JP2022137128A - Ash1l阻害剤及びそれを用いた治療方法 - Google Patents
Ash1l阻害剤及びそれを用いた治療方法 Download PDFInfo
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- JP2022137128A JP2022137128A JP2022106297A JP2022106297A JP2022137128A JP 2022137128 A JP2022137128 A JP 2022137128A JP 2022106297 A JP2022106297 A JP 2022106297A JP 2022106297 A JP2022106297 A JP 2022106297A JP 2022137128 A JP2022137128 A JP 2022137128A
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- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
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- 229950009016 tesetaxel Drugs 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
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- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
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- 229960001295 tocopherol Drugs 0.000 description 1
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- 238000011200 topical administration Methods 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
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- 108700012359 toxins Proteins 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
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- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 229960005526 triapine Drugs 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- MYMLGBAVNHFRJS-UHFFFAOYSA-N trifluoromethanamine Chemical compound NC(F)(F)F MYMLGBAVNHFRJS-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 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
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 190014017283 triplatin tetranitrate Chemical compound 0.000 description 1
- 229950002860 triplatin tetranitrate Drugs 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UGBMEXLBFDAOGL-INIZCTEOSA-N zd6126 Chemical compound C1C[C@H](NC(C)=O)C2=CC(OP(O)(O)=O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC UGBMEXLBFDAOGL-INIZCTEOSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
Description
本出願は、2016年5月12日出願の米国仮特許出願第62/335,160号に対する優先利益を主張するものであり、その全体が参照により本明細書に組み込まれる。
[式中、XはS、O、NH、またはCH2であり;
R1は、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、チオアルキル、ハロゲン、ケトン、アミド、シアノ、スルホニル、ジアルキルホスフィンオキシド、炭素環、芳香環、置換芳香環、芳香族複素環、置換芳香族複素環、置換または非置換の非芳香族複素環、別の芳香環と縮合された芳香族炭素環または芳香族複素環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく;
RD1-RD5は、存在する場合、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環、置換炭素環、芳香環、置換芳香環、芳香族複素環、置換芳香族複素環、置換または非置換の非芳香族複素環、別の芳香環と縮合された芳香族炭素環または芳香族複素環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから独立して選択され;
RG1-RG5は、存在する場合、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、チオアルキル、ハロゲン、ケトン、アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環、芳香環、置換芳香環、芳香族複素環、置換芳香族複素環、置換または非置換の非芳香族複素環、別の芳香環と縮合された芳香族炭素環または芳香族複素環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから独立して選択され;
Yは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Yの構成要素CまたはNのいずれかが場合により置換されていてもよく、Yの構成要素が0の場合、Yの位置に
Zは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Zの構成要素CまたはNのいずれかが場合により置換されていてもよく、Zの構成要素が0の場合、Zの位置に
RA1-RA5は、存在する場合、H、アルキル、置換アルキル、分枝鎖アルキル、置換分枝鎖アルキル(例えば、ハロゲン置換分枝鎖アルキル)、ヒドロキシ、アルコキシ、アミン、置換アミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環、置換炭素環、芳香環、置換芳香環、芳香族複素環、置換芳香族複素環、置換または非置換の非芳香族複素環(例えば、ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン(化合物263を参照)、スルホンアミド置換ピペリジン(化合物268を参照))、別の芳香環と縮合された芳香族炭素環または芳香族複素環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから独立して選択され;
RE1-RE5は、存在する場合、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、アルキルアミン、置換アルキルアミン(例えば、化合物290)、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、アルキルアミド、置換アルキルアミド(例えば、化合物289)、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環、置換炭素環、芳香環、置換芳香環、芳香族複素環、置換芳香族複素環、置換または非置換の非芳香族複素環、別の芳香環と縮合された芳香族炭素環または芳香族複素環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから独立して選択され;
RM1-RM5は、存在する場合、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環、置換炭素環、芳香環、置換芳香環、芳香族複素環、置換芳香族複素環、置換または非置換の非芳香族複素環、別の芳香環と縮合された芳香族炭素環または芳香族複素環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから独立して選択される]。
式中、J、Q1、またはJ1のうちの1つは、存在する場合、D環、G環、A環、E環、またはM環の1つに結合しており;
