JP5980812B2 - Paskの阻害のための複素環化合物 - Google Patents
Paskの阻害のための複素環化合物 Download PDFInfo
- Publication number
- JP5980812B2 JP5980812B2 JP2013548530A JP2013548530A JP5980812B2 JP 5980812 B2 JP5980812 B2 JP 5980812B2 JP 2013548530 A JP2013548530 A JP 2013548530A JP 2013548530 A JP2013548530 A JP 2013548530A JP 5980812 B2 JP5980812 B2 JP 5980812B2
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- JP
- Japan
- Prior art keywords
- tetrahydroquinolin
- quinoxaline
- mmol
- methyl
- carboxylate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Description
[式中:
R1 は、そのいずれも(either of which)が、水素、ハロ、アルキル、アルケニル、アルキニル、シクロアルキル、ハロアルキル、アリール、アラルキル、ヘテロシクリル、ヘテロアリール、ヘテラリールアルキル(heterarylalkyl)、CN、アルコキシ、アルキルアミノ、ジアルキルアミノ、 NHSO2R12、NHSO2NHR12、NHCOR12、NHCONHR12、CONHR12、CONR12aR12b、ヒドロキシ、CF3、CHF2、CH2F、SO2R12、SO2NHR12、OCF3、OCHF2およびOCH2Fから選択される一以上の置換基により置換されていてもよい、アリールおよびヘテロアリールから選択され;
R3 は、水素およびヒドロキシルから選択され;
R12、R12aおよびR12bは、独立して、水素、C1-C6 アルキル、アリール、ヘテロアリール、アラルキルおよびヘテロアラルキルから選択され、あるいは一緒になって、R12aおよびR12b は、そのいずれもが(any of which)置換されていてもよい、ヘテロシクロアルキルまたはヘテロアリールを形成していてもよく;
R19 は、水素、低級アルキル、アルケニル、アルキニル、ヒドロキシ、アルコキシ、CF3、CHF2、CH2F、-COOH、OCF3、OCHF2、OCH2F、ハロ、アルキルスルホニル、シアノ、ニトロ、アルキルアミノ、ジアルキルアミノ、NHSO2R12、NHSO2NHR12、NHCOR12、NHCONHR12、CONHR12、CONR12aR12b、SO2NR12aR12b、アリール、およびヘテロアリールから選択され;
X3 は、CH2、NR12、およびOから選択され; および
nは、0 - 4の整数である]
を有するか、またはその医薬上許容される塩、エステル、またはプロドラッグである。
a.治療上有効量の上記の化合物;および、
b.別の治療薬
の投与を含むPASK-媒介疾患の治療方法がさらに提供される。
a) 抗糖尿病薬、例えば、インスリン、インスリン誘導体および模倣薬; インスリン分泌促進剤、例えば、スルホニル尿素、例えば、グリピジド、グリブリドおよびアマリール; インスリン分泌促進スルホニル尿素受容体リガンド、例えば、メグリチニド、例えば、ナテグリニドおよびレパグリニド; インスリン増感剤、例えば、タンパク質チロシンホスファターゼ-lB (PTP-1B) 阻害剤、例えば、PTP-112; GSK3 (グリコーゲン合成酵素キナーゼ-3) 阻害剤、例えば、SB-517955、SB-4195052、SB-216763、NN-57-05441および NN-57-05445; RXR リガンド、例えば、 GW-0791 および AGN-194204; ナトリウム-依存性グルコース共輸送体阻害剤、例えば、T-1095; グリコーゲンホスホリラーゼ A 阻害剤、例えば、BAY R3401; ビグアニド、例えば、メトホルミン; アルファ-グルコシダーゼ阻害剤、例えば、アカルボース; GLP-1 (グルカゴン様ペプチド-1)、GLP-1 類似体、例えば、エキセンジン-4およびGLP-1 模倣薬; DPPIV (ジペプチジルペプチダーゼ IV) 阻害剤、例えば、DPP728、LAF237 (ビルダグリプチン - WO 00/34241の実施例 1)、MK-0431、サクサグリプチン、GSK23A ; AGE 遮断剤(breaker);チアゾリジンジオン誘導体 (グリタゾン)、例えば、ピオグリタゾンまたはロシグリタゾン; および非-グリタゾン型 PPARδ アゴニスト、例えば、GI-262570;
b) 脂質低下薬、例えば、3-ヒドロキシ-3-メチル-グルタリル補酵素 A (HMG-CoA) レダクターゼ阻害剤、例えば、ロバスタチン、ピタバスタチン、シンバスタチン、プラバスタチン、セリバスタチン、メバスタチン、ベロスタチン(velostatin)、フルバスタチン、ダルバスタチン、アトルバスタチン、ロスバスタチンおよびリバスタチン; スクアレンシンターゼ阻害剤; FXR (ファルネソイド X 受容体)およびLXR (肝臓X 受容体) リガンド; コレスチラミン ; フィブラート; ニコチン酸およびアスピリン;
c)抗肥満薬または食欲制御剤、例えば、フェンテルミン、レプチン、ブロモクリプチン、デクスアンフェタミン、アンフェタミン、フェンフルラミン、デクスフェンフルラミン、シブトラミン、オルリスタット、デクスフェンフルラミン、マジンドール、フェンテルミン、フェンジメトラジン、ジエチルプロピオン、フルオキセチン、ブプロピオン、トピラマート、ジエチルプロピオン、ベンズフェタミン、フェニルプロパノールアミンまたはエコピパム、エフェドリン、プソイドエフェドリンまたはカンナビノイド受容体アンタゴニスト;
d) 抗高血圧薬、例えば、ループ利尿薬、例えば、エタクリン酸、フロセミドおよびトラセミド; 利尿薬、例えば、 チアジド誘導体、クロロチアジド、ヒドロクロロチアジド、アミロリド; アンギオテンシン変換酵素 (ACE) 阻害剤、例えば、ベナゼプリル、カプトプリル、エナラプリル、フォシノプリル、リシノプリル、モエキシプリル、ペリノドプリル(perinodopril)、キナプリル、ラミプリルおよびトランドラプリル; Na-K-ATPase 膜ポンプの阻害剤、例えば、ジゴキシン; 中性エンドペプチダーゼ (NEP) 阻害剤、例えば、 チオルファン、テルテオ(terteo)- チオルファン、SQ29072; ECE 阻害剤、例えば、SLV306; ACE/NEP 阻害剤、例えば、 オマパトリラト、サムパトリラトおよびファシドトリル; アンジオテンシン n アンタゴニスト、例えば、 カンデサルタン、エプロサルタン、イルベサルタン、ロサルタン、テーニサルタン(tehnisartan)およびバルサルタン、特に、バルサルタン; レニン阻害剤、例えば、アリスキレン、テルラキレン、ジテキレン、RO 66-1132、RO-66-1168; β-アドレナリン受容体遮断薬、例えば、アセブトロール、アテノロール、ベタキソロール、ビソプロロール、トプロロール、ナドロール、プロプラノロール、ソタロールおよびチモロール; 変力薬、例えば、ジゴキシン、ドブタミンおよびミルリノン; カルシウムチャンネル遮断薬、例えば、 アムロジピン、ベプリジル、ジルチアゼム、フェロジピン、ニカルジピン、ニモジピン、ニフェジピン、ニソルジピンおよびベラパミル; アルドステロン受容体アンタゴニスト; およびアルドステロンシンターゼ阻害剤;
e) HDL 上昇化合物;
f) コレステロール吸収調節剤、例えば、エチジミベ(etizimibe)およびKT6-971;
g) Apo-Al 類似体および模倣薬;
h) トロンビン阻害剤、例えば、キシメラガトラン;
i) アルドステロン阻害剤、例えば、アナストラゾール(anastrazole)、ファドラゾール(fadrazole)、およびエプレレノン;
j)血小板凝集の阻害剤、例えば、アスピリン、およびクロピドグレル硫酸水素塩;
k) エストロゲン、テストステロン、選択的エストロゲン受容体調節剤、および選択的アンドロゲン受容体調節剤;
1)化学療法剤、例えば、アロマターゼ阻害剤、例えば、フェマーラ、抗-エストロゲン、トポイソメラーゼ I 阻害剤、トポイソメラーゼ II 阻害剤、微小管活性薬剤、アルキル化剤、抗腫瘍性代謝拮抗物質、白金(platin)化合物、およびタンパク質キナーゼ活性を低下させる化合物、例えば、PDGF 受容体チロシンキナーゼ阻害剤、例えば、ミアチニブ(miatinib); および
m) 5-HT3 受容体と相互作用する剤および/または5-HT4 受容体と相互作用する剤、 例えば、米国特許第5510353号において実施例 13として記載されるテガセロド、マレイン酸水素テガセロド、シサプリド、およびシランセトロン。
