TWI530483B - 作為激酶抑制劑的吲哚啉酮化合物 - Google Patents
作為激酶抑制劑的吲哚啉酮化合物 Download PDFInfo
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- TWI530483B TWI530483B TW098133446A TW98133446A TWI530483B TW I530483 B TWI530483 B TW I530483B TW 098133446 A TW098133446 A TW 098133446A TW 98133446 A TW98133446 A TW 98133446A TW I530483 B TWI530483 B TW I530483B
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- Prior art keywords
- keto
- tetrahydro
- indol
- porphyrin
- methylene
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- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title claims 3
- 229940043355 kinase inhibitor Drugs 0.000 title 1
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 20
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- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Description
本發明係關於吲哚啉酮化合物以及以該等化合物降低蛋白質激酶活性與治療蛋白質激酶相關疾病的方法。
相關申請案之參考文獻
本申請案主張2009年6月26日申請之美國發明申請案第12/492,281號之優惠,該第12/492,281號係主張2009年1月12日申請之美國臨時專利申請案第61/144,065號之優惠,其等之全部內容以引用形式併入本文作為參考文獻。
蛋白質激酶(PKs)在調控例如分化、增生、移動與凋亡之各種細胞功能的細胞信號途徑中扮演要角。
異常的PK活性已於包括癌症的數種疾病中相連結與觀察得到。參照K Novak,MedGenMed. 2004;6(2):25。因此,蛋白質激酶為具吸引力之治療標靶。PK抑制劑,即阻隔PKs活性之化合物,已開發且廣泛使用於臨床應用。例如,酪胺酸激酶抑制劑有用於抑制T-細胞增生且因而可使用作為移植手術後預防或治療移植物排斥的免疫壓制劑,且亦可使用於預行或治療自體免疫疾患(例如類風濕性關節炎、牛皮癬及HIV-AIDS)。
雖然已有超過三十種PK抑制劑正處於癌症治療之臨床試驗中,但仍需要治療各種疾患之新穎PK抑制劑的開發。
本發明係基於預料外之發現某些吲哚啉酮化合物可抑制蛋白質激酶(例如Aurora A與B、c-Met、VEGFr-2、FGFr-1、c-kit、PDGFr-與FLT3激酶)的活性,其使該等化合物應用於治療包括癌症之蛋白質激酶相關疾病。
於一態樣中,本發明提供式(I)之吲哚啉酮化合物:
式中,A為O或S;R1為H、烷基、烯基、炔基、鹵基、硝基、氰基、環烷基、雜環烷基、環烯基、雜環烯基、ORa、NRaRb、-S(O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb、-N=CRaRb或-NRaC(O)NHRb,其中Ra與Rb之各者獨立地為H、烷基、烯基、炔基、芳基、芳氧基、烷氧基、羥基、雜芳基、環烷基、雜環烷基、環烯基或雜環烯基,或Ra與Rb與其所鍵結之氮原子共同為雜芳基、雜環烷基或雜環烯基;R2、R3與R4之各者獨立地為H、鹵基、硝基、氰基、芳基、雜芳基、環烷基、雜環烷基、環烯基、雜環烯基、ORa、NRaRb、-S(O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb、-N=CRaRb或-NRaC(O)NHRb;以及R5為-C(O)ORc、-C(O)Rc、-C(O)NRcRd或-CH2NRcRd,其中Rc與Rd之各者獨立地為H、烷基、烯基或炔基,或Rc與Rd與其所鍵結之氮原子共同為雜芳基、雜環烷基或雜環烯基。
上述吲哚啉酮化合物之一亞群包括化合物,其中R5為-C(O)NRcRd,Rc與Rd與其所鍵結之氮原子共同為吡咯啶基、六氫吡啶基、六氫吡嗪基稠合、嗎啉基(各視需要地與芳基或雜芳基稠合)或雜芳基。該等化合物中,R2可為鹵基、-S(O)2Ra、-S(O)2NRaRb或-NRaS(O)2Rb,Ra與Rb之各者獨立地為H、視需要經芳基取代之烷基、芳基或雜芳基,或Ra與Rb與其所鍵結之氮原子共同為雜芳基、雜環烷基或雜環烯基;或R1、R3與R4之各者可為H。
上述吲哚啉酮化合物之另一亞群包括化合物,其中R1、R2、R3與R4之至少一者為-N=CRaRb或-NRaC(O)NHRb。
上述吲哚啉酮化合物之再一亞群包括化合物,其中R5為-C(O)ORc且Rc為H或烷基,或R5為-C(O)NRcRd,且其中Rc與Rd之一者為H且另一者為經烷基胺基取代之烷基。該等化合物中,R2可為鹵基、-S(O)2Ra、-S(O)2NRaRb或-NRaS(O)2Rb,其中Ra與Rb之各者獨立地為H或視需要經芳基取代之烷基、芳基或雜芳基,或Ra與Rb與其所鍵結之氮原子共同為雜芳基、雜環烷基或雜環烯基;或R1、R3與R4之各者可為H。
詞語「烷基」意指直鏈或支鏈之單價飽和烴,除非另行指明,該烴含有1至20個碳原子(例如C1-C10、C1-C6或C1-C4)。烷基之例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、與第三丁基。詞語「烯基」意指直鏈或支鏈單價烴,該烴含有2至20個碳原子(例如C2-C10)與個或多個雙鍵。烯基之例包括但不限於乙烯基、丙烯基、烯丙基與1,4-丁二烯基。詞語「炔基」意指直鏈或支鏈單價烴,該烴含有2至20個碳原子(例如C2-C10)與一個或多個叁鍵。炔基之例包括但不限於乙炔基、1-丙炔基、1-與2-丁炔基與1-甲基-2-丁炔基。詞語「烷氧基」意指-O-烷基基團。烷氧基之例包括但不限於甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基與第三丁氧基。詞語「醯氧基」意指-O-C(O)-R基團,其中R可為H、烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基或雜芳基。詞語「胺基」意指NH2。詞語「烷基胺基」意指-N(R)-烷基基團,其中R可為H、烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基或雜芳基。詞語「醯胺基」與「胺甲醯基」分別意指-NRC(O)R’與-C(O)NRR’基團,其中R與R’之各者獨立地可為H、烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基或雜芳基。
詞語「環烷基」意指單價飽和烴環系統,該烴環系統具有3至30個碳原子(例如C3-C12)。環烷基之例包括但不限於環丙基、環丁基、環戊基、環己基、環庚基、環辛基與金剛烷基。詞語「環烯基」意指單價非芳香族烴環系統,該烴環系統具有3至30個碳原子(例如C3-C12)與一個或多個雙鍵。其例包括環戊烯基、環己烯基與環庚烯基。詞語「雜環烷基」意指單價非芳香族之5至8員單環、8至12員雙環或11至14員叁環之環系統,該環系統具有一個或多個雜原子(如O、N、S或Se)。雜環烷基之例包括但不限於六氫吡嗪基、吡咯啶基、六氫吡啶基、二氧雜環己基、嗎啉基與四氫呋喃基。詞語「雜環烯基」意指單價非芳香族之5至8員單環、8至12員雙環或11至14員叁環之環系統,該環系統具有一個或多個雜原子(如O、N、S或Se)與一個或多個雙鍵。
詞語「芳基」意指單價6-碳單環、10-碳雙環、14-碳叁環之芳香族環系統。芳基之例包括但不限於苯基、萘基與蒽基。詞語「芳基氧基」意指-O-芳基。詞語「芳基胺基」意指-N(R)-芳基,其中R可為H、烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基或雜芳基。詞語「雜芳基」意指單價芳香族之5至8員單環、8至12員雙環或11至14員叁環之環系統,該環系統具有一個或多個雜原子(如O、N、S或Se)。雜芳基之例包括吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基、噻唑基、吡咯基、異喹啉基、嘌呤基、噁唑基、吡唑基與咔唑基。
上述之烷基、烯基、炔基、環烷基、雜環烷基、環烯基、雜環烯基、胺基、烷基胺基、芳基胺基、烷氧基、芳氧基、芳基與雜芳基包括經取代者與未經取代者。於胺基、烷基胺基、芳基胺基、烷氧基、芳氧基、環烷基、雜環烷基、環烯基、雜環烯基、芳基與雜芳基之可能取代基包括但不限於C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20環烷基、C3-C20環烯基、C1-C20雜環烷基、C1-C20雜環烯基、C1-C10烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1-C10烷基胺基、芳基胺基、羥基、鹵基、酮基(O=)、硫酮基(S=)、硫基、矽烷基、C1-C10烷基硫基、芳基硫基、C1-C10烷基磺醯基、芳基磺醯基、醯基胺基、胺基醯基、胺基硫基醯基、甲脒基、巰基、醯胺基、硫脲基、氰硫基,碸醯胺基、胍基、脲基、氰基、硝基、醯基、硫基醯基、醯基氧基、胺甲醯基、胺甲醯基(-C(O)NH2)、羧基(-COOH)與羧酸酯。另一方面,於烷基、烯基或炔基之可能取代基包括所有上述取代基,排除C1-C10烷基。環烷基、環烯基、雜環烷基、雜環烯基、芳基與雜芳基亦可彼此稠合。
另一態樣中,本發明關於式(II)之吲哚啉酮化合物:
式(II)中,A為O或S;R1、R2、R3與R4之各者獨立地為H、鹵基、硝基、氰基、芳基、雜芳基、環烷基、雜環烷基、環烯基、雜環烯基、ORa、NRaRb、-S(O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb、-N=CRaRb或-NRaC(O)NHRb,其中Ra與Rb之各者獨立地為H、烷基、烯基、炔基、芳基、芳氧基、烷氧基、羥基、雜芳基、環烷基、雜環烷基、環烯基或雜環烯基或Ra與Rb與其所鍵結之氮原子共同為雜芳基、雜環烷基或雜環烯基;R5為-C(O)ORc、-C(O)Rc、-C(O)NRcRd或-CH2NRcRd,其中Rc與Rd之各者獨立地為H、烷基、烯基或炔基,或Rc與Rd與其所鍵結之氮原子共同為雜芳基、雜環烷基或雜環烯基;R6與R7之各者獨立地為H或烷基;以及n為1或2。特別地,該吲哚啉酮為式(III)化合物:
上述吲哚啉酮化合物之一亞群包括化合物,其中R1、R2、R3與R4之至少一者為-N=CRaRb或-NRaC(O)NHRb。該等化合物中,R2與R3之一者可為-N=CRaRb或-NRaC(O)NHRb且另一者可為H;R1與R4之各者可為H且R5可為-C(O)ORc;或R6與R7兩者皆可為H或甲基。
吲哚啉酮化合物之另一亞群包括化合物,其中R5為-C(O)NRcRd,且Rc與Rd與其所鍵結之氮原子共同為吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基(各視需要地與芳基或雜芳基稠合)或雜芳基。該等化合物中,其中R2與R3之一者可為鹵基、-S(O)2Ra或-S(O)2NRaRb且另一者可為H;R1與R4之一者可為H;或R6與R7兩者皆可為H或甲基。
上述吲哚啉酮化合物之再另一亞群包括化合物,其中R2、R3與R4之至少一者為NRaRb、-S(O)2NRaRb或-C(O)NRaRb,且Ra與Rb,與其所鍵結之氮原子共同為吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基(各視需要地與芳基或雜芳基稠合)或雜芳基。該等化合物中,R5可為-C(O)ORc;R1、R3與R4之各者可為H。
上述吲哚啉酮化合物之再另一亞群包括化合物,其中n為2。該等化合物中,R2可為-NRaS(O)2Rb;R5可為-C(O)ORc;或R1、R3、R4、R6與R7之各者可為H。
上述吲哚啉酮化合物亦具有另一亞群,其中R5為-C(O)ORc,Rc為H或烷基。此亞群化合物中,R2與R3之一者可為H且另一者可為H、鹵基、硝基、芳基、-S(O)2Ra、-S(O)2NRaRb或-NRaS(O)2Rb;R1與R4之各者可為H;或R6與R7兩者皆可為H或甲基。
本文所述吲哚啉酮化合物包括化合物本身,以及可應用之其鹽類(包括醫藥上可接受鹽類)、其溶劑合物(包括醫藥上可接受溶劑合物)以及其前藥。鹽類,例如可形成於陰離子與吲哚啉酮化合物之正電荷基團(例如胺基)之間。合適的陰離子包括氯、溴、碘、硫酸根、硫酸氫根、胺磺酸根、硝酸根、磷酸根、磷酸氫根、檸檬酸根、氫氯酸根、氫溴酸根、磺酸根、甲烷磺酸根、對-甲苯磺酸根、2-羥基乙基磺酸根、苯甲酸根、水楊酸根、硬脂酸根、三氟乙酸根、麩胺酸根、葡萄糖醛酸根、戊二酸根、蘋果酸根、琥珀酸根、反丁烯二酸根、酒石酸根、甲苯磺酸根、水楊酸根、乳酸根、萘磺酸根與乙酸根。同樣地,鹽可形成於陽離子與吲哚啉酮化合物之負電荷基團(例如羧酸根)之間。合適的陽離子包括鈉離子、鉀離子、每離子、鈣離子與例如四甲基銨離子之銨離子。吲哚啉酮化合物亦包括含有四級氮原子之鹽類。前藥之例包括酯類、醯胺類與其他醫藥上可接受衍生物,其係投藥至對象時能提供活性吲哚啉酮化合物。