J、J1、J2、J3、及びJ4はそれぞれ、存在する場合、共有結合、H、アルキル1-15、アルケニル1-6、アルキニル1-6、(CH2)0-6C(S)NH2、(CH2)0-6C(O)NH2、O、S、NH、(CH2)0-6C(O)NH(CH2)1-6、(CH2)0-6NHC(O)(CH2)1-6、アルキルスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0-6C(S)NH(CH2)1-6、(CH2)0-6O(CH2)1-6、(CH2)0-6OH、(CH2)0-6S(CH2)1-6、(CH2)0-6SH、(CH2)0-6NH(CH2)1-6、(CH2)0-6N(CH2)1-6(CH2)1-6(例えば、化合物80を参照)、(CH2)0-6NH2、(CH2)0-6SO2(CH2)1-6、(CH2)0-6NHSO2(CH2)1-6、(CH2)0-6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0-6CH2F、(CH2)0-3CHF(CH2)0-2CH3、またはBr、Cl、もしくはIでの同様のもの)、ジハロアルキル(例えば、(CH2)0-6CF2H、(CH2)0-3CF2(CH2)0-2CH3、またはBr、Cl、もしくはIでの同様のもの)、トリハロアルキル(例えば、(CH2)0-6CF3、またはBr、Cl、もしくはIでの同様のもの)、鎖に沿って2つ以上の位置に1~3個のハロゲンを有するアルキル(例えば、化合物126、144、194、195、200、207、245、251などを参照)、(CH2)1-4SP(Ph)2=S(例えば、化合物52を参照)、(CH2)0-6NH(CH2)1-5OH、(CH2)0-6NH(CH2)1-5NH2、(CH2)0-6NH(CH2)1-5SH、(CH2)0-6O(CH2)1-5OH、(CH2)0-6O(CH2)1-5NH2、(CH2)0-6O(CH2)1-5SH、(CH2)0-6S(CH2)1-5OH、(CH2)0-6S(CH2)1-5NH2、(CH2)0-6S(CH2)1-5SH、(CH2)0-6O(CH2)1-6NH(CH2)1-5OH、(CH2)0-6O(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6O(CH2)1-6NH(CH2)1-5SH、(CH2)0-6O(CH2)1-6O(CH2)1-5OH、(CH2)0-6O(CH2)1-6O(CH2)1-5NH2、(CH2)0-6O(CH2)1-6O(CH2)1-5SH、(CH2)0-6O(CH2)1-6S(CH2)1-5OH、(CH2)0-6O(CH2)1-6S(CH2)1-5NH2、(CH2)0-6O(CH2)1-6S(CH2)1-5SH、(CH2)0-6S(CH2)1-6NH(CH2)1-5OH、(CH2)0-6S(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6S(CH2)1-6NH(CH2)1-5SH、(CH2)0-6S(CH2)1-6O(CH2)1-5OH、(CH2)0-6S(CH2)1-6O(CH2)1-5NH2、(CH2)0-6S(CH2)1-6O(CH2)1-5SH、(CH2)0-6S(CH2)1-6S(CH2)1-5OH、(CH2)0-6S(CH2)1-6S(CH2)1-5NH2、(CH2)0-6S(CH2)1-6S(CH2)1-5SH、(CH2)0-6NH(CH2)1-6NH(CH2)1-5OH、(CH2)0-6NH(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6NH(CH2)1-5SH、(CH2)0-6NH(CH2)1-6O(CH2)1-5OH、(CH2)0-6NH(CH2)1-6O(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6O(CH2)1-5SH、(CH2)0-6NH(CH2)1-6S(CH2)1-5OH、(CH2)0-6NH(CH2)1-6S(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6S(CH2)1-5SH、(CH2)0-3C(O)O(CH2)0-3、(CH2)0-3C(S)O(CH2)0-3、(CH2)0-3C(O)S(CH2)0-3、(CH2)0-3C(S)S(CH2)0-3、(CH2)0-3C(O)NH(CH2)0-3、(CH2)0-3C(S)NH(CH2)0-3、(CH2)0-3NHC(O)(CH2)0-3、(CH2)0-3NHC(S)(CH2)0-3、(CH2)0-3OC(O)(CH2)0-3、(CH2)0-3OC(S)(CH2)0-3、(CH2)0-3SC(O)(CH2)0-3、(CH2)0-3SC(S)(CH2)0-3、(CH2)0-3NHC(O)NH(CH2)0-3、(CH2)0-3NHC(S)NH(CH2)0-3、(CH2)0-3OC(O)NH(CH2)0-3、(CH2)0-3OC(S)NH(CH2)0-3、(CH2)0-3SC(O)NH(CH2)0-3、(CH2)0-3SC(S)NH(CH2)0-3、(CH2)0-3NHC(O)O(CH2)0-3、(CH2)0-3NHC(S)O(CH2)0-3、(CH2)0-3OC(O)O(CH2)0-3、(CH2)0-3OC(S)O(CH2)0-3、(CH2)0-3SC(O)O(CH2)0-3、(CH2)0-3SC(S)O(CH2)0-3、(CH2)0-3NHC(O)S(CH2)0-3、(CH2)0-3NHC(S)S(CH2)0-3、(CH2)0-3OC(O)S(CH2)0-3、(CH2)0-3OC(S)S(CH2)0-3、(CH2)0-3SC(O)S(CH2)0-3、(CH2)0-3SC(S)S(CH2)0-3、(CH2O)1-6、及びトリメチルメタンからなる群から独立して選択され;
Q、Q1、及びQ2はそれぞれ、存在する場合、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンゾイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソオキサゾール、ベンゾイソオキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3-トリアジン;1,2,4-トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド類)、オキシラン(エチレンオキシド類、エポキシド類)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソオキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ピペラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、トリチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3-シクロヘキサジエン、1,4-シクロヘキサジエン、1,5-シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3~C7シクロアルキル基、及び表1a、1b、2、3、4、または5に示す環構造のいずれかからなる群から独立して選択され;
Q、Q1、及びQ2はそれぞれ、存在する場合、Q環上の任意の位置に1つ以上の追加のJ基が存在してもよく;
上記いずれのアルキル基または(CH2)x-y基が、直鎖であっても分枝鎖であってもよく(例えば、化合物103、104、138、245などを参照);
上記いずれのアルキル基または(CH2)x-y基が、1個以上の炭素に、OH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えばF)の置換基をさらに含んでもよく;
上記の基の末端位置の水素数は、上記の基が追加の基と結合されているか(例えば、CH3がCH2に調整され、OHがOに調整されるなど)、または上記の基が末端にあるか(例えば、CH2がCH3に調整され、OがOHに調整されるなど)に応じて調整される場合があり;ならびに
式(IIa~q)のいずれかが、末端フルオロフォア(例えば、フルオレセイン)、固体表面、酵素リガンド(例えば、サリドマイド(例えば、化合物198、199、301、286、291)、またはVHLリガンド(例えば、(2S,4R)-1-((S)-2-アミノ-3,3-ジメチルブタノイル)-4-ヒドロキシ-N-(4-(4-メチルチアゾール-5-イル)ベンジル)ピロリジン-2-カルボキサミド(例えば、化合物302)など)、または親和性タグをさらに含んでもよい。
本明細書に記載するものと同様または同等であるいかなる方法及び材料も本明細書に記載の実施形態の実施または試験に使用することができるが、一部の好ましい方法、組成物、装置、及び材料を本明細書に記載する。しかしながら、本発明の材料及び方法を記載するにあたり、本発明は本明細書に記載される特定の分子、組成物、方法論、またはプロトコールに限定されず、通常の実験及び至適化に応じてこれらを変更できるものと理解されるべきである。また、本明細書で使用される用語は特定の変法または実施形態の記載のみを目的としており、本明細書に記載の実施形態の範囲を限定することを意図しないものと理解されるべきである。
アミノ-メチル置換基は
「ヘテロシクリルオキシ」とは、-O-ヘテロシクリル部分を指し、ヘテロシクリル部分は炭素原子を介して酸素に結合しており、酸素はその部分を分子の残部に結合させるリンカーとして機能する。本明細書で特に明記しない限り、ヘテロシクリルオキシは置換されていてもよい。
本明細書では、ASH1L活性の小分子阻害剤及びASH1Lの分解を促進する小分子、ならびに急性白血病、固形癌、及びASH1Lの活性に依存する他の疾患を含む疾患の治療にそれを使用する方法を提供する。
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく(例えば、Nと
Yは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Yの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Yの構成要素が0の場合、Y(すなわち、
