JP6936007B2 - Chk1阻害剤とatr阻害剤との組み合わせを使用してがんを処置する方法 - Google Patents
Chk1阻害剤とatr阻害剤との組み合わせを使用してがんを処置する方法 Download PDFInfo
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- JP6936007B2 JP6936007B2 JP2016573589A JP2016573589A JP6936007B2 JP 6936007 B2 JP6936007 B2 JP 6936007B2 JP 2016573589 A JP2016573589 A JP 2016573589A JP 2016573589 A JP2016573589 A JP 2016573589A JP 6936007 B2 JP6936007 B2 JP 6936007B2
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Images
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Enzymes And Modification Thereof (AREA)
Description
ATR(「ATMおよびRad3関連」)は、複製タンパク質A(RPA)によってコーティングされた1本鎖DNAの区域によって特徴付けられるDNA損傷構造への細胞応答の重要なメディエーターである。RPAコーティングされた1本鎖DNAは、未解決のDNA損傷病巣を通じて細胞がDNAを複製しようとする場合に起こる複製ストレスの結果として一般に起こる。複製ストレスの修復の失敗は、致死的な2本鎖破壊もしくは有害なDNA変異をもたらし得る。ATRは、その基質とともに、複製ストレスに応答して、細胞周期制御、DNA複製およびDNA損傷修復を含む複数の細胞機能を協調させる。Chk1は、ATRの重要な基質である。
がん細胞は、代表的には、腫瘍遺伝子発現、低酸素症もしくは他の修復経路(例えば、塩基除去修復)における欠陥から生じ得る、高いレベルのバックグラウンド複製ストレスを有する。これは、いくつかのがん細胞において、生存のためにATRに対する依存性をもたらし得る。さらに、細胞は、多くのDNA損傷薬物および電離放射線での処置後に、または塩基除去修復を遮断するPARP阻害剤のような他の修復経路を遮断する剤での処置から、複製ストレスを解決することをATRに要求する。
本発明は、Chk1プロテインキナーゼの阻害剤として有用な化合物と組み合わせて、ATRプロテインキナーゼの阻害剤として有用な化合物を投与することによって、患者におけるがんを処置するための方法に関する。前述の組み合わせは、標的とされるプロテインキナーゼが同じ生物学的経路内にあるにも関わらず、がんを処置するにあたって驚くべき相乗効果を示した。さらに、本発明はまた、患者にATRプロテインキナーゼの阻害剤として有用な化合物を投与する工程;Chk1プロテインキナーゼの阻害剤として有用な化合物を投与する工程;ならびに1またはより多くのDNA損傷因子を投与する工程によって、がんを処置するための方法に関する。
本発明は、例えば、以下の項目を提供する。
(項目1)
患者においてがんを処置する方法であって:
ATRプロテインキナーゼを阻害する化合物を投与する工程;および
Chk1プロテインキナーゼを阻害する化合物を投与する工程
を包含する、方法。
(項目2)
前記患者に、DNA損傷因子から独立して選択される1つまたはより多くのさらなる治療剤を投与する工程をさらに包含し;ここで該さらなる治療剤は、処置されている疾患に適切であり;そして該さらなる治療剤は、1個の剤形として前記化合物と一緒にか、または複数の剤形の一部として前記化合物とは別に投与される、項目1に記載の方法。
(項目3)
前記DNA損傷因子は、化学療法または放射線治療から選択される、項目2に記載の方法。
(項目4)
前記DNA損傷因子は、電離放射線、放射線類似作用ネオカルチノスタチン、白金製剤、Topo I阻害剤、Topo II阻害剤、代謝拮抗物質、アルキル化剤、アルキルスルホネート、または抗生物質から独立して選択される、項目2に記載の方法。
(項目5)
前記DNA損傷因子は、電離放射線、白金製剤、Topo I阻害剤、Topo II阻害剤、代謝拮抗物質、アルキル化剤、またはアルキルスルホネートから独立して選択される、項目4に記載の方法。
(項目6)
前記DNA損傷因子は、電離放射線、白金製剤、Topo I阻害剤、Topo II阻害剤、または抗生物質から独立して選択される、項目4に記載の方法。
(項目7)
前記白金製剤は、シスプラチン、オキサリプラチン、カルボプラチン、ネダプラチン、ロバプラチン、トリプラチンテトラニトレート、ピコプラチン、サトラプラチン、プロリンダクおよびアロプラチンから独立して選択され;前記Topo I阻害剤は、カンプトテシン、トポテカン、イリノテカン/SN38、ルビテカンおよびベロテカンから選択され;前記Topo II阻害剤は、エトポシド、ダウノルビシン、ドキソルビシン、アクラルビシン、エピルビシン、イダルビシン、アムルビシン、ピラルビシン、バルルビシン、ゾルビシンおよびテニポシドから選択され;前記代謝拮抗物質は、アミノプテリン、メトトレキサート、ペメトレキセド、ラルチトレキセド、ペントスタチン、クラドリビン、クロファラビン、フルダラビン、チオグアニン、メルカプトプリン、フルオロウラシル、カペシタビン、テガフール、カルモフール、フロクスウリジン、シタラビン、ゲムシタビン、アザシチジンおよびヒドロキシウレアから選択され;前記アルキル化剤は、メクロレタミン、シクロホスファミド、イホスファミド、トロフォスファミド、クロラムブシル、メルファラン、プレドニムスチン、ベンダムスチン、ウラムスチン、エストラムスチン、カルムスチン、ロムスチン、セムスチン、フォテムスチン、ニムスチン、ラニムスチン、ストレプトゾシン、ブスルファン、マンノスルファン、トレオスルファン、カルボクオン、チオテパ、トリアジクオン、トリエチレンメラミン、プロカルバジン、ダカルバジン、テモゾロミド、アルトレタミン、ミトブロニトール、アクチノマイシン、ブレオマイシン、マイトマイシンおよびプリカマイシンから選択される、項目6に記載の方法。
(項目8)
前記白金製剤は、シスプラチン、オキサリプラチン、カルボプラチン、ネダプラチン、またはサトラプラチンから独立して選択され;前記Topo I阻害剤は、カンプトテシン、トポテカン、イリノテカン/SN38、ルビテカンから選択され;前記Topo II阻害剤は、エトポシドから選択され;前記代謝拮抗物質は、メトトレキサート、ペメトレキセド、チオグアニン、フルダラビン、クラドリビン、シタラビン、ゲムシタビン、6−メルカプトプリン、または5−フルオロウラシルから選択され;前記アルキル化剤は、ナイトロジェンマスタード、ニトロソウレア、トリアゼン、アルキルスルホネート、プロカルバジン、またはアジリジンから選択され;そして前記抗生物質は、ヒドロキシウレア、アントラサイクリン、アントラセンジオン、またはストレプトミセス属ファミリーから選択される、項目7に記載の方法。
(項目9)
前記DNA損傷因子は白金製剤である、項目4〜6のいずれか1項に記載の方法。
(項目10)
前記DNA損傷因子は、シスプラチンから選択される白金製剤である、項目9に記載の方法。
(項目11)
前記DNA損傷因子は、カルボプラチンから選択される白金製剤である、項目9に記載の方法。
(項目12)
前記DNA損傷因子は電離放射線である、項目4に記載の方法。
(項目13)
前記DNA損傷因子は、ゲムシタビンから選択される代謝拮抗物質である、項目4に記載の方法。
(項目14)
前記DNA損傷因子は、カンプトテシン、トポテカン、イリノテカン/SN38、ルビテカンまたはベロテカンから選択されるTopo I阻害剤である、項目4に記載の方法。
(項目15)
前記DNA損傷因子は、エトポシドから選択されるTopo II阻害剤である、項目4に記載の方法。
(項目16)
前記DNA損傷因子は、テモゾロミドから選択されるアルキル化剤である、項目4に記載の方法。
(項目17)
