fundamentally different from the conventional phosphatase inhibition in that it increases the GSK3 kinase activity inside the cell nucleus by inhibiting the nuclear export function of GSK3 by Axin, rather than inhibiting the kinase domain. The concept is different.
구체적으로, 본 발명자들은 GSK3와 Axin2의 결합을 억제하는 신규 저해제를 개발하기 위하여, 우선 GSK3-Axin2의 X-ray 구조를 분석하였고, 이를 통하여, GSK3에 결합하는 Axin2의 구조적, 기능적 특징(pharmacophore)에 대한 새로운 정보를 획득하였다. 이를 근거로 하여, 여러 단계의 유기화학반응을 통하여 얻어진 최종 생성물 39개 화합물을 얻고, 그 구조를 NMR과 Mass 실험 장비를 통하여 확인하였다. pharmacophore에 대해 fitness score가 높은 화합물을 선정하고, 선정된 화합물에 대해 기대되는 약리활성은 docking 연구를 통하여 예측되었으며, 화합물의 실제 약리활성은 in vitro screeening 실험을 통하여 확인되었다.Specifically, the present inventors first analyzed the X-ray structure of GSK3-Axin2 to develop a new inhibitor that inhibits the binding of GSK3 and Axin2, and through this, the structural and functional pharmacophore of Axin2 binding to GSK3 Obtained new information on On the basis of this, 39 compounds of the final product obtained through several stages of organic chemical reaction were obtained, and their structure was confirmed through NMR and Mass experiment equipment. The pharmacological activity is for pharmacophore fitness score is ranked higher compound, expected for the selected compounds have been predicted through the docking studies, the actual pharmacological activity of the compound was confirmed by in vitro experiments screeening.
본 발명은 일 관점에서, 하기 화학식 2로 표시되는 화합물, 그의 약학적으로 허용가능한 염, 전구약물, 또는 이성질체를 포함하는 세포핵에서 세포질로의 GSK3 이동 억제용 조성물, 다시말해, 세포핵에서 세포질로의 GSK3 이동 관련 질환의 치료 또는 예방용 약학적 조성물에 관한 것이다:In one aspect, the present invention provides a composition for inhibiting GSK3 migration from the nucleus to the cytoplasm comprising a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt, a prodrug, or an isomer thereof, in other words, from the nucleus to the cytoplasm. A pharmaceutical composition for treating or preventing GSK3 migration-related diseases:
화학식 2 Formula 2
Figure PCTKR2010001445-appb-I000005
Figure PCTKR2010001445-appb-I000005
상기 식에서, Where
상기 A와 D 사이의 결합은 단일 결합 또는 이중결합; The bond between A and D is a single bond or a double bond;
상기 A와 D 사이의 결합이 단일 결합일 때, A는 C=O, C=S, SO2, CHRa, O, S 또는 NRa이거나, A와 D 사이의 결합이 이중 결합일 때, A는 CRa 또는 N;When the bond between A and D is a single bond, A is C═O, C═S, SO 2 , CHR a , O, S or NR a, or when the bond between A and D is a double bond, A Is CR a or N;
상기 A와 D 사이의 결합이 단일 결합일 때, D는 CHRd 또는 NRd이거나, A와 D 사이의 결합이 이중 결합일 때, D는 CRd 또는 N;When the bond between A and D is a single bond, D is CHR d or NR d, or when the bond between A and D is a double bond, D is CR d or N;
상기 Ra와 Rd는 각각 독립적으로 수소, 할로겐, -OH, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 -(CR1R2)n-T1-(CH2)nT2-(CH2)n-T3;R a and R d are each independently hydrogen, halogen, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or-(CR 1 R 2 ) n- T 1- (CH 2 ) n T 2- (CH 2 ) n -T 3 ;
상기 R1과 R2는 각각 독립적으로 수소, 할로겐, -(CH2)n-CN, -(CH2)n-NO2, -(CH2)n-C(O)OH, -(CH2)n-C(O)H, -(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-C(O)NH2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 치환된 또는 비치환된 아미노; R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 , substituted or unsubstituted alkyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
상기 n은 0, 1, 2, 3, 4, 5 또는 6;N is 0, 1, 2, 3, 4, 5 or 6;
상기 T1 은 공유결합,-C(O)-(CR1R2)n-, -N(R1)-(CR1R2)n-, -O-(CR1R2)n-, -C(O)N(R1)-(CR1R2)n-, -N(R1)C(O)-(CR1R2)n-, -S(O)p-(CR1R2)n-, -S(O)pN(R1)-(CR1R2)n-, -N(R1)S(O)p-(CR1R2)n-, -OC(O)N(R1)-(CR1R2)n-, -N(R1)C(O)O-(CR1R2)n-, -N(R1)C(O)N(R1)-(CR1R2)n-, 또는 -N(R1)C(S)N(R1)-(CR1R2)n-; T 1 is a covalent bond, -C (O)-(CR 1 R 2 ) n- , -N (R 1 )-(CR 1 R 2 ) n- , -O- (CR 1 R 2 ) n- , -C (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O)-(CR 1 R 2 ) n- , -S (O) p- (CR 1 R 2 ) n- , -S (O) p N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) S (O) p- (CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O) O- (CR 1 R 2 ) n- , -N (R 1 ) C (O) N (R 1 )-(CR 1 R 2 ) n- , or -N (R 1 ) C (S) N (R 1 )-(CR 1 R 2 ) n- ;
상기 p는 1 또는 2;P is 1 or 2;
상기 T2 는 공유결합, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 아릴알킬, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤지미다졸릴, 이미다졸릴, 인도릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 헤테로아릴알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 시클로알킬알킬,
Figure PCTKR2010001445-appb-I000006
, 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일 또는 바이시클릭 고리, 퀴놀리닐, 퀴녹사리닐, 퀴나졸리닐, 이소퀴놀리닐 및 프탈라지닐을 포함하는, 각각의 고리에 6개의 원자를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로시클, 또는 이미다조피리미디닐, 이미다조이미다졸릴, 이미다조티아졸릴, 나프틸, 테트라히드로나프틸, 벤조티에닐, 벤족사졸릴, 벤즈이미다졸릴, 벤조이속사졸릴 및 벤조티아졸릴을 비롯한 하나의 방향족 고리가 다섯 개의 원자를 가지고 다른 하나의 방향족 고리가 6개의 고리를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로시클;T 2 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
Figure PCTKR2010001445-appb-I000006
Substituted or unsubstituted non-aromatic single or bicyclic rings, quinolinyl, quinoxari, including, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl Substituted or unsubstituted bicyclic aromatic heterocycles having 6 atoms in each ring, or imidazopyrimidinyl, imidazoy, including nil, quinazolinyl, isoquinolinyl and phthalazinyl One aromatic ring, including midazolyl, imidazothiazolyl, naphthyl, tetrahydronaphthyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoisoxazolyl and benzothiazolyl has five atoms and the other A substituted or unsubstituted bicyclic aromatic heterocycle in which the aromatic ring of has six rings;
상기 T3는 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 알케닐, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는, 디플루오로페닐, 디메톡시페닐, 메톡시히드록시페닐, 디메틸피라졸릴, 디메틸몰포리닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 옥사졸릴, 옥사디아졸릴, 이속사졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴, 벤조퓨라닐, 벤조트리아졸릴, 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐, 또는
Figure PCTKR2010001445-appb-I000007
를 비롯한 단일- 또는 다중치환된 또는 비치환된 방향족 또는 비-방향족 고리;T 3 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -Arylalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or difluorophenyl, dimethoxyphenyl, methoxyhydroxyphenyl, dimethylpyrazolyl, dimethylmorpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, oxazolyl, oxdiazolyl, isoxazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzo Furanyl, benzotriazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, or
Figure PCTKR2010001445-appb-I000007
Mono- or polysubstituted or unsubstituted aromatic or non-aromatic rings, including;
상기 G와 J사이의 결합은 단일 결합 또는 이중결합; The bond between G and J is a single bond or a double bond;
G와 J 사이 결합이 단일 결합일 경우, G는 CHRg 또는 NRg, 또는, G와 J 사이 결합이 이중 결합일 경우, G는 CRg 또는 N; When the bond between G and J is a single bond, G is CHR g or NR g , or when the bond between G and J is a double bond, G is CR g or N;
상기 Rg는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 비-방향족 단일- 또는 바이 시클릭 고리, 또는 -(CR1R2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R g is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic mono- or bicyclic Ring, or-(CR 1 R 2 ) n -T 4- (CR 1 R 2 ) n -T 1- (CH 2 ) n -T 3 ;
상기 T4는 공유결합, 페닐, 히드록시페닐, 플루오로페닐, 피리디닐, 피리미디닐, 피라지닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 아릴 또는 헤테로아릴 단일- 또는 바이시클릭 고리, 또는 피페리디닐, 피페라지닐, 몰포리닐, 테트라히드로퓨라닐, 피롤리디닐 또는 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일- 또는 바이시클릭 고리;T 4 is a covalent bond, phenyl, hydroxyphenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxa Substituted or unsubstituted aryl or heteroaryl single, including diazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Or substituted or unsubstituted non-aromatic mono- or bicyclic, including bicyclic rings or piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazolidinyl ring;
상기 G와 J 사이의 결합이 이중 결합인 경우 상기 J는 CHRj 또는 NRj , 또는 J와 G가 이중 결합인 경우, 상기 J 는 CRj 또는 N;When the bond between G and J is a double bond, J is CHR j or NR j , or when J and G is a double bond, J is CR j or N;
상기 Rj는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R j is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
상기 Y 는 Y1 (
Figure PCTKR2010001445-appb-I000008
) 또는 Y2 (
Figure PCTKR2010001445-appb-I000009
);Y is Y 1 (
Figure PCTKR2010001445-appb-I000008
) Or Y 2 (
Figure PCTKR2010001445-appb-I000009
);
Y가 Y1인 경우, 상기 W는 CHRw 또는 NRw 또는 Y가 Y2인 경우, 상기 W는 CRw 또는 N; When Y is Y 1 , W is CHR w or NR w or when Y is Y 2 , W is CR w or N;
상기 Rw는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리;R w is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings;
상기 Y가 Y1인 경우, 상기 M은 CHRm 또는 NRm 또는 상기 Y가 Y2인 경우, 상기 M은 CRm 또는 N;When Y is Y 1 , M is CHR m or NR m or when Y is Y 2 , M is CR m or N;
상기 Rm은 독립적으로 수소, 할로겐, -(CR1R2)n-O-알킬, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T2-(CH2)n-T3;R m is independently hydrogen, halogen,-(CR 1 R 2 ) n -O-alkyl, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 2- (CH 2 ) n- T 3 ;
상기 Y가 Y1인 경우, 상기 Q는 CHRq 또는 NRq, 또는 상기 Y가 Y2인 경우, 상기 Q는 CRq 또는 N;When Y is Y 1 , Q is CHR q or NR q , or when Y is Y 2 , Q is CR q or N;
상기 Rq는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R q is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
상기 Y가 Y1인 경우, 상기 Z는 CHRz 또는 NRz 또는 상기 Y가 Y2인 경우, 상기 Z 는 CRz 또는 N; 및When Y is Y 1 , Z is CHR z or NR z or when Y is Y 2 , Z is CR z or N; And
상기 Rz는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리.R z is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings.
본 발명에 있어서, 상기 A는 C=O이고, D는 NH이며, G는 CRg이고, J는 N이며, Y는 Y1일 수 있다. In the present invention, A may be C = O, D is NH, G is CR g , J is N, and Y may be Y 1 .
본 발명에 있어서, 상기 Y는 Y1인 경우, W는 CHRw이고, M은 NRm이며, Q는 CHRq일 수 있다. 또는, 상기 Y는 Y1인 경우, W는 CHRw이고, M은 CHRm이며, Q는 NRq일 수 있다. In the present invention, when Y is Y 1 , W is CHR w , M is NR m , and Q may be CHR q . Alternatively, when Y is Y 1 , W may be CHR w , M may be CHR m , and Q may be NR q .
