TWI418351B - 用於治療或預防纖維化疾病之藥劑 - Google Patents
用於治療或預防纖維化疾病之藥劑 Download PDFInfo
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- TWI418351B TWI418351B TW094146425A TW94146425A TWI418351B TW I418351 B TWI418351 B TW I418351B TW 094146425 A TW094146425 A TW 094146425A TW 94146425 A TW94146425 A TW 94146425A TW I418351 B TWI418351 B TW I418351B
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- Prior art keywords
- phenyl
- methylene
- anilino
- amino
- group
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Description
本發明係關於下通式之吲哚啉酮
其在6位置經取代,其互變體,非對映體,對映體,混合物,及鹽,特別是其生理可接受鹽之新穎用途。
上述通式I之化合物,其互變體,非對映體,對映體,混合物,及鹽,特別是生理可接受鹽,已述於WO 01/27081及WO 04/13099,具有有價值之藥理學性質,特別是對於各種激酶,特別是受體酪胺酸激酶,如VEGFR2、PDGFRα、PDGFRβ、FGFR1、FGFR3、EGFR、HER2、IGF1R及HGFR,以及CDK(環素(Cyclin)依賴性激酶),如CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8及CDK9,與其特異性環素(cyclins)(A、B1、B2、C、D1、D2、D3、E、F、G1、G2、H、I及K)及病毒環素(參考L.Mengtao,J.Virology 71(3),1984-1991(1997))之複合物,對於培養之人類細胞,特別是內皮細胞之增生,例如在血管形成中,亦對於其他細胞,特別是腫瘤細胞之增生具有抑制作用。
然而,這些化合物用於治療或預防本發明中所述纖維化疾病之用途並未述及。
重新塑造為組織受傷及發炎之正常反應,可見於身體之許多組織。在發炎消除及組織傷害修復後,組織一般回復至其原來情況。過度不被控制之組織修復或不能停止不再需要之重新塑造導致稱為纖維化之症狀。纖維化之特徵在於細胞外基質成份之過量沉積及纖維母細胞之過度生長。纖維化可發生於所有組織,但是特別普遍於常暴露於化學及生物學危害之器官,包括肺,皮膚,消化道,腎,及肝(Eddy,1996,J Am Soc Nephrol,7(12):2495-503;Dacic et al.,2003,Am J Respir Cell Mol Biol,29S:S5-9;Wynn,2004,Nat Rev Immunol,4(8):583-94)。纖維化通常嚴重地損害器官之正常功能,許多纖維化疾病事實上威脅生命或嚴重地毀形,如自發性肺纖維化(IPF),肝硬化,硬皮病,或腎纖維化。這些疾病之治療方式通常限於器官移植,為危險而昂貴之手術。
許多文獻指出血小板衍生之生長因子(PDGF),纖維母細胞生長因子(FGF),血管內皮生長因子(VEGF),表皮生長因子(EGF),及變形生長因子β(TGFb)之生長因子族涉及纖維化之誘發或持續(Levitzki,Cytokine Growth Factor Rev,2004,15(4):229-35;Strutz et al.,Kidney Intl,2000,57:1521-38;Strutz et al.,2003,Springer Semin Immunopathol,24:459-76;Rice et al.,1999,Amer J Pathol,155(1):213-221;Broekelmann et al.,1991,Proc Nat Acad Sci,88:6642-6;Wynn,2004,Nat Rev Immunol,4(8):583-94)。
PDGF、EGF及FGF族成員為間葉細胞如平滑肌細胞,肌纖維母細胞,及纖維母細胞之有效力有絲分裂素(Benito et al.,1993,Growth Regul 3(3):172-9;Simm et al.,1998,Basic Res Cardiol,93(S3):40-3;Klagsburn,Prog Growth Factor Res,1989,1(4):207-35;Kirkland et al.,1998,J Am Soc Nephrol,9(8):1464-73),這些細胞在纖維化中取代正常組織,相信在組織重新塑造中居要角(Abboud,1995,Annu Rev Physiol.,57:297-309;Jinnin et al.,2004,J Cell Physiol,online;Martinet et al.,1996,Arch Toxicol 18:127-39;Desmouliere,Cell Biology International,1995,19:471-6;Jelaska et al.,Springer Semin Immunopathol,2000,21:385-95)。
在實驗模型中PDGF之抑制減弱肝纖維化及肺纖維化,暗示不同器官之纖維化可能有一個共同來源(Bork-ham-Kamphorst et al.,2004,Biochem Biophys Res Commun;Rice et al.,1999,Amer J Pathol,155(1):213-221)。一種EGF受體激酶抑制劑在此肺纖維化模型中亦有效。一個EGF族成員HB-EGF在鼠胰臟胰島中三倍過度表現足以引起外分泌及內分泌室發生纖維化(Means et al.,2003,Gastroenterology,124(4):1020-36)。
相似地,缺乏FGF1/FGF2之鼠在長期暴露於四氯化碳(CC14)後顯示肝纖維化劇烈減少(Yu et al.,2003,Am J Pathol,163(4):1653-62)。在人類腎間質纖維化中,其與間質結疤極有關(Strutz et al.,2000,Kidney Intl,57:1521-38),及在實驗肺纖維化模型中(Barrios et al.,1997,Am J Physiol,273(2 Pt 1):L451-8),FGF之表現增加再次使人相信各組織中纖維化有一個共同基礎之概念。
此外,VEGF之量增加已發現於氣喘者之幾個研究中(Hoshino et al.,2001,J Allergy Clin Immunol 107:1034-39;Hoshino et al.,2001,J Allergy Clin Immunol 107:295-301;Kanazawa et al.,2002,Thorax 57:885-8;Asai et al.,J Allergy Clin Immunol 110:571-5,2002;Kanazawa et al.,2004,Am J Respir Crit Care Med,169:1125-30)。在一個轉基因鼠模型中VEGF之誘發表現誘發一種似氣喘之表型,水腫,血管形成,及平滑肌過度增生(Lee et al.,2004,Nature Med 10:1095-1103)。
最後,TGFb刺激細胞外基質蛋白質包括纖維連接蛋白(fibronectin)及膠原之產生,相信在許多組織之纖維化中居要角(Leask et al.,2004,FASEB J 18(7):816-27;Bartram et al.,2004,Chest 125(2):754-65;Strutz et al.,2003,Sprin-ger Semin Immuno-pathol,24:459-76;Wynn,2004,Nat Rev Immunol,4(8):583-94)。TGFb產生及傳訊途徑之抑制劑在許多纖維化動物模型中有效(Wang et al.,2002,Exp Lung Res,28:405-17;Laping,2003,Curr Opin Pharmacol,3(2):204-8)。
如上述,幾種生長因子在纖維化中調升,在纖維化模型中單一因子之抑制似乎可減少纖維化之嚴重性。
令人驚奇地,吾等發現上述通式I之化合物在治療及預防特定纖維化疾病中有效。
因此,本發明係關於上述通式I化合物用於製備一種治療或預防特定纖維化疾病之藥物之用途。
本發明亦關於一種治療或預防特定纖維化疾病之方法,由對於需要之病人施用一種醫藥組合物,包含一種上述通式I之化合物與一種醫藥適合之載劑一起。術語「病人」意為包含哺乳類動物,較佳為人類。
本發明另關於一種用於治療或預防特定纖維化疾病之醫藥組合物,其包含一種上述通式I之化合物單獨或合併一或多種其他治療劑。
根據本發明,上述通式I之化合物為下式化合物
其中X表一個氧或硫原子,R1
表一個氫原子或一個前藥基,如C1 - 4
-烷氧基羰基或C2 - 4
-烷醯基,R2
表一個羧基,直鏈或分支之C1 - 6
-烷氧基-羰基,C4 - 7
-環烷氧基-羰基,或芳基氧基羰基,一個直鏈或分支之C1 - 6
-烷氧基-羰基,其烷基末端經一個苯基,雜芳基,羧基,C1 - 3
-烷氧基-羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,或二-(C1 - 3
-烷基)-胺基羰基取代,一個直鏈或分支之C2 - 6
-烷氧基-羰基,其烷基末端經一個氯原子,或羥基,C1 - 3
-烷氧基,胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,一個胺基羰基或甲基胺基羰基,一個乙基胺基羰基選擇性在乙基之2位置經一個羥基或C1 - 3
-烷氧基或二-(C1 - 2
-烷基)-胺基羰基取代,R3
表一個氫原子,C1 - 6
-烷基,C3 - 7
-環烷基,三氟甲基,或雜芳基,一個苯基或萘基,一個苯基或萘基經一個氟,氯,溴,或碘原子,三氟甲基,C1 - 3
-烷基,或C1 - 3
-烷氧基一或二取代,若二取代,取代基可相同或不同,其中上述未經取代以及經一及二取代之苯基及萘基可另經下列取代:一個羥基,羥基-C1 - 3
-烷基,或C1 - 3
-烷氧基-C1 - 3
-烷基,一個氰基,羧基,羧基-C1 - 3
-烷基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,或二-(C1 - 3
-烷基)-胺基羰基,一個硝基,一個胺基,C1 - 3
-烷基胺基,二-(C1 - 3
-烷基)-胺基,或胺基-C1 - 3
-烷基,一個C1 - 3
-烷基羰基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基-羰基胺基,C1 - 3
-烷基羰基胺基-C1 - 3
-烷基,N-(C1 - 3
-烷基)-C1 - 3
-烷基羰基胺基-C1 - 3
-烷基,C1 - 3
-烷基-磺醯基胺基,C1 - 3
-烷基磺醯基胺基-C1 - 3
-烷基,N-(C1 - 3
-烷基)-C1 - 3
-烷基磺醯基胺基-C1 - 3
-烷基,或芳基-C1 - 3
-烷基磺醯基胺基,一個環烷基胺基,伸環烷基亞胺基,伸環烷基亞胺基羰基,伸環烷基亞胺基-C1 - 3
-烷基,伸環烷基亞胺基羰基-C1 - 3
-烷基,或伸環烷基亞胺基磺醯基-C1 - 3
-烷基,在各情況中具有4至7個環成員,在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可以一個氧或硫原子,一個亞磺醯基,磺醯基,-NH或-N(C1 - 3
-烷基)替代,或一個雜芳基或雜芳基-C1 - 3
-烷基,R4
表一個C3 - 7
-環烷基,在6或7員環烷基之4位置中亞甲基可以一個胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,或以一個-NH或-N-(C1 - 3
-烷基)替代,或一個苯基經R6
基取代,其可另經氟,氯,溴,或碘原子,C1 - 5
-烷基,三氟甲基,羥基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基,乙醯基胺基,C1 - 3
-烷基-磺醯基胺基,胺基羰基,C1 - 3
-烷基-胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,胺基磺醯基,C1 - 3
-烷基-胺基磺醯基,二-(C1 - 3
-烷基)-胺基磺醯基,硝基,或氰基一或二取代,其中取代基可相同或不同,及其中R6
表一個氫,氟,氯,溴,或碘原子,一個氰基,硝基,胺基,C1 - 5
-烷基,C3 - 7
-環烷基,三氟甲基,苯基,四唑基,或雜芳基,一個下式之基
其中結合於氮原子之氫原子在各情況可相互獨立地以一個C1 - 3
-烷基替代,一個C1 - 3
-烷氧基,C1 - 3
-烷氧基-C1 - 3
-烷氧基,苯基-C1 - 3
-烷氧基,胺基-C2 - 3
-烷氧基,C1 - 3
-烷基胺基-C2 - 3
-烷氧基,二-(C1 - 3
-烷基)-胺基-C2 - 3
-烷氧基,苯基-C1 - 3
-烷基胺基-C2 - 3
-烷氧基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基-C2 - 3
-烷氧基,C5 - 7
-伸環烷基亞胺基-C2 - 3
-烷氧基,或C1 - 3
-烷基巰基,一個羧基,C1 - 4
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,N-(C1 - 5
-烷基)-C1 - 3
-烷基胺基羰基,苯基-C1 - 3
-烷基胺基-羰基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基-羰基,哌羰基,或N-(C1 - 3
-烷基)-哌羰基,一個C1 - 3
-烷基胺基羰基或N-(C1 - 5
-烷基)-C1 - 3
-烷基胺基羰基,其中一個烷基經一個羧基或C1 - 3
-烷氧基羰基取代,或在2或3位置經一個二-(C1 - 3
-烷基)-胺基,哌基,N-(C1 - 3
-烷基)-哌基,或一個4至7員伸環烷基亞胺基取代,一個C3 - 7
-環烷基-羰基,其中在6或7員環烷基之4位置中亞甲基可經一個胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,或以一個-NH或-N(C1 - 3
-烷基)替代,一個4至7員伸環烷基亞胺基,其中連接於亞胺基之亞甲基可以一個羰基或磺醯基替代,或伸環烷基可稠合於一個苯環,或一或二個氫原子各可以一個C1 - 3
-烷基替代,及/或在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可經一個羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,苯基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基取代,或可以一個氧或硫原子,或亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,一個C1 - 4
-烷基經R7
取代,其中R7
表一個C3 - 7
-環烷基,在一個6或7員環烷基之4位置中亞甲基可經一個胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,或經一個-NH或-N(C1 - 3
-烷基)替代,或在一個5至7員環烷基中-(CH2
)2
基可以一個-CO-NH基替代,-(CH2
)3
基可以一個-NH-CO-NH或-CO-NH-CO基替代,或-(CH2
)4
基可以一個-NH-CO-NH-CO基替代,在各情況中結合於氮原子之一個氫原子可以一個C1 - 3
-烷基替代,一個芳基或雜芳基,一個羥基或C1 - 3
-烷氧基,一個胺基,C1 - 7
-烷基胺基,二-(C1 - 7
-烷基)-胺基,苯基胺基,N-苯基-C1 - 3
-烷基-胺基,苯基-C1 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基,或二-(苯基-C1 - 3
-烷基)-胺基,一個ω-羥基-C2 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-ω-羥基-C2 - 3
-烷基-胺基,二-(ω-羥基-C2 - 3
-烷基)-胺基,二-(ω-(C1 - 3
-烷氧基)-C2 - 3
-烷基)-胺基,或N-(二氧戊環(dioxolan)-2-基)-C1 - 3
-烷基-胺基,一個C1 - 3
-烷基羰基胺基-C2 - 3
-烷基-胺基,或C1 - 3
-烷基羰基胺基-C2 - 3
-烷基-N-(C1 - 3
-烷基)-胺基,一個C1 - 3
-烷基磺醯基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基-磺醯基胺基,C1 - 3
-烷基磺醯基胺基-C2 - 3
-烷基-胺基,或C1 - 3
-烷基磺醯基胺基-C2 - 3
-烷基-N-(C1 - 3
-烷基)-胺基,一個羥基羰基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-羥基羰基-C1 - 3
-烷基-胺基,一個胍基,其中一或二個氫原子各可以一個C1 - 3
-烷基替代,一個下式之基-N(R8
)-CO-(CH2
)n
-R9
(II),其中R8
表一個氫原子或C1 - 3
-烷基,n表數目0、1、2或3之一,R9
表一個胺基,C1 - 4
-烷基胺基,二-(C1 - 4
-烷基)-胺基,苯基胺基,N-(C1 - 4
-烷基)-苯基胺基,苯甲基胺基,N-(C1 - 4
-烷基)-苯甲基胺基,或C1 - 4
-烷氧基,一個4至7員伸環烷基亞胺基,在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可以一個氧或硫原子,亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,或若n表數目1、2或3之一,其亦可表一個氫原子,一個下式之基-N(R1 0
)-(CH2
)m
-(CO)o
-R1 1
(III),其中R1 0
表一個氫原子,C1 - 3
-烷基,C1 - 3
-烷基羰基,芳基羰基,苯基-C1 - 3
-烷基-羰基,C1 - 3
-烷基磺醯基,芳基磺醯基,或苯基-C1 - 3
-烷基磺醯基,m表數目1、2、3或4之一,o表數目1,或若m表2、3或4之一,o亦可表數目0,R1 1
表一個胺基,C1 - 4
-烷基胺基,二-(C1 - 4
-烷基)-胺基,苯基胺基,N-(C1 - 4
-烷基)-苯基胺基,苯甲基胺基,N-(C1 - 4
-烷基)-苯甲基胺基,C1 - 4
-烷氧基或C1 - 3
-烷氧基-C1 - 3
-烷氧基,一個二-(C1 - 4
-烷基)-胺基-C1 - 3
-烷基胺基選擇性在1位置經一個C1 - 3
-烷基或一個4至7員伸環烷基亞胺基取代,其中伸環烷基可稠合於一個苯環,或在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可以一個氧或硫原子,亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,一個C4 - 7
-環烷基胺基,C4 - 7
-環烷基-C1 - 3
-烷基胺基,或C4 - 7
-環烯基胺基,其中環之1位置不涉及雙鍵,及其中上述基在胺基之氮原子各可另經一個C5 - 7
-環烷基,C2 - 4
-烯基,或C1 - 4
-烷基取代,一個4至7員伸環烷基亞胺基,其中伸環烷基可稠合於一個苯基或一個唑基,咪唑基,噻唑基,吡啶基,吡基,或嘧啶基,選擇性經一個氟,氯,溴,或碘原子,硝基,C1 - 3
-烷基,C1 - 3
-烷氧基,或胺基取代,及/或一或二個氫原子各可以一個C1 - 3
-烷基,C5 - 7
-環烷基,或苯基替代,及/或一個5員伸環烷基亞胺基之3位置中亞甲基可經一個羥基,羥基-C1 - 3
-烷基,C1 - 3
-烷氧基,或C1 - 3
-烷氧基-C1 - 3
-烷基取代,在一個6或7員伸環烷基亞胺基之3或4位置中亞甲基在各情況中可經一個羥基,羥基-C1 - 3
-烷基,C1 - 3
-烷氧基,C1 - 3
-烷氧基-C1 - 3
-烷基,羧基,C1 - 4
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,苯基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基-胺基取代,或可以一個氧或硫原子,一個亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基-),-N(苯基),-N(苯基-C1 - 3
-烷基-),-N(C1 - 3
-烷基-羰基-),-N(C1 - 4
-烷基-羥基-羰基-),-N(C1 - 4
-烷氧基-羰基-),-N(苯甲醯基-),或-N(苯基-C1 - 3
-烷基-羰基-)替代,其中連接於伸環烷基亞胺基之亞胺基之氮原子之一個亞甲基可以一個羰基或磺醯基替代,或在一個5至7員單環伸環烷基亞胺基或一個稠合於苯基之伸環烷基亞胺基中連接於亞胺基之氮原子之二個亞甲基各可以一個羰基替代,或R6
表一個C1 - 4
-烷基,其經一個羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基,或一個4至7員伸環烷基亞胺基羰基取代,一個N-(C1 - 3
-烷基)-C2 - 4
-烷醯基胺基,其在烷基另經一個羧基或C1 - 3
-烷氧基羰基取代,一個下式之基-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
表一個氫原子,C1 - 6
-烷基,或C3 - 7
-環烷基,或一個C1 - 3
-烷基末端經一個苯基,雜芳基,三氟甲基,羥基,C1 - 3
-烷氧基,胺基羰基,C1 - 4
-烷基胺基-羰基,二-(C1 - 4
-烷基)-胺基-羰基,C1 - 3
-烷基-羰基,C1 - 3
-烷基-磺醯基-胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基-磺醯基胺基,C1 - 3
-烷基-胺基磺醯基,或二-(C1 - 3
-烷基)-胺基磺醯基取代,及p表數目0、1、2或3之一,及R1 3
假定為上述R7
之意義,或若p表數目1、2或3之一,其亦可表一個氫原子,一個下式之基-N(R1 4
)-(CH2
)q
-(CO)r
-R1 5
(V),其中R1 4
表一個氫原子,C1 - 4
-烷基,C1 - 3
-烷基羰基,芳基羰基,苯基-C1 - 3
-烷基羰基,雜芳基羰基,雜芳基-C1 - 3
-烷基羰基,C1 - 4
-烷基磺醯基,芳基磺醯基,苯基-C1 - 3
-烷基磺醯基,雜芳基磺醯基,或雜芳基-C1 - 3
-烷基-磺醯基,q表數目1、2、3或4之一,r表數目1,或若q為數目2、3或4之一,其亦可表數目0,及R1 5
假定為上述R7
之意義,一個下式之基-N(R1 6
)-SO2
-R1 7
(VI),其中R1 6
表一個氫原子或一個C1 - 4
-烷基末端選擇性經一個氰基,三氟甲基-羰基胺基,或N-(C1 - 3
-烷基)-三氟甲基-羰基-胺基取代,及R1 7
表一個C1 - 3
-烷基,一個胺基經一個二-(C1 - 3
-烷基)-胺基-C1 - 3
-烷基-羰基或二-(C1 - 3
-烷基)-胺基-C1 - 3
-烷基-磺醯基及一個二-(C1 - 3
-烷基)-胺基羰基-C1 - 3
-烷基取代,或一個N-(C1 - 3
-烷基)-C1 - 5
-烷基磺醯基胺基或N-(C1 - 3
-烷基)-苯基磺醯基胺基,其中烷基另經一個氰基或羧基取代,其中R6
所述基中所含之所有單一結合或稠合之苯基可經氟,氯,溴,或碘原子,C1 - 5
-烷基,三氟甲基,羥基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 4
-烷基胺基-羰基,二-(C1 - 4
-烷基)-胺基-羰基,胺基磺醯基,C1 - 3
-烷基-胺基磺醯基,二-(C1 - 3
-烷基)-胺基磺醯基,C1 - 3
-烷基-磺醯基胺基,硝基,或氰基一或二取代,其中取代基可相同或不同,或苯基之二個相鄰氫原子可以一個亞甲基二氧基替代,及R5
表一個氫原子或C1 - 3
-烷基,其中芳基意為一個苯基或萘基選擇性經一個氟,氯,溴,或碘原子,一個氰基,三氟甲基,硝基,羧基,胺基羰基,C1-3-烷基,或C1-3-烷氧基一或二取代,及雜芳基意為一個單環5或6員雜芳基在碳骨架中選擇性經一個C1 - 3
-烷基取代,其中6員雜芳基含有一,二,或三個氮原子,及5員雜芳基含有一個亞胺基選擇性經一個C1 - 3
-烷基或苯基-C1 - 3
-烷基取代,一個氧或硫原子,或一個亞胺基選擇性經一個C1 - 3
-烷基或苯基-C1 - 3
-烷基取代或一個氧或硫原子及另外一個氮原子,或一個亞胺基選擇性經一個C1 - 3
-烷基或苯基-C1 - 3
-烷基取代及二個氮原子,此外,一個苯環可經由二個相鄰碳原子稠合於上述單環雜環基,結合係經由雜環基或稠合苯環之一個氮原子或碳原子發生,上述烷基及烷氧基中或上述定義之式I之各基中所含烷基中一些或所有氫原子選擇性以氟原子替代,上述定義之各基中存在之具有多於2個碳原子之飽和烷基及烷氧基亦包括其分支之異構物,例如異丙基,第三丁基,異丁基,除非另外說明,及此外,任何羧基之氫原子或結合於氮原子之氫原子,例如胺基,烷胺基,或亞胺基,或飽和之N-雜環基如哌啶基之一個氫原子各可以一個可在活體內裂解之基替代。
一個可在活體內由亞胺基或胺基裂解之基意為例如一個羥基,醯基如苯甲醯基或吡啶醯基,或C1 - 1 6
-烷醯基,如甲醯基,乙醯基,丙醯基,丁醯基,戊醯基,或己醯基,烯丙基氧基羰基,C1 - 1 6
-烷氧基羰基,如甲氧基羰基,乙氧基羰基,丙氧基羰基,異丙氧基羰基,丁氧基羰基,第三丁氧基羰基,戊氧基羰基,己氧基羰基,辛氧基羰基,壬氧基羰基,癸氧基羰基,十一氧基羰基,十二氧基羰基,或十六氧基羰基,苯基-C1 - 6
-烷氧基羰基,如苯甲氧基羰基,苯基乙氧基羰基,或苯基丙氧基羰基,C1 - 3
-烷基磺醯基-C2 - 4
-烷氧基羰基,C1 - 3
-烷氧基-C2 - 4
-烷氧基-C2 - 4
-烷氧基羰基,或Re
CO-O-(Rf
CRg
)-O-CO基,其中Re
表一個C1 - 8
-烷基,C5 - 7
-環烷基,苯基,或苯基-C1 - 3
-烷基,Rf
表一個氫原子,C1 - 3
-烷基,C5 - 7
-環烷基,或苯基,及Rg
表一個氫原子,C1 - 3
-烷基,或Re
CO-O-(Rf
CRg
)-O基,其中Re
至Rg
如上述定義,其中胺基另可為酞醯亞胺基,上述酯基亦可用作一個可在活體內轉化為羧基之基。
特別可提及之一次群之通式I之化合物包含其中X,R1
及R3
至R5
如上述定義,及R2
表一個直鏈或分支之C1 - 6
-烷氧基-羰基,C4 - 7
-環烷氧基-羰基,或芳基氧基羰基,一個直鏈或分支之C1 - 6
-烷氧基-羰基,其烷基末端經一個苯基,雜芳基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基取代,一個直鏈或分支之C2 - 6
-烷氧基-羰基,其烷基末端經一個氯原子,或羥基,C1 - 3
-烷氧基,胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之第二次群之通式I之化合物包含其中X,R1
及R3
至R5
如上述定義,及R2
表一個胺基羰基或甲基胺基羰基,一個乙基胺基羰基選擇性在乙基之2位置經一個羥基或C1 - 3
-烷氧基或二-(C1 - 2
-烷基)-胺基羰基取代,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之第三次群之通式I之化合物包含其中X,R1
至R3
及R5
如上述定義,及R4
表一個R7
-(C1 - 4
-烷基)-苯基,其中R7
表一個胺基,C1 - 7
-烷基胺基,二-(C1 - 7
-烷基)-胺基,苯基胺基,N-苯基-C1 - 3
-烷基-胺基,苯基-C1 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-苯基-C1- 3
-烷基胺基,或二(苯基-C1 - 3
-烷基)-胺基,或一個苯基經下式之基取代-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
,p及R1 3
如上述定義,其互變體,非對映體,對映體,混合物,及鹽。
較佳之通式I之化合物為其中R1
及R3
如上述定義,及X表一個氧原子,R2
表一個羧基,直鏈或分支之C1 - 6
-烷氧基-羰基,C5 - 7
-環烷氧基羰基,或苯氧基羰基,一個直鏈或分支之C1 - 3
-烷氧基-羰基,其烷基末端經一個苯基,雜芳基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基取代,一個直鏈或分支之C2 - 3
-烷氧基-羰基,其烷基末端經一個氯原子,羥基,C1 - 3
-烷氧基,胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,一個胺基羰基或甲基胺基羰基,一個乙基胺基羰基選擇性在乙基之2位置經一個羥基或C1 - 3
-烷氧基或二-(C1 - 2
-烷基)-胺基羰基取代,R4
表一個C3 - 7
-環烷基,在6或7員環烷基之4位置中亞甲基可經一個胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,或以一個-NH或-N(C1 - 3
-烷基)替代,或一個苯基經R6
基取代,其可另經氟,氯,或溴原子,C1 - 3
-烷基,三氟甲基,羥基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基,乙醯基胺基,胺基羰基,C1 - 3
-烷基-胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,硝基,或氰基一或二取代,其中取代基可相同或不同,及其中R6
表一個氫,氟,氯,溴,或碘原子,一個氰基,硝基,胺基,C1 - 5
-烷基,C3 - 7
-環烷基,三氟甲基,苯基,四唑基,或雜芳基,一個下式之基
其中結合於氮原子之氫原子可以一個C1 - 3
-烷基替代,一個C1 - 3
-烷氧基,胺基-C2 - 3
-烷氧基,C1 - 3
-烷基胺基-C2 - 3
-烷氧基,二-(C1 - 3
-烷基)-胺基-C2 - 3
-烷氧基,苯基-C1 - 3
-烷基胺基-C2 - 3
-烷氧基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基-C2 - 3
-烷氧基,吡咯啶基-C2 - 3
-烷氧基,哌啶基-C2 - 3
-烷氧基,或C1 - 3
-烷基巰基,一個羧基,C1 - 4
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,苯基-C1 - 3
-烷基胺基-羰基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基-羰基,一個C3 - 7
-環烷基-羰基,其中在6或7員環烷基之4位置中亞甲基可以一個-NH或-N(C1 - 3
-烷基)替代,一個4至7員伸環烷基亞胺基,其中連接於亞胺基之亞甲基可以一個羰基或磺醯基替代,或一或二個氫原子各可以一個C1 - 3
-烷基替代,及/或在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可經一個羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,苯基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基取代,或可以一個氧或硫原子,亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基)替代,一個C1 - 4
-烷基末端經R7
取代,其中R7
表一個C5 - 7
-環烷基,在一個6或7員環烷基之4位置中亞甲基可以一個-NH或-N(C1 - 3
-烷基)替代,或在一個5至7員環烷基中-(CH2
)2
基可以一個-CO-NH基替代,-(CH2
)3
基可以一個-NH-CO-NH-基替代,或-(CH2
)4
基可以一個-NH-CO-NH-CO基替代,在各情況中結合於氮原子之一個氫原子可以一個C1 - 3
-烷基替代,一個苯基或雜芳基,一個羥基或C1 - 3
-烷氧基,一個胺基,C1 - 6
-烷基胺基,二-(C1 - 6
-烷基)-胺基,苯基胺基,N-苯基-C1 - 3
-烷基-胺基,苯基-C1 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基,或二(苯基-C1 - 3
-烷基)-胺基,一個ω-羥基-C2 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-ω-羥基-C2 - 3
-烷基-胺基,二-(ω-羥基-C2 - 3
-烷基)-胺基,二-(ω-(C1 - 3
-烷氧基)-C2 - 3
-烷基)-胺基,或N-(二氧戊環-2-基)-C1 - 3
-烷基-胺基,一個C1 - 3
-烷基羰基胺基-C2 - 3
-烷基-胺基,或C1 - 3
-烷基羰基胺基-C2 - 3
-烷基-N-(C1 - 3
-烷基)-胺基,一個C1 - 3
-烷基磺醯基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基-磺醯基胺基,C1 - 3
-烷基磺醯基胺基-C2 - 3
-烷基-胺基,或C1 - 3
-烷基磺醯基胺基-C2 - 3
-烷基-N-(C1 - 3
-烷基)-胺基,一個羥基羰基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-羥基羰基-C1 - 3
-烷基-胺基,一個胍基,其中一個氫原子可以一個C1 - 3
-烷基替代,一個下式之基-N(R8
)-CO-(CH2
)n
-R9
(II),其中R8
表一個氫原子或C1 - 3
-烷基,n表數目0、1、2或3之一,R9
表一個胺基,C1 - 3
-烷基胺基,二-(C1 - 3
-烷基)-胺基,苯基胺基,苯甲基胺基或C1 - 4
-烷氧基,一個5至7員伸環烷基亞胺基,其中在哌啶基之4位置中亞甲基可以一個氧或硫原子,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,或若n表數目1、2或3之一,其亦可表一個氫原子,一個下式之基-N(R1 0
)-(CH2
)m
-(CO)o
-R1 1
(III),其中R1 0
表一個氫原子,C1 - 3
-烷基,C1 - 3
-烷基羰基,或C1 - 3
-烷基磺醯基,m表數目1、2或3之一,o表數目1,或若m表2或3之一,o亦可表數目0,R1 1
表一個胺基,C1 - 3
-烷基胺基,二-(C1 - 3
-烷基)-胺基,C1 - 4
-烷氧基或C1 - 3
-烷氧基-C1 - 3
-烷氧基,或一個5至7員伸環烷基亞胺基,其中哌啶基之4位置中亞甲基可以一個氧或硫原子,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,一個C4 - 7
-環烷基胺基或C4 - 7
-環烯基胺基,其中環之1位置不涉及雙鍵,一個4至7員伸環烷基亞胺基,其中伸環烷基可稠合於一個苯基,或一或二個氫原子各可以一個C1 - 3
-烷基替代,及/或吡咯啶基之3位置中亞甲基可經一個羥基或C1 - 3
-烷氧基取代,在各情況中一個6或7員伸環烷基亞胺基之3或4位置中亞甲基可經一個羥基,羥基-C1 - 3
-烷基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,苯基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基-胺基取代,或可以一個氧或硫原子,一個亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基-),-N(苯基),-N(苯基-C1 - 3
-烷基),-N(C1 - 3
-烷基-羰基),-N(C1 - 4
-烷氧基-羰基),-N(苯甲醯基),或-N(苯基-C1 - 3
-烷基-羰基-)替代,其中連接於伸環烷基亞胺基之亞胺基之氮原子之一個亞甲基可以一個羰基或磺醯基替代,或在一個5至6員單環伸環烷基亞胺基或一個稠合於苯環之伸環烷基亞胺基中連接於亞胺基之氮原子之二個亞甲基各可以一個羰基替代,或R6
表一個C1 - 4
-烷基,其末端經一個羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基,或一個4至7員伸環烷基亞胺基羰基取代,一個下式之基-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
表一個氫原子,C1 - 3
-烷基,C5 - 7
-環烷基,苯基-C1 - 3
-烷基,或雜芳基-C1 - 3
-烷基,及p表數目0、1、2或3之一,及R1 3
假定為上述R7
之意義,或若p表數目1、2或3之一,其亦可表一個氫原子,一個下式之基-N(R1 4
)-(CH2
)q
-(CO)r
-R1 5
(V),其中R1 4
表一個氫原子,C1 - 4
-烷基,C1 - 3
-烷基羰基,苯基羰基,苯基-C1 - 3
-烷基羰基,雜芳基羰基,雜芳基-C1 - 3
-烷基羰基,C1 - 4
-烷基磺醯基,苯基磺醯基,苯基-C1 - 3
-烷基磺醯基,雜芳基磺醯基,或雜芳基-C1 - 3
-烷基-磺醯基,q表數目1、2、3或4之一,r表數目1,或若q為數目2、3或4之一,其亦可表數目0,及R1 5
假定為上述R7
之意義,一個下式之基-N(R1 6
)-SO2
-R1 7
(VI),其中R1 6
表一個氫原子或一個C1 - 4
-烷基末端選擇性經一個氰基,三氟甲基-羰基胺基,或N-(C1 - 3
-烷基)-三氟甲基-羰基-胺基取代,及R1 7
表一個C1 - 3
-烷基,一個胺基經一個二-(C1 - 3
-烷基)-胺基-C1 - 3
-烷基-羰基或二-(C1 - 3
-烷基)-胺基-C1 - 3
-烷基-磺醯基及一個二-(C1 - 3
-烷基)-胺基羰基-C1 - 3
-烷基取代,其中R6
所述基中所含之所有單一結合或稠合之苯基可經氟,氯,或溴原子,C1 - 3
-烷基,三氟甲基,羥基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,胺基磺醯基,C1 - 3
-烷基-胺基磺醯基,硝基,或氰基一或二取代,其中取代基可相同或不同,或苯基之二個相鄰氫原子可以一個亞甲基二氧基替代,及R5
表一個氫原子或C1 - 3
-烷基,其中上述雜芳基意為一個吡啶基,吡基,嘧啶基,嗒基,吡咯基,呋喃基,噻吩基,唑基,噻唑基,吡唑基,咪唑基,或四唑基,在碳骨架中選擇性經一個C1 - 3
-烷基取代,其中結合於氮原子之氫原子可以一個C1 - 3
-烷基或苯基-C1 - 3
-烷基替代,及其中含有至少一個亞胺基之5員雜芳基係經由一個碳或氮原子結合,上述基中結合於氮原子之氫原子可以一個可在活體內裂解之基,特別是乙醯基或第三丁氧基羰基替代,上述基中所含之羧基各可經一個可在活體內裂解之基取代,可呈例如第三丁氧基羰基之形式,上述烷基及烷氧基中或上述定義之式I之各基中所含烷基中一些或所有氫原子選擇性以氟原子替代,及上述基中含有多於2個碳原子之飽和烷基及烷氧基可為直鏈或分支,除非另外說明,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之一次群之通式I之較佳化合物包含其中X,R1
及R3
至R5
如上述定義,及R2
表一個直鏈或分支之C1 - 6
-烷氧基-羰基,C5 - 7
-環烷氧基-羰基,或苯氧基羰基,一個直鏈或分支之C1 - 3
-烷氧基-羰基,其烷基末端經一個苯基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基取代,一個直鏈或分支之C2 - 3
-烷氧基-羰基,其烷基末端經一個羥基,C1 - 3
-烷氧基,胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之第二次群之通式I之較佳化合物包含其中X,R1
及R3
至R5
如上述定義,及R2
表一個胺基羰基或甲基胺基羰基,一個乙基胺基羰基選擇性在乙基之2位置經一個羥基或C1 - 3
-烷氧基或二-(C1 - 2
-烷基)-胺基羰基取代,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之第三次群之通式I之較佳化合物包含其中X,R1
至R3
及R5
如上述定義,及R4
表一個R7
-(正C1 - 4
-烷基)-苯基,其中R7
表一個胺基,C1 - 6
-烷基胺基,二-(C1 - 6
-烷基)-胺基,苯基胺基,N-苯基-C1 - 3
-烷基-胺基,苯基-C1 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基,或二(苯基-C1 - 3
-烷基)-胺基,或一個苯基經下式之基取代-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
,p及R1 3
如上述定義,其互變體,非對映體,對映體,混合物,及鹽。
特佳之通式I之化合物為其中X表一個氧原子,R1
表一個氫原子,R2
表一個羧基,直鏈或分支之C1 - 4
-烷氧基-羰基,或苯氧基羰基,一個直鏈或分支之C1 - 3
-烷氧基-羰基,其烷基末端經一個苯基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基取代,一個直鏈或分支之C2 - 3
-烷氧基-羰基,其烷基末端經一個羥基,C1 - 3
-烷氧基,胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,一個胺基羰基或甲基胺基羰基,一個乙基胺基羰基選擇性在乙基之2位置經一個羥基或C1 - 3
-烷氧基或二-(C1 - 2
-烷基)-胺基羰基取代,R3
表一個C1 - 4
-烷基或一個苯基可經一個氟,氯,或溴原子,一個三氟甲基,C1 - 3
-烷基,羥基,或C1 - 3
-烷氧基取代,R4
表一個C5 - 6
-環烷基,其中在環己基之4位置中亞甲基可經一個胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,或以一個-NH或-N(C1 - 3
-烷基)替代,一個苯基,一個苯基經C1 - 3
-烷基,C1 - 3
-烷氧基,或硝基二取代,其中取代基可相同或不同,或一個苯基經R6
基取代,其可另經一個氟,氯,或溴原子,或一個胺基或硝基取代,其中R6
表一個氟,氯,或溴原子,一個C1 - 3
-烷基,C1 - 3
-烷氧基,硝基,胺基,或C5 - 6
-環烷基,一個吡咯基,吡唑基,咪唑基,三唑基,或四唑基經由一個碳原子結合,其中上述雜芳基在碳骨架中可經一個C1 - 3
-烷基取代,或結合於氮原子之氫原子可以一個C1 - 3
-烷基或苯基-C1 - 3
-烷基替代,一個下式之基
一個羰基,C1 - 4
-烷氧基羰基,苯基-C1 - 3
-烷基胺基-羰基,或C5 - 7
-環烷基-羰基,一個5或6員伸環烷基亞胺基,其中哌啶基之4位置中亞甲基可以氧或硫原子,一個-NH或-N(C1 - 3
-烷基)替代,一個不分支之C1 - 3
-烷基末端經R7
取代,其中R7
表一個C5 - 7
-環烷基,其中在一個5或6員環烷基中-(CH2
)2
基可以一個-CO-NH基替代,-(CH2
)3
基可以一個-NH-CO-NH-基替代,或-(CH2
)4
基可以一個-NH-CO-NH-CO基替代,在各情況中結合於氮原子之一個氫原子可以一個C1 - 3
-烷基替代,一個苯基或吡啶基或吡咯基,吡唑基,咪唑基,或三唑基經由一個碳或氮原子結合,其中上述雜芳基在碳骨架中可經一個C1 - 3
-烷基取代,或結合於氮原子之氫原子可以一個C1 - 3
-烷基替代,一個羥基或C1 - 3
-烷氧基,一個胺基,C1 - 6
-烷基胺基,二-(C1 - 6
-烷基)-胺基,苯基胺基,N-苯基-C1 - 3
-烷基-胺基,苯基-C1 - 3
-烷基-胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基,一個ω-羥基-C2 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-ω-羥基-C2 - 3
-烷基-胺基,二-(ω-羥基-C2 - 3
-烷基)-胺基,或二-(ω-(C1 - 3
-烷氧基)-C2 - 3
-烷基)-胺基,一個C1 - 3
-烷基羰基胺基-C2 - 3
-烷基-胺基,或C1 - 3
-烷基羰基胺基-C2 - 3
