JP2016518337A - 高活性抗新生物薬及び抗増殖剤 - Google Patents
高活性抗新生物薬及び抗増殖剤 Download PDFInfo
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- JP2016518337A JP2016518337A JP2016503044A JP2016503044A JP2016518337A JP 2016518337 A JP2016518337 A JP 2016518337A JP 2016503044 A JP2016503044 A JP 2016503044A JP 2016503044 A JP2016503044 A JP 2016503044A JP 2016518337 A JP2016518337 A JP 2016518337A
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- alkylene
- compound
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- substituted
- alkyl
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Abstract
Description
本出願は、2013年3月15日に出願の米国仮特許出願番号第61/798,772号、2013年8月1日に出願の米国仮特許出願番号第61/861,374号、2013年12月3日に出願の仮米国特許出願番号第61/911,354号、及び2014年3月7日に出願の米国特許出願番号第61/949,795号に関連し、かつ、これらの利益を主張するものである。これらの出願の全部が、全ての目的のために参照事項としてここに包含される。
米国政府は、本発明に対して、アレルギー及び感染症学会により与えられる承認番号5R44AI084284号の支持に基づく権利を有する。
従って、特定の癌及び細胞過剰増殖に対する活性の高い化合物への、継続した必要性が存在する。
要約すると、本発明は、以下の特徴を含む:
A)T細胞癌及びその他のT細胞媒介異常症の治療のための化学療法剤としての使用のための、選択的化合物、方法及び組成物。
B)B細胞癌及び他のB細胞媒介異常症の治療のための、化学療法剤としての使用のための選択的化合物、方法及び組成物。
C)免疫抑制剤及び抗炎症薬としての使用のための選択的化合物、方法及び組成物
D)自己免疫異常症に対する使用のための選択的化合物、方法及び組成物。
E)内科治療で使用するための、ここに記載される式I、II、III、IV及びVの化合物、又はそれらの薬理学的に許容される組成物、塩及びプロドラッグ。
F)T細胞癌及びその他のT細胞媒介異常症に対する使用のための、ここに記載される式I、II、III、IV及びVの化合物、又はそれらの薬理学的に許容される組成物、塩及びそれらのプロドラッグ。
G)B細胞癌及びB細胞媒介異常症に対する使用のための、ここに記載される式I、II、III、IV及びVの化合物、又はそれらの薬理学的に許容される組成物、塩及びそれらのプロドラッグ。
H)免疫不全又は炎症状態の治療で使用するための、ここに記載される式I、II、III、IV及びVの化合物、又はそれらの薬理学的に許容される組成物、塩及びそれらのプロドラッグ。
I)自己免疫不全の治療で使用するための、ここに記載される式I、II、III、IV及びVの化合物、又はそれらの薬理学的に許容される組成物、塩及びそれらのプロドラッグ。
J)有効量のここに記載される式I、II、III、IV及びVの化合物を含む、治療製品の作製のための方法。
K)治療使用のために意図される、式I、II、III、IV及びVの薬剤を製造する方法。
L)1つ以上の他の治療薬と組み合わせた、式I、II、III、IV及びVの化合物の使用のために選択された化合物、方法及び組成物。
及び
M)他の1つ以上の付加的な治療薬と組み合わせて使用するための、ここに記載される式I、II、III、IV及びVの化合物又はそれらの薬理学的に許容される組成物、塩及びそれらのプロドラッグ。
特に、造血細胞、特に、T細胞、B細胞及びNK細胞の、癌及び増殖異常症を治療するための、化合物及び方法が、提供される。
また、炎症性異常症、自己免疫状態及び免疫不全を治療するために選択された活性化合物も、有用である。
一実施形態では、本発明は、式I、II、III、IV又はV、又は、その薬理学的に許容される塩、の化合物又はこれらの化合物の使用に関し:
各Xは、独立してCH又はNであり;
各X’は、独立してCH又はNであり;
X’’は、独立してCH2、S又はNHであり、構成部分が安定5員環となるよう配置され;
R、R8及びR11は、独立してH、C1-C3のアルキル又はハロアルキル、シクロアルキル、又は、N、O又はSから選択される1つ以上のヘテロ原子を含んだシクロアルキル;
−(アルキレン)m-C3-C8シクロアルキル、−(アルキレン)m-アリール、−(アルキレン)m、-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4;
−(アルキレン)m-0-R5、−(アルキレン)m- S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であり、これらのいずれかは、価電子(valance)で与えられる1つ以上のR基で任意に独立に置換されてもよく、同じ又は隣接した原子に結合した2つのRx基を任意に組み合せて環を形成してもよい;
各R1は独立して、アリール、アルキル、シクロアルキル又はハロアルキルであり、前記アルキル、シクロアルキル及びハロアルキル基の各々は、鎖中の炭素の代わりに任意にO又はNヘテロ原子を含み、
隣接した環原子又は同じ環原子の2つのR1,のものは、環原子と共に、任意に結合される3-8員環を形成し;
yは、0、1、2,3又は4であり;
R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4;−(アルキレン)m-C(O)-O-アルキル;−(アルキレン)m-O-R5、−(アルキレン)m-S(O)n-R5、又は−(アルキレン)m-S(O)n-NR3R4であり、
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は、任意に組み合わされて環を形成してもよく、
mは0又は1、nは0、1又は2であり;
R3及びR4はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキル
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は、任意に組み合わされて環を形成してもよく、
又は、R3及びR4は、これらが結合される窒素原子と共に組み合わされて、価電子で与えられる1つ以上のRx基で任意に独立して置換されるヘテロシクロ環を形成してもよく、
同じ又は隣接した原子に結合した2つのRx基は、任意に組み合わされて環を形成してもよく、
R5及びR5*はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく;
Rxは、その発生毎に独立して、ハロ、シアノ、ニトロ、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキル、−(アルキレン)m-OR5、−(アルキレン)m-O-アルキレン-OR5、−(アルキレン)m-S(O)n-R5、−(アルキレン)m-NR3R4、−(アルキレン)m-CN、−(アルキレン)m-C(O)-R5、−(アルキレン)m-C(S)-R5、−(アルキレン)m-C(O)-OR5、−(アルキレン)m-O-C(O)-R5、−(アルキレン)m-C(S)-OR5、−(アルキレン)m-C(O)-(アルキレン)m-NR3R4、−(アルキレン)m-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-NR3R4、−(アルキレン)m-N(R3)-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-R5、−(アルキレン)m-N(R3)-C(S)-R5、−(アルキレン)m-O-C(O)-NR3R4、−(アルキレン)m-O-C(S)-NR3R4、−(アルキレン)m-SO2-NR3R4、−(アルキレン)m-N(R3)-SO2-R5、−(アルキレン)m-N(R3)-SO2-NR3R4、−(アルキレン)m-N(R3)-C(O)-OR5、−(アルキレン)m-N(R3)-C(S)-OR5、又は−(アルキレン)m-N(R3)-SO2-R5であり;
ここで、前記アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル及びヘテロシクロアルキル基は、以下の1つ以上でさらに独立して置換されてもよい:
−(アルキレン)m-CN、−(アルキレン)m-OR5*、−(アルキレン)m-S(O)n-R5*、−(アルキレン)m-NR3*R4*、−(アルキレン)m-C(O)-R5*、−(アルキレン)m-C(=S)R5*、−(アルキレン)m-C(=O)OR5*、−(アルキレン)m-OC(=O)R5*、−(アルキレン)m-C(S)-OR5*、−(アルキレン)m-C(O)-NR3*R4*、−(アルキレン)m-C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-NR3*R4*、−(アルキレン)m-N(R3*)−C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-R5*、−(アルキレン)m-N(R3*)−C(S)-R5*、−(アルキレン)m-O-C(O)-NR3*R4*、−(アルキレン)m-O-C(S)-NR3*R4*、−(アルキレン)m-SO2-NR3*R4*、−(アルキレン)m-N(R3*)−SO2R5*、−(アルキレン)m-N(R3*)−SO2NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-OR5*、−(アルキレン)m-N(R3*)−C(S)-OR5*、又は−(アルキレン)m-N(R3*)−SO2R5*、の1つ以上でさらに独立して置換されてもよく;
nは、0、1又は2であり、mは0又は1であり;
R3*及びR4*は、独立してその発生毎に以下の通りであり:
(i)水素又は
(ii)アルキル、アルケニル、アルキニルシクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであって、
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
又は
R3*及びR4*は、それらに結合される窒素原子と共に組合せられて、価電子によって与えられる1つ以上のRx基と任意に独立して置換されるヘテロシクロ環を形成してもよく;
R6はH又は低級アルキル、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、
R10は
(i) NHRAであり、
ここで、RAは非置換又は置換C1-C8アルキル、シクロアルキルアルキル、又は、-TT-RR、C1-C8シクロアルキル、又は、N、O及びSから選択されるヘテロ原子を1つ以上含むシクロアルキルであり;
TTは、非置換又は置換C1-C8アルキル又はC3-C8シクロアルキルリンカーであり;
そして、RRはヒドロキシル、非置換又は置換C1-C6アルコキシ、アミノ、非置換又は置換C1-C6アルキルアミノ、非置換又は置換ジC1-C6アルキルアミノ、非置換又は置換C6-C10アリール、1又は2個の5員又は6員環及びN、O及びSから選択される1-4個のヘテロ原子を含む非置換又は置換ヘテロアリール、非置換又は置換C3-C10炭素環、又は、1又は2個の5員又は6員環及びN、O及びSから選択される1-4個のヘテロ原子を含む非置換又は置換ヘテロ環であり;
又は
(ii)-C(O)-R12又は-C(O)O-R13、ここで、R12はNHRA又はRAであり、R13はRAであり;又はその薬理学的に許容される塩、プロドラッグ又はアイソトープ変種、たとえば、一部又は全部に重水素を導入した形態である。
ある態様では、化合物は、式IIIであり:変種は、式IおよびIIの化合物及びその薬理学的に許容される塩と定義される。
ある態様では、R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4であり、;
−(アルキレン)m-O-R5−(アルキレン)m-S(O)n-R5又は−(アルキレン)m-S(O)n-NR3R4のいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、
mは0又は1、nは0、1又は2である。
ある態様では、R8は、水素又はC1-C3アルキルである。
ある態様では、Rは、水素又はC1-C3アルキルである。
ある態様では、R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4、−(アルキレン)m-C(O)-O-アルキル又は−(アルキレン)m-OR5であり、
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、
ある態様では、R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4、−(アルキレン)m-C(O)-O-アルキル又は−(アルキレン)m-OR5であり、さらなる置換はない。
ある態様では、R2におけるmは、1である。
更なる態様では、R2のアルキレンは、メチレン基である。
ここで、各mは、独立して0又は1であり;
Pは、4員〜8員の単環又は二環式飽和ヘテロシクリル基であり;
各Rx1は、独立して、−(アルキレン)m-(C(O))m-(アルキレン)m-(N(Rn))m-(アルキル)m、ここで各mは、独立して0又は1であるが、少なくとも一つのmは1、−(C(O))-O-アルキル、−(アルキレン)m-シクロアルキル、ここでmは0又は1、-N(Rn)-シクロアルキル、-C(O)-シクロアルキル、−(アルキレン)m-ヘテロシクリル、ここでmは0又は1、又は、-N(Rn)-ヘテロシクリル、-C(O)-ヘテロシクリル、-S(O)2−(アルキレン)m、ここでmは、1又は2であり、、
ここで、RNは、H、C1〜C4アルキル又はC1〜C6ヘテロアルキルであり、
そして、2個のRx1は、Pに結合する原子(これは同じ原子でもよい)と共に、環を形成することができ;tは、0、1又は2である。
ある態様では、各Rx1は、非置換のアルキル、ハロゲン又はヒドロキシによって任意に置換されるのみである。
ある態様では、Rx1は、水素又は非置換のC1〜C4アルキルである。
ある態様では、少なくとも1つのRx1は、−(アルキレン)m-ヘテロシクリルであり、ここで、mは0又は1である。
ある態様では、R2は:
R2*は、結合、アルキレン、−(アルキレン)m-O-(アルキレン)m-、−(アルキレン)m-C(O)-(アルキレン)m-、−(アルキレン)m-S(O)2−(アルキレン)m-及び−(アルキレン)m-NH-(アルキレン)m-であり
ここで、各mは、独立して0又は1であり;
Pは、4員〜8員の単環又は二環式飽和ヘテロシクリル基であり;
P1は、4員〜6員の単環式飽和ヘテロシクリル基であり;
各Rx2は、独立して水素又はアルキルであり;
sは0、1又は2である。
ある態様では、前述の全ての態様におけるR2*のあらゆるアルキレンは、さらに置換されない。
ある態様では、R2は、図1〜3に示される構造から選択される。
ある態様では、化合物は、一般式Iaを有する:
ある実施形態では、化合物は式Iaを有し、Rはアルキルである。
ある実施形態では、化合物は式Iaを有し、RはHである。
ある実施形態では、化合物は、式Iaを有し、R2は:
ある実施形態では、化合物は式Iaを有し、R2は:
Rx1は、水素又は非置換のC1〜C4アルキルであり、
及び
R2*は、あらかじめ定義されている通りである。
ある実施形態では、化合物は式Ibを有し、Rはアルキルである。
ある実施形態では、化合物は式Ibを有し、RはHである。
ある実施形態では、化合物は、式Ibを有し、R2は:
ある実施形態では、化合物は、式Ibを有し、R2は:
ある実施形態では、化合物は式Icを有し、Rはアルキルである。
ある実施形態では、化合物は式Icを有し、RはHである。
ある実施形態では、化合物は式Icを有し、R2は:
ある実施形態では、化合物は式Icを有し、R2は:
ある実施形態では、化合物は式Idを有し、Rはアルキルである。
ある実施形態では、化合物は式Idを有し、RはHである。
ある実施形態では、化合物は、式Idを有し、R2は:
ある実施形態では、化合物は、式Idを有し、R2は:
ある実施形態では、化合物は式Ieを有し、RはHである。
ある実施形態では、化合物は式Ieを有し、R2は:
ある実施形態では、化合物は式Ieを有し、R2は:
ある実施形態では、化合物は式Ifを有し、RはHである。
ある実施形態では、化合物は式Ifを有し、R2は:
ある実施形態では、化合物は式Ifを有し、R2は:
ある実施形態では、化合物は式Igを有し、RはHである。
ある実施形態では、化合物は式Igを有し、R2は:
ある実施形態では、化合物は式Igを有し、R2は:
ある実施形態では、化合物は式Ihを有し、RはHである。
ある実施形態では、化合物は、式Ihを有し、R2は:
ある実施形態では、化合物は、式Ihを有し、R2は:
ある実施形態では、化合物は式Iiを有し、RはHである。
ある実施形態では、化合物は式Iiを有し、R2は:
ある実施形態では、化合物は式Iiを有し、R2は:
ある実施形態では、化合物は式Ijを有し、RはHである。
ある実施形態では、化合物は式Ijを有し、R2は:
ある実施形態では、化合物は式Ijを有し、R2は:
ある実施形態では、化合物は式Ijを有し、RはHであり、両方のXはNである。
ある実施形態では、化合物は式Ikを有し、R2は:
ある実施形態では、
化合物は式Ilを有し、R2は:
ある実施形態では、化合物は式Imを有し、R2は:
ある実施形態では、化合物は、式IIaを有し、R2は:
ある実施形態では、化合物は式Imを有し、R2は:
本発明は、同位体の量が自然の存在率より多くなるよう、すなわち富化され、望ましい原子の同位体で置換する、化合物及び化合物の使用を含む。同位元素は、同じ原子番号であるが異なる質量数を有している、すなわち、中性子の数が異なるが陽子の数は同じである原子である。
ある実施形態では、望ましい位置で90、95又は99 %に濃縮される重水素である。
本発明の範囲内に含まれ、ここに開示された治療及び組成物の方法に使用可能な、更に具体的な化合物は、下記の表1に列挙される構造を含み得る。