본 발명에 있어서, 상기 A는 CHRa이고, D는 CRd이며, G는 CRg이고, J는 N이며, Y는 Y2일 수 있다. In the present invention, A is CHR a , D is CR d , G is CR g , J is N, Y may be Y 2 .
본 발명에 있어서, 상기 Y는 Y2인 경우, W는 NRw이고, M은 CHRm이며, Q는 CRq일 수 있다. In the present invention, when Y is Y 2 , W is NR w , M is CHR m , and Q may be CR q .
본 발명에 있어서, 상기 화합물은 구체적으로, 다음의 실시예에 따른 화합물일 수 있다. In the present invention, specifically, the compound may be a compound according to the following examples.
실시예 1 (화합물 18) : N-(4-에틸펜에틸)나프탈렌-1-설폰아미드Example 1 (Compound 18): N- (4-ethylphenethyl) naphthalene-1-sulfonamide
Figure PCTKR2010001445-appb-I000010
Figure PCTKR2010001445-appb-I000010
실시예 2 (화합물 30번) : N-(2,3-디히드로-1H-인덴-2-일)나프탈렌-2-설폰아미드Example 2 (Compound No. 30): N- (2,3-dihydro-1H-inden-2-yl) naphthalene-2-sulfonamide
Figure PCTKR2010001445-appb-I000011
Figure PCTKR2010001445-appb-I000011
실시예 3 (화합물 35) : N-부틸퀴놀린-8-설폰아미드Example 3 (Compound 35): N-butylquinoline-8-sulfonamide
Figure PCTKR2010001445-appb-I000012
Figure PCTKR2010001445-appb-I000012
실시예 4 (화합물 46) : N-(2-(3-(피리딘-4-일)-1H-1,2,4-트리아졸-5-일)에틸)퀴놀Example 4 (Compound 46): N- (2- (3- (pyridin-4-yl) -1H-1,2,4-triazol-5-yl) ethyl) quinol
린-8-카복스아미드Lean-8-carboxamide
Figure PCTKR2010001445-appb-I000013
Figure PCTKR2010001445-appb-I000013
실시예 5 (화합물 61) : 2-(1-(4-히드록시-4-(피리딘-2-일)피리딘-1-일)-1-옥소프Example 5 (Compound 61): 2- (1- (4-hydroxy-4- (pyridin-2-yl) pyridin-1-yl) -1-oxop
로판-2-일)프탈라진-1(2H)-온Ropan-2-yl) phthalazine-1 (2H) -one
Figure PCTKR2010001445-appb-I000014
Figure PCTKR2010001445-appb-I000014
실시예 6 (화합물 65) : 2-(4-메틸피페리딘-1-일)-7-(1H-피라졸-3-카보닐)-Example 6 (Compound 65): 2- (4-Methylpiperidin-1-yl) -7- (1H-pyrazole-3-carbonyl)-
5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000015
Figure PCTKR2010001445-appb-I000015
실시예 7 (화합물 70) : N1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)피페리딘-Example 7 (Compound 70): N1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) piperidine-
1,4-디카복스아미드1,4-dicarboxamide
Figure PCTKR2010001445-appb-I000016
Figure PCTKR2010001445-appb-I000016
실시예 8 (화합물 73) : 1-알릴-3-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)유레Example 8 (Compound 73): 1-allyl-3- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) urea
아Ah
Figure PCTKR2010001445-appb-I000017
Figure PCTKR2010001445-appb-I000017
실시예 9 (화합물 74) : 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-((테트라Example 9 (Compound 74): 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3-((tetra
히드로퓨란-2-일)메틸)유레아.Hydrofuran-2-yl) methyl) urea.
Figure PCTKR2010001445-appb-I000018
Figure PCTKR2010001445-appb-I000018
실시예 10 (화합물 75) : 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포Example 10 (Compound 75): 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpho
리노에틸)유레아Linoethyl) urea
Figure PCTKR2010001445-appb-I000019
Figure PCTKR2010001445-appb-I000019
실시예 11 (화합물 76) : 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도Example 11 (Compound 76): 6- (2-Methylbenzyl) -2-morpholino-5,6,7,8-tetrahydropyrido
[4,3-d]피리미딘-4(3H)-온[4,3-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000020
Figure PCTKR2010001445-appb-I000020
실시예 12 (화합물 77) : 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸-2-일)메틸Example 12 (Compound 77): 2-methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl
)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000021
Figure PCTKR2010001445-appb-I000021
실시예 13 (화합물 79) : 7-(2-히드록시-4-메톡시벤질)-2-메틸-5,6,7,8-테트라히드Example 13 (Compound 79): 7- (2-hydroxy-4-methoxybenzyl) -2-methyl-5,6,7,8-tetrahydrate
로피리도[3,4-d]피리미딘-4(3H)-온 Ropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000022
Figure PCTKR2010001445-appb-I000022
실시예 14 (화합물 88) : 6-((1,5-디메틸-1H-피라졸-4-일)메틸)-2-(4-메틸피페리딘Example 14 (Compound 88): 6-((1,5-dimethyl-1H-pyrazol-4-yl) methyl) -2- (4-methylpiperidine
-1-일)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온-1-yl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000023
Figure PCTKR2010001445-appb-I000023
실시예 15 (화합물 89) : 6-(2,5-디플루오로벤질)-2-(4-메틸피페리딘-1-일)-Example 15 (Compound 89): 6- (2,5-Difluorobenzyl) -2- (4-methylpiperidin-1-yl)-
5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000024
Figure PCTKR2010001445-appb-I000024
실시예 16 (화합물 90) : 2-(2,6-디메틸몰포리노)-7-(4-이소프로필벤질)-5,6,7,8-Example 16 (Compound 90): 2- (2,6-dimethylmorpholino) -7- (4-isopropylbenzyl) -5,6,7,8-
테트라히드로피리도[3,4-d]피리미딘-4(3H)-온 Tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000025
Figure PCTKR2010001445-appb-I000025
실시예 17 (화합물 91) : 7-(2-플루오로벤질)-2-(4-메틸피페리딘-1-일)-5,6,7,8-테Example 17 (Compound 91): 7- (2-fluorobenzyl) -2- (4-methylpiperidin-1-yl) -5,6,7,8-te
트라히드로피리도[3,4-d]피리미딘-4(3H)-온Trahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000026
Figure PCTKR2010001445-appb-I000026
실시예 18 (화합물 92) : 2-몰포리노-7-(2-페닐프로파노일)-5,6,7,8-테트라히드로Example 18 (Compound 92): 2-morpholino-7- (2-phenylpropanoyl) -5,6,7,8-tetrahydro
피리도[3,4-d]피리미딘-4(3H)-온Pyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000027
Figure PCTKR2010001445-appb-I000027
실시예 19 (화합물 93) : 7-(4-이소프로필벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라Example 19 (Compound 93): 7- (4-isopropylbenzyl) -2- (piperidin-1-yl) -5,6,7,8-tetra
히드로피리도[3,4-d]피리미딘-4(3H)-온Hydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000028
Figure PCTKR2010001445-appb-I000028
실시예 20 (화합물 115) : 1-(퓨란-2-일메틸)-3-(4-히드록시-1,5-나프티리딘-3-일)Example 20 (Compound 115): 1- (furan-2-ylmethyl) -3- (4-hydroxy-1,5-naphthyridin-3-yl)
유레아Urea
Figure PCTKR2010001445-appb-I000029
Figure PCTKR2010001445-appb-I000029
실시예 21 (화합물 116) :. 1-(6-에톡시-4-히드록시-1,5-나프티리딘-3-일)-3-(2-몰Example 21 (Compound 116). 1- (6-ethoxy-4-hydroxy-1,5-naphthyridin-3-yl) -3- (2-mol
포리노에틸)유레아Pinoethyl) urea
Figure PCTKR2010001445-appb-I000030
Figure PCTKR2010001445-appb-I000030
실시예 22 (화합물 117) : 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(1-(피Example 22 (Compound 117): 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (1- (blood
리딘-4-일)에틸)유레아Lidin-4-yl) ethyl) urea
Figure PCTKR2010001445-appb-I000031
Figure PCTKR2010001445-appb-I000031
실시예 23 (화합물 118) : 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-(4-Example 23 (Compound 118): 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2- (4-
메틸피페리딘-1-일)에틸)유레아Methylpiperidin-1-yl) ethyl) urea
Figure PCTKR2010001445-appb-I000032
Figure PCTKR2010001445-appb-I000032
실시예 24 (화합물 119) : 1-(4-(퓨란-2-일)부탄-2-일)-3-(4-히드록시-6-메톡시-Example 24 (Compound 119): 1- (4- (furan-2-yl) butan-2-yl) -3- (4-hydroxy-6-methoxy-
1,5-나프티리딘-3-일)유레아1,5-naphthyridin-3-yl) urea
Figure PCTKR2010001445-appb-I000033
Figure PCTKR2010001445-appb-I000033
실시예 25 (화합물 136) : N-(4-((4-옥소-2-(피리딘-3-일)-3,4,5,6-테트라히드로피Example 25 (Compound 136): N- (4-((4-oxo-2- (pyridin-3-yl) -3,4,5,6-tetrahydropy
리도[3,4-d]피리미딘-7(8H)-일)메틸)페닐)아세트아미드Lido [3,4-d] pyrimidin-7 (8H) -yl) methyl) phenyl) acetamide
Figure PCTKR2010001445-appb-I000034
Figure PCTKR2010001445-appb-I000034
실시예 26 (화합물 144) : 4-(2-옥소-2-(4-(피리딘-4-일)피페리딘-1-일)에틸)프탈Example 26 (Compound 144): 4- (2-oxo-2- (4- (pyridin-4-yl) piperidin-1-yl) ethyl) phthal
라진-1(2H)-온Razin-1 (2H) -On
Figure PCTKR2010001445-appb-I000035
Figure PCTKR2010001445-appb-I000035
실시예 27 (화합물 146) : 4-(1-(4-니코티노일피페리딘-1-일)-1-옥소프로판-2-일)Example 27 (Compound 146): 4- (1- (4-nicotinoylpiperidin-1-yl) -1-oxopropan-2-yl)
프탈라진-1(2H)-온Phthalazine-1 (2H) -on
Figure PCTKR2010001445-appb-I000036
Figure PCTKR2010001445-appb-I000036
실시예 28 (화합물 150) : N-(2-(1-메틸-4-옥소-1,2,3,4-테트라히드로피리도[2,3-Example 28 (Compound 150): N- (2- (1-methyl-4-oxo-1,2,3,4-tetrahydropyrido [2,3-
d]피리미딘-2-일)페닐)니코틴아미드. d] pyrimidin-2-yl) phenyl) nicotinamide.
Figure PCTKR2010001445-appb-I000037
Figure PCTKR2010001445-appb-I000037
실시예 29 (화합물 155) : N-(2-(1-((2-메틸피리미딘-5-일)메틸)피페리딘-4-일)퀴Example 29 (Compound 155): N- (2- (1-((2-methylpyrimidin-5-yl) methyl) piperidin-4-yl) qui
놀린-3-일)아세트아미드Nolin-3-yl) acetamide
Figure PCTKR2010001445-appb-I000038
Figure PCTKR2010001445-appb-I000038
실시예 30 (화합물 158) : 2-몰포리노-7-(4-(피페리딘-1-일메틸)벤조일)-5,6,7,8-Example 30 (Compound 158): 2-morpholino-7- (4- (piperidin-1-ylmethyl) benzoyl) -5,6,7,8-
테트라히드로피리도[3,4-d]피리미딘-4(3H)-온.Tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one.
