JP2017526726A - ヘテロ環化合物およびその用途 - Google Patents
ヘテロ環化合物およびその用途 Download PDFInfo
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- JP2017526726A JP2017526726A JP2017514422A JP2017514422A JP2017526726A JP 2017526726 A JP2017526726 A JP 2017526726A JP 2017514422 A JP2017514422 A JP 2017514422A JP 2017514422 A JP2017514422 A JP 2017514422A JP 2017526726 A JP2017526726 A JP 2017526726A
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- Prior art keywords
- alkyl
- nhr
- substituents
- nhc
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- 125000003944 tolyl group Chemical group 0.000 description 1
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- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
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- 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
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- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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- 229940078499 tricalcium phosphate Drugs 0.000 description 1
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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- 150000004917 tyrosine kinase inhibitor derivatives Chemical group 0.000 description 1
- GFNNBHLJANVSQV-UHFFFAOYSA-N tyrphostin AG 1478 Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1 GFNNBHLJANVSQV-UHFFFAOYSA-N 0.000 description 1
- TUCIOBMMDDOEMM-RIYZIHGNSA-N tyrphostin B42 Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCC1=CC=CC=C1 TUCIOBMMDDOEMM-RIYZIHGNSA-N 0.000 description 1
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- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 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
- 208000024523 vestibulocochlear nerve neoplasm Diseases 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-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
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 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
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229960000641 zorubicin Drugs 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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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
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Abstract
Description
本出願は35U.S.C.§119(e)により、2014年9月15日に出願された米国仮出願第62/050,723号の利益を主張するものであり、該出願は参照することにより本願明細書に組み込まれる。
[式中:
(i)Y1およびY2はNであり、Y3はCR2であり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;
(ii)Y1はCであり、Y2はNであり、Y3はNR2であり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;
(iii)Y1はNであり、Y2はCHであり、Y3はCR2であり、Y4はNであり、かつ、Y5はNであるか;
(iv)Y1はNであり、Y2はCHであり、Y3はNであり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;または
(v)Y1はCであり、Y2はCHであり、Y3はNR2であり、Y4はNであり、かつ、Y5はNであり;
Lは置換されていてもよいC1−4アルキレン、置換されていてもよい重水素化C1−4アルキレン、または置換されていてもよい−C(R4)(R5)であり、ここでR4およびR5はそれぞれ独立してH、D、ハロゲン、−OH、C1−6アルキル、重水素化C1−6アルキル、C2−6アルケニル、C2−6アルキニル、アリール、アリール−C1−4アルキル、C1−6アルコキシ、C3−6シクロアルキル、C3−6シクロアルキル−C1−4アルキル、ヘテロシクロアルキル、ヘテロシクロアルキル−C1−4アルキル、ヘテロアリール、ヘテロアリール−C1−4アルキル、C1−6ハロアルキル、C1−6ハロアルコキシ、もしくはRaであるか;またはR4およびR5はそれらが結合している炭素原子と一緒になってO、N、およびSから選択される0〜2個のヘテロ原子もしくはオキソを有する置換されていてもよい3〜6員環を形成し;ここで、Raはハロゲン、CN、−OH、−NH2、−NO2、−C(O)OH、−C(S)OH、−C(O)NH2、−C(S)NH2、−S(O)2NH2、−NHC(O)NH2、−NHC(S)NH2、−NHS(O)2NH2、−C(NH)NH2、−ORb、−SRb、−OC(O)Rb、−OC(S)Rb、−C(O)Rb、−C(S)Rb、−C(O)ORb、−C(S)ORb、−S(O)Rb、−S(O)2Rb、−C(O)NHRb、−C(S)NHRb、−C(O)NRbRb、−C(S)NRbRb、−S(O)2NHRb、−S(O)2NRbRb、−C(NH)NHRb、−C(NH)NRbRb、−NHC(O)Rb、−NHC(S)Rb、−NRbC(O)Rb、−NRbC(S)Rb、−NHS(O)2Rb、−NRbS(O)2Rb、−NHC(O)NHRb、−NHC(S)NHRb、−NRbC(O)NH2、−NRbC(S)NH2、−NRbC(O)NHRb、−NRbC(S)NHRb、−NHC(O)NRbRb、−NHC(S)NRbRb、−NRbC(O)NRbRb、−NRbC(S)NRbRb、−NHS(O)2NHRb、−NRbS(O)2NH2、−NRbS(O)2NHRb、−NHS(O)2NRbRb、−NRbS(O)2NRbRb、−NHRb、Rb、および−NRbRbから選択され、ここで各RbはC1−6アルキル、アリール、アリール−C1−4アルキル、C3−6シクロアルキル、C3−6シクロアルキル−C1−4アルキル、ヘテロアリール、ヘテロアリール−C1−4アルキル、ヘテロシクロアルキル、およびヘテロシクロアルキル−C1−4アルキルから独立して選択され、そのそれぞれは置換されていてもよく;または同一の窒素原子と結合している2個のRb基はそれらが結合している窒素原子と一緒になって置換されていてもよい4、5、もしくは6員環を形成し;
R1は水素、D、置換されていてもよいアリール、置換されていてもよいシクロアルキル、置換されていてもよいヘテロアリール、または置換されていてもよいヘテロシクロアルキルであり;
R2は水素、D、ハロゲン、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいアリール−C1−2アルキル、または置換されていてもよいヘテロアリール−C1−2アルキルであり;
R3は環員としてO、N、およびSから選択される1〜4個のヘテロ原子を有する5員ヘテロアリールであり、ここで該ヘテロアリールは1〜2個のC1−2アルキルで置換され、該アルキルはハロゲン、OH、およびCNから独立して選択される1〜3個のメンバーで置換されていてもよく;かつ、
記号
