JP7356546B2 - タンパク質キナーゼのモジュレータとしてのジアリール大環状化合物 - Google Patents
タンパク質キナーゼのモジュレータとしてのジアリール大環状化合物 Download PDFInfo
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- JP7356546B2 JP7356546B2 JP2022110613A JP2022110613A JP7356546B2 JP 7356546 B2 JP7356546 B2 JP 7356546B2 JP 2022110613 A JP2022110613 A JP 2022110613A JP 2022110613 A JP2022110613 A JP 2022110613A JP 7356546 B2 JP7356546 B2 JP 7356546B2
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- alkyl
- fluoro
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- methyl
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
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Description
本出願は、米国特許法第119条(e)の下で、2014年1月24日出願の米国仮特許出願第61/931,506号、2014年9月11日出願の第62/049,326号及び2015年1月22日出願の第62/106,301号の優先権を主張し、それらの内容の全体が、それらの全体の参照によりここに組み込まれる。
所望の医薬特性を有する、これらの多様なタンパク質標的、すなわちチロシンキナーゼ標的の低分子阻害剤に対するニーズが存続している。特定のジアリール大環状化合物が、本発明の文脈において、この有利な活性プロファイルを有することが見出された。
用語「アルキル」とは、直鎖または分岐鎖のアルキル基であって、当該連鎖中に1~12の炭素原子を有する上記基をいう。アルキル基の例としては、メチル(Me)、エチル(Et)、n-プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル(tBu)、ペンチル、イソペンチル、tert-ペンチル、ヘキシル、イソヘキシル、及び本技術分野の通常の技量及び本明細書に提示される教示に照らして、上述の例のいずれかの1と等価と考えられる基が挙げられる。
いくつかの式(I-A)の実施形態において、環A’は単環のアリールまたは複素アリールであり、環B’は二環複素アリールである。いくつかの実施形態において、環A’は二環複素アリールであり、環B’は単環のアリールまたは複素アリールである。いくつかの実施形態において、環A’はフェニルまたは6員複素アリールである。他の実施形態において、環B’は1、2、または3の窒素環原子を含有する二環複素アリールである。他の実施形態において、環A’はフェニルまたはピリジルである。
R1a及びR2aのそれぞれは独立に、H、重水素、C1~6アルキル、C3~6シクロアルキル、C6~10アリール、-C(O)ORa’、-C(O)NRa’Rb’、-NRa’Rb’、-SRa’、-S(O)Ra’、-S(O)NRa’、-S(O)2Ra’、-S(O)2NRa’または-ORa’であり、但し、C1~6アルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-NHC(O)C1~4アルキル、-N(C1~4アルキル)C(O)C1~4アルキル、-NHC(O)NHC1~4アルキル、-N(C1~4アルキル)C(O)NHC1~4アルキル、NHC(O)N(C1~4アルキル)2、-N(C1~4アルキル)C(O)N(C1~4アルキル)2、-NHC(O)OC1~4アルキル、-N(C1~4アルキル)C(O)OC1~4アルキル、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、-SC1~4アルキル、-S(O)C1~4アルキル、-S(O)2C1~4アルキル、-S(O)NH(C1~4アルキル)、-S(O)2NH(C1~4アルキル)、-S(O)N(C1~4アルキル)2、-S(O)2N(C1~4アルキル)2、C3~6シクロアルキル、または3~7員複素シクロアルキルによって置換され、
オキサトリアザシクロトリデシン-16(13H)-オン、8-クロロ-9-フルオロ-6-メチル-6,7,14,15-テトラヒドロ-2H-3,5-(アゼノメテノ)ピラゾロ[3,4-f][1,4,8,10]ベンゾオキサトリアザシクロトリデシン-16(13H)-オン、8-クロロ-9-フルオロ-6-メチル-6,7,14,15-テトラヒドロ-2H-3,5-(アゼノメテノ)ピラゾロ[3,4-f][1,4,10]ベンゾオキサジアザシクロトリデシン-16(13H)-オン、12-クロロ-11-フルオロ-5,14-ジメチル-6,7,13,14-テトラヒドロ-2H-1,15-(アゼノメテノ)ピロロ[3,4-f][1,4,10]ベンゾオキサジアザシクロトリデシン-4(5H)-オン、(8R)-10-フルオロ-8,16-ジメチル-15,16-ジヒドロ-8H-3,6-エテノイミダゾ[5,1-f][1,10,4,7,8]ベンゾジオキサトリアザシクロトリデシン-17(14H)-オン、10-フルオロ-8,16-ジメチル-15,16-ジヒドロ-8H-3,6-エテノイミダゾ[5,1-f][1,10,4,7,8]ベンゾジオキサトリアザシクロトリデシン-17(14H)-オン、(7R)-9-フルオロ-7,15-ジメチル-14,15-ジヒドロ-2H,7H-3,5-(アゼノメテノ)ピロロ[3,4-f][1,10,4,8]ベンゾジオキサジアザシクロトリデシン-16(13H)-オン、及び9-フルオロ-7,15-ジメチル-14,15-ジヒドロ-2H,7H-3,5-(アゼノメテノ)ピロロ[3,4-f][1,10,4,8]ベンゾジオキサジアザシクロトリデシン-16(13H)-オンからなる群より選択されるか、または薬学的に許容されるその塩である。
