TWI770858B - 嘧啶化合物及其醫藥用途 - Google Patents
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- TWI770858B TWI770858B TW110107928A TW110107928A TWI770858B TW I770858 B TWI770858 B TW I770858B TW 110107928 A TW110107928 A TW 110107928A TW 110107928 A TW110107928 A TW 110107928A TW I770858 B TWI770858 B TW I770858B
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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Abstract
Description
本發明涉及一種嘧啶化合物及其醫藥用途。
Aurora A激酶是一種絲胺酸(serine)/蘇胺酸(threonine)激酶,可調節有絲分裂進程(mitotic progression)、中心體成熟(centrosome maturation)及紡錘體組裝(spindle assembly)。這種激酶在穩定MYC族致癌蛋白(oncoproteins)中起著重要作用,根據美國癌症基因體圖譜計畫(The Cancer Genome Atlas,TCGA),已經在28%的癌症中觀察到其基因擴增(gene amplifications)。誘導Aurora A激酶之DFG環(DFG-loop)構造變化(conformational change)的小分子抑制劑可導致MYC族致癌蛋白降解,從而對癌症治療具潛力。
已經鑑定出了包括化合物CD532在內的Aurora A激酶抑制劑。參見WO 2014/190207A1。然而,CD532的體內療效較弱。
因此,亟需開發有效抑制Aurora A激酶活性的新穎化合物。
本發明係基於發現某些嘧啶化合物於體外及體內皆可有效抑制Aurora A激酶活性。
於一態樣,本發明涉及以下所示的式(I)化合物:
於此式中,A為CH或N;R1為C1-6烷基、C1-6烷氧基、C3-10環烷基、芳基或雜芳基;R2為H、C1-6烷基、R5NDNR6R7或C1-10雜環烷基,其中R5、R6及R7各自獨立為H或C1-6烷基,D為C1-6二價脂肪族基團(C1-6 bivalent aliphatic radical);R3為C1-6烷基、C1-6烷氧基、C3-10環烷基、C7-12芳烷基、C1-12雜芳烷基、-C(O)R8或-S(O)2R8,其中R8為芳基或雜芳基;R4為C1-6烷基,或較佳為H;以及m及n各自獨立為1或2。
C1-6烷基、C1-6烷氧基、C3-10環烷基、C1-10雜環烷基、C7-12芳烷基、C1-12雜芳烷基、芳基及雜芳基各自獨立為以鹵素、OH、CN、NH2、NO2、SO2、C1-6烷基、C1-6鹵化烷基(C1-6 haloalkyl)、C3-13環烷基、C2-8雜環烷基、C1-6烷氧基、C1-6鹵化烷氧基(C1-6 haloalkoxyl)、C1-6烷胺基、C2-6二烷胺基、C7-12芳烷基、C1-12雜芳烷基、芳基、雜芳基、-C(O)R9、-C(O)OR9或-C(O)NR9R10進行單取代、雙取代或三取代,R9及R10各自獨立為H、鹵素、OH、CN、COOH、乙醯基、乙醯胺、二烷胺基、烷胺基、C1-6烷基、C1-6多鹵化烷基(C1-6 multihaloalkyl)、C1-6烷氧基、C1-6多鹵化烷氧基(C1-6 multihaloalkoxyl)、C3-8環烷基、C1-10雜環烷基、芳基或雜芳基。
本文中之術語「烷基」是指含有1-20(例如1-10及1-6)個碳原子的直鏈或支鏈烴基。實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基。本文中之術語「鹵化烷基」是指以一個或多個鹵素(氯、氟、溴或碘)原子取代之烷基。實例包括三氟甲基、溴甲基及4,4,4-三氟丁基。術語「烷氧基」是指-O-烷基。實例包括甲氧基、乙氧基、丙氧基及異丙氧基。術語「鹵化烷氧基」是指以一個或多個鹵素原子取代之烷氧基。實例包括-O-CH2Cl及-O-CHClCH2Cl。
術語「環烷基」是指具有3至12個碳的飽和及部分未飽和單環、雙環、三環或四環烴基。環烷基的實例包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基及環辛基。
術語「雜環烷基」是指具有一個或多個雜原子(例如O、N、P及S)的非芳香族5-8元單環、8-12元雙環或11-14元三環系統。雜環烷基的實例包括但不限於哌嗪基(piperazinyl)、咪唑啶基(imidazolidinyl)、氮雜烷基(azepanyl)、吡咯啶基(pyrrolidinyl)、二氫噻二唑基(dihydrothiadiazolyl)、二噁烷基(dioxanyl)、嗎啉基(morpholinyl)、四氫吡喃基(tetrahydropuranyl)及四氫呋喃基(tetrahydrofuranyl)。
術語「芳基」是指6個碳的單環、10個碳的雙環、14個碳的三環芳香族環系統,其中每個環可具有1至5個取代基。芳基的實例包括苯基、萘基及蒽基。術語「亞芳基(arylene)」是指二價芳基。術語「芳烷基」是指被芳基取代的烷基。
術語「雜芳基」是指具有一個或多個雜原子(例如O、N、P及S)的芳香族5-8元單環、8-12元雙環或11-14元三環系統。實例包括三唑基
(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)及苯並噻唑基(benzothiazolyl)。術語「雜芳烷基」是指被雜芳基取代的烷基。
術語「鹵代」是指氟、氯、溴或碘基。術語「胺基」是指衍生自胺的基團,其未被取代或被烷基、芳基、環烷基、雜環烷基或雜芳基單取代/雙取代。術語「烷胺基」是指烷基-NH-。術語「二烷胺基」是指烷基-N(烷基)-。
術語「醯基」是指-C(O)-烷基、-C(O)-芳基、-C(O)-環烷基、-C(O)-雜環烷基或-C(O)-雜芳基。
本文提及的烷基、環烷基、雜環烷基、芳基、雜芳基、芳烷基、雜芳烷基、烷氧基及芳氧基包括取代及未取代的部分。取代基的實例包括但不限於鹵素、羥基、胺基、氰基、硝基、巰基(mercapto)、烷氧羰基(alkoxycarbonyl)、醯胺基(amido)、羧基(carboxy)、烷烴磺醯基(alkanesulfonyl)、烷基羰基(alkylcarbonyl)、脲基(carbamido)、胺甲醯基(carbamyl)、羧基(carboxyl)、硫脲基(thioureido)、氰硫基(thiocyanato)、磺醯胺基(sulfonamido)、烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基及雜環烷基,其中可以進一步取代烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基及雜環烷基。
於另一態樣,本發明涉及一種治療癌症之方法。該方法包括給予一需要主體一有效量的上述式(I)化合物。
當提及式(I)化合物時,術語「化合物」還涵蓋其鹽類、溶劑化物及前驅藥。可以在陰離子與化合物上帶正電荷的基團(例如胺基)之間形成鹽類;
適合的陰離子的實例包括氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根、檸檬酸根、甲磺酸根(methanesulfonate)、三氟乙酸根、乙酸根、蘋果酸根(malate)、甲苯磺酸根(tosylate)、酒石酸根(tartrate)、富馬酸根(fumurate)、谷胺酸根(glutamate)、葡萄醣醛酸根(glucuronate)、乳酸根(lactate)、戊二酸根(glutarate)及順丁烯二酸根(maleate)。也可以在陽離子與帶負電荷的基團之間形成鹽類;適合的陽離子的實例包括鈉離子、鉀離子、鎂離子、鈣離子及銨陽離子(諸如四甲基銨離子)。鹽類更包括含有季氮原子的鹽類。溶劑化物是指在活性化合物與藥學上可接受的溶劑之間形成的複合物。藥學上可接受的溶劑的實例包括水、乙醇、果丙醇、乙酸乙酯、乙酸及乙醇胺(ethanolamine)。前驅藥是指在給藥後被代謝為藥學上的活性藥物的藥物或化合物。前驅藥的實例包括酯類及其他藥學上可接受的衍生物,其在給予主體時能夠提供活性嘧啶化合物。
於下方描述中闡述了本發明的一個或多個實施例的細節。根據說明書及申請專利範圍,本發明的其他特徵、目的及優點將是顯而易見的。
圖1顯示兩種代表性化合物(即化合物41及化合物86)在降低NCI-H82及SK-N-BE(2)細胞中cMYC及MYCN的表現量(expression level)方面的體外功效。
圖2顯示兩種代表性化合物(即化合物71及化合物122)以及兩種對照化合物(即MLN8237及LY3295668)在NCI-H446異種移植致瘤性小鼠中的體內抗腫瘤療效。
圖3顯示化合物71在降低cMYC蛋白質含量及誘導細胞凋亡方面的體內療效。
下文詳細描述的是下式(I)之嘧啶化合物,以及其合成和抗癌功效。
R1-R4、m、n及A已在上文的「發明內容」段落中定義。
於式(I)所涵蓋的化合物的另一較佳組中,m及n各自為2;A為N;R1為C3-10環烷基或5員雜芳基;R2為H、C1-6烷基、、、、、
、、、、、、或;R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
本發明的化合物可以透過本領域眾所周知的合成方法來製備。參見,例如R.Larock,《Comprehensive Organic Transformations》(第2版,VCH出版1999);P.G.M.Wuts及T.W.Greene,《Greene’s Protective Groups in Organic Synthesis》(第四版,John Wiley and Sons,2007);L.Fieser及M.Fieser,《Fieser and Fieser’s Reagents for Organic Synthesis》(John Wiley and Sons 1994);以及L.Paquette編輯,《Encyclopedia of Reagents for Organic Synthesis》(第二版,John Wiley and Sons 2009)及其後續版本。
本文提及的化合物可包括非芳香族雙鍵及一個或多個非對稱中心(asymmetric centers)。因此,每種化合物以外消旋物(racemate)或外消旋混合物(racemic mixture)、單R對映異構體(enantiomer)、單S對映異構體、單獨非對映異構體(individul diastereomer)、非對映異構體混合物或順式或反式異構體形式存在。所有這些異構體形式的化合物都在本發明的範圍內。
如此製備的式(I)化合物可以使用下文實施例2中描述的酶性Aurora A激酶活性抑制試驗初步篩選其抑制Aurora A激酶活性的能力。可以隨後使用體外試驗(例如實施例3中所述的MYC-或MYCN-擴增的癌細胞株試驗以及實施例4及實施例5中所述的細胞增殖(cell proliferation)抑制試驗)對其抑制癌細胞增殖的功效進行評估。選定的化合物可以進一步測試以驗證其在治療癌症方面的功效。例如,如實施例6及實施例7所述,可以將化合物施用於具有異種移植腫瘤的動物(例如小鼠),以評估其治療效果。
本發明也包括治療癌症的方法。該方法包括給予需求主體有效量的式(I)的化合物。癌症的實例包括白血病、肺癌、神經母細胞瘤、胰臟癌、大腸癌、前列腺癌、乳癌、肝癌、腦癌及膽管癌(cholangiocarcinoma)。
本發明還涉及含有式(I)化合物及藥物載體的醫藥組成物。該醫藥組成物可以用於治療癌症。
為了實施本發明之方法,可以將具有一種或多種上述嘧啶化合物的組成物經腸胃外(parenterally)、口服(orally)、經鼻(nasally)、經直腸(rectally)、局部(topically)或經頰(buccally)給藥。如本文所用,術語「腸胃外」是指皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、腹膜內(intraperitoneal)、肌肉內(intramuscular)、關節內(intraarticular)、動脈內(intraarterial)、滑膜內(intrasynovial)、胸骨內(intrasternal)、脊椎內(intrathecal)、病灶內(intralesional)或顱內注射(intracranial injection)、以及任何適合的輸注技術。
無菌注射用組成物可以是在無毒的腸胃外可接受的稀釋劑或溶劑中的溶液或懸浮液,諸如在1,3-丁二醇(1,3-butanediol)中的溶液。可以使用的
可接受賦形劑(vehicles)及溶劑包括甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)及等滲透壓的氯化鈉溶液。此外,常規上使用不揮發性油作為溶劑或懸浮介質(例如合成的甘油單酯或甘油二酯(mono-or di-glycerides))。脂肪酸(諸如油酸(oleic acid)及其甘油酯(glyceride)衍生物)可用於製備注射劑,天然藥學上可接受的油(諸如橄欖油及蓖麻油,特別是其聚氧乙烯化形式)也可用於製備注射劑。這些油性溶液或懸浮液也可以含有長鏈醇類稀釋劑或分散劑、羧甲基纖維素(carboxymethyl cellulose)或類似的分散劑。也可以將其他常用的表面活性劑(諸如Tweens及Spans或其他類似的乳劑或生物利用度增強劑(bioavailability enhancers))用於藥學上可接受的固體、液體或其他劑型的製備中,以用於配製目的。
口服給藥的組成物可以是任何口服可接受的劑型,包括膠囊、片劑、乳劑及水性懸浮液、分散液及溶液。對於片劑來說,常用的載體包括乳糖及王米澱粉。通常也添加諸如硬脂酸鎂(magnesium stearate)的潤滑劑。對於以膠囊形式的口服給藥而言,有用的稀釋劑包括乳糖及乾燥的玉米澱粉。當口服給予水性懸浮液或乳劑時,可以將活性成分懸浮或溶解在與乳劑或懸浮劑結合的油相中。如果需要,可以添加某些甜味劑、調味劑或著色劑。口服固體劑型可以透過噴霧乾燥技術來製備;熱熔擠出策略、微粉化及奈米研磨技術。
可以依據藥物製劑領域中已知的技術來製備鼻用氣霧劑或吸入組成物。例如,可以使用本領域已知的苯甲醇(benzyl alcohol)或其他適合的防腐劑、提升生物利用度的吸收促進劑、碳氟化合物(fluorocarbons)及/或其他助溶劑或分散劑,將此種組成物製備為在鹽水中的溶液。具有活性化合物之組成物也可以以栓劑(suppositories)的形式用於直腸給藥。
醫藥組成物中的載體在與組成物的活性成分之相容性上須為「可接受的」(且較佳能夠穩定活性成分),並且對於治療的主體無害。可以將一種或多種增溶劑用作藥物賦形劑以傳遞活性化合物。其他載體的實例包括膠體氧化矽、硬脂酸鎂、纖維素、硫酸月桂酯鈉(sodium lauryl sulfate)以及D&C Yellow #10。
術語「治療(treating)」是指將化合物施用於或給予主體,以治癒、緩解、減輕、改變、矯正(remedy)、改善、或影響疾病、症狀、或其傾向(predisposition)。「有效量」是指賦予主體期望的效果所需的化合物之量。如本領域技術人員所知,有效量取決於給藥途徑、賦形劑用法、以及與其他治療方法(諸如其他活性劑的使用)共同使用的可能性而變化。
無須進一步闡述,相信本領域的技術人員可基於以上描述最大程度地利用本發明。以下實施例被解釋為僅是說明性的,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透過全文併入做為參考。
以下列出本發明的127種示例性化合物之結構:
以下提供製備上述化合物及本發明其他化合物的示例性方法,以及確定其抗癌活性的示例性方法。
實施例1. 製備化合物1-127
根據下文所示的方案製備化合物41、化合物71及化合物72,該方案包括6個步驟。
步驟1:製備化合物B
於-70℃下,在1小時內將(S)-3-胺基吡咯烷-1-羧酸叔丁酯(Tert-butyl(S)-3-aminopyrrolidine-1-carboxylate)(20g,105.7mmol)逐滴加入起始原料4,6-二氯-2-(甲基磺醯基)嘧啶(4,6-dichloro-2-(methylsulfonyl)pyrimidine)(20g,88.1mmol)、三乙胺(triethylamine)(25.5mL,176.2mmol)的THF(200mL)溶液中。將反應混合物加熱至室溫,攪拌6小時,然後用鹽水(100mL)淬火。用乙酸乙酯(ethyl acetate)(3×200mL)萃取水相。用水及鹽水洗滌合併的有機萃取物,以硫酸鎂乾燥並過濾。濃縮濾液,得到粗殘餘物。該殘餘物透過矽膠快速管柱層析法以正己烷(n-hexane)/乙酸乙酯(4:1)純化,得到為白色固體的化合物B(16.4g,49.3mmol,產率56%)。
1H NMR(400MHz,CDCl3)δ 6.65(s,1H),5.42(brs,1H),4.60-4.47(m,1H),3.69(dd,J=11.2,6.0Hz,1H),3.52-3.40(m,3H),3.35-3.15(m,1H),2.23(m,1H),1.85-1.75(m,1H),1.47(s,9H).ESMS m/z:355.1(M+23).