以下は、必ずしも網羅的ではないが、読者の便宜のために提供される、本明細書において引用される文献のリストである。本明細書において引用されるすべての引用文献、特許、および特許出願は、あたかも本明細書においてそれらの全体が記載されているかのように引用により本明細書に含まれる。これら引用文献の教示が本明細書において明確に提示されている教示と矛盾する場合は、本開示が優先する。
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以下のスキームを一般的に本発明を実施するために用いることができる。
塩化チオニル (6.5 g、54.62 mmol、1.01 当量) を、250-mL の丸底フラスコ中の4-フルオロ-3-ニトロ安息香酸 (10 g、54.05 mmol、1.00 当量)のメタノール溶液 (60 mL)に、撹拌しながら0℃で滴下し、次いで油浴中で3時間還流しながら(at reflux)攪拌した。結果として得られた混合物を減圧下で濃縮し、100 mLのEtOAcで希釈し、溶液のpHをNaHCO3水溶液(飽和)を用いて7-8に調整した。溶液を次いで6x50 mLの酢酸エチルで抽出し、有機層を合わせ、無水硫酸ナトリウムで乾燥させ、減圧下で濃縮し、12.42 g (粗)の メチル 4-フルオロ-3-ニトロベンゾエートを白色固体として得た。
DMF (30 mL)中のメチル 2-アミノ-2-フェニルアセテート塩酸塩 (2.5 g、12.38 mmol、1.00 当量)の溶液、メチル 4-フルオロ-3-ニトロベンゾエート (5 g、25.13 mmol、2.00 当量)、およびDIEA (5 g、38.76 mmol、3.13 当量) を100-mLの丸底フラスコ中で一晩30℃で反応させた。反応を次いで200 mLの水の添加によりクエンチし、固体をろ過により収集した。シリカゲルカラム (石油エーテル /EtOAc (50:1))での精製により、3.82 g (90%)のメチル 4-(2-メトキシ-2-オキソ-1-フェニルエチルアミノ)-3-ニトロベンゾエート を黄色固体として得た。LC-MS (ES、m/z): 345 [M+H]+。
鉄 (34.89 g、623.04 mmol、5.00 当量) をメタノール (300 mL)中の、メチル 4-(2-メトキシ-2-オキソ-1-フェニルエチルアミノ)-3-ニトロベンゾエート (42.87 g、124.62 mmol、1.00 当量)およびNH4Cl水溶液(32.1 g、600.00 mmol、5.00 当量、80 mL) の攪拌溶液に一部ずつ添加した。結果として得られた溶液を還流しながら5時間加熱した。冷却すると、固体がろ過により除かれた。結果として得られたろ液を減圧下で濃縮し、19.81 g (56%)のメチル 3-オキソ-2-フェニル-1,2,3,4- テトラヒドロキノキサリン-6-カルボキシラートを黄色固体として得た。 LC-MS (ES、m/z): 283 [M+H]+。
DDQ (21.25 g、93.6 mmol、2.62 当量) を、ジオキサン (750 mL)中の、メチル 3-オキソ-2-フェニル-1,2,3,4- テトラヒドロキノキサリン-6-カルボキシラート (10.07 g、35.7 mmol、1.00 当量) の攪拌溶液に添加し、撹拌しながら、一晩室温で反応させた。固体をろ過により収集した。ろ過ケーキを2x500 mLの K2CO3水溶液(飽和) により洗浄した。この結果、7.29 g (粗)の メチル 3-オキソ-2-フェニル-3,4-ジヒドロキノキサリン-6-カルボキシラートがオフホワイト固体として得られた。 LC-MS (ES、m/z): 281 [M+H]+。
1000-mLの丸底フラスコ中のCH3CN (120 mL)中の、メチル 3-オキソ-2-フェニル-3,4-ジヒドロキノキサリン-6-カルボキシラート (2.1 g、7.50 mmol、1.00 当量)およびPOBr3 (21.5 g、74.91 mmol、10.00 当量)の溶液を油浴中で還流しながら一晩加熱した。結果として得られた混合物を減圧下で濃縮し; pH 値を重炭酸ナトリウム水溶液 (飽和)を用いて7-8に調整し、溶液を4x100 mLのジクロロメタンで抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥させ、減圧下で濃縮し、2 g (78%)の メチル 3-ブロモ-2-フェニルキノキサリン-6-カルボキシラートを白色固体として得た。LC-MS (ES、m/z): 343 [M+H]+。 1H-NMR (300 MHz、DMSO-d6) 8.620-8.615 (d、J=1.5Hz、1H)、8.38-8.35 (q、J=3.3Hz、1H)、8.28-8.25 (d、J=8.7Hz、1H)、7.85-7.82 (q、J=6Hz、2H)、7.60-7.58 (t、J=2.4Hz、3H)、3.99 (s、3H)。
1H-NMR (300 MHz、CDCl3) δ 8.74 - 8.77 (m、1H)、8.31 - 8.37 (m、1H)、7.37 - 7.43 (m、1H)、3.99 (s、3H)。
1H-NMR (300 MHz、CDCl3) δ 8.91 (d、J = 1.8 Hz、1H)、8.64 (b、1H)、8.02 - 8.06 (m、1H)、7.26 - 7.30 (m、2H)、6.88 - 6.95 (m、3H)、4.53 (d、J = 5.4 Hz、1H)、3.91 (s、3H)、3.83 (s、3H)。
1H-NMR (300 MHz、CDCl3) δ 7.57 - 7.60 (m、1H)、7.44 (d、J = 1.8 Hz、1H)、7.28 - 7.33 (m、2H)、6.90 - 6.94 (m、2H)、6.63 (d、J = 8.1 Hz、1H)、4.33 (s、2H)、3.86 (s、3H)、3.83 (s、3H)。
1H-NMR (300 MHz、DMSO) δ 12.22 (s、1H)、7.80 (s、1H)、7.61 - 7.62 (d、J = 1.8 Hz、1H)、7.25 - 7.33 (m、3H)、6.86 - 6.89 (d、J = 8.7 Hz、1H)、5.31 (s、2H)、3.83 (s、3H)、3.70 (s、3H)。
1H-NMR (300 MHz、DMSO) δ 8.25 (d、J = 1.8 Hz、1H)、8.07 - 8.11 (m、1H)、7.61 (d、J = 9.0 Hz、1H)、7.27 - 7.30 (d、J = 8.7 Hz、2H)、6.86 - 6.90 (m、2H)、5.46 (s、2H)、3.83 (s、3H)、3.71 (s、3H)。
1H-NMR (300 MHz、CDCl3): δ 13.20 (b、1H)、8.21 (d、J = 1.8 Hz、1H)、8.10 - 8.12 (m、1H)、7.43 (d、J = 8.7 Hz、1H)、3.88 (s、3H)。
C19H17N3O3について計算値: 335.13. (ES、m/z): [M+H]+ 336.0。
1H-NMR (300 MHz、DMSO): δ 12.49 (s、1H)、7.99 (d、J = 1.8 Hz、1H )、7.84 - 7.88 (m、1H )、7.30 (d、J = 8.4 Hz、1H)、7.13 - 7.16 (m、1H)、6.89 - 7.04 (m、3H)、3.88 - 3.93 (t、J = 6.3 Hz、2H)、3.85 (s、3H)、 2.73 - 2.78 (t、J = 6.6 Hz、2H)、1.91 - 1.99 (m、2H)。
C25H20FN3O2について計算値: 413.15. (ES、m/z): [M+H]+ 414.0
1H-NMR (300 MHz、CDCl3): δ 8.74 (s、1H)、8.21 - 8.24 (dd、J1 = J2 = 1.5 Hz、1H)、8.12 (d、J = 8.4 Hz、1H)、7.72 - 7.76 (m、2H)、6.93 - 7.02 (m、3H)、6.79 - 6.83 (m、2H)、6.62 (s、1H)、4.02 (s、3H)、3.93 - 3.97 (t、J = 6.0 Hz、2H)、2.79 - 2.84 (t、J = 6.3 Hz、2H)、2.09 - 2.14 (t、J = 6.3 Hz、2H)
C24H18FN3O2について計算値: 399.14 (ES、m/z): [M+H]+ 400.0
1H-NMR (300 MHz、DMSO): δ 8.36 (s、1H)、8.09 (d、J = 2.10 Hz、2H)、7.72 - 7.78 (m、2H)、7.06 - 7.12 (t、J = 9.0 Hz、2H)、6.98 - 7.00 (m、1H)、6.69 - 6.73 (m、2H)、6.57 - 6.59 (m、1H)、3.81 - 3.85 (t、J = 6.3 Hz、2H)、2.70 - 2.81 (t、J = 6.3 Hz、2H)、1.98 - 2.02 (t、J = 6.3 Hz、2H)
