JP2009528991A - プロテインキナーゼの阻害剤として有用なピロロ(3,2−c)ピリジン - Google Patents
プロテインキナーゼの阻害剤として有用なピロロ(3,2−c)ピリジン Download PDFInfo
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Abstract
Description
The Protein Kinase Facts Book、IおよびII、Academic Press、サンディエゴ市、カリフォルニア州:1995年 FASEB J.1995年、9巻、576〜596頁 Science 1991年、253巻、407〜414頁 Cell 1992年、70巻、419〜429頁 Cell 1993年、73巻、585〜596頁 EMBO J.、1994年、13巻、2352〜2361頁 Annu. Rev. Cell Dev. Biol.1997年、13巻、513頁 Pharmacol.Ther.1998年、77巻、81頁;Tatosyanおよび Mizenina、Biochemistry(Moscow)2000年、65巻、49〜58頁 Drugs of the Future 2000年、25巻(7号)、717頁 Biochemistry(Moscow)2000年、65巻、49〜58頁 Cell 1992年、69巻、551頁 Cell 1991年、64巻、693頁 J.Clin.Invest.1999年、104巻、137頁 Drugs of the Future 2000年、25巻(7号)、717頁 EMBO J.1999年、18巻、5019頁 Mol.Cell.Biol.1997年、17巻、6427頁
R1は、C1〜6ハロアルキル、Q、または−Z−Qであり;
R2は、H、ハロ、CN、NO2、C1〜4ハロ脂肪族、C3〜6環式脂肪族、またはC1〜6脂肪族であり;
環Aは、O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環であり;
R4は、H、C1〜6脂肪族、C3〜6環式脂肪族、または−(Y)n−V1であり;式中、
nは、0または1であり;
Yは、0〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−で場合により置き換えられている非置換のC1〜6脂肪族であり;
V1は、C3〜6環式脂肪族、ハロ(C1〜4脂肪族)、3〜6員のヘテロシクリル、ハロ、NO2、CN、OH、OR”、SH、SR”、NH2、NHR”、N(R”)2、COH、COR”、CO2H、CO2R”、CONH2、CONHR”、CONR”2、OCOR”、OCONH2、OCONHR”、OCON(R”)2、NHCOR”、NR”COR”、NHCO2R”、NR”CO2R”、NHCO2H、NR”CO2H、NHCONH2、NHCONHR”、NHCON(R”)2、SO2NH2、SO2NHR”、SO2N(R”)2、NHSO2R”、またはNR”SO2R”であり;
R”は、非置換のC1〜4脂肪族であり;
T1は、0〜3個の−NR−、−O−、−S−、−C(O)−、−C(=NR)−、−C(=NOR)−、−SO−、または−SO2−で場合により置き換えられているC1〜6脂肪族であり;各T1は、場合により0〜2個のJTで置換されており;
R5は、H;0〜2個のO、N、およびSで場合により置き換えられているC1〜6脂肪族;O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環であり;各R5は、場合により0〜5個のJ5で置換されており;
R7は、Hまたはハロであり;
Zは、0〜3個の−NR−、−O−、−S−、−C(O)−、−C(S)−、−C(=NR)−、−C(=NOR)−、−SO−、または−SO2−で場合により置き換えられているC1〜6脂肪族であり;各Zは、場合により0〜2個のJZで置換されており;
Qは、H;C1〜6脂肪族;O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環であり;各Qは、場合により0〜5個のJQで置換されており;
各JZは、独立に、H、ハロ、C1〜6脂肪族、C3〜6環式脂肪族、NO2、CN、−NH2、−NH(C1〜4脂肪族)、−N(C1〜4脂肪族)2、−OH、−O(C1〜4脂肪族)、−CO2H、−CO2(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、またはハロ(C1〜4脂肪族)であり;
