TWI826795B - 用於治療非酒精性脂肪肝疾病及非酒精性脂肪肝炎之帶有碳酸酯的紫檀芪胺基酸的新穎類似物 - Google Patents
用於治療非酒精性脂肪肝疾病及非酒精性脂肪肝炎之帶有碳酸酯的紫檀芪胺基酸的新穎類似物 Download PDFInfo
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- TWI826795B TWI826795B TW110121538A TW110121538A TWI826795B TW I826795 B TWI826795 B TW I826795B TW 110121538 A TW110121538 A TW 110121538A TW 110121538 A TW110121538 A TW 110121538A TW I826795 B TWI826795 B TW I826795B
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
- C07C329/02—Monothiocarbonic acids; Derivatives thereof
- C07C329/04—Esters of monothiocarbonic acids
- C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/48—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
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Abstract
合成一系列之帶有碳酸酯的水溶性紫檀芪胺基酸的新穎類似物，其顯示活性於治療非酒精性脂肪肝疾病及非酒精性脂肪肝炎(NASH)。
Description
本發明係關於用於治療非酒精性脂肪性肝疾病(NAFLD)及非酒精性脂肪性肝炎(NASH)之帶有碳酸酯的紫檀芪胺基酸的新穎類似物。
非酒精性脂肪性肝疾病(NAFLD)由一系列之起始於肝臟的單純脂肪性浸潤的組織學變化所組成，也已知為非酒精性脂肪性肝疾病(1)。非酒精性脂肪性肝炎(NASH)係NAFLD的嚴重惡化型。其可能進展為纖維化肝硬化、肝衰竭及肝細胞癌(HCC)且可快速地轉為對晚期肝疾病或肝臟移植C(2,3)的主要癌症。NAFLD係最為盛行的慢性肝疾病且全世界成人族群的四分之一罹患NAFLD(4)。
根據目前的估算，於2027年合併日本、英國、法國、德國、義大利及西班牙中經診斷患有NASH的成人族群的盛行率將接近1800萬。生活型態干預，如膳食卡洛里限制及運動，為目前對於NASH之基本治療療法，但其等難以改良及維持，更不用述及其等無法符合對於醫藥的緊急需求(2)。
雖然對於開發中的NASH-藥物候選者有數個臨床試驗(5-7)，但暫時沒有經US FDA核准用於治療NASH的藥物。在臨床試驗的藥劑中，奧貝膽酸(Obeticholic acid)(Ocaliva)，已知主要作為膽汁性膽管炎藥物，係目前唯一的三期臨床試驗藥物候選者，於抑制NASH藥效中達成正向結果，且後續將向US FDA提出申請(新藥申請)(8,9)。總而言之，為新穎、安全且有效的NASH/NAFLD治療或預防藥物的開發係即時優先。
紫檀芪(反式-3,5-二甲氧基-4-羥基芪)為天然產生的植物化學化合物，主要可見於藍莓、葡萄及各種樹木的木材(10-12)。紫檀芪已知具有多種優勢於預防及治療某些疾病，包括癌症、血脂異常、糖尿病及認知性功能退化(10,11,13)。
近來，已報導紫檀芪於肥胖大鼠種降低肝脂肪變性及修飾肝脂肪酸趨勢(14,15)。於動物及人類試驗使用紫檀芪的結果已顯示低毒性及高安全性(16)。因此，高度可能為紫檀芪可開發為用於治療NAFLD/NASH的臨床藥物。然而，紫檀芪具有不佳的水溶解度，0.011mg/mL，(www.vcclab.org)，其無法進行臨床研究。一些醫藥化學家已將其衍生至水可溶磷酸鹽衍生物(17)。一般而言，酚系磷酸鹽具有不佳安定性，因此很少製造為口服劑型。至今，沒有文獻關於紫檀芪磷酸鹽的口服活體藥效。僅有靜脈注射(iv)動物研究被報導(18)。稍後，Chava satyanarayana等人製造紫檀芪磷酸鹽及希格列汀(sitagliptin)(一種口服活性二肽基肽酶-4，(DPP-IV)酵素抑制劑)為醫藥組成物，包含治療有效量的希格列汀紫檀芪磷酸鹽呈結晶型(或無定型)(Chava satyanarayana等人，專利案號：WO2014147641)。此化合物系基於希格列汀。該專利，相關於希格列汀紫檀芪磷
酸鹽，含有用於製備希格列汀紫檀芪磷酸鹽的方法及相同的醫藥組成物，但無任何體內藥效結果。
Azzolini M等人合成一系列的紫檀芪胺基酸胺甲酸酯的水可溶衍生物(19)，測試其藥物動力學及分布趨勢，且發現吸收的增加以及代謝的減低，但無進一步的測試其體內藥效。可能的原因為胺甲酸酯的酯鏈結於體內分解過於緩慢以致於胺甲酸酯衍生物無法轉化為生物活性代謝物(例如，依立替康irinotecan)。此外，Gonzalez-Alfonso JL等人合成一系列新穎的八臂-聚乙二醇紫檀芪衍生物，其具有良好的水可溶性，但僅進行用於測試其抗腫瘤活性的IV方法(20)。Kuo等人合成用於鱗狀癌及肝癌作為抑制劑的一系列芪類(Kuo Sheng-Chu et al.美國專利案號9.266.813 B2.2016)。在所合成的芪類中，一些水溶性的類紫檀芪為不安定的，以及一些安定的類紫檀芪為不佳水溶解姓。其水溶解度增加，但沒有報導其體內藥效(20)。
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14. Aguirre L, Palacios-Ortega S, Fernandez-Quintela A, Hijona E, Bujanda L, Portillo MP. Pterostilbene Reduces Liver Steatosis and Modifies Hepatic Fatty Acid Profile in Obese Rats. Nutrients. 2019;11(5).
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18. Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. 2011;68(3):593-601.
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本發明之一目的係提供一系列具有下述式之化合物：
其中n為1至3；m為2至6；
Q、X及Y獨立地為O、S或NH；Ra、Rb及Rc獨立地為H、鹵素、C1-C6直鏈烷基、C1-C6直鏈烷氧基、C3-C6支鏈烷基、C3-C6支鏈烷氧基或C1-C6氟烷氧基；Rd及Re獨立地為H、鹵素、C1-C6直鏈烷基、C1-C6直鏈烷氧基、C3-C6支鏈烷基、C3-C6支鏈烷氧基或C1-C6氟烷氧基，或Rd及Re係鏈結以形成環結構，使得
，其中j為1至3；或其醫藥可接受鹽。
本發明之另一目的係提供本發明化合物或其醫藥可接受鹽之新用途，係用於製造醫藥用以於患者治療非酒精性脂肪性肝疾病及非酒精性脂肪性肝炎。
本發明之又另一目的係提供醫藥組成物，用於個體治療非酒精性脂肪性肝疾病或非酒精性脂肪性肝炎，該醫藥組成物包含本發明之化合物或其醫藥可接受鹽之用於該治療的治療有效量。
本發明進一步提供一種方法用於治療非酒精性脂肪性肝疾病或非酒精性脂肪性肝炎，該方法包含對有需要該治療之罹患非酒精性脂肪性肝疾病或非酒精性脂肪性肝炎的個體投藥有效量之本發明之化合物或其醫藥可接受鹽。
本發明亦提供一種有用於合成本發明之化合物或其醫藥可接受鹽之中間體化合物，其具有下述式：
其中m、Rc、Rd及Re係如上述定義，以及Boc為建構組件官能基。
本發明之較佳具體例包括(但不限於)於本說明書末所附的申請專利範圍中所記載的特徵。。
圖1為照相圖(放大率：200X)顯示五群中之小鼠的肝臟樣品：偽組(非-MCD膳食)；MCD膳食組；MCD膳食+75mg/kg本發明化合物5c；MCD膳食+100mg/kg化合物5c；以及MCD膳食+150mg/kg化合物5c，其中該肝臟樣品係藉由蘇木精-伊紅(H&E)染色使用相位差顯微鏡照相。
圖2顯示化合物5c於H2O中，於25℃於24小時的溶解度。
根據本發明之較佳具體例合成一系列水可溶之帶有碳酸酯的紫檀芪胺基酸的新穎類似物，其顯示活性於治療非酒精性脂肪性肝疾病及非酒精性脂肪性肝炎(NASH)。
1.化學合成
1-1.材料及儀器
起始材料、試劑及溶劑係由商業購應商(Sigma-Aldrich、Acros、TCI、Alfa、Combi-Blocks、Matrix及Fischer)購得且無進一步純化而直接使用。1H及13C-NMR光譜係於Varian AS500 500 NMR-光譜儀或Agilent Technologies VnmrJ 500 NMR-光譜儀於指示的溶劑中獲得。化學偏移係相對於作為內標準的TMS表示為ppm(δ單位)。快速管柱層析係於填裝有Merck矽膠60(0.063-0.200μm)的管柱進行。化合物或最終化合物的純化係利用逆相高效液體層析(RP-HPLC)以UV偵測於220或254nm(Jasco UV-975 detector)使用Inertsil ODS-3 C18(5μm,30mm X 250mm)管柱進行。移動相係由H2O及CH3CN(沖提液A，70% ACN或80% CAN，等強度，42mL/min流速；沖提液B，梯度，詳細敘述於試驗)構成。利用電子撞擊的質譜(MS)係由API 3200 LC/MS/MS紀錄。溶劑為試劑等級，以及當必要時，其等可藉由標準方法予以純化及除水。反應溶液的濃度涉及減壓使用旋轉蒸發器。
1-2 目標化合物5a-10的合成
1-2-1.化合物5a-5s的合成
目標化合物5a-5s係根據方案1合成。各種胺基酸(1a-1s)與乙醇胺於1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDCI)、二異丙基乙基胺(DIPEA)及N,N-二甲基胺基吡啶(DMAP)於CH2Cl2或1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]嘧啶鎓3-氧化物六氟磷酸鹽(HATU)及DIPEA的存在下反應以獲得對應的羥基醯胺衍生物(化合物2a-2s)。2a-2s與氯甲酸p-硝基苯基酯的反應產生對應的碳酸p-硝基苯基酯(3a-3s)，其無進一步純化而與紫檀芪反應以獲得對應的4a-4s。化合物4a-4s與4M HCl於1,4-二噁烷或三氟乙酸(TFA)及三異丙基矽烷(TIPS)於CH2Cl2的後續脫保護以提供目標化合物5a-5s。
試劑與條件：(a)EDCI、DIPEA、DMAP、CH2Cl2或HATU、DIPEA、CH2Cl2；(b)NEt3、CH2Cl2；(c)DMAP、CAN，50℃；(d)4M HCl於1,4-二噁烷，或TFA、TIPS、CH2Cl2。
(2-((2-羥基乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(2a)
對乙醇胺(3.03g,49.6mmol)、Boc-Gly-OH 1a(7.2g,41.3mmol)及DIPEA(16g,124mmol)於CH2Cl2(80mL)的攪拌溶液添加EDCI(61.7g,46.6mmol)。反應混合物於室溫攪拌12小時。反應後，溶劑於真空移除，殘質藉由管柱層析純化(正己烷至EA/正己烷=1/5(V/V))以提供目標產物2a(3.3g,37%產率)呈白色粉末。
1H-NMR(CDCl3,500MHz),δ(ppm)：6.98(s,NH),5.62(s,NH),3.80(s,2H),3.70-3.68(m,2H),3.43-3.40(m,2H),3.25(s,OH),1.44(s,9H).
(1-((2-羥基乙基)胺基)-1-側氧基丙烷-2-基)胺甲酸第三丁基酯(2b)
2b由Boc-Ala-OH 1b獲得，使用如2a的相同合成步驟。
產率37%。1H-NMR(CDCl3,500MHz),δ(ppm)：6.90(s,NH),5.37(s,NH),4.13-4.10(m,2H),3.69-3.68(m,2H),3.44-3.43(m,1H),3.37-3.36(m,1H),1.43(s,9H),1.35(d,J=6.5Hz,3H).
(1-((2-羥基乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(2c)
對乙醇胺(335mg,5.4819mmol)、Boc-Val-OH 1c(1191mg,5.5mmol)及DIPEA(2387uL,13.7mmol)於CH2Cl2(40mL)的攪拌溶液添加HATU(2501mg,6.6mmol)。反應混合物於室溫攪拌12小時。反應後，溶劑於真空移除，殘質藉由管柱層析純化(正己烷至EA/正己烷=3/1(V/V))以提供目標產物2c(1113mg,78%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：6.65(s,NH),5.15(s,NH),3.86(t,J=7.5Hz,1H),3.70(s,2H),3.49-3.41(m,1H),3.40-3.36(m,1H),3.07(s,1H),2.11-2.10(m,1H)1.43(s,9H),0.96(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H).
(1-((2-羥基乙基)胺基)-4-甲基-1-側氧基戊烷-2-基)胺甲酸第三丁基酯(2d)
2d由Boc-Leu-OH 1d獲得，使用如2a的相同合成步驟。
產率70%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.05(s,NH),5.31(s,NH),4.13-4.12(m,1H),3.70-3.67(m,2H),3.47-3.44(m,1H),3.38-3.34(m,1H),1.67-1.60(m,2H),1.52-1.47(m,1H),1.42(s,9H),0.94-0.91(m,6H).
(1-((2-羥基乙基)胺基)-3-甲基-1-側氧基戊烷-2-基)胺甲酸第三丁基酯(2e)
2e由Boc-Ile-OH 1e獲得，使用如2a的相同合成步驟。
產率64%。1H-NMR(CDCl3,500MHz),δ(ppm)：6.73(s,NH),5.19(s,NH),3.90(t,J=7.0Hz,1H),3.71-3.69(m,2H),3.49-3.44(m,1H),3.39-3.36(m,1H),2.48-2.46(m,1H),1.86-1.84(m,1H),1.56-1.53(m,1H),1.43(s,9H),0.94-0.89(m,6H).
(1-((2-羥基乙基)胺基)-4-(甲基硫基)-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(2f)
2f由Boc-Met-OH 1f獲得，使用如2c的相同合成步驟。
產率32%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.30(s,NH),5.73(s,NH),4.14-4.12(m,1H),3.59-3.58(m,2H),3.39-3.24(m,2H),2.49-2.46(m,2H),2.05(s,3H),2.02-1.98(m,1H),1.85-1.82(m,1H),1.38(s,9H).
(3-(第三丁氧基)-1-((2-羥基乙基)胺基)-1-側氧基丙烷-2-基)胺甲酸第三丁基酯(2g)
2g由Boc-Ser(tBu)-OH 1g獲得，使用如2a的相同合成步驟。
產率41%。1H-NMR(CDCl3,500MHz),δ(ppm)：6.93(s,NH),5.42(s,NH),4.19-4.17(m,1H),3.76(s,OH),3.75-3.69(m,2H),3.42-3.40(m,2H),2.55-2.52(m,1H)1.43(s,9H),1.17(s,9H).
(3-(第三丁氧基)-1-((2-羥基乙基)胺基)-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(2h)
2h由Boc-Thr(tBu)-OH 1h獲得，使用如2a的相同合成步驟。
產率24%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.12(s,NH),5.62(s,NH),4.13-4.09(m,2H),3.72-3.70(m,2H),3.49-3.48(m,1H),3.38-3.37(m,1H),1.45(s,9H),1.24(s,9H),1.06(d,J=5.5Hz,3H).