C27H21N3O3について計算値: 435.16. (ES、m/z): [M+H]+ 436.0
1H-NMR (300 MHz、CDCl3): δ 8.75 (s、1H)、8.18 - 8.28 (m、2H)、7.35 - 7.42 (m、2H)、7.17 - 7.20 (m、1H)、7.04 - 7.07 (m、2H)、6.74 - 6.76 (t、J = 4.5 Hz、2H)、6.57 (s、1H)、4.11 - 4.18 (m、5H)、3.00 - 3.03 (t、J = 6.6 Hz、2H)、2.22 - 2.26 (t、J = 6.0 Hz、2H)
C26H19N3O3について計算値: 421.14. (ES、m/z): [M+H]+ 422.0
1H-NMR (300 MHz、DMSO) δ 8.36 (s、1H)、8.16 - 8.20 (dd、J1 = J2 = 1.8 Hz、1H)、8.11(d、J = 8.7 Hz、1H)、7.53 - 7.66 (m、3H)、7.33 - 7.38 (m、1H)、7.20 - 7.25 (m、1H)、7.06 - 7.09 (m、1H)、6.66 - 6.73 (m、2H)、6.50 - 6.53 (dd、J1 = J2 = 0.9 Hz、1H )、3.87 - 3.92 (t、J = 6.0 Hz、2H)、2.90 - 3.00 (t、J = 6.3 Hz、2H)、2.08 - 2.17 (m、2H)
C27H20FN3O3について計算値: 453.15. (ES、m/z): [M+H]+ 454.0
1H-NMR (300 MHz、CDCl3): δ 8.65 (d、J = 1.5 Hz、1H)、8.19 - 8.27 (m、2H)、7.50 - 7.56 (m、3H)、7.34 - 7.37 (m、1H)、7.19 - 7.25 (m、1H)、7.09 - 7.13 (m、1H)、6.75 - 6.80 (m、2H)、6.59 - 6.61 (m、1H)、4.02 (s、3H)、3.96 - 3.98 (t、J = 6.0 Hz、2H)、3.00 - 3.04 (t、J = 6.6 Hz、2H)、2.19 - 2.24 (t、J = 6.0 Hz、2H)
C26H18FN3O3について計算値: 439.13. (ES、m/z): [M+H]+ 440.0
1H-NMR (300 MHz、DMSO) δ 12.40 (s、1H)、8.36 (s、1H)、8.15 (s、2H)、7.44 - 7.59 (m、3H)、7.17 - 7.22 (t、J = 6.9 Hz、1H)、7.06 (d、J = 5.4 Hz、1H )、6.57 - 6.69 (m、3H)、3.85 - 3.92 (m、2H)、2.85 - 2.93 (m、2H)、212 - 2.22 (m、2H)
C27H23N3O4について計算値: 453.17. (ES、m/z): [M+H]+ 454.0
1H-NMR (300 MHz、CDCl3): δ 8.70 (s、1H)、8.14 - 8.22 (m、2H)、7.29 - 7.34 (m、2H)、7.05 - 7.25 (m、2H)、6.83 - 6.86 (m、2H)、6.76 (d、J = 8.4 Hz 、1H)、4.21 - 4.25 (m、4H)、4.01 (s、3H)、3.87 - 3.91 (t、J = 6.3 Hz、2H)、2.82 - 2.86 (t、J = 6.6 Hz、2H),2.07 - 2.11 (t、J = 6.0 Hz、2H)
C26H21N3O4について計算値: 439.15. (ES、m/z): [M+H]+ 440.0
1H-NMR (300 MHz、DMSO): δ 13.25 (b、1H)、8.31 (d、J = 1.2 Hz、1H)、8.03 - 8.11 (m、2H)、7.25 - 7.30 (m、2H)、7.02 - 7.05 (t、J = 3.6 Hz、1H)、6.75 - 6.79 (m、3H)、6.61 - 6.64 (m、1H)、4.19 (d、J = 2.1 Hz、4H)、3.70 - 3.74 (t、J = 6.0 Hz、2H)、2.73 - 2.77 (t、J = 6.3 Hz、2H)、1.94 - 1.98 (t、J = 6.0 Hz、2H)
(ES、m/z): [M+H]+ 366.0
LC/MS (ES、m/z): [M+H]+ 444.0
1H-NMR (300 MHz、CDCl3) δ 8.76 (d、J = 1.8 Hz、1H)、8.17 - 8.21 (dd、J1 = J2 = 1.8 Hz、1H)、8.08 (d、J = 8.4 Hz、1H)、7.68 - 7.73 (m、2H)、6.93 - 6.99 (t、J = 8.7 Hz、2H)、6.56 - 6.60 (m、2H)、6.35 - 6.39 (m、1H)、4.01 (s、3H)、3.93 - 3.97 (t、J = 6.0 Hz、2H)、2.75 - 2.79 (t、J = 6.6 Hz、2H)、2.06 - 2.12 (m、2H)
LC/MS (ES、m/z): [M+H]+ 430.0
1H-NMR (300 MHz、DMSO) δ 8.31 (s、1H)、8.04 (s、2H)、7.71 - 7.76 (m、2H)、7.07 - 7.13 (t、J = 8.7 Hz、2H)、6.57 - 6.62 (m、2H)、6.30 - 6.33 (m、2H)、3.74 - 3.79 (t、J = 6.6 Hz、2H)、3.61 (s、3H)、2.68 - 2.73 (t、J = 6.3 Hz、2H)、1.94 - 1.99 (t、J = 6.3 Hz、2H)
LC/MS (ES、m/z): [M+H]+ 152.0
1H-NMR (300 MHz、CDCl3): δ 6.68 - 6.74 (m、2H)、6.43 - 6.48 (m、1H)、3.27 - 3.31 (m、2H)、2.74 - 2.79 (t、J = 6.6 Hz、2H)、1.91 - 1.99(m、2H)
LC/MS (ES、m/z): [M+H]+ 354.0
1H-NMR (300 MHz、DMSO) δ 12.50 (s、1H)、7.98 (d、J = 1.5 Hz,1H)、7.83 - 7.87 (m、1H)、7.31 (d、J = 8.7 Hz、1H)、6.95 - 7.03 (m、2H)、6.83 - 6.89 (m、1H)、3.85 - 3.93 (m、5H)、2.73 - 2.77 (t、J = 6.6 Hz、2H)、1.91 - 1.95 (t、J = 6.3 Hz、2H)
LC/MS (ES、m/z): [M+H]+ 432.0
1H-NMR (300 MHz、CDCl3) δ 8.67 (s、1H)、8.19 - 8.23 (m、1H)、8.10 (d、J = 8.7 Hz、1H)、7.72 - 7.77 (m、2H)、6.96 - 7.14 (m、2H)、6.74 - 6.78 (m、1H)、6.49 - 6.60 (m、2H)、4.02 (s、3H)、3.86 - 3.90 (t、J = 6.0 Hz、2H)、2.77 - 2.81 (t、J = 6.3 Hz、2H)、2.07 - 2.11(t、J = 6.9 Hz、2H)
LC/MS (ES、m/z): [M+H]+ 418.0
1H-NMR (300 MHz、DMSO) δ 8.34 (d、J = 1.2Hz、1H)、8.05 - 8.11 (m、2H)、7.72 - 7.77 (m、2H)、7.09 - 7.16 (m、2H)、6.85 - 6.89 (m、1H)、6.64 - 6.69 (m、1H)、6.51 - 6.57 (m、1H)、3.77 - 3.82 (t、J = 6.3 Hz、2H)、2.71 - 2.76 (t、J = 6.6 Hz、2H)、1.95 - 2.00 (t、J = 6.3 Hz、2H)
(ES、m/z): [M+H]+ 484.0
1H-NMR (300 MHz、CDCl3) δ 8.61 (d、J = 1.8 Hz、1H)、8.13 - 8.22 (m、2H)、7.36 - 7.42 (m、2H)、7.17 - 7.21 (m、1H)、7.01 - 7.08 (m、1H)、6.65 (d、J = 2.7 Hz、1H)、6.56 (d、J = 8.7 Hz、1H)、 6.33 - 6.37 (m、1H)、4.01 (s、3H)、3.95 - 3.99 (t、J = 6.3 Hz、2H)、3.63 (s、3H)、2.93 - 2.98 (t、J = 6.6 Hz、2H)、2.13 - 2.21 (m、2H)
LC/MS (ES、m/z): [M+H]+ 470.0