又一態樣中,本發明關於藉由使至少一種蛋白質激酶與上述一種或多種吲哚啉酮化合物接觸而降低至少一種蛋白質激酶活性的方法。標的之蛋白質激酶為Aurora A激酶、Aurora B激酶、VEGFr-2、FGFr-1、PDGFr-β、c-kit、c-Met或FLT3。
再者,本發明關於藉由對有需要之對象投藥有效量之上述一種或多種吲哚啉酮化合物而治療蛋白質激酶相關疾患之治療方法。該蛋白質激酶相關疾患可為過度增生疾患(例如癌症)、糖尿病、腎疾患(例如腎臟之過度增生疾患)、希-林氏症(von Hippel-Lindau disease)、纖維化、骨關節炎、自體免疫疾患(例如牛皮癬與類風濕性關節炎)或血管增生疾患(例如動脈粥樣硬化與再狹窄)。特別地,該蛋白質激酶相關疾患為癌症。
亦涵括於本發明範疇者為醫藥組成物,該醫藥組成物含有一種或多種上述吲哚啉酮化合物,使用於治療例如癌症之蛋白質激酶相關疾患,以及該等化合物之此治療用途與製造治療該疾患用之醫藥的用途。
本發明前述之一種或多種具體例的詳細內容說明於下文。本發明之其他特徵、目標以及優勢將由具體例之詳細說明以及本文所附之申請專利範圍而臻明確。
本發明之例示化合物示於下表1。
本發明之吲哚啉酮化合物可藉由傳統化學轉移法(包括保護基方法)而製備,該等方法例如揭示於R. Larock,Comprehensive Organic Transformations,VCH Publishers(1989);T.W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999);L. Fieser and M. Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and Sons(1994);and L. Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)以及其後續出版者。
示於下文流程1之途徑例示本發明吲哚啉酮化合物之合成。1,3-環己二酮(1)、5-胺基-左旋糖酸鹽酸鹽(2)、乙酸鈉與H2O之反應混合物於100℃加熱16小時而製得3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚(3)。3於乙醇(100mL)之溶液添加硫酸。所得反應混合物迴流12小時而製得3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚(4)呈黃色固體。然後於0℃,正甲酸三甲酯添加至含有4於三氟乙酸之溶液(47mL)。所形成之反應混合物於0℃攪拌30分鐘後,溫熱至室溫後攪拌2.0小時。混合物添加乙酸乙酯、水與NaOH。收集有機層,以飽和NaHCO3水溶液清洗,以MgSO4(固體)脫水後,減壓濃縮。純化油狀殘質而製得3-(3-乙氧基-3-酮基丙基)-2-甲醯基-4-酮基-4,5,6,7-四氫-1H-吲哚(5)呈黃色固體。其次,5與吲哚啉-2-酮(6)之混合物添加至EtOH與六氫吡啶。所得溶液迴流12小時。過濾所得沉澱且以EtOH清洗而製得對應之(Z)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮(7)。為獲得對應之羧酸(8),3.0N NaOH水溶液添加至7於EtOH之溶液;所得混合物迴流2小時後冷卻至室溫;然後以6NHCl酸化該溶液至pH 3.0;過濾所得沉澱且以MeOH清洗。為提供對應之鈉鹽(9),NaOH水溶液、MeOH與8之混合物可攪拌且加熱至沸騰;然後緩慢添加2-丙醇至該混合物;攪拌該溶液12小時。
所合成之吲哚啉酮化合物可進一步藉由快速管柱層析、高效液相層析、結晶或任何其他合適方法純化。
本文所述之吲哚啉酮化合物可含有非芳香族雙鍵與一個或多個不對稱中心。因此,其可產生為消旋物與消旋混合物、單一鏡像異構物、個別非鏡像異構物、非鏡像異構物混合物以及順式-或反式-異構物形式。本發明涵括所有該等異構物。
亦於本發明範疇為(1)醫藥組成物,其含有有效量之至少一種本發明吲哚啉酮化合物以及醫藥上可接受載劑;(2)藉由對有需藥治療之對象投藥有效量之該吲哚啉酮化合物以治療蛋白質激酶相關疾患(例如癌症)之治療方法;以及(3)藉由使至少一種蛋白質激酶與至少一種本發明吲哚啉酮化合物接觸而降低該至少一種蛋白質激酶活性之方法。
如使用於本文,詞語「蛋白質激酶相關疾患」意指特徵為異常PK活性之疾患或症狀,或者可以改變至少一種PK活性而加以治療之疾患或症狀。異常PK活性可造成結果為PK表現程度增加,或PK表現存在於正常狀況不發生的情況。本文之PK相關疾患包括但不限於癌症、糖尿病、過度增生疾患、腎臟之過度增生疾患、希-林氏症(von Hippel-Lindau disease)、再狹窄(restenosis)、纖維化、牛皮癬、骨關節炎、類風濕性關節炎、炎性疾患、免疫疾患如自體免疫疾患(例如AIDS、狼瘡等)、心血管疾患(例如動脈粥樣硬化)與血管增生疾患如血管新生異常。
詞語「治療」意指對具有蛋白質激酶相關疾患或具有預測導向該等疾患之症候群之對象投藥吲哚啉酮化合物,而期望治療、治癒、緩和、緩解、改變、治療、改善、改良、影響或減低疾患風險、導向該等疾患之症候群。例如,治療癌症意指治療結果為抑制癌症生長或癌細胞生長、延緩癌生長的進程(亦即減低可偵測癌之大小)或癌消失。詞語「有效量」意指於對象確認所欲治療效果之活性藥劑所需量。有效量可為此項技術領域中具有通常知識者,根據投藥途徑、賦形劑用量、及共同使用之其他藥劑之可能性,而加以變化。需要治療之對象可為哺乳動物。詞語「哺乳動物」意指人類或非人類哺乳動物,例如犬、貓、豬、牛、羊、山羊、馬、大鼠或小鼠。
可藉由本發明方法治療之癌症可為任何異常之細胞或組織生長,例如腫瘤,不論其為惡性,惡性前或非惡性。其特徵為細胞的不受調控的增生,而該細胞可為未侵入周圍組織,且因此可為或不為惡性移轉至新的體內位點。癌症涵括表皮細胞癌之細胞癌;細胞癌包括鱗狀細胞癌、細胞腺癌、黑色細胞瘤與肝癌。癌症亦涵括為間質起源腫瘤之肉瘤;肉瘤包括骨性肉瘤、白血症與淋巴癌。癌症可涉及一種或多種新生細胞形態。詞語癌症包括為非限制性例之肺癌、大腸癌、大腸直腸癌、乳癌、***癌、肝癌、胰臟癌、膀胱癌、胃癌、腎癌、唾液腺癌、卵巢癌、子宮癌、子宮頸癌、口腔癌、皮膚癌、腦癌、淋巴癌與白血病。亦包括藥物抗性癌(包括但不限於多藥物抗性癌)。
本文所述化合物可與放射療法、免疫療法、單株抗體療法、荷爾蒙療法、使用其他藥劑之化學療法及/或手術予以組合而投藥。組合時,療法不需要為同時,但可彼此為連續的或交替的及/或停止與恢復期間。
於一具體例中,蛋白質激酶相關疾患,例如癌症,係以包括投藥有效量之至少一種本發明吲哚啉酮與至少一種化療劑至哺乳動物之方法。至哺乳動物之方法。化療劑之非限制性例包本發所述者除外之PK抑制劑(例如甲磺酸依馬替尼(imatinib mesylate)、吉非替尼(gefitinib)、達沙替尼(dasatinib)、埃羅替尼(erlotinib)、拉帕替尼(lapatinib)、舒尼替尼(sunitinib)、尼羅替尼(nilotinib)與索拉非尼(sorafenib);抗體包括例如曲妥株單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)與貝伐株單抗(bevacizumab);米托蒽醌(mitoxantrone);***(dexamethasone);潑尼松(prednisone);與替莫唑胺(temozolomide))、烷基化劑(美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消胺(busulfan)、噻替哌(thiotepa)、依佛斯醯胺(ifosfamide)、卡莫斯汀(carmustine)、洛莫斯汀(lomustine)、斯莫斯汀(semustine)、鏈脲菌素(streptozocin)、氮烯咪胺(decarbazine)與環磷醯胺(cyclophosphamide))、有絲***抑制劑、抗代謝劑(例如卡培他濱(capecitibine)、健他西濱(gemcitabine)、5-氟脲嘧啶或5-氟脲嘧啶/甲葉酸(leucovorin)、氟達拉濱(fludarabine)、賽達拉濱(cytarabine)、巰嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、噴司他汀(pentostatin)與甲胺蝶呤(methotrexate))、細胞週期抑制劑、酵素類、荷爾蒙類、抗荷爾蒙類、生長因子抑制劑、植物生物鹼類(plant alkaloids)與萜類(terpenoids)、拓樸酶抑制劑(依托泊(etoposide)、替尼泊(teniposide)、喜樹鹼(camptothecin)、拓樸替康(topotecan)、依立替康(irinotecan)、多柔比星(doxorubicin)與道諾比星(daunorubicin))、抗腫瘤抗生素(例如放線菌素D、博來黴素(bleomycin)、撕裂黴素(mitomycin)C、阿黴素(adriamycin)、道諾比星(daunorubicin)、依達比星(idarubicin)、多柔比星(doxorubicin)與聚乙二醇微脂體(pegylated liposomal)多柔比星)、長春花生物鹼類(vinca alkaloids)(例如長春新鹼(vincristine)與長春鹼(vinblastin))、紫杉類(taxanes)(例如紫杉醇(paclitaxel)與多西紫杉醇(docetaxel))、鉑製劑(例如順鉑(cisplatin)、卡鉑(carboplatin)與草酸鉑(oxaliplatin))、沙利賣竇(thalidomide)與相關類似物(例如CC-5013與CC-4047)、單株抗體與抗血管新生劑。
如使用於本文,詞語「接觸」意指將本發明化合物與至少一種PK帶進一方式以使該化合物可減低該至少一種PK的活性,或直接地(亦即藉由作用於該蛋白質激酶本身)、或間接地(亦即藉由作用於另一分子而該至少一種PK的活性係取決於該分子)。「接觸」可發生於活體外或活體內。例如於含有至少一種PK的試管中;具有完整細胞生長的培養盤中;或於本發明化合物投藥之哺乳動物中。標靶PK之例包括但不限Aurora A & B激酶、MAP、CDK2、Raf、NEK(包括NEK 4a、NEK 4b、NEK 5NEK 6)、BUB1、VEGFR、C-MET、HER2、HER3、HER4、IR、IGF-IR、IRR、PDGFRct、PDGFRO、CSFIR、C-Kit、C-fms、F1k-1R、F1k4、KDR1F1k-1、FLT-1、FLT3、FGFR-1、FGFR-2、FGFR-3、FGFR4、Src、Frk、Btk、Csk、Abl、ZAP70、Fes、Fps、Fak、Jak、Ack、Yes、Fyn、Lyn、Lck、Blk、Hck、Fgr、Aur2與Yrk。
為實施本發明方法,上述醫藥組成物投藥可為經口地、腸道外地、藉由吸入噴霧、局部地、直腸地、鼻內地、口腔地、***內或經由植入儲存器。使用於本文之詞語「腸道外地」包括皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內、胸骨內、腦脊髓膜內、病灶內與顱內注射或輸注技術。於一具體例中,本發明吲哚啉酮化合物係靜脈內投藥,合適的載劑可包括但不限於生理鹽水或磷酸鹽緩衝鹽水(PBS),且溶液含有黏稠劑與溶解劑,如葡萄糖、聚乙二醇與聚丙二醇,以及其等之混合物。
無菌注射組成物,例如無菌注射水性或油性懸浮液,可根據此項技術領域習知之技術,使用合適的分散劑或濕潤劑(如Tween 80)與懸浮劑而調配。無菌注射製劑亦可為於無毒性腸道外可接受稀釋劑或溶劑中之無菌注射溶液或懸浮液,例如於1,3-丁二醇之溶液。可應用之可接受媒劑與溶劑為甘露醇、水可應用之可接受媒劑與溶劑為甘露醇、水、林格式液(Ringer’s solution)與等張氯化鈉溶液。此外,無菌之固體油為傳統上應用作為溶劑或懸浮媒介(例如合成之單或二甘油酯)。脂肪酸,如油酸與其甘油酯衍生物有用於注射劑製備,此乃因其為天然醫藥可接受油類,如橄欖油或蓖麻油,特別是其聚乙二醇化物。該等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑,或羧甲基纖維素或類似的分散劑。常使用於製造醫藥可接受固體、液體或其他劑量形式之其他常用的界面活性劑,如Tween或Spans,或其他類似的乳化劑或生物可利用性提升劑,亦可使用於調配目的。
經口投藥用組成物可為任何醫藥可接受形式,包括但不限於膠囊、錠劑、乳化物與水性懸浮物、分散物與溶液。於經口使用之啶劑的情況中,常使用之載劑包括乳糖與玉米澱粉。典型地亦添加潤滑劑,如硬脂酸鎂。經口投藥微膠囊形式時,有用的稀釋劑包括乳糖與乾燥玉米澱粉。當經口投藥水性懸浮物或乳化物時,活性成分可懸浮或溶解於組合有乳化劑或懸浮劑之油相。必要時,可添加某些甜味劑、矯味劑或著色劑。鼻之噴霧或吸入組成物可根據醫藥調配領域習知技術而製備。含吲哚啉酮化合物之組成物意可以栓劑形式投藥用於直腸投藥。
醫藥組成物中之載劑必須為「可接受」之意在於可與調配物之活性成分相容(且較佳地為可溶解)且對治療對向無不良處。可使用與活性吲哚啉酮化合物形成溶解性複合物之一種或多種溶解劑(例如環糊精),作為醫藥載劑以傳遞活性化合物。其他載劑之例包括膠體二氧化矽、硬脂酸鎂、月桂基硫酸鈉與D&C Yellow # 10。
可使用合適的活體外分析以預先評估本發明吲哚啉酮化合物於抗癌症活性(例如抑制腫瘤細胞生長)之效果。可進一步檢測該等化合物治療癌症的效果。例如,化合物可投藥至具有癌症之動物(例如老鼠模式)然後評定其治療效果。根據該等結果,亦可決定是當的劑量範圍與投藥途徑。
無須進一步說明,咸信上述揭示已充分使本發明能據以實施。因此,下述實施例僅作為例示說明,且不以任何方式侷限其餘揭示。所有公開文獻之全部內容以引用形式併入本文。