-烷基-N-(C1 - 3
-烷基)-胺基,一個C1 - 3
-烷基磺醯基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基-磺醯基胺基,C1 - 3
-烷基磺醯基胺基-C2 - 3
-烷基胺基,或C1 - 3
-烷基磺醯基胺基-C2 - 3
-烷基-N-(C1 - 3
-烷基)-胺基,一個羥基羰基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-羥基羰基-C1 - 3
-烷基-胺基,一個胍基,其中一個氫原子可以一個C1 - 3
-烷基替代,一個下式之基-N(R8
)-CO-(CH2
)n
-R9
(II),其中R8
表一個氫原子或C1 - 3
-烷基,n表數目0、1、2或3之一,R9
表一個胺基,C1 - 3
-烷基胺基,二-(C1 - 3
-烷基)-胺基,或C1 - 4
-烷氧基,一個5或6員伸環烷基亞胺基,其中在哌啶基之4位置中亞甲基可以一個-NH,-N(C1 - 3
-烷基),或-N(C1 - 3
-烷基-羰基)替代,或若n表數目1、2或3之一,R9
亦可表一個氫原子,一個下式之基-N(R1 0
)-(CH2
)m
-(CO)o
-R1 1
(III),其中R1 0
表一個氫原子或C1 - 3
-烷基,m表數目1、2或3之一,o表數目1,或若m表2或3之一,o亦可表數目0,R1 1
表一個胺基,C1 - 3
-烷基胺基,二-(C1 - 3
-烷基)-胺基,C1 - 4
-烷氧基或甲氧基-C1 - 3
-烷氧基,或一個5或6員伸環烷基亞胺基,其中哌啶基之4位置中亞甲基可以一個-NH,-N(C1 - 3
-烷基),或-N(C1 - 3
-烷基-羰基)替代,一個氮呾基,吡咯啶基,哌啶基,2,6-二甲基-哌啶基,3,5-二甲基-哌啶基,或氮呯基,其中吡咯啶基之3位置中亞甲基可經一個羥基取代,哌啶基之4位置中亞甲基可經一個羥基,羥基-C1 - 3
-烷基,或C1 - 3
-烷氧基取代,或可以一個氧或硫原子,一個亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基-),-N(C1 - 3
-烷基-羰基),-N(苯甲醯基),或-N(苯基-C1 - 3
-烷基-羰基-)替代,其中連接於吡咯啶基,哌啶基,或哌基之亞胺基之氮原子之一個亞甲基可以一個羰基替代,或R6
表一個直鏈C1 - 3
-烷基,其末端經一個羧基或C1 - 3
-烷氧基羰基取代,一個下式之基-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
表一個氫原子,C1 - 3
-烷基,或苯基-C1 - 3
-烷基,p表數目0、1或2之一,及R1 3
表一個胺基,C1 - 4
-烷基胺基,二-(C1 - 4
-烷基)-胺基,苯甲基胺基,N-(C1 - 3
-烷基)-苯甲基胺基,C1 - 3
-烷氧基-C1 - 3
-烷基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷氧基-C1 - 3
-烷基胺基,二(2-甲氧基-乙基)-胺基,二(ω-羥基-C2 - 3
-烷基)-胺基,或胺基羰基-甲基-N-(甲基)-胺基,一個吡咯基,吡唑基,或咪唑基經由一個氮原子結合及選擇性經一個C1 - 3
-烷基取代,一個吡咯啶基,哌啶基,嗎啉基,硫嗎啉基,或哌基選擇性在4位置經一個C1 - 3
-烷基,苯基-C1 - 3
-烷基,C1 - 3
-烷基羰基,或C1 - 4
-烷氧基羰基取代,或若n表1或2,其亦可表一個氫原子,一個下式之基-N(R1 4
)-(CH2
)q
-(CO)r
-R1 5
(V),其中R1 4
表一個氫原子,C1 - 4
-烷基,C1 - 3
-烷基羰基,苯基羰基,苯基-C1 - 3
-烷基羰基,呋喃基-羰基,吡啶基-羰基,呋喃基-C1 - 3
-烷基羰基,吡啶基-C1 - 3
-烷基羰基,C1 - 4
-烷基磺醯基,苯基磺醯基,或苯基-C1 - 3
-烷基磺醯基,q表數目1、2或3之一,r表數目1,或若q為數目2或3之一,其亦可表數目0,及R1 5
表一個胺基,C1 - 4
-烷基胺基,二-(C1 - 4
-烷基)-胺基,苯基胺基,N-(C1 - 4
-烷基)-苯基胺基,苯甲基胺基,或N-(C1 - 4
-烷基)-苯甲基胺基,或一個下式之基-N(R1 6
)-SO2
-R1 7
(VI)
其中R1 6
表一個氫原子或一個C1 - 3
-烷基末端選擇性經一個氰基,三氟甲基-羰基胺基,或N-(C1 - 3
-烷基)-三氟甲基-羰基-胺基取代,及R1 7
表一個C1 - 3
-烷基,其中R6
所述基中所含之所有單一結合或稠合之苯基可經一個氟,氯,或溴原子,甲基,三氟甲基,甲氧基,硝基,或氰基取代,及R5
表一個氫原子,其中上述基中結合於氮原子之氫原子可以一個乙醯基或第三丁氧基羰基替代,上述基中所含之羧基亦可以第三丁氧基羰基前驅基之形式存在,及上述基中含有多於2個碳原子之飽和烷基及烷氧基可為直鏈或分支,除非另外說明,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之一次群之通式I之特佳化合物包含其中X,R1
,R3
及R5
如上述定義,R2
表一個直鏈或分支之C1 - 4
-烷氧基羰基或苯氧基羰基,一個直鏈或分支之C1 - 3
-烷氧基羰基,其烷基末端經一個苯基,羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基取代,或一個直鏈或分支之C2 - 3
-烷氧基-羰基,其烷基末端經一個羥基,C1 - 3
-烷氧基,胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基取代,R4
表一個R7
-(正C1 - 3
-烷基)-苯基,其中R7
表一個胺基,C1 - 6
-烷基胺基,二-(C1 - 4
-烷基)-胺基,ω-羥基-C2 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-ω-羥基-C2 - 3
-烷基-胺基,二-(ω-羥基-C2 - 3
-烷基)-胺基,或二-(ω-(C1 - 3
-烷氧基)-C2 - 3
-烷基)-胺基,或一個苯基經下式之基取代-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
、p及R1 3
如上述定義,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之第二次群之通式I之特佳化合物包含其中X,R1
,R3
及R5
如上述定義,及R2
表一個胺基羰基或甲基胺基羰基,一個乙基胺基羰基選擇性在乙基之2位置經一個羥基或C1 - 3
-烷氧基或二-(C1 - 2
-烷基)-胺基羰基取代,R4
表一個R7
-(正C1 - 3
-烷基)-苯基,其中R7
表一個胺基,C1 - 6
-烷基胺基,二-(C1 - 4
-烷基)-胺基,ω-羥基-C2 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-ω-羥基-C2 - 3
-烷基-胺基,二-(ω-羥基-C2 - 3
-烷基)-胺基,或二-(ω-(C1 - 3
-烷氧基)-C2 - 3
-烷基)-胺基,或一個苯基經下式之基取代-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
、p及R1 3
如上述定義,其互變體,非對映體,對映體,混合物,及鹽。
最特佳之通式I之化合物為其中X表一個氧原子,R1
及R5
各表一個氫原子,R2
表一個甲氧基羰基,乙氧基羰基,或胺基羰基,R3
表一個苯基,R4
表一個苯基經R6
基一取代,其中R6
表一個N-甲基-咪唑-2-基,一個未分支之C1 - 3
-烷基,其末端經一個C1 - 4
-烷基胺基,二-(C1 - 4
-烷基)-胺基,哌啶基,或2,6-二甲基-哌啶基取代,一個下式之基-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
表一個C1 - 3
-烷基,p表數目1或2之一,及R1 3
表一個二-(C1 - 3
-烷基)-胺基,或一個下式之基-N(R1 4
)-(CH2
)q
-(CO)r
-R1 5
(V),其中R1 4
表一個C1 - 3
-烷基羰基或C1 - 3
-烷基磺醯基,q表數目1、2或3之一,r表數目1,或若q為數目2或3之一,r亦可表數目0,及R1 5
表一個二-(C1 - 3
-烷基)-胺基,其中上述基中含有多於2個碳原子之飽和烷基可為直鏈或分支,除非另外說明,其互變體,非對映體,對映體,混合物,及鹽。
特別可提及之一次群之通式I之最特佳化合物包含其中X,R1
,R3
及R5
如上述定義,R2
表一個甲氧基羰基或乙氧基羰基,及R4
表一個二-(C1 - 3
-烷基)-胺基-C1 - 3
-烷基苯基,或一個苯基經下式之基取代-N(R1 2
)-CO-(CH2
)p
-R1 3
(IV),其中R1 2
、p及R1 3
如上述定義,其互變體,非對映體,對映體,混合物,及鹽。
下列係述及特佳化合物之實例:(a)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮,(b)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮,(c)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(d)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮,(e)3-Z-[1-(4-((2,6-二甲基-哌啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮,(f)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮,(g)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮,(h)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮,(i)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(j)3-Z-[1-(4-(N-乙醯基-N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(k)3-Z-[1-(4-乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(1)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(m)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(n)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(o)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(p)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(q)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(r)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,(s)3-Z-[1-(4-甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,其互變體,立體異構物,或生理可接受鹽。
另一次群之通式I之化合物包含其中X表一個氧或硫原子,R1
表一個氫原子或一個前藥基,如C1 - 4
-烷氧基羰基或C2 - 4
-烷醯基,R2
表一個羧基,直鏈或分支之C1 - 6
-烷氧基-羰基,C5 - 7
-環烷氧基-羰基,或苯基-C1 - 3
-烷氧基羰基,胺基羰基,或C1 - 2
-烷基胺基羰基,或若R4
不表一個胺基磺醯基-苯基或N-(C1 - 5
-烷基)-C1 - 3
-烷基胺基羰基-苯基,表一個二-(C1 - 2
-烷基)-胺基羰基,R3
表一個氫原子,C1 - 6
-烷基,C3 - 7
-環烷基,三氟甲基,或雜芳基,一個苯基或萘基,一個苯基或萘基經一個氟,氯,溴,或碘原子,三氟甲基,C1 - 3
-烷基,或C1 - 3
-烷氧基一或二取代,若二取代,取代基可相同或不同,其中上述未經取代以及經一及二取代之苯基及萘基可另經下列取代:一個羥基,羥基-C1 - 3
-烷基,或C1 - 3
-烷氧基-C1 - 3
-烷基,一個氰基,羧基,羧基-C1 - 3
-烷基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,或二-(C1 - 3
-烷基)-胺基羰基,一個硝基,一個胺基,C1 - 3
-烷基胺基,二-(C1 - 3
-烷基)-胺基,或胺基-C1 - 3
-烷基,一個C1 - 3
-烷基羰基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基-羰基胺基,C1 - 3
-烷基羰基胺基-C1 - 3
-烷基,N-(C1 - 3
-烷基)-C1 - 3
-烷基羰基胺基-C1 - 3
-烷基,C1 - 3
-烷基-磺醯基胺基,C1 - 3
-烷基磺醯基胺基-C1 - 3
-烷基,N-(C1 - 3
-烷基)-C1 - 3
-烷基磺醯基胺基-C1 - 3
-烷基,或芳基-C1 - 3
-烷基磺醯基胺基,一個環烷基胺基,伸環烷基亞胺基,伸環烷基亞胺基羰基,伸環烷基亞胺基-C1 - 3
-烷基,伸環烷基亞胺基羰基-C1 - 3
-烷基,或伸環烷基亞胺基磺醯基-C1 - 3
-烷基,在各情況中具有4至7個環成員,在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可以一個氧或硫原子,一個亞磺醯基,磺醯基,-NH或-N(C1 - 3
-烷基)替代,或一個雜芳基或雜芳基-C1 - 3
-烷基,R4
表一個C3 - 7
-環烷基,在6或7員環烷基之4位置中亞甲基可以一個胺基,C1 - 3
-烷基胺基,或二-(C1 - 3
-烷基)-胺基替代,或以一個-NH或-N(C1 - 3
-烷基)替代,或一個苯基經R6
基取代,其可另經一個氟,氯,溴,或碘原子,C1 - 5
-烷基,三氟甲基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基磺醯基,硝基,或氰基取代,其中R6
一個氫,氟,氯,溴,或碘原子,一個氰基,硝基,C1 - 5
-烷基,C3 - 7
-環烷基,三氟甲基,苯基,四唑基,或雜芳基,一個C1 - 3
-烷氧基選擇性經1至3個氟原子取代,C1 - 3
-烷氧基-C1 - 3
-烷氧基,苯基-C1 - 3
-烷氧基,胺基-C2 - 3
-烷氧基,C1 - 3
-烷基胺基-C2 - 3
-烷氧基,二-(C1 - 3
-烷基)-胺基-C2 - 3
-烷氧基,苯基-C1 - 3
-烷基胺基-C2 - 3
-烷氧基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基-C2 - 3
-烷氧基,C5 - 7
-伸環烷基亞胺基-C2 - 3
-烷氧基,或C1 - 3
-烷基巰基,一個羧基,C1 - 4
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基-羰基,N-(C1 - 5
-烷基)-C1 - 3
-烷基胺基羰基,苯基-C1 - 3
-烷基胺基-羰基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基-羰基,哌羰基,或N-(C1 - 3
-烷基)-哌羰基,一個C1 - 3
-烷基胺基羰基或N-(C1 - 5
-烷基)-C1 - 3
-烷基胺基羰基,其中一個烷基經一個羧基或C1 - 3
-烷氧基羰基取代,或在2或3位置經一個二-(C1 - 3
-烷基)-胺基,哌基,N-(C1 - 3
-烷基)-哌基,或一個4至7員伸環烷基亞胺基取代,一個4至7員伸環烷基亞胺基,其中連接於亞胺基之亞甲基可以一個羰基或磺醯基替代,或伸環烷基可稠合於一個苯環,或一或二個氫原子各可以一個C1 - 3
-烷基替代,及/或在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可經一個羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,苯基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基取代,或可以一個氧或硫原子,亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,一個C1 - 4
-烷基,可經下列取代:一個羥基或C1 - 3
-烷氧基,一個胺基,C1 - 7
-烷基胺基,二-(C1 - 7
-烷基)-胺基,二-N-(C1 - 3
-烷基)-胺基-C2 - 3
-烷基胺基,三-N,N,N'-(C1 - 3
-烷基)-胺基-C2 - 3
-烷基胺基,苯基胺基,N-苯基-C1 - 3
-烷基-胺基,苯基-C1 - 3
-烷基-胺基,N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基胺基,或二(苯基-C1 - 3
-烷基)-胺基,一個C1 - 3
-烷基羰基胺基,N-(C1 - 3
-烷基)-C1 - 3
-烷基羰基胺基,C1 - 3
-烷氧基羰基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-C1 - 3
-烷氧基羰基-C1 - 3
-烷基胺基,一個C4 - 7
-環烷基胺基,C4 - 7
-環烷基-C1 - 3
-烷基胺基,或C4 - 7
-環烯基胺基,其中環之1位置不涉及雙鍵,及其中上述基在胺基之氮原子各可另經一個C1 - 3
-烷基,其中一些或所有氫原子以氟原子替代,一個C5 - 7
-環烷基,C2 - 4
-烯基,或C1 - 4
-烷基取代,一個4至7員伸環烷基亞胺基,其中連接於亞胺基之亞甲基可以一個羰基或磺醯基替代,或伸環烷基可稠合於一個苯基或一個唑基,咪唑基,噻唑基,吡啶基,吡基,或嘧啶基選擇性經一個氟,氯,溴,或碘原子,硝基,C1 - 3
-烷基,C1 - 3
-烷氧基,或胺基取代,或一或二個氫原子各可以一個C1 - 3
-烷基,C5 - 7
-環烷基,或苯基替代,及/或在各情況中在一個6或7員伸環烷基亞胺基之3或4位置中亞甲基可經一個羥基,羧基,C1 - 4
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,二-(C1 - 3
-烷基)-胺基羰基,苯基-C1 - 3
-烷基胺基,或N-(C1 - 3
-烷基)-苯基-C1 - 3
-烷基-胺基取代,或可以一個氧或硫原子,一個亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,一個羧基,C1 - 3
-烷氧基羰基,胺基羰基,C1 - 3
-烷基胺基羰基,或二-(C1 - 3
-烷基)-胺基羰基,或一個4至7員伸環烷基亞胺基羰基,一胺基,吡咯啶基,哌啶基,嗎啉基,苯甲醯基胺基,或N-(C1 - 3
-烷基)-苯甲醯基胺基,一個N-(C1 - 3
-烷基)-C2 - 4
-烷醯基胺基,其在烷基另經一個羧基或C1 - 3
-烷氧基羰基取代,一個下式之基-N(R8
)-CO-(CH2
)n
-R9
(II),其中R8
表一個氫原子或C1 - 3
-烷基,n表數目0、1、2或3之一,R9
表一個胺基,C1 - 4
-烷基胺基,苯基胺基,N-(C1 - 4
-烷基)-苯基胺基,苯甲基胺基,N-(C1 - 4
-烷基)-苯甲基胺基,或二-(C1 - 4
-烷基)-胺基,一個4至7員伸環烷基亞胺基,在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可以一個氧或硫原子,亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,若n表數目1、2或3之一,其亦可表一個氫原子,一個下式之基-N(R1 0
)-(CH2
)m
-(CO)o
-R1 1
(III),其中R1 0
表一個氫原子,C1 - 3
-烷基,C1 - 3
-烷基羰基,芳基羰基,苯基-C1 - 3
-烷基-羰基,C1 - 3
-烷基磺醯基,芳基磺醯基,或苯基-C1 - 3
-烷基磺醯基,m表數目1、2、3或4之一,o表數目0或1,R1 1
表一個胺基,C1 - 4
-烷基胺基,苯基胺基,N-(C1 - 4
-烷基)-苯基胺基,苯甲基胺基,N-(C1 - 4
-烷基)-苯甲基胺基,或二-(C1 - 4
-烷基)-胺基,一個4至7員伸環烷基亞胺基,其中伸環烷基可稠合於一個苯環,或在各情況中在6或7員伸環烷基亞胺基之4位置中亞甲基可以一個氧或硫原子,亞磺醯基,磺醯基,-NH,-N(C1 - 3
-烷基),-N(苯基),-N(C1 - 3
-烷基-羰基),或-N(苯甲醯基)替代,一個C1 - 3
-烷氧基或二-(C1 - 4
-烷基)-胺基-C1 - 3
-烷基胺基在1位置選擇性經一個C1 - 3
-烷基取代,或一個N-(C1 - 3
-烷基)-C1 - 5
-烷基磺醯基胺基或N-(C1 - 3
-烷基)-苯基磺醯基胺基,其中烷基另經一個氰基或羧基取代,其中R6
所述基中所含之所有單一結合或稠合之苯基可經氟,氯,溴,或碘原子,C1 - 5
-烷基,三氟甲基,C1 - 3
-烷氧基,羧基,C1 - 3
-烷氧基羰基,胺基磺醯基,硝基,或氰基一或二取代,其中取代基可相同或不同,或苯基之二個相鄰氫原子可以一個亞甲基二氧基替代,及R5
表一個氫原子或C1 - 3
-烷基,其中芳基意為一個苯基或萘基選擇性經一個氟,氯,溴,或碘原子,一個三氟甲基,C1 - 3
-烷基,或C1 - 3
-烷氧基一或二取代,及雜芳基意為一個單環5或6員雜芳基選擇性經一個C1 - 3
-烷基取代,其中6員雜芳基含有一,二,或三個氮原子,及5員雜芳基含有一個亞胺基選擇性經一個C1 - 3
-烷基取代,一個氧或硫原子,或一個亞胺基選擇性經一個C1 - 3
-烷基取代及一個氧或硫原子或一或二個氮原子,此外一個苯環可經由二個相鄰碳原子稠合於上述單環雜環基,上述定義之各基中存在之含有多於2個碳原子之飽和烷基及烷氧基亦包括其分支之異構物,例如異丙基,第三丁基,或異丁基,除非另外說明,及此外,任何存在之羧基,胺基,或亞胺基可以一個可在活體內裂解之基取代,其異構物及鹽。
可特別提及之另一次群之通式I之化合物為其中通式I之經取代之吲哚啉酮之6位置中之取代基包含一個經取代之醯胺基之次群。
上述例示之化合物,其互變體,立體異構物,或生理可接受鹽,及其製造方法已述於WO 01/27081,其內容併入本文供參考。
在本發明之意義中較佳之其他上述通式I之化合物為下列化合物:(t)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(u)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(v)3-Z-[1-(3-氰基-4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(w)3-Z-[1-(3-甲氧基-4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(x)3-Z-[1-(4-(N-胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(y)3-Z-[1-(4-(N-(N-(2-二甲基胺基-乙基)-N-甲基-胺基甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(z)3-Z-[1-(4-(N-(二-(2-羥基-乙基)-胺基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(aa)3-Z-[1-(4-(N-(咪唑-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ab)3-Z-[1-(4-(N-二甲基胺基甲基羰基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ac)3-Z-[1-(4-(N-((4-甲基-[1,4]二氮-1-基)-甲基羰基)-甲基-胺基)苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ad)3-Z-[1-(4-(N-((1-甲基-哌啶-4-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ae)3-Z-[1-(2,3-二甲基-4-(N-((4-甲基-哌-1-基)-甲基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(af)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ag)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ah)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ai)3-Z-[1-(4-(N-((3-二甲基胺基-丙基)-胺基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(aj)3-Z-[1-苯胺基-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ak)3-Z-[1-(4-(N-甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(a1)3-Z-[1-環己基胺基-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(am)3-Z-[1-(4-(4-甲基-哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(an)3-Z-[1-(4-甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(ao)3-Z-[1-(4-(嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(ap)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(aq)3-Z-[1-(4-(二-(2-羥基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(ar)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(as)3-Z-[1-(4-(N-(嗎啉-4-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(at)3-Z-[1-(4-(N-(N-(2-二甲基胺基-乙基)-N-甲基胺基甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(au)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(av)3-Z-[1-環己基胺基-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(aw)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ax)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ay)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(az)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-(4-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ba)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bb)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bc)3-Z-[1-((1-甲基-哌啶-4-基)-胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bd)3-Z-[1-(反式-4-二甲基胺基-環己基胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(be)3-Z-[1-(4-(2-二乙基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bf)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-丙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bg)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bh)3-Z-[1-環己基胺基-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bi)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bj)3-Z-[1-(3-二乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bk)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(b1)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bm)3-Z-[1-苯胺基-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bn)3-Z-[1-(4-乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bo)3-Z-[1-(4-((2-二乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bp)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bq)3-Z-[1-(4-(N-甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(br)3-Z-[1-(4-甲氧基羰基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bs)3-Z-[1-(4-羧基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bt)3-Z-[1-(4-(N-(二甲基胺基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(bu)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(bv)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(bw)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(bx)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(by)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(bz)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(ca)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cb)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cc)3-Z-[1-(4-胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(cd)3-Z-[1-(4-(N-(2-二乙基胺基-乙基)-胺基甲醯基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(ce)3-Z-[1-(4-((4-甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(cf)3-Z-[1-(4-((4-甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cg)3-Z-[1-(4-((4-乙基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(ch)3-Z-[1-(4-(N-乙基-N-(2-二甲基胺基-乙基)-胺基甲醯基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(ci)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-二乙基胺基甲醯基-2-吲哚啉酮(cj)3-Z-[1-(4-((順式-3,5-二甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(ck)3-Z-[1-(4-((4-乙基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cl)3-Z-[1-(4-(N-(2-二乙基胺基-乙基)-胺基甲醯基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(cm)3-Z-[1-(4-((順式-3,5-二甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cn)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(co)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(cp)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(cq)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(cr)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cs)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(ct)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(cu)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮
其互變體,立體異構物,或生理可接受鹽。
這些化合物可相似於WO 01/27081之化合物使用下文所述之方法製備。
所用之簡寫:HOBt=1-羥基-1H-苯并三唑TBTU=四氟硼酸O-苯并三唑-1-基-N,N,N',N'-四甲基DEPC=焦碳酸二乙酯n.d.=未測定
下列通式II之化合物係相似於WO 01/27081中所述之化合物製備:
下列化合物係相似地製備:(al)3-Z-(1-環己基胺基-1-苯基-亞甲基)-6-甲氧基羰基-2-吲哚啉酮Rf
值:0.60(矽膠,二氯甲烷/甲醇=9:1)熔點:236-243℃ C2 3
H2 4
N2
O3
質譜:m/z=377[m+H]+
下列通式III之化合物係相似於WO 01/27081中所述之化合物製備:
下列化合物係相似地製備:(av)3-Z-(1-環己基胺基-1-苯基-亞甲基)-6-羧基-2-吲哚啉酮Rf
值:0.50(矽膠,二氯甲烷/甲醇=9:1)熔點:347-350℃ C2 2
H2 2
N2
O3
質譜:m/z=363[m+H]+
(aw)3-Z-[1-(3-(二甲基胺基甲基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ax)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(ay)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(az)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-(4-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮
起始化合物之製備:(I.1)1-乙醯基-3-(1-羥基-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮6.00克1-乙醯基-6-甲氧基羰基-2-吲哚啉酮,6.30克3-(2-乙氧基羰基-乙基)-苯甲酸(相似於Tetrahedron 1997,53,7335-7340製備),及9.10克TBTU溶於80毫升二甲基甲醯胺中,13.5毫升二異丙基甲基胺及4.34克HOBt加入,混合物在周圍溫度攪拌12小時。然後溶劑移除,稀鹽酸加入,殘餘物由二氯甲烷/甲醇中再結晶。
產量:10.6克(94%理論值)Rf
值:0.50(矽膠,二氯甲烷/甲醇=19:1)熔點:80-84℃ C2 4
H2 3
NO7
質譜:m/z=438[m+H]+
下列化合物相似地製備:(I.2)1-乙醯基-3-(1-羥基-1-(4-(2-甲氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮由1-乙醯基-6-甲氧基羰基-2-吲哚啉酮及4-(2-甲氧基羰基-乙基)-苯甲酸(相似於Tetrahedron 1997,53,7335-7340製備)製備Rf
值:0.60(矽膠,二氯甲烷/甲醇=19:1)熔點:188-192℃ C2 3
H2 1 N
O7
質譜:m/z=422[m-H]+
(II.1)1-乙醯基-3-(1-甲氧基-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮7.17克四氟硼酸三甲基氧鎓(oxonium)緩慢加入10.6克1-乙醯基-3-(1-羥基-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質I.1)及12.5毫升乙基二異丙基胺於100毫升二氯甲烷中之溶液內。在周圍溫度攪拌4小時後,3.50克四氟硼酸三甲基氧鎓加入,混合物在周圍溫度攪拌12小時。然後混合物以水洗二次,有機相以硫酸鎂乾燥,溶劑移除。殘餘物經矽膠管柱以二氯甲烷/甲醇(97:3)作為溶離劑純化。
產量:4.56克(42%理論值)Rf
值:0.90(矽膠,二氯甲烷/甲醇=20:1)C2 5
H2 5
NO7
質譜:m/z=452[m+H]+
下列化合物相似地製備:(II.2)1-乙醯基-3-(1-甲氧基-1-(4-(2-甲氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮由1-乙醯基-3-(1-羥基-1-(4-(2-甲氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質I.2)製備Rf
值:0.80(矽膠,二氯甲烷/甲醇=19:1)熔點:112-117℃ C2 4
H2 3
NO7
質譜:m/z=438[m+H]+
(III.1)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮1.2克1-乙醯基-3-(1-甲氧基-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質II.1)及0.32克4-(二甲基胺基甲基)-苯胺溶於10毫升二甲基甲醯胺中,在110℃攪拌3天。在冷卻後,溶劑蒸發,殘餘物吸收入5毫升甲醇中,200毫克20%乙醇鈉於乙醇中之溶液加入。混合物在周圍溫度攪拌1.5小時,溶劑移除,殘餘物吸收入水中。水相以醋酸乙酯萃取三次,合併之有機相以硫酸鈉乾燥。在溶劑蒸發後,殘餘物經矽膠管柱以二氯甲烷/甲醇(9:1)作為溶離劑純化。
產量:0.33克(35%理論值)Rf
值:0.35(矽膠,二氯甲烷/甲醇=9:1)熔點:129-134℃ C3 1
H3 3
N3
O5
質譜:m/z=528[m+H]+
下列化合物相似地製備:(III.2)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮由1-乙醯基-3-(1-甲氧基-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質II.1)製備Rf
值:0.30(矽膠,二氯甲烷/甲醇=9:1)熔點:174-177℃ C3 2
H3 5
N3
O5
質譜:m/z=542[m+H]+
(III.3)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮由1-乙醯基-3-(1-甲氧基-1-(3-(2-乙氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質II.1)製備Rf
值:0.45(矽膠,二氯甲烷/甲醇=9:1)熔點:102℃ C3 2
H3 0
N4
O5
質譜:m/z=551[m+H]+
(III.4)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-(4-(2-甲氧基羰基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮由1-乙醯基-3-(1-甲氧基-1-(4-(2-甲氧基羰基-乙基)-苯基)-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質II.2)製備Rf
值:0.50(矽膠,二氯甲烷/甲醇=9:1)熔點:226-229℃ C3 0
H3 1 N 3
O5
質譜:m/z=512[m-H]+
最終化合物之製備:下列通式IV之化合物係相似於WO 01/27081中所述之化合物製備,由上述起始物質開始: *
溶劑:(A):逆相RP8,甲醇/鹽水(5%)=4:1(B):矽膠,二氯甲烷/甲醇9:1
起始化合物之製備:(IV)3-(1-羥基-1-苯基-亞甲基)-6-羧基-2-吲哚啉酮11.0克1-乙醯基-3-(1-甲氧基-1-苯基-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(製備述於WO 01/27081)溶於500毫升甲醇中,160毫升1 N氫氧化鈉溶液加入。混合物在周圍溫度攪拌1小時,在回流攪拌6小時。然後20毫升1 N氫氧化鈉溶液加入,混合物在回流再攪拌3小時。160毫升1 N鹽酸加入,生成之殘餘物濾出,在100℃乾燥。殘餘物不進一步純化而使用。
產量:7.60克(86%理論值)
(V.1)3-(1-羥基-1-苯基-亞甲基)-6-(N-乙基-甲基胺基甲醯基)-2-吲哚啉酮5.50克3-(1-羥基-1-苯基-亞甲基)-6-羧基-2-吲哚啉酮(起始物質IV),7.54克TBTU,3.60克HOBt,及17.1毫升乙基二異丙基胺溶於200毫升二甲基甲醯胺中。2.70毫升N-甲基-乙胺之94%溶液加入,混合物在周圍溫度攪拌12小時。然後溶劑蒸發,殘餘物經矽膠管柱以二氯甲烷/甲醇/氨(9:1:0.1)作為溶離劑純化。
產量:6.10克(97%理論值)Rf
值:0.35(矽膠,二氯甲烷/甲醇/氨=9:1:0.1)C1 9
H1 8
N2
O3
質譜:m/z=323[m+H]+
下列化合物相似地製備:(V.2)3-(1-羥基-1-苯基-亞甲基)-6-乙基胺基甲醯基-2-吲哚啉酮由3-(1-羥基-1-苯基-亞甲基)-6-羧基-2-吲哚啉酮(起始物質IV)及乙胺製備C1 8
H1 6
N2
O3
質譜:m/z=309[m+H]+
最終化合物之製備:(ba)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-(N-乙基-甲基胺基甲醯基)-2-吲哚啉酮250毫克3-(1-羥基-1-苯基-亞甲基)-6-(N-乙基-甲基胺基甲醯基)-2-吲哚啉酮(起始物質V.1)及382毫克4-(2-二甲基胺基-乙基)-苯胺溶於3毫升四氫呋喃中,569毫升三甲基矽烷基咪唑加入,混合物在一個微波烘箱中於170℃攪拌。在冷卻後,溶劑蒸發,殘餘物吸收入水中。殘餘物濾出,在90℃真空乾燥。