1H-NMR (300 MHz、DMSO) δ 13.38 (s、1H)、8.30 (s、1H)、8.07 - 8.13 (t、J = 8.7 Hz、2H)、7.55 - 7.59 (m、1H)、7.42 - 7.46 (m、2H)、7.16 - 7.23 (m、1H)、6.67 (d、J = 2.7 Hz、1H)、6.59 (d、J = 8.7 Hz、1H)、 6.30 - 6.34 (m、1H)、3.84 - 3.88 (t、J = 6.3 Hz、2H )、3.53 (s、3H)、2.87 - 2.91 (t、J = 6.3 Hz、2H)、2.01 - 2.09 (m、2H)
(ES、m/z): [M+H]+ 488.0
1H-NMR (300 MHz、DMSO) δ 8.63 (d、J = 1.5 Hz、1H)、8.18 - 8.26 (m、2H)、7.53 (d、J = 2.1 Hz、1H)、7.37 - 7.41 (t、J = 4.2 Hz、2H)、7.30 (d、J = 2.1 Hz、1H)、6.81 - 6.85 (m、1H)、6.46 - 6.58 (m、2H)、4.02 (s、3H)、3.96 - 4.00 (m、2H)、2.96 - 3.00 (t、J = 6.6 Hz、2H)、2.15 - 2.24 (m、2H)
(ES、m/z): [M+H]+ 374.0
1H-NMR (300 MHz、DMSO) δ 8.30 (d、J = 1.5 Hz、1H)、8.07 - 8.17 (m、2H)、7.75 (d、J = 2.1 Hz、1H)、7.61 (d、J = 9.0Hz、1H)、7.49 (s、1H)、7.36 - 7.39(m,1H)、6.91 - 6.96 (m、1H)、6.52 - 6.68 (m、1H)、3.85 - 3.89 (t、J = 6.0 Hz、2H)、2.90 - 2.95 (t、J = 6.6 Hz、2H)、2.05 - 2.10 (t、J = 6.0 Hz、2H)
(ES、m/z): [M+H]+ 500.0
1H-NMR (300 MHz、CDCl3) δ 8.61 (d、J = 1.5 Hz、1H)、8.13 - 8.22 (m、2H)、7.51 (d、J = 2.1 Hz、1H)、7.25 - 7.40 (m、3H)、6.65 (d、J = 2.7 Hz、1H)、6.56 (d、J = 8.7 Hz、1H)、 6.32 - 6.36 (m、1H)、4.01 (s、3H)、3.96 - 3.99 (t、J = 6.3 Hz、2H)、2.93 - 2.98 (t、J = 6.6 Hz、2H)、2.13 - 2.21 (m、2H)
LC/MS (ES、m/z): [M+H]+ 486.0
1H-NMR (300 MHz、DMSO) δ 13.35 (s、1H)、8.30 (d、J = 1.2 Hz、1H)、8.09 (s、1H)、7.71 (d、J = 2.1 Hz、1H)、7.56 (d、J = 8.7 Hz、1H)、7.42 (s、1H)、7.34 - 7.38 (m、1H)、6.67 (d、J = 2.7 Hz、1H)、6.59 (d、J = 8.7 Hz、1H)、 6.29 - 6.33 (m、1H)、3.84 - 3.88 (t、J = 6.3 Hz、2H)、3.53 (s、3H)、2.86 - 2.90 (t、J = 6.30 Hz、2H)、2.03 - 2.09 (m、2H)
メタノール (30 mL)中のメチル 2-オキソ-3-(1,2,3,4- テトラヒドロキノリン-1-イル)-1,2-ジヒドロキノキサリン-6-カルボキシラート (50 mg、0.15 mmol) の溶液に、水酸化カリウム (33.33 mg、0.60 mmol) および水 (1 mL)を一晩室温で撹拌しながら添加した。反応混合物を減圧下で濃縮し、水 (30 mL) に溶解し、HCl (3 N)を用いてpH 4に調整し、沈殿を得、これをろ過により収集し、 2-オキソ-3-(1,2,3,4- テトラヒドロキノリン-1-イル)-1,2-ジヒドロキノキサリン-6-カルボン酸を明黄色固体 (40.0 mg、79 %)として得た。
(ES、m/z): [M+H]+ 322.0
1H-NMR (300 MHz、DMSO) 7.98 (d、J = 1.5 Hz、1H )、7.83 - 7.86 (dd、J1 = J2 = 1.80 Hz、1H )、7.31 (d、J = 8.4 Hz、1H)、7.13 - 7.15 (dd、J1 = J2 = 1.5 Hz、1H)、6.87 - 7.04 (m、3H)、3.88 - 3.92 (t、J = 6.3 Hz、2H)、 2.73 - 2.78 (t、J = 6.6Hz、2H)、1.91 - 1.99 (s、2H)
LC/MS (ES、m/z): [M+H]+ 472.0
1H-NMR (300 MHz、CDCl3) δ 8.65 (d、J = 1.5 Hz、1H)、8.16 - 8.27 (m、2H)、7.37 - 7.43 (m、2H)、7.19 - 7.23 (m、1H)、7.03 - 7.10 (m、1H)、6.80 - 6.84 (m、1H)、6.47 - 6.59 (m、2H)、4.02 (s、3H)、3.98 - 4.00 (m、2H)、2.96 - 3.01 (t、J = 6.6 Hz、2H)、2.15 - 2.24 (m、2H)
LC/MS (ES、m/z): [M+H]+ 458.0
1H-NMR (300 MHz、DMSO) δ 8.33 (s、1H)、8.10 - 8.17 (m、2H)、7.57 - 7.62 (m,1H)、7.52 (s、1H)、7.45 - 7.49 (m、1H)、7.17 - 7.25 (m、1H)、6.92 - 6.96 (m,1H)、6.66 - 6.71 (m、1H)、6.53 - 6.59 (m、1H)、3.85 - 3.90 (t、J = 6.0 Hz、2H)、2.90 - 2.95 (t、J = 6.6 Hz、2H)、2.06 - 2.09 (m、2H)
[M+H]+ 425.1
1H-NMR (300 MHz、CD3OD) δ 8.56 (d、J = 1.2 Hz、1H)、8.30 - 8.33 (m、1H)、8.07 (d、J = 8.7 Hz、1H)、7.77 - 7.82 (m、2H)、7.33 (d、J = 1.8 Hz、1H)、7.06 - 7.12 (m、3H)、6.52 (d、J = 8.4 Hz、1H)、3.92 - 3.96 (t、J = 6.0 Hz、2H)、2.84 - 2.88 (t、J = 6.6 Hz、2H)、2.08 - 2.12 (t、J = 6.0 Hz、2H)
LC/MS (ES、m/z): [M+H]+ 338.0
1H-NMR (300 MHz、DMSO) δ 10.67 (s、1H)、8.41 (d、J = 2.1 Hz、1H)、7.93 - 7.96 (m、1H)、7.14 (d、J = 2.1 Hz、1H)、7.02 - 7.09 (m、3H)、6.88 - 6.93 (m、1H)、4.10 - 4.14 (m、2H)、3.96 (s、3H)、2.84 - 2.89 (t、J = 6.6 Hz、2H)、1.99 - 2.15 (m、2H)
LC/MS (ES、m/z): [M+H]+ 416
1H-NMR (300 MHz、CDCl3) δ 8.66 (d、J = 1.5 Hz 、1H)、8.19 - 8.23 (m、1H)、8.08 (d、J = 8.7 Hz 、1H)、7.72 - 7.79 (m、2H)、7.02 - 7.05 (m、3H)、6.76 - 6.82 (m、2H)、6.59 - 6.63 (m、1H)、4.02 (s 、3H)、3.86 - 3.90 (m、2H)、2.79 - 2.84 (t、J = 6.3Hz、2H)、2.08 - 2.12 (t、J = 6.3Hz、2H)
LC/MS(ES、m/z): [M+H]+ 495
1H-NMR (300 MHz、CDCl3) δ 8.64 (d、J = 1.8 Hz 、1H)、8.22 - 8.25 (m、1H)、8.09 (d、J = 8.7 Hz、1H)、7.76 - 7.81 (m、2H)、7.18 (s、1H)、7.00 - 7.05 (m、2H)、6.92 - 6.95 (m、1H)、6.51 (d、J = 8.7 Hz、1H)、4.01 (s、3H)、3.77 - 3.81 (t、J = 6.3Hz、2H)、2.78 - 2.79 (t、J = 6.6 Hz、2H)、2.05 - 2.10 (m ,2H)
LC/MS (ES、m/z): [M+H]+ 480.0
1H-NMR (300 MHz、DMSO) δ 8.37 (s、1H)、8.07 - 8.36 (m、2H)、7.75 - 7.80 (m、2H)、7.13 - 7.20 (m、3H)、6.85 - 6.89 (m、1H)、6.58 (d、J = 8.7 Hz、1H)、3.76 - 3.80 (t、J = 6.0 Hz、2H)、2.73 - 2.77 (t、J = 6.3Hz、2H)、1.95 - 1.99 (t、J = 6.0 Hz、2H)
LC/MS(ES、m/z):[M+H]+ 212.1
