JP2019519599A - 統合ストレス経路のモジュレーター - Google Patents
統合ストレス経路のモジュレーター Download PDFInfo
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- JP2019519599A JP2019519599A JP2019510577A JP2019510577A JP2019519599A JP 2019519599 A JP2019519599 A JP 2019519599A JP 2019510577 A JP2019510577 A JP 2019510577A JP 2019510577 A JP2019510577 A JP 2019510577A JP 2019519599 A JP2019519599 A JP 2019519599A
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- C—CHEMISTRY; METALLURGY
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
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Abstract
【選択図】なし
Description
本出願は、参照によりその全体で本明細書に組み込まれる2016年5月5日出願の米国特許出願第62/332,280号による優先権を主張する。
eIF2Bは、複雑な分子マシンであり、5種の異なるサブユニット、eIF2B1からeIF2B5から構成される。eIF2B5は、GDP/GTP交換反応を触媒し、部分的に相同するサブユニットeIF2B3と一緒に、「触媒コア」を構成する(Williams,D.D.et al,J Biol Chem(2001)276:24697−24703)。残りの3種のサブユニット(eIF2B1、eIF2B2、及びeIF2B4)も、相互に高度に相同性であり、eIF2Bの基質eIF2のための結合部位を提供する「調節サブ複合体(regulatory sub−complex)」を形成する(Dev,K.et al,Mol Cell Biol(2010)30:5218−5233)。eIF2におけるGDPからGTPへの交換は、その専用のグアニンヌクレオチド交換因子(GEF)eIF2Bにより触媒される。eIF2Bは、十量体(B12B22B32B42B52)または2つの五量体の二量体として細胞内に存在する(Gordiyenko,Y.et al,Nat Commun(2014)5:3902;Wortham,N.C.et al,FASEB J(2014)28:2225−2237)。ISRIBなどの分子は、eIF2B二量体構造と相互作用し、それを安定化させ、それにより、固有のGEF活性を増強し、eIF2αのリン酸化の細胞作用に対する細胞の感受性を低くしている(Sidrauski,C.et al,eLife(2015)e07314;Sekine,Y.et al,Science(2015)348:1027−1030)。したがって、eIF2B活性をモジュレートすることができる小分子治療薬は、UPRのPERKブランチ及びISR全体を減弱させる可能性を有し得、したがって、神経変性疾患、白質ジストロフィー、がん、炎症性疾患、筋骨格疾患、または代謝性疾患などの様々な疾患の予防及び/または処置において使用され得る。
化学的定義
具体的な官能基及び化学用語の定義を下記でより詳細に記載する。化学元素は、元素周期表(CAS版、Handbook of Chemistry and Physics、第75版の内表紙)に従って同定されており、具体的な官能基は概して、本明細書において記載されているとおりに定義される。加えて、有機化学の一般原理、さらには、具体的な官能部分及び反応性は、Thomas Sorrell,Organic Chemistry,University Science Books,Sausalito,1999;Smith and March,March’s Advanced Organic Chemistry,5th Edition,John Wiley & Sons,Inc.,New York,2001;Larock,Comprehensive Organic Transformations,VCH Publishers,Inc.,New York,1989;及びCarruthers,Some Modern Methods of Organic Synthesis,3rd Edition,Cambridge University Press,Cambridge,1987に記載されている。
一態様では、本発明は、式(I)の化合物:
化合物を調製することができる手段を図示する次の合成スキーム及び方法に関連づけると、本発明の化合物をより良好に理解することができる。本発明の化合物は、様々な合成手順により調製することができる。代表的な合成手順を、これらだけに限定されないが、スキーム1に示されている手順において例示する。変項A、D、W、L1、L2、R1、及びR2は、本明細書において、例えば、要約において詳述するとおりに定義される。
本発明は、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を含む医薬組成物に関する。一部の実施形態では、医薬組成物はさらに、薬学的に許容される添加剤を含む。一部の実施形態では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、立体異性体を、医薬組成物において有効量で提供する。一部の実施形態では、有効量は、治療有効量である。特定の実施形態では、有効量は、予防的有効量である。
本発明は、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を含む、化合物、組成物、及び方法に関する。一部の実施形態では、化合物、組成物、及び方法を、疾患、障害、または状態の予防または処置において使用する。例示的な疾患、障害、または状態には、これらだけに限定されないが、神経変性疾患、白質ジストロフィー、がん、炎症性疾患、筋骨格疾患、または代謝性疾患を含む。
一部の実施形態では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を、神経変性疾患を処置するために使用する。本明細書で使用する場合、用語「神経変性疾患」は、対象の神経系の機能が損傷を受ける疾患または状態を指す。本明細書に記載の化合物、医薬組成物、または方法で処置され得る神経変性疾患の例には、アレキサンダー病、アルパース病、アルツハイマー病、筋萎縮性側索硬化症、毛細血管拡張性運動失調、バッテン病(シュピールマイヤー−フォークト−シェーグレン−バッテン病としても公知)、ウシ海綿状脳障害(BSE)、キャナバン病、コケーン症候群、大脳皮質基底核変性症、クロイツフェルト−ヤコブ病、前頭側頭型認知症、ゲルストマン−シュトロイスラー−シャインカー症候群、ハンチントン病、HIV関連認知症、ケネディ病、クラッベ病、クールー病、レビー小体型認知症、マチャド−ジョセフ病(3型脊髄小脳失調)、多発性萎縮症、ナルコレプシー、神経ボレリア症、パーキンソン病、ペリツェウス−メルツバッハー病、ピック病、原発性側索硬化症、プリオン病、レフサム病、サンドホフ病、シルダー病、悪性貧血に続発する脊髄の亜急性連合性変性、統合失調症、脊髄小脳失調(様々な特徴を有する複数の型)、脊髄性筋萎縮症、スティール−リチャードソン−オルスゼフスキー病、または脊髄ろうが含まれる。
一部の実施形態では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を、がんを処置するために使用する。本明細書で使用する場合、「がん」は、ヒトがん及び癌腫、肉腫、腺癌、リンパ腫、白血病、黒色腫などを指し、固形及びリンパのがん、腎臓、乳房、肺、膀胱、結腸、卵巣、前立腺、膵臓、胃、脳、頭頚部、皮膚、子宮、精巣、膠腫、食道、肝臓(肝細胞癌を含む)の癌、リンパ腫(B急性リンパ芽球性リンパ腫、非ホジキンリンパ腫(例えば、バーキット、小細胞、及び大細胞リンパ腫)、ホジキンリンパ腫を含む)、白血病(AML、ALL、及びCMLを含む)、及び/または多発性骨髄腫を含む。一部のさらなる事例では、「がん」は、肺癌、乳癌、卵巣癌、白血病、リンパ腫、黒色腫、膵臓癌、肉腫、膀胱癌、骨癌、脳癌、子宮頸癌、結腸癌、食道癌、胃癌、肝臓癌、頭頚部癌、腎臓癌、骨髄腫、甲状腺癌、前立腺癌、転移癌、または癌腫を指す。
一部の実施形態では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を、炎症性疾患を処置するために使用する。本明細書で使用する場合、用語「炎症性疾患」は、異常な炎症(例えば、疾患に罹患していない健康なヒトなどの対照と比較して、炎症レベルの上昇)により特徴づけられる疾患または状態を指す。炎症性疾患の例には、手術後認知機能不全、関節炎(例えば、関節リウマチ、乾癬性関節炎、若年性特発性関節炎)、全身性エリテマトーデス(SLE)、重症筋無力症、若年発症型糖尿病、1型糖尿病、ギラン−バレー症候群、橋本脳炎、橋本甲状腺炎、強直性脊椎炎、乾癬、シェーグレン症候群、脈管炎、糸球体腎炎、自己免疫甲状腺炎、ベーチェット病、クローン病、潰瘍性大腸炎、水疱性類天疱瘡、サルコイドーシス、魚鱗癬、グレーブス眼障害、炎症性腸疾患、アジソン病、白斑、喘息(例えば、アレルギー性喘息)、尋常性ざそう、セリアック病、慢性前立腺炎、炎症性腸疾患、骨盤内炎症性疾患、再灌流傷害、サルコイドーシス、移植拒絶、間質性膀胱炎、アテローム硬化症、及びアトピー性皮膚炎が含まれる。炎症及び炎症性疾患と関連するタンパク質(例えば、異常な発現が疾患の症状または原因またはマーカーである)には、インターロイキン−6(IL−6)、インターロイキン−8(IL−8)、インターロイキン−18(IL−18)、TNF−a(腫瘍壊死因子−アルファ)、及びC反応性タンパク質(CRP)が含まれる。
一部の実施形態では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を筋骨格疾患を処置するために使用する。本明細書で使用する場合、用語「筋骨格疾患」は、対象の筋骨格系(例えば、筋肉、靱帯、腱、軟骨、または骨)の機能が損傷を受ける疾患または状態を指す。式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体で処置され得る例示的な筋骨格疾患には、筋ジストロフィー(例えば、デュシェンヌ型筋ジストロフィー、ベッカー筋ジストロフィー、遠位筋ジストロフィー、先天性筋ジストロフィー、エメリー−ドレフュス型筋ジストロフィー、顔面肩甲上腕型筋ジストロフィー、または緊張性筋ジストロフィー)、多発性硬化症、筋委縮性側索硬化症、原発性側索硬化症、進行性筋委縮症、進行性球麻痺、偽性延髄麻痺、脊髄性筋萎縮症、進行性球脊髄性筋委縮症、脊髄痙縮、脊髄性筋萎縮症、重症筋無力症、神経痛、線維筋痛症、マチャド−ジョセフ病、有痛性痙縮−線維束性収縮症候群(cramp fasciculation syndrome)、フリードライヒ運動失調、筋消耗障害(例えば、筋萎縮症、サルコペニア、悪液質)、封入体筋障害、運動ニューロン疾患、または麻痺が含まれる。
一部の実施形態では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を、代謝性疾患を処置するために使用する。本明細書で使用する場合、用語「代謝性疾患」は、対象において代謝プロセスに影響を及ぼす疾患または状態を指す。式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体で処置され得る例示的な代謝性疾患には、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪肝疾患(NAFLD)、肝臓線維症、肥満、心疾患、アテローム硬化症、関節炎、シスチン蓄積症、糖尿病(例えば、I型糖尿病、II型糖尿病、または妊娠性糖尿病)、フェニルケトン尿症、増殖性網膜障害、またはカーンズ−セイヤ病が含まれる。
別の態様では、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体は、タンパク質産生量の増加が望ましい用途、例えば、タンパク質産生のためのin vitro無細胞系において有用であり得る。
一態様では、本発明は、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体、さらには第2の薬剤(例えば、第2の治療薬)を含む医薬組成物に関する。一部の実施形態では、医薬組成物は、第2の薬剤(例えば、第2の治療薬)を治療有効量で含む。一部の実施形態では、第2の薬剤は、がん、神経変性疾患、白質ジストロフィー、炎症性疾患、筋骨格疾患、代謝性疾患、あるいはeIF2B、eIF2α、またはeIF2経路もしくはISR経路の成分の機能減少と関連する疾患または障害を処置するための薬剤である。
「抗がん薬」は、その明白な通常の意味に従って使用され、細胞の成長または増殖を阻害する抗新生物特性または能力を有する組成物(例えば、化合物、薬物、アンタゴニスト、阻害薬、モジュレーター)を指す。一部の実施形態では、抗がん薬は、化学療法薬である。一部の実施形態では、抗がん薬は、がんを処置する方法において有用性を有すると本明細書において同定される薬剤である。一部の実施形態では、抗がん薬は、がんを処置するために、FDAまたは米国以外の国の同様の規制当局により認可されている薬剤である。抗がん薬の例には、これらだけに限定されないが、MEK(例えば、MEK1、MEK2、またはMEK1及びMEK2)阻害薬(例えば、XL518、CI−1040、PD035901、セルメチニブ/AZD6244、GSK1120212/トラメチニブ、GDC−0973、ARRY−162、ARRY−300、AZD8330、PD0325901、U0126、PD98059、TAK−733、PD318088、AS703026、BAY869766)、アルキル化薬(例えば、シクロフォスファミド、イホスファミド、クロラムブシル、ブスルファン、メルファラン、メクロレタミン、ウラムスチン、チオテパ、ニトロソウレア、ナイトロジェンマスタード(例えば、メクロロエタミン、シクロフォスファミド、クロラムブシル、メイファラン)、エチレンイミン及びメチルメラミン(例えば、ヘキサメチルメラミン、チオテパ)、スルホン酸アルキル(例えば、ブスルファン)、ニトロソウレア(例えば、カルムスチン、ロムスチン(lomusitne)、セムスチン、ストレプトゾシン)、トリアゼン(デカルバジン)、代謝拮抗薬(例えば、5−アザチオプリン、ロイコボリン、カペシタビン、フルダラビン、ゲムシタビン、ペメトレキセド、ラルチトレキセド、葉酸類似体(例えば、メトトレキサート)、またはピリミジン類似体(例えば、フルオロウラシル、フロキソウリジン、シタラビン)、プリン類似体(例えば、メルカプトプリン、チオグアニン、ペントスタチン)など)、植物アルカロイド(例えば、ビンクリスチン、ビンブラスチン、ビノレルビン、ビンデシン、ポドフィロトキシン、パクリタキセル、ドセタキセルなど)、トポイソメラーゼ阻害薬(例えば、イリノテカン、トポテカン、アムサクリン、エトポシド(VP16)、エトポシドホスファート、テニポシドなど)、抗腫瘍抗生物質(例えば、ドキソルビシン、アドリアマイシン、ダウノルビシン、エピルビシン、アクチノマイシン、ブレオマイシン、マイトマイシン、ミトキサントロン、プリカマイシンなど)、白金ベースの化合物(例えば、シスプラチン、オキサロプラチン、カルボプラチン)、アントラセンジオン(例えば、ミトキサントロン)、置換尿素(例えば、ヒドロキシ尿素)、メチルヒドラジン誘導体(例えば、プロカルバジン)、副腎皮質抑制薬(例えば、ミトタン、アミノグルテチミド)、エピポドフィロトキシン(例えば、エトポシド)、抗生物質(例えば、ダウノルビシン、ドキソルビシン、ブレオマイシン)、酵素(例えば、L−アスパラギナーゼ)、マイトジェン活性化プロテインキナーゼシグナル伝達の阻害薬(例えば、U0126、PD98059、PD184352、PD0325901、ARRY−142886、SB239063、SP600125、BAY43−9006、ウォルトマニン、またはLY294002、Syk阻害薬、mTOR阻害薬、抗体(例えば、リツキサン)、ゴシホール(gossyphol)、ジェナセンス、ポリフェノールE、クロロフシン、全トランス−レチノイン酸(ATRA)、ブリオスタチン、腫瘍壊死因子関連アポトーシス誘導性リガンド(TRAIL)、5−アザ−2’−デオキシシチジン、全トランスレチノイン酸、ドキソルビシン、ビンクリスチン、エトポシド、ゲムシタビン、イマチニブ(Gleevec(登録商標))、ゲルダナマイシン、17−N−アリルアミノ−17−デメトキシゲルダナマイシン(17−AAG)、フラボピリドール、LY294002、ボルテゾミブ、トラスツズマブ、BAY11−7082、PKC412、PD184352、20−epi−l、25ジヒドロキシビタミンD3;5−エチニルウラシル;アビラテロン;アクラルビシン;アシルフルベン;アデシペノール;アドゼレシン;アルデスロイキン;ALL−TKアンタゴニスト;アルトレタミン;アムバムスチン;アミドックス;アミフォスチン;アミノレブリン酸;アムルビシン;アムサクリン;アナグレライド;アナストロゾール;アンドログラホリド;血管新生阻害薬;アンタゴニストD;アンタゴニストG;アンタレリックス;抗背方化形態形成タンパク質(anti