前記DNA損傷因子は、以下:シスプラチン、カルボプラチン、ゲムシタビン、エトポシド、テモゾロミド、または電離放射線のうちの1つまたはより多くから選択される、項目4に記載の方法。
(項目18)
前記がんは、塩基除去修復タンパク質に欠陥を有する、項目1に記載の方法。
(項目19)
前記塩基除去修復タンパク質は、UNG、SMUG1、MBD4、TDG、OGG1、MYH、NTH1、MPG、NEIL1、NEIL2、NEIL3(DNAグリコシラーゼ);APE1、APEX2(APエンドヌクレアーゼ);LIG1、LIG3(DNAリガーゼIおよびIII);XRCC1(LIG3アクセサリー);PNK、PNKP(ポリヌクレオチドキナーゼおよびホスファターゼ);PARP1、PARP2(ポリ(ADP−リボース)ポリメラーゼ);PolB、PolG(ポリメラーゼ);FEN1(エンドヌクレアーゼ)またはアプラタキシンである、項目18に記載の方法。
(項目20)
前記塩基除去修復タンパク質は、PARP1またはPARP2である、項目19に記載の方法。
(項目21)
前記患者にさらなる治療剤を投与する工程をさらに包含し、ここで該剤は、塩基除去修復タンパク質を阻害または調節する、項目18〜20のいずれか1項に記載の方法。
(項目22)
前記塩基除去修復タンパク質は、PARP1またはPARP2から選択される、項目21に記載の方法。
(項目23)
前記患者に、DNA損傷因子から選択されるさらなる治療剤を投与する工程をさらに包含する、項目22に記載の方法。
(項目24)
前記DNA損傷因子は電離放射線である、項目23に記載の方法。
(項目25)
前記DNA損傷因子はシスプラチンである、項目23に記載の方法。
(項目26)
前記がんは、以下のがん:口部、肺、胃腸:尿生殖路、肝臓、骨、神経系、婦人科、皮膚、甲状腺、または副腎から選択される固形腫瘍である、項目1〜25のいずれか1項に記載の方法。
(項目27)
前記がんは、以下のがん:口部:口腔、口唇、舌、口、咽頭;心臓:肉腫(血管肉腫、線維肉腫、横紋筋肉腫、脂肪肉腫)、粘液腫、横紋筋腫、線維腫、脂肪腫、および奇形種;肺:気管支癌(扁平細胞または類表皮、未分化小細胞、未分化大細胞、腺癌)、肺胞(細気管支)癌、気管支腺腫、肉腫、リンパ腫、軟骨性過誤腫、中皮腫;胃腸:食道(扁平上皮癌、喉頭、腺癌、平滑筋肉腫、リンパ腫)、胃(癌、リンパ腫、平滑筋肉腫)、膵臓(膵管腺癌、膵島細胞腺腫、グルカゴノーマ、ガストリノーマ、類癌腫瘍、ビポーマ)、小腸(腺癌、リンパ腫、類癌腫瘍、カポジ肉腫、平滑筋腫、血管腫、脂肪腫、神経線維腫、線維腫)、大腸(腺癌、管状腺腫、絨毛腺腫、過誤腫、平滑筋腫)、結腸、結腸・直腸、結腸直腸;直腸、尿生殖路:腎臓(腺癌、ウィルムス腫瘍[腎芽腫]、リンパ腫)、膀胱および尿道(扁平上皮癌、移行上皮癌、腺癌)、前立腺(腺癌、肉腫)、精巣(精上皮腫、奇形腫、胎生期癌、奇形癌腫、絨毛腫瘍、肉腫、間質細胞癌、線維腫、線維腺腫、類腺腫瘍、脂肪腫);肝臓:肝癌(肝細胞癌)、胆管癌、肝芽細胞腫、血管肉腫、肝細胞腺腫、血管腫、胆道;骨:骨原性肉腫(骨肉腫)、線維肉腫、悪性線維性組織球腫、軟骨肉腫、ユーイング肉腫、悪性リンパ腫(細網肉腫)、多発性骨髄腫、悪性巨細胞脊索腫、骨軟骨腫(骨軟骨性外骨症)、良性軟骨腫、軟骨芽細胞腫、軟骨粘液線維腫、類骨骨腫および巨細胞腫瘍;神経系:頭蓋(骨腫、血管腫、肉芽腫、黄色腫、変形性骨炎)、髄膜(髄膜腫、髄膜肉腫、神経膠腫症)、脳(星状細胞腫、髄芽腫、神経膠腫、上衣腫、胚細胞腫[松果体腫]、多形膠芽細胞腫、乏突起神経膠腫、神経鞘腫、網膜芽腫、先天性腫瘍)、脊髄神経線維腫、髄膜腫、神経膠腫、肉腫);婦人科:子宮(子宮内膜癌)、子宮頸部(子宮頸部癌、前癌子宮頸部異形成)、卵巣(卵巣癌[漿液性嚢胞腺癌、粘液性嚢胞腺癌、非分類癌]、顆粒膜・莢膜細胞腫、セルトリ・ライディッヒ細胞腫、未分化胚細胞腫、悪性奇形種)、外陰(扁平上皮癌、上皮内癌、腺癌、線維肉腫、黒色腫)、膣(明細胞癌、扁平上皮癌、ブドウ状肉腫(胎児性横紋筋肉腫)、卵管(癌)、乳房;皮膚:悪性黒色腫、基底細胞癌、扁平上皮癌、カポジ肉腫、角化棘細胞腫、異形成母斑、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬、甲状腺:甲状腺乳頭癌、甲状腺濾胞癌;甲状腺髄様癌、多発性内分泌腺腫瘍2A型、多発性内分泌腺腫瘍2B型、家族性甲状腺髄様がん、褐色細胞腫、傍神経節腫、ならびに副腎:神経芽腫から選択される固形腫瘍である、項目26に記載の方法。
(項目28)
前記がんは、非小細胞肺がん、小細胞肺がん、膵臓がん、胆管がん、頭頸部がん、膀胱がん、結腸直腸がん、膠芽腫、食道がん、乳がん、肝細胞癌、または卵巣がんから選択される、項目1〜27のいずれか1項に記載の方法。
(項目29)
前記がんは、非小細胞肺がん、小細胞肺がん、およびトリプルネガティブ乳がんから選択される、項目28に記載の方法。
(項目30)
前記さらなる治療剤は、ゲムシタビンまたはシスプラチンであり、そして前記がんは、
非小細胞肺がんの扁平上皮サブタイプである、項目28に記載の方法。
(項目31)
がん細胞において細胞死を促進する方法であって:
ATRプロテインキナーゼを阻害する化合物を投与する工程;および
Chk1プロテインキナーゼを阻害する化合物を投与する工程
を包含する、方法。
(項目32)
前記がん細胞は、ATMシグナル伝達カスケードに欠損を有する、項目31に記載の方法。
(項目33)
前記欠損は、以下:ATM、p53、CHK2、MRE11、RAD50、NBS1、53BP1、MDC1、H2AX、MCPH1/BRIT1、CTIP、またはSMC1のうちの1つまたはより多くの変化した発現または活性である、項目32に記載の方法。
(項目34)
前記欠損は、以下:ATM、p53、CHK2、MRE11、RAD50、NBS1、53BP1、MDC1またはH2AXのうちの1つまたはより多くの変化した発現または活性である、項目33に記載の方法。
(項目35)
前記がん細胞は、DNA損傷がん遺伝子を発現している、項目31に記載の方法。
(項目36)
前記がん細胞は、以下:K−Ras、N−Ras、H−Ras、Raf、Myc、Mos、E2F、Cdc25A、CDC4、CDK2、サイクリンE、サイクリンAおよびRbのうちの1つまたはより多くの変化した発現または活性を有する、項目35に記載の方法。
(項目37)
前記Chk1を阻害する化合物は、AZD7762、LY2603618、MK−8776、CHIR−124、およびPF−477736から独立して選択される、項目1〜36のいずれか1項に記載の方法。
(項目38)
前記ATRを阻害する化合物は、式I;
またはその薬学的に受容可能な塩によって表され、式Iにおいて、
R 1 は、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する5員〜6員の単環式のアリール環またはヘテロアリール環であり、ここで該単環式のアリール環またはヘテロアリール環は、別の環と必要に応じて縮合して、独立して窒素、酸素、または硫黄から選択される0個〜6個のヘテロ原子を有する8員〜10員の二環式のアリール環またはヘテロアリール環を形成し;R 1 の各々は、1個〜5個のJ 1 基で必要に応じて置換されており;
R 2 は、独立して窒素、酸素、または硫黄から選択される0個〜3個のヘテロ原子を有する5員〜6員の単環式のアリール環またはヘテロアリール環であり、ここで該単環式のアリール環またはヘテロアリール環は、別の環と必要に応じて縮合して、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する8員〜10員の二環式のアリール環またはヘテロアリール環を形成し;R 2 の各々は、1個〜5個のJ 2 基で必要に応じて置換されており;
Lは、−C(O)NH−または−C(O)N(C 1〜6 アルキル)−であり;
nは、0または1であり;
J 1 およびJ 2 の各々は独立して、ハロ、−CN、−NO 2 、−V 1 −R、または−(V 2 ) m −Qであり;
V 1 は、0個〜3個のメチレン単位がO、NR”、S、C(O)、S(O)、またはS(O) 2 で必要に応じて独立して置き換えられたC 1〜10 脂肪族鎖であり;V 1 は、1個〜6個の存在のJ V1 で必要に応じて置換されており;