治療目的のために、本明細書に記載の化合物を含む医薬組成物は、1種または複数種の薬学的に許容される添加剤を更に含んでもよい。薬学的に許容される添加剤とは、非毒性であり、且つ対象に対する投与に関して他の点で生物学的に相応しい物質である。かかる添加剤は本明細書に記載の化合物の投与を容易にし、活性成分と適合性がある。薬学的に許容される添加剤の例としては、安定剤、潤滑剤、界面活性剤、希釈剤、抗酸化剤、結合剤、着色剤、増量剤、乳化剤、または味覚改変剤が挙げられる。好ましい実施形態において、本発明に係る医薬組成物は無菌組成物である。医薬組成物は、当業者に公知のまたは当業者が利用可能になる配合技法を用いて製剤することができる。
本明細書に記載の本発明の化合物は、医薬組成物または方法において、本明細書に記載の疾患及び障害の治療における、1種または複数種の更なる活性成分との組み合わせで用いられてもよい。一層更なる活性成分としては、意図する疾患の標的に対する治療薬の悪影響を軽減する他の治療薬すなわち薬剤を包含する。かかる組み合わせは、効能を増加させる、他の疾患症状を改善する、1種若しくは複数種の副作用を低減する、または発明の化合物の必要な用量を低減する役割を果たすことができる。上記更なる活性成分は、本発明の化合物とは異なる医薬組成物中で投与されてもよく、または単一の医薬組成物中に、本発明の化合物と共に含まれてもよい。上記更なる活性成分は、本発明の化合物の投与と同時に、その前に、またはその後に投与されてもよい。
ここで、本発明の方法において有用な代表的な化学物質が、以下のそれらの一般化された調製に関する例示的な合成スキーム、及びそれらに続く具体的な例に言及することによって説明されることとなる。当業者は、本明細書において種々の化合物を得るためには、最終的に所望する置換基が、必要に応じて保護を伴うかまたは伴わずに、当該反応スキームを通じて維持され、所望の生成物を与えることとなるように、出発物質を適宜に選択することができることを認識しよう。あるいは、最終的に所望する置換基の位置において、当該反応スキームを通じて維持することができ、所望の置換基と必要に応じて置換することができる適宜の基を用いることが必要または望ましい場合がある。更に、当業者は、以下のスキームに示される変換が、特定のペンダント基の官能性に見合う任意の順序で実施されてもよいことを認識しよう。一般化されたスキームに記載された各反応は、好ましくは、約0℃から用いる有機溶媒の還流温度までの温度で行われる。別段の指定がない限りにおいて、変数は、式(I)に関して上記に定義した通りである。本明細書に記載の同位体標識化合物は、適宜に標識された出発物質を用いて、下記の方法に従って調製される。かかる物質は、一般的に、放射標識化学反応剤の市販品供給者より入手可能である。
以下の例は本発明を例証するために提示するものであって、本発明を限定するためのものではない。当業者は、以下の合成反応及びスキームが、式(I)または(I-A)の他の化合物を手に入れるための適宜の出発物質及び反応剤の選択によって、改変し得ることを認識しよう。本合成方法において用いるための、適宜の官能基を有する二環複素芳香族の群は市販されている。
略記 本明細書に記載の例は、当業者に公知の以下の略記によって記載される物質を始めとする、但しそれらに限定されない物質を用いる。
結晶多形相1である例20の試料を、PXRD分析用のゼロバックグラウンドプレートに移した。製造元推奨の手順に従い、ブルカー社D8X線回折計を用いてPXRDデータを得た。走査パラメータ:2θ範囲:4.5~39.1度、ステップ幅:0.02度、ステップ時間:1秒、分析時間:180秒。
図2に示すDSC測定を、セイコー社モデルSSC/5200示差走査熱量計を用いて実施した。結晶多形相1である例20の7.92mgの試料を36℃でquilibrateし、次いで10℃/分の速度で380℃まで昇温した。結晶多形相1である例20の試料は、298.9℃の融点を示した。
MET/ALK/AXL/TRK酵素阻害は、Omnia(インビトロジェン社)連続蛍光アッセイによって測定することができる。反応を96ウェルプレート中、30℃で、50μL容量で行う。混合物は、1nMヒト組換え標的キナーゼドメイン、2μMホスホアクセプタペプチド、被験化合物(11水準の薬量、3倍段階希釈、2%のDMSO最終濃度)またはDMSO単独、0.2mM DTT、及び10mM MgCl2の20mM HEPES溶液を含み、pH7.5であり、反応を、20分間の予備インキュベーションに続いてATP(100μMの最終濃度)を添加することにより開始させる。励起に対して360nm及び発光に対して485nmの波長設定で、テカン社サファイアマイクロプレートリーダーを用いて、ホスホペプチド生成の初期速度を20分間にわたって測定する。非線形回帰法(グラフパッドプリズム、グラフパッドソフトウェア社、カリフォルニア州サンディエゴ)を用いて、データを競合阻害に関する式に対して最適化することによって、Ki値を算出する。