步驟2:製備化合物C
將化合物B(7g,21.0mmol)、3-胺基-5-甲基吡唑(3-amino-5-methylpyrazole)(8.1g,84.0mmol)、三乙胺(3.5mL,25.2mmol)及NaI(4.7g,31.5mmol)的DMSO(70mL)溶液在90℃下攪拌16小時。將該溶液冷卻至室溫並倒入水中。收集形成的沉澱物,並透過矽膠快速管柱層析法以正己烷/乙酸乙酯(1:1)純化,得到為黃色固體的化合物C(7g,17.9mmol,產率85%)。
1H NMR(400MHz,CDCl3)δ 6.32(s,1H),5.93(s,1H),4.48(brs,1H),3.85-3.60(m,1H),3.60-3.40(m,4H),2.31(s,3H),1.46(s,9H).ESMS m/z:394.1(M+1).
步驟3:製備化合物D
將化合物C(7g,17.8mmol)、1-乙基哌嗪(1-ethylpiperazine)(4.1g,35.6mmol)的1-戊醇(1-pentanol)(14mL)溶液在140℃下加熱2小時,然後用鹽水(100mL)淬火。用乙酸乙酯(3×200mL)萃取水相。用水及鹽水洗滌合併的有機萃取物,以硫酸鎂乾燥並過濾。濃縮濾液,得到粗殘餘物,將其透過矽膠快速管柱層析法以乙酸乙酯/甲醇(90:10)純化,得到為黃色固體的化合物D(7g,14.9mmol,產率84%)。
1H NMR(400MHz,CDCl3)δ 5.87(s,1H),5.62(s,1H),4.70-4.39(m,1H),3.80-3.30(m,7H),2.52-2.40(m,6H),2.27(s,3H),2.24-2.04(m,2H),1.46(s,9H),1.11(t,J=7.2Hz,3H).ESMS m/z:472.1(M+1).
步驟4:製備化合物E
於室溫下,將2N鹽酸的乙醚(52mL,104mmol)溶液加入化合物D(9.8g,20.8mmol)的二氯甲烷/甲醇(2:1,75mL)溶液中。將所得混合物在室溫下攪拌4小時,然後真空濃縮,得到為黃色油狀的化合物E(9.9g,2.1mmol,產率99%)。
1H NMR(400MHz,DMSO-d6)δ 6.34(s,1H),5.86(s,1H),4.39(s,1H),3.56-2.98(m,8H),2.98-2.49(m,6H),2.25(s,3H),2.03-1.98(m,2H),1.28(t,J=7.6Hz,3H).ESMS m/z:372.66(M+1).
步驟5:製備化合物41
於室溫下,將化合物E(9g,18.7mmol)、三乙胺(15.7mL,112.0mmol)及4-氯-2-氟苯甲酸(3.6g,20.6mmol)的溶液以及丙烷膦酸酐(propanephosphonic acid anhydride)(T3P;在乙酸乙酯中50wt%;17.9g,28.1mmol)加入銨鹽的DMF/二氯甲烷(1:3,50mL)溶液中。將所得混合物在室溫攪拌16小時,然後用鹽水(100mL)淬火。用乙酸乙酯(3×200mL)萃取水相。用水及鹽水洗滌合併的有機萃取物,以硫酸鎂乾燥並過濾。濃縮濾液,得到粗殘餘物,將其透過矽膠快速管柱層析法以乙酸乙酯/甲醇(85:15)純化,得到為白色固體的化合物41(8.4g,15.9mmol,產率85%)。
1H NMR(400MHz,CD3OD)δ 7.46-7.25(m,3H),5.95-5.75(m,1H),5.62-5.45(m,1H),4.53 and 4.36(brs,1H),3.98-3.64(m,3H),3.63-3.56(m,2H),3.54-3.40(m,4H),2.60-2.40(m,6H),2.36-2.29(m,1H),2.23 and 2.22(s,3H),2.10-1.90(m,1H),1.15 and 1.14(t,J=7.2Hz,3H).ESMS m/z:528.2(M+1).
步驟6:製備化合物71及化合物72
於140℃下,將丙酸酐(propionic anhydride)(1.7mL,13.29mmol)的1,4-二噁烷(1,4-dioxane)(10mL)溶液加入化合物41(5.4g,10.23mmol)的1,4-二噁烷(100mL)溶液中。將得到的混合物在140℃下攪拌30分鐘,冷卻至室溫,然後真空濃縮。該殘餘物透過矽膠快速管柱層析法以正己烷/乙酸乙酯/三乙胺(60:35:5)純化,得到為淡黃色固體的化合物71(3.34g,5.73mmol,產率56%)及化合物72(1.67g,2.86mmol,產率28%)。
化合物71:1H NMR(300MHz,CDCl3)δ 9.88 and 9.84(brs,1H),7.34 and 7.32(t,J=7.7Hz,1H),7.12(q,J=8.3Hz,1H),7.05(d,J=9.3Hz,1H),6.51 and 6.42(s,1H),5.30 and 5.25(s,1H),4.72(brs,1H),4.60-4.40(m,1H),4.00-3.60(m,3H),3.60-3.15(m,5H),3.06 and 3.05(q,J=8.3Hz,2H),2.65-2.37(m,6H),2.35-2.23(m,1H),2.19 and 2.17(s,3H),2.03-1.92(m,1H),1.23-1.07(m,6H).ESMS m/z:584.3(M+1).
化合物72:1H NMR(400MHz,CDCl3)δ 7.35(q,J=6.8Hz,1H),7.15(q,J=9.7Hz,1H),7.09(d,J=9.6Hz,1H),6.35 and 6.30(s,1H),6.04 and 6.00(s,1H),5.03 and 4.93(brs,1H),4.55 and 4.44(d,J=5.7Hz,1H),4.03-3.34(m,7H),3.30-3.16(m,1H),3.04(t,J=7.8Hz,2H),2.60-2.36(m,5H),2.47-2.36(m,4H),2.35-2.18(m,2H),1.29-1.19(m,3H),1.11(t,J=7.0Hz,3H).ESMS m/z:584.3(M+1).
根據以下所示的方案製備化合物86、化合物122及化合物123,該方案包括5個步驟。
步驟1:製備化合物F
於-70℃下,在1小時內將4-胺基哌啶-1-甲酸叔丁酯(Tert-butyl 4-aminopiperidine-1-carboxylate)(20g,100mmol)逐滴加入起始材料4,6-二氯-2-(甲基磺醯基)嘧啶(20g,88.1mmol)、三乙胺(25.5mL,176.2mmol)的THF(200mL)溶液中。將反應混合物加熱至室溫,攪拌6小時,然後用鹽水(100mL)淬火。用乙酸乙酯(3×200mL)萃取水相。用水及鹽水洗滌合併的有機萃取物,以硫酸鎂乾燥並過濾。濃縮濾液,得到粗殘餘物。該殘餘物透過矽膠快速管柱層析法以正己烷/乙酸乙酯(4:1)純化,得到為白色固體的化合物F(16.4g,49.3mmol,產率56%)。
1H NMR(400MHz,CDCl3)δ 6.64(s,1H),5.27(brs,1H),4.25-3.80(m,4H),2.97(t,J=11.9Hz,2H),2.03(d,J=9.6Hz,2H),1.49(s,9H),1.46-1.34(m,1H).ESMS m/z:369.1(M+23).
步驟2:製備化合物G
於90℃下,將化合物F(40g,115mmol)、3-胺基-5-甲基吡唑(44.7g,461mmol)、三乙胺(32mL,230mmol)及NaI(19g,115mmol)的二甲基亞碸(DMSO)(60mL)溶液攪拌24小時。將該溶液冷卻至室溫並倒入水中,形成並收集沉澱物,並透過矽膠快速管柱層析法以正己烷/乙酸乙酯(1:1)純化,得到為黃色固體的化合物G(35g,86mmol,產率75%)。
1H NMR(400MHz,CDCl3)δ 6.35(s,1H),6.08(s,1H),4.20-3.87(m,4H),2.97(t,J=11.6Hz,2H),2.34(s,3H),2.05(d,J=13.3Hz,2H),1.49(s,9H),1.46-1.34(m,1H).ESMS m/z:408.2(M+1).
步驟3:製備化合物H
將化合物G(20g,49.1mmol)、1-乙基哌嗪(11.2g,98.3mmol)的1-戊醇(1-pentanol)(20mL)溶液在140℃下加熱3小時,然後用鹽水(100mL)淬火。用乙酸乙酯(3×200mL)萃取水相。用水及鹽水洗滌合併的有機萃取物,以硫酸鎂乾燥並過濾。濃縮濾液,得到粗殘餘物,將其透過矽膠快速管柱層析法以乙酸乙酯/甲醇(90:10)純化,得到為黃色固體的化合物H(17.7g,36.3mmol,產率74%)。
1H NMR(400MHz,CDCl3)δ 5.86(s,1H),5.80(s,1H),4.04(brs,1H),3.94(brs,1H),3.68-3.52(m,4H),2.97(t,J=11.7Hz,2H),2.54-2.49(m,6H),2.50-2.43(m,4H),2.30(s,3H),2.04(d,J=8.0Hz,2H),1.49(s,9H),1.47-1.37(m,1H),1.14(t,J=7.2Hz,3H).ESMS m/z:486.3(M+1).
步驟4:製備化合物86
於室溫下,將2N鹽酸的乙醚(129mL,257mmol)溶液加入化合物H(25g,51.5mmol)的二氯甲烷/甲醇(2:1,129mL)溶液中。將所得混合物在室溫下攪拌3小時,然後真空濃縮,得到化合物H的氯化氫鹽,無需進一步純化。
然後,將三乙胺(10.8mL,77.3mmol)及3-氯-2-氟苯甲酸(3-chloro-2-fluorobenzoic acid)(9.9g,56.7mmol)的溶液以及在二氯甲烷(100mL)中的丙烷膦酸酐(T3P)(在乙酸乙酯中50wt%;39g,61.9mmol)攪拌2小時。於室溫下,將混合物加入化合物H的氯化氫鹽及三乙胺(28.7mL,206mmol)的二氯甲烷(250mL)溶液中。將所得混合物在室溫下攪拌16小時,然後用鹽水(100mL)淬火。用乙酸乙酯(3×500mL)萃取水相。用水及鹽水洗滌合併的有機萃取物,以硫酸鎂乾燥並過濾。濃縮濾液,得到粗殘餘物。該殘餘物透過矽膠快速管柱層析法以乙酸乙酯/甲醇(85:15)純化,得到為白色固體的化合物86(23g,42.5mmol,產率81%)。
化合物86:1H NMR(400MHz,CDCl3)δ 7.44(t,J=7.8Hz,1H),7.29-7.22(m,1H),7.14(t,J=7.8Hz,1H),5.86(s,1H),5.66(s,1H),4.58(d,J=13.0Hz,1H),4.09-3.98(m,1H),3.57-3.47(m,5H),3.29-3.02(m,2H),2.50-2.38(m,6H),2.28(s,3H),2.16(d,J=13.0Hz,1H),2.06(d,J=13.0Hz,1H),1.62-1.46(m,2H),1.11(t,J=7.2Hz,3H).ESMS m/z:542.2(M+1).
步驟5:製備化合物122及化合物123
於40℃下,將丙酸酐(1.4g,10.8mmol)的二氯甲烷(200mL)溶液加入化合物86(5g,9.2mmol)的二氯甲烷(800mL)溶液中。將所得混合物在40℃下攪拌4小時,冷卻至室溫,然後真空濃縮。該殘餘物透過矽膠快速管柱層析法
以正己烷/乙酸乙酯/三乙胺(60:35:5)純化,得到為淡黃色固體的化合物122(3.1g,5.2mmol,產率56%)及化合物123(1.4g,2.4mmol,產率26%)。
化合物122:1H NMR(300MHz,CDCl3)δ 9.88(brs,1H),7.45(td,J=7.8,1.8Hz,1H),7.31-7.26(m,1H),7.16(t,J=7.8Hz,1H),6.55(s,1H),5.33(s,1H),4.71(brs,1H),4.64(d,J=14.0Hz,1H),4.14-3.97(m,1H),3.57(d,J=14.0Hz,1H),3.54(t,J=5.0Hz,4H),3.47(q,J=7.0Hz,1H),3.23-3.00(m,3H),2.53-2.39(m,6H),2.25(s,3H),2.22(d,J=14.0Hz,1H),2.10(d,J=14.0Hz,1H),1.58-1.47(m,2H),1.24 and 1.21(t,J=7.0Hz,3H),1.12(t,J=7.0Hz,3H).ESMS m/z:598.3(M+1).
