JP2023002643A - Cbp/ep300の複素環式インヒビターおよびがんの処置におけるそれらの使用 - Google Patents
Cbp/ep300の複素環式インヒビターおよびがんの処置におけるそれらの使用 Download PDFInfo
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Abstract
Description
本願は、2016年5月24日に出願された国際特許出願第PCT/CN2016/083124号からの優先権を主張する。国際特許出願第PCT/CN2016/083124の全内容がこれにより本明細書において参考として援用される。
本発明は、CBP/EP300のインヒビターとして有用な化合物、およびこのようなインヒビターを使用してがんを処置する方法に関する。
クロマチンは、染色体を構成するDNAとタンパク質の複雑な組み合わせである。クロマチンは真核細胞の核内に見出され、ヘテロクロマチン形態(凝集型)とユークロマチン(弛緩型)形態に分類される。クロマチンの主な成分はDNAおよびタンパク質である。ヒストンは、クロマチンの主なタンパク質成分であり、DNAが巻き付くスプールとして作用する。クロマチンの機能は、細胞内で適合するようにDNAをより小さな体積にパッケージングし、DNAを強化して有糸分裂および減数分裂を可能にし、発現およびDNA複製の調節機構としての機能を果たすことである。クロマチン構造は、ヒストンタンパク質(特に、ヒストンH3およびH4、最も一般的にはコアヌクレオソーム構造を超えて伸長する「ヒストンテール」内)に対する一連の翻訳後修飾によって調節される。ヒストンテールは、タンパク質間相互作用を受けない傾向があり、最も翻訳後修飾を受ける傾向のあるヒストン部分でもある。これらの修飾には、アセチル化、メチル化、リン酸化、ユビキチン化、およびSUMO化が含まれる。これらのエピジェネティックマークは、ヒストンテール内の特異的残基上にタグを配置する特異的酵素によって書き込まれ、かつ消去され、それにより、エピジェネティック暗号を形成し、次いで、細胞によってクロマチン構造が遺伝子特異的に制御され、それにより転写されるように解釈される。
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式(I)または式(II)の化合物
1つの態様は、式(I)もしくは式(II):
R1は、水素、-NRaRb、C1~6アルキル、C2~6アルケニル、C2~6アルキニルおよび3~8員カルボシクリルであり、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニルおよび3~8員カルボシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C1~6アルコキシ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~C6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換され;
各R2は、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、-F、-Cl、-Br、-I、-NO2、-N(Rt)2、-CN、-C(O)-N(Rt)2、-
O-Rt、-O-C(O)-Rt、-C(O)-Rtおよび-C(O)-O-Rtからなる群から独立して選択され、ここで、C1~6アルキル、C2~6アルケニルおよびC2~6アルキニルはいずれも、1つまたは複数のハロで任意選択的に置換され;
R3は、3~12員炭素環または3~12員複素環であり、ここで、R3の3~12員炭素環および3~12員複素環の各々は、1つまたは複数の基Ruで任意選択的に置換され;
Yは、OまたはN(Rc)であり;
mは、0、1、2、3または4であり;
nは、0、1、2、3または4であり;
pは、0、1、2、3または4であり;
環Aは、ベンゾおよび6員複素環からなる群から選択される縮合環であり;
各R4は、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rxおよび-C(O)-O-Rwからなる群から独立して選択され、ここで、C1~6アルキル、C2~6アルケニルおよびC2~6アルキニルはいずれも、1つまたは複数のオキソまたはハロで任意選択的に置換され;
各R5は、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-O-Rw、-O-C(O)-Rw、-C(O)-Rxおよび-C(O)-O-Rwからなる群から独立して選択され、ここで、C1~6アルキル、C2~6アルケニルおよびC2~6アルキニルはいずれも、1つまたは複数のオキソまたはハロで任意選択的に置換され;
R6は、-N(Rz)-C(O)-Rx、3~12員炭素環または3~12員複素環であり、ここで、R6の3~12員炭素環および3~12員複素環の各々は、1つまたは複数の基Rxで任意選択的に置換され;
Xは、NまたはC(R7)であり;
R7はHであるか、またはオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~C6アルキルであり;
RaおよびRbの各々は、水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C1~6アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~C6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;またはRaおよびRbは、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~3アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されたヘテロシクリルを形成し;
Rcは、水素、C1~6アルキル、C2~6アルケニルまたはC2~6アルキニルであり、ここで、C1~6アルキル、C2~6アルケニルおよびC2~6アルキニルの各々は、オキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換され;
各Rtは、水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C1~6アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC
1~C6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのRtは、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~3アルキルから独立して選択される1つまたは複数の基で任意選択的に置換された3~12員ヘテロシクリルを形成し;
各Ruは、オキソ、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリル、3~12員ヘテロシクリル、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2および-N(Rv)-S(O)2-N(Rv)2から独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリル、3~12員ヘテロシクリルはいずれも、オキソ、ハロ、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、3~12員炭素環、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換され;
各Rvは、水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C1~6アルコキシ、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C1~6アルコキシ、カルボシクリルおよびヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C1~6アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~C6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのRwは、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~3アルキルから独立して選択される1つまたは複数の基で任意選択的に置換された3~12員ヘテロシクリルを形成し;
各Rwは、水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C1~6アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~C6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのRtは、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~3アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されたヘテロシクリルを形成し;
各Rxは、オキソ、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリル、3~12員ヘテロシクリル、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry
、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2および-N(Ry)-S(O)2-N(Ry)2から独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルはいずれも、オキソ、ハロ、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、3~12員炭素環、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換され;
各Ryは、水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C1~6アルコキシ、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C1~6アルコキシ、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C1~6アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~C6アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのRyは、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC1~3アルキルから独立して選択される1つまたは複数の基で任意選択的に置換された3~12員ヘテロシクリルを形成し;そして、
各Rzは、水素、C1~6アルキルから独立して選択される)の化合物またはその塩である。
定義
定義および用語を以下により詳細に記載する。化学元素を、元素周期表、CASバージョン、Handbook of Chemistry and Physics,75th Edに従って同定する。
で、任意の上記方法によって分離するか、または不斉合成によって調製し、任意選択的にさらに富化することができる。例えば、Jacquesら、Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Wilenら、Tetrahedron 33:2725(1977);Eliel,E.L.Stereochemistry of
Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)を参照のこと。
5、C0~C3、C1~C12、C1~C10、C1~C8、C1~C6、C1~C5、C1~C4、またはC1~C3である。C0アルキルは、結合をいう。アルキル基の例には、メチル(Me、-CH3)、エチル(Et、-CH2CH3)、1-プロピル(n-Pr、n-プロピル、-CH2CH2CH3)、2-プロピル(i-Pr、i-プロピル、-CH(CH3)2)、1-ブチル(n-Bu、n-ブチル、-CH2CH2CH2CH3)、2-メチル-1-プロピル(i-Bu、i-ブチル、-CH2CH(CH3)2)、2-ブチル(s-Bu、s-ブチル、-CH(CH3)CH2CH3)、2-メチル-2-プロピル(t-Bu、t-ブチル、-C(CH3)3)、1-ペンチル(n-ペンチル、-CH2CH2CH2CH2CH3)、2-ペンチル(-CH(CH3)CH2CH2CH3)、3-ペンチル(-CH(CH2CH3)2)、2-メチル-2-ブチル(-C(CH3)2CH2CH3)、3-メチル-2-ブチル(-CH(CH3)CH(CH3)2)、3-メチル-1-ブチル(-CH2CH2CH(CH3)2)、2-メチル-1-ブチル(-CH2CH(CH3)CH2CH3)、1-ヘキシル(-CH2CH2CH2CH2CH2CH3)、2-ヘキシル(-CH(CH3)CH2CH2CH2CH3)、3-ヘキシル(-CH(CH2CH3)(CH2CH2CH3))、2-メチル-2-ペンチル(-C(CH3)2CH2CH2CH3)、3-メチル-2-ペンチル(-CH(CH3)CH(CH3)CH2CH3)、4-メチル-2-ペンチル(-CH(CH3)CH2CH(CH3)2)、3-メチル-3-ペンチル(-C(CH3)(CH2CH3)2)、2-メチル-3-ペンチル(-CH(CH2CH3)CH(CH3)2)、2,3-ジメチル-2-ブチル(-C(CH3)2CH(CH3)2)、3,3-ジメチル-2-ブチル(-CH(CH3)C(CH3)3、ヘプチル、オクチル、ノニル、デシル、ウンデシル、およびドデシルが含まれる。
つかの実施形態では、ヘテロシクリルまたは複素環は、飽和環系(3~12員飽和ヘテロシクリル環系など)をいう。いくつかの実施形態では、ヘテロシクリルまたは複素環は、ヘテロアリール環系(5~14員ヘテロアリール環系など)をいう。ヘテロシクリルまたは複素環は、本明細書中に定義の置換基から独立して選択される1つまたは複数の置換基で任意選択的に置換されてよい。
~3個の窒素原子を含む5員ヘテロシクリルまたは複素環の例は、チアゾリル(チアゾール-2-イルおよびチアゾール-2-イルN-オキシドが含まれる)、チアジアゾリル(1,3,4-チアジアゾール-5-イルおよび1,2,4-チアジアゾール-5-イルが含まれる)、オキサゾリル(例えば、オキサゾール-2-イル)、およびオキサジアゾリル(1,3,4-オキサジアゾール-5-イルおよび1,2,4-オキサジアゾール-5-イルなど)である。2~4個の窒素原子を含む5員環ヘテロシクリルまたは複素環の例には、イミダゾリル(イミダゾール-2-イルなど);トリアゾリル(1,3,4-トリアゾール-5-イル;1,2,3-トリアゾール-5-イル、1,2,4-トリアゾール-5-イルなど)、およびテトラゾリル(1H-テトラゾール-5-イルなど)が含まれる。ベンゾ縮合5員ヘテロシクリルまたは複素環の例は、ベンゾオキサゾール-2-イル、ベンゾチアゾール-2-イル、およびベンゾイミダゾール-2-イルである。1~3個の窒素原子および任意選択的な硫黄原子または酸素原子を含む6員ヘテロシクリルまたは複素環の例は、例えば、ピリジル(ピリド-2-イル、ピリド-3-イル、およびピリド-4-イルなど);ピリミジル(ピリミド-2-イルおよびピリミド-4-イルなど);トリアジニル(1,3,4-トリアジン-2-イルおよび1,3,5-トリアジン-4-イルなど);ピリダジニル(特に、ピリダジン-3-イル)、およびピラジニル)である。ピリジンN-オキシドおよびピリダジンN-オキシドならびにピリジル、ピリミド-2-イル、ピリミド-4-イル、ピリダジニル、および1,3,4-トリアジン-2-イルの各基は、ヘテロシクリル基の他の例である。
グリコール酸、グルコン酸、乳酸、ピルビン酸、シュウ酸、リンゴ酸、マレイン酸、マロン酸(maloneic acid)、コハク酸、フマル酸、酒石酸、クエン酸、アスパラギン酸、アスコルビン酸、グルタミン酸、アントラニル酸、安息香酸、桂皮酸、マンデル酸、エンボン酸、フェニル酢酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、およびサリチル酸など)を用いて形成される。
的または間接的な病理的帰結の縮小、疾患状態の安定化(すなわち、悪化しない)、転移の防止、疾患の進行速度の低下、病状の改善または寛解、処置を受けていない場合および緩解または改善された予後の場合に期待される生存期間を比較したときの生存期間の延長のうちの1つまたは複数が含まれる。ある特定の実施形態では、式Iまたは式IIの化合物を、疾患または障害の発症を遅延させるか、疾患または障害の進行を緩慢にするために使用する。処置を必要とする個体には、既に状態または障害を有する個体および(例えば、遺伝子もしくはタンパク質の遺伝的な変異または異常な発現によって)状態または障害を有する傾向のある個体が含まれる。
式(I)の化合物
薬学的に許容され得る組成物
ne glycol)などの賦形剤を使用した軟ゼラチンカプセルおよび硬ゼラチンカプセル中の充填剤として使用することもできる。
化する。
ンインヒビターは、クロマチン(例えば、DNAと会合したヒストン)へのCBPおよび/またはEP300の結合を阻害する。いくつかの実施形態では、CBP/EP300ブロモドメインインヒビターは、クロマチン(例えば、DNAと会合したヒストン)へのCBPブロモドメインおよび/またはEP300ブロモドメインの結合を阻害しおよび/または減少させる。いくつかの実施形態では、CBP/EP300ブロモドメインインヒビターは、クロマチンへのCBPおよび/またはEP300の他のドメインの会合に影響を及ぼさない。いくつかの実施形態では、CBP/EP300ブロモドメインインヒビターは、CBPブロモドメインおよび/またはEP300ブロモドメインとの接触および/または相互作用を介して、CBPおよび/またはEP300に主に(例えば、それらのみに)結合する。いくつかの実施形態では、CBP/EP300ブロモドメインインヒビターは、CBPブロモドメインおよび/またはEP300ブロモドメインならびにさらなるCBPおよび/またはEP300残基および/またはドメインとの接触および/または相互作用を介して、CBPおよび/またはEP300に結合する。クロマチンとの会合をアッセイする方法は当技術分野で公知であり、クロマチン分画、BRETアッセイ(Promega)、FRAPアッセイ、クロマチン免疫沈降(ChIP)、生物物理学的結合アッセイおよび/またはヒストン会合アッセイ(Histone Association Assay)が含まれる
が、これらに限定されない。例えば、Dasら、BioTechniques 37:961-969(2004)を参照のこと。
