JP2021167351A - 5’ヌクレオチダーゼ,エクトのモジュレーター及びその使用 - Google Patents
5’ヌクレオチダーゼ,エクトのモジュレーター及びその使用 Download PDFInfo
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- 229960001028 zanamivir Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Abstract
【解決手段】5’−ヌクレオチダーゼ,エクトによるAMPからアデノシンへの変換を調節する化合物、及び前記化合物を含む組成物、及び前記化合物を合成する方法が本明細書に記載される。5’−ヌクレオチダーゼ,エクトによって媒介される癌及び免疫関連障害を含む多様な疾患、障害、及び状態の治療及び/又は予防のための、このような化合物及び組成物の使用もまた提供される。
【選択図】図1
Description
本出願は、35 U.S.C.第119条(e)のもとに、2016年1月8日に出願された米国仮出願第62/276,564号、及び2016年4月18日に出願された米国仮出願第62/324,077号(これらのそれぞれは、参照のためその全体が本明細書に組み込まれる)の優先権利益を主張する出願である。
適用なし。
適用なし。
(発明の分野)
プリンヌクレオチド及びヌクレオシド、例えばATP及びアデノシンによって媒介される細胞外シグナル伝達の一種であるプリン性シグナル伝達は、細胞及び/又は近傍の細胞におけるプリン性受容体の活性化を伴い、細胞機能の調節をもたらす。ほとんどの細胞はヌクレオチドを放出する能力を有し、これは一般に、調節されたエキソサイトーシスを介して生じる(Praetorius, H. A.; Leipziger, J. (1 March 2010) Ann Rev Physiology 72(1): 377-393 参照)。放出されたヌクレオチドは、次にエクトヌクレオチダーゼと呼ばれる種々の細胞膜結合酵素によって、細胞外で加水分解され得る。
本発明は、5’−ヌクレオチダーゼ,エクト(NT5E又は5NT;CD73としても知られている)によるAMPのアデノシンへの変換を調節する化合物、及び前記化合物を含む組成物(例えば医薬組成物)に関する。そのような化合物、その合成方法、及び組成物が、以下に詳細に記載される。
(i)Rc及びReが水素であり、かつRaが、−OEt、−OCH2Ph、−SCH2Ph、−NH2、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、N−メチル−N−エチルアミノ、フェニルアミノ、ベンジルアミノ、2−フェニルエチルアミノ、N−ベンジル−N−エチルアミノ、ジベンジルアミノ、4−アミノベンジルアミノ、4−クロロベンジルアミノ、4−ニトロベンジルアミノ、又は4−スルファモイルベンジルアミノであるか;又は
(ii)Rcが水素であり、Raが−NH2であり、かつReが、ブロモ、クロロ、アミノメチル、又はチオエチルであるか;又は
(iii)Rcが水素であり、Raがベンジルアミノであり、かつReがブロモである]を与える化合物である。
本発明をさらに説明する前に、本発明は本明細書に記載の特定の実施態様に限定されないこと、そして本明細書で使用される用語は特定の実施態様を説明するためのものであって、本発明を限定するものではないことも理解すべきである。
癌と診断された被験者の数及び癌に起因する死亡者の数は増加し続けている。化学療法及び放射線療法を含む伝統的な治療アプローチは、癌(例えば腫瘍)がそのような治療を回避するように進化するにつれて、一般的に患者が許容することが困難になり、効果が少なくなっている。最近の実験的証拠は、CD73阻害剤が癌(例えば乳癌)治療のための重要な新しい治療法であることを示している。
定義
ヒトCD73(5’−ヌクレオチダーゼ,エクト;NT5E;又は5NTとも呼ばれる)は、574個のアミノ酸残基のタンパク質である(受け入れ番号AAH6593)。真核生物CD73は、2つの構造ドメインを有する非共有結合性ホモダイマーとして機能し、N端部及びC末端ドメインはヒンジ領域によって連結され、これは、酵素が大きなドメイン移動を受け、開いたコンフォメーションと閉じたコンフォメーション間で切り替えることを可能にする(Knapp, K. et al. (2012) Structure 20:2161-73)。
本発明は、部分的には、少なくとも治療に関連する特性又は特徴を有するCD73の阻害剤の同定に関する。候補阻害剤は、例えば当該技術分野で認められているアッセイ又はモデルを用いて同定することができ、その例は当業者には明らかであろう。本明細書に記載の化合物のCD73阻害活性を決定するために使用されるアッセイは、実験欄に記載されている。
式(I):
各R1は、水素、場合により置換されたC1〜C6アルキル、場合により置換されたアリール、及び−C(R2R2)−O−C(O)−OR3から成る群から独立して選択されるか、又は2つのR1基が場合により組合わさって、5〜7員環を形成し;
各R2は、H及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;
各R3は、H、C1〜C6アルキル、及び場合により置換されたアリールからなる群から独立して選択され;
R5は、H及び場合により置換されたC1〜C6アルキルからなる群から選択され;
Xは、O、CH2、及びSから成る群から選択され;
Aは、以下:
Zは、CH2、CHR6、NR6、及びOから成る群から選択され;
各R6は、H、CH3、OH、CN、F、場合により置換されたC1〜C6アルキル、及びOC(O)−C1〜C6からなる群から独立して選択され;及び、場合により隣接する環頂点上の2つのR6基は一緒に結合して、環頂点として少なくとも1個のヘテロ原子を有する5〜6員環を形成し;及び
Hetは、
ここで、波線は化合物の残りの部分への結合点を示し、
Raは、H、NH2、NHR7、NHC(O)R7、NR7R7、R7、OH、SR7、及びOR7からなる群から選択され;
Rbは、H、ハロゲン、NH2、NHR7、NR7R7、R7、OH、及びOR7からなる群から選択され;
Rc及びRdは、H、ハロゲン、ハロアルキル、NH2、NHR7、NR7R7、R7、OH、OR7、SR7、SO2R7、−X1−NH2、−X1−NHR7、−X1−NR7R7、−X1−OH、−X1−OR7、−X1−SR7、及び−X1−SO2R7からなる群から独立して選択され;
Re及びRfは、H、ハロゲン、及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;そして、
各X1はC1〜C4アルキレンであり、そして
各R7は、場合により置換されたC1〜C10アルキル、場合により置換されたC2〜C10アルケニル、場合により置換されたC2〜C10アルキニル、場合により置換されたC3〜C7シクロアルキル、場合により置換されたC3〜C7シクロアルキルC1〜C4アルキル、場合により置換された4〜7員シクロヘテロアルキル、場合により置換された4〜7員シクロヘテロアルキルC1〜C4アルキル、場合により置換されたアリール、場合により置換されたアリールC1〜C4アルキル、場合により置換されたアリールC2〜C4アルケニル、場合により置換されたアリールC2〜C4アルキニル、場合により置換されたヘテロアリール、場合により置換されたヘテロアリールC1〜C4アルキル、場合により置換されたヘテロアリールC1〜C4アルケニル、場合により置換されたヘテロアリールC2〜C4アルキニル、及び、場合により、窒素原子に結合した2つのR7基は一緒に結合されて、場合によりアリール環に縮合した4〜7員複素環を形成し;
但し、前記化合物は、X、A、及びHetの組み合わせが、
(i)Rc及びReが水素であり、Raが、−OEt、−OCH2Ph、−SCH2Ph、−NH2、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、N−メチル−N−エチルアミノ、フェニルアミノ、ベンジルアミノ、2−フェニルエチルアミノ、N−ベンジル−N−エチルアミノ、ジベンジルアミノ、4−アミノベンジルアミノ、4−クロロベンジルアミノ、4−ニトロベンジルアミノ、又は4−スルファモイルベンジルアミノであるか;又は
(ii)Rcが水素であり、Raが−NH2であり、Reが、ブロモ、クロロ、アミノメチル、又はチオエチルであるか;又は
(iii)Rcが水素であり、Raがベンジルアミノであり、Reがブロモである]を与える化合物以外のものである。
