JP6273621B2 - ヒストンデメチラーゼ阻害剤 - Google Patents
ヒストンデメチラーゼ阻害剤 Download PDFInfo
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- JP6273621B2 JP6273621B2 JP2015549863A JP2015549863A JP6273621B2 JP 6273621 B2 JP6273621 B2 JP 6273621B2 JP 2015549863 A JP2015549863 A JP 2015549863A JP 2015549863 A JP2015549863 A JP 2015549863A JP 6273621 B2 JP6273621 B2 JP 6273621B2
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- optionally substituted
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- acceptable salt
- compound
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- 108010074870 Histone Demethylases Proteins 0.000 title claims description 15
- 102000008157 Histone Demethylases Human genes 0.000 title claims description 15
- 229940122680 Demethylase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 467
- -1 2,3-dihydrobenzofuranyl Chemical group 0.000 claims description 175
- 150000003839 salts Chemical class 0.000 claims description 141
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- 125000002947 alkylene group Chemical group 0.000 claims description 82
- 239000001257 hydrogen Substances 0.000 claims description 67
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 44
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 39
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 19
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 10
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 10
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- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 9
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- 230000007062 hydrolysis Effects 0.000 description 15
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- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 15
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
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- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 230000018044 dehydration Effects 0.000 description 11
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 101001088883 Homo sapiens Lysine-specific demethylase 5B Proteins 0.000 description 10
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- 125000004122 cyclic group Chemical group 0.000 description 10
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- 125000005843 halogen group Chemical group 0.000 description 10
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- FASOJOLGUAUEPU-UHFFFAOYSA-N methyl 3-bromopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1Br FASOJOLGUAUEPU-UHFFFAOYSA-N 0.000 description 9
