JP2022521724A - ピリド-ピリミジニル化合物及び使用の方法 - Google Patents
ピリド-ピリミジニル化合物及び使用の方法 Download PDFInfo
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- ZNKJDROOAJTXAQ-UHFFFAOYSA-N tert-butyl N-[4-[[6-[3-fluoro-4-(propylsulfonylamino)phenyl]-8-methylpyrido[3,2-d]pyrimidin-2-yl]amino]cyclohexyl]carbamate Chemical compound FC=1C=C(C=CC=1NS(=O)(=O)CCC)C=1C=C(C=2N=C(N=CC=2N=1)NC1CCC(CC1)NC(OC(C)(C)C)=O)C ZNKJDROOAJTXAQ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
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- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- HSGCNVAFJQEHSB-UHFFFAOYSA-J tetrasodium molecular oxygen tetrachlorite hydrate Chemical compound O.[Na+].[Na+].[Na+].[Na+].O=O.[O-][Cl]=O.[O-][Cl]=O.[O-][Cl]=O.[O-][Cl]=O HSGCNVAFJQEHSB-UHFFFAOYSA-J 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- WXZSUBHBYQYTNM-WMDJANBXSA-N tetrazomine Chemical compound C=1([C@@H]2CO[C@@H]3[C@H]4C[C@@H](CO)[C@H](N4C)[C@@H](N23)CC=1C=C1)C(OC)=C1NC(=O)C1NCCC[C@H]1O WXZSUBHBYQYTNM-WMDJANBXSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
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- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 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
- 230000005751 tumor progression Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
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- 210000002700 urine Anatomy 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- XLQGICHHYYWYIU-UHFFFAOYSA-N veramine Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CC=C3C2(C)C(C)C21CCC(C)CN2 XLQGICHHYYWYIU-UHFFFAOYSA-N 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Description
本出願は、2019年2月18日に出願された国際出願第PCT/CN2019/075328号の優先権の利益を主張するものであり、その全体があらゆる目的のために参照により本明細書に組み込まれる。
本明細書で提供されるのは、式:
[式中、
環BはR4-置換若しくは非置換C3~7シクロアルキル、R4-置換若しくは非置換3~7員ヘテロシクロアルキル、R4-置換若しくは非置換C5~7アリール、又はR4-置換若しくは非置換5~7員ヘテロアリールであり;
L1は-NHSO2-、-SO2NH-、-NH-、-NHC(O)-、-C(O)NH-、又はピロリジン-2-オンであり;
X1及びX2は、独立して、-N-又は-CR2-であり;
X3は-N-又は-CR3-であり、ここでX1、X2、及びX3のうちの1つは-N-であり;
R1はR6-置換若しくは非置換C1~6アルキル、R6-置換若しくは非置換C1~6ハロアルキル、R6-置換若しくは非置換C3~7シクロアルキル、又はR6-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R2は、独立して、水素、ハロゲン、-OR7、R10-置換若しくは非置換C1-6アルキル、R10-置換若しくは非置換C3-7シクロアルキル、又はR10-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
R3は水素、ハロゲン、-CN、-OR7、-NO2、-C(O)R7、-C(O)OR7、-C(O)OR7、-C(O)NR7AR7B、-OC(O)R7、-OC(O)NR7AR7B、-SR7A、-S(O)R7、-S(O)2R7、-S(O)(=NR7A)R7B、-S(O)2NR7AR7B、-NR7AR7B、-NR7AC(O)R7、-NR7AC(O)OR7、-N(R7A)C(O)NR7AR7B、-NR7AS(O)2R7、-NR7AS(O)2NR7AR7B、-P(O)(R7)2、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、R10-置換若しくは非置換3~7員ヘテロシクロアルキル;R10-置換若しくは非置換C5~7アリール、又はR10-置換若しくは非置換5~7員ヘテロアリールであり;
各R4は水素、ハロゲン、-OR7、-CN、-S(O)2R7、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、又はR10-置換若しくは非置換C3~7シクロアルキルであり;
nは、0、1、2、3、又は4であり;
R5はR10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、R10-置換若しくは非置換3~7員ヘテロシクロアルキル、R10-置換若しくは非置換C5~7アリール、又はR10-置換若しくは非置換5~7員ヘテロアリールであり;
或いは、R5上の原子が、L1及び環B上の原子と共に、4~7員ヘテロシクロアルキル又は5~7員ヘテロアリールを形成し;
各R6は、独立して、水素、ハロゲン、-OR7、-NR6AR6B、R10-置換若しくは非置換C1~6アルキル、又はR10-置換若しくは非置換C1~6ハロアルキルであり;
R6A及びR6Bは、独立して、水素又はR10-置換若しくは非置換C1~6アルキルであるか、或いはR6A及びR6Bは、それらが結合する窒素原子と一緒に、R10-置換若しくは非置換4~7員ヘテロシクロアルキルを形成し;
