JP6463680B2 - 脾臓チロシンキナーゼi(syk)阻害剤としての2−(2−アミノシクロヘキシル)アミノピリミジン−5−カルボキサミド類 - Google Patents
脾臓チロシンキナーゼi(syk)阻害剤としての2−(2−アミノシクロヘキシル)アミノピリミジン−5−カルボキサミド類 Download PDFInfo
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- JP6463680B2 JP6463680B2 JP2015531648A JP2015531648A JP6463680B2 JP 6463680 B2 JP6463680 B2 JP 6463680B2 JP 2015531648 A JP2015531648 A JP 2015531648A JP 2015531648 A JP2015531648 A JP 2015531648A JP 6463680 B2 JP6463680 B2 JP 6463680B2
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- Prior art keywords
- amino
- aminocyclohexyl
- pyrimidine
- carboxamide
- indol
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Description
R1は、(i)(a)1〜4個のN原子、もしくは(b)1個のO原子もしくはS原子および0〜3個のN原子のいずれかを含有し、1個のR3基および1〜3個のR4基で任意選択により置換されている9員の二環式芳香族複素環であるか、または(ii)1〜3個のR4基で任意選択により置換されているビフェニル基、ベンジルフェニル基、フェノキシフェニル基もしくはフェニルチオフェニル基であり;
R2は、HまたはOHであり;
R3は、−(CH2)n−Ar(式中、nは0〜4であり、Arは1〜3個のR4基で任意選択により置換されたフェニル基である)であり;
R4は、C1〜C6アルキル、C3〜C8シクロアルキル、ハロ、−CN、−OR5、−NR6R7、−SR5、−SOR8、−SO2R8、−COR5、−OCOR5、−COOR5、−NR5COR5、−CONR6R7、−NR5SO2R8、−SO2NR6R7、−NR5CONR6R7、−NR5COOR8、−NR5SO2NR6R7、−COR9および−COOR9からそれぞれ独立して選択されるが、但し、−COR9および−COOR9はR1のN原子を介してのみ結合し、
R5は、H、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R6およびR7は、それぞれ独立して、H、C1〜C6アルキルもしくはC3〜C8シクロアルキルであるか、または、それらが結合している窒素原子と一緒になって、1〜2個の窒素原子もしくは1個の窒素原子および1個の酸素原子を含有し、1個以上のC1〜C6アルキル基もしくはC3〜C8シクロアルキル基で任意選択により置換されている4員、5員もしくは6員の飽和複素環式環を形成し;
R8は、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R9は、ハロ、OH、C1〜C6アルキルおよびS−C1〜C6アルキルで任意選択により置換されたピリジル、ベンジルまたはフェニルである。
R2がHであり、且つR1がビフェニルである場合、前記ビフェニルは置換されていなければならず、R4はF、SO2CH3またはNR6R7(式中、R6およびR7は、それらが結合しているN原子と一緒になって、ピペリジン環、ピロリジン環またはモルホリン環を形成している)であってはならず;
R2がHまたはOHである場合、R1は非置換フェノキシフェニルであってはならない。
式(Ib)の化合物については、式中、
R2がHであり、且つR1がインドールである場合、前記インドールは置換されていなければならず、R4はC1〜C6アルキルであってはならない。
R2がHであり、且つR1がインドールである場合、前記インドールは2位がフェニルで置換されていてはならない。
R2がHである場合、R1は非置換インダゾールであってはならない。
式(Ia)の化合物が特に好ましく
R1は、好ましくは、1個のR3基および1〜3個のR4基で任意選択により置換されているインドールもしくはテトラヒドロイソキノリンであるか;または、
1〜3個のR4基で任意選択により置換されているビフェニル、ベンジルフェニル&フェニルチオフェニルであり;
より好ましくは、R1は、インドール;または1個のR3基および1〜3個のR4基で任意選択により置換されているテトラヒドロイソキノリン;または1〜3個のR4基で置換されているビフェニルであり;
R2は、好ましくはHであり、