アルキル基、ハロゲン、−OR’、−NR’R”、−SR’、−SiR’R”R”’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R”、−OC(O)NR’R”、−NR”C(O)R’、−NR’−C(O)NR”R”’、−NR”C(O)2R’、−CN、及び−NO2。R’、R”、及びR”’はそれぞれ独立して、水素、非置換C1〜C4アルキル、又はC1〜C4ハロアルキルである。R’とR”が同じ窒素原子に結合しているとき、又はR”とR'''が同じ窒素に結合しているとき、これらはその窒素原子と組合わさって、3、4、5、6、又は7員環を形成する。例えば、−NR'R”は、1−ピロリジニル及び4−モルホリニルを含むことを意味する。
シクロアルキル基とシクロヘテロアルキル基:「アルキル基」について上記で挙げた選択された置換基は、シクロアルキル及びシクロヘテロアルキル基についても有用である。さらに、シクロアルキル及びシクロヘテロアルキル基の各々は、オキソ(=O)で場合により置換されていてもよい。
アルキル基及びヘテロアリール基:−ハロゲン、−OR’、−OC(O)R’、−NR’R”、−R’、−CN、−NO2、−CO2R’、CONR’R”、C(O)R’、−OC(O)NR’R”、−NR”C(O)R’、−NR”C(O)2R’、−NR’−C(O)NR”R”’、−S(O)2R’、S(O)2NR’R”、NR’S(O)2R”、及びペルフルオロ(C1〜C4)アルキル、ここで、R’、R”、及びR”’は、水素、C1〜C4アルキル、C1〜C4ハロアルキル、及びC3〜C6シクロアルキルから独立して選択される。
各R1は、水素、場合により置換されたC1〜C6アルキル、場合により置換されたアリール、及び−C(R2R2)−O−C(O)−OR3から成る群から独立して選択されるか、又は2つのR1基が場合により組合わされて5〜7員環を形成し;
各R2は、H及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;
各R3は、H、C1〜C6アルキル、及び場合により置換されたアリールからなる群から独立して選択され;
R5は、H及び場合により置換されたC1〜C6アルキルから成る群から選択され;
XはOであり;
Aは、
Hetは、
ここで、波線は化合物の残りの部分への結合点を示し、
Raは、H、NH2、NHR7、NHC(O)R7、NR7R7、R7、OH、SR7、及びOR7からなる群から選択され;
Rbは、H、ハロゲン、NH2、NHR7、NR7R7、R7、OH、及びOR7からなる群から選択され;
Rc及びRdは、H、ハロゲン、ハロアルキル、NH2、NHR7、NR7R7、R7、OH、OR7、SR7、SO2R7、−X1−NH2、−X1−NHR7、−X1−NR7R7、−X1−OH、−X1−OR7、−X1−SR7、及び−X1−SO2R7からなる群から独立して選択され;
Re及びRfは、H、ハロゲン、及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;そして、
各X1はC1〜C4アルキレンであり、そして
各R7は、場合により置換されたC1〜C10アルキル、場合により置換されたC2〜C10アルケニル、場合により置換されたC2〜C10アルキニル、場合により置換されたC3〜C7シクロアルキル、場合により置換されたC3〜C7シクロアルキルC1〜C4アルキル、場合により置換された4〜7員シクロヘテロアルキル、場合により置換された4〜7員シクロヘテロアルキルC1〜C4アルキル、場合により置換されたアリール、場合により置換されたアリールC1〜C4アルキル、場合により置換されたアリールC2〜C4アルケニル、場合により置換されたアリールC2〜C4アルキニル、場合により置換されたヘテロアリール、場合により置換されたヘテロアリールC1〜C4アルキル、場合により置換されたヘテロアリールC1〜C4アルケニル、場合により置換されたヘテロアリールC2〜C4アルキニル、及び、場合により、窒素原子に結合した2つのR7基は一緒に結合されて、場合によりアリール環に縮合した4〜7員複素環を形成する。
一般に、本明細書で提供される化合物は、以下の実施例に記載されるような従来の方法によって調製することができる。
本明細書に開示される治療様式の1つ以上の物理的特性、及び/又はそれらが実施される様式を改善することは、しばしば有益であり時には不可欠である。物理的特性の改善には、例えば、水溶性、生物学的利用能、血清半減期、及び/又は治療的半減期を増加させる方法;及び/又は生物活性を調節する方法が含まれる。
本発明は、広い範囲の疾患、障害、及び/又は状態、及び/又はその症状の治療又は予防における、本明細書に記載のCD73阻害剤の使用を企図する。以下では特定の用途が詳細に説明されるが、本発明はこれに限定されないことを理解されたい。さらに、特定の疾患、障害、及び状態の一般的なカテゴリーが以下に述べられるが、いくつかの疾患、障害、及び状態は、2つ以上のカテゴリーのメンバーであり得て、そして他は、開示されるカテゴリーのいずれのメンバーでもないことがあり得る。
本発明のCD73阻害剤は、対象への投与に適した組成物の形態であり得る。一般にそのような組成物は、CD73阻害剤と、1つ以上の医薬的に許容し得る又は生理学的に許容し得る希釈剤、担体、又は賦形剤とを含む「医薬組成物」である。特定の実施態様においてCD73阻害剤は、治療上許容される量で存在する。医薬組成物は、本発明の方法において使用することができる。したがって、例えば医薬組成物は、本明細書に記載の治療方法及び予防方法及び使用を実施するために、エクスビボ又はインビボで対象に投与することができる。
インプラント(例えば、移植可能なポンプ)及びカテーテルシステム、低速注入ポンプ、及び装置(これらの全てが当業者に周知である)を含む、CD73阻害剤を送達するために、任意のの薬物送達装置を使用することができる。
本発明は、任意の適切な方法によるCD73阻害剤及びその組成物の投与を企図する。適切な投与経路には、経口、非経口(例えば、筋肉内、静脈内、皮下(例えば注射又は移植)、腹腔内、嚢内、関節内、腹腔内、脳内(脳実質内、脳室内)、鼻内、膣内、舌下、眼内、直腸内、局所(例えば経皮)、口腔及び吸入)が含まれる。一般に皮下又は筋肉内に投与されるデポー注射剤もまた、定義された期間にわたって本明細書に開示されたCD73阻害剤を放出するために利用され得る。
本発明は、1種以上の活性治療薬(例えば化学療法剤)又は他の予防的若しくは治療的方法(例えば放射線)と組み合わせたCD73阻害剤の使用を企図する。そのような併用療法では、種々の活性薬剤はしばしば、異なる相補的な作用メカニズムを有する。そのような併用療法は、1種以上の薬剤の用量低減を可能にし、それにより1種以上の薬剤に関連する有害作用を低減又は排除することによって、特に有利であり得る。さらに、そのような併用療法は、根底にある疾患、障害、又は状態に対して相乗的な治療又は予防効果を有し得る。
本発明のCD73阻害剤は、例えば投与の目標(例えば、所望の分解能の程度);製剤が投与されている対象の年齢、体重、性別、及び健康状態及び身体状態;投与経路;ならびに疾患、障害、状態、又はこれらの症状の性質に依存する量で対象に投与することができる。投与処方はまた、投与される薬剤に関連する有害作用の存在、性質、及び程度を考慮に入れることができる。有効な投与量及び投与処方は、例えば、安全性及び用量漸増試験、インビボ試験(例えば、動物モデル)、及び当業者に公知の他の方法から容易に決定することができる。
キット
以下の実施例は、本発明をどのように作成し使用するかについての完全な開示及び説明を当業者に提供するために提示されるものであり、発明者が発明と見なすものの範囲を限定することを意図するものではなく、以下の実験が行われたこと、又はそれらが実行される可能性のある実験のすべてであることを示すことを意図するものでもない。現在時制で記載されている例示的な記載は、必ずしも実行されたものではなく、その記載は、その説明された性質のデータ等を生成するため行わうことができることを、理解されたい。使用される数(例えば、量、温度など)に関して正確さを保つための努力がなされているが、いくらかの実験誤差及び偏差が考慮されるべきである。
フラッシュカラム:ISCO Rf +
逆相HPLC:ISCO-EZ;カラム:Kinetex 5μm EVO C18 100 A;250×21.2mm(Phenomenex)
[実施例1]
[({[(2R,3S,4R,5R)−5−[6−(シクロペンチルアミノ)−2−クロロ−9H−プリン−9−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例2]
(((((2R,3S,4R,5R)−5−(6−((4−(tert−ブチル)ベンジル)アミノ)−2−クロロ−9H−プリン−9−イル)(3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例3]