(1-((2-羥基乙基)胺基)-1-側氧基-3-(三苯甲基硫基)丙烷-2-基)胺甲酸第三丁基酯(2i)
2i由Boc-Cys(Trt)-OH 1i獲得，使用如2c的相同合成步驟。
產率71%。1H-NMR(CDCl3,500MHz),δ(ppm)：.7.42-7.40(m,6H),7.31-7.27(m,6H),7.26-7.20(m,3H),6.42(s,NH),4.88(s,NH),3.81-3.80(m,1H),3.64-3.63(m,2H),3.34-3.33(m,2H),2.69-2.66(m,1H),2.57-2.53(m,1H),1.41(s,9H).
(1-((2-羥基乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(2j)
2j由Boc-Phe-OH 1j獲得，使用如2c的相同合成步驟。
產率88%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.33-7.30(m,2H),7.25-7.21(m,3H),6.21(brs,1H,NH),5.11(brs,1H,NH),4.29(d,J=7.0Hz,1H),3.58-3.57(m,2H),3.32(s,2H),3.10-3.01(m,2H),2.44(brs,1H,OH),1.44(s,9H).
(3-(4-(第三丁氧基)苯基)-1-((2-羥基乙基)胺基)-1-側氧基丙烷-2-基)胺甲酸第三丁基酯(2k)
2k由Boc-Tyr(tBu)-OH 1k獲得，使用如2c的相同合成步驟。
產率34%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.09(d,J=8.5Hz,2H),6.91(d,J=8.5Hz,2H),6.39(s,NH),5.22(s,NH),4.27-4.26(m,1H),3.59-3.56(m,2H),3.31-3.30(m,2H),2.99-2.97(m,2H),1.40(s,9H),1.32(s,9H).
3-(2-((第三丁氧基羰基)胺基)-3-((2-羥基乙基)胺基)-3-側氧基丙基)-1H-吲哚-1-羧酸第三丁基酯(2l)
2l由Boc-Trp(Boc)-OH 1l獲得，使用如2a的相同合成步驟。
產率35%。1H-NMR(CDCl3,500MHz),δ(ppm)：8.13-8.11(m,1H),7.60(d,J=7.5Hz,1H),7.47(s,1H),7.33(t,J=7.5Hz,1H),7.28-7.25(m,1H),6.20(s,NH),5.18(s,NH),4.39-4.38(m,1H),3.60-3.52(m,2H),3.31-3.28(m,2H),3.21-3.14(m,2H),1.67(s,9H),1.43(s,9H).
(1-((2-羥基乙基)胺基)-1-側氧基-3-(1-三苯甲基-1H-咪唑-2-基)丙烷-2-基)胺甲酸第三丁基酯(2m)
2m由Boc-His(Trt)-OH 1m獲得，使用如2c的相同合成步驟。
產率67%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.37(s,1H),7.34-7.33(m,9H),7.11-7.10(m,6H),6.34(s,1H),6.57(s,NH),5.79(s,NH),4.33(s,1H),3.73-3.60(m,2H),3.51(brs,1H),3.21(brs,1H),3.08-3.02(m,2H),1.43(s,9H).
(6-((2-羥基乙基)胺基)-6-側氧基己烷-1,5-二基)二胺甲酸二-第三丁基酯(2n)
2n由Boc-Lys(Boc)-OH 1n獲得，使用如2c的相同合成步驟。
產率70%。1H-NMR(CDCl3,500MHz),δ(ppm)：6.88(s,NH),5.43(s,NH),4.78(s,NH),4.07-4.04(m,1H),3.70-3.68(m,2H),3.41-3.40(m,2H),3.10-3.09(m,2H),1.85-1.79(m,1H),1.66-1.62(m,1H),1.49-1.46(m,2H),1.42(s,18H),1.39-1.37
(m,2H).
(1-((2-羥基乙基)胺基)-1-側氧基-5-(3-((2,2,4,6,7-五甲基-2,3-二氫苯并呋喃-5-基)磺醯基)胍基)戊烷-2-基)胺甲酸第三丁基酯(2o)
2o由Boc-Arg(Pbf)-OH 1o獲得，使用如2a的相同合成步驟。
產率50%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.42(s,NH),6.37(s,NH),5.81(s,NH),4.23-4.18(m,1H),3.72-3.71(m,2H),3.42-3.41(m,2H),3.31-3.26(m,2H),2.92(s,3H),2.57(s,3H),2.50(s,3H),2.09(s,3H),1.90-1.56(m,4H),1.46(s,6H),1.42(s,9H).
(1-((2-羥基乙基)胺基)-1,4-二側氧基-4-(三苯甲基胺基)丁烷-2-基)胺甲酸第三丁基酯(2p)
2p由Boc-Asn(Trt)-OH 1p獲得，使用如2a的相同合成步驟。
產率37%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.30-7.23(m,9H),7.19-7.17(m,6H),7.11(s,NH),6.91(s,NH),6.06(s,NH),4.41(m,1H),3.57-3.55(m,2H),3.31-3.29(m,2H),3.06-3.03(m,1H),2.62-2.58(m,1H),1.93(s,1H),1.42(s,9H).
(1-((2-羥基乙基)胺基)-1,5-二側氧基-5-(三苯甲基胺基)戊烷-2-基)胺甲酸第三丁基酯(2q)
2q由Boc-Gln(Trt)-OH 1q獲得，使用如2c的相同合成步驟。
產率51%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.30-7.23(m,15H),6.83(s,NH),5.67(s,NH),4.11-3.98(m,1H),3.54-3.53(m,2H),3.32-3.22(m,2H),2.48-2.46(m,1H),2.37-2.34(m,1H),2.04-1.98(m,1H),1.85-1.84(m,1H),1.41(s,9H).
3-((第三丁氧基羰基)胺基)-4-((2-羥基乙基)胺基)-4-側氧基丁酸
第三丁基酯(2r)
2r由Boc-Asp(tBu)-OH 1r獲得，使用如2a的相同合成步驟。
產率37%。1H-NMR(CDCl3,500MHz),δ(ppm)：6.93(s,NH),5.63(s,NH),4.43-4.40(m,1H),3.70-3.68(m,2H),3.44-3.37(m,2H),2.87-2.83(m,1H),2.66-2.64(m,1H),1.44(s,9H),1.43(s,9H).
4-((第三丁氧基羰基)胺基)-5-((2-羥基乙基)胺基)-5-側氧基戊酸第三丁基酯(2s)
2s由Boc-Glu(tBu)-OH 1s獲得，使用如2a的相同合成步驟。
產率37%。1H-NMR(CDCl3,500MHz),δ(ppm)：6.96(s,NH),5.52(s,NH),4.13-4.10(m,1H),3.69-3.68(m,2H),3.41-3.40(m,2H),2.39-2.30(m,2H),2.05-2.03(m,1H),1.91-1.88(m,1H),1.43(s,9H),1.42(s,9H).
(E)-(2-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(4a)的合成
對化合物2a(2.02g,9.3mmol)於無水CH2Cl2(15ml)的攪拌溶液添加三乙基胺(3.22mL,23.1mmol)及於0℃滴加氯甲4-硝基苯基酯溶液(1.96g,9.7mmol於10mL CH2Cl2)。反應混合物於0℃攪拌15分鐘，且溫熱至室溫。混合物於室溫攪拌額外的4小時。反應完成後(以TLC確認)，藉由蒸發移除溶劑。粗製中間體混合紫檀芪(2.50g,9.8mmol)及DMAP(2.27g,18.6mmol)於ACN(20ml)中。所得混合物加熱至50℃持續1小時。反應後，於真空移除溶劑。殘質取至EA且以飽和檸檬酸溶液清洗。收集有機層，以Na2SO4乾燥後蒸發。殘質藉由管柱層析純化(矽膠，0至25%的EtOAc/正己烷)以提供粗製產物，其進一步藉由製
備型HPLC純化(70% ACN,30% H2O)以提供目標化合物4a(2.22g,48%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.52(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.5Hz,2H),6.51(brs,NH),6.41(t,J=2.5Hz,1H),5.10(brs,NH),4.35(t,J=5.5Hz,2H),3.84-3.79(m,8H),3.67(q,J=5.5Hz,2H),1.46(s,9H).質量觀察值[M-Boc+H]+=402.2；[M+H]+=502.2,[M+Na]+=524.2,[2M+H]+=902.4.
中間體4b-4s係根據如使用於4a的類似合成步驟合成。
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基丙烷-2-基)胺甲酸第三丁基酯(4b)
4b由2b獲得，使用如4a的相同合成步驟。
產率56%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.67(s,2H),6.58(s,1H),6.41(s,1H),4.94(s,1H),4.34(t,J=5.0Hz,2H),4.17(s,1H),3.84(s,6H),3.65-3.64(m,1H),1.46(s,9H),1.38(d,J=7.5Hz,3H).質量觀察值[M-Boc+H]+=416.2；[M+H]+=516.3,[M+Na]+=538.3.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(4c)
4c由2c獲得，使用如4a的相同合成步驟。
產率78%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.5Hz,2H),7.17(d,J=9.0Hz,2H),7.06(d,J=16.0Hz,1H),6.99(d,J=16.0Hz,1H),6.66(d,J=2.0Hz,2H),6.41-6.60(m,2H),5.03(s,1H),4.34(t,J=5.0Hz,2H),3.93-3.83(m,1H),3.70(s,6H),3.68-3.63(m,2H),2.17-2.16(m,1H)1.45(s,9H),0.98(d,J=6.5
Hz,3H),0.93(d,J=6.5Hz,3H).質量觀察值[M-Boc+H]+=444.1；[M+Na]+=566.1.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-4-甲基-1-側氧基戊烷-2-基)胺甲酸第三丁基酯(4d)
4d由2d獲得，使用如4a的相同合成步驟。
產率32%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.5Hz,2H),7.18(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.98(d,J=16.5Hz,1H),6.67(d,J=2.0Hz,2H),6.55(s,NH),6.41(s,1H),4.84(s,NH),4.33(t,J=5.0Hz,2H),4.11(s,1H),3.84(s,6H),3.64(dd,J=5.0,10.5Hz,2H),1.73-1.66(m,2H),1.51-1.47(m,1H),1.45(s,9H),0.96-0.94(m,6H).質量觀察值[M-Boc+H]+=457.3；[M-Boc+Na]+=479.2；[M+Na]+=579.3；[2M+Na]+=1135.5.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-3-甲基-1-側氧基戊烷-2-基)胺甲酸第三丁基酯(4e)
4e由2e獲得，使用如4a的相同合成步驟。
產率27%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.17(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.5Hz,2H),6.41-6.40(m,2H),5.02(s,NH),4.34(t,J=5.0Hz,2H),3.98-3.94(m,1H),3.83(s,6H),3.71-3.61(m,2H),1.92-1.91(m,1H),1.57-1.51(m,1H),1.45(s,9H),1.18-1.09(m,1H),0.95-0.88(m,6H).質量觀察值[M-Boc+H]+=457.3；[M+Na]+=579.3；[2M+H]+=1135.5.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)
胺基)-4-(甲基硫基)-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(4f)
4f由2f獲得，使用如4a的相同合成步驟。
產率49%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.52(d,J=8.0Hz,2H),7.18(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.64(s,NH),6.41(t,J=2.0Hz,1H),5.16(s,1H),4.34(t,J=5.0Hz,2H),4.32-4.28(m,1H),3.84(s,6H),3.69-3.61(m,2H),2.63-2.52(m,2H),2.16-2.08(m,4H),1.98-1.92(m,1H),1.45(s,9H).質量觀察值[M-Boc+H]+=476.2；[M+H]+=576.3；[M+Na]+=598.3.
(E)-(3-(第三丁氧基)-1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基丙烷-2-基)胺甲酸第三丁基酯(4g)
4g由2g獲得，使用如4a的相同合成步驟。
產率46%.1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.5Hz,2H),7.16(d,J=8.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.41(t,J=2.0Hz,1H),5.44(s,NH),4.33(t,J=5.0Hz,2H),4.19(s,1H),3.84(s,6H),3.80(s,1H),3.68-3.64(m,2H),3.41-3.39(m,1H),1.46(s,9H),1.20(s,9H).質量觀察值[M-Boc-tBu+H]+=432.3；[M+H]+=588.5；[M+Na]+=610.4；[2M+H]+=1174.8；[2M+Na]+=1196.9.
(E)-(3-(第三丁氧基)-1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(4h)
4h由2h獲得，使用如4a的相同合成步驟。
產率48%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.34(s,NH),7.16(d,J=8.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),
6.66(d,J=2.5Hz,2H),6.41(t,J=2.5Hz,1H),5.64(d,J=5.0Hz,NH),4.37-4.31(m,2H),4.15-4.13(m,2H),3.84(s,6H),3.69-3.65(m,2H),1.46(s,9H),1.28(s,9H),1.07(d,J=6.0Hz,3H).質量觀察值[M-Boc-tBu+H]+=446.2；[M+H]+=602.5；[M+Na]+=624.4；[2M+H]+=1202.9；[2M+Na]+=1224.9.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基-3-(三苯甲基硫基)丙烷-2-基)胺甲酸第三丁基酯(4i)
4i由2i獲得，使用如4a的相同合成步驟。
產率27%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.49(d,J=8.5Hz,2H),7.44-7.42(m,6H),7.31-7.28(m,6H),7.24-7.21(m,3H),7.14(d,J=8.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.0Hz,1H),6.66(d,J=2.5Hz,2H),6.41(t,J=2.0Hz,1H),6.40(s,1H),4.79(s,1H),4.28(t,J=5.0Hz,2H),3.84(s,6H),3.57-3.56(m,2H),2.80-2.77(m,1H),2.58-2.56(m,1H),1.42(s,9H)，質量觀察值[M+H]+=789.3；[M+Na]+=811.3.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(4j)
4j由2j獲得，使用如4a的相同合成步驟。
產率46%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.52(d,J=9.0Hz,2H),7.33-7.30(m,2H),7.24-7.21(m,3H),7.17(d,J=9.0Hz,2H),7.07(d,J=16.5Hz,1H),7.00(d,J=16.5Hz,1H),6.67(s,2H),6.41(s,1H),6.13(brs,NH),5.03(brs,NH),4.34(s,1H),4.24-4.23(m,1H),4.17(s,1H),3.84(s,6H),3.56(s,2H),3.11-3.02(m,2H),1.42(s,9H).質量觀察值[M-Boc+H]+=492.2；[M+H]+=592.4；[M+Na]+=614.3.
(E)-(3-(4-(第三丁氧基)苯基)-1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基丙烷-2-基)胺甲酸第三丁基酯(4k)
4k由2k獲得，使用如4a的相同合成步驟。
產率39%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.18(d,J=9.0Hz,2H),7.10(d,J=7.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.93(d,J=8.5Hz,2H),6.66(d,J=2.0Hz,2H),6.41(s,1H),6.18(t,J=6.0Hz,NH),5.01(brs,NH),4.31-4.24(m,2H),4.23-4.19(m,1H),3.84(s,6H),3.60-3.52(m,2H),3.07-2.99(m,2H),1.45(s,9H),1.32(s,9H).質量觀察值[M-Boc-tBu+H]+=508.2；[M-Boc+H]+=564.3；[M+H]+=664.4,[M+Na]+=686.4；[M+K]+=702.4.
