JP5208516B2 - キナーゼモジュレーターとしてのピリミジン誘導体および使用方法 - Google Patents
キナーゼモジュレーターとしてのピリミジン誘導体および使用方法 Download PDFInfo
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- JP5208516B2 JP5208516B2 JP2007549634A JP2007549634A JP5208516B2 JP 5208516 B2 JP5208516 B2 JP 5208516B2 JP 2007549634 A JP2007549634 A JP 2007549634A JP 2007549634 A JP2007549634 A JP 2007549634A JP 5208516 B2 JP5208516 B2 JP 5208516B2
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- alkyl
- heterocyclyl
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- 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
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000004474 valine Substances 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
- 208000009540 villous adenoma Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Description
本願は、米国仮特許出願第60/640,439号(これは、2004年12月30日に出願された)、および米国仮特許出願第第60/704,863(これは、2005年8月1日に出願された)(これらの両方の内容は、それらの全体として、本明細書中で参考として援用されている)から優先権を主張している。
本発明は、プロテインキナーゼ酵素活性を調節するための化合物、ならびに増殖、分化、プログラム細胞死、移動(migration)、化学的侵襲(chemoinvasion)および代謝のような細胞活性の得られた調節に関連する。より具体的には、本発明は、上記のような細胞活性における変化に関連したキナーゼレセプターシグナル伝達経路を阻害、制御および/または調節する化合物、これらの化合物を含有する組成物、およびそれらを使用してキナーゼ依存性の疾患および状態を処置する方法に関する。
種々の疾患(例えば、癌、代謝疾患および炎症疾患)を処置するために使用される因子の特異性の改良は、これらの因子の投与に関係する副作用が減少されるか否かが確認されるという治療的利益に起因して、相当に興味深い。伝統的に、癌の処置における劇的な改良は、新規の機構を通じて作用する治療因子の同定に関連する。
Gorre ME,Mohammed M,Ellwood Kら,Science 2001;293:876−80 Shah NP,Nicoll JM,Nagar Bら,Cancer Cell 2002;2:117−25 Branford,S.ら,Blood 99,3472−3475(2002) Branford,S.ら,Blood 102,276−283(2003) Branford,S.ら,Blood 104,2926−2932(2004) Hochhaus,A.ら,Leukemia 16,2190−2196(2002) Roche−Lestienne,C.ら,Blood 100,1014−1018(2002) Roche−Lestienne,C.,Lai,J.L.,Darre,S.,Facon,T.& Preudhomme,C.,N.Engl.J.Med.348,2265−2266(2003) Martinelli G,Soverini S,Rosti G,Cilloni D,Baccarani M.,Haematologica 2005;90:534−41 Shah NP,Sawyers CL,Kantarjian HMら、「Correlation of Clinical Response to BMS−354825 with BCR−ABL Mutation Status in Imatinib−Resistant Patients with Chronic Myeloid Leukemia(CML)and Philadelphia Chromosome−Associated Acute Lymphoblastic Leukemia(Ph+ ALL)」;ASCO Annual Meeting 2005;Abstract #6521
一局面では、本発明は、IGF1Rの活性を調節する化合物および組成物(医薬組成物を含めて)、ならびにこれらの組成物およびそれらの医薬組成物を使用してIGF1Rの活性により媒介される疾患を治療する方法を提供する。
本発明の組成物は、異常な細胞活性、および、または、統制されていない細胞活性に関連した疾患を処置するために、使用される。本明細書中で提供される方法および組成物によって処置され得る疾患状態としては、癌(以下でさらに議論される)、免疫学的障害(例えば、慢性関節リウマチ、移植片−宿主疾患、多発性硬化症、乾癬);心臓血管疾患(例えば、動脈硬化症(artheroscrosis)、心筋梗塞(myocardioinfarction)、虚血、発作および.再狭窄);代謝障害および疾患(例えば、糖尿病、肥満および高コレステロール血症);ならびに他の炎症性疾患および変性疾患(例えば、腸間疾患(interbowel diseases)、変形性関節症(osteoarthritus)、黄斑変性、糖尿病性網膜症)が挙げられる。
Vは、NR1R1a、またはO−R1であり、ここで、
R1は、H、CN、ハロ、−NR13R14、C(O)NR13R14、C1〜C6アルキル、−C(O)−C1〜C6アルキル、−C0〜C6アルキル−R20であり、ここで、R20は、アリール、ヘテロアリール、ヘテロシクリル、あるいは5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、0個〜4個の環原子を含有し、該環原子は、N、OおよびSから選択され、ここで、アリール、ヘテロアリール、C3〜C7ヘテロシクリル、または該5員〜12員環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、C1〜C6アルキル、および−C0〜C6アルキル−R21から選択される;
