JP5585892B2 - キナーゼ阻害剤としての化合物 - Google Patents
キナーゼ阻害剤としての化合物 Download PDFInfo
- Publication number
- JP5585892B2 JP5585892B2 JP2011523883A JP2011523883A JP5585892B2 JP 5585892 B2 JP5585892 B2 JP 5585892B2 JP 2011523883 A JP2011523883 A JP 2011523883A JP 2011523883 A JP2011523883 A JP 2011523883A JP 5585892 B2 JP5585892 B2 JP 5585892B2
- Authority
- JP
- Japan
- Prior art keywords
- yloxy
- methoxy
- azaspiro
- methyl
- heptan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims description 111
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- -1 4-Fluoro-2-methyl-1H-indol-5-yloxy Chemical group 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- IVJLQSOJUNXMDA-UHFFFAOYSA-N 5,8-dioxa-10-azadispiro[2.0.4^{4}.3^{3}]undecane Chemical compound C1CC11C2(OCCO2)CNC1 IVJLQSOJUNXMDA-UHFFFAOYSA-N 0.000 claims description 11
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 230000033115 angiogenesis Effects 0.000 claims description 6
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005466 alkylenyl group Chemical group 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- QOBCXBGAHZODHC-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxy-7-[2-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)ethoxy]quinoline Chemical compound COC1CN(CCOC=2C(=CC3=C(OC=4C(=C5C=C(C)NC5=CC=4)F)C=CN=C3C=2)OC)CC11CC1 QOBCXBGAHZODHC-UHFFFAOYSA-N 0.000 claims description 2
- WSLGJXMGVWVBJL-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxy-7-[3-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)propoxy]quinoline Chemical compound COC1CN(CCCOC=2C(=CC3=C(OC=4C(=C5C=C(C)NC5=CC=4)F)C=CN=C3C=2)OC)CC11CC1 WSLGJXMGVWVBJL-UHFFFAOYSA-N 0.000 claims description 2
- ZYKPCTHQZTVAKG-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxy-7-[3-(7-methylidene-5-azaspiro[2.4]heptan-5-yl)propoxy]quinoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)C=CN=C2C=C1OCCCN(C1)CC(=C)C21CC2 ZYKPCTHQZTVAKG-UHFFFAOYSA-N 0.000 claims description 2
- XCODGQCZRWSYIQ-UHFFFAOYSA-N 6-[6-methoxy-7-[2-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)ethoxy]quinolin-4-yl]oxy-n,2-dimethyl-1-benzofuran-3-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=C(C)OC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCN(C1)CC(OC)C21CC2 XCODGQCZRWSYIQ-UHFFFAOYSA-N 0.000 claims description 2
- HKUVKHXLHADTCL-UHFFFAOYSA-N 6-[6-methoxy-7-[2-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)ethoxy]quinolin-4-yl]oxy-n-methylnaphthalene-1-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCN(C1)CC(OC)C21CC2 HKUVKHXLHADTCL-UHFFFAOYSA-N 0.000 claims description 2