產量:0.18克(50%理論值)Rf
值:0.30(矽膠,二氯甲烷/甲醇/氨=9:1:0.1)熔點:195-200℃ C2 9
H3 2
N4
O2
質譜:m/z=469[m+H]+
下列通式V之化合物係相似於上述化合物(ba)依據WO 01/27081中所述之程序製備:
起始化合物之製備:(VI)1-乙醯基-3-(1-乙氧基-亞甲基)-6-甲氧基羰基-2-吲哚啉酮8.00克1-乙醯基-6-甲氧基羰基-2-吲哚啉酮及17.2毫升原甲酸三乙酯溶於70毫升醋酸酐中,在110℃攪拌5.5小時。在冷卻後,殘餘物濾出,以醚洗,在100℃真空乾燥。
產量:8.80克(89%理論值)Rf
值:0.35(矽膠,石油醚/二氯甲烷/醋酸乙酯=5:4:1)熔點:187-189℃ C1 5
H1 5
NO5
質譜:m/z=290[m+H]+
最終化合物之製備:下列通式VI之化合物係相似於WO 01/27081中所述之化合物製備: *
溶劑:(A):矽膠,二氯甲烷/甲醇/氨9:1:0.1
起始化合物之製備:(VII)3-(1-羥基-亞甲基)-6-羧基-2-吲哚啉酮5.00克1-乙醯基-3-(1-乙氧基-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(起始物質VI)溶於150毫升甲醇中,86.4毫升1 N氫氧化鈉溶液加入。混合物回流8.5小時。然後86.4毫升1 N鹽酸加入。殘餘物濾出,在90℃乾燥。
產量:2.50克(71%理論值)C1 0
H7
NO4
質譜:m/z=206[m+H]+
(VIII)3-(1-羥基-亞甲基)-6-乙基胺基甲醯基-2-吲哚啉酮400毫克3-(1-羥基-亞甲基)-6-羧基-2-吲哚啉酮(起始物質VII),689毫克TBTU,291毫克HOBt,及1.35毫升三乙胺溶於20毫升二甲基甲醯胺中。在0℃ 1.95毫升2M乙胺於THF中之溶液加入,混合物在周圍溫度攪拌12小時。然後溶劑蒸發,殘餘物經一個矽膠管柱以二氯甲烷/乙醇/醋酸(5:1:0.01)作為溶離劑純化。
產量:160毫克(35%理論值)Rf
值:0.20(矽膠,二氯甲烷/乙醇/醋酸=5:1:0.01)熔點:146-150℃ C1 2
H1 2
N2
O3
質譜:m/z=233[m+H]+
最終化合物之製備:(cr)3-Z-[1-(4-(N-(4-甲基-哌-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮160毫克3-(1-羥基-亞甲基)-6-乙基胺基甲醯基-2-吲哚啉酮(起始物質VIII)及543毫克N-[(4-甲基-哌-1-基)-甲基羰基]-N-甲基-對-苯二胺溶於3毫升四氫呋喃中,506毫升三甲基矽烷基咪唑加入,混合物在一個微波烘箱中於170℃攪拌25分鐘。在冷卻後,溶劑蒸發,殘餘物經一個氧化鋁管柱(活性2-3)以二氯甲烷/乙醇(19:1)作為溶離劑純化。殘餘物由醚中再結晶,在80℃真空乾燥。
產量:0.17克(52%理論值)Rf
值:0.60(矽膠,二氯甲烷/甲醇=9:1)熔點:255-260℃ C2 6
H3 2
N6
O3
質譜:m/z=477[m+H]+
下列通式VII之化合物係相似於上述化合物(ct)依據WO 01/27081中所述之程序製備:
這些化合物之互變體,立體異構物,或生理可接受鹽亦包含在本發明之範圍內,可使用WO 01/27081中所述之方法獲得,其內容併入本文供參考。
一個特佳化合物為3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮之一乙磺酸鹽,揭示於例如WO 04/13099,其內容併入本文供參考。
化合物3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮一乙磺酸鹽之代謝物以及此化合物或這些代謝物經由例如整個分子或該分子之一或多個化學基之化學或非化學衍化所獲得之前藥亦包含在本發明之意義中。關於此方面,請參考WO 04/13099,其述及化合物3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮一乙磺酸鹽之代謝物及前藥。
下列特定化合物之名單為本發明之例示,並非用於限制其範圍:(1)3-Z-(1-苯胺基-1-苯基-亞甲基)-6-乙氧基羰基-2-吲哚啉酮(2)3-Z-[1-(4-硝基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(3)3-Z-[1-(4-氟-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(4)3-Z-[1-(4-氯-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(5)3-Z-[1-(4-碘-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(6)3-Z-[1-(4-氰基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(7)3-Z-[1-(4-甲氧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(8)3-Z-[1-(4-乙氧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(9)3-Z-[1-(4-三氟甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(10)3-Z-[1-(4-甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(11)3-Z-[1-(4-甲基巰基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(12)3-Z-[1-(4-胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(13)3-Z-[1-(4-(異丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(14)3-Z-[1-(4-(苯胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(15)3-Z-[1-(4-(丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(16)3-Z-[1-(4-(丁基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(17)3-Z-[1-(4-(異丁基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(18)3-Z-[1-(4-(環己基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(19)3-Z-[1-(4-(苯甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(20)3-Z-[1-(4-((N-乙基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(21)3-Z-[1-(4-((N-甲基-N-丙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(22)3-Z-[1-(4-((N-異丙基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(23)3-Z-[1-(4-((N-乙基-N-丙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(24)3-Z-[1-(4-((N-乙基-N-異丙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(25)3-Z-[1-(4-(二丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(26)3-Z-[1-(4-(二異丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(27)3-Z-[1-(4-((N-苯甲基-N-乙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(28)3-Z-[1-(4-(二苯甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(29)3-Z-[1-(4-(3,6-二氫-2H-吡啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(30)3-Z-[1-(4-(3,5-二甲基-哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(31)3-Z-[1-(4-(氮-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(32)3-Z-[1-(4-(哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(33)3-Z-[1-(4-(嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(34)3-Z-[1-(4-(硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(35)3-Z-[1-(4-(1-氧基-硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(36)3-Z-[1-(4-(1,1-二氧基-硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(37)3-Z-[1-(4-(乙醯基胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(38)3-Z-[1-(4-(2-胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(39)3-Z-[1-(4-(2-甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(40)3-Z-[1-(4-(2-乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(41)3-Z-[1-(4-(2-二乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(42)3-Z-[1-(4-(2-哌啶-1-基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(43)3-Z-[1-(4-(2-乙醯基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(44)3-Z-[1-(4-(3-胺基-丙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(45)3-Z-[1-(4-(3-二甲基胺基-丙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(46)3-Z-[1-(4-(N-胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(47)3-Z-[1-(4-(N-甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(48)3-Z-[1-(4-(N-乙基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(49)3-Z-[1-(4-(N-二乙基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(50)3-Z-[1-(4-(N-(哌啶-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(51)3-Z-[1-(4-(N-(嗎啉-4-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(52)3-Z-[1-(4-(N-(哌-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(53)3-Z-[1-(4-(N-(2-胺基-乙基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(54)3-Z-[1-(4-(N-(2-甲基胺基-乙基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(55)3-Z-[1-(4-(N-(2-二乙基胺基-乙基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(56)3-Z-[1-(4-(N-乙醯基-N-(2-胺基乙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(57)3-Z-[1-(4-(N-乙醯基-N-(2-甲基胺基-乙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(58)3-Z-[1-(4-(N-乙醯基-N-(2-甲基胺基-丙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(59)3-Z-[1-(4-(N-乙醯基-N-(2-哌啶-1-基-乙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(60)3-Z-[1-(4-(N-乙醯基-N-(胺基羰基甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(61)3-Z-[1-(4-(N-乙醯基-N-(二甲基胺基羰基甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(62)3-Z-[1-(4-(N-乙醯基-N-(哌啶-1-基-羰基甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(63)3-Z-[1-(4-(N-甲基-N-(胺基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(64)3-Z-[1-(4-(N-甲基-N-(甲基胺基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(65)3-Z-[1-(4-(N-甲基-N-(二甲基胺基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(66)3-Z-[1-(4-(N-甲基-N-(哌啶-1-基-羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(67)3-Z-[1-(4-(N-(2-胺基乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(68)3-Z-[1-(4-(N-(2-甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(69)3-Z-[1-(4-(N-(2-乙基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(70)3-Z-[1-(4-(N-(2-二乙基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(71)3-Z-[1-(4-(N-(2-吡咯啶-1-基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(72)3-Z-[1-(4-(N-(2-哌啶-1-基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(73)3-Z-[1-(4-(N-(2-哌-1-基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(74)3-Z-[1-(4-(N-(2-(嗎啉-4-基)-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(75)3-Z-[1-(4-(N-(胺基羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(76)3-Z-[1-(4-(N-(甲基胺基羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(77)3-Z-[1-(4-(N-(乙基胺基羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(78)3-Z-[1-(4-(N-(N-(2-二甲基胺基-乙基)-N-甲基-胺基)-羰基甲基)-N-甲基磺醯基-胺基)苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(79)3-Z-[1-(4-(N-(二乙基胺基羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(80)3-Z-[1-(4-(N-(吡咯啶-1-基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(81)3-Z-[1-(4-(N-(哌啶-1-基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(82)3-Z-[1-(4-(N-(哌-1-基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(83)3-Z-[1-(4-(N-((嗎啉-4-基)-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(84)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(85)3-Z-[1-(4-(3-二甲基胺基-丙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(86)3-Z-[1-(4-(胺基羰基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(87)3-Z-[1-(4-(2-胺基羰基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(88)3-Z-[1-(4-(吡啶-2-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(89)3-Z-[1-(4-(吡啶-3-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(90)3-Z-[1-(4-(吡啶-4-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(91)3-Z-[1-(4-(N-乙醯基-N-甲基胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(92)3-Z-[1-(4-(N-乙基羰基-N-(二甲基胺基羰基-甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(93)3-Z-[1-(胺基甲醯基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(94)3-Z-[1-(4-二甲基胺基甲醯基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(95)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(96)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(97)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(98)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(99)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞乙基]-6-乙氧基羰基-2-吲哚啉酮(100)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(101)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(102)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(103)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(104)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(105)3-Z-[1-(4-四唑-5-基-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(106)3-Z-[1-(4-四唑-5-基-苯胺基)-亞乙基]-6-乙氧基羰基-2-吲哚啉酮(107)3-Z-[1-(4-四唑-5-基-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(108)3-Z-[1-(4-四唑-5-基-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(109)3-Z-[1-(4-羧基-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(110)3-Z-[1-(4-羧基-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(111)3-Z-[1-(4-羧基-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(112)3-Z-[1-(4-(N-(3-二甲基胺基-丙醯基)-N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(113)3-Z-[1-(4-(N-(4-二甲基胺基-丁醯基)-N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(114)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-(2-二甲基胺基-乙基磺醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(115)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-(3-二甲基胺基-丙基磺醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(116)3-Z-[1-(4-((2-羥基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(117)3-Z-[1-(4-((2-甲氧基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(118)3-Z-[1-(4-((2-二甲基胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(119)3-Z-[1-(4-((3-二甲基胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(120)3-Z-[1-(4-((N-第三丁氧基羰基-2-胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(121)3-Z-[1-(4-((N-第三丁氧基羰基-3-胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(122)3-Z-[1-(4-((2-胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(123)3-Z-[1-(4-((3-胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(124)3-Z-[1-(4-((2-乙醯基胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(125)3-Z-[1-(4-((3-乙醯基胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(126)3-Z-[1-(4-((2-甲基磺醯基胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(127)3-Z-[1-(4-((3-甲基磺醯基胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(128)3-Z-[1-(4-(N-(N-第三丁氧基羰基-2-胺基乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(129)3-Z-[1-(4-(N-(2-胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(130)3-Z-[1-(4-(N-(2-乙醯基胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(131)3-Z-[1-(4-(N-(2-甲基磺醯基胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(132)3-Z-[1-(4-(羧基甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(133)3-Z-[1-(4-(乙氧基羰基甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(134)3-Z-[1-(4-(胺基甲醯基甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(135)3-Z-[1-(4-(二甲基胺基甲醯基-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(136)3-Z-[1-(4-(甲基胺基甲醯基-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(137)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(138)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-硝基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(139)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-乙醯基胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(140)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-甲基磺醯基胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(141)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-氰基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(142)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-羥基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(143)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-甲氧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(144)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-乙氧基羰基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(145)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-羧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(146)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(147)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-氯-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(148)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-氟-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(149)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-溴-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(150)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(151)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-三氟甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(152)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3,5-二溴-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(153)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3,5-二氯-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(154)3-Z-[1-(4-(二甲基胺基甲基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(155)3-Z-[1-(4-(二甲基胺基甲基)-3-硝基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(156)3-Z-[1-(4-(二甲基胺基甲基)-3-乙醯基胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(157)3-Z-[1-(4-(二甲基胺基甲基)-3-(甲基磺醯基胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(158)3-Z-[1-(4-(二甲基胺基甲基)-3-氰基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(159)3-Z-[1-(4-(二甲基胺基甲基)-3-羥基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(160)3-Z-[1-(4-(二甲基胺基甲基)-3-甲氧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(161)3-Z-[1-(4-(二甲基胺基甲基)-3-(乙氧基羰基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(162)3-Z-[1-(4-(二甲基胺基甲基)-3-羧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(163)3-Z-[1-(4-(二甲基胺基甲基)-3-胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(164)3-Z-[1-(4-(二甲基胺基甲基)-3-氯-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(165)3-Z-[1-(4-(二甲基胺基甲基)-3-氟-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(166)3-Z-[1-(4-(二甲基胺基甲基)-3-溴-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(167)3-Z-[1-(4-(二甲基胺基甲基)-3-甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(168)3-Z-[1-(4-(二甲基胺基甲基)-3-三氟甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(169)3-Z-[1-(4-(二甲基胺基甲基)-3,5-二溴-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(170)3-Z-[1-(4-(二甲基胺基甲基)-3,5-二氯-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(171)3-Z-[1-(4-(N-((4-甲基哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(172)3-Z-[1-(4-(N-(哚唑-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(173)3-Z-[1-(4-(N-(酞醯亞胺-2-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(174)3-Z-[1-(4-(N-胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(175)3-Z-[1-(4-(N-乙醯基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(176)3-Z-[1-(4-(N-甲基磺醯基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(177)3-Z-[1-(4-(N-((N-(2-甲氧基乙基)-N-甲基-胺基)-甲基羰基)-N-甲基胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(178)3-Z-[1-(4-(N-((N-(2-二甲基胺基乙基)-N-甲基-胺基)-甲基羰基)-N-甲基胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(179)3-Z-[1-(4-(N-((二-(2-羥基乙基)-胺基)-甲基羰基)-N-甲基胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(180)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(181)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞乙基]-6-乙氧基羰基-2-吲哚啉酮(182)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(183)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(184)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(185)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞乙基]-6-乙氧基羰基-2-吲哚啉酮(186)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞丙基]-6-乙氧基羰基-2-吲哚啉酮(187)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞丁基]-6-乙氧基羰基-2-吲哚啉酮(188)3-Z-[1-(4-(N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(189)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(190)3-Z-[1-(4-((亞咪唑啶-2,4-二酮-5-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(191)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(192)3-Z-[1-(4-(N-第三丁氧基羰基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(193)3-Z-[1-(4-(2-氧基-吡咯啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(194)3-Z-[1-(4-(N-胺基羰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(195)3-Z-[1-(4-(N-氰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(196)3-Z-[1-(4-(2-(咪唑-4-基)-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(197)3-Z-[1-(4-((2-(N-苯甲基-N-甲基-胺基)-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(198)3-Z-[1-(4-環己基胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(199)3-Z-[1-(4-(咪唑-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(200)3-Z-[1-(4-(咪唑-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(201)3-Z-[1-(N-甲基-哌啶-4-基-胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(202)3-Z-[1-(4-(咪唑-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(203)3-Z-[1-(4-((4-羥基-哌啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(204)3-Z-[1-(4-((4-甲氧基-哌啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(205)3-Z-[1-(4-苯甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(206)3-Z-[1-(4-(N-(3-三氟乙醯基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(207)3-Z-[1-(4-(4-第三丁氧基羰基-哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(208)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(209)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(210)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(211)3-Z-[1-(4-((3-(N-苯甲基-N-甲基-胺基)-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(212)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(213)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丁醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(214)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-異丁醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(215)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-苯甲醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(216)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(217)3-Z-[1-(4-(4-羥基甲基-哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(218)3-Z-[1-(4-(2-(4-羥基-哌啶-1-基)-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(219)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丙基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(220)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丁基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(221)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-苯基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(222)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-苯甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(223)3-Z-[1-(4-((咪唑啶-2,4-二酮-5-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(224)3-Z-[1-(4-((3-羥基-吡咯啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(225)3-Z-[1-(4-(環己基-甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(226)3-Z-[1-(4-(環己基-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(227)3-Z-[