TWI753995B - 醯胺化合物及其應用 - Google Patents

醯胺化合物及其應用 Download PDF

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TWI753995B
TWI753995B TW107102334A TW107102334A TWI753995B TW I753995 B TWI753995 B TW I753995B TW 107102334 A TW107102334 A TW 107102334A TW 107102334 A TW107102334 A TW 107102334A TW I753995 B TWI753995 B TW I753995B
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amino
oxy
benzamido
biphenyl
trifluoromethyl
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TW107102334A
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TW201838967A (zh
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鍾政和
曾喜樑
楊永寧
陳彥甫
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昊運股份有限公司
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract

本揭露提供一種下式(I)所示之化合物及其藥學上可接受之鹽類：
Figure 107102334-A0305-02-0001-1
 其中，R1、R2、R3、R4、R5、A1、A2、A3、A4、X和Y各自如說明書所定義。本揭露亦提供一種使用式(I)之化合物或其鹽類及包含其之醫藥組成物來降低血糖含量和治療由升糖素引發的相關疾病之方法。

Description

醯胺化合物及其應用
本揭露涉及用作升糖素受體(glucagon receptor)之拮抗劑(antagonist)或反促效劑(inverse agonist)的化合物、包含該化合物的醫藥組成物、及該化合物或該組成物的用途。
糖尿病為重大的公共衛生問題，且影響全球數百萬人。調節血糖恆定(homeostasis)的主要兩種激素(hormone)：胰島素(insulin)和升糖素(glucagon)在糖尿病中扮演重要角色。升糖素藉由胰臟α細胞分泌，並且可以刺激肝糖分解(glycogenolysis)和葡萄糖新生(gluconeogenesis)。此外，升糖素信號也可能影響脂質代謝、食物攝取、心血管系統(cardiovascular system)、和脂肪組織(adipose tissue)質量。長久以來，升糖素信號的拮抗作用(antagonism)一直被奉行為糖尿病的潛在療法。主要的機制是透過干擾受體-配體結合而完成的。升糖素受體為B類G-蛋白耦合受體，且主要於肝臟中表達，在其他組織中較少表達。升糖素受體的拮抗作用藉由小分子減少下游二級訊息傳遞子(secondary messenger)，包含cAMP和鈣離子(其會導致葡萄糖生成基因(gluconeogenic gene)表達和隨後的血糖升高)。升糖素受體-/-小鼠表現出對飲食誘導的肥胖和鏈佐黴素(streptozotocin)誘導的糖尿病產生抵抗。目前幾種小分子升糖素受體拮抗劑已進入臨床試驗， 且與安慰劑相比顯示出顯著的血糖降低。升糖素受體拮抗作用也可能通過保護心肌細胞(cardiomyocyte)對心血管疾病有益處。在升糖素受體失活(inactivated)的小鼠模型中，動物在心肌梗塞(myocardial infarction)後顯示出更高的存活率和更低的心臟衰竭(heart failure)。
有需要開發新的升糖素受體調節劑(modulator)，其對治療用途具有更少的且較少的有害副作用。
本揭露涉及某些醯胺化合物作為升糖素受體調節劑用於治療升糖素相關的疾病。出乎意料地，與已知的治療劑相比，這些作為升糖素受體的拮抗劑或反促效劑的化合物在調節升糖素受體用以降低血糖含量(glycemic level)產生更高的效果。
本揭露之一態樣為以下式(I)化合物及其藥學上可接受的鹽類：
Figure 107102334-A0305-02-0004-4
在該式中，A1、A2、A3、和A4各自獨立為CR6或氮，條件是A1、A2、A3、和A4中不超過兩個為氮。X為-CH2-、-NH-、-O-、-S-或一直接鍵結。Y為-(C=O)-、-CH2-或一直接鍵結。R1為C1-6之烷基、C1-6之烷氧基、芳基、雜芳基、C3-12之環烷基、C1-12之雜環烷基或-(C1-6烷基)-(C3-12環烷基)；所述C1-6之環烷基選擇性地具有一至三個取代基選自由鹵素、羥基、C1-6之烷氧基、芳基和雜芳基所 組成之群組；所述C1-6之烷氧基、芳基、雜芳基、C3-12之環烷基、和C1-12之雜環烷基各自選擇性地具有一至三個取代基選自由鹵素、芳基、選擇性地以一至三個鹵素取代之C1-6之烷基、和選擇性地以一至三個鹵素取代之C1-6之烷氧基所組成之群組；所述雜芳基選擇性地與一芳基基團稠合；以及所述芳基選擇性地以 雜芳基或與一芳基基團稠合之雜芳基取代；R2為C1-6之烷基、
Figure 107102334-A0305-02-0005-555
、
Figure 107102334-A0305-02-0005-553
、
Figure 107102334-A0305-02-0005-7
、
Figure 107102334-A0305-02-0005-8
、或
Figure 107102334-A0305-02-0005-556
；R3為氫、甲基、或乙基；R4 為氫、C1-6之烷基、或C1-6之烷氧基，所述C1-6之烷基和C1-6之烷氧基選擇性地以一至三個鹵素取代；R5為四唑基、-CH2-四唑基、-CH2CH2CO2R10、-CH2CH(OH)CO2H、或-(CH2)2SO3H；R6為氫、鹵素、C1-6之烷基、或C1-6之烷氧基，所述C1-6之烷基和C1-6之烷氧基各自選擇性地以一至三個鹵素取代；R7為氫、鹵素、C1-6之烷基、或C1-6之烷氧基；R8為氫、鹵素、C1-6之烷基、或C1-6之烷氧基；R9為氫、鹵素、C1-6之烷基、C1-6之烷氧基、C3-12之環烷基、芳基、或雜芳基；所述C1-6之烷基選擇性地以一至三個鹵素取代；所述C1-6之烷氧基、C3-12之環烷基、芳基、和雜芳基各自選擇性地以一至三選自由鹵素、芳基、選擇性地以一至三個鹵素取代之C1-6之烷基、選擇性地以一至三個鹵素取代之C1-6之烷氧基、胺基和CN所組成之群組之基團取代；以及所述雜芳基選擇性地與一芳基基團或一雜芳基基團稠合；R10為氫、或C1-6之烷基；以及J1、J2、J3和J4各自獨立為碳或氮，但條件為J1、J2、J3和J4中不超過兩個為氮。
在此，術語「烷基」是指直鏈或支鏈的烴基團，包含1-6個碳原子。例子包含甲基、乙基、正丙基、異丙基、正丁基、異丁基、和叔丁基。
術語「環烷基」是指飽和及部分飽和且具有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。
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-/二-取代。
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)。
在此，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，可使用之其藥學上可接受的鹽類和溶劑合物也包含在本揭露中。鹽類可由在化合物上的正電荷基團(例如胺基)與陰離子之間形成。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。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)。包括含有四級(quaternary)氮的相關鹽類。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與升糖素相關病症的醫藥組成物，例如與升糖素相關的代謝病症(例如I型糖尿病和II型糖尿病)。
醫藥組成物包含上述式(I)化合物之一者，或其藥學上可接受的鹽類、和藥學上可接受的載體、賦形劑、或稀釋劑。
本揭露也涵蓋這種組合物用於製造用於治療與升糖素相關的病症(例如代謝病症)的藥物的用途。
用於口服給予的組合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、熱熔擠出策略、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。
於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(compatible)(且優選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。
用於治療與升糖素相關病症(例如代謝病症)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」是指在受試者達到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、和優點將從說明書和請求項中顯而易見。
本揭露之第一實施例為式(I)之化合物或其藥學上可接受之鹽類：
Figure 107102334-A0305-02-0010-11
其中，R1、R2、R3、R4、R5、A1、A2、A3、A4、X和Y各自如發明內容中定義。
本揭露之第二實施例為第一實施例之化合物或其藥學上可接受之鹽類，其中，R3為氫，以及R4為氫。
本揭露之第三實施例為第一實施例或第二實施例之化合物或其 藥學上可接受之鹽類，其中，
Figure 107102334-A0305-02-0010-558
為
Figure 107102334-A0305-02-0010-559
、
Figure 107102334-A0305-02-0010-560
、或
Figure 107102334-A0305-02-0010-561
。
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-O-或-S-，Y為-CH2-，R2為
Figure 107102334-A0305-02-0011-656
，R3 為氫，以及R4為氫。
本揭露之第五實施例為第四實施例之化合物或其藥學上可接受 之鹽類，其中，R2為
Figure 107102334-A0305-02-0011-563
，R7為氫、鹵素、C1-6之烷基、或C1-6之烷氧基， 以及R8為氫、鹵素、或C1-6之烷基。
本揭露之第六實施例為第四實施例或第五實施例之化合物或其藥學上可接受之鹽類，其中，R7與R8相同，且R7和R8為氫、甲基、乙基、丙基、異丙基、丁基、叔丁基、氟、或氯。
本揭露之第七實施例為第四實施例或第五實施例之化合物或其藥學上可接受之鹽類，其中，R7為氟、氯、甲氧基、乙氧基、丙氧基、或異丁氧基，R8為氫。
本揭露之第八實施例為第四實施例之化合物或其藥學上可接受 之鹽類，其中，R2為
Figure 107102334-A0305-02-0011-657
，R7為氟、或氯，R8為氫、氟、或氯。
本揭露之第九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，R2為
Figure 107102334-A0305-02-0011-564
、
Figure 107102334-A0305-02-0011-565
、
Figure 107102334-A0305-02-0011-566
、
Figure 107102334-A0305-02-0011-567
、或
Figure 107102334-A0305-02-0011-568
，以及R7為C1-6之烷基。
本揭露之第十實施例為第三實施例或第九實施例之化合物或其藥學上可接受之鹽類，其中，R7為甲基、或乙基。
本揭露之第十一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-CH2-，Y為一直接鍵結，R2為
Figure 107102334-A0305-02-0012-569
， R3為氫，以及R4為氫。
本揭露之第十二實施例為第一至第三實施例和第十一實施例之任一者之化合物或其藥學上可接受之鹽類，其中，R7和R8為氫。
本揭露之第十三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-CH2-，Y為一直接鍵結，R2為
Figure 107102334-A0305-02-0012-28
， R3為氫，以及R4為氫。
本揭露之第十四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和Y為一直接鍵結，R2為
Figure 107102334-A0305-02-0012-31
，R3為氫， 以及R4為氫。
本揭露之第十五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-O-，Y為-CH2-，R2為
Figure 107102334-A0305-02-0012-30
，R3為氫， 以及R4為氫。
本揭露之第十六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-NH-，Y為-(C=O)-，R2為
Figure 107102334-A0305-02-0012-659
，R3 為氫，以及R4為氫。
本揭露之第十七實施例為第一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，R1為甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、正戊基、異戊基、甲氧基、乙氧基甲基、1-甲氧基丙基、1-甲氧基-2-甲基丙基、乙氧基、正丙氧基、異丙氧基、3-異丁氧基丙-2-基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、苯基、芐基、聯苯基、萘基、苯並呋喃基(benzofuranyl)、或吲哚基(indolyl)；所述甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、正戊基、和異戊基各自選擇性地具有一至三個取代基選自由氟、氯、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、苯基、芐基、和萘基所組成之群組；所述甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、和叔丁氧基各自選擇性地以一至三個氟或氯取代；所述苯基、聯苯基、萘基、和吲哚基(indolyl)各自選擇性地具有一至三個取代基選自由氟、氯、甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、三氟甲基、苯並呋喃基(benzofuranyl)和以甲氧基取代之嘧啶基(pyrimidyl)所組成之群組。
本揭露之第十八實施例為第一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，R5為四唑基(tetrazolyl)、-CH2-四唑基、-CH2CH2CO2H、-CH2CH2CO2Et、-CH2CH2CO2Me、-CH2CH(OH)CO2H、或-(CH2)2SO3H。
本揭露之第十九實施例為第一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，R9為甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、苯基、芐基、聯苯基、萘基、吡啶基(pyridinyl)、 嗒嗪基(pyridazinyl)、苯並呋喃基(benzofuranyl)、苯並噻唑基(benzothiazolyl)、咪唑並吡啶基(imidazopyridinyl)、噁二唑基(oxadiazol)、苯並噁唑基(benzooxazol)、吡唑基(pyrazol)、或吲哚基(indolyl)；所述甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基各自選擇性地具有一至三個取代基選自由氟、氯、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、苯基、聯苯基、和萘基所組成之群組；所述甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、和叔丁氧基各自選擇性地以一至三個氟、氯、或胺基取代；所述苯基、芐基、聯苯基、萘基、吡啶基(pyridinyl)、嗒嗪基(pyridazinyl)、苯並呋喃基(benzofuranyl)、苯並噻唑基(benzothiazolyl)、咪唑並吡啶基(imidazopyridinyl)、噁二唑基(oxadiazol)、苯並噁唑基(benzooxazol)、吡唑基(pyrazol)、和吲哚基(indolyl)各自選擇性地具有一至三個取代基選自由氟、氯、甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、-CF3、-OCF3、和苯基所組成之群組。
本揭露之第二十實施例為第一至第十九實施例之任一者之化合物或其藥學上可接受之鹽類，其中，R6為氫、或C1-6之烷基。
本揭露之第二十一實施例為第一至第十九實施例之任一者之化合物或其藥學上可接受之鹽類，其中，式(I)之化合物可為以下式(II)之化合物：
Figure 107102334-A0305-02-0014-32
本揭露之第二十一實施例為選自由化合物1-1至1-54、化合物2-1至2-13、化合物3-1至3-24、化合物4-1至4-5、化合物5-1至5-3、化合物6-1至6-3、化合物7-1至7-11、化合物8-1至8-25、化合物9-1至9-6、化合物10-1至10-19、化合物11-1至11-2、化合物12-1至12-11、化合物13-1至13-14、化合物14-1和14-2、化合物15-1至15-37、化合物16-1和16-2、化合物17-1至17-12、化合物18-1至18-9、化合物19-1至19-34、化合物20-1至20-7、化合物21-1至21-3、化合物22-1至22-20、化合物23-1至23-35、和化合物24-1至24-28所組成之群組，其列於以下表1至24中。
於本揭露之一態樣中，該化合物可以選自由化合物1-2、化合物1-8、化合物1-9、化合物1-12、化合物1-16、化合物1-17、化合物1-18、化合物1-19、化合物1-20、化合物1-22、化合物1-25、化合物1-30、化合物1-32、化合物1-48、化合物1-52、化合物1-54、化合物2-4、化合物2-6、化合物2-9、化合物2-10、化合物3-2、化合物3-3、化合物3-4、化合物3-5、化合物3-8、化合物3-9、化合物3-10、化合物3-12、化合物3-13、化合物3-14、化合物3-15、化合物3-19、化合物3-20、化合物3-22、化合物3-24、化合物4-2、化合物7-1、化合物7-5、化合物7-8、化合物7-11、化合物8-3、化合物8-5、化合物8-8、化合物8-11、化合物8-13、化合物8-15、化合物8-16、化合物8-20、化合物8-22、化合物8-23、化合物8-25、化合物9-1、化合物11-1、化合物11-2、化合物13-1、化合物13-2、化合物13-3、化合物13-4、化合物13-6、化合物13-7、化合物13-8、化合物13-9、化合物13-10、化合物13-11、化合物13-14、化合物14-2、化合物15-3、化合物15-7、化合物15-9、化合物15-10、化合物15-13、化合物15-22、化合物15-28、化合物15-29、化合物18-2、化合物18-3、化合物18-7、化合物18-8、化合物19-5、化合 物22-1、化合物22-18、化合物23-1、化合物23-5、和化合物23-10所組成之群組之任一者。
本揭露之化合物可以含有不對稱或手性中心，以及以不同的立體異構形式存在。除非另有說明，否則本揭露之化合物的所有立體異構形式以及其混合物，包含外消旋混合物在本揭露之範圍內。此外，本揭露之化合物也可以以不同的幾何以及位置異構物存在。例如順式-和反式-兩者，以及具有雙鍵或稠合環之化合物的混合物也在本揭露之範圍內。
非鏡像異構混合物(diastereomeric mixtures)可藉由任何方法，例如色層分析法和/或分段結晶(fractional crystallization)分離成非鏡像異構物(diastereoisomer)。鏡像異構物可藉由使用掌性的HPLC管柱，或藉由與合適的光學活性化合物反應，將鏡像異構混合物轉換成非鏡像異構混合物以分離非鏡像異構物，並將非鏡像異構物轉換成純的鏡像異構物。特定的立體異構物(stereoisomer)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。
在本揭露之化合物中，與NR3和Y連接的碳可以具有R或S的立體異構構型(stereoisomeric configuration)，並且這樣的化合物可以具有90%或更高(例如≧95%和≧99%)的鏡像異構物超越值(enantiomeric excess)。
也在本揭露之範圍內的為醫藥組成物，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。該組合物也可以另包含至少一種藥物(pharmaceutical agent)，例如抗肥胖(anti-obesity)藥物和/或抗糖尿病(anti-diabetic)藥物。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治療與升糖素(glucagon)相關的疾病、病症(condition)、或異常(disorder)之藥物。
本揭露另揭示用於降低受試者血糖含量的方法，其包含向有需要的受試者施予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。
本揭露進一步涵蓋治療與升糖素相關的疾病、病症、或異常的方法，其包含向有需要的受試者施予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，前述的受試者可為哺乳動物，例如人類。
在本揭露中，所述與升糖素相關的疾病、病症、或異常可為例如高血糖症(hyperglycemia)、第II型糖尿病(Type II diabetes)、代謝症候群(metabolic syndrome)、葡萄糖耐受不良(impaired glucose tolerance)、葡萄糖尿症(glucosuria)、糖尿病性腎病變(diabetic nephropathy)、糖尿病性神經病變(diabetic neuropathy)、糖尿病性視網膜病變(diabetic retinopathy)、高胰島素血症(hyperinsulinemia)、胰島素抗性症候群(insulin resistance syndrome)、白內障(cataracts)、肥胖(obesity)、血脂異常(dyslididemia)、高血壓(hypertension)、和心肌梗塞(myocardial infarction)。然而，本揭露並不局限於此，且本揭露之化合物或其藥學上可接受之鹽類可應用於與升糖素信號傳導途徑相關的任何其他疾病、病症、或異常。於本揭露之一態樣中，所述與升糖素相關的疾病、病症、或異常為高血糖症、第II型糖尿病、葡萄糖耐受不良、胰島素抗性症候群、以及肥胖。於本揭露之另一態樣中，所述與升糖素相關的疾病、病症、或異常為第II型糖尿病。
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肥胖(anti-obesity)試劑和/或抗糖尿病(anti-diabetic)試劑合併施用。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、賦型劑、或稀釋劑，以及至少一種額外的藥學試劑的單-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。
合適的抗糖尿病試劑包含乙醯基-CoA羧化酶-2(acetyl-CoA carboxylase-2，ACC-2)抑制劑、A2拮抗劑、雙胍(biguanide)(例如二甲雙胍(metformin))、二醯基甘油O-醯基轉移酶1(diacylglycerol O-acyltransferase 1，DGAT-1)抑制劑、二肽基肽酶-IV(dipeptidyl peptidase IV，DPP-IV)抑制劑(例如阿格列汀(alogliptin)、西他列汀(sitagliptin)、沙格列汀(saxagliptin)、和維格列汀(vildagliptin))、脂肪酸氧化抑制劑、類升糖素肽1(glucagon-like peptide 1，GLP-1))促效劑(例如艾塞那肽-3(Exendin-3)艾塞那肽-4(Exendin-4))、糖原磷酸化酶(glycogen phosphorylase)抑制劑、胰島素(insulin)、類胰島素(insulin mimetic)、胰島素促泌素(insulin secreatagogue)、美格列奈(meglitinide)、磷酸二酯酶(phosphodiesterase，PDE)-10抑制劑、蛋白酪胺酸磷酸酶-1B(protein tyrosine phosphatase-1B，PTP-1B)抑制劑(例如西替歐醛提取物(hyrtiosal extract)和曲度奎明(trodusquemine))、磺醯尿素(sulfonylurea)(例如乙醯苯磺醯環己脲(acetohexamide)、氯磺丙脲(chlorpropamide)、特泌胰(diabinese)、格列本脲(glibenclamide)、甲磺吡脲(gliclazide)、格列美脲(glimepiride)、格列戊脲(glipentide)、吡磺環己脲(glipizide)、格列喹酮(gliquidone)、格列索脲 (glisolamide)、優降糖(glyburide)、妥拉磺脲(tolazamide)和甲苯磺丁脲(tolbutamide))、α-澱粉酶(α-amylase)抑制劑(例如澱粉酶抑肽(tendamistat)、萃他汀(trestatin)、和AL-3688)、α-葡萄糖水解酶(α-glucoside hydrolase)抑製劑(例如阿卡波糖(acarbose))、α-葡萄醣苷酶(α-glucosidase)抑制劑(例如脂解素(adiposine)、卡格列波糖(camiglibose)、乙格列酯(emiglitate)、米格列醇(miglitol)、伏格列波糖(voglibose)、帕地黴素-Q(pradimicin-Q)、和沙波塔定(salbostatin))、PPARγ促效劑(例如巴格列酮(balaglitazone)、環格列酮(ciglitazone)、達格列酮(darglitazone)、恩格列酮(englitazone)、伊薩列酮(isaglitazone)、吡格列酮(pioglitazone)、羅格列酮(rosiglitazone)、和曲格列酮(troglitazone))、PPAR α/γ促效劑(例如CLX-0940、GW-1536、GW-1929、GW-2433、KRP-297、L-796449、LR-90、MK-0767和SB-219994)、SIRT-1抑制劑(例如白藜蘆醇(resveratrol))、SGLT1抑制劑、SGLT2抑制劑(例如達格列淨(dapagliflozin)、瑞格列嗪(remogliflozin)、舍格列淨(sergliflozin)、和AVE2268)、c-Jun胺基終端激酶(c-Jun amino-terminal kinase，JNK)抑制劑、VPAC2受體促效劑。在本揭露之一實施例中，合適的抗糖尿病試劑可以包含二甲雙胍、SGLT2抑制劑和/或DPP-IV抑制劑。
合適的抗肥胖試劑可以包含11β-羥基類固醇脫氫酶-1(11β-hydroxy steroid dehydrogenase-1，11β-HSD type 1)抑制劑、5HT2c促效劑(5HT2c agonist)(例如氯卡色林(lorcaserin))、食慾抑制劑(anorectic agent)(例如鈴蟾素促效劑(bombesin agonist))、睫狀神經營養因子(ciliary neurotrophic factor)(例如阿索開(AxokineTM)、膽囊收縮素-A(cholecystokinin-A，CCK-A)促效劑(例如N-苄基-2-[4-(1H-吲哚-3-基甲基)-5-側氧基-1-苯基-4,5-二氫-2,3,6,10b-四氮雜-苯並[e]薁-6-基]-N-異丙基-乙醯胺 (N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide)、脫氫表雄固酮(dehydroepiandrosterone)或其類似物、多巴胺促效劑(dopamine agonist)(例如溴麥角環肽(bromocriptine))、甘丙胺素拮抗劑(galanin antagonist)、腦腸肽拮抗劑(ghrelin antagonist)、類升糖素肽-1促效劑(glucagon-like peptide-1 agonist)、糖皮質素(glucocorticoid)促效劑或拮抗劑、組織胺3(histamine 3)拮抗劑或反促效劑、人豚鼠相關蛋白(human agouti-related protein，AGRP)抑制劑、瘦蛋白(leptin)類似物、瘦蛋白(leptin)促效劑、脂酶抑制劑(lipase inhibitors)(例如四氫利普司他汀(tetrahydrolipstatin)，即奧利司他(orlistat)和西替利司他(cetilistat))、MCR-4促效劑、黑色素凝集激素(melanin concentrating hormone)拮抗劑、瘦蛋白(leptin)(OB蛋白)、黑色素細胞刺激激素(melanocyte-stimulating hormone)類似物、單胺回收抑制劑monoamine reuptake inhibitor)(例如西布曲明(sibutramine))、MTP/ApoB抑制劑(例如腸選擇性(gut-selective)MTP抑制劑，例如特洛達派(dirlotapide)、米瑞達派(mitratapide)和依萊達派(implitapide)、R56918(CAS No.403987)和CAS No.913541-47-6)、神經胜肽-Y(neuropeptide-Y)拮抗劑(例如NPY Y5拮抗劑)、神經介素U促效劑(neuromedin U agonist)、類鴉片拮抗劑(opioid antagonist)(例如納曲酮(naltrexone))、食慾激素(orexin)拮抗劑、PYY3-36或其類似物、硬脂醯基-CoA去飽和酶-1(stearoyl-CoA desaturase-1，SCD-1)抑制劑、擬交感神經劑(sympathomimetic agents)、擬甲狀腺素劑(thyromimetic agent)、和β3腎上腺素促效劑(β3 adrenergic agonist)。在本揭露之-實施例中，合適的抗肥胖試劑可以包含5HT2c促效劑、CCK-A促效劑、腸選擇性(gut-selective)MTP抑制劑、脂酶抑制劑(lipase inhibitors)、MCR-4促效劑、PYY3-36類鴉片拮抗劑(opioid antagonist)、 溴麥角環肽(bromocriptine)、艾塞那肽(exenatide)、瘦蛋白(leptin)、利拉魯肽(liraglutide)、奧尼匹肽(obinepitide)、odistat、油醯雌酮(oleoyl-estrone)、普蘭林肽(pramlintide)、特索芬辛(tesofensine)、西布曲明(sibutramine)和AOD-9604。
用於合成式(I)化合物之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; and L. Hu, S. Magesh, L. Chen, T.Lewis, B. Munoz, L. Wang “Direct inhibitors of keap 1-nrf2 interaction as antioxidant inflammation modulators,” WO2013/067036.
由此製備的式(I)化合物可以先使用體外測定法，例如下文所述之升糖素cAMP抑制劑測定法和I125-升糖素結合測定法，篩選他們與升糖素受體拮和以及抑制下游(downstream)cAMP的效力，隨後可以使用本領域已知的體內測定法來評估。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。
做出以下實施例以清楚地表現出本公開的上述和其他技術內容、特徵和/或效果而做的。通過具體實施例的說明，人們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所附申請範圍包含。
實施例
不需要進-步詳述，相信習知技術者可以基於以上描述最大程度地利用本揭露。以下具體實施例，即實施例1-26應被解釋為僅僅是說明性地，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。
在具體實施例中，實施例1-24闡述用於製備某些中間體和390種例示性式(I)之化合物的步驟，以及由此製備的化合物的分析數據；實施例25和26闡述用於測試這些化合物的方案。
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，否則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，60F254)的玻璃背板(5cm_10cm)以分析薄層層析法監測，在紫外燈(λ=254nm)下觀察所得色譜影像，接著進入含有乙酸(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(heatgun)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-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)用於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，對這種需要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(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、芐基、對甲氧基芐基(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。
反應流程I和II說明可用於合成本揭露之以下式(I)之化合物的一般步驟。
反應流程I
Figure 107102334-A0305-02-0024-33
反應流程II
Figure 107102334-A0305-02-0025-34
中間體1之製備：(S)-叔丁基-1-(4-溴苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-(4-bromophenoxy)-3-methylbutan-2-ylcarbamate)
Figure 107102334-A0305-02-0025-35
步驟I：甲磺醯化(Mesiylation)
取(S)-叔丁基-1-羥基-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate，4.26g，21.1mmol)溶於無水二氯甲烷(80mL)，於溶液中加入三乙胺(3.52mL，25.29mmol)。逐滴加入溶於二氯甲烷 (10mL)之甲磺醯氯(1.96mL，25.3mmol)於混合物中，反應混合物攪拌3小時後，將混合物倒入冷水中產生白色固體沉澱，得到粗產物(S)-2-(叔丁氧基羰基胺基)-3-甲基丁基甲磺酸酯((S)-2-(tert-butoxycarbonylamino)-3-methylbutyl methanesulfonate)(5.91g，定性產率(qualitatively yield))，其具有適合的純度可直接用於下-步反應。
步驟II：SN2
於500mL圓底燒瓶中加入碳酸銫(15.6g，48mmol)，在100℃下以氮氣乾燥碳酸銫，接著將DMF加入燒瓶中。在60℃下加入溶於DMF(90mL)之4-溴苯酚(2.77g，16mmol)，並將混合物在60-70℃於氮氣條件下攪拌18小時。加入(S)-2-(叔丁氧基羰基胺基)-3-甲基丁基甲磺酸酯((S)-2-(tert-butoxycarbonylamino)-3-methylbutyl methanesulfonate，5.91g，21mmol)，再過40小時後，將其在乙酸乙酯和水之間分層，水層以乙酸乙酯萃取2次，並將合併的有機層以碳酸氫鈉溶液洗。乾燥(硫酸鎂)並濃縮以提供油狀殘餘物，藉由矽膠管柱層析純化以得到白色固體(S)-叔丁基-1-(4-溴苯酚)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-(4-bromophenoxy)-3-methylbutan-2-ylcarbamate，2.86g，50%)。1H NMR(400MHz,CDCl3)：δ 7.30-7.38(m,2H),6.71-6.79(m,2H),4.74(d,J=8.8Hz,1H),3.85-4.02(m,2H),3.67(t,J=8.3Hz,1H),1.97(dq,J=13.7,6.8Hz,1H),1.43(s,9H),0.93-0.99(m,6H)。
中間體2之製備：(S)-叔丁基-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-ylcarbamate)
Figure 107102334-A0305-02-0027-36
步驟III：Suzuki偶合
取(S)-叔丁基-1-(4-溴苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-(4-bromophenoxy)-3-methylbutan-2-ylcarbamate，2.86g，8mmol)、2-苯並呋喃硼酸(2-benzofuranylboronic acid，1.61g，10mmol)、乙酸鈀(II)(66mg，0.8mmol)、三苯基膦(420mg，1.6mmol)和2M碳酸鉀(14mL，28mmol)溶於乙醇/甲苯(2mL/12mL)，在90℃下加熱18小時。將反應混合物冷卻，倒入半飽合碳酸氫鈉溶液中並以乙酸乙酯萃取，合併有機層以硫酸鎂乾燥並真空濃縮。殘餘物藉由矽膠層析法純化以提供(S)-叔丁基-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-ylcarbamate)(2.21g，70%)。1H NMR(400MHz,CDCl3)：δ 7.74-7.80(m,2H),7.50-7.56(m,1H),7.47(d,J=8.3Hz,1H),7.16-7.24(m,2H),6.91-7.00(m,2H),6.87(d,J=1.0Hz,1H),4.79(d,J=8.8Hz,1H),4.08(dd,J=9.3,2.9Hz,1H),4.00(dd,J=9.3,3.9Hz,1H),3.71(br.s.,1H),1.94-2.07(m,1H),1.44(s,9H),0.94-1.02(m,6H)。
中間體3之製備：4-(苯並呋喃-2-基)苯酚(4-(benzofuran-2-yl)phenol)
Figure 107102334-A0305-02-0027-37
於圓底燒瓶(1L)中加入碳酸鉀(28g，203mol)並以水(102mL)溶解，加入溶於苯並呋喃-2-基硼酸(benzofuran-2-ylboronic acid，11.3g，70mmol)、4-溴苯酚(10g，58mmol)，接著加入甲苯(232ml)、乙醇(58ml)和三苯基膦(PPh3，3.04g，11.6mmol)。混合物以氮氣冒泡30分鐘後，加入乙酸鈀(Pd(OAc)2，1.3g，5.8mmol)並升溫至回流。反應攪拌至隔夜，以日本酸噴霧(Japanese acid spray)終止反應，並通過矽藻土純化。混合物以乙酸乙酯萃取，並以硫酸鎂乾燥，通過管柱層析法純化，得到白色固體的4-(苯並呋喃-2-基)苯酚(4-(benzofuran-2-yl)phenol，8.8g，72%)。1H NMR(400MHz,CDCl3)：δ 7.71-7.77(m,2H),7.51-7.56(m,1H),7.45-7.50(m,1H),7.16-7.26(m,2H),6.87-6.92(m,2H),6.85-6.87(m,1H),4.90(s,1H)。
中間體4之製備：(S)-叔丁基-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-ylcarbamate)
Figure 107102334-A0305-02-0028-570
去質子燒瓶(Deprotonation flask)：於圓底燒瓶(500mL)中將碳酸銫(37g，113mmol)在100℃下以氮氣乾燥，接著於燒瓶中加入二甲基甲醯胺(DMF)。在60℃下加入4-(苯並呋喃-2-基)苯酚(8.74g，42mmol)，並將混合物於60-70℃在氮氣條件下攪拌18小時。
於圓底燒瓶(250mL)中，取(S)-叔丁基-1-羥基-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate，11.4g，56mmol)溶於無水二氯甲烷(110mL)，並藉由冰浴冷卻至5℃，逐滴加入三乙胺(11.33g，112mmol)和甲基磺醯氯(MsCl，7.7g，67.2mmol)超過10分鐘，將反應在室溫下攪拌2小時。以水終止反應，並以二氯甲烷萃取，硫酸鎂乾燥，合併有機層並藉由真空移除溶劑，準備進行下-個反應。將(S)-2-(叔丁氧基羰基胺基)-3-甲基丁基甲磺酸酯((S)-2-(tert-butoxycarbonylamino)-3-methylbutyl methanesulfonate)溶於DMF(40mL)，並倒入去質子燒瓶中，反應在60-70℃下攪拌24小時，混合物藉由過濾移除鹽類，以及藉由真空移除溶劑，以乙酸乙酯和水萃取，有機層以水洗並以硫酸鎂乾燥。粗產物通過管柱層析法純化，得到(S)-叔丁基-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-ylcarbamate，8.31g，50%)。1H NMR(400MHz,CDCl3)：δ 7.74-7.80(m,2H),7.50-7.56(m,1H),7.47(d,J=8.3Hz,1H),7.16-7.24(m,2H),6.91-7.00(m,2H),6.87(d,J=1.0Hz,1H),4.79(d,J=8.8Hz,1H),4.08(dd,J=9.3,2.9Hz,1H),4.00(dd,J=9.3,3.9Hz,1H),3.71(br.s.,1H),1.94-2.07(m,1H),1.44(s,9H),0.94-1.02(m,6H)。
中間體5之製備：(S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-胺((S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-amine)
Figure 107102334-A0305-02-0029-40
將化合物(S)-叔丁基-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基胺基甲酸酯((S)-tert-butyl1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-ylcarbamate(574mg，13.4mmol)懸浮在三氟乙酸(15mL，200mmol)於無水二氯甲烷(150mL)中，在室溫下反應至隔夜。反應後，逐滴加入碳酸鈉溶液中和過量的三氟乙酸直到pH=10，接著以二氯甲烷萃取，合併有機層以無水硫酸鎂乾燥，並以真空濃縮以得到粗產物。粗產物進-步藉由急速管柱層析法純化(矽膠，以二氯甲烷和甲醇作為沖提液)，以得到白色固體之化合物。1H NMR(400MHz,CDCl3)：δ 7.74-7.80(m,2H),7.51-7.56(m,1H),7.46-7.50(m,1H),7.21(m,2H),6.94-6.99(m,2H),6.87(d,J=1.0Hz,1H),4.03(dd,J=8.8,3.9Hz,1H),3.83(dd,J=9.3,7.8Hz,1H),2.97(ddd,J=7.8,5.9,3.9Hz,1H),1.80(dq,J=13.1,6.7Hz,1H),1.34(s,2H),0.99(m,6H)。
實施例1：化合物1-1至1-54之合成
化合物1-1：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0030-571
取(S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-胺((S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-amine，7.40g，25mmol)、3-(4- 碘苯甲醯胺基)丙酸乙酯(ethyl 3-(4-iodobenzamido)propanoate，10g，29mmol)、2-異丁醯基環己-1-酮(2-isobutyrylcyclohexan-1-one，0.84g，5mmol)、和碳酸銫(16.3g，50mmol)溶於DMF(無水的，25ml)，並將溶液以氮氣(g)冒泡10分鐘後加入碘化銅(0.48g，2.5mmol)，反應在室溫下攪拌5天，接著將反應以乙酸乙酯(100mL)稀釋，通過矽藻土過濾，並以乙酸乙酯(2×100mL)萃取，合併有機層以食鹽水洗，以硫酸鈉乾燥、過濾、並濃縮以得到粗產物，藉由管柱層析法純化(0-70%乙酸乙酯/己烷)，得到白色固體(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanote，5.20g，40%)。1H NMR(400MHz,CDCl3)：δ 7.72-7.79(m,2H),7.56-7.63(m,2H),7.51-7.55(m,1H),7.43-7.49(m,1H),7.16-7.24(m,2H),6.89-6.96(m,2H),6.87(s,1H),6.57-6.65(m,3H),4.10-4.21(m,3H),4.07(dd,J=4.4,2.0Hz,2H),3.67(q,J=6.2Hz,2H),3.55-3.63(m,1H),2.56-2.64(m,2H),2.09-2.21(m,1H),1.24(t,J=7.1Hz,3H),1.04(d,J=6.4Hz,3H),1.05(d,J=6.8Hz,3H).MS(M+1)：515。
化合物1-2：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0031-42
取(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate，5.15g，10mmol)溶於四氫呋喃(THF，50mL)，加入2N氫氧化鋰水溶液(20mL，40mmol)，反應在室溫下攪拌3小時。在真空下移除四氫呋喃，並以二氯甲烷萃取。將水層以3N鹽酸水溶液酸化至pH=4，並以乙酸乙酯(2×100mL)萃取，合併有機層以食鹽水洗，以硫酸鈉乾燥、過濾並濃縮，以得到白色固體(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid，4.47g，92%)。1H NMR(400MHz,DMSO-d6)：δ 12.14(s,1H),8.05-8.02(m,1H),7.81-7.85(m,2H),7.57-7.62(m,4H),7.21-7.30(m,3H),7.04-7.07(m,2H),6.66(d,J=8.8Hz,1H),6.11(d,J=8.9Hz,1H),4.02-4.14(m,2H),3.64-3.70(m,1H),3.38-3.43(m,2H),2.45-2.47(m,2H),2.01-2.09(m,1H),1.01(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).MS(M+1)：487。
化合物1-3：3-(4-(((2S,3S)-1-((4'-(叔丁基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0032-43
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=7.8Hz,2H),7.36-7.52(m,6H),6.90(d,J=8.8Hz,2H),6.63-6.72(m,1H),6.57(d,J=8.3Hz,2H),4.05(br.s.,2H),3.58-3.72(m,3H),2.57-2.70(m,2H),1.79-1.92(m,1H),1.56-1.71(m,1H),1.16-1.29(m,1H),0.99(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：517。
化合物1-4：3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0033-44
1H NMR(400MHz,CDCl3)：δ 7.74(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.50-7.54(m,1H),7.46(d,J=8.3Hz,1H),7.16-7.23(m,2H),6.90(d,J=8.8Hz,2H),6.85(s,1H),6.74(t,J=5.6Hz,1H),6.57(d,J=8.3Hz,2H),4.00-4.09(m,2H),3.59-3.70(m,3H),2.65(t,J=5.6Hz,2H),1.79-1.90(m,1H),1.63(ddd,J=13.2,7.3,3.9Hz,1H),1.18-1.28(m,1H),0.98(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：501。
化合物1-5：3-(4-(((2S)-3-甲基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-3-methyl-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0034-45
1H NMR(400MHz,CDCl3)：δ 7.55-7.64(m,6H),7.48(d,J=8.8Hz,2H),6.90-6.93(d,J=8.8Hz,2H),6.58(d,J=8.3Hz,2H),4.02-4.10(m,2H),3.60-3.70(m,3H),2.61-2.67(m,2H),1.80-1.92(m,1H),1.64(ddd,J=13.1,7.5,3.9Hz,1H),1.18-1.28(m,1H),0.99(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：529。
化合物1-6：3-(4-(((2S,3S)-3-甲基-1-((4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0034-47
1H NMR(400MHz,DMSO-d6)：δ 8.26(t,J=5.2Hz,1H),7.71(d,J=8.8Hz,2H),7.57(t,J=8.8Hz,4H),7.39(d,J=8.3Hz,2H),7.01(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),6.14(d,J=8.8Hz,1H),4.06-4.15(m,1H),3.96-4.05(m,1H),3.61-3.72(m,1H),2.13(t,J=6.8Hz,2H),1.72-1.83(m,1H),1.54-1.66(m,1H),1.18-1.34(m,1H),0.94(d,J=6.8Hz,3H),0.89(t,J=7.4Hz,3H).MS(M+1)：545。
化合物1-7：3-(4-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0035-48
1H NMR(400MHz,CDCl3)：δ 7.57(d,J=8.3Hz,2H),7.44(d,J=2.0Hz,1H),7.18-7.32(m,4H),6.90(d,J=8.3Hz,2H),6.79-6.86(m,1H),6.57(d,J=8.3Hz,2H),4.02-4.09(m,2H),3.60-3.70(m,3H),2.64(t,J=5.6Hz,2H),1.81-1.92(m,1H),1.57-1.70(m,1H),1.18-1.30(m,1H),0.99(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：529。
化合物1-8：N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0035-572
1H NMR(400MHz,DMSO-d6)：δ 8.70(t,J=5.4Hz,1H),7.83(d,J=8.8Hz,2H),7.67(d,J=8.3Hz,2H),7.52-7.64(m,2H),7.18-7.32(m,3H),7.05(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),6.26(d,J=8.8Hz,1H),4.68(d,J=5.9Hz,2H),4.15(dd,J=10.0,3.7Hz,1H),3.99-4.08(m,1H),3.66-3.75(m,1H),1.72-1.87(m,1H),1.61(ddd,J=13.1,7.5,3.9Hz,1H),1.19-1.32(m,1H),0.96(d,J=6.8Hz,3H),0.90(t,J=7.3Hz,3H).MS(M+1)：511。
化合物1-9：(R)-3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)
Figure 107102334-A0305-02-0036-50
1H NMR(400MHz,DMSO-d6)：δ 8.02(t,J=5.4Hz,1H),7.83(d,J=8.3Hz,2H),7.54-7.69(m,4H),7.18-7.31(m,3H),7.05(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),6.19(d,J=8.8Hz,1H),4.09-4.17(m,2H),4.04(dd,J=10.0,6.1Hz,1H),3.70(br.s.,1H),3.48-3.60(m,1H),3.34-3.45(m,1H),1.69-1.85(m,1H),1.51-1.69(m,1H),1.26(dt,J=13.8,8.0Hz,1H),0.95(d,J=6.8Hz,3H),0.90(t,J=7.3Hz,3H).MS(M+1)：517。
化合物1-10：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0036-51
1H NMR(400MHz,CDCl3)：δ 7.49-7.65(m,4H),7.32-7.46(m,3H),7.13(q,J=7.4,1.2Hz,2H),6.64-6.82(m,3H),6.29-6.45(m,2H),3.61-3.80(m, 2H),3.41-3.55(m,3H),2.39-2.51(m,2H),1.49-1.61(m,1H),1.32-1.42(m,1H),1.03-1.20(m,4H),0.71(t,J=6.9Hz,3H).MS(M+1)：501。
化合物1-11：(S)-3-(4-((1-((4'-(叔丁基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0037-573
1HNMR(400MHz,CDCl-)：δ 7.59(d,J=8.8Hz,2H),7.39-7.52(m,6H),6.91(d,J=8.3Hz,2H),6.69-6.77(m,1H),6.58(d,J=8.8Hz,2H),3.93-4.06(m,2H),3.71-3.79(m,1H),3.62-3.72(m,2H),2.63-2.69(m,2H),1.76-1.87(m,1H),1.54-1.69(m,1H),1.26-1.44(m,4H),0.89(t,J=7.1Hz,3H).MS(M+1)：517。
化合物1-12：(S)-3-(4-((1-((4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0037-53
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.04(t,J=5.4Hz,1H),7.59(d,J=8.8Hz,2H),7.48-7.42(m,4H),6.94(d,J=8.8,2H),6.76(d,J=8.8,2H),6.66(d,J=8.8Hz,2H),6.11(d,J=8.8,1H),4.07-3.96(m,2H),3.66-3.63(m,1H),3.43-3.38(m,2H),2.47(t,J=7.3Hz,2H),2.08-2.02(m,1H),1.01-0.96(m,6H).MS(M+1)：490。
化合物1-13：N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0038-54
1H NMR(400MHz,DMSO-d6)：δ 8.74(t,J=5.6Hz,1H),7.61-7.73(m,3H),7.44-7.50(m,1H),7.36-7.42(m,1H),7.34(d,J=8.3Hz,2H),7.01(d,J=8.3Hz,2H),6.68(d,J=8.8Hz,2H),6.26(d,J=8.8Hz,1H),4.69(d,J=5.4Hz,2H),4.09-4.17(m,1H),4.03(dd,J=9.8,5.9Hz,1H),3.65-3.78(m,1H),1.74-1.86(m,1H),1.53-1.68(m,1H),1.27(dt,J=13.8,8.0Hz,1H),0.96(d,J=6.8Hz,3H),0.90(t,J=7.3Hz,3H).MS(M+1)：539。
化合物1-14：(R)-3-(4-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)
Figure 107102334-A0305-02-0039-55
1H NMR(400MHz,DMSO-d6)：δ 8.05(br.s.,1H),7.57-7.68(m,3H),7.42-7.49(m,1H),7.37(d,J=8.3Hz,1H),7.32(d,J=8.8Hz,2H),7.00(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),6.17(d,J=8.8Hz,1H),4.06-4.16(m,1H),3.97-4.06(m,1H),3.89(br.s.,1H),3.68(br.s.,1H),3.42(br.s.,2H),1.72-1.85(m,1H),1.60(ddd,J=13.1,7.5,3.9Hz,1H),1.19-1.34(m,1H),0.94(d,J=6.8Hz,3H),0.89(t,J=7.3Hz,3H).MS(M+1)：545。
化合物1-15：(S)-3-(4-((1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0039-574
1H NMR(400MHz,DMSO-d6)：δ 8.06(t,J=5.4Hz,1H),7.82(d,J=8Hz,2H),7.75(d,J=8Hz,2H),7.66(d,J=8.8Hz,2H),7.60(d,J=8.8Hz,2H),7.04(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),3.95-4.06(m,2H),3.73-3.86(m,1H),3.38-3.42(m,2H),2.45-2.49(m,2H),1.65-1.79(m,1H),1.57(td,J=8.9,5.1Hz,1H),1.25-1.48(m,4H),0.87(t,J=7.3Hz,3H).MS(M+1)：529。
化合物1-16：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0040-57
1H NMR(400MHz,DMSO-d6)：δ 8.73-8.80(m,1H),7.81-7.85(m,2H),7.74-7.79(m,2H),7.63-7.69(m,4H),7.05(d,J=8.8Hz,2H),6.67(d,J=9.3Hz,2H),6.20-6.27(m,1H),4.69(d,J=5.4Hz,2H),4.01(d,J=4.9Hz,2H),3.76-3.88(m,1H),1.68-1.78(m,1H),1.49-1.64(m,1H),1.32(br.s.,4H),0.84-0.90(m,3H)；MS(M+1)：539。
化合物1-17：(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0040-58
1H NMR(400MHz,CDCl3)：δ 7.61(d,J=8.8Hz,2H),7.46(d,J=2.0Hz,1H),7.32(d,J=8.8Hz,2H),7.21-7.28(m,3H),6.93(d,J=8.8Hz,2H),6.69(t,J=5.9Hz,1H),6.60(d,J=8.8Hz,2H),3.97-4.09(m,2H),3.74-3.82(m,1H),3.69 (q,J=5.9Hz,2H),2.68(t,J=5.9Hz,2H),1.77-1.91(m,1H),1.57-1.72(m,1H),1.30-1.54(m,4H),0.91(t,J=7.1Hz,3H)；MS(M+1)：529。
化合物1-18：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0041-59
1H NMR(400MHz,DMSO-d6)：δ 8.75(t,J=5.4Hz,1H),7.68(d,J=2.4Hz,1H),7.65(d,J=8.8Hz,2H),7.47(dd,J=8.3,2.0Hz,1H),7.39(d,J=8.3Hz,1H),7.34(d,J=8.8Hz,2H),7.00(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),6.21(d,J=8.3Hz,1H),4.68(d,J=5.4Hz,2H),4.00(d,J=5.4Hz,2H),3.75-3.86(m,1H),1.66-1.80(m,1H),1.51-1.64(m,1H),1.27-1.48(m,4H),0.87(t,J=7.1Hz,3H)；MS(M+1)：539。
化合物1-19：(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0041-575
1H NMR(400MHz,DMSO-d6)：δ 7.70(d,J=1.0Hz,3H),7.59(d,J=8.8Hz,2H),7.52(dd,J=8.1,1.2Hz,1H),7.40(d,J=7.8Hz,1H),7.32-7.35(m,2H),6.90-6.98(m,2H),6.77(t,J=5.9Hz,1H),6.58(d,J=8.8Hz,2H),3.97-4.06(m,2H),3.73-3.81(m,1H),3.67(q,J=5.9Hz,2H),2.65(t,J=5.9Hz,2H),1.76-1.88(m,1H),1.58-1.69(m,1H),1.29-1.50(m,4H),0.89(t,J=7.1Hz,3H).MS(M+1)：563。
化合物1-20：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺benzamide((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0042-61
1H NMR(400MHz,DMSO-d6)：δ 8.76(t,J=5.6Hz,1H),7.94(d,J=1.0Hz,1H),7.76(dd,J=8.1,1.2Hz,1H),7.66(d,J=8.8Hz,2H),7.60(d,J=7.8Hz,1H),7.41(d,J=8.8Hz,2H),7.04(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),6.23(d,J=8.3Hz,1H),4.69(d,J=5.4Hz,2H),4.02(d,J=5.4Hz,2H),3.77-3.88(m,1H),1.69-1.81(m,1H),1.53-1.64(m,1H),1.26-1.50(m,4H),0.88(t,J=7.1Hz,3H).MS(M+1)：573。
化合物1-21：(R)-3-(4-(((S)-1-((4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((S)-1-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)
Figure 107102334-A0305-02-0043-62