實施例1:合成(Z)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮(DCB-70049)與(Z)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮(DCB-70052)。除非另行指明,化合物編號係參照上述流程1。
3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚(3):5-胺基左旋糖酸 鹽酸鹽(2,50.0g,0.298mol)、1,3-環己二酮(1,40.2g,0.359mol)與乙酸鈉(48.8g,0.595mol)之混合物添加H2O(125mL)。反應混合物於100℃攪拌16小時。溶液冷卻至室溫且過濾所得沉澱,以水(200mL×2)清洗後,風乾而製得3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚(3,50.5g,0.245mol)呈黃色固體,產率82%。
3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚(4):3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚(3,52.0g,0.251mol)於乙醇(100mL)添加硫酸(1.0mL)。反應混合物加熱迴流12小時。減壓濃縮溶液且所得固體以水(200mL×2)清洗。風乾固體而製得 3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚(4,59.0g,0.251mol)呈黃色固體,產率>99%。
3-(3-乙氧基-3-酮基丙基)-2-甲醯基-4-酮基-4,5,6,7-四氫-1H-吲哚(5):於0℃,對含有3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚(4,10.0g,42.5mmol)之三氟乙酸溶液(47mL),添加正甲酸三甲酯(13.6g,128mmol)。反應於0℃攪拌30分鐘後,溫熱至室溫且攪拌2小時。該溶液添加乙酸乙酯(250mL)、水(200mL)與NaOH(18g)。收集有機層且以飽和NaHCO3水溶液(200mL)清洗,以MgSO4(s)脫水後,減壓濃縮。油狀殘質藉由管柱層析(50% EtOAc於己烷)純化而製得3-(3-乙氧基-3-酮基丙基)-2-甲醯基-4-酮基-4,5,6,7-四氫-1H-吲哚(5,2.1g,8.0mmol)呈黃色固體,產率19%。
(Z)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮(DCB-70049):化合物5(0.50mmol)與吲哚啉-2-酮(0.50mmol)之混合物添加EtOH(5.0mL)與六氫吡啶(0.1mL)。反應加熱迴流12小時。過濾所得沉澱且以EtOH清洗而提供所欲產物。1H NMR(CDCl3)δ7.93(s,1H),7.61(s,1H),7.59(d,1H、ArH),7.19(dd,1H),7.09(dd,1H),6.89(d,1H),4.07(q,2H),3.27(t,2H),2.91(t,2H),2.74(t,2H),2.52(t,2H),2.14-2.19(m,2H),1.18(t,3H).
(Z)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮(DCB-70052):對含有(Z)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮(0.50mmol)之EtOH溶液(3.0mL)添加3.0N NaOH水溶液(1.0mL)。反應加熱迴流2.0小時後冷卻至室溫。溶液以6N HCl酸化至pH 3.0。過濾所得沉澱且以MeOH清洗而提供所欲產物。1H NMR(DMSO-d 6 )δ13.76(s,1H),11.01(s,1H),7.77(s,1H),7.76(d,1H),7.17(dd,1H),7.01(dd,1H),6.89(dd,1H、),3.15(t,2H),2.91(t,2H),2.36-2.41(m,2H),2.06(t,2H).
實施例2:合成列於表1之其他化合物。
列於上述表1之其他吲哚啉酮化合物係以實施例1之類似方式合成。其質譜數據提供如下。
DCB-70053: 1H NMR(CDCl3)δ7.73(s,1H),7.59(s,1H),7.30(dd,ArH),6.89(m,1H),6.81(dd,1H),4.07(q,2H),3.27(t,2H),2.92(t,2H),2.74(t,2H),2.52(t,2H),2.15-2.20(m,2H),1.19(t,3H).
DCB-70055: 1H NMR(d 6-DMSO)δ13.79(s,1H),11.01(s,1H),7.83(s,1H),7.75(dd,1H),6.95-6.99(m,1H),(dd,1H),3.17(t,2H),2.91(t,2H),2.40-2.47(m,2H,),2.07(t,2H).
DCB-70056: 1H NMR(d 6-DMSO)δ13.74(s,1H),11.11(s,1H),8.10(d,1H),7.83(s,1H),7.30(dd,1H),6.83(d,1H),4.01(q,2H),3.23(t,2H),2.91(t,2H),2.57(t,2H),2.40(t,2H),2.04-2.09(m,2H),1.14(t,3H).
DCB-70057: 1H NMR(d 6-DMSO)δ13.74(s,1H),11.12(s,1H),8.08(d,1H),7.88(s,1H),7.31(dd,1H),6.84(d,1H),3.19(t,2H),2.92(t,2H),2.36-2.42(m,2H),2.07(t,2H).
DCB-70058: 1H NMR(DMSO-d 6)δ13.84(s,1H),11.04(s,1H),9.02(s,1H),8.04(s,1H),7.86(s,1H),7.41(d,1H),7.20(d,1H),7.10(dd,1H),6.93(d,1H),6.85(d,1H),3.98(q,2H),3.87(s,1H),3.24(t,2H),2.92(t,2H),2.61(t,2H),2.41(t,2H),2.00-2.09(m,2H),1.10(t,3H).
DCB-70059: 1H NMR(DMSO-d 6)δ13.73(s,1H,NH),8.08(s,1H,OH),8.02(s,1H,ArH),7.38(d,J=8.1Hz,1H,ArH),7.22(d,1H),7.20(d,1H),7.09(m,1H),6.90(m,1H),6.84(m,1H),3.86(s,3H),3.16(m,2H),2.89(m,2H),2.38(m,2H),2.16(m,2H),2.06(m,2H).
DCB-70062: 1H NMR(DMSO-d 6)δ13.61(s,1H),8.84(s,1H),8.11(m,2H),7.06(d,1H),4.02(q,2H),3.27(m,2H),2.94(m,2H),2.60(m,2H),2.41(m,2H),2.06(m,2H),1.14(t,3H).
DCB-70063: 1H NMR(DMSO-d 6)δ13.52(s,1H),11.57(s,1H),8.73(d,1H),8.02-8.05(m,2H),6.99(d,1H),3.18(m,2H),2.89(m,2H),2.48(m,2H),2.39(m,2H),2.05(m,2H).
DCB-70064: 1H NMR(DMSO-d 6)δ13.72(s,1H),11.42(s,1H),8.23(d,1H),7.91(s,1H),7.59(dd,1H),7.25(dd,1H),7.07(d,1H),4.00(q,2H),3.23(t,2H),2.93(t,2H),2.62(t,2H),2.40-2.42(m,5H),2.03-2.10(m,2H),1.12(t,3H).
DCB-70065: 1H NMR(DMSO-d 6)δ13.72(s,1H),11.42(s,1H),8.22(d,1H),7.91(s,1H),7.60(dd,1H),7.25(d,1H),7.07(d,1H),3.23(t,2H),2.93(m,2H),2.61(m,2H),2.41(m,4H),2.06(m,2H),1.12(t,3H).
DCB-70066: 1H NMR(DMSO-d 6)δ13.74(s,1H),11.06(s,1H,),9.57(s,1H),7.81(d,1H),7.71(s,1H),7.47,(d,2H),7.24(d,1H),7.04(s,1H),6.85(d,2H),4.00(q,2H),3.20(m,2H),2.92(m,2H),2.60(m,2H),2.41(m,2H),2.06(m,2H),1.12(t,3H).
DCB-70067: 1H NMR(DMSO-d 6)δ13.84(s,1H),11.07(s,1H),8.07(s,2H),7.43(s,1H),7.20(m,2H),6.88-6.99(m,2H),3.98(q,2H),3.86(s,3H),3.79(s,3H),3.16(t,2H,),2.88(t,2H),2.37(m,2H),2.00(m,2H).
DCB-70068: 1H NMR(DMSO-d 6)δ13.70(s,1H),11.03(s,1H),8.03(s,2H),7.41(d,1H),7.19(m,2H),6.91-7.01(m,2H),3.85(s,3H),3.77(s,3H),3.15(t,2H),2.89(t,2H),2.37(m,2H),2.04(m,2H).
DCB-70069: 1H NMR(DMSO-d 6)δ13.80(s,1H,NH),11.21(s,1H),8.29(s,1H),7.95(m,2H),7.83(m,2H),7.56(t,1H),7.34-7.39(m,2H),7.00(d,1H),4.01(q,2H),3.29(m,2H),2.93(m,2H),2.64(m,2H),2.42(m,2H),2.07(m,2H),1.13(t,3H).
DCB-70070: 1H NMR(DMSO-d 6)δ13.61(s,1H),8.19(s,1H),8.08(s,1H),7.92(d,1H),7.77(d,2H),7.45(d,1H),7.29-7.37(m,2H),6.91(s,1H),3.18(m,2H),2.81(m,2H),2.35(m,2H),2.28(m,2H),2.01(m,2H).
DCB-70071: 1H NMR(DMSO-d 6)δ13.66(s,1H),8.19(s,1H),8.18(s,1H),7.43(q,1H),7.30(m,3H),7.20(m,2H),7.01(d,1H),4.61(s,2H),3.20(m,2H),2.93(m,2H),2.53(m,2H),2.44(m,2H),2.07(m,2H).
DCB-70072: 1H NMR(DMSO-d 6)δ13.67(s,1H),12.11(s,1H),11.49(s,1H),8.22(s,1H),7.94(s,1H),7.40(m,1H),7.22(m,2H),7.13(m,2H),7.01(d,1H),4.63(s,2H),3.21(m,2H),2.94(m,2H),2.53(m,2H),2.43(m,2H),2.07(m,2H).
DCB-70073: 1H NMR(DMSO-d 6)δ13.65(s,1H),11.52(s,1H),8.21(s,1H),7.94(s,1H),7.47-7.51(m,3H),7.37-7.40(m,1H),7.06(d,1H),3.20(m,2H),2.93(m,2H),2.52(m,2H),2.42(m,2H),2.06(m,2H),1.05(m,2H).
DCB-70074: 1H NMR(DMSO-d 6)δ13.82(s,1H),11.02(s,1H),10.22(s,1H),8.04-8.07(m,3H),7.63(s,1H),7.48-7.50(m,1H),7.35-7.39(m,2H),6.89(d,1H),3.99(q,2H),3.15(m,2H),2.92(m,2H),2.63(m,2H),2.41(m,2H),2.06(m,2H),1.11(t,3H).
DCB-70075: 1H NMR(DMSO-d 6)δ13.72(s,1H),12.06(brs,1H),11.05(s,1H),9.58(s,1H),7.78(d,1H),7.73(s,1H),7.47(d,2H),7.23(m,1H),7.03(d,1H),6.85(d,2H),3.16(m,2H),2.91(m,2H),2.51(m,2H),2.40(m,2H),2.05(m,2H).
DCB-70076: 1H NMR(DMSO-d 6)δ13.79(s,1H),11.00(s,1H),10.22(s,1H),8.06(m,2H),7.98(s,1H),7.66(s,1H),7.53(m,1H),7.36(m,2H),6.88(m,1H),3.12(m,2H),2.91(m,2H),2.53(m,2H),2.40(m,2H),2.06(m,2H).
DCB-70077: 1H NMR(DMSO-d 6)δ13.74(s,1H),7.80(d,1H),7.70(s,1H),7.20(d,1H),6,92-7.03(m,3H),6.81(d,1H),4.00(q,2H),3.19(m,2H),2.92(m,2H),2.60(m,2H),2.41(m,2H),2.06(m,2H),1.12(t,3H).