(E)-3-(2-((第三丁氧基羰基)胺基)-3-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-3-側氧基丙基)-1H-吲哚-1-羧酸第三丁基酯(4l)
4l由2l獲得，使用如4a的相同合成步驟。
產率30%。1H-NMR(CDCl3,500MHz),δ(ppm)：8.14-8.12(m,1H),7.59(d,J=7.5Hz,1H),7.51-7.47(m,3H),7.32(t,J=8.5Hz,1H),7.26-7.24(m,2H),7.14(d,J=8.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.41(t,J=2.5Hz,1H),6.30(s,NH),5.18(s,NH),4.22-4.18(m,1H),4.18-4.10(m,1H),3.83(s,6H),3.52-3.51(m,2H),3.22-3.17(m,2H),1.65(s,9H)1.42(s,9H).質量觀察值[M-2Boc+H]+=530.2；[M-Boc+H]+=630.2；[M+H]+=730.2；[2M+H]+=1459.5.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)
胺基)-1-側氧基-3-(1-三苯甲基-1H-咪唑-2-基)丙烷-2-基)胺甲酸第三丁基酯(4m)
4m由2m獲得，使用如4a的相同合成步驟。
產率62%。1H-NMR(CDCl3,500MHz),δ(ppm)：8.18(s,1H),7.46(d,J=8.5Hz,2H),7.43-7.38(m,9H),7.15(d,J=8.5Hz,2H),7.12-7.10(m,6H),7.03(d,J=16.5Hz,1H),6.96(d,J=16.5Hz,1H),6.91(s,1H),6.66(d,J=2.5Hz,2H),6.41(t,J=2.5Hz,1H),5.69(d,J=8.0Hz,NH),4.50-4.45(m,1H),4.37-4.32(m,1H),4.28-4.26(m,1H),3.84(s,6H),3.64-3.50(m,2H),3.28-3.23(m,1H),3.08-3.06(m,1H),1.38(s,9H).質量觀察值[M+H]+=832.4.
(6-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-6-側氧基己烷-1,5-二基)(E)-二胺甲酸二-第三丁基酯(4n)
4n由2n獲得，使用如4a的相同合成步驟。
產率39%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.18(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.62(brs,NH),6.41(t,J=2.0Hz,1H),5.13(brs,NH),4.61(brs,NH),4.34(t,J=5.0Hz,2H),4.07(s,1H),3.84(s,6H),3.69-3.62(m,2H),3.12-3.11(m,2H)1.90-1.83(m,1H),1.67-1.61(m,1H),1.57-1.47(m,2H),1.45-1.42(m,18H),1.40-1.37(m,2H).質量觀察值[M-2Boc+H]+=473.0；[M-Boc+H]+=573.4；[M+H]+=673.4,[M+Na]+=695.4,[M+K]+=711.4.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基-5-(3-((2,2,4,6,7-五甲基-2,3-二氫苯并呋喃-5-基)磺醯基)胍基)戊烷-2-基)胺甲酸第三丁基酯(4o)
4o由2o獲得，使用如4a的相同合成步驟。
產率29%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.46(d,J=8.0Hz,2H),7.39(brs,NH),7.13(d,J=9.0Hz,2H),7.04(d,J=16.5Hz,1H),6.97(d,J=16.5Hz,1H),6.65(d,J=1.0Hz,2H),6.40(s,1H),6.27(brs,NH),5.57(d,J=6.0Hz,NH),4.33-4.29(m,2H),4.25(s,1H),3.83(s,6H),3.68-3.62(m,1H),3.59-3.55(m,1H),3.30-3.25(m,2H),2.93(s,2H),2.57(s,3H),2.50(s,3H),2.08(s,3H),1.69-1.55(m,4H),1.44(s,6H),1.42(s,9H).質量觀察值[M+H]+=852.3.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1,4-二側氧基-4-(三苯甲基胺基)丁烷-2-基)胺甲酸第三丁基酯(4p)
4p由2p獲得，使用如4a的相同合成步驟。
產率28%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.50(d,J=8.5Hz,2H),7.31-7.23(m,11H),7.20-7.15(m,6H),7.06(d,J=16.5Hz,1H),6.99(brs,NH),6.98(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.41(t,J=2.0Hz,1H),6.19(brs,NH),4.46-4.42(m,1H),4.31-4.19(m,2H),3.84(s,6H),3.64-3.51(m,2H),3.11-3.09(m,1H),2.60-2.57(m,1H),1.42(s,9H).質量觀察值[M+H]+=799.5.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1,5-二側氧基-5-(三苯甲基胺基)戊烷-2-基)胺甲酸第三丁基酯(4q)
4q由2q獲得，使用如4a的相同合成步驟。
產率27%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.48(d,J=8.5Hz,2H),7.30-7.28(m,15H),7.15(d,J=8.5Hz,2H),7.05(d,J=16.5Hz,1H),6.98(d,J=16.5Hz,1H),6.76(brs,NH),6.67(s,2H),6.62(brs,NH),6.41(s,1H),5.53(brs,NH),4.27-4.26(m,1H),4.15-4.12(m,1H),3.99-3.96(m,1H),3.84(s,6H),3.56-3.54(m,1H),3.47-3.46(m,1H),2.53-2.50(m,1H),2.45-2.40(m,1H),2.04-1.87(m,2H),1.42(s,9H).質量觀察值[M+H]+=814.3.
(E)-3-((第三丁氧基羰基)胺基)-4-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-4-側氧基丁酸第三丁基酯(4r)
4r由2r獲得，使用如4a的相同合成步驟。
產率48%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.07(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.93(brs,NH),6.66(d,J=2.0Hz,2H),6.41(s,1H),5.68(brs,NH),4.47(s,1H),4.32(t,J=5.5Hz,2H),3.83(s,6H),3.64-3.63(m,2H),2.90(dd,J=5.0,17.5Hz,1H),2.62(dd,J=6.5,17.0Hz,1H),1.46(s,9H),1.45(s,9H).質量觀察值[M-Boc-tBu+H]+=460.1；[M+H]+=616.3；[M+Na]+=638.3.
(E)-4-((第三丁氧基羰基)胺基)-5-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-5-側氧基戊酸第三丁基酯(4s)
4s由2s獲得，使用如4a的相同合成步驟。
產率55%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.18(d,J=8.5Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.76(brs,NH),6.66(d,J=2.0Hz,2H),6.41(d,J=2.0Hz,1H),5.29(brs,NH),4.33(t,J=5.5Hz,2H),4.14(s,1H),3.83(s,6H),3.69-3.63(m,2H),2.46-2.40(m,1H),2.35-2.29(m,1H),2.13-2.06(m,1H),1.94-1.87(m,1H),1.46(s,9H),1.44(s,9H).質量觀察值[M-Boc-OtBu+H]+=456.1,[M-Boc-tBu+H]+=474.0；[M+H]+=630.4；[M+Na]+=652.3.
碳酸(E)-2-(2-胺基乙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5a)
對化合物4a(726mg,1.5mmo1)於DCM(10mL)的攪拌溶液添加4M HCl於1,4-二噁(7.25mL)且混合物於室溫攪拌3小時。然後蒸發反應溶液且進行pre-HPLC純化(TFA作為緩衝液，詳細梯度，請參照下述資訊)。然後水性分液以數滴的濃HCl處理後冷凍乾燥以提供化合物5a(602mg,95%產率)呈白色固體。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.14(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.71(d,J=2.5Hz,2H),6.40(t,J=2.5Hz,1H),4.33(t,J=5.5Hz,2H),3.80(s,6H),3.71(s,2H),3.61(t,J=5.5Hz,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：166.26,161.12,153.66,150.50,139.18,135.47,128.95,127.43,127.19,120.96,104.22,99.60,66.73,54.39,40.09,38.13；質量觀察值[M-HCl+H]+=402.2；[M-HCl+Na]+=424.2；[M-HCl+K]+=440.1；[2M-2HCl+H]+=802.3；[2M-2HCl+Na]+=824.4.
管柱：Inertsil ODS-3 C18，5um，30*250mm
流速：38ml/min
溶劑A：10%ACN於H2O中+0.1%TFA
溶劑B：90% ACN於H2O中+0.1%TFA
梯度：
碳酸(E)-2-(2-胺基丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯
基)酯 鹽酸鹽(5b)
5b由4b獲得，使用如5a的相同合成步驟。
產率98%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),7.17(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.37-4.31(m,2H),3.97-3.93(m,1H),3.80(s,6H),3.67-3.62(m,1H),3.59-3.54(m,1H),1.50(d,J=7.0Hz,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：169.97,161.14,153.67,150.51,139.18,135.48,128.96,127.42,127.18,120.95,104.21,99.59,66.62,54.39,48.86,38.22,16.24；質量觀察值[M-HCl+H]+=416.2；[M-HCl+Na]+=438.2；[2M-HCl+H]+=830.5；[2M-2HCl+Na]+=852.4.
碳酸(E)-2-(2-胺基-3-甲基丁醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5c)
5c由4c獲得，使用如5a的相同合成步驟。
產率99%。1H-NMR(CDCl3,500MHz),δ(ppm)：7.43(d,J=7.0Hz,2H),7.13(d,J=7.0Hz,2H),6.99-6.88(m,2H),6.60(s,2H),6.36(s,1H),4.37-4.30(m,2H),4.15(brs,1H),3.77(s,6H),3.50(brs,1H),2.98-2.92(m,2H),2.34-2.33(m,1H),1.10-1.05(m,6H)；13C-NMR(CDCl3,125MHz),δ(ppm)：168.94,160.94,153.59,150.23,138.99,135.32,129.23,127.78,127.55,121.33,104.61,100.11,66.81,58.91,55.32,38.42,30.18,18.60,18.16；質量觀察值[M-HCl+H]+=444.1；[M-HCl+Na]+=466.1.
碳酸(E)-2-(2-胺基-4-甲基戊醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5d)
5d由4d獲得，使用如5a的相同合成步驟。
產率95%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.40-4.30(m,2H),3.88-3.86(m,1H),3.80(s,6H),3.72-3.67(m,1H),3.55-3.50(m,1H),1.75-1.67(m,3H),1.00(t,J=5.5Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：169.66,161.15,153.61,150.51,139.19,135.49,128.98,127.42,127.18,120.92,104.23,99.61,66.53,54.39,51.70,43.34,38.21,24.05,21.61,20.82；質量觀察值[M-HCl+H]+=457.2；[2M-2HCl+H]+=913.3.
碳酸(E)-2-(2-胺基-3-甲基戊醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5e)
5e由4e獲得，使用如5a的相同合成步驟。
產率98%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.59(d,J=8.5Hz,2H),7.17(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.40-4.36(m,1H),4.33-4.28(m,1H),3.80(s,6H),3.78-3.72(m,2H),3.52-3.47(m,1H),1.95-1.92(m,1H),1.63-1.58(m,1H),1.28-1.22(m,1H),1.05(d,J=7.0Hz,3H),0.98(t,J=7.0Hz,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.41,161.15,153.56,150.50,139.19,135.49,128.97,127.43,127.18,120.92,104.23,99.61,66.60,57.68,54.39,38.05,36.62,24.19,13.66,10.32；質量觀察值[M-HCl+H]+=457.2；[2M-2HCl+H]+=913.3.
碳酸(E)-2-(2-胺基-4-(甲基硫基)丁醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5f)
5f由4f獲得，使用如5a的相同合成步驟。
產率85%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.59(d,J=8.5Hz,2H),7.19(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.42-4.38(m,1H),4.33-4.28(m,1H),3.99(t,J=6.5Hz,1H),3.80(s,6H),3.78-3.73(m,1H),3.52-3.47(m,1H),2.60(t,J=7.5Hz,2H),2.18-2.11(m,2H),2.09(s,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.70,161.14,153.62,150.49,139.18,135.49,128.97,127.43,127.18,120.99,104.21,99.60,66.58,54.39,52.32,38.21,30.70,28.33,13.69；質量觀察值[M-HCl+H]+=476.2；[M-HCl+Na]+=498.2；[2M-HCl+H]+=950.4.
碳酸(E)-2-(2-胺基-3-羥基丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5g)
5g由4g獲得，使用如5a的相同合成步驟。
產率76%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.14(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.34(t,J=5.0Hz,2H),3.98-3.94(m,2H),3.86-3.81(m,1H),3.80(s,6H),3.62-3.60(m,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：167.21,161.13,153.69,150.51,139.20,135.47,128.96,127.44,127.19,120.97,104.23,99.61,66.64,60.30,54.93,54.40,38.29；質量觀察值[M-HCl+H]+=431.2；[2M-2HCl+H]+=861.2.
碳酸(E)-2-(2-胺基-3-羥基丁醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5h)
5h由4h獲得，使用如5a的相同合成步驟。
產率74%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),7.17(d,J=8.5Hz,2H),7.15(d,J=16.0Hz,1H),7.07(d,J=16.0Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.38-4.31(m,2H),4.06-4.01(m,1H),3.80(s,6H),3.72-3.65(m,2H),3.58-3.53(m,1H),1.31(d,J=6.0Hz,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：167.54,161.14,153.58,150.50,139.19,135.49,128.97,127.43,127.18,120.95,104.23,99.61,66.61,65.97,59.12,54.40,38.14,18.91；質量觀察值[M-HCl+H]+=445.2；[2M-2HCl+H]+=889.2.
碳酸(E)-2-(2-胺基-3-巰基丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5i)
對化合物4i(760mg,1.0mmol)於DCM(15mL)的攪拌溶液添加TFA(14.9mL)及三異丙基矽烷(TIPS,790uL,3.9mmol)，所得混合物於室溫攪拌2小時。然後蒸發反應溶液且進行pre-HPLC純化(TFA作為緩衝液，詳細梯度，請參照下述資訊).然後水性分液以數滴的濃HCl處理後冷凍乾燥以提供化合物5i(354mg,76%)呈白色固體。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=1.5Hz,2H),6.40(s,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),4.05(t,J=5.5Hz,1H),3.80(s,6H),3.74-3.69(m,1H),3.57-3.52(m,1H),3.06(dd,J=5.5,14.5Hz,1H),2.98(dd,J=6.5,15.0Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：167.31,161.14,153.63,150.50,139.19,135.50,128.97,127.43,127.18,120.97,104.23,99.62,66.61,54.69,54.39,38.28,24.96；質量觀察值[M-HCl+H]+=448.2；[M-HCl+Na]+=470.2；[2M-2HCl+H]+=894.4.
管柱：Inertsil ODS-3 C18，5um，30*250mm
流速：38mL/min
溶劑A：10%ACN於H2O+0.1%TFA
溶劑B：90%ACN於H2O+0.1%TFA
梯度：
碳酸(E)-2-(2-胺基-3-苯基丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5j)
5j由4j獲得，使用如5a的相同合成步驟。
產率90%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),7.38-7.35(m,2H),7.31-7.29(m,3H),7.18(d,J=8.5Hz,2H),7.14(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(d,J=2.0Hz,1H),4.24-4.20(m,2H),4.07(t,J=7.5Hz,1H),3.80(s,6H),3.65-3.60(m,1H),3.48-3.44(m,1H),3.19(dd,J=7.5,14.0Hz,1H),3.09(dd,J=7.5,14.0Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.49,161.14,153.51,150.50,139.19,135.49,134.15,129.12,128.98,128.71,127.48,127.42,127.19,120.92,104.23,99.61,66.66,54.40,54.40,38.02,37.29；質量觀察值[M-HCl+H]+=491.3；[M-HCl+Na]+=513.2.