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.10(dd,J=8.8,3Hz,1H),7.90(d,J=8.8Hz,1H),7.69(d,J=8,1H),7.62-7.56(m,3H),7.43(d,J=1.5Hz,1H),7.34(dt,J=8,1.5Hz,1H),7.27(dt,J=8.8,1.5Hz,1H),7.22(d,J=3Hz,1H),7.09(dd,J=8.8,3Hz,1H),6.67(d,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),4.17-4.05(m,2H),3.69-3.60(m,2H),3.44-3.38(m,1H),3.21-3.17(m,1H),2.06-2.01(m,1H),1.02-0.97(m,6H).MS(M+1)：506。
化合物1-22：(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0043-63
1H NMR(400MHz,DMSO-d6)：δ 8.08(br.s.,1H),7.94(s,1H),7.76(d,J=7.8Hz,1H),7.53-7.63(m,3H),7.35-7.45(m,2H),6.99-7.08(m,2H),6.66(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.00-4.14(m,2H),3.61-3.72(m,2H),3.39(d,J=5.4Hz,3H),2.40(t,J=7.1Hz,2H),1.98-2.11(m,1H),0.94-1.06(m,6H).MS(M+1)：549。
化合物1-23：3-(4-((2-(4-(苯並呋喃-2-基)苯氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-(4-(benzofuran-2-yl)phenoxy)-1-phenylethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0044-576
1H NMR(400MHz,CDCl3)：δ 7.77(d,J=8.8Hz,3H),7.28-7.54(m,13H),7.17-7.26(m,9H),6.96(d,J=9.3Hz,3H),6.88(s,1H),6.54(d,J=8.8Hz,4H),4.72-4.89(m,1H),4.22-4.37(m,1H),3.63-3.77(m,6H),2.66(t,J=5.9Hz,2H).MS(M+1)：521。
化合物1-24：(S)-3-(4-((3-甲基-1-(4-(5-(三氟甲基)吡啶-2-基)苯氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(5-(trifluoromethyl)pyridin-2-yl)phenoxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0044-577
1H NMR(400MHz,DMSO-d6)：δ 8.96(s,1H),8.16-8.22(m,1H),8.11(d,J=8.8Hz,3H),7.49-7.63(m,2H),7.03-7.11(m,2H),6.66(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.01-4.17(m,3H),3.62-3.72(m,2H),3.36(br.s.,2H), 2.20-2.32(m,2H),2.05(dq,J=13.0,6.6Hz,1H),0.99(d,J=5.9Hz,3H),0.99(d,J=19.1Hz,3H).MS(M+1)：516。
化合物1-25：(S)-3-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0045-66
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.03(t,J=5.4Hz,1H),7.74-7.71(m,2H),7.64-7.59(m,3H),7.54-7.52(m,2H),7.06(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.13-4.02(m,2H),3.70-3.63(m,1H),3.44-3.39(m,2H),2.47(t,J=6.8Hz,2H),2.09-2.01(m,1H),1.02-0.97(m,6H).MS(M+1)：533。
化合物1-26：3-(4-(((2S,3S)-1-((2',4'-二氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0045-67
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=8.8Hz,2H),7.35-7.39(m,2H),7.31(td,J=8.8,6.4Hz,1H),6.81-6.93(m,4H),6.77(t,J=5.9Hz,1H),6.57(d,J=8.8Hz,2H),4.00-4.08(m,2H),3.60-3.70(m,3H),2.64(t,J=5.9Hz,2H),1.79-1.92(m,1H),1.58-1.69(m,1H),1.17-1.27(m,1H),0.98(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：497。
化合物1-27：(S)-3-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0046-68
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.8Hz,2H),7.34-7.52(m,5H),6.94(d,J=8.8Hz,2H),6.79(t,J=5.9Hz,1H),6.58(d,J=8.8Hz,2H),4.01(tt,J=9.5,4.6Hz,2H),3.72-3.80(m,1H),3.66(q,J=5.9Hz,2H),2.64(t,J=5.6Hz,2H),1.76-1.86(m,1H),1.57-1.68(m,1H),1.29-1.49(m,4H),0.89(t,J=7.1Hz,3H).MS(M+1)：547。
化合物1-28：3-(4-((1-苯基-2-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)乙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-phenyl-2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0047-69
1H NMR(400MHz,CDCl3)：δ 7.58-7.65(m,4H),7.48-7.53(m,4H),7.24-7.43(m,5H),6.86-7.08(m,2H),6.69(t,J=5.9Hz,1H),6.52(d,J=8.8Hz,2H),4.79(dd,J=7.8,3.9Hz,1H),4.27(dd,J=9.8,3.9Hz,1H),4.04-4.15(m,1H),3.62(q,J=5.9Hz,2H),2.61(t,J=5.9Hz,2H)。
化合物1-29：(S)-3-(4-((3-甲基-1-(4-(6-(三氟甲基)嗒嗪-3-基)苯氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(6-(trifluoromethyl)pyridazin-3-yl)phenoxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0047-578
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.46(d,J=8.8Hz,1H),8.26-8.20(m,3H),8.03(t,J=5.4Hz,1H),7.59(d,J=8.8Hz,2H),7.14(d,J=8.8,3Hz,2H),6.67(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.18-4.06(m,2H),3.72-3.65(m,1H),3.43-3.39(m,2H),2.46(t,J=6.8Hz,2H),2.09-1.98(m,1H),1.02-0.98(m,6H).MS(M+1)：517。
化合物1-30：(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl (S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0048-71
1H NMR(400MHz,CDCl3)：δ 7.97-8.03(m,3H),7.86(d,J=7.3Hz,1H),7.57-7.64(m,2H),7.41-7.48(m,1H),7.30-7.37(m,1H),6.91-6.98(m,2H),6.56-6.65(m,3H),4.07-4.20(m,5H),3.68(q,J=5.9Hz,2H),3.56-3.64(m,1H),2.56-2.63(m,2H),2.09-2.21(m,1H),1.21-1.28(m,3H),1.04(d,J=6.8Hz,3H),1.05(d,J=6.8Hz,3H).MS(M+1)：532。
化合物1-31：(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸甲酯(Methyl(S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0048-72
1H NMR(DMSO-d6)：δ 8.04-8.13(m,2H),7.96-8.04(m,3H),7.55-7.65(m,2H),7.52(td,J=7.6,1.5Hz,1H),7.39-7.45(m,1H),7.07-7.14(m,2H),6.67(d,J=8.8Hz,2H),6.14(d,J=8.8Hz,1H),4.04-4.20(m,2H),3.64-3.74(m,1H),3.57-3.63(m,3H),3.39-3.48(m,2H),2.55(t,J=7.1Hz,2H),2.05(dq,J=13.2,6.5Hz,1H),0.98(d,J=6.8Hz,3H),1.01(d,J=6.8Hz,3H).MS(M+1)：518。
化合物1-32：(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0049-579
1H NMR(400MHz,DMSO-d6)：δ 8.06-8.15(m,2H),7.97-8.05(m,3H),7.55-7.63(m,J=8.3Hz,2H),7.47-7.54(m,1H),7.38-7.46(m,1H),7.11(d,J=9.3Hz,2H),6.61-6.71(m,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.15(dd,J=10.0,4.2Hz,1H),4.07(dd,J=10.0,6.1Hz,1H),3.64-3.72(m,2H),3.34-3.42(m,2H),2.35-2.44(m,2H),2.05(dq,J=12.8,6.6Hz,1H),1.00(d,J=5.4Hz,3H),1.00(d,J=19.1Hz,3H).MS(M+1)：504。
化合物1-33：(S)-2-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0049-74
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.09(t,J=5.4Hz,1H),7.75-7.71(m,2H),7.64-7.62(m,1H),7.54-7.52(m,4H),7.07(d,J=8.8Hz,2H), 6.67(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.13-4.02(m,2H),3.70-3.63(m,1H),3.50-3.45(m,2H),2.64(t,J=6.8Hz,2H),2.10-1.99(m,1H),1.02-0.97(m,6H).MS(M+1)：569。
化合物1-34：(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0050-75
1HNMR(400MHz,DMSO-d6)：δ 12.14(s,1H),8.05-8.02(m,1H),7.81-7.85(m,2H),7.57-7.62(m,4H),7.21-7.30(m,3H),7.04-7.07(m,2H),6.66(d,J=8.8Hz,1H),6.11(d,J=8.9Hz,1H),4.02-4.14(m,2H),3.64-3.70(m,1H),3.38-3.43(m,2H),2.45-2.47(m,2H),2.01-2.09(m,1H),1.01(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).MS(M+1)：487。
化合物1-35：(R)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0050-76
1H NMR(400MHz,DMSO-d6)：δ 8.08(br.s.,1H),7.94(s,1H),7.76(d,J=7.8Hz,1H),7.53-7.63(m,3H),7.35-7.45(m,2H),6.99-7.08(m,2H),6.66(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.00-4.14(m,2H),3.61-3.72(m,2H),3.39(d,J=5.4Hz,3H),2.40(t,J=7.1Hz,2H),1.98-2.11(m,1H),0.94-1.06(m,6H).MS(M+1)：549。
化合物1-36：(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0051-77
1H NMR(400MHz,DMSO-d6)：δ 8.02(t,1H),7.68(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,2H),7.43-7.50(dd,1H),7.27-7.42(d,3H),6.91-6.99(dt,2H),6.70(d,J=8.8Hz,2H),5.99(d,J=9.8Hz,1H),4.22-4.35(dd,1H),3.88-4.09(m,2H),3.62-3.71(m,1H),2.46(t,J=7.1Hz,2H),1.02(s,9H).MS(M+1)：529。
化合物1-37：(S)-3-(4-((1-((2'-氯-4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0052-78
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.04(t,J=5.6Hz,1H),7.58(d,J=8.8Hz,2H),7.26(d,J=8.8Hz,2H),7.15(d,J=8.8Hz,1H),6.94(d,J=8.8Hz,2H),6.76-6.71(m,2H),6.66(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.06-3.97(m,2H),3.67-3.62(m,1H),2.46(t,J=6.8Hz,2H),2.08-2.02(m,1H),1.01-0.96(m,6H).MS(M+1)：524。
化合物1-38：3-(4-(((2S,3S)-1-((2'-氯-4'-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-4'-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0052-580
1H NMR(400MHz,Acetone-d6)：δ 7.68(d,J=8.3Hz,2H),7.45-7.50(m,1H),7.25-7.33(m,3H),7.05(d,J=2.4Hz,1H),6.92-7.01(m,3H),6.73(d,J=8.8Hz,2H),5.48-5.56(m,1H),4.18(dd,J=16.9,4.6Hz,2H),3.85(s,3H),3.59(d,J=5.9Hz,2H),2.61(t,J=6.6Hz,2H),1.88-1.95(m,1H),1.68-1.80(m,1H),1.28-1.41(m,1H),1.05(d,J=6.8Hz,3H),0.96(t,J=7.6Hz,3H).MS(M+1)：525。
化合物1-39：(S)-3-(4-((1-(4-(咪唑並[1,2-a]吡啶-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-(4-(imidazo[1,2-a]pyridin-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0053-80
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.48(d,J=7.8Hz,1H),8.26(s,1H),8.03(t,J=5.6Hz,1H),7.86(d,J=8.8Hz,2H),7.59(d,J=8.8Hz,2H),7.53(d,J=7.8Hz,1H),7.23-7.19(m,1H),6.98(d,J=8.8Hz,2H),6.86(t,J=7.8Hz,1H),6.66(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.11-3.99(m,2H),3.67-3.63(m,1H),2.47(t,J=6.8Hz,2H),2.08-2.03(m,1H),1.01-0.97(m,6H).MS(M+1)：487。
化合物1-40：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0053-81
1H NMR(400MHz,DMSO-d6)：δ 8.00-8.07(m,1H),7.81(d,J=8.8Hz,1H),7.54-7.63(m,3H),7.20-7.31(m,2H),7.00(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,1H),5.97-6.03(m,1H),4.27-4.34(m,1H),3.94-4.01(m,1H),3.64-3.72(m,1H),3.40(d,J=5.4Hz,2H),2.42-2.48(m,2H),1.03(s,9H).MS(M+1)：501。
化合物1-41：(S)-3-(4-((1-(4-(呋喃並[3,2-b]吡啶-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(furo[3,2-b]pyridin-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0054-82
1H NMR(400MHz,DMSO-d6)：δ 8.46(dd,1H),8.02-8.09(m,1H),7.98(d,1H),7.91(dt,2H),7.58(d,2H),7.47(s,1H),7.28m(q,1H),7.09(dt,2H),6.66(d,2H),6.12(d,1H),4.01-4.17(m,2H),3.62-3.73(m,2H),2.45(t,2H),2.00-2.11(m,1H),1.24(s,1H),0.99(m,6H).MS(M+1)：488。
化合物1-42：(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0054-83
1H NMR(400MHz,CDCl3)：δ 7.69(s,1H),7.58(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,1H),7.39(d,J=7.8Hz,1H),7.32(d,J=8.8Hz,2H),6.89(d,J=8.3Hz,2H),6.63(d,J=8.3Hz,3H),4.20(dd,J=9.5,4.2Hz,1H),4.03(dd,J=9.3, 4.9Hz,1H),3.68(d,J=4.4Hz,2H),3.57(t,J=4.6Hz,1H),2.68(br.s.,2H),1.07(s,9H).MS(M+1)：563。
化合物1-43：3-(4-((3-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯氧基)丁-2-基)胺基)苯甲醯胺基)丙酸(3-(4-((3-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenoxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0055-84
1H NMR(400MHz,CDCl3)：δ 7.98(d,J=8.0Hz,2H),7.58(d,J=8.8Hz,2H),6.96(d,J=8.0Hz,2H),6.80(t,J=5.9Hz,1H),6.58(d,J=8.8Hz,2H),4.09(d,J=4.0Hz,2H),3.60-3.72(m,2H),2.64(t,J=5.6Hz,2H),2.11(dq,J=13.4,6.8Hz,1H),0.95-1.09(m,6H).MS(M+1)：507。
化合物1-44：3-(4-((3-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-((3-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenoxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0055-85
1H NMR(400MHz,CDCl3)：δ 7.97(d,J=8.0Hz,2H),7.58(d,J=8.4Hz,2H),6.96(d,J=8.8Hz,2H),6.85(t,J=5.4Hz,1H),6.57(d,J=8.8Hz,2H), 4.03-4.15(m,2H),3.59-3.70(m,3H),2.62(t,J=5.6Hz,2H),1.79-1.89(m,1H),1.51-1.70(m,1H),1.10-1.31(m,2H),0.98(d,J=6.8Hz,3H),0.88-0.95(t,J=8.0Hz,3H).MS(M+1)：521。
化合物1-45：3-(4-(((2S,3S)-1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0056-86
1H NMR(400MHz,CDCl3)：δ 7.90(d,J=8.8Hz,2 H),7.58(d,J=8.8Hz,2 H),6.91(d,J=8.8Hz,2 H),6.88-6.81(m,1 H),6.56(d,J=8.3Hz,2 H),4.14-4.01(m,2 H),3.69-3.58(m,3 H),2.67-2.58(m,2 H),1.89-1.78(m,1 H),1.68-1.57(m,1 H),1.44(s,9 H),1.30-1.18(m,1 H),0.98(d,J=6.8Hz,3 H),0.92(t,J=7.3Hz,3 H).MS(M+1)：509。
化合物1-46：3-(4-(((2S,3S)-3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0056-87
1H NMR(400MHz,CDCl3)：δ 8.16-8.05(m,2 H),8.04-7.96(m,2 H),7.59(d,J=8.3Hz,2 H),7.53-7.42(m,3 H),6.95(d,J=8.8Hz,2 H),6.83-6.69(m,1 H),6.58(d,J=8.3Hz,2 H),4.16-4.03(m,2 H),3.72-3.59(m,3 H),2.72-2.60(m,2 H),1.91-1.78(m,1 H),1.72-1.57(m,1 H),1.30-1.19(m,1 H),1.00(d,J=6.8Hz,3 H),0.93(t,J=7.3Hz,3 H).MS(M+1)：529.HPLC 99%。
化合物1-47：(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0057-88
1H NMR(400MHz,DMSO-d6)：δ 8.09-8.16(m,2H),8.05(t,J=5.4Hz,1H),7.71-7.79(m,2H),7.54-7.62(m,2H),7.34-7.42(m,2H),7.11-7.18(m,2H),6.61-6.71(m,J=8.8Hz,2H),6.13(d,J=9.3Hz,1H),4.14-4.22(m,1H),4.01-4.12(m,3H),3.65-3.75(m,1H),3.38-3.47(m,2H),2.52-2.55(m,2H),2.05(dq,J=13.2,6.7Hz,1H),1.17(t,J=7.1Hz,3H),0.98(d,J=6.8Hz,3H),1.01(d,J=6.8Hz,3H),MS(M+1)：516.HPLC 95%。
化合物1-48：(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0058-89
1H NMR(400MHz,DMSO-d6)：δ 12.16(br.s.,1H),8.09-8.15(m,2H),8.04(t,J=5.6Hz,1H),7.71-7.78(m,2H),7.56-7.63(m,J=8.8Hz,2H),7.35-7.42(m,2H),7.11-7.18(m,2H),6.67(d,J=9.3Hz,2H),6.13(d,J=9.3Hz,1H),4.17(dd,J=10.0,4.2Hz,1H),4.08(dd,J=10.0,6.1Hz,1H),3.63-3.74(m,1H),3.37-3.45(m,2H),2.42-2.48(m,2H),2.05(dq,J=12.9,6.8Hz,1H),1.01(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).MS(M+1)：488。
化合物1-49：(S)-3-(4-((1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0058-90
1H NMR(400MHz,CDCl3)：δ 7.91(d,J=8.8Hz,2 H),7.59(d,J=8.3Hz,2 H),6.92(d,J=9.3Hz,2 H),6.83-6.71(m,1 H),6.57(d,J=8.8Hz,2 H),4.04-4.00(m,2 H),3.81-3.7-3(m,1 H),3.71-3.61(m,2 H),2.71-2.59(m,2 H),1.87-1.72(m,1 H),1.70-1.56(m,1 H),1.45(s,9 H),1.41-1.28(m,4 H),0.89(t,J=6.6Hz,3 H).MS(M+1)：509。
化合物1-50：(S)-3-(4-((1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0059-581
1H NMR(400MHz,CDCl3)：δ 8.07(td,J=2.3,5.1Hz,2 H),8.02-7.95(m,2 H),7.59(d,J=8.3Hz,2 H),7.53-7.44(m,3 H),6.97-6.81(m,3 H),6.60-6.53(m,2 H),4.04-3.96(m,2 H),3.80-3.72(m,1 H),3.69-3.61(m,2 H),2.67-2.60(m,2 H),1.85-1.73(m,1 H),1.60(d,J=4.9Hz,1 H),1.47-1.28(m,4 H),0.87(t,J=7.1,3 H).MS(M+1)：529。
化合物1-51：(R)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0059-92
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.13(m,5H),7.56-7.64(m,J=8,8Hz,2H),7.51(d,J=1.0Hz,1H),7.43(d,J=8.3Hz,1H),7.06-7.16(m,2H),6.67(d,J=8.8Hz,2H),6.12(s,1H),4.06(q,J=6.8Hz,4H),3.64-3.75(m,1H),3.44 (d,J=5.4Hz,2H),2.52-2.56(m,2H),2.05(dq,J=13.3,6.7Hz,1H),1.17(t,J=7.1Hz,3H),1.00(d,J=4.9Hz,3H),1.00(d,J=18.6Hz,3H).MS(M+1)：532。
化合物1-52：(R)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0060-93
1H NMR(400MHz,DMSO-d6)：δ 7.97-8.12(m,5H),7.56-7.63(m,J=8.8Hz,2H),7.51(td,J=7.7,1.2Hz,1H),7.38-7.46(m,1H),7.04-7.14(m,2H),6.67(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.01-4.18(m,2H),3.63-3.73(m,1H),3.35-3.44(m,2H),2.44(t,J=7.1Hz,2H),2.05(dq,J=13.1,6.7Hz,1H),0.99(d,J=5.4Hz,3H),0.99(d,J=19.1Hz,3H).MS(M+1)：504。
化合物1-53：(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0060-582
1H NMR(400MHz,DMSO-d6)：δ 8.08-8.16(m,J=8.8Hz,2H),8.00-8.08(m,1H),7.68-7.77(m,2H),7.59(d,J=8.3Hz,2H),7.33-7.42(m,2H),7.14(d,J=7.3Hz,2H),6.63-6.72(m,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),4.13-4.22(m,1H),3.98-4.13(m,3H),3.64-3.74(m,1H),3.38-3.48(m,2H),2.52-2.57(m,2H),2.05(dq,J=13.3,6.7Hz,1H),1.17(t,J=7.1Hz,3H),1.00(dd,J=12.2,6.8Hz,6H).MS(M+1)：516。
化合物1-54：(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0061-95
1H NMR(400MHz,DMSO-d6)：δ 8.12(d,J=8,3Hz,2H),8.01-8.08(m,1H),7.70-7.79(m,2H),7.60(dd,J=8.8,1.5Hz,2H),7.34-7.42(m,2H),7.14(dd,J=8.8,1.5Hz,2H),6.67(d,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),4.16(d,J=6.8Hz,1H),4.08(dd,J=9.8,6.4Hz,1H),3.63-3.73(m,1H),3.36-3.44(m,2H),2.40-2.48(m,2H),2.05(dq,J=13.3,6.7Hz,1H),1.01(d,J=6.4Hz,3H),0.98(d,J=6.8Hz,3H).MS(M+1)：488。
實施例2：化合物2-1至2-13之合成
化合物2-1：(R)-3-(4-((1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸 ((R)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0062-96
1H NMR(400MHz,DMSO-d6)：δ 8.03-8.12(m,1H),7.78(d,J=7.8Hz,2H),7.60(dd,J=8.8,2.0Hz,2H),7.23-7.42(m,6H),7.14-7.23(m,1H),6.68-6.76(m,2H),6.65(d,J=8.8Hz,2H),6.27(d,J=7.8Hz,1H),3.91-4.09(m,3H),3.40(d,J=6.4Hz,3H),3.02(dd,J=13.7,5.9Hz,1H),2.91(dd,J=13.7,7.3Hz,1H),2.40-2.48(m,2H),1.85-1.94(m,6H).MS(M+1)：591。
化合物2-2：(R)-3-(4-((1-((2,6-二甲基-4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0062-97
1H NMR(400MHz,CDCl3)：δ 7.56-7.64(m,J=8.8Hz,2H),7.15-7.31(m,8H),7.06-7.13(m,2H),6.80-6.91(m,1H),6.59-6.65(m,2H),6.52-6.59(m,2H),3.86-4.01(m,4H),3.63(d,J=5.4Hz,2H),3.02(d,J=6.4Hz,2H),2.59(br.s.,2H),1.95(s,6H).MS(M+1)：591。
化合物2-3：(S)-3-(4-((1-((2,6-二甲基-4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0063-98
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=7.8Hz,2H),7.36(br.s.,1H),7.15-7.21(m,2H),7.01-7.09(m,2H),6.56-6.65(m,2H),6.40-6.48(m,2H),3.93-4.04(m,1H),3.76-3.93(m,2H),3.71(br.s.,1H),3.48(br.s.,2H),3.28-3.43(m,1H),2.40(br.s.,2H),1.88-1.93(m,6H),1.62-1.75(m,1H),0.82-0.92(m,6H).MS(M+1)：573。
化合物2-4：(S)-3-(4-((1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0063-99
1H NMR(400MHz,CDCl3)：δ 7.60(d,J=8.3Hz,2H),7.63(d,J=7.8Hz,2H),7.21(d,J=7.3Hz,2H),6.87(br.s.,1H),6.47-6.74(m,4H),5.47(br.s.,1H),3.89-4.18(m,2H),3.65(br.s.,2H),3.56(br.s.,1H),2.64(br.s.,2H),2.15(m,1H),1.94(br.s.,6H),0.91-1.14(m,6H).MS(M+1)：543。
化合物2-5：(S)-3-(4-((1-((4'-(叔丁基)-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((4'-(tert-butyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0064-100
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.8Hz,2H),7.30-7.43(m,J=7.8Hz,2H),6.93-7.06(m,J=7.8Hz,2H),6.74-6.84(m,1H),6.49-6.68(m,4H),3.95-4.09(m,2H),3.67(q,J=5.7Hz,2H),3.48-3.60(m,1H),2.66(t,J=5.6Hz,2H),2.14(dq,J=13.4,6.8Hz,1H),1.98(s,6H),1.34(s,9H),1.03(dd,J=6.8,2.0Hz,6H).MS(M+1)：531。
化合物2-6：3-(4-(((2S,3S)-1-((4'-(叔丁基)-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4'-(tert-butyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0064-101
1H NMR(400MHz,Acetone-d6)：δ 7.66-7.72(m,2H),7.45-7.48(m,2H),7.01-7.06(m,2H),6.73(d,J=8.8Hz,2H),6.67(s,2H),4.13(dd,J=12.0,4.6Hz,2H),3.71-3.82(m,1H),3.59(t,J=6.8Hz,2H),2.61(t,J=6.8Hz,2H),1.95(s,6H),1.36(s,9H),1.05(d,J=6.8Hz,3H),0.93-0.99(m,3H)。
化合物2-7：3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3,5-二甲基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3,5-dimethylphenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0065-102
1H NMR(400MHz,CDCl3)：δ 7.56-7.62(m,3H),7.47(d,J=7.8Hz,1H),7.20-7.29(m,2H),6.71(t,J=6.1Hz,1H),6.63(s,2H),6.56-6.60(m,3H),4.01-4.19(m,2H),3.58-3.72(m,3H),2.66(t,J=5.9Hz,2H),2.19(s,6H),1.81-1.91(m,1H),1.59-1.71(m,1H),1.19-1.31(m,1H),1.00(d,J=6.8Hz,3H),0.94(t,J=7.3Hz,3H).MS(M+1)：529。
化合物2-8：3-(4-(((2S,3S)-1-((2,6-二甲基-4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,6-dimethyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0065-103
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.8Hz,2H),7.22(d,J=8.3Hz,2H),7.1(d,J=8.8Hz,2H),6.70-6.82(m,1H),6.62(s,2H),6.58(d,J=8.3Hz,2H),4.04(d,J=4.4Hz,2H),3.57-3.71(m,3H),2.65(t,J=5.6Hz,2H),1.6(s,6H), 1.80-1.88(m,1H),1.58-1.74(m,1H),1.19-1.31(m,1H),1.00(d,J=6.8Hz,3H),0.94(t,J=7.3Hz,3H).MS(M+1)：573。
化合物2-9：3-(4-(((2S,3S)-1-((2',4'-二氯-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0066-104
1H NMR(400MHz,CDCl3)：δ 7.53-7.60(m,2H),6.76(br.s.,1H),6.53-6.64(m,4H),6.48(s,2H),3.98(d,J=4.4Hz,2H),3.65(q,J=5.4Hz,2H),3.58(d,J=6.4Hz,1H),2.63(t,J=5.6Hz,2H),2.24(s,6H),1.77-1.88(m,1H),1.57-1.68(m,1H),1.15-1.25(m,1H),0.97(d,J=6.8Hz,3H),0.89-0.94(m,3H).MS(M+1)：557。
化合物2-10：3-(4-(((2S,3S)-1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0066-105
1H NMR(400MHz,DMSO-d6)：δ 8.00-8.12(m,1H),7.78(d,J=7.8Hz,2H),7.59(d,J=8.8Hz,2H),7.35(d,J=7.8Hz,2H),6.71(s,2H),6.64(d,J=8.8Hz,2H),6.04-6.19(m,1H),3.94-4.11(m,2H),3.61-3.72(m,1H),3.39(q,2H),2.45(t,2H),1.91(s,6H),1.73-1.84(m,1H),1.56-1.67(m,1H),1.20-1.34(m,1H),0.96(d,3H),0.91(t,3H).MS(M+1)：557。
化合物2-11：(S)-3-(4-((1-((2'-氯-2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0067-583
1H NMR(400MHz,DMSO-d6)：δ 8.02(t,J=5.4Hz,1H),7.53-7.63(m,2H),6.78(s,1H),6.64(d,J=8.8Hz,2H),6.47-6.57(m,1H),6.03(dd,J=8.8,4.9Hz,1H),3.88-4.07(m,2H),3.54-3.68(m,1H),3.38-3.45(m,2H),2.46(t,J=7.1Hz,2H),2.30(s,3H),2.20(s,3H),1.97-2.07(m,1H),0.90-1.03(m,6H)。
化合物2-12：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二甲基苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-dimethylphenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0068-107
1H NMR(400MHz,CDCl3)：δ 7.55-7.65(m,3H),7.47(d,J=7.8Hz,1H),7.17-7.31(m,2H),6.77-6.88(m,1H),6.53-6.70(m,4H),3.99(dd,J=8.3,4.4Hz,2H),3.75(br.s.,1H),3.62-3.71(m,2H),2.66(t,J=5.6Hz,2H),2.20(s,6H),1.72-1.88(m,1H),1.54-1.70(m,1H),1.29-1.51(m,4H),0.90(t,J=6.8Hz,3H)；MS(M+1)：529。
化合物2-13：(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3,5-二甲基苯氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3,5-dimethylphenoxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0068-584
1H NMR(400MHz,DMSO-d6)：δ 8.77(t,J=5.6Hz,1H),7.62-7.70(m,3H),7.56(d,J=8.3Hz,1H),7.22-7.32(m,2H),6.86(s,1H),6.76(s,2H),6.67(d,J=8.8Hz,2H),6.22(d,J=8.3Hz,1H),4.70(d,J=5.9Hz,2H),3.95-4.03(m,2H),3.74-3.86(m,1H),2.15(s,6H),1.68-1.80(m,1H),1.50-1.64(m,1H),1.27-1.50(m,4H),0.88(t,J=7.1Hz,3H)；MS(M+1)：539。
實施例3：化合物3-1至3-24之合成
化合物3-1：N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylpentan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0069-109
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.68(t,J=5.9Hz,1H),7.91(d,J=8.8Hz,1H),7.70-7.60(m,4H),7.43(s,1H),7.34(t,J=8.3Hz,1H),7.27(t,J=8.3Hz,1H),7.22(d,J=2.5Hz,1H),7.09(dd,J=8.8,2.5Hz,1H),6.67(d,J=8.8Hz,2H),6.26(d,J=8.8Hz,1H),4.67(d,J=5.9Hz,2H),4.21-4.07(m,2H),3.75-3.68(m,1H),1.78-1,70(m,1H),1.64-1.59(m,1H),1.30-1.26(m,1H),0.96(d,J=6.9Hz,3H),0.90(t,J=7.3Hz,3H).MS(M+1)：545。
化合物3-2：(R)-3-(4-(((S)-1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((S)-1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)
Figure 107102334-A0305-02-0069-110
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.10-8.07(m,1H),7.98(s,1H),7.79(d,J=7.8Hz,1H),7.59-7.53(m,3H),7.27(d,J=8.8Hz,1H),7.23-7.19(m,1H),7.04-7.01(m,1H),6.68-6.63(m,2H),6.15-6.07(m,1H),4.15-3.98(m,3H),3.67-3.60(m,3H),2.06-2.01(m,1H),1.02-0.94(m,6H).MS(M+1)：599。
化合物3-3：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0070-111
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.72-8.69(m,1H),7.99(s,1H),7.79(d,J=7.8Hz,1H),7.67-7.55(m,3H),7.29-7.18(m,2H),7.05-7.00(m,1H),6.69(d,J=8.8Hz,2H),6.20(d,J=8.8Hz,1H),4.67(d,J=4.9Hz,2H),4.17-4.06(m,2H),3.71-3.65(m,1H),2.06-2.03(m,1H),1.02-0.98(m,6H).MS(M+1)：593。
化合物3-4：(S)-3-(4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0071-112
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.17(pseudo-brs,1H),7.99(d,J=1.5Hz,1H),7.79(dd,J=8,1.5Hz,1H),7.61-7.55(m,3H),7.28-7.18(m,2H),7.01(dt,J=8,3Hz,1H),6.66(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.12-4.05(m,2H),3.38-3.35(m,3H),3.42-3.37(m,2H),2.29(t,J=8.8Hz,2H),2.09-2.00(m,1H),1.02-0.97(m,6H).MS(M+1)：583。
化合物3-5：(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0071-113
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.64(t,J=5.9Hz,1H),7.90(d,J=8.8Hz,1H),7.70-7.60(m,4H),7.43(s,1H),7.34(t,J=8.3Hz,1H),7.27(t,J=8.3Hz,1H),7.22(d,J=2.5Hz,1H),7.09(dd,J=8.8,2.5Hz,1H),6.69(d,J=8.8Hz,2H),6.19(d,J=8.8Hz,1H),4.67(d,J=5.9Hz,2H),4.19-4.06(m,2H),3.72-3.65(m,1H),2.08-2.01(m,1H),1.02-0.97(m,6H).MS(M+1)：531。
化合物3-6：(R)-3-(4-(((S)-1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸 ((R)-3-(4-(((S)-1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)
Figure 107102334-A0305-02-0072-114
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.10(dd,J=8.8,3Hz,1H),7.90(d,J=8.8Hz,1H),7.69(d,J=8,1H),7.62-7.56(m,3H),7.43(d,J=1.5Hz,1H),7.34(dt,J=8,1.5Hz,1H),7.27(dt,J=8.8,1.5Hz,1H),7.22(d,J=3Hz,1H),7.09(dd,J=8.8,3Hz,1H),6.67(d,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),4.17-4.05(m,2H),3.69-3.60(m,2H),3.44-3.38(m,1H),3.21-3.17(m,1H),2.06-2.01(m,1H),1.02-0.97(m,6H).MS(M+1)：537。
化合物3-7：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0072-115
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.12(t,J=5.9Hz,1H),7.89(d,J=8.8Hz,1H),7.69(d,J=7.8Hz,1H),7.62-7.58(m,3H),7.42(s,1H),7.33(dt,J=8,3Hz,1H),7.27(t,J=8Hz,1H),7.21(d,J=3Hz,1H),7.08(dd,J=8.8,2.5Hz,1H),6.66(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.17-4.05(m,2H), 3.68-3.64(m,1H),3.40-3.35(m,2H),2.31(t,J=8.8Hz,2H),2.05-2.00(m,1H),1.02-0.96(m,6H).MS(M+1)：521。
化合物3-8：(S)-3-(4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0073-585
1H NMR(400MHz,CDCl3)：δ 7.71(d,J=1.0Hz,1H),7.60(d,J=8.3Hz,2H),7.54(dd,J=8.1,1.2Hz,1H),7.35(d,J=7.8Hz,1H),7.12(d,J=8.8Hz,1H),7.01(d,J=2.4Hz,1H),6.84(dd,J=8.6,2.7Hz,1H),6.70(t,J=6.1Hz,1H),6.59(d,J=8.8Hz,2H),3.96-4.04(m,2H),3.74-3.81(m,1H),3.68(q,J=5.9Hz,2H),2.67(t,J=5.9Hz,2H),1.76-1.86(m,1H),1.57-1.68(m,1H),1.31-1.49(m,4H),0.90(t,J=7.1Hz,3H).MS(M+1)：597。
化合物3-9：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0074-586
1H NMR(400MHz,DMSO-d6)：δ 8.77(t,J=5.6Hz,1H),7.99(d,J=1.0Hz,1H),7.79(dd,J=8.1,1.2Hz,1H),7.67(d,J=8.8Hz,2H),7.56(d,J=7.8Hz,1H),7.28(d,J=8.8Hz,1H),7.16-7.20(m,1H),6.99-7.05(m,1H),6.67(d,J=8.8Hz,2H),6.24(d,J=8.3Hz,1H),4.69(d,J=5.9Hz,2H),4.05(d,J=5.4Hz,2H),3.77-3.87(m,1H),1.67-1.79(m,1H),1.53-1.64(m,1H),1.27-1.50(m,4H),0.88(t,J=7.1Hz,3H).MS(M+1)：606。
化合物3-10：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0074-587
1H NMR(400MHz,CDCl3)：δ 7.90(d,J=8.8Hz,1H),7.55-7.62(m,2H),7.47(d,J=8.3Hz,1H),7.34(s,1H),7.17-7.29(m,2H),6.98(d,J=2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.78(t,J=5.9Hz,1H),6.57(d,J=8.8Hz,2H),3.90-4.01(m,2H),3.70-3.77(m,1H),3.66(q,J=5.9Hz,2H),2.65(t,J=5.6Hz,2H),1.72-1.83(m,1H),1.53-1.65(m,1H),1.30-1.45(m,4H),0.88(t,J=7.1Hz,3H).MS(M+1)：535。
化合物3-11：(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0075-588
1H NMR(400MHz,DMSO-d6)：δ 8.69(t,J=5.4Hz,1H),7.91(d,J=8.8Hz,1H),7.64-7.71(m,3H),7.61(d,J=8.3Hz,1H),7.43(s,1H),7.24-7.37(m,2H),7.21(d,J=2.4Hz,1H),7.09(dd,J=8.8,2.4Hz,1H),6.66(d,J=8.8Hz,2H),6.22(d,J=8.3Hz,1H),4.67(d,J=5.4Hz,2H),4.06(d,J=4.9Hz,2H),3.77-3.86(m,1H),1.66-1.79(m,1H),1.58(td,J=8.7,4.6Hz,1H),1.28-1.49(m,4H),0.87(t,J=7.1Hz,3H).；MS(M+1)：545。
化合物3-12：(S)-3-(4-((1-((2,2',4'-三氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2',4'-trichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0075-120
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.8Hz,2H),7.46(d,J=2.0Hz,1H),7.26(dd,J=8.3,2.0Hz,1H),7.09-7.17(m,2H),6.98(d,J=2.4Hz,1H), 6.82(dd,J=8.3,2.4Hz,1H),6.72(t,J=5.9Hz,1H),6.58(d,J=8.8Hz,2H),3.95-4.03(m,2H),3.73-3.80(m,1H),3.67(q,J=5.9Hz,2H),2.66(t,J=5.9Hz,2H),1.75-1.87(m,1H),1.57-1.68(m,1H),1.31-1.48(m,4H),0.89(t,J=7.1Hz,3H)；MS(M+1)：563。
化合物3-13：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2',4'-三氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2',4'-trichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0076-589
1H NMR(400MHz,DMSO-d6)：δ 8.76(t,J=5.4Hz,1H),7.73(d,J=2.0Hz,1H),7.67(d,J=8.3Hz,2H),7.49(dd,J=8.3,2.4Hz,1H),7.33(d,J=8.4Hz,1H),7.21-7.27(m,1H),7.15(d,J=2.0Hz,1H),6.97-7.01(m,1H),6.67(d,J=8.8Hz,2H),6.22(d,J=8.3Hz,1H),4.69(d,J=5.4Hz,2H),4.04(d,J=4.9Hz,2H),3.76-3.86(m,1H),1.72(td,J=9.2,5.1Hz,1H),1.51-1.63(m,1H),1.26-1.49(m,4H),0.88(t,J=7.1Hz,3H)；MS(M+1)：573。
化合物3-14：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-2,5-二氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-2,5-dichlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0077-122
1H NMR(400MHz,DMSO-d6)：δ 7.98(s,1H),7.57-7.76(m,4H),7.50(d,J=6.8Hz,2H),7.24-7.39(m,2H),6.69(d,J=8.8Hz,2H),6.03(d,J=8.8Hz,1H),4.10-4.31(m,2H),3.66-3.74(m,1H),3.36-3.47(m,2H),2.44-2.48(m,1H),2.02-2.16(m,1H),1.01(dd,J=8.8,6.8Hz,6H).MS(M+1)：521。
化合物3-15：3-(4-((2-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-1-phenylethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0077-123
1H NMR(400MHz,CDCl3)：δ 7.69-7.72(m,1H),7.48-7.54(m,3H),7.24-7.44(m,8H),6.94-6.98(m,2H),6.64(t,J=6.1Hz,1H),6.49-6.56(m,2H),4.80(dd,J=7.8,3.9Hz,1H),4.29(dd,J=9.8,3.9Hz,1H),4.01-4.19(m,1H),3.63(q,J=5.9Hz,2H),2.62(t,J=5.9Hz,2H).MS(M+1)：583。
化合物3-16：(S)-3-(4-((1-((2-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0078-124
1H NMR(400MHz,CDCl3)：δ 7.60(d,J=8.8Hz,2H),7.36-7.41(m,2H),7.16-7.25(m,3H),6.96-7.00(m,1H),6.86(t,J=5.9Hz,1H),6.82(dd,J=8.8,2.4Hz,1H),6.58(d,J=8.8Hz,2H),3.93-4.03(m,2H),3.71-3.80(m,1H),3.66(q,J=5.9Hz,2H),2.64(t,J=5.9Hz,2H),1.73-1.86(m,1H),1.55-1.67(m,1H),1.30-1.48(m,4H),0.89(t,J=7.1Hz,3H).MS(M+1)：563。
化合物3-17：(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0078-125
1H NMR(400MHz,DMSO-d6)：δ 8.76(t,J=5.6Hz,1H),7.64-7.71(m,2H),7.47-7.56(m,2H),7.39-7.45(m,2H),7.30-7.38(m,1H),7.09-7.16(m,1H),6.96-7.06(m,1H),6.67(d,J=8.8Hz,2H),6.21(d,J=8.8Hz,1H),4.69(d,J=5.9Hz,2H),4.03(d,J=4.9Hz,2H),3.73-3.87(m,1H),1.63-1.79(m,1H),1.51-1.63(m,1H),1.20-1.45(m,4H),0.88(t,J=7.1Hz,3H).MS(M+1)：573。
化合物3-18：(S)-2-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0079-126
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.13(t,J=5.4Hz,1H),7.89(d,J=8.8Hz,1H),7.68(d,J=8.3Hz,1H),7.61-7.55(m,3H),7.41(s,1H),7.32(dt,J=8,1.5Hz,1H),7.27-7.24(m,1H),7.19(d,J=2.4Hz,1H),7.07(dd,J=8.8,3Hz,1H),6.67(d,J=8.8Hz,2H),6.16(d,J=8Hz,1H),4.15-4.06(m,2H),3.64(brs,1H),3.53-3.48(m,2H),2.69(t,J=6.8Hz,2H),2.05-2.00(m,1H),1.00-0.95(m,6H).MS(M+1)：558。
化合物3-19：3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-2,5-二氯苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-2,5-dichlorophenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0079-127
1H NMR(400MHz,CDCl3)：δ 7.85-8.12(m,2h),7.55-7.67(m,2H),7.28-7.52(m,2H),6.91-7.04(m,1H),6.54-6.68(m,3H),3.99-4.21(m,3H), 3.63-3.78(m,2H),2.69(t,J=5.6Hz,1H),1.93(dd,J=7.3,3.4Hz,1H),1.64-1.72(m,1H),1.20-1.28(m,2H),0.87-1.10(m,6H).MS(M+1)：569。
化合物3-20：3-(4-(((2S,3S)-3-甲基-1-((2,2',5-三氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((2,2',5-trichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0080-128
1H NMR(400MHz,CDCl3)：δ 7.72-7.77(m,1H),7.55-7.65(m,3H),7.33-7.40(m,1H),7.01(s,1H),6.61-6.68(m,3H),4.10-4.22(m,2H),3.71(q,J=6.0Hz,3H),2.71(t,J=6.0Hz,2H),1.95(ddd,J=12.4,7.2,3.6Hz,1H),1.72(ddd,J=12.4,7.2,3.6Hz,1H),1.07(d,J=7.2Hz,3H),0.99(t,J=7.2Hz,3H).MS(M+1)：631。
化合物3-21：3-(4-(((2S,3S)-1-((2,5-二氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,5-dichloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0080-590
1H NMR(400MHz,CDCl3)：δ 7.55-7.65(m,3H),7.36-7.51(m,2H),6.94-7.03(m,1H),6.57-6.72(m,3H),4.02-4.22(m,3H),3.63-3.76(m,3H),2.70(t,J=5.6Hz,2H),1.84-2.01(m,1H),1.61-1.78(m,1H),1.05(dd,J=13.2,7.2Hz,3H),0.97(q,J=7.2Hz,3H).MS(M+1)：615。
化合物3-22：(S)-3-(4-((1-((2-氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0081-130
1H NMR(400MHz,CDCl3)：δ 7.60(d,J=8.8Hz,2H),7.34-7.47(m,3H),7.14-7.21(m,1H),6.97-7.03(m,1H),6.76-6.88(m,2H),6.58(d,J=8.8Hz,2H),3.99(tt,J=9.0,4.6Hz,2H),3.70-3.81(m,1H),3.59-3.70(m,2H),2.65(t,J=5.9Hz,2H),1.71-1.86(m,1H),1.56-1.66(m,1H),1.29-1.47(m,4H),0.89(t,J=6.8Hz,3H).MS(M+1)：581。