化合物123:1H NMR(300MHz,CDCl3)δ 7.45(t,J=7.8Hz,1H),7.31-7.26(m,1H),7.15(t,J=7.8Hz,1H),6.69(brs,1H),6.22(s,1H),6.09(s,1H),4.66-4.54(m,2H),4.11-3.95(m,1H),3.59(t,J=4.8Hz,4H),3.57-3.48(m,1H),3.21-2.99(m,4H),2.57(s,3H),2.53-2.39(m,6H),2.18(d,J=14.0Hz,1H),2.06(d,J=14.0Hz,1H),1.59-1.49(m,2H),1.25(t,J=7.2Hz,3H),1.14 and 1.12(t,J=7.2Hz,3H).ESMS m/z:598.3(M+1).
使用與上述相似的步驟來製備化合物1-40、化合物42-70、化合物73-85、化合物87-121及化合物124-127。
化合物1:1H NMR(400MHz,CDCl3)δ 9.49(brs,1H),7.87 and 7.86(s,1H),7.43(t,J=7.8Hz,1H),7.22 and 7.20(dd,J=8.4,2.0Hz,1H),7.17 and 7.12(dd,J=9.2,2.0Hz,1H),5.38 and 5.34(s,1H),5.04 and 4.98(brs,1H),4.75-4.50(m,1H),4.08-3.69(m,2H),3.62-3.25(m,6H),2.53-2.26(m,7H),2.13-2.00(m,1H),1.12 and 1.12(t,J=7.2Hz,3H).ESMS m/z:556.2(M+1).
化合物2:1H NMR(400MHz,CDCl3)δ 9.30(brs,1H),8.03(s,1H),7.45-7.37(m,1H),7.29-7.08(m,2H),5.39 and 5.35(s,1H),5.01 and 4.95(brs,1H),4.84-4.54(m,1H),4.34(quin,J=6.8Hz,2H),4.09-3.64(m,2H),3.63-3.23(m,6H),
2.52-2.38(m,5H),2.35 and 2.34(s,3H),2.13-2.00(m,1H),1.38 and 1.36(t,J=7.2Hz,3H).ESMS m/z:589.2(M+1).
化合物3:1H NMR(400MHz,DMSO-d6)δ 7.95 and 7.93(s,1H),7.59-7.46(m,2H),7.42-7.37(m,1H),5.67 and 5.61(s,1H),4.74-4.50(m,1H),3.85-3.04(m,8H),2.70-2.54(m,4H),2.49-2.41(m,3H),2.34-2.12(m,1H),2.09-1.92(m,1H).ESMS m/z:561.2(M+1).
化合物4:1H NMR(300MHz,CDCl3)δ 7.48-7.41(m,1H),7.29-7.22(m,1H),7.09 and 7.07(t,J=7.8Hz,1H),6.46 and 6.43(s,1H),5.92 and 5.88(s,1H),5.72(brs,1H),5.30 and 5.10(brs,1H),4.58-4.40(m,1H),3.87-3.22(m,8H),2.45 and 2.37(t,J=4.9Hz,4H),2.34-2.26(m,6H),2.25-2.12(m,1H),2.02-1.84(m,1H).ESMS m/z:531.2(M+1).
化合物5:1H NMR(300MHz,CDCl3)δ 7.41 and 7.41(t,J=8.9Hz,1H),7.22 and 7.22(dd,J=8.9,6.2Hz,1H),7.16 and 7.15(t,J=8.9Hz,1H),6.04 and 5.99(brs,1H),5.98 and 5.94(s,1H),4.76-4.55(m,1H),4.15-3.32(m,9H),2.75-2.50(m,6H),2.29 and 2.28(s,3H),2.24-2.01(m,2H),1.21 and 1.19(t,J=7.1Hz,3H).ESMS m/z:529.2(M+1).
化合物6:1H NMR(300MHz,CDCl3)δ 7.41-7.31(m,2H),7.23-7.08(m,2H),6.93(d,J=3.6Hz,1H),6.48 and 6.43(s,1H),4.62-4.40(m,1H),4.06-3.71(m,2H),3.71-3.17(m,6H),2.57-2.39(m,6H),2.37-1.95(m,2H),1.13(t,J=7.4Hz,3H).ESMS m/z:515.2(M+1).
化合物7:1H NMR(400MHz,CDCl3)δ 7.38 and 7.37(t,J=8.6Hz,1H),7.19 and 7.18(t,J=8.6Hz,1H),7.14 and 7.11(dd,J=9.6,2.0Hz,1H),4.90 and 4.86(s,1H),4.69(brs,1H),4.58-4.37(m,1H),4.07-3.94(m,1H),3.84-3.43(m,6H),3.43-3.14(m,1H),2.52-2.14(m,9H),1.99-1.65(m,6H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:502.2(M+1).
化合物8:1H NMR(400MHz,CDCl3)δ 7.32-7.26(m,1H),7.12-7.09(m,2H),5.90 and 5.85(s,1H),5.30 and 5.27(s,1H),4.70-4.53(m,1H),4.08-3.89(m,
3H),3.82-3.66(m,4H),3.51-3.10(m,2H),2.29 and 2.28(s,3H),2.20 and 2.18(s,6H),2.15-2.00(m,2H).ESMS m/z:514.2(M+1).
化合物9:1H NMR(300MHz,CDCl3)δ 7.31-7.24(m,1H),7.19-7.09(m,2H),5.89 and 5.86(s,1H),5.55 and 5.52(s,1H),4.72-4.47(m,1H),4.37-4.00(m,2H),3.90-3.57(m,2H),3.54-3.13(m,4H),2.69-2.55(m,1H),2.34-2.03(m,7H),1.27-1.02(m,6H).ESMS m/z:528.2(M+1).
化合物10:1H NMR(400MHz,CDCl3)δ 7.31 and 7.30(t,J=7.7Hz,1H),7.18-7.09(m,2H),5.90 and 5.85(s,1H),5.64 and 5.62(s,1H),4.68-4.51(m,1H),4.21-3.97(m,3H),3.80-3.66(m,2H),3.54-3.23(m,2H),2.94-2.75(m,2H),2.48-2.33(m,2H),2.30 and 2.29(s,3H),2.26-2.04(m,2H),1.36(d,J=6.4Hz,3H),1.14(d,J=6.4Hz,3H).ESMS m/z:528.2(M+1).
化合物11:1H NMR(300MHz,CD3OD)δ 7.49(t,J=8.4Hz,1H),7.40-7.31(m,2H),5.80(m,1H),4.71-4.51(m,2H),4.06-3.34(m,7H),2.44-2.30(m,5H),2.23-2.02(m,2H).ESMS m/z:512.1(M+1).
化合物12:1H NMR(300MHz,CDCl3)δ 7.32-7.24(m,1H),7.18-7.09(m,2H),5.91 and 5.86(s,1H),5.64 and 5.62(s,1H),4.74-4.50(m,1H),4.17-4.02(m,1H),3.83-3.22(m,11H),2.31 and 2.30(s,3H),2.26-2.14(m,2H),2.13 and 2.12(s,3H).ESMS m/z:542.2(M+1).
化合物13:1H NMR(400MHz,CDCl3)δ 7.30-7.25(m,1H),7.17-7.09(m,2H),5.91 and 5.86(s,1H),5.61 and 5.59(s,1H),4.72-4.52(m,1H),4.16-3.98(m,1H),3.80-3.64(m,2H),3.62-3.41(m,7H),3.40-3.22(m,5H),2.60(q,J=5.5Hz,2H),2.54(t,J=4.8Hz,2H),2.50(t,J=4.8Hz,2H),2.30 and 2.29(s,3H),2.26-2.17(m,1H),2.15-2.04(m,1H).ESMS m/z:558.2(M+1).
化合物14:1H NMR(400MHz,CDCl3)δ 8.01(s,1H),7.29-7.24(m,1H),7.17-7.09(m,2H),5.92 and 5.86(s,1H),5.61 and 5.58(s,1H),4.74-4.51(m,1H),4.19-4.05(m,1H),3.81-3.23(m,7H),3.04-2.96(m,2H),2.70(t,J=4.8Hz,2H),2.66(t,J=4.8Hz,2H),2.30 and 2.29(s,3H),2.27-2.03(m,2H).ESMS m/z:582.2(M+1).
化合物15:1H NMR(400MHz,CDCl3)δ 7.30-7.27(m,1H),7.17-7.09(m,2H),5.92 and 5.86(s,1H),5.60 and 5.58(s,1H),4.70-4.51(m,1H),4.16-3.90(m,3H),3.80-3.64(m,2H),3.52-3.24(m,2H),2.69-2.55(m,2H),2.30 and 2.29(s,3H),2.28 and 2.27(s,3H),2.25-2.03(m,5H),1.16-1.07(m,6H).ESMS m/z:542.2(M+1).
化合物16:1H NMR(400MHz,CDCl3)δ 7.29-7.22(m,1H),7.17-7.08(m,2H),5.91 and 5.86(s,1H),5.61 and 5.58(s,1H),4.73-4.51(m,5H),4.18-4.05(m,1H),3.80-3.22(m,8H),2.36(t,J=5.0Hz,2H),2.32(t,J=5.0Hz,2H),2.29 and 2.28(s,3H),2.27-2.03(m,2H).ESMS m/z:556.1(M+1).
化合物17:1H NMR(400MHz,CDCl3)δ 7.34-7.26(m,1H),7.18-7.09(m,2H),5.92 and 5.87(s,1H),5.55 and 5.52(s,1H),4.65-4.50(m,1H),4.10-3.99(m,1H),3.80-3.46(m,5H),3.46-3.21(m,5H),3.01 and 2.97(s,3H),2.29 and 2.28(s,3H),2.25-2.16(m,2H).ESMS m/z:503.2(M+1).
化合物18:1H NMR(400MHz,CDCl3)δ 7.33-7.27(m,1H),7.19-7.09(m,2H),5.92 and 5.86(s,1H),5.40 and 5.37(s,1H),4.71-4.52(m,1H),4.08-3.98(m,1H),3.82-3.06(m,7H),2.83-2.68(m,1H),2.35-2.00(m,12H),1.91-1.74(m,1H).ESMS m/z:528.2(M+1).
化合物19:1H NMR(300MHz,CDCl3)δ 7.33(t,J=7.2Hz,1H),7.20-7.08(m,2H),5.87 and 5.83(s,1H),5.36 and 5.33(s,1H),4.64-4.50(m,1H),4.34-4.02(m,2H),3.91-3.61(m,5H),3.57-3.35(m,1H),3.32 and 3.31(s,3H),3.28-3.16(m,1H),2.28 and 2.27(s,3H),2.26-2.10(m,2H).ESMS m/z:501.1(M+1).
化合物20:1H NMR(300MHz,CDCl3)δ 7.42(t,J=7.6Hz,1H),7.25-7.19(m,1H),7.10 and 7.09(t,J=7.6Hz,1H),5.93 and 5.87(s,1H),5.39 and 5.36(s,1H),4.75-4.52(m,1H),4.11-3.98(m,1H),3.82-3.06(m,7H),2.83-2.67(m,1H),2.34-2.00(m,12H),1.92-1.74(m,1H).ESMS m/z:528.2(M+1).
化合物21:1H NMR(300MHz,CDCl3)δ 7.43(t,J=7.2Hz,1H),7.26-7.18(m,1H),7.09(t,J=7.8Hz,1H),5.92 and 5.86(s,1H),5.66 and 5.63(s,1H),
4.75-4.52(m,1H),4.41-4.20(m,2H),4.15-4.00(m,1H),3.84-3.21(m,3H),2.83-2.64(m,2H),2.53-2.36(m,1H),2.35-2.26(m,9H),2.25-2.02(m,2H),1.92-1.75(m,2H),1.54-1.32(m,2H).ESMS m/z:542.2(M+1).
化合物22:1H NMR(300MHz,CDCl3)δ 7.47-7.40(m,1H),7.33-7.27(m,1H),7.16-7.08(m,1H),5.90 and 5.85(s,1H),5.46-5.36(m,2H),4.59(brs,1H),4.10-3.60(m,3H),3.60-3.10(m,5H),2.88-2.75(m,1H),2.35-2.24(m,11H),1.96-1.80(m,2H).ESMS m/z:528.2(M+1).
化合物23:1H NMR(300MHz,CDCl3)δ 7.43(t,J=7.5Hz,1H),7.25-7.17(m,1H),7.10(t,J=7.8Hz,1H),5.94 and 5.88(s,1H),5.43 and 5.41(s,1H),4.75-4.56(m,1H),4.39-4.00(m,2H),3.84-3.54(m,3H),3.53-3.15(m,7H),2.29 and 2.28(s,3H),2.24-2.08(m,2H),2.07-1.81(m,4H).ESMS m/z:529.2(M+1).
化合物24:1H NMR(400MHz,CDCl3)δ 7.42(t,J=7.4Hz,1H),7.21(t,J=6.6Hz,1H),7.09(t,J=8.0Hz,1H),5.95 and 5.89(s,1H),5.43 and 5.40(s,1H),4.72-4.52(m,1H),4.33-4.07(m,2H),3.83-3.64(m,2H),3.52-3.10(m,8H),2.29 and 2.28(s,3H),2.27-2.06(m,2H),2.06-1.85(m,4H).ESMS m/z:529.2(M+1).
化合物25:1H NMR(300MHz,CDCl3)δ 7.42 and 7.42(t,J=7.2Hz,1H),7.24-7.17(m,1H),7.09(t,J=7.8Hz,1H),5.91 and 5.85(s,1H),5.29 and 5.26(s,1H),4.71 and 4.58(brs,1H),4.09-3.90(m,3H),3.81-3.65(m,4H),3.51-3.10(m,3H),2.29 and 2.28(s,3H),2.23-2.03(m,8H).ESMS m/z:514.2(M+1).