(((((2R,3S,4R,5R)−5−(2−クロロ−6−(イソプロピルアミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例4]
(((((2R,3S,4R,5R)−5−(2−クロロ−6−(シクロプロピルアミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例5]
(((((2R,3S,4R,5R)−5−(2−クロロ−6−(ネオペンチルアミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例6]
(((((2R,3S,4R,5R)−5−(2−クロロ−6−(イソプロピル(メチル)アミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例7]
(((((2R,3S,4R,5R)−5−(6−((3,5−ビス(トリフルオロメチル)ベンジル)アミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例8]
(((((2R,3S,4R,5R)−5−(6−((4−ブロモベンジル)アミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例9]
(((((2R,3S,4R,5R)−5−(6−((4−(tert−ブチル)ベンジル)アミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例10]
(((((2R,3S,4R,5R)−5−(6−(([1,1’−ビフェニル]−4−イルメチル)アミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例11]
(((((2R,3S,4R,5R)−3,4−ジヒドロキシ−5−(6−((4−(トリフルオロメチル)ベンジル)アミノ)−9H−プリン−9−イル)テトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例12]
(((((2R,3S,4R,5R)−3,4−ジヒドロキシ−5−(6−((4−メチルベンジル)アミノ)−9H−プリン−9−イル)テトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例13]
(((((2R,3S,4R,5R)−5−(6−((3,5−ジクロロベンジル)アミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例14]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−メチル−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
メチレンビス(ホスホン酸ジクロリ)(504mg、2ミリモル、5当量)の氷冷溶液を滴下して加えた。反応混合液を0℃で3時間撹拌し、次に0.5M重炭酸トリエチルアンモニウム溶液(8mL)で注意深くクエンチし、0℃で15分間、次に室温で2時間攪拌した。反応混合液を逆相HPLC(C18カラム、アセトニトリルの0〜30%勾配及び0.1%TFAを含む水)により精製して、生成物を白色の固体として得た:1H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.32 (m, 2H), 7.38 - 7.18 (m, 5H), 5.92 (d, J = 6.0 Hz, 1H), 4.71 (s, 2H), 4.55 (t, J = 5.5 Hz, 1H), 4.19 - 3.98 (m, 4H), 2,44 (s, 3H), 2.23 (t, J = 20.5 Hz, 2H). C19H25N5O9P2 のESI MS [M-H]-, 計算値 528.1, 実測値 528.2。
[実施例15]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−ビニル−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例16]
(((((2R,3S,4R,5R)−5−(2−アリル−6−(ベンジルアミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例17]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−プロピル−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例18]
[({[(2R,3S,4R,5R)−5−[6−(ベンジルアミノ)−2−メトキシ−9H−プリン−9−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例19]
[({[(2R,3S,4R,5R)−5−[6−(ベンジルアミノ)−2−(メチルアミノ)−9H−プリン−9−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例20]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−(ジメチルアミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例21]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−(ピロリジン−1−イル)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例22]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−(ピペリジン−1−イル)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例23]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−モルホリノ−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成の合成
[実施例24]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−(イソプロピルチオ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例25]
(((((2R,3S,4R,5R)−5−(6−(ベンジルアミノ)−2−(イソプロピルスルホニル)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例26]
(((((2R,3S,4S,5R)−5−(6−アミノ−2−フルオロ−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例27]
(((((2R,3R,4R,5R)−5−(6−アミノ−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例28]
[({[(2R,3R,4S,5R)−5−(6−アミノ−2−クロロ−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例29]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−クロロ−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例30]