J5は、Mまたは−Y−Mであり;
各Yは、独立に、0〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−で場合により置き換えられている非置換のC1〜6脂肪族であり;
各Mは、独立に、H、C1〜6脂肪族、C3〜8環式脂肪族、ハロ(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、3〜8員のヘテロシクリル、ハロ、NO2、CN、OH、OR’、SH、SR’、NH2、NHR’、N(R’)2、COH、COR’、CO2H、CO2R’、CONH2、CONHR’、CONR’2、OCOR’、OCONH2、OCONHR’、OCON(R’)2、NHCOR’、NR’COR’、NHCO2R’、NR’CO2R’、NHCO2H、NR’CO2H、NHCONH2、NHCONHR’、NHCON(R’)2、SO2NH2、SO2NHR’、SO2N(R’)2、NHSO2R’、NR’SO2R’、POR’、PO2R’、PO(R’)2、またはPO(OR’)2であり;
JQは、M1または−Y1−M1であり;
各Y1は、独立に、0〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−で場合により置き換えられている非置換のC1〜6脂肪族であり;
各M1は、独立に、H、C1〜6脂肪族、C3〜8環式脂肪族、ハロ(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、3〜8員のヘテロシクリル、5〜6員のヘテロアリール、フェニル、ハロ、NO2、CN、OH、OR’、SH、SR’、NH2、NHR’、N(R’)2、COH、COR’、CO2H、CO2R’、CONH2、CONHR’、CONR’2、OCOR’、OCONH2、OCONHR’、OCON(R’)2、NHCOR’、NR’COR’、NHCO2R’、NR’CO2R’、NHCO2H、NR’CO2H、NHCONH2、NHCONHR’、NHCON(R’)2、SO2NH2、SO2NHR’、SO2N(R’)2、NHSO2R’、NR’SO2R’、POR’、PO2R’、PO(R’)2、またはPO(OR’)2であり;
各MおよびM1は、独立におよび場合により、0〜5個のJMで置換されており、
Rは、Hまたは非置換のC1〜6脂肪族であり;
R’は、非置換のC1〜6脂肪族であるか;または、2個のR’基が、それらが結合している原子と一緒になって、O、N、およびSから独立に選択される0〜1個のヘテロ原子を有する非置換で3〜8員の非芳香族単環を形成しており;
各JTおよびJMは、独立に、H、ハロ、C1〜6脂肪族、C3〜6環式脂肪族、NO2、CN、−NH2、−NH(C1〜4脂肪族)、−N(C1〜4脂肪族)2、−OH、−O(C1〜4脂肪族)、COH、−CO(C1〜4脂肪族)、CONH2、CONH(C1〜4脂肪族)、CON(C1〜4脂肪族)2、−CO2H、−CO2(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、またはハロ(C1〜4脂肪族)である。
Qが、OおよびSから選択される1〜3個のヘテロ原子を有する場合により置換されている5員の飽和環である場合、JQは−(CH2)q−PO(OR)2ではなく、式中、
qは、0または1であり、および
Rは、Hまたは非置換のC1〜6脂肪族であり;
R1およびR2の両方がHの場合、環Aは
Pd(PPh3)4 テトラキス(トリフェニルホスフィン)パラジウム(0)
dba ジベンジリデンアセトン
BINAP 2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフチル
TsCl パラ−トルエンスルホニルクロリド
N,N−DMF N,N−ジメチルホルムアミド
EtOAc 酢酸エチル
PE 石油エーテル
DMSO ジメチルスルホキシド
TCA トリクロロ酢酸
ATP アデノシン三リン酸
Ac アセチル
Ph フェニル
Me メチル
NaOtBu ナトリウムtert−ブトキシド
HEPES 4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルフォン酸
BSA ウシ血清アルブミン
DTT ジチオスレイトール
NMR 核磁気共鳴
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー−質量分析
Rt 保持時間
本発明の幾つかの態様において、R2はHである。
カラム:ACE C8カラム、4.6×150mm
