TWI770246B - 新穎化合物及包含其之醫藥組成物 - Google Patents
新穎化合物及包含其之醫藥組成物 Download PDFInfo
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Abstract
Description
本揭露係關於可抑制癌細胞生長之化合物、包含該化合物之醫藥組成物、以及該化合物或組成物之用途。
近年來,食品或食品添加劑以及環境污染已經成為促進癌症的原因或催化劑。並非巧合,相同的事件也發生在已開發國家和全世界,此為一讓人擔憂的跡象,即癌症的發病率極高。根據美國癌症協會(American Cancer Society)公布的數據,癌症被證明是對公眾健康最重大的威脅。
一般用於治療癌症的方法包含手術、放療、化療和免疫療法。近年來,幾個治療劑的開發已透過新的抗癌機制來治療癌症,且已經證明用這些治療劑治療可以增加患者的存活率。通常,治療劑可以透過抑制細胞週期行進(cell cycle progression)、血管生成(angiogenesis)、法尼基轉移酶(farnesyl transferase)和酪胺酸激酶(tyrosine kinases)來治療癌症。
雖然已經知道某些試劑對癌症存在治療效果,但這些試劑有其侷限。例如「吉非替尼(Gefitinib)」為用於抑制非小細胞肺癌(non-small cell lung cancer)的藥物,但在大多數情況下其不能治癒。此外,他對阻斷乳癌和結腸直
腸癌(colorectal cancer)的行進沒有效果。此外,抗癌藥物的治療效果也取決於腫瘤細胞的位置、患者的遺傳變異(genetic variation)以及藥物的副作用。此外,癌細胞可能變成惡性並通過淋巴系統(lymphatic system)或血流(bloodstream)從其原始位置擴散至標的位置,從而產生轉移性癌症(metastatic cancer)。
由於發展癌症的風險一般隨著年齡增加,隨著更多人活到老年和大規模生活方式的改變,癌症的發生率上升。因此,開發治療和預防癌症之新藥劑係長久以來之需求。
本揭露係關於可以抑制癌細胞生長的特定化合物。
在此式中,Z1為N或C-R2;Z2為C或N;以及Z3為N或C-X-R1,但條件為Z1、Z2和Z3中不超過兩個為N。X為一直接鍵結、-(CH2)n-、-O-、-NRa-、-(C=O)NH-或-(C=O)-,其中,n為1、2或3,且Ra為氫或烷基。Y為-CH-、-NRb-、O或S,其中,Rb為氫或烷基。L為一直接鍵結、-(CH2)m-或-NH-,其中,m為1、2或3。R1為氫、鹵素、氰基、烷基、烷氧基、環烷基、雜環烷基、芳基、或雜芳基,其中,烷氧基、環烷基、雜環烷基、芳基、和雜芳基各自選擇性地以一至三個選自由鹵素、羥基、硝基、氰基、-NRcRd、低烷基胺甲醯基(lower alkyl carbamoyl)、雜環烷基、選擇性地被一至三個鹵素或芳基取代之烷基、和選擇性
地被一至三個鹵素、烷氧基、環烷基、雜環烷基、-NReRf、或芳基取代之烷氧基所組成之群組之基團取代,其中,Rc、Rd、Re和Rf各自獨立為氫或烷基。R2為氫、鹵素、烷基、烷氧基、環烷基、雜環烷基、芳基、或雜芳基,其中,烷氧基、環烷基、雜環烷基、芳基、和雜芳基各自選擇性地以一至三個選自由鹵素、羥基、硝基、氰基、-NRgRh、低烷基胺甲醯基(lower alkyl carbamoyl)、炔基、選擇性地被一至三個鹵素取代之烷基、和選擇性地被一至三個鹵素或烷氧基取代之烷氧基所組成之群組之基團取代,其中,Rg、Rh各自獨立為氫或烷基。R3為
或,其中,M為O或S。以及R4為氫或烷基。
在此,術語「烷基」是指直鏈或支鏈的烴基團,包含1-12個碳原子(例如C1-C10、C1-C8和C1-C6)。例子包含甲基、乙基、正丙基、異丙基、正丁基、異丁基和叔丁基。
在此,術語「炔基」是指直鏈或支鏈的一價或二價烴包含2-20個碳原子(例如C2-C16、C2-C12、C2-C8、C2-C6和C2-C4)和一或多個三鍵。炔的例子包含但不限於乙炔基、亞乙炔基、1-丙炔基、1-和2-丁炔基、以及1-甲基2-丁炔基。
術語「環烷基」是指飽和及部分不飽和且具有3-12個(例如3-10個和3-7個)碳原子的單環、雙環、三環、或四環烴基團。例子包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、和環辛基。
術語「雜環烷基」是指非芳香族的5-8員單環、8-12員雙環、或11-14員三環的環系統,其具有一或多個雜原子(例如O、N、P、和S)。例子包含哌嗪基(piperazinyl)、咪唑啶基(imidazolidinyl)、氮雜環庚基(azepanyl)、吡咯啶基
(pyrrolidinyl)、二氫噻二唑基(dihydrothiadiazolyl)、二氧環己基(dioxanyl)、嗎啉基(morpholinyl)、四氫吡喃基(tetrahydropuranyl)、和四氫呋喃基。
術語「烷氧基」是指-O-烷基基團。例子包含甲氧基、乙氧基、丙氧基、和異丙氧基。
術語「鹵素」是指氟、氯、溴、或碘之自由基。
術語「胺基」是指衍生自胺的基團,其為未經取代或經烷基、芳基、環烷基、雜環烷基、或雜芳基單-/雙-取代之基團。
術語「芳基」是指6-碳單環、10-碳雙環、14-碳三環的芳香環系統。芳基基團的例子包含苯基、萘基、和蒽基(anthracenyl)。
術語「雜芳基」是指芳香族的5-8元單環、8-12元雙環、或11-14元三環的環系統,其具有一或多個雜原子(例如O、N、P、和S)。例子包含苯硫基(thiophenyl)、三唑基(triazolyl)、噁唑基(oxazolyl)、噻二唑基(thiadiazolyl)、四唑基(tetrazolyl)、吡唑基(pyrazolyl)、吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯並咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、噻吩基(thienyl)、喹啉基(quinolinyl)、吲哚基(indolyl)、噻唑基(thiazolyl)、和苯並噻唑基(benzothiazolyl)。
術語「低烷基胺甲醯基(lower alkyl carbamoyl)」是指-N(烷基)2-C(=O)-O-基團,其中,烷基是指直鏈或支鏈包含1-4個碳原子的烴基團,例如甲基或乙基。
在此提及的烷基、環烷基、雜環烷基、烷氧基、芳基、和雜芳基包含經取代及未經取代的部分。環烷基、雜環烷基、烷氧基、芳基、和雜芳基上可能的取代基包含但不限於C1-6之烷基、C2-6之烯基、C2-6之炔基、C3-12之環烷
基、C3-12之環烯基、C1-12之雜環烷基、C1-12之雜環烯基、C1-6之烷氧基、芳基、芳氧基(aryloxy)、雜芳基、雜芳氧基(heteroaryloxy)、胺基、C1-6之烷基胺基、C1-20之二烷基胺基、芳基胺基、二芳基胺基、C1-6之烷基磺胺基(alkylsulfonamino)、芳基磺胺基(arylsulfonamino)、C1-6之烷基亞胺基(alkylimino)、芳基亞胺基(arylimino)、C1-6之烷基磺亞胺基(alkylsulfonimino)、芳基磺亞胺基(arylsulfonimino)、羥基、鹵素、硫基、C1-6之烷硫基(alkylthio)、芳硫基(arylthio)、C1-6之烷基磺醯基(alkylsulfonyl)、芳基磺醯基(arylsulfonyl)、醯胺基(acylamino)、胺醯基(aminoacyl)、胺基硫醯基(aminothioacyl)、醯胺基(amido)、脒基(amidino)、胍基(guanidine)、脲基(ureido)、硫脲基(thioureido)、氰基、硝基、亞硝基(nitroso)、疊氮基(azido)、醯基(acyl)、硫醯基、醯氧基(acyloxy)、羧基、和羧酸酯。另一方面,烷基可能的取代基除了C1-6之烷基外包含所有上述取代基。環烷基、雜環烷基、芳基、和雜芳基也可以彼此稠合。
除了上述式(I)之化合物外,在可應用的情況下,其藥學上可接受的鹽類和溶劑合物也包含在本揭露中。鹽類可由陰離子與在化合物上的正電荷基團(例如胺基)之間形成。合適的陰離子之例子包含氯化物、溴化物、碘化物、硫酸鹽、硝酸鹽、磷酸鹽、檸檬酸鹽、甲磺酸鹽(methanesulfonate)、三氟乙酸鹽,乙酸鹽,蘋果酸鹽(malate)、甲苯磺酸鹽(tosylate)、酒石酸鹽(tartrate)、富馬酸鹽(fumurate)、麩胺酸鹽(glutamate)、葡萄糖醛酸鹽(glucuronate)、乳酸鹽、戊二酸鹽、和順丁烯二酸鹽(maleate)。鹽類也可由陽離子與負電荷基團之間形成。合適的陽離子之例子包含鈉離子、鉀離子、鎂離子、鈣離子、和銨陽離子,如四甲基銨離子(tetramethylammonium ion)。鹽類更包含那些含有四級氮原子的化合物。溶劑合物是指在活性化合物與藥學上可接受的溶劑之間所形成的複合物。
藥學上可接受的溶劑之例子包含水、乙醇、異丙醇、乙酸乙酯、乙酸、和乙醇胺。
本揭露之另一態樣為用於治療癌症的醫藥組成物。
醫藥組成物包含上述式(I)之化合物之一者或其藥學上可接受的鹽類以及藥學上可接受之載體、賦形劑或稀釋劑。
本揭露也涵蓋這種組成物用於製造治療癌症的藥物的用途。
用於口服給予的組成物可以是任何口服可接受的劑型,包括膠囊、片劑、乳劑、和水性懸浮液、分散劑、和溶液劑。在片劑的情況下,常用的載體包括乳糖和玉米澱粉。通常也加入潤滑劑,例如硬脂酸鎂。對於以膠囊形式口服給藥,有用的稀釋劑包括乳糖和乾燥的玉米澱粉。當以水性懸浮液或乳劑口服給藥時,活性成分可以懸浮或溶解於與乳化劑或懸浮劑結合的油相中。若有需要,可添加某些甜味劑、調味劑或著色劑。口服固體劑型可以藉由噴霧乾燥技術、熱熔擠出方法、微粉化(micronization)、和奈米研磨技術(nano milling technologies)來製備。
鼻用噴霧劑(nasal aerosol)或吸入劑(inhalation)組成物可根據藥物製劑領域已知的技術來製備。舉例來說,可以採用苯甲醇或其他合適的防腐劑(preservative)、吸收促進劑(absorption promoter)、氟碳化合物(fluorocarbon)、和/或其他本領域已知的助溶劑或分散劑將這種組成物製備為鹽水溶液。具有活性化合物的組成物也可以以用於直腸給藥的塞劑(suppository)劑型給予。
在醫藥組成物中的載體、賦形劑和稀釋劑必須為「可接受的」,意思是其可以與組成物的活性成分相容(且較佳地為能夠穩定活性成分),並且對受試者無害。一或多種助溶劑可以作為用於傳遞活性化合物的藥物賦形劑。其
他載體的例子包括膠體氧化矽(colloidal silicon oxide)、硬脂酸鎂、纖維素、十二烷基硫酸鈉(sodium lauryl sulfate)、和D&C黃色#10。
用於治療癌症的方法仍包含在本揭露的範圍內。
該方法包含向有需要的受試者施予一有效劑量的式(I)化合物或其藥學上可接受的鹽類。
上述化合物或含有他們中的一或多種的醫藥組成物可以通過口服、腸胃外(parenterally)、經由吸入噴霧(inhalation spray)、局部、直腸、鼻腔、口頰(buccally)、或經由植入的儲存器(implanted reservoir)向受試者給藥。在此,術語「腸胃外」是指包含皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、肌內(intramuscular)、關節內(intraarticular)、動脈內(intraarterial)、滑腔內(intrasynovial)、胸骨內(intrasternal)、鞘膜內(intrathecal)、病灶內(intralesional)、和顱內注射(intracranial injection)或輸液技術(infusion techniques)。
術語「治療」是指為了治癒、緩解、緩和、改變、補救、改善、或影響疾病、症狀、或傾向(predisposition)之目的,向受試者施用或施予該化合物。「有效劑量」是指在受試者獲得期望效果所需要的化合物含量。如習知技術者所知,有效劑量會根據給藥途徑、賦形劑的使用、和其他治療處理(例如使用其他活性劑)共同使用的可能性而變化。
在下面的描述中闡述了本揭露的一或多個實施例的細節。本揭露的其他特徵、目的、和優點可自說明書和請求項明顯得知。
其中,取代基L、R3、R4、Y、Z1、Z2、及Z3各自如在發明內容中之定義。
本揭露之第四實施例為第一至第三實施例之任一者之化合物或其藥學上可接受之鹽類,其中,X為一直接鍵結。
本揭露之第六實施例為第一至第五實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R1為芳基或雜芳基,其中,芳基和雜芳基各自選擇性地以一至三個選自由鹵素、羥基、硝基、氰基、-NRcRd、低烷基胺甲醯基、雜環烷基、選擇性地被一至三個鹵素或芳基取代之烷基、和選擇性地被一至三個鹵素、烷氧基、環烷基、雜環烷基、-NReRf、或芳基取代之烷氧基所組成之群組之基團取代,其中,Rc、Rd、Re和Rf各自獨立為氫、甲基或乙基。
本揭露之第七實施例為第一至第六實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R1為苯基或吡啶基,其中,苯基或吡啶基各自選擇性地被一至三個烷氧基取代,所述烷氧基選擇性地被一至三個鹵素、烷氧基、環烷基、雜環烷基、-NeRf或芳基取代,其中,Rc、Rd、Re和Rf各自獨立為氫、甲基或乙基。
本揭露之第八實施例為第一至第七實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R4為氫或甲基。
本揭露之第九實施例為第一至第八實施例之任一者之化合物或
其藥學上可接受之鹽類,其中L為-CH2-;R3為;R4為氫或甲基;
以及R1為苯基或吡啶基,其中,苯基或吡啶基各自選擇性地以一或兩個乙氧基、丁氧基、被乙氧基取代之甲氧基、或被二甲基胺基取代之乙氧基取代。
本揭露之第十一實施例為第一、第二和第十實施例之任一者之化合物或其藥學上可接受之鹽類,其中,X為一直接鍵結、-CH2-、-O-、-N(CH3)-、-(C=O)NH-、或-(C=O)-。
本揭露之第十四實施例為第一、第二、第十至第十三實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R1為氫、鹵素、氰基、烷氧基、芳基、或雜芳基,其中,芳基和雜芳基各自選擇性地以一至三個選自由鹵素、羥基、硝基、氰基、-NRcRd、低烷基胺甲醯基(lower alkyl carbamoyl)、雜環烷基、選擇性地被一至三個鹵素或芳基取代之烷基、和選擇性地被一至三個鹵素、烷氧基、環烷基、雜環烷基、-NReRf或芳基取代之烷氧基所組成之群組之基團取代,其中,Rc、Rd、Re和Rf各自獨立為氫、甲基或乙基。
本揭露之第十五實施例為第一、第二、第十至第十四實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R1為苯基,所述苯基選擇性地以一至三個選自由鹵素、和選擇性被一至三個鹵素取代之烷基所組成之群組之基團取代。
本揭露之第十六實施例為第一、第二、第十至第十五實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R2為芳基或雜芳基,其中,芳基和雜芳基各自選擇性地以一至三個選自由鹵素、硝基、氰基、低烷基胺甲醯基(lower alkyl carbamoyl)、炔基、選擇性地被一至三個鹵素取代之烷基、和選擇性地以一至三個鹵素或烷氧基取代之烷氧基所組成之群組之基團取代。
本揭露之第十七實施例為第一、第二、第十至第十六實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R2為苯基,所述苯基選擇性地
以一至三個選自由鹵素、選擇性地被一至三個鹵素取代之烷基、和烷氧基所組成之群組之基團取代。
本揭露之第十八實施例為第一、第二、第十至第十七實施例之任一者之化合物或其藥學上可接受之鹽類,其中,R4為氫或甲基。
本揭露之第十九實施例為第一、第二、第十至第十八實施例之任一者之化合物或其藥學上可接受之鹽類,其中,X為-O-;L為一直接鍵結;R3
為,其中M為S;R4為氫;R1為苯基,所述苯基選擇性地以氟、三級
戊基(tert-pentyl)、或三氟甲基取代;以及R2為被乙氧基、丁氧基、氟、叔丁基、三級戊基、或三氟甲基取代之苯基。
本揭露之第二十實施例為第一、第二、第十至第十八實施例之任一者之化合物或其藥學上可接受之鹽類,其中,X為一直接鍵結;L為一直接鍵
結;R3為,其中M為S;R4為氫;R1為苯基,所述苯基選擇性地以一
或兩個氟取代;以及R2為被叔丁基或三級戊基取代之苯基。
本揭露之第二十一實施例為一化合物,其選自由化合物1-1至1-37、化合物2-1至2-4、化合物3-1至3-14、化合物4-1至4-4、化合物5-1至5-108、和化合物6-1至6-61所組成之群組,其列於下表1至6中。
本揭露的化合物可以含有不對稱或手性中心,並以不同的立體異構物形式存在。除非另有說明,本揭露的化合物的所有立體異構物形式以及其混合物、包含外消旋混合物,皆在本揭露的範圍內。此外,本揭露的化合物也可以不同的幾何或位置異構物存在。例如順式-和反式-兩種形式,以及具有雙鍵或稠合環的化合物的混合物也在本揭露的範圍內。
非鏡像異構混合物(diastereomeric mixtures)可以任何方法,例如藉由層析法(chromatography)和/或分段結晶法(fractional crystallization)分離成他們各自的非鏡像異構物。鏡像異構物可經由使用手性HPLC管柱、或藉由與適當的光學活性化合物反應,將鏡像混合物轉換成非鏡像混合物,以分離非鏡像異構物,並將各個非鏡像異構物轉換成純的鏡像異構物。特定的立體異構物可以通過不對稱轉變(asymmetric transformation)、通過使用光學活性起始物、或通過使用光學活性試劑、催化劑、作用物(substrate)或溶劑之不對稱合成,將一種立體異構物轉換成另一種立體異構物。
本揭露亦包括一醫藥組成物,包含:(1)本揭露之化合物或其藥學上可接受之鹽類;以及(2)藥學上可接受之載體、賦形劑或稀釋劑。該組成物也可包含至少一種額外的藥劑,例如抗癌劑。本揭露之化合物或其藥學上可接受之鹽類或組成物可以用於製備抑制腫瘤細胞生長或治療癌症的藥物。
本揭露另包括一用於治療癌症之方法,其包含向有需要的受試者施予一有效劑量的本揭露之化合物或其藥學上可接受之鹽類的步驟。
本揭露更涵蓋一抑制腫瘤細胞生長的方法,其包含向有需要的受試者施予一有效劑量的本揭露之化合物或其藥學上可接受之鹽類的步驟。
在本揭露中,上述的受試者可以是哺乳動物,例如人類。
在本揭露中,本揭露之化合物或其藥學上可接受之鹽類可以抑制腫瘤細胞的生長,以達到治療癌症的目的。癌症的例子包含但不限於胃癌、大腸癌、結直腸癌、乳癌、肺癌、前列腺癌、膀胱癌、胰腺癌、肝癌、子宮癌、子宮頸癌、子宮內膜癌、食道癌、白血病、淋巴瘤、腎癌、骨肉瘤、卵巢癌、皮膚癌、小腸癌、胸腺癌、甲狀腺癌、神經系癌、骨癌、腦癌、或頭頸部癌。
本揭露之化合物或其藥學上可接受之鹽類可以與至少一種額外的藥學試劑例如抗癌劑合併施用。施用製劑可以是例如(a)包含本揭露之化合物或其藥學上可接受之鹽類、藥學上可接受之載體、賦形劑或稀釋劑,以及至少一種額外的藥學試劑的單一製劑;或(b)兩種製劑同時或以任何順序依序施用,其中,一種製劑包含本揭露之化合物或其藥學上可接受之鹽類、藥學上可接受之載體、復形劑、或稀釋劑,以及另一種包含至少一種額外的藥學試劑。
合適的抗癌劑可包含賀癌平(Herceptin)、利妥昔單抗(Rituximab)、歐洲紫杉醇(Docetaxel)、卡西他濱(Capecitabine)、西妥昔單抗(Cetuximab)、吉非替尼(Gefitinib)、程序性死亡蛋白(PD-1)、甲苯磺酸索拉非尼(Sorafenib tosylate)或伊馬替尼(Imatinib),但本揭露並不局限於此。本領域已知的任何其他抗癌劑也可以用於本揭露中。
用於合成式(I)之化合物的方法為本領域已知的。參見例如R.Larock,Comprehensive Organic Transformations(2nd Ed.,VCH Publishers 1999);P.G.M.Wuts and T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4th Ed.,John Wiley and Sons 2007);L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994);L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(2nd ed.,John Wiley and Sons 2009);P.Roszkowski,J.K.Maurin,Z.Czarnocki“Enantioselective synthesis of(R)-(-)-praziquantel(PZQ)”Tetrahedron:Asymmetry 17(2006)1415-1419;和L.Hu,S.Magesh,L.Chen,T.Lewis,B.Munoz,L.Wang“Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators,”WO2013/067036。
由此製備的式(I)化合物可以使用體外測定法,例如NCI-60篩選平台(screening platform)或MTS方法進行初步篩選,隨後可以使用本領域已知的
體內測定法依序評估他們。所選擇的化合物可以進一步測試以確認他們在疾病相關功效和不良反應模型(adverse effects models)中的功效。根據結果,可以確定適當的劑量範圍和施用途徑。
以下實施例可以清楚地表現出本揭露的上述和其他技術內容、特徵和/或效果。通過具體實施例的說明,習知技術者將更進一步了解本揭露所採用的技術手段和效果,以達到上述目的。此外,在此揭露的內容應易於理解,且可被習知技術者實施,不背離本揭露之概念的所有等同的變化或修飾應被申請專利範圍所包括。
實施例
習知技術者可以基於以上描述最大程度地利用本揭露,而無須進一步詳述。以下具體實施例,即實施例1-6應被解釋為僅僅是說明性,而不以任何方式限制本揭露的其餘部分。本文所引用的所有出版物都通過引用整體併入。
在具體的實施例中(實施例1至6)闡述了用於製備某些中間物和228種例示性式(I)之化合物的方法,以及因此製備的化合物的分析數據;且實施例7及實施例8闡述了用於測試這些化合物的方法。
以下描述用於合成本揭露之例示性化合物的步驟。
除非另有說明,所有使用的起始物均可由商業購得,並按照提供使用。需要無水條件的反應在火焰乾燥的(flame-dried)玻璃器皿中進行,並在氬氣或氮氣氣氛下冷卻。除非另有說明,否則反應在氬氣或氮氣下進行並藉由塗覆有矽膠(Merck,60 F254)的玻璃背板(5cm_10cm)以分析薄膜層析法監測,以及在紫外燈(λ=254nm)下觀察所得色譜影像,接著浸入含有乙酸(3%v/v)之茚三酮(Ninhydrin,0.3%w/v)的正丁醇溶液或磷鉬酸(2.5%w/v)的乙醇溶液中,並以熱風槍(heat gun)吹。用於反應的溶劑在使用前如下在氬氣或氮氣下乾燥,四氫呋
喃、甲苯、和二氯甲烷通過乾燥的分子篩(5A,LC technology solution Inc)的管柱乾燥。以氫化鈣乾燥的或無水的N,N-二甲基甲醯胺(DMF)是商業可購得的。以常規使用急速管柱層析(RediSep Rf矽膠一次性急速管柱,Gold® 20-40/40-60微米矽膠和可重複使用的RediSep Rf Gold® C18逆相管柱,20-40微米,由RediSep提供)純化和分離產物混合物。沖提系統為體積/體積濃度。以Bruker AVIII(400MHz)記錄13C和1H NMR光譜。使用氯仿-d或二甲基氬碸-d6和CD3OD作為溶劑,TMS(δ 0.00ppm)作為內標。化學位移值以δ單位相對於TMS以ppm表示。多重性記錄為s(單峰),br s(寬單峰),d(二重峰),t(三重峰),q(四重峰),dd(雙二重峰(doublet of doublet)),dt(雙三重峰(doublet of triplet)),m(多重峰)。偶合常數(J)以Hz表示。使用Thermo LTQ XL質譜儀記錄電灑質譜(ESMS)。光譜數據紀錄為m/z值。