碳酸(E)-2-(2-胺基-3-(4-羥基苯基)丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5k)
5k由4k獲得，使用如5a的相同合成步驟。
產率84%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.57(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.14(d,J=16.5Hz,1H),7.11(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.79(d,J=9.0Hz,2H),6.71(d,J=2.0Hz,2H),6.40(s,1H),4.27-4.24(m,2H),4.00(t,J=7.5Hz,1H),3.80(s,6H),3.66-3.61(m,1H),3.50-3.45(m,1H),3.10(dd,J=7.0,14.0Hz,1H),2.98(dd,J=7.0,14.0Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.67,161.14,156.89,153.57,150.51,139.19,135.47,130.22,128.96,127.43,127.18,124.55,121.00,115.42,104.22,99.61,66.68,54.61,54.39,38.05,36.54；質量觀察值[M-HCl+H]+=507.2；[2M-2HCl+H]+=1013.2.
碳酸(E)-2-(2-胺基-3-(1H-indol-3-基)丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5l)
5l由4l獲得，使用如5a的相同合成步驟。
產率78%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.65(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,2H),7.39(d,J=8.5Hz,1H),7.23(s,1H),7.17-7.15(m,3H),7.12(d,J=16.5Hz,1H),7.10(d,J=16.5Hz,1H),7.06-7.03(m,1H),6.70(d,J=2.0Hz,2H),6.40(s,1H),4.25-4.21(m,1H),4.18-4.10(m,2H),3.80(s,6H),3.60-3.55(m,1H),3.50-3.45(m,1H),3.39(dd,J=6.5,15.0Hz,1H),3.25(dd,J=8.0,15.0Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：169.10,161.13,153.54,150.50,139.18,136.88,135.47,128.95,127.41,127.17,126.91,124.19,121.52,120.95,118.88,117.69,111.26,106.58,104.22,99.61,66.53,54.40,54.38,53.74,38.17,27.51；質量觀察值[M-HCl+H]+=530.3；[2M-2HCl+H]+=1059.4.
碳酸(E)-2-(2-胺基-3-(1H-咪唑-2-基)丙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯二鹽酸鹽(5m)
5m由4m獲得，使用如5a的相同合成步驟。
產率82%。1H-NMR(CD3OD,500MHz),δ(ppm)：8.90(s,1H),7.59(d,J=8.5Hz,2H),7.53(s,1H),7.20(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.41(t,J=2.0Hz,1H),4.36-4.32(m,1H),4.31-4.27(m,2H),3.81(s,6H),3.71-3.66(m,1H),3.55-3.50(m,1H),3.42-3.35(m,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：167.46,161.15,153.55,150.48,139.17,135.54,134.43,129.00,127.40,127.18,126.62,121.05,118.36,104.23,99.61,66.58,54.40,51.96,38.30,26.20；質量觀察值[M-HCl+H]+=482.2；[M-HCl+Na]+=504.1；[2M-2HCl+H]+=962.3.
(E)-2-(2,6-二胺基己醯胺基)乙基(4-(3,5-二甲氧基苯乙烯基)苯基)酯二鹽酸鹽(5n)
5n由4n獲得，使用如5a的相同合成步驟。
產率78%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.60(d,J=8.5Hz,2H),7.20(d,J=8.5Hz,2H),7.16(d,J=16.5Hz,1H),7.09(d,J=16.5Hz,1H),6.72(d,J=2.0Hz,2H),6.41(s,1H),4.42-4.38(m,1H),4.35-4.30(m,1H),3.93(t,J=6.5Hz,1H),3.80(s,6H),3.75-3.70(m,1H),3.56-3.51(m,1H),2.93(t,J=8.0Hz,2H),1.97-1.87(m,2H),1.75-1.69(m,2H),1.56-1.50(m,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.97,161.15,153.63,150.50,139.18,135.54,129.01,127.41,127.21,121.03,104.23,99.60,66.68,54.42,54.39,52.81,38.88,38.17,30.66,26.71,21.44；質量觀察值[M-2HCl+H]+=472.2.
碳酸(E)-2-(2-胺基-5-胍基戊醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯二鹽酸鹽(5o)
5o由4o獲得，使用如的相同合成步驟5i.
產率64%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=7.5Hz,2H),7.19(d,J=7.5Hz,2H),7.14(d,J=16.5Hz,1H),7.06(d,J=16.5Hz,1H),6.70(s,2H),6.39(s,1H),4.37-4.33(m,2H),3.96(s,1H),3.79(s,6H),3.72-3.69(m,1H),3.60-3.55(m,1H),3.22(s,2H),1.94(s,2H),1.71(s,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.87,161.12,157.19,153.70,150.49,139.18,135.50,128.98,127.43,127.22,121.05,104.24,99.63,66.69,54.42,52.64,40.43,38.21,28.31,23.92；質量觀察值[M-2HCl+H]+=500.1.
碳酸(E)-2-(2,4-二胺基-4-側氧基丁醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5p)
5p由4p獲得，使用如5i的相同合成步驟。
產率68%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.59(d,J=8.5Hz,2H),7.19(d,J=8.5Hz,2H),7.16(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.5Hz,2H),6.41(t,J=2.5Hz,1H),4.35-4.32(m,2H),4.22-4.19(m,1H),3.80(s,6H),3.67-3.60(m,1H),3.59-3.55(m,1H),2.90(dd,J=4.5,17.5Hz,1H),2.79(dd,J=4.0,17.0Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：171.80,168.41,161.14,153.69,150.50,139.18,135.50,128.97,127.42,127.19,120.99,104.22,99.59,66.65,54.39,49.90,38.29,34.82；質量觀察值[M-HCl+H]+=459.2；[M-HCl+Na]+=481.1；[2M-2HCl+H]+=916.4.
碳酸(E)-2-(2,5-二胺基-5-側氧基戊醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5q)
5q由4q獲得，使用如5i的相同合成步驟。
產率62%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),
7.18(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(s,2H),6.40(s,1H),4.41-4.35(m,1H),4.34-4.30(m,1H),3.97(t,J=6.5Hz,1H),3.80(s,6H),3.72-3.68(m,1H),3.58-3.53(m,1H),2.50-2.47(m,2H),2.16-2.09(m,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：175.66,168.78,161.14,153.64,150.50,139.20,135.50,128.97,127.45,127.19,121.00,104.23,99.64,66.66,54.40,52.65,38.21,30.19,26.78；質量觀察值[M-HCl+H]+=473.3；[M-HCl+Na]+=495.3；[2M-2HCl+H]+=944.6.
(E)-3-胺基-4-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-4-側氧基丁酸 鹽酸鹽(5r)
5r由4r獲得，使用如5a的相同合成步驟。
產率82%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.59(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.37-4.32(m,2H),4.22-4.19(m,1H),3.80(s,6H),3.69-3.64(m,1H),3.58-3.54(m,1H),2.99(dd,J=4.0,18.0Hz,1H),2.89(dd,J=4.0,18.0Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：171.18,168.13,161.14,153.67,150.52,139.19,135.48,128.96,127.44,127.18,120.99,104.23,99.60,66.54,54.39,49.63,38.35,34.60；質量觀察值[M-HCl+H]+=459.1；[2M-2HCl+H]+=917.2.
(E)-4-胺基-5-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-5-側氧基戊酸 鹽酸鹽(5s)
5s由4s獲得，使用如5a的相同合成步驟。
產率88%。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.14(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.71(d,
J=2.0Hz,2H),6.40(s,1H),4.41-4.36(m,1H),4.33-4.29(m,1H),3.96(t,J=6.5Hz,1H),3.80(s,6H),3.75-3.70(m,1H),3.55-3.50(m,1H),2.52(t,J=7.5Hz,2H),2.18-2.13(m,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：174.27,168.72,161.12,153.64,150.51,139.21,135.45,128.93,127.47,127.18,121.00,104.23,99.60,66.61,54.43,52.44,38.15,28.69,26.30；質量觀察值[M-HCl+H]+=473.0.
1-2-2.目標化合物5t的合成
化合物5t係根據類似於方案1的方案2合成。
試劑及條件：(a)HATU，DIPEA，CH2Cl2，41%；(b)NEt3，CH2Cl2，0℃；(c)DMAP，ACN，50℃，57%；(d)4M HCl於1,4-二噁烷，CH2Cl2，92%。
碳酸(E)-4-(3,5-二甲氧基苯乙烯基)苯基酯(2-(吡咯啶-2-胺甲醯基)乙基)酯 鹽酸鹽(5t)
化合物5t由1t獲得，使用如5a的類似合成步驟。
白色粉末。92%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.14(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.71(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),4.39-4.32(m,2H),4.31-4.27(m,1H),3.80(s,6H),3.69-3.61(m,1H),3.59-3.54(m,1H),3.43-3.36(m,1H),3.34-3.31(m,1H),2.46-2.40(m,1H),2.08-2.01(m,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.66,161.15,153.67,150.52,139.18,135.50,128.98,127.41,127.18,120.95,104.23,99.61,66.62,59.77,54.39,45.95,38.46,29.56,23.59；質量觀察值[M-HCl+H]+=442.0；[M-HCl+Na]+=464.1；[2M-2HCl+H]+=882.4；[2M-2HCl+Na]+=904.4.
1-2-3.目標化合物5u的合成
化合物5u係根據類似於方案1的方案3合成。
方案3：化合物5u的合成
試劑及條件：(a)EDCI，DIPEA，CH2Cl2，45%；(b)NEt3，CH2Cl2，0℃；(c)DMAP，ACN，50℃，33%；(d)4M HCl於二噁烷，CH2Cl2，90%。
碳酸(E)-3-(2-胺基-3-甲基丁醯胺基)丙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 鹽酸鹽(5u)
5u的化合物由1c及3-胺基丙烷-1-醇，使用如5a的類似合成步驟獲得。
白色粉末。90%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.57(d,J=8.5Hz,2H),7.16(d,J=8.5Hz,2H),7.14(d,J=16.5Hz,1H),7.06(d,J=16.5Hz,1H),6.70(d,J=1.5Hz,2H),6.40(s,1H),4.30(t,J=6.5Hz,2H),3.80(s,6H),3.65(d,J=5.5Hz,1H),3.47-3.41(m,1H),3.39-3.34(m,1H),2.21-2.17(m,1H),2.00-1.95(m,3H),1.06(t,J=7.5Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.22,161.12,
153.66,150.56,139.21,135.40,128.91,127.46,127.18,120.97,104.23,99.61,65.92,58.54,54.40,35.77,30.05,28.09,17.51,16.62；質量觀察值[M-HCl+H]+=457.3；[M-HCl+Na]+=479.2；[2M-2HCl+Na]+=935.4.
1-2-3.目標化合物5v及5w的合成
如示於方案4，化合物5a或5c係以碳酸鈉中和後以菸鹼酸裡以獲得對應的菸鹼酸鹽類5v、5w。
試劑及條件：(a)1. K2CO3，H2O，CH2Cl2，1小時；2.菸鹼酸，乙醇，3小時。
碳酸(E)-2-(2-胺基乙醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 菸鹼酸鹽(5v)
對化合物5a(0.42g,1.0mmol)於CH2Cl2(20ml)的攪拌溶液添加was added K2CO3(0.182g,1.3mmol)於H2O(0.4mL)中且反應混合物於室溫攪拌1小時。於真空移除溶劑以獲得游離胺，將其溶解於10mL乙醇且添加菸鹼酸(0.145g,1.2mmol)。反應混合物於室溫攪拌3小時。蒸發溶劑且粗製產物由乙醇及無水醚再結晶以獲得化合物5v呈白色粉末(0.39g,78%產率)。1H-NMR(CDCl3,500MHz),δ(ppm)：9.07(s,1H),8.57-8.56(m,1H),8.34(t,J=2.0Hz,1H),7.59(d,J=
8.5Hz,2H),7.47-7.44(m,1H),7.18-7.14(m,3H),7.08(d,J=16.5Hz,1H),6.72(d,J=2.5Hz,2H),6.41(t,J=2.5Hz,1H),4.33(t,J=5.0Hz,2H),3.81(s,6H),3.68-3.66(m,2H),3.61(t,J=5.0Hz,2H).
碳酸(E)-2-(2-胺基-3-甲基丁醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)苯基)酯 菸鹼酸鹽(5w)
5w由5c獲得，使用如5v的相同合成步驟。
白色粉末。產率79%。1H-NMR(CDCl3,500MHz),δ(ppm)：9.19(s,1H),8.70(d,J=3.5Hz,1H),8.32-8.30(m,1H),7.47(d,J=8.5Hz,2H),7.40-7.37(m,1H),7.13(d,J=8.5Hz,2H),7.03(d,J=16.5Hz,1H),6.96(d,J=16.5Hz,1H),6.63(d,J=2.5Hz,2H),6.38(t,J=2.5Hz,1H),4.33-4.28(m,2H),3.80(s,6H),3.67-3.62(m,2H),3.56-3.53(m,1H),2.20-2.05(m,1H),1.02-0.90(m,6H).
1-2-5.目標化合物6a-6h的合成
化合物6a-6h係根據方案5合成。如所示，起始的4-羥基苯甲醛(11a-11b)以咪唑及TIPS處理以形成對應的矽基醚類(12a-12b)，將其以NaBH4還原以獲得對應的碳醇類(13a-13b)。化合物13a-13以亞磷酸三乙基酯及ZnI2處理以提供對應的膦酸酯類(14a-14b)。化合物14a-14b係分別地與市售可得的醛類(15a-15d)偶合，以產生對應的16a-16d，其後續以Bu4NF於THF處理以獲得所期望的化合物17a-17d。另一方面，化合物2a、2c及2j係與氯甲酸p-硝基苯基酯反應以產生對應的18a、18c及18j，其無進一步純化而分開地與17a-17d於DMAP的存在下反應以獲得對應的碳酸酯類19a-19h。19a-19h以4M HCl於1,4-二噁烷之後續的脫保護以提供目標化合物6a-6h。
方案5：化合物6a-6h的合成
試劑及條件：(a)咪唑，TIPSCl，CH2Cl2，16小時；(b)NaBH4，THF，MeOH，0℃，1小時；(c)ZnI2，亞磷酸三乙基酯，THF，80℃，16小時；(d)t-BuOK，THF，0℃，3小時；(e)1.0M Bu4NF於THF，THF；(f)NEt3，CH2Cl2，0℃；(g)DMAP，ACN，50℃；(h)4M HCl於1,4-二噁烷，CH2Cl2.
4-((三異丙基矽基)氧基)苯甲醛(12a)
對4-羥基苯甲醛11a(50g,409.8mmol)於DCM(500mL)的溶液添加咪唑
(41.8g,614.7mmol)，接著滴加TIPSCl(86.5g,450.8mmol)。混合物攪拌16小時後倒入至冰/水，以DCM萃取。有機層以鹽水清洗，於Na2SO4乾燥後蒸發。殘質藉由矽膠管柱層析純化(沖提溶劑：乙酸乙酯/石油醚=1/50)以獲得化合物12a(95g,99%)呈黃色油。1H-NMR(CDCl3,500MHz),δ(ppm)：9.88(s,1H,CHO),7.78(dd,J=2.0,8.5Hz,2H),6.98(d,J=8.5Hz,2H),1.32-1.25(m,3H),1.11(d,J=8.0Hz,18H).
