JP2018150331A - ヒストン脱アセチル化酵素阻害剤 - Google Patents
ヒストン脱アセチル化酵素阻害剤 Download PDFInfo
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- JP2018150331A JP2018150331A JP2018088646A JP2018088646A JP2018150331A JP 2018150331 A JP2018150331 A JP 2018150331A JP 2018088646 A JP2018088646 A JP 2018088646A JP 2018088646 A JP2018088646 A JP 2018088646A JP 2018150331 A JP2018150331 A JP 2018150331A
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- alkyl
- mmol
- acid
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- phenyl
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- 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
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Classifications
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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Abstract
Description
その開示が参照により完全に組み込まれる、2013年3月15日に出願されたUS特許出願第13/843,261号の利益を主張する。
特徴とする:
I.n=1の場合、ZはR1−X−Ar/Hetであり、ここでは:
Ar/Hetは:
(i)ピラゾリル、チアゾリル、オキサゾリル、イミダゾリル、チエニル、フラニル、イソオキサゾリル、イソチアゾリル、チアジアゾリル、オキサジアゾリル及び1,2,4−トリアゾリルからなる群から選択される5員ヘテロアリール(いくつかの実施形態では、Ar/Hetの定義には、3,5−ジメチルピラゾリルをさらに含めることができる);または
(ii)ベンゾフラニル、ベンゾチエニル、ベンゾチアゾリル、インドリル、インダゾリル、キノロニル、ナフチリジニル、インドリジニル、ピロロピリミジニル、ピラゾロピリジニル、イミダゾピリジニル、イミダゾピリダジニル、トリアゾロピリジニル、イミダゾチアゾリル、イミダゾオキサゾリル、トリアゾロチアゾリル及びトリアゾロオキサゾリルからなる群から選択される、二環式の8、9または10員ヘテロアリールであり;
Xは:
(i)−Y−[C(Ra)2]a−A−[C(Rb)2]b−B−であり;式中
Yは結合、CRc=CRd、O、NReまたはS(O)mであり;
A及びBのそれぞれは独立に、結合、O、NRfまたはS(O)mであり;
aは1〜3(例えば1または2、例えば1)であり;
bは0〜3(例えば0、または0以外、例えば1;または2もしくは3)であり;
mは0〜2であり;
Ra及びRbの各存在は、H、F、OH、C1〜C6アルキル、C3〜C6シクロアルキル、NH2、OCO−(C1〜C6アルキル)、OCO−(C3〜C6シクロアルキル)、C1〜C6アルコキシ、C1〜C6フルオロアルコキシ及びシアノから独立に選択され;または
以下の1つもしくは複数をRa及びRbに対して適用することができ:
任意の2つのRaは、それぞれが結合している炭素と共に、3〜6個の環原子を含む、C3〜C6シクロアルキルもしくはヘテロシクリルを一緒に形成し、ここでは、ヘテロシクリル環原子のうちの1つはO;S(O)m及びNRgから選択され;これらの実施形態では、Raの任意の残りの存在及びRbの任意の存在は、Ra及びRbに関係する上記もしくは下記の定義のいずれか1つまたは複数に従って、それぞれ独立に定義され;または
1つのRa及び1つのRbは、それぞれが結合している炭素と共に、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを形成し、ここでは、ヘテロシクリル環原子のうちの1つはO;S(O)m及びNRgから選択され;これらの実施形態では、他のRa、他のRb並びにRa及びRbの任意の他の残りの存在は、Ra及びRbに関係する上記もしくは下記の定義の任意の1つもしくは複数に従って、それぞれ独立に定義され;または