実験は、論文(Christensen, J.ら、「Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma」、Mol. Cancer Ther. 2007、6(12):3314~3322)に記載の方法に基づいて実施する。全ての実験を標準条件(37℃及び5% CO2)下で行う。マイクロソフトエクセルに基づく4パラメータ法を用いて、濃度/応答曲線を最適化することによって、IC50値を算出する。細胞を、10%ウシ胎児血清(FBS)を補った培地中、96ウェルプレートに播種し、24時間後に血清を含まない[0.04%ウシ血清アルブミンを含む]培地に移す。リガンド依存性RTKリン酸化を検討する実験においては、対応する増殖因子を20分間まで添加する。阻害剤と共に1時間及び/または適宜のリガンドと共に所定の時間細胞をインキュベートした後、細胞を1mmol/L Na3VO4を補ったHBSSで1回洗浄し、細胞からタンパク質溶解物を生成させる。続いて、選択したタンパク質キナーゼのリン酸化を、96ウェルプレートに塗布する特異的捕捉抗体及びリン酸化チロシン残基に対して特異的な検出抗体を用いたサンドウィッチELISA法によって評価する。抗体を塗布したプレートを、(a)タンパク質溶解物の存在下、4℃で終夜インキュベートし、(b)1% Tween 20のPBS溶液中で7回洗浄し、(c)西洋ワサビペルオキシダーゼ複合化抗総リン酸化チロシン(PY-20)抗体(1:500)中で30分間インキュベートし、(d)再度7回洗浄し、(e)3,3,5,5-テトラメチルベンジジンペルオキシダーゼ基質(バイオ・ラッド社)中でインキュベートし、発色反応を開始させ、0.09N H2SO4の添加により同反応を停止させ、(f)分光光度計を用いて450nmにおける吸光度について測定する。個々のキナーゼに対して用いられる細胞株としては、METに対してはA549、ALKに対してはカーパス299、AXLに対しては293-AXL、TRKAに対してはPAET RKA、TRKBに対してはPAE-TRKBが挙げられる。
キナーゼ結合アッセイを、DiscoveRx社において、一般的なKINOMEscan Kdプロトコル(Fabian, M. A.ら、「A small molecule-kinase interaction map for clinical kinase inhibitors」、Nat. Biotechnol. 2005、23(3):329~36)を用いて実施した。殆どのアッセイに関し、キナーゼでタグ付けしたT7ファージ株をBL21株由来の大腸菌宿主中で調製した。大腸菌を対数期まで培養し、T7ファージに感染させ、32℃で振とうしながらインキュベートした後、溶解させた。溶解物を遠心分離及びろ過して細胞デブリを除去した。残余のキナーゼはHEK-293細胞中で産生させ、次いでqPCR検知用のDNAでタグ付けした。ストレプトアビチン塗布磁性ビーズを、室温で30分間、ビオチン化した低分子リガンドで処理し、キナーゼアッセイ用の親和性樹脂を生成させた。リガンドを結合させたビーズを過剰のビオチンでブロックし、ブロッキング緩衝液(SeaBlock(Pierce)、1% BSA、0.05% Tween 20、1mM DTT)で洗浄して、未結合のリガンドを除去し、非特異的結合を低減させた。キナーゼ、リガンドを結合した親和性ビーズ、及び被験化合物を1x結合緩衝液(20% SeaBlock、0.17xPBS、0.05% Tween 20、6mM DTT)中で組み合わせることによって、結合反応を組み立てた。全ての反応を、ポリスチレン製96ウェルプレート中、0.135mLの最終容量で行った。このアッセイプレートを室温で振とうしながら1時間インキュベートし、親和性ビーズを洗浄緩衝液(1xPBS、0.05% Tween 20)で洗浄した。次いでこのビーズを溶離緩衝液(1xPBS、0.05% Tween 20、0.5μMの非ビオチン化親和性リガンド)中に再度懸濁させ、室温で振とうしながら30分間インキュベートした。溶離液中のキナーゼ濃度をqPCRによって測定した。このアッセイにおける被験化合物に対する結果を表2に示す。この方法によれば、例20もまたPLK4キナーゼと結合親和性を有していた(Kd 2.9nM)。
TRKA Ba/F3細胞増殖アッセイをACD(アドバンスト・セルラー・ダイナミクス)社によって行った。Ba/F3細胞株を、10%ウシ胎児血清及び抗生物質を含有するPRMI-1640培養培地中に保持した。対数増殖期にある細胞を回収し、5,000細胞を、50μLの増殖培地中、384ウェルプレートの各ウェルに分配した。50ナノリットルの希釈した化合物を適宜のウェルに、同一試料×2で添加し、細胞を37℃、湿潤化した5% CO2インキュベータ中で培養した。15μLのCellTiter-Gloを添加し、蛍光を測定することによって生存率を測定し、秒当たりのカウントで測定した相対的光単位(relative light unit)(RLU)として報告する。各化合物に関するデータ(RLU)を、ビヒクル(DMSO)のみの存在時に得られた平均最大応答に規格化した。これらのデータを用いてパーセント記阻害(100-%記最大応答)を導き出し、2つのデータポイント/濃度の平均を用い、グラフパッドプリズムソフトウェア(グラフパッド社、カリフォルニア州サンディエゴ)を使用した非線形回帰解析によって、IC50値(細胞生存の最大半量阻害を起こす濃度)を算出した。この方法によれば、例20は、TRKA Ba/F3細胞の細胞増殖を3.0nMのIC50値で阻害した。このアッセイにおける被験化合物に対するデータを表3に示す。