AFLTLARDKHWEFSSLRRSKWSTLCMLVELHTQGQD(UniProt番号Q92793(配列番号1)のアミノ酸残基1321~1701)の1つまたは複数の残基に実質的に結合しない。いくつかの実施形態では、CBP/EP300のブロモドメインインヒビターは、アミノ酸配列ENKFSAKRLPSTRLGTFLENRVNDFLRRQNHPESGEVTVRVVHASDKTVEVKPGMKARFVDSGEMAESFPYRTKALFAFEEIDGVDLCFFGMHVQEYGSDCPPPNQRRVYISYLDSVHFFRPKCLRTAVYHEILIGYLEYVKKLGYTTGHIWACPPSEGDDYIFHCHPPDQKIPKPKRLQEWYKKMLDKAVSERIVHDYKDIFKQATEDRLTSAKELPYFEGDFWPNVLEESIKELEQEEEERKREENTSNESTDVTKGDSKNAKKKNNKKTSKNKSSLSRGNKKKPGMPNVSNDLSQKLYATMEKHKEVFFVIRLIAGPAANSLPPIVDPDPLIPCDLMDGRDAFLTLARDKHLEFSSLRRAQWSTMCMLVELHTQSQD(UniProt番号Q09472(配列番号2)のアミノ酸残基1285~1664)の1つまたは複数の残基に実質的に結合しない。いくつかの実施形態では、CBP/EP300ブロモドメインインヒビターは、CBPおよび/またはEP300のヒストンアセチルトランスフェラーゼ(HAT)触媒活性を阻害しない。
6A、AMY2B、GPR183、MYOF、IL29、AIDA、SPRYI、ENOPH1、IL1RN、SLAMF1、PGM2L1、SSBP3、MMP23B、HISTlH3J、MYO1B、BEND5、S1PR1、CDK6、GPR56、ZC3HIZA、DOK5、DUSPI、CYB5R2、KCNAB2、LAG3、KLF10、GK、SHC4、IL12RB2、CD109、HAVCR2(TIM-3)、LTA、FAM40B、HMGCSI、HSPAlA、ZNF705A、CMAH、KIF3A、CHN1、KBTBD8、TNF、MOP-1、RASGRP4、INSIG1、SLAMF7、ORl0H4、LPL、HIST1H2BJ、LIF、IGF1、ILl8RAP、OR52N4、OR1D2、CCR4、CXCR5、IL1R1、MICAL2、NRNl、PICALM、B3GNT5、IFI44L、CXCR3、ICOS、IFIT2、NCR3、HSPA1B、CD80、GNG2、C7orf68、GPRl71、RPSl0P7、IL23A、LOC283174、PLK2、EMP1、FNBP1L、CD226、RBMS3、IL23R、PTGER4、GZMB、F5および/またはHIST1H2BKの1つまたは複数の減少した発現レベルを有する個体における(例えば、腫瘍部位における)Treg細胞を特徴とする。いくつかの実施形態では、Treg細胞バイオマーカーは、LAG3、CTLA4および/またはFOXP3の1つまたは複数である。免疫機能を増強する方法のいくつかの実施形態では、増強された免疫機能は、Treg細胞の存在下で、CD3/CD28刺激に対する増強されたナイーブT細胞応答性を特徴とする。いくつかの実施形態では、CD8 T細胞プライミングは、CD8 T細胞におけるT細胞増殖の増加および/または細胞溶解活性の増強を特徴とする。いくつかの実施形態では、CD8 T細胞活性化は、T-IFN+CD8 T細胞の頻度の上昇を特徴とする。いくつかの実施形態では、CD8 T細胞は、抗原特異的T細胞である。いくつかの実施形態では、免疫回避が阻害される。
Pおよび/またはEP300媒介障害は、線維性疾患である。特定の線維性疾患には、例えば、肺線維症、珪肺症、嚢胞性線維症、腎線維症、肝線維症、肝硬変、原発性硬化性胆管炎、原発性胆汁性肝硬変、心内膜心筋線維症、縦隔線維症、骨髄線維症、後腹膜線維症、進行性塊状線維症、腎性全身性線維症、クローン病、ケロイド、心筋梗塞、全身性硬化症または関節線維症が含まれ得る。
形態では、肺がんはNSCLCである。ある特定の実施形態では、がんは乳がんである。
ある特定の実施形態では、がんは黒色腫である。
互に近い時間に投与する。さらに、化合物を同一の投薬形態で投与するかどうかは問わない(例えば、ある化合物を局所的に投与することができ、別の化合物を経口投与することができる)。
テゾミブ(ベルケイド(登録商標)、Millennium Pharm.)、ジスルフィラム、没食子酸エピガロカテキン、サリノスポラミドA、カルフィルゾミブ、17-AAG(ゲルダナマイシン)、ラジシコール、乳酸デヒドロゲナーゼA(LDH-A)、フルベストラント(ファスロデックス(登録商標)、AstraZeneca)、スニチブ(スーテント(登録商標)、Pfizer/Sugen)、レトロゾール(フェマラ(登録商標)、Novartis)、メシル酸イマチニブ(グリベック(登録商標)、Novartis)、フィナスナート(バタラニブ(登録商標)、Novartis)、オキサリプラチン(エロキサチン(登録商標)、Sanofi)、5-FU(5-フルオロウラシル)、ロイコボリン、ラパマイシン(シロリムス、ラパミューン(登録商標)、Wyeth)、ラパチニブ(タイケルブ(登録商標)、GSK572016、Glaxo Smith Kline)、ロナファミブ(SCH66336)、ソラフェニブ(ネクサバール(登録商標)、Bayer Labs)、ゲフィチニブ(イレッサ(登録商標)、AstraZeneca)、AG1478、アルキル化剤(チオテパおよびサイトキサン(登録商標)シクロホスファミド(cyclosphosphamide)など);スルホン酸アルキル(ブスルファン、インプロスルファン、およびピポスルファンなど);アジリジン(ベンゾドーパ、カルボコン、メツレドーパ、およびウレドーパなど);エチレンイミンおよびメチルメラミン(methylamelamine)(アルトレタミン、トリエチレンメラミン、トリエチレンホスホラミド、トリエチレンチオホスホラミド、およびトリメチルメラミン(trimethylomelamine)が含まれる);アセトゲニン(特に、ブタラシンおよびブタラシノン);カンプトテシン(トポテカンおよびイリノテカンが含まれる);ブリオスタチン;カリスタチン;CC-1065(そのアドゼレシン、カルゼレシン、およびビセレシンの合成アナログが含まれる);クリプトフィシン(特に、クリプトフィシン1およびクリプトフィシン8);副腎皮質ステロイド(プレドニゾンおよびプレドニゾロンが含まれる);酢酸シプロテロン;5α-レダクターゼ(フィナステリドおよびデュタステリドが含まれる);ボリノスタット、ロミデプシン、パノビノスタット、バルプロ酸、モセチノスタットドラスタチン;アルデスロイキン、タルクデュオカルマイシン(合成アナログのKW-2189、およびCB1-TM1が含まれる);エロイテロビン;パンクラチスタチン;サルコジクチイン;スポンギスタチン;ナイトロジェンマスタード(クロラムブシル、クロマファジン、クロロホスファミド、エストラムスチン、イフォスファミド、メクロレタミン、メクロレタミンオキシド塩酸塩、メルファラン、ノブエンビキン、フェネステリン、プレドニムスチン、トロホスファミド、ウラシルマスタードなど);ニトロソ尿素(カルムスチン、クロロゾトシン、ホテムスチン、ロムスチン、ニムスチン、およびラミムスチン(ranimnustine)など);抗生物質(エンジイン抗生物質(例えば、カリチアマイシン、特に、カリチアマイシンγ1Iおよびカリチアマイシンω1I(Angew Chem. Intl. Ed. Engl. 1994 33:183-186)など);ジネミシン(ジネミシンAが含まれる);ビスホスホナート(クロドロナートなど);エスペラミシン;ならびにネオカルチノスタチン発色団および関連色素タンパク質エンジイン抗生物質発色団)、アクラシノマイシン、アクチノマイシン、アウスラマイシン、アザセリン、ブレオマイシン、カクチノマイシン、カラビシン、カミノマイシン、カルジノフィリン、クロモマイシニス、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、アドリアマイシン(登録商標)(ドキソルビシン)、モルホリノ-ドキソルビシン、シアノモルホリノ-ドキソルビシン、2-ピロリノ-ドキソルビシン、およびデオキシドキソルビシン)、エピルビシン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン(マイトマイシンCなど)、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポルフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン;代謝拮抗物質(メトトレキサートおよび5-フルオロウラシル(5-FU)など);葉酸アナログ(デノプテリン、メトトレキサート、プテロプテリン、トリメトレキサートなど);プリンアナログ(フルダラビン、6-メルカプトプリン、
チアミプリン、チオグアニンなど);ピリミジンアナログ(アンシタビン、アザシチジン、6-アザウリジン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フロクスウリジンなど);アンドロゲン(カルステロン、ドロモスタノロンプロピオネート、エピチオスタノール、メピチオスタン、テストラクトンなど);抗アドレナル(アミノグルテチミド、ミトタン、トリロスタンなど);葉酸補給剤(フォリン酸(frolinic acid)など);アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ベストラブシル;ビサントレン;エダトラキサート;デフォファミン;デメコルシン;ジアジクオン;エルフォミチン;エリプチニウムアセタート;エポチロン;エトグルシド;硝酸ガリウム;ヒドロキシ尿素;レンチナン;ロニダイニン;メイタンシノイド(メイタンシンおよびアンサミトシンなど);ミトグアゾン;ミトキサントロン;モピダムノール;ニトラエリン;ペントスタチン;フェナメット;ピラルビシン;ロソキサントロン;ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;PSK(登録商標)ポリサッカリド複合体(JHS Natural Products,Eugene,Oreg.);ラゾキサン;リゾキシン;シゾフラン;スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2’,2’’-トリクロロトリエチルアミン;トリコテセン(特に、T-2毒素、ベラクリンA、ロリジンA、およびアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン;アラビニノシド(「Ara-C」);シクロホスファミド;チオテパ;タキソイド(例えば、タキソール(パクリタキセル;Bristol-Myers Squibb Oncology,Princeton,N.J.)、アブラキサン(登録商標)(クレモフォール非含有)、パクリタキセルのアルブミン結合ナノ粒子製剤(American Pharmaceutical Partners,Schaumberg,Ill.)、およびタキソテール(登録商標)(ドセタキセル、ドキセタキセル;Sanofi-Aventis));クロランムブシル;ジェムザール(登録商標)(ゲムシタビン);6-チオグアニン;メルカプトプリン;メトトレキサート;白金アナログ(シスプラチンおよびカルボプラチンなど);ビンブラスチン;エトポシド(VP-16);イフォスファミド;ミトキサントロン;ビンクリスチン;ナベルビン(登録商標)(ビノレルビン);ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;カペシタビン(ゼローダ(登録商標));イバンドロナート;CPT-11;トポイソメラーゼインヒビターRFS2000;ジフルオロメチルオルニチン(DMFO);レチノイド(レチノイン酸など);ならびに上記のいずれかの薬学的に許容され得る塩、酸、および誘導体が含まれる。
質キナーゼインヒビター;(vi)アンチセンスオリゴヌクレオチド(特に、異常な細胞増殖に関与するシグナル伝達経路における遺伝子発現を阻害するもの)(例えば、PKC-α、Ralf、およびH-Rasなど);(vii)リボザイム(VEGF発現インヒビター(例えば、アンギオザイム(登録商標))およびHER2発現インヒビターなど);(viii)ワクチン(遺伝子療法ワクチン(例えば、アロベクチン(登録商標)、ロイベクチン(登録商標)、およびバキシド(登録商標));プロリュウキン(登録商標)、rIL-2;トポイソメラーゼ1インヒビター(ルルトテカン(登録商標)など);アバレリクス(登録商標)rmRHなど);ならびに(ix)上記のいずれかの薬学的に許容され得る塩、酸、および誘導体も含まれる。
bgenix/Amgenを参照のこと)など);EMD55900(Stragliottoら、Eur.J.Cancer 32A:636-640(1996));EMD7200(マツズマブ)(EGFおよびTGF-αの両方とEGFR結合を競合するEGFRに指向するヒト化EGFR抗体)(EMD/Merck);ヒトEGFR抗体、HuMax-EGFR(GenMab);E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3、およびE7.6.3として公知であり、米国特許第6,235,883号に記載の完全ヒト抗体;MDX-447(Medarex Inc);ならびにmAb806またはヒト化mAb806(Johnsら、J. Biol. Chem. 279(29):30375-30384(2004))が含まれる。抗EGFR抗体を、細胞毒性剤とコンジュゲートさせ、それにより、免疫コンジュゲートを生成することができる(例えば、欧州特許第659,439A2号、Merck Patent GmbHを参照のこと)。EGFRアンタゴニストには、低分子(米国特許第5,616,582号、同第5,457,105号、同第5,475,001号、同第5,654,307号、同第5,679,683号、同第6,084,095号、同第6,265,410号、同第6,455,534号、同第6,521,620号、同第6,596,726号、同第6,713,484号、同第5,770,599号、同第6,140,332号、同第5,866,572号、同第6,399,602号、同第6,344,459号、同第6,602,863号、同第6,391,874号、同第6,344,455号、同第5,760,041号、同第6,002,008号、および同第5,747,498号、ならびに以下のPCT公開:WO98/14451号、WO98/50038号、WO99/09016号、およびWO99/24037に記載の化合物など)が含まれる。特定の低分子EGFRアンタゴニストには、OSI-774(CP-358774、エルロチニブ、タルセバ(登録商標)Genentech/OSI Pharmaceuticals);PD183805(CI1033、2-プロペンアミド,N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-7-[3-(4-モルホリニル)プロポキシ]-6-キナゾリニル]-,ジヒドロクロリド,Pfizer Inc.);ZD1839、ゲフィチニブ(イレッサ(登録商標))4-(3’-クロロ-4’-フルオロアニリノ)-7-メトキシ-6-(3-モルホリノプロポキシ)キナゾリン、AstraZeneca);ZM105180((6-アミノ-4-(3-メチルフェニル-アミノ)-キナゾリン、Zeneca);BIBX-1382(N8-(3-クロロ-4-フルオロ-フェニル)-N2-(1-メチル-ピペリジン-4-イル)-ピリミド[5,4-d]ピリミジン-2,8-ジアミン、Boehringer Ingelheim);PKI-166((R)-4-[4-[(1-フェニルエチル)アミノ]-1H-ピロロ[2,3-d]ピリミジン-6-イル]-フェノール);(R)-6-(4-ヒドロキシフェニル)-4-[(1-フェニルエチル)アミノ]-7H-ピロロ[2,3-d]ピリミジン);CL-387785(N-[4-[(3-ブロモフェニル)アミノ]-6-キナゾリニル]-2-ブチンアミド);EKB-569(N-[4-[(3-クロロ-4-フルオロフェニル)アミノ]-3-シアノ-7-エトキシ-6-キノリニル]-4-(ジメチルアミノ)-2-ブテンアミド)(Wyeth);AG1478(Pfizer);AG1571(SU5271;Pfizer);デュアルEGFR/HER2チロシンキナーゼインヒビター(ラパチニブ(タイケルブ(登録商標)、GSK572016、またはN-[3-クロロ-4-[(3フルオロフェニル)メトキシ]フェニル]-6[5[[[2メチルスルホニル)エチル]アミノ]メチル]-2-フラニル]-4-キナゾリンアミン)など)が含まれる。
現する細胞を阻害するEKB-569(Wyethから入手可能)など);ラパチニブ(GSK572016;Glaxo-SmithKlineから入手可能)、経口HER2およびEGFRチロシンキナーゼインヒビター;PKI-166(Novartisから入手可能);pan-HERインヒビター(カネルチニブ(CI-1033;Pharmacia)など);Raf-1インヒビター(Raf-1シグナル伝達を阻害するISIS Pharmaceuticalsから入手可能なアンチセンス剤ISIS-5132など);非HER標的化TKインヒビター(メシル酸イマチニブ(グリベック(登録商標)、Glaxo SmithKlineから入手可能)など);多標的化チロシンキナーゼインヒビター(スニチニブ(スーテント(登録商標)、Pfizerから入手可能)など);VEGF受容体チロシンキナーゼインヒビター(バタラニブ(PTK787/ZK222584、Novartis/Schering AGから入手可能)など);MAPK細胞外制御キナーゼIインヒビターCI-1040(Pharmaciaから入手可能);キナゾリン(PD153035、4-(3-クロロアニリノ)キナゾリンなど);ピリドピリミジン;ピリミドピリミジン;ピロロピリミジン(CGP59326、CGP60261、およびCGP62706など);ピラゾロピリミジン、4-(フェニルアミノ)-7H-ピロロ[2,3-d]ピリミジン;クルクミン(ジフェルロイルメタン、4,5-ビス(4-フルオロアニリノ)フタルイミド);ニトロチオフェン部分を含むチロホスチン;PD-0183805(Warner-Lamber);アンチセンス分子(例えば、HERコード核酸に結合するもの);キノキサリン(米国特許第5,804,396号);トリホスチン(米国特許第5,804,396号);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);pan-HERインヒビター(CI-1033(Pfizer)など);アフィニタク(ISIS 3521;Isis/Lilly);メシル酸イマチニブ(グリベック(登録商標));PKI166(Novartis);GW2016(Glaxo SmithKline);CI-1033(Pfizer);EKB-569(Wyeth);セマキシニブ(Pfizer);ZD6474(AstraZeneca);PTK-787(Novartis/Schering AG);INC-1C11(Imclone)、ラパマイシン(シロリムス、ラパミューン(登録商標));または以下の特許公報のいずれかに記載のもの:米国特許第5,804,396号;WO1999/09016号(American Cyanamid);WO1998/43960号(American Cyanamid);WO1997/38983号(Warner Lambert);WO1999/06378号(Warner Lambert);WO1999/06396号(Warner Lambert);WO1996/30347号(Pfizer、Inc);WO1996/33978号(Zeneca);WO1996/3397号(Zeneca)、およびWO1996/33980号(Zeneca)も含まれる。
