JP5161110B2 - Pi−3キナーゼ阻害剤として使用されるピリミジン誘導体 - Google Patents
Pi−3キナーゼ阻害剤として使用されるピリミジン誘導体 Download PDFInfo
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- JP5161110B2 JP5161110B2 JP2008551469A JP2008551469A JP5161110B2 JP 5161110 B2 JP5161110 B2 JP 5161110B2 JP 2008551469 A JP2008551469 A JP 2008551469A JP 2008551469 A JP2008551469 A JP 2008551469A JP 5161110 B2 JP5161110 B2 JP 5161110B2
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
本発明は、新規のホスファチジルイノシトール (PI) 3−キナーゼ阻害化合物、その薬学的に許容される塩およびそのプロドラッグ;薬学的に許容される担体と、該新規化合物単独または少なくとも1種のさらなる治療薬と組み合わせた組成物;および、幾つかの疾患、特に増殖因子、受容体チロシンキナーゼ、タンパク質セリン/トレオニンキナーゼ、Gタンパク質結合受容体およびリン脂質キナーゼおよびホスファターゼの異常な活性によって特徴付けられる疾患の予防または処置における、該新規化合物単独または少なくとも1種のさらなる治療薬と組み合わせた使用に関する。
ホスファチジルイノシトール 3−キナーゼ(PI3K)は、脂質およびセリン/トレオニンキナーゼのファミリーを含み、該酵素はリン酸基のイノシトール脂質のD−3'位への移動を触媒し、ホスホイノシトール−3−ホスフェート(PIP)、ホスホイノシトール−3,4−ジホスフェート(PIP2)およびホスホイノシトール−3,4,5−トリホスフェート(PIP3)を生成し、これらは次いで、プレクストリン相同領域含有タンパク質、FYVE、Phoxおよび他のリン脂質結合ドメインを含むタンパク質を、しばしば細胞膜で、種々のシグナル複合体にドッキングすることによって、シグナルカスケードにおける第2メッセンジャーとして作用する(Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001))。クラス1 PI3K、クラス1A PI3Kの2つからなるヘテロダイマーは、制御サブユニット(p85α、p55α、p50α、p85βまたはp55γ)に構造的に結合している触媒p110サブユニット(α、β、δアイソフォーム)で構成される。クラス1Bサブクラスは、2つの制御サブユニットp101およびp84の1つと結合している触媒p110γサブユニットから構成されるヘテロダイマーである1個のファミリーのメンバーを有する (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Biol. 15:566 (2005))。p85/55/50サブユニットのモジュラードメインは、活性化された受容体および細胞質チロシンキナーゼ上の特定の配列におけるホスホチロシン残基と結合し、その結果クラス 1A PI3Kの活性化および局在化を起こすSrc相同性(SH2)ドメインを含む。クラス 1B PI3Kは、広い範囲のペプチドおよび非ペプチドリガンドと結合するGタンパク質結合受容体によって直接活性化される(Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001))。結果として、クラスI PI3Kの得られたリン脂質生成物は、上流の受容体を、増殖、生存、走化性、細胞輸送、運動性、代謝、炎症およびアレルギー応答、転写および翻訳を含む下流の細胞の活動に関連付ける(Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992))。
本発明は、新規のホスファチジルイノシトール 3−キナーゼ(PI3K)阻害化合物、該化合物を含む医薬製剤、ホスファチジルイノシトール 3−キナーゼ(PI3K)を阻害する方法、および増殖性疾患の処置方法を提供する。
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、
(6) スルホンアミド
からなる群から選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR1a、
(13) −CO2R1a、
(14) −CONR1aR1b、
(15) −NR1aR1b、
(16) −NR1aCOR1b、
(17) −NR1aSO2R1b、
(18) −OCOR1a、
(19) −OR1a、
(20) −SR1a、
(21) −SOR1a、
(22) −SO2R1a、および
(23) −SO2NR1aR1b
からなる群から選択され、
ここで、R1aおよびR1bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R4は、
(1) 水素、および
(2) ハロゲン、
からなる群から選択される。]
の化合物、またはその立体異性体、互変異性体もしくは薬学的に許容される塩を提供する。
(1) 置換および非置換アルキル、
(2) 置換および非置換アリール、
(3) 置換および非置換ヘテロアリール、
(4) 置換および非置換ヘテロ環、
(5) 置換および非置換シクロアルキル、
(6) −OR1a、および
(7) −NR1aR1b
からなる群から選択され、
ここで、R1aおよびR1bは、
(a) 置換および非置換ヘテロアリール、および
(b) 置換および非置換ヘテロ環
からなる群から独立して選択される。
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) ハロゲン、
(5) アミノ、
(6) メチル、および
(7) トリフルオロメチル
からなる群から選択される。
(1) シアノ、
(2) ニトロ、
(3) ハロゲン、
(4) ヒドロキシ、
(5) アミノ、および
(6) トリフルオロメチル
からなる群から選択される。
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
Xは、O、S、NH、または直接結合であり;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
(1) 水素、および
(2) ハロゲン
からなる群から選択され;
R5は、
(1) 置換および非置換シクロアルキル、
(2) 置換および非置換ヘテロ環、
(3) 置換および非置換アリール、および
(4) 置換および非置換ヘテロアリール
からなる群から選択される。]
を有する化合物またはその立体異性体、互変異性体もしくは薬学的に許容される塩を提供する。
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) アミノ、
(5) ハロゲン、および
(6) 置換および非置換C1−3アルキル
からなる群から選択される。
(1) 水素、
(2) シアノ、
(3) チオ、
(4) ハロゲン、
(5) ニトロ、
(6) 置換および非置換アルキル、
(7) 置換および非置換アルケニル、
(8) 置換および非置換アルキニル、
(9) −OR3a、
(10) −NR3aR3b、
(11) −COR3a、および
(12) −NR3aCOR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択される。
(1) 置換または非置換モルホリニル、
(2) 置換または非置換テトラヒドロピラニル、および
(3) 置換または非置換テトラヒドロフラニル
からなる群から選択される。
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
(1) 水素、および
(2) ハロゲン
からなる群から選択され;
R6は、
(1) 水素、
(2) 置換および非置換アルキル、および
(3) 置換および非置換シクロアルキル
からなる群から選択される。]
を有する化合物、またはその立体異性体、互変異性体もしくは薬学的に許容される塩を提供する。
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) ハロゲン、
(5) アミノ、
(6) メチル、および
(7) トリフルオロメチル
からなる群から選択される。
(1) シアノ、
(2) ニトロ、
(3) ハロゲン、
(4) ヒドロキシ、
(5) アミノ、および
(6) トリフルオロメチル
からなる群から選択される。
(1) 水素、
(2) メチル、および
(3) エチル
からなる群から選択される。
本発明の前述の態様および多くの付帯する利点は、それらが添附の図面と共に下記の説明を参照してよりよく理解されるようになるに従い、より容易に認識されるようになるであろう。
図1は、コントロール・ビークルと比較した2種の投与量での代表的な本発明の化合物の腫瘍増殖阻害を示したグラフである。
図2は、コントロール・ビークルと比較した3種の投与量での代表的な本発明の化合物の腫瘍増殖阻害を示したグラフである。
図3は、コントロール・ビークルと比較した2種の投与量での代表的な本発明の化合物の腫瘍増殖阻害を示したグラフである。
図4は、コントロール・ビークルと比較した2種の投与量での代表的な本発明の化合物の腫瘍増殖阻害を示したグラフである。
図5は、コントロール・ビークルと比較した代表的な本発明の化合物の腫瘍増殖阻害を示したグラフである。