V 2 は、0個〜3個のメチレン単位がO、NR”、S、C(O)、S(O)、またはS(O) 2 で必要に応じて独立して置き換えられたC 1〜10 脂肪族鎖であり;V 2 は、1個〜6個の存在のJ V2 で必要に応じて置換されており;
mは、0または1であり;
Qは、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する3員〜8員の飽和または不飽和の単環式環、あるいは独立して窒素、酸素、または硫黄から選択される0個〜6個のヘテロ原子を有する9員〜10員の飽和または不飽和の二環式環であり;Qの各々は、0個〜5個のJ Q で必要に応じて置換されており;
J V1 またはJ V2 の各々は独立して、ハロゲン、CN、NH 2 、NO 2 、C 1〜4 脂肪族、NH(C 1〜4 脂肪族)、N(C 1〜4 脂肪族) 2 、OH、O(C 1〜4 脂肪族)、CO 2 H、CO 2 (C 1〜4 脂肪族)、C(O)NH 2 、C(O)NH(C 1〜4 脂肪族)、C(O)N(C 1〜4 脂肪族) 2 、NHCO(C 1〜4 脂肪族)、N(C 1〜4 脂肪族)CO(C 1〜4 脂肪族)、SO 2 (C 1〜4 脂肪族)、NHSO 2 (C 1〜4 脂肪族)、またはN(C 1〜4 脂肪族)SO 2 (C 1〜4 脂肪族)であり、ここで該C 1〜4 脂肪族は、ハロで必要に応じて置換されており;
Rは、HまたはC 1〜6 脂肪族であり、ここで該C 1〜6 脂肪族は、1個〜4個の存在のNH 2 、NH(C 1〜4 脂肪族)、N(C 1〜4 脂肪族) 2 、ハロゲン、C 1〜4 脂肪族、OH、O(C 1〜4 脂肪族)、NO 2 、CN、CO 2 H、CO 2 (C 1〜4 脂肪族)、CO(C 1〜4 脂肪族)、O(ハロC 1〜4 脂肪族)、またはハロC 1〜4 脂肪族で必要に応じて置換されており;
J Q の各々は独立して、ハロ、オキソ、CN、NO 2 、X−R、または−(X) p −Q 4 であり;
pは、0または1であり;
XはC 1〜10 脂肪族であり;ここで該C 1〜6 脂肪族の1個〜3個のメチレン単位は、−NR、−O−、−S−、C(O)、S(O) 2 、またはS(O)で必要に応じて置き換えられており;ここでXは、1個〜4個の存在のNH 2 、NH(C 1〜4 脂肪族)、N(C 1〜4 脂肪族) 2 、ハロゲン、C 1〜4 脂肪族、OH、O(C 1〜4 脂肪族)、NO 2 、CN、CO(C 1〜4 脂肪族)、CO 2 H、CO 2 (C 1〜4 脂肪族)、C(O)NH 2 、C(O)NH(C 1〜4 脂肪族)、C(O)N(C 1〜4 脂肪族) 2 、SO(C 1〜4 脂肪族)、SO 2 (C 1〜4 脂肪族)、SO 2 NH(C 1〜4 脂肪族)、SO 2 N(C 1〜4 脂肪族) 2 、NHC(O)(C 1〜4 脂肪族)、N(C 1〜4 脂肪族)C(O)(C 1〜4 脂肪族)で必要に応じて独立して置換されており、ここで該C 1〜4 脂肪族は、1個〜3個の存在のハロで必要に応じて置換されており;
Q 4 は、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する3員〜8員の飽和または不飽和の単環式環、あるいは独立して窒素、酸素、または硫黄から選択される0個〜6個のヘテロ原子を有する8員〜10員の飽和または不飽和の二環式環であり;Q 4 の各々は、1個〜5個のJ Q4 で必要に応じて置換されており;
J Q4 は、ハロ、CN、または2個までのメチレン単位がO、NR * 、S、C(O)、S(O)、もしくはS(O) 2 で必要に応じて置き換えられたC 1〜4 アルキルであり;
Rは、HまたはC 1〜4 アルキルであり、ここで該C 1〜4 アルキルは、1個〜4個のハロで必要に応じて置換されており;
R’、R”、およびR * は各々独立して、H、C 1〜4 アルキルであるか、または存在せず;ここで該C 1〜4 アルキルは、1個〜4個のハロで必要に応じて置換されており;
ここで前記がんは、ATMシグナル伝達経路において1つまたはより多くの欠損を有する、
項目1〜37のいずれか1項に記載の方法。
(項目39)
前記ATRを阻害する化合物は
である、項目1〜38のいずれか1項に記載の方法。
(項目40)
前記ATRを阻害する化合物は、式I−a:
によって表され、式I−aにおいて:
環Aは
であり、
J 5 oは、H、F、Cl、C 1〜4 脂肪族、O(C 1〜3 脂肪族)、またはOHであり;
J 5 pは
であり;
J 5 p1は、H、C 1〜4 脂肪族、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニルであり;ここでJ 5 p1は、1個〜2個の存在のOHまたはハロで必要に応じて置換されており;
J 5 p2は、H、メチル、エチル、CH 2 F、CF 3 、またはCH 2 OHであり;
J 2 oは、H、CN、またはSO 2 CH 3 であり;
J 2 mは、H、F、Cl、またはメチルであり;
J 2 pは、−SO 2 (C 1〜6 アルキル)、−SO 2 (C 3〜6 シクロアルキル)、−SO 2 (4員〜6員ヘテロシクリル)、−SO 2 (C 1〜4 アルキル)N(C 1〜4 アルキル) 2 、または−SO 2 (C 1〜4 アルキル)−(4員〜6員ヘテロシクリル)であり、ここで該ヘテロシクリルは、酸素、窒素、または硫黄から選択される1個のヘテロ原子を含み;そしてここで該J 2 pは、1個〜3個存在するハロ、OH、またはO(C 1〜4 アルキル)で必要に応じて置換されている、
項目1〜38のいずれか1項に記載の方法。
(項目41)
環Aは
である、項目40に記載の方法。
(項目42)
環Aは
である、項目40に記載の方法。
(項目43)
前記ATRを阻害する化合物は
である、項目40に記載の方法。
(項目44)
前記ATRを阻害する化合物は、式II:
またはその薬学的に受容可能な塩あるいは誘導体によって表され、式IIにおいて:
R 10 は、フルオロ、クロロ、または−C(J 10 ) 2 CNから独立して選択され;
J 10 は、HまたはC 1〜2 アルキルから独立して選択されるか;あるいは
2個存在するJ 10 は、これらが結合している炭素原子と一緒になって、3員〜4員の必要に応じて置換された炭素環式環を形成し;
R 20 は、H;ハロ;−CN;NH 2 ;0個〜3個の存在のフルオロで必要に応じて置換されたC 1〜2 アルキル;または脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z で必要に応じて置き換えられたC 1〜3 脂肪族鎖から独立して選択され;
R 3 は、H;ハロ;1個〜3個の存在のハロで必要に応じて置換されたC 1〜4 アルキル;C 3〜4 シクロアルキル;−CN;または脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z で必要に応じて置き換えられたC 1〜3 脂肪族鎖から独立して選択され;
R 4 は、Q 1 、または脂肪族鎖の4個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z −で必要に応じて置き換えられたC 1〜10 脂肪族鎖から独立して選択され;R 4 の各々は、0個〜5個の存在のJ Q1 で必要に応じて置換されているか;あるいは
R 3 およびR 4 は、これらが結合している原子と一緒になって、酸素、窒素または硫黄から選択される0個〜2個のヘテロ原子を有する5員〜6員の芳香族または非芳香族の環を形成し;R 3 およびR 4 によって形成される該環は、0個〜3個の存在のJ Z で必要に応じて置換されており;
Q 1 は、3員〜7員の完全飽和、部分不飽和、もしくは芳香族の単環式環であって、該3員〜7員の環は、酸素、窒素または硫黄から選択される0個〜3個のヘテロ原子を有する環;または酸素、窒素、もしくは硫黄から選択される0個〜5個のヘテロ原子を有する7員〜12員の完全飽和、部分不飽和、もしくは芳香族の二環式環から独立して選択され;
J z は、C 1〜6 脂肪族、=O、ハロ、または→Oから独立して選択され;