Figure PCTKR2010001445-appb-I000039
Figure PCTKR2010001445-appb-I000039
실시예 31 (화합물 159) : 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트Example 31 (Compound 159): 7- (2,4-dimethoxybenzyl) -2- (pyrrolidin-1-yl) -5,6,7,8-tet
라히드로피리도[3,4-d]피리미딘-4(3H)-온Lahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000040
Figure PCTKR2010001445-appb-I000040
실시예 32 (화합물 160) : 7-(4-(디에틸아미노)-2-히드록시벤질)-2-(피페리딘-1-Example 32 (Compound 160): 7- (4- (diethylamino) -2-hydroxybenzyl) -2- (piperidine-1-
일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온Yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000041
Figure PCTKR2010001445-appb-I000041
실시예 33 (화합물 161) : 6-(3,4-디메톡시벤질)-2-(4-메틸피페리딘-1-일)-Example 33 (Compound 161): 6- (3,4-Dimethoxybenzyl) -2- (4-methylpiperidin-1-yl)-
5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000042
Figure PCTKR2010001445-appb-I000042
실시예 34 (화합물 162) : 6-(2-히드록시-4-메톡시벤질)-2-(피리딘-2-일)-5,6,7,8-Example 34 (Compound 162): 6- (2-hydroxy-4-methoxybenzyl) -2- (pyridin-2-yl) -5,6,7,8-
테트라히드로피리도[4,3-d]피리미딘-4-올Tetrahydropyrido [4,3-d] pyrimidin-4-ol
실시예 35 (화합물 163) : 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-Example 35 (Compound 163): 7-((5,6-dihydro-1,4-dioxin-2-yl) methyl) -2- (pyridine-4-
일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온Yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000044
Figure PCTKR2010001445-appb-I000044
실시예 36 (화합물 164) : 2-(4-(3,4-디플루오로벤조일)피페라진-1-일)-5,6,7,8-테Example 36 (Compound 164): 2- (4- (3,4-difluorobenzoyl) piperazin-1-yl) -5,6,7,8-te
트라히드로퀴나졸린-4(3H)-온Trahydroquinazolin-4 (3H) -one
Figure PCTKR2010001445-appb-I000045
Figure PCTKR2010001445-appb-I000045
실시예 37 (화합물 165) : 7-(3-(1H-벤조[d][1,2,3]트리아졸-1-일)프로파노일)-2-(Example 37 (Compound 165): 7- (3- (1H-Benzo [d] [1,2,3] triazol-1-yl) propanoyl) -2- (
피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온Piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000046
Figure PCTKR2010001445-appb-I000046
실시예 38 (화합물 166) : 2-(3-메틸피페리딘-1-일)-6-(퀴놀린-6-일메틸)-5,6,7,8-Example 38 (Compound 166): 2- (3-Methylpiperidin-1-yl) -6- (quinolin-6-ylmethyl) -5,6,7,8-
테트라히드로피리도[4,3-d]피리미딘-4(3H)-온Tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000047
Figure PCTKR2010001445-appb-I000047
실시예 39 (화합물 167) : 7-이소부티릴-2-몰포리노-5,6,7,8-테트라히드로피리도Example 39 (Compound 167): 7-isobutyryl-2-morpholino-5,6,7,8-tetrahydropyrido
[3,4-d]피리미딘-4(3H)-온[3,4-d] pyrimidin-4 (3H) -one
Figure PCTKR2010001445-appb-I000048
Figure PCTKR2010001445-appb-I000048
바람직하게는, 상기 화합물은 N1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)피페리딘-1,4-디카복스아미드, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸-2-일)메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 7-(2-히드록시-4-메톡시벤질)-2-메틸-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-이소프로필벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-(디에틸아미노)-2-히드록시벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 또는 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온일 수 있고, 더욱 바람직하게는, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸-2-일)메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 또는 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온인 것을 특징으로 할 수 있다. Preferably, the compound is N1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) piperidine-1,4-dicarboxamide, 1- (4-hydroxy -6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2-methylbenzyl) -2-morpholino-5,6,7,8 Tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl)- 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 7- (2-hydroxy-4-methoxybenzyl) -2-methyl-5, 6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4-isopropylbenzyl) -2- (piperidin-1-yl) -5 , 6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (2,4-dimethoxybenzyl) -2- (pyrrolidin-1-yl ) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4- (diethylamino) -2-hydroxybenzyl) -2 -(Piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, or 7-((5,6-di Hydro-1,4-dioxin-2-yl) methyl) -2- (Pyridin-4-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, more preferably 1- (4-hydrate Roxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2-methylbenzyl) -2-morpholino-5,6,7, 8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 7- (2,4-dimethoxybenzyl) -2- (pyrrolidine-1 -Yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, or 7-((5,6-dihydro-1,4-di Auxin-2-yl) methyl) -2- (pyridin-4-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one can do.
본 발명에 따른 상기 화합물들은 LeadQuest사, Asinex사 등 상용화된 화합물 라이브러리 판매회사로부터 입수가능하거나, 알려진 합성 방법을 통해 화합물 합성이 가능하다. The compounds according to the present invention are available from commercial compound library vendors such as LeadQuest, Asinex, or can be synthesized through known synthetic methods.
본 발명에서는 상기 화합물들이 Axin과 경쟁적으로 GSK3에 결합함으로써 GSK3의 nuclear export function을 억제하는 것을 확인하였다. 즉, 본 발명에 따른 화합물들은 Axin과의 결합에 의해 세포핵에서 세포질로의 GSK3 이동을 억제하고, 이를 통해 GSK의 세포내 활성을 촉진하거나, GSK3 농도나 활성 저하를 억제하거나 유지 및 증가시켜 세포핵 내 GSK3 농도 감소에 의해 발생되는 질병의 치료에 유용하다.In the present invention, it was confirmed that the compounds inhibit the nuclear export function of GSK3 by binding to GSK3 competitively with Axin. That is, the compounds according to the present invention inhibit GSK3 migration from the cell nucleus to the cytoplasm by binding to Axin, thereby promoting intracellular activity of GSK, or inhibiting or maintaining and increasing GSK3 concentration or activity decrease in the cell nucleus. It is useful for the treatment of diseases caused by decreasing GSK3 concentration.
상기 "세포핵에서 세포질로의 GSK3 이동 관련 질환"은, GSK3를 통해 매개된 질병, 예를 들어 예를 들어 암, 당뇨병, C형 니이만-픽병(Niemann Pick's disease type C), 양극성 장애(특히 조울증), 알츠하이머병, FTDP-17(파킨슨병과 관련된 전두측두성 치매), 피질-기저 퇴행(cortico-basal degeneration), 진행성 핵상 마비(progressive supranuclear palsy), 다발성전신위축증(Multiple system atrophy), 피크병(Pick's disease), 권투선수치매(dementia Pugilistica), 에이즈관련 치매 (AIDS associated dementia), 치매, 뇌졸중(stroke), 괌형 파킨슨-치매 증후군 (Guam parkinsonism-dementia complex), 뇌염후 파킨슨 증후군(postencephalic Parkinsonism), 전두엽 퇴행(frontal lobe degeneration), 은친화성 입자 질환(argyrophilic grains disease), 우울장애(depression), 정신분열증(Schizophrenia), 헌팅턴병(Huntington's disease), 근육긴장성 이영양증(myotonic dystrophy), 아급성경화범뇌염(subacute sclerotizing panencephalitis), 프리온 질병(prion disease), 다운증후군, 알러지나 천식, 다발성 경화증, 류마티스 관절염, 동맥경화증, 염증성 장질환(inflammatory bowel disease)과 같은 염증성 질환, 대머리 등의 피부질환, 동통 중 특히 신경병증성 동통, 골관절염, 백혈구감소증 등이 있으며, 본 발명에 따른 화합물은 이러한 GSK3의 세포핵에서 세포질로의 이동을 억제함으로써, GSK의 기능이 억제되어, 상기 질환을 예방 및 치료하는데 유용할 수 있다. 또한 정자운동을 억제하는데 사용될 수 있으며, 따라서 남성 피임제로서 사용될 수 있다. 특히, 본 발명의 화합물은 암의 예방 또는 치료에 유용하다.The above-mentioned diseases related to the movement of GSK3 from the nucleus to the cytoplasm may include diseases mediated through GSK3, such as cancer, diabetes, Niemann Pick's disease type C, bipolar disorder (especially manic depression). ), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, and peak disease ( Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, postencephalic Parkinsonism, Frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dystrophy, Subacute sclerotizing panencephalitis, prion disease, Down syndrome, allergic or asthma, multiple sclerosis, inflammatory diseases such as rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, baldness, etc. Among skin diseases, pain, in particular neuropathic pain, osteoarthritis, leukopenia, etc., the compound according to the present invention inhibits the movement of GSK3 from the nucleus of the cell to the cytoplasm, thereby inhibiting the function of GSK, preventing and It can be useful for treatment. It can also be used to inhibit sperm movement and thus can be used as a male contraceptive. In particular, the compounds of the present invention are useful for the prevention or treatment of cancer.
상술한 약리학적 특성의 관점에서, 화학식 2의 화합물 또는 그의 약학적으로 허용되는 염, 전구약물, 또는 이성질체는 의약으로서 사용될 수 있다. 특히, 본 화합물은 세포핵에서 세포질로의 GSK3 이동 관련 질환을 치료하거나 예방하기 위한 의약을 제조하는데 사용될 수 있다. 더욱 특히는, 본 화합물은 관절염을 비롯한 면역질환, 암을 치료하거나 예방하기 위한 의약을 제조하는데 사용될 수 있다. In view of the above pharmacological properties, the compound of formula (2) or a pharmaceutically acceptable salt, prodrug, or isomer thereof can be used as a medicament. In particular, the compounds can be used to prepare a medicament for treating or preventing GSK3 migration-related diseases from the nucleus to the cytoplasm. More particularly, the compounds can be used to prepare a medicament for treating or preventing immune diseases, including arthritis, and cancer.
따라서, 본 발명은 다른 관점에서, 상기 화학식 2로 표시되는 화합물, 그의 약학적으로 허용가능한 염, 전구약물 또는 이성질체를 유효성분으로 함유하는 암 세포의 성장 및 전이 억제용 약학적 조성물과 면역 질환 치료용 약학 조성물에 관한 것이다. 구체적으로, 상기 조성물은 상기 화합물 18, 30, 35, 46, 61, 65, 70, 73 내지 77, 79, 88 내지 93, 115 내지 119, 136, 144, 146, 150, 155, 158 내지 167를 함유할 수 있다.  Accordingly, the present invention, in another aspect, the pharmaceutical composition for inhibiting the growth and metastasis of cancer cells containing the compound represented by the formula (2), a pharmaceutically acceptable salt, prodrug or isomer thereof as an active ingredient and the treatment of immune diseases It relates to a pharmaceutical composition. Specifically, the composition is a compound 18, 30, 35, 46, 61, 65, 70, 73 to 77, 79, 88 to 93, 115 to 119, 136, 144, 146, 150, 155, 158 to 167 It may contain.
본 발명에 따른 화합물은 Wnt 신호 전달에 의해 촉진되는 암 세포의 전이뿐만 아니라 류마티스성 관절염과 같은 자가면역, 퇴행성 질환의 발생과 진행을 억제하는데 유용하게 사용할 수 있다.The compounds according to the present invention can be usefully used to inhibit the development and progression of autoimmune and degenerative diseases such as rheumatoid arthritis as well as metastasis of cancer cells promoted by Wnt signal transduction.
본 발명에 따른 화합물은 그 자체를 사용하거나 약제학적으로 허용가능한 산부가염 또는 금속 복합체, 예를 들어, 아연, 철 등과 같은 염의 형태로 사용할 수 있다. 보다 구체적으로, 산부가염은 염화수소, 브롬화수소, 황산염, 인산염, 말레산염, 아세트염, 시트로산염, 벤조산염, 숙신산염, 말린산염, 아스코로브산염 및 타르탈산염으로 구성된 군에서 선택된 것을 사용하는 것이 바람직하다.The compounds according to the invention can be used by themselves or in the form of pharmaceutically acceptable acid addition salts or salts of metal complexes such as zinc, iron and the like. More specifically, the acid addition salt may be selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfate, phosphate, maleate, acetate, citralate, benzoate, succinate, dried salt, ascorbate and tartalate. It is preferable.