在製備本發明的化合物中,中間體的偏遠官能基(例如一級或二級胺)的保護可能是必須的,對這種需保護的需求可能根據偏遠官能基的性質和製備方法的條件而不同。合適的胺基保護基團(amino protecting groups,NHPg)包含例如乙醯基、三氟乙醯基、叔丁氧基羰基(t-butoxycarbonyl,BOC)、9-茀基亞甲基氧基羰基(9-fluorenylmethyleneoxycarbonyl,Fmoc)、和苯甲氧基羰基(benzyloxycarbonyl,CBz)。相似地,「羥基保護基團」是指阻斷或保護羥基官能基的羥基基團的取代基,合適的羥基保護基團(hydroxyl protecting groups,OPg)包含例如烯丙基、乙醯基、矽基、苯甲基、對甲氧基苯甲基(paramethoxy benzyl)、三苯甲基(trityl)等。習知技術者很容易確認這種保護的需要。
實施例1之化合物的典型合成方法
5-(3-乙氧基苯基)-1,3,4-噻二唑-2-胺(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-amine)的合成
取3-乙氧基苯甲酸(2.38g,10mmol)和硫胺脲(thiosemicarbazide,1.37g,15mmol)及三氯氧磷(phosphorus oxychloride,5mL)的混合物溫和回流2小時。冷卻後加入水(50mL),並將混合物再次回流7小時後過濾,以50%氫氧化鉀中和。以水洗沉澱物並用乙醇再結晶,以獲得標題產物(1.22g,55%)。
(6-(2-((5-(3-乙氧基苯基)-1,3,4-噻二唑-2-基)胺基)-2-側氧基乙基)苯並[d]噻唑-2-基)胺基甲酸叔丁酯(tert-butyl(6-(2-((5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate)的合成
取5-(3-乙氧基苯基)-1,3,4-噻二唑-2-胺(0.44g,2mmol)和羥基苯並三唑(HOBt,0.27g,2mmol)、1-乙基-(3-二甲基氨基丙基)碳醯二亞胺(EDCI,0.46g,2.4mmol)、2-(2-((叔丁氧基羰基)胺基)苯並[d]噻唑-6-基)乙酸(2-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)acetic acid,0.74g,2.4mmol)溶於乾燥的二甲基甲醯胺(DMF,12mL),反應在室溫下攪拌至隔夜後加入水,以水洗沉澱物並用甲醇再結晶,以獲得標題產物(0.75g,73%)。
Synthesis of 2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-乙氧基苯基-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)的合成
在室溫下,向溶於無水二氯甲烷(15mL)的2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide,0.75g,1.46mmol)的劇烈攪拌的溶液中加入三氟乙酸(1.5mL,20mmol)並攪拌至隔夜。藉由逐滴加入的碳酸鈉溶液中和過量的三氟乙酸直到pH=10。以水和甲醇洗沉澱物後,進一步藉由矽膠急速管柱層析法(以二氯甲烷和甲醇做為沖提液)純化,並濃縮以獲得白色固體(0.95g,65%)。
實施例1:化合物1-1至1-37
化合物1-1
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.88(br.s.,1 H),7.61(d,J=1.96Hz,1 H),7.36-7.49(m,6 H),7.29(d,J=7.82Hz,1 H),7.18(dd,J=8.31,1.96Hz,1 H),7.02-7.10(m,1 H),4.10(q,J=6.85Hz,2 H),3.84(s,2 H),1.35(t,J=6.85Hz,4 H).MS(M+1):412.
化合物1-2
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)-1,3,4-噻二唑-2-yl)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.76(s,1H),7.80-7.87(m,2H),7.60(d,J=1.96Hz,1H),7.41(s,2H),7.28(d,J=8.31Hz,1H),7.17(dd,J=8.31,1.96Hz,1H),7.02-7.10(m,2H),4.09(q,J=7.01Hz,2H),3.83(s,2H),1.34(t,J=7.09Hz,3H).MS(M+1):412
化合物1-3
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-羥基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.61(br.s.,1H),8.26(dd,J=8.1,1.2Hz,1H),7.44-7.52(m,1H),7.22(d,J=8.3Hz,1H),7.10(t,J=7.6Hz,1H),6.92(s,1H),6.87(d,J=7.8Hz,1H),6.80(d,J=7.8Hz,1H),5.98(s,2H),4.26(q,J=6.8Hz,2H),3.74(s,2H),1.45(t,J=6.8Hz,3H).MS(M+1):384.
化合物1-4
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-硝基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 13.01(s,1H),8.04-8.08(m,1H),7.82-7.89(m,2H),7.59-7.63(m,2H),7.29(d,J=8.3Hz,2H),7.15-7.21(m,2H),3.86(s,2H).MS(M+1):413
化合物1-5
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 13.02(s,1H),8.14(d,J=7.8Hz,2H),7.87(d,J=8.3Hz,3H),7.65(d,J=2.0Hz,1H),7.60(br.s.,2H),7.32(d,J=7.8Hz,1H),3.88(s,2H).MS(M+1):436.
化合物1-6
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-甲氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.69(s,1H),8.26(dd,J=7.8,1.5Hz,1H),7.41(td,J=7.6,1.0Hz,2H),7.22-7.33(m,2H),7.07-7.22(m,2H),3.94-4.01(m,4H),3.83(s,2H).MS(M+1):398
化合物1-7
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-溴苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.91(s,1H),7.87(d,J=8.3Hz,2H),7.68-7.76(m,2H),7.60(s,1H),7.42(s,2H),7.28(d,J=8.3Hz,1H),7.17(d,J=7.8Hz,1H),3.84(s,2H).MS(M+1):446
化合物1-8
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-硝基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 13.06(br.s.,1H),8.31-8.41(m,2H),8.18-8.27(m,2H),7.61(d,J=1.5Hz,1H),7.42(s,2H),7.29(d,J=8.3Hz,1H),7.18(dd,J=8.3,1.5Hz,1H),3.86(s,2H).MS(M+1):413.
化合物1-9
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-(二甲基胺基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(dimethylamino)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.67(s,1H),7.68-7.74(m,2H),7.60(d,J=1.5Hz,1H),7.42(s,2H),7.28(d,J=8.3Hz,1H),7.17(dd,J=8.1,1.7Hz,1H),6.75-6.81(m,J=8.8Hz,2H),3.81(s,2H),2.98(s,6H).MS(M+1):411
化合物1-10
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-propoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.66(s,1H),8.28(dd,J=7.8,2.0Hz,1H),7.61(d,J=1.5Hz,1H),7.48(td,J=7.8,2.0Hz,1H),7.43(s,2H),7.29(d,J=8.3Hz,1H),7.15-7.26(m,2H),7.10(t,J=7.6Hz,1H),4.17(t,J=6.6Hz,2H),3.83(s,2H),1.79-1.92(m,2H),1.06(t,J=7.6Hz,3H).MS(M+1):426.
化合物1-11
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(三氟甲氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.95(s,1H),8.27-8.33(m,1H),7.67(d,J=6.8Hz,1H),7.56-7.64(m,3H),7.42(s,2H),7.26-7.32(m,1H),7.19(d,J=2.0Hz,1H),3.86(s,2H).MS(M+1):452.
化合物1-12
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-碘苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.92(br.s.,1H),7.86-7.91(m,2H),7.69-7.73(m,2H),7.60(d,J=2.0Hz,1H),7.43(s,2H),7.28(d,J=8.3Hz,1H),7.17(dd,J=8.3,1.5Hz,1H),3.80-3.87(m,2H).MS(M+1):494
化合物1-13
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-溴-3-硝基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromo-3-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 13.04(s,1H),8.55(d,J=2.0Hz,1H),8.12(dd,J=8.3,2.0Hz,1H),8.05(d,J=8.3Hz,1H),7.61(d,J=1.5Hz,1H),7.46(s,2H),7.29(d,J=8.3Hz,1H),7.18(dd,J=8.3,2.0Hz,1H),3.86(s,2H).MS(M+1):491.
化合物1-14
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-異丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.80(s,1H),7.86(br.s.,2H),7.76-7.85(m,2H),7.65(d,J=1.5Hz,1H),7.31(dd,J=8.6,4.6Hz,1H),7.22(dd,J=8.3,1.5Hz,1H),6.99-7.08(m,2H),4.69(spt,J=6.0Hz,1H),3.84(s,2H),1.35(s,3H),1.22(s,3H).MS(M+1):460
化合物1-15
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-異丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.67(s,1H),8.28(dd,J=8.0,1.6Hz,1H),7.86(br,2H),7.66(d,J=1.6Hz,1H),7.49-7.44(m,1H),7.32(d,J=8.4Hz,1H),7.26-7.21(m,2H),7.10-7.06(m,1H),4.90(quin,J=6.0Hz,1H),3.85(s,2H),1.37(d,J=6.0Hz,6H).MS(M+1):426.
化合物1-16
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-(戊-3-基氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(pentan-3-yloxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):812.80(s,1H),7.81(d,J=8.8Hz,2H),7.80(br.s.,2H),7.64(d,J=1.5Hz,1H),7.31(d,J=8.3Hz,1H),7.21(dd,J=8.3,1.5Hz,1H),7.05(d,J=8.8Hz,2H),4.32(quin,J=5.7Hz,1H),3.84(s,2H),1.56-1.72(m,2H),0.90(t,J=7.6Hz,3H).MS(M+1):454.
化合物1-17
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-propoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.78(br.s.,1H),7.80-7.86(m,J=8.8Hz,2H),7.64-7.68(m,1H),7.33(d,J=7.8Hz,1H),7.23(dd,J=8.1,1.2Hz,1H),7.02-7.08(m,J=8.8Hz,2H),3.99(t,J=6.6Hz,2H),1.69-1.79(m,2H),1.51(s,2H),0.98(t,J=7.3Hz,3H).MS(M+1):440.
化合物1-18
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4-二乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺
(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.61(s,1H),8.32(br.s.,2H),8.16(d,J=8.8Hz,1H),7.70(d,J=1.5Hz,1H),7.35(d,J=8.3Hz,1H),7.27(dd,J=8.1,1.7Hz,1H),6.65-6.75(m,2H),4.24(q,J=6.8Hz,2H),4.11(q,J=7.2Hz,2H),3.85(s,2H),1.43(t,J=6.8Hz,3H),1.34(t,J=6.8Hz,3H).MS(M+1):456.
化合物1-19
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-羥基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.77(s,1H),8.19(br.s.,2H),7.73(d,J=8.8Hz,2H),7.68(s,1H),7.30-7.40(m,1H),7.21-7.30(m,1H),6.68(d,J=8.8Hz,2H),3.85(s,2H).MS(M+1):384.
化合物1-20
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丁氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-butoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.71(s,1H),8.42(br.s.,2H),8.27(dd,J=7.8,2.0Hz,1H),7.72(s,1H),7.44-7.53(m,1H),7.34-7.40(m,1H),7.27-7.34(m,1H),7.23(d,J=8.3Hz,1H),7.10(t,J=7.6Hz,1H),4.21(t,J=6.4Hz,2H),3.87(s,2H),1.77-1.88(m,2H),1.52(sxt,J=7.4Hz,2H),0.94(t,J=7.6Hz,3H).MS(M+1):440.
化合物1-21
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-丁氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-butoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.81(br.s.,1H),11.71(br.s.,1H),7.88(s,1H),7.80-7.85(m,J=8.8Hz,2H),7.63(d,J=8.3Hz,1H),7.36(dd,J=8.3,1.5Hz,1H),7.01-7.07(m,J=8.8Hz,2H),4.02(t,J=6.6Hz,2H),3.93(s,1H),1.51(s,7H),0.93(t,J=7.3Hz,3H).MS(M+1):440.
化合物1-22
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(戊-3-基氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(pentan-3-yloxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.71(br.s.,1H),9.15(br.s.,2H),8.29(dd,J=7.8,1.5Hz,1H),7.79(s,1H),7.41-7.48(m,2H),7.33-7.39(m,1H),7.24(d,J=8.3Hz,1H),7.06(t,J=7.6Hz,1H),4.58(t,J=5.6Hz,1H),3.90(s,2H),1.67-1.76(m,4H),0.89(t,J=7.3Hz,6H).MS(M+1):454
化合物1-23
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丁氧基-4-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-butoxy-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.57(s,1H),8.16(d,J=8.8Hz,1H),7.79(br.s.,2H),7.65(d,J=1.5Hz,1H),7.31(d,J=7.8Hz,1H),7.22(dd,J=8.3,1.5Hz,1H),6.72(d,J=2.0Hz,1H),6.68(dd,J=8.6,2.2Hz,1H),4.19(t,J=6.6Hz,2H),4.11(q,J=6.8Hz,2H),3.83(s,2H),1.75-1.88(m,2H),1.47-1.56(m,2H),1.34(t,J=7.1Hz,3H),0.94(t,J=7.6Hz,3H).MS(M+1):484.
化合物1-24
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4,6-三乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4,6-triethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 7.59(d,J=1.5Hz,1H),7.38(s,2H),7.27(d,J=8.3Hz,1H),7.16(dd,J=8.3,1.5Hz,1H),6.28(s,2H),4.08(q,J=1.0Hz,2H),3.99(q,J=1.0Hz,4H),3.75(s,2H),1.33(t,J=1.0Hz,4H),1.17(t,J=1.0Hz,6H).MS(M+1):500.
化合物1-25
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-乙氧基吡啶-4-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxypyridin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.87(br s,1H),8.60(s,1H),8.34(d,J=4.8Hz,1H),8.16(d,J=4.8Hz,1H),7.60(d,J=2.0Hz,1H),7.42(s,2H),7.29(d,J=8.4Hz,1H),7.17(dd,J=8.4,1.6Hz,1H),4.40(q,J=6.8Hz,2H),3.84(s,2H),1.46(t,J=6.8Hz,3H).MS(M+1):413.
化合物1-26
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(乙氧基甲氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(ethoxymethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.61(br s,1H),8.17(d,J=9.2Hz,1H),7.60(d,J=1.2Hz,1H),7.42(s,2H),7.28(d,J=8.4Hz,1H),7.17(dd,J=9.2,1.6Hz,1H),6.81(d,J=2.4Hz,1H),6.74(dd,J=8.8,2.8Hz,1H),5.45(s,2H),4.09(q,J=6.8Hz,2H),3.81(s,2H),3.68(q,J=6.8Hz,2H),1.35(t,J=7.2Hz,3H),1.11(t,J=7.2Hz,3H).MS(M+1):486.
化合物1-27
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(2-(4-乙基哌嗪-1-基)乙氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.53(br s,1H),8.15(d,J=8.8Hz,1H),7.60(d,J=1.6Hz,1H),7.40(s,2H),7.28(d,J=8.4Hz,1H),7.17(dd,J=8.4,2.0Hz,1H),6.75(d,J=2.4Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),4.25(t,J=5.6Hz,2H),4.12(q,J=6.8Hz,2H),3.80(s,2H),2.77(t,J=5.6Hz,2H),2.24-2.20(m,4H),2.06(s,3H),1.35(t,J=6.8Hz,3H).MS(M+1):554.
化合物1-28
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(3-(二甲基胺基)丙氧基)-4-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(3-(dimethylamino)propoxy)-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.57(br s,1H),8.15(d,J=8.8Hz,1H),7.60(d,J=1.6Hz,1H),7.42(s,2H),7.28(d,J=8.4Hz,1H),7.17(dd,J=8.0,1.6Hz,1H),6.71(d,J=2.0Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),4.21(t,J=6.4Hz,2H),4.11(q,J=6.8Hz,2H),3.81(s,2H),2.46(t,J=6.8Hz,2H),2.13(s,6H),1.95(quin,J=6.8Hz,2H),1.34(t,J=6.8Hz,3H).MS(M+1):513.