各R7は、独立して、水素、R8-置換若しくは非置換C1~6アルキル、R8-置換若しくは非置換C1~8ハロアルキル、R6-置換若しくは非置換C3~7シクロアルキル、又はR8-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R7A及びR7Bは、独立して、水素、R8A-置換若しくは非置換C1~6アルキル、R8A-置換若しくは非置換C1~6ハロアルキル、R8A-置換若しくは非置換C3~7シクロアルキル、又はR8A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R8Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル;非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R8は、独立して、水素、ハロゲン、オキソ、-CN、-OR8B、-NO2、-C(O)R8B、-C(O)OR8B、-C(O)OR8B、-C(O)NR8CR8D、-OC(O)R8B、-OC(O)NR8CR8D、-SR8C、-S(O)R8B、-S(O)2R8B、-S(O)(=NR8C)R8D、-S(O)2NR8CR8D、-NR8CR8D、-NR8CC(O)R8B、-NR8CC(O)OR8B、-N(R8C)C(O)NR8CR8D、-NR8CS(O)2R8B、-NR8CS(O)2NR8CR8D、-P(O)(R8B)2、R9-置換若しくは非置換C1~6アルキル、R9-置換若しくは非置換C1~6ハロアルキル、R9-置換若しくは非置換C3~7シクロアルキル、R9-置換若しくは非置換3~6員ヘテロシクロアルキル;R9-置換若しくは非置換C5~7アリール、又はR9-置換若しくは非置換5~7員ヘテロアリールであり;
各R8b、R8C、及びR8Dは、独立して、水素、R9A-置換若しくは非置換C1~6アルキル、R9A-置換若しくは非置換C1~6ハロアルキル、R9A-置換若しくは非置換C3~7シクロアルキル、又はR9A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R9Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル;非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R9は、独立して、水素、ハロゲン、オキソ、-CN、-OR9B、-NO2、-C(O)R9B、-C(O)OR9B、-C(O)OR9B、-C(O)NR9CR9D、-OC(O)R9B、-OC(O)NR9CR9D、-SR9C、-S(O)R9B、-S(O)2R9B、-S(O)(=NR9C)R9D、-S(O)2NR9CR9D、-NR9CR9D、-NR9CC(O)R9B、-NR9CC(O)OR9B、-N(R9C)C(O)NR9CR9D、-NR9CS(O)2R9B、-NR9CS(O)2NR9CR9D、-P(O)(R9B)2、R12-置換若しくは非置換C1~6アルキル、R12-置換若しくは非置換C1~6ハロアルキル、R12-置換若しくは非置換C3~7シクロアルキル、R12-置換若しくは非置換3~6員ヘテロシクロアルキル;R12-置換若しくは非置換C5~7アリール、又はR12-置換若しくは非置換5~7員ヘテロアリールであり;
各R9bR9C、及びR9Dは、独立して、水素、R10A-置換若しくは非置換C1~6アルキル、R10A-置換若しくは非置換C1~6ハロアルキル、R10A-置換若しくは非置換C3~7シクロアルキル、又はR10A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R10Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル;非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R10は、独立して、水素、ハロゲン、オキソ、-CN、-OR11A、-NO2、-C(O)R11A、-C(O)OR11A、-C(O)OR11A、-C(O)NR11BR11C、-OC(O)R11A、-OC(O)NR11BR11C、-SR11B、-S(O)R11A、-S(O)2R11A、-S(O)(=NR11B)R11C、-S(O)2NR11BR11C、-NR11BR11C、-NR11BC(O)R11A、-NR11BC(O)OR11A、-N(R11B)C(O)NR11BR11C、-NR11BS(O)2R11A、-NR11BS(O)2NR11BR11C、-P(O)(R11A)2、R11-置換若しくは非置換C1~6アルコキシ、R11-置換若しくは非置換C1~6アルキル、R11-置換若しくは非置換C1~6ハロアルキル、R11-置換若しくは非置換C3~7シクロアルキル、R11-置換若しくは非置換3~6員ヘテロシクロアルキル;R11-置換若しくは非置換C5~7アリール、又はR11-置換若しくは非置換5~7員ヘテロアリールであり;
各R11A、R11B及びR11Cは、独立して、水素、R12A-置換若しくは非置換C1~6アルキル、R12A-置換若しくは非置換C1~6ハロアルキル、R12A-置換若しくは非置換C3~7シクロアルキル、又はR12A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R12Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル;非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R11は、独立して、水素、ハロゲン、オキソ、-CN、-OR12B、-NO2、-C(O)R12B、-C(O)OR12B、-C(O)OR12B、-C(O)NR12CR12D、-OC(O)R12B、-OC(O)NR12CR12D、-SR12C、-S(O)R12B、-S(O)2R12B、-S(O)(=NR12C)R12D、-S(O)2NR12CR12D、-NR12CR12D、-NR12CC(O)R12B、-NR12CC(O)OR12B、-N(R12C)C(O)NR12CR12D、-NR12CS(O)2R12B、-NR12CS(O)2NR12CR12D、-P(O)(R12B)2、R12-置換若しくは非置換C1~6アルキル、R12-置換若しくは非置換C1~6ハロアルキル、R12-置換若しくは非置換C3~7シクロアルキル、R12-置換若しくは非置換3~6員ヘテロシクロアルキル;R12-置換若しくは非置換C5~7アリール、又はR12-置換若しくは非置換5~7員ヘテロアリールであり;
各R12B、R12C及びR12Dは、独立して、水素、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、又は非置換3~7員ヘテロシクロアルキルであり;
各R12は、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6アルコキシ、非置換C1~6ハロアルキル、非置換C1~6ハロアルコキシ、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル;非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;且つ
R13は水素、ハロゲン、又はR10-置換若しくは非置換C1~6アルキルである]
で示される化合物、又は、その立体異性体、互変異性体、若しくは薬学的に許容される塩。
で示される化合物又はその薬学的に許容される塩を形成する環Aであり、
式中、X1、X2、X3、L1、R4、R5、R6、及びR13は本明細書に定義される通りであり;
環Aは、例えば、R1について本明細書で定義されるように、R6-置換若しくは非置換C3~7シクロアルキル、又はR6-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
且つmは0、1、2、3、4、又は5である。
式中、R4A、R4B、R4C、及びR4Dは、各々が独立して、水素、ハロゲン、-CN、-OR7、-S(O)2R7、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~6シクロアルキル、R10-置換若しくは非置換C1~6アルコキシ、又はR10-置換若しくは非置換C1~6ハロアルコキシであり、ここでR7及びR10は本明細書で定義される通りである(例えばR4に関して)。