化合物26:1H NMR(300MHz,CD3OD)δ 7.59(q,J=8.2Hz,1H),7.43-7.32(m,1H),7.32-7.21(m,1H),5.97-5.73(m,2H),4.55 and 4.40(quin,J=5.6Hz,1H),4.00-3.77(m,1H),3.76-3.37(m,7H),3.07 and 2.97(t,J=5.3Hz,4H),2.40-2.24(m,1H),2.24 and 2.22(s,3H),2.14-1.97(m,1H).ESMS m/z:500.1(M+1).
化合物27:1H NMR(400MHz,CDCl3)δ 7.43(t,J=7.6Hz,1H),7.25-7.20(m,1H),7.10(t,J=7.8Hz,1H),5.93 and 5.88(s,1H),5.51 and 5.49(s,1H),4.69 and 4.60(brs,1H),4.15-4.04(m,1H),3.83-3.44(m,5H),3.42-3.25(m,1H),2.98
and 2.94(s,3H),2.41-2.35(m,2H),2.32-2.25(m,7H),2.23(s,3H),2.20-2.05(m,1H).ESMS m/z:516.2(M+1).
化合物28:1H NMR(400MHz,CDCl3)δ 7.43(t,J=7.4Hz,1H),7.24-7.18(m,1H),7.09(t,J=7.8Hz,1H),5.92 and 5.87(s,1H),5.65 and 5.62(s,1H),4.74-4.54(m,1H),4.17-4.03(m,1H),3.99-3.66(m,3H),3.52-3.07(m,8H),2.30 and 2.29(s,3H),2.27-2.04(m,2H),1.95-1.80(m,2H),1.63-1.42(m,2H).ESMS m/z:529.2(M+1).
化合物29:1H NMR(400MHz,CDCl3)δ 7.42 and 7.42(d,J=8.4Hz,2H),7.36 and 7.34(d,J=8.4Hz,2H),5.91 and 5.85(s,1H),5.62 and 5.57(s,1H),4.69 and 4.56(brs,1H),4.20-4.14(m,1H),3.77-3.66(m,2H),3.64-3.40(m,8H),2.50-2.40(m,6H),2.29 and 2.28(s,3H),2.26-2.17(m,1H),2.14-2.05(m,1H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:510.2(M+1).
化合物30:1H NMR(300MHz,CDCl3)δ 7.34-7.26(m,2H),7.04(t,J=8.0Hz,1H),5.82(s,1H),5.58(s,1H),4.60-4.46(m,1H),3.71(s,2H),3.54(t,J=5.0Hz,4H),2.88-2.77(m,2H),2.70-2.62(m,1H),2.51-2.39(m,5H),2.38-2.27(m,4H),2.26(s,3H),1.75-1.61(m,1H).ESMS m/z:500.2(M+1).
化合物31:1H NMR(400MHz,CDCl3)δ 7.32-7.26(m,2H),7.04(td,J=7.8,1.2Hz,1H),5.83(s,1H),5.57(s,1H),4.60-4.48(m,1H),3.70(s,2H),3.54(t,J=5.0Hz,4H),2.88-2.76(m,2H),2.74-2.66(m,1H),2.49-2.38(m,7H),2.36-2.26(m,1H),2.24(s,3H),1.72-1.61(m,1H),1.10(t,J=7.2Hz,3H).ESMS m/z:514.2(M+1).
化合物32:1H NMR(400MHz,CDCl3)δ 7.42 and 7.41(d,J=11.8Hz,1H),7.25-7.23(m,1H),7.22 and 7.20(t,J=7.6Hz,1H),5.91 and 5.86(s,1H),5.65 and 5.64(s,1H),4.57(brs,1H),4.11-4.00(m,1H),3.80-3.68(m,1H),3.63-3.47(m,5H),3.45-3.14(m,2H),2.51-2.40(m,6H),2.29 and 2.28(s,3H),2.27-2.02(m,2H),1.12(t,J=7.6Hz,3H).ESMS m/z:544.2(M+1).
化合物33:1H NMR(400MHz,CDCl3)δ 7.36-7.30(m,2H),7.23 and 7.23(d,J=8.0Hz,1H),5.91 and 5.84(s,1H),5.64 and 5.61(s,1H),4.65 and 4.56(brs,1H),4.12-4.00(m,1H),3.80-3.70(m,2H),3.65-3.40(m,6H),2.53-2.40(m,6H),2.36(s,3H),2.29 and 2.28(s,3H),2.25-2.16(m,1H),2.15-2.03(m,1H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:524.3(M+1).
化合物34:1H NMR(400MHz,CDCl3)δ 7.22-7.07(m,3H),5.91 and 5.86(s,1H),5.66(s,1H),4.55(brs,1H),4.15-4.05(m,1H),3.79-3.32(m,7H),3.20-3.13(m,1H),2.54-2.40(m,6H),2.30-2.25(m,6H),2.15-2.05(m,2H),1.13 and 1.12(t,J=7.0Hz,3H).ESMS m/z:524.3(M+1).
化合物35:1H NMR(300MHz,CDCl3)δ 7.43(t,J=6.6Hz,1H),7.24-7.18(m,1H),7.09(t,J=7.8Hz,1H),5.93 and 5.87(s,1H),5.63 and 5.60(s,1H),4.72 and 4.78(brs,1H),4.17-4.07(m,1H),3.82-3.24(m,8H),2.46-2.37(m,4H),2.35-2.28(m,6H),2.57-2.04(m,2H).ESMS m/z:514.2(M+1).
化合物36:1H NMR(300MHz,CDCl3)δ 7.31-7.26(m,1H),7.18-7.08(m,2H),5.92 and 5.86(s,1H),5.63 and 5.61(s,1H),4.73-4.51(m,1H),4.16-4.01(m,1H),3.82-3.54(m,3H),3.54-3.23(m,4H),2.49-2.37(m,4H),2.33 and 2.31(s,3H),2.30 and 2.29(s,3H),2.27-2.19(m,1H),2.16-2.03(m,1H).ESMS m/z:514.2(M+1).
化合物37:1H NMR(400MHz,CDCl3)δ 7.39-7.30(m,2H),7.06 and 7.03(t,J=8.8Hz,1H),5.89 and 5.85(s,1H),5.73 and 5.71(s,1H),4.56(brs,1H),3.99-3.80(m,1H),3.80-3.50(m,6H),3.46-3.24(m,2H),2.62-2.45(m,6H),2.31 and 2.29(s,3H),2.23-2.15(m,2H),1.17 and 1.15(t,J=7.2Hz,3H).ESMS m/z:528.2(M+1).
化合物38:1H NMR(400MHz,CDCl3)δ 7.43 and 7.43(t,J=7.5Hz,1H),7.21 and 7.20(q,J=7.5Hz,1H),7.09(t,J=7.5Hz,1H),5.93 and 5.87(s,1H),5.62 and 5.59(s,1H),4.72 and 4.58(brs,1H),4.13(m,1H),3.82-3.66(m,2H),3.62-3.42(m,5H),3.41-3.25(m,1H),2.51-2.40(m,6H),2.31 and 2.29(s,3H),
2.28-2.21(m,1H),2.16-2.05(m,1H),1.12 and 1.12(t,J=7.2Hz,3H).ESMS m/z:528.3(M+1).
化合物39:1H NMR(700MHz,DMSO-d6)δ 8.70(brs,1H),7.68 and 7.64(t,J=8.1Hz,1H),7.60 and 7.57(dd,J=9.8,1.4Hz,1H),6.51(brs,1H),6.06(brs,1H),5.80(brs,1H),4.41 and 4.20(brs,1H),3.85-3.73(m,1H),3.67-3.62(m,1H),3.61-3.50(m,1H),3.50-3.40(m,3H),2.49-2.22(m,6H),2.16 and 2.13(s,3H),2.11-2.09(m,1H),2.03-1.86(m,1H),1.07-0.99(m,3H).ESMS m/z:528.2(M+1).
化合物40:1H NMR(700MHz,CDCl3)δ 7.18(t,J=7.0Hz,1H),7.04(s,1H),5.93 and 5.87(s,1H),5.63 and 5.60(s,1H),4.70 and 4.58(brs,1H),4.11(m,1H),3.79-3.68(m,2H),3.60-3.57(m,1H),3.56-3.46(m,4H),3.41-3.27(m,1H),2.50-2.41(m,6H),2.30 and 2.29(s,3H),2.27-2.22(m,1H),2.16-2.08(m,1H),1.12 and 1.11(t,J=7.0Hz,3H).ESMS m/z:546.2(M+1).
化合物42:1H NMR(400MHz,CDCl3)δ 7.33-7.23(m,1H),7.01-6.92(m,1H),5.87 and 5.84(s,1H),5.74 and 5.72(s,1H),4.54(brs,1H),3.96-3.80(m,2H),3.78-3.50(m,5H),3.49-3.26(m,2H),2.60-2.50(m,6H),2.31 and 2.30(s,3H),2.22-2.03(m,2H),1.17 and 1.16(t,J=7.0Hz,3H).ESMS m/z:530.3(M+1).
化合物43:1H NMR(400MHz,CDCl3)δ 7.23-7.10(m,2H),5.91 and 5.86(s,1H),5.70 and 5.68(s,1H),4.63 and 4.58(brs,1H),4.02-3.95(m,1H),3.80-3.70(m,2H),3.65-3.47(m,5H),3.44-3.25(m,1H),2.55-2.42(m,6H),2.30 and 2.29(s,3H),2.22-2.03(m,2H),1.14 and 1.13(t,J=7.2Hz,3H).ESMS m/z:546.2(M+1).
化合物44:1H NMR(400MHz,CDCl3)δ 7.34 and 7.32(t,J=8.0Hz,1H),6.92-6.78(m,2H),5.92 and 5.86(s,1H),5.63 and 5.60(s,1H),4.73-4.53(m,1H),4.15-4.04(m,1H),3.80-3.52(m,3H),3.52-3.25(m,4H),2.52-2.39(m,6H),2.31 and 2.29(s,3H),2.28-2.18(m,1H),2.17-2.05(m,1H),1.11 and 1.11(t,J=7.2Hz,3H).ESMS m/z:512.3(M+1).
化合物45:1H NMR(400MHz,CDCl3)δ 7.18 and 7.15(d,J=7.0Hz,2H),5.88 and 5.84(s,1H),5.76 and 5.73(s,1H),4.57(brs,1H),4.01-3.85(m,1H),3.82-3.53(m,6H),3.52-3.40(m,2H),2.58-2.45(m,6H),2.30 and 2.29(s,3H),2.20-2.15(m,2H),1.20-1.10(m,3H).ESMS m/z:546.2(M+1).
化合物46:1H NMR(300MHz,CD3OD)δ 7.74-7.55(m,3H),5.87 and 5.82(s,1H),4.56 and 4.42(brs,1H),4.01-3.77(m,1H),3.77-3.62(m,4H),3.62-3.57(m,3H),3.57-3.40(m,1H),2.83-2.57(m,6H),2.40-2.30(m,1H),2.24 and 2.22(s,3H),2.15-2.02(m,1H),1.27-1.14(m,3H).ESMS m/z:562.3(M+1).
化合物47:1H NMR(400MHz,CDCl3)δ 7.10-6.95(m,2H),5.88 and 5.85(s,1H),5.76 and 5.74(s,1H),4.58(brs,1H),4.21-3.87(m,2H),3.80-3.68(m,1H),3.67-3.47(m,5H),3.43-3.17(m,1H),2.57-2.43(m,6H),2.38-2.30(m,1H),2.29 and 2.28(s,3H),2.24-2.25(m,1H),1.14 and 1.14(t,J=7.2Hz,3H).ESMS m/z:546.2(M+1).
化合物48:1H NMR(300MHz,CDCl3)δ 7.65(t,J=7.2Hz,1H),7.60-7.52(m,1H),7.31-7.21(m,1H),5.91 and 5.86(s,1H),5.71 and 5.68(s,1H),4.72-4.53(m,1H),4.12-3.98(m,1H),3.85-3.44(m,6H),3.44-3.24(m,1H),2.57-2.38(m,6H),2.28 and 2.27(s,3H),2.25-2.06(m,2H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:562.2(M+1).
化合物49:1H NMR(300MHz,CDCl3)δ 7.82 and 7.78(s,1H),7.59(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),5.91 and 5.85(s,1H),5.66 and 5.62(s,1H),4.74-4.53(m,1H),4.20-4.02(m,1H),3.82-3.47(m,6H),3.47-3.37(m,1H),2.55-2.39(m,6H),2.28(s,3H),2.26-2.18(m,1H),2.18-2.00(m,1H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:578.2(M+1).
化合物50:1H NMR(300MHz,CDCl3)δ 7.50(q,J=8.2Hz,1H),7.43-7.35(m,1H),5.88 and 5.85(s,1H),5.76 and 5.74(s,1H),4.73-4.54(m,1H),3.96-3.74(m,2H),3.74-3.34(m,6H),2.57-2.43(m,6H),2.30 and 2.29(s,3H),2.25-2.05(m,2H),1.14 and 1.13(t,J=7.2Hz,3H).ESMS m/z:529.3(M+1).
化合物51:1H NMR(300MHz,CDCl3)δ 8.41 and 8.39(d,J=1.2Hz,1H),7.59 and 7.56(dd,J=8.4,1.2Hz,1H),5.89 and 5.86(s,1H),5.65 and 5.63(s,1H),4.76-4.58(m,1H),4.01-3.60(m,4H),3.60-3.39(m,4H),2.59-2.43(m,6H),2.29(s,3H),2.25-2.06(m,2H),1.14 and 1.13(t,J=7.2Hz,3H).ESMS m/z:529.2(M+1).
化合物52:1H NMR(400MHz,CDCl3)δ 8.53 and 8.52(d,J=2.8Hz,1H),7.80-7.76(m,1H),7.36 and 7.35(d,J=8.4Hz,1H),5.90 and 5.84(s,1H),5.65 and 5.63(s,1H),4.71-4.55(m,1H),4.16-4.01(m,1H),3.84-3.58(m,3H),3.58-3.40(m,4H),2.53-2.42(m,6H),2.29 and 2.28(s,3H),2.26-2.05(m,2H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:511.2(M+1).