任意の2つのRbは、それぞれが結合している炭素と共に、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを形成し、ここでは、環原子のうちの1つはO;S(O)m及びNRgから選択され;これらの実施形態では、Raの各存在及びRbの任意の他の残りの存在は、Ra及びRbに関係する上記または下記の定義の任意の1つもしくは複数に従って、それぞれ独立に定義され;
Rc及びRdのそれぞれは、独立に、H、F、OH、C1〜C6アルキル、C3〜C5シクロアルキル、NH2、OCO−(C1〜C6アルキル)、OCO−(C3〜C5シクロアルキル)、C1〜C6アルコキシ、C1〜C6フルオロアルコキシ及びシアノから選択され;
またはRc及びRdは、それぞれが結合している炭素と共に、3〜6個の環原子を含むC5〜C7シクロアルキルもしくはヘテロシクリルを形成し、ここでは、1〜2のヘテロシクリル環原子は、O;S(O)m及びNRg’から独立に選択され;
Re、Rf、Rg及びRg’の各存在は、H、C1〜C6アルキル、−C(=O)H、−C(=O)Rh、C(=O)O(C1〜C6アルキル)、C(=O)N(Ri)2、SO2−Rhから独立に選択され、Rhは、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから選択され;Riの各存在は、H、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから独立に選択され(実施形態では、Rh及びRiのアリール及びヘテロアリール部分は、例えば、1つまたは複数の独立に選択される置換基、例えばF、C1〜C6アルキル、フルオロC1〜C6アルキル、C3〜C6シクロアルキル、C1〜C6アルコキシ、C1〜C6フルオロアルコキシまたはシアノで任意に置換され得る);
さらにここで:
(a)A及びBのそれぞれが結合であり、bが0である場合、Xは、次の式:−Y−[C(Ra)2]a−を有し;
(b)bが0もしくは1(例えば0)である場合、A及びBは両方ともヘテロ原子とすることはできず(すなわち、O、NReまたはS(O)mで定義された通り);
(c)AもしくはBがAr/Hetに対するXの結合点として働き、Ar/HetがAr/Het中の窒素環原子を介してXに連結している場合、AもしくはB結合子はヘテロ原子とすることはできず(すなわち、O、NReまたはS(O)mで定義された通り);
またはXは:
(ii)直接結合;もしくは
(iii)C=O、C(Rj)2−C(=O)もしくはC(=O)−C(Rj)2、SO2−NRk、NRk−SO2、C(=O)NRk及びNRk−C(=O)であり;ここでは:
Rjの各存在は、H、F、OH、C1〜C6アルキル、C3〜C6シクロアルキル、NH2、OCO−(C1〜C6アルキル)、OCO−(C3〜C6シクロアルキル)、C1〜C6アルコキシ、C1〜C6フルオロアルコキシ及びシアノから独立に選択され;
もしくはRj−C−Rjは、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを一緒に形成し、ここでは、ヘテロシクリル環原子のうちの1つは、O;S(O)m及びNRj’から選択され;
Rj’及びRkの各存在は、H、C1〜C6アルキル、−C(=O)H、−C(=O)Rm、C(=O)O(C1〜C6アルキル)、C(=O)N(Rn)2及びSO2−Rmから独立に選択され、ここでは、Rmは、C1〜C6アルキル、CH2−ヘテロアリール、CH2−アリール及びアリールから選択され;Rnの各存在は、H、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから独立に選択され(実施形態では、Rm及びRn中のアリール及びヘテロアリール部分は、例えば、1つもしくは複数の独立に選択される置換基、例えばF、C1〜C6アルキル、フルオロC1〜C6アルキル、C3〜C6シクロアルキル、C1〜C6アルコキシ、C1〜C6フルオロアルコキシもしくはシアノで任意に置換され得る);
R4及びR5のそれぞれは、独立に、H、C1〜C6アルキル及びFから選択され;
R1は:
(i)水素;または
(ii)1〜3個のRoで任意に置換された、C6〜C10アリール;または
(iii)1〜3個のRoで任意に置換された、5〜10個の環原子を含む単環式もしくは二環式ヘテロアリール(ここでは、1〜4個の環原子は、O、N、N−H、N−Ro及びSから独立に選択されるヘテロ原子である;または
