JP2015524480A - ブルトン型チロシンキナーゼ(btk)阻害剤としてのヘテロ芳香族化合物 - Google Patents
ブルトン型チロシンキナーゼ(btk)阻害剤としてのヘテロ芳香族化合物 Download PDFInfo
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- JP2015524480A JP2015524480A JP2015526696A JP2015526696A JP2015524480A JP 2015524480 A JP2015524480 A JP 2015524480A JP 2015526696 A JP2015526696 A JP 2015526696A JP 2015526696 A JP2015526696 A JP 2015526696A JP 2015524480 A JP2015524480 A JP 2015524480A
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- alkyl
- heterocycle
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- 238000001665 trituration Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
Description
本願は、2012年8月10日に出願された米国仮出願番号 61/681,684に基づく利益を請求するものである。
1.技術分野
本発明は、BTKを阻害する新規化合物及び医薬としてのその使用に関する。
ヒト酵素のプロテインキナーゼファミリーのメンバーは、リン酸基の付加を介しての特定のタンパク質の翻訳後修飾のため、多数の異なるシグナル伝達過程において重要な調節性の役割を果たしている(Hunter, Cell, 1987 50, 823-829)。ブルトン型チロシンキナーゼ(BTK)は、チロシンキナーゼのTecファミリーのメンバーであり、B細胞の発生、活性化及び抗体産生において決定的な役割を果たしている。
本発明は、新規な種類の複素芳香環化合物、ならびにそれを製造し、使用する方法を含む。これらの化合物は、それらがBTKについて、良好な阻害作用を示す自己免疫及びアレルギー性疾患の処置に有用である。
第一の一般的態様では、式(I):
[式中、
環Aは、
であり;
R1は、N(R3)2又は水素であり;
Cyは、アリール又はヘテロアリールであり、それぞれは、R2により置換されており、そして場合により、ハロゲン、ハロC1−4アルキル、C1−4アルキル又はC1−4アルコキシにより置換されており;
R2は、
L−Ar、C1−6アルキル及びC1−6アルコキシから選択され、Ar、C1−6アルキル及びC1−6アルコキシのそれぞれは、場合により、ハロゲン、ハロC1−4アルキル、C1−4アルキル、R3−S(O)m−、−CN、−C(O)−N(R3)2又はC1−4アルコキシにより置換されており;
Lは、結合、O、>C(O)、−(CH2)n−、−O−(CH2)n−、−N(R3)−、−N(R3)−(CH2)n−、−(CH2)n−N(R3)−、−C(O)−N(R3)−、−C(O)−N(R3)−(CH2)n−、−N(R3)−C(O)−N(R3)−、−N(R3)−C(O)−、−S(O)m−N(R3)−及び−N(R3)−S(O)m−から選択されるリンカーであり、ここで各L中の−CH2−は、C1−3アルキルで置き換えられている1〜2個の水素を有することができ、当該C1−3アルキル基は、場合により、環化してC3−6シクロアルキル環を形成することができ;
Arは、炭素環、複素環又はヘテロアリールであり;
X1は、結合、−(CH2)n−から選択されるリンカーであり;
Yは、場合により、0〜1個の環窒素原子を含むC7-C10スピロ環、窒素含有単環もしくは二環式複素環、炭素環、アリールから選択され、それぞれは、一つのR4で置換されており;
R4は、
(ここで、R5は、水素であることはできない)、
であり;
それぞれのnは、独立して、1〜4であり;
それぞれのmは、独立して、0〜2であり;
それぞれのR3は、独立して、水素又はC1−4アルキルから選択され;
それぞれのR5は、独立して、水素、C1−4アルキル、C1−4アルコキシ、C1−4アルキルC1−4アルコキシ、−(CH2)n−複素環及び複素環から選択され、それぞれの複素環は、場合により、ハロゲン、OH又はR3−S(O)m−により置換されており;
Cy、R1〜R5、X1及びYについて上記で定義された各基は、可能であれば、部分的に又は完全にハロゲン化されうる]
の化合物
又は薬学的に許容しうるその塩が提供される。
Cyが、フェニル、ピリジニル、ピリダジニル、ピリミジニル又はピラジニルであり、それぞれは、R2により置換されており、そして場合により、F、Cl又はC1−4アルコキシにより置換されており;
R2が:
L−Ar及びC1−3アルコキシから選択され、Ar及びC1−3アルコキシのそれぞれは、場合により、F、Cl、C1−4アルキル、R3−S(O)2−、−CN、−C(O)−NH(R3)及びC1−3アルコキシにより置換されており;
Lが、結合、O、>C(O)、−CH2−、−O−CH2−、−NH−、−NH−CH2−、−CH2−NH−、−C(O)−NH−CH2−、−NH−C(O)−NH−及び−N(R3)−S(O)m−から選択されるリンカーであり;
Arが、フェニル、ピリジニル、ピリダジニル、ピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル、ピペリジニル、ピペラジニル又はピロリジニルである、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
Cyが、フェニル又はピリジニルであり、それぞれは、R2により置換されており、場合により、F、Cl又はC1−2アルコキシにより置換されており;
R2が:
L−Ar及びC1−3アルコキシから選択され、Ar及びC1−3アルコキシのそれぞれは、場合により、F、Cl、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(R3)及び(又は)C1−2アルコキシにより置換されており;
Lが、結合、O、>C(O)、−CH2−、−O−CH2−、−NH−、−NH−CH2−、−CH2−NH−、−C(O)−NH−CH2−、−NH−C(O)−NH−及び−N(R3)−S(O)m−から選択されるリンカーであり;
Arが、フェニル、ピリジニル、ピリダジニル、ピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル又はピペリジニルである、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
Cyが、フェニル又はピリジニルであって、それぞれが、R2により置換されており、場合により、F、Cl又はC1−2アルコキシにより置換されており;
R2が:
L−Ar及びC1−3アルコキシから選択され、Ar及びC1−3アルコキシのそれぞれは、場合により、F、Cl、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(CH3)又はC1−2アルコキシにより置換されており;
Lが、結合、O、>C(O)、−CH2−、−O−CH2−、−NH−、−NH−CH2−、−CH2−NH−、−C(O)−NH−CH2−、−NH−C(O)−NH−及び−N(H)−S(O)2−から選択されるリンカーであり;
Arが、フェニル、ピリジニル、ベンゾオキサゾリル又はピペリジニルである、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
X1が、結合及び−(CH2)n−から選択されるリンカーであり;
Yが、
から選択されるスピロ環;
ピペリジニル及びピロリジニルから選択される複素環;ならびに
フェニル(それぞれの複素環又はフェニルは、一つのR4により置換されている);
から選択され;
R4が、
(ここで、R5は、水素であることはできない、
それぞれのR4は、場合により、ハロゲン化されている)
であり;
それぞれのR5が、独立して、水素、C1−3アルキル、ハロC1−3アルキル、C1−3アルキルC1−3アルコキシ、−CH2−複素環及び複素環から選択され、それぞれの複素環は、場合によりF、Cl、OH又はCH3−S(O)2−により置換されており、それぞれの複素環は、ピロリジニル、ピペリジニル、モルホリニル及び1,4−オキサゼパンから選択される、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
X1が、結合及び−(CH2)n−から選択されるリンカーであり;
Yが、
から選択されるスピロ環;
ピペリジニル及びピロリジニルから選択される複素環;ならびに
フェニル(それぞれの複素環又はフェニルは、一つのR4により置換されている);
から選択され;
R4が、
であり、
それぞれのR5が、独立して、水素、C1−3アルキル、−CF3、C1−3アルキルC1−3アルコキシ、−CH2−複素環及び複素環から選択され、それぞれの複素環は、場合により、F、Cl、OH及びCH3−S(O)2−により置換されており、それぞれの複素環は、ピロリジニル、ピペリジニル及び1,4−オキサゼパンから選択される、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
R2が、L−Arであり;
Lが、結合、O及び−O−(CH2)n−から選択されるリンカーであり;
nが、1〜3であり;
Arが、炭素環又は複素環である、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
Arが、C3−5シクロアルキル又はテトラヒドロフラニルであり;
n=1である、
式(I)の化合物又は薬学的に許容しうるその塩が提供される。