特に明記しない限り、明細書及び特許請求の範囲を含む本出願に用いられる以下の用語は、以下の定義を有する。明細書及び添付の特許請求の範囲にて用いられているように、文脈が明らかに指図しない限り、単数形「an」及び「the」は複数指示物を含む。標準化学物質用語の定義は、Carey and Sundberg (2007) Advanced Organic chemistry 5th Ed.Vols. A and B, Springer Science+Business Media LLC, New Yorkを含む参考図書の中に見出されてもよい。本発明の実施には、特に明記しない限り、有機合成化学、質量分析、クロマトグラフィーの準備及び分析法、タンパク質化学、生化学、組換えDNA技術及び薬理学といった従来法を用いることにする。有機化学の従来法は、March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition M.B. Smith and J. March, John Wiley & Sons, Inc., Hoboken, NJ, 2007に含まれるそれらを含む。
ここで用いられる用語「ニトロ」は、-NO2を想定する。ここで用いられる用語「シアノ」は、-CNを想定する。
特定の態様では、本発明は、選択された癌、腫瘍、高増殖性状態若しくは、炎症性又は免疫不全を有するホスト、典型的にはヒト、を治療するための、ここに記載される化合物又はその薬理学的に許容される塩、プロドラッグ又は同位体的変種の有効量の、任意に医薬品組成物中の、使用を含む。開示された化合物の一部は、T細胞増殖に対して高活性である。T細胞癌及び異常増殖に対して薬剤が不足する場合を考えると、この使用の確認は、これらの疾病に対する内科治療における実質的な改善を示す。
本発明の一つの態様では、ここに開示される化合物は、有益的、追加的又は協力的効果のため、他の治療療法と組み合わせて有益に投与することができる。
ベバシズマブに結合されれば、VEGFは、その細胞レセプタと相互作用することができず、新しい血液血管の成長に至るシグナリングを防止する。同様に、セツキシマブ及びパニツムマブは上皮生長因子レセプタ(EGFR)をターゲットにし、トラスツズマブはヒト上皮生長因子レセプタ2(HER-2)をターゲットにする。細胞表面に生長因子レセプタを結合するMAbは、ターゲットのレセプタが通常の生育促進信号を送ることを防止する。それらは、アポトーシスを誘発し、免疫系を活性化して、腫瘍細胞を破壊する。癌治療MAbの他のグループは、免疫複合体である。イムノトキシン又は抗体-薬剤接合体と呼ばれることもあるこれらのMAbは、植物等の細胞死滅物質、又は細菌毒素、化学療法剤薬剤又は放射性分子に結合される抗体から成る。抗体は、癌細胞の表面上のその特定の抗原に接着し、細胞死滅物質は細胞に吸収される。このように作用するFDA認可の複合MAbは、CD20抗原をターゲットにして、放射性イットリウム90をB細胞非ホジキンリンパ腫細胞に供給する90Y-イブリツモマブチウキセタン;CD20抗原をターゲットにして放射性沃素131を非ホジキンリンパ腫細胞に供給する131I-トシツモマブ;及びHER-2分子をターゲットにして、細胞増殖を抑制する薬剤DM1を、転移乳癌細胞が発現しているHER-2に供給するアドトラスツズマブエムタンシン、を含む。
原発性縦隔B細胞リンパ腫:R-CHOP
ろ胞性リンパ腫:単一の化学療法薬剤(たとえばベンダムスチン又はフルダラビン)又は例えばCHOP又はCVP(シクロホスファミド、ビンクリスチン、プレドニソン)等の薬剤の組合せのいずれかの、化学療法を併用したリツキシマブ(Rituxan)療法。放射性単クローン抗体、イブリツモマブ(ゼバリン)及びトシツモマブ(Bexxar)は、可能な治療オプションでもある。さらに集中的な化学療法が認容できない患者に対して、単独でリツキシマブ、よりマイルドな化学療法薬剤(たとえばクロラムブシル又はシクロホスファミド)。
慢性リンパ性白血病/小型リンパ性リンパ腫:R-CHOP。
マントル細胞リンパ腫:フルダラビン、クラドリビン又はペントスタチン;ボルテゾミブ(Velcade)及びレナリドマイド(Revlimid)及びイブルチニブ(イムブルビカ)。
節外性周縁帯B細胞リンパ腫粘膜関連のリンパ系組織(MALT)リンパ腫:リツキシマブ;クロラムブシル又はフルダラビン又はCVP等の組合せ、しばしばリツキシマブに加える。
節性濾胞辺縁帯B細胞リンパ腫:単一の化学療法薬剤(たとえばベンダムスチン又はフルダラビン)又は例えばCHOP又はCVP(シクロホスファミド、ビンクリスチン、プレドニソン)等の薬剤の組合せのいずれかの、化学療法を併用したリツキシマブ(Rituxan)療法。
放射性単クローン抗体、イブリツモマブ(ゼバリン)及びトシツモマブ(Bexxar)は、可能な治療オプションでもある。さらに集中的な化学療法が認容できない患者に対して、単独でリツキシマブ、よりマイルドな化学療法薬剤(たとえばクロラムブシル又はシクロホスファミド)。
脾臓周縁帯B細胞リンパ腫:リツキシマブ;HepC抗ウイルスを有する患者:バーキット-リンパ種:メトトレキセート;ハイパーCVAD−シクロホスファミド、ビンクリスチン、ドキソルビシン(別名アドリアマイシン)、及びデキサメタゾン。過程Bは、メトトレキセート及びシタラビンから成る;CODOX-M−シクロホスファミド、ドキソルビシン、高用量メトトレキサート/イホスファミド、エトポシド及び高用量シタラビン;エトポシド、ビンクリスチン、ドキソルビシン、シクロホスファミド及びプレドニソン(エポック)リンパ形質細胞性リンパ腫-リツキシマブ
有毛細胞白血病−クラドリビン(2-CdA)又はペントスタチン;リツキシマブ;インターフェロンアルファ
T細胞リンパ腫の現行の治療法は、以下を含む:
前駆体Tリンパ芽球性リンパ腫/白血病−シクロホスファミド、ドキソルビシン(アドリアマイシン)、ビンクリスチン、エルアスパラギナーゼ、メトトレキセート、プレドニソン及び、ときに、シタラビン(ara-C)。脳及び脊髄へ広がるリスクがあるため、メトトレキセート等の化学療法薬剤は、脊髄液にも与えられる。皮膚リンパ腫:ゲムシタビンリポソームドキソルビシン(Doxil);メトトレキセート;クロラムブシル;シクロホスファミド;ペントスタチン;エトポシド;テモゾロマイド;プララトレキサート;R-CHOP。
血管免疫芽細胞性T細胞リンパ腫:プレドニソン又はデキサメタゾン。
節外性ナチュラルキラー/T細胞リンパ腫、鼻型タイプ:CHOP
未分化大細胞型リンパ腫:CHOP;プララトレキサート(Folotyn)、ボルテゾミブ(Velcade)等のターゲットの薬剤又はロミデプシン(Istodax)、又はアレムツズマブ(Campath)およびデニロイキンジフチトクス(Ontak)等の免疫療法薬剤、原発性中枢神経系(CNS)リンパ腫−メトトレキセート;リツキシマブ。
1-デヒドロテストステロン、5‐フルオロウラシルダカルバジン、6‐メルカプトプリン、6‐チオグアニン、アクチノマイシンD、アドリアマイシン、アルデスロイキン、アルキル化剤、アロプリノールナトリウム、アルトレタミン、アミホスチン、アナストロゾール、アントラマイシン(AMC))、抗分裂剤、シスジクロロジアミンプラチナ(II)(DDP)シスプラチン)、
ジアミノジクロロプラチナ、アンスラサイクリン、抗生物質、アンチメタボライ、アスパラギナーゼ、BCGライブ(膀胱内)、リン酸ベタメタゾンナトリウム及び酢酸ベタメタゾン、ビカルタミド、硫酸ブレオマイシン、ブスルファン、カルシウムロイコボリン、カリケアマイシン、カペシタビン、カルボプラチン、ロムスチン(CCNU)、カルマスティン(BSNU)、クロラムブシル、シスプラチン、クラドリビン、コルヒチン、複合エストロゲン、シクロホスファミド、シクロホスファミド、シタラビン、シタラビン、サイトカラシンB、シトキサン、ダカルバジン、ダクチノマイシン、ダクチノマイシン(以前はアクチノマイシン)、ダウノルビシンHCL、ダウノルビシンクエン酸塩、デニロイキンディフィトックス、デクスラゾキサン、ジブロモマンニトール、ジヒドロキシアントラシンジオン、ドセタキセル、ドラセトロンメシル酸塩、ドキソルビシンHCL、ドロナビノール、大腸菌L−アスパラギナーゼ、エメチン、エポエチンα、エルウィニア属エルアスパラギナーゼ、エストロゲンエステル、エストラジオール、リン酸エストラムスチンナトリウム、エチジウムブロマイド、エチニルエストラジオール、エチドロン酸、エトポシドシトロボラム因子、リン酸エトポシド、フィルグラスチム、フロキシウリジン、フルコナゾール、リン酸フルダラビン、フルオロウラシル、フルタミド、フォリン酸、ゲムシタビンHCL、グルココルチコイド、ゴセレリン酢酸塩、グラミシジンD、グラニセトロンHCL、ヒドロキシウレア、イダルビシンHCL、イホスファミド、インターフェロンα-2b、イリノテカンHCL、レトロゾール、ロイコボリンカルシウム、酢酸ロイプロリド、レバミゾールHCL、リドカイン、ロムスチン、メイタンシノイド、メクロレタミンHCL、メドロキシプロゲステロンアセテート、メゲストロールアセテート、メルファランHCL、メルカプトプリン、メスナ、メトトレキセート、メチルテストステロン、ミトラマイシン、マイトマイシンC、ミトタン、ミトキサントロン、ニルタミド、オクトレオチド酢酸塩、オンダンセトロンHCL、パクリタキセル、パミドロン酸二ナトリウム、ペントスタチン、ピロカルピンHCL、プリカマイシン、カルマスティン注入によるポリフェプロサン20、ポルフィマーナトリウム、プロカイン、プロカルバジンHCL、プロプラノロール、リツキシマブ、サルグラモスチム、ストレプトゾトシン、タモキシフェン、タキソール、テニポシド、テニポシド、テストラクトン、テトラカイン、チオテパクロラムブシル、チオグアニン、チオテパ、トポテカンHCL、トレミフェンクエン酸塩、トラスツズマブ、トレチノイン、バルビシン、硫酸ビンブラスチン、硫酸ビンクリスチン及び酒石酸ビノレルビンが挙げられる。
一実施形態では、ここに記載される目的のための活性化合物の活性は、罹病又は異常増殖している細胞をターゲットにする又は活性、デリバリー、薬物動態学又は他の有益な特性を改良する薬剤への接合を通して、増大させてもよい。
本発明に使用可能な製品の発現のターゲットの種類は、以下のレビューに見出すことができる。
Casi, G. and Neri, D., Antibody−drug conjugates: basic concepts, examples and future perspectives, J. Control Release 161(2):422−428, 2012, Chari, R.V., Targeted cancer therapy: conferring specificity to cytotoxic drugs, Acc. Chem. Rev., 41(1):98−107, 2008, Sapra, P. and Shor, B., Monoclonal antibody−based therapies in cancer: advances and challenges, Pharmacol. Ther., 138(3):452−69, 2013, Schliemann, C. and Neri, D., Antibody−based targeting of the tumor vasculature, Biochim. Biophys. Acta., 1776(2): 175−92, 2007, Sun, Y., Yu, F., and Sun, B.W., Antibody−drug conjugates as targeted cancer therapeutics, Yao Xue Xue Bao, 44(9):943−52, 2009, Teicher, B.A., and Chari, R.V., Antibody conjugate therapeutics: challenges and potential, Clin. Cancer Res., 17(20):6389−97, 2011, Firer, M.A., and Gellerman, G.J., Targeted drug delivery for cancer therapy: the other side of antibodies, J. Hematol. Oncol, 5:70, 2012, Vlachakis, D. and Kossida, S., Antibody Drug Conjugate bioinformatics: drug delivery through the letterbox, Comput. Math. Methods Med., 2013; 2013:282398, Epub 2013 Jun 19, Lambert, J.M., Drug−conjugated antibodies for the treatment of cancer, Br. J. Clin. Pharmacol, 76(2):248−62, 2013, Concalves, A., Tredan, O., Villanueva, C. and Dumontet, C, Antibody−drug conjugates in oncology: from the concept to trastuzumab emtansine (T−DM1), Bull. Cancer, 99(12): 1183− 1191 , 2012, Newland, AM, Brentuximab vedotin: a CD−30−directed antibody−cytotoxic drug conjugate, Pharmacotherapy, 33(1):93−104, 2013, Lopus, M., Antibody−DMl conjugates as cancer therapeutics, Cancer Lett., 307(2): 113−118, 2011,Chu, Y.W. and Poison, A., Antibody−drug conjugates for the treatment of B−cell non−Hodgkin's lymphoma and leukemia, Future Oncol, 9(3):355−368, 2013, Bertholjotti, I., Antibody−drug conjugate−−a new age for personalized cancer treatment, Chimia, 65(9): 746−748, 2011, Vincent, K.J., and Zurini, M., Current strategies in antibody engineering: Fc engineering and pH−dependent antigen binding, bispecific antibodies and antibody drug conjugates, Biotechnol. J., 7(12): 1444−1450, 2012,
Haeuw, J.F., Caussanel, V., and Beck, A., Immunoconjugates, drug−armed antibodies to fight against cancer, Med. Sci., 25(12): 1046−1052, 2009 及び Govindan, S.V., and Goldenberg, D.M., Designing immunoconjugates for cancer therapy, Expert Opin. Biol. Ther., 12(7):873−890, 2012。
ここに記載される活性化合物又はそれらの塩又はプロドラッグは、所望された治療結果を達成するあらゆる適切なアプローチを用いて、ホストに投与することができる。
開示された化合物は、以下の汎用のスキームによって製造されてもよい。
tert-ブチルN−[2−[(5-ブロモ2クロロピリミジン-4イル)アミノ]エチル]カルバメートの合成、化合物1
1HNMR (d6-DMSO) δ ppm 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M + H).
tert-ブチルN−[2−[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4-イル]アミノ]エチル]カルバメートの合成、化合物2
1HNMR (d6-DMSO) δ ppm 8.18 (s, 1H), 7.63 (brs, 1H), 7.40 (brs, 1H), 5.55 (s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.15 (m, 2H), 1.19 - 1.16 (m, 15H). LCMS (ESI) 399 (M + H).
tert-ブチルN−[2−[2-クロロ-6-(ジエトキシメチル)ピロロ[2,3-d]ピリミジン-7-イル]エチル]カルバメートの合成、化合物3
1HNMR (d6-DMSO) δ ppm 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M + H).
tert-ブチルN−[2−(2-クロロ-6-ホルミル-ピロロ[2,3-d]ピリミジン-7-イル)エチル]カルバメートの合成、化合物4
1HNMR (d6-DMSO) δ ppm 9.98 (s, 1H), 9.18 (s, 1H), 7.66 (s, 1H), 6.80 (brs, 1H), 4.52 (m, 2H), 4.36 (m, 2H), 1.14 (s, 9H). LCMS (ESI) 325 (M + H).
7-[2−(第三級ブトキシカルボニルアミノ)エチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6-カルボン酸の合成、化合物5
1HNMR (d6-DMSO) δ ppm 9.11 (s, 1H), 7.39 (s, 1H), 4.38 (m, 2H), 4.15 (m, 2H), 1.48 (m, 9H). LCMS (ESI) 341(M + H).
メチル7-[2−(第三級ブトキシカルボニルアミノ)エチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6-カルボン酸塩の合成、化合物6
1HNMR (d6-DMSO) δ ppm 9.10 (s, 1H), 7.45 (s, 1H), 6.81 (brs, 1H) 4.60 (m, 2H), 3.91 (s, 3H), 3.29 (m, 2H), 1.18 (m, 9H) LCMS (ESI) 355 (M + H).
クロロ三環系アミドの合成、化合物7
1HNMR (d6-DMSO) δ ppm 9.08 (s, 1H), 8.48 (brs, 1H), 7.21 (s, 1H) 4.33 (m, 2H), 3.64 (m, 2H). LCMS (ESI) 223 (M + H).
クロロ-N-メチル三環アミドの合成、化合物8
1HNMR (d6-DMSO) δ ppm 9.05 (s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H). LCMS (ESI) 237 (M + H).