好ましくは、R3は−(CH2)n−Ar(式中、nは0〜4であり、Arは1〜2個のR4基で任意選択により置換されたフェニル基である)であり;
R4は、好ましくは、C1〜C6アルキル、C3〜C8シクロアルキル、ハロ、−CN、NR6R7、−SR5、−SOR8、−SO2R8、−COR5、−OCOR5、−COOR5、−COR9、−COOR9、OR5であるが、但し、−COR9および−COOR9はR1のN原子を介してのみ結合し、
R5は、好ましくはHまたはC1〜C6アルキルであり;
より好ましくは、R5はHまたはCH3である。
5−リポキシゲナーゼ活性化タンパク質(FLAP)拮抗薬;
LTB4、LTC4、LTD4、LTE4、CysLT1またはCysLT2の拮抗薬などのロイコトリエン拮抗薬(LTRA)、例えば、モンテルカストまたはザフィルルカスト;
ヒスタミン1型受容体拮抗薬またはヒスタミン2型受容体拮抗薬などのヒスタミン受容体拮抗薬、例えば、ロラチジン、フェキソフェナジン、デスロラチジン、レボセチリジン、メタピリレンまたはセチリジン;
α1−アドレノセプター作動薬またはα2−アドレノセプター作動薬、例えば、フェニレフリン、メトキサミン、オキシメタゾリンまたはメチルノルエフリン;
ムスカリンM3受容体拮抗薬、例えば、チオトロピウムまたはイプラトロピウム;
二重作用(dual)ムスカリンM3受容体アンタゴノニスト/β2作動薬;
PDE3阻害剤、PDE4阻害剤またはPDE5阻害剤などのPDE阻害剤、例えば、テオフィリン、シルデナフィル、バルデナフィル、タダラフィル、イブジラスト、シロミラストまたはロフルミラスト;
クロモグリク酸ナトリウムまたはネドクロミルナトリウム;
非選択的阻害剤(例えば、アスピリンもしくはイブプロフェン)または選択的阻害剤(例えば、セレコキシブもしくはバルデコキシブ)などのシクロオキシゲナーゼ(COX)阻害剤;
グルココルチコステロイド、例えば、フルチカゾン、モメタゾン、デキサメタゾン、プレドニゾロン、ブデソニド、シクレソニドまたはベクラメタゾン;
抗炎症性モノクローナル抗体、例えば、インフリキシマブ、アダリムマブ、タネズマブ(tanezumab)、ラニビズマブ、ベバシズマブまたはメポリズマブ;
β2作動薬、例えば、サルメテロール、アルブテロール、サルブタモール、フェノテロールまたはホルモテロール、特に、持効性β作動薬;
インチグリン拮抗薬、例えば、ナタリズマブ;
VLA−4拮抗薬などの接着分子阻害剤;
キニンB1またはB2受容体拮抗薬;
IgE経路の阻害剤(例えば、オマリズマブ)またはシクロスポリンなどの免疫抑制剤;
MMP−9またはMMP−12の阻害剤などのマトリックスメタロプロテアーゼ(MMP)阻害剤;
タキキニンNK1、NK2またはNK3受容体拮抗薬;
エラスターゼ、キマーゼまたはカテオプシンGの阻害剤などのプロテアーゼ阻害剤;
アデノシンA2a受容体作動薬;
アデノシンA2b受容体拮抗薬;
ウロキナーゼ阻害剤;
ドーパミン受容体作動薬(例えば、ロピニロール)、特に、ドーパミンD2受容体作動薬(例えば、ブロモクリプチン);
IKK阻害剤などのNFκB経路の調節剤;
SYKキナーゼ、sykキナーゼ、p38キナーゼ、SPHK−1キナーゼ、Rhoキナーゼ、EGF−RまたはMK−2の阻害剤などのサイトカインシグナル伝達経路の別の調節剤;
粘液溶解剤、粘液クリアランス補助(mucokinetic)剤または鎮咳剤
抗生物質;
抗ウイルス剤;
ワクチン;
ケモカイン;
上皮ナトリウムチャネル(ENaC)遮断薬または上皮ナトリウムチャネル(ENaC)阻害剤;
P2Y2作動薬などのヌクレオチド受容体作動薬;
トロンボキサン阻害剤;
ナイアシン;
5−リポキシゲナーゼ(5−LO)阻害剤、例えば、ジロイトン(Zileuton);
VLAM、ICAMまたはELAMなどの接着因子;
CRTH2受容体(DP2)拮抗薬;
プロスタグランジンD2受容体(DP1)拮抗薬;
造血プロスタグランジンD2合成酵素(HPGDS)阻害剤;
インターフェロン−β;
可溶性ヒトTNF受容体、例えば、エタネルセプト;
HDAC阻害剤;
ホスホイノシトチド3−キナーゼγ(PI3Kγ)阻害剤;
ホスホイノシチド3−キナーゼδ(PI3Kδ)阻害剤;
CXCR−1またはCXCR−2受容体拮抗薬;
IRAK−4阻害剤;および
TLR−4またはTLR−9阻害剤;
が挙げられ、
これには、具体的に名前を挙げた化合物の薬学的に許容される塩ならびに前記具体的に名前を挙げた化合物および塩の薬学的に許容される溶媒和物が含まれる。
AcOHは酢酸であり;
APCI(質量分析に関する)は大気圧化学イオン化であり;
BOPは(ベンゾトリアゾール−1−イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェートであり;
Calcは計算値であり;
CDCl3は重水素化クロロホルムであり;