(iv)1〜3個のRoで任意に置換された、4〜10個の環原子を含むヘテロシクリルであり(ここでは、1〜4個の環原子は、O、N、N−H、N−Ro及びSから独立に選択されるヘテロ原子である);
(いくつかの実施形態では、R1はH以外である);
Roの各存在は、以下(ハロゲンから始まり以下のニトロまでが含まれる)からなる群から独立に選択され:
・ハロゲン;
・C1〜C6アルキル;フルオロ(C1〜C6)アルキル;
・ヒドロキシル;
・ヒドロキシ(C1〜C4)アルキル;
・C1〜C6アルコキシ;フルオロ(C1〜C6)アルコキシ;
・(C1〜C6アルキル)C(O)−;
・(C1〜C6アルキル)NH−;(C1〜C6アルキル)2N−(例えば、−NMe2、−NMe(iPr)を含む);
・N*(Ro’)2(ここでは、Ro’−N*−Ro’は、5または6個の環原子を有する飽和環を一緒に形成し、1または2個の環原子(すなわち、N*環原子に加えて1または2個の環原子)は、任意に、NH、N(アルキル)、OまたはSから任意に独立に選択されるヘテロ原子である)(−N*(Ro’)2は、例えば、ピロリジニル及びモルホリニルなどの環式のアミノを含む);
・ホルミル;ホルミル(C1〜C4)アルキル;シアノ;シアノ(C1〜C4)アルキル;
・ベンジル;ベンジルオキシ;
・ヘテロシクリル)−(C0〜C6、例えばC1〜C6)アルキル(ここでは、ヘテロシクリル部分は、5または6個の環原子を含み、1または2個の環原子は、NH、N(アルキル)、OまたはSから独立に選択されるヘテロ原子であり、前記アルキル部分が存在する場合(すなわち、C1〜C6)、前記アルキル部分は、R1に対する結合点として働き(すなわち、(ヘテロシクリル)−(C1〜C6)アルキルは、アルキル部分を介してR1に結合する);そうでなければ、C0アルキル(すなわち、アルキル部分が存在しない)の場合には、ヘテロシクリル炭素環原子は、R1に対するヘテロシクリルの結合点として働く);
・5〜6の環原子を含むフェニルまたはヘテロアリール(ここでは、1〜4個の環原子は、O、N、N−H、N−Ro’’及びSから独立に選択されるヘテロ原子であり、これらのそれぞれは、1〜3個のRo’’で任意に置換されている);
・SO2−(C1〜C6)アルキル;SO−(C1〜C6)アルキル;並びに
・ニトロ;
・実施形態では、Roは、上に列挙した置換基のいずれか1つ(もしくは複数)でもよく、及び/またはRoは、上に列挙した置換基のサブセットのいずれか1つもしくは複数(例えば、上記で黒丸で示したもの)でもよく;例えば、Roは、本明細書に記載の化合物中に存在する置換基のいずれか1つ(もしくは複数)でもよく、及び/または本明細書に記載の化合物中に存在するものを包含する置換基のいずれか1つ(もしくは複数)でもよく;
Ro’’の各存在は、以下(ハロゲンから始まり以下のニトロまでが含まれる)からなる群から独立に選択され:
・ハロゲン;
・C1〜C6アルキル;フルオロ(C1〜C6)アルキル;
・ヒドロキシル;
・ヒドロキシ(C1〜C4)アルキル;
・C1〜C6アルコキシ;フルオロ(C1〜C6)アルコキシ;
・(C1〜C6アルキル)C(O)−;
・(C1〜C6アルキル)NH−;(C1〜C6アルキル)2N−(例えば、−NMe2、−NMe(iPr)を含む);
・−ホルミル;ホルミル(C1〜C4)アルキル;シアノ;シアノ(C1〜C4)アルキル;
・ベンジル;ベンジルオキシ;
・ヘテロシクリル)−(C0〜C6、例えばC1〜C6)アルキル(ここでは、ヘテロシクリル部分は、5または6個の環原子を含み、1または2個の環原子は、NH、N(アルキル)、OまたはSから独立に選択されるヘテロ原子であり、前記アルキル部分が存在する場合(すなわち、C1〜C6)、前記アルキル部分は、R1に対する結合点として働き(すなわち、(ヘテロシクリル)−(C1〜C6)アルキルは、アルキル部分を介してR1に結合する);そうでなければ、C0アルキル(すなわち、アルキル部分が存在しない)の場合には、ヘテロシクリル炭素環原子は、R1に対するヘテロシクリルの結合点として働く);
・5〜6の環原子を含むフェニルまたはヘテロアリール(ここでは、1〜4個の環原子は、O、N、N−H、N−(C1〜C6アルキル)及びSから独立に選択されるヘテロ原子である);
・SO2−(C1〜C6)アルキル;SO−(C1〜C6)アルキル;並びに
・ニトロ;
・実施形態では、Ro’’は、上に列挙した置換基のいずれか1つ(もしくは複数)でもよく、及び/またはRo’’は上に列挙した置換基のサブセットのいずれか1つもしくは複数(例えば、上記で黒丸で示したもの)でもよく;例えば、Ro’’は本明細書に記載の化合物中に存在する置換基のいずれか1つ(もしくは複数)でもよく、及び/または本明細書に記載の化合物中に存在するものを包含する置換基のいずれか1つ(もしくは複数)でもよい;