- RAXLPWJMFWUICZ-UHFFFAOYSA-N 6-[6-methoxy-7-[2-(7-methylidene-5-azaspiro[2.4]heptan-5-yl)ethoxy]quinolin-4-yl]oxy-n,2-dimethyl-1-benzofuran-3-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=C(C)OC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCN(C1)CC(=C)C21CC2 RAXLPWJMFWUICZ-UHFFFAOYSA-N 0.000 claims description 2
- DBZDLQWZCADRIM-UHFFFAOYSA-N 6-[6-methoxy-7-[2-(7-methylidene-5-azaspiro[2.4]heptan-5-yl)ethoxy]quinolin-4-yl]oxy-n-methylnaphthalene-1-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCN(C1)CC(=C)C21CC2 DBZDLQWZCADRIM-UHFFFAOYSA-N 0.000 claims description 2
- CUYKTVTVEKQIOG-UHFFFAOYSA-N 6-[6-methoxy-7-[3-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)propoxy]quinolin-4-yl]oxy-n-methylnaphthalene-1-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCCN(C1)CC(OC)C21CC2 CUYKTVTVEKQIOG-UHFFFAOYSA-N 0.000 claims description 2
- HZJUJWOZDAOIHQ-UHFFFAOYSA-N 6-[6-methoxy-7-[3-(7-methylidene-5-azaspiro[2.4]heptan-5-yl)propoxy]quinolin-4-yl]oxy-n-methylnaphthalene-1-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCCN(C1)CC(=C)C21CC2 HZJUJWOZDAOIHQ-UHFFFAOYSA-N 0.000 claims description 2
- LAXICOVSKMJWRH-UHFFFAOYSA-N 6-[6-methoxy-7-[3-(7-oxo-5-azaspiro[2.4]heptan-5-yl)propoxy]quinolin-4-yl]oxy-n,2-dimethyl-1-benzofuran-3-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=C(C)OC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCCN(C1)CC(=O)C21CC2 LAXICOVSKMJWRH-UHFFFAOYSA-N 0.000 claims description 2
- WGYOTFJPHQHRAI-UHFFFAOYSA-N 6-[7-[2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)ethoxy]-6-methoxyquinolin-4-yl]oxy-n,2-dimethyl-1-benzofuran-3-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=C(C)OC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCN(C1)CC(O)C21CC2 WGYOTFJPHQHRAI-UHFFFAOYSA-N 0.000 claims description 2
- VDFPQQRIJLWRJT-UHFFFAOYSA-N 6-[7-[2-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)ethoxy]-6-methoxyquinolin-4-yl]oxy-n-methylnaphthalene-1-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCN(C1)CC(O)C21CC2 VDFPQQRIJLWRJT-UHFFFAOYSA-N 0.000 claims description 2
- AHHVDMLPZJPQSD-UHFFFAOYSA-N 6-[7-[3-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)propoxy]-6-methoxyquinolin-4-yl]oxy-n,2-dimethyl-1-benzofuran-3-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=C(C)OC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCCN(C1)CC(O)C21CC2 AHHVDMLPZJPQSD-UHFFFAOYSA-N 0.000 claims description 2