CO2Etはカルボン酸エチルであり;
DCCはN,N’−ジシクロヘキシルカルボジイミドであり;
DCMはジクロロメタンであり;
DEAはジエチルアミンであり;
DIADはアゾジカルボン酸ジイソプロピルであり;
DIEAは、N,N−ジイソプロピルエチルアミンであり;
DIPEAは、N,N−ジイソプロピルエチルアミンであり;
DMAは、N,N−ジメチルアセトアミドであり;
DMFは、N,N−ジメチルホルムアミドであり;
DMF−DMAは、N,N−ジメチルホルムアミドジメチルアセタールであり;
DMSOは、ジメチルスルホキシドであり;
DMSO−d6は、完全に重水素化されたジメチルスルホキシドであり;
EDC/EDCI/EDC.Clは、N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩であり;
ES(質量分析に関する)は、エレクトロスプレーであり;
Etは、エチルであり;
EtOAcは、酢酸エチルであり
Exは、実施例であり;
hは、時間であり;
HATUは、N,N,N’,N’−テトラメチル−O−(7−アザベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェートであり;
HBTUは、N,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェートであり;
HClは、塩酸であり;
1H NMRまたは1H NMRは、プロトン核磁気共鳴であり;
HOAtは、1−ヒドロキシ−7−アザベンゾトリアゾールであり;
HOBtは、1−ヒドロキシベンゾトリアゾールであり;
HPLCは、高速液体クロマトグラフィーであり;
H2SO4は、硫酸であり;
IPAは、イソプロピルアルコールであり;
iPrは、イソプロピルであり;
K2CO3は、炭酸カリウムであり;
KMnO4は、過マンガン酸カリウムであり;
KOHは、水酸化カリウムであり;
KOAcは、酢酸カリウムであり;
LCMSは、液体クロマトグラフィー質量分析であり;
LRMSは、低分解能質量分析であり;
m−CPBAは、m−クロロ過安息香酸であり
Meは、メチルであり;
MeCNは、アセトニトリルであり;
MeOHは、メタノールであり;
MeOD−d4は、完全に重水素化されたメタノールであり;
MgSO4は、硫酸マグネシウムであり;
2−MeTHFは、2−メチルテトラヒドロフランであり;
minは、分であり;
MSは、質量分析であり;
NaClは、塩化ナトリウムであり;
NaOHは、水酸化ナトリウムであり;
NaHは、水素化ナトリウムであり;
NBSは、N−ブロモスクシンイミドであり;
NISは、N−ヨードスクシンイミドであり;
NMMは、4−メチルモルホリンであり;
NMPは、N−メチルピロリジンであり;
Obsは、実測値であり;
Pd(OAc)2は、酢酸パラジウム(II)であり;
RTは、保持時間であり;
SEM−Clは、(2−クロロメトキシエチル)トリメチルシランであり;
SPhosは、2−ジシクロヘキシルホスフィノ−2’,6’−ジメトキシビフェニルであり;
STABは、ナトリウム(トリアセトキシ)ボロハイドライドであり;
TBTUは、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボレートであり;
TEAは、トリエチルアミンであり;
TFAは、トリフルオロ酢酸であり;
THFは、テトラヒドロフランであり;
tBMEは、2−メトキシ−2−メチル−プロパンであり;
p−TsOHは、p−トルエンスルホン酸である。
・治療を必要とする患者に式(Ia)、(Ib)または(Ic)の化合物と別の治療剤とのこのような組み合わせを同時投与することであって、この場合、このような成分は、前記成分を前記患者に実質的に同時に放出する単一の剤形に一緒に製剤化されている、
・治療を必要とする患者に式(I)の化合物と別の治療剤とのこのような組み合わせを実質的に同時投与することであって、この場合、このような成分は、前記患者により実質的に同時に摂取されると、前記成分が前記患者に実質的に同時に放出される別々の剤形に互いに別々に製剤化されている、
・治療を必要とする患者に式(Ia)、(Ib)または(Ic)の化合物と別の治療剤とのこのような組み合わせを逐次投与することであって、この場合、このような成分は、前記患者により各投与間にかなりの時間間隔を空けて順次摂取されると、前記成分が実質的に異なる時間に前記患者に投与される別々の剤形に互いに別々に製剤化されている;および
・治療を必要とする患者に式(Ia)、(Ib)または(Ic)の化合物と別の治療剤とのこのような組み合わせを逐次投与することであって、この場合、このような成分は前記成分を制御放出する単一の剤形に一緒に製剤化されている。