dorsalizing morphogenetic protein)−1;抗アンドロゲン、前立腺癌;抗エストロゲン;アンチネオプラストン;アンチセンスオリゴヌクレオチド;アフィディコリングリシナート;アポトーシス遺伝子モジュレーター;アポトーシスレギュレーター;アプリン酸;ara〜CDP−DL−PTBA;アルギニンデアミナーゼ;アスラクリン;アタメスタン;アトリムスチン;アキシナスタチン1;アキシナスタチン2;アキシナスタチン3;アザセトロン;アザトキシン;アザチロシン;バッカチンIII誘導体;バラノール;バチマスタット;BCR/ABLアンタゴニスト;ベンゾクロリン;ベンゾイルスタウロスポリン;ベータラクタム誘導体;ベータ−アレチン;ベタクラマイシンB;ベツリン酸;bFGF阻害薬;ビカルタミド;ビサントレン;ビスアジリジニルスペルミン;ビスナフィド;ビストラテンA;ビゼレシン;ブレフラート;ブロピリミン;ブドチタン;ブチオニンスルホキシイミン;カルシポトリオール;カルフォスチンC;カンプトテシン誘導体;カナリアポックスIL−2;カペシタビン;カルボキサミド−アミノ−トリアゾール;カルボキシアミドトリアゾール;CaRest M3;CARN700;軟骨由来阻害薬;カルゼレシン;カゼインキナーゼ阻害薬(ICOS);カスタノスペルミン;セクロピンB;セトロレリクス;クロリン;クロロキノキサリンスルホンアミド;シカプロスト;cis−ポルフィリン;クラドリビン;クロミフェン類似体;クロトリマゾール;コリスマイシンA;コリスマイシンB;コンブレタスタチンA4;コンブレタスタチン類似体;コナゲニン;クラムベシジン816;クリスナトール;クリプトフィシン8;クリプトフィシンA誘導体;クラシンA;シクロペンタントラキノン;シクロプラタム(cycloplatam);シペマイシン;シタラビンオクホスファート;細胞溶解因子;サイトスタチン;ダクリキシマブ(dacliximab);デシタビン;デヒドロジデムニンB;デスロレリン;デキサメタゾン;デキシホスファミド(dexifosfamide);デクスラゾキサン;デクスベラパミル;ジアジコン;ジデムニンB;ジドックス;ジエチルノルスペルミン;ジヒドロ−5−アザシチジン;9−ジオキサマイシン;ジフェニルスピロムスチン;ドコサノール;ドラセトロン;ドキシフルリジン;ドロロキシフェン;ドロナビノール;デュオカルマイシンSA;エブセレン;エコムスチン;エデルホシン;エドレコロマブ;エフロルニチン;エレメン;エミテフール;エピルビシン;エプリステリド;エストラムスチン類似体;エストロゲンアゴニスト;エストロゲンアンタゴニスト;エタニダゾール;エトポシドリン酸塩;エキセメスタン;ファドロゾール;ファザラビン;フェンレチニド;フィルグラスチム;フィナステリド;フラボピリドール;フレゼラスチン;フルアステロン;フルダラビン;塩酸フルオロダウノルニシン(fluorodaunorunicin);ホルフェニメクス;ホルメスタン;フォストリエシン;フォテムスチン;ガドリニウムテキサフィリン;硝酸ガリウム;ガロシタビン;ガニレリックス;ゲラチナーゼ阻害薬;ゲムシタビン;グルタチオン阻害薬;ヘプスルファム;ヘレグリン;ヘキサメチレンビスアセトアミド;ヒペリシン;イバンドロン酸;イダルビシン;イドキシフェン;イドラマントン;イルモホシン;イロマスタット;イミダゾアクリドン(imidazoacridone);イミキモド;免疫刺激ペプチド;インスリン様成長因子−1受容体阻害薬;インターフェロンアゴニスト;インターフェロン;インターロイキン;イオベングアン;ヨードドキソルビシン;イポメアノール、4−;イロプラクト(iroplact);イルソグラジン;イソベンガゾール(isobengazole);イソホモハリコンドリン(isohomohalicondrin)B;イタセトロン;ジャスプラキノライド;カハラリドF;ラメラリン−Nトリアセタート;ランレオチド;レイナマイシン;レノグラスチム;硫酸レンチナン(lentinan sulfate);レプトルスタチン;レトロゾール;白血病阻害因子;白血球アルファインターフェロン;ロイプロリド+エストロゲン+プロゲステロン;ロイプロレリン;レバミゾール;リアロゾール;直鎖ポリアミン類似体;親油性二糖類ペプチド;親油性白金化合物;リッソクリナミド7;ロバプラチン;ロンブリシン;ロメテレキソール;ロニダミン;ロソキサントロン;ロバスタチン;ロキソリビン;ラルトテカン;ルテチウムテキサフィリン;リソフィリン;溶解ペプチド;メイタンシン(maitansine);マンノスタチンA;マリマスタット;マソプロコール;マスピン;マトリライシン阻害薬;マトリックスメタロプロテイナーゼ阻害薬;メノガリル;メルバロン;メテレリン;メチオニナーゼ;メトクロプラミド;MIF阻害薬;ミフェプリストン;ミルテホシン;ミリモスチム;ミスマッチ二本鎖RNA;ミトグアゾン;ミトラクトール;マイトマイシン類似体;ミトナフィド;マイトトキシン線維芽細胞成長因子−サポリン;ミトキサントロン;モファロテン;モルグラモスチム;モノクローナル抗体;ヒト絨毛性ゴナドトロピン(gonadotrophin);モノホスホリルリピドA+ミオバクテリウム(myobacterium)細胞壁sk;モピダモール;多剤耐性遺伝子阻害薬;多発腫瘍サプレッサー1−ベース療法;マスタード抗ガン薬;ミカペルオキシドB;ミコバクテリア細胞壁抽出物;ミリアポロン;N−アセチルジナリン;N−置換ベンズアミド;ナファレリン;ナグレスチップ(nagrestip);ナロキソン+ペンタゾシン;ナパビン(napavin);ナフテルピン;ナルトグラスチム;ネダプラチン;ネモルビシン;ネリドロン酸;中性エンドペプチダーゼ;ニルタミド;ニサマイシン;酸化窒素モジュレーター;ニトロキシド抗酸化薬;ニトルリン(nitrullyn);06−ベンジルグアニン;オクトレオチド;オキセノン;オリゴヌクレオチド;オナプリストン;オンダンセトロン;オンダンセトロン;オラシン;経口サイトカイン誘導因子;オルマプラチン;オサテロン;オキサリプラチン;オキサウノマイシン;パラウアミン;パルミトイルリゾキシン;パミドロン酸;パナキシトリオール;パノミフェン;パラバクチン;パゼリプチン;ペグアスパラガーゼ;ペルデシン;ポリ硫酸ペントサンナトリウム;ペントスタチン;ペントロゾール(pentrozole);ペルフルブロン;ペルホスファミド;ペリリルアルコール;フェナジノマイシン;酢酸フェニル;ホスファターゼ阻害薬;ピシバニール;ピロカルピン塩酸塩;ピラルビシン;ピリトレキシム;プラセチン(placetin)A;プラセチンB;プラスミノーゲン活性化因子阻害薬;白金錯体;白金化合物;白金−トリアミン錯体;ポルフィマーナトリウム;ポルフィロマイシン;プレドニゾン;プロピルビス−アクリドン;プロスタグランジンJ2;プロテアソーム阻害薬;プロテインAベースの免疫モジュレーター;プロテインキナーゼC阻害薬;プロテインキナーゼC阻害薬(微細藻);タンパク質チロシンホスファターゼ阻害薬;プリンヌクレオシドホスホリラーゼ阻害薬;プルプリン;ピラゾロアクリジン;ピリドキシル化ヘモグロビンポリオキシエチレンコンジュゲート;rafアンタゴニスト;ラルチトレキセド;ラモセトロン;rasフ
ァルネシルタンパク質トランスフェラーゼ阻害薬;ras阻害薬;ras−GAP阻害薬;脱メチル化レテリプチン;エチドロン酸レニウムRe186(rhenium Re 186 etidronate);リゾキシン;リボザイム;RIIレチンアミド;ログレチミド;ロヒツキン;ロムルチド;ロキニメックス;ルビギノンB1;ルボキシル;サフィンゴール;サイントピン;SarCNU;サルコフィトールA;サルグラモスチム;Sdi1模倣体;セムスチン;老化由来阻害薬1;センスオリゴヌクレオチド;シグナル伝達阻害薬;シグナル伝達モジュレーター;単鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ボロカプト酸ナトリウム(sodium borocaptate);フェニル酢酸ナトリウム;ソルベロール(solverol);ソマトメジン結合タンパク質;ソネルミン;スパルホス酸;スピカマイシンD;スピロムスチン;スプレノペンチン;スポンジスタチン1;スクアラミン;幹細胞阻害薬;幹細胞分裂阻害剤;スチピアミド;ストロメライシン阻害薬;スルフィノシン;超活性血管作動性腸管ペプチドアンタゴニスト;スラジスタ(suradista);スラミン;スワインソニン;合成グリコサミノグリカン;タリムスチン;タモキシフェンメチオジド;タウロムスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリリウム;テロメラーゼ阻害薬;テモポルフィン;テモゾロマイド;テニポシド;テトラクロロデカオキシド;テトラゾミン;タリブラスチン;チオコラリン;トロンボポイエチン;トロンボポイエチン模倣体;チマルファシン;チモポエチン受容体アゴニスト;チモトリナン;甲状腺刺激ホルモン;エチルエチオプルプリンスズ;チラパザミン;二塩化チタノセン;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害薬;トレチノイン;トリアセチルウリジン;トリシリビン;トリメトレキサート;トリプトレリン;トロピセトロン;ツロステリド;チロシンキナーゼ阻害薬;チルホスチン;UBC阻害薬;ウベニメクス;尿生殖洞由来成長阻害因子;ウロキナーゼ受容体アンタゴニスト;バプレオチド;バリオリンB;ベクター系、赤血球遺伝子療法;ベラレソール;ベラミン(veramine);ベルジン;ベルテポルフィン;ビノレルビン;ビンキサルチン(vinxaltine);ビタキシン;ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;ジノスタチンスチマラマー、アドリアマイシン、ダクチノマイシン、ブレオマイシン、ビンブラスチン、シスプラチン、アシビシン;アクラルビシン;塩酸アコダゾール;アクロニン;アドゼレシン;アルデスロイキン;アルトレタミン;アンボマイシン;酢酸アメタントロン;アミノグルテチミド;アムサクリン;アナストロゾール;アントラマイシン;アスパラギナーゼ;アスペルリン;アザシチジン;アゼテパ;アゾトマイシン;バチマスタット;ベンゾデパ;ビカルタミド;塩酸ビサントレン;ジメシル酸ビスナフィド;ビゼレシン;硫酸ブレオマイシン;ブレキナルナトリウム;ブロピリミン;ブスルファン;カクチノマイシン;カルステロン;カラセミド;カルベチマー;カルボプラチン;カルムスチン;塩酸カルビシン;カルゼレシン;セデフィンゴール;クロラムブシル;シロレマイシン;クラドリビン;メシル酸クリスナトール;シクロホスファミド;シタラビン;ダカルバジン;塩酸ダウノルビシン;デシタビン;デキソルマプラチン;デザグアニン;メシル酸デザグアニン;ジアジクオン;ドキソルビシン;塩酸ドキソルビシン;ドロロキシフェン;クエン酸ドロロキシフェン;プロピオン酸ドロモスタノロン;デュアゾマイシン;エダトレキセート;塩酸エフロルニチン;エルサミトルシン;エンロプラチン;エンプロメート;エピプロピジン;塩酸エピルビシン;エルブロゾール;塩酸エソルビシン;エストラムスチン;リン酸エストラムスチンナトリウム;エタニダゾール;エトポシド;リン酸エトポシド;エトプリン;塩酸ファドロゾール;ファザラビン;フェンレチニド;フロクスウリジン;リン酸フルダラビン;フルオロウラシル;フルオロシタビン;ホスキドン;ホストリエシンナトリウム;ゲムシタビン;塩酸ゲムシタビン;ヒドロキシ尿素;塩酸イダルビシン;イホスファミド;イルモホシン;インターロイキンII(組換えインターロイキンII、又はrlL2を含む)、インターフェロンアルファ−2a;インターフェロンアルファ−2b;インターフェロンアルファ−n1;インターフェロンアルファ−n3;インターフェロンベータ−1a;インターフェロンガンマ−1b;イプロプラチン;塩酸イリノテカン;酢酸ランレオチド;レトロゾール;酢酸ロイプロリド;塩酸リアロゾール;ロメテレキソールナトリウム;ロムスチン;塩酸ロソキサントロン;マソプロコール;メイタンシン;塩酸メクロレタミン;酢酸メゲステロール;酢酸メレンゲストロール;メルファラン;メノガリル;メルカプトプリン;メトトレキサート;メトトレキサートナトリウム;メトプリン;メツレデパ;ミチンドロミド;マイトカルシン;マイトクロミン;マイトギリン;マイトマルシン;マイトマイシン;マイトスペル;ミトタン;塩酸ミトキサントロン;ミコフェノール酸;ノコダゾール;ノガラマイシン;オルマプラチン;オキシスラン;ペグアスパラガーゼ;ペリオマイシン;ペンタムスチン;硫酸ペプロマイシン;ペルホスファミド;ピポブロマン;ピポスルファン;塩酸ピロキサントロン;プリカマイシン;プロメスタン;ポルフィマーナトリウム;ポルフィロマイシン;プレドニムスチン;塩酸プロカルバジン;ピューロマイシン;塩酸ピューロマイシン;ピラゾフリン;リボプリン;ログレチミド;サフィンゴール;塩酸サフィンゴール;セムスチン;シムトラゼン;スパルホサートナトリウム;スパルソマイシン;塩酸スピロゲルマニウム;スピロムスチン;スピロプラチン;ストレプトニグリン;ストレプトゾシン;スロフェヌル;タリソマイシン;テコガランナトリウム;テガフール;塩酸テロキサントロン;テモポルフィン;テニポシド;テロキシロン;テストラクトン;チアミプリン;チオグアニン;チオテパ;チアゾフリン;チラパザミン;クエン酸トレミフェン;酢酸トレステロン;リン酸トリシリビン;トリメトレキサート;グルクロン酸トリメトレキサート;トリプトレリン;塩酸ツブロゾール;ウラシルマスタード;ウレデパ;バプレオチド;ベルテポルフィン;硫酸ビンブラスチン;硫酸ビンクリスチン;ビンデシン;硫酸ビンデシン;硫酸ビネピジン;硫酸ビンクリシナート;硫酸ビンロイロシン;酒石酸ビノレルビン;硫酸ビンロシジン;硫酸ビンゾリジン;ボロゾール;ゼニプラチン;ジノスタチン;塩酸ゾルビシン、細胞をG2−M期で停止させる、及び/または微小管の形成または安定性をモジュレートする薬剤(例えば、タキソール(すなわち、パクリタキセル)、タキソテール、タキサン骨格を含む化合物、エルブロゾール(すなわち、R−55104)、ドラスタチン10(すなわち、DLS−10及びNSC−376128)、イセチオン酸ミボブリン(すなわち、CI−980)、ビンクリスチン、NSC−639829、ディスコデルモリド(すなわち、NVP−XX−A−296)、ABT−751(Abbott、すなわち、E−7010)、アルトリルチン(例えば、アルトリルチンA及びアルトリルチンC)、スポンジスタチン(例えば、スポンジスタチン1、スポンジスタチン2、スポンジスタチン3、スポンジスタチン4、スポンジスタチン5、スポンジスタチン6、スポンジスタチン7、スポンジスタチン8、及びスポンジスタチン9)、塩酸セマドチン(すなわち、LU−103793及びNSC−D−669356)、エポチロン(例えば、エポチロンA、エポチロンB、エポチロンC(すなわち、デスオキシエポチロンAまたはdEpoA)、エポチロンD(すなわち、KOS−862、dEpoB、及びデスオキシエポチロンB)、エポチロンE、エポチロンF、エポチロンB N−オキシド、エポチロンA N−オキシド、16−アザ−エポチロンB、21−アミノエポチロンB(すなわち、BMS−310705)、21−ヒドロキシエポチロンD(すなわち、デスオキシエポチロンF及びdEpoF)、26−フルオロエポチロン、オーリスタチンPE(すなわち、NSC−654663)、ソブリドチン(すなわち、TZT−1027)、LS−4559−P(Pharmacia、すなわち、LS−4577)、LS−4578(Pharmacia、すなわち、LS−477−P)、LS−4477(Pharmacia)、LS−4559(Pharmacia)、RPR−112378(Aventis)、硫酸ビンクリスチン、DZ−3358(Daiichi)、FR−182877(Fujisawa、すなわち、WS−9885B)、GS−164(Takeda)、GS−198(Takeda)、KAR−2(Hungarian