R1aは、HまたはC1〜C6アルキルである;あるいは
Vが、NR1R1aであるとき、R1およびR1aは、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルまたはヘテロアリール基は、該窒素に加えて、2個までの追加ヘテロ原子を含有し、該追加ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のC1〜C6アルキル、−NR13R14またはC3〜C7シクロアルキルで置換されている;
Xは、H、ハロ、C1〜C6アルキル、NO2、モノ−、ジ−またはトリ−ハロ置換メチル、NR13R14、C(O)O−C1〜C6アルキル、あるいはN(R13)−C(O)−C1〜C6アルキルである;
Yは、H、ハロ、OH、C1〜C6アルキル、C0〜C6アルキル−NR15R16、C1〜C6アルコキシ、−N(R13)−(CH2)n−NR15R16、−C(O)O−C1〜C6アルキル、−O−(CH2)n−NR15R16、−C(O)−C1〜C6アルキル、−C0〜C6−アルキル−R21、−O−R21、−C(O)−R21、−O−(CH2)n−R21、−C(O)−NR13R14、−C(O)−N(R13)−アリール、−C(O)−N(R13)−(CH2)n−NR15R16、−C(O)−N(R13)−(CH2)n−アリール、−C(O)−N(R13)−(CH2)n−ヘテロシクリルである;
あるいはXおよびYは、それらが結合する原子と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルまたはヘテロアリール基は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、ここで、該ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、アリール−C1〜C6アルキル−、アリール−(CH2)n−O−(CH2)n−アリール−、アリールOH、C3〜C7シクロアルキル、ヘテロシクリル、−アリール−N(R13)C(O)−C3〜C7シクロアルキル−C(O)−N(R14)−アリール、または式−L−M−Qの基から選択され、ここで、
Lは、結合またはC3〜C7シクロアルキルであり、
Mは、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、
Qは、NR13R14、N(R13)C(O)−C1〜C6アルキル、ヘテロシクリル、または飽和縮合二環式環であり、該環は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、
ここで、XおよびYにより形成された基上の各アリール、ヘテロアリールまたはヘテロシクリル置換基は、必要に応じて、1個または2個の部分でさらに置換されており、該部分は、別個に、ハロ、C(O)O−(CH2)n−フェニル、およびC(O)−C1〜C6アルキルから選択される;
Zは、H、NR2R3、−S−R2a、または−O−R2aであり、ここで、
R2は、−C1〜C6アルキル、−C1〜C6アルキル−NR13R14、−C(O)−アリール、−C0〜C6−アルキル−アリール、−C0〜C6−アルキル−ヘテロアリール、−C0〜C6−アルキル−(C3〜C7−シクロアルキル)、−C0〜C6−アルキル−ヘテロシクリル、あるいは−C0〜C6アルキル−5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、0個〜4個の環原子を含有し、該環原子は、N、OおよびSから選択され、ここで、
各アルキルは、必要に応じて、フェニルで置換されており、そして
各アリール、ヘテロアリール、C3〜C7シクロアルキル、ヘテロシクリル、または5員〜12員環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチルまたはメトキシ、CN、NO2、NR13R14、C(O)O−C1〜C6アルキル、N(R13)C(O)−C1〜C6アルキル、−SO2NR13R14、−O−C(O)−NR13R14、−C0〜C6アルキル−C(O)NR15R16、C1〜C6アルコキシ、C1〜C6チオアルコキシ、−O−(CH2)n−NR15R16、−C1〜C6アルキル−NR13R14、−N(R13)−C(O)−C1〜C6アルキル、−N(R13)−C(O)−アリール、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−アリール、−O−(CH2)n−C(O)−N(R13)−(CH2)n−NR15R16、−O−(CH2)n−C(O)−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−O−C1〜C6アルキル、−C0〜C6アルキル−N(R13)−C(O)O−C1〜C6アルキル、−C0〜C6アルキル−C(O)−ヘテロシクリル、−C0〜C6アルキル−C(O)−ヘテロアリール、−C0〜C6アルキル−C(O)−アリール、−C0〜C6−アルキル−R21、アリールオキシ、−O−(CH2)n−R21、−SO2−ヘテロシクリル、N(R13)−C(O)−C3〜C7−シクロアルキル、−C0〜C6アルキル C(O)O−R21、C3〜C7−シクロアルキル、−C0〜C6アルキルR21、−SC1〜C6アルキルまたはC1〜C6アルキルから選択され、必要に応じて、ハロまたはシアノで置換されており、
ここで、各アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリル置換基は、必要に応じて、1個〜3個の基で置換されており、該基は、別個に、ハロ、CF3、C1〜C6アルキル、C1〜C6ハロアルコキシ、NR13R14およびC1〜C6アルコキシから選択される;
R3は、HまたはC1〜C6アルキル;
あるいはR2およびR3は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルまたはヘテロアリール基は、3個までのヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、該ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のハロまたはC1〜C6アルキルで置換されている;