1-(4-二乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(228)3-Z-[1-(4-(N-(正-己基)-N-甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(229)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(呋喃-2-羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(230)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(2-甲氧基-苯甲醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(231)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(吡啶-3-羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(232)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(苯基-乙醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(233)3-Z-[1-(4-(咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(234)3-Z-[1-(4-(1-乙基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(235)3-Z-[1-(4-(1-苯甲基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(236)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-異丙基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(237)3-Z-[1-(4-(N-((4-苯甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(238)3-Z-[1-(4-(N-(吡咯啶-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(239)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-3-溴-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(240)3-Z-[1-(4-(5-甲基-咪唑-4-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(241)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(242)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(243)3-Z-[1-(4-(N-丁基-N-第三丁氧基羰基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(244)3-Z-[1-(4-(N-((N-胺基羰基甲基-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(245)3-Z-[1-(4-(N-((N-苯甲基-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(246)3-Z-[1-(4-(N-(二-(2-甲氧基乙基)-胺基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(247)3-Z-[1-(4-(N-((2-(4-第三丁氧基羰基-哌-1-基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(248)3-Z-[1-(4-(N-((2-(哌啶-1-基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(249)3-Z-[1-(4-(N-((2-(N-苯甲基-N-甲基-胺基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(250)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(251)3-Z-[1-(4-(N-(哌啶-1-基-甲基羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(252)3-Z-[1-(4-(N-((4-第三丁氧基羰基-哌-1-基)-甲基羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(253)3-Z-[1-(4-(N-((N-苯甲基-N-甲基-胺基)-甲基羰基)-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(254)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(255)3-Z-[1-(4-(N-(哌啶-1-基-甲基羰基)-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(256)3-Z-[1-(4-(1,2,4-三唑-2-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(257)3-Z-[1-(4-(1,2,3-三唑-2-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(258)3-Z-[1-(4-(1,2,3-三唑-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(259)3-Z-[1-(4-((N-胺基羰基甲基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(260)3-Z-[1-(4-((二-(2-甲氧基-乙基)-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(261)3-Z-[1-(4-((二-(2-羥基-乙基)-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(262)3-Z-[1-(4-((N-乙氧基羰基甲基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(263)3-Z-[1-(4-(氮呾-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(264)3-Z-[1-(4-(N-丙基-N-第三丁氧基羰基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(265)3-Z-[1-(4-((N-(2-(2-甲氧基-乙氧基)-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(266)3-Z-[1-(4-((N-(第三丁氧基羰基-3-胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(267)3-Z-[1-(4-((N-(甲基胺基甲醯基-甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(268)3-Z-[1-(4-((N-(二甲基胺基甲醯基-甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(269)3-Z-[1-(4-((N-丙基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(270)3-Z-[1-(4-((N-(2-二甲基胺基-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(271)3-Z-[1-(4-((N-(3-二甲基胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(272)3-Z-[1-(4-((N-(2-甲氧基-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(273)3-Z-[1-(4-((N-(2-羥基-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(274)3-Z-[1-(4-((N-(二氧戊環-2-基-甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(275)3-Z-[1-(4-(3-氧基-哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(276)3-Z-[1-(4-(N-(哌-1-基-甲基羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(277)3-Z-[1-(4-(N-((2-(哌-1-基)-乙基)-羰基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(278)3-Z-[1-(4-((N-(3-胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(279)3-Z-[1-(4-(N-(3-甲基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(280)3-Z-[1-(4-脲基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(281)3-Z-[1-(4-胍基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(282)3-Z-[1-(4-(N-甲基磺醯基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(283)3-Z-[1-(4-(4-苯甲醯基-哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(284)3-Z-[1-(4-((N-(3-乙醯基胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(285)3-Z-[1-(4-((N-(3-甲基磺醯基胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(286)3-Z-[1-(4-((N-羧基甲基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(287)3-Z-(1-苯胺基-1-苯基-亞甲基)-6-甲氧基羰基-2-吲哚啉酮(288)3-Z-[1-(4-硝基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(289)3-Z-[1-(4-氟-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(290)3-Z-[1-(4-氯-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(291)3-Z-[1-(4-溴-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(292)3-Z-[1-(4-碘-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(293)3-Z-[1-(4-氰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(294)3-Z-[1-(4-羧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(295)3-Z-[l-(4-甲氧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(296)3-Z-[1-(4-乙氧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(297)3-Z-[1-(4-三氟甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(298)3-Z-[1-(4-甲基巰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(299)3-Z-[1-(4-(異丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(300)3-Z-[1-(4-(苯胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(301)3-Z-[1-(4-(異丁基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(302)3-Z-[1-(4-(環己基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(303)3-Z-[1-(4-(苯甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(304)3-Z-[1-(4-((N-甲基-N-丙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(305)3-Z-[1-(4-((N-異丙基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(306)3-Z-[1-(4-((N-乙基-N-丙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(307)3-Z-[1-(4-((N-乙基-N-異丙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(308)3-Z-[1-(4-(二丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(309)3-Z-[1-(4-(二異丙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(310)3-Z-[1-(4-((N-苯甲基-N-乙基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(311)3-Z-[1-(4-(二苯甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(312)3-Z-[1-(4-(3,6-二氫-2H-吡啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(313)3-Z-[1-(4-(3,5-二甲基-哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(314)3-Z-[1-(4-(氮-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(315)3-Z-[1-(4-(2-胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(316)3-Z-[1-(4-(2-甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(317)3-Z-[1-(4-(2-乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(318)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(319)3-Z-[1-(4-(2-二乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(320)3-Z-[1-(4-(2-哌啶-1-基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(321)3-Z-[1-(4-(2-乙醯基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(322)3-Z-[1-(4-(3-胺基-丙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(323)3-Z-[1-(4-(3-二甲基胺基-丙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(324)3-Z-[1-(4-(N-胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(325)3-Z-[1-(4-(N-乙基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(326)3-Z-[1-(4-(N-二乙基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(327)3-Z-[1-(4-(N-二丙基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(328)3-Z-[1-(4-(N-((N-乙基-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(329)3-Z-[1-(4-(N-((N-乙基-N-丙基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(330)3-Z-[1-(4-(N-((N-甲基-N-丙基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(331)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-乙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(332)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(333)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-丁基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(334)3-Z-[1-(4-(N-(2-胺基-乙基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(335)3-Z-[1-(4-(N-(2-二乙基胺基-乙基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(336)3-Z-[1-(4-(N-乙醯基-N-(2-胺基乙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(337)3-Z-[1-(4-(N-乙醯基-N-(2-甲基胺基乙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(338)3-Z-[1-(4-(N-乙醯基-N-(3-甲基胺基-丙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(339)3-Z-[1-(4-(N-乙醯基-N-(2-哌啶-1-基乙基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(340)3-Z-[1-(4-(N-乙醯基-N-(胺基羰基甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(341)3-Z-[1-(4-(N-乙醯基-N-(哌啶-1-基羰基甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(342)3-Z-[1-(4-(N-甲基-N-(胺基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(343)3-Z-[1-(4-(N-甲基-N-(甲基胺基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(344)3-Z-[1-(4-(N-甲基-N-(二甲基胺基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(345)3-Z-[1-(4-(N-甲基-N-(哌啶-1-基-羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(346)3-Z-[1-(4-(N-(2-乙基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(347)3-Z-[1-(4-(N-(2-二乙基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(348)3-Z-[1-(4-(N-(2-吡咯啶-1-基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(349)3-Z-[1-(4-(N-(2-哌啶-1-基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(350)3-Z-[1-(4-(N-(2-哌-1-基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(351)3-Z-[1-(4-(N-(2-(4-嗎啉-1-基)-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(352)3-Z-[1-(4-(N-(乙基胺基羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(353)3-Z-[1-(4-(N-(二乙基胺基羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(354)3-Z-[1-(4-(N-(吡咯啶-1-基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(355)3-Z-[1-(4-(N-(哌啶-1-基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(356)3-Z-[1-(4-(N-(哌-1-基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(357)3-Z-[1-(4-(N-((嗎啉-4-基)-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(358)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(359)3-Z-[1-(4-(3-二甲基胺基-丙氧基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(360)3-Z-[1-(4-(胺基羰基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(361)3-Z-[1-(4-(2-胺基羰基-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(362)3-Z-[1-(4-(吡啶-2-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(363)3-Z-[1-(4-(吡啶-3-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(364)3-Z-[1-(4-((N-苯乙基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(365)3-Z-[1-(4-(N-乙醯基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(366)3-Z-[1-(4-(N-乙基羰基-N-(二甲基胺基羰基-甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(367)3-Z-[1-(4-(N-甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(368)3-Z-[1-(4-羧基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(369)3-Z-[1-(4-胺基甲醯基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(370)3-Z-[1-(4-二甲基胺基甲醯基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(371)3-Z-[1-(4-四唑-5-基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(372)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(373)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(374)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(375)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(376)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(377)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(378)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(379)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(380)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(381)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(382)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(383)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(384)3-Z-[1-(4-四唑-5-基-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(385)3-Z-[1-(4-四唑-5-基-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(386)3-Z-[1-(4-四唑-5-基-苯胺基)-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(387)3-Z-[1-(4-四唑-5-基-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(388)3-Z-[1-(4-羧基-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(389)3-Z-[1-(4-羧基-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(390)3-Z-[1-(4-羧基-苯胺基)-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(391)3-Z-[1-(4-羧基-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(392)3-Z-[1-(4-(N-苯甲基-N-甲基-胺基甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(393)3-Z-[1-(4-(2,3,4,5-四氫-苯并(d)氮呯-3-基甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(394)3-Z-[1-(4-((苯并(1,3)二茂(dioxol)-5-基-甲基)-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(395)3-Z-[1-(4-(N-苯乙基-N-甲基-胺基甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(396)3-Z-[1-(4-(N-(3,4-二甲氧基-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(397)3-Z-[1-(4-(N-(4-氯-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(398)3-Z-[1-(4-(N-(4-甲基苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(399)3-Z-[1-(4-(N-(4-氟-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(400)3-Z-[1-(4-(N-(4-溴-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(401)3-Z-[1-(4-(N-(3-二甲基胺基-丙醯基)-N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(402)3-Z-[1-(4-(N-(4-二甲基胺基-丁醯基)-N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(403)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-(2-二甲基胺基-乙基磺醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(404)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-(3-二甲基胺基-丙基磺醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(405)3-Z-[1-(4-((2-羥基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(406)3-Z-[1-(4-((2-甲氧基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(407)3-Z-[1-(4-((2-二甲基胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(408)3-Z-[1-(4-((3-二甲基胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(409)3-Z-[1-(4-((N-第三丁氧基羰基-2-胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(410)3-Z-[1-(4-((N-第三丁氧基羰基-3-胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(411)3-Z-[1-(4-((2-胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(412)3-Z-[1-(4-((3-胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(413)3-Z-[1-(4-((2-乙醯基胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(414)3-Z-[1-(4-((3-乙醯基胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(415)3-Z-[1-(4-((2-甲基磺醯基胺基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(416)3-Z-[1-(4-((3-甲基磺醯基胺基-丙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(417)3-Z-[1-(4-(N-(N-第三丁氧基羰基-2-胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(418)3-Z-[1-(4-(N-(2-胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(419)3-Z-[1-(4-(N-(2-乙醯基胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(420)3-Z-[1-(4-(N-(2-甲基磺醯基胺基-乙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(421)3-Z-[1-(4-(羧基甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(422)3-Z-[1-(4-(乙氧基羰基甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(423)3-Z-[1-(4-(胺基甲醯基甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(424)3-Z-[1-(4-(二甲基胺基甲醯基-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(425)3-Z-[1-(4-(甲基胺基甲醯基-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(426)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(427)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-硝基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(428)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-乙醯基胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(429)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-甲基磺醯基胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(430)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-氰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(431)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-羥基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(432)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-甲氧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(433)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-乙氧基羰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(434)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-羧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(435)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(436)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-氯-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(437)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-氟-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(438)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-溴-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(439)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(440)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3-三氟甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(441)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3,5-二溴-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(442)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-3,5-二氯-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(443)3-Z-[1-(4-(二甲基胺基甲基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(444)3-Z-[1-(4-(二甲基胺基甲基)-3-硝基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(445)3-Z-[1-(4-(二甲基胺基甲基)-3-乙醯基胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(446)3-Z-[1-(4-(二甲基胺基甲基)-3-甲基磺醯基胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(447)3-Z-[1-(4-(二甲基胺基甲基)-3-氰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(448)3-Z-[1-(4-(二甲基胺基甲基)-3-羥基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(449)3-Z-[1-(4-(二甲基胺基甲基)-3-甲氧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(450)3-Z-[1-(4-(二甲基胺基甲基)-3-乙氧基羰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(451)3-Z-[1-(4-(二甲基胺基甲基)-3-羧基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(452)3-Z-[1-(4-(二甲基胺基甲基)-3-胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(453)3-Z-[1-(4-(二甲基胺基甲基)-3-氯-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(454)3-Z-[1-(4-(二甲基胺基甲基)-3-氟-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(455)3-Z-[1-(4-(二甲基胺基甲基)-3-溴-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(456)3-Z-[1-(4-(二甲基胺基甲基)-3-甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(457)3-Z-[1-(4-(二甲基胺基甲基)-3-三氟甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(458)3-Z-[1-(4-二甲基胺基甲基-3,5-二溴-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(459)3-Z-[1-(4-(二甲基胺基甲基)-3,5-二氯-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(460)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-[(2-羥基-乙氧基)-羰基]-2-吲哚啉酮(461)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-[(乙氧基羰基-甲氧基)-羰基]-2-吲哚啉酮(462)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-[(羧基-甲氧基)-羰基]-2-吲哚啉酮(463)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-[(胺基甲醯基-甲氧基)-羰基]-2-吲哚啉酮(464)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(2-羥基-乙氧基)-羰基]-2-吲哚啉酮(465)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(乙氧基羰基-甲氧基)-羰基]-2-吲哚啉酮(466)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(羧基-甲氧基)-羰基]-2-吲哚啉酮(467)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(胺基甲醯基-甲氧基)-羰基]-2-吲哚啉酮(468)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(2-甲氧基-乙氧基)-羰基]-2-吲哚啉酮(469)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(2-二甲基胺基-乙氧基)-羰基]-2-吲哚啉酮(470)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(2-(N-第三丁氧基羰基-胺基)-乙氧基)-羰基]-2-吲哚啉酮(471)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(2-胺基-乙氧基)-羰基]-2-吲哚啉酮(472)