で示される化合物、またはその医薬的に許容される塩、プロドラッグ、溶媒和物、水和物、互変異性体、異性体、もしくは重水素化類似体を提供する。
I.定義
特段の記載がない限り、本願明細書で用いられている用語には以下の定義が適用される。
本開示は、ブロモドメインの調節因子である式(I)、(II)、(Ia)、(Ia−1)、(Ia−2)、(Ib)、(Ib−1)、(Ib−2)、(Ic)、(Id)、(Id−1)、(Id−2)、または(Ie)、および全ての部分一般式で示される化合物、特許請求の範囲に記載された化合物、ならびに本願明細書に記載された化合物、ならびに疾患または状態の治療における該化合物の使用に関する。
1つの態様では、本開示は式(I):
[ここで可変基R1、R2、R3、L、Y1、Y2、Y3、Y4、Y5、および記号
で示される化合物、またはその医薬的に許容される塩、プロドラッグ、溶媒和物、互変異性体、異性体、もしくは重水素化類似体を提供する。式(I)で示される化合物のいくつかの実施態様では、R3は環員としてO、N、およびSから選択される1〜3個のヘテロ原子を有する6員ヘテロアリールまたは6員ヘテロシクロアルキルであり、ここで該ヘテロアリールまたはヘテロシクロアルキルは1〜2個のメチルまたはエチル基で置換されている。式(I)で示される化合物の1つの実施態様では、記号
CH2CH3、−O−CH(CH3)2、−Cl、−F、−CH2F、−CHF2、CF3、−OCF3、−OCHF2、−OCH2F、C1−6アルキル、4−モルホリニル、4−モルホリニルカルボニル、シクロプロピル、シクロプロピルメチル、シクロプロピルカルボニル、1−ピペラジニル、4−メチル−1−ピペラジニル、1−ピロリジニル、1−ピペラジニルカルボニル、1−ピペリジニルカルボニル、1−ピロリジニルカルボニル、ジメチルアミノ、2−(4−モルホリニル)エトキシ、3−メトキシプロポキシ、アセトアミド、プロパノイル、メチルスルホニルアミノ(methylsofonylamino)、メチルスルホニル、プロパノイルアミノ、ジメチルカルバモイル、およびエトキシカルボニルアミノから独立して選択される1〜3個のRq基で置換されていてもよい。他の場合では、Riはハロゲン、C1−6アルキル、フェニル、全重水素化フェニル、ベンジル、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、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロヘキシルメチル、2−ピリジル、3−ピリジル、4−ピリジル、2−チアゾリル、4−チアゾリル、5−チアゾリル、3−ピラゾリル、4−ピラゾリル、2−ピリミジニル、4−ピリミジニル、5−ピリミジニル、2−オキサゾリル、5−オキサゾリル、4−オキサゾリル、2−チオフェニル、3−チオフェニル、1−ピペリジニル、4−ピペリジニル、4−モルホリニル、4−モルホリニルカルボニル、シクロプロピルカルボニル、1−ピペラジニル、4−メチル−1−ピペラジニル、1−ピロリジニル、1−ピペラジニルカルボニル、1−ピペリジニルカルボニル、1−ピロリジニルカルボニル、ジメチルアミノ、2−(4−モルホリニル)エトキシ、3−メトキシプロポキシ、ジメチルカルバモイル、アセトアミド、プロパノイル、4−チオモルホリノ、4−チオモルホリノ−S,S−オキシド、1−ピロリジニル、メチルスルホニルアミノ、メチルスルホニル、プロパノイルアミノ、1−シクロペンテニル、1−シクロヘキセニル、1,2,3,6−テトラヒドロピリジン−4−イル、1,2,3,6−テトラヒドロピリジン−5−イル、2,5−ジヒドロ−1H−ピロール−3−イル、2,5−ジヒドロ−ピロール−1−イル、もしくは2−ノルボルニルであり、そのそれぞれは1〜3個のRq基で置換されていてもよく;または芳香環上の2個の隣接するRk基は一緒になって、環員としてO、N、およびSから選択される0〜2個のヘテロ原子を有する5または6員環を形成し、ここで5または6員環は1〜2個のRq基で置換されていてもよい。他の場合では、Ri、Rm、またはRkはそれぞれ独立してC1−6アルキルまたはC1−4アルコキシであり、そのそれぞれはC1−6アルキル、メトキシ、フェニル、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、2−ピリジル、3−ピリジル、4−ピリジル、2−チアゾリル、4−チアゾリル、5−チアゾリル、3−ピラゾリル、4−ピラゾリル、2−ピリミジニル、4−ピリミジニル、5−ピリミジニル、2−オキサゾリル、5−オキサゾリル、4−オキサゾリル、2−チオフェニル、3−チオフェニル、1−ピペリジニル、4−ピペリジニル、および4−モルホリニルから選択されるメンバーで置換されていてもよい。さらに他の場合では、RnはC1−6アルキル、−CN、−OCH3、−OCH2CH3、−O−CH(CH3)2、−Cl、−F、−CH2F、−CHF2、CF3、−OCF3、−OCHF2、−OCH2F、−NH−C1−6アルキル、および−N(C1−6アルキル)(C1−6アルキル)から選択される。その他の全ての可変基は、本願明細書に記載された式(I)の実施態様のいずれかに定義した通りである。
いくつかの実施態様では、式(I)で示される化合物は、部分式(Ia):
[式中、Y4はCHまたはNである]を有する。1つの実施態様では、Y4はNである。別の実施態様では、Y4はCHである。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
[式中、Y4はCHまたはNである]を有する。1つの実施態様では、Y4はNである。別の実施態様では、Y4はCHである。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
[式中、Y4はCHまたはNである]を有する。1つの実施態様では、Y4はNである。別の実施態様では、Y4はCHである。可変基および置換基R1、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
を有する。可変基および置換基R1、R2、R3、およびLは、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
[式中、
Eは水素または重水素であり、
(i)Y1およびY2はNであり、Y3はCR2であり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;
(ii)Y1はCであり、Y2はNであり、Y3はNR2であり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;
(iii)Y1はNであり、Y2はCHであり、Y3はCR2であり、Y4はNであり、かつ、Y5はNであるか;
(iv)Y1はNであり、Y2はCHであり、Y3はNであり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;または
(v)Y1はCであり、Y2はCHであり、Y3はNR2であり、Y4はNであり、かつ、Y5はNである]
を有する。
いくつかの実施態様では、R1およびR5置換基が結合したキラル炭素中心はR立体配置を有する。他の実施態様では、R1およびR5置換基が結合したキラル炭素中心はS立体配置を有する。いくつかの実施態様では、式(II)で示される化合物の光学純度は、90、92、95、97、99、または99.9%鏡像体過剰率より大きい。他の実施態様では、式(II)で示される化合物の光学純度は、100%鏡像体過剰率である。1つの実施態様では、式(II)で示される化合物はRエナンチオマーである。別の実施態様では、式(II)で示される化合物はSエナンチオマーである。可変基および置換基R1、R2、R3、およびR5は、式(I)で示される化合物の実施態様のいずれかまたは本願明細書に記載されたいずれかの実施態様に定義した通りである。
潜在的調節因子の製造を促進する多様な有機合成技術が当該技術分野に存在する。これらの有機合成方法の多くは、当業者が利用する標準的な参考文献に詳細に記載されている。該参考文献の1例として、1994年3月発行の、Advanced Organic Chemistry;Reactions,Mechanisms and Structure,New York,McGraw Hillを挙げることができる。それゆえ、ブロモドメイン機能の潜在的調節因子を合成するのに有用な技術は、有機化学合成の当業者が容易に利用することができる。
本願明細書で意図されている化合物は、一般式および特定の化合物の両方を参照して記載されている。さらに、本開示の化合物は多数の異なる形態または誘導体で存在してよいが、それらは全て本開示の範囲内に包含される。代替的形態または誘導体は、例えば、(a)プロドラッグ、および活性代謝物、(b)互変異性体、異性体(立体異性体および位置異性体を含む)、およびラセミ混合物、(c)医薬的に許容される塩、ならびに(d)固体形態、例えば異なる結晶形、多形、または非晶質固体、例えばその水和物および溶媒和物、ならびに他の形態を含む。
本願明細書の式および本願明細書に記載された化合物に加えて、本開示はプロドラッグ(一般的には医薬的に許容されるプロドラッグ)、活性代謝誘導体(活性代謝物)、およびそれらの医薬的に許容される塩も含む。
いくつかの化合物は互変異性を示してもよいと理解されたい。そのような場合、本願明細書で提供されている式は、可能な互変異性体型の1つだけを明示的に示している。それゆえ、本願明細書で提供されている式は示された化合物のいずれかの互変異性体型を表すことを意図しており、化学式によって示された特定の互変異性体型のみに限定されないことを理解されたい。