1-メチル-4-(6-ニトロ-3-ピリジル)ピペラジンの合成、化合物9
1HNMR (d6-DMSO) δ ppm 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).
5-(4-メチルピペラジン-1-イル)ピリジン-2-アミンの合成、化合物10
1HNMR (d6-DMSO) δ ppm 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).
tert-ブチルN−[2−(ベンジルオキシカルボニルアミノ)-3-メチルブチル]カルバメートの合成、化合物12
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.89 (d, J=6.73 Hz, 3 H) 0.92 (d, J=6.73 Hz, 3 H) 1.38 (s, 9 H) 1.70 - 1.81 (m, 1 H) 3.18 (d, J=5.56 Hz, 2 H) 3.47 - 3.60 (m, 1 H) 4.76 (s, 1 H) 4.89 (d, J=7.90 Hz, 1 H) 5.07 (s, 2 H) 7.25 - 7.36 (m, 5 H). LCMS (ESI) 337 (M + H).
tert-ブチルN−[2−(ベンジルオキシカルボニルアミノ)-4-メチル-ペンチル]カルバメートの合成、化合物13
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.89 (d, J=6.73 Hz, 6 H) 1.25 - 1.34 (m, 1 H) 1.39 (s, 9 H) 1.57 - 1.71 (m, 2 H) 3.04 - 3.26 (m, 2 H) 3.68 - 3.80 (m, 1 H) 4.72 - 4.89 (m, 2 H) 5.06 (s, 2 H) 7.25 - 7.38 (m, 5 H). LCMS (ESI) 351 (M + H).
tert-ブチルN−[(2R)-2−(ベンジルオキシカルボニルアミノ)-3-メチルブチル]カルバメートの合成、化合物14
tert-ブチルN−[(2S)-2−(ベンジルオキシカルボニルアミノ)-3-メチルブチル]カルバメートの合成、化合物15
tert-ブチルN−[(1S)-1−(アミノメチル)-2メチル-プロピル]カルバメートの合成、化合物16
LCMS (ESI) 203 (M + H).
tert-ブチルN−[(1R)-1−(アミノメチル)-2メチル-プロピル]カルバメートの合成、化合物17
tert-ブチルN−[(2s)-2−(ベンジルオキシカルボニルアミノ)-4-メチル-ペンチル]カルバメートの合成、化合物18
tert-ブチルN−[(2S)-2−(ベンジルオキシカルボニルアミノ)-2-フェニルエチル]カルバメートの合成、化合物19
1HNMR (600 MHz, DMSO-d6) δ ppm 1.20 - 1.33 (m, 9 H) 3.11 (t, J=6.29 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 4.88 - 5.01 (m, 2 H) 6.81 (t, J=5.42 Hz, 1 H) 7.14 - 7.35 (m, 10 H) 7.69 (d, J=8.49 Hz, 1 H). LCMS (ESI) 371 (M + H).
tert-ブチルN−[(2S)-2−(ベンジルオキシカルボニルアミノ)-3-メチル-ペンチル]カルバメートの合成、化合物20
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.85 - 0.92 (m, 6 H) 1.05 - 1.15 (m, 1 H) 1.35 - 1.41 (m, 9 H) 1.45 - 1.56 (m, 2 H) 3.14 - 3.24 (m, 2 H) 3.54 - 3.64 (m, 1 H) 4.78 (s, 1 H) 4.96 (d, J=7.91 Hz, 1 H) 5.06 (s, 2 H) 7.27 - 7.37 (m, 5 H). LCMS (ESI) 351 (M + H).
tert-ブチルN−[(2S)-2−(ベンジルオキシカルボニルアミノ)-3、3-ジメチルブチル]カルバメートの合成、化合物21
LCMS (ESI) 351.
tert-ブチルN−[[1−(ベンジルオキシカルボニルアミノ)シクロヘキシル]メチル]カルバメートの合成、化合物22
1HNMR (600 MHz, DMSO-d6) δ ppm 0.92 - 1.54 (m, 17 H) 1.76 - 2.06 (m, 2 H) 3.09 (d, J=6.15 Hz, 2 H) 4.92 (s, 2 H) 6.63 (d, J=17.27 Hz, 1 H) 7.16 - 7.49 (m, 6 H). LCMS (ESI) 363 (M + H).
tert-ブチルN−[[1−(ベンジルオキシカルボニルアミノ)シクロペンチル]メチル]カルバメートの合成、化合物23
LCMS (ESI) 349 (M + H).
2-ニトロ-5-[4−(1-ピペリジル)-1-ピペリジル]ピリジンの合成、化合物24
1HNMR (600 MHz, DMSO-d6) δ ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H)
5-[4−(1-ピペリジル)-1-ピペリジル]ピリジン-2-アミンの合成、化合物25
1HNMR (600 MHz, DMSO-d6) δ ppm 1.13 - 1.37 (m, 6 H) 1.40 - 1.63 (m, 6 H) 1.71 (m, 2 H), 2.24 (m, 1H) 2.43 (m, 2 H) 3.33 (d, J=12.30 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1 H). LCMS (ESI) 261 (M + H).
4−[1−(6-ニトロ-3-ピリジル)-4-ピペリジル]モルホリンの合成、化合物26
1HNMR (600 MHz, DMSO-d6) δ ppm 1.41 (m, 2 H) 1.82 (m, 2 H) 2.42 (m, 5 H) 2.98 (t, J=12.44 Hz, 2 H) 3.52 (s, 4 H) 4.04 (d, J=12.88 Hz, 2 H) 7.42 (d, J=9.37 Hz, 1 H) 8.08 (d, J=9.08 Hz, 1 H) 8.21 (s, 1 H).
5-(4-モルホリノ-1-ピペリジル)ピリジン-2-アミンの合成、化合物27
1HNMR (600 MHz, DMSO-d6) δ ppm 1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43 (m, 4 H) 3.32 (d, J=12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.11 (dd, J=8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H). LCMS (ESI) 263 (M + H).
4−[1−(6-ニトロ-3-ピリジル)-4-ピペリジル]チオモルホリンの合成、化合物28
1HNMR (600 MHz, DMSO-d6) δ ppm 1.40 - 1.52 (m, 2 H) 1.71 (m, 2 H) 2.49 - 2.55 (m, 4 H) 2.56 - 2.63 (m, 1 H) 2.68 - 2.75 (m, 4 H) 2.88 - 2.98 (m, 2 H) 4.09 (d, J=13.18 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=3.22 Hz, 1 H)
5-(4-チオモルホリノ-1-ピペリジル)ピリジン-2-アミンの合成、化合物29
1HNMR (600 MHz, DMSO-d6) δ ppm 1.47 - 1.59 (m, 2 H) 1.65 (m, 2 H) 2.22 - 2.38 (m, 1 H) 2.50 - 2.59 (m, 6 H) 2.68 - 2.82 (m, 4 H) 3.33 (d, J=12.00 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J=9.08 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1 H). LCMS (ESI) 279 (M + H)
2-ニトロ-5-(1-ピペリジル)ピリジンの合成、化合物30
1HNMR (600 MHz, DMSO-d6) δ ppm 1.56 (m, 6 H) 3.49 (d, J=4.39 Hz, 4 H) 7.30 - 7.47 (m, 1 H) 8.02 - 8.12 (m, 1 H) 8.15 - 8.26 (m, 1 H).
5-(1-ピペリジル)ピリジン-2-アミンの合成、化合物31
1HNMR (600 MHz, DMSO-d6) δ ppm 1.39 - 1.46 (m, 2 H) 1.51 - 1.62 (m, 4 H) 2.75 - 2.92 (m, 4 H) 5.30 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.09 (dd, J=8.78, 2.93 Hz, 1 H) 7.54 (d, J=2.93 Hz, 1 H). LCMS (ESI) 178 (M + H).
4−(6-ニトロ-3-ピリジル)チオモルホリンの合成、化合物32
1HNMR (600 MHz, DMSO-d6) δ ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd, J=9.22, 3.07 Hz, 1 H) 8.10 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.93 Hz, 1 H).
5-チオモルホリノピリジン-2-アミンの合成、化合物33
1HNMR (600 MHz, DMSO-d6) δ ppm 2.59 - 2.73 (m, 4 H) 3.04 - 3.20 (m, 4 H) 5.41 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.57 (d, J=2.64 Hz, 1 H). LCMS (ESI) 196 (M + H).
tert-ブチル(4R)-5-(6-ニトロ-3-ピリジル)-2、5-ジアザビシクロ[2.2.1]ヘプタン-2-カルボン酸塩の合成、化合物34
1HNMR (600 MHz, DMSO-d6) δ ppm 1.33 (d, J=32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d, J=10.25 Hz, 1 H) 3.58 (m, 1 H) 4.46 (m, 1 H) 4.83 (s, 1 H) 7.16 (s, 1 H) 7.94 (s, 1 H) 8.05 - 8.16 (m, 1 H).
tert-ブチル(4R)-5-(6アミノ3-ピリジル)-2、5-ジアザビシクロ[2.2.1]ヘプタン-2-カルボン酸塩の合成、化合物35
1HNMR (600 MHz, DMSO-d6) δ ppm 1.31 (d, J=31.91 Hz, 11 H) 1.83 (m, 2 H) 2.71 - 2.82 (m, 1 H) 3.44 (m,1 H) 4.30 (d, 2H) 5.08 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 6.77 - 6.91 (m, 1 H) 7.33 (s, 1 H). LCMS (ESI) 291 (M + H).
N,N-ジメチル-1−(6-ニトロ-3-ピリジル)ピペリジン-4-アミンの合成、化合物36
1HNMR (600 MHz, DMSO-d6) δ ppm 1.30 - 1.45 (m, 2 H) 1.79 (m, 2 H) 2.14 (s, 6 H) 2.33 (m, 1 H) 2.92 - 3.04 (m, 2 H) 4.03 (d, J=13.76 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.21 (d, J=2.93 Hz, 1 H).
5-[4−(ジメチルアミノ)-1-ピペリジル]ピリジン-2-アミンの合成、化合物37
1HNMR (600 MHz, DMSO-d6) δ ppm 1.35 - 1.50 (m, 2 H) 1.69 - 1.81 (m, 2 H) 2.00 - 2.10 (m, 1 H) 2.11 - 2.22 (s, 6 H) 3.17 - 3.36 (m, 4 H) 5.19 - 5.38 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.63 Hz, 1 H). LCMS (ESI) 221 (M + H).
4−(6-ニトロ-3-ピリジル)モルホリンの合成、化合物38
5-モルホリノピリジン-2-アミンの合成、化合物39
1HNMR (600 MHz, クロロホルム-d) δ ppm 2.91 - 3.00 (m, 4 H) 3.76 - 3.84 (m, 4 H) 4.19 (br. s., 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93 Hz, 1 H) 7.72 (d, J=2.93 Hz, 1 H).
5-(4-イソブチルピペラジン-1-イル)ピリジン-2-アミンの合成、化合物40
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.88 (d, J=6.73 Hz, 6 H) 1.71 - 1.84 (m, 1 H) 2.10 (d, J=7.32 Hz, 2 H) 2.46 - 2.58 (m, 4 H) 2.97 - 3.07 (m, 4 H) 4.12 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.14 (dd, J=8.78, 2.93 Hz, 1 H) 7.75 (d, J=2.93 Hz, 1 H). LCMS (ESI) 235 (M + H).
5-(4-イソプロピルピペラジン-1-イル)ピリジン-2-アミンの合成、化合物41
1HNMR (600 MHz, クロロホルム-d) δ ppm 1.06 (d, J=6.44 Hz, 6 H) 2.59 - 2.75 (m, 5 H) 2.97 - 3.10 (m, 4 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.15 (dd, J=9.08, 2.93 Hz, 1 H) 7.76 (d, J=2.93 Hz, 1 H). LCMS (ESI) 221 (M + H).
5-[(2R,6S)-2,6-ジメチルモルホリン-4-イル]ピリジン-2-アミンの合成、化合物42
1HNMR (600 MHz, クロロホルム-d) δ ppm 1.20 (d, J=6.44 Hz, 6 H) 2.27 - 2.39 (m, 2 H) 3.11 - 3.21 (m, 2 H) 3.70 - 3.84 (m, 2 H) 4.15 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93 Hz, 1 H) 7.72 (d, J=2.63 Hz, 1 H). LCMS (ESI) 208 (M + H).
5-[(3R,5S)-3,5-ジメチルピペラジン-1-イル]ピリジン-2-アミンの合成、化合物43
1HNMR (600 MHz, クロロホルム-d) δ ppm 1.09 (d, J=6.44 Hz, 6 H) 2.20 (t, J=10.83 Hz, 2 H) 2.95 - 3.08 (m, 2 H) 3.23 (dd, J=11.71, 2.05 Hz, 2 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.14 (dd, J=8.78, 2.93 Hz, 1 H) 7.73 (d, J=2.63 Hz, 1 H). LCMS (ESI) 207 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 0.77 - 0.85 (d, J=6.5 Hz, 3 H) 0.87 (d, J=6.73 Hz, 3 H) 1.31 - 1.39 (m, 9 H) 1.82 - 1.93 (m, 1 H) 2.94 (d, J=5.56 Hz, 1 H) 3.08 - 3.22 (m, 2 H) 3.98 (d, J=8.20 Hz, 1 H) 6.96 (d, J=8.78 Hz, 1 H) 8.21 (s, 1 H). LCMS (ESI) 393 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.44 Hz, 3 H) 1.18 (t, J=7.03 Hz, 6 H) 1.21 - 1.26 (m, 12 H) 2.88 (br. s., 1 H) 3.43 - 3.78 (m, 6 H) 3.97 - 4.08 (m, 1 H) 5.61 (s, 1 H) 6.65 (s, 1 H) 6.71 - 6.78 (m, 1 H) 8.87 (s, 1 H). LCMS (ESI) 441 (M + H).
有機層を分離し、乾燥し、その後真空下で濃縮した。このように得られた粗反応生成物を、DMF中に溶解し、その後オキソンを添加し、内容物を3時間撹拌した。酢酸エチルの添加の後、CELITETMを通して反応物混合物をろ過し、真空下で濃縮した。粗製品を、ヘキサン/酢酸エチル(0〜100%)を用いたシリカゲル上のカラムクロマトグラフィーにかけて、7-[1−[(第三級ブトキシカルボニルアミノ)メチル]-2メチル-プロピル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6-カルボン酸を提供した。
1HNMR (600 MHz, DMSO-d6) δ ppm 0.85 (d, J=7.03 Hz, 3 H) 0.97 (d, J=6.73 Hz, 3 H) 1.52 (s, 9 H) 1.99 - 2.23 (m, 1 H) 3.98 (dd, J=14.05, 3.51 Hz, 1 H) 4.47 - 4.71 (m, 2 H) 7.47 (s, 1 H) 9.17 (s, 1 H). LCMS (ESI) 383 (M + H).
DCM(1.5ml)中の7-[1−[(第三級ブトキシカルボニルアミノ)メチル]-2メチル-プロピル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6カルボン酸(0.050g、0.00013モル)に、DIC(32.7mg)及びDMAP(10mg)を添加した。内容物を、2時間撹拌した。その後、トリフルオロ酢酸(0.4ml)を添加し、さらに撹拌を30分間続けた。過剰な酸を中和する飽和NaHCO3の添加の後、酢酸エチルを添加し、有機層を分離して、硫酸マグネシウムを用いて乾燥し、その後真空下で濃縮した。ヘキサン/酢酸エチル(0- 100 %)を用いたシリカゲルカラムクロマトグラフィーにより、粗製品を精製し、製品を提供した。
1HNMR (600 MHz, DMSO-d6) δ ppm 0.72 (d, J=6.73 Hz, 3 H) 0.97 (d, J=6.73 Hz, 3 H) 2.09 - 2.22 (m, 1 H) 3.57 (dd, J=13.18, 4.98 Hz, 1 H) 3.72 (dd, J=13.61, 4.25 Hz, 1 H) 4.53 (dd, J=8.05, 3.95 Hz, 1 H) 7.20 (s, 1 H) 8.34 (d, J=4.98 Hz, 1 H) 9.08 (s, 1 H). LCMS (ESI) 265 (M + H).