J Q1 は、−CN;ハロ;=O;Q 2 ;または脂肪族鎖の3個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z −で必要に応じて置き換えられたC 1〜8 脂肪族鎖から独立して選択され;J Q1 の各存在は、0個〜3個の存在のJ R によって必要に応じて置換されているか;あるいは
同じ原子上に2個存在するJ Q1 は、これらが結合している原子と一緒になって、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成し;ここで2個存在するJ Q1 によって形成される該環は、0個〜3個の存在のJ X で必要に応じて置換されているか;あるいは
2個存在するJ Q1 は、Q 1 と一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
Q 2 は、酸素、窒素、もしくは硫黄から選択される0個〜3個のヘテロ原子を有する3員〜7員の完全飽和、部分不飽和、もしくは芳香族の単環式環;または酸素、窒素、もしくは硫黄から選択される0個〜5個のヘテロ原子を有する7員〜12員の完全飽和、部分不飽和、もしくは芳香族の二環式環から独立して選択され;
J R は、−CN;ハロ;=O;→O;Q 3 ;または脂肪族鎖の3個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z −で必要に応じて置き換えられたC 1〜6 脂肪族鎖から独立して選択され;J R の各々は、0個〜3個の存在のJ T で必要に応じて置換されているか;あるいは
同じ原子上に2個存在するJ R は、これらが結合している原子と一緒になって、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成し;ここで2個存在するJ R によって形成される該環は、0個〜3個の存在のJ X で必要に応じて置換されているか;あるいは
2個存在するJ R は、Q 2 と一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
Q 3 は、酸素、窒素、もしくは硫黄から選択される0個〜3個のヘテロ原子を有する3員〜7員の完全飽和、部分不飽和、もしくは芳香族の単環式環;または酸素、窒素、もしくは硫黄から選択される0個〜5個のヘテロ原子を有する7員〜12員の完全飽和、部分不飽和、もしくは芳香族の二環式環であり;
J X は、−CN;=O;ハロ;または脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z −で必要に応じて置き換えられたC 1〜4 脂肪族鎖から独立して選択され;
J T は、ハロ、−CN;→O;=O;−OH;脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z −で必要に応じて置き換えられたC 1〜6 脂肪族鎖;または酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の非芳香族環から独立して選択され;J T の各存在は、0個〜3個の存在のJ M で必要に応じて置換されているか;あるいは
同じ原子上に2個存在するJ T は、これらが結合している原子と一緒になって、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成するか;あるいは
2個存在するJ T は、Q 3 と一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
J M は、ハロまたはC 1〜6 脂肪族から独立して選択され;
Jは、HまたはClであり;
zは、0、1または2であり;そして
R a は、HまたはC 1〜4 脂肪族から独立して選択される、
項目1〜36のいずれか1項に記載の方法。
(項目45)
R 1 およびR 3 はフルオロである、項目44に記載の方法。
(項目46)
R 4 はQ 1 である、項目45に記載の方法。
(項目47)
Q 1 は、ピペリジニルおよびイミダゾリルから独立して選択される、項目46に記載の方法。
(項目48)
前記ATRを阻害する化合物は、構造:
によって表される、項目47に記載の方法。
(項目49)
前記ATRを阻害する化合物は、式II−a:
またはその薬学的に受容可能な塩あるいはプロドラッグによって表され、式II−aにおいて:
R 10 は、フルオロ、クロロ、または−C(J 10 ) 2 CNから独立して選択され;
J 10 は、HまたはC 1〜2 アルキルから独立して選択されるか;あるいは
2個存在するJ 1 は、これらが結合している炭素原子と一緒になって、必要に応じて置換された3員〜4員の炭素環式環を形成し;
R 3 は、H;クロロ;フルオロ;1個〜3個の存在のハロで必要に応じて置換されたC 1〜4 アルキル;C 3〜4 シクロアルキル;−CN;または脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z で必要に応じて置き換えられたC 1〜3 脂肪族鎖から独立して選択され;
L 1 は、H;酸素、窒素もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜7員の芳香族もしくは非芳香族の環;または脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z で必要に応じて置き換えられたC 1〜6 脂肪族鎖であり;L 1 の各々は、C 1〜4 脂肪族;−CN;ハロ;−OH;または酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の非芳香族環で必要に応じて置換されており;
L 2 は、H;酸素、窒素もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜7員の芳香族もしくは非芳香族の環;または脂肪族鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z で必要に応じて置き換えられたC 1〜6 脂肪族鎖であり;L 2 の各々は、C 1〜4 脂肪族;−CN;ハロ;−OH;または酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の非芳香族環で必要に応じて置換されているか;あるいは
L 1 およびL 2 は、これらが結合している窒素と一緒になって、環Dを形成し;環Dは、0個〜5個の存在のJ G で必要に応じて置換されており;
L 3 は、H;C 1〜3 脂肪族;またはCNであり;
環Dは、酸素、窒素もしくは硫黄から選択される1個〜2個のヘテロ原子を有する3員〜7員のヘテロシクリル環;または酸素、窒素、もしくは硫黄から選択される1個〜5個のヘテロ原子を有する7員〜12員の完全不飽和もしくは部分不飽和の二環式環から独立して選択され;
J G は、ハロ;−CN;−N(R°) 2 ;→O;3員〜6員のカルボシクリル;酸素、窒素、もしくは硫黄から選択される1個〜2個のヘテロ原子を有する3員〜6員のヘテロシクリル;またはアルキル鎖の2個までのメチレン単位が−O−、−NR a −、−C(O)−、もしくは−S(O) z で必要に応じて置き換えられたC 1〜4 アルキル鎖から独立して選択され;J G の各々は、0個〜2個の存在のJ K で必要に応じて置換されており、
同じ原子上に2個存在するJ G は、これらが結合している原子と一緒になって、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成するか;あるいは
2個存在するJ G は、環Dと一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
J K は、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜7員の芳香族もしくは非芳香族の環であり;
zは、0、1、または2であり;そして
R a およびR°は、HまたはC 1〜4 アルキルである、
項目44に記載の方法。