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-[(2,2,2-三氟乙氧基)-羰基]-2-吲哚啉酮(473)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(474)3-Z-[1-(4-(N-(咪唑-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(475)3-Z-[1-(4-(N-(酞醯亞胺-2-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(476)3-Z-[1-(4-(N-胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(477)3-Z-[1-(4-(N-乙醯基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(478)3-Z-[1-(4-(N-甲基磺醯基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(479)3-Z-[1-(4-(N-((N-(2-甲氧基乙基)-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(480)3-Z-[1-(4-(N-((N-(2-二甲基胺基乙基)-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(481)3-Z-[1-(4-(N-((二-(2-羥基乙基)-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(482)3-Z-[1-(4-第三丁氧基羰基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(483)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(484)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(485)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(486)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(487)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(488)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞乙基]-6-甲氧基羰基-2-吲哚啉酮(489)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞丙基]-6-甲氧基羰基-2-吲哚啉酮(490)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-亞丁基]-6-甲氧基羰基-2-吲哚啉酮(491)3-Z-[1-(4-第三丁基氧基羰基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(492)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(493)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(494)3-Z-[1-(4-(N-甲基-乙醯基胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(495)3-Z-[1-(4-(咪唑-4-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(496)3-Z-[1-(4-((N-(二氧戊環-2-基-甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(497)3-Z-[1-(4-(N-苯甲基-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(498)3-Z-[1-(4-(2,3,4,5-四氫-苯并(d)氮呯-3-基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(499)3-Z-[1-(4-((苯并(1,3)二茂-5-基-甲基)-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(500)3-Z-[1-(4-(N-苯乙基-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(501)3-Z-[1-(4-(N-(3,4-二甲氧基-苯甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(502)3-Z-[1-(4-(N-(4-氯-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(503)3-Z-[1-(4-(N-(4-甲基-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(504)3-Z-[1-(4-(N-(4-氟-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(505)3-Z-[1-(4-(N-(4-溴-苯甲基)-N-甲基-胺基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(506)3-Z-[1-(4-((N-(2-甲氧基-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(507)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-[(2-胺基-乙氧基)-羰基]-2-吲哚啉酮(508)3-Z-[1-(4-((N-(3-甲基磺醯基胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(509)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(510)3-Z-(1-苯胺基-1-苯基-亞甲基)-6-胺基甲醯基-2-吲哚啉酮(511)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(512)3-Z-[1-(4-(2-二乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(513)3-Z-[1-(4-(嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(514)3-Z-[1-(4-(1-氧基-硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(515)3-Z-[1-(4-(1,1-二氧基-硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(516)3-Z-[1-(4-(苯甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(517)3-Z-[1-(4-(胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(518)3-Z-[1-(4-(2,6-二甲基-哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(519)3-Z-[1-(4-(吡咯啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(520)3-Z-[1-(3-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(521)3-Z-[1-(3-(N-甲基-N-乙基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(522)3-Z-[1-(3-(甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(523)3-Z-[1-(3-羥基甲基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(524)3-Z-[1-(4-(甲氧基羰基甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(525)3-Z-[1-(4-(N-甲基磺醯基-N-(二甲基胺基羰基-甲基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(526)3-Z-[1-(4-(N-乙醯基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(527)3-Z-[1-(3,4-二甲氧基-苯胺基)-1-苯基-亞甲基]-6-照基甲醯基-2-吲哚啉酮(528)3-Z-[1-(4-(嗎啉-4-基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(529)3-Z-[1-(4-乙醯基胺基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(530)3-Z-[1-(4-胺基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(531)3-Z-[1-(4-N-甲基-N-乙醯基-胺基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(532)3-Z-[1-(4-乙氧基羰基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(533)3-Z-[1-(4-羧基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(534)3-Z-[1-(4-苯甲基胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(535)3-Z-[1-(環己基-胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(536)3-Z-[1-(4-胺基-環己基-胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(537)3-Z-[1-(N-甲基-哌啶-4-基-胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(538)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(539)3-Z-[1-(3-二甲基胺基甲基-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(540)3-Z-[1-(4-(N-甲基-N-苯甲基-胺基甲基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(541)3-Z-[1-(4-(N-甲基磺醯基-N-(2-二甲基胺基乙基)-胺基)-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(542)3-Z-[1-(4-氯-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(543)3-Z-[1-(3-氯-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(544)3-Z-[1-(4-甲氧基羰基-苯胺基)-1-甲基-亞甲基]-6-照基甲醯基-2-吲哚啉酮(545)3-Z-[1-(4-羧基-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(546)3-Z-[1-(4-甲基-3-硝基-苯胺基)-1-甲基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(547)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(548)3-Z-[1-(3-二甲基胺基甲基-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(549)3-Z-[1-(4-(N-甲基-N-苯甲基-胺基甲基)-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(550)3-Z-[1-(4-(N-甲基磺醯基-N-(2-二甲基胺基乙基)-胺基)-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(551)3-Z-[1-(4-氯-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(552)3-Z-[1-(3-氯-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(553)3-Z-[1-(4-甲氧基羰基-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(554)3-Z-[1-(4-羧基-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(555)3-Z-[1-(4-甲基-3-硝基-苯胺基)-1-丙基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(556)3-Z-[1-(3-(哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(557)3-Z-[1-(3-(二乙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(558)3-Z-[1-(3-(苯甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(559)3-Z-[1-(3-(N-甲基-N-苯甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(560)3-Z-[1-(3-(丁基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(561)3-Z-[1-(3-(胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(562)3-Z-[1-(3-(N-(3-二甲基胺基丙基)-N-甲基-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(563)3-Z-[1-(3-(N-(2-二甲基胺基乙基)-N-甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮-三氟醋酸鹽(564)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(565)3-Z-[1-(4-溴-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(566)3-Z-[1-(3-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(567)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(568)3-Z-[1-(4-[(2,6-二甲基-哌啶-1-基)甲基]-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(569)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(570)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(571)3-Z-[1-(4-第三丁氧基羰基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(572)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(573)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(574)3-Z-[1-(4-(4-甲基-哌-1-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(575)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(576)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(577)3-Z-[1-(4-(N-甲基-乙醯基胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(578)3-Z-[1-(4-(N-甲基-N-甲基磺胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(579)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(580)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(581)3-Z-[1-(4-(咪唑-4-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(582)3-Z-[1-(4-(四唑-5-基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(583)3-Z-[1-(3-(N-苯甲基-N-甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(584)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(585)3-Z-[1-(4-(吡咯啶-1-基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(586)3-Z-[1-(4-(N-甲基-N-苯乙基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(587)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(588)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(589)3-Z-[1-(4-(N-第三丁氧基羰基-N-乙基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(590)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-1-乙基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(591)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-乙基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(592)3-Z-[1-(4-(二甲基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(593)3-Z-[1-(4-[(2,6-二甲基-哌啶-1-基)-甲基]-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(594)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(595)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(596)3-Z-[1-(4-(N-二甲基胺基羰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(597)3-Z-[1-(4-(N-乙醯基-N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(598)3-Z-[1-(4-(N-二甲基胺基羰基甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(599)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(600)3-Z-[1-(4-(N-甲基胺基羰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(601)3-Z-[1-(4-((亞咪唑啶-2,4-二酮-5-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(602)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(603)3-Z-[1-(4-(N-第三丁氧基羰基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(604)3-Z-[1-(4-(2-氧基-吡咯啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(605)3-Z-[1-(4-(N-胺基羰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(606)3-Z-[1-(4-(硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(607)3-Z-[1-(4-(1,1-二氧基-硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(608)3-Z-[1-(4-(N-氰基甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(609)3-Z-[1-(4-(N-第三丁氧基羰基-乙基胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(610)3-Z-[1-(4-(N-苯甲基-N-甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(611)3-Z-[1-(4-(1-氧基-硫嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(612)3-Z-[1-(4-(2-(咪唑-4-基)-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(613)3-Z-[1-(4-(嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(614)3-Z-[1-(4-((4-甲基-哌-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(615)3-Z-[1-(4-((2-(N-苯甲基-N-甲基-胺基)-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(616)3-Z-[1-(4-環己基胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(617)3-Z-[1-(4-(吡啶-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(618)3-Z-[1-(4-(咪唑-1-基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(619)3-Z-[1-(4-(咪唑-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(620)3-Z-[1-(N-甲基-哌啶-4-基-胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(621)3-Z-[1-(4-(咪唑-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(622)3-Z-[1-(4-((4-羥基-哌啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(623)3-Z-[1-(4-((4-甲氧基-哌啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(624)3-Z-[1-(4-苯甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(625)3-Z-[1-(4-(N-(3-三氟乙醯基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(626)3-Z-[1-(4-第三丁氧基羰基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(627)3-Z-[1-(4-第三丁氧基羰基-苯胺基)-1-乙基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(628)3-Z-[1-(4-(4-第三丁氧基羰基-哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(629)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(630)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-3-硝基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(631)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(632)3-Z-[1-(4-((3-(N-苯甲基-N-甲基-胺基)-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(633)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-3-氯-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(634)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(635)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(636)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(637)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丁醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(638)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-異丁醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(639)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-苯甲醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(640)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-3-胺基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(641)3-Z-[1-(4-(4-羥基甲基-哌啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(642)3-Z-[1-(4-(2-(4-羥基-哌啶-1-基)-乙基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(643)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丙基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(644)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-丁基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(645)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-苯基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(646)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-苯甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(647)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(648)3-Z-[1-(4-((咪唑啶-2,4-二酮-5-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(649)3-Z-[1-(4-((3-羥基-吡咯啶-1-基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(650)3-Z-[1-(4-(環己基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(651)3-Z-[1-(4-(環己基-羰基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(652)3-Z-[1-(4-二乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(653)3-Z-[1-(4-(N-(正己基)-N-甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(654)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(呋喃-2-羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(655)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(2-甲氧基-苯甲醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(656)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(吡啶-3-羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(657)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-(苯基-乙醯基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(658)3-Z-[1-(4-(N-乙基-N-甲基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮-(659)3-Z-[1-(4-(咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(660)3-Z-[1-(4-(1-乙基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(661)3-Z-[1-(4-(1-苯甲基-咪唑-2-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(662)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-異丙基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(663)3-Z-[1-(4-(N-(哌啶-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(664)3-Z-[1-(4-(N-(嗎啉-4-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(665)3-Z-[1-(4-(N-((4-苯甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(666)3-Z-[1-(4-(N-(吡咯啶-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(667)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-3-溴-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(668)3-Z-[1-(4-(5-甲基-咪唑-4-基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(669)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(670)3-Z-[1-(4-(N-((2-二甲基胺基-乙基)-羰基)-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(671)3-Z-[1-(4-(N-丁基-N-第三丁氧基羰基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(672)3-Z-[1-(4-(N-((N-胺基羰基甲基-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(673)3-Z-[1-(4-(N-((N-苯甲基-N-甲基-胺基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(674)3-Z-[1-(4-(N-(二-(2-甲氧基乙基)-胺基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(675)3-Z-[1-(4-(N-((2-(4-第三丁氧基羰基-哌-1-基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(676)3-Z-[1-(4-(N-((2-(哌啶-1-基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(677)3-Z-[1-(4-(N-((2-(N-苯甲基-N-甲基-胺基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(678)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(679)3-Z-[1-(4-(N-(哌啶-1-基-甲基羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(680)3-Z-[1-(4-(N-((4-第三丁氧基羰基-哌-1-基)-甲基羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(681)3-Z-[1-(4-(N-((N-苯甲基-N-甲基-胺基)-甲基羰基)-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(682)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(683)3-Z-[1-(4-(N-(哌啶-1-基-甲基羰基)-N-苯甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(684)3-Z-[1-(4-(1,2,4-三唑-2-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(685)3-Z-[1-(4-(1,2,3-三唑-2-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(686)3-Z-[1-(4-(1,2,3-三唑-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(687)3-Z-[1-(4-((N-胺基羰基甲基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(688)3-Z-[1-(4-((二-(2-甲氧基-乙基)-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(689)3-Z-[1-(4-(比咯啶-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(690)3-Z-[1-(4-((二-(2-羥基-乙基)-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(691)3-Z-[1-(4-((N-乙氧基羰基甲基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(692)3-Z-[1-(4-(氮呾-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(693)3-Z-[1-(4-(N-丙基-N-第三丁氧基羰基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(694)3-Z-[1-(4-((N-(2-(2-甲氧基-乙氧基)-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(695)3-Z-[1-(4-((N-(第三丁氧基羰基-3-胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(696)3-Z-[1-(4-((N-(甲基胺基甲醯基-甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(697)3-Z-[1-(4-((N-(二甲基胺基甲醯基-甲基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(698)3-Z-[1-(4-甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(699)3-Z-[1-(4-((N-丙基-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(700)3-Z-[1-(4-((N-(2-羥基-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(701)3-Z-[1-(4-((N-(2-二甲基胺基-乙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(702)3-Z-[1-(4-((N-(3-二甲基胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(703)3-Z-[1-(4-(3-氧基-哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(704)3-Z-[1-(4-羧基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(705)3-Z-[1-(4-胺基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(706)3-Z-[1-(4-乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(707)3-Z-[1-(4-羧基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(708)3-Z-[1-(4-羧基-苯胺基)-1-乙基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(709)3-Z-[1-(4-(哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲采啉酮(710)3-Z-[1-(4-丁基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(711)3-Z-[1-(4-乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙氧基羰基-2-吲哚啉酮(712)3-Z-[1-(4-乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-胺基甲醯基-2-吲哚啉酮(713)3-Z-[1-(4-(N-(哌-1-基-甲基羰基)-N-異丙基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(714)3-Z-[1-(4-(N-((2-(哌-1-基)-乙基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(715)3-Z-[1-(4-(N-丙基-胺基甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(716)3-Z-[1-(4-((N-(3-胺基-丙基)-N-甲基-胺基)-甲基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(717)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(718)3-Z-[1-(3-氰基-4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(719)3-Z-[1-(3-甲氧基-4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(720)3-Z-[1-(4-(N-胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(721)3-Z-[1-(4-(N-(N-(2-二甲基胺基-乙基)-N-甲基-胺基甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(722)3-Z-[1-(4-(N-(二-(2-羥基-乙基)-胺基甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(723)3-Z-[1-(4-(N-(咪唑-1-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(724)3-Z-[1-(4-(N-二甲基胺基甲基羰基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(725)3-Z-[1-(4-(N-((4-甲基-[1,4]二氮-