JP2017517502A - ヘテロシクリル−ブタンアミド誘導体 - Google Patents
ヘテロシクリル−ブタンアミド誘導体 Download PDFInfo
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- JP2017517502A JP2017517502A JP2016566920A JP2016566920A JP2017517502A JP 2017517502 A JP2017517502 A JP 2017517502A JP 2016566920 A JP2016566920 A JP 2016566920A JP 2016566920 A JP2016566920 A JP 2016566920A JP 2017517502 A JP2017517502 A JP 2017517502A
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- methyl
- oxo
- dmso
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- mhz
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- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
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Abstract
Description
本発明は、有用な特性を有する新規な化合物、特に医薬の調製のために使用することができるものを見出す目的を有していた。
本発明は、特に、タンキラーゼ1および2を阻害する式Iで表される化合物、これらの化合物を含む組成物、ならびに、TANKに誘導される疾患および愁訴の処置のためのその使用のための方法に関する。
E. Wahlberg et al., Nature Biotechnology (2012), 30(3), 283。
M. D. Shultz et al., Journal of Medicinal Chemistry 2013(公表11.07.2013)
同一の刊行物において、以下のベンゾイルピペリジン誘導体が、タンキラーゼ阻害剤として記載されている:
H. Bregman et al., Journal of Medicinal Chemistry (2013), 56(3), 1341
本発明の化合物は、著しくより活性である。
他のタンキラーゼ阻害剤は、WO 2013/012723、WO 2013/010092およびWO 2013/008217に記載されている。
がんの処置のためのオキソキナゾリニル−ブタンアミド誘導体は、WO 2015/014442 A1に記載されている。
比較データは、表3に示される。
本発明は、式I
Wは、
ここで*は、プロピレン部分への付着の点を示し、
Xは、O、COを示すかまたは不存在であり、
Yは、ArまたはHet1を示し、
R1は、H、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2は、HまたはCH3を示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1つのまたは隣接していない2つのCHおよび/またはCH2基は、NまたはO原子によって置き換えられていてもよく、かつここで1〜7個のH原子は、FまたはClおよび/またはOHによって置き換えられていてもよく、
Halは、F、Cl、BrまたはIを示し、
mは、0、1または2を示し、
nは、1または2を示す、
で表される化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物に関する。
さらに、本発明は、式Iで表される化合物の薬学的に許容し得る誘導体に関する。
薬学的に許容し得る誘導体という用語は、例えば、本発明の化合物の塩、またいわゆるプロドラッグ化合物をも意味するものと解釈される。
加えて、「治療的有効量」の表現は、この量を施与されていない対応する対象と比較して、以下の結果:
疾患、症候群、状態、愁訴、障害もしくは副作用の改善された処置、治癒、防止または解消、あるいはまた疾患、愁訴もしくは障害の進行の低減
を有する量を示す。
表現「治療的有効量」はまた、正常な生理学的機能を増大させるのに有効である量をも包含する。
これらは、特に好ましくは立体異性の化合物の混合物である。
式II
で表される化合物を、
式III
およびLは、Cl、Br、Iまたは遊離の、もしくは反応的に官能的に修飾されたOH基を示す、
で表される化合物と反応させ、
ならびに/あるいは
式Iで表される塩基または酸をその塩の1種に変換する
ことを特徴とする、前記方法に関する。
さらに、Aは、好ましくはCH2OCH3、CH2CH2OHまたはCH2CH2OCH3を示す。
R1は、好ましくはH、F、Cl、CH3またはCH2OHを示す。
R3は、好ましくはHまたはCH3を示す。
Arは、好ましくはフェニルを示し、それは、非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されている。
Het2は、好ましくはピリミジル。
Ar1は、好ましくはフェニルを示す。
式Iで表される化合物は、1つまたは2つ以上のキラル中心を有していてもよく、したがって様々な立体異性体の形態で存在し得る。式Iは、すべてのこれらの形態を包含する。
Ibにおいて、Het1は、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジルまたはピリダジニルを示し、その各々は、非置換であるか、またはAr1、CN、A、OR3、N(R3)2、Het2および/もしくは=Oによって単置換もしくは二置換されており、
Icにおいて、Het2は、ピリミジルを示し;
Idにおいて、Ar1は、フェニルを示し;
式中、*は、プロピレン部分への付着の点を示し、
Yは、ArまたはHet1を示し、
R1は、H、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2は、HまたはCH3を示し、
Arは、フェニルを示し、それは、非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されており、
Het2は、ピリミジルを示し、
Ar1は、フェニルを示し、
R3は、Hまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、1または2を示し;
式中、*は、プロピレン部分への付着の点を示し、
式中、*は、プロピレン部分への付着の点を示し、
Yは、ArまたはHet1を示し、
R1は、H、FまたはCH3を示し、
R2は、HまたはCH3を示し、
Het1は、ピラゾリルまたはピリジルを示し、その各々は、非置換であるか、またはA、OR3、N(R3)2および/もしくはHet2によって単置換もしくは二置換されており、
Het2は、ピリミジルを示し、
R3は、Hまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、1を示し;
式中、*は、プロピレン部分への付着の点を示し、
Yは、ArまたはHet1を示し、
R1は、H、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2は、HまたはCH3を示し、
Arは、フェニルを示し、それは、非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されており、
Het2は、ピリミジルを示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1つまたは2つの隣接していないCHおよび/またはCH2基は、NまたはO原子によって置き換えられていてもよく、かつここで1〜7個のH原子は、F、Clおよび/またはOHによって置き換えられていてもよく、
R3は、Hまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、1または2を示し;
式中、*は、プロピレン部分への付着の点を示し、
Yは、ArまたはHet1を示し、
R1は、H、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2は、HまたはCH3を示し、
Arは、フェニルを示し、それは、非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されており、
Het2は、ピリミジルを示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
R3は、Hまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、1または2を示し;
式中、*は、プロピレン部分への付着の点を示し、
Yは、ArまたはHet1を示し、
R1は、H、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2は、HまたはCH3を示し、
Arは、フェニルを示し、それは、非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されており、
Het2は、ピリミジルを示し、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
R3は、Hまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
nは、1または2を示す;
ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体であり、あらゆる比率でのそれらの混合物を含む。
式IIIで表される化合物において、Lは、好ましくは、Cl、Br、Iあるいは遊離の、または反応的に修飾されたOH基、例えば1〜6個のC原子を有する活性化されたエステル、イミダゾリドもしくはアルキルスルホニルオキシ(好ましくはメチルスルホニルオキシもしくはトリフルオロメチルスルホニルオキシ)または6〜10個のC原子を有するアリールスルホニルオキシ(好ましくはフェニルもしくはp−トリルスルホニルオキシ)を示す。
アルカリもしくはアルカリ土類金属水酸化物、炭酸塩もしくは重炭酸塩またはアルカリもしくはアルカリ土類金属の、好ましくはカリウム、ナトリウム、カルシウムもしくはセシウムの弱酸の別の塩の添加はまた、好ましい場合がある。
使用する条件に依存して、反応時間は数分〜14日であり、反応温度は約−30°〜140°、通常−10°〜90°、特に約0°〜約70°である。
特に好ましいのは、アセトニトリル、1,2−ジクロロエタン、ジクロロメタンおよび/またはDMFである。
本発明の前述の化合物を、それらの最終的な非塩形態で用いることができる。一方、本発明はまた、これらの化合物を、当該分野で公知の手順によって、種々の有機および無機酸類および塩基類から誘導し得るそれらの薬学的に許容し得る塩の形態で用いることを包含する。式Iで表される化合物の薬学的に許容し得る塩の形態は、大部分、慣用的な方法によって製造される。式Iで表される化合物がカルボキシル基を含む場合は、この好適な塩の1種を、当該化合物を好適な塩基と反応させて対応する塩基付加塩を得ることによって生成することができる。かかる塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを含むアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウムおよび水酸化カルシウム;アルカリ金属アルコキシド類、例えばカリウムエトキシドおよびナトリウムプロポキシド;ならびに種々の有機塩基、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンである。
さらに、式Iで表される化合物が同位体で標識されたその形態を含むことを、意図する。式Iで表される化合物の同位体で標識された形態は、化合物の1個または2個以上の原子が通常天然に存在する原子の原子質量または質量数と異なる原子質量または質量数を有する原子(単数)または原子(複数)によって置き換えられているという事実とは別に、この化合物と同一である。
局所投与に適合した医薬化合物を、軟膏、クリーム、懸濁液、ローション、散剤、溶液、ペースト、ゲル、スプレー、エアゾールまたは油として処方することができる。
口における局所的適用に適合した医薬製剤は、薬用キャンディー、トローチおよび洗口剤を包含する。
直腸内投与に適合した医薬製剤を、坐剤または浣腸剤の形態で投与することができる。
膣内投与に適合した医薬製剤を、膣坐薬、タンポン、クリーム、ゲル、ペースト、発泡体またはスプレー製剤として投与することができる。
(a)式Iで表される化合物ならびに/またはそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物の有効量、
ならびに
(b)さらなる医薬活性成分の有効量
の別個のパックからなるセット(キット)に関する。
ならびに、溶解した形態または凍結乾燥形態での有効量のさらなる医薬活性成分
を含む個別のアンプルを含んでもよい。
本化合物は、がん、多発性硬化症、心血管疾患、中枢神経系損傷および種々の形態の炎症の処置における哺乳動物のための、特にヒトのための医薬活性成分として好適である。
式Iで表される化合物およびそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物に関する。
特に好ましくは、本発明は、疾患ががんである方法に関し、投与が、同時、連続的または少なくとも1種の他の活性薬剤の投与との交互である。
例えばアルトレタミン、ベンダムスチン、ブスルファン、カルムスチン、クロラムブシル、クロルメチン、シクロホスファミド、ダカルバジン、イホスファミド、インプロスルファン、トシラート、ロムスチン、メルファラン、ミトブロニトール、ミトラクトール、ニムスチン、ラニムスチン、テモゾロミド、チオテパ、トレオスルファン、メクロレタミン、カルボコン;アパジコン、ホテムスチン、グルホスファミド(glufosfamide)、パリホスファミド(palifosfamide)、ピポブロマン、トロホスファミド、ウラムスチン(uramustine)、TH−3024、VAL−0834;
例えばカルボプラチン、シスプラチン、エプタプラチン(eptaplatin)、ミリプラチン水和物、オキサリプラチン、ロバプラチン(lobaplatin)、ネダプラチン、ピコプラチン、サトラプラチン;ロバプラチン、ネダプラチン、ピコプラチン、サトラプラチン;
例えばアムルビシン、ビサントレン(bisantrene)、デシタビン、ミトキサントロン、プロカルバジン、トラベクテジン、クロファラビン;アムサクリン、ブロスタリシン(brostallicin)、ピクサントロン、ラロムスチン(laromustine)1、3;
例えばエトポシド、イリノテカン、ラゾキサン、ソブゾキサン、テニポシド、トポテカン;アモナフィド(amonafide)、ベロテカン(belotecan)、エリプチニウムアセタート(elliptinium acetate)、ボレロキシン;
例えばカバジタキセル、ドセタキセル、エリブリン、イクサベピロン、パクリタキセル、ビンブラスチン、ビンクリスチン、ビノレルビン、ビンデシン、ビンフルニン;フォスブレタブリン、テセタキセル(tesetaxel);
例えばアスパラギナーゼ3、アザシチジン、レボホリナートカルシウム、カペシタビン、クラドリビン、シタラビン、エノシタビン、フロクスウリジン、フルダラビン、フルオロウラシル、ゲムシタビン、メルカプトプリン、メトトレキサート、ネララビン、ペメトレキセド、プララトレキサート、アザチオプリン、チオグアニン、カルモフール;ドキシフルリジン、エラシタラビン(elacytarabine)、ラルチトレキセド、サプラシタビン(sapacitabine)、テガフール2、3、トリメトレキサート;
例えばブレオマイシン、ダクチノマイシン、ドキソルビシン、エピルビシン、イダルビシン、レバミソール、ミルテホシン、マイトマイシンC、ロミデプシン、ストレプトゾシン、バルルビシン、ジノスタチン、ゾルビシン、ダウノルビシン、プリカマイシン;アクラルビシン、ペプロマイシン、ピラルビシン;
例えばアバレリックス、アビラテロン、ビカルタミド、ブセレリン、カルステロン、クロロトリアニセン、デガレリクス、デキサメタゾン、エストラジオール、フルオコルトロン、フルオキシメステロン、フルタミド、フルベストラント、ゴセレリン、ヒストレリン、リュープロレリン、メゲストロール、ミトタン、ナファレリン、ナンドロロン、ニルタミド、オクトレオチド、プレドニゾロン、ラロキシフェン、タモキシフェン、サイロトロピンアルファ、トレミフェン、トリロスタン、トリプトレリン、ジエチルスチルベストロール;アコルビフェン(acolbifene)、ダナゾール、デスロレリン(deslorelin)、エピチオスタノール、オルテロネル(orteronel)、エンザルタミド1,3;
例えばアミノグルテチミド、アナストロゾール、エキセメスタン、ファドロゾール、レトロゾール、テストラクトン;ホルメスタン;
例えばクリゾチニブ、ダサチニブ、エルロチニブ、イマチニブ、ラパチニブ、ニロチニブ、パゾパニブ、レゴラフェニブ、ルキソリチニブ、ソラフェニブ、スニチニブ、バンデタニブ、ベムラフェニブ、ボスチニブ、ゲフィチニブ、アキシチニブ;アファチニブ、アリサーチブ(alisertib)、ダブラフェニブ、ダコミチニブ(dacomitinib)、ジナシクリブ(dinaciclib)、ドビチニブ(dovitinib)、エンザスタウリン、ニンテダニブ、レンバチニブ、リニファニブ、リンシチニブ(linsitinib)、マシチニブ(masitinib)、ミドスタウリン(midostaurin)、モテサニブ、ネラチニブ、オランチニブ(orantinib)、ペリフォシン、ポナチニブ、ラドチニブ(radotinib)、リゴセルチブ(rigosertib)、ティピファニブ、チバンチニブ、チボザニブ、トラメチニブ、ピマセルチブ(pimasertib)、ブリバニブアラニナート、セジラニブ、アパチニブ(apatinib)4、カボザンチニブS−マラート1,3、イブルチニブ1,3、イコチニブ(icotinib)4、ブパルリシブ(buparlisib)2、シパチニブ(cipatinib)4、コビメチニブ1,3、イデラリシブ1,3、フェドラチニブ(fedratinib)1、XL−6474;
例えばメトキサレン3;ポルフィマーナトリウム、タラポルフィン、テモポルフィン;
例えばアレムツズマブ、ベシレソマブ、ブレンツキシマブベドチン、セツキシマブ、デノスマブ、イピリムマブ、オファツムマブ、パニツムマブ、リツキシマブ、トシツモマブ、トラスツズマブ、ベバシズマブ、ペルツズマブ2,3;カツマキソマブ、エロツズマブ、エプラツズマブ、ファーレツズマブ、モガムリズマブ、ネシツムマブ、ニモツズマブ(nimotuzumab)、オビヌツズマブ、オカラツズマブ(ocaratuzumab)、オレゴボマブ、ラムシルマブ、リロツムマブ、シルツキシマブ、トシリズマブ、ザルツムマブ、ザノリムマブ、マツズマブ、ダロツズマブ(dalotuzumab)1,2,3、オナルツズマブ(onartuzumab)1,3、ラコツモマブ(racotumomab)1、タバルマブ(tabalumab)1,3、EMD−5257974、ニボルマブ1,3;
例えばアルデスロイキン、インターフェロンアルファ2、インターフェロンアルファ2a3、インターフェロンアルファ2b2、3;セルモロイキン、タソネルミン、テセロイキン、オプレルベキン1,3、組換えインターフェロンベータ−1a4;
例えばデニロイキンジフチトクス、イブリツモマブチウキセタン、イオベングアン(iobenguane)I123、プレドニムスチン、トラスツズマブエムタンシン、エストラムスチン、ゲムツズマブ、オゾガマイシン、アフリベルセプト;シトレデキンベスドトックス(cintredekin besudotox)、エドトレオチド(edotreotide)、イノツズマブオゾガマイシン、ナプツモマブ・エスタフェナトクス、オポルツズマブモナトックス(oportuzumab monatox)、テクネチウム(99mTc)アルシツモマブ1,3、ビンタフォリド1,3;
例えばシプロイセル3;ビテスペン3、エメペピムト(emepepimut)−S3、oncoVAX4、リンドペピムト(rindopepimut)3、troVax4、MGN−16014、MGN−17034;
アリトレチノイン、ベキサロテン、ボルテゾミブ、エベロリムス、イバンドロン酸、イミキモド、レナリドミド、レンチナン、メチロシン、ミファムルチド、パミドロン酸、ペグアスパルガーゼ、ペントスタチン、シプロイセル3、シゾフィラン、タミバロテン、テムシロリムス、サリドマイド、トレチノイン、ビスモデギブ、ゾレドロン酸、ボリノスタット;セレコキシブ、シレンジチド(cilengitide)、エンチノスタット(entinostat)、エタニダゾール、ガネテスピブ(ganetespib)、イドロノキシル(idronoxil)、イニパリブ(iniparib)、イキサゾミブ(ixazomib)、ロニダミン、ニモラゾール、パノビノスタット、ペレチノイン、プリチデプシン(plitidepsin)、ポマリドミド、プロコダゾール(procodazol)、リダフォロリムス、タスキニモド(tasquinimod)、テロトリスタット(telotristat)、チマルファシン(thymalfasin)、チラパザミン、トレドスタット(tosedostat)、トラベデルセン、ウベニメクス、バルスポダル(valspodar)、ゲンジシン(gendicine)4、ピシバニール4、レオリシン(reolysin)4、レタスピマイシン塩酸塩1、3、トレバナニブ(trebananib)2,3、ビルリジン(virulizin)4、カーフィルゾミブ1,3、エンドスタチン4、イムコテル(immucothel)4、ベリノスタット(belinostat)3、MGN−17034;
1Prop. INN(提唱された国際一般的名称(Proposed International Nonproprietary Name))
2Rec. INN(推奨された国際一般的名称(Recommended International Nonproprietary names))
3USAN(米国一般名(United States Adopted Name))
4INNなし。
aq(水性)、h(時間)、g(グラム)、L(リットル)、mg(ミリグラム)、MHz(メガヘルツ)、min.(分)、mm(ミリメートル)、mmol(ミリモル)、mM(ミリモル)、m.p.(融点)、eq(当量)、mL(ミリリットル)、L(マイクロリットル)、ACN(アセトニトリル)、AcOH(酢酸)、CDCl3(重水素化クロロホルム)、CD3OD(重水素化メタノール)、CH3CN(アセトニトリル)、c−hex(シクロヘキサン)、DCC(ジシクロヘキシルカルボジイミド)、DCM(ジクロロメタン)、DIC(ジイソプロピルカルボジイミド)、DIEA(ジイソプロピルエチル−アミン)、DMF(ジメチルホルムアミド)、DMSO(ジメチルスルホキシド)、DMSO−d6(重水素化ジメチルスルホキシド)、EDC(1−(3−ジメチル−アミノ−プロピル)−3−エチルカルボジイミド、ESI(エレクトロスプレーイオン化)、EtOAc(酢酸エチル)、Et2O(ジエチルエーテル)、EtOH(エタノール)、HATU(ジメチルアミノ−([1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)−メチレン]−ジメチル−アンモニウムヘキサフルオロホスファート)、HPLC(高速液体クロマトグラフィー)、i−PrOH(2−プロパノール)、K2CO3(炭酸カリウム)、LC(液体クロマトグラフィー)、MeOH(メタノール)、MgSO4(硫酸マグネシウム)、MS(質量分析)、MTBE(メチルtert−ブチルエーテル)、NaHCO3(重炭酸ナトリウム)、NaBH4(水素化ホウ素ナトリウム)、NMM(N−メチルモルホリン)、NMR(核磁気共鳴)、PyBOP(ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノ−ホスホニウムヘキサフルオロホスファート、RT(室温)、Rt(保持時間)、SPE(固相抽出)、TBTU(2−(1−H−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ラート、TEA(トリエチルアミン)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、TLC(薄層クロマトグラフィー)、UV(紫外線)。