化合物3-23：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0081-131
1H NMR(400MHz,Acetone-d6)：δ 7.93(d,J=8.8Hz,1H),7.67(d,J=8.8Hz,3H),7.54(d,J=1.0Hz,1H),7.41(s,1H),7.33(td,1H),7.26(td,1H),7.12(d,J=2.4Hz,1H),7.03(dd,1H),6.78(d,J=8.8Hz,2H),4.45(q,1H),4.18(q,1H),3.76-3.84(m,1H),3.58(t,2H),2.62(t,J=6.6Hz,2H),1.12(s,9H).MS(M+1)：535。
化合物3-24：(S)-3-(4-((1-((2-氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0082-132
1H NMR(400MHz,Acetone-d6)：δ 7.84(s,1H),7.70-7.75(m,1H),7.67(d,J=8.3Hz,2H),7.60(d,J=7.8Hz,1H),7.41(d,2H),7.01(d,2H),6.78(d,J=8.3Hz,2H),4.39(dd,J=10.0,3.7Hz,1H),4.12(dd,J=9.8,6.8Hz,1H),3.75-3.83(m,1H),3.59(q,2H),2.62(t,J=6.8Hz,2H),1.13(s,9H).MS(M+1)：581。
實施例4：化合物4-1至4-5之合成
化合物4-1：(S)-3-(6-((3-甲基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((3-methyl-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)butan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0083-133
白色固體。1H NMR(400MHz,DMSO-d6)：δ 8.48(d,J=4Hz,1H),8.20(t,J=4Hz,1H),7.83-7.74(m,5H),7.66(d,J=8Hz,2H),7.08-7.04(m,3H),6.59(d,J=8Hz,1H),4.30-4.28(m,1H),4.13-4.06(m,2H),3.74-3.71(m,1H),3.42(quartet,J=8Hz,2H),2.48(t,J=8Hz,2H),2.10-1.98(m,1H),0.99-0.96(m,6H).MS(M+1)：516。
化合物4-2：(S)-3-(6-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0083-134
1H NMR(400MHz,DMSO-d6)：δ 8.48(d,J=2.4Hz,1H),8.23(t,J=5.4Hz,1H),7.80-7.86(m,2H),7.78(dd,J=8.8,2.4Hz,1H),7.55-7.64(m,2H),7.20-7.31(m,3H),7.00-7.14(m,3H),6.59(d,J=8.8Hz,1H),4.29(br.s.,1H),4.05-4.15(m,2H),3.33-3.46(m,2H),2.39-2.47(m,3H),2.07(dq,J=13.4,6.8Hz,1H),0.98(t,J=6.8Hz,6H)；MS(M+1)：488。
化合物4-3：3-(6-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)菸鹼醯胺基)丙酸 (3-(6-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0084-135
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.46(d,J=1.9Hz,1H),8.18(t,J=5.4Hz,1H),7.76(dd,J=8.4,1.9Hz,1H),7.68(d,J=1.9Hz,1H),7.47(dd,J=8.4,1.9Hz,1H),7.39(d,J=8.8Hz,1H),7.33(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,1H),7.02(d,J=8.8Hz,2H),6.56(d,J=8.8Hz,1H),4.31(brs,1H),4.10(d,J=4.9Hz,1H),3.35-3.32(m,2H),2.47(t,J=7Hz,2H),1.85-1.82(m,1H),1.59-1.56(m,1H),1.27-1.22(m,1H),0.95(d,J=6.8Hz,3H),0.88(t,J=6.8Hz,3H).MS(M+1)：530。
化合物4-4：3-(6-(((2S,3S)-1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)苯氧基)-3-甲基戊-2-基)胺基)菸鹼醯胺基)丙酸(3-(6-(((2S,3S)-1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenoxy)-3-methylpentan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0084-136
1H NMR(400MHz,CDCl3)：δ 8.25-8.18(d,J=9.3Hz,1 H),8.16-8.09(m,1 H),7.90(d,J=8.8Hz,2 H),7.77-7.69(m,1 H),6.90(d,J=9.3Hz,2 H),6.79-6.69(d,J=9.3Hz,1 H),4.24-4.14(m,1 H),4.13-4.07(m,1 H),3.89-3.78(m,1 H),3.75-3.60(m,2 H),2.58-2.48(m,2 H),1.94-1.82(m,1 H),1.66-1.56(m,1 H), 1.43(s,9 H),1.37-1.30(m,1 H),1.03(d,J=6.8Hz,3 H),0.93(t,J=7.3Hz,3 H).MS(M+1)：510。
化合物4-5：3-(6-(((2S,3S)-3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)戊-2-基)胺基)菸鹼醯胺基)丙酸(3-(6-(((2S,3S)-3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)pentan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0085-137
1H NMR(400MHz,CDCl3)：δ 8.19(s,1 H),8.15(d,J=8.8Hz,1 H),8.04(dd,J=2.0,7.3Hz,2 H),7.96(d,J=8.8Hz,2 H),7.73-7.65(m,1 H),7.50-7.42(m,3 H),6.91(d,J=8.8Hz,2 H),6.70(d,J=9.3Hz,1 H),4.21-4.14(m,1 H),4.14-4.08(m,1 H),3.85(br.s.,1 H),3.70-3.60(m,2 H),2.53(dd,J=4.2,6.6Hz,2 H),1.92-1.81(m,1 H),1.61(ddd,J=3.9,7.6,13.4Hz,1 H),1.35-1.25(m,1 H),1.02(d,J=6.8Hz,3 H),0.95-0.87(m,3 H).MS(M+1)：530。
實施例5：化合物5-1至5-3之合成
化合物5-1：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)硫基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)thio)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0086-591
1H NMR(400MHz,DMSO-d6)：δ 8.03(t,J=5.4Hz,1H),7.78-7.88(m,2H),7.55-7.71(m,4H),7.36-7.44(m,3H),7.23-7.36(m,2H),6.50-6.65(m,2H),6.12(d,J=9.3Hz,1H),3.46-3.70(m,1H),3.36-3.46(m,2H),3.30(dd,J=12.7,4.4Hz,1H),3.08(dd,J=12.7,8.3Hz,1H),2.43-2.49(m,2H),1.91-2.03(m,1H),0.84-1.02(m,6H).MS(M+1)：503。
化合物5-2：3-(4-(((2S,3S)-3-甲基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)硫基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)thio)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0086-139
1H NMR(400MHz,CDCl3)：δ 7.51-7.68(m,6H),7.45(d,J=8.8Hz,2H),7.32-7.41(m,2H),7.24(s,1H),6.73(br.s.,1H),6.38-6.50(m,2H),5.06(br.s.,1H),3.65(q,J=5,9Hz,2H),3.56(q,J=5.9Hz,1H),3.21(dd,J=13.2,4.4Hz,1H),3.04(dd,J=13.2,6.8Hz,1H),2.64(t,J=5.9Hz,2H),1.69-1.84(m,1H),1.37-1.61(m,1H),1.04-1.31(m,1H),0.78-0.98(m,6H).MS(M+1)：545。
化合物5-3：3-(4-(((2S,3S)-1-((4-(苯並呋喃-2-基)苯基)硫基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((4-(benzofuran-2-yl)phenyl)thio)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0087-140
1H NMR(400MHz,CDCl3)：δ 7.67-7.73(m,2H),7.46-7.57(m,4H),7.18-7.34(m,5H),6.96(d,J=1.0Hz,1H),6.65(t,J=5.6Hz,1H),6.44(d,J=8.8Hz,2H),3.65(d,J=5.9Hz,1H),3.65(d,J=16.6Hz,1H),3.49-3.60(m,1H),3.20(dd,J=13.2,4.9Hz,1H),3.02(dd,J=13.2,6.8Hz,1H),2.65(br.s.,2H),1.72-1.82(m,1H),1.47-1.59(m,1H),1.04-1.30(m,1H),0.80-0.96(m,6H).MS(M+1)：517。
實施例6：化合物6-1至6-3之合成
化合物6-1：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)(甲基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)(methyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0087-141
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.11(t,J=5.4Hz,1H),7.80(d,J=8.8Hz,2H),7.67(d,J=8.8Hz,2H),7.61-7.57(m,2H),7.29-7.21(m,3H),6.98(d,J=8.8,2H),6.80(d,J=8.8Hz,2H),4.27-4.42(m,2H),4.01-3.96(m, 1H),3.45-3.40(m,2H),2.83(s,3H),2.48(t,J=6.8,2H),2.15-2.10(m,1H),1.07(d,J=6.4Hz,3H),0.84(d,J=6,4Hz,3H)；MS(M+1)：501。
化合物6-2：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)(乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)(ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0088-142
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.10(t,J=5.4Hz,1H),7.82(d,J=8.8Hz,2H),7.66(d,J=8.8Hz,2H),7.62-7.57(m,2H),7.29-7.21(m,3H),7.01(d,J=8.8,2H),6.80(d,J=8.8Hz,2H),4.27-4.25(m,2H),4.04-3.97(m,1H),3.45-3.40(m,4H),2.83(s,3H),2.48(t,J=6.8,2H),2.15-2.12(m,1H),1.08-1.01(m,6H),0.84(d,J=6.4Hz,3H)；MS(M+1)：515。
化合物6-3：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-乙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-ethoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0088-143
1H-NMR(400MHz,DMSO-d6)：δ 12.14(s,1H),8.08-8.06(t,1H),7.87-7.84(d,1H),7.63-7.61(d,2H),7.48-7.47(d,1H),7.43-7.40(d,2H),7.30-7.22(m,2H),7.04-7.01(d,2H),6.70-6.68(d,2H),6.21-6.19(d,1H),4.17-4.08(m,2H),4.04-3.98(m,1H),3.59-3.57(d,2H),3.54-3.46(m,2H),3.43-3.38(q,2H),2.47-2.45(t,2H),1.14-1.10(t,3H),MS(M+1)：503。
實施例7：化合物7-1至7-11之合成
化合物7-1：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-difluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0089-144
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.04(t,J=5.4Hz,1H),7.70(d,J=8.8Hz,1H),7.64-7.58(m,3H),7.35(dt,J=7,1.4Hz,1H),7.31-7.27(m,1H),7.18(d,J=1Hz,1H),6.94(dd,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),6.12(d,J=8Hz,1H),4.19-4.06(m,2H),3.70-3.64(m,1H),3.43-3.38(m,2H),2.46(t,J=6.8Hz,2H),2.05-1.98(m,1H),1.01-0.96(m,6H).MS(M+1)：523。
化合物7-2：(S)-3-(4-((1-((2'-氯-2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0090-592
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.06-8.02(m,2H),7.83(d,J=8.3Hz,1H),7.70(d,J=8.3Hz,1H),7.60-7.57(m,2H),7.69-7.70(m,2H),7.12-7.07(m,2H),6.08(d,J=8.8Hz,1H),4.17-4.01(m,2H),3.69-3.64(m,1H),3.43-3.37(m,2H),2.47(t,J=7Hz,2H),2.05-1.97(m,1H),1.02-0.97(m,6H).MS(M+1)：585。
化合物7-3：(S)-3-(4-((1-((2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0090-146
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.04(t,J=5.4Hz,1H),7.83(d,J=8.8Hz,2H),7.64(d,J=8.8Hz,2H),7.59(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.38-4.34(m,1H),4.16-4.04(m,2H),3.68-3.63(m,1H),3.43-3.37(m,2H),2.46(t,J=7Hz,2H),2.05-1.96(m,1H),1.01-0.96(m,6H).MS(M+1)：551。
化合物7-4：(S)-3-(4-((3-甲基-1-((2,2',6-三氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((3-methyl-1-((2,2',6-trifluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0091-147
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.03(t,J=5.4Hz,1H),7.85(d,J=8.4Hz,1H),7.71-7.70(m,2H),7.60-7.57(m,2H),6.93(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),6.11(d,J=8.8Hz,1H),4.17-4.05(m,2H),3.68-3.65(m,1H),3.34-3.38(m,2H),2.47(t,J=7Hz,2H),1.81-1.74(m,1H),2.05-1.91(m,1H),1.01-0.97(m,6H).MS(M+1)：569。
化合物7-5：(S)-3-(4-((1-((2'-氯-2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0091-148
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.07(t,J=5.4Hz,1H),8.02(s,1H),7.80(d,J=7.8Hz,1H),7.69-7.61(m,3H),6.87(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.04-4.01(m,2H),3.87-3.83(m,1H),3.45-3.41(m,2H),2.48(t,J=7Hz,2H),1.80-1.75(m,1H),1.56-1.52(m,2H),0.94(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：599。
化合物7-6：(S)-3-(4-((1-((2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0092-149
1H NMR(400MHz,DMSO-d6)：δ 8.06(t,J=5.4Hz,1H),7.81(d,J=7.8Hz,1H),7.63-7.60(m,4H),6.85(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.02-4.01(m,2H),3.87-3.82(m,1H),3.44-3.39(m,2H),2.47(t,J=7Hz,2H),1.80-1.74(m,1H),1.56-1.47(m,2H),0.94(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：565。
化合物7-7：(S)-3-(4-((4-甲基-1-((2,2',6-三氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((2,2',6-trifluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0092-150
1H NMR(400MHz,DMSO-d6)：δ 12.2(s,1H),8.07-8.06(m,1H),7.82-7.61(m,4H),6.88(d,J=8.8Hz,2H),6.67-6.61(m,2H),6.10-6.04(m,1H),4.04-3.95(m,2H),3.86-3.81(m,1H),3.44-3.38(m,2H),2.48(t,J=7Hz,2H), 1.80-1.73(m,1H),1.56-1.46(m,2H),0.93(t,J=6.8Hz,3H),0.87(t,J=6.8Hz,3H).MS(M+1)：583。
化合物7-8：(S)-3-(4-((1-((2',4'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0093-151
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.05(t,J=5.4Hz,1H),7.78(d,J=1.9Hz,1H),7.61(d,J=8.8Hz,2H),7.54-7.44(m,2H),6.85(d,J=8.8Hz,2H),6.55-6.59(m,2H),6.09(d,J=8.8Hz,1H),4.05-4.00(m,1H),3.87-3.82(m,1H),3.44-3.39(m,2H),2.47(t,J=7Hz,2H),1.79-1.74(m,1H),1.57-1.48(m,2H),0.94(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).MS(M+1)：565。
化合物7-9：(S)-3-(4-((1-((3',5'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((3',5'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0093-152
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.05(t,J=5.4Hz,1H),7.65-7.59(m,3H),7.47-7.415(m,2H),6.84(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),6.08(d,J=8.8Hz,1H),4.03-4.00(m,2H),3.87-3.82(m,1H),3.44-3.39(m,2H),2.47(t,J=7Hz,2H),1.79-1.74(m,1H),1.56-1.47(m,2H),0.94(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：565。
化合物7-10：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二氟苯氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-difluorophenoxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0094-593
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.06(t,J=5.4Hz,1H),7.69(d,J=7.8Hz,1H),7.62-7.58(m,3H),7.36-7.26(m,2H),7.17(s,1H),6.90(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.04-3.95(m,2H),3.88-3.79(m,1H),3.42-3.39(m,2H),2.47(t,J=7Hz,2H),1.79-1.74(m,1H),1.57-1.46(m,2H),0.94(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：537。
化合物7-11：(S)-3-(4-((1-((2',4'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2',4'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0095-154
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.05(t,J=5.6Hz,1H),7.78(d,J=2.4Hz,1H),7.58(d,J=8.8Hz,2H),7.54-7.51(m,1H),7.45(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,2H),6.65(d,J=8.8Hz,2H),6.11(d,J=8.8Hz,1H),4.14-4.03(m,2H),3.68-3.62(m,1H),2.47(t,J=6.8Hz,2H),2.04-2.00(m,1H),1.00-0.95(m,6H).MS(M+1)：551。
實施例8：化合物8-1至8-25之合成
化合物8-1：(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[l,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0095-155
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.3Hz,2H)(m,2H),7.36-7.48(m,3H),7.21-7.27(m,1H),6.65-6.78(m,3H),6.59(d,J=8.3Hz,2H),4.00-4.05(m,2H),3.66(q,J=5.9Hz,2H),3.54-3.60(m,1H),2.62-2.67(m,2H),2.06-2.15(m,1H),0.99-1.06(m,6H).MS(M+1)：551。
化合物8-2：(S)-2-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸 ((S)-2-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0096-156
1H NMR(400MHz,DMSO-d6)：δ 8.11(t,J=4.9Hz,1H),7.78(d,J=9.3Hz,1H),7.64-7.71(m,2H),7.54(d,J=8.8Hz,2H),7.35-7.43(m,1H),7.00(dd,J=11.5,2.2Hz,1H),6.92(dd,J=8.8,2.4Hz,1H),6.64-6.70(m,2H),6.13(d,J=8.8Hz,1H),4.10-4.16(m,1H),4.02-4.08(m,1H),3.62-3.71(m,1H),3.46-3.54(m,2H),2.68(t,J=6.1Hz,2H),1.99-2.09(m,1H),0.99(m,6H).MS(M+1)：587。
化合物8-3：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-三氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0096-157
1H NMR(400MHz,CDCl3)：δ 7.87(t,J=8.8Hz,1H),7.53-7.62(m,3H),7.47(d,J=7.8Hz,1H),7.16-7.28(m,2H),7.05(d,J=2.9Hz,1H),6.81(t,J=5.9Hz,1H),6.72(dd,J=8.8,2.4Hz,1H),6.66(dd,J=12.7,2.4Hz,1H),6.57(d,J=8.8Hz,2H),3.99(d,J=4.4Hz,2H),3.66(q,J=5.5Hz,2H),3.52-3.58(m,1H),2.64(t,J=5.9Hz,2H),2.02-2.13(m,1H),0.96-1.03(m,6H).MS(M+1)：505。
化合物8-4：(S)-2-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0097-158
1H NMR(400MHz,DMSO-d6)：δ 8.11(t,J=5.1Hz,1H),7.87(t,J=9.0Hz,1H),7.59-7.68(m,2H),7.54(d,J=8.3Hz,2H),7.23-7.34(m,2H),7.16(d,J=2.9Hz,1H),7.04(dd,J=13.7,2.4Hz,1H),6.94(dd,J=8.8,2.4Hz,1H),6.67(d,J=8.8Hz,2H),6.14(d,J=8.8Hz,1H),4.00-4.20(m,2H),3.67(dd,J=8.6,4.6Hz,1H),3.44-3.55(m,2H),2.68(t,J=6.8Hz,2H),1.94-2.08(m,1H),0.93-1.08(m,6H).MS(M+1)：541。
化合物8-5：(S)-3-(4-((1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0097-159
1H NMR(400MHz,CDCl3)：δ 7.71(d,J=1.0Hz,1H),7.59(d,J=8.8Hz,2H),7.53(dd,J=7.8,1.0Hz,1H),7.39(d,J=7.8Hz,1H),7.16(t,J=8.6Hz,1H),6.76-6.85(m,1H),6.64-6.76(m,2H),6.59(d,J=8.8Hz,2H),4.00-4.06(m,2H),3.66(q,J=5.9Hz,2H),3.54-3.61(m,1H),2.65(t,J=5.6Hz,2H),2.08-2.16(m,1H),1.02(d,J=6.8Hz,3H),1.03(d,J=6.8Hz,3H).MS(M+1)：567。
化合物8-6：(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0098-594
1H NMR(400MHz,DMSO-d6)：δ 7.54-7.64(m,2H),7.35-7.49(m,3H),6.49-6.80(m,5H),3.79-4.03(m,3H),3.63-3.73(m,2H),2.67(t,J=5.6Hz,2H),1.44-1.88(m,3H),0.85-1.05(m,6H).MS(M+1)：565。
化合物8-7：3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0098-595
1H NMR(400MHz,CDCl3)：δ 7.87(t,J=8.6Hz,1H),7.52-7.62(m,3H),7.47(d,J=7.8Hz,1H),7.34(t,J=8.3Hz,1H),7.15-7.28(m,2H),7.05(d,J=3.4Hz,1H),6.72-6.75(m,1H),6.67(dd,J=13.0,2.2Hz,1H),6.62(dd,J=10.3,2.9Hz,1H),6.55(d,J=8.8Hz,2H),3.98-4.07(m,1H),3.89-3.97(m,1H),3.54-3.70(m,3H),2.64(t,J=5.4Hz,2H),1.74-1.90(m,1H),1.53-1.66(m,1H),1.18-1.28(m,1H),0.90-0.99(m,6H).MS(M+1)：519。
化合物8-8：3-(4-(((2S,3S)-1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0099-162
1H NMR(400MHz,CDCl3)：δ 7.71(s,1H),7.59(d,J=8.3Hz,2H),7.53(d,J=8.3Hz,1H),7.39(d,J=8.3Hz,1H),7.16(t,J=8.6Hz,1H),6.63-6.82(m,3H),6.58(d,J=8.8Hz,2H),4.01-4.11(m,2H),3.59-3.72(m,3H),2.65(t,J=5.9Hz,2H),1.80-1.90(m,1H),1.55-1.69(m,1H),1.16-1.23(m,1H),1.00(d,J=6.4Hz,3H),0.94(t,J=7.3Hz,3H).MS(M+1)：581。
化合物8-9：(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0100-163
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=8.8Hz,2H),7.44-7.46(m,1H),7.23-7.27(m,1H),7.19(d,J=8.3Hz,1H),7.10-7.16(m,1H),6.77-6.89(m,1H),6.62-6.72.(m,2H),6.57(dd,J=8.6,1.2Hz,2H),3.97-4.05(m,2H),3.66(d,J=3.4Hz,2H),3.56(q,J=4.6Hz,1H),2.61-2.67(m,2H),2.11(ddd,J=13.2,6.8,1.5Hz,1H),0.99-1.05(m,6H).MS(M+1)：533
化合物8-10：3-(4-(((2S,3S)-1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0100-164
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.8Hz,2H),7.42-7.46(m,2H),7.38(d,J=9.8Hz,1H),7.21-7.28(m,1H),6.77-6.87(m,1H),6.65-6.76(m,2H),6.57(d,J=8.8Hz,2H),4.01-4.07(m,2H),3.60-3.69(m,3H),2.64(t,J=4.9Hz,2H),1.79-1.89(m,1H),1.63(ddd,J=13.1,7.5,3.9Hz,1H),1.18-1.29(m,1H),0.98(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,2H).MS(M+1)：565。
化合物8-11：3-(4-(((2S,3S)-1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0101-165
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=8.8Hz,2H),7.45(d,J=2.0Hz,1H),7.23-7.27(m,1H),7.16-7.20(m,1H),7.13(t,J=8.3Hz,1H),6.79(t,J=5.4Hz,1H),6.62-6.72(m,2H),6.57(d,J=8.3Hz,2H),3.98-4.07(m,2H),3.59-3.70(m,3H),2.64(t,J=5.4Hz,2H),1.79-1.90(m,1H),1.64(ddd,J=13.3,7.5,3.7Hz,1H),1.17-1.28(m,1H),0.99(d,J=6.8Hz,3H),0.93(t,J=7.6Hz,3H).MS(M+1)：547。
化合物8-12：(S)-3-(4-((1-((3',5'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((3',5'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0101-166
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=8.8Hz,2H),7.34(t,J=1.5Hz,2H),7.27-7.30(m,1H),7.21-7.27(m,1H),6.77(d,J=5.4Hz,1H),6.62-6.71(m,2H),6.58(d,J=8.8Hz,2H),3.98-4.03(m,2H),3.66(q,J=5.4Hz,2H),3.53-3.59 (m,1H),2.64(t,J=5.6Hz,2H),2.05-2.14(m,1H),1.01(dd,J=6.6,4.6Hz,6H).MS(M+1)：533。
化合物8-13：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0102-168
1H NMR(400MHz,CDCl3)：δ 7.87(t,J=8.6Hz,1H),7.57(dd,J=15.9,7.6Hz,3H),7.47(d,J=8.3Hz,1H),7.17-7.27(m,2H),7.05(d,J=3.4Hz,1H),6.58-6.76(m,3H),6.55(d,J=8.3Hz,2H),3.84-3.99(m,2H),3.60-3.74(m,3H),2.62(t,J=5.6Hz,2H),1.66-1.82(m,1H),1.49-1.64(m,1H),1.23-1.42(m,4H),0.88(t,J=6.9Hz,3H).MS(M+1)：519。
化合物8-14：3-(4-(((2S,3S)-1-((2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0102-169
1H NMR(400MHz,CDCl3)：δ 7.51-7.68(m,6H),7.30(t,J=8.8Hz,1H),6.82(t,J=5.9Hz,1H),6.64-6.76(m,2H),6.52-6.61(m,2H),4.00-4.08(m,2H),3.60-3.68(m,3H),2.63(t,J=5.6Hz,2H),1.78-1.90(m,1H),1.57-1.69(m,1H),1.21-1.27(m,1H),0.90-1.00(m,6H).MS(M+1)：547.HPLC：97%。
化合物8-15：(S)-3-(4-((1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0103-170
1H NMR(400MHz,CDCl3)：δ 7.71(d,J=1.0Hz,1H),7.60(d,J=8.3Hz,2H),7.52(dd,J=8.1,1.2Hz,1H),7.39(d,J=8.3Hz,1H),7.14-7.20(m,1H),6.89(t,J=5.6Hz,1H),6.66-6.76(m,2H),6.58(d,J=8.8Hz,2H),3,95-4.03(m,2H),3.73-3.80(m,1H),3.65(q,J=5.9Hz,2H),2.63(t,J=5.6Hz,2H),1.75-1.84(m,1H),1.56-1.67(m,1H),1.31-1.49(m,4H),0.89(t,J=7.1Hz,3H).MS(M+1)：581。
化合物8-16：(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0104-171
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.3Hz,2H),7.43-7.46(m,1H),7.23-7.27(m,1H),7.17-7.21(m,1H),7.13(t,J=8.3Hz,1H),6.80-6.91(m,1H),6.63-6.73(m,2H),6.56(d,J=8.3Hz,2H),3.91-4.02(m,2H),3.71-3.80(m,1H),3.61-3.69(m,2H),2.59-2.66(m,2H),1.73-1.85(m,1H),1.55-1.66(m,1H),1.29-1.47(m,4H),0.88(t,J=7.1Hz,3H).MS(M+1)：547。
化合物8-17：(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0104-172
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.3Hz,2H),7.41-7.48(m,2H),7.38(d,J=9.8Hz,1H),7.21-7.27(m,1H),6.81-6.96(m,1H),6.66-6.77(m,2H),6.57(d,J=8.8Hz,2H),3.93-4.02(m,2H),3.72-3.80(m,1H),3.65(q,J=5.4Hz,2H),2.63(t,J=5.4Hz,2H),1.74-1.85(m,1H),1.56-1.67(m,1H),1.29-1.49(m,4H),0.88(t,J=6.8Hz,3H).MS(M+1)：565。
化合物8-18：(S)-3-(4-((1-((2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0105-173
1H NMR(400MHz,CDCl3)：δ 7.54-7.65(m,6H),7.30(t,J=8.8Hz,1H),6.86(d,J=4.9Hz,1H),6.64-6.76(m,2H),6.51-6.62(m,2H),3.88-4.02(m,2H),3.57-3.80(m,3H),2.61(br.s.,2H),1.71-1.86(m,1H),1.51-1.66(m,1H),1.27-1.46(m,4H),0.88(t,J=6.8Hz,3H).MS(M+1)：547。
化合物8-19：(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benza.mido)propanoic acid)
Figure 107102334-A0305-02-0105-174
1H NMR(400MHz,DMSO-d6)：δ 8.06(t,J=5.4Hz,1H),7.73(d,J=2.0Hz,1H),7.56-7.62(m,J=8.8Hz,2H),7.48-7.52(m,1H),7.39(d,J=8.8Hz,1H),7.21-7.29(m,1H),6.92(dd,J=11.7,2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),6.61-6.67(m,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),3.99(d,J=4.9Hz,2H),3.79-3.90(m,1H),3.36-3.43(m,2H),2.45(t,J=7.2Hz,2H),1.72-1.84(m,1H),1.50-1.57(m,2H),0.95(d,J=6.8Hz,3H),0.88(d,J=6.8Hz,3H).MS(M+1)：547。
化合物8-20：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0106-175
1H NMR(400MHz,DMSO-d6)：δ 8.08(br.s.,1H),7.88(t,J=9.0Hz,1H),7.67(dd,J=7.2,1.2Hz,1H),7.56-7.63(m,3H),7.32(td,J=7.6,1.6Hz,1H),7.23-7.29(m,1H),7.14-7.18(m,1H),7.02(dd,J=13.6,2.4Hz,1H),6.94(dd,J=8.8,2.4Hz,1H),6.64(d,J=8.8Hz,2H),6.09(d,J=8.4Hz,1H),4.02(d,J=5.4Hz,2H),3.80-3.91(m,1H),3.36-3.43(m,3H),2.43(t,J=7.2Hz,2H),1.72-1.83(m,1H),1.48-1.58(m,2H),0.95(d,J=6.8Hz,4H),0.88(d,J=6.8Hz,4H).MS(M+1)：518。
化合物8-21：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0106-176
1H NMR(400MHz,DMSO-d6)：δ 7.99-8.10(m,1H),7.85(s,1H),7.57(d,J=8.8Hz,4H),7.22-7.38(m,2H),7.12-7.18(m,1H),6.97-7.05(m,1H),6.82-6.91(m,1H),6.70(d,J=8.8Hz,2H),5.97-6.05(m,1H),4.27-4.39(m,1H),3.96-4.06(m,1H),3.60-3.78(m,1H),2.39-2.48(m,2H),1.02(s,9H).MS(M+1)：519。
化合物8-22：(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0107-177
1H NMR(400MHz,Acetone-d6)：δ 7.67(d,J=8.8Hz,2h),7.60(d,J=2.0Hz,1H),7.41-7.47(m,2H),7.38(d,1H),7.22(t,1H),6.74-6.84(m,4H),5.38(d,1H),4.41(dd,J=9.8,3.9Hz,1H),4.13(dd,J=10.0,7.1Hz,1H),3.75-3.83(m,1H),3.54-3.63(q,2H),2.61(t,J=6.8Hz,3H),1.12(s,9H).MS(M+1)：547。
化合物8-23：(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0107-178
1H NMR(400MHz,Acetone-d6)：δ 7.84-7.91(m,1H),7.56-7.80(m,4H),7.42-7.52(m,1H),7.23-7.33(m,1H),6.74-6.90(m,4H),5.31-5.44(m,1H),4.38-4.45(m,1H),4.09-4.20(m,1H),3.75-3.87(m,1H),3.53-3.65(m,2H),2.56-2.62(m,3H),1.12(s,9H).MS(M+1)：565。
化合物8-24：(S)-3-(4-((1-(3-氟-4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(3-fluoro-4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0108-179
1H NMR(400MHz,DMSO-d6)：δ 8.04(t,J=6.0Hz,1H),8.00(t,J=8.8Hz,1H),7.59(d,J=8.8Hz,2H),7.16(dd,J=13.2,2.4Hz,1H),7.02(dd,J=9.0,2.2Hz,1H),6.63(d,J=8.8Hz,2H),6.01-6.24(m,1H),4.10(d,J=5.4Hz,2H),3.74-3.89(m,1H),3.37-3.42(m,2H),2.44-2.48(m,2H),1.51-1.78(m,2H),1.23-1.47(m,5H),0.85-0.87(t,J=8.0Hz,3H).MS(M+1)：539。
化合物8-25：(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)-3-氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0109-180
1H NMR(400MHz,DMSO-d6)：δ 12.16(br.s.,1H),8.48(d,J=2.4Hz,1H),8.23-8.31(m,1H),8.20(t,J=5.4Hz,1H),8.14(d,J=7.8Hz,1H),8.06(d,J=7.8Hz,1H),7.78(dd,J=8.8,2.4Hz,1H),7.51-7.61(m,1H),7.41-7.51(m,1H),7.17(d,J=13.7Hz,1H),7.03(d,J=8.8Hz,1H),7.07(d,J=8.3Hz,1H),6.59(d,J=8.8Hz,1H),4.31(br.s.,1H),4.09-4.23(m,2H),3.38-3.46(m,2H),2.43-2.48(m,2H),1.99-2.13(m,1H),0.98(t,J=6.6Hz,6H).MS(M+1)：522。
實施例9：化合物9-1至9-6之合成
化合物9-1：(S)-3-(5-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)吡嗪基-2-甲醯胺基)丙酸((S)-3-(5-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)pyrazine-2-carboxamido)propanoic acid)
Figure 107102334-A0305-02-0109-181
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.51(d,J=1.0Hz,1H),8.27(t,J=5.8Hz,1H),8.00(d,J=1.0Hz,1H),7.83(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,1H),7.62-7.57(m,2H),7.30-7.21(m,3H),7.07(d,J=8.8Hz,2H),4.32-4.27(m,1H),4.16-4.12(m,2H),3.48-3.43(m,2H),2.48(t,J=8.8Hz,2H),2.13-2.06(m,1H),1.00-0.97(m,6H).MS(M+1)：489。
化合物9-2：3-(5-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)吡嗪基-2-甲醯胺基)丙酸(3-(5-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)pyrazine-2-carboxamido)propanoic acid)
Figure 107102334-A0305-02-0110-182
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.50(d,J=1.9Hz,1H),8.25(t,J=5.4Hz,1H),7.98(d,J=1.9Hz,1H),7.78(d,J=8.4Hz,1H),7.68(d,J=1.9Hz,1H),7.47(d,J=8.8,1.9Hz,1H),7.39(d,J=8.8Hz,1H),7.33(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),4.32(brs,1H),4.17-4.12(m,1H),3.48-3.43(m,2H),2.48(t,J=7Hz,2H),1.87-1.84(m,1H),1.59-1.55(m,1H),1.28-1.22(m,1H),0.97(d,J=6.8Hz,3H),0.89(t,J=6.8Hz,3H).MS(M+1)：531。
化合物9-3：(S)-3-(5-((3-甲基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)丁-2-基)胺基)吡啶胺基)丙酸((S)-3-(5-((3-methyl-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)butan-2-yl)amino)picolinamido)propanoic acid)
Figure 107102334-A0305-02-0110-183
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.31(t,J=6Hz,1H),8.06(d,J=1.5Hz,1H),7.82(d,J=8Hz,2H),7.76-7.73(m,3H),7.66(d,J=8Hz, 2H),7.11(dd,J=8,4Hz,1H),7.04(d,J=8Hz,1H),6.50(d,J=10Hz,1H),4.15(dd,J=10,6Hz,1H),4.04(dd,J=10,6Hz,1H),3.74-3.71(m,1H),3.46(quartet,J=6.8Hz,2H),2.48(t,J=6.8Hz,2H),2.09-2.01(m,1H),1.02-0.99(m,6H).MS(M+1)：516。
化合物9-4：(S)-3-(6-((1-((2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-((2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0111-184
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.50(d,J=2.4Hz,1H),8.22(t,J=5.6Hz,1H),7.83-7.77(m,3H),7.64(d,J=8.3Hz,2H),7.06(d,J=7.8Hz,1H),6.94(d,J=8.8Hz,2H),6.53(d,J=8.8Hz,1H),4.44(brs,1H),4.12-3.95(m,2H),3.44-3.39(m,2H),2.47(t,J=6.8Hz,2H),1.73-1.71(m,1H),1.58-1.50(m,2H),0.92(d,J=6.4Hz,3H),0.85(d,J=6.4Hz,3H).MS(M+1)：566。
化合物9-5：(S)-3-(6-((1-(4-(苯並[d]噻唑-2-基)-3-氟苯氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-(4-(benzo[d]thiazol-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0112-185
1H NMR(400MHz,DMSO-d6)：δ 12.16(br.s.,1H),8.48(d,J=2.4Hz,1H),8.23-8.31(m,1H),8.20(t,J=5.4Hz,1H),8.14(d,J=7.8Hz,1H),8.06(d,J=7.8Hz,1H),7.78(dd,J=8.8,2.4Hz,1H),7.51-7.61(m,1H),7.41-7.51(m,1H),7.17(d,J=13.7Hz,1H),7.03(d,J=8.8Hz,1H),7.07(d,J=8.3Hz,1H),6.59(d,J=8.8Hz,1H),4.31(br.s.,1H),4.09-4.23(m,2H),3.38-3.46(m,2H),2.43-2.48(m,2H),1.99-2.13(m,1H),0.98(t,J=6.6Hz,6H).MS(M+1)：523。
化合物9-6：(S)-3-(4-((1-((1-(2,4-二氟苯基)-1H-吡唑-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0112-186
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.04(t,J=5.4Hz,1H),7.89(d,J=1.9Hz,1H),7.76-7.70(m,1H),7.59-7.57(m,3H),7.52-7.47(m,1H),7.24-7.20(m,1H),6.61(d,J=8.8Hz,2H),6.07(d,J=8.8Hz,1H),3.92-3.85(m,2H),3.84-3.76(m,1H),2.46(t,J=6.8Hz,2H),1.77-1.73(m,1H),1.52-1.48(m,2H),0.93(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).MS(M+1)：487。
實施例10：化合物10-1至10-19之合成
化合物10-1：(S)-3-(4-((3-甲基-1-((6-(4-(三氟甲基)苯基)吡啶-3-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0113-187
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.38(d,J=3Hz,1H),8.21(d,J=8.8Hz,2H),8.05(t,J=5.4Hz,1H),7.99(d,J=8.8Hz,1H),7.78(d,J=8.8Hz,2H),7.61(d,J=8.8Hz,2H),7.50(dd,J=8.8,2.5Hz,1H),6.67(d,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),4.42-4.10(m,2H),3.71-3.65(m,1H),3.44-3.39(m,2H),2.48(t,J=7Hz,2H),2.07-2.02(m,1H),1.01-0.97(m,6H).MS(M+1)：516。
化合物10-2：(S)-3-(4-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0113-188
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.40(d,J=3Hz,1H),8.06-8.05(m,1H),7.94-7.92(m,1H),7.88(s,1H),7.68-7.60(m,3H),7.53-7.49(m, 1H),6.69-6.66(m,2H),6.10-6.04(m,1H),6.13(d,J=8.8Hz,1H),4.22-4.12(m,2H),3.70-3.67(m,1H),3.44-3.39(m,2H),2.48(t,J=7Hz,2H),2.09-2.03(m,1H),1.02-0.98(m,6H).MS(M+1)：550。
化合物10-3：(S)-3-(4-((1-((6-(2-氟-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0114-189
白色固體。1HNMR(400MHz,DMSO-d6)：δ 12.18(brs,1H),8.43(d,J=3Hz,1H),8.14-8.04(m,2H),7.81-7.73(m,2H),7.66-7.60(m,3H),7.52(dd,J=8.8,2.5Hz,1H),6.67(d,J=8.8Hz,2H),6.13(d,J=8.8Hz,1H),6.55-6.59(m,2H),6.09(d,J=8.8Hz,1H),4.22-4.12(m,2H),3.72-3.65(m,1H),3.45-3.40(m,2H),2.48(t,J=7Hz,2H),2.09-2.01(m,1H),1.02-0.97(m,6H).MS(M+1)：534。
化合物10-4：(S)-3-(4-((1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0114-190
1H NMR(400MHz,DMSO-d6)：δ 8.36(d,J=3Hz,1H),8.04(t,J=5.4Hz,1H),7.69(d,J=3Hz,1H),7.61-7.56(m,4H),7.51-7.47(m,2H),6.67(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.21-4.02(m,2H),3.69-3.66(m,1H),3.44-3.39(m,2H),2.47(t,J=7Hz,2H),2.07-2.02(m,1H),1.02-0.97(m,6H).MS(M+1)：516。
化合物10-5：(S)-3-(4-((1-((6-(3,5-二氯苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(3,5-dichlorophenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0115-596
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.35(d,J=3Hz,1H),8.04-8.02(m,4H),7.60-7.57(m,3H),7.51-7.48(m,1H),6.66(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.21-4.09(m,2H),3.69-3.66(m,1H),3.43-3.38(m,2H),2.47(t,J=7Hz,2H),2.07-2.03(m,1H),1.01-0.97(m,6H).MS(M+1)：516。
化合物10-6：(S)-3-(4-((1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0115-192
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.36(d,J=3Hz,1H),8.05(t,J=5.4Hz,1H),7.88(d,J=8.8Hz,1H),7.67(d,J=7.8Hz,1H),7.63-7.60(m,3H),7.52(dd,J=7.8,3Hz,1H),7.38(s,1H),7.33(dt,J=7.8,1.9Hz,1H),7.26(dt,J=7.8,1.9Hz,1H),6.67(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.22-4.01(m,2H),3.70-3.67(m,1H),3.44-3.39(m,2H),2.48(t,J=7Hz,2H),2.09-2.02(m,1H),1.02-0.97(m,6H).MS(M+1)：488。
化合物10-7：(S)-3-(4-((1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0116-193
1H NMR(400MHz,CDCl3)：δ 8.38(d,J=2.9Hz,1H),7.59(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,1H),7.43-7.47(m,2H),7.28(dd,J=8.3,2.4Hz,1H),7.21-7.26(m,1H),6.79(br.s.,1H),6.58(d,J=8.3Hz,2H),4.00-4.11(m,2H),3.79(dd,J=7.3,5.9Hz,1H),3.65(d,J=5.4Hz,2H),2.55-2.66(m,2H),1.76-1.86(m,1H),1.56-1.69(m,1H),1.30-1.50(m,4H),0.84-0.94(t,J=7.1Hz,3H).MS(M+1)：530。
化合物10-8：(S)-3-(4-((1-((6-(2-氟-4-(三氟甲基)苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0117-194
1H NMR(400MHz,CDCl3)：δ 8.40(d,J=2.9Hz,3H),7.99(t,J=8.1Hz,3H),7.70(d,J=8.8Hz,1H),7.59(d,J=8.8Hz,2H),7.45(d,J=8.3Hz,1H),7.37(d,J=10.8Hz,1H),7.20-7.26(m,1H),6.89(dt,J=11.4,5.3Hz,1H),6.52-6.62(m,2H),4.00-4.07(m,2H),3.78(br.s.,1H),3.64(d,J=5.9Hz,2H),2.61(br.s.,2H),1.74-1.86(m,1H),1.55-1.68(m,1H),1.28-1.46(m,4H),0.87(t,J=6.8Hz,3H).MS(M+1)：548。
化合物10-9：(S)-3-(4-((1-((6-(4-(三氟甲基)苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0117-195
1H NMR(400MHz,CDCl3)：δ 8.33-8.42(m,1H),7.96(d,J=7.8Hz,2H),7.53-7.71(m,5H),7.24(dt,J=5.9,2.9Hz,1H),6.81(t,J=5.9Hz,1H),6.54-6.62(m,2H),4.01-4.09(m,2H),3.78(dd,J=7.3,5.9Hz,1H),3.65(q,J=5.9Hz,2H),2.63(t,J=5.9Hz,2H),1.75-1.85(m,1H),1.57-1.69(m,1H),1.30-1.48(m,4H),0.88(t,J=7.1Hz,3H).MS(M+1)：530。
化合物10-10：(S)-3-(4-((1-((6-(3,5-二氯苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(3,5-dichlorophenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0118-597
1H NMR(400MHz,CDCl3)：δ 8.33(d,J=2.9Hz,1H),7.75(d,J=2.0Hz,2H),7.57(dd,J=13.2,8.8Hz,3H),7.30(t,J=1.7Hz,1H),7.20(dd,J=8.8,2.9Hz,1H),6.77(t,J=5.9Hz,1H),6.57(d,J=8.8Hz,2H),4.00-4.07(m,2H),3.78(dd,J=7.3,5.9Hz,1H),3.62-3.69(m,2H),2.63(t,J=5.6Hz,2H),1.74-1.87(m,1H),1.57-1.68(m,1H),1.30-1.48(m,4H),0.86-0.91(t,J=7.1Hz,3H).MS(M+1)：530。