Zは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Zの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Zの構成要素が0の場合、Zの位置(すなわち、
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく(例えば、Nと
Yは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Yの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Yの構成要素が0の場合、Y(すなわち、
Zは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Zの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Zの構成要素が0の場合、Zの位置(すなわち、
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく(例えば、Nと
Yは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Yの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Yの構成要素が0の場合、Y(すなわち、
Zは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Zの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Zの構成要素が0の場合、Zの位置(すなわち、
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく(例えば、Nと
Yは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Yの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Yの構成要素が0の場合、Y(すなわち、
Zは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Zの構成要素CまたはNのいずれかは本明細書に記載の任意の好適な置換基(例えば、ペンダント基)で場合により置換されていてもよく、Zの構成要素が0の場合、Zの位置(すなわち、
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく(例えば、Nと
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく(例えば、Nと
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
式中:
X=S、O、NH、またはCH2であり;
R1は、本明細書に記載の任意の好適な置換基(例えば、ペンダント基)であり;
単一原子:H、Cl、Br、F、またはI;
アルキル基:メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、または任意の好適な直鎖もしくは分枝鎖のC1~C10アルキル基;
アルケニル:エテニル、プロペニル、ブテニル、ペンテニル、ヘキセニル、または任意の好適なC1~C10アルケニル基;
アルキニル:エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、または任意の好適なC1~C10アルケニル基;
シクロアルキル:シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、または任意の好適なC3~C7シクロアルキル基;さらに置換されていてもよい(例えば、化合物186~190);
シクロアルケニル:シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3-シクロヘキサジエン、1,4-シクロヘキサジエン、1,5-シクロオクタジエン;さらに置換されていてもよい;
アリールまたはヘテロアリール:フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンゾイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソオキサゾール、ベンゾイソオキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、トリアジン(例えば、1,2,3-トリアジン;1,2,4-トリアジン;1,3,5トリアジンなど)、チアジアゾールなど;さらに置換されていてもよい;
非芳香族複素環:アジリジン、チイラン(エピスルフィド類)、オキシラン(エチレンオキシド類、エポキシド類)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソオキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ピペラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、トリチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピランなど;
ハロアルカン:ハロメタン(例えば、クロロメタン、ブロモメタン、フルオロメタン、ヨードメタン)、ジハロメタン及びトリハロメタン(例えば、トリクロロメタン、トリブロモメタン、トリフルオロメタン、トリヨードメタン)、1-ハロエタン、2-ハロエタン、1,2-ジハロエタン、1-ハロプロパン、2-ハロプロパン、3-ハロプロパン、1,2-ジハロプロパン、1,3-ジハロプロパン、2,3-ジハロプロパン、1,2,3-トリハロプロパン、及びアルカン(または置換アルカン)及びハロゲン(例えば、Cl、Br、F、Iなど)の任意の他の好適な組み合わせ、ならびに分枝鎖ハロアルカン(例えば、化合物195~200);
アルコール:OH、メタノール、エタノール、プロパノール、ブタノール、ペンタノール、ヘキサノール、環式アルコール(例えばシクロヘキサノール)、芳香族アルコール(例えばフェノール)、またはOH部分と第2の部分との任意の他の好適な組み合わせ、分枝鎖アルコール(例えば、化合物123及び151);
ケトン:メチルメチルケトン(アセトン)、メチルエチルケトン(ブタノン)、プロピルエチルケトン(ペンタノン)、またはアルキル鎖と=Oとの任意の他の好適な組み合わせ;
アルデヒド:メタナール、エタナール、プロパナール、ブタナール、ペンタナール、ヘキサナール、またはアルキル鎖と=Oとの任意の他の好適な組み合わせ;
カルボキシレート:メタノアート、エタノアート、プロパノアート、ブタノアート、ペンタノアート、ヘキサノアート、またはアルキル鎖とOO-との任意の他の好適な組み合わせ;
カルボン酸:メタン酸、エタン酸、プロパン酸、ブタン酸、ペンタン酸、ヘキサン酸、またはアルキル鎖とOOHとの任意の他の好適な組み合わせ;
エーテル:メトキシ、エトキシ、メチルメトキシ、エチルメトキシ、またはO周囲のアルキル鎖の任意の他の好適な組み合わせ;
アミド:メタンアミド(CONH2)、エタンアミド(CH2CONH2)、プロパンアミド((CH2)2CONH2)、アルカンnアミド((CH2)nCONH2)、n-メチルアルカンnアミド((CH2)nCONHCH3)、c-メチルアルカンnアミド((CH2)nNHCOCH3)、n-アルキルアルカンnアミド((CH2)nCONH(CH2)mCH3)、c-メチルアルカンnアミド((CH2)nNHCO(CH2)mCH3)など;
第1級アミン:NH2、メチルアミン、エチルアミン、シクロプロピルアミンなど;
第2級アミン:アミノメチル(NHCH3)、アミノエチル(NHCH2CH3)、メチル-アミノメチル(CH2NHCH3;別称メチルアミン-メタン)、アルキルn-アミノメタン((CH2)nNHCH3)など;
第3級アミン:ジメチルアミン(N(CH3)2)、ジメチルアミン(N(CH3)2)、メチル-エチル-アミン(NCH3CH2CH3)、メタン-ジエチルアミン(CH2N(CH2CH3)2;別称メチルアミン-ジエタン)など;
アジド:メチルアジド(CH2NNN)、エチルアジド((CH2)2NNN)、アルキルnアジド((CH2)nNNN)など;
シアネート:メチルシアネート(CH2OCN)、エチルシアネート((CH2)2OCN)、アルキルnシアネート((CH2)nOCN)など;
シアノ:シアノ(-CN)、メチルカルボニトリル(CH2CN)、エチルカルボニトリル((CH2)2CN)、アルキルnカルボニトリル((CH2)nCN)など、
チオール:メタンチオール(CH2SH)、エタンチオール((CH2)2SH)、アルカンnチオール((CH2)nSH)など、
スルフィド:ジメチルスルフィド(CH2SCH3)、メチル-エチルスルフィド(CH2SCH2CH3)、アルキルn-アルキルmスルフィド((CH2)nS(CH2)m-1CH3)など;
スルホキシド:ジメチルスルホキシド(CH2SOCH3)、メチル-エチルスルホキシド(CH2SOCH2CH3)、アルキルn-アルキルmスルホキシド((CH2)nSO(CH2)m-1CH3)など;
スルホン:ジメチルスルホン(CH2SO2CH3;別名メチル-スルホン-メチル)、メチル-エチルスルホン(CH2SO2CH2CH3;別名メチル-スルホン-エチル)、アルキルn-アルキルmスルホン((CH2)nSO2(CH2)m-1CH3;別名アルキルn-スルホン-アルキルm)、RxSO2Ry(式中、Rx及びRyは独立して、本一覧に示す部分のいずれかまたはその組み合わせから選択される)など;