본 발명에 따른 화합물을 유효성분으로 함유하는, 다시말해, 치료 유효량 또는 예방 유효량 함유하는, 약학 조성물은 통상적인 투여방법, 투여형태 및 치료목적에 따라 상기 유효성분을 약제학적으로 허용가능한 부형제 또는 매트릭스인 담체와 함께 혼합하여 희석하거나, 용기 형태의 담체 내에 봉입시키는 것이 바람직하다. 또한, 다른 골 결함 치료에 유익한 다른 약재와 배합하여 사용할 수 있다. 이때, 목적하는 pH, 등장성, 안정성 등을 갖는 생리적으로 수용 가능한 단백질 조성물의 제법은 본 발명의 분야에서 따르는 통상적인 기술범위 내에 있는 것을 사용할 수 있다. 본 발명에서 상기 매트릭스는 생물접합성, 생물분해성, 기계적 특성, 미용적 외관 및 접촉 특성에 따라 황산칼슘, 트리칼슘포스페이브, 하드록시아파리트, 폴리락트산, 포릴무수물과 같은 생물 분해성 및 화학적 물질이나; 뼈 또는 피부 콜라겐, 기타 순수 단백질 또는 세포의 매트릭스 성분과 같은 생물 분해성 및 생물학적 물질; 소결된 히드록시아파티트, 바이오글래스, 알루미네이트 또는 기타 세라믹과 같은 비-생물 분해성 및 화학성 물질; 폴리락트산, 히드록시아파티트, 콜라겐 및 트리칼슘포스페이트와 같은 상술한 물질의 배합물을 사용하는 것이 바람직하다. 하지만, 상기 담체로 본 발명이 제한되는 것은 아니다.Pharmaceutical compositions containing a compound according to the invention as an active ingredient, in other words a therapeutically effective amount or a prophylactically effective amount, may contain a pharmaceutically acceptable excipient or matrix according to conventional administration methods, dosage forms and therapeutic purposes. Mixing and dilution with a phosphorus carrier or encapsulation in a carrier in the form of a container is preferred. It can also be used in combination with other medicines that are beneficial for the treatment of other bone defects. At this time, the preparation of a physiologically acceptable protein composition having a desired pH, isotonicity, stability and the like can be used within the conventional technical scope in the field of the present invention. In the present invention, the matrix is a biodegradable and chemical substance such as calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, or polyanhydride, depending on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and contact properties; Biodegradable and biological substances such as bone or skin collagen, other pure proteins or matrix components of cells; Non-biodegradable and chemical materials such as sintered hydroxyapatite, bioglass, aluminate or other ceramics; Preference is given to using combinations of the foregoing materials such as polylactic acid, hydroxyapatite, collagen and tricalcium phosphate. However, the present invention is not limited to the carrier.
본 발명에서 부형제는 락토즈, 덱스트로즈, 수크로즈, 소르비톨, 만니톨, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈 (polyvinylpyrrolidone), 마그네슘 스타아레이트, 물, 메틸하이드록시벤조에이트 (methylhydroxybenzoate), 프로필하이드록시벤조에이트 (propylhydroxybenzoate), 탈크 (talc), 광물유 등을 사용할 수 있다.Excipients in the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, magnesium stanrate, water, methylhydroxy Benzoate (methylhydroxybenzoate), propylhydroxybenzoate (propylhydroxybenzoate), talc (talc), mineral oil and the like can be used.
암을 예방 또는 치료하는데 의약으로서 사용될 경우, 화학식 2의 화합물은 암을 치료하는데 사용되는 다른 통상의 약물, 예컨데 백금 배위 화합 물, 예를 들어 시스플라틴 또는 카보플라틴; 탁산 화합물, 예를 들어 파클리탁셀 또는 독세탁셀; 캄프토테신 화합물, 예를 들어 이리노테칸 또는 토포테칸; 항-종양 빈카 알칼로이드, 예를 들어 빈블라스틴, 빈크리스틴 또는 비노렐빈; 항-종양 뉴클레오시드 유도체, 예를 들어 5-플루오로우라실, 겜시타빈 또는 카페시타빈; 질소 머스타드 또는 니트로소우레아 알킬화제, 예를 들어 시클로포스파미드, 클로람부실, 카무스틴 또는 로무스틴; 항-종양 안트라시클린 유도체, 예를 들어 다우노루비신, 독소루비신 또는 이다루비신; HER2 항체, 예를 들어 트라스트주마브; 및 항-종양 포도필로톡신 유도체, 예를 들어 에토포시드 또는 테니포시드; 및 에스트로겐 수용체 길항제 또는 선택적 에스트로겐 수용체 조절제를 포함한 항에스트로겐 제제, 바람직하게는 타목시펜 또는 별도로 토레미펜, 드롤록시펜, 파슬로덱스 및 랄록시펜; 아로마타제 억제제, 예를 들어 엑세메스탄, 아나스트로졸, 레트라졸 및 보로졸; 분화 제제(differentiating agent), 예를 들어 레티노이드, 비타민 D 및 DNA 메틸 트랜스퍼라제 억제제, 예를들어 아자사이티딘; 키나제 억제제, 예를 들어 플라보페리돌 및 이마티니브 메실레이트 또는 파르네실트랜스퍼라제 억제제, 예를 들어 R115777과 배합하여 사용될 수 있다. 따라서, 본 발명은 또한 화학식 2의 화합물 및 암을 예방 또는 치료할 수 있는 또 다른 제제의 배합물에 관한 것이다. 상기 배합물은 의약으로서 사용될 수 있다. 본 발명은 또한 암의 예방 또는 치료에 동시에, 분리하여 또는 연속적으로 사용하기 위한 배합 제제로서 (a) 화학식 2 및 (b) 암을 예방 또는 치료할 수 있는 또 다른 제제를 함유하는 제품에 관한 것이다. 상이한 약물이 약제학적으로 허용되는 담체와 함께 단일 제제로 배합될 수 있다.When used as a medicament in preventing or treating cancer, the compounds of formula (2) may be used in other conventional drugs used to treat cancer, such as platinum coordination compounds such as cisplatin or carboplatin; Taxane compounds such as paclitaxel or docetaxel; Camptothecin compounds such as irinotecan or topotecan; Anti-tumor vinca alkaloids such as vinblastine, vincristine or vinorelbine; Anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine; Nitrogen mustard or nitrosourea alkylating agents such as cyclophosphamide, chlorambucil, carmustine or romustine; Anti-tumor anthracycline derivatives such as daunorubicin, doxorubicin or idarubicin; HER2 antibodies such as trastuzumab; And anti-tumor grapephytotoxin derivatives such as etoposide or teniposide; And antiestrogenic agents including estrogen receptor antagonists or selective estrogen receptor modulators, preferably tamoxifen or separately toremifene, droroxifene, parslodex and raloxifene; Aromatase inhibitors such as exemestane, anastrozole, retrazole and borosol; Differentiating agents such as retinoids, vitamin D and DNA methyl transferase inhibitors such as azacytidine; It can be used in combination with kinase inhibitors such as flaboferridol and imatinib mesylate or farnesyltransferase inhibitors such as R115777. Thus, the present invention also relates to a combination of a compound of formula 2 and another agent capable of preventing or treating cancer. The combination can be used as a medicament. The present invention also relates to a product containing (a) Formula (2) and (b) another agent capable of preventing or treating cancer as a combination formulation for simultaneous, separate or continuous use in the prevention or treatment of cancer. Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.
염증성 질환을 예방 또는 치료하는데 의약으로서 사용될 경우, 화학식 2의 화합물은 염증성 질환을 치료하는데 사용되는 다른 통상의 약물, 예컨데 스테로이드, 시클로옥시게나제-2 억제제, 비스테로이드성-항-염증성 약물, TNF-α 항체, 예를 들어 아세틸 살리실산, 부펙사맥, 디클로페낙 포타슘, 슐린닥, 디클로페낙 소듐, 케토롤락 트로메타몰, 톨메틴, 이부프로펜, 나프록센, 나프록센 소듐, 트리아프로펜산, 플루비프로펜, 메페나믹산, 니플루미닉산, 메클로페나메이트, 인도메타신, 프로글루메타신, 케토프로펜, 나부메톤, 파라세타몰, 피록시캄, 테녹시캄, 니메술리드, 페닐부타존, 트라마돌, 베클로메타손 디프로피오네이트, 베 타메타손, 베클라메타손, 부데소니드, 플루티카손, 모메타손, 덱사메타손, 하이드로코르티손, 메틸프레드니솔론, 프레드니솔론, 프레드니손, 트리암시놀론, 셀레콕시브, 로페콕When used as a medicament in preventing or treating an inflammatory disease, the compounds of formula (2) may be used in other conventional drugs used to treat inflammatory diseases such as steroids, cyclooxygenase-2 inhibitors, nonsteroidal-anti-inflammatory drugs, TNF -α antibodies, for example acetyl salicylic acid, bufexamac, diclofenac potassium, schlindax, diclofenac sodium, ketorolac tromethamol, tolmethine, ibuprofen, naproxen, naproxen sodium, triaprofenic acid, flubiprofen, mefenamic acid , Niflumic acid, meclofenamate, indomethacin, proglumetacin, ketoprofen, nabumethone, paracetamol, pyroxhamm, tenoxycam, nimesulide, phenylbutazone, tramadol, beclomethasone Dipropionate, betamethasone, beclomethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, predney Ron, prednisone, triamcinolone, celecoxib, rofecoxib to
시브, 인플릭시마브, 레플루노미드, 에타네르셉, CPH 82, 메토트렉세이트, 설파살라진과 배합하여 사용될 수 있다.It can be used in combination with sieve, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine.
따라서, 본 발명은 또한 화학식 2의 화합물, 그의 약학적으로 허용가능한 염, 전구약물, 또는 이성질체 및 염증성 질환을 예방 또는 치료할 수 있는 또 다른 제제의 배합물에 관한 것이다. 상기 배합물은 의약으로서 사용될 수 있다. 본 발명은 또한 염증성 질환을 예방 또는 치료에 동시에, 분리하여 또는 연속으로 사용하기 위한 배합 제제로서 (a) 화학식 2의 화합물, 그의 약학적으로 허용가능한 염, 전구약물, 또는 이성질체의 화합물 및 (b) 염증성 질환을 예방 또는 치료할 수 있는 또 다른 제제를 함유하는 제품에 관한 것이다. 상이한 약물이 약제학적으로 허용되는 담체와 함께 단일 제제로 배합될 수 있다.Accordingly, the present invention also relates to a combination of a compound of formula (2), a pharmaceutically acceptable salt, prodrug, or isomer and another agent capable of preventing or treating an inflammatory disease. The combination can be used as a medicament. The invention also provides a combination formulation for use simultaneously, separately or continuously in the prevention or treatment of an inflammatory disease, comprising: (a) a compound of formula (2), a pharmaceutically acceptable salt, a prodrug, or an isomer thereof; and (b The present invention relates to a product containing another agent capable of preventing or treating an inflammatory disease. Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.