(((((2R,3R,4S,5R)−5−(6−(ベンジル(メチル)アミノ)−2−クロロ−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例31a]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(メチルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例31b]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(エチルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例32]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(イソプロピルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例33]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロプロピルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例34]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((シクロプロピルメチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例35]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例36]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(((S)−テトラヒドロフラン−3−イル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例37]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(((R)−テトラヒドロフラン−3−イル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例38]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((テトラヒドロ−2H−ピラン−4−イル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例39]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(ピロリジン−1−イル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例40]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(ピペリジン−1−イル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例41]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−モルホリノ−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例42]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(イソインドリン−2−イル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例43]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((4−クロロベンジル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例44]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((4−フルオロベンジル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例45]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((3−メチルベンジル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例46]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((3−フルオロベンジル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例47]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((3−クロロベンジル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例48]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((2−クロロベンジル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例49]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((2−クロロベンジル)(メチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例50]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−((ピリジン−4−イルメチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例51]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(フェネチルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例52]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−メチル−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例53]
(((((2R,3R,4S,5R)−5−(6−(シクロペンチルアミノ)−2−メチル−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例54]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−(トリフルオロメチル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例55]
(((((2R,3R,4S,5R)−5−(6−(シクロペンチルアミノ)−2−(トリフルオロメチル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例56]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−フェニル−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例57]
(((((2R,3R,4S,5R)−5−(2−ベンジル−6−(ベンジルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例58]
(((((2R,3R,4S,5R)−5−(6−(シクロペンチルアミノ)−2−(ピペリジン−1−イルメチル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例59]
(((((2R,3R,4S,5R)−5−(6−(シクロペンチルアミノ)−2−(メトキシメチル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例60]
(((((2R,3R,4S,5R)−5−(6−(シクロペンチルアミノ)−2−(ヒドロキシ(フェニル)メチル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例61]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−(フェニルエチニル)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例62]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−フェネチル−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例63]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−エチニル−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例64]
[({[(2R,3S,4S,5R)−5−[6−(ベンジルオキシ)−2−クロロ−9H−プリン−9−イル]−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例65]