略語:
GST=グルタチオン−S−転移酵素
FRET=蛍光共鳴エネルギー移動
HTRF(登録商標)=(均質時間分解蛍光)
HEPES=4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸緩衝液
DTT=ジチオトレイトール
BSA=ウシ血清アルブミン
CHAPS=洗浄剤;
CHAPS=3−[(3−クロルアミドプロピル)ジメチルアンモニオ]−1−プロパンスルホナート
タンキラーゼがAxin2の細胞レベルを変調させると記載されている(Huang et al., 2009;Nature)ので、Axin2レベルの増加を、Luminexに基づくアッセイにおいてタンキラーゼの細胞阻害の決定についての読み出しとして使用する。
PARP−1の生化学的活性試験:オートパラジレーションアッセイ
オートパラジレーションアッセイを、2ステップにおいて行う:Hisタグ付加Parp−1がビオチン化ADP−リボース/ADP−リボースをそれ自体に、補助基質としてのビオチン化NAD/NADから移行させた酵素反応ならびに酵素のHisタグに結合したクリプタート標識抗His抗体とビオチン−パラジレーション残基に結合したXlent(登録商標)標識ストレプトアビジンとの間の時間分解FRETを分析する検出反応。オートパラジレーション活性は、HTRFシグナルの増加によって直接検出可能である。
TNKS1および2の生化学的活性試験:活性ELISA(オートパラジレーションアッセイ)
TNKS1および2のオートパラジレーション活性の分析のために、活性ELISAを行う:最初のステップにおいて、GSTタグ付加TNKSを、グルタチオンでコーティングしたプレート上で捕獲する。次に、ビオチン化NADでの活性アッセイを、化合物の非存在/存在下で行う。酵素反応の間に、GSTタグ付加TNKSは、ビオチン化ADPリボースをそれ自体に、補助基質としてのビオチン化NADから移行させた。検出のために、ストレプトアビジン−HRP複合体を加え、それはビオチン化TNKSに結合し、それによってプレートに捕獲される。それぞれビオチン化された、およびオートパラジレートされたTNKSの量を、HRPについてのルミネセンス基質で検出する。ルミネセンスシグナルのレベルは、オートパラジレートされたTNKSの量と、およびしたがってTNKSの活性と直接相関している。
ミクロソーム安定性アッセイを使用して、in vitroクリアランス(Clint)を測定する。アッセイは、代謝するべきその固有の姿勢により、化合物の消失の速度を測定することを含む(「固有の」は、消失が他の特性、例えばin vivoクリアランスを定量するときに役割を果たす透過性、結合などによって影響されないことを意味する)。ミクロソーム安定性(固有のクリアランス、Clint)およびしたがって代謝安定性は、一般にμl/min/mgタンパク質として示される。それを、1mgのミクロソームが化合物を1分でクリアーすることができる溶液の容積として視覚化することができる。
Tecan Genesisワークステーション(RSP150/8)を使用して、ミクロソームインキュベーションを行った。分析を、ABSciex API3000質量分析計に結合したWaters ACQUITY UPLCシステムを使用して行った。データ分析を、Assay Explorer (Symyx)を使用して行った。
カラム:Acquity UPLC BEH C18、2.1×50mm、1.7μm(Waters)
移動相:A=水中の0.1%ギ酸;B=アセトニトリル
流量:0.750mL/min;検出:ESI, MRM;注入:10μL;カラム温度:50℃
・リン酸カリウム緩衝液:1mMのMgCl2を含む0.05Mリン酸カリウム緩衝液、pH7.4
・NADPH(ニコチンアミドアデニンジヌクレオチドリン酸):1.8mlのリン酸カリウム緩衝液中の22.5mgのNADPH−Na4
・アセトニトリル:50体積%のアセトニトリル(1体積アセトニトリル、1容積水)
・DMSO:水中の20体積%のDMSO
・リン酸緩衝液中の20mg/mlのヒトまたはマウス肝臓ミクロソーム(タンパク質)/mlの原液
・100%DMSO中の10mM化合物の原液
勾配:5.5minにおいてA:B=90:10〜0:100;流量:2.75ml/min
A:水+TFA(0.01体積%);B:アセトニトリル+TFA(0.01体積%)
カラム:Chromolith SpeedROD RP 18e 50-4.6
波長:220nm
HPLC条件(2):
勾配:5.5minにおいてA:B=99:1〜0:100;流量:2.75ml/min
A:水+TFA(0.01体積%);B:アセトニトリル+TFA(0.01体積%)
カラム:Chromolith SpeedROD RP 18e 50-4.6
波長:220nm
勾配:A:B=3.4minにおいて96:4〜0:100;流量:2.40ml/min
A:水+ギ酸(0.05%);B:アセトニトリル+ギ酸(0.04%)
カラム:Chromolith SpeedROD RP-18e、50×4.6mm2
波長:220nm
HPLC/MS条件(B):
勾配:0min:5%のB、8min:100%のB、8.1min:100%のB、8.5min:5%のB、10min 5%のB
流量:2.0mL/min
A:水+TFA(0.1体積%);B:アセトニトリル+TFA(0.1体積%)
カラム:XBridge C8、3.5μm、4.6×50mm
波長:220nm
勾配:0min:0%のB、0.4min:0%のB、3.2min:100%のB、3.8min:100%のB、3.81min:0%のB、4.5min 0%のB;流量:2.0mL/min
A:水+ギ酸(0.05%);B:アセトニトリル+ギ酸(0.04%)
カラム:Chromolith SpeedROD RP-18e、100−3mm
波長:220nm
HPLC/MS条件(D):
勾配:0min:5%のB、8min:100%のB、8.1min:100%のB、8.5min:5%のB、10min 5%のB;
流量:1ml/min;
A:水+10mM NH4HCO3;B:ACN
カラム:XBridge C8、3.5μm、4.6×50mm
勾配:0min:0%のB、1.4min:100%のB、2.0min:100%のB、2.01min:0%のB、2.5min 0%のB;流量:2.0mL/min
A:水+ギ酸(0.05%);B:アセトニトリル+ギ酸(0.04%)
カラム:Kinetex XB-C18 2.6μm 50−4.6mm
波長:220nm
HPLC/MS条件(F):
勾配:0min:10%のB、2.5min:95%のB、4.5min:95%のB、4.6min:10%のB、6min 10%のB
流量:1.5mL/min
A:水+TFA(0.1体積%);B:アセトニトリル+TFA(0.1体積%)
カラム:Atlantis dC18、4.6×50mm、5μm
波長:220nm
表3に示す化合物は、本発明による特に好ましい化合物である。
6−ブロモ−5−オキソ−ヘキサン酸メチルエステル(BrおよびCl生成物の混合物)
4−メチル−1H−ピロール−2−カルボン酸エチルエステル(500.0mg;3.264mmol)および6−ブロモ−5−オキソ−ヘキサン酸メチルエステル(1.42g;4.896mmol)を、乾燥アセトン(8mL)に溶解し、炭酸カリウム(0.90g;6.528mmol)を加えた。反応混合物を、室温で1h、50℃で14hおよび60℃で7h撹拌した。反応混合物を水(50mL)で希釈し、酢酸エチルで抽出した。合わせた有機層をブラインで洗浄し、Na2SO4で乾燥し、ろ過し、蒸発乾固させた。粗生成物を、フラッシュクロマトグラフィー(Companion RF;80gのSi50シリカゲルカラム)によって精製した;収量:964mg(100%)の無色油(純度:100%;Rt:2.77min)。
1−(5−メトキシカルボニル−2−オキソ−ペンチル)−4−メチル−1H−ピロール−2−カルボン酸エチルエステル(0.96g;3.264mmol)および酢酸アンモニウム(7.00g;90.812mmol)に、氷酢酸(7mL)を加え、混合物を110℃で4.5h撹拌し、周囲温度に冷却し、14h放置した。反応混合物を水(30mL)で希釈し、ジクロロメタンで抽出した。合わせた有機層を飽和NaHCO3溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥し、吸引によってろ過し、蒸発乾固させた。油状残留物を、フラッシュクロマトグラフィー(Companion RF;80gのSi50シリカゲルカラム)によって精製した;収量:183mg(22%)の茶色油(純度:99.2%;Rt:2.06min)。
1H−ピロール−2−カルボン酸メチルエステル(5.00g;38.761mmol)を、アセトニトリル(100mL)に溶解し、セレクトフルオル(15.90g;42.637mmol)を加え、混合物の温度を5min以内に室温から60℃に上昇させた。反応混合物を氷水(400mL)で希釈し、ジクロロメタンで抽出した。合わせた有機層を水で洗浄し、硫酸ナトリウムで乾燥し、吸引によってろ過し、蒸発乾固させた。残留物を、フラッシュクロマトグラフィー(Companion RF;330gのSi50シリカゲルカラム)によって精製した;収量:911mg(15%)の淡黄色固体(純度:91.9%;Rt:1.76min);LC/MS(A)、Rt:1.59min;(M+H)144。
イソシアノ酢酸エチルエステル(5.46mL;50.00mmol)および1−tert−ブトキシ−N,N,N’,N’−テトラメチル−メタンジアミン(20.65mL;100.00mmol)を、室温で14h撹拌した。反応混合物を蒸発乾固させ、残留物(8.4g、茶色油)をさらに精製せずに次のステップにおいて使用した。
(Z)−3−ジメチルアミノ−2−イソシアノ−アクリル酸エチルエステル(4.87g;28.967mmol)およびベンジルアミン(3.41mL、31.864mmol)を、70℃で14h撹拌した。反応混合物を蒸発乾固させ、残留物をクロマトグラフィー(330gのシリカゲルカラム;ジクロロメタン/メタノール)によって精製して、3.93g(57%)を茶色油として得た(純度:97%;Rt:2.09min)。
1−ベンジル−1H−イミダゾール−4−カルボン酸エチルエステル(3.93g;17.067mmol)および塩化アンモニウム(274.0mg、5.120mmol)を、アンモニア溶液(32%;45mL)に溶解し、オートクレーブ中で105℃および6.2barで14h加熱した。生成物を吸引によってろ過し、水で洗浄し、50℃で14h真空の下で乾燥した;収量:2.13g(63%)のベージュ色固体;(純度:99.5%;Rt:1.35min)。
5−メチル−2H−ピラゾール−3−カルボン酸エチルエステル(771mg、5.00mmol)および6−ブロモ−5−オキソ−ヘキサン酸メチルエステル(1.19g、5.35mmol)をTHF(10ml)に溶解した溶液に、炭酸リチウム(406mg、5.50mmol)を加える。得られた懸濁液を、閉じた反応バイアル中で100℃で15h撹拌する。反応混合物を室温に到達させ、蒸発乾固させ、残留物を、シクロヘキサン/酢酸エチルを溶離剤としてシリカゲルカラム上のクロマトグラフィーによって精製して、2−(5−メトキシカルボニル−2−オキソ−ペンチル)−5−メチル−2H−ピラゾール−3−カルボン酸エチルエステルを茶色油として得る;HPLC/MS(C)、Rt:2.55min;[M+H]297;
2−(5−メトキシカルボニル−2−オキソ−ペンチル)−5−メチル−2H−ピラゾール−3−カルボン酸エチルエステル(945mg;3.19mmol)を酢酸(5.83ml)に溶解した溶液に、酢酸アンモニウム(2.46g、31.9mmol)を加える。懸濁液を100℃に加熱し、この温度で16h撹拌する。反応混合物を室温に到達させ、水とジクロロメタンとの間で分割する。有機相を硫酸ナトリウムで乾燥し、蒸発乾固させる。残留物を、ジクロロメタン/メタノールを溶離剤としてシリカゲルカラム上のクロマトグラフィーによって精製して、4−(2−メチル−4−オキソ−4,5−ジヒドロ−ピラゾロ[1,5−a]ピラジン−6−イル)−酪酸メチルエステルを白色固体として得る;HPLC/MS(C)、Rt:2.02min;[M+H]250。
2−メチル−1H−イミダゾール−4−カルボン酸(5.0g;37.665mmol)を、乾燥メタノール(75mL)に溶解し、濃硫酸(2.41mL;45.198mmol)を、室温で攪拌しながら加えた。数分後、透明な黄色溶液が生成した。それを加熱還流させ、24h撹拌した。さらなる濃硫酸(1mL;18.761mmol)を滴加し、混合物をさらに24h撹拌した。これをもう一度繰り返し、反応混合物を次に後処理した。溶液を周囲温度に冷却し、5分の1の容積に蒸発させた。油状残留物を、2N NaOHで塩基性にし(pH9)、ジクロロメタンで徹底的に抽出した。合わせた有機層を、硫酸ナトリウムで乾燥し、吸引によってろ過し、蒸発乾固させた;収量:4.15g(78%)の無色固体(純度:98.9%;Rt(2):0.65min);LC/MS(A)、Rt:0.34〜0.40min;(M+H)141.1。
2−メチル−1H−イミダゾール−4−カルボン酸メチルエステル(1.50g;10.586mmol)および炭酸セシウム(6.90g;21.172mmol)を、アセトニトリル(20mL)に懸濁させた。アルゴンの下で撹拌しながら、臭化ベンジル(1.32mL;11.115mmol)を、滴加した。反応混合物を、室温で14h撹拌した。得られた沈殿を吸引によってろ過し、濾液を蒸発乾固させた。残留物(2.68gの黄色油;純度94.8%;Rt:1.55min)を、さらに精製せずに次のステップにおいて使用した。
3−アミノ−4−メチル−チオフェン−2−カルボン酸メチルエステル(5.00g;29.20mmol)を水(75mL)に溶解した溶液に、水酸化ナトリウム(5.84g;146.01mmol)を室温で加えた。反応混合物を、90℃で2h加熱した。反応の完了の後、反応混合物を0℃に冷却し、1.5N HCl溶液で酸性化した(pH6〜7)。沈殿をろ過し、水で洗浄し、乾燥して、3−アミノ−4−メチル−チオフェン−2−カルボン酸(3.0g;61%)を無色固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.18 (s, 1H), 6.38 (bs, 2H), 2.00 (s, 3H). LC/MS (B), Rt: 2.23 min.
3−アミノ−4−メチル−チオフェン−2−カルボン酸(3.00g;19.09mmol)をTHF(60mL)およびDMF(3mL)に溶解した溶液に、N,N−ジイソプロピルエチルアミン(16.83ml;95.43mmol)、HOBt(3.95g;28.63mmol)およびEDCI(5.72g;28.63mmol)を、0℃で加えた。反応混合物を、室温で30min撹拌した。炭酸アンモニウム(9.17g;95.43mmol)を室温で加え、反応混合物を室温で15h撹拌した。反応混合物を酢酸エチルで希釈し、水、ブライン、硫酸ナトリウムで洗浄し、蒸発させた。残留物を、DCMおよびMeOH(9:1)を溶離剤として使用してカラムクロマトグラフィーによって精製して、3−アミノ−4−メチル−チオフェン−2−カルボン酸アミド(1.50g;47%)をオフホワイト固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.04 (s, 1H), 6.81 (bs, 2H), 6.27 (bs, 2H), 1.98 (s, 3H); LC/MS (D), Rt: 2.95 min; (M+H) 157.
メチル−ヒドラジン(377.0mg;8.255mmol)のエタノール(20mL)中の混合物に、2−[1−エトキシ−(E)−メチリデン]−ブタ−3−インニトリル(1.0g;8.255mmol)を、分割して25〜26℃で窒素雰囲気下で加えた。反応混合物を、90℃に2h加熱した。反応混合物を25〜26℃に冷却し、その間固体が沈殿した。固体を吸引によってろ過し、乾燥して、表題化合物(0.60g;60%)を無色固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.49 (s, 1H), 6.52 (bs, 2H), 3.50 (s, 3H); LC/MS (D), Rt: 1.95 min; (M+H) 123.
5−アミノ−1−メチル−1H−ピラゾール−4−カルボニトリル(12.0g;0.098mol)を、硫酸(36mL)に室温で分割して加え、窒素雰囲気下で4h撹拌した。反応混合物を、氷冷水中にゆっくり注いだ。溶液のpHを、アンモニア水溶液を使用してpH8に調整した。沈殿が生成し、それをろ過し、水(20mL)で洗浄し、真空の下で乾燥して、表題化合物(13.0g;94%)をオフホワイト固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 7.50 (s, 1H), 7.13 (bs, 1H), 6.75 (bs, 1H), 6.31 (s, 2H), 3.48 (s, 3H); LC/MS (D), Rt: 0.95 min; (M+H) 141.2.
5−メチル−1H−ピロール−2−カルボン酸エチルエステル(10.00g;62.02mmol)をDMF(200.0ml)に溶解した溶液に、リチウムビス(トリメチルシリル)アミド溶液(THFに溶解した1.0M;93.03mL;93.03mmol)を、窒素の下で−10℃で滴加した。反応混合物を−10℃で1h撹拌し、次にDMF(200.0mL)中のO−ジフェニルホスホリルヒドロキシルアミン(27.40g;111.63mmol)を窒素の下で−10℃で滴加した。反応混合物を、RTにゆっくり加温し、12h撹拌した。反応混合物を飽和NH4Cl溶液で反応停止し、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧下で濃縮した。粗生成物を、石油エーテル中の30%酢酸エチルを使用してフラッシュカラムクロマトグラフィーによって精製して、表題化合物(10.00g;95%)を得た。LC/MS(B)、Rt:3.42min;(M+H)169.0。
1−アミノ−5−メチル−1H−ピロール−2−カルボン酸エチルエステル(10.00g;58.74mmol)を水(150.00mL)に溶解した溶液に、水酸化ナトリウム(11.75g;293.71mmol)を、RTで加えた。反応混合物を、90℃で2h撹拌した。反応混合物を0℃に冷却し、1.5N HCl溶液でpH6〜7に酸性化した。得られた固体をろ過し、水で洗浄し、乾燥して、表題化合物(4.00g;49%)を得た。LC/MS(B)、Rt:1.41min;(M+H)141.0。
1−アミノ−5−メチル−1H−ピロール−2−カルボン酸(4.00g;26.83mmol)をTHF(80.00mL)に溶解した溶液に、HOBt(5.55g;40.25mmol)およびEDC.HCl(8.04g;40.25mmol)を、0℃で加えた。反応混合物を、室温で15min撹拌した。炭酸アンモニウム(14.32g;134.15mmol)を加え、反応混合物を室温で12h撹拌した。反応混合物を酢酸エチルで希釈し、水、ブラインおよび硫酸ナトリウムで洗浄し、蒸発乾固させた。粗製の残留物を、DCMおよびMeOH(9:1)を溶離剤として使用してカラムクロマトグラフィーによって精製して、1−アミノ−5−メチル−1H−ピロール−2−カルボン酸アミド(0.80g、21%)を得た。LC/MS(B)、Rt:0.99min;(M+H)140.0。
4−カルバムイミドイル−酪酸エチルエステル(1.80g;7.70mmol)および4−オキソ−テトラヒドロ−ピラン−3−カルボン酸メチルエステル(1.54g;9.24mmol)をメタノール(18.00mL)に溶解した溶液に、トリエチルアミン(2.18mL;15.41mmol)を、窒素雰囲気下で加えた。反応混合物を、室温で18h撹拌した。溶媒を真空の下で除去し、残留物をDCM(250mL)に溶解し、水(2×100mL)で洗浄し、硫酸ナトリウムで乾燥し、蒸発乾固させた。粗生成物を、DCM/メタノールを溶離剤として使用してカラムクロマトグラフィーによって精製して、4−(4−オキソ−3,5,7,8−テトラヒドロ−4H−ピラノ[4,3−d]ピリミジン−2−イル)−酪酸エチルエステル(1.20g;57%)を淡黄色油として得た。エチルおよびメチルエステルの混合物を含むクロマトグラフィーからの単離した生成物をそれとして次のステップのために採用した。
ジイソプロピルアミン(4.863mL;0.034mol)を、窒素雰囲気下でTHF(70.0mL)に溶解し、溶液を−78℃に冷却した。n−ブチルリチウム(ヘキサン中1.6M;18.70mL;0.030mol)を30minの期間にわたって−78℃で滴加し、溶液を−10℃に加温し、30min撹拌した。溶液を、再び−78℃に冷却し、次にTHF(70.0mL)に溶解した4−tert−ブトキシカルボニルアミノ−チオフェン−3−カルボン酸メチルエステル(3.500g;0.014mol)を、30minの期間にわたって滴加し、反応混合物を−78℃で1h撹拌した。THF(35.0mL)に溶解したヨードメタン(0.941mL;0.015mol)を、−78℃で滴加し、反応混合物を0℃にゆっくり加温し、この温度で1h撹拌した。反応混合物を−5℃に冷却し、5%塩化アンモニウム溶液(100mL)で反応停止し、酢酸エチルで抽出した。合わせた有機層を、水およびブラインで洗浄し、硫酸ナトリウムで乾燥し、濃縮した。粗製の混合物を、メタノール(2%)を含むDCMを溶離剤として使用してカラムクロマトグラフィーで精製して、4−tert−ブトキシカルボニルアミノ−5−メチル−チオフェン−3−カルボン酸メチルエステル(1.80g;0.006mol;47%)を黄色固体として得た;LC/MS(B)、Rt:4.48min;(M+H−BOC)172.0。
A18.1(1.26g;4.64mmol)をメタノール(13.0mL)に溶解した撹拌した溶液に、オートクレーブ中で、アンモニアをメタノールに溶解した溶液(7M;130.0mL)を加え、反応混合物を70℃に20h加熱した。反応混合物を室温に冷却し、真空の下で濃縮した。粗生成物を、DCM/メタノール(1%)を溶離剤として使用してカラムクロマトグラフィーによって精製した;収量:0.78g(66%)の薄茶色固体;
A18.2(0.274g;1.07mmol)を1,4−ジオキサン(3.0mL)に溶解した撹拌した溶液に、0℃で、ジオキサン中のHCl(6.0mL)を加え、室温で4h撹拌した。反応混合物を蒸発乾固させ、残留物をエーテルで粉末にし、固体をろ過し、乾燥し、さらに精製せずに次のステップのために使用した。
反応を、A13.4に記載したように、2オキソ−シクロヘキサンカルボン酸エチルエステルを使用して行った;収量:2.24g(26%)の淡黄色ガム状物質;LC/MS(F)、Rt:1.62min;(M+H)265.2。
2,2−ジメトキシ−エチル)−メチル−アミン(16.40mL;149.86mmol)をDCM(96mL)に溶解した溶液に、マロノニトリル(10.00g;149.86mmol)を窒素雰囲気下で加え、反応混合物を10min撹拌した。トルエン−4−スルホン酸(52.67g;299.72mmol)を加え、反応混合物を室温で16h撹拌した。反応混合物を真空の下で濃縮し、10%重炭酸ナトリウム溶液で塩基性にし、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、ろ過し、真空の下で濃縮した。粗製物を、酢酸エチル/石油エーテルを使用してカラムクロマトグラフィーによって精製した;収量:3.27g(18.0%)の薄茶色固体。
A20.1(0.50g;3.64mmol)およびジヒドロ−ピラン−2,6−ジオン(0.42g;3.64mmol)のトルエン(10.0mL)中の混合物を、窒素雰囲気下で16h還流させ、溶媒を真空の下で蒸発させた。残留物を酢酸エチルで粉末にし、吸引によってろ過し、乾燥した;収量:0.23g(27%)の茶色固体。