II.n=0である場合、Zは、R1−V−Cy−U−Ar’/Het’であり、ここでは:
Ar’/Het’は:
(i)フェニル、ピリジルもしくはピリミジニル(これらのそれぞれは、1〜3個のRpで任意に置換されており;但し、Uに対する前記フェニル、ピリジルもしくはピリミジニルの結合点(すなわち、式Iの結合U−Ar’/Het’)及びアミドカルボニルに対する前記フェニル、ピリジルもしくはピリミジニルの結合点(すなわち、式Iの結合Ar’/Het’−C(=O))が前記フェニル、ピリジルもしくはピリミジニル上で互いに1,2関係をもたらさない(すなわち、前記フェニル、ピリジルもしくはピリミジニル上でのU及びC(O)に対する結合点が互いにオルトでないという条件下であり;それぞれの出現におけるRpは、独立に、H、F、クロロ、CH3、CF3、OCH3、OCF3及びOCHF2から選択される);または
(ii)ピラゾリル、ピロリル、チアゾリル、チエニル、フラニル、イミダゾリル、オキサゾリル、オキサジアゾリル、チアジアゾリル、イソオキサゾリル、イソチアゾリルから選択される5員ヘテロアリール(これらのそれぞれが1〜3個のRpで任意に置換されており;但し、前記5員ヘテロアリールのUに対する結合点(すなわち、式Iの結合U−Ar’/Het’)及び前記5員ヘテロアリールのアミドカルボニルに対する結合点(すなわち、式Iの結合Ar’/Het’−C(=O))が前記5員ヘテロアリール上で互いに1,2関係をもたらさない(すなわち、前記5員ヘテロアリール上でのU及びC(O)に対する結合点が互いに隣接しない)という条件下である);または
(iii)ベンゾチエニル、ベンゾフラニル、ベンゾチオアゾリル、ベンゾオキサゾリル、インドリル、イソインドロニル、インドリジニル、ピロロピリミジニル、ピラゾロピリジニル、イミダゾピリジニル、イミダゾピリダジニル、トリアゾロピリジニル、イミダゾチアゾリル、イミダゾオキサゾリル、キノリニル及びナフチリジニルから選択される、8、9または10員の二環式ヘテロアリール(これらのそれぞれは、1〜3個のRpで任意に置換されている);
(いくつかの実施形態では、Ar’/Het’は、ベンゾチエニル、ベンゾフラニル、ベンゾチオアゾリル、ベンゾオキサゾリル、インドリル、イソインドロニル、インドリジニル、ピロロピリミジニル、ピラゾロピリジニル、イミダゾピリジニル、イミダゾピリダジニル、トリアゾロピリジニル、イミダゾチアゾリル、イミダゾオキサゾリル、キノリニル及びナフチリジニルから選択される、8、9または10員の二環式ヘテロアリール以外であり;これらのそれぞれは、1〜3個のRpで任意に置換されている);
R1は:
(i)水素;または
(ii)1〜3個のRqで任意に置換された、C6〜C10アリール;または
(iii)1〜3個のRqで任意に置換された、5〜10個の環原子を含む単環式もしくは二環式ヘテロアリール(ここでは、1〜4個の環原子は、O、N、N−H、N−Rq及びSから独立に選択されるヘテロ原子である);または
(iv)1〜3個のRqで任意に置換された、4〜10個の環原子を含むヘテロシクリル(ここでは、1〜4個の環原子は、O、N、N−H、N−Rq及びSから独立に選択されるヘテロ原子である)であり;
Rqの各存在は、以下(ハロゲンから始まり以下のニトロまでが含まれる)からなる群から独立に選択される:
・ハロゲン;
・C1〜C6アルキル;フルオロ(C1〜C6)アルキル;
・ヒドロキシル;
・ヒドロキシ(C1〜C4)アルキル;
・C1〜C6アルコキシ;フルオロ(C1〜C6)アルコキシ;
・(C1〜C6アルキル)C(O)−;
・(C1〜C6アルキル)NH−;(C1〜C6アルキル)2N−(例えば、−NMe2、−NMe(iPr)を含む);
・−N*(Rq’)2(ここでは、Rq’−N*−Rq’は、5または6個の環原子を有する飽和環を一緒に形成する(1または2個の環原子(すなわち、N*環原子に加えて1または2個の環原子)は、任意に、NH、N(アルキル)、OまたはSから独立に選択されるヘテロ原子である)(−N*(Rq’)2は、例えば、ピロリジニル及びモルホリニルなどの環式のアミノを含む);
・ホルミル;ホルミル(C1〜C4)アルキル;シアノ;シアノ(C1〜C4)アルキル;
・ベンジル;ベンジルオキシ;