ン、6-TG、チオテパ、トポテカン、トレミフェン、トシツモマブ、トラスツズマブ、トレチノイン、ATRA、ウラシルマスタード、バルルビシン、ビンブラスチン、ビンクリスチン、ビノレルビン、ゾレドロナートまたはゾレドロン酸のいずれか1つまたは複数から選択される抗増殖剤または化学療法剤と組み合わせて投与される。
少させ、遮断し、阻害し、抑止しまたは妨害する他の分子が含まれる。1つの実施形態では、PD-1結合アンタゴニストは、PD-1を介したシグナル伝達によって媒介されるTリンパ球上で発現される細胞表面タンパク質によってまたはそれを介して媒介される負の共刺激シグナルを低下させて、機能障害性T細胞の機能障害を緩和する(例えば、抗原認識に対するエフェクター応答を増強する)。いくつかの実施形態では、PD-1結合アンタゴニストは、抗PD-1抗体である。特定の態様では、PD-1結合アンタゴニストは、本明細書中に記載のニボルマブ(MDX-1106-04、MDX-1106、ONO-4538、BMS-936558およびOPDIVO(登録商標)としても公知である)である。別の特定の態様では、PD-1結合アンタゴニストは、本明細書中に記載のペムブロリズマブ(MK-3475、Merck 3475、KEYTRUDA(登録商標)およびSCH-900475としても公知である)である。別の特定の態様では、PD-1結合アンタゴニストは、本明細書中に記載のCT-011(hBATまたはhBAT-1としても公知である)である。さらに別の特定の態様では、PD-1結合アンタゴニストは、本明細書中に記載のAMP-224(B7-DCIgとしても公知である)である。
クロスポリン、FK506、ラパマイシン、ミコフェノール酸モフェチル、レフルノミド、NSAID(例えば、イブプロフェン)、コルチコステロイド(例えば、プレドニゾロン)、ホスホジエステラーゼインヒビター、アデノシンアゴニスト(adensosine agonist)、抗血栓剤、補体インヒビター、アドレナリン作動剤、TNFまたはIL-lなどの炎症誘発性サイトカインによるシグナル伝達を干渉する薬剤(例えば、NIK、IKK、p38、またはMAPキナーゼインヒビター)、IL-l変換酵素インヒビター、T細胞シグナル伝達インヒビター(例えば、キナーゼインヒビター)、メタロプロテイナーゼインヒビター、スルファサラジン、6-メルカプトプリン、アンギオテンシン変換酵素インヒビター、可溶性サイトカイン受容体(例えば、可溶性p55TNF受容体またはp75TNF受容体ならびに誘導体p75TNFRigG(エタネルセプト)およびp55TNFRigG(レネルセプト)、siL-lRI、siL-lRII、siL-6R)、抗炎症性サイトカイン(例えば、IL-4、IL-l0、IL-11、IL-13、およびTGF)、セレコキシブ、葉酸、硫酸ヒドロキシクロロキン、ロフェコキシブ、エタネルセプト、インフリキシマブ、アダリムマブ、セルトリズマブ、トシリズマブ、アバタセプト、ナプロキセン、バルデコキシブ、スルファサラジン、メチルプレドニゾロン、メロキシカム、酢酸メチルプレドニゾロン、金チオリンゴ酸ナトリウム、アスピリン、トリアムシノロンアセトニド、ナプシル酸プロポキシフェン/apap、フォラート(folate)、ナブメトン、ジクロフェナク、ピロキシカム、エトドラク、ジクロフェナクナトリウム、オキサプロジン、オキシコドンHCl、重酒石酸ヒドロコドン/apap、ジクロフェナクナトリウム/ミソプロストール、フェンタニル、アナキンラ、トラマドールHCl、サルサラート、スリンダク、シアノコバラミン/fa/ピリドキシン、アセトアミノフェン、アレンドロネートナトリウム、プレドニゾロン、コルチゾン、ベタメタゾン、硫酸モルヒネ、塩酸リドカイン、インドメタシン、グルコサミンスルフ(glucosamine sulf)/コンドロイチン、アミトリプチリンHCl、スルファジアジン、
オキシコドンHCVアセトアミノフェン、オロパタジンHClミソプロストール、ナプロキセンナトリウム、オメプラゾール、シクロホスファミド、リツキシマブ、IL-l TRAP、MRA、CTLA4-IG、IL-18BP、抗IL-12、抗ILlS、BIRB-796、SCI0-469、VX-702、AMG-548、VX-740、ロフルミラスト、IC-485、CDC-801、SlPlアゴニスト(FTY720など)、PKCファミリーインヒビター(例えば、ルボキシスタウリン、またはAEB-071)、またはメソプラムと共投与することができる。ある特定の実施形態では、式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を、メトトレキサートまたはレフルノミドと共投与することができる。中程度または重症な関節リウマチの症例では、式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を、上記のシクロスポリンおよび抗TNF抗体と共投与することができる。式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を、以下と共投与することもできる:ブデノシド;上皮成長因子;コルチコステロイド;シクロスポリン、スルファサラジン;アミノサリチラート;6-メルカプトプリン;アザチオプリン;メトロニダゾール;リポキシゲナーゼインヒビター;メサラミン;オルサラジン;バルサラジド;抗酸化剤;トロンボキサンインヒビター;IL-l受容体アンタゴニスト;抗IL-lモノクローナル抗体;抗IL-6モノクローナル抗体;成長因子;エラスターゼインヒビター;ピリジニル-イミダゾール化合物;他のヒトサイトカインまたは成長因子(例えば、TNF、LT、IL-l、IL-2、IL-6、IL-7、IL-8、IL-12、IL-15、IL-16、IL-23、EMAP-II、GM-CSF、FGF、およびPDGF)の抗体またはアンタゴニスト;細胞表面分子(例えば、CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69、もしくはCD90またはそのリガンド);メトトレキサート;シクロスポリン;FK506;ラパマイシン;ミコフェノール酸モフェチル;レフルノミド;NSAID(例えば、イブプロフェン);コルチコステロイド(例えば、プレドニゾロン);ホスホジエステラーゼインヒビター;アデノシンアゴニスト;抗血栓剤;補体インヒビター;アドレナリン作動剤;TNF5またはIL-l
などの炎症誘発性サイトカインによるシグナル伝達を干渉する薬剤(例えば、NIK、IKK、またはMAPキナーゼインヒビター);IL-l変換酵素インヒビター;TNF変換酵素インヒビター;T細胞シグナル伝達インヒビター(キナーゼインヒビターなど);メタロプロテイナーゼインヒビター;スルファサラジン;アザチオプリン;6-メルカプトプリン;アンギオテンシン変換酵素インヒビター;可溶性サイトカイン受容体(例えば、可溶性p55TNF受容体またはp75TNF受容体、siL-lRI、siL-lRII、siL-6R)、および抗炎症性サイトカイン(例えば、IL-4、IL-l0、IL-11、IL-13、またはTGF)。
容され得る塩を、CD2、CD3、CD4、CD8、CD19、CD20、CD25、CD28、CD30、CD40、CD45、CD69、CD80、CD86、CD90またはそのリガンドなどの細胞表面分子の抗体と共投与することができる。式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を、メトトレキサート、シクロスポリン、FK506、ラパマイシン、ミコフェノール酸モフェチル、レフルノミド、SlPlアゴニスト、NSAID(例えば、イブプロフェン)、コルチコステロイド(例えば、プレドニゾロン)、ホスホジエステラーゼインヒビター、アデノシンアゴニスト、抗血栓剤、補体インヒビター、アドレナリン作動剤、TNFまたはIL-lなどの炎症誘発性サイトカインによるシグナル伝達を干渉する薬剤(例えば、NIK、IKK、p38、またはMAPキナーゼインヒビター)、IL-l変換酵素インヒビター、TACEインヒビター、T細胞シグナル伝達インヒビター(例えば、キナーゼインヒビター)、メタロプロテイナーゼインヒビター、スルファサラジン、アザチオプリン、6-メルカプトプリン、アンギオテンシン変換酵素インヒビター、可溶性サイトカイン受容体(例えば、可溶性のp55TNF受容体またはp75TNF受容体、siL-lRI、siL-lRII、またはsiL-6R)、または抗炎症性サイトカイン(例えば、IL-4、IL-l0、IL-13、またはTGF)と共投与することもできる。
クラート、グアイフェネシン/d-メトルファン、p-エフェドリン/cod/-クロルフェニル、ガチフロキサシン、塩酸セチリジン、モメタゾンフロアート、キシナホ酸サルメテロール、ベンゾナタート、セファレキシン、pe/ヒドロコドン/クロルフェニル、セチリジンHCl/プソイドエフェド、フェニレフリン/cod/プロメタジン、コデイン/プロメタジン、セフプロジル、デキサメタゾン、グアイフェネシン/プソイドエフェドリン、クロルフェニラミン/ヒドロコドン、ネドクロミルナトリウム、硫酸テルブタリン、エピネフリン、メチルプレドニゾロン、抗IL-13抗体、または硫酸メタプロテレノールと共投与することができる。
メチンナトリウム、カルシポトリエン、シクロスポリン、ジクロフェナクナトリウム/ミソプロストール、フルオシノニド、硫酸グルコサミン、金チオリンゴ酸ナトリウム、重酒石酸ヒドロコドン/apap、イブプロフェン、リセドロン酸ナトリウム、スルファジアジン、チオグアニン、バルデコキシブ、アレファセプト、D2E7(アダリムマブ)、またはエファリズマブと共投与することができる。
-イル)キナゾリン-4-アミン,ジ4-メチルベンゼンスルホナートまたはその薬学的に許容され得る塩(例えば、ラパチニブ)である。
alkyloid)である。ある特定の実施形態では、ビンカアルカロイドはビノレルビンである。任意の方法のある特定の実施形態では、化学療法薬はヌクレオシドアナログである。ある特定の実施形態では、ヌクレオシドアナログはゲムシタビンである。
以下の実施例に示すように、ある特定の例示的な実施形態では、化合物を以下の一般的手順に従って調製することができる。本明細書中に記載のように、一般的方法には本発明のある特定の化合物の合成を示しているが、以下の一般的方法および当業者に公知の他の方法を全ての化合物ならびにこれらの各化合物のサブクラスおよび種に適用することができると理解されたい。
れないが、ナトリウムtert-ブトキシドまたは炭酸セシウムの存在下、適切な溶媒、例えば1,4-ジオキサン中、高温で、ハロゲン化物(31または32)をテトラヒドロキノリン(30)とクロスカップリングして、式(33)の化合物を得ることができる。
1H NMR (400 MHz, CDCl3) δ 7.37 - 7.28 (m, 2H), 6.91 (d, J = 8.4
Hz, 1H), 4.40 (s, 2H), 4.35 (s, 1H), 4.12 - 4.05 (m, 2H), 3.85 -
3.78 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H). LCMS M/Z (M+H) 285.
1H NMR (400 MHz, CDCl3, 15 / 17 H) δ 7.19 - 7.06 (m, 2H), 6.86 (td, J = 7.4, 1.2 Hz, 1H), 6.76 (dd, J = 8.0, 1.1 Hz, 1H), 4.35 (s, 2H), 3.97 (s, 1H), 3.75 - 3.67 (m, 2H), 3.23 - 3.15 (m, 2H), 2.75 (d, J = 4.7 Hz, 3H). LCMS M/Z (M+H) 206.
1H NMR (400 MHz, CDCl3) δ 7.34 - 7.25 (m, 1H), 7.19 (dd, J = 8.3, 2.3 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.33 (s, 2H), 4.30 (s, 1H), 3.97 (s, 1H), 3.71 - 3.64 (m, 2H), 3.19 (dt, J = 5.1, 3.2 Hz, 2H), 2.78 (d, J = 4.7 Hz, 3H). LCMS M/Z (M+H) 284.
1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 9.03 (d, J = 2.8 Hz, 1H), 8.56 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz,
1H), 7.93 (d, J = 8.4 Hz, 1H), 7.55 - 7.52 (m, 1H).
1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 2.8 Hz, 1H), 8.15 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.44 - 7.41 (m, 1H), 6.78 (t, J = 56.0 Hz, 1H).
混合物を飽和NaHCO3水溶液(1L)に0℃で注ぎ入れ、DCM(200mL×2)で抽出した。合わせた有機層をNa2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣をシリカゲルクロマトグラフィ(石油エーテル/EtOAc=20:1)によって精製して、表題化合物(8.0g、56%)を褐色油状物として得た。
1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.50 (t, J = 56.8 Hz, 1H), 3.33 (t,
J = 5.6 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 1.98 - 1.92 (m, 2H).
1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 6.78 (t, J = 55.2 Hz, 1H), 6.72 (s, 1H), 3.31 (t, J = 5.2 Hz, 2H), 2.74 (t, J = 6.0 Hz,
2H), 1.95 - 1.87 (m, 2H).
1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.39 (s, 1H), 6.96 (s, 1H
), 6.81 (s, 1H), 6.54 (t, J = 55.2 Hz, 1H), 4.12 - 4.01 (m, 1H), 3.95 (s, 3H), 3.35 (t, J = 5.2 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.01 - 1.91 (m, 2H). LCMS M/Z (M+H) 264. LCMS M/Z (M+H) 264.
1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.37 (s, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.89 - 7.86 (m, 1H), 7.72 - 7.70 (m, 2H), 3.92
(s, 3H).
LCMS M/Z (M+H) 336.
1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.57 - 8.51 (m, 2H), 8.31 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H),
7.78 (d, J = 5.6 Hz, 1H), 7.73 - 7.63 (m, 1H), 3.91 (s, 3H).
1H NMR (400 MHz, CDCl3, 16 / 17 H) δ 7.59 (s, 1H), 4.32 (s, 2H),
3.67 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 1.48 (s, 9H).
1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 4.31 (t, J = 1.6 Hz, 2H), 3.69 (t, J = 5.8 Hz, 2H), 3.57 (s, 3H), 2.69 (t, J = 1.7 Hz,
2H), 1.49 (s, 9H).
1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 4.6 Hz, 1H), 4.53 - 4.32
(m, 2H), 3.88 - 3.74 (m, 2H), 3.57 (d, J = 1.3 Hz, 3H), 2.82 -
2.64 (m, 2H), 2.17 (d, J = 9.4 Hz, 3H).
2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(4.2mg、0.0053mmol)および2-(ジシクロヘキシルホスフィノ)-2’,4’,6’-トリイソプロピルビフェニル(5.1mg、0.010mmol)を添加した。混合物を窒素雰囲気下、80℃で16時間撹拌した。反応混合物を室温に冷却し、1-ブロモイソキノリン(25mg、0.12mmol)、K3PO4・H2O(71mg、0.30mmol)、水(0.3mL)およびクロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(4.2mg、0.0053mmol)を添加した。反応混合物を窒素雰囲気下、70℃で4時間撹拌した。次いで、反応混合物を室温に冷却し、真空中で濃縮した。粗残渣をジクロロメタン(5mL)で希釈し、無水MgSO4で乾燥させ、セライトで濾過し、真空中で濃縮した。得られた混合物を逆相クロマトグラフィ(アセトニトリル20-60%/0.1%水酸化アンモニウムを含む水)によって精製して、表題化合物(8.4mg、14%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 5.7 Hz, 1H), 8.07 (td, J = 8.0, 1.1 Hz, 2H), 7.87 - 7.76 (m, 2H), 7.73 (d, J = 2.3 Hz,
1H), 7.66 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.52 (dd, J = 8.2, 2.3 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.55 (q, J = 4.3 Hz, 1H),
4.56 (s, 2H), 4.11 (dd, J = 5.2, 3.6 Hz, 2H), 3.76 (dd, J = 5.2, 3.4 Hz, 2H), 2.55 (d, J = 4.3 Hz, 3H). LCMS M/Z (M+H) 334.