(i)式(Ia)、(Ib)または(Ic)の化合物がカルボン酸官能基(−COOH)を含有する場合、そのエステル、例えば、式(Ia)、(Ib)または(Ic)の化合物のカルボン酸官能基の水素がC1〜C8アルキル(例えば、エチル)または(C1〜C8アルキル)C(=O)OCH2−(例えば、tBuC(=O)OCH2−)で置き換えられている化合物など;
(ii)式(Ia)、(Ib)または(Ic)の化合物がアルコール官能基(−OH)を含有する場合、そのエステル、例えば、式(Ia)、(Ib)または(Ic)の化合物のアルコール官能基の水素が−CO(C1〜C8アルキル)(例えば、メチルカルボニル)で置き換えられている、またはアルコールがアミノ酸でエステル化されている化合物;
(iii)式(Ia)、(Ib)または(Ic)の化合物がアルコール官能基(−OH)を含有する場合、そのエーテル、例えば、式(Ia)、(Ib)または(Ic)の化合物のアルコール官能基の水素が(C1〜C8アルキル)C(=O)OCH2−または−CH2OP(=O)(OH)2で置き換えられている化合物;
(iv)式(Ia)、(Ib)または(Ic)の化合物がアルコール官能基(−OH)を含有する場合、そのホスフェート、例えば、式(Ia)、(Ib)または(Ic)の化合物のアルコール官能基の水素が−P(=O)(OH)2または−P(=O)(ONa)2または−P(=O)(O−)2Ca2+で置き換えられている化合物;
(v)式(Ia)、(Ib)または(Ic)の化合物が第一級または第二級アミノ官能基(−NH2または−NHR、式中、R≠H)を含有する場合、そのアミド、例えば、場合により、式(Ia)、(Ib)または(Ic)の化合物のアミノ官能基の一方または両方の水素が(C1〜C10)アルカノイル、−COCH2NH2で置き換えられている、またはアミノ基がアミノ酸で誘導体化されている化合物;
(vi)式(Ia)、(Ib)または(Ic)の化合物が第一級または第二級アミノ官能基(−NH2または−NHR、式中、R≠H)を含有する場合、そのアミン、例えば、場合により、式(Ia)、(Ib)または(Ic)の化合物のアミノ官能基の一方または両方の水素が−CH2OP(=O)(OH)2で置き換えられている化合物;
が挙げられる。
(i)式(Ia)、(Ib)または(Ic)の化合物を所望の酸または塩基と反応させることにより;
(ii)式(Ia)、(Ib)もしくは(Ic)の化合物の好適な前駆体から酸もしくは塩基に対して不安定な保護基を除去することにより、または、好適な環状前駆体、例えば、ラクトンもしくはラクタムを、所望の酸もしくは塩基を使用して開環させることにより;あるいは
(iii)適切な酸もしくは塩基との反応によりまたは好適なイオン交換カラムで、式(Ia)、(Ib)または(Ic)の化合物の1種の塩を別の塩に変換することにより;
製造することができる。
(i)式(Ia)、(Ib)または(Ic)の化合物がメチル基を含有する場合、そのヒドロキシメチル誘導体(−CH3−>−CH2OH):
(ii)式(Ia)、(Ib)または(Ic)の化合物がアルコキシ基を含有する場合、そのヒドロキシ誘導体(−OR−>−OH);
(iii)式(Ia)、(Ib)または(Ic)の化合物が第三級アミノ基を含有する場合、その第二級アミノ誘導体(−NRR’−>−NHRまたは−NHR’);
(iv)式(Ia)、(Ib)または(Ic)の化合物が第二級アミノ基を含有する場合、その第一級誘導体(−NHR−>−NH2);
(v)式(Ia)、(Ib)または(Ic)の化合物がフェニル部分を含有する場合、そのフェノール誘導体(−Ph−>−PhOH);および
(vi)式(Ia)、(Ib)または(Ic)の化合物がアミド基を含有する場合、そのカルボン酸誘導体(−CONH2−>COOH);
が挙げられる。
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−(1H−インドール−4−イルアミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン
LCMS:m/z 343 MH+.
LCMS:m/z 315 MH+.
LCMS:m/z ES+314(MH+).
LCMS:m/z 324、MH+.
LCMS:m/z 340(MH+).
工程(5)のスルホキシド(14mg、0.04mmol)およびcis−1,2−シクロヘキサンジアミン25mg(5当量)をDMSO1mL中で混合し、100℃で終夜一緒に撹拌した。分取HPLC(方法A)で精製した。
LCMS m/z +390(MH+).
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−({1−[3−(4−ヒドロキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド
LCMS:m/z 437 M35ClH+.
LCMS:m/z 514 MH+.