化合物53:1H NMR(400MHz,CDCl3)δ 7.82 and 7.82(t,J=8.2Hz,1H),7.29-7.24(m,1H),5.90 and 5.85(s,1H),5.68 and 5.66(s,1H),4.63 and 4.59(brs,1H),4.04-3.93(m,1H),3.83-3.72(m,2H),3.63-3.26(m,6H),2.53-2.42(m,6H),2.31 and 2.30(s,3H),2.22-2.04(m,2H),1.13 and 1.13(t,J=7.2Hz,3H).ESMS m/z:529.2(M+1).
化合物54:1H NMR(400MHz,CDCl3)δ 7.60 and 7.55(d,J=8.0Hz,1H),7.28(d,J=8.0Hz,1H),5.93 and 5.87(s,1H),5.63 and 5.62(s,1H),4.68-4.54(m,1H),4.17-4.01(m,1H),3.81-3.45(m,5H),3.45-3.16(m,2H),2.52-2.40(m,6H),2.37-2.22(m,4H),2.18-2.04(m,1H),1.12(t,J=7.2Hz,3H).ESMS m/z:545.2(M+1).
化合物55:1H NMR(300MHz,CDCl 3 )δ 8.29 and 8.29(s,1H),7.43 and 7.40(s,1H),5.90 and 5.86(s,1H),5.67 and 5.66(s,1H),4.59(m,1H),4.14-3.97(m,1H),3.84-3.61(m,3H),3.61-3.14(m,4H),2.62-2.42(m,6H),2.36-2.20(m,4H),2.20-2.02(m,1H),1.16 and 1.15(t,J=7.2Hz,3H).ESMS m/z:545.2(M+1).
化合物56:1H NMR(300MHz,CD3OD)δ 7.95 and 7.91(d,J=7.5Hz,1H),5.87(s,1H),5.82(s,1H),4.63-4.38(m,1H),3.99-3.59(m,6H),3.59-3.36(m,2H),3.04-2.95(m,2H),2.95-2.79(m,4H),2.42-2.28(m,1H),2.25 and 2.24(s,3H),2.17-2.01(m,1H),1.28 and 1.28(t,J=7.2Hz,3H).ESMS m/z:563.2(M+1).
化合物57:1H NMR(400MHz,CDCl3)δ 8.42 and 8.41(d,J=2.0Hz,1H),7.90 and 7.88(d,J=2.0Hz,1H),5.91 and 5.85(s,1H),5.65 and 5.64(s,1H),4.70-4.56(m,1H),4.15-3.99(m,1H),3.84-3.54(m,4H),3.54-3.43(m,3H),2.52-2.39(m,6H),2.30 and 2.29(s,3H),2.28-2.20(m,1H),2.18-2.04(m,1H),1.12 and 1.11(t,J=7.2Hz,3H).ESMS m/z:545.2(M+1).
化合物58:1H NMR(300MHz,CDCl3)δ 7.43(t,J=7.6Hz,1H),7.24-7.16(m,1H),7.09(t,J=7.6Hz,1H),5.93 and 5.87(s,1H),5.62 and 5.59(s,1H),4.77-4.52(m,1H),4.20-4.03(m,1H),3.84-3.53(m,3H),3.53-3.22(m,4H),2.53-2.38(m,6H),2.30 and 2.29(s,3H),2.27-2.19(m,1H),2.16-2.03(m,1H),1.11 and 1.11(t,J=7.2Hz,3H).ESMS m/z:528.2(M+1).
化合物59:1H NMR(300MHz,CDCl3)δ 7.43(t,J=7.8Hz,1H),7.24-7.17(m,1H),7.09(t,J=7.8Hz,1H),5.92 and 5.87(s,1H),5.63 and 5.61(s,1H),4.75-4.53(m,1H),4.18-4.02(m,1H),3.84-3.53(m,3H),3.53-3.22(m,4H),2.50-2.37(m,4H),2.33 and 2.31(s,3H),2.31 and 2.29(s,3H),2.27-2.19(m,1H),2.17-2.03(m,1H).ESMS m/z:514.2(M+1).
化合物60:1H NMR(400MHz,CDCl 3 )δ 7.42-7.33(m,1H),7.23-7.08(m,2H),6.84 and 6.78(brs,1H),5.85 and 5.83(s,1H),5.63 and 5.60(s,1H),5.32-5.03(m,1H),3.97-3.86(m,1H),3.67-3.25(m,9H),2.57-2.38(m,6H),2.28-2.18(m,4H),2.15-2.07(m,1H),1.21-1.05(m,6H).ESMS m/z:556.3(M+1).
化合物61:1H NMR(400MHz,CDCl3)δ 7.91(d,J=2.0Hz,1H),7.64(dd,J=8.4,2.0Hz,1H),7.57(d,J=8.4Hz,1H),5.86(s,1H),5.72(s,1H),4.44-4.38(m,1H),3.57-3.42(m,7H),3.40-3.30(m,1H),2.51-2.41(m,6H),2.30(s,3H),2.13-1.88(m,2H),1.12(t,J=7.2Hz,3H).ESMS m/z:580.2(M+1).
化合物62:1H NMR(300MHz,CDCl 3 )δ 7.86(d,J=8.2Hz,1H),7.32(s,1H),7.29(d,J=8.2Hz,1H),5.90(s,1H),5.65(s,1H),4.67-4.56(m,1H),3.64-3.41(m,7H),3.39-3.27(m,1H),2.63(s,3H),2.52-2.39(m,6H),2.31(s,3H),
2.16-2.02(m,1H),1.99-1.88(m,1H),1.12(t,J=7.2Hz,3H).ESMS m/z:560.2(M+1).
化合物63:1H NMR(400MHz,CDCl3)δ 8.02(d,J=8.4Hz,1H),7.53(d,J=2.0Hz,1H),7.36(dd,J=8.4,2.0Hz,1H),5.88(s,1H),5.68(s,1H),4.61-4.53(m,1H),3.69-3.59(m,2H),3.57-3.42(m,6H),2.50-2.40(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.08-1.99(m,1H),1.11(t,J=7.2Hz,3H).ESMS m/z:580.2(M+1).
化合物64:1H NMR(300MHz,CD3OD)δ 7.81 and 7.80(t,J=7.5Hz,1H),7.34-7.28(m,2H),5.82(s,1H),5.57(s,1H),4.27(brs,1H),3.80-3.66(m,4H),3.63-3.45(m,5H),3.02-2.80(m,6H),2.26(s,3H),2.23-2.15(m,1H),2.04-1.93(m,1H),1.28 and 1.27(t,J=7.1Hz,3H).ESMS m/z:564.2(M+1).
化合物65:1H NMR(300MHz,CDCl3)δ 7.81(ddd,J=7.8,6.0,1.8Hz,1H),7.61(ddd,J=7.8,6.0,1.8Hz,1H),7.21(td,J=7.8,1.2Hz,1H),5.89(s,1H),5.66(s,1H),4.61-4.49(m,1H),3.71-3.59(m,1H),3.59-3.42(m,7H),2.51-2.39(m,6H),2.31(s,3H),2.15-2.00(m,2H),1.11(t,J=7.2Hz,3H).ESMS m/z:564.2(M+1).
化合物66:1H NMR(400MHz,CDCl3)δ 7.61(d,J=8.6Hz,1H),7.58-7.51(m,2H),5.87(s,1H),5.71(s,1H),4.46-4.38(m,1H),3.57-3.41(m,7H),3.38-3.30(m,1H),2.51-2.40(m,6H),2.30(s,3H),2.12-2.01(m,1H),2.00-1.90(m,1H),1.12(t,J=7.2Hz,3H).ESMS m/z:564.2(M+1).
化合物67:1H NMR(300MHz,CDCl3)δ 7.85(d,J=7.2Hz,2H),7.65-7.50(m,3H),5.91(s,1H),5.63(s,1H),4.56-4.45(m,1H),3.62-3.41(m,6H),3.33-3.18(m,2H),2.41(t,J=4.8Hz,4H),2.32(s,3H),2.31(s,3H),2.06-1.84(m,2H).ESMS m/z:498.2(M+1).
化合物68:1H NMR(400MHz,CDCl3)δ 7.77(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),5.88(s,1H),5.68(s,1H),4.49-4.42(m,1H),3.56-3.43(m,
6H),3.41-3.32(m,1H),3.30-3.24(m,1H),2.50-2.40(m,6H),2.31(s,3H),2.03-1.93(m,2H),1.11(t,J=7.2Hz,3H).ESMS m/z:546.2(M+1).
化合物69:1H NMR(400MHz,CDCl3)δ 8.13(d,J=2.0Hz,1H),7.92(dd,J=8.6,2.0Hz,1H),7.64(d,J=8.6Hz,1H),5.86(s,1H),5.71(s,1H),4.46-4.38(m,1H),3.58-3.42(m,7H),3.41-3.32(m,1H),2.51-2.41(m,6H),2.30(s,3H),2.15-2.03(m,1H),2.01-1.92(m,1H),1.12(t,J=7.2Hz,3H).ESMS m/z:614.2(M+1).
化合物70:1H NMR(300MHz,CDCl3)δ 9.80(brs,1H),7.43-7.35(m,1H),7.24-7.08(m,2H),6.57 and 6.50(s,1H),5.36 and 5.32(s,1H),4.84 and 4.78(brs,1H),4.65-4.44(m,1H),4.11-3.71(m,2H),3.68-3.32(m,6H),2.66 and 2.65(s,3H),2.57-2.41(m,6H),2.30-2.13(m,4H),2.09-1.97(m,1H),1.13(t,J=7.2Hz,3H).ESMS m/z:570.2(M+1).
化合物73:1H NMR(400MHz,CDCl3)δ 7.42-7.35(m,1H),7.23-7.09(m,2H),6.55 and 6.50(s,1H),5.87 and 5.84(s,1H),4.92 and 4.79(brs,1H),4.56 and 4.47(q,J=5.7Hz,1H),4.06-3.79(m,1H),3.77-3.55(m,5H),3.54-3.19(m,2H),2.56-2.40(m,9H),2.36-2.22(m,1H),2.03-1.94(m,1H),1.53 and 1.51(s,9H),1.16-1.12(m,3H).ESMS m/z:612.3(M+1).
化合物74:1H NMR(400MHz,CDCl3)δ 7.39 and 7.37(dd,J=8.0,4.8Hz,1H),7.21 and 7.18(dd,J=8.4,2.0Hz,1H),7.15 and 7.11(dd,J=9.4,2.0Hz,1H),6.83 and 6.76(brs,1H),6.53 and 6.49(s,1H),5.86 and 5.83(s,1H),4.74 and 4.68(brs,1H),4.60-4.42(m,1H),4.08-3.70(m,2H),3.68-3.45(m,5H),3.45-3.18(m,1H),2.58-2.48(m,5H),2.48-2.40(m,4H),2.37-2.18(m,1H),2.03-1.91(m,1H),1.53 and 1.51(s,9H),1.13 and 1.13(t,J=7.2Hz,3H).ESMS m/z:612.3(M+1).
化合物75:1H NMR(400MHz,CDCl3)δ 7.39 and 7.37(dd,J=8.2,7.0Hz,1H),7.20 and 7.17(dd,J=8.2,2.0Hz,1H),7.14 and 7.11(dd,J=9.4,2.0Hz,1H),6.95(brs,1H),6.02 and 5.98(s,1H),5.90 and 5.89(s,1H),5.87(s,2H),5.07 and 4.90(brs,1H),4.61-4.41(m,1H),4.04-3.69(m,2H),3.66-3.45(m,5H),3.45-3.18(m,
1H),2.55-2.41(m,6H),2.32 and 2.31(s,3H),2.27-2.17(m,1H),2.03-1.92(m,1H),1.18 and 1.17(s,9H),1.13 and 1.12(t,J=7.2Hz,3H).ESMS m/z:642.3(M+1).
化合物76:1H NMR(400MHz,CDCl3)δ 9.35 and 9.31(brs,1H),7.38(q,J=7.3Hz,1H),7.22-7.07(m,2H),6.56 and 6.48(s,1H),5.37 and 5.33(s,1H),4.90 and 4.84(brs,1H),4.62-4.44(m,3H),4.04-3.68(m,2H),3.66-3.45(m,4H),3.43-3.21(m,2H),2.57-2.40(m,6H),2.38-2.29(m,1H),2.27 and 2.26(s,3H),2.06-1.95(m,1H),1.47 and 1.46(t,J=7.2Hz,3H),1.13 and 1.12(t,J=7.2Hz,3H).ESMS m/z:600.3(M+1).
化合物77:1H NMR(400MHz,CDCl3)δ 7.37(q,J=7.5Hz,1H),7.17(q,J=10.3Hz,1H),7.10(d,J=9.6Hz,1H),6.31 and 6.26(s,1H),5.97 and 5.89(s,1H),4.98 and 4.88(brs,1H),4.58-4.39(m,3H),4.04-3.67(m,2H),3.65-3.51(m,4H),3.50-3.19(m,2H),2.53 and 2.52(s,3H),2.50-2.42(m,6H),2.35-2.17(m,2H),1.43 and 1.42(t,J=7.0Hz,3H),1.13 and 1.12(t,J=7.2Hz,3H).ESMS m/z:600.3(M+1).
化合物78:1H NMR(400MHz,CDCl3)δ 9.33(brs,1H),7.43-7.32(m,1H),7.24-7.06(m,2H),6.55 and 6.48(s,1H),5.38 and 5.33(s,1H),4.85 and 4.79(brs,1H),4.65-4.44(m,1H),4.23 and 4.22(d,J=6.8Hz,1H),4.07-3.70(m,2H),3.67-3.20(m,6H),2.53-2.39(m,6H),2.38-2.31(m,1H),2.28 and 2.27(s,3H),2.24-2.13(m,1H),2.08-1.96(m,1H),1.12(t,J=6.8Hz,3H),1.02 and 1.01(d,J=6.6Hz,6H).ESMS m/z:628.3(M+1).