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(726)3-Z-[1-(4-(N-((1-甲基-哌啶-4-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(727)3-Z-[1-(2,3-二甲基-4-(N-((4-甲基-哌-1-基)-甲基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(728)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(729)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(730)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(731)3-Z-[1-(4-(N-((3-二甲基胺基-丙基)-胺基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(732)3-Z-[1-苯胺基-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(733)3-Z-[1-(4-(N-甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(734)3-Z-[1-環己基胺基-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(735)3-Z-[1-(4-(4-甲基哌-1-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(736)3-Z-[1-(4-甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(737)3-Z-[1-(4-(嗎啉-4-基-甲基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(738)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(739)3-Z-[1-(4-(二-(2-羥基-乙基)-胺基-甲基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(740)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(741)3-Z-[1-(4-(N-(嗎啉-4-基-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(742)3-Z-[1-(4-(N-(N-(2-二甲基胺基-乙基)-N-甲基-胺基甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(743)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(744)3-Z-[1-環己基胺基-1-苯基-亞甲基]-6-羧基-2-吲哚啉酮(745)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(746)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(747)3-Z-[1-(4-(1-甲基-咪唑-2-基)-苯胺基)-1-(3-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(748)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-(4-(2-羧基-乙基)-苯基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(749)3-Z-[1-(4-(2-二甲基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(750)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(751)3-Z-[1-(1-甲基-哌啶-4-基)-胺基-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(752)3-Z-[1-(反式-4-二甲基胺基-環己基胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(753)3-Z-[1-(4-(2-二乙基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(754)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-丙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(755)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(756)3-Z-[1-環己基胺基-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(757)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(758)3-Z-[1-(3-二乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(759)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(760)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(761)3-Z-[1-苯胺基-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(762)3-Z-[1-(4-乙基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(763)3-Z-[1-(4-((2-二乙基胺基-乙基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(764)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(765)3-Z-[1-(4-(N-甲基-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(766)3-Z-[1-(4-甲氧基羰基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(767)3-Z-[1-(4-羧基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(768)3-Z-[1-(4-(N-(二甲基胺基-羰基甲基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(769)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(770)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(771)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(772)3-Z-[1-(4-(2-二甲基胺基-乙氧基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(773)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(774)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(775)3-Z-[1-(4-(N-(2-二甲基胺基-乙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(776)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(777)3-Z-[1-(4-胺基甲醯基-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(778)3-Z-[1-(4-(N-(2-二乙基胺基-乙基)-胺基甲醯基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(779)3-Z-[1-(4-((4-甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(780)3-Z-[1-(4-((4-甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(781)3-Z-[1-(4-((4-乙基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(782)3-Z-[1-(4-(N-乙基-N-(2-二甲基胺基-乙基)-胺基甲醯基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(783)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-二乙基胺基甲醯基-2-吲哚啉酮(784)3-Z-[1-(4-((順式-3,5-二甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(785)3-Z-[1-(4-((4-乙基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(786)3-Z-[1-(4-(N-(2-二乙基胺基-乙基)-胺基甲醯基)-苯胺基)-1-苯基-亞甲基]-6-乙基甲基胺基甲醯基-2-吲哚啉酮(787)3-Z-[1-(4-((順式-3,5-二甲基-哌-1-基)-羰基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(788)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-甲基磺醯基-胺基)-苯胺基)-1-苯基-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(789)3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(790)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(791)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-亞甲基]-6-甲氧基羰基-2-吲哚啉酮(792)3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(793)3-Z-[1-(4-二甲基胺基甲基-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(794)3-Z-[1-(4-(哌啶-1-基-甲基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮(795)3-Z-[1-(4-(N-(3-二甲基胺基-丙基)-N-乙醯基-胺基)-苯胺基)-亞甲基]-6-乙基胺基甲醯基-2-吲哚啉酮及其互變體,立體異構物,或生理可接受鹽。
通式I化合物,其互變體,立體異構物,或生理可接受鹽適合用於預防或治療一種選自下列之特定纖維化疾病:慢性阻塞性肺病(COPD),慢性支氣管炎,及肺氣腫中肺組織之纖維化及重新塑造(remodeling);肺纖維化及具有纖維化成份之肺疾病包括,但不限於,自發性肺纖維化(IPF),巨細胞間質肺炎(GIP),肉狀瘤病,囊腫纖維化,呼吸窘迫徵候群(ARDS),肉芽腫病,矽肺病,藥物誘發之肺纖維化(例如博萊黴素(bleomycin),雙氯亞硝基脲,環磷醯胺,乙胺碘夫酮(amiodarone),普魯卡因醯胺,青黴胺,金或硝基呋喃妥因(nitrofurantoin)藥物所誘發者),石綿沈著病,全身性硬皮病;氣喘中纖維化及重新塑造;類風濕性關節炎中纖維化;病毒所誘發之肝硬化,例如C型肝炎;放射所誘發之纖維化;血管造形術後再狹窄;腎病,包括慢性絲球性腎炎,接受環孢靈(cyclosporine)之病人之腎纖維化,及由於高血壓造成之腎纖維化;具有纖維化成份之皮膚疾病,包括,但不限於,硬皮病,肉狀瘤病,全身性紅斑狼瘡;過度結疤。
在根據本發明之一個較佳具體實施例中,通式I之化合物,其互變體,立體異構物,或生理可接受鹽特別適合用於預防或治療自發性肺纖維化。
下列實驗結果例示本發明,並非限制其範圍。
在下列實例B1之實驗中,實例A表化合物3-Z-[1-(4-(N-二甲基胺基甲基羰基-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,其為較佳化合物名單之化合物(m)(A)一種代表性化合物對於博萊黴素所誘發之肺纖維化之肺形態學之影響。
材料及方法博萊黴素硫酸鹽(博萊黴素HEXALT M
)由一間當地藥房購買。
博萊黴素施用及治療方法所有實驗係根據德國動物福利之指導,由合格之動物工作者進行,及由負責機構核准。雄性威士塔(Wistar)鼠在暴露於麻醉藥異氟烷(Isofluorane)5分鐘後使用一支導管(0.5毫米內徑,1.0毫米外徑)經由鼻通道經氣管內注射博萊黴素硫酸鹽(10U/公斤體重於300微升鹽水中)或僅鹽水(鹽水對照)。次日,鼠以實例A(化合物(m))或鹽水懸浮於1毫升0.1%纖維素羥乙基醚(Natrosol)中(媒液對照)口服治療。
探查總共25隻鼠,分組並處理如表1所示。
博萊黴素滴入後21天,鼠以NarcorenT M
(戊巴比妥(Pentobarbital)鈉,Rhone Merieux)之致死腹膜內注射殺死。然後取出肺,吸乾,一半於液態氮中迅速冷凍,貯存在-80℃。另一半固定於4%福馬林(formalin)中用於其後石蠟包埋及組織學。
組織學固定於4%福馬林中之肺組織包埋於石蠟中,使用一個顯微鏡用薄片切片機(microtome)(Leica SM200R)切5微米切片,放於塗覆聚-L-離胺酸之玻片上。然後切片在玻片上乾燥(60℃ 2小時),然後在室溫冷卻。使用馬森(Masson's)三色(Trichrome)染色評估膠原之沉積。
結果圖1A顯示經氣管內接受鹽水及媒液替代博萊黴素之對照組所獲得之結果。
經氣管內以博萊黴素及媒液處理之鼠發生嚴重之肺纖維化,如圖1B所示。肺泡由纖維母細胞及細胞外基質大量替代,正常肺結構幾乎消滅。
博萊黴素處理之鼠每天以50毫克/公斤實例A(化合物(m))治療,在此模型中顯示肺纖維化不斷地幾乎完全恢復。典型實例示於圖1C。肺泡完整,極少或無纖維母細胞浸潤或細胞外基質沉積發生。正常肺結構維持,由圖1C與圖1A之比較證明。
(B)一種代表性化合物對於博萊黴素誘發肺纖維化後纖維化標記基因表現之影響。
mRNA之萃取及cDNA之合成用於基因表現探查之一部份冷凍肺組織使用一個滅菌小刀切成小片。然後約100毫克組織放入一支2毫升伊潘杜夫(Eppendorf)管中,1.5毫升Trizol(Invitrogen)加入。然後一粒滅菌之碳化鎢珠粒(Qiagen)加入管中,管放入一個Retsch MM300組織崩解器(Qiagen)中於30.0 Hz頻率歷時8分鐘。然後珠粒移除,樣品在12000 rpm離心10分鐘以移除組織碎屑。RNA係使用製造者方法之修釋法供應Trizol萃取。簡言之,0.3毫升氯仿加入管中,管劇烈搖動,然後在室溫培育5分鐘,然後管在4℃於12000 rpm離心15分鐘。然後收集上層無色水相,加入750微升異丙醇中。然後劇烈搖動,在-80℃貯存過夜。然後樣品在室溫培育15分鐘,然後在4℃於12000 rpm離心40分鐘。然後上清液移除,500微升70%乙醇加入以清洗沉積粒子,然後樣品在4℃於12000 rpm離心10分鐘,此步驟重複二次,然後沉積粒子乾燥10-15分鐘。最後沉積粒子再懸浮於20微升不含RNA酶之水中,貯存於-80℃。然後各樣品之濃度使用一個光譜光度計測量。
使用SuperscriptT M
III(Invitrogen,Paisley,UK)RT第一股合成套組,各2微克mRNA樣品使用製造者方法之修釋法逆向轉錄。簡言之,2微克RNA,1微升任意六聚體引子(primers)(50奈克(ng)/微升),1微升dNTP混合物(10 mM)之混合物與DEPC處理之水組成10微升,在65℃培育5分鐘,然後放在冰上5分鐘。然後2微升RT緩衝液(10X),4微升MgCl2
(25mM),2微升DTT(0.1M),1微升RNaseOUTT M
(40U/微升),及1微升SuperScriptT M
III酶(200U/微升)加入各反應混合物中,混合物放入一個熱循環器(Applied Biosystems)中,在下列條件下:25℃歷10分鐘,50℃歷50分鐘,及85℃歷5分鐘,然後1微升RNA酶H加入,在37℃培育20分鐘。合成之cDNA係使用假定RT反應完全轉錄所有mRNA至cDNA及濃度為100奈克/徵升稀釋至5奈克/微升。
使用實際時間PCR探查基因表現各樣品中基因表現係使用Applied Biosystems 7700序列偵測系統探查。18S內生性對照及TGFb1之引子係以預先發展之分析試劑套組購買,而前膠原I及纖維連接蛋白(fibronectin)之引子及探針(參見下表2)係使用Primer ExpressT M
(Applied Biosystems)設計,確保各組中引子或探針之至少一個與一個內作用基因(intron)/外作用基因(exon)接頭重疊,因此去除放大cDNA樣品中任何污染基因組DNA之可能性。購買之PDARs亦僅放大cDNA。
實際時間PCR係在25微升反應混合物中進行,每一反應混合物使用25奈克(5微升)cDNA。購買一種定量PCR核心套組(Eurogentec),如下組成一種主混合物用於100個反應:500微升10X反應緩衝液,500微升MgCl2
(50 mM),200微升dNTP混合物溶液(5 mM),25微升Hot Goldstar酶,75微升18S PDAR,22.5微升正向引子,22.5微升逆向引子,15微升探針,及640微升DEPC處理之水。然後20微升此主混合物加入25奈克(5微升)目標cDNA中。各分析進行三組。
為定量基因表現,對於各組引子建立一個標準曲線,包括於各板上。標準係由所有探查之cDNA之混合物組成;此cDNA混合物一系列稀釋10、20、50、100、100倍。一個標準曲線係由所獲得之CT
(放大達到一定閾之週期)對於稀釋因子之LOG1 0
建立。曲線係對於目標基因及18S rRNA內生性對照繪製。然後各樣品之二目標之CT
值使用標準曲線轉化為稀釋倍數,目標基因值對於18S基因值標準化。
統計所有統計分析係使用GraphPad Prism V 4.02軟體進行。使用一種非參數T-試驗(Mann-Whitney U試驗)比較,顯著值視為p0.05。
結果結果示於圖2(前膠原I)及3(纖維連接蛋白)。各數據點表由一隻鼠之肺分離之RNA。
經氣管內施用博萊黴素及隨後僅以媒液處理顯示肺內前膠原I及纖維連接蛋白之基因表現大量增加,如圖2及3所示,與圖1B所示組織學上明顯肺纖維化一致。
博萊黴素處理之鼠每天以50毫克/公斤實例A(化合物(m))治療顯示此模型中纖維化標記基因之表現顯著(p0.0001)抑制,如圖2及3所示。
此實驗證明纖維化標記基因之表現及因此細胞外基質之沉積可以實例A(化合物(m))治療而大大減少。
在下列實例B2之實驗中,使用化合物3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮,其為較佳化合物名單之化合物(u)。
使用之所有方法相同於實例B1之實驗中所述之方法,然而使用化合物(u)替代化合物(m)。
(A)一種代表性化合物對於博萊黴素所誘發之肺纖維化之肺形態學之影響。
樣品係由上述實驗實例B1(A)之表1所示處理之鼠製備。
結果圖4A顯示經氣管內接受鹽水及媒液替代博萊黴素之對照組所獲得之結果。
經氣管內以博萊黴素及媒液處理之鼠發生嚴重之肺纖維化,如圖4B所示。肺泡由纖維母細胞及細胞外基質大量替代,正常肺結構幾乎消滅。
博萊黴素處理之鼠每天以50毫克/公斤化合物(u)治療,在此模型中顯示肺纖維化不斷地幾乎完全恢復。典型實例示於圖4C。肺泡完整,極少或無纖維母細胞浸潤或細胞外基質沉積發生。正常肺結構維持,由圖4C與圖4A之比較證明。
(B)一種代表性化合物對於博萊黴素誘發肺纖維化後纖維化標記基因表現之影響。
此實驗係使用上述實例B1(B)所示之方法進行。
結果示於圖5(前膠原I)及圖6(TGFb)。各數據點表由一隻鼠之肺分離之RNA。
經氣管內施用博萊黴素及隨後僅以媒液處理顯示肺內前膠原I及TGFb之基因表現大量增加,如圖5及6所示,與圖1B所示組織學上明顯肺纖維化一致。
博萊黴素處理之鼠每天以50毫克/公斤化合物(u)治療顯示此模型中纖維化標記基因之表現顯著(p≦0.0001)抑制,如圖5及6所示。
此實驗證明纖維化標記基因之表現及因此細胞外基質之沉積可以本發明之另一代表性化合物,即化合物(u),治療而大大減少。
由生物學性質,根據本發明之化合物可單獨治療使用或與其他藥理學上活性化合物連合使用。該藥理學上活性化合物可為例如在治療纖維化中亦為藥理學上活性之化合物。該藥理學上活性化合物亦可為具有分泌溶解(secretolytic),支氣管擴張(broncholytic)及/或抗發炎活性之物質。
在根據本發明之一個較佳具體實施例中,該藥理學上活性化合物較佳選自抗膽素激導劑,β-2擬似物,類固醇,PDE-IV抑制劑,p38 MAP激酶抑制劑,NK1
拮抗劑,LTD4拮抗劑,EGFR抑制劑,及內皮素拮抗劑。
抗膽素激導劑較佳可選自硫托品(tiotropium)鹽,托品(oxitropium)鹽,氟托品(flutropium)鹽,衣巴托品(ipratropium)鹽,糖吡咯(glycopyrronium)鹽,及托螺吡咯(trospium)鹽。
β-2擬似物較佳可選自例如US 4,460,581中所揭示之β-2擬似物,其併入本文供參考。
PDE-IV抑制劑較佳可選自因普葉素(enprofyllin),茶葉鹼(theophyllin),羅福米拉(roflumilast),阿里福洛(ariflo)(西洛米拉(cilomilast)),CP-325,366,BY343,D-4396(Sch-351591),AWD-12-281(GW-842470),N-(3,5-二氯-1-氧基-吡啶-4-基)-4-二氟甲氧基-3-環丙基甲氧基苯甲醯胺,NCS-613,蒲馬芬亭(pumafentine),(-)-對-[(4aR*
,10bS*
)-9-乙氧基-1,2,3,4,4a,10b-六氫-8-甲氧基-2-甲基苯并[s][1,6]萘啶-6-基]-N,N-二異丙基苯甲醯胺,(R)-(+)-1-(4-溴苯甲基)-4-[(3-環戊基氧基)-4-甲氧基苯基]-2-吡咯啶酮,3-(環戊基氧基-4-甲氧基苯基)-1-(4-N'-[N-2-氰基-S-甲基-異硫脲基]苯甲基)-2-吡咯啶酮,順式[4-氰基-4-(3-環戊基氧基-4-甲氧基苯基)環己烷-1-碳酸],2-甲氧羰基-4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)-環己烷-1-酮,順式[4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環己烷-1-醇],(R)-(+)-乙基[4-(3-環戊基氧基-4-甲氧基苯基)亞吡咯啶-2-基]醋酸酯,(S)-(-)-乙基[4-(3-環戊基氧基-4-甲氧基苯基)亞吡咯啶-2-基]醋酸酯,CDP 840,Bay-198004,D-4418,PD-168787,T-440,T-2585,芳葉素(arofyllin),阿替卓元(atizoram),V-11294A,Cl-1018,CDC-801,CDC-3052,D-22888,YM-58997,Z-15370,9-環戊基-5,6-二氫-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-a]吡啶,及9-環戊基-5,6-二氫-7-乙基-3-(第三丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-a]吡啶。這些化合物,如可得,可以其消旋物,對映體,或非對映體之形式,或以其藥理學上可接受之酸加成鹽形式,或以其溶劑化物及/或水合物形式使用。
類固醇較佳可選自強的松龍(prednisolone),強的松(pred-nisone),布替索可丙酸鹽(butixocortpropionate),RPR-106541,氟尼索利(flunisolid),氯地米松(beclomethasone),去炎松(triamcinolone),布地松(budesonid),氟替可松(flutica-sone),莫米它松(mometasone),西可來松(ciclesonid),羅福彭尼(rofleponid),ST-126,地塞米松(dexamethasone),6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羥基-16α-甲基-3-氧基-雄-1,4-二烯-17β-硫羧酸(S)-氟甲基酯,及6α,9α-二氟-11β-羥基-16α-甲基-3-氧基-17α-丙醯基氧基-雄-1,4-二烯-17β-硫羧酸(S)-(2-氧基-四氫呋喃-3S-基)酯。這些化合物,如可得,可以其消旋物,對映體,或非對映體之形式,或以其藥理學上可接受之酸加成鹽形式,或以其溶劑化物及/或水合物形式使用。
P38 MAP激酶抑制劑較佳可選自例如US 5,716,972、US 5,686,455、US 5,656,644、US 5,593,992、US 5,593,991、US 5,663,334、US 5,670,527、US 5,559,137、US 5,658,903、US 5,739,143、US 5,756,499、US 6,277,989、US 6,340,685、及US 5,716,955、及PCT申請案WO 92/12154、WO 94/19350、WO 95/09853、WO 95/09851、WO 95/09847、WO 95/09852、WO 97/25048、WO 97/25047、WO 97/33883、WO 97/35856、WO 97/35855、WO 97/36587、WO 97/47618、WO 97/16442、WO 97/16441、WO 97/12876、WO 98/25619、WO 98/06715、WO 98/07425、WO 98/28292、WO 98/56377、WO 98/07966、WO 98/56377、WO 98/22109、WO 98/24782、WO 98/24780、WO 98/22457、WO 98/52558、WO 98/52559、WO 98/52941、WO 98/52937、WO 98/52940、WO 98/56788、WO 98/27098、WO 98/47892、WO 98/47899、WO 98/50356、WO 98/32733、WO 99/58523、WO 99/01452、WO 99/01131、WO 99/01130、WO 99/01136、WO 99/17776、WO 99/32121、WO 99/58502、WO 99/58523、WO 99/57101、WO 99/61426、WO 99/59960、WO 99/59959、WO 99/00357、WO 99/03837、WO 99/01441、WO 99/01449、WO 99/03484、WO 99/15164、WO 99/32110、WO 99/32111、WO 99/32463、WO 99/64400、WO 99/43680、WO 99/17204、WO 99/25717、WO 99/50238、WO 99/61437、WO 99/61440、WO 00/26209、WO 00/18738、WO 00/17175、WO 00/20402、WO 00/01688、WO 00/07980、WO 00/07991、WO 00/06563、WO 00/12074、WO 00/12497、WO 00/31072、WO 00/31063、WO 00/23072、WO 00/31065、WO 00/35911、WO 00/39116、WO 00/43384、WO 00/41698、WO 00/69848、WO 00/26209、WO 00/63204、WO 00/07985、WO 00/59904、WO 00/71535、WO 00/10563、WO 00/25791、WO 00/55152、WO 00/55139、WO 00/17204、WO 00/36096、WO 00/55120、WO 00/55153、WO 00/56738、WO 1/21591、WO 01/29041、WO 01/29042、WO 01/62731、WO 01/05744、WO 01/05745、WO 01/05746、WO 01/05749、WO 01/05751、WO 01/27315、WO 01/42189、WO 01/00208、WO 01/42241、WO 01/34605、WO 01/47897、WO 01/64676、WO 01/37837、WO 01/38312、WO 01/38313、WO 01/36403、WO 01/38314、WO 01/47921、WO 01/27089、DE 19842833,及JP 2000 86657中所揭示之p38激酶抑制劑,其揭示全部併入本文供參考。其中特別有利於根據本發明合併者為US 6,277,989、US 6,340,685、WO 00/12074、WO 00/12497、WO 00/59904、WO 00/71535、WO 01/64676、WO 99/61426、WO 00/10563、WO 00/25791、WO 01/37837、WO 01/38312、WO 01/38313、WO 01/38314、WO 01/47921、WO 99/61437、WO 99/61440、WO 00/17175、WO 00/17204、WO 00/36096、WO 98/27098、WO 99/00357、WO 99/58502、WO 99/64400、WO 99/01131、WO 00/43384、WO 00/55152、WO 00/55139,及WO 01/36403中所揭示之p38抑制劑。在一個較佳具體實施例中,p38激酶抑制劑係選自WO 99/01131中所揭示之下式(I)之化合物
其中R1
為4-吡啶基,嘧啶基,4-嗒基,1,2,4-三井-5-基,喹啉基,異喹啉基,或喹唑啉-4-基環,該環經Y-Ra
及選擇性經另一個選自C1 - 4
烷基,鹵素,羥基,C1 - 4
烷氧基,C1 - 4
烷基硫基,C1 - 4
烷基亞磺醯基,CH2
OR1 2
,胺基,一及二-C1 - 6
烷基取代之胺基,N-雜環基環,該環具有5至7員及選擇性含有另一個雜原子選自氧,硫,或NR1 5
,N(R1 0
)C(O)Rb
或NHRa
之獨立取代基取代;Y為氧或硫;R4
為苯基,萘-1-基或萘基,或雜芳基,其選擇性經一或二個各獨立選擇之取代基取代,對於4-苯基,4-萘-1-基,5-萘-2-基,或6-萘-2-基取代基,為鹵素,氰基,硝基,C(Z)N-R7
R1 7
,C(Z)OR1 6
,(CR1 0
R2 0
)v
COR1 2
,SR5
,SOR5
,OR1 2
,經鹵取代之C1 - 4
烷基,C1 - 4
烷基,ZC(Z)R1 2
,NR1 0
C(Z)R1 6
,或(CR1 0
R2 0
)v
NR1 0
R2 0
,對於其他取代位置,為鹵素,氰基,C(Z)NR1 3
R1 4
,C(Z)OR3
,(CR1 0
R2 0
)m "
COR3
,S(O)m
R3
,OR3
,經鹵取代之C1 - 4
烷基,C1 - 4
烷基,(CR1 0
R2 0
)m "
R1 0
C(Z)R3
,NR1 0
S(O)m '
R8
,NR1 0
S(O)m '
NR7
R1 7
,ZC(Z)R3
,或(CR1 0
R2 0
)m "
-NR1 3
R1 4
;Z為氧或硫;n為一個1至10之整數;m為0,或整數1或2;m'為整數1或2;m"為0,或一個1至5之整數;v為0,或一個1至2之整數;R2
為-C(H)(A)(R2 2
);A為選擇性經取代之芳基,雜環基,或雜芳基環,或A為經取代之C1 - 1 0
烷基;R2 2
為選擇性經取代之C1 - 1 0
烷基;Ra
為芳基,芳基C1 - 6
烷基,雜環基,雜環基C1 - 6
烷基,雜芳基,雜芳基C1 - 6
烷基,其中這些基各可選擇性經取代;Rb
為氫,C1 - 6
烷基,C3 - 7
環烷基,芳基,芳基C1 - 4
烷基,雜芳基,雜芳基C1 - 4
烷基,雜環基,或雜環基C1 - 4
烷基,其中這些基各可選擇性經取代;R3
為雜環基,雜環基C1 - 1 0
烷基,或R8
;R5
為氫,C1 - 4
烷基,C2 - 4
烯基,C2 - 4
炔基,或NR7
R1 7
,排除SR5
為SNR7
R1 7
及SOR5
為SOH;R6
為氫,一個醫藥可接受之陽離子,C1 - 1 0
烷基,C3 - 7
環烷基,芳基,芳基C1 - 4
烷基,雜芳基,雜芳基C1 - 4
烷基,雜環基,芳基,或C1 - 1 0
烷醯基;R7
及R1 7
各獨立選自氫或C1 - 4
烷基,或R7
及R1 7
與相接之氮一起形成一個5至7員雜環,該環選擇性含有另一個雜原子選自氧,硫,或NR1 5
;R8
為C1 - 1 0
烷基,經鹵取代之C1 - 1 0
烷基,C2 - 1 0
烯基,C2 - 1 0
炔基,C3 - 7
環烷基,C5 - 7
環烯基,芳基,芳基C1 - 1 0
烷基,雜芳基,雜芳基C1 - 1 0
烷基,(CR1 0
R2 0
)n
OR1 1
,(CR1 0
R2 0
)n
-S(O)m
R1 8
,(CR1 0
R2 0
)n
NHS(O)2
R1 8
,(CR1 0
R2 0
)n
NR1 3
R1 4
;其中芳基,芳基烷基,雜芳基,雜芳基烷基可選擇性經取代;R9
為氫,C(Z)R1 1
或選擇性經取代之C1 - 1 0
烷基,S(O)2
-R1 8
,選擇性經取代之芳基或選擇性經取代之芳基C1 - 4
烷基;R1 0
及R2 0
各獨立選自氫或C1 - 4
烷基;R1 1
為氫,C1 - 1 0
烷基,C3 - 7
環烷基,雜環基,雜環基C1 - 1 0
烷基,芳基,芳基C1 - 1 0
烷基,雜芳基,或雜芳基C1 - 1 0
烷基,其中這些基可選擇性經取代;R1 2
為氫或R1 6
;R1 3
及R1 4
各獨立選自氫或選擇性經取代之C1 - 4
烷基,選擇性經取代之芳基,或選擇性經取代之芳基C1 - 4
烷基,或與相接之氮一起形成一個5至7員雜環,該環選擇性含有另一個雜原子選自氧,硫,或NR9
;R1 5
為R1 0
或C(Z)-C1 - 4
烷基;R1 6
為C1 - 4
烷基,經鹵取代之C1 - 4
烷基,或C3 - 7
環烷基;R1 8
為C1 - 1 0
烷基,C3 - 7
環烷基,雜環基,芳基,芳基C1 - 1 0
烷基,雜環基,雜環基-C1 - 1 0
烷基,雜芳基,或雜芳基C1 - 1 0
烷基;或其醫藥可接受鹽。
NK1
拮抗劑較佳可選自N-[2-(3,5-雙-三氟甲基-苯基)-乙基]-2-{4-環丙基甲基-哌-1-基}-N-甲基-2-苯基-乙醯胺(BIIF 1149)、CP-122721、FK-888、NKP 608C、NKP 608A、CGP 60829、SR 48968(Saredutant)、SR 140333(Nolpitan-tium苯磺酸鹽/氯化物)、LY 303 870(Lanepitant)、MEN-114 20(Nepadutant)、SB 223412、MDL-105172A、MDL-103896、MEN-11149、MEN-11467、DNK 333A、SR-144190、YM-492 44、YM-44778、ZM-274773、MEN-10930、S-19752、紐若龍(Neuronorm)、YM-35375、DA-5018、阿普利比(Aprepitant)(MK-869)、L-754030、CJ-11974、L-758298、DNK-33A、6b-I、CJ-11974、TAK-637、GR 205171,及下通式(VIII)之芳基甘胺酸醯胺衍生物
其中R1
及R2
與相接之N原子一起形成一個下式之環
其中r及s獨立表數目2或3;R6
表H,-C1
-C5
-烷基,C3
-C5
-烯基,丙炔基,羥基(C2
-C4
)烷基,甲氧基(C2
-C4
)烷基,二-(C1
-C3
)烷基胺基(C2
-C4
)烷基,胺基(C2
-C4
)烷基,胺基,二-(C1
-C3
)烷基胺基,一氟至全氟(C1
-C2
)烷基,N-甲基哌啶基,吡啶基,嘧啶基,吡基,或嗒基,R7
表下列(a)至(d)定義之任一基:(a)羥基(b)4-哌啶基哌啶基
其中R1 6
及R1 7
獨立表H,(C1
-C4
)烷基,(C3
-C6
)環烷基,羥基(C2
-C4
)烷基,二羥基(C2
-C4
)烷基,(C1
-C3
)烷氧基(C2
-C4
)烷基,苯基(C1
-C4
)烷基,或二-(C1
-C3
)烷基胺基(C2
-C4
)烷基,及R8
表H,選擇性呈對映體,對映體之混合物,或消旋物之形式。
上述式(VIII)化合物述於WO 96/32386,WO 97/32865,及WO 02/32865。這些國際專利申請案之揭示全部併入本文供參考。
LTD4拮抗劑較佳選自蒙特魯卡司(montelukast),1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羥基-2-丙基)苯基)硫基)甲基)環丙烷-醋酸鹽,1-(((1(R)-3-(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羥基-1-甲基乙基)苯基)丙基)硫基)甲基)環丙烷-醋酸鹽,普元魯卡司(pranlukast),扎佛魯卡司(zafirlukast),[2[[2-(4-第三丁基-2-噻唑基)-5-苯并呋喃基]氧基甲基]苯基]醋酸鹽,MCC-847(ZD-3523),MN-001,MEN-91507(LM-1507),VUF-5078,VUF-K-8707,及L-733321。這些化合物,如可得,可以其消旋物,對映體,或非對映體之形式,或以其藥理學上可接受之酸加成鹽形式,或以其溶劑化物及/或水合物形式使用。