1H-NMR (300 MHz、CDCl3) δ 7.03 - 7.07 (m、2H)、6.35 - 6.38 (m、1H)、3.51 - 3.55 (m、2H)、2.73 - 2.80 (m、2H)、1.89 - 1.99 (m、2H)
LC/MS (ES、m/z): [M+H]+ 159.1
1H-NMR (300 MHz、CDCl3) δ 7.20 - 7.23 (m、2H)、6.40 (d、J = 8.1 Hz、1H)、3.36 - 3.40 (t、J = 5.7 Hz、2H)、2.72 - 2.77 (t、J = 6.3Hz、2H)、1.90 - 1.97 (m、2H)
LC/MS(ES、m/z): [M+H]+ 361.1
1H-NMR (300 MHz、DMSO) δ 12.67 (s、1H)、8.07 (d、J = 1.8 Hz、1H)、7.92 - 7.96 (m、1H)、7.60 (d、J = 1.8 Hz、1H)、7.35 - 7.43 (m、2H)、7.04 (d、J = 8.7 Hz、1H)、3.89 - 3.94 (m、2H)、3.87 (s、3H)、2.80 - 2.83 (t、J = 6.6 Hz、2H)、1.95 - 1.99 (t、J = 6.9 Hz、1H)
LC/MS(ES、m/z): [M+H]+ 439.1
1H-NMR (300 MHz、CDCl3) δ 8.67 (d、J = 1.8 Hz、1H)、8.30 - 8.33 (m、1H)、8.15 (d、J = 8.7 Hz、1H)、7.78 - 7.82 (m、2H)、7.33 (s、1H)、6.93 - 7.14 (m、3H)、6.60 (d、J = 8.4 Hz、1H)、4.13 (s、3H)、3.78 - 3.82 (t、J = 6.0 Hz、2H)、2.84 - 2.88 (t、J = 6.6 Hz、2H)、2.03 - 2.11 (m、2H)
(ES、m/z): [M+H]+ 443.1
1H-NMR (300 MHz、DMSO) δ 8.40 (d、J = 1.2 Hz、1H)、8.11 - 8.19 (m、2H)、7.79 - 7.83 (m、2H)、7.66 (s、1H)、7.55 (d、J = 1.2 Hz、1H)、7.27 - 7.30 (m、1H)、7.12 - 7.18 (m、2H)、7.03 (s、1H)、6.61 (d、J = 8.4 Hz、1H)、3.80 - 3.84 (t、J = 6.0 Hz、2H)、2.74 - 2.81 (m、J = 6.6 Hz、2H)、1.99 - 2.03 (m、J = 6.60 Hz、2H)
(ES、m/z): [M+H]+ 527.0
1H-NMR (300 MHz、DMSO): δ 8.43 (s、1H)、8.13 (s、2H)、7.68 - 7.73 (m、2H)、7.04 - 7.12 (m、3H)、6.69 (d、J = 8.4 Hz、1H)、6.57 (d、J = 8.1 Hz、1H )、3.96 (s、5H)、3.57 (s、4H)、 2.74 - 2.78 (t、J = 6.6 Hz、2H)、2.02 - 2.06 (t、J = 5.7 Hz、2H)
(ES、m/z): [M+H]+ 513.2
1H-NMR (300 MHz、DMSO): δ 8.41 (s、1H)、8.12 (s、2H)、 7.66 - 7.71 (m、2H)、7.02 - 7.10 (m、3H)、6.68 (d、J = 6.6 Hz、1H)、6.53 (d、J = 8.4 Hz、1H)、3.93 - 3.97 (t、J = 6.3Hz、2H)、3.56 (s、4H)、3.38 (s、3H)、2.73 - 2.77 (m、2H)、2.01 - 2.05 (m、2H)
(ES、m/z): [M+H]+ 512.0
1H-NMR (300 MHz、CDCl3): δ 8.70 (d、J = 1.5 Hz、1H)、8.35 - 8.38 (m、1H)、 8.18 (d、J = 4.2 Hz、1H)、7.77 - 7.82 (m、2H)、7.71 (d、J = 2.1 Hz、1H)、7.48 - 7.52 (m、1H)、7.11 - 7.16 (m、2H)、6.67 (d、J = 9.0 Hz、1H)、4.04 (s、3H)、3.76 - 3.80 (t、J = 6.0 Hz、2H)、2.92 - 2.96 (t、J = 6.3Hz、2H)、2.07 - 2.12 (m、2H)
(ES、m/z): [M+H]+ 521.0
1H-NMR (300 MHz、CDCl3): δ 8.68 (d、J = 1.5 Hz、1H)、8.28 - 8.31 (m、1H)、 8.14 (d、J = 5.7 Hz、1H)、7.72 - 7.78 (m、2H)、7.43 (d、J = 2.1 Hz、1H)、7.15 - 7.19 (m、1H)、6.96 - 7.02 (m、2H)、6.57 (d、J = 8.4 Hz、1H)、4.04 (s、3H)、3.95 - 3.99 (t、J = 6.0 Hz、2H)、2.87 - 2.91 (t、J = 6.9 Hz、2H)、2.61 (s、6H)、2.09 - 2.18 (m、2H)
(ES、m/z): [M+H]+ 507.1
1H-NMR (300 MHz、DMSO): δ 8.43 (s、1H)、8.22 - 8.25 (m、1H)、 8.04 (d、J = 8.4 Hz、1H)、7.70 - 7.75 (m、2H)、7.30 (d、J = 2.1 Hz、1H)、7.08 - 7.14 (t、J = 9.0 Hz、2H)、6.97 - 7.01 (m、1H)、6.62 (d、J = 8.4 Hz、1H)、3.99 - 4.03 (t、J = 6.0 Hz、2H)、2.82 - 2.86 (t、J = 6.0 Hz、2H)、2.51 (s、6H)、2.04 - 2.18 (m、2H)
(ES、m/z):[M+H]+ 245.1
1H-NMR (300 MHz、CDCl3) δ 8.80 - 8.82 (m、1H)、8.01 - 8.14 (m、2H)、7.47 - 7.51 (m、1H)、7.30 - 7.38 (m、1H)、6.90 - 7.10 (m、1H)、1.56 (s、9H)
LC/MS (ES、m/z):[M+H]+ 145.1
1H-NMR (300 MHz、CDCl3) δ 8.67 - 8.69(m、1H)、7.91 - 7.95(m、2H)、7.28 - 7.31(m、1H)、7.16 - 7.20(m、1H)、6.92 (s、1H)、3.96 (s、2H)
LC/MS (ES、m/z):[M+H]+ 173.1
1H-NMR (300 MHz、CDCl3) δ 8.59 - 8.61 (m、1H)、7.94 - 8.00 (m、2H)、7.37 - 7.41 (m、1H)、7.27 - 7.32 (m、1H)、6.81 (d、J = 2.7 Hz、1H)、3.07 (s、6H)
LC/MS (ES、m/z):[M+H]+ 177.1
LC/MS(ES、m/z):[M+H]+ 378.1
1H-NMR (300 MHz、CDCl3) δ 10.29 (s,1H)、8.28 (d、J = 1.5 Hz、1H)、7.84 - 7.91 (m、1H)、7.02 - 7.07 (m、1H)、6.85 (d、J =8.7 Hz、1H)、6.62 (s、2H)、4.06 - 4.16 (m、2H)、3.95 (s、3H)、2.98 (s,6H)、2.81 - 2.91 (m、2H)、2.38 - 2.41 (m、2H)
LC/MS (ES、m/z):[M+H]+ 456.1
1H-NMR (300 MHz、CDCl3): δ 8.56 (s、1H)、8.13 - 8.20 (m、1H)、8.02 - 8.05 (m、1H)、7.73 - 7.85 (m、2H)、6.91 - 6.99 (m、3H)、6.75 - 6.85 (m、1H)、6.30 - 6.40 (m、2H)、4.01 - 4.03 (s、3H)、3.75 - 3.80 (m、2H)、2.86 (s、6H)、2.75 - 2.79 (m、2H)、2.02 - 2.06 (m、2H)
LCMS (ES、m/z):[M+H]+ 443.1
1H-NMR (300 MHz、CD3OD): δ 8.48 (s、1H)、8.11 - 8.15 (m、1H)、7.96 (d、J = 8.4 Hz、1H)、7.67 - 7.71 (m、2H)、6.91 - 6.97 (t、J = 9.0 Hz、2H)、6.20 - 6.60 (m、3H)、3.85 - 4.05 (m、2H)、2.60 - 2.90 (m、8H)、2.07 - 2.11 (t、J = 6.6 Hz、2H)
LC/MS (ES、m/z): [M+H]+ 168.0
1H-NMR (300 MHz、CDCl3) δ 6.90 - 6.98 (m、2H)、6.39 - 6.42 (t、J = 1.2 Hz、1H)、3.23 - 3.35 (m、2H)、2.73 - 2.81 (m、2H)、1.91 - 1.96 (m、2H)
