TWI675835B - 用於治療癌症及免疫及自體免疫疾病之細胞凋亡誘導劑 - Google Patents
用於治療癌症及免疫及自體免疫疾病之細胞凋亡誘導劑 Download PDFInfo
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- TWI675835B TWI675835B TW103108809A TW103108809A TWI675835B TW I675835 B TWI675835 B TW I675835B TW 103108809 A TW103108809 A TW 103108809A TW 103108809 A TW103108809 A TW 103108809A TW I675835 B TWI675835 B TW I675835B
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- pyridin
- dimethylcyclohex
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Abstract
本文揭示抑制抗細胞凋亡Bcl-2蛋白之活性之化合物、含有該等化合物之組合物及使用該等化合物治療疾病之方法。
Description
本發明係關於抑制Bcl-2抗細胞凋亡蛋白之活性之化合物、含有該等化合物之組合物及使用該等化合物治療疾病之方法。
Bcl-2家族蛋白係有核細胞中線粒體依賴性細胞凋亡之關鍵調控子且包括抗細胞凋亡成員(Bcl-xL、Bcl-2、Bcl-w、Al、Mcl-1)及促細胞凋亡成員(Bak、Bax、Bid、Bim、Bad、Bik、Bmf、Noxa、Puma)二者。通常,Bcl-2蛋白之表現與許多生理功能(包括抑制體內細胞凋亡)相關,其在一些情形下會受Bcl-2抑制之影響而導致細胞增殖。因此,Bcl-2蛋白之抑制可降低細胞增殖,從而改良與治療相關之結果並預防癌症。
抗細胞凋亡Bcl-2蛋白與多種疾病相關。Bcl-2蛋白可參與膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌、脾臟癌及諸如此類。另外,Bcl-2可參與免疫及自體免疫疾病以及關節炎。在免疫系統之各種癌症及病症中,Bcl-2蛋白之過表現與對化學療法之抗性、臨床結果、疾病進展、總體預後或其組合相關。
治療領域持續需要抑制抗細胞凋亡Bcl-2蛋白之活性之化合物。
本發明之一個實施例係關於化合物及其治療上可接受之鹽、前藥、代謝物或前藥之鹽,該等可用作抗細胞凋亡Bcl-2蛋白之抑制劑。該等化合物包括:4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2R)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5s,8s)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5r,8r)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-羥基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜螺[4.5]癸-8-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2S)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[4-(羥基甲基)四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[3-(羥基甲基)氧雜環丁-3-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基-3-甲基丁基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基三環[3.3.1.13,7]癸-1-基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧雜二環[3.1.0]己-6-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-羥基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]
吡啶-5-基氧基)苯甲醯胺;4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯基]胺磺醯基}-2-硝基苯基)胺基]甲基}四氫-2H-吡喃-4-甲酸甲酯;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[2-(四氫-2H-吡喃-4-基)肼基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-硫吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(氧雜環丁-3-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-
基)-N-[(4-{[(6-羥基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4,4-二氟-1-羥基環己基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲氧基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3,3-二氟環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺醯基]六氫吡啶-4-基}甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[1-(甲基磺醯基)六氫吡啶-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1-氧離子基四氫-2H-硫吡喃-4-基)甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氫呋喃-3-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-甲基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(反式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(順式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-
(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(1,1-二氧離子基四氫-2H-硫吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-氰基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;N-[(4-{[(1-乙醯基六氫吡啶-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-乙基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-
基)-N-({4-[(1,4-二氧雜環庚-6-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-環丙基苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基環己-1-烯-1-基}甲基)六氫吡嗪-1-基]-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺。
另一實施例係關於治療以下疾病之組合物:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、慢性淋巴球性白血病、骨髓瘤、前列腺癌、小細胞肺癌或脾臟癌,該組合物包含賦形劑及治療有效量之本發明化合物。
另一實施例係關於在需要治療之個體中治療以下疾病之方法:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、慢性淋巴球性白血病、骨髓瘤、前列腺癌、小細胞肺癌或脾臟癌,該方法包括向該患者投與治療有效量之本發明化合物。
另一實施例係關於在需要治療之個體中治療以下疾病之方法:
膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、慢性淋巴球性白血病、骨髓瘤、前列腺癌、小細胞肺癌或脾臟癌,該方法包括向該個體投與治療有效量之一種其他治療劑或一種以上其他治療劑。
另一實施例係關於用於治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群(Sjogren’s Syndrome)之組合物,該組合物包含賦形劑及治療有效量之本發明化合物。
另一實施例係關於在需要治療之個體中治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之方法,該方法包括向該個體投與治療有效量之本發明化合物。
另一實施例係關於在需要治療之個體中治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之方法,該方法包括向該個體投與治療有效量之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
除非本文中另有定義,否則與本發明結合使用之科學及技術術語應具有彼等熟習此項技術者通常所瞭解之含義。應明確該等術語之含義及範圍,然而,倘若有任何潛在歧義,則本文所提供定義優先於任何字典或外在定義。在本申請案中,除非另有說明,否則使用「或」意指「及/或」。此外,使用術語「包括(including)」以及其他形式(例如「包括(includes)」及「包括(included)」)不具有限制意義。此專利申請案(包括申請專利範圍)中關於詞語「包含(comprise)」或
「包含(comprises)」或「包含(comprising)」之使用,申請者應注意,除非上下文另有需要,否則彼等詞語係基於且明確瞭解其應解釋為具有包括性而非排他性以及申請者在解釋此專利申請案(包括下文之申請專利範圍)時意欲將彼等詞語中之每一者進行如此解釋來使用。對於在任一取代基或本發明化合物或本文中任一另一式中出現一次以上之變量,其定義在每次出現時獨立於其在每一其他出現時之定義。取代基之組合係可容許的,只要該等組合產生穩定化合物即可。穩定化合物係可以有用純度自反應混合物分離之化合物。
術語「治療(treat、treating及treatment)」係指減輕或消除疾病及/或其伴隨症狀之方法。
術語「預防(prevent、preventing及prevention)」係指預防疾病及/或其伴隨症狀發作或使個體免於獲得疾病之方法。本文所用「預防(prevent、preventing及prevention)」亦包括延遲疾病及/或其伴隨症狀之發作及降低個體獲得疾病之風險。
術語「治療有效量」係指所投與化合物足以預防所治療病況或病症之症狀中之一或多者之發生或將其減輕至一定程度之量。
術語「調節」係指化合物增加或減少Bcl-2蛋白之功能或活性之能力。
本文所用術語「組合物」意欲涵蓋包含指定量指定成份之產品以及任何直接或間接地由指定量指定成份組合而成之產品。「醫藥上可接受」意指載劑、稀釋劑或賦形劑必須與調配物之其他成份相容且對其接受者無害。
術語「個體」在本文中定義為包括動物,例如哺乳動物,包括(但不限於)靈長類(例如人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠及諸如此類。在適宜實施例中,個體係人類。
本發明之一個實施例係關於化合物及其治療上可接受之鹽、前藥、代謝物或前藥之鹽,該等可用作抗細胞凋亡Bcl-2蛋白之抑制劑。
一個實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2R)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5s,8s)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5r,8r)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-羥基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯
胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜螺[4.5]癸-8-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2S)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[4-(羥基甲基)四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[3-(羥基甲基)氧雜環丁-3-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基-3-甲基丁基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-
基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基三環[3.3.1.13,7]癸-1-基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧雜二環[3.1.0]己-6-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-羥基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯基]胺磺醯基}-2-硝基苯基)胺基]甲基}四氫-2H-吡喃-4-甲酸甲酯;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[2-(四氫-2H-吡喃-4-基)肼基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其
治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-硫吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(氧雜環丁-3-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-羥基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-
基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4,4-二氟-1-羥基環己基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲氧基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3,3-二氟環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺醯基]六氫吡啶-4-基}甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[1-(甲基磺醯基)六氫吡啶-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1-氧離子基四氫-2H-硫吡喃-
4-基)甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氫呋喃-3-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-甲基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(反式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(順式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(1,1-二氧離子基四氫-2H-硫吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二噁烷-2-基]甲
基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-氰基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於N-[(4-{[(1-乙醯基六氫吡啶-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-乙基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜環庚-6-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(4-環丙基苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-(4-{[2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
另一實施例係關於4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基環己-1-烯-1-基}甲基)六氫吡嗪-1-基]-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及其治療上可接受之鹽、前藥、代謝物或前藥之鹽。
本發明化合物可包含幾何異構物。本發明化合物可含有呈E或Z組態之碳-碳雙鍵或碳-氮雙鍵,其中術語「E」代表碳-碳或碳-氮雙鍵之相對側上之較高順序取代基,且術語「Z」代表碳-碳或碳-氮雙鍵之相同側上之較高順序取代基,如藉由Cahn-Ingold-Prelog優先規則所確定。本發明化合物亦可以「E」與「Z」異構物之混合物形式存在。環烷基或雜環烷基周圍之取代基指定為具有順式或反式組態。此外,本發明涵蓋得自對金剛烷環系統周圍取代基之處理之各種異構物及其混合物。金剛烷環系統內單環周圍之兩個取代基指定為具有Z或E相對組態。例如參見C.D.Jones,M.Kaselj,R.N.Salvatore,W.J.le Noble J.Org.Chem. 1998,63,2758-2760。
本發明化合物可含有呈R或S組態之不對稱取代之碳原子,其中術語「R」及「S」係如IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem.(1976)45,13-10所定義。具有等量R及S組態之不對稱取代碳原子之化合物在彼等碳原子
處外消旋。將具有超過另一者之一個組態的原子分配給以較高量存在之組態,較佳地超過約85%-90%、更佳地超過約95%-99%且仍更佳地超過約99%以上。因此,本發明包括外消旋混合物、相對及絕對立體異構物及相對及絕對立體異構物之混合物。
本發明化合物可以選擇性Bcl-2抑制劑化合物之前藥形式存在。前藥係活性藥物之衍生物,其經設計以改善一些經鑒定之不合意的物理或生物性質。物理性質通常係溶解性(脂質或水溶解性太強或不足)或相關穩定性,而難確定之生物性質包括過快代謝或差生物利用性,其本身可與物理化學性質相關。前藥通常係藉由以下來製備:a)形成活性藥物之酯、半酯、碳酸酯、硝酸酯、醯胺、異羥肟酸、胺基甲酸酯、亞胺、曼尼西鹼(Mannich base)、磷酸鹽、磷酸酯及烯胺,b)用偶氮化合物、糖苷、肽及醚官能基將藥物官能化,c)使用藥物之胺縮醛、半胺縮醛、聚合物、鹽、複合物、磷醯胺、縮醛、半縮醛及縮酮形式。例如,參見Andrejus Korolkovas’s,「Essentials of Medicinal Chemistry」,John Wiley-Interscience Publications,John Wiley and Sons,New York(1988),第97頁至第118頁,其以全文引用方式併入本文中。
本發明化合物可以經同位素標記或富集之形式存在,該形式含有一或多個原子質量或質量數不同於自然界中最大量發現之原子質量或質量數的原子。同位素可為放射性或非放射性同位素。諸如氫、碳、磷、硫、氟、氯及碘等原子之同位素包括(但不限於)2H、3H、13C、14C、15N、18O、32P、35S、18F、36Cl及125I。含有該等原子及/或其他原子之其他同位素的化合物屬於本發明範圍。
在另一實施例中,經同位素標記之化合物含有氘(2H)、氚(3H)或14C同位素。本發明之同位素標記化合物可藉由熟習此項技術者所熟
知之一般方法來製備。該等同位素標記化合物可藉由實施本文所揭示實例及方案中所揭示程序、藉由用容易獲得之同位素標記試劑代替未標記試劑來方便地製備。在一些情形下,化合物可經同位素標記試劑處理以利用同位素交換其正常原子,例如可藉由氘酸(例如D2SO4/D2O)之作用將氫交換為氘。除上述以外,相關程序及中間體亦揭示於(例如)以下文獻中:Lizondo,J等人,Drugs Fut,21(11),1116(1996);Brickner,S J等人,J Med Chem,39(3),673(1996);Mallesham,B等人,Org Lett,5(7),963(2003);PCT公開案WO 1997010223、WO2005099353、WO1995007271、WO2006008754;美國專利第7538189號、第7534814號、第7531685號、第7528131號、第7521421號、第7514068號、第7511013號;及美國專利申請公開案第20090137457號、第20090131485號、第20090131363號、第20090118238號、第20090111840號、第20090105338號、第20090105307號、第20090105147號、第20090093422號、第20090088416號及第20090082471號,該等方法以引用方式併入本文中。
本發明之同位素標記化合物可用作標準物來確定Bcl-2抑制劑在結合分析中之有效性。已在醫藥研究中使用含同位素化合物藉由評估非同位素標記之母體化合物之作用機制及代謝途徑來研究化合物之活體內代謝命運(Blake等人,J.Pharm.Sci.64,3,367-391(1975))。該等代謝研究對於安全、有效之治療藥物之設計而言甚為重要,此乃因投與個體活性化合物或自母體化合物產生之代謝物在活體內證明有毒或致癌(Foster等人,Advances in Drug Research第14卷,第2頁至第36頁,Academic press,London,1985;Kato等人,J.Labelled Comp Radiopharmaceut.,36(10):927-932(1995);Kushner等人,Can.J.Physiol.Pharmacol.,77,79-88(1999))。
另外,含有非放射活性同位素之藥物(例如,稱作「重藥物」之氘化藥物)可用於治療與Bcl-2活性相關之疾病及病況。存於化合物中之同位素之量增加至高於其天然豐度稱作富集。富集量之實例包括約0.5mol%、1mol%、2mol%、3mol%、4mol%、5mol%、6mol%、7mol%、8mol%、9mol%、10mol%、12mol%、16mol%、21mol%、25mol%、29mol%、33mol%、37mol%、42mol%、46mol%、50mol%、54mol%、58mol%、63mol%、67mol%、71mol%、75mol%、79mol%、84mol%、88mol%、92mol%、96mol%至約100mol%。已在哺乳動物(包括齧齒動物及狗)中實現高達約15%正常原子經重同位素之置換且維持數天至數週之時段,且所觀察到之不利效應最小(Czajka D M及Finkel A J,Ann.N.Y.Acad.Sci.1960 84:770;Thomson J F,Ann.New York.Sci 1960 84:736;Czakja D M等人,Am.J.Physiol.1961 201:357)。發現人類體液中經氘高達15%-23%之急性置換不會導致毒性(Blagojevic N等人,「Dosimetry & Treatment Planning for Neutron Capture Therapy」,Zamenhof R,Solares G及Harling O Eds.1994.Advanced Medical Publishing,Madison Wis.第125頁至第134頁;Diabetes Metab 23:251(1997))。
對藥物進行穩定同位素標記可改變其物理化學性質,例如pKa及脂質溶解性。若同位素取代影響配體-受體相互作用中所涉及之區域,則該等效應及變化可影響藥物分子之藥效動力學反應。儘管穩定同位素標記分子之一些物理性質不同於彼等未標記者,但化學及生物性質係相同的,一個重要情況例外:由於重同位素之質量增加,故涉及重同位素與另一原子之任一鍵將強於輕同位素與該原子間之同一鍵。因此,相對於非同位素化合物,在代謝或酶轉化位點納入同位素將減慢該等反應,從而潛在地改變藥物動力學特性或功效。
另一實施例係關於醫藥組合物,其包含本發明化合物及賦形劑。
又一實施例係關於治療表現抗細胞凋亡Bcl-2蛋白之疾病之組合物,該等組合物包含賦形劑及治療有效量之本發明化合物。
又一實施例係關於治療以下疾病之組合物:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌或脾臟癌,該等組合物包含賦形劑及治療有效量之本發明化合物。
又一實施例係關於治療表現抗細胞凋亡Bcl-2蛋白之疾病之組合物,該等組合物包含賦形劑及治療有效量之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
又一實施例係關於治療以下疾病之組合物:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、慢性淋巴球性白血病、骨髓瘤、前列腺癌、小細胞肺癌或脾臟癌,該等組合物包含賦形劑及治療有效量之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
又一實施例係關於治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之組合物,該等組合物包含賦形劑及治療有效量之本發明化合物。
又一實施例係關於治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之組合物,該等組合物包含賦形劑及治療有效量之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
藉由活體外或活體內代謝過程所產生本發明化合物之代謝物亦可用於治療與抗細胞凋亡Bcl-2蛋白相關之疾病。
可活體外或活體內代謝而形成本發明化合物之某些前體化合物亦可用於治療與抗細胞凋亡Bcl-2蛋白之表現相關之疾病。
本發明化合物可以酸加成鹽、鹼加成鹽或兩性離子形式存在。化合物之鹽係在分離化合物期間或在純化化合物後製備。化合物之酸加成鹽係彼等自化合物與酸反應獲得者。例如,預期本發明涵蓋化合物之以下鹽:乙酸鹽、己二酸鹽、海藻酸鹽、碳酸氫鹽、檸檬酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡萄糖酸鹽、甲酸鹽、富馬酸鹽、甘油磷酸鹽、麩胺酸鹽、半硫酸鹽、庚酸鹽、已酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、乳糖酸鹽、乳酸鹽、馬來酸鹽、均三甲苯磺酸鹽、甲烷磺酸鹽、伸萘基磺酸鹽、菸鹼酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、磷酸鹽、苦味酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫氰酸鹽、三氯乙酸鹽、三氟乙酸鹽、對-甲苯磺酸鹽及十一烷酸鹽。化合物之鹼加成鹽係彼等自化合物與諸如鋰、鈉、鉀、鈣及鎂等陽離子之氫氧化物、碳酸鹽或碳酸氫鹽反應所獲得者。
本發明化合物可(例如)經頰、經眼、經口、經滲透壓、非經腸(經肌內、經腹膜內、經胸骨內、經靜脈內、經皮下)、經直腸、經局部、經皮或經陰道投與。
治療有效量之本發明化合物取決於治療之接受者、所治療之病症及其嚴重程度、含有該化合物之組合物、投與時間、投與路徑、治療持續時間、化合物效能、其清除速率及是否共投與另一藥物。用以製備以單一劑量或分開劑量每日投與個體之組合物之本發明化合物之量為約0.001mg/kg至約1000mg/kg,或約0.01mg/kg至約500mg/kg,或約0.1mg/kg至約300mg/kg。單一劑量組合物含有該等量或其多次
分量之組合。