本明細書に記載の化合物及びその薬学的に許容される塩は、特に本明細書に含まれる説明に照らして、化学分野で周知のプロセスに類似するプロセス、及び以下に記載される他の複素環のプロセスを含む合成経路によって合成することができる:Comprehensive Heterocyclic Chemistry II,Editors Katritzky and Rees、Elsevier,1997,e.g. Volume 3;Liebigs Annalen der Chemie,(9):1910-16,(1985);Helvetica Chimica Acta,41:1052-60,(1958);Arzneimittel-Forschung,40(12):1328-31,(1990)。これらの各々は、参照により明示的に組み込まれる。出発物質は一般に、Aldrich Chemicals(ウィスコンシン州ミルウォーキー)などの商業的供給源から入手可能であるか、又は方法を使用して容易に調製される(例えば、Louis F. Fieser and Mary Fieser、Reagents for Organic Synthesis,v. 1-23、Wiley,N.Y.(1967-2006 ed.)、又はBeilsteins Handbuch der organischen Chemie,4,Aufl. ed. Springer-Verlag,Berlin、付録含む(Beilsteinオンラインデータベースを介しても入手可能)に概要が記載された方法により調製される)。本明細書に記載の化合物及びその薬学的に許容される塩は、米国特許第8476434号、米国特許第7880000号、国際公開公報第2005/113494号、米国特許第7868177号、及び国際公開公報第2007/100646号に見出される手順に従って製造することができる。
本明細書に記載の化合物又はその薬学的に許容される塩は、治療される状態に適切な任意の経路によって投与することができる。適切な経路には、経口、非経口(皮下、筋肉内、静脈内、動脈内、皮内、髄腔内、及び硬膜外)、経皮、経直腸、経鼻、局所(口腔内及び舌下を含む)、膣内、腹腔内、肺内、及び鼻腔内が含まれる。局所的な免疫抑制治療のために、化合物を、移植前にグラフトを灌流又は他の方法で阻害剤と接触させることを含む、病変内投与により投与することができる。好ましい経路は、例えば、レシピエントの病態により変動し得ることが理解されるであろう。化合物が経口投与される場合、それは、薬学的に許容される担体又は賦形剤と共に丸薬、カプセル、錠剤などとして製剤化することができる。好ましい実施形態では、化合物又はその薬学的に許容される塩は、経口投与用に、丸薬、カプセル、又は錠剤として製剤化される。化合物又はその薬学的に許容される塩が非経口投与される場合、それは、下記に詳述されるように、薬学的に許容される非経口ビヒクルと共に注射用単位剤形で製剤化することができる。
本明細書で提供される一態様では、化合物又はその薬学的に許容される塩は、がんなどのUPR経路に関連する異常な細胞増殖、機能又は挙動;免疫障害;心臓血管疾患;ウイルス感染;炎症;代謝/内分泌障害;又は神経学的障害に起因する疾患又は障害を有する患者を、本明細書に記載の化合物又はその薬学的に許容される塩の有効量を投与することにより治療するために有用である。本明細書で提供される方法の一実施形態において、化合物又はその薬学的に許容される塩は、がんなどのUPR経路に関連する異常な細胞増殖、機能又は挙動;免疫障害;心臓血管疾患;ウイルス感染;炎症;代謝/内分泌障害;又は神経学的障害に起因するIRE1関連疾患又は障害を有する患者を、本明細書に記載の化合物又はその薬学的に許容される塩の有効量を投与することにより治療するために有用である。
本明細書に記載の化合物又はその薬学的に許容される塩は、医薬組成物として標準的な薬務に従って製剤化することができる。したがって、本明細書では、化合物又はその薬学的に許容される塩と1種以上の薬学的に許容される賦形剤とを含む医薬組成物が、更に提供される。
本明細書に記載の化合物又はその薬学的に許容される塩は、単独で、又は炎症若しくは過剰増殖性障害(例えば、がん)などの本明細書に記載される疾患若しくは障害を治療するための追加の治療薬と組み合わせて使用することができる。一部の実施形態では、本明細書に記載の化合物又はその薬学的に許容される塩は、抗炎症若しくは抗過剰増殖特性を有する、又は炎症、免疫応答障害若しくは過剰増殖性障害(例えば、がん)を治療するのに有用である追加の第2の治療用化合物との、医薬組み合わせ製剤で、又は併用療法としての投与レジメンで組み合わせられる。追加の治療剤は、Bcl-2阻害剤、JAK阻害剤、PI3K阻害剤、mTOR阻害剤、抗炎症剤、免疫調節剤、本明細書に記載の抗がん剤、アポトーシスエンハンサ、ニューロトロフィック因子、心臓血管疾患治療剤、肝疾患治療剤、抗ウイルス剤、血液疾患治療剤、糖尿病治療剤、及び免疫不全障害治療剤であり得る。第2の治療剤は、NSAID抗炎症剤であり得る。第2の治療剤は、本明細書に記載の抗がん剤であり得る。医薬組み合わせ製剤又は投与レジメンの第2の化合物は、好ましくは、互いに悪影響を与えないように、本明細書に記載の化合物又はその薬学的に許容される塩に対して相補的な活性を有する。このような化合物は、意図される目的に有効な量の組み合わせで適切に存在する。一実施形態において、本明細書で提供される組成物は、化合物、又はその立体異性体、互変異性体、溶媒和物、代謝産物、又は薬学的に許容される塩を、NSAIDのような治療剤と組み合わせて含む。
本明細書では、本明細書に記載の化合物又はその薬学的に許容される塩のインビボ代謝産物も提供される。このような生成物は、例えば、投与された化合物の酸化、還元、加水分解、アミド化、脱アミド化、エステル化、脱エステル化、及び酵素的切断などから生じ得る。したがって、本明細書では、本明細書に記載の化合物又はその薬学的に許容される塩を、その代謝産物を得るのに十分な時間にわたり、哺乳動物と接触させることを含むプロセスによって製造された化合物が提供される。
また、本明細書では、上記の疾患及び障害(例えば、がん)の治療に有用な物質を含有する製造物品、又はキットが提供される。一実施形態において、キットは、本明細書に記載の化合物又はその薬学的に許容される塩を含む容器を含む。本キットは、容器上の、又は容器に不随したラベル又は添付文書を更に含むことができる。適切な容器としては、例えば、瓶、バイアル、シリンジ、ブリスターパックなどが挙げられる。容器は、金属、ガラス又はプラスチックなどの、当技術分野において既知の様々な材料から形成することができる。容器は、状態を治療するのに有効な化合物若しくはその薬学的に許容される塩、又はその製剤を保持することができ、滅菌アクセスポートを有することができる(例えば、容器は静注液バッグ又は皮下注射針で貫通可能なストッパを有するバイアルとすることができる)。組成物中の少なくとも1つの活性薬剤が、本明細書に記載の化合物又はその薬学的に許容される塩である。ラベル又は添付文書は、本組成物ががんなどの選択された状態を治療するために使用されることを示す。加えて、ラベル又は添付文書は、治療される患者が、過剰増殖性障害、アテローム性動脈硬化症、神経変性、心臓肥大、疼痛、片頭痛若しくは神経外傷性疾患、又は事象などの障害を有する患者であることを示すことができる。一実施形態において、ラベル又は添付文書は、本明細書に記載の化合物又はその薬学的に許容される塩を含む組成物を使用して、異常な細胞増殖に起因する障害を治療することができることを示す。一実施形態において、ラベル又は添付文書は、本明細書に記載の化合物又はその薬学的に許容される塩を含む組成物を使用して、アテローム性動脈硬化症に起因する障害を治療することができることを示す。ラベル又は添付文書は、組成物が他の障害を治療するために使用され得ることを示すこともできる。代替的に又は追加的に、製造物品は、薬学的に許容される緩衝液、例えば、注射用静菌水(BWFI)、リン酸緩衝化生理食塩水、リンゲル液及びデキストロース溶液を含む第2の容器を更に備えることができる。製造物品は、他の緩衝剤、希釈剤、フィルタ、針、及びシリンジを含む、商業的観点及びユーザの観点から望ましい他の材料を更に含むことができる。