化合物1-29
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(2-(二甲基胺基)乙氧基)-4-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(2-(dimethylamino)ethoxy)-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.55(br s,1H),8.16(d,J=8.4Hz,1H),7.60(d,J=1.6Hz,1H),7.42(s,2H),7.28(d,J=8.4Hz,1H),7.18(dd,J=8.4,1.2Hz,1H),6.76(d,J=2.0Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),4.26(t,J=6.0Hz,2H),4.12(q,J=6.8Hz,2H),3.81(s,2H),2.76(t,J=6.0Hz,2H),2.25(s,6H),1.35(t,J=6.0Hz,3H).MS(M+1):499.
化合物1-30
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(5-乙氧基吡啶-2-基)-1,3,4-噻二唑-2-基)乙醯胺
(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(5-ethoxypyridin-2-yl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.79(br s,1H),8.16(d,J=8.4Hz,1H),7.60(d,J=1.6Hz,1H),7.42(s,2H),7.28(d,J=8.4Hz,1H),7.18(dd,J=8.4,1.2Hz,1H),6.76(d,J=2.0Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),4.26(t,J=6.0Hz,2H),4.12(q,J=6.8Hz,2H),3.81(s,2H),2.76(t,J=6.0Hz,2H),2.25(s,6H),1.35(t,J=6.0Hz,3H).MS(M+1):413.
化合物1-31
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-(2-(二甲基胺基)乙氧基)吡啶-4-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-(2-(dimethylamino)ethoxy)pyridin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.84(br s,1H),8.65(s,1H),8.35(d,J=5.2Hz,1H),8.16(d,J=4.8Hz,1H),7.60(d,J=1.6Hz,1H),7.43(s,2H),7.29(d,J=8.4Hz,1H),7.18(dd,J=8.4,1.6Hz,1H),4.42(t,J=5.6Hz,2H),3.85(s,2H),2.77(t,J=6.0Hz,2H),2.24(s,6H).MS(M+1):456.
化合物1-32
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(2-甲氧基乙氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺
(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-methoxyethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.54(br s,1H),8.16(d,J=8.8Hz,1H),7.60(d,J=1.6Hz,1H),7.41(br s,2H),7.28(d,J=8.0Hz,1H),7.18(dd,J=8.0,1.6Hz,1H),6.74(d,J=2.0Hz,1H),6.69(dd,J=8.8,2.4Hz,1H),4.30-4.32(m,2H),4.11(q,J=7.2Hz,2H),3.81(s,2H),3.77-3.75(m,2H),3.34(s,3H),1.35(t,J=7.4Hz,3H).MS(M+1):486.
化合物1-33
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-丙基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-propylphenyl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.82(s,1H),7.78-7.86(m,2H),7.60(d,J=1.5Hz,1H),7.42(s,2H),7.32-7.38(m,J=8.3Hz,2H),7.28(d,J=7.8Hz,1H),7.17(dd,J=8.1,1.7Hz,1H),3.83(s,2H),2.61(t,J=7.6Hz,2H),1.57-1.70(m,2H),0.90(t,J=7.3Hz,3H).MS(M+1):410.
化合物1-34
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基吡啶-3-基)-1,3,4-噻二唑-2-基)乙醯胺
(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.77(br,1H),9.19(s,1H),8.49(d,J=6.0Hz,1H),7.59(d,J=2.0Hz,1H),7.40(br,2H),7.29(d,J=8.4Hz,1H),7.24(d,J=6.0Hz,1H),7.17(dd,J=8.4,2.0Hz,1H),4.32(q,J=6.8Hz,2H),3.83(s,2H),1.42(t,J=6.8Hz,3H).MS(M+1):413.
化合物1-35
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4,6-二乙氧基吡啶-3-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4,6-diethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.71(br,1H),8.84(s,1H),7.60(d,J=1.2Hz,1H),7.42(s,2H),7.28(d,J=8.4Hz,1H),7.17(dd,J=8.4,1.6Hz,1H),6.57(s,1H),4.36(q,J=6.8Hz,2H),4.29(q,J=6.8Hz,2H),3.82(s,2H),1.42(t,J=6.8Hz,3H),1.32(t,J=6.8Hz,3H).MS(M+1):457.
化合物1-36
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4-二乙氧基苯基)-1,3,4-噻二唑-2-基)-N-甲基乙醯胺
(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1,3,4-thiadiazol-2-yl)-N-methylacetamide
1H NMR(400MHz,DMSO-d6):δ 12.79(br s,1H),8.16(d,J=8.4Hz,1H),7.60(d,J=1.6Hz,1H),7.42(s,2H),7.28(d,J=8.4Hz,1H),7.18(dd,J=8.4,1.2Hz,1H),6.76(d,J=2.0Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),4.26(t,J=6.0Hz,2H),4.12(q,J=6.8Hz,2H),3.81(s,2H),2.76(t,J=6.0Hz,2H),2.25(s,6H),1.35(t,J=6.0Hz,3H).MS(M+1):470.
化合物1-37
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4,6-二乙氧基吡啶-3-基)-1,3,4-噻二唑-2-基)-N-甲基乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4,6-diethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)-N-methylacetamide)
1H NMR(400MHz,DMSO-d6):δ 8.83(s,1H),7.55(s,1H),7.43(s,2H),7.30(d,J=8.0Hz,1H),7.12(dd,J=8.4,1.6Hz,1H),6.56(s,1H),4.36(q,J=6.8Hz,2H),4.28(q,J=6.8Hz,2H),4.16(s,2H),3.81(s,3H),1.40(t,J=6.8Hz,3H),1.32(t,J=6.8Hz,3H).MS(M+1):471.
實施例2之化合物的典型合成方法
步驟1:4-乙氧基苯亞甲基肼甲醯胺類(4-ethoxybenzylidene hydrazinecarboxamides)的合成
將半卡肼鹽酸鹽(Semicarbazide hydrochloride,1.11g,10mmol)和醋酸鈉(1.64g,20mmol)溶於在平底燒瓶中的蒸餾水(15-20ml)。取4-乙氧基苯甲醛(1.5g,10mmol)溶於乙醇,將此溶液緩慢加入至半卡肼鹽酸鹽的溶液中,過濾沉澱物、乾燥並以熱乙醇(95%)再結晶,以獲得4-乙氧基苯亞甲基肼甲醯胺。
步驟2:4-乙氧基苯基-1,3,4-噁二唑-2-胺類(4-ethoxyphenyl-1,3,4-Oxadiazol-2-amines)的合成
取醋酸鈉(20mmol)和4-乙氧基苯亞甲基肼甲醯胺(2.1g,10mmol)溶於連續攪拌的冰醋酸(glacial acetic acid,30-40ml)中,緩慢加入溴(Bromine,0.7ml溶於5ml冰醋酸)。溶液攪拌1小時並倒在碎冰上,將生成的固體分離、乾燥並用熱乙醇再結晶(95%),以提供4-乙氧基苯基-1,3,4-噁二唑-2-胺。
(6-(2-((5-(4-乙氧基苯基)-1,3,4-噁二唑-2-基)胺基)-2-側氧基乙基)苯並[d]噻唑-2-基)胺基甲酸叔丁酯(tert-butyl(6-(2-((5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate)的合成
取4-乙氧基苯基-1,3,4-噁二唑-2-胺(0.41g,2mmol)和HOBt(0.27g,2mmol)、EDCI(0.46g,2.4mmol)、2-(2-((叔丁氧基羰基)胺基)苯並[d]噻唑-6-基)乙酸(0.74g,2.4mmol)溶於乾燥的DMF(12mL),反應在室溫下攪拌至隔夜後加水,將沉澱物
以水洗並用甲醇再結晶,以得到(6-(2-((5-(4-乙氧基苯基)-1,3,4-噁二唑-2-基)胺基)-2-側氧基乙基)苯並[d]噻唑-2-基)胺基甲酸叔丁酯(0.74g,75%)。
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)的合成
在室溫下,向溶於無水二氯甲烷(15mL)的(6-(2-((5-(4-乙氧基苯基)-1,3,4-噁二唑-2-基)胺基)-2-側氧基乙基)苯並[d]噻唑-2-基)胺基甲酸叔丁酯(0.74g,1.50mmol)的劇烈攪拌的溶液中加入三氟乙酸(1.5mL,20mmol)並攪拌至隔夜。藉由逐滴加入的碳酸鈉溶液中和過量的三氟乙酸直到pH=10。以水和甲醇洗沉澱物後,進一步藉由矽膠急速管柱層析法(以二氯甲烷和甲醇做為沖提液)純化,並濃縮以得到白色固體(0.35g,60%)。
實施例2:化合物2-1至2-4
化合物2-1
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 11.87(br.s.,1H),7.99-8.07(m,1H),7.79-7.86(m,2H),7.67-7.74(m,5H),7.59(d,J=1.0Hz,1H),7.42(s,2H),7.28(d,J=8.3Hz,1H),7.12-7.20(m,3H),4.09(q,J=7.01Hz,2H),3.76(s,2H),1.34(t,J=7.09Hz,4H).MS(M+1):356.
化合物2-2
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-乙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 11.89(br.s.,1H),8.04(br.s.,1H),7.71-7.74(m,1H),7.55(ddd,J=8.6,7.3,1.7Hz,1H),7.33(d,J=7.8Hz,1H),7.23(dd,J=8.3,2.0Hz,2H),7.06-7.11(m,2H),4.14(q,J=1.0Hz,2H),3.80(s,2H),1.33(t,J=1.0Hz,3H).MS(M+1):396.
化合物2-3
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-propoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 11.82(br.s.,1H),7.73(dd,J=7.8,2.0Hz,1H),7.50-7.62(m,1H),7.40(s,2H),7.18-7.32(m,2H),7.16(dd,J=8.1,1.7Hz,1H),7.05-7.12(m,2H),4.03(t,J=6.4Hz,2H),3.76(s,2H),1.65-1.77(m,2H),0.94(t,J=7.3Hz,3H).MS(M+1):410.
化合物2-4
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(三氟甲氧基)苯基)-1,3,4-噁二唑-2-基)乙醯胺
(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 10.55(s,1H),7.61-7.71(m,2H),7.49-7.55(m,2H),7.40(s,2H),7.25(d,J=8.3Hz,1H),7.08(dd,J=8.3,2.0Hz,1H),3.54(s,2H).MS(M+1):436.
實施例3和實施例4之化合物的典型合成方法
2-溴-2-(3-硝基苯基)-1-(對-甲苯基)乙-1-酮(2-bromo-2-(3-nitrophenyl)-1-(p-tolyl)ethan-1-one)的合成
取2-(3-硝基苯基)-1-(對-甲苯基)乙-1-酮(25.5g,100mmol)和氯化鋁(AlCl3,30mg,0.23mmol)溶於氯仿(CHCl3,20mL)。接著藉由冰浴在0℃下,以加成漏斗逐滴加入溶於氯仿(100mL)的溴(22g,120mmol),反應在室溫下攪拌2小時後萃取,以硫酸鈉乾燥並在減壓下濃縮,粗反應混合物直接藉由矽膠急速層析法(二氯甲烷/己烷=5:1)純化,分離出標題化合物以獲得白色固體(30.0g,89%)。
5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-胺(5-(3-nitrophenyl)-4
-(p-tolyl)thiazol-2-amine)的合成
此化合物通過回流溶於乙醇(30ml)的2-溴-2-(3-硝基苯基)-1-(對-甲苯基)乙-1-酮(16.7g,50mmol)和硫脲(4.28g,55mmol)1小時來製備,再加入飽和碳酸鈉反應,將粗產物過濾並用水洗至中性,接著用乙醇再結晶,以獲得淡黃色晶體(7.78g,80%)。
(6-(2-((5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)胺基)-2-側氧基乙基)苯並[d]噻唑-2-基)胺基甲酸叔丁酯(tert-butyl(6-(2-((5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)amino)-2-oxoethyl)benzo[d]thiazol-2-yl)carbamate)的合成
取5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-胺(0.62g,2mmol)、2-(2-((叔丁氧基羰基)胺基)苯並[d]噻唑-6-基)乙酸(0.62g,2mmol)、EDCI(0.76g,4mmol)和HOBt(0.54g,4mmol)溶於無水二氯甲烷(20mL),反應在室溫下攪拌至隔夜後加入水,並以二氯甲烷萃取及濃縮得到一粗殘餘物,粗殘餘物藉由管柱層析法(以乙酸乙酯/己烷=0:100-30:70做為沖提液)純化並濃縮,以提供橘色固體(0.84g,70%)。
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)的合成
在室溫下,向溶於無水二氯甲烷(15mL)的(6-(2-((5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)胺基)-2-側氧基乙基)苯並[d]噻唑-2-基)胺基甲酸叔丁酯(0.84g,1.40mmol)的劇烈攪拌的溶液中加入三氟乙酸(1.5mL,20mmol)並攪拌至隔夜。藉由逐滴加入碳酸鈉溶液中和過量的三氟乙酸直到pH=10。以水和甲醇洗沉澱物後,進一步藉由矽膠急速管柱層析法(以二氯甲烷和甲醇做為沖提液)純化,並濃縮以得到白色固體(0.45g,64%)。
實施例3:化合物3-1至3-14
化合物3-1
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.68(s,1H),8.16(dt,J=7.1,1.3Hz,1H),8.06(t,J=2.0Hz,1H),7.61-7.75(m,4H),7.31(t,J=7.8Hz,3H),7.20(dd,J=8.3,1.5Hz,1H),7.15(d,J=8.3Hz,2H),3.81(s,2H),2.30(s,3H).MS(M+1):440.
化合物3-2
2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(4-溴苯基)-5-苯基噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-bromophenyl)-5-phenylthiazol-2-yl)acetamide)
1H NMR(400MHz,CDCl3):δ 9.09(br.s.,1H),7.49-7.57(m,2H),7.32-7.39(m,2H),7.25-7.32(m,7H),7.20(d,J=7.8Hz,1H),5.29(br.s.,2H),3.81(s,2H).MS(M+1):521.
化合物3-3
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-溴苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.61(s,1H),8.16(br.s.,2H),7.68(d,J=1.5Hz,1H),7.53-7.59(m,2H),7.28-7.38(m,3H),7.19-7.28(m,3H),7.14(d,J=8.3Hz,2H),3.81(s,2H),2.29(s,3H).MS(M+1):535.
化合物3-4
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-氟苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-fluorophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.57(s,1H),8.18(br.s.,2H),7.26-7.41(m,6H),7.15-7.26(m,3H),7.06-7.15(m,2H),3.81(s,2H),2.28(s,3H).MS(M+1):475.
化合物3-5
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3,4-二甲氧基苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3,4-dimethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.49(s,1H),8.39(br.s.,2H),7.71(d,J=1.0Hz,1H),7.31-7.41(m,3H),7.25-7.31(m,1H),7.09-7.16(m,2H),6.91-6.99(m,1H),6.78-6.87(m,2H),3.82(s,2H),3.76(s,3H),3.58(s,3H),2.28(s,3H).MS(M+1):517.
化合物3-6
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-氟苯基)-4-(4-丙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-fluorophenyl)-4-(4-propoxyphenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.53(s,1H),7.92(br.s.,2H),7.66(s,1H),7.29-7.38(m,5H),7.14-7.29(m,3H),6.81-6.91(m,2H),3.91(t,J=6.6Hz,3H),3.80(s,2H),1.65-1.76(m,2H),0.96(t,J=7.3Hz,3H).MS(M+1):519.
化合物3-7
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3,5-雙(三氟甲基)苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,CDCl3):δ 9.39(br.s.,1H),7.71(s,3H),7.50-7.54(m,2H),7.17-7.23(m,3H),7.08(d,J=7.8Hz,2H),5.28(d,J=10.8Hz,2H),3.80(s,2H),2.31(s,3H).MS(M+1):593.
化合物3-8
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-溴-4-(3-甲氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-bromo-4-(3-methoxyphenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,CDCl3):δ 9.14(br.s.,1H),7.49-7.56(m,2H),7.34-7.38(m,1H),7.30-7.34(m,1H),7.26-7.30(m,1H),7.20(dd,J=8.3,2.0Hz,1H),6.88(ddd,J=8.2,2.6,1.0Hz,1H),5.28(br.s.,2H),3.81(s,2H),3.80(s,3H).MS(M+1):475.
化合物3-9
2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(4-乙氧基苯基)-5-(4-氟苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-ethoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.51(s,1H),7.98(br.s.,2H),7.63-7.69(m,1H),7.28-7.37(m,5H),7.16-7.28(m,3H),6.80-6.90(m,2H),4.01(q,J=7.2Hz,2H),3.80(s,2H),1.31(t,J=7.1Hz,3H).MS(M+1):505.
化合物3-10
2-(2-胺基苯並[d]噻唑-6-基)-N-(4,5-雙(4-溴苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4,5-bis(4-bromophenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.59(s,1H),7.52-7.61(m,5H),7.40(s,2H),7.33-7.38(m,2H),7.21-7.32(m,3H),7.17(dd,J=8.1,1.7Hz,1H),3.79(s,2H).MS(M+1):599.
化合物3-11
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 7.68(s,1H),7.58(d,J=1.5Hz,1H),7.44-7.49(m,2H),7.40(s,2H),7.27(d,J=7.8Hz,1H),7.16(dd,J=8.3,2.0Hz,1H),6.92-6.98(m,3H),6.86-6.90(m,1H),4.03(q,J=6.8Hz,2H),3.74(s,2H),1.32(t,J=6.8Hz,3H).MS(M+1):411.
化合物3-12
2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(2,4-二乙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(2,4-diethoxyphenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.30(s,1H),7.99(d,J=8.0Hz,1H),7.60(m,1H),7.48(s,1H),7.41(br s,2H),7.29(d,J=7.6Hz,1H),7.17(dd,J=8.4,1.6Hz,1H),6.61-6.58(m,2H),4.13(q,J=6.8Hz,2H),4.06(q,J=6.8Hz,2H),3.76(s,2H),1.43(t,J=6.8Hz,3H),1.33(t,J=6.8Hz,3H).MS(M+1):455
化合物3-13
2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.44(s,1H),7.77-7.74(m,2H),7.59(d,J=2.0Hz,1H),7.43(s,2H),7.38-7.34(m,2H),7.28(d,J=2.0Hz,1H),7.18-7.08(m,4H),6.95-6.92(m,2H),4.01(q,J=6.8Hz,2H),3.75(s,2H),1.30(t,J=6.8Hz,3H).LCMS,[M+1]+:503.
化合物3-14
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-苄基-4-(4-乙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 12.29(s,1H),7.47-7.59(m,3H),7.41(s,2H),7.23-7.34(m,3H),7.10-7.23(m,5H),6.93-7.01(m,2H),4.17(s,2H),4.04(q,J=7.0Hz,2H),3.71(s,2H),1.32(t,J=7.1Hz,3H).LCMS[M+1]+:501.
實施例4:化合物4-1至4-4
化合物4-1
1-(2-胺基苯並[d]噻唑-6-基)-3-(5-(4-乙氧基苯基)-1,3,4-噻二唑-2-基)脲(1-(2-aminobenzo[d]thiazol-6-yl)-3-(5-(4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)urea)
1H NMR(400MHz,DMSO-d6):δ 10.96(br.s.,1H),8.97(br.s.,1H),7.88(br.s.,1H),7.75-7.84(m,J=8.8Hz,2H),7.37(br.s,2H),7.26(q,J=8.3Hz,2H),7.00-7.10(m,J=8.8Hz,2H),4.09(q,J=7.2Hz,2H),1.34(t,J=6.8Hz,3H).MS(M+1):413.
化合物4-2
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)噻吩-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)thiophen-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 11.36(s,1H),7.92(br.s.,2H),7.64(d,J=1.5Hz,1H),7.42-7.48(m,2H),7.32(d,J=8.3Hz,1H),7.21(dd,J=8.3,2.0Hz,1H),7.07(d,J=3.9Hz,1H),6.90-6.93(m,2H),6.64(d,J=3.9Hz,1H),4.02(q,J=6.8Hz,2H),3.68(s,2H),1.31(t,J=6.8Hz,3H).MS(M+1):410.
化合物4-3
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(2-甲氧基乙氧基)苯基)-1H-咪唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 11.53(br s,1H),7.74(d,J=8.0Hz,1H),7.62(d,J=2.0Hz,1H),7.53(br s,2H),7.27-7.30(m,2H),7.19(dd,J=8.0,1.6Hz,1H),6.61(d,J=2.4Hz,1H),6.57(dd,J=8.0,2.0Hz,1H),4.19-4.17(m,2H),4.04(q,J=6.8Hz,2H),3.75-7.32(m,2H),3.71(s,2H),3.31(s,3H),1.32(t,J=6.8Hz,3H).MS(M+1):468.