化合物10-11：(S)-3-(4-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0118-197
1H NMR(400MHz,CDCl3)：δ 8.39(d,J=2.4Hz,1H),7.47-7.76(m,6H),7.19-7.28(m,1H),6.77-6.97(m,1H),6.57(dd,J=8.6,2.2Hz,2H), 3.96-4.12(m,2H),3.78(m,1H),3.62(m,2H),2.58(m,2H),1.72-1.85(m,1H),1.54-1.69(m,1H),1.27-1.51(m,4H),0.88(t,J=6.8Hz,3H).MS(M+1)：564。
化合物10-12：(S)-3-(4-((1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0119-198
1H NMR(400MHz,CDCl3)：δ 8.28-8.39(m,1H),7.76(td,J=8.2,4.2Hz,1H),7.44-7.66(m,4H),7.11-7.34(m,4H),6.80-7.00(m,1H),6.47-6.59(m,2H),3.92-4.02(m,2H),3.56-3.78(m,3H),2.63(br.s.,2H),1.66-1.84(m,1H),1.48-1.66(m,1H),1.23-1.40(m,4H),0.80-0.89(m,3H).MS(M+1)：502。
化合物10-13：3-(4-(((2S,3S)-1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0119-199
1H NMR(400MHz,CDCl3)：δ 8.32(d,J=2.9Hz,1H),7.76(d,J=8.8Hz,1H),7.57(t,J=7.8Hz,3H),7.48(d,J=8.3Hz,1H),7.15-7.31(m,4H),6.91 (br.s.,1H),6.54(d,J=8.3Hz,2H),4.00-4.12(m,2H),3.52-3.75(m,3H),2.64(d,J=4.9Hz,2H),1.73-1.87(m,1H),1.48-1.67(m,1H),1.10-1.23(m,1H),0.95(d,J=5.9Hz,3H),0.90(t,J=7.3Hz,3H).MS(M+1)：502。
化合物10-14：3-(4-(((2S,3S)-1-((6-(2-氟-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0120-598
1H NMR(400MHz,CDCl3)：δ 8.39(d,J=2.9Hz,1H),8.00(t,J=7.8Hz,1H),7.66-7.74(m,1H),7.58(d,J=8.8Hz,2H),7.46(d,J=8.3Hz,1H),7.37(d,J=10.8Hz,1H),7.17-7.27(m,1H),6.76-6.89(m,1H),6.57(d,J=8.3Hz,2H),4.04-4.17(m,2H),3.59-3.69(m,3H),2.62(t,J=5.1Hz,2H),1.78-1.91(m,1H),1.57-1.71(m,1H),1.16-1.29(m,1H),0.98(d,J=6.4Hz,3H),0.92(t,J=7.3Hz,3H).MS(M+1)：548.HPLC 99%。
化合物10-15：3-(4-(((2S,3S)-1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0121-201
1H NMR(400MHz,CDCl3)：δ 8.36(d,J=2.9Hz,1H),7,58(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,1H),7.43-7.47(m,2H),7.29(dd,J=8.3,2.0Hz,1H),7.22(dd,J=8.8,2.9Hz,1H),6.76(t,J=5.4Hz,1H),6.58(d,J=8.8Hz,2H),4.07-4.17(m,2H),3.60-3.69(m,3H),2.62(t,J=5.6Hz,2H),1.80-1.91(m,1H),1.65(ddd,J=13.6,7.5,3.9Hz,1H),1.19-1.29(m,1H),1.00(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：530.HPLC 99%。
化合物10-16：3-(4-(((2S,3S)-1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0121-202
1H NMR(400MHz,CDCl3)：δ 8.38(d,J=2.9Hz,1H),7.70(d,J=1.0Hz,1H),7.62-7.68(m,1H),7.53-7,62(m,4H),7.24(dt,J=5.5,2.9Hz,1H),6.77(t,J=5.6Hz,1H),6.58(d,J=8.8Hz,2H),4.07-4.18(m,2H),3.62-3.69(m,3H),2.62(t,J=5.6Hz,2H),186(qd,J=6.4,3.4Hz,1H),1.65(ddd,J=13.6,7.5,3.9Hz,1H),1.18-1.30(m,1H),1.00(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：564.HPLC 99%。
化合物10-17：(S)-3-(4-((4-甲基-1-((6-(4-(三氟甲基)苯基)吡啶-3-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0122-203
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.38(d,J=1.9Hz,1H),8.22(d,J=7.8Hz,2H),8.05-7.97(m,2H),7.79(d,J=7.8Hz,2H),7.60(d,J=8.8Hz,2H),7.51-7.48(m,1H),6.65(d,J=8.8Hz,2H),6.11(d,J=8.8Hz,1H),4.13-4.02(m,2H),3.70-3.63(m,1H),3.50-3.45(m,2H),2.64(t,J=6.8Hz,2H),2.10-1.99(m,1H),1.02-0.97(m,6H).MS(M+1)：530。
化合物10-18：(S)-3-(4-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0122-204
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.39(d,J=1.9Hz,1H),8.04(t,J=5.4Hz,1H),7.96(s,1H),7.82-7.76(m,2H),7.68(d,J=8.8Hz,1H),7.60(d,J=8.8Hz,2H),7.52-7.49(m,1H),6.65(d,J=8.8Hz,2H),6.12(d,J=8.8Hz, 1H),4.08(d,J=4.9Hz,2H),3.91-3.85(m,1H),3.42-3.37(m,2H),2.47(t,J=6.8Hz,2H),1.81-1.76(m,1H),1.58-1.54(m,2H),0.96(d,J=6.4Hz,3H),0.88(d,J=6.4Hz,3H).MS(M+1)：564。
化合物10-19：(S)-3-(4-((1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0123-599
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.36(d,J=1.9Hz,1H),8.04(t,J=5.6Hz,1H),7.70(d,J=1.9Hz,1H),7.61-7.56(m,4H),7.52-7.45(m,2H),6.64(d,J=8.8Hz,2H),6.11(d,J=8.8Hz,1H),4.08(d,J=4.9Hz,2H),3.89-3.85(m,2H),3.42-3.37(m,2H),2.45(t,J=6.8Hz,2H),1.80-1.75(m,1H),1.58-1.53(m,2H),0.95(d,J=6.4Hz,3H),0.88(d,J=6.4Hz,3H).MS(M+1)：530。
實施例11：化合物11-1至11-2之合成
化合物11-1：(S)-3-(6-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0124-206
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.47(d,J=1.9Hz,1H),8.42(d,J=3Hz,1H),8.19(t,J=5.6Hz,1H),7.96(s,1H),7.82-7.76(m,3H),7.69(d,J=8.8Hz,1H),7.58-7.55(m,1H),7.08(d,J=8.8Hz,1H),6.58(d,J=8.8Hz,1H),4.31(brs,1H),4.20-4.19(m,2H),3.34-3.39(m,2H),2.47(t,J=6.8Hz,2H),2.11-2.06(m,1H),1.00-0.97(m,6H).MS(M+1)：551。
化合物11-2：(S)-3-(6-((1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0124-207
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.49-8.48(m,1H),8.37(m,1H),8.21(t,J=5.6Hz,1H),7.88(d,J=7.8Hz,1H),7.79-7.76(m,1H),7.68-7.56(m,3H),7.38-7.24(m,3H),7.08(d,J=8.8Hz,1H),6.58(d,J=8.8Hz,1H),4.31(brs,1H),4.19-4.18(m,2H),2.48(t,J=6.8Hz,2H),2.09-2.05(m,1H),0.99-0.96(m,6H).MS(M+1)：489。
實施例12：化合物12-1至12-11之合成
化合物12-1：(S)-3-(4-((4-甲基-1-((2-(3-甲基-4-(三氟甲基)-1H-吡唑-1-基)嘧啶-5-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((2-(3-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0125-210
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.94(s,1H),8.59(s,2H),8.04(t,J=5.4Hz,1H),8.04(t,J=5.6Hz,1H),7.59(d,J=8.8Hz,2H),6.63(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.16(d,J=5.4Hz,2H),3.89-3.86(m,1H),3.42-3.37(m,2H),2.46(t,J=6.8Hz,2H),1.80-1.75(m,1H),1.57-1.52(m,2H),0.95(d,J=6.4Hz,3H),0.87(d,J=6.4Hz,3H).MS(M+1)：535。
化合物12-2：(S)-3-(4-((1-((2-(苯並呋喃-2-基)嘧啶-5-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(benzofuran-2-yl)pyrimidin-5-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0125-211
1H NMR(400MHz,DMSO-d6)：δ 8.64(s,2H),8.04(t,J=5.4Hz,1H),7.74(d,J=7.3Hz,1H),7.67(d,J=8.8Hz,1H),7.55-7.63(m,3H),7.37-7.43(m, 1H),7.27-7.34(m,1H),6.66(d,J=8.8Hz,2H),6.14(d,J=8.8Hz,1H),4.32(dd,J=10.0,4.2Hz,1H),4.23(dd,J=9.8,6.4Hz,1H),3.71(dd,J=8.8,4.4Hz,1H),2.44-2.48(m,2H),2.04(dd,J=13.2,6.4Hz,1H),1.09(t,J=7.1Hz,2H),0.99(d,J=9.3Hz,3H),1.01(d,J=9.3Hz,3H).；MS(M+1)：489。
化合物12-3：(S)-3-(4-((1-((2-(苯並呋喃-2-基)嘧啶-5-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(benzofuran-2-yl)pyrimidin-5-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0126-212
1H NMR(400MHz,DMSO-d6)：δ 8.63(s,2H),8.03-8.06(m,1H),7.74(d,J=7.3Hz,1H),7.64-7.69(m,1H),7.57-7.62(m,3H),7.37-7.43(m,1H),7.28-7.33(m,1H),6.65(d,J=9.3Hz,2H),6.13(d,J=8.8Hz,1H),4.19(d,J=4.9Hz,2H),3.84-3.94(m,1H),3.37-3.44(m,2H),2.44-2.48(m,2H),1.73-1.84(m,1H),1.55(dt,J=8.3,5.4Hz,2H),0.96(d,J=6.8Hz,3H),0.88(d,J=6.8Hz,3H).MS(M+1)：503。
化合物12-4：(S)-3-(4-((1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid
Figure 107102334-A0305-02-0127-213
1H NMR(400MHz,DMSO-d6)：δ 8.70(s,2H),7.96-8.06(m,2H),7.87-7.92(m,1H),7.81-7.87(m,1H),7.57-7.60(m,J=8.8Hz,2H),6.63-6.69(m,J=8.8Hz,2H),6.14(d,J=8.8Hz,1H),4.33(dd,J=10.0,4.2Hz,1H),4.24(dd,J=10.3,6.4Hz,1H),3.67-3.75(m,1H),3.37-3.43(m,2H),2.44-2.48(m,2H),2.00-2.10(m,1H),1.00(d,J=9.8Hz,3H),1.01(d,J=9.8Hz,3H).MS(M+1)：551。
化合物12-5：(S)-3-(4-((1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0127-214
1H NMR(400MHz,DMSO-d6)：δ 8.70(s,2H),8.01-8.07(m,1H),7.98(s,1H),7.90(d,J=7.8Hz,1H),7.83(dd,J=8.1,1.2Hz,1H),7.57-7.62(m,J=8.8Hz,2H),6.61-6.65(m,J=8.8Hz,2H),6.16(d,J=8.3Hz,1H),4.22(d,J=5.4Hz,2H),3.84(d,J=4.9Hz,1H),3.38-3.43(m,2H),2.45-2.48(m,2H),1.73(dd,J=9.0,4.2Hz,1H),1.53-1.64(m,1H),1.41-1.47(m,1H),1.32(d,J=6.8Hz,3H),0.88(t,J=7.1Hz,3H).MS(M+1)：565。
化合物12-6：(S)-3-(4-((1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0128-215
1H NMR(400MHz,DMSO-d6)：δ 8.66(s,2H),7.99-8.07(m,2H),7.67-7.75(m,2H),7.56-7.62(m,J=8.3Hz,2H),7.51-7.56(m,1H),6.62-6.69(m,J=8.8Hz,2H),4.31(dd,J=9.8,4.4Hz,1H),4.22(dd,J=10.3,6.4Hz,1H),3.39-3.43(m,4H),2.44-2.48(m,2H),2.04(dq,J=13.2,6.7Hz,1H),1.01(d,J=6.8Hz,3H),0.99(d,J=6.8Hz,3H).MS(M+1)：517。
化合物12-7：(S)-3-(4-((1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0128-216
1H NMR(400MHz,DMSO-d6)：δ 8.66(s,2H),8.04(s,2H),7.69-7.74(m,2H),7.56-7.62(m,J=8.8Hz,2H),7.52-7.56(m,1H),6.61-6.65(m,J=9.3Hz,2H),4.21(d,J=5.4Hz,2H),3.82-3.85(m,1H),3.37-3.40(m,2H),2.44-2.48 (m,2H),1.69-1.77(m,1H),1.59(td,J=9.2,5.1Hz,1H),1.1-1.50(m,1H),1.30-1.37(m,3H),0.86-0.89(m,3H).MS(M+1)：531。
化合物12-8：3-(4-(((2S)-1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0129-217
1H NMR(400MHz,DMSO-d6)：δ 8.01-8.05(m,2H),7.90(d,J=8.3Hz,1H),7.83(dd,J=8.3,1.5Hz,1H),7.55-7.63(m,J=8.8Hz,2H),6.59-6.68(m,J=8.8Hz,2H),6.19(d,J=8.8Hz,1H),4.35(dd,J=10.3,3.4Hz,1H),4.25(dd,J=10.3,6.4Hz,1H),3.69-3.79(m,1H),3.40-3.44(m,2H),2.44-2.48(m,2H),1.75-1.85(m,1H),1.68-1.57(m,1H),1.25-1.32(m,1H),0.97(d,J=6.8Hz,3H),0.91(t,J=7.3Hz,3H).MS(M+1)：565.HPLC：97.2%。
化合物12-9：(S)-3-(4-((1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0129-218
1H NMR(400MHz,DMSO-d6)：δ 7.96-8.05(m,2H),7.86-7.92(m,1H),7.78-7.86(m,1H),7.52-7.65(m,J=8.8Hz,2H),6.58-6.69(m,J=8.8Hz,2H),6.12(d,J=8.3Hz,1H),4.20(d,J=4.9Hz,2H),3.94-3.82(m,1H),3.39-3.44(m,2H),2.44-2.48(m,2H),1.71-1.86(m,1H),1.46-1.63(m,2H),0.96(d,J=6.4Hz,3H),0.88(d,J=6.4Hz,3H).MS(M+1)：565.HPLC：93.5%。
化合物12-10：3-(4-(((2S)-1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0130-219
1H NMR(400MHz,DMSO-d6)：δ 8.02(s,1H),7.69-7.74(m,2H),7.56-7.61(m,J=8.8Hz,2H),7.53(dd,J=8.3,2.0Hz,1H),6.61-6.65(m,J=8.8Hz,2H),6.19(d,J=8.8Hz,1H),4.34(dd,J=10.3,3.9Hz,1H),4.23(dd,J=10.3,6.4Hz,1H),3.69-3.77(m,1H),3.39-3.44(m,2H),2.44-2.48(m,2H),1.75-1.83(m,1H),1.55-1.65(m,1H),1.24-1.32(m,1H),0.97(d,J=6.8Hz,3H),0.91(t,J=7.3Hz,3H).MS(M+1)：531.HPLC：92.1%。
化合物12-11：(S)-3-(4-((1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0131-220
1H NMR(400MHz,DMSO-d6)：δ 8.01-8.04(m,1H),7.66-7.74(m,2H),7.55-7.63(m,J=8.8Hz,2H),7.53(dd,J=8.3,2.0Hz,1H),6.60-6.68(m,J=8.3Hz,2H),6.12(d,J=8.3Hz,1H),4.18(d,J=4.9Hz,2H),3.82-3.95(m,1H),3.37-3.43(m,2H),2.44-2.48(m,2H),1.72-1.84(m,1H),1.47-1.63(m,2H),0.96(d,J=6.8Hz,3H),0.88(d,J=6.8Hz,3H).MS(M+1)：531.HPLC：94.3%。
實施例13：化合物13-1至13-14之合成
化合物13-1：3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-甲氧基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3-methoxyphenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0131-600
1H NMR(400MHz,CDCl3)：δ 7.92(d,J=8.3Hz,1H),7.58(d,J=8.3Hz,2H),7.51-7.55(m,1H),7.45(d,J=7.8Hz,1H),7.15-7.23(m,3H),6.68(br.s.,1H),6.57(d,J=8.8Hz,2H),6.53(dd,J=8.6,2.2Hz,1H),6.49(d,J=2.0Hz,1H),4.02-4.10(m,2H),3.91(s,3H),3.64(dd,J=10.3,5.9Hz,3H),2.65(br.s.,2H),1.85(m,1H),1.63(m,1H),1.22-1.29(m,1H),0.99(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：531。
化合物13-2：3-(4-(((2S,3S)-1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0132-222
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=8.8Hz,2H),7.42(d,J=2.4Hz,1H),7.20-7.24(m,1H),7.16(d,J=7.8Hz,1H),7.02(d,J=8.8Hz,1H),6.68-6.76(m,1H),6.58(d,J=8.3Hz,2H),6.48(dq,J=4.3,2.3Hz,2H),4.02-4.09(m,2H),3.70(s,3H),3.65(dd,J=12.2,5.9Hz,3H),2.65(br.s.,2H),1.83-1.92(m,1H),1.65(br.s.,1H),1.20-1.30(m,1H),1.00(d,J=6.8Hz,3H),0.94(t,J=7.3Hz,3H).MS(M+1)：559.HPLC 95%。
化合物13-3：3-(4-(((2S,3S)-1-((2'-氯-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0132-223
1H NMR(400MHz,CDCl3)：δ 7.68(d,J=1.0Hz,1H),7.59(d,J=8.3Hz,2H),7.49(dd,J=8.1,1.2Hz,1H),7.36(d,J=8.3Hz,1H),7.04(d,J=9.3Hz, 1H),6.70-6.78(m,1H),6.59(d,J=8.8Hz,2H),6.48-6.52(m,2H),4.05-4.10(m,2H),3.71(s,3H),3.62-3.69(m,3H),2.66(br.s.,2H),1.88(d,J=5.4Hz,1H),1.66(br.s.,1H),1.23-1.29(m,1H),1.01(d,J=6.8Hz,3H),0.95(t,J=7.6Hz,3H).MS(M+1)：593.HPLC 94%。
化合物13-4：3-(4-(((2S,3S)-1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0133-224
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.3Hz,2H),7.37-7.44(m,2H),7.34(d,J=10.3Hz,1H),7.12(d,J=8.8Hz,1H),6.80-6.72(m,1H),6.58(d,J=8.8Hz,2H),6.51(dq,J=4.5,2.3Hz,2H),4.04-4.12(m,2H),3.73(s,3H),3.65(dd,J=10.8,6.4Hz,3H),2.68-2.62(m,2H),1.82-1.92(m,1H),1.61-1.70(m,1H),1.28-1.22(m,1H),1.00(d,J=6.8Hz,3H),0.94(t,J=7.3Hz,3H).MS(M+1)：577.HPLC 94%。
化合物13-5：(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-甲氧基苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-methoxyphenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0134-601
1H NMR(400MHz,CDCl3)：δ 7.92(d,J=8.3Hz,1H),7.58(d,J=8.8Hz,2H),7.50-7.55(m,1H),7.45(d,J=7.8Hz,1H),7.13-7.24(m,3H),6.70(t,J=6.1Hz,1H),6.58(d,J=8.8Hz,2H),6.54(dd,J=8.8,2.4Hz,1H),6.49(d,J=2.4Hz,1H),4.05(d,J=4.4Hz,2H),3.91(s,3H),3.63-3.70(m,2H),3.57(d,J=6.4Hz,1H),2.65(t,J=5.9Hz,2H),2.12(m,1H),1.02(dd,J=6.8,2.0Hz,6H).MS(M+1)：517。
化合物13-6：(S)-3-(4-((1-((2'-氯-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-hloro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0134-226
1H NMR(400MHz,CDCl3)：δ 7.67(d,J=1.0Hz,1H),7.59(d,J=8.8Hz,2H),7.49(dd,J=8.1,1.2Hz,1H),7.35(d,J=7.8Hz,1H),7.04(d,J=8.8Hz,1H),6.71(br.s.,1H),6.59(d,J=8.8Hz,2H),6.45-6.53(m,2H),4.06(dd,J=4.4,2.4Hz,2H),3.71(s,3H),3.63-3.69(m,2H),3.58(d,J=6.4Hz,1H),2.65(t,J=5.6Hz,2H),2.14(d,J=6.8Hz,1H),1.04(d,J=6.8Hz,6H).MS(M+1)：579.HPLC 99%。
化合物13-7：(S)-3-(4-((1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0135-228
1H NMR(400MHz,CDCl3)：δ 7.58(d,J=8.8Hz,2H),7.42(d,J=2.0Hz,1H),7.19-7.26(m,1H),7.12-7.18(m,1H),6.98-7.06(m,1H),6.75(br.s.,1H),6.58(d,J=8.8Hz,2H),6.48(dq,J=4.3,2.3Hz,2H),4.05(dd,J=4.2,2.7Hz,2H),3.70(s,3H),3.62-3.68(m,2H),3.60-3.53(m,1H),2.65(t,J=5.6Hz,2H),2.19-2.09(m,1H),1.03(d,J=6.8Hz,6H).MS(M+1)：545.HPLC 93%。
化合物13-8：(S)-3-(4-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid
Figure 107102334-A0305-02-0135-231
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.8Hz,2H),7.37-7.44(m,2H),7.33(d,J=9.8Hz,1H),7.10-7.14(m,1H),6.72-6.83(m,1H),6.59(d,J=8.8Hz,2H),6.51(dq,J=4.5,2.3Hz,2H),4.05(dd,J=4.2,1.7Hz,2H),3.73(s,3H),3.66 (q,J=5.9Hz,2H),3.61-3.55(m,1H),2.65(t,J=5.4Hz,2H),2.19-2.09(m,1H),1.03(dd,J=6.8,1.5Hz,6H).MS(M+1)：563.HPLC 97%。
化合物13-9：(S)-3-(4-((1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid
Figure 107102334-A0305-02-0136-232
1H NMR(400MHz,CDCl3)：δ 7.59(d,J=8.3Hz,2H),7.43(d,J=2.0Hz,1H),7.21-7.24(m,1H),7.15-7.18(m,1H),7.02(d,J=8.3Hz,1H),6.69(t,J=5.9Hz,1H),6.59(d,J=8.8Hz,2H),6.47-6.52(m,2H),4.01(t,J=4.9Hz,2H),3.73-3.79(m,1H),3.71(s,3H),3.67(q,J=5.9Hz,2H),2.66(t,J=5.9Hz,2H),1.77-1.87(m,1H),1.58-1.68(m,1H),1.32-1.47(m,4H),0.90(t,J=7.1Hz,3H).MS(M+1)：559.HPLC 95%。
化合物13-10：(S)-3-(4-((1-((2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid
Figure 107102334-A0305-02-0136-234
1H NMR(400MHz,CDCl3)：δ 7.53-7.62(m,6H),7.16-7.20(m,1H),6.75(br.s.,1H),6.59(d,J=8.8Hz,2H),6.49-6.53(m,2H),4.02-4.09(m,2H),3.75(s,3H),3.66(d,J=5.4Hz,2H),3.54-3.60(m,1H),2.65(br.s.,2H),2.09-2.19(m,1H),1.03(dd,J=6.8,1.5Hz,6H).MS(M+1)：545.HPLC 96%。
化合物13-11：(S)-3-(4-((1-((2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0137-235
1H NMR(400MHz,CDCl3)：δ 7.53-7.64(m,6H),7.14-7.23(m,1H),6.69(br.s.,1H),6.59(d,J=8.8Hz,2H),6.48-6.55(m,2H),4.02(t,J=4.6Hz,2H),3.76(s,3H),3.68(q,J=5.9Hz,2H),2.67(t,J=5.6Hz,2H),1.77-1.88(m,1H),1.56-1.70(m,1H),1.29-1.49(m,4H),0.90(t,J=7.Hz,3H).MS(M+1)：559。
化合物13-12：3-(4-(((2S,3S)-1-(3-甲氧基-4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(3-methoxy-4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0137-236
1H NMR(400MHz,CDCl3)：δ 8.07 (dd,J=2.4,7.3Hz,2 H),7.87(d,J=8.3Hz,1 H),7.59 (d,J=8.8Hz,2 H),7.54-7.43(m,3 H),6.86(t,J=5.9Hz,1 H),6.61-6.49(m,3 H),6.46(d,J=2.0Hz,1 H),4.15-4.05(m,2 H),3.85(s,3 H),3.69-3.61(m,3 H),2.64(t,J=5.6Hz,2 H),1.87-1.80(m,1 H),1.68-1.59(m,1 H),1.30-1.25(m,1 H),1.00(d,J=6.8Hz,3 H),0.93(t,J=7.3Hz,3 H).MS(M+1)：559.HPLC 98%。
化合物13-13：3-(4-(((2S,3S)-1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)-3-甲氧基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-3-methoxyphenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0138-237
1H NMR(400MHz,CDCl3)：δ 7.73(d,J=8.8Hz,1 H),7.57(d,J=8.8Hz,2 H),6.84-6.75(m,1 H),6.54(d,J=8.3Hz,3 H),6.43-6.37(m,1 H),4.18-4.13(m,1 H),4.07-4.03(m,1 H),3.79(s,3 H),3.71-3.59(m,3 H),2.68-2.61(m,2 H),1.89-1.77(m,1 H),1.70-1.57(m,1 H),1.43(s,9 H),1.31-1.26(m,1 H),1.00(d,J=6.8Hz,3 H),0.94(t,J=7.6Hz,3 H).MS(M+1)：539。
化合物13-14：(S)-3-(4-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0139-238
1H NMR(400MHz,CDCl3)：δ 7.60(d,J=8.8Hz,2 H),7.45-7.38(m,2 H),7.34(d,J=9.8Hz,1 H),7.13(d,J=8.3Hz,1 H),6.72-6.64(m,1 H),6.59(d,J=8.3Hz,2 H),6.54-6.49(m,2 H),4.02(t,J=4.9Hz,2 H),3.85-3.76(m,1 H),3.75(s,3 H),3.71-3.64(m,2 H),2.67(t,J=5.9Hz,2 H),1.88-1.79(m,1 H),1.70-1.58(m,1 H),1.48-1.33(m,4 H),0.90(t,J=7.1Hz,3 H).MS(M+1)：577。
實施例14：化合物14-1至14-2之合成
化合物14-1：(S)-3-(6-((1-(4-(苯並呋喃-2-基)-3-甲氧基苯氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-(4-(benzofuran-2-yl)-3-methoxyphenoxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0139-239
1H NMR(400MHz,CDCl3)：δ 8.19(d,J=8.8Hz,1 H),8.11-8.06(m,1 H),7.90(d,J=8.3Hz,1 H),7.77-7.70(m,1 H),7.51(d,J=7.3Hz,1 H),7.43(d,J=7.8Hz,1 H),7.22-7.10(m,3 H),6.74(d,J=9.3Hz,1 H),6.53(dd,J=2.0,8.8Hz,1 H),6.45(d,J=2.0Hz,1 H),4.23-4.04(m,2 H),3.89(s,3 H),3.77-3.62(m,3 H), 2.55(d,J=4.4Hz,2 H),2.22-2.08(m,1 H),1.11-1.02(m,6 H).S(M+1)：518.HPLC 99%。
化合物14-2：(S)-3-(6-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0140-241
1H NMR(400MHz,CDCl3)：δ 8.26-8.15(m,2 H),7.82-7.75(m,1 H),7.43-7.36(m,2 H),7.32(d,J=9.8Hz,1 H),7.11(d,J=7.8Hz,1 H),6.78(d,J=9.3Hz,1 H),6.52-6.47(m,2 H),4.06(dd,J=2.4,4.9Hz,2 H),3.95(d,J=3.4Hz,1 H),3.73(s,3 H),3.68(d,J=3.9Hz,2 H),2.59-2.49(m,2 H),1.86-1.78(m,1 H),1.76-1.66(m,1 H),1.51-1.35(m,4 H),0.90(t,J=6.8Hz,3 H).MS(M+1)：578.HPLC 98%。
反應流程III說明可用於合成本揭露之以下式(I)之化合物的一般步驟。
反應流程III
Figure 107102334-A0305-02-0141-242
步驟I
Figure 107102334-A0305-02-0141-244
在0℃下於溶於乾燥四氫呋喃(20mL)之氫化鈉(2.08g，52mmol)懸浮液中加入溶於乾燥四氫呋喃(60mL)之(S)-叔丁基-1-羥基-3-甲基丁-2-基胺甲酸酯((S)-tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate，9.75g，48mmol)，將反應混合物攪拌20分鐘後，加入溶於乾燥四氫呋喃(50mL)之5-溴-2-氟吡啶(7.04g，20mmol)，在室溫下攪拌至隔夜。將冰水(100mL)倒入混合物中，接著混合物以乙酸乙酯萃取，藉由迴旋蒸發(rotary evaporation)移除有機溶劑。粗反 應產物藉由管柱純化，以得到白色固體之(S)-叔丁基-1-(5-溴吡啶-2-基氧基)-3-甲基丁-2-基胺甲酸酯((S)-tert-butyl 1-(5-bromopyridin-2-yloxy)-3-methylbutan-2-ylcarbamate，7.4g，58%)。
步驟II：Suzuki偶合
Figure 107102334-A0305-02-0142-245
取(S)-叔丁基-1-(5-溴吡啶-2-基氧基)-3-甲基丁-2-基胺甲酸酯((S)-tert-butyl 1-(5-bromopyridin-2-yloxy)-3-methylbutan-2-ylcarbamate，3.7g，10.3mmol)、(4-(三氟甲基)苯基)硼酸(2.34g，12.36mmol)、碳酸鈉(2M，12mL)溶於乙醇/甲苯(12mL/40mL)中以氮氣吹30分鐘。加入四(三苯基膦)鈀(Pd(PPh3)4，0.57g，0.5mmol)並在110℃下加熱12小時，將反應混合物冷卻並以乙酸乙酯萃取，有機層以硫酸鎂乾燥並在真空下濃縮。殘餘物藉由矽膠層析法純化，以提供(S)-叔丁基-3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-基胺基甲酸酯((S)-tert-butyl 3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-ylcarbamate(3.8g，87%)。
步驟III：去質子
Figure 107102334-A0305-02-0142-246
取(S)-叔丁基-3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-基胺基甲酸酯((S)-tert-butyl 3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-ylcarbamate，3.8g，8.95mmol)懸浮於三氟醋酸(10mL，134mmol)溶於無水二氯甲烷(90mL)，在室溫下攪拌12小時，待反應完成後，逐滴加入碳酸鈉中和過量的三氟醋酸直到pH=10。接著以二氯甲烷萃取，合併有機層以無水硫酸鎂乾燥並在真空下濃縮，以得到粗產物，化合物III-d。
步驟IV：鈀-偶合(Pd-coupling)
Figure 107102334-A0305-02-0143-247
取Pd(OAc)2(0.18g，0.8mmol)、2,2'-雙二苯膦基-1,1'-聯萘(BINAP，1g，1.6mmol)、碳酸銫(1.95g，6mmol)、(S)-3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-胺((S)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-amine，1.3g，4mmol)、以及4-(三氟甲基磺醯基氧基)苯甲酸乙酯(ethyl 4-(trifluoromethylsulfonyloxy)benzoate，1.43g，4.8mmol)溶於甲苯(40mL)，以氮氣吹30分鐘，將混合物置於油浴下在100℃攪拌18小時，將混合物冷卻至環境溫度，以乙酸乙酯稀釋，以矽藻土過濾並以乙酸乙酯洗。將混合物以水和食鹽水洗、有機層以硫酸鈉乾燥並濃縮，以得到粗混合物。殘餘物藉由矽膠層析法純 化，以提供(S)-乙基-4-(3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-基胺基)苯甲酸酯((S)-ethyl 4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-ylamino)benzoate(1.8g，95%)。
步驟V：水解(Hydrolysis)
Figure 107102334-A0305-02-0144-602
取(S)-乙基-4-(3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-基胺基)苯甲酸酯((S)-ethyl 4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-ylamino)benzoate(1.8g，4mmol)溶於1,4-二噁烷(40mL)，接著加入氫氧化鋰(20mL)，將反應混合物於油浴下在100℃攪拌至隔夜，反應藉由薄層層析法(TLC)監控，待反應完成後，以迴旋蒸發移除溶劑，並添加鹽酸(1.0M，15mL)至混合物中，藉由抽氣過濾(suction filtration)收集白色固體，並提供(S)-4-(3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-基胺基)苯甲酸((S)-4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-ylamino)benzoic acid，1.7g，100%)。
步驟VI：醯胺化
Figure 107102334-A0305-02-0144-250
取化合物(S)-4-(3-甲基-1-(5-(4-(三氟甲基)苯基)吡啶-2-基氧基)丁-2-基胺基)苯甲酸((S)-4-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)pyridin-2-yloxy)butan-2-ylamino)benzoic acid，0.66g，1.5mmol)、(EtCO2CH2CH2)NH2HCl、1-乙基-(3-二甲基氨基丙基)碳醯二亞胺(EDCI，0.58g)、以及羥基苯並三唑(HOBt，0.3g)溶於二甲基甲醯胺(DMF，9mL)，接著加入三乙胺(0.4mL)，將混合物於室溫下攪拌至隔夜，以TLC監控，於混合物中加入水、碳酸氫鈉水溶液，並以乙酸乙酯萃取，有機層以硫酸鎂乾燥，接著藉由迴旋蒸發移除溶劑，殘餘物藉由矽膠層析法純化，以提供化合物III-h(0.8g，100%)。
步驟VII：水解(選擇性)
Figure 107102334-A0305-02-0145-251
取化合物III-h(0.8g，1.47mmol)溶於四氫呋喃/甲醇(7.5/7.5mL)，接著加入氫氧化鋰(7.5mL)，將反應混合物在室溫下攪拌至隔夜，反應藉由TLC監控，待反應完成後，藉由迴旋蒸發移除溶劑，並加入鹽酸(1.0M，5mL)至混合物，節油抽氣過濾收集白色固體，並提供化合物III-i(0.4g，53%)。
實施例15：化合物15-1至15-37之合成
化合物15-1：(S)-N-((2H-四唑-5-基)甲基)-4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺 ((S)-N-((2H-tetrazol-5-yl)methyl)-4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamide)
Figure 107102334-A0305-02-0146-252
1H NMR(400MHz,DMSO-d6)：δ 8.69-8.76(m,2H),8.22(dd,J=8.8,2.4Hz,1H),7.58-7.67(m,4H),7.50(d,J=7.3Hz,2H),7.24-7.42(m,6H),7.06(d,J=7.8Hz,1H),6.98(d,J=8.8Hz,1H),6.62(d,J=8.3Hz,2H),4.96-5.03(m,1H),4.67(d,J=5.4Hz,2H),4.50-4.62(m,2H).MS(M+1)：532。
化合物15-2：(S)-N-((1H-四唑-5-基)甲基)-4-((3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamide)
Figure 107102334-A0305-02-0146-603
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.69(t,J=5.5Hz,1H),8.56(d,J=2.5Hz,1H),8.08(dd,J=8.8,2.5Hz,1H),7.90(d,J=8.8Hz,2H),7.81(d,J=8.8Hz,2H),7.64(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,2H),6.18(d,J=8.8Hz,1H),4.67(d,J=6Hz,2H),4.42-4.33(m,2H),3.76-3.70(m,1H),2.05-1.91(m,1H),1.02-0.97(m,6H).MS(M+1)：526。
化合物15-3：(S)-3-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0147-604
1H NMR(400MHz,DMSO-d6)：δ 8.72(d,J=2.4Hz,1H),8.17(dd,J=8.6,2.7Hz,1H),8.06(t,J=5.4Hz,1H),7.54-7.70(m,4H),7.20-7.35(m,2H),6.90(d,J=8.8Hz,1H),6.68(d,J=8.3Hz,2H),6.09(d,J=8.8Hz,1H),4.30-4.46(m,2H),3.64-3.76(m,1H),3.42(q,J=6.8Hz,2H),2.48(t,J=6.8Hz,2H),2.06-1.96(m,1H),0.92-1.07(m,6H).MS(M+1)：488。
化合物15-4：(S)-3-(4-((2-((5-(4-(叔丁基)苯基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(4-(tert-butyl)phenyl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0147-255
1H NMR(400MHz,CDCl3)：δ 8.36(d,J=2.4Hz,1H),7.78(dd,J=8.6,2.7Hz,1H),7.40-7.49(m,8H),7.22-7.36(m,3H),6.80(d,J=9.3Hz,2H),6.46 (d,J=8.8Hz,2H),4.73-4.86(m,1H),4.51-4.63(m,2H),3.61(s,1H),3.60(s,1H),2.59(t,J=5.9Hz,2H),1.34(s,9H).MS(M+1)：538。
化合物15-5：(S)-3-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0148-256
1H NMR(400MHz,DMSO-d6)：δ 12.14(br.s.,1H),8.74(d,J=2.4Hz,1H),8.20(ddt,J=8.6,4.4,2.3Hz,1H),8.03(dd,J=7.1,4.6Hz,1H),7.48-7.66(m,6H),7.23-7.40(m,6H),6.93-7.05(m,2H),6.57-6.64(m,2H),4.93-5.01(m,1H),4.49-4.61(m,2H),4.00-4.05(m,1H),3.25-3.49(m,4H),2.42-2.53(m,3H),1.98(s,1H),1.1-1.32(m,1H).MS(M+1)：522。
化合物15-6：(R)-3-(4-(((S)-2-((5-(4-(叔丁基)苯基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)-2-羥基丙酸(R)-3-(4-(((S)-2-((5-(4-(tert-butyl)phenyl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamido)-2-hydroxypropanoic acid
Figure 107102334-A0305-02-0148-257
1H NMR(400MHz,CDCl3)：δ 8.37(br.s.,1H),7.79(d,J=7.3Hz,1H),7.39-7.57(m,8H),7.13-7.39(m,4H),6.62-6.88(m,2H),6.46(d,J=7.8Hz,2H),4.83(br.s.,1H),4.48-4.70(m,2H),4.30(br.s.,1H),3.85(d,J=13.7Hz,1H),3.73(d,J=13.7Hz,1H),1.34(s,9H).MS(M+1)：554。
化合物15-7：(S)-3-(4-((3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0149-258
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.56(d,J=3Hz,1H),8.07-8.04(m,2H),7.88(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),7.59(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.40-4.32(m,2H),3.86-3.67(m,1H),3.41(quartet,J=8Hz,2H),2.45(t,J=8Hz,2H),2.06-1.98(m,1H),1.01-0.96(m,6H).MS(M+1)：516。
化合物15-8：(R)-2-羥基-3-(4-(((S)-3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((R)-2-hydroxy-3-(4-(((S)-3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0150-259
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.54(d,J=2.5Hz,1H),8.15(brs,1H),8.07-8.04(m,1H),7.88(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7.67(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,1H),6.68(d,J=8.8Hz,2H),6.17(d,J=8.8Hz,1H),4.40-4.32(m,2H),4.04(pseudo-brs,1H),3.72-3.66(m,2H),3.42-3.37(m,1H),2.03-1.97(m,1H),1.00-0.95(m,6H).MS(M+1)：532。
化合物15-9：(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0150-260
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.27(d,J=2Hz,1H),8.10(brs,1H),7.99(d,J=0.9Hz,1H),7.90-7.78(m,3H),7.68(d,J=8.3Hz,1H),7.58(d,J=8.8Hz,2H),6.69(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.40-4.33(m,2H),3.75-3.68(m,1H),3.40-3.35(m,2H),3.38(t,J=6.8Hz,2H),2.05-1.95(m,1H),1.01-0.96(m,6H).MS(M+1)：551。
化合物15-10：(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0151-261
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.26(d,J=2.4Hz,1H),8.03-7.98(m,3H),7.85(dd,J=8.8,2.4Hz,1H),7.80(d,J=8Hz,1H),7.68(d,J=8Hz,1H),7.59(d,J=8.8Hz,1H),6.90(d,J=8.8Hz,2H),6.66(d,J=8.8Hz,2H),6.06(d,J=8.8Hz,1H),4.36-4.32(m,1H),4.24-4.20(m,1H),3.91-3.88(m,1H),3.40-3.35(m,2H),2.46(t,J=7Hz,2H),1.79-1.74(m,1H),1.54-1.50(m,2H),0.94(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).MS(M+1)：564。
化合物15-11：(S)-3-(4-((4-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0151-262
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.56(d,J=2.5Hz,1H),8.09(dd,J=8.4,2.5Hz,1H),8.02(t,J=5.4Hz,1H),7.90(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),7.60(d,J=8.8Hz,2H),6.91(d,J=8.4Hz,1H),6.68(d,J=8.8Hz,2H),6.06(d,J=8.4Hz,1H),4.38-4.34(m,1H),4.24-4.20(m,1H),3.92-3.86(m,1H),3.43-3.38(m,2H),2.46(t,J=7Hz,2H),1.81-1.74(m,1H),1.54-1.50(m,2H),0.94(d,J=6.3Hz,3H),0.84(d,J=6.3Hz,3H).MS(M+1)：530。
化合物15-12：3-(4-(((2S,3S)-3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0152-263
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.57(d,J=2.5Hz,1H),8.09(dd,J=8.4,2.5Hz,1H),8.10-8.07(m,2H),7.90(d,J=7.8Hz,2H),7.80(d,J=7.8Hz,2H),7.58(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,2H),6.05(d,J=8.4Hz,1H),4.38-4.34(m,1H),4.23-4.19(m,1H),3.91-3.88(m,1H),3.39-3.35(m,2H),2.38-2.33(m,2H),1.80-1.75(m,1H),1.54-1.50(m,1H),0.94(d,J=6.4Hz,3H),0.84(d,J=6.4Hz,3H).MS(M+1)：530。
化合物15-13：3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0153-264
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.26(d,J=2.5Hz,1H),8.00-7.95(m,2H),7.85(dd,J=8.4,2.5Hz,1H),7.80(d,J=8.4Hz,1H),7.68(d,J=8.3Hz,1H),7.60(d,J=8.3Hz,2H),6.90(d,J=8.3Hz,1H),6.66(d,J=8.3Hz,2H),6.05(d,J=8.3Hz,1H),4.36-4.32(m,1H),4.24-4.20(m,1H),3.91-3.88(m,1H),3.42-3.40(m,2H),2.37(brs,2H),1.80-1.74(m,1H),1.54-1.50(m,1H),0.94(d,J=6.4Hz,3H),0.84(d,J=6.4Hz,3H).MS(M+1)：564。
化合物15-14：3-(4-(((2S,3S)-1-((5-(2-氟-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0153-265
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.41(brs,1H),8.15-8.07(m,1H),7.97-7.94(m,1H),7.83-7.79(m,2H),7.68-7.66(m,1H),7.59-7.57 (m,2H),6.93(d,J=8.3Hz,1H),6.67(d,J=8.3Hz,2H),6.05(d,J=8.3Hz,1H),4.38-4.34(m,1H),4.24-4.20(m,1H),3.91-3.86(m,1H),3.43-3.34(m,2H),2.39-2.33(m,2H),1.79-1.74(m,1H),1.54-1.50(m,1H),0.94(d,J=6.4Hz,3H),0.83(d,J=6.4Hz,3H).MS(M+1)：548。
化合物15-15：3-(4-(((2S,3S)-1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0154-266
1H NMR(400MHz,DMSO-d6)：δ 8.72(d,J=2.4Hz,1H),8.18(dd,J=8.8,2.4Hz,1H),8.03(t,J=5.6Hz,1H),7.50-7.71(m,4H),7.19-7.35(m,2H),6.90(d,J=8.8Hz,1H),6.64(d,J=8.8Hz,2H),6.15(d,J=8.8Hz,1H),4.27-4.52(m,2H),3.75(dt,J=13.0,6.2Hz,1H),3.38-3.45(m,2H),2.45-2.50(m,2H),1.69-1.84(m,1H),1.51-1.68(m,1H),1.18-1.37(m,1H),0.95(d,J=6.8Hz,3H),0.90(t,J=7.3Hz,2H).MS(M+1)：502。
化合物15-16：(S)-3-(4-((1-((5-(2-氟-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0155-267
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.41(s,1H),8.03(t,J=5.4Hz,1H),7.85(dt,J=8.4,1.9Hz,1H),7.94-7.79(m,2H),7.68(d,J=8.4Hz,1H),7.60(d,J=8.8Hz,2),6.93(d,J=8.8Hz,1),6.67(d,J=8.8Hz,2H),6.08(d,J=8.8Hz,1H),4.38-4.34(m,1H),4.24-4.20(m,1H),3.92-3.86(m,1H),3.34-3.38(m,2H),2.46(t,J=7Hz,2H),1.81-1.74(m,1H),1.54-1.50(m,2H),0.94(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H).MS(M+1)：548。
化合物15-17：(S)-3-(4-((1-((5-(2,4-二氯苯基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0155-268
1H NMR(400MHz,CDCl3)：δ 8.13(d,J=2.0Hz,2H),7.61(dd,J=8.3,2.4Hz,1H),7.55(d,J=8.3Hz,2H),7.46(d,J=2.0Hz,1H),7.23-7.29(m,1H),7.18-7.22(m,1H),6.80(t,J=5.6Hz,1H),6.72(d,J=8.8Hz,1H),6.57(d,J=8.8Hz,2H), 4.43-4.49(m,1H),4.32-4.38(m,1H),3.59-3.70(m,3H),2.62(t,J=5.6Hz,2H),1.98-2.13(m,1H),1.01(t,J=6.4Hz,6H).MS(M+1)：516。
化合物15-18：(S)-2-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0156-269
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.27(d,J=2.5Hz,1H),8.08(t,J=4.9Hz,1H),7.99(s,1H),7.85(dd,J=8.8,2.4Hz,2H),7.69(d,J=8Hz,1H),7.53(d,J=8Hz,2H),6.91(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.36-4.33(m,1H),4.25-4.21(m,1H),3.92-3.85(m,1H),3.50-3.45(m,2H),2.64(t,J=7Hz,2H),1.81-1.74(m,1H),1.55-1.50(m,2H),0.94(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).MS(M+1)：600。
化合物15-19：(S)-3-(4-((4-甲基-1-((5-(6-(三氟甲基)嗒嗪-3-基)吡啶-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((5-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0157-270
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 9.05(d,J=2.4Hz,1H),8.58-8.54(m,2H),8.34(d,J=8.8Hz,1H),8.04(t,J=5.6Hz,1H),7.60(d,J=8.8Hz,2H),7.01(d,J=8.8,3Hz,1H),6.68(d,J=8.8Hz,2H),6.10(d,J=8.8Hz,1H),4.43-4.26(m,2H),3.96-3.89(m,1H),3.42-3.37(m,2H),2.46(t,J=6.8Hz,2H),1.82-1.75(m,1H),1.59-1.48(m,2H),0.95(d,J=6.4Hz,3H),0.85(d,J=6.4Hz,3H).MS(M+1)：532。
化合物15-20：3-(4-(((2S,3S)-1-((5-(2,4-二氟苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0157-605
1H NMR(400MHz,CDCl3)：δ 8.23(s,1H),7.67(dt,J=8.8,2.0Hz, 1H),7.55(d,J=8.3Hz,2H),7.31(td,J=8.6,6.4Hz,1H),6.82-6.97(m,2H),6.67-6.80(m,2H),6.56(d,J=8.8Hz,2H),4.33-4.51(m,3H),3.61-3.74(m,3H), 2.64(t,J=5.9Hz,2H),1.74-1.86(m,1H),1.59-1.70(m,1H),1.17-1.30(m,1H),0.98(d,J=6.8Hz,3H),0.93(t,J=7.3Hz,3H).MS(M+1)：498。