LC/MS (ES、m/z): [M+H]+ 370.0
LC/MS(ES、m/z): [M+H]+ 448.0
1H-NMR (300 MHz、DMSO) δ 8.39 (s、1H)、8.12 (d、J = 1.2 Hz、2H)、7.75 - 7.80 (m、2H)、7.07 - 7.18 (m、3H)、6.65 - 6.77 (m、2H)、3.95 (s、3H)、3.79 - 3.92 (m、2H)、2.72 - 2.77 (t、J = 6.6 Hz、2H)、1.94 - 2.02 (m、2H)
LC/MS (ES、m/z): [M+H]+ 434.0
1H-NMR (300 MHz、DMSO) δ 8.37 (s、1H)、8.05 - 8.16 (m、2H)、7.75 - 7.79 (m、2H)、7.07 - 7.19 (m、3H)、6.62 - 6.70 (m、1H)、6.73 - 6.77 (m、1H)、3.77 - 3.81 (t、J = 6.0 Hz、2H)、2.72 - 2.77 (t、J = 6.3Hz、2H)、1.95 - 2.01 (m、2H)
1H-NMR (300 MHz、CDCl3) δ 8.93 - 8.98 (m、1H)、8.43 - 8.46 (m、H)、7.92 (d、J = 8.4 Hz、1H)、7.62 - 7.78 (m、1H)、7.41 - 7.49 (m、1H)、7.22 - 7.26 (m、1H)
LC/MS (ES、m/z): [M+H]+ 152.0
1H-NMR (300 MHz、CDCl3) δ 6.87 - 6.95 (m、2H)、6.26 - 6.40 (m、2H)、3.28 - 3.31 (m、2H)、2.72 - 2.77 (t、J = 6.60 Hz、2H)、1.92 - 1.98 (m、2H)
LC/MS (ES、m/z): [M+H]+ 354.0
LC/MS (ES、m/z): [M+H]+ 432.0
1H-NMR (300 MHz、CDCl3) δ 8.63 (d、J = 1.8 Hz、1H)、8.22 - 8.26 (m、1H)、8.09 (d、J = 2.7 Hz、1H)、7.82 - 7.88 (m、2H)、7.01 - 7.09 (m、2H)、6.76 - 6.84 (m、1H)、6.45 - 6.58 (m、2H)、4.01 (s、3H)、3.71 - 3.77 (m、2H)、2.81 - 2.85 (t、J = 6.9 Hz、2H)、2.02 - 2.10 (m、2H)
LC/MS(ES、m/z): [M+H]+ 418.1
1H-NMR (300 MHz、DMSO) δ 8.54 (s、1H)、8.09 - 8.38 (m、2H)、7.81 - 7.90 (m、2H)、7.16 - 7.22 (m、2H)、6.73 - 6.80 (m、1H)、6.46 - 6.59 (m、2H)、3.73 - 3.76 (t、J = 6.0 Hz、2H)、2.71 - 2.75 ( t、J = 6.6 Hz、2H)、1.97 - 2.06 (m、2H)
LC/MS(ES、m/z): [M+H]+ 417.0
1H-NMR (300 MHz、CDCl3): δ 8.60 (d、J = 1.5 Hz、1H)、8.20 - 8.23 (m、1H)、7.99 (d、J = 8.7 Hz、1H)、6.93-6.98 (m、1H)、6.78 - 6.85 (m、1H)、6.57 (d、J = 4.8 Hz、1H)、4.02(s、3H)、3.92 - 3.96 (m、2H)、2.87 - 2.92 (m、2H)、2.13 - 2.17 (m、2H)
LC/MS (ES、m/z): [M+H]+ 467.0
1H-NMR (300 MHz、CDCl3): δ 8.62 (d、J = 1.5 Hz、1H)、8.20 - 8.26 (m、2H)、7.99 - 8.02 (m、2H)、7.60 (d、J = 9.0 Hz、1H)、7.22 (d、J = 6.6 Hz、1H)、6.79 - 6.83 (m、1H)、6.72 - 6.75 (m、1H)、6.57 - 6.71 (m、1H)、6.23 (s、1H)、4.01(s、3H)、3.68 - 3.72 (m、2H)、2.72 - 2.83 (m、2H)、2.46 (s、3H)、1.98 - 2.02 (m、2H)
LC/MS (ES、m/z): [M+H]+ 453.1
1H-NMR (300 MHz、DMSO): δ 10.99 (s、1H)、8.24 (s、1H)、8.09 - 8.12 (m、1H)、7.91 - 7.95 (m、2H)、7.51 (d、J =1.5 Hz、1H)、7.48 (d、J = 1.5 Hz、1H)、6.81 - 6.85 (m、1H)、6.71 - 6.75 (m、1H)、6.56 - 6.62 (m、1H)、6.15 (s、1H)、3.61 - 3.68 (m、2H)、2.74 - 2.81 (m、2H)、2.49 (s、3H)、1.92 - 1.95 (m,2H)
LC/MS (ES、m/z):[M+H]+ 454.0
1H-NMR (300 MHz、CDCl3): δ 8.61 (d、J = 1.8 Hz、1H)、8.19 - 8.26 (m、2H)、8.08 - 8.18 (m,2H)、7.87 - 7.95 (m、1H)、7.43 - 7.49 (m、1H)、6.66 - 6.71 (m、2H)、6.47 - 6.53 (m、1H)、4.02 (s、3H)、3.76 - 3.80 (t、J = 6.0 Hz、2H)、2.78 - 2.82 (t、J = 6.3Hz、2H)、 2.01 - 2.09 (m、2H)
LC/MS (ES、m/z): [M+H]+ 440.1
1H-NMR (300 MHz、DMSO) δ 13.11(s、1H)、8.33 (s、1H)、8.20 (s、1H)、8.05 - 8.10 (m,3H)、7.74 - 7.77 (m、1H)、7.46 (d、J = 8.7 Hz、1H)、6.72 - 6.81 (m、2H)、6.49 - 6.56 (m、1H)、3.71 - 3.75 (t、J = 6.0 Hz、2H)、2.74 - 2.78 (t、J = 6.3Hz、2H)、 1.93 - 1.97 (t、J = 6.3Hz、2H)
LC/MS (ES、m/z): [M+H]+ 160.0
1H-NMR (300 MHz、CDCl3): δ 8.84 - 8.86 (m、1H)、8.07 - 8.11 (m、1H)、7.70 - 7.73 (t、J = 5.1 Hz、1H)、7.44 (d、J = 2.4 Hz、1H)、7.20 - 7.30 (m、2H)、3.95 (s、3H)
LC/MS (ES、m/z): [M+H]+ 164.0
1H-NMR (300 MHz、CD3OD): δ 6.76 (d、J = 8.4 Hz、1H)、6.09 - 6.17 (m、2H)、3.69 (s、1H)、3.19 - 3.23 (m、2H)、2.64 - 2.69 (t、J = 6.6 Hz、2H)、1.85 - 1.93 (m、2H)
LC/MS (ES、m/z): [M+H]+ 366.1
1H-NMR (300 MHz、CD3OD): δ 8.21 (d、J = 1.8 Hz、1H)、7.93 - 7.96 (m、1H)、7.28 (d、J = 8.4 Hz、1H)、7.05 (d、J = 8.4 Hz、1H)、6.60 - 6.63 (m、1H)、6.43 (d、J = 2.4 Hz、1H)、3.92 - 4.02 (m、1H)、3.88 (s、3H)、3.69 (s、3H)、2.76 - 2.81 (t、J = 6.6 Hz、2H)、1.99 - 2.09 (m、2H)
LC/MS(ES、m/z): [M+H]+ 444.0
1H-NMR (300 MHz、CD3OD): δ 8.64 (d、J = 1.8 Hz、1H)、8.19 - 8.23 (m、1H)、8.08 (d、J = 2.1 Hz、1H)、7.72 - 7.80 (m、2H)、6.92 - 7.02 (m、3H)、6.35 - 6.39 (m、1H)、6.13 (d、J = 2.4 Hz、1H)、4.02 (s、3H)、3.77 - 3.90 (m、2H)、3.59 (s、3H)、2.74 - 2.78 (t、J = 6.6 Hz、2H)、2.02 - 2.11 (m、2H)
LC/MS (ES、m/z): [M+H]+ 430.1
1H-NMR (300 MHz、DMSO): δ δ 8.37 (s、1H)、8.10 (s、1H)、7.73 - 7.78 (m、2H)、7.08 - 7.14 (m、2H)、6.87 (d、J = 8.4Hz、1H)、6.28 - 6.31 (m、1H)、6.13 (d、J = 2.4Hz、1H)、3.80 - 3.85 (m、2H)、3.47 (s,3H)、2.65 - 2.71 (m、2H)、1.90 - 2.10 (m、2H)