EML4-ALK野生型遺伝子(バリアント1)をジェンスクリプト社において合成し、pCDH-CMV-MCS-EFl-Puroプラスミド(システムバイオサイエンシーズ社)にクローン化した。Ba/F3細胞にEML4-ALK野生型を含むレンチウィルスを感染させることにより、Ba/F3-EML4-ALK野生型細胞株を生成させた。ピューロマイシン処理及びそれに続くIL-3除去によって安定細胞株を選択した。5000細胞を384ウェル白色プレートに終夜播種し、その後化合物処理を行った。CellTiter-Gloルシフェラーゼに基づくATP検知アッセイ(プロメガ社)を用い、製造元のプロトコルに従って、種々の化合物濃度での48時間のインキュベーション後に、細胞増殖を測定した。IC50の決定は、グラフパッドプリズムソフトウェア(グラフパッド社、カリフォルニア州サンディエゴ)を用いて行った。このアッセイにおける被験化合物に関するデータを表3に示す。
大腸がん細胞株KM12(内在性のTPM3-TRKA融合遺伝子をもつ)細胞を、10%ウシ胎児血清及び100U/mLのペニシリン/ストレプトマイシンを補ったDMEM培地中で培養した。5000細胞を384ウェル白色プレートに24時間播種し、その後化合物処理を行った。CellTiter-Gloルシフェラーゼに基づくATP検知アッセイ(プロメガ社)を用い、製造元のプロトコルに従って、72時間のインキュベーション後に、細胞増殖を測定した。IC50の決定は、グラフパッドプリズムソフトウェア(グラフパッド社、カリフォルニア州サンディエゴ)を用いて行った。
大腸がん細胞株KM12(内在性のTPM3-TRKA融合遺伝子をもつ)細胞を、10%ウシ胎児血清及び100U/mLのペニシリン/ストレプトマイシンを補ったDMEM培地中で培養した。100万細胞を6ウェルプレートに24時間播種し、その後化合物処理を行った。5時間の処理後に細胞を1xPBSで洗浄して回収し、10mM EDTA、Haltプロテアーゼ及びホスファターゼ阻害剤(サーモサイエンティフィック社)を補ったRIPA緩衝液(50mM Tris、pH7.4、150mM NaCl、1% NP-40、0.5%デオキシコール酸塩、0.1% SDS)中で溶解した。タンパク質溶解液(20μg)を、4~12% Bolt Bis-Trisプレキャストゲル上でMESランニングバッファー(ライフテクノロジーズ社)を用いて分析し、トランスブロットTurbo転写システム(バイオラッド社)を用いてニトロセルロース膜へ転写し、リン酸化TRKA(セルシグナリングテクノロジー社、Y496、Y680、Y681、クローンC50F3;1:1000希釈液)、総TRKA(サンタクルーズバイオテクノロジー社、sc-11;クローンC-14、1:2000希釈液)、リン酸化AKT(セルシグナリング社、S473、D9E、#9271;1:5000希釈液)、総AKT(セルシグナリングテクノロジー社、40D4;1:2000希釈液)、リン酸化ERK(セルシグナリングテクノロジー社、Thr 202/204、D13.14.4E、#4370;1:2000希釈液)、総ERK(セルシグナリングテクノロジー社;1:1000希釈液)、及びチューブリン(シグマ社、T4026、1:5000希釈液)を標的とする抗体を用いて検知した。一般的には、抗体を穏やかに振とうしながら4℃で終夜インキュベートし、続いて洗浄し、適宜のHRP複合化二次抗体と共にインキュベートした。膜を室温で5分間化学発光物質(SuperSignal West Femto、サーモサイエンティフィック社)に接触させた。C-Digit画像システム(LI-CORバイオサイエンシーズ社)を用いて画像を得た。LICOR社のImage Studio Digitsによってバンドの相対的密度を得た。グラフパッドプリズムソフトウェア(グラフパッド社、カリフォルニア州サンディエゴ)による非線形回帰解析を用いて、半量阻害濃度(IC50)値を算出した。この方法によれば、例20は、KM12細胞中で、TPM3-TRKAの自己リン酸化を1.07nMのIC50で、その下流のシグナル伝達標的AKT及びERKのリン酸化を、それぞれ2.80nM及び2.0nMのIC50で阻害した。
KM12細胞を、10%ウシ胎児血清及び抗生物質を補ったDMEM培地中に保持した。500,000細胞を12ウェルプレートに播種し、種々の濃度の化合物を72時間導入した。陽性対照として、スタウロスポリン処理のために500nMのSTSを60時間の時点で添加し、12時間のインキュベーション。全ての細胞を回収し、1xPBSで2回洗浄し、次いでHaltプロテアーゼ及びホスファターゼ阻害剤(サーモサイエンティフィック社)を補った溶解緩衝液(20mM HEPES、150mM NaCl、10mM KCl、5mM EDTA、1% NP40)中で溶解させた。カスパーゼアッセイに関して、概略20μL(20μg)の細胞溶解液を、20μLのカスパーゼ3glo試薬(プロメガ社)と共にインキュベートし、37℃で20分間のインキュベーション後に蛍光の放出によって酵素活性を測定した。ウェスタンブロット法については、細胞溶解液を煮沸し、PARPまたはアクチン抗体を用いたSDS-PAGE/免疫ブロット法によって分析した。この方法によれば、例20はKM12細胞のアポトーシスを誘発した。