工程(3)のアニソール(62mg、0.12mmol)のDCM(500uL)溶液を、BBr3の1M DCM溶液(1.20mL、1.20mmol)で処理した。混合物を室温で3時間撹拌した。混合物をアンモニア水(880)(2mL)で処理した。混合物を室温で1時間撹拌した。混合物を濾過した。得られた粘性物質をMeOHに溶解した。MeOH溶液を減圧蒸発させた。残渣を分取HPLC(方法A)で精製した。
LCMS:m/z 500 MH+.
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−[(4’−ヒドロキシビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド
工程(1):4−(3−ヨードフェニルアミノ)−2−メチルスルファニルピリミジン−5−カルボン酸
LCMS:m/z 388 MH+,386(M−H)−.
濾過により沈殿を回収し、白色固体4.13gを得た。
LCMS m/z 387 MH+,385(M−H).
LCMS:m/z 419 MH+,417(M−H).
ISCO Redisep 80gで、ヘプタン:EtOAc、100:0〜0:100で溶出して精製し、所望の化合物をクリーム状の固体として得た。
LCMS:m/z 553 MH+.
LCMS:m/z 419 MH+,417(M−H)−.
Promega ADP−Glo Kinase Assayは、キナーゼ反応中に生成するADPの量を定量することによりキナーゼ活性を測定する、汎用の均質で高スループットのスクリーニング方法を提供する発光ADP検出アッセイである。
Promega V9102、キット使用説明書の通り調製。
http://www.promega.com/tbs/tm313/tm313.pdf
化合物プレートを(100%DMSO中、0.4ul)100rpmで1分間回転させる。
1ウェル当たり化合物賦形剤30ulを化合物プレートに添加=52.6uM
2ul/ウェルを少量アッセイプレートに移す。
1 酵素をプレートに添加する
− 4ul/ウェル 酵素を化合物プレートに添加する前に、酵素をダミープレートに流す(チューブをコーティングする)。室温で15分間インキュベートする。
2 ペプチド/ATP混合物を添加し、反応を開始させる
− 4ul/ウェル ATP/ペプチド混合物を化合物プレートに添加する前に、ATP/ペプチド混合物をダミープレートに流す(チューブをコーティングする)。室温で60分間インキュベートする。
3 反応時間の終わりに、ADP−Glo試薬を添加する
− 4ul/ウェル 室温で60分間インキュベートする
4 ADP−Glo検出試薬を添加する
− 8ul/ウェル 室温で30分間インキュベートする
5 Analyst(Protocol 401)またはEnvision(Standard USM Luminescence)[ADP Glo(LF)]のいずれかで発光を読み取る
化合物2ul(5倍希釈)
酵素4ul(2.5倍希釈)
ペプチド/ATP混合物4ul(2.5倍希釈)
Claims (15)
- 式(Ia)の化合物:
R1は、1個のR3基および任意選択により1〜3個のR4基で置換されているインドールであり;
R2は、HまたはOHであり;
R3は、−(CH2)n−Ar(式中、nは1、2、3または4であり、Arは1〜3個のR4基で任意選択により置換されたフェニル基である)であり;
R4は、C1〜C6アルキル、C3〜C8シクロアルキル、ハロ、−CN、−OR5、−NR6R7、−SR5、−SOR8、−SO2R8、−COR5、−OCOR5、−COOR5、−NR5COR5、−CONR6R7、−NR5SO2R8、−SO2NR6R7、−NR5CONR6R7、−NR5COOR8、−NR5SO2NR6R7、−COR9および−COOR9からそれぞれ独立して選択されるが、但し、−COR9および−COOR9はR1のN原子を介してのみ結合し;
R5は、H、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R6およびR7は、それぞれ独立して、H、C1〜C6アルキルもしくはC3〜C8シクロアルキルであるか、またはそれらが結合している窒素原子と一緒になって、1〜2個の窒素原子もしくは1個の窒素原子および1個の酸素原子を含有し、1個以上のC1〜C6アルキル基もしくはC3〜C8シクロアルキル基で任意選択により置換されている4員、5員もしくは6員の飽和複素環式環を形成し;
R8は、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R9は、ハロ、OH、C1〜C6アルキルおよびS−C1〜C6アルキルで任意選択により置換されているピリジル、ベンジルまたはフェニルである;
化合物もしくはその薬学的に許容される塩、または前記化合物もしくは薬学的に許容される塩の薬学的に許容される溶媒和物。 - 式(Ia)の化合物:
R1は、(i)任意選択により1個のR3基および1〜3個のR4基で置換されているテトラヒドロイソキノリン;または、
(ii)任意選択により1〜3個のR4基で置換されているベンジルフェニルまたはフェニルチオフェニルであり;
R2は、HまたはOHであり;
R3は、−(CH2)n−Ar(式中、nは0、1、2、3または4であり、Arは1〜3個のR4基で任意選択により置換されたフェニル基である)であり;
R4は、C1〜C6アルキル、C3〜C8シクロアルキル、ハロ、−CN、−OR5、−NR6R7、−SR5、−SOR8、−SO2R8、−COR5、−OCOR5、−COOR5、−NR5COR5、−CONR6R7、−NR5SO2R8、−SO2NR6R7、−NR5CONR6R7、−NR5COOR8、−NR5SO2NR6R7、−COR9および−COOR9からそれぞれ独立して選択されるが、但し、−COR9および−COOR9はR1のN原子を介してのみ結合し;
R5は、H、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R6およびR7は、それぞれ独立して、H、C1〜C6アルキルもしくはC3〜C8シクロアルキルであるか、またはそれらが結合している窒素原子と一緒になって、1〜2個の窒素原子もしくは1個の窒素原子および1個の酸素原子を含有し、1個以上のC1〜C6アルキル基もしくはC3〜C8シクロアルキル基で任意選択により置換されている4員、5員もしくは6員の飽和複素環式環を形成し;
R8は、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R9は、ハロ、OH、C1〜C6アルキルおよびS−C1〜C6アルキルで任意選択により置換されているピリジル、ベンジルまたはフェニルである;
化合物もしくはその薬学的に許容される塩、または前記化合物もしくは薬学的に許容される塩の薬学的に許容される溶媒和物。 - 式(Ia)の化合物:
R1は、任意選択により1〜3個のR4基で置換されているビフェニルであり;
R2は、HまたはOHであり;
R4は、C1〜C6アルキル、C3〜C8シクロアルキル、ハロ、−CN、−OH、−SR5、−SOR8、−SO2R8、−COR5、−OCOR5、−COOR5、−NR5COR5、−CONR6R7、−NR5SO2R8、−SO2NR6R7、−NR5CONR6R7、−NR5COOR8、−NR5SO2NR6R7、−COR9および−COOR9からそれぞれ独立して選択され;
R5は、H、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R6およびR7は、それぞれ独立して、H、C1〜C6アルキルもしくはC3〜C8シクロアルキルであるか、またはそれらが結合している窒素原子と一緒になって、1〜2個の窒素原子もしくは1個の窒素原子および1個の酸素原子を含有し、1個以上のC1〜C6アルキル基もしくはC3〜C8シクロアルキル基で任意選択により置換されている4員、5員もしくは6員の飽和複素環式環を形成し;