化合物79:1H NMR(300MHz,CDCl3)δ 7.43-7.33(m,1H),7.24-7.07(m,2H),6.91 and 6.81(brs,1H),6.22 and 6.17(s,1H),6.13 and 6.06(s,1H),4.84 and 4.75(brs,1H),4.62-4.39(m,1H),4.17 and 4.17(d,J=6.4Hz,1H),4.08-3.68(m,2H),3.68-3.17(m,6H),2.59-2.38(m,9H),2.36-2.19(m,1H),2.18-2.05(m,1H),2.05-1.92(m,1H),1.12(t,J=7.2Hz,3H),1.03 and 1.02(d,J=7.0Hz,6H).ESMS m/z:628.3(M+1).
化合物80:1H NMR(400MHz,CDCl3)δ 9.44 and 9.42(brs,1H),7.39(q,J=7.7Hz,1H),7.24-7.09(m,2H),6.55 and 6.47(s,1H),5.39 and 5.35(s,1H),4.83 and 4.78(brs,1H),4.63-4.45(m,2H),4.23-4.00(m,2H),3.92-3.72(m,2H),3.65-3.48(m,2H),3.47-3.23(m,1H),2.55-2.39(m,4H),2.39-2.32(m,2H),2.28 and 2.27(s,3H),2.07-1.99(m,2H),1.56(s,9H),1.14 and 1.12(t,J=7.2Hz,3H).ESMS m/z:628.3(M+1).
化合物81:1H NMR(400MHz,CDCl3)δ 7.38 and 7.37(dd,J=8.2,6.6Hz,1H),7.20 and 7.18(dd,J=8.2,2.0Hz,1H),7.15 and 7.11(dd,J=9.4,2.0Hz,1H),7.00(brs,1H),6.27 and 6.18(s,1H),6.12 and 6.09(s,1H),4.87 and 4.78(brs,1H),4.60-4.41(m,1H),4.05-3.69(m,2H),3.68-3.52(m,5H),3.52-3.19(m,1H),2.54-2.40(m,9H),2.36-2.17(m,1H),2.04-1.92(m,1H),1.63 and 1.62(s,9H),1.12 and 1.12(t,J=7.2Hz,3H).ESMS m/z:628.3(M+1).
化合物82:1H NMR(400MHz,CDCl3)δ 8.13(d,J=2.0Hz,1H),7.92(dd,J=8.6,2.0Hz,1H),7.64(d,J=8.6Hz,1H),5.86(s,1H),5.71(s,1H),4.46-4.38(m,1H),3.58-3.42(m,7H),3.41-3.32(m,1H),2.51-2.41(m,6H),2.30(s,3H),2.15-1.92(m,2H),1.12(t,J=7.2Hz,3H).ESMS m/z:630.2(M+1).
化合物83:1H NMR(400MHz,CDCl3)δ 7.45 and 7.42(t,J=7.8Hz,1H),7.22-7.16(m,1H),7.16-7.10(m,1H),6.65-6.35(m,1H),6.24 and 6.21(s,1H),4.56-4.42(m,3H),4.24-3.53(m,9H),3.47-3.24(m,4H),3.22-2.86(m,6H),2.50(s,3H),2.31-2.18(m,1H),2.13-2.01(m,1H),1.44-1.36(m,3H).ESMS m/z:630.3(M+1).
化合物84:1H NMR(300MHz,CDCl3)δ 7.44(t,J=7.8Hz,1H),7.34(s,1H),7.29-7.22(m,1H),7.14(t,J=7.8Hz,1H),6.93(s,1H),6.48(s,1H),4.57(d,J=13.0Hz,1H),4.12-3.97(m,1H),3.67-3.46(m,5H),3.28-3.00(m,2H),2.54-2.38(m,6H),2.14(d,J=13.0Hz,1H),2.04(d,J=13.0Hz,1H),1.67-1.46(m,2H),1.12 and 1.10(t,J=7.2Hz,3H).ESMS m/z:529.2(M+1).
化合物85:1H NMR(300MHz,CDCl3)δ 7.45(t,J=7.8Hz,1H),7.30-7.23(m,1H),7.15(t,J=7.8Hz,1H),6.08(s,1H),5.99(s,1H),4.80(brs,1H),4.57(d,J=14.0Hz,1H),4.10-3.94(m,1H),3.60(t,J=5.2Hz,4H),3.58-3.48(m,1H),3.27-3.02(m,2H),2.52-2.39(m,6H),2.37(s,3H),2.16(d,J=14.0Hz,1H),2.05(d,J=14.0Hz,1H),1.63-1.46(m,2H),1.10(t,J=7.2Hz,3H).ESMS m/z:543.2(M+1).
化合物87:1H NMR(400MHz,CDCl3)δ 7.45(t,J=8.0Hz,1H),7.31-7.24(m,1H),7.16(t,J=8.0Hz,1H),6.57(brs,1H),5.82(s,1H),5.49(s,1H),4.91(d,J=13.0Hz,1H),4.82-4.64(m,1H),3.61(d,J=13.0Hz,1H),3.56(t,J=4.9Hz,4H),3.48(q,J=7.2Hz,2H),3.31-3.03(m,1H),2.92-2.79(m,1H),2.52-2.40(m,6H),2.27(s,3H),1.94(d,J=13.0Hz,1H),1.89-1.73(m,3H),1.22(t,J=7.2Hz,3H),1.12(t,J=7.2Hz,3H).ESMS m/z:570.3(M+1).
化合物88:1H NMR(300MHz,CDCl3)δ 7.34-7.26(m,2H),7.05(t,J=8.0Hz,1H),6.65(brs,1H),5.83(s,1H),5.58(s,1H),4.66(brs,1H),3.85-3.70(m,1H),3.61(s,2H),3.55(t,J=4.8Hz,4H),2.85(d,J=13.0Hz,2H),2.51-2.38(m,6H),2.27(s,3H),2.23(d,J=13.0Hz,2H),2.05(d,J=13.0Hz,2H),1.63-1.43(m,2H),1.11(t,J=7.2Hz,3H).ESMS m/z:528.3(M+1).
化合物89:1H NMR(400MHz,CDCl3)δ 7.44(t,J=8.0Hz,1H),7.29-7.24(m,1H),7.15(t,J=8.0Hz,1H),5.84(s,1H),5.31(s,1H),4.57(d,J=13.0Hz,1H),4.10-4.01(m,1H),4.00(t,J=8.0Hz,2H),3.81(t,J=8.0Hz,2H),3.53(d,J=13.0Hz,1H),3.28-3.02(m,3H),2.27(s,3H),2.22-2.12(m,7H),2.09-1.96(m,1H),1.68-1.48(m,2H).ESMS m/z:528.2(M+1).
化合物90:1H NMR(400MHz,CDCl3)δ 7.45(t,J=7.5Hz,1H),7.26-7.26(m,1H),7.15(t,J=7.5Hz,1H),5.85(s,1H),5.68(s,1H),4.65-4.38(m,1H),4.16-4.01(m,1H),3.69(m,5H),3.48-3.05(m,2H),2.47-2.44(m.4H),2.33(s,3H),2.30(s,3H),2.18-2.03(m,2H),1.30-1.26(m,2H).ESMS m/z:528.2(M+1).
化合物91:1H NMR(400MHz,CDCl3)δ 7.45(t,J=7.4Hz,1H),7.32-7.26(m,1H),7.15(t,J=7.4Hz,1H),5.84-5.68(m.2H),4.65-4.40(m,2H),4.08-3.98(m,2H),3.61-3.39(m,8H),3.34-2.98(m,2H),2.27(s,3H),2.16-2.02(m,1H),1.41-1.38(m,2H).ESMS m/z:514.2(M+1).
化合物92:1H NMR(400MHz,CDCl3)δ 7.44(t,J=7.6Hz,1H),7.26-7.25(m,1H),7.15(t,J=7.6Hz,1H),5.84(s,1H),5.68(s,1H),4.57(brs,1H),4.33-7.30(m,2H),4.04(brs,1H),3.56-3.52(m,2H),3.27-3.17(m,4H),2.77(t,J=12Hz,2H),2.53-2.38(m,2H),2.32(s,6H),2.28(s,3H),2.18-2.05(m,2H),1.58-1.25(m,4H).ESMS m/z:556.3(M+1).
化合物93:1H NMR(400MHz,CDCl3)δ 7.46(t,J=7.7Hz,1H),7.33-7.26(m,1H),7.16(t,J=7.7Hz,1H),5.86(s,1H),5.67(s,1H),4.64-4.10(m,2H),3.80-3.62(m,6H),3.38-3.05(m,2H),2.34(s,3H),2.22-2.12(m,4H),2.10(s,3H),2.05-1.98(m,1H),1.44-1.21(m,2H).ESMS m/z:556.3(M+1).
化合物94:1H NMR(400MHz,CDCl3)δ 7.44(t,J=7.6Hz,1H),7.29-7.26(m,1H),7.15(t,J=7.6Hz,1H),5.86(s,1H),5.37(s,1H),4.19-4.11(m,2H),3.66-3.58(m,2H),3.48-3.10(m,4H),2.86-2.77(m,2H),2.69-2.39(m,2H),2.33(s,3H),2.30(s,6H),2.24-1.90(m,2H),1.35-1.20(m,2H).ESMS m/z:542.2(M+1).
化合物95:1H NMR(400MHz,CDCl3)δ 7.44(t,J=7.4Hz,1H),7.30-7.26(m,1H),7.15(t,J=7.4Hz,1H),5.86(s,1H),5.51(s,1H),4.63-4.51(m,2H),4.08-3.98(m,2H),3.70-3.49(m,4H),3.31-3.01(m,2H),3.00(s,3H),2.50-2.46(m,2H),2.30(s,6H),2.28(s,3H),2.19-2.04(m,1H).ESMS m/z:530.3(M+1).
化合物96:1H NMR(400MHz,CDCl3)δ 7.45(t,J=8.0Hz,1H),7.30-7.24(m,1H),7.15(t,J=8.0Hz,1H),5.85(s,1H),5.44(s,1H),4.13-4.00(m,2H),3.70-3.50(m,3H),3.49-3.36(m,6H),3.34-3.05(m,8H),2.28(s,3H),2.17-1.91(m,1H),1.72-1.52(m,2H).ESMS m/z:542.2(M+1).
化合物97:1H NMR(400MHz,CD3OD)δ 7.60(t,J=7.8Hz,1H),7.38-7.32(m,1H),7.29(t,J=7.8Hz,1H),4.10-4.00(m,2H),4.53-4.50(m,2H),
4.20-4.03(m,2H),3.85-3.60(m,4H),3.59-3.44(m,3H),3.25-3.11(m,3H),2.33(s,3H),2.23(s,3H),1.68-1.48(m,4H).ESMS m/z:543.2(M+1).
化合物98:1H NMR(400MHz,CD3OD)δ 7.59(t,J=7.8Hz,1H),7.36-7.32(m,1H),7.28(t,J=7.8Hz,1H),5.78(s,1H),5.39(s,1H),4.53-4.50(m,2H),4.11-3.98(m,2H),3.68(t,J=8.0Hz,2H),3.57-3.54(m,2H),3.34(s,3H),3.00(s,3H),2.98-2.95(m,1H),2.23(s,3H),2.19-1.98(m,2H),1.68-1.49(m,2H).ESMS m/z:517.3(M+1).
化合物99:1H NMR(400MHz,CD3OD)δ 7.61(t,J=8.0Hz,1H),7.40-7.26(m,1H),7.29(t,J=8.0Hz,1H),5.76(s,1H),5.12(s,1H),4.59-4.55(m,1H),4.39-4.28(m,3H),3.96-3.93(m,2H),3.59-3.55(m,2H),3.34(s,3H),3.24-3.16(m,2H),2.29(s,3H),2.19-2.04(m,2H),1.67-1.57(m,2H).ESMS m/z:515.2(M+1).
化合物100:1H NMR(400MHz,CDCl3)δ 7.45(t,J=8.0Hz,1H),7.31-7.22(m,1H),7.15(t,J=8.0Hz,1H),5.84(s,1H),5.67(s,1H),4.88-4.80(m,1H),4.62-4.54(m,1H),4.13-3.96(m,3H),3.57-3.53(m,1H),3.37-3.00(m,3H),2.75-2.55(m,2H),2.28(s,6H),220-2.07(m,2H),1.58-1.55(m,2H),1.17(d,J=6.2Hz,6H).ESMS m/z:556.2(M+1).
化合物101:1H NMR(400MHz,CDCl3)δ 7.44(t,J=8.0Hz,1H),7.30-7.24(m,1H),7.15(t,J=8.0Hz,1H),5.84(s,1H),5.66(s,1H),4.76(brs,1H),4.58(brs,1H),4.08-4.01(m,1H),3.57-3.52(m,8H),3.36(s,3H),3.29-3.02(m,2H),2.60(t,J=8.0Hz,2H),2.54-2.52(m,4H),2.28(s,3H),2.20-2.04(m,2H),1.50-1.36(m,2H).ESMS m/z:572.3(M+1).
化合物102:1H NMR(400MHz,CDCl3)δ 7.45(t,J=8.0,1H),7.31-7.24(m,1H),7.15(t,J=8.0Hz,1H),5.84(s,1H),5.71(s,1H),4.57(brs,1H),4.13-4.04(m,3H),3.57-3.49(m,1H),3.32-3.07(m,2H),2.92-2.80(m,2H),2.38(t,J=8.0Hz,2H),2.28(s,3H),2.20-2.05(m,2H),2.62-2.46(m,2H),1.14(d,J=6.3Hz,6H).ESMS m/z:542.2(M+1).
化合物103:1H NMR(400MHz,CDCl3)δ 7.45(t,J=8.0Hz,1H),7.31-7.23(m,1H),7.15(t,J=8.0Hz,1H),5.85(s,1H),5.70(s,1H),4.70-4.60(m,5H),4.08-4.01(m,1H),3.59-3.53(m,4H),3.51-3.47(m,2H),3.35-3.03(m,2 H),2.38-2.35(m,4H),2.28(s,3H),2.19-2.05(m,2H),1.54-1.42(m,2H).ESMS m/z:570.3(M+1).
化合物104:1H NMR(400MHz,CDCl3)δ 7.45(t,J=8.0Hz,1H),7.32-7.23(m,1H),7.15(t,J=8.0Hz,1H),5.98-5.74(m,1H),5.58-5.25(m,1H),4.89-4.72(m,1H),4.62-4.59(m,1H),4.32-4.11(m,1H),4.14-3.99(m,1H),3.47-3.49(m,2H),3.46-3.38(m,2H),3.49-3.34(m,4H),3.23(t,J=8.0Hz,2H),3.18-3.06(m,2H),2.27(s,3H),2.22-1.94(m,5H).ESMS m/z:543.2(M+1).