(((((2R,3R,4S,5R)−5−(6−(ベンジルアミノ)−2−クロロ−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例66]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例67]
((((1−(6−(ベンジルアミノ)−9H−プリン−9−イル)プロパン−2−イル)オキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例68]
(((2−(6−(ベンジルアミノ)−9H−プリン−9−イル)プロポキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例69]
(((((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチルアミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホリル)ビス(オキシ)ビス(メチレン)ジイソプロピルビス(カーボネート)の合成
[実施例70]
[({[(2S,3S,4R,5R)−5−{2−クロロ−6−[シクロペンチル(メチル)アミノ]−9H−プリン−9−イル}−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例71]
[({1−[(2S,3S,4R,5R)−5−[6−(ベンジルアミノ)−2−クロロ−9H−プリン−9−イル]−3,4−ジヒドロキシオキソラン−2−イル]エトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例72]
[({1−[(2S,3S,4R,5R)−5−[6−(ベンジルアミノ)−2−クロロ−9H−プリン−9−イル]−3,4−ジヒドロキシオキソラン−2−イル]プロポキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例73]
[({[(2R,3R,4R,5R)−5−[2−クロロ−6−(シクロペンチルアミノ)−9H−プリン−9−イル]−3,4−ジヒドロキシ−4−メチルオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例74]
((2R,3S,4R,5R)−5−(2−クロロ−6−(シクロペンチルアミノ)−9H−プリン−9−イル)−3,4−ジヒドロキシテトラヒドロフラン−2−イル)メチル水素((ヒドロキシ(メトキシ)ホスホリル)メチル)ホスホン酸塩の合成
[実施例75]
[(2R,3S,4R,5R)−5−{2−クロロ−6−[シクロペンチル(メチル)アミノ]−9H−プリン−9−イル}−3,4−ジヒドロキシオキソラン−2−イル]メチルフェニル[(ジフェノキシホスホリル)メチル]ホスホン酸塩の合成
[実施例76]
ビス(3−クロロフェニル)[({[(2R,3S,4R,5R)−5−{2−クロロ−6−[シクロペンチル(メチル)アミノ]−9H−プリン−9−イル}−3、4−ジヒドロキシオキソラン−2−イル]メトキシ}(3−クロロフェノキシ)ホスホリル)メチル]ホスホン酸塩の合成
[実施例77]
ビス(3,4−ジクロロフェニル)[({[(2R,3S,4R,5R)−5−{2−クロロ−6−[シクロペンチル(メチル)アミノ]−9H−プリン−9−イル}3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(3,4−ジクロロフェノキシ)ホスホリル)メチル]ホスホン酸塩の合成
[実施例78]
メチル2−({[(2R,3S,4R,5R)−5−{2−クロロ−6−[シクロペンチル(メチル)アミノ]−9H−プリン−9−イル}−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}[2−(メトキシカルボニル)フェノキシ]ホスホリル)メチル][2−(メトキシカルボニル)フェノキシ]ホスホリル}オキシ)ベンゾネートの合成
[実施例79]
[({[(2R,3R,4S,5R)−5−(2−クロロ−6−{[(1S)−1−(4−フルオロフェニル)エチル)アミノ]−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例80]
[({[(2R,3R,4S,5R)−5−(2−クロロ−6−{[(1R)−1−フェニルエチル]アミノ}−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例81]
[({[(2R,3R,4S,5R)−5−(2−クロロ−6−{[(1S)−1−フェニルエチル]アミノ}−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例82]
[({[(2R,3R,4S,5R)−5−[6−(シクロペンチルアミノ)−2−[ヒドロキシ(オキサン−4−イル)メチル]−9H−プリン−9−イル]−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]−ホスホン酸の合成
[実施例83]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチル(メチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(ヒドロキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例84]
((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチル(メチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メチル水素((ヒドロキシ(メトキシ)ホスホリル)メチル)ホスホネートの合成
[実施例85]
((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチル(メチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メチル水素((ジメトキシホスホリル)メチル)ホスホネートの合成、及び
メチル水素(((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチル(メチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(メトキシ)ホスホリル)メチル)ホスホネートの合成
[実施例86]
(((((2R,3R,4S,5R)−5−(2−クロロ−6−(シクロペンチル(メチル)アミノ)−9H−プリン−9−イル)−4−フルオロ−3−ヒドロキシテトラヒドロフラン−2−イル)メトキシ)(メトキシ)ホスホリル)メチル)ホスホン酸の合成
[実施例87]
[({[(2R,3S,4R,5R)−5−[6−クロロ−4−(シクロペンチルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル]ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例88]
[({[(2R,3S,4R,5R)−5−[4−(ベンジルアミノ)−6−クロロ−1H−ピラゾロ[3,4−d]ピリミジン−1−イル]−3−,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例89]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例90]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1R)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例91]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(4−クロロフェニル)メチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例92]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−(2−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例93]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1R)−1−(2−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例94]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−(3−