DCB-70078: 1H NMR(DMSO-d 6)δ13.72(s,1H),11.04(s,1H),9.07(d,2H),7.73-7.78(m,2H),7.18-7.20(m,1H),6.92-7.03(m,3H),6.81(d,1H),3.16(m,2H),2.91(m,2H),2.41(m,2H),2.06(m,2H).
DCB-70079: 1H NMR(DMSO-d 6)δ.13.74(s,1H),7.71-7.96(m,5H),7.24-7.48(m,4H),4.00(m,2H),3.21(m,2H),2.92(m,2H),2.60(m,2H),2.41(m,2H),2.01(m,2H),1.12(m,3H).
DCB-70080: 1H NMR(DMSO-d 6)δ13.57(s,1H),11.39(brs,1H),7.72-8.05(m,5H),7.21-7.38(m,4H),3.16(m,2H),2.91(m,2H),2.41(m,2H),2.14(m,2H),1.97(m,2H).
DCB-70081: 1H NMR(DMSO-d 6)δ13.76(s,1H),11.06(s,1H),9.14(s,1H),7.82(d,1H),7.72(s,1H),7.29(m,1H),7.17(m,1H),7.07(m,2H),6.86(d,1H),4.00(q,2H),3.86(s,3H),3.20(m,2H),2.92(m,2H),2.61(m,2H),2.41(m,2H),2.06(m,2H),1.13(t,3H).
DCB-70082: 1H NMR(DMSO-d 6)δ13.74(s,1H),11.05(s,1H),7.78(m,2H),7.27(m,1H),7.17(1H),7.06(m,2H),6.86(m,1H),3.86(s,3H),3.16(m,2H),2.92(m,2H),2.41(m,2H),2.06(m,2H).
DCB-70083: 1H NMR(DMSO-d 6)δ.14.79(s,1H),7.88-8.01(m,2H),7.02-7.25(m,3H),3.95(m,2H),3.31(m,2H),3.00(m,2H),2.63(m,2H),2.45(m,2H),2.08(m,2H),1.10(m,3H).
DCB-70084: 1H NMR(DMSO-d 6)δ9.72(s,1H),8.23(s,1H),6.80-6.98(m,3H),6.60-6.58(m,2H),3.06(m,2H),2.73(m,2H),2.27(m,2H),2.06(m,2H).
DCB-70085: 1H NMR(DMSO-d 6)δ14.69(s,1H),7.83-8.03(m,2H),7.16-7.33(m,2H),3.94(m,2H),3.37(m,2H),2.95(m,2H),2.61(m,2H),2.45(m,2H),2.07(m,2H),1.08(m,3H).
DCB-70086: 1H NMR(DMSO-d 6)δ9.69(s,1H),6.68-7.06(m,5H),3.02(m,2H),2.72(m,2H),2.28(m,2H),2.20(m,2H).
DCB-70087: 1H NMR(DMSO-d 6)δ13.73(s,1H),8.25(s,1H),8.03(s,1H),7.61(d,1H),7.08(s,1H),3.22(m,2H),3.16(m,4H),2.93(m,2H),2.53(m,2H),2.42(m,2H),2.04(m,2H),1.64(m,4H).
DCB-70088: 1H NMR(DMSO-d 6)δ13.71(s,1H),11.49(s,1H),8.18(s,1H),8.01(s,1H),7.54(d,1H),7.11(d,1H),3.64(m,4H),3.21(m,2H),2.93(m,6H),2.53(m,2H),2.41(m,2H),2.05(m,2H).
DCB-70091: 1H NMR(DMSO-d 6)δ13.83(s,1H),10.91(s,1H),8.49(s,1H),8.46(s,1H),7.77(s,1H),7.61(s,1H),7.33(m,2H),7.18(m,1H),7.07(m,2H),6.81(d,1H),3.99(q,2H),3.15(m,2H),2.92(m,2H),2.62(m,2H),2.49(m,2H),2.23(s,3H),2.03(m,2H),1.10(t,3H).
DCB-70092: 1H NMR(DMSO-d 6)δ13.83(s,1H),10.93(s,1H),8.49(s,1H),8.46(s,1H),7.77(s,1H),7.61(s,1H),7.32(m,2H),7.18(m,1H),7.07(m,2H),6.81(m,1H),3.98(q,2H),3.15(m,2H),2.91(m,2H),2.61(m,1H),2.38(m,2H),2.23(s,3H),2.04(m,2H),1.10(t,3H).
DCB-70093: 1H NMR(DMSO-d 6)δ13.83(s,1H),10.90(s,1H),8.42(s,1H),8.41(s,1H),7.77(s,1H),7.60(s,1H),7.34(m,2H),7.18(m,1H),6.85(m,3H),3.97(q,2H),3.69(s,3H),3.29(m,2H),2.90(m,2H),2.61(m,2H),2.40(m,2H),2.05(m,2H),1.10(t,3H).
DCB-70093: 1H NMR(DMSO-d 6)δ13.84(s,1H),11.92(s,1H),10.98(s,1H),8.51(d,1H),7.78(d,1H),6.88-7.18(m,6H),3.18(m,2H),3.07(m,2H),2.63(m,2H),2.41(m,2H),2.06(m,2H).
DCB-70094: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.91(s,1H),11.03(s,1H),8.50(s,1H),8.45(s,1H),7.81(s,1H),7.69(s,1H),6.89-7.24(m,6H),3.76(s,1H),3.17(m,2H),3.05(m,2H),2.63(m,2H),2.40(m,2H),2.05(m,2H).
DCB-70095: 1H NMR(DMSO-d 6)δ11.67(s,1H),8.21(s,1H),7.86(s,1H),7.65(m,1H),7.21(s,1H),7.02(d,1H),3.16(m,2H),2.91(m,2H),2.53(m,2H),2.40(m,2H),2.05(m,2H).
DCB-70096: 1H NMR(DMSO-d 6)δ13.83(s,1H),11.03(s,1H),10.21(s,1H),7.97-8.06(m,3H),7.51-7.63(m,5H),6.90(d,1H),3.99(q,2H),3.16(m,2H),2.92(m,2H),2.63(m,2H),2.41(m,2H),2.06(m,2H),1.11(t,3H).
DCB-70097: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.01(s,1H),10.20(s,1H),7.99(m,3H),7.57(m,5H),6.89(d,1H),3.12(m,2H),2.92(m,2H),2.40(m,2H),2.06(m,2H).
DCB-70098: 1H NMR(DMSO-d 6)δ7.85(m,1H),7.75(s,1H),7.68(m,2H),7.27(m,3H),7.10(s,1H),3.97(q,2H),3.19(m,2H),2.91(m,2H),2.59(m,2H),2.40(m,2H),2.04(m,2H),1.10(t,3H).
DCB-70099: 1H NMR(DMSO-d 6)δ13.71(s,1H),11.12(s,1H),7.83(t,2H),7.68(t,2H),7.28(m,3H),7.10(s,1H),3.15(m,2H),2.91(m,2H),2.41(m,4H),2.01(m,2H).
DCB-70100: 1H NMR(DMSO-d 6)δ7.89(d,1H),7.79(s,1H),7.42(m,3H),7.17(m,2H),3.97(q,2H),3.19(m,2H),2.91(m,2H),2.59(m,2H),2.04(m,2H),1.10(t,3H).
DCB-70101: 1H NMR(DMSO-d 6)δ13.73(s,1H),11.17(s,1H),7.86(m,2H),7.42(m,3H),7.21(m,2H),3.17(m,2H),2.92(m,2H),2.41(m,2H),2.01(m,2H).
DCB-70102: 1H NMR(DMSO-d 6)δ13.74(s,1H),11.12(s,1H),7.71(m,2H),7.56(m,4H),7.45(s,1H),6.74(m,2H),3.99(q,2H),3.15(m,2H),2.90(m,2H),2.62(m,2H),2.41(m,2H),2.04(m,2H),1.09(t,3H).
DCB-70103: 1H NMR(DMSO-d 6)δ13.70(s,1H),10.96(s,1H),7.73(s,1H),7.54-7.60(m,4H),7.40(m,1H),6.74(m,2H),2.90(m,2H),2.42(m,2H),2.05(m,2H).
DCB-70104: 1H NMR(DMSO-d 6)δ13.79(s,1H),10.94(s,1H),9.84(s,1H),7.77(s,1H),7.60(s,1H),7.39(m,1H),6.82(s,1H),3.10(m,2H),2.91(m,2H),2.53(m,2H),2.41(m,2H),2.06(m,2H),2.02(s,1H).
DCB-70106: 1H NMR(DMSO-d 6)δ13.60(s,1H),11.42(s,1H),8.27(s,1H),7.93(s,1H),7.55-7.60(m,2H),7.12-7.20(m,2H),6.95-6.99(m,2H),3.92(t,2H),3.23(m,2H),2.91(m,4H),2.51(m,2H),2.42(m,2H),2.05(m,2H).
DCB-70107: 1H NMR(DMSO-d 6)δ13.76(s,1H),11.58(s,1H),8.23(s,1H),8.02(s,1H),7.57(m,1H),7.14(d,1H),3.22(m,6H),2.94(m3H),2.64(m,3H),2.53(m,2H),2.43(m,2H),2.06(m,2H).
DCB-70108: 1H NMR(DMSO-d 6)δ13.82(s,1H),11.10(s,1H),8.12(s,1H),7.89(s,1H),7.73(m,2H),7.46(m,1H),7.29(m,2H),6.97(d,1H),3.98(q,2H),3.24(m,2H),2.92(m,2H),2.61(m,2H),2.41(m,2H),2.06(m,2H),1.10(t,3H).
DCB-70109: 1H NMR(DMSO-d 6)δ13.68(s,1H),8.14(s,1H),8.06(s,1H),7.76(m,2H),7.41(m,1H),7.24(m,2H),6.94(d,1H),3.14(m,2H),2.89(m,2H),2.38(m,2H),2.05(m,2H).
DCB-70114: 1H NMR(DMSO-d 6)δ13.73(s,1H),11.45(s,1H),8.17(s,1H),8.01(s,1H),7.52(d,1H),7.09(d,1H),3.22(m,2H),2.89-2.93(m,6H),2.53(m,2H),2.41(m,2H),2.06(m,2H),1.55(m,4H),1.35(m,2H).
DCB-70115: 1H NMR(DMSO-d 6)δ13.67(s,1H),11.48(s,1H),8.32(s,1H),7.99(s,1H),7.62(d,1H),7.08(d,1H),5.71-5.73(m,1H),5.31(d,1H),5.24(d,1H),4.08(d,2H),3.20(m,2H),2.93(m,2H),2.54(m,2H),2.41(m,2H),2.06(m,2H).
DCB-70116: 1H NMR(DMSO-d 6)δ13.69(s,1H),11.49(s,1H),8.35(s,1H),8.01(s,1H),7.67(d,1H),7.10(d,1H),3.19-3.27(m,4H),2.93(m,2H),2.53(m,2H),2.41(m,2H),2.06(m,2H),1.13(t,3H).
DCB-70117: 1H NMR(DMSO-d 6)δ13.70(s,1H),11.41(s,1H),8.17(s,1H),7.87(s,1H),7.59(d,1H),7.26(d,1H),7.07(d,1H),3.18(m,2H),3.92(m,2H),2.58(m,2H),2.42(m,5H),2.12(m,9H).
DCB-70118: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.04(s,1H),9.46(s,1H),7.64(s,1H),7.58(s,1H),7.05(d,1H),6.87(d,1H),3.99(q,2H),3.17(m,2H),3.03(m,2H),2.93(m,2H),2.63(m,2H),2.41(m,2H),2.06(m,2H),1.11(t,3H).
DCB-70119: 1H NMR(DMSO-d 6)δ13.79(s,1H),11.03(s,1H),9.44(s,1H),7.68(s,1H),7.55(s,1H),7.21(s,1H),7.06(d,1H),6.87(d,1H),6,65(s,1H),3.13(m,2H),3.03(m,2H),2.92(m,2H),2.63(m,2H),2.42(m,2H),2.01(m,2H).
DCB-70120: 1H NMR(DMSO-d 6)δ13.70(s,1H),8.23(s,1H),7.98(s,1H),7.61(d,1H),7.08(d,1H),3.24(m,4H),3.17(m,2H),2.94(m,2H),2.57(m,2H),2.43(m,2H),2.06-2.13(m,9H).
DCB-70121: 1H NMR(DMSO-d 6)δ13.73(s,1H),12.04(s,1H),11.45(s,1H),8.21(s,1H),8.02(s,1H),7.55(d,1H),7.10(d,1H),3.22(m,2H),2.93(m,2H),2.62(s,6H),2.53(m,2H),2.42(m,2H),2.06(m,2H).
DCB-70122: 1H NMR(DMSO-d 6)δ13.61(s,1H),11.15(s,1H),7.83(m,1H),7.72(m,1H),6.84(m,1H),6.71(m,1H),3.98(q,2H),3.19(m,2H),2.91(m,2H),2.58(m,2H),2.40(m,2H),2.06(m,2H),1.13(t,3H).