본 발명은 또 다른 관점에서, 세포핵에서 세포질로의 GSK3 이동 관련 질환으로 고통받고 있는 인간을 포함한 포유동물을 치료 또는 예방하는 방법, 더욱 특히는 암, 관절염을 비롯한 면역질환, 알츠하이머병, 당뇨병, 특히 2형 당뇨병, 또는 양극성 장애를 치료하거나 예방하는 방법이 제공된다. 상기 방법은 유효량의 화학식 2의 화합물 또는 그의 약학적으로 허용되는 염, 전구약물, 또는 이성질체를 인간을 포함한 포유 동물에 투여하는 것을 포함한다.In another aspect, the present invention provides methods for treating or preventing mammals, including humans suffering from GSK3 migration-related diseases from the nucleus to the cytoplasm, more particularly immune diseases including cancer, arthritis, Alzheimer's disease, diabetes, in particular Methods of treating or preventing type 2 diabetes, or bipolar disorder, are provided. The method comprises administering to a mammal, including a human, an effective amount of a compound of Formula 2 or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
한편, 본 발명에 따른 화합물을 함유하는 약학 조성물은 다양한 제형으로 제조할 수 있으며, 치료 효과를 기대하는 부위에 주입하기 위해 점성형으로 주사되거나 캡술화하여 사용하는 것이 바람직하다. 본 발명에 따른 조성물의 투여량은 사용되는 부형제나 매트릭스 등의 담체 종류, 환자의 치료 부위, 환자의 나이, 성별 및 다이어트, 감염의심도, 투여시간 및 기타 임상적 요인을 고려하여 조절될 수 있기 때문에 한정되지 않으나, 통상적으로 공지된 유효량은 체중을 고려하여 적정량을 연속적 또는 나누어 투여하고, 치료 효과를 관찰하며 추가 투여를 결정할 수 있다.On the other hand, the pharmaceutical composition containing the compound according to the present invention can be prepared in a variety of formulations, it is preferable to use injectable or capsulated in a viscous form for injection into the site where the therapeutic effect is expected. The dosage of the composition according to the present invention can be adjusted in consideration of the type of carrier such as the excipient or matrix used, the treatment site of the patient, the age, sex and diet of the patient, the severity of the infection, the time of administration and other clinical factors. Although not limited thereto, a conventionally known effective amount can be administered continuously or dividedly, in consideration of weight, to observe the therapeutic effect and to determine further administration.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예에는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실험예 1: 본 발명에 따른 화합물들에 대한 Axin2와 GSK3β의 in vitro 결합 억제 효과 확인Experimental Example 1: Confirmation of the in vitro binding inhibitory effect of Axin2 and GSK3β to the compounds according to the invention
본 발명에 따른 실시예 화합물들 중 화합물 70, 75 내지 77, 79, 93, 159, 160, 163 에 대하여 Axin2와 GSK3β의 in vitro 결합 억제 효과를 확인하기 위하여 하기와 같은 실험을 수행하였다. In order to determine the in vitro binding inhibitory effect of Axin2 and GSK3β with respect to compounds 70, 75 to 77, 79, 93, 159, 160, 163 of the compound according to the present invention was carried out as follows.
(1) Axin2 과발현 세포의 제작 (1) Preparation of Axin2 Overexpressing Cells
Axin2 발현벡터인 pcDNA3.1-Axin2-His 발현벡터를 얻기 위해, Axin2-His cDNA는 A549세포에서 PCR로 증폭하여 얻었고, pcDNA3.1-hyg(+) (invitrogen) 벡터의 HindIII와 BamHI 부위에 증폭된 Axin2-His cDNA를 넣어 제작하여, E.coli DH5α에서 증폭하여 pcDNA3.1-Axin2-His 발현벡터를 얻었다. In order to obtain the pcDNA3.1-Axin2-His expression vector, the Axin2 expression vector, Axin2-His cDNA was obtained by PCR amplification in A549 cells and amplified at the HindIII and BamHI sites of the pcDNA3.1-hyg (+) (invitrogen) vector. Axin2-His cDNA was prepared and amplified in E. coli DH5α to obtain pcDNA3.1-Axin2-His expression vector.
MCF7 세포(American Tyle of Cell Culture, ATCC HTB-26)에 episomal Axin2-His 발현벡터인 pcDNA3.1-Axin2-His 발현벡터를 형질감염(transfection)시킨 후에, 200 μg/ml의 하이그로마이신(hygromycin)을 처리하여 Axin2-His 과발현 세포를 수득하였다.After transfection of the episomal Axin2-His expression vector, pcDNA3.1-Axin2-His expression vector, to MCF7 cells (ATCC HTB-26), 200 μg / ml of hygromycin (hygromycin) ) Was treated to obtain Axin2-His overexpressing cells.
(2) 면역침전법(Imunoprecipitation)(2) immunoprecipitation
상기 얻어진 Axin2-His 과발현 세포에 Triton X-100 lysis buffer를 첨가하여 세포 용해물을 얻었다. Ni-NTA bead를 중화시키기 위하여 비드(bead) 20㎕에 1000㎕의 Triton X-100 lysis buffer를 첨가하고, 2000rpm에서 1분 동안 침전시키는 작업을 3회 반복하였다. 중화된 bead에 상기 세포 용해물과 본 발명에 따른 화합물 중 화합물 70, 75, 76, 77, 79, 93, 159, 160, 및 163으로 표시되는 화합물들을 각각 10μM을 넣고, Triton X-100 lysis buffer로 전체 부피를 1000㎕로 맞추었다. 4℃에서 5시간 동안 흔들어 준 후, 2000rpm에서 1분 동안 침전시켰다. 1000㎕의 Triton X-100 lysis buffer를 첨가하여 2번 세척한 후, 1000㎕의 1x TBS로 2번 세척하였다. 비드에 500mM 이미다졸(immidazole)이 포함된 2x 샘플 버퍼(50mM Tris-Hcl, pH6.8, 4% SDS, 25% glycerol, 14.1mM 2-mercaptoetanol, 0.1% bromophenol blue) 20㎕를 첨가한 후, 이를 끓여서 10㎕를 SDS-PAGE 젤에 로딩하였다.Triton X-100 lysis buffer was added to the obtained Axin2-His overexpressing cells to obtain cell lysate. In order to neutralize the Ni-NTA bead, 1000 µl of Triton X-100 lysis buffer was added to 20 µl of beads, and the procedure of precipitation for 1 minute at 2000 rpm was repeated three times. 10 μM of the cell lysate and the compounds represented by the compounds 70, 75, 76, 77, 79, 93, 159, 160, and 163 of the compound according to the present invention were added to the neutralized bead, and Triton X-100 lysis buffer was added. The total volume was adjusted to 1000 μl. After shaking for 5 hours at 4 ℃, it was precipitated at 2000 rpm for 1 minute. After washing twice with the addition of 1000 μl of Triton X-100 lysis buffer, it was washed twice with 1000 μl of 1 × TBS. 20 μl of 2 × sample buffer containing 50 mM immidazole (50 mM Tris-Hcl, pH6.8, 4% SDS, 25% glycerol, 14.1 mM 2-mercaptoetanol, 0.1% bromophenol blue) was added to the beads, It was boiled and 10 μl was loaded onto the SDS-PAGE gel.
(3) 면역블롯팅(immunoblot analysis) (3) immunoblot analysis
상기 각각의 화합물 처리에 따른 Axin2와 GSK3β의 in vitro 결합 효과 억제를 확인하기 위하여, GSK3β 발현을 면역블롯팅을 이용하여 조사하였다. In order to confirm the inhibition of the in vitro binding effect of Axin2 and GSK3β according to the treatment of each compound, GSK3β expression was examined using immunoblotting.
상기 면역침전법 수행 후, 니트로셀룰로오스 막(Pall Corp., NY)에 트랜스퍼하고, 이 막을 5% fat-free dry milk에서 1시간 동안 blocking한 후에 일차 항체를 넣어 3시간 동안 반응시켰다. 일차항체로는, anti-conductin(Sigma)와 anti-GSK3β(BD Bioscience)를 사용였고, 단백질 발현 정도는 단백질 발현 정도는 horseradish peroxidase (HRP)-conjugate된 이차항체와 enhanced chemiluminescence (ECL) detection kit (Intron, Korea)를 사용하여 x-ray 필름에 감광하여 관찰하였다. After performing the immunoprecipitation method, it was transferred to a nitrocellulose membrane (Pall Corp., NY), and the membrane was blocked for 1 hour in 5% fat-free dry milk, and then reacted for 3 hours with a primary antibody. The primary antibodies were anti-conductin (Sigma) and anti-GSK3β (BD Bioscience), and protein expression level was horseradish peroxidase (HRP) -conjugated secondary antibody and enhanced chemiluminescence (ECL) detection kit ( Intron, Korea) was used to sensitize the x-ray film.
상기 실험과정에 나타난 것처럼, Axin2를 과발현시킨 세포 내에서 Axin2와 GSK3β가 결합된 용해물을 Ni-NTA bead에 결합시킨 다음, Axin2에 대하여 면역침전법을 시행하고, Axin2와 결합한 GSK3β 정도를 면역블롯팅으로 확인하였다. As shown in the above experiment, in the cells overexpressing Axin2, Axin2 and GSK3β bound lysates were bound to Ni-NTA bead, and immunoprecipitation was performed on Axin2, and GSK3β bound to Axin2 was immunoblotted. Confirmed by lotting.
표 1 및 도 4에 나타난 바와 같이, 본 발명에 따른 화합물 처리에 의해 GSK3β의 발현이 억제된 것은, 화합물에 의해 Axin2과 GSK3β의 결합이 억제된 것으로 나타났다. 도 4에 나타난 바와 같이, CTL은 대조군이고, 화합물 70, 75 내지 77, 79, 93, 159, 160, 163 이 모두 활성을 보였으며, 그 중 활성이 특히 강한 것은 화합물 75 내지 77, 159, 163이였다. As shown in Table 1 and Figure 4, the expression of GSK3β was suppressed by the compound treatment according to the present invention, it was shown that the binding of Axin2 and GSK3β by the compound. As shown in Figure 4, the CTL is a control, compounds 70, 75 to 77, 79, 93, 159, 160, 163 all showed the activity, of which the particularly strong activity is compound 75 to 77, 159, 163 This was.