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例95]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1R)−1−(3−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例96]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−(4−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例97]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1R)−1−(4−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例98]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(2−クロロフェニル)メチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例99]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(2−クロロフェニル)メチル](メチル)アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例100]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[2−(2−クロロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例101]
[({[(2R,3S,4R,5R)−5−{4−[ベンジル(メチル)アミノ]−6−クロロ−1H−ピラゾロ[3,4−d]ピリミジン−1−イル}3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例102]
[({[(2R,3S,4R,5R)−5−{6−クロロ−4−[シクロペンチル(メチル)アミノ]−1H−ピラゾロ[3,4−d]ピリミジン−1−イル}3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例103]
[({[(2R,3S,4R,5R)−5−[6−クロロ−4−(メチルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例104]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1R)−2,2,2−トリフルオロ−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例105]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(3S)−オキソラン−3−イル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例106]
[({[(2R,3S,4R,5R)−5−[6−クロロ−4−(シクロペンチルアミノ)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}({[(プロパン−2−イルオキシ)カルボニル]オキシ}メトキシ)ホスホリル)メチル]({[(プロパン−2−イルオキシ)カルボニル]オキシ}メトキシ)ホスフィン酸の合成
[実施例107]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}({[(プロパン−2−イルオキシ)カルボニル]オキシ}−メトキシ)ホスホリル)メチル]({[(プロパン−2−イルオキシ)カルボニル]オキシ}メトキシ)ホスフィン酸の合成
[実施例108]
[({[(2R,3R,4S,5R)−5−[4−(ベンジルアミノ)−6−クロロ−1H−ピラゾロ[3,4−d]ピリミジン−1−イル]−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例109]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1S)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例110]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1R)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例111]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1S)−1−(2−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例112]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1R)−1−(2−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例113]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1S)−1−(3−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例114]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1R)−1−(2−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例115]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1S)−1−(4−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例116]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1R)−1−(4−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例117]
[({[(2R,3S,4R,5R)−5−[5−クロロ−7−(シクロペンチルアミノ)−3H−イミダゾ[4,5−b]ピリジン−3−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例118]
[({[(2R,3R,4S,5R)−5−[5−クロロ−7−(シクロペンチルアミノ)−3H−イミダゾ[4,5−b]ピリジン−3−イル]−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例119]
[({[(2R,3S,4R,5R)−5−[6−クロロ−4−(シクロペンチルアミノ)−1H−ピラゾロ[3,4−b]ピリジン−1−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]−ホスホン酸の合成
[実施例120]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−b]ピリジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]−ホスホン酸の合成
[実施例121]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1R)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−b]ピリジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]−ホスホン酸の合成
[実施例122]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−(2−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−b]ピリジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例123]
[({[(2R,3S,4R,5R)−5−(6−クロロ−4−{[(1S)−1−(4−フルオロフェニル)エチル]アミノ}−1H−ピラゾロ[3,4−b]ピリジン−1−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例124]