化合物4-4
2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4-二乙氧基)-1H-咪唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1H-imidazol-2-yl)acetamide)
1H NMR(400MHz,DMSO-d6):δ 11.41(s,1H),11.35(s,1H),7.84(d,J=8.4Hz,1H),7.59(d,J=1.2Hz,1H),7.40(br s,2H),7.27(d,J=8.4Hz,1H),7.19-7.15(m,2H),6.54(s,1H),4.09(q,J=6.8Hz,2H),4.02(q,J=6.8Hz,2H),3.66(s,2H),141(t,J=6.8Hz,3H),1.32(t,J=6.8Hz,3H).MS(M+1):438.
實施例5之化合物的典型合成方法
1-(4-乙氧基-苯基)-乙酮(1-(4-Ethoxy-phenyl)-ethanone)的合成
在不斷攪拌下,將碳酸鉀(20.73g,150mmol)加入至溶於乙腈(200ml)的1-(4-羥基-苯基)-乙酮(13.62g,100mmol)溶液中,加入溴乙烷(23.4g,150mmol)並將反應混合物加熱至80℃反應20小時。加入水(100ml)並將反應混合物以乙酸乙酯萃取,將有機相以食鹽水洗、乾燥(硫酸鈉)並在真空下濃縮。粗殘餘物藉由管柱層析法(以乙酸乙酯/己烷=0:100-5:95作為沖提液)純化。產率(14.43g,88%)。LCMS:MH+ 165.
2-溴-1-(4-乙氧基苯基)乙酮(2-Bromo-1-(4-ethoxyphenyl)ethanone)的合成
取N-溴代丁二醯亞胺(NBS,16.5g,91mmol)、對甲苯磺酸(PTSA):水合物(hydrate)(27g,142mmole)、1-(4-乙氧基-苯基)-乙酮(11.6g,71mmol)溶於乙腈(348ml),並將生成的混合物在82℃下回流後,降至室溫攪拌2小時,接著移除乙腈並加入水(400ml),以乙酸乙酯(450ml)萃取,有機相以食鹽水洗、乾燥(硫
酸鈉)並在真空下濃縮,且獲得的粗產物(17.5g,產率99%)不需進一步純化即可用於接下來的步驟。
4-(4-乙氧基苯基)噻唑-2-胺(4-(4-ethoxyphenyl)thiazol-2-amine)的合成
向硫脲(6.58g)和2-溴-1-(4-乙氧基苯基)乙-1-酮(17.50g)的混合物中加入乙醇(90mL),反應混合物加熱回流2.5小時。將反應冷卻至室溫,在真空下移除乙醇以提供棕色固體的殘餘物。以水(100ml)和飽和碳酸氫鈉(50ml)洗直到觀察到水溶液為黃色以獲得混合物,抽吸(suction)混合物以移除水分,接著以水(50ml)洗濾餅(cake)。粗產物以熱乙醇(75ml)漿液(slurry)2小時後,藉由蒸餾移除乙醇(40ml),並將溶液冷卻至室溫,接著抽吸以提供固體粉末4-(4-乙氧基苯基)噻唑-2-胺(15.84g)。MS(ES+)m/z 221(MH+).
5-溴-4-(4-乙氧基苯基)噻唑-2-胺(5-bromo-4-(4-ethoxyphenyl)thiazol-2-amine)的合成
取N-溴琥珀醯亞胺(N-bromosuccinimide,4.84g,27.2mmol)溶於丙酮(200mL),藉由冰浴在0℃下加入4-(4-乙氧基苯基)噻唑-2-胺(5.00g,22.7mmol)超過30分鐘。一小時後,將反應在真空下濃縮,接著將殘餘物以乙酸乙酯(100mL)和硫代硫酸鈉萃取兩次。合併有機層的溶劑以食鹽水洗、乾燥並蒸發。其純度
足夠直接使用。5-溴-4-(4-乙氧基苯基)噻唑-2-胺(6.31g,93%)。MS(ES+)m/z 299(MH+).
4-(4-乙氧基苯基)-5-苯氧基噻唑-2-胺(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-amine)的合成
向5-溴-4-(4-乙氧基苯基)噻唑-2-胺(3.1g,10.4mmol)、苯酚(1.27g,13.5mmol)和碳酸銫(4.40g,13.5mmol)的混合物中加入丙酮(100mL),將反應混合物加熱至50℃並攪拌10小時。移除溶劑,粗產物藉由急速層析法(乙酸乙酯:hexane=0:1-1:4)純化,以提供4-(4-乙氧基苯基)-5-苯氧基噻唑-2-胺(2.23g)。MS(ES+)m/z 313(MH+).
N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻酚-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)的合成
取5-硝基噻酚-2-羧酸(1.71g,10mmol)、4-(4-乙氧基苯基)-5-苯氧基噻唑-2-胺(3.12g,10mmol)、1-乙基-3-[3-(二甲基胺基)丙基]碳化二亞胺(EDCl,3.83g,20mmol)和HOBt(2.70g,20mmol)溶於二氯甲烷(50mL),反應在室溫下攪拌至隔夜。粗產物藉由急速層析法(二氯甲烷:乙酸乙酯=1:0-4:1)純化,以提供
紅色固體的N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻酚-2-甲醯胺(產量:4.22g,90%)。
實施例5:化合物5-1至5-108
化合物5-1
N-(4-(4-溴苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 9.69(br,1H),7.85(d,J=4.4Hz,1H),7.75-7.72(m,2H),7.51(d,J=4.4Hz,1H),7.48-7.44(m,2H),7.36-7.31(m,2H),7.16-7.09(m,3H).MS(M+1):502.
化合物5-2
N-(4-(4-溴苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.57(br,1H),7.89(d,J=4.4Hz,1H),7.74-7.71(m,2H),7.58(d,J=4.4Hz,1H),7.50-7.47(m,2H),7.22-7.17(m,2H),7.12-7.09(m,2H).MS(M+1):586.
化合物5-3
5-硝基-N-(4-(3-硝基苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(3-nitrophenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.63(br,1H),8.82(s,1H),8.25(d,J=8.0Hz,1H),8.11(d,J=7.6Hz,1H),7.93(d,J=4.4Hz,1H),7.66(d,J=4.4Hz,1H),7.52(t,J=8.0Hz,1H),7.38-7.34(m,2H),7.19-7.14(m,3H).MS(M+1):469.
化合物5-4
N-(4-(3-甲氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(3-methoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.85(br,1H),7.72(d,J=4.4Hz,1H),7.45(d,J=4.4Hz,1H),7.38-7.31(m,4H),7.23-7.19(m,1H),7.14-7.11(m,3H),6.77-6.74(m,1H),3.71(s,3H).MS(M+1):454.
化合物5-5
N-(4-(2-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(2-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.44(br s,1H),7.72(d,J=4.4Hz,1H),7.62(dd,J=8.0,1.6Hz,1H),7.53(d,J=4.4Hz,1H),7.34-7.29(m,2H),7.25-7.21(m,1H),7.13-7.08(m,3H),6.92-6.86(m,2H),4.08(q,J=6.8Hz,2H),1.40(t,J=6.8Hz,3H).MS(M+1):468.
化合物5-6
N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.03(br.s,1H),7.71(d,J=4.4Hz,1H),7.68-7.65(m,2H),7.49(d,J=4.4Hz,1H),7.35-7.30(m,2H),7.13-7.09(m,3H),6.82-6.78(m,2H),3.97(q,J=6.8Hz,2H),1.37(t,J=6.8Hz,3H).MS(M+1):468.
化合物5-7
N-(4-(4-溴苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.87(br.s,1H),7.86(d,J=4.4Hz,1H),7.69-7.66(m,2H),7.59(d,J=8.8Hz,2H),7.57(d,J=4.4Hz,1H),7.48-7.45(m,2H),7.17(d,J=8.4Hz,2H),1.22(s,9H).MS(M+1):570.
化合物5-8
5-硝基-N-(4-(4-丙氧基苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.59(br.s,1H),7.70(d,J=4.4Hz,1H),7.67-7.63(m,2H),7.39(d,J=4.0Hz,1H),7.17(d,J=8.0Hz,2H),7.12-7.08(m,2H),6.83-6.79(m,2H),3.86(q,J=6.8Hz,2H),1.77(sex,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).MS(M+1):570.
化合物5-9
5-硝基-N-(5-苯氧基-4-(4-丙氧基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-propoxyphenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.32(br.s.,1H),8.17-8.27(m,2H),7.77-7.83(m,J=8.8Hz,2H),7.37-7.43(m,2H),7.13-7.19(m,3H),6.94-6.99(m,2H),3.92(t,J=6.6Hz,2H),1.66-1.76(m,2H),0.96(t,J=7.3Hz,3H).MS(M+1):482.
化合物5-10
N-(4-(4-異丙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-isopropoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.33(br.s.,1H),8.18-8.26(m,2H),7.80(d,J=8.8Hz,2H),7.37-7.44(m,2H),7.14-7.19(m,3H),6.95(d,J=9.3Hz,2H),4.61(spt,J=6.0Hz,1H),1.25(d,J=5.9Hz,6H).MS(M+1):482
化合物5-11
N-(4-(4-溴苯基)-5-(3-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.45(br.s.,1H),8.22-8.25(m,1H),8.19-8.22(m,1H),7.82(d,J=8.3Hz,2H),7.63(d,J=8.3Hz,4H),7.53-7.58(m,2H),7.47-7.51(m,1H).MS(M+1):570
化合物5-12
N-(4-(2,4-二乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(2,4-diethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.68(br,1H),7.67(d,J=4.4Hz,1H),7.48-7.45(m,2H),7.33-7.28(m,2H),7.12-7.06(m,3H),6.38-6.34(m,2H),4.00(q,J=7.2Hz,2H),3.95(q,J=7.2Hz,2H),1.39-1.34(m,6H).MS(M+1):512.
化合物5-13
5-硝基-N-(4-(4-丙氧基苯基)-5-(吡啶-3-基氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(pyridin-3-yloxy)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.38(br.s.,1H),8.53(d,J=2.9Hz,1H),8.35-8.40(m,1H),8.18-8.25(m,2H),7.78(d,J=8.8Hz,2H),7.56(ddd,J=8.6,2.9,1.2Hz,1H),7.42(dd,J=8.6,4.6Hz,1H),6.97(d,J=8.8Hz,2H),3.92(t,J=6.6Hz,2H),1.66-1.76(m,2H),0.96(t,J=7.3Hz,3H).MS(M+1):483
化合物5-14
N-(4-(4-(叔丁基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.37(br.s.,1H),8.22(br.s.,2H),7.84(d,J=8.3Hz,2H),7.38-7.48(m,4H),7.19(br.s.,3H),1.27(br.s.,9H).MS(M+1):480.
化合物5-15
N-(4-(4-(2-甲氧基乙氧基)苯基)-5-(吡啶-3-基氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(2-methoxyethoxy)phenyl)-5-(pyridin-3-yloxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.39(br,1H),8.54(d,J=2.8Hz,1H),8.39-8.37(m,1H),8.23-8.20(m,2H),7.79(d,J=8.8Hz,2H),7.59-7.55(m,1H),7.44-7.41(m,1H),7.02-6.98(m,2H),4.11-4.08(m,2H),3.65-3.63(m,2H),3.29(s,3H).MS(M+1):499.
化合物5-16
N-(4-(4-(2-甲氧基乙氧基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(2-methoxyethoxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.35(br,1H),7.74(d,J=4.0Hz,1H),7.72-7.69(m,2H),7.43(d,J=4.4Hz,1H),7.34-7.30(m,2H),7.13-7.10(m,3H),6.87-6.84(m,2H),4.08-4.06(m,2H),3.73-3.70(m,2H),3.42(s,3H).MS(M+1):498.
化合物5-17
5-硝基-N-(4-(4-丙氧基苯基)-5-(3-(三氟甲基)苯氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.39(br.s.,1H),8.18-8.26(m,2H),7.75-7.81(m,J=8.8Hz,2H),7.60-7.66(m,1H),7.48-7.55(m,2H),7.45(dd,J=8.3,2.0Hz,1H),6.93-6.99(m,J=9.3Hz,2H),3.92(t,J=6.6Hz,2H),1.70(sxt,J=7.1Hz,2H),0.95(t,J=7.3Hz,3H).MS(M+1):550
化合物5-18
N-(4-(4-溴苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.42(br.s.,1H),8.23(s,1H),8.18-8.21(m,1H),7.79-7.84(m,2H),7.61-7.66(m,2H),7.38-7.44(m,2H),7.29-7.33(m,2H).MS(M+1):585
化合物5-19
N-(4-(4-溴苯基)-5-(2-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.50(br.s.,1H),8.19-8.26(m,2H),7.77-7.86(m,3H),7.63-7.69(m,3H),7.38(t,J=7.6Hz,1H),7.30(d,J=8.3Hz,1H).MS(M+1):569.571
化合物5-20
N-(4-(4-(叔丁基)苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.36(br.s.,1H),8.16-8.29(m,2H),7.79-7.86(m,J=8.3Hz,2H),7.41-7.48(m,J=8.8Hz,2H),7.18-7.27(m,4H),1.27(s,9H).MS(M+1):498
化合物5-21
N-(5-(2-乙氧基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-ethoxyphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.73(d,J=8.8Hz,2H),7.63(d,J=4.4Hz,1H),7.33(d,J=4.0Hz,1H),7.12-7.05(m,2H),6.98(dd,J=8.4,1.6Hz,1H),6.88-6.83(m,1H),6.81-6.78(m,2H),4.12(t,J=6.8Hz,2H),3.85(t,J=6.8Hz,2H),1.75(sex,J=7.2Hz,2H),1.39(t,J=6.8Hz,3H),1.00(t,J=7.2Hz,3H).MS(M+1):526.
化合物5-22
N-(4-(4-(叔丁基)苯基)-5-(3-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.42(br.s.,1H),8.18-8.32(m,2H),7.81(d,J=8.8Hz,2H),7.39-7.48(m,3H),7.06-7.13(m,1H),6.97-7.05(m,2H),1.27(s,9H)MS(M+1):498
化合物5-23
N-(4-(4-乙氧基苯基)-5-(3-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.39(br.s.,1H),8.18-8.28(m,2H),7.75-7.81(m,J=8.8Hz,2H),7.60-7.67(m,1H),7.49-7.56(m,2H),7.43-7.48(m,1H),6.93-6.99(m,J=8.8Hz,2H),4.02(q,J=6.8Hz,2H),1.31(t,J=6.8Hz,3H).MS(M+1):536
化合物5-24
N-(5-(3-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.39(s,1H),8.25-8.21(m,2H),7.78(d,J=8.8Hz,2H),7.46-7.40(m,1H),7.08(td,J=10.4,2.4Hz,1H),7.03-6.97(m,4H),3.93(t,J=6.8Hz,2H),1.71(sex,J=6.8Hz,2H),0.96(t,J=7.2Hz,3H).MS(M+1):500.
化合物5-25
N-(4-(4-乙氧基苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.42(br.s.,1H),8.18-8.29(m,2H),7.72-7.80(m,4H),7.34(d,J=8.8Hz,2H),6.92-6.99(m,2H),4.01(q,J=6.8Hz,2H),1.30(t,J=6.8Hz,3H).MS(M+1):536
化合物5-26
5-硝基-N-(4-(4-丙氧基苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.42(br.s.,1H),8.18-8.29(m,2H),7.76(d,J=8.8Hz,4H),7.34(d,J=8.3Hz,2H),6.93-7.00(m,2H),3.91(t,J=6.6Hz,2H),1.65-1.75(m,2H),0.95(t,J=7.6Hz,3H).MS(M+1):550
化合物5-27
N-(5-(4-溴苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.37(br.s.,1H),8.16-8.29(m,2H),7.76(d,J=9.3Hz,2H),7.52-7.60(m,2H),7.07-7.16(m,2H),6.92-7.01(m,2H),3.92(t,J=6.6Hz,2H),1.65-1.76(m,2H),0.95(t,J=7.6Hz,3H).MS(M+1):559,561
化合物5-28
N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.34(br.s.,1H),8.21(br.s.,2H),7.78(d,J=6.8Hz,2H),6.91-7.09(m,4H),3.93(br.s.,2H),2.34(br.s.,6H),1.71(d,J=6.4Hz,2H),0.92-1.00(m,3H).MS(M+1):588.
化合物5-29
N-(5-(4-(叔丁基)苯氧基)-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.31(br.s.,1H),8.21(br.s.,2H),7.82(d,J=7.8Hz,2H),7.36-7.46(m,J=8.3Hz,2H),7.04-7.13(m,J=8.3Hz,2H),6.97(d,J=8.3Hz,2H),4.03(q,J=6.7Hz,2H),1.31(t,J=6.8Hz,3H),1.26(s,9H).MS(M+1):524
化合物5-30
N-(5-(4-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.27(br,1H),7.62-7.58(m,3H),7.28(d,J=4.4Hz,1H),7.09-6.98(m,4H),6.78-6.74(m,2H),7.04-6.98(m,2H),6.84-6.80(m,2H),3.83(t,J=6.8Hz,2H),1.75(sex,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).MS(M+1):500.
化合物5-31
N-(4-(4-氟苯基)-5-(2-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.88(d,J=3.9Hz,1H),7.80-7.87(m,2H),7.65-7.71(m,1H),7.61(d,J=4.4Hz,1H),7.41-7.48(m,1H),7.17-7.23(m,1H),7.01-7.08(m,3H).MS(M+1):510.
化合物5-32
N-(4-(4-氟苯基)-5-(2-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(2-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.02(br.s.,1H),7.79-7.87(m,3H),7.54(d,J=4.4Hz,1H),7.35(dt,J=7.9,1.4Hz,1H),7.18-7.23(m,1H),7.11-7.18(m,1H),7.00-7.10(m,3H).MS(M+1):526.
化合物5-33
N-(4-(4-氟苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.05(br.s.,1H),7.84(d,J=3.9Hz,1H),7.77-7.83(m,2H),7.53-7.56(m,1H),7.15-7.22(m,2H),7.07-7.14(m,2H),7.00-7.07(m,2H).MS(M+1):526.
化合物5-34
N-(4-(4-甲氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-methoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.79(d,J=4.4Hz,1H),7.73(d,J=8.8Hz,2H),7.49(d,J=4.4Hz,1H),7.28-7.37(m,2H),7.06-7.16(m,3H),6.85(d,J=8.8Hz,2H),3.77(s,3H).MS(M+1):454.
化合物5-35
N-(5-(4-氟苯氧基)-4-(4-(甲基胺甲醯基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺
(N-(5-(4-fluorophenoxy)-4-(4-(methylcarbamoyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.40(s,1H),8.41(q,1H),8.24(d,J=4.4Hz,1H),8.21(d,J=4.4Hz,1H),7.97(d,J=8.8Hz,2H),7.88(d,J=8.4Hz,2H),7.30-7.23(m,4H),2.78(d,J=4.4Hz,3H).MS(M+1):499.
化合物5-36
N-(4-(3,5-二乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(3,5-diethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.28(s,1H),8.24(br,1H),8.20(d,J=4.4Hz,1H),7.45-7.39(m,2H),7.20-7.16(m,3H),7.03(d,J=2.4Hz,2H),6.41(t,J=2.4Hz,2H),3.94(q,J=6.8Hz,4H),1.27(t,J=6.8Hz,6H).MS(M+1):512.
化合物5-37
N-(5-(2,4-二氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2,4-difluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.37(s,1H),8.22-8.20(m,2H),7.81(d,J=8.8Hz,2H),7.55-7.50(m,1H),7.32-7.26(m,1H),7.10-7.06(m,1H),7.03-6.99(m,2H),3.94(t,J=6.8Hz,2H),1.72(sex,J=7.2Hz,2H),0.97(t,J=7.2Hz,3H).MS(M+1):512.
化合物5-38
N-(5-(2-氯-4-(三氟甲基)苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.48(s,1H),8.25-8.21(m,2H),8.07(d,J=2.0Hz,1H),7.75(d,J=8.8Hz,2H),7.68(dd,J=8.8,1.6Hz,1H),7.30(d,J=8.4Hz,1H),7.00-6.96(m,2H),3.93(t,J=6.8Hz,2H),1.70(sex,J=7.2Hz,2H),0.95(t,J=7.2Hz,3H).MS(M+1):584.