勾配:0〜100%アセトニトリル+メタノール 60:40(20mM リン酸トリス)
流速:1.5mL/分
検出:225nm。
THF(60mL)中のアミン(2.18g、14.2mmol)の溶液にMnO2(7g、80.5mmol)を加え、混合物を加熱して還流させた。5時間後、MnO2(3g、34.5mmol)をさらに加え、一晩攪拌し続けた。反応物をセライトに通して濾過し、濃縮して白色固体(1.95g、91%)を得た。
1H NMR(DMSO)7.48(1H,d),7.80(1H,s),8.00(1H,d)。
p−TsCl(1.33g、6.95mmol)をN,N−DMF(35mL)中の炭酸カリウム(3.66g、26.5mmol)およびインドール(1.53g、6.62mmol)に室温で加えた。3時間後、p−TsCl(1.33g、6.95mmol)をさらに加えた。さらに30分攪拌後、反応物を真空下で濃縮し、次いで、水およびEtOAc(少量のTHFおよびMeOHを含む)を加えた。EtOAcで再抽出し、次いで、有機物を塩水で洗浄した。有機物を濃縮すると生成物(2.00g、78%)が白色固体として沈殿し、フリット上に回収した。MS(ES+)m/e=387。1H NMR(DMSO)2.37(3H,s),7.47(2H,d),8.03(2H,d),8.04(1H,d),8.30(1H,d),8.40(1H,s)。
トルエン(25mL)およびエタノール(5mL)中の臭化物(554mg、1.44mmol)、Pd(PPh3)4(164mg、0.14mmol)、2MのK2CO3(2.14mL、4.28mmol)、4−フェノキシフェニルボロン酸(399mg、1.86mmol)の混合物を、140℃で1時間マイクロ波加熱した。次いで、反応混合物をEtOAc中に抽出し、乾燥(MgSO4)し、濾過および濃縮した。次いで、残渣をシリカプラグに通し(1/1のPE/EtOAcで溶出)、次いで濃縮した。この材料にMeOH(10mL)および2MのNaOH(6mL)を加え、反応フラスコを70℃の油浴に浸けた。40分後、CH2Cl2および飽和水性NaHCO3を加えた。水層を再抽出し、次いで、有機物を合わせて乾燥(MgSO4)し、濾過および濃縮した。カラムクロマトグラフィー(EtOAcで溶出)で精製し、標記の化合物(96mg、21%)を得た。MS(ES+)m/e=321。
NaH(鉱油中の60%分散物;140mg、3.50mmol)を、無水DMF(1.5mL)中のインドール(56mg、0.18mmol)に室温で加えた。10分後、臭化シクロペンチル(264mg、0.18mmol)を加え、次いで、反応混合物を一晩攪拌した。次いで、水、次いでEtOAcを注意深く加え、抽出した。有機層を塩水で洗浄し、次いで乾燥(MgSO4)、濾過および濃縮した。カラムクロマトグラフィー(EtOAc/PE、1/1で溶出)で精製し、標記の化合物(45mg、76%)を得た。MS(ES+)m/e=389。
無水トルエン(5mL)中のBINAP(12.5mg、0.02mmol)、tert−ブトキシドナトリウム(36mg、0.38mmol)、ベンゾフェノンイミン(49mg、0.27mmol)および出発物質である塩化物(52mg、0.13mmol)の混合物に、トリス(ジベンジリデンアセトン)ジパラジウム(0)(6mg、0.007mmol)を窒素下で加え、混合物を110℃まで90分で加熱した。反応混合物を冷却し、次いでEtOAcを用いてセライトを通過させ、次いで濃縮した。残渣をメタノール(8mL)に溶解し、次いで水(2mL)中のヒドロキシルアミン塩酸塩(183mg、2.63mmol)、その後、重炭酸ナトリウム(221mg、2.63mmol)を加え、混合物を3時間攪拌した。有機物を真空下で除去し、次いで、EtOAcおよび塩水を加えた。水層をEtOAcで再抽出し、有機物を合わせて乾燥(MgSO4)し、濾過および濃縮した。分取HPLCによる精製で、白色固体として芳香族アミン(15mg、27%)を得た。MS(ES+)m/e=370。1H NMR(CDCl3)1.72−2.09(6H,m),2.20−2.32(2H,m),4.78(1H,五重線),5.42(2H,br s),6.81(1H,d),7.07−7.12(5H,m),7.17(1H,t),7.41(2H,t),7.44(2H,d),7.72(1H,d). HPLC rt(分): 12.1。
化合物を、ヒトSrcキナーゼの阻害剤として分光学的アッセイを使用して検討した。