438mmol)、(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)メタンスルホネート(9.4mg、0.010mmol)および2-(ジシクロヘキシルホスフィノ)-2’,4’,6’-トリイソプロピルビフェニル(5.1mg、0.010mmol)を添加した。混合物を窒素雰囲気下、90℃で16時間撹拌した。次いで、反応混合物を室温に冷却し、真空中で濃縮した。粗残渣をジクロロメタン(5mL)で希釈し、無水MgSO4で乾燥させ、セライトで濾過し、真空中で濃縮した。得られた混合物を逆相クロマトグラフィ(アセトニトリル20-60%/0.1%水酸化アンモニウムを含む水)によって精製して、表題化合物(52mg、82%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 1.0 Hz, 1H), 7.53 (dd, J = 8.5, 1.0 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.25 (dd, J = 8.2, 2.2 Hz, 1H), 7.09 (d, J = 8.2 Hz,
1H), 6.54 (q, J = 4.3 Hz, 1H), 4.51 (s, 2H), 4.11 - 4.05 (m, 2H), 4.04 (s, 3H), 3.78 - 3.71 (m, 2H), 2.55 (d, J = 4.2 Hz, 3H), 2.32 (s, 3H). LCMS M/Z (M+H) 351.
7-[7-(ジフルオロメチル)-6-(1-メチルピラゾール-4-イル)-3,4-ジヒドロ-2H-キノリン-1-イル]-N-メチル-1,2,3,5-テトラヒドロ-1,4-ベンゾジアゼピン-4-カルボキサミド
20-60%/超臨界CO2)によって精製して、表題化合物(9.2mg、12%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6, 27 / 28 H) δ 7.72 (s, 1H), 7.47 (d, J
= 0.8 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.06 (s, 1H), 6.96 - 6.82 (m, 2H), 6.75 - 6.55 (m, 1H), 6.27 (q, J = 4.3 Hz, 1H), 5.59
(t, J = 3.5 Hz, 1H), 4.29 (s, 2H), 3.86 (s, 3H), 3.55 - 3.42 (m, 4H), 3.03 (s, 2H), 2.83 (d, J = 12.8 Hz, 2H), 2.52 (d, J = 4.2
Hz, 3H), 2.04 - 1.94 (m, 2H). LCMS M/Z (M+H) 467.
1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H).
1H NMR (400 MHz, CDCl3) δ 7.32 - 7.29 (m, 2H), 7.20 (dd, J = 1.5, 0.6 Hz, 1H), 3.45 (s, 3H).
= 8.4 Hz, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.26 (d, J = 2.1 Hz,
1H), 7.18 - 7.14 (m, 1H), 7.11 (dd, J = 8.4, 2.1 Hz, 1H), 6.87 - 6.77 (m, 2H), 3.87 (s, 3H), 3.70 - 3.63 (m, 2H), 3.38 (s, 3H),
2.86 (t, J = 6.4 Hz, 2H), 2.06 - 1.96 (m, 2H). LCMS M/Z (M+H) 427.
1,2,3,4-テトラヒドロキノリン(中間体C、200mg、0.760mmol)、メチル4-ブロモキノリン-6-カルボキシラート(243mg、0.912mmol)、ジクロロ[1,3-ビス(2,6-ジ-3-ペンチルフェニル)イミダゾール-2-イリデン](3-クロロピリジル)パラジウム(II)(95.2mg、0.114mmol)、t-BuONa(146.0mg、1.519mmol)および1,4-ジオキサン(1.52mL)を添加した。混合物をアルゴンバルーンでスパージし、次いで、アルゴン雰囲気下で16時間120℃に加熱した。反応物を室温に冷却した後、DCM(4mL)を添加し、反応物をセライトで濾過し、減圧下で濃縮した。残渣をシリカゲルクロマトグラフィ(1%TEAを含むヘプタンから、100%EtOAcへの勾配)によって精製して、表題化合物(23.6g、7%)を黄色固体として得た。
1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 4.9 Hz, 1H), 8.76 (dd, J
= 2.0, 0.6 Hz, 1H), 8.31 (dd, J = 8.8, 1.9 Hz, 1H), 8.18 (dd, J
= 8.8, 0.6 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.45 (d, J = 0.7
Hz, 1H), 7.31 - 7.27 (m, 1H), 7.18 (t, J = 1.1 Hz, 1H), 6.88 (s, 1H), 6.58 - 6.30 (m, 1H), 3.96 (s, 3H), 3.96 (s, 3H), 3.80 (dd, J = 6.7, 4.2 Hz, 2H), 3.03 (t, J = 6.6 Hz, 2H), 2.18 - 2.08 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 4.8 Hz, 1H), 8.69 (q, J
= 4.5 Hz, 1H), 8.46 (dd, J = 2.0, 0.6 Hz, 1H), 8.19 (dd, J = 8.8, 1.9 Hz, 1H), 8.13 (dd, J = 8.8, 0.6 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.26 (s, 1H), 6.87 - 6.50 (m, 2H), 3.87 (s, 3H), 3.73 (t, J = 5.4
Hz, 2H), 3.00 (t, J = 6.5 Hz, 2H), 2.80 (d, J = 4.5 Hz, 3H), 2.19 - 1.90 (m, 2H). LCMS M/Z (M+H) 448.
1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.2, 1.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 3.26 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.39 (m, 1H), 7.22 (dd, J = 8.3, 1.9 Hz, 1H), 7.16 (dd, J = 8.3, 0.4 Hz, 1H), 3.86 (q, J = 7.2 Hz, 2H), 3.32 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). LCMS M/Z (M+H) 255.
1H NMR (400 MHz, DMSO-d6, 22 / 25 H) δ 7.72 (d, J = 0.9 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 7.08 (s, 1H), 6.97 (dd, J = 8.2, 2.0 Hz, 1H), 6.88 - 6.54 (m, 2H), 3.95 - 3.79 (m, 5H), 3.65 - 3.56 (m, 2H), 2.87 (t, J = 6.1 Hz, 2H), 2.07 - 1.96 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). LCMS M/Z (M+H) 437.
4-クロロ-6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 11.05 (s, 1H), 7.21 (d,
J = 1.6 Hz, 1H), 7. 04 (d, J = 1.6 Hz, 1H).
クロマトグラフィ(石油エーテル/EtOAc=5:1)によって精製して、表題化合物(150mg、79%)を白色固体として得た。
LCMS M/Z (M+H) 275.
4-クロロ-6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.42 (s, 1H), 7.07 (s, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.88 (s, 1H), 6.80 (d, J = 1.6 Hz,
1H), 6.49 (t, J = 55.6 Hz, 1H), 3.96 (s, 3H), 3.76 (s, 3H), 3.64
- 3.61 (m, 2H), 3.38 (s, 3H), 2.92 - 2.89 (m, 2H), 2.11 - 2.09 (m, 2H). LCMS M/Z (M+H) 458.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3,4-トリメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
た後、EtOAc(20mL)を添加し、水(20mL×3)およびブライン(20mL)で洗浄した。有機相を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル35-65%/0.2%ギ酸を含む水)によって精製して、表題化合物(7mg、7%)を黄色固体として得た。
1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 6.81 (s, 1H), 6.75 - 6.74 (m, 2H), 6.47 (t, J = 55.6 Hz, 1H),
3.95 (s, 3H), 3.70 (s, 3H), 3.63 (t, J = 5.2 Hz, 2H), 3.37 (s, 3H), 2.91 (t, J = 5.2 Hz, 2H), 2.61 (s, 3H), 2.14 - 2.08 (m, 2H).
LCMS M/Z (M+H) 438.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-(ジメチルアミノ)-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 6.48 (t, J = 56.0 Hz, 1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.66 (t, J = 5.6 Hz, 2H), 3.37
(s, 3H), 2.92 (t, J = 5.6 Hz, 2H), 2.72 (s, 6H), 2.15 - 2.09 (m, 2H). LCMS M/Z (M+H) 467.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3,6-トリメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 6.74 (s, 1H), 6.64 (s, 1H), 4.89 - 4.85 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.49 (s, 1H), 3.31 (s, 6H).
5-クロロ-6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
LCMS M/Z (M+H) 458.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3,6-トリメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 7.08 - 7.06 (m, 2H), 6.67 (t, J = 55.2 Hz, 1H), 6.10 (s, 1 H), 3.85 (s, 3H), 3.66 - 3.57 (m, 1H), 3.34 (s, 4H), 3.29 (s, 3H),
2.94 - 2.81 (m, 2H), 2.14 (s, 3H), 2.09 - 2.01 (m, 2H). LCMS M/Z
(M+H) 438.
LCMS M/Z (M+H) 437.
1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.66 (s, 1H), 7.54 (s, 1H
), 7.44 - 7.36 (m, 2H), 7.22 - 7.20 (m, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.45 (t, J = 56.0 Hz, 1H), 5.90 - 5.88 (m, 1H), 3.95 (s,
3H), 3.84 (s, 3H), 3.71 (t, J = 5.6 Hz, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.93 (t, J = 5.6 Hz, 2H), 2.16 - 2.11 (m, 2H). LCMS M/Z
(M+H) 450.
1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.43 - 7.38
(m, 2H), 5.48 (s, 2H), 3.94(s, 3H), 3.47 (t, J = 8.0 Hz, 2H), 0.89 (t, J = 8.0 Hz, 2H), -0.03 (s, 9H).
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボン酸
LCMS M/Z (M+H) 553.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボキサミド
LCMS M/Z (M+H) 566.
1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.02 (d, J = 1.2Hz, 1H
), 8.00 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 4.4 Hz, 1H), 7.72 (s,
1H), 7.50 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.07 (s, 1H), 7.05
- 7.03 (m, 1H), 6.68 (t, J = 55.2 Hz, 1H), 6.49 (s, 1H), 3.85 (s, 3H), 3.65 - 3.55 (m, 2H), 2.91 - 2.86 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.11 - 1.98 (m, 2H). LCMS M/Z (M+H) 436.
7-クロロ-5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,1-ジメチル-1H-インドール-3-カルボキサミド
て添加した。混合物を窒素雰囲気下で12時間48℃に加熱した。室温に冷却した後、混合物を氷水(20mL)に注ぎ入れ、DCM(20mL×3)で抽出した。合わせた有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物(9g、粗製)を褐色固体として得、これは、さらなる精製は不要であった。
1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.64 - 8.47 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H).
1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.42 (s, 1H), 3.94 (s, 3H).
1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 4.16 (s, 3H), 3.92 (s, 3H).
メチル7-クロロ-5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-メチル-1H-インドール-3-カルボキシラート
LCMS M/Z (M+H) 485.
LCMS M/Z (M+H) 471.
7-クロロ-5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,1-ジメチル-1H-インドール-3-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.97 - 7.96 (m, 2H), 7.74 (s, 1H), 7.49 (s, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 6.72 (t, J = 55.2 Hz, 1H), 6.56 (s, 1H), 4.13 (s, 3H), 3.86 (s, 3H), 3.62 - 3.58 (m, 2H), 2.89 - 2.85 (m, 2H), 2.74 (d, J = 4.4 Hz, 3H), 2.04
- 2.01 (m, 2H). LCMS M/Z (M+H) 484.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-イソプロピル-N-メチル-1H-インドール-3-カルボキサミド
化合物(330mg、76%)を淡黄色固体として得た。
LCMS M/Z (M+H) 418.
メチル7-クロロ-5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボキシラート
LCMS M/Z (M+H) 601
メチル5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-(プロパ-1-エン-2-イル)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボキシラート
LCMS M/Z (M+H) 607.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-(プロパ-1-エン-2-イル)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボン酸
LCMS M/Z (M+H) 593.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-7-(プロパ-1-エン-2-イル)-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボキサミド
LCMS M/Z (M+H) 607.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-イソプロピル-N-メチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-インドール-3-カルボキサミド
LCMS M/Z (M+H) 608.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-イソプロピル-N-メチル-1H-インドール-3-カルボキサミド
1H NMR (400 MHz, CDCl3) δ 11.59 (s, 1H), 8.00 - 7.99 (m, 1H), 7.86 - 7.85 (m, 2H), 7.72 (s, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 6.68 (t, J = 55.6 Hz, 1H), 6.58 (s, 1H), 3.85 (s, 3H), 3.84 - 3.79 (m, 1H), 3.64 - 3.61 (m, 2H), 2.90 - 2.85 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 2.06 - 2.03 (m, 2H), 1.27 (d, J = 7.2 Hz, 6H). LCMS M/Z (M+H) 478.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,7-ジメチル-1H-ピロロ[2,3-c]ピリジン-3-カルボキサミド
LCMS M/Z (M+H) 167.
せ、濾過し、真空中で濃縮した。粗残渣をシリカゲルクロマトグラフィ(石油エーテル/EtOAc=3:1)によって精製して、表題化合物(5.0g、66%)を褐色固体として得た。
LCMS M/Z (M+H) 225.
LCMS M/Z (M+H) 355.
メチル5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-メチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-c]ピリジン-3-カルボキシラート
LCMS M/Z (M+H) 582.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-メチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-c]ピリジン-3-カルボン酸
イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-メチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-c]ピリジン-3-カルボキシラート(550mg、0.95mmol)を含むMeOH(2mL)、THF(5mL)および水(1mL)の溶液に、水酸化リチウム一水和物(397mg、9.45mmol)を添加した。混合物を窒素雰囲気下で12時間50℃に加熱した。反応物を室温に冷却した後、混合物を真空中で濃縮した。水(10mL)を添加し、混合物をHCl(2N)でpH4に酸性化し、次いで、DCM(20mL×3)で抽出した。合わせた有機層をブライン(20mL)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物(500mg、93%)を黄色油状物として得た。
LCMS M/Z (M+H) 568.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,7-ジメチル-1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピロロ[2,3-c]ピリジン-3-カルボキサミド
LCMS M/Z (M+H) 581.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,7-ジメチル-1H-ピロロ[2,3-c]ピリジン-3-カルボキサミド
1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.07 (s, 1H), 6.53 (t, J = 55.6 Hz, 1H), 5.93 - 5.86 (m, 1H), 3.96 (s, 3H), 3.88 (t, J = 4.8 Hz, 2H), 2.99 (d, J = 5.2 Hz, 3H), 2.90 - 2.83 (m, 2H),
2.68 (s, 3H), 2.07 - 2.04 (m, 2H). LCMS M/Z (M+H) 451.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチルイミダゾ[1,2-b]ピリダジン-3-カルボキサミド
状物として得た。
LCMS M/Z (M+H) 453.
LCMS M/Z (M+H) 425.
1H NMR (400 MHz, CDCl3) δ 8.46 - 8.40 (m, 1H), 8.33 (s, 1H), 7.89
(s, 1H), 7.86 (s, 1H), 7.61 (d, J = 12 Hz, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.60 (t, J = 55.6 Hz, 1H), 4.00 (s, 3H), 3.95 (t, J = 6.4 Hz, 2H), 3.03 (d, J = 4.8 Hz, 3H), 2.86 (t, J = 6.4 Hz,
2H), 2.19 - 2.12 (m, 2H). LCMS M/Z (M+H) 438.
7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-1-(7-(1-メチル-1H-ピラゾール-4-イル)-5H-ピロロ[2,3-b]ピラジン-2-イル)-1,2,3,4-テトラヒドロキノリン
、5.66mmol)を滴下して添加し、混合物を室温でさらに2時間撹拌した。混合物を飽和NH4Cl水溶液(30mL)で洗浄し、EtOAc(30mL×2)で抽出した。合わせた有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮して、表題化合物(1.4g、82%)を黄色固体として得、これは、さらなる精製は不要であった。
1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.24 (d, J = 4.0 Hz, 1H), 8.20 - 8.15 (m, 2H), 7.74 - 7.67 (m, 1H), 7.64 - 7.59 (m, 2H),
6.85 (d, J = 4.0 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.72 (d, J = 3.6 Hz, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 6.60 (t, J = 56.0 Hz, 1H), 6.56 (d, J = 4.4 Hz,1H), 3.96 (s, 3H), 3.90
(t, J = 6.0 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.15 - 2.09 (m,
2H).