[({[(2R,3R,4S,5R)−5−[6−クロロ−4−(シクロペンチルアミノ)−1H−ピラゾロ[3,4−b]ピリジン−1−イル]−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例125]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1S)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−b]ピリジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例126]
[({[(2R,3R,4S,5R)−5−(6−クロロ−4−{[(1R)−1−フェニルエチル]アミノ}−1H−ピラゾロ[3,4−b]ピリジン−1−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例127]
[({[(2R,3S,4R,5R)−5−(2−クロロ−4−{[(1S)−1−(2−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例128]
[({[(2R,3S,4R,5R)−5−(2−クロロ−4−{[(1S)−1−(3−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例129]
[({[(2R,3S,4R,5R)−5−(2−クロロ−4−{[(1S)−1−(4−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例130]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1R)−1−フェニルエチル]アミノ)−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例131]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1S)−1−フェニルエチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例132]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1S)−1−(3−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例133]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1R)−1−(4−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例134]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1S)−1−(4−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例135]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1S)−1−(2−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例136]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1R)−1−(2−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例137]
[({[(2R,3R,4S,5R)−5−(2−クロロ−4−{[(1R)−1−(3−フルオロフェニル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−7−イル)−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例138]
[({[(2R,3S,4R,5R)−5−[6−クロロ−4−(シクロペンチルアミノ)−1H−イミダゾ[4,5−c]ピリジン−1−イル]−3,4−ジヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例139]
[({[(2R,3R,4S,5R)−5−[6−クロロ−4−(シクロペンチルアミノ)−1H−イミダゾ[4,5−c]ピリジン−1−イル]−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
[実施例140]
[({[(2R,3R,4S,5R)−5−{6−クロロ−4−[シクロペンチル(メチル)アミノ]−1H−イミダゾ[4,5−c]ピリジン−1−イル}−4−フルオロ−3−ヒドロキシオキソラン−2−イル]メトキシ}(ヒドロキシ)ホスホリル)メチル]ホスホン酸の合成
材料と方法
示されている場合、以下の一般的な材料及び方法を使用したか、又は以下の実施例で使用することができる:
Claims (50)
- 式:
各R1は、水素、場合により置換されたC1〜C6アルキル、場合により置換されたアリール、及び−C(R2R2)−O−C(O)−OR3からなる群から独立して選択されるか、又は2個のR1基が場合により結合して5〜7員環を形成し;
各R2は、H及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;
各R3は、H、C1〜C6アルキル、及び場合により置換されたアリールからなる群から独立して選択され;
R5は、H及び場合により置換されたC1〜C6アルキルからなる群から選択され;
Xは、Oであり;
Aは、
Hetは、
ここで、波線は化合物の残りの部分への結合点を示し、そして、ここで、
Raは、H、NH2、NHR7、NHC(O)R7、NR7R7、R7、OH、SR7、及びOR7からなる群から選択され;
Rbは、H、ハロゲン、NH2、NHR7、NR7R7、R7、OH、及びOR7からなる群から選択され;
Rc及びRdは、H、ハロゲン、ハロアルキル、NH2、NHR7、NR7R7、R7、OH、OR7、SR7、SO2R7、−X1−NH2、−X1−NHR7、−X1−NR7R7、−X1−OH、−X1−OR7、−X1−SR7、及び−X1−SO2R7からなる群から独立して選択され;
Re及びRfは、H、ハロゲン、及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;
各X1はC1〜C4アルキレンであり;そして
各R7は、場合により置換されたC1〜C10アルキル、場合により置換されたC2〜C10アルケニル、場合により置換されたC2〜C10アルキニル、場合により置換されたC3〜C7シクロアルキル、場合により置換されたC3〜C7シクロアルキルC1〜C4アルキル、場合により置換された4〜7員シクロヘテロアルキル、場合により置換された4〜7員シクロヘテロアルキルC1〜C4アルキル、場合により置換されたアリール、場合により置換されたアリールC1〜C4アルキル、場合により置換されたアリールC2〜C4アルケニル、場合により置換されたアリールC2〜C4アルキニル、場合により置換されたヘテロアリール、場合により置換されたヘテロアリールC1〜C4アルキル、場合により置換されたヘテロアリールC1〜C4アルケニル、および場合により置換されたヘテロアリールC2〜C4アルキニルから成る群から独立して選択され、そして場合により、窒素原子に結合している2個のR7基は一緒に結合して、場合によりアリール環に縮合している4〜7員複素環を形成する]。 - Raが、NH2、NHR7、NR7R7、SR7、及びOR7から成る群から選択される、請求項4に記載の化合物、又はその医薬的に許容し得る塩、水和物、若しくは溶媒和物。
- Rcが、ハロゲン、R7、OR7、SR7、SO2R7、−X1−NH2、−X1−NHR7、−X1−NR7R7、−X1−OH、−X1−OR7、−X1−SR7、及び−X1−SO2R7から成る群から選択される、請求項4に記載の化合物、又はその医薬的に許容し得る塩、水和物、若しくは溶媒和物。
- ReがHである、請求項4に記載の化合物、又はその医薬的に許容し得る塩、水和物、若しくは溶媒和物。
- 式:
各R1は、水素、場合により置換されたC1〜C6アルキル、場合により置換されたアリール、及び−C(R2R2)−O−C(O)−OR3からなる群から独立して選択されるか、又は2個のR1基が場合により結合して5〜7員環を形成し;
各R2は、H及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;
各R3は、H、C1〜C6アルキル、及び場合により置換されたアリールからなる群から独立して選択され;