25mMのHEPES(pH7.5)、10mMのMgCl2、250μMのNADH、3mMのホスホエノールピルビン酸塩、60μg/mLのピルビン酸キナーゼ、21μg/mLの乳酸脱水素酵素、113μMのATPおよび28nMのSrcより成るアッセイ緩衝溶液を調製した。96穴プレート中において、60μLの本溶液に2μLの試験化合物DMSO原液を加え、混合物を10分間30℃で放置して平衡化した。25mMのHEPES(pH7.5)中で調製された10mg/mLのポリGlu,Tyr(4:1)を5μL加えて、酵素反応を開始した。SrcおよびATPのアッセイ終濃度は、それぞれ25nMおよび100μMであった。初速度のデータは、10分にわたり30℃において、Molecular Devices Spectramaxプレート読取機(サニーベール市、カリフォルニア州)を使用し、340nM(NADHの化学量論的消費に対応)における吸光度の変化速度より決定した。各Kiを決定するために、0〜7.5μMの試験化合物濃度範囲にわたる8個のデータ点を2回ずつ得た。Kiの値は、Prismソフトウェアパッケージ(Prism 4.0a、Graphpad Software、サンディエゴ市、カリフォルニア州)を使用し、非線形回帰分析によって、初速度のデータより計算した。
化合物を、ヒトLckキナーゼの阻害剤として分光学的アッセイを使用して検討した。
25mMのHEPES(pH7.5)、10mMのMgCl2、250μMのNADH、3mMのホスホエノールピルビン酸塩、43μg/mLのピルビン酸キナーゼ、14μg/mLの乳酸脱水素酵素、560μMのATPおよび67nMのLckより成るアッセイ緩衝溶液を調製した。96穴プレート中において、60μLの本溶液に2μLの試験化合物DMSO原液を加え、混合物を10分間30℃で放置して平衡化した。25mMのHEPES(pH7.5)中で調製された15mg/mLのポリGlu,Tyr(4:1)を5μL加えて、酵素反応を開始した。LckおよびATPのアッセイ終濃度は、それぞれ60nMおよび500μMである。初速度のデータは、10分にわたり30℃において、Molecular Devices Spectramaxプレート読取機(サニーベール市、カリフォルニア州)を使用し、340nM(NADHの化学量論的消費に対応)における吸光度の変化速度より決定した。各Kiを決定するために、0〜7.5μMの試験化合物の化合物濃度範囲にわたる8個のデータ点を2回ずつ得る。Kiの値は、Prismソフトウェアパッケージ(Prism 4.0a、Graphpad Software、サンディエゴ市、カリフォルニア州)を使用し、非線形回帰分析によって、初速度のデータより計算する。
Claims (34)
- 式Iの化合物
R1は、C1〜6ハロアルキル、Q、または−Z−Qであり;
R2は、H、ハロ、CN、NO2、C1〜4ハロ脂肪族、C3〜6環式脂肪族、またはC1〜6脂肪族であり;
環Aは、O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環であり;
R4は、H、C1〜6脂肪族、C3〜6環式脂肪族、または−(Y)n−V1であり;式中、
nは、0または1であり;
Yは、0〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−で場合により置き換えられている非置換のC1〜6脂肪族であり;
V1は、C3〜6環式脂肪族、ハロ(C1〜4脂肪族)、3〜6員のヘテロシクリル、ハロ、NO2、CN、OH、OR”、SH、SR”、NH2、NHR”、N(R”)2、COH、COR”、CO2H、CO2R”、CONH2、CONHR”、CONR”2、OCOR”、OCONH2、OCONHR”、OCON(R”)2、NHCOR”、NR”COR”、NHCO2R”、NR”CO2R”、NHCO2H、NR”CO2H、NHCONH2、NHCONHR”、NHCON(R”)2、SO2NH2、SO2NHR”、SO2N(R”)2、NHSO2R”、またはNR”SO2R”であり;
R”は、非置換のC1〜4脂肪族であり;
T1は、0〜3個の−NR−、−O−、−S−、−C(O)−、−C(=NR)−、−C(=NOR)−、−SO−、または−SO2−で場合により置き換えられているC1〜6脂肪族であり;各T1は、0〜2個のJTで場合により置換されており;
R5は、H;0〜2個のO、N、およびSで場合により置き換えられているC1〜6脂肪族;O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環であり;各R5は、場合により0〜5個のJ5で置換されており;
R7は、Hまたはハロであり;