1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.27 (s, 1H), 7.99 (d,
J = 2.4 Hz, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.39 (s, 1H), 7.25
(s, 1H), 6.84 (t, J = 54.8 Hz, 1H), 3.92 - 3.81 (m, 2H), 3.89 (s, 3H), 2.86 (t, J = 6.0 Hz, 2H), 2.07 - 1.93 (m, 2H).
7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-1-(7-(1-メチル-1H-ピラゾール-4-イル)-5H-ピロロ[2,3-b]ピラジン-2-イル)-1,2,3,4-テトラヒドロキノリン
1H NMR (400 MHz, DMSO-d6) δ 11.90 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 6.87 (t, J = 52.0, 1H), 3.93 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 2.87 (t, J = 6.0 Hz, 2H), 2.08 - 1.98 (m, 2H). LCMS M/Z (M+Na) 483.
7-(2-(ジフルオロメチル)-6-メチル-3-(1-メチル-1H-ピラゾール-4-イル)フェニル)-N-メチル-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキサミド
LCMS M/Z (M+Na) 398.
1H NMR (400 MHz, CD3OD) δ 7.39 - 7.38 (m, 2H), 7.35 (t, J = 52.0
Hz, 1H), 2.42 (s, 3H).
ルホスフィノ)フェロセン]ジクロロパラジウム(II)(131mg、0.18mmol)およびNa2CO3(572mg、5.4mmol)を添加した。混合物を90℃で0.5時間マイクロ波照射した。EtOAc(70mL)を添加し、水(60mL×2)、ブライン(60mL)で洗浄した。有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣をシリカゲルカラムクロマトグラフィ(石油エーテル/EtOAc=3:1)によって精製して、表題化合物(400mg、52%)を白色固体として得た。
1H NMR (400 MHz, CD3OD) δ 7.44 - 7.38 (m, 2H), 7.16 - 7.06 (m, 1H), 7.05 - 6.94 (m, 2H), 6.54 (t, J = 54.0 Hz, 1H), 4.58 - 4.41 (m, 2H), 4.22 - 4.00 (m, 2H), 3.93 - 3.71 (m, 2H), 2.03 - 1.97 (m, 3H), 1.39 - 1.35 (m, 9H).
tert-ブチル7-(2-(ジフルオロメチル)-6-メチル-3-(1-メチル-1H-ピラゾール-4-イル)フェニル)-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキシラート
LCMS M/Z (M+H) 470.
LCMS M/Z (M+H) 370.
7-(2-(ジフルオロメチル)-6-メチル-3-(1-メチル-1H-ピラゾール-4-イル)フェニル)-N-メチル-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキサミド
1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.52 (s, 1H), 7.37 (d, J
= 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 3H), 6.48 (t, J = 54.0 Hz, 1H), 4.54 - 4.32 (m, 3H), 4.27 - 4.18 (m, 1H), 4.16 - 4.06 (m, 2H), 3.98 (s, 3H), 3.78 - 3.72 (m, 1H), 2.75
(d, J = 4.0 Hz, 3H), 2.07 (s, 3H). LCMS M/Z (M+Na) 449.
1-(7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-イル)プロパン-1-オン
LCMS M/Z (M+Na) 228.
LCMS M/Z (M+H) 285.
1-(7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-イル)プロパン-1-オン
1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.34 - 6.98 (m, 4H), 6.90 - 6.58 (m, 2H), 4.60 - 4.55 (m, 2H), 4.20 - 4.00
(m, 2H), 3.88 - 3.78 (m, 5H), 3.63 - 3.51 (m, 2H), 2.86 - 2.82 (m, 2H), 2.39 - 2.22 (m, 2H), 2.00 - 1.96 (m, 2H), 0.97 - 0.91 (m, 3H). LCMS M/Z (M+Na) 489.
(S)-5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-3-メチル-3,4-ジヒドロキノキサリン-2(1H)-オン
LCMS M/Z (M+H) 403.
LCMS M/Z (M+H) 472.
(S)-5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-3-メチル-3,4-ジヒドロキノキサリン-2(1H)-オン
1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.71 (s, 1H), 7.46 (s,
1H), 7.14 - 7.03 (m, 1H), 6.87 - 6.55 (m, 4H), 6.34 - 6.25 (m, 1H), 5.43 - 5.40 (m, 1H), 4.01 - 3.72 (m, 1H), 3.86 (s, 3H), 2.89
- 2.85 (m, 2H), 2.27 - 1.91 (m, 4H), 1.30 - 1.06 (m, 3H). LCMS M/Z (M+H) 424.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-インダゾール-5-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.12 - 8.09 (m, 1H), 7.47 (d, J = 8.8 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.20 - 4.16 (m, 2H), 3.97 (s, 3H), 3.67 - 3.55 (m, 2H), 2.47 - 2.36 (m, 2H), 2.00 -
1.96 (m, 2H).
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-インダゾール-5-カルボン酸
LCMS M/Z (M+H) 508.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-インダゾール-5-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 8.45 - 8.42 (m, 1H), 8.07 (s, 1H), 7.93 - 7.88 (m, 1H), 7.86 - 7.80 (m, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 7.19 (s, 1H), 6.94 (s, 1H), 6.74 (t, J = 56 Hz, 1H), 4.96 - 4.90 (m, 1H), 4.02 - 3.99 (m, 2H), 3.90 - 3.81 (m, 2H), 3.87 (s, 3H), 3.59 - 3.54 (m, 2H), 2.96 - 2.92 (m, 2H), 2.76 (d, J = 4.4 Hz, 3H), 2.16 - 2.03 (m, 4H), 1.93 - 1.90 (m, 2H). LCMS M/Z (M+H) 521.
1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 2.3 Hz, 1H), 7.29 - 7.12 (m, 5H), 6.95 (d, J = 8.3 Hz, 1H), 6.38 (q, J = 4.4 Hz, 1H), 4.36 (s, 2H), 3.59 - 3.51 (m, 2H), 3.01 - 2.94 (m, 2H), 2.88 (s, 3H), 2.53 (d, J = 4.3 Hz, 3H), 2.26 (s, 3H). LCMS M/Z (M+H) 310.
LCMS M/Z (M+H) 303.
KOAc(52mg、0.53mmol)、クロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(4.2mg、0.0053mmol)および2-(ジシクロヘキシルホスフィノ)-2’,4’,6’-トリイソプロピルビフェニル(5.1mg、0.010mmol)を添加した。混合物を窒素雰囲気下、80℃で16時間撹拌した。反応混合物を室温に冷却し、5-ブロモ-2-(4-メトキシフェニル)イミダゾ[1,2-a]ピリジン(36mg、0.12mmol)、K3PO4・H2O(71mg、0.30mmol)、水(0.3mL)、ジオキサン(0.5mL)およびクロロ(2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル)[2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(4.2mg、0.0053mmol)を添加した。反応混合物を窒素雰囲気下、70℃で5時間撹拌した。次いで、反応混合物を室温に冷却し、真空中で濃縮した。粗残渣をジクロロメタン(5mL)で希釈し、無水MgSO4で乾燥させ、セライトで濾過し、真空中で濃縮した。得られた混合物を逆相クロマトグラフィ(アセトニトリル20-60%/0.1%水酸化アンモニウムを含む水)によって精製して、表題化合物(7.8mg、10%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.99 - 7.89 (m, 2H), 7.84 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 8.1, 1.9 Hz, 2H), 7.34 (dd, J = 9.0, 7.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.01 - 6.93 (m, 2H), 6.86 (dd, J = 7.0, 1.2 Hz, 1H), 6.59 - 6.48 (m, 1H), 4.55
(s, 2H), 4.12 (dd, J = 5.5, 3.3 Hz, 2H), 3.83 - 3.74 (m, 5H), 2.56 (d, J = 4.3 Hz, 3H). LCMS M/Z (M+H) 429.
をDCM(50mL×2)で抽出した。合わせた有機層をブライン(30mL)で洗浄し、無水Na2SO4で乾燥させ、次いで、減圧下で濃縮した。残渣をシリカゲルクロマトグラフィ(100%ヘプタンから、50%EtOAcを含むヘプタンへの勾配)によって精製して、表題化合物(2.32g、88%)を淡黄色油状物として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.05 (m, 4H), 3.81 (t, J = 6.6 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H), 2.24 (s, 3H), 1.97 (p, J =
6.6 Hz, 2H).
1H NMR (400 MHz, CDCl3) δ 7.40 - 7.03 (m, 3H), 3.76 (t, J = 6.5
Hz, 2H), 2.71 (t, J = 6.6 Hz, 2H), 2.22 (s, 3H), 2.04 - 1.86 (m, 2H).
アルゴン雰囲気下で16時間120℃に加熱した。反応物を室温に冷却した後、DCM(3mL)を添加し、反応物をセライトで濾過し、減圧下で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル30-70%/0.1%水酸化アンモニウムを含む水)によって精製して、表題化合物(40.5mg、32%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6, 330 K) δ 7.72 (s, 1H), 7.53 (s, 1H), 7.48 (d, J = 0.8 Hz, 1H), 7.13 - 7.02 (m, 3H), 6.87 - 6.60 (m, 2H), 3.86 (s, 3H), 3.73 - 3.67 (m, 2H), 3.62 - 3.55 (m, 2H), 2.83 (t, J = 6.5 Hz, 2H), 2.71 (t, J = 6.6 Hz, 2H), 2.18 (s, 3H), 2.03
- 1.95 (m, 2H), 1.93 - 1.84 (m, 2H). LCMS M/Z (M+H) 437.
1H NMR (400 MHz, DMSO-d6) δ 8.92 (dt, J = 16.1, 0.9 Hz, 1H), 8.32
- 8.26 (m, 1H), 8.06 (q, J = 1.3, 0.8 Hz, 2H), 7.87 (d, J = 8.3 Hz, 1H), 7.74 (ddd, J = 8.3, 7.0, 3.6 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.40 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 4.48 (d, J = 17.7 Hz, 2H), 3.91 (s, 3H), 3.78 (t, J = 5.9 Hz, 2H), 3.51 (s, 3H), 3.02 - 2.93 (m, 1H), 2.92 - 2.83 (m, 1H), 2.51 - 2.07 (m, 3H). LCMS
M/Z (M+H) 414.
1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.9, 1.0 Hz, 1H), 7.32 -
7.28 (m, 1H), 7.08 (d, J = 1.5 Hz, 1H), 3.25 (d, J = 0.6 Hz, 3H).
し、減圧下で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル30-70%/0.1%水酸化アンモニウムを含む水)によって精製して、表題化合物(86.6mg、18%)を赤色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.85 (m, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36 (d, J =
1.3 Hz, 1H), 7.09 - 6.77 (m, 3H), 3.90 (s, 3H), 3.86 - 3.78 (m,
2H), 3.11 (s, 3H), 2.80 (t, J = 6.4 Hz, 2H), 1.99 (t, J = 6.2 Hz, 2H). LCMS M/Z (M+H) 423.
1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 0.8 Hz, 1H), 7.50 (d, J
= 0.8 Hz, 1H), 7.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.12 (d, J = 1.2 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.91 - 6.86 (m, 1H), 6.86 -
6.59 (m, 2H), 3.86 (s, 3H), 3.70 - 3.59 (m, 2H), 3.55 (d, J = 1.1 Hz, 2H), 3.09 (s, 3H), 2.85 (t, J = 6.3 Hz, 2H), 2.08 - 1.94 (m, 2H). LCMS M/Z (M+H) 409.
0.190mmol)、4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン(11.0mg、0.0190mmol)、クロロ[(4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン)-2-(2’-アミノ-1,1’-ビフェニル)]パラジウム(II)(16.9mg、0.0190mg)、Cs2CO3(124mg、0.380mmol)、次いで、トルエン(1.3mL)を添加した。混合物をアルゴンバルーンでスパージし、次いで、アルゴン雰囲気下で14時間120℃に加熱した。反応物を室温に冷却した後、DCM(3mL)を添加し、反応物をセライトで濾過し、減圧下で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル30-70%/0.1%水酸化アンモニウムを含む水)によって精製して、表題化合物(20.7mg、27%)を固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.78 - 7.71 (m, 1H), 7.49 (d, J = 0.8 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 7.02 (dd, J = 8.5, 2.2 Hz, 1H), 6.91 - 6.58
(m, 2H), 3.86 (s, 3H), 3.64 - 3.57 (m, 2H), 3.34 - 3.32 (m, 3H),
2.86 (s, 2H), 2.06 - 1.96 (m, 2H). LCMS M/Z (M+H) 411.
(S)-6-[7-(ジフルオロメチル)-6-(1-メチルピラゾール-4-イル)-3,4-ジヒドロ-2H-キノリン-1-イル]-1,3-ジメチル-インドリン-2-オンおよび(R)-6-[7-(ジフルオロメチル)-6-(1-メチルピラゾール-4-イル)-3,4-ジヒドロ-2H-キノリン-1-イル]-1,3-ジメチル-インドリン-2-オン
7-(ジフルオロメチル)-6-(1-メチルピラゾール-4-イル)-3,4-ジヒドロ-2H-キノリン-1-イル]-1,3-ジメチル-インドリン-2-オン(実施例93、4.2mg、第2のピーク)を得た。絶対配置は、各ジアステレオマーに任意に割り当てた。実施例92:
1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 0.8 Hz, 1H), 7.47 (d, J
= 0.8 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.08 (s, 1H), 6.98 (dd, J =
8.2, 2.0 Hz, 1H), 6.64 (s, 2H), 3.89 - 3.83 (m, J = 4.1 Hz, 4H), 3.67 - 3.56 (m, 2H), 3.37 - 3.34 (m, 3H), 2.86 (d, J = 6.6 Hz,
2H), 2.08 - 1.98 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). LCMS M/Z (M+H) 423.2
実施例93:
1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 0.8 Hz, 1H), 7.47 (d, J
= 0.8 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.08 (s, 1H), 6.98 (dd, J =
8.2, 2.0 Hz, 1H), 6.64 (s, 2H), 3.89 - 3.83 (m, J = 4.1 Hz, 4H), 3.67 - 3.56 (m, 2H), 3.37 - 3.34 (m, 3H), 2.86 (d, J = 6.6 Hz,
2H), 2.08 - 1.98 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). LCMS M/Z (M+H) 423.
1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.4 Hz, 1H), 7.12 (d, J
= 2.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.41 (s, 6H).
LCMS M/Z (M+H) 289.
1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H
), 7.85 (s, 1H), 7.82 - 7.76 (m, 1H), 7.66 - 7.44 (m, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.15 (s, 1H) 7.11 (d, J
= 8.0 Hz, 1H), 3.99 (s, 3H), 3.52 (s, 3H), 3.47 (s, 3H). LCMS M/Z (M+H) 370.
1,3-ジメチル-5-(4-メチル-6-(1-メチル-1H-ピラゾール-4-イル)-7-(トリフルオロメチル)-3,4-ジヒドロキノキサリン-1(2H)-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
アミノ)エタノール(4g、11.7mmol)およびピリジン(0.94mL、11.7mmol)を含むDCM(40mL)の溶液に、塩化チオニル(1.7mL、23.3mmol)を0℃で滴下して添加した。混合物を室温で16時間撹拌した。DCM(50mL)を添加し、飽和NaHCO3水溶液(50mL×3)、ブライン(50mL×2)で洗浄した。有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣をシリカゲルクロマトグラフィ(石油エーテル/EtOAc=3:1)によって精製して、表題化合物(2.7g、64%)を黄色油状物として得た。
LCMS M/Z (M+H) 333.