LC/MS (ES、m/z): [M+H]+ 202.0
1H-NMR (300 MHz、CDCl3): δ 7.51 - 7.62 (m、1H)、7.31 - 7.41 (m、1H)、7.16 (d、J = 8.1 Hz、1H)、6.83 - 6.89 (m、1H)、3.89 - 3.93 (m、2H)、2.82 - 2.87 (m、2H)
LCMS (ES、m/z): [M+H]+ 166.0
1H-NMR (300 MHz、CDCl3): δ 8.73 (s、1H)、7.10 - 7.19 (m、1H)、6.71 - 6.79 (m、1H)、6.56 - 6.70 (m、1H)、2.98 - 3.05 (m、2H)、2.64 - 2.69 (m、2H)
LC/MS (ES、m/z): [M+H]+ 152.0
1H-NMR (300 MHz、CDCl3): δ 6.86 - 6.94 (m、1H)、6.15 - 6.26 (m、1H)、6.27 - 6.35 (m、1H)、3.92 (s、1H)、3.29 - 3.33 (m、2H)、2.72 - 2.78 (m、2H)、1.91 - 2.00 (m、2H)
LC/MS (ES、m/z): [M+H]+ 432.0
1H-NMR (300 MHz、CDCl3): δ 8.67 (d、J = 1.8 Hz、1H)、8.23 - 8.27 (m、1H)、8.12 (d、J = 8.7 Hz、1H)、7.76 - 7.81 (m、2H)、6.93 - 7.05 (m、2H)、6.46 - 6.53 (m、1H)、6.28 - 6.33 (m、1H)、4.03 (s、3H)、3.81 - 3.85 (m、2H)、2.76 - 2.81 (m、2H)、2.03 - 2.11 (m、2H)
LC/MS (ES、m/z): [M+H]+ 418.1
1H-NMR (300 MHz、DMSO): δ 8.39 (d、J = 1.2 Hz、1H)、8.09 - 8.17 (m、2H)、7.76 - 7.81 (m、2H)、7.14 - 7.20 (m、2H)、6.98 - 7.03 (m、1H)、6.49 - 6.54 (m、2H)、6.75 - 6.79 (m、2H)、2.70 - 2.74 (m、2H)、1.94 - 1.98 (m、2H)
LC/MS (ES、m/z): [M+H]+ 266.0
1H-NMR (300 MHz、CDCl3): δ 8.10 (d、J = 15.9 Hz、1H)、7.57 (s、1H)、7.01 (s、1H)、6.25 (d、J =15.6 Hz、1H)、6.15 (d、J = 8.7 Hz、2H)、4.27 - 4.34 (m、2H)、1.34 - 1.39 (t、J = 7.2 Hz、3H)
LC/MS (ES、m/z): [M+H]+ 192.0
1H-NMR (300 MHz、CD3OD): δ 6.69 (s、1H)、6.45 (d、J = 5.4 Hz、1H)、5.90 (s、2H)、2.83 - 2.88 (m、2H)、2.49 - 2.55 (m、2H)
LC/MS (ES、m/z): [M+H]+ 178.0
1H-NMR (300 MHz、CDCl3): δ 6.48 (s、1H)、6.12 (s、1H)、5.82 (s、2H)、3.24 - 3.27 (m、2H)、2.68 - 2.72 (t、J = 6.3Hz、2H)、1.88 - 1.96 (m、2H)
LC/MS (ES、m/z): [M+H]+ 380.0
1H-NMR (300 MHz、CDCl3): δ10.31 (s、1H)、8.30 - 8.36 (m、1H)、7.92 - 9.95 (m、1H)、7.06 (d、J = 8.7 Hz、1H)、6.68 (d、J = 9.0 Hz、1H)、6.50 (d、J = 7.5 Hz、1H)、5.92 (s、2H)、4.02 - 4.08 (m、2H)、3.96 (s、3H)、2.75 - 2.79 (t、J = 6.3Hz、2H)、2.00 - 2.08 (m、2H)
LC/MS (ES、m/z): [M+H]+ 458.0
1H-NMR (300 MHz、CDCl3): δ 8.69 (d、J = 1.5 Hz、1H)、8.17 - 8.21 (m、1H)、8.07 (d、J = 8.7 Hz、1H)、7.72 - 7.76 (m、2H)、6.98 - 7.04 (m、2H)、6.53 (s、1H)、6.19 (s,1H)、5.80 (s、2H)、4.02 (s、3H)、3.80 - 3.85 (t、J = 6.6 Hz、2H)、2.68 - 2.73 (t、J = 6.3Hz、2H)、2.02 - 2.06 (t、J = 6.6 Hz、2H)
LC/MS (ES、m/z): [M+H]+ 444.1
1H-NMR (300 MHz、DMSO): δ 8.30 (s、1H)、8.08 (d、J = 8.7l Hz、1H)、7.98 (d、J = 8.4 Hz、1H)、7.73 - 7.77 (m、2H)、7.13 - 7.19 (m、2H)、6.61 (s、1H)、6.39 (s、1H)、5.79 (s、2H)、3.62 - 3.66 (t、J = 6.3Hz、2H)、2.61 - 2.66 (t、J = 6.3Hz、2H)、1.87 - 1.91 (t、J = 6.3Hz、2H)
PAS キナーゼFRET アッセイ
FRET アッセイの目的は、被験化合物の標的化(targeted)キナーゼに対する阻害能力を決定することである。このアッセイプラットフォームは、キナーゼ反応の後の溶液におけるホスホ-基質の量を定量することにより、キナーゼ活性を測定するための均質なスクリーニング方法を提供する。
Claims (14)
- 3-(1,2,3,4-テトラヒドロキノリン-1(2H)-イル)-2-(4-フルオロフェニル)キノキサリン-6-カルボン酸;
2-(ベンゾフラン-2-イル)-3-(1,2,3,4- テトラヒドロキノリン-1(2H)-イル)キノキサリン-6-カルボン酸;
3-(1,2,3,4-テトラヒドロキノリン-1(2H)-イル)-2-(5-フルオロベンゾフラン-2-イル)キノキサリン-6-カルボン酸;
2-(2,3-ジヒドロ-1,4-ベンゾジオキシン-6-イル)-3-(1,2,3,4-テトラヒドロキノリン-1-イル)キノキサリン-6-カルボン酸;
2-(4-フルオロフェニル)-3-(6-メトキシ-1,2,3,4- テトラヒドロキノリン-1-イル)キノキサリン-6-カルボン酸;
3-(6-フルオロ-1,2,3,4- テトラヒドロキノリン-1-イル)-2-(4-フルオロフェニル)キノキサリン-6-カルボン酸;
2-(5-フルオロ-1-ベンゾフラン-2-イル)-3-(6-メトキシ-1,2,3,4- テトラヒドロキノリン-1-イル)キノキサリン-6-カルボン酸;
2-(5-クロロ-1-ベンゾフラン-2-イル)-3-(6-フルオロ-1,2,3,4- テトラヒドロキノリン-1-イル)キノキサリン-6-カルボン酸;
2-(5-クロロ-1-ベンゾフラン-2-イル)-3-(6-メトキシ-1,2,3,4- テトラヒドロキノリン-1-イル)キノキサリン-6-カルボン酸;
3-(6-フルオロ-3,4-ジヒドロキノリン-1(2H)-イル)-2-(5-フルオロベンゾフラン-2-イル)キノキサリン-6-カルボン酸;
3-(6-クロロ-1,2,3,4- テトラヒドロキノリン-1-イル)-2-(4-フルオロフェニル)キノキサリン-6-カルボン酸;
2-(4-フルオロフェニル)-3-(7-メトキシ-1,2,3,4- テトラヒドロキノリン-1-イル)キノキサリン-6-カルボン酸;
- 3-(6-フルオロ-1,2,3,4- テトラヒドロキノリン-1-イル)-2-(4-フルオロフェニル)キノキサリン-6-カルボン酸である請求項1記載の化合物またはその医薬上許容される塩。
- 2-オキソ-3-(1,2,3,4- テトラヒドロキノリン-1-イル)-1,2-ジヒドロキノキサリン-6-カルボン酸である化合物またはその医薬上許容される塩。
- 請求項1〜3のいずれか記載の化合物またはその医薬上許容される塩を医薬上許容される担体とともに含む医薬組成物。
- 請求項1〜3のいずれか記載の化合物またはその医薬上許容される塩を含む、PASKを阻害するための医薬。
- 請求項1〜3のいずれか記載の化合物またはその医薬上許容される塩を含む、癌および代謝性疾患から選択される疾患の治療用医薬。
- 該疾患が代謝性疾患である請求項6記載の医薬。
- 該代謝性疾患が、メタボリック・シンドローム、糖尿病、脂質異常症、脂肪肝疾患、非アルコール性脂肪性肝炎、肥満、およびインスリン抵抗性から選択される、請求項7記載の医薬。
- 該糖尿病が2型糖尿病である請求項8記載の医薬。
- 該脂質異常症が高脂血症である請求項8記載の医薬。
- 患者において効果を達成するための医薬であって、請求項1〜3のいずれか記載の化合物またはその医薬上許容される塩を含み、ここで、該効果が、トリグリセリドの低下、コレステロールの低下、およびヘモグロビン A1cの低下からなる群から選択される、医薬。