Zは、0〜3個の−NR−、−O−、−S−、−C(O)−、−C(S)−、−C(=NR)−、−C(=NOR)−、−SO−、または−SO2−で場合により置き換えられているC1〜6脂肪族であり;各Zは、0〜2個のJZで場合により置換されており;
Qは、H;C1〜6脂肪族;O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環であり;各Qは、場合により0〜5個のJQで置換されており;
各JZは、独立に、H、ハロ、C1〜6脂肪族、C3〜6環式脂肪族、NO2、CN、−NH2、−NH(C1〜4脂肪族)、−N(C1〜4脂肪族)2、−OH、−O(C1〜4脂肪族)、−CO2H、−CO2(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、またはハロ(C1〜4脂肪族)であり;
J5は、Mまたは−Y−Mであり;
各Yは、独立に、0〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−で場合により置き換えられている非置換のC1〜6脂肪族であり;
各Mは、独立に、H、C1〜6脂肪族、C3〜8環式脂肪族、ハロ(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、3〜8員のヘテロシクリル、ハロ、NO2、CN、OH、OR’、SH、SR’、NH2、NHR’、N(R’)2、COH、COR’、CO2H、CO2R’、CONH2、CONHR’、CONR’2、OCOR’、OCONH2、OCONHR’、OCON(R’)2、NHCOR’、NR’COR’、NHCO2R’、NR’CO2R’、NHCO2H、NR’CO2H、NHCONH2、NHCONHR’、NHCON(R’)2、SO2NH2、SO2NHR’、SO2N(R’)2、NHSO2R’、NR’SO2R’、POR’、PO2R’、PO(R’)2、またはPO(OR’)2であり;
JQは、M1または−Y1−M1であり;
各Y1は、独立に、0〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−で場合により置き換えられている非置換のC1〜6脂肪族であり;
各M1は、独立に、H、C1〜6脂肪族、C3〜8環式脂肪族、ハロ(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、3〜8員のヘテロシクリル、5〜6員のヘテロアリール、フェニル、ハロ、NO2、CN、OH、OR’、SH、SR’、NH2、NHR’、N(R’)2、COH、COR’、CO2H、CO2R’、CONH2、CONHR’、CONR’2、OCOR’、OCONH2、OCONHR’、OCON(R’)2、NHCOR’、NR’COR’、NHCO2R’、NR’CO2R’、NHCO2H、NR’CO2H、NHCONH2、NHCONHR’、NHCON(R’)2、SO2NH2、SO2NHR’、SO2N(R’)2、NHSO2R’、NR’SO2R’、POR’、PO2R’、PO(R’)2、またはPO(OR’)2であり;
各MおよびM1は、独立におよび場合により、0〜5個のJMで置換されており、
Rは、Hまたは非置換のC1〜6脂肪族であり;
R’は、非置換のC1〜6脂肪族であるか;または、2個のR’基が、それらが結合している原子と一緒になって、O、N、およびSから独立に選択される0〜1個のヘテロ原子を有する非置換で3〜8員の非芳香族単環を形成しており;
各JTおよびJMは、独立に、H、ハロ、C1〜6脂肪族、C3〜6環式脂肪族、NO2、CN、−NH2、−NH(C1〜4脂肪族)、−N(C1〜4脂肪族)2、−OH、−O(C1〜4脂肪族)、COH、−CO(C1〜4脂肪族)、CONH2、CONH(C1〜4脂肪族)、CON(C1〜4脂肪族)2、−CO2H、−CO2(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、またはハロ(C1〜4脂肪族)であり;
但し、環Aは、
Qが、OおよびSから選択される1〜3個のヘテロ原子を有する、場合により置換されている5員の飽和環である場合、JQは−(CH2)q−PO(OR)2ではなく、式中、
qは、0または1であり、および
Rは、Hまたは非置換のC1〜6脂肪族であり;
R1およびR2の両方がHの場合、環Aは
- R2がHである、請求項1に記載の化合物。
- R1がQである、請求項1または請求項2に記載の化合物。