Academy of Sciences)、BSF−223651(BASF、すなわち、ILX−651及びLU−223651)、SAH−49960(Lilly/Novartis)、SDZ−268970(Lilly/Novartis)、AM−97(Armad/Kyowa Hakko)、AM−132(Armad)、AM−138(Armad/Kyowa Hakko)、IDN−5005(Indena)、クリプトフィシン52(すなわち、LY−355703)、AC−7739(Ajinomoto、すなわち、AVE−8063A及びCS−39.HC1)、AC−7700(Ajinomoto、すなわち、AVE−8062、AVE−8062A、CS−39−L−Ser.HCl、及びRPR−258062A)、ビチレブアミド、ツブリシンA、カナデンソール、センタウレイジン(すなわち、NSC−106969)、T−138067(Tularik、すなわち、T−67、TL−138067及びTI−138067)、COBRA−1(Parker Hughes Institute、すなわち、DDE−261及びWHI−261)、H10(Kansas State University)、H16(Kansas State University)、オンコシジンA1(すなわち、BTO−956及びDIME)、DDE−313(Parker Hughes Institute)、フィジアノリドB、ラウリマリド、SPA−2(Parker Hughes Institute)、SPA−1(Parker Hughes Institute、すなわち、SPIKET−P)、3−IAABU(Cytoskeleton/Mt.Sinai School of Medicine、すなわち、MF−569)、ナルコシン(NSC−5366としても公知)、ナスカピン(Nascapine)、D−24851(Asta Medica)、A−105972(Abbott)、ヘミアステリン、3−BAABU(Cytoskeleton/Mt.Sinai School of Medicine、すなわち、MF−191)、TMPN(Arizona State University)、バナドセンアセチルアセトナート、T−138026(Tularik)、モンサトロール(Monsatrol)、イナノシン(Inanocine)(すなわち、NSC−698666)、3−IAABE(Cytoskeleton/Mt.Sinai School of Medicine)、A−204197(Abbott)、T−607(Tularik、すなわち、T−900607)、RPR−115781(Aventis)、エロイテロビン(デスメチルエロイテロビン、デスアセチルエロイテロビン、イソエロイテロビンA、及びZ−エロイテロビンなど)、カリベオシド、カリベオリン、ハリコンドリンB、D−64131(Asta Medica)、D−68144(Asta Medica)、ジアゾナミドA、A−293620(Abbott)、NPI−2350(Nereus)、タッカロノリドA、TUB−245(Aventis)、A−259754(Ab
bott)、ジオゾスタチン、(−)−フェニルアヒスチン(すなわち、NSCL−96F037)、D−68838(Asta Medica)、D−68836(Asta Medica)、ミオセベリンB、D−43411(Zentaris、すなわち、D−81862)、A−289099(Abbott)、A−318315(Abbott)、HTI−286(すなわち、SPA−110、トリフルオロ酢酸塩)(Wyeth)、D−82317(Zentaris)、D−82318(Zentaris)、SC−12983(NCI)、レスベラスタチンホスファートナトリウム、BPR−OY−007(National Health Research Institutes)、及びSSR−250411(Sanofi)、ステロイド(例えば、デキサメタゾン)、フィナステリド、アロマターゼ阻害薬、生殖腺刺激ホルモン放出ホルモンアゴニスト(GnRH)、例えば、ゴセレリンまたはロイプロリド、副腎皮質ステロイド(例えば、プレドニゾン)、プロゲスチン(例えば、ヒドロキシプロゲステロンカプロナート、酢酸メゲストロール、酢酸メドロキシプロゲステロン)、エストロゲン(例えば、ジエチルスチルベストロール、エチニルエストラジオール)、抗エストロゲン(例えば、タモキシフェン)、アンドロゲン(例えば、プロピオン酸テストステロン、フルオキシメステロン)、抗アンドロゲン(例えば、フルタミド)、免疫賦活薬(例えば、カルメット−ゲラン桿菌(BCG)、レバミゾール、インターロイキン−2、アルファ−インターフェロンなど)、モノクローナル抗体(例えば、抗CD20、抗HER2、抗CD52、抗HLA−DR、及び抗VEGFモノクローナル抗体)、免疫毒素(例えば、抗CD33モノクローナル抗体−カリケアマイシンコンジュゲート、抗CD22モノクローナル抗体−シュードモナス外毒素コンジュゲートなど)、放射性免疫療法(例えば、U1ln、90Y、または131Iなどにコンジュゲートした抗CD20モノクローナル抗体)、トリプトリド、ホモハリングトニン、ダクチノマイシン、ドキソルビシン、エピルビシン、トポテカン、イトラコナゾール、ビンデシン、セリバスタチン、ビンクリスチン、デオキシアデノシン、セルトラリン、ピタバスタチン、イリノテカン、クロファジミン、5−ノニルオキシトリプタミン、ベムラフェニブ、ダブラフェニブ、エルロチニブ、ゲフィチニブ、EGFR阻害薬、上皮成長因子受容体(EGFR)標的療法または治療薬(例えば、ゲフィチニブ(Iressa(商標))、エルロチニブ(Tarceva(商標))、セツキシマブ(Erbitux(商標))、ラパチニブ(Tykerb(商標))、パニツムマブ(Vectibix(商標))、バンデタニブ(Caprelsa(商標))、アファチニブ/BIBW2992、CI−1033/カネルチニブ、ネラチニブ/HKI−272、CP−724714、TAK−285、AST−1306、ARRY334543、ARRY−380、AG−1478、ダコミチニブ/PF299804、OSI−420/デスメチルエルロチニブ、AZD8931、AEE788、ペリチニブ/EKB−569、CUDC−101、WZ8040、WZ4002、WZ3146、AG−490、XL647、PD153035、BMS−599626)、ソラフェニブ、イマチニブ、スニチニブ、ダサチニブなどが含まれる。
一部の実施形態では、本明細書に記載の化合物(例えば、式(I)の化合物)またはその組成物と組み合わせて使用するための第2の薬剤は、神経変性疾患、白質ジストロフィー、炎症性疾患、筋骨格疾患、または代謝性疾患を処置する際に使用するための薬剤である。一部の実施形態では、本明細書に記載の化合物(例えば、式(I)の化合物)またはその組成物と組み合わせて使用するための第2の薬剤は、本明細書に記載の疾患、障害、または状態を処置するために、FDAまたは米国以外の国の同様の規制当局により認可されている薬剤である。
本明細書において提供する化合物は、当業者にはよく分かるであろう下記の具体的な合成プロトコルの変更形態を使用して、容易に入手可能な出発物質から調製することができる。典型的な、または好ましいプロセス条件(すなわち、反応温度、時間、反応物のモル比、溶媒、圧力など)が示されている場合に、別段に述べない限り、他のプロセス条件も使用することができることは分かるであろう。最適な反応条件は、使用される特定の反応物または溶媒で変動し得るが、そのような条件は、当業者であれば、ルーチン的な最適化手順により決定することができる。加えて、本発明の例示化合物を作製する方法に関する一般スキームを、化合物を作製する方法と題されたセクションにおいて記載する。
APCIは、大気圧化学イオン化;DMSOはジメチルスルホキシド;HPLCは高速液体クロマトグラフィー;MSは質量スペクトル;及びNMRは核磁気共鳴である。
実施例1A:メチル3−(2−(4−クロロフェノキシ)アセトアミド)ビシクロ[1.1.1]ペンタン−1−カルボキシラート
N,N−ジメチルホルムアミド(150mL)中の2−(4−クロロフェノキシ)酢酸(10.88g、58.5mmol)の溶液に、メチル3−アミノビシクロ[1.1.1]ペンタン−1−カルボキシラート(Pharmablock、10.5g、53.2mmol)、N,N−ジイソプロピルエチルアミン(27.5g、213mmol)及び2−(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イル)−1,1,3,3−テトラメチルイソウロニウムヘキサフルオロホスファート(V)(30.3g、80mmol)を添加した。反応混合物を周囲温度で3時間にわたって撹拌し、次いで、酢酸エチル(250mL)と水(250mL)との間で分配した。水層を酢酸エチル(3×200mL)で抽出した。合わせた有機層をブライン(5×300mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮した。粗製の生成物を、フラッシュクロマトグラフィー(シリカゲル、10〜20%酢酸エチル/ヘプタン)により精製して、標題化合物15.4g(94%)を薄黄色の固体として得た。MS (APCI) m/z 310 (M+H)+。
テトラヒドロフラン(3mL)中の実施例1A(0.52g、0.169mmol)の溶液を、1N LiOH溶液(3.34mL)で処理し、周囲温度で0.5時間にわたって撹拌した。反応混合物を濃縮し、6N HClで中和した。得られた沈澱物を濾取し、水で洗浄し、真空炉内で乾燥させて、標題化合物を得た。MS (APCI) m/z 296 (M+H)+。
N,N−ジメチルホルムアミド(0.5mL)中の実施例1B(0.025g、0.085mmol)の溶液に、2−(4−クロロフェノキシ)エタン−1−アミン(0.015g、0.085mmol)、N,N−ジイソプロピルエチルアミン(0.04mL、0.212mmol)及び2−(7−アザ−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ヘキサフルオロホスファート(0.035g、0.093mmol)を周囲温度で添加した。反応混合物を3時間にわたって撹拌し、次いで、酢酸エチル(20mL)と水(20mL)との間で分配した。水層を酢酸エチル(3×20mL)で抽出した。合わせた有機層をブライン(5×30mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮した。残渣をHPLC(Phenomenex(登録商標)Luna(登録商標)C18(2)5μm 100Å AXIA(商標)カラム250mm×21.2mm、流速25mL/分、緩衝液(水中の0.1%トリフルオロ酢酸)中のアセトニトリルの10〜80%勾配)により精製して、標題化合物0.028g(74%)を薄黄色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 8.65 (s, 1H), 7.96 (t, J = 5.7 Hz, 1H), 7.40 − 7.25 (m, 4H), 7.05 − 6.90 (m, 4H), 4.38 (s, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.35 (q, J = 5.9 Hz, 2H), 2.13 (s, 6H). MS (APCI) m/z 450 (M+H)+。
N,N−ジメチルホルムアミド(1.0mL)中の実施例1B(25mg、0.08mmol)の溶液を、N,N−ジメチルホルムアミド(0.5mL)中の2−(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イル)−1,1,3,3−テトラメチルイソウロニウムヘキサフルオロホスファート(V)(35mg、0.09mmol)の溶液で処理した。次いで、N,N−ジメチルアセトアミド(0.15mL)中の2−(m−トリルオキシ)エタンアミン(12mg、0.08mmol)の溶液を、続いて、N,N−ジイソプロピルエチルアミン(0.037mL、0.21mmol)を添加した。反応物を周囲温度で終夜、振盪し、HPLC(2つの連結したC8 5μm 100Åカラム(それぞれ30mm×75mm)、50mL/分の流速、緩衝液(水中の0.1%トリフルオロ酢酸)中のアセトニトリルの5〜90%勾配)により精製して、標題化合物を得た。1H NMR (400 MHz, DMSO−d6/D2O,温度=27℃) δ ppm 8.06 (t, J = 5.7 Hz, 1H), 7.36 − 7.29 (m, 2H), 7.15 (t, J = 8.0 Hz, 1H), 7.01 − 6.93 (m, 2H), 6.77 − 6.68 (m, 3H), 4.40 (s, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.43 − 3.31 (m, 2H), 2.25 (s, 3H), 2.17 (s, 6H). MS (APCI+) m/z 429.2 (M+H)+。
標題化合物を、実施例2に記載の方法を使用して、2−(m−トリルオキシ)エタンアミンを2−(4−フルオロフェノキシ)エタンアミン(12.4mg、0.08mmol)に置き換えることにより調製した。1H NMR (400 MHz, DMSO−d6/D2O,温度=27℃) δ ppm 8.07 (t, J = 5.7 Hz, 1H), 7.38 − 7.32 (m, 2H), 7.15 − 7.06 (m, 2H), 7.02 − 6.90 (m, 4H), 4.40 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 3.46 − 3.36 (m, 2H), 2.17 (s, 6H). MS (APCI+) m/z 433.2 (M+H)+。
標題化合物を、実施例2に記載の方法を使用して、2−(m−トリルオキシ)エタンアミンを2−(4−クロロ−3−メチルフェノキシ)エタンアミン(14.8mg、0.08mmol)に置き換えることにより調製した。1H NMR (400 MHz, DMSO−d6/D2O,温度=27℃) δ ppm 8.07 (t, J = 5.7 Hz, 1H), 7.37 − 7.31 (m, 2H), 7.27 (d, J = 8.7 Hz, 1H), 7.03 − 6.96 (m, 2H), 6.95 − 6.91 (m, 1H), 6.83 − 6.77 (m, 1H), 4.40 (s, 2H), 3.97 (t, J = 5.9 Hz, 2H), 3.45 − 3.35 (m, 2H), 2.27 (s, 3H), 2.17 (s, 6H). MS (APCI+) m/z 463.2 (M+H)+。
標題化合物を、実施例2に記載の方法を使用して、2−(m−トリルオキシ)エタンアミンを2−(3−フルオロフェノキシ)エタンアミン(12.4mg、0.08mmol)に置き換えることにより調製した。1H NMR (400 MHz, DMSO−d6/D2O,温度=27℃) δ ppm 8.75 (s, 1H), 8.08 (t, J = 5.7 Hz, 1H), 7.36 − 7.28 (m, 3H), 7.03 − 6.93 (m, 2H), 6.82 − 6.74 (m, 3H), 4.40 (s, 2H), 4.00 (t, J = 5.8 Hz, 2H), 3.43 − 3.34 (m, 2H), 2.17 (s, 6H). MS (APCI+) m/z 433.2 (M+H)+。
標題化合物を、実施例2に記載の方法を使用して、2−(m−トリルオキシ)エタンアミンを2−(p−トリルオキシ)エタンアミン(12.4mg、0.08mmol)に置き換えることにより調製した。1H NMR (400 MHz, DMSO−d6/D2O,温度=27℃) δ ppm 8.75 (s, 1H), 8.06 (t, J = 5.7 Hz, 1H), 7.39 − 7.31 (m, 2H), 7.12 − 7.05 (m, 2H), 7.01 − 6.94 (m, 2H), 6.86 − 6.78 (m, 2H), 4.40 (s, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.43 − 3.34 (m, 2H), 2.21 (s, 3H), 2.17 (s, 6H). MS (APCI+) m/z 429.2 (M+H)+。