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 9
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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- 210000001550 testis Anatomy 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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- XPARCVGSTPKNNR-UHFFFAOYSA-M zinc;ethyl butanoate;bromide Chemical compound [Zn+2].[Br-].CCOC(=O)CC[CH2-] XPARCVGSTPKNNR-UHFFFAOYSA-M 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Description
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、随意に置換されたテトラリニリル(tetralinyl)、随意に置換されたテトラヒドロキノリニル、置換されたピリジル、随意に置換されたナフチル、随意に置換されたインドリル、随意に置換されたベンゾフラニル、随意に置換されたアダマンチル(adamantyl)、または随意に置換されたインダニルである。
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、アルケニル、アルキニル、フルオロ、クロロ、フルオロアルキル、ニトロ、随意に置換されたアラルキル、随意に置換されたアラルケニル、随意に置換されたアラルキニル、随意に置換されたカルボシクリル、随意に置換されたカルボシクリルアルキル、随意に置換されたヘテロシクリル、随意に置換されたヘテロシクリルアルキル、随意に置換されたヘテロアリール、随意に置換されたヘテロアリールアルキル、−Rb−ORa、−Rb−OC(O)−Ra、−Rb−OC(O)−ORa、−Rb−OC(O)−N(Ra)2、−Rb−N(Ra)2、−Rb−C(O)Ra、−Rb−C(O)ORa、−Rb−O−Rc−C(O)N(Ra)2、−Rb−N(Ra)C(O)ORa、−Rb−N(Ra)C(O)Ra、−Rb−N(Ra)S(O)tRa、−Rb−S(O)tORa、−Rb−S(O)tORa、および−Rb−S(O)tN(Ra)2で置換されたフェニルであり、
式中、
それぞれのRaは独立して、水素、アルキル、フルオロアルキル、シクロアルキル、シクロアルキルアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、またはヘテロアリールアルキルであり、
それぞれのRbは独立して、直接結合、あるいは直鎖または分枝鎖のアルキレンまたはアルケニレン鎖であり、
それぞれのRcは直鎖または分枝鎖のアルキレンまたはアルケニレン鎖であり、tは1または2である。
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yはカルボシクリル、ヘテロシクリル、アリールあるいはヘテロアリールであり、
ただし、Gは以下ではないこと条件とする。
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、随意に置換されたテトラリニル、随意に置換されたクロマニル、随意に置換されたテトラヒドロキノリニル、随意に置換されたベンゾフラニル、随意に置換された2,3−ジヒドロベンゾフラニル、随意に置換された2,3−ジヒドロベンゾ[b][1,4]ジオキシニル(dioxinyl)、随意に置換されたナフチル、随意に置換されたインドリル、随意に置換された1,2−ジヒドロナフチル(dihydronaphthyl)、随意に置換されたインダニル、または随意に置換されたチオクロマニル(thiochromanyl)である。
R1は水素、メチル、または−OHであり、
それぞれのR4は独立して、水素、フルオロ、またはメチルであり、
R5、R6、R7、およびR8はそれぞれ、水素、ハロゲン、−OH、−CN、随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される。
R1は水素、メチル、または−OHであり、
R5、R6、R7、およびR8はそれぞれ、水素、ハロゲン、−OH、−CN、随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される。
本明細書で明記されるすべての公開物、特許、および特許出願は、個々の公開物、特許、または特許出願がそれぞれ参照により組み込まれるべく特別かつ個別に示されるかのような同じ程度で、参照により本明細書に組み込まれる。
本明細書と請求項で使用されるように、反対に指定されない限り、以下の用語は意味を下に示す意味を有する。
ヒストンデメチラーゼ酵素を阻害する置換されたピリジンおよびピリダジンの誘導体化合物が本明細書に記載されている。これらの化合物とこれらの化合物を含む組成物は、癌と腫瘍性疾患の処置に役立つ。したがって、本明細書に記載される化合物は、前立腺癌、乳癌、膀胱癌、肺癌、および/または黒色腫などを治療するのに役立つこともある。
Rは水素またはアルキルであり、
Gは−X−Yであり、
Xは−C1−C5アルキレン、−(C1−C5アルキレン)−Z−(C1−C5アルキレン)−、または−(C1−C5アルキレン)−Z−であり、
Yはカルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり、および、
Zは
ただし、Gは
Rは水素またはアルキルであり、
Gは−X−Yであり、