DCB-70123: 1H NMR(DMSO-d 6)δ13.58(s,1H),11.13(s,1H),7.79(m,1H),7.73(s,1H),6.83(m,1H),6.71(m,1H),3.15(m,2H),2.91(m,2H),2.40(m,2H),2.05(m,2H).
DCB-70124:1H NMR(DMSO-d 6)δ13.80(s,1H),10.99(s,1H),7.83(s,1H),7.75(m,1H),6.97(m,1H),6.85(m,1H),3.21(m,6H),2.92(m,2H),2.53(m,2H),2.41(m,2H),2.05(m,2H),0.98(m,6H).
DCB-70125: 1H NMR(DMSO-d 6)δ13.80(s,1H),11.00(s,1H),7.74-7.85(m,2H),6.97(m,1H),6.85(m,1H),3.38-3.48(m,6H),3.18(m,2H),2.91(m,2H),2.51(m,2H),2.41(m,2H),2.05(m,2H).
DCB-70128: 1H NMR(DMSO-d 6)δ13.75(s,1H),7.83(d,1H),7.74(s,1H),7.27(d,1H),7.23(s,1H),7.13(d,1H),7.05(s,1H),7.00(d,1H),6.07(s,2H),3.99(q,2H),3.22(m,2H),2.92(m,2H),2.60(m,2H),2.41(m,2H),2.06(m,2H),1.12(t,3H).
DCB-70129: 1H NMR(DMSO-d 6)δ13.84(s,1H),10.94(s,1H),10.25(s,1H),8.95(s,1H),8.74(s,1H),7.84-8.13(m,3H),7.45-7.65(m,5H),7.21(m,1H),6.76(m,1H),3.99(q,2H),3.17(m,2H),2.92(m,2H),2.63(m,2H),2.41(m,2H),2.06(m,2H),1.11(t,3H).
DCB-70130: 1H NMR(DMSO-d 6)δ13.67(s,1H),11.15(s,1H),7.79(s+d,2H),7.21(d,1H),7.04(s,1H),3.98(q,2H),3.19(m,2H),2.92(m,2H),2.60(m,2H),2.41(m,2H),2.06(m,2H),1.12(t,2H).
DCB-70131: 1H NMR(DMSO-d 6)δ13.92(s,1H),10.60(s,1H),7.21-7.49(m,6H),7.05(s,1H),6.61(d,1H),6.45(m,1H),4.28(d,2H),3.98(q,2H),3.14(m,2H),2.89(m,2H),2.61(m,2H),2.38(m,2H),2.05(m,2H),1.10(t,3H).
DCB-70132: 1H NMR(DMSO-d 6)δ13.73(s,1H),11.13(s,1H),6.99-7.77(m,9H),3.17(m,2H),2.92(m,2H),2.63(m,2H),2.46(m,2H),2.06(m,2H).
DCB-70133: 1H NMR(DMSO-d 6)δ13.67(s,1H),7.83(s,1H),7.54(s,1H),6.99-7.09(m,2H),3.10(m,2H),2.87(m,2H),2.38(m,2H),2.04(m,2H).
DCB-70134: 1H NMR(DMSO-d 6)δ13.85(s,1H),10.93(s,1H),8.62(s,1H),8.53(s,1H),7.80(s,1H),7.64(s,1H),7.48(m,2H),7.29(m,2H),7.22-7.30(m,2H),6.97(m,1H),6.84(m,1H),4.01(q,2H),3.18(m,2H),2.93(m,2H),2.64(m,2H),2.48(m,2H),2.08(m,2H),1.13(t,3H).
DCB-70135: 1H NMR(DMSO-d 6)δ13.85(s,1H),10.94(s,1H),8.78(s,1H),8.57(s,1H),7.81(s,1H),7.64(s,1H),7.43(m,6H),7.20(m,1H),6.84(m,1H),4.01(q,2H),3.18(m,2H),2.93(m,2H),2.64(m,2H),2.43(m,2H),2.07(m,2H),1.13(t,3H).
DCB-70136: 1H NMR(DMSO-d 6)δ13.85(s,1H),10.93(s,1H),8.65(s,1H),8.52(s,1H),7.80(s,1H),7.63(s,1H),7.48(m,2H),7.11-7.22(m,3H),6.84(m,1H),4.01(q,2H),3.18(m,2H),2.93(m,2H),2.64(m,2H),2.43(m,2H),2.07(m,2H),1.13(t,3H).
DCB-70137: 1H NMR(DMSO-d 6)δ13.85(s,1H),10.96(s,1H),9.13(s,1H),8.70(s,1H),8.14(s,1H),7.81(s,1H),7.61-7.67(m,3H),7.22(m,1H),6.85(m,1H),4.01(q,2H),3.19(m,2H),2.93(m,2H),2.63(m,2H),2.43(m,2H),2.08(m,2H),1.13(t,3H).
DCB-70138: 1H NMR(DMSO-d 6)δ13.88(s,1H),11.00(s,1H),7.78(m,2H),6.96(m,1H),6.86(m,1H),4.00(q,2H),3.21(m,2H),3.02(m,2H),2.62(m,2H),1.79-1.86(m,4H),1.13(t,3H).
DCB-70139: 1H NMR(DMSO-d 6)δ13.86(s,1H),10.99(s,1H),7.81(s,1H),7.74(m,1H),6.96(m,1H),6.86(m,1H),3.15(m,2H),3.02(m,2H),2.62(m,2H),2.46(m,2H),1.79-1.86(m,4H).
DCB-70140: 1H NMR(DMSO-d 6)δ11.06(s,1H),10.53(s,1H),8.39(m,2H),8.22(m,2H),8.06(s,1H),7.65(s,1H),7.53(m,1H),6.92(m,1H),4.00(q,2H),3.17(m,2H),2.93(m,2H),2.64(m,2H),2.42(m,2H),2.07(m,2H),1.11(t,3H).
DCB-70141: 1H NMR(DMSO-d 6)δ13.84(s,1H),11.01(s,1H),10.05(s,1H),8.05(s,1H),7.98(d,2H),7.63(s,1H),7.50(d,1H),7.06(d,2H),6.88(m,2H),4.00(q,2H),3.84(s,1H),3.16(m,2H),2.93(m,2H),2.63(m,2H),2.42(m,2H),2.07(m,2H),1.12(t,3H).
DCB-70142: 1H NMR(DMSO-d 6)δ13.83(s,1H),11.06(s,1H),10.54(s,1H),8.37(m,2H),8.23(m,2H),8.02(s,1H),7.75(s,1H),7.57(m,1H),6.93(m,1H),3.13(m,2H),2.93(m,2H),2.42(m,2H),2.07(m,2H).
DCB-70143: 1H NMR(DMSO-d 6)δ13.83(s,1H),11.01(s,1H),10.06(s,1H),8.00(m,3H),7.66(br,1H),7.53(br,1H),7.07(br,2H),6.87(br,1H),3.84(s,1H),3.20(m,2H),2.92(m,2H),2.41(m,2H),2.06(m,2H).
DCB-70144: 1H NMR(DMSO-d 6)δ13.76(s,1H),11.00(s,1H),9.94(s,1H),7.76(m,2H),7.60(s,1H),7.49(s,1H),7.39(m,2H),6.74(brs,2H),4.00(q,3H),3.16(s,1H),2.91(s,1H),2.62(s,1H),2.41(s,1H),1.99(t,3H).
DCB-70145: 1H NMR(DMSO-d 6)δ13.75(s,1H),12.05(br,1H),10.99(s,1H),9.95(s,1H),7.78(m,2H),7.64(9,1H),7.48(s,1H),7.39(m,2H),6.74(m,2H),3.13(s,1H),2.91(s,1H),2.54(s,1H),2.41(s,1H),2.06(t,3H).
DCB-70146: 1H NMR(DMSO-d 6)δ13.83(s,1H),10.96(s,1H),9.92(s,1H),7.72(m,2H),7.45-7.60(m,5H),6.74(m,2H),4.01(q,2H),3.16(m,2H),3.02(m,2H),2.55-2.64(m,4H),1.79-1.86(m,4H),1.11(t,3H).
DCB-70147: 1H NMR(DMSO-d 6)δ13.81(s,1H),12.09(brs,1H),10.99(s,1H),9.95(s,1H),7.74(m,2H),7.53-7.62(m,4H),6.74(m,2H),3.12(m,2H),3.02(m,2H),2.63(m,2H),2.47(m,2H),1.79-1.86(m,4H).
DCB-70148: 1H NMR(DMSO-d 6)δ13.81(s,13.66),8.01(s,1H),7.90(s,1H),7.36(m,2H),7.24(m,2H),7.15(m,1H),7.02(m,1H),3.14-3.21(m,5H),2.93(m,2H),2.52(m,2H),2.42(m,2H),2.06(m,2H).
DCB-70149: 1H NMR(DMSO-d 6)δ13.63(s,1H),11.43(s,1H),10.37(s,1H),8.23(s,1H),7.92(s,1H),7.53(d,1H),7.25-7.31(m,2H),7.10(m,1H),7.02(m,1H),3.19(m,2H),2.92(m,2H),2.53(m,2H),2.41(m,2H),2.05(m,2H).
DCB-70150: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.05(s,1H),9.59(s,1H),7.80(d,1H),7.69(s,1H),7.48(d,2H),7.24(m,1H),7.04(s,1H),6.85(m,2H),3.99(q,2H),3.15(m,2H),3.02(m,2H),2.64(m,2H),2.55(m,2H),1.95(m,4H),1.12(t,3H).
DCB-70151: 1H NMR(DMSO-d 6)δ13.79(s,1H),11.03(s,1H),9.58(s,1H),7.72-7.77(m,2H),7.47(d,2H),7.23(d,1H),7.04(s,1H),6.85(d,2H),3.14(m,2H),3.01(m,2H),2.62(m,2H),2.46(m,2H),1.79-1.88(m,4H).
DCB-70152: 1H NMR(DMSO-d 6)δ13.64(s,1H),8.21(s,1H),7.94(s,1H),7.47-7.49(m,3H),7.38(m,3H),7.05(d,1H),4.89(s,2H),3.21-3.32(m,4H),2.93(m,2H),2.41(m,2H),2.06(m,2H),1.83(m,2H),1.72(m,2H).
DCB-70153: 1H NMR(DMSO-d 6)δ13.66(s,1H),8.21(s,1H),7.90(s,1H),7.48(m,3H),7.38(m,1H),7.05(d,1H),4.88(s,2H),3.38(m,4H),3.20(m,2H),2.93(m,2H),2.57(m,2H),2.42(m,2H),2.06-2.16(m,9H).
DCB-70154: 1H NMR(DMSO-d 6)δ13.96(s,1H),10.81(s,1H),7.70(s,1H),7.45(s,1H),6.74-6.80(m,2H),3.99(q,2H),3.77(s,3H),3.21(m,2H),3.01(m,2H),2.62(m,2H),2.51(m,2H),1.86(m,4H),1.12(t,3H).
DCB-70155: 1H NMR(DMSO-d 6)δ13.94(s,1H),10.80(s,1H),7.74(s,1H),6.77(m,2H),3.77(s,3H),3.16(m,2H),3.01(m,2H),2.62(m,2H),2.47(m,2H),1.79-1.86(m,4H).
DCB-70156: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.01(s,1H),7.75(m,2H),6.96(s,1H),6.86(s,1H),3.18(m,2H),2.91(m,2H),2.54(m,2H),2.41(m,2H),2.33(m,4H),2.23(m,3H),2.05(m,2H).
DCB-70157: 1H NMR(DMSO-d 6)δ13.61(s,1H),8.22(s,1H),7.90(s,1H),7.72(m,1H),7.48-7.50(m,3H),7.37-7.41(m,1H),7.06(d,1H),4.88(s,2H),3.21(m,2H),2.94(m,2H),2.50(s,3H),2.36-2.43(m,4H),2.07(m,2H).
DCB-70158: 1H NMR(DMSO-d 6)δ13.69(s,1H),8.26(s,1H),7.93(s,1H),7.48-7.50(m,3H),7.39(m,1H),7.06(d,1H),4.88(s,2H),4.01(q,2H),3.25(m,2H),2.84(s,2H),2.61(m,2H),2.33(s,2H),1.12(t,3H),1.05(s,6H).
DCB-70159: 1H NMR(DMSO-d 6)δ13.29(s,1H),7.85(s,1H),7.90(s,1H),7.49(m,2H),7.40(m,1H),7.26(m,2H),6.79(d,1H),4.90(s,2H),3.11(t,2H),2.79(s,2H),2.26-2.30(m,4H),1.04(s,6H).
DCB-70160: 1H NMR(DMSO-d 6)δ13.65(s,1H),11.44(s,1H),8.32(s,1H),7.92(s,1H),7.55-7.59(m,2H),7.12-7.18(m,2H),6.93-7.00(m,2H),3.92-4.00(m,4H),3.29(m,2H),2.91(m,2H),2.82(s,2H),2.62(m,2H),2.32(s,2H),1.10(t,3H),1.05(s,6H).