化合物105:1H NMR(400MHz,CD3OD)δ 7.60(t,J=7.2Hz,1H),7.33-7.26(m,2H),5.76(s,1H),5.51(s,1H),4.54-4.51(m,1H),4.00-3.95(m,1H),3.55-3.41(m,5H),3.35-3.31(m,4H),3.19-2.98(m,2H),2.33(s,3H),2.14-1.92(m,4H),1.64-1.38(m,4H).ESMS m/z:543.2(M+1).
化合物106:1H NMR(400MHz,CD3OD)δ 7.60(t,J=7.8Hz,1H),7.38-7.31(m,1H),7.29(t,J=7.8Hz,1H),6.20-5.80(m,1H),5.69-5.20(m,1H),4.53-4.50(m,1H),4.10-4.02(m,1H),3.62-3.49(m,5H),3.40-3.22(m,2H),3.10(q,J=9.6Hz,2H),2.71-2.69(m,4H),2.23(s,3H),2.17-2.01(m,2H),1.60-1.58(m,2H).ESMS m/z:596.3(M+1).
化合物107:1H NMR(600MHz,CD3OD)δ 7.59(t,J=8.0Hz,1H),7.38-7.32(m,1H),7.28(t,J=8.0Hz,1H),6.25-5.88(m,1H)5.70-5.43(m,1H),4.54-4.48(m,1H),4.08-4.01(m,1H),3.57-3.52(m,1H),3.25-3.19(m,4H),2.91(d,J=8.0Hz,1H),2.74-7.68(m,1H),2.59(d,J=8.0Hz,1H),2.39(t,J=8.0Hz,1H),2.23(s,3H),2.16-2.03(m,2H),1.65-1.47(m,2H),1.29-1.14(m,6H).ESMS m/z:542.2(M+1).
化合物108:1H NMR(300MHz,CD3OD)δ 7.78(d,J=5.4Hz,1H),6.43-5.97(m,2H),3.78-3.65(m,1H),3.65-3.52(m,1H),2.26(s,3H),2.08(d,J=11.4Hz,2H),1.99(d,J=11.4Hz,2H),1.51-1.24(m,4H).ESMS m/z:289.2(M+1).
化合物109:1H NMR(400MHz,CD3OD)δ 7.62(td,J=7.2,1.8Hz,1H),7.50-7.35(m,1H),7.31(t,J=7.8Hz,1H),5.83(s,1H),5.68(s,1H),4.74-4.50(m,2H),3.75-3.60(m,5H),3.48(t,J=12.8Hz,2H),3.44-3.34(m,1H),3.34-3.23(m,4H),3.15(t,J=12.8Hz,2H),3.10-3.01(m,1H),2.31(s,3H),2.08-1.78(m,4H),1.42(t,J=7.2Hz,3H),1.41-1.33(m,3H).ESMS m/z:570.2(M+1).
化合物110:1H NMR(300MHz,CD3OD)δ 8.09-7.75(m,1H),7.72-7.61(m,2H),7.34(t,J=8.0Hz,1H),6.61-6.30(m,2H),4.53(s,2H),4.32-4.00(m,1H),3.68(d,J=12.0Hz,2H),3.58-3.47(m,1H),3.36(d,J=12.0Hz,1H),2.42(s,3H),2.38-2.15(m,2H),2.12-1.89(m,2H).ESMS m/z:416.2(M+1).
化合物111:1H NMR(300MHz,CDCl3)δ 7.39-7.27(m,2H),7.06(t,J=7.8Hz,1H),6.70(brs,1H),6.04(s,1H),5.94(s,1H),4.70-4.55(m,1H),3.65(s,2H),3.05(s,3H),3.01(d,J=11.0Hz,2H),2.28(s,3H),2.27-2.17(m,5H),1.95-1.77(m,2H),1.76-1.64(m,2H).ESMS m/z:444.2(M+1).
化合物112:1H NMR(300MHz,CD3OD)δ 7.84-7.64(m,5H),6.22-6.04(m,2H),4.65-4.47(m,1H),4.12-3.99(m,1H),3.76-3.59(m,1H),3.37-3.05(m,2H),2.27(s,3H),2.23-1.94(m,2H),1.70-1.42(m,2H).ESMS m/z:446.2(M+1).
化合物113:1H NMR(300MHz,CD3OD)δ 7.81(d,J=6.0Hz,1H),7.44-7.33(m,1H),7.32-7.24(m,1H),7.23-7.13(m,1H),6.32-5.90(m,2H),4.59(d,J=13.5Hz,1H),4.14-3.97(m,1H),3.59(d,J=13.5Hz,1H),3.30-3.09(m,2H),2.26(s,3H),2.17(d,J=13.5Hz,1H),2.03(d,J=13.5Hz,1H),1.72-1.42(m,2H).ESMS m/z:414.2(M+1).
化合物114:1H NMR(400MHz,CDCl3)δ 7.25-7.09(m,3H),6.12(s,1H),6.05(s,1H),4.57(d,J=14.0Hz,1H),4.16-4.03(m,1H),3.57(d,J=14.0Hz,
1H),3.29-3.07(m,2H),2.31(s,3H),2.23(s,3H),2.19(d,J=11.6Hz,1H),2.06(d,J=11.6Hz,1H),1.66-1.38(m,2H).ESMS m/z:428.2(M+1).
化合物115:1H NMR(400MHz,CDCl3)δ 9.97(brs,1H),7.45(d,J=3.8Hz,1H),7.36-7.30(m,2H),7.08(t,J=7.8Hz,1H),6.88(d,J=3.8Hz,1H),5.88(s,1H),4.88-4.77(m,1H),3.67(s,2H),3.14(s,3H),3.02(d,J=11.0Hz,2H),2.35-2.24(m,5H),1.96-1.83(m,2H),1.80-1.70(m,2H).ESMS m/z:447.2(M+1).
化合物116:1H NMR(400MHz,DMSO-d6)δ 7.49(t,J=7.8Hz,1H),7.43-7.36(m,2H),7.22(t,J=7.8Hz,1H),7.11(d,J=3.6Hz,1H),6.97(brs,1H),6.01(s,1H),3.97-3.83(m,1H),3.57(s,2H),2.83(d,J=11.6Hz,2H),2.20-2.13(m,2H),2.12(s,3H),1.96-1.83(m,2H),1.56-1.42(m,2H).ESMS m/z:433.2(M+1).
化合物117:1H NMR(300MHz,CD3OD)δ 7.79(s,1H),7.61(d,J=8.1Hz,1H),7.44(t,J=8.1Hz,1H),7.27(d,J=8.1Hz,1H),6.41-5.88(m,2H),4.16(d,J=13.5Hz,2H),4.12-3.99(m,1H),3.12(t,J=11.7Hz,2H),2.27(s,3H),2.19(s,3H),2.11(d,J=13.0Hz,1H),1.61-1.45(m,2H).ESMS m/z:475.2(M+1).
化合物118:1H NMR(300MHz,CD3OD)δ 7.81(d,J=6.0Hz,1H),7.63 and 7.62(dd,J=7.8,1.8Hz,1H),7.42 and 7.41(t,J=7.8Hz,1H),7.34 and 7.29(dd,J=7.8,1.8Hz,1H),6.39-5.83(m,2H),4.66-4.52(m,1H),4.11-3.95(m,1H),3.52-3.37(m,1H),3.29-3.06(m,2H),2.26(s,3H),2.17(d,J=14.0Hz,1H),2.00(d,J=14.0Hz,1H),1.72-1.36(m,2H).ESMS m/z:446.1(M+1).
化合物119:1H NMR(300MHz,CD3OD)δ 7.47-7.31(m,2H),7.15(td,J=7.8,1.2Hz,1H),6.39-6.15(s,1H),6.13-5.85(s,1H),3.86-3.71(m,1H),3.68(s,2H),2.92(d,J=11.7Hz,2H),2.38-2.25(m,2H),2.24(s,3H),2.16(s,3H),2.04(d,J=11.7Hz,2H),1.70-1.50(m,2H).ESMS m/z:430.2(M+1).
化合物120:1H NMR(400MHz,CDCl3)δ 7.45(t,J=7.8Hz,1H),7.30-7.24(m,1H),7.15(t,J=7.8Hz,1H),6.12(s,1H),6.04(s,1H),5.15(brs,1H),4.59(d,J=14.0Hz,1H),4.15-4.04(m,1H),3.54(d,J=14.0Hz,1H),3.30-3.04(m,
2H),2.31(s,3H),2.22(s,3H),2.19(d,J=14.0Hz,1H),2.07(d,J=14.0Hz,1H),1.63-1.49(m,2H).ESMS m/z:444.1(M+1).
化合物121:1H NMR(400MHz,CDCl3)δ 7.48 and 7.47(dd,J=7.8,1.2Hz,1H),7.29-7.15(m,2H),6.11 and 6.10(s,1H),6.04 and 6.02(s,1H),5.44 and 5.29(brs,1H),4.65-4.51(m,1H),4.15-4.01(m,1H),3.50-3.37(m,1H),3.27-3.06(m,2H),2.30 and 2.29(s,3H),2.26-2.15(m,4H),2.09-1.97(m,1H),1.67-1.29(m,2H).ESMS m/z:460.1(M+1).
化合物124:1H NMR(400MHz,CDCl3)δ 9.95(brs,1H),7.45(t,J=7.8Hz,1H),7.31-7.25(m,1H),7.15(t,J=7.8Hz,1H),6.56(s,1H),5.32(s,1H),4.72(brs,1H),4.58(d,J=12.8Hz,1H),4.11-4.00(m,1H),3.86(sep,J=6.8Hz,1H),3.62-3.47(m,5H),3.32-3.00(m,2H),2.47(t,J=4.8Hz,4H),2.44(q,J=7.2Hz,2H),2.25(s,3H),2.24-2.17(m,1H),2.06(d,J=12.8Hz,1H),1.64-1.48(m,2H),1.26(d,J=6.8Hz,6H),1.11(t,J=7.2Hz,3H).ESMS m/z:612.3(M+1).
化合物125:1H NMR(400MHz,CDCl3)δ 9.89(brs,1H),7.45(t,J=7.8Hz,1H),7.31-7.25(m,1H),7.15(t,J=7.8Hz,1H),6.56(s,1H),5.33(s,1H),4.73(brs,1H),4.63(d,J=12.4Hz,1H),4.12-4.00(m,1H),3.64-3.48(m,5H),3.33-3.02(m,4H),2.48(t,J=4.8Hz,4H),2.44(q,J=7.2Hz,2H),2.29-2.17(m,4H),2.09(d,J=12.4Hz,1H),1.83-1.71(m,2H),1.65-1.47(m,2H),1.11(t,J=7.2Hz,3H),1.02(t,J=7.4Hz,3H).ESMS m/z:612.3(M+1).
化合物126:1H NMR(400MHz,CDCl3)δ 9.93(brs,1H),7.45(t,J=8.0Hz,1H),7.31-7.26(m,1H),7.16(t,J=8.0Hz,1H),6.59(s,1H),5.30(s,1H),4.72(brs,1H),4.63(d,J=12.0Hz,1H),4.12-4.00(m,1H),3.62-3.47(m,5H),3.19-3.03(m,2H),2.51-2.40(m,6H),2.28(s,3H),2.22(d,J=13.0Hz,1H),2.10(d,J=13.0Hz,1H),1.66-1.51(m,3H),1.25-1.20(m,2H),1.16-1.07(m,5H).ESMS m/z:610.3(M+1).
化合物127:1H NMR(300MHz,CDCl3)δ 9.32(brs,1H),7.43(t,J=7.8Hz,1H),7.30-7.22(m,1H),7.14(t,J=7.8Hz,1H),6.55(s,1H),5.34(s,1H),4.77
(brs,1H),4.61(d,J=12.3Hz,1H),4.50(q,J=7.3Hz,2H),4.12-3.97(m,1H),3.62-3.41(m,5H),3.32-2.99(m,2H),2.47(t,J=4.7Hz,4H),2.43(q,J=7.1Hz,2H),2.26(s,3H),2.20(d,J=15.0Hz,1H),2.08(d,J=12.3Hz,1H),1.64-1.47(m,2H),1.46(t,J=7.1Hz,3H),1.11(t,J=7.1Hz,3H).ESMS m/z:614.3(M+1).