化合物15-21：2-(4-(((2S,3S)-1-((5-(2,4-二氟苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸(2-(4-(((2S,3S)-1-((5-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0158-272
1H NMR(400MHz,DMSO-d6)：δ 8.31(s,1H),8.08(t,J=5.1Hz,1H),7.81-7.87(m,1H),7.49-7.64(m,3H),7.29-7.43(m,1H),7.12-727(m,1H),6.87(d,J=9.3Hz,1H),6.64(d,J=8.8Hz,2H),6.16(d,J=8.8Hz,1H),4.26-4.47(m,2H),3.73(dd,J=7.8,5.4Hz,1H),3.43-3.54(m,2H),2.66(t,J=6.8Hz,2H),1.71-1.80(m,1H),1.60(ddd,J=13.3,7.5,4.2Hz,1H),1.17-1.31(m,1H),0.94(d,J=6.8Hz,3H),0.90(t,J=7.3Hz,3H).MS(M+1)：534。
化合物15-22：(S)-3-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0159-606
1H NMR(400MHz,CDCl3)：δ 8.61(d,J=2.4Hz,1H),7.95(dt,J=8.7,2.0Hz,1H),7.43-7.62(m,4H),7.14-7.31(m,2H),6.80-6.98(m,2H),6.75(d,J=8.8Hz,1H),6.57(d,J=8.3Hz,2H),4.36-4.47(m,1H),4.27(dd,J=10.5,4.6Hz,1H),3.76(d,J=4.9Hz,1H),3.64(d,J=5.9Hz,2H),2.62(t,J=5.1Hz,2H),1.67-1.78(m,1H),1.48-1.63(m,1H),1.25-1.45(m,4H),0.86(t,J=6.8Hz,3H).MS(M+1)：502。
化合物15-23：(S)-2-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0159-274
1H NMR(400MHz,DMSO-d6)：δ 8.72(d,J=2.4Hz,1H),8.20(dd,J=8.3,2.4Hz,1H),7.54-7.67(m,4H),7.39(s,1H),7.19-7.35(m,2H),6.93(d,J=8.8Hz,1H),6.86(br.s.,2H),6.76(d,J=6.8Hz,2H),4.39(dd,J=10.8,5.4Hz,1H),4.24(dd,J=10.8,5.9Hz,1H),3.77-3.86(m,1H),3.51(t,J=7.1Hz,2H),2.66-2.75(m,2H), 1.65-1.78(m,1H),1.58(td,J=8.7,4.2Hz,1H),1.19-1.45(m,4H),0.84(t,J=7.1Hz,3H).MS(M+1)：538。
化合物15-24：(S)-3-(4-((1-((5-(2,4-二氯苯基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0160-275
1H NMR(400MHz,CDCl3)：δ 8.13(d,J=2.0Hz,1H),7.62(dd,J=8.8,2.4Hz,1H),7.56(d,J=8.3Hz,2H),7.45(d,J=2.0Hz,1H),7.23-7.29(m,1H),7.18-7.22(m,1H),6.90(t,J=5.9Hz,1H),6.75(d,J=8.8Hz,1H),6.57(d,J=8.8Hz,2H),4.42(dd,J=10.8,4.9Hz,1H),4.28(dd,J=10.3,4.9Hz,1H),3.78(m,J=6.1Hz,1H),3.63(q,J=5.9Hz,2H),2.61(t,J=5.9Hz,2H),1.69-1.80(m,1H),1.52-1.62(m,1H),1.28-1.44(m,4H),0.86(t,J=7.1Hz,3H).MS(M+1)：530。
化合物15-25：(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0161-276
1H NMR(400MHz,CDCl3)：δ 8.18(d,J=2.0Hz,1H),7.71(d,J=1.0Hz,1H),7.67(dd,J=8.3,2.4Hz,1H),7.52-7.60(m,3H),7.40(d,J=7.8Hz,1H),6.88(t,J=5.9Hz,1H),6.78(d,J=8.3Hz,1H),6.58(d,J=8.8Hz,2H),4.44(dd,J=10.8,4.9Hz,1H),4.30(dd,J=10.8,4.9Hz,1H),3.76-3.83(m,1H),3.64(q,J=5.9Hz,2H),2.62(t,J=5.9Hz,2H),1.69-1.81(m,1H),1.53-1.65(m,1H),1.30-1.48(m,4H),0.87(t,J=7.1Hz,3H).MS(M+1)：564。
化合物15-26：(S)-3-(4-((1-((5-(2-氟-4-(三氟甲基)苯基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0161-277
1H NMR(400MHz,CDCl3)：δ 8.30(d,J=1.5Hz,1H,7.74(dt,J=8.7,2.0Hz,1H),7.57(d,J=8.3Hz,2H),7.43-7.51(m,2H),7.39(d,J=10.3Hz,1H),6.90(t,J=5.9Hz,1H),6.79(d,J=8.3Hz,1H),6.58(d,J=8.8Hz,2H),4.44(dd,J=10.8,4.9Hz,1H),4.29(dd,J=10.8,5.4Hz,1H),3.79(t,J=6.4Hz,1H),3.64(q,J= 5.5Hz,2H),2.61(t,J=5.6Hz,2H),1.71-1.81(m,1H),1.52-1.63(m,1H),1.24-1.48(m,4H),0.86(t,J=7.3Hz,3H).MS(M+1)：548.HPLC：97%。
化合物15-27：(S)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-2-((5-(三氟甲基)吡啶-2-基)氧基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0162-278
1H NMR(400MHz,DMSO-d6)：δ 12.13(br.s.,1H),8.57-8.63(m,1H),8.07(dd,J=8.8,2.4Hz,1H),8.01(t,J=5.6Hz,1H),7.84-7.93(m,J=7.8Hz,2H),7.75-7.83(m,J=8.3Hz,2H),7.68-7.75(m,J=8.3Hz,2H),7.59-7.67(m,J=8.8Hz,2H),7.48-7.58(m,J=8.8Hz,2H),6.97-7.08(m,2H),6.56-6.65(m,J=8.8Hz,2H),4.99-5.11(m,1H),4.53-4.66(m,2H),3.35-3.43(m,2H),2.44(t,J=7.1Hz,2H).MS(M+1)：618。
化合物15-28：(S)-2-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0163-279
1H NMR((400MHz,DMSO-d6)：δ 8.75(d,J=2.4Hz,1H),8.22(dd,J=8.8,2.4Hz,1H),8.08(t,J=5.1Hz,1H),7.84-7.92(m,J=8.3Hz,2H),7.76-7.83(m,J=8.8Hz,2H),7.70-7.76(m,2H),7.60-7.67(m,4H),7.44-7.53(m,J=8.8Hz,2H),7.41(s,1H),7.21-7.36(m,2H),7.05(d,J=7.3Hz,1H),7.01(d,J=8.8Hz,1H),6.58-6.68(m,J=8.8Hz,2H),5.00-5.11(m,1H),4.52-4.67(m,2H),3.44(q,J=6.4Hz,2H),2.60(t,J=7.1Hz,2H).MS(M+1)：702.HPLC純度：98%。
化合物15-29：(S)-3-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0163-282
1H NMR((400MHz,DMSO-d6)：δ 12.13(br.s.,1H),8.75(d,J=2.4Hz,1H),8.23(dd,J=8.8,2.4Hz,1H),8.02(t,J=5.4Hz,1H),7.84-7.92(m,J=7.8Hz,2H),7.76-7.82(m,J=8.3Hz,2H),7.69-7.76(m,2H),7.59-7.67(m,4H),7.51-7.58(m,J=8.8Hz,2H),7.41(s,1H),7.22-7.36(m,2H),6.96-7.08(m,2H),6.56-6.67(m,J=8.8Hz,2H),5.06(q,J=6.8Hz,1H),4.52-4.64(m,2H),3.35-3.41(m,2H),2.44(t,J=7.3Hz,2H).MS(M+1)：666.HPLC純度：99%。
化合物15-30：(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0164-283
1H NMR(400MHz,CDCl3)：δ 8.80(d,J=2.4Hz,1 H),8.23-8.14(m,1 H),7.63(s,4 H),7.57-7.48(m,6 H),6.85(d,J=8.8Hz,1 H),6.79-6.69(m,1 H),6.50(d,J=8.3Hz,2 H),4.94-4.84(m,1 H),4.73-4.58(m,2 H),3.65-3.54(m,2 H),2.63-2.53(m,2 H),1.46(s,9 H).MS(M+1)：674。
化合物15-31：(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2'-flu oro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0164-284
1H NMR(400MHz,CDCl3)：δ 8.81(d,J=2.4Hz,1 H),8.24-8.18(m,1 H),7.59-7.48(m,7 H),7.48-7.36(m,2 H),6.88(d,J=8.8Hz,1 H),6.66-6.56 (m,1 H),6.53(d,J=8.8Hz,2 H),5.33-5.25(m,1 H),4.95-4.87(m,1 H),4.75-4.59(m,2 H),4.11(q,J=7.1Hz,2 H),3.63(q,J=5.9Hz,2 H),2.56(t,J=5.9Hz,2 H),1.47(s,9 H),1.22(t,J=7.3Hz,3 H).MS(M+1)：720.HPLC 97.8%。
化合物15-32：(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic)
Figure 107102334-A0305-02-0165-607
1H NMR(400MHz,CDCl3)：δ 8.79(d,J=2.4Hz,1 H),8.22-8.14(m,1 H),7.55-7.46(m,7 H),7.46-7.41(m,1 H),7.40-7.34(m,1 H),6.85(d,J=8.8Hz,1 H),6.81-6.71(m,1 H),6.50(d,J=8.8Hz,2 H),4.94-4.82(m,1 H),4.75-4.57(m,2 H),3.65-3.52(m,2 H),2.64-2.51(m,2 H),1.45(s,9 H).MS(M+1)：692.HPLC 96.4%。
化合物15-33：(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2',4'-二氯-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0166-286
1H NMR(400MHz,CDCl3)：δ 8.81(s,1 H),8.26-8.16(m,1 H),7.57-7.43(m,5 H),7.39(d,J=8.3Hz,2 H),7.32-7.20(m,2 H),6.88(d,J=9.3Hz,1 H),6.64-6.57(m,1 H),6.54(d,J=8.8Hz,2 H),5.26-5.19(m,1 H),4.96-4.86(m,1 H),4.78-4.61(m,2 H),4.12(d,J=6.8Hz,2 H),3.67-3.59(m,2 H),2.56(s,2 H),1.47(s,9 H),1.23(t,J=7.1Hz,3 H).MS(M+1)：702。
化合物15-34：(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2',4'-二氯-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0166-608
1H NMR(400MHz,CDCl3)：δ 8.80(d,J=2.0Hz,1 H),8.26-8.12(m,1 H),7.54-7.45(m,5 H),7.38(d,J=8.3Hz,2 H),7.25-7.23(m,2 H),6.86(d,J=8.8Hz,1 H),6.64-6.59(m,1 H),6.52(d,J=8.3Hz,2 H),4.92-4.88(m,1 H),4.74-4.62(m,2 H),3.67-3.61(m,2 H),2.63(s,2 H),1.47(s,9 H).MS(M+1)：674。
化合物15-35：(S)-2-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4-(5-甲氧基嘧啶-2-基)苯基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸 ((S)-2-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4-(5-methoxypyrimidin-2-yl)phenyl)ethyl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0167-288
1H NMR(400MHz,DMSO-d6)：δ 12.29(br.s.,1H),8.74(d,J=2.4Hz,1H),8.63(s,2H),8.27(d,J=8.3Hz,2H),8.22(dd,J=8.3,2.4Hz,1H),8.08(t,J=5.4Hz,1H),7.57-7.67(m,4H),7.44-7.53(m,J=8.8Hz,2H),7.39-7.43(m,1H),7.21-7.34(m,2H),7.10(d,J=7.3Hz,1H),6.99(d,J=9.3Hz,1H),6.58-6.66(m,J=8.8Hz,2H),4.99-5.08(m,1H),4.52-4.67(m,2H),3.94(s,3H),3.40-3.49(m,2H),2.61-2.79(m,2H),MS(M+1)：666。
化合物15-36：(S)-3-(4-((1-((5-(苯並[d]噻唑-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((5-(benzo[d]thiazol-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0167-289
白色固體。1H-NMR(DMSO-d6,400MHz)：δ 8.81(d,J=1.6Hz,1H),8.27(dd,J=8.8,2.9Hz,1H),8.04(d,J=8.3Hz,1H),7.89(d,J=8.3Hz,1H),7.60(d,J=8.8Hz,2H),7.51-7.46(m,1H),7.47-7.36(m,1H),6.80(d,J=8.8Hz,1H),6.63(d,J=8.8Hz,2H),4.57(dd,J=11.2,5.8Hz,1H),4.43(dd,J=10.7,5.4Hz,1H), 4.22(d,J=8.8Hz,1H),4.15(q,J=8.8Hz,2H),3.71-3.66(m,3H),2.61(t,J=6.8Hz,2H),2.12-2.08(m,1H),1.28(t,J=6.8Hz,3H),1.06(t,J=6.8Hz,3H),0.82(t,J=6.8Hz,3H).MS(M+1)：533。
化合物15-37：(S)-3-(4-((1-((5-(苯並[d]噻唑-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzo[d]thiazol-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0168-290
白色固體。1H-NMR(DMSO-d6,400MHz)：δ 8.87(d,J=1.9Hz,1H),8.34(dd,J=8.8,5.4Hz,1H),8.14(d,J=8.8Hz,1H),8.05-8.02(m,2H),7.59-7.44(m,4H),6.95(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,2H),6.09(d,J=8.8Hz,1H),4.46-4.37(m,3H),3.75-3.69(m,2H),2.46(t,J=6.8Hz,2H),2.05-2.00(m,1H),1.01-0.97(m,6H).MS(M+1)：505。
實施例16：化合物16-1至16-2之合成
化合物16-1：(S)-3-(6-((1-((5-(2,4-二氯苯基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-((5-(2,4-dichlorophenyl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0169-609
1H NMR(400MHz,CDCl3)：δ 8.09-8.21(m,4H),7.78(t,J=4.9Hz,1H),7.57-7.61(m,1H),7.44(d,J=2.0Hz,1H),7.23-7.29(m,1H),7.19(d,J=8.3,1H),6.78(d,J=9.3Hz,1H),6.67(d,J=8.8Hz,1H),4.51-4.57(m,1H),4.42(dd,J=11.2,7.3Hz,1H),3.80(br.s.,1H),3.63-3.71(m,2H),2.54(dd,J=7.1,4.2Hz,2H),2.05-2.18(m,1H),1.07(t,J=6.4Hz,6H).MS(M+1)：517。
化合物16-2：(S)-3-(6-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)菸鹼醯胺基)丙酸((S)-3-(6-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)nicotinamido)propanoic acid)
Figure 107102334-A0305-02-0169-292
1H NMR(400MHz,DMSO-d6)：δ 8.71(d,J=2.0Hz,1H),8.44(d,J=2.4Hz,1H),8.18(dd,J=8.8,2.4Hz,2H),7.72-7.80(m,1H),7.59-7.67(m,2H),7.38(s,1H),7.23-7.34(m,2H),7.04(d,J=8.3Hz,1H),6.91(d,J=8.8Hz,1H),6.55(d,J=8.8Hz,1H),4.40-4.51(m,1H),4.25-4.40(m,2H),3.37-3.43(m,2H),2.45(d,J=7.1Hz,2H),1.99-2.07(m,1H),0.97(dd,J=6.8,4.4Hz,6H).MS(M+1)：489。
實施例17：化合物17-1至17-12之合成
化合物17-1：(S)-3-(4-((1-((6-(2,4-二氟苯基)嗒嗪-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-difluorophenyl)pyridazin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0170-293
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.06-7.89(m,3H),7.62-7.58(m,2H),7.43-7.38(m,1H),7.28-7.23(m,2H),6.68(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.54-4.40(m,2H),4.03-3.96(m,1H),3.42-3.39(m,2H),2.48(t,J=7Hz,2H),1.82-1.75(m,1H),1.59-1.53(m,2H),0.94(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H).MS(M+1)：499。
化合物17-2：(S)-3-(4-((1-((6-(2,4-二氯苯基)嗒嗪-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridazin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0170-610
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.04(t,J=5.4Hz,1H),7.86(d,J=8.8Hz,1H),7.79(d,J=2.0Hz,1H),7.64(d,J=8.8Hz,1H),7.58(d,J=8.8Hz,3H),7.27(d,J=8.8Hz,1H),6.66(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.53-4.40(m,1H),4.03-3.96(m,1H),3.34-3.38(m,2H),2.46(t,J=7Hz,2H),1.80-1.77(m,1H),1.57-1.52(m,2H),0.95(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：531。
化合物17-3：3-(4-(((2S,3S)-3-甲基-1-((6-(4-(三氟甲基)苯基)嗒嗪-3-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0171-295
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.28(d,J=8.3Hz,2H),8.24(d,J=9.3Hz,1H),8.02(t,J=5.4Hz,1H),7.89(d,J=8.3Hz,2H),7.58(d,J=8.8Hz,2H),7.29(d,J=8.8Hz,1H),6.63(d,J=8.8Hz,2H),6.21(d,J=8.8Hz,1H),4.67-4.52(m,2H),3.84-3.81(m,1H),3.42-3.37(m,2H),2.46(t,J=7Hz,2H),2.03-1.97(m,1H),1.79-1.76(m,1H),1.63-1.60(m,1H),0.97(d,J=6.8Hz,3H),0.92(t,J=6.8Hz,3H).MS(M+1)：531。
化合物17-4：3-(4-(((2S,3S)-1-((6-(2-氯-4-(三氟甲基)苯基)嗒嗪-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0172-296
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.05-8.01(m,2H),7.94-7.82(m,3H),7.58(d,J=8.8Hz,2H),7.30(d,J=8.8Hz,1H),6.64(d,J=8.8Hz,1H),6.21(d,J=8.8Hz,1H),4.66.4.53(m,2H),3.85-3.82(m,1H),3.42-3.37(m,2H),2.45(t,J=7Hz,2H),2.03-1.97(m,1H),1.79-1.65(m,1H),1.65-1.60(m,1H),0.98(d,J=6.8Hz,3H),0.92(t,J=6.8Hz,3H).MS(M+1)：565。
化合物17-5：3-(4-(((2S,3S)-1-((6-(2-氟-4-(三氟甲基)苯基)嗒嗪-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0172-611
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.12(t,J=8.4Hz,1H),8.04-7.99(m,2H),7.87(d,J=8.8Hz,1H),7.80-7.75(m,1H),7.56(d,J=8.8Hz,2H),7.31(d,J=8.8Hz,2H),6.20(d,J=8.8Hz,1H),4.67-4.53(m,2H),3.85-3.82(m, 1H),3.42-3.39(m,2H),2.46(t,J=7Hz,2H),1.80-1.78(m,1H),1.78-1.62(m,1H),0.97(d,J=6.8Hz,3H),0.91(t,J=6.8Hz,3H).MS(M+1)：549。
化合物17-6：3-(4-(((2S,3S)-1-((6-(2,4-二氟苯基)嗒嗪-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2,4-difluorophenyl)pyridazin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0173-298
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.03(t,J=5.4Hz,1H),7.97-7.89(m,2H),7.58(d,J=8.8Hz,2H),7.46-7.41(m,1H),7.26(d,J=8.8Hz,2H),6.63(d,J=8.8Hz,2H),6.20(d,J=8.8Hz,1H),4.65-4.51(m,2H),3.84-3.80(m,1H),3.42-3.37(m,2H),2.46(t,J=7Hz,2H),1.80-1,77(m,1H),1.65-1.60(m,1H),0.97(d,J=6.8Hz,3H),0.91(t,J=6.8Hz,3H).MS(M+1)：499。
化合物17-7：(S)-3-(4-((4-甲基-1-((6-(4-(三氟甲基)苯基)嗒嗪-3-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0174-299
白色固體。1HNMR(400MHz,DMSO-d6)：δ 8.30-8.24(m,3H),8.04(t,J=5.4Hz,1H),7.89(d,J=8.8Hz,2H),7.59(d,J=8.8Hz,2H),7.31(d,J=8.8Hz,1H),6.67(d,J=8.8Hz,2H),6.12(d,J=8.8Hz,1H),4.55-4.41(m,2H),3.99-3.96(m,1H),3.42-3.39(m,2H),2.46(t,J=7Hz,2H),1.81-1.76(m,1H),1.57-1.53(m,2H),0.95(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：531。
化合物17-8：(S)-3-(4-((1-((6-(苯並呋喃-2-基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(benzofuran-2-yl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0174-612
1H NMR(400MHz,CDCl3)：δ 7.26-7.97(m,9H),6.58(t,J=8.8Hz,2H),4.48-4.82(m,2H),3.67(d,J=5.4Hz,4H),2.62-2.72(m,2H),0.99-1.11(m,6H).MS(M+1)：489。
化合物17-9：(S)-3-(4-((1-((6-(2-氟-4-(三氟甲基)苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 (S)-3-(4-((1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0175-301
1H NMR(400MHz,CDCl3)：δ 7.58(dd,J=8.8,2.0Hz,3H),7.43-7.51(m,1H),6.82-7.03(m,1H),6.54-6.66(m,3H),4.44-4.93(m,2H),3.74-3.84(m,1H),3.71(q,J=6.0Hz,2H),2.66-2.75(m,2H),2.00-2.15(m,1H),1.09(t,J.=7.2Hz,3H),1.06(t,J=7.2Hz,3H).MS(M+1)：535。
化合物17-10：(S)-3-(4-((1-((6-(4-氟苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(4-fluorophenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0175-302
1H NMR(400MHz,CDCl3)：δ 7.85-8.01(m,2H),7.67(s,1H),7.55(d,J=8.8Hz,2H),7.09-7.20(m,2H),6.93(d,J=9.3Hz,1H),6.60(s,2H),4.57-4.79(m,1H),3.61-3.96(m,2H),2.64-2.73(m,1H),1.24(s,2H),0.94-1.14(m,6H).MS(M+1)：467。
化合物17-11：(S)-3-(4-((1-((6-(2,4-二氟苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-difluorophenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0176-303
1H NMR(400MHz,CDCl3)：δ 7.98-8.13(m,1H),7.76(dd,J=9.3,2.0Hz,1H),7.50-7.60(m,2H),6.87-7.10(m,3H),6.52-6.65(m,2H),4.56-4.83(m,1H),3.59-3.87(m,3H),2.58-2.75(m,2H),1.24(t,J=7.10Hz,2H),0.95-1.13(m,6H).MS(M+1)：485。
化合物17-12：(S)-3-(4-((1-((6-(4-(叔丁基)苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(4-(tert-butyl)phenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0176-304
1H NMR(400MHz,CDCl3)：δ 7.89-7.95(m,2H),7.82-7.89(m,1H),7.74(d,J=9.2Hz,1H),7.55-7.61(m,2H),7.45-7.55(m,3H),6.94(d,J=9.2Hz, 1H),6.70(t,J=6.0Hz,1H),6.56-6.64(m,2H),4.77(dd,J=11.2,6.8Hz,1H),4.63(dd,J=11.2,4.4Hz,1H),3.74-3.82(m,2H),3.70(q,J=6.0Hz,2H),2.66-2.72(m,2H),1.99-2.15(m,1H),1.38(s,9H),1.00-1.10(m,6H).MS(M+1)：505。
實施例18：化合物18-1至18-9之合成
化合物18-1：(S)-3-(4-((1-((5-(苯並呋喃-2-基)-6-甲基吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)-6-methylpyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0177-613
1H NMR(400MHz,CDCl3)：δ 7.99(d,J=8.3Hz,1H),7.53-7.62(m,3H),7.48(d,J=7.8Hz,1H),7.19-7.31(m,2H),6.80(s,1H),6.64(dd,J=8.3,3.9Hz,3H),4.48-4.57(m,1H),4.25(dd,J=10.8,5.4Hz,1H),3.74-3.83(m,1H),3.67(d,J=5.4Hz,2H),2.69(s,3H),2.66(br.s.,2H),1.69-1.82(m,1H),1.57(d,J=8.3Hz,1H),1.30-1.46(m,4H),0.81-0.92(t,J=7.1Hz,3H).MS(M+1)：516.HPLC 99%。
化合物18-2：(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0178-307
1H NMR(400MHz,CDCl3)：δ 7.73(d,J=1.5Hz,1H),7.53-7.60(m,3H),7.28-7.35(m,2H),6.66-6.71(m,1H),6.59-6.66(m,3H),4.46-4.54(m,1H),4.21-4.29(m,1H),3.76-3.84(m,1H),3.67(q,J=5.9Hz,2H),2.65(t,J=5.6Hz,2H),2.23(s,3H),1.71-1.85(m,1H),1.53-1.64(m,1H),1.31-1.49(m,4H),0.89(t,J=7.3Hz,3H).MS(M+1)：578.HPLC 99%。
化合物18-3：3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0178-308
1H NMR(400MHz,CDCl3)：δ 7.72(d,J=1.0Hz,1H),7.52-7.60(m,3H),7.26-7.35(m,2H),6.70(s,1H),6.54-6.63(m,3H),4.47(dd,J=10.8,5.4Hz,1H),4.33-4.43(m,1H),3.62-3.76(m,3H),2.65(t,J=5.6Hz,2H),2.22(s,3H),1.78-1.88(m,1H),1.59-1.71(m,1H),1.23-1.32(m,1H),1.00(d,J=6.8Hz,3H),0.95(t,J=7.3Hz,3H).MS(M+1)：578.HPLC 94%。
化合物18-4：3-(4-(((2S,3S)-1-((5-(苯並呋喃-2-基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(benzofuran-2-yl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0179-309
1H NMR(400MHz,CDCl3)：δ 7.97(d,J=8.3Hz,1H),7.53-7.61(m,3H),7.45-7.50(m,1H),7.19-7.30(m,2H),6.80(s,1H),6.65(s,1H),6.60(dd,J=11.0,8.6Hz,3H),4.45-4.55(m,1H),4.37-4.43(m,1H),3.68(dq,J=17.7,5.7Hz,3H),2.68(s,3H),2.65(t,J=5.6Hz,2H),1.77-1.88(m,1H),1.60-1.72(m,1H),1.23-1.32(m,1H),0.99(d,J=6.8Hz,3H),0.95(t,J=7.3Hz,3H).MS(M+1)：516.HPLC 99%。
化合物18-5：3-(4-(((2S,3S)-1-((5-(2,4-二氯苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2,4-dichlorophenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0179-310
1H NMR(400MHz,CDCl3)：δ 7.56(d,J=8.3Hz,2H),7.47(d,J=2.0Hz,1H),7.25-7.30(m,2H),7.11(d,J=7.8Hz,1H),6.68(t,J=5.9Hz,1H),6.53-6.61(m,3H),4.43-4.53(m,1H),4.33-4.42(m,1H),3.63-3.74(m,3H),2.65(t,J=5.9Hz,2H),2.22(s,3H),1.87-1.79(m,1H),1.71-1.62(m,1H),1.24-1.30(m,1H),1.00(d,J=6.8Hz,3H),0.95(t,J=7.3Hz,3H).MS(M+1)：544.HPLC 95%。
化合物18-6：3-(4-(((2S,3S)-1-((5-(2-氟-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0180-311
1H NMR(400MHz,CDCl3)：δ 7.56(d,J=7.8Hz,2H),7.45(d,J=7.8Hz,1H),7.30-7.41(m,3H),6.75-6.67(m,1H),6.58(d,J=8.3Hz,3H),4.44-4.51(m,1H),4.36-4.42(m,1H),3.63-3.74(m,3H),2.69-2.60(m,2H),2.31(s,3H),1.78-1.87(m,1H),1.66(ddd,J=13.3,7.5,4.2Hz,1H),1.24-1.29(m,1H),0.99(d,J=6.8Hz,3H),0.94(t,J=7.3Hz,3H).MS(M+1)：562.HPLC 97%。
化合物18-7：(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0181-312
白色固體。1H-NMR((400MHz,DMSO-d6)：δ 8.04(t,J=5.6Hz,1H),8.01(s,1H),7.80(d,J=8.8Hz,1H),7.59(d,J=8.8Hz,3H),7.51(d,J=8.8Hz,1H),6.73-6.70(m,3H),6.07(d,J=8.8Hz,1H),4.40-4.36(m,1H),4.13-4.08(m,1H),3.90-3.89(m,1H),2.46(t,J=6.8Hz,2H),2.19(s,3H),1.80-1.75(m,1H),1.54-1.51(m,2H),0.94(d,J=6.3Hz,3H),0.83(d,J=6.3Hz,3H).MS(M+1)：578。
化合物18-8：(S)-3-(4-((1-((5-(2,4-二氯苯基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0181-614
白色固體。1H-NMR((400MHz,DMSO-d6)：δ 8.04(t,J=5.6Hz,1H),7.75(s,1H),7.59(d,J=8.8Hz,2H),7.52-7.44(m,2H),7.39-7.36(m,1H),6.72-6.68(m,3H),6.07(d,J=8.8Hz,1H),4.40-4.35(m,1H),4.13-4.05(m,1H),3.90-3.88(m,1H),2.46(t,J=6.8Hz,2H),2.18(s,3H),1.81-1.75(m,1H),1.53-1.50(m,2H),0.94(d,J=6.3Hz,3H),0.83(d,J=6.3Hz,3H).MS(M+1)：544。
化合物18-9：(S)-3-(4-((1-((5-(苯並呋喃-2-基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0182-314
白色固體。1H-NMR(400MHz,DMSO-d6)：δ 8.10-8.04(m,2H),7.68(d,J=7.8Hz,1H),7.61(d,J=8.8Hz,3H),7.34-7.25(m,2H),7.16(s,1H),6.78(d,J=7.8Hz,1H),6.72(d,J=8.8Hz,2H),6.08(d,J=8.8Hz,1H),4.45-4.41(m,1H),4.15-4.11(m,1H),3.91-3.86(m,1H),2.47(t,J=6.8Hz,2H),1.98(s,3H),1.81-1.75(m,1H),1.54-1.50(m,2H),0.94(d,J=6.3Hz,3H),0.82(d,J=6.3Hz,3H).MS(M+1)：516。
反應流程IV說明可用於合成本揭露之以下式(I)之化合物的一般步驟。
反應流程IV HOBt,EDCI嗎啉二氯甲烷
Figure 107102334-A0305-02-0183-316
(R)-(3-(4-碘苯基)-1-嗎啉基-1-側氧基丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(3-(4-iodophenyl)-1-morpholino-1-oxopropan-2-yl)carbamate)
步驟I：醯胺形成
Figure 107102334-A0305-02-0183-317
取(R)-2-((叔丁氧基羰基)胺基)-3-(4-碘苯基)丙酸((R)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid，20g，51.1mmol)溶於二氯甲烷(200mL)，與嗎林(morpholine，8.9ml，102.2mmol)、1-乙基-(3-二甲基氨基丙基)碳醯二亞胺‧鹽酸(EDC‧HCl，11.8g，102.2mmol)、HOBt(8.30g，61.3mmol)、以及三乙胺(14.2mL，102.2mmol)合併，將生成的溶液 在室溫下攪拌至隔夜，反應接著以額外的水(100mL)終止反應，將生成的混合物以1M鹽酸(2 x 100mL)和飽和的碳酸氫鈉(1 x 100mL)洗，接著以無水硫酸鎂乾燥並在真空下濃縮，藉由急速矽膠管柱層析法純化，以產生白色固體之(R)-(3-(4-碘苯基)-1-嗎林基-1-側氧基丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(3-(4-iodophenyl)-1-morpholino-1-oxopropan-2-yl)carbamate(20.5g，87%)。
(R)-(1-嗎林基-1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(1-morpholino-1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate)
步驟II：Suzuki偶合
Figure 107102334-A0305-02-0184-318
將溶於1,4-二噁烷(200mL)之(R)-(3-(4-碘苯基)-1-嗎林基-1-側氧基丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(3-(4-iodophenyl)-1-morpholino-1-oxopropan-2-yl)carbamate，18.3g，42.2mmol)、(4-(三氟甲基)苯基)硼酸((4-(trifluoromethyl)phenyl)boronic acid，9.60g，50.6mmol)、(1,1'-雙(二苯基膦)二茂鐵)二氯化鈀(Pd(dppf)Cl2，3.1g，4.2mmol)、以及2M碳酸鉀(65mL，126.7mmol)的除氣溶液在90℃下加熱18小時，將反應混合物冷卻、倒入水中，並以乙酸乙酯萃取，合併有機層以硫酸鎂乾燥並在真空下濃縮，藉由矽膠層析法純化殘餘物，以提供(R)-(1-嗎林基-1-側氧基 -3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(1-morpholino-1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate(18g，90%)。
(R)-(3-側氧基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(3-oxo-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate)
步驟III：tertibutyl之形成
Figure 107102334-A0305-02-0185-615
在溶於四氫呋喃(60mL)之(R)-(1-側氧基-1-(哌啶-1-基)-3-(4'-(三氟甲基)[1,1'-聯苯基]-4-基)丙-2-基)胺基甲酸酯((R)-(1-oxo-1-(piperidin-1-yl)-3-(4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate，5g，10.4mmol)攪拌的醯胺溶液中，在0℃下逐滴加入正-丙基氯化鎂(n-Propylmagnesium chloride，26mL，52.2mmol，2M溶於四氫呋喃)溶液，混合物在0℃下攪拌1小時並在室溫下攪拌1時，接著在0℃下小心地加入鹽酸水溶液(1M，100mL)。將水層以乙酸乙酯萃取(3 x 100mL)，合併有機層以水(100mL)和食鹽水(100mL)洗，硫酸鎂乾燥、過濾，並在真空下濃縮。殘餘物藉由急速矽膠管柱層析法純化，以得到(R)-(3-側氧基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl (R)-(3-oxo-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate，3.3g，73%)。
((2R)-3-羥基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl((2R)-3-hydroxy-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate)
步驟IV：還原
Figure 107102334-A0305-02-0186-616
在0℃下於溶於四氫呋喃(20mL)之(R)-(3-側氧基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(3-oxo-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate，2.0g，4.45mmol)的攪拌溶液中加入氫化鋁鋰(LAH，0.17g，4.45mmol)，混合物在0℃下攪拌2小時，將冷卻的反應混合物緩慢地以飽和硫酸鈉(0.3mL)和1M氫氧化鈉(0.3mL)終止反應，將沉澱的固體濾出並以二氯甲烷(50mL)洗，濾液在真空下濃縮。殘餘物藉由急速矽膠管柱層析法純化，以得到((2R)-3-羥基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl((2R)-3-hydroxy-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexam-2-yl)carbamate，1.33g，68%)。
(2R)-2-((叔丁氧基羰基)胺基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-3-基甲磺酸酯((2R)-2-((tert-butoxycarbonyl)amino)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-3-yl methanesulfonate)
步驟V：甲磺醯化
Figure 107102334-A0305-02-0187-617
取((2R)-3-羥基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl((2R)-3-hydroxy-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate，0.68g，1.7mmol)溶於無水二氯甲烷(5mL)，並將三乙胺(0.47mL，3.3mmol)將入溶液中，逐滴加入甲磺醯氯(0.14mL，1.8mmol)溶液於混合物中，將反應混合物攪拌3小時後，將混合物倒入冷水中，沉澱出白色固體，以得到粗產物(2R)-2-((叔丁氧基羰基)胺基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-3-基甲磺酸酯((2R)-2-((tert-butoxycarbonyl)amino)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-3-yl methanesulfonate，0.85g，定性產率)，其具有合適的純度以直接用於下一步反應。
(S)-(1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl(S)-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate)
步驟VI：還原消去反應(Reductive Elimination)
Figure 107102334-A0305-02-0188-618
取(2R)-2-((叔丁氧基羰基)胺基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-3-基甲磺酸酯((2R)-2-((tert-butoxycarbonyl)amino)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-3-yl methanesulfonate，0.8g，1.64mmol)溶於無水四氫呋喃(10mL)，在0℃下加入氫化雙(2-甲氧基乙氧基)鋁鈉(Red-Al，1.4mL，4.92mmol，3.5M於四氫呋喃)，混合物在0℃下攪拌3小時，將冷卻的反應混合物緩慢地以飽和硫酸鈉溶液(0.3mL)和1M氫氧化鈉(0.3mL)終止反應，將沉澱的固體濾出並以二氯甲烷(50mL)洗，濾液在真空下濃縮。殘餘物藉由急速矽膠管柱層析法純化，以得到(S)-(1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl(S)-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate，0.22g，33%)。
(S)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-胺((S)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-amine)
步驟VII：去保護
Figure 107102334-A0305-02-0188-323
在室溫下取懸浮於三氟醋酸(1.3mL，16.86mmol)之(S)-(1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基甲酸叔丁基酯(tert-butyl(S)-(1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)carbamate，235mg， 0.56mmol)溶於無水二氯甲烷(5mL)反應2小時，反應後過量的三氟醋酸藉由逐滴加入的碳酸鈉溶液中和直到pH=10。接著以二氯甲烷萃取，合併有機層以無水硫酸鎂乾燥並在真空下濃縮，以得到粗產物。使用二氯甲烷和甲醇作為沖提液，藉由急速矽膠管柱層析法進一步純化，以得到(S)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-胺((S)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-amine，220mg，定性產率)。
(S)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoate)
步驟VIII：烏耳曼反應(Ullmann Reaction)
Figure 107102334-A0305-02-0189-324
在密封管中裝入碘化銅(13mg，0.068mmol)、碳酸鉀(207mg，1.5mmol)、(S)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-胺((S)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-amine，220mg，0.68mmol)、3-(4-碘苯甲醯胺基)丙酸乙酯(ethyl 3-(4-iodobenzamido)propanoate，260mg，0.75mmol)、和DMF(6mL)，將密封管裝上隔膜(septum)並以氮氣吹。接著蓋上測試管並在90℃的油浴下攪拌24小時，將混合物冷卻至環境溫度，以乙酸乙酯稀釋，通過矽膠墊或矽藻土過濾以乙酸乙酯洗，並蒸發溶劑以獲得粗混 合物。或者，將反應混合物在食鹽水或飽和碳酸氫鈉水溶液與乙酸乙酯之間分離，以硫酸鈉乾燥有機層並濃縮，以獲得粗產物。殘餘物藉由矽膠層析法純化，以提供(S)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoate，39mg，11%)。
(S)-5-側氧基-5-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯基)戊酸((S)-5-oxo-5-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)phenyl)pentanoic acid)
步驟IX：水解
Figure 107102334-A0305-02-0190-326
取酯化合物IV-i(50mg，0.09mmol)溶於甲醇/四氫呋喃(2mL/2mL)，接著加入氫氧化鋰(2.0M，0.5mL)，將反應混合物在室溫下攪拌至隔夜，反應藉由TLC監控，待反應完成後，藉由迴旋蒸發移除溶劑，並加入鹽酸(2.0M，5mL)於混合物中，將水溶液層以乙酸乙酯(3 x 100mL)萃取，合併有機層以硫酸鈉乾燥、過濾，並在真空下濃縮，以得到相對應的酸IV-j，(S)-3-(4-(1-(4'-(三氟甲基)聯苯基-4-基)己-2-基胺基)苯甲醯胺基)丙酸((S)-3-(4-(1-(4'-(trifluoromethyl)biphenyl-4-yl)hexan-2-ylamino)benzamido)propanoic acid，42mg，88%)。準確質量：512.2；m/z：512.23(100.0%),513.23(32.6%),514.24(4.9%)。
化合物19-1：(R)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0191-327
1H NMR(400MHz,DMSO-d6)：δ 8.01(t,J=5.6Hz,1H),7.84-7.88(m,J=8.3Hz,2H),7.76-7.80(m,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),7.56-7.60(m,J=8.8Hz,2H),7.33-7.39(m,J=8.3Hz,2H),6.58(d,J=8.8Hz,2H),6.04(d,J=8.8Hz,1H),3.61-3.72(m,1H),3.36-3.43(m,2H),2.75-2.86(m,2H),2.46(t,J=7.3Hz,2H),1.47-1.56(m,1H),1.36-1.47(m,2H),1.21-1.31(m,3H),0.82(t,J=7.1Hz,3H).MS(M+1)：513。
化合物19-2：(S)-3-(4-((1-(2',4'-二氯-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0191-328
1H NMR(400MHz,DMSO-d6)：δ 8.04(d,J=2.4Hz,1H),7.57-7.63(m,2H),7.48(dd,J=8.3,2.0Hz,1H),7.41(d,J=8.3Hz,1H),7.35(s,2H),7.15 -7.31(m,2H),6.59(t,J=9.3Hz,2H),3.66-3.83(m,1H),3.40(d,J=6.4Hz,2H),2.82-2.95(m,1H),2.57-2.73(m,1H),2.44-2.49(m,2H),1.04-1.15(m,3H).MS(M+1)：471。
化合物19-3：(S)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0192-329
1H NMR(400MHz,DMSO-d6)：δ 7.86-7.89(m,J=8.3Hz,2H),7.77-7.81(m,J=8.3Hz,2H),7.66(d,J=8.3Hz,2H),7.59-7.63(m,J=8.8Hz,2H),7.38(d,J=8.3Hz,2H),6.57-6.64(m,J=8.8Hz,2H),3.74-3.83(m,1H),3.43(br.s.,2H),2.91(dd,J=13.2,5.9Hz,1H),2.71(dd,J=13.7,6.8Hz,1H),2.44-2.49(m,2H),1.12(d,J=6.4Hz,3H).MS(M+1)：471。
化合物19-4：(S)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0192-330
1H NMR(400MHz,DMSO-d6)：δ 7.60(d,J=8.8Hz,2H),7.55(dd,J=8.3,2.4Hz,4H),7.45(d,J=8.3Hz,2H),7.31(d,J=8.3Hz,2H),6.60(d,J=8.3Hz,2H),3.65-3.35(m,1H),3.40(d,J=5.9Hz,2H),2.75-2.65(m,1H),2.69(d,J=6.8Hz,1H),2.45-2.48(m,2H),1.31(s,9H),1.11(d,J=6.4Hz,3H).MS(M+1)：459。
化合物19-5：(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0193-331
1H NMR(400MHz,DMSO-d6)：δ 8.04(s,1H),7.82(d,J=8.3Hz,2H),7.64(dd,J=7.8,1.5Hz,1H),7.58(d,J=8.8Hz,2H),7.25-7.37(m,5H),6.60(d,J=8.8Hz,2H),3.75-3.65(m,1H),3.39(d,J=5.4Hz,2H),2.78(s,2H),2.46(t,J=7.1Hz,2H),1.22-1.31(m,3H),0.88(d,J=6.4Hz,3H),0.78(d,J=6.4Hz,3H).MS(M+1)：485。
化合物19-6：(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)庚-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)heptan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0194-332
1H NMR(400MHz,DMSO-d6)：δ 8.04(s,1H),7.81(d,J=7.8Hz,2H),7.56-7.65(m,5H),7.34-7.36(m,3H),7.23-7.32(m,3H),6.58(d,J=8.8Hz,2H),3.67(br.s.,1H),3.38-3.41(m,2H),2.79(t,J=5.6Hz,2H),2.46(t,J=7.1Hz,2H),1.47(br.s.,1H),1.38-1.44(m,2H),1.17-1.26(m,6H),0.78-0.85(m,4H).MS(M+1)：499。
化合物19-7：(R)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0194-333
1H NMR(400MHz,DMSO-d6)：δ 7.52-7.59(m,6H),7.43-7.46(m,2H),7.29(d,J=8.3Hz,2H),6.58(d,J=8.8Hz,2H),3.68-3.60(m,1H),3.42-3.36(m,2H),1.82-1.72(m,2H),2.46(s,2H),1.30-1.31(m,9H),1.52-1.36(m,3H),1.22-1.26(m,3H),0.80-0.85(m,3H).MS(M+1)：501。
化合物19-8：(R)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 ((R)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0195-334
1H NMR(400MHz,DMSO-d6)：δ 7.52-7.60(m,7H),7.45(d,J=8.8Hz,2H),7.27(d,J=8.3Hz,2H),6.60(d,J=8.8Hz,2H),3.40(d,J=5.4Hz,2H),2.76(s,2H),2.46(t,J=7.1Hz,2H),1.74-1.83(m,1H),1.45-1.35(m,1H),1.31(s,9H),0.88(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).MS(M+1)：501。
化合物19-9：(S)-3-(4-((1-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)庚-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)heptan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0195-335
1H NMR(400MHz,DMSO-d6)：δ 7.74(d,J=8.8Hz,2H),7.58(dd,J=8.3,5.9Hz,4H),7.41(d,J=8.3Hz,2H),7.32(d,J=7.8Hz,2H),6.59(d,J=8.8Hz,2H),6.03(d,J=8.3Hz,1H),3.60-3.69(m,1H),3.41(br.s.,2H),2.72-2.85(m,2H),2.43-2.48(m,2H),1.36-1.52(m,3H),1.21-1.34(m,5H),0.81(t,J=6.6Hz,3H).MS(M+1)：543。
化合物19-10：(S)-3-(4-((5-甲基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((5-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0196-336
1H NMR(400MHz,DMSO-d6)：δ 7.81-7.88(m,4H),7.78(t,J=7.6Hz,2H),7.55-7.67(m,6H),3.41-3.47(m,5H),2.79(br.s.,1H),2.44-2.47(m,1H),1.38-1.57(m,3H),1.22(br.s.,2H),0.81(d,J=6.8Hz,6H).MS(M+1)：527。
化合物19-11：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0196-619
1H NMR(400MHz,DMSO-d6)：δ 7.99-8.06(m,3H),7.76-7.94(m,2H),7.54-7.68(m,3H),7.20-7.44(m,4H),6.58(d,J=8.3Hz,1H),3.35-3.42(m,5H),2.79(br.s.,1H),2.41-2.48(m,1H),1.61-1.79(m,1H),1.32-1.61(m,3H),1.19-1.32(m,4H),0.77-0.89(m,3H).；MS(M+1)：485。
化合物19-12：(S)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0197-620
1H NMR(400MHz,Acetone-d6)：δ 7.68(d,J=8.0Hz,2H),7.52-7.61(m,4H),7.48(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),6.71(d,J=8.0Hz,2H),3.85-4.01(m,1H),3.55-3.63(m,2H),3.47(dd,J=4.9,2.4Hz,2H),3.36-3.43(m,2H),3.02(d,J=6.4Hz,1H),2.93(d,J=6.8Hz,1H),2.60(t,J=6.8Hz,2H),1.53-1.64(m,2H),1.34(s,9H),0.93(t,J=7.3Hz,3H).MS(M+1)：517。
化合物19-13：(R)-3-(4-((1-丙氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸(R)-3-(4-((1-propoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid
Figure 107102334-A0305-02-0197-340