実施例7A:エチル1,4−ジオキサスピロ[4.5]デカン−8−カルボキシラート
トルエン(200mL)中のエチル4−オキソシクロヘキサンカルボキシラート(11.70mL、73.4mmol)、エタン−1,2−ジオール(12.29mL、220mmol)、及びp−トルエンスルホン酸一水和物(1.397g、7.34mmol)の混合物を120℃で、ディーンスタークトラップ装置を用いて180分間にわたって撹拌した。反応混合物をN−エチル−N−イソプロピルプロパン−2−アミンで中和し、次いで、濃縮した。残渣をシリカゲル上で精製して(ヘプタン中の0〜30%酢酸エチル)、標題化合物12.77gを透明な油状物として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 4.01 (q, J = 7.1 Hz, 2H), 3.81 (s, 4H), 2.32 (tt, J = 10.4, 3.8 Hz, 1H), 1.83 − 1.71 (m, 2H), 1.66 − 1.57 (m, 1H), 1.62 − 1.38 (m, 5H), 1.13 (t, J = 7.1 Hz, 3H)。
テトラヒドロフラン(25mL)中のジイソプロピルアミン(5.19mL、36.4mmol)の溶液に、0℃で、n−ブチルリチウムを5℃未満でゆっくり添加した。30分間にわたって撹拌した後に、溶液を窒素下で−78℃に冷却し、テトラヒドロフラン(3mL)中の実施例7A(6.0g、28.0mmol)の溶液をゆっくり添加し、得られた混合物を30分間にわたって同じ温度で撹拌した。次いで、塩化アセチル(2.59mL、36.4mmol)をゆっくり添加し、温度を−60℃未満に維持し、混合物を−70℃で2時間にわたって撹拌した。反応物を飽和NH4Cl溶液でクエンチし、水相を酢酸エチルで抽出した。有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過した。濾液を濃縮し、残渣をシリカゲル上で精製して(ヘプタン中の0〜70%酢酸エチル)、標題化合物6.78gを透明な油状物として得た。1H NMR (500 MHz, DMSO−d6) δ ppm 4.19 − 4.11 (m, 2H), 3.85 (s, 4H), 2.13 (s, 3H), 2.10 − 2.01 (m, 2H), 1.90 (ddd, J = 13.9, 9.6, 4.6 Hz, 2H), 1.54 (th, J = 13.6, 4.7 Hz, 4H), 1.18 (dd, J = 7.6, 6.5 Hz, 3H)。
アセトン(60mL)中の実施例7B(6.5g、25.4mmol)及びHCl(21.13mL、127mmol)の混合物を周囲温度で終夜、撹拌した。揮発性物質を減圧下で除去し、残渣を水とジクロロメタンとの間で分配した。有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過した。濾液を濃縮して、標題化合物5.46gを透明な油状物として得、さらに精製せずに使用した。1H NMR (400 MHz, DMSO−d6) δ ppm 4.16 (q, J = 7.1 Hz, 2H), 2.17 (s, 3H), 2.35 2.07 (m, 8H), 1.17 (t, J = 7.1 Hz, 3H)。
トルエン(100mL)中の実施例7C(9.7g、45.7mmol)、ベンジルアミン(14.98mL、137mmol)、及びp−トルエンスルホン酸一水和物(0.087g、0.457mmol)の混合物を130℃で、ディーンスタークトラップ装置を用いて終夜、撹拌した。混合物を濃縮し、残渣を酢酸エチル(50mL)及び3N HCl(100mL)の混合物と共に30分間にわたって撹拌した。沈殿物を濾取し、酢酸エチル/ヘプタンの混合物で洗浄し、空気乾燥させて、標題化合物11.3gをHCl塩として得た。濾液を6N NaOHで中和し、酢酸エチル(100mL×2)で抽出した。有機層をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過した。残渣をシリカゲル上で精製して(ヘプタン中の0〜70%酢酸エチル)、さらなる標題化合物0.77gを黄色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 9.73 (t, J = 6.2 Hz, 2H), 7.87 − 7.12 (m, 5H), 4.09 (m, 4H), 2.88 (s, 2H), 2.08 (dt, J = 20.7, 13.4 Hz, 6H), 1.16 (t, J = 7.1 Hz, 3H);MS (ESI+) m/z 302.1 (M+H)+。
50mL圧力ボトル内のテトラヒドロフラン(110mL)中の実施例7D(11.2g、33.2mmol)の混合物に、20%Pd(OH)2/C、湿潤(2.2g、1.598mmol)を添加し、反応物を50℃で、水素50psi下で、22時間にわたって振盪した。反応混合物を周囲温度に冷却し、固体を濾過により除去し、メタノール(1L)で洗浄した。濾液及び洗浄液を濃縮して、標題化合物7.9gを薄黄色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 8.46 (s, 3H), 4.07 (q, J = 7.1 Hz, 2H), 2.62 (s, 2H), 2.17 − 2.05 (m, 2H), 2.04 − 1.78 (m, 6H), 1.14 (t, J = 7.1 Hz, 3H)。
N,N−ジメチルホルムアミド(200mL)中の実施例7E(7.8g、31.5mmol)、N−エチル−N−イソプロピルプロパン−2−アミン(22.00mL、126mmol)及び2−(4−クロロ−3−フルオロフェノキシ)酢酸(7.41g、36.2mmol)の懸濁液に、2−(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イル)−1,1,3,3−テトラメチルイソウロニウムヘキサフルオロホスファート(V)(14.97g、39.4mmol)を添加し、得られた茶色の溶液を周囲温度で16時間にわたって撹拌した。水を添加し、混合物を15分間にわたって撹拌した。沈殿物を濾取し、水で洗浄し、空気乾燥させて、標題化合物12.1gをオフホワイト色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 7.87 (s, 1H), 7.45 (t, J = 8.9 Hz, 1H), 7.00 (dd, J = 11.4, 2.9 Hz, 1H), 6.79 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.45 (s, 2H), 4.06 (q, J = 7.1 Hz, 2H), 2.73 (s, 2H), 2.07 (m, 1H), 2.01 − 1.84 (m, 6H), 1.14 (t, J = 7.1 Hz, 3H);MS (ESI+) m/z 398.0 (M+H)+。
メタノール(100mL)中の実施例7F(11.37g、28.6mmol)及び水酸化ナトリウム(7.15mL、57.2mmol、8M溶液)の懸濁液を周囲温度で、16時間にわたって撹拌した。揮発性物質を除去し、残渣を1N HClで酸性化した。沈殿物を濾取し、真空炉内で乾燥させて、標題化合物9.9gを白色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 12.49 (s, 1H), 7.86 (s, 1H), 7.45 (t, J = 8.9 Hz, 1H), 7.00 (dd, J = 11.4, 2.9 Hz, 1H), 6.83 − 6.74 (m, 1H), 4.45 (s, 2H), 2.71 (s, 2H), 2.01 − 1.81 (m, 7H);MS (ESI−) m/z 368.1 (M−H)−。
メタノール(50.0mL)中の実施例7G(2.6g、7.03mmol)及びホウ水素化ナトリウム(1.330g、35.2mmol)(8M溶液)懸濁液を周囲温度で、30分間にわたって撹拌した。混合物を濃縮し、残渣を1N HClで酸性化した。得られた沈澱物を濾取し、真空炉内で乾燥させて、生成物2.63gを白色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 11.93 (s, 1H), 7.50 − 7.39 (m, 2H), 6.98 (dd, J = 11.4, 2.8 Hz, 1H), 6.77 (ddd, J = 9.0, 2.8, 1.2 Hz, 1H), 4.79 (d, J = 4.9 Hz, 1H), 4.40 (s, 2H), 4.02 (dd, J = 8.9, 4.1 Hz, 1H), 2.20 (ddd, J = 12.7, 9.4, 2.9 Hz, 1H), 2.02 (tdd, J = 11.4, 4.4, 2.0 Hz, 1H), 1.85 − 1.44 (m, 8H);MS (ESI+) m/z 372.0 (M+H)+。
N,N−ジメチルホルムアミド(1.5mL)中の実施例7G(50mg、0.135mmol)、(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミン(29.8mg、0.169mmol)及びN−エチル−N−イソプロピルプロパン−2−アミン(0.059mL、0.338mmol)の混合物を、2−(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イル)−1,1,3,3−テトラメチルイソウロニウムヘキサフルオロホスファート(V)(77mg、0.203mmol)で処理し、反応物を周囲温度で16時間にわたって撹拌した。混合物を濃縮し、残渣をジクロロメタン/メタノール(1:1混合物、2mL)に溶解させ、ホウ水素化ナトリウム(25.6mg、0.676mmol)で処理した。混合物を周囲温度で1時間にわたって撹拌した。混合物を真空下で濃縮し、粗製の残渣を、HPLC(Phenomenex(登録商標)Luna(登録商標)C18(2)5μm 100Å AXIA(商標)カラム(250mm×21.2mm)で行った。アセトニトリル(A)及び水中0.1%トリフルオロ酢酸(B)の勾配を25mL/分の流速で使用する。約10分かけてA約5%からA約95%への直線勾配を使用する。検出方法は218nM及び254nMの波長のUVである)により精製して、生成物46mgを白色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 8.82 (d, J = 2.2 Hz, 1H), 8.17 (t, J = 5.9 Hz, 1H), 8.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.53 − 7.40 (m, 3H), 6.99 (dd, J = 11.4, 2.8 Hz, 1H), 6.78 (dd, J = 8.9, 2.8 Hz, 1H), 4.40 (d, J = 6.0 Hz, 4H), 4.07 (dd, J = 9.4, 2.7 Hz, 1H), 2.23 (ddd, J = 12.6, 9.2, 2.8 Hz, 1H), 2.11 (td, J = 11.9, 3.7 Hz, 1H), 1.86 (tt, J = 15.4, 7.8 Hz, 1H), 1.78 − 1.54 (m, 7H);MS (ESI+) m/z 530.2 (M+H)+。
標題化合物を、実施例7に記載の方法を使用して、2−(4−クロロフェノキシ)エタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.64 (t, J = 5.6 Hz, 1H), 7.50 − 7.39 (m, 2H), 7.28 (d, J = 8.9 Hz, 2H), 7.03 − 6.87 (m, 3H), 6.77 (dd, J = 9.0, 2.9 Hz, 1H), 4.89 (s, 1H), 4.40 (s, 2H), 4.03 − 3.88 (m, 3H), 3.37 (t, J = 5.9 Hz, 2H), 2.18 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 1.99 (tt, J = 12.0, 3.3 Hz, 1H), 1.90 − 1.77 (m, 1H), 1.74 − 1.57 (m, 5H), 1.52 (tt, J = 12.2, 5.2 Hz, 2H);MS (ESI+) m/z 525.1 (M+H)+。
標題化合物を、実施例7に記載の方法を使用して、(5−クロロピリジン−2−イル)メタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.47 (d, J = 2.5 Hz, 1H), 8.10 (t, J = 6.0 Hz, 1H), 7.88 − 7.75 (m, 1H), 7.56 − 7.32 (m, 2H), 7.27 (d, J = 8.5 Hz, 1H), 6.99 (dd, J = 11.4, 2.8 Hz, 1H), 6.78 (dd, J = 8.8, 2.7 Hz, 1H), 4.41 (s, 2H), 4.30 (d, J = 5.9 Hz, 2H), 4.06 (dd, J = 9.4, 2.7 Hz, 1H), 2.22 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.08 (tt, J = 11.7, 3.2 Hz, 1H), 1.85 (ddd, J = 23.0, 14.3, 8.5 Hz, 2H), 1.69 (qt, J = 12.7, 2.7 Hz, 6H), 1.65 − 1.53 (m, 1H);MS (ESI+) m/z 496.2 (M+H)+。
標題化合物を、実施例7に記載の方法を使用して、3−イソプロピル−イソオキサゾール−5−イルメチルアミンヒドロクロリドを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.03 (t, J = 5.9 Hz, 1H), 7.46 (dd, J = 18.3, 9.4 Hz, 2H), 6.99 (dd, J = 11.4, 2.9 Hz, 1H), 6.77 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 6.13 (s, 1H), 4.96 (s, 1H), 4.40 (s, 2H), 4.28 (d, J = 5.8 Hz, 2H), 4.04 (d, J = 9.1 Hz, 1H), 2.90 (hept, J = 6.9 Hz, 1H), 2.21 (ddd, J = 12.7, 9.2, 2.8 Hz, 1H), 2.10 − 1.99 (m, 1H), 1.85 (td, J = 11.9, 7.9 Hz, 1H), 1.75 − 1.50 (m, 7H), 1.15 (d, J = 6.9 Hz, 6H);MS (ESI+) m/z 494.1 (M+H)+。
標題化合物を、実施例7に記載の方法を使用して、(4−(トリフルオロメチル)フェニル)メタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.05 (t, J = 6.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.49 − 7.37 (m, 3H), 6.99 (dd, J = 11.4, 2.9 Hz, 1H), 6.78 (dt, J = 8.8, 1.8 Hz, 1H), 4.93 (s, 1H), 4.41 (s, 2H), 4.31 (d, J = 5.9 Hz, 2H), 4.06 (dt, J = 9.2, 2.2 Hz, 1H), 2.21 (ddd, J = 12.6, 9.2, 2.8 Hz, 1H), 2.14 − 2.02 (m, 1H), 1.86 (tdd, J = 11.4, 5.4, 1.7 Hz, 1H), 1.78 − 1.53 (m, 7H);MS (ESI+) m/z 529.2 (M+H)+。