EGFR抑制劑較佳可選自4-[(3-氯-4-氟苯基)胺基]-6-{[4-(嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉(chinazoline),4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二乙基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-{[4-(嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{[4-((R)-6-甲基-2-氧基-嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{[4-((R)-6-甲基-2-氧基-嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-[(S)-(四氫呋喃-3-基)氧基]-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{[4-((R)-2-甲氧基甲基-6-氧基-嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基]胺基)-6-[2-((S)-6-甲基-2-氧基-嗎啉-4-基)-乙氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-胺基]-1-氧基-2-丁烯-1-基}胺基)-7-環丙基甲氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-環戊基氧基-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-{[4-(N,N-雙-(2-甲氧基-乙基)-胺基)-1-氧基-2-丁烯-1-基]胺基}-7-環丙基甲氧基-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-({4-[N-(2-甲氧基-乙基)-N-乙基-胺基]-1-氧基-2-丁烯-1-基}胺基)-7-環丙基甲氧基-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-胺基]-1-氧基-2-丁烯-1-基}胺基)-7-環丙基甲氧基-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-({4-[N-(四氫哌喃-4-基)-N-甲基-胺基]-1-氧基-2-丁烯-1-基}胺基)-7-環丙基甲氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-((R)-四氫呋喃-3-基氧基)-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-((S)-四氫呋喃-3-基氧基)-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-胺基]-1-氧基-2-丁烯-1-基]胺基}-7-環戊基氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N-環丙基-N-甲基-胺基)-1-氧基-2-丁烯-1-基]胺基}-7-環戊基氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-[(R)-(四氫呋喃-2-基)甲氧基]-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-[(S)-(四氫呋喃-2-基)甲氧基]-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6,7-雙-(2-甲氧基-乙氧基)-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-7-[3-(嗎啉-4-基)-丙基氧基]-6-[(乙烯基羰基)胺基]-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-(4-羥基-苯基)-7H-吡咯并[2,3-d]嘧啶,3-氰基-4-[(3-氯-4-氟苯基)胺基]-6-{[4-(N,N-二甲基胺基)-1-氧基-2-丁烯-1-基]胺基}-7-乙氧基-唑啉,4-{[3-氯-4-(3-氟-苯甲基氧基)-苯基]胺基}-6-(5-{[(2-甲基磺醯基-乙基)胺基]甲基}-呋喃-2-基)-喹唑啉,4-[(R)-(1-苯基-乙基)胺基]-6-{[4-((R)-6-甲基-2-氧基-嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-{[4-(嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-7-[(四氫呋喃-2-基)甲氧基]-喹唑啉,4-[(3-氯-4-氟苯基)胺基]-6-({4-[N,N-雙-(2-甲氧基-乙基)-胺基]-1-氧基-2-丁烯-1-基}胺基)-7-[(四氫呋喃-2-基)甲氧基]-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-{[4-(5,5-二甲基-2-氧基-嗎啉-4-基)-1-氧基-2-丁烯-1-基]胺基}-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[2-(2,2-二甲基-6-氧基-嗎啉-4-基)-乙氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[2-(2,2-二甲基-6-氧基-嗎啉-4-基)-乙氧基]-7-[(R)-(四氫呋喃-2-基)甲氧基]-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-7-[2-(2,2-二甲基-6-氧基-嗎啉-4-基)-乙氧基]-6-[(S)-(四氫呋喃-2-基)甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{2-[4-(2-氧基-嗎啉-4-基)-哌啶-1-基]-乙氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[1-(第三丁基氧基羰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(反式-4-胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(反式-4-甲磺醯基胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(四氫哌喃-3-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(嗎啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(甲氧基甲基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(哌啶-3-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[1-(2-乙醯基胺基-乙基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(四氫哌喃-4-基氧基)-7-乙氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-((S)-四氫呋喃-3-基氧基)-7-羥基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(四氫哌喃-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{反式-4-[(二甲基胺基)磺醯基胺基]-環己-1-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{反式-4-[(嗎啉-4-基)羰基胺基]-環己-1-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{反式-4-[(嗎啉-4-基)磺醯基胺基]-環己-1-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(四氫哌喃-4-基氧基)-7-(2-乙醯基胺基-乙氧基)-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(四氫哌喃-4-基氧基)-7-(2-甲基磺醯基胺基-乙氧基)-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(哌啶-1-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-胺基羰基甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-{N-[(四氫哌喃-4-基)羰基]-N-甲基-胺基}-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-{N-[(嗎啉-4-基)羰基]-N-甲基-胺基}-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-{N-[(嗎啉-4-基)磺醯基]-N-甲基-胺基}-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(反式-4-乙磺醯基胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-甲磺醯基-哌啶-4-基氧基)-7-乙氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-甲磺醯基-哌啶-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[1-(2-甲氧基-乙醯基)-哌啶-4-基氧基]-7-(2-甲氧基-乙氧基)-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-乙醯基胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-[1-(第三丁基氧基羰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-(四氫哌喃-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-{N-[(哌啶-1-基)羰基]-N-甲基-胺基}-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-{N-[(4-甲基-哌-1-基)羰基]-N-甲基-胺基}-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{順式-4-[(嗎啉-4-基)羰基胺基]-環己-1-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[2-(2-氧基吡咯啶-1-基)-乙基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(嗎啉-4-基)羰基]-哌啶-4-基氧基}-7-(2-甲氧基-乙氧基)-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-(1-乙醯基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-(1-甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-(1-甲磺醯基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-甲基-哌啶-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-異丙氧基羰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(順式-4-甲基胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{順式-4-[N-(2-甲氧基-乙醯基)-N-甲基-胺基]-環己-1-基氧基}-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-(哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-[1-(2-甲氧基-乙醯基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉,4-[(3-乙炔基-苯基)胺基]-6-{1-[(嗎啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(順式-2,6-二甲基-嗎啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(2-甲基-嗎啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[((S,S)-(2-(oxa)-5-氮雜-雙環[2.2.1]庚-5-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(N-甲基-N-2-甲氧基乙基胺基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-乙基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(2-甲氧基乙基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-{1-[(3-甲氧基丙基-胺基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[順式-4-(N-甲磺醯基-N-甲基-胺基)-環己-1-基氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[順式-4-(N-乙醯基-N-甲基-胺基)-環己-1-基氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(反式-4-甲基胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[反式-4-(N-甲磺醯基-N-甲基-胺基)-環己-1-基氧基]-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(反式-4-二甲基胺基-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(反式-4-{N-[(嗎啉-4-基)羰基]-N-甲基-胺基}-環己-1-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-[2-(2,2-二甲基-6-氧基-嗎啉-4-基)-乙氧基]-7-[(S)-(四氫呋喃-2-基)甲氧基]-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-甲磺醯基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,4-[(3-氯-4-氟-苯基)胺基]-6-(1-氰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,西土希麥(Cetuximab),它卒注麥(Trastuzumab),ABX-EGF及Mab ICR-62。這些化合物,如可得,可以其消旋物,對映體,或非對映體之形式,或以其藥理學上可接受之酸加成鹽形式,或以其溶劑化物及/或水合物形式使用。這些化合物揭示於先前技藝,例如WO 96/30347、WO 97/02266、WO 99/35146、WO 00/31048、WO 00/78735、WO 01/34574、WO 01/61816、WO 01/77104、WO 02/18351、WO 02/18372、WO 02/18373、WO 02/18376、WO 02/50043、WO 03/082290,Cancer Research 2004,64:11(3958-3965),Am J Health-Syst Pharm 2000,57(15),2063-2076,Clinical Therapeutics 1999,21(2),309-318,WO 98/50433,及WO 95/20045。
內皮素拮抗劑較佳可選自帖卓山坦(tezosentan),玻山坦(bosentan),因拉山坦(enrasentan),希塔山坦(sixtasentan),T-0201、BMS-193884、K-8794,PD-156123,PD-156707,PD-160874,PD-180988,S-0139,及ZD-1611。本發明範圍內任何述及內皮素拮抗劑包括可由內皮素拮抗劑形成之鹽,較佳為藥理學上可接受之酸加成鹽,或衍生物。
這些合併物可同時或依序施用。
用於醫藥,根據本發明之化合物較佳用於溫血脊椎動物,特別是人類,以0.0001-100毫克/公斤體重之劑量。
這些化合物可以單獨或與其他活性物質連合經靜脈內,經皮下,經肌肉內,經腹膜內,或經鼻內途徑,經吸入,或經皮,或經口施用,氣溶膠調配物特別適合用於吸入。
彼等與一或多種習知惰性固體,半固體,或液體載劑,例如澱粉,不同種類之纖維素,乳糖,甘露糖醇,山梨糖醇,葡萄糖,磷酸鈣,硬脂,脂肪醇,甘油,中鏈三酸甘油酯及有關酯,聚乙二醇,精製特級油,水,水/乙醇,水/甘油,水/山梨糖醇,水/聚乙二醇,丙二醇,及/或功能賦形劑,例如聚乙烯基吡咯啶酮,羥基丙基甲基纖維素,羧基甲基纖維素鈉,澱粉羥乙酸鈉,二氧化矽,聚山梨酸酯,泊洛沙姆(poloxamers),單硬脂酸甘油酯(gelucires),硬脂酸鎂,檸檬酸,酒石酸,或其適當混合物調配於習知蓋倫(galenic)製劑中,如普通或包衣錠,膠囊,粉末,注射溶液,安瓿(ampoules),懸浮液,溶液,噴液,或栓劑施用。
下列調配物實例係例示本發明,並非限制其範圍。
組成1錠核心含有:
製備(直接壓縮)活性物質與所有成份混合,過篩,在一個製錠機中壓縮,形成所欲形狀之錠。
核心之重量:230毫克核心之表觀:9毫米,雙凸面
所產生之錠核心塗覆一層主要包含羥基丙基甲基纖維素之薄膜。
包衣錠之重量:240毫克
組成1錠含有:
製備(濕顆粒化)活性物質,乳糖,及澱粉混合在一起,以羥基丙基甲基纖維素之水溶液均勻潤濕。在濕組合物過篩(2.0毫米網目大小)及在一個架(rack)型乾燥器中於50℃乾燥後,再過篩(1.5毫米網目大小),潤滑劑加入。完成之混合物壓縮形成錠。
錠之重量:220毫克錠之表觀:10毫米,扁平面具有斜邊及中斷刻痕在一面上
組成1錠含有:
製備(乾顆粒化)活性物質與乳糖,聚乙烯基吡咯啶酮,及部份微晶纖維素,硬脂酸鎂混合,壓縮,例如在一個輥壓縮器上。螺條(ribbons)經一個0.8毫米網目大小之篩斷裂成細小顆粒。在隨後經一個0.5毫米網目大小之篩篩過及與剩餘成份摻合後,由混合物壓成錠。
錠之重量:300毫克錠之表觀:10毫米,扁平
組成1膠囊含有:
製備活性物質與乳糖,聚乙烯基吡咯啶酮,及部份微晶纖維素,硬脂酸鎂混合,壓縮,例如在一個輥壓縮器上。螺條經一個0.8毫米網目大小之篩斷裂成細小顆粒。在隨後經一個0.5毫米網目大小之篩篩過及與剩餘成份摻合後,完成之混合物裝入1號硬明膠膠囊中。
膠囊填充:約300毫克膠囊殼:1號硬明膠膠囊
1栓劑含有:
製備在栓劑物質已熔解後,活性物質均勻分布於其中,熔解物倒入冷模中。
100毫升懸浮液含有:活性物質 1.00克羧基甲基纖維素鈉 0.10克對-羥基苯甲酸甲酯 0.05克對-羥基苯甲酸丙酯 0.01克葡萄糖 10.00克甘油 5.00克70%山梨糖醇溶液 20.00克調味劑 0.30克蒸餾水 加至 100毫升
製備蒸餾水加熱至70℃。對-羥基苯甲酸甲酯及丙酯與甘油及羧基甲基纖維素之鈉鹽一起攪拌溶於其中。溶液冷卻至周圍溫度,活性物質加入,以攪拌均勻分散於其中。在糖,山梨糖醇溶液,及調味劑加入及溶解後,懸浮液以攪拌抽空以去除空氣。
因此,5毫升懸浮液含有50毫克活性物質。
組成:活性物質 10.0毫克0.01 N鹽酸 適量再蒸餾水 加至2.0毫升
製備活性物質溶於需要量之0.01 N HCl中,以氯化鈉作成等張,過濾滅菌,移入一個2毫升安瓿中。
組成:活性物質 50.0毫克0.01 N鹽酸 適量再蒸餾水 加至10.0毫升
製備活性物質溶於需要量之0.01 N HCl中,以氯化鈉作成等張,過濾滅菌,移入一個10毫升安瓿中。
1膠囊含有:
製備活性物質與吸入用乳糖混合。混合物在一個膠囊製造機中填充入膠囊(空膠囊之重量約50毫克)。
膠囊之重量:70.0毫克膠囊之大小=3號
1噴含有:活性物質 2.500毫克氯化苯甲烴銨 0.001毫克1 N鹽酸 適量乙醇/水(50/50) 加至15.000毫克
製備活性物質及氯化苯甲烴銨(benzalkonium)溶於乙醇/水(50/50)中。溶液之pH以1 N鹽酸調節。生成之溶液過濾,移入用於手持霧化器之適當容器(藥筒)中。
容器之含量:4.5克
圖1A顯示經氣管內接受鹽水及媒液替代博萊黴素之對照組所獲得之結果。
圖1B顯示經氣管內以博萊黴素及媒液處理之鼠發生嚴重之肺纖維化。
圖1C顯示博萊黴素處理之鼠每天以50毫克/公斤實例A(化合物(m))治療顯示肺纖維化不斷地幾乎完全恢復。
圖2顯示使用實際時間PCR探查基因表現之結果(前膠原I)。
圖3顯示使用實際時間PCR探查基因表現之結果(纖維連接蛋白(fibronectin))。
圖4A顯示經氣管內接受鹽水及媒液替代博萊黴素之對照組所獲得之結果。
圖4B顯示經氣管內以博萊黴素及媒液處理之鼠發生嚴重之肺纖維化。
圖4C顯示博萊黴素處理之鼠每天以50毫克/公斤化合物(u)治療顯示肺纖維化不斷地幾乎完全恢復。
圖5顯示經氣管施用博萊黴素及然後僅媒液顯示肺內前膠原I之基因表現大量增加。
圖6顯示經氣管施用博萊黴素及然後僅媒液顯示肺內TGFb之基因表現大量增加。
Claims (2)
- 一種3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮或其鹽之用途,其選擇性與一或多種醫藥可接受之載劑或賦形劑一起用以製備用於治療自發性肺纖維化之藥物。
- 如請求項1之用途,其中使用3-Z-[1-(4-(N-((4-甲基-哌-1-基)-甲基羰基)-N-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧基羰基-2-吲哚啉酮之單乙磺酸鹽製備該藥物。
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Families Citing this family (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
US20060154939A1 (en) * | 2004-12-24 | 2006-07-13 | Boehringer Ingelheim International Gmbh | Medicaments for the Treatment or Prevention of Fibrotic Diseases |
EP2167465A1 (en) * | 2007-06-12 | 2010-03-31 | Boehringer Ingelheim International GmbH | Indolinone derivatives and their use in treating disease-states such as cancer |
DK2170827T3 (da) | 2007-06-21 | 2013-11-18 | Janssen Pharmaceutica Nv | Indolin-2-oner og aza-indolin-2-oner |
RS57142B1 (sr) * | 2008-06-06 | 2018-07-31 | Boehringer Ingelheim Int | Farmaceutski dozni oblik u vidu kapsule koji sadrži formulaciju suspenzije indolinon derivata |
UA107560C2 (uk) * | 2008-06-06 | 2015-01-26 | Фармацевтична лікарська форма для негайного вивільнення похідної індолінону | |
AU2015227503B2 (en) * | 2008-06-06 | 2017-02-23 | Boehringer Ingelheim International Gmbh | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative |
NZ588957A (en) * | 2008-06-06 | 2013-03-28 | Boehringer Ingelheim Int | Pharmaceutical combination of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid |
US20170065529A1 (en) | 2015-09-09 | 2017-03-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical dosage form for immediate release of an indolinone derivative |
PE20110213A1 (es) | 2008-07-29 | 2011-04-16 | Boehringer Ingelheim Int | Derivados de indolinona como inhibidores de quinasa |
US8802384B2 (en) | 2009-03-12 | 2014-08-12 | Boehringer Ingelheim International Gmbh | Method or system using biomarkers for the monitoring of a treatment |
WO2010130757A1 (en) * | 2009-05-14 | 2010-11-18 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of oncological and fibrotic diseases |
WO2010130758A1 (en) * | 2009-05-14 | 2010-11-18 | Boehringer Ingelheim International Gmbh | New combination therapy in treatment of cancer and fibrotic diseases |
US20120107304A1 (en) | 2010-04-27 | 2012-05-03 | Boehringer Ingelheim International Gmbh | Combination therapy in treatment of oncological and fibrotic diseases |
US8381108B2 (en) * | 2010-06-21 | 2013-02-19 | Microsoft Corporation | Natural user input for driving interactive stories |
CA2808866A1 (en) | 2010-08-20 | 2012-02-23 | The Hospital For Sick Children | Compositions and methods for treatment of cystic fibrosis and diseases associated with aberrant protein cellular processing |
CN103102352B (zh) * | 2011-11-15 | 2015-08-12 | 山东亨利医药科技有限责任公司 | 酪氨酸激酶抑制剂吲哚满酮衍生物 |
CN103130775B (zh) * | 2011-11-22 | 2015-09-30 | 山东亨利医药科技有限责任公司 | 作为酪氨酸激酶抑制剂的吲哚满酮衍生物 |
WO2013112959A1 (en) | 2012-01-26 | 2013-08-01 | Angion Biomedica Corp. | Antifibrotic compounds and uses thereof |
CN103848814B (zh) * | 2012-12-06 | 2016-08-17 | 山东亨利医药科技有限责任公司 | 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物 |
US20140350022A1 (en) | 2013-05-10 | 2014-11-27 | Boehringer Ingelheim International Gmbh | Efficacious treatment of NSCLC and predictive clinical marker of the responsiveness of a tumour to a treatment |
CN104003925B (zh) * | 2013-06-05 | 2016-03-30 | 四川大学 | 吲哚酮化合物或其衍生物及其用途 |
WO2015009889A1 (en) * | 2013-07-18 | 2015-01-22 | Concert Pharmaceuticals, Inc. | Deuterated intedanib derivatives and their use for the treatment of proliferative disorders |
WO2015017728A1 (en) * | 2013-07-31 | 2015-02-05 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
US10450295B2 (en) * | 2013-08-09 | 2019-10-22 | Acclaim BioMed USA LLC | Method of using an indolinone molecule and derivatives for inhibiting liver fibrosis and hepatitis |
EP3102190A4 (en) | 2014-02-07 | 2017-09-06 | Auspex Pharmaceuticals, Inc. | Novel pharmaceutical formulations |
CN106432042A (zh) * | 2015-08-13 | 2017-02-22 | 南京华威医药科技开发有限公司 | 尼达尼布乙磺酸水合物的药物新晶型 |
CA3001489C (en) * | 2015-10-07 | 2024-01-16 | Diane Tang-Liu | Compositions and methods of treating skin fibrotic disorders |
KR20180128390A (ko) * | 2015-12-24 | 2018-12-03 | 레스피버트 리미티드 | 인돌리논 화합물과 섬유성 질환의 치료에서 이의 용도 |
CN107019697A (zh) * | 2016-02-02 | 2017-08-08 | 瑞阳(苏州)生物科技有限公司 | 预防或治疗纤维化疾病的药物组合物及其应用 |
EP3426649B1 (en) | 2016-03-08 | 2020-07-22 | Respivert Limited | Indole derivatives and their use as protein kinase inhibitors |
EP3442534A1 (en) | 2016-04-13 | 2019-02-20 | Boehringer Ingelheim International GmbH | Pharmaceutical combination of nintedanib, trifluridine and tipiracil for treating colorectal cancer |
EP3246029A1 (en) | 2016-05-19 | 2017-11-22 | Boehringer Ingelheim International Gmbh | Pharmaceutical combination of nintedanib and capecitabine for the treatment of colorectal cancer |
EP3464240A1 (en) | 2016-05-27 | 2019-04-10 | Boehringer Ingelheim International GmbH | Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone |
EP3463353A1 (en) | 2016-06-01 | 2019-04-10 | Boehringer Ingelheim International GmbH | Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone |
JP7168456B2 (ja) | 2016-07-08 | 2022-11-09 | アリゾナ ボード オブ リージェンツ オン ビハーフ オブ ザ ユニバーシティ オブ アリゾナ | インドリン誘導体およびそれらを使用するならびに生産する方法 |
CN108066343A (zh) * | 2016-11-08 | 2018-05-25 | 瑞阳(苏州)生物科技有限公司 | 一种预防或治疗肾纤维化疾病的药物 |
CN110062625A (zh) | 2016-12-12 | 2019-07-26 | 勃林格殷格翰国际有限公司 | 尼达尼布通过与奥达特罗共给予用于治疗间质性肺病的方法 |
CN106692150B (zh) * | 2016-12-21 | 2019-08-20 | 中国人民解放军第三〇二医院 | 尼达尼布在制备预防和治疗肝纤维化与肝硬化的药物中的用途 |
US20190388407A1 (en) * | 2017-02-12 | 2019-12-26 | Aiviva Biopharma, Inc. | Multikinase inhibitors of vegf and tfg beta and uses thereof |
WO2018177893A1 (en) | 2017-03-28 | 2018-10-04 | Boehringer Ingelheim International Gmbh | Nintedanib for use in methods for the treatment of muscular dystrophy |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
WO2019071147A1 (en) | 2017-10-05 | 2019-04-11 | Fulcrum Therapeutics, Inc. | INHIBITORS OF KINASE P38 REDUCING EXPRESSION OF DUX4 GENE AND DOWNSTREAM GENES FOR THE TREATMENT OF FSHD |
CN111278442B (zh) * | 2017-10-23 | 2023-06-06 | 勃林格殷格翰国际有限公司 | 用于治疗进行性纤维化间质性肺病(pf-ild)的活性剂的新组合 |
JOP20200212A1 (ar) | 2018-03-07 | 2020-09-01 | Pliant Therapeutics Inc | مركبات حمض أميني وطرق استخدامها |
JP7061310B2 (ja) * | 2018-04-05 | 2022-04-28 | 国立大学法人 大分大学 | 慢性脂肪性疾患の予防および治療用医薬 |
EP3784213B1 (en) | 2018-04-23 | 2023-09-06 | InspirMed Corp. | Inhalable liposomal sustained release composition for use in treating pulmonary diseases |
CN108358827A (zh) * | 2018-05-07 | 2018-08-03 | 日照市普达医药科技有限公司 | 一种治疗牛皮癣的2-氧代-吲哚类衍生物及其制备方法 |
CN113292537B (zh) | 2018-06-15 | 2024-04-05 | 汉达癌症医药责任有限公司 | 激酶抑制剂的盐类及其组合物 |
CN109134431B (zh) * | 2018-10-10 | 2021-06-04 | 成都理工大学 | 作为囊性纤维化跨膜传导调节因子抑制剂的氨基咪唑偶联吡啶酮衍生物 |
GB201905375D0 (en) | 2019-04-16 | 2019-05-29 | Mission Therapeutics Ltd | Novel compounds |
GB201905371D0 (en) | 2019-04-16 | 2019-05-29 | Mission Therapeutics Ltd | Novel compounds |
GB201912674D0 (en) | 2019-09-04 | 2019-10-16 | Mission Therapeutics Ltd | Novel compounds |
CA3160410A1 (en) | 2019-12-04 | 2021-06-10 | Idorsia Pharmaceuticals Ltd | Combination of an azetidine lpa1 receptor antagonist with pirfenidone and/or nintedanib for use in the treatment of fibrotic diseases |
EP4125890A1 (en) | 2020-04-01 | 2023-02-08 | Boehringer Ingelheim International GmbH | Use of biomarkers in the treatment of fibrotic conditions |
KR20230006487A (ko) | 2020-04-08 | 2023-01-10 | 미션 테라퓨틱스 엘티디 | Usp30 억제제로서의 활성을 갖는 n-시아노피롤리딘 |
GB202006079D0 (en) | 2020-04-24 | 2020-06-10 | Vicore Pharma Ab | New composition |
GB202006074D0 (en) | 2020-04-24 | 2020-06-10 | Vicore Pharma Ab | New composition |
US20230219939A1 (en) | 2020-05-28 | 2023-07-13 | Mission Therapeutics Limited | N-(1-cyano-pyrrolidin-3-yl)-5-(3-(trifluoromethyl)phenyl)oxazole-2-carboxamide derivatives and the corresponding oxadiazole derivatives as usp30 inhibitors for the treatment of mitochondrial dysfunction |
WO2021245186A1 (en) | 2020-06-04 | 2021-12-09 | Mission Therapeutics Limited | N-cyanopyrrolidines with activity as usp30 inhibitors |
CN115836073B (zh) | 2020-06-08 | 2024-08-27 | 特殊治疗有限公司 | 用于治疗线粒体功能障碍、癌症和纤维化的作为usp30抑制剂的1-(5-(2-氰基吡啶-4-基)噁唑-2-羰基)-4-甲基六氢吡咯并[3,4-b]吡咯-5(1h)-甲腈 |
GB202016800D0 (en) | 2020-10-22 | 2020-12-09 | Mission Therapeutics Ltd | Novel compounds |
WO2023099561A1 (en) | 2021-12-01 | 2023-06-08 | Mission Therapeutics Limited | Substituted n-cyanopyrrolidines with activity as usp30 inhibitors |
AU2022443590A1 (en) | 2022-02-28 | 2024-10-17 | Nuformix Technologies Limited | Compositions and methods for treatment of idiopathic pulmonary fibrosis |
WO2024037982A1 (en) | 2022-08-16 | 2024-02-22 | Boehringer Ingelheim International Gmbh | Pharmaceutical formulations of nintedanib for intraocular use |
CN118772038A (zh) * | 2023-01-03 | 2024-10-15 | 天津征程医药科技有限公司 | 2-吲哚酮衍生物及其用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999015500A1 (en) * | 1997-09-05 | 1999-04-01 | Glaxo Group Limited | Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors |
WO2000056710A1 (en) * | 1999-03-04 | 2000-09-28 | Glaxo Group Limited | 3-(anilinomethylene) oxindoles as protein tyrosine kinase and protein serine/threonine kinase inhibitors |
WO2004013099A1 (en) * | 2002-07-24 | 2004-02-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition |
WO2004017948A2 (en) * | 2002-08-16 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of lck inhibitor for treatment of immunologic diseases |
Family Cites Families (174)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4460581A (en) | 1982-10-12 | 1984-07-17 | Boehringer Ingelheim Kg | (1-Hydroxy-2-amino-alkyl)-substituted benzoxazinones and benzoxazolinones |
JPH06502178A (ja) | 1990-12-31 | 1994-03-10 | 藤沢薬品工業株式会社 | イミダゾトリアジン誘導体 |
GB9816837D0 (en) | 1998-08-04 | 1998-09-30 | Zeneca Ltd | Amide derivatives |
US5656644A (en) | 1994-07-20 | 1997-08-12 | Smithkline Beecham Corporation | Pyridyl imidazoles |
US5716972A (en) | 1993-01-13 | 1998-02-10 | Smithkline Beecham Corporation | Pyridyl substituted imidazoles |
IL104369A0 (en) | 1992-01-13 | 1993-05-13 | Smithkline Beecham Corp | Novel compounds and compositions |
GB9303993D0 (en) | 1993-02-26 | 1993-04-14 | Fujisawa Pharmaceutical Co | New heterocyclic derivatives |
US5593992A (en) | 1993-07-16 | 1997-01-14 | Smithkline Beecham Corporation | Compounds |
US5670527A (en) | 1993-07-16 | 1997-09-23 | Smithkline Beecham Corporation | Pyridyl imidazole compounds and compositions |
US5593991A (en) | 1993-07-16 | 1997-01-14 | Adams; Jerry L. | Imidazole compounds, use and process of making |
DE69434721T2 (de) | 1993-10-01 | 2006-11-09 | Novartis Ag | Pharmacologisch wirksame pyrimidinderivate und verfahren zu deren herstellung |
US5543520A (en) | 1993-10-01 | 1996-08-06 | Ciba-Geigy Corporation | Pyrimidine derivatives |
NZ273617A (en) | 1993-10-01 | 1996-11-26 | Ciba Geigy Ag | N-phenyl-2-pyrimidineamine derivatives pharmaceutical compositions |
US5612340A (en) | 1993-10-01 | 1997-03-18 | Ciba-Geigy Corporation | Pyrimidineamine derivatives and processes for the preparation thereof |
GB9401182D0 (en) | 1994-01-21 | 1994-03-16 | Inst Of Cancer The Research | Antibodies to EGF receptor and their antitumour effect |
US5559137A (en) | 1994-05-16 | 1996-09-24 | Smithkline Beecham Corp. | Compounds |
WO2000023072A1 (en) | 1998-10-20 | 2000-04-27 | Omeros Medical Systems, Inc. | Irrigation solution containing mapk inhibitors and their use for treating pain and inflammation |
EP3103799B1 (en) | 1995-03-30 | 2018-06-06 | OSI Pharmaceuticals, LLC | Quinazoline derivatives |
TW449590B (en) | 1995-04-14 | 2001-08-11 | Boehringer Ingelheim Kg | New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds |
US5739143A (en) | 1995-06-07 | 1998-04-14 | Smithkline Beecham Corporation | Imidazole compounds and compositions |
US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
IL118544A (en) | 1995-06-07 | 2001-08-08 | Smithkline Beecham Corp | History of imidazole, the process for their preparation and the pharmaceutical preparations containing them |
CA2224435C (en) | 1995-07-06 | 2008-08-05 | Novartis Ag | Pyrrolopyrimidines and processes for the preparation thereof |
JP3382951B2 (ja) | 1995-10-06 | 2003-03-04 | メルク エンド カムパニー インコーポレーテッド | 抗がん活性及びサイトカン阻害活性を有する置換イミダゾール |
WO1997016441A1 (en) | 1995-10-31 | 1997-05-09 | Merck & Co., Inc. | Substituted aryl pyrroles, compositions containing such compounds and methods of use |
JPH11514651A (ja) | 1995-10-31 | 1999-12-14 | メルク エンド カンパニー インコーポレーテッド | 置換ピリジルピロール、前記化合物を含む組成物及び使用方法 |
AP9700912A0 (en) | 1996-01-11 | 1997-01-31 | Smithkline Beecham Corp | Novel cycloalkyl substituted imidazoles |