- GEKDAGBAGNWNLY-UHFFFAOYSA-N 6-[7-[3-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)propoxy]-6-methoxyquinolin-4-yl]oxy-n-methylnaphthalene-1-carboxamide Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCCCN(C1)CC(O)C21CC2 GEKDAGBAGNWNLY-UHFFFAOYSA-N 0.000 claims description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
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- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
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- 239000012453 solvate Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
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- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims 4
- QQRYOBZMVPCAAL-UHFFFAOYSA-N 7-methylidene-5-azaspiro[2.4]heptane Chemical compound C=C1CNCC11CC1 QQRYOBZMVPCAAL-UHFFFAOYSA-N 0.000 claims 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims 1
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- DQJCHOQLCLEDLL-UHFFFAOYSA-N tricyclazole Chemical compound CC1=CC=CC2=C1N1C=NN=C1S2 DQJCHOQLCLEDLL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- 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
- A61K31/4709—Non-condensed quinolines and containing further 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Rは、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、ヒドロキシ、低級アルコキシ、低級アルコキシアルコキシ、低級アルケニル、低級アルキニル、アミノ、アルキルアミノ、アルコキシアミノ、シクロアルキル、シクロアルケニル、アリール、またはヘテロシクリルから各々独立に選択され;
R1は、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、ヒドロキシ、低級アルコキシ、低級アルコキシアルコキシ、低級アルケニル、または低級アルキニルから選択され;
Aは、直接結合または−N(R’)−から選択され;
Bは、直接結合、O、−N(R’)−、−C(=Z)−、−C(=Z)N(R’)−、低級アルキレニル−C(=Z)−、または低級アルキレニル−C(=Z)N(R’)−から選択され;
Zは、OまたはSから選択され;
aは、1、2、3、4、または5から選択され;
b、c、およびdは、1、2、または3から各々独立に選択され;
Gは、C−R、C−(CN)、またはNから選択され;
XおよびYが、(i)XがYと化合して酸素またはメチレンになる、(ii)Xが水素であり、Yが水素である、(iii)Xが水素であり、Yがヒドロキシまたはその光学異性体である、から選択される場合、R’およびR’’は示されず;
XおよびYが、(i)Xが水素であり、YがO、S、またはその光学異性体である、(ii)XおよびYが両方ともOまたはSである、あるいは(iii)XがOであり、YがSである、から選択される場合、R’およびR’’は、ハロゲノ低級アルキル、低級アルキル、低級アルコキシ、ヒドロキシ、低級アルキルヒドロキシから各々独立に選択され;任意でR’およびR’’は化合して、X、Yと5〜7員環を形成し、該環は、置換されていなくてもよく、または最大3個の置換基で独立に置換されていてもよい。)
環Qは、
Rは、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、ヒドロキシ、低級アルコキシ、低級アルコキシアルコキシ、低級アルケニル、低級アルキニル、アミノ、アルキルアミノ、アルコキシアミノ、シクロアルキル、シクロアルケニル、アリール、またはヘテロシクリルから各々独立に選択され;好ましくは、H、ハロゲン、ハロゲノ低級アルキル、低級アルキルから選択され;
R1は、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、ヒドロキシ、低級アルコキシ、低級アルコキシアルコキシ、低級アルケニル、または低級アルキニルから選択され;好ましくは、H、ハロゲン、ハロゲノ低級アルキル、低級アルキルから選択され;