項1. 以下の式(I-A)
式中、
環A’及び環B’はそれぞれ独立に、単環若しくは二環のアリールまたは複素アリールであり、但し、環A’及び環B’の一方は単環のアリールまたは複素アリールであり、他方は二環複素アリールであり、且つ、環A’及び環B’の少なくとも一方は、少なくとも1の窒素環員を含み、
L1及びL2のそれぞれは独立に、-C(R1’)(R2’)-、-O-、-N(Rk’)-、-S-、-S(O)-または-S(O)2-であり、
R1’及びR2’のそれぞれは独立に、H、重水素、ハロゲン、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリール、-ORa’、-OC(O)Ra’、-OC(O)NRa’Rb’、-OS(O)Ra’、-OS(O)2Ra’、-SRa’、-S(O)Ra’、-S(O)2Ra’、-S(O)NRa’Rb’、-S(O)2NRa’Rb’、-OS(O)NRa’Rb’、-OS(O)2NRa’Rb’、-NRa’Rb’、-NRa’C(O)Rb’、-NRa’C(O)ORb’、-NRa’C(O)NRa’Rb’、-NRa’S(O)Rb’、-NRa’S(O)2Rb’、-NRa’S(O)NRa’Rb’、-NRa’S(O)2NRa’Rb’、-C(O)Ra’、-C(O)ORa’、-C(O)NRa’Rb’、-PRa’Rb’、-P(O)Ra’Rb’、-P(O)2Ra’Rb’、-P(O)NRa’Rb’、-P(O)2NRa’Rb’、-P(O)ORa’、-P(O)2ORa’、-CN、または-NO2であるか、あるいは、R1’及びR2’が結合する1または複数の炭素と共に統合されたR1’及びR2’が、C3~6シクロアルキルまたは4~6員複素シクロアルキルを形成し、但し、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10アリール、単環若しくは二環複素アリール、4~6員複素シクロアルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、C1~6アルキル、C1~6ハロアルキル、-ORe’、-OC(O)Re’、-OC(O)NRe’Rf’、-OS(O)Re’、-OS(O)2Re’、-OS(O)NRe’Rf’、-OS(O)2NRe’Rf’、-SRe’、-S(O)Re’、-S(O)2Re’、-S(O)NRe’Rf’、-S(O)2NRe’Rf’、-NRe’Rf’、-NRe’C(O)Rf’、-NRe’C(O)ORf’、-NRe’C(O)NRe’Rf’、-NRe’S(O)Rf’、-NRe’S(O)2Rf’、-NRe’S(O)NRe’Rf’、-NRe’S(O)2NRe’Rf’、-C(O)Re’、-C(O)ORe’、-C(O)NRe’Rf’、-PRe’Rf’、-P(O)Re’Rf’、-P(O)2Re’Rf’、-P(O)NRe’Rf’、-P(O)2NRe’Rf’、-P(O)ORe’、-P(O)2ORe’、-CN、または-NO2によって置換され、
各Rk’は独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリールであり、但し、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリール中の各水素原子は独立に、任意選択で、重水素、ハロゲン、C1~6アルキル、C1~6ハロアルキル、-ORe’、-OC(O)Re’、-OC(O)NRe’Rf’、-OS(O)Re’、-OS(O)2Re’、-OS(O)NRe’Rf’、-OS(O)2NRe’Rf’、-SRe’、-S(O)Re’、-S(O)2Re’、-S(O)NRe’Rf’、-S(O)2NRe’Rf’、-NRe’Rf’、-NRe’C(O)Rf’、-NRe’C(O)ORf’、-NRe’C(O)NRe’Rf’、-NRe’S(O)Rf’、-NRe’S(O)2Rf’、-NRe’S(O)NRe’Rf’、-NRe’S(O)2NRe’Rf’、-C(O)Re’、-C(O)ORe’、-C(O)NRe’Rf’、-PRe’Rf’、-P(O)Re’Rf’、-P(O)2Re’Rf’、-P(O)NRe’Rf’、-P(O)2NRe’Rf’、-P(O)ORe’、-P(O)2ORe’、-CN、または-NO2によって置換され、
R3’及びR4’のそれぞれは独立に、重水素、ハロゲン、-ORc’、-OC(O)Rc’、-OC(O)NRc’Rd’、-OC(=N)NRc’Rd’、-OS(O)Rc’、-OS(O)2Rc’、-OS(O)NRc’Rd’、-OS(O)2NRc’Rd’、-SRc’、-S(O)Rc’、-S(O)2Rc’、-S(O)NRc’Rd’、-S(O)2NRc’Rd’、-NRc’Rd’、-NRc’C(O)Rd’、-NRc’C(O)ORd’、-NRc’C(O)NRc’Rd’、-NRc’C(=N)NRc’Rd’、-NRc’S(O)Rd’、-NRc’S(O)2Rd’、-NRc’S(O)NRc’Rd’、-NRc’S(O)2NRc’Rd’、-C(O)Rc’、-C(O)ORc’、-C(O)NRc’Rd’、-C(=N)NRc’Rd’、-PRc’Rd’、-P(O)Rc’Rd’、-P(O)2Rc’Rd’、-P(O)NRc’Rd’、-P(O)2NRc’Rd’、-P(O)ORc’、-P(O)2ORc’、-CN、-NO2、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリールであるか、あるいは、任意の2のR3’基または任意の2のR4’基であって、当該R3’基またはR4’基が結合する環と共に統合された前記R3’基またはR4’基が、C5~8シクロアルキルまたは5~8員複素シクロアルキルを形成し、但し、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10アリール、単環若しくは二環複素アリール、C5~8シクロアルキルまたは5~8員複素シクロアルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、C1~6アルキル、C1~6ハロアルキル、-ORe’、-OC(O)Re’、-OC(O)NRe’Rf’、-OS(O)Re’、-OS(O)2Re’、-OS(O)NRe’Rf’、-OS(O)2NRe’Rf’、-SRe’、-S(O)Re’、-S(O)2Re’、-S(O)NRe’Rf’、-S(O)2NRe’Rf’、-NRe’Rf’、-NRe’C(O)Rf’、-NRe’C(O)ORf’、-NRe’C(O)NRe’Rf’、-NRe’S(O)Rf’、-NRe’S(O)2Rf’、-NRe’S(O)NRe’Rf’、-NRe’S(O)2NRe’Rf’、-C(O)Re’、-C(O)ORe’、-C(O)NRe’Rf’、-PRe’Rf’、-P(O)Re’Rf’、-P(O)2Re’Rf’、-P(O)NRe’Rf’、-P(O)2NRe’Rf’、-P(O)ORe’、-P(O)2ORe’、-CN、または-NO2によって置換され、
R7’は、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリールであり、但し、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリール中の各水素原子は独立に、任意選択で、重水素、ハロゲン、-ORi’、-OC(O)Ri’、-OC(O)NRi’Rj’、-OS(O)Ri’、-OS(O)2Ri’、-OS(O)NRi’Rj’、-OS(O)2NRi’Rj’、-SRi’、-S(O)Ri’、-S(O)2Ri’、-S(O)NRi’Rj’、-S(O)2NRi’Rj’、-NRi’Rj’、-NRi’C(O)Rj’、-NRi’C(O)ORj’、-NRi’C(O)NRi’Rj’、-NRi’S(O)Rj’、-NRi’S(O)2Rj’、-NRi’S(O)NRi’Rj’、-NRi’S(O)2NRi’Rj’、-C(O)Ri’、-C(O)ORi’、-C(O)NRi’Rj’、-PRi’Rj’、-P(O)Ri’Rj’、-P(O)2Ri’Rj’、-P(O)NRi’Rj’、-P(O)2NRi’Rj’、-P(O)ORi’、-P(O)2ORi’、-CN、または-NO2によって置換され、
Ra’、Rb’、Rc’、Rd’、Re’、Rf’、Ri’、Rj’のそれぞれは独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10アリール、及び複素アリールからなる群より選択され、
m’は2、3、4、または5であり、
n’は2、3、または4であり、
p’は0、1、2、3、または4であり、
q’は0、1、2、3、または4である
の化合物、あるいは薬学的に許容されるその塩。
MはCHまたはNであり、
X1及びX1’は独立に、-C(R1a)(R2a)-、-S-、-S(O)-、-S(O)2-、-O-または-N(Rk’)-であり、
R1a及びR2aのそれぞれは独立に、H、重水素、C1~6アルキル、C3~6シクロアルキル、C6~10アリール、-C(O)ORa’、-C(O)NRa’Rb’、-NRa’Rb’、-SRa’、-S(O)Ra’、-S(O)NRa’、-S(O)2Ra’、-S(O)2NRa’または-ORa’であり、但し、C1~6アルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-NHC(O)C1~4アルキル、-N(C1~4アルキル)C(O)C1~4アルキル、-NHC(O)NHC1~4アルキル、-N(C1~4アルキル)C(O)NHC1~4アルキル、-NHC(O)N(C1~4アルキル)2、-N(C1~4アルキル)C(O)N(C1~4アルキル)2、-NHC(O)OC1~4アルキル、-N(C1~4アルキル)C(O)OC1~4アルキル、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、-SC1~4アルキル、-S(O)C1~4アルキル、-S(O)2C1~4アルキル、-S(O)NH(C1~4アルキル)、-S(O)2NH(C1~4アルキル)、-S(O)N(C1~4アルキル)2、-S(O)2N(C1~4アルキル)2、C3~6シクロアルキル、または3~7員複素シクロアルキルによって置換され、
R3a及びR3bはそれぞれ独立に、H、重水素、フルオロ、クロロ、ブロモ、メチル、エチル、プロピル、イソプロピル、メトキシ、エトキシ、イソプロポキシ、-CN、または-CF3であり、
R7aはH、C1~6アルキルまたは3~7員複素シクロアルキルであり、但し、C1~6アルキルまたは3~7員複素シクロアルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、-CN、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、シクロアルキル、または単環複素シクロアルキルによって置換され、