(項目50)
R 1 およびR 3 はフルオロである、項目49に記載の方法。
(項目51)
前記ATRを阻害する化合物は、構造:
によって表される、項目50に記載の方法。
(項目52)
患者においてがんを処置するための医薬の製造のための、ATRキナーゼを阻害するための第一の化合物の、Chk1キナーゼを阻害するための第二の化合物と組み合わせての使用。
(項目53)
前記第一の化合物および第二の化合物は、項目2〜25のいずれか1項における剤から選択される1つまたはより多くのさらなる治療剤と組み合わせられる、項目52に記載の使用。
(項目54)
前記がんは、項目1〜30におけるいずれか1つから選択される、項目52に記載の使用。
(項目55)
前記ATRキナーゼを阻害するための化合物は、式I:
またはその薬学的に受容可能な塩によって表され、式Iにおいて、可変物は、項目38において定義されるとおりである、項目52に記載の使用。
(項目56)
前記ATRキナーゼを阻害するための化合物は、項目39〜43のいずれか1項から選択される、項目55に記載の使用。
(項目57)
前記ATRキナーゼを阻害するための化合物は、式II:
またはその薬学的に受容可能な塩によって表され、式IIにおいて、可変物は、項目44において定義されるとおりである、項目52に記載の使用。
(項目58)
前記ATRキナーゼを阻害するための化合物は、項目45〜51のいずれか1項から選択される、項目57に記載の使用。
(項目59)
がん細胞において細胞死を促進するための医薬の製造のための、ATRキナーゼを阻害するための第一の化合物の、Chk1キナーゼを阻害するための第二の化合物と組み合わせての使用。
本発明の1またはより多くの局面は、ATRプロテインキナーゼを阻害する第一の化合物を投与する工程;およびChk1プロテインキナーゼを阻害する第二の化合物を投与する工程を包含する、患者においてがんを処置するための方法を提供する。本発明の別の局面は、ATRプロテインキナーゼを阻害する第一の化合物を投与する工程;Chk1プロテインキナーゼを阻害する第二の化合物を投与する工程;および1またはより多くのさらなる治療剤を投与する工程を包含する、患者においてがんを処置するための方法を提供する。
本発明の別の局面において、このATRプロテインキナーゼを阻害する化合物は、式I:
R1は、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する5員〜6員の単環式のアリール環またはヘテロアリール環であり、ここでこの単環式のアリール環またはヘテロアリール環は、別の環と必要に応じて縮合して、独立して窒素、酸素、または硫黄から選択される0個〜6個のヘテロ原子を有する8員〜10員の二環式のアリール環またはヘテロアリール環を形成し;R1の各々は、1個〜5個のJ1基で必要に応じて置換されており;
R2は、独立して窒素、酸素、または硫黄から選択される0個〜3個のヘテロ原子を有する5員〜6員の単環式のアリール環またはヘテロアリール環であり、ここでこの単環式のアリール環またはヘテロアリール環は、別の環と必要に応じて縮合して、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する8員〜10員の二環式のアリール環またはヘテロアリール環を形成し;R2の各々は、1個〜5個のJ2基で必要に応じて置換されており;
Lは、−C(O)NH−または−C(O)N(C1〜6アルキル)−であり;
nは、0または1であり;
J1およびJ2の各々は独立して、ハロ、−CN、−NO2、−V1−R、または−(V2)m−Qであり;
V1は、0個〜3個のメチレン単位がO、NR”、S、C(O)、S(O)、またはS(O)2で必要に応じて独立して置き換えられたC1〜10脂肪族鎖であり;V1は、1個〜6個の存在のJV1で必要に応じて置換されており;
V2は、0個〜3個のメチレン単位がO、NR”、S、C(O)、S(O)、またはS(O)2で必要に応じて独立して置き換えられたC1〜10脂肪族鎖であり;V2は、1個〜6個の存在のJV2で必要に応じて置換されており;
mは、0または1であり;
Qは、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する3員〜8員の飽和または不飽和の単環式環、あるいは独立して窒素、酸素、または硫黄から選択される0個〜6個のヘテロ原子を有する9員〜10員の飽和または不飽和の二環式環であり;Qの各々は、0個〜5個のJQで必要に応じて置換されており;
JV1またはJV2の各々は独立して、ハロゲン、CN、NH2、NO2、C1〜4脂肪族、NH(C1〜4脂肪族)、N(C1〜4脂肪族)2、OH、O(C1〜4脂肪族)、CO2H、CO2(C1〜4脂肪族)、C(O)NH2、C(O)NH(C1〜4脂肪族)、C(O)N(C1〜4脂肪族)2、NHCO(C1〜4脂肪族)、N(C1〜4脂肪族)CO(C1〜4脂肪族)、SO2(C1〜4脂肪族)、NHSO2(C1〜4脂肪族)、またはN(C1〜4脂肪族)SO2(C1〜4脂肪族)であり、ここでこのC1〜4脂肪族は、ハロで必要に応じて置換されており;
Rは、HまたはC1〜6脂肪族であり、ここでこのC1〜6脂肪族は、1個〜4個の存在のNH2、NH(C1〜4脂肪族)、N(C1〜4脂肪族)2、ハロゲン、C1〜4脂肪族、OH、O(C1〜4脂肪族)、NO2、CN、CO2H、CO2(C1〜4脂肪族)、CO(C1〜4脂肪族)、O(ハロC1〜4脂肪族)、またはハロC1〜4脂肪族で必要に応じて置換されており;
JQの各々は独立して、ハロ、オキソ、CN、NO2、X−R、または−(X)p−Q4であり;
pは、0または1であり;
Xは、C1〜10脂肪族であり;ここでこのC1〜6脂肪族の1個〜3個のメチレン単位は、−NR、−O−、−S−、C(O)、S(O)2、またはS(O)で必要に応じて置き換えられており;ここでXは、1個〜4個の存在のNH2、NH(C1〜4脂肪族)、N(C1〜4脂肪族)2、ハロゲン、C1〜4脂肪族、OH、O(C1〜4脂肪族)、NO2、CN、CO(C1〜4脂肪族)、CO2H、CO2(C1〜4脂肪族)、C(O)NH2、C(O)NH(C1〜4脂肪族)、C(O)N(C1〜4脂肪族)2、SO(C1〜4脂肪族)、SO2(C1〜4脂肪族)、SO2NH(C1〜4脂肪族)、SO2N(C1〜4脂肪族)2、NHC(O)(C1〜4脂肪族)、N(C1〜4脂肪族)C(O)(C1〜4脂肪族)で必要に応じて独立して置換されており、ここでこのC1〜4脂肪族は、1個〜3個の存在のハロで必要に応じて置換されており;
Q4は、独立して窒素、酸素、または硫黄から選択される0個〜4個のヘテロ原子を有する3員〜8員の飽和または不飽和の単環式環、あるいは独立して窒素、酸素、または硫黄から選択される0個〜6個のヘテロ原子を有する8員〜10員の飽和または不飽和の二環式環であり;Q4の各々は、1個〜5個のJQ4で必要に応じて置換されており;
JQ4は、ハロ、CN、または2個までのメチレン単位がO、NR*、S、C(O)、S(O)、もしくはS(O)2で必要に応じて置き換えられたC1〜4アルキルであり;
Rは、HまたはC1〜4アルキルであり、ここでこのC1〜4アルキルは、1個〜4個のハロで必要に応じて置換されており;
R’、R”、およびR*は各々独立して、H、C1〜4アルキルであるか、または存在せず;ここでこのC1〜4アルキルは、1個〜4個のハロで必要に応じて置換されている。
いくつかの実施形態において、Lは−C(O)NH−であり;そしてR1およびR2はフェニルである。
環Aは
J5oは、H、F、Cl、C1〜4脂肪族、O(C1〜3脂肪族)、またはOHであり;
J5pは
J5p1は、H、C1〜4脂肪族、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニルであり;ここでJ5p1は、1個〜2個の存在のOHまたはハロで必要に応じて置換されており;
J5p2は、H、メチル、エチル、CH2F、CF3、またはCH2OHであり;
J2oは、H、CN、またはSO2CH3であり;
J2mは、H、F、Cl、またはメチルであり;