化合物45の合成
化合物46の合成
化合物47の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.74 (d, J=6.73 Hz, 3 H) 0.91 (d, J=6.73 Hz, 3 H) 2.04 - 2.20 (m, 1 H) 3.04 (s, 3 H) 3.69 (dd, J=13.76, 1.17 Hz, 1 H) 3.96 (dd, J=13.76, 4.68 Hz, 1 H) 4.58 (dd, J=7.32, 3.51 Hz, 1 H) 7.16 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H).
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.91 (d, J=6.44 Hz, 3 H) 0.94 (d, J=6.44 Hz, 3 H) 1.32 - 1.51 (m, 11 H) 1.55 - 1.67 (m, 1 H) 3.28 (t, J=5.86 Hz, 2 H) 4.21 - 4.42 (m, 1 H) 4.84 (s, 1 H) 5.84 (d, J=7.32 Hz, 1 H) 8.07 (s, 1 H). LCMS (ESI) 407 (M + H).
LCMS (ESI) 455 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.44 Hz, 3 H) 0.97 (d, J=6.44 Hz, 3 H) 1.47 (s, 9 H) 1.49 - 1.54 (m, 1 H) 1.56 (t, J=7.17 Hz, 2 H) 3.98 (dd, J=13.91, 3.07 Hz, 1 H) 3.76 (dd, J=13.31, 4.13 Hz, 1 H) 4.38 (d, J=14.05 Hz, 1 H) 4.90 (t, J=7.17 Hz, 1 H) 7.41 (s, 1 H) 9.11 (s, 1 H). LCMS (M + H) 397.
1HNMR (600 MHz, DMSO-d6) δ ppm 0.82 (d, J=6.73 Hz, 3 H) 0.97 (d, J=6.44 Hz, 3 H) 1.34 - 1.46 (m, 1 H) 1.48 - 1.65 (m, 2 H) 3.40 (dd, J=13.32, 5.42 Hz, 1 H) 3.76 (dd, J=13.47, 4.10 Hz, 1 H) 4.76 - 4.92 (m, 1 H) 7.17 (s, 1 H) 8.34 (d, J=5.27 Hz, 1 H) 9.04 (s, 1 H). LCMS (ESI) 279 (M + H)
化合物49の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.82 (d, J=6.44 Hz, 3 H) 0.97 (d, J=6.44 Hz, 3 H) 1.37 - 1.68 (m, 3 H) 3.04 (s, 3 H) 3.56 (d, J=13.47 Hz, 1 H) 4.00 (dd, J=13.32, 4.25 Hz, 1 H) 4.82 - 4.94 (m, 1 H) 7.16 (s, 1 H) 9.03 (s, 1 H). LCMS (ESI) 293 (M + H).
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.88 - 0.95 (m, 6 H) 1.11 - 1.20 (m, 1 H) 1.34 (s, 9 H) 1.44 - 1.54 (m, 1 H) 1.64 - 1.72 (m, 1 H) 3.17 - 3.27 (m, 1 H) 3.33 - 3.43 (m, 1 H) 4.11 - 4.21 (m, 1 H) 4.81 (s, 1 H) 5.92 (d, J=8.20 Hz, 1 H) 8.05 (s, 1 H). LCMS (ESI) 407.
1HNMR (600 MHz, DMSO-d6) δ ppm 0.76 - 0.89 (m, 6 H) 1.03 (q, J=7.22 Hz, 3 H) 1.10 - 1.17 (m, 3 H) 1.25 - 1.42 (m, 11 H) 1.59 - 1.73 (m, 1 H) 3.35 - 3.47 (m, 4 H) 3.51 - 3.73 (m, 2 H) 3.99 - 4.11 (m, 1 H) 5.52 - 5.56 (m, 1 H) 6.76 - 7.03 (m, 2 H) 8.12 - 8.23 (m, 1 H). LCMS (ESI) 455 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 0.80 (t, J=7.47 Hz, 3 H) 0.86 (d, J=7.03 Hz, 3 H) 1.06 - 1.30 (m, 2 H) 1.48 (s, 9 H) 1.79 - 1.96 (m, 1 H) 3.95 (dd, J=14.05, 3.22 Hz, 1 H) 4.52 (d, J=14.35 Hz, 1 H) 4.61 - 4.73 (m, 1 H) 7.43 (s, 1 H) 9.13 (s, 1 H). LCMS (ESI) 397 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 0.74 (t, J=7.32 Hz, 3 H) 0.89 (d, J=6.73 Hz, 3 H) 1.00 - 1.12 (m, 2 H) 1.82 - 1.94 (m, 1 H) 3.55 (dd, J=13.91, 4.83 Hz, 1 H) 3.70 (dd, J=13.61, 4.25 Hz, 1 H) 4.57 (dd, J=7.91, 4.10 Hz, 1 H) 7.17 (s, 1 H) 8.31 (d, J=5.27 Hz, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H).
化合物51の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.77 (t, J=7.47 Hz, 3 H) 0.84 (d, J=6.73 Hz, 3 H) 1.07 - 1.16 (m, 2 H) 1.82 - 1.95 (m, 1 H) 3.03 (s, 3 H) 3.68 (d, J=13.76 Hz, 1 H) 3.96 (dd, J=13.76, 4.39 Hz, 1 H) 4.59 - 4.70 (m, 1 H) 7.16 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 293 (M + H).
LCMS (ESI) 407 (M + H).
LCMS (ESI) 455 (M + H).
LCMS (ESI) 397 (M + H).
LCMS (ESI) 279 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H) 3.29 - 3.50 (m, 2 H) 5.12 - 5.24 (m, 1 H) 7.10 (t, J=5.27 Hz, 1 H) 7.21 (t, J=6.88 Hz, 1 H) 7.26 - 7.34 (m, 4 H) 7.89 (d, J=7.32 Hz, 1 H) 8.24 (s, 1 H). LCMS (ESI) 427 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.03 Hz, 6 H) 1.32 (s, 9 H) 3.39 (s, 2 H) 3.52 - 3.61 (m, 2 H) 3.64 - 3.73 (m, 2 H) 5.17 - 5.26 (m, 1 H) 5.57 (s, 1 H) 7.07 - 7.14 (m, 1 H) 7.20 - 7.25 (m, 1 H) 7.26 - 7.33 (m, 4 H) 7.90 (d, J=7.61 Hz, 1 H) 8.19 (s, 1 H). LCMS (ESI) 475 (M + H).
LCMS (ESI) 417 (M + H).
化合物44について記載されたと類似の合成シーケンスを用いて、化合物54を合成した。
1HNMR (600 MHz, DMSO-d6) δ ppm 3.58 - 3.69 (m, 1 H) 4.13 (dd, J=13.47, 4.39 Hz, 1 H) 6.07 (d, J=3.81 Hz, 1 H) 6.85 (d, J=7.32 Hz, 2 H) 7.19 - 7.31 (m, 3 H) 7.34 (s, 1 H) 8.27 (d, J=5.27 Hz, 1 H) 9.13 (s, 1 H). LCMS (ESI) 299 (M + H).
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.95 - 1.02 (m, 6 H) 1.35 - 1.45 (m, 9 H) 1.75 - 1.90 (m, 1 H) 3.35 - 3.48 (m, 1 H) 3.52 - 3.61 (m, 1 H) 3.64 - 3.76 (m, 1 H) 4.56 (d, J=8.49 Hz, 1 H) 6.47 (s, 1 H) 8.07 (s, 1 H). LCMS (ESI) 393 (M + H).
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.90 - 1.00 (m, 6 H) 1.18 - 1.25 (m, 6 H) 1.34 - 1.36 (m, 9 H) 1.69 - 1.90 (m, 1 H) 3.34 - 3.82 (m, 6 H) 4.53 - 4.77 (m, 1 H) 5.45 - 5.55 (m, 1 H) 6.37 (dd, J=15.37, 6.59 Hz, 1 H) 6.56 (s, 1 H) 8.05 (s, 1 H). LCMS (ESI) 441 (M + H).
1HNMR (600 MHz, クロロホルム-d) δ ppm 0.90 (d, J=6.73 Hz, 3 H) 0.96 (d, J=7.03 Hz, 3 H) 1.55 - 1.66 (m, 10 H) 4.14 (dd, J=13.61, 3.95 Hz, 1 H) 4.52 - 4.63 (m, 1 H) 4.84 (dd, J=13.61, 1.32 Hz, 1 H) 7.37 (s, 1 H) 8.95 (s, 1 H). LCMS (ESI) 383 (M + H).
化合物44について記載されたものと類似の合成シーケンスを用いて、化合物55を合成した。
LCMS (ESI) 265 (M + H).
化合物56の合成
分析データは、その鏡像異性体(化合物55)について記載されたものと一致していた。
1HNMR (600 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.44 Hz, 6 H) 1.73 - 1.86 (m, 1 H) 3.67 - 3.76 (m, 2 H) 4.11 - 4.21 (m, 1 H) 7.13 - 7.19 (m, 1 H) 8.56 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 265 (M + H).
LCMS (ESI) 379 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.11 - 1.22 (m, 6 H) 1.31 - 1.45 (m, 15 H) 3.10 - 3.24 (m, 2 H) 3.51 - 3.76 (m, 4 H) 5.60 (s, 1 H) 6.94 (s, 1 H) 7.33 (t, J=6.44 Hz, 1 H) 8.18 (s, 1 H). LCMS (ESI) 427 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 1.73 (s, 6 H) 4.06 (s, 2 H) 7.46 (s, 1 H) 9.23 (s, 1H). LCMS (ESI) 369 (M + H).
化合物44について記載されたものと類似の合成シーケンスを用いて、化合物57を合成した。
1HNMR (600 MHz, DMSO-d6) δ ppm 1.73 (s, 6 H) 3.50 (d, J=2.93 Hz, 2 H) 7.25 (s, 1 H) 8.46 - 8.55 (m, 1 H) 9.07 (s, 1 H). LCMS (ESI) 251 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.18 - 1.54 (m, 17 H) 2.23 (d, J=14.35 Hz, 2 H) 3.36 (d, J=6.44 Hz, 2 H) 5.82 (s, 1 H) 6.93 (s, 1 H) 8.22 (s, 1 H). LCMS (ESI) 419 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.08 - 1.16 (m, 6 H) 1.17 - 1.54 (m, 17 H) 2.13 (br. s., 2 H) 3.36 (d, J=6.73 Hz, 2 H) 3.50 - 3.69 (m, 4 H) 5.72 (s, 1 H) 6.94 (s, 1 H) 5.72 (br. s., 1H) 8.17 (s, 1 H). LCMS (ESI) 467 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.37 - 1.54 (m, 13 H) 1.75 (br. s., 4 H) 2.74 (br. s., 2 H) 3.78 - 3.84 (m, 2 H) 7.44 - 7.51 (m, 1 H) 8.23 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 409 (M + H).
化合物44について記載されたものと類似の合成シーケンスを用いて、化合物58を合成した。
1HNMR (600 MHz, DMSO-d6) δ ppm 1.28 (br. s., 2 H) 1.42 (br. s., 2 H) 1.70 (br. s., 4 H) 1.85 - 1.95 (m, 2 H) 2.69 (m, 2 H) 7.16 - 7.25 (m, 1 H) 8.41 (br. s., 1 H) 9.04 (s, 1 H). LCMS 291 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.34 (s, 9 H) 1.50 - 1.58 (m, 2 H) 1.63 - 1.78 (m, 4 H) 1.96 - 2.06 (m, 2 H) 3.25 (d, J=6.15 Hz, 2 H) 6.71 (s, 1 H) 7.18 (t, J=6.29 Hz, 1 H) 8.20 (s, 1 H). LCMS (ESI) 405 (M + H).
LCMS (ESI) 453 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.47 (s, 9 H) 1.74 (br. s., 2 H) 1.88 (br. s., 2 H) 2.04 (br. s., 2 H) 2.41 - 2.45 (m, 2 H) 4.06 (s, 2 H) 7.45 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 395 (M + H).
化合物44について記載されたものと類似の合成シーケンスを用いて、化合物59を合成した。
1HNMR (600 MHz, DMSO-d6) δ ppm 1.72 (br. s., 2 H) 1.86 - 1.93 (m, 2 H) 1.99 (d, J=3.81 Hz, 2 H) 2.40 (br. s., 2 H) 3.48 (d, J=2.34 Hz, 2 H) 7.22 (s, 1 H) 8.53 (br. s., 1 H) 9.05 (s, 1 H). LCMS (ESI) 277 (M + H).
1HNMR (600 MHz, クロロホルム-d) δ ppm 1.21 - 1.31 (m, 12 H) 1.38 - 1.46 (m, 11 H) 1.70 (m, 1H) 3.24 (m, 2 H) 3.65 - 3.82 (m, 4 H) 4.86 (br s., 1H), 5.65 (s, 1 H) 5.85 (br s., 1H) 6.94 (s, 1 H) 8.21 (s, 1 H). LCMS (ESI) 455 (M + H).
化合物44のために記載されたものと類似の合成シーケンスを用いて、化合物60を合成した。分析データは、L-異性体について記載されたものと一致していた。
化合物61の合成
飽和NaHCO3の添加の後、酢酸エチルを添加した。有機層の分離の後、硫酸マグネシウムによる乾燥及び真空下での濃縮により、製品を提供した。分析データは、化合物49と同様だった。
1HNMR (600 MHz, DMSO-d6) δ ppm 1.27 (s, 9 H) 1.42 - 1.54 (m, 2 H) 1.56 - 1.65 (m, 2 H) 1.80 - 1.88 (m, 1 H) 1.96 - 2.01 (m, 1 H) 3.88 - 3.96 (m, 1 H) 4.03 - 4.09 (m, 1 H) 6.91 (d, J=8.20 Hz, 1 H) 7.41 (d, J=7.32 Hz, 1 H) 8.18 (s, 1 H). LCMS (ESI) 391 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.13 (t, 6 H) 1.28 (s, 9 H) 1.42 - 1.52 (m, 2 H) 1.58 - 1.65 (m, 2 H) 1.81 - 1.90 (m, 1 H) 1.99 - 2.08 (m, 1 H) 3.49 - 3.60 (m, 2 H) 3.63 - 3.71 (m, 2 H) 3.84 - 3.93 (m, 1 H) 3.96 - 4.04 (m, 1 H) 5.53 (s, 1 H) 6.96 (d, J=7.90 Hz, 1 H) 7.34 (d, J=7.03 Hz, 1 H) 8.14 (s, 1 H). LCMS (ESI) 439 (M + H).
1HNMR (600 MHz, DMSO-d6) δ ppm 1.41 - 1.52 (m, 9 H) 1.55 - 1.68 (m, 1 H) 1.88 - 2.00 (m, 2 H) 2.05 - 2.15 (m, 1 H) 2.26 - 2.35 (m, 1 H) 2.71 - 2.89 (m, 1 H) 4.01 - 4.16 (m, 1 H) 4.28 - 4.45 (m, 1 H) 7.41 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 381 (M + H).
化合物44に対して記載されたものと類似の合成シーケンスを用いて、化合物62を合成した。
1HNMR (600 MHz, DMSO-d6) δ ppm 1.48 - 1.60 (m, 1 H) 1.88 - 1.98 (m, 3 H) 1.99 - 2.08 (m, 1 H) 2.66 - 2.75 (m, 1 H) 3.63 - 3.74 (m, 1 H) 3.99 - 4.12 (m, 1 H) 7.21 (s, 1 H) 8.89 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 263 (M + H).
化合物63の合成
1HNMR (d6-DMSO) δ ppm 11.13 (brs, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.03 (br m 1H), 7.99 (s, 1H), 7.67 (brm, 1H), 7.18 (s, 1H), 4.33 (m, 2H), 3.79 (m, 2H), 3.64 (m, 2H), 3.50 (m, 2H), 3.16 (m, 4H), 2.79 (s, 3H). LCMS (ESI) 379 (M + H).