2−メチル−3−オキソ−酪酸エチルエステル(5.00g;34.68mmol)を、圧力管中に採取し、aq.アンモニア(100.0mL)を室温で加え、次に反応混合物を、50℃で16h加熱した。反応混合物を室温に冷却し、減圧下で濃縮した;収量:3.27g(82%)のオフホワイト固体。
A22.1(0.85g;7.38mmol)をo−キシレン(20.0mL)に懸濁させた懸濁液を、115℃に加熱し、アンモニアガスを、反応混合物中にこの温度で5hバブリングした。反応混合物を室温に冷却し、アンモニアを窒素でパージすることにより除去し、反応混合物を次に減圧下で濃縮した。残留物を乾燥し(0.30g;オフホワイト固体)、さらに精製せずに次のステップのために使用した。
3H−イソベンゾフラン−1−オン(10.00g;73.06mmol)、1−ブロモ−ピロリジン−2,5−ジオン(13.79g;76.72mmol)および過酸化ジベンゾイル(1.05g;3.65mmol)の混合物を、テトラクロロ−メタン(100.0mL)中で窒素雰囲気下で3h還流させた。反応混合物を蒸発させ、残留物をクロマトグラフィーによって精製した;収量:12.04g(77%)の無色固体;LC/MS(A)、Rt:2.01min;(M+H)212.9/214.9。
A25.1(1.26g;5.929mmol)およびトリフェニル−ホスファン(1.57g;5.929mmol)に、アセトニトリル(10.0mL)を加え、混合物を90℃で3h撹拌した。反応混合物を室温に冷却し、蒸発乾固させた。残留物をジエチルエーテルで粉末にし、ろ過し、ジエチルエーテルで洗浄し、真空中で乾燥した;収量:2.71g(96%)の無色固体;LC/MS(A)、Rt:1.71min;(M+H)395.1。
A25.2(2.71g;5.736mmol)を、ジクロロメタン(40.0mL)に懸濁させた。攪拌しながら、4−オキソ−酪酸メチルエステル(0.67mL;5.736mmol)をアルゴンの下で加え、続いてトリエチルアミン(874.6μL;6.309mmol)を滴加した。混合物を、室温で14h撹拌した。反応混合物をジクロロメタンで希釈し、水で2回洗浄し、硫酸ナトリウムで乾燥し、吸引によってろ過し、蒸発乾固させた。固体残留物をMTBエーテル中で粉末にし、吸引によってろ過して、MTBエーテルで洗浄した。濾液を蒸発乾固させ、残留物(1.04g、黄色固体)をさらに精製せずに次のステップにおいて使用した。
A25.3(1.633g;4.486mmol)をエタノール(20.0mL)に溶解し、0〜5℃に冷却した。水酸化ヒドラジニウム(0.44mL;8.973mmol)を5minの期間にわたって滴加し、混合物を0〜5℃で1h撹拌した。混合物を室温に加温し、1h撹拌し、蒸発乾固させた。油状残留物を酢酸エチルに溶解し、水およびブラインで洗浄し、硫酸ナトリウムで乾燥し、吸引によってろ過し、蒸発乾固させた。油状残留物を、クロマトグラフィーによって精製した。合わせた画分を蒸発させて水性残留物とし、それを飽和NaHCO3溶液で塩基性にし、酢酸エチルで3回抽出した。合わせた有機層を、ブラインで洗浄し、硫酸ナトリウムで乾燥し、ろ過し、蒸発乾固させた。残留物をMTBエーテルで粉末にし、吸引によってろ過し、少量のMTBエーテルで洗浄し、乾燥した;収量:0.54g(49%)の無色固体;LC/MS(A)、Rt:1.61min;(M+H)247.1。
A25.4(500.0mg;2.016mmol)を、アセトニトリル(5.0mL)に懸濁させた。オキシ塩化リン(0.37mL;4.032mmol)をアルゴン雰囲気下で加え、混合物を50℃に14h撹拌した。反応混合物を氷水(50mL)で反応停止し、酢酸エチルで3回抽出した。合わせた有機層を、飽和NaHCO3溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥し、吸引によってろ過し、蒸発乾固させた;収量:455mg(85%)の茶色固体;LC/MS(A)、Rt:1.87min;(M+H)265.1/267.0。
A25.5(100.0mg;0.378mmol)およびトリメチルアミン(63.0μL;0.453mmol)を、THF(10.0mL)に溶解し、室温および常圧でPd−C(5%)で水素化した。反応混合物を吸引によってろ過し、残留物をTHFおよびメタノールで洗浄した。濾液を蒸発乾固させ、さらに精製せずに次のステップにおいて使用した。
3−(2−ブロモ−エチル)−ベンゾ[d]イソオキサゾール(2.50g;10.95mmol)をDMF(100.0mL)に溶解した溶液に、シアン化ナトリウム(1.07g;21.90mmol)を室温で加え、反応混合物を、70℃で18h撹拌した。反応混合物を酢酸エチルで希釈し、水およびブラインで洗浄し、硫酸ナトリウムで乾燥し、蒸発乾固させた。粗生成物を、フラッシュカラムクロマトグラフィーによって精製した:収量:1.17g(61%);LC/MS(F)、Rt:2.37min;(M+H)173.0。
水酸化カリウム(16.77g;269.086mmol)を水(94mL)に溶解した溶液に、エタノール(24mL)に溶解したA26.1(1.17g;6.73mmol)を、0℃で窒素雰囲気下で滴加した。反応混合物を、75℃で16h加熱した。反応の完了の後、混合物を減圧下で濃縮し、濃HClで酸性化し、沈殿した生成物を吸引によってろ過し、乾燥ヘキサンで洗浄し、乾燥した;収量:0.92g(71%);LC/MS(F)、Rt:2.17min;(M+H)192.0。
3−ベンゾ[d]イソオキサゾール3−イル−プロピオン酸(0.92g;4.764mmol)をTHF(18mL)に溶解した溶液に、ボランジメチルスルフィド(2.44mL;23.820mmol)を、窒素雰囲気下で0℃で滴加した。反応混合物を、室温に徐々に加温し、18h撹拌した。反応混合物を0℃で5minメタノール(10mL)で反応停止し、次に70℃で2h加熱した。反応混合物を減圧下で濃縮し、残留物をジクロロメタンに溶解し、1M炭酸ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥し、蒸発乾固させた;収量:0.47g(55%);LC/MS(F)、Rt:2.15min;(M+H)178.0。
A26.3(0.47g;2.626mmol)をベンゼン(19mL)に溶解した溶液に、三臭化リン(0.50ml;5.252mmol)を、0℃で窒素雰囲気下で滴加した。反応混合物を、70℃で18h加熱し、室温に冷却し、減圧下で濃縮した。粗生成物を、ジクロロメタンで希釈し、10%重炭酸ナトリウム溶液およびブラインで洗浄し、硫酸ナトリウムで乾燥し、蒸発乾固させた。粗生成物を、カラムクロマトグラフィーによって精製した;収量:0.32g(50%);LC/MS(F)、Rt:2.92min;(M+H)240.0/242.0。
A26.4(0.32g;1.319mmol)をDMF(13mL)に溶解した溶液に、シアン化ナトリウム(0.13g;2.639mmol)を、室温で加え、混合物を、この温度で18h撹拌した。反応混合物を、酢酸エチルで希釈し、水およびブラインで洗浄し、硫酸ナトリウムで乾燥し、ろ過し、蒸発乾固させた。粗生成物を、フラッシュカラムクロマトグラフィーによって精製した。収量:0.24g(97%);LC/MS(F)、Rt:2.50min;(M+H)187.0。
5−ブロモ−1−メチル−1H−ピラゾール−4−カルボニトリル(1.50g;8.06mmol)をジオキサン(30.00mL)に溶解した撹拌した溶液に、ヘキサ−5−イン酸メチルエステル(1.53g;12.10mmol)、エチル−ジイソプロピル−アミン(4.26mL;24.19mmol)、1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)、ジクロロメタンとの錯体(0.68g;0.81mmol)およびヨウ化銅(0.16g;0.81mmol)を加えた。反応混合物を、100℃で16h撹拌し、室温に冷却し、セライトを通してろ過した。濾液を真空の下で濃縮し、残留物をカラムクロマトグラフィー(ヘキサン中の15〜25%酢酸エチル)によって精製した;収量:0.60g(27%);LC/MS(F)、Rt:2.48min;(M+H)232.0。
A27.1(150.00mg;0.65mmol)を硫酸(1.50mL)に溶解した溶液を、周囲温度で12h撹拌し、氷水中に注ぎ、ジクロロメタンで抽出した。合わせた有機層を、無水硫酸ナトリウムで乾燥し、ろ過し、真空の下で濃縮した。残留物(160mg)は、メチルエステルおよび酸の混合物であり、さらに精製せずに次のステップにおいて使用した。
ピペリジン−1,4−ジカルボン酸モノ−tert−ブチルエステル(25.00g、107.72mmol)をDMF(250mL)に溶解した溶液に、N,N−ジイソプロピルエチルアミン(57.01mL、323.16mmol)、1−ヒドロキシベンゾトリアゾール水和物(1.67g、10.77mmol)、(3−ジメチルアミノ−プロピル)−エチル−カルボジイミド塩酸塩(25.03g、129.27mmol)を加え、続いてO,N−ジメチル−ヒドロキシルアミン塩酸塩(11.68g、118.49mmol)を窒素雰囲気下で0℃で少量に分割して加える。反応混合物を、室温で18h撹拌する。反応の完了の後、溶媒を減圧下で蒸発させる。残留物を、酢酸エチル(300mL)に溶解し、10%重炭酸ナトリウム(2×200mL)、0.5N HCl(2×100mL)、水(200mL)およびブライン(200mL)で洗浄する。有機層を無水Na2SO4で乾燥し、真空の下で蒸発させて、4−(メトキシ−メチル−カルバモイル)−ピペリジン−1−カルボン酸tert−ブチルエステルを無色液体として得る;
THF(40mL)に溶解したヨウ素(0.93mg)および5mLの4−ブロモ−2−メチルアニソール(5.96g、29.06mmol)を、削り屑状マグネシウム(0.72g、29.06mmol)を乾燥THF(40mL)に懸濁させた懸濁液に、窒素雰囲気下で加えた。混合物を、室温で15min撹拌し、次に50℃に加温した。混合物を室温に冷却し、4−ブロモ−2−メチルアニソールをTHFに溶解した残りの溶液を20minの期間の間滴加した。混合物を室温でさらに2h撹拌して、マグネシウムの溶解を完了させた。このグリニャール試薬溶液を、4−(メトキシ−メチル−カルバモイル)−ピペリジン−1−カルボン酸tert−ブチルエステル(4.00g、14.53mmol)をTHF(40.00mL)に溶解した溶液に、−78℃で滴加した。反応混合物を、室温で15h放置して撹拌した。
4−(4−メトキシ−3−メチル−ベンゾイル)−ピペリジン−1−カルボン酸tert−ブチルエステル(1.50g、4.36mmol)をジオキサン/HCl(3M、14.53mL、43.60mmol)に溶解した溶液を、窒素雰囲気下で室温で6h撹拌した。溶媒を減圧下で蒸発乾固させて、(4−メトキシ−3−メチル−フェニル)−ピペリジン−4−イル−メタノン塩酸塩を無色固体として得た。
1H NMR (400 MHz, DMSO-d6): δ 9.25 (brs, 1H), 8.92 (brs, 1H), 7.90 (dd, J = 2.2, 8.6 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 3.87 (s, 3H), 3.75-3.67 (m, 1H), 3.29-3.25 (m, 2H), 3.06-2.97 (m, 2H), 2.19 (s, 3H), 1.89-1.86 (m, 2H), 1.81-1.78 (m, 2H); LC/MS (B): 234.3 (M+H), Rt: 2.65 min.
5−ブロモ−2−メトキシ−ピリジン(6.60g;34.40mmol)をTHF(132mL)に溶解した溶液に、窒素雰囲気下で、n−ブチルリチウム(ヘキサン中1.6M)(25.80mL;41.28mmol)を、−78℃で滴加し、同じ温度で1h撹拌した。4−(メトキシ−メチル−カルバモイル)−ピペリジン−1−カルボン酸tert−ブチルエステル(10.52g;37.84mmol)をTHF(25mL)に溶解した溶液を、−78℃で滴加し、−78℃で4h撹拌した。反応混合物を、次にゆっくり放置して室温に到達させ、12h撹拌した。反応混合物を、飽和NH4Cl(250mL)によって反応停止し、酢酸エチル(2×300mL)で抽出した。合わせた有機層を、水(200mL)、ブライン(200mL)で洗浄し、無水硫酸ナトリウムで乾燥し、濃縮した。粗生成物を、シリカゲル(60〜120)および石油エーテル/酢酸エチルを勾配溶離として使用してカラムクロマトグラフィーによって精製して、4−(6−メトキシ−ピリジン−3−カルボニル)−ピペリジン−1−カルボン酸tert−ブチルエステル(5.00g;44.5%)を淡黄色油として得た;
LC/MS (B): 265 (M+H; BOC-cleaved mass), Rt: 4.64 min.
Boc切断によって、表題化合物が得られた;無色固体;LC/MS (A):194.2(M+H)、Rt:0.34/0.47min。
2−アミノ−ニコチノニトリル(0.50g;4.11mmol)を酢酸(10mL)に溶解した溶液に、炭酸ナトリウム(0.48g;4.52mmol)を0℃で加え、続いて臭素(0.74g;4.52mmol)を滴加した。反応混合物を、周囲温度で2h撹拌した。溶媒を真空の下で蒸発させ、残留物を水(50mL)に懸濁させ、吸引によってろ過し、乾燥して、表題化合物(0.60g;73%)を得た。生成物を、さらに精製せずに次のステップにおいて使用した;1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.26 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 7.13 (brs, 2H); LC/MS (B), Rt: 2.59 min; (M+2H) 200.
2−アミノ−5−ブロモ−ニコチノニトリル(0.60g;3.02mmol)をジオキサン(24mL)および水(6mL)に溶解した溶液に、4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸tert−ブチルエステル(1.04g;3.32mmol)およびNa2CO3(0.98g;9.05mmol)を加え、混合物を30min脱気した。1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)ジクロロメタン錯体(0.13g;0.15mmol)を加え、反応混合物を90℃に10h加熱した。反応混合物を周囲温度に冷却し、セライトを通してろ過し、溶媒を減圧下で濃縮した。残留物を、石油エーテルおよび酢酸エチル(5:5)を使用してフラッシュカラムクロマトグラフィーによって精製して、表題化合物(450.0mg;50%)を淡黄色固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.32 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 6.92 (s, 2H), 6.08 (s, 1H), 3.94 (s, 2H), 3.49 (t, J = 5.6 Hz, 2H), 2.37 (d, J = 1.5 Hz, 2H), 1.40 (s, 9H); LC/MS (B), Rt: 3.50 min; (M+H) 301.2.
6−アミノ−5−シアノ−3’,6’−ジヒドロ−2’H−[3,4’]ビピリジニル−1’−カルボン酸tert−ブチルエステル(5.00g;16.63mmol)を、メタノール(150mL)に溶解し、炭素上のパラジウム(10% w/w)(1.77g;1.66mmol)で15h水素化した。反応混合物を濃縮し、残留物をさらに精製せずに次のステップにおいて使用した;収量:4.50g(87%)の淡黄色固体(純度:97%);1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.11 (d, J = 2.4 Hz, 2H), 7.76 (d, J = 2.4 Hz, 2H), 4.05-4.01 (m, 2H), 2.85-2.55 (m, 2H), 2.59-2.53 (m, 1H), 1.67 (d, J = 12.2 Hz, 2H), 1.47-1.38 (m, 11H); LC/MS (B), Rt: 3.27 min; (M+H-t-Butyl) 247.
6−アミノ−5−シアノ−3’,4’,5’,6’−テトラヒドロ−2’H−[3,4’]ビピリジニル−1’−カルボン酸tert−ブチルエステル(4.50g;14.43mmol)を1,4−ジオキサン(45mL)に溶解した溶液に、HCl(1,4−ジオキサン中4M)(10.82ml;43.30mmol)を0℃で加え、反応を、室温で2h撹拌した。溶媒を減圧下で除去して、表題化合物(3.50g;85%)を無色固体として得た:1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.22-8.95 (m, 2H), 8.15-7.98 (m, 5H), 3.38-3.29 (m, 2H), 2.95-2.87 (m, 2H), 2.85-2.70 (m, 1H), 1.92-1.81 (m, 2H), 1.80-1.58 (m, 2H); LC/MS (B), Rt: 2.13 min; (M+H) 203.2.
(2−フルオロ−3−ピリジル)ボロン酸(6.00g;40.45mmol)を1,4−ジオキサン(108mL)および水(12mL)に溶解した溶液に、2−ブロモ−ピリミジン(6.56g;40.45mmol)およびNa2CO3(13.12g;121.36mmol)を加え、溶液を30min脱気した。1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)ジクロロメタン錯体(1.70g;2.02mmol)を、次に加え、反応混合物を90℃に6h加熱した。反応混合物を室温で冷却し、セライトを通してろ過し、溶媒を減圧下で濃縮した。残留物を、石油エーテル−酢酸エチル(8:2)を使用してフラッシュカラムクロマトグラフィーによって精製して、表題化合物(3.00g;42%)をオフホワイト固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.99 (d, J = 4.9 Hz, 2H), 8.57 (t, J = 9.8 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.57-7.52 (m, 2H); LC/MS (B), Rt: 1.77 min; (M+H) 176.
2−(2−フルオロ−ピリジン−3−イル)−ピリミジン(11.0g;62.55mmol)をTHF(110mL)に溶解した溶液に、アンモニア(THF中6M)(330mL)を−20℃で加えた。反応混合物を、オートクレーブ中で70℃に40h加熱した。反応を室温に冷却し、溶媒を減圧下で除去した。残留物を、シリカゲル(230〜400)および石油エーテル−酢酸エチル(2:8)を溶離剤として使用してカラムクロマトグラフィーによって精製して、表題化合物(6.50g;60%)をオフホワイト固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.91 (d, J = 4.9 Hz, 2H), 8.64 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 6.6 Hz, 1H), 7.40 (t, J = 4.8 Hz, 1H), 6.70-6.67 (m, 1H); LC/MS (B), Rt: 1.49 min; (M+H) 173.
3−ピリミジン−2−イル−ピリジン−2−イルアミン(6.30g;36.22mmol)をアセトニトリル(315mL)に溶解した溶液に、NBS(7.89g;43.47mmol)を、0℃で5minにわたって窒素雰囲気下で加えた。反応物を、室温で2h放置して攪拌した。反応混合物を、減圧下で50mLに濃縮し、続いて熱ろ過した。残留物を石油エーテルで洗浄して、5−ブロモ−3−ピリミジン−2−イル−ピリジン−2−イルアミン(8.50g;93%)を黄色固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.93 (d, J = 4.9 Hz, 2H), 8.72 (s, 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.46 (t, J = 4.9 Hz, 1H); LC/MS (B), Rt: 2.25 min; (M+2H) 253/255.
5−ブロモ−3−ピリミジン−2−イル−ピリジン−2−イルアミン(4.80g;19.03mmol)を1,4−ジオキサン(192mL)および水(48mL)に溶解した溶液に、4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−3,6−ジヒドロ−2H−ピリジン−1−カルボン酸tert−ブチルエステル(6.54g;20.94mmol)およびNa2CO3(6.18g;57.10mmol)を加え、溶液を30min脱気した。1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)ジクロロメタン錯体(0.80g;0.95mmol)を次に反応混合物に加え、90℃に10h加熱した。反応混合物を室温に冷却し、セライトを通してろ過し、溶媒を減圧下で濃縮した。残留物を、石油エーテル−酢酸エチル(5:5)を使用してフラッシュカラムクロマトグラフィーによって精製して、表題化合物(6.20g;90%)を淡黄色固体として得た;1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.93 (s, 2H), 8.70 (s, 1H), 8.27 (s, 1H), 7.94 (bs, 2H), 7.42 (t, J = 4.8 Hz, 1H), 6.06 (s, 1H), 3.98-3.98 (m, 2H), 3.56-3.53 (m, 2H), 2.49-2.48 (m, 2H), 1.42 (s, 9H); LC/MS (B), Rt: 3.52 min; (M+H) 354.2.
6−アミノ−5−ピリミジン−2−イル−3’,6’−ジヒドロ−2’H−[3,4’]ビピリジニル−1’−カルボン酸tert−ブチルエステル(1.20g;3.31mmol)を、メタノール(36mL)に溶解し、炭素上のパラジウム(10% w/w)(0.24g;0.23mmol)で室温で10h水素化した。反応混合物を蒸発乾固させて、表題化合物(1.00g;77%)を淡黄色固体として得た;LC/MS(B)、Rt:3.51min;(M+H)356.3。
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.29 (brs, 1H), 8.98 (brs, 1H), 7.89-7.81 (m, 2H), 7.32-7.28 (t, 16.8 Hz, 1H), 3.92 (s, 3H), 3.79-3.67 (m, 1H), 3.31-3.22 (m, 2H), 3.06-2.95 (m, 2H), 1.95-1.84 (m, 2H), 1.83-1.70 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.29 (brs, 1H), 8.97 (brs, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 3.80-3.70 (m, 1H), 3.35-3.23 (m, 2H), 3.10-2.98 (m, 2H), 2.39 (s, 3H), 1.98-1.87 (m, 2H), 1.85-1.73 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.02 (brs, 1H), 8.71 (brs, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 5.20 (s, 1H), 3.79-3.69 (m, 1H), 3.35-3.24 (m, 2H), 3.08-2.96 (m, 2H), 1.94-1.88 (m, 2H), 1.80-1.68 (m, 2H), 1.43 (s, 6H).