- Qが、O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、または完全不飽和単環である、請求項1から3のいずれか一項に記載の化合物。
- Qが、O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和単環である、請求項4に記載の化合物。
- Qが、0個のヘテロ原子を有する3〜8員の飽和単環である、請求項5に記載の化合物。
- Qがシクロヘキシルまたはシクロペンチルである、請求項6に記載の化合物。
- JQが3〜8員のヘテロシクリルである、請求項1から7のいずれか一項に記載の化合物。
- JQが、1〜2個の窒素原子を含む6員のヘテロシクリルである、請求項8に記載の化合物。
- 環Aが完全不飽和(即ち、芳香族)である、請求項1から9のいずれか一項に記載の化合物。
- 環Aが部分不飽和または飽和である、請求項1から9のいずれか一項に記載の化合物。
- 環Aが単環である、請求項10または請求項11に記載の化合物。
- 環Aが5員環である、請求項12に記載の化合物。
- 環Aが6員環である、請求項12に記載の化合物。
- −T−R5がメタまたはパラ置換されている、請求項13または14に記載の化合物。
- 環Aが二環である、請求項10から15のいずれか一項に記載の化合物。
- Tが−C(O)NR−または−NRC(O)−である、請求項10から16のいずれか一項に記載の化合物。
- RがHである、請求項17に記載の化合物。
- R5が、O、N、およびSから独立に選択される0〜3個のヘテロ原子を有する3〜8員の飽和、部分不飽和、もしくは完全不飽和単環;またはO、N、およびSから独立に選択される0〜5個のヘテロ原子を有する8〜12員の飽和、部分不飽和、もしくは完全不飽和二環である、請求項12または請求項16に記載の化合物。
- R5が完全不飽和(即ち、芳香族)である、請求項19に記載の化合物。
- R5が部分不飽和または飽和である、請求項19に記載の化合物。
- R4が、H、ハロ、C1〜6脂肪族、C3〜6環式脂肪族、NO2、CN、−NH2、−NH(C1〜4脂肪族)、−N(C1〜4脂肪族)2、−OH、−O(C1〜4脂肪族)、CONH2、CONH(C1〜4脂肪族)、CON(C1〜4脂肪族)2、COH、−CO(C1〜4脂肪族)、−CO2H、−CO2(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、またはハロ(C1〜4脂肪族)である、請求項12から21のいずれか一項に記載の化合物。
- 請求項1から23のいずれか一項に記載の化合物と、薬学的に許容可能な担体、アジュバント、またはビヒクルとを含む組成物。
- 生物試料中のプロテインキナーゼ活性を阻害する方法であって、前記生物試料を
a)請求項24に記載の組成物;または
b)請求項1から23のいずれか一項に記載の化合物
と接触させる工程を含む方法。 - 前記プロテインキナーゼがLckである、請求項25に記載の方法。
- 患者の自己免疫疾患、炎症性疾患、骨疾患、代謝性疾患、神経系もしくは神経変性疾患、癌、循環器疾患、アレルギー、喘息、アルツハイマー病、またはホルモン関連疾患を治療する方法であって、
a)請求項24に記載の組成物;または
b)請求項1から23のいずれか一項に記載の化合物
を該患者に投与する工程を含む方法。 - 前記疾患が、自己免疫疾患、炎症性疾患、増殖性もしくは過剰増殖性疾患、または免疫介在性疾患である、請求項27に記載の方法。
- 前記患者に、化学療法薬もしくは抗増殖薬、アルツハイマー病治療薬、パーキンソン病治療薬、多発性硬化症(MS)治療薬、喘息治療薬、抗炎症薬、免疫調節もしくは免疫抑制薬、神経栄養因子、循環器疾患治療薬、破壊的骨障害治療薬、肝疾患治療薬、抗ウイルス薬、血液障害治療薬、糖尿病治療薬、または免疫不全障害治療薬から選択される追加治療薬を投与する工程を含み、
a)前記追加治療薬は、治療される疾患に適切であり;