J2pは、−SO2(C1〜6アルキル)、−SO2(C3〜6シクロアルキル)、−SO2(4員〜6員ヘテロシクリル)、−SO2(C1〜4アルキル)N(C1〜4アルキル)2、または−SO2(C1〜4アルキル)−(4員〜6員ヘテロシクリル)であり、ここでこのヘテロシクリルは、酸素、窒素、または硫黄から選択される1個のヘテロ原子を含み;そしてこのJ2pは、1個〜3個存在するハロ、OH、またはO(C1〜4アルキル)で必要に応じて置換されている。
R10は、フルオロ、クロロ、または−C(J10)2CNから独立して選択され;
J10は、HまたはC1〜2アルキルから独立して選択されるか;あるいは
2個存在するJ10は、これらが結合している炭素原子と一緒になって、3員〜4員の必要に応じて置換された炭素環式環を形成し;
R20は、H;ハロ;−CN;NH2;0個〜3個の存在のフルオロで必要に応じて置換されたC1〜2アルキル;または脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)zで必要に応じて置き換えられたC1〜3脂肪族鎖から独立して選択され;
R3は、H;ハロ;1個〜3個の存在のハロで必要に応じて置換されたC1〜4アルキル;C3〜4シクロアルキル;−CN;または脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)zで必要に応じて置き換えられたC1〜3脂肪族鎖から独立して選択され;
R4は、Q1、または脂肪族鎖の4個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)z−で必要に応じて置き換えられたC1〜10脂肪族鎖から独立して選択され;R4の各々は、0個〜5個の存在のJQ1で必要に応じて置換されているか;あるいは
R3およびR4は、これらが結合している原子と一緒になって、酸素、窒素もしくは硫黄から選択される0個〜2個のヘテロ原子を有する5員〜6員の芳香族または非芳香族の環を形成し;R3およびR4によって形成されるこの環は、0個〜3個の存在のJZで必要に応じて置換されており;
Q1は、3員〜7員の完全飽和、部分不飽和、もしくは芳香族の単環式環であって、この3員〜7員の環は、酸素、窒素もしくは硫黄から選択される0個〜3個のヘテロ原子を有する、環;または酸素、窒素、もしくは硫黄から選択される0個〜5個のヘテロ原子を有する7員〜12員の完全飽和、部分不飽和、もしくは芳香族の二環式環から独立して選択され;
Jzは、C1〜6脂肪族、=O、ハロ、または→Oから独立して選択され;
JQ1は、−CN;ハロ;=O;Q2;または脂肪族鎖の3個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)z−で必要に応じて置き換えられたC1〜8脂肪族鎖から独立して選択され;JQ1の各存在は、0個〜3個の存在のJRによって必要に応じて置換されているか;あるいは
同じ原子上に2個存在するJQ1は、これらが結合している原子と一緒になって、酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成し;ここで2個存在するJQ1によって形成されるこの環は、0個〜3個の存在のJXで必要に応じて置換されているか;あるいは
2個存在するJQ1は、Q1と一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
Q2は、酸素、窒素、もしくは硫黄から選択される0個〜3個のヘテロ原子を有する3員〜7員の完全飽和、部分不飽和、もしくは芳香族の単環式環;または酸素、窒素、もしくは硫黄から選択される0個〜5個のヘテロ原子を有する7員〜12員の完全飽和、部分不飽和、もしくは芳香族の二環式環から独立して選択され;
JRは、−CN;ハロ;=O;→O;Q3;または脂肪族鎖の3個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)z−で必要に応じて置き換えられたC1〜6脂肪族鎖から独立して選択され;JRの各々は、0個〜3個の存在のJTで必要に応じて置換されているか;あるいは
同じ原子上に2個存在するJRは、これらが結合している原子と一緒になって、酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成し;ここで2個存在するJRによって形成されるこの環は、0個〜3個の存在のJXで必要に応じて置換されているか;あるいは
2個存在するJRは、Q2と一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
Q3は、酸素、窒素、もしくは硫黄から選択される0個〜3個のヘテロ原子を有する3員〜7員の完全飽和、部分不飽和、もしくは芳香族の単環式環;または酸素、窒素、もしくは硫黄から選択される0個〜5個のヘテロ原子を有する7員〜12員の完全飽和、部分不飽和、もしくは芳香族の二環式環であり;
JXは、−CN;=O;ハロ;または脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)z−で必要に応じて置き換えられたC1〜4脂肪族鎖から独立して選択され;
JTは、ハロ、−CN;→O;=O;−OH;脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)z−で必要に応じて置き換えられたC1〜6脂肪族鎖;または酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の非芳香環から独立して選択され;JTの各存在は、0個〜3個の存在のJMで必要に応じて置換されているか;あるいは
同じ原子上に2個存在するJTは、これらが結合している原子と一緒になって、酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成するか;あるいは
2個存在するJTは、Q3と一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
JMは、ハロまたはC1〜6脂肪族から独立して選択され;
Jは、HまたはClであり;
zは、0、1または2であり;そして
Raは、HまたはC1〜4脂肪族から独立して選択される。
R10は、フルオロ、クロロ、または−C(J10)2CNから独立して選択され;
J10は、HまたはC1〜2アルキルから独立して選択されるか;あるいは
2個存在するJ1は、これらが結合している炭素原子と一緒になって、必要に応じて置換された3員〜4員の炭素環式環を形成し;
R3は、H;クロロ;フルオロ;1個〜3個の存在のハロで必要に応じて置換されたC1〜4アルキル;C3〜4シクロアルキル;−CN;または脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)zで必要に応じて置き換えられたC1〜3脂肪族鎖から独立して選択され;
L1は、H;酸素、窒素もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜7員の芳香族もしくは非芳香族の環;または脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)zで必要に応じて置き換えられたC1〜6脂肪族鎖であり;L1の各々は、C1〜4脂肪族;−CN;ハロ;−OH;または酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の非芳香環で必要に応じて置換されており;
L2は、H;酸素、窒素もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜7員の芳香族もしくは非芳香族の環;または脂肪族鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)zで必要に応じて置き換えられたC1〜6脂肪族鎖であり;L2の各々は、C1〜4脂肪族;−CN;ハロ;−OH;または酸素、窒素、もしくは硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の非芳香環で必要に応じて置換されているか;あるいは
L1およびL2は、これらが結合している窒素と一緒になって、環Dを形成し;環Dは、0個〜5個の存在のJGで必要に応じて置換されており;