N,N−ジメチルホルムアミド(1.5mL)中の実施例7H(48mg、0.129mmol)、(4,6−ジメチルピリジン−3−イル)メタンアミン(21.98mg、0.161mmol)及びN−エチル−N−イソプロピルプロパン−2−アミン(0.056mL、0.323mmol)の混合物を、2−(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イル)−1,1,3,3−テトラメチルイソウロニウムヘキサフルオロホスファート(V)(73.6mg、0.194mmol)で処理し、反応混合物を周囲温度で16時間にわたって撹拌した。反応混合物を濃縮し、粗製の残渣をHPLC(0.1%トリフルオロ酢酸/水中の10〜100%アセトニトリル、25mL/分で、Phenomenex(登録商標)C18 5μmカラム(250mm×21.2mm)で)により精製して、標題化合物69mgを白色の固体として得た。1H NMR (400 MHz, DMSO−d6) δ ppm 8.22 (t, J = 5.8 Hz, 1H), 7.53 (s, 1H), 7.50 − 7.38 (m, 2H), 7.37 (s, 1H), 6.99 (dd, J = 11.4, 2.8 Hz, 1H), 6.78 (ddd, J = 9.0, 3.0, 1.2 Hz, 1H), 4.48 − 4.37 (m, 4H), 4.06 (dt, J = 8.9, 2.4 Hz, 1H), 2.57 (s, 3H), 2.42 (s, 3H), 2.24 (ddd, J = 12.5, 9.2, 2.9 Hz, 1H), 2.11 (td, J = 11.6, 4.0 Hz, 1H), 1.95 − 1.78 (m, 1H), 1.78 − 1.63 (m, 7H);MS (ESI+) m/z 494.2 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、(5−フルオロピリジン−3−イル)メタンアミンを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.39 (d, J = 2.9 Hz, 1H), 8.31 (s, 1H), 8.04 (t, J = 6.0 Hz, 1H), 7.56 − 7.37 (m, 3H), 6.99 (dd, J = 11.4, 2.8 Hz, 1H), 6.77 (dd, J = 9.0, 2.7 Hz, 1H), 4.40 (s, 2H), 4.39 − 4.22 (m, 2H), 4.05 (dd, J = 9.9, 2.8 Hz, 1H), 2.21 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.07 (td, J = 11.8, 3.8 Hz, 1H), 1.91 − 1.75 (m, 1H), 1.76 − 1.51 (m, 7H);MS (ESI+) m/z 480.2 (M+H)+。
標題化合物を、実施例7のキラル分取SFC(超臨界流体クロマトグラフィー)により、第2の溶離ピークとして単離した。分取SFCを、SuperChrom(商標)ソフトウェア制御下で操作するTHAR/Waters SFC80システムで行った。分取SFCシステムは、8ウェイ分取カラムスイッチャー、CO2ポンプ、調整ポンプ(modifier pump)、自動バックプレッシャーレギュレーター(ABPR)、UV検出器、及び6ポジションフラクションコレクターを備えていた。移動相は、メタノールの調整剤を含む、350psiまで加圧された絶乾非認定CO2のデュワーにより70g/分の流速で供給される超臨界CO2からなった。カラムは周囲温度にあり、バックプレッシャーレギュレーターを、100バールを維持するように設定した。サンプルをメタノール/ジクロロメタン(1:1)の混合物に14mg/mLの濃度で溶解させた。サンプルを注入物1mL(10mg)で調整剤流に装填した。移動相を30%メタノール:CO2で定組成に保持した。画分収集を時間駆動させた。機器に、21mm内径×250mm長さの寸法で、5μm粒子を有するChiralpak(登録商標)AD−Hカラムを装着した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.82 (dt, J = 2.2, 0.9 Hz, 1H), 8.17 (t, J = 5.9 Hz, 1H), 8.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.53 − 7.40 (m, 3H), 6.99 (dd, J = 11.4, 2.9 Hz, 1H), 6.78 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 5.01 (d, J = 4.2 Hz, 1H), 4.40 (d, J = 6.3 Hz, 4H), 2.23 (ddd, J = 12.5, 9.2, 2.9 Hz, 1H), 2.16 − 2.06 (m, 1H), 1.87 (td, J = 11.7, 4.9 Hz, 1H), 1.78 − 1.55 (m, 7H);MS (ESI+) m/z 530.1 (M+H)+。
標題化合物を実施例7のキラル分取SFCにより、実施例14に記載の方法を使用してカラムから溶離される第1のピークとして単離した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.82 (dt, J = 1.8, 0.9 Hz, 1H), 8.17 (t, J = 5.9 Hz, 1H), 8.09 (dd, J = 8.4, 2.4 Hz, 1H), 7.53 − 7.39 (m, 3H), 6.99 (dd, J = 11.4, 2.9 Hz, 1H), 6.78 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 5.01 (d, J = 4.2 Hz, 1H), 4.40 (d, J = 6.5 Hz, 4H), 4.08 (dq, J = 8.6, 3.4, 2.8 Hz, 1H), 2.23 (ddd, J = 12.6, 9.1, 2.9 Hz, 1H), 2.16 − 2.01 (m, 1H), 1.87 (td, J = 11.3, 4.7 Hz, 1H), 1.78 − 1.62 (m, 6H), 1.61 (td, J = 11.5, 4.2 Hz, 1H);MS (ESI+) m/z 530.2 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、4−オキサゾールメタンアミンヒドロクロリドを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.87 (t, J = 5.8 Hz, 1H), 7.75 (s, 1H), 7.52 − 7.39 (m, 2H), 6.98 (dd, J = 11.4, 2.9 Hz, 1H), 6.77 (dd, J = 9.1, 2.8 Hz, 1H), 4.39 (s, 2H), 4.11 (d, J = 5.6 Hz, 2H), 4.06 − 3.98 (m, 1H), 2.20 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.02 (tt, J = 11.8, 3.3 Hz, 1H), 1.84 (td, J = 11.6, 5.1 Hz, 1H), 1.68 (ddd, J = 12.4, 8.2, 4.7 Hz, 5H), 1.64 − 1.48 (m, 2H);MS (ESI+) m/z 452.2 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、(1−メチル−1H−ピラゾール−3−イル)メタンアミンジヒドロクロリドを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.81 (t, J = 5.8 Hz, 1H), 7.54 − 7.46 (m, 2H), 7.43 (t, J = 8.9 Hz, 1H), 6.98 (dd, J = 11.4, 2.9 Hz, 1H), 6.77 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 6.00 (d, J = 2.3 Hz, 1H), 4.47 (s, 1H), 4.39 (s, 2H), 4.14 (d, J = 5.7 Hz, 2H), 4.02 (dt, J = 8.9, 2.1 Hz, 1H), 3.71 (s, 3H), 2.19 (ddd, J = 12.5, 9.2, 2.9 Hz, 1H), 2.01 (tt, J = 11.8, 3.4 Hz, 1H), 1.83 (ddd, J = 12.9, 10.9, 4.7 Hz, 1H), 1.76 − 1.48 (m, 7H);MS (ESI+) m/z 465.2 (M+H)+。
実施例18A:3−(2−(4−クロロ−3−フルオロフェノキシ)アセトアミド)ビシクロ[1.1.1]ペンタン−1−カルボン酸
2−(4−クロロ−3−フルオロフェノキシ)酢酸(Aldlab)を2−(4−クロロフェノキシ)酢酸の代わりに用いる実施例1A及び実施例1Bに記載の反応及び精製条件により、標題化合物を得た。MS (APCI+) m/z 314 (M+H)+。
実施例18Aの生成物(52mg、0.166mmol)をジクロロメタン(2mL)に懸濁させ、N,N−ジメチルホルムアミド1滴を添加し、続いて、塩化オキサリル(ジクロロメタン中2.0M溶液、0.124mL)を一度に添加した。周囲温度で10分間にわたって撹拌した後に、反応混合物を減圧下で濃縮した。残渣をジクロロメタン(1mL)に入れ、混合物を4−クロロベンジルアミン(Aldrich、23.5mg、0.166mmol)のピリジン(2mL)溶液に移した。得られた溶液を周囲温度で20分間にわたって撹拌し、減圧下で濃縮した。残渣をN,N−ジメチルホルムアミド(3mL)に入れ、ガラスマイクロファイバーフリットを通して濾過し、分取HPLC[YMC TriArt(商標)C18 Hybrid 20μmカラム、25×150mm、流速80mL/分、緩衝液(0.025M炭酸水素アンモニウム水溶液、水酸化アンモニウムでpH10に調節)中のアセトニトリルの5〜100%勾配]により精製して、標題化合物(41mg、0.094mmol、収率57%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.74 (s, 1H), 8.39 (t, J = 6.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.39 − 7.32 (m, 2H), 7.26 − 7.20 (m, 2H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.46 (s, 2H), 4.22 (d, J = 6.1 Hz, 2H), 2.20 (s, 6H);MS (ESI+) m/z 437 (M+H)+。
テトラヒドロフラン(3mL)中の実施例18Aの生成物(70mg、0.223mmol)、(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミン(47.2mg、0.27mmol)、N−[(ジメチルアミノ)−1H−1,2,3−トリアゾロ−[4,5−b]ピリジン−1−イルメチレン]−N−メチルメタンアミニウムヘキサフルオロホスファートN−オキシド(HATU、102mg、0.27mmol)、及びトリエチルアミン(0.062mL、0.45mmol)の混合物を16時間にわたって撹拌した。反応混合物を、水及びブラインで処理し、酢酸エチルで抽出した。合わせた有機層を減圧下で濃縮し、残渣をPhenomenex(登録商標)Zorbax Rx−C18カラム(250×21.2mm、7μm粒径)上で行われる逆相HPLCにより、18mL/分の流速で30分かける10%〜95%アセトニトリル/0.1%トリフルオロ酢酸水溶液の勾配を使用して精製して、標題化合物(38.0mg、0.081mmol、収率36%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.89 (dt, J = 1.9, 1.0 Hz, 1H), 8.73 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 8.23 − 8.11 (m, 1H), 7.57 − 7.39 (m, 2H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.86 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.48 (s, 2H), 4.43 (d, J = 6.0 Hz, 2H), 2.24 (s, 6H);MS (ESI+) m/z 472.1 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、(5−メチルピラジン−2−イル)メタンアミンを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.43 − 8.36 (m, 2H), 8.12 (t, J = 5.9 Hz, 1H), 7.47 (dd, J = 17.3, 8.5 Hz, 2H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.79 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.42 (s, 2H), 4.34 (d, J = 5.8 Hz, 2H), 4.07 (dt, J = 9.0, 2.2 Hz, 1H), 2.43 (s, 3H), 2.23 (ddd, J = 12.7, 9.3, 2.9 Hz, 1H), 2.10 (tt, J = 11.6, 3.3 Hz, 1H), 1.88 (td, J = 11.0, 10.6, 4.6 Hz, 1H), 1.78 − 1.54 (m, 7H);MS (ESI+) m/z 477.2 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、(4−(トリフルオロメチル)ピリジン−2−イル)メタンアミンヒドロクロリドを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.74 (d, J = 5.2 Hz, 1H), 8.18 (t, J = 5.9 Hz, 1H), 7.59 (d, J = 4.5 Hz, 2H), 7.52 (s, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.6 Hz, 1H), 4.50 − 4.37 (m, 2H), 4.43 (s, 2H), 4.12 − 4.06 (m, 1H), 2.25 (ddd, J = 12.7, 9.3, 3.0 Hz, 1H), 2.12 (td, J = 12.0, 4.1 Hz, 1H), 1.89 (td, J = 11.7, 5.0 Hz, 1H), 1.79 − 1.57 (m, 7H);MS (ESI+) m/z 530.2 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、(5−(メチルスルホニル)ピリジン−2−イル)メタンアミンを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.92 (d, J = 2.3 Hz, 1H), 8.23 − 8.15 (m, 2H), 7.53 − 7.39 (m, 3H), 6.99 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 − 6.73 (m, 1H), 4.98 (s, 1H), 4.41 (d, J = 6.3 Hz, 1H), 4.41 (s, 2H), 4.12 − 4.04 (m, 1H), 3.26 (s, 3H), 2.23 (ddd, J = 12.7, 9.3, 2.9 Hz, 1H), 2.12 (tt, J = 12.2, 6.2 Hz, 1H), 1.86 (tt, J = 14.6, 7.3 Hz, 1H), 1.73 − 1.50 (m, 7H);MS (ESI+) m/z 540.2 (M+H)+。
実施例23A:4−(2−(4−フルオロフェノキシ)アセトアミド)−2−オキソビシクロ[2.2.2]オクタン−1−カルボン酸