各Rk’は独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリールであり、但し、Rk’中のC1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリール中の各水素原子は独立に、任意選択で、重水素、ハロゲン、C1~6アルキル、C1~6ハロアルキルまたは-ORa’によって置換され、
但し、Ra’及びRb’のそれぞれは独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10アリール、または複素アリールであり、
各Z1、Z2、Z3、Z4、Z5、Z6またはZ7は独立に、Z1、Z2、Z3、Z4、Z5、Z6またはZ7の少なくとも1がNまたはNHであるとの条件で、N、NH、またはC(Rx)であり、但し、存在する場合に各Rxは独立に、H、重水素、ハロゲン、C1~4アルキル、-O-C1~4アルキル、-OH、-NH2、-NH(C1~4アルキル)、-NH(フェニル)、-NH(複素アリール)、CN、または-CF3であり、
m’は2または3である
の化合物、あるいは薬学的に許容されるその塩。
MはCHまたはNであり、
X1及びX1’は独立に、-C(R1a)(R2a)-、-S-、-S(O)-、-S(O)2-、-O-または-N(Rk’)-であり、
R1a及びR2aのそれぞれは独立に、H、重水素、C1~6アルキル、C3~6シクロアルキル、C6~10アリール、-C(O)ORa’、-C(O)NRa’Rb’、-NRa’Rb’、-SRa’、-S(O)Ra’、-S(O)NRa’、-S(O)2Ra’、-S(O)2NRa’または-ORa’であり、但し、C1~6アルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-NHC(O)C1~4アルキル、-N(C1~4アルキル)C(O)C1~4アルキル、-NHC(O)NHC1~4アルキル、-N(C1~4アルキル)C(O)NHC1~4アルキル、-NHC(O)N(C1~4アルキル)2、-N(C1~4アルキル)C(O)N(C1~4アルキル)2、-NHC(O)OC1~4アルキル、-N(C1~4アルキル)C(O)OC1~4アルキル、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、-SC1~4アルキル、-S(O)C1~4アルキル、-S(O)2C1~4アルキル、-S(O)NH(C1~4アルキル)、-S(O)2NH(C1~4アルキル)、-S(O)N(C1~4アルキル)2、-S(O)2N(C1~4アルキル)2、C3~6シクロアルキル、または3~7員複素シクロアルキルによって置換され、
R3a及びR3bはそれぞれ独立に、H、フルオロ、クロロ、ブロモ、メチル、エチル、プロピル、イソプロピル、メトキシ、エトキシ、イソプロポキシ、-CN、または-CF3であり、
R7aはH、C1~6アルキルまたは3~7員複素シクロアルキルであり、但し、C1~6アルキルまたは3~7員複素シクロアルキル中の各水素原子は独立に、任意選択で、ハロゲン、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、シクロアルキル、または単環複素シクロアルキルによって置換され、
各Rk’は独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリールであり、但し、Rk’中のC1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリール中の各水素原子は独立に、任意選択で、重水素、ハロゲン、C1~6アルキル、C1~6ハロアルキルまたは-ORa’によって置換され、
但し、Ra’及びRb’のそれぞれは独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10アリール、または複素アリールであり、
各Z1、Z2、Z3、Z4、Z5、Z6またはZ7は独立に、Z1、Z2、Z3、Z4、Z5、Z6またはZ7の少なくとも1がNまたはNHであるとの条件で、N、NH、またはC(Rx)であり、但し、存在する場合に各Rxは独立に、H、重水素、ハロゲン、C1~4アルキル、-O-C1~4アルキル、-OH、-NH2、-NH(C1~4アルキル)、-NH(フェニル)、-NH(複素アリール)、CN、または-CF3であり、
m’は2または3である
の化合物、あるいは薬学的に許容されるその塩。
MはCHまたはNであり、
X1及びX1’は独立に、-C(R1a)(R2a)-、-S-、-S(O)-、-S(O)2-、-O-または-N(Rk’)-であり、
R1a及びR2aのそれぞれは独立に、H、重水素、C1~6アルキル、C3~6シクロアルキル、C6~10アリール、-C(O)ORa’、-C(O)NRa’Rb’、-NRa’Rb’、-SRa’、-S(O)Ra’、-S(O)NRa’、-S(O)2Ra’、-S(O)2NRa’または-ORa’であり、但し、C1~6アルキル中の各水素原子は独立に、任意選択で、重水素、ハロゲン、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-NHC(O)C1~4アルキル、-N(C1~4アルキル)C(O)C1~4アルキル、-NHC(O)NHC1~4アルキル、-N(C1~4アルキル)C(O)NHC1~4アルキル、-NHC(O)N(C1~4アルキル)2、-N(C1~4アルキル)C(O)N(C1~4アルキル)2、-NHC(O)OC1~4アルキル、-N(C1~4アルキル)C(O)OC1~4アルキル、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、-SC1~4アルキル、-S(O)C1~4アルキル、-S(O)2C1~4アルキル、-S(O)NH(C1~4アルキル)、-S(O)2NH(C1~4アルキル)、-S(O)N(C1~4アルキル)2、-S(O)2N(C1~4アルキル)2、C3~6シクロアルキル、または3~7員複素シクロアルキルによって置換され、