・ヘテロシクリル)−(C0〜C6、例えばC1〜C6)アルキル(ここでは、ヘテロシクリル部分は、5または6個の環原子を含み、1または2個の環原子は、NH、N(アルキル)、OまたはSから独立に選択されるヘテロ原子であり、前記アルキル部分が存在する場合(すなわち、C1〜C6)、前記アルキル部分は、R1に対する結合点として働き(すなわち、(ヘテロシクリル)−(C1〜C6)アルキルは、アルキル部分を介してR1に結合する);そうでなければ、C0アルキル(すなわち、アルキル部分が存在しない)の場合には、ヘテロシクリル炭素環原子は、R1に対するヘテロシクリルの結合点として働く);
・5〜6の環原子を含むフェニルまたはヘテロアリール(ここでは、1〜4個の環原子は、O、N、N−H、N−Rq’’及びSから独立に選択されるヘテロ原子であり、これらのそれぞれは、1〜3個のRq’’で任意に置換されている);
・SO2−(C1〜C6)アルキル;SO−(C1〜C6)アルキル;並びに
・ニトロ;
・実施形態では、Rqは、上に列挙した置換基のいずれか1つ(もしくは複数)でもよく、及び/またはRqは、上に列挙した置換基のサブセットのいずれか1つもしくは複数でもよく;例えば、Rqは、本明細書に記載の化合物中に存在する置換基のいずれか1つ(もしくは複数)でもよく、及び/または本明細書に記載の化合物中に存在するものを包含する置換基のいずれか1つ(もしくは複数)でもよく;
Rq’’の各存在は、以下(ハロゲンから始まり以下のニトロまでが含まれる)からなる群から独立に選択される:
・ハロゲン;
・C1〜C6アルキル;フルオロ(C1〜C6)アルキル;
・ヒドロキシル;
・ヒドロキシ(C1〜C4)アルキル;
・C1〜C6アルコキシ;フルオロ(C1〜C6)アルコキシ;
・(C1〜C6アルキル)C(O)−;
・(C1〜C6アルキル)NH−;(C1〜C6アルキル)2N−(例えば、−NMe2、−NMe(iPr)を含む);
・−ホルミル;ホルミル(C1〜C4)アルキル;シアノ;シアノ(C1〜C4)アルキル;
・ベンジル;ベンジルオキシ;
・ヘテロシクリル)−(C0〜C6、例えばC1〜C6)アルキル(ここでは、ヘテロシクリル部分は、5または6個の環原子を含み、1または2個の環原子は、NH、N(アルキル)、OまたはSから独立に選択されるヘテロ原子であり、前記アルキル部分が存在する場合(すなわち、C1〜C6)、前記アルキル部分は、R1に対する結合点として働き(すなわち、(ヘテロシクリル)−(C1〜C6)アルキルは、アルキル部分を介してR1に結合する);そうでなければ、C0アルキル(すなわち、アルキル部分が存在しない)の場合には、ヘテロシクリル炭素環原子は、R1に対するヘテロシクリルの結合点として働く);
・5〜6の環原子を含むフェニルまたはヘテロアリール(ここでは、1〜4個の環原子は、O、N、N−H、N−(C1〜C6アルキル)及びSから独立に選択されるヘテロ原子である);
・SO2−(C1〜C6)アルキル;SO−(C1〜C6)アルキル;並びに
・ニトロ;
・実施形態では、Rq’’は、上に列挙した置換基のいずれか1つ(もしくは複数)でもよく、及び/またはRq’’は、上に列挙した置換基のサブセットのいずれか1つもしくは複数でもよく;例えば、Rq’’は、本明細書に記載の化合物中に存在する置換基のいずれか1つ(もしくは複数)でもよく、及び/または本明細書に記載の化合物中に存在するものを包含する置換基のいずれか1つ(もしくは複数)でもよく;
Uは以下から選択され:
(i)=CRr(明確にするために、これらの実施形態では、=CRr中の炭素原子はCyの環原子(例えば、環炭素原子)に二重結合し、それによって、環外二重結合を形成しており、例えば、化合物F1〜F7を参照されたい);または
(ii)−U’−C(Rs)2−もしくは−C(Rs)2−U’−;ここでは、
Rrは、水素、F、C1〜C6アルキル、フルオロC1〜C6アルキル、C3〜C6シクロアルキル、C1〜C6アルコキシ C1〜C6フルオロアルコキシ及びシアノであり;
Rsの各存在は、H、F、OH、C1〜C6アルキル、C3〜C6シクロアルキル、NH2、OCO−(C1〜C6アルキル)、OCO−(C3〜C6シクロアルキル)、C1〜C6アルコキシ C1〜C6フルオロアルコキシ及びシアノから独立に選択され;または
Rs−C−Rsは、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを一緒に形成し、ここでは、ヘテロシクリル環原子のうちの1つは、O;S(O)m及びNRuから選択され;