化合物64の合成
窒素下、ジオキサン(3.5ml)中のクロロ三環系ラクタム(0.075g、0.338mモル)に、tert-ブチル4−(6アミノ3-ピリジル)ピペラジン-1-カルボン酸塩(0.098g、1.05eq)を添加し、続いて、Pd2(dba)3(27mg)、BINAP(36mg)及びtert-ブトキシドナトリウム(45mg)を添加した。内容物を、加熱して11時間還流した。粗反応物をシリカゲルカラム上に充填し、DCM/MeOH(0〜10%)で溶出して、所望の製品(32mg)を提供した。
1HNMR (d6-DMSO) δ ppm 9.48 (s, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.42 (m, 1H), 6.98 (s, 1H), 4.23 (m, 2H), 3.59 (m, 2H), 3.45 (m, 4H), 3.50 (m, 2H), 3.05 (m, 4H). LCMS (ESI) 465 (M + H).
化合物65の合成
内容物を、16時間撹拌した。
反応物混合物を濃縮し、塩酸塩を提供した。
1HNMR (d6-DMSO) δ ppm 9.01 (s, 1H), 7.94 (m, 1H), 7.86 (m, 1H), 7.23 (s, 1H), 4.30 (m, 2H), 3.64 (m, 2H), 3.36 (m, 4H), 3.25 (m, 4H). LCMS (ESI) 465 (M + H).
化合物66の合成
シリカゲルカラムクロマトグラフィーを用いて、ジクロロメタン/メタノール(0〜5%)の溶出剤で、粗製品を精製し、所望の製品(44mg)を提供した。
1HNMR (d6-DMSO) δ ppm 9.49 (s, 1H), 8.85 (s, 1H), 8.32 (m, 1H), 8.02 (s, 1H), 7.44 (m, 1H), 7.00 (s, 1H), 4.33 (m, 2H), 3.80 (m, 2H), 3.48 (m, 4H), 3.07 (m, 4H), 3.05 (s, 3H), 1.42 (s, 9H). LCMS (ESI) 479 (M + H)
化合物67の合成
濃縮により、塩酸塩が提供された。
1HNMR (d6-DMSO) δ ppm 9.13 (m, 2H), 8.11 (m, 1H), 8.10 (s, 1H), 7.62 (m, 1H), 7.21 (s, 1H), 4.43 (m, 2H), 3.85 (m, 2H), 3.41 (m, 4H), 3.28 (m, 4H), 3.08 (s, 3H). LCMS (ESI) 379 (M + H).
化合物68の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.79 (d, J=7.03 Hz, 3 H) 1.01 (d, J=6.73 Hz, 3 H) 1.35 - 1.48 (m, 9 H) 2.16 (dd, J=14.64, 6.73 Hz, 1 H) 3.00 - 3.14 (m, 4 H) 3.40 - 3.51 (m, 4 H) 3.51 - 3.60 (m, 1 H) 3.63 - 3.74 (m, 1 H) 4.44 (dd, J=7.90, 3.81 Hz, 1 H) 6.99 (s, 1 H) 7.46 (dd, J=8.93, 2.78 Hz, 1 H) 7.94 - 8.09 (m, 2 H) 8.31 (dd, J=9.08, 1.46 Hz, 1 H) 8.85 (s, 1 H) 9.46 (s, 1 H). LCMS (ESI) 507 (M + H) .
化合物69の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.77 - 0.86 (m, 3 H) 0.96 (d, J=7.03 Hz, 3 H) 2.10 - 2.24 (m, 1 H) 3.07 (s, 3 H) 3.37 - 3.79 (m, 8 H) 4.00 (dd, J=13.61, 4.54 Hz, 2 H) 4.63 - 4.73 (m, 1 H) 7.20 (s, 1 H) 7.58 - 7.71 (m, 1 H) 7.99 (d, J=2.34 Hz, 1 H) 8.12 (d, J=9.37 Hz, 1 H) 9.11 (s, 1 H) 9.41 (br. s., 2 H) 11.76 (br. s., 1 H). LCMS (ESI) 421 (M + H).
化合物70の合成
化合物71の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.79 (d, J=6.73 Hz, 3 H) 1.01 (d, J=6.73 Hz, 3 H) 2.18 (dd, J=14.49, 7.17 Hz, 1 H) 3.18 - 3.84 (m, 10 H) 4.53 - 4.71 (m, 1 H) 7.24 (s, 1 H) 7.65 (d, J=9.37 Hz, 1 H) 8.01 (d, J=2.64 Hz, 1 H) 8.14 (d, J=1.46 Hz, 1 H) 8.35 (d, J=5.27 Hz, 1 H) 9.14 (s, 1 H) 9.46 (s, 2 H) 11.80 (s, 1 H) LCMS (ESI) 407 (M+H).
化合物72(化合物UUU)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.77 (d, J=7.03 Hz, 3 H) 0.99 (d, J=6.73 Hz, 3 H) 2.10 - 2.24 (m, 1 H) 3.18 - 3.81 (m, 10 H) 4.54 - 4.69 (m, 1 H) 7.22 (s, 1 H) 7.63 (d, J=9.08 Hz, 1 H) 7.99 (d, J=2.63 Hz, 1 H) 8.11 (s, 1 H) 8.33 (d, J=5.27 Hz, 1 H) 9.12 (s, 1 H) 9.43 (s, 2 H) 11.77 (s, 1 H). LCMS (ESI) 407 (M+H).
化合物73の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.84 (d, J=6.73 Hz, 3 H) 0.98 (d, J=6.73 Hz, 3 H) 2.12 - 2.26 (m, 1 H) 3.09 (s, 3 H) 3.22 - 3.81 (m, 8 H) 4.01 (dd, J=13.61, 4.25 Hz, 2 H) 4.59 - 4.72 (m, 1 H) 7.19 (s, 1 H) 7.74 (s, 1 H) 7.96 - 8.10 (m, 2 H) 9.08 (s, 1 H) 9.22 (s, 2 H). LCMS (ESI) 421 (M+H).
化合物74の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.85 (d, J=4.98 Hz, 3 H) 0.95 (d, J=4.98 Hz, 3 H) 1.42 - 1.70 (m, 3 H) 2.77 (d, J=2.93 Hz, 3 H) 3.07 - 4.14 (m, 10 H) 4.95 (s, 1 H) 7.20 (s, 1 H) 7.66 (d, J=9.66 Hz, 1 H) 7.94 (s, 1 H) 8.08 - 8.16 (m, 1 H) 8.33 (d, J=4.68 Hz, 1 H) 9.09 (s, 1 H) 11.38 (s, 1 H) 11.71 (s, 1 H). LCMS (ESI) 435 (M+H).
化合物75の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.15 Hz, 3 H) 0.94 (d, J=6.15 Hz, 3 H) 1.57 (d, J=84.61 Hz, 3 H) 3.05 (s, 3 H) 3.13 - 3.55 (m, 8 H) 3.69 (d, J=78.17 Hz, 2 H) 4.90 (s, 1 H) 7.15 (s, 1 H) 7.63 - 7.85 (m, 1 H) 7.93 (s, 1 H) 8.26 (s, 1 H) 9.03 (s, 1 H) 9.20 (s, 2 H). LCMS (ESI) 421 (M+H).
化合物76の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.44 Hz, 3 H) 0.95 (d, J=6.44 Hz, 3 H) 1.43 - 1.70 (m, 3 H) 2.78 (d, J=2.93 Hz, 3 H) 3.05 (s, 3 H) 3.24 - 3.84 (m, 8 H) 4.01 (d, J=9.66 Hz, 2 H) 4.89 - 5.01 (m, 1 H) 7.15 (s, 1 H) 7.77 (s, 1 H) 7.91 - 8.05 (m, 2 H) 9.03 (s, 1 H) 10.96 - 11.55 (m, 2 H). LCMS (ESI) 449 (M+H).
化合物77の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.83 - 0.88 (d, J=6.15 Hz, 3 H) 0.95 (d, J=6.15 Hz, 3 H) 1.40 - 1.71 (m, 3 H) 3.28 - 3.83 (m, 8 H) 4.00 (d, J=3.22 Hz, 2 H) 4.91 - 5.08 (m, 1 H) 7.17 (s, 1 H) 7.68 (d, J=9.66 Hz, 1 H) 7.93 (s, 1 H) 8.07 (s, 1 H) 9.06 (s, 1 H) 9.40 (s, 2 H) 11.59 (s, 1 H). LCMS (ESI) 435 (M+H).
化合物78の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.75 (t, J=7.47 Hz, 3 H) 0.91 (d, J=6.73 Hz, 3 H) 1.04 - 1.20 (m, 2 H) 1.80 - 1.98 (m, 1 H) 2.77 (d, J=3.81 Hz, 3 H) 2.94 - 3.90 (m, 10 H) 4.54 - 4.68 (m, 1 H) 7.06 - 7.23 (m, 2 H) 7.56 - 7.75 (m, 1 H) 7.90 - 8.12 (m, 2 H) 8.29 (s, 1 H) 9.07 (s, 1 H) 10.98 - 11.74 (m, 2 H). LCMS (ESI) 435 (M + H).
化合物79の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.75 (t, J=7.32 Hz, 3 H) 0.90 (d, J=6.73 Hz, 3 H) 1.07 - 1.15 (m, 2 H) 1.85 - 1.94 (m, 1 H) 3.17 - 3.75 (m, 10 H) 4.58 - 4.67 (m, 1 H) 7.17 (s, 1 H) 7.71 (s, 1 H) 7.96 (s, 1 H) 7.98 - 8.05 (m, 1 H) 8.28 (d, J=4.10 Hz, 1 H) 9.06 (s, 1 H) 9.39 (s, 2 H). LCMS (ESI) 421 (M+H).
化合物80の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.78 (t, J=7.32 Hz, 3 H) 0.86 (d, J=6.73 Hz, 3 H) 1.13 - 1.21 (m, 2 H) 1.84 - 1.96 (m, 1 H) 2.77 (d, J=4.39 Hz, 3 H) 3.04 (s, 3 H) 3.11 - 3.84 (m, 8 H) 3.98 (dd, J=13.61, 4.25 Hz, 2 H) 4.66 - 4.74 (m, 1 H) 7.17 (s, 1 H) 7.64 (s, 1 H) 7.96 (d, J=2.34 Hz, 1 H) 8.03 - 8.13 (m, 1 H) 9.08 (s, 1 H) 11.26 (s, 1 H) 11.66 (s, 1 H). LCMS (ESI) 449 (M+H).
化合物81の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.78 (t, J=7.32 Hz, 3 H) 0.85 (d, J=6.73 Hz, 3 H) 1.10 - 1.27 (m, 2 H) 1.82 - 1.99 (m, 1 H) 3.04 (s, 3 H) 3.28 - 3.77 (m, 8 H) 3.97 (dd, J=13.91, 4.54 Hz, 2 H) 4.62 - 4.75 (m, 1 H) 7.07 - 7.24 (m, 1 H) 7.62 - 7.75 (m, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.97 - 8.08 (m, 1 H) 9.05 (s, 1 H) 9.29 (s, 2 H). LCMS (ESI) 435 (M+H).
化合物82の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.96 (s, 9 H) 3.15 - 3.87 (m, 10 H) 4.42 - 4.53 (m, 1 H) 6.99 (s, 1 H) 7.24 (s, 1 H) 8.06 (s, 1 H) 8.11 - 8.21 (m, 1 H) 8.79 - 8.98 (m, 2 H) 9.25 (s, 2 H) 9.88 (s, 1 H). LCMS (ESI) 421 (M+H).
化合物83の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.95 (s, 9 H) 2.79 (d, J=4.10 Hz, 3 H) 3.06 - 3.86 (m, 10 H) 4.56 - 4.67 (m, 1 H) 7.17 (s, 1 H) 7.70 (s, 1 H) 7.96 (d, J=2.63 Hz, 1 H) 7.99 - 8.08 (m, 1 H) 8.26 (s, 1 H) 9.06 (s, 1 H) 10.80 (s, 1 H). LCMS (ESI) 435 (M+H).
化合物84の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 2.75 - 2.81 (m, 3 H) 3.12 - 3.16 (m, 2 H) 3.46 - 3.54 (m, 4 H) 3.60 - 3.69 (m, 2 H) 3.72 - 3.79 (m, 1 H) 4.07 - 4.18 (m, 2 H) 6.06 - 6.09 (m, 1 H) 6.90 (d, J=7.61 Hz, 2 H) 7.20 - 7.31 (m, 3 H) 7.33 (s, 1 H) 7.49 - 7.55 (m, 1 H) 7.62 - 7.70 (m, 1 H) 7.92 (d, J=2.93 Hz, 1 H) 8.22 (s, 1 H) 9.14 (s, 1 H). LCMS (ESI) 455 (M + H).
化合物85の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 3.21 (s, 4 H) 3.35 - 3.67 (m, 5 H) 4.07 - 4.20 (m, 2 H) 6.13 (s, 1 H) 6.90 (d, J=7.32 Hz, 2 H) 7.22 - 7.31 (m, 3 H) 7.36 (s, 1 H) 7.48 (d, J=9.37 Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.25 (d, J=4.98 Hz, 1 H) 9.17 (s, 1 H) 11.77 (br, s., 1H). LCMS (ESI) 441 (M + H).
化合物86の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.15 Hz, 6 H) 1.72 - 1.89 (m, 1 H) 3.15 - 3.92 (m, 9 H) 4.10 - 4.46 (m, 2 H) 7.18 (s, 1 H) 7.59 (d, J=8.78 Hz, 1 H) 8.00 (s, 1 H) 8.13 (d, J=9.37 Hz, 1 H) 8.55 (s, 1 H) 9.09 (s, 1 H) 9.67 (s, 2 H) 11.91 (s, 1 H). LCMS (ESI) 407 (ESI).
化合物87の合成
化合物88の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.78 (s, 6 H) 3.40 - 3.53 (m, 6 H) 3.64 - 3.73 (m, 4 H) 7.27 (s, 1 H) 7.66 (d, J=9.37 Hz, 1 H) 7.98 (d, J=2.34 Hz, 1 H) 8.12 (br. s., 1 H) 8.47 (br. s., 1 H) 9.11 (s, 1 H) 9.45 (br. s., 2 H) 11.62 (br. s., 1 H). LCMS (ESI) 393 (M + H).
化合物89(化合物Tとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.47 (br. s., 6 H) 1.72 (br. s., 2 H) 1.92 (br. s., 2 H) 2.77 (br. s., 3 H) 3.18 (br. s., 2 H) 3.46 (br. s., 2 H) 3.63 (br. s., 2 H) 3.66 (d, J=6.15 Hz, 2 H) 3.80 (br. s., 2 H) 7.25 (s, 1 H) 7.63 (br. s., 2 H) 7.94 (br. s., 1 H) 8.10 (br. s., 1 H) 8.39 (br. s., 1 H) 9.08 (br. s., 1 H) 11.59 (br. s., 1 H). LCMS (ESI) 447 (M + H).
化合物90(化合物Qとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.27 - 1.64 (m, 6 H) 1.71 (br. s., 2 H) 1.91 (br. s., 2 H) 2.80 (br. s., 1 H) 3.17 - 3.24 (m, 2 H) 3.41 (br. s., 4 H) 3.65 (br. s., 4 H) 7.26 (br. s., 1 H) 7.63 (br. s., 1 H) 7.94 (br. s., 1 H) 8.13 (br. s., 1 H) 8.40 (br. s., 1 H) 9.09 (br. s., 1 H) 9.62 (br. s., 1 H) 11.71 (br. s., 1 H). LCMS (ESI) 433 (M + H).
化合物91(化合物ZZとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.64 - 1.75 (m, 2 H) 1.83 - 1.92 (m, 2 H) 1.96 - 2.06 (m, 2 H) 2.49 - 2.58 (m, 2 H) 2.79 (d, J=3.81 Hz, 3 H) 3.06 - 3.18 (m, 4 H) 3.59 - 3.69 (m, 2 H) 3.73 - 3.83 (m, 2 H) 4.04 - 4.12 (m, 2 H) 7.17 (br. s., 1 H) 7.60 - 7.70 (m, 2 H) 7.70 - 7.92 (m, 2 H) 7.96 (br. s., 1 H) 8.41 (br. s., 1 H) 8.98 (br. s., 1 H) 10.77 (br. s., 1 H). LCMS (ESI) 433 (M + H).