표 1
실시예 번호 화합물 번호 생물학적 활성
7 70 +
10 75 +++
11 76 +++
12 77 +++
13 79 +
19 93 +
31 159 +++
32 160 +
35 163 +++
Table 1
Example number Compound number Biological activity
7 70 +
10 75 +++
11 76 +++
12 77 +++
13 79 +
19 93 +
31 159 +++
32 160 +
35 163 +++
이상 설명한 바와 같이, 본 발명은 핵 내부의 GSK3 농도 감소로 인해 발생하는, 세포핵에서 세포질로의 GSK3 이동에 의해 발생되는 질환의 발생 및 진행 억제용 조성물을 제공하는 효과가 있다. 본 발명에 따른 화합물은 Axin에 의한 GSK3의 nuclear export function을 억제하고, 핵 내부의 GSK3 농도를 증가시킴으로써 핵 내부의 GSK3 농도가 낮아져서 발생하는 다양한 질환의 치료 또는 예방에 유용하다.As described above, the present invention has an effect of providing a composition for inhibiting the development and progression of a disease caused by the GSK3 migration from the cell nucleus to the cytoplasm, which occurs due to a decrease in the concentration of GSK3 in the nucleus. The compounds according to the present invention are useful for the treatment or prevention of various diseases caused by a decrease in the GSK3 concentration in the nucleus by inhibiting the nuclear export function of GSK3 by Axin and increasing the GSK3 concentration in the nucleus.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Having described the specific parts of the present invention in detail, it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, thereby not limiting the scope of the present invention. something to do. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

  1. 다음 화학식 2로 표시되는 화합물, 그의 약학적으로 허용가능한 염, 전구약물, 또는 이성질체를 유효성분으로 함유하는 세포핵에서 세포질로의 GSK3 이동 관련 질환의 치료 또는 예방용 약학적 조성물:A pharmaceutical composition for treating or preventing a disease related to GSK3 migration from the nucleus to the cytoplasm containing the compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient:
    화학식 2Formula 2
    Figure PCTKR2010001445-appb-I000049
    Figure PCTKR2010001445-appb-I000049
    상기 식에서, Where
    상기 A와 D 사이의 결합은 단일 결합 또는 이중결합; The bond between A and D is a single bond or a double bond;
    상기 A와 D 사이의 결합이 단일 결합일 때, A는 C=O, C=S, SO2, CHRa, O, S 또는 NRa이거나, A와 D 사이의 결합이 이중 결합일 때, A는 CRa 또는 N;When the bond between A and D is a single bond, A is C═O, C═S, SO 2 , CHR a , O, S or NR a, or when the bond between A and D is a double bond, A Is CR a or N;
    상기 A와 D 사이의 결합이 단일 결합일 때, D는 CHRd 또는 NRd이거나, A와 D 사이의 결합이 이중 결합일 때, D는 CRd 또는 N;When the bond between A and D is a single bond, D is CHR d or NR d, or when the bond between A and D is a double bond, D is CR d or N;
    상기 Ra와 Rd는 각각 독립적으로 수소, 할로겐, -OH, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 -(CR1R2)n-T1-(CH2)nT2-(CH2)n-T3;R a and R d are each independently hydrogen, halogen, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or-(CR 1 R 2 ) n- T 1- (CH 2 ) n T 2- (CH 2 ) n -T 3 ;
    상기 R1과 R2는 각각 독립적으로 수소, 할로겐, -(CH2)n-CN, -(CH2)n-NO2, -(CH2)n-C(O)OH, -(CH2)n-C(O)H, -(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-C(O)NH2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 치환된 또는 비치환된 아미노; R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 , substituted or unsubstituted alkyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
    상기 n은 0, 1, 2, 3, 4, 5 또는 6;N is 0, 1, 2, 3, 4, 5 or 6;
    상기 T1 은 공유결합,-C(O)-(CR1R2)n-, -N(R1)-(CR1R2)n-, -O-(CR1R2)n-, -C(O)N(R1)-(CR1R2)n-, -N(R1)C(O)-(CR1R2)n-, -S(O)p-(CR1R2)n-, -S(O)pN(R1)-(CR1R2)n-, -N(R1)S(O)p-(CR1R2)n-, -OC(O)N(R1)-(CR1R2)n-, -N(R1)C(O)O-(CR1R2)n-, -N(R1)C(O)N(R1)-(CR1R2)n-, 또는 -N(R1)C(S)N(R1)-(CR1R2)n-; T 1 is a covalent bond, -C (O)-(CR 1 R 2 ) n- , -N (R 1 )-(CR 1 R 2 ) n- , -O- (CR 1 R 2 ) n- , -C (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O)-(CR 1 R 2 ) n- , -S (O) p- (CR 1 R 2 ) n- , -S (O) p N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) S (O) p- (CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O) O- (CR 1 R 2 ) n- , -N (R 1 ) C (O) N (R 1 )-(CR 1 R 2 ) n- , or -N (R 1 ) C (S) N (R 1 )-(CR 1 R 2 ) n- ;
    상기 p는 1 또는 2;P is 1 or 2;
    상기 T2 는 공유결합, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 아릴알킬, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤지미다졸릴, 이미다졸릴, 인도릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 헤테로아릴알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 시클로알킬알킬,
    Figure PCTKR2010001445-appb-I000050
    , 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일 또는 바이시클릭 고리, 퀴놀리닐, 퀴녹사리닐, 퀴나졸리닐, 이소퀴놀리닐 및 프탈라지닐을 포함하는, 각각의 고리에 6개의 원자를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로시클, 또는 이미다조피리미디닐, 이미다조이미다졸릴, 이미다조티아졸릴, 나프틸, 테트라히드로나프틸, 벤조티에닐, 벤족사졸릴, 벤즈이미다졸릴, 벤조이속사졸릴 또는 벤조티아졸릴을 포함하는 하나의 방향족 고리가 다섯 개의 원자를 가지고 다른 하나의 방향족 고리가 6개의 고리를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로시클;    T 2 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
    Figure PCTKR2010001445-appb-I000050
    Substituted or unsubstituted non-aromatic single or bicyclic rings, quinolinyl, quinoxari, including, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl Substituted or unsubstituted bicyclic aromatic heterocycles having 6 atoms in each ring, or imidazopyrimidinyl, imidazoy, including nil, quinazolinyl, isoquinolinyl and phthalazinyl One aromatic ring comprising midazolyl, imidazothiazolyl, naphthyl, tetrahydronaphthyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoisoxazolyl or benzothiazolyl has five atoms and the other Substituted or unsubstituted bicyclic aromatic heterocycle in which one aromatic ring has six rings;
    상기 T3는 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 알케닐, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는, 디플루오로페닐, 디메톡시페닐, 메톡시히드록시페닐, 디메틸피라졸릴, 디메틸몰포리닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 옥사졸릴, 옥사디아졸릴, 이속사졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴, 벤조퓨라닐, 벤조트리아졸릴, 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐, 또는
    Figure PCTKR2010001445-appb-I000051
    를 포함하는 단일- 또는 다중치환된 또는 비치환된 방향족 또는 비-방향족 고리;    T 3 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -Arylalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or difluorophenyl, dimethoxyphenyl, methoxyhydroxyphenyl, dimethylpyrazolyl, dimethylmorpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, oxazolyl, oxdiazolyl, isoxazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzo Furanyl, benzotriazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, or
    Figure PCTKR2010001445-appb-I000051
    Mono- or polysubstituted or unsubstituted aromatic or non-aromatic rings comprising;
    상기 G와 J사이의 결합은 단일 결합 또는 이중결합; The bond between G and J is a single bond or a double bond;
    G와 J 사이 결합이 단일 결합일 경우, G는 CHRg 또는 NRg, 또는, G와 J 사이 결합이 이중 결합일 경우, G는 CRg 또는 N; When the bond between G and J is a single bond, G is CHR g or NR g , or when the bond between G and J is a double bond, G is CR g or N;
    상기 Rg는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 비-방향족 단일- 또는 바이 시클릭 고리, 또는 -(CR1R2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R g is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic mono- or bicyclic Ring, or-(CR 1 R 2 ) n -T 4- (CR 1 R 2 ) n -T 1- (CH 2 ) n -T 3 ;
    상기 T4는 공유결합, 페닐, 히드록시페닐, 플루오로페닐, 피리디닐, 피리미디닐, 피라지닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 아릴 또는 헤테로아릴 단일- 또는 바이시클릭 고리, 또는 피페리디닐, 피페라지닐, 몰포리닐, 테트라히드로퓨라닐, 피롤리디닐 또는 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일- 또는 바이시클릭 고리;T 4 is a covalent bond, phenyl, hydroxyphenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxa Substituted or unsubstituted aryl or heteroaryl single, including diazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Or substituted or unsubstituted non-aromatic mono- or bicyclic, including bicyclic rings or piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazolidinyl ring;
    상기 G와 J 사이의 결합이 이중 결합인 경우 상기 J는 CHRj 또는 NRj , 또는 J와 G가 이중 결합인 경우, 상기 J 는 CRj 또는 N;When the bond between G and J is a double bond, J is CHR j or NR j , or when J and G is a double bond, J is CR j or N;
    상기 Rj는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R j is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
    상기 Y 는 Y1 (
    Figure PCTKR2010001445-appb-I000052
    ) 또는 Y2 (
    Figure PCTKR2010001445-appb-I000053
    );    Y is Y 1 (
    Figure PCTKR2010001445-appb-I000052
    ) Or Y 2 (
    Figure PCTKR2010001445-appb-I000053
    );
    Y가 Y1인 경우, 상기 W는 CHRw 또는 NRw 또는 Y가 Y2인 경우, 상기 W는 CRw 또는 N; When Y is Y 1 , W is CHR w or NR w or when Y is Y 2 , W is CR w or N;
    상기 Rw는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리;R w is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings;
    상기 Y가 Y1인 경우, 상기 M은 CHRm 또는 NRm 또는 상기 Y가 Y2인 경우, 상기 M은 CRm 또는 N;When Y is Y 1 , M is CHR m or NR m or when Y is Y 2 , M is CR m or N;
    상기 Rm은 독립적으로 수소, 할로겐, -(CR1R2)n-O-알킬, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T2-(CH2)n-T3;R m is independently hydrogen, halogen,-(CR 1 R 2 ) n -O-alkyl, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 2- (CH 2 ) n- T 3 ;
    상기 Y가 Y1인 경우, 상기 Q는 CHRq 또는 NRq, 또는 상기 Y가 Y2인 경우, 상기 Q는 CRq 또는 N;When Y is Y 1 , Q is CHR q or NR q , or when Y is Y 2 , Q is CR q or N;
    상기 Rq는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R q is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
    상기 Y가 Y1인 경우, 상기 Z는 CHRz 또는 NRz 또는 상기 Y가 Y2인 경우, 상기 Z 는 CRz 또는 N; 및When Y is Y 1 , Z is CHR z or NR z or when Y is Y 2 , Z is CR z or N; And
    상기 Rz는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리.R z is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings.
  2. 제1항에 있어서, 상기 A는 C=O이고, D는 NH이며, G는 CRg이고, J는 N이며, Y는 Y1인 것을 특징으로 하는 화합물.2. The compound of claim 1, wherein A is C═O, D is NH, G is CR g , J is N, and Y is Y 1 .
  3. 제2항에 있어서, 상기 Y는 Y1인 경우, W는 CHRw이고, M은 NRm이며, Q는 CHRq인 것을 특징으로 하는 화합물. The compound of claim 2, wherein when Y is Y 1 , W is CHR w , M is NR m , and Q is CHR q .
  4. 제2항에 있어서, 상기 Y는 Y1인 경우, W는 CHRw이고, M은 CHRm이며, Q는 NRq인 것을 특징으로 하는 조성물. The composition of claim 2 wherein when Y is Y 1 , W is CHR w , M is CHR m , and Q is NR q .
  5. 제1항에 있어서, 상기 A는 CHRa이고, D는 CRd이며, G는 CRg이고, J는 N이며, Y는 Y2인 것을 특징으로 하는 조성물.The composition of claim 1, wherein A is CHR a , D is CR d , G is CR g , J is N, and Y is Y 2 .
  6. 제5항에 있어서, 상기 Y는 Y2인 경우, W는 NRw이고, M은 CHRm이며, Q는 CRq인 것을 특징으로 하는 조성물. 6. The composition of claim 5, wherein when Y is Y 2 , W is NR w , M is CHR m , and Q is CR q .