1H NMR (400 MHz, DMSO-d6) δ [ppm] 9.27 (brs, 1H), 8.75 (brs, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 4.20-4.11 (m, 2H), 3.31-3.22 (m, 3H), 2.99-2.88 (m, 2H), 1.93-1.68 (m, 4H), 1.42-1.31 (m, 3H).
3−{4−[4−(4−メトキシ−ベンゾイル)−ピペリジン−1−イル]−4−オキソ−ブチル}−6−メチル−2H−ピロロ[1,2−a]ピラジン−1−オン(「C1」)
1H (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.99 (dd, J = 1.4, 7.8 Hz, 2H), 7.75 (d, J = 1.0 Hz, 1H), 7.62-7.56 (m, 3H), 4.30 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 13.7 Hz, 1H), 3.43-3.34 (m, 1H), 3.28-3.21 (m, 1H), 2.91-2.82 (m, 1H), 2.70-2.54 (m, 2H), 2.48-2.41 (m, 2H), 2.28 (s, 3H), 2.14-2.05 (m, 2H), 2.02-1.93 (m, 2H), 1.81-1.71 (m, 1H), 1.68-1.54 (m, 1H); LC/MS (B), Rt: 3.50; (M+H) 464.2.
6−{4−[4−(6−メトキシ−ピリジン−3−カルボニル)−ピペリジン−1−イル]−4−オキソ−ブチル}−1−メチル−1,5−ジヒドロ−ピラゾロ[3,4−d]ピリミジン−4−オン(「C43」)
1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.37 (s, 1H), 6.68 (s, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.88 (s, 3H), 3.21 (tt, J = 11.3, 3.6 Hz, 1H), 3.15-3.05 (m, 1H), 2.67 (t, J = 12.2 Hz, 1H), 2.43 (t, J = 7.4 Hz, 2H), 2.38-2.32 (m, 2H), 2.31 (s, 3H), 1.88-1.71 (m, 5H), 1.49 (m, 1H), 1.35 (m, 1H); LC/MS (C), Rt: 2.03 min; (M+H) 411.1.
1H NMR (400 MHz, DMSO-d6) δ12.35 (s, 1H), 7.99 (dd, J = 1.4, 7.8 Hz, 2H), 7.75 (d, J = 1.0 Hz, 1H), 7.62-7.56 (m, 3H), 4.30 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 13.7 Hz, 1H), 3.43-3.34 (m, 1H), 3.28-3.21 (m, 1H), 2.91-2.82 (m, 1H), 2.70-2.54 (m, 2H), 2.48-2.41 (m, 2H), 2.28 (s, 3H), 2.14-2.05 (m, 2H), 2.02-1.93 (m, 2H), 1.81-1.71 (m, 1H), 1.68-1.54 (m, 1H); LC/MS (B), Rt: 3.82 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ12.33 (s, 1H), 8.07 (dd, J = 3.4, 6.8 Hz, 2H), 7.77 (s, 1H), 7.36 (t, J = 8.8 Hz, 2H), 4.48-4.33 (m, 1H), 3.99-3.82 (m, 1H), 3.71-3.61 (m, 1H), 3.22-3.08 (m, 1H), 2.72-2.61 (m, 3H), 2.48-2.39 (m, 2H), 2.27 (s, 3H), 2.00-1.89 (m, 2H), 1.81-1.70 (m, 2H), 1.58-1.41 (m,1H), 1.39-1.29 (m, 1H); LC/MS (B), Rt: 3.88 min; (M+H) 442.3.
1H NMR (400 MHz, DMSO-d6) δ12.35 (s, 1H), 7.88 (dd, J = 2.0, 8.4 Hz, 1H), 7.80-7.77 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 4.48-4.32 (m, 1H), 3.96-3.89 (m, 1H), 3.86 (s, 3H), 3.69-3.59 (m, 1H), 3.28-3.04 (m, 1H), 2.79-2.61 (m, 3H), 2.47-2.33 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H), 2.01-1.90 (m, 2H), 1.82-1.71 (m, 2H), 1.57-1.43 (m,1H), 1.38-1.28 (m, 1H); LC/MS (B), Rt: 3.88 min; (M+H) 442.3.
1H NMR (400 MHz, DMSO-d6) δ12.35 (bs, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.77 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 5.30 (bs, 1H), 4.44-4.33 (m, 1H), 3.98-3.85 (m, 1H), 3.69-3.61 (m, 1H), 3.29-3.11 (m, 1H), 2.79-2.61 (m, 3H), 2.48-2.31 (m, 2H), 2.28 (s, 3H), 2.00-1.91 (m, 2H), 1.81-1.73 (m, 2H), 1.55-1.45 (m, 1H), 1.43 (s, 6H), 1.38-1.31 (m, 1H); LC/MS (B), Rt: 3.35 min; (M+H) 482.2.
1H NMR (400 MHz, DMSO-d6) δ11.02 (brs, 1H), 7.96 (s, 1H), 7.89-7.86 (m, 1H), 7.83-7.80 (m, 1H), 7.29 (t, J = 8.4 Hz, 1H), 4.40-4.37 (m, 1H), 3.92-3.86 (m, 7H), 3.69-3.63 (m, 1H), 3.19-3.13 (m, 1H), 2.75-2.65 (m, 3H), 2.40-2.38 (m, 2H), 1.98-1.90 (m, 2H), 1.77-1.74 (m, 2H), 1.52-1.43 (m, 1H), 1.35-1.27 (m, 1H); LC/MS (B), Rt: 3.39 min; (M+H) 456.2.
1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.97-7.92 (m, 3H), 7.61 (d, J = 8.4 Hz, 2H), 5.18 (s, 1H), 4.48 (d, J = 12.9 Hz, 1H), 3.92-3.84 (m, 4H), 3.71-3.63 (m, 1H), 3.17 (t, J = 12.0 Hz, 1H), 2.76-2.62 (m, 3H), 2.42-2.36 (m, 2H), 1.98-1.89 (m, 2H), 1.80-1.71 (m, 2H), 1.55-1.45 (m, 1H), 1.43 (s, 6H), 1.35-1.25 (m, 1H); LC/MS (B), Rt: 2.95 min; (M+H) 466.2.
1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.90 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 2.4, 8.8 Hz, 1H), 7.77 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.44-4.35 (m, 1H), 3.94 (s, 3H), 3.93-3.89 (m, 1H), 3.69-3.60 (m, 1H), 3.22-3.01 (m, 1H), 2.79-2.61 (m, 3H), 2.48-2.33 (m, 2H), 2.28 (s, 3H), 2.01-1.89 (m, 2H), 1.79-1.62 (m, 2H), 1.51-1.42 (m, 1H), 1.40-1.23 (m, 1H); LC/MS (B), Rt: 3.39 min; (M+H) 455.3.
1H NMR (400 MHz, DMSO-d6) δ8.89 (d, J = 4.8 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.60 (bs, 2H), 7.39 (t, J = 4.8 Hz, 1H), 4.59-4.51 (m, 1H), 4.08-3.94 (m, 1H), 3.22-3.05 (m, 1H), 2.78-2.62 (m, 4H), 2.48-2.39 (m, 2H), 2.27 (s, 3H), 2.05-1.91 (m, 2H), 1.85-1.74 (m, 2H), 1.61-1.52 (m, 1H), 1.48-1.35 (m, 1H); LC/MS (B), Rt: 2.66 min; (M+H) 490.2.
1H NMR (400 MHz, DMSO-d6) δ10.63 (s, 1H), 8.42 (s, 1H), 8.18-8.15 (m, 1H), 7.96-7.93 (m, 1H), 7.67 (s, 1H), 7.22 (s, 1H), 4.45-4.33 (m, 1H), 3.96-3.80 (m, 4H), 3.28-3.16 (m, 1H), 3.16-3.04 (m, 1H), 2.72-2.60 (m, 1H), 2.42-2.32 (m, 4H), 1.86-1.71 (m, 4H), 1.56-1.41 (m, 1H), 1.41-1.27 (m, 1H); LC/MS (A), Rt: 0.34 min; (M+H) 397.2.
1H NMR (500 MHz, DMSO-d6) δ11.10 (s, 1H), 8.03-7.97 (m, 2H), 7.25-7.18 (m, 1H), 7.11 (s, 1H), 7.09-7.01 (m, 2H), 4.45-4.36 (m, 1H), 3.95-3.81 (m, 4H), 3.66 (tt, J = 11.2, 3.4 Hz, 1H), 3.23-3.13 (m, 1H), 2.80-2.71 (m, 1H), 2.46 (t, J = 7.4 Hz, 2H), 2.42-2.32 (m, 5H), 1.86 (q, J = 7.3 Hz, 2H), 1.82-1.73 (m, 2H), 1.59-1.42 (m, 1H), 1.42-1.28 (m, 1H); LC/MS (A), Rt: 1.62 min; (M+H) 437.2.
1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.38 (dd, J = 3.3, 1.9 Hz, 1H), 7.05 (s, 1H), 6.62 (d, J = 1.8 Hz, 1H), 4.40 (d, J = 13.0 Hz, 1H), 3.92-3.84 (m, 4H), 3.22 (tt, J = 11.4, 3.7 Hz, 1H), 3.10 (t, J = 12.1 Hz, 1H), 2.67 (t, J = 11.8 Hz, 1H), 2.43-2.27 (m, 4H), 1.87 -1.70 (m, 4H), 1.55-1.42 (m, 1H), 1.391.29 (m, 1H); LC/MS (E), Rt: 1.17 min; (M+H) 414.1.
1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.42 (s, 1H), 7.96-7.94 (m, 1H), 6.90 (s, 1H), 6.74 (d, J = 3.8 Hz, 1H), 6.29-6.25 (m, 1H), 4.40 (d, J = 13.2 Hz, 1H), 3.93-3.84 (m, 4H), 3.27-3.17 (m, 1H), 3.16-3.06 (m, 1H), 2.73-2.63 (m, 1H), 2.42-2.31 (m, 7H), 1.87-1.72 (m, 4H), 1.55-1.28 (m, 2H); LC/MS (A), Rt: 1.60 min; (M+H) 410.2.
1H NMR (400 MHz, DMSO-d6) δ10.55 (s, 1H), 8.42 (s, 1H), 7.97-7.93 (m, 1H), 7.57 (s, 1H), 7.04 (s, 1H), 4.44-4.35 (m, 1H), 3.94-3.82 (m, 4H), 3.27-3.16 (m, 1H), 3.15-3.05 (m, 1H), 2.72-2.62 (m, 1H), 2.48 (s, 3H), 2.42-2.31 (m, 4H), 1.88-1.71 (m, 4H), 1.56-1.27 (m, 2H); LC/MS (A), Rt: 1.16 min; (M+H) 411.1.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 4.2 Hz, 1H), 6.30 (d, J = 3.8 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 3.98-3.85 (m, 1H), 3.84 (s, 3H), 3.69-3.59 (m, 1H), 3.38-3.10 (m, 1H), 2.79-2.66 (m, 1H), 2.59-2.50 (m, 2H), 2.49-2.43 (m, 2H), 2.42-2.31 (m, 3H), 2.02-1.90 (m, 2H), 1.89-1.71 (m, 2H), 1.58-1.32 (m, 1H), 1.31-0.82 (m, 1H); LC/MS (B), Rt: 4.0 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.81 (dd, J = 2.0, 12.3 Hz, 1H), 7.29 (t, J = 8.6 Hz, 1H), 6.75 (d, J = 4.2 Hz, 1H), 6.31-6.28 (m, 1H), 4.58-4.29 (m, 1H), 3.92 (s, 3H), 3.90-3.83 (m, 1H), 3.71-3.60 (m, 1H), 3.38-3.11 (m, 1H), 2.78-2.61 (m, 1H), 2.59-2.50 (m, 2H), 2.49-2.39 (m, 2H), 2.36 (s, 3H), 2.02-1.82 (m, 2H), 1.79-1.71 (m, 2H), 1.50-1.42 (m, 1H), 1.39-1.19 (m, 1H); LC/MS (B), Rt: 4.1 min; (M+H) 455.3.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.06-7.92 (m, 2H), 7.68-7.51 (m, 3H), 6.75 (d, J = 4.4 Hz, 1H), 6.29 (dd, J = 0.4, 4.2 Hz, 1H), 4.29 (d, J = 13.5 Hz, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.41-3.30 (m, 1H), 3.29-3.11 (m, 1H), 2.86-2.79 (m, 1H), 2.59-2.50 (m, 2H), 2.49-2.40 (m, 2H), 2.35 (s, 3H), 2.18-2.00 (m, 2H), 1.97-1.94 (m, 2H), 1.93-1.91 (m, 1H), 1.89-1.72 (m, 1H); LC/MS (B), Rt: 3.87 min; (M+H) 447.3.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.79-7.70 (m, 2H), 7.17-7.13 (m, 2H), 6.75 (d, J = 4.2 Hz, 1H), 6.29 (dd, J = 0.7, 4.2 Hz, 1H), 4.79-4.70 (m, 1H), 3.91-3.80 (m, 1H), 3.78-3.61 (m, 1H), 3.35 (s, 3H), 3.38-3.20 (m, 1H), 3.19-3.11 (m, 1H), 2.59-2.50 (m, 2H), 2.49-2.39 (m, 2H), 2.36 (s, 3H), 2.09-1.81 (m, 1H), 1.59-1.50 (m, 1H), 1.49-1.18 (m, 1H); LC/MS (B), Rt: 4.16 min; (M+H) 420.2.
1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.12-7.95 (m, 2H), 7.38-7.34 (m, 2H), 6.75 (d, J = 4.2 Hz, 1H), 6.31-6.28 (m, 1H), 4.38 (d, J = 12.8 Hz, 1H), 3.90 (d, J = 13.3 Hz, 1H), 3.74-3.63 (m, 1H), 3.19-3.13 (m, 1H), 2.76-2.68 (m, 1H), 2.55-2.51 (m, 2H), 2.45-2.37 (m, 2H), 2.35 (s, 3H), 1.94-1.86 (m, 2H), 1.82-1.73 (m, 2H), 1.53-1.42 (m, 1H), 1.38-1.26 (m, 1H); LC/MS (B), Rt: 4.13 min; (M+H) 425.2.
1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 4.2 Hz, 1H), 6.30 (d, J = 4.2 Hz, 1H), 4.39 (d, J = 12.5 Hz, 1H), 3.92-3.86 (m, 4H), 3.67-3.61 (m, 1H), 3.22-3.13 (m, 1H), 2.76-2.64 (m, 1H), 2.55-2.51 (m, 2H), 2.49-2.39 (m, 2H), 2.36 (s, 3H), 2.19 (s, 3H), 1.97-1.86 (m, 2H), 1.79-1.72 (m, 2H), 1.49-1.41 (m, 1H), 1.36-1.26 (m, 1H); LC/MS (B), Rt: 4.45 min; (M+H) 451.2.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 4.2 Hz, 1H), 6.29 (d, J = 4.1 Hz, 1H), 5.18 (s, 1H), 4.38 (d, J = 13.0 Hz, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.72-3.64 (m, 1H), 3.17-3.14 (m, 1H), 2.73 (t, J = 12.4 Hz, 1H), 2.54-2.51 (m, 2H), 2.47-2.38 (m, 2H), 2.36 (s, 3H), 1.96-1.86 (m, 2H), 1.80-1.71 (m, 2H), 1.54-1.45 (m, 1H), 1.43 (s, 6H), 1.34-1.24 (m, 1H); LC/MS (B), Rt: 3.64 min; (M+H) 465.2.
1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.98 (d, J = 7.0 Hz, 2H), 7.63-7.62 (m, 1H), 7.04 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 2.1 Hz, 1H), 4.38 (d, J = 13.5 Hz, 1H), 3.92-3.84 (m, 1H), 3.81 (s, 3H), 3.67-3.61 (m, 1H), 3.18-3.12 (m, 1H), 2.74-2.68 (m, 1H), 2.53-2.51 (m, 2H), 2.41-2.36 (m, 2H), 1.92-1.86 (m, 2H), 1.80-1.70 (m, 2H), 1.52-1.44 (m, 1H), 1.36-1.28 (m, 1H); LC/MS (B), Rt: 3.97 min; (M+H) 441.2.
1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.7 Hz, 1H), 7.83-7.78 (m, 1H), 7.62 (s, 1H), 7.29 (t, J = 8.6 Hz, 1H), 6.68 (s, 1H), 4.37 (d, J = 13.1 Hz, 1H), 3.93-3.86 (m, 4H), 3.69-3.62 (m, 1H), 3.15 (t, J = 12.0 Hz, 1H), 2.74-2.64 (m, 1H), 2.55-2.51 (m, 2H), 2.41-2.34 (m, 2H), 1.92-1.84 (m, 2H), 1.79-1.60 (m, 2H), 1.54-1.42 (m, 1H), 1.36-1.26 (m, 1H); LC/MS (B), Rt: 4.17 min; (M+H) 459.2.
1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.00 (s, 1H), 6.82 (t, J = 4.7 Hz, 1H), 6.22 (t, J = 4.1 Hz, 1H), 4.59-4.34 (m, 1H), 4.06-3.84 (m, 4H), 3.33-3.22 (m, 1H), 3.22-3.08 (m, 1H), 2.82-2.65 (m, 1H), 2.51-2.29 (m, 4H), 1.96-1.75 (m, 4H), 1.65-1.48 (m, 1H), 1.48-1.32 (m, 1H); LC/MS (A), Rt: 1.61 min; (M+H) 414.2.
1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.52 (dd, J = 1.6, 2.6 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 6.80 (dd, J =1.6, 4.3 Hz, 1H), 6.51-6.43 (m, 1H), 4.39 (d, J = 12.4 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.84 (s, 3H), 3.64 (t, J = 11.6 Hz, 1H), 3.16 (t, J = 11.0 Hz, 1H), 2.79-2.62 (m, 1H), 2.60-2.46 (m, 2H), 2.45-2.33 (m, 2H), 1.99-1.81 (m, 2H), 1.78-1.63 (m, 2H), 1.56-1.45 (m, 1H), 1.39-1.22 (m, 1H); LC/MS (B), Rt: 3.71 min; (M+H) 423.3.
1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.95-7.80 (m, 2H), 7.52 (t, J = 2.3 Hz, 1H), 7.29 (t, J = 8.6 Hz, 1H), 6.88-6.81 (m, 1H), 6.48 (dd, J = 2.6, 4.2 Hz, 1H), 4.38 (d, J = 13.1 Hz, 1H), 3.91 (s, 3H), 3.98-3.82 (m, 1H), 3.66 (t, J = 11.7 Hz, 1H), 3.16 (t, J = 12.2 Hz, 1H), 2.78-2.69 (m, 1H), 2.59-2.43 (m, 2H), 2.45-2.33 (m, 2H), 2.01-1.83 (m, 2H), 1.89-1.71 (m, 2H), 1.51-1.42 (m, 1H), 1.39-1.20 (m, 1H); LC/MS (B), Rt: 3.85 min; (M+H) 441.2.
1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.22 (dd, J = 2.4, 8.8 Hz, 1H), 7.52 (dd, J = 1.7, 2.6 Hz, 1H), 6.97-6.92 (m, 1H), 6.82 (dd, J = 1.7, 4.3 Hz, 1H), 6.48 (dd, J = 2.6, 4.3 Hz, 1H), 4.38 (d, J = 12.8 Hz, 1H), 3.94 (s, 3H), 3.92-3.90 (m, 1H), 3.69-3.60 (m, 1H), 3.16 (t, J = 10.9 Hz, 1H), 2.78-2.64 (m, 1H), 2.59-2.45 (m, 2H), 2.43-2.32 (m, 2H), 2.01-1.90 (m, 2H), 1.88-1.73 (m, 2H), 1.55-1.43 (m, 1H), 1.38-1.20 (m, 1H); LC/MS (B), Rt: 3.41 min; (M+H) 424.0.
1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.40 Hz, 1H), 7.52 (dd, J = 1.7, 2.6 Hz, 1H), 6.83 (dd, J = 1.7, 4.3 Hz, 1H), 6.70 (s, 2H), 6.48 (dd, J = 2.6, 4.3 Hz, 1H), 4.50 (d, J = 13.7 Hz, 1H), 3.94 (d, J = 12.6 Hz, 1H), 3.08-2.91 (m, 1H), 2.71-2.46 (m, 3H), 2.45-2.41 (m, 1H), 2.40-2.39 (m, 2H), 1.99-1.83 (m, 2H), 1.70 (t, J = 13.4 Hz, 2H), 1.58-1.42 (m, 1H), 1.47-1.18 (m, 1H); LC/MS (B), Rt: 2.44 min; (M+H) 406.0.
1H NMR (400 MHz, DMSO-d6) δ11.56 (s, 1H), 8.04-7.94 (m, 2H), 7.65-7.54 (m, 3H), 7.50 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 1.7, 4.3 Hz, 1H), 6.46 (dd, J = 2.6, 4.2 Hz, 1H), 4.29 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.4 Hz, 1H), 3.39-3.26 (m, 1H), 3.23-3.19 (m, 1H), 2.86 (t, J = 10.6 Hz, 1H), 2.58-2.45 (m, 2H), 2.43-2.39 (m, 2H), 2.30-1.99 (m, 2H), 1.97-1.84 (m, 2H), 1.80-1.72 (m, 1H), 1.69-1.51 (m, 1H); LC/MS (B), Rt: 3.50 min; (M+H) 433.3.