実施形態1:式(I):
[式中、
環BはR4-置換若しくは非置換C3~7シクロアルキル、R4-置換若しくは非置換3~7員ヘテロシクロアルキル、R4-置換若しくは非置換C5~7アリール、又はR4-置換若しくは非置換5~7員ヘテロアリールであり;
L1は-NHSO2-、-SO2NH-、-NH-、-NHC(O)-、-C(O)NH-、又はピロリジン-2-オンであり;
X1及びX2は、独立して、-N-又は-CR2-であり;
X3は-N-又は-CR3-であり、ここでX1、X2、及びX3のうちの1つは-N-であり;
R1はR6-置換若しくは非置換C1~6アルキル、R6-置換若しくは非置換C1~6ハロアルキル、R6-置換若しくは非置換C3~7シクロアルキル、又はR6-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R2は、独立して、水素、ハロゲン、-OR7、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C3~7シクロアルキル、又はR10-置換若しくは非置換3~7員ヘテロシクロアルキルであり、
R3は水素、ハロゲン、-CN、-OR7、-NO2、-C(O)R7、-C(O)OR7、-C(O)OR7、-C(O)NR7AR7B、-OC(O)R7、-OC(O)NR7AR7B、-SR7A、-S(O)R7、-S(O)2R7、-S(O)(=NR7A)R7B、-S(O)2NR7AR7B、-NR7AR7B、-NR7AC(O)R7、-NR7AC(O)OR7、-N(R7A)C(O)NR7AR7B、-NR7AS(O)2R7、-NR7AS(O)2NR7AR7B、-P(O)(R7)2、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、R10-置換若しくは非置換3~7員ヘテロシクロアルキル;R10-置換若しくは非置換C5~7アリール、又はR10-置換若しくは非置換5~7員ヘテロアリールであり;
各R4は水素、ハロゲン、-OR7、-CN、-S(O)2R7、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、又はR10-置換若しくは非置換C3~7シクロアルキルであり;
nは、0、1、2、3、又は4であり;
R5はR10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、R10-置換若しくは非置換3~7員ヘテロシクロアルキル、R10-置換若しくは非置換C5~7アリール、又はR10-置換若しくは非置換5~7員ヘテロアリールであり;
各R6は、独立して、水素、ハロゲン、-OR7、-NR6AR6B、R10-置換若しくは非置換C1~6アルキル、又はR10-置換若しくは非置換C1~6ハロアルキルであり;
R6A及びR6Bは、独立して、水素又はR10-置換若しくは非置換C1~6アルキルであるか、或いはR6A及びR6Bは、それらが結合する窒素原子と一緒に、R10-置換若しくは非置換4~7員ヘテロシクロアルキルを形成し;
各R7は、独立して、水素、R8-置換若しくは非置換C1~6アルキル、R8-置換若しくは非置換C1~8ハロアルキル、R6-置換若しくは非置換C3~7シクロアルキル、又はR8-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R7A及びR7Bは、独立して、水素、R8A-置換若しくは非置換C1~6アルキル、R8A-置換若しくは非置換C1~6ハロアルキル、R8A-置換若しくは非置換C3~7シクロアルキル、又はR8A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R8Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R8は、独立して、水素、ハロゲン、オキソ、-CN、-OR8B、-NO2、-C(O)R8B、-C(O)OR8B、-C(O)OR8B、-C(O)NR8CR8D、-OC(O)R8B、-OC(O)NR8CR8D、-SR8C、-S(O)R8B、-S(O)2R8B、-S(O)(=NR8C)R8D、-S(O)2NR8CR8D、-NR8CR8D、-NR8CC(O)R8B、-NR8CC(O)OR8B、-N(R8C)C(O)NR8CR8D、-NR8CS(O)2R8B、-NR8CS(O)2NR8CR8D、-P(O)(R8B)2、R9-置換若しくは非置換C1~6アルキル、R9-置換若しくは非置換C1~6ハロアルキル、R9-置換若しくは非置換C3~7シクロアルキル、R9-置換若しくは非置換3~6員ヘテロシクロアルキル;R9-置換若しくは非置換C5~7アリール、又はR9-置換若しくは非置換5~7員ヘテロアリールであり;
各R8b、R8C、及びR8Dは、独立して、水素、R9A-置換若しくは非置換C1~6アルキル、R9A-置換若しくは非置換C1~6ハロアルキル、R9A-置換若しくは非置換C3~7シクロアルキル、又はR9A-置換若しくは非置換3~7員ヘテロシクロアルキルであり、
各R9Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R9は、独立して、水素、ハロゲン、オキソ、-CN、-OR9B、-NO2、-C(O)R9B、-C(O)OR9B、-C(O)OR9B、-C(O)NR9CR9D、-OC(O)R9B、-OC(O)NR9CR9D、-SR9C、-S(O)R9B、-S(O)2R9B、-S(O)(=NR9C)R9D、-S(O)2NR9CR9D、-NR9CR9D、-NR9CC(O)R9B、-NR9CC(O)OR9B、-N(R9C)C(O)NR9CR9D、-NR9CS(O)2R9B、-NR9CS(O)2NR9CR9D、-P(O)(R9B)2、R12-置換若しくは非置換C1~6アルキル、R12-置換若しくは非置換C1~6ハロアルキル、R12-置換若しくは非置換C3~7シクロアルキル、R12-置換若しくは非置換3~6員ヘテロシクロアルキル;R12-置換若しくは非置換C5~7アリール、又はR12-置換若しくは非置換5~7員ヘテロアリールであり;
各R9b、R9C、及びR9Dは、独立して、水素、R10A-置換若しくは非置換C1~6アルキル、R10A-置換若しくは非置換C1~6ハロアルキル、R10A-置換若しくは非置換C3~7シクロアルキル、又はR10A-置換若しくは非置換3~7員ヘテロシクロアルキルであり、
各R10Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R10は、独立して、水素、ハロゲン、オキソ、-CN、-OR11A、-NO2、-C(O)R11A、-C(O)OR11A、-C(O)OR11A、-C(O)NR11BR11C、-OC(O)R11A、-OC(O)NR11BR11C、-SR11B、-S(O)R11A、-S(O)2R11A、-S(O)(=NR11B)R11C、-S(O)2NR11BR11C、-NR11BR11C、-NR11BC(O)R11A、-NR11BC(O)OR11A、-N(R11B)C(O)NR11BR11C、-NR11BS(O)2R11A、-NR11BS(O)2NR11BR11C、-P(O)(R11A)2、R11-置換若しくは非置換C1~6アルコキシ、R11-置換若しくは非置換C1~6アルキル、R11-置換若しくは非置換C1~6ハロアルキル、R11-置換若しくは非置換C3~7シクロアルキル、R11-置換若しくは非置換3~6員ヘテロシクロアルキル;R11-置換若しくは非置換C5~7アリール、又はR11-置換若しくは非置換5~7員ヘテロアリールであり;