可對劑量方案加以調節以提供最佳期望反應(例如,治療性或預防性反應)。例如,可投與單次推注,可經一段時間投與若干分開劑量或可如治療狀況緊急情況所指示按比例減少或增加劑量。以劑量單元形式來調配非經腸組合物尤其有利於方便投與及劑量一致性。本文所用劑量單元形式係指適宜作為單位劑量供欲治療哺乳動物個體使用之物理離散單元;各單元含有經計算可產生期望治療效應之預定量活性化合物與所需醫藥載劑。本發明劑量單位形式之規格取決於且直接依賴於以下因素:(a)活性化合物之獨特特性及欲達成之特定治療或預防效應,及(b)混合此一活性化合物以治療個體敏感性之技術固有的限制。
本發明化合物可連同或不連同賦形劑一起投與。賦形劑包括(例如)囊封材料或添加劑,例如吸收加速劑、抗氧化劑、黏合劑、緩衝劑、包衣劑、著色劑、稀釋劑、崩解劑、乳化劑、增量劑、填充劑、矯味劑、保濕劑、潤滑劑、香料、防腐劑、推進劑、釋放劑、滅菌劑、甜味劑、增溶劑、潤濕劑及其混合物。該等賦形劑可為醫藥上可接受之賦形劑。
用於製備欲以固體劑型經口投與之包含本發明化合物之組合物之賦形劑包括(例如)瓊脂、海藻酸、氫氧化鋁、苄基醇、苯甲酸苄基酯、1,3-丁二醇、卡波姆(carbomer)、蓖麻油、纖維素、乙酸纖維素、可可油、玉米澱粉、玉米油、棉籽油、交聯聚維酮、甘油二酯、乙醇、乙基纖維素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明膠、胚芽油、葡萄糖、甘油、花生油(groundnut oil)、羥基丙基甲基纖維素、異丙醇、等滲鹽水、乳糖、氫氧化鎂、硬脂酸鎂、麥芽、甘露醇、甘油單酯、橄欖油、花生油(peanut oil)、磷酸鉀鹽、馬鈴薯澱粉、聚維酮、丙二醇、林格氏溶液(Ringer’s solution)、紅花油、芝麻油、羧甲基纖維素鈉、磷酸鈉鹽、月桂基硫酸鈉、山梨醇鈉、大豆油、硬脂
酸、富馬酸硬脂基酯、蔗糖、表面活性劑、滑石粉、黃耆膠、四氫糠醇、甘油三酯、水及其混合物。用製備欲以液體劑型經眼或經口投與之包含本發明化合物之組合物的賦形劑包括(例如)1,3-丁二醇、蓖麻油、玉米油、棉籽油、乙醇、去水山梨醇之脂肪酸酯、胚芽油、花生油、甘油、異丙醇、橄欖油、聚乙二醇、丙二醇、芝麻油、水及其混合物。用於製備欲經滲透壓投與之包含本發明化合物之組合物的賦形劑包括(例如)氯氟烴、乙醇、水及其混合物。用於製備欲非經腸投與之包含本發明化合物之組合物的賦形劑包括(例如)1,3-丁二醇、蓖麻油、玉米油、棉籽油、右旋糖、胚芽油、花生油、脂質體、油酸、橄欖油、花生油、林格氏溶液、紅花油、芝麻油、大豆油、U.S.P.或等滲氯化鈉溶液、水及其混合物。用於製備欲經直腸或經陰道投與之包含本發明化合物之組合物的賦形劑包括(例如)可可油、聚乙二醇、蠟及其混合物。
預計本發明化合物在與以下各項一起使用時有用:烷基化劑、血管生成抑制劑、抗體、抗代謝物、抗有絲分裂物、抗增殖物、抗病毒劑、極光激酶抑制劑(aurora kinase inhibitor)、其他細胞凋亡促進劑(例如Bcl-xL、Bcl-w及Bfl-1)抑制劑、死亡受體途徑激活劑、Bcr-Abl激酶抑制劑、BiTE(雙特異性T細胞銜接體(Engager))抗體、抗體藥物偶聯物、生物反應改良劑、細胞週期蛋白依賴性激酶抑制劑、細胞週期抑制劑、環氧合酶-2抑制劑、DVD、白血病病毒致癌基因同源物(ErbB2)受體抑制劑、生長因子抑制劑、熱休克蛋白(HSP)-90抑制劑、組蛋白去乙醯酶(HDAC)抑制劑、激素療法、免疫劑、細胞凋亡蛋白抑制劑(IAP)、嵌入抗生素、激酶抑制劑、驅動蛋白抑制劑、Jak2抑制劑、哺乳動物雷帕黴素(rapamycin)靶標抑制劑、微RNA、促分裂原活化之細胞外信號調控激酶抑制劑、多價結合蛋白、非類固醇消炎藥(NSAID)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制劑、鉑
化學治療劑、保羅樣(polo-like)激酶(Plk)抑制劑、磷酸肌醇-3激酶(PI3K)抑制劑、蛋白體抑制劑、嘌呤類似物、嘧啶類似物、受體酪胺酸激酶抑制劑、類視色素/三角肌植物生物鹼、小抑制核糖核酸(siRNA)、拓撲異構酶抑制劑、泛素連接酶抑制劑及諸如此類,以及與一或多種該等藥劑之組合。
BiTE抗體係藉由同時結合兩種細胞而引導T細胞攻擊癌細胞之雙特異性抗體。隨後T細胞攻擊靶標癌細胞。BiTE抗體之實例包括阿德木單抗(adecatumumab)(Micromet MT201)、布理莫單抗(blinatumomab)(Micromet MT103)及諸如此類。不受限於理論,T細胞引發靶標癌細胞細胞凋亡之一種機制係溶細胞顆粒組份(其包括穿孔蛋白及粒酶B)之胞吐作用。就此而言,已顯示Bcl-2可減弱穿孔蛋白及粒酶B二者對於細胞凋亡之誘導。該等數據表明抑制Bcl-2可增強T細胞在靶向癌細胞時引發之細胞毒性效應(V.R.Sutton,D.L.Vaux及J.A.Trapani,J.of Immunology 1997,158(12),5783)。
SiRNA係具有內源性RNA鹼基或化學改質核苷酸之分子。改質不會消除細胞活性,而是賦予增加之穩定性及/或增加之細胞效能。化學改質之實例包括硫代磷酸酯基團、2’-去氧核苷酸、含有2’-OCH3之核糖核苷酸、2’-F-核糖核苷酸、2’-甲氧基乙基核糖核苷酸、其組合及諸如此類。siRNA可具有不同長度(例如,10-200bp)及結構(例如,髮夾形、單鏈/雙鏈、凸起、凹痕/空隙、失配)且可在細胞中處理以提供活性基因沉默。雙鏈siRNA(dsRNA)可在各鏈(鈍端)或不對稱端(突出端)上具有相同數量之核苷酸。1至2個核苷酸之突出端可存在於有義鏈及/或反義鏈上,亦可存在於給定鏈之5’-及/或3’末端。例如,已顯示靶向Mcl-1之siRNA可增強ABT-263(即,N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-環己-1-烯-1-基)甲基)六氫吡嗪-1-基)苯甲醯基)-4-(((1R)-3-(嗎啉-4-基)-1-((苯基硫基)甲基)丙基)胺基)-3-((三氟甲基)磺醯基)苯
磺醯胺)或ABT-737(即,N-(4-(4-((4’-氯(1,1’-聯苯)-2-基)甲基)六氫吡嗪-1-基)苯甲醯基)-4-(((1R)-3-(二甲基胺基)-1-((苯基硫基)甲基)丙基)胺基)-3-硝基苯磺醯胺)在多個腫瘤細胞系中之活性(Tse等人,Cancer Research 2008,68(9),3421及其中的參考文獻)。
多價結合蛋白係包含兩個或更多個抗原結合位點之結合蛋白。多價結合蛋白經改造具有三個或更多個抗原結合位點且通常為非天然抗體。術語「多特異性結合蛋白」意指能夠結合兩個或更多個相關或不相關靶標之結合蛋白。雙重可變結構域(DVD)結合蛋白係結合包含兩個或更多個抗原結合位點之蛋白質之四價或多價結合蛋白。該等DVD可具有單特異性(即,能夠結合一種抗原)或多特異性(即,能夠結合兩種或更多種抗原)。包含兩條重鏈DVD多肽及兩條輕鏈DVD多肽之DVD結合蛋白稱作DVD Ig。DVD Ig之每一半部包含重鏈DVD多肽、輕鏈DVD多肽及兩個抗原結合位點。各結合位點包含重鏈可變結構域及輕鏈可變結構域,每個抗原結合位點具有總共6個參與抗原結合之CDR。
烷基化劑包括六甲蜜胺(altretamine)、AMD-473、AP-5280、阿帕茲醌(apaziquone)、苯達莫司汀(bendamustine)、布羅他辛(brostallicin)、白消安(busulfan)、卡波醌(carboquone)、卡莫司汀(carmustine)(BCNU)、苯丁酸氮芥(chlorambucil)、CLORETAZINE®(拉羅司汀(laromustine),VNP 40101M)、環磷醯胺、達卡巴嗪(decarbazine)、雌莫司汀(estramustine)、福莫司汀(fotemustine)、葡磷醯胺(glufosfamide)、異環磷醯胺(ifosfamide)、KW-2170、洛莫司汀(lomustine)(CCNU)、馬磷醯胺(mafosfamide)、美法侖(melphalan)、二溴甘露醇(mitobronitol)、二溴衛矛醇(mitolactol)、尼莫司汀(nimustine)、氮芥N-氧化物、雷莫司汀(ranimustine)、替莫唑胺(temozolomide)、噻替哌(thiotepa)、
TREANDA®(苯達莫司汀)、曲奧舒凡(treosulfan)、曲磷胺(rofosfamide)及諸如此類。
血管生成抑制劑包括內皮特異性受體酪胺酸激酶(Tie-2)抑制劑、表皮生長因子受體(EGFR)抑制劑、胰島素生長因子-2受體(IGFR-2)抑制劑、基質金屬蛋白酶-2(MMP-2)抑制劑、基質金屬蛋白酶-9(MMP-9)抑制劑、血小板源性生長因子受體(PDGFR)抑制劑、凝血酶敏感蛋白類似物、血管內皮生長因子受體酪胺酸激酶(VEGFR)抑制劑及諸如此類。
抗代謝物包括ALIMTA®(培美曲塞二鈉(pemetrexed disodium)、LY231514、MTA)、5-阿紮胞苷(5-azacitidine)、XELODA®(卡培他濱(capecitabine))、卡莫氟(carmofur)、LEUSTAT®(克拉屈濱(cladribine))、氯法拉濱(clofarabine)、阿糖胞苷(cytarabine)、阿糖胞苷十八烷基磷酸鹽(cytarabine ocfosfate)、胞嘧啶阿拉伯糖苷、地西他濱(decitabine)、去鐵胺、去氧氟尿苷、依氟鳥胺酸(eflornithine)、EICAR(5-乙炔基-1-β-D-核糖呋喃基咪唑-4-甲醯胺)、依諾他濱(enocitabine)、乙炔基胞苷、氟達拉濱(fludarabine)、單獨5-氟尿嘧啶或與甲醯四氫葉酸(leucovorin)之組合、GEMZAR®(吉西他濱(gemcitabine))、羥基脲、ALKERAN®(美法侖)、巰基嘌呤、6-巰基嘌呤核糖苷、胺甲蝶呤、黴酚酸(mycophenolic acid)、耐拉濱(nelarabine)、諾拉曲塞(nolatrexed)、十八烷基磷酸鹽(ocfosfate)、皮利曲松(pelitrexol)、噴司他汀(pentostatin)、雷替曲塞(raltitrexed)、利巴韋林(Ribavirin)、特立平(triapine)、曲美沙特(trimetrexate)、S-1、噻唑呋林(tiazofurin)、替加氟(tegafur)、TS-1、阿糖腺苷(vidarabine)、UFT及諸如此類。
抗病毒劑包括利托那韋(ritonavir)、羥氯喹及諸如此類。
極光激酶抑制劑包括ABT-348、AZD-1152、MLN-8054、VX-
680、極光A特異性激酶抑制劑、極光B特異性激酶抑制劑、泛極光激酶抑制劑及諸如此類。
Bcl-2蛋白抑制劑包括AT-101((-)棉籽酚(gossypol))、GENASENSE®(G3139或奧利默森(oblimersen)(Bcl-2-靶向反義寡核苷酸))、IPI-194、IPI-565、N-(4-(4-((4’-氯(1,1’-聯苯)-2-基)甲基)六氫吡嗪-1-基)苯甲醯基)-4-(((1R)-3-(二甲基胺基)-1-((苯基硫基)甲基)丙基)胺基)-3-硝基苯磺醯胺)(ABT-737)、N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-環己-1-烯-1-基)甲基)六氫吡嗪-1-基)苯甲醯基)-4-(((1R)-3-(嗎啉-4-基)-1-((苯基硫基)甲基)丙基)胺基)-3-((三氟甲基)磺醯基)苯磺醯胺(ABT-263)、4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(t四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺(ABT-199)、GX-070(奧巴克拉(obatoclax))及諸如此類。
Bcr-Abl激酶抑制劑包括DASATINIB®(BMS-354825)、GLEEVEC®(伊馬替尼(imatinib))及諸如此類。
CDK抑制劑包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、夫拉平度(flavopyridol)、GPC-286199、MCS-5A、PD0332991、PHA-690509、司利昔布(seliciclib)(CYC-202或R-羅克韋汀(R-roscovitine))、ZK-304709、地那昔布(dinaciclib)及諸如此類。
COX-2抑制劑包括ABT-963、ARCOXIA®(依託考昔(etoricoxib))、BEXTRA®(伐地考昔(valdecoxib))、BMS347070、CELEBREX®(塞來考昔(celecoxib))、COX-189(魯米考昔(lumiracoxib))、CT-3、DERAMAXX®(地拉考昔(deracoxib))、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-胺磺醯基苯基-1H-吡咯)、MK-663(依託考昔)、NS-398、帕瑞考昔(parecoxib)、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VIOXX®(羅非考昔
(rofecoxib))及諸如此類。
EGFR抑制劑包括ABX-EGF、抗-EGFR免疫脂質體、EGF-疫苗、EMD-7200、ERBITUX®(西土西單抗(cetuximab))、HR3、IgA抗體、IRESSA®(吉非替尼(gefitinib))、TARCEVA®(埃羅替尼(erlotinib)或OSI-774)、TP-38、EGFR融合蛋白、TYKERB®(拉帕替尼(lapatinib))及諸如此類。
ErbB2受體抑制劑包括CP-724-714、CI-1033(卡納替尼(canertinib))、HERCEPTIN®(曲妥珠單抗(trastuzumab))、TYKERB®(拉帕替尼)、OMNITARG®(2C4、帕妥珠單抗(petuzumab))、TAK-165、GW-572016(羅那法尼(lonafarnib))、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER-2疫苗)、抗-HER/2neu雙特異性抗體、B7.her2IgG3、AS HER2三功能雙特異性抗體、mAB AR-209、mAB 2B-1及諸如此類。
組蛋白去乙醯酶抑制劑包括縮肽、LAQ-824、MS-275、曲普辛(trapoxin)、辛二醯基苯胺異羥肟酸(SAHA)、TSA、丙戊酸及諸如此類。
HSP-90抑制劑包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格爾德黴素(geldanamycin)、IPI-504、KOS-953、MYCOGRAB®(HSP-90之人類重組抗體)、NCS-683664、PU24FCl、PU-3、根赤殼菌素(radicicol)、SNX-2112、STA-9090VER49009及諸如此類。
細胞凋亡蛋白抑制劑包括HGS-1029、GDC-0145、GDC-0152、LCL-161、LBW-242及諸如此類。
抗體藥物偶聯物包括抗-CD22-MC-MMAF、抗-CD22-MC-MMAE、抗-CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19AmSGN-35、SGN-75、曲妥珠單抗美坦辛
(trastuzumab emtansine)及諸如此類。
死亡受體途徑活化劑包括TRAIL及靶向TRAIL或死亡受體(例如,DR4及DR5)之抗體或其他藥劑,例如阿泊單抗(apomab)、可那木單抗(conatumumab)、ETR2-ST01、GDC0145(來沙木單抗(lexatumumab))、HGS-1029、LBY-135、PRO-1762及曲妥珠單抗。
驅動蛋白抑制劑包括Eg5抑制劑,例如AZD4877、ARRY-520;CENPE抑制劑,例如GSK923295A及諸如此類。
JAK-2抑制劑包括CEP-701(來他替尼(lestaurtinib))、XL019及INCB018424及諸如此類。
MEK抑制劑包括ARRY-142886、ARRY-438162、PD-325901、PD-98059及諸如此類。
mTOR抑制劑包括AP-23573、CCI-779、依維莫司(everolimus)、RAD-001、雷帕黴素、替西羅莫司(temsirolimus)、ATP-競爭性TORC1/TORC2抑制劑(包括PI-103、PP242、PP30、Torin 1)及諸如此類。
非類固醇消炎藥物包括AMIGESIC®(雙水楊酯)、DOLOBID®(雙氟尼酸(diflunisal))、MOTRIN®(布洛芬(ibuprofen))、ORUDIS®(酮洛芬(ketoprofen))、RELAFEN®(萘丁美酮(nabumetone))、FELDENE®(吡羅昔康(piroxicam))、布洛芬乳霜、ALEVE®(萘普生(naproxen))及NAPROSYN®(萘普生)、VOLTAREN®(雙氯芬酸(diclofenac))、INDOCIN®(吲哚美辛(indomethacin))、CLINORIL®(舒林酸(sulindac))、TOLECTIN®(托美汀(tolmetin))、LODINE®(依託度酸(etodolac))、TORADOL®(酮咯酸(ketorolac))、DAYPRO®(奧沙普嗪(oxaprozin))及諸如此類。
PDGFR抑制劑包括C-451、CP-673、CP-868596及諸如此類。
鉑化學治療劑包括順鉑、ELOXATIN®(奧沙利鉑(oxaliplatin))依
鉑(eptaplatin)、洛鉑(lobaplatin)、奈達鉑(nedaplatin)、PARAPLATIN®(卡鉑(carboplatin))、沙鉑(satraplatin)、吡鉑(picoplatin)及諸如此類。
保羅樣激酶抑制劑包括BI-2536及諸如此類。
磷酸肌醇-3激酶((PI3K))抑制劑包括渥曼青黴素(wortmannin)、LY294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765及諸如此類。
凝血酶敏感蛋白類似物包括ABT-510、ABT-567、ABT-898、TSP-1及諸如此類。
VEGFR抑制劑包括AVASTIN®(貝伐珠單抗(bevacizumab))、ABT-869、AEE-788、ANGIOZYMETM(抑制血管生成之核酶(Ribozyme Pharmaceuticals(Boulder公司)及Chiron(Emeryville,CA))、阿西替尼(axitinib)(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN(派加他尼鈉(pegaptanib))、NEXAVAR®(索拉非尼(sorafenib),BAY43-9006)、帕唑帕尼(pazopanib)(GW-786034)、瓦他拉尼(vatalanib)(PTK-787、ZK-222584)、SUTENT®(舒尼替尼(sunitinib)、SU-11248)、VEGF trap、ZACTIMATM(凡德他尼(vandetanib)、ZD-6474)及諸如此類。
抗生素包括嵌入抗生素阿柔比星(aclarubicin)、放線菌素D(actinomycin D)、胺柔比星(amrubicin)、脂質體蒽環黴素(annamycin)、阿黴素(adriamycin)、BLENOXANE®(博萊黴素(bleomycin))、柔紅黴素(daunorubicin)、CAELYX®或MYOCET®(脂質體多柔比星(liposomal doxorubicin))、依沙蘆星(elsamitrucin)、表柔比星(epirubcin)、加柔比星(galarubicin)、ZAVEDOS®(伊達比星(idarubicin))、絲裂黴素C(mitomycin C)、奈莫柔比星(nemorubicin)、新製癌菌素(neocarzinostatin)、培洛黴素(peplomycin)、吡柔比星
(pirarubicin)、蝴蝶黴素(rebeccamycin)、司替馬拉莫(stimalamer)、鏈脲黴素(streptozocin)、VALSTAR®(戊柔比星(valrubicin))、淨司他丁(zinostatin)及諸如此類。
拓撲異構酶抑制劑包括阿柔比星、9-胺基喜樹鹼、胺萘非特(amonafide)、安吖啶(amsacrine)、貝特卡令(becatecarin)、貝洛替康(belotecan)、BN-80915、CAMPTOSAR®(鹽酸伊立替康(irinotecan鹽酸鹽))、喜樹鹼、CARDIOXANE®(右雷佐生(dexrazoxane))、二氟替康(diflomotecan)、伊多替卡林(edotecarin)、ELLENCE®或PHARMORUBICIN®(表柔比星)、依託泊苷(etoposide)、依喜替康(exatecan)、10-羥基喜樹鹼、吉馬替康(gimatecan)、勒托替康(lurtotecan)、米托蒽醌(mitoxantrone)、奧拉塞星(orathecin)、吡柔比星、匹杉瓊(pixantrone)、魯比替康(rubitecan)、索布佐生(sobuzoxane)、SN-38、他氟泊苷(tafluposide)、拓撲替康(topotecan)及諸如此類。
抗體包括AVASTIN®(貝伐珠單抗)、CD40特異性抗體、chTNT-1/B、地諾單抗(denosumab)、ERBITUX®(西土西單抗)、HMMAX-CD4®(紮木單抗(zanolimumab))、IGF1R特異性抗體、林妥珠單抗(lintuzumab)、PANOREX®(依決洛單抗(edrecolomab))、RENCAREX®(WX G250)、RITUXAN®(利妥昔單抗(rituximab))、替西木單抗(ticilimumab)、曲妥珠單抗(trastuzimab)、I型及II型CD20抗體及諸如此類。
激素療法包括ARIMIDEX®(阿那曲唑(anastrozole))、AROMASIN®(依西美坦(exemestane))、阿佐昔芬(arzoxifene)、CASODEX®(比卡魯胺(bicalutamide))、CETROTIDE®(西曲瑞克(cetrorelix))、地加瑞克(degarelix)、地洛瑞林(deslorelin)、DESOPAN®(曲洛司坦(trilostane))、地塞米松(dexamethasone)、
DROGENIL®(氟他米特(flutamide))、EVISTA®(雷洛昔芬(raloxifene))、AFEMATM(法屈唑(fadrozole))、FARESTON®(托瑞米芬(toremifene))、FASLODEX®(氟維司群(fulvestrant))、FEMARA®(來曲唑(letrozole))、福美司坦(formestane)、糖皮質激素、HECTOROL®(度骨化醇(doxercalciferol))、RENAGEL®(碳酸司維拉姆(sevelamer carbonate))、拉索昔芬(lasofoxifene)、乙酸亮丙瑞林(leuprolide acetate)、MEGACE®(甲地孕酮(megesterol))、MIFEPREX®(米非司酮(mifepristone))、NILANDRONTM(尼魯米特(nilutamide))、NOLVADEX®(檸檬酸他莫昔芬(tamoxifen citrate))、PLENAXISTM(阿巴瑞克(abarelix))、強的松(prednisone)、PROPECIA®(非那雄胺(finasteride))、瑞洛司坦(rilostane)、SUPREFACT®(布舍瑞林(buserelin))、TRELSTAR®(黃體生成激素釋放激素(LHRH))、VANTAS®(組胺瑞林(Histrelin)植入物)、VETORYL®(曲洛司坦或莫卓司坦(modrastane))、ZOLADEX®(福斯瑞林(fosrelin)、戈舍瑞林(goserelin))及諸如此類。
三角肌及類視色素包括西奧骨化醇(seocalcitol)(EB1089、CB1093)、來沙骨化醇(lexacalcitrol)(KH1060)、芬維A胺(fenretinide)、PANRETIN®(阿利維A酸(aliretinoin))、ATRAGEN®(脂質體維生素A酸(liposomal tretinoin))、TARGRETIN®(貝沙羅汀(bexarotene))、LGD-1550及諸如此類。
PARP抑制劑包括ABT-888(維利帕尼(ve1iparib))、奧拉帕尼(olaparib)、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231及諸如此類。
植物生物鹼包括(但不限於)長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)、長春瑞濱(vinorelbine)及諸如此類。
蛋白酶體抑制劑包括VELCADE®(硼替佐米(bortezomib))、MG132、NPI-0052、PR-171、來那度胺(carfilzomib)及諸如此類。
免疫劑之實例包括干擾素及其他免疫增強劑。干擾素包括干擾素α、干擾素α-2a、干擾素α-2b、干擾素β、干擾素γ-1a、ACTIMMUNE®(干擾素γ-1b)或干擾素γ-n1、其組合及諸如此類。其他藥劑包括ALFAFERONE®(IFN-α)、BAM-002(氧化麩胱甘肽)、BEROMUN®(他索那明(tasonermin))、BEXXAR®(托西莫單抗(tositumomab))、CAMPATH®(阿侖單抗(alemtuzumab))、CTLA4(細胞毒性淋巴球抗原4)、達卡巴嗪、地尼白介素(denileukin)、依帕珠單抗(epratuzumab)、GRANOCYTE®(來格司亭(lenograstim))、香菇多糖(lentinan)、白細胞α干擾素、咪喹莫特(imiquimod)、MDX-010(抗CTLA-4)、黑色素瘤疫苗、米妥莫單抗(mitumomab)、莫拉司亭(molgramostim)、MYLOTARGTM(吉妥珠單抗奧佐米星(gemtuzumab ozogamicin))、NEUPOGEN®(非格司亭(filgrastim))、OncoVAC-CL、OVAREX®(奧戈伏單抗(oregovomab))、皮托莫單抗(pemtumomab)(Y-muHMFGl)、PROVENGE®(西普魯塞T(sipuleucel-T))、沙格司汀(sargramostim)、西索非蘭(sizofilan)、替西白介素(teceleukin)、THERACYS®(卡介菌劑(Bacillus Calmette-Guerin))、烏苯美司(ubenimex)、VIRULIZIN®(免疫治療劑,Lorus Pharmaceuticals)、Z-100(丸山真男特定物質(Specific Substance of Maruyama,SSM))、WF-10(四氯十氧化物(TCDO))、PROLEUKIN®(阿地白介素(aldesleukin))、ZADAXIN®(胸腺法新(thymalfasin))、ZENAPAX®(達利珠單抗(daclizumab))、ZEVALIN®(90Y-替伊莫單抗(90Y-Ibritumomab tiuxetan))及諸如此類。
生物反應改良劑係可改良活的有機體或生物反應(例如組織細胞之存活、生長或分化)之防禦機制以使其具有抗腫瘤活性的試劑且包
括雲芝多糖(krestin)、香菇多糖、西索非蘭(sizofiran)、溶鏈菌製劑(picibanil)PF-3512676(CpG-8954)、烏苯美司及諸如此類。
嘧啶類似物包括阿糖胞苷(araC或阿拉伯糖苷C)、胞嘧啶阿拉伯糖苷、去氧氟尿苷、FLUDARA®(氟達拉濱)、5-FU(5-氟尿嘧啶)、氟尿苷、GEMZAR®(吉西他濱)、TOMUDEX®(雷替曲塞(ratitrexed))、TROXATYLTM(三乙醯基尿苷曲沙他濱(triacetyluridine troxacitabine))及諸如此類。
嘌呤類似物包括LANVIS®(硫鳥嘌呤)及PURI-NETHOL®(巰基嘌呤)。
抗有絲分裂劑包括巴他布林(batabulin)、埃博黴素D(epothilone D)(KOS-862)、N-(2-((4-羥基苯基)胺基)吡啶-3-基)-4-甲氧基苯磺醯胺、伊沙匹隆(ixabepilone)(BMS 247550)、紫杉醇(paclitaxel)、TAXOTERE®(多西他賽(docetaxel))、PNU100940(109881)、帕土匹隆(patupilone)、XRP-9881(拉羅他塞(larotaxel))、長春氟寧(vinflunine)、ZK-EPO(合成埃博黴素)及諸如此類。
泛素連接酶抑制劑包括MDM2抑制劑(例如紐特林(nutlin))、NEDD8抑制劑(例如MLN4924)及諸如此類。
本發明化合物亦可用作增強放射療法功效之放射敏化劑。放射療法之實例包括外部光束放射療法、遠隔放射療法、近程放射療法及密封、未密封源放射療法及諸如此類。
另外,本發明化合物可與其他化學治療劑組合,該等其他化學治療劑係(例如)ABRAXANETM(ABI-007)、ABT-100(法呢基轉移酶抑制劑)、ADVEXIN®(Ad5CMV-p53疫苗)、ALTOCOR®或MEVACOR®(洛伐他汀(lovastatin))、AMPLIGEN®(聚I:聚C12U,一種合成RNA)、APTOSYN®(依昔舒林(exisulind))、AREDIA®(帕米膦酸(pamidronic acid))、阿格拉賓(arglabin)、L-天冬醯胺酶、阿他美坦