1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.76 (dd, J = 2.0, 6.8 Hz, 2H), 7.52 (dd, J = 1.7, 2.6 Hz, 1H), 7.19-7.11 (m, 2H), 6.82 (dd, J = 1.6, 4.3 Hz, 1H), 6.48 (dd, J = 2.6, 4.3 Hz, 1H), 4.80-4.71 (m, 1H), 3.91-3.81 (m, 1H), 3.79-3.62 (m, 1H), 3.37-3.23 (m, 1H), 3.22-3.12 (m, 1H), 2.58-2.44 (m, 2H), 2.41 (t, J = 7.3 Hz, 2H), 2.11-1.85 (m, 4H), 1.69-1.53 (m, 1H), 1.51-1.40 (m, 1H); LC/MS (B), Rt: 3.77 min; (M+H) 406.2.
1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.08 (dd, J = 5.6, 8.8 Hz, 2H), 7.52 (s, 1H), 7.36 (t, J = 8.8 Hz, 2H), 6.82 (dd, J = 1.6, 4.3 Hz, 1H), 6.48 (dd, J = 2.6, 4.2 Hz, 1H), 4.38 (d, J = 12.4 Hz, 1H), 3.90 (d, J = 12.3 Hz, 1H), 3.69 (t, J = 11.4 Hz, 1H), 3.16 (t, J = 11.4 Hz, 1H), 2.79-2.69 (m, 1H), 2.58-2.43 (m, 2H), 2.40-2.32 (m, 2H), 1.98-1.83 (m, 2H), 1.79-1.69 (m, 2H), 1.59-1.43 (m, 1H), 1.39-1.29 (m, 1H); LC/MS (B), Rt: 3.83 min; (M+H) 411.2.
1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.89 (dd, J = 2.1, 8.6 Hz, 1H), 7.80 (s, 1H), 7.53 (dd, J = 1.7, 2.6 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.82 (dd, J = 1.6, 4.2 Hz, 1H), 6.48 (dd, J = 2.6, 4.3 Hz, 1H), 4.39 (d, J = 12.8 Hz, 1H), 3.91 (s, 3H), 3.90-3.82 (m, 1H), 3.64 (t, J = 11.2 Hz, 1H), 3.16 (t, J = 13.8 Hz, 1H), 2.72 (t, J = 12.5 Hz, 1H), 2.59-2.45 (m, 2H), 2.44-2.31 (m, 2H), 2.19 (s, 3H), 1.99-1.82 (m, 2H), 1.79-1.69 (m, 2H), 1.58-1.41 (m, 1H), 1.39-1.21 (m, 1H); LC/MS (B), Rt: 4.08 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.52 (dd, J = 1.7, 2.6 Hz, 1H), 6.82 (dd, J = 1.6, 4.3 Hz, 1H), 6.48 (dd, J = 2.6, 4.3 Hz, 1H), 5.18 (s, 1H), 4.38 (d, J = 13.0 Hz, 1H), 3.97-3.88 (m, 1H), 3.78-3.61 (m, 1H), 3.17 (t, J = 11.3 Hz, 1H), 2.73 (t, J = 10.8 Hz, 1H), 2.59-2.42 (m, 2H), 2.40-2.32 (m, 2H), 2.01-1.95 (m, 2H), 1.94-1.88 (m, 2H), 1.86-1.48 (m, 1H), 1.43 (s, 6H), 1.39-1.18 (m, 1H); LC/MS (B), Rt: 3.38 min; (M+H) 451.2.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.64-7.62 (m, 1H), 7.15 (d, J = 9.0 Hz, 2H), 6.70-6.68 (m, 1H), 4.78-4.74 (m, 1H), 3.89-3.82 (m, 1H), 3.74-3.67 (m, 1H), 3.35-3.32 (m, 1H), 3.21-3.16 (m, 1H), 2.55-2.51 (m, 2H), 2.42-2.36 (m, 2H), 1.99-1.74 (m, 4H), 1.64-1.55 (m, 1H), 1.51-1.41 (m, 1H); LC/MS (B), Rt: 4.09 min; (M+H) 424.2.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.12-8.06 (m, 2H), 7.64-7.61 (m, 1H), 7.39-7.34 (m, 2H), 6.68 (s, 1H), 4.38 (d, J = 12.0 Hz, 1H), 3.89 (d, J = 13.1 Hz, 1H), 3.72-3.66 (m, 1H), 3.18-3.11 (m, 1H), 2.75-2.66 (m, 1H), 2.54-2.51 (m, 2H), 2.42-2.36 (m, 2H), 1.94-1.85 (m, 2H), 1.80-1.72 (m, 2H), 1.54-1.46 (m, 1H), 1.37-1.23 (m, 1H); LC/MS (B), Rt: 4.16 min; (M+H) 429.2.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.89 (dd, J = 2.2, 8.6 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.64-7.62 (m, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 4.38 (d, J = 12.5 Hz, 1H), 3.87-3.75 (m, 4H), 3.66-3.61 (m, 1H), 3.19-3.11 (m, 1H), 2.74-2.66 (m, 1H), 2.54-2.51 (m, 2H), 2.41-2.32 (m, 2H), 2.19 (s, 3H), 1.93-1.84 (m, 2H), 1.78-1.71 (m, 2H), 1.52-1.42 (m, 1H), 1.33-1.23 (m, 1H); LC/MS (B), Rt: 4.36 min; (M+H) 455.3.
1H NMR (400 MHz, DMSO-d6) δ 12.01 (s,1H), 8.44 (s, 1H), 7.97-7.95 (m, 2H), 4.38 (d, J = 12.0 Hz, 1H), 3.94-3.86 (m, 7H), 3.67-3.62 (m, 1H), 3.19-3.13 (m, 1H), 2.80 (s, 3H), 2.48-2.39 (m, 2H), 1.98-1.90 (m, 2H), 1.78-1.72 (m, 2H), 1.53-1.45 (m, 1H), 1.38-1.24 (m, 1H); LC/MS (B), Rt: 2.20 min; (M+H) 412.3.
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.93-3.87 (m, 4H), 3.28-3.23 (m, 1H), 3.22-3.07 (m, 1H), 2.69-2.63 (m, 3H), 2.48-2.39 (m, 2H), 2.28 (s, 3H), 1.99-1.93 (m, 2H), 1.78-1.71 (m, 2H), 1.49-1.42 (m, 1H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 2.71 min; (M+H) 428.3.
1H NMR (400 MHz, DMSO-d6) δ11.58 (s, 1H), 8.90 (d, J = 4.9 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 1.7, 2.6, 2H), 7.39 (d, J = 4.9, 1H), 6.82 (dd, J = 1.6, 4.3 Hz, 1H), 6.47 (dd, J = 2.6, 4.3 Hz, 1H), 4.53 (d, J = 13.1 Hz, 1H), 3.98 (d, J = 12.7 Hz, 1H), 3.08 (t, J = 10.92 Hz, 1H), 2.79-2.68 (m, 1H), 2.64-2.50 (m, 1H), 2.49-2.44 (m, 3H), 2.43-2.39 (m, 2H), 1.99-1.73 (m, 2H), 1.58-1.50 (m, 2H), 1.48-1.40 (m, 1H), 1.38-1.20 (m, 1H); LC/MS (B), Rt: 2.71 min; (M+H) 459.0.
1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 7.98 (d, J = 7.0 Hz, 2H), 7.33-7.31 (m, 1H), 7.05 (d, J = 7.0 Hz, 2H), 6.63-6.61 (m, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.92-3.86 (m, 1H), 3.84 (s, 3H), 3.69-3.61 (m, 1H), 3.15 (t, J = 12.8 Hz, 1H), 2.75-2.68 (m, 1H), 2.54-2.51 (m, 2H), 2.40-2.36 (m, 2H), 2.13 (s, 3H), 1.90-1.83 (m, 2H), 1.79-1.70 (m, 2H), 1.55-1.42 (m, 1H), 1.38-1.23 (m, 1H); LC/MS (B), Rt: 3.97 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 7.88 (dd, J = 1.6, 8.6 Hz, 1H), 7.82 (dd, J = 2.4, 12.2 Hz, 1H), 7.33-7.27 (m, 2H), 6.63-6.61 (m, 1H), 4.38 (d, J = 13.0 Hz, 1H), 3.94-3.84 (m, 4H), 3.70-3.62 (m, 1H), 3.20-3.11 (m, 1H), 2.77-2.68 (m, 1H), 2.48-2.46 (m, 2H), 2.42-2.35 (m, 2H), 2.13 (s, 3H), 1.94-1.83 (m, 2H), 1.80-1.72 (m, 2H), 1.54-1.42 (m, 1H), 1.38-1.22 (m, 1H); LC/MS (B), Rt: 4.01 min; (M+H) 455.3.
1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.82 (s, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.18-7.21 (m, 1H), 6.87-6.83 (m, 2H), 4.61 (d, J = 12.2 Hz, 1H), 4.04 (s, 3H), 4.01-3.95 (m, 1H), 3.49-3.41 (m, 1H), 3.28 (t, J = 12.7 Hz, 1H), 2.91 (t, J = 11.5 Hz, 1H), 2.68-2.62 (m, 2H), 2.59-2.51 (m, 2H), 2.24 (s, 3H), 2.16-2.05 (m, 2H), 1.98-1.82 (m, 3H), 1.73-1.60 (m, 1H); LC/MS (D), Rt: 4.94 min; (M+H) 438.2.
1H NMR (400 MHz, DMSO-d6) δ11.49 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.29-7.33 (m, 1H), 6.70 (s, 2H), 6.64-6.61 (m, 1H), 4.49 (d, J = 12.7 Hz, 1H), 3.93 (d, J = 13.9 Hz, 1H), 3.02 (t, J = 12.8 Hz, 1H), 2.68-2.59 (m, 1H), 2.56-2.51 (m, 3H), 2.39 (t, J = 7.3 Hz, 2H), 2.13 (s, 3H), 1.90 (t, J = 7.3 Hz, 2H), 1.75-1.66 (m, 2H), 1.56-1.47 (m, 1H), 1.40-1.33 (m, 1H); LC/MS (B), Rt: 2.69 min; (M+H) 420.2.
1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.90 (d, J = 4.9 Hz, 2H), 8.51 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.58 (brs, 2H), 7.39 (t, J = 4.9 Hz, 1H), 7.31 (s, 1H), 6.62 (d, J = 1.1 Hz, 1H), 4.54 (d, J = 12.8 Hz, 1H), 3.97 (d, J = 13.7 Hz, 1H), 3.08 (t, J = 12.2 Hz, 1H), 2.74 (t, J = 11.7 Hz, 1H), 2.62-2.53 (m, 3H), 2.45-2.37 (m, 2H), 2.11 (s, 3H), 1.95-1.88 (m, 2H), 1.85-1.74 (m, 2H), 1.58-1.51 (m, 1H), 1.40-1.32 (m, 1H); LC/MS (B), Rt: 2.87 min; (M+H) 473.2.
1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 7.99 (dd, J = 1.9, 7.9 Hz, 2H), 7.63-7.56 (m, 3H), 7.30 (d, J = 0.8 Hz, 1H), 6.62 (d, J = 1.2 Hz, 1H), 4.29 (d, J = 13.4 Hz, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.38-3.34 (m, 1H), 3.22 (t, J = 11.3 Hz, 1H), 2.86 (t, J = 10.8 Hz, 1H), 2.53-2.51 (m, 2H), 2.43-2.38 (m, 2H), 2.14-2.02 (m, 5H), 1.95-1.86 (m, 2H), 1.80-1.68 (m, 1H), 1.66-1.54 (m, 1H); LC/MS (B), Rt: 3.75 min; (M+H) 447.3.
1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.62 (s, 1H), 4.79-4.70 (m, 1H), 3.91-3.82 (m, 1H), 3.72-3.67 (m, 1H), 3.36-3.32 (m, 1H), 3.23-3.16 (m, 1H), 2.53-2.51 (m, 2H), 2.41-2.36 (m, 2H), 2.13 (s, 3H), 1.97-1.81 (m, 4H), 1.62-1.52 (m, 1H), 1.51-1.42 (m, 1H); LC/MS (D), Rt: 5.32 min; (M+H) 420.2.
1H NMR (400 MHz, CDCl3) δ 10.74 (s, 1H), 8.02-7.96 (m, 2H), 7.20-7.15 (m, 3H), 6.86 (s, 1H), 4.58 (d, J = 13.0 Hz, 1H), 3.97 (d, J = 13.0 Hz, 1H), 3.52-3.47 (m, 1H), 2.91 (t, J = 11.5 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.58-2.53 (m, 2H), 2.23 (s, 3H), 2.21-2.20 (m, 1H), 2.14-2.07 (m, 2H), 1.97-1.78 (m, 3H), 1.67-1.58 (m, 1H); LC/MS (B), Rt: 4.11 min; (M+H) 425.0.
1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 7.89 (dd, J = 2.2, 8.6 Hz, 1H), 7.82-7.78 (m, 1H), 7.33-7.30 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.63-6.61 (m, 1H), 4.38 (d, J = 12.8 Hz, 1H), 3.92-3.87 (m, 4H), 3.67-3.61 (m, 1H), 3.16 (t, J = 12.4 Hz, 1H), 2.75-2.68 (m, 1H), 2.54-2.51 (m, 2H), 2.41-2.35 (m, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.92-1.85 (m, 2H), 1.76-1.70 (m, 2H), 1.52-1.42 (m, 1H), 1.37-1.26 (m, 1H); LC/MS (B), Rt: 4.42 min; (M+H) 451.2.
1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 6.62 (s, 1H), 5.18 (s, 1H), 4.38 (d, J = 12.8 Hz, 1H), 3.89 (d, J = 13.6 Hz, 1H), 3.70-3.62 (m, 1H), 3.16 (t, J = 12.0 Hz, 1H), 2.76-2.66 (m, 1H), 2.54-2.51 (m, 2H), 2.40-2.32 (m, 2H), 2.13 (s, 3H), 1.90-1.82 (m, 2H), 1.78-1.72 (m, 2H), 1.54-1.48 (m, 1H), 1.43 (s, 6H), 1.36-1.24 (m, 1H); LC/MS (B), Rt: 3.61 min; (M+H) 465.2.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.90 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.69 (s, 1H), 4.38 (d, J = 13.4 Hz, 1H), 3.94 (s, 3H), 3.89 (d, J = 13.6 Hz, 1H), 3.65 (t, J = 11.6 Hz, 1H), 3.15 (t, J = 11.8 Hz, 1H), 2.74-2.66 (m, 1H), 2.55-2.51 (m, 2H), 2.44-2.41 (m, 2H), 1.91-1.85 (m, 2H), 1.83-1.74 (m, 2H), 1.53-1.42 (m, 1H), 1.41-1.21 (m, 1H); LC/MS (B), Rt: 3.65 min; (M+H) 442.3.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.90 (d, J = 4.9 Hz, 2H), 8.51 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.65-7.63 (m, 3H), 7.40 (t, J = 4.9 Hz, 1H), 6.69 (t, J = 1.0 Hz, 1H), 4.53 (d, J = 12.6 Hz, 1H), 3.97 (d, J = 12.9 Hz, 1H), 3.08 (t, J = 13.3 Hz, 1H), 2.76-2.67 (m, 1H), 2.60-2.53 (m, 3H), 2.45-2.42 (m, 2H), 1.95-1.88 (m, 2H), 1.82-1.76 (m, 2H), 1.59-1.50 (m, 1H), 1.49-1.30 (m, 1H); LC/MS (B), Rt: 2.88 min; (M+H) 477.2.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.00-7.98 (m, 2H), 7.62-7.56 (m, 4H), 6.69 (s, 1H), 4.29 (d, J = 13.1 Hz, 1H), 3.90 (d, J = 12.8 Hz, 1H), 3.37-3.32 (m, 1H), 3.22 (t, J = 12.4 Hz, 1H), 2.86 (t, J = 11.8 Hz, 1H), 2.57-2.51 (m, 2H), 2.45-2.40 (m, 2H), 2.12-2.01 (m, 2H), 1.89-1.81 (m, 2H), 1.79-1.66 (m, 1H), 1.56-1.45 (m, 1H); LC/MS (B), Rt: 3.74 min; (M+H) 451.2.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.64-7.58 (m, 3H), 6.69 (s, 1H), 5.18 (s, 1H), 4.38 (d, J = 13.1 Hz, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.72-3.64 (m, 1H), 3.16 (t, J = 12.4 Hz, 1H), 2.73 (t, J = 10.8 Hz, 1H), 2.54-2.52 (m, 2H), 2.42-2.37 (m, 2H), 1.93-1.85 (m, 2H), 1.82-1.73 (m, 2H), 1.54-1.47 (m, 1H), 1.43 (s, 6H), 1.34-1.27 (m, 1H); LC/MS (B), Rt: 3.65 min; (M+H) 469.0.
1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.53-7.51 (m, 1H), 6.82 (d, J = 4.3 Hz, 1H), 6.48 (d, J = 4.3 Hz, 1H), 4.39 (d, J = 12.8 Hz, 1H), 3.91-3.82 (m, 4H), 3.23-3.21 (m, 1H), 3.19-3.14 (m, 1H), 3.12-3.03 (m, 1H), 2.66-2.53 (m, 1H), 2.52-2.49 (m, 1H), 2.48-2.32 (m, 2H), 1.93-1.88 (m, 2H), 1.78-1.71 (m, 2H), 1.51-1.47 (m, 1H), 1.35-1.22 (m, 1H); LC/MS (B), Rt: 2.70 min; (M+H) 397.0.
1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.33-7.30 (m, 1H), 6.62 (d, J = 1.2 Hz, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.92-3.82 (m, 4H), 3.25-3.22 (m, 1H), 3.21-3.06 (m, 1H), 2.68-2.65 (m, 1H), 2.62-2.51 (m, 2H), 2.40-2.35 (m, 2H), 2.13 (s, 3H), 1.92-1.82 (m, 2H), 1.78-1.69 (m, 2H), 1.55-1.40 (m, 1H), 1.38-1.22 (m, 1H); LC/MS (B), Rt: 2.93 min; (M+H) 411.2.
1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.64 (s, 1H), 6.69 (s, 1H), 4.38 (d, J = 12.9 Hz, 1H), 3.92-3.87 (m, 4H), 3.32-3.23 (m, 1H), 3.22-3.06 (m, 1H), 2.70-2.60 (m, 1H), 2.55-2.49 (m, 2H), 2.39-2.35 (m, 2H), 1.92-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.55-1.44 (m, 1H), 1.39-1.25 (m, 1H); LC/MS (B), Rt: 2.98 min; (M+H) 415.0.
1H NMR (400 MHz, DMSO-d6) δ 11.75 (brs, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.62-7.58 (m, 1H), 6.69 (s, 2H), 6.64 (s, 1H), 4.49 (d, J = 11.3 Hz, 1H), 3.94 (d, J = 14.5 Hz, 1H), 3.02 (t, J = 12.3 Hz, 1H), 2.61-2.56 (m, 4H), 2.44-2.38 (m, 2H), 1.94-1.86 (m, 2H), 1.76-1.67 (m, 2H), 1.57-1.47 (m, 1H), 1.45-1.30 (m, 1H); LC/MS (B), Rt: 2.66 min; (M+H) 424.2.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.98 (d, J = 7.0 Hz, 2H), 7.05 (d, J = 6.9 Hz, 2H), 4.39 (d, J = 13.1 Hz, 1H), 4.33 (s, 2H), 3.90 (d, J = 11.4 Hz, 1H), 3.85-3.81 (m, 5H), 3.68-3.62 (m, 1H), 3.17-3.13 (m, 2H), 2.76-2.70 (m, 1H), 2.55-2.51 (m, 3H), 2.38-2.31 (m, 2H), 1.91-1.84 (m, 2H), 1.82-1.72 (m, 2H), 1.55-1.43 (m, 1H), 1.39-1.28 (m, 1H); LC/MS (B), Rt: 2.94 min; (M+H) 440.2.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.88 (dd, J = 1.2, 8.6 Hz, 1H), 7.82 (dd, J = 2.1, 12.3 Hz, 1H), 7.30 (t, J = 8.6 Hz, 1H),, 4.38 (d, J = 12.1 Hz, 1H), 4.33 (s, 2H), 3.94-3.88 (m, 4H), 3.82 (t, J = 5.6 Hz, 2H), 3.69-3.62 (m, 1H), 3.29-3.20 (m, 1H), 2.76-2.66 (m, 1H), 2.54-2.51 (m, 4H), 2.39-2.31 (m, 2H), 1.88-1.82 (m, 2H), 1.79-1.71 (m, 2H), 1.51-1.41 (m, 1H), 1.36-1.28 (m, 1H); LC/MS (B), Rt: 3.04 min; (M+H) 458.3.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.90 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.22 (dd, J = 2.5, 8.8 Hz, 1H), 6.94 (dd, J = 0.4, 8.8 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.33 (s, 2H), 3.96-3.87 (m, 4H), 3.82 (t, J = 5.6 Hz, 2H), 3.70-3.62 (m, 1H), 3.21-3.11 (m, 1H), 2.77-2.68 (m, 1H), 2.54-2.51 (m, 4H), 2.40-2.32 (m, 2H), 1.91-1.84 (m, 2H), 1.82-1.74 (m, 2H), 1.54-1.44 (m, 1H), 1.39-1.27 (m, 1H); LC/MS (B), Rt: 2.60 min; (M+H) 441.2.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 6.70 (s, 2H), 4.50 (d, J = 12.8 Hz, 1H), 4.33 (s, 2H), 3.95 (d, J = 13.8 Hz, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.03 (t, J = 12.8 Hz, 1H), 2.69-2.62 (m, 1H), 2.58-2.52 (m, 5H), 2.36 (t, J = 7.4 Hz, 2H), 1.92-1.84 (m, 2H), 1.76-1.67 (m, 2H), 1.58-1.45 (m, 1H), 1.44-1.32 (m, 1H); LC/MS (B), Rt: 3.39 min; (M+H) 423.0.