Xは−C1−C5アルキレン、−(C1−C5アルキレン)−Z−(C1−C5アルキレン)−、または−(C1−C5アルキレン)−Z−であり、
Yはカルボシクリルまたはヘテロシクリルであり、および、
Zは
Rは水素またはアルキルであり、
GはR1またはR2であり、
R1は、−CO−R3、−CO2−R3、または−CO−N(R4)2であり、
R3はアルキルであり、
R4はHまたはアルキルであり、ここで、随意に、両方のR4基がアルキルである場合、これらは、付いている窒素と一緒に結合して環を形成し、
R2は−XYであり、
Xは−C1−C5アルキレン、−CO−C1−C5アルキレン、−(C1−C5アルキレン)−Z−(C1−C5アルキレン)−、−(C1−C5アルキレン)−Z−、−CO−(C1−C5アルキレン)−Z−(C1−C5アルキレン)、−CO−(C1−C5アルキレン)−Z−、または−C(=N−Oアルキル)−であり、
Yはカルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり、
Zは
ただし、Gは
Qは、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Gは−X−Yであり、
Xは−C1−C5アルキレン、−(C1−C5アルキレン)−Z−(C1−C5アルキレン)−、または−(C1−C5アルキレン)−Z−であり、
Yはカルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり、
および、
Zは
Qは、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Gは−X−Yであり、
Xは−C1−C5アルキレン、−(C1−C5アルキレン)−Z−(C1−C5アルキレン)−、または−(C1−C5アルキレン)−Z−であり、
Yはカルボシクリルまたはヘテロシクリルであり、および、
Zは
Qは、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
GはR1またはR2であり、
R1は、−CO−R3、−CO2−R3、または−CO−N(R4)2であり、
R3はアルキルであり、
R4はHまたはアルキルであり、ここで、随意に、両方のR4基がアルキルである場合、これらは、付いている窒素と一緒に結合して環を形成し、
R2は−XYであり、
Xは−C1−C5アルキレン、−CO−C1−C5アルキレン、−(C1−C5アルキレン)−Z−(C1−C5アルキレン)−、−(C1−C5アルキレン)−Z−、−CO−(C1−C5アルキレン)−Z−(C1−C5アルキレン)、−CO−(C1−C5アルキレン)−Z−、または−C(=N−Oアルキル)−であり、
Yはカルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり、
および、
Zは
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、随意に置換されたテトラリニリル(tetralinyl)、随意に置換されたテトラヒドロキノリニル、置換されたピリジル、随意に置換されたナフチル、随意に置換されたインドリル、随意に置換されたベンゾフラニル、随意に置換されたアダマンチル(adamantyl)、または随意に置換されたインダニルである。
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、アルケニル、アルキニル、フルオロ、クロロ、フルオロアルキル、ニトロ、随意に置換されたアラルキル、随意に置換されたアラルケニル、随意に置換されたアラルキニル、随意に置換されたカルボシクリル、随意に置換されたカルボシクリルアルキル、随意に置換されたヘテロシクリル、随意に置換されたヘテロシクリルアルキル、随意に置換されたヘテロアリール、随意に置換されたヘテロアリールアルキル、−Rb−ORa、−Rb−OC(O)−Ra、−Rb−OC(O)−ORa、−Rb−OC(O)−N(Ra)2、−Rb−N(Ra)2、−Rb−C(O)Ra、−Rb−C(O)ORa、−Rb−O−Rc−C(O)N(Ra)2、−Rb−N(Ra)C(O)ORa、−Rb−N(Ra)C(O)Ra、−Rb−N(Ra)S(O)tRa、−Rb−S(O)tORa、−Rb−S(O)tORa、および−Rb−S(O)tN(Ra)2で置換されたフェニルであり、
式中、
それぞれのRaは独立して、水素、アルキル、フルオロアルキル、シクロアルキル、シクロアルキルアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、またはヘテロアリールアルキルであり、
それぞれのRbは独立して、直接結合、あるいは直鎖または分枝鎖のアルキレンまたはアルケニレン鎖であり、
それぞれのRcは直鎖または分枝鎖のアルキレンまたはアルケニレン鎖であり、tは1または2である。
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yはカルボシクリル、ヘテロシクリル、アリール、またはヘテロアリールであり、
ただし、Gは
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、随意に置換されたテトラリニル、随意に置換されたクロマニル、随意に置換されたテトラヒドロキノリニル、随意に置換されたベンゾフラニル、随意に置換された2,3−ジヒドロベンゾフラニル、随意に置換された2,3−ジヒドロベンゾ[b][1,4]ジオキシニル(dioxinyl)、随意に置換されたナフチル、随意に置換されたインドリル、随意に置換された1,2−ジヒドロナフチル(dihydronaphthyl)、随意に置換されたインダニル、または随意に置換されたチオクロマニル(thiochromanyl)である。
R1は水素、メチル、または−OHであり、
それぞれのR4は独立して、水素、フルオロ、またはメチルであり、