ホスファチジルイノシトール−3 キナーゼ(PI3K)は、細胞増殖および生存を制御する種々の成長因子からのシグナルを媒介する。セリン/トレオニン(Ser/ThrまたはS/T)タンパク質キナーゼ(末端にAktがある)は、PI 3−キナーゼの下流の標的と定義されている。このタンパク質キナーゼは、そのプレクストリン相同ドメインと、PI3K生成物であるホスファチジルイノシトール−3,4,5−トリホスフェート(PIP3)およびホスファチジルイノシトール−3,4−ビホスフェート(PIP2)の相互作用によって、細胞膜に動員される。そこで、当該タンパク質キナーゼは、3−ホスホイノシチド依存キナーゼ−1(PDK−1)による、その触媒ドメインのリン酸化によって活性化される。Aktは、さらに、他の候補キナーゼ(PDK−2)による、そのC末端疎水モチーフ中のセリンのリン酸化によって活性化される。Aktの活性化は、さらなるキナーゼを制御するために下流に作用し、当該キナーゼの多くが生存、増殖、代謝および増殖翻訳を制御する細胞のプロセスに関係している。PI3Kはまた、Aktが関与しない平行的経路による、形質転換、細胞増殖、細胞骨格再配列および生存に影響する細胞のプロセスを駆動し得る(Hennessy et al., Nat. Rev. Drug Disc. 4:988-1004 (2005))。2つのこれらの経路は、小さいGTP結合タンパク質Cdc42およびRac1の活性化、ならびに血清およびグルココルチコイド誘導型キナーゼ(SGK)の活性化である。Cdc42およびRac1は、細胞骨格移動および細胞運動性を制御し、過剰発現した際には癌遺伝子として機能し得るものであり、これらはまたRAS経路と関連している。従って、PI3K活性は、3'−ホスファチジルイノシトール脂質を生じ、当該脂質は、多様な下流のシグナル経路を刺激するための節点として作用する。
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR1a、
(13) −CO2R1a、
(14) −CONR1aR1b、
(15) −NR1aR1b、
(16) −NR1aCOR1b、
(17) −NR1aSO2R1b、
(18) −OCOR1a、
(19) −OR1a、
(20) −SR1a、
(21) −SOR1a、
(22) −SO2R1a、および
(23) −SO2NR1aR1b
からなる群から選択され、
ここで、R1aおよびR1bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R4は、
(1) 水素、および
(2) ハロゲン
からなる群から選択される。]
を有するか、またはその立体異性体、互変異性体もしくは薬学的に許容される塩である。
(1) 置換および非置換アルキル、
(2) 置換および非置換アリール、
(3) 置換および非置換ヘテロアリール、
(4) 置換および非置換ヘテロ環、
(5) 置換および非置換シクロアルキル、
(6) −OR1a、および
(7) −NR1aR1b
からなる群から選択され、
ここで、R1aおよびR1bは、
(a) 置換および非置換ヘテロアリール、および
(b) 置換および非置換ヘテロ環
からなる群から独立して選択される。
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) ハロゲン、
(5) アミノ、
(6) メチル、および
(7) トリフルオロメチル
からなる群から選択される。
(1) シアノ、
(2) ニトロ、
(3) ハロゲン、
(4) ヒドロキシ、
(5) アミノ、および
(6) トリフルオロメチル
からなる群から選択される。
一つの態様において、R3はトリフルオロメチルである。一つの態様において、R3はシアノである。
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
Xは、O、S、NH、または直接結合であり;
R2は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R4は、
(1) 水素、および
(2) ハロゲン
からなる群から選択され;
R5は、
(1) 置換および非置換シクロアルキル、
(2) 置換および非置換ヘテロ環、
(3) 置換および非置換アリール、および
(4) 置換および非置換ヘテロアリール
からなる群から選択される。]
を有するか、またはその立体異性体、互変異性体もしくは薬学的に許容される塩である。
一つの態様において、WはNである。より特定的な態様において、R3は=Oである。
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) アミノ、
(5) ハロゲン、および
(6) 置換および非置換C1−3アルキル
からなる群から選択される。
(1) 水素、
(2) シアノ、
(3) −SR3a、
(4) ハロゲン、
(5) ニトロ、
(6) 置換および非置換アルキル、
(7) 置換および非置換アルケニル、
(8) 置換および非置換アルキニル、
(9) −OR3a、
(10) −NR3aR3b、
(11) −COR3a、および
(12) −NR3aCOR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択される。
(1) 置換または非置換モルホリニル、
(2) 置換または非置換テトラヒドロピラニル、および
(3) 置換または非置換テトラヒドロフラニル
からなる群から選択される。
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
(1) 水素、および
(2) ハロゲン
からなる群から選択され;
R6は、
(1) 水素、
(2) 置換および非置換アルキル、および
(3) 置換および非置換シクロアルキル
からなる群から選択される。]
を有するか、またはその立体異性体、互変異性体もしくは薬学的に許容される塩である。
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) ハロゲン、
(5) アミノ、
(6) メチル、および
(7) トリフルオロメチル
からなる群から選択される。
(1) シアノ、
(2) ニトロ、
(3) ハロゲン、
(4) ヒドロキシ、
(5) アミノ、および
(6) トリフルオロメチル
からなる群から選択される。
(1) 水素、
(2) メチル、および
(3) エチル
からなる群から選択される。
本発明の組成物と組み合わせて抗癌剤として使用するためのキナーゼ阻害剤は、上皮増殖因子受容体(EGFR)キナーゼ阻害剤を含み、例えば小分子キナゾリン類、例えばゲフィチニブ(US 5457105、US 5616582 および US 5770599)、ZD-6474 (WO 01/32651)、エルロチニブ(Tarceva(登録商標)、US 5,747,498 および WO 96/30347)、およびラパチニブ(US 6,727,256 および WO 02/02552);血管内皮増殖因子受容体(VEGFR)キナーゼ阻害剤 [SU-11248 (WO 01/60814)、SU 5416 (US 5,883,113 および WO 99/61422)、SU 6668 (US 5,883,113 および WO 99/61422)、CHIR-258 (US 6,605,617 および US 6,774,237)、バタラニブまたはPTK-787 (US 6,258,812)を含む]、VEGF−トラップ(WO 02/57423)、B43−ゲニステイン(WO-09606116)、フェンレチニド(レチノイン酸p−ヒドロキシフェニルアミン)(US 4,323,581)、IM-862 (WO 02/62826)、ベバシズマブ、または Avastin(登録商標)(WO 94/10202)、KRN-951、3−[5−(メチルスルホニルピペラジンメチル)−インドリル]−キノロン、AG-13736 および AG-13925、ピロロ[2,1−f][1,2,4]−トリアジン類、ZK-304709、Veglin(登録商標)、VMDA-3601、EG-004、CEP-701 (US 5,621,100)、Cand5(WO 04/09769);Erb2チロシンキナーゼ阻害剤、例えばペルツズマブ(pertuzumab)(WO 01/00245)、トラスツズマブ、およびリツキシマブ;Aktタンパク質キナーゼ阻害剤、例えばRX-0201;タンパク質キナーゼC(PKC)阻害剤、例えばLY-317615 (WO 95/17182)、およびペリホシン(perifosine)(US 2003171303);Raf/Map/MEK/Rasキナーゼ阻害剤 [ソラフェニブ(BAY 43-9006)、ARQ-350RP、LErafAON、BMS-354825 AMG-548、およびWO 03/82272に開示された他のものを含む];線維芽細胞増殖因子受容体(FGFR)キナーゼ阻害剤;細胞依存性キナーゼ(CDK)阻害剤 [CYC-202またはロスコビチン(WO 97/20842 および WO 99/02162)を含む];血小板由来増殖因子受容体(PGFR)キナーゼ阻害剤、例えばCHIR-258、3G3 mAb、AG-13736、SU-11248、およびSU6668;およびBcr−Ablキナーゼ阻害剤、および融合タンパク質、例えばSTI-571またはGleevec(登録商標)(イマチニブ)を含む。
本発明の組成物と組み合わせて抗癌治療に使用するためのエストロゲン標的薬物は、選択的エストロゲンモジュレーター(SERM)[タモキシフェン、トレミフェン、ラロキシフェンを含む];アロマターゼ阻害剤 [Arimidex(登録商標)またはアナストロゾールを含む];エストロゲン受容体ダウンレギュレーター(ERD)[Faslodex(登録商標)またはフルベストラントを含む]を含む。
本発明の組成物と組み合わせて抗癌治療に使用するためのアンドロゲン標的薬物は、フルタミド、ビカルタミド、フィナステリド、アミノグルテチミド(aminoglutethamide)、ケトコナゾールおよびコルチコステロイドを含む。
本発明の組成物と組み合わせて抗癌剤として使用するための他の阻害剤は、タンパク質ファルネシルトランスフェラーゼ阻害剤[ティピファルニブ(tipifarnib)またはR-115777(US 2003 134846およびWO 97/21701)、BMS-214662、AZD-3409、およびFTI-277を含む];トポイソメラーゼ阻害剤[メルバロン(merbarone)およびジフロモテカン(diflomotecan)(BN-80915)を含む];有糸分裂キネシン紡錘体タンパク質(KSP)阻害剤[SB-743921およびMKI-833を含む];プロテアーゼ・モジュレーター、例えばボルテゾミブまたはVelcade(登録商標)(US 5,780,454)、XL-784;およびシクロオキシゲナーゼ−2(COX−2)阻害剤[非ステロイド性抗炎症剤I(NSAID類)を含む]を含む。