特に反対の記載がない限り、本願明細書での化合物の特定は、該化合物の医薬的に許容される塩を含む。それゆえ、本願明細書に記載され、特許請求の範囲のいずれかに記載された化合物は、医薬的に許容される塩の形態であってよく、または医薬的に許容される塩として製剤化されてよい。意図される医薬的に許容される塩形態は、限定されるものではないが、モノ、ビス、トリス、およびテトラキス等を含む。医薬的に許容される塩は、それらが投与される量および濃度で無毒性である。該塩の製造は、その生理的効果の発揮を妨げることなく化合物の物理的特性を変化させることによって、薬理学的使用を促進しうる。物性の有用な変化は、例えば融点を低下させて経粘膜投与を促進することや、溶解度を増加させてより高濃度の薬物の投与を促進することを含む。本開示の化合物は、十分に酸性の官能基、十分に塩基性の官能基、または両方の官能基を有してもよく、それによって多数の無機または有機塩基のいずれか、ならびに無機および有機酸のいずれかと反応して医薬的に許容される塩を形成してもよい。
薬剤が固体である場合、化合物および塩は異なる結晶形もしくは多形で存在してよく、または共結晶として製剤化されてよく、または非晶質形であってよく、またはそのいずれかの組み合わせ(例えば部分的結晶、部分的非晶質、または多形の混合物)であってよく、その全ては本開示および特定された式の範囲内に包含されることを意図していることを当業者は理解できるであろう。塩が酸/塩基付加によって形成される、すなわち、対象化合物の遊離塩基または遊離酸がそれぞれ対応する付加塩基または付加酸と酸/塩基反応を形成し、イオン電荷相互作用をもたらす一方、共結晶は中性化合物の間に形成される新たな化学種であり、同一の結晶構造中に存在する化合物と付加的な分子種をもたらす。
別の態様では、本開示は、医薬的に許容される担体、賦形剤、および/または希釈剤、ならびに本願明細書に記載された本開示の化合物またはその医薬的に許容される塩もしくは溶媒和物を含む医薬組成物を提供する。例となる実施態様では、本開示は、本願明細書に記載された化合物を含む医薬製剤を提供する。いくつかの実施態様では、本開示は、式(I)、(II)、(Ia)、(Ia−1)、(Ia−2)、(Ib)、(Ib−1)、(Ib−2)、(Ic)、(Id)、(Id−1)、(Id−2)、もしくは(Ie)のいずれか、または本願明細書に記載された部分一般式のいずれかを有する化合物、または本願明細書に記載された化合物、ならびに医薬的に許容される担体、賦形剤、および/または希釈剤を含む医薬組成物を提供する。
ブロモドメインに関連する例示的な疾患
式(I)、(II)、(Ia)、(Ia−1)、(Ia−2)、(Ib)、(Ib−1)、(Ib−2)、(Ic)、(Id)、(Id−1)、(Id−2)、もしくは(Ie)、またはその部分式のいずれかで示される化合物、および本願明細書に記載された化合物は、エピジェネティック調節に関与する1個以上のタンパク質、例えば、ブロモドメインとしても知られているアセチル−リジン認識モチーフを含有するタンパク質(例えば、BETタンパク質、例えばBRD2、BRD3、BRD4、および/またはBRDT等)等に関連する障害、例えば、ブロモドメインの異常発現に関連する疾患、特に細胞増殖性障害、癌、慢性自己免疫状態、または炎症状態の治療に有用である。
活性調節因子をアッセイし、および/または特定のブロモドメインもしくは基についての調節因子の特異性を決定するために、ブロモドメイン活性用の多数の異なるアッセイを利用することができる。以下の実施例に記載しているアッセイに加えて、当業者であれば、利用することができる他のアッセイを知ることができ、特定の適用のためにアッセイを修正することができるであろう。
別の態様では、本開示はブロモドメインタンパク質を調節または阻害する方法を提供する。該方法は、式(I)、(II)、(Ia)、(Ia−1)、(Ia−2)、(Ib)、(Ib−1)、(Ib−2)、(Ic)、(Id)、(Id−1)、(d−2)、もしくは(Ie)、もしくは本願明細書に記載された部分一般式のいずれかで示される化合物のいずれか、表1に記載されている化合物、もしくは本願明細書に記載された化合物、もしくはその医薬的に許容される塩、水和物、溶媒和物、互変異性体、もしくは異性体、または本願明細書に記載された式のいずれかで示される化合物を含む組成物の有効量を対象に投与し、それによって、ブロモドメインを調節または阻害する工程を含む。いくつかの実施態様では、該方法は、細胞をインビボまたはインビトロで、式(I)、(II)、(Ia)、(Ia−1)、(Ia−2)、(Ib)、(Ib−1)、(Ib−2)、(Ic)、(Id)、(Id−1)、(Id−2)、もしくは(Ie)、もしくは本願明細書に記載された部分式のいずれかで示される化合物、表1に記載されている化合物、もしくは本願明細書に開示されている化合物、もしくはその医薬的に許容される塩、水和物、溶媒和物、互変異性体、もしくは異性体、または本願明細書に記載された式のいずれかで示される化合物を含む組成物と接触させる工程を含む。
別の態様では、本開示は、ブロモドメインの阻害が役割を果たすかまたは有用性を提供するブロモドメイン媒介性疾患または状態を患うか、またはその危険性がある対象を治療する方法を提供する。該方法は、式(I)、(II)、(Ia)、(Ia−1)、(Ia−2)、(Ib)、(Ib−1)、(Ib−2)、(Ic)、(Id)、(Id−1)、(Id−2)、もしくは(Ie)のいずれかで示される化合物、実施例に開示された化合物、表1に記載されている化合物、もしくは本願明細書に記載された化合物、もしくはその医薬的に許容される塩、水和物、溶媒和物、互変異性体、もしくは異性体、または本願明細書に記載された式のいずれかで示される化合物を含む組成物の有効量を対象に投与する工程を含む。特定の実施態様では、該方法は本願明細書に記載されたいずれか1個または複数の化合物の有効量を、該疾患または状態のための1個以上の他の治療または治療剤と組み合わて対象に投与する工程を伴う。いくつかの実施態様では、該方法は本願明細書に記載されたいずれか1個または複数の化合物の有効量を、該疾患または状態のための1個以上の他の治療剤と組み合わせて対象に投与する工程を伴う。いくつかの実施態様では、ブロモドメインはBETファミリーのメンバーである。
ブロモドメイン調節因子は、特に本願明細書に記載された癌、他の疾患、および適応症の治療において別の薬理活性化合物、または2個以上の他の薬理活性化合物と有用に組み合わせてもよい。1つの実施態様では、組成物は同一の適応症について治療上有効な1個以上の化合物であって、該適応症に対して相乗効果を有する化合物と共に本願明細書に記載されたいずれか1個または複数の化合物を含む。1つの実施態様では、該組成物は癌を治療するのに有効な本願明細書に記載されたいずれか1個または複数の化合物と、同一の癌を治療するのに有効な1個以上の他の化合物であって、さらに該癌を治療するのに相乗的に有効な化合物を含む。
以下の実施例は例示目的で提供されており、本開示を限定するものではない。
1−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル]−4−ニトロベンゼンスルホネート(中間体A)
スキーム1.
水浴中で冷却したエチル 4,4−ジフルオロシクロヘキサンカルボキシレート(1、11.5g、60mmol)のテトラヒドロフラン(「THF」)(200ml)溶液に、重水素化リチウムアルミニウム(3.2g、76mmol)を加えた。反応を室温で一晩攪拌した。反応に硫酸ナトリウム十水和物(〜10g)を加え、一晩攪拌した。反応を濾過し、酢酸エチルで洗浄し、濃縮し、粗生成物2(〜9.0g、98%)を得た。
ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メタノール(2、9g、59mmol)の塩化メチレン(150ml)溶液に、トリエチルアミン(17mL、121.97mmol)および4−ニトロベンゼンスルホニルクロライド(14.42g、65.06mmol)を加えた。反応を室温で一晩攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、10%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物中間体A(16.0g、80%)を得た。
2−[ブロモ(フェニル)メチル]ピリジン(中間体B)
スキーム2.
氷浴中(0℃)で冷却したフェニル(2−ピリジル)メタノン(5.1g、27.84mmol)のメタノール(100ml)溶液に、水素化ホウ素ナトリウム(1.08mL、30.62mmol)を加えた。反応を室温まで一晩温めた。反応を濃縮し、次いで1N HClを加えて粗生成物を溶解した。粗生成物を水性炭酸カリウムに注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、粗生成物4(4.9g、95%)を得た。
氷浴中(0℃)で冷却したフェニル(2−ピリジル)メタノール(4.4g、23.76mmol)の塩化メチレン(150ml)溶液に、臭化チオニル(3.3mL、42.76mmol)を加えた。反応を室温まで一晩温めた。反応を濃縮し、水性炭酸カリウムに注ぎ、酢酸エチルで抽出した。有機層を水および食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜80%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物中間体Bをピンク色がかった固体(4.9g、83%)として得た。
4−[5−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル]−3−(3,5−ジメチルイソオキサゾール−4−イル)ピロロ[2,3−b]ピラジン−7−イル]安息香酸(P−2044)
スキーム3.