實施例2:體外抑制Aurora A激酶活性
如下所述,使用Kinase-Glo®螢光激酶試驗(Promega,美國)評估75種式(I)化合物在體外抑制Aurora A激酶活性的功效。這75種化合物為化合物1、化合物2、化合物8、化合物12-17、化合物19-41、化合物43-44、化合物47-50、化合物54、化合物58、化合物62-63、化合物65、化合物86-90、化合物92-97、化合物99-104、化合物106-107、化合物109-111、化合物113-116及化合物118-123。
重組麩胺基硫S-轉移酶(glutathione S-transferase,GST)標記的N-末端截斷(N-terminal truncated)人類Aurora A(胺基酸123-401)在Sf9昆蟲細胞中表現,然後透過麩胺基硫(glutathione)親和層析法純化,得到重組Aurora A。於37℃下,重組Aurora A(150ng)與在50μL的50mM三羥甲基胺基甲烷鹽酸鹽(Tris-HCl)pH 7.4、10mM氯化鈉(NaCl)、10mM氯化鎂(MgCl2)、0.01%胎牛血清蛋白素(bovine serum albumin)、5.0μM ATP、1mM二硫蘇糖醇(dithiothreitol)、15μM tetra(-LRRASLG)胜肽中的每種測試化合物(100nM)反應120分鐘。然後,向反應中加入50μL Kinase-Glo Plus試劑。將所得混合物在25℃下培養20分鐘。將混合物的70μL等分試樣轉移到黑色微升孔盤中。使用Wallac Vector 1420多標記計數器(PerkinElmer,美國)測量螢光。
如表1所示,每種測試化合物的IC50值均低於100nM。
這些結果表明式(I)化合物在抑制Aurora A激酶活性方面具有高的體外功效。
實施例3:降低cMYC/MYCN擴增癌細胞中的cMYC及MYCN蛋白質含量
如下所示,測試了兩個由式(I)所涵蓋的化合物41及化合物86,以評估它們在降低人類小細胞肺癌(“SCLC”)細胞株NCI-H82(ATCC®HTB-175,美國)中cMYC致癌蛋白(oncoprotein)含量及在人類神經母細胞瘤(human neuroblastoma)細胞株SK-N-BE(2)(ATCC®CRL-2271,美國)中的MYCN致癌蛋白含量方面的功效。
NCI-H82養在補充有10%胎牛血清(FBS,HyClone,美國)及抗生素的RPMI1640培養基(ThermoFisher Scientific,美國)中。SK-N-BE(2)養在補充有10%胎牛血清(HyClone,美國)及抗生素的最低必需培養基(Minimum Essential Medium,MEM,ThermoFisher Scientific,美國)中。以4種不同化合物濃度(即50nM、200nM、500nM及1000nM)的化合物41及化合物86處理來自每種細胞株的癌細胞。24小時之後,每種癌細胞溶液均用1×磷酸鹽緩衝鹽水(PBS)洗滌,溶解在1×Laemmli蛋白樣品緩衝液中,並在100℃下煮沸10分鐘。透過SDS-PAGE分離每種溶解產物(lysate),轉移至聚偏二氟乙烯(polyvinylidene fluoride,PVDF,Millipore,美國)薄膜上,並用抗體點墨。用於西方墨點法(Western blotting)的初級抗體(Primary antibodies)是cMYC(細胞訊息傳導,Cat No.5605S)、MYCN(細胞訊息傳導,9405S)、PARP-1(Abcam,ab32378)及GAPDH(Genetex,GTX100118)。用初級抗體點墨後,將薄膜用1×點墨緩衝液(在1×PBS中的0.2%酪蛋白(Casein))洗滌,然後加入對應的鹼性磷酸酶共軛(alkaline phosphatase-conjugated)的第二抗體(Sigma-Aldrich)。墨點透過化學發光顯影(PerkinElmer,美國)。分裂的PARP1(cPARP-1)用作細胞凋亡的指標,GAPDH用作控制組。
如圖1所示,化合物41及化合物86大幅降低了兩種類型的人類癌細胞(即SCLC及神經母細胞瘤)中cMYC及MYCN的蛋白質含量。
這些結果表明,式(I)化合物在降低癌細胞中的cMYC及MYCN蛋白質含量方面具有高的體外功效。
實施例4:小細胞肺癌細胞增殖抑制試驗
使用PrestoBlueTM細胞活性試劑(ThermoFisher Scientific,美國)確定74種式(I)化合物抑制癌細胞增殖的功效。這74種化合物為化合物1-2、化合物8-10、化合物12-19、化合物21-22、化合物25-27、化合物31-32、化合物35-41、化合物43-44、化合物47-50、化合物54、化合物62-63、化合物65、化合物70-75、化合物78-83、化合物86、化合物88-90、化合物92-107、化合物122-125及化合物127。
小細胞肺癌細胞NCI-H82(ATCC®HTB-175,cMYC擴增)、NCI-H446(ATCC®HTB-171,cMYC擴增)及NCI-H69(ATCC®HTB-119,MYCN擴增)以每孔5000-10000個細胞的密度接種在96孔盤中。24小時之後,以各種濃度(0-10μM)的每種化合物處理癌細胞,然後再培養72小時。基於重複的8點滴定法計算IC50值。
如表2所示,每種測試化合物在三種類型的小細胞肺癌細胞中的一種或多種表現出的IC50值均低於1.0μM。
這些結果表明式(I)化合物在抑制小細胞肺癌細胞的增殖方面具有高的體外功效。
實施例5:各種癌細胞的增殖抑制試驗
使用PrestoBlueTM細胞活性試劑(ThermoFisher Scientific,美國)確定式(I)化合物41及化合物86在抑制11種癌細胞的增殖方面的功效。11種癌細胞
為小細胞肺癌、非小細胞肺癌、肝癌、胰臟癌、乳癌、大腸癌、前列腺癌、神經母細胞瘤、腦癌、白血病及膽管癌。
更具體地,11種癌細胞株,即NCI-H82(ATCC®HTB-175)、NCI-H446(ATCC®HTB-171)、NCI-H69(ATCC®HTB-119)、NCI-H146(ATCC®HTB-173)、NCI-H1792(ATCC®CRL-5895)、NCI-H1299(ATCC®CRL-5803)、SNU-398(ATCC®CRL-2233)、PSN-1(ATCC®CRL-3211)、MIA PaCa-2(ATCC®CRL-1420)、MDA-MB-231(ATCC®HTB-26)、LOVO(ATCC®CCL-229)、COLO 205(ATCC®CCL-222)、PC-3(ATCC®CRL-1435)、SK-N-BE(2)(ATCC®CRL-2271)、D341 Med(ATCC®HTB-187)、K562(ATCC®CCL-243)、MOLM-13(DSMZ-德國微生物及細胞培養有限公司,ACC 554號)及SNU-478(KCLB 00478)以每孔4000-10000個細胞的密度接種在96孔盤中24小時。然後以各種濃度(0-10Mm)的每種化合物處理癌細胞,接著再培養72小時。基於重複的8點滴定法計算IC50值。
如表3所示,化合物41及化合物86在抑制所有11種癌細胞的增殖中均出乎意料地顯示出低於10.0μM的IC50值。更具體地,這兩種化合物出乎意料地顯示出IC50值(i)在抑制小細胞肺癌、肝癌、神經母細胞瘤、腦癌及白血病細胞的增殖方面低於0.2μM;(ii)在抑制乳癌細胞的增殖方面低於0.3μM;(iii)在抑制非小細胞肺癌、胰臟癌及大腸癌細胞的增殖方面低於1.0μM;(iv)在抑制膽管癌細胞的增殖方面低於2.0μM;(v)在抑制前列腺癌細胞增殖方面低於10.0μM。
這些結果表明化合物41及化合物86具有高的體外抗癌療效。
實施例6:抑制小鼠異種移植腫瘤生長
如下,使用NCI-H446-異種移植致瘤性小鼠模型確定兩種式(I)化合物(即化合物71及化合物122)在抑制腫瘤生長方面的功效。
將6週齡的雄性無胸腺nu/nu裸鼠(BioLASCO,台灣)飼養在無菌籠中,該籠保持在12小時的明/暗循環下,並控制溫度及濕度。小鼠皮下接種1×106 NCI-H446細胞(ATCC®HTB-171)懸浮在與50%Metrigel Matrix(Corning,美國)混合的鹽水。用數位卡尺(GMC-190;Goldsun電子公司)測量異種移植腫瘤的尺寸,並使用以下算法計算:腫瘤體積(mm3)=長度×(寬度)2/2。每周至少測量體重及腫瘤尺寸兩次。當異種移植腫瘤尺寸達到200mm3時,將化合物71、化合物122、對照化合物MLN8237(結構如下所示)及對照化合物LY3295668(結構亦如下所示)分別以100mg/kg的劑量及5-on-2-off的給藥方案口服給予小鼠2至4週,用賦形劑處理的小鼠作為控制組。
如圖2A及圖2C所示,以100mg/kg的化合物71在10天內出乎意料地將小鼠的腫瘤尺寸實質上從約250mm3縮小到小於50mm3,並且在14天內從大於750mm3縮小到小於50mm3。這些結果表明化合物71出乎意料地誘導超過80%的腫瘤消退。
同樣如圖2A所示,化合物71出乎意料地表現出比對照化合物MCLN8237更高的療效。儘管兩種化合物都以100mg/kg的劑量在10天內將腫瘤尺寸從約250mm3縮小到小於50mm3,但在治療停止後6週,與用化合物MCLN8237處理的小鼠的腫瘤尺寸相比,用化合物71治療的小鼠的腫瘤尺寸仍小於50mm3,而MCLN8237增大至大於700mm3。
圖2B顯示化合物122出乎意料地誘導超過80%的腫瘤消退,並且比對照化合物LY3295668具有更高的療效。具體地,雖然100mg/kg的化合物122將腫瘤尺寸實質上從約250mm3縮小到小於50mm3,但是100mg/kg的化合物LY3295668卻將腫瘤尺寸從約250mm3增大到大於350mm3。
上述結果表明,式(I)化合物在抑制腫瘤生長方面具有出乎意料的高體內療效。
實施例7:體內cMYC蛋白質含量降低及細胞凋亡誘導
如下,使用NCI-H446異種移植致瘤性小鼠模型評估式(I)化合物(即化合物71)在降低cMYC蛋白質含量及誘導細胞凋亡方面的療效。
將6週齡的雄性無胸腺nu/nu裸鼠(BioLASCO,台灣)飼養在無菌籠中,該籠保持在12小時的光照/黑暗循環下,並控制溫度及濕度。小鼠接種1×106 NCI-H446細胞(ATCC®HTB-171)懸浮在與50%Metrigel Matrix(Corning,美國)混合的鹽水。用數位卡尺(GMC-190;Goldsun電子公司)測量異種移植腫瘤的尺寸,並使用以下算法計算:腫瘤體積(mm3)=長度×(寬度)2/2。每周至少測量體重及腫瘤大小兩次。當異種移植腫瘤尺寸達到500mm3時,對異種移植瘤裸鼠口服(PO)給予化合物71,劑量為100mg/kg。給藥後2小時、4小時、8小時及24小時取下腫瘤。對腫瘤的組織溶解產物進行西方墨點分析。使用的初級抗體為cMYC(細胞訊息傳導,Cat No.5605S)、PARP-1(Abcam,ab32378)及β-ACTIN(Sigma-Aldrich,A1978)。
如下圖3所示,化合物71顯著誘導細胞凋亡,如在施用化合物71後24小時內,超過80%的異種移植腫瘤中分裂的PARP-1(cPARP-1)的量增加所表明。再者,在超過50%的異種移植腫瘤中,化合物71降低了cMYC蛋白質含量。
其他實施例
此說明書中揭示的所有特徵可以以任何組合進行結合。此說明書中揭示的每個特徵可以由具有相同、等同或相似目的的替代特徵取代。因此,除非另有明確地說明,否則所揭示的每個特徵僅是一系列等同或相似特徵的示例。
再者,依據以上描述,本領域技術人員可以容易地確定本發明的實質特徵,並在不脫離其精神及範圍的情況下,可以對本發明進行各種改變及修改以使其適用於各種用途及條件。因此,其他實施例也在申請專利範圍之內。
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Claims (30)
- 一種式(I)之化合物,
- 如請求項1所述的化合物,其中m及n之總和為3。
- 如請求項2所述的化合物,其中R1為C3-10環烷基或5員雜芳基。
- 如請求項4所述的化合物,其中R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
- 如請求項3所述的化合物,其中R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
- 如請求項2所述的化合物,其中R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
- 如請求項1所述的化合物,其中m及n各自為2。
- 如請求項11所述的化合物,其中R1為C3-10環烷基或5員雜芳基。
- 如請求項13所述的化合物,其中R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
- 如請求項12所述的化合物,其中R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
- 如請求項11所述的化合物,其中R3為C7-12芳烷基、-C(O)R8或-S(O)2R8。
- 如請求項1所述的化合物,其中R4為H。
- 一種如請求項1所述的化合物之用途,用以製備治療癌症之藥物。
- 如請求項22所述的用途,其中該癌症為白血病、肺癌、大腸癌(colon cancer)、乳癌、胰臟癌、前列腺癌或神經母細胞瘤(neuroblastoma)。
- 如請求項22所述的用途,其中該化合物為如請求項2所述的化合物。
- 如請求項24所述的用途,其中該癌症為白血病、肺癌、大腸癌、乳癌、胰臟癌、前列腺癌或神經母細胞瘤。
- 如請求項22所述的用途,其中該化合物為如請求項11所述的化合物。
- 如請求項26所述的用途,其中該癌症為白血病、肺癌、大腸癌、乳癌、胰臟癌、前列腺癌或神經母細胞瘤。
- 如請求項22所述的用途,其中該癌症為肝癌、腦癌或膽管癌(cholangiocarcinoma)。
- 如請求項24所述的用途,其中該癌症為肝癌、腦癌或膽管癌。
- 如請求項26所述的用途,其中該癌症為肝癌、腦癌或膽管癌。
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- 2021-03-03 EP EP21763754.5A patent/EP4087574A4/en active Pending
- 2021-03-03 JP JP2022553672A patent/JP2023517205A/ja active Pending
- 2021-03-03 WO PCT/US2021/020594 patent/WO2021178485A1/en unknown
- 2021-03-03 CN CN202180013903.1A patent/CN116348116A/zh active Pending
- 2021-03-03 AU AU2021230288A patent/AU2021230288A1/en active Pending
- 2021-03-03 US US17/802,307 patent/US20230131830A1/en active Pending
- 2021-03-03 CA CA3170252A patent/CA3170252A1/en active Pending
- 2021-03-03 KR KR1020227030196A patent/KR20220151617A/ko unknown
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Patent Citations (4)
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CN101103017A (zh) * | 2004-10-29 | 2008-01-09 | 万有制药株式会社 | 具有Aurora-A选择性抑制作用的新型氨基吡啶衍生物 |
US20100310675A1 (en) * | 2005-11-03 | 2010-12-09 | Vertex Pharmaceuticals Incorporated | Aminopyrimidines useful as kinase inhibitors |
CN102573483A (zh) * | 2009-06-08 | 2012-07-11 | 加利福尼亚资本权益有限责任公司 | 三嗪衍生物及其治疗应用 |
TWI667236B (zh) * | 2017-06-13 | 2019-08-01 | 財團法人國家衛生研究院 | 作為蛋白激酶抑制劑的胺基噻唑化合物 |
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EP4087574A1 (en) | 2022-11-16 |
US20230131830A1 (en) | 2023-04-27 |
AU2021230288A1 (en) | 2022-09-01 |
KR20220151617A (ko) | 2022-11-15 |
EP4087574A4 (en) | 2024-01-17 |
JP2023517205A (ja) | 2023-04-24 |
CA3170252A1 (en) | 2021-09-10 |
WO2021178485A1 (en) | 2021-09-10 |
TW202146404A (zh) | 2021-12-16 |
CN116348116A (zh) | 2023-06-27 |
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