各R11A、R11B及びR11Cは、独立して、水素、R12A-置換若しくは非置換C1~6アルキル、R12A-置換若しくは非置換C1~6ハロアルキル、R12A-置換若しくは非置換C3~7シクロアルキル、又はR12A-置換若しくは非置換3~7員ヘテロシクロアルキルであり、
各R12Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R11は、独立して、水素、ハロゲン、オキソ、-CN、-OR12B、-NO2、-C(O)R12B、-C(O)OR12B、-C(O)OR12B、-C(O)NR12CR12D、-OC(O)R12B、-OC(O)NR12CR12D、-SR12C、-S(O)R12B、-S(O)2R12B、-S(O)(=NR12C)R12D、-S(O)2NR12CR12D、-NR12CR12D、-NR12CC(O)R12B、-NR12CC(O)OR12B、-N(R12C)C(O)NR12CR12D、-NR12CS(O)2R12B、-NR12CS(O)2NR12CR12D、-P(O)(R12B)2、R12-置換若しくは非置換C1~6アルキル、R12-置換若しくは非置換C1~6ハロアルキル、R12-置換若しくは非置換C3~7シクロアルキル、R12-置換若しくは非置換3~6員ヘテロシクロアルキル;R12-置換若しくは非置換C5~7アリール、又はR12-置換若しくは非置換5~7員ヘテロアリールであり;
各R12B、R12C及びR12Dは、独立して、水素、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、又は非置換3~7員ヘテロシクロアルキルであり、
各R12は、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6アルコキシ、非置換C1~6ハロアルキル、非置換C1~6ハロアルコキシ、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル;非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;且つ
R13は水素、ハロゲン、又はR10-置換若しくは非置換C1~6アルキルである]
で示される化合物、又は、その立体異性体、互変異性体、若しくは薬学的に許容される塩。
[式中、
環AはR6-置換若しくは非置換C3~6シクロアルキル又はR6-置換若しくは非置換3~6員ヘテロシクロアルキルであり、
mは、0、1、2、3、4又は5である]
で示される、実施形態1に記載の化合物、又は、その立体異性体、互変異性体、若しくは薬学的に許容される塩。
で示される、実施形態1~42のいずれか一項に記載の化合物又はその薬学的に許容される塩。
a)実施形態59に記載の医薬組成物;及び
b)使用説明書
を含むキット。
ACN:アセトニトリル
DCM:ジクロロメタン
DMF:N,N-ジメチルホルムアミド
DMSO:ジメチルスルホキシド
EtOAc:酢酸エチル
EtOH:エタノール
h:時間
HCl:塩酸
HPLC:高速液体クロマトグラフィー
IPA:酢酸イソプロピル
LCMS:液体クロマトグラフィー質量分析
Na2SO4:硫酸ナトリウム
THF:テトラヒドロフラン
1H NMR(400MHz,CDCl3)δ 7.47(d,J=8.5Hz,1H)、7.28(d,J=2.5Hz,1H)、7.09(dd,J=8.5,2.6Hz,1H)、3.89(t,J=6.6Hz,2H)、2.99(t,J=6.6Hz,2H).
Claims (98)
- 式(I):
[式中、
環BはR4-置換若しくは非置換C3~7シクロアルキル、R4-置換若しくは非置換3~7員ヘテロシクロアルキル、R4-置換若しくは非置換C5~7アリール、又はR4-置換若しくは非置換5~7員ヘテロアリールであり;
L1は-NHSO2-、-SO2NH-、-NH-、-NHC(O)-、-C(O)NH-、又はピロリジン-2-オンであり;
X1及びX2は、独立して、-N-又は-CR2-であり;
X3は-N-又は-CR3-であり、ここでX1、X2、及びX3のうちの1つは-N-であり;
R1はR6-置換若しくは非置換C1~6アルキル、R6-置換若しくは非置換C1~6ハロアルキル、R6-置換若しくは非置換C3~7シクロアルキル、又はR6-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R2は、独立して、水素、ハロゲン、-OR7、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C3~7シクロアルキル、又はR10-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
R3は水素、ハロゲン、-CN、-OR7、-NO2、-C(O)R7、-C(O)OR7、-C(O)OR7、-C(O)NR7AR7B、-OC(O)R7、-OC(O)NR7AR7B、-SR7A、-S(O)R7、-S(O)2R7、-S(O)(=NR7A)R7B、-S(O)2NR7AR7B、-NR7AR7B、-NR7AC(O)R7、-NR7AC(O)OR7、-N(R7A)C(O)NR7AR7B、-NR7AS(O)2R7、-NR7AS(O)2NR7AR7B、-P(O)(R7)2、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、R10-置換若しくは非置換3~7員ヘテロシクロアルキル、R10-置換若しくは非置換C5~7アリール、又はR10-置換若しくは非置換5~7員ヘテロアリールであり;
各R4は水素、ハロゲン、-OR7、-CN、-S(O)2R7、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、又はR10-置換若しくは非置換C3~7シクロアルキルであり;
nは、0、1、2、3、又は4であり;
R5はR10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、R10-置換若しくは非置換3~7員ヘテロシクロアルキル、R10-置換若しくは非置換C5~7アリール、又はR10-置換若しくは非置換5~7員ヘテロアリールであり;
或いは、R5上の原子が、L1及び環B上の原子と共に、4~7員ヘテロシクロアルキル又は5~7員ヘテロアリールを形成し;
各R6は、独立して、水素、ハロゲン、-OR7、-NR6AR6B、R10-置換若しくは非置換C1~6アルキル、又はR10-置換若しくは非置換C1~6ハロアルキルであり;
R6A及びR6Bは、独立して、水素又はR10-置換若しくは非置換C1~6アルキルであるか、或いはR6A及びR6Bは、それらが結合する窒素原子と一緒に、R10-置換若しくは非置換4~7員ヘテロシクロアルキルを形成し;