3−ブロモ−5H−ピロロ[2,3−b]ピラジン(1g、5.05mmol)のジメチルホルムアミド(25ml)溶液に、室温で水素化ナトリウム(60%、300mg、7.5mmol)を加えた。10分後、1−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル] 4−ニトロベンゼンスルホネート(中間体A、1.8g、5.34mmol)を加えた。反応を室温で一晩攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、20%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物6(1.5g、89%)を得た。
3−ブロモ−5−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル]ピロロ[2,3−b]ピラジン(6、0.3g、0.9mmol)のアセトニトリル(12ml)溶液に、3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(0.3g、1.34mmol)、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.05g、0.07mmol)、および1M炭酸カリウムの水(5ml)溶液を加えた。反応をマイクロ波照射下にて125℃で35分間加熱した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、2%〜15%メタノールの塩化メチレン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2038(0.28g、89%)MS(ESI)MH(+)=349.1を得た。
4−[5−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル]ピロロ[2,3−b]ピラジン−3−イル]−3,5−ジメチル−イソオキサゾール(7、0.27g、0.775mmol)のアセトニトリル(20mL)溶液に、室温でN−ヨードスクシンイミド(0.2g、0.9mmol)を加えた。反応を週末にかけて室温で攪拌した。反応を水性炭酸カリウムに注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、20%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2039(0.3g、82%)MS(ESI)MH(+)=475.1を得た。
4−[5−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル]−7−ヨード−ピロロ[2,3−b]ピラジン−3−イル]−3,5−ジメチル−イソオキサゾール(P−2039、0.07g、0.15mmol)のTHF(18ml)溶液に、メチル 4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾエート(0.05g、0.19mmol)、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.02g、0.03mmol)、および1M炭酸カリウムの水(8ml)溶液を加えた。反応を70℃で2時間攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、20%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2043(0.05g、70%)MS(ESI)MH(+)=483.2を得た。
メチル 4−[5−[ジジュウテリオ−(4,4−ジフルオロシクロヘキシル)メチル]−3−(3,5−ジメチルイソオキサゾール−4−イル)ピロロ[2,3−b]ピラジン−7−イル]ベンゾエート(P−2043、0.04g、0.08mmol)のTHF(3ml)溶液に、2M水酸化リチウム(2ml)を加えた。反応混合物を60℃で3時間攪拌した。反応を水に注ぎ、1NのHCl(4mL)でpH〜6まで酸性化し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮乾固し、酢酸エチルおよびヘキサンで洗浄し、生成物P−2044(35mg、89%)MS(ESI)MH(+)=468.9を得た。
3,5−ジメチル−4−[3−(1−メチルピラゾール−4−イル)−1−[フェニル(2−ピリジル)メチル]インダゾール−6−イル]イソオキサゾール(P−2004)
スキーム4.
6−ブロモ−1H−インダゾール(11、1.2g、6.09mmol)のアセトニトリル(60ml)溶液に、3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(2.04g、9.14mmol)、1M炭酸カリウムの水(20ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.46g、0.61mmol)を加えた。反応混合物を油浴中100℃で16時間加熱した。反応が完了しなかったため、追加の3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(1グラム)および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(300mg)を反応混合物に加え、100℃で6時間加熱した。この手順をさらに5回繰り返し、反応を完了させた。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜80%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物12(553mg、43%)MS(ESI)MH(+)=213.9を得た。
氷浴中で0〜5℃まで冷却した4−(1H−インダゾール−6−イル)−3,5−ジメチル−イソオキサゾール(12、0.55g、2.58mmol)のN,N−ジメチルホルムアミド(10ml)溶液に、水酸化カリウム(0.579g、10.3mmol)とヨウ素(1.31g、5.16mmol)を加えた。得られた混合物を室温まで温め、4時間攪拌した。反応混合物を飽和チオ硫酸ナトリウム(Na2S2O3)溶液(10mL)でクエンチし、酢酸エチルで抽出した(2x200mL)。合わせた有機層を飽和チオ硫酸ナトリウム(Na2S2O3)溶液(10mL)、水、食塩水で洗浄し、次いで硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物13(745mg、85%)MS(ESI)MH(+)=339.7を得た。
4−(3−ヨード−1H−インダゾール−6−イル)−3,5−ジメチル−イソオキサゾール(13、0.25g、0.74mmol)のTHF(20ml)溶液に、炭酸セシウム(0.72g、2.21mmol)と2−[ブロモ(フェニル)メチル]ピリジン(0.22g、0.88mmol)を加えた。混合物を50℃まで17時間加熱した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜80%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2003(192mg、51%)MS(ESI)MH(+)=507.1を得た。
4−[3−ヨード−1−[フェニル(2−ピリジル)メチル]インダゾール−6−イル]−3,5−ジメチル−イソオキサゾール(P−2003、0.03g、0.06mmol)のアセトニトリル(4ml)溶液に、1−メチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピラゾール(0.02g、0.08mmol)、1M炭酸カリウムの水(1.5ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(5mg、0.006mmol)を加えた。反応混合物をマイクロ波反応器内にて120℃で30分間加熱した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、不純な生成物P−2004を得た。RP−HPLCを用いてこの物質をさらに精製し、生成物P−2004(2.6mg、9%)MS(ESI)MH(+)=461.0を得た。
3,5−ジメチル−4−[1−[フェニル(2−ピリジル)メチル]イミダゾ[4,5−b]ピリジン−6−イル]イソオキサゾール(P−2103)および3,5−ジメチル−4−[3−[フェニル(2−ピリジル)メチル]イミダゾ[4,5−b]ピリジン−6−イル]イソオキサゾール(P−2104)
スキーム5.
6−ブロモ−1H−イミダゾ[4,5−b]ピリジン(16、0.2g、1.01mmol)のTHF(20ml)溶液に、炭酸セシウム(0.99g、3.03mmol)と2−[ブロモ(フェニル)メチル]ピリジン(0.28g、1.11mmol)を加えた。混合物を70℃で一晩攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物17(190mg、51%)および生成物18(80mg、22%)を得た。
6−ブロモ−1−[フェニル(2−ピリジル)メチル]イミダゾ[4,5−b]ピリジン(17、0.08g、0.22mmol)のアセトニトリル(3ml)溶液に、3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(0.07g、0.29mmol)、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.05g、0.07mmol)、および1M炭酸カリウムの水(1.2ml)溶液を加えた。反応をマイクロ波中、160℃で15分間加熱した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥し、濃縮し、5%〜15%メタノールの塩化メチレン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、P−2103を得た。生成物をRP−HPLC(5〜90%)によってさらに精製し、生成物P−2103(11mg、27%)MS(ESI)MH(+)=381.9を得た。
6−ブロモ−3−[フェニル(2−ピリジル)メチル]イミダゾ[4,5−b]ピリジン(18、0.09g、0.24mmol)のアセトニトリル(3ml)溶液に、3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(0.07g、0.31mmol)、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.05g、0.07mmol)、および1M炭酸カリウムの水(1.2ml)溶液を加えた。反応をマイクロ波中、160℃で15分間加熱した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥し、濃縮し、5%〜15%メタノールの塩化メチレン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2104(6.5mg、7%)MS(ESI)MH(+)=381.8を得た。
6−[7−[(4,4−ジフルオロシクロヘキシル)メチル]−2−(3,5−ジメチルイソオキサゾール−4−イル)ピロロ[2,3−b]ピラジン−5−イル]ピリジン−3−カルボン酸(P−2078)
スキーム6.
2−ブロモ−5H−ピロロ[2,3−b]ピラジン(21、1.36g、6.87mmol)のアセトニトリル(51ml)溶液に、窒素下で3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(1.87g、8.39mmol)、1M炭酸カリウムの水(17ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.2g、0.26mmol)を加えた。反応をマイクロ波中、160℃で20分間加熱した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、0%〜60%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物22(1.118g、76%)を得た。
3,5−ジメチル−4−(5H−ピロロ[2,3−b]ピラジン−2−イル)イソオキサゾール(22、1.11g、5.18mmol)のメタノール(50mL)溶液に、4,4−ジフルオロシクロヘキサンカルバルデヒド(0.9g、6.08mmol)と水酸化カリウム(1.0g、17.8mmol)を加えた。反応を室温で一晩攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥し、濃縮し、0%〜40%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物23(0.5g、27%)を得た。
(4,4−ジフルオロシクロヘキシル)−[2−(3,5−ジメチルイソオキサゾール−4−イル)−5H−ピロロ[2,3−b]ピラジン−7−イル]メタノール(23、0.5g、1.38mmol)のジクロロエタン(50ml)溶液に、トリフルオロ酢酸(1mL、12.98mmol)とトリエチルシラン(2mL、12.52mmol)を加えた。反応を80℃で2時間攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、0%〜60%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2077(350mg、73%)MS(ESI)MH(+)=346.9を得た。
4−[7−[(4,4−ジフルオロシクロヘキシル)メチル]−5H−ピロロ[2,3−b]ピラジン−2−イル]−3,5−ジメチル−イソオキサゾール(P−2077、0.1g、0.29mmol)のN−メチル−2−ピロリドン(「NMP」)(20ml)溶液に、エチル 6−クロロピリジン−3−カルボキシレート(0.125g、0.67mmol)と炭酸セシウム(1g、3.07mmol)を加えた。反応を80℃で一晩攪拌した。LCMSは反応が完了していないことを示した。反応をマイクロ波中、180℃で20分間加熱した。LCMSは反応が完了したことを示した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、0%〜60%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、分取RP−HPLCによってさらに精製し、生成物P−2078(34mg、25%)MS(ESI)MH(+)=468.9を得た。
2−[4−[6−(3,5−ジメチルイソオキサゾール−4−イル)−1−[(1S)−1−(2−ピリジル)エチル]ピラゾロ[4,3−b]ピリジン−3−イル]フェニル]酢酸(P−2094)
スキーム7.