R8は、C1〜C6アルキルまたはC3〜C8シクロアルキルであり;
R9は、ハロ、OH、C1〜C6アルキルおよびS−C1〜C6アルキルで任意選択により置換されているピリジル、ベンジルまたはフェニルである;
化合物であって、
ここで、R2がHであるとき、R1は置換されていなければならず、R4はFまたはSO2CH3であってはならない、
化合物もしくはその薬学的に許容される塩、または前記化合物もしくは薬学的に許容される塩の薬学的に許容される溶媒和物。 - 以下からなる群から選択される化合物:
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−(1H−インドール−4−イルアミノ)ピリド[4,3−d]ピリミジン−5(6H)−オン;および
2−{[(1R,2S)−2−アミノシクロヘキシル]アミノ}−4−[(4’−ヒドロキシビフェニル−3−イル)アミノ]ピリド[4,3−d]ピリミジン−5(6H)−オン、
もしくはその薬学的に許容される塩、または前記化合物もしくは薬学的に許容される塩の薬学的に許容される溶媒和物。 - R2がHである、請求項1〜3のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または前記化合物もしくは塩の薬学的に許容される溶媒和物。
- R3が−(CH2)n−Ar(式中、nは1、2、3または4であり、Arは1〜2個のR4基で任意選択により置換されたフェニル基である)である、請求項1または2に記載の化合物。
- R5がHまたはC1〜C6アルキルである、請求項1、2、3、5、または6に記載の化合物。
- R4がC1〜C6アルキル、C3〜C8シクロアルキル、ハロ、−CN、−SR5、−SOR8、−SO2R8、−COR5、−OCOR5、−COOR5、−COR9、−COOR9、または−OHである、請求項1、2、3、5、6、または7に記載の化合物。
- 請求項1に記載の化合物であって、前記化合物が、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(4−ヒドロキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(3−ヒドロキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−{[1−(4−メチルベンジル)−1H−インドール−4−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(3−メトキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−{[1−(3−メチルベンジル)−1H−インドール−4−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロヘキシル]アミノ}−4−[(1−ベンジル−1H−インドール−4−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(4−ヒドロキシフェニル)]エチル−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(4−メトキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(4−メトキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(4−クロロベンジル)−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(3−ヒドロキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(2−メトキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(2−ヒドロキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−[(1−ベンジル−1H−インドール−5−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(4−ヒドロキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(4−ヒドロキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−{[1−(3−ヒドロキシベンジル)−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(3−フェニルプロピル)−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(3−メトキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(4−メトキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[2−(2−メトキシフェニル)エチル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−フェニルエチル)−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(4−メトキシフェニル)プロピル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロヘキシル]アミノ}−4−[(1−ベンジル−1H−インドール−6−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[3−(メチルチオ)ベンジル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−ヒドロキシベンジル)−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−フルオロベンジル)−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({1−[4−(メチルチオ)ベンジル]−1H−インドール−4−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−メチルベンジル)−1H−インドール−4−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−クロロベンジル)−1H−インドール−4−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(3−クロロベンジル)−1H−インドール−4−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(3−メトキシベンジル)−1H−インドール−6−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(4−メトキシベンジル)−1H−インドール−6−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−メトキシベンジル)−1H−インドール−6−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(4−ヒドロキシベンジル)−1H−インドール−6−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−{[1−(4−ヒドロキシベンジル)−1H−インドール−4−イル]アミノ}ピリミジン−5−カルボキサミド、または、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[1−(2−メトキシベンジル)−1H−インドール−5−イル]アミノ}ピリミジン−5−カルボキサミド、