(atamestane)(1-甲基-3,17-二酮-雄甾-1,4-二烯)、AVAGE®(他紮羅汀(tazarotene))、AVE-8062(康布瑞他汀(combreastatin)衍生物)、BEC2(米妥莫單抗)、惡病質素(cachectin)或卡車星(cachexin)(腫瘤壞死因子α)、康伐星(canvaxin)(疫苗)、CEAVAC®(癌症疫苗)、CELEUK®(西莫白介素(celmoleukin))、CEPLENE®(組胺二鹽酸鹽)、CERVARIX®(人類乳頭瘤病毒疫苗)、CHOP®(C:CYTOXAN®(環磷醯胺);H:ADRIAMYCIN®(羥基多柔比星);O:長春新鹼(ONCOVIN®);P:(強的松)、CYPATTM(乙酸環丙孕酮(acetate cyproterone))、康布瑞他汀A4P、DAB(389)EGF(經由His-Ala連接體融合至人類表皮生長因子之白喉毒素的催化及轉運結構域)或TransMID-107RTM(白喉毒素)、達卡巴嗪、放線菌素D、5,6-二甲基呫噸酮-4-乙酸(DMXAA)、恩尿嘧啶(eniluracil)、EVIZONTM(乳酸角鯊胺(squalaminelactate))、DIMERICINE®(T4N5脂質體洗劑)、圓皮海綿內酯(discodermolide)、DX-8951f(甲磺酸依喜替康)、恩紮妥林(enzastaurin)、EPO906(埃坡黴素B)、GARDASIL®(四價人類乳頭瘤病毒(6、11、16、18型)重組疫苗)、GASTRIMMUNE®、GENASENSE®、GMK(神經節苷脂偶聯物疫苗)、GVAX®(前列腺癌疫苗)、鹵夫酮(halofuginone)、組胺瑞林(histerelin)、羥基脲、伊班膦酸(ibandronic acid)、IGN-101、IL-13-PE38、IL-13-PE38QQR(貝辛白介素(cintredekin besudotox))、IL-13-假單胞菌外毒素(IL-13-pseudomonas exotoxin)、干擾素-α、干擾素-γ、JUNOVANTM或MEPACTTM(米伐木肽(mifamurtide))、洛那法尼、5,10-亞甲基四氫葉酸酯、米替福新(miltefosine)(十六烷基磷膽鹼)、NEOVASTAT®(AE-941)、NEUTREXIN®(曲美沙特葡萄糖醛酸酯)、NIPENT®(噴司他汀)、ONCONASE®(一種核糖合核酸酶)、ONCOPHAGE®(黑色素瘤疫苗治療)、ONCOVAX®(IL-2疫苗)、ORATHECINTM(魯比替康)、OSIDEM®(基於抗體之細胞藥物)、
OVAREX® MAb(鼠類單株抗體)、紫杉醇、PANDIMEXTM(來自包含20(S)原人參二醇(aPPD)及20(S)原人參三醇(aPPT)之人參的苷配基皂苷)、帕尼單抗(panitumumab)、PANVAC®-VF(調查研究用癌症疫苗)、培加帕加司(pegaspargase)、PEG干擾素A、苯妥帝爾(phenoxodiol)、甲苄肼(procarbazine)、瑞比斯塔(rebimastat)、REMOVAB®(卡妥索單抗(catumaxomab))、REVLIMID®(雷利度胺(lenalidomide))、RSR13(乙丙昔羅(efaproxiral))、SOMATULINE® LA(蘭瑞肽(lanreotide))、SORIATANE®(維生素A酸(acitretin))、星形孢菌素(staurosporine)(鏈黴菌星形孢子(Streptomyces staurospores))、他波司他(talabostat)(PT100)、TARGRETIN®(貝沙羅汀)、TAXOPREXIN®(DHA-紫杉醇)、TELCYTA®(坎磷醯胺(canfosfamide)、TLK286)、特米利芬(temilifene)、TEMODAR®(替莫唑胺)、替米利芬(tesmilifene)、沙立度胺(thalidomide)、THERATOPE®(STn-KLH)、塞米他(thymitaq)(2-胺基-3,4-二氫-6-甲基-4-側氧基-5-(4-吡啶巰基)喹唑啉二鹽酸鹽)、TNFERADETM(腺病毒載體:含有腫瘤壞死因子-α之基因的DNA載體)、TRACLEER®或ZAVESCA®(骨化三醇(bosentan))、維甲酸(tretinoin)(蕾婷A(Retin-A))、粉防己鹼(tetrandrine)、TRISENOX®(三氧化二砷)、VIRULIZIN®、尿激酶(ukrain)(來自較大白屈菜(celandine)植物之生物鹼的衍生物)、維他辛(vitaxin)(抗αvβ3抗體)、XCYTRIN®(莫特沙芬釓(motexafin gadolinium))、XINLAYTM(阿曲生坦(atrasentan))、XYOTAXTM(聚麩胺酸紫杉醇(paclitaxel poliglumex))、YONDELIS®(曲貝替定(trabectedin))、ZD-6126、ZINECARD®(右雷佐生)、ZOMETA®(唑來膦酸(zolendronic acid))、佐柔比星(zorubicin)及諸如此類。
許多蛋白質已與一般自體免疫及發炎反應相關。因此,可組合本發明之選擇性Bcl-2抑制劑與能夠改變與一般自體免疫及發炎反應
相關之其他蛋白之功能之化合物。與自體免疫及發炎反應相關之蛋白質之實例包括C5、CCL1(I-309)、CCL11(嗜伊紅趨化因子(eotaxin))、CCL13(mcp-4)、CCL15(MIP-1d)、CCL16(HCC-4)、CCL17(TARC)、CCL18(PARC)、CCL19、CCL2(mcp-1)、CCL20(MIP-3a)、CCL21(MIP-2)、CCL23(MPIF-1)、CCL24(MPIF-2/嗜伊紅趨化因子-2)、CCL25(TECK)、CCL26、CCL3(MIP-1a)、CCL4(MIP-1b)、CCL5(RANTES)、CCL7(mcp-3)、CCL8(mcp-2)、CXCL1、CXCL10(IP-10)、CXCL11(I-TAC/IP-9)、CXCL12(SDF1)、CXCL13、CXCL14、CXCL2、CXCL3、CXCL5(ENA-78/LIX)、CXCL6(GCP-2)、CXCL9、IL13、IL8、CCL13(mcp-4)、CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CX3CR1、IL8RA、XCR1(CCXCR1)、IFNA2、IL10、IL13、IL17C、IL1A、IL1B、IL1F10、IL1F5、IL1F6、IL1F7、IL1F8、IL1F9、IL22、IL5、IL8、IL9、LTA、LTB、MIF、SCYE1(內皮單核球活化細胞因子)、SPP1、TNF、TNFSF5、IFNA2、ABCF1、BCL6、C3、C4A、CEBPB、CRP、ICEBERG、IL1R1、IL1RN、IL8RB、LTB4R、TOLLIP、FADD、IRAK-M、IRAK1、IRAK2、IRAK4、MYD88、NCK2、TNFAIP3、TRADD、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、ACVR1、ACVR1B、ACVR2、ACVR2B、ACVRL1、CD28、CD3E、CD3G、CD3Z、CD69、CD80、CD86、CNR1、CTLA4、CYSLTR1、FCER1A、FCER2、FCGR3A、GPR44、HAVCR2、OPRD1、P2RX7、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、BLR1、CCL1、CCL2、CCL3、CCL4、CCL5、CCL7、CCL8、CCL11、CCL13、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、
CCR7、CCR8、CCR9、CX3CL1、CX3CR1、CXCL1、CXCL2、CXCL3、CXCL5、CXCL6、CXCL10、CXCL11、CXCL12、CXCL13、CXCR4、GPR2、SCYE1、SDF2、XCL1、XCL2、XCR1、AMH、AMHR2、BMPR1A、BMPR1B、BMPR2、C19orf10(IL27w)、CER1、CSF1、CSF2、CSF3、DKFZp451J0118、FGF2、GFI1、IFNA1、IFNB1、IFNG、IGF1、IL1A、IL1B、IL1R1、IL1R2、IL2、IL2RA、IL2RB、IL2RG、IL3、IL4、IL4R、IL5、IL5RA、IL6、IL6R、IL6ST、IL7、IL8、IL8RA、IL8RB、IL9、IL9R、IL10、IL10RA、IL10RB、IL11、IL11RA、IL12A、IL12B、IL12RB1、IL12RB2、IL13、IL13RA1、IL13RA2、IL15、IL15RA、IL16、IL17、IL17R、IL18、IL18R1、IL19、IL20、KITLG、LEP、LTA、LTB、LTB4R、LTB4R2、LTBR、MIF、NPPB、PDGFB、TBX21、TDGF1、TGFA、TGFB1、TGFB1I1、TGFB2、TGFB3、TGFBI、TGFBR1、TGFBR2、TGFBR3、TH1L、TNF、TNFRSF1A、TNFRSF1B、TNFRSF7、TNFRSF8、TNFRSF9、TNFRSF11A、TNFRSF21、TNFSF4、TNFSF5、TNFSF6、TNFSF11、VEGF、ZFPM2、RNF110(ZNF144)、FGF家族、PLGF、DLL4、NPR-1、Fc γ受體IIB調節劑、抗類漿細胞細胞調節劑、免疫複合物清除改良劑(例如RNase或DNase)、原癌基因抑制劑(例如(但不限於)c-kit及b-raf)、1型纖維母細胞生長因子受體調節劑、二氫乳清酸脫氫酶調節劑、雌性激素受體調節劑、DNA指導之DNA聚合酶抑制劑、CD85γ調節劑及表觀遺傳改良劑。
治療自體免疫及發炎疾病之組合可包括本發明化合物及非類固醇消炎藥物(亦稱作NSAID),其包括如布洛芬等藥物。其他組合可包括皮質類固醇(包括潑尼松龍(prednisolone));可藉由逐漸減少當與本發明組合治療個體時所需類固醇之劑量來減少或甚至消除類固醇利用
之熟知副效應。
可與本發明之選擇性Bcl-2抑制劑組合用於治療狼瘡之治療劑之非限制性實例包括以下:細胞因子阻抑消炎藥物(CSAID);其他人類細胞因子或生長因子(例如,TNF、LT、IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-16、IL-17A、IL-17F、IL-18、IL-21、IL-22、IL-23、IL-25、IL-33、干擾素(例如,α、β、γ等)、Tweak、BAFF/BlyS、April、趨化因子)之抗體或拮抗劑。本發明化合物亦可與細胞表面分子(例如CD2、CD3、CD4、CD8、CD16、CD19、CD20、CD22、CD25、CD28、CD30、CD32、CD40、CD45、CD47、CD52、CD54、CD64、CD69、CD72、CD79、CD80(B7.1)、CD86(B7.2)、CD90、CD100、CD200、CTLA、ICOS-1、B7RP、BR3、TACI、BCMA)或其配體(包括CD154(gp39或CD40L))之抗體組合。
本發明化合物亦可與以下組合:其他藥劑,例如癌得星(cytoxan)、6-MP、硫唑嘌呤柳氮磺胺吡啶(azathioprine sulphasalazine)、美沙拉嗪(mesalazine)、奧沙拉嗪氯喹(olsalazine chloroquinine)、青黴胺(penicillamine)、金硫蘋果酸鹽(aurothiomalate)(肌內及經口)、硫唑嘌呤、秋水仙素(colchicine)、皮質類固醇(經口、吸入及局部注射)、選擇性糖皮質激素受體調節劑(SGRM)、O β-2腎上腺素受體激動劑(舒喘靈(salbutamol)、特布他林(terbutaline)、沙美特羅(salmeterol))、黃嘌呤(茶鹼、胺茶鹼)、色甘酸鹽、奈多羅米(nedocromil)、酮替芬(ketotifen)、異丙托銨(ipratropium)及氧托銨(oxitropium)、環孢素(cyclosporin)、FK506、來氟米特(leflunomide)、皮質類固醇(例如潑尼松龍)、磷酸二酯酶抑制劑、腺苷激動劑、抗血栓形成劑、補體抑制劑、腎上腺素劑、藉由促發炎細胞因子(例如TNF-α或IL-1)干擾信號傳導之藥劑(例如,IRAK、
NIK、IKK、p38或MAP激酶抑制劑)、IL-1β轉化酶抑制劑、JAK抑制劑、BTK抑制劑、SYK抑制劑、PKC家族抑制劑、TNF-α轉化酶(TACE)抑制劑、T細胞信號傳導抑制劑例如激酶抑制劑、金屬蛋白酶抑制劑、柳氮磺胺吡啶、6-巰基嘌呤、血管收縮素轉化酶抑制劑、可溶性細胞因子受體及其衍生物(例如,可溶性p55或p75 TNF受體及衍生物p75TNFRIgG(EnbrelTM及p55TNFRIgG(來那西普(Lenercept)))、sIL-1RI、sIL-1RII、sIL-6R)、消炎細胞因子(例如,IL-4、IL-6、IL-10、IL-11、IL12、IL-13、IL-17、IL-18、IL-33及TGFβ)、葉酸、硫酸羥氯喹、依那西普(etanercept)、英利昔單抗(infliximab)、甲基潑尼松龍、美洛昔康(meloxicam)、乙酸甲基潑尼松龍、硫蘋果酸金鈉、阿司匹林(aspirin)、曲安奈德(triamcinolone acetonide)、萘磺酸丙氧芬(propoxyphene napsylate)/apap、葉酸鹽、雙氯芬酸鈉、鹽酸氧可酮(oxycodone HCl)、重酒石酸氫可酮(hydrocodone bitartrate)/apap、雙氯芬酸鈉/米索前列醇(misoprostol)、芬太尼(fentanyl)、阿那白滯素(anakinra)、人類重組體、鹽酸曲馬朵(tramadol HCl)、氰鈷胺素(cyanocobalamin)/fa/吡哆醇(pyridoxine)、乙醯胺酚(acetaminophen)、阿侖膦酸鈉(alendronate sodium)、潑尼松龍、硫酸嗎啡(morphine sulfate)、鹽酸利多卡因(lidocaine hydrochloride)、硫酸葡萄糖胺(glucosamine sulf)/軟骨素、鹽酸阿米替林(amitriptyline HCl)、磺胺嘧啶、鹽酸奧洛他定(olopatadine HCl)、米索前列醇、奧美拉唑(omeprazole)、IL-1 TRAP、MRA、CTLA4-IG、IL-18 BP、抗IL-18、抗IL15、BIRB-796、SCIO-469、VX-702、AMG-548、VX-740、羅氟司特(Roflumilast)、IC-485、CDC-801、美索普拉(Mesopram)。組合另外可包括來氟米特、環孢素及S1P激動劑。
可與本發明化合物組合用於SLE(狼瘡)及狼瘡性腎炎之治療劑之實例包括以下:NSAID,例如,雙氯芬酸、萘普生、布洛芬、吡羅昔
康、吲哚美辛;COX2抑制劑,例如,塞來考昔、羅非考昔、伐地考昔;抗瘧疾劑,例如,羥氯喹;類固醇,例如,強的松、潑尼松龍、布地奈德、地塞米松;細胞毒性劑,例如,硫唑嘌呤、環磷醯胺、嗎替麥考酚酯(mycophenolate mofetil)、胺甲蝶呤;PDE4之抑制劑或嘌呤合成抑制劑,例如驍悉(Cellcept)。納入本發明方法中之結合蛋白亦可與諸如以下等藥劑組合:柳氮磺胺吡啶、5-胺基水楊酸、奧沙拉嗪、依木蘭(Imuran)及干擾促發炎細胞因子(例如IL-1)之合成、產生或作用之藥劑,例如,半胱天冬酶抑制劑如IL-1β轉化酶抑制劑及IL-1ra。本發明亦可與以下一起使用:T細胞信號傳導抑制劑,例如,酪胺酸激酶抑制劑;或靶向T細胞活化分子之分子,例如,CTLA-4-IgG或抗B7家族抗體(例如B7RP、抗PD-1家族抗體)。本發明可與以下組合:IL-11或抗細胞因子抗體,例如,芳妥珠單抗(fonotolizumab)(抗IFNg抗體)、抗干擾素α或抗受體受體抗體,例如,抗IL-6受體抗體(包括gp130)及B細胞表面分子抗體。本發明亦可與HMGB1、HDGF之抑制劑一起使用。本發明亦可與鐸受體1、2、3、4、7及9之抑制劑一起使用。本發明亦可與樹突細胞標記物(BDCA-1、2及3、DEC205、CD11c、Bst2(PDCA-1)、蘭格素(Langerin)及SiglecH)之抑制劑一起使用。本發明亦可與促進調控T細胞功能之藥劑一起使用。本發明亦可與以下一起使用:LJP 394(阿貝莫司(abetimus));抑制補體之藥劑,例如,抗C5、抗C5a、衰竭或無活性B細胞,例如,利妥昔單抗(抗CD20抗體)、淋巴母細胞-B(抗BlyS抗體)、抗CD22;TNF拮抗劑,例如,抗TNF抗體,阿達木單抗(Adalimumab)(PCT公開案第WO 97/29131號;HUMIRA)、CA2(REMICADE),CDP 571,TNFR-Ig構築體(p75TNFRIgG(ENBREL)及p55TNFRIgG(來那西普LENERCEPT));及其他bcl-2家族成員(例如Bcl-xL、Mcl-1、A-1等)之抑制劑。
可與本發明之選擇性Bcl-2抑制劑組合用以治療修格連氏症候群之治療劑之實例可包括(但不限於)人工淚液、環孢素、西維美林(cevimeline)、匹魯卡品(pilocarpine)、NSAID、皮質類固醇、免疫阻抑劑、改良疾病之抗風濕藥物(DMARD)(例如胺甲蝶呤及羥氯喹)。
本發明之實施例係關於治療哺乳動物之癌症之方法,其包含向該哺乳動物投與治療上可接受量之本發明化合物。
又一實施例係關於治療哺乳動物之自體免疫疾病之方法,其包含向該哺乳動物投與治療上可接受量之本發明化合物。
又一實施例係關於治療表現抗細胞凋亡Bcl-2蛋白之個體之疾病之方法,該等方法包括向該個體投與治療有效量之本發明化合物。
又一實施例係關於治療個體之以下疾病之方法:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌或脾臟癌,該等方法包括向該患者投與治療有效量之本發明化合物。
又一實施例係關於治療表現抗細胞凋亡Bcl-2蛋白之個體之疾病之方法,該等方法包括向該個體投與治療有效量之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
又一實施例係關於治療個體之以下疾病之方法:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、慢性淋巴球性白血病、骨髓瘤、前列腺癌、小細胞肺癌或脾臟癌,該等方法包括向該個體投與治療有效量
之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
又一實施例係關於治療個體之全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之方法,該等方法包括向該個體投與治療有效量之本發明化合物。
又一實施例係關於治療個體之全身性紅斑狼瘡、狼瘡性腎炎及修格連氏症候群之方法,該等方法包括向該個體投與治療有效量之本發明化合物及治療有效量之一種其他治療劑或一種以上其他治療劑。
由於本發明化合物會與Bcl-2結合,因此預期其亦可用作針對具有與Bcl-2之結構緊密同源之抗細胞凋亡蛋白(例如抗細胞凋亡Bcl-XL、Bcl-w、Mcl-1及Bfl-1/A1蛋白)之黏合劑。
Bcl-2蛋白涉及膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌、脾臟癌及諸如此類中之關係已闡述於共同擁有之PCT/US2004/036770(以WO 2005/049593公開)、PCT/US2004/037911(以WO 2005/049594公開)及PCT/US01/29432(以WO02/24636公開)中。
Bcl-2蛋白涉及免疫及自體免疫疾病中之關係已闡述於以下中:Current Allergy and Asthma Reports 2003,3,378-384;British Journal of Haematology 2000,110(3),584-90;Blood 2000,95(4),1283-92;及New England Journal of Medicine 2004,351(14),1409-1418。Bcl-2蛋白在關節炎中之參與揭示於共同擁有之PCT/US2008/083478(以WO 2009/064938公開)中。Bcl-2蛋白涉及治療全身性紅斑狼瘡、狼瘡性腎炎及修格連氏症候群之方法中之關係已闡述於共同擁有之
PCT/US2011/061769(以WO 2012/071374公開)中。Bcl-2蛋白涉及骨髓移植排斥中之關係已揭示於共同擁有之美國專利申請案第11/941,196號中。
在免疫系統之各種癌症及病症中,Bcl-2蛋白之過表現與對化學療法之抗性、臨床結果、疾病進展、總體預後或其組合相關。癌症包括(但不限於)血液學及實體腫瘤類型,例如聽神經瘤、急性白血病、急性淋巴胚細胞性白血病、急性骨髓性白血病(單核球性白血病、骨髓胚細胞性白血病、腺癌、血管肉瘤、星形細胞瘤、骨髓單核球性白血病及前髓細胞性白血病)、急性t細胞白血病、基底細胞癌、膽管癌、膀胱癌、腦癌、乳癌(包括雌性激素受體陽性乳癌)、支氣管癌、伯基特淋巴瘤(Burkitt's lymphoma)、子宮頸癌、軟骨肉瘤、脊索瘤、絨膜癌、慢性白血病、慢性淋巴球性白血病、慢性髓細胞性(粒球性)白血病、慢性骨髓性白血病、結腸癌、結腸直腸癌、顱咽管瘤、囊腺癌、增殖異常性變化(發育不良及組織變形)、胚胎性癌、子宮內膜癌、內皮肉瘤、室管膜瘤、上皮癌、紅白血病、食道癌、雌性激素受體陽性乳癌、自發性血小板增多症、尤因氏腫瘤(Ewing’s tumor)、纖維肉瘤、胃癌、生殖細胞睪丸癌、妊娠滋養細胞疾病、膠質母細胞瘤、頭頸癌、重鏈病、血管母細胞瘤、肝細胞瘤、肝細胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌(包括小細胞肺癌腳及非小細胞肺癌)、淋巴管內皮肉瘤、淋巴管肉瘤、淋巴胚細胞性白血病、淋巴瘤(淋巴瘤,包括彌漫性大B細胞淋巴瘤、濾泡性淋巴瘤、何傑金氏淋巴瘤(Hodgkin’s lymphoma)及非何傑金氏淋巴瘤)、膀胱、乳腺、結腸、肺、卵巢、胰腺、前列腺、皮膚及子宮之惡性腫瘤及過度增殖性病症、T細胞或B細胞源性淋巴樣惡性腫瘤、白血病、髓樣癌、神經管胚細胞瘤、黑色素瘤、腦膜瘤、間皮瘤、多發性骨髓瘤、骨髓性白血病、骨髓瘤、黏液肉瘤、神經胚細胞瘤、少突神經膠質
瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、乳頭狀腺癌、乳頭狀癌、外周T細胞淋巴瘤、松果體瘤、真性紅血球增多症、前列腺癌(包括激素不敏感性(頑固性)前列腺癌)、直腸癌症、腎細胞癌、視網膜母細胞瘤、橫紋肌肉瘤、肉瘤、皮脂腺癌、精原細胞瘤、皮膚癌症、小細胞肺癌、實體腫瘤(癌及肉瘤)、胃癌、鱗狀細胞癌、滑膜瘤、汗腺癌、睪丸癌(包括生殖細胞睪丸癌)、甲狀腺癌、瓦爾登斯特倫氏巨球蛋白血症(Waldenström’s macroglobulinemia)、睪丸瘤、子宮癌、維爾姆斯氏腫瘤(Wilms’tumor)及諸如此類。
亦預計,本發明化合物可抑制表現Bcl-2蛋白之細胞之生長,該等細胞衍生自小兒癌症或贅瘤,包括胚胎性橫紋肌肉瘤、小兒急性淋巴胚細胞性白血病、小兒急性骨髓性白血病、小兒小泡型橫紋肌肉瘤、小兒間變性室管膜瘤、小兒間變性大細胞淋巴瘤、小兒間變性神經管胚細胞瘤、小兒中樞神經系統非典型畸胎樣/橫紋肌樣腫瘤、小兒雙表型急性白血病、小兒伯基特淋巴瘤、小兒尤因氏腫瘤家族(例如原發性神經外胚層瘤)之癌症、小兒彌漫性間變性維爾姆斯氏腫瘤、小兒良好組織型維爾姆斯氏腫瘤、小兒膠質母細胞瘤、小兒神經管胚細胞瘤、小兒神經胚細胞瘤、衍生自小兒神經胚細胞瘤之髓細胞瘤病、小兒前B細胞癌症(例如白血病)、小兒骨肉瘤、小兒橫紋肌樣腎瘤、小兒橫紋肌肉瘤及小兒T細胞癌症(例如淋巴瘤及皮膚癌)及諸如此類。
自體免疫病症包括獲得性免疫缺陷疾病症候群(AIDS)、自體免疫淋巴增殖性症候群、溶血性貧血、發炎疾病及血小板減少症、與器官移植相關之急性或慢性免疫疾病、阿狄森氏病(Addison's disease)、過敏性疾病、脫髮、斑禿、動脈粥樣化疾病/動脈硬化、動脈粥樣硬化、關節炎(包括骨關節炎、幼年型慢性關節炎、膿毒性關節炎、萊姆關節炎(Lyme arthritis)、牛皮癬關節炎及反應性關節炎)、自體免疫
大皰病、無β脂蛋白血症、獲得性免疫缺陷相關疾病、與器官移植相關之急性免疫疾病、獲得性手足發紺、急性及慢性寄生或感染過程、急性胰腺炎、急性腎衰竭、急性風濕熱、急性橫貫性脊髓炎、腺癌、心房異位搏動、成人(急性)呼吸窘迫症候群、AIDS癡呆複合症、酒精性肝硬化、酒精誘發之肝損傷、酒精誘發之肝炎、過敏性結膜炎、過敏性接觸性皮炎、過敏性鼻炎、過敏症及氣喘、同種異體移植排斥、α-1-抗胰蛋白酶缺乏、阿茲海默氏病(Alzheimer's disease)、肌萎縮性側索硬化、貧血、心絞痛、關節黏連性脊椎炎相關性肺病、前角細胞退化、抗體介導之細胞毒性、抗磷脂症候群、抗受體超敏反應、主動脈及外周動脈瘤、主動脈夾層、動脈高血壓、動脈硬化、動靜脈瘺、關節病、乏力、氣喘、共濟失調、異位性過敏症、心房顫動(持續性或突發性)、心房撲動、房室傳導阻滯、萎縮性自體免疫甲狀腺功能減退、自體免疫溶血性貧血、自體免疫肝炎、1型自體免疫肝炎(典型自體免疫或類狼瘡性肝炎)、自體免疫介導之低血糖症、自體免疫嗜中性白血球減少症、自體免疫血小板減少症、自體免疫甲狀腺疾病、B細胞淋巴瘤、骨移植排斥、骨髓移植(BMT)排斥、閉塞性細支氣管炎、束支傳導阻滯、燒傷、惡病質、心律不齊、心臟頓抑症候群、心臟腫瘤、心肌病、心肺繞道術發炎反應、軟骨移植排斥、小腦皮質退化、小腦病症、紊亂性或多源性房性心動過速、化學療法相關性病症、衣原體病、膽汁淤積、慢性酒精中毒、慢性活動性肝炎、慢性疲勞症候群、與器官移植相關之慢性免疫疾病、慢性嗜酸性球性肺炎、慢性發炎病狀、慢性黏膜皮膚念珠菌病、慢性阻塞性肺病(COPD)、慢性水楊酸鹽中毒、常見性多變性免疫缺陷(常見性變異性低丙球蛋白血症)、結膜炎、與間質性肺病相關之結締組織疾病、接觸性皮炎、庫姆斯陽性溶血性貧血(Coombs positive haemolytic anaemia)、肺源性心臟病、克羅伊茨費爾特-雅各布病(Creutzfeldt-Jakob disease)、
隱原性自體免疫肝炎、隱原性纖維化肺泡炎、培養物陰性膿毒症、囊性纖維化、細胞因子療法相關性病症、克羅恩氏病(Crohn's disease)、拳擊員癡呆、去髓鞘疾病、登革出血熱(dengue hemorrhagic fever)、皮炎、硬皮病、皮膚病況、皮肌炎/多肌炎相關性肺病、糖尿病、糖尿病性動脈硬化性疾病、糖尿病、彌漫性路易體病(Diffuse Lewy body disease)、擴張性心肌病、擴張性充血性心肌病、盤狀紅斑狼瘡、基底神經節病症、彌散性血管內凝血、中年唐氏症候群(Down's Syndrome in middle age)、藥物誘導之間質性肺病、藥物誘發之肝炎、藉由阻斷CNS多巴胺受體之藥物誘導之藥物誘導型運動病症、藥物敏感性、濕疹、腦脊髓炎、心內膜炎、內分泌病、腸病性滑膜炎、會厭炎、愛潑斯坦-巴爾病毒感染(Epstein-Barr virus infection)、紅斑性肢痛病、錐體束外及小腦病症、家族性嗜血球性淋巴組織細胞增殖症、胎胸腺植入物排斥、弗裏德賴希共濟失調症(Friedreich's ataxia)、功能性外周動脈病症、雌性不育、纖維化、纖維化肺病、真菌性膿毒症、氣性壞疽、胃潰瘍、巨細胞性動脈炎、腎小球腎炎、腎絲球腎炎、古德帕斯丘症候群(Goodpasture's syndrome)、甲狀腺腫自體免疫甲狀腺功能減退症(橋本病(Hashimoto's disease))、痛風性關節炎、任一器官或組織之移植排斥、移植物抗宿主病、革蘭氏陰性膿毒症(gram negative sepsis)、革蘭氏陽性膿毒症(gram positive sepsis)、因胞內有機體所致之肉芽腫、B群鏈球菌(group B streptococci)(GBS)感染、格雷夫斯氏病(Grave's disease)、鐵質沉著出血相關性肺病、毛細胞白血病、哈勒沃登-施帕茨病(Hallerrorden-Spatz disease)、橋本甲狀腺炎、花粉熱、心臟移植排斥、血色病、造血系統惡性腫瘤(白血病及淋巴瘤)、溶血性貧血、溶血性尿毒癥症候群/溶栓性血小板減少性紫癜、出血、亨諾赫-舍恩萊因紫癜(Henoch-Schoenlein purpurea)、A型肝炎、B型肝炎、C型肝炎、HIV感染/HIV神經病、何
傑金氏病、甲狀旁腺功能減退症、亨廷頓舞蹈症(Huntington's chorea)、運動過度性運動病症、過敏反應、過敏性肺炎、甲狀腺功能亢進症、運動功能減退性運動病症、下丘腦-垂體-腎上腺軸評估、特發性阿狄森氏病、特發性白血球減少症、特發性肺纖維化、特發性血小板減少症、特應性肝病、嬰兒脊髓性肌萎縮、傳染性疾病、主動脈發炎、發炎性腸病、應激性腸病、胰島素依賴性糖尿病、間質性肺炎、虹膜啶狀體炎/葡萄膜炎/視神經炎、局部缺血再灌注損傷、局部缺血性中風、幼年型惡性貧血、幼年型類風濕性關節炎、幼年型脊髓性肌萎縮、卡波西肉瘤(Kaposi's sarcoma)、川畸病(Kawasaki's disease)、腎移植排斥、軍團病桿菌病(legionella)、利什曼病(leishmaniasis)、麻風病、皮質脊髓系統損傷、線狀IgA病、脂血症、肝移植排斥、萊姆病(Lyme disease)、淋巴水腫、淋巴球浸潤性肺病、瘧疾、雄性不育特發性或NOS、惡性組織細胞增多症、惡性黑色素瘤、腦膜炎、腦膜炎球菌血症、顯微腎臟血管炎、偏頭痛、線粒體性多系統病症、混合性結締組織病、混合性結締組織病相關性肺病、單株γ球蛋白病、多發性骨髓瘤、多系統退化(Mencel Dejerine-Thomas Shi-Drager及Machado-Joseph)、肌痛性腦炎/慢性疲勞症候群(Royal Free Disease)、重症肌無力、顯微腎臟血管炎、鳥胞內分枝桿菌病(mycobacterium avium intracellulare)、結核分枝桿菌病(mycobacterium tuberculosis)、脊髓發育不良症候群、心肌梗塞、心肌局部缺血性病症、鼻咽癌、新生兒慢性肺病、腎炎、腎病變、腎病症候群、神經退化性疾病、神經性I型肌萎縮、嗜中性粒球減少性發熱、非酒精性脂肪性肝炎、腹主動脈及其分枝阻塞、阻塞性動脈病症、器官移植排斥、睪丸炎/附睪炎、睪丸炎/輸精管複通術手術、器官巨大症、骨關節病、骨質疏鬆症、卵巢衰竭、胰臟移植排斥、寄生蟲病、甲狀旁腺移植排斥、帕金森病(Parkinson's disease)、盆腔發炎