6−ブロモ−1H−ピラゾロ[4,3−b]ピリジン(26、2.17g、10.96mmol)のTHF(50ml)溶液に、トリエチルアミンと4−メチルベンゼンスルホニルクロライド(2.3g、12.05mmol)を加えた。反応混合物を室温で20時間攪拌した。反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を減圧濃縮して固体27を得、そのまま次の反応に用いた。
6−ブロモ−1−(p−トリルスルホニル)ピラゾロ[4,3−b]ピリジン(27、3.0g、8.52mmol)のアセトニトリル(30ml)溶液に、3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(2.47g、11.07mmol)、1M炭酸カリウムの水(15ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(661mg、0.85mmol)を加えた。反応混合物をマイクロ波反応器中、110℃まで15分間加熱した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜100%のジクロロメタンのヘキサン溶液、次いで0%〜20%の酢酸エチルのジクロロメタン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物28(1.98g、63%)MS(ESI)MH(+)=369.2を得た。
3,5−ジメチル−4−[1−(p−トリルスルホニル)ピラゾロ[4,3−b]ピリジン−6−イル]イソオキサゾール(28、1.98g、5.38mmol)に、1M水酸化カリウムのMeOH(40mL)溶液を加えた。反応混合物を室温で3時間攪拌した。LC−MSは反応が完了したことを示した。反応混合物を水で希釈し、6N HClを加え、酢酸エチルで抽出した。有機層を水および食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を減圧濃縮して固体を得た。残渣をアセトニトリルに懸濁し、1時間超音波処理した。得られた固体沈殿物を減圧濾過によって収集し、アセトニトリルで洗浄し、生成物29(1.13g、98%)を得た。
氷浴中で0〜5℃まで冷却した4−(1H−インダゾール−6−イル)−3,5−ジメチル−イソオキサゾール(29、1.13g、5.28mmol)のN,N−ジメチルホルムアミド(50ml)溶液に、水酸化カリウム(1.18g、21mmol)とヨウ素(2.68g、10.6mmol)を加えた。得られた混合物を室温まで温め、4時間攪拌した。反応混合物を飽和チオ硫酸ナトリウム(Na2S2O3)溶液(10mL)でクエンチし、酢酸エチルで抽出した。合わせた有機層を飽和チオ硫酸ナトリウム(Na2S2O3)溶液、水、食塩水で洗浄し、次いで硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物30(1.44g、80%)を得た。
4−(3−ヨード−1H−ピラゾロ[4,3−b]ピリジン−6−イル)−3,5−ジメチル−イソオキサゾール(30、0.27g、0.8mmol)、トリフェニルホスフィン(0.28g、1.08mmol)、および((1R)−1−(2−ピリジル)エタノール(0.2g、1.62mmol)を溶解したTHF(20ml)溶液を氷水浴中で0〜5℃まで冷却し、ジイソプロピルアゾジカルボキシレート(0.22g、1.08mmol)を20分間かけて滴下した。反応混合物を氷水浴中0〜5℃で1時間攪拌し、さらに1時間室温まで温めた。反応を減圧濃縮した。粗物質を0%〜75%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2091(60mg、17%)MS(ESI)MH(+)=446.2を得た。
4−[3−ヨード−1−[(1S)−1−(2−ピリジル)エチル]ピラゾロ[4,3−b]ピリジン−6−イル]−3,5−ジメチル−イソオキサゾール(P−2091、50mg、0.11mmol)のアセトニトリル(5ml)溶液に、メチル 2−[4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル]アセテート(50mg、0.18mmol))、1M炭酸カリウムの水(2.5ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(9mg、0.01mmol)を加えた。反応混合物を75℃で3時間攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜50%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物32(15mg、29%)MS(ESI)MH(+)=468.0を得た。
メチル 2−[4−[6−(3,5−ジメチルイソオキサゾール−4−イル)−1−[(1S)−1−(2−ピリジル)エチル]ピラゾロ[4,3−b]ピリジン−3−イル]フェニル]アセテート(32、15mg、0.032mmol)のTHF(10ml)溶液に、1M水酸化リチウム(5ml)の水溶液を加えた。反応混合物を50℃で4時間攪拌した。反応を水に注ぎ(1N HClを加えて酸性にした)、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、RP−HPLCによって精製し、凍結乾燥後に生成物P−2094(9mg、62%)MS(ESI)MH(+)=454.5を得た。
4−[3−ベンジル−5−(3,5−ジメチルイソオキサゾール−4−イル)インダゾール−1−イル]−3−フルオロ−安息香酸(P−2037)
スキーム8.
工程1−4−(1H−インダゾール−5−イル)−3,5−ジメチル−イソオキサゾール(35)の製造:
5−ブロモ−1H−インダゾール(34、2.20g、11.2mmol)のアセトニトリル(51ml)溶液に、窒素下で3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(4.98g、22.3mmol)、1M炭酸カリウムの水(17ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.85g、0.11mmol)を加えた。反応をマイクロ波中、160℃で20分間加熱した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥し、濾過した。濾液を濃縮し、0%〜60%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物35(1.74g、73%)を得た。
4−(1H−インダゾール−5−イル)−3,5−ジメチル−イソオキサゾール(35、1.22g、5.7mmol)のN,N−ジメチルホルムアミド(40ml)溶液を0〜5℃まで冷却し、次いで水酸化カリウム(1.28g、23mmol)とヨウ素(2.9g、11mmol)を加えた。得られた混合物を0〜5℃で1時間攪拌し、次いで2時間かけてゆっくりと室温まで温めた。反応混合物を飽和チオ硫酸ナトリウム(Na2S2O3)溶液(10mL)でクエンチし、酢酸エチルで抽出した。合わせた有機層を飽和チオ硫酸ナトリウム(Na2S2O3)溶液、水、食塩水で洗浄し、次いで硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物36(1010mg、52%)MS(ESI)MH(+)=339.8を得た。
4−(3−ヨード−1H−インダゾール−5−イル)−3,5−ジメチル−イソオキサゾール(36、550mg、1.62mmol)の20mLのTHF溶液に、−50℃で窒素下、2Mクロロ(イソプロピル)マグネシウム(1.78ml)のTHF溶液をゆっくりと加えた。反応を70分間かけて5℃まで温めた。次いで、反応を−45℃まで冷却し、次いでベンズアルデヒド(344mg、3.24mmol)を加えた。反応混合物を2〜3時間かけて室温まで温めた。反応混合物を1N HClでクエンチした。反応を水と酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜75%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物37(195mg、38%)MS(ESI)MH(+)=319.9を得た。
[5−(3,5−ジメチルイソオキサゾール−4−イル)−1H−インダゾール−3−イル]−フェニル−メタノール(37、195mg、0.61mmol)の25mLの1,2−ジクロロエタン溶液に、トリエチルシラン(4mL、25.1mmol)とトリフルオロ酢酸(2mL、25.96mmol)を加えた。混合物を80℃で2時間攪拌した。反応混合物を減圧濃縮した。残渣を1N炭酸水素ナトリウムと酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜75%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2035(153mg、83%)MS(ESI)MH(+)=304.2を得た。
4−(3−ベンジル−1H−インダゾール−5−イル)−3,5−ジメチル−イソオキサゾール(P−2035、52g、0.17mmol)のN−メチル−2−ピロリドン(2.5ml)溶液に、炭酸セシウム(200mg、0.61mmol)とエチル 3,4−ジフルオロベンゾエート(60mg、0.32mmol)を加えた。反応混合物をマイクロ波中、150℃で2時間攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜50%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2036(48mg、60%)MS(ESI)MH(+)=470.0を得た。
エチル 4−[3−ベンジル−5−(3,5−ジメチルイソオキサゾール−4−イル)インダゾール−1−イル]−3−フルオロ−ベンゾエート(P−2036、45mg、0.1mmol)のTHF(10ml)溶液に、1M水酸化リチウム(5ml)水溶液を加えた。反応混合物を50℃で20時間攪拌した。反応を水に注ぎ(1N HClを加えて酸性にした)、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮して固体を得、アセトニトリルを加え、懸濁液を1時間超音波処理した。沈殿物を減圧濾過によって収集し、化合物P−2037(18mg、43%)MS(ESI)MH(+)=441.9を得た。
4−[3−ベンジル−5−(3,5−ジメチルイソオキサゾール−4−イル)ピラゾロ[3,4−b]ピリジン−1−イル]−3−フルオロ−安息香酸(P−2102)
スキーム9.