b)前記追加治療薬は、前記組成物と共に単回剤形として投与されるか、または前記組成物とは別に多回剤形の一部として投与される、請求項27または請求項28に記載の方法。 - 喘息、急性鼻炎、アレルギー性鼻炎、萎縮性鼻炎、慢性鼻炎、膜性鼻炎、季節性鼻炎、サルコイドーシス、農夫肺、肺線維症、特発性間質性肺炎、関節リウマチ、血清反応陰性脊椎関節症(強直性脊椎炎、乾癬性関節炎およびライター病が挙げられる)、ベーチェット病、シェーグレン症候群、全身性硬化症、乾癬、全身性硬化症、アトピー性皮膚炎、接触性皮膚炎および他の湿疹性皮膚炎、脂漏性皮膚炎、扁平苔癬、天疱瘡、水疱性天疱瘡、表皮水疱症、じんま疹、皮膚脈管炎、血管炎、紅斑、皮膚好酸球増加症、ブドウ膜炎、脱毛症、限局性春季カタル、セリアック病、直腸炎、好酸球性胃腸炎、肥満細胞症、膵臓炎、クローン病、潰瘍性大腸炎、食品関連アレルギー、多発性硬化症、アテローム性動脈硬化症、後天性免疫不全症侯群(AIDS)、紅斑性狼瘡、全身性狼瘡、エリテマトーデス、橋本甲状腺炎、重症筋無力症、I型糖尿病、ネフローゼ症候群、好酸球増加性筋膜炎、高IgE症候群、らい腫らい、セザリー症候群および特発性血小板減少性紫斑病、血管形成後再狭窄、腫瘍、アテローム性動脈硬化症、全身性紅斑性狼瘡、同種移植拒絶(以下に限定されないが、例えば、腎臓、心臓、肝臓、肺、骨髄、皮膚および角膜の移植の後の急性および慢性同種移植拒絶が含まれる);または慢性移植片対宿主病を治療する方法であって、
a)請求項24に記載の組成物;または
b)請求項1から23のいずれか一項に記載の化合物
を、それを必要とする患者に投与する工程を含む方法。 - 自己免疫疾患、アレルギー、関節リウマチ、または白血病を治療する方法であって、
a)請求項24に記載の組成物;または
b)請求項1から23のいずれか一項に記載の化合物
を患者に投与する工程を含む方法。 - 高カルシウム血症、再狭窄、骨粗鬆症、変形性関節症、骨転移の症状処置、関節リウマチ、炎症性腸疾患、多発性硬化症、乾癬、狼瘡、移植片対宿主病、T細胞介在性過敏性疾患、橋本甲状腺炎、ギラン−バレー症候群、慢性閉塞性肺障害、接触性皮膚炎、癌、パジェット病、喘息、虚血性もしくは再潅流傷害、アレルギー性疾患、アトピー性皮膚炎、またはアレルギー性鼻炎を治療する方法。
- 埋め込み型デバイスをコーティングするための組成物であって、請求項1から23のいずれか一項に記載の化合物と、該埋め込み型デバイスをコーティングするために適切な担体とを含む組成物。
- 請求項33に記載の組成物でコーティングされた埋め込み型デバイス。
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PCT/US2007/003767 WO2007095223A2 (en) | 2006-02-14 | 2007-02-12 | Pyrrolo(3,2-c) pyridines useful as inhibitors of protein kinases |
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US (1) | US7659283B2 (ja) |
EP (1) | EP2004645A2 (ja) |
JP (1) | JP2009528991A (ja) |
CN (1) | CN101848909A (ja) |
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US9512125B2 (en) | 2004-11-19 | 2016-12-06 | The Regents Of The University Of California | Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents |
UA95940C2 (uk) | 2006-01-17 | 2011-09-26 | Вертекс Фармасьютикалс Інкорпорейтед | Азаіндоли як інгібітори кіназ януса |
GB2453058A (en) | 2006-04-04 | 2009-03-25 | Univ California | Kinase antagonists |
US8247421B2 (en) | 2006-12-21 | 2012-08-21 | Vertex Pharmaceuticals Incorporated | 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors |
US20110160232A1 (en) | 2007-10-04 | 2011-06-30 | Pingda Ren | Certain chemical entities and therapeutic uses thereof |
WO2009145814A2 (en) * | 2008-03-10 | 2009-12-03 | Vertex Pharmaceuticals Incorporated | Pyrimidines and pyridines useful as inhibitors of protein kinases |