標題化合物を、実施例7F〜7Gに記載の方法を使用して、2−(4−フルオロフェノキシ)酢酸を2−(4−クロロ−3−フルオロフェノキシ)酢酸の代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.81 (s, 1H), 7.16 − 7.04 (m, 2H), 6.97 − 6.87 (m, 2H), 4.39 (s, 2H), 2.73 (s, 2H), 2.10 − 1.83 (m, 7H);MS (ESI+) m/z 336.0 (M+H)+。
標題化合物を、実施例7H〜7Iに記載の方法を使用して、実施例23Aを実施例7Gの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.82 (d, J = 2.2 Hz, 1H), 8.18 (t, J = 5.9 Hz, 1H), 8.09 (dd, J = 8.3, 2.4 Hz, 1H), 7.49 − 7.39 (m, 2H), 7.14 − 7.03 (m, 2H), 6.95 − 6.84 (m, 2H), 4.43 − 4.29 (m, 4H), 4.07 (dd, J = 9.2, 2.7 Hz, 1H), 2.23 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.10 (td, J = 12.2, 3.4 Hz, 1H), 1.87 (td, J = 11.7, 5.0 Hz, 1H), 1.78 − 1.54 (m, 7H);MS (ESI+) m/z 496.2 (M+H)+。
標題化合物を、実施例23に記載の方法を使用して、(4−(トリフルオロメチル)フェニル)メタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.05 (t, J = 6.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.44 − 7.37 (m, 3H), 7.14 − 7.03 (m, 2H), 6.95 − 6.84 (m, 2H), 4.37 − 4.27 (m, 4H), 4.06 (dd, J = 9.4, 2.6 Hz, 1H), 2.22 (ddd, J = 12.7, 9.2, 2.9 Hz, 1H), 2.07 (tt, J = 11.7, 3.1 Hz, 1H), 1.86 (td, J = 12.1, 11.4, 5.0 Hz, 1H), 1.77 − 1.53 (m, 7H);MS (ESI+) m/z 496.2 (M+H)+。
実施例7Hの生成物(37mg、0.10mmol)及び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ァート(HATU、57mg、0.15mmol)をN,N−ジメチルアセトアミド(1.0mL)中で混合した。m−トリルメタンアミン(15mg、0.12mmol)及びN,N−ジイソプロピルエチルアミン(43μL、0.25mmol)を添加した。反応混合物を室温で16時間にわたって撹拌し、その後、逆相クロマトグラフィー:Phenomenex(登録商標)Luna(登録商標)C8(2)5μm 100Å AXIA(商標)カラム(50mm×30mm)により精製したが、その際、アセトニトリル(A)及びH2O中の0.1%トリフルオロ酢酸(B)の勾配を、40mL/分の流速(0〜0.5分は5%A、0.5〜6.5分は直線勾配5〜100%A、6.5〜8.5分は100%A、8.5〜9.0分は直線勾配100〜5%A、9.0〜10.0分は5%A)で使用して、標題化合物(33mg、69%)を得た。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.08 − 6.95 (m, 4H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.23 (s, 2H), 4.10 (dt, J = 8.9, 2.0 Hz, 1H), 2.27 (m, 4H), 2.08 (dd, J = 12.9, 9.6 Hz, 1H), 1.90 (td, J = 11.3, 10.6, 4.8 Hz, 1H), 1.80 − 1.54 (m, 7H);MS (ESI+) m/z 475 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、p−トリルメタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.11 (s, 4H), 7.01 (dd, J = 11.3, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.22 (s, 2H), 4.08 (dt, J = 8.8, 2.1 Hz, 1H), 2.26 (s, 4H), 2.07 (dd, J = 13.4, 10.1 Hz, 1H), 1.89 (td, J = 11.5, 5.2 Hz, 1H), 1.80 − 1.52 (m, 6H);MS (ESI+) m/z 475 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(3−フルオロ−5−(トリフルオロメチル)フェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.52 − 7.44 (m, 3H), 7.38 (d, J = 9.5 Hz, 1H), 7.01 (dt, J = 11.4, 3.1 Hz, 1H), 6.82 (ddt, J = 9.1, 3.4, 1.7 Hz, 1H), 4.43 (s, 2H), 4.36 (t, J = 5.1 Hz, 2H), 4.16 − 4.02 (m, 1H), 2.28 (td, J = 9.6, 4.8 Hz, 1H), 2.11 (t, J = 12.2 Hz, 1H), 1.90 (td, J = 11.8, 4.9 Hz, 1H), 1.85 − 1.52 (m, 7H);MS (ESI+) m/z 547 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(3−メトキシフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.25 − 7.15 (m, 1H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 − 6.73 (m, 4H), 4.44 (s, 2H), 4.25 (s, 2H), 4.10 (dt, J = 8.9, 2.2 Hz, 1H), 3.72 (s, 3H), 2.27 (ddd, J = 12.5, 9.2, 2.9 Hz, 1H), 2.15 − 2.03 (m, 1H), 1.90 (td, J = 11.5, 11.0, 5.1 Hz, 1H), 1.82 − 1.56 (m, 7H);MS (ESI+) m/z 491 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−メトキシフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.47 (t, J = 8.9 Hz, 1H), 7.20 − 7.10 (m, 2H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.89 − 6.76 (m, 3H), 4.43 (s, 2H), 4.20 (s, 2H), 4.08 (dt, J = 9.0, 2.1 Hz, 1H), 3.72 (s, 3H), 2.26 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.12 − 1.99 (m, 1H), 1.89 (td, J = 11.5, 11.1, 5.2 Hz, 1H), 1.80 − 1.53 (m, 7H);MS (ESI+) m/z 491 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(3−フルオロフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.38 − 7.24 (m, 1H), 7.13 − 6.91 (m, 4H), 6.83 (ddd, J = 9.2, 2.8, 1.2 Hz, 1H), 4.44 (s, 2H), 4.29 (d, J = 4.7 Hz, 2H), 4.10 (dt, J = 9.1, 2.3 Hz, 1H), 2.28 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.10 (t, J = 11.6 Hz, 1H), 1.90 (td, J = 11.5, 5.1 Hz, 1H), 1.81 − 1.52 (m, 7H);MS (ESI+) m/z 479 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−フルオロフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.31 − 7.20 (m, 2H), 7.15 − 7.07 (m, 2H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.1, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.25 (s, 2H), 4.09 (dt, J = 9.0, 2.1 Hz, 1H), 2.27 (ddd, J = 12.6, 9.2, 2.9 Hz, 1H), 2.15 − 2.02 (m, 1H), 1.90 (td, J = 11.6, 5.2 Hz, 1H), 1.68 (dddd, J = 33.6, 17.3, 12.2, 6.7 Hz, 7H);MS (ESI+) m/z 479 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(3−クロロフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.33 (dd, J = 8.7, 7.4 Hz, 1H), 7.29 − 7.25 (m, 2H), 7.19 (dt, J = 7.5, 1.4 Hz, 1H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (ddd, J = 8.8, 2.9, 1.1 Hz, 1H), 4.44 (s, 2H), 4.27 (d, J = 4.9 Hz, 2H), 4.10 (dt, J = 9.0, 2.4 Hz, 1H), 2.28 (ddd, J = 12.6, 9.3, 2.8 Hz, 1H), 2.10 (t, J = 11.6 Hz, 1H), 1.90 (td, J = 11.6, 5.1 Hz, 1H), 1.71 (qt, J = 15.5, 6.8 Hz, 7H);MS (ESI+) m/z 495 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−クロロフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.38 − 7.31 (m, 2H), 7.28 − 7.18 (m, 2H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.30 − 4.20 (m, 2H), 4.09 (dt, J = 9.0, 2.1 Hz, 1H), 2.27 (ddd, J = 12.7, 9.3, 2.9 Hz, 1H), 2.09 (t, J = 11.8 Hz, 1H), 1.90 (td, J = 11.5, 5.1 Hz, 1H), 1.68 (dddd, J = 29.0, 18.0, 8.8, 4.6 Hz, 7H);MS (ESI+) m/z 495 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−(トリフルオロメトキシ)フェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.38 − 7.31 (m, 2H), 7.27 (dd, J = 8.6, 1.1 Hz, 2H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.34 − 4.23 (m, 2H), 4.16 − 4.01 (m, 1H), 2.27 (ddd, J = 12.5, 9.2, 2.8 Hz, 1H), 2.10 (t, J = 11.7 Hz, 1H), 1.90 (td, J = 11.5, 5.1 Hz, 1H), 1.79 − 1.56 (m, 7H);MS (ESI+) m/z 545 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−(ジメチルアミノ)フェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.36 − 7.23 (m, 4H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.44 (s, 2H), 4.26 (s, 2H), 4.09 (dt, J = 9.0, 2.2 Hz, 1H), 3.07 (s, 6H), 2.27 (ddd, J = 12.7, 9.1, 2.8 Hz, 1H), 2.08 (t, J = 11.6 Hz, 1H), 1.90 (td, J = 11.5, 5.1 Hz, 1H), 1.84 − 1.50 (m, 7H);MS (ESI+) m/z 504 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(3−(トリフルオロメチル)フェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.58 − 7.52 (m, 4H), 7.48 (t, J = 8.9 Hz, 1H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.44 (s, 2H), 4.38 − 4.27 (m, 2H), 4.14 − 4.03 (m, 1H), 2.28 (ddd, J = 12.5, 9.2, 2.8 Hz, 1H), 2.11 (t, J = 11.6 Hz, 1H), 1.90 (td, J = 11.5, 5.0 Hz, 1H), 1.82 − 1.56 (m, 7H);MS (ESI+) m/z 529 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(3−(トリフルオロメトキシ)フェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.51 − 7.38 (m, 2H), 7.26 (dt, J = 7.7, 1.2 Hz, 1H), 7.20 (d, J = 6.7 Hz, 2H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.83 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.44 (s, 2H), 4.34 − 4.24 (m, 2H), 4.10 (d, J = 8.7 Hz, 1H), 2.28 (ddd, J = 12.5, 9.2, 2.8 Hz, 1H), 2.10 (t, J = 11.5 Hz, 1H), 1.90 (td, J = 11.5, 5.1 Hz, 1H), 1.82 − 1.50 (m, 7H);MS (ESI+) m/z 545 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−tert−ブチルフェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.48 (t, J = 8.9 Hz, 1H), 7.37 − 7.26 (m, 2H), 7.19 − 7.08 (m, 2H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.23 (s, 