スルホンアミド:SO2NH2、メチルスルホンアミド(CH2SO2NH2)、エチルスルホンアミド((CH2)2SO2NH2)、アルキルnスルホンアミド((CH2)nSO2NH2)、メチルメチルスルホンアミド(CH2SO2NHCH3)、アルキルnアルキルmスルホンアミド((CH2)nSO2NH(CH2)mCH3など;
スルフィン酸:SO2H、メチルスルフィン酸(CH2SO2H)、エチルスルフィン酸((CH2)2SO2H)、アルキルnスルフィン酸((CH2)nSO2H)など;
チオシアネート:SCN、メチルチオシアネート(CH2SCN)、エチルチオシアネート((CH2)2SCN)、アルキルnチオシアネート((CH2)nSCN)など;
ホスフェート:OP(=O)(OH)2、メチルホスフェート(CH2OP(=O)(OH)2)、エチルホスフェート((CH2)2OP(=O)(OH)2)、アルキルnホスフェート((CH2)nOP(=O)(OH)2)など;
及びそれらの好適な組み合わせ。例えば、いくつかの実施形態では、R1、RD1-5、RG1-5、RA1-5、RE1-5、及びRM1-5置換基(存在している場合)は独立して以下から選択される:H、アルキル基(例えば、直鎖アルキル(例えば、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシルなど)、分枝鎖アルキル基(例えば、イソプロピル、2-メチル-ヘキシル、3-メチル、2-プロピル-オクチルなど)、シクロアルキル(例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルなど)、分枝鎖環状アルキル(例えば、メチルシクロヘキシル、エチルシクロブチル、プロピルシクロヘキシルなど))、置換アルキル基(例えば、ハロゲン置換アルキル基(例えば、トリハロブタン(例えば、トリフルオロブタン)、ジハロブタン(例えば、ジフルオロブタン)、モノハロブタン(例えば、モノフルオロブタン)、トリハロプロパン(例えば、トリフルオロプロパン)、ジハロプロパン(例えば、ジフルオロプロパン)、モノハロプロパン(例えば、モノフルオロプロパン)、トリハロエタン(例えば、トリフルオロエタン)、ジハロエタン(例えば、ジフルオロエタン)、ハロエタン(例えば、フルオロエタン)、ハロメタン(例えば、フルオロメタン)、ジハロメタン(例えば、ジフルオロメタン)、トリハロメタン(例えば、トリフルオロメタン)、複数の炭素がハロゲンで置換されたアルキル基(例えば、3-フルオロ,4-トリフルオロイソブタン(例えば、化合物245のRA置換基を参照)、2-ジフルオロ,3-フルオロプロパンなど)など)、アルケン(例えば、CH=CH2、CH2CH=CH2、CH=CHCH3など)、アルキン(例えば、C≡CH、C≡CCH3、CH2C≡CHなど)、アルコキシ基(例えば、ヒドロキシル(例えば、(CH2)0-6OH、エーテル((CH2)0-6O(CH2)0-6))、ハロゲン置換アルコキシ(4-トリフルオロ,3-イソブタノール(例えば、化合物252を参照)、3-ジフルオロ,2-プロパノールなど)、アミン(例えば、NH2)、アルキルアミン(例えば、第1級アミン(例えば、エチルアミン、イソブチルアミン)、n-プロピルアミン、sec-ブチルアミン、イソプロピルアミン、イソアミルアミン、メチルアミン、ジメチルアミン、n-アミルアミンなど)、第2級アミン(例えば、ジメチルアミン、メチルエタノールアミン、ジフェニルアミンなど)、第3級アミン(例えば、トリメチルアミン、トリフェニルアミンなど)、チオアルキル(例えば、チオール(例えば、(CH2)0-6-SH)、チオエーテル(例えば、(CH2)0-6-S-(CH2)0-6)など)、置換エーテル及びチオエーテル(例えば、化合物266を参照)、それらの組み合わせなど)、置換シクロアルキル基(例えば、ハロゲン置換シクロアルキル基、シクロアルコキシ基、シクロアルキルアミンなど)、ハロゲン置換アルキルアミン(例えば、トリフルオロメチルアミン、トリフルオロエチルアミン(例えば、化合物248を参照)、トリフルオロブチルアミンなど)、ハロゲン(例えば、F、Cl、Br、I、及びAt)、ケトン、アミド、アルキルアミド、シアノ基、メチルカルボニトリル(例えば、CH2CN)、-SO2CH3基、-SO2NH2基、スルホニル基(例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル)、置換アルキルスルホニル(例えば、トリフルオロエチルスルホニル)など)、スルホアミン(例えば、(CH2)0-6SO2NH2(例えば、化合物268を参照)、(CH2)0-6NHSO2、(CH2)0-6NHSO2(CH2)0-6(例えば、化合物309を参照)、(CH2)0-6SO2NH(CH2)0-6など)、ジアルキルホスフィンオキシド(例えば、-PO(CH3)2))、炭素環(置換または非置換)、複素環(置換(例えば、化合物274を参照)または非置換)、芳香環、置換芳香環(例えば、分枝鎖芳香環(例えば、エチルベンゼン、メチルベンゼンなど)、ハロベンゼン(例えば、クロロベンゼン、フルオロベンゼンなど))、炭素環式(置換または非置換)、炭素環アリール(置換または非置換)、ヘテロアリール(置換(例えば、スルホニル置換(例えば、化合物263を参照)、ハロ置換など)または非置換)、アルキル結合炭素環(置換または非置換)、アルキル結合複素環(置換または非置換)、アルキル結合芳香環(置換または非置換)、アルキル結合置換芳香環、アルキル結合ハロベンゼン(例えば、クロロベンゼン、フルオロベンゼンなど))、アルキル結合炭素環式(置換(例えば、ハロ置換(例えば、化合物258を参照)、トリハロ-アルキル置換(例えば、化合物257を参照)など)または非置換)、アルキル結合炭素環アリール(置換または非置換)、アルキル結合ヘテロアリール(置換または非置換)、アミン結合炭素環(置換または非置換)、アミン結合複素環(置換または非置換)、アミン結合芳香環(置換または非置換)、アミン結合置換芳香環、アミン結合ハロベンゼン、アミン結合炭素環式(置換または非置換)、アミン結合炭素環アリール(置換または非置換)、アミン結合ヘテロアリール(置換(例えば、化合物271を参照)または非置換)、アルキルアミン結合炭素環(置換または非置換)、アルキルアミン結合複素環(置換または非置換)、アルキルアミン結合芳香環(置換または非置換)、アルキルアミン結合置換芳香環、アルキルアミン結合ハロベンゼン、アルキルアミン結合炭素環式(置換または非置換)、アルキルアミン結合炭素環アリール(置換または非置換)、アルキルアミン結合ヘテロアリール(置換または非置換)、エーテル結合炭素環(置換または非置換)、エーテル結合複素環(置換または非置換)、エーテル結合芳香環(置換または非置換)、エーテル結合置換芳香環、エーテル結合ハロベンゼン、エーテル結合炭素環式(置換または非置換)、エーテル結合炭素環アリール(置換または非置換)、エーテル結合ヘテロアリール(置換または非置換)、チオエーテル結合炭素環(置換または非置換)、チオエーテル結合複素環(置換または非置換)、チオエーテル結合芳香環(置換または非置換)、チオエーテル結合置換芳香環、チオエーテル結合ハロベンゼン、チオエーテル結合炭素環式(置換または非置換)、チオエーテル結合炭素環アリール(置換または非置換)、チオエーテル結合ヘテロアリール(置換または非置換)、スルホニル結合炭素環(置換または非置換)、スルホニル結合複素環(置換または非置換)、スルホニル結合芳香環(置換または非置換)、スルホニル結合置換芳香環、スルホニル結合ハロベンゼン、スルホニル結合炭素環式(置換または非置換)、スルホニル結合炭素環アリール(置換または非置換)、スルホニル結合ヘテロアリール(置換または非置換)、スルホンアミド結合炭素環(置換または非置換)、スルホンアミド結合複素環(置換または非置換)、スルホンアミド結合芳香環(置換または非置換)、スルホンアミド結合置換芳香環、スルホンアミド結合ハロベンゼン、スルホンアミド結合炭素環式(置換または非置換)、スルホンアミド結合炭素環アリール(置換または非置換)、スルホンアミド結合ヘテロアリール(置換または非置換)、アミド結合炭素環(置換または非置換)、アミド結合複素環(置換または非置換)、アミド結合芳香環(置換または非置換)、アミド結合置換芳香環、アミド結合ハロベンゼン、アミド結合炭素環式(置換または非置換)、アミド結合炭素環アリール(置換または非置換)、アミド結合ヘテロアリール(置換(例えば、アルキルピロール(例えば、化合物293を参照)、ピロールアミン(例えば、化合物296を参照)、ピロールエーテル(例えば、化合物297を参照)など)または非置換(例えば、イミダゾール(例えば、化合物273を参照)、インドール(例えば、化合物293及び294を参照)など))、アルキルアミド結合炭素環(置換または非置換)、アルキルアミド結合複素環(置換または非置換)、アルキルアミド結合芳香環(置換または非置換)、アルキルアミド結合置換芳香環(置換または非置換)、アルキルアミド結合ハロベンゼン、アルキルアミド結合炭素環式(置換または非置換)、アルキルアミド結合炭素環アリール(置換または非置換)、アルキルアミド結合ヘテロアリール(置換または非置換)、カルバミド結合炭素環(置換または非置換)、カルバミド結合複素環(置換または非置換)、カルバミド結合芳香環(置換または非置換)、カルバミド結合置換芳香環、カルバミド結合ハロベンゼン、カルバミド結合炭素環式(置換または非置換)、カルバミド結合炭素環アリール(置換または非置換)、カルバミド結合ヘテロアリール(置換または非置換(例えば、化合物314を参照))、架橋炭素環(置換または非置換)、架橋複素環(置換(例えば、化合物272を参照)または非置換)、架橋芳香環(置換または非置換)、架橋置換芳香環、架橋ハロベンゼン、架橋炭素環式(置換または非置換)、架橋炭素環アリール(置換または非置換)、架橋ヘテロアリール(置換または非置換)、及び/またはそれらの組み合わせ。