DCB-70161: 1H NMR(DMSO-d 6)δ13.63(s,1H),12.10(s,1H),11.43(s,1H),8.28(s,1H),7.93(s,1H),7.55-7.59(m,2H),7.20(m,1H),7.13(d,1H),6.94-7.00(m,2H),3.92(q,2H),3.25(m,2H),2.89(m,2H),2.82(s,2H),2.52(m,2H),2.33(s,2H),1.04(s,6H).
DCB-70166: 1H NMR(DMSO-d 6)δ13.90(s,1H),10.84(s,1H),7.74(s,1H),7.47(s,1H),6.74-6.80(m,2H),3.99(q,2H),3.77(s,3H),3.20(m,2H),2.91(m,2H),2.59(m,2H),2.40(m,2H),2.06(m,2H),1.12(t,3H).
DCB-70167: 1H NMR(DMSO-d 6)δ13.88(s,1H),10.82(s,1H),7.75(s,1H),7.42(s,1H),6.74-6.80(m,2H),3.77(s,3H),3.17(m,2H),2.90(m,2H),2.40(m,2H),2.05(m,2H).
DCB-70168: 1H NMR(DMSO-d 6)δ13.88(s,1H),10.99(s,1H),7.72(d,2H),7.52-7.71(m,5H),6.74(m,2H),5.32(s,1H),3.98(q,2H),3.32(m,2H),2.81(s,2H),2.63(m,2H),2.32(s,2H),1.04(s,6H).
DCB-70169: 1H NMR(DMSO-d 6)δ 11.01(s,1H),9.95(s,1H),7.73(d,2H),7.52-7.60(m,4H),7.43(s,1H),6.72-6.77(m,2H),3.12(m,2H),2.81(s,2H),2.53(m,2H),2.36(s,2H),1.04(s,6H).
DCB-70170: 1H NMR(DMSO-d 6)δ 11.04(s,1H),7.74-7.78(m,2H),7.03-7.05(m,2H),6.83(s,1H)3.99(q,2H),3.19(m,2H),2.92(m,2H),2.58(m,2H),2.45(m,4H),2.06(m,2H),0.87-1.31(m,14H).
DCB-70171: 1H NMR(DMSO-d 6)δ 13.67(s,1H),11.02(s,1H),7.74(m,2H),7.01(s,1H),6.81(s,1H),3.15(m,2H),2.90(m,2H),2.61(m,2H),2.39(m,4H),2.05(m,2H),0.86-1.52(m,11H).
DCB-70172: 1H NMR(DMSO-d 6)δ 13.73(s,1H),11.12(s,1H),7.91(s,1H),7.83(s,1H),7.18(d,1H),6.85(d,1H),4.01(q,2H),3.22(m,2H),2.91(m,2H),2.55(m,2H),2.39(m,4H),2.06(m,2H),0.86-1.54(m,14H).
DCB-70173: 1H NMR(DMSO-d 6)δ 13.70(s,1H),12.00(brs,1H),11.09(s,1H),7.86(s,1H),7.83(s,1H),7.16(d,1H),6.83(d,1H),3.17(m,2H),2.90(m,2H),2.62(m,2H),2.38(m,4H),2.06(m,2H),0.83-1.52(m,11H).
DCB-70174: 1H NMR(DMSO-d 6)δ 13.85(s,1H),10.84(s,1H),8.11(s,1H),7.70(s,1H),7.55(s,1H),7.04(m,1H),6.75(m,1H),5.80(s,1H),4.00(q,2H),3.15(m,2H),2.91(m,2H),2.63(m,2H),2.38(m,2H),2.02(m,6H),1.93(m,6H),1.63(m,6H),1.11(t,3H).
DCB-70175: 1H NMR(DMSO-d 6)δ 13.92(s,1H),10.60(s,1H),7.49(s,1H),7.31(d,2H),7.04(s,1H),6.87(d,2H),6.60(d,1H),6.45(m,1H),5.77(m,1H),4.19(m,2H),3.98(q,2H),3.71(s,3H),2.81(m,2H),2.70(m,2H),2.51(m,2H),2.46(m,2H),2.08(m,2H),1.10(t,3H).
DCB-70176: 1H NMR(DMSO-d 6)δ13.91(s,1H),10.61(s,1H),7.49(s,1H),7.43(m,2H),7.13(m,2H),7.03(s,1H),6.61(m,1H),6.42(m,1H),5.82(m,1H),4.28(d,2H),3.97(q,2H),3.14(m,2H),2.89(m,2H),2.61(m,2H),2.40(m,2H),2.05(m,2H),1.10(t,3H).
DCB-70177: 1H NMR(DMSO-d 6)δ13.82(s,1H),11.12(s,1H),9.08(s,1H),8.80(s,1H),8.69(d,1H),8.32(d,1H),7.93(d,1H),7.86(s,1H),7.55(m,1H),7.22(m,1H),6.95(d,1H),4.00(q,2H),3.21(m,2H),2.93(m,2H),2.61(m,2H),2.41(m,2H),2.01(m,2H),1.13(t,3H).
DCB-70178: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.12(s,1H),8.82(s,1H),8.31-8.34(m,2H),7,92(s,1H),7.85(s,1H),7.70(m,1H),7.22(m,1H),6.95(m,1H),4.00(q,2H),3.22(m,2H),2.93(m,2H),2.59(m,2H),2.46(m,2H),2.01(m,2H),1.12(t,3H).
DCB-70179: 1H NMR(DMSO-d 6)δ13.85(s,1H),10.56(s,1H),7.40(m,3H),7.27(m,2H),7.15(m,1H),6.95(s,1H),6.53(d,1H),6.34(m,1H),5.85(m,1H),4.50(q,1H),4.00(q,2H),3.13(m,2H),2.88(m,2H),2.62(m,2H),2.38(m,2H),2.04(m,2H),1.41(d,3H),1.11(t,3H).
DCB-70180: 1H NMR(DMSO-d 6)δ13.93(s,1H),10.61(s,1H),7.52(s,1H),7.46(d,1H),7.39(d,1H),7.08-7.13(m,2H),6.63(d,1H),6.50(d,1H),5,71(m,1H),4.27(d,2H),3.99(q,2H),3.16(m,2H),2.90(m,2H),2.61(m,2H),2.46(m,2H),2.05(m,2H),1.11(t,3H).
DCB-70183: 1H NMR(DMSO-d 6)δ13.83(s,1H),10.94(s,1H),8.90(s,1H),8.47(s,1H),8.11(m,1H),7.78(s,1H),7.63(s,1H),7.30(m,1H),7.22(m,1H),7.05(m,1H),6.83(d,1H),4.00(q,2H),3.16(m,2H),2.92(m,2H),2.63(m,2H),2.41(m,2H),2.06(m,2H),1.11(t,3H).
DCB-70184: 1H NMR(DMSO-d 6 )δ13.83(s,1H),10.95(s,1H),9.43(s,1H),8.35(s,1H),8.24(d,1H),7.79(s,1H),7.62(m,2H),7.38(m,1H),7.25(m,1H),6.85(m,1H),3.99(q,2H),3.16(m,2H),2.92(m,2H),2.62(m,2H),2.40(m,2H),2.06(m,2H),1.11(t,3H).
DCB-70186: 1H NMR(DMSO-d 6 )δ13.76(s,1H),10.96(s,1H),9.17(s,1H),7.63-7.73(m,2H),7.43-7.55(m,5H),7.12(m,2H),6.66-6.75(m,3H),6.41(s,1H),3.21(m,2H),2.96(m,2H),2.67(m,2H),2.45(m,2H),2.01(m,2H).
DCB-70187: 1H NMR(DMSO-d 6 )δ7.80(s,1H),7.74(d,2H),6.96(d,1H),6.86(m,1H),3.20(t,2H),2.61(m,2H),2.38-2.46(m,5H).
DCB-70188: 1H NMR(DMSO-d 6 )δ8.25(s,1H),7.90(s,1H),7.58(m,2H),7.20(m,1H),7.13(m,1H),6.92-7.01(m,2H),3.92(q,2H),3.28(m,2H),2.90(m,2H),2.62(s,3H),2.45-2.47(m,5H).
DCB-70189: 1H NMR(DMSO-d 6 )δ13.75(s,1H),11.03(s,1H),10.16(s,1H),7.59-7.64(m,2H),7.53(s,1H),7.39(s,2H),6.75-6.79(m,2H),3.99(q,2H),3.16(m,2H),2.91(m,2H),2.61(m,2H),2.41(m,2H),2.06(m,2H),1.10(t,3H).
DCB-70190: 1H NMR(DMSO-d 6 )δ13.74(s,1H),11.03(s,1H),10.16(s,1H),7.68(s,1H),7.61(m,1H),7.52(s,1H),7.40(d,1H),6.73-6.78(m,2H),3.13(m,2H),2.91(m,2H),2.53(m,2H),2.41(m,2H),2.05(m,2H).
DCB-70191: 1H NMR(DMSO-d 6 )δ13.74(s,1H),10.95(s,1H),10.05(s,1H),8.37(s,1H),8.09(d,2H),8.00(d,1H),7.50-7.79(m,5H),6.76(d,1H),6.69(d,1H),3.95(q,2H),3.13(m,2H),2.90(m,2H),2.61(m,2H),2.40(m,2H),2.01(m,2H),1.06(t,3H).
DCB-70192: 1H NMR(DMSO-d 6)δ13.72(s,1H),10.94(s,1H),10.04(s,1H),8.37(s,1H),8.10(d,2H),8.01(d,1H),7.77-7.80(m,1H),7.59-7.68(m,2H),7.50(s,1H),6.67-6.75(m,2H),3.10(m,2H),2.89(m,2H),2.40(m,2H),2.04(m,2H).
DCB-70193: 1H NMR(DMSO-d 6)δ13.77(s,1H),1.87(s,1H),7.64(d,2H),7.60(s,1H),7.43(s,1H),6.74(s,2H),4.00(q,2H),3.17(m,2H),2.91(m,2H),2.61(m,2H),2.41(m,2H),2.06(m,2H),1.10(t,3H).
DCB-70194: 1H NMR(DMSO-d 6)δ13.75(s,1H),11.04(s,1H),10.15(s,1H),7.95(s,1H),7.68(s,3H),7.50(s,1H),6.73-6.80(m,2H),3.14(m,2H),2.91(m,2H),2.41(m,2H),2.01(m,2H).
DCB-70195: 1H NMR(DMSO-d 6)δ13.76(s,1H),10.99(s,1H),9.92(s,1H),7.58(s,1H),7.43-7.49(m,2H),7.17-7.28(m,3H),6.76(m,2H),4.00(q,2H),3.75(s,3H),3.16(m,2H),2.91(m,2H),2.62(m,2H),2.41(m,1H),2.06(m,2H),1.10(t,3H).
DCB-70196: 1H NMR(DMSO-d 6)δ13.75(s,1H),10.98(s,1H),9.91(s,1H),7.61(s,1H),7.43-7.46(m,2H),7.16-7.29(m,3H),6.73-6.78(m,2H),3.76(s,1H),3.12(m,2H),2.91(m,2H),2.41(m,2H),2.05(m,2H).
DCB-70197: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.04(s,1H),9.55(s,1H),7.61(s,1H),7.50(s,1H),7.32-7.37(m,5H),7.03(m,1H),6.87(d,2H),4.41(s,2H),3.99(q,2H),3.17(m,2H),2.92(m,2H),2.64(m,2H),2.42(m,2H),2.06(m,2H),1.10(t,3H).
DCB-70198: 1H NMR(DMSO-d 6)δ13.81(s,1H),11.05(s,1H),9.55(s,1H),7.66(s,1H),7.50(s,1H),7.34-7.36(m,5H),7.03(m,1H),6.88(m,1H),4.41(s,2H),3.15(m,2H),2.94(m,2H),2.65(m,2H),2.43(m,2H),2.02(m,2H).
DCB-70200: 1H NMR(DMSO-d 6)δ13.84(s,1H),7.73(d,2H),7.51-7.58(m,4H),7.35(s,1H),6.70-6.76(m,2H),3.14(m,2H),2.63(m,2H),2.51(s,3H),2.45(s,3H).
DCB-70201: 1H NMR(DMSO-d 6)δ13.88(s,1H),10.96(s,1H),7.71(m,2H),7.59(m,1H),7.53(m,3H),7.45(s,1H),6.73(s,1H),4.01(q,2H),3.19(m,2H),2.63(s,3H),2.46(m,5H),2.04(m,2H),1.11(t,3H).
DCB-70202: 1H NMR(DMSO-d 6)δ13.80(s,1H),8.17(s,1H),7.90(s,1H),7.49(m,3H),7.39(m,1H),7.06(d,1H),4.87(s,2H),3.22(m,2H),2.63(s,3H),2.46(m,5H).
DCB-70205: 1H NMR(DMSO-d 6)δ13.79(s,1H),11.50(s,1H),8.18(s,1H),7.86(s,1H),7.47(m,3H),7.38(m,1H),7.06(d,1H),4.89(s,1H),3.33(m,2H),2.63(s,3H),2.51(m,2H),2.45(s,3H),2.13(m,7H).