化合物5-39
N-(5-(4-氰基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-cyanophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.44(s,1H),8.25-8.21(m,2H),7.90-7.86(m,2H),7.74(d,J=8.8Hz,2H),7.35-7.31(m,2H),6.98-6.95(m,2H),3.92(t,J=6.8Hz,2H),1.71(sex,J=7.2Hz,2H),0.95(t,J=7.2Hz,3H).MS(M+1):507.
化合物5-40
N-(5-(4-氰基-2-甲氧基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-cyano-2-methoxyphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.39(s,1H),8.23-8.20(m,2H),7.76(d,J=8.8Hz,2H),7.68(d,J=2.0Hz,1H),7.39(dd,J=8.4,2.0Hz,1H),7.15(d,J=8.4Hz,1H),6.99-6.96(m,2H),3.95(s,3H),3.93(t,J=6.8Hz,2H),1.71(sex,J=7.2Hz,2H),0.96(t,J=7.2Hz,3H).MS(M+1):537.
化合物5-41
N-(4-(5-(3,3-二甲基丁-1-炔-1-基)噻吩-2-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(5-(3,3-dimethylbut-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.77-10.06(m,2H),7.85(d,J=4.4Hz,2H),7.54(d,J=4.4Hz,2H),7.31-7.37(m,4H),7.24(s,1H),7.23(s,1H),7.10-7.17(m,6H),6.96(d,J=3.9Hz,2H),1.28(s,9H).MS(M+1):510
化合物5-42
N-(4-(5-溴噻吩-2-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(5-bromothiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.90(br.s.,1H),7.85-7.88(m,1H),7.56(d,J=4.4Hz,1H),7.32-7.38(m,2H),7.10-7.18(m,4H),6.92-6.95(m,1H).MS(M+1):509.
化合物5-43
5-硝基-N-(4-(4-丙氧基苯基)-5-(吡啶-4-基氧基)噻唑-2-基)噻吩-2-甲酰胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(pyridin-4-yloxy)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.14(d,J=4.4Hz,2H),7.98(d,J=4.4Hz,1H),7.39-7.45(m,2H),7.26-7.30(m,2H),7.15-7.21(m,3H),3.74(s,2H),2.41(s,6H).MS(M+1):511.
化合物5-44
N-(5-(3,4-二氯苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,4-dichlorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.03(br,1H),7.65(d,J=4.4Hz,1H),7.61-7.57(m,2H),7.37-7.35(m,2H),7.18(d,J=2.8Hz,1H),6.95(dd,J=8.8,2.8Hz,1H),6.80-6.77(m,2H),3.85(t,J=6.4Hz,2H),1.76(sex,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).MS(M+1):550.
化合物5-45
N-(5-(2-氯-4-氟苯基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-chloro-4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.05(br,1H),7.68-7.65(m,2H),7.63(d,J=4.0Hz,1H),7.32(d,J=4.4Hz,1H),7.20(dd,J=7.6,2.8Hz,1H),7.02(dd,J=8.8,4.8Hz,1H),6.91-6.86(m,1H),6.81-6.77(m,2H),3.85(t,J=6.8Hz,2H),1.76(sex,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).MS(M+1):534.
化合物5-46
N-(4-(5-(3-(二甲基胺基)丙-1-炔-1-基)噻吩-2-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(5-(3-(dimethylamino)prop-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.14(d,J=4.4Hz,2H),7.98(d,J=4.4Hz,1H),7.39-7.45(m,2H),7.26-7.30(m,2H),7.15-7.21(m,3H),3.74(s,2H),2.41(s,6H).MS(M+1):511.
化合物5-47
N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基呋喃-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrofuran-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 12.94(br,1H),7.82-7.80(m,4H),7.42-7.38(m,2H),7.17-7.14(m,3H),6.97-6.94(m,2H),4.03(q,J=6.8Hz,2H),1.31(t,J=7.2Hz,3H).LCMS,[M+1]+:452.
化合物5-48
5-硝基-N-(5-苯氧基-4-(4-丙氧基苯基)噻唑-2-基)呋喃-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-propoxyphenyl)thiazol-2-yl)furan-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 7.82-7.77(m,4H),7.42-7.37(m,2H),7.17-7.14(m,3H),6.98-6.94(m,2H),3.92(t,J=6.8Hz,2H),1.71(sex,J=7.2Hz,2H),0.96(t,J=7.2Hz,3H).LCMS,[M+1]+:466.
化合物5-49
N-(5-(4-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基呋喃-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.83(br,1H),7.73-7.69(m,2H),7.31(d,J=4.0Hz,1H),7.26(d,J=4.0Hz,1H),7.12-7.07(m,2H),7.04-6.98(m,2H),6.84-6.80(m,2H),3.88(t,J=6.4Hz,2H),1.77(sex,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).LCMS,[M+1]+:484.
化合物5-50
N-(5-(3,5-二氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,5-difluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.51(br,1H),7.74(d,J=4.4Hz,1H),7.64-7.61(m,2H),7.44(d,J=4.0Hz,1H),6.84-6.80(m,2H),6.65-6.58(m,2H),6.58-6.52(m,1H),3.87(t,J=6.8Hz,2H),1.77(sex,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).MS(M+1):518.
化台物5-51
N-(4-(6-乙氧基吡啶-3-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(6-ethoxypyridin-3-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 8.68(d,J=2.4Hz,1H),8.04(dd,J=8.8,2.4Hz,1H),7.88(d,J=4.4Hz,1H),7.61(d,J=4.4Hz,1H),7.35-7.30(m,2H),7.14-7.08(m,3H),6.70(d,J=8.8Hz,1H),4.33(q,J=6.8Hz,2H),1.36(t,J=6.8Hz,3H).MS(M+1):469.
化合物5-52
5-硝基-N-(4-(4-丙氧基苯基)-5-(喹啉-8-基氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(quinolin-8-yloxy)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.27(br,1H),8.99(dd,J=4.4,1.6Hz,1H),8.46(dd,J=8.4,1.6Hz,1H),8.21-8.17(m,2H),7.94-7.90(m,2H),7.80(dd,J=8.4,0.8Hz,1H),7.66(dd,J=8.4,4.4Hz,1H),7.55(t,J=8.0Hz,1H),7.39(dd,J=8.0,0.8Hz,1H),6.95-6.91(m,2H),3.90(t,J=6.4Hz,2H),1.68(sex,J=6.8Hz,2H),0.93(t,J=7.2Hz,3H).MS(M+1):533.
化合物5-53
N-(4-(4-乙氧基-2-氟苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxy-2-fluorophenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.68(br,1H),7.60(d,J=4.0Hz,1H),7.37(t,J=8.8Hz,1H),7.34-7.29(m,3H),7.13-7.09(m,3H),6.56(dd,J=8.8,2.4Hz,1H),6.43(dd,J=12.0,2.4Hz,1H),3.91(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H).MS(M+1):486.
化合物5-54
N-(4-(4-乙氧基苯基)-5-(3-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(3-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.06(br,1H),7.63(d,J=4.4Hz,1H),7.62-7.59(m,2H),7.32(d,J=4.4Hz,1H),7.30-7.25(m,1H),6.89(dd,J=8.8,2.0Hz,1H),6.84-6.79(m,2H),6.79-6.75(m,2H),3.95(q,J=6.8Hz,2H),1.37(t,J=6.8Hz,3H).MS(M+1):486.
化合物5-55
N-(4-(4-乙氧基苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.33(br,1H),7.75(d,J=4.4Hz,1H),7.71-7.67(m,2H),7.44(d,J=4.4Hz,1H),7.08-7.04(m,2H),7.03-6.98(m,2H),6.84-6.81(m,2H),6.84-6.80(m,2H),3.99(q,J=6.8Hz,2H),1.38(t,J=6.8Hz,3H).MS(M+1):486.
化合物5-56
N-(4-(4-丁氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.73(d,J=4.4Hz,1H),7.64-7.71(m,2H),7.43(d,J=4.4Hz,1H),7.28-7.37(m,2H),7.07-7.16(m,3H),6.78-6.86(m,2H),3.91(t,J=6.6Hz,2H),1.68-1.78(m,2H),1.39-1.51(m,3H),0.95(t,J=7.3Hz,3H).MS(M+1):496.
化合物5-57
N-(4-(4-乙氧基苯基)-5-(2-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):13.36(br,1H),8.16-8.28(m,2H),7.79-7.85(m,J=8.8Hz,2H),7.38-7.47(m,1H),7.16-7.25(m,3H),6.97-7.02(m,J=9.3Hz,2H),4.04(q,J=7.2Hz,2H),1.32(t,J=7.1Hz,3H).MS(M+1):486.
化合物5-58
N-(5-(2-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):13.35(br,1H),8.15-8.29(m,2H),7.75-7.87(m,J=8.8Hz,2H),7.42(ddd,J=11.4,8.2,2.0Hz,1H),7.15-7.25(m,3H),6.96-7.03(m,2H),3.94(t,J=6.6Hz,2H),1.66-1.77(m,2H),0.97(t,J=7.3Hz,3H).MS(M+1):500.
化合物5-59
5-硝基-N-(4-(4-(三級戊基)苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-(tert-pentyl)phenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.64-7.68(m,2H),7.59(d,J=4.4Hz,1H),7.32-7.38(m,2H),7.27(d,J=3.9Hz,1H),7.20-7.24(m,2H),7.11-7.17(m,3H),1.55(q,J=7.3Hz,2H),1.19(s,6H),0.56-0.62(m,3H).MS(M+1):494.
化合物5-60
5-硝基-N-(4-(4-硝基苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-nitrophenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.17(br.s.,1H),8.20-8.26(m,2H),8.08-8.16(m,2H),7.93(d,J=4.4Hz,1H),7.61(d,J=3.9Hz,1H),7.34-7.42(m,2H),7.12-7.22(m,3H).MS(M+1):469.
化合物5-61
5-硝基-N-(5-苯氧基-4-(3,4,5-三甲氧基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.31(br.s.,1H),7.80(d,J=4.4Hz,1H),7.50(d,J=4.4Hz,1H),7.30-7.40(m,2H),7.06-7.16(m,3H),7.05(s,2H),3.80(s,3H),3.68-3.77(m,8H),1.23(t,J=6.8Hz,3H).MS(M+1):514.
化合物5-62
N-(4-(4-氟苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.12(br.s.,1H),7.81-7.87(m,2H),7.76-7.81(m,1H),7.46(d,J=4.4Hz,1H),7.25-7.32(m,2H),6.96-7.09(m,4H),1.61(q,J=7.3Hz,2H),1.25(s,6H),0.67(t,J=7.3Hz,3H).MS(M+1):512.
化合物5-63
N-(5-(4-氟苯氧基)-4-(4-(三級戊基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.14(br.s.,1H),7.60-7.73(m,3H),7.35(dd,J=4.4,2.0Hz,1H),7.14-7.29(m,2H),7.06-7.14(m,2H),6.95-7.06(m,2H),1.57(q,J=7.3Hz,2H),1.21(s,6H),0.61(t,J=7.6Hz,3H).MS(M+1):512.
化合物5-64
N-(5-(4-(叔丁基)苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.83(br.s.,1H),7.82-7.91(m,3H),7.52(d,J=4.4Hz,1H),7.29-7.39(m,2H),6.99-7.09(m,4H),1.29(s,9H).MS(M+1):498.
化合物5-65
N-(5-(4-丁基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.02(br.s.,1H),7.77-7.89(m,3H),7.46(d,J=4.4Hz,1H),7.08-7.18(m,2H),6.99-7.06(m,4H),2.50-2.63(m,2H),1.50-1.59(m,2H),1.33(dq,J=15.0,7.2Hz,2H),0.84-0.95(m,3H).MS(M+1):498.
化合物5-66
N-(5-(4-丁氧基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butoxyphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.79-7.90(m,3H),7.52(d,J=3.9Hz,1H),6.98-7.09(m,4H),6.80-6.88(m,2H),3.92(t,J=6.4Hz,2H),1.69-1.79(m,3H),1.42-1.53(m,3H),0.96(t,J=7.3Hz,3H).MS(M+1):514.
化合物5-67
N-(4-(4-(己氧基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(hexyloxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.73(br.s.,1H),7.61-7.72(m,3H),7.28-7.40(m,3H),7.07-7.16(m,3H),6.79(d,J=8.8Hz,2H),3.88(t,J=6.6Hz,2H),1.67-1.79(m,2H),1.38-1.49(m,2H),1.25-1.38(m,4H),0.84-0.94(m,3H).MS(M+1):524.
化合物5-68
N-(5-(4-(叔丁基)苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.83(br.s.,1H),7.82-7.91(m,3H),7.52(d,J=4.4Hz,1H),7.29-7.39(m,2H),6.99-7.09(m,4H),1.29(s,9H).MS(M+1):498.
化合物5-69
N-(5-(4-丁基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.02(br.s.,1H),7.77-7.89(m,3H),7.46(d,J=4.4Hz,1H),7.08-7.18(m,2H),6.99-7.06(m,4H),2.50-2.63(m,2H),1.50-1.59(m,2H),1.33(dq,J=15.0,7.2Hz,2H),0.84-0.95(m,3H).MS(M+1):498.
化合物5-70
N-(5-(4-丁氧基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butoxyphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.79-7.90(m,3H),7.52(d,J=3.9Hz,1H),6.98-7.09(m,4H),6.80-6.88(m,2H),3.92(t,J=6.4Hz,2H),1.69-1.79(m,3H),1.42-1.53(m,3H),0.96(t,J=7.3Hz,3H).MS(M+1):514.
化合物5-71
5-硝基-N-(5-(4-(三級戊基)苯氧基)-4-(4-(三氟甲基)苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-(4-(tert-pentyl)phenoxy)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):13.42(br.s.,1H),8.23(d,J=7.34Hz,2H),8.14(d,J=6.85Hz,2H),7.82(d,J=6.85Hz,2H),7.38(d,J=7.34Hz,2H),7.17(d,J=7.34Hz,2H),1.52-1.64(m,2H),1.23(s,6H),0.62(s,3H).MS(M+1):562.
化合物5-72
N-(4-(4-丁氧基苯基)-5-(2-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.88(br.s.,1H),7.61-7.73(m,3H),7.31(d,J=4.4Hz,1H),7.12-7.21(m,1H),7.00-7.12(m,3H),6.77-6.84(m,2H),3.89(t,J=6.4Hz,2H),1.68-1.76(m,2H),1.40-1.50(m,2H),0.95(t,J=7.3Hz,3H).MS(M+1):514.
化合物5-73
N-(4-(4-丁氧基苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.57-7.65(m,3H),7.31(d,J=4.4Hz,1H),6.98-7.09(m,4H),6.73-6.81(m,2H),3.88(t,J=6.6Hz,2H),1.67-1.76(m,2H),1.39-1.51(m,2H),0.95(t,J=7.3Hz,3H).MS(M+1):514.
化合物5-74
N-(4-(4-(叔丁基)苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.46(br.s.,1H),8.18-8.27(m,2H),7.78(dd,J=8.8,6.8Hz,4H),7.44(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H),1.26(s,9H).MS(M+1):548.
化合物5-75
N-(4-(4-(叔丁基)苯基)-5-(2-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.48(br.s.,1H),8.18-8.29(m,2H),7.79-7.87(m,3H),7.62-7.70(m,1H),7.42-7.48(m,2H),7.36(t,J=7.6Hz,1H),7.24(d,J=8.3Hz,1H),1.27(s,9H).MS(M+1):548.
化合物5-76
5-硝基-N-(4-(4-(戊氧基)苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-(pentyloxy)phenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.69(br.s.,1H),7.63-7.73(m,3H),7.29-7.39(m,3H),7.06-7.16(m,3H),6.79(d,J=8.8Hz,2H),3.88(t,J=6.4Hz,2H),1.74(quin,J=7.0Hz,2H),1.31-1.45(m,4H),0.85-0.95(m,3H).MS(M+1):510.
化合物5-77
5-硝基-N-(5-苯氧基-4-(4-丙基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-propylphenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.04(br.s.,1H),7.61-7.70(m,3H),7.31-7.39(m,3H),7.11-7.16(m,3H),7.08(d,J=8.3Hz,2H),2.42-2.57(m,2H),1.48-1.58(m,2H),0.81-0.96(m,3H).MS(M+1):466.
化合物5-78
N-(5-(2-氟苯氧基)-4-(4-丙基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-propylphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.48(br.s.,1H),7.65(d,J=8.3Hz,2H),7.46-7.62(m,1H),7.02-7.23(m,7H),2.38-2.56(m,2H),1.44-1.58(m,2H),0.76-0.98(m,3H).MS(M+1):484.
化合物5-79
N-(4-(4-丁基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.58-7.66(m,J=7.8Hz,2H),7.57(d,J=4.4Hz,1H),7.29-7.38(m,2H),7.26(d,J=4.4Hz,1H),7.09-7.16(m,3H),7.02-7.09(m,J=8.3Hz,2H),2.41-2.61(m,2H),1.41-1.52(m,2H),1.28(dq,J=15.0,7.2Hz,2H),0.81-0.95(m,3H).MS(M+1):480.
化合物5-80
N-(4-(4-丁基苯基)-5-(2-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-(2-f1uorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.68(d,J=7.8Hz,2H),7.63(d,J=4.4Hz,1H),7.30(d,J=3.9Hz,1H),7.16-7.24(m,1H),7.03-7.16(m,5H),2.47-2.59(m,2H),1.45-1.54(m,2H),1.24-1.35(m,2H),0.85-0.93(m,3H).MS(M+1):498.
化合物5-81
5-硝基-N-(5-苯氧基-4-(4-(三氟甲基)苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 1000(br.s.,1H),7.92-8.03(m,J=8.3Hz,2H),7.82(d,J=4.4Hz,1H),7.55-7.62(m,J=8.3Hz,2H),7.51(d,J=4.4Hz,1H),7.29-7.42(m,2H),7.09-7.20(m,3H).MS(M+1):492.
化合物5-82
N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-N-甲基-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-N-methyl-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):7.86(d,J=4.0Hz,1H),7.70(d,J=4.4Hz,1H),7.29-7.24(m,4H),7.08(t,J=8.0Hz,1H),7.01-6.99(m,2H),6.97-6.94(m,2H),4.04(q,J=6.8Hz,2H),3.66(s,3H),1.41(t,J=6.8Hz,3H).MS(M+1):482.
化合物5-83
N-(5-(2-氟苯氧基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.87(br.s.,1H),8.01-8.08(m,J=8.3Hz,2H),7.81-7.87(m,1H),7.59-7.66(m,J=8.3Hz,2H),7.54(d,J=3.9Hz,1H),7.04-7.23(m,4H).MS(M+1):510.
化合物5-84
5-硝基-N-(5-苯氧基-4-(4-(三氟甲氧基)苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.87(br.s.,1H),7.87-7.92(m,2H),7.84(d,J=4.4Hz,1H),7.51-7.54(m,1H),7.32-7.38(m,2H),7.10-7.21(m,5H).MS(M+1):508.
化合物5-85
N-(5-(2-氟苯氧基)-4-(4-(三氟甲氧基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.58(br.s.,1H),7.88(d,J=8.8Hz,2H),7.74(d,J=4.4Hz,1H),7.42(d,J=4.4Hz,1H),7.04-7.23(m,6H).MS(M+1):526.
化合物5-86
N-(5-(4-溴苯氧基)-4-(4-丁氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenoxy)-4-(4-butoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 9.94(br.s.,1H),7.82(d,J=4.4Hz,1H),7.63-7.73(m,2H),7.47-7.54(m,1H),7.35-7.45(m,2H),6.93-7.02(m,2H),6.79-6.89(m,2H),3.93(t,J=6.6Hz,2H),1.69-1.79(m,2H),1.40-1.50(m,2H),0.95(t,J=7.3Hz,3H).MS(M+1):574.
化合物5-87
N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-丁氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-butoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.75(d,J=4.4Hz,1H),7.65-7.70(m,2H),7.45(d,J=4.4Hz,1H),6.80-6.85(m,4H),3.92(t,J=6.6Hz,2H),2.36(s,6H),1.69-1.77(m,2H),1.41-1.49(m,2H),0.95(t,J=7.6Hz,3H).MS(M+1):602.