式中、J、Q1、またはJ1のうち1つは、存在する場合、D環、G環、A環、E環、またはM環の1つに結合しており;
J、J1、J2、J3、及びJ4はそれぞれ、存在する場合、共有結合、H、アルキル1-15、アルケニル1-6、アルキニル1-6、(CH2)0-6C(S)NH2、(CH2)0-6C(O)NH2、O、S、NH、(CH2)0-6C(O)NH(CH2)1-6、(CH2)0-6C(S)NH(CH2)1-6、(CH2)0-6O(CH2)1-6、(CH2)0-6OH、(CH2)0-6S(CH2)1-6、(CH2)0-6SH、(CH2)0-6NHC(O)(CH2)1-6、アルキルスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0-6NH(CH2)1-6、(CH2)0-6N(CH2)1-6(CH2)1-6(例えば、化合物80を参照)、(CH2)0-6NH2、(CH2)0-6SO2(CH2)1-6、(CH2)0-6NHSO2(CH2)1-6、(CH2)0-6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0-6CH2F、(CH2)0-3CHF(CH2)0-2CH3、またはBr、Cl、もしくはIでの同様のもの)、ジハロアルキル(例えば、(CH2)0-6CF2H、(CH2)0-3CF2(CH2)0-2CH3、またはBr、Cl、もしくはIでの同様のもの)、トリハロアルキル(例えば、(CH2)0-6CF3、またはBr、Cl、もしくはIでの同様のもの)、鎖に沿って2つ以上の位置に1~3個のハロゲンを有するアルキル(例えば、化合物126、144、194、195、200、207、245、251などを参照)、(CH2)1-4SP(Ph)2=S(例えば、化合物52を参照)、(CH2)0-6NH(CH2)1-5OH、(CH2)0-6NH(CH2)1-5NH2、(CH2)0-6NH(CH2)1-5SH、(CH2)0-6O(CH2)1-5OH、(CH2)0-6O(CH2)1-5NH2、(CH2)0-6O(CH2)1-5SH、(CH2)0-6S(CH2)1-5OH、(CH2)0-6S(CH2)1-5NH2、(CH2)0-6S(CH2)1-5SH、(CH2)0-6O(CH2)1-6NH(CH2)1-5OH、(CH2)0-6O(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6O(CH2)1-6NH(CH2)1-5SH、(CH2)0-6O(CH2)1-6O(CH2)1-5OH、(CH2)0-6O(CH2)1-6O(CH2)1-5NH2、(CH2)0-6O(CH2)1-6O(CH2)1-5SH、(CH2)0-6O(CH2)1-6S(CH2)1-5OH、(CH2)0-6O(CH2)1-6S(CH2)1-5NH2、(CH2)0-6O(CH2)1-6S(CH2)1-5SH、(CH2)0-6S(CH2)1-6NH(CH2)1-5OH、(CH2)0-6S(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6S(CH2)1-6NH(CH2)1-5SH、(CH2)0-6S(CH2)1-6O(CH2)1-5OH、(CH2)0-6S(CH2)1-6O(CH2)1-5NH2、(CH2)0-6S(CH2)1-6O(CH2)1-5SH、(CH2)0-6S(CH2)1-6S(CH2)1-5OH、(CH2)0-6S(CH2)1-6S(CH2)1-5NH2、(CH2)0-6S(CH2)1-6S(CH2)1-5SH、(CH2)0-6NH(CH2)1-6NH(CH2)1-5OH、(CH2)0-6NH(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6NH(CH2)1-5SH、(CH2)0-6NH(CH2)1-6O(CH2)1-5OH、(CH2)0-6NH(CH2)1-6O(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6O(CH2)1-5SH、(CH2)0-6NH(CH2)1-6S(CH2)1-5OH、(CH2)0-6NH(CH2)1-6S(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6S(CH2)1-5SH、(CH2)0-3C(O)O(CH2)0-3、(CH2)0-3C(S)O(CH2)0-3、(CH2)0-3C(O)S(CH2)0-3、(CH2)0-3C(S)S(CH2)0-3、(CH2)0-3C(O)NH(CH2)0-3、(CH2)0-3C(S)NH(CH2)0-3、(CH2)0-3NHC(O)(CH2)0-3、(CH2)0-3NHC(S)(CH2)0-3、(CH2)0-3OC(O)(CH2)0-3、(CH2)0-3OC(S)(CH2)0-3、(CH2)0-3SC(O)(CH2)0-3、(CH2)0-3SC(S)(CH2)0-3、(CH2)0-3NHC(O)NH(CH2)0-3、(CH2)0-3NHC(S)NH(CH2)0-3、(CH2)0-3OC(O)NH(CH2)0-3、(CH2)0-3OC(S)NH(CH2)0-3、(CH2)0-3SC(O)NH(CH2)0-3、(CH2)0-3SC(S)NH(CH2)0-3、(CH2)0-3NHC(O)O(CH2)0-3、(CH2)0-3NHC(S)O(CH2)0-3、(CH2)0-3OC(O)O(CH2)0-3、(CH2)0-3OC(S)O(CH2)0-3、(CH2)0-3SC(O)O(CH2)0-3、(CH2)0-3SC(S)O(CH2)0-3、(CH2)0-3NHC(O)S(CH2)0-3、(CH2)0-3NHC(S)S(CH2)0-3、(CH2)0-3OC(O)S(CH2)0-3、(CH2)0-3OC(S)S(CH2)0-3、(CH2)0-3SC(O)S(CH2)0-3、(CH2)0-3SC(S)S(CH2)0-3、(CH2O)1-6、及びトリメチルメタンからなる群から独立して選択され;
Q、Q1、及びQ2はそれぞれ、存在する場合、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンゾイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソオキサゾール、ベンゾイソオキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3-トリアジン;1,2,4-トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド類)、オキシラン(エチレンオキシド類、エポキシド類)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソオキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ピペラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、トリチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3-シクロヘキサジエン、1,4-シクロヘキサジエン、1,5-シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3~C7シクロアルキル基、及び表1a、1b、2、3、4または5に示す環構造のいずれかからなる群から独立して選択され;
Q、Q1、及びQ2はそれぞれ、存在する場合、Q環上の任意の位置に1つ以上の追加のJ基が存在してもよく;
上記のいずれのアルキル基または(CH2)x-y基も、直鎖であっても分枝鎖であってもよく(例えば、化合物103、104、138、245などを参照);
上記のいずれのアルキル基または(CH2)x-y基も、1個以上の炭素に、OH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えばF)の置換基をさらに含んでもよく;
上記の基の末端位置の水素数は、上記の基が追加の基と結合されているか(例えば、CH3がCH2に調整され、OHがOに調整されるなど)、または上記の基が末端にあるか(例えば、CH2がCH3に調整され、OがOHに調整されるなど)に応じて調整される場合があり;ならびに
式(IIa~q)のいずれかが、末端フルオロフォア(例えば、フルオレセイン)、固体表面、酵素リガンド(例えば、サリドマイド(例えば、化合物198、199、301、286、291)、またはVHLリガンド(例えば、(2S,4R)-1-((S)-2-アミノ-3,3-ジメチルブタノイル)-4-ヒドロキシ-N-(4-(4-メチルチアゾール-5-イル)ベンジル)ピロリジン-2-カルボキサミド(例えば、化合物302)など)、または親和性タグをさらに含んでもよい。
ある特定の実施形態では、本明細書に開示される任意の好適な置換基及び官能基を有する、式(I)、(I-A)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-I)、及び(I-J)のうちいずれか1つである化合物または塩を1種以上の追加薬剤と組み合わせて医薬組成物を形成する。医薬組成物は、活性化合物の薬学的に使用可能な製剤への加工を容易にする賦形剤及び補助剤を含む1種以上の生理学的に許容される担体を使用して従来の方法で製剤化することができる。適切な製剤は、選択された投与経路に応じて異なる。本明細書に記載の医薬組成物に適した賦形剤に関するさらなる詳細については、例えば、Remington:The Science and Practice of Pharmacy,Nineteenth Ed(Easton,Pa.:Mack Publishing Company,1995);Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,H.A.and Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;及びPharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed.(Lippincott Williams & Wilkins1999)で参照することができ、このような開示の参照により本明細書に組み込まれる。