  7. 제1항에 있어서, 상기 화합물은 N-(4-에틸펜에틸)나프탈렌-1-설폰아미드, N-(2,3-디히드로-1H-인덴-2-일)나프탈렌-2-설폰아미드, N-부틸퀴놀린-8-설폰아미드, N-(2-(3-(피리딘-4-일)-1H-1,2,4-트리아졸-5-일)에틸)퀴놀린-8-카복스아미드, 2-(1-(4-히드록시-4-(피리딘-2-일)피리딘-1-일)-1-옥소프로판-2-일)프탈라진-1(2H)-온, 2-(4-메틸피페리딘-1-일)-7-(1H-피라졸-3-카보닐)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, N1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)피페리딘-1,4-디카복스아미드, 1-알릴-3-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)유레아, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-((테트라히드로퓨란-2-일)메틸)유레아, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸-2-일)메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 7-(2-히드록시-4-메톡시벤질)-2-메틸-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 6-((1,5-디메틸-1H-피라졸-4-일)메틸)-2-(4-메틸피페리딘-1-일)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 6-(2,5-디플루오로벤질)-2-(4-메틸피페리딘-1-일)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-(2,6-디메틸몰포리노)-7-(4-이소프로필벤질)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(2-플루오로벤질)-2-(4-메틸피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 2-몰포리노-7-(2-페닐프로파노일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-이소프로필벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 1-(퓨란-2-일메틸)-3-(4-히드록시-1,5-나프티리딘-3-일)유레아, 1-(6-에톡시-4-히드록시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(1-(피리딘-4-일)에틸)유레아, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-(4-메틸피페리딘-1-일)에틸)유레아, 1-(4-(퓨란-2-일)부탄-2-일)-3-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)유레아, N-(4-((4-옥소-2-(피리딘-3-일)-3,4,5,6-테트라히드로피리도[3,4-d]피리미딘-7(8H)-일)메틸)페닐)아세트아미드, 4-(2-옥소-2-(4-(피리딘-4-일)피페리딘-1-일)에틸)프탈라진-1(2H)-온, 4-(1-(4-니코티노일피페리딘-1-일)-1-옥소프로판-2-일)프탈라진-1(2H)-온, N-(2-(1-메틸-4-옥소-1,2,3,4-테트라히드로피리도[2,3-d]피리미딘-2-일)페닐)니코틴아미드, N-(2-(1-((2-메틸피리미딘-5-일)메틸)피페리딘-4-일)퀴놀린-3-일)아세트아미드, 2-몰포리노-7-(4-(피페리딘-1-일메틸)벤조일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-(디에틸아미노)-2-히드록시벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 6-(3,4-디메톡시벤질)-2-(4-메틸피페리딘-1-일)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 6-(2-히드록시-4-메톡시벤질)-2-(피리딘-2-일)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4-올, 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 2-(4-(3,4-디플루오로벤조일)피페라진-1-일)-5,6,7,8-테트라히드로퀴나졸린-4(3H)-온, 7-(3-(1H-벤조[d][1,2,3]트리아졸-1-일)프로파노일)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 2-(3-메틸피페리딘-1-일)-6-(퀴놀린-6-일메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 또는 7-이소부티릴-2-몰포리노-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온인 것을 특징으로 하는 조성물.The compound of claim 1, wherein the compound is N- (4-ethylphenethyl) naphthalene-1-sulfonamide, N- (2,3-dihydro-1H-inden-2-yl) naphthalene-2-sulfonamide, N-butylquinoline-8-sulfonamide, N- (2- (3- (pyridin-4-yl) -1H-1,2,4-triazol-5-yl) ethyl) quinoline-8-carboxamide , 2- (1- (4-hydroxy-4- (pyridin-2-yl) pyridin-1-yl) -1-oxopropan-2-yl) phthalazine-1 (2H) -one, 2- (4-methylpiperidin-1-yl) -7- (1H-pyrazole-3-carbonyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine-4 (3H) -one, N1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) piperidine-1,4-dicarboxamide, 1-allyl-3- (4 -Hydroxy-6-methoxy-1,5-naphthyridin-3-yl) urea, 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- ( (Tetrahydrofuran-2-yl) methyl) urea, 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6 -(2-methylbenzyl) -2-morpholino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2 -Methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-4 (3H) -one, 7- (2-hydroxy-4-methoxybenzyl) -2-methyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine-4 (3H ) -One, 6-((1,5-dimethyl-1H-pyrazol-4-yl) methyl) -2- (4-methylpiperidin-1-yl) -5,6,7,8-tetra Hydropyrido [4,3-d] pyrimidin-4 (3H) -one, 6- (2,5-difluorobenzyl) -2- (4-methylpiperidin-1-yl) -5, 6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2- (2,6-dimethylmorpholino) -7- (4-isopropylbenzyl) -5 , 6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (2-fluorobenzyl) -2- (4-methylpiperidine-1- Yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 2-morpholino-7- (2-phenylpropanoyl) -5, 6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4-isopropylbenzyl) -2- (piperidin-1-yl) -5 , 6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 1- (furan-2-ylme Tyl) -3- (4-hydroxy-1,5-naphthyridin-3-yl) urea, 1- (6-ethoxy-4-hydroxy-1,5-naphthyridin-3-yl) -3 -(2-morpholinoethyl) urea, 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (1- (pyridin-4-yl) ethyl) urea , 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2- (4-methylpiperidin-1-yl) ethyl) urea, 1- ( 4- (furan-2-yl) butan-2-yl) -3- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) urea, N- (4-((4 Oxo-2- (pyridin-3-yl) -3,4,5,6-tetrahydropyrido [3,4-d] pyrimidin-7 (8H) -yl) methyl) phenyl) acetamide, 4 -(2-oxo-2- (4- (pyridin-4-yl) piperidin-1-yl) ethyl) phthalazine-1 (2H) -one, 4- (1- (4-nicotinoylpy Ferridin-1-yl) -1-oxopropan-2-yl) phthalazine-1 (2H) -one, N- (2- (1-methyl-4-oxo-1,2,3,4- Tetrahydropyrido [2,3-d] pyrimidin-2-yl) phenyl) nicotinamide, N- (2- (1-((2-methylpyrimidin-5-yl) methyl) piperidine-4 -Yl) quinolin-3-yl) acetamide, 2-morpholino-7- (4- ( Ferridin-1-ylmethyl) benzoyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (2,4-dimethoxybenzyl ) -2- (pyrrolidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4- (di Ethylamino) -2-hydroxybenzyl) -2- (piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine-4 (3H)- On, 6- (3,4-dimethoxybenzyl) -2- (4-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine -4 (3H) -one, 6- (2-hydroxy-4-methoxybenzyl) -2- (pyridin-2-yl) -5,6,7,8-tetrahydropyrido [4,3- d] pyrimidin-4-ol, 7-((5,6-dihydro-1,4-dioxin-2-yl) methyl) -2- (pyridin-4-yl) -5,6,7, 8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 2- (4- (3,4-difluorobenzoyl) piperazin-1-yl) -5,6, 7,8-tetrahydroquinazolin-4 (3H) -one, 7- (3- (1H-benzo [d] [1,2,3] triazol-1-yl) propanoyl) -2- ( Piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 2- (3-methyl Ferridin-1-yl) -6- (quinolin-6-ylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, or 7 Isobutyryl-2-morpholino-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one.
  8. 제7항에 있어서, 상기 화합물은 N1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)피페리딘-1,4-디카복스아미드, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸-2-일)메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 7-(2-히드록시-4-메톡시벤질)-2-메틸-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-이소프로필벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-(디에틸아미노)-2-히드록시벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 또는 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온인 것을 특징으로 하는 조성물. 8. The compound of claim 7, wherein the compound is N1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) piperidine-1,4-dicarboxamide, 1- (4- Hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2-methylbenzyl) -2-morpholino-5,6,7 , 8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl ) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 7- (2-hydroxy-4-methoxybenzyl) -2-methyl- 5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4-isopropylbenzyl) -2- (piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (2,4-dimethoxybenzyl) -2- (pyrrolidine-1 -Yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4- (diethylamino) -2-hydroxybenzyl) -2- (piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, or 7-((5,6 -Dihydro-1,4-dioxin-2-yl) methyl)- 2- (pyridin-4-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one.
  9. 제8항에 있어서, 상기 화합물은 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 또는 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온인 것을 특징으로 하는 조성물. The compound of claim 8, wherein the compound is 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2- Methylbenzyl) -2-morpholino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl- 1H-benzo [d] imidazolmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, or 7- (2,4-dimethoxy Benzyl) -2- (pyrrolidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7-((5, 6-dihydro-1,4-dioxin-2-yl) methyl) -2- (pyridin-4-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine -4 (3H) -one.
  10. 제1항 내지 제9항 중 어느 한 항에 있어서, 상기 세포핵에서 세포질로의 GSK3 이동에 의해 발생되는 질환은 암, 당뇨병, C형 니이만-픽병(Niemann Pick's disease type C), 양극성 장애, 알츠하이머병, FTDP-17(파킨슨병과 관련된 전두측두성 치매), 피질-기저 퇴행(cortico-basal degeneration), 진행성 핵상 마비(progressive supranuclear palsy), 다발성전신위축증(Multiple system atrophy), 피크병(Pick's disease), 권투선수치매(dementia Pugilistica), 에이즈관련 치매 (AIDS associated dementia), 치매, 뇌졸중(stroke), 괌형 파킨슨-치매 증후군 (Guam parkinsonism-dementia complex), 뇌염후 파킨슨 증후군(postencephalic Parkinsonism), 전두엽 퇴행(frontal lobe degeneration), 은친화성 입자 질환(argyrophilic grains disease), 우울장애(depression), 정신분열증(Schizophrenia), 헌팅턴병(Huntington's disease), 근육긴장성 이영양증(myotonic dystrophy), 아급성경화범뇌염(subacute sclerotizing panencephalitis), 프리온 질병(prion disease), 다운증후군, 알러지, 천식, 다발성 경화증, 류마티스 관절염, 동맥경화증, 염증성 장질환(inflammatory bowel disease), 염증성 질환, 피부질환, 동통, 골관절염 및 백혈구감소증으로 구성된 군에서 선택된 하나 이상인 것을 특징으로 하는 조성물. 10. The disease according to any one of claims 1 to 9, wherein the disease caused by GSK3 migration from the cell nucleus to the cytoplasm is cancer, diabetes, Niemann Pick's disease type C, bipolar disorder, Alzheimer's disease. Disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease Dementia Pugilistica, AIDS associated dementia, Dementia, Stroke, Guam parkinsonism-dementia complex, Postencephalic Parkinsonism, Frontal lobe degeneration frontal lobe degeneration, argyrophilic grains disease, depression, schizophrenia, Huntington's disease, myotonic dystrophy, subacute Suvacute sclerotizing panencephalitis, prion disease, Down syndrome, allergy, asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, inflammatory disease, skin disease, pain, osteoarthritis and Leukopenia is a composition characterized in that at least one selected from the group consisting of.