工程1−3,5−ジメチル−4−(1H−ピラゾロ[3,4−b]ピリジン−5−イル)イソオキサゾール(42)の製造:
5−ブロモ−1H−ピラゾロ[3,4−b]ピリジン(41、1.5g、7.58mmol)のアセトニトリル(18ml)溶液に、3,5−ジメチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)イソオキサゾール(3.38g、15.15mmol)、1M炭酸カリウムの水(9ml)溶液、および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(0.58g、0.76mmol)を加えた。反応を110℃でマイクロ波中、15分間攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物42(900mg、55%)を得た。
3,5−ジメチル−4−(1H−ピラゾロ[3,4−b]ピリジン−5−イル)イソオキサゾール(42、860mg、4.0mmol)のN,N−ジメチルホルムアミド(20ml)溶液を0〜5℃まで冷却し、次いで水酸化カリウム(901mg、16.1mmol)とヨウ素(2.0g、7.88mmol)を加えた。反応混合物を0〜5℃で1時間攪拌し、次いで4時間かけて室温までゆっくりと温めた。反応混合物を飽和チオ硫酸ナトリウム(Na2S2O3)溶液(10mL)でクエンチし、酢酸エチルで抽出した。合わせた有機層を飽和チオ硫酸ナトリウム(Na2S2O3)溶液、水、食塩水で洗浄し、次いで硫酸マグネシウムで乾燥し、濾過した。揮発性物質を減圧下で濾液から除去し、粗物質を0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物43(880mg、80%)MS(ESI)MH(+)=340.8を得た。
4−(3−ヨード−1H−ピラゾロ[3,4−b]ピリジン−5−イル)−3,5−ジメチル−イソオキサゾール(43、445mg、1.31mmol)の20mLのTHF溶液に、−78℃で窒素下、2Mクロロ(イソプロピル)マグネシウム(1.37ml)のTHF溶液をゆっくりと滴下した。反応を−78℃で2時間攪拌した。次いで、ベンズアルデヒド(347mg、3.27mmol)を反応混合物に加え、2時間かけてゆっくりと5℃まで温めた。反応混合物を1N HClでクエンチした。反応を水と酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜100%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物44(215mg、51%)MS(ESI)MH(+)=321.2を得た。
[5−(3,5−ジメチルイソオキサゾール−4−イル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−フェニル−メタノール(44、415mg、1.3mmol)の25mLの1,2−ジクロロエタン溶液に、トリエチルシラン(4mL、25mmol)とトリフルオロ酢酸(2mL、26mmol)を加えた。混合物を80℃で2時間攪拌した。反応混合物を減圧濃縮した。残渣を1N炭酸水素ナトリウムと酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2100(304mg、77%)MS(ESI)MH(+)=305.2を得た。
4−(3−ベンジル−1H−ピラゾロ[3,4−b]ピリジン−5−イル)−3,5−ジメチル−イソオキサゾール(P−2100、90mg、0.30mmol)のN−メチル2−ピロリドン(3ml)溶液に、炭酸セシウム(200mg、0.61mmol)とエチル 3,4−ジフルオロベンゾエート(100mg、0.54mmol)を加えた。反応混合物をマイクロ波中、160℃で2時間攪拌した。反応を水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮し、0%〜80%の酢酸エチルのヘキサン溶液で溶出するシリカゲルカラムクロマトグラフィーによって精製し、生成物P−2101(55mg、40%)MS(ESI)MH(+)=471.0を得た。
エチル 4−[3−ベンジル−5−(3,5−ジメチルイソオキサゾール−4−イル)ピラゾロ[3,4−b]ピリジン−1−イル]−3−フルオロ−ベンゾエート(P−2101、40mg、0.09mmol)のTHF(15ml)溶液に、1M水酸化リチウム(7.5ml)の水溶液を加えた。反応混合物を50℃で20時間攪拌した。反応を水に注ぎ(1N HClを加えて酸性にした)、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥し、濾過した。濾液を濃縮して固体を得、アセトニトリルを加え、懸濁液を1時間超音波処理した。沈殿物を減圧濾過によって収集し、化合物P−2102(14mg、37%)MS(ESI)MH(+)=442.9を得た。
いずれかのブロモドメインおよびその変異体に対する化合物の阻害活性が疾患の治療におけるそれらの活性に重要である一方、本願明細書に記載された化合物は医薬としてさらに利点を提供する好ましい性質を示す。
式(I)で示される化合物とブロモドメイン2、3、および4の結合を、Alphascreen結合アッセイを用いて評価した。ブロモドメインとそのアセチル化標的タンパク質(Filippakopoulos P et al.2012)の間の相互作用の阻害を、組換えBRDタンパク質、アセチル化ヒストン4ペプチド、およびAlphaScreen(商標)技術を用いて定量的に測定した。阻害がない場合、AlphaScreen(商標)ニッケルキレート受容体ビーズと結合したBRDタンパク質は、AlphaScreen(商標)ストレプトアビジンコーティングビーズによって固定化されたアセチル化ヒストン4ペプチドと相互作用することができる。この相互作用によってドナーと受容体ビーズが近接する。非常に近接しているため、ドナービーズのレーザー励起によって生じた一重項の酸素が受容体ビーズに到達することができ、発光シグナルを生じる。BRD阻害剤は、BRD−アセチル化ペプチド相互作用を阻害することによって、近接シグナルの減少をもたらす。
全成分は50mM HEPES pH7.5、100mM NaCl、0.01%BSA、0.01%トリトンX−100、および2mM DTTで構成された緩衝液中で製造した。7μLのブロモドメインタンパク質と7μLのペプチドを、1μLの様々な濃度の式(I)で示される試験化合物またはDMSOビヒクルを含有するAlphaplate(PerkinElmer GA、USA)中のウェルに加え、室温で1時間インキュベートした。次いで4μLのドナーおよび受容体ビーズ混合物を最終濃度が7.5μg/mlとなるように加えた。ビーズ添加の30分後、AlphaシグナルをEnvision分光計(λEx680nm、λEm520〜620nm)で読み取った。ブロモドメインタンパク質とペプチドの最終濃度は以下に示す通りである。
Y=a+(b−a)/(1+(x/c)^d)
式中、「a」は最小値、「b」は最大値、「c」はpIC50、および「d」はヒル勾配を示す。
N末端ブロモドメイン(BRD2−BD1(71〜194)、BRD3−BD1(24〜144)およびBRD4−BD1(44〜164))、または二重ブロモドメイン(BRD4−BD12(1〜477)、BRD4−BD12(1〜472))を含有する組換えヒトブロモドメインをN末端に6−Hisタグをつけて大腸菌細胞内で(改変したpETベクターにて)発現させ、IMAC(Ni親和性)およびサイズ排除クロマトグラフィー工程の両方を組み合わせて精製した。
公開されているブロモドメイン阻害剤JQ1およびiBET151は、様々な癌細胞、例えば白血病およびリンパ腫、多発性骨髄腫細胞、NUT正中線癌、ならびに神経膠芽腫細胞において活性を示している(Dawson MA et al.2011;Delmore JE 2011;Chen Z et al.2013;Filippakopoulos P et al.2010;Mertz JA et al.2011;およびOtt CJ et al.2012)。本研究では、異なる癌細胞株において化合物を試験した。MV−4−11およびMOLM−13は、それぞれMLL−AF4およびMLL−AF9転座を持つAML細胞株である。MM.1Sは多発性骨髄腫細胞株である。SK−N−AS、IMR−32、およびSK−N−BE(2)は、神経芽細胞腫細胞株である。IMR−32およびSK−N−BE(2)細胞株はMYCN増幅を持つ。