Delivery Systems,Sixth Ed.(1995)を参照のこと。好ましくは、これらの組成物及び製剤は、好適な非毒性の薬学的に許容される成分を用いて調製される。好適な担体の選択は、望ましい経鼻剤形、例えば溶液、懸濁液、軟膏、またはゲルの厳密な性質によるところが大きい。経鼻剤形は一般に、活性成分に加えて多量の水を含有する。少量の他の成分、例えば、pH調整剤、乳化剤もしくは分散剤、防腐剤、界面活性剤、ゲル化剤、または緩衝剤、ならびに他の安定剤及び可溶化剤もまた存在してもよい。好ましくは、経鼻剤形は鼻分泌物と等張性にすべきである。
本開示は、ASH1Lの活性を阻害する化合物及び方法を提供する。ある特定の実施形態では、本開示は、ASH1Lに結合する及び/またはその活性を阻害する化合物を提供する。
本明細書では、他の経路を調節することが知られている薬剤、または同じ経路の他の成分、あるいはさらに一連の重複する標的酵素を、本明細書に開示される任意の好適な置換基及び官能基を有する、式(I)、(I-A)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-I)、及び(I-J)のうちいずれか1つである化合物または塩と併用する併用療法の方法を提供する。一態様では、そのような療法は、相乗的または相加的な治療効果が得られる、本発明の1つ以上の化合物と化学療法剤、標的薬、治療抗体、及び放射線治療との組み合わせを含むが、これに限定されない。
本明細書に記載の治療用途に使用されるキット及び製造物品も提供する。いくつかの実施形態では、そのようなキットは、担体、パッケージ、またはバイアル、チューブなどの1つ以上の容器を入れるように区画された容器を含み、各容器(複数可)は本明細書に記載の方法で使用される独立した構成要素のうち1つを含む。好適な容器としては、例えば、ボトル、バイアル、注射器、及び試験管が挙げられる。容器は、ガラスまたはプラスチックなどの様々な材料から作製される。
スキーム1-式I-Eを有する化合物の一般的な合成戦略
125.1, 125.9, 129.3, 130.4, 131.9, 132.2,133.1, 136.3, 142.6。
125.5, 126.7, 128.2, 131.2, 132.3, 136.2,139.5, 140.9, 202.1;[M+H]+のHRMS(ESI)計算値252.07、実測値:253.0795。
NMR (400 MHz, CD3OD) δ 9.99 (s, 1H), 7.98 (s, 1H), 7.67 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (m, 2H)。
2H)。
(s, 1H), 7.94 (m, 2H), 7.85 (m, 2H), 7.71 (dd, J = 8.0, 1.3 Hz, 1H), 7.55 (m, 3H), 4.35 (t, J = 6.4 Hz, 2H), 2.20 (m, 4H)。
4.04 - 4.15 (m, 2H) 4.39 (dd, J=7.2, 3.1 Hz,
2H)。
NMR (600 MHz, アセトニトリル-d3) δ ppm 7.63 - 7.71(m, 2 H) 7.93 - 7.96 (m, 1 H) 7.99 - 8.05 (m,2 H) 8.05 - 8.09 (m, 2 H) 8.47 - 8.50 (m, 1 H)10.00 - 10.40 (bs, 1 H)。
(150 MHz, アセトニトリル-d3) δ ppm 45.5, 46.2, 61.7, 109.1, 114.2, 116.4, 116.7, 120.2, 120.8, 131.1, 131.2, 131.8, 132.9, 135.3, 136.9,
137.4, 144.7。
8.05 (dd, J = 8.8, 1.8 Hz, 1H) 8.09 (d, J = 8.1 Hz, 1H) 8.13 - 8.19 (m, 2H) 8.37 (m, 1H) 8.66 (d, J = 1.8 Hz, 1H)。
Hz, 1H) 7.33 - 7.39 (m, 2H) 7.53 (d, J = 8.4Hz, 1H) 7.62 (d, J = 8.1 Hz, 1H) 7.66 (d, J =8.1 Hz, 1 H) 8.05 (m, 1H) 9.47 (br. s., 1H) 9.81 (br. s., 1H);13C NMR (150 MHz, DMSO-d6)δ ppm 40.7 (J = 18 Hz), 42.2, 80.7, 81.8, 93.4, 110.7, 115.0, 117.0, 119.8, 124.0, 124.2, 124.9, 128.3, 128.6, 135.4, 138.6, 140.1,
144.8, 200.6 C19H19F2N3SのHR-MS[ESI,M+H+]計算値:360.1346、実測値:360.1341。
2H), 1.95 (m, 4H), 1.95 (m, 2H)。[M+H]+のLCMS(ESI)計算値302、実測値302。
J = 6.0 Hz, 1H), 7.71 (m, 2H), 7.42 (t, J = 6.0 Hz, 2H), 6.93 (s, 1H), 6.74 (d, J = 6.0 Hz, 1H), 4.80 (m, 1H), 2.23 (m, 2H), 1.95 (m, 4H), 1.95 (m, 2H)。13C NMR (150 MHz, CD3OD) δ204.1, 142.6, 141.7, 139.9, 137.7, 134.5, 130.6, 130.2, 129.9, 126.9, 124.8, 122.4, 121.2, 116.9, 112.8, 58.1, 33.3, 30.6, 27.7。[M+H]+のHRMS(ESI)計算値336.1529、実測値336.1529。
(m, 1H) 7.63 - 7.72 (m, 2H) 7.78 - 7.86 (m, 1H) 8.02 - 8.09 (m, 1H);13C NMR (150 MHz, CDCl3, HSQC) δ ppm 40.4, 41.7, 80.2, 81.3, 93.8, 110.2, 119.6, 123.7, 123.7, 124.8, 128.2,
129.0;C19H20F2N3OのHR-MS[ESI,M+H+]計算値:344.1574、実測値:344.1567。
MHz, CDCl3) δ ppm 1.50 (s, 3H) 1.53 (s, 3H)2.08 - 2.14 (m, 1H) 3.59 - 3.65 (m, 2H) 4.07- 4.13 (m, 2H) 4.59 (d, J=8.1 Hz, 2H) 7.53 -7.62 (m, 3H) 7.76 (dd, J=8.2, 0.9 Hz, 1H) 7.88 (d, J = 7.7 Hz, 1H) 7.92 (m, 1H) 7.98 (d, J=8.1 Hz, 1H) 8.01 - 8.05 (m, 2H) 10.11 (s, 1H)。
Hz, 2H) 7.91 (m, 1H);13C NMR (150 MHz, CDCl3) δ ppm 20.1, 21.2, 27.8, 34.7, 45.8, 61.3,
67.0, 98.5, 98.7, 110.5, 112.9, 115.0, 119.1, 119.7, 121.5, 125.8, 127.6, 129.2, 129.6, 130.5, 131.4, 136.7, 136.9, 171.0。
(m, 1H) 4.39 (d, J = 7.3 Hz, 2H) 4.45 - 4.53(m, 2H) 4.53 - 4.61 (m, 2H) 5.28 (s, 2H) 7.28
(m, 1H) 7.37 (m, 1H) 7.45 (m, 1H) 7.53 - 7.60 (m, 2H) 7.86 - 7.91 (m, 2H) 7.92 (m, 1H) 13C NMR (150 MHz, CDCl3) δ ppm 21.0, 41.7 (J =18Hz), 42.9, 66.9, 80.2, 81.3, 110.0, 113.0, 115.6, 119.0, 121.7, 125.8, 127.2, 129.4,
129.6, 130.5, 131.4, 136.4, 136.9, 170.9。
(150 MHz, AcCN-d3) δ ppm 41.7, 42.7, 44.2,65.8, 82.2, 83.3, 109.7, 117.1, 120.9, 121.3, 125.9, 126.4, 126.8, 128.6, 130.1, 131.2, 136.9, 138.1, 138.7, 141.6, 204.1;C20H21F2N2OSのHR-MS[ESI,M+H+]計算値:375.1343、実測値:375.1335。