1H NMR (400 MHz, DMSO-d6) δ 6.72 (s, 1H), 6.63 (s 1H), 6.07 (s, 1H), 3.29 - 3.26 (m, 2H), 3.24 - 3.21 (m, 2H), 2.83 (s, 3H).
LCMS M/Z (M+H) 297.
1,3-ジメチル-5-(4-メチル-6-(1-メチル-1H-ピラゾール-4-イル)-7-(トリフルオロメチル)-3,4-ジヒドロキノキサリン-1(2H)-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.43 (s, 1H), 7.00 - 6.90
(m, 2H), 6.87 (s, 1H), 6.78 (s, 1H), 6.55 (s, 1H), 3.95 (s, 3H),
3.77 - 3.75 (m, 2H), 3.50 - 3.47 (m, 2H) 3.45 (s, 3H), 3.41 (s,
3H), 3.00 (s, 3H). LCMS M/Z (M+H) 457.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-イソプロピル-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-(プロパ-1-エン-2-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
LCMS M/Z (M+H) 464.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-イソプロピル-1,3-ジメチル
-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.73 (s, 1H), 6.72 (t, J = 55.2 Hz, 1H), 3.86 (s, 3H), 3.63 - 3.61 (m, 3H), 3.58 (s, 3H), 3.30 (s, 3H), 2.86 (t, J = 5.6 Hz, 2H), 2.05 -
2.00 (m, 2H), 1.24 (d, J = 6.4 Hz, 6H). LCMS M/Z (M+H) 466.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-(3,6-ジヒドロ-2H-ピラン-4-イル)-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
LCMS M/Z (M+H) 506.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.09 (s, 1H), 6.99 (d, J = 1.2 Hz, 1H), 6.86 (s, 1H), 6.73 (t, J = 55.2 H
z, 1H), 6.72, (s, 1H), 3.93 - 3.90 (m, 2H), 3.86 (s, 3H), 3.64 - 3.62 (m, 1H), 3.61 (s, 3H), 3.53 - 3.48 (m, 4H), 3.30 (s, 3H), 2.88 - 2.84 (m, 2H), 2.03 - 2.01 (m, 2H), 1.75 - 1.65 (m, 4H). LCMS
M/Z (M+H) 508.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-(1-オキシド-3,6-ジヒドロ-2H-チオピラン-4-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-(3,6-ジヒドロ-2H-チオピラン-4-イル)-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
して、表題化合物(320mg、56%)を白色固体として得た。
LCMS M/Z (M+H) 522.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-(1-オキシド-3,6-ジヒドロ-2H-チオピラン-4-イル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 7.41 (s, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 6.79 (s, 1H), 6.48 (t, J = 55.6 Hz, 1H), 5.73 - 5.69 (m, 1H), 3.96 (s, 3H), 3.67 - 3.64 (m, 2H), 3.51 (s, 3H), 3.40 (s, 3H), 3.28 - 3.25 (m, 1H), 3.11 - 2.91 (m, 5H), 2.65 - 2.61 (m, 2H), 2.12 - 2.10 (m, 2H). LCMS M/Z (M+H) 538.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-プロピル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
mmol)を含むトルエン(4mL)および水(0.4mL)の溶液に、カリウムイソプロピルトリフルオロボレート(49mg、0.33mmol)、クロロ[(ジ(1-アダマンチル)-n-ブチルホスフィン)-2-(2-アミノビフェニル)]パラジウム(II)(15mg、0.022mmol)およびCs2CO3(213mg、0.66mmol)を添加した。混合物を窒素雰囲気下で16時間100℃に加熱した。反応物を室温に冷却した後、EtOAc(20mL)を添加し、水(20mL×3)およびブライン(20mL)で洗浄した。有機相を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル38-68%/0.2%ギ酸を含む水)によって精製して、表題化合物(1mg、1%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.47 (s, 1H), 7.07 (s, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.71 (t, J = 55.6 Hz, 1H), 6.66 (s, 1H), 3.86 (s, 3H), 3.60 - 3.58 (m, 2H), 3.55 (s, 3H), 3.30 (s, 3H), 2.86 - 2.85 (m, 4H), 2.02 - 1.99
(m, 2H), 1.63 - 1.58 (m, 2H), 0.93 (t, J = 6.8 Hz, 3H). LCMS M/Z (M+H) 466.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-メトキシ-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 6.73 (t, J = 55.2 Hz, 1H), 6.68 - 6.67 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.62 - 3.59 (m, 2H), 3.51 (s, 3H), 3.27 (s, 3H), 2.86 (t, J = 5.6 Hz, 2H), 2.03 - 2.01 (m, 2H). LCMS
M/Z (M+H) 454.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-エチニル-1,3-ジメチル-1
H-ベンゾ[d]イミダゾール-2(3H)-オン
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-4-((トリイソプロピルシリル)エチニル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
LCMS M/Z (M+H) 604.
6-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-4-エチニル-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (s, 1H), 7.23 - 7.22 (m, 1H), 7.11 (s, 1H), 7.01 - 7.00 (m, 1H), 6.74 (t, J = 54.8
Hz, 1H), 6.61 (s, 1H), 4.49 (s, 1H), 3.86 (s, 3H), 3.63 (s, 3H),
3.60 - 3.56 (m, 2H), 3.31 (s, 3H), 2.87 - 2.84 (m, 2H), 2.02 - 2.00 (m, 2H). LCMS M/Z (M+H) 448.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-6-エチニル-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1,3-ジメチル-6-((トリイソプロピルシリル)エチニル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
LCMS M/Z (M+H) 604.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-6-エチニル-1,3-ジメチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 6.69 (t, J = 55.2 Hz, 1H), 6.25
(s, 1H), 4.08 (s, 1H), 3.85 (s, 3H), 3.59 - 3.55 (m, 2H), 3.36 (s,
3H), 3.31 (s, 3H), 2.88 - 2.84 (m, 2H), 2.06 - 2.02 (m, 2H). LCMS M/Z (M+H) 448.
LCMS M/Z (M+H) 414.
LCMS M/Z (M+H) 400.
1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.32 (s, 1H), 8.27 - 8.26 (m, 1H), 8.23 (s, 1H), 8.13 - 8.06 (m, 2H), 7.95 - 7.91 (m, 1H), 7.78 - 7.74 (m, 1H), 7.70 - 7.68 (m, 1H), 7.42 - 7.40 (m, 1H),
7.20 (s, 1H), 3.91 (s, 3H), 3.51 (s, 3H), 2.67 (d, J = 4.4 Hz, 3H). LCMS M/Z (M+H) 413.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-
3,4-ジヒドロキノリン-1(2H)-イル)-N,1,7-トリメチル-1H-インドール-3-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 1.8 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.72 (s, 1H), 7.47 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H),
6.69 (t, J = 55.2 Hz, 1H), 6.51 (s, 1H), 4.08 (s, 3H), 3.85 (s,
3H), 3.57 (t, J = 5.6 Hz, 2H), 2.89 - 2.85 (m, 2H), 2.80 - 2.69
(m, 6H), 2.07 - 2.01 (m, 2H). LCMS M/Z (M+H) 464.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,1-ジメチル-7-(テトラヒドロ-2H-ピラン-4-イル)-1H-インドール-3-カルボキサミド
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-(3,6-ジヒドロ-2H-ピラン-4-イル)-N,1-ジメチル-1H-インドール-3-カルボキサミド
LCMS M/Z (M+H) 532.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,1-ジメチル-7-(テトラヒドロ-2H-ピラン-4-イル)-1H-インドール-3-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.89 (m, 1H), 7.82 - 7.79 (m,
2H), 7.70 (s, 1H), 7.45 (s, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 6.67
(t, J = 55.2 Hz, 1H), 6.60 (s, 1H), 4.05 (s, 3H), 3.92 - 3.91 (
m, 2H), 3.83 (s, 3H), 3.61 - 3.59 (m, 2H), 3.54 - 3.48 (m, 2H),
2.87 - 2.83 (m, 2H), 2.71 (d, J = 4.4 Hz, 3H), 2.03 - 2.00 (m,
2H), 1.76 - 1.71 (m, 4H). LCMS M/Z (M+H) 534.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-メトキシ-N,1-ジメチル-1H-インドール-3-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 7.83 - 7.78 (m, 2H), 7.72 (s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.70 (t, J =
55.2 Hz, 1H), 6.64 - 6.59 (m, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.61 (t, J = 5.2 Hz, 2H), 2.89 - 2.86 (m, 2H), 2.73
(d, J = 4.4 Hz, 3H), 2.08 - 2.00 (m, 2H). LCMS M/Z (M+H) 480.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,1-ジメチル-7-(プロパ-1-エン-2-イル)-1H-インドール-3-カルボキサミド
メチル5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-メチル-7-(プロパ-1-エン-2-イル)-1H-インドール-3-カルボキシラート
LCMS M/Z (M+H) 491.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-メチル-7-(プロパ-1-エン-2-イル)-1H-インドール-3-カルボン酸
して得、これは、さらなる精製は不要であった。
LCMS M/Z (M+H) 477.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,1-ジメチル-7-(プロパ-1-エン-2-イル)-1H-インドール-3-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 8.01 - 7.95 (m, 1H), 7.90 (s, 1H) , 7.88 - 7.84 (m, 1H), 7.73 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 6.82 (s, 1H), 6.70 (t, J = 54.8 Hz, 1H), 6.64 (s, 1H), 5.38 (s, 1H),
4.98 (s, 1H), 3.86 (s, 3H), 3.65 - 3.60 (m, 2H), 3.31 (s, 3H), 2.89 - 2.85 (m, 2H), 2.74 (d, J = 4.4 Hz, 3H), 2.15 (s, 3H), 2.05
- 2.01 (m, 2H). LCMS M/Z (M+H) 490.
5-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-7-イソプロピル-N,1-ジメチル-1H-インドール-3-カルボキサミド
1-エン-2-イル)-1H-インドール-3-カルボキサミド(実施例107、40mg、0.08mmol)を含むMeOH(5mL)の溶液に、10%Pd/C(30mg)を添加した。混合物を水素雰囲気(15Psi)下、室温で3時間撹拌した。混合物を濾過し、濾液を真空中で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル25-55%/0.05%NH4OHを含む水)によって精製して、表題化合物(6mg、16%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.91 - 7.90 (m, 1H), 7.84 - 7.81 (m,
2H), 7.72 (s, 1H), 7.47 (s, 1H), 7.07 (s, 1H), 7.02 - 7.01 (m, 1H), 6.69 (t, J = 55.6 Hz, 1H), 6.64 (s, 1H), 4.06 (s, 3H), 3.86 (s, 3H), 3.85 - 3.79 (m, 1H), 3.63 (t, J = 5.2 Hz, 2H), 2.90 - 2.85 (m, 2 H), 2.74 (d, J = 4.4 Hz, 3H), 2.05 - 2.03 (m, 2H), 1.28
(d, J = 6.8 Hz, 6H). LCMS M/Z (M+H) 492.
LCMS M/Z (M-Boc+H) 240.
1H NMR (400 MHz, DMSO-d6) 7.33 - 7.23 (m, 4H), 7.17 - 7.13 (m, 2H), 4.55 - 4.47 (m, 2H), 4.20 - 4.10 (m, 2H), 3.76 (s, 2H), 2.23 (s, 3H), 1.36 - 1.30 (m, 9H).
LCMS M/Z (M+H) 331.
1H NMR (400 MHz, DMSO-d6) δ 7.31 - 7.15 (m, 5H), 7.04 (d, J = 2.0 Hz, 1H), 6.52 - 6.48 (m, 1H), 4.43 (s, 2H), 4.02 - 3.94 (m, 2H), 3.75 - 3.68 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 2.52 (s, 3H), 2.24 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H). LCMS M/Z (M+H) 325.
LCMS M/Z (M+H) 337.
、0.39mmol)を含むMeOH(10mL)の溶液に、10%Pd/C(100mg)を添加した。得られた混合物を水素雰囲気(15psi)によって室温で16時間パージした。反応混合物を濾過し、真空中で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル55-85%/0.05%NH4OHを含む水)によって精製して、表題化合物(48mg、36%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.29 - 7.16 (m, 5H), 7.05 (s, 1H), 6.48 - 6.44 (m, 1H), 4.41 (s, 2H), 3.95 - 3.94 (m, 2H), 3.74 - 3.70
(m, 2H), 3.28 - 3.24 (m, 1H), 2.51 (s, 3H), 2.22 (s, 3H), 1.15 (d, J = 6.8 Hz, 6H). LCMS M/Z (M+H) 339.
1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.38 (s, 1H), 7.31 - 7.23 (m, 3H), 7.21 - 7.17 (m, 1H), 6.53 - 6.52 (m, 1H), 4.51 (s, 2H), 4.11 - 4.06 (m, 2H), 3.79 - 3.74 (m, 2H), 2.52 (d, J = 4.0 Hz, 3H), 2.25 (s, 3H). LCMS M/Z (M+H) 375.
1H NMR (400 MHz, DMSO-d6) δ 7.25 - 7.20 (m, 4H), 6.92 (d, J = 1.8 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.48 - 6.45 (m, 1H), 4.42 (s, 2H), 3.97 - 3.90 (m, 2H), 3.73 (s, 3H), 3.71 - 3.67 (m, 2H), 2.49 (d, J = 6.4 Hz, 3H), 2.23 (s, 3H). LCMS M/Z (M+H) 327.
1-(7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-イル)エタノン
tert-ブチル7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキシラート
LCMS M/Z (M+H) 511.
LCMS M/Z (M+H) 411
1-(7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-イル)エタノン
ゾ[f][1,4]オキサゼピン(150mg、0.37mmol)およびTEA(0.25mL、1.83mmol)を含むDCM(3mL)の溶液に、無水酢酸(0.1mL、1.1mmol)を滴下して添加した。混合物を室温で10時間撹拌した。水(30mL)を添加し、DCM(20mL×2)で抽出した。合わせた有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル37-67%/0.2%ギ酸を含む水)によって精製して、表題化合物(90mg、53%)を白色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.15 - 7.00 (m, 3H), 6.89 - 6.58 (m, 2H), 4.62 - 4.48 (m, 2H), 4.19 - 4.01 (m, 2H), 3.93 - 3.77 (m, 5H), 3.62 -
3.50 (m, 2H), 2.86 - 2.82 (m, 2H), 2.07 - 1.88 (m, 5H). LCMS M/Z
(M+Na) 475.
7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキサミド
1H NMR (400MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (s, 1H), 7.31 (d, J
= 2.2 Hz, 1H), 7.13 - 7.04 (m, 2H), 7.03 - 6.96 (m, 1H), 6.90 -
6.59 (m, 2H), 6.48 - 6.43 (m, 1H), 4.42 (s, 2H), 4.01 - 3.98 (m,
2H), 3.86 (s, 3H), 3.72 - 3.69 (m, 2H), 3.59 - 3.51 (m, 2H), 2.88 - 2.79 (m, 2H), 2.52 (s, 3H), 2.03 - 1.92 (m, 2H). LCMS M/Z (M+Na) 490.
7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,2-ジメチル-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキサミド
LCMS M/Z (M+H) 260.
LCMS M/Z (M-Boc) 260.
LCMS M/Z (M+H) 342.
tert-ブチル7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2-メチル-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキシラート
LCMS M/Z (M+H) 525.
7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2-メチル-2,3,4,5-テトラヒドロベンゾ[f][1,4]オキサゼピン
LCMS M/Z (M+H) 425
7-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N,2-ジメチル-2,3-ジヒドロベンゾ[f][1,4]オキサゼピン-4(5H)-カルボキサミド
1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.42 (s, 1H), 7.12 - 7.06
(m, 4H), 6.97 (s, 1H), 6.49 (t, J = 55.2 Hz, 1H), 4.45 - 4.28 (m, 3H), 4.21 - 4.17 (m, 1H), 4.05 - 4.03 (m, 1H), 3.96 (s, 3H), 3.62 (t, J = 5.6 Hz, 2H), 3.30 - 3.24 (m, 1H), 2.94 - 2.85 (m, 2
H), 2.78 (d, J = 4.4 Hz, 3H), 2.09 - 2.05 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H). LCMS M/Z (M+Na) 504
(R)-8-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2-メチル-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オン
LCMS M/Z (M+H) 242.