化合物92の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.64 - 1.75 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.96 - 2.05 (m, 2 H) 2.48 - 2.56 (m, 2 H) 3.22 (br. s., 4 H) 3.42 - 3.48 (m, 4 H) 3.60 - 3.69 (m, 2 H) 4.05 - 4.13 (m, 1 H) 7.18 (s, 1 H) 7.65 (d, J=13.47 Hz, 1 H) 7.70 - 7.77 (m, 1 H) 7.94 (d, J=1.76 Hz, 1 H) 8.42 (br. s., 1 H) 9.00 (s, 1 H) 9.15 (br. s., 2 H). LCMS (ESI) 419 (M + H).
化合物93の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.76 (br. s., 2 H) 1.89 (br. s., 2 H) 2.03 (br. s., 2 H) 2.47 - 2.58 (m, 2 H) 3.04 (s, 3 H) 3.22 (br. s., 4 H) 3.39 (br. s., 4 H) 3.66 (s, 2 H) 7.21 (s, 1 H) 7.67 (d, J=9.37 Hz, 1 H) 7.93 (br. s., 1 H) 7.98 - 8.09 (m, 1 H) 9.04 (s, 1 H) 9.34 (br. s., 2 H) 11.31 (br. s., 1 H). LCMS (ESI) 433 (M + H).
化合物94の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m, 2 H) 1.96 - 2.08 (m, 2 H) 2.48 - 2.57 (m, 2 H) 3.36 - 3.52 (m, 4 H) 3.60 - 3.80 (m, 6 H) 7.21 (s, 1 H) 7.53 - 7.74 (m, 2 H) 7.86 (s, 1 H) 8.02 (s, 1 H) 8.45 (s, 1 H) 9.03 (s, 1 H) 11.19 (br. s., 1 H). LCMS (ESI) 420 (M+H).
化合物95の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.65 - 1.79 (m, 2 H) 1.85 - 1.95 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.47 - 2.54 (m, 2 H) 3.40 - 3.58 (m, 5 H) 3.65 (dd, J=21.67, 5.56 Hz, 1 H) 3.69 - 3.78 (m, 4 H) 7.24 (s, 1 H) 7.97 - 8.17 (m, 2 H) 8.48 (s, 1 H) 9.08 (s, 1 H) 11.81 (s, 1 H). LCMS (ESI) 421 (M+H).
化合物96の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.55 - 1.74 (m, 2 H) 1.80 - 1.98 (m, 4 H) 2.48 - 2.60 (m, 2 H) 3.40 - 3.50 (m, 4 H) 3.57 - 3.72 (m, 2 H) 3.90 - 4.20 (m, 4 H) 7.08 (s, 1 H) 7.37 - 7.57 (m, 2 H) 7.70 (m, 2 H) 8.32 (s, 1 H) 8.88 (s, 1 H) 9.98 (s, 1 H). LCMS (ESI) 419 (M+H).
化合物97(化合物IIIとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.30 (d, J=5.27 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.83 - 1.95 (m, 2 H) 1.97 - 2.10 (m, 2 H) 2.45 - 2.55 (m, 2H) 3.25 - 3.36 (m, 1 H) 3.39 - 3.48 (m, 4 H) 3.60 - 3.70 (m, 4 H) 3.75 - 4.15 (m, 2 H) 7.24 (s, 1 H) 7.54 - 7.75 (m, 2 H) 7.95 (s, 1 H) 8.10 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H) 11.25 (s, 1 H) 11.48 (s, 1 H). LCMS (ESI) 461 (M+H).
化合物98の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 0.99 (d, J=6.15 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.90 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.08 - 2.17 (m, 1 H) 2.45 - 2.55 (m, 2H) 2.88 - 3.02 (m, 2 H) 3.33 - 3.48 (m, 4 H) 3.50 - 3.90 (m, 6 H) 7.24 (s, 1 H) 7.67 (s, 2 H) 7.94 (s, 1 H) 8.12 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H) 10.77 (s, 1 H) 11.51 (s, 1 H). LCMS (ESI) 475 (M+H).
化合物99の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.13 (d, J=5.86 Hz, 6 H) 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m, 2 H) 1.97 - 2.09 (m, 2 H) 2.40 - 2.53 (m, 2 H) 3.37 - 3.49 (m, 2 H) 3.50 - 3.59 (m, 2 H) 3.59 - 3.73 (m, 4 H) 7.23 (s, 1 H) 7.64 (m, 3 H) 7.85 (s, 1 H) 8.11 (s, 1 H) 8.47 (s, 1 H) 9.05 (s, 1 H). 11.35 (br s., 1H). LCMS (ESI) 448 (M+H).
化合物100の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.50 - 1.57 (m, 2 H) 1.62 - 1.68 (m, 3 H) 1.68 - 1.75 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.48 - 2.53 (m, 2 H) 3.14 - 3.23 (m, 4 H) 3.43 - 3.47 (m, 2 H) 3.58 - 3.70 (m, 2 H) 7.22 (s, 1 H) 7.58 - 7.70 (m, 2 H) 7.85 - 8.00 (m, 1 H) 8.16 (d, 1 H) 8.46 (s, 1 H) 9.04 (s, 1 H) 11.37 (br s., 1H). LCMS (ESI) 418 (M + H).
化合物101(化合物WWとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.72 (s, 2 H) 1.90 (s, 4 H) 2.03 (s, 2 H) 2.21 (s, 2 H) 2.48 - 2.54 (m, 2 H) 2.73 (s, 2 H) 3.03 (s, 2 H) 3.25 - 3.35 (m, 1 H) 3.38 - 3.48 (m, 4 H) 3.65 - 3.99 (m, 5 H) 7.23 (s, 1 H) 7.63 (d, J=9.66 Hz, 1 H) 7.90 (s, 1 H) 8.13 (s, 1 H) 8.47 (s, 1 H) 9.06 (s, 1 H) 10.50 (br s., 1H). LCMS (ESI) 503 (M + H).
化合物102(化合物HHHとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.63 - 1.85 (m, 6 H) 1.87 - 1.92 (m, 2 H) 1.99 - 2.06 (m, 2 H) 2.15 - 2.23 (m, 2 H) 2.47 - 2.53 (m, 1 H) 2.69 - 2.79 (m, 2 H) 2.81 - 2.91 (m, 2 H) 2.98 - 3.08 (m, 2 H) 3.32 - 3.48 (m, 4 H) 3.57 - 3.72 (m, 4 H) 3.77 - 3.85 (m, 2 H) 7.22 (s, 1 H) 7.60 - 7.68 (m, 2 H) 7.90 (s, 1 H) 8.07 (s, 1 H) 8.46 (s, 1 H) 9.04 (s, 1 H). 11.41 (br s., 1H). LCMS (ESI) 501 (M + H).
化合物103の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.64 - 1.76 (m, 2 H) 1.87 - 1.93 (m, 2 H) 2.00 - 2.07 (m, 2 H) 2.48 - 2.53 (m, 2 H) 2.67 - 2.72 (m, 4 H) 3.44 - 3.47 (m, 2 H) 3.50 - 3.55 (m, 4 H) 7.24 (s, 1 H) 7.61 (d, J=9.37 Hz, 2 H) 7.86 (d, J=2.63 Hz, 1 H) 8.09 (d, J=12.88 Hz, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 11.41 (br s., 1H). LCMS (ESI) 436 (M + H).
化合物104の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.73 Hz, 6 H) 1.66 - 1.79 (m, 2 H) 1.84 - 1.95 (m, 2 H) 1.98 - 2.09 (m, 2 H) 2.46 - 2.55 (m, 2 H) 3.29 - 3.39 (m, 2H) 3.58 - 3.70 (m, 4H) 3.77 - 3.86 (m, 4H) 7.24 (s, 1 H) 7.66 (d, J=9.37 Hz, 1 H) 7.96 (d, J=2.93 Hz, 1 H) 8.08 (s, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 9.28 (s, 1 H) 9.67 (s, 1 H) 11.36 (s, 1H). LCMS (ESI) 447 (M + H).
化合物105の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.73 (s, 2 H) 1.76 - 1.85 (m, 2 H) 1.85 - 1.94 (m, 2 H) 1.98 - 2.07 (m, 2 H) 2.19 - 2.26 (m, 2 H) 2.48 - 2.52 (m, 1 H) 2.70 - 2.81 (m, 4 H) 3.13 - 3.20 (m, 1 H) 3.30 - 3.48 (m, 3 H) 3.58 - 3.71 (m, 4 H) 3.78 - 3.84 (m, 4 H) 7.24 (s, 1 H) 7.62 (d, J=9.37 Hz, 2 H) 7.89 (d, J=1.17 Hz, 1 H) 8.09 - 8.18 (m, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 11.46 (br s., 1H). LCMS (ESI) 519 (M + H).
化合物106の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.65 - 1.75 (m, 2 H) 1.85 - 1.93 (m, 2 H) 1.93 - 1.99 (m, 1 H) 2.00 - 2.06 (m, 2 H) 2.08 - 2.14 (m, 1 H) 2.47 - 2.55 (m, 2 H) 3.07 - 3.25 (m, 2 H) 3.25 - 3.69 (m, 5 H) 4.46 (s, 1 H) 4.67 (s, 1 H) 7.22 (s, 1 H) 7.58 - 7.69 (m, 2 H) 8.46 (s, 1 H) 9.02 (s, 1 H) 9.34 (s, 1 H) 9.65 (s, 1 H). LCMS (ESI) 431 (M + H).
化合物107(化合物YYとも呼ばれる)の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.65 - 1.82 (m, 3 H) 1.89 (br. s., 2 H) 1.98 - 2.08 (m, 2 H) 2.13 (br. s., 2 H) 2.47 - 2.55 (m, 2 H) 2.68 (d, J=4.98 Hz, 6 H) 2.71 - 2.80 (m, 2 H) 3.29 - 3.71 (m, 10 H) 7.16 - 7.26 (m, 1 H) 7.67 (d, J=9.66 Hz, 2 H) 7.91 (d, J=2.05 Hz, 1 H) 8.14 (br. s., 1 H) 8.48 (br. s., 1 H) 9.05 (s, 1 H) 11.14 (br. s., 1 H) 11.43 (br. s., 1 H). LCMS (ESI) 461 (M + H).
化合物108の合成
化合物109の合成
化合物110の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.50 - 1.65 (m, 1 H) 1.92 - 2.02 (m, 3 H) 2.06 - 2.15 (m, 1 H) 2.78 (d, J=3.81 Hz, 4 H) 3.10 - 3.20 (m, 4 H) 3.47 - 3.51 (m, 2 H) 3.64 - 3.71 (m, 1 H) 3.76 - 3.83 (m, 2 H) 3.98 - 4.14 (m, 1 H) 7.20 (s, 2 H) 7.77 (s, 1 H) 7.97 (s, 2 H) 8.81 (s, 1 H) 9.03 (s, 1 H) 10.97 (br s., 1H). LCMS (ESI) 419 (M + H).
化合物111の合成
1HNMR (600 MHz, DMSO-d6) δ ppm 1.54 - 1.59 (m, 1 H) 1.92 - 2.01 (m, 3 H) 2.06 - 2.15 (m, 1 H) 2.76 - 2.84 (m, 1 H) 3.17 - 3.24 (m, 6 H) 3.64 - 3.71 (m, 2 H) 4.02 - 4.11 (m, 2 H) 7.22 (s, 2 H) 7.64 (s, 1 H) 7.97 (s, 2 H) 8.75 (s, 1 H) 8.97 (s, 1 H) 9.21 (s, 1 H). LCMS (ESI) 405 (M + H).
tert-ブチルN−[2−[(5-ブロモ2クロロピリミジン-4イル)アミノ]エチル]カルバメートの合成、化合物113
LCMS (ESI) 351 (M + H).
tert-ブチルN−[2−[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4イル]アミノ]エチル]カルバメートの合成、化合物114
内容物を、70度で24時間加熱した。CELITE(登録商標)を通して濾過した後、ヘキサン/酢酸エチル(0〜20%)を用いて、粗反応物をカラムに充填し、所望の製品(3.9g)を提供した。ヘキサン/酢酸エチル(0〜30%)を用いて、得られた残留物のカラムクロマトグラフィーを行い、tert-ブチルN−[2−[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4-イル]アミノ]エチル]カルバメートを提供した。
LCMS (ESI) 399 (M + H).
tert−ブチルN−[2−[2-クロロ-6-(ジエトキシメチル)ピロロ[2,3-d]ピリミジン-7-イル]エチル]カルバメートの合成、化合物115
1HNMR (d6-DMSO) δ ppm 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M+H).
tert−ブチルN−[2−[2-クロロ6-(ジエトキシメチル)-5ヨードピロロ[2,3-d]ピリミジン-7-イル]エチル]カルバメートの合成、化合物116
LCMS (ESI) 525 (M + H).
tert−ブチルN−[2−[2-クロロ-6-(ジエトキシメチル)-5-(o-トリル)ピロロ[2,3-d]ピリミジン-7-イル]エチル]カルバメートの合成、化合物117
LCMS (ESI) 489 (M + H).
7-[2−(tert-ブトキシカルボニルアミノ)エチル]-2-クロロ-5-(o-トリル)ピロロ[2,3-d]ピリミジン-6カルボン酸の合成、化合物118
LCMS (ESI) 431 (M + H).
化合物119の合成
LCMS (ESI) 313 (M + H).
化合物120の合成
LCMS (ESI) 455 (M + H). 1HNMR (600 MHz, DMSO-d6) δ ppm 2.14 (s, 3 H) 3.23 - 3.50 (m, 2 H) 3.57 - 3.73 (m, 2 H), 3.81 - 3.92 (m, 8H), 7.11 - 7.31 (m, 4 H) 7.31 - 7.48 (m, 1 H) 7.58 - 7.73 (m, 1 H) 7.77 - 7.95 (m, 2 H) 8.05 - 8.21 (m, 1 H) 8.44 (s, 1 H) 9.85 - 10.01 (m, 1 H).
化合物121の合成
LCMS (ESI) 392(M + H). 1HNMR (600 MHz, DMSO-d6) δ ppm 1.23 (d,J=8.78Hz,4H)1.84(br.s.,4H)2.11(s,3H)3.34−3.43(m,1H)3.55(br.s.,2H)3.72(br.s.,1H)4.13(br.s.,2H)4.50(br.s.,1H)7.03(br.s.,1H)7.12−7.28(m,4H)7.96(br.s.,1H)8.18(br.s.,1H).
7-[2−(tert-ブトキシカルボニルアミノ)エチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6カルボン酸の合成、化合物122
LCMS (ESI) 341 (M + H).
化合物123の合成
LCMS (ESI) 223 (M + H).
化合物124の合成
LCMS (ESI) 302 (M + H).
tert−ブチルN−[2−[(5-ブロモ-2-クロロ-ピリミジン-4-イル)アミノ]-2メチル-プロピル]カルバメートの合成、化合物125
LCMS (ESI) (M+H) 379.
tert−ブチルN−[2−[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4-イル]アミノ]-2メチル-プロピル]カルバメートの合成、化合物126
LCMS (ESI) (M+H) 427.
tert−ブチルN−[2−[2-クロロ-6-(ジエトキシメチル)ピロロ[2,3-d]ピリミジン-7-イル]-2メチル-プロピル]カルバメートの合成、化合物127
LCMS (ESI) (M+H) 427.
7-[2−(tert-ブトキシカルボニルアミノ)-1,1-ジメチルエチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6カルボン酸の合成、化合物128
LCMS (ESI) 369 (M + H).
化合物129の合成
LCMS (ESI) 251 (M + H).
化合物130の合成
LCMS (ESI) 330 (M + H). 1HNMR (600 MHz, DMSO-d6) δ ppm 1.07 - 1.34 (m, 4 H) 1.47 - 2.05 (m, 10 H) 3.09 (m, 1H) 3.51 (d, J = 2.91 Hz, 2 H) 3.57 (m, 1H) 4.50 (br. s., 1 H) 6.89 (s, 1 H) 6.94 - 7.05 (m, 1 H) 8.04 (br. s., 1 H) 8.60 (s, 1 H) 9.00 (br. s., 1 H).
ベンジルN−[1−[[(5-ブロモ-2-クロロ-ピリミジン-4-イル)アミノ]メチル]プロピル]カルバメートの合成、化合物131
tert−ブチルN−[2−[(5-ブロモ-2-クロロ-ピリミジン-4-イル)アミノ]エチル]カルバメートの合成に対して記載されたと同様の実験条件を用いて、ベンジルN−[1−(アミノメチル)プロピル]カルバメートで5-ブロモ-2、4−-ジクロロピリミジンを処理することにより、ベンジルN−[1−[[(5-ブロモ-2-クロロ-ピリミジン-4-イル)アミノ]メチル]プロピル]カルバメートを合成した。
LCMS (ESI) (M+H) 413.