Ruの各存在は、H、C1〜C6アルキル、−C(=O)H、−C(=O)Rv、C(=O)O(C1〜C6アルキル)、C(=O)N(Rw)2、SO2−Rvから独立に選択され、ここでは、Rvは、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから選択され;Rwの各存在は、H、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから独立に選択され(例えば、実施形態では、Rv及びRwのアリール及びヘテロアリール部分は、例えば、1つまたは複数の独立に選択される置換基、例えばF、C1〜C6アルキル、フルオロC1〜C6アルキル、C3〜C6シクロアルキル、C1〜C6アルコキシ、C1〜C6フルオロアルコキシまたはシアノで任意に置換され得る);
U’は、結合;O;NRu;S(O)m(m=0〜2);CH2;及びU’’−CH2−であり;ここでは、U’’はO;NRu;S(O)m(m=0〜2)であり;
Cyは、4〜10(例えば、4〜8、4〜6)個の環原子を含む、C4〜C10(例えば、C4〜C8、C4〜C6)シクロアルキルまたは飽和ヘテロシクリルであり、これらのそれぞれは、1〜3個のRx(Rxの各存在は、F、OH、C1〜C6アルキル、フルオロC1〜C6アルキル、C3〜C6シクロアルキル、C1〜C6アルコキシ C1〜C6フルオロアルコキシ及びシアノから独立に選択される)で任意に置換されており、1〜3個のヘテロ原子は、O、N−H、NRx’(Rx’はRq’’と定義される)及びS(O)m(m=0〜2)から独立に選択され;ヘテロシクリルがその構造の一部として2級アミンを含む場合は:
(i)Vは、ヘテロシクリルの2級アミン部分の窒素を介して連結しており;
(ii)Uは、Cy環炭素原子を介してCyに連結しており;UとCy環炭素の間の結合は単結合または二重結合であり;
(iii)V−Cy及びCy−Uは1,2関係をもたらさず(すなわち、Uに結合しているCy環炭素原子は、Vに結合しているCy環窒素原子に隣接しない);
明確にするために、本明細書で使用する場合、フレーズ「ヘテロシクリルがその構造の一部として2級アミンを含む」及び「その構造の一部として2級アミンを含むヘテロシクリル」は、親複素環がその構造の一部として次の式:
Vは以下から選択され:
(i)−V’−C(Ry)2−もしくは−C(Ry)2−V’−;または
(ii)O、NRzもしくはS(O)m(m=0〜2);または
(iii)−CH=CH−、C=O、C(Ry)2−C(=O)、−C(=O)−C(Ry)2−、−SO2NRzt、NRzSO2、−C(=O)NRz及びNRzC(=O);ここでは:
Ryの各存在は、H、F、OH、C1〜C6アルキル、C3〜C6シクロアルキル、NH2、OCO−(C1〜C6アルキル)、OCO−(C3〜C6シクロアルキル)、C1〜C6アルコキシ C1〜C6フルオロアルコキシ及びシアノから独立に選択され;または
Ry−C−Ryは、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを一緒に形成し、ここでは、ヘテロシクリル環原子のうちの1つは、O;S(O)m及びNRaaから選択され;
Rz及びRaaの各存在は、H、C1〜C6アルキル、−C(=O)H、−C(=O)Rv、C(=O)O(C1〜C6アルキル)、C(=O)N(Rw)2、SO2−Rvから独立に選択され、ここでは、Rvは、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから選択され;Rwの各存在は、H、C1〜C6アルキル、CH2−(5〜10個の環原子を含むヘテロアリール)、CH2−(C6〜C10アリール)及びC6〜C10アリールから独立に選択され;
V’は、結合;O;NRu;S(O)m(m=0〜2);−C(O)−O−(CRy 2)0〜2−、−(CRy 2)0〜2−O−C(O)−、C(Ry)2、C(Ry)2−C(Ry)2;−(Ry)2−V’’;及びV’’−C(Ry)2−であり;ここでは、V’’は、O;NRz;S(O)m(m=0〜2)であり;Ryの各存在は、独立に、上記のように定義され;
(いくつかの実施形態では、V’は、結合;O;NRu;S(O)m(m=0〜2);−C(O)−O−(CH2)0〜2−、−(CH2)0〜2−O−C(O)−、CH2;−CH2−V’’;及びV’’−CH2−であり;ここでは、V’’は、O;NRz;S(O)m(m=0〜2)である);
R2は、H、F、Cl、CF3、CF2CF3、CH2CF3、OCF3、OCHF2、フェニルから選択され;置換フェニル(例えば、F、OH、C1〜C6アルキル、フルオロ(C1〜C6)アルキル C3〜C6シクロアルキル、NH2、C1〜C6アルコキシ、C1〜C6フルオロアルコキシ及びシアノから独立に選択される1〜3個の置換基で置換されたフェニル);チエニル;チアゾリル;並びにピラゾール−l−イルであり;
R3は、H、FもしくはClである。