R5は、H及び場合により置換されたC1〜C6アルキルからなる群から選択され;
Xは、O、CH2、及びSから成る群から選択され;
Aは、
Zは、CH2、CHR6、NR6、及びOから成る群から選択され;
各R6は、H、CH3、OH、CN、F、場合により置換されたC1〜C6アルキル、及びOC(O)−C1〜C6アルキルから成る群から独立して選択され;そして場合により、隣接する環頂点上の2個のR6基は一緒に結合して、環頂点として少なくとも1個のヘテロ原子を有する5〜6員環を形成し;
Hetは、
ここで、波線は化合物の残りの部分への結合点を示し、そして、ここで、
Raは、H、NH2、NHR7、NHC(O)R7、NR7R7、R7、OH、SR7、及びOR7からなる群から選択され;
Rbは、H、ハロゲン、NH2、NHR7、NR7R7、R7、OH、及びOR7からなる群から選択され;
Rc及びRdは、H、ハロゲン、ハロアルキル、NH2、NHR7、NR7R7、R7、OH、OR7、SR7、SO2R7、−X1−NH2、−X1−NHR7、−X1−NR7R7、−X1−OH、−X1−OR7、−X1−SR7、及び−X1−SO2R7からなる群から独立して選択され;
Re及びRfは、H、ハロゲン、及び場合により置換されたC1〜C6アルキルからなる群から独立して選択され;
各X1はC1〜C4アルキレンであり;そして
各R7は、場合により置換されたC1〜C10アルキル、場合により置換されたC2〜C10アルケニル、場合により置換されたC2〜C10アルキニル、場合により置換されたC3〜C7シクロアルキル、場合により置換されたC3〜C7シクロアルキルC1〜C4アルキル、場合により置換された4〜7員シクロヘテロアルキル、場合により置換された4〜7員シクロヘテロアルキルC1〜C4アルキル、場合により置換されたアリール、場合により置換されたアリールC1〜C4アルキル、場合により置換されたアリールC2〜C4アルケニル、場合により置換されたアリールC2〜C4アルキニル、場合により置換されたヘテロアリール、場合により置換されたヘテロアリールC1〜C4アルキル、場合により置換されたヘテロアリールC1〜C4アルケニル、場合により置換されたヘテロアリールC2〜C4アルキニルから成る群から独立して選択され、そして場合により、窒素原子に結合している2個のR7基は一緒に結合して、場合によりアリール環に縮合している4〜7員複素環を形成するが;
但し、前記化合物は、X、A、及びHetの組み合わせが、
(i)Rc及びReが水素であり、Raが、−OEt、−OCH2Ph、−SCH2Ph、−NH2、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、N−メチル−N−エチルアミノ、フェニルアミノ、ベンジルアミノ、1−フェニルエチルアミノ、2−フェニルエチルアミノ、N−ベンジル−N−エチルアミノ、N−ベンジル−N−メチルアミノ、ジベンジルアミノ、4−アミノベンジルアミノ、2−クロロベンジルアミノ、3−クロロベンジルアミノ、4−クロロベンジルアミノ、4−ヒドロキシベンジルアミノ、4−メトキシベンジルアミノ、4−ニトロベンジルアミノ、又は4−スルファモイルベンジルアミノであるか;又は
(ii)Rcが水素であり、Raが−NH2であり、Reが、ブロモ、クロロ、アミノメチル、又はチオエチルであるか;又は
(iii)Rcが水素であり、Raがベンジルアミノであり、Reがブロモであるか;又は
(iv)Rcがアミノであり、Reが水素であり、及びRqが、−NH2、ジメチルアミノ、ジエチルアミノ、ベンジルアミノ、又はN−ベンジル−N−メチルアミノであるか;又は
(v)Rcがクロロであり、Reが水素であり、Raが、−NH2、ベンジルアミノ、2−クロロベンジルアミノ、1−フェニルエチルアミノ、(S)−1−フェニルエチルアミノ、(R)−1−フェニルエチルアミノ、若しくはN−ベンジル−N−メチルアミノであるか;又は
(vi)Rcがヨードであり、Reが水素であり、及びRaが−NH2、ベンジルアミノ、若しくはN−ベンジル−N−メチルアミノであるか;又は
(vii)Raがアミノであり、Reが水素であり、及びRcがピペラジニル、チオアリル、若しくはシクロヘキシルエチルチオである}
を与える化合物以外のものである]。 - Rcが水素以外である、請求項12に記載の化合物。
- Xが酸素である、請求項14に記載の化合物。
- Reが水素である、請求項15に記載の化合物。
- Rgが水素である、請求項16に記載の化合物。
- R5がHである、請求項8に記載の化合物。
- R5がHであり、XがOである、請求項8に記載の化合物。
- R5がHであり、XがOであり、各R1がHである、請求項8に記載の化合物。
- R5がHであり、XがOであり、各R1がHである、請求項21に記載の化合物。
- R5がHであり、XがOであり、各R1がHであり、ReがHであり、そしてRaが、NH2、NHR7、及びN(R7)2から成る群から選択される、請求項21に記載の化合物。
- R5がHであり、XがOであり、各R1がHであり、ReがHであり、RcがH以外であり、かつRaがNHR7である、請求項21に記載の化合物。
- 表1の化合物から選択される、請求項8に記載の化合物。
- 請求項8に記載の化合物と医薬的に許容し得る賦形剤とを含む医薬組成物。
- 必要な対象に請求項8に記載の化合物の有効量を投与することを含む、少なくとも一部がCD73により媒介される、疾患、障害、又は状態を治療する方法。
- 前記化合物が、CD73媒介免疫抑制の進行を逆転又は停止させるのに有効な量で投与される、請求項31に記載の方法。
- 前記疾患、障害、又は状態が癌である、請求項31に記載の方法。
- 前記癌が、前立腺、結腸、直腸、膵臓、子宮頸部、胃、子宮内膜、脳、肝臓、膀胱、卵巣、精巣、頭部、頸部、皮膚(黒色腫及び基底癌を含む)、中皮内層(mesothelial lining)、白血球(リンパ腫及び白血病を含む)、食道、乳房、筋肉、結合組織、肺(小細胞肺癌及び非小細胞癌を含む)、副腎、甲状腺、腎臓、若しくは骨の癌であるか;又は、神経膠芽腫、中皮腫、腎細胞癌、胃癌、肉腫(カポジ肉腫を含む)、絨毛癌、皮膚基底細胞癌、及び睾丸セミノーマである、請求項33に記載の方法。
- 前記癌が、黒色腫、結腸癌、膵臓癌、乳癌、前立腺癌、肺癌、白血病、脳腫瘍、リンパ腫、卵巣癌、又はカポジ肉腫から成る群から選択される、請求項33に記載の方法。
- 前記疾患、障害、又は状態が、関節リウマチ、腎不全、狼瘡、喘息、乾癬、大腸炎、膵炎、アレルギー、線維症、貧血線維筋痛、アルツハイマー病、うっ血性心不全、脳卒中、大動脈弁狭窄症、動脈硬化症、骨粗鬆症、パーキンソン病、感染症、クローン病、潰瘍性大腸炎、アレルギー性接触性皮膚炎及び他の湿疹、全身性硬化症、及び多発性硬化症から成る群から選択される、免疫関連疾患、障害、又は状態である、請求項31に記載の方法。
- 請求項8に記載の化合物と少なくとも1種の追加の治療薬とを含む組合せ。
- 少なくとも1種の追加の治療薬が、化学療法剤、免疫及び/又は炎症調節剤、高コレステロール血症治療薬、又は抗感染症薬である、請求項37に記載の組合せ。
- 少なくとも1種の追加の治療薬が免疫チェックポイント阻害剤である、請求項37に記載の組合せ。
- 請求項8に記載の化合物と少なくとも1種の追加の治療薬とを含むキット。
- 少なくとも1種の追加の治療薬が、化学療法剤、免疫及び/又は炎症調節剤、高コレステロール血症治療薬、又は抗感染症薬である、請求項40に記載のキット。
- 少なくとも1種の追加の治療薬が免疫チェックポイント阻害剤である、請求項40に記載のキット。
- 対象に、有効量の請求項8に記載の化合物と免疫チェックポイント阻害剤とを投与することを含む、前記対象の癌を治療する方法。
- 前記投与は、放射線治療の前、同時、又は後に行われる、請求項43に記載の方法。
- 前記化合物及び前記免疫チェックポイント阻害剤は組合せて投与される、請求項43に記載の方法。
- 前記化合物及び前記免疫チェックポイント阻害剤は連続して投与される、請求項43に記載の方法。
- 前記化合物は前記免疫チェックポイント阻害剤の後に投与される、請求項43に記載の方法。
- 前記化合物は前記免疫チェックポイント阻害剤の前に投与される、請求項43に記載の方法。
- 前記免疫チェックポイント阻害剤は、イプリムマブ、ニボルマブ、及びラムブロリズマブから成る群から選択される、請求項39、42、43のいずれか1項に記載の組合せ、キット、又は方法。
- 対象に、有効量の請求項29に記載の化合物と免疫チェックポイント阻害剤とを投与することを含む、前記対象の癌を治療する方法。
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