1H NMR(400MHz,Acetone-d6)：δ 7.86(d,J=8.0Hz,2H),7.77(d,J=8.0Hz,2H),7.68(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),7.43(d,J=8.0 Hz,2H),6.71(d,J=8.0Hz,2H),3.89-4.01(m,1H),3.59(t,J=8.0Hz,2H),3.44-3.51(m,2H),3.37-3.43(t,J=8.0Hz,2H),3.04-3.11(m,1H),2.91-2.98(m,1H),2.61(t,J=6.6Hz,2H),1.52-1.65(m,2H),0.93(t,J=7.3Hz,3H).MS(M+1)：528。
化合物19-14：(S)-3-(4-((1-丙氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0198-341
1H NMR(400MHz,Acetone-d6)：δ 7.75(d,J=8.0Hz,2H),7.68(d,J=8.0Hz,2H),7.59(d,J=8.0Hz,2H),7.36-7.44(m,4H),6.70(d,J=8.0Hz,2H),3.88-4.00(m,1H),3.59(t,J=6.8Hz,2H),3.43-3.51(m,2H),3.37-3.43(m,2H),3.02-3.10(m,1H),2.89-2.97(m,1H),2.61(t,J=6.8Hz,2H),1.52-1.63(m,2H),0.93(t,J=7.6Hz,3H).MS(M+1)：545。
化合物19-15：(S)-3-(4-((1-(2',4'-二氯-[1,1'-聯苯基]-4-yl)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0199-342
1H NMR(400MHz,Acetone-d6)：δ 7.87(d,J=8.0Hz,2H),7.56(d,J=4.0Hz,1H),7.33-7.45(m,6H),6.69(d,J=8.0Hz,2H),3.95(m,1H),3.59(t,J=6.8Hz,2H),3.44-3.52(m,2H),3.38-3.44(m,2H),3.03-3.11(m,1H),2.90-2.97(m,1H),2.61(t,J=6.8Hz,2H),1.53-1.64(m,2H),0.92(t,J=8.0Hz,3H).MS(M+1)：529。
化合物19-16：(S)-3-(4-((1-丙氧基-3-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0199-343
1H NMR(400MHz,Acetone-d6)：δ 7.65(d,J=8.8Hz,2H),7.43(br.s.,1H),7.36(d,J=7.8Hz,2H),7.01(d,J=7.8Hz,2H),6.89(s,2H),6.67(d,J=8.8Hz,2H),3.94(br.s.,1H),3.55-3.64(m,2H),3.45-3.53(m,2H),3.41(t,J=6.4Hz,2H),3.05(m,1H),2.92(m,1H),2.61(t,J=6.8Hz,2H),2.27(s,3H),1.92(s,6H),1.58(q,J=6.8Hz,2H),0.93(t,J=7.3Hz,3H).MS(M+1)：503。
化合物19-17：(R)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0200-345
1H NMR(400MHz,Acetone-d6)：δ 7.68(d,J=8.8Hz,2H),7.54-7.59(m,4H),7.48(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H),6.71(d,J=8.8Hz,2H),3.90-3.98(m,1H),3.58(t,J=6.8Hz,3H),3.44-3.49(m,2H),3.22(d,J=6.8Hz,2H),3.03(m,1H),2.82(m,1H),2.61(t,J=6.8Hz,3H),1.86(m,1H),1.34(s,9H),0.92(dd,J=6.8,2.4Hz,6H).MS(M+1)：531。
化合物19-18：(R)-3-(4-((1-異丁氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0200-346
1H NMR(400MHz,Acetone-d6)：δ 7.86(d,J=7.8Hz,2H),7.77(d,J=7.8Hz,2H),7.64-7.69(m,4H),7.43(d,J=7.8Hz,2H),6.71(d,J=8.3Hz,2H),3.96(m,J=4.9Hz,1H),3.59(t,J=6.4Hz,2H),3.42-3.52(m,2H),3.22(d,J= 6.4Hz,2H),3.09(m,1H),2.91(m,1H),2.61(t,J=6.6Hz,2H),1.86(m,1H),0.92(dd,J=6.4,2.4Hz,6H).；MS(M+1)：543。
化合物19-19：(R)-3-(4-((1-異丁氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0201-347
1H NMR(400MHz,Acetone-d6)：δ 7.73-7.79(m,2H),7.65-7.71(m,2H),7.57-7.63(m,2H),7.45(br.s.,1H),7.37-7.43(m,4H),6.70(d,J=8.8Hz,2H),5.23-5.41(m,1H),3.95(br.s.,1H),3.55-3.64(m,2H),3.47(dd,J=4.9,1.5Hz,2H),3.22(d,J=6.8Hz,2H),3.07(dd,J=13.7,6.8Hz,2H),2.94(dd,J=13.7,6.8Hz,2H),2.60(t,J=6.8Hz,2H),1.86(dt,J=13.2,6.6Hz,1H),0.89-0.95(m,6H).；MS(M+1)：559。
化合物19-20：(R)-3-(4-((1-(2',4'-二氯-[1,1'-聯苯基]-4-基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0201-348
1H NMR(400MHz,Acetone-d6)：δ 7.68(d,J=8.0Hz,2H),7.57(d,J=2.0Hz,2H),7.41-7.45(m,1H),7.32-7.41(m,5H),6.70(d,J=8.0Hz,2H),3.89-4.03(m,1H),3.60(t,J=6.8Hz,2H),3.44-3.53(m,2H),3.18-3.26(m,2H),3.05-3.11(m,1H),2.94(m,1H),2.62(t,J=6.8Hz,2H),1.86(m,1H),0.91(dd,J=6.6,2.2Hz,6H).；MS(M+1)：543。
化合物19-21：(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0202-621
1H NMR(400MHz,Acetone-d6)：δ 7.83-7.87(m,2H),7.66-7.70(m,2H),7.61-7.64(m,1H),7.52-7.57(m,1H),7.44-7.50(m,1H),7.42(d,J=8.3Hz,2H),7.27-7.33(m,1H),7.21-7.26(m,2H),6.68-6.74(m,2H),5.09-5.55(m,1H),3.97(br.s.,1H),3.56-3.62(m,2H),3.47(d,J=4.4Hz,2H),3.22(d,J=6.8Hz,2H),3.04-3.12(m,1H),2.91-2.98(m,1H),2.61(t,J=6.6Hz,2H),1.81-1.93(m,1H),0.90.0.95(m,6H).MS(M+1)：515。
化合物19-22：(S)-3-(4-((1-丙氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0203-350
1H NMR(400MHz,Acetone-d6)：δ 7.84-7.88(m,2H),7.75-7.80(m,5H),7.63-7.71(m,10H),7.45-7.51(m,1H),7.43(d,J=8.3Hz,2H),6.67-6.73(m,2H),5.35(br.s.,1H),3.96(br.s.,1H),3.55-3.63(m,2H),3.43-3.52(m,2H),3.36-3.43(m,2H),3.03-3.13(m,1H),2.94(dd,J=13.7,6.8Hz,1H),2.61(t,J=6.6Hz,2H),1.58(sxt,J=7.0Hz,2H),0.93(t,J=7.6Hz,3H).MS(M+1)：529。
化合物19-23：(S)-3-(4-((1-丙氧基-3-(3'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0203-351
1H NMR(400MHz,Acetone-d6)：δ 7.89-7.97(m,2H),7.62-7.72(m,14H),7.45-7.50(m,1H),7.43(d,J=8.3Hz,2H),6.67-6.74(m,5H),5.35(d,J=4.9Hz,2H),3.95(br.s.,1H),3.55-3.62(m,2H),3.44-3.51(m,2H),3.37-3.43(m,2H),3.07(dd,J=13.7,6.8Hz,1H),2.90-2.98(m,1H),2.61(t,J=6.6Hz,2H),1.53-1.64(m,2H),0.93(t,J=7.3Hz,3H).MS(M+1)：529。
化合物19-24：(S)-3-(4-((1-丙氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-propoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0204-352
1H NMR(400MHz,Acetone-d6)：δ 7.73-7.79(m,2H),7.64-7.71(m,2H),7.57-7.62(m,2H),7.43-7.50(m,1H),7.35-7.43(m,4H),6.67-6.73(m,2H),5.24-5.42(m,1H),3.90-4.00(m,1H),3.55-3.62(m,2H),3.47(dd,J=4.9,2.9Hz,2H),3.41(td,J=6.6,1.0Hz,2H),3.03-3.08(m,2H),2.93(dd,J=13.7,6.8Hz,2H),2.60(t,J=6.8Hz,2H),1.54-1.63(m,2H),0.93(t,J=7.3Hz,3H).；MS(M+1)：545。
化合物19-25：(S)-3-(4-((1-丙氧基-3-(3'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0204-353
1H NMR(400MHz,Acetone-d6)：δ 7.65-7.70(m,3H),7.60-7.64(m,2H),7.55-7.60(m,2H),7.46(br.s.,1H),7.42(d,J=8.3Hz,2H),7.27-7.33(m,1H),6.70(d,J=8.8Hz,2H),5.24-5.42(m,1H),3.95(d,J=5.9Hz,1H),3.56-3.62(m,2H),3.44-3.50(m,2H),3.38-3.43(m,2H),3.07(dd,J=13.7,6.4Hz,1H),2.94 (dd,J=13.7,6.8Hz,1H),2.60(t,J=6.8Hz,2H),1.53-1.64(m,2H),0.93(t,J=7.3Hz,3H).MS(M+1)：545。
化合物19-26：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0205-354
1H NMR(400MHz,Acetone-d6)：δ 7.83-7.87(m,2H),7.66-7.70(m,4H),7.61-7.65(m,1H),7.52-7.58(m,1H),7.42(d,J=8.3Hz,3H),7.28-7.33(m,1H),7.21-7.26(m,2H),6.68-6.73(m,2H),5.14-5.51(m,1H),3.87-4.05(m,1H),3.55-3.62(m,2H),3.47(dd,J=4.9,2.0Hz,2H),3.38-3.44(m,2H),3.04-3.10(m,1H),2.94(dd,J=13.7,6.8Hz,1H),2.61(t,J=6.8Hz,2H),1.53-1.64(m,2H),0.91-0.97(m,3H).MS(M+1)：501。
化合物19-27：(S)-3-(4-((1-(4-(1H-吲哚-2-基)苯基)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(1H-indol-2-yl)phenyl)-3-propoxypropan-2-yl)amino)benzamido)pronanoic acid)
Figure 107102334-A0305-02-0205-355
1H NMR(400MHz,Acetone-d6)：δ 10.59(br.s.,1H),7.75-7.78(m,2H),7.66-7.70(m,2H),7.54(d,J=7.8Hz,1H),7.41-7.49(m,1H),7.34-7.40(m,3H),6.98-7.11(m,2H),6.83-6.87(m,1H),6.68-6.73(m,2H),5.11-5.54(m,1H),3.94(d,J=3.9Hz,1H),3.56-3.62(m,2H),3.44-3.50(m,2H),3.41(t,J=6.4Hz,2H),3.04(dd,J=13.7,6.4Hz,1H),2.88-2.94(m,1H),2.61(t,J=6.8Hz,2H),1.54-1.63(m,2H),0.93(t,J=7.3Hz,3H).MS(M+1)：501。
化合物19-28：(S)-3-(4-((1-異丁氧基-3-(3'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0206-622
1H NMR(400MHz,Acetone-d6)：δ 7.90-7.97(m,2H),7.63-7.72(m,6H),7.40-7.52(m,3H),6.68-6.73(m,2H),5.19-5.49(m,1H),3.97(d,J=4.9Hz,1H),3.56-3.62(m,2H),3.43-3.51(m,2H),3.19-3.26(m,2H),3.09(dd,J=13.7,6.4Hz,1H),2.95(dd,J=13.4,6.6Hz,1H),2.60(t,J=6.8Hz,2H),1.87(dt,J=13.3,6.8Hz,1H),0.92(dd,J=6.6,2.7Hz,6H).MS(M+1)：543。
化合物19-29：(S)-3-(4-((1-異丁氧基-3-(2'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0207-623
1H NMR(400MHz,Acetone-d6)：δ 7.80(d,J=7.8Hz,1H),7.65-7.70(m,6H),7.56-7.60(m,2H),7.47(br.s.,2H),7.37(d,J=7.8Hz,5H),7.25(d,J=7.8Hz,4H),6.68-6.74(m,2H),5.34(br.s.,1H),3.96(br.s.,1H),3.57-3.62(m,2H),3.48(d,J=4.4Hz,2H),3.22(d,J=6.4Hz,2H),3.08(dd,J=13.7,6.4Hz,1H),2.92-2.99(m,1H),2.61(t,J=6.6Hz,2H),1.86(dt,J=13.3,6.8Hz,1H),0.92(dd,J=6.8,2.9Hz,6H).MS(M+1)：543。
化合物19-30：(S)-3-(4-((1-異丁氧基-3-(3'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0207-358
1H NMR(400MHz,Acetone-d6)：δ 7.65-7.71(m,3H),7.60-7.64(m,2H),7.54-7.60(m,2H),7.47(t,J=5.4Hz,1H),7.42(d,J=8.3Hz,2H),7.30(ddd,J=9.3,2.4,1.0Hz,1H),6.66-6.73(m,2H),5.34(d,J=8.3Hz,1H),3.96(br.s.,1H),3.59(q,J=6.4Hz,2H),3.43-3.50(m,2H),3.23(d,J=1.0Hz,2H),3.08(dd,J=13.7,6.4Hz,5H),2.94(dd,J=13.4,6.6Hz,3H),2.60(t,J=6.8Hz,2H),1.86(dt,J=13.3,6.8Hz,1H),0.92(dd,J=6.8,2.4Hz,6H).；MS(M+1)：559。
化合物19-31：(S)-3-(4-((1-異丁氧基-3-(3',4',5'-三氟-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0208-359
1H NMR(400MHz,Acetone-d6)：δ 7.65-7.70(m,2H),7.57-7.64(m,2H),7.43-7.52(m,3H),7.39-7.43(m,2H),6.66-6.72(m,2H),5.34(br.s.,1H),3.96(br.s.,1H),3.55-3.63(m,2H),3.42-3.51(m,2H),3.17-3.26(m,2H),3.08(dd,J=13.7,6.4Hz,1H),2.93(dd,J=13.7,6.8Hz,1H),2.60(t,J=6.8Hz,2H),1.86(dt,J=13.4,6.5Hz,1H),0.88-0.94(m,6H).MS(M+1)：529。
化合物19-32：(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0208-361
1H NMR(400MHz,Acetone-d6)：δ 7.81-7.88(m,2H),7.65-7.70(m,2H),7.60-7.65(m,1H),7.51-7.58(m,1H),7.43(d,J=8.3Hz,3H),7.29(dd,J=7.8,1.5Hz,1H),7.20-7.27(m,2H),6.65-6.77(m,2H),5.24-5.41(m,1H),3.89-4.05 (m,1H),3.55-3.62(m,2H),3.43-3.51(m,2H),3.23(d,J=5.9Hz,2H),3.06(d,J=6.4Hz,1H),2.97(d,J=6.4Hz,1H),2.61(t,J=6.8Hz,2H),1.80-1.94(m,1H),0.92(dd,J=6.4,2.4Hz,6H).MS(M+1)：515。
化合物19-33：(S)-3-(4-((1-異丁氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0209-362
1H NMR(400MHz,Acetone-d6)：δ 7.73-7.78(m,2H),7.64-7.70(m,2H),7.56-7.62(m,2H),7.37-7.44(m,4H),6.66-6.74(m,2H),3.95(s,1H),3.58(t,J=6.8Hz,2H),3.43-3.51(m,2H),3.22(d,J=5.9Hz,2H),3.04-3.12(m,1H),2.94(dd,J=13.7,6.8Hz,1H),2.61(t,J=6.8Hz,2H),1.80-1.92(m,1H),0.92(dd,J=6.8,2.4Hz,6H).MS(M+1)：559。
化合物19-34：(S)-3-(4-((1-異丁氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0209-363
1H NMR(400MHz,Acetone-d6)：δ 7.83-7.90(m,2H),7.73-7.81(m,2H),7.63-7.70(m,4H),7.44(d,J=8.3Hz,3H),6.68-6.74(m,2H),5.33(br.s.,1H),3.97(br.s.,1H),3.55-3.63(m,2H),3.43-3.52(m,2H),3.19-3.26(m,2H),3.09(dd,J=13.7,6.4Hz,1H),2.95(dd,J=13.7,6.8Hz,1H),2.61(t,J=6.8Hz,2H),1.87(dt,J=13.3,6.8Hz,1H),0.92(dd,J=6.4,2.4Hz,6H).MS(M+1)：543。
反應流程V說明可用於合成本揭露之以下式(I)之化合物的一般步驟。
Figure 107102334-A0305-02-0210-667
步驟I：(S)-叔丁基-(3-(4-碘苯基)-1-(2-(3-甲基苯並呋喃-2-羰基)聯胺基)-1-側氧基丙-2-基)胺基甲酸酯 ((S)-tert-butyl-(3-(4-iodophenyl)-1-(2-(3-methylbenzofuran-2-carbonyl)hydrazinyl)-1-oxopropan-2-yl)carbamate)之製備
Figure 107102334-A0305-02-0211-365
取3-甲基苯並呋喃-2-卡肼(3-methylbenzofuran-2-carbohydrazide)、(S)-2-(叔丁氧基羰基胺基)-3-(4-碘苯基)丙酸((S)-2-(tert-butoxycarbonylamino)-3-(4-iodophenyl)propanoic acid)、EDCI、和HOBt溶於DMF，反應在室溫下攪拌至隔夜後，在真空下濃縮，加入水至殘餘物中，且水層溶液層以乙酸乙酯萃取，在真空下進一步濃縮以得到殘餘物。粗油狀殘餘物藉由管柱層析法純化(己烷/乙酸乙酯=100：20)，以提供灰白色(pale white)固體產物(S)-叔丁基-(3-(4-碘苯基)-1-(2-(3-甲基苯並呋喃-2-羰基)聯胺基)-1-側氧基丙-2-基)胺基甲酸酯((S)-tert-butyl 3-(4-iodophenyl)-1-(2-(3-methylbenzofuran-2-carbonyl)hydrazinyl)-1-oxopropan-2-ylcarbamate)。
步驟II：(S)-叔丁基-2-(4-碘苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基胺基甲酸酯((S)-tert-butyl 2-(4-iodophenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate)之製備
Figure 107102334-A0305-02-0211-625
取(S)-叔丁基-(3-(4-碘苯基)-1-(2-(3-甲基苯並呋喃-2-羰基)聯胺基)-1-側氧基丙-2-基)胺基甲酸酯((S)-tert-butyl 3-(4-iodophenyl)-1-(2-(3-methylbenzofuran-2-carbonyl)hydrazinyl)-1-oxopropan-2-yl)carbamate，16.90g，30mmol)、對甲基苯基磺醯氯(TsCl，1.5當量)、和三乙胺(3當量)混合於乙腈(50ml)中，在室溫下攪拌10分鐘，將反應溶液濃縮以移除甲醇，並以乙酸乙酯萃取，有機層以水洗，並以無水硫酸鎂乾燥，過濾後在減壓下蒸發溶劑，獲得棕色油狀粗產物(S)-叔丁基-2-(4-碘苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基胺基甲酸酯((S)-tert-butyl 2-(4-iodophenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate，9.93g，產率61%)，且在後續步驟中使用不需任何進一步純化。
步驟III：(S)-叔丁基-(2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基甲酸酯((S)-tert-butyl-(2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate)之製備
Figure 107102334-A0305-02-0212-626
取(S)-叔丁基-2-(4-碘苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基胺基甲酸酯((S)-tert-butyl 2-(4-iodophenyl)-1-(5-(3-methylbenzofuram-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate，8.5g，15.5mmol)、2-苯並呋喃基硼酸(2-benzofuranylboronic acid，3.02g，18.6mmol)、乙酸鈀(II)(palladium acetate(II)，0.36g，1.6mmol)、三苯基膦(0.81g，3.2mmol)溶於乙醇/甲苯(20mL/40mL)，以氮氣吹30分鐘，加入溶於水(20mL)之碳酸鉀(7.50g，54.25mmol)並以氮氣吹另外10分鐘，將混合物在90℃下加熱12小 時，反應混合物冷卻並以乙酸乙酯萃取，有機層以硫酸鎂乾燥並在真空下濃縮。 殘餘物藉由矽膠層析法純化，以提供白色固體之(S)-叔丁基-(2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基胺基甲酸酯((S)-tert-butyl 2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate，3.09g，37%)。
步驟IV：(S)-2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙-1-胺((S)-2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethan-1-amine)之製備
Figure 107102334-A0305-02-0213-627
取化合物(S)-叔丁基-(2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基胺基甲酸酯((S)-tert-butyl 2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate，3.09g，5.7mmol)懸浮於三氟乙酸(6.6mL，86.25mmol)，在室溫下溶於無水二氯甲烷(30mL)2小時，反應完後，藉由逐滴加入碳酸氫鈉水溶液中和過多的三氟乙酸直到pH=10，接著以二氯甲烷萃取，合併有機層以無水硫酸鎂乾燥，並在真空下濃縮，以得到粗產物(S)-2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙胺((S)-2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethanamine)。
步驟V：(S)-4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲酸乙酯(ethyl(S)-4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzoate)之製備
Figure 107102334-A0305-02-0214-628
在溶於甲苯(40mL)之(S)-2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙-1-胺(S)-2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethan-1-amine，1.74g，4mmol)、BINAP(1g，1.6mmol)、碳酸銫(1.95g，6mmol)和3-(4-(((三氟甲基)磺醯基)氧基)苯甲醯胺基)丙酸乙酯(ethyl 3-(4-(((trifluoromethyl)sulfonyl)oxy)benzamido)propanoate，1.78g，4.8mmol)的除氣溶液中，以氮氣吹30分鐘，接著加入Pd(OAc)2(0.18g，0.8mmol)，混合物在油浴中於100℃下攪拌18小時，將混合物冷卻至環境溫度，以乙酸乙酯稀釋，通過矽藻土過濾以乙酸乙酯洗，有機層以硫酸鈉乾燥並濃縮，以得到粗混合物。殘餘物藉由矽膠層析法純化，以提供(S)-4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲酸酯((S)-4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzoate。
步驟VI：(S)-4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲酸 ((S)-4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzoic acid)之製備
Figure 107102334-A0305-02-0215-370
取(S)-4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲酸乙酯(Ethyl(S)-4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)dhyl)amino)benzoate，1.00g，1.67mmol)溶於二噁烷(20mL)，接著加入2M氫氧化鋰溶液(20mL)，將反應混合物加熱至隔夜，反應藉由TLC監控，完成反應後，藉由迴旋蒸發移除溶劑，並加入鹽酸至pH=4~5，混合物以乙酸乙酯萃取，合併有機層以無水硫酸鈉乾燥，並在真空下濃縮，以得到棕色油狀產物(S)-4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲酸((S)-4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzoic acid，0.74g，77%)。
步驟VII：(S)-3-(4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(S)-3-(4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzamido)propanoate)之製備
Figure 107102334-A0305-02-0216-629
取(S)-4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲酸((S)-4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzoic acid)、β-丙胺酸乙酯鹽酸鹽(β-alanine ethyl ester：HCl)、EDCI、三乙胺和HOBt溶於無水四氫呋喃，反應在室溫下攪拌至隔夜後，在真空下濃縮，加入水至殘餘物中，並將水溶液層以乙酸乙酯萃取，在真空下進一步濃縮以得到殘餘物。粗油狀殘餘物藉由管柱層析法純化(己烷/乙酸乙酯=100：40)，以提供無色油狀產物，化合物V-h(0.65g，48%)。
步驟VIII：(S)-3-(4-(2-(4-(苯並呋喃-2-基)苯基)-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)乙基胺基)苯甲醯胺基)丙酸((S)-3-(4-(2-(4-(benzofuran-2-yl)phenyl)-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)ethylamino)benzamido)propanoic acid)之製備
Figure 107102334-A0305-02-0216-372
取化合物V-h(0.66g，1.00mmol)溶於四氫呋喃(20mL)，接著加入2M氫氧化鋰溶液(20mL)，將反應混合物在室溫下攪拌至隔夜，反應藉由TLC監控，反應完成後，藉由迴旋蒸發移除溶劑，並加入鹽酸至pH=4~5，混合物以乙酸乙酯萃取，合併有機層以無水硫酸鈉乾燥，並在真空下濃縮，以得到棕色油狀產物，化合物V-i。
化合物20-1：(S)-3-(4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0217-373
1H NMR(400MHz,DMSO-d6)：δ 8.10(s,1H),7.84(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.55-7.66(m,6H),7.47(d,J=8.4Hz,2H),7.37(s,1H),7.22-7.32(m,2H),6.98(d,J=8.4Hz,1H),6.75(d,J=8.8Hz,2H),5.30-5.32(m,1H),3.35-3.43(m,4H),2.43(t,J=4.0Hz,2H),1.28(s,9H).MS(M+1)：629。
化合物20-2：3-(4-(((1S)-2-甲基-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-2-methyl-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)butyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0217-374
1H NMR(400MHz,DMSO-d6)：δ 8.10(t,J=5.4Hz,1H),7.77(d,J=7.8Hz,1H),7.58-7.69(m,3H),7.45-7.50(m,1H),7.33-7.39(m,1H),6.69-6.80(m,2H),4.77-4.91(m,1H),3.54(t,J=7.2Hz,2H),2.54(d,J=3.2Hz,2H),2.45(t,J =7.2Hz,2H),2.09-2.30(m,1H),1.41-1.49(m,1H),1.09(d,J=6.4Hz,2H),0.83-0.97(m,6H).MS(M+1)：477。
化合物20-3：3-(4-(((1S)-1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-2-methylbutyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0218-375
1H NMR(400MHz,CDCl3)：δ 7.89(d,J=8.4Hz,2H),7.56(d,J8.8Hz,2H),7.39-7.50(m,2H),6.97(s,1H),6.65(d,J=8.8Hz,2H),4.67-4.81(m,1H),3.63(d,J=6.0Hz,2H),2.60(t,J=6.0Hz,2H),2.02-2.16(m,1H),1.15-1.39(m,10H),1.08(d,J=6.8Hz,2H),0.76-1.01(m,6H).MS(M+1)：479。
化合物20-4：(S)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-2-methylpropyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0218-630
1H NMR(400MHz,CDCl3)：δ 7.87-7.92(m,2H),7.58(d,J=8.8Hz,2H),7.41-7.51(m,2H),7.24(s,1H),6.68(d,J=8.8Hz,2H),4.67(d,J=6.8Hz, 1H),3.66(d,J=5.4Hz,2H),2.63(t,J=5.6Hz,2H),1.31(s,9H),1.12(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H).MS(M+1)：465。
化合物20-5：(S)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)-2-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(2',4',6'-trimethyl-[1,1' -biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0219-377
1H NMR(400MHz,DMSO-d6)：δ 10.42(s,1H),10.35(s,1H),8.08(s,1H),7.84(d,J=8.3Hz,2H),7.47-7.60(m,4H),7.32-7.47(m,J=7.8Hz,2H),6.95-7.04(m,J=7.8Hz,2H),6.88(s,2H),6.63(d,J=8.8Hz,2H),6.53(d,J=8.8Hz,1H),3.18(br.s.,3H),2.39-2.54(m,4H),2.24(s,3H),1.88(s,6H),1.30(s,9H).S(M+1)：631。
化合物20-6：(S)-3-(4-((1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)-2-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0219-378
1H NMR(400MHz,DMSO-d6)：δ 10.41(s,1H),8.10(t,J=5.6Hz,1H),7.88(d,J=6.0Hz,2H),7.72-7.80(m,3H),7.48-7.69(m,8H),7.36(t,J=8.0Hz, 1H),6.65(d,J=8.8Hz,2H),6.55(d,J=8.8Hz,1H),4.36(td,J=9.2,4.0Hz,1H),3.30-3.46(m,2H),3.23(dd,J=12.0-8.0Hz,1H),3.05(m,1H),2.55(s,3H),2.45-2.49(m,2H).MS(M+1)：655。
化合物20-7：(S)-2-(4-((1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)-2-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0220-379
1H NMR(400MHz,DMSO-d6)：δ 10.43(s,1H),8.15(d,J=8.8Hz,1H),7.98(dd,J=8.6,2.7Hz,2H),7.84-7.91(m,3H),7.65-7.81(m,8H),7.48-7.63(m,1H),6.76-6.91(d,J=8.8Hz,2H),6.65-6.74(m,1H),4.54(br.s.,1H),4.39(br.s.,2H),3.19-3.43(m,2H),2.98-3.19(m,2H),2.55(s,3H).MS(M+1)：661。
實施例21：化合物21-1至21-3之合成
化合物21-1：(S)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-3-yl)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0220-631
1H NMR(400MHz,CDCl3)：δ 8.00(d,J=8.0Hz,2H),7.56(d,J=8.0Hz,2H),7.51(d,J=8.8Hz,2H),6.81(s,1H),6.58(d,J=8.0Hz,2H),3.92(m,1H),3.65(m,2H),2.99(t,J=6.0Hz,2H),2.63(t,J=6.0Hz,2H),1.56(m.,2H),1.19-1.42(m,13H),0.78-1.01(m,4H).MS(M+1)：493。
化合物21-2：3-(4-(((2R)-1-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2R)-1-(5-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0221-381
1H NMR(400MHz,CDCl3)：δ 7.95-7.99(m,2H),7.39-7.56(m,4H),7.24(s,1H),6.55(d,J=8.8Hz,3H),3.82-3.99(m,1H),3.64(s,2H),2.89-3.03(m,2H),2.64(t,J=5.9Hz,2H),1.32(s,9H),1.24(s,2H),0.80-1.04(m,6H).MS(M+1)：493。
化合物21-3：(R)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0221-382
1H NMR(400MHz,CDCl3)：δ 7.97(d,J=8.4Hz,3H),7.37-7.60(m,4H),6.55(d,J=8.4Hz,2H),3.74-3.90(m,1H),3.57-3.73(m,2H),2.89-3.04(m,2H),2.62(m,2H),1.83-1.99(m,1H),1.15-1.38(m,13H),0.98(m,6H).MS(M+1)：479。
反應流程VI說明可用於合成本揭露之以下式(1)之化合物的一般步驟。
Figure 107102334-A0305-02-0222-668
步驟I：OH保護
Figure 107102334-A0305-02-0223-385
取L-己氨醇(L-Norleucinol，10.40g，88mmol)溶於無水二氯甲烷(150mL)、加入叔丁基二苯基氯矽烷(TBDPSCl，48.78g，117mmol)和三乙胺(26mL，195mmol)於溶液中，將反應混合物攪拌至隔夜，水溶液層以二氯甲烷萃取，以硫酸鎂乾燥並濃縮以得到粗產物，粗油狀殘餘物藉由管柱層析法純化(乙酸乙酯：己烷=15：100)，以提供無色油狀產物，化合物VI-a。
步驟II：Pd-偶合
Figure 107102334-A0305-02-0223-386
取Pd(OAc)2(0.22g，1mmol)、BINAP(1.24g，2mmol)、碳酸銫(6.51g，20mmol)、4-(三氟甲基磺醯基)苯甲酸乙酯(ethyl 4-(trifluoromethylsulfonyloxy)benzoate，3.57g，12mmol)、和L-己氨醇-TBDPS(L-Norleucinol-TBDPS)、化合物VI-a(3.55g，10mmol)溶於甲苯(100mL)，以氮氣吹30分鐘，將混合物在油浴於90℃下攪拌至隔夜，混合物冷卻至環境溫度，以乙酸乙酯稀釋，通過矽藻土過濾以乙酸乙酯洗，將混合物以水和食鹽水洗，有機層以硫酸鎂乾燥並濃縮以獲得粗混合物。殘餘物藉由矽膠層析法純化，以得到棕色油狀產物化合物VI-b。
步驟III：去保護
Figure 107102334-A0305-02-0224-387
取起始化合物VI-b(9.2g，17.1mmol)溶於四氫呋喃(20mL)，在室溫下加入四正丁基氟化銨(TBAF，52mL，52mmol，1M溶於四氫呋喃)，將混合物攪拌至隔夜，以水稀釋並以乙酸乙酯萃取，合併有機層以食鹽水洗並以硫酸鎂乾燥，在真空下小心地移除溶劑。殘餘物藉由急速管柱層析法純化(矽膠，乙酸乙酯：己烷=15：100)，以得到淡黃色液體，化合物VI-c(4.24g，93%)。
1H NMR(400MHz,CDCl-)：δ 7.80-7.84(m,2H),6.54-6.58(m,2H),4.08-4.12(m,1H),3.70-3.74(m,1H),3.56-3.61(m,1H),1.45-1.65(m,2H),1.27-1.37(m,6H),0.84-0.91(m,3H)。
步驟IV
Figure 107102334-A0305-02-0224-633
在氮氣下，於帶有攪拌子的乾淨的烘箱乾燥的250mL燒瓶中裝入1,1-羰基二咪唑(1,1-carbonyldiimidazole，3.40g，21mmol)和四氫呋喃(20mL)，將燒瓶於冰浴下冷卻，緩慢加入溶於四氫呋喃(20mL)之醇-化合物VI-c(2.79g，10.5mmol)並攪拌0.5小時，在真空下藉由迴旋蒸發器(rotavaporator)移除大部分地溶劑，得到黃色液體之粗產物(化合物VI-c’，4.6g，122%)，不須進一步純化直接用於下一步驟。
步驟V：(S)-2-(4-(乙氧基羰基)苯基胺基)己基聯胺羧酸酯((S)-2-(4-(ethoxycarbonyl)phenylamino)hexyl hydrazinecarboxylate)之合成
Figure 107102334-A0305-02-0225-634
將水合聯胺(hydrazine hydrate，1.05g，21mmol)逐滴加入溶於四氫呋喃(100mL)之化合物VI-c’(4.6g，10.5mmol)的溶液中，反應混合物在室溫下攪拌0.5小時，將混合物濃縮並以乙酸乙酯萃取，以獲得白色固體粗產物化合物VI-d(3.7g，109%)。不須進一步純化直接用於下一步驟。
步驟VI：(S)-2-(4-(乙氧基羰基)苯基胺基)己基2-(4-叔丁基苯甲醯基)聯胺羧酸酯((S)-2-(4-(ethoxycarbonyl)phenylamino)hexyl 2-(4-tert-butylbenzoyl)hydrazinecarboxylate)之合成
Figure 107102334-A0305-02-0225-390
取化合物VI-d(1.90g，5.88mmol)、叔丁基苯甲酸(1.15g，6.47mmol)、EDCI(1.69g，8.81mmol)和HOBt(1.35g，8.81mmol)溶於DMF(20mL)，反應在室溫下攪拌至隔夜後，在真空下濃縮，於殘餘物中加入水並將水溶液層以乙酸乙酯萃取，在真空下進一步濃縮以得到粗產物。粗油狀殘餘物藉由管柱 層析法純化(乙酸乙酯：己烷=25：100)，以提供無色油狀產物化合物VI-d’(2.2g，75%)。
步驟VII：增環反應(Annulations)
Figure 107102334-A0305-02-0226-391
取化合物VI-d’(2.20g，4.42mmol)、TsCl(1.34，13.26mmol)、和三乙胺(2mL，13.26mmol)混合於乙腈(20mL)在室溫下攪拌1小時，對該反應溶液濃縮以移除甲醇，並以乙酸乙酯萃取，有機層以水洗並以無水硫酸鎂乾燥，過濾後在減壓下蒸發溶劑。粗油狀殘餘物藉由管柱層析法純化(乙酸乙酯：己烷=20：100)，以提供無色油狀產物化合物VI-e。
步驟VIII：水解
Figure 107102334-A0305-02-0226-635
取化合物VI-e(2.05g，4.42mmol)溶於二噁烷(20mL)，接著加入2M氫氧化鋰(aq)(20mL)，將反應混合物加熱至60℃ 1小時，反應藉由TLC監控，待反應完全後，藉由迴旋蒸發移除溶劑，並加入鹽酸至pH=4~5，混合化合物以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥，並在真空下濃縮乙得到白色固體粗產物，化合物VI-f(1.50g，兩步驟產率：78%)。
步驟IX：醯胺化
Figure 107102334-A0305-02-0227-393
取化合物VI-f、β-丙胺酸乙酯鹽酸鹽(β-alanine ethyl ester hydrochloride)、EDCI、Et3N和HOBt溶於乾燥的四氫呋喃，反應在室溫下攪拌至隔夜後，在真空下濃縮，於殘餘物中加入水並將水溶液層以乙酸乙酯萃取，在真空下進一步濃縮以得到殘餘物。粗油狀殘餘物藉由管柱層析法純化(乙酸乙酯：己烷=60：100)，以提供無色油狀產物化合物VI-g。
步驟X：水解
Figure 107102334-A0305-02-0227-636
取化合物VI-g(1.84g，3.43mmol)溶於四氫呋喃(20mL)，接著加入2M氫氧化鋰溶液(20mL)，將反應混合物在室溫下攪拌至隔夜，反應藉由TLC監控，待反應完成後，藉由迴旋蒸發移除溶劑，並加入鹽酸至pH=4~5，混合化和物以乙酸乙酯萃取，合併有機層以無水硫酸鎂乾燥並在真空下濃縮，以得到棕色油狀產物化合物VI-h。
實施例22：化合物22-1至22-20之合成
化合物22-1：3-(4-(((2S,3S)-1-((5-(2-氟-4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0228-395
1H NMR(400MHz,DMSO-d6)：δ 10.37(d,J=2.0Hz,1H),8.47(m,1H),7.82-7.95(m,4H),7.70-7.82(m,2H),7.59-7.70(m,1H),4.85(dt,J=7.6,4.0Hz,1H),4.41-4.57(m,2H),3.41-3.55(m,2H),2.51-2.55(m,2H),1.78-1.92(m,1H),1.28-1.46(m,1H),1.07-1.28(m,1H),0.81-0.96(m,3H),0.75(d,J=6.8Hz,3H).MS(M+1)：539。
化合物22-2：(S)-3-(4-((1-((5-(4-(三氟甲氧基)苯基)-1,3,4-噁二唑-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0228-637
1H NMR(400MHz,DMSO-d6)：δ 10.40(s,1H),8.40-8.56(m,1H),7.92(d,J=8.8Hz,2H),7.85(s,4H),7.43(d,J=7.6Hz,2H),4.63-4.86(m,1H),4.48-4.61(m,1H),4.24-4.44(m,1H),2.52(m,2H),1.46-1.75(m,2H),1.07-1.39(m,4H),0.82(t,J=6.8Hz,3H).MS(M+1)：537。
化合物22-3：(S)-3-(4-((1-((5-(2-氟-4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0229-397
1H NMR(400MHz,DMSO-d6)：δ 10.41(d,J=2.0Hz,1H),8.47(t,J=5.6Hz,1H),7.74-7.89(m,6H),7.62-7.69(m,1H),4.68-4.79(m,1H),4.52-4.67(m,1H),4.34-4.43(m,1H),3.43-3.52(m,2H),2.51-2.57(m,2H),1.46-1.71(m,2H),1.11-1.36(m,4H),0.78-0.90(m,3H).MS(M+1)：539。
化合物22-4：(S)-3-(4-((1-((5-(苯並呋喃-2-基)-1,3,4-噁二唑-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0229-398
1H NMR(400MHz,DMSO-d6)：δ 10.28(s,1H),8.47(t,J=5.6Hz,1H),7.82-7.91(m,6H),7.76(d,J=7.8Hz,2H),7.67(d,J=8.3Hz,2H),7.54(s,1H),7.45(ddd,J=8.4,7.2,1.5Hz,1H),7.28-7.37(m,2H),4.79(br.s.,1H),4.60(t,J=8.1Hz,1H),4.42(dd,J=8.6,3.2Hz,1H),3.44-3.50(m,3H),1.49-1.75(m,3H),1.26(td,J=14.3,6.6Hz,6H),0.83(t,J=6.8Hz,3H).MS(M+1)：493。
化合物22-5：(S)-3-(4-((1-((5-(4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0230-638
1H NMR(400MHz,DMSO-d6)：δ 10.51(s,1H),8.50(t,J=5.4Hz,2H),8.00(d,J=7.8Hz,4H),7.79-7.90(m,12H),4.72-4.83(m,2H),4.57(t,J=7.8Hz,2H),4.37(dd,J=8.6,3.2Hz,2H),3.43-3.48(m,6H),1.51-1.74(m,4H),1.13-1.40(m,11H),0.77-0.89(m,8H).MS(M+1)：521。
化合物22-6：(S)-3-(4-((1-((5-(2,4-二氯苯基)-1,3,4-噁二唑-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0230-400
1H NMR(400MHz,DMSO-d6)：δ 10.37(s,1H),8.47(t,J=5.4Hz,1H),7.79-7.91(m,4H),7.42-7.48(m,2H),4.57(t,J=8.1Hz,1H),3.42-3.49(m,4H),1.13-1.40(m,7H),0.73-0.91(m,5H).MS(M+1)：522。
化合物22-7：3-(4-(((2S,3S)-1-((5-(苯並呋喃-2-基)-1,3,4-噁二唑-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0231-401
1H NMR(400MHz,Acetone-d6)：δ 9.42(s,1H),7.94-7.99(m,2H),7.88-7.94(m,2H),7.83(br.s.,1H),7.76(d,J=7.8Hz,1H),7.60(dd,J=8.3,1.0Hz,1H),7.42-7.51(m,2H),7.29-7.37(m,1H),4.89-4.97(m,1H),4.58-4.72(m,2H),3.61-3.69(m,2H),2.62-2.69(m,2H),1.43-1.56(m,1H),1.23-1.36(m,1H),0.98(t,J=7.3Hz,3H),0.86(d,J=6.8Hz,3H).MS(M+1)：493。
化合物22-8：3-(4-(((2S)-3-甲基-1-((5-(4-(三氟甲氧基)苯基)-1,3,4-噁二唑-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-3-methyl-1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)oxy)pentam-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0231-402
1H NMR(400MHz,DMSO-d6)：δ 10.35(s,1H),8.46(t,J=4.0Hz,1H),7.93(d,J=8.0Hz,2H),7.87(s,4H),7.43(d,J=8.0Hz,2H),4.85(m,1H),4.39-4.54(m,2H),3.47(m,2H),2.45-2.58(m,2H),1.77-1.90(m,1H),1.30-1.44(m,1H),1.12-1.22(m,1H),0.84-0.96(d,J=8.0Hz,3H),0.76(d,J=8.0Hz,3H).MS(M+1)：537。
化合物22-9：3-(4-(((2S)-1-((5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-1-((5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0232-403
1H NMR(400MHz,DMSO-d6)：δ 10.07(s,1H),8.46(s,1H),7.87(s,4H),7.74(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),4.83-4.85(m,1H),4.44-4.47(m,2H),3.46-3.49(m,2H),2.50-2.55(m,2H),1.77-1.94(m,1H),1.32-1.46(m,1H),1.30(s,9H),1.07-1.25(m,1H),0.90(t,J=8.0Hz,3H),0.76(d,J=8.0Hz,3H).MS(M+1)：509。
化合物22-10：3-(4-(((2S,3S)-3-甲基-1-((5-(4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0232-404
1H NMR(400MHz,DMSO-d6)：δ 10.48(s,1H),8.48(s,1H),8.00(d,J=7.8Hz,2H),7.87(s,4H),7.82(d,J=8.3Hz,4H),4.81-4.90(m,1H),4.42-4.54(m,2H),3.46(d,J=5.9Hz,3H),1.78-1.90(m,1H),1.38(s,1H),1.12-1.23(m,1H),0.90(t,J=7.3Hz,3H),0.76(d,J=6.8Hz,3H).MS(M+1)：521。
化合物22-11：3-(4-(((2S,3S)-1-((5-(2,4-二氯苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0233-405
1H NMR(400MHz,DMSO-d6)：δ 10.33(s,1H),8.47(t,J=5.4Hz,2H),7.80-7.91(m,7H),7.45(s,3H),4.84(dt,J=7.6,3.5Hz,1H),4.43-4.55(m,3H),1.08-1.46(m,3H),0.88-0.92(m,3H),0.74(d,J=6.8Hz,3H).MS(M+1)：522。
化合物22-12：(S)-3-(4-((1-((5-(苯並呋喃-2-基)-1,3,4-噁二唑-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0233-406
1H NMR(400MHz,DMSO-d6)：δ 10.26(s,1H),8.48(t,J=5.4Hz,2H),7.83-7.93(m,8H),7.76(d,J=7.3Hz,2H),7.67(d,J=8.3Hz,2H),7.53(d,J=1.0Hz,2H),7.45(td,J=7.7,1.2Hz,2H),7.29-7.37(m,2H),4.76-4.85(m,1H),4.49-4.58(m,2H),3.44-3.50(m,2H),2.11(d,J=3.4Hz,1H),0.92(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).MS(M+1)：479。
化合物22-13：(S)-3-(4-((3-甲基-1-((5-(4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0234-407
1H NMR(400MHz,DMSO-d6)：δ 10.49(s,1H),8.52(t,J=5.4Hz,2H),8.00(d,J=8.3Hz,5H),7.84-7.92(m,9H),7.82(d,J=8.3Hz,5H),4.74-4.83(m,2H),4.48(d,J=5.9Hz,5H),3.42-3.48(m,6H),2.46(t,J=7.1Hz,5H),2.11(td,J=6.8,3.4Hz,2H),0.91(d,J=7.3Hz,6H),0.78(d,J=6.8Hz,3H).MS(M+1)：507。
化合物22-14：(S)-3-(4-((1-((5-(2,4-二氯苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0234-408
1H NMR(400MHz,DMSO-d6)：δ 8.05(t,J=5.4Hz,1H),7.85-7.92(m,2H),7.83(d,J=8.3Hz,3H),7.62-7.65(m,2H),7.61(d,J=8.3Hz,2H),7.57(d,J=8.8Hz,3H),7.22-7.43(m,9H),7.10(d,J=8.8Hz,1H),4.12(d,J=8.3Hz,1H),3.79(dd,J=13.9,6.6Hz,2H),2.98(d,J=7.8Hz,3H),2.46(t,J=7.3Hz,3H),1.00(d,J=6.4Hz,4H),0.90(d,J=6.4Hz,3H).MS(M+1)：508。
化合物22-15：(S)-3-(4-((3-甲基-1-((5-(4-(三氟甲氧基)苯基)-1,3,4-噁二唑-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0235-409
1H NMR(400MHz,DMSO-d6)：δ 12.19(br.s.,1H),10.35(s,1H),8.46(m,1H),7.82-7.95(m,6H),7.43(d,J=8.0Hz,2H),4.70-4.81(m,1H),4.47(m,-2H),3.40-3.62(m,2H),2.51-2.55(m,2H),2.06-2.19(m,1H),0.91(d,J=6.8Hz,3H),0,78(d,J=6,8Hz,3H).MS(M+1)：523。
化合物22-16：(S)-3-(4-((1-((5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0235-410
1H NMR(400MHz,DMSO-d6)：δ 10.08(s,1H),8.46(s,1H),7.87-7.92(m,4H),7.74(d,J=8.4Hz,2H),7.42-7.56(m,2H),4.76-4.77(m,1H),4.46-4.47(m,2H),3.46-3.48(m,2H),2.50-2.57(m,2H),1.30(s,9H),0.91(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).MS(M+1)：495。
化合物22-17：(S)-3-(4-((1-((5-(2-氟-4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0236-411
1H NMR(400MHz,DMSO-d6)：δ 10.38(s,1H),8.47(t,J=5.6Hz,1H),7.74-7.91(m,6H),7.62-7.69(m,1H),4.67-4.81(m,1H),4.42-4.62(m,2H),3.37-3.59(m,2H),2.46-2.55(m,2H),1.98-2.16(m,1H),0.89-0.96(d,J=6.4Hz,3H),0.76(d,J=6.4Hz,3H).MS(M+1)：525。
化合物22-18：(S)-3-(4-((1-((5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0236-412
1H NMR(400MHz,DMSO-d6)：δ 12.21(br.s.,1H),10.12(s,1H),8.47(t,J=5.6Hz,1H),7.87(s,4H),7.76(d,J=8.4Hz,2H),7.45(d,J=8.4Hz,2H),4.74(m,1H),4.54(m,1H),4.35(m,1H),3.40-3.59(m,2H),3.35(m,1H),2.44-2.61(m,2H),1.58-1.66(m,1H),1.16-1.29(m,13H),0.83(t,J=6.8Hz,3H).MS(M+1)：509。
化合物22-19：3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0237-413
1H NMR(400MHz,CDCl3)：δ 7.72-7.85(m,3H),7.60-7.70(m,3H),7.50-7.59(m,2H),4.60(dt,J=7.8,3.9Hz,1H),4.49(t,J=8.0Hz,1H),4.32-4.37(m,1H),3.65(t,J=6.0Hz,2H),2.64(t,J=6.0Hz,2H),1.84-1.97(m,1H),1.09-1.34(m,2H),0.83-0.96(t,J=8.0Hz,3H),0.78(d,J=6.8Hz,3H).MS(M+1)：555。
化合物22-20：3-(4-(((2S,3S)-1-((5-(2-氟-4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸甲酯(Methyl 3-(4-(((2S,3S)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0237-414
1H NMR(400MHz,CDCl3)：δ 8.24(t,J=7.6Hz,1H),7.75(d,J=8.8Hz,2H),7.65(d,J=8.0Hz,2H),7.49(dd,J=8.0,1.2Hz,1H),7.36(d,J=8.0Hz,1H),7.29(dd,J=8.0Hz,8.0Hz,1H),4.56-4.59(m,1H),4.50(t,J=8.4Hz,1H),4.37(dd,J=8.0,4.0Hz,1H),3.66(s,3H),3.63(t,J=6.4Hz,2H),2.62(t,J=6.4Hz,2H), 1.85-1.99(m,1H),1.23-1.36(m,1H),1.09-1.23(m,1H),0.91(tJ=8.0Hz,3H),0.78(d,J=6.8Hz,3H).MS(M+1)：553。
反應流程VII說明可用於合成本揭露之以下式(I)之化合物的一般步驟。
Figure 107102334-A0305-02-0238-666
在此，反應流程VII’為反應流程VII之一實施例以說明可用於合成本揭露之以下式(I)之化合物的一般步驟。
流程VII’
Figure 107102334-A0305-02-0239-416
步驟I：(R)-叔丁基-3-(4-碘苯基)-1-側氧基-1-(4-(三氟甲氧基)苯基胺基)丙-2-基胺基甲酸酯((R)-tert-butyl 3-(4-iodophenyl)-1-oxo-1-(4-(trifluoromethoxy)phenylamino)propan-2-ylcarbamate)之合成
Figure 107102334-A0305-02-0239-417