本発明の組成物と組み合わせて抗癌剤として使用するための特定の癌化学療法剤は、アナストロゾール(Arimidex(登録商標))、ビカルタミド(Casodex(登録商標))、ブレオマイシン硫酸塩(Blenoxane(登録商標))、ブスルファン(Myleran(登録商標))、ブスルファン輸液(Busulfex(登録商標))、カペシタビン(Xeloda(登録商標))、N4−ペントキシカルボニル−5−デオキシ−5−フルオロシチジン、カルボプラチン(Paraplatin(登録商標))、カルムスチン(BiCNU(登録商標))、クロラムブシル(Leukeran(登録商標))、シスプラチン(Platinol(登録商標))、クラドリビン(Leustatin(登録商標))、シクロホスファミド(Cytoxan(登録商標)またはNeosar(登録商標))、シタラビン、シトシン アラビノシド(Cytosar-U(登録商標))、シタラビン・リポソーム輸液(DepoCyt(登録商標))、ダカルバジン(DTIC-Dome(登録商標))、ダクチノマイシン(アクチノマイシン D、Cosmegan)、塩酸ダウノルビシン(Cerubidine(登録商標))、クエン酸ダウノルビシン・リポソーム輸液(Daunoxome(登録商標))、デキサメタゾン、ドセタキセル(Taxotere(登録商標)、US 2004 073044)、塩酸ドキソルビシン(Adriamycin(登録商標)、Rubex(登録商標))、エトポシド(Vepesid(登録商標))、リン酸フルダラビン(Fludara(登録商標))、5−フルオロウラシル(Adrucil(登録商標)、Efudex(登録商標))、フルタミド(Eulexin(登録商標))、テザシタビン(tezacitibine)、ゲムシタビン(ジフルオロデオキシシチジン)、ヒドロキシ尿素(Hydrea(登録商標))、イダルビシン(Idamycin(登録商標))、イホスファミド(IFEX(登録商標))、イリノテカン(Camptosar(登録商標))、L−アスパラギナーゼ(ELSPAR(登録商標))、ロイコボリン カルシウム、メルファラン(Alkeran(登録商標))、6−メルカプトプリン(Purinethol(登録商標))、メトトレキサート(Folex(登録商標))、ミトキサントロン(Novantrone(登録商標))、マイロターグ、パクリタキセル(Taxol(登録商標))、フェニックス(イットリウム90/MX−DTPA)、ペントスタチン、ポリフェプロサン20−カルムスチン・インプラント(Gliadel(登録商標))、クエン酸タモキシフェン(Nolvadex(登録商標))、テニポシド(Vumon(登録商標))、6−チオグアニン、チオテパ、チラパザミン(Tirazone(登録商標))、注射用塩酸トポテカン(Hycamptin(登録商標))、ビンブラスチン(Velban(登録商標))、ビンクリスチン(Oncovin(登録商標))、およびビノレルビン(Navelbine(登録商標))を含む。
本発明の組成物と組み合わせて抗癌治療に使用するためのアルキル化剤は、VNP-40101MまたはCloretizine、オキサリプラチン(US 4,169,846、WO 03/24978 および WO 03/04505)、グルフォスファミド、マフォスファミド(mafosfamide)、Etopophos (US 5,041,424)、プレドニムスチン;トレオスルファン;ブスルファン;イロフルベン(Irofluven)(アシルフルベン(acylfulvene));ペンクロメジン(penclomedine);ピラゾロアクリジン (PD-115934);O6−ベンジルグアニン;デシタビン(5−アザ−2−デオキシシチジン);ブロスタリシン(brostallicin);マイトマイシンC(MitoExtra);TLK-286 (Telcyta(登録商標));テモゾロミド;トラベクテジン(US 5,478,932);AP-5280 (シスプラチンの白金酸製剤);ポルフィロマイシン;およびClearazide(メクロレタミン)を含む。
本発明の組成物と組み合わせて抗癌治療に使用するためのキレート化剤は、テトラチオモリブデート(WO 01/60814);RP-697;キメラ T84.66 (cT84.66);ガドホスベセット(gadofosveset)(Vasovist(登録商標));デフェロキサミン;および所望によりエレクトロポレーション(EPT)と組み合わせたブレオマイシンを含む。
本発明の組成物と組み合わせて抗癌治療に使用するための生物学的応答調節物質、例えば免疫モジュレーターは、スタウロスポリンおよびそのマクロサイクリック・アナログ(UCN-01、CEP-701 およびミドスタウリンを含む)(WO 02/30941、WO 97/07081、WO 89/07105、US 5,621,100、WO 93/07153、WO 01/04125、WO 02/30941、WO 93/08809、WO 94/06799、WO 00/27422、WO 96/13506 および WO 88/07045 を参照のこと);スクアラミン(WO 01/79255);DA-9601 (WO 98/04541 および US 6,025,387);アレムツズマブ;インターフェロン(例えばIFN−a、IFN−bなど);インターロイキン類、特にIL−2またはアルデスロイキン、ならびにIL−1、IL−3、IL−4、IL−5、IL−6、IL−7、IL−8、IL−9、IL−10、IL−11、IL−12、およびネイティブのヒトの配列の70%以上のアミノ酸配列を有するその生物学的に活性な変異体;アルトレタミン(Hexalen(登録商標));SU 101 またはレフルノミド(WO 04/06834 および US 6,331,555);イミダゾキノリン類、例えばレジキモド(resiquimod)およびイミキモド(US 4,689,338、5,389,640、5,268,376、4,929,624、5,266,575、5,352,784、5,494,916、5,482,936、5,346,905、5,395,937、5,238,944、および5,525,612);およびSMIP類(ベンゾアゾール類、アントラキノン類、チオセミカルバゾン類、およびトリプタントリン類を含む)(WO 04/87153、WO 04/64759 および WO 04/60308)を含む。
本発明の組成物と組み合わせて使用するための癌ワクチンは、Avicine(登録商標)(Tetrahedron Letters 26, 1974, 2269-70);オレゴボマブ(OvaRex(登録商標));Theratope(登録商標) (STn-KLH);黒色腫ワクチン;GI-4000 シリーズ(GI-4014、GI-4015、およびGI-4016)(Rasタンパク質中の5個の変異体に指向性である);GlioVax-1;MelaVax;Advexin(登録商標)、または INGN-201 (WO 95/12660);Sig/E7/LAMP-1 (HPV-16 E7をコードする);MAGE-3 ワクチンまたはM3TK(WO 94/05304);HER-2VAX;ACTIVE (腫瘍に特異的なT細胞を刺激する);GM-CSF 癌ワクチン;およびリステリア・モノサイトゲネスをベースとするワクチンを含む。
本発明の組成物と組み合わせて抗癌剤として使用するための抗癌剤はまた、アンチセンス組成物、例えば AEG-35156 (GEM-640);AP-12009 および AP-11014 (TGF−β2特異的アンチセンスオリゴヌクレオチド);AVI-4126;AVI-4557;AVI-4472;オブリメルセン(oblimersen)(Genasense(登録商標));JFS2;アプリノカルセン(aprinocarsen)(WO 97/29780);GTI-2040 (R2リボヌクレオチド・リダクターゼmRNAアンチセンスオリゴ) (WO 98/05769);GTI-2501 (WO 98/05769);リポソーム被包c−Rafアンチセンスオリゴデオキシヌクレオチド(LErafAON) (WO 98/43095);および Sirna-027 (RNAiをベースとする治療標的 VEGFR−1 mRNA)を含む。
下記の実施例の記載のように、本発明の化合物を、本明細書に記載している方法、または当技術分野で既知の他の方法を用いて合成した。
融点を、Laboratory Devices Mel Temp 装置(Holliston, MA)で決定した。
本発明は、例示のために本明細書に示した態様に限定されず、上の開示の範囲内の全てのこのような形態を含む。
式Iおよび/またはIIの化合物の製造方法が提供される。該方法は、4−ハロ−2−モルホリノピリミジンを反応性ボロン酸エステル置換基を含む置換ピリジニルまたはピリミジニル基と、パラジウム触媒の存在下で反応させることを含む。一つの態様において、反応性ボロン酸エステル置換基を含む置換ピリジニルまたはピリミジニル基は、ボロン酸エステルに対してパラ位に位置する−NH2基を有する。他の態様において、反応性ボロン酸エステル置換基を含む置換ピリジニルまたはピリミジニル基は、ボロン酸エステルに対してパラ位に位置する−NH2基、およびボロン酸エステルに対してオルト位に位置する他の非水素置換基を有する。特定の態様において、非水素置換基は、−CF3、−CN、−NH2、ハロ、または、置換または非置換C1−3アルキルである。
LCMS (m/z): 140 (ボロン酸のMH+, LC上での生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.58 (s, 2H), 5.74 (s, 2H), 1.32 (s, 12H).