R2aは、アリールまたはC0〜C6アルキル−ヘテロアリールであり、ここで、該アリールおよびヘテロアリールは、必要に応じて、アリール、−N(R13)−C(O)−C3〜C7シクロアルキルまたは−C(O)NR13R14で置換されている;
R13およびR14は、別個に、HまたはC1〜C6アルキルである;
R15およびR16は、別個に、H、C1〜C6アルキル、ヘテロアリール、またはヘテロシクリルであるか、あるいはR15およびR16は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、または−C(O)O−C1〜C6アルキルから選択される;
R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、−S(O)2−C0〜C1アルキル、−C(O)−C0〜C1アルキル、−C(O)−H、−C0〜C1アルキル−アリール、C1〜C6アルキル、NR13R14、およびヘテロシクリルから選択される;
nは、0〜6である;
但し、VがNH2であるとき、X、YおよびZは、同時にはHにならない。
R1は、H、CN、ハロ、−NR13R14、C(O)NR13R14、C1〜C6アルキル、−C(O)−C1〜C6アルキル、−C0〜C6アルキル−R20であり、ここで、R20は、アリール、ヘテロアリール、ヘテロシクリル、あるいは5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、0個〜4個の環原子を含有し、該環原子は、N、OおよびSから選択され、ここで、アリール、ヘテロアリール、C3〜C7ヘテロシクリル、または該5員〜12員環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、C1〜C6アルキル、および−C0〜C6アルキル−R21から選択される;
Xは、H、ハロ、C1〜C6アルキル、NO2、モノ−、ジ−またはトリ−ハロ置換メチル、NR13R14、C(O)O−C1〜C6アルキル、またはN(R13)−C(O)−C1〜C6アルキルである;
Yは、H、ハロ、OH、C1〜C6アルキル、NR15R16、C1〜C6アルコキシ、−N(R13)−(CH2)n−NR15R16、−C(O)O−C1〜C6アルキル、−O−(CH2)n−NR15R16、−C(O)−C1〜C6アルキル、−C0〜C6−アルキル−R21、−O−R21、−C(O)−R21、−O−(CH2)n−R21、−C(O)−NR13R14、−C(O)−N(R13)−アリール、−C(O)−N(R13)−(CH2)n−NR15R16、−C(O)−N(R13)−(CH2)n−アリール、−C(O)−N(R13)−(CH2)n−ヘテロシクリルであり、ここで、R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、NR13R14、およびヘテロシクリルから選択される;
あるいはXおよびYは、それらが結合する原子と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルまたはヘテロアリール基は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、ここで、該ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、アリール−C1〜C6アルキル−、アリール−(CH2)n−O−(CH2)n−アリール−、アリールOH、C3〜C7シクロアルキル、ヘテロシクリル、−アリール−N(R13)C(O)−C3〜C7シクロアルキル−C(O)−N(R14)−アリール、または式−L−M−Qの基から選択され、ここで、
Lは、結合またはC3〜C7シクロアルキルであり、
Mは、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、
Qは、NR13R14、N(R13)C(O)−C1〜C6アルキル、ヘテロシクリル、または飽和縮合二環式環であり、該環は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、
ここで、XおよびYにより形成された基上の各アリール、ヘテロアリールまたはヘテロシクリル置換基は、必要に応じて、1個または2個の部分でさらに置換されており、該部分は、別個に、ハロ、C(O)O−(CH2)n−フェニル、およびC(O)−C1〜C6アルキルから選択される;
R2は、−C1〜C6アルキル、−C1〜C6アルキル−NR13R14、−C(O)−アリール、−C0〜C6−アルキル−アリール、−C0〜C6−アルキル−ヘテロアリール、−C0〜C6−アルキル−(C3〜C7−シクロアルキル)、−C0〜C6−アルキル−ヘテロシクリル、あるいは−C0〜C6アルキル−5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、0個〜4個の環原子を含有し、該環原子は、N、OおよびSから選択され、ここで、
各アルキルは、必要に応じて、フェニルで置換されており、そして
各アリール、ヘテロアリール、C3〜C7シクロアルキル、ヘテロシクリル、または5員〜12員環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチルまたはメトキシ、CN、NO2、NR13R14、C(O)O−C1〜C6アルキル、N(R13)C(O)−C1〜C6アルキル、−SO2NR13R14、−O−C(O)−NR13R14、−C0〜C6アルキル−C(O)NR15R16、C1〜C6アルコキシ、C1〜C6チオアルコキシ、−O−(CH2)n−NR15R16、−C1〜C6アルキル−NR13R14、−N(R13)−C(O)−C1〜C6アルキル、−N(R13)−C(O)−アリール、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−アリール、−O−(CH2)n−C(O)−N(R13)−(CH2)n−NR15R16、−O−(CH2)n−C(O)−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−O−C1〜C6アルキル、−C0〜C6アルキル−N(R13)−C(O)O−C1〜C6アルキル、−C0〜C6アルキル−C(O)−ヘテロシクリル、−C0〜C6アルキル−C(O)−ヘテロアリール、−C0〜C6アルキル−C(O)−アリール、−C0〜C6−アルキル−R21、アリールオキシ、−O−(CH2)n−R21、−SO2−ヘテロシクリル、N(R13)−C(O)−C3〜C7−シクロアルキル、−C0〜C6アルキル C(O)O−R21、C3〜C7−シクロアルキル、−C0〜C6アルキルR21、−SC1〜C6アルキルまたはC1〜C6アルキルから選択され、必要に応じて、ハロまたはシアノで置換されており、