- 該コレステロールが、LDLおよびVLDLコレステロールから選択される請求項11記載の医薬。
- 該トリグリセリドが、血漿トリグリセリドおよび肝臓トリグリセリドから選択される請求項11記載の医薬。
- 以下を含む、PASK-媒介疾患の治療用組合せ剤:
a. 請求項1〜3のいずれか記載の化合物またはその医薬上許容される塩;および、
b.別の治療薬。
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JP6139415B2 (ja) * | 2011-03-02 | 2017-05-31 | バイオエナジェニックス | Paskの阻害のための複素環化合物 |
US20150374687A1 (en) | 2013-02-07 | 2015-12-31 | Merck Patent Gmbh | Substituted quinoxaline derivatives and their use as positive allosteric modulators of mglur4 |
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EA202191286A1 (ru) * | 2019-01-08 | 2021-11-19 | Керин Фармасьютикал Ко., Лтд. | Ингибитор 15-pgdh |
KR102543789B1 (ko) * | 2021-03-08 | 2023-06-20 | 주식회사 온코크로스 | 토르세미드 및 크로몰린을 포함하는 대사질환 예방 또는 치료용 조성물 |
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CH419399A (de) | 1962-07-18 | 1966-08-31 | Ciba Geigy | Verfahren zur Herstellung neuer Küpenfarbstoffe |
US6331555B1 (en) | 1995-06-01 | 2001-12-18 | University Of California | Treatment of platelet derived growth factor related disorders such as cancers |
US6245760B1 (en) * | 1997-05-28 | 2001-06-12 | Aventis Pharmaceuticals Products, Inc | Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases |
DE10013318A1 (de) | 2000-03-17 | 2001-09-20 | Merck Patent Gmbh | Formulierung enthaltend Chinoxalinderivate |
FR2816940A1 (fr) | 2000-11-23 | 2002-05-24 | Lipha | Derives de 4-(biphenylcarbonylamino)-piperidine, compositions les contenant et leur utilisation |
US6319679B1 (en) | 2001-01-26 | 2001-11-20 | Board Of Regents, The University Of Texas System | PAS kinase |
US20040204450A1 (en) * | 2003-03-28 | 2004-10-14 | Pfizer Inc | Quinoline and quinoxaline compounds |
US7189724B2 (en) | 2003-04-15 | 2007-03-13 | Valeant Research And Development | Quinoxaline derivatives having antiviral activity |
WO2005007099A2 (en) | 2003-07-10 | 2005-01-27 | Imclone Systems Incorporated | Pkb inhibitors as anti-tumor agents |
AU2004281154A1 (en) * | 2003-10-16 | 2005-04-28 | Novartis Vaccines And Diagnostics, Inc. | 2,6-disubstituted quinazolines, quinoxalines, quinolines and isoquinolines as inhibitors of Raf kinase for treatment of cancer |
JP2008527002A (ja) | 2005-01-13 | 2008-07-24 | サートリス ファーマシューティカルズ, インコーポレイテッド | 神経変性障害および血液凝固障害を予防および処置するための新規組成物 |
WO2006079021A2 (en) | 2005-01-20 | 2006-07-27 | Sirtris Pharmaceuticals, Inc. | Use of sirtuin-activating compounds for treating flushing and drug induced weight gain |
WO2006091395A2 (en) | 2005-02-14 | 2006-08-31 | Merck & Co., Inc. | Inhibitors of akt activity |
WO2006138418A2 (en) | 2005-06-14 | 2006-12-28 | President And Fellows Of Harvard College | Improvement of cognitive performance with sirtuin activators |
US20100256220A1 (en) | 2006-06-08 | 2010-10-07 | University Of Utah Research Foundation | PAS Kinase Regulates Energy Homeostasis |
AR066879A1 (es) * | 2007-06-08 | 2009-09-16 | Novartis Ag | Derivados de quinoxalina como inhibidores de la actividad de cinasa de tirosina de las cinasas janus |
JP2012517448A (ja) | 2009-02-11 | 2012-08-02 | リアクション バイオロジー コープ. | 選択的キナーゼ阻害剤 |
DK2440546T3 (da) | 2009-06-12 | 2023-03-27 | Abivax | Forbindelser, der er anvendelige til behandling af for tidlig aldring og især progeria |
BR112012004533B1 (pt) * | 2009-09-03 | 2021-11-09 | Bioenergenix | Composto, composição farmacêutica, e uso do composto |
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CN103391932B (zh) | 2015-10-14 |
EP2661431A4 (en) | 2014-06-25 |
KR20140034747A (ko) | 2014-03-20 |
BR112013017164B1 (pt) | 2021-05-04 |
AU2012204353B2 (en) | 2016-12-08 |
NZ613181A (en) | 2015-07-31 |
KR101858292B1 (ko) | 2018-05-15 |
US9073902B2 (en) | 2015-07-07 |
JP2014505053A (ja) | 2014-02-27 |
WO2012094462A2 (en) | 2012-07-12 |
US20120220589A1 (en) | 2012-08-30 |
CA2823753C (en) | 2019-03-12 |
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CA2823753A1 (en) | 2012-07-12 |
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