Aは、直接結合または−N(R’)−から選択され;好ましくは、直接結合または−NH−から選択され;
Bは、直接結合、O、−N(R’)−、−C(=Z)−、−C(=Z)N(R’)−、低級アルキレニル−C(=Z)−、または低級アルキレニル−C(=Z)N(R’)−から選択され;好ましくは、−NH−、−C(=O)−、または−C(=O)NH−から選択され;
Zは、OまたはS;好ましくは、Oから選択され;
aは、1、2、3、4、または5;好ましくは、1、2、または3から選択され;
b、c、およびdは、1、2、または3;好ましくは、1または2から各々独立に選択され;
Gは、C−R、C−(CN)またはN;好ましくは、C−RまたはN、より好ましくは、CHから選択され;
XおよびYが、(i)XがYと化合して酸素またはメチレンになる、(ii)Xが水素であり、Yが水素である、(iii)Xが水素であり、Yがヒドロキシまたはその光学異性体である、から選択される場合、R’およびR’’は示されず;好ましい部分は、ケトン、メチレン、またはヒドロキシもしくは該ヒドロキシの光学異性体から各々独立に選択され;
XおよびYが、(i)Xが水素であり、YがO、S、またはその光学異性体である、(ii)XおよびYが両方ともOまたはSである、あるいは(iii)XがOであり、YがSである、から選択される場合、R’およびR’’は、ハロゲノ低級アルキル、低級アルキル、低級アルコキシ、ヒドロキシ、低級アルキルヒドロキシから各々独立に選択され;任意でR’およびR’’は化合して、X、Yと5〜7員環を形成し、該環は、置換されていなくてもよく、または最大3個の置換基で独立に置換されていてもよく、好ましい部分は、アルコキシもしくは該アルコキシの光学異性体、環状ケタール、環状チオケタール、または環状チオキソランから各々独立に選択され、これらは、置換されていなくてもよく、または低級アルキル、アリール、もしくはヘテロシクリルで置換されていてもよい。
実施例1 0.09 0.2
実施例2 0.1 0.3
実施例3 0.1 0.4
実施例4 0.08 0.4
実施例5 0.1 0.4
実施例6 0.08 0.4
実施例7 0.09 0.2
実施例8 0.1 0.3
実施例9 0.1 0.4
実施例10 0.1 0.4
実施例11 0.2 0.7
実施例12 0.3 0.9
実施例13 0.2 0.9
実施例14 0.2 0.7
実施例15 0.3 0.9
実施例16 0.2 0.7
実施例17 0.3 0.9
実施例18 0.5 0.8
実施例19 0.2 0.7
実施例20 0.3 0.9
実施例21 0.8 1.1
実施例22 0.7 1.1
実施例23 0.8 1.2
実施例24 1.0 1.5
実施例25 0.3 0.9
実施例26 0.8 1.1
実施例27 0.4 0.9
実施例28 1.0 1.5
実施例29 0.3 0.9
実施例30 0.9 1.0
反応式I
環Qは、
EtOH:エタノール、MeOH:メタノール、RT:室温、DIPEA:ジイソプロピルエチルアミン、DCM:ジクロロメタン、DMF:N,N−ジメチルホルムアミド、DMAP:ジメチルアミノピリジン、EtOAc:酢酸エチル、Et2O:ジメチルエーテル、MsCl:塩化メタンスルホニル、eq:当量、g:グラム、mg:ミリグラム、ml:ミリリットル、μl:マイクロリットル、min:分
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−ベンジルオキシキノリンの調製
方法A:
4−クロロ−7−ベンジルオキシ−6−メトキシ−キノリン(国際公開公報第2008112407号、1.5g)をジオキサン(20ml)中でDMAP(1.5eq)、2−メチル−4−フルオロ−5−ヒドロキシインドール(国際公開公報第0047212号)(1eq)と混合した。反応液を3日間還流し、EtOAc、水で希釈し、EtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−ベンジルオキシキノリン(600mg)を得た。
4−クロロ−7−ベンジルオキシ−6−メトキシ−キノリン(国際公開公報第2008112407号、1.5g)をジオキサン(30ml)中で3−(2,2−ジメトキシプロピル)−2−フルオロ−4−ニトロフェノール(国際公開公報第0047212号)(1.5eq)と混合した。反応液を3日間還流し、EtOAc、水で希釈し、EtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、7−(ベンジルオキシ)−4−(3−(2,2−ジメトキシプロピル)−2−フルオロ−4−ニトロフェノキシ)−6−メトキシキノリン(650mg)を得た。この生成物を2ΝのHC1(3ml)およびアセトン(30ml)と混合し、6時間還流した。反応液をEtOAcで希釈し、飽和NaHCO3で中和し、さらにEtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、1−(3−(7−(ベンジルオキシ)−6−メトキシキノリン−4−イルオキシ)−2−フルオロ−6−ニトロフェニル)プロパン−2−オン(500mg)を得、これをEtOH/H2O(20ml、4/1)中で鉄(500mg)およびNH4Cl(50mg)と混合した。反応液を4時間還流し、セライトに通して濾過し、蒸発させた。残渣をEtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−ベンジルオキシキノリン(250mg)を得た。