ここで、各アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリル置換基は、必要に応じて、1個〜3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチル、C1〜C6アルキル、C1〜C6ハロアルコキシ、NR13R14およびC1〜C6アルコキシから選択される;
R13およびR14は、別個に、HまたはC1〜C6アルキルであるか、あるいはR13およびR14は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のハロ、C1〜C6アルキル、またはC1〜C6アルコキシで置換されている;
R15およびR16は、別個に、H、C1〜C6アルキル、ヘテロアリール、またはヘテロシクリルであるか、あるいはR15およびR16は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のハロ、C1〜C6アルキル、または−C(O)O−C1〜C6アルキルで置換されている;そして
nは、1〜6である。
mは、1または2である;
R5は、各存在にて、別個に、H、C1〜C6アルキル、C3〜C7シクロアルキル、アリール、またはヘテロアリールである;
Xは、H、ハロ、C1〜C6アルキル、NO2、モノ−、ジ−またはトリ−ハロ置換メチル、NR13R14、C(O)O−C1〜C6アルキル、またはN(R13)−C(O)−C1〜C6アルキルである;
Yは、H、ハロ、OH、C1〜C6アルキル、NR15R16、C1〜C6アルコキシ、−N(R13)−(CH2)n−NR15R16、−C(O)O−C1〜C6アルキル、−O−(CH2)n−NR15R16、−C(O)−C1〜C6アルキル、−C0〜C6−アルキル−R21、−O−R21、−C(O)−R21、−O−(CH2)n−R21、−C(O)−NR13R14、−C(O)−N(R13)−アリール、−C(O)−N(R13)−(CH2)n−NR15R16、−C(O)−N(R13)−(CH2)n−アリール、−C(O)−N(R13)−(CH2)n−ヘテロシクリルであり、ここで、R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、NR13R14、およびヘテロシクリルから選択される;
あるいはXおよびYは、それらが結合する原子と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルまたはヘテロアリール基は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、ここで、該ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、アリール−C1〜C6アルキル−、アリール−(CH2)n−O−アリール−、C3〜C7シクロアルキル、ヘテロシクリル、−アリール−N(R13)C(O)−C3〜C7シクロアルキル−C(O)−N(R14)−アリール、および式−L−M−Qの基から選択され、ここで、
Lは、結合またはC3〜C7シクロアルキルであり、
Mは、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、
Qは、NR13R14、N(R13)C(O)−C1〜C6アルキル、ヘテロシクリル、または飽和縮合二環式環であり、該飽和縮合二環式環は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、
ここで、XおよびYにより形成された基上の各アリール、ヘテロアリールまたはヘテロシクリル置換基は、必要に応じて、1個または2個の部分でさらに置換されており、該部分は、別個に、ハロ、C(O)O−(CH2)n−フェニル、およびC(O)−C1〜C6アルキルから選択される;
R2は、−C1〜C6アルキル、−C1〜C6アルキル−NR13R14、−C(O)−アリール、−C0〜C6−アルキル−アリール、−C0〜C6−アルキル−ヘテロアリール、−C0〜C6−アルキル−(C3〜C7−シクロアルキル)、−C0〜C6−アルキル−ヘテロシクリル、または−C0〜C6アルキル−5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、0個〜4個の環原子を含有し、該環原子は、N、OおよびSから選択され、ここで、
各アルキルは、必要に応じて、フェニルで置換されており、そして
各アリール、ヘテロアリール、C3〜C7シクロアルキル、ヘテロシクリル、または5員〜12員環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチルまたはメトキシ、CN、NO2、NR13R14、C(O)O−C1〜C6アルキル、N(R13)C(O)−C1〜C6アルキル、−SO2NR13R14、−O−C(O)−NR13R14、−C0〜C6アルキル−C(O)NR15R16、C1〜C6アルコキシ、C1〜C6チオアルコキシ、−O−(CH2)n−NR15R16、−C1〜C6アルキル−NR13R14、−N(R13)−C(O)−C1〜C6アルキル、−N(R13)−C(O)−アリール、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−アリール、−O−(CH2)n−C(O)−N(R13)−(CH2)n−NR15R16、−O−(CH2)n−C(O)−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−O−C1〜C6アルキル、−C0〜C6アルキル−N(R13)−C(O)O−C1〜C6アルキル、−C0〜C6アルキル−C(O)−ヘテロシクリル、−C0〜C6アルキル−C(O)−ヘテロアリール、−C0〜C6アルキル−C(O)−アリール、−C0〜C6−アルキル−R21、アリールオキシ、−O−(CH2)n−R21、−SO2−ヘテロシクリル、N(R13)−C(O)−C3〜C7−シクロアルキル、またはC1〜C6アルキルから選択され、該C1〜C6アルキルは、必要に応じて、ハロまたはシアノで置換されており、