2H), 4.12 − 4.00 (m, 1H), 2.27 (ddd, J = 12.4, 9.1, 2.8 Hz, 1H), 2.08 (t, J = 11.7 Hz, 1H), 1.90 (td, J = 11.4, 5.0 Hz, 1H), 1.81 − 1.52 (m, 7H), 1.26 (s, 9H);MS (ESI+) m/z 517 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−(トリフルオロメチル)フェニル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.64 (d, J = 8.0 Hz, 2H), 7.51 − 7.34 (m, 3H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.43 (s, 2H), 4.08 − 3.92 (m, 1H), 3.30 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.23 (ddd, J = 12.7, 9.2, 2.9 Hz, 1H), 1.99 (dd, J = 13.5, 10.0 Hz, 1H), 1.87 (td, J = 11.8, 11.4, 5.2 Hz, 1H), 1.80 − 1.38 (m, 7H);MS (ESI+) m/z 543 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、ピリジン−2−イルメタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.74 − 8.64 (m, 1H), 8.32 (td, J = 7.9, 1.6 Hz, 1H), 7.79 − 7.67 (m, 2H), 7.48 (t, J = 8.9 Hz, 1H), 7.01 (dd, J = 11.3, 2.8 Hz, 1H), 6.82 (ddt, J = 9.1, 3.2, 1.6 Hz, 1H), 4.53 (s, 2H), 4.44 (s, 2H), 4.10 (dt, J = 9.1, 2.4 Hz, 1H), 2.29 (ddd, J = 12.6, 9.1, 2.8 Hz, 1H), 2.18 − 2.06 (m, 1H), 1.93 (qd, J = 11.3, 10.5, 5.0 Hz, 1H), 1.81 − 1.59 (m, 7H);MS (ESI+) m/z 462 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、1−(ピリジン−3−イル)エタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.84 − 8.64 (m, 2H), 8.45 (ddt, J = 8.1, 4.1, 1.7 Hz, 1H), 8.01 − 7.90 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 5.05 (p, J = 7.1 Hz, 1H), 4.44 (s, 2H), 4.20 − 4.03 (m, 1H), 2.33 − 2.20 (m, 1H), 2.18 − 1.98 (m, 1H), 1.98 − 1.81 (m, 1H), 1.80 − 1.56 (m, 7H), 1.45 (d, J = 7.2 Hz, 3H);MS (ESI+) m/z 476 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(5−シアノピリジン−2−イル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.90 (dd, J = 2.1, 0.8 Hz, 1H), 8.21 (dd, J = 8.2, 2.2 Hz, 1H), 7.52 − 7.39 (m, 2H), 7.02 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (ddd, J = 9.1, 2.9, 1.2 Hz, 1H), 4.44 (d, J = 4.1 Hz, 4H), 4.11 (dt, J = 8.9, 2.2 Hz, 1H), 2.29 (ddd, J = 12.6, 9.3, 2.9 Hz, 1H), 2.18 − 2.07 (m, 1H), 1.92 (td, J = 11.5, 4.9 Hz, 1H), 1.82 − 1.54 (m, 7H);MS (ESI+) m/z 487 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(5−メチルピリジン−2−イル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.56 (t, J = 5.9 Hz, 1H), 7.71 − 7.61 (m, 2H), 7.54 − 7.35 (m, 1H), 7.01 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.51 (d, J = 5.9 Hz, 2H), 4.45 (d, J = 5.5 Hz, 3H), 4.17 − 4.03 (m, 1H), 2.40 − 2.24 (m, 1H), 2.20 − 2.06 (m, 1H), 2.00 − 1.84 (m, 2H), 1.81 − 1.57 (m, 8H);MS (ESI+) m/z 476 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(4−メチルピリジン−2−イル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.65 − 8.51 (m, 1H), 8.24 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.01 (dd, J = 11.4, 2.9 Hz, 1H), 6.83 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.50 (s, 2H), 4.44 (s, 2H), 4.14 − 4.03 (m, 1H), 2.43 (s, 3H), 2.29 (ddd, J = 12.7, 9.3, 2.9 Hz, 1H), 2.12 (dt, J = 11.9, 6.1 Hz, 1H), 1.92 (td, J = 11.6, 4.7 Hz, 1H), 1.84 − 1.55 (m, 6H);MS (ESI+) m/z 476 (M+H)+。
標題化合物を、実施例25に記載の方法を使用して、(ピラジン−2−イル)メタンアミンをm−トリルメタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.57 − 8.40 (m, 3H), 7.48 (t, J = 8.9 Hz, 1H), 7.02 (dd, J = 11.4, 2.9 Hz, 1H), 6.83 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.52 − 4.36 (m, 4H), 4.11 (dt, J = 9.0, 2.4 Hz, 1H), 2.28 (ddd, J = 12.5, 9.3, 2.8 Hz, 1H), 2.17 − 2.06 (m, 1H), 1.91 (td, J = 11.5, 4.9 Hz, 1H), 1.85 − 1.55 (m, 7H);MS (ESI+) m/z 463 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、N−メチル−1−(4−(トリフルオロメチル)フェニル)メタンアミンを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 7.66 (d, J = 8.1 Hz, 2H), 7.52 (s, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.00 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 − 6.76 (m, 1H), 4.64 (q, J = 16.0 Hz, 2H), 4.42 (s, 2H), 4.36 (ddd, J = 9.4, 3.9, 1.6 Hz, 1H), 2.99 (s, 3H), 2.26 (ddd, J = 12.5, 9.3, 2.9 Hz, 1H), 2.15 (tdt, J = 11.2, 6.2, 2.4 Hz, 1H), 1.94 − 1.69 (m, 7H), 1.65 (ddd, J = 12.8, 3.9, 2.1 Hz, 1H);MS (ESI+) m/z 543.2 (M+H)+。
標題化合物を、実施例12に記載の方法を使用して、(5−(ジフルオロメトキシ)ピリジン−2−イル)メタンアミンを(4,6−ジメチルピリジン−3−イル)メタンアミンの代わりに用いて調製した。1H NMR (400 MHz, DMSO−d6) δ ppm 8.34 (d, J = 2.8 Hz, 1H), 8.10 (t, J = 5.9 Hz, 1H), 7.58 (dd, J = 8.6, 2.9 Hz, 1H), 7.53 − 7.40 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.08 − 6.95 (m, 1H), 6.78 (dd, J = 9.0, 2.8 Hz, 1H), 4.41 (s, 2H), 4.32 (d, J = 5.8 Hz, 2H), 4.06 (dd, J = 9.5, 2.8 Hz, 1H), 2.22 (ddd, J = 12.7, 9.2, 2.9 Hz, 1H), 2.09 (tt, J = 11.5, 3.2 Hz, 1H), 1.86 (td, J = 11.6, 5.1 Hz, 1H), 1.71 (q, J = 3.9 Hz, 2H), 1.72 − 1.53 (m, 5H);MS (ESI+) m/z 528.2 (M+H)+。
N,N−ジメチルホルムアミド(2mL)、トリエチルアミン(0.079mL、0.57mmol)及び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ァート(79mg、0.208mmol、HATU)を、実施例18Aの生成物(59.4mg、0.189mmol)及び(5−(ジフルオロメトキシ)ピリジン−2−イル)メタンアミン(Enamine、33mg、0.189mg)の混合物に順番に添加した。次いで、反応混合物を周囲温度で30分間にわたって撹拌した。得られた溶液を、ガラスマイクロファイバーフリットを通して濾過し、分取HPLC[YMC TriArt(商標)C18 Hybrid 5μmカラム、50×100mm、流速90mL/分、緩衝液(0.025M炭酸水素アンモニウム水溶液、水酸化アンモニウムでpH10に調節)中のアセトニトリルの5〜100%勾配]により精製して、標題化合物(56mg、0.119mmol、収率63%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.73 (s, 1H), 8.44 (t, J = 6.1 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.64 (dd, J = 8.6, 2.9 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.29 (dd, J = 8.6, 0.7 Hz, 1H), 7.27 (t, J = 73.5 Hz, 1H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.86 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.47 (s, 2H), 4.33 (d, J = 6.1 Hz, 2H), 2.22 (s, 6H);MS (ESI+) m/z 470 (M+H)+。
実施例49A:3−(2−(3,4−ジクロロフェノキシ)アセトアミド)ビシクロ[1.1.1]ペンタン−1−カルボン酸
2−(3,4−ジクロロフェノキシ)酢酸(Aldrich)を2−(4−クロロフェノキシ)酢酸の代わりに用いる実施例1A及び実施例1Bに記載の反応及び精製条件により、標題化合物を得た。MS (APCI+) m/z 330 (M+H)+。
実施例49Aの生成物を実施例18Aの生成物の代わりに用いる実施例48に記載の反応及び精製条件により、標題化合物を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.73 (s, 1H), 8.45 (t, J = 6.1 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 8.6, 2.9 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 73.5 Hz, 1H), 7.27 (d, J = 2.9 Hz, 1H), 6.99 (dd, J = 8.9, 2.9 Hz, 1H), 4.49 (s, 2H), 4.33 (d, J = 6.1 Hz, 2H), 2.22 (s, 6H);MS (ESI+) m/z 486 (M+H)+。
3−(アミノメチル)−6−(トリフルオロメチル)ピリジン(Matrix)を(5−(ジフルオロメトキシ)ピリジン−2−イル)メタンアミンの代わりに用いる実施例48に記載の反応及び精製条件により、標題化合物を得た。1H NMR (400 MHz, DMSO−d6) δ ppm 8.73 (s, 1H), 8.64 (d, J = 1.9 Hz, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.93 − 7.84 (m, 2H), 7.49 (t, J = 8.8 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.47 (s, 2H), 4.37 (d, J = 6.0 Hz, 2H), 2.22 (s, 6H);MS (ESI+) m/z 472 [M+H]+。
実施例49Aの生成物を実施例18Aの生成物の代わりに用いる、及び3−(アミノメチル)−6−(トリフルオロメチル)ピリジン(Matrix)を(5−(ジフルオロメトキシ)ピリジン−2−イル)メタンアミンの代わりに用いる実施例48に記載の反応及び精製条件により、標題化合物を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.73 (s, 1H), 8.65 − 8.63 (m, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.92 − 7.86 (m, 2H), 7.55 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.99 (dd, J = 9.0, 2.9 Hz, 1H), 4.48 (s, 2H), 4.37 (d, J = 6.0 Hz, 2H), 2.22 (s, 6H);MS (ESI+) m/z 488 (M+H)+。
(1,3−ジメチル−1H−ピラゾール−5−イル)メタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いる実施例19に記載の反応及び精製条件により、標題化合物(56mg、0.105mmol、収率82%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.71 (s, 1H), 8.25 (t, J = 5 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 7.05 (dd, J = 9, 3 Hz, 1H), 6.83 (br d, J = 8 Hz, 1H), 5.86 (s, 1H), 4.46 (s, 2H), 4.21 (d, J = 5 Hz, 2H), 3.65 (s, 3H), 2.20 (s, 6H), 2.06 (s, 3H);MS (ESI+) m/z 421 (M+H)+。