R5、R6、R7、およびR8はそれぞれ、水素、ハロゲン、−OH、−CN、随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される。
別の実施形態は、それぞれのR4が水素である式(XIa)の化合物を提供する。別の実施形態は、R4がそれぞれフルオロである式(XIa)の化合物を提供する。別の実施形態は、R4がそれぞれメチルである式(XIa)の化合物を提供する。別の実施形態は、1つのR4が水素である式(XIa)の化合物を提供する。別の実施形態は、1つのR4がフルオロである式(XIa)の化合物を提供する。
R5、R6、R7、およびR8はそれぞれ、水素、ハロゲン、−OH、−CN、随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される。
本明細書に記載される反応において使用される化合物は、市販の化学製品および/または化学の文献に記載される化合物から始めて、当業者に知られている有機合成技術に従って作られる。「市販の化学製品」とは、Acros Organics(ペンシルバニア州ピッツバーグ)、Aldrich Chemical(ウィスコンシン州ミルウォーキー。Sigma Chemical and Flukaを含む)、Apin Chemicals Ltd.(英国・ミルトンパーク)、Avocado Research(英国・ランカシャー)、BDH Inc.(カナダ・トロント)、Bionet(英国・コーンウォール)、Chemservice Inc.(ペンシルベニア州ウェストチェスター)、Crescent Chemical Co.(ニューヨーク州ホーポージ)、Eastman Organic Chemicals, Eastman Kodak Company(ニューヨーク州ロチェスター)、Fisher Scientific Co.(ペンシルベニア州ピッツバーグ)、Fisons Chemicals(英国・レスタシャー)、Frontier Scientific(ユタ州ローガン)、ICN Biomedicals,Inc.(カリフォルニア州コスタメサ)、Key Organics(英国・コーンウォール)、Lancaster Synthesis(ニューハンプシャー州ウィンダム)、Maybridge Chemical Co. Ltd.(英国・コーンウォール)、Parish Chemical Co. (ユタ州オレム)、Pfaltz & Bauer,Inc.(コネチカット州ウォーターベリー)、Polyorganix(テキサス州ヒューストン)、Pierce Chemical Co.(イリノイ州ロックフォード)、Riedel de Haen AG(ドイツ・ハノーファー)、Spectrum Quality Product, Inc. (ニュージャージー州ニューブランズウィック)、TCI America(オレゴン州ポートランド)、Trans World Chemicals, Inc.(メリーランド州ロックヴィル)、およびWako Chemicals(バージニア州リッチモンド)を含む、標準的な商用源から得られる。
特定の実施形態において、式(I)、(III)、(V)、(XI)、(XIa)、(XIb)、(XIII)、または(XV)によって記載されるような置換されたアミドピリジンまたはアミドピリダジンの誘導体化合物は、純粋な化学物質として投与される。他の実施形態では、式(I)、(III)、(V)、(XI)、(XIa)、(XIb)、(XIII)、または(XV)によって記載されるような置換されたアミドピリジンまたはアミドピリダジンの誘導体化合物は、薬学的に適切なまたは許容可能な担体(選択される投与経路と、例えば、Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)に記載されるような標準的な薬務に基づいて選択された、薬学的に適切な(または許容可能な)賦形剤、生理学的に適切な(または許容可能な)賦形剤、あるいは生理学的に適切な(または許容可能な)担体とも本明細書では呼ばれる)と組み合わされ、この文献の開示は全体として参照することで本明細書に組み込まれる。
染色質は染色体を構成するDNAとタンパク質の複合体である。ヒストンは染色質の主要なタンパク質成分であり、DNAが巻きつくスプールとして作用する。染色質構造の変化は、ヒストンタンパク質の共有結合修飾、および非ヒストン結合タンパク質による影響を受ける。様々な部位でヒストンを共有結合的に修正することができる複数のクラスの酵素が知られている。
タンパク質のJMJD2ファミリーは、トリメチル化およびジメチル化されたH3−K9を脱メチル化することが知られているヒストンデメチラーゼのファミリーであり、初めて同定されたヒストントリメチルデメチラーゼであった。とりわけ、JMJD2ファミリーメンバーの異所性発現は、トリメチル化およびジメチル化したH3−K9の値を劇的に減少させ、その一方で、異質染色質タンパク質1(HP1)を局在化して生体内の異質染色質の全般的なレベルを低下させるモノメチル化H3−K9のレベルを上昇させることが分かった。十文字タンパク質のJMJD2サブファミリーのメンバーは、JMJD2CとそのホモログJMJD2A、JMJD2B、JMJD2D、およびJMJD2Eを含んでいる。十文字タンパク質のJMJD2サブファミリーで見られる共通の構造的特徴は、JmjN、JmjC、PHD、およびTdrの配列を含む。
本明細書で使用されるように、「JARIDタンパク質」は、JARID1サブファミリー(例えば、JARID1A、JARID1B、JARID1C、およびJARID1Dのタンパク質)、JARID2サブファミリー中のタンパク質とそのホモログを含んでいる。JARIDタンパク質のさらなる記載とリストは、Klose et al. (2006) Nature Reviews/Genetics 7:715−727で見つことができる。JARID1ファミリーは、いくつかの保存ドメイン:JmjN、ARID、JmjC、PHD、およびC5HC2ジンクフィンガー(zing finger)を含んでいる。