WO2009114870A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Kinase inhibitors and methods of use |
WO2009114874A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Benzothiazole kinase inhibitors and methods of use |
EP2313414B1 (en) | 2008-07-08 | 2015-11-04 | Intellikine, LLC | Kinase inhibitors and methods of use |
US20110224223A1 (en) | 2008-07-08 | 2011-09-15 | The Regents Of The University Of California, A California Corporation | MTOR Modulators and Uses Thereof |
WO2010148197A1 (en) | 2009-06-17 | 2010-12-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
KR101173678B1 (ko) | 2010-10-20 | 2012-08-13 | 한국과학기술연구원 | 피롤로[3,2-c]피리딘 유도체 및 그의 제조 방법 |
CN103492381A (zh) | 2010-12-16 | 2014-01-01 | 沃泰克斯药物股份有限公司 | 流感病毒复制的抑制剂 |
UA118010C2 (uk) | 2011-08-01 | 2018-11-12 | Вертекс Фармасьютікалз Інкорпорейтед | Інгібітори реплікації вірусів грипу |
MX370814B (es) | 2011-09-02 | 2020-01-08 | Univ California | Pirazolo[3,4-d]pirimidinas sustituidas y usos de las mismas. |
CN104995192A (zh) | 2012-09-26 | 2015-10-21 | 加利福尼亚大学董事会 | Ire1的调节 |
TR201907147T4 (tr) | 2013-07-18 | 2019-06-21 | Taiho Pharmaceutical Co Ltd | Fgfr inhibitörünün aralıklı uygulanmasına yönelik anti-tümör ilaç. |
EP3023101B1 (en) | 2013-07-18 | 2020-08-19 | Taiho Pharmaceutical Co., Ltd. | Therapeutic agent for fgfr inhibitor-resistant cancer |
JP6615755B2 (ja) | 2013-11-13 | 2019-12-04 | バーテックス ファーマシューティカルズ インコーポレイテッド | インフルエンザウイルスの複製の阻害剤 |
SG10201804021TA (en) | 2013-11-13 | 2018-07-30 | Vertex Pharma | Methods of preparing inhibitors of influenza viruses replication |
WO2016019228A1 (en) | 2014-07-31 | 2016-02-04 | Merck Patent Gmbh | Indolizine derivatives which are applicable to neurodegenerative diseases |
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WO2016183116A1 (en) | 2015-05-13 | 2016-11-17 | Vertex Pharmaceuticals Incorporated | Methods of preparing inhibitors of influenza viruses replication |
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