(R)-8-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-2-メチル-2H-ベンゾ[b][1,4]オキサジン-3(4H)-オン
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.05 - 6.96 (m, 3H), 6.72 - 6.68 (m, 2H), 6.49 (t, J = 55.6 Hz, 1H), 4.61 (d, J = 6.4 Hz, 1H), 3.96 (s, 3H), 3.63 - 3.58 (m, 2H), 2.94 - 2.90 (m, 2H), 2.10 (t, J = 6.4 Hz, 2H), 1.44 (d, J =
6.4 Hz, 3H). LCMS M/Z (M+H) 425.
PO(336mg、1.39mmol)を添加した。反応混合物を12時間80℃に加熱した。反応物を室温に冷却した後、混合物を真空中で濃縮した。EtOAc(20mL)を添加し、水(20mL×2)およびブライン(20mL)で洗浄した。有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣をシリカゲルカラムクロマトグラフィ(石油エーテル/EtOAc=4:1)によって精製して、表題化合物(3.2g、78%)を黄色固体として得た。
マトグラフィ(石油エーテル/EtOAc=4:1)によって精製して、表題化合物(400mg、51%)を黄色固体として得た。
1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.0 Hz, 1H), 7.04 - 6.99
(m, 1H), 6.65 (d, J = 7.2 Hz, 1H), 4.47 (s, 2H), 3.06 (s, 3H).
1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.34 (s, 1H), 7.16 (s, 1H), 7.00 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 6.54 - 6.25 (m, 3H), 4.22 (s, 2H), 3.88 (s, 3H), 2.91 - 2.86 (m, 2H), 2.88 (s, 3H), 2.06 - 2.03 (m, 2H), 1.52 - 1.49 (m, 2H). LCMS M/Z (M+H) 424.
(S)-2-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-6,7-ジヒドロ-5H-シクロペンタ[b]ピリジン-7-カルボキサミドおよび(R)-2-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-6,7-ジヒドロ-5H-シクロペンタ[b]ピリジン-7-カルボキサミド
LCMS M/Z (M+H) 212.
2-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-6,7-ジヒドロ-5H-シクロペンタ[b]ピリジン-7-カルボン酸
LCMS M/Z (M+H) 425.
(S)-2-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-6,7-ジヒド
ロ-5H-シクロペンタ[b]ピリジン-7-カルボキサミドおよび(R)-2-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-6,7-ジヒドロ-5H-シクロペンタ[b]ピリジン-7-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.93 (m, 1H), 7.80 (s, 1H), 7.56 - 7.50 (m, 2H), 7.43 (s, 1H), 7.20 (s, 1H), 6.97 - 6.93 (m, 1H), 6.82 (d, J = 55.2 Hz, 1H), 3.86 (s, 3H), 3.81 - 3.69 (m, 3H),
2.94 - 2.75 (m, 4H), 2.59 (d, J = 4.8 Hz, 3H), 2.26 - 2.17 (m,
2H), 1.94 - 1.86 (m, 2H). LCMS M/Z (M+H) 438.
実施例118:
1H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.96 (m, 1H), 7.82 (s, 1H), 7.56 - 7.50 (m, 2H), 7.46 (s, 1H), 7.22 (s, 1H), 6.99 - 6.96 (m, 1H), 6.84 (d, J = 55.2 Hz, 1H), 3.88 (s, 3H), 3.79 - 3.42 (m, 3H),
2.94 - 2.75 (m, 4H), 2.58 - 2.59 (m, 3H), 2.30 - 2.17 (m, 2H), 1.98 - 1.84 (m, 2H). LCMS M/Z (M+H) 438.
LCMS M/Z (M+H) 266.
LCMS M/Z (M+H) 435.
1H NMR (400 MHz,CDCl3) δ 9.41 (s, 1H), 8.83 (d, J = 4.4 Hz, 1H),
8.58 (s, 1H), 8.38 - 8.33 (m, 2H), 8.14 (d, J = 9.2 Hz, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.19 (s, 1H), 6.65 (t, J = 55.2 Hz, 1H), 6.12 (s, 1H), 3.85 (s, 3H), 3.70 (t, J = 5.6 Hz, 2H), 3.02 - 2.99 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.17 - 2.16 (m, 2H). LCMS
M/Z (M+H) 448.
LCMS M/Z (M+H) 265.
1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.4 Hz, 1H), 8.13 (d, J
= 8.4 Hz, 1H), 7.97 - 7.95 (m, 1H), 7.84 - 7.80 (m, 1H), 7.79 -
7.72 (m, 3H), 7.51 (s, 1H), 7.22 (s, 1H), 6.67 (t, J = 56.0 Hz,
1H), 6.45 (s, 1H), 3.86 (s, 3H), 2.99 - 2.96 (m, 2H), 2.76 (d, J
= 5.2 Hz, 3H), 2.57 - 2.53 (m, 2H), 2.11 - 2.06 (m, 2H). LCMS M/Z (M+H) 448.
LCMS M/Z (M+H) 385.
LCMS M/Z (M+H) 371.
1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.97 (s, 1H), 8.48 (d, J
= 6.8 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.05 (d,
J = 8.0 Hz, 1H), 7.91(s, 1H), 7.85 - 7.81 (m, 2H), 7.59 - 7.57 (m, 1H), 4.03 (s, 3H), 3.23 (d, J = 4.8 Hz, 3H). LCMS M/Z (M+H) 384.
1H NMR (400 MHz, CDCl3) δ 7.55 - 7.48 (m, 1H), 7.31 (d, J = 8.0
Hz, 1H), 7.19 (t, J = 4.0 Hz, 2H), 1.44 (s, 9H).
LCMS M/Z (M+H) 456.
LCMS M/Z (M+H) 356.
1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.62 - 7.51 (m, 2H), 7.47 (s, 1H), 7.28 (s, 1H), 6.90 (t, J = 55.2 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.74 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H), 2.48 (s, 3H), 1.96 - 1.90 (m, 2H). LCMS M/Z (M+H) 413.
II)(168mg、0.75mmol)および4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン(433mg、0.75mmol)を添加した。反応混合物を窒素雰囲気下で16時間100℃に加熱した。反応物を室温に冷却した後、水(100mL)を添加し、EtOAc(50mL×3)で抽出した。合わせた有機層をブライン(50mL×2)で洗浄し、無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣をシリカゲルカラムクロマトグラフィ(石油エーテル/EtOAc=9:1)によって精製して、表題化合物(900mg、39%)を白色固体として得た。
LCMS M/Z (M+H) 303.
mL)の溶液に、トリフルオロ酢酸(0.076mL、1.03mmol)を0℃で添加した。反応混合物を室温で5時間撹拌し、真空中で濃縮して、表題化合物(80mg、粗製)を黄色油状物として得、これは、さらなる精製は不要であった。
LCMS M/Z (M+H) 386.
1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H),7.06 (s, 1H), 6.58 (t, J = 55.2 Hz,
1H), 6.17 (s, 1H), 5.75 (s, 1H), 3.99 (s, 3H), 3.81 - 3.76 (m, 2H), 3.79 (s, 3H), 2.82 - 2.80 (m, 2H), 2.70 (d, J = 4.0 Hz, 3H),
2.06 (t, J = 6.0 Hz, 2H). LCMS M/Z (M+H) 443.
1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 8.02 (d, J = 6.4 Hz, 2H), 7.89 (d, J = 7.6 Hz, 2H), 7.69 (s, 1H), 7.58 - 7.40 (m, 3H), 7.35 - 7.34 (m, 2H), 7.24 - 7.02 (m, 5H), 6.54 - 6.50 (m, 1H), 3.98 (s, 3H).
1H NMR (400MHz, DMSO-d6) δ 9.72 (s, 1H), 8.69 (s, 1H), 8.36 - 8.34
(m, 2H), 7.80 - 7.75 (m, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.28 (s, 1H), 8.33 (s,
1H), 8.17 (s, 1H), 8.08 - 8.06 (m, 2H), 7.77 - 7.71 (m, 2H), 7.69 - 7.64 (m, 1H), 4.01 (s, 3H), 3.92 (s, 3H).
LCMS M/Z (M+H) 391.
LCMS M/Z (M+H) 377.
1H NMR (400 MHz, DMSO-d6) δ 9.57 - 9.53 (m, 1H), 9.39 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.09 - 8.07 (m, 2H), 7.84 - 7.69 (m, 3H), 4.03 (s, 3H), 3.91 (s, 3H), 2.78 (d, J = 4.4 Hz, 3H). LCMS M/Z
(M+H) 390.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ピラゾロ[4,3-b]ピリジン-5-カルボキサミド
LCMS M/Z (M+H) 256.
1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 8.8 Hz, 1H), 8.17 (d, J
= 8.8 Hz, 1H), 5.13 - 4.19 (m, 1H), 4.03 - 4.00 (m, 2H), 3.94 (s, 3 H), 3.54 (t, J = 11.6 Hz, 2H), 2.12 - 2.06 (m, 2H), 1.96 -
1.93 (m, 2 H).
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ピラゾロ[4,3-b]ピリジン-5-カルボン酸
LCMS M/Z (M+H) 509.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ピラゾロ[4,3-b]ピリジン-5-カルボキサミド
1H NMR (400 MHz, DMSO-d6) δ 8.40 - 8.29 (m, 2H), 8.08 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.57 - 7.51 (m, 1H), 7.20 (s, 1H), 6.82 (t, J = 55.6 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.24 -
4.18 (m, 2H), 4.02 - 3.98 (m, 2H), 3.88 (s, 3 H), 3.55 (t, J = 11.2 Hz, 2H), 2.96 - 2.89 (m, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.14
- 2.03(m, 4H), 1.94 - 1.91 (m, 2H). LCMS M/Z (M+H) 522.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-(テトラヒドロ-2H-ピラン-4-イル)-4,5,6,7-テトラヒドロ-1H-インダゾール-5-カルボキサミド
LCMS M/Z (M+H) 279.
1H NMR (400 MHz, CDCl3) δ 4.18 (q, J = 7.2 Hz, 2H), 4.12 - 4.08
(m, 2H), 3.51 - 3.45 (m, 2H), 2.82 - 2.55 (m, 5H), 2.33 - 2.23 (m, 3H), 1.96 - 1.76 (m, 3H), 1.29 (t, J = 7.2 Hz, 3H). LCMS M/Z
(M+H) 357.
エチル3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-4,5,6,7-テトラヒドロ-1H-インダゾール-5-カルボキシラート
して得た。
LCMS M/Z (M+H) 540.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-4,5,6,7-テトラヒドロ-1H-インダゾール-5-カルボン酸
LCMS M/Z (M+H) 512.
3-(7-(ジフルオロメチル)-6-(1-メチル-1H-ピラゾール-4-イル)-3,4-ジヒドロキノリン-1(2H)-イル)-N-メチル-1-(テトラヒドロ-2H-ピラン-4-イル)-4,5,6,7-テトラヒドロ-1H-インダゾール-5-カルボキサミド
)を添加した。反応混合物を室温で1時間撹拌した。EtOAc(30mL)を添加し、水(30mL×3)、ブライン(30mL)で洗浄した。有機層を無水Na2SO4で乾燥させ、濾過し、真空中で濃縮した。粗残渣を逆相クロマトグラフィ(アセトニトリル30-60%/0.05%NH4OHを含む水)によって精製して、表題化合物(53mg、57%)を黄色固体として得た。
1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.71 (m, 2H), 7.48 (s, 1H), 7.06 (s, 1H), 6.77 (s, 1H), 6.76 (t, J = 55.2 Hz, 1H), 4.30 - 4.21
(m, 1H), 3.97 - 3.92 (m, 2H), 3.86 (s, 3H), 3.66 - 3.58 (m, 1H),
3.53 - 3.42 (m, 3H), 2.90 - 2.80 (m, 3H), 2.66 - 2.58 (m, 1H), 2.55 (d, J = 4.4 Hz, 3H), 2.40 - 2.30 (m, 1H), 2.27 - 2.23 (m, 2H), 2.04 - 1.90 (m, 5H), 1.85 - 1.67 (m, 3H). LCMS M/Z (M+H) 525.