甲氧基-4-((三異丙基矽基)氧基)苯甲醛(12b)
12b由11b獲得，使用如12a的相同合成步驟。
黃色油。98%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：9.83(s,1H,CHO),7.39(d,J=1.5Hz,1H),7.35(dd,J=1.5,8.0Hz,1H),6.98(d,J=8.0Hz,1H),3.87(s,3H),1.31-1.25(m,3H),1.09(d,J=7.5Hz,18H).
(4-((三異丙基矽基)氧基)苯基)甲醇(13a)
於0℃對化合物12a(100g,359.7mmol)於MeOH/THF(1：1,1L)的溶液添加NaBH4(27.3g,719.4mmol)且攪拌1小時。反應混合物倒入至冰/水且以DCM萃取。有機層以鹽水清洗，於Na2SO4乾燥後蒸發。殘質藉由矽膠管柱層析純化(沖提溶劑：乙酸乙酯/石油醚=1/20)以獲得化合物13a(88g,99%產率)呈黃色油。1H-NMR(CDCl3,500MHz),δ(ppm)：7.21(d,J=8.5Hz,2H),6.86(d,J=8.5Hz,2H),4.60(d,J=5.0Hz,2H),1.29-1.22(m,3H),1.10-1.06(m,18H).
(3-甲氧基-4-((三異丙基矽基)氧基)苯基)甲醇(13b)
13b由12b獲得，使用如13a的相同合成步驟。
黃色油。95%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：6.89(s,1H),6.84(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),4.61(s,2H),3.81(s,3H),1.57(s,1H),1.28-1.22(m,3H),1.09(d,J=7.5Hz,18H).
(4-((三異丙基矽基)氧基)苄基)膦酸二乙基酯(14a)
對化合物13a(85g,303.6mmol)於THF(850mL)的溶液添加ZnI2(145.3g,455.4mmol)及亞磷酸三乙基酯(100.8g,607.2mmol)。混合物回流16小時及蒸發。殘質添加2N NaOH(500mL)且以醚萃取。有機層以鹽水清洗，於Na2SO4乾燥後蒸發。殘質藉由矽膠管柱層析純化(沖提溶劑：乙酸乙酯/石油醚=1/30)以獲得化合物14a(90g,75%產率)呈黃色油。1H-NMR(CDCl3,500MHz),δ(ppm)：7.16(dd,J=2.5,8.5Hz,2H),6.81(d,J=8.5Hz,2H),4.07-4.03(m,4H),3.20(d,J=21.0Hz,2H),1.65-1.21(m,9H),1.08(d,J=7.0Hz,18H).
(3-甲氧基-4-((三異丙基矽基)氧基)苄基)膦酸二乙基酯(14b)
14b由13b獲得，使用如14a的相同合成步驟。
黃色油。78%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：6.83-6.79(m,2H),6.71(d,J=8.0Hz,1H),4.17-3.90(m,4H),3.79(s,3H),3.07(d,J=21.0Hz,2H),1.38-1.19(m,9H),1.08-1.03(m,18H).
(E)-(4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)三異丙基矽烷(16a)
於0℃，對化合物14a(7.0g,17.5mmol)於THF(175mL)的溶液添加化合物15a(3.0g,17.5mmol)及t-BuOK(4.1g,36.7mmol)且於0℃攪拌3小時。反應混合物倒入至冰/水且以EA萃取。有機層以鹽水清洗，於Na2SO4乾燥後蒸發。殘質藉由矽膠管柱層析純化(沖提溶劑：乙酸乙酯/正己烷=1/8)以獲得化合物16a(5.6g,76%產率)呈白色固體。1H-NMR(CDCl3,500MHz),δ(ppm)：7.37(d,J=8.0Hz,2H),7.03(d,J=16.5Hz,1H),6.91-6.86(m,3H),6.65(s,2H),6.37(d,J=2.0Hz,
1H),1.29-1.24(m,3H),1.12(d,J=7.5Hz,18H).
(E)-(4-(3,5-二乙氧基苯乙烯基)苯氧基)三異丙基矽烷(16b)
16b由14b及15b獲得，使用如16a的相同合成步驟。
白色粉末。75%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.36(d,J=8.5Hz,2H),7.01(d,J=16.0Hz,1H),6.88(d,J=16.0Hz,1H),6.87(d,J=8.5Hz,2H),6.63(d,J=2.0Hz,2H),6.37(t,J=2.0Hz,1H),4.05(q,J=7.0Hz,4H),1.43(t,J=7.0Hz,6H),1.29-1.25(m,3H),1.11(d,J=7.5Hz,18H).
(E)-(4-(3,5-二甲氧基苯乙烯基)-2-甲氧基苯氧基)三異丙基矽烷(16c)
16c由14c及15c獲得，使用如16a的相同合成步驟。
白色固體。78%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.03-7.00(m,2H),6.96(d,J=8.0Hz,1H),6.91(s,1H),6.88-6.85(m,1H),6.65(s,2H),6.38(s,1H),3.87(s,3H),3.83(s,6H),1.30-1.23(m,3H),1.11(d,J=7.5Hz,18H).
(E)-(4-(3,5-二甲氧基苯乙烯基)-2-甲氧基苯氧基)三異丙基矽烷(16d)
16d由14d及15d獲得，使用如16a的相同合成步驟。
淺黃色固體。77%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.30(d,J=9.0Hz,2H),6.91(dd,J=10.5,16.5Hz,1H),6.84(d,J=9.0Hz,2H),6.81(dd,J=10.5,16.5Hz,1H),6.62(d,J=16.5Hz,1H),6.59(d,J=2.0Hz,2H),6.55(d,J=16.5Hz,1H),6.36(t,J=2.0Hz,1H),3.81(s,6H),1.30-1.22(m,3H),1.11(d,J=7.5Hz,18H).
(E)-4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)酚(17a)
化合物16a(0.80g,1.9mmol)於無水THF(15mL)及氟化四丁基銨(1.0M in THF,2.50mL,2.5mmol)的溶液於N2氛圍於室溫攪拌2小時。反應混合物以EtOAc稀釋且有機層以水清洗。有機層於Na2SO4乾燥後蒸發且殘質藉由管柱層析於矽膠純化(沖提溶劑：乙酸乙酯/正己烷=1/8)以獲得產物17a(0.46g,91%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.39(d,J=8.5Hz,2H),7.03(d,J=16.5Hz,1H),6.92-6.82(m,3H),6.65(d,J=2.5Hz,2H),6.38(t,J=2.5Hz,1H).
(E)-4-(3,5-二乙氧基苯乙烯基)酚(17b)
17b由16b獲得，使用如17a的相同合成步驟。
白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.38(d,J=8.5Hz,2H),7.01(d,J=16.0Hz,1H),6.89-6.81(m,3H),6.63(d,J=2.5Hz,2H),6.37(t,J=2.5Hz,1H),4.08-4.04(m,4H),1.42(t,J=7.5Hz,6H).
(E)-4-(3,5-二甲氧基苯乙烯基)-2-甲氧基酚(17c)
17c由16c獲得，使用如17a的相同合成步驟。
白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.04-7.00(m,3H),6.92-6.87(m,2H),6.66(s,2H),6.39(s,1H),5.68(brs,1H,OH),3.96(s,3H),3.83(s,6H).
4-((1E,3E)-4-(3,5-二甲氧基苯基)丁-1,3-二烯-1-基)酚(17d)
17d由16d獲得，使用如17a的相同合成步驟。
白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.33(d,J=8.0Hz,2H),6.91(dd,J=10.0,15.5Hz,1H),6.83-6.78(m,3H),6.62(d,J=15.5Hz,1H),6.59(d,J=2.0Hz,2H),6.55(d,J=15.5Hz,1H),6.37(t,J=2.0Hz,1H),4.94(brs,1H,OH),3.82(s,6H).
(E)-(2-((2-(((4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)羰基)氧基)乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(19a)
對化合物2a(1.12g,5.1mmol)於無水CH2Cl2(15ml)的攪拌溶液添加三乙基胺(2.15mL,15.4mmol)後於0℃滴加氯甲酸4-硝基苯基酯溶液(1.15g,5.7mmol於10mL CH2Cl2)。反應混合物於0℃攪拌15分鐘，且溫熱至室溫。混合物於室溫攪拌額外4小時。反應完成後(以TLC確認)，藉由蒸發移除溶劑。粗製中間體與紫檀芪衍生物17a(1.41g,5.4mmol)及DMAP(1.26g,10.3mmol)於ACN(30ml)混合。所得混合物加熱至50℃持續1小時。反應後，溶劑於真空移除以獲得粗製殘質，其藉由管柱層析純化(EA/正己烷=1/5(V/V))以提供粗製產物。粗製產物藉由製備型HPLC純化(70% ACN,30% H2O)以提供目標化合物19a(0.99g,38%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.52(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.53(brs,NH),6.40(t,J=2.0Hz,1H),5.12(brs,NH),4.35(t,J=5.5Hz,2H),3.83(d,J=5.5Hz,2H),3.66(q,J=5.5Hz,aH),1.46(s,9H).質量觀察值[M-Boc+H]+=408.3；[M+H]+=508.4；[M+Na]+=530.4,[2M+H]+=914.6.
(E)-(2-((2-(((4-(3,5-二乙氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(19b)
19b由2a及17b獲得，使用如19a的相同合成步驟。
白色粉末。45%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.50(d,J=9.0Hz,2H),7.17(d,J=9.0Hz,2H),7.05(d,J=16.5Hz,1H),6.97(d,J=16.5Hz,1H),6.64(d,J=2.0Hz,2H),6.53(brs,NH),6.40(t,J=2.0Hz,1H),5.12(brs,NH),4.35
(t,J=5.5Hz,2H),4.06(q,J=7.0Hz,4H),3.83(d,J=5.5Hz,2H),3.66(q,J=5.5Hz,2H),1.46(s,9H),1.43(t,J=7.0Hz,6H).質量觀察值[M-Boc+H]+=430.3；[M+H]+=530.3；[M+Na]+=552.2,[2M+H]+=1058.6,[2M+Na]+=1080.6.
(E)-(1-((2-(((4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)羰基)氧基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(19c)
19c由2c及17a獲得，使用如19a的相同合成步驟。
白色粉末。42%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.52(d,J=9.0Hz,2H),7.18(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),6.39(brs,NH),5.03(brs,NH),4.34(t,J=5.5Hz,2H),3.93-3.91(m,1H),3.70-3.61(m,2H),2.17-2.16(m,1H),1.44(s,9H),0.98(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H).質量觀察值[M-Boc+H]+=450.2；[M+H]+=550.4；[M+Na]+=572.4.
(E)-(1-((2-(((4-(3,5-二乙氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(19d)
19d由2c及17b獲得，使用如19a的相同合成步驟。
白色粉末。41%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.50(d,J=9.0Hz,2H),7.17(d,J=9.0Hz,2H),7.05(d,J=16.0Hz,1H),6.97(d,J=16.0Hz,1H),6.64(d,J=2.0Hz,2H),6.39(t,J=2.0Hz,1H),6.38(brs,NH),5.03(brs,NH),4.34(t,J=5.5Hz,2H),4.05(q,J=7.0Hz,4H),3.93-3.90(m,1H),3.70-3.61(m,2H),2.19-2.16(m,1H),1.45(s,9H),1.43(t,J=7.0Hz,6H),0.98(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H).質量觀察值[M-Boc+H]+=472.3；[M+H]+=572.4；[M+Na]+=594.4；[2M+H]+=1142.8；[2M+Na]+=1164.9.
(E)-(1-((2-(((4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(19e)
19e由2j及17a獲得，使用如19a的相同合成步驟。
白色粉末。47%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.52(d,J=9.0Hz,2H),7.33-7.30(m,2H),7.25-7.21(m,3H),7.17(d,J=9.0Hz,2H),7.07(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),6.16(brs,NH),5.04(brs,NH),4.34-4.33(m,1H),4.26-4.22(m,1H),4.17-4.16(m,1H),3.56-3.54(m,2H),3.13-3.09(m,1H),3.07-3.02(m,1H),1.42(s,9H).質量觀察值[M-Boc+H]+=498.3；[M+Na]+=620.4；[2M+H]+=1194.9；[2M+Na]+=1216.9.
(E)-(1-((2-(((4-(3,5-二乙氧基苯乙烯基)苯氧基)羰基)氧基)乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(19f)
19f由2j及17b獲得，使用如19a的相同合成步驟。
白色粉末。47%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=9.0Hz,2H),7.33-7.30(m,2H),7.25-7.21(m,3H),7.16(d,J=9.0Hz,2H),7.05(d,J=16.0Hz,1H),6.97(d,J=16.0Hz,1H),6.64(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),6.15(brs,NH),5.04(brs,NH),4.33-4.32(m,1H),4.26-4.22(m,1H),4.17-4.16(m,1H),4.06(q,J=7.0Hz,4H),3.59-3.51(m,2H),3.13-3.09(m,1H),3.07-3.02(m,1H),1.44-1.42(m,15H).質量觀察值[M-Boc+H]+=519.2；[M+H]+=619.2；[M+Na]+=641.2；[2M+Na]+=1259.5.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)-2-甲氧基苯氧基)羰基)氧
基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(19g)
19g由2c及17c獲得，使用如19a的相同合成步驟。
白色粉末。37%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.11-7.08(m,3H),7.05(d,J=16.0Hz,1H),6.98(d,J=16.0Hz,1H),6.67(s,2H),6.41(s,1H),6.37(brs,NH),5.04(brs,NH),4.34(t,J=5.5Hz,2H),3.98-3.92(m,4H),3.84(s,6H),3.69-3.65(m,2H),2.17-2.16(m,1H),1.45(s,9H),0.97(d,J=7.0Hz,3H),0.92(d,J=7.0Hz,3H).質量觀察值[M-Boc+H]+=474.3；[M+H]+=574.4；[M+Na]+=596.4.
(1-((2-(((4-((1E,3E)-4-(3,5-二甲氧基苯基)丁-1,3-二烯-1-基)苯氧基)羰基)氧基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(19h)
19h由2c及17d獲得，使用如19a的相同合成步驟。
白色粉末。35%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.45(d,J=9.0Hz,2H),7.15(d,J=9.0Hz,2H),6.95-6.86(m,2H),6.67(d,J=16.5Hz,1H),6.63(d,J=16.5Hz,1H),6.60(d,J=2.0Hz,2H),6.38(t,J=2.0Hz,1H),6.37(brs,NH),5.03(brs,NH),4.33(t,J=5.5Hz,2H),3.93-3.90(m,1H),3.83(s,6H),3.70-3.61(m,2H),2.18-2.16(m,1H),1.45(s,9H),0.98(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H).質量觀察值[M-Boc+H]+=470.0；[M+H]+=570.3；[M+Na]+=592.3.
碳酸(E)-2-(2-胺基乙醯胺基)乙基酯(4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯基)酯 鹽酸鹽(6a)
對化合物19a(639mg,1.3mmol)於DCM(20mL)的攪拌溶液添加4M HCl於1,4-二噁烷(6.3mL)且於室溫攪拌3小時。然後蒸發反應溶液且進行pre-HPLC純化(TFA作為緩衝液，詳細梯度，請參照下述資訊)然後水性分液以數滴的濃
HCl處理後冷凍乾燥以提供化合物6a(491mg,92%產率)呈白色固體。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=8.5Hz,2H),7.18(d,J=8.5Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.5Hz,2H),6.40(t,J=2.5Hz,1H),4.34(t,J=5.5Hz,2H),3.71(s,2H),3.62(t,J=5.5Hz,2H)；13C-NMR(CD3OD,125MHz),δ(ppm)：166.23,161.14,153.66,150.50,139.18,135.49,128.98,127.40,127.18,120.95,104.18,99.58,66.72,40.06,38.13；質量觀察值[M-HCl+H]+=408.3；[M-HCl+Na]+=430.2；[2M-2HCl+H]+=814.5；[2M-2HCl+Na]+=836.5.