本明細書には、一般的に、または1つ以上の明確な標的遺伝子に対して、細胞におけるまたは被検体における脱メチル反応を調整する方法が開示されている。脱メチル化は、限定されないが、分化;増殖;アポプトーシス;腫瘍形成、白血病誘発、または他の発がん性形質転換の事象;脱毛;または、性分化、を含む様々な細胞の機能を制御するために調整することができる。例えば、特定の実施形態では、本発明は、JmjCドメイン(例えば、JHDMタンパク質などのヒストンデメチラーゼ)を含むデメチラーゼ活性を調整することによって、必要としている被検体のヒストンのメチル化および/または脱メチル化によって制御される疾患を処置する方法を提供する。
特段明記のない限り、商用供給源から入手するような試薬と溶媒を使用した。無水の溶媒とオーブンで乾燥させたガラス器具は湿気および/または酸素に感度の高い合成形質転換に使用した。収率は最適化しなかった。反応時間は近似であり、最適化しなかった。別段の定めのない限り、カラムクロマトグラフィーと薄層クロマトグラフィー(TLC)をシリカゲル上で行なった。スペクトルはppm(δ)で与え、結合定数Jはヘルツで報告した。陽子スペクトルについては、溶媒のピークを参照ピークとして用いた。
例1:生体外の酵素阻害アッセイ
このアッセイは、試験化合物がJarid1A、Jarid1B、およびJMJD2Cのデメチラーゼ活性を阻害する能力を決定する。バキュロウィルスは、BPS Bioscience(Cat#50110)から購入したJarid1A(GenBank Accession#NM_001042603,AA1−1090)を発現した。バキュロウィルスは、BPS Bioscience(Cat#50121)から購入した、またはMolecularThroughputによって注文で作られたJarid1B(GenBank Accession#NM_006618,AA 2−751)を発現した。バキュロウィルスは、BPS Bioscience(Cat#50105)から購入したJMJD2C(GenBank Accession#BC143571,AA 2−372)を発現した。
Jarid1A活性の酵素アッセイは、時間分解蛍光共鳴エネルギー転移(TR−FRET)検出に基づく。Jarid1Aの活性を阻害する試験化合物の能力は、以下の反応条件下:1nM Jarid1A、300nM H3K4me3ビオチンで標識化されたペプチド(Anaspec cat#64357)、50mM HEPESの分析バッファー中の2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mM TCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2μMのアンモニウム鉄(II)硫酸塩:で、384ウェルのプレートフォーマットで決定された。反応生成物は、25nMと1nMのそれぞれの最終濃度で、LANCE検出バッファー(PerkinElmer)中の5mMのEDTAの存在下における、検出試薬Phycolink ストレプトアビジン−アロフィコシアニン(allophycocyanin)(Prozyme)とEuropiumの抗モノメチル化またはジメチル化ヒストンH3リジン4(H3K4me1−2)抗体(PerkinElmer)を追加した後に、TR−FRETによって定量的に決定された。
Jarid1Bの活性を阻害する試験化合物の能力は、以下の反応条件:0.8nM Jarid1B、300nM H3K4me3ビオチン標識化されたペプチド(Anaspec cat#64357)、50mM HEPESの分析バッファー中の2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mM TCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2μMのアンモニウム鉄(II)硫酸塩:下で、384ウェルのプレートフォーマットで決定された。反応生成物は、25nMと1nMのそれぞれの最終濃度で、LANCE検出バッファー(PerkinElmer)中の5mMのEDTAの存在下における、検出試薬Phycolink ストレプトアビジン−アロフィコシアニン(allophycocyanin)(Prozyme)とEuropiumの抗モノメチル化またはジメチル化ヒストンH3リジン4(H3K4me1−2)抗体(PerkinElmer)を追加した後に、TR−FRETによって定量的に決定された。
JMJD2Cの活性を阻害する試験化合物の能力は、以下の反応条件:0.3nMのJMJD2C、300nMのH3K9me3ビオチンで標識化したペプチド(Anaspec cat#64360)、50mMのHEPESの分析バッファー中の2μMのα−ケトグルタル酸、pH7.3、0.005%のBrij35、0.5mM TCEP、0.2mg/mlのBSA、50μMのL−アスコルビン酸ナトリウム、および2μMのアンモニウム鉄(II)硫酸塩:で、384ウェルのプレートフォーマットで決定された。反応生成物は、50nMと1nMのそれぞれの最終濃度で、LANCE検出バッファー(PerkinElmer)中の5mMのEDTAの存在下における、検出試薬Phycolink ストレプトアビジン−アロフィコシアニン(allophycocyanin)(Prozyme)とEuropiumの抗ジメチル化ヒストンH3リジン9(H3K9me2)抗体(PerkinElmer)を追加した後に、TR−FRETによって定量的に決定された。