LCMS (m/z): 188.0/190.0 (MH+).
LCMS (m/z): 154 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.58 (s, 2H), 5.56 (s, 1H), 3.02 (d, 3H), 1.32 (s, 12H).
LCMS (m/z): 188.0/190.0 (MH+).
1H NMR (CDCl3): δ 8.22 (s, 1H), 5.02 (bs, 2H), 2.44 (s, 3H).
LCMS (m/z): 154 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.52 (s, 1H), 5.14 (bs, 2H), 2.56 (d, 3H), 1.32 (s, 12H).
LCMS (m/z): 241/243 (MH+).
1H NMR (CDCl3): δ 8.28(s, 1H), 6.77(s, 1H), 4.78(bs, 2H).
LCMS (m/z): 207 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.50 (s, 1H), 6.72 (s, 1H), 4.80 (bs, 2H), 1.34 (s, 12H).
LCMS (m/z): 242/244 (MH+).
1H NMR (CDCl3): δ 8.52 (s, 1H), 5.38 (bs, 2H).
LCMS (m/z): 208 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.72 (s, 1H), 5.50 (bs, 2H), 1.34 (s, 12H).
LCMS (m/z): 206.9/208.9 (MH+).
1H NMR (CDCl3): δ 8.18 (s, 1H), 6.62 (s, 1H), 4.52 (bs, 2H).
LCMS (m/z): 173 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.36 (s, 1H), 6.46 (s, 1H), 4.70 (bs, 2H), 1.38 (s, 12H).
LCMS (m/z): 189/191 (MH+).
1H NMR (DMSO-d6): δ 7.78 (s, 1H), 6.58 (bs, 2H), 6.08 (bs, 2H).
LCMS (m/z): 155 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3+CD3OD): δ 8.16 (s, 1H), 1.34 (s, 12H).
LCMS (m/z): 126 (MH+).
1H NMR (CDCl3): δ 8.00 (d, J = 5.7 Hz, 1H), 6.08 (d, J = 5.7 Hz, 1H), 4.98 (bs, 2H), 3.84 (s, 3H).
LCMS (m/z): 204/206 (MH+).
1H NMR (CDCl3): δ 8.10 (s, 1H), 4.93 (bs, 2H), 3.96 (s, 3H).
LCMS (m/z): 170 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導).
1H NMR (CDCl3): δ 8.42 (s, 1H), 5.22 (bs, 2H), 3.90 (s, 3H), 1.34 (s, 12H).
LCMS (m/z): 190.9/192.9 (MH+);
1H NMR (CDCl3): δ 7.59 (t, J = 8.7 Hz, 1H), 6.25 (dd, J = 8.1, 1.2 Hz, 1H), 4.58 (bs, 1H).
LCMS (m/z): 157 (ボロン酸のMH+, LC上での in situ 生成物加水分解から誘導)
1H NMR (CDCl3): δ 7.86 (t, J = 8.4 Hz, 1H), 6.29 (dd, J = 8.1, 2.7 Hz, 1H), 4.70 (bs, 1H), 1.32 (s, 12H).
LC/MS (m/z): 190.9/192.9 (MH+), Rt 1.02分.
LC/MS (m/z): 157.0 (ボロン酸のMH+, LC上での生成物加水分解により形成), Rt 0.34分.
LC/MS (m/z): 197.9 (MH+), Rt 2.92分.
LC/MS (m/z): 164.0 (ボロン酸のMH+, LC上での生成物加水分解により形成), Rt 0.37分.
3−フルオロ−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン−2−アミンの合成
LC/MS (m/z): 153.1 (MH+), Rt 0.5分.
LC/MS (m/z): 113.0 (MH+), Rt 0.41分.
LC/MS (m/z): 191.0/193.0 (MH+), Rt 1.18分.
LC/MS (m/z): 157.0 (MH+), Rt 0.36分.
LC/MS (m/z): 153.0 (MH+), Rt 1.13分.
LC/MS (m/z): 113.0 (MH+), Rt 0.40分.
LC/MS (m/z): 190.9/192.9 (MH+), Rt 1.02分.
LC/MS (m/z): 157.0 (MH+), Rt 0.34分.
LC/MS (m/z): 212.2 (MH+), Rt 1.28分.
LC/MS (m/z): 182.1 (MH+), Rt 0.36分.
LC/MS (m/z): 238.0 (MH+), Rt 1.59分.
LC/MS (m/z): 208.2 (MH+), Rt 0.34分.
LC/MS (m/z): 324.3 (MH+), Rt 3.33分
LC/MS (m/z): 224.3 (MH+), Rt 1.64分
LC/MS (m/z): 266.3 (MH+), Rt 1.85分.
LC/MS (m/z): 236.3 (MH+), Rt 0.38分.
LC/MS (m/z): 221.1 (MH+), Rt 2.54分.
LC/MS (m/z): 252.9 (MH+), Rt 1.82分.
LC/MS (m/z): 223.0 (MH+), Rt 1.10分.
LC/MS (m/z): 175.1 (MH+), Rt 1.54分.
LC/MS (m/z): 190.9 (MH+), Rt 1.97分.
LC/MS (m/z): 288.1 (MH+), Rt 1.80分.
LC/MS (m/z): 258.1 (MH+), Rt 0.33分.
1N HCl(300ml)中の3−メトキシ−フェニルアミン塩酸塩(4.6g, 28.9mmol)に、150mlの水中の2−ニトロ−マロンアルデヒド(2.7g, 19.3mmol)の溶液を加えた。30分後、沈殿物を濾過し、0.1N HClで濯いだ。ブフナー漏斗中で18時間空気乾燥し、3.36g(78%)の明黄色/緑色の粉末を得た。
LC/MS (m/z): 245.1 (MH+ +Na), Rt 2.21分.
30mlの酢酸中の3−メトキシ−フェニルアミン塩酸塩(4.7g, 29.7mmol)に、3−(3−メトキシ−フェニルアミノ)−2−ニトロ−プロペナール(3.3g, 14.9mmol)を加えた。該反応混合物を還流し、チオフェノール(0.3ml, 2.98mmol)を加えた。22時間後、該反応混合物を室温まで冷却し、溶媒を真空で除去した。70mlのEtOAcを添加し、濾過し、固体の副生成物、7−メトキシ−3−ニトロ−キノリン、および濾液を得た。該濾液は不純な5−メトキシ−3−ニトロ−キノリンを含む。濾液をシリカカラムに負荷し、ヘキサン中5%から25% EtOAcで、85ml/分で、30分間で溶出した。生成物が多いフラクションを濃縮し、5−および7−メトキシ置換3−ニトロキノリンの混合物として次の段階に用いた。
LC/MS (m/z): 205.1 (MH+), Rt 2.26分.
LC/MS (望ましい異性体) (m/z): 175.0 (MH+), Rt 1.54分;
LC/MS (望ましくない異性体) (m/z): 175.0 (MH+), Rt 1.53分.
ナトリウム チオメトキシド(140mg, 1.98mmol)を、NMP(0.65ml)中の2−クロロピリジン−4−アミン(150mg, 1.17mmol)の溶液に、圧力容器中で加えた。該容器を密封し、マイクロ波で、200℃で800秒間加熱した。シリカのフラッシュクロマトグラフィーによって精製し、8% MeOH/DCMで溶出し、2−(メチルチオ)ピリジン−4−アミンを得た(435mg, 収率50%)。
LC/MS (m/z): 140.9 (MH+), Rt 0.59分.
LC/MS (m/z): 173.0 (MH+), Rt 0.34分.
LC/MS (m/z): 198.1 (MH+), Rt 0.51分.
LC/MS (m/z): 233.9 (MH+), Rt 2.95分.
LC/MS (m/z): 248.1 (MH+).
LC/MS (m/z): 262.1 (MH+), Rt 3.59分.
LC/MS (m/z): 216.0 (MH+), Rt 0.63分.
LC/MS (m/z): 251.9 (MH+), Rt 3.22分.
LC/MS (m/z): 316.8/318.7 (MH+), Rt 2.78分.