管柱：Inertsil ODS-3 C18，5um，30*250mm
流速：38ml/min
溶劑A：10%ACN於H2O+0.1%TFA
溶劑B：90%ACN於H2O+0.1%TFA
梯度：
對6b-6h的最終化合物係藉由記載於6a的實驗步驟而製備，具有某些非重要性的變動。
碳酸(E)-2-(2-胺基乙醯胺基)乙基酯(4-(3,5-二乙氧基苯乙烯基)苯
基)酯 鹽酸鹽(6b)
6b由19b獲得，使用如6a的相同合成步驟。
白色固體。95%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.17(d,J=9.0Hz,2H),7.13(d,J=16.5Hz,1H),7.07(d,J=16.5Hz,1H),6.69(d,J=2.5Hz,2H),6.38(t,J=2.5Hz,1H),4.34(t,J=5.5Hz,2H),4.06-4.02(m,4H),3.71(s,2H),3.62(t,J=5.5Hz,2H),1.39(t,J=7.0Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：166.24,160.36,153.66,150.48,139.09,135.51,129.06,127.27,127.16,120.93,104.74,100.71,66.72,63.15,40.08,38.14,13.77；質量觀察值[M-HCl+H]+=430.3；[M-HCl+Na]+=452.2；[2M-2HCl+H]+=858.5；[2M-2HCl+Na]+=880.5.
碳酸(E)-2-(2-胺基-3-甲基丁醯胺基)乙基酯(4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯基)酯 鹽酸鹽(6c)
6c由19c獲得，使用如6a的相同合成步驟。
白色固體。89%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.17(d,J=9.0Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=2.5Hz,2H),6.40(t,J=2.5Hz,1H),4.40-4.32(m,1H),4.31-4.29(m,1H),3.73-3.72(m,1H),3.67(d,J=6.0Hz,1H),3.54-3.49(m,1H),2.22-2.16(m,1H),1.08(t,J=6.5Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.45,161.14,153.58,150.50,139.18,135.50,128.98,127.40,127.17,120.93,104.19,99.58,66.62,58.46,38.04,30.09,17.37,16.60；質量觀察值[M-HCl+H]+=449.3；[M-HCl+Na]+=471.3；[2M-2HCl+Na]+=919.4.
碳酸(E)-2-(2-胺基-3-甲基丁醯胺基)乙基酯(4-(3,5-二乙氧基苯乙
烯基)苯基)酯 鹽酸鹽(6d)
6d由19d獲得，使用如6a的相同合成步驟。
白色固體。93%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.58(d,J=9.0Hz,2H),7.17(d,J=9.0Hz,2H),7.13(d,J=16.0Hz,1H),7.06(d,J=16.0Hz,1H),6.69(d,J=2.0Hz,2H),6.38(t,J=2.0Hz,1H),4.40-4.34(m,1H),4.33-4.30(m,1H),4.06-4.02(m,4H),3.77-3.72(m,1H),3.66(d,J=6.0Hz,1H),3.54-3.49(m,1H),2.23-2.16(m,1H),1.39(t,J=7.0Hz,6H),1.08(t,J=7.0Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.48,160.36,153.58,150.47,139.10,135.52,129.06,127.28,127.16,120.93,104.77,100.73,66.62,63.16,58.48,38.05,30.10,17.37,16.62,13.78；質量觀察值[M-HCl+H]+=472.3；[M-HCl+Na]+=494.3；[2M-2HCl+H]+=942.6；[2M-2HCl+Na]+=964.6.
碳酸(E)-2-(2-胺基-3-苯基丙醯胺基)乙基酯(4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯基)酯 鹽酸鹽(6e)
6e由19e獲得，使用如6a的相同合成步驟。
白色固體。90%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.59(d,J=9.0Hz,2H),7.39-7.36(m,2H),7.32-7.29(m,3H),7.18(d,J=9.0Hz,2H),7.15(d,J=16.5Hz,1H),7.08(d,J=16.5Hz,1H),6.71(d,J=1.5Hz,2H),6.40(s,1H),4.27-4.19(m,2H),4.06(t,J=7.0Hz,1H),3.66-3.61(m,1H),3.48-3.43(m,1H),3.19(dd,J=7.0,13.5Hz,1H),3.08(dd,J=7.0,13.5Hz,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.48,161.14,153.51,150.50,139.18,135.50,134.15,129.13,129.00,128.71,127.48,127.40,127.19,120.92,104.20,99.59,66.66,54.41,38.03,37.29；質量觀察值[M-HCl+H]+=498.2；[M-HCl+Na]+=520.4；[2M-2HCl+H]+=994.6.
碳酸(E)-2-(2-胺基-3-苯基丙醯胺基)乙基酯(4-(3,5-二乙氧基苯乙烯基)苯基)酯 鹽酸鹽(6f)
6f由19f獲得，使用如6a的相同合成步驟。
白色固體。92%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.57(d,J=8.5Hz,2H),7.38-7.35(m,2H),7.32-7.29(m,3H),7.17(d,J=8.5Hz,2H),7.12(d,J=16.5Hz,1H),7.05(d,J=16.5Hz,1H),6.68(d,J=2.0Hz,2H),6.38(t,J=2.0Hz,1H),4.24-4.20(m,2H),4.07-4.02(m,5H),3.65-3.60(m,1H),3.48-3.43(m,1H),3.19(dd,J=7.5,14.0Hz,1H),3.08(dd,J=7.5,14.0Hz,1H),1.38(t,J=7.5Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.48,160.36,153.51,150.47,139.10,135.52,134.15,129.12,129.07,128.71,127.48,127.27,127.18,120.91,104.77,100.74,66.65,63.16,54.41,38.03,37.29,13.78；質量觀察值[M-HCl+H]+=519.2；[2M-2HCl+H]+=1037.4.
碳酸(E)-2-(2-胺基-3-甲基丁醯胺基)乙基酯(4-(3,5-二甲氧基苯乙烯基)-2-甲氧基苯基)酯 鹽酸鹽(6g)
6g由19g獲得，使用如6a的相同合成步驟。
白色固體。85%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.29(d,J=1.5Hz,1H),7.17-7.13(m,2H),7.12-7.07(m,2H),6.73(d,J=2.0Hz,2H),6.41(t,J=2.0Hz,1H),4.38-4.28(m,2H),3.90(s,3H),3.80(s,6H),3.75-3.64(m,2H),3.54-3.51(m,1H),2.20(s,1H),1.08(t,J=7.0Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.43,161.14,153.30,151.30,139.40,139.18,136.92,129.09,127.81,121.97,118.72,110.16,104.24,99.61,66.65,58.47,55.10,54.39,38.11,30.10,17.41,16.63；質量觀察值[M-HCl+H]+=474.2；[M-HCl+Na]+=496.2；[2M-2HCl+H]+=946.5；[2M-2HCl+Na]+=968.5.
碳酸2-(2-胺基-3-甲基丁醯胺基)乙基酯(4-((1E,3E)-4-(3,5-二甲氧基苯基)丁-1,3-二烯-1-基)苯基)酯 鹽酸鹽(6h)
6h由19h獲得，使用如6a的相同合成步驟。
白色固體。80%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.49(d,J=8.5Hz,2H),7.14(d,J=8.5Hz,2H),7.01-6.95(m,2H),6.71-6.62(m,4H),6.38(s,1H),4.39-4.35(m,1H),4.33-4.29(m,1H),3.78(s,6H),3.77-3.71(m,1H),3.68(d,J=6.0Hz,1H),3.53-3.49(m,1H),2.22-2.18(m,1H),1.07(t,J=7.0Hz,6H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.46,161.09,153.56,150.39,139.36,135.65,133.01,131.38,129.53,129.33,126.99,120.94,104.09,99.55,66.62,58.45,54.39,38.04,30.09,17.37,16.63；質量觀察值[M-HCl+H]+=469.0；[M-HCl+Na]+=491.1；[2M-2HCl+H]+=937.0.
1-2-6.目標化合物7a-7f的合成
化合物7a-7f係根據方案6而合成。如所示，N-(2-胺基乙基)胺甲酸苄基酯鹽酸鹽係與N-Boc-胺基酸(化合物1a、1c及1j)於EDCI及DMAP的存在下反應以獲得對應的醯胺衍生物(化合物20a-20c)。化合物20a-20c係於Pd/C氫化以提供對應的化合物21a-21c。另一方面，紫檀芪或17a係以三光氣於NEt3存在下處理以提供對應的22a-22b，其無進一步純化而分別與化合物21a-21c反應以獲得對應的23a-23f。23a-23f以4M HCl於1,4-二噁烷之後續脫保護以提供目標化合物7a-7f。
方案6：化合物7a-7f的合成
試劑及條件：(a)EDCI，DIPEA，CH2Cl2，RT，12小時；(b)10% Pd/C，MeOH，RT，12小時；(c)三乙基胺，0℃至RT，1.5小時；(d)三甲基胺，RT，1.5小時；(e)4M HCl於1,4-二噁烷。
(2-(2-((第三丁氧基羰基)胺基)乙醯胺基)乙基)胺甲酸苄基酯(20a)
對(2-胺基乙基)胺甲酸苄基酯HCl(8.5g,36.8mmol)、Boc-Gly-OH 1a(5.3g,30.4mmol)及DIPEA(9.5g,73.6mmol)於CH2Cl2(80mL)的攪拌溶液添加EDCI(8.6g,45.0mmol)，,且反應混合物於室溫攪拌12小時。反應後，減壓移除溶劑，殘質藉由管柱層析純化(正己烷至EA/正己烷=1/5(V/V))以提供目標產物20a(8.0g,74%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.33-7.30(m,5H),6.86(brs,NH),5.56(brs,NH),5.07(s,2H),3.71(s,2H),3.37-3.30(m,4H),1.42(s,9H).
(2-(2-((第三丁氧基羰基)胺基)-3-甲基丁醯胺基)乙基)胺甲酸苄基酯(20b)
20b由1c獲得，使用如20a的相同合成步驟。
白色粉末。41%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.34-7.31(m,5H),6.55(brs,NH),5.35(brs,NH),5.05(s,2H),5.03(brs,NH),3.86-3.83(m,1H),3.40-3.33(m,4H),2.12-2.10(m,1H),1.42(s,9H),0.93(d,J=7.0Hz,3H),0.88(d,J=7.0Hz,3H).
(2-(2-((第三丁氧基羰基)胺基)-3-苯基丙醯胺基)乙基)胺甲酸苄基酯(20c)
20c由1j獲得，使用如20a的相同合成步驟。
白色粉末。48%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.36-7.18(m,11H),6.18(brs,NH),5.07(s,2H),5.04(brs,NH),4.26(d,J=7.0Hz,1H),3.48-3.17(m,4H),3.04-3.01(m,2H),1.40(s,9H).
(2-((2-胺基乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(21a)
化合物20a(4.0g11.4mm)溶解於MeOH(50mL)且以10% Pd/C(0.6g)處理，反應混合物於室溫於氫氛圍攪拌12小時。反應混合物經由矽藻土過濾。蒸發濾液的溶劑且殘質以管柱層析純化(CH2Cl2/甲醇=1/19(V/V))以提供化合物21a(2.35g,95%)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.16(brs,NH),5.62(brs,NH),3.79(brs,2H),3.38-3.36(m,2H),2.90-2.88(m,2H),1.42(s,9H).
(1-((2-胺基乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(21b)
21b由20b獲得，使用如21a的相同合成步驟。
白色粉末。95%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：6.93(brs,NH),5.24(brs,NH),3.89-3.86(m,1H),3.40-3.37(m,1H),3.32-3.29(m,1H),2.87-2.85(m,2H),2.13-2.09(m,1H),1.42(s,9H),0.94(d,J=7.0Hz,3H),0.91(d,J=7.0Hz,3H).
(1-((2-胺基乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(21c)
21c由20c獲得，使用如21a的相同合成步驟。
白色粉末。95%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.29-7.19(m,5H),6.77(brs,NH),5.34(s,NH),4.32-4.31(m,1H),3.24-3.23(m,2H),3.06-3.02(m,2H),2.79(s,2H),2.71(s,NH2),1.37(s,9H).
(E)-(2-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)胺基)乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(23a)
對紫檀芪(1.41g,5.51mmol)及三光氣(0.54g,1.82mm)於無水CH2Cl2(15ml)的溶液於0℃滴加三乙基胺(1.36g,13.4mmol)。反應混合物於0℃攪拌30分
鐘後溫熱至室溫以提供中間體22a溶液。The溶液of化合物21a(1.17g,5.9mmol)及三乙基胺(1.36g,13.4mmol)於無水CH2Cl2(15ml)的溶液滴加至中間體22a溶液。所得混合物攪拌另外的1.5小時。反應後，真空移除溶劑且殘質取入至EA且以飽和檸檬酸溶液清洗。收集有機層，於Na2SO4乾燥後蒸發。殘質藉由管柱層析純化(矽膠，0至67百分比之EtOAc/正己烷)以提供粗製產物。粗製產物藉由製備型HPLC純化(70% ACN,30% H2O)以提供目標化合物23a(0.86g,32%產率，2步驟)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.47(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),7.05(d,J=16.0Hz,1H),6.96(d,J=16.0Hz,1H),6.70(brs,NH),6.65(d,J=2.5Hz,2H),6.40(t,J=2.5Hz,1H),5.74(brs,NH),5.19(brs,NH),3.83(s,6H),3.79(d,J=5.5Hz,2H),3.50-3.46(m,2H),3.43-3.40(m,2H),1.44(s,9H).質量觀察值[M+Na]+=522.0,[2M+Na]+=1021.3.
(E)-(2-((2-(((4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)羰基)胺基)乙基)胺基)-2-側氧基乙基)胺甲酸第三丁基酯(23b)
23b由21a及22b獲得，使用如23a的相同合成步驟。
白色粉末。27%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.48(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),7.05(d,J=16.0Hz,1H),6.96(d,J=16.0Hz,1H),6.69(brs,NH),6.65(d,J=2.0Hz,2H),6.39(t,J=2.0Hz,1H),5.73(brs,NH),5.19(brs,NH),3.79(d,J=5.5Hz,2H),3.49-3.47(m,2H),3.43-3.40(m,2H),1.44(s,9H).質量觀察值[M+Na]+=528.2,[2M+Na]+=1033.4.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)胺基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(23c)
23c由21b及22a獲得，使用如23a的相同合成步驟。
白色粉末。18%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.48(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),7.05(d,J=16.0Hz,1H),6.97(d,J=16.0Hz,1H),6.66(d,J=2.0Hz,2H),6.52(brs,NH),6.40(t,J=2.0Hz,1H),5.77(brs,NH),5.03(brs,NH),3.87-3.85(m,1H),3.83(s,6H),3.47-3.41(m,4H),2.18-2.16(m,1H)1.45(s,9H),0.97(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H).質量觀察值[M-Boc+H]+=443.3；[M+H]+=543.4；[M+Na]+=565.3.