JMJD2C阻害のための最初の細胞アッセイは、168時間化合物をインキュベートした後にブロモデオキシウリジン(BrdU)の取り込みを介しての細胞増殖を測定するアッセイである。試験された細胞株はJMJD2C遺伝子増幅細胞株KYSE−150を含んでいる。これは細胞増殖の直接の読み出しとしてS相の間のBrdUのDNAの取り込みを測定する定量的ELISAアッセイである。
0.72mgの17−βエストラジオールを含む持続放出型のペレット剤をnu/nuマウスに皮下移植する。MCF−7細胞を5% CO2、37°Cで10%FBSを含むRPMIで成長させる。1X107細胞/mL中で50%RPMI(血清を含まない)と50%Matrigelにおいて細胞を沈降させ、再懸濁する。ペレット剤の移植後2−3日、右横腹にMCF−7細胞を皮下注射し(100μL/動物)、腫瘍の容積(長さx幅2/2)を隔週モニタリングする。腫瘍が〜200mm3の平均容積に達すると、動物を無作為化して処置を始める。動物を4週間毎日ビヒクルまたは化合物で処置する。腫瘍の容積と体重は研究を通して隔週モニタリングされる。処置期間の終わりに、薬物動態学的および薬力学的分析のそれぞれのために血漿と腫瘍のサンプルを取る。
例1:経口錠剤
48重量%の式(I)の化合物あるいはその薬学的に許容可能な塩、45重量%の微結晶性セルロース、5重量%の低置換ヒドロキシプロピルセルロース、および2重量%のステアリン酸マグネシウムを混合することによって、錠剤を調製する。錠剤は直接圧縮により調製する。圧縮した錠剤の総重量は250−500mgで維持される。
Claims (52)
- 式(XI)の化合物、またはその薬学的に許容可能な塩を提供し、
Qは、−CO2R、−C(O)N(H)CN、−C(O)N(H)OH、またはテトラゾリルであり、
Rは水素または随意に置換されたアルキルであり、
Gは−X−Yであり、
Xは−C1アルキレンであり、
Yは、随意に置換されたテトラリニル、随意に置換されたクロマニル、随意に置換されたテトラヒドロキノリニル、随意に置換されたベンゾフラニル、随意に置換された2,3−ジヒドロベンゾフラニル、随意に置換された2,3−ジヒドロベンゾ[b][1,4]ジオキシニル、随意に置換されたナフチル、随意に置換されたインドリル、随意に置換された1,2−ジヒドロナフチル、随意に置換されたインダニル、または随意に置換されたチオクロマニルである、
化合物、またはその薬学的に許容可能な塩。 - Qは−CO2Rである、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- Qは−C(O)N(H)CNである、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- Qは−C(O)N(H)OHである、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- Qはテトラゾリルである、請求項1に記載の化合物、またはその薬学的に許容可能な塩。
- Rは水素である、請求項1乃至5のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Rは随意に置換されたアルキルである、請求項1乃至5のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたテトラリニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたクロマニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたテトラヒドロキノリニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたベンゾフラニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換された2,3−ジヒドロベンゾフラニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたナフチルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたインドリルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換された1,2−ジヒドロナフチルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたインダニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- Yは随意に置換されたチオクロマニルである、請求項1乃至7のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- 随意に置換されたテトラリニルは随意に置換された1−テトラリニルである、請求項8に記載の化合物、またはその薬学的に許容可能な塩。
- 式(XI)の化合物は以下の構造を有し、
R1は水素、メチル、または−OHであり、
それぞれのR4は独立して、水素、フルオロ、またはメチルであり、
R5、R6、R7、およびR8はそれぞれ、水素、ハロゲン、−OH、−CN、随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される、請求項18に記載の化合物、またはその薬学的に許容可能な塩。 - 随意に置換されたクロマニルは随意に置換された4−クロマニルである、請求項9に記載の化合物、またはその薬学的に許容可能な塩。
- 式(XI)の化合物は以下の構造を有し、
R5、R6、R7、およびR8はそれぞれ、水素、ハロゲン、−OH、−CN、随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される、請求項20に記載の化合物、またはその薬学的に許容可能な塩。 - R1は水素である、請求項19または21に記載の化合物、またはその薬学的に許容可能な塩。
- それぞれのR4は水素である、請求項19に記載の化合物、またはその薬学的に許容可能な塩。