(1,3−ジメチル−1H−ピラゾール−4−イル)メタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いる実施例19に記載の反応及び精製条件により、標題化合物(47mg、0.088mmol、収率69%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.68 (s, 1H), 7.98 (t, J = 5 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 7.40 (s, 1H), 7.05 (dd, J = 9, 3 Hz, 1H), 6.83 (br d, J = 8 Hz, 1H), 4.44 (s, 2H), 4.00 (d, J = 5 Hz, 2H), 3.69 (s, 3H), 2.15 (s, 6H), 2.05 (s, 3H);MS (ESI+) m/z 421 (M+H)+。
2−(ピリジン−2−イル)エタンアミンを(5−(トリフルオロメチル)ピリジン−2−イル)メタンアミンの代わりに用いる実施例19に記載の反応及び精製条件により、標題化合物(40mg、0.075mmol、収率59%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.70 (s, 1H), 8.68 (s, 1H), 8.18 (br t, J = 8 Hz, 1H), 7.90 (br t, J = 8 Hz, 1H), 7.63 (m, 2H), 7.50 (t, J = 8 Hz, 1H), 7.06 (dd, J = 9, 3 Hz, 1H), 6.84 (br d, J = 8 Hz, 1H), 4.46 (s, 2H), 3.44 (m, 2H), 3.03 (t, J = 7 Hz, 2H), 2.13 (s, 6H);MS (ESI+) m/z 418 (M+H)+。
(1,3−ジメチル−1H−ピラゾール−5−イル)メタンアミンを(5−(ジフルオロメトキシ)ピリジン−2−イル)メタンアミンの代わりに用いる実施例49Bに記載の反応及び精製条件により、標題化合物(48mg、0.087mmol、68%)を得た。1H NMR (501 MHz, DMSO−d6) δ ppm 8.73 (s, 1H), 8.28 (t, J = 5 Hz, 1H), 7.54 (d, J = 9 Hz, 1H), 7.26 (d, J = 3 Hz, 1H), 6.98 (dd, J = 9, 3 Hz, 1H), 5.87 (s, 1H), 4.48 (s, 2H), 4.22 (d, J = 5 Hz, 2H), 3.65 (s, 3H), 2.20 (s, 6H), 2.08 (s, 3H);MS (ESI+) m/z 437 (M+H)+。
細胞状況において本発明の例示化合物を試験するために、安定なVWMD細胞系を初めに構築した。Sidrauski et al(eLife 2013)に記載されているとおりに、イニシエーターメチオニンを欠いたホタルルシフェラーゼ(FLuc)コード配列の前にヒト全長ATF4 5’−UTR(NCBI Accession No. BC022088.2)を融合することにより、ATF4レポーターを調製した。この構築物を使用して、標準的な方法を使用して組換えレトロウイルスを生成し、得られたウイルス上清を使用して、HEK293T細胞に形質導入し、続いて、そのHEK293T細胞を、安定な細胞系を生成するためにピューロマイシンで選択した。
請求項において、冠詞、例えば、「a」、「an」、及び「the」は、反対に示されていない限り、または別段に文脈から明らかでない限り、1つ、または1つより多くを意味し得る。群の1つまたは複数のメンバー間に「または」を含む請求項または記述は、反対に示されていない限り、または別段に文脈から明らかでない限り、1つ、1つより多く、またはすべての群メンバーが、所与の生成物またはプロセス中に存在し、使用され、または別段にこれらに関連する場合に、満たされるとみなされる。本発明は、群の正確に1つのメンバーが、所与の生成物またはプロセス中に存在し、使用され、または別段にこれらに関連する実施形態を含む。本発明は、1つより多い、またはすべての群メンバーが、所与の生成物またはプロセス中に存在し、使用され、または別段にこれらに関連する実施形態を含む。
Claims (40)
- 式(I)の化合物:
[式中、
Dは、架橋単環式シクロアルキル、架橋単環式ヘテロシクリル、またはクバニルであり、ここで、各架橋単環式シクロアルキル、架橋単環式ヘテロシクリル、またはクバニルは、1〜4個のRXで任意選択で置換されており;
L1及びL2はそれぞれ独立に、C1〜C6アルキレンまたは2〜7員のヘテロアルキレンであり、ここで、各C1〜C6アルキレンまたは2〜7員のヘテロアルキレンは、1〜5個のRXで任意選択で置換されており;
R1及びR2はそれぞれ独立に、水素、C1〜C6アルキル、C1〜C6アルコキシ−C1〜C6アルキル、ヒドロキシ−C1〜C6アルキル、シリルオキシ−C1〜C6アルキルであり;
A及びWはそれぞれ独立に、フェニルまたは5〜6員のヘテロアリールであり、ここで、各フェニルまたは5〜6員のヘテロアリールは、1〜5個のRYで任意選択で置換されており;
各RXは、C1〜C6アルキル、ヒドロキシ−C1〜C6アルキル、ハロ−C1〜C6アルキル、アミノ−C1〜C6アルキル、シアノ−C1〜C6アルキル、オキソ、ハロ、シアノ、−ORA、−NRBRC、−NRBC(O)RD、−C(O)NRBRC、−C(O)RD、−C(O)OH、−C(O)ORD、−SRE、−S(O)RD、及び−S(O)2RDからなる群から独立に選択され;
各RYは、水素、C1〜C6アルキル、ヒドロキシ−C1〜C6アルキル、C1〜C6アルコキシ−C1〜C6アルキル、ハロ−C1〜C6アルキル、ハロ−C1〜C6アルコキシ、アミノ−C1〜C6アルキル、シアノ−C1〜C6アルキル、オキソ、ハロ、シアノ、−ORA、−NRBRC、−NRBC(O)RD、−C(O)NRBRC、−C(O)RD、−C(O)OH、−C(O)ORD、−S(RF)m、−S(O)RD、−S(O)2RD、及びG1からなる群から独立に選択されるか;または
隣接する原子上の2個のRY基は、それらが結合している原子と一緒に、1〜5個のRXで任意選択で置換されている3〜7員の縮合シクロアルキル、3〜7員のヘテロシクリル、アリール、または5〜6員のヘテロアリールを形成しており;
各G1は独立に、C3〜C6シクロアルキル、4〜7員のヘテロシクリル、アリール、または5〜6員のヘテロアリールであり、ここで、各C3〜C6シクロアルキル、4〜7員のヘテロシクリル、アリール、または5〜6員のヘテロアリールは、1〜3個のRZで任意選択で置換されており;
各RZは、C1〜C6アルキル、ヒドロキシ−C1〜C6アルキル、ハロ−C1〜C6アルキル、ハロ、シアノ、−ORA、−NRBRC、−NRBC(O)RD、−C(O)NRBRC、−C(O)RD、−C(O)OH、−C(O)ORD、及び−S(O)2RDからなる群から独立に選択され;
RAは出現する毎に独立に、水素、C1〜C6アルキル、ハロ−C1〜C6アルキル、−C(O)NRBRC、−C(O)RD、−C(O)OH、または−C(O)ORDであり;
RB及びRCのそれぞれは独立に、水素またはC1〜C6アルキルであるか;または
RB及びRCは、それらが結合している原子と一緒に、1〜3個のRZで任意選択で置換されている3〜7員のヘテロシクリルを形成しており;
各RDは独立に、C1〜C6アルキル、ハロ−C1〜C6アルキル、または−NRB1RC1であり;
各REは独立に、水素、C1〜C6アルキル、またはハロ−C1〜C6アルキルであり;
各RFは独立に、水素、C1〜C6アルキル、ハロ、またはハロ−C1〜C6アルキルであり;
RB1及びRC1のそれぞれは独立に、水素またはC1〜C6アルキルであり;
mは、1、3、または5である]。 - Dが、1〜4個のRXで任意選択で置換されている架橋単環式シクロアルキルである、請求項1に記載の化合物。
- Dが、1〜4個のRXで任意選択で置換されている架橋4〜6員の単環式シクロアルキルである、請求項1〜2のいずれか1項に記載の化合物。
- Dが、1〜4個のRXで任意選択で置換されているビシクロ[1.1.1]ペンタンである、請求項1〜3のいずれか1項に記載の化合物。
- Dが、
- Dが、
- Dが、0個のRXで置換されている、請求項1〜6のいずれか1項に記載の化合物。
- Dが、
- L1及びL2の少なくとも1個が独立に、1〜5個のRXにより任意選択で置換されている2〜7員のヘテロアルキレンである、請求項1〜8のいずれか1項に記載の化合物。
- L1が、2〜7員のヘテロアルキレンであり、L2が、C1〜C6アルキレンまたは2〜7員のヘテロアルキレンから独立に選択され、ここで、各アルキレン及びヘテロアルキレンが、1〜5個のRXにより任意選択で置換されている、請求項1〜9のいずれか1項に記載の化合物。
- L1及びL2の両方が独立に、0個のRXにより置換されている2〜7員のヘテロアルキレンである、請求項1〜10のいずれか1項に記載の化合物。
- 各L1及びL2が、−CH2−*、−CH2CH2−*、CH2CH2CH2−*、−CH2(CH3)−*、−CH2(CH3)CH2−*、CH2O−*またはCH2CH2O−*から独立に選択され、「−*」が、それぞれA及びWへの結合点を示す、請求項1〜10のいずれか1項に記載の化合物。
- L1が、CH2O−*またはCH2CH2O−*から独立に選択され、L2が、−CH2−*、−CH2CH2−*、CH2CH2CH2−*、−CH2(CH3)−*、−CH2(CH3)CH2−*、CH2O−*またはCH2CH2O−*から独立に選択され、「−*」が、それぞれA及びWへの結合点を示す、請求項1〜12のいずれか1項に記載の化合物。
- R1及びR2がそれぞれ、水素またはC1〜C6アルキルである、請求項1〜13のいずれか1項に記載の化合物。
- Aが、フェニルであり、Wが独立に、1〜5個のRYで任意選択で置換されているフェニルまたは5〜6員のヘテロアリールである、請求項1〜14のいずれか1項に記載の化合物。
- A及びWのそれぞれが、
- Aが、
- 各RYが独立に、C1〜C6アルキル、C1〜C6アルコキシ−C1〜C6アルキル、ハロ−C1〜C6アルキル、ハロ−C1〜C6アルコキシ、ハロ、シアノ、−ORA、−NRBRC、−S(O)2RD、−S(RF)m、またはG1であるか、または隣接する原子上の2個のRY基が、それらが結合している原子と一緒に、1〜5個のRXで任意選択で置換されている3〜7員の縮合シクロアルキル、3〜7員のヘテロシクリル、アリール、または5〜6員のヘテロアリールを形成している、請求項1〜17のいずれか1項に記載の化合物。
- RYが、クロロ、フルオロ、−CH3、−CH2CH3、CH2CH2CH3、−CH2CH2CH2CH3、−CH(CH3)2、−CH2CH(CH3)2、−C(CH3)3、−CF3、−CH2OCH3、−OCH3、−OCH2CH3、−OCH(CH3)2、−OCHF2、−OCF3、−OCH2CHF2、N(CH3)2、−S(O)2CH3、−S(O)2NH2、またはSCF3である、請求項18に記載の化合物。
- G1が、1〜3個のRZで任意選択で置換されているフェニルである、請求項1〜19のいずれか1項に記載の化合物。
- 各RZが、C1〜C6アルキル(例えば、CH3)である、請求項20に記載の化合物。
- 式(I)の化合物が、式(I−b)の化合物:
- 式(I)の化合物が、式(I−d)の化合物:
- 式(I)の化合物が、式(I−e)の化合物:
- 式(I)の化合物が、式(I−f)の化合物:
- 式(I)の化合物が、式(I−g)の化合物:
- 表1に記載のいずれかの化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体から選択される、先行請求項のいずれか1項に記載の化合物。
- 先行請求項のいずれか1項に記載の化合物及び薬学的に許容される担体を含む、薬学的に許容される組成物。
- 先行請求項のいずれか1項に記載の式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を含む、対象において、神経変性疾患、白質ジストロフィー、がん、炎症性疾患、筋骨格疾患、または代謝性疾患を処置する際に使用するための組成物。
- 前記神経変性疾患が、白質ジストロフィー、白質脳症、ミエリン形成不全もしくは脱髄疾患、知的障害症候群、認知障害、神経膠細胞機能不全、または脳損傷(例えば、外傷性脳損傷または毒素誘発性脳損傷)を含む、請求項28に記載の組成物。
- 前記神経変性疾患が、白質消失病、CNSミエリン形成不全を伴う小児期運動失調、アルツハイマー病、筋萎縮性側索硬化症、クロイツフェルト−ヤコブ病、前頭側頭型認知症、ゲルストマン−シュトラウスラー−シャインカー病、ハンチントン病、認知症(例えば、HIV関連認知症またはレビー小体型認知症)、クールー病、多発性硬化症、パーキンソン病、またはプリオン病を含む、請求項29または30のいずれか1項に記載の組成物。
- 前記神経変性疾患が白質消失病を含む、請求項29〜31のいずれか1項に記載の組成物。
- 前記がんが、膵臓癌、乳癌、多発性骨髄腫、または分泌細胞の癌を含む、請求項29に記載の組成物。
- 前記炎症性疾患が、手術後認知機能不全、関節炎(例えば、関節リウマチ、乾癬性関節炎、または若年性特発性関節炎)、全身性エリテマトーデス(SLE)、重症筋無力症、糖尿病(例えば、若年発症型糖尿病または1型糖尿病)、ギラン−バレー症候群、橋本脳炎、橋本甲状腺炎、強直性脊椎炎、乾癬、シェーグレン症候群、脈管炎、糸球体腎炎、自己免疫甲状腺炎、ベーチェット病、クローン病、潰瘍性大腸炎、水疱性類天疱瘡、サルコイドーシス、魚鱗癬、グレーブス眼症、炎症性腸疾患、アジソン病、白斑、喘息(例えば、アレルギー性喘息)、尋常性ざそう、セリアック病、慢性前立腺炎、骨盤内炎症性疾患、再灌流傷害、サルコイドーシス、移植拒絶、間質性膀胱炎、アテローム硬化症、またはアトピー性皮膚炎を含む、請求項29に記載の組成物。
- 前記筋骨格疾患が、筋ジストロフィー(例えば、デュシェンヌ型筋ジストロフィー、ベッカー筋ジストロフィー、遠位筋ジストロフィー、先天性筋ジストロフィー、エメリー−ドレフュス型筋ジストロフィー、顔面肩甲上腕型筋ジストロフィー、または緊張性筋ジストロフィー)、多発性硬化症、筋委縮性側索硬化症、原発性側索硬化症、進行性筋委縮症、進行性球麻痺、偽性延髄麻痺、脊髄性筋萎縮症、進行性球脊髄性筋委縮症、脊髄痙縮、脊髄性筋萎縮症、重症筋無力症、神経痛、線維筋痛症、マチャド−ジョセフ病、有痛性痙縮−線維束性収縮症候群、フリードライヒ運動失調、筋消耗障害(例えば、筋萎縮症、サルコペニア、悪液質)、封入体筋障害、運動ニューロン疾患、または麻痺を含む、請求項29に記載の組成物。
- 前記代謝性疾患が、非アルコール性脂肪性肝炎(NASH)、非アルコール性脂肪肝疾患(NAFLD)、肝臓線維症、肥満、心疾患、アテローム硬化症、関節炎、シスチン蓄積症、糖尿病(例えば、I型糖尿病、II型糖尿病、または妊娠性糖尿病)フェニルケトン尿症、増殖性網膜障害、またはカーンズ−セイヤ病を含む、請求項29に記載の組成物。
- 対象に、式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体、あるいはその組成物を、第2の薬剤(例えば、がん、神経変性疾患、白質ジストロフィー、炎症性疾患、筋骨格疾患、代謝性疾患、あるいはeIF2B、eIF2α、またはeIF2経路もしくはISR経路の成分の機能減少と関連する疾患または障害を処置するための薬剤)と組み合わせて投与することを含む、請求項29〜36に記載の組成物。
- 先行請求項のいずれか1項に記載の式(I)の化合物またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体、もしくは立体異性体を含む、eIF2B活性もしくはレベル、eIF2α活性もしくはレベル、またはeIF2経路もしくはISR経路の成分の活性もしくはレベルのモジュレーションと関連する疾患を処置する際に使用するための組成物。
- 前記モジュレーションが、eIF2B活性もしくはレベルの上昇、eIF2α活性もしくはレベルの上昇、またはeIF2経路もしくはISR経路の成分の活性もしくはレベルの上昇を含む、請求項38に記載の組成物。
- 前記疾患が、eIF2経路(例えば、eIF2αシグナル伝達経路)のメンバーに関する遺伝子またはタンパク質配列に対する変異に起因し得る、請求項38に記載の組成物。
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