8.26 (s, 1H), 7.93 (d, J = 12.0 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.75 (d, J = 6.0 Hz, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.47 (t, J = 6.0 Hz, 1H), 7.21 (d, J = 12.0 Hz, 1H), 5.95 (tt, J = 60.0, 6.0 Hz, 1H), 4.47 (t, J = 6.0 Hz, 2H), 2.43 (m, 2H)。13C NMR (150 MHz, CD3OD)
δ 204.5, 141.8, 138.3, 137.1, 130.9, 129.5, 127.5, 127.3, 126.9, 125.1, 121.1, 120.8,
117.5, 117.4 (t, J = 237.0 Hz), 65.9, 40.8 (t, J = 6.0 Hz), 35.8 (t, J = 21.0 Hz)。[M+H]+のHRMS(ESI)計算値361.1181、実測値361.1175。
[タンパク質精製]
ASH1L SETタンパク質を、22℃でE.coli BL21(DE3)T1R細胞にMOCR融合タンパク質として発現させた。50mM Tris(pH7.5)、500mM NaCl、1mM トリス(2-カルボキシエチル)ホスフィン(TCEP)、及び20mMイミダゾールを含有する緩衝液Aに形質転換細胞を溶解した。細胞破片を遠心分離によりペレット化し、上清をニッケル-ニトリロ三酢酸ビーズを充填したカラムに入れた。カラムは緩衝液Aで洗浄し、500mMイミダゾールを含有する緩衝液Aまで100mLの直線勾配でタンパク質を溶出した。50mM Tris(pH7.5)、100mM NaCl、及び1mM TCEPに対する一晩の透析中に、タバコエッチウイルス(TEV)プロテアーゼでMOCRタグを切断した。ニッケルカラム精製を繰り返し、フロースルー画分及び低イミダゾール画分中のASH1Lを回収することによって、切断されたASH1LをMOCRから単離した。50mM Tris(pH7.5)、100mM NaCl、及び1mM TCEPを含有する緩衝液Bで平衡化したSuperdex-75カラムを用いたゲル濾過クロマトグラフィーによりASH1Lをさらに精製した。ASH1LのSET-PHD及びSET-BAHタンパク質を同様に精製したが、以下の違いがあった。発現は18℃で行った。TEVによる切断及び第2のニッケルカラムを省略してタンパク質の安定性を維持し、ゲル濾過をSuperdex-200カラムで行った。
ニワトリモノ/ジヌクレオソーム(HMT-35-179)、ニワトリオリゴヌクレオソーム(HMT-35-177)、及びHeLaヌクレオソーム(HMT-35-123)をReaction Biologyから購入した。試験化合物用に、0.25μMのASH1L SET-BAH構築物(アミノ酸2069~2833)を0.7μMのSAM、0.2μMのニワトリモノ/ジヌクレオソーム、及びHMTase緩衝液(50mM
Tris(pH8.5)、25mM NaCl、2mM MgCl2、及び1mM DTT)中の濃度範囲500~0.2μMの化合物、総容積15μlと30℃で1時間インキュベートした。反応混合物5μLをP81セルロース角形(Reaction Biology)にスポットして反応を停止させた。P81角形を45分間乾燥させ、50mM重炭酸ナトリウム(pH9.0)で5回、1回あたり10分間洗浄した。次いで、P81角形を1時間乾燥させ、10mLのUltima Goldシンチレーションカクテル(PerkinElmer)に加え、Beckmanシンチレーションカウンターを用いて分析した。
ASH1L SETをITC緩衝液(50mMリン酸ナトリウムpH7.5、50mM
NaCl、1mM TCEP)に対して4℃で広範囲に透析した。化合物126をDMSOに溶解し、ITC緩衝液で5%DMSO中0.1mMの最終濃度に希釈した。タンパク質溶液はDMSO最終濃度が5%になるように調整した。ASH1Lの安定性を維持するために、タンパク質と化合物の両方の溶液を50μM SAMに調整した。滴定は、VP-ITC滴定熱量測定システム(MicroCal)を使用して25℃で行った。ASH1L(10μM)を含有する熱量測定細胞を、10μl容積で注入される化合物(0.1mM)に滴定した。Origin 7.0(OriginLab)を使用してデータを解析し、熱力学的パラメーターを得た。
MA9(MLL-AF9形質転換)、HM2(Hoxa9/Meis1形質転換)マウス骨髄細胞(BMC)、MV4;11、及びMOL13ヒト白血病細胞を、24ウェルプレートに1×105細胞/mlで播種し、0.25%DMSOまたは化合物で処理し、37℃で12日間培養した。4日ごとに、DMSO処理した細胞の1×105個の細胞に相当する容積を遠沈させ、新鮮な化合物を加えた新鮮な培地に再懸濁した。0日目及び4日間隔ごとに、100μlアリコートの細胞懸濁液を4連の96ウェルプレートに移した。4連の試料を37℃で4日間インキュベートした後、MTT細胞増殖アッセイキット(Roche)を使用して生存細胞を測定した。PHERAstar(BMG)マイクロプレートリーダーを使用して570nmの吸光度を読み取った。
RNeasyミニキット(QIAGEN)を使用して全RNAを細胞から抽出した後、100~2000ngの全RNAをHigh Capacity cDNA Reverse Transcription Kit(Applied Biosystems)を使用して製造業者のプロトコールに従って逆転写した。CFX96リアルタイムPCR検出システム(Biorad)を使用してリアルタイムPCRを実施した。マウスGapdh(Mm99999915)、マウスAsh1l(Mm00467322)、マウスHoxa7(Mm00657963)、マウスHoxa9(Mm00439364)、マウスHoxa10(Mm00433966)、マウスMeis1(Mm00487664)、及びマウスB-アクチン(Mm00607939)用のTaqMan遺伝子発現マスターミックス及びTaqMan遺伝子発現アッセイをThermo Fisherから購入した。各遺伝子転写産物の相対的な定量化を、Biorad Real-Time PCR Applications Guideに記載される通り、ΔΔCt法を用いて実施した。
化合物で処理した1×105のMA9マウスBMCを採取し、Shandon EZ Single Cytofunnel(Thermo Fisher)に入れた。試料を600rpmで5分間遠心分離した。スライドを風乾した後、Hema-3キット(Thermo Fisher)で染色した。
以下の参考文献(その一部は、番号/文字によって上記に引用されている)は、その全体が参照により本明細書に組み込まれる。
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Claims (18)
- 式(I):
の構造を含む化合物またはその塩。
[式中、XはS、O、NH、またはCH2であり;
Lは0~3個のC、S、O、及び/またはNで構成され、Lの構成要素が0の場合、Lの位置に結合はなく;
は、0~5位がRD1-RD5置換基により置換されていてもよい5~7員のアリール、ヘテロアリール、炭素環、または複素環であり;
は、場合により存在する、
と環系を形成する4~7員の炭素環、複素環、アリール環、またはヘテロアリール環であり、0~5位がRG1-RG5置換基により置換されていてもよく;
Yは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Yの構成要素CまたはNのいずれかが場合により置換されていてもよく、Yの構成要素が0の場合、Yの位置に
の共有結合があり;
Zは0~3個のC、S、O及び/またはNで構成されるリンカーであり、その場合、Zの構成要素CまたはNのいずれかが場合により置換されていてもよく、Zの構成要素が0の場合、Zの位置に
の結合はなく;
は、0~5位がRA1-RA5置換基により置換されていてもよい5~7員のアリール、ヘテロアリール、炭素環、または複素環であり;
は、場合により存在する、
と環系を形成する5~7員の炭素環、複素環、アリール、またはヘテロアリールであり、0~5位がRE1-RE5置換基により置換されていてもよく;
は、場合により存在する、
と環系を形成する4~7員の炭素環、複素環、アリール、またはヘテロアリールであり、0~5位がRM1-RM5置換基により置換されていてもよく;かつ
式(I)、(I-A)、(I-B)、(I-C)、(I-D)、(I-E)、(I-F)、(I-G)、(I-H)、(I-I)、及び(I-J)のうちいずれか1つである化合物に存在する場合、R1、RD1-D5、RG1-G5、RA1-A5、RE1-E5、及びRM1-M5置換基のいずれかが、式(IIa~IIq):
のうちの1つであり;
式中、J、Q1、またはJ1のうち1つは、存在する場合、D環、G環、A環、E環、またはM環の1つに結合しており;