  11. 다음 화학식 2로 표시되는 화합물, 그의 약학적으로 허용가능한 염, 전구약물, 또는 이성질체를 유효성분으로 함유하는 암 세포의 성장 및 전이 억제용 약학적 조성물:A pharmaceutical composition for inhibiting growth and metastasis of cancer cells containing a compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt, a prodrug thereof, or an isomer thereof as an active ingredient:
    화학식 2Formula 2
    Figure PCTKR2010001445-appb-I000054
    Figure PCTKR2010001445-appb-I000054
    상기 식에서, Where
    상기 A와 D 사이의 결합은 단일 결합 또는 이중결합; The bond between A and D is a single bond or a double bond;
    상기 A와 D 사이의 결합이 단일 결합일 때, A는 C=O, C=S, SO2, CHRa, O, S 또는 NRa이거나, A와 D 사이의 결합이 이중 결합일 때, A는 CRa 또는 N;When the bond between A and D is a single bond, A is C═O, C═S, SO 2 , CHR a , O, S or NR a, or when the bond between A and D is a double bond, A Is CR a or N;
    상기 A와 D 사이의 결합이 단일 결합일 때, D는 CHRd 또는 NRd이거나, A와 D 사이의 결합이 이중 결합일 때, D는 CRd 또는 N;When the bond between A and D is a single bond, D is CHR d or NR d, or when the bond between A and D is a double bond, D is CR d or N;
    상기 Ra와 Rd는 각각 독립적으로 수소, 할로겐, -OH, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 -(CR1R2)n-T1-(CH2)nT2-(CH2)n-T3;R a and R d are each independently hydrogen, halogen, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or-(CR 1 R 2 ) n- T 1- (CH 2 ) n T 2- (CH 2 ) n -T 3 ;
    상기 R1과 R2는 각각 독립적으로 수소, 할로겐, -(CH2)n-CN, -(CH2)n-NO2, -(CH2)n-C(O)OH, -(CH2)n-C(O)H, -(CH2)n-OH, -(CH2)n-NH2, -(CH2)n-C(O)NH2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 또는 치환된 또는 비치환된 아미노; R 1 and R 2 are each independently hydrogen, halogen,-(CH 2 ) n -CN,-(CH 2 ) n -NO 2 ,-(CH 2 ) n -C (O) OH,-(CH 2 ) n -C (O) H,-(CH 2 ) n -OH,-(CH 2 ) n -NH 2 ,-(CH 2 ) n -C (O) NH 2 , substituted or unsubstituted alkyl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino;
    상기 n은 0, 1, 2, 3, 4, 5 또는 6;N is 0, 1, 2, 3, 4, 5 or 6;
    상기 T1 은 공유결합,-C(O)-(CR1R2)n-, -N(R1)-(CR1R2)n-, -O-(CR1R2)n-, -C(O)N(R1)-(CR1R2)n-, -N(R1)C(O)-(CR1R2)n-, -S(O)p-(CR1R2)n-, -S(O)pN(R1)-(CR1R2)n-, -N(R1)S(O)p-(CR1R2)n-, -OC(O)N(R1)-(CR1R2)n-, -N(R1)C(O)O-(CR1R2)n-, -N(R1)C(O)N(R1)-(CR1R2)n-, 또는 -N(R1)C(S)N(R1)-(CR1R2)n-; T 1 is a covalent bond, -C (O)-(CR 1 R 2 ) n- , -N (R 1 )-(CR 1 R 2 ) n- , -O- (CR 1 R 2 ) n- , -C (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O)-(CR 1 R 2 ) n- , -S (O) p- (CR 1 R 2 ) n- , -S (O) p N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) S (O) p- (CR 1 R 2 ) n- , -OC (O) N (R 1 )-(CR 1 R 2 ) n- , -N (R 1 ) C (O) O- (CR 1 R 2 ) n- , -N (R 1 ) C (O) N (R 1 )-(CR 1 R 2 ) n- , or -N (R 1 ) C (S) N (R 1 )-(CR 1 R 2 ) n- ;
    상기 p는 1 또는 2;P is 1 or 2;
    상기 T2 는 공유결합, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 아릴알킬, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤지미다졸릴, 이미다졸릴, 인도릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐을 포함하는 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 헤테로아릴알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 시클로알킬알킬,
    Figure PCTKR2010001445-appb-I000055
    , 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐을 포함하는 치환된 또는 비치환된 비-방향족 단일 또는 바이시클릭 고리, 6치환된 또는 비치환된 바이시클릭 방향족 헤테로 퀴놀리닐, 퀴녹사리닐, 퀴나졸리닐, 이소퀴놀리닐 그리고 프탈라지닐, 또는 이미다조피리미디닐, 이미다조이미다졸릴, 이미다조티아졸릴, 나프틸, 테트라히드로나프틸, 벤조티에닐, 벤족사졸릴, 벤즈이미다졸릴, 벤조이속사졸릴 또는 벤조티아졸릴을 포함하는 하나의 방향족 고리가 다섯 개의 원자를 가지고 다른 하나의 방향족 고리가 6개의 고리를 가지는 치환된 또는 비치환된 바이시클릭 방향족 헤테로 시클;    T 2 is a covalent bond, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl and benzofuranyl Substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
    Figure PCTKR2010001445-appb-I000055
    , Substituted or unsubstituted non-aromatic single or bicyclic ring including 6, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, 6-substituted or unsubstituted Bicyclic aromatic heteroquinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl and phthalazinyl, or imidazopyrimidinyl, imidazoimidazolyl, imidazothiazolyl, naphthyl, tetrahydro One aromatic ring comprising naphthyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoisoxazolyl or benzothiazolyl having five atoms and the other aromatic ring having six rings or substituted Unsubstituted bicyclic aromatic heterocycle;
    상기 T3는 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 알케닐, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는, 디플루오로페닐, 디메톡시페닐, 메톡시히드록시페닐, 디메틸피라졸릴, 디메틸몰포리닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 피리디닐, 피리미디닐, 피라지닐, 옥사졸릴, 옥사디아졸릴, 이속사졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴, 벤조퓨라닐, 벤조트리아졸릴, 피페리디닐, 피페라지닐, 테트라히드로퓨라닐, 몰포리닐, 피롤리디닐, 피라졸리디닐, 또는
    Figure PCTKR2010001445-appb-I000056
    를 포함하는 단일- 또는 다중치환된 또는 비치환된 방향족 또는 비-방향족 고리;    T 3 is hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-(CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n- N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -Arylalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or difluorophenyl, dimethoxyphenyl, methoxyhydroxyphenyl, dimethylpyrazolyl, dimethylmorpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, pyridinyl, Pyrimidinyl, pyrazinyl, oxazolyl, oxdiazolyl, isoxazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzo Furanyl, benzotriazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, or
    Figure PCTKR2010001445-appb-I000056
    Mono- or polysubstituted or unsubstituted aromatic or non-aromatic rings comprising;
    상기 G와 J사이의 결합은 단일 결합 또는 이중결합; The bond between G and J is a single bond or a double bond;
    G와 J 사이 결합이 단일 결합일 경우, G는 CHRg 또는 NRg, 또는, G와 J 사이 결합이 이중 결합일 경우, G는 CRg 또는 N; When the bond between G and J is a single bond, G is CHR g or NR g , or when the bond between G and J is a double bond, G is CR g or N;
    상기 Rg는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 아릴, 치환된 또는 비치환된 헤테로아릴, 치환된 또는 비치환된 비-방향족 단일- 또는 바이 시클릭 고리, 또는 -(CR1R2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R g is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic mono- or bicyclic Ring, or-(CR 1 R 2 ) n -T 4- (CR 1 R 2 ) n -T 1- (CH 2 ) n -T 3 ;
    상기 T4는 공유결합, 치환된 또는 비치환된 아릴 또는 헤테로아릴 단일- 또는 바이시클릭 고리 페닐을 포함하는, 히드록시페닐, 플루오로페닐, 피리디닐, 피리미디닐, 피라지닐, 피롤릴, 피라졸릴, 트리아졸릴, 테트라졸릴, 퓨라닐, 이속사졸릴, 옥사졸릴, 옥사디아졸릴, 티에닐, 티아졸릴, 티아디아졸릴, 벤즈이미다졸릴, 이미다졸릴, 인돌릴, 인다졸릴, 벤조이소티아졸릴 및 벤조퓨라닐, 또는 치환된 또는 비치환된 비-방향족 단일- 또는 바이시클릭 고리 피페리디닐을 포함하는, 피페라지닐, 몰포리닐, 테트라히드로퓨라닐, 피롤리디닐 또는 피라졸리디닐;T 4 is hydroxyphenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, including covalent, substituted or unsubstituted aryl or heteroaryl single- or bicyclic ring phenyl Pyrazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxdiazolyl, thienyl, thiazolyl, thiadiazolyl, benzimidazolyl, imidazolyl, indolyl, indazolyl, benzoiso Piperazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl or pyrazoli, including thiazolyl and benzofuranyl, or substituted or unsubstituted non-aromatic single- or bicyclic ring piperidinyl Denyl;
    상기 G와 J 사이의 결합이 이중 결합인 경우 상기 J는 CHRj 또는 NRj , 또는 J와 G가 이중 결합인 경우, 상기 J 는 CRj 또는 N;When the bond between G and J is a double bond, J is CHR j or NR j , or when J and G is a double bond, J is CR j or N;
    상기 Rj는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R j is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
    상기 Y 는 Y1 (
    Figure PCTKR2010001445-appb-I000057
    ) 또는 Y2 (
    Figure PCTKR2010001445-appb-I000058
    );    Y is Y 1 (
    Figure PCTKR2010001445-appb-I000057
    ) Or Y 2 (
    Figure PCTKR2010001445-appb-I000058
    );
    Y가 Y1인 경우, 상기 W는 CHRw 또는 NRw 또는 Y가 Y2인 경우, 상기 W는 CRw 또는 N; When Y is Y 1 , W is CHR w or NR w or when Y is Y 2 , W is CR w or N;
    상기 Rw는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리;R w is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings;
    상기 Y가 Y1인 경우, 상기 M은 CHRm 또는 NRm 또는 상기 Y가 Y2인 경우, 상기 M은 CRm 또는 N;When Y is Y 1 , M is CHR m or NR m or when Y is Y 2 , M is CR m or N;
    상기 Rm은 독립적으로 수소, 할로겐, -(CR1R2)n-O-알킬, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T2-(CH2)n-T3;R m is independently hydrogen, halogen,-(CR 1 R 2 ) n -O-alkyl, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 2- (CH 2 ) n- T 3 ;
    상기 Y가 Y1인 경우, 상기 Q는 CHRq 또는 NRq, 또는 상기 Y가 Y2인 경우, 상기 Q는 CRq 또는 N;When Y is Y 1 , Q is CHR q or NR q , or when Y is Y 2 , Q is CR q or N;
    상기 Rq는 독립적으로 수소, 할로겐, 치환된 또는 비치환된 알킬, 또는 -(CR1R2)n-T1-(CH2)n-T4-(CR1R2)n-T1-(CH2)n-T3;R q is independently hydrogen, halogen, substituted or unsubstituted alkyl, or-(CR 1 R 2 ) n -T 1- (CH 2 ) n -T 4- (CR 1 R 2 ) n -T 1 -(CH 2 ) n -T 3 ;
    상기 Y가 Y1인 경우, 상기 Z는 CHRz 또는 NRz 또는 상기 Y가 Y2인 경우, 상기 Z 는 CRz 또는 N; 및When Y is Y 1 , Z is CHR z or NR z or when Y is Y 2 , Z is CR z or N; And
    상기 Rz는 독립적으로 수소, 할로겐, -(CR1R2)n-CN, -(CR1R2)n-NO2, -(CR1R2)n-C(O)OH, -(CR1R2)n-C(O)H, -(CR1R2)n-OH, -(CR1R2)n-C(O)N(R1)R2, -(CR1R2)n-N(R1)R2, 치환된 또는 비치환된 알킬, 치환된 또는 비치환된 시클로알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴알킬, 치환된 또는 비치환된 -(CR1R2)n-아릴, 치환된 또는 비치환된 -(CR1R2)n-헤테로아릴, 치환된 또는 비치환된 -(CR1R2)n-알콕시, 또는 단일- 또는 다중 치환된 또는 비치환된 방향족 또는 비-방향족 고리.R z is independently hydrogen, halogen,-(CR 1 R 2 ) n -CN,-(CR 1 R 2 ) n -NO 2 ,-(CR 1 R 2 ) n -C (O) OH,-( CR 1 R 2 ) n -C (O) H,-(CR 1 R 2 ) n -OH,-(CR 1 R 2 ) n -C (O) N (R 1 ) R 2 ,-(CR 1 R 2 ) n -N (R 1 ) R 2 , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted-(CR 1 R 2 ) n -arylalkyl, substituted or Unsubstituted-(CR 1 R 2 ) n -aryl, substituted or unsubstituted-(CR 1 R 2 ) n -heteroaryl, substituted or unsubstituted-(CR 1 R 2 ) n -alkoxy, or Mono- or multi-substituted or unsubstituted aromatic or non-aromatic rings.
  12. 제11항에 있어서, 상기 화합물은 N1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)피페리딘-1,4-디카복스아미드, 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸-2-일)메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 7-(2-히드록시-4-메톡시벤질)-2-메틸-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-이소프로필벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 7-(4-(디에틸아미노)-2-히드록시벤질)-2-(피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 또는 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온인 것을 특징으로 하는 조성물. The compound of claim 11, wherein the compound is N 1-(4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) piperidine-1,4-dicarboxamide, 1- (4- Hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2-methylbenzyl) -2-morpholino-5,6,7 , 8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl ) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 7- (2-hydroxy-4-methoxybenzyl) -2-methyl- 5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4-isopropylbenzyl) -2- (piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (2,4-dimethoxybenzyl) -2- (pyrrolidine-1 -Yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 7- (4- (diethylamino) -2-hydroxybenzyl) -2- (piperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, or 7-((5,6 -Dihydro-1,4-dioxin-2-yl) methyl) 2- (pyridin-4-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one.
  13. 제12항에 있어서, 상기 화합물은 1-(4-히드록시-6-메톡시-1,5-나프티리딘-3-일)-3-(2-몰포리노에틸)유레아, 6-(2-메틸벤질)-2-몰포리노-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 2-메틸-6-((1-프로필-1H-벤조[d]이미다졸메틸)-5,6,7,8-테트라히드로피리도[4,3-d]피리미딘-4(3H)-온, 7-(2,4-디메톡시벤질)-2-(피롤리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온, 또는 7-((5,6-디히드로-1,4-디옥신-2-일)메틸)-2-(피리딘-4-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4(3H)-온인 것을 특징으로 하는 조성물. 13. The compound according to claim 12, wherein the compound is 1- (4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl) -3- (2-morpholinoethyl) urea, 6- (2- Methylbenzyl) -2-morpholino-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 2-methyl-6-((1-propyl- 1H-benzo [d] imidazolmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one, 7- (2,4-dimethoxybenzyl ) -2- (pyrrolidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, or 7-((5, 6-dihydro-1,4-dioxin-2-yl) methyl) -2- (pyridin-4-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine -4 (3H) -one.
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