本明細書において具体的に定義されていない語は、全般的開示及び全体としての内容の観点から当業者にとって明らかである意味を有する。
一般的合成方法
最適な反応条件及び反応時間は、用いる特定の反応物質に応じて変化しうる。別途特定しない限り、溶媒、温度、圧力及びその他の反応条件は、当業者によって容易に選択されうる。具体的操作は、合成実施例の節において提供される。中間体及び生成物は、シリカゲルクロマトグラフィー、再結晶及び/又は逆相HPLC(RHPLC)により精製されうる。個々のエナンチオマーは、キラルHPLCを用いて、ラセミ生成物の分割により得られうる。RHPLC精製法は、0.1%ギ酸又は0.1%TFAを含有する、水中0〜100%のアセトニトリルをどこでも使用し、下記カラムの一つを使用する。
a) Waters Sunfire OBD C18 5μm 30x150 mmカラム
b) Waters XBridge OBD C18 5μm 30x150 mmカラム
c) Waters ODB C8 5μm 19x150 mmカラム
d) Waters Atlantis ODB C18 5μm 19x50 mmカラム
e) Waters Atlantis T3 OBD 5μm 30x100 mmカラム
f) Phenomenex Gemini Axia C18 5μm 30x100 mmカラム
HPLC法:
分析用LC/MS分析方法A:
カラム:Thermo Scientific、Aquasil C18、50 x 2.1 mm、5μmカラム
グラジエント:
カラム:Waters BEH 2.1x50mm C18 1.7 μmカラム
グラジエント:
方法1
中間体I−1の合成
中間体I−4の合成、及びジアステレオマーI−5及びI−6の分割
中間体I−8の合成
中間体I−9の合成
中間体I−10の合成
中間体I−14の合成
中間体I−19の合成
中間体I−21の合成
中間体I−26の合成
中間体I−30の合成
中間体I−41の合成
中間体I−43の合成
中間体I−46の合成
中間体I−51の合成
中間体I−54の合成
実施例9の合成
実施例1〜8、10〜27、94〜96
実施例28の合成
実施例38の合成
実施例31、32、43、48、49、56
実施例37の合成
実施例30、36
実施例40の合成
実施例86、89(アクリル酸の替わりにR−10を使用)
実施例60の合成
実施例61
実施例72の合成
実施例62〜71、73〜76
実施例90の合成
実施例93の合成
実施例58の合成
実施例78、85、52、53
実施例79の合成
実施例34、50、51、57、84
実施例77の合成
実施例98〜100
実施例80の合成
実施例35、44、54、81、82
実施例41の合成
実施例83、91、92
実施例87の合成
実施例59、46(R−10の替わりにアクリル酸を使用)
実施例97の合成
実施例101の合成
実施例102〜103、110
実施例122の合成
実施例114、117〜120、123、150〜152
実施例104の合成
実施例104、106〜109、111〜113、115〜116、124、133、134〜136、138〜139、141〜144、147〜149、166
実施例130、132、145〜146、153、155〜156、159、162〜163、165
実施例126の合成
実施例131
実施例140の合成
実施例128、137、154、157〜158、160〜161、164、167〜168
実施例127の合成
実施例129
BTKアッセイ
基質のBTK介在リン酸化に対する試験化合物の阻害能を定量化するために、HTRFアッセイ(Cisbio KinEASE-TK cat # 62TK0PEC)を行った。アッセイは、384ウエルプレートで構築され、そこで6nMの全長ヒトHis付きBTK(Life Technologies cat # PV3587)及び各種濃度の試験化合物を、28℃で15分間あらかじめインキュベートした。次いで、1μMのTK基質−ビオチン及び30μMのATPを加え、28℃で更に30分間インキュベートした。62.5nMのストレプトアビジン−XL665及びTK−抗体クリプタート[HTRG検出緩衝液(Cisbio cat # 62SDBRDF)中で1:100に希釈]を加え、室温で60分間インキュベートすることにより、リン酸化を検出した。プレートを、Envisionプレートリーダーで読み取り、蛍光を620nm(クリプタート)及び665nm(XL665)で測定する。比率を算出し(665/620)、対照及びブランクのウエルに対するPOCに変換する。
アッセイ緩衝液:
50mM HEPES(Invitrogen #15630)、0.01% Brij−35(sigma #B4184)、10mM MgCl2(Sigma M1028)、1mM EGTA(Ambion AM9262)及び100μMオルトバナジン酸ナトリウム(sodium orthovanedate)(Sigma S6508)、1mM DTT(Sigma D5545)及び10nM補助的酵素緩衝液(supplemental enzyme buffer)(Cisbio cat# 61SEBALB)。