4−(1−イソプロピルピペリジン−4−イルオキシ)アニリンの合成
4−(2−メトキシ−4−ニトロフェノキシ)ピペリジン−1−カルボン酸t−ブチルの合成
LC/MS (m/z): 353.2 (MH+), Rt 3.23分
LC/MS (m/z): 253.2(MH+), Rt 1.81分.
LC/MS (m/z): 295.2 (MH+), Rt 1.96分.
LC/MS (m/z): 265.2 (MH+), Rt 0.33分.
4−(1−イソプロピルピペリジン−4−イルオキシ)−3−メトキシアニリンの合成;
4−(2−メトキシ−4−ニトロフェノキシ)ピペリジン−1−カルボン酸tert−ブチルの合成
LC/MS (m/z): 353.2 (MH+), Rt 3.23分
LC/MS (m/z): 253.2(MH+), Rt 1.81分.
LC/MS (m/z): 295.2 (MH+), Rt 1.96分.
LC/MS (m/z): 265.2 (MH+), Rt 0.33分.
N−(6−クロロ−2−モルホリノピリミジン−4−イル)−4−フェニルチアゾール−2−アミンの合成
LC/MS (m/z): 374 および 376 (MH+), Rt 3.40分.
N−(6−(2−アミノピリミジン−5−イル)−2−モルホリノピリミジン−4−イル)キノリン−3−アミンの製造
LC/MS (m/z): 293.1 (MH+), Rt 1.92分
LC/MS (m/z): 401.4 (MH+).
N−(6−(6−アミノピリジン−3−イル)−2−モルホリノピリミジン−4−イル)キノリン−3−アミンの製造
5−(6−クロロ−2−モルホリン−4−イル−ピリミジン−4−イル)ピリジン−2−イルアミン
LC/MS (m/z): 292.1 (MH+), Rt 2.06分.
LC/MS (m/z): 380.1 (MH+), Rt 1.82分.
5−(6−[2−(メチルスルホンアミド)ピリジン]−3−イル)−2−モルホリノ−ピリミジン−4−イル)ピリジン−2−アミンの製造
5−[6−(2−フルオロ−ピリジン−3−イル)−2−モルホリン−4−イル−ピリミジン−4−イル]−ピリジン−2−イルアミン
LC/MS (m/z): 353.3 (MH+), 1.84分.
LC/MS (m/z): 428.3 (MH+), Rt 1.80分.
N−(6−(6−アミノ−4−フルオロピリジン−3−イル)−2−モルホリノピリミジン−4−イル)キノリン−3−アミンの製造
N−(6−ブロモ−2−モルホリノピリミジン−4−イル)キノリン−3−アミン
LC/MS (m/z): 386.1 (MH+).
LC/MS (m/z): 418.0 (MH+), Rt 2.31分.
2−アミノ−5−[2−モルホリン−4−イル−6−(キノリン−3−イルアミノ)−ピリミジン−4−イル]−イソニコチノニトリルの製造
LC/MS (m/z): 425.0 (MH+), Rt 2.03分.
テトラヒドロ−2H−ピラン−4−アミン(90mg, 0.9mmol)を、ACN(0.8ml)中のホルムアルデヒド(37%水溶液, 0.091ml, 1.13mmol)および酢酸(0.162ml)の溶液に加えた。5分間撹拌した後、Na(CN)BH3(60mg, 1.13mmol)を室温で一度に加えた。1時間後、過剰のCs2CO3を、該反応物に、アルカリ性になるまで加えた。15分間撹拌した後、該反応物を濾過して固体を除き、溶媒を減圧下で蒸発させた。粗生成物N−メチルテトラヒドロ−2H−ピラン−4−アミンを、次の置換に、さらに精製することなく用いた。
LC/MS (m/z): 116.1 (MH+), Rt 0.34分.
粗製のN−メチルテトラヒドロ−2H−ピラン−4−アミン(104mg, 0.9mmol)を、NMP(0.8ml)に溶解した。該溶液に、Cs2CO3(366mg, 1.13mmol)および4−(4,6−ジクロロピリミジン−2−イル)モルホリン(方法22で製造)(80mg, 0.34mmol)を、室温で加えた。該反応混合物を95℃に加熱した。90分後、該反応混合物を室温まで冷却し、濾過し、逆相分取HPLCによって精製し、24mg(23%)の純粋な6−クロロ−N−メチル−2−モルホリノ−N−(テトラヒドロ−2H−ピラン−4−イル)ピリミジン−4−アミンを得た。
LC/MS (m/z): 313.2 (MH+), Rt 2.61分.
THF(0.8ml)および水性Na2CO3(2M, 0.27ml)中の5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリミジン−2−アミン(42mg, 0.19mmol)、6−クロロ−N−メチル−2−モルホリノ−N−(テトラヒドロ−2H−ピラン−4−イル)ピリミジン−4−アミン(12mg, 0.038mmol)のアルゴンをフラッシュした混合物に、圧力容器中で、ジクロロ[1,1'−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II) ジクロロメタン付加物(8mg, 0.0095mmol)を一度に加えた。該圧力容器を密封し、該混合物を、マイクロ波中、120℃で600秒間加熱した。粗製の混合物を濾過し、減圧下で濃縮し、逆相分取HPLCによって精製し、N6−メチル−2−モルホリノ−N6−(テトラヒドロ−2H−ピラン−4−イル)−4,5'−ビピリミジン−2',6−ジアミンを得た(4.6mg, 32%)。
LC/MS (m/z): 372.2 (MH+), Rt 1.76分.
N−(6−(2−アミノピリミジン−5−イル)−2−モルホリノピリミジン−4−イル)−5−メトキシキノリン−3−アミンの製造
LC/MS (m/z): 431.2 (MH+), Rt 2.03分.
5−(2−モルホリノ−6−(ピリジン−3−イルオキシ)ピリミジン−4−イル)ピリミジン−2−アミンの製造
LC/MS (m/z): 352.1 (MH+), Rt 1.83分.
6−(2−アミノピリミジン−5−イル)−2−モルホリノ−N−(6−(ピペラジン−1−イル)ピリジン−3−イル)ピリミジン−4−アミンの製造
LC/MS (m/z): 435.2 (MH+), Rt 1.52分.
4−(トリフルオロメチル)−5−(2,6−ジモルホリノピリミジン−4−イル)ピリジン−2−アミンの製造
LCMS (m/z): 285.0 (MH+),
1H NMR (CDCl3): δ 5.86 (s, 1H), 3.71-3.76(m, 12H), 3.52-3.56(m, 4H).
LCMS (m/z): 411.3 (MH+);
1H NMR (CDCl3): δ 8.27 (s, 1H), 6.78 (s, 1H), 5.97 (s, 1H), 4.77 (bs, 2H), 3.59-3.80(m, 12H), 3.58-3.61(m, 4H).
N−(6−(1−イソプロピルピペリジン−4−イルオキシ)ピリジン−3−イル)−6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−アミンの製造
LC/MS (m/z): 559.2 (MH+), Rt 1.92分.
1H NMR (DMSO): δ 10.27 (1H, bs, NH); 8.41 (1H, bs); 8.17 (1H, s); 7.98 and 7.94 (1H, 2 b doublets, J= 9.0 Hz, 2種の配座異性体); 6.97 (1H, s); 6.90 and 6.84 (1H, 2 doublets, J= 9.0 Hz, 2種の配座異性体); 6.23 (1H, bs); 5.25 and 5.15 (1H, 2 multiplets, 2種の配座異性体); 3.66 (8H, bs); 3.44 (1H, m); 3.35 (2H, m); 3.10 (2H, m); 2.22 (2H, m); 2.03 (2H, m); 1.27 (6H, 配座異性体のためにダブレットが重なっている, 見かけ上triplet, J= 5.7 Hz).
N−(5−((ジエチルアミノ)メチル)チアゾール−2−イル)−6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−アミンの製造
5−((ジエチルアミノ)メチル)チアゾール−2−アミン
LC/MS (m/z): 186.2 (MH+), Rt 0.33分.
LC/MS (m/z): 509.2 (MH+), Rt 1.98分.
1H NMR (DMSO): δ 11.0 (2H, bs, NH2), 8.17 (1H, s); 7.63 (1H, s); 7.08 (1H, bs), 6.40 (1H, s); 4.48 (2H, bd, J= 4.2 Hz); 3.80 (4H, m); 3.68 (4H, m); 3.03 (4H, bq, J= 6.9 Hz ); 1.30 (6H, t, J= 6.9 Hz).