(E)-(1-((2-(((4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)羰基)胺基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(23d)
23d由21b及22b獲得，使用如23a的相同合成步驟。
白色粉末。28%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.48(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),7.06(d,J=16.0Hz,1H),6.97(d,J=16.0Hz,1H),6.65(d,J=2.0Hz,2H),6.47(brs,NH),6.39(t,J=2.5Hz,1H),5.73(brs,NH),5.00(brs,NH),3.87-3.84(m,1H),3.52-3.42(m,4H),2.17-2.14(m,2H),1.45(s,9H),0.98(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H).質量觀察值[M+Na]+=570.3,[2M+Na]+=1117.6.
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)胺基)乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(23e)
23e由21c及22a獲得，使用如23a的相同合成步驟。
白色粉末。27%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.48(d,J=8.5Hz,2H),7.35-7.27(m,3H),7.23-7.22(m,2H),7.11(d,J=8.5Hz,2H),7.06(d,J=16.0Hz,1H),6.97(d,J=16.0Hz,1H),6.66(d,J=2.0Hz,2H),6.40(t,J=2.0Hz,1H),6.15(brs,NH),5.42(brs,NH),5.03(brs,NH),4.31-4.26(m,1H),3.81(s,6H),3.38-3.33(m,2H),3.31-3.25(m,2H),3.11-3.03(m,2H),1.45(s,9H).質量觀察值[M
-Boc+H]+=491.0；[M+H]+=591.4；[M+Na]+=613.3.
(E)-(1-((2-(((4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯氧基)羰基)胺基)乙基)胺基)-1-側氧基-3-苯基丙烷-2-基)胺甲酸第三丁基酯(23f)
23f由21c及22b獲得，使用如23a的相同合成步驟。
白色粉末。30%產率。1H-NMR(CDCl3,500MHz),δ(ppm)：7.48(d,J=8.5Hz,2H),7.34-7.27(m,3H),7.25-7.22(m,2H),7.10(d,J=8.5Hz,2H),7.06(d,J=16.0Hz,1H),6.97(d,J=16.0Hz,1H),6.65(d,J=2.0Hz,2H),6.39(t,J=2.0Hz,1H),6.19(brs,NH),5.44(brs,NH),5.05(brs,NH),4.31-4.27(m,1H),3.38-3.33(m,2H),3.32-3.24(m,2H),3.11-3.03(m,2H),1.41(s,9H).質量觀察值[M-Boc+H]+=497.3；[M+H]+=597.4；[M+Na]+=619.5；[2M+H]+=1192.9；[2M+Na]+=1214.8.
(2-(2-胺基乙醯胺基)乙基)胺甲酸(E)-4-(3,5-二甲氧基苯乙烯基)苯基酯 鹽酸鹽(7a)
對化合物23a(760mg,1.5mmol)於DCM(10mL)的攪拌溶液添加4M HCl於1,4-二噁烷(7.60mL)且混合物於室溫攪拌3小時。蒸發反應混合物且進行-HPLC純化(TFA作為緩衝液，詳細梯度，請參照下述資訊)然後水性分液以數滴的濃HCl處理後冷凍乾燥以提供化合物7a(614mg,93 percent產率)呈白色固體。1H-NMR(CD3OD,500MHz),δ(ppm)：7.55(d,J=8.0Hz,2H),7.14(d,J=16.5Hz,1H),7.10(d,J=8.0Hz,2H),7.05(d,J=16.5Hz,1H),6.70(d,J=2.0Hz,2H),6.40(s,1H),3.80(s,6H),3.42-3.40(m,2H),3.35-3.31(m,4H)；13C-NMR(CD3OD,125MHz),δ(ppm)：166.19,161.13,155.99,150.61,139.31,134.66,128.46,127.67,127.01,121.56,104.16,99.52,54.40,40.10,39.94,39.12；質量觀察值[M-HCl+
H]+=400.2；[2M-2HCl+H]+=799.3.
管柱：Inertsil ODS-3 C18，5um，30*250mm
流速：38ml/min
溶劑A：10%ACN於H2O+0.1%TFA
溶劑B：90%ACN於H2O+0.1%TFA
梯度：
(2-(2-胺基乙醯胺基)乙基)胺甲酸(E)-4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯基酯 鹽酸鹽(7b)
7b由23b獲得，使用如7a的相同合成步驟。
白色固體。95%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.55(d,J=8.0Hz,2H),7.13(d,J=16.5Hz,1H),7.10(d,J=8.0Hz,2H),7.05(d,J=16.5Hz,1H),6.70(d,J=2.0Hz,2H),6.39(t,J=2.0Hz,1H),3.42-3.40(m,2H),3.35-3.31(m,4H)；13C-NMR(CD3OD,125MHz),δ(ppm)：166.19,161.13,155.99,150.61,139.31,134.66,128.47,127.66,127.01,121.56,104.13,99.50,40.10,39.94,39.12；質量觀察值[M-HCl+H]+=406.3；[2M-2HCl+H]+=811.3.
(2-(2-胺基-3-甲基丁醯胺基)乙基)胺甲酸(E)-4-(3,5-二甲氧基苯乙
烯基)苯基酯 鹽酸鹽(7c)
7c由23c獲得，使用如7a的相同合成步驟。
白色固體。92%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.56(d,J=9.0Hz,2H),7.15(d,J=16.5Hz,1H),7.09(d,J=9.0Hz,2H),7.06(d,J=16.5Hz,1H),6.71(d,J=2.5Hz,2H),6.40(t,J=2.5Hz,1H),3.80(s,6H),3.61(d,J=5.5Hz,1H),3.50-3.45(m,1H),3.41-3.35(m,3H),2.21-2.17(m,1H),1.07(d,J=7.0Hz,3H),1.05(d,J=7.0Hz,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.44,161.13,155.92,150.57,139.30,134.67,128.47,127.65,127.01,121.54,104.14,99.49,58.57,54.37,39.96,38.97,29.97,17.51,16.52；質量觀察值[M-HCl+H]+=443.0；[M-HCl+Na]+=465.2；[2M-2HCl+H]+=884.5；[2M-2HCl+Na]+=906.5.
(2-(2-胺基-3-甲基丁醯胺基)乙基)胺甲酸(E)-4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯基酯 鹽酸鹽(7d)
7d由23d獲得，使用如7a的相同合成步驟。
白色固體。93%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.55(d,J=8.5Hz,2H),7.14(d,J=16.5Hz,1H),7.09(d,J=8.5Hz,2H),7.05(d,J=16.5Hz,1H),6.70(d,J=1.5Hz,2H),6.39(t,J=1.5Hz,1H),3.65(d,J=5.0Hz,1H),3.64-3.35(m,4H),2.23-2.16(m,1H),1.07(d,J=7.0Hz,3H),1.05(d,J=7.0Hz,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.45,161.12,155.90,150.58,139.31,134.66,128.47,127.65,127.01,121.54,104.13,99.49,58.57,39.96,38.96,29.97,17.51,16.55；質量觀察值[M-HCl+H]+=448.3；[M-HCl+Na]+=470.2；[2M-2HCl+Na]+=1149.5.
(2-(2-胺基-3-苯基丙醯胺基)乙基)胺甲酸(E)-4-(3,5-二甲氧基苯乙
烯基)苯基酯 鹽酸鹽(7e)
7e由23e獲得，使用如7a的相同合成步驟。
白色固體。90%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.53(d,J=8.5Hz,2H),7.41-7.31(m,2H),7.33-7.29(m,3H),7.13(d,J=17.0Hz,1H),7.09(d,J=8.5Hz,2H),7.04(d,J=17.0Hz,1H),6.70(d,J=2.0Hz,2H),6.40(s,1H),4.04(t,J=7.0Hz,1H),3.80(s,6H),3.75-3.57(m,1H),3.40-3.34(m,2H),3.28-3.20(m,2H),3.08-3.04(m,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.50,161.12,155.91,150.55,139.30,134.68,134.31,129.09,128.75,128.47,127.65,127.49,127.02,121.55,104.15,99.50,54.52,54.39,39.84,39.04,37.26；質量觀察值[M-HCl+H]+=491.2；[M-HCl+Na]+=513.3；[2M-2HCl+H]+=980.5.
(2-(2-胺基-3-苯基丙醯胺基)乙基)胺甲酸(E)-4-(3,5-雙(甲氧基-d3)苯乙烯基-d6)苯基酯 鹽酸鹽(7f)
7f由23f獲得，使用如7a的相同合成步驟。
白色固體。96%產率。1H-NMR(CD3OD,500MHz),δ(ppm)：7.53(d,J=9.0Hz,2H),7.39-7.36(m,2H),7.33-7.29(m,3H),7.13(d,J=17.0Hz,1H),7.09(d,J=9.0Hz,2H),7.04(d,J=17.0Hz,1H),6.69(d,J=2.0Hz,2H),6.39(t,J=2.0Hz,1H),4.05(t,J=7.0Hz,1H),3.39-3.34(m,2H),3.29-3.20(m,3H),3.08-3.04(m,1H)；13C-NMR(CD3OD,125MHz),δ(ppm)：168.48,161.13,155.89,150.56,139.30,134.69,134.31,129.09,128.74,128.49,127.64,127.49,127.00,121.55,104.14,99.50,54.52,39.84,39.04,37.26；質量觀察值[M-HCl+H]+=496.3；[2M-2HCl+H]+=991.4.
1-2-7.目標化合物8的合成
方案7記載化合物8的合成。如所示，乙酸2-羥基乙酯係與第三丁基氯二苯基矽烷(TPDPS-Cl)於NEt3及DMAP的存在下反應以提供化合物24，其進一步以甲氧基鈉(NaOMe)去乙醯化以獲得化合物25。化合物25係與was coupled with Boc-Val-OH(1c)於EDCI及DMAP的存在下偶合以獲得化合物26，接著藉由以TBAF脫保護TBDPS基團以獲得羥基化合物27。化合物27係與氯甲酸p-硝基苯基酯反應以獲得對應的化合物28，其無進一步純化與紫檀芪反應所期望的以獲得碳酸酯29，接著藉由脫保護Boc基團而提供目標化合物8。
2-((第三丁基二苯基矽基)氧基)乙酸乙酯(24)
對2-羥基乙酸乙酯(3.12g,30.0mmol)於CH2Cl2(25mL)的攪拌溶液添加第三丁基氯二苯基矽烷(TBDPS-Cl)(8.65g,31.5mmol)、Et3N(4.6mL,33.0mmol)及DMAP(110mg,0.9mmol)，然後於室溫攪拌直到起始材料完全消耗(12小時)。反應混合物以CH2Cl2(25mL)稀釋且以水(25mL)清洗。有機層經乾燥(Na2SO4)、過濾及蒸發。殘質進行快速層析(矽膠，0至2%的EtOAc/正己烷)以提供化合物24呈無色油(4.59g,43%產率)。1H-NMR(500MHz,CDCl3),δ(ppm)：7.69-7.67(m,4H),7.43-7.37(m,6H),4.18(t,J=4.5Hz,2H),3.85(t,J=4.5Hz,2H),2.03(s,3H),1.06(s,9H).
2-((第三丁基二苯基矽基)氧基)乙醇(25)
對化合物24(4589mg,13.4mmol)於MeOH(100mL)的攪拌溶液滴加5.4M甲氧化鈉於MeOH(4.96mL,26.8mmol)。混合物於室溫攪拌2小時。溶劑於真空蒸發，且殘質進行快速層析(矽膠，0至17百分比的EtOAc/正己烷)以提供化合物25呈無色油(4.00g,99%產率)。1H-NMR(500MHz,CDCl3),δ(ppm)：7.71-7.67(m,4H),7.45-7.37(m,6H),3.77(t,J=4.5Hz,2H),3.68(t,J=4.5Hz,2H),1.58(brs,OH,1H),1.05(s,9H).
2-((第三丁氧基羰基)胺基)-3-甲基丁酸2-((第三丁基二苯基矽基)氧基)乙基酯(26)
對化合物25(2871mg,9.6mmol)、Boc-Val-OH 1c(2076mg,9.6mmol)及
NEt3(1598uL,11.5mmol)於CH2Cl2(100mL)的攪拌溶液添加EDCI(2198mg,11.5mmol)及DMAP(350mg,2.9mmol)。反應混合物於室溫攪拌12小時。反應後，溶劑於真空移除，殘質藉由管柱層析純化(矽膠，0至5% of EtOAc/正己烷)以提供目標產物26(2719mg,57%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.67-7.66(m,4H),7.44-7.26(m,6H),5.03(d,J=8.5Hz,NH,1H),4.25-4.11(m,3H),3.88-3.85(m,2H),2.15-2.04(m,1H),1.44(s,9H),1.04(s,9H),0.94(d,J=6.5Hz,3H),0.89(d,J=6.5Hz,3H).
2-((第三丁氧基羰基)胺基)-3-甲基丁酸羥基乙基酯(27)
對化合物26(2719mg,5.4mmol)於THF(25mL)的攪拌溶液滴加1.0M TBAF於THF(10.88mL,10.9mmol)。反應混合物於室溫攪拌1小時。反應後，於真空移除溶劑，殘質藉由管柱層析純化(矽膠，0至30% of EtOAc/正己烷)以提供目標產物27(1022mg,72%產率)呈淺黃色油。1H-NMR(CDCl3,500MHz),δ(ppm)：5.00(brs,1H),4.35-4.22(m,2H),4.20-4.14(m,1H),3.82(s,2H),2.33(brs,OH,1H),2.17-2.13(m,1H),1.44(s,9H),0.96(d,J=6.5Hz,3H),0.93(d,J=6.5Hz,3H).
2-((第三丁氧基羰基)胺基)-3-甲基丁酸(E)-2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基酯(29)
對化合物27(1022mg,3.9mmol)於無水CH2Cl2(20ml)的攪拌溶液添加三乙基胺(1363ul,9.8mmol)後於0℃滴加氯甲酸4-硝基苯基酯溶液(867mg,4.3mmol)於30mL CH2Cl2。反應混合物於0℃攪拌30分鐘後，溫熱至室溫。於室溫攪拌另外4小時後，於真空移除溶劑以獲得粗製中間體28，其與紫檀芪(1002mg,3.9mmol)及DMAP(956mg,7.8mmol)於ACN(30ml)混合。所得混合物加熱至50
℃持續1小時。反應後，於真空移除溶劑，殘質取入至EA且以飽和檸檬酸溶液清洗。收集有機層，於Na2SO4乾燥及蒸發。殘質藉由管柱層析純化(矽膠，0至33% of EtOAc/正己烷)以提供粗製產物。粗製產物藉由製備型HPLC純化(80% ACN,20% H2O)以提供化合物29(600mg,28%產率，2步驟)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),7.06(d,J=16.0Hz,1H),6.98(d,J=16.0Hz,1H),6.66(s,2H),6.41(s,2H),5.02(d,J=9.5Hz,NH,1H),4.52-4.45(m,3H),4.42-4.39(m,1H),4.30-4.29(m,1H),3.83(s,6H),2.19-2.17(m,1H)1.45(s,9H),0.99(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H).質量觀察值[M-Boc+H]+=445.1；[M+H]+=545.1,[M+Na]+=567.1.