始原CD19+細胞を、健康な凍結末梢血単核細胞(AllCells, Emeryville, CA)から精製し、磁気分離により、>97%の純度で、ネガティブセレクションに付した(Stemcell Technologies, Vancouver, CA)。細胞を集め、10%FBSを含有するRPMI培地中、2×105/ウエルの濃度で、96フラットボトムプレートにプレートし、37℃で1時間安置した。細胞を、1%DMSO最終濃度で、阻害剤により二重に、又はビヒクル対照により、37℃、5%CO2で1時間処理した。細胞を次に12.5μg/mlのヤギF(ab’)2抗ヒトIgD(SouthernBiotech, Birmingham, AL)により、37℃、5%CO2で18〜24時間刺激した。細胞を集め、APC−CD19、クローンHIB19、及びPE−CD69、クローンFN50(BD Bioscience, San Jose, CAから購入した抗体)により染色した。BD LSRII又はBD FACsCanto Flow Cytometerを用いた流動細胞計測法によりB細胞を分析した。生存細胞をゲートし、FlowJoソフトウエアを用いてCD69のパーセントを決定した。
A431細胞(ATCC # CRL-1555 FZ)を解凍し、10%FBSを含有するDMEM中、384ウエルの組織培養処理プレートに、15,000細胞/ウエルでプレートする。37℃、5%CO2で24時間インキュベートした後、細胞を試験化合物(1%DMSO最終濃度)で処理し、37℃、5%CO2で16時間インキュベートする。EFG(Millipore, 01-107)を最終濃度60ng/mLで加え、10分間インキュベートする。培地を除去し、細胞を融解し、ホスホEGFRを測定する(Meso Scale Diagnostics, N31CB-1)。
その生物学的特性に基づき、本発明による式(I)の化合物、又はその互変異性体、ラセミ体、エナンチオマー、ジアステレオマー、これらの混合物、及び上記のすべての形態の塩は、それらがBTKについて、良好な阻害効果を示す自己免疫及びアレルギー性疾患の処置に適している。
Claims (21)
- 式(I):
[式中、
環Aは、
であり;
R1は、N(R3)2又は水素であり;
Cyは、アリール又はヘテロアリールであり、それぞれは、R2により置換されており、そして場合により、ハロゲン、ハロC1−4アルキル、C1−4アルキル又はC1−4アルコキシにより置換されており;
R2は、
L−Ar、C1−6アルキル及びC1−6アルコキシから選択され、Ar、C1−6アルキル及びC1−6アルコキシのそれぞれは、場合により、ハロゲン、ハロC1−4アルキル、C1−4アルキル、R3−S(O)m−、−CN、−C(O)−N(R3)2又はC1−4アルコキシにより置換されており;
Lは、結合、O、>C(O)、−(CH2)n−、−O−(CH2)n−、−N(R3)−、−N(R3)−(CH2)n−、−(CH2)n−N(R3)−、−C(O)−N(R3)−、−C(O)−N(R3)−(CH2)n−、−N(R3)−C(O)−N(R3)−、−N(R3)−C(O)−、−S(O)m−N(R3)−及び−N(R3)−S(O)m−から選択されるリンカーであり、ここで各L中の−CH2−は、C1−3アルキルで置き換えられている1〜2個の水素を有することができ、当該C1−3アルキル基は、場合により環化してC3−6シクロアルキル環を形成することができ;
Arは、炭素環、複素環又はヘテロアリールであり;
X1は、結合、−(CH2)n−から選択されるリンカーであり;
Yは、場合により、0〜1個の環窒素原子を含むC7-C10スピロ環、窒素含有単環もしくは二環式複素環、炭素環、アリールから選択され、それぞれは、一つのR4で置換されており;
R4は、
(ここで、R5は、水素であることはできない)、
であり;
それぞれのnは、独立して、1〜4であり;
それぞれのmは、独立して、0〜2であり;
それぞれのR3は、独立して、水素又はC1−4アルキルから選択され;
それぞれのR5は、独立して、水素、C1−4アルキル、C1−4アルコキシ、C1−4アルキルC1−4アルコキシ、−(CH2)n−複素環及び複素環から選択され、それぞれの複素環は、場合により、ハロゲン、OH又はR3−S(O)m−により置換されており;
Cy、R1〜R5、X1及びYについて上記で定義された各基は、可能であれば、部分的に又は完全にハロゲン化されうる]
の化合物
又は薬学的に許容しうるその塩。 - 請求項2記載の化合物であって、
Cyが、フェニル、ピリジニル、ピリダジニル、ピリミジニル又はピラジニルであり、それぞれは、R2により置換されており、そして場合により、F、Cl又はC1−4アルコキシにより置換されており;
R2が:
L−Ar及びC1−3アルコキシから選択され、Ar及びC1−3アルコキシのそれぞれは、場合により、F、Cl、C1−4アルキル、R3−S(O)2−、−CN、−C(O)−NH(R3)又はC1−3アルコキシにより置換されており;