1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.90 (d, J = 4.9 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.60 (brs, 2H), 7.40 (t, J = 4.9 Hz, 1H), 4.54 (d, J = 13.6 Hz, 1H), 4.33 (s, 2H), 3.98 (d, J = 13.6 Hz, 1H), 3.81 (t, J = 5.6 Hz, 2H), 3.08 (t, J = 12.4 Hz, 1H), 2.78-2.70 (m, 1H), 2.63-2.51 (m, 5H), 2.42-2.36 (m, 2H), 1.94-1.87 (m, 2H), 1.85-1.76 (m, 2H), 1.60-1.51 (m, 1H), 1.48-1.36 (m, 1H); LC/MS (B), Rt: 2.13 min; (M+H) 476.0.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.02-7.97 (m, 2H), 7.63-7.55 (m, 3H), 4.35-4.27 (m, 3H), 3.95-3.86 (m, 1H), 3.81 (t, J = 5.6 Hz, 2H), 3.37-3.34 (m, 1H), 3.28-3.18 (m, 1H), 2.87 (t, J = 10.7 Hz, 1H), 2.54-2.51 (m, 4H), 2.41-2.36 (m, 2H), 2.14-2.04 (m, 2H), 1.93-1.84 (m, 2H), 1.80-1.72 (m, 1H), 1.68-1.58 (m, 1H); LC/MS (B), Rt: 2.77 min; (M+H) 450.2.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 4.79-4.73 (m, 1H), 4.33 (s, 2H), 3.92-3.86 (m, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.73-3.67 (m, 1H), 3.29-3.27 (m, 1H), 3.24-3.17 (m, 1H), 2.54-2.51 (m, 4H), 2.37 (t, J = 7.3 Hz, 2H), 2.02-1.82 (m, 4H), 1.64-1.56 (m, 1H), 1.54-1.46 (m, 1H); LC/MS (B), Rt: 2.98 min; (M+H) 423.3.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.12-8.06 (m, 2H), 7.36 (t, J = 8.8 Hz, 2H), 4.39 (d, J = 13.6 Hz, 1H), 4.33 (s, 2H), 3.90 (d, J = 13.6 Hz, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.74-3.65 (m, 1H), 3.20-3.11 (m, 1 H), 2.76-2.68 (m, 1H), 2.54-2.51 (m, 4H), 2.38-2.33 (m, 2H), 1.90-1.74 (m, 4H), 1.54-1.42 (m, 1H), 1.38-1.26 (m, 1H); LC/MS (B), Rt: 3.08 min; (M+H) 428.0.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.89 (dd, J = 2.4, 8.6 Hz, 1H), 7.80 (s, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.40 (d, J = 12.8 Hz, 1H), 4.33 (s, 2H), 3.93-3.86 (m, 4H), 3.82 (t, J = 5.6 Hz, 2H), 3.69-3.61 (m, 1H), 3.19-3.12 (m, 1H), 2.76-2.68 (m, 1H), 2.55-2.51 (m, 4H), 2.39-2.31 (m, 2H), 2.19 (s, 3H), 1.90-1.83 (m, 2H), 1.79-1.72 (m, 2H), 1.54-1.42 (m, 1H), 1.38-1.28 (m, 1H); LC/MS (B), Rt: 3.31 min; (M+H) 454.2.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 5.19 (s, 1H), 4.39 (d, J = 12.9 Hz, 1H), 4.33 (s, 2H), 3.90 (d, J = 13.4 Hz, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.72-3.64 (m, 1H), 3.17 (t, J = 12.1 Hz, 1H), 2.74 (t, J = 12.3 Hz, 1H), 2.55-2.51 (m, 4H), 2.39-2.33 (m, 2H), 1.90-1.84 (m, 2H), 1.82-1.76 (m, 2H), 1.54-1.45 (m, 1H), 1.43 (s, 6H), 1.36-1.27 (m, 1H); LC/MS (B), Rt: 2.62 min; (M+H) 468.2.
1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.33 (s, 2H), 3.92-3.87 (m, 4H), 3.86-3.80 (m, 2H), 3.23-3.19 (m, 1H), 3.14-3.06 (m, 1H), 2.66-2.63 (m, 1H), 2.54-2.51 (m, 4H), 2.37-2.33 (m, 2H), 1.87-1.82 (m, 2H), 1.78-1.71 (m, 2H) 1.53-1.45 (m, 1H), 1.35-1.26 (m, 1H); LC/MS (B), Rt: 1.93 min; (M+H) 414.2.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 2.4, 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 4.2 Hz, 1H), 6.30 (d, J = 4.1 Hz, 1H), 4.39 (d, J = 13.1 Hz, 1H), 3.94 (s, 3H), 3.93-3.89 (m, 1H), 3.64 (t, J = 11.3 Hz, 1H), 3.16 (t, J = 12.6 Hz, 1H), 2.72 (t, J = 11.8 Hz, 1H), 2.58-2.51 (m, 2H), 2.49-2.39 (m, 2H), 2.36 (s, 3H), 1.98-1.82 (m, 2H), 1.80-1.71 (m, 2H), 1.58-1.42 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (D), Rt: 3.67 min; (M+H) 438.3.
1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 4.2 Hz, 1H), 6.70 (s, 2H), 6.30 (dd, J = 0.7, 4.3 Hz, 1H), 4.50 (d, J = 12.5 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.03 (t, J = 13.0 Hz, 1H), 2.69-2.59 (m, 1H), 2.57-2.47 (m, 3H), 2.45-2.37 (m, 2H), 2.35 (s, 3H), 1.99-1.79 (m, 2H), 1.75-1.63 (t, J = 12.2 Hz, 2H), 1.59-1.43 (m, 1H), 1.42-1.31 (m, 1H); LC/MS (B), Rt: 2.72 min; (M+H) 420.2.
1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.90 (d, J = 4.9 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.61 (brs, 2H), 7.39 (t, J = 4.9 Hz, 1H), 6.76 (d, J = 4.2 Hz, 1H), 6.30 (dd, J = 0.6, 4.2 Hz, 1H), 4.53 (d, J = 13.1 Hz, 1H), 3.98 (d, J = 14.2 Hz, 1H), 3.12-3.04 (m 1H), 2.79-2.69 (m, 1H), 2.60-2.52 (m, 3H), 2.50-2.39 (m, 2H), 2.36 (s, 3H), 2.01-1.90 (m, 2H), 1.898-1.73 (m, 2H), 1.60-1.54 (m, 2H), 1.48-1.33 (m, 1H); LC/MS (B), Rt: 2.91 min; (M+H) 473.2.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 6.76 (d, J = 4.2 Hz, 1H), 6.30 (d, J = 4.1 Hz, 1H), 4.38 (d, J = 12.8 Hz, 1H), 3.92-3.87 (m, 4H), 3.24-3.16 (m, 1H), 3.09 (t, J = 12.8 Hz, 1H), 2.69-2.61 (m, 1H), 2.54-2.51 (m, 2H), 2.46-2.42 (m, 2H), 2.36 (s, 3H), 1.95-1.89 (m, 2H), 1.78-1.71 (m, 2H), 1.52-1.43 (m, 1H), 1.36-1.22 (m, 1H); LC/MS (B), Rt: 2.94 min; (M+H) 411.2.
1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.35 (dd, J = 2.5, 1.6 Hz, 1H), 7.13 (s, 1H), 6.85-6.78 (m, 1H), 6.48 (dd, J = 3.9, 2.5 Hz, 1H), 4.55 (hept, J = 6.7 Hz, 1H), 4.47-4.36 (m, 1H), 3.94-3.82 (m, 1H), 3.32-3.22 (m, 1H), 3.18-3.07 (m, 1H), 2.75-2.62 (m, 1H), 2.42-2.31 (m, 4H), 1.88-1.72 (m, 4H), 1.56-1.28 (m, 8H); LC/MS (A), Rt: 1.69 min; (M+H) 424.3.
1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.50 (s, 1H), 7.98 (s, 1H), 6.91 (s, 1H), 6.76 (d, J = 3.8 Hz, 1H), 6.30-6.27 (m, 1H), 4.55 (hept, J = 6.7 Hz, 1H), 4.46-4.37 (m, 1H), 3.95-3.85 (m, 1H), 3.32-3.22 (m, 1H), 3.18-3.06 (m, 1H), 2.74-2.64 (m, 1H), 2.43-2.32 (m, 7H), 1.89-1.74 (m, 4H), 1.57-1.29 (m, 8H); LC/MS (A), Rt: 1.77 min; (M+H) 438.3.
1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.90 (d, J = 1.9 Hz, 1H), 8.22 (dd, J = 8.7, 2.2 Hz, 1H), 7.34 (s, 1H), 7.11 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 3.5 Hz, 1H), 6.56-6.38 (m, 1H), 4.49-4.29 (m, 1H), 3.95 (s, 3H), 3.92-3.80 (m, 1H), 3.73-3.57 (m, 1H), 3.24-3.07 (m, 1H), 2.82-2.66 (m, 1H), 2.44-2.23 (m, 4H), 1.92-1.71 (m, 4H), 1.58-1.42 (m, 1H), 1.42-1.25 (m, 1H); LC/MS (A), Rt: 1.81 min; (M+H) 423.2.
1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 6.74 (d, J = 3.8 Hz, 1H), 6.27 (d, J = 3.7 Hz, 1H), 4.48-4.33 (m, 1H), 3.95 (s, 3H), 3.93-3.81 (m, 1H), 3.72-3.58 (m, 1H), 3.24-3.10 (m, 1H), 2.82-2.68 (m, 1H), 2.45-2.28 (m, 7H), 1.88-1.73 (m, 4H), 1.58-1.43 (m, 1H), 1.43-1.28 (m, 1H); LC/MS (A), Rt: 1.89 min; (M+H) 437.2.
1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 6.93 (s, 1H), 6.75 (t, J = 4.8 Hz, 1H), 6.15 (t, J = 4.1 Hz, 1H), 4.55 (hept, J = 6.7 Hz, 1H), 4.45-4.33 (m, 1H), 3.97-3.82 (m, 1H), 3.33-3.18 (m, 1H), 3.18-3.04 (m, 1H), 2.76-2.60 (m, 1H), 2.43-2.28 (m, 4H), 1.90-1.71 (m, 4H), 1.61-1.27 (m, 8H); LC/MS (A), Rt: 1.79 min; (M+H) 442.2.
1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 8.7, 2.4 Hz, 1H), 7.57 (s, 1H), 7.04 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.46-4.34 (m, 1H), 3.95 (s, 3H), 3.93-3.85 (m, 1H), 3.71-3.60 (m, 1H), 3.21-3.05 (m, 1H), 2.79-2.66 (m, 1H), 2.48 (s, 3H), 2.42-2.28 (m, 4H), 1.89-1.71 (m, 4H), 1.61-1.42 (m, 1H), 1.42-1.18 (m, 1H); LC/MS (A), Rt: 1.40 min; (M+H) 438.2.
1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.14-7.10 (m, 1H), 7.01 (s, 1H), 6.62-6.58 (m, 1H), 4.40 (d, J = 13.0 Hz, 1H), 3.92-3.83 (m, 4H), 3.22 (tt, J = 11.3, 3.7 Hz, 1H), 3.14-3.06 (m, 1H), 2.71-2.63 (m, 1H), 2.37-2.29 (m, 4H), 2.13 (s, 3H), 1.83-1.72 (m, 4H), 1.53-1.42 (m, 1H), 1.39-1.29 (m, 1H); LC/MS (A), Rt: 1.61 min; (M+H) 410.2.
1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 10.4 Hz, 1H), 7.81 (dd, J = 2.3, 12.4 Hz, 1H), 7.28 (t, J = 8.6 Hz, 1H), 4.45-4.37 (m, 1H), 3.92 (s, 3H), 3.95-3.85 (m, 1H), 3.69-3.62 (m, 1H), 3.21-3.12 (m, 1H), 2.79-2.70 (m, 1H), 2.54 (s, 3H), 2.58-2.48 (m, 2H), 2.41-2.35 (m, 2H), 1.99-1.86 (m, 2H), 1.80-1.70 (m, 2H), 1.52-1.40 (m, 1H), 1.34-1.24 (m, 1H); LC/MS (B), Rt: 3.60 min; (M+H) 472.0.
1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 5.18 (s, 1H), 4.38 (d, J = 12.8 Hz, 1H), 3.92-3.83 (m, 1H), 3.75-3.61 (m, 1H), 3.23-3.12 (m, 1H), 2.79-2.69 (m, 1H), 2.54 (s, 3H), 2.52-2.45 (m, 2H), 2.43-2.35 (m, 2H), 1.99-1.90 (m, 2H), 1.81-1.71 (m, 2H), 1.61-1.49 (m, 1H), 1.41 (s, 6H), 1.40-1.35 (m, 1H); LC/MS (B), Rt: 3.16 min; (M+H) 482.0.
1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.14 (s, 1H), 7.97 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 4.42-4.32 (m, 1H), 3.93-3.89 (m, 1H), 3.83 (s, 3H), 3.66-3.60 (m, 1H), 3.23-3.13 (m, 1H), 2.76-2.69 (m, 1H), 2.57 (s, 3H), 2.56-2.50 (m, 2H), 2.43-2.38 (m, 2H), 1.99-1.89 (m, 2H), 1.81-1.69 (m, 2H), 1.58-1.45 (m, 1H), 1.39-1.30 (m, 1H); LC/MS (B), Rt: 3.47 min; (M+H) 454.2.
1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.91 (t, J = 4.9 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1H), 8.14 (s, 2H), 8.05 (d, J = 2.4 Hz , 1H), 7.78 (bs, 1H), 7.40 (t, J = 4.8 Hz, 1H), 4.55 (d, J = 10.3 Hz, 1H), 4.00 (d, J = 13.4 Hz, 1H), 3.10 (t, J = 12.5 Hz, 1H), 2.81-2.70 (m, 1H), 2.59 (s, 3H), 2.61-2.48 (m, 3H), 2.44-2.38 (m, 2H), 2.08-1.82 (m, 2H), 1.80 (t, J = 11.6 Hz, 2H), 1.66-1.51 (m, 1H), 1.49-1.35 (m, 1H); LC/MS (B), Rt: 2.59 min; (M+H) 490.0.
1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.16 (s, 1H), 8.00 (dd, J = 1.6, 7.6 Hz, 2H), 7.63-7.60 (m, 3H), 4.26 (d, J = 12.0 Hz, 1H), 3.92 (d, J = 9.7 Hz, 1H), 3.53-3.42 (m, 1H), 3.41-3.38 (m, 1H), 3.30-3.24 (m, 1H), 2.94-2.81 (m, 1H), 2.67 (s, 3H), 2.64-2.51 (m, 1H), 2.49-2.30 (m, 2H), 2.18-2.00 (m, 2H), 1.99-1.91 (m, 2H), 1.84-1.71 (m, 1H), 1.69-1.54 (m, 1H); LC/MS (B), Rt: 3.29 min; (M+H) 464.2.
1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.13 (s, 1H), 8.08 (dd, J = 5.6, 8.8 Hz, 2H), 7.36 (t, J = 9.0 Hz, 2H), 4.42-4.33 (m, 1H), 3.98-3.88 (m, 1H), 3.72-3.61 (m, 1H), 3.25-3.11 (m, 1H), 2.78-2.68 (m, 1H), 2.55 (s, 3H), 2.51-2.50 (m, 2H), 2.48-2.39 (m, 2H), 1.98-1.88 (m, 2H), 1.82-1.72 (m, 2H), 1.55-1.42 (m, 1H), 1.38-1.25 (m, 1H); LC/MS (B), Rt: 3.59 min; (M+H) 442.0.
1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.14 (s, 1H), 7.89 (dd, J = 1.6, 7.6 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 4.46-4.33 (m, 1H), 3.97-3.91 (m, 1H), 3.86 (s, 3H), 3.69-3.58 (m, 1H), 3.20-3.11 (m, 1H), 2.72 (t, J = 12.1 Hz, 1H), 2.58-2.44 (m, 5H), 2.41-2.39 (m, 2H), 2.19 (s, 3H), 1.99-1.87 (m, 2H), 1.78-1.70 (m, 2H), 1.54-1.46 (m, 1H), 1.41-1.26 (m, 1H); LC/MS (B), Rt: 3.84 min; (M+H) 468.0.
1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.22 (dd, J = 8.7, 2.4 Hz, 1H), 7.37 (dd, J = 3.1, 2.0 Hz, 1H), 7.04 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 4.48-4.31 (m, 1H), 3.95 (s, 3H), 3.92-3.83 (m, 1H), 3.65 (tt, J = 11.2, 3.4 Hz, 1H), 3.22-3.07 (m, 1H), 2.81-2.67 (m, 1H), 2.43-2.27 (m, 4H), 1.88-1.70 (m, 4H), 1.57-1.42 (m, 1H), 1.42-1.27 (m, 1H); LC/MS (A), Rt: 1.90 min; (M+H) 441.2.
1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.67 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 2.4, 8.7 Hz, 1H), 7.92 (s, 1H), 6.71 (d, J = 9.1 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.71 (s, 3H) 3.69-3.56 (m, 1H), 3.49-3.39 (m, 1H), 2.98-2.88 (m, 1H), 2.54-2.43 (m, 1H), 2.32 (s, 3H), 2.28-2.15 (m, 2H), 1.77-1.65 (m, 2H), 1.61-1.50 (m, 2H), 1.32-1.20 (m, 1H), 1.18-1.03 (m, 1H); LC/MS (B), Rt: 3.15 min; (M+H) 455.3.
1H NMR (400 MHz, DMSO-d6) δ11.60 (s, 1H), 8.16 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 6.80 (bs, 2H), 4.50 (d, J = 12.8 Hz, 1H), 3.96 (d, J = 9.2 Hz, 1H), 3.04 (t, J = 12.7 Hz, 1H), 2.69-2.61 (m, 1H), 2.60-2.50 (m, 6H), 2.48-2.38 (m, 2H), 2.01-1.90 (m, 2H), 1.78-1.63 (m, 2H), 1.56-1.48 (m, 1H), 1.46-1.31 (m, 1H); LC/MS (B), Rt: 2.29 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.14 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.15 (t, J = 8.8 Hz, 1H), 4.84-4-69 (m, 1H), 3.99-3.72 (m, 1H), 3.71-3.62 (m, 1H), 3.38-3.33 (m, 1H), 3.26-3.12 (m, 1H), 2.63-2.11 (m, 6H), 2.48-2.38 (m, 2H), 2.01-1.85 (m, 4H), 1.64-1.53 (m, 1H), 1.52-1.42 (m, 1H); LC/MS (B), Rt: 3.52 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 4.39 (d, J = 13.6 Hz, 1H), 3.93-3.90 (m, 1H), 3.87 (s, 3H) 3.29-3.21 (m, 1H), 3.19-3.09 (m, 1H), 2.60-2.50 (m, 6H), 2.46-2.38 (m, 2H), 1.99-1.89 (m, 2H), 1.80-1.70 (m, 2H), 1.52-1.41 (m, 1H), 1.39-1.23 (m, 1H); LC/MS (B), Rt: 2.51 min; (M+H) 428.0.
1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.48 (s, 1H), 7.97-7.95 (m, 2H), 4.39 (d, J = 12.9 Hz, 1H), 4.15 (q, J = 7.3 Hz, 2H), 3.92-3.88 (m, 1H), 3.86 (s, 3H), 3.26-3.19 (m, 1H), 3.12-3.06 (m, 1H), 2.69-2.62 (m, 3H), 2.42-2.36 (m, 2H), 1.97-1.90 (m, 2H), 1.78-1.71 (m, 2H), 1.55-1.42 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.37-1.25 (m, 1H); LC/MS (B), Rt: 2.46 min; (M+H) 426.2.
1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.52 (dd, J = 1.8, 2.5 Hz, 1H), 6.81 (dd, J = 1.7, 4.3 Hz, 1H), 6.48 (dd, J = 2.6, 4.3 Hz, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.89 (d, J = 13.6 Hz, 1H), 3.26-3.18 (m, 1H), 3.12-3.06 (m, 1H), 2.68-2.61 (m, 1H), 2.54-2.51 (m, 2H), 2.42-2.36 (m, 2H), 1.93-1.86 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.44 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.36-1.26 (m, 1H); LC/MS (B), Rt: 2.90 min; (M+H) 411.2.
1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.63 (dd, J = 2.2, 3.2 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 4.38 (d, J = 13.2 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 3.88 (d, J =13.5 Hz, 1H), 3.26-3.20 (m, 1H), 3.12-3.06 (m, 1H), 2.68-2.62 (m, 1H), 2.54-2.51 (m, 2H), 2.40-2.36 (m, 2H), 1.90-1.82 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 3.22 min; (M+H) 429.0.
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 4.39 (d, J = 13.2 Hz 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.91 (d, J = 13.2 Hz, 1H), 3.25-3.19 (m, 1H), 3.10 (t, J = 11.6 Hz, 1H), 2.68-2.61 (m, 3H), 2.43-2.36 (m, 2H), 2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H), 1.32-1.26 (m, 1H); LC/MS (B), Rt: 3.00 min; (M+H) 442.0.