疾病、尋常型天皰瘡、落葉型天皰瘡、類天皰瘡、常年性鼻炎、心包疾病、外周動脈硬化性疾病、外周血管病症、腹膜炎、惡性貧血、晶狀體源性葡萄膜炎、卡氏肺囊蟲肺炎(pneumocystis carinii pneumonia)、肺炎、POEMS症候群(多神經病、器官巨大症、內分泌病、單株γ球蛋白病及皮膚變化症候群)、灌注後症候群、幫浦後症候群、MI心切開術後症候群、感染後間質性肺病、卵巢早衰、原發性膽汁性肝硬化、原發性硬化性肝炎、原發性黏液性水腫、原發性肺性高血壓、原發性硬化性膽管炎、原發性血管炎、進行性核上性麻痹、牛皮癬、1型牛皮癬、2型牛皮癬、牛皮癬性關節病、結締組織病繼發性肺性高血壓、結節性多發性動脈炎之肺表現、發炎後間質性肺病、放射纖維化、放射療法、雷諾現象(Raynaud's phenomenon)及疾病、雷勞病(Raynoud's disease)、雷夫蘇姆病(Refsum's disease)、經常性窄QRS心動過速、賴特爾病(Reiter's disease)、腎病性NOS、腎血管性高血壓、再灌注損傷、限制性心肌病、類風濕性關節炎相關性間質性肺病、類風濕性脊椎炎、類肉瘤病、施密特氏症候群(Schmidt's syndrome)、硬皮病、老年舞蹈症、路易體型老年性癡呆、膿毒症症候群、膿毒性休克、血清陰性關節病、休克、鐮狀細胞性貧血、修格連氏病(Sjögren's disease)相關性肺病、修格連氏症候群、皮膚同種異體移植排斥、皮膚變化症候群、小腸移植排斥、精子自體免疫、多發性硬化(所有亞型)、脊髓性共濟失調、脊髓小腦退化、脊椎關節病、I型散發性多腺性缺陷、II型散發性多腺性缺陷、斯蒂爾病(Still's disease)、鏈球菌性肌炎、中風、小腦結構性損傷、亞急性硬化性全腦炎、交感性眼炎、暈厥、心臟血管系統梅毒、全身性過敏反應、全身性發炎反應症候群、全身性幼年類風濕性關節炎、全身性紅斑狼瘡、全身性紅斑狼瘡相關性肺病、全身性硬化、全身性硬化相關性間質性肺病、T細胞或FAB ALL、塔卡亞薩病(Takayasu's disease)/動脈
炎、毛細管擴張、Th2型及Th1型介導之疾病、閉塞性血栓性血管炎、血小板減少症、甲狀腺炎、毒性、中毒性休克症候群、移植物、創傷/出血、2型自體免疫肝炎(抗LKM抗體肝炎)、具有黑棘皮症之B型胰島素抗性、III型過敏反應、IV型過敏性、潰瘍性結腸炎性關節病、潰瘍性結腸炎、不穩定性心絞痛、尿素症、尿膿毒症、蕁麻疹、葡萄膜炎、瓣膜性心臟病、靜脈曲張、血管炎、血管炎性彌漫性肺病、靜脈疾病、靜脈血栓形成、心室顫動、白癲風急性肝病、病毒性及真菌性感染、病毒性腦炎/無菌性腦膜炎、病毒相關性嗜血球症候群、韋格納肉芽腫病(Wegener's granulomatosis)、韋尼克-克薩克夫症候群(Wernicke-Korsakoff syndrome)、威爾森氏病(Wilson's disease)、器官或組織之異種移植物排斥、耶氏桿菌(yersinia)及沙氏桿菌(salmonella)相關性關節病及諸如此類。
以下縮寫具有所指示含義。ADDP意指1,1’-(偶氮二羰基)二六氫吡啶;AD-mix-β意指(DHQD)2PHAL、K3Fe(CN)6、K2CO3與K2SO4之混合物;9-BBN意指9-硼二環(3.3.1)壬烷;Boc意指第三丁氧基羰基;(DHQD)2PHAL意指二氫奎尼丁1,4-酞嗪二基二乙基醚;DBU意指1,8-二氮雜二環[5.4.0]十一-7-烯;DIBAL意指二異丁基氫化鋁;DIEA意指二異丙基乙基胺;DMAP意指N,N-二甲基胺基吡啶;DMF意指N,N-二甲基甲醯胺;dmpe意指1,2-雙(二甲基膦基)乙烷;DMSO意指二甲基亞碸;dppb意指1,4-雙(二苯基膦基)-丁烷;dppe意指1,2-雙(二苯基膦基)乙烷;dppf意指1,1’-雙(二苯基膦基)二茂鐵;dppm意指1,1-雙(二苯基膦基)甲烷;EDAC.HCl意指1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺鹽酸鹽;Fmoc意指茀基甲氧基羰基;HATU意指六氟磷酸O-(7-氮雜苯并三唑-1-基)-N,N'N'N'-四甲基脲鎓;HMPA意指六甲基磷醯
胺;IPA意指異丙醇;MP-BH3意指大孔甲基聚苯乙烯氰基硼氫化三乙基銨;TEA意指三乙胺;TFA意指三氟乙酸;THF意指四氫呋喃;NCS意指N-氯琥珀醯亞胺;NMM意指N-甲基嗎啉;NMP意指N-甲基吡咯啶;PPh3意指三苯基膦。
本發明化合物可藉由合成化學製程製得,其實例示於本文中。最有用且最易於理解之本發明程序及概念性態樣之闡述之例示性方案揭示於共同擁有之美國專利申請案第12/951344號中。其意欲理解為,製程中之步驟順序可有所改變,試劑、溶劑及反應條件可取代為彼等所特定提及者,且若需要可對易受損部分實施保護及去保護。
熟習此項技術者將易於明瞭,本文所闡述之本發明化合物之其他適宜修改及改變係顯而易見的且可使用適宜等效形式作出,而並不背離本發明或本文所揭示實施例之範圍。現在詳細描述本發明之後,藉由參照以下實例將更明確地瞭解本發明,該等實例僅出於闡釋目的納入而並非意欲限制本發明。
給出以下實例以提供據信為最有用且最易於理解之本發明程序及概念性態樣之闡述。每一例示化合物及中間體係使用ACD/ChemSketch Build 59026(2012年9月03日)、Advanced Chemistry Development公司,Toronto,Ontario)或ChemDraw® Ver.9.0.7(CambridgeSoft,Cambridge,MA)來命名。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2R)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4,4-二甲基-2-(三氟甲基磺醯基氧基)環己-1-烯甲酸甲酯
在0℃下向己烷洗滌之NaH(17g)於二氯甲烷(700mL)中之懸浮液
中逐滴添加5,5-二甲基-2-甲氧基羰基環己酮(38.5g)。在攪拌30分鐘後,使混合物冷卻至-78℃並添加三氟甲磺酸酐(40mL)。使反應混合物升溫至室溫並攪拌24小時。用鹽水洗滌有機層,乾燥(Na2SO4),過濾並濃縮,從而得到標題化合物。
2-(4-氯苯基)-4,4-二甲基環己-1-烯甲酸甲酯
將於2:1二甲氧基乙烷/甲醇(600mL)中之實例1A(62.15g)、4-氯苯基酸(32.24g)、CsF(64g)及四(三苯基膦)鈀(0)(2g)加熱至70℃並保持24小時。濃縮混合物。添加乙醚(4×200mL)並過濾混合物。濃縮合併之乙醚溶液,從而得到標題化合物。
(2-(4-氯苯基)-4,4-二甲基環己-1-烯基)甲醇
藉由注射器向LiBH4(13g)、實例1B(53.8g)及乙醚(400mL)之混合物中緩慢添加甲醇(25mL)。將混合物在室溫下攪拌24小時。在冰冷卻下用1N HCl水溶液淬滅反應物。用水稀釋混合物並用乙醚(3×100mL)萃取。乾燥(Na2SO4)萃取物,過濾,並濃縮。在矽膠上用0-30%乙酸乙酯/己烷層析粗製產物。
4-((2-(4-氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-甲酸第三丁基酯
在0℃下經由注射器將甲基磺醯氯(7.5mL)添加至於CH2Cl2(500mL)中之實例1C(29.3g)及三乙胺(30mL)中,並將混合物攪拌1分鐘。添加N-第三丁氧基羰基六氫吡嗪(25g)並將混合物在室溫下攪拌24小時。用鹽水洗滌懸浮液,乾燥(Na2SO4),過濾並濃縮。在矽膠上用10-20%乙酸乙酯/己烷層析粗製產物。
1-((2-(4-氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪
在二氯甲烷(10mL)、三氟乙酸(10mL)及三乙基矽烷(1mL)中將實例1D(1g)攪拌1小時。濃縮混合物,將其吸收於二氯甲烷(100mL)及飽和Na2CO3水溶液(20mL)之混合物中並攪拌10分鐘。分離各層,並將有機層經Na2SO4乾燥,過濾並濃縮,從而得到標題化合物。
5-溴-1-(三異丙基矽烷基)-1H-吡咯并[2,3-b]吡啶
向5-溴-1H-吡咯并[2,3-b]吡啶(15.4g)於四氫呋喃(250mL)中之混合物中添加於四氫呋喃(86mL)中之1M六甲基二矽烷胺化鋰,且在10分鐘後,添加TIPS-Cl(三異丙基氯矽烷)(18.2mL)。將混合物在室溫下攪拌24小時。用乙醚稀釋反應物,並用水將所得溶液洗滌兩次。乾燥(Na2SO4)萃取物,過濾,並濃縮。在矽膠上用10%乙酸乙酯/己烷層析粗製產物。
1-(三異丙基矽烷基)-1H-吡咯并[2,3-b]吡啶-5-醇
在-78℃下向實例1F(24.3g)於四氫呋喃(500mL)中之混合物中添加於己烷(30.3mL)中之2.5M BuLi。在2分鐘後,添加硼酸三甲酯(11.5mL),並經1小時使混合物升溫至室溫。將反應物傾倒於水中,用乙酸乙酯萃取三次,並用鹽水洗滌合併之萃取物並濃縮。在0℃下將粗製產物吸收於四氫呋喃(200mL)中,並相繼添加1M NaOH水溶液(69mL)及30% H2O2水溶液(8.43mL),並將溶液攪拌1小時。添加Na2S2O3(10g),並用濃HCl及固體NaH2PO4將pH調節至4-5。用乙酸乙酯將溶液萃取兩次,並用鹽水洗滌合併之萃取物,乾燥(Na2SO4),過濾並濃縮。在矽膠上用5-25%乙酸乙酯/己烷層析粗製產物。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-氟苯甲酸甲酯
將實例1G(8.5g)、2,4-二氟苯甲酸甲酯(7.05g)及K3PO4(9.32g)於二甘二甲醚(40mL)中之混合物在115℃下攪拌24小時。冷卻反應物,用乙醚(600mL)稀釋,並用水及鹽水洗滌兩次,並濃縮。在矽膠上用2-50%乙酸乙酯/己烷層析粗製產物。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸甲酯
將實例1H(1.55g)、實例1E(2.42g)及HK2PO4(1.42g)於二甲基亞碸(20mL)中之混合物在135℃下攪拌24小時。冷卻反應物,用乙醚(400mL)稀釋,並用1M NaOH水溶液及鹽水洗滌三次,並濃縮。在矽膠上用10-50%乙酸乙酯/己烷層析粗製產物。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸
將於二噁烷(10mL)及1M NaOH水溶液(6mL)中之實例1I(200mg)在50℃下攪拌24小時。冷卻反應物,添加至NaH2PO4溶液中,並用乙酸乙酯萃取三次。用鹽水洗滌合併之萃取物,並濃縮,從而得到標題化合物。
(S)-4-甲基苯磺酸(1,4-二噁烷-2-基)甲酯
向於甲苯(17mL)中之2-氯乙醇(9.1mL)中添加Et2O‧BF3(0.30mL),且使用溫水浴來使混合物升溫至38℃。逐滴添加S-(+)-表氯醇(3.4mL),使溫度保持<45℃。將反應物在約35℃下攪拌20分鐘,冷卻至15℃,並逐滴添加20% NaOH(21mL),使溫度保持<18℃。然後,使反應物升溫至室溫並保持1小時。添加水(10mL),分離各層,用甲苯萃取水層,用水洗滌合併之甲苯層,並將有機層濃縮成油。將
NaOH(20%(wt)水溶液,50g)加熱至90℃,然後添加上述油,並將混合物加熱1小時,並冷卻至室溫。然後,相繼添加二氯甲烷(12mL)及添加對甲苯磺醯氯(8.0g)。將二相反應物於室溫下攪拌過夜。添加水(10mL),並用二氯甲烷(10mL)將水層萃取兩次。用1/1水/鹽水洗滌合併之二氯甲烷層並經Na2SO4乾燥。在過濾及濃縮後,在矽膠上用65/35庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
(R)-2-(疊氮基甲基)-1,4-二噁烷
將實例1K(2.5g)溶解於N,N-二甲基甲醯胺(12mL)中,然後,添加疊氮化鈉(1.0g)並將反應物在80℃下加熱3小時。然後,冷卻反應物,並用水稀釋並用乙酸乙酯萃取。用鹽水洗滌有機層並用乙酸乙酯萃取合併之水層。將合併之有機層經Na2SO4乾燥。在過濾及濃縮後,在矽膠上用3/1庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
(R)-(1,4-二噁烷-2-基)甲胺
將實例1L(916mg)溶解於四氫呋喃(20mL)及水(5mL)中。然後,添加三甲基膦(6.4mL,1.0M於四氫呋喃中),並將反應混合物在室溫下攪拌90分鐘。然後,添加2N LiOH水溶液(6mL),並用乙酸乙酯萃取。用鹽水將有機層洗滌兩次,然後經Na2SO4乾燥。在過濾及濃縮後,產物未經純化即用於下一步驟中。
(R}4-((1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺
將實例1M(160mg)溶解於四氫呋喃(3mL)中,然後,相繼添加4-氟-3-硝基苯磺醯胺(164mg)及N-乙基-N-異丙基丙-2-胺(0.25mL),並將混合物在45℃下加熱過夜。然後,濃縮反應混合物並添加甲醇(3mL)並將混合物攪拌過夜。過濾出固體,並用更多甲醇洗滌濾餅,從
而得到標題化合物。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2R)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
將實例1N(170mg)、實例1J(340mg)、1-乙基-3-[3-(二甲基胺基)丙基]-碳化二亞胺鹽酸鹽(150mg)及4-二甲基胺基吡啶(130mg)在CH2Cl2(5mL)中攪拌過夜。然後,添加N1,N1-二甲基乙烷-1,2-二胺(0.19mL),並將混合物攪拌90分鐘。添加二氯甲烷(15mL),並用於水(2×12mL)中之10%乙酸:0.75% NaCl洗滌反應混合物。用二氯甲烷反萃取合併之水層,並用鹽水洗滌合併之有機物,並經Na2SO4乾燥。在過濾及濃縮後,在矽膠上用3/7二氯甲烷/乙酸乙酯層析粗製物質。然後,在矽膠上使用含於二氯甲烷中之1.5-2.5% CH3OH層析該物質。用CH3CN研磨該物質,從而得到標題化合物。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.65(s,1H),8.55(t,1H),8.54(d,1H),8.01(d,1H),7.81(dd,1H),7.50(m,3H),7.32(d,2H),7.07(d,1H),7.02(d,2H),6.66(dd,1H),6.37(m,1H),6.18(d,1H),3.77(m,3H),3.63(m,2H),3.47(m,2H),3.31(m,2H),3.06(br m,4H),2.74(br s,2H),2.19(br m,4H),2.13(br m,2H),1.94(br m,2H),1.37(t,2H),0.90(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(S)-3-硝基-4-((1-(四氫-2H-吡喃-4-基)乙基)胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用(S)-1-(四氫-2H-吡喃-4-基)乙胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1S)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例2A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.68(s,1H),11.36(bs,1H),8.57(d,1H),8.30(d,1H),8.06(d,1H),7.82(dd,1H),7.56(d,1H),7.52-7.48(m,2H),7.34(dt,2H),7.16(d,1H),7.03(dt,2H),6.68(dd,1H),6.40(dd,1H),6.18(d,1H),3.92-3.82(m,2H),3.76(q,1H),3.27(td,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.10(m,6H),1.95(bs,2H),1.80(m,1H),1.71-1.53(m,2H),1.38(t,2H),1.33-1.23(m,2H),1.19(d,3H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(R)-3-硝基-4-((1-(四氫-2H-吡喃-4-基)乙基)胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用(R)-1-(四氫-2H-吡喃-4-基)乙胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R)-1-(四氫-2H-吡喃-4-基)乙基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例3A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.68(s,1H),11.36(bs,1H),8.57(d,1H),8.30(d,1H),8.06(d,1H),7.82(dd,1H),7.56(d,1H),7.52-7.48(m,2H),7.34(dt,2H),7.16(d,1H),7.03(dt,2H),6.68(dd,1H),6.40(dd,1H),6.18(d,1H),3.92-3.82(m,2H),3.76(q,1H),3.27(td,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.10(m,6H),1.95(bs,2H),1.80(m,1H),1.71-1.53(m,2H),1.38(t,2H),1.33-1.23(m,2H),1.19(d,3H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5s,8s)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
1-氧雜螺[4.5]癸烷-8-甲腈
在0℃下將第三丁醇鉀(1.68g)逐份添加至1-氧雜螺[4.5]癸-8-酮(0.96g)及TosMIC試劑(對甲苯磺醯基甲基異腈,1.46g)於1,2-二甲氧基乙烷(30mL)及乙醇(0.5mL)中之混合物中。使反應混合物使升溫至室溫並攪拌4小時,然後加熱至40℃並保持24小時。冷卻反應混合物,用乙醚(600mL)稀釋,用水及鹽水洗滌兩次,並濃縮。在矽膠上用1-20%乙酸乙酯/己烷層析粗製產物,從而得到標題化合物。
1-氧雜螺[4.5]癸烷-8-基甲基胺
在0℃下將LiAlH4(9.1mL,1M於四氫呋喃中)添加至於四氫呋喃(30mL)中之實例4A(0.96g)中。使反應混合物升溫至室溫並攪拌1小時。藉由添加2mL水及10mL 1M NaOH水溶液淬滅反應混合物,並將混合物攪拌1小時。用乙醚(100mL)稀釋反應混合物,過濾並濃
縮,從而得到標題化合物。
4-(((5s,8s)-1-氧雜螺[4.5]癸-8-基甲基)胺基)-3-硝基苯磺醯胺
將於四氫呋喃(12mL)中之4-氟-3-硝基苯磺醯胺(650mg)、實例4B(500mg)及三乙胺(0.41mL)在50℃下加熱2小時。濃縮反應混合物。在矽膠上用50%乙酸乙酯/己烷層析粗製產物,從而得到標題化合物。
4-(((5r,8r)-1-氧雜螺[4.5]癸-8-基甲基)胺基)-3-硝基苯磺醯胺
該標題化合物亦係自實例4C以較晚洗脫之流份分離得來。
N-((4-(((5s,8s)-1-氧雜螺[4.5]癸-8-基甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4’-氯-5,5-二甲基-3,4,5,6-四氫-[1,1’-聯苯]-2-基)甲基)六氫吡嗪-1-基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例4C取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.69(s,1H),11.35(br s,1H),8.59(m,1H),8.56(s,1H),8.04(s,1H),7.79(d,1H),7.51(m,2H),7.34(d,2H),7.07(d,1H),7.04(d,2H),6.67(d,1H),6.38(d,1H),6.19(s,1H),3.68(t,2H),3.26(m,6H),3.07(m,4H),2.74(s,2H),2.19(s,2H),2.14(m,2H),1.97(s,2H),1.82(m,2H),1.60(m,2H),1.57(m,4H),1.36(m,2H),1.32(m,4H),0.92(m,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5r,8r)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例4D取代實例1N來製備。
1H NMR(300MHz,二甲基亞碸-d6)δ 11.69(s,1H),11.35(br s,1H),8.60(m,1H),8.57(s,1H),8.05(s,1H),7.81(d,1H),7.51(m,2H),7.34(d,2H),7.09(d,1H),7.03(d,2H),6.67(d,1H),6.39(d,1H),6.19(s,1H),3.67(t,2H),3.27(m,6H),3.07(m,4H),2.75(s,2H),2.20(s,2H),2.14(m,2H),1.95(s,2H),1.81(m,2H),1.75(m,2H),1.65(m,2H),1.63(m,2H),1.38(m,2H),1.32(m,2H),1.09(m,2H),0.92(m,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-羥基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((4-羥基四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用4-(胺基甲基)四氫-2H-吡喃-4-醇取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-羥基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例6A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),8.66(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.52(d,1H),7.49(d,2H),7.34(d,2H),7.16(d,1H),7.04(d,2H),6.66(dd,1H),6.39(dd,1H),6.19(d,1H),4.99(bs,1H),3.63(d,4H),3.38(d,2H),3.07(bs,4H),2.75(bs,2H),2.23-2.11(m,6H),1.95(bs,2H),1.66-1.57(m,2H),1.54-1.48(m,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜螺[4.5]癸-8-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
1,4-二氧雜螺[4.5]癸烷-8-甲腈
該標題化合物係藉由在實例4A中用1,4-二氧雜螺[4.5]癸-8-酮取代1-氧雜螺[4.5]癸-8-酮來製備。
1,4-二氧雜螺[4.5]癸-8-基甲胺
該標題化合物係藉由在實例4B中用實例7A取代實例4A來製備。
4-((1,4-二氧雜螺[4.5]癸-8-基甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例7B取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜螺[4.5]癸-8-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例7C取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.60(s,1H),8.48(d,2H),7.99(d,1H),7.71(dd,1H),7.53(d,1H),7.38-7.48(m,1H),7.34(d,2H),7.04(d,2H),6.95(d,1H),6.65(dd,1H),6.35(dd,1H),6.21(d,1H),3.84(s,4H),3.25(t,3H),3.04(s,4H),2.72(s,2H),2.08-2.25(m,6H),1.95(s,2H),1.69(t,5H),1.34-1.52(m,4H),1.25(d,2H),0.85-1.00(m,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-
基)-N-{[4-(嗎啉-4-基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-嗎啉基-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用嗎啉取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例8A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.68(s,1H),11.42(bs,1H),8.27(d,1H),8.03(d,1H),7.86(d,1H),7.53-7.48(m,3H),7.35(d,2H),7.24(d,1H),7.05(d,2H),6.67(dd,1H),6.40(dd,1H),6.20(d,1H),3.69(t,4H),3.16-3.02(m,8H),2.76(bs,2H),2.28-2.11(m,6H),1.96(bs,2H),1.39(t,2H),0.93(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2S)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(R)-甲烷磺酸(1,4-二噁烷-2-基)甲酯
該標題化合物係藉由在實例1K中用R-(-)-表氯醇取代S-(+)-表氯醇來製備。
(S)-2-(疊氮基甲基)-1,4-二噁烷
該標題化合物係藉由在實例1L中用實例9A取代實例1K來製備。
(S)-(1,4-二噁烷-2-基)甲胺
將實例9B(400mg)溶解於四氫呋喃(15mL)中,冷卻至0℃,並添加氫化鋰鋁(2.0mL,2.0M於四氫呋喃中)。將反應混合物在0℃下攪拌50分鐘,然後在室溫下再攪拌75分鐘。使反應混合物冷卻至0℃,然後小心地相繼添加水(0.16mL)及20% NaOH水溶液(0.16mL)及額外水(0.48mL)。將混合物攪拌15分鐘,添加MgSO4並添加乙醚(20mL)。將混合物攪拌15分鐘,藉助矽藻土過濾,並用乙醚沖洗。濃縮濾液,得到標題化合物,其未經額外純化即用於下一步驟中。
(S)-4-((1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例9C取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2S)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例9D取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.65(s,1H),8.55(t,1H),8.54(d,1H),8.01(d,1H),7.81(dd,1H),7.50(m,3H),7.32(d,2H),7.07(d,1H),7.02(d,2H),6.66(dd,1H),6.37(m,1H),6.18(d,1H),3.77(m,3H),3.63(m,2H),3.47(m,2H),3.31(m,2H),3.06(br m,4H),2.74(br s,2H),2.19(br m,4H),2.13(br m,2H),1.94(br m,2H),1.37(t,2H),0.90(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[4-(羥基甲基)四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]
磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((4-(羥基甲基)四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用(4-(胺基甲基)四氫-2H-吡喃-4-基)甲醇取代實例1M來製備。
4-(((4-(((第三丁基二甲基矽烷基)氧基)甲基)四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
將實例10A(648mg)溶解於N,N-二甲基甲醯胺(9mL)中,並添加三氟甲烷磺酸第三丁基二甲基矽烷基酯(546mg)。將該溶液於室溫下攪拌16小時,且在真空下去除溶劑。藉由急驟管柱層析在矽膠上使用存於庚烷中之50-70%乙酸乙酯來純化粗製物質。
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-(((第三丁基二甲基矽烷基)氧基)甲基)四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(4-((4’-氯-5,5-二甲基-3,4,5,6-四氫-[1,1’-聯苯]-2-基)甲基)六氫吡嗪-1-基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例10B取代實例1N來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[4-(羥基甲基)四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
將實例10C(488mg)溶解於四氫呋喃(3mL)中。添加四丁基氟化銨(1M於四氫呋喃中,1.45mL),且將溶液在室溫下攪拌30分鐘。用飽和碳酸氫鈉水溶液淬滅反應混合物並用乙酸乙酯稀釋。分離各相,
並用鹽水洗滌有機相,且然後經無水硫酸鈉乾燥。在過濾及濃縮後,藉由急驟管柱層析在矽膠上使用乙酸乙酯(增加至於二氯甲烷中之5-10%甲醇)純化粗製物質。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.69(s,1H),9.08(t,1H),8.59(d,1H),8.08(d,1H),7.83(dd,1H),7.56-7.52(m,3H),7.38(d,2H),7.18(d,1H),7.08(d,2H),6.72(dd,1H),6.43(dd,1H),6.24(d,1H),5.26(t,1H),3.68-3.58(m,4H),3.56(d,2H),3.10(bs,4H),3.05(m,2H),2.77(bs,2H),2.27-2.15(m,6H),1.99(bs,2H),1.51(m,4H),1.42(t,2H),0.96(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[3-(羥基甲基)氧雜環丁-3-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((3-(羥基甲基)氧雜環丁-3-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用(3-(胺基甲基)氧雜環丁-3-基)甲醇取代實例1M來製備。
4-(((3-(((第三丁基二甲基矽烷基)氧基)甲基)氧雜環丁-3-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例10B中用實例11A取代實例10A來製備。
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((3-(((第三丁基二甲基矽烷基)氧基)甲基)氧雜環丁-3-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(4-((4’-氯-5,5-二甲基-3,4,5,6-四氫-[1,1’-聯苯]-2-基)甲基)六氫吡嗪-1-基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例11B取代實例1N來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[3-(羥基甲基)氧雜環丁-3-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例10D中用實例11C取代實例10C來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.65(s,1H),11.40(bs,1H),8.90(t,1H),8.56(d,1H),8.04(d,1H),7.83(dd,1H),7.53-7.47(m,3H),7.34(d,2H),7.13(d,1H),7.04(d,2H),6.68(dd,1H),6.39(dd,1H),6.20(d,1H),5.34(t,1H),4.37(s,4H),3.77(d,2H),3.69(d,2H),3.07(bs,4H),2.74(bs,2H),2.25-2.11(m,6H),1.95(bs,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基-3-甲基丁基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-((3-羥基-3-甲基丁基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用4-胺基-2-甲基丁-2-醇取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基-3-甲基丁基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例12A取代實例1N來製
備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.37(bs,1H),8.95(t,1H),8.56(d,1H),8.05(d,1H),7.82(dd,1H),7.54(d,1H),7.52-7.48(m,2H),7.34(d,2H),7.06-6.98(m,3H),6.68(dd,1H),6.39(dd,1H),6.20(d,1H),4.67(s,1H),3.45(q,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.11(m,6H),1.95(bs,2H),1.74(t,2H),1.38(t,2H),1.18(s,6H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(3-羥基三環[3.3.1.13,7]癸-1-基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-((3-羥基金剛烷-1-基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用3-胺基金剛烷-1-醇取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[3-羥基三環[3.3.1.13,7]癸-1-基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例13A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.45(bs,1H),8.57(d,1H),8.45(s,1H),8.04(d,1H),7.82(dd,1H),7.57-7.47(m,3H),7.41-7.32(m,3H),7.04(d,2H),6.68(dd,1H),6.39(dd,1H),6.18(d,1H),4.68(s,1H),3.06(bs,4H),2.75(bs,2H),2.28-2.10(m,8H),1.97-1.88(m,8H),1.72-1.55(m,4H),1.48(d,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧雜二環[3.1.0]己-6-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(1R,5S,6r)-3-氧雜二環[3.1.0]己烷-6-甲酸第三丁基酯
經4小時將重氮第三丁基酯(135g,15%於甲苯中)添加至於二氯甲烷(250mL)中之2,5-二氫呋喃(100g)及乙酸銠(II)二聚物(0.95g)中,並將反應混合物攪拌24小時。濃縮反應混合物,並在矽膠上用1-15%乙酸乙酯/己烷層析粗製產物,從而分別得到產物及其非鏡像異構物(比率為2:1)。
(1R,5S,6r)-3-氧雜二環[3.1.0]己烷-6-甲酸
將實例14A(4g)在二氯甲烷(20mL)及TFA(20mL)中攪拌2小時,並濃縮。將粗製物質吸收於二氯甲烷(200mL)及飽和Na2CO3溶液(20mL)中。將反應混合物攪拌10分鐘,並分離有機層並經Na2SO4乾燥。在過濾後,濃縮混合物,從而得到標題化合物。
(1R,5S,6r)-3-氧雜二環[3.1.0]己烷-6-甲醯胺
將草醯氯(2.05mL)添加至於二氯甲烷(40mL)中之實例14B(4g)中,並將反應混合物攪拌24小時,並濃縮。將粗製物質吸收於二氯甲烷(30mL)中,添加飽和NH4OH溶液(3mL),並將反應混合物攪拌30分鐘。添加二氯甲烷(30mL)及飽和Na2CO3溶液(20mL),並分離有機層,經Na2SO4乾燥,過濾並濃縮,從而得到標題化合物。
3-硝基-4-{[(1R,5S,6s)-3-氧雜二環[3.1.0]己-6-基甲基]胺基}苯磺醯胺
將硼烷-四氫呋喃複合物(2.5mL,1M於四氫呋喃中)添加至於四氫呋喃(2mL)中之實例14C(160mg)中,並將反應混合物在50℃下攪拌24小時。藉由緩慢添加1M HCl水溶液淬滅反應混合物,用二氯甲烷(20mL)稀釋,並添加濃度最小之NaOH溶液以鹼化溶液。向此混合物中添加4-氟-3-硝基苯磺醯胺(277mg)及三乙胺(2mL)並將反應混合物攪拌1小時。濃縮反應混合物並在矽膠上用10-100%乙酸乙酯/己烷層析粗製產物,從而得到標題化合物。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1R,5S,6s)-3-氧雜二環[3.1.0]己-6-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例14D取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.68(s,1H),11.40(br s,1H),8.60(m,1H),8.58(s,1H),8.05(s,1H),7.83(d,1H),7.51(m,2H),7.34(d,2H),7.09(d,1H),7.04(d,2H),6.69(d,1H),6.39(d,1H),6.20(s,1H),3.74(d,2H),3.54(m,2H),3.31(m,3H),3.07(m,4H),2.76(s,2H),2.20(s,4H),2.14(m,2H),1.95(s,2H),1.71(m,2H),1.38(m,2H),1.05(m,1H),0.92(m,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-羥基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((3-羥基氧雜環丁-3-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用3-(胺基甲基)氧雜環丁-3-醇取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-羥基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例15A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.66(s,1H),11.38(bs,1H),8.56(d,1H),8.54(t,1H),8.05(d,1H),7.83(dd,1H),7.54-7.48(m,3H),7.34(dt,2H),7.19(d,1H),7.04(dt,2H),6.68(dd,1H),6.39(dd,1H),6.35(s,1H),6.20(d,1H),4.47(dd,4H),3.72(d,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.10(m,6H),1.95(bs,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(嗎啉基胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用嗎啉-4-胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-(嗎啉-4-基胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例16A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.43(bs,1H),9.26(s,1H),8.54(d,1H),8.04(d,1H),7.83(dd,1H),7.64(d,
1H),7.54-7.47(m,3H),7.34(d,2H),7.04(d,2H),6.67(dd,1H),6.39(dd,1H),6.19(d,1H),3.90-3.52(m,4H),3.07(bs,4H),2.85(bs,4H),2.75(bs,2H),2.26-2.11(m,6H),1.95(bs,2H),1.38(t,2H),0.92(s,6H)。
4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯基]胺磺醯基}-2-硝基苯基)胺基]甲基}四氫-2H-吡喃-4-甲酸甲酯
4-(((2-硝基-4-胺磺醯基苯基)胺基)甲基)四氫-2H-吡喃-4-甲酸甲酯
該標題化合物係藉由在實例1N中用4-(胺基甲基)四氫-2H-吡喃-4-甲酸甲酯取代實例1M來製備。
4-{[(4-{[4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯基]胺磺醯基}-2-硝基苯基)胺基]甲基}四氫-2H-吡喃-4-甲酸甲酯
該標題化合物係藉由在實例1O中用實例17A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.41(bs,1H),8.56(d,1H),8.54(t,1H),8.04(d,1H),7.84(dd,1H),7.53-7.46(m,3H),7.34(d,2H),7.13(d,1H),7.04(d,2H),6.68(dd,1H),6.39(dd,1H),6.19(d,1H),3.79(dt,2H),3.62(s,3H),3.59(d,2H),3.33(m,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.11(m,6H),2.02(d,2H),1.95(bs,2H),1.62(m,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-
基)-N-({3-硝基-4-[2-(四氫-2H-吡喃-4-基)肼基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-肼基-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用肼單水合物取代實例1M來製備。
3-硝基-4-(2-(四氫-2H-吡喃-4-基)肼基)苯磺醯胺
將實例18A(250mg)吸收於二氯甲烷(10mL)及1-甲基吡咯啶酮(5mL)中,然後,添加二氫-2H-吡喃-4(3H)-酮(119mg),並將溶液在室溫下攪拌20分鐘。添加三乙醯氧基硼氫化鈉(479mg),並將混合物在室溫下攪拌16小時。用乙酸乙酯稀釋混合物,用飽和水碳酸氫鈉溶液洗滌,用水洗滌兩次,用鹽水洗滌,並經無水硫酸鈉乾燥。在過濾及濃縮後,自乙酸乙酯重結晶粗製物質。用乙醚洗滌該固體物質,並在真空下乾燥,從而得到標題化合物。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[2-(四氫-2H-吡喃-4-基)肼基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例18B取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.65(s,1H),10.81(s,1H),8.56(d,1H),8.02(d,1H),7.90(dd,1H),7.72(d,1H),7.51-7.47(m,3H),7.34(d,2H),7.03(d,2H),6.68(dd,1H),6.37(dd,1H),6.21(d,1H),3.79(m,4H),3.27(td,2H),3.08(bs,4H),2.77(bs,2H),2.55(dt,4H),2.25-2.11(m,6H),1.95(bs,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
氧雜環庚-4-酮
在-25℃下經由注射器向二氫-2H-吡喃-4(3H)-酮(8.5g)及三氟化硼乙醚(15mL)於二氯甲烷(400mL)中之攪拌溶液中緩慢添加(三甲基矽烷基)重氮甲烷(60mL,120mmol,2.0M於己烷中)。將反應混合物在-25℃下攪拌2.5小時。用水(300mL)稀釋反應混合物並用二氯甲烷(300mL)萃取。分離有機層,用10:1飽和NH4Cl水溶液:飽和NH4OH水溶液洗滌,用鹽水洗滌,經硫酸鎂乾燥,過濾並在真空中濃縮。藉由矽膠層析純化所得粗製產物,從而得到標題化合物。
氧雜環庚烷-4-甲腈
該標題化合物係在實例4A中藉由用實例19A取代1-氧雜螺[4.5]癸-8-酮來製備。
氧雜環庚-4-基甲胺
該標題化合物係藉由在實例4B中用實例19B取代實例4A來製備。
(R)-3-硝基-4-(氧雜環庚-4-基甲基胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用實例19C取代實例1M來製備。使用改良之Berger Instruments PrepSFCTM系統分離鏡像異構物。手動版Berger系統整合有用於試樣注射之Gilson 232自動進樣器及經定製在大氣壓下進行流份收集之Cavro MiniPrepTM移液器(Olson,J.;Pan,J.;Hochlowski,J.;Searle,P.;Blanchard,D.JALA 2002,7,69-
74)。定製設計之收集管頭使得可收集至18×150mm管中,且甲醇洗滌系統使得可在流份之間洗滌管頭以最大化回收率且避免流份交叉污染。使用SFC ProNToTM軟體(第1.5.305.15版)控制該系統且使用AbbVie研發之Visual Basic應用控制自動進樣器及流份收集器。出口壓力為100巴,烘箱溫度為35℃,且流動相流速為40mL/分鐘。所用管柱為Chiralpak IA,21×250mm,5微米。流動相為35% CH3OH(含有0.3%二乙胺)/65%超臨界CO2。以於1.9mL CH3OH:DMSO 1:1中之溶液注射試樣。使用SFC ProNToTM軟體(第1.5.305.15版)控制製備型SFC系統且使用定製軟體控制自動進樣器及流份收集器。基於UV信號臨限值收集流份,且使用線上Thermo MSQ質譜以正性模式使用ESI離子化來確定分子質量。使用Navigator 4.0軟體獲得質譜且使用AbbVie研發之Visual Basic界面來與SFC控制軟體通信。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4R)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例19D取代實例1N來製備。1H NMR(300MHz二甲基亞碸-d6)δ ppm 11.67(s,1H),8.49-8.67(m,2H),8.04(d1H),7.80(dd,1H),7.45-7.58(m,3H),7.34(d,2H),6.97-7.14(m,3H),6.67(dd,1H),6.39(dd,1H),6.19(d,1H),3.44-3.76(m,4H),3.00-3.13(m,4H),2.74(s,2H),2.07-2.27(m,6H),1.83-2.00(m,3H),1.68-1.85(m,3H),1.54-1.65(m,1H),1.27-1.47(m,4H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-
(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(S)-3-硝基-4-((氧雜環庚-4-基甲基)胺基)苯磺醯胺
該標題化合物亦係如在實例19D中所闡述獲得。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(4S)-氧雜環庚-4-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例20A取代實例1N來製備。1H NMR(300MHz二甲基亞碸-d6)δ ppm 11.67(s,1H),8.49-8.67(m,2H),8.04(d,1H),7.80(dd,1H),7.45-7.58(m,3H),7.34(d,2H),6.97-7.14(m,3H),6.67(dd,1H),6.39(dd,1H),6.19(d,1H),3.44-3.76(m,4H),3.00-3.13(m,4H),2.74(s,2H),2.07-2.27(m,6H),1.83-2.00(m,3H),1.68-1.85(m,3H),1.54-1.65(m,1H),1.27-1.47(m,4H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((4-甲基四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
將三乙醯氧基硼氫化鈉(3513mg)添加至三氟甲基乙酸(30mL)中。添加4-胺基-3-硝基苯磺醯胺(800mg)並將溶液在室溫下攪拌10分鐘。逐滴添加溶解於二氯甲烷(10mL)中之4-甲基四氫-2H-吡喃-4-甲醛(991mg)。在添加後,將混合物在室溫下攪拌16小時。將混合物傾倒於冰冷飽和碳酸氫鈉溶液上並用乙酸乙酯萃取。用水及鹽水洗滌有
機層並經無水硫酸鈉乾燥。在過濾及濃縮後,藉由自乙酸乙酯重結晶純化粗製物質。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例21A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.38(bs,1H),8.56(d,1H),8.48(t,1H),8.03(d,1H),7.80(dd,1H),7.54-7.46(m,3H),7.34(d,2H),7.22(d,1H),7.04(d,2H),6.68(dd,1H),6.38(dd,1H),6.20(d,1H),3.72-3.63(m,2H),3.52(m,2H),3.30(m,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.10(m,6H),1.95(bs,2H),1.53(m,2H),1.38(t,2H),1.31(d,2H),1.06(s,3H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-硫吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
3-硝基-4-(((四氫-2H-硫吡喃-4-基)甲基)胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用(四氫-2H-硫吡喃-4-基)甲胺鹽酸鹽取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-硫吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例22A取代實例1N來製
備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.68(s,1H),11.37(bs,1H),8.59(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.55-7.47(m,3H),7.34(d,2H),7.08(d,1H),7.04(d,2H),6.68(dd,1H),6.39(dd,1H),6.19(d,1H),3.28(t,2H),3.07(bs,4H),2.75(bs,2H),2.58(m,4H),2.25-2.11(m,6H),2.02(dd,2H),1.95(bs,2H),1.70(m,1H),1.38(t,2H),1.36-1.28(m,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(氧雜環丁-3-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
3-硝基-4-((氧雜環丁-3-基甲基)胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用氧雜環丁-3-基甲胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(氧雜環丁-3-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例23A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.39(bs,1H),8.66(t,1H),8.55(d,1H),8.04(d,1H),7.80(dd,1H),7.54-7.46(m,3H),7.34(d,2H),7.09(d,1H),7.03(d,2H),6.68(dd,1H),6.39(dd,1H),6.20(d,1H),4.66(dd,2H),4.36(t,2H),4.01(bs,1H),3.71(t,2H),3.07(bs,4H),2.75(bs,2H),2.26-2.10(m,6H),1.95(bs,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(R)-((2-(烯丙基氧基)丙氧基)甲基)苯
將(R)-1-(苄基氧基)丙-2-醇(5g)及烯丙基溴(3.5mL)溶解於四氫呋喃(45mL)中。使混合物冷卻至5℃,並經10分鐘以四份添加95% NaH(1.1g)。使混合物升溫至溫度並在乾燥管中攪拌過夜。用水稀釋反應物並用乙醚萃取。用鹽水洗滌有機層並用乙醚反萃取合併之水層。將合併之有機層經Na2SO4乾燥。過濾並濃縮濾液,得到標題化合物,其未經進一步純化即用於下一步驟中。
2-(((R)-1-(苄基氧基)丙-2-基氧基)甲基)環氧乙烷
將實例24A(6.2g)溶解於二氯甲烷(200mL)中,冷卻至0℃,添加間氯過氧苯甲酸(13.5g)。將反應混合物冷攪拌1小時,然後在室溫下攪拌過夜。添加Na2SO3水溶液(10%,100mL),將混合物攪拌5分鐘,並分離各層。用飽和NaHCO3(2×150mL)及鹽水洗滌有機層。在經Na2SO4乾燥後,過濾並濃縮,將粗製物質溶解於乙醚中,然後用10% Na2S2O3、飽和NaHCO3(3次)及鹽水洗滌。在經Na2SO4乾燥後,過濾並濃縮,得到粗製油。在矽膠上用85/15庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
(S)-2-(((R)-1-(苄基氧基)丙-2-基氧基)甲基)環氧乙烷
將R,R-(salen)Co(II)錯合物(56mg)添加至純淨實例24B(4.0g)中,然後,相繼添加四氫呋喃(180μL)及乙酸(20.7μL)。使混合物冷卻至0℃,添加水(180μL),並使反應物在開放25mL燒瓶中達到室
溫過夜。然後,在矽膠上用85/15庚烷/乙酸乙酯直接層析反應物,從而得到標題化合物。
(R)-2-((S)-環氧乙烷-2-基甲氧基)丙-1-醇
將實例24C(2.3g)溶解於乙酸乙酯(65mL)中,添加碳載Pd(OH)2(20%乾Pd wt/總共50%水,100mg)並將反應混合物在氫氣球下攪拌2小時。在藉助矽藻土過濾及濃縮後,返回不完全反應物,此時使用四氫呋喃代替乙酸乙酯。在矽膠上用35/65庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
((2R,5R)-5-甲基-1,4-二噁烷-2-基)甲醇