ZA97175B (en) | 1996-01-11 | 1997-11-04 | Smithkline Beecham Corp | Novel substituted imidazole compounds. |
AU715900B2 (en) | 1996-01-11 | 2000-02-10 | Smithkline Beecham Corporation | Novel substituted imidazole compounds |
JP2001508395A (ja) | 1996-01-11 | 2001-06-26 | スミスクライン・ビーチャム・コーポレイション | 新規シクロアルキル置換イミダゾール |
DE19608665A1 (de) | 1996-03-06 | 1997-09-11 | Boehringer Ingelheim Kg | Neue Arylglycinamidderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
WO1997033883A1 (en) | 1996-03-13 | 1997-09-18 | Smithkline Beecham Corporation | Novel pyrimidine compounds useful in treating cytokine mediated diseases |
US6235760B1 (en) | 1996-03-25 | 2001-05-22 | Smithkline Beecham Corporation | Treatment for CNS injuries |
US6096739A (en) | 1996-03-25 | 2000-08-01 | Smithkline Beecham Corporation | Treatment for CNS injuries |
CA2250232A1 (en) | 1996-04-03 | 1997-10-09 | Allen I. Oliff | A method of treating cancer |
JP3418624B2 (ja) | 1996-06-10 | 2003-06-23 | メルク エンド カンパニー インコーポレーテッド | サイトカイン阻害活性を有する置換イミダゾール類 |
WO1998006715A1 (en) | 1996-08-09 | 1998-02-19 | Smithkline Beecham Corporation | Novel piperazine containing compounds |
DE19633640C2 (de) | 1996-08-21 | 1999-05-06 | Ford Global Tech Inc | Vorrichtung zur Winkelverstellung einer Welle gegenüber einem Antriebsrad |
WO1998007425A1 (en) | 1996-08-21 | 1998-02-26 | Smithkline Beecham Corporation | Imidazole compounds, compositions and use |
ATE264318T1 (de) | 1996-11-19 | 2004-04-15 | Amgen Inc | Aryl und heteroaryl substituierte kondensierte pyrrole als entzündunghemmende mittel |
WO1998022109A1 (en) | 1996-11-20 | 1998-05-28 | Merck & Co., Inc. | Triaryl substituted imidazoles as glucagon antagonists |
AU735901C (en) | 1996-12-05 | 2004-02-12 | Amgen, Inc. | Substituted pyrimidinone and pyridone compounds and methods of use |
TW520362B (en) | 1996-12-05 | 2003-02-11 | Amgen Inc | Substituted pyrimidine compounds and pharmaceutical composition comprising same |
ZA9711092B (en) | 1996-12-11 | 1999-07-22 | Smithkline Beecham Corp | Novel compounds. |
US6147080A (en) | 1996-12-18 | 2000-11-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
WO1998028292A1 (en) | 1996-12-23 | 1998-07-02 | Smithkline Beecham Corporation | Novel piperidine containing compounds |
ATE242208T1 (de) | 1997-01-29 | 2003-06-15 | Pfizer | Sulfonylharnstoff-derivate und ihre verwendung in der kontrolle der interleukin-1-aktivität |
WO1998047899A1 (en) | 1997-04-24 | 1998-10-29 | Ortho-Mcneil Corporation, Inc. | Substituted pyrrolopyridines useful in the treatment of inflammatory diseases |
US5965583A (en) | 1997-04-24 | 1999-10-12 | Ortho-Mcneil Pharmaceutical, Inc. | Substituted imidazoles useful in the treatment of inflammatory disease |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
EP0984930B1 (en) | 1997-05-07 | 2005-04-06 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
EP0983260A2 (en) | 1997-05-22 | 2000-03-08 | G.D. Searle & Co. | 3(5)-HETEROARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS |
US6514977B1 (en) | 1997-05-22 | 2003-02-04 | G.D. Searle & Company | Substituted pyrazoles as p38 kinase inhibitors |
AU7726898A (en) | 1997-05-22 | 1998-12-11 | G.D. Searle & Co. | Pyrazole derivatives as p38 kinase inhibitors |
GEP20033053B (en) | 1997-05-22 | 2003-08-25 | Searle & Co | Substituted Pyrazoles as P38 Kinase Inhibitors, Methods for their Production, Pharmaceutical Compositions Containing Them and Methods for Treatment |
WO1998052558A1 (en) | 1997-05-23 | 1998-11-26 | Bayer Corporation | INHIBITION OF p38 KINASE ACTIVITY BY ARYL UREAS |
CA2291065C (en) | 1997-05-23 | 2010-02-09 | Bayer Corporation | Raf kinase inhibitors |
CZ9904452A3 (cs) | 1997-06-12 | 2002-02-13 | Rhone-Poulenc Rorer Limited | Cyklické acetaly imidazolylu, způsob jejich přípravy, jejich pouľití a farmaceutický prostředek, který je obsahuje |
AU7966198A (en) | 1997-06-13 | 1998-12-30 | Smithkline Beecham Corporation | Novel pyrazole and pyrazoline substituted compounds |
US6093742A (en) | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
GB9713726D0 (en) | 1997-06-30 | 1997-09-03 | Ciba Geigy Ag | Organic compounds |
KR20010014288A (ko) | 1997-06-30 | 2001-02-26 | 오르토-맥네일 파마슈티칼, 인코퍼레이티드 | 염증성 질환의 치료에 유용한 2-치환된 이미다졸 |
US5939421A (en) | 1997-07-01 | 1999-08-17 | Signal Pharmaceuticals, Inc. | Quinazoline analogs and related compounds and methods for treating inflammatory conditions |
TW517055B (en) | 1997-07-02 | 2003-01-11 | Smithkline Beecham Corp | Novel substituted imidazole compounds |
AU8381098A (en) | 1997-07-02 | 1999-01-25 | Smithkline Beecham Corporation | Novel cycloalkyl substituted imidazoles |
AR016294A1 (es) | 1997-07-02 | 2001-07-04 | Smithkline Beecham Corp | Compuesto de imidazol sustituido, composicion farmaceutica que la contiene, su uso en la fabricacion de un medicamento y procedimiento para supreparacion |
US5981710A (en) | 1997-07-21 | 1999-11-09 | Baxter International, Inc. | Therapeutic hemoglobin composition having isotropically increased size |
WO1999015164A1 (en) | 1997-09-23 | 1999-04-01 | Zeneca Limited | Amide derivatives for the treatment of diseases mediated by cytokines |
US5975738A (en) | 1997-09-30 | 1999-11-02 | Lsi Logic Corporation | Method for detecting failure in redundant controllers using a private LUN |
EP1041989A4 (en) | 1997-10-08 | 2002-11-20 | Smithkline Beecham Corp | NEW SUBSTITUTED CYCLOALCENYL COMPOUNDS |
AU1053399A (en) | 1997-11-14 | 1999-06-07 | Sankyo Company Limited | Pyridylpyrrole derivatives |
AR017219A1 (es) | 1997-12-19 | 2001-08-22 | Smithkline Beecham Corp | Derivados de imidazol 1,4,5 sustituidos, composiciones que los comprenden, procedimiento para la preparacion de dichos derivados, uso de los derivados parala manufactura de un medicamento |
ES2154253T3 (es) | 1997-12-22 | 2012-01-27 | Bayer Healthcare Llc | Inhibición de la actividad de p38 cinasa usando ureas heterocíclicas sustituidas. |
EP1616865A1 (en) | 1997-12-22 | 2006-01-18 | Bayer Pharmaceuticals Corporation | Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas |
WO1999032110A1 (en) | 1997-12-22 | 1999-07-01 | Bayer Corporation | INHIBITION OF p38 KINASE ACTIVITY USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREAS |
RS49779B (sr) | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
DE69917005T2 (de) | 1998-02-26 | 2005-03-24 | Ortho-Mcneil Pharmaceutical, Inc. | Substituierte pyrrolobenzimidazolderivate zur entzündungshemmung |
WO1999050238A1 (fr) | 1998-03-26 | 1999-10-07 | Santen Pharmaceutical Co., Ltd. | Nouveaux derives d'uree |
DE19815020A1 (de) | 1998-04-03 | 1999-10-07 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
DE19816624A1 (de) | 1998-04-15 | 1999-10-21 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
EP1075467B1 (en) | 1998-05-05 | 2005-03-30 | F. Hoffmann-La Roche Ag | Pyrazole derivatives as p-38 map kinase inhibitors |
US6316466B1 (en) | 1998-05-05 | 2001-11-13 | Syntex (U.S.A.) Llc | Pyrazole derivatives P-38 MAP kinase inhibitors |
MY132496A (en) | 1998-05-11 | 2007-10-31 | Vertex Pharma | Inhibitors of p38 |
EP1077971A1 (en) | 1998-05-14 | 2001-02-28 | G.D. SEARLE & CO. | 1,5-DIARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS |
PT1077930E (pt) | 1998-05-15 | 2005-03-31 | Astrazeneca Ab | Derivados de benzamida para o tratamento de doencas mediadas por citocinas |
SK286123B6 (sk) | 1998-05-15 | 2008-04-07 | Astrazeneca Ab | Benzamidové deriváty, spôsob ich prípravy, farmaceutická kompozícia a ich použitie na prípravu liečiva na liečenie chorôb sprostredkovaných cytokínmi |
JP2002516322A (ja) | 1998-05-22 | 2002-06-04 | スミスクライン・ビーチャム・コーポレイション | 新規2−アルキル置換イミダゾール化合物 |
NZ508790A (en) | 1998-05-22 | 2003-10-31 | Scios Inc | Heterocyclic compounds and methods to treat cardiac failure and other disorders |
US6589954B1 (en) | 1998-05-22 | 2003-07-08 | Scios, Inc. | Compounds and methods to treat cardiac failure and other disorders |
US6340685B1 (en) | 1998-05-22 | 2002-01-22 | Scios, Inc. | Compounds and methods to treat cardiac failure and other disorders |
WO1999061440A1 (en) | 1998-05-26 | 1999-12-02 | Smithkline Beecham Corporation | Novel substituted imidazole compounds |
DE19824922A1 (de) * | 1998-06-04 | 1999-12-09 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
JP2002517486A (ja) | 1998-06-12 | 2002-06-18 | 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 | p38のインヒビター |
AU4395399A (en) | 1998-07-02 | 2000-01-24 | Sankyo Company Limited | Five-membered heteroaryl compounds |
US6207687B1 (en) | 1998-07-31 | 2001-03-27 | Merck & Co., Inc. | Substituted imidazoles having cytokine inhibitory activity |
JP2002522421A (ja) | 1998-08-04 | 2002-07-23 | アストラゼネカ アクチボラグ | サイトカイン産生の阻害剤として有用なアミド誘導体 |
KR100663143B1 (ko) | 1998-08-05 | 2007-01-02 | 산텐 세이야꾸 가부시키가이샤 | 질소 포함 방향족 헤테로고리를 갖는 신규 우레아 유도체 |
EP1112070B1 (en) | 1998-08-20 | 2004-05-12 | Smithkline Beecham Corporation | Novel substituted triazole compounds |
US6184226B1 (en) | 1998-08-28 | 2001-02-06 | Scios Inc. | Quinazoline derivatives as inhibitors of P-38 α |
CN1261098C (zh) | 1998-08-28 | 2006-06-28 | 西奥斯股份有限公司 | p38-α激酶的抑制剂 |
JP4191825B2 (ja) | 1998-09-10 | 2008-12-03 | あすか製薬株式会社 | 5−アミノイソキサゾール誘導体 |
DE19842833B4 (de) | 1998-09-18 | 2005-04-14 | Merckle Gmbh | 2-Arylalkylthio-imidazole, 2-Arylalkenylthio-imidazole und 2-Arylalkinylthio-imidazole als Entzündungs-Hemmstoffe und Hemmstoffe der Cytokin-Freisetzung |
JP2002526482A (ja) | 1998-09-18 | 2002-08-20 | 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 | p38のインヒビター |
AR023659A1 (es) | 1998-09-18 | 2002-09-04 | Vertex Pharma | Un compuesto inhibidor de p38, una composicion farmaceutica que lo comprende y el uso de dicha composicion en el tratamiento y prevencion de estados patologicos |
ID28267A (id) | 1998-09-25 | 2001-05-10 | Astrazeneca Ab | Turunan benzamida dan penggunaannya sebagai inhibitor sitokina |
WO2000018734A1 (de) | 1998-09-25 | 2000-04-06 | Boehringer Ingelheim Pharma Kg | Neue substituierte indolinone mit inhibierender wirkung auf verschiedene kinasen und cyclin/cdk-komplexe |
EP1117653B1 (en) | 1998-10-01 | 2003-02-05 | AstraZeneca AB | Quinoline and quinazoline derivatives and their use as inhibitors of cytokine mediated diseases |
WO2000026209A1 (en) | 1998-11-03 | 2000-05-11 | Novartis Ag | Anti-inflammatory 4-phenyl-5-pyrimidinyl-imidazoles |
DE69914357T2 (de) | 1998-11-04 | 2004-11-11 | Smithkline Beecham Corp. | Pyridin-4-yl oder pyrimidin-4-yl substituierte pyrazine |
NZ527718A (en) | 1998-11-19 | 2004-11-26 | Warner Lambert Co | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases |
PT1131318E (pt) | 1998-11-20 | 2004-07-30 | Searle Llc | Processo para a producao de pirazoles 5-substituidos utilizando ditietanos |
US6350744B1 (en) | 1998-11-20 | 2002-02-26 | Merck & Co., Inc. | Compounds having cytokine inhibitory activity |
CA2355075C (en) | 1998-12-16 | 2009-12-08 | Aventis Pharma Limited | Heteroaryl-cyclic acetals |
WO2000036096A1 (en) | 1998-12-16 | 2000-06-22 | Vertex Pharmaceuticals Incorporated | Crystallized p38 complexes |
CN1326848C (zh) | 1998-12-25 | 2007-07-18 | 帝国脏器制药株式会社 | 氨基吡唑衍生物 |
CA2359244C (en) | 1999-01-13 | 2013-10-08 | Bayer Corporation | .omega.-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors |
UA73492C2 (en) | 1999-01-19 | 2005-08-15 | Aromatic heterocyclic compounds as antiinflammatory agents | |
WO2000055139A2 (en) | 1999-03-12 | 2000-09-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Heterocyclic urea and related compounds useful as anti-inflammatory agents |
DE60023853T2 (de) | 1999-03-12 | 2006-05-24 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Aromatische heterozyklische verbindungen als antientzündungwirkstoffe |
JP2002539187A (ja) | 1999-03-17 | 2002-11-19 | アストラゼネカ アクチボラグ | アミド誘導体 |
BR0009083B1 (pt) | 1999-03-17 | 2011-11-01 | derivado de amida compreendendo um núcleo de quinazolinona, processo para a preparação de um derivado de amida, composição farmacêutica, e, uso de um derivado de amida. | |
GB9906566D0 (en) | 1999-03-23 | 1999-05-19 | Zeneca Ltd | Chemical compounds |
CO5170501A1 (es) | 1999-04-14 | 2002-06-27 | Novartis Ag | AZOLES SUSTITUIDOS UTILES PARA EL TRATAMIENTO DE ENFERMEDADES MEDIADAS POR TNFa eIL-1 Y ENFERMEDADES DEL METABOLISMO OSEO |
US6492516B1 (en) | 1999-05-14 | 2002-12-10 | Merck & Co., Inc. | Compounds having cytokine inhibitory activity |
ATE376547T1 (de) | 1999-05-21 | 2007-11-15 | Scios Inc | Derivate des indol-typs als p38 kinase inhibitoren |
DE19924401A1 (de) | 1999-05-27 | 2000-11-30 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
UA71976C2 (en) | 1999-06-21 | 2005-01-17 | Boehringer Ingelheim Pharma | Bicyclic heterocycles and a medicament based thereon |
US6403596B1 (en) | 1999-06-28 | 2002-06-11 | Merck & Co., Inc. | Substituted pyridones having cytokine inhibitory activity |
AU769138B2 (en) | 1999-07-16 | 2004-01-15 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Aminobenzophenones as inhibitors of IL-1beta and TNF-alpha |
RU2247719C2 (ru) | 1999-07-16 | 2005-03-10 | Лео Фармасьютикал Продактс Лтд.А/С (Левенс Кемиске Фабрик Продукционсактиесельскаб) | Аминобензофеноны как ингибиторы il-1 бета и tnf-альфа, фармацевтическая композиция и способ лечения и/или профилактики воспалительных заболеваний |
EP1202957B1 (en) | 1999-07-16 | 2004-09-29 | Leo Pharma A/S | Aminobenzophenones as inhibitors of il-1beta and tnf-alpha |
HUP0201911A3 (en) | 1999-07-16 | 2002-11-28 | Leo Pharm Prod Ltd | Aminobenzophenones as inhibitors of il-1betha and tnf-alpha and pharmaceutical compositions containing them |
CA2379316A1 (en) | 1999-07-16 | 2001-01-25 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsa Ktieselskab) | Novel aminobenzophenones |
MXPA02002097A (es) | 1999-08-27 | 2002-11-07 | Boehringer Ingelheim Pharma | Indolinas sustituidas como inhibidoras de la tirosina cinasa. |
DE19949209A1 (de) | 1999-10-13 | 2001-04-19 | Boehringer Ingelheim Pharma | In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
UA75054C2 (uk) | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
US6762180B1 (en) * | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
WO2001027315A2 (en) | 1999-10-13 | 2001-04-19 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | For substances acting on msk1 or msk2 |
GB9924092D0 (en) | 1999-10-13 | 1999-12-15 | Zeneca Ltd | Pyrimidine derivatives |
TR200201058T2 (tr) | 1999-10-21 | 2002-07-22 | F.Hoffmann-La Roche Ag | P38 protein kinaz inhibitörleri olarak, alkilaminoyla ornatılmış bisiklik, azotlu heterosikller |
JP3961830B2 (ja) | 1999-10-21 | 2007-08-22 | エフ.ホフマン−ラ ロシュ アーゲー | p38プロテインキナーゼのインヒビターとしてのヘテロアルキルアミノ置換二環式窒素複素環 |
PT1140939E (pt) | 1999-11-10 | 2005-05-31 | Ortho Mcneil Pharm Inc | 2-aril-3-(heteroaril)- imidazo [1,2-alfa] pirimidinas substituidas, e formulacoes farmaceuticas e metodos relacionados |
UA74803C2 (uk) | 1999-11-11 | 2006-02-15 | Осі Фармасьютікалз, Інк. | Стійкий поліморф гідрохлориду n-(3-етинілфеніл)-6,7-біс(2-метоксіетокси)-4-хіназолінаміну, спосіб його одержання (варіанти) та фармацевтичне застосування |
US6492393B1 (en) | 1999-11-16 | 2002-12-10 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
AU1782301A (en) | 1999-11-23 | 2001-06-04 | Smithkline Beecham Corporation | 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p39 kinase inhibitors |
WO2001038312A1 (en) | 1999-11-23 | 2001-05-31 | Smithkline Beecham Corporation | 3,4-DIHYDRO-(1H)QUINAZOLIN-2-ONE COMPOUNDS AS CSBP/p38 KINASE INHIBITORS |
JP2003517471A (ja) | 1999-11-23 | 2003-05-27 | スミスクライン・ビーチャム・コーポレイション | 3,4−ジヒドロ−(1H)−キナゾリン−2−オンおよびそのCSBP/p38キナーゼ阻害剤としての使用 |
ES2241675T3 (es) | 1999-11-23 | 2005-11-01 | Smithkline Beecham Corporation | Compuestos de 3,4-dihidro-(1h)quinazolin-2-ona como inhibidores de cspb/p38 quinasa. |
EA200200411A1 (ru) | 1999-11-30 | 2002-10-31 | Пфайзер Продактс Инк. | 2,4-диаминопиримидиновые соединения, полезные в качестве иммуносупрессоров |
HUP0203813A3 (en) | 1999-12-06 | 2008-03-28 | Leo Pharma As | Aminobenzophenones as inhibitors of il-1betha and tnf-alpha, pharmaceutical compositions containing them and their use |
US6602872B1 (en) | 1999-12-13 | 2003-08-05 | Merck & Co., Inc. | Substituted pyridazines having cytokine inhibitory activity |
AU2735201A (en) | 1999-12-28 | 2001-07-09 | Pharmacopeia, Inc. | Pyrimidine and triazine kinase inhibitors |
DE20002820U1 (de) | 2000-02-16 | 2000-05-25 | Igus Spritzgußteile für die Industrie GmbH, 51147 Köln | Energieführungskette |
US6537996B2 (en) | 2000-02-23 | 2003-03-25 | Iconix Pharmaceuticals, Inc. | Modulators of p38 MAP kinase |
AU2001241927A1 (en) | 2000-02-28 | 2001-09-12 | Scios Inc. | Inhibitors of p38-alpha kinase |
AR035851A1 (es) | 2000-03-28 | 2004-07-21 | Wyeth Corp | 3-cianoquinolinas, 3-ciano-1,6-naftiridinas y 3-ciano-1,7-naftiridinas como inhibidoras de proteina quinasas |
ES2280375T3 (es) | 2000-04-08 | 2007-09-16 | BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG | Heterociclos biciclicos, medicamentos que contienen estos compuestos, su uso y procedimiento para su preparacion. |
DE10042062A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Hertellung |
DE10042060A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE10042058A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE10042059A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE10051320A1 (de) | 2000-10-17 | 2002-04-25 | Boehringer Ingelheim Pharma | Neue Neurokininantagonisten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen |
US6638965B2 (en) | 2000-11-01 | 2003-10-28 | Boehringer Ingelheim Pharma Kg | Substituted indolinones, preparation thereof and their use as pharmaceutical compositions |
DE10054019A1 (de) | 2000-11-01 | 2002-05-23 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
DE10063435A1 (de) | 2000-12-20 | 2002-07-04 | Boehringer Ingelheim Pharma | Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE10117204A1 (de) | 2001-04-06 | 2002-10-10 | Boehringer Ingelheim Pharma | In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
AU2003226705B2 (en) | 2002-03-30 | 2008-11-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 4-(N-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors |
US20040204458A1 (en) | 2002-08-16 | 2004-10-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of Lck inhibitors for treatment of immunologic diseases |
US7148249B2 (en) | 2002-09-12 | 2006-12-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinones substituted by heterocycles, the preparation thereof and their use as medicaments |
US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
PE20061155A1 (es) | 2004-12-24 | 2006-12-16 | Boehringer Ingelheim Int | Derivados de indolinona como agentes para el tratamiento o la prevencion de enfermedades fibroticas |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
US20060154939A1 (en) | 2004-12-24 | 2006-07-13 | Boehringer Ingelheim International Gmbh | Medicaments for the Treatment or Prevention of Fibrotic Diseases |
NZ588957A (en) | 2008-06-06 | 2013-03-28 | Boehringer Ingelheim Int | Pharmaceutical combination of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999015500A1 (en) * | 1997-09-05 | 1999-04-01 | Glaxo Group Limited | Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors |
WO2000056710A1 (en) * | 1999-03-04 | 2000-09-28 | Glaxo Group Limited | 3-(anilinomethylene) oxindoles as protein tyrosine kinase and protein serine/threonine kinase inhibitors |
WO2004013099A1 (en) * | 2002-07-24 | 2004-02-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition |
WO2004017948A2 (en) * | 2002-08-16 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of lck inhibitor for treatment of immunologic diseases |
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