任意の2つのRaは、それぞれが結合している炭素と共に、3〜6個の環原子を含む、C3〜C6シクロアルキルもしくはヘテロシクリルを一緒に形成し、ここでは、ヘテロシクリル環原子のうちの1つはO;S(O)m及びNRgから選択され;これらの実施形態では、Raの任意の残りの存在及びRbの任意の存在は、Ra及びRbに関係する上記もしくは下記の定義のいずれか1つもしくは複数に従って、それぞれ独立に定義される;または
1つのRa及び1つのRbは、それぞれが結合している炭素と共に、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを形成し、ここでは、ヘテロシクリル環原子のうちの1つはO;S(O)m及びNRgから選択され;これらの実施形態では、他のRa、他のRb並びにRa及びRbの任意の他の残りの存在は、Ra及びRbに関係する上記もしくは下記の定義の任意の1つもしくは複数に従って、それぞれ独立に定義される;または
任意の2つのRbは、それぞれが結合している炭素と共に、3〜6個の環原子を含むC3〜C6シクロアルキルもしくはヘテロシクリルを形成し、ここでは、環原子のうちの1つはO;S(O)m及びNRgから選択され;これらの実施形態では、Raの各存在及びRbの任意の他の残りの存在は、Ra及びRbに関係する上記の定義のいずれか1つまたは複数に従って、それぞれ独立に定義される。
aは2または3(例えば2)であり、bは0であり;A及びBのそれぞれは結合である。
aは2または3(例えば2)であり、bは0以外(例えば1または2)であり、A及びBのそれぞれは結合である。
aは2または3(例えば2)であり、bは0以外(例えば2または3)であり、Aは結合以外、例えばOまたはNRf、例えばOであり、Bは結合である。
(i)Vは、ヘテロシクリルの2級アミン部分の窒素を介して連結しており;
(ii)Uは、Cy環炭素原子を介してCyに連結しており;UとCy環炭素の間の結合は単結合または二重結合であり;
(iii)V−Cy及びCy−Uは1,2関係をもたらさない(すなわち、Uに結合しているCy環炭素原子は、Vに結合しているCy環窒素原子に隣接しない)。
定義
式(I)の化合物の合成
使用
医薬組成物
実施例
方法A
実施例1:(E)−N−(2−アミノフェニル)−3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリルアミドの塩酸塩A6
1MのKOH水溶液(2.2mL)を、(E)−エチル3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリレート(0.19g、0.88mmol)のEtOH:THF(1:1v/v)溶液(10mL)に加えた。得られた溶液を50oCで3時間加熱した。反応が終了してから、この反応混合物を蒸発させて、水(10mL)を残留物に加えた。この溶液を、3MのHCl水溶液で慎重にpH4に酸性化した。生成物の(E)−3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリル酸は水溶性であるので、この溶液を減圧下で濃縮して、固体の残留物を次のステップに直接使用した。ES+ (M+H)+ 189。
ジイソプロピルエチルアミン(DIPEA、0.34g、2.63mmol)を、(E)−3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリル酸(0.17g、0.88mmol)の20mLジクロロメタン(DCM)溶液に加えた。Tert−ブチル−2−アミノフェニルカルバミン酸(0.22g、1.65mmol)及び2−(1H−7−アザベンゾトリアゾル−l−イル)−−1,1,3,3−テトラメチルウロニウムヘキサフルオロリン酸(HATU、0.43g、1.14mmol)を加えてから、この反応混合物を、窒素雰囲気下において室温で一晩攪拌した。HPLCによって示された様に、反応を終了してから、この反応混合物を、飽和重炭酸ナトリウム(NaHCO3)及びブラインで洗浄した。これをNa2SO4で乾燥させ、濾過し、蒸発させて、粗製の(E)−tert−ブチル(2−(3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリルアミド)フェニル)カルバミン酸を得た。この固体を酢酸エチル(50mL)及び飽和NaHCO3で洗浄し、淡色固体として純粋な生成物を得た(0.11g)。ES+ (M+H)+ 379。