方法C:
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−ヒドロキシキノリン(400mg)をDMF(5ml)中で1,2−ジブロモエタン(2eq)およびK2CO3(2eq)と混合した。反応液を100℃で5時間加熱し、EtOAc、水で希釈し、EtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製した。生成物をアセトニトリル(15ml)中でNaI(250mg)と混合し、30分間還流した。反応液を冷却し、DIPEA(500μL)および5,8−ジオキサ−10−アザジスピロ[2.0.4.3]−ウンデカン(300mg)を反応液に添加して、これを一晩還流した。反応液をEtOAc、水で希釈し、EtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、表題化合物(150mg)を得た。質量:(M+1)、520。
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−ヒドロキシキノリン(400mg)をDMF(5ml)中で2−ブロモ−1,1−ジメトキシエタン(2eq)およびK2CO3(2eq)と混合した。反応液を100℃で8時間加熱し、EtOAc、水で希釈し、EtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製した。生成物をEtOH(10ml)中で1NのHCl(2ml)と混合し、5時間還流した。反応液を蒸発させ、飽和NaHCO3で中和し、さらにEtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、アルデヒド付加体(400mg)を得、これをDCM(10ml)中でNaBH(OAc)3(2eq)とともに5,8−ジオキサ−10−アザジスピロ[2.0.4.3]−ウンデカン(200mg)と混合した。反応液をRTで2時間撹拌した後、EtOAc、水で希釈し、EtOAcで3回抽出した。合わせた有機層を水、ブラインで洗浄し、乾燥させた。溶液を蒸発させ、シリカゲルカラムで精製して、表題化合物(250mg)を得た。質量:(M+1)、520。
上記の実施例1からの生成物(100mg)を1NのHCl(4ml)およびアセトン(20ml)と混合した。反応液を一晩還流し、蒸発させた。溶液を2NのNaOHで塩基性化し、EtOAcで抽出した。合わせた有機層を、H2O、次いでブラインで洗浄し、Na2SO4上で乾燥させ、蒸発させた。残渣をカラムクロマトグラフィーで精製して、表題化合物(75mg)を得た。質量:(M+1)、476。
上記の実施例2からの生成物(75mg)をMeOH(8ml)に溶解し、RTで撹拌した。反応液にNaBH4(75mg)を添加し、RTで30分間撹拌した。反応液を蒸発させ、カラムクロマトグラフィーで精製して、表題化合物(60mg)を得た。質量:(M+1)、478。
上記の実施例2からの生成物(60mg)をDMF(4ml)に溶解し、0℃で冷却した。反応液にNaH(1.1eq)を添加し、10分間撹拌した。反応液にTsOMe(1.2eq)を添加し、溶液を80℃で2時間加熱した。反応液を水でクエンチし、EtOAcで抽出した後、水、次にブラインで洗浄し、Na2SO4上で乾燥させた。反応液を蒸発させ、シリカカラムで精製して、表題生成物を得た。質量:(M+1)、492。
上記の実施例2からの生成物(50mg)を無水テトラヒドロフラン(5ml)に溶解し、反応液にNysted試薬(1.5eq、20%溶液)を添加した。反応液をRTで2日間撹拌し、NH4Cl溶液でクエンチし、EtOAcで抽出した後、水、次にブラインで洗浄し、Na2SO4上で乾燥させ、シリカゲルカラムで精製して、表題化合物を得た。質量:(M+1)、474。
表題化合物は、方法Cで1,2−ジブロモエタンの代わりに1,3−ジブロモプロパンを用いることによって;または方法Dで2−ブロモ−1,1−ジメトキシエタンの代わりに3−ブロモ−1,1−ジメトキシプロパンを用いることによって、実施例1と同様の方法で調製した。質量:(M+1)、534。
表題化合物は、実施例6の化合物から出発して、実施例2と同様の方法で調製した。質量:(M+1)、490。
表題化合物は、実施例7の化合物から出発して、実施例3と同様の方法で調製した。質量:(M+1)、492。
表題化合物は、実施例8の化合物から出発して、実施例4と同様の方法で調製した。質量:(M+1)、506。
表題化合物は、実施例7の化合物から出発して、実施例5と同様の方法で調製した。質量:(M+1)、488。
表題化合物は、方法Aで2−メチル−4−フルオロ−5−ヒドロキシインドールの代わりに6−ヒドロキシ−N,2−ジメチルベンゾフラン−3−カルボキサミドを用いることによって、実施例1と同様の方法で調製した。質量:(M+1)、560。
表題化合物は、実施例11の化合物から出発して、実施例2と同様の方法で調製した。質量:(M+1)、516。
表題化合物は、実施例12の化合物から出発して、実施例3と同様の方法で調製した。質量:(M+1)、518。
表題化合物は、実施例13の化合物から出発して、実施例4と同様の方法で調製した。質量:(M+1)、532。
表題化合物は、実施例12の化合物から出発して、実施例5と同様の方法で調製した。質量:(M+1)、514。
表題化合物は、2−メチル−4−フルオロ−5−ヒドロキシインドールの代わりに6−ヒドロキシ−N,2−ジメチルベンゾフラン−3−カルボキサミドを用いることによって、実施例6と同様の方法で調製した。質量:(M+1)、574。