Lが、結合、O、>C(O)、−CH2−、−O−CH2−、−NH−、−NH−CH2−、−CH2−NH−、−C(O)−NH−CH2−、−NH−C(O)−NH−及び−N(R3)−S(O)m−から選択されるリンカーであり;
Arが、フェニル、ピリジニル、ピリダジニル、ピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル、ピペリジニル、ピペラジニル又はピロリジニルである化合物。 - 請求項3記載の化合物であって、
Cyが、フェニル又はピリジニルであり、それぞれは、R2により置換されており、場合により、F、Cl又はC1−2アルコキシにより置換されており;
R2が:
L−Ar及びC1−3アルコキシから選択され、Ar及びC1−3アルコキシのそれぞれは、場合により、F、Cl、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(R3)又はC1−2アルコキシにより置換されており;
Lが、結合、O、>C(O)、−CH2−、−O−CH2−、−NH−、−NH−CH2−、−CH2−NH−、−C(O)−NH−CH2−、−NH−C(O)−NH−及び−N(R3)−S(O)m−から選択されるリンカーであり;
Arが、フェニル、ピリジニル、ピリダジニル、ピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル又はピペリジニルである化合物。 - 請求項4記載の化合物であって、
Cyが、フェニル又はピリジニルであって、それぞれが、R2により置換されており、場合により、F、Cl又はC1−2アルコキシにより置換されており;
R2が:
L−Ar及びC1−3アルコキシから選択され、Ar及びC1−3アルコキシのそれぞれは、場合により、F、Cl、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(CH3)又はC1−2アルコキシにより置換されており;
Lが、結合、O、>C(O)、−CH2−、−O−CH2−、−NH−、−NH−CH2−、−CH2−NH−、−C(O)−NH−CH2−、−NH−C(O)−NH−及び−N(H)−S(O)2−から選択されるリンカーであり;
Arが、フェニル、ピリジニル、ベンゾオキサゾリル又はピペリジニルである化合物。 - 請求項5記載の化合物であって、
X1が、結合及び−(CH2)n−から選択されるリンカーであり;
Yが、
から選択されるスピロ環;
ピペリジニル及びピロリジニルから選択される複素環;ならびに
フェニル(それぞれの複素環又はフェニルは、一つのR4により置換されている);
から選択され;
R4が、
(ここで、R5は、水素であることはできない)、
(それぞれのR4は、場合によりハロゲン化されている)
であり、
それぞれのR5が、独立して、水素、C1−3アルキル、ハロC1−3アルキル、C1−3アルキルC1−3アルコキシ、−CH2−複素環及び複素環から選択され、それぞれの複素環は、場合により、F、Cl、OH及びCH3−S(O)2−により置換されており、それぞれの複素環は、ピロリジニル、ピペリジニル、モルホリニル及び1,4−オキサゼパンから選択される化合物。 - 請求項6記載の化合物であって、
X1が、結合及び−(CH2)n−から選択されるリンカーであり;
Yが、
から選択されるスピロ環;
ピペリジニル及びピロリジニルから選択される複素環;ならびに
フェニル(それぞれの複素環又はフェニルは、一つのR4により置換されている);
から選択され;
R4が、
であり、
それぞれのR5が、独立して、水素、C1−3アルキル、−CF3、C1−3アルキルC1−3アルコキシ、−CH2−複素環及び複素環から選択され、それぞれの複素環は、場合により、F、Cl、OH又はCH3−S(O)2−により置換されており、それぞれの複素環は、ピロリジニル、ピペリジニル又は1,4−オキサゼパンから選択される化合物。 - 請求項2記載の化合物であって、
R2が、L−Arであり;
Lが、結合、O及び−O−(CH2)n−から選択されるリンカーであり;
nが、1〜3であり;
Arが、炭素環又は複素環である化合物。 - 請求項14記載の化合物であって、
Arが、C3−5シクロアルキル又はテトラヒドロフラニルであり;
nが1である化合物。 - 治療的に有効な量の請求項1記載の化合物を含む医薬組成物。
- 関節リウマチ、全身性エリテマトーデス(systemic lupus erythromatosis)、強皮症、喘息、アレルギー性鼻炎、アレルギー性湿疹、B細胞リンパ腫、多発性硬化症、若年性関節リウマチ、若年性特発性関節炎、炎症性腸疾患、移植片対宿主病、乾癬性関節炎、強直性脊椎炎及びブドウ膜炎から選択される疾患を処置する方法であって、治療的に有効な量の請求項1記載の化合物を患者に投与することを含む方法。
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