J、J1、J2、J3、及びJ4はそれぞれ、存在する場合、共有結合、H、アルキル1-15、アルケニル1-6、アルキニル1-6、(CH2)0-6C(S)NH2、(CH2)0-6C(O)NH2、O、S、NH、(CH2)0-6C(O)NH(CH2)1-6、(CH2)0-6NHC(O)(CH2)1-6、アルキルスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0-6C(S)NH(CH2)1-6、(CH2)0-6O(CH2)1-6、(CH2)0-6OH、(CH2)0-6S(CH2)1-6、(CH2)0-6SH、(CH2)0-6NH(CH2)1-6、(CH2)0-6N(CH2)1-6(CH2)1-6(例えば、化合物80を参照)、(CH2)0-6NH2、(CH2)0-6SO2(CH2)1-6、(CH2)0-6NHSO2(CH2)1-6、(CH2)0-6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0-6CH2F、(CH2)0-3CHF(CH2)0-2CH3、またはBr、Cl、もしくはIでの同様のもの)、ジハロアルキル(例えば、(CH2)0-6CF2H、(CH2)0-3CF2(CH2)0-2CH3、またはBr、Cl、もしくはIでの同様のもの)、トリハロアルキル(例えば、(CH2)0-6CF3、またはBr、Cl、もしくはIでの同様のもの)、鎖に沿って2つ以上の位置に1~3個のハロゲンを有するアルキル(例えば、化合物126、144、194、195、200、207、245、251などを参照)、(CH2)1-4SP(Ph)2=S(例えば、化合物52を参照)、(CH2)0-6NH(CH2)1-5OH、(CH2)0-6NH(CH2)1-5NH2、(CH2)0-6NH(CH2)1-5SH、(CH2)0-6O(CH2)1-5OH、(CH2)0-6O(CH2)1-5NH2、(CH2)0-6O(CH2)1-5SH、(CH2)0-6S(CH2)1-5OH、(CH2)0-6S(CH2)1-5NH2、(CH2)0-6S(CH2)1-5SH、(CH2)0-6O(CH2)1-6NH(CH2)1-5OH、(CH2)0-6O(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6O(CH2)1-6NH(CH2)1-5SH、(CH2)0-6O(CH2)1-6O(CH2)1-5OH、(CH2)0-6O(CH2)1-6O(CH2)1-5NH2、(CH2)0-6O(CH2)1-6O(CH2)1-5SH、(CH2)0-6O(CH2)1-6S(CH2)1-5OH、(CH2)0-6O(CH2)1-6S(CH2)1-5NH2、(CH2)0-6O(CH2)1-6S(CH2)1-5SH、(CH2)0-6S(CH2)1-6NH(CH2)1-5OH、(CH2)0-6S(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6S(CH2)1-6NH(CH2)1-5SH、(CH2)0-6S(CH2)1-6O(CH2)1-5OH、(CH2)0-6S(CH2)1-6O(CH2)1-5NH2、(CH2)0-6S(CH2)1-6O(CH2)1-5SH、(CH2)0-6S(CH2)1-6S(CH2)1-5OH、(CH2)0-6S(CH2)1-6S(CH2)1-5NH2、(CH2)0-6S(CH2)1-6S(CH2)1-5SH、(CH2)0-6NH(CH2)1-6NH(CH2)1-5OH、(CH2)0-6NH(CH2)1-6NH(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6NH(CH2)1-5SH、(CH2)0-6NH(CH2)1-6O(CH2)1-5OH、(CH2)0-6NH(CH2)1-6O(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6O(CH2)1-5SH、(CH2)0-6NH(CH2)1-6S(CH2)1-5OH、(CH2)0-6NH(CH2)1-6S(CH2)1-5NH2、(CH2)0-6NH(CH2)1-6S(CH2)1-5SH、(CH2)0-3C(O)O(CH2)0-3、(CH2)0-3C(S)O(CH2)0-3、(CH2)0-3C(O)S(CH2)0-3、(CH2)0-3C(S)S(CH2)0-3、(CH2)0-3C(O)NH(CH2)0-3、(CH2)0-3C(S)NH(CH2)0-3、(CH2)0-3NHC(O)(CH2)0-3、(CH2)0-3NHC(S)(CH2)0-3、(CH2)0-3OC(O)(CH2)0-3、(CH2)0-3OC(S)(CH2)0-3、(CH2)0-3SC(O)(CH2)0-3、(CH2)0-3SC(S)(CH2)0-3、(CH2)0-3NHC(O)NH(CH2)0-3、(CH2)0-3NHC(S)NH(CH2)0-3、(CH2)0-3OC(O)NH(CH2)0-3、(CH2)0-3OC(S)NH(CH2)0-3、(CH2)0-3SC(O)NH(CH2)0-3、(CH2)0-3SC(S)NH(CH2)0-3、(CH2)0-3NHC(O)O(CH2)0-3、(CH2)0-3NHC(S)O(CH2)0-3、(CH2)0-3OC(O)O(CH2)0-3、(CH2)0-3OC(S)O(CH2)0-3、(CH2)0-3SC(O)O(CH2)0-3、(CH2)0-3SC(S)O(CH2)0-3、(CH2)0-3NHC(O)S(CH2)0-3、(CH2)0-3NHC(S)S(CH2)0-3、(CH2)0-3OC(O)S(CH2)0-3、(CH2)0-3OC(S)S(CH2)0-3、(CH2)0-3SC(O)S(CH2)0-3、(CH2)0-3SC(S)S(CH2)0-3、(CH2O)1-6、及びトリメチルメタンからなる群から独立して選択され;
Q、Q1、及びQ2はそれぞれ、存在する場合、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンゾイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソオキサゾール、ベンゾイソオキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3-トリアジン;1,2,4-トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド類)、オキシラン(エチレンオキシド類、エポキシド類)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソオキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ピペラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、トリチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3-シクロヘキサジエン、1,4-シクロヘキサジエン、1,5-シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3~C7シクロアルキル基、及び表1a、1b、2、3、4または5に示す環構造のいずれかからなる群から独立して選択され;
Q、Q1、及びQ2はそれぞれ、存在する場合、Q環上の任意の位置に1つ以上の追加のJ基が存在してもよく;
上記のいずれのアルキル基または(CH2)x-y基も、直鎖であっても分枝鎖であってもよく;
上記のいずれのアルキル基または(CH2)x-y基も、1個以上の炭素に、OH、=O、NH2、CN、ジハロアルキル、トリハロアルキル、またはハロゲンの置換基をさらに含んでもよく;
上記の基の末端位置の水素数は、上記の基が追加の基と結合されているか、または上記の基が末端にあるかに応じて調整される場合があり;ならびに
式(IIa~q)のいずれかが、末端フルオロフォア、固体表面、酵素リガンド、または親和性タグをさらに含んでもよい] - 前記化合物が、表6もしくは表7に示す化合物または表6もしくは表7に示す化合物に存在する置換基の組み合わせによって得られる化合物から選択される、請求項1または2に記載の化合物。
- 先行請求項のいずれか1項に記載の化合物及び薬学的に許容される担体を含む医薬組成物。
- 前記医薬組成物が経口投与用に製剤化される、請求項4に記載の医薬組成物。
- 前記医薬組成物が注射用に製剤化される、請求項4に記載の医薬組成物。
- ASH1Lを有効量の請求項1~3のいずれか1項に記載の化合物と接触させることを含む、ASH1Lの活性を阻害する方法。
- 前記接触工程に、ASH1Lを発現する細胞との接触を含む、請求項7に記載の方法。
- 分解酵素のリガンドに結合された有効量の請求項1~3のいずれか1項に記載の化合物とASH1Lを接触させることを含む、ASH1Lを分解する方法。
- 前記接触工程に、ASH1Lを発現する細胞との接触を含む、請求項9に記載の方法。
- ASH1Lの活性を阻害するのに有効な量で、請求項4~6のいずれか1項に記載の医薬組成物を対象に投与することを含む、疾患の治療方法。
- 前記疾患ががんである、請求項11に記載の方法。
- 前記疾患または病態が白血病、血液悪性腫瘍、固形腫瘍癌、乳癌、前立腺癌、肝臓癌、または甲状腺癌を含む、請求項12に記載の方法。
- 前記疾患または病態が、AML、ALL、混合系統白血病、またはMLLの部分的タンデム重複を伴う白血病を含む、請求項13に記載の方法。
- 11q23番染色体の染色体再編成が媒介する障害の治療を必要とする対象での治療方法であって、前記方法が請求項1または2のいずれか1項に記載の化合物の治療有効量を前記対象に投与することを含む、前記治療方法。
- 前記医薬組成物を追加治療薬と共投与する、請求項12に記載の方法。
- 前記対象がヒトである、請求項11に記載の方法。
- 請求項1~3のいずれか1項に記載の化合物の疾患治療への使用。
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JP2021502388A (ja) * | 2017-11-10 | 2021-01-28 | ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン | Ash1l阻害剤及びそれを用いた治療方法 |
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AU2023200873A1 (en) | 2023-03-16 |
CN109414596B (zh) | 2023-09-29 |
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