Y=a+(b−a)/(1+(x/c)^d)
式中、「a」は最小値、「b」は最大値、「c」はpIC50、および「d」はヒル勾配を示す。
これらのデータは、上記アッセイで試験したブロモドメイン阻害剤が腫瘍細胞株の細胞増殖を阻害することを立証している。
MV−4−11細胞において、BRD2、BRD3、およびBRD4はMYCのプロモーター領域に結合し、その転写を制御する(Dawson MA et al.2011)。該文献のブロモドメイン阻害剤iBET151は、MYCプロモーターへのBRD4動員を妨害することができ、その後にc−myc転写を下方制御することができる(Dawson MA et al.2011)。Mycタンパク質は転写因子であり、必須のパートナーMaxとヘテロ二量体化し、細胞増殖、分化、およびアポトーシスに重要な遺伝子の転写を制御する。このMycレポーターアッセイは、式(I)で示される化合物のMyc依存性遺伝子発現に対する阻害効果をモニターするために用いた。有効な化合物は、Myc誘導性腫瘍に対する潜在的治療効果を有しうる。
Y=a+(b−a)/(1+(x/c)^d)
式中、「a」は最小値、「b」は最大値、「c」はpIC50、および「d」はヒル勾配を示す。
Claims (33)
- 式(I):
[式中:
(i)Y1およびY2はNであり、Y3はCR2であり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;
(ii)Y1はCであり、Y2はNであり、Y3はNR2であり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;
(iii)Y1はNであり、Y2はCHであり、Y3はCR2であり、Y4はNであり、かつ、Y5はNであるか;
(iv)Y1はNであり、Y2はCHであり、Y3はNであり、Y4はCHもしくはNであり、かつ、Y5はCHであるか;または
(v)Y1はCであり、Y2はCHであり、Y3はNR2であり、Y4はNであり、かつ、Y5はNであり;
Lは置換されていてもよいC1−4アルキレン、置換されていてもよい重水素化C1−4アルキレン、または置換されていてもよい−C(R4)(R5)であり、ここでR4およびR5はそれぞれ独立してH、D、ハロゲン、−OH、C1−6アルキル、重水素化C1−6アルキル、C2−6アルケニル、C2−6アルキニル、アリール、アリール−C1−4アルキル、C1−6アルコキシ、C3−6シクロアルキル、C3−6シクロアルキル−C1−4アルキル、ヘテロシクロアルキル、ヘテロシクロアルキル−C1−4アルキル、ヘテロアリール、ヘテロアリール−C1−4アルキル、C1−6ハロアルキル、C1−6ハロアルコキシ、もしくはRaであるか;またはR4およびR5はそれらが結合している炭素原子と一緒になってO、N、およびSから選択される0〜2個のヘテロ原子もしくはオキソを有する置換されていてもよい3〜6員環を形成し;ここでRaはハロゲン、CN、−OH、−NH2、−NO2、−C(O)OH、−C(S)OH、−C(O)NH2、−C(S)NH2、−S(O)2NH2、−NHC(O)NH2、−NHC(S)NH2、−NHS(O)2NH2、−C(NH)NH2、−ORb、−SRb、−OC(O)Rb、−OC(S)Rb、−C(O)Rb、−C(S)Rb、−C(O)ORb、−C(S)ORb、−S(O)Rb、−S(O)2Rb、−C(O)NHRb、−C(S)NHRb、−C(O)NRbRb、−C(S)NRbRb、−S(O)2NHRb、−S(O)2NRbRb、−C(NH)NHRb、−C(NH)NRbRb、−NHC(O)Rb、−NHC(S)Rb、−NRbC(O)Rb、−NRbC(S)Rb、−NHS(O)2Rb、−NRbS(O)2Rb、−NHC(O)NHRb、−NHC(S)NHRb、−NRbC(O)NH2、−NRbC(S)NH2、−NRbC(O)NHRb、−NRbC(S)NHRb、−NHC(O)NRbRb、−NHC(S)NRbRb、−NRbC(O)NRbRb、−NRbC(S)NRbRb、−NHS(O)2NHRb、−NRbS(O)2NH2、−NRbS(O)2NHRb、−NHS(O)2NRbRb、−NRbS(O)2NRbRb、−NHRb、Rb、および−NRbRbから選択され、ここで各RbはC1−6アルキル、アリール、アリール−C1−4アルキル、C3−6シクロアルキル、C3−6シクロアルキル−C1−4アルキル、ヘテロアリール、ヘテロアリール−C1−4アルキル、ヘテロシクロアルキル、およびヘテロシクロアルキル−C1−4アルキルから独立して選択され、そのそれぞれは置換されていてもよく;または同一の窒素原子と結合している2個のRb基はそれらが結合している窒素原子と一緒になって置換されていてもよい4、5、もしくは6員環を形成し;
R1は水素、D、置換されていてもよいアリール、置換されていてもよいシクロアルキル、置換されていてもよいヘテロアリール、または置換されていてもよいヘテロシクロアルキルであり;
R2は水素、D、ハロゲン、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいアリール−C1−2アルキル、または置換されていてもよいヘテロアリール−C1−2アルキルであり;
R3は環員としてO、N、およびSから選択される1〜4個のヘテロ原子を有する5員ヘテロアリールであり、ここで該ヘテロアリールは1〜2個のC1−2アルキルで置換されており、該アルキルはハロゲン、OH、およびCNから独立して選択される1〜3個のメンバーで置換されていてもよく;かつ、
記号
で示される化合物、またはその医薬的に許容される塩、プロドラッグ、溶媒和物、水和物、互変異性体、異性体、もしくは重水素化類似体。 - Lが−CHR5であり、ここでR5がH、D、ハロゲン、−OH、C1−6アルキル、重水素化C1−6アルキル、C2−6アルケニル、C2−6アルキニル、アリール、アリール−C1−4アルキル、C1−6アルコキシ、C3−6シクロアルキル、C3−6シクロアルキル−C1−4アルキル、ヘテロシクロアルキル、ヘテロシクロアルキル−C1−4アルキル、ヘテロアリール、ヘテロアリールアルキル、C1−6ハロアルキル、C1−6ハロアルコキシ、またはRaであり、ここでR5の脂肪族または芳香族部分がハロゲン、CN、−OH、−NH2、−NO2、−C(O)OH、−CH=CH2、−C≡CH、−C(S)OH、−C(O)NH2、−C(S)NH2、−S(O)2NH2、−NHC(O)NH2、−NHC(S)NH2、−NHS(O)2NH2、−C(NH)NH2、−ORd、−SRd、−OC(O)Rd、−OC(S)Rd、−P(=O)HRd、−P(=O)RdRd、−PH(=O)ORd、−P(=O)(ORd)2、−OP(=O)(ORd)2、−C(O)Rd、−C(S)Rd、−C(O)ORd、−C(S)ORd、−S(O)Rd、−S(O)2Rd、−C(O)NHRd、−C(S)NHRd、−C(O)NRdRd、−C(S)NRdRd、−S(O)2NHRd、−S(O)2NRdRd、−C(NH)NHRd、−C(NH)NRdRd、−NHC(O)Rd、−NHC(S)Rd、−NRdC(O)Rd、−NRdC(S)Rd、−NHS(O)2Rd、−NRdS(O)2Rd、−NHC(O)NHRd、−NHC(S)NHRd、−NRdC(O)NH2、−NRdC(S)NH2、−NRdC(O)NHRd、−NRdC(S)NHRd、−NHC(O)NRdRd、−NHC(S)NRdRd、−NRdC(O)NRdRd、−NRdC(S)NRdRd、−NHS(O)2NHRd、−NRdS(O)2NH2、−NRdS(O)2NHRd、−NHS(O)2NRdRd、−NRdS(O)2NRdRd、−NHRd、−NRdRd、およびRdから独立して選択される1〜3個のRcメンバーでさらに置換されていてもよく、ここで各Rdが独立してC1−6アルキルもしくはアリールであり;または同一の窒素原子と結合している2個のRd基が、それらが結合している