ベンジルN−[1−[[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4-イル]アミノ]メチル]プロピル]カルバメートの合成、化合物132
LCMS (ESI) (M+H) 461.
カルバミン酸ベンジルN−[1−[[2-クロロ-6-(ジエトキシメチル)ピロロ[2,3-d]ピリミジン-7-イル]メチル]プロピル]の合成、化合物133
LCMS (ESI) (M+H) 461.
7-[2−(ベンジルオキシカルボニルアミノ)ブチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6カルボン酸の合成、化合物134
LCMS (ESI) 403 (M + H).
化合物135の合成
LCMS (ESI) 251 (M + H).
化合物136の合成
LCMS (ESI) 330 (M + H). 1HNMR (600 MHz, DMSO-d6) δ ppm 0.80 - 0.95 (m, 3 H) 1.35 - 1.92 (m, 10 H) 3.66 (br. m., 3 H) 4.17 (br. s., 2 H) 4.47 (br. s., 1 H) 6.85 (s, 1 H) 6.96 (br. s., 1 H) 8.15 (br. s., 1 H) 8.62 (br. s., 1 H).
tert−ブチルN−[1−[[(5-ブロモ-2-クロロ-ピリミジン-4-イル)アミノ]メチル]シクロペンチル]カルバメートの合成、化合物137
LCMS (ESI) 405 (M+H).
tert−ブチルN−[1−[[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4-イル]アミノ]メチル]シクロペンチル]カルバメートの合成、化合物138
LCMS (ESI) 453 (M+H).
tert−ブチルN−[1−[[2-クロロ-6-(ジエトキシメチル)ピロロ[2,3-d]ピリミジン-7-イル]メチル]シクロペンチル]カルバメートの合成、化合物139
LCMS (ESI) 453 (M+H).
7-[[1−(tert-ブトキシカルボニルアミノ)シクロペンチル]メチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6カルボン酸の合成、化合物140
LCMS (ESI) 395 (M + H).
化合物141の合成
LCMS (ESI) 277 (M + H).
化合物142の合成
LCMS (ESI) 356 (M + H). 1HNMR (600 MHz, DMSO-d6) δ ppm 1.08 - 1.32 (m, 8 H) 1.60 - 2.09 (m, 8 H) 3.03 - 3.17 (m, 1 H) 3.35 (s, 2 H) 3.54 - 3.62 (m, 1 H) 4.51 (d, J=4.39 Hz, 1 H) 6.88 (s, 1 H) 6.96 (br. s., 1 H) 8.07 (br. s., 1 H) 8.58 (s, 1 H).
tert−ブチルN−[[1−[(5-ブロモ-2-クロロ-ピリミジン-4-イル)アミノ]シクロペンチル]メチル]カルバメートの合成、化合物143
LCMS (ESI) 405 (M+H).
tert−ブチルN−[2−[[2-クロロ-5-(3、3-ジエトキシプロプ-1-イニル)ピリミジン-4-イル]アミノ]-2メチル-プロピル]カルバメートの合成、化合物144
LCMS (ESI) 453 (M+H).
tert−ブチルN−[[1−[2-クロロ-6-(ジエトキシメチル)ピロロ[2,3-d]ピリミジン-7-イル]シクロペンチル]メチル]カルバメートの合成、化合物145
LCMS (ESI) 4534 (M+H).
7-[2−(tert-ブトキシカルボニルアミノ)-1,1-ジメチルエチル]-2-クロロ-ピロロ[2,3-d]ピリミジン-6カルボン酸の合成、化合物146
LCMS (ESI) 395 (M + H).
化合物147の合成
LCMS (ESI) 277 (M + H).
化合物148の合成
LCMS (ESI) 356 (M + H). 1HNMR (600 MHz, DMSO-d6) δ ppm 1.06 - 1.35 (m, 8 H) 1.45 - 1.95 (m, 8 H) 3.10 (m, 1 H) 3.58 (br. s., 2 H) 3.95 (br. s., 1 H) 4.49 (br. s., 1 H) 6.84 (s, 1 H) 6.85 - 6.93 (m, 1 H) 8.29 (s, 1 H) 8.61 (br. s., 1 H).
化合物149の合成
ステップ2:Boc保護された化合物59を、CO2(1気圧)の下、DMI中の5mol% NiCl2(Ph3)2、0.1eqトリフェニルホスフィン、3eq Mn、0.1eqヨウ化テトラエチルアンモニウムで、25℃で20時間処理して、ハロゲン化アリール誘導体をカルボン酸に変換する。
ステップ3:ステップ2からのカルボン酸を、標準的な条件を用いて、対応する酸塩化物に変換する。
ステップ4:ステップ3からの酸塩化物を、Nメチルピペラジンと反応させて、対応するアミドを生成する。
ステップ5:ステップ4からのアミドを、ジクロロメタン中のトリフルオロ酢酸を用いて脱保護して、ターゲット化合物を生成する。
化合物149を、シリカゲルカラムクロマトグラフィーにより、ジクロロメタン-メタノール勾配で溶出させて、精製して、化合物149を提供する。
化合物119〜147のそれぞれ及び様々なR8、R1及びZの定義を含む対応する各化合物は、水素化ナトリウム及びハロゲン化アルキル又は他のハロゲン化物と反応してもよく、これにより、化合物120の合成に対して上記したように、アミンによる反応物への前に所望のR置換を挿入して、式I、II、III、IV又はVの所望の製品を生成させてもよい。
細胞増殖の阻害
図9は、PD0332991(丸)又は化合物T(表1;正方形)で処理したSupT1細胞(ヒトT細胞リンパ芽球性白血病)の細胞増殖を示すグラフである。図10は、化合物Q(表1;丸)又は化合物GG(表1;正方形)で処理したSupT1細胞(ヒトT細胞リンパ芽球性白血病)の細胞増殖を示すグラフである。SupT1細胞を、Coster社(米国マサチューセッツ州テュークスバリー)3093号、96ウェル組織培養処理白壁/透明底板、に播種した。10μMから1nMへの9点ドーズ応答希釈物系列を行い、CellTiter-Glo(登録商標)アッセイ(CTG; Promega、マディソン、ウィスコンシン、アメリカ合衆国)を用いて、製造者の推奨に従い、細胞生存能力を4日間後に測定した。プレートは、BioTek社(バーモント州Winooski)のSyngergy2マルチモードプレートリーダで読み込まれた。
可変モル濃度から相対発光量(RLU)をプロットし、Graphpad社の(カリフォルニア州LaJolla)プリズム5統計ソフトウェアを用いてデータを分析し、各化合物についてIC50を決定した。
T細胞及びB-細胞特異的癌細胞における細胞増殖の阻害
SupT1(ヒトT細胞リンパ芽球性白血病)及びダウディ細胞(バーキットリンパ腫患者からのヒトB-リンパ芽細胞)を用いて、表1にリストされる化合物に対して、細胞増殖の阻害のための検証を行った。図9及び10及び実施例150は、EC50がどのように計測されたかについて説明するものである。検証された大部分の化合物は、SupT1 T細胞リンパ芽球白血病細胞系統に対して大きな阻害を示した。SupT1 T細胞リンパ芽球白血病細胞増殖の阻害のために必要な、被検証化合物のEC50の範囲は、9.3nM〜3037nMであった。また、化合物の多くが、B細胞リンパ芽細胞系統(ダウディ細胞)の阻害に対して、大きな作用を示した。ダウディ細胞B細胞リンパ芽細胞増殖の阻害のために必要な、被検証化合物のEC50の範囲は、111nM〜3345nMであった。
Claims (67)
- 式I、II、III、IV又はVの化合物又はその薬理学的に許容される塩の有効量を、それを必要とするホストに投与することを含む、異常T細胞増殖の治療のための方法であって、
各Xは、独立してCH又はNであり、
各X’は、独立してCH又はNであり、
X’’は、独立してCH2、S又はNHであり、構成部分が安定5員環となるよう配置され、R、R8及びR11は、独立してH、C1-C3のアルキル又はハロアルキル、シクロアルキル、又は、N、O又はSから選択される1つ以上のヘテロ原子を含んだシクロアルキル、−(アルキレン)m、-C3-C8シクロアルキル、−(アルキレン)m-アリール、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であって、これらのいずれかは、価電子(valance)で与えられる1つ以上のR基で任意に独立に置換されてもよく、同じ又は隣接した原子に結合した2つのRx基を任意に組み合せて環を形成してもよく、
各R1は独立して、アリール、アルキル、シクロアルキル又はハロアルキルであり、前記アルキル、シクロアルキル及びハロアルキル基の各々は、鎖中の炭素の代わりに任意にO又はNヘテロ原子を含み、及び隣接した環原子又は同じ環原子の2つのR1,は、環原子と共に、任意に結合される3-8員環を形成し、
yは、0、1,2、3又は4であり、
R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4、−(アルキレン)m-C(O)-O-アルキル、−(アルキレン)m-O-R5、−(アルキレン)m-S(O)n-R5、または−(アルキレン)m-S(O)n-NR3R4であり、
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、
mは0又は1、nは0、1又は2であり、
R3及びR4はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキル、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、又は
R3及びR4は、これらが結合される窒素原子と共に組み合わされて、価電子で与えられる1つ以上のRx基で任意に独立して置換されるヘテロシクロ環を形成してもよく、
同じ又は隣接した原子に結合した2つのRx基は、任意に組み合わされて環を形成してもよく、
R5及びR5*はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
Rxは、その発生毎に独立して、ハロ、シアノ、ニトロ、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキル、−(アルキレン)m-OR5、−(アルキレン)m-O-アルキレン-OR5、−(アルキレン)m-S(O)n-R5、−(アルキレン)m-NR3R4、−(アルキレン)m-CN、−(アルキレン)m-C(O)-R5、−(アルキレン)m-C(S)-R5、−(アルキレン)m-C(O)-OR5、−(アルキレン)m-O-C(O)-R5、−(アルキレン)m-C(S)-OR5、−(アルキレン)m-C(O)-(アルキレン)m-NR3R4、−(アルキレン)m-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-NR3R4、−(アルキレン)m-N(R3)-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-R5、−(アルキレン)m-N(R3)-C(S)-R5、−(アルキレン)m-O-C(O)-NR3R4、−(アルキレン)m-O-C(S)-NR3R4、−(アルキレン)m-SO2-NR3R4、−(アルキレン)m-N(R3)-SO2-R5、−(アルキレン)m-N(R3)-SO2-NR3R4、−(アルキレン)m-N(R3)-C(O)-OR5、−(アルキレン)m-N(R3)-C(S)-OR5、又は−(アルキレン)m-N(R3)-SO2-R5であり、
ここで、前記アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル及びヘテロシクロアルキル基は:
−(アルキレン)m-CN、−(アルキレン)m-OR5*、−(アルキレン)m-S(O)n-R5*、−(アルキレン)m-NR3*R4*、−(アルキレン)m-C(O)-R5*、−(アルキレン)m-C(=S)R5*、−(アルキレン)m-C(=O)OR5*、−(アルキレン)m-OC(=O)R5*、−(アルキレン)m-C(S)-OR5*、−(アルキレン)m-C(O)-NR3*R4*、−(アルキレン)m-C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-NR3*R4*、−(アルキレン)m-N(R3*)−C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-R5*、−(アルキレン)m-N(R3*)−C(S)-R5*、−(アルキレン)m-O-C(O)-NR3*R4*、−(アルキレン)m-O-C(S)-NR3*R4*、−(アルキレン)m-SO2-NR3*R4*、−(アルキレン)m-N(R3*)−SO2R5*、−(アルキレン)m-N(R3*)−SO2NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-OR5*、−(アルキレン)m-N(R3*)−C(S)-OR5*、又は−(アルキレン)m-N(R3*)−SO2R5*、の1つ以上でさらに独立して置換されてもよく、
nは、0、1又は2であり、mは0又は1であり、
R3*及びR4*は、独立してその発生毎に以下の通りであり:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、又は
R3*及びR4*は、それらに結合される窒素原子と共に組合せられて、価電子によって与えられる1つ以上のRx基と任意に独立して置換されるヘテロシクロ環を形成してもよく、
R6はH又は低級アルキル、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、R10は
(i) NHRAであり、
ここで、RAは非置換又は置換C1-C8アルキル、シクロアルキルアルキル、又は、-TT-RR、C1-C8シクロアルキル、又は、N、O及びSから選択されるヘテロ原子を1つ以上含むシクロアルキルであり、TTは、非置換又は置換C1-C8アルキル又はC3-C8シクロアルキルリンカーであり、RRはヒドロキシル、非置換又は置換C1-C6アルコキシ、アミノ、非置換又は置換C1-C6アルキルアミノ、非置換又は置換ジ-C1-C6アルキルアミノ、非置換又は置換C6-C10アリール、1又は2個の5員又は6員環及びN、O及びSから選択される1〜4個のヘテロ原子を含む非置換又は置換ヘテロアリール、非置換又は置換C3-C10炭素環、又は、1又は2個の5員又は6員環及びN、O及びSから選択される1〜4個のヘテロ原子を含む非置換又は置換ヘテロ環であり、又は
(ii)−C(O)−R12又は-C(O)O-R13であり、R12は、NHRA又はRAであり、R13は、RAである、前記方法。 - 前記化合物が、化合物Q又はその薬理学的に許容される塩である、請求項2に記載の方法。
- 前記化合物が、化合物T又はその薬理学的に許容される塩である、請求項2に記載の方法。
- 前記化合物が、化合物U又はその薬理学的に許容される塩である、請求項2に記載の方法。
- 前記化合物が、化合物GG又はその薬理学的に許容される塩である、請求項2に記載の方法。
- 前記化合物が、化合物A〜化合物Z又はその薬理学的に許容される塩から成る群より選択される、請求項2に記載の方法。
- 前記化合物が、化合物AA〜ZZ又はその薬理学的に許容される塩から成る群より選択される、請求項2に記載の方法。
- 前記化合物が、化合物AAA〜ZZZ又はその薬理学的に許容される塩から成る群より選択される、請求項2に記載の方法。
- 前記異常T細胞増殖が、T細胞リンパ腫である、請求項1に記載の方法。
- 前記異常T細胞増殖が、T細胞白血病である、請求項1に記載の方法。
- 前記異常T細胞リンパ腫が、ホジキンリンパ腫である、請求項10に記載の方法。
- 前記T細胞リンパ腫が、非ホジキンリンパ腫である、請求項10に記載の方法。
- 前記化合物が、ターゲッティング薬剤に接合される、請求項1に記載の方法。
- 前記ターゲッティング薬剤が、抗体又は抗体フラグメントである、請求項14に記載の方法。
- 前記化合物が、放射性同位体に接合される、請求項1に記載の方法。
- 前記ホストが、ヒトである、請求項1に記載の方法。
- 前記ホストが、ヒトである、請求項10に記載の方法。
- 前記ホストが、ヒトである、請求項11に記載の方法。
- 式I、II、III、IV又はVの化合物又はその薬理学的に許容される塩の有効量を、それを必要とするホストに投与することを含む、異常B細胞増殖の治療のための方法であって、
各Xは、独立してCH又はNであり、
各X’は、独立してCH又はNであり、
X’’は、独立してCH2、S又はNHであり、構成部分が安定5員環となるよう配置され、R、R8及びR11は、独立してH、C1-C3のアルキル又はハロアルキル、シクロアルキル、又は、N、O又はSから選択される1つ以上のヘテロ原子を含んだシクロアルキル、−(アルキレン)m、-C3-C8シクロアルキル、−(アルキレン)m-アリール、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であって、これらのいずれかは、価電子(valance)で与えられる1つ以上のR基で任意に独立に置換されてもよく、同じ又は隣接した原子に結合した2つのRx基を任意に組み合せて環を形成してもよく、
各R1は独立して、アリール、アルキル、シクロアルキル又はハロアルキルであり、前記アルキル、シクロアルキル及びハロアルキル基の各々は、鎖中の炭素の代わりに任意にO又はNヘテロ原子を含み、及び隣接した環原子又は同じ環原子の2つのR1,は、環原子と共に、任意に結合される3-8員環を形成し、
yは、0、1,2、3又は4であり、
R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4、−(アルキレン)m-C(O)-O-アルキル、−(アルキレン)m-O-R5、−(アルキレン)m-S(O)n-R5、または−(アルキレン)m-S(O)n-NR3R4であり、
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、
mは0又は1、nは0、1又は2であり、
R3及びR4はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキル、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、又は