6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−N−(4−(2−(ジエチルアミノ)エチル)チアゾール−2−イル)−2−モルホリノピリミジン−4−アミンの合成
2−(2−アミノチアゾール−4−イル)−N,N−ジエチルアセトアミド
LC/MS (m/z): 214.0 (MH+), Rt 1.13分.
LC/MS (m/z): 200.1, (MH+), Rt 0.34分.
LC/MS (m/z): 523.1 (MH+), Rt 2.11分.
1H-NMR (DMSO): δ 8.15 (1H, s); 7.08 (1H, s); 6.96 (1H, s); 6.38 (1H, s); 3.78 (4H, m); 3.65 (4H, m); 3.31 (2H, m); 3.13 (4H, q, J = 7.2 Hz); 3.02 (2H, m); 1.20 (6H, t, J = 7.2 Hz).
N 6 −(2−メトキシエチル)−2−モルホリノ−4,5'−ビピリミジン−2',6−ジアミンの製造
LC/MS (m/z): 332.2 (MH+), Rt 1.44分.
2−モルホリノ−6−(2−フェニルモルホリノ)−4,5'−ビピリミジン−2'−アミンの製造
LC/MS (m/z): 420.1 (MH+), Rt 2.20分.
N 6 −tert−ブチル−2−モルホリノ−4,5'−ビピリミジン−2',6−ジアミンの製造
LC/MS (m/z): 330.2 (MH+), Rt 1.96分.
1−(2−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−6−モルホリノ−ピリミジン−4−イル)ピペリジン−2−オンの製造
5−(2−クロロ−6−モルホリノピリミジン−4−イルアミノ)ペンタン酸
LC/MS (m/z): 315.0 (MH+), Rf 1.79分.
LC/MS (m/z): 297.0 (MH+), Rt 2.74分.
LC/MS (m/z): 423.0 (MH+), Rt 2.25分.
1−(6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−イル)−3−フェニルイミダゾリジン−2−オンの製造
N1−(6−クロロ−2−モルホリノピリミジン−4−イル)−N2−フェニルエタン−1,2−ジアミン
LC/MS (m/z): 334.0 (MH+), Rt 1.94分.
LC/MS (m/z): 360.1 (MH+), Rt 3.41分.
LC/MS (m/z): 448.1 (MH+), Rt 3.29分.
1−(4−(6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−イルオキシ)ピペリジン−1−イル)エタノンの製造
段階1:2−モルホリノ−4,6−ジクロロピリミジンのアルコキシル化
LCMS (m/z): 399.1 (MH+).
1H NMR (CDCl3): δ 6.00 (s, 1H), 5.18 (m, 1H), 3.74 (s, 8H), 3.64-3.74 (m, 2H), 3.28-3.38 (m, 2H), 1.86-1.96 (m, 2H), 1.68-1.78 (m, 2H), 1.44 (s, 9H).
LCMS (m/z): 525.2 (MH+).
LCMS (m/z): 425.1 (MH+).
LCMS (m/z): 467.1 (MH+).
5−(6−((S)−ピペリジン−3−イルオキシ)−2−モルホリノピリミジン−4−イル)−4−(トリフルオロメチル)ピリジン−2−アミンの製造
LCMS (m/z): 399.1(MH+).
該Boc保護中間体を、実施例19の段階2で示されたスズキ反応によって製造し、SiO2のクロマトグラフィーによって精製した(30〜60% EtOAc/ヘキサン;78%)。
LCMS (m/z): 526.0 (MH+).
実施例19の段階3で示したN−Boc保護基の切断によって表題化合物を製造した。
LCMS (m/z): 425.1 (MH+).
5−(6−((R)−ピペリジン−3−イルオキシ)−2−モルホリノピリミジン−4−イル)−4−(トリフルオロメチル)ピリジン−2−アミンの製造
LCMS (m/z): 399.1 (MH+).
該Boc保護中間体を、実施例19の段階2で示したスズキ反応によって製造し、シリカゲルのクロマトグラフィーによって精製した(30〜60% EtOAc/ヘキサン, 54%)。
LCMS (m/z): 526.0 (MH+).
実施例19の段階3で示したN−Boc保護基の切断によって表題化合物を製造した。
LCMS (m/z): 425.1 (MH+).
1−((R)−3−(6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−イルオキシ)ピロリジン−1−イル)エタノンの製造
LCMS (m/z): 385.0 (MH+).
LCMS (m/z): 511.0 (MH+).
実施例19の段階3で示した通りに、N−Boc保護基の切断を行った。
LCMS (m/z): 411.0 (MH+).
表題化合物を実施例19の段階4で製造した。
LCMS (m/z): 453.1 (MH+), Rt 2.18.
1−((S)−3−(6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−イルオキシ)ピロリジン−1−イル)エタノンの製造
LCMS (m/z): 385.0 (MH+).
該Boc保護中間体を、実施例19の段階2で示したスズキ反応によって製造し、逆相HPLCによって精製し、塩基性にした上でEtOAcで抽出した後に、遊離塩基として単離した(72%)。
LCMS (m/z): 511.0 (MH+).
実施例19の段階3で示した通りに、N−Boc保護基を切断した。
LCMS (m/z): 411.0 (MH+).
表題化合物を実施例19の段階4で製造した。
LCMS (m/z): 453.1 (MH+), Rt 2.18.
4−(トリフルオロメチル)−5−(2−モルホリノ−6−(テトラヒドロ−2H−ピラン−4−イルオキシ)ピリミジン−4−イル)ピリジン−2−アミンの製造
LCMS (m/z): 300.1 (MH+).
表題化合物を、実施例19の段階2で示したスズキ反応によって製造した。
LC/MS (m/z): 426.1 (MH+), Rt 2.26分.
5−(6−((R)−テトラヒドロフラン−3−イルオキシ)−2−モルホリノピリミジン−4−イル)−4−(トリフルオロメチル)ピリジン−2−アミンの製造
LCMS (m/z): 286.1 (MH+).
表題化合物を、実施例19の段階2で示したスズキ反応によって製造した。
LC/MS (m/z): 412.1 (MH+).
5−(6−((S)−テトラヒドロフラン−3−イルオキシ)−2−モルホリノピリミジン−4−イル)−4−(トリフルオロメチル)ピリジン−2−アミンの製造
LCMS (m/z): 286.1 (MH+).
表題化合物を、実施例19の段階2で示したスズキ反応によって製造した。
LC/MS (m/z): 412.1 (MH+).
4−(トリフルオロメチル)−5−(2−モルホリノ−6−(ピペリジン−4−イルオキシ)ピリミジン−4−イル)ピリミジン−2−アミンの製造
LCMS (m/z): 526.0 (MH+).
実施例19の段階3で示したN−Boc保護基の切断によって表題化合物を製造した。
LCMS (m/z): 426.0 (MH+).
5−(2−モルホリノ−6−(ピペリジン−4−イルオキシ)ピリミジン−4−イル)ピリミジン−2,4−ジアミンの製造
LCMS (m/z): 473.1 (MH+).
実施例19の段階3で示したN−Boc保護基の切断によって表題化合物を製造した。
LCMS (m/z): 373.0 (MH+).
1−((R)−3−(6−(2,4−ジアミノピリミジン−5−イル)−2−モルホリノピリミジン−4−イルオキシ)ピペリジン−1−イル)エタノンの製造
LCMS (m/z): 473.1 (MH+).
実施例19の段階3で示した通りに、N−Boc保護基を切断した。
LCMS (m/z): 373.0 (MH+).
表題化合物を、実施例19の段階4で示した通りに合成した。
LCMS (m/z): 460.1 (MH+), Rt 2.51.
2−アミノ−5−(2−モルホリノ−6−(N−アシル−ピペリジン−4−イルオキシ)ピリミジン−4−イル)ピリミジン−4(3H)−オンの製造
LCMS (m/z): 374.1 (MH+).
表題化合物を、実施例19の段階4で示した第2級アミノ基のアシル化によって製造した。
LCMS (m/z): 416.0 (MH+), Rt 1.67.
2−アミノ−5−(2−モルホリノ−6−(N−メトキシカルボニル−ピペリジン−4−イルオキシ)ピリミジン−4−イル)ピリミジン−4(3H)−オンの製造
LCMS (m/z): 432.0 (MH+), Rt 2.05.
6−[6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル]−N−[4−(1−イソプロピルピペリジン−4−イルオキシ)フェニル]−2−モルホリノピリミジン−4−アミンの製造
LC/MS (m/z): 558.3(MH+), Rt 1.90分.