L3は、H;C1〜3脂肪族;またはCNであり;
環Dは、酸素、窒素もしくは硫黄から選択される1個〜2個のヘテロ原子を有する3員〜7員のヘテロシクリル環;または酸素、窒素もしくは硫黄から選択される1個〜5個のヘテロ原子を有する7員〜12員の完全飽和もしくは部分不飽和の二環式環から独立して選択され;
JGは、ハロ;−CN;−N(R°)2;→O;3員〜6員のカルボシクリル(carbocycyl);酸素、窒素、もしくは硫黄から選択される1個〜2個のヘテロ原子を有する3員〜6員のヘテロシクリル;またはアルキル鎖の2個までのメチレン単位が−O−、−NRa−、−C(O)−、もしくは−S(O)zで必要に応じて置き換えられたC1〜4アルキル鎖から独立して選択され;JGの各々は、0個〜2個の存在のJKで必要に応じて置換されている。
同じ原子上に2個存在するJGは、これらが結合している原子と一緒になって、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜6員の環を形成するか;あるいは
2個存在するJGは、環Dと一緒になって、6員〜10員の飽和または部分不飽和の有橋環系を形成し;
JKは、酸素、窒素、または硫黄から選択される0個〜2個のヘテロ原子を有する3員〜7員の芳香族または非芳香族の環であり;
zは、0、1、または2であり;そして
RaおよびR°は、HまたはC1〜4アルキルである。
薬学的に受容可能な塩、溶媒和物、包接化合物(chlatrate)、プロドラッグ、および他の誘導体
治療用途
薬学的組成物
さらなる治療剤
投与様式および剤形
生物学的サンプル
プロテインキナーゼの研究
処置方法
医薬の製造
略語
DMSO ジメチルスルホキシド
ATP アデノシン三リン酸
1HNMR プロトン核磁気共鳴
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー−質量分析
TLC 薄層クロマトグラフィー
Rt 保持時間
HATU 1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスフェート
TBTU 2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムテトラフルオロボレート
T3P プロピルホスホン酸無水物
COMU 1−[(1−(シアノ−2−エトキシ−2−オキソエチリデンアミノオキシ)−ジメチルアミノ−モルホリノ)]ウロニウムヘキサフルオロホスフェート
TCTU [(6−クロロベンゾトリアゾール−1−イル)オキシ−(ジメチルアミノ)メチレン]−ジメチル−アンモニウム テトラフルオロボレート
HBTU O−ベンゾトリアゾール−N,N,N’,N’−テトラメチル−ウロニウム−ヘキサフルオロ−ホスフェート
DMF ジメチルホルムアミド
PTSA p−トルエンスルホン酸
DIPEA N,N−ジイソプロピルエチルアミン
DCM ジクロロメタン
NMP N−メチル−2−ピロリドン
EDCI 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
これらの化合物を、WO 2010/071837およびWO 2014089379に記載されるスキームおよび実施例に従って調製し得る。これらの内容は、本明細書中に参考として援用される。これらの化合物を、公知の方法(LCMS(液体クロマトグラフィー質量分析)およびNMR(核磁気共鳴)が挙げられるが、これらに限定されない)によって分析し得る。以下の一般スキームは、本開示の化合物を調製する方法を図示する。いずれの実施例も、説明のみを目的とするのであり、本発明の範囲をいかなる方法でも限定すると解釈されるべきではない。1H−NMRスペクトルを、400 MHzで、Bruker DPX 400機器を使用して記録した。質量分析サンプルを、エレクトロスプレーイオン化を用いて、シングルMSモードで動作するMicroMass Quattro Micro質量分光計で分析した。
スキームI−A1:−L−R1が芳香族アミドである化合物の調製
スキームI−A2:−L−R1が芳香族アミドである化合物の調製
スキームI−B1:環Aが1,3,4−オキサジアゾールである化合物の調製
スキームI−B2:環Aが1,3,4−オキサジアゾールである化合物の調製
スキームI−B3:環Aが1,3,4−オキサジアゾールである化合物の調製
スキームI−C1:環Aが1,2,4−オキサジアゾールである化合物の調製
スキームI−C2:環Aが1,2,4−オキサジアゾールである化合物の調製
スキームI−D1:環Aが1,3,4−チアジアゾールである化合物の調製
スキームI−D2:環Aが1,3,4−チアジアゾールである化合物の調製
スキームI−E1:環Aがイソオキサゾールである化合物の調製
スキームI−E2:環Aがイソオキサゾールである化合物の調製
スキームI−E3:環Aがイソオキサゾールである化合物の調製
スキームI−F1:環Aが1,2,4−トリアゾールである化合物の調製
スキームI−F2:環Aが1,2,4−トリアゾールである化合物の調製
スキームI−G1:環Aがベンゾオキサゾールである化合物の調製
スキームI−H1:環Aがベンゾチアゾールである化合物の調製
スキームI−H2:ベンゾチアゾールである化合物の調製
スキームI−I1: 環Aがイミダゾールである化合物の調製
スキームI−I2:環Aがイミダゾールである化合物の調製
スキームIIa:式IIの化合物の調製のための一般アプローチ
スキームIIb:式IIの化合物の調製のための代替のアプローチ
工程1
工程2
工程3
ATR/Chk1併用療法
実施例1:Chk1阻害およびATR阻害は、高レベルのDNA損傷をもたらす
実施例2a:Chk1の阻害またはChk1の不活性変異形態の発現は、がん細胞をATR阻害に対して感作させる
実施例2b:cMYC腫瘍遺伝子の発現は、ATRおよびChk1阻害の併用に対して細胞を感作させる
実施例2c:p53およびRBの機能の喪失ならびに腫瘍遺伝子H−RASの発現は、ATRおよびChk1阻害の併用に対して細胞を感作させる
実施例3:Chk1の阻害は、ATR阻害に対して腫瘍を感作させる
実施例4:Chk1の阻害は、ATR阻害剤および代表的DNA損傷因子の併用処理に対してがん細胞を感作させる
実施例5:Chk−1阻害剤によるATRの活性化は、がん細胞において高いが、正常細胞においては高くない
実施例6:ATR阻害剤およびChk−1阻害剤の併用は、1本鎖DNA形成を誘発する
実施例7:ATR阻害剤およびChk1阻害剤の併用は、がん細胞を相乗作用的に死滅させるが、正常細胞を死滅させない
実施例8:Chk1およびATRの阻害は、正常細胞において高レベルのDNA損傷をもたらさない
実施例9:ATR阻害剤VE−822は、種々のChk阻害剤と相乗作用を示す
アッセイ
実施例10:細胞ATR阻害アッセイ:
実施例11:ATR阻害アッセイ:
実施例12:シスプラチン感作アッセイ
実施例13:単剤HCT116活性
実施例14:ATR複合体阻害アッセイ
Claims (38)
- 1つまたはより多くのDNA損傷因子をさらに含み;ここで該DNA損傷因子は、処置されている疾患に適切であり;そして該DNA損傷因子は、1個の剤形として前記化合物と一緒にか、または複数の剤形の一部として前記化合物とは別に投与される、請求項1に記載の組み合わせ物。
- 前記組み合わせ物は、化学療法剤または放射線治療と組み合わせて投与される、請求項2に記載の組み合わせ物。
- 前記DNA損傷因子は、電離放射線、放射線類似作用ネオカルチノスタチン、白金製剤、Topo I阻害剤、Topo II阻害剤、代謝拮抗物質、アルキル化剤、アルキルスルホネート、および抗生物質から独立して選択される、請求項3に記載の組み合わせ物。
- 前記DNA損傷因子は、電離放射線、白金製剤、Topo I阻害剤、Topo II阻害剤、代謝拮抗物質、アルキル化剤、およびアルキルスルホネートから選択される、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、電離放射線、白金製剤、Topo I阻害剤、Topo II阻害剤、および抗生物質から独立して選択される、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、シスプラチン、オキサリプラチン、カルボプラチン、ネダプラチン、ロバプラチン、トリプラチンテトラニトレート、ピコプラチン、サトラプラチン、プロリンダク、アロプラチン、カンプトテシン、トポテカン、イリノテカン/SN38、ルビテカン、ベロテカン、エトポシド、ダウノルビシン、ドキソルビシン、アクラルビシン、エピルビシン、イダルビシン、アムルビシン、ピラルビシン、バルルビシン、ゾルビシン、テニポシド、アミノプテリン、メトトレキサート、ペメトレキセド、ラルチトレキセド、ペントスタチン、クラドリビン、クロファラビン、フルダラビン、チオグアニン、メルカプトプリン、フルオロウラシル、カペシタビン、テガフール、カルモフール、フロクスウリジン、シタラビン、ゲムシタビン、アザシチジン、ヒドロキシウレア、メクロレタミン、シクロホスファミド、イホスファミド、トロフォスファミド、クロラムブシル、メルファラン、プレドニムスチン、ベンダムスチン、ウラムスチン、エストラムスチン、カルムスチン、ロムスチン、セムスチン、フォテムスチン、ニムスチン、ラニムスチン、ストレプトゾシン、ブスルファン、マンノスルファン、トレオスルファン、カルボクオン、チオテパ、トリアジクオン、トリエチレンメラミン、プロカルバジン、ダカルバジン、テモゾロミド、アルトレタミン、ミトブロニトール、アクチノマイシン、ブレオマイシン、マイトマイシンおよびプリカマイシンから選択される、請求項4に記載の組み合わせ物。
- 前記白金製剤は、シスプラチン、オキサリプラチン、カルボプラチン、ネダプラチン、およびサトラプラチンから独立して選択され;前記Topo I阻害剤は、カンプトテシン、トポテカン、イリノテカン/SN38、およびルビテカンから選択され;前記Topo II阻害剤は、エトポシドから選択され;前記代謝拮抗物質は、メトトレキサート、ペメトレキセド、チオグアニン、フルダラビン、クラドリビン、シタラビン、ゲムシタビン、6−メルカプトプリン、ヒドロキシウレアおよび5−フルオロウラシルから選択され;前記アルキル化剤は、ナイトロジェンマスタード、ニトロソウレア、トリアゼン、アルキルスルホネート、プロカルバジン、およびアジリジンから選択され;そして前記抗生物質は、アントラサイクリン、アントラセンジオン、ブレオマイシン、マイトマイシンC、アクチノマイシンおよびプリカマイシンから選択される、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は白金製剤である、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、シスプラチンおよびカルボプラチンから選択される白金製剤である、請求項9に記載の組み合わせ物。
- 前記DNA損傷因子は電離放射線である、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、ゲムシタビンから選択される代謝拮抗物質である、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、カンプトテシン、トポテカン、イリノテカン/SN38、ルビテカンおよびベロテカンから選択されるTopo I阻害剤である、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、エトポシドから選択されるTopo II阻害剤である、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、テモゾロミドから選択されるアルキル化剤である、請求項4に記載の組み合わせ物。
- 前記DNA損傷因子は、以下:シスプラチン、カルボプラチン、ゲムシタビン、エトポシド、テモゾロミド、または電離放射線のうちの1つまたはより多くから選択される、請求項4に記載の組み合わせ物。
- 前記がんは、塩基除去修復タンパク質に欠陥を有する、請求項1に記載の組み合わせ物。
- 前記塩基除去修復タンパク質は、UNG、SMUG1、MBD4、TDG、OGG1、MYH、NTH1、MPG、NEIL1、NEIL2、NEIL3(DNAグリコシラーゼ);APE1、APEX2(APエンドヌクレアーゼ);LIG1、LIG3(DNAリガーゼIおよびIII);XRCC1(LIG3アクセサリー);PNK、PNKP(ポリヌクレオチドキナーゼおよびホスファターゼ);PARP1、PARP2(ポリ(ADP−リボース)ポリメラーゼ);PolB、PolG(ポリメラーゼ);FEN1(エンドヌクレアーゼ)またはアプラタキシンである、請求項17に記載の組み合わせ物。
- 前記塩基除去修復タンパク質は、PARP1またはPARP2である、請求項18に記載の組み合わせ物。
- さらなる治療剤を含み、ここで該剤は、塩基除去修復タンパク質を阻害または調節する、請求項17〜19のいずれか1項に記載の組み合わせ物。
- 前記塩基除去修復タンパク質は、PARP1またはPARP2である、請求項20に記載の組み合わせ物。
- DNA損傷因子をさらに含む、請求項21に記載の組み合わせ物。
- 前記DNA損傷因子は電離放射線である、請求項22に記載の組み合わせ物。
- 前記DNA損傷因子はシスプラチンである、請求項22に記載の組み合わせ物。
- 前記がんは、口部がん、肺がん、胃腸がん、尿生殖路がん、肝臓がん、骨がん、神経系がん、婦人科がん、皮膚がん、甲状腺がん、および副腎がんから選択される固形腫瘍である、請求項1〜24のいずれか1項に記載の組み合わせ物。
- 前記がんは、非小細胞肺がん、小細胞肺がん、膵臓がん、胆管がん、頭頸部がん、膀胱がん、結腸直腸がん、膠芽腫、食道がん、乳がん、肝細胞癌、または卵巣がんから選択される、請求項1〜24のいずれか1項に記載の組み合わせ物。
- 前記がんは、非小細胞肺がん、小細胞肺がん、およびトリプルネガティブ乳がんから選択される、請求項26に記載の組み合わせ物。
- 前記さらなる治療剤は、ゲムシタビンまたはシスプラチンであり、そして前記がんは、非小細胞肺がんの扁平上皮サブタイプである、請求項26に記載の組み合わせ物。
- 前記Chk1プロテインキナーゼを阻害する化合物が、AZD7762、LY2603618、MK−8776、CHIR−124、およびPF−477736から独立して選択される、請求項1〜28のいずれか一項に記載の組み合わせ物。
- 前記ATRプロテインキナーゼを阻害する化合物および前記Chk1プロテインキナーゼを阻害する化合物が、別個の医薬組成物として投与される、請求項1〜29のいずれか一項に記載の組み合わせ物。
- 前記がん細胞は、ATMシグナル伝達カスケードに欠損を有する、請求項31に記載の組み合わせ物。
- 前記欠損は、以下:ATM、p53、CHK2、MRE11、RAD50、NBS1、53BP1、MDC1、H2AX、MCPH1/BRIT1、CTIP、またはSMC1のうちの1つまたはより多くの変化した発現または活性である、請求項32に記載の組み合わせ物。
- 前記欠損は、以下:ATM、p53、CHK2、MRE11、RAD50、NBS1、53BP1、MDC1およびH2AXのうちの1つまたはより多くの変化した発現または活性である、請求項33に記載の組み合わせ物。
- 前記がん細胞は、DNA損傷がん遺伝子を発現している、請求項31に記載の組み合わせ物。
- 前記がん細胞は、以下:K−Ras、N−Ras、H−Ras、Raf、Myc、Mos、E2F、Cdc25A、CDC4、CDK2、サイクリンE、サイクリンAおよびRbのうちの1つまたはより多くの変化した発現または活性を有する、請求項35に記載の組み合わせ物。
- 前記Chk1を阻害する化合物は、AZD7762、LY2603618、MK−8776、CHIR−124、およびPF−477736から独立して選択される、請求項31〜36のいずれか1項に記載の組み合わせ物。
- 前記ATRプロテインキナーゼを阻害する化合物および前記Chk1プロテインキナーゼを阻害する化合物が、別個の医薬組成物として投与される、請求項31〜37のいずれか一項に記載の組み合わせ物。
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