化合物5-88
N-(4-(4-(叔丁基)苯基)-5-(4-丙基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-propylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.23(br.s.,1H),7.54-7.65(m,J=8.3Hz,2H),7.45(d,J=4.4Hz,1H),7.23(d,J=8.3Hz,2H),7.11-7.19(m,3H),7.00-7.11(m,2H),2.56(t,J=7.6Hz,2H),1.54-1.68(m,2H),0.93(t,J=7.3Hz,3H).MS(M+1):522.
化合物5-89
N-(4-(4-(叔丁基)苯基)-5-(4-丁基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-butylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.66(br.s.,1H),7.59-7.69(m,2H),7.55(d,J=4.4Hz,1H),7.23-7.29(m,3H),7.11-7.18(m,2H),6.99-7.08(m,2H),2.52-2.64(m,2H),1.50-1.60(m,2H),1.30-1.42(m,2H),1.20-1.26(m,9H),0.92(t,J=7.3Hz,3H).MS(M+1):536.
化合物5-90
N-(4-(4-丁氧基苯基)-5-(4-(叔丁基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-(tert-butyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.58(d,J=8.3Hz,2H),7.47(d,J=3.9Hz,1H),7.27-7.42(m,J=8.3Hz,2H),7.17(d,J=3.4Hz,1H),6.95-7.12(m,J=8.3Hz,2H),6.71(d,J=8.3Hz,2H),3.84(t,J=6.1Hz,2H),1.60-1.85(m,2H),1.37-1.60(m,2H),1.30(s,9H),0.95(t,J=7.3Hz,3H).MS(M+1):552.
化合物5-91
N-(4-(4-丁氧基苯基)-5-(4-氰基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-cyanophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.82(d,J=4.4Hz,1H),7.57-7.66(m,4H),7.55(d,J=4.4Hz,1H),7.10-7.18(m,2H),6.77-6.87(m,2H),3.91(t,J=6.6Hz,2H),1.68-1.77(m,2H),1.40-1.51(m,2H),0.94(t,J=7.3Hz,3H).MS(M+1):521.
化合物5-92
N-(4-(4-((5-胺基戊基)氧基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-((5-aminopentyl)oxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.32(br.s.,1H),8.21(d,J=1.00Hz,1H),7.81(d,J=8.80Hz,2H),7.73(br.s.,2H),7.37-7.45(m,2H),7.13-7.20(m,2H),6.96-7.00(m,2H),3.98(t,J=6.36Hz,2H),2.79(br.s,2H),2.51-2.54(m,2H),1.67-l.78(m,2H),1.54-1.64(m,2H),1.40-1.50(m,2H).MS(M+1):525.
化合物5-93
N-(4-(4-丁氧基苯基)-5-(4-丙基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-propylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.28(br.s.,1H),7.48-7.66(m,J=8.8Hz,2H),7.42(d,J=3.9Hz,1H),7.08-7.21(m,3H),6.97-7.08(m,J=8.3Hz,2H),6.69(d,J=8.8Hz,2H),3.83(t,J=6.4Hz,2H),2.55(t,J=7.6Hz,2H),1.66-1.84(m,2H),1.50-1.66(m,2H),1.44(dq,J=14.7,7.5Hz,2H),0.94(d,J=7.8Hz,3H),0.82-1.05(m,3H).MS(M+1):538.
化合物5-94
N-(4-(4-丁基苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.99(br.s.,1H),7.58-7.68(m,3H),7.35(d,J=4.4Hz,1H),7.05-7.17(m,4H),6.95-7.05(m,2H),2.45-2.58(m,2H),1.47-1.57(m,2H),1.25-1.36(m,2H),0.85-0.95(m,3H).MS(M+1):498.
化合物5-95
N-(4-(4-(叔丁基)苯基)-5-(4-丙氧基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-propoxyphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.80(br.s.,1H),7.69-7.75(m,2H),7.68(d,J=4.4Hz,1H),7.36(d,J=4.4Hz,1H),7.29-7.35(m,2H),7.02-7.10(m,2H),6.79-6.90
(m,2H),3.88(t,J=6.6Hz,2H),1.73-1.84(m,2H),1.26(s,9H),1.02(t,J=7.3Hz,3H).MS(M+1):538.
化合物5-96
N-(5-(4-(叔丁基)苯氧基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ ll.18(br.s.,1H),7.66-7.71(m,2H),7.62(d,J=4.4Hz,1H),7.33-7.38(m,2H),7.27-7.32(m,3H),7.04-7.10(m,2H),1.30(s,9H),1.24(s,9H).MS(M+1):536.
化合物5-97
N-(4-(4-(叔丁基)苯基)-5-(4-(2,4,4-三甲基戊-2-基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.94(br.s.,1H),7.62(d,J=8.3Hz,2H),7.50(d,J=3.9Hz,1H),7.29-7.39(m,J=8.8Hz,2H),7.22-7.28(m,2H),7.20(d,J=4.4Hz,1H),6.99-7.10(m,J=8.8Hz,2H),1.71(s,3H),1.35(s,6H),1.21(s,9H),0.71(s,9H).MS(M+1):592.
化合物5-98
N-(4-(4-丁氧基苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.07(br.s.,1H),7.64-7.70(m,2H),7.63(d,J=4.4Hz,1H),7.32(d,J=3.9Hz,1H),7.25-7.29(m,2H),7.01-7.08(m,2H),6.74-6.81(m,2H),3.89(t,J=6.6Hz,2H),1.67-1.79(m,2H),1.57-1.64(m,2H),1.39-1.51(m,2H),1.25(s,6H),0.95(t,J=7.3Hz,3H),0.67(t,J=7.3Hz,3H).MS(M+1):566.
化合物5-99
N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.16(br.s.,1H),7.64-7.69(m,1H),7.59-7.64(m,2H),7.33(d,J=4.4Hz,1H),7.26-7.31(m,2H),6.86(s,2H),2.38(s,6H),1.24(s,9H).MS(M+1):586.
化合物5-100
N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.90(d,J=4.4Hz,1H),7.79-7.87(m,2H),7.59(d,J=4.4Hz,1H),7.02-7.10(m,2H),6.83(s,2H),2.37(s,6H).MS(M+1):548.
化合物5-101
N-(4-(4-(叔丁基)苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.18(br.s.,1H),7.69(d,J=8.3Hz,2H),7.62(d,J=4.4Hz,1H),7.25-7.37(m,5H),7.02-7.14(m,2H),1.59-1.65(m,2H),1.26(s,6H),1.24(s,9H),0.67(t,J=7.3Hz,3H).MS(M+1):550.
化合物5-102
N-(5-(4-(叔丁基)苯氧基)-4-(4-乙基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-ethylphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.47(br.s.,1H),7.64(d,J=8.3Hz,2H),7.57(d,J=4.4Hz,1H),7.31-7.38(m,2H),7.26(d,J=3.9Hz,1H),7.03-7.10(m,4H),2.54(q,J=7.5Hz,2H),1.30(s,9H),1.15(t,J=7.6Hz,3H).MS(M+1):508.
化合物5-103
N-(4-(4-乙基苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethylphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.64(br.s.,1H),7.62(d,J=8.3Hz,2H),7.53(d,J=3.9Hz,1H),7.25-7.33(m,2H),7.21-7.25(m,1H),7.03-7.11(m,4H),2.53(q,J=7.8Hz,2H),1.56-1.64(m,2H),1.26(s,6H),1.14(t,J=7.6Hz,3H),0.67(t,J=7.3Hz,3H).MS(M+1):522.
化合物5-104
N-(4-(4-丁基苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.23(br.s.,1H),7.65(d,J=7.8Hz,2H),7.56-7.62(m,1H),7.25-7.32(m,3H),7.00-7.14(m,4H),2.51(t,J=7.8Hz,2H),
1.57-1.65(m,2H),1.44-1.52(m,2H),1.27-1.34(m,2H),1.22-1.27(m,6H),0.89(t,J=7.3Hz,3H),0.67(t,J=7.6Hz,3H).MS(M+1):550.
化合物5-105
N-(4-(4-(叔丁基)苯基)-5-(對-甲苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(p-tolyloxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.29(br.s.,1H),7.66(d,J=8.8Hz,2H),7.60(d,J=3.9Hz,1H),7.26-7.36(m,3H),7.09-7.17(m,J=8.3Hz,2H),6.97-7.08(m,2H),2.32(s,3H),1.24(s,9H)
MS(M+1):494.
化合物5-106
N-(4-(4-丁氧基苯基)-5-(3,5-二甲基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(3,5-dimethylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.00(br.s.,1H),7.60-7.70(m,3H),7.32(dd,J=4.4,1.0Hz,1H),6.74-6.81(m,3H),6.73(s,2H),3.89(t,J=6.6Hz,2H),2.28(s,6H),1.67-1.77(m,2H),1.39-1.51(m,2H),0.95(t,J=7.3Hz,3H).MS(M+1):524.
化合物5-107
N-(4-(4-(叔丁基)苯基)-5-(4-(二甲基胺基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(dimethylamino)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 762-7.75(m,2H),7.58(d,J=4.4Hz,1H),7.28-7.33(m,2H),7.27(d,J=4.4Hz,1H),7.00-7.11(m,2H),6.63-6.76(m,2H),2.92(s,6H),1.24(s,9H).MS(M+1):523.
化合物5-108
N-(4-(4-(叔丁基)苯基)-5-(4-嗎啉基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-morpholinophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.13(br.s.,1H),7.66-7.74(m,2H),7.62(d,J=3.9Hz,1H),7.26-7.35(m,3H),7.05-7.12(m,2H),6.83-6.92(m,2H),3.85(dd,J=5.6,4.2Hz,4H),3.04-3.15(m,4H),1.25(s,9H).MS(M+1):565.
實施例6之化合物的典型合成方法
1-(4-(叔丁基)苯基)-2-(4-氟苯基)乙-1-酮(1-(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)ethan-1-one)的合成
在冰浴下,取叔丁基苯(tert-butylbenzene,9.33g,69.5mmol)溶於氯仿(40mL),於0℃攪拌20分鐘後加入氯化鋁(9.3g,70mmol),接著在0℃下,逐滴加
入溶於氯仿(20mL)的2-(4-氟苯基)乙醯氯(10.0g,58mmol)。移除冰浴並在室溫下攪拌1小時,之後,以冷水(250mL)終止反應,並以二氯甲烷萃取,在真空下通過旋轉蒸發移除溶劑。粗產物藉由急速層析法(己烷:乙酸乙酯=1:0-9:1)純化,以提供紅色固體的1-(4-(叔丁基)苯基)-2-(4-氟苯基)乙-1-酮(12.9g,產率82%)。
形成2-溴-1-(4-乙氧基苯基)乙酮(2-Bromo-1-(4-ethoxyphenyl)ethanone formation)的合成
藉由冰浴在0℃下,取1-(4-(叔丁基)苯基)-2-(4-氟苯基)乙-1-酮(12.0g,44mmol)溶於氯仿(55mL),加入氯化鋁(0.3g,2.22mmol)。藉由冰浴在0℃下,將生成的混合物加入至溶於氯仿(55mL)的溴(7.8g,49mmol)中,並在室溫下攪拌4小時。接著加入水(400mL)並以二氯甲烷(200mL)萃取,有機相以食鹽水洗,硫酸鈉乾燥並在真空下濃縮。粗產物藉由急速層析法(己烷:乙酸乙酯=1:0-9:1)純化,以提供2-溴-1-(4-(叔丁基)苯基)-2-(4-氟苯基)乙-1-酮(12.4g,產率80%)。
4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-胺(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-amine)的合成
向硫脲(3.24g,42.6mmol)和2-溴-1-(4-(叔丁基)苯基)-2-(4-氟苯基)乙-1-酮(12.4g,35.5mmol)的混合物中加入乙醇(62mL),將反應混合物加熱回流16小時。接著,反應冷卻至40℃並移除乙醇,以乙酸乙酯(200ml)和飽和溶液(150ml)萃
取。粗產物藉由急速層析法(己烷:乙酸乙酯=1:0-8:2)純化,以提供黃色粉末的4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-胺(8.8g,產率75%)。
N-(4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻酚-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)的合成
取5-硝基噻酚-2-羧酸(5.1g,29.4mmol)、4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-胺(8.0g,24.5mmol)、EDCl(11.3g,58.8mmol)和HOBt(7.95g,58.8mmol)溶於二氯甲烷(600mL)在室溫下攪拌至隔夜,萃取並移除溶劑。粗產物藉由急速層析法(己烷:乙酸乙酯=1:0-7:3)純化,以提供紅色固體粉末(13.6g)。粗產物以二氯甲烷(500mL)在40℃(以0.45uM過濾)下和乙醇(450mL)在80℃下漿液化(slurry)1小時,藉由蒸餾移除二氯甲烷和乙醇(200mL),並將溶液冷卻至室溫,然後抽吸以提供紅色固體粉末的N-(4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻酚-2-甲醯胺(8.8g,74%)。
實施例6:化合物6-1至6-61
化合物6-1
5-硝基-N-(4-(3-硝基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(3-nitrophenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.41(br.s.,1H),8.81(t,J=1.7Hz,1H),8.40(d,J=8.3Hz,1H),8.28(d,J=4.4Hz,1H),8.22-8.24(m,1H),8.20(dd,J=8.1,1.7Hz,1H),8.09(s,1H),7.76(t,J=8.1Hz,1H).MS(M+1):377.
化合物6-2
N-(5-(4-溴苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.75(br.s.,1H),7.55(d,J=4.4Hz,1H),7.46-7.42(m,2H),7.23-7.15(m,5H),6.96(d,J=8.0Hz,2H),2.23(s,3H).MS(M+1):500.
化合物6-3
5-硝基-N-(5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.26(br,1H),8.21(t,J=2.0Hz,1H),8.16-8.14(m,1H),7.69(d,J=44Hz,1H),7.64-7.62(m,1H),7.48(t,J=8.4Hz,1H),7.40(d,J
=4.4Hz,1H),7.20(d,J=8.0Hz,1H),7.03(d,J=8.0Hz,1H),2.28(s,3H).MS(M+1):467.
化合物6-4
N-(5-(3,4-二甲氧基苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,4-dimethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.58(br,1H),7.59(d,J=4.0Hz,1H),7.29(d,J=4.4Hz,1H),7.21(d,J=7.6Hz,2H),6.98(d,J=7.6Hz,2H),6.93(dd,J=8.4,2.0Hz,1H),6.82(d,J=8.4Hz,1H),6.79(d,J=2.0Hz,1H),3.88(s,3H),3.67(s,3H),2.24(s,3H).MS(M+1):482
化合物6-5
N-(5-(3,5-雙(三氟甲基)苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.84(br,1H),7.78(s,1H),7.75(s,2H),7.56(d,J=4.4Hz,1H),7.24(d,J=4.0Hz,1H),7.14(d,J=8.4Hz,2H),6.99(d,J=8.4Hz,2H),2.25(s,3H).MS(M+1):558.
化合物6-6
N-(5-(4-氟苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.09(br,1H),7.49(d,J=4.4Hz,1H),7.33-7.28(m,2H),7.18(d,J=4.4Hz,1H),7.14(d,J=8.4Hz,2H),7.05-6.99(m,2H),6.93(d,J=7.6Hz,2H),2.21(s,3H).MS(M+1):440.
化合物6-7
N-(4-(4-溴苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 804(s,1H),7.84(d,J=3.6Hz,1H),7.64-7.61(m,3H),7.53-7.49(m,2H),7.21(s,1H).MS(M+1):410.
化合物6-8
N-(4-(3-甲氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(3-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.75(br,1H),7.77(d,J=4.0Hz,1H),7.48(d,J=4.4Hz,1H),7.29-7.26(m,3H),7.20(s,1H),6.85-6.82(m,1H).MS(M+1):362.
化合物6-9
N-(4-(4-溴苯基)-5-苯基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-phenylthiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.79(d,J=4.4Hz,1H),7.65(d,J=4.4Hz,1H),7.40-7.36(m,2H),7.35-7.29(m,5H),7.24-7.21(m,2H).MS(M+1):486.
化合物6-10
N-(5-溴-4-(4-溴苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(4-bromophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.67(br,1H),8.24-8.21(m,2H),7.87-7.84(m,2H),7.74-7.70(m,2H).MS(M+1):485.
化合物6-11
5-硝基-N-(4-(2-硝基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(2-nitrophenyl)thiazol-2-yl)thiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.28(br,1H),8.25(br,1H),8.20(d,J=4.4Hz,1H),7.95(d,J=7.6Hz,1H),7.81-7.75(m,2H),7.67-7.64(m,2H).MS(M+1):377.
化合物6-12
N-(5-溴-4-(2-硝基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(2-nitrophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.61(br,1H),8.22-8.20(m,2H),8.14-8.11(m,1H),7.89-7.85(m,1H),7.78-7.73(m,2H).MS(M+1):455.
化合物6-13
N-(5-溴-4-(3-硝基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(3-nitrophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,丙酮-d6):δ 12.19(br,1H),8.12(t,J=2.0Hz,1H),8.51-8.48(m,1H),8.32-8.29(m,1H),8.28(d,J=4.4Hz,1H),8.14(d,J=4.4Hz,1H),7.83(t,J=8.0Hz,1H).MS(M+1):455.
化合物6-14
N-(5-溴-4-(3-甲氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(3-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,丙酮-d6):δ 12.07(br,1H),8.25(d,J=4.4Hz,1H),8.13(d,J=4.4Hz,1H),7.53-7.47(m,2H),7.41(t,J=8.0Hz,1H),7.02-6.99(m,1H),3.86(s,3H).MS(M+1):440.
化合物6-15
N-(4-(4-乙氧基苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.60(d,J=4.0Hz,1H),7.33-7.29(m,3H),7.21-7.18(m,2H),7.04-6.99(m,2H),6.69-6.66(m,2H),3.93(q,J=6.8Hz,2H),1.37(t,J=6.8Hz,3H).MS(M+1):470.
化合物6-16
N-(5-(4-氟苯基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.08(br,1H),7.55(d,J=4.4Hz,1H),7.32-7.27(m,3H),7.19-7.16(m,2H),7.04-6.98(m,2H),6.67-6.64(m,2H),3.80(t,J=6.4Hz,2H),1.76(sex,J=7.2Hz,2H),1.01(t,J=7.2Hz,3H).MS(M+1):484.
化合物6-17
N-(5-溴-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.20(d,J=3.9Hz,1H),7.84(s,1H),7.73(d,J=8.3Hz,1H),7.38(d,J=8.8Hz,1H),6.99(d,J=8.8Hz,1H),6.92(d,J=8.3Hz,1H),4.05(dd,J=14.4,7.1Hz,2H),1.33(q,J=7.3Hz,3H).MS(M+1):455
化合物6-18
N-(4-(4-丁氧基苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.29(br.s,1H),7.47(d,J=4.4Hz,1H),7.34-7.29(m,2H),7.16-7.13(m,3H),7.04-6.99(m,2H),6.63-6.59(m,2H),3.81(t,J=5.6Hz,2H),1.74-1.67(m,2H),1.45(sex,J=7.2Hz,2H),0.96(t,J=7.2Hz,3H).MS(M+1):498.
化合物6-19
N-(4-(4-乙氧基苯基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.26(br.s,1H),8.20(d,J=3.9Hz,1H),7.85(d,J=8.8Hz,1H),7.73(d,J=8.3Hz,1H),7.50-7.61(m,1H),7.38(d,J=8.8Hz,1H),6.99(d,J=8.8Hz,1H),6.92(d,J=8.3Hz,1H),4.05(dq,J=14.3,7.0Hz,2H),1.33(q,J=7.3Hz,3H).MS(M+1):520
化合物6-20
N-(5-(4-溴-3-乙氧基苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3-ethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.87(br,1H),7.57(d,J=4.4Hz,1H),7.52(d,J=8.8Hz,1H),7.29(d,J=4.4Hz,1H),7.16(d,J=8.8Hz,2H),6.93(d,J=8.0Hz,2H),6.86(d,J=3.2Hz,1H),6.81(dd,J=8.8,2.8Hz,1H),4.10(q,J=7.2Hz,2H),2.20(s,3H),1.34(t,J=6.8Hz,3H).MS(M+1):544.