6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−N−(4−(1−イソプロピルピペリジン−4−イルオキシ)−3−メトキシフェニル)−2−モルホリノピリミジン−4−アミンの製造
LC/MS (m/z): 588.3(MH+), Rt 1.92分.
N−(6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−2−モルホリノピリミジン−4−イル)−4−フェニルチアゾール−2−アミンの合成
LC/MS (m/z): 500 (MH+), Rt 2.46分.
N−(6−(6−アミノ−4−(トリフルオロメチル)ピリジン−3−イル)−5−メチル−2−モルホリノピリミジン−4−イル)−4−フェニルチアゾール−2−アミンの製造
LC/MS (m/z): 514 (MH+), Rt 2.62分.
リン酸化アッセイ
アッセイ1: 均一溶液相アッセイ
試験すべき化合物をDMSOに溶解し、384ウェル・フラッシュプレートに、1.25μl/ウェルで直接分配する。反応を開始させるために、20μlの6nM PI3キナーゼをそれぞれのウェルに加え、続いて微量の放射能標識ATPおよび900nM 1α−ホスファチジルイノシトール(PI)を含む20μlの400nM ATPを加える。該プレートを手短に遠心分離して気泡を除く。反応を15分間行い、次いで20μlの100mM EDTAを添加することによって停止させる。停止させた反応物を室温で終夜インキュベートし、液体の基質をフラッシュプレートの表面に疎水相互作用によって結合させる。次いでウェル中の液体を洗い、標識された基質をシンチレーション計数で検出する。
この方法は、脂質基質(1−α−ホスファチジルイノシトール(PIP))を始めにコーティング緩衝液に溶解させ、フラッシュプレート上で室温で終夜インキュベートし、脂質基質を疎水相互作用によってフラッシュプレート表面に結合させる以外、アッセイ1と類似している。次いで、非結合基質を洗浄して除く。アッセイの日に、20μlの6nM PI3キナーゼをそれぞれのウェルに加え、続いて微量の放射能標識ATPを含む20μlの400nM ATPを加える。化合物を酵素およびATPと共に、脂質で被覆されたプレートに加える。該プレートを手短に遠心分離して気泡を除く。反応を2から3時間行う。20μlの100mM EDTAを添加することによって、またはすぐにプレートを洗浄することによって、反応を停止させる。リン酸化された脂質基質をシンチレーション計数によって検出する。
試験すべき化合物をDMSOに溶解し、黒色384ウェルプレートに、1.25μl/ウェルで直接分配する。反応を開始させるために、25μlの10nM PI3キナーゼおよび5μg/mLの1α−ホスファチジルイノシトール(PI)をそれぞれのウェルに加え、続いて25μlの2μM ATPを加える。約50%のATPが欠乏するまで反応を行い、次いで25μlの KinaseGlo 溶液(Promegaより購入)を添加することによって停止させる。停止させた反応物を5分間インキュベートし、次いで残ったATPをルミネセンスにより検出する。
PI3K経路をモニターするためのpSer473 Akt アッセイ
この方法において、代表的な本発明の阻害化合物での処置後のPI3K介在pSer473−Akt状態を測定するためのアッセイが記載されている。
卵巣癌異種移植片モデルにおける薬理学的標的調節および力価試験
George Coukos (Fox Chase Cancer Center, University of Pennsylvania, Philadelphia, PA)から得たA2780卵巣癌細胞を、10% 熱不活性化ウシ胎児血清と1% グルタミンを加えたDMEM(Invitrogen, Inc.)中に維持した。Dr. Coukosらによって推奨される通りに細胞を増殖させた。メスのnu/nuマウス(8〜12週齢, 20〜25g, Charles River)を全ての in vivo 薬理試験に用いた。マウスを収容し、ヒトの処置および実験動物の世話についての州連邦ガイドラインに従って維持し、食物と水を適宜与えた。癌細胞を対数増殖期中期の培養物から、トリプシン−EDTA(Invitrogen, Inc.)を用いて収穫した。5,000,000細胞を、それぞれのマウスの右脇腹に皮下注射した。腫瘍の大きさがPK/PD試験で300〜400mm3、力価試験で200〜300mm3に至ったとき、化合物処置を開始した。全ての化合物処置を経口投与で行った。腫瘍体積を、StudyDirector software を用いることによって決定した。
本発明の化合物が細胞増殖を阻害し得る能力を、Cell Titer Glo (Promega Corporationより市販のアッセイ)を用いることによって決定した。A2780 卵巣癌細胞を、TC処理96ウェルプレートに、1,000個/ウェルの密度で、DMEM、10% FBS、1% ピルビン酸ナトリウム、および1% ペニシリン ストレプトマイシン中、本化合物の添加の最大2時間前に播種した。試験化合物のそれぞれの濃度で、2μl(500×)アリコートの化合物、または100% DMSOを、500μlの培養培地で、2×濃度に希釈し、次いで細胞で1×に希釈した。細胞を、72時間、37℃、5% CO2でインキュベートした。72時間インキュベートした後、Cell Titer Glo 試薬を加えて、本化合物の曝露後の生存細胞の数を決定し、EC50値を計算した。該アッセイを製造者の指示書(Promega Corporation, Madison, WI. USA)に従って行った。それぞれの実験条件をデュプリケートで行った。結果を表1に示した。
Claims (54)
- 式I:
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、
(6) スルホンアミド
からなる群から選択され;
R1は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR1a、
(13) −CO2R1a、
(14) −CONR1aR1b、
(15) −NR1aR1b、
(16) −NR1aCOR1b、
(17) −NR1aSO2R1b、
(18) −OCOR1a、
(19) −OR1a、
(20) −SR1a、
(21) −SOR1a、
(22) −SO2R1a、および
(23) −SO2NR1aR1b
からなる群から選択され、
ここで、R1aおよびR1bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R2は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
R3は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R4は、
(1) 水素、および
(2) ハロゲン
からなる群から選択される。]
の化合物、またはその立体異性体、互変異性体もしくは薬学的に許容される塩。 - WがNである、請求項1に記載の化合物。
- WがCHである、請求項1に記載の化合物。
- R1が、
(1) 置換および非置換アルキル、
(2) 置換および非置換アリール、
(3) 置換および非置換ヘテロアリール、
(4) 置換および非置換ヘテロ環、
(5) 置換および非置換シクロアルキル、
(6) −OR1a、および
(7) −NR1aR1b
からなる群から選択され、
ここで、R1aおよびR1bが、
(a) 置換および非置換ヘテロアリール、および
(b) 置換および非置換ヘテロ環
からなる群から独立して選択される、請求項1に記載の化合物。 - R1が、置換または非置換ヘテロ環、または、置換または非置換−O−ヘテロ環である、請求項4に記載の化合物。
- R1が、置換または非置換モルホリニルである、請求項4に記載の化合物。
- R1が非置換N結合モルホリニルである、請求項6に記載の化合物。
- R1が、置換または非置換テトラヒドロピラン、または、置換または非置換テトラヒドロピラニルオキシである、請求項4に記載の化合物。
- R1が、非置換4−テトラヒドロピラニルオキシである、請求項8に記載の化合物。
- R1が、置換または非置換テトラヒドロフラン、または、置換または非置換テトラヒドロフラニルオキシである、請求項4に記載の化合物。
- R1が、非置換3−テトラヒドロフラニルオキシである、請求項10に記載の化合物。
- R2が、
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) ハロゲン、
(5) アミノ、
(6) メチル、および
(7) トリフルオロメチル
からなる群から選択される、請求項1に記載の化合物。 - R2が、水素またはハロゲンである、請求項1に記載の化合物。
- R2が水素である、請求項1に記載の化合物。
- R3が、
(1) シアノ、
(2) ニトロ、
(3) ハロゲン、
(4) ヒドロキシ、
(5) アミノ、および
(6) トリフルオロメチル
からなる群から選択される、請求項1に記載の化合物。 - R3が、トリフルオロメチルである、請求項1に記載の化合物。
- R3が、シアノである、請求項1に記載の化合物。