將實例24D(800mg)溶解於二氯甲烷(45mL)中,添加(1S)-(+)-樟腦磺酸(415mg),並將反應混合物在室溫下攪拌過夜。添加飽和NaHCO3,分離各層,且用二氯甲烷(3×50mL)萃取水層。將合併之有機層經Na2SO4乾燥。在過濾及濃縮後,在矽膠上用35/65庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
甲烷磺酸((2S,5R)-5-甲基-1,4-二噁烷-2-基)甲酯
將實例24E(400mg)及三乙胺(0.58mL)溶解於二氯甲烷(12mL)中。使反應混合物冷卻至0℃,並逐滴添加甲烷磺醯氯(0.28mL)。將反應混合物在室溫下攪拌1小時。添加飽和NaHCO3(10mL),並用二氯甲烷(3×7mL)萃取水層。將合併之有機層經Na2SO4乾燥。過濾並濃縮濾液,得到標題化合物,其未經進一步純化即用於下一步驟中。
(2R,5R)-2-(疊氮基甲基)-5-甲基-1,4-二噁烷
該標題化合物係藉由在實例1L中用實例24F取代實例1K來製備。
((2R,5R)-5-甲基-1,4-二噁烷-2-基)甲胺
該標題化合物係藉由在實例9C中用實例24G取代實例9B來製備。
4-(((2R,5R)-5-甲基-1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例24H取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例24I取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.65(s,1H),8.57(d,1H),8.55(t,1H),8.03(d,1H),7.83(dd,1H),7.50(m,3H),7.34(d,2H),7.10(d,1H),7.02(d,2H),6.67(dd,1H),6.38(m,1H),6.20(d,1H),3.86,3.78,3.70,3.67(所有m,5H),3.54,3.49(both m,3H),3.08(br m,4H),2.76(br s,2H),2.20(br m,4H),2.13(br m,2H),1.94(br m,2H),1.37(t,2H),1.09(d,3H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-羥基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
1,4-二氧雜環庚-6-酮
向乙烷-1,2-二醇(12.9g)及2-重氮乙酸乙酯(47.5g)於二氯甲烷(400mL)中之冷卻(0℃)溶液中逐滴添加BF3Et2O(0.3mL)。在添加後
觀察到氣體放出。使溫度上升至室溫並將混合物攪拌24小時。然後,在真空下濃縮混合物且殘餘物未經進一步純化即直接用於下一反應中。向2,2’-(乙烷-1,2-二基雙(氧基))二乙酸二乙酯(52.75g)於DMF中之溶液中添加第三丁氧基鋰(36g)。將混合物於90℃下攪拌過夜。將混合物傾倒於10% HCl水溶液(200mL)上並用乙酸乙酯萃取三次。用水及鹽水將合併之萃取物洗滌三次,並經Na2SO4乾燥。過濾並濃縮得到粗製產物,其未經進一步純化即用於下一反應中。將6-側氧基-1,4-二氧雜環庚烷-5-甲酸乙酯(16.2g)於10% HCl水溶液(100mL)中之混合物在回流下攪拌4小時。冷卻混合物,用乙酸乙酯萃取三次。用鹽水洗滌合併之萃取物,且經Na2SO4乾燥。在過濾後,濃縮,得到標題化合物。
6-(硝基甲基)-1,4-二氧雜環庚-6-醇
向乙氧鈉(14g,21%w)於乙醇(20mL)中之溶液中添加實例25A(3.2g)及硝基甲烷(3.75g)之溶液。將反應混合物攪拌4小時。將反應混合物傾倒於NH4Cl水溶液(200mL)中。用乙酸乙酯將水層萃取三次。合併有機層並經MgSO4乾燥。在過濾及濃縮後,在Analogix系統上用600g管柱用於己烷中之0-40%乙酸乙酯洗脫來純化粗製物質,從而得到標題化合物。
6-(胺基甲基)-1,4-二氧雜環庚-6-醇
向實例25B(1.2g)於乙醇(60mL)中之溶液中添加Pd/C(10%,120mg)。將混合物在氫氣球下攪拌過夜。過濾混合物並濃縮,從而得到粗製產物,其未經進一步純化即用於下一反應中。
4-(((6-羥基-1,4-二氧雜環庚-6-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例25C取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-羥基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例25D取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),8.64(t,1H),8.57(d,1H),8.05(d,1H),7.81(dd,1H),7.45-7.57(m,3H),7.33(t,2H),7.11(d,1H),6.97-7.07(m,2H),6.68(dd,1H),6.39(dd,1H),6.19(d,1H),5.46-5.58(m,1H),3.58-3.83(m,9H),3.34-3.46(m,3H),2.99-3.16(m,5H),2.67-2.83(m,2H),2.08-2.31(m,7H),1.86-1.98(m,2H),1.32-1.44(m,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4,4-二氟-1-羥基環己基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((4,4-二氟-1-羥基環己基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用1-(胺基甲基)-4,4-二氟環己醇取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4,4-二氟-1-羥基環己基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例26A取代實例1N來製
備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.73(s,1H),11.40(bs,1H),8.73(t,1H),8.63(d,1H),8.11(d,1H),7.87(dd,1H),7.62-7.53(m,3H),7.40(d,2H),7.25(d,1H),7.10(d,2H),6.74(dd,1H),6.45(dd,1H),6.25(d,1H),5.12(s,1H),3.49-3.42(m,2H),3.13(bs,4H),2.81(bs,2H),2.30-2.18(m,6H),2.15-1.90(m,6H),1.81(d,2H),1.66(td,2H),1.44(t,2H),0.98(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲氧基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((4-甲氧基四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用(4-甲氧基四氫-2H-吡喃-4-基)甲胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-甲氧基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例27A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.69(s,1H),11.36(bs,1H),8.58(d,1H),8.42(t,1H),8.05(d,1H),7.87(dd,1H),7.56-7.48(m,3H),7.34(d,2H),7.12(d,1H),7.04(d,2H),6.68(d,1H),6.40(dd,1H),6.19(d,1H),3.68-3.62(m,2H),3.56(td,2H),3.47(d,2H),3.17(s,3H),3.07(bs,4H),2.76(bs,2H),2.20(bs,4H),2.14(t,2H),1.95(bs,2H),1.75(d,2H),1.60(m,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3,3-二氟環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((3,3-二氟環丁基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用(3,3-二氟環丁基)甲胺鹽酸鹽取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3,3-二氟環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例28A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.41(bs,1H),8.62(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.54-7.46(m,3H),7.34(d,2H),7.11(d,1H),7.04(d,2H),6.68(d,1H),6.39(dd,1H),6.20(d,1H),3.53(t,2H),3.07(bs,4H),2.74(bs,2H),2.70-2.59(m,2H),2.46-2.35(m,2H),2.25-2.10(m,7H),1.95(bs,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺醯基]六氫吡啶-4-基}甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
3-硝基-4-(((1-((三氟甲基)磺醯基)六氫吡啶-4-基)甲基)胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用(1-((三氟甲基)磺醯基)六氫吡
啶-4-基)甲胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[({1-[(三氟甲基)磺醯基]六氫吡啶-4-基}甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例29A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.39(bs,1H),8.63(t,1H),8.56(d,1H),8.04(d,1H),7.81(dd,1H),7.54-7.48(m,3H),7.34(d,2H),7.13(d,1H),7.04(d,2H),6.68(d,1H),6.39(dd,1H),6.19(d,1H),3.82(d,2H),3.36(t,2H),3.17(t,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.11(m,6H),1.95(bs,2H),1.86(m,3H),1.38(t,2H),1.27(m,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[1-(甲基磺醯基)六氫吡啶-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((1-(甲基磺醯基)六氫吡啶-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用(1-(甲基磺醯基)六氫吡啶-4-基)甲胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[1-(甲基磺醯基)六氫吡啶-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例30A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.40(bs,
1H),8.62(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.54-7.48(m,3H),7.34(d,2H),7.12(d,1H),7.04(d,2H),6.68(d,1H),6.39(dd,1H),6.19(d,1H),3.56(d,2H),3.34(t,2H),3.07(bs,4H),2.83(s,3H),2.75(bs,2H),2.67(td,2H),2.25-2.10(m,6H),1.95(bs,2H),1.81(m,3H),1.38(t,2H),1.27(m,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(2R,6S)-2,6-二甲基四氫-4H-吡喃-4-酮
將2,6-二甲基-4H-吡喃-4-酮(14g)及四氫呋喃(140mL)加至含在250mL SS壓力瓶中之10%乾燥Pd/C(2.8g)中,並將混合物在50psi下攪拌2小時。藉助尼龍(nylon)膜過濾混合物並濃縮。在矽膠上使用5-50%乙酸乙酯/己烷層析粗製產物,從而得到標題化合物。
外消旋-(2R,6S)-2,6-二甲基四氫-2H-吡喃-4-甲腈
該標題化合物係藉由在實例4A中用實例31A取代1-氧雜螺[4.5]癸-8-酮來製備
4-({[(2R,4r,6S)-2,6-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯磺醯胺
將LiAlH4(14.4mL,1M四氫呋喃溶液)添加至於四氫呋喃(40mL)中之實例31B(2g)中,並將混合物攪拌1小時。藉由添加飽和酒石酸鉀鈉溶液(5mL)淬滅反應混合物,並將混合物攪拌30分鐘。自鹽倒出溶液並濃縮。將粗製物質吸收於四氫呋喃(50mL)中,並添加三乙胺
(2.0mL)及4-氟-3-硝基苯磺醯胺(3.16g)。將反應混合物攪拌1小時。用乙酸乙酯(200mL)稀釋反應混合物,用NaH2PO4溶液及鹽水洗滌兩次,並濃縮。在矽膠上用10-50%乙酸乙酯/己烷層析粗製產物,從而分別得到標題化合物及其非鏡像異構物。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2R,4r,6S)-2,6-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例31C取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.69(s,1H),11.40(br s,1H),8.60(m,1H),8.56(s,1H),8.04(s,1H),7.80(d,1H),7.51(m,2H),7.34(d,2H),7.09(d,1H),7.04(d,2H),6.68(d,1H),6.40(d,1H),6.19(s,1H),3.39(m,2H),3.28(m,2H),3.07(m,4H),2.75(s,2H),2.19(s,4H),2.14(m,2H),1.95(s,2H),1.65(m,2H),1.38(m,2H),1.09(s,6H),0.92(m,6H),0.84(m,4H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(1-氧離子基四氫-2H-硫吡喃-4-基)甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
將實例22B(450mg)溶解於二氯甲烷(8mL)中,並添加3-氯過氧苯甲酸(76%,88mg)。將反應混合物在室溫下攪拌三天。藉由急驟管柱層析在矽膠上使用於二氯甲烷中之10-20%甲醇來純化粗製物質。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.41(bs,1H),8.68-8.56(m,1H),8.55(d,1H),8.03(d,1H),7.78(d,1H),7.52-7.47(m,3H),7.34(d,2H),7.09(m,1H),7.04(d,2H),6.67(d,1H),6.39(dd,1H),6.20(d,1H),3.25(m,2H),3.06(bs,4H),2.86(d,2H),
2.73(bs,2H),2.66-2.53(m,2H),2.25-2.00(m,6H),1.95(bs,2H),1.87(m,3H),1.69(m,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(S)-4-(((2,2-二甲基四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用外消旋(2,2-二甲基四氫-2H-吡喃-4-基)甲胺鹽酸鹽取代實例1M並如實例19D中所闡述實施對掌性純化來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4S)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例33A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.41(bs,1H),8.60-8.52(m,2H),8.04(d,1H),7.80(dd,1H),7.53-7.47(m,3H),7.34(d,2H),7.10(d,1H),7.04(d,2H),6.68(d,1H),6.39(dd,1H),6.19(d,1H),3.59(td,1H),3.52(td,1H),3.25(t,2H),3.07(bs,4H),2.74(bs,2H),2.28-2.00(m,8H),1.95(bs,2H),1.58(dd,2H),1.38(t,2H),1.25(m,1H),1.12(s,6H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯
基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(R)-4-(((2,2-二甲基四氫-2H-吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物亦係如在實例33A中所闡述來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(4R)-2,2-二甲基四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例34A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.40(bs,1H),8.60-8.52(m,2H),8.04(d,1H),7.80(dd,1H),7.53-7.47(m,3H),7.34(d,2H),7.10(d,1H),7.04(d,2H),6.68(d,1H),6.39(dd,1H),6.19(d,1H),3.59(td,1H),3.52(td,1H),3.25(t,2H),3.07(bs,4H),2.74(bs,2H),2.28-2.00(m,8H),1.95(bs,2H),1.58(dd,2H),1.38(t,2H),1.25(m,1H),1.12(s,6H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(R)-1-(第三丁基二苯基矽烷基氧基)丙-2-醇
將(R)-丙烷-1,2-二醇(5g)及咪唑(4.5g)溶解於二氯甲烷(200mL)中。使混合物冷卻至0℃,並逐滴添加第三丁基氯二苯基矽烷(18.1g)於二氯甲烷(50mL)中之溶液。將反應混合物在乾燥管下在0℃下維持過夜。藉助矽藻土過濾反應混合物,並濃縮。在矽膠上用9/1庚烷/乙
酸乙酯層析粗製物質,從而得到標題化合物。
將實例35A(16.8g)、苄基溴(9.5mL)、N-乙基-N-異丙基丙-2-胺(15.0mL)及碘化鈉(0.82g)在150℃及N2下加熱3天。使反應物冷卻至室溫並將其分配在乙酸乙酯與1M KHSO4之間。使用鹽水洗滌有機層並藉由Na2SO4乾燥。在過濾及濃縮後,在矽膠上用98.5/1.5庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
(R)-2-(苄基氧基)丙-1-醇
將實例35B(5.6g)溶解於四氫呋喃(50mL)中,添加四丁基氟化銨(15mL,1.0M於95/5四氫呋喃/H2O中),並將反應物攪拌過夜。濃縮反應混合物並在矽膠上用3/1庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
(R)-((1-(烯丙基氧基)丙-2-基氧基)甲基)苯
該標題化合物係藉由在實例24A中用實例35C取代(R)-1-(苄基氧基)丙-2-醇來製備。
2-(((R)-2-(苄基氧基)丙氧基)甲基)環氧乙烷
該標題化合物係藉由在實例24B中用實例35D取代實例24A來製備。
(R)-2-(((R)-2-(苄基氧基)丙氧基)甲基)環氧乙烷
該標題化合物係藉由在實例24C中用實例35E取代實例24B並用S,S-(salen)Co(II)錯合物(CAS編號188264-84-8)取代R,R-(salen)Co(II)
錯合物來製備。
(R)-1-((R)-環氧乙烷-2-基甲氧基)丙-2-醇
將實例35F(780mg)溶解於四氫呋喃(20mL)中,並添加碳載Pd(OH)2(20%乾燥Pd wt/總共50%水,80mg)。將反應混合物於氫下氣球攪拌3小時。藉助矽藻土過濾並濃縮,得到標題化合物,其未經進一步純化即用於下一步驟中。
((2S,6R)-6-甲基-1,4-二噁烷-2-基)甲醇
該標題化合物係藉由在實例24E中用實例35G取代實例24D來製備。
甲烷磺酸((2R,6R)-6-甲基-1,4-二噁烷-2-基)甲酯
該標題化合物係藉由在實例24F中用實例35H取代實例24E來製備。
(2S,6R)-2-(疊氮基甲基)-6-甲基-1,4-二噁烷
該標題化合物係藉由在實例1L中用實例35I取代實例1K來製備。
((2S,6R)-6-甲基-1,4-二噁烷-2-基)甲胺
該標題化合物係藉由在實例9C中用實例35J取代實例9B來製備。
4-(((2S,6R)-6-甲基-1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例35J取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-
基)-N-{[4-({[(2S,6R)-6-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例35L取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.66(s,1H),11.35(v br s,1H),8.59(t,1H),8.55(d,1H),8.03(d,1H),7.81(dd,1H),7.50(m,3H),7.34(d,2H),7.08(d,1H),7.03(d,2H),6.68(dd,1H),6.38(m,1H),6.20(d,1H),3.86(m,1H),3.79(dd,1H),3.70(m,2H),3.48(m,1H),3.35(m,2H),3.21(t,1H),3.06(br m,5H),2.76(br s,2H),2.20(br m,4H),2.14(br m,2H),1.95(br m,2H),1.38(t,2H),1.01(d,3H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氫呋喃-3-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(S)-(四氫呋喃-3-基)甲醇
使於四氫呋喃(7.5mL)中之(R)-四氫呋喃-3-甲酸(0.50g)冷卻至0℃,並逐滴添加硼烷四氫呋喃複合物(14mL,1.0M於四氫呋喃中),使溫度保持<6℃。將反應混合物在室溫及氮下攪拌45分鐘。使反應混合物冷卻至0℃並小心添加5N NaOH(2.3mL)。將反應混合物攪拌數分鐘,並添加水及乙醚。用鹽水洗滌分離之有機層,並用乙醚反萃取合併之水層。將合併之有機層經Na2SO4乾燥,過濾並濃縮。在矽膠上用3/7庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
(R)-甲烷磺酸(四氫呋喃-3-基)甲基酯
該標題化合物係藉由在實例24F中用實例36A取代實例24E來製
備。
(S)-3-(疊氮基甲基)四氫呋喃
該標題化合物係藉由在實例1L中用實例36B取代實例1K來製備。
(S)-(四氫呋喃-3-基)甲胺
該標題化合物係藉由在實例9C中用實例36C取代實例9B來製備。
(S)-3-硝基-4-((四氫呋喃-3-基)甲基胺基)苯磺醯胺
該標題化合物係藉由在實例1N中用實例36D取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(3S)-四氫呋喃-3-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例36E取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.68(s,1H),11.33(v br s,1H),8.62(t,1H),8.57(d,1H),8.03(d,1H),7.81(dd,1H),7.50(m,3H),7.34(d,2H),7.09(d,1H),7.03(d,2H),6.68(dd,1H),6.39(m,1H),6.19(d,1H),3.80(m,1H),3.71(dd,1H),3.63(dd,1H),3.52(m,2H),3.08(br m,4H),2.76(br s,2H),2.58(m,1H),2.20(br m,4H),2.00(m,1H),2.14(br m,2H),1.65(m,1H),1.95(br m,2H),1.38(t,2H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯
基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(烯丙基氧基)乙酸甲酯
經10-15分鐘將羥乙酸甲酯(25g)逐滴添加至NaH(7.7g,95%)於DMF(280mL)中之0℃懸浮液中。然後,經10-15分鐘逐滴添加羥乙酸甲酯(25g)。使反應物升溫至室溫,攪拌1小時,並冷卻返回至0℃。經10-15分鐘逐滴添加烯丙基溴(36.7g),並將反應物在室溫下攪拌1小時。將反應混合物傾倒於飽和水NH4Cl溶液(700mL)中並用乙酸乙酯(3×350mL)萃取。用鹽水洗滌合併之有機層且經Na2SO4乾燥。在過濾及濃縮後,使用維格羅分餾頭(Vigeraux head)及vac=3.4mmHg蒸餾粗製產物,從而得到標題化合物與DMF之混合物。將此混合物溶解於醚(10mL)中,用水(2×10mL)及鹽水洗滌,然後經MgSO4乾燥。過濾及濃縮,得到標題化合物。
1-(烯丙基氧基)-2-甲基丙-2-醇
將實例37A(12g)溶解於四氫呋喃(200mL)中並冷卻至0℃。逐滴添加CH3MgCl(100mL,3.0M於四氫呋喃中)。將反應混合物在N2下冷攪拌3.5小時。緩慢添加飽和NH4Cl(60mL),隨後添加水及乙醚。用鹽水洗滌有機層並經Na2SO4乾燥。過濾並濃縮濾液,得到標題化合物,其未經進一步純化即用於下一步驟中。
((1-(烯丙基氧基)-2-甲基丙-2-基氧基)甲基)苯
該標題化合物係藉由在實例35B中用實例37B取代實例35A來製備。
2-((2-(苄基氧基)-2-甲基丙氧基)甲基)環氧乙烷
該標題化合物係藉由在實例24B中用實例37C取代實例24A來製備。
(R)-2-((2-(苄基氧基)-2-甲基丙氧基)甲基)環氧乙烷
該標題化合物係藉由在實例24C中用實例37D取代實例24B並用S,S-(salen)Co(II)錯合物(CAS編號188264-84-8)取代R,R-(salen)Co(II)錯合物來製備。
(R)-2-甲基-1-(環氧乙烷-2-基甲氧基)丙-2-醇
該標題化合物係藉由在實例35G中用實例37E取代實例35F來製備。
(S)-(6,6-二甲基-1,4-二噁烷-2-基)甲醇
該標題化合物係藉由在實例24E中用實例37F取代實例24D來製備。
(R)-甲烷磺酸(6,6-二甲基-1,4-二噁烷-2-基)甲酯
該標題化合物係藉由在實例24F中用實例37G取代實例24E來製備。
(S)-6-(疊氮基甲基)-2,2-二甲基-1,4-二噁烷
該標題化合物係藉由在實例1L中用實例37H取代實例1K來製備。
(S)-(6,6-二甲基-1,4-二噁烷-2-基)甲胺
該標題化合物係藉由在實例9C中用實例37I取代實例9B來製備。