化合物6-21
N-(4-(4-(叔丁基)苯基)-5-苯基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-phenylthiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.87(br.s,1H),7.59(d,J=4.4Hz,1H),7.38-7.31(m,6H),7.28-7.25(m,2H),7.19-7.17(m,2H),1.22(s,9H).MS(M+1):464.
化合物6-22
N-(5-(4-甲基哌嗪-1-基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-methylpiperazin-1-yl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 12.85(br,1H),8.18(d,J=4.4Hz,1H),8.15(d,J=4.4Hz,1H),8.05-8.01(m,2H),7.01-6.97(m,2H),3.96(t,J=6.8Hz,2H),2.90(t,J=4.4Hz,4H),2.55(br,4H),2.29(s,3H),1.74(sex,J=7.2Hz,2H),0.99(t,J=7.2Hz,3H).MS(M+1):488.
化合物6-23
2-(5-硝基噻吩-2-甲醯胺基)-4-(4-丙氧基苯基)噻唑-5-甲酸乙酯(ethyl 2-(5-nitrothiophene-2-carboxamido)-4-(4-propoxyphenyl)thiazole-5-carboxylate)
1H NMR(400MHz,DMSO-d6):δ 13.70(br,1H),8.23-8.20(m,2H),7.72(d,J=8.8Hz,2H),7.01-6.97(m,2H),4.22(q,J=7.2Hz,2H),3.99(t,J=6.8Hz,2H),1.76(sex,J=7.2Hz,2H),1.24(t,J=7.2Hz,3H),1.00(t,J=7.2Hz,3H).MS(M+1):462.
化合物6-24
N-(4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.59(d,J=4.4Hz,1H),7.36-7.31(m,2H),7.29(d,J=4.4Hz,1H),7.26-7.23(m,2H),7.19(d,J=8.4Hz,2H),7.06-7.01(m,2H),1.22(s,9H).MS(M+1):482.
化合物6-25
N-(4-(2,4-二乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(2,4-diethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.21(s,1H),8.26-8.20(m,2H),8.05(br,1H),7.63(br,1H),6.63-6.61(m,2H),4.16(q,J=6.8Hz,2H),4.08(q,J=6.8Hz,2H),1.45(t,J=6.8Hz,3H),1.34(t,J=6.8Hz,3H).MS(M+1):420.
化合物6-26
N-(4-(4-二甲基胺基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(dimethylamino)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.27(s,1H),8.25-8.20(m,2H),7.75(d,J=8.8Hz,2H),7.42(br,1H),6.79-6.75(m,2H),2.94(s,6H).MS(M+1):375.
化合物6-27
N-(3,5-二氟苯基)-4-(4-乙氧基苯基)-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲醯胺(N-(3,5-difluorophenyl)-4-(4-ethoxyphenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.66(br,1H),10.62(s,1H),8.25-8.22(m,2H),7.66(d,J=8.8Hz,2H),7.34-7.29(m,2H),6.99-6.94(m,3H),4.06(q,J=6.8Hz,2H),1.33(t,J=6.8Hz,3H).MS(M+1):531.
化合物6-28
N-(4-(4-乙氧基苯基)-5-(甲基(苯基)胺基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(methyl(phenyl)amino)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.28(br.s.,1H),8.21(d,J=4.4Hz,2H),7.74(d,J=7.8Hz,2H),7.23(t,J=7.8Hz,2H),6.93(d,J=8.8Hz,2H),6.76-6.85(m,3H),4.02(q,J=6.8Hz,2H),3.19(s,3H),1.31(t,J=6.8Hz,3H).MS(M+1):481.
化合物6-29
N-(5-(嗎啉基-4-羰基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(morpholine-4-carbonyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.19-8.16(m,2H),7.53(d,J=8.8Hz,2H),7.04(d,J=8.8Hz,2H),3.96(t,J=6.4Hz,2H),3.16(br,8H),1.73(sex,J=6.8Hz,2H),0.97(t,J=7.2Hz,3H).MS(M+1):503.
化合物6-30
N-(5-(4-甲基哌嗪-1-羰基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-methylpiperazine-1-carbonyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.16(d,J=4.4Hz,1H),8.07(d,J=4.4Hz,1H),7.53(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),3.97(t,J=6.8Hz,2H),2.19(br,10H),1.74(sex,J=6.8Hz,2H),0.98(t,J=7.2Hz,3H).MS(M+1):516.
化合物6-31
N-(2,4-二氟苯基)-2-(5-硝基噻吩-2-甲醯胺基)-4-(4-丙氧基苯基)噻唑-5-甲醯胺(N-(2,4-difluorophenyl)-2-(5-nitrothiophene-2-carboxamido)-4-(4-propoxyphenyl)thiazole-5-carboxamide)
1H NMR(400MHz,CDCl3):δ 10.12(s,1H),8.30-8.24(m,1H),7.85(d,J=4.4Hz,1H),7.71(s,1H),7.53-7.50(m,3H),7.02-6.98(m,2H),6.86-6.82(m,1H),6.76-6.71(m,1H),3.96(t,J=6.8Hz,2H),1.84(sex,J=6.8Hz,2H),1.05(t,J=7.2Hz,3H).MS(M+1):545.
化合物6-32
N-(5-(4-溴苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基呋喃基-2-甲醯胺(N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.41(br s,1H),7.91(br s,1H),7.83(d,J=4.0Hz,1H),7.60-7.56(m,2H),7.34(d,J=7.6Hz,2H),7.29(d,J=7.2Hz,2H),7.17(d,J=8.0Hz,2H),2.31(s,3H).LCMS,[M+1]+:484.
化合物6-33
N-(5-苄基-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基呋喃基-2-甲醯胺(N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrofuran-2-carboxamid)
1H NMR(400MHz,CDCl3):δ 7.39-7.46(m,2H),7.26-7.35(m,4H),7.20-7.26(m,6H),6.84-6.90(m,2H),4.21(s,2H),4.03(q,J=6.8Hz,2H),1.41(t,J=7.1Hz,3H).LCMS,[M+1]+:450.
化合物6-34
N-(5-苄基-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.55-7.62(m,1H),7.25-7.34(m,6H),7.17-7.23(m,2H),6.79(d,J=8.8Hz,2H),4.16(s,2H),3.97(q,J=6.8Hz,2H),1.39(t,J=7.1Hz,3H).MS(M+1):466
化合物6-35
N-(4-(4-乙氧基苯基)-5-(4-氟苄基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.51(d,J=3.9Hz,1H),7.20-7.29(m,2H),7.11-7.20(m,3H),6.99(t,J=8.8Hz,2H),6.71-6.78(m,2H),4.13(s,2H),3.95(q,J=6.8Hz,2H),1.39(t,J=7.1Hz,3H).MS(M+1):484.
化合物6-36
N-(4-(4-乙氧基苯基)-5-(3-氟苄基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(3-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.77(br.s.,1H),7.56(d,J=4.4Hz,1H),7.24-7.32(m,4H),6.99(d,J=8.3Hz,1H),6.94(td,J=8.3,2.4Hz,1H),6.85-6.90(m,
1H),6.73-6.81(m,2H),4.16(s,2H),3.96(q,J=7.0Hz,2H),1.39(t,J=6.8Hz,3H).MS(M+1):484.
化合物6-37
N-(4-(4-(叔丁基)苯基)-5-(4-氟苄基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.54(d,J=3.9Hz,1H),7.31(d,J=2.4Hz,4H),7.21-7.26(m,2H),7.18(dd,J=8.8,5.4Hz,2H),7.01(t,J=8.8Hz,2H),4.18(s,2H),1.23-1.27(m,9H).MS(M+1):496.
化合物6-38
N-(4-(4-(叔丁基)苯基)-5-(3,5-二氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3,5-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.59(d,J=4.4Hz,1H),7.20-7.28(m,5H),6.87(dd,J=8.1,2.2Hz,2H),6.77(s,1H),1.23(s,9H).MS(M+1):500.
化合物6-39
N-(4-(4-(叔丁基)苯基)-5-(2,4-二氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2,4-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.53(d,J=4.4Hz,1H),7.28(d,J=6.4Hz,1H),7.14-7.23(m,5H),6.84-6.95(m,2H),1.18-1.23(m,9H).MS(M+1):500.
化合物6-40
N-(5-(4-氟苯基)-4-(4-(三級戊基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenyl)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.06-8.13(m,2H),7.29-7.37(m,5H),7.21-7.27(m,2H),7.13-7.21(m,2H),1.54(q,J=7.3Hz,2H),1.19(s,6H),0.57(t,J=7.3Hz,3H).MS(M+1):496.
化合物6-41
N-(4-(4-(叔丁基)苯基)-5-(3-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.61(d,J=4.4Hz,1H),7.28-7.34(m,2H),7.25-7.28(m,2H),7.19-7.23(m,2H),7.16(dt,J=7.8,1.2Hz,1H),6.99-7.08(m,2H),1.20-1.25(m,9H).MS(M+1):482.
化合物6-42
4-(4-(叔丁基)苯基)-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲酸乙酯(ethyl 4-(4-(tert-butyl)phenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxylate)
1H NMR(400MHz,CDCl3):δ 11.32(br.s.,1H),7.67(d,J=3.9Hz,1H),7.52-7.60(m,2H),7.30-7.38(m,2H),7.25(d,J=4.4Hz,1H),4.30(q,J=7.3Hz,2H),1.31(t,J=7.1Hz,3H),1.27(s,9H).MS(M+1):460.
化合物6-43
N-(4-(4-(叔丁基)苯基)-5-(4-甲基哌嗪-1-羰基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-methylpiperazine-1-carbonyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 8.19(d,J=4.4Hz,2H),8.12(d,J=4.4Hz,2H),7.56(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),3.30-3.38(m,8H),2.14(s,3H),1.32(s,9H).MS(M+1):514.
化合物6-44
4-(4-(叔丁基)苯基)-N-環丙基-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲醯胺(4-(4-(tert-butyl)phenyl)-N-cyclopropyl-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.51(br.s.,1H),8.34(d,J=4.4Hz,1H),8.21(d,J=4.4Hz,1H),7.64(d,J=8.3Hz,2H),7.47(d,J=8.3Hz,2H),2.72-2.84(m,1H),1.32(s,9H),0.55-0.71(m,2H),0.39-0.51(m,2H).MS(M+1):471
化合物6-45
4-(4-乙氧基苯基)-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲酸乙酯(ethyl 4-(4-ethoxyphenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxylate)
1H NMR(400MHz,CDCl3):δ 11.04(br.s.,1H),7.70(d,J=3.9Hz,1H),7.48-7.61(m,J=8.8Hz,2H),7.32(d,J=4.4Hz,1H),6.75-6.87(m,J=8.8Hz,2H),4.29(q,J=7.3Hz,2H),4.00(q,J=7.0Hz,2H),1.41(t,J=7.1Hz,3H),1.31(t,J=7.1Hz,3H).MS(M+1):448.
化合物6-46
N-(4-(4-(叔丁基)苯基)-5-(3,4-二氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3,4-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.31(br.s.,1H),7.48(d,J=3.9Hz,1H),7.07-7.22(m,8H),1.20(s,9H).MS(M+1):500.
化合物6-47
N-(5-(2,4-二氟苯基)-4-(4-(三級戊基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2,4-difluorophenyl)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.13(br.s.,1H),7.52(d,J=4.4Hz,1H),7.27(td,J=8.3,6.4Hz,1H),7.21(d,J=8.3Hz,2H),7.19(d,J=4.4Hz,1H),7.10(d,J=8.3Hz,2H),6.84-6.94(m,2H),1.50(q,J=7.5Hz,2H),1.15(s,6H),0.57(t,J=7.3Hz,3H).MS(M+1):514.
化合物6-48
N-(4-(4-(叔丁基)苯基)-5-(2-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.99(s,1H),7.54(d,J=4.4Hz,1H),7.27-7.42(m,2H),7.20-7.27(m,3H),7.08-7.18(m,4H),1.20(s,9H).MS(M+1):482.
化合物6-49
N-(4-(4-(叔丁基)苯基)-5-(嗎啉-4-羰基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(morpholine-4-carbonyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 8.22(s,2H),7.58(d,J=8.31Hz,2H),7.52(d,J=8.80Hz,2H),3.54(br.s.,4H),3.11(br.s.,4H),1.31(s,9H).MS(M+1):501.
化合物6-50
N-(4-(4-(叔丁基)苯基)-5-氰基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-cyanothiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 14.17(br.s.,1H),8.22(s,2H),7.94-8.01(m,J=8.8Hz,2H),7.57-7.64(m,J=8.3Hz,2H),1.33(s,9H).MS(M+1):413.
化合物6-51
N-(4-(4-(叔丁基)苯基)-5-(3,4,5-三氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3,4,5-trifluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.63(br.s.,1H),7.29(br.s.,1H),7.12-7.24(m,4H),6.84-7.02(m,3H).MS(M+1):518.
化合物6-52
N-(4-(4-(叔丁基)苯基)-5-(2,4,6-三氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2,4,6-trifluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.62(d,J=4.4Hz,1H),7.29(d,J=4.4Hz,1H),7.22-7.27(m,6H),7.17-7.22(m,2H),6.75(dd,J=8.6,7.1Hz,2H),1.22(s,9H).MS(M+1):518.
化合物6-53
N-(5-(4-溴苯基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.92(br.s.,1H),7.59(d,J=4.4Hz,1H),7.46-7.56(m,2H),7.25-7.30(m,7H),7.20-7.25(m,2H),1.26(s,10H).MS(M+1):542.
化合物6-54
N-(4-(4-(叔丁基)苯基)-5-(4-甲氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.46(d,J=4.4Hz,1H),7.26-7.32(m,2H),7.21-7.25(m,3H),7.10-7.16(m,3H),6.84-6.91(m,2H),3.83(s,3H),1.16-1.21(m,9H).MS(M+1):494.
化合物6-55
N-(4-(4-(叔丁基)苯基)-5-(2-氯苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.60(d,J=3.9Hz,1H),7.51(dd,J=8.1,1.2Hz,1H),7.32-7.40(m,2H),7.25-7.32(m,2H),7.18-7.23(m,2H),7.12-7.18(m,2H),1.20(s,9H).MS(M+1):498.
化合物6-56
N-(4-(4-(叔丁基)苯基)-5-(3-氯苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.10(br.s.,1H),7.52(d,J=3.9Hz,1H),7.35(t,J=1.7Hz,1H),7.25-7.32(m,2H),7.20-7.24(m,3H),7.15-7.20(m,3H),1.21(s,9H).MS(M+1):498.
化合物6-57
N-(5-(2-溴苯基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 7.57(d,J=4.4Hz,1H),7.50(t,J=1.7Hz,1H),7.45(dt,J=7.8,1.5Hz,1H),7.24-7.31(m,3H),7.16-7.24(m,4H),1.22(s,10H).MS(M+1):542.
化合物6-58
N-(5-(3-溴苯基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 12.21(br.s.,1H),7.69-7.74(m,1H),7.53(d,J=4.4Hz,1H),7.26-7.37(m,3H),7.21(d,J=4.4Hz,1H),7.15-7.20(m,2H),7.08-7.14(m,2H),1.18(s,9H).MS(M+1):542.
化合物6-59
N-(4-(4-(叔丁基)苯基)-5-(4-氯苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.47(br.s.,1H),7.62(br.s.,1H),7.24-7.33(m,7H),7.17-7.23(m,2H),1.23(s,10H).MS(M+1):498.
化合物6-60
N-(5-溴-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,CDCl3):δ 11.44(br.s.,1H),7.59-7.70(m,3H),7.29-7.41(m,2H),7.24-7.29(m,1H),1.27(s,9H).MS(M+1):466.
化合物6-61
N-(3-(4-溴苯基)-1H-吡唑-5-基)-5-硝基噻吩-2-甲醯胺(N-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-5-nitrothiophene-2-carboxamide)
1H NMR(400MHz,DMSO-d6):δ 13.19(s,1H),11.55(s,1H),8.18(d,J=4.4Hz,1H),8.15(d,J=4.4Hz,1H),7.72(d,J=8.4Hz,2H),7.67(d,J=8.4Hz,2H),7.06(d,J=2.0Hz,1H).MS(M+1):393.