- R3が、=Oである、請求項2に記載の化合物。
- 式II:
Wは、CRwまたはNであり、
ここで、Rwは、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
Xは、O、S、NH、または直接結合であり;
R2は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
R3は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R4は、
(1) 水素、および
(2) ハロゲン
からなる群から選択され;
R5は、
(1) 置換および非置換シクロアルキル、
(2) 置換および非置換ヘテロ環、
(3) 置換および非置換アリール、および
(4) 置換および非置換ヘテロアリール
からなる群から選択される。]
を有する化合物またはその立体異性体、互変異性体もしくは薬学的に許容される塩。 - R2が、
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) アミノ、
(5) ハロゲン、および
(6) 置換および非置換C1−3アルキル
からなる群から選択される、請求項19に記載の化合物。 - R3が、
(1) 水素、
(2) シアノ、
(3) チオ、
(4) ハロゲン、
(5) ニトロ、
(6) 置換および非置換アルキル、
(7) 置換および非置換アルケニル、
(8) 置換および非置換アルキニル、
(9) −OR3a、
(10) −NR3aR3b、
(11) −COR3a、および
(12) −NR3aCOR3b
からなる群から選択され、
ここで、R3aおよびR3bが、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択される、請求項19に記載の化合物。 - R3がトリフルオロメチルである、請求項19に記載の化合物。
- WがCHである、請求項19に記載の化合物。
- R2がHである、請求項19に記載の化合物。
- R5が、
(1) 置換または非置換モルホリニル、
(2) 置換または非置換テトラヒドロピラニル、および
(3) 置換または非置換テトラヒドロフラニル
からなる群から選択される、請求項19に記載の化合物。 - Xが直接結合であり、R5が非置換N結合モルホリニルである、請求項19に記載の化合物。
- XがOであり、R5が4−テトラヒドロピラニルである、請求項19に記載の化合物。
- XがOであり、R5が3−テトラヒドロフラニルである、請求項19に記載の化合物。
- WがNである、請求項19に記載の化合物。
- R3が=Oである、請求項19に記載の化合物。
- 式III:
Wは、CRwまたはNであり、
ここで、Rwが、
(1) 水素、
(2) シアノ、
(3) ハロゲン、
(4) メチル、
(5) トリフルオロメチル、および
(6) スルホンアミド
からなる群から選択され;
R2は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) ヒドロキシ、
(6) アミノ、
(7) 置換および非置換アルキル、
(8) −COR2a、および
(9) −NR2aCOR2b
からなる群から選択され、
ここで、R2aおよびR2bは、
(a) 水素、および
(b) 置換または非置換アルキル
からなる群から独立して選択され;
R3は、
(1) 水素、
(2) シアノ、
(3) ニトロ、
(4) ハロゲン、
(5) 置換および非置換アルキル、
(6) 置換および非置換アルケニル、
(7) 置換および非置換アルキニル、
(8) 置換および非置換アリール、
(9) 置換および非置換ヘテロアリール、
(10) 置換および非置換ヘテロ環、
(11) 置換および非置換シクロアルキル、
(12) −COR3a、
(13) −NR3aR3b、
(14) −NR3aCOR3b、
(15) −NR3aSO2R3b、
(16) −OR3a、
(17) −SR3a、
(18) −SOR3a、
(19) −SO2R3a、および
(20) −SO2NR3aR3b
からなる群から選択され、
ここで、R3aおよびR3bは、
(a) 水素、
(b) 置換または非置換アルキル、
(c) 置換および非置換アリール、
(d) 置換および非置換ヘテロアリール、
(e) 置換および非置換ヘテロ環、および
(f) 置換および非置換シクロアルキル
からなる群から独立して選択され;
R4は、
(1) 水素、および
(2) ハロゲン
からなる群から選択され;
R6は、
(1) 水素、
(2) 置換および非置換アルキル、および
(3) 置換および非置換シクロアルキル
からなる群から選択される。]
を有する化合物、またはその立体異性体、互変異性体もしくは薬学的に許容される塩。 - R2が、
(1) 水素、
(2) シアノ、
(3) ヒドロキシ、
(4) ハロゲン、
(5) アミノ、
(6) メチル、および
(7) トリフルオロメチル
からなる群から選択される、請求項31に記載の化合物。 - R3が、
(1) シアノ、
(2) ニトロ、
(3) ハロゲン、
(4) ヒドロキシ、
(5) アミノ、および
(6) トリフルオロメチル
からなる群から選択される、請求項31に記載の化合物。 - R6が、
(1) 水素、
(2) メチル、および
(3) エチル
からなる群から選択される、請求項31に記載の化合物。 - ヒトまたは動物において、Aktのリン酸化を阻害するための、有効量の請求項1〜35の何れか1項に記載の化合物を含む、医薬組成物。
- ヒトまたは動物において、PI3−K活性を阻害するための、薬学的に許容される担体および有効量の請求項1〜35の何れか1項に記載の化合物を含む、医薬組成物。
- ヒトまたは動物において、PI3−Kα活性を阻害するための、請求項37に記載の医薬組成物。
- さらに、少なくとも1種のさらなる癌処置用薬物を含む、請求項37に記載の医薬組成物。
- 少なくとも1種のさらなる癌処置用薬物が、バタラニブ、イマチニブ、ゲフィチニブ、エルロチニブ、ペルツズマブ、トラスツズマブ、カペシタビン、イリノテカン、パクリタキセル、シスプラチン、カルボプラチン、フルベストラント、デキサメタゾン、ベバシズマブ、ドセタキセル、ラパチニブ、ゲムシタビン、またはテモゾロミドである、請求項39に記載の医薬組成物。
- PI3−K活性を調節するための、有効量の請求項1〜35の何れか1項に記載の化合物を含む、医薬組成物。
- 該化合物が、PI3Kの阻害に関して1μM未満のIC50値を有する、請求項41に記載の医薬組成物。
- 癌を処置するための、請求項41に記載の医薬組成物。
- ヒトまたは動物において癌を処置するための、該ヒトまたは動物においてPI3−K活性を阻害するのに有効な量の請求項1〜35の何れか1項に記載の化合物を含む、医薬組成物。
- 少なくとも1種のさらなる癌処置用薬物をさらに含む、請求項44に記載の医薬組成物。
- 少なくとも1種のさらなる癌処置用薬物が、バタラニブ、イマチニブ、ゲフィチニブ、エルロチニブ、ペルツズマブ、トラスツズマブ、カペシタビン、イリノテカン、パクリタキセル、シスプラチン、カルボプラチン、フルベストラント、デキサメタゾン、ベバシズマブ、ドセタキセル、ラパチニブ、ゲムシタビン、またはテモゾロミドである、請求項45に記載の医薬組成物。
- 該癌が、乳癌、膀胱癌、大腸癌、神経膠腫、神経膠芽腫、肺癌、肝細胞癌、胃癌、黒色腫、甲状腺癌、子宮内膜癌、腎臓癌、子宮頚癌、膵癌、食道癌、前立腺癌、脳癌または卵巣癌である、請求項44に記載の医薬組成物。
- Aktのリン酸化を調節するための、請求項1〜35の何れか1項に記載の化合物を含む医薬組成物。
- 該化合物が、pAKTの阻害に関して1μM未満のEC50値を有する、請求項48に記載の医薬組成物。
- 癌の処置に使用するための、請求項1〜35の何れか1項に記載の化合物。
- 癌を処置するための医薬の製造における、請求項1〜35の何れか1項に記載の化合物の使用。
- 請求項1〜35の何れか1項に記載の化合物と、PI3−K阻害量の該化合物を投与することによって細胞増殖性疾患を処置するための指示書を含む添付文書または他のラベルとを含むキット。
- 該癌が、肺癌;気管支癌;前立腺癌;乳癌;膵臓癌;大腸癌;直腸癌;甲状腺癌;肝臓癌;肝内胆管癌;肝細胞癌;胃癌;神経膠腫;神経膠芽腫;子宮内膜癌;黒色腫;腎臓癌;腎盂癌;膀胱癌;子宮体癌;子宮頚癌;卵巣癌;多発性骨髄腫;食道癌;急性骨髄性白血病;慢性骨髄性白血病;リンパ性白血病;骨髄性白血病;脳癌;口腔癌;咽頭癌;喉頭癌;小腸癌;非ホジキンリンパ腫;黒色腫;または腸繊毛腺腫から選択される、請求項50に記載の使用のための化合物。
- 該癌が、肺癌;気管支癌;前立腺癌;乳癌;膵臓癌;大腸癌;直腸癌;甲状腺癌;肝臓癌;肝内胆管癌;肝細胞癌;胃癌;神経膠腫;神経膠芽腫;子宮内膜癌;黒色腫;腎臓癌;腎盂癌;膀胱癌;子宮体癌;子宮頚癌;卵巣癌;多発性骨髄腫;食道癌;急性骨髄性白血病;慢性骨髄性白血病;リンパ性白血病;骨髄性白血病;脳癌;口腔癌;咽頭癌;喉頭癌;小腸癌;非ホジキンリンパ腫;黒色腫;または腸繊毛腺腫から選択される、請求項51に記載の使用。
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