各R7は、独立して、水素、R8-置換若しくは非置換C1~6アルキル、R8-置換若しくは非置換C1~6ハロアルキル、R8-置換若しくは非置換C3~7シクロアルキル、又はR8-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R7A及びR7Bは、独立して、水素、R8A-置換若しくは非置換C1~6アルキル、R8A-置換若しくは非置換C1~6ハロアルキル、R8A-置換若しくは非置換C3~7シクロアルキル、又はR8A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R8Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R8は、独立して、水素、ハロゲン、オキソ、-CN、-OR8B、-NO2、-C(O)R8B、-C(O)OR8B、-C(O)OR8B、-C(O)NR8CR8D、-OC(O)R8B、-OC(O)NR8CR8D、-SR8C、-S(O)R8B、-S(O)2R8B、-S(O)(=NR8C)R8D、-S(O)2NR8CR8D、-NR8CR8D、-NR8CC(O)R8B、-NR8CC(O)OR8B、-N(R8C)C(O)NR8CR8D、-NR8CS(O)2R8B、-NR8CS(O)2NR8CR8D、-P(O)(R8B)2、R9-置換若しくは非置換C1~6アルキル、R9-置換若しくは非置換C1~6ハロアルキル、R9-置換若しくは非置換C3~7シクロアルキル、R9-置換若しくは非置換3~6員ヘテロシクロアルキル、R9-置換若しくは非置換C5~7アリール、又はR9-置換若しくは非置換5~7員ヘテロアリールであり;
各R8b、R8C、及びR8Dは、独立して、水素、R9A-置換若しくは非置換C1~6アルキル、R9A-置換若しくは非置換C1~6ハロアルキル、R9A-置換若しくは非置換C3~7シクロアルキル、又はR9A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R9Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R9は、独立して、水素、ハロゲン、オキソ、-CN、-OR9B、-NO2、-C(O)R9B、-C(O)OR9B、-C(O)OR9B、-C(O)NR9CR9D、-OC(O)R9B、-OC(O)NR9CR9D、-SR9C、-S(O)R9B、-S(O)2R9B、-S(O)(=NR9C)R9D、-S(O)2NR9CR9D、-NR9CR9D、-NR9CC(O)R9B、-NR9CC(O)OR9B、-N(R9C)C(O)NR9CR9D、-NR9CS(O)2R9B、-NR9CS(O)2NR9CR9D、-P(O)(R9B)2、R12-置換若しくは非置換C1~6アルキル、R12-置換若しくは非置換C1~6ハロアルキル、R12-置換若しくは非置換C3~7シクロアルキル、R12-置換若しくは非置換3~6員ヘテロシクロアルキル、R12-置換若しくは非置換C5~7アリール、又はR12-置換若しくは非置換5~7員ヘテロアリールであり;
各R9b、R9C、及びR9Dは、独立して、水素、R10A-置換若しくは非置換C1~6アルキル、R10A-置換若しくは非置換C1~6ハロアルキル、R10A-置換若しくは非置換C3~7シクロアルキル、又はR10A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R10Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R10は、独立して、水素、ハロゲン、オキソ、-CN、-OR11A、-NO2、-C(O)R11A、-C(O)OR11A、-C(O)OR11A、-C(O)NR11BR11C、-OC(O)R11A、-OC(O)NR11BR11C、-SR11B、-S(O)R11A、-S(O)2R11A、-S(O)(=NR11B)R11C、-S(O)2NR11BR11C、-NR11BR11C、-NR11BC(O)R11A、-NR11BC(O)OR11A、-N(R11B)C(O)NR11BR11C、-NR11BS(O)2R11A、-NR11BS(O)2NR11BR11C、-P(O)(R11A)2、R11-置換若しくは非置換C1~6アルコキシ、R11-置換若しくは非置換C1~6アルキル、R11-置換若しくは非置換C1~6ハロアルキル、R11-置換若しくは非置換C3~7シクロアルキル、R11-置換若しくは非置換3~6員ヘテロシクロアルキル、R11-置換若しくは非置換C5~7アリール、又はR11-置換若しくは非置換5~7員ヘテロアリールであり;
各R11A、R11B及びR11Cは、独立して、水素、R12A-置換若しくは非置換C1~6アルキル、R12A-置換若しくは非置換C1~6ハロアルキル、R12A-置換若しくは非置換C3~7シクロアルキル、又はR12A-置換若しくは非置換3~7員ヘテロシクロアルキルであり;
各R12Aは、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;
各R11は、独立して、水素、ハロゲン、オキソ、-CN、-OR12B、-NO2、-C(O)R12B、-C(O)OR12B、-C(O)OR12B、-C(O)NR12CR12D、-OC(O)R12B、-OC(O)NR12CR12D、-SR12C、-S(O)R12B、-S(O)2R12B、-S(O)(=NR12C)R12D、-S(O)2NR12CR12D、-NR12CR12D、-NR12CC(O)R12B、-NR12CC(O)OR12B、-N(R12C)C(O)NR12CR12D、-NR12CS(O)2R12B、-NR12CS(O)2NR12CR12D、-P(O)(R12B)2、R12-置換若しくは非置換C1~6アルキル、R12-置換若しくは非置換C1~6ハロアルキル、R12-置換若しくは非置換C3~7シクロアルキル、R12-置換若しくは非置換3~6員ヘテロシクロアルキル、R12-置換若しくは非置換C5~7アリール、又はR12-置換若しくは非置換5~7員ヘテロアリールであり;
各R12B、R12C及びR12Dは、独立して、水素、非置換C1~6アルキル、非置換C1~6ハロアルキル、非置換C3~7シクロアルキル、又は非置換3~7員ヘテロシクロアルキルであり、
各R12は、独立して、水素、ハロゲン、オキソ、-CN、-NO2、-C(O)H、-C(O)CH3、-C(O)OH、-C(O)OCH3、-C(O)NH2、-OH、-OCH3、-OCF3、-OC(O)H、-OC(O)CH3、-OC(O)NH2、-SH、-S(O)H、-S(O)2H、-S(O)(=NH)H、-S(O)2NH2、-NH2、-NH(CH3)、-N(CH3)2、-NHC(O)H、-NHC(O)OH、-N(H)C(O)NH2、-NHS(O)2H、-NHS(O)2NH2、又は-P(O)(CH3)2、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、非置換C1~6アルコキシ、非置換C1~6アルキル、非置換C1~6アルコキシ、非置換C1~6ハロアルキル、非置換C1~6ハロアルコキシ、非置換C3~7シクロアルキル、非置換3~6員ヘテロシクロアルキル、非置換C5~7アリール、又は非置換5~7員ヘテロアリールであり;且つ
R13は水素、ハロゲン、又はR10-置換若しくは非置換C1~6アルキルである]
で示される化合物、又は、その立体異性体、互変異性体、若しくは薬学的に許容される塩。 - R2が、独立して、水素、OR7、又はR10-置換若しくは非置換C1~6アルキルである、請求項1~4のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R7が水素、R8-置換若しくは非置換C1~6アルキル、又はR8-置換若しくは非置換C1~6ハロアルキルである、請求項5に記載の化合物又はその薬学的に許容される塩。
- R7が非置換C1~6アルキル、又は非置換C1~6ハロアルキルである、請求項6に記載の化合物又はその薬学的に許容される塩。
- R7がR8-置換若しくは非置換C3~7シクロアルキル又はR8-置換若しくは非置換3~7員ヘテロシクロアルキルである、請求項5に記載の化合物又はその薬学的に許容される塩。
- R7がR8-置換若しくは非置換3~7員ヘテロシクロアルキルである、請求項8に記載の化合物又はその薬学的に許容される塩。