DCB-70206: 1H NMR(DMSO-d 6)δ13.73(s,1H),8.20(s,1H),7.84(s,1H),7.52-7.58(m,2H),7.12-7.18(m,2H),6.94-7.00(m,2H),3.95(q,2H),3.27(m,2H),2.89(m,2H),2.61(s,1H),2.56(m,2H),2.44(s,3H),2.10(m,7H).
DCB-70207: 1H NMR(DMSO-d 6)δ13.92(s,1H),10.98(s,1H),7.68-7.73(m,2H),6.86(m,1H),6.60(m,1H),3.32(m,2H),3.19(m,2H),2.61(s,3H),2.43(s,3H),2.12(m,7H).
DCB-70209: 1H NMR(DMSO-d 6)δ13.68(s,1H),8.27(s,1H),7.95(s,1H),7.48-7.51(m,3H),7.39(m,1H),7.06(m,1H),4.88(s,2H),4.01(q,2H),3.25(m,2H),2.94(m,2H),2.61(m,2H),2.44(m,2H),2.06(m,2H),1.14(t,3H).
DCB-70210: 1H NMR(DMSO-d 6)δ13.64(s,1H),11.44(s,1H),8.32(s,1H),7.94(s,1H),7.55-7.59(m,2H),7.13-7.18(m,2H),6.95-7.00(m,2H),3.92-4.02(m,4H),3.28(m,2H),2.92(m,4H),2.62(m,2H),2.42(m,2H),2.05(m,2H),1.12(t,3H).
DCB-70212: 1H NMR(DMSO-d 6)δ13.76(s,1H),8.17(s,1H),7.86(s,1H),7.65(m,1H),7.49(m,3H),7.06(m,1H),4.87(s,2H),3.24(m,2H),2.97(m,2H),2.61(s,3H),2.45(s,3H),2.19-2.34(m,8H),0.75-0.78(t,6H).
DCB-70213: 1H NMR(DMSO-d 6)δ13.84(s,1H),10.97(s,1H),7.72(s,1H),7.65(m,1H),7.58(m,1H),6.95(m,1H),6.85(m,1H),3.21(m,2H),2.95(m,2H),2.59(s,3H),2.44(s,3H),2.18-2.33(m,8H),0.77(t,6H).
DCB-70214: 1H NMR(DMSO-d 6)δ13.64(s,1H),8.18(s,1H),7.82(s,1H),7.66(m,1H),7.52-7.59(m,2H),7.17(m,1H),7.11(d,1H),6.93-6.99(m,2H),3.98(q,2H),3.26(m,2H),2.93(m,2H),2.58(s,3H),2.43(s,3H),2.35(m,2H),2.08-2.16(m,6H),0.65(t,6H).
DCB-70218: 1H NMR(DMSO-d 6)δ13.75(s,1H),10.96(s,1H),7.73(d,sH),7.53-7.59(m,4H),7.41(s,1H),6.72-6.78(m,2H),3.41(m,4H),3.13(m,2H),2.91(m,2H),2.01-2.14(m,12H).
DCB-70219: 1H NMR(DMSO-d 6)δ13.87(s,1H),10.94(s,1H),7.74(d,2H),7.48-7.59(m,4H),7.39(s,1H),6.72-6.76(m,2H),3.39(m,2H),3.15(m,2H),2.60(s,3H),2.43(m,6H),2.10(m,9H).
DCB-70222: 1H NMR(DMSO-d 6)δ13.62(s,1H),8.10(s,1H),7.89(s,1H),7.48-7.51(m,4H),7.38-7.41(m,2H),7.07(d,1H),4.87(s2H),2.98(m,4H),2.41(m,6H),2.06(m,2H),1.68(m,2H),0.91(t,6H);ESI-MS:614(M+1).
DCB-70223: 1H NMR(DMSO-d 6)δ13.60(s,1H),8.19(s,1H),7.89(s,1H),7.64(m,1H),7.50(m,3H),7.40(m,1H),7.06(m,1H),4.87(s,2H),3.22(m,2H),2.94-2.99(m,4H),2.07-2.43(m,12H),0.77(t,6H).
DCB-70224: 1H NMR(DMSO-d 6)δ13.69(s,1H),10.98(s,1H),7.73(s,1H),7.60-7.64(m,2H),6.94-6.97(m,1H),6.83-6.86(m,1H),3.18(m,2H),2.86-2.95(m,4H),2.04-2.39(m,12H),0.77(t,6H).
DCB-70225: 1H NMR(DMSO-d 6)δ13.50(s,1H),8.21(s,1H),7.87(s,1H),7.51-7.66(m,3H),7.11-7.20(m,2H),6.93-7.00(m,2H),3.97(m,2h),3.25(m,2H),2.94(m,6H),2.36-2.43(m,4H),2.05-2.18(m,12H),0.67(t,3H).
DCB-70226: 1H NMR(DMSO-d 6)δ13.50(s,1H),11.39(s,1H),8.36(s,1H),7.86(s,1H),7.17(m,2H),7.07(m,1H),6.89(m,1H),6.58(s,1H),4.07(m,2H),3.66(s,1H),3.20(m,2H),3.05(m,2H),2.91(m,2H),2.54(m,2H),2.50(m,2H),2.06(m,2H).
測試式(I)、(II)與(III)各種化合物之抑制各種蛋白質激酶之活性,如Aurora A & B激酶、VEGFr-2、FGFr-1、PDGFr-β、c-kit、c-Met與FLT3。不同分析之簡要說明係如下文所述。
藉由本文所揭示化合物之Aurora激酶抑制係經由將Aurora激酶、受質與側式化合物一起培養一段時間後,接著定量所產ㄥ磷酸化產物而測定。具體地,於96-孔圓底盤之孔中,製備25μL含有下述者之反應混合物:(1)本文所述測試化合物(由9μM稀釋至所欲濃度)、[γ-33P]ATP/ATP混合物(10μM)、CHOCKtide(1μg,Genesis Biotech Inc.)與Aurora-A(1ng,由Upstate購得);或(2)本文所述測試化合物(由9μM稀釋至所欲濃度)、[γ-33P]ATP/ATP混合物(40μM)、CHOCKtide(1μg,Genesis Biotech Inc.)與Aurora-B(2.5ng,由Cell signaling購得);且於33℃培養30分鐘。然後反應藉由添加5μL之3%磷酸終止。所得溶液(30μL)稍後藉由UniFilter Plate GF/B(PerkinElmer)收集後添加30μL之scintillation cocktail(MicroScint 20,PerkinElmer)至孔。殘留於過濾膜之放射性藉由發光計數器(luminescence counter(PerkinElmer))測定。藉由列於表1之各種化合物之Aurora A激酶與Aurora B激酶之抑制係總結與示於表2。IC50值係定義為達成激酶活性之一半最大抑制率之測試化合物濃度。
藉由本文所述化合物之VEGFR2激酶活性之抑制性,係藉由測量於化合物存在下,[33P]併入受質的量而定量。具體地,具有最終體積25μL且含有6.25ng之VEGFR2激酶(由桿狀病毒表現之重組N-終端6x His-標記VEGFR2激酶域構築物純化所獲得)、5μg之受質(Poly(Glu-Tyr,4:1,Sigma))、激酶反應緩衝液(20mM MOPS pH 7.0、1mM EDTA、5%甘油、0.01% Brij-35、0.1%β-巰乙醇、1mg/mL BSA、100μM ATP、每孔0.1μCi之[33P]-γ-ATP(2,500-3,000 Ci/mmol)與500nM測試化合物(DMSO之最終濃度為4%)或4% DMSO單獨(作為對照樣本)之反應混合物,於30℃培養30分鐘。然後反應藉由添加5μL之3%磷酸終止。所得溶液移轉且藉由過濾盤(UniFilter-96 GF/B,PerkinElmer)收集。然後過濾盤以d.d. H2O、5分鐘清洗20次後,添加30μL之MicroScintTM-20 Cocktail(PerkinElmer)。將盤密封後,殘留於過濾器之放射性使用TopCount閃爍偵測器(PerkinElmer)計數。測試化合物抑制率百分比,係以測試樣本之殘留放射性除以對照樣本之殘留放射性計算且示於表3。
藉由本文所述化合物之PDGFR-β激酶活性之抑制性,係藉由測量於化合物存在下,[33P]併入受質的量而定量。簡要地,具有最終體積25μL且含有55ng之PDGFR-β激酶(由桿狀病毒表現之重組N-終端6x His-標記PDGFR-β激酶域構築物純化所獲得)、2.5μg之受質(Poly(Glu-Tyr,4:1,Sigma))、激酶反應緩衝液(20mM MOPS pH 7.0、1mM EDTA、5%甘油、0.01% Brij-35、0.1% β-巰乙醇、1mg/mL BSA、2mM MnCl2、30μM ATP、每孔0.1μCi之[33P]-γ-ATP(2,500-3,000Ci/mmol)與測試化合物(500nM,以4%DMSO稀釋)或DMSO(作為對照)之反應混合物,於30℃培養30分鐘。然後反應藉由添加5μL之3%磷酸終止。所得溶液移轉且藉由過濾盤(UniFilter-96 GF/B,PerkinElmer)收集。然後過濾盤以d.d. H2O、5分鐘清洗20次後,添加30μL之MicroScintTM-20 Cocktail(PerkinElmer)。將盤密封後,殘留於過濾器之放射性使用TopCount閃爍偵測器(PerkinElmer)計數。測試化合物抑制率百分比,係以測試樣本之殘留放射性除以對照樣本之殘留放射性計算且示於表3。
藉由本文所述化合物之c-Met激酶活性之抑制性,係藉由測量於化合物存在下,[33P]併入受質的量而定量。簡要地,具有最終體積25μL且含有5ng之c-Met激酶(由桿狀病毒表現之重組N-終端6x His-標記c-Met激酶域構築物純化所獲得)、1μg之受質(Poly(Glu-Tyr,4:1,Sigma))、激酶反應緩衝液(20mM MOPS pH 7.0、1mM EDTA、5%甘油、0.01% Brij-35、0.1% β-巰乙醇、1mg/mL BSA、100μM ATP、每孔0.1μCi之[33P]-γ-ATP(2,500-3,000Ci/mmol)與測試化合物(500nM,以4%DMSO稀釋)或DMSO(作為對照)之反應混合物,於30℃培養30分鐘。然後反應藉由添加5μL之3%磷酸終止。所得溶液移轉且藉由過濾盤(UniFilter-96GF/B,PerkinElmer)收集。然後過濾盤以d.d. H2O、5分鐘清洗20次後,添加30μL之MicroScintTM-20 Cocktail(PerkinElmer)。將盤密封後,殘留於過濾器之放射性使用TopCount閃爍偵測器(PerkinElmer)計數。測試化合物抑制率百分比,係以測試樣本之殘留放射性除以對照樣本之殘留放射性計算且示於表3。
藉由本文所述化合物之Flt3激酶活性之抑制性,係藉由測量於化合物存在下,[33P]併入受質的量而定量。具體地,具有最終體積25μL且含有5ng之Flt3激酶(由桿狀病毒表現之重組N-終端6x His-標記Flt3激酶域構築物純化所獲得)、5μg之受質(Poly(Glu-Tyr,4:1,Sigma))、激酶反應緩衝液(20mM MOPS pH 7.0、1mM EDTA、5%甘油、0.01% Brij-35、0.1% β-巰乙醇、1mg/mL BSA、100μM ATP、每孔0.1μCi之[33P]-γ-ATP(2,500-3,000Ci/mmol)與測試化合物(100nM,以4% DMSO稀釋)或DMSO(作為對照)之反應混合物,於30℃培養30分鐘。然後反應藉由添加5μL之3%磷酸終止。所得溶液移轉且藉由過濾盤(UniFilter-96GF/B,PerkinElmer)收集。然後過濾盤以d.d. H2O、5分鐘清洗20次後,添加30μL之MicroScintTM-20 Cocktail(PerkinElmer)。將盤密封後,殘留於過濾器之放射性使用TopCount閃爍偵測器(PerkinElmer)計數。測試化合物抑制率百分比,係以測試樣本之殘留放射性除以對照樣本之殘留放射性計算且示於表3。
COLO 205(1×106 cell/mouse)腫瘤細胞皮下注射至5週齡雄性NOD/SCID小鼠(BioLASCO,台灣)的右側。一旦腫瘤為可明顯察覺(移植後10至15日內),則以數位卡尺(digital caliper)測量腫瘤體積。於1至3週後當腫瘤達到平均體積為50至100mm3時,開始化合物治療。小鼠如下表4所示分為5組且每日一次給予靜脈內注射不同劑量(5mg/kg、10mg/kg或20mg/kg)之測試化合物、SU11248(20mg/kg,陽性對照)或媒劑對照(DMSO:聚氧乙烯醚(Cremophor):PBS(pH 7.4)=5:10:8.5)。測試化合物,DCB-70055,調配為5% DMSO、10%聚氧乙烯醚與85% PBS之溶液。陽性對照,SU11248溶解於100% PBS。每2至3日測量小鼠體重且每2至3日藉由數位卡尺測量小鼠不同組之腫瘤尺寸。結果顯示DCB-70055於活體內抑制腫瘤生長且不誘發顯著的體重減輕。
揭示於本說明書之所有特徵可以任何方式組合。揭示於本說明書之各特徵可以作為相同、均等或類似目的之替代特徵予以置換。因此,無非明確指出,否則所揭示之各特徵僅為均等或類似特徵之廣泛示例。
由上述說明可知,於此項技術領域中具有通常知識者可容易地明白本發明之基本特徵,且於不悖離本發明之精神與範疇的情況下,達成本發明之各種改變與變化以合於各種用途與條件。因此,其他具體例亦涵括於下述申請專利範圍之範疇。
Claims (22)
- 一種式(II)化合物,
- 如申請專利範圍第1項之化合物,其中,該化合物為式(III)化合物:
- 如申請專利範圍第1項之化合物,其中,R2為-N=CRaRb或-NRaC(O)NHRb。
- 如申請專利範圍第1項之化合物,其中,R3為H。
- 如申請專利範圍第4項之化合物,其中,R5為-C(O)ORc。
- 如申請專利範圍第5項之化合物,其中,R6與R7為H或甲基。
- 如申請專利範圍第2項之化合物,其中,R5為-C(O)NRcRd,且其中Rc與Rd與其所鍵結之氮原子共同為吡咯啶基、六氫吡啶基、六氫吡嗪基、或嗎啉基。
- 如申請專利範圍第7項之化合物,其中,R2為鹵 基、-S(O)2Ra或-S(O)2NRaRb,且R3為H或鹵基。
- 如申請專利範圍第8項之化合物,其中,R6與R7為H或甲基。
- 如申請專利範圍第2項之化合物,其中,R2為NRaRb、-S(O)2NRaRb或-C(O)NRaRb,且其中Ra與Rb與其所鍵結之氮原子共同為吡咯啶基、六氫吡啶基、六氫吡嗪基、或嗎啉基。
- 如申請專利範圍第10項之化合物,其中,R5為-C(O)ORc。
- 如申請專利範圍第10項之化合物,其中,R3為H。
- 如申請專利範圍第2項之化合物,其中,n為2。
- 如申請專利範圍第13項之化合物,其中,R2為-NRaS(O)2Rb。
- 如申請專利範圍第14項之化合物,其中,R5為-C(O)ORc且R3、R6與R7之各者為H。
- 如申請專利範圍第2項之化合物,其中,R5 為-C(O)ORc,且其中Rc為H或烷基。
- 如申請專利範圍第16項之化合物,其中,R2為H;且R3為H、鹵基或芳基。
- 如申請專利範圍第17項之化合物,其中,R6與R7為H或甲基。
- 如申請專利範圍第1項之化合物,其中,該化合物為(Z)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-氟-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-氟-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-溴-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-溴-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-羥基-3-甲氧基苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-羥基-3-甲氧基苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-硝基-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-硝基-3-((3-羧基乙基 -4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(N-甲基胺磺醯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(N-甲基胺磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(4-羥基苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(3,4-二甲氧基苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(3,4-二甲氧基苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(苯并[b]噻吩-2-基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(苯并[b]噻吩-2-基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-苯甲基磺醯基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-氟苯甲基磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(2,6-二氯苯甲基磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-氟苯甲醯胺基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(4-羥基苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-氟苯甲醯胺基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基) 亞甲基)吲哚啉-2-酮、(Z)-6-(3,4-二羥基苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(3,4-二羥基苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(苯并[b]噻吩-2-基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(苯并[b]噻吩-2-基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(4-羥基-3-甲氧基苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(4-羥基-3-甲氧基苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-硫酮、3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-硫酮、6-溴-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-硫酮、6-溴-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-硫酮、(Z)-5-(吡咯啶-1-基磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(N-嗎啉基)磺醯基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(3-對-甲苯基脲基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(3-(4-甲氧基苯基)脲基)-3-((3-(3-乙氧基-3-酮基 丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(3-對-甲苯基脲基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(3-(4-甲氧基苯基)脲基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-胺磺醯基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-苯甲醯胺基-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-苯甲醯胺基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(4-氟苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(4-氟苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(3,5-二氟苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-(3,5-二氟苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-苯基磺醯胺基-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-苯基磺醯胺基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-乙醯胺基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(吲哚啉-1-基磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-甲基六氫吡嗪-1-基磺 醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮鹽酸鹽、(Z)-5-(4-氟苯基)-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(4-氟苯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(六氫吡啶-1-基磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-乙烯基磺醯基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-乙基磺醯基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-N-甲基-3-((3-(3-(4-甲基六氫吡嗪-1-基)-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)-2-酮基吲哚啉-5-磺醯胺、(Z)-5-乙基磺醯胺基-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-乙基磺醯胺基-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-3-((3-(3-(4-甲基六氫吡嗪-1-基)-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)-5-(吡咯啶-1-基磺醯基)吲哚啉-2-酮、(Z)-5-(N,N-二甲基胺磺醯基)-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-氟-3-((3-(3-乙氧基-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-6-氟-3-((3-羧基乙基-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-N,N-二乙基-3-(2-((5-氟-2-酮基吲哚啉-3-亞基)甲基)-4- 酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙醯胺、(Z)-5-氟-3-((3-(3-(N-嗎啉基)-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-3-(2-((6-(苯并[d][1,3]二氧雜環戊-5-基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-萘-1-基脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((6-溴-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(苯甲基胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(苯甲基胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((6-溴-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(4-酮基-2-((2-酮基-5-(3-苯基脲基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-(4-溴苯基)脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-(4-氟苯基)脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-(4-氯-3-(三氟甲基)苯基)脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-氟-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸乙酯、(Z)-3-(2-((5-氟-2-酮基吲哚啉-3-亞基)甲基)-4-酮基 -1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸、(Z)-3-(2-((5-(4-硝基苯甲醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、3-(2-((5-(4-甲氧基苯甲醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(4-硝基苯甲醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(4-甲氧基苯甲醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(4-氟苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(4-氟苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(4-酮基-2-((2-酮基-5-(苯基磺醯胺基)吲哚啉-3-亞基)甲基)-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸乙酯、(Z)-3-(4-酮基-2-((2-酮基-5-(苯基磺醯胺基)吲哚啉-3-亞基)甲基)-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸、(Z)-3-(2-((5-(N-(3-氯苯基)-N-甲基胺磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸、(Z)-3-(2-((5-(N-(3-氯-4-氟苯基)胺磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸、(Z)-3-(2-((6-(4-羥基苯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸乙酯、(Z)-3-(2-((6-(4-羥基苯基)-2-酮基吲哚啉-3-亞基) 甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸、(Z)-5-(2,6-二氯苯甲基磺醯基)-3-((4-酮基-3-(3-酮基-3-(吡咯啶-1-基)丙基)-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-5-(2,6-二氯苯甲基磺醯基)-3-((3-(3-(4-甲基六氫吡嗪-1-基)-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-3-(2-((5-甲氧基-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸乙酯、(Z)-3-(2-((5-甲氧基-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-1,4,5,6,7,8-六氫環庚并[b]吡咯-3-基)丙酸、(Z)-5-氟-3-((3-(3-(4-甲基六氫吡嗪-1-基)-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-3-(2-((5-(2,6-二氯苯甲基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)-N-甲基丙醯胺,(Z)-3-(2-((5-(2,6-二氯苯甲基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-6,6-二甲基-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(2,6-二氯苯甲基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-6,6-二甲基-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(吲哚啉-1-基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-6,6-二甲基-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(吲哚啉-1-基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-6,6-二甲基-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-甲氧基-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-甲氧基-2-酮基吲哚啉-3-亞基)甲基)-4-酮基 -4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(6,6-二甲基-4-酮基-2-((2-酮基-5-(苯基磺醯胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(6,6-二甲基-4-酮基-2-((2-酮基-5-(苯基磺醯胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((6-(辛-1-炔基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((6-(辛-1-炔基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(辛-1-炔基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(辛-1-炔基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、3-(2-((Z)-(5-(3-(1-金剛烷基)脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(4-甲氧基苯甲基胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(4-氟苯甲基胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、3-(4-酮基-2-((Z)-(2-酮基-5-((E)-吡啶-4-基亞甲基胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、3-(2-((Z)-(5-((E)-4-氟-3-(三氟甲基)苯甲亞基胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(4-酮基-2-((2-酮基-5-(1-苯基乙基胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、3-(4-酮基 -2-((Z)-(2-酮基-5-((E)-噻吩-3-基亞甲基胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-(2,4-二氟苯基)脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-(2,4-二氯苯基)脲基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-N-(2-胺基苯基)-3-(4-酮基-2-((2-酮基-5-(苯基磺醯胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙醯胺、(Z)-3-(4-乙醯基-2-((5-氟-2-酮基吲哚啉-3-亞基)甲基)-5-甲基-1H-吡咯-3-基)丙酸、(Z)-3-(4-乙醯基-2-((5-(吲哚啉-1-基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-5-甲基-1H-吡咯-3-基)丙酸、(Z)-3-(2-((5-(3,5-二氟苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3,5-二氟苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(萘-2-磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(萘-2-磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(3,5-二氯苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3,5-二氯苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(3-甲氧基苯基磺醯胺基)-2-酮基吲哚啉-3-亞 基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(3-甲氧基苯基磺醯胺基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(4-酮基-2-((2-酮基-5-(苯基甲基磺醯胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(4-酮基-2-((2-酮基-5-(苯基甲基磺醯胺基)吲哚啉-3-亞基)甲基)-4,5,6,7-四氫-1H-吲哚-3-基)丙酸、(Z)-3-(2-((5-(2,6-二氯苯甲基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-3-(2-((5-(吲哚啉-1-基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸乙酯、(Z)-N-(3-((3-(3-(4-甲基六氫吡嗪-1-基)-3-酮基丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)-2-酮基吲哚啉-5-基)苯磺醯胺、(Z)-5-(2,6-二氯苯甲基磺醯基)-3-((3-(3-(二乙基胺基)丙基)-4-酮基-4,5,6,7-四氫-1H-吲哚-2-基)亞甲基)吲哚啉-2-酮、(Z)-3-(2-((5-(2,6-二氯苯甲基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)-N-(2-(二乙基胺基)乙基)丙醯胺、(Z)-N-(2-(二乙基胺基)乙基)-3-(2-((5-氟-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙醯胺、(Z)-N-(2-(二乙基胺基)乙基)-3-(2-((5-(吲哚啉-1-基磺醯基)-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙醯胺或(Z)-3-(2-((5-(吲哚啉-1-基磺醯基)-6-甲氧基-2-酮基吲哚啉-3-亞基)甲基)-4-酮基-4,5,6,7-四氫-1H-吲哚-3-基)丙酸。
- 一種醫藥組成物,包括申請專利範圍第1項之化合物與醫藥可接受載劑。
- 一種申請專利範圍第1項之化合物或其醫藥可接受鹽之用途,係用於製造於個體治療大腸癌之醫藥。
- 一種申請專利範圍第1項之化合物或其醫藥可接受鹽之用途,係用於製造於個體降低至少一種蛋白質激酶活性之醫藥,其中該至少一種蛋白質激酶係選自下述所成組群:Aurora A激酶、Aurora B激酶、VEGFr-2、FGFr-1、PDGFr-β、c-kit、c-Met、及FLT3。
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AR035721A1 (es) * | 2000-12-20 | 2004-07-07 | Sugen Inc | Indolinonas 4-aril sustituidas; sus composiciones farmaceuticas y metodo para modular la actividad catalitica de una proteina quinasa |
CA2459879A1 (en) * | 2001-09-10 | 2003-03-20 | Sugen, Inc. | 3-(4,5,6,7-tetrahydroindol-2-ylmethylidiene)-2-indolinone derivatives as kinase inhibitors |
US20040186160A1 (en) * | 2002-12-13 | 2004-09-23 | Sugen, Inc. | Hexahydro-cyclohepta-pyrrole oxindole as potent kinase inhibitors |
US20040266843A1 (en) * | 2003-03-07 | 2004-12-30 | Sugen, Inc. | Sulfonamide substituted indolinones as inhibitors of DNA dependent protein kinase (DNA-PK) |
WO2006001954A2 (en) | 2004-05-20 | 2006-01-05 | Puget Sound Blood Center And Program | Methods for promoting the formation of platelets and for treating blood and bone marrow disorders |
US20060094682A1 (en) * | 2004-10-29 | 2006-05-04 | Odyssey Thera, Inc. | Kinase inhibitors for the treatment of diabetes and obesity |
-
2009
- 2009-06-26 US US12/492,281 patent/US7897602B2/en active Active
- 2009-10-01 TW TW098133446A patent/TWI530483B/zh active
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Publication number | Publication date |
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TW201026665A (en) | 2010-07-16 |
US20100179146A1 (en) | 2010-07-15 |
US7897602B2 (en) | 2011-03-01 |
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