窒素原子と一緒になって4〜6員環を形成し;ここで各Rdがハロゲン、CN、−OH、−NH2、−NO2、−C(O)OH、−C(S)OH、−C(O)NH2、−C(S)NH2、−S(O)2NH2、−NHC(O)NH2、−NHC(S)NH2、−NHS(O)2NH2、−C(NH)NH2、−ORf、−SRf、−OC(O)Rf、−OC(S)Rf、−P(=O)HRf、−P(=O)RfRf、−PH(=O)ORf、−P(=O)(ORf)2、−OP(=O)(ORf)2、−C(O)Rf、−C(S)Rf、−C(O)ORf、−C(S)ORf、−S(O)Rf、−S(O)2Rf、−C(O)NHRf、−C(S)NHRf、−C(O)NRfRf、−C(S)NRfRf、−S(O)2NHRf、−S(O)2NRfRf、−C(NH)NHRf、−C(NH)NRfRf、−NHC(O)Rf、−NHC(S)Rf、−NRfC(O)Rf、−NRfC(S)Rf、−NHS(O)2Rf、−NRfS(O)2Rf、−NHC(O)NHRf、−NHC(S)NHRf、−NRfC(O)NH2、−NRfC(S)NH2、−NRfC(O)NHRf、−NRfC(S)NHRf、−NHC(O)NRfRf、−NHC(S)NRfRf、−NRfC(O)NRfRf、−NRfC(S)NRfRf、−NHS(O)2NHRf、−NRfS(O)2NH2、−NRfS(O)2NHRf、−NHS(O)2NRfRf、−NRfS(O)2NRfRf、−NHRf、−NRfRf、およびRfから独立して選択される1〜3個のRe置換基でさらに置換されていてもよく、ここで各Rfが独立してC1−6アルキルであり;または同一の窒素原子と結合している2個のRf基が、それらが結合している窒素原子と一緒になって4〜6員環を形成している、請求項1〜10のいずれか1項に記載の化合物。
- R5がH、C1−6アルキル、アリール、シクロアルキル、ヘテロアリール、またはヘテロシクロアルキルであり、そのそれぞれが1〜3個の独立して選択されたRc置換基または1〜3個の独立して選択されたRe置換基で置換されていてもよい、請求項11に記載の化合物。
- R5がC1−6アルキル、アリール、シクロアルキル、またはヘテロアリールであり、そのそれぞれが1〜3個の独立して選択されたRc置換基または1〜3個の独立して選択されたRe置換基で置換されていてもよい、請求項11に記載の化合物。
- R1がH、D、シクロアルキル、アリール、ヘテロアリール、またはヘテロシクロアルキルであり、そのそれぞれが1〜3個の独立して選択されたRc置換基または1〜3個の独立して選択されたRe置換基で置換されていてもよい、請求項1〜14のいずれか1項に記載の化合物。
- R1がC3−6シクロアルキル、アリール、またはヘテロアリールであり、そのそれぞれが1〜3個の独立して選択されたハロゲンで置換されていてもよい、請求項1〜15のいずれか1項に記載の化合物。
- R1がシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、フェニル、または2−ピリジルであり、そのそれぞれが1〜3個の独立して選択されたハロゲンで置換されていてもよい、請求項1〜16のいずれか1項に記載の化合物。
- R2がH、D、ハロゲン、アリール、ヘテロアリール、アリール−C1−2アルキル、またはヘテロアリール−C1−2アルキルであり、そのそれぞれが1〜3個の独立して選択されたRc置換基または1〜3個の独立して選択されたRe置換基で置換されていてもよい、請求項1〜17のいずれか1項に記載の化合物。
- R2がH、ハロゲン、アリール、ヘテロアリール、アリール−C1−2アルキル、またはヘテロアリール−C1−2アルキルであり、そのそれぞれがハロゲン、CN、C1−6アルキル、C1−6ハロアルキル、C1−6アルコキシ、C3−6シクロアルキル、フェニル、カルボキシ、−C1−6アルキル−C(O)OH、−C1−6アルキル−C(O)O−C1−6アルキル、および−C(O)O−C1−6アルキルから独立して選択される1〜3個のRg基で置換されていてもよく、ここでRg基がハロゲン、OH、C1−6アルキル、C1−6アルコキシ、カルボキシ、および−C(O)O−C1−6アルキルから独立して選択される1〜3個のメンバーでさらに置換されていてもよい、請求項1〜17のいずれか1項に記載の化合物。
- R2が4−ピラゾリル、フェニル、2−ピリジル、3−ピリジル、4−ピリジル、5−ピリミジニル、ベンジル、または2−ピリジル−メチルであり、そのそれぞれが1〜3個の独立して選択されたRc置換基、1〜3個の独立して選択されたRe置換基、または1〜3個の独立して選択されたRg置換基で置換されていてもよく、ここでRg基がハロゲン、−OH、C1−6アルキル、C1−6アルコキシ、カルボキシ、および−C(O)O−C1−6アルキルから独立して選択される1〜3個のメンバーでさらに置換されていてもよい、請求項1〜17のいずれか1項に記載の化合物。
- R2が4−ピラゾリル、フェニル、2−ピリジル、3−ピリジル、4−ピリジル、5−ピリミジニル、ベンジル、または2−ピリジル−メチルであり、そのそれぞれが1〜3個の独立して選択されたRg置換基で置換され、ここでRg基がハロゲン、−OH、C1−6アルキル、C1−6アルコキシ、カルボキシ、および−C(O)O−C1−6アルキルから独立して選択される1〜3個のメンバーでさらに置換されていてもよい、請求項19〜20のいずれか1項に記載の化合物。
- R2が4−ピラゾリル、フェニル、2−ピリジル、3−ピリジル、4−ピリジル、5−ピリミジニル、ベンジル、または2−ピリジル−メチルであり、そのそれぞれがハロゲン、−OH、−CN、メチル、−CD3、−CH2OH、−CD2OH、フェニル、メトキシ、−CHF2、−CF3、−CFH2、CF3CH2−、−COOH、−CH2COOH、−CH2COOMe、−COOMe、1−カルボキシシクロプロピル、およびC3−6シクロアルキルから独立して選択される1〜3個のRh基で置換されている、請求項1〜17のいずれか1項に記載の化合物。
- R3が環員としてO、N、およびSから選択される1〜3個のヘテロ原子を有する5員ヘテロアリールであり、ここで該ヘテロアリールが1〜2個のメチル基で置換され、該メチル基がハロゲン、OH、およびCNから独立して選択される1〜2個のメンバーで置換されていてもよい、請求項1〜22のいずれか1項に記載の化合物。
- 請求項1〜25のいずれか1項に記載の化合物および医薬的に許容される賦形剤または担体を含む医薬組成物。
- 請求項1〜25のいずれか1項に記載の化合物および別の治療剤を含む医薬組成物。
- ブロモドメインを調節する方法であって、請求項1〜25のいずれか1項に記載の化合物または請求項26もしくは27に記載の組成物を、それを必要とする対象に投与する工程を含む方法。
- ブロモドメインを調節する方法であって、細胞を請求項1〜25のいずれか1項に記載の化合物または請求項26もしくは27に記載の組成物と接触させる工程を含む方法。
- ブロモドメインによって媒介される疾患または状態を患うか、またはその危険性がある対象を治療する方法であって:
請求項1〜25のいずれか1項に記載の化合物または請求項26もしくは27に記載の組成物の有効量を、それを必要とする対象に投与する工程を含む方法。 - 疾患または状態が癌、自己免疫状態、炎症状態、およびその組み合わせから選択される、請求項30に記載の方法。
- ブロモドメインがBETファミリーのメンバーである、請求項28〜31のいずれか1項に記載の方法。
- 本願明細書に記載された化合物、組成物、および方法。
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TW201613911A (en) | 2016-04-16 |
EP3194392B1 (en) | 2020-01-01 |
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WO2016044067A1 (en) | 2016-03-24 |
AU2015318233B2 (en) | 2020-03-12 |
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