在實施例1至6中,如果其合成步驟與前述化合物的步驟相似,則不重複一些化合物的詳細合成步驟。
實施例7:在體外測定法中評估式(I)之化合物
藉由對肝細胞癌株Hep3B細胞生長抑制能力來判斷所選擇的化合物的效力。在37℃、5%二氧化碳和95%相對濕度下,將Hep3B細胞以選擇的化合物處理48小時。
通過GE InCell 2200系統測定處理細胞的數量,且處理的細胞以Hoechst 33342染色,其可以顯示培養板中剩餘的細胞核。接著以處理的/未處理
的細胞的比率計算存活細胞的比例。通過以下NCI-60篩選平台的方案評估所選擇的化合物的生長抑制/細胞毒性效果。在化合物處理前24小時,將人類腫瘤細胞株以固定密度接種在96孔盤上,接著,化合物以多種濃度添加至每一孔中再培養48小時。通過MTS方法評估細胞存活率(cell viability),並且通過MTS結果計算的50%之生長抑制(GI50)和半數致死濃度(LC50)表示化合物的效力。
在兩個體外測定法中測試實施例1-6中所製備的化合物,且結果顯示於下表1-6中。在此,下表1-6中的「10μM(%)中的比例」是指以10μM所選擇的化合物處理的腫瘤細胞的數量與未處理的腫瘤細胞的數量的比例。
表1至表6顯示了例示性式(I)之化合物的結構和體外活性,發現大部分揭露的化合物抑制Hep3B細胞的生長。
實施例8:在體外MTS方法中評估式(I)之化合物
基於NCI-60篩選方法(NCI-60 screening methodology)(Nat.Rev.Cancer 6,813-823,2006)量測細胞存活率。簡要地,將細胞以最佳接種密度接種在96孔盤中,經過24小時後,對兩盤中的一盤的每個細胞株進行處理,以藉由MTS檢測(Promega)確定零時(time zero)的細胞存活率(Tz)。化合物以2倍序列稀釋提供總共5種藥物濃度加上DMSO控制組,將孔盤再培養2天後,接著藉由MTS檢測[控制組生長(C)和在藥物存在下5種濃度水平的測試組生長(Ti)]量測細胞存活率。由[(Ti-Tz)/(C-Tz)]x 100=50計算50%的生長抑制(GI50),這是在藥物培養期間導致比控制組細胞減少50%的藥物濃度。由[(Ti-Tz)/Tz]x 100=-50計算半數致死濃度(LC50),這是在藥物處理結束時與開始時相比導致減少50%的藥物濃度。
在兩個體外測定法中測試實施例1至6製備的化合物,且結果顯示於下表7至8中。在此,Hep3B是指肝細胞癌株,SW480是指結腸腺癌細胞株,NCI-H460是指人類肺癌細胞株。
表7至表8顯示了例示性式(I)之化合物的體外活性。結果指出,本揭露之化合物的確具有用於抑制各種腫瘤細胞生長的效果。
其他實施例
在此說明書中揭露的所有特徵可以任何組合結合。本說明書揭露的每個特徵可以由相同、等同或相似目的的替代特徵代替。因此,除非另有明確地說明,否則揭露的每個特徵僅為一系列等同或相似特徵的一個例子。
此外,從以上描述中,習知技術者可輕易地明白本揭露的必要特徵,且在不背離其精神和範圍下,可以對本揭露進行各種改變及修飾,以使其適應各種用途和條件。因此,其他實施例也在請求項涵蓋之範圍內。
Claims (23)
- 一種式(I)之化合物或其藥學上可接受之鹽類:
- 如申請專利範圍第2項所述之化合物或其藥學上可接受之鹽類,其中,X為一直接鍵結。
- 如申請專利範圍第2項所述之化合物或其藥學上可接受之鹽類,其中,R1為苯基、吡啶基或喹啉基,其中,苯基、吡啶基和喹啉基各自選擇性地以一至三個選自由鹵素、羥基、硝基、氰基、-NRcRd、低烷基胺甲醯基、雜環烷基、選擇性地被一至三個鹵素或芳基取代之烷基、和選擇性地被一至三個鹵 素、烷氧基、環烷基、雜環烷基、-NReRf、或芳基取代之烷氧基所組成之群組之基團取代,其中,Rc、Rd、Re和Rf各自獨立為氫、甲基或乙基。
- 如申請專利範圍第5項所述之化合物或其藥學上可接受之鹽類,其中,R1為苯基或吡啶基,其中,苯基和吡啶基各自選擇性地被一至三個烷氧基取代,所述烷氧基選擇性地被一至三個鹵素、烷氧基、環烷基、雜環烷基、-NReRf或芳基取代,其中,Rc、Rd、Re和Rf各自獨立為氫、甲基或乙基。
- 如申請專利範圍第2項所述之化合物或其藥學上可接受之鹽類,其中,R4為氫或甲基。
- 如申請專利範圍第9項所述之化合物或其藥學上可接受之鹽類,其中,X為一直接鍵結、-CH2-、-O-、-N(CH3)-、-(C=O)NH-、或-(C=O)-。
- 如申請專利範圍第9項所述之化合物或其藥學上可接受之鹽類,其中,R1為氫、鹵素、氰基、烷氧基、苯基、吡啶基或喹啉基,其中,苯基、吡啶基和喹啉基各自選擇性地以一至三個選自由鹵素、羥基、硝基、氰基、-NRcRd、低烷基胺甲醯基、雜環烷基、選擇性地被一至三個鹵素或芳基取代之烷基、和選擇性地被一至三個鹵素、烷氧基、環烷基、雜環烷基、-NReRf或芳基取代之烷氧基所組成之群組之基團取代,其中,Rc、Rd、Re和Rf各自獨立為氫、甲基或乙基。
- 如申請專利範圍第13項所述之化合物或其藥學上可接受之鹽類,其中,R1為苯基,所述苯基選擇性地以一至三個選自由鹵素、和選擇性被一至三個鹵素取代之烷基所組成之群組之基團取代。
- 如申請專利範圍第9項所述之化合物或其藥學上可接受之鹽類,其中,R2為苯基、噻吩基或吡啶基,其中,苯基、噻吩基和吡啶基各自選擇性地以一至三個選自由鹵素、硝基、氰基、低烷基胺甲醯基、炔基、選擇性地被一至三個鹵素取代之烷基、和選擇性地以一至三個鹵素或烷氧基取代之烷氧基所組成之群組之基團取代。
- 如申請專利範圍第15項所述之化合物或其藥學上可接受之鹽類,其中,R2為苯基,所述苯基選擇性地以一至三個選自由鹵素、選擇性地被一至三個鹵素取代之烷基、和烷氧基所組成之群組之基團取代。
- 如申請專利範圍第9項所述之化合物或其藥學上可接受之鹽類,其中,R4為氫或甲基。
- 如申請專利範圍第1項所述之化合物或其藥學上可接受之鹽類,其選自由2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)-1,3,4-噻二唑-2-yl)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-羥基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-硝基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)乙醯胺 (2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-甲氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-溴苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-硝基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-(二甲基胺基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(dimethylamino)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-propoxyphenyl)-l,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(三氟甲氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(trifluoromethoxy)phenyl)-l,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-碘苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-iodophenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-溴-3-硝基苯基)-1,3,4-噻二唑-2-基)乙醯胺 (2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromo-3-nitrophenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-異丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-異丙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-(戊-3-基氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-(pentan-3-yloxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-丙氧基苯基)-l,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-propoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4-二乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-羥基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丁氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-butoxyphenyl)-1,3,4-thiadiazol-2-yl)aceta mide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-丁氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-butoxyphenyl)-l,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(戊-3-基氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(pentan-3-yloxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丁氧基-4-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-butoxy-4-ethoxyphenyl)-l,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4,6-三乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4,6-triethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-乙氧基吡啶-4-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-ethoxypyridin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(乙氧基甲氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(ethoxymethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(2-(4-乙基哌嗪-1-基)乙氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6- 基)-N-(5-(2-(3-(二甲基胺基)丙氧基)-4-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(3-(dimethylamino)propoxy)-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(2-(二甲基胺基)乙氧基)-4-乙氧基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(2-(dimethylamino)ethoxy)-4-ethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(5-乙氧基吡啶-2-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(5-ethoxypyridin-2-yl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-(2-(二甲基胺基)乙氧基)吡啶-4-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-(2-(dimethylamino)ethoxy)pyridin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(2-甲氧基乙氧基)苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-methoxyethoxy)phenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-丙基苯基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-propylphenyl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基吡啶-3-基)-1,3,4-噻二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4,6-二乙氧基吡啶-3-基)-1,3,4-噻二唑-2-基)乙醯胺 (2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4,6-diethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4-二乙氧基苯基)-1,3,4-噻二唑-2-基)-N-甲基乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1,3,4-thiadiazol-2-yl)-N-methylacetamide、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4,6-二乙氧基吡啶-3-基)-1,3,4-噻二唑-2-基)-N-甲基乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4,6-diethoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)-N-methylacetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-乙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-丙氧基苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-propoxyphenyl)-1,3,4-oxadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2-(三氟甲氧基)苯基)-1,3,4-噁二唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)acetam ide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(4-溴苯基)-5-苯基噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-bromophenyl)-5-phenylthiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-溴苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-氟苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-fluorophenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3,4-二甲氧基苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3,4-dimethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-氟苯基)-4-(4-丙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-fluorophenyl)-4-(4-propoxyphenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(3,5-雙(三氟甲基)苯基)-4-(對-甲苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(p-tolyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-溴-4-(3-甲氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-bromo-4-(3-methoxyphenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(4-乙氧基苯基)-5-(4-氟苯基)噻唑-2-基)乙醯胺 (2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-ethoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(4,5-雙(4-溴苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4,5-bis(4-bromophenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(2,4-二乙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(2,4-diethoxyphenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-苄基-4-(4-乙氧基苯基)噻唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基苯基)噻吩-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxyphenyl)thiophen-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(4-乙氧基-2-(2-甲氧基乙氧基)苯基)-1H-咪唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(4-ethoxy-2-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)acetamide)、2-(2-胺基苯並[d]噻唑-6-基)-N-(5-(2,4-二乙氧基)-1H-咪唑-2-基)乙醯胺(2-(2-aminobenzo[d]thiazol-6-yl)-N-(5-(2,4-diethoxyphenyl)-1H-imidazol-2-yl)acetamide)、N-(4-(4-溴苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、 N-(4-(4-溴苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(3-硝基苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(3-nitrophenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)、N-(4-(3-甲氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(3-methoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(2-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(2-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-溴苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-丙氧基苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)thiophene-2-carboxamide)、5-硝基-N-(5-苯氧基-4-(4-丙氧基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-propoxyphenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-異丙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-isopropoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-溴苯基)-5-(3-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene -2-carboxamide)、N-(4-(2,4-二乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(2,4-diethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-丙氧基苯基)-5-(吡啶-3-基氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(pyridin-3-yloxy)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(2-甲氧基乙氧基)苯基)-5-(吡啶-3-基氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(2-methoxyethoxy)phenyl)-5-(pyridin-3-yloxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(2-甲氧基乙氧基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(2-methoxyethoxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-丙氧基苯基)-5-(3-(三氟甲基)苯氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-溴苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-溴苯基)-5-(2-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene -2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2-乙氧基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-ethoxyphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(3-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(3-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(3-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(3-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-丙氧基苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)thiophene-2-carboxamide)、N-(5-(4-溴苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(5-(4-bromophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-(叔丁基)苯氧基)-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-氟苯基)-5-(2-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-氟苯基)-5-(2-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(2-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-氟苯基)-5-(4-(三氟甲氧基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(4-(trifluoromethoxy)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-甲氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-methoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氟苯氧基)-4-(4-(甲基胺甲醯基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-(methylcarbamoyl)phenyl)thiazol-2-yl)-5-nitrothiophe ne-2-carboxamide)、N-(4-(3,5-二乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(3,5-diethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2,4-二氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2,4-difluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2-氯-4-(三氟甲基)苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氰基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-cyanophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氰基-2-甲氧基苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-cyano-2-methoxyphenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(5-(3,3-二甲基丁-1-炔-1-基)噻吩-2-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(5-(3,3-dimethylbut-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(5-溴噻吩-2-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(5-bromothiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-丙氧基苯基)-5-(吡啶-4-基氧基)噻唑-2-基)噻吩-2-甲酰胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(pyridin-4-yloxy)thiazol-2-yl)thiophene-2-carbox amide)、N-(5-(3,4-二氯苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,4-dichlorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2-氯-4-氟苯基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-chloro-4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(5-(3-(二甲基胺基)丙-1-炔-1-基)噻吩-2-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(5-(3-(dimethylamino)prop-1-yn-1-yl)thiophen-2-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基呋喃-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrofuran-2-carboxamide)、5-硝基-N-(5-苯氧基-4-(4-丙氧基苯基)噻唑-2-基)呋喃-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-propoxyphenyl)thiazol-2-yl)furan-2-carboxamide)、N-(5-(4-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基呋喃-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide)、N-(5-(3,5-二氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,5-difluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(6-乙氧基吡啶-3-基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(6-ethoxypyridin-3-yl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-丙氧基苯基)-5-(喹啉-8-基氧基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-propoxyphenyl)-5-(quinolin-8-yloxy)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-乙氧基-2-氟苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-ethoxy-2-fluorophenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(3-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(3-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(2-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2-氟苯氧基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-(三級戊基)苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-(tert-pentyl)phenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)、5-硝基-N-(4-(4-硝基苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-nitrophenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)、5-硝基-N-(5-苯氧基-4-(3,4,5-三甲氧基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-氟苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-fluorophenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氟苯氧基)-4-(4-(三級戊基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenoxy)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-ca rboxamide)、N-(5-(4-(叔丁基)苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-丁基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-丁氧基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butoxyphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(己氧基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(hexyloxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-(叔丁基)苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-丁基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-丁氧基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-butoxyphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(5-(4-(三級戊基)苯氧基)-4-(4-(三氟甲基)苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-(4-(tert-pentyl)phenoxy)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(2-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-butoxyphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(2-(三氟甲基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(4-(戊氧基)苯基)-5-苯氧基噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(4-(pentyloxy)phenyl)-5-phenoxythiazol-2-yl)thiophene-2-carboxamide)、5-硝基-N-(5-苯氧基-4-(4-丙基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-propylphenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(5-(2-氟苯氧基)-4-(4-丙基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-propylphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁基苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁基苯基)-5-(2-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-(2-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(5-苯氧基-4-(4-(三氟甲基)苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-苯氧基噻唑-2-基)-N-甲基-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-phenoxythiazol-2-yl)-N-methyl-5-nitrothiophene-2-carbox amide)、N-(5-(2-氟苯氧基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(5-苯氧基-4-(4-(三氟甲氧基)苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-phenoxy-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(5-(2-氟苯氧基)-4-(4-(三氟甲氧基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-fluorophenoxy)-4-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴苯氧基)-4-(4-丁氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenoxy)-4-(4-butoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-丁氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-butoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-丙基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-propylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-丁基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-butylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(4-(叔丁基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-butoxyphenyl)-5-(4-(tert-butyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(4-氰基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-cyanophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-((5-胺基戊基)氧基)苯基)-5-苯氧基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-((5-aminopentyl)oxy)phenyl)-5-phenoxythiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(4-丙基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-propylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁基苯基)-5-(4-氟苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-(4-fluorophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-丙氧基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-propoxyphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-(叔丁基)苯氧基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-(2,4,4-三甲基戊-2-基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(4-(三級戊基)苯氧基)噻唑 -2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴-3,5-二甲基苯氧基)-4-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3,5-dimethylphenoxy)-4-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-(叔丁基)苯氧基)-4-(4-乙基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-(tert-butyl)phenoxy)-4-(4-ethylphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙基苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethylphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁基苯基)-5-(4-(三級戊基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butylphenyl)-5-(4-(tert-pentyl)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(對-甲苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-(tert-butyl)phenyl)-5-(p-tolyloxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(3,5-二甲基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-butoxyphenyl)-5-(3,5-dimethylphenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-(二甲基胺基)苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-(dimethylamino)phenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-嗎啉基苯氧基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-morpholinophenoxy)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(3-硝基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(3-nitrophenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(5-(4-溴苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(5-(3-硝基苯基)-4-(對-甲苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(5-(3-nitrophenyl)-4-(p-tolyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(5-(3,4-二甲氧基苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,4-dimethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(3,5-雙(三氟甲基)苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3,5-bis(trifluoromethyl)phenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氟苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-溴苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-bromophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(3-甲氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(3-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-溴苯基)-5-苯基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-bromophenyl)-5-phenylthiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-溴-4-(4-溴苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(4-bromophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、5-硝基-N-(4-(2-硝基苯基)噻唑-2-基)噻吩-2-甲醯胺(5-nitro-N-(4-(2-nitrophenyl)thiazol-2-yl)thiophene-2-carboxamide)、N-(5-溴-4-(2-硝基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(2-nitrophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-溴-4-(3-硝基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(3-nitrophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-溴-4-(3-甲氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(3-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氟苯基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-溴-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-丁氧基苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-butoxyphenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴-3-乙氧基苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromo-3-ethoxyphenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-苯基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-phenylthiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-甲基哌嗪-1-基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-methylpiperazin-1-yl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、2-(5-硝基噻吩-2-甲醯胺基)-4-(4-丙氧基苯基)噻唑-5-甲酸乙酯(ethyl 2-(5-nitrothiophene-2-carboxamido)-4-(4-propoxyphenyl)thiazole-5-carboxylate)、N-(4-(4-(叔丁基)苯基)-5-(4-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(2,4-二乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(2,4-diethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-二甲基胺基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(dimethylamino)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(3,5-二氟苯基)-4-(4-乙氧基苯基)-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲醯胺(N-(3,5-difluorophenyl)-4-(4-ethoxyphenyl)-2-(5-nitrothiophene-2-carboxamido)thia zole-5-carboxamide)、N-(4-(4-乙氧基苯基)-5-(甲基(苯基)胺基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(methyl(phenyl)amino)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(嗎啉基-4-羰基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(morpholine-4-carbonyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-甲基哌嗪-1-羰基)-4-(4-丙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-methylpiperazine-1-carbonyl)-4-(4-propoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(2,4-二氟苯基)-2-(5-硝基噻吩-2-甲醯胺基)-4-(4-丙氧基苯基)噻唑-5-甲醯胺(N-(2,4-difluorophenyl)-2-(5-nitrothiophene-2-carboxamido)-4-(4-propoxyphenyl)thiazole-5-carboxamide)、N-(5-(4-溴苯基)-4-(對-甲苯基)噻唑-2-基)-5-硝基呋喃基-2-甲醯胺(N-(5-(4-bromophenyl)-4-(p-tolyl)thiazol-2-yl)-5-nitrofuran-2-carboxamide)、N-(5-苄基-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基呋喃基-2-甲醯胺(N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrofuran-2-carboxamid)、N-(5-苄基-4-(4-乙氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-benzyl-4-(4-ethoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(4-氟苄基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(4-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-乙氧基苯基)-5-(3-氟苄基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-ethoxyphenyl)-5-(3-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxam ide)、N-(4-(4-(叔丁基)苯基)-5-(4-氟苄基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-fluorobenzyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(3,5-二氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3,5-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(2,4-二氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2,4-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-氟苯基)-4-(4-(三級戊基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-fluorophenyl)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(3-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、4-(4-(叔丁基)苯基)-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲酸乙酯(ethyl4-(4-(tert-butyl)phenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxylate)、N-(4-(4-(叔丁基)苯基)-5-(4-甲基哌嗪-1-羰基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-methylpiperazine-l-carbonyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、4-(4-(叔丁基)苯基)-N-環丙基-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲醯胺(4-(4-(tert-butyl)phenyl)-N-cyclopropyl-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxamide)、4-(4-乙氧基苯基)-2-(5-硝基噻吩-2-甲醯胺基)噻唑-5-甲酸乙酯(ethyl4-(4-ethoxyphenyl)-2-(5-nitrothiophene-2-carboxamido)thiazole-5-carboxylate) 、N-(4-(4-(叔丁基)苯基)-5-(3,4-二氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3,4-difluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2,4-二氟苯基)-4-(4-(三級戊基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2,4-difluorophenyl)-4-(4-(tert-pentyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(2-氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2-fluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(嗎啉-4-羰基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(morpholine-4-carbonyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-氰基噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-cyanothiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(3,4,5-三氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3,4,5-trifluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(2,4,6-三氟苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2,4,6-trifluorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(4-溴苯基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(4-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-甲氧基苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺 (N-(4-(4-(tert-butyl)phenyl)-5-(4-methoxyphenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(2-氯苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(2-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(3-氯苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(3-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(2-溴苯基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(2-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-(3-溴苯基)-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-(3-bromophenyl)-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(4-(4-(叔丁基)苯基)-5-(4-氯苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(4-(4-(tert-butyl)phenyl)-5-(4-chlorophenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(5-溴-4-(4-(叔丁基)苯基)噻唑-2-基)-5-硝基噻吩-2-甲醯胺(N-(5-bromo-4-(4-(tert-butyl)phenyl)thiazol-2-yl)-5-nitrothiophene-2-carboxamide)、N-(3-(4-溴苯基)-1H-吡唑-5-基)-5-硝基噻吩-2-甲醯胺(N-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-5-nitrothiophene-2-carboxamide)所組成之群組中之任一者。
- 一種醫藥組成物,包含一如申請專利範圍第1項所述之化合物或其藥學上可接受之鹽類以及一藥學上可接受之載體。
- 一種如申請專利範圍第1項所述之化合物或其藥學上可接受之鹽類之用途,用以製備治療癌症之藥物。
- 如申請專利範圍第22項所述之用途,其中該癌症選自由胃癌、大腸癌、結直腸癌、乳癌、肺癌、前列腺癌、膀胱癌、胰腺癌、肝癌、子宮癌、 子宮頸癌、子宮內膜癌、食道癌、白血病、淋巴瘤、腎癌、骨肉瘤、卵巢癌、皮膚癌、小腸癌、胸腺癌、甲狀腺癌、神經系癌、骨癌、腦癌、及頭頸部癌所組成之群組。
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US20040157827A1 (en) * | 1998-10-30 | 2004-08-12 | Paolo Pevarello | 2-Ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents |
US20060135782A1 (en) * | 2004-12-22 | 2006-06-22 | 4Sc Ag | Benzazole analogues and uses thereof |
WO2009158118A2 (en) * | 2008-05-30 | 2009-12-30 | University Of Notre Dame Du Lac | Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria |
EP1558607B1 (en) * | 2002-10-30 | 2010-05-05 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of rock and other protein kinases |
US20100179121A1 (en) * | 2007-06-11 | 2010-07-15 | Bristol-Meyers Squibb Company | 1,3-dihydroxy substituted phenylamide glucokinase activators |
US20120028918A1 (en) * | 2010-05-05 | 2012-02-02 | Glaxo Wellcome Manufacturing Pte Ltd. | Pharmaceutical compositions and methods of making same |
US20160101096A1 (en) * | 2013-10-01 | 2016-04-14 | Ann Marie Schmidt | Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof |
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JPS57136579A (en) * | 1981-01-21 | 1982-08-23 | Mitsui Toatsu Chem Inc | Thiazolylurea derivative, its preparation, and pharmaceutical composition containing the same |
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US20040157827A1 (en) * | 1998-10-30 | 2004-08-12 | Paolo Pevarello | 2-Ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents |
EP1558607B1 (en) * | 2002-10-30 | 2010-05-05 | Vertex Pharmaceuticals Incorporated | Compositions useful as inhibitors of rock and other protein kinases |
US20060135782A1 (en) * | 2004-12-22 | 2006-06-22 | 4Sc Ag | Benzazole analogues and uses thereof |
US20100179121A1 (en) * | 2007-06-11 | 2010-07-15 | Bristol-Meyers Squibb Company | 1,3-dihydroxy substituted phenylamide glucokinase activators |
WO2009158118A2 (en) * | 2008-05-30 | 2009-12-30 | University Of Notre Dame Du Lac | Anti-bacterial agents from benzo[d]heterocyclic scaffolds for prevention and treatment of multidrug resistant bacteria |
US20120028918A1 (en) * | 2010-05-05 | 2012-02-02 | Glaxo Wellcome Manufacturing Pte Ltd. | Pharmaceutical compositions and methods of making same |
US20160101096A1 (en) * | 2013-10-01 | 2016-04-14 | Ann Marie Schmidt | Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof |
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