ここで、各アリール、ヘテロアリール、シクロアルキル、またはヘテロシクリル置換基は、必要に応じて、1個〜3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチル、C1〜C6アルキル、およびC1〜C6アルコキシから選択される;
R13およびR14は、別個に、HまたはC1〜C6アルキルであるか、あるいはR13およびR14は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のハロ、C1〜C6アルキル、またはC1〜C6アルコキシで置換されている;
R15およびR16は、別個に、H、C1〜C6アルキル、ヘテロアリール、またはヘテロシクリルであるか、あるいはR15およびR16は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、および−C(O)O−C1〜C6アルキルから選択される;そして
nは、1〜6である。
R1は、H、CN、ハロ、−NR13R14、C(O)NR13R14、C1〜C6アルキル、−C(O)−C1〜C6アルキル、−C0〜C6アルキル−R20であり、ここで、R20は、アリール、ヘテロアリール、ヘテロシクリル、あるいは5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、0個〜4個の環原子を含有し、該環原子は、N、OおよびSから選択され、ここで、アリール、ヘテロアリール、C3〜C7ヘテロシクリル、または該5員〜12員環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、C1〜C6アルキル、および−C0〜C6アルキル−R21から選択される;
Xは、H、ハロ、C1〜C6アルキル、NO2、モノ−、ジ−またはトリ−ハロ置換メチル、NR13R14、C(O)O−C1〜C6アルキル、またはN(R13)−C(O)−C1〜C6アルキルである;
Yは、H、ハロ、OH、C1〜C6アルキル、NR15R16、C1〜C6アルコキシ、−N(R13)−(CH2)n−NR15R16、−C(O)O−C1〜C6アルキル、−O−(CH2)n−NR15R16、−C(O)−C1〜C6アルキル、−C0〜C6−アルキル−R21、−O−R21、−C(O)−R21、−O−(CH2)n−R21、−C(O)−NR13R14、−C(O)−N(R13)−アリール、−C(O)−N(R13)−(CH2)n−NR15R16、−C(O)−N(R13)−(CH2)n−アリール、−C(O)−N(R13)−(CH2)n−ヘテロシクリルであり、ここで、R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、NR13R14、およびヘテロシクリルから選択される;
あるいはXおよびYは、それらが結合する原子と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルまたはヘテロアリール基は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、ここで、該ヘテロシクリルおよびヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、ハロ、C1〜C6アルキル、アリール−C1〜C6アルキル−、アリール−(CH2)n−O−アリール−、C3〜C7シクロアルキル、ヘテロシクリル、−アリール−N(R13)C(O)−C3〜C7シクロアルキル−C(O)−N(R14)−アリール、および式−L−M−Qの基から選択され、ここで、
Lは、結合またはC3〜C7シクロアルキルであり、
Mは、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、
Qは、NR13R14、N(R13)C(O)−C1〜C6アルキル、ヘテロシクリル、または飽和縮合二環式環であり、該環は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、
ここで、XおよびYにより形成された基上の各アリール、ヘテロアリール、およびヘテロシクリルは、必要に応じて、1個または2個の部分でさらに置換されており、該部分は、ハロ、C(O)O−(CH2)n−フェニル、およびC(O)−C1〜C6アルキルから選択される;
R6は、各存在にて、別個に、H、ハロ、モノ−、ジ−またはトリ−ハロ置換メチルまたはメトキシ、CN、NO2、NR13R14、C(O)O−C1〜C6アルキル、N(R13)C(O)−C1〜C6アルキル、−SO2NR13R14、−O−C(O)−NR13R14、−C0〜C6アルキル−C(O)NR15R16、C1〜C6アルコキシ、C1〜C6チオアルコキシ、−O−(CH2)n−NR15R16、−C1〜C6アルキル−NR13R14、−N(R13)−C(O)−C1〜C6アルキル、−N(R13)−C(O)−アリール、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−アリール、−O−(CH2)n−C(O)−N(R13)−(CH2)n−NR15R16、−O−(CH2)n−C(O)−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−O−C1〜C6アルキル、−C0〜C6アルキル−N(R13)−C(O)O−C1〜C6アルキル、−C0〜C6アルキル−C(O)−ヘテロシクリル、−C0〜C6アルキル−C(O)−ヘテロアリール、−C0〜C6アルキル−C(O)−アリール、−C0〜C6−アルキル−R21、アリールオキシ、−O−(CH2)n−R21、−SO2−ヘテロシクリル、N(R13)−C(O)−C3〜C7−シクロアルキル、またはC1〜C6アルキルであり、該C1〜C6アルキルは、必要に応じて、ハロまたはシアノで置換されており、
ここで、各アリール、ヘテロアリール、シクロアルキル、またはヘテロシクリル置換基は、必要に応じて、1個〜3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチル、C1〜C6アルキル、およびC1〜C6アルコキシから選択される;
R13およびR14は、別個に、HまたはC1〜C6アルキルであるか、あるいはR13およびR14は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のハロ、C1〜C6アルキル、またはC1〜C6アルコキシで置換されている;