CBP TR-FRET結合アッセイを使用したインヒビターのIC50測定
ンキュベーションした。インキュベーション後、捕捉プレートを300ul/ウェルの1×洗浄緩衝液で3回洗浄し、100ulのアンプリファイアをプレートに添加して、55℃で60分間インキュベーションした。捕捉プレートを300ul/ウェルの1×洗浄緩衝液で3回再度洗浄し、100ulのラベルプロープをプレートに添加して、50℃で60分間インキュベーションした。次いで、捕捉プレートを300ul/ウェルの1×洗浄緩衝液で3回洗浄し、100ulの2.0基質をプレートの各ウェルに添加した。プレートを、暗所において室温で5分間インキュベーションし、積分時間を0.2秒に設定した発光プロトコールを使用して、Envisionによって読み取った。
である。
(項1)
式(I)もしくは式(II):
の化合物またはその塩であって、式中、
R 1 は、水素、-NR a R b 、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニルおよび3~8員カルボシクリルであり、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニルおよび3~8員カルボシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C 1~6 アルコキシ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換され;
各R 2 は、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、-F、-Cl、-Br、-I、-NO 2 、-N(R t ) 2 、-CN、-C(O)-N(R t ) 2 、-O-R t 、-O-C(O)-R t 、-C(O)-R t および-C(O)-O-R t からなる群から独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニルおよびC 2~6 アルキニルはいずれも、1つまたは複数のハロで任意選択的に置換され;
R 3 は、3~12員炭素環または3~12員複素環であり、ここで、R 3 の3~12員炭素環および3~12員複素環の各々は、1つまたは複数の基R u で任意選択的に置換され;
Yは、OまたはN(R c )であり;
mは、0、1、2、3または4であり;
nは、0、1、2、3または4であり;
pは、0、1、2、3または4であり;
環Aは、ベンゾおよび6員複素環からなる群から選択される縮合環であり;
各R 4 は、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、-F、-Cl、-Br、-I、-NO 2 、-N(R w ) 2 、-CN、-C(O)-N(R w ) 2 、-O-R w 、-O-C(O)-R w 、-C(O)-R x および-C(O)-O-R w からなる群から独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニルおよびC 2~6 アルキニルはいずれも、1つまたは複数のオキソまたはハロで任意選択的に置換され;
各R 5 は、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、-F、-Cl、-Br、-I、-NO 2 、-N(R w ) 2 、-CN、-C(O)-N(R w ) 2 、-O-R w 、-O-C(O)-R w 、-C(O)-R x および-C(O)-O-R w からなる群から独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニルおよびC 2~6 アルキニルはいずれも、1つまたは複数のオキソまたはハロで任意選択的に置換され;
R 6 は、-N(R z )-C(O)-R x 、3~12員炭素環または3~12員複素環であり、ここで、R 6 の3~12員炭素環および3~12員複素環の各々は、1つまたは複数の基R x で任意選択的に置換され;
Xは、NまたはC(R 7 )であり;
R 7 はHであるか、またはオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルであり;
R a およびR b の各々は、水素、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 ア
ルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C 1~6 アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;またはR a およびR b は、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~3 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されたヘテロシクリルを形成し;
R c は、水素、C 1~6 アルキル、C 2~6 アルケニルまたはC 2~6 アルキニルであり、ここで、C 1~6 アルキル、C 2~6 アルケニルおよびC 2~6 アルキニルの各々は、オキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換され;
各R t は、水素、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C 1~6 アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのR t は、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~3 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換された3~12員ヘテロシクリルを形成し;
各R u は、オキソ、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリル、3~12員ヘテロシクリル、-F、-Cl、-Br、-I、-NO 2 、-N(R v ) 2 、-CN、-C(O)-N(R v ) 2 、-S(O)-N(R v ) 2 、-S(O) 2 -N(R v ) 2 、-O-R v 、-S-R v 、-O-C(O)-R v 、-O-C(O)-O-R v 、-C(O)-R v 、-C(O)-O-R v 、-S(O)-R v 、-S(O) 2 -R v 、-O-C(O)-N(R v ) 2 、-N(R v )-C(O)-OR v 、-N(R v )-C(O)-N(R v ) 2 、-N(R v )-C(O)-R v 、-N(R v )-S(O)-R v 、-N(R v )-S(O) 2 -R v 、-N(R v )-S(O)-N(R v ) 2 および-N(R v )-S(O) 2 -N(R v ) 2 から独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリル、3~12員ヘテロシクリルはいずれも、オキソ、ハロ、-NO 2 、-N(R v ) 2 、-CN、-C(O)-N(R v ) 2 、-S(O)-N(R v ) 2 、-S(O) 2 -N(R v ) 2 、-O-R v 、-S-R v 、-O-C(O)-R v 、-C(O)-R v 、-C(O)-O-R v 、-S(O)-R v 、-S(O) 2 -R v 、-C(O)-N(R v ) 2 、-N(R v )-C(O)-R v 、-N(R v )-S(O)-R v 、-N(R v )-S(O) 2 -R v 、3~12員炭素環、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換され;
各R v は、水素、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、C 1~6 アルコキシ、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、C 1~6 アルコキシ、カルボシクリルおよびヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C 1~6 アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルから独立して選択される1つまたは複数の基で任
意選択的に置換されるか;または2つのR w は、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~3 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換された3~12員ヘテロシクリルを形成し;
各R w は、水素、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C 1~6 アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのR t は、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~3 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されたヘテロシクリルを形成し;
各R x は、オキソ、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリル、3~12員ヘテロシクリル、-F、-Cl、-Br、-I、-NO 2 、-N(R y ) 2 、-CN、-C(O)-N(R y ) 2 、-S(O)-N(R y ) 2 、-S(O) 2 -N(R y ) 2 、-O-R y 、-S-R y 、-O-C(O)-R y 、-O-C(O)-O-R y 、-C(O)-R y 、-C(O)-O-R y 、-S(O)-R y 、-S(O) 2 -R y 、-O-C(O)-N(R y ) 2 、-N(R y )-C(O)-OR y 、-N(R y )-C(O)-N(R y ) 2 、-N(R y )-C(O)-R y 、-N(R y )-S(O)-R y 、-N(R y )-S(O) 2 -R y 、-N(R y )-S(O)-N(R y ) 2 および-N(R y )-S(O) 2 -N(R y ) 2 から独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、3~12員カルボシクリルおよび3~12員ヘテロシクリルはいずれも、オキソ、ハロ、-NO 2 、-N(R y ) 2 、-CN、-C(O)-N(R y ) 2 、-S(O)-N(R y ) 2 、-S(O) 2 -N(R y ) 2 、-O-R y 、-S-R y 、-O-C(O)-R y 、-C(O)-R y 、-C(O)-O-R y 、-S(O)-R y 、-S(O) 2 -R y 、-C(O)-N(R y ) 2 、-N(R y )-C(O)-R y 、-N(R y )-S(O)-R y 、-N(R y )-S(O) 2 -R y 、3~12員炭素環、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換され;
各R y は、水素、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、C 1~6 アルコキシ、3~12員カルボシクリルおよび3~12員ヘテロシクリルから独立して選択され、ここで、C 1~6 アルキル、C 2~6 アルケニル、C 2~6 アルキニル、C 1~6 アルコキシ、3~12員カルボシクリルおよび3~12員ヘテロシクリルの各々は、オキソ、ハロ、アミノ、ヒドロキシル、C 1~6 アルコキシ、3~12員カルボシクリル、3~12員ヘテロシクリル、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1 ~C 6 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換されるか;または2つのR y は、それらが結合する窒素とともに、オキソ、ハロ、ならびにオキソおよびハロから独立して選択される1つまたは複数の基で任意選択的に置換されたC 1~3 アルキルから独立して選択される1つまたは複数の基で任意選択的に置換された3~12員ヘテロシクリルを形成し;そして、
各R z は、水素、C 1~6 アルキルから独立して選択される、
化合物またはその塩。
(項2)
前記化合物が式(I):
の化合物であり、
但し、R 3 が
ではない、上記項1に記載の化合物または塩。
(項3)
式(Ia):
の化合物またはその塩である、上記項1に記載の化合物または塩。
(項4)
式(Ib):
の化合物またはその塩である、上記項1に記載の化合物または塩。
(項5)
R 1 が-NHR b である、上記項1~4のいずれか1項に記載の化合物または塩。
(項6)
R b がC 1~6 アルキルである、上記項5に記載の化合物または塩。
(項7)
R 1 がメチルまたは-NH(CH 3 )である、上記項1~4のいずれか1項に記載の化合物または塩。
(項8)
mが0である、上記項1~3のいずれか1項に記載の化合物または塩。
(項9)
mが1である、上記項1~3のいずれか1項に記載の化合物または塩。
(項10)
R 2 が-O-R t である、上記項1~7および9のいずれか1項に記載の化合物または塩。
(項11)
R 2 が-OMeである、上記項1~7および9のいずれか1項に記載の化合物または塩。
(項12)
R 3 が、1つまたは複数の基R u で任意選択的に置換された3~12員炭素環である、上記項1~11のいずれか1項に記載の化合物または塩。
(項13)
R 3 が、1つまたは複数の基R u で任意選択的に置換されたフェニルである、上記項1~11のいずれか1項に記載の化合物または塩。
(項14)
R 3 が、1つまたは複数の基R u で任意選択的に置換された3~12員複素環である、上記項1~11のいずれか1項に記載の化合物または塩。
(項15)
R 3 が、1つまたは複数の基R u で任意選択的に置換された9~10員複素環である、上記項1~11のいずれか1項に記載の化合物または塩。
(項16)
R 3 が、
からなる群から選択される、上記項1~11のいずれか1項に記載の化合物または塩。
(項17)
ならびにそれらの塩からなる群から選択される、上記項1に記載の化合物または塩。
(項18)
前記化合物が式(II):
の化合物であり、
但し、R 6 が
ではない、上記項1に記載のまたは塩化合物。
(項19)
前記化合物が式(IIa):
の化合物である、上記項18に記載の化合物または塩。
(項20)
前記化合物が式(IIb):
の化合物である、上記項18に記載の化合物または塩。
(項21)
前記化合物が式(IIc):
の化合物である、上記項18に記載の化合物または塩。
(項22)
前記化合物が式(IId):
の化合物である、上記項1に記載の化合物または塩。
(項23)
前記化合物が式(IIe):
の化合物である、上記項18に記載の化合物または塩。
(項24)
前記化合物が式(IIf):
の化合物である、上記項18に記載の化合物または塩。
(項25)
前記化合物が式(IIg):
の化合物である、上記項18に記載の化合物または塩。
(項26)
XがNである、上記項1および18~25のいずれか1項に記載の化合物または塩。
(項27)
XがC(R 7 )である、上記項1および18~25のいずれか1項に記載の化合物または塩。
(項28)
R 7 がHである、上記項27に記載の化合物または塩。
(項29)
R 7 がジフルオロメチルである、上記項27に記載の化合物または塩。
(項30)
前記化合物が式(IIh):
の化合物である、上記項18に記載の化合物または塩。
(項31)
pが0である、上記項1および18~29のいずれか1項に記載の化合物または塩。
(項32)
pが1、2、3または4である、上記項1および18~29のいずれか1項に記載の化合物または塩。
(項33)
R 6 が、1つまたは複数の基R x で任意選択的に置換された3~12員複素環である、上記項1および18~32のいずれか1項に記載の化合物または塩。
(項34)
R 6 が、1つまたは複数の基R x で任意選択的に置換された
からなる群から選択される、上記項1および18~32のいずれか1項に記載の化合物または塩。
(項35)
R 6 が、
からなる群から選択される、上記項1および18~25のいずれか1項に記載の化合物または塩。
(項36)
ならびにそれらの塩からなる群から選択される、上記項1に記載の化合物または塩。
(項37)
上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩、および薬学的に許容され得るアジュバント、担体、またはビヒクルを含む組成物。
(項38)
さらなる治療剤と組み合わせての、上記項37に記載の組成物。
(項39)
前記さらなる治療剤が化学療法剤である、上記項38に記載の組成物。
(項40)
動物におけるCBPおよび/またはEP300媒介障害を処置する方法であって、上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を該動物に投与する工程を含む、方法。
(項41)
前記障害ががん、炎症性障害、または自己免疫疾患である、上記項40に記載の方法。
(項42)
前記がんが、聴神経腫、急性白血病、急性リンパ球性白血病、急性骨髄球性白血病、急性T細胞白血病、基底細胞癌、胆管癌、膀胱がん、脳がん、乳がん、気管支原性癌、子宮頸がん、軟骨肉腫、脊索腫、絨毛癌、慢性白血病、慢性リンパ球性白血病、慢性骨髄球性白血病、慢性骨髄性白血病、結腸がん、結腸直腸がん、頭蓋咽頭腫、嚢胞腺癌、びまん性大細胞型B細胞リンパ腫、増殖異常性変化、胎児性癌、子宮内膜がん、内皮肉腫、上衣腫、上皮癌、赤白血病、食道がん、エストロゲン受容体陽性乳がん、本態性血小板血症、ユーイング腫瘍、線維肉腫、濾胞性リンパ腫、胚細胞精巣がん、神経膠腫、膠芽腫、神経膠肉腫、重鎖病、頭頸部がん、血管芽細胞腫、ヘパトーマ、肝細胞がん、ホルモン非感受性前立腺がん、平滑筋肉腫、白血病、脂肪肉腫、肺がん、リンパ管内皮肉腫、リンパ管肉腫、リンパ芽球性白血病、リンパ腫、T細胞またはB細胞起源のリンパ系悪性疾患、髄様癌、髄芽腫、黒色腫、髄膜腫、中皮腫、多発性骨髄腫、骨髄性白血病、骨髄腫、粘液肉腫、神経芽細胞腫、NUTミッドラインカルシノーマ(NMC)、非小細胞肺がん、乏突起膠腫、口腔がん、骨原性肉腫、卵巣がん、膵臓がん、乳頭腺癌、乳頭状癌、松果体腫、真性赤血球増加症、前立腺がん、直腸がん、腎細胞癌、網膜芽細胞腫、横紋筋肉腫、肉腫、脂腺癌、セミノーマ、皮膚がん、小細胞性肺癌、固形腫瘍(癌腫および肉腫)、小細胞肺がん、胃がん、扁平上皮癌、滑膜腫、汗腺癌、甲状腺がん、ワルデンシュトレームマクログロブリン血症、精巣腫瘍、子宮がん、およびウィルムス腫瘍から選択される、上記項41に記載の方法。
(項43)
前記がんが、肺がん、乳がん、膵臓がん、結腸直腸がんおよび黒色腫から選択される、上記項41に記載の方法。
(項44)
前記炎症性障害または前記自己免疫疾患が、アジソン病、急性痛風、強直性脊椎炎、喘息、アテローム性動脈硬化症、ベーチェット病、水疱性皮膚疾患、慢性閉塞性肺疾患、クローン病、皮膚炎、湿疹、巨細胞性動脈炎、線維症、糸球体腎炎、肝血管閉塞、肝炎、下垂体炎、免疫不全症候群、炎症性腸疾患、川崎病、ループス腎炎、多発性硬化症、心筋炎、筋炎、腎炎、臓器移植拒絶、変形性関節症、膵炎、心膜炎、結節性多発動脈炎、肺臓炎、原発性胆汁性肝硬変、乾癬、乾癬性関節炎、関節リウマチ、強膜炎、硬化性胆管炎、敗血症、全身性エリテマトーデス、高安動脈炎、毒性ショック、甲状腺炎、I型糖尿病、潰瘍性大腸炎、ブドウ膜炎、白斑、血管炎およびウェゲナー肉芽腫症から選択される、上記項41に記載の方法。
(項45)
医薬療法における使用のための、上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩。
(項46)
CBPおよび/またはEP300媒介障害の予防的処置または治療的処置のための、上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩。
(項47)
動物におけるCBPおよび/またはEP300媒介障害の処置のための医薬を調製するための、上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩の使用。
(項48)
動物における細胞毒性剤を含むがん処置の有効性を増大させる方法であって、有効量の上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を該動物に投与することを含む、方法。
(項49)
前記細胞毒性剤を前記動物に投与することをさらに含む、上記項48に記載の方法。
(項50)
動物におけるがん治療に対する応答の持続時間を延長させる方法であって、該方法は、上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を該がん治療を受けている動物に投与することを含み、該式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を投与したときの該がん治療に対する応答の持続時間が、該式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩を投与しない該がん治療に対する応答の持続時間を超えて延長される、方法。
(項51)
個体におけるがんを処置する方法であって、(a)上記項1~36のいずれか1項に記載の式(I)もしくは式(II)の化合物またはその薬学的に許容され得る塩、および(b)細胞毒性剤を該個体に投与することを含む、方法。
(項52)
前記細胞毒性剤が、抗微小管剤、白金配位錯体、アルキル化剤、抗生物質製剤、トポイソメラーゼIIインヒビター、代謝拮抗物質、トポイソメラーゼIインヒビター、ホルモンおよびホルモンアナログ、シグナル伝達経路インヒビター、非受容体チロシンキナーゼ血管形成インヒビター、免疫治療剤、アポトーシス促進剤、LDH-Aのインヒビター、脂肪酸生合成のインヒビター、細胞周期シグナル伝達インヒビター、HDACインヒビター、プロテアソームインヒビター、およびがん代謝のインヒビターから選択される、上記項51に記載の方法。
(項53)
前記細胞毒性剤がタキサンである、上記項51に記載の方法。
(項54)
前記タキサンがパクリタキセルまたはドセタキセルである、上記項53に記載の方法。
(項55)
前記細胞毒性剤が白金製剤である、上記項51に記載の方法。
(項56)
前記細胞毒性剤がEGFRのアンタゴニストである、上記項51に記載の方法。
(項57)
前記EGFRのアンタゴニストが、N-(3-エチニルフェニル)-6,7-ビス(2-メトキシエトキシ)キナゾリン-4-アミンまたはその薬学的に許容され得る塩である、上記項56に記載の方法。
(項58)
前記細胞毒性剤がRAFインヒビターである、上記項51に記載の方法。
(項59)
前記RAFインヒビターが、BRAFインヒビターまたはCRAFインヒビターである、上記項58に記載の方法。
(項60)
前記RAFインヒビターがベムラフェニブである、上記項58に記載の方法。
(項61)
前記細胞毒性剤がPI3Kインヒビターである、上記項51に記載の方法。
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US11168070B2 (en) | 2021-11-09 |
US20200399244A1 (en) | 2020-12-24 |
MA45122A (fr) | 2019-04-10 |
EP4067347B1 (en) | 2024-06-19 |
EP3464270A2 (en) | 2019-04-10 |
WO2017205536A3 (en) | 2018-01-04 |
EP4067347A1 (en) | 2022-10-05 |
US20190152949A1 (en) | 2019-05-23 |
JP7160688B2 (ja) | 2022-10-25 |
JP2019516757A (ja) | 2019-06-20 |
US10696655B2 (en) | 2020-06-30 |
EP3464270B1 (en) | 2022-02-23 |
CN109476641B (zh) | 2022-07-05 |
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