1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 7.37 (s, 1H), 6.68 (s, 1H), 4.54 (hept, J = 6.7 Hz, 1H), 4.46-4.33 (m, 1H), 3.95-3.81 (m, 1H), 3.29-3.19 (m, 1H), 3.19-3.02 (m, 1H), 2.75-2.60 (m, 1H), 2.47-2.39 (m, 2H), 2.40-2.30 (m, 2H), 2.31 (s, 3H), 1.89-1.7 9 (m, 2H), 1.77-1.71 (m, 2H), 1.55-1.45 (m, 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.40-1.27 (m, 1H); LC/MS (A), Rt: 1.66 min; (M+H) 439.2.
1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.50 (s, 1H), 7.98-7.96 (m, 2H), 4.58-4.50 (m, 1H), 4.40 (d, J =13.5 Hz, 1H), 3.92-3.84 (m, 4H), 3.29-3.22 (m, 1H), 3.14-3.07 (m, 1H), 2.69-2.61 (m, 3H), 2.42-2.36 (m, 2H), 1.98-1.91 (m, 2H), 1.83-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.42 (d, J = 6.7 Hz, 6H), 1.34-1.25 (m, 1H); LC/MS (B), Rt: 2.71 min; (M+H) 440.2.
1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 7.52 (s, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.49-6.46 (m, 1H), 4.57-4.50 (m, 1H), 4.40 (d, J = 13.3 Hz, 1H), 3.89 (d, J = 12.7 Hz, 1H), 3.26-3.20 (m, 1H), 3.10 (t, J = 12.5 Hz, 1H), 2.69-2.61 (m, 1H), 2.54-2.51 (m, 2H), 2.41-2.36 (m, 2H), 1.94-1.86 (m, 2H), 1.83-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.44 (d, J = 6.6 Hz, 6H), 1.36-1.26 (m, 1H); LC/MS (B), Rt: 3.17 min; (M+H) 425.2.
1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 7.32 (s, 1H), 6.62 (s, 1H), 4.57-4.50 (m, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.89 (d, J = 13.4 Hz, 1H), 3.26-3.21 (m, 2H), 3.12-3.06 (m, 1H), 2.69-2.61 (m, 2H), 2.41-2.32 (m, 2H), 2.13 (s, 3H), 1.90-1.83 (m, 2H), 1.83-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.42 (d, J = 6.6 Hz, 6H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 3.77 min; (M+H) 439.0.
1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 7.65-7.63 (m, 1H), 6.69-6.68 (m, 1H), 4.58-4.50 (m, 1H), 4.38 (d, J = 13.4 Hz, 1H), 3.89 (d, J = 13.5 Hz, 1H), 3.29-3.22 (m, 1H), 3.10 (t, J = 12.0 Hz, 1H), 2.69-2.62 (m, 1H), 2.54-2.51 (m, 2H), 2.41-2.38 (m, 2H), 1.92-1.85 (m, 2H), 1.79-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.43 (d, J = 6.7 Hz, 6H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 3.56 min; (M+H) 443.0.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 6.76 (d, J = 4.2 Hz, 1H), 6.30 (d, J = 4.2 Hz, 1H), 4.39 (d, J = 13.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 13.4 Hz, 1H), 3.27-3.21 (m, 1H), 3.13-3.07 (m, 1H), 2.69-2.63 (m, 1H), 2.54-2.51 (m, 2H), 2.44-2.40 (m, 2H), 2.36 (s, 3H), 1.95-1.87 (m, 2H), 1.79-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 3.53 min; (M+H) 425.0.
1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 6.76 (d, J = 4.2 Hz, 1H), 6.30 (d, J = 4.1 Hz, 1H), 4.59-4.51 (m, 1H), 4.40 (d, J =13.1 Hz, 1H), 3.91 (d, J = 13.4 Hz, 1H), 3.29-3.21 (m, 1H), 3.10 (t, J = 12.0 Hz, 1H), 2.66 (t, J = 11.0 Hz, 1H), 2.56-2.51 (m, 2H), 2.43-2.38 (m, 2H), 2.36 (s, 3H), 1.95-1.87 (m, 2H), 1.78-1.71 (m, 2H), 1.50-1.42 (m, 1H), 1.43 (d, J = 6.6 Hz, 6H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 3.82 min; (M+H) 438.9.
1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.11 (s, 1H), 4.42-4.20 (m 1H), 4.20-4.10 (m, 2H), 3.95-3.59 (m, 1H), 3.26-3.22 (m, 1H), 3.17-3.09 (m, 1H), 2.67-2.61 (m, 1H), 2.55-2.51 (m, 5H), 2.43-2.33 (m, 2H), 1.96-1.88 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.37-1.26 (m, 1H); LC/MS (B), Rt: 2.74 min; (M+H) 442.0.
1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 4.57-4.50 (m, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 13.6 Hz, 1H), 3.28-3.21 (m, 1H), 3.11 (t, J = 12.4 Hz, 1H), 2.69-2.61 (m, 3H), 2.43-2.36 (m, 2H), 2.28 (s, 3H), 1.99-1.92 (m, 2H), 1.78-1.71 (m, 2H), 1.53-1.46 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.35-1.26 (m, 1H); LC/MS (B), Rt: 3.19 min; (M+H) 456.0.
1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.50 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 4.57-4.49 (m, 1H), 4.39 (d, J = 12.8, 1H), 3.92 (d, J = 12.8 Hz, 1H), 3.26-3.21 (m, 1H), 3.16-3.08 (m, 1H), 2.69-2.61 (m, 1H), 2.56-2.51(m, 5H), 2.43-2.36 (m, 2H), 1.96-1.89 (m, 2H), 1.78-1.72 (m, 2H), 1.54-1.46 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 2.96 min; (M+H) 456.2.
1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.5 (d, J = 8.8 Hz, 2H), 4.43-4.37 (m, 1H), 3.93-3.81 (m, 4H), 3.69-3.60 (m, 1H), 3.21-3.11 (m, 1H), 2.78-2.68 (m, 1H), 2.49-2.40 (m, 4H), 2.46-2.35 (m, 2H), 2.34-2.26 (m, 2H), 1.90-1.58 (m, 8H), 1.54-1.42 (m, 1H), 1.39-1.25 (m, 1H); LC/MS (B), Rt: 3.14 min; (M+H) 438.3.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.48 (s, 1H), 7.97 (s, 1H), 4.40 (d, J = 13.2 Hz, 1H), 4.33 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 13.2 Hz, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.28-3.18 (m, 1H), 3.14-3.06 (m, 1H), 2.68-2.61 (m, 1H), 2.54-2.51 (m, 3H), 2.36-2.28 (m, 2H), 1.88-1.81 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.46 (m, 2H), 1.41-1.30 (m, 4H); LC/MS (B), Rt: 2.15 min; (M+H) 428.3.
1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.50 (s, 1H), 7.97 (s, 1H), 4.57-4.51 (m, 1H), 4.39 (d, J = 13.2 Hz, 1H), 4.33 (s, 2H), 3.85 (d, J = 13.2 Hz, 1H), 3.81 (t, J = 5.6 Hz, 2H), 3.29-3.20 (m, 1H), 3.12-3.06 (m, 1H), 2.67-2.61 (m, 1H), 2.57-2.51 (m, 4H), 2.36-2.28 (m, 3H), 1.87-1.81 (m, 2H), 1.78-1.71 (m, 2H), 1.54-1.46 (m, 1H), 1.43-1.41 (m, 6H), 1.34-1.26 (m, 1H); LC/MS (B), Rt: 2.43 min; (M+H) 442.3.
1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.96 (s, 1H), 4.41-4.36 (m, 1H), 3.23-3.12 (m, 4H), 2.68-2.60 (m, 2H), 2.50-2.59 (m, 1H), 2.49-2.28 (m, 4H), 1.95-1.84 (m, 2H), 1.80-1.60 (m, 6H), 1.55-1.42 (m, 1H), 1.38-1.26 (m, 1H); LC/MS (B), Rt: 2.16 min; (M+H) 412.3.
1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 8.7, 2.5 Hz, 1H), 7.38 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.69 (s, 1H), 4.42-4.34 (m, 1H), 3.95 (s, 3H), 3.91 -3.84 (m, 1H), 3.64 (tt, J = 11.1, 3.6 Hz, 1H), 3.21-3.11 (m, 1H), 2.78-2.68 (m, 1H), 2.43 (t, J = 7.4 Hz, 2H), 2.38-2.32 (m, 2H), 2.31 (s, 3H), 1.87-1.74 (m, 4H), 1.56-1.43 (m, 1H), 1.40-1.28 (m, 1H); LC/MS (A), Rt: 1.77 min; (M+H) 438.2.
1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.76 (brs, 2H), 4.52-4.48 (m, 1H), 3.99-3.90 (m, 1H), 3.15-2.85 (m, 3H), 2.70-2.55 (m, 5H), 2.45-2.25 (m, 4H), 1.95-1.85 (m, 2H), 1.78-1.61 (m, 6H), 1.58-1.44 (m, 1H), 1.42-1.30 (m, 1H); LC/MS (B), Rt: 1.97 min; (M+H) 421.3.
1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.04 (s, 1H), 7.39 (d, 1H), 6.69 (s, 1H), 4.51-4.43 (m, 1H), 4.28-4.20 (m, 2H), 4.01-3.92 (m, 1H), 3.39-3.28 (m, 1H), 3.22-3.12 (m, 1H), 2.76-2.68 (m, 2H), 2.46-2.31 (m, 2H) 2.20 (s, 3H), 1.99-1.91 (m, 3H), 1.88-1.78 (m, 2H), 1.62-1.48 (m, 1H), 1.46 (t, J = 8.0 Hz, 3H), 1.43-1.30 (m, 1H); LC/MS (B), Rt: 3.17 min; (M+H) 425.2.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.01 (d, J = 7.0 Hz, 2H), 7.06 (d, J = 7.0 Hz, 2H), 7.02 (d, J = 3.2 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.43 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.88 (s, 3H), 3.72-3.62 (m, 4H), 3.16 (t, J = 11.6 Hz, 1H), 2.78-2.70 (m, 1H), 2.68-2.58 (m, 2H), 2.48-2.32 (m, 2H), 2.00-1.91 (m, 2H), 1.85-1.75 (m, 2H), 1.56-1.42 (m, 1H), 1.39-1.26 (m, 1H); LC/MS (B), Rt: 3.38 min; (M+H) 437.3.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.12-8.09 (m, 2H), 7.34-7.30 (m, 2H), 7.00 (d, J = 4.2 Hz, 1H), 6.38 (d, J = 4.4 Hz, 1H), 4.42-4.35 (m, 1H), 3.95-3.89 (m, 1H), 3.75-7.63 (m, 4H), 3.24-3.15 (m, 1H), 2.80-2.60 (m, 3H), 2.47-2.32 (m, 2H), 1.99-1.89 (m, 2H), 1.84-1.77 (m, 2H), 1.58-1.43 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 3.48 min; (M+H) 425.2.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 2.0, 12.4 Hz, 1H), 7.31 (t, J = 8.4 Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.40 (d, J = 13.2 Hz, 1H), 3.99-3.88 (m, 4H), 3.73-3.62 (m, 4H), 3.22-3.12 (m, 1H), 2.77-2.71 (m, 1H), 2.68-2.61 (m, 2H), 2.41-2.36 (m, 2H), 1.98-1.92 (m, 2H), 1.82-1.74 (m, 2H) 1.55-1.46 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 3.49 min; (M+H) 455.3.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.23 (dd, J = 8.8, 2.4 Hz, 1H), 7.02 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.00-3.88 (m, 4H), 3.71-3.62 (m, 4H), 3.21-3.12 (m, 1H), 2.79-2.70 (m, 1H), 2.69-2.60 (m, 2H), 2.48-2.36 (m, 2H), 1.98-1.89 (m, 2H), 1.84-1.73 (m, 2H), 1.58-1.46 (m, 1H), 1.41-1.28 (m, 1H); LC/MS (B), Rt: 3.03 min; (M+H) 438.3.
1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.99 (d, J = 6.4 Hz, 2H), 7.64-7.58 (m, 3H), 7.01 (d, J = 3.2 Hz, 1H), 6.39 (d, J = 3.6 Hz, 1H), 4.32 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.67 (s, 3H), 3.40-3.19 (m, 2H), 2.92-2.83 (m, 1H), 2.69-2.61 (m, 2H), 2.47-2.39 (m, 2H), 2.17-2.04 (m, 2H), 1.99-1.91 (m, 2H), 1.82-1.71 (m,1H), 1.69-1.58 (m,1H); LC/MS (B), Rt: 3.19 min; (M+H) 447.3.
1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.91 (d, J = 4.9 Hz, 2H), 8.53 (s, 1H), 8.05 (s, 1H), 7.62 (brs, 2H), 7.41 (t, J = 4.4 Hz, 1H), 7.01 (s, 1H), 6.39 (d, J = 3.3 Hz, 1H), 4.56 (d, J = 13.2 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.67 (s, 3H), 3.15-3.08 (m, 2H), 2.80-2.63 (m, 3H), 2.47-2.39 (m, 2H), 2.03-1.92 (m, 2H), 1.87-1.76 (m, 2H), 1.62-1.51 (m, 1H), 1.49-1.30 (m, 1H); LC/MS (B), Rt: 2.47 min; (M+H) 473.2.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.00 (d, J = 3.2 Hz, 1H), 6.69 (s, 2H), 6.39 (d, J = 3.2 Hz, 1H), 4.52 (d, J = 13.2 Hz, 1H), 3.96 (d, J = 13.2 Hz, 1H), 3.67 (s, 3H), 3.13-3.02 (m, 2H), 2.70-2.60 (m, 3H), 2.47-2.38 (m, 2H), 2.01-1.93 (m, 2H), 1.76-1.68 (m, 2H), 1.58-1.46 (m, 1H), 1.44-1.30 (m, 1H); LC/MS (B), Rt: 2.14 min; (M+H) 420.2.
1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.00 (d, J = 2.8 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.44-4.39 (m, 1H), 3.95-3.85 (m, 4H), 3.67 (s, 3H), 3.30-3.20 (m, 1H), 3.18-3.10 (m, 1H), 2.70-2.60 (m, 3H), 2.46-2.35 (m, 2H), 1.98-1.91 (m, 2H), 1.80-1.70 (m, 2H), 1.55-1.41 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 2.36 min; (M+H) 411.2.
1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.98 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.40 (d, J = 13.2 Hz, 1H), 3.99-3.87 (m, 4H), 3.68 (t, J = 11.2 Hz, 1H), 3.18 (q, J = 8.0 Hz, 1H), 2.80-2.65 (m, 3H), 2.46-2.38 (m, 5H), 2.01-1.91 (m, 2H), 1.82-1.73 (m, 2H), 1.56-1.45 (m, 1H), 1.42-1.28 (m, 1H); LC/MS (B), Rt: 3.49 min; (M+H) 422.2.
1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 1.6, 2.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 2H), 6.83 (dd, J = 1.6, 4.0 Hz, 1H), 6.49 (dd, J = 2.4, 4.2 Hz, 1H), 4.45-4.38 (m, 1H), 3.96-3.89 (m, 1H), 3.75-3.62 (m, 1H), 3.22-3.13 (m, 1H), 2.76-2.68 (m, 1H), 2.56-2.53 (m, 2H), 2.45-2.39 (m, 5H), 1.95-1.89 (m, 2H), 1.83-1.74 (m, 2H), 1.58-1.45 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 3.98 min; (M+H) 407.3.
1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.03 (d, J = 6.4 Hz, 2H), 7.98 (s, 1H), 7.62 (d, J = 6.8 Hz, 2H), 4.40 (d, J = 13.2 Hz, 1H), 3.94-3.87 (m, 4H), 3.74-3.66 (m, 1H), 3.18 (t, J = 11.2 Hz, 1H), 2.77-2.65 (m, 3H), 2.46-2.39 (m, 2H), 2.00-1.91 (m, 2H), 1.82-1.73 (m, 2H), 1.57-1.43 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 3.69 min; (M+H) 442.3.
1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.54-7.51 (m, 1H), 6.83 (dd, J = 1.2, 4.2 Hz, 1H), 6.49 (dd, J = 2.8, 4.0 Hz, 1H), 4.45-4.34 (m, 1H), 3.96-3.88 (m, 1H), 3.73-3.64 (m, 1H), 3.22-3.11 (m, 1H), 2.79-2.68 (m, 1H), 2.56-2.51 (m, 2H), 2.46-2.35 (m, 2H), 1.98-1.71 (m, 4H), 1.58-1.43 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 4.23 min; (M+H) 427.0.
1H NMR (700 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 6.88 (d, J = 5.2 Hz, 1H), 4.39 (d, J = 13.1, 1H), 3.95-3.86 (m, 4H), 3.23 (t, J = 11.5 Hz, 1H), 3.11 (t, J = 13.1 Hz, 1H), 2.66 (t, J = 12.7 Hz, 1H), 2.57 (t, J = 7.4 Hz, 2H), 2.47-2.34 (m, 2H), 1.94-1.86 (m, 2H), 1.79-1.73 (m, 2H), 1.53-1.45 (m, 1H), 1.37-1.28 (m, 1H); LC/MS (A), Rt: 1.73 min; (M+H) 433.2.
1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.95-7.91 (m, 2H), 7.01-6.98 (m, 2H), 4.38-4.30 (m, 1H), 3.89-3.80 (m, 1H), 3.79 (s, 3H), 3.64-3.53 (m, 1H), 3.17-3.06 (m, 1H), 2.71-2.63 (m, 1H), 2.45-2.38 (m, 1H), 2.37-2.23 (m, 2H), 2.10 (s, 3H), 1.85-1.65 (m, 7H), 1.49-1.37 (m, 1H), 1.35-1.20 (m, 1H); LC/MS (B), Rt: 2.93 min; (M+H) 412.3.
1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.12-8.08 (m, 2H), 7.41-7.35 (m, 2H), 4.44-4.38 (m, 1H), 3.96-3.88 (m, 1H), 3.75-3.66 (m, 1H), 3.22-3.12 (m, 1H), 2.79-2.69 (m, 1H), 2.48-2.40 (m, 1H), 2.42-2.30 (m, 2H), 2.12 (s, 3H), 1.91-1.75 (m, 7H), 1.56-1.42 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 3.02 min; (M+H) 400.2.
1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.23 (dd, J = 2.8, 8.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.46-4.39 (m, 1H), 3.95 (s, 3H), 3.94-3.88 (m, 1H), 3.70-3.63 (m, 1H), 3.22-3.14 (m, 1H), 2.80-2.68 (m, 1H), 2.50-2.45 (m, 1H), 2.41-2.32 (m, 2H), 2.17 (s, 3H), 1.93-1.75 (m, 7H), 1.68-1.55 (m, 1H), 1.32-1.30 (m, 1H); LC/MS (B), Rt: 2.59 min; (M+H) 413.3.
1H NMR (400 MHz, DMSO-d6) δ 12.30 (brs, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 4.48-4.41 (m, 1H), 3.98-3.88 (m, 4H), 3.40-3.22 (m, 1H), 3.21-3.07 (m, 1H), 2.72-2.59 (m, 2H), 2.42-2.30 (m, 2H), 2.18 (s, 3H), 1.95-1.73 (m, 7H), 1.58-1.44 (m, 1H), 1.40-1.26 (m, 1H); LC/MS (B), Rt: 1.89 min; (M+H) 386.2.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.50 (s, 1H), 7.98 (s, 1H), 7.02 (d, J = 3.2 Hz, 1H), 6.40 (d, J = 3.6 Hz, 1H), 4.41-4.47 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.97-3.91 (m, 1H), 3.68 (s, 3H), 3.34-3.22 (m, 1H), 3.20-3.09 (m, 1H), 2.72-2.61 (m, 2H), 2.48-2.39 (m, 2H), 1.99-1.91 (m, 2H), 1.82-1.72 (m, 2H), 1.58-1.26 (m, 5H); LC/MS (B), Rt: 2.59 min; (M+H) 425.2.
1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.02 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.55 (hept, J = 6.8 Hz, 1H), 4.49-4.41 (m, 1H), 3.98-3.91 (m, 1H), 3.68 (s, 3H), 3.34-3.24 (m, 1H), 3.18-3.10 (m, 1H), 2.72-2.59 (m, 3H), 2.47-2.38 (m, 2H), 1.99-1.90 (m, 2H), 1.82-1.73 (m, 2H), 1.58-1.26 (m, 8H); LC/MS (B), Rt: 2.85 min; (M+H) 439.3.
1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 4.44-4.33 (m, 1H), 3.96-3.89 (m, 1H), 3.87 (s, 3H), 3.73 (tt, J = 11.2, 3.6 Hz, 1H), 3.24-3.14 (m, 1H), 2.80-2.71 (m, 1H), 2.67 (t, J = 7.4 Hz, 2H), 2.45-2.33 (m, 2H), 2.00 (t, J = 19.0 Hz, 3H), 1.98-1.92 (m, 2H), 1.85-1.76 (m, 2H), 1.51 (qd, J = 13.0, 3.9 Hz, 1H), 1.34 (qd, J = 12.5, 4.0 Hz, 1H); LC/MS (A), Rt: 1.97 min; (M+H) 472.2.
1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.07 (ddd, J = 11.3, 7.9, 2.1 Hz, 1H), 7.97 (s, 1H), 7.94-7.90 (m, 1H), 7.62 (dt, J = 10.3, 8.3 Hz, 1H), 4.44-4.35 (m, 1H), 3.95-3.89 (m, 1H), 3.88 (s, 3H), 3.71 (tt, J = 11.2, 3.5 Hz, 1H), 3.25-3.13 (m, 1H), 2.79-2.71 (m, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.45-2.38 (m, 2H), 1.96 (p, J = 7.4 Hz, 2H), 1.86-1.76 (m, 2H), 1.49 (qd, J = 12.6, 3.8 Hz, 1H), 1.33 (qd, J = 12.5, 4.0 Hz, 1H); LC/MS (A), Rt: 1.88 min; (M+H) 444.2.