- R5は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R6は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R7は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R8は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R5とR7は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R5とR8は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R7とR8は水素である、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R6は水素ではない、請求項19または21乃至23のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC1−C6アルキル、随意に置換されたC1−C6アルコキシ、随意に置換されたC3−C7カルボシクリル、随意に置換されたC3−C7カルボシクリルオキシ、随意に置換されたC4−C12カルボシクリルアルキル、随意に置換されたC4−C12カルボシクリルアルコキシ、随意に置換されたC1−C6アルキニル、随意に置換されたC1−C6アルケニル、随意に置換されたC6−C10アリール、随意に置換されたC6−C10アリールオキシ、随意に置換されたC6−C10アリール−S−、随意に置換されたC7−C14アラルコキシ、随意に置換されたヘテロアリール、および随意に置換されたヘテロアリールオキシから独立して選択される、請求項19、21乃至24、または26乃至31のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC1−C6アルキルから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC1−C6アルコキシから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC3−C7カルボシクリルから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC3−C7カルボシクリルオキシから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC4−C12カルボシクリルアルキルから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC4−C12カルボシクリルアルコキシから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC1−C6アルキニルから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC1−C6アルケニルから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC6−C10アリールから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は、随意に置換されたC6−C10アリールオキシ、または随意に置換されたC6−C10アリール−S−から選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたC7−C14アラルコキシから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたヘテロアリールから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- R6は随意に置換されたヘテロアリールオキシから選択される、請求項32に記載の化合物、またはその薬学的に許容可能な塩。
- 以下から選択される化合物またはその薬学的に許容可能な塩。
- 以下から選択される化合物またはその薬学的に許容可能な塩。
- 以下から選択される化合物またはその薬学的に許容可能な塩。
- 以下から選択される化合物またはその薬学的に許容可能な塩。
- 薬学的に許容可能な担体と、請求項1乃至49のいずれか1つに記載の化合物、またはその薬学的に許容可能な塩を含む、医薬組成物。
- ヒストンデメチラーゼ酵素を阻害するための製剤の製造における請求項1乃至49のいずれか1つに記載の化合物またはその薬学的に許容可能な塩を含む組成物の使用。
- 癌を処置するための製剤の製造における請求項1乃至49のいずれか1つに記載の化合物またはその薬学的に許容可能な塩を含む組成物の使用。
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PCT/US2013/077539 WO2014100818A1 (en) | 2012-12-21 | 2013-12-23 | Histone demethylase inhibitors |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US11639333B2 (en) | 2012-12-21 | 2023-05-02 | Celgene Quanticel Research, Inc | Histone demethylase inhibitors |
JP2017523152A (ja) * | 2014-06-25 | 2017-08-17 | セルジーン クオンティセル リサーチ,インク. | ヒストンデメチラーゼ阻害剤 |
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