表題化合物は、実施例16の化合物から出発して、実施例7と同様の方法で調製した。質量:(M+1)、530。
表題化合物は、実施例17の化合物から出発して、実施例8と同様の方法で調製した。質量:(M+1)、532。
表題化合物は、実施例18の化合物から出発して、実施例9と同様の方法で調製した。質量:(M+1)、546。
表題化合物は、実施例17の化合物から出発して、実施例10と同様の方法で調製した。質量:(M+1)、528。
表題化合物は、方法Aで2−メチル−4−フルオロ−5−ヒドロキシインドールの代わりに6−ヒドロキシ−N−メチル−1−ナフトアミドを用いることによって、実施例1と同様の方法で調製した。質量:(M+1)、556。
表題化合物は、実施例21の化合物から出発して、実施例2と同様の方法で調製した。質量:(M+1)、512。
表題化合物は、実施例22の化合物から出発して、実施例3と同様の方法で調製した。質量:(M+1)、514。
表題化合物は、実施例23の化合物から出発して、実施例4と同様の方法で調製した。質量:(M+1)、528。
表題化合物は、実施例22の化合物から出発して、実施例5と同様の方法で調製した。質量:(M+1)、510。
表題化合物は、2−メチル−4−フルオロ−5−ヒドロキシインドールの代わりに6−ヒドロキシ−N−メチル−1−ナフトアミドを用いることによって、実施例6と同様の方法で調製した。質量:(M+1)、570。
表題化合物は、実施例26の化合物から出発して、実施例7と同様の方法で調製した。質量:(M+1)、526。
表題化合物は、実施例27の化合物から出発して、実施例8と同様の方法で調製した。質量:(M+1)、528。
表題化合物は、実施例28の化合物から出発して、実施例9と同様の方法で調製した。質量:(M+1)、542。
表題化合物は、実施例27の化合物から出発して、実施例10と同様の方法で調製した。質量:(M+1)、524。
実施例1(または実施例2〜実施例30)からの化合物(100mg)をEtOAc(5ml)に溶解し、この溶液に2NのHCl/エーテル溶液(0.5ml)を添加した。溶液を蒸発させて、固体をそのHCl塩として得た。
以下は処方例であるが、これらは純粋に例示的なものであり、決して限定的なものとして解釈されるべきものではない。
各カプセルは、次のものを含む:
実施例1(または実施例2〜実施例30)の化合物 100.0mg
トウモロコシデンプン 23.0mg
カルシウムカルボキシメチルセルロース 22.5mg
ヒドロキシプロピルメチルセルロース 3.0mg
ステアリン酸マグネシウム 1.5mg
150.0mg
溶液は、次のものを含む:
実施例20(または実施例2〜実施例30)の化合物 1〜10g
酢酸または水酸化ナトリウム 0.5〜1g
p−ヒドロキシ安息香酸エチル 0.1g
精製水 88.9〜98.4g
100.0 g
飼料と混合するための粉末は、次のものを含む:
実施例20(または実施例2〜実施例30)の化合物 1〜10g
トウモロコシデンプン 98.5〜89.5g
軽質無水ケイ酸 0.5g
100.0g
Claims (7)
- 4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−[2−(5,8−ジオキサ−10−アザジスピロ[2.0.4.3]−ウンデカン)エトキシ]キノリン
5−(2−(4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシキノリン−7−イルオキシ)エチル)−5−アザスピロ[2.4]−ヘプタン−7−オン
5−(2−(4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシキノリン−7−イルオキシ)エチル)−5−アザスピロ[2.4]−ヘプタン−7−オール
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−(2−(7−メトキシ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−(2−(7−メチレン−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−[3−(5,8−ジオキサ−10−アザジスピロ[2.0.4.3]−ウンデカン)プロポキシ]キノリン
5−(3−(4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシキノリン−7−イルオキシ)プロピル)−5−アザスピロ[2.4]−ヘプタン−7−オン
5−(3−(4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシキノリン−7−イルオキシ)プロピル)−5−アザスピロ[2.4]−ヘプタン−7−オール
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−(3−(7−メトキシ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン
4−(4−フルオロ−2−メチル−1H−インドール−5−イルオキシ)−6−メトキシ−7−(3−(7−メチレン−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン
6−(6−メトキシ−7−[2−(5,8−ジオキサ−10−アザジスピロ[2.0.4.3]ウンデカン)エトキシ]キノリン−4−イルオキシ)−N,2−ジメチルベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−(2−(7−オキソ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン−4−イルオキシ)−N,2−ジメチルベンゾフラン−3−カルボキサミド
6−(7−(2−(7−ヒドロキシ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)−6−メトキシキノリン−4−イルオキシ)−N,2−ジメチルベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−(2−(7−メトキシ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン−4−イルオキシ)−N,2−ジメチルベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−(2−(7−メチレン−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン−4−イルオキシ)−N,2−ジメチル−ベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−[3−(5,8−ジオキサ−10−アザジスピロ[2.0.4.3]ウンデカン)プロポキシ]キノリン−4−イルオキシ)−N,2−ジメチルベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−(3−(7−オキソ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン−4−イルオキシ)−N,2−ジメチル−ベンゾフラン−3−カルボキサミド
6−(7−(3−(7−ヒドロキシ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)−6−メトキシキノリン−4−イルオキシ)−N,2−ジメチル−ベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−(3−(7−メトキシ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン−4−イルオキシ)−N,2−ジメチル−ベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−(3−(7−メチレン−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン−4−イルオキシ)−N,2−ジメチルベンゾフラン−3−カルボキサミド
6−(6−メトキシ−7−[2−(5,8−ジオキサ−10−アザジスピロ[2.0.4.3]ウンデカン)エトキシ]キノリン−4−イルオキシ)−N−メチル−
1−ナフトアミド
6−(6−メトキシ−7−(2−(7−オキソ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(7−(2−(7−ヒドロキシ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)−6−メトキシキノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(6−メトキシ−7−(2−(7−メトキシ−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(6−メトキシ−7−(2−(7−メチレン−5−アザスピロ[2.4]ヘプタン−5−イル)エトキシ)キノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(6−メトキシ−7−[3−(5,8−ジオキサ−10−アザジスピロ[2.0.4.3]ウンデカン)プロポキシ]キノリン−4−イルオキシ)−N−メチル−
1−ナフトアミド
6−(6−メトキシ−7−(3−(7−オキソ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(7−(3−(7−ヒドロキシ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)−6−メトキシキノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(6−メトキシ−7−(3−(7−メトキシ−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン−4−イルオキシ)−N−メチル−1−ナフトアミド
6−(6−メトキシ−7−(3−(7−メチレン−5−アザスピロ[2.4]ヘプタン−5−イル)プロポキシ)キノリン−4−イルオキシ)−N−メチル−1−ナフトアミド、からなる群から選択される、請求項1に記載の化合物、あるいは塩酸塩、臭化水素酸塩、硫酸塩、硝酸塩、リン酸塩;またはコハク酸塩、マレイン酸塩、酢酸塩、フマル酸塩、クエン酸塩、酒石酸塩、安息香酸塩、p−トルエンスルホン酸塩、メタンスルホン酸塩、もしくはナフタレンスルホン酸塩から選択される医薬として許容される塩。 - 以下の化学反応過程:
環Qは、
Rは、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、ヒドロキシ、低級アルコキシ、低級アルコキシアルコキシ、低級アルケニル、低級アルキニル、アミノ、アルキルアミノ、アルコキシアミノ、シクロアルキル、シクロアルケニル、アリール、またはヘテロシクリルから各々独立に選択され;