(S)-4-((6,6-二甲基-1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺該標題化合物係藉由在實例1N中用實例37J取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S)-6,6-二甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例37K取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ ppm 11.66(s,1H),11.33(v br s,1H),8.57(t,1H),8.56(d,1H),8.03(d,1H),7.82(dd,1H),7.50(m,3H),7.34(d,2H),7.06(d,1H),7.03(d,2H),6.69(dd,1H),6.38(m,1H),6.20(d,1H),4.06(m,1H),3.81(dd,1H),3.49(d,1H),3.43(m,1H),3.29(m,1H),3.18(m,2H),3.08(br m,4H),2.76(br s,2H),2.20(br m,4H),2.14(br m,2H),1.95(br m,2H),1.38(t,2H),1.27(s,3H),1.08(s,3H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-甲基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((3-甲基氧雜環丁-3-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用(3-甲基氧雜環丁-3-基)甲胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-甲基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例38A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.66(s,1H),11.41(bs,1H),8.67(t,1H),8.57(d,1H),8.03(d,1H),7.83(dd,1H),7.52-7.47(m,3H),7.34(d,2H),7.17(d,1H),7.04(d,2H),6.68(d,1H),6.38(dd,1H),6.20(d,1H),4.45(d,2H),4.31(d,2H),3.57(td,2H),3.07(bs,4H),2.75(bs,2H),2.25-2.11(m,6H),1.95(bs,2H),1.38(t,2H),1.32(s,3H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
6-((二苄基胺基)甲基)-1,4-二氧雜環庚-6-醇
向實例25C(1.8g)於二氯甲烷(30mL)中之溶液中相繼添加苯甲醛(3.82g)及乙酸(0.5mL)以及樹脂載氰基硼氫化鈉(2.4mmol/g,4.5g)。將混合物攪拌過夜。然後,過濾該混合物並在真空下濃縮濾液。將殘餘物裝載於矽膠管柱上並用於己烷中之30%乙酸乙酯洗脫,從而得到標題化合物。
N,N-二苄基-1-(6-氟-1,4-二氧雜環庚-6-基)甲胺
向實例39A(256mg)於二氯甲烷(33mL)中之溶液中添加雙(2-甲氧基乙基)胺基三氟化硫(2mL,於四氫呋喃中之1M溶液)。將混合物攪拌過夜。然後,將混合物傾倒於冰水中並用二氯甲烷(50mL)萃取三次。用NaHCO3水溶液、水及鹽水洗滌合併之有機萃取物,並經Na2SO4乾燥。在過濾及濃縮後,藉由管柱層析使用於庚烷中之20%乙酸乙酯純化粗製物質,從而得到標題化合物。
向實例39B(200mg)於甲醇(20mL)中之溶液中添加雷尼(Raney)Ni(30mg)。將混合物在30psi氫下攪拌過夜。過濾及濃縮,得到標題化合物。
4-(((6-氟-1,4-二氧雜環庚-6-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例39C取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-氟-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例39D取代實例1N來製備。1H NMR(300MHz二甲基亞碸-d6)δ ppm 11.70(s,1H),11.60-11.67(m,1H),9.48-9.71(m,1H),8.52-8.70(m,2H),8.04(d,1H),7.83(dd,1H),7.46-7.62(m,3H),7.39(d,2H),7.20(d,1H),7.08(d,2H),6.71(dd,1H),6.40(dd,1H),6.25(s,1H),3.49-4.03(m,9H),2.99-3.19(m,2H),2.62-2.84(m,2H),2.15-2.31(m,4H),1.97-2.05(m,4H),1.37-1.53(m,4H),0.94(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
N,N-二苄基-1-(6-甲氧基-1,4-二氧雜環庚-6-基)甲胺
向實例39A(300mg)於四氫呋喃(3mL)及HMPA(六甲基磷醯胺,3mL)中之溶液中添加NaH(200mg,60%於礦物油中)。將混合物攪拌30分鐘,之後添加CH3I(0.6g)。然後,將混合物在50℃下攪拌過夜。將混合物傾倒於NH4Cl水溶液上並用乙酸乙酯(100mL)萃取三次。用水及鹽水將合併之有機萃取物洗滌三次,並經Na2SO4乾燥。在過濾及濃縮後,蒸發溶劑,得到粗製產物,將其裝載於矽膠管柱上並用於己烷中之20%乙酸乙酯洗脫,從而得到標題化合物。
(6-甲氧基-1,4-二氧雜環庚-6-基)甲胺
向實例40A(200mg)於甲醇(20mL)中之溶液中添加雷尼Ni(50mg)。將混合物在30psi氫下攪拌過夜。在過濾後,真空蒸發溶劑,得到標題化合物。
4-(((6-甲氧基-1,4-二氧雜環庚-6-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例40B取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(6-甲氧基-1,4-二氧雜環庚-6-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例40C取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.68(s,1H),8.57(d,1H),8.49(t,1H),8.05(d,1H),7.43-7.58(m,3H),7.34(d,2H),7.12(d,1H),7.04(d,2H),6.68(dd,1H),6.39(dd,1H),6.19(d,1H),3.87-4.09(m,3H),3.61-3.81(m,5H),3.38-3.51(m,2H),2.99-3.15(m,4H),2.70-2.90(m,2H),2.08-2.33(m,5H),1.90-2.01(m,3H),1.39
(t,2H),1.17(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(反式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
反式-3-(羥基甲基)環丁烷甲腈
將兒茶酚硼烷(7.1mL)添加至於四氫呋喃(25mL)中之3-亞甲基環丁烷甲腈(5.6g)中,並將混合物攪拌24小時。藉由緩慢添加乙醇(25mL)淬滅反應混合物,並將混合物傾倒於乙醇(75mL)及四氫呋喃(100mL)中。向此中添加2M NaOH水溶液(150mL)並經1小時緩慢添加30% H2O2水溶液(150mL)。將混合物再攪拌3小時,並用乙酸乙酯(500mL)稀釋。分離各層並用1M NaOH水溶液及鹽水將有機層洗滌兩次,並濃縮。在矽膠上用5-100%乙酸乙酯/己烷層析粗製產物,從而分別得到標題化合物及其順式-非鏡像異構物。
甲烷磺酸反式-3-氰基環丁基)甲酯
在-20℃下將甲基磺醯氯(1.0mL)添加至於二氯甲烷(50mL)中之實例41A(1.35g)及二異丙基乙胺(2.33mL)中。將混合物攪拌1小時。將反應混合物傾倒於二氯甲烷(200mL)中並用水及鹽水洗滌兩次,並濃縮。在矽膠上用10-100%乙酸乙酯/己烷層析粗製產物,從而分別得到標題化合物。
4-(((反式-3-氰基環丁基)甲基)胺基)-3-硝基苯磺醯胺
將疊氮化鈉(1.1g)添加至於N,N-二甲基甲醯胺(15mL)中之實例41B(5.6g)中,並將混合物攪拌24小時。將反應混合物傾倒於水(75
mL)中,並用乙醚(100mL)萃取兩次。合併有機層並濃縮至10mL。添加四氫呋喃(25mL)且向所得混合物中添加三苯基膦(2.2g)及水(0.3mL),並將反應物攪拌24小時。添加硫酸鈉(5g)及4-氟-3-硝基苯磺醯胺(1.86g),並將反應物在40℃下攪拌2小時。用乙酸乙酯(300mL)稀釋混合物。分離各層且用鹽水洗滌有機層,並濃縮。在矽膠上用50%乙酸乙酯/己烷層析粗製產物,從而得到標題化合物。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(反式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例41C取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.67(s,1H),11.35(br s,1H),8.56(m,1H),8.54(s,1H),8.04(s,1H),7.80(d,1H),7.51(m,2H),7.34(d,2H),7.09(d,1H),7.04(d,2H),6.69(d,1H),6.39(d,1H),6.19(s,1H),3.51(m,2H),3.40(m,1H),3.07(m,4H),2.78(m,1H),2.75(m,2H),2.38(m,2H),2.20(m,6H),1.95(s,2H),1.38(t,2H),1.24(m,1H),0.92(m,6H),0.85(m,2H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(順式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
順式-3-(羥基甲基)環丁烷甲腈
該標題化合物亦係自實例41A分離得來。
甲烷磺酸順式-3-氰基環丁基)甲酯
該標題化合物係藉由在實例41B中用實例42A取代實例41A來製備。
4-(((順式-3-氰基環丁基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例41C中用實例42B取代實例41B來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(順式-3-氰基環丁基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例42C取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.68(s,1H),11.35(br s,1H),8.55(m,2H),8.04(s,1H),7.81(d,1H),7.51(m,2H),7.34(d,2H),7.06(d,1H),7.04(d,2H),6.69(d,1H),6.39(d,1H),6.19(s,1H),3.47(m,2H),3.32(m,1H),3.07(m,4H),2.75(m,2H),2.65(m,1H),2.38(m,2H),2.20(m,6H),1.95(s,2H),1.38(t,2H),1.24(m,1H),0.92(m,6H),0.86(m,2H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(1,1-二氧離子基四氫-2H-硫吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-(((1,1-二氧離子基四氫-2H-硫吡喃-4-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用4-(胺基甲基)四氫-2H-硫吡喃1,1-二氧化物鹽酸鹽取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(1,1-二氧離子基四氫-2H-硫吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例43A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ ppm 11.67(s,1H),11.42(bs,1H),8.66(t,1H),8.56(d,1H),8.04(d,1H),7.81(dd,1H),7.56-7.48(m,3H),7.34(d,2H),7.13(d,1H),7.04(d,2H),6.68(d,1H),6.39(dd,1H),6.19(d,1H),3.37(t,2H),3.17-3.00(m,8H),2.73(bs,2H),2.26-2.03(m,9H),1.95(bs,2H),1.68(m,2H),1.38(t,2H),0.92(s,6H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(R)-2-(((R)-1-(苄基氧基)丙-2-基氧基)甲基)環氧乙烷
該標題化合物係藉由在實例24C中用S,S-(salen)Co(II)錯合物(CAS編號188264-84-8)取代R,R-(salen)Co(II)錯合物(CAS編號176763-62-5)來製備。
(R)-2-((R)-環氧乙烷-2-基甲氧基)丙-1-醇
該標題化合物係藉由在實例35G中用實例44A取代實例35F來製備。
((2S,5R)-5-甲基-1,4-二噁烷-2-基)甲醇
該標題化合物係藉由在實例24E中用實例44B取代實例24D來製
備。
甲烷磺酸((2R,5R)-5-甲基-1,4-二噁烷-2-基)甲酯
該標題化合物係藉由在實例24F中用實例44C取代實例24E來製備。
(2S,5R)-2-(疊氮基甲基)-5-甲基-1,4-二噁烷
該標題化合物係藉由在實例1L中用實例44D取代實例1K來製備。
((2S,5R)-5-甲基-1,4-二噁烷-2-基)甲胺
該標題化合物係藉由在實例9C中用實例44E取代實例9B來製備。
4-(((2S,5R)-5-甲基-1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例44F取代實例1M來製備。
實例44H
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例44G取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ 11.66(s,1H),8.57(t,1H),8.55(d,1H),8.03(d,1H),7.83(dd,1H),7.50(m,3H),7.34(d,2H),7.10(d,1H),7.03(d,2H),6.67(dd,1H),6.38(m,1H),6.19(d,1H),3.81(ddd,2H),3.72(m,1H),3.52(m,2H),3.36(m,2H),3.20(dd,1H),3.07(br m,4H),2.76(br s,2H),2.20(br m,4H),2.14(br m,2H),1.95(br m,2H),1.38(t,2H),0.98(d,3H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺實例45A
(S)-((2-(烯丙基氧基)丙氧基)甲基)苯
該標題化合物係藉由在實例24A中用(S)-1-(苄基氧基)丙-2-醇取代(R)-1-(苄基氧基)丙-2-醇來製備。
(S)-2-((R)-環氧乙烷-2-基甲氧基)丙-1-醇
該標題化合物係藉由在實例24B中用實例45A取代實例24A來製備。
(R)-2-(((S)-1-(苄基氧基)丙-2-基氧基)甲基)環氧乙烷
該標題化合物係藉由在實例24C中用S,S-(salen)Co(II)錯合物(CAS編號188264-84-8)取代R,R-(salen)Co(II)錯合物(CAS編號176763-62-5)並用實例45B取代實例24B來製備。
(S)-2-((S)-環氧乙烷-2-基甲氧基)丙-1-醇
該標題化合物係藉由在實例35G中用實例45C取代實例35F來製備。
((2S,5S)-5-甲基-1,4-二噁烷-2-基)甲醇
該標題化合物係藉由在實例24E中用實例45D取代實例24D來製備。
甲烷磺酸((2R,5S)-5-甲基-1,4-二噁烷-2-基)甲酯
該標題化合物係藉由在實例24F中用實例45E取代實例24E來製備。
(2S,5S)-2-(疊氮基甲基)-5-甲基-1,4-二噁烷
該標題化合物係藉由在實例1L中用實例45F取代實例1K來製備。
((2S,5S)-5-甲基-1,4-二噁烷-2-基)甲胺
該標題化合物係藉由在實例9C中用實例45G取代實例9B來製備。
4-(((2S,5S)-5-甲基-1,4-二噁烷-2-基)甲基胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例45H取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5S)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例45I取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ 11.67(s,1H),8.57(d,1H),8.55(t,1H),8.03(d,1H),7.83(dd,1H),7.50(m,3H),7.34(d,2H),7.11(d,1H),7.03(d,2H),6.68(dd,1H),6.38(m,1H),6.20(d,1H),3.84,3.78,3.70,3.66(所有m,5H),3.54,3.49(both m,3H),3.08(br m,4H),2.76(br s,2H),2.20(br m,4H),2.14(br m,2H),1.95(br m,2H),1.38(t,2H),1.09(d,3H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-
基)-N-[(4-{[(4-氰基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(4-胺甲醯基-四氫-吡喃-4-基甲基)-胺基甲酸第三丁基酯
在乙腈(30mL)及1-甲基吡咯啶酮(10mL)中攪拌4-(胺基甲基)四氫-2H-吡喃-4-甲醯胺(1000mg)。相繼添加N,N-二甲基吡啶-4-胺(77mg)及二碳酸二-第三丁基酯(1.45g)。將混合物在室溫下攪拌1小時,且然後藉由在減壓下蒸發去除溶劑之乙腈部分。將混合物添加至乙酸乙酯中並用水洗滌三次。然後,用鹽水洗滌混合物並經無水硫酸鈉乾燥。在過濾後,去除溶劑,且該物質未經進一步純化即使用。
(4-氰基-四氫-吡喃-4-基甲基)-胺基甲酸第三丁基酯
將實例46A(1.63g)溶解於四氫呋喃(60mL)中,並添加1-甲氧基-N-三乙基銨基磺醯基-甲醯亞胺酯(1.58g)。將混合物在室溫下攪拌16小時。在真空下去除溶劑且將物質吸收於乙酸乙酯中。用水將溶液洗滌三次,用鹽水洗滌,並經無水硫酸鈉乾燥。在過濾後,去除溶劑,且該物質未經進一步純化即使用。
4-(胺基甲基)四氫-2H-吡喃-4-甲腈三氟乙酸鹽
將實例46B(610mg)溶解於二氯甲烷(20mL)中。添加2,2,2-三氟乙酸(1.95mL),並將混合物在室溫下攪拌4小時。在真空下去除溶劑,將粗製物質吸收於二氯甲烷中,並在真空下再次去除溶劑。然後,用乙醚研磨物質,且在真空上乾燥。
4-[(4-氫基-四氫-吡喃-4-基甲基)-胺基]-3-硝基-苯磺醯胺
該標題化合物係藉由在實例1N中用實例46C取代實例1M來製
備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-氰基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例46D取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.66(s,1H),11.37(bs,1H),8.65(t,1H),8.57(d,1H),8.04(d,1H),7.85(dd,1H),7.52(dd,2H),7.49(d,1H),7.44(d,1H),7.34(d,2H),7.04(d,2H),6.68(dd,1H),6.38(t,1H),6.20(d,1H),3.92(dd,2H),3.83(d,2H),3.46(t,2H),3.08(s,4H),2.76(s,2H),2.27-2.12(m,6H),1.95(s,2H),1.89(d,2H),1.74(td,2H),1.38(t,2H),0.92(s,6H)。
N-[(4-{[(1-乙醯基六氫吡啶-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
(1-乙醯基-六氫吡啶-4-基甲基)-胺基甲酸第三丁基酯
將(六氫吡啶-4-基甲基)胺基甲酸第三丁基酯(600mg)溶解於二氯甲烷(20mL)中。添加三乙胺(1.17mL),且添加乙酸酐(0.26mL)。將該溶液在室溫下混合16小時,且在真空下去除溶劑。該物質未經進一步純化即繼續使用。
1-(4-(胺基甲基)六氫吡啶-1-基)乙酮三氟乙酸鹽
將實例47A(718mg)溶解於二氯甲烷(20mL)中。添加2,2,2-三氟乙酸(4.32mL),並將溶液在室溫下攪拌4小時。在真空下去除溶劑,
將物質吸收於二氯甲烷中,且在真空下再次去除溶劑。然後,用乙醚研磨物質,且在真空上乾燥。
4-[(1-乙醯基-六氫吡啶-4-基甲基)-胺基]-3-硝基-苯磺醯胺
該標題化合物係藉由在實例1N中用實例47B取代實例1M來製備。
N-[(4-{[(1-乙醯基六氫吡啶-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例47C取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.68(s,1H),11.35(bs,1H),8.62(t,1H),8.57(d,1H),8.04(d,1H),7.81(dd,1H),7.52(dd,2H),7.49(d,1H),7.34(d,2H),7.11(d,1H),7.04(d,2H),6.68(dd,1H),6.39(t,1H),6.19(d,1H),4.38(d,1H),3.81(d,1H),3.07(s,4H),2.98(t,1H),2.75(s,2H),2.48(t,1H),2.24-2.11(m,6H),1.98(s,3H),1.95(s,2H),1.88(m,2H),1.72(t,2H),1.38(t,2H),1.22-0.98(m,3H),0.92(s,6H)。
4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯甲酸甲酯
(2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯基)甲醇
該標題化合物係藉由在實例1C中用實例48A取代實例1B來製備。
2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯甲醛
將實例48B(500mg)溶解於二氯甲烷(19mL)中,添加戴斯-馬丁(Dess-Martin)過碘烷(950mg),並將反應物在室溫下攪拌2小時。然後,濃縮反應物,且將粗製物質分配在乙醚與2M Na2CO3水溶液之間。用鹽水洗滌有機層,經Na2SO4乾燥,過濾並濃縮。在矽膠上用9/1庚烷/乙酸乙酯層析粗製物質,從而得到標題化合物。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(六氫吡嗪-1-基)苯甲酸甲酯
將實例1H(20.5g)及六氫吡嗪(37.0g)於二甲基亞碸(200mL)中之混合物加熱至110℃並保持24小時,並使混合物冷卻至室溫。將混合物傾倒於水(1L)中,並用二氯甲烷萃取三次。用水將合併之萃取物洗滌兩次,用鹽水洗滌,過濾並濃縮,從而得到標題化合物。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸甲酯
向實例48C(450mg)及實例48D(600mg)於二氯甲烷(6mL)中之溶液中添加三乙醯氧基硼氫化鈉(540mg)。將混合物攪拌過夜。用乙酸乙酯(200mL)稀釋混合物並用飽和NaHCO3水溶液、水及鹽水洗滌。在經Na2SO4乾燥後,過濾粗製物質,並在矽膠上用1/1庚烷/乙酸乙酯層析,從而得到標題化合物。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸
該標題化合物係藉由在實例1J中用實例48E取代實例1I來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(六氫吡嗪-1-基)苯甲酸甲酯
該標題化合物係藉由在實例1N中用(四氫-2H-吡喃-4-基)甲胺取代實例1M來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)-N-(3-硝基-4-((四氫-2H-吡喃-4-基)甲基胺基)苯基磺醯基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例48F取代實例1J並用實例48G取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ 11.68(s,1H),8.61(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.50(m,3H),7.35(dd,1H),7.21(dd,1H),7.10(m,2H),6.68(dd,1H),6.39(m,1H),6.20(d,1H),3.85(dd,2H),3.27(m,4H),3.07(br m,4H),2.67(br s,2H),2.17(br m,6H),1.90(br m,2H),1.88(m,1H),1.61(dd,2H),1.40(t,2H),1.27(ddd,2H),0.92(s,6 H)。
4-(4-{[2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯甲酸甲酯
(2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯基)甲醇
該標題化合物係藉由在實例1C中用實例49A取代實例1B來製備。
2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯甲醛
該標題化合物係藉由在實例48C中用實例49B取代實例48B來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸甲酯
該標題化合物係藉由在實例48E中用實例49C取代實例48C來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸
該標題化合物係藉由在實例1J中用實例49D取代實例1I來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-氯-3-氟苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)-N-(3-硝基-4-((四氫-2H-吡喃-4-基)甲基胺基)苯基磺醯基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例49E取代實例1J並用實例48G取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ 11.69(s,1H),8.61(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.50(m,3H),7.32(dd,1H),7.23(dd,1H),7.11(d,1H),7.03(m,1H),6.68(dd,1H),6.39(m,1H),6.20(d,1H),3.85(dd,2H),3.27(m,4H),3.07(br m,
4H),2.75(br s,2H),2.21(br m,4H),2.14(br m,2H),1.96(s,2H),1.89(m,1H),1.61(dd,2H),1.38(t,2H),1.26(ddd,2H),0.92(s,6 H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-乙基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
4-[(4-乙基-四氫-吡喃-4-基甲基)-胺基]-3-硝基-苯磺醯胺