- R2が水素であり、R3が水素でない、請求項1~4のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R3が水素、ハロゲン、-OR7、-NR7AR7B、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、R10-置換若しくは非置換C3~7シクロアルキル、又はR10-置換若しくは非置換3~7員ヘテロシクロアルキルである、請求項1~9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R3が水素である、請求項1~9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R3が-OR7又は-NR7AR7Bである、請求項1~9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R7がR8-置換若しくは非置換C1~6アルキル、R8-置換若しくは非置換C1~6ハロアルキル、R8-置換若しくは非置換C3~7シクロアルキル、又はR8-置換若しくは非置換3~7員ヘテロシクロアルキルである、請求項13に記載の化合物又はその薬学的に許容される塩。
- R7A及びR7Bが、独立して、水素又はR8A-置換若しくは非置換C1~6アルキルである、請求項13に記載の化合物又はその薬学的に許容される塩。
- R3がR10-置換若しくは非置換C1~6アルキル又はR10-置換若しくは非置換C1~6ハロアルキルである、請求項1~9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R3がメチル、エチル、プロピル、又はイソプロピルである、請求項16に記載の化合物又はその薬学的に許容される塩。
- R3が-C(CH3)2F、-C(CH3)F2、-CH2F、-CHF2、又は-CF3である、請求項16に記載の化合物又はその薬学的に許容される塩。
- R3がR10-置換若しくは非置換C3~7シクロアルキル又はR10-置換若しくは非置換3~7員ヘテロシクロアルキルである、請求項1~9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R3がR10-置換若しくは非置換3~7員ヘテロシクロアルキルである、請求項19に記載の化合物又はその薬学的に許容される塩。
- R4がハロゲンであり、nが1、2、又は3である、請求項1~20のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R4がFであり、nが1、2、又は3である、請求項1~21のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R4が-OR7であり、nが1である、請求項1~20のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R7がR8-置換若しくは非置換C1~6アルキル又はR8-置換若しくは非置換C1~6ハロアルキルである、請求項1~20のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- L1が-NHSO2-、-NHC(O)-、又はピロリジン-2-オンである、請求項1~24のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- L1が-NHSO2-である、請求項1~25のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- L1が-NHC(O)-である、請求項1~25のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R5がR10-置換若しくは非置換ベンジル、R10-置換若しくは非置換ピロリジニル、R10-置換若しくは非置換ピペリジニル、又はR10-置換若しくは非置換C1~6ハロアルキルである、請求項1~27のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R5がR10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、又はR10-置換若しくは非置換3~6員シクロアルキルである、請求項1~27のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R10がハロゲン、-CN、R11-置換若しくは非置換C1~6アルコキシ、R11-置換若しくは非置換C1~6アルキル、又はR11-置換若しくは非置換C1~6ハロアルキルである、請求項28又は29に記載の化合物又はその薬学的に許容される塩。
- R10が水素、ハロゲン、-OH、-CN、-CF3、-CHF2、-CH2F、-C(CH3)2F、-C(CH3)F2、メチル、プロピル、又はエチルである、請求項28又は29に記載の化合物又はその薬学的に許容される塩。
- R6が、独立して、水素、ハロゲン、R10-置換若しくは非置換C1~6アルキル、R10-置換若しくは非置換C1~6ハロアルキル、又は-NR6AR6Bである、請求項1~31のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R6が、独立して、水素、ハロゲン、又はR10-置換若しくは非置換C1~6アルキルである、請求項1~32のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R6が、独立して、水素、R10-置換若しくは非置換C1~6アルキル、又はR10-置換若しくは非置換C1~6ハロアルキである、請求項1~32のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R6が、独立して、水素又は-NR8R9である、請求項1~32のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- 少なくとも1つのR6が-NR6AR6Bであり、ここでR6A及びR6Bは各々がR10-置換若しくは非置換C1~6アルキルである、請求項35に記載の化合物又はその薬学的に許容される塩。
- R1がR6-置換若しくは非置換C1~6アルキルである、請求項1~36のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R1がR6-置換C3~6シクロアルキル又はR6-置換3~6員ヘテロシクロアルキルである、請求項1~36のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R1がR6-置換シクロヘキシル又はR6-置換ピペリジニルである、請求項1~36のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- 環BがR4-置換若しくは非置換C5~7アリールである、請求項1~40のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- 環BがR4-置換若しくは非置換フェニルである、請求項1~41のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- R4A、R4B、R4C、及びR4Dは、各々が独立して、水素、ハロゲン、-CN、R10-置換若しくは非置換C1~6アルキル、又はR10-置換若しくは非置換C1~6ハロアルキルである、請求項43に記載の化合物又はその薬学的に許容される塩。
- R4A、R4B、R4C、及びR4Dは、各々が独立して、水素又はハロゲンである、請求項43又は44に記載の化合物又はその薬学的に許容される塩。
- X1が-N-である、請求項1~45のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- X2が-N-である、請求項1~45のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- X3が-N-である、請求項1~45のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- 表1の化合物又はその薬学的に許容される塩。