R15およびR16は、別個に、H、C1〜C6アルキル、ヘテロアリール、またはヘテロシクリルであるか、あるいはR15およびR16は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、ハロ、C1〜C6アルキル、または−C(O)O−C1〜C6アルキルから選択される;そして
mは、1または2である;そしてnは、1〜6である。
mは、別個に、1または2である;
R5は、各存在にて、別個に、H、C1〜C6アルキル、C3〜C7シクロアルキル、アリール、またはヘテロアリールである;
Xは、H、ハロ、C1〜C6アルキル、NO2、モノ−、ジ−またはトリ−ハロ置換メチル、NR13R14、C(O)O−C1〜C6アルキル、またはN(R13)−C(O)−C1〜C6アルキルである;
Yは、H、ハロ、OH、C1〜C6アルキル、NR15R16、C1〜C6アルコキシ、−N(R13)−(CH2)n−NR15R16、−C(O)O−C1〜C6アルキル、−O−(CH2)n−NR15R16、−C(O)−C1〜C6アルキル、−C0〜C6−アルキル−R21、−O−R21、−C(O)−R21、−O−(CH2)n−R21、−C(O)−NR13R14、−C(O)−N(R13)−アリール、−C(O)−N(R13)−(CH2)n−NR15R16、−C(O)−N(R13)−(CH2)n−アリール、−C(O)−N(R13)−(CH2)n−ヘテロシクリルであり、ここで、R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、C1〜C6アルキル、NR13R14、およびヘテロシクリルから選択される;
あるいはXおよびYは、それらが結合する原子と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、該ヘテロシクリルおよびヘテロアリール基は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、ここで、該ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、ハロ、C1〜C6アルキル、アリール−C1〜C6アルキル−、アリール−(CH2)n−O−アリール−、C3〜C7シクロアルキル、ヘテロシクリル、−アリール−N(R13)C(O)−C3〜C7シクロアルキル−C(O)−N(R14)−アリール、および式−L−M−Qの基から選択され、ここで、
Lは、結合またはC3〜C7シクロアルキルであり、
Mは、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、
Qは、NR13R14、N(R13)C(O)−C1〜C6アルキル、ヘテロシクリル、または飽和縮合二環式環であり、該飽和縮合二環式環は、1個または2個のヘテロ原子を含有し、該ヘテロ原子は、別個に、O、NおよびSから選択され、
ここで、XおよびYにより形成された基上の各アリール、ヘテロアリールまたはヘテロシクリル置換基は、必要に応じて、1個または2個の部分でさらに置換されており、該部分は、ハロ、C(O)O−(CH2)n−フェニル、およびC(O)−C1〜C6アルキルから選択される;
R6は、各存在にて、別個に、H、ハロ、モノ−、ジ−またはトリ−ハロ置換メチルまたはメトキシ、CN、NO2、NR13R14、C(O)O−C1〜C6アルキル、N(R13)C(O)−C1〜C6アルキル、−SO2NR13R14、−O−C(O)−NR13R14、−C0〜C6アルキル−C(O)NR15R16、C1〜C6アルコキシ、C1〜C6チオアルコキシ、−O−(CH2)n−NR15R16、−C1〜C6アルキル−NR13R14、−N(R13)−C(O)−C1〜C6アルキル、−N(R13)−C(O)−アリール、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−アリール、−O−(CH2)n−C(O)−N(R13)−(CH2)n−NR15R16、−O−(CH2)n−C(O)−NR15R16、−C0〜C6アルキル−C(O)−N(R13)−(CH2)n−O−C1〜C6アルキル、−C0〜C6アルキル−N(R13)−C(O)O−C1〜C6アルキル、−C0〜C6アルキル−C(O)−ヘテロシクリル、−C0〜C6アルキル−C(O)−ヘテロアリール、−C0〜C6アルキル−C(O)−アリール、−C0〜C6−アルキル−R21、アリールオキシ、−O−(CH2)n−R21、−SO2−ヘテロシクリル、N(R13)−C(O)−C3〜C7−シクロアルキル、またはC1〜C6アルキルであり、該C1〜C6アルキルは、必要に応じて、ハロまたはシアノで置換されており、
ここで、各アリール、ヘテロアリール、シクロアルキル、またはヘテロシクリルは、必要に応じて、1個〜3個の基で置換されており、該基は、別個に、ハロ、モノ−、ジ−またはトリ−ハロ置換メチル、C1〜C6アルキル、およびC1〜C6アルコキシから選択される;
R13およびR14は、別個に、HまたはC1〜C6アルキルであるか、あるいはR13およびR14は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルまたはヘテロアリール基は、必要に応じて、1個または2個のハロ、C1〜C6アルキル、またはC1〜C6アルコキシで置換されている;
R15およびR16は、別個に、H、C1〜C6アルキル、ヘテロアリール、またはヘテロシクリルであるか、あるいはR15およびR16は、それらが結合する窒素と一緒になって、4員〜7員ヘテロシクリルまたはヘテロアリール基を形成し、ここで、1個または2個の環炭素は、それぞれ、必要に応じて、ヘテロ原子で置き換えられ、該ヘテロ原子は、別個に、O、NおよびSから選択され、そして、ここで、各ヘテロシクリルおよびヘテロアリール基は、必要に応じて、1個または2個の部分で置換されており、該部分は、ハロ、C1〜C6アルキル、および−C(O)O−C1〜C6アルキルから選択される;そして
nは、1〜6である。
Vは、NR1R1aであり、ここで、
R1は、−C0〜C6アルキル−R20であり、ここで、R20ヘテロアリール、ここで、該ヘテロアリールは、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、C1〜C6アルキル、および−C0〜C6アルキル−R21から選択される;
R1aは、Hである;
Xは、Hまたはハロである;