1H NMR (400 MHz, Methanol-d4) δ 7.91 (d, J = 6.8 Hz, 2H), 7.44 (d, J = 6.8 Hz, 2H), 4.43-4.38 (m, 3H), 3.93 (d, J = 13.6 Hz, 1H), 3.89-3.83 (m, 2H), 3.72-3.65 (m, 1H), 2.82-2.73 (m, 1H), 2.68-2.57 (m, 4H), 2.49-2.41 (m, 2H), 2.01-1.90 (m, 2H), 1.85-1.76 (m, 2H), 1.61-1.38 (m, 2H); LC/MS (B), Rt: 3.42 min; (M+H) 444.0.
1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.07 (ddd, J = 11.3, 7.9, 2.1 Hz, 1H), 8.01-7.83 (m, 1H), 7.62 (dt, J = 10.3, 8.3 Hz, 1H), 7.01 (d, J = 3.3 Hz, 1H), 6.39 (d, J = 3.3 Hz, 1H), 4.40 (d, J = 13.1 Hz, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.78-3.64 (m, 4H), 3.18 (t, J = 11.9 Hz, 1H), 2.75 (t, J = 11.5 Hz, 1H), 2.63 (t, J = 7.4 Hz, 2H), 2.41 (td, J = 7.3, 2.8 Hz, 2H), 2.00-1.88 (m, 2H), 1.88-1.75 (m, 2H), 1.49 (qd, J = 12.9, 4.4 Hz, 1H), 1.33 (qd, J = 12.4, 11.9, 3.8 Hz, 1H); LC/MS (A), Rt: 1.94 min; (M+H) 443.2.
1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 3.3 Hz, 1H), 6.38 (d, J = 3.3 Hz, 1H), 4.39 (d, J = 13.5 Hz, 1H), 3.91 (d, J = 12.6 Hz, 1H), 3.77-3.68 (m, 1H), 3.67 (s, 3H), 3.19 (t, J = 11.9 Hz, 1H), 2.76 (t, J = 11.5 Hz, 1H), 2.63 (t, J = 7.5 Hz, 2H), 2.40 (td, J = 7.2, 3.1 Hz, 2H), 2.05-1.90 (m, 5H), 1.87-1.74 (m, 2H), 1.60-1.43 (m, 1H), 1.43-1.28 (m, 1H); LC/MS (A), Rt: 2.03 min; (M+H) 471.2.
1H NMR (400 MHz, DMSO-d6) δ9.54 (s, 1H), 8.42-8.35 (m, 1H), 8.18-8.12 (m, 1H), 8.08-7.95 (m, 4H), 7.16-6.98 (m, 2H), 4.51-4.39 (m, 1H), 3.98-3.88 (m, 1H), 3.85 (s, 3H), 3.66 (tt, J = 11.2, 3.6 Hz, 1H), 3.34 (dd, J = 8.7, 6.8 Hz, 2H), 3.26-3.13 (m, 1H), 2.83-2.71 (m, 1H), 2.56-2.48 (m, 2H, overlapped with DMSO-d6), 2.09-1.97 (m, 2H), 1.82-1.71 (m, 2H), 1.58-1.44 (m, 1H), 1.44-1.29 (m, 1H); LC/MS (A), Rt: 1.77 min; (M+H) 418.2.
1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.02 (s, 1H), 4.41 (d, J = 12.8 Hz, 1H), 3.89-3.86 (m, 1H), 3.85 (s, 3H), 3.73-3.63 (m, 1H), 3.24-3.12 (m, 1H), 2.78-2.68 (m, 1H), 2.61-2.55 (m, 2H), 2.46-2.34 (m, 4H), 1.93-1.84 (m, 2H), 1.81-1.72 (m, 2H), 1.58-1.44 (m, 1H), 1.41-1.28 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H); LC/MS (B), Rt: 3.01 min; (M+H) 412.3.
1H NMR (400 MHz, DMSO-d6) δ 8.14-8.06 (m, 2H), 7.38 (t, J = 8.8 Hz, 2H), 6.07 (s, 1H), 4.39 (d, J = 12.8 Hz, 1H), 3.90 (d, J = 13.2 Hz, 1H), 3.77-3.68 (m, 1H), 3.17 (t, J = 12.0 Hz, 1H), 2.78-2.69 (m, 1H), 2.62-2.54 (m, 2H), 2.48-2.38 (m, 4H), 1.97-1.77 (m, 4H), 1.57-1.43 (m, 1H), 1.40-1.28 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H); LC/MS (B), Rt: 3.16 min; (M+H) 400.0.
1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 2.4 Hz, 1H), 8.23 (dd, J = 2.4, 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 4.40 (d, J = 13.2 Hz, 1H), 3.96 (s, 3H), 3.94 (d, J = 13.6 Hz, 1H), 3.71-3.62 (m, 1H), 3.22-3.13 (m, 1H), 2.79-2.69 (m, 1H), 2.61-2.54 (m, 2H), 2.48-2.36 (m, 4H), 1.95-1.75 (m, 4H), 1.57-1.43 (m, 1H), 1.40-1.28 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H); LC/MS (B), Rt: 2.73 min; (M+H) 413.2.
1H NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J = 2.0, 7.2 Hz, 2H), 7.06 (dd, J = 1.6, 7.0 Hz, 2H), 6.05 (s, 1H), 4.40 (d, J = 12.8 Hz, 1H), 4.01-3.81 (m, 4H), 3.71-3.61 (m, 1H), 3.23-3.13 (m, 1H), 2.80-2.56 (m, 4H), 2.45-2.38 (m, 2H), 1.97-1.8 (m, 2H), 1.82-1.72 (m, 2H), 1.58-1.43 (m, 1H), 1.40-1.28 (m,1H), 1.15 (d, J = 6.8 Hz, 6H); LC/MS (B), Rt: 3.32 min; (M+H) 426.2.
1H NMR (400 MHz, DMSO-d6) δ 8.12-8.08 (m, 2H), 7.40-7.36 (m, 2H), 6.08 (s, 1H), 4.39 (d, J = 13.2 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.77-3.68 (m, 1H), 3.17 (t, J = 11.2 Hz, 1H), 2.81-2.58 (m, 4H), 2.47-2.38 (m, 2H), 1.98-1.87 (m, 2H), 1.85-1.75 (m, 2H), 1.57-1.42 (m, 1H), 1.40-1.28 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). LC/MS (B), Rt: 3.42 min; (M+H) 414.2
1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 2.4 Hz, 1H), 8.23 (dd, J = 2.4, 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.06 (s, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.00-3.85 (m, 4H), 3.72-3.62 (m, 1H), 3.17 (t, J = 12.0 Hz, 1H), 2.80-2.55 (m, 4H), 2.47-2.38 (m, 2H), 1.97-1.76 (m, 4H), 1.58-1.43 (m,1H), 1.41-1.28 (m,1H), 1.15 (d, J = 6.8 Hz, 6H); LC/MS (B), Rt: 3.00 min; (M+H) 427.2.
1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.96 (s, 1H), 6.10 (s, 1H), 4.40 (d, J = 12.8 Hz, 1H), 3.95-3.85 (m, 4H), 3.29-3.19 (m, 1H), 3.11 (t, J = 12.0 Hz, 1H), 2.74-2.58 (m, 4H), 2.44-2.38 (m, 2H), 1.96-1.85 (m, 2H), 1.81-1.72 (m, 2H), 1.57-1.43 (m, 1H), 1.40-1.28 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H); LC/MS (B), Rt: 2.31 min; (M+H) 400.2.
1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.68-7.63 (m, 1H), 7.43-7.38 (m, 1H), 7.06 (d, J = 9.2 Hz, 2H), 4.43 (d, J = 12.8 Hz, 1H), 3.96-3.83 (m, 4H), 3.71-3.62 (m, 1H), 3.22-3.12 (m, 1H), 3.08-3.00 (m, 2H), 2.81-2.71 (m, 1H), 2.49-2.42 (m, 2H), 2.07-1.97 (m, 2H), 1.82-1.74 (m, 2H), 1.56-1.29 (m, 2H); LC/MS (B), Rt: 4.57 min; (M+H) 407.0.
1H NMR (400 MHz, DMSO-d6) δ 8.12-8.09 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.69-7.62 (m, 1H), 7.43-7.34 (m, 3H), 4.43 (d, J = 13.2 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.77-3.68 (m, 1H), 3.22-3.13 (m, 1H), 3.07-3.00 (m, 2H), 2.81-2.72 (m, 1H), 2.49-2.42 (m, 2H), 2.07-1.97 (m, 2H), 1.85-1.76 (m, 2H), 1.55-1.29 (m, 2H); LC/MS (B), Rt: 4.69 min; (M+H) 395.0.
1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 2.4 Hz,1H), 8.27-8.21 (m, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.68-7.62 (m, 1H), 7.42-7.38 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.43 (d, J = 13.2 Hz, 1H), 3.95 (s, 3H), 3.93-3.88 (m, 1H), 3.71-3.62 (m, 1H), 3.22-3.12 (m, 1H), 3.07-3.00 (m, 2H), 2.81-2.71 (m, 1H), 2.49-2.42 (m, 2H), 2.08-1.97 (m, 2H), 1.85-1.77 (m, 2H), 1.57-1.29 (m, 2H); LC/MS (B), Rt: 4.26 min; (M+H) 408.0.
1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.69-7.63 (m, 1H), 7.43-7.38 (m, 1H), 4.44 (d, J = 13.2 Hz, 1H), 3.95-3.84 (m, 4H), 3.28-3.19 (m, 1H), 3.18-3.07 (m, 1H), 3.06-2.99 (m, 2H), 2.75-2.65 (m, 1H), 2.58-2.40 (m, 2H), 1.96-2.07 (m, 2H), 1.81-1.72 (m, 2H), 1.46-1.29 (m, 2H); LC/MS (B), Rt: 3.47 min; (M+H) 381.0.
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.06 (ddd, J = 11.3, 7.9, 2.1 Hz, 1H), 7.95-7.87 (m, 1H), 7.61 (dt, J = 10.3, 8.3 Hz, 1H), 4.44-4.36 (m, 1H), 4.33 (s, 2H), 3.95-3.88 (m, 1H), 3.83 (t, J = 5.6 Hz, 2H), 3.70 (tt, J = 11.2, 3.6 Hz, 1H), 3.22-3.11 (m, 1H), 2.79-2.70 (m, 1H), 2.57-2.51 (m, 4H), 2.43-2.30 (m, 2H), 1.92-1.83 (m, 2H), 1.83-1.76 (m, 2H), 1.48 (qd, J = 12.6, 3.9 Hz, 1H), 1.33 (qd, J = 12.5, 4.0 Hz, 1H); LC/MS (A), Rt: 1.80 min; (M+H) 446.2.
1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 4.43-4.36 (m, 1H), 4.34 (s, 2H), 3.95-3.87 (m, 1H), 3.83 (t, J = 5.6 Hz, 2H), 3.73 (tt, J = 11.2, 3.6 Hz, 1H), 3.23-3.14 (m, 1H), 2.80-2.72 (m, 1H), 2.56-2.51 (m, 4H), 2.43-2.30 (m, 2H), 2.00 (t, J = 19.0 Hz, 3H), 1.88 (p, J = 7.7 Hz, 2H), 1.84-1.75 (m, 2H), 1.50 (qd, J = 12.8, 3.7 Hz, 1H), 1.35 (qd, J = 12.6, 4.0 Hz, 1H); LC/MS (A), Rt: 1.90 min; (M+H) 474.2.
1H NMR (500 MHz, DMSO-d6) δ9.55 (d, J = 0.9 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.18-8.14 (m, 1H), 8.08-8.00 (m, 2H), 7.97 (d, J = 0.7 Hz, 1H), 4.45 (d, J = 12.7 Hz, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.89 (s, 3H), 3.38-3.33 (m, 2H), 3.25 (tt, J = 11.4, 3.9 Hz, 1H), 3.17-3.10 (m, 1H), 2.72 (td, J = 12.6, 2.7 Hz, 1H), 2.56-2.52 (m, 2H), 2.11-2.00 (m, 2H), 1.84-1.73 (m, 2H), 1.50 (qd, J = 12.2, 4.1 Hz, 1H), 1.38 (qd, J = 12.3, 4.2 Hz, 1H). LC/MS (A), Rt: 1.30/1.36 min; (M+H) 392.2.
1H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.43 (s, 1H), 7.95 (d, J = 0.4 Hz, 1H), 6.81-6.77 (m, 1H), 6.21 (dd, J = 4.6, 3.7 Hz, 1H), 4.44-4.34 (m, 1H), 3.97-3.83 (m, 4H), 3.22 (tt, J = 11.4, 3.6 Hz, 1H), 3.15-3.07 (m, 1H), 2.71-2.63 (m, 1H), 2.55 (t, J = 7.4 Hz, 2H), 2.41 (td, J = 7.2, 2.4 Hz, 2H), 1.91 (p, J = 7.4 Hz, 2H), 1.80-1.72 (m, 2H), 1.49 (qd, J = 12.7, 3.9 Hz, 1H), 1.34 (qd, J = 12.6, 4.1 Hz, 1H); LC/MS (A), Rt: 1.62 min; (M+H) 415.3.
例A:注射バイアル
100gの式Iで表される活性成分および5gのリン酸水素二ナトリウムを3lの2回蒸留水に溶解させた溶液を、2N塩酸を用いてpH6.5に調整し、滅菌濾過し、注射バイアル中に移し、滅菌条件下で凍結乾燥させ、滅菌条件下で密封する。各々の注射バイアルは、5mgの活性成分を含む。
20gの式Iで表される活性成分の100gの大豆レシチンおよび1400gのココアバターとの混合物を、溶融し、型中に注入し、放冷する。各々の座剤は、20mgの活性成分を含む。
940mlの2回蒸留水中の1gの式Iで表される活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから、溶液を調製する。pHを6.8に調整し、溶液を1lにし、放射線により滅菌する。この溶液を、点眼剤の形態で用いることができる。
500mgの式Iで表される活性成分を、99.5gのワセリンと、無菌条件下で混合する。
1kgの式Iで表される活性成分、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、慣用の方法で圧縮して、錠剤を得、各々の錠剤が10mgの活性成分を含むようにする。
例Eと同様にして、錠剤を圧縮し、次に、慣用の方法で、スクロース、ジャガイモデンプン、タルク、トラガカントおよび染料の被膜で被覆する。
2kgの式Iで表される活性成分を、硬質ゼラチンカプセル中に、慣用の方法で導入して、各々のカプセルが20mgの活性成分を含むようにする。
1kgの式Iで表される活性成分を60lの2回蒸留水に溶解させた溶液を、滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥させ、滅菌条件下で密封する。各々のアンプルは、10mgの活性成分を含む。
Claims (16)
- 式I
Wは、
ここで*は、プロピレン部分への付着の点を示し、
Xは、O、COを示すかまたは不存在であり、
Yは、ArまたはHet1を示し、
R1は、H、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2は、HまたはCH3を示し、
Arは、フェニルを示し、それは、非置換であるかまたはHal、NO2、CN、A、OR3、S(O)mR3、N(R3)2、COA、COOR3、CON(R3)2、SO2N(R3)2、NR3COR3、NR3SO2A、NR3CON(R3)2および/もしくはHet2によって単置換、二置換もしくは三置換されており、
Het1は、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジルまたはピリダジニルを示し、その各々は、非置換であるか、またはHal、NO2、Ar1、CN、A、OR3、N(R3)2、CON(R3)2、Het2および/もしくは=Oによって単置換もしくは二置換されており、
Het2は、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジルまたはピリダジニルを示し、その各々は、非置換であるか、またはHal、NO2、Ar1、CN、A、OR3、N(R3)2、CON(R3)2および/もしくは=Oによって単置換もしくは二置換されており、
Ar1は、フェニルを示し、それは、非置換であるか、またはHal、NO2、CN、A、OR3、S(O)mR3、N(R3)2、COA、COOR3、CON(R3)2、NR3COR3および/もしくはNR3SO2Aによって単置換、二置換もしくは三置換されており、
Aは、1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1つのまたは隣接していない2つのCHおよび/またはCH2基は、NまたはO原子によって置き換えられていてもよく、かつここで1〜7個のH原子は、F、ClまたはOHによって置き換えられていてもよく、
R3は、Hまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
Halは、F、Cl、BrまたはIを示し、
mは、0、1または2を示し、
nは、1または2を示す、
で表される化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Wが
請求項1に記載の化合物、ならびにそれらの薬学的に許容し得る溶媒和物、塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Arがフェニルを示し、それが非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されている、
請求項1に記載の化合物、ならびにそれらの薬学的に許容し得る溶媒和物、塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Het1がフリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジルまたはピリダジニルを示し、その各々が非置換であるか、またはAr1、CN、A、OR3、N(R3)2、Het2および/もしくは=Oによって単置換もしくは二置換されている、
請求項1〜3のいずれか一項に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Het2がピリミジルを示す、
請求項1〜4のいずれか一項に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Ar1がフェニルを示す、
請求項1〜5のいずれか一項に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Wが
式中、*がプロピレン部分への付着の点を示し、
XがO、COを示すかまたは不存在であり、
YがArまたはHet1を示し、
R1がH、F、Cl、CN、CH3、CF3、CHF2、CH2OHまたはOCH3を示し、
R2がHまたはCH3を示し、
Arがフェニルを示し、それが非置換であるか、またはHal、CN、Aおよび/もしくはOR3によって単置換、二置換もしくは三置換されており、
Het1がフリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリミジルまたはピリダジニルを示し、その各々が非置換であるか、またはAr1、CN、A、OR3、N(R3)2、Het2および/もしくは=Oによって単置換もしくは二置換されており、
Het2がピリミジルを示し、
Ar1がフェニルを示し、
Aが1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1つまたは2つの隣接していないCHおよび/またはCH2基がNまたはO原子によって置き換えられていてもよく、かつここで1〜7個のH原子がF、Clおよび/またはOHによって置き換えられていてもよく、
R3がHまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
HalがF、Cl、BrまたはIを示し、
nが1または2を示す、
請求項1に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - Wが
式中、*がプロピレン部分への付着の点を示し、
XがCOを示すかまたは不存在であり、
YがArまたはHet1を示し、
R1がH、FまたはCH3を示し、
R2がHまたはCH3を示し、
Arがフェニルを示し、それがHalおよび/またはOR3によって単置換または二置換されており、
Het1がピラゾリルまたはピリジルを示し、その各々が非置換であるか、またはA、OR3、N(R3)2および/もしくはHet2によって単置換もしくは二置換されており、
Het2がピリミジルを示し、
Aが1〜8個のC原子を有する非分枝状または分枝状アルキルを示し、
R3がHまたは1、2、3もしくは4個のC原子を有する非分枝状もしくは分枝状アルキルを示し、
HalがF、Cl、BrまたはIを示し、
nが1を示す、
請求項1に記載の化合物、ならびにそれらの薬学的に許容し得る塩、互変異性体および立体異性体、ならびにあらゆる比率でのそれらの混合物。 - 以下の群
- 請求項1〜9のいずれか一項に記載の式Iで表される化合物ならびにそれらの薬学的に許容し得る塩、溶媒和物、互変異性体および立体異性体の製造方法であって、
式II
で表される化合物を、
式III
およびLは、Cl、Br、Iまたは遊離の、もしくは反応的に官能的に修飾されたOH基を示す、
で表される化合物
と反応させ、
ならびに/あるいは
式Iで表される塩基または酸をその塩の1種に変換する
ことを特徴とする、前記方法。 - 式Iで表される少なくとも1種の化合物、および/または、その薬学的に許容し得る溶媒和物、塩、互変異性体または立体異性体、あるいは、あらゆる比率でのそれらの混合物、および任意に、薬学的に許容し得る担体、賦形剤またはビヒクルを含む、医薬。
- がん、多発性硬化症、心血管疾患、中枢神経系損傷および種々の形態の炎症の処置および/または防止のための使用のための、式Iで表される化合物、または、その薬学的に許容し得る溶媒和物、塩、互変異性体または立体異性体、あるいは、あらゆる比率でのそれらの混合物。
- 頭部、頸部、目、口、喉、食道、気管支、喉頭、咽頭、胸部、骨、肺、結腸、直腸、胃、前立腺、膀胱、子宮、子宮頸部、乳房、卵巣、精巣または他の生殖器、皮膚、甲状腺、血液、リンパ節、腎臓、肝臓、膵臓、脳、中枢神経系のがん、固形腫瘍および血液由来の腫瘍の群から選択される疾患の処置および/または防止のための使用のための、請求項10に記載の化合物。
- 式Iで表される少なくとも1種の化合物、および/または、その薬学的に許容し得る溶媒和物塩、互変異性体または立体異性体、あるいは、あらゆる比率でのそれらの混合物、および、少なくとも1つのさらなる医薬活性成分を含む、医薬。
- (a)式Iで表される化合物、および/または、その薬学的に許容し得る溶媒和物、塩、互変異性体または立体異性体、あるいは、あらゆる比率でのそれらの混合物の有効量、
ならびに
(b)さらなる医薬活性成分の有効量
の別個のパックからなる、セット(キット)。 - 化合物
3−{4−[3−(4−メトキシ−ベンゾイル)−アゼチジン−1−イル]−4−オキソ−ブチル}−2H−ピロロ[1,2−a]ピラジン−1−オン(「D1」)
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