該標題化合物係藉由在實例1N中用(4-乙基四氫-2H-吡喃-4-基)甲胺取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-乙基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例50A取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.68(s,1H),11.37(bs,1H),8.57(d,1H),8.37(t,1H),8.05(d,1H),7.84(dd,1H),7.52(dd,2H),7.49(d,1H),7.34(d,2H),7.22(d,1H),7.04(d,2H),6.68(dd,1H),6.39(t,1H),6.19(d,1H),3.68-3.52(m,4H),3.35(q,2H),3.07(s,4H),2.76(s,2H),2.25-2.11(m,6H),1.95(s,2H),1.55-1.35(m,8H),0.92(s,6H),0.82(t,3H)。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜環庚-6-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(1,4-二氧雜環庚-6-亞基)乙酸第三丁基酯
經20分鐘向2-(二乙氧基磷醯基)乙酸第三丁基酯(16.9g)於THF(250mL)中之冷卻(0℃)溶液中逐份添加氫化鈉(60%於礦物油中,2.7g),並將混合物再攪拌10分鐘。添加於THF(10mL)中之實例25A(6.5g),並將反應混合物攪拌1小時,同時使溫度上升至室溫。然後,將混合物傾倒於水(200mL)中,並用乙醚(2×300mL)萃取。用水及鹽水洗滌合併之乙醚萃取物,經Na2SO4乾燥,過濾並濃縮。在矽膠上使用於庚烷中之10%乙酸乙酯層析,得到標題化合物。
2-(1,4-二氧雜環庚-6-基)乙酸第三丁基酯
將實例51A(8.4g)及THF(100mL)在250mL SS壓力瓶中添加至5% Pd/C(濕JM編號9,1.6g)中,並將混合物在30psi下攪拌30分鐘。藉助尼龍膜過濾混合物並濃縮。
2-(1,4-二氧雜環庚-6-基)乙酸
將實例51B(8.4g)在二氯甲烷(100mL)/TFA(100mL)中攪拌1小時,並濃縮混合物,從而得到標題化合物。
((1,4-二氧雜環庚-6-基)甲基)胺基甲酸苄酯
將實例51C(3.88g)、疊氮磷酸二苯酯(6.67g)、苄基醇(5.04mL)及三乙胺(3.4mL)於甲苯(50mL)中之溶液在90℃下攪拌48小時。冷卻混合物,且傾倒於水(100mL)中,並用乙醚(2×200mL)萃取。用水及鹽水洗滌合併之萃取物,經Na2SO4乾燥,過濾並濃縮。在矽膠上使用於庚烷中之5-20%乙酸乙酯層析,得到標題化合物。
(1,4-二氧雜環庚-6-基)甲胺
將實例51D(4g)及乙醇(60mL)在250mL SS壓力瓶中添加至20% Pd(OH)2/C(濕的,0.4g)中,並將反應混合物在30psi及50℃下攪拌30分鐘。藉助尼龍膜過濾混合物並濃縮,從而得到標題化合物。
4-(((1,4-二氧雜環庚-6-基)甲基)胺基)-3-硝基苯磺醯胺
該標題化合物係藉由在實例1N中用實例51E取代實例1M來製備。
4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜環庚-6-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例51F取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.68(s,1H),11.35(br s,1H),8.70(m,1H),8.56(s,1H),8.04(s,1H),7.81(d,1H),7.50(m,3H),7.34(d,2H),7.07(d,1H),7.04(d,2H),6.69(d,1H),6.39(d,1H),6.19(s,1H),3.86(dd,2H),3.68(m,4H),3.64(dd,2H),3.37(m,2H),3.07(m,4H),2.76(m,2H),2.35(m,1H),2.20(m,4H),2.14(m,2H),1.95(m,2H),1.38(m,2H),0.92(m,6H)。
4-(4-{[2-(4-環丙基苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(4-環丙基苯基)-4,4-二甲基環己-1-烯甲酸甲酯
(2-(4-環丙基苯基)-4,4-二甲基環己-1-烯基)甲醇
該標題化合物係藉由在實例1C中用實例52A取代實例1B來製備。
2-(4-環丙基苯基)-4,4-二甲基環己-1-烯甲醛
該標題化合物係藉由在實例48C中用實例52B取代實例48B來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-環丙基苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸甲酯
該標題化合物係藉由在實例48E中用實例52C取代實例48C來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-環丙基苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸
該標題化合物係藉由在實例1J中用實例52D取代實例1I來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(4-環丙基苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)-N-(3-硝基-4-((四氫-2H-吡喃-4-基)甲基胺基)苯基磺醯基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例52E取代實例1J並用實例48G取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ 11.67(s,1H),8.59(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.50(m,3H),7.09(d,1H),6.97(d,2H),6.87(d,2H),6.68(dd,1H),6.39(m,1H),6.20(d,1H),3.85(dd,2H),3.27(m,4H),3.08(br m,4H),2.78(br s,2H),2.20(br m,4H),2.13(br m,2H),1.93(s,2H),1.86(m,2H),
1.61(dd,2H),1.37(t,2H),1.27(ddd,2H),0.92(s,6 H),0.89(m,2H),0.61(m,2H)。
4-(4-{[2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯甲酸甲酯
(2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯基)甲醇
該標題化合物係藉由在實例1C中用實例53A取代實例1B來製備。
2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯甲醛
該標題化合物係藉由在實例48C中用實例53B取代實例48B來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸甲酯
該標題化合物係藉由在實例48E中用實例53C取代實例48C來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)苯甲酸
該標題化合物係藉由在實例1J中用實例53D取代實例1I來製備。
2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-4-(4-((2-(3,4-二氯苯基)-4,4-二甲基環己-1-烯基)甲基)六氫吡嗪-1-基)-N-(3-硝基-4-((四氫-2H-吡喃-4-基)甲基胺基)苯基磺醯基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例53E取代實例1J並用實例48G取代實例1N來製備。1H NMR(400MHz,二甲基亞碸-d6)δ 11.68(s,1H),8.60(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.52(m,4H),7.29(d,1H),7.11(d,1H),7.02(dd,1H),6.68(dd,1H),6.39(m,1H),6.20(d,1H),3.85(dd,2H),3.27(m,4H),3.07(br m,4H),2.76(br s,2H),2.21(br m,4H),2.14(br m,2H),1.96(s,2H),1.89(m,1H),1.61(dd,2H),1.38(t,2H),1.26(ddd,2H),0.92(s,6H)。
4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基環己-1-烯-1-基}甲基)六氫吡嗪-1-基]-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
2-(4-二氟甲基-苯基)-4,4-二甲基-環己-1-烯甲酸甲酯
[2-(4-二氟甲基-苯基)-4,4-二甲基-環己-1-烯基]-甲醇
該標題化合物係藉由在實例1C中用實例54A取代實例1B來製備。
2-(4-二氟甲基-苯基)-4,4-二甲基-環己-1-烯甲醛
該標題化合物係藉由在實例48C中用實例54B取代實例48B來製備。
4-{4-[2-(4-二氟甲基-苯基)-4,4-二甲基-環己-1-烯基甲基]-六氫吡嗪-1-基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酸甲酯
該標題化合物係藉由在實例48E中用實例54C取代實例48C來製備。
4-{4-[2-(4-二氟甲基-苯基)-4,4-二甲基-環己-1-烯基甲基]-六氫吡嗪-1-基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)-苯甲酸
該標題化合物係藉由在實例1J中用實例54D取代實例1I來製備。
4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基環己-1-烯-1-基}甲基)六氫吡嗪-1-基]-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺
該標題化合物係藉由在實例1O中用實例54E取代實例1J並用實例48G取代實例1N來製備。1H NMR(300MHz,二甲基亞碸-d6)δ 11.67(s,1H),11.38(bs,1H),8.59(t,1H),8.56(d,1H),8.04(d,1H),7.80(dd,1H),7.53-7.47(m,5H),7.16(d,2H),7.11(d,1H),6.99(t,1H),6.68(dd,1H),6.39(t,1H),6.19(d,1H),3.85(dd,2H),3.27(m,4H),3.07(s,4H),2.75(s,2H),2.23-2.13(m,6H),1.97(s,2H),1.89(m,1H),1.62(d,2H),1.40(t,2H),1.36(m,2H),0.93(s,6H)。
使用時間解析螢光共振能量轉移(Time Resolved-螢光Resonance Energy Transfer,TR-FRET)分析確定本發明化合物作為抗細胞凋亡Bcl-2蛋白之黏合劑及其抑制劑之效用。Tb-抗GST抗體係購自Invitrogen(目錄號PV4216)。
除非另有說明,否則所使用之所有試劑皆獲得自供貨商。肽合成試劑(包括二異丙基乙胺(DIEA)、二氯甲烷(DCM)、N-甲基吡咯啶酮(NMP)、六氟磷酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓(HBTU)、N-羥基苯并三唑(HOBt)及六氫吡啶)係獲自Applied Biosystems公司(ABI)、Foster City,CA或American Bio分析型,Natick,MA。預加載之9-茀基甲基氧基羰基(Fmoc)胺基酸筒柱(Fmoc-Ala-OH、Fmoc-Cys(Trt)-OH、Fmoc-Asp(tBu)-OH、Fmoc-Glu(tBu)-OH、Fmoc-Phe-OH、Fmoc-Gly-OH、Fmoc-His(Trt)-OH、Fmoc-Ile-OH、Fmoc-Leu-OH、Fmoc-Lys(Boc)-OH、Fmoc-Met-OH、Fmoc-Asn(Trt)-OH、Fmoc-Pro-OH、Fmoc-Gln(Trt)-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Val-OH、Fmoc-Trp(Boc)-OH、Fmoc-Tyr(tBu)-OH)係獲自ABI或Anaspec,San Jose,CA。肽合成樹脂(Fmoc-Rink醯胺MBHA樹脂)及Fmoc-Lys(Mtt)-OH係獲自Novabiochem,San Diego,CA。單一異構物6-羧基螢光素琥珀醯亞胺基酯(6-FAM-NHS)係獲自Anaspec。三氟乙酸(TFA)係獲自Oakwood Products,West Columbia,SC。大茴香硫醚、苯酚、三異丙基矽烷(TIS)、3,6-二氧雜-1,8-辛烷二硫醇(DODT)及異丙醇係獲自Aldrich Chemical公司,Milwaukee,WI。基質輔助雷射脫附離子化質譜(Matrix-assisted laser desorption ionization mass-spectra,MALDI-MS)係在Applied Biosystems Voyager DE-PRO MS上記錄。電噴射質譜(ESI-MS)係在Finnigan SSQ7000(Finnigan公司,San Jose,CA)上以正離子模式及負離子模式二者進行記錄。
在ABI 433A肽合成儀上使用250μmol級FastmocTM偶合循環利用至多250μmol預加載Wang樹脂/器皿合成肽。預加載之筒柱含有1mmol標準Fmoc-胺基酸,但螢光團附接之位置除外,其中將1mmol
Fmoc-Lys(Mtt)-OH置於筒柱中,該筒柱係在電導率反饋監測下使用。藉由在標準偶合條件下在筒柱中使用1mmol乙酸來完成N-末端乙醯基化。
用DCM將來自合成儀之樹脂洗滌三次且保持濕潤。經30分鐘使150mL 95:4:1二氯甲烷:三異丙基矽烷:三氟乙酸流經樹脂床。混合物變為深黃色,然後褪成淺黃色。經15分鐘使100mL DMF流經該床。然後,用DMF將樹脂洗滌三次並過濾。茚三酮測試顯示一級胺之強信號。
在1% DIEA/DMF中用2當量6-FAM-NHS處理樹脂並在環境溫度下攪拌或振盪過夜。當完成時,將樹脂排乾,用DMF洗滌三次,用(1×DCM及1×甲醇)洗滌三次,並乾燥,從而得到橙色樹脂,藉由茚三酮測試該樹脂為陰性。
藉由在環境溫度下在由80% TFA、5%水、5%大茴香硫醚、5%苯酚、2.5% TIS及2.5% EDT組成之裂解混合液(1mL/0.1g樹脂)中振盪3小時自樹脂裂解肽。藉由過濾去除樹脂並用TFA沖洗兩次。使TFA自濾液蒸發,且用乙醚(10mL/0.1g樹脂)使產物沈澱,藉由離心回收,用乙醚(10mL/0.1g樹脂)洗滌兩次並乾燥,從而得到粗製肽。
在運行Unipoint®分析軟體之Gilson製備型HPLC系統(Gilson公司,Middleton,WI)上,在含有兩個裝有具有100Å孔徑之Delta-PakTM C18 15μm粒子之25×100mm片段之徑向壓縮管柱上,且用下文所列示梯度方法中之一者進行洗脫來純化粗製肽。每次注入純化1毫升至2毫升粗製肽溶液(10mg/mL,於90% DMSO/水中)。彙集來自每次運行
之含有產物之波峰部分並將其凍乾。所有製備運行皆係利用緩衝液A:0.1% TFA-水及緩衝液B:乙腈作為洗脫劑以20mL/min來運行。
在具有二極體陣列檢測器及運行HPLC 3D ChemStation軟體第A.03.04版之Hewlett-Packard 1046A螢光檢測器(Hewlett-Packard.Palo Alto,CA)之Hewlett-Packard 1200系列系統上,在裝有具有120Å孔徑之ODS-AQ 5μm粒子之4.6×250mm YMC管柱上,且在起始條件下預平衡7分鐘後用下文所列示梯度方法中之一者進行洗脫實施分析型HPLC。洗脫劑為緩衝液A:0.1% TFA-水及緩衝液B:乙腈。所有梯度之流速皆為1mL/min。
F-Bak:肽探針乙醯基-(SEQ ID NO:1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH2
使用一般肽合成程序使Fmoc-Rink醯胺MBHA樹脂延伸,從而得到經保護之樹脂結合肽(1.020g)。去除Mtt基團,用6-FAM-NHS標記,並如上文所闡述進行裂解及去保護,從而得到橙色固體狀粗製產物(0.37g)。藉由RP-HPLC純化此產物。藉由分析型RP-HPLC測試跨越主峰之流份,且分離並凍乾純流份,其中主峰提供黃色固體狀標題化合物(0.0802g);MALDI-MS m/z=2137.1[(M+H)+]。
肽探針F-Bak:乙醯基-(SEQ ID NO:1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH2之替代合成
在0.25mmol Fmoc-Rink醯胺MBHA樹脂(Novabiochem)上,在運行FastmocTM偶合循環之Applied Biosystems 433A自動肽合成儀上,使用預加載之1mmol胺基酸筒柱(螢光素(6-FAM)標記之離胺酸除外,其中1mmol Fmoc-Lys(4-甲基三苯甲基)稱重至筒柱中)聚集經保護肽。藉由將1mmol乙酸放入筒柱中且如上文所闡述進行偶合納入N-末端乙醯基基團。使95:4:1 DCM:TIS:TFA(v/v/v)之溶液流經樹脂達15分
鐘,隨後利用二甲基甲醯胺流淬滅來選擇性去除4-甲基三苯甲基基團。使單一異構物6-羧基螢光素-NHS在存於DMF中之1% DIEA中與離胺酸側鏈反應,並藉由茚三酮測試確定完成。自樹脂裂解肽且藉由用80:5:5:5:2.5:2.5 TFA/水/苯酚/大茴香硫醚/三異丙基矽烷:3,6-二氧雜-1,8-辛烷二硫醇(v/v/v/v/v/v)進行處理去保護側鏈,且藉由利用乙醚進行沈澱來回收粗製肽。藉由反相高效液相層析純化粗製肽,且藉由分析型逆相高效液相層析及基質輔助雷射脫附質譜確定其純度及一致性(m/z=2137.1((M+H)+))。
在二甲基亞碸(DMSO)中以50μM(2×起始濃度;10% DMSO)開始系列稀釋代表性化合物,並將10μL轉移至384孔板中。然後,將10μL蛋白質/探針/抗體混合物添加至每一孔中,最終濃度如表1中所列示。然後,將試樣在振盪器上混合1分鐘並在室溫下再培育3小時。對於每一分析,在每一分析板上分別納入探針/抗體及蛋白/探針/抗體作為陰性對照及陽性對照。在Envision(Perkin Elmer)上使用340/35nm激發濾波器及520/525(F-Bak肽)及495/510nm(Tb標記之抗組胺酸抗體)發射濾波器量測螢光。下表2中顯示解離常數(Ki)且其係使用王氏方程式(Wang’s equation)(Wang Z.-X.,An Exact Mathematical Expression For Describing Competitive Binding Of Two Different Ligands To A Protein Molecule.FEBS Lett. 1995,360:111-4)來確定。
6-FAM=6-羧基螢光素.;Tb=鋱;GST=麩胱甘肽S轉移酶
然後,將試樣在振盪器上混合1分鐘並在室溫下再培育3小時。對於每一分析,在每一分析板上分別納入探針/抗體及蛋白/探針/抗體作為陰性對照及陽性對照。在Envision(Perkin Elmer)上使用340/35nm激發濾波器及520/525(F-Bak肽)及495/510nm(Tb標記之抗組胺酸抗體)發射濾波器量測螢光。
使用王氏方程式(Wang Zx,An Exact Mathematical Expression For Describing Competitive Binding Of Two Different Ligands To A Protein Molecule.FEBS Lett. 1995,360:111-4)確定化合物之抑制常數(Ki)。倘若化合物之Ki以「<」(小於)某一數值代表,則其意指結合親和力值(例如,對於Bcl-2)低於所用分析之檢測限。表2中顯示本發明化合物之抑制常數(Ki)。
nd=沒有數據
抑制常數(Ki)係酶-抑制劑複合物或蛋白質/小分子複合物之裂解常數,其中小分子抑制一種蛋白質與另一蛋白質或肽之結合。因此,大Ki值指示低結合親和力且小Ki值指示高結合親和力。表2顯示Bak BH3肽探針對Bcl-2蛋白抑制之抑制常數且指示本發明化合物對抗細胞凋亡Bcl-2蛋白具有高結合親和力。因此,預計該等化合物可用於治療表現抗細胞凋亡Bcl-2蛋白之疾病。
使用急性淋巴胚細胞性白血病(ALL)細胞系RS4;11作為人類原代細胞系來評估Bcl-2選擇劑在活體外之細胞活性及其活體內功效。先前研究已藉由BH3譜分析(BH3 profiling,一種對內在細胞凋亡途徑中之阻斷進行分類之線粒體分析)顯示,RS4;11細胞之存活高度依賴於BCL-2且對Bcl-2家族成員抑制劑ABT-737敏感(Blood,2008,第111卷,2300-2309)。Bcl-2在RS4;11中普遍與促細胞凋亡BH3蛋白Bim複合表明,該等細胞係藉由其存活所依賴之抗細胞凋亡蛋白Bcl-2之拮抗來「初免」或因該拮抗而更易於細胞死亡。
在補充有2mM L-麩醯胺酸、10% FBS、1mM丙酮酸鈉、2mM HEPES、1%青黴素(penicillin)/鏈黴素(streptomycin)(Invitrogen)、4.5g/L葡萄糖之RPMI-1640中培養RS4;11細胞並維持在37C與5% CO2下。為測試活體外化合物之細胞活性,將細胞在具有5% CO2之增濕室中在96孔微量滴定板中在存在10%人類血清下以50,000個細胞/孔處理48小時。使用CellTiter Glo(Promega)根據製造商之推薦評估細胞毒性EC50值。EC50值經確定為處理後的活力細胞與未經處理之對照細胞相比之百分比。
表3顯示本發明化合物在細胞情形中在功能上抑制抗細胞凋亡Bcl-2蛋白之效用。已藉由BH3譜分析(一種對內在細胞凋亡途徑中之阻斷進行分類之線粒體分析)顯示急性淋巴胚細胞性白血病(ALL)細胞系RS4;11之存活高度依賴於Bcl-2且對Bcl-2家族成員抑制劑ABT-737敏感(Blood,2008,第111卷,2300-2309)。化合物殺死RS4;11細胞之能力係化合物能夠抑制抗細胞凋亡Bcl-2蛋白功能之直接量度。本發明化合物在殺死RS4;11細胞中極有效,如藉由低EC50值證明。
業內已知對Bcl-2家族蛋白之某些成員之抑制可誘導劑量限制性血小板減少症。人們認為嚴重限制針對自體免疫適應症之一些非選擇性Bcl-2抑制劑之治療使用之劑量限制性血小板減少症係因對Bcl-xL之抑制而起(See Mason,K.D.等人,Programmed anuclear cell death delimits platelet life span.CELL,2007.128(6):第1173頁至第1186頁)。
實施實驗來評價Bcl-2選擇性/Bcl-xL不足之化合物對免疫細胞及血小板之效應,如在C57Bl/6小鼠中所評價。利用化合物(30mg/kg之劑量,每天藉由腹膜內注射投與)將小鼠處理4天,且在第一次及最後一次劑量後24小時利用Cell Dyn血液學分析儀量測細胞數。藉由使用在最後一次劑量後1小時、6小時、10小時及24小時之時間點計算化合物之暴露(曲線下面積)。此實驗之結果闡釋於表4中。
表4. 經1個及4個劑量Bcl-2選擇性抑制劑(30mg/kg)處理之C57BL/6小鼠中之淋巴球減少
nd=淋巴球未減少
該等數據與活體外選擇性特性一致且分別強調Bcl-2對淋巴球及Bcl-xL對血小板存活之基本作用。此藥效動力學研究闡釋該等化合物能夠作為選擇性Bcl-2抑制劑有效減少淋巴球,且沒有與非選擇性Bcl-2抑制劑相關之不利效應。
Claims (18)
- 一種化合物,其係選自由以下組成之群:4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2R)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5R,8R)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-羥基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜螺[4.5]癸-8-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2S)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[4-(羥基甲基)四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-羥基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-氰基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;及4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基環己-1-烯-1-基}甲基)六氫吡嗪-1-基]-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺;或其治療上可接受之鹽。
- 一種組合物,其用於治療膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌或脾臟癌,該組合物包含賦形劑及治療有效量之如請求項1之化合物或其治療上可接受之鹽。
- 一種如請求項1之化合物或其治療上可接受之鹽之用途,其係用於製備用於治療以下疾病之藥物:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌或脾臟癌。
- 一種如請求項1之化合物或其治療上可接受之鹽之用途,其係用於製備用於治療以下疾病之藥物:膀胱癌、腦癌、乳癌、骨髓癌、子宮頸癌、慢性淋巴球性白血病、結腸直腸癌、食道癌、肝細胞癌、淋巴胚細胞性白血病、濾泡性淋巴瘤、T細胞或B細胞源性淋巴樣惡性腫瘤、黑色素瘤、骨髓性白血病、骨髓瘤、口腔癌、卵巢癌、非小細胞肺癌、前列腺癌、小細胞肺癌或脾臟癌,其中該藥物進一步包含其他治療劑或進一步與其他治療劑併用。
- 一種組合物,其用於治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群(Sjogren’s Syndrome),該組合物包含賦形劑及治療有效量之如請求項1之化合物或其治療上可接受之鹽。
- 一種如請求項1之化合物或其治療上可接受之鹽之用途,其係用於製備用於治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之藥物。
- 一種如請求項1之化合物或其治療上可接受之鹽之用途,其係用於製備用於治療全身性紅斑狼瘡、狼瘡性腎炎或修格連氏症候群之藥物,其中該藥物進一步包含其他治療劑或進一步與其他治療劑併用。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[(2S,5R)-5-甲基-1,4-二噁烷-2-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2R)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(3-硝基-4-{[(5R,8R)-1-氧雜螺[4.5]癸-8-基甲基]胺基}苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-羥基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({4-[(1,4-二氧雜螺[4.5]癸-8-基甲基)胺基]-3-硝基苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(2S)-1,4-二噁烷-2-基甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-{[4-({[4-(羥基甲基)四氫-2H-吡喃-4-基]甲基}胺基)-3-硝基苯基]磺醯基}-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(3-羥基氧雜環丁-3-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-[(4-{[(4-氰基四氫-2H-吡喃-4-基)甲基]胺基}-3-硝基苯基)磺醯基]-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-(4-{[2-(4-氯-2-氟苯基)-4,4-二甲基環己-1-烯-1-基]甲基}六氫吡嗪-1-基)-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
- 一種化合物,其係4-[4-({2-[4-(二氟甲基)苯基]-4,4-二甲基環己-1-烯-1-基}甲基)六氫吡嗪-1-基]-N-({3-硝基-4-[(四氫-2H-吡喃-4-基甲基)胺基]苯基}磺醯基)-2-(1H-吡咯并[2,3-b]吡啶-5-基氧基)苯甲醯胺或其治療上可接受之鹽。
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