である、
化合物。 - 請求項2に記載の化合物であって、前記化合物が、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(ピリジン−3−イルカルボニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(シクロブチルカルボニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(フェニルアセチル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(2−プロピオニル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(2−イソニコチノイル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(4−ヒドロキシベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
メチル7−[2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−5−カルバモイルピリミジン−4−イル)アミノ]−3,4−ジヒドロイソキノリン−2(1H)−カルボキシレート、
エチル7−[2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−5−カルバモイルピリミジン−4−イル)アミノ]−3,4−ジヒドロイソキノリン−2(1H)−カルボキシレート、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(エチルスルフォニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(2−ヒドロキシベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
フェニル7−[2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−5−カルバモイルピリミジン−4−イル)アミノ]−3,4−ジヒドロイソキノリン−2(1H)−カルボキシレート、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(3−ヒドロキシベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(2−ベンゾイル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({2−[3−(メチルチオ)ベンゾイル]−1,2,3,4−テトラヒドロイソキノリン−7−イル}アミノ)ピリミジン−5−カルボキサミド、
イソプロピル7−[2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−5−カルバモイルピリミジン−4−イル)アミノ]−3,4−ジヒドロイソキノリン−2(1H)−カルボキシレート、
4−[(2−アセチル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]−2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}ピリミジン−5−カルボキサミド、
ベンジル7−[2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−5−カルバモイルピリミジン−4−イル)アミノ]−3,4−ジヒドロイソキノリン−2(1H)−カルボキシレート、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(3−フルオロベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
シクロプロピル7−[2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−5−カルバモイルピリミジン−4−イル)アミノ]−3,4−ジヒドロイソキノリン−2(1H)−カルボキシレート、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(メチルスルフォニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(シクロプロピルスルフォニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(4−フルオロベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(3−エチルベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(シクロへキシルカルボニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(イソプロピルスルフォニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(4−メチルベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(2−クロロベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(2−フルオロベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(4−クロロベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(シクロペンチルカルボニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(3−メチルベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(シクロプロピルカルボニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({2−[4−(メチルチオ)ベンゾイル]−1,2,3,4−テトラヒドロイソキノリン−7−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(4−エチルベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(2−エチルベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(3−クロロベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[2−(ピリジン−2−イルカルボニル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({2−[2−(メチルチオ)ベンゾイル]−1,2,3,4−テトラヒドロイソキノリン−7−イル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(2−ベンジル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−([2−(2−メチルベンゾイル)−1,2,3,4−テトラヒドロイソキノリン−7−イル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(2−メチル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−(1,2,3,4−テトラヒドロイソキノリン−7−イルアミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(2−イソブチリル−1,2,3,4−テトラヒドロイソキノリン−7−