R3及びR4は、これらが結合される窒素原子と共に組み合わされて、価電子で与えられる1つ以上のRx基で任意に独立して置換されるヘテロシクロ環を形成してもよく、
同じ又は隣接した原子に結合した2つのRx基は、任意に組み合わされて環を形成してもよく、
R5及びR5*はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
Rxは、その発生毎に独立して、ハロ、シアノ、ニトロ、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキル、−(アルキレン)m-OR5、−(アルキレン)m-O-アルキレン-OR5、−(アルキレン)m-S(O)n-R5、−(アルキレン)m-NR3R4、−(アルキレン)m-CN、−(アルキレン)m-C(O)-R5、−(アルキレン)m-C(S)-R5、−(アルキレン)m-C(O)-OR5、−(アルキレン)m-O-C(O)-R5、−(アルキレン)m-C(S)-OR5、−(アルキレン)m-C(O)-(アルキレン)m-NR3R4、−(アルキレン)m-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-NR3R4、−(アルキレン)m-N(R3)-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-R5、−(アルキレン)m-N(R3)-C(S)-R5、−(アルキレン)m-O-C(O)-NR3R4、−(アルキレン)m-O-C(S)-NR3R4、−(アルキレン)m-SO2-NR3R4、−(アルキレン)m-N(R3)-SO2-R5、−(アルキレン)m-N(R3)-SO2-NR3R4、−(アルキレン)m-N(R3)-C(O)-OR5、−(アルキレン)m-N(R3)-C(S)-OR5、又は−(アルキレン)m-N(R3)-SO2-R5であり、
ここで、前記アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル及びヘテロシクロアルキル基は:
−(アルキレン)m-CN、−(アルキレン)m-OR5*、−(アルキレン)m-S(O)n-R5*、−(アルキレン)m-NR3*R4*、−(アルキレン)m-C(O)-R5*、−(アルキレン)m-C(=S)R5*、−(アルキレン)m-C(=O)OR5*、−(アルキレン)m-OC(=O)R5*、−(アルキレン)m-C(S)-OR5*、−(アルキレン)m-C(O)-NR3*R4*、−(アルキレン)m-C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-NR3*R4*、−(アルキレン)m-N(R3*)−C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-R5*、−(アルキレン)m-N(R3*)−C(S)-R5*、−(アルキレン)m-O-C(O)-NR3*R4*、−(アルキレン)m-O-C(S)-NR3*R4*、−(アルキレン)m-SO2-NR3*R4*、−(アルキレン)m-N(R3*)−SO2R5*、−(アルキレン)m-N(R3*)−SO2-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-OR5*、−(アルキレン)m-N(R3*)−C(S)-OR5*、又は−(アルキレン)m-N(R3*)−SO2R5*、の1つ以上でさらに独立して置換されてもよく、
nは、0、1又は2であり、mは0又は1であり、
R3*及びR4*は、独立してその発生毎に以下の通りであり:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、又は
R3*及びR4*は、それらに結合される窒素原子と共に組合せられて、価電子によって与えられる1つ以上のRx基と任意に独立して置換されるヘテロシクロ環を形成してもよく、
R6はH又は低級アルキル、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、R10は
(i) NHRAであり、
ここで、RAは非置換又は置換C1-C8アルキル、シクロアルキルアルキル、又は、-TT-RR、C1-C8シクロアルキル、又は、N、O及びSから選択されるヘテロ原子を1つ以上含むシクロアルキルであり、TTは、非置換又は置換C1-C8アルキル又はC3-C8シクロアルキルリンカーであり、RRはヒドロキシル、非置換又は置換C1-C6アルコキシ、アミノ、非置換又は置換C1-C6アルキルアミノ、非置換又は置換ジ-C1-C6アルキルアミノ、非置換又は置換C6-C10アリール、1又は2個の5員又は6員環及びN、O及びSから選択される1〜4個のヘテロ原子を含む非置換又は置換ヘテロアリール、非置換又は置換C3-C10炭素環、又は、1又は2個の5員又は6員環及びN、O及びSから選択される1〜4個のヘテロ原子を含む非置換又は置換ヘテロ環であり、又は
(ii)−C(O)−R12又は-C(O)O-R13であり、R12は、NHRA又はRAであり、R13は、RAである、前記方法。 - 前記化合物が、化合物Q又はその薬理学的に許容される塩である、請求項21に記載の方法。
- 前記化合物が、化合物T又はその薬理学的に許容される塩である、請求項21に記載の方法。
- 前記化合物が、化合物U又はその薬理学的に許容される塩である、請求項21に記載の方法。
- 前記化合物が、化合物GG又はその薬理学的に許容される塩である、請求項21に記載の方法。
- 前記化合物が、化合物A〜化合物Z又はその薬理学的に許容される塩から成る群より選択される、請求項21に記載の方法。
- 前記化合物が、化合物AA〜ZZ又はその薬理学的に許容される塩から成る群より選択される、請求項21に記載の方法。
- 前記化合物が、化合物AAA〜ZZZ又はその薬理学的に許容される塩から成る群より選択される、請求項21に記載の方法。
- 前記異常B細胞増殖が、B細胞リンパ腫である、請求項20に記載の方法。
- 前記異常B細胞増殖が、B細胞白血病である、請求項20に記載の方法。
- 前記化合物が、ターゲッティング薬剤に接合される、請求項20に記載の方法。
- 前記ターゲッティング薬剤が、抗体又は抗体フラグメントである、請求項31に記載の方法。
- 前記化合物が、放射性同位体に接合される、請求項20に記載の方法。
- 前記ホストが、ヒトである、請求項20に記載の方法。
- 前記ホストが、ヒトである、請求項21に記載の方法。
- 前記ホストが、ヒトである、請求項29に記載の方法。
- 前記ホストが、ヒトである、請求項30に記載の方法。
- 式I、II、III、IV又はVの化合物又はその薬理学的に許容される塩の有効量を、それを必要とするホストに投与することを含む、自己免疫疾患の治療のための方法であって、
各Xは、独立してCH又はNであり、
各X’は、独立してCH又はNであり、
X’’は、独立してCH2、S又はNHであり、構成部分が安定5員環となるよう配置され、R、R8及びR11は、独立してH、C1-C3のアルキル又はハロアルキル、シクロアルキル、又は、N、O又はSから選択される1つ以上のヘテロ原子を含んだシクロアルキル、−(アルキレン)m、-C3-C8シクロアルキル、−(アルキレン)m-アリール、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であって、これらのいずれかは、価電子(valance)で与えられる1つ以上のR基で任意に独立に置換されてもよく、同じ又は隣接した原子に結合した2つのRx基を任意に組み合せて環を形成してもよく、
各R1は独立して、アリール、アルキル、シクロアルキル又はハロアルキルであり、前記アルキル、シクロアルキル及びハロアルキル基の各々は、鎖中の炭素の代わりに任意にO又はNヘテロ原子を含み、及び隣接した環原子又は同じ環原子の2つのR1,は、環原子と共に、任意に結合される3-8員環を形成し、
yは、0、1,2、3又は4であり、
R2は、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(O)-NR3R4、−(アルキレン)m-C(O)-O-アルキル、−(アルキレン)m-O-R5、−(アルキレン)m-S(O)n-R5、または−(アルキレン)m-S(O)n-NR3R4であり、
これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、
mは0又は1、nは0、1又は2であり、
R3及びR4はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキル、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、又は
R3及びR4は、これらが結合される窒素原子と共に組み合わされて、価電子で与えられる1つ以上のRx基で任意に独立して置換されるヘテロシクロ環を形成してもよく、
同じ又は隣接した原子に結合した2つのRx基は、任意に組み合わされて環を形成してもよく、
R5及びR5*はその発生毎に、独立して以下の通りである:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
Rxは、その発生毎に独立して、ハロ、シアノ、ニトロ、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキル、−(アルキレン)m-OR5、−(アルキレン)m-O-アルキレン-OR5、−(アルキレン)m-S(O)n-R5、−(アルキレン)m-NR3R4、−(アルキレン)m-CN、−(アルキレン)m-C(O)-R5、−(アルキレン)m-C(S)-R5、−(アルキレン)m-C(O)-OR5、−(アルキレン)m-O-C(O)-R5、−(アルキレン)m-C(S)-OR5、−(アルキレン)m-C(O)-(アルキレン)m-NR3R4、−(アルキレン)m-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-NR3R4、−(アルキレン)m-N(R3)-C(S)-NR3R4、−(アルキレン)m-N(R3)-C(O)-R5、−(アルキレン)m-N(R3)-C(S)-R5、−(アルキレン)m-O-C(O)-NR3R4、−(アルキレン)m-O-C(S)-NR3R4、−(アルキレン)m-SO2-NR3R4、−(アルキレン)m-N(R3)-SO2-R5、−(アルキレン)m-N(R3)-SO2-NR3R4、−(アルキレン)m-N(R3)-C(O)-OR5、−(アルキレン)m-N(R3)-C(S)-OR5、又は−(アルキレン)m-N(R3)-SO2-R5であり、
ここで、前記アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル及びヘテロシクロアルキル基は:
−(アルキレン)m-CN、−(アルキレン)m-OR5*、−(アルキレン)m-S(O)n-R5*、−(アルキレン)m-NR3*R4*、−(アルキレン)m-C(O)-R5*、−(アルキレン)m-C(=S)R5*、−(アルキレン)m-C(=O)OR5*、−(アルキレン)m-OC(=O)R5*、−(アルキレン)m-C(S)-OR5*、−(アルキレン)m-C(O)-NR3*R4*、−(アルキレン)m-C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-NR3*R4*、−(アルキレン)m-N(R3*)−C(S)-NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-R5*、−(アルキレン)m-N(R3*)−C(S)-R5*、−(アルキレン)m-O-C(O)-NR3*R4*、−(アルキレン)m-O-C(S)-NR3*R4*、−(アルキレン)m-SO2-NR3*R4*、−(アルキレン)m-N(R3*)−SO2−R5*、−(アルキレン)m-N(R3*)−SO2−NR3*R4*、−(アルキレン)m-N(R3*)−C(O)-OR5*、−(アルキレン)m-N(R3*)−C(S)-OR5*、又は−(アルキレン)m-N(R3*)−SO2−R5*、の1つ以上でさらに独立して置換されてもよく、
nは、0、1又は2であり、mは0又は1であり、
R3*及びR4*は、独立してその発生毎に以下の通りであり:
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル又はヘテロアリールアルキルであり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、又は
R3*及びR4*は、それらに結合される窒素原子と共に組合せられて、価電子によって与えられる1つ以上のRx基と任意に独立して置換されるヘテロシクロ環を形成してもよく、
R6はH又は低級アルキル、−(アルキレン)m-ヘテロシクロ、−(アルキレン)m-ヘテロアリール、−(アルキレン)m-NR3R4、−(アルキレン)m-C(0)-NR3R4、−(アルキレン)m-0-R5、−(アルキレン)m-S(0)n-R5、又は−(アルキレン)m-S(0)n-NR3R4であり、これらのいずれかは、価電子で与えられる1つ以上のRx基で任意に独立して置換されてもよく、
同じ又は隣接した原子に結合した2つのRx基は任意に組み合わされて環を形成してもよく、R10は
(i) NHRAであり、
ここで、RAは非置換又は置換C1-C8アルキル、シクロアルキルアルキル、又は、-TT-RR、C1-C8シクロアルキル、又は、N、O及びSから選択されるヘテロ原子を1つ以上含むシクロアルキルであり、TTは、非置換又は置換C1-C8アルキル又はC3-C8シクロアルキルリンカーであり、RRはヒドロキシル、非置換又は置換C1-C6アルコキシ、アミノ、非置換又は置換C1-C6アルキルアミノ、非置換又は置換ジ-C1-C6アルキルアミノ、非置換又は置換C6-C10アリール、1又は2個の5員又は6員環及びN、O及びSから選択される1〜4個のヘテロ原子を含む非置換又は置換ヘテロアリール、非置換又は置換C3-C10炭素環、又は、1又は2個の5員又は6員環及びN、O及びSから選択される1〜4個のヘテロ原子を含む非置換又は置換ヘテロ環であり、又は
(ii)−C(O)−R12又は-C(O)O-R13であり、R12は、NHRA又はRAであり、R13は、RAである、前記方法。 - 前記化合物が、化合物Q又はその薬理学的に許容される塩である、請求項39に記載の方法。
- 前記化合物が、化合物T又はその薬理学的に許容される塩である、請求項39に記載の方法。
- 前記化合物が、化合物U又はその薬理学的に許容される塩である、請求項39に記載の方法。
- 前記化合物が、化合物GG又はその薬理学的に許容される塩である、請求項39に記載の方法。
- 前記化合物が、化合物A〜化合物Z又はその薬理学的に許容される塩から成る群より選択される、請求項39に記載の方法。
- 前記化合物が、化合物AA〜ZZ又はその薬理学的に許容される塩から成る群より選択される、請求項39に記載の方法。
- 前記化合物が、化合物AAA〜ZZZ又はその薬理学的に許容される塩から成る群より選択される、請求項39に記載の方法。
- 前記自己免疫性疾患が、関節炎である、請求項38に記載の方法。
- 前記自己免疫性疾患が、乾癬である、請求項38に記載の方法。
- 前記自己免疫性疾患が、クローン病である、請求項38に記載の方法。
- 前記自己免疫性疾患が、狼瘡である、請求項38に記載の方法。
- 前記化合物が、ターゲッティング薬剤に接合される、請求項38に記載の方法。
- 前記ターゲッティング薬剤が、抗体又は抗体フラグメントである、請求項51に記載の方法。
- 前記化合物が、放射性同位体に接合される、請求項38に記載の方法。
- 前記ホストが、ヒトである、請求項47に記載の方法。
- 前記ホストが、ヒトである、請求項48に記載の方法。
- 前記ホストが、ヒトである、請求項49に記載の方法。
- 前記化合物が、第2の活性剤との併用療法で投与される、請求項1に記載の方法。
- 前記化合物が、第2の活性剤との併用療法で投与される、請求項20に記載の方法。
- ホストにおける異常T細胞増殖の治療のための、請求項1に記載の化合物の使用。
- ホストにおける異常B細胞増殖の治療のための、請求項20に記載の化合物の使用。
- ホストにおける自己免疫性疾患の治療のための、請求項38に記載の化合物の使用。
- 前記ホストが、ヒトである、請求項59に記載の化合物の使用。
- 前記ホストが、ヒトである、請求項60に記載の化合物の使用。
- 前記ホストが、ヒトである、請求項61に記載の化合物の使用。
- ホストにおける異常T細胞増殖の治療のための薬剤の製造における、請求項1に記載の化合物の使用。
- ホストにおける異常B細胞増殖の治療のための薬剤の製造における、請求項20に記載の化合物の使用。
- ホストにおける自己免疫性疾患の治療のための薬剤の製造における、請求項38に記載の化合物の使用。
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CA2906157A1 (en) | 2014-09-18 |
US20160310499A1 (en) | 2016-10-27 |
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CA2906157C (en) | 2022-05-17 |
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JP2019094324A (ja) | 2019-06-20 |
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CN107417691A (zh) | 2017-12-01 |
CA3152117A1 (en) | 2014-09-18 |
WO2014144740A2 (en) | 2014-09-18 |
HK1222766A1 (zh) | 2017-07-14 |
JP6435315B2 (ja) | 2018-12-05 |
US20180015096A1 (en) | 2018-01-18 |
EP2967050A2 (en) | 2016-01-20 |
WO2014144740A3 (en) | 2014-11-27 |
EP2967050A4 (en) | 2016-09-28 |
CN105407723A (zh) | 2016-03-16 |
US10709711B2 (en) | 2020-07-14 |
JP6703583B2 (ja) | 2020-06-03 |
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