- 表2の化合物又はその薬学的に許容される塩。
- 請求項1~58のいずれか一項に記載の化合物又はその薬学的に許容される塩と、1つ以上の薬学的に許容される添加物とを含む医薬組成物。
- IRE1関連疾患又は障害を治療する方法であって、有効量の、請求項1~58のいずれか一項に記載の化合物、若しくはその薬学的に許容される塩、又は請求項59に記載の医薬組成物を、IRE1関連疾患又は障害を有する対象に投与することを含む方法。
- IRE1関連疾患又は障害が、がんである、請求項60に記載の方法。
- がんが扁平上皮癌、小細胞肺がん、非小細胞肺がん(NSCLC)、肺腺癌、肺扁平上皮がん、腹膜がん、肝細胞がん、胃がん、消化管がん、食道がん、膵臓がん、神経膠芽腫、子宮頸がん、卵巣がん、肝臓がん、膀胱がん、乳がん、結腸がん、直腸がん、結腸直腸がん、子宮内膜がん、子宮がん、唾液腺癌、腎臓がん、前立腺がん、外陰部がん、甲状腺がん、肝細胞癌(HCC)、肛門癌、陰茎癌、又は頭頸部がんである、請求項61に記載の方法。
- がんがリンパ腫、リンパ性白血病、多発性骨髄腫(MM)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、骨髄異形成症候群(MDS)、又は骨髄増殖性疾患(MPD)である、請求項61に記載の方法。
- がんが多発性骨髄腫である、請求項61に記載の方法。
- がんがトリプルネガティブ乳がん(TNBC)である、請求項61に記載の方法。
- 抗炎症剤、コルチコステロイド、免疫調節剤、抗がん剤、アポトーシスエンハンサ、ニューロトロフィック因子、心臓血管疾患治療剤、肝疾患治療剤、抗ウイルス剤、血液疾患治療剤、糖尿病治療剤、代謝障害治療剤、自己免疫障害治療剤、及び免疫不全障害治療剤からなる群から選択される1つ以上の追加の治療剤を投与することを更に含む、請求項60~65のいずれか一項に記載の方法。
- 追加の治療剤が、コルチコステロイド、プロテアソーム阻害剤、免疫調節剤、抗CD38抗体、抗VEGF-A抗体、抗PD-1抗体、抗PD-L1抗体、若しくは抗インターロイキン-6抗体、又はこれらの組み合わせである、請求項66に記載の方法。
- コルチコステロイドがデキサメタゾンを含む、請求項67に記載の方法。
- プロテアソーム阻害剤が、カルフィルゾミブ、イキサゾミブ、又はボルテゾミブを含む、請求項67に記載の方法。
- 免疫調節剤が、レナリドマイド又はポマリドミドを含む、請求項67に記載の方法。
- 抗PD-L1抗体が、アベルマブ、デュルバルマブ、又はアテゾリズマブを含む、請求項67に記載の方法。
- 抗PD-1抗体が、ペンブロリズマブ又はニボルマブを含む、請求項67に記載の方法。
- 放射線療法の適用を更に含む、請求項60~72のいずれか一項に記載の方法。
- IRE1関連疾患又は障害の治療のための薬品の製造における、請求項1~58のいずれか一項に記載の化合物、若しくはその薬学的に許容される塩、又は請求項59に記載の医薬組成物の使用。
- IRE1関連疾患又は障害が、がんである、請求項74に記載の使用。
- がんが扁平上皮癌、小細胞肺がん、非小細胞肺がん(NSCLC)、肺腺癌、肺扁平上皮がん、腹膜がん、肝細胞がん、胃がん、消化器がん、食道がん、膵臓がん、神経膠芽腫、子宮頸がん、卵巣がん、肝臓がん、膀胱がん、乳がん、結腸がん、直腸がん、結腸直腸がん、子宮内膜がん、子宮がん、唾液腺癌、腎臓がん、前立腺がん、外陰部がん、甲状腺がん、肝細胞癌(HCC)、肛門癌、陰茎癌、又は頭頸部がんである、請求項75に記載の使用。
- がんがリンパ腫、リンパ性白血病、多発性骨髄腫(MM)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、骨髄異形成症候群(MDS)、又は骨髄増殖性疾患(MPD)である、請求項75に記載の使用。
- がんが多発性骨髄腫である、請求項75に記載の使用。
- がんがトリプルネガティブ乳がん(TNBC)である、請求項75に記載の使用。
- IRE1関連疾患又は障害を治療するための方法における使用のための、請求項1~58のいずれか一項に記載の化合物、若しくはその薬学的に許容される塩、又は請求項59に記載の医薬組成物。
- IRE1関連疾患又は障害が、がんである、請求項80に記載の使用のための化合物。
- がんが扁平上皮癌、小細胞肺がん、非小細胞肺がん(NSCLC)、肺腺癌、肺扁平上皮がん、腹膜がん、肝細胞がん、胃がん、消化器がん、食道がん、膵臓がん、神経膠芽腫、子宮頸がん、卵巣がん、肝臓がん、膀胱がん、乳がん、結腸がん、直腸がん、結腸直腸がん、子宮内膜がん、子宮がん、唾液腺癌、腎臓がん、前立腺がん、外陰部がん、甲状腺がん、肝細胞癌(HCC)、肛門癌、陰茎癌、又は頭頸部がんである、請求項81に記載の使用のための化合物。
- がんがリンパ腫、リンパ性白血病、多発性骨髄腫(MM)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、骨髄異形成症候群(MDS)、又は骨髄増殖性疾患(MPD)である、請求項81に記載の使用のための化合物。
- がんが多発性骨髄腫である、請求項81に記載の使用のための化合物。
- がんがトリプルネガティブ乳がん(TNBC)である、請求項81に記載の使用のための化合物。
- 抗炎症剤、コルチコステロイド、免疫調節剤、抗がん剤、アポトーシスエンハンサ、ニューロトロフィック因子、心臓血管疾患治療剤、肝疾患治療剤、抗ウイルス剤、血液疾患治療剤、糖尿病治療剤、代謝障害治療剤、自己免疫障害治療剤、及び免疫不全障害治療剤からなる群から選択される1つ以上の追加の治療剤を投与することを更に含む、請求項80~85のいずれか一項に記載の使用のための化合物。
- 追加の治療剤が、コルチコステロイド、プロテアソーム阻害剤、免疫調節剤、抗CD38抗体、抗VEGF-A抗体、抗PD-1抗体、抗PD-L1抗体、若しくは抗インターロイキン-6抗体、又はこれらの組み合わせである、請求項86に記載の使用のための化合物。
- コルチコステロイドがデキサメタゾンを含む、請求項87に記載の使用のための化合物。
- プロテアソーム阻害剤が、カルフィルゾミブ、イキサゾミブ、又はボルテゾミブを含む、請求項87に記載の使用のための化合物。
- 免疫調節剤が、レナリドマイド又はポマリドミドを含む、請求項87に記載の使用のための化合物。
- 抗PD-L1抗体が、アベルマブ、デュルバルマブ、又はアテゾリズマブを含む、請求項87に記載の使用のための化合物。
- 抗PD-1抗体が、ペンブロリズマブ又はニボルマブを含む、請求項87に記載の使用のための化合物。
- 放射線療法の適用を更に含む、請求項80~92のいずれか一項に記載の使用のための化合物。
- Ire1を発現するがん細胞を阻害又は殺傷する方法であって、Ire1を発現するがん細胞を、請求項1~58のいずれか一項に記載の化合物若しくはその薬学的に許容される塩、又は請求項59に記載の医薬組成物と接触させることを含む方法。
- 阻害又は殺傷することがインビボで実施される、請求項94に記載の方法。
- Ire1を発現するがん細胞が、ヒトにある、請求項94に記載の方法。
- Ire1活性を調節する方法であって、Ire1を、請求項1~58のいずれか一項に記載の化合物若しくはその薬学的に許容される塩、又は請求項59に記載の医薬組成物と接触させることを含む方法。
- IRE1によって媒介される疾患を治療するためのキットであって:
a)請求項59に記載の医薬組成物、及び
b)使用説明書
を含むキット。
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