Yは、H、C1〜C6アルキル、NR15R16、C0〜C6アルキル−NR15R16、−N(R13)−(CH2)n−NR15R16、−O−(CH2)n−NR15R16、−C0〜C6−アルキル−R21、−O−R21または−O−(CH2)n−R21である;
Zは、NR2R3、または−O−R2aであり、ここで、
R2は、−C0〜C6−アルキル−ヘテロアリールであり、ここで、該ヘテロアリールは、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、−C0〜C6−アルキル−R21またはC1〜C6アルキルから選択される;
R3は、Hである;
R2aは、C0〜C6アルキル−ヘテロアリールであり、ここで、該ヘテロアリールは、必要に応じて、アリールで置換されている;
R13は、Hである;
R15およびR16は、別個に、H、C1〜C6アルキルまたはヘテロシクリルであり、該ヘテロシクリルは、必要に応じて、C1〜C6アルキルで置換されている;
R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、−S(O)2−C0〜C1アルキル、−C(O)−C0〜C1アルキル、−C(O)−H、−C0〜C1アルキル−アリール、C1〜C6アルキルまたはNR13R14から選択される;そして
nは、1〜4である。
mは、1または2または3である;
R5は、C1〜C6アルキル、および−C0〜C6アルキル−R21である;
Xは、Hまたはハロである;
Yは、−C0〜C6−アルキル−R21;
R6は、−C0〜C6−アルキル−R21またはC1〜C6アルキルである;
R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アルキル、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、−S(O)2−C0〜C1アルキル、−C(O)−C0〜C1アルキル、−C(O)−H、−C0〜C1アルキル−アリール、C1〜C6アルキルまたはNR13R14から選択される。
本明細書中で使用する以下の用語および語句は、一般に、それらが使用される文脈がそれ以外の意味を指示しているか異なる何かを意味すると明白に定義されている場合を除いて、以下で述べる意味を有すると解釈される。
純粋形態かまたは適切な薬学的組成物での、本発明の化合物またはそれらの薬学的に受容可能な塩の投与は、任意の容認された投与の様式、または同様の有用性を与える薬剤を介して行われ得る。したがって、投与は、例えば、経口的、経鼻的、非経口的(静脈内、筋内、または皮下)、局所的、経皮的、膣内、膀胱内、槽内、または直腸内への、固体投薬形態、半固体投薬形態、凍結乾燥粉末投薬形態、または液体投薬形態の形状(例えば、錠剤、坐剤、丸剤、柔らかな弾性材料および硬いゼラチンのカプセル剤、粉剤、液剤、懸濁液、またはエーロゾル剤など)であり得、好ましくは、正確な投薬量の単回投与のために適切な単位投薬形態である。
例えば、IGF1Rに結合する候補因子に関するスクリーニングの方法において本発明の化合物を使用するために、タンパク質は支持体に結合され、そして本発明の化合物がアッセイのために添加される。代替的に、本発明の化合物は上記支持体に結合され、そしてタンパク質が添加される。探求され得る新規の結合因子の中で候補因子の分類は、特異的抗体、化学的ライブラリーのスクリーニングにおいて同定された非天然結合因子、ペプチドアナログなどが挙げられる。特に関心があるものは、ヒト細胞に対して低い毒性を有する候補因子に関するスクリーニングアッセイである。広範な種々のアッセイは、この目的のために使用され得る。このアッセイとしては、標識化インビトロタンパク質−タンパク質結合アッセイ、電気泳動移動度変化アッセイ、タンパク質結合に関する免疫学的アッセイ、機能的アッセイ(リン酸化アッセイなど)などが挙げられる。
以下の略語および用語は、本明細書全体を通じて、以下で指定した意味を有する:
キナーゼアッセイを、固定化したミエリン塩基性タンパク質(MBP)へのγ−33P ATPの取り込みを測定することによって行った。高結合能白色384ウェルプレート(Greiner)を、MBP(Sigma #M−1891)を用いて、Tris緩衝化生理食塩水(TBS;50mM Tris pH8.0,138mM NaCl,2.7mM KCl)中の20μg/ml MBPを60μl/ウェルで4℃にて24時間インキュベーションすることによってコーティングした。プレートを、100μl TBSで3回洗浄した。キナーゼ反応を、キナーゼ緩衝液(5mM Hepes pH7.6,15mM NaCl,0.01% ウシγグロブリン(Sigma #I−5506),10mM MgCl2,1mM DTT,0.02% TritonX−100)中の34μlの総容量で行った。化合物の希釈を、DMSO中で行い、アッセイウェルに添加して最終DMSO濃度を1%にした。各データポイントを二連で測定し、少なくとも2回の二連アッセイを、個々の化合物の決定について行った。酵素を、例えば、10nMまたは20nMの最終濃度まで添加した。非標識ATPおよびγ−33P ATPの混合物を添加して反応を開始した(代表的に、1ウェルあたり2×106cpmのγ−33P ATP(3000Ci/ミリモル)、10μMまたは30μMのいずれかの非標識ATP)。反応を、1時間室温で浸透しながら行った。プレートをTBSで7回洗浄し、その後、50μl/ウェルのシンチレーション流体(Wallac)を添加した。放射能をWallac Triluxカウンターを用いて測定した。これは、そのようなアッセイの単に1つの形態であり、当業者に公知であるような他の種々の形態が可能である。
キナーゼ活性および化合物阻害は、以下に記載される3つのアッセイ形式のうちの1つ以上を用いて研究される。各アッセイについてのATP濃度は、個々のキナーゼについてのMichaelis−Menten定数(KM)と近くなるように選択される。用量応答実験を、384ウェルプレート形式で10種の異なるインヒビター濃度にて行う。データを以下の4つのパラメータの式(2)に適合させる;式(2)において、Yは、観察されたシグナルであり、Xは、インヒビター濃度であり、Minは、酵素の非存在下でのバックグラウンドシグナル(0% 酵素活性)であり、Maxは、インヒビターの非存在下でのシグナル(100% 酵素活性)であり、IC50は、50%酵素阻害でのインヒビター濃度であり、そしてHは、協同性を測定するための経験的なHillスロープを表す。代表的に、Hは、1に近い。