R 1 は、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、ヒドロキシ、低級アルコキシ、低級アルコキシアルコキシ、低級アルケニル、または低級アルキニルから選択され;
Aは、直接結合または−N(R’)−から選択され;
Bは、直接結合、O、−N(R’)−、−C(=Z)−、−C(=Z)N(R’)−、低級アルキレニル−C(=Z)−、または低級アルキレニル−C(=Z)N(R’)−から選択され;
Zは、OまたはSから選択され;
aは、1、2、3、4、または5から選択され;
b、c、およびdは、1、2、または3から各々独立に選択され;
Gは、C−R、C−(CN)、またはNから選択され;
XおよびYが、(i)XがYと化合して酸素またはメチレンになる、(ii)Xが水素であり、Yが水素である、(iii)Xが水素であり、Yがヒドロキシまたはその光学異性体である、から選択される場合、R’およびR’’は示されず;
XおよびYが、(i)Xが水素であり、YがO、S、またはその光学異性体である、(ii)XおよびYが両方ともOまたはSである、あるいは(iii)XがOであり、YがSである、から選択される場合、R’およびR’’は、ハロゲノ低級アルキル、低級アルキル、低級アルコキシ、ヒドロキシ、低級アルキルヒドロキシから各々独立に選択され;任意にR’およびR’’は化合して、X、Yと5〜7員環を形成し、該環は、置換されていなくてもよく、または最大3個の置換基で独立に置換されていてもよい。) - 請求項1〜3のいずれか1項に定義される化合物もしくは該化合物の医薬として許容される塩、または該化合物の水和物もしくは溶媒和物と医薬として許容される担体とを活性成分として含む医薬組成物。
- 有効量の請求項1〜3のいずれか1項に記載の前記化合物を投与することにより対象の癌を治療する方法で使用するのに適している化合物。
- 有効量の請求項1〜3のいずれか1項に記載の前記化合物を投与することにより対象の血管新生を治療する方法で使用するのに適している化合物。
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US8990808P | 2008-08-19 | 2008-08-19 | |
US61/089,908 | 2008-08-19 | ||
US12/540,300 | 2009-08-12 | ||
US12/540,300 US8211911B2 (en) | 2008-08-19 | 2009-08-12 | Compounds as kinase inhibitors |
PCT/US2009/053779 WO2010021918A1 (en) | 2008-08-19 | 2009-08-13 | Compounds as kinase inhibitors |
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US7977346B2 (en) | 2006-01-17 | 2011-07-12 | Guoqing Paul Chen | Spiro compounds and methods of use |
US8148532B2 (en) | 2007-03-14 | 2012-04-03 | Guoqing Paul Chen | Spiro substituted compounds as angiogenesis inhibitors |
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CN102159078B (zh) | 2014-05-21 |
US20100048599A1 (en) | 2010-02-25 |
ES2617678T3 (es) | 2017-06-19 |
IL210573A0 (en) | 2011-03-31 |
MX2010011813A (es) | 2010-12-01 |
EP2312950B1 (en) | 2016-11-30 |
WO2010021918A1 (en) | 2010-02-25 |
JP2012500269A (ja) | 2012-01-05 |
AU2009282962B2 (en) | 2015-10-08 |
EP2312950A4 (en) | 2012-10-24 |
BRPI0912475A2 (pt) | 2018-01-09 |
AU2009282962A1 (en) | 2010-02-25 |
US8211911B2 (en) | 2012-07-03 |
NZ590954A (en) | 2012-11-30 |
BRPI0912475B8 (pt) | 2021-05-25 |
BRPI0912475A8 (pt) | 2018-03-20 |
KR101727757B1 (ko) | 2017-04-17 |
CA2733250A1 (en) | 2010-02-25 |
EP2312950A1 (en) | 2011-04-27 |
BRPI0912475B1 (pt) | 2020-12-29 |
WO2010021918A8 (en) | 2011-01-27 |
CN102159078A (zh) | 2011-08-17 |
KR20110044749A (ko) | 2011-04-29 |
IL210573A (en) | 2016-05-31 |
CA2733250C (en) | 2016-06-21 |
AU2009282962A8 (en) | 2011-11-10 |
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