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[3−(4−メトキシベンジル)フェニル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[3−(4−クロロベンジル)フェニル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[3−(3−メチルベンジル)フェニル]アミノ}ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(3−ベンジルフェニル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(4−ベンジルフェニル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({3−[(3−ヒドロキシフェニル)チオ]フェニル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({3−[(4−ヒドロキシフェニル)チオ]フェニル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({3−[(4−メトキシフェニル)チオ]フェニル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({3−[(4−クロロフェニル)チオ]フェニル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({3−[(3−メチルフェニル)チオ]フェニル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−({3−[(3−メトキシフェニル)チオ]フェニル}アミノ)ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[3−(フェニルチオ)フェニル]アミノ}ピリミジン−5−カルボキサミド、または、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−{[4−(フェニルチオ)フェニル]アミノ}ピリミジン−5−カルボキサミド、
である、
化合物。 - 請求項3に記載の化合物であって、前記化合物が、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(4’−ヒドロキシビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(3’−ヒドロキシビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−[(3’−ヒドロキシビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R,2S)−2−アミノシクロへキシル]アミノ}−4−[(4’−ヒドロキシビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(3’−メチルビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(4’−クロロ−3’−ヒドロキシビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、または、
2−{[(1R*,2S*)−2−アミノシクロへキシル]アミノ}−4−[(4’−クロロビフェニル−3−イル)アミノ]ピリミジン−5−カルボキサミド、
である、
化合物。 - 請求項1〜11のいずれか一項に記載の化合物と、薬学的に許容される医薬品添加物とを含む医薬組成物。
- 治療を必要とする対象における、SYK阻害剤の適応疾患または症状を治療するために用いられる、請求項12に記載の医薬組成物。
- 請求項13に記載の医薬組成物であって、前記疾患または症状が、アレルギー性鼻炎、鼻閉、鼻漏、通年性鼻炎、鼻の炎症、喘息、慢性閉塞性肺疾患(COPD)、慢性または急性気管支収縮、慢性気管支炎、末梢気道閉塞、肺気腫、慢性好酸球性肺炎、成人呼吸窮迫症候群、他の薬物療法の結果として起こる気道反応亢進の増悪、肺血管疾患(肺動脈高血圧症を含む)、急性肺損傷、気管支拡張症、副鼻腔炎、アレルギー性結膜炎、特発性肺線維症またはアトピー性皮膚炎、特に、喘息またはアレルギー性鼻炎またはアトピー性皮膚炎またはアレルギー性結膜炎、炎症、関節炎、疼痛、発熱、肺サルコイドーシス、珪肺症、心血管疾患(アテローム性動脈硬化症、心筋梗塞、血栓症、うっ血性心不全および心臓再灌流障害を含む)、心筋症、脳卒中、虚血、再灌流障害、脳浮腫、脳外傷、神経変性、肝疾患、炎症性腸疾患(クローン病および潰瘍性大腸炎を含む)、腎炎、網膜炎、網膜症、黄斑変性、緑内障、糖尿病(1型および2型糖尿病を含む)、ドライアイ症、糖尿病性神経障害、ウイルスおよび細菌感染、筋痛症、内毒素ショック、中毒性ショック症候群、自己免疫疾患、骨粗鬆症、多発性硬化症、子宮内膜症、月経性痙攣、膣炎、カンジダ症、癌、結膜炎、食物アレルギー、線維症、肥満、筋ジストロフィー、多発筋炎、アルツハイマー病、皮膚潮紅、湿疹、乾癬、アトピー性皮膚炎、酒さ、円板状エリテマトーデス、結節性痒疹、脱毛症ならびに日焼けから選択される、
医薬組成物。 - 請求項13に記載の医薬組成物であって、前記疾患または症状が、喘息、COPD、アレルギー性鼻炎、慢性副鼻腔炎、アトピー性皮膚炎、乾癬、酒さ、脱毛症、アレルギー性結膜炎およびドライアイ症から選択される、
医薬組成物。
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WO2016133967A2 (en) * | 2015-02-18 | 2016-08-25 | Parion Sciences, Inc. | Sodium channel blockers for skin disorders |
WO2018031990A1 (en) * | 2016-08-12 | 2018-02-15 | Nanjing Gator Meditech Company, Ltd. | Protein kinase regulators |
KR102383561B1 (ko) * | 2017-09-07 | 2022-04-06 | 한국화학연구원 | 테트라히드로이소퀴놀린기로 치환된 피리미딘 유도체 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용 가능한 염, 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 조성물 |
WO2019136204A1 (en) * | 2018-01-04 | 2019-07-11 | Rush University Medical Center | Methods for treating neutrophilic dermatoses with syk inhibitors |
BR112020018377A2 (pt) * | 2018-03-09 | 2021-03-09 | Portola Pharmaceuticals, Inc | Métodos de uso e composições farmacêuticas de um inibidor de syk seletivo |
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US20220143049A1 (en) | 2019-03-21 | 2022-05-12 | Onxeo | A dbait molecule in combination with kinase inhibitor for the treatment of cancer |
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