R3a及びR3bはそれぞれ独立に、H、フルオロ、クロロ、ブロモ、メチル、エチル、プロピル、イソプロピル、メトキシ、エトキシ、イソプロポキシ、-CN、または-CF3であり、
R7aはH、C1~6アルキルまたは3~7員複素シクロアルキルであり、但し、C1~6アルキルまたは3~7員複素シクロアルキル中の各水素原子は独立に、任意選択で、ハロゲン、-OH、-OC1~4アルキル、-NH2、-NH(C1~4アルキル)、-N(C1~4アルキル)2、-CO2H、-CO2C1~4アルキル、-CONH2、-CONH(C1~4アルキル)、-CON(C1~4アルキル)2、シクロアルキル、または単環複素シクロアルキルによって置換され、
各Rk’は独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリールであり、但し、Rk’中のC1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10のアリール、または単環若しくは二環複素アリール中の各水素原子は独立に、任意選択で、重水素、ハロゲン、C1~6アルキル、C1~6ハロアルキルまたは-ORa’によって置換され、
但し、Ra’及びRb’のそれぞれは独立に、H、重水素、C1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~6シクロアルキル、3~7員複素シクロアルキル、C6~10アリール、または複素アリールであり、
各Z1、Z2、Z3、Z4、Z5、Z6またはZ7は独立に、Z1、Z2、Z3、Z4、Z5、Z6またはZ7の少なくとも1がNまたはNHであるとの条件で、N、NH、またはC(Rx)であり、但し、存在する場合に各Rxは独立に、H、重水素、ハロゲン、C1~4アルキル、-O-C1~4アルキル、-OH、-NH2、-NH(C1~4アルキル)、-NH(フェニル)、-NH(複素アリール)、CN、または-CF3であり、
m’は2または3である
からなる群より選択される化合物、あるいは薬学的に許容されるその塩。
、8-クロロ-9-フルオロ-6-メチル-6,7,14,15-テトラヒドロ-2H-3,5-(アゼノメテノ)ピラゾロ[3,4-f][1,4,8,10]ベンゾオキサトリアザシクロトリデシン-16(13H)-オン、8-クロロ-9-フルオロ-6-メチル-6,7,14,15-テトラヒドロ-2H-3,5-(アゼノメテノ)ピラゾロ[3,4-f][1,4,10]ベンゾオキサジアザシクロトリデシン-16(13H)-オン、12-クロロ-11-フルオロ-5,14-ジメチル-6,7,13,14-テトラヒドロ-2H-1,15-(アゼノメテノ)ピロロ[3,4-f][1,4,10]ベンゾオキサジアザシクロトリデシン-4(5H)-オン、(8R)-10-フルオロ-8,16-ジメチル-15,16-ジヒドロ-8H-3,6-エテノイミダゾ[5,1-f][1,10,4,7,8]ベンゾジオキサトリアザシクロトリデシン-17(14H)-オン、10-フルオロ-8,16-ジメチル-15,16-ジヒドロ-8H-3,6-エテノイミダゾ[5,1-f][1,10,4,7,8]ベンゾジオキサトリアザシクロトリデシン-17(14H)-オン、(7R)-9-フルオロ-7,15-ジメチル-14,15-ジヒドロ-2H,7H-3,5-(アゼノメテノ)ピロロ[3,4-f][1,10,4,8]ベンゾジオキサジアザシクロトリデシン-16(13H)-オン、及び9-フルオロ-7,15-ジメチル-14,15-ジヒドロ-2H,7H-3,5-(アゼノメテノ)ピロロ[3,4-f][1,10,4,8]ベンゾジオキサジアザシクロトリデシン-16(13H)-オンからなる群より選択される、項1に記載の化合物、または薬学的に許容されるその塩。
項55. (a)項1~54のいずれか1項に記載の少なくとも1種の化合物または薬学的に許容されるその塩、及び(b)薬学的に許容される添加剤を含む、医薬組成物。
項56. がん、疼痛、神経性疾患、自己免疫疾患、及び炎症の治療方法であって、かかる治療を必要とする対象に、有効量の、項1~54のいずれか1項に記載の少なくとも1種の化合物または薬学的に許容されるその塩を投与することを含む、前記治療方法。
Claims (11)
- 第一の塩基が炭酸カリウムであり、第一の溶媒がDMFである、請求項5に記載の方法。
- 第一の溶液を80℃に加熱することを含む、請求項6に記載の方法。
- 第二の塩基が水酸化リチウム水溶液であり、第二の溶媒がメタノールおよびTHFである、請求項5に記載の方法。
- 第二の溶液を70℃に加熱することを含む、請求項8に記載の方法。
- 酸が塩酸であり、第三の溶液がジクロロメタンおよび1,4-ジオキサンである、請求項5に記載の方法。
- カップリング剤がジフェニルホスフィン酸ペンタフルオロフェニルであり、第四の溶液がDMFである、請求項5に記載の方法。
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