IGF1Rキナーゼの生化学的活性を、ルシフェラーゼ共役型化学発光キナーゼアッセイ(Luciferase−Coupled Chemiluminescent Kinase assay(LCCA))形式を用いて評価した。キナーゼ活性を、キナーゼ反応の後に残存するATPの割合として測定した。残存するATPを、ルシフェラーゼ−ルシフェリン共役型(luciferase−luciferin−coupled)化学発光によって検出した。具体的には、反応を、試験化合物、3μM ATP、4μM ポリEYペプチドおよび4nM IGF1R(バキュロウイルスにより発現されたヒトIGF1Rキナーゼドメイン残基M954−C1367)を、20μLのアッセイ緩衝液(20mM Tris−HCL pH7.5,10mM MgCl2,0.02% Triton X−100,1mM DTT,2mM MnCl2)中で混合することによって開始した。その混合物を、周囲温度で2時間インキュベートし、その後、20μLのルシフェラーゼ−ルシフェリンミックスを添加し、化学発光シグナルをWallac Victor2リーダーを用いて読み取る。ルシフェラーゼ−ルシフェリンミックスは、50mM HEPES(pH7.8)、8.5ug/mL シュウ酸(pH7.8)、5(もしくは50)mM DTT、0.4% Triton X−100、0.25mg/mL 補酵素A、63μM AMP、28μg/mL ルシフェリンおよび40,000ユニットの光/mL ルシフェラーゼからなる。
野生型Abl(ProQinase,Freiburg,Germany)およびT315I Abl(Upstate,NY)のキナーゼ活性を、ルシフェラーゼ−ルシフェリン結合型化学発光の後に消費されたATPの割合として測定する。反応を、384ウェルの白色の中結合能マイクロタイタープレート(Greiner)で行った。キナーゼ反応を、試験化合物、ATP、ポリ(Glu,Tyr)およびキナーゼを、20μLの容積で混ぜ合わせることによって開始した(最終濃度:1μM ATP、2μM ポリ(Glu,Tyr)、10nM 野生型Ablまたは5nM T315I Abl)。その反応混合物を、周囲温度で2時間インキュベートした。キナーゼ反応の後、ルシフェラーゼ−ルシフェリンミックス(Promega,Madison,WI)の20μLアリコートを添加し、Victor2プレートリーダー(Perkin Elmer)を用いて化学発光シグナルを測定した。
表2および表3は、選択された本発明の化合物についての構造活性相関データを示す。阻害は、IC50として、以下の記号を用いて示されている:A=50nM未満のIC50、B=50nMよりも大きいが、500nM未満のIC50、C=500nMよりも大きいが、5000nM未満のIC50、そしてD=5000nM以上のIC50。
Claims (19)
- 式VIの化合物、
あるいはそれらの薬学的に受容可能な塩または水和物であって、ここで、
mは、1または2または3である;
R5は、C1〜C6アルキル、または−C0〜C6アルキル−R21である;
Xは、Hまたはハロである;
Yは、−C0〜C6−アルキル−R21;
R6は、−C0〜C6−アルキル−R21またはC1〜C6アルキルである;
R21は、ヘテロシクリル、アリール、ヘテロアリール、またはC3〜C7シクロアルキルであり、そして、ここで、アリール、ヘテロアリール、C3〜C7シクロアルキル、およびヘテロシクリルは、必要に応じて、1個または2個の部分で置換されており、該部分は、別個に、ハロ、−S(O)2−C1アルキル、−C(O)−C1アルキル、−C(O)−H、−C0〜C1アルキル−アリール、C1〜C6アルキルおよびNR13R14、ここで、R13およびR14は、別個に、HまたはC1〜C6アルキルから選択される、から選択される、
上記化合物あるいはそれらの薬学的に受容可能な塩または水和物。 - Yが、ヘテロシクリルであり、該ヘテロシクリルが、必要に応じて、C1〜C3アルキルで置換されており、Xが、Hまたはハロであり、R5が、C3〜C4シクロアルキルであり、そしてR6が、C1〜C4アルキルである、請求項1に記載の化合物あるいはそれらの薬学的に受容可能な塩または水和物。
- Yが、ヘテロシクリルであり、該ヘテロシクリルが、必要に応じて、メチル、エチル、プロピルまたはイソプロピルで置換されており、Xが、Hであり、R5が、シクロプロピルであり、そしてR6が、メチル、エチル、プロピルまたはイソプロピルである、請求項2に記載の化合物あるいはそれらの薬学的に受容可能な塩または水和物。
- 請求項1〜6のいずれか一項に記載の化合物あるいはそれらの薬学的に受容可能な塩または水和物と、薬学的に受容可能なキャリア、賦形剤または希釈剤とを含有する、医薬組成物。
- IGF1Rのインビボ活性を調節するための組成物であって、請求項7に記載の医薬組成物の有効IGF1R調節量を含む、組成物。
- 哺乳動物においてIGF1Rにより直接的または間接的に制御できない異常および/または不要な細胞活性効果に関連した疾患または障害を治療するための組成物であって、請求項7に記載の医薬組成物の治療有効量を含む、組成物。
- 前記哺乳動物が、ヒトである、請求項9に記載の組成物。
- 1つの細胞または複数の細胞における増殖活性を阻害するための組成物であって、請求項1〜6のいずれか一項に記載の化合物あるいはそれらの薬学的に受容可能な塩または水和物の有効量を含む、組成物。
- 1つの細胞または複数の細胞における野生型Ablを阻害するための組成物であって、請求項1〜6のいずれか一項に記載の化合物あるいはそれらの薬学的に受容可能な塩または水和物の有効量を含む、組成物。
- 前記野生型Ablが、T3l5I変異体である、請求項12に記載の組成物。
- 変異Abl悪性腫瘍を有する哺乳動物における疾患または障害を治療するための組成物であって、請求項7に記載の医薬組成物の治療有効量を含む、組成物。
- 前記哺乳動物が、ヒトである、請求項14に記載の組成物。
- 前記疾患が、癌である、請求項9に記載の組成物。
- 前記癌が、結腸癌、乳癌、前立腺癌、卵巣癌、肝細胞癌、または多発性骨髄腫である、請求項10に記載の組成物。
- 前記癌が、骨髄増殖性疾患である、請求項10に記載の組成物。
- 前記骨髄増殖性疾患が、慢性骨髄性白血病(CML)または急性リンパ芽球性白血病である、請求項18に記載の組成物。
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