4MのHClのジオキサン(2.5mL)溶液を、(E)−tert−ブチル(2−(3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリルアミド)フェニル)カルバミン酸(0.11g、0.29mmol)のジオキサン溶液(2.5mL)に加えた。この混合物を室温で3時間攪拌した。沈殿形成が観察された。HPLC/MSによって示されたときに反応を終了してから、この反応混合物をジエチルエーテル(20mL)で希釈し、その塩を濾過し、エーテルで洗浄し、一晩乾燥させて、(E)−N−(2−アミノフェニル)−3−(イミダゾ[1,2−a]ピリジン−3−イル)アクリルアミドのHCl塩(80mg)を灰白色固体として得た。1H NMR (CD3OD) δ: 9.04 − 9.13(m, 1H), 8.67 (s, 1H), 8.17 (d, J = 15.8 Hz, 1H), 8.00 − 8.13(m, 2H), 7.66 (td, J = 6.9, 1.4 Hz, 1H), 7.42 − 7.58 (m, 4H), 7.21(d, J = 15.8 Hz, 1H);ES+ (M+H)+ 279.2
実施例2:進んだ中間体(E)−tert−ブチル(2−(3−(1H−ピラゾール−4−イル)アクリルアミド)フェニル)カルバミン酸
実施例3:(E)−N−(2−アミノフェニル)−3−(1−(2−(3−クロロ−5−フルオロフェノキシ)エチル)−1H−ピラゾール−4−イル)アクリルアミドの塩酸塩B5
実施例4:(E)−N−(2−アミノフェニル)−3−(1−(2−(3,5−ジフルオロフェノキシ)エチル)−1H−ピラゾール−4−イル)アクリルアミドの塩酸塩B3
実施例5:(E)−N−(2−アミノ−5−フルオロフェニル)−3−(1−メチル−1H−ピラゾール−4−イル)アクリルアミドC2
実施例6:(E)−N−(2−アミノ−4−フルオロフェニル)−3−(1−メチル−1H−ピラゾール−4−イル)アクリルアミドC3
実施例7:(E)−N−(2−アミノフェニル)−3−(1−(2−フェノキシエチル)−1H−ピラゾール−4−イル)アクリルアミドD3
実施例8:(E)−N−(2−アミノ−4−フルオロフェニル)−3−(1−シンナミル−1H−ピラゾール−4−イル)アクリルアミドの塩酸塩D2
[(エトキシカルボニル)メチレン]トリフェニルホスホラン(0.836g、2.4mmol)を、1H−ピラゾール−4−カルバルデヒド(0.192g、2mmol)のTHF(6mL)溶液に室温で加えた。この溶液を、窒素雰囲気下において70oCで8時間加熱した。HPLC/MS解析によって、反応の完了が示され、生成物のE及びZ異性体の両方が観察された。この反応混合物を室温に冷却し、真空中で蒸発させて、粗生成物を得た。この粗生成物を溶出液として0〜80%EtOAcのヘキサン溶液を使用して、シリカゲルカラムクロマトグラフィーによって精製して、プールした画分を蒸発させた後に、純粋な(E)−エチル3−(1H−ピラゾール−4−イル)アクリレート(0.198g、60%)を白色固体として得た。ES+ (M+H)+ 167
実施例9:(E)−N−(2−アミノフェニル)−3−(6−(エトキシメチル)イミダゾ[2,1−b]チアゾール−2−イル)アクリルアミドE1
実施例10:(E)−N−(2−アミノフェニル)−3−(2−シンナミルチアゾール−4−イル)アクリルアミド、E2
方法F
実施例11:4−((1−((1H−インドール−6−イル)メチル)アゼチジン−3−イリデン)メチル)−N−(2−アミノフェニル)−3−クロロベンズアミドF5
実施例12:(E)−N−(2−アミノフェニル)−3−(1−((1−メチルピペリジン−4−イル)メチル)−1H−ピラゾール−4−イル)アクリルアミドG1
実施例13:(E)−N−(2−アミノフェニル)−3−(1−シンナミル−3,5−ジメチル−1H−ピラゾール−4−イル)アクリルアミドG2
脳透過性研究
細胞内での脱アセチル化酵素阻害アッセイ(DACアッセイ)
細胞増殖アッセイ
フラタキシン(FXN)mRNAの発現に対するHDAC阻害剤の効果
Claims (1)
- 式(II)の構造を有する化合物または医薬的に許容可能なその塩
RAはHまたはFであり;
RCはH、ClまたはFであり;
Hetは、オキセタニル、アゼチンジニル、ピペリジニル及び8−アザビシクロ[3.2.1]オクタニルから選択され、Hetがアゼチンジニル、ピペリジニルまたは8−アザビシクロ[3.2.1]オクタニルの場合は、環窒素はRBで置換され;
RBは、C1〜C6アルキル、C1〜C6ヒドロキシアルキル、C1〜C3アルキレン−C3〜C6シクロアルキル、C1〜C3アルキレン−フェニルまたはC1〜C3アルキレン−ピリジルであり;フェニルまたはピリジル環は、メチルで任意に置換されている)。
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