在0℃下取(R)-2-((叔丁氧基羰基)胺基)-3-(4-碘苯基)丙酸((R)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid，3.91g，10mmol)、EDCI(2.30g，12mmol)和HOBt(1.51g，11mmol)溶於無水四氫呋喃(50ml)並攪拌30分鐘，加入4-(三氟甲氧基)苯胺(4-(trifluoromethoxy)benzenamine，2.13g，12mmol)和N-乙基二異丙基胺(N-Ethyldiisopropylamine，3.48ml，20mmol)，且反應於室溫下攪拌16小時，將反應混合物先以1N鹽酸洗，再以飽和碳酸氫鈉洗，有機層以無水硫酸鈉乾燥並在真空下濃縮。粗產物藉由管柱層析法純化(矽膠，乙酸乙酯：己烷=1：4)，以得到期望的無色液體產物，化合物VII-a(4.4g，產率：80%)。
步驟II：(R)-(1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)carbamate)之合成
Figure 107102334-A0305-02-0240-418
取(R)-3-(4-碘苯基)-1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(3-(4-iodophenyl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)carbamate，1.50g，2.81mmol)、4-三氟甲基苯基硼酸(4-trifluromethylphenyl boronic acid，640mg，3.37mmol)、乙酸鈀(II)(65mg，0.28mmol)、三苯基膦(150mg，0.56mmol)和2M碳酸鉀(5mL，9.83mmol)溶於乙醇/甲苯(1mL/6mL)，在90℃下加 熱18小時，將反應混合物冷卻，倒入半飽和的(half-saturated)碳酸氫鈉溶液中，並以乙酸乙酯萃取，合併有機層以硫酸鎂乾燥並在真空下濃縮，殘餘物藉由矽膠層析法純化，以提供(R)-(1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)carbamate，871mg，56.2%)。
步驟III：(R)-2-胺基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-N-(4-(三氟甲基)苯基)丙醯胺((R)-2-amino-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-N-(4-(trifluoromethyl)phenyl)propanamide)之合成
Figure 107102334-A0305-02-0241-419
在室溫下，取化合物(R)-(1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基甲酸叔丁基酯(tert-butyl(R)-(1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)carbamate，871mg，1.58mmol)懸浮於三氟乙酸(1.8mL，23.65mmol)溶於無水二氯甲烷(20mL)反應至隔夜，反應後逐滴加入碳酸鈉溶液中合過量的三氟乙酸至pH=10，接著以二氯甲烷萃取，合併有機層以硫酸鎂乾燥，並在真空下濃縮以得到粗產物。藉由矽膠急速管柱層析法(使用二氯甲烷和甲醇作為沖提液)進一步純化，以得到化合物(R)-2-胺基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-N-(4-(三氟甲基)苯基)丙醯胺 ((R)-2-amino-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-N-(4-(trifluoromethyl)phenyl)propanamide(695.2mg，97.5%)。
步驟IV：(R)-3-(4-((1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(ethyl(R)-3-(4-((1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)之合成
Figure 107102334-A0305-02-0242-420
於密封試管中填入碘化銅(21mg，0.11mmol，10mol%)、碳酸鉀(465mg，3.36mmol)、3-(4-碘苯甲醯胺)丙酸乙酯(ethyl 3-(4-iodobenzamido)propanoate，430mg，1.23mmol)和(R)-2-胺基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-N-(4-(三氟甲基)苯基丙醯胺((R)-2-amino-3-(4'-(trifluoromethyl)-[1,1'-biphehyl]-4-yl)-N-(4-(trifluoromethyl)phenyl)propanamide，506mg，1.12mmol)，在加入DMF(1.5mL)，將密封管裝上隔膜(septum)並以氮氣吹。接著蓋上測試管並在100℃的油浴下攪拌2天，將反應混合物冷卻至室溫，並以乙酸乙酯洗，將濾液(25mL)以氯化銨洗，且酸萃取液以乙酸乙酯洗，有機層以硫酸鎂乾燥、過濾、並濃縮。藉由矽膠急速管柱層析法(使用二氯甲烷和甲醇作為沖提液)進一步純化，以得到化合物(R)-3-(4-((1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(ethyl (R)-3-(4-((1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate，385mg，51.3%)。
步驟V：(R)-3-(4-((1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)之合成
Figure 107102334-A0305-02-0243-421
取(R)-3-(4-((1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate，100mg，0.15mmol)溶於甲醇(2mL)/四氫呋喃(2mL)，接著加入氫氧化鋰(2.0M，1.0mL)，將反應混合物在室溫下攪拌至隔夜，反應藉由TLC監控，待反應完成後，藉由迴旋蒸發移除溶劑，並加入鹽酸(2.0M，5mL)至混合物中，藉由抽氣過濾收集白色固體並風乾(air-dried)，以得到相對應的酸，產生標題化合物(R)-3-(4-((1-側氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-oxo-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid，51.9mg，58%)。
實施例23：化合物23-1至23-35之合成
化合物23-1：(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-4-甲基-1-側氧基物-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0244-422
此化合物的質譜數據列於下表23中。
化合物23-2：(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0244-640
此化合物的質譜數據列於下表23中。
化合物23-3：(S)-3-(4-((1-側氧基-3-苯基-1-((2',4',6'-三甲基-[1,1'-聯苯基]-4-基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-oxo-3-phenyl-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0245-424
此化合物的質譜數據列於下表23中。
化合物23-4：(S)-3-(4-((4-甲基-1-側氧基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)胺基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-oxo-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0245-426
1H NMR(400MHz,DMSO-d6)：δ 11.78-12.46(m,1H),10.03-10.42(m,1H),8.00-8.09(m,1H),7.85(s,2H),7.79(s,2H),7.72(d,J=5.9Hz,4H),7.59(s,2H),6.67(d,J=8.8Hz,2H),6.35-6.43(m,1H),4.05-4.18(m,1H),3.36-3.42(m,2H),2.45(s,2H),1.56-1.85(m,3H),0.98(d,J=6.4Hz,3H),0.92(d,J=6.4Hz,3H).MS(M+1)：542。
化合物23-5：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0246-427
此化合物的質譜數據列於下表23中。
化合物23-6：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0246-428
此化合物的質譜數據列於下表23中。
化合物23-7：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0246-429
此化合物的質譜數據列於下表23中。
化合物23-8：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0247-641
1H NMR(400MHz,DMSO-d6)：δ 10.32(s,1H),8.05(t,J=5.6Hz,1H),7.82-7.88(m,4H),7.69(d,J=8.8Hz,2H),7.55-7.65(m,4H),7.34-7.39(m,2H),7.16-7.32(m,6H),6.66(d,J=8.8Hz,3H),6.58(d,J=8.8Hz,2H),4.37(d,J=5.9Hz,1H),3.00-3.17(m,2H),2.44(t,J=7.1Hz,2H).MS(M+1)：548。
化合物23-9：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(4-氟苯基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0247-642
此化合物的質譜數據列於下表23中。
化合物23-10：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(4-氟苯基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0248-432
此化合物的質譜數據列於下表23中。
化合物23-11：(S)-3-(4-((1-((4-(苯並[b]噻吩-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzo[b]thiophen-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0248-433
此化合物的質譜數據列於下表23中。
化合物23-12：(S)-3-(4-((1-((4-(苯並[b]噻吩-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基丙酸((S)-3-(4-((1-((4-(benzo[b]thiophen-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0248-434
1H NMR(400MHz,DMSO-d6)：δ 10.25(s,1H),8.05(s,1H),7.94(d,J=7.8Hz,1H),7.81(d,J=7.3Hz,1H),7.69-7.78(m,5H),7.60(d,J=8.8Hz,3H),7.36(dd,J=7.6,1.2Hz,1H),7.34(dd,J=7.6,1.2Hz,1H),6.67(d,J=8.8Hz,3H),6.39(d,J=8.3Hz,1H),4.05-4.17(m,1H),3.37-3.41(m,3H),2.45(t,J=7.1Hz,3H),1.55-1.86(m,4H),0.98(d,J=6.4Hz,3H),0.92(d,J=6.4Hz,3H).MS(M+1)：530。
化合物23-13：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(萘基-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino))-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0249-435
此化合物的質譜數據列於下表23中。
化合物23-14：(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0249-436
此化合物的質譜數據列於下表23中。
化合物23-15：(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0250-437
此化合物的質譜數據列於下表23中。
化合物23-16：(R)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0250-438
1H NMR(400MHz,DMSO-d6)：δ 8.83(s,1H),8.29(t,J=5.6Hz,2H),7.74-7.86(m,7H),7.56-7.64(m,4H),7.21-7.30(m,9H),7.12-7.17(m,3H),3.41-3.48(m,4H),3.00-3.17(m,2H),2.44(t,J=6.8Hz,2H).MS(M+1)：598。
化合物23-17：(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl (S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0251-439
此化合物的質譜數據列於下表23中。
化合物23-18：(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0251-440
此化合物的質譜數據列於下表23中。
化合物23-19：(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0252-441
此化合物的質譜數據列於下表23中。
化合物23-20：(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0252-442
1H NMR(400MHz,DMSO-d6)：δ 10.40-10.71(m,1H),8.24-8.51(m,1H),7.69-7.93(m,6H),7.50-7.55(m,4H),7.40-7.49(m,6H),7.25(d,J=8.8Hz,3H),7.03-7.14(m,1H),6.68(d,J=8.8Hz,3H),4.34-4.46(m,1H),2.13(s,3H),1.22(s,9H).MS(M+1)：538。
化合物23-21：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0253-443
此化合物的質譜數據列於下表23中。
化合物23-22：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0253-643
此化合物的質譜數據列於下表23中。
化合物23-23：(S)-3-(4-((1-側氧基-3-苯基-1-((2'-(三氟甲基)-[1,1'-聯苯基]-4-基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-oxo-3-phenyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0253-445
此化合物的質譜數據列於下表23中。
化合物23-24：(S)-2-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0254-644
1H NMR(400MHz,DMSO-d6)：δ 10.29(s,1H),7.92-8.28(m,1H),7.80-7.90(m,2H),7.65-7.73(m,2H),7.57-7.65(m,2H),7.52(d,J=8.8Hz,2H),7.33-7.38(m,2H),7.16-7.32(m,6H),6.67(d,J=8.8Hz,2H),4.37(dd,J=8.1,6.1Hz,1H),3.42-3.49(m,2H),2.97-3.20(m,2H),2.63(t,J=7.1Hz,2H).MS(M+1)：584。
化合物23-25：(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-1-側氧基-3-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-1-oxo-3-(2',4'-6'-trimethyl-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0254-450
此化合物的質譜數據列於下表23中。
化合物23-26：(S)-2-(4-((1-((4-(叔丁基)苯基)胺基)-1-側氧基-3-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((4-(tert-butyl)phenyl)amino)-1-oxo-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)ethane-1-sulfonic acid)
Figure 107102334-A0305-02-0255-452
1H NMR(400MHz,DMSO-d6)：δ 9.93(s,1H),7.87-8.30(m,1H),7.51(d,J=8.8Hz,3H),7.34-7.44(m,5H),7.22-7.30(m,3H),6.98(d,J=7.8Hz,3H),6.87(s,3H),6.69(d,J=8.8Hz,3H),4.39(s,2H),3.46(t,J=7.1Hz,3H),3.10(d,J=7.3Hz,3H),2.61-2.66(m,3H),2.23(s,4H),1.82(s,8H),1.23(s,13H).MS(M+1)：642。
化合物23-27：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(1H-吲哚-3-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0255-453
此化合物的質譜數據列於下表23中。
化合物23-28：(S)-3-(4-((1-((4-(1H-吲哚-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸甲酯(Methyl(S)-3-(4-((1-((4-(1H-indol-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0256-454
此化合物的質譜數據列於下表23中。
化合物23-29：(S)-3-(4-((1-((4-(1H-吲哚-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(1H-indol-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0256-455
此化合物的質譜數據列於下表23中。
化合物23-30：3-(4-(((2S,3S)-1-((6-甲氧基萘-2-基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-methoxynaphthalen-2-yl)amino)-3-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0257-456
1H NMR(400MHz,DMSO-d6)：δ 10.29(s,1H),8.07(t,1H),7.83-7.89(m,2H),7.71-7.76(m,2H),7.55-7.65(m,4H),7.21-7.32(m,3H),6.71(d,2H),6.35(d,1H),4.04(q,2H),3.89(t,1H),3.41(t,2H),1.85-1.95(m,1H),1.63-1.72(m,1H),1.25-1.36(m,1H),1.15(t,3H),0.98(d,3H),0.88(t,3H).MS(M+1)：542。
化合物23-31：3-(4-(((2S,3S)-1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0257-457
此化合物的質譜數據列於下表23中。
化合物23-32：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0258-458
此化合物的質譜數據列於下表23中。
化合物23-33：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0258-460
此化合物的質譜數據列於下表23中。
化合物23-34：(S)-2-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)benzamido)ethana-1-sulfonic acid)
Figure 107102334-A0305-02-0258-461
此化合物的質譜數據列於下表23中。
化合物23-35：(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxohexan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0259-462
1H NMR(400MHz,Acetone-d6)：δ 9.52(s,1H),7.86(d,J=8.0Hz,2H),7.79(d,J=8.0Hz,2H),7.70(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,1H),7.54(d,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H),7.23(t,J=8.0Hz,1H),7.19(s,1H),6.74(d,J=8.0Hz,2H),5.73(s,1H),3.98-4.12(m,1H),3.53-3.63(m,2H),2.60(d,J=8.0Hz,2H),1.84-1.95(m,2H),1.46-1.59(m,2H),1.34-1.43(m,2H),0.91(t,J=7.3Hz,3H).MS(M+1)：514。
實施例24：化合物24-1至24-28之合成
化合物24-1：(R)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0259-463
此化合物的質譜數據列於下表24中。
化合物24-2：(R)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0260-464
1H NMR(400MHz,DMSO-d6)：δ 10.26(s,1H),7.96-8.14(m,1H),7.86(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.63(dd,J=7.8,1.5Hz,1H),7.57-7.61(m,3H),7.20-7.34(m,3H),6.67(d,J=8.8Hz,2H),6.34-6.45(m,1H),4.05-4.19(m,1H),3.38(d,J=5.9Hz,3H),2.45(t-J=7.3Hz,2H),1.56-1.86(m,3H),0.98(d,J=6.4Hz,3H),0.92(d,J=6.8Hz,3H).MS(M+1)：514。
化合物24-3：(R)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0260-466
此化合物的質譜數據列於下表24中。
化合物24-4：(R)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0261-467
1H NMR(400MHz,DMSO-d6)：δ 10.44(s,1H),8.04(s,2H),7.70-7.79(m,4H),7.63-7.69(m,4H),7.57(d,J=8.8Hz,4H),7.31-7.38(m,4H),7.27(t,J=7.6Hz,4H),7.19(d,J=7.3Hz,2H),6.64(d,J=8.8Hz,4H),6.59(d,J=8.8Hz,2H),4.28-4.44(m,1H),3.37(d,J=5.9Hz,2H),2.99-3.16(m,2H),2.44(t-J=7.1Hz,2H).MS(M+1)：500。
化合物24-5：(S)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0261-468
此化合物的質譜數據列於下表24中。
化合物24-6：(S)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0262-469
1H NMR(400MHz,DMSO-d6)：δ 11.91-12.33(m,1H),10.21-10.61(m,1H),7.92-8.11(m,1H),7.71-7.79(m,2H),7.62-7.69(m,2H),7.53-7.61(m,2H),7.23-7.37(m,4H),7.15-7.22(m,1H),6.61-6.69(m,2H),6.53-6.61(m,1H),4.30-4.43(m,1H),3.34-3.41(m,2H),3.07-3.17(m,1H),2.97-3.07(m,1H),2.62-2.74(m,1H),2.40-2.47(m,2H).MS(M+1)：500。
化合物24-7：3-(4-(((2S,3S)-1-((6-甲氧基萘-2-基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl3-(4-(((2S,3S)-1-((6-methoxynaphthalen-2-yl)amino)-3-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0262-470
此化合物的質譜數據列於下表24中。
化合物24-8：3-(4-(((2S,3S)-1-((6-甲氧基萘-2-基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((6-methoxynaphthalen-2-yl)amino)-3-methyl-1-oxopentam-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0263-471
1H NMR(400MHz,DMSO-d6)：δ 12.12(s,1H),10.16(s,2H),8.15(d,J=1.5Hz,2H),8.03(t,J=5.6Hz,2H),7.74(dd,J=12.7-8.8Hz,4H),7.52-7.64(m,7H),7.25(d,J=2.4Hz,2H),7.12(dd,J=8.8,2.4Hz,2H),6.72(d,J=8.8Hz,4H),6.32(d,J=8.8Hz,2H),3.90(t,J=8.6Hz,1H),3.34-3.43(m,2H),2.45(t,J=7.1Hz,2H),1.84-1.99(m,1H),1.60-1.75(m,1H),1.22-1.39(m,1H),0.98(d,J=6-8Hz,3H),0.90(t,J=7.6Hz,3H).MS(M+1)：478。
化合物24-9：(R)-3-(4-((4-甲基-1-側氧基-1-((4-(三氟甲基)苯基)胺基)戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((4-methyl-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)pentan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0263-472
此化合物的質譜數據列於下表24中。
化合物24-10：(R)-3-(4-((4-甲基-1-側氧基-1-((4-(三氟甲基)苯基)胺基)戊-2-基)胺基)苯甲醯胺基)丙酸 ((R)-3-(4-((4-methyl-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)pentan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0264-473
1H NMR(400MHz,DMSO-d6)：δ 10.45(s,1H),8.05(s,2H),7.81(d,J=8.8Hz,4H),7.66(d,J=8.8Hz,4H),7.59(d,J=8.8Hz,4H),6.65(d,J=8.8Hz,4H),6.42(d,J=8.3Hz,2H),4.11(s,2H),3.35-3.41(m,5H),2.44(t,J=7.3Hz,4H),1.56-1.84(m,6H),0.97(d,J=6.4Hz,6H),0.90(d,J=6.4Hz,3H).MS(M+1)：466。
化合物24-11：(S)-3-(4-((1-(異丙基胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(isopropylamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0264-474
此化合物的質譜數據列於下表24中。
化合物24-12：(S)-3-(4-((1-(異丙基胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(isopropylamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0265-475
1H NMR(400MHz,DMSO-d6)：δ 11.85-12.36(m,1H),8.15(d,J=8.3Hz,2H),8.05(t,J=5.6Hz,2H),7.91(d,J=6.8Hz,2H),7.79(d,J=7.8Hz,4H),7.49-7.60(m,7H),7.38-7.46(m,4H),6.58(d,J=8.8Hz,4H),4.19(br.s.,2H),3.75(dd,J=14.2,6.8Hz,2H),3.42-3.52(m,2H),3.35-3.40(m,5H),2.45(t,J=7.1Hz,4H),0.96(d,J=6.8Hz,5H),0.78(d,J=6-4Hz,3H).MS(M+1)：448。
化合物24-13：(S)-3-(4-((1-(異丙基胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(isopropylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0265-476
此化合物的質譜數據列於下表24中。
化合物24-14：(S)-3-(4-((1-(異丙基胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(isopropylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0265-477
1H NMR(400MHz,DMSO-d6)：δ 8.04(s,1H),7.72-7.89(m,9H),7.56(d,J=8.8Hz,2H),7.41-7.51(m,3H),6.60(d,J=8.8Hz,2H),6.31-6.44(m,1H),4.12-4.26(m,1H),3.69-3.84(m,1H),3.38(d,J=5.4Hz,2H),3.10(d,J=2.0Hz,2H),2.45(t,J=7.1Hz,2H),0.98(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H).MS(M+1)：448。
化合物24-15：(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0266-478
此化合物的質譜數據列於下表24中。
化合物24-16：(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0266-645
此化合物的質譜數據列於下表24中。
化合物24-17：(R)-3-(4-((3-(2',4'-二氯-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0267-646
此化合物的質譜數據列於下表24中。
化合物24-18：(R)-3-(4-((3-(2',4'-二氯-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0267-481
此化合物的質譜數據列於下表24中。
化合物24-19：(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0268-482
此化合物的質譜數據列於下表24中。
化合物24-20：(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0268-483
此化合物的質譜數據列於下表24中。
化合物24-21：(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-(異丙基胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-(isopropylamino)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0268-647
此化合物的質譜數據列於下表24中。
化合物24-22：(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-(異丙基胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸 ((R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-(isopropylamino)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0269-648
此化合物的質譜數據列於下表24中。
化合物24-23：(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-((3,5-二氟苯基)胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-((3,5-difluorophenyl)amino)-1-oxopropan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0269-649
此化合物的質譜數據列於下表24中。
化合物24-24：(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-((3,5-二氟苯基)胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-((3,5-difluorophenyl)amino)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0269-487
此化合物的質譜數據列於下表24中。
化合物24-25：(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0270-488
此化合物的質譜數據列於下表24中。
化合物24-26：(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0270-489
此化合物的質譜數據列於下表24中。
化合物24-27：(R)-3-(4-((1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoate)
Figure 107102334-A0305-02-0271-490
此化合物的質譜數據列於下表24中。
化合物24-28：(R)-3-(4-((1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)
Figure 107102334-A0305-02-0271-491
此化合物的質譜數據列於下表24中。
在實施例1至24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25：於體外測定法中評估式(I)之化合物升糖素cAMP抑制劑測定法
以Cisbio cAMP Dynamic 2套組檢測藉由升糖素誘導的下游次級傳訊子(secondary messenger)cAMP。將測試化合物各自配置成濃度為10mM的二甲亞碸(DMSO)溶液。為了評估化合物在抑制cAMP產生的效力，以序列稀釋的化合物處理升糖素受體(GCGR)過量表達的CHO-K1細胞或人類初級肝細胞(human primary hepatocyte)，將細胞再懸浮於包含0.1%(w/v)牛血清白蛋白(bovine serum albumin)和800nM異丁基-1-甲基黃嘌呤(isobutyl-1-methylxanthine，IBMX) 之漢克氏平衡鹽溶液(Hank's Balanced Salt solution，HBSS)中，並接種至低體積384白色孔盤中，接著將稀釋的化合物加入盤中預培養30分鐘，其中DMSO的最終濃度為1%。在室溫下，用等於EC50(給予半最大反應之藥物濃度的標記)濃度的升糖素刺激細胞30分鐘，培養完後，以含有cAMP抗體和螢光受體之裂解緩衝液加入至每一孔中再額外培養60分鐘。結果藉由具有HTRF Detection Cartridges之Molecular Devices SpectraMax Paradigm紀錄，並且基於cAMP產生的量以非線性回歸計算每一化合物在抑制cAMP產生的IC50值。
I125-升糖素結合測定法
藉由I125-升糖素競爭測定法評估每一化合物的結合親和力。由GCGR過度表達之CHO-K1細胞獲得GCGR膜部分(membrane fraction)，作為1mg/ml濃度之原液(stock)。為了評估與GCGR結合的化合物的IC50，將GCGR膜部分與序列稀釋的化合物處理。在含有50mM Tris pH 7.4和0.5%(w/v)牛血清蛋白之70μL分析緩衝液中將膜部分稀釋至7.5μg/孔，並加至96孔盤中。接著將膜部分與10μL稀釋的化合物混合。預培養5分鐘後，將20μL之I125標記的升糖素(Perkin Elmer)以最終濃度0.0625nM加至每一孔中。將分析混合物在25℃下培養30分鐘，接著轉移至塗佈有0.5%(w/v)聚乙亞胺(polyethyleneimine)的Millipore MultiScreen GF/B盤中。過濾板以含有50mM Tris pH 7.4之緩衝溶液沖洗2分鐘，每次300μL。藉由Hidex CHAMELEON V micro-beta計數器檢測殘留的同位素，並藉由非線性回歸計算每一化合物結合至GCGR之IC50值。
實施例1至24中製備的化合物在下述兩種體外測定法中測試。結果如下表1至24所示。
表1
Figure 107102334-A0305-02-0273-650
Figure 107102334-A0305-02-0274-651
Figure 107102334-A0305-02-0275-494
表2
Figure 107102334-A0305-02-0276-495
表3
Figure 107102334-A0305-02-0277-652
Figure 107102334-A0305-02-0278-497
Figure 107102334-A0305-02-0278-498
Figure 107102334-A0305-02-0278-499
Figure 107102334-A0305-02-0279-500
Figure 107102334-A0305-02-0279-501
Figure 107102334-A0305-02-0279-502
Figure 107102334-A0305-02-0280-503
Figure 107102334-A0305-02-0280-504
Figure 107102334-A0305-02-0281-505
Figure 107102334-A0305-02-0281-506
Figure 107102334-A0305-02-0281-507
Figure 107102334-A0305-02-0282-508
Figure 107102334-A0305-02-0282-509
Figure 107102334-A0305-02-0282-510
Figure 107102334-A0305-02-0283-511
Figure 107102334-A0305-02-0283-512
Figure 107102334-A0305-02-0284-513
Figure 107102334-A0305-02-0284-514
Figure 107102334-A0305-02-0285-515
Figure 107102334-A0305-02-0286-516
Figure 107102334-A0305-02-0286-517
表17
Figure 107102334-A0305-02-0287-518
Figure 107102334-A0305-02-0287-519
Figure 107102334-A0305-02-0288-520
Figure 107102334-A0305-02-0288-521
Figure 107102334-A0305-02-0289-522
Figure 107102334-A0305-02-0289-524
Figure 107102334-A0305-02-0290-523
Figure 107102334-A0305-02-0290-525
Figure 107102334-A0305-02-0290-526
Figure 107102334-A0305-02-0291-527
Figure 107102334-A0305-02-0291-528
Figure 107102334-A0305-02-0292-529
Figure 107102334-A0305-02-0293-530
Figure 107102334-A0305-02-0293-531
Figure 107102334-A0305-02-0294-532
表1-24中顯示了390種式(I)之示例性化合物的結構和體外活性。 發現所有390種化合物皆與升糖素(glucagon)受體結合並抑制升糖素下游cAMP的含量(level)至不同程度，如他們的IC50值所示(IC50為減少一半反應或結合的抑制劑的濃度)，其包含於上述表中。
其他實施例
本說明書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，本領域之技術人員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範圍內。
Figure 107102334-A0305-02-0002-654

Claims (23)

  1. 一種式(I)之化合物或其藥學上可接受之鹽類：
    Figure 107102334-A0305-02-0296-533
     其中A1、A2、A3和A4各自獨立為CR6；X為-CH2-、-NH-、-O-、-S-、或一直接鍵結；Y為-(C=O)-、-CH2-、或一直接鍵結；R1為C1-6之烷基、C1-6之烷氧基、芳基、雜芳基、C3-12之環烷基、C1-12之雜環烷基、或-(C1-6之烷基)-(C3-12之環烷基)；所述C1-6之環烷基選擇性地以一至三選自由鹵素、羥基、C1-6之烷氧基、芳基和雜芳基所組成之群組之基團取代；所述C1-6之烷氧基、芳基、雜芳基、C3-12之環烷基和C1-12之雜環烷基各自選擇性地以一至三選自由鹵素、芳基、選擇性地以一至三個鹵素取代之C1-6之烷基和選擇性地以一至三個鹵素取代之C1-6之烷氧基所組成之群組之基團取代；所述雜芳基選擇性地與一芳基基團稠合；以及所述芳基選擇性地以雜芳基或與一芳基基團稠合之雜芳基取代； R2為C1-6之烷基、
    Figure 107102334-A0305-02-0296-534
    、
    Figure 107102334-A0305-02-0296-535
    、
    Figure 107102334-A0305-02-0296-663
    、
    Figure 107102334-A0305-02-0296-665
    、或
    Figure 107102334-A0305-02-0296-538
    ； R3為氫、甲基、或乙基； R4為氫、C1-6之烷基、或C1-6之烷氧基，所述C1-6之烷基和C1-6之烷氧基選擇性地以一至三個鹵素取代；R5為四唑基、-CH2-四唑基、-CH2CH2CO2R10、-CH2CH(OH)CO2H、或-(CH2)2SO3H；R6為氫；R7為氫、鹵素、C1-6之烷基、或C1-6之烷氧基；R8為氫、鹵素、C1-6之烷基、或C1-6之烷氧基；R9為氫、鹵素、C1-6之烷基、C1-6之烷氧基、C3-12之環烷基、芳基、或雜芳基；所述C1-6之烷基選擇性地以一至三個鹵素取代；所述C1-6之烷氧基、C3-12之環烷基、芳基、和雜芳基各自選擇性地以一至三選自由鹵素、芳基、選擇性地以一至三個鹵素取代之C1-6之烷基、選擇性地以一至三個鹵素取代之C1-6之烷氧基、胺基和CN所組成之群組之基團取代；以及所述雜芳基選擇性地與一芳基基團或一雜芳基基團稠合；R10為氫、或C1-6之烷基；J1、J2、J3和J4各自獨立為碳或氮，但條件為J1、J2、J3和J4中不超過兩個為氮；其中芳基是指6-碳單環、10-碳雙環、14-碳三環的芳香環系統；其中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，其具有一個以上O、N、P、或S之雜原子；其中當X為一直接鍵結且Y為一直接鍵結時，R 2 不為C 1-6 烷基；其中當X及Y中之一者為一直接鍵結且X及Y中之另一者為-CH 2 -時，R 2 不為C 1-6 烷基； 其中當R2為
    Figure 107102334-A0305-02-0298-539
    時，Y不為-CH2-且X不為-O-；以及 其中當X為-NH-且Y為-(C=O)-時，R 5 不為-(CH 2 ) 2 SO 3 H。
  2. 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，其中，R3為氫，且R4為氫。
  3. 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 中，X為-O-、或-S-，Y為-CH2-，R2為
    Figure 107102334-A0305-02-0298-540
    ，R3為氫，且R4為氫。
  4. 如申請專利範圍第3項所述之化合物或其藥學上可接受之鹽類，其 中，R2為
    Figure 107102334-A0305-02-0298-541
    ，R7為氫、鹵素、C1-6之烷基、或C1-6之烷氧基，且R8為氫、 鹵素、或C1-6之烷基。
  5. 如申請專利範圍第4項所述之化合物或其藥學上可接受之鹽類，其中，R7和R8相同，且R7和R8為H、甲基、乙基、丙基、異丙基、丁基、叔丁基、氟、或氯。
  6. 如申請專利範圍第4項所述之化合物或其藥學上可接受之鹽類，其中，R7為氟、氯、甲氧基、乙氧基、丙氧基、或異丁氧基，且R8為氫。
  7. 如申請專利範圍第3項所述之化合物或其藥學上可接受之鹽類，其 中，R2為
    Figure 107102334-A0305-02-0298-542
    ，R7為氟或氯，R8為氫、氟、或氯。
  8. 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 中，R2為
    Figure 107102334-A0305-02-0299-543
    、
    Figure 107102334-A0305-02-0299-653
    、
    Figure 107102334-A0305-02-0299-545
    、
    Figure 107102334-A0305-02-0299-546
    、或
    Figure 107102334-A0305-02-0299-547
    ，且R7 為C1-6之烷基。
  9. 如申請專利範圍第8項所述之化合物或其藥學上可接受之鹽類，其中，R7為甲基、或乙基。
  10. 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， 其中，X為-CH2-，Y為一直接鍵結，R2為
    Figure 107102334-A0305-02-0299-548
    ，R3為H，且R4為氫。
  11. 如申請專利範圍第10項所述之化合物或其藥學上可接受之鹽類，其中，R7和R8為氫。
  12. 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， 其中，X為-CH2-，Y為一直接鍵結，R2為
    Figure 107102334-A0305-02-0299-549
    ，R3為氫，且R4為氫。
  13. 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， 其中，X和Y為直接鍵結，R2為
    Figure 107102334-A0305-02-0299-550
    ，R3為氫，且R4為氫。
  14. 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， 其中，X為-NH-，Y為-(C=O)-，R2為
    Figure 107102334-A0305-02-0299-551
    ，R3為氫，且R4為氫。
  15. 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，其中，R1為甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、正戊基、異戊基、甲氧基、乙氧基甲基、1-甲氧基丙基、1-甲氧基-2-甲基丙基、乙氧基、正丙氧基、異丙氧基、3-異丁氧基丙-2基、2-丁氧基、正丁氧基、異丁 氧基、叔丁氧基、苯基、苄基、聯苯基、萘基、苯並呋喃基、或吲哚基；所述甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、正戊基、和異戊基各自選擇性地以一至三選自由氟、氯、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、苯基、聯苯基、和萘基所組成之群組之基團取代；所述甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、和叔丁氧基各自選擇性地以一至三個氟或氯取代；所述苯基、聯苯基、和萘基各自選擇性地以一至三選自由氟、氯、甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、三氟甲基、苯並呋喃基、和甲氧基取代之嘧啶基所組成之群組之基團取代；以及所述吲哚基選擇性地以一至三選自由氟、氯、甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、和三氟甲基所組成之群組之基團取代。
  16. 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，其中，R5為四唑基、-CH2-四唑基、-CHCH2CO2H、-CH2CH2CO2Et、-CH2CH2CO2Me、-CH2CH(OH)CO2H、或-(CH2)2SO3H。
  17. 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，其中，R9為甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、苯基、聯苯基、萘基、吡啶基、噠嗪基、苯並呋喃基、苯並噻唑基、咪唑並吡啶基、噁二唑基、苯並噁唑基、吡唑基、或吲哚基；所述甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、和叔丁基各自選擇性地以一至三選自由氟、和氯所組成之群組之基團取代；所述甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、和叔丁氧基各自選擇性地以一至三個 氟、氯、或胺基取代；所述苯基、苄基、聯苯基、萘基、吡啶基、噠嗪基、苯並呋喃基、苯並噻唑基、咪唑並吡啶基、噁二唑基、苯並噁唑基、吡唑基、和吲哚基各自選擇性地以一至三選自由氟、氯、甲基、乙基、正丙基、異丙基、2-丁基、正丁基、異丁基、叔丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、2-丁氧基、正丁氧基、異丁氧基、叔丁氧基、-CF3、-OCF3、和苯基所組成之群組之基團取代。
  18. 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， 其由以下式(II)所表示：
    Figure 107102334-A0305-02-0301-552
    。
  19. 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，其選自由化合物(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((4'-(叔丁基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S)-3-甲基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-3-methyl-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)bemzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-((4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamide)、(R)-3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4'-(叔丁基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido) propanoic acid)、(S)-3-(4-((1-((4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamide)、(R)-3-(4-(((2S,3S)-1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((2S,3S)-1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-3-(4-((1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺benzamide((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(R)-3-(4-(((S)-1-((4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((S)-1-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-((2-(4-(苯並呋喃-2-基)苯氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-(4-(benzofuran-2-yl)phenoxy)-1-phenylethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((3-甲基-1-(4-(5-(三氟甲基)吡啶-2-基)苯氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(5-(trifluoromethyl)pyridin-2-yl)phenoxy)butan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-difluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amin o)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-((1-苯基-2-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)乙基)胺基)苯甲醯胺基)丙酸(3-(4-((1-phenyl-2-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)ethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((3-甲基-1-(4-(6-(三氟甲基)嗒嗪-3-基)苯氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-(4-(6-(trifluoromethyl)pyridazin-3-yl)phenoxy)butan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸甲酯(Methyl(S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-2-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)、(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯 氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氯-4'-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-4'-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(咪唑並[1,2-a]吡啶-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(imidazo[1,2-a]pyridin-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(呋喃並[3,2-b]吡啶-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-(4-(furo[3,2-b]pyridin-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-((3-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯氧基)丁-2-基)胺基)苯甲醯胺基)丙酸(3-(4-((3-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenoxy)butan-2-yl)amino)benzamido)propanoic acid)、3-(4-((3-甲基-1-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-((3-methyl-1-(4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenoxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamid o)propanoic acid)、(S)-3-(4-((1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-((2,6-二甲基-4'-(三氟甲 氧基)-[1,1'-聯苯基]-4-基)氧基)-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,6-二甲基-4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4'-(叔丁基)-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(tert-butyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((4'-(叔丁基)-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4'-(tert-butyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3,5-二甲基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3,5-dimethylphenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2,6-二甲基-4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,6-dimethyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((2',4'-dichloro-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2-6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二甲基苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-dimethylphenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3,5-二甲基苯氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3,5-dimethylphenoxy)hexan-2-yl)amino)benzamide)、N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylpentan-2-yl)amino)benzamide)、(R)-3-(4-(((S)-1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((S)-1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺 ((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamide)、(R)-3-(4-(((S)-1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((S)-1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)hexan-2-yl)amino)benzamido)pr opanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2,2',4'-三氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2',4'-trichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2',4'-三氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2',4'-trichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-2,5-二氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-2,5-dichlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-((2-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-((2'-chloro-4'-(trifluolomethyl)-[1,1'-biphenyl]-4-yl)oxy)-1-phenylethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-2-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧 基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)ethana-1-sulfbnic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-2,5-二氯苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-2,5-dichlorophenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-((2,2',5-三氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((2,2',5-trichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2,5-二氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,5-dichloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)硫基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)thio)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)硫基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)thio)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((4-(苯並呋喃-2-基)苯基)硫基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4-(benzofuran-2-yl)phenyl)thio)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)(甲基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)(methyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)(乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)(ethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-乙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-ethoxypropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-difluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3- methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((3-甲基-1-((2,2',6-三氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((2,2',6-trifluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)butan-2-yl)amino)benzamido)Propanoic acid)、(S)-3-(4-((1-((2'-氯-2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((4-甲基-1-((2,2',6-三氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((2,2',6-trifluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((3',5'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((3',5'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二氟苯 氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-difluorophenoxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2',4'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutam-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-2-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-三氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-2-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((3',5'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((3',5'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)ppopanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)hexan-2-yl)amino)benzamido) propanoic acid)、3-(4-(((2S,3S)-1-((2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-3,3-二甲基 丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutam-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3,(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(3-氟-4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(3-fluoro-4-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)phenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)-3-氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((1-(2,4-二氟苯基)-1H-吡唑-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((3-甲基-1-((6-(4-(三氟甲基)苯基)吡啶-3-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-氟-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-4-二氯苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(3,5-二氯苯基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(3,5-dichlorophenyl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-氟-4-(三氟甲基)苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(4-(三氟甲基)苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)hexan-2-yl)amino) benzamido)propanoic acid)、(S)-3-(4-((1-((6-(3,5-二氯苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(3,5-dichlorophenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-(苯並呋喃-2-基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(benzofuran-2-yl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-(2-氟-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((4-甲基-1-((6-(4-(三氟甲 基)苯基)吡啶-3-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-氯-4-(三氟甲基)苯基)吡啶-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2,4-二氯苯基)吡啶-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((4-甲基-1-((2-(3-甲基-4-(三氟甲基)-1H-吡唑-1-基)嘧啶-5-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((2-(3-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(苯並呋喃-2-基)嘧啶-5-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(benzofuran-2-yl)pyrimidin-5-yl)oxy)-3-methylbutan-2-yl)anino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(苯並呋喃-2-基)嘧啶-5-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(benzofuran-2-yl)pyrimidin-5-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(2-4-二氯苯基)嘧啶-5-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S)-1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(2-氯-4-(三氟甲基)苯基)嘧啶-5-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2-chloro-4-(trifluoromethyl)phenyl)pyrimidin-5-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S)-1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S)-1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-(2,4-二氯苯基)嘧啶-5-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-(2,4-dichlorophenyl)pyrimidin-5-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-甲氧基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-3-methoxyphenoxy)-3-methylpentan-2-yl)ami no)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氯-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-甲氧基苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-methoxyphenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-hloro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-m ethylbutan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(3-甲氧基-4-(5-苯基-1,3,4-噁二唑-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(3-methoxy-4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(5-(叔丁基)-1,3,4-噁二唑-2-基)-3-甲氧基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-3-methoxyphenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1-1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((2H-四唑-5-基)甲基)-4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺((S)-N-((2H-tetrazol-5-yl)methyl)-4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamide)、(S)-N-((1H-四唑-5-基)甲基)-4-((3-甲基-1-((5-(4-(三 氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamide)、(S)-3-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((2-((5-(4-(叔丁基)苯基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(4-(tert-butyl)phenyl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamido)propanoic acid)、(R)-3-(4-(((S)-2-((5-(4-(叔丁基)苯基)吡啶-2-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)-2-羥基丙酸(R)-3-(4-(((S)-2-((5-(4-(tert-butyl)phenyl)pyridin-2-yl)oxy)-1-phenylethyl)amino)benzamido)-2-hydroxypropanoic acid、(S)-3-(4-((3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)、(R)-2-羥基-3-(4-(((S)-3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((R)-2-hydroxy-3-(4-(((S)-3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylbuten-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((4-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2-氟-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氟-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpent an-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2,4-二氯苯基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-2-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((4-甲基-1-((5-(6-(三氟甲基)嗒嗪-3-基)吡啶-2-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((5-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2,4-二氟苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、2-(4-(((2S,3S)-1-((5-(2,4-二氟苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸(2-(4-(((2S,3S)-1-((5-(2,4-difluorophenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(ben2ofuran-2-yl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-2-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((1-((5-(2,4-二氯苯基)吡啶-2-基)氧基)己-2-基)胺 基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlolophenyl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氟-4-(三氟甲基)苯基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)-2-((5-(三氟甲基)吡啶-2-基)氧基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)ethyl)amino)benzamido)propanoic acid)、(S)-2-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸乙酯(S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoate)、(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic)、(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2',4'-二氯-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoate)、(S)-3-(4-((2-((5-(5-(叔丁基)-1,3,4-噁二唑-2-基)吡啶-2-基)氧基)-1-(2',4'-二氯-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)oxy)-1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)、(S)-2-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4-(5-甲氧基嘧啶-2-基)苯基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4-(5-methoxypyrimidin-2-yl)phenyl)ethyl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((1-((5-(苯並[d]噻 唑-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((5-(benzo[d]thiazol-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((5-(苯並[d]噻唑-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzo[d]thiazol-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2,4-二氟苯基)嗒嗪-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-difluorophenyl)pyridazin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2,4-二氯苯基)嗒嗪-3-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-dichlorophenyl)pyridazin-3-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-((6-(4-(三氟甲基)苯基)嗒嗪-3-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-(2-氯-4-(三氟甲基)苯基)嗒嗪-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-chloro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-(2-氟-4-(三氟甲基)苯基)嗒嗪-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propancic acid)、3-(4-(((2S,3S)-1-((6-(2,4-二氟苯基)嗒嗪-3-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-((6-(2,4-difluorophenyl)pyridazin-3-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((4-甲基-1-((6-(4-(三氟甲基)苯基)嗒嗪-3-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-((6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(苯並呋喃-2基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(benzofuran-2-yl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2-氟-4-(三氟甲基)苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(4-氟苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(4-fluorophenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(2,4-二氟苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(2,4-difluorophenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((6-(4-(叔丁基)苯基)嗒嗪-3-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((6-(4-(tert-butyl)phenyl)pyridazin-3-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(苯並呋喃-2-基)-6-甲基吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)-6-methylpyridin-2-yl)oxy)hexan-2-yl)amino)benz amido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(苯並呋喃-2-基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(benzofuran-2-yl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2,4-二氯苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2,4-dichlorophenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2-氟-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2,4-二氯苯基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(苯並呋喃-2-基)-6-甲基吡啶 -2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(2',4'-二氯-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)庚-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)heptan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-4-甲基戊-2-基)胺基)苯甲 醯胺基)丙酸((R)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)庚-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)heptan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((5-甲基-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((5-methyl-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-丙氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸(R)-3-(4-((1-propoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-(2',4'-二氯-[1,1'-聯苯基]-4-yl)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-丙氧基-3-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-propoxy-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-3-isobutoxypropan-2-yl)amiro)benzamido)propanoic acid)、(R)-3-(4-((1-異丁氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-異丁氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(2',4'-二氯-[1,1'-聯苯基]-4-基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-丙氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-丙氧基-3-(3'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino )benzamido)propanoic acid)、(S)-3-(4-((1-丙氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-丙氧基-3-(3'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-propoxy-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(1H-吲哚-2-基)苯基)-3-丙氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(1H-indol-2-yl)phenyl)-3-propoxypropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-異丁氧基-3-(3'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-異丁氧基-3-(2'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-異丁氧基-3-(3'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-異丁氧基-3-(3',4',5'-三氟-[1,1'-聯苯 基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-3-異丁氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-3-isobutoxypropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-異丁氧基-3-(4'-(三氟甲氧基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((,S)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-異丁氧基-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-isobutoxy-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((2-(4-(苯並呋喃-2-基)苯基)-1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-(4-(benzofuran-2-yl)phenyl)-1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)ethyl)amino)benzamido)propanoic acid)、3-(4-(((1S)-2-甲基-1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-2-methyl-1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)butyl)amino)benzamido)propanoic acid)、3-(4-(((1S)-1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)-2-甲基丁基)胺基)苯甲醯胺基)丙酸(3-(4-(((1S)-1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-2-methylbutyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)-2-甲基丙基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-2-methylpropyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,3,4-噁二唑-2-基)-2-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-2-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(5-(3-甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)-2-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)、(S)-2-(4-((1-(5-(3甲基苯並呋喃-2-基)-1,3,4-噁二唑-2-基)-2-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((1-(5-(3-methylbenzofuran-2-yl)-1,3,4-oxadiazol-2-yl)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-3-yl)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2R)-1-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2R)-1-(5-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(5-(4-(叔丁基)苯基)-1,2,4-噁二唑-3-基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(5-(4-(tert-butyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylbutan-2-yl)ami no)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-4-甲基-1-側氧基物-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-側氧基-3-苯基-1-((2',4',6'-三甲基-[1,1'-聯苯基]-4-基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-oxo-3-phenyl-1-((2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((4-甲基-1-側氧基-1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)胺基)戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((4-methyl-1-oxo-1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopehtan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基-3- 苯基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(4-氟苯基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(4-氟苯基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並[b]噻吩-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzo[b]thiophen-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(苯並[b]噻吩-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基丙酸((S)-3-(4-((1-((4-(benzo[b]thiophen-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(萘基-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-1-側氧基-3-苯基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl (S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(naphthalen-2-yl)-1-oxopropan-2 -yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-側氧基-3-苯基-1-((2'-(三氟甲基)-[1,1'-聯苯基]-4-基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-oxo-3-phenyl-1-((2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(叔丁基)苯基)胺基)-1-側氧基-3-(2',4',6'-三甲基-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(tert-butyl)phenyl)amino)-1-oxo-3-(2',4',6'-trimethyl-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(1H-吲哚-3-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(1H-吲哚-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸甲酯(Methyl(S)-3-(4-((1-((4-(1H-indol-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(1H-吲哚-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(1H-indol-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-甲氧基萘-2-基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-methoxynaphthalen-2-yl)amino)-3-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxopentan-2-yl)a mino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-甲基-1-側氧基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-methyl-1-oxobutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-1-側氧基己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-1-oxohexan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propar-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺 基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-側氧基-3-苯基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-oxo-3-phenyl-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((6-甲氧基萘-2-基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl3-(4-(((2S,3S)-1-((6-methoxynaphthalen-2-yl)amino)-3-methyl-1-oxopentan-2-yl)amino)benzamido)propanoate)、3-(4-(((2S,3S)-1-((6-甲氧基萘-2-基)胺基)-3-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((6-methoxynaphthalen-2-yl)amino)-3-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((4-甲基-1-側氧基-1-((4-(三氟甲基)苯基)胺基)戊-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((4-methyl-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)pentan-2-yl)amino)benzanido)propanoate)、(R)-3-(4-((4-甲基-1-側氧基-1-((4-(三氟甲基)苯基)胺基)戊-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((4-methyl-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(異丙基胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(isopropylamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(異丙基胺基)-3-(萘-1-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-(isopropylamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(異丙基胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(isopropylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(異丙基胺基)-3-(萘-2-基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(isopropylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((3-(2',4'-二氯-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((3-(2',4'-二氯-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(2',4'-dichloro-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((3-(4-(苯並呋喃 -2-基)苯基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-側氧基-1-((4-(三氟甲基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-oxo-1-((4-(trifluoromethyl)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-(異丙基胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-(isopropylamino)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-(異丙基胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-(isopropylamino)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-((3,5-二氟苯基)胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-((3,5-difluorophenyl)amino)-1-oxopropan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((3-(4-(苯並呋喃-2-基)苯基)-1-((3,5-二氟苯基)胺基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4-(benzofuran-2-yl)phenyl)-1-((3,5-difluorophenyl)amino)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethoxy)phen yl)amino)propan-2-yl)amino)benzamido)propanoate)、(R)-3-(4-((3-(4'-(叔丁基)-[1,1'-聯苯基]-4-基)-1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((3-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)propan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(R)-3-(4-((1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoate)、和(R)-3-(4-((1-側氧基-1-((4-(三氟甲氧基)苯基)胺基)-3-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)丙-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-oxo-1-((4-(trifluoromethoxy)phenyl)amino)-3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)propan-2-yl)amino)benzamido)propanoic acid)所組成之群組中之任一者。
  20. 如申請專利範圍第19項所述之化合物或其藥學上可接受之鹽類，其選自由(S)-3-(4-((1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、N-((1H-四唑-5-基)甲基)-4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺(N-((1H-tetrazol-5-yl)methyl)-4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamide)、(R)-3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)苯氧基)-3- 甲基戊-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)phenoxy)-3-methylpentan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-3-(4-((1-((4'-(二甲基胺基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺benzamide((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan -2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸乙酯(Ethyl(S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoate)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並[d]噻唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)phenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並[d]噁唑-2-基)苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzo[d]oxazol-2-yl)phenoxy)-3-methylbutan-2-yl)amnino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((4'-(叔丁基)-2,6-二甲 基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((4'-(tert-butyl)-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoie acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-2,6-二甲基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2,6-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2,6-二甲基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2,6-dimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-(((S)-1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)-2-羥基丙酸((R)-3-(4-(((S)-1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)-2-hydroxypropanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)-3-methylbutan-2-yl)amino)benzamide)、(S)-3-(4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯 基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2'-二氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)he,exan-2-yl)amino)benzamide)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氯苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-chlorophenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2',4'-三氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2,2',4'-trichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-N-((1H-四唑-5-基)甲基)-4-((1-((2,2',4'-三氯-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺((S)-N-((1H-tetrazol-5-yl)methyl)-4-((1-((2,2',4'-trichloro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamide)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-2,5-二氯苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-2,5-dichlorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-((2-((2'-氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-1-苯基乙基)胺基)苯甲醯胺基)丙酸(3-(4-((2-((2'-chloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-1-phehylethyl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-2,5-二氯苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸 (3-(4-(((2S,3S)-1-(4-(benzofuran-2-yl)-2,5-dichlorophenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-3-甲基-1-((2,2',5-三氯-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-3-methyl-1-((2,2',5-trichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)pentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2-氯-2'-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-chloro-2'-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3,5-二氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3,5-difluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2,6-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2,6-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2,6-二氟-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2',4'-dichloro-2,6-difluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-y l)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-三氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2-氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-chloro-2-fluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並呋喃-2-基)-3-氟苯氧基)-4-甲基戊-2- 基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzofuran-2-yl)-3-fluorophenoxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-氟-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-fluoro-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2,2'-二氟-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3,3-二甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2,2'-difluoro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3,3-dimethylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-(4-(苯並[d]噻唑-2-基)-3-氟苯氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-(4-(benzo[d]thiazol-2-yl)-3-fluorophenoxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-(4-(苯並呋喃-2-基)-3-甲氧基苯氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-(4-(benzofurar-2-yl)-3-methoxyphenoxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氯-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((2'-chloro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基) 丙酸(3-(4-(((2S,3S)-1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氯-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2'-hloro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-mathylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2',4'-二氯-2-甲氧基-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2',4'-dichloro-2-methoxy-[1,1'-biphenyl]-4-yl)oxy)hexam-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸(S)-3-(4-((1-((2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid、(S)-3-(4-((1-((2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2'-氟-2-甲氧基-4'-(三氟甲基)-[1,1'-聯苯基]-4-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸 ((S)-3-(4-((1-((2'-fluoro-2-methoxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((3-甲基-1-((5-(4-(三氟甲基)苯基)吡啶-2-基)氧基)丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((3-methyl-1-((5-(4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)butan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基丁-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylbutan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(benzofuran-2-yl)pynidin-2-yl)oxy)hexar-2-yl)amino)benzamido)propanoic acid)、(S)-2-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)乙烷-1-磺酸((S)-2-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-bip henyl]-4-yl)ethyl)amino)benzamido)ethane-1-sulfonic acid)、(S)-3-(4-((2-((5-(苯並呋喃-2-基)吡啶-2-基)氧基)-1-(4'-(三氟甲基)-[1,1'-聯苯基]-4-基)乙基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((2-((5-(benzofuran-2-yl)pyridin-2-yl)oxy)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)己-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)hexan-2-yl)amino)benzamido)propanoic acid)、3-(4-(((2S,3S)-1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-3-甲基戊-2-基)胺基)苯甲醯胺基)丙酸(3-(4-(((2S,3S)-1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-3-methylpentan-2-yl)amino)benzamido)ppopanoic acid)、(S)-3-(4-((1-((5-(2-氯-4-(三氟甲基)苯基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2-chloro-4-(trifluoromethyl)phenyl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((5-(2,4-二氯苯基)-6-甲基吡啶-2-基)氧基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((5-(2,4-dichlorophenyl)-6-methylpyridin-2-yl)oxy)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(R)-3-(4-((1-(4-(苯並呋喃-2-基)苯基)-4-甲基戊-2-基)胺基)苯甲醯胺基)丙酸((R)-3-(4-((1-(4-(benzofuran-2-yl)phenyl)-4-methylpentan-2-yl)amino)benzamido)propanoic acid)、(S)-3-(4-((1-((2',4'-二氯-[1,1'-聯苯基]-4-基)胺基)-4-甲基-1-側氧基物-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((2',4'-dichloro-[1,1'-biphenyl]-4-yl)amino)-4-methyl-1-oxopentan-2-yl) amino)benzamido)propanoic acid)、(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-4-甲基-1-側氧基戊-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-4-methyl-1-oxopentan-2-yl)amino)benzamido)propanoic acid)、和(S)-3-(4-((1-((4-(苯並呋喃-2-基)苯基)胺基)-3-(4-氟苯基)-1-側氧基丙-2-基)胺基)苯甲醯胺基)丙酸((S)-3-(4-((1-((4-(benzofuran-2-yl)phenyl)amino)-3-(4-fluorophenyl)-1-oxopropan-2-yl)amino)benzamido)propanoic acid)所組成之群組中之任一者。
  21. 一種醫藥組成物，包含如申請專利範圍第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。
  22. 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，用以製備降低血糖含量之藥物。
  23. 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，用以製備治療與升糖素相關病症之藥物。
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