2-胺基-3-甲基丁酸(E)-2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)氧基)乙基酯 鹽酸鹽(8)
於50mL圓底燒瓶饋入化合物29(561mg,1.0mmol)及4M HCl於1,4-二噁烷(5.16ml)。所得混合物於室溫攪拌3小時。減壓移除溶劑後經冷凍乾燥以獲得所期望的產物8呈白色粉末(446mg,90%產率)。1H-NMR(CDCl3,500MHz),δ(ppm)：8.90(brs,NH2,HCl,3H),7.48(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,2H),7.03(d,J=16.0Hz,1H),6.96(d,J=16.0Hz,1H),6.64(s,2H),6.40(s,1H),4.58-4.49(m,4H),4.04(s,1H),3.81(s,6H),2.50(s,1H),1.18-1.16(m,6H)；13C-NMR(CDCl3,125MHz),δ(ppm)：168.29,160.99,153.33,150.30,139.05,135.34,129.23,127.90,127.54,121.30,104.61,100.14,65.82,63.39,58.65,55.37,29.98,18.35,18.28；質量觀察值[M-HCl+H]+=445.2；[M-HCl+Na]+=467.2；[2M-2HCl+H]+=888.6.
1-2-8.目標化合物9的合成
化合物9係根據方案8合成。如所示，2-溴乙醇以疊氮化鈉(NaN3)的置換反應完成化合物30，其與Boc-Val-OH(1c)偶合經由EDCI活化以提供酯31，然後進一步的N3基團氫化為胺32。化合物32係與氯甲酸p-硝基苯基酯反應以獲得對應的胺甲酸第三丁基酯33，其無進一步純化而與紫檀芪反應以獲得所期望的胺甲酸第三丁基酯34，接著藉由Boc基團的脫保護，提供胺基衍生物9。
試劑及條件：(a)NaN3，水，80℃，24小時；(b)Boc-Val-OH 1c，EDCI，三乙基胺，DMAP，CH2Cl2，12小時；(c)H2，10% Pd/C，EtOAc，MeOH，2小時；(d)三乙基胺，CH2Cl2，0℃；(e)DMAP，ACN，50℃，1小時；(f)4M HCl於1,4-二噁烷，3小時。
疊氮基乙醇(30)
對100mL圓底燒瓶添加2-溴乙醇(5827mg,46.6mmol)及疊氮化鈉(6062mg,93.3mmol)於水(50mL)。混合物於80℃攪拌24小時，然後冷卻至室溫。溶液以乙酸乙酯(30ml x 4)萃取且有機層於Na2SO4乾燥及過濾。蒸發濾液的溶劑且殘質藉由管柱層析純化(矽膠，0至25% of EtOAc/正己烷)以提供目標化合物30呈淺黃色液體(3735mg,92%產率)。1H-NMR(CDCl3,500MHz),δ(ppm)：3.78(d,J=4.0Hz,2H),3.45(s,2H),1.86(s,OH,1H).
2-((第三丁氧基羰基)胺基)-3-甲基丁酸2-疊氮基乙基酯(31)
對2-疊氮基乙醇30(683mg,7.9mmol)、Boc-Val-OH 1c(1705mg,7.9mmol)及NEt3(1313uL,9.4mmol)於CH2Cl2(50mL)的攪拌溶液添加EDCI(1805mg,9.4mmol)及DMAP(288mg,2.4mmol)。反應混合物於室溫攪拌12小時。反應後，溶劑於真空移除，殘質藉由管柱層析純化(矽膠，0至11% of EtOAc/正己烷)以提供目標產物31(1527mg,68%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：4.99(d,J=6.5Hz,NH,1H),4.31-4.27(m,3H),3.51-3.50(m,2H),2.18-2.17(m,1H),1.44(s,9H),0.95(d,J=6.5Hz,3H),0.91(d,J=6.5Hz,3H).
胺基乙基2-((第三丁氧基羰基)胺基)-3-甲基丁酸酯(32)
1527mg的化合物31溶解於25mL甲醇及25mL EA，添加568mg的10% Pd/C且於氫氛圍於室溫攪拌2小時。濾除Pd/C且以15mL甲醇清洗。於真空移除溶劑。殘質添加10mL水後冷凍乾燥以產生產物32呈油(1319mg,95%產率)。1H-NMR(CDCl3,500MHz),δ(ppm)：5.08(brs,NH,1H),4.20-4.10(m,1H),3.86-3.84(m,1H),3.73-3.71(m,1H),3.49-3.41(m,1H),3.01-2.97(m,1H),2.30(brs,
NH2,2H),2.12(s,1H),1.44(s,9H),0.97-0.88(m,6H).
2-((第三丁氧基羰基)胺基)-3-甲基丁酸(E)-2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)胺基)乙基酯(34)
對化合物32(1469mg,5.6mmol)於無水CH2Cl2(30ml)的攪拌溶液添加三乙基胺(1966ul,14.1mmol)以及然後於0℃滴加氯甲酸4-硝基苯基酯溶液(1251mg,6.2mmol於30mL CH2Cl2)。反應混合物於0℃攪拌30分鐘，且溫熱至室溫。於室溫攪拌另外的4小時後，於真空移除溶劑以獲得粗製中間體33，其與紫檀芪(1446mg,5.6mmol)及DMAP(1379mg,11.3mmol)於ACN(30ml)混合。所得混合物加熱至50℃持續1小時。反應後蒸發溶劑。殘質取至EA且以飽和檸檬酸溶液清洗。收集有機層，於Na2SO4乾燥且蒸發。殘質藉由管柱層析純化(矽膠，0至30% of EtOAc/正己烷)以提供粗製產物。粗製產物進一步藉由製備型HPLC純化(80% ACN,20% H2O)以提供34(320mg,11%產率，2步驟)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=7.0Hz,2H),7.17(d,J=7.0Hz,2H),7.06(d,J=16.0Hz,1H),6.99(d,J=16.0Hz,1H),6.66(s,2H),6.41(s,1H),6.36(brs,NH,1H),5.02(brs,NH,1H),4.33(s,2H),3.91(t,J=7.5Hz,1H),3.83(s,6H),3.65(s,2H),2.17(s,1H)1.44(s,9H),0.97(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H).質量觀察值[M-Boc+H]+=444.3；[M+H]+=544.3,[M+Na]+=566.3.
2-胺基-3-甲基丁酸(E)-2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)胺基)乙基酯 鹽酸鹽(9)
於50mL圓底燒瓶置入化合物34(320mg,0.6mmol)及4M HCl於1,4-二噁烷(2.95mL)。所得混合物於室溫攪拌3小時。減壓移除溶劑後冷凍乾燥以獲
得所期望的粗製產物化合物9呈白色粉末(249mg,88%)。1H-NMR(d6-DMSO,500MHz),δ(ppm)：8.80(t,J=5.0Hz,NH,1H),8.22(brs,NH2,HCl,3H),7.63(d,J=8.0Hz,2H),7.28(d,J=16.0Hz,1H),7.21(d,J=8.0Hz,2H),7.15(d,J=16.0Hz,1H),6.76(d,J=2.0Hz,2H),6.41(s,1H),4.30-4.27(m,1H),4.24-4.20(m,1H),3.76(s,6H),3.64-3.60(m,3H),2.10-2.06(m,1H),0.95-0.90(m,6H)；13C-NMR(d6-DMSO,125MHz),δ(ppm)：168.64,161.13,153.35,150.49,139.37,135.53,129.37,128.26,128.04,121.92,105.00,100.44,67.38,57.93,55.69,38.01,30.11,18.60,18.37；質量觀察值[M+H]+=444.3；[M+Na]+=466.3.
1-2-9.目標化合物10的合成
方案9記載化合物10的合成。Carboxylic acid of Boc-Val-OH(1c)的羧酸藉由N-羥基琥珀醯亞胺(NHS)及二環己基碳二亞胺(DCC)活化而允許半胱胺經由其胺基的接合且獲得所預期的胺35。化合物35係與氯甲酸p-硝基苯基酯反應以獲得對應的硫基碳酸p-硝基苯基酯36，其無進一步純化而與紫檀芪反應以獲得預期的硫基碳酸酯37。後續的脫保護Boc基團以提供目標化合物10。
方案9：化合物10的合成
試劑及條件：(a)1. NHS，DCC，THF，24小時；2. DIPEA，CH2Cl2，24小時；(b)DIPEA，CH2Cl2，0℃；(c)DMAP，ACN，50℃，2小時；(d)4M HCl於1,4-二噁烷，CH2Cl2。
(1-((2-巰基乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(35)
對溶液of Boc-Val-OH 1c(3.23g,14.9mmol)於THF(16mL)的溶液添加NHS(1.72g,15.0mmol)及DCC(3.1g,15.0mmol)。反應混合物於室溫攪拌24小時且過濾。蒸發濾液的溶劑且殘質取入至CH2Cl2(12mL)，然後添加DIPEA(5.7g,44.2mmol)及半胱胺鹽酸鹽(1.23g,15.9mmol)以及反應混合物攪拌24小時。添加水(5mL)且反應混合物以EA(3×20mL)萃取。合併的有機層以1N HCl(2
×10mL)及brine(10mL)清洗。有機層於MgSO4乾燥且蒸發以及殘質藉由管柱層析純化(矽膠，正己烷/EtOAc,(4：1,v/v))以獲得35(1.67g,41%產率)呈白色固體。1H-NMR(500MHz,CDCl3),δ(ppm)：6.41(s,1H),5.05(s,1H),3.88-3.85(m,1H),3.49-3.42(m,2H),2.69-2.65(m,2H),2.17-2.15(m,1H)1.45(s,9H),0.96(d,J=7.0Hz,3H),0.92(d,J=7.0Hz,3H).
(E)-(1-((2-(((4-(3,5-二甲氧基苯乙烯基)苯氧基)羰基)硫基)乙基)胺基)-3-甲基-1-側氧基丁烷-2-基)胺甲酸第三丁基酯(37)
對化合物35(1.26g,4.6mmol)於無水CH2Cl2(40ml)的攪拌溶液添加DIPEA(1.78g,13.8mmol)後於0℃滴加氯甲酸4-硝基苯基酯溶液(1.02g,5.1mmol)於10mL CH2Cl2。反應混合物於0℃攪拌15分鐘，然後溫熱至室溫。於室溫攪拌另外的4小時後，於真空移除溶劑以獲得粗製中間體36，其與紫檀芪(1.19g,4.7mmol)及DMAP(1.13g,9.3mmol)於ACN(30ml)混合。所得混合物加熱至50℃持續2小時。反應後，於真空移除溶劑。殘質藉由管柱層析純化(EA/正己烷=1/5(V/V))以提供粗製產物。粗製產物進一步藉由製備型HPLC純化(80% ACN,20% H2O)以提供目標化合物37(1.46g,56%產率)呈白色粉末。1H-NMR(CDCl3,500MHz),δ(ppm)：7.51(d,J=8.0Hz,2H),7.15(d,J=8.0Hz,2H),7.05(d,J=16.5Hz,1H),6.99(d,J=16.5Hz,1H),6.66(d,J=2.5Hz,2H),6.41(t,J=2.5Hz,1H),6.38(brs,NH),5.00(brs,NH),3.98-3.85(m,1H),3.82(s,6H),3.65-3.54(m,2H),3.13-3.07(m,2H),2.17-2.16(m,1H),1.48(s,9H),0.90(d,J=7.0Hz,3H),0.87(d,J=7.0Hz,3H)；質量觀察值[M-Boc+H]+=460.2；[M+H]+=560.3；[M+Na]+=582.3.
硫代碳酸(E)-S-(2-(2-胺基-3-甲基丁醯胺基)乙基)酯O-(4-(3,5-二
甲氧基苯乙烯基)苯基)酯 鹽酸鹽(10)
對化合物37(805mg,1.4mmol)於DCM(15mL)的攪拌溶液添加4M HCl於1,4-二噁烷(7.20mL)且混合物於室溫攪拌3小時。然後蒸發反應溶液且進行pre-HPLC純化(TFA作為緩衝液，詳細梯度，請參照下述資訊)。然後水性分液以數滴的濃HCl處理後冷凍乾燥以提供化合物10(647mg,91%產率)呈白色固體。1H-NMR(CD3OD,500MHz),δ(ppm)：7.57(d,J=9.0Hz,2H),7.15-7.12(m,3H),7.07(d,J=16.5Hz,1H),6.70(d,J=2.0Hz,2H),6.40(s,1H),3.80(s,6H),3.68-3.62(m,2H),3.52-3.46(m,1H),3.17-3.10(m,2H),2.22-2.18(m,1H),1.08(d,J=6.5Hz,3H),1.06(d,J=6.5Hz,3H)；13C-NMR(CD3OD,125MHz),δ(ppm)：169.66,168.37,161.13,150.53,139.16,135.69,129.09,127.38,127.23,121.15,104.25,99.66,58.48,54.42,38.55,30.22,30.05,17.52,16.55；質量觀察值[M-HCl+H]+=459.2；[2M-2HCl+H]+=917.3.
管柱：Inertsil ODS-3 C18，5um，30*250mm
流速：38ml/min
溶劑A：10%ACN於H2O+0.1%TFA
溶劑B：90%ACN於H2O+0.1%TFA
梯度：
2.目標化合物於活體研究之抗-NAFLD及抗-NASH
2-1.材料及方法
動物及試驗程序：雄性C57BL/6小鼠，4週齡，購自國家實驗室動物中心(台北，台灣)根據國家衛生研究烷(台北，台灣)機構動物照護及使用機構委員會提供的步驟和指南予以維持。動物係維持自由攝取粒狀食物及水於不鏽鋼籠中，於溫度21±2℃具有12小時的光/暗週期。所有試驗係於機構動物照護及使用機構委員會的監督，中國醫藥大學，台中，具程序編號(CMUIACUC-2020-117)。
合成的目標化合物(5a、5b、5c、5d、5e、5f、5g、5h、5j、5m、5p、5t、5v、5w、6a、6b、6g、7c、7e)係溶解於PG/TPSG(1：1)。小鼠係投與MCD膳食14日後投與PG/TPSG(1：1)作為對照，以及100mg/kg的所有化合物每日一次經口投與且週間5次持續42日。小鼠係隨機分為5群且處理如下：(1)MCD膳食+PG/TPSG(2)MCD膳食+100mg/kg所有化合物。28日後，犧牲動物用以收集血液以測定血漿ALT及AST濃度，以及肝臟樣品用於H&E染色。
小鼠係投予MCD膳食14日後以DDW投與75,100 and 150mg/kg化合物5c經口每日一次且一週5次持續42日。小鼠隨機分為5群且處理如下：(1)偽組(Non-MCD膳食)(2)MCD膳食(3)MCD膳食+75mg/kg化合物5c(4)MCD膳食+100mg/kg化合物5c(5)MCD膳食+150mg/kg化合物5c。28日後，犧牲動物用以收集血液以測定血漿ALT及AST濃度，以及肝臟樣品用於H&E染色。
2-2.結果及討論
進行組織學研究以測定所有化合物(5a、5b、5c、5d、5e、5f、5g、5h、5j、5m、5p、5t、5v、5w、6a、6b、6g、7c、7e)對於由MCD膳食所誘發的肝的脂肪變性的發展的功效。H&E染色結果顯示MCD膳食餵食誘發顯著的肝的脂肪變性、肝細胞損傷及炎性細胞浸潤、腫脹及纖維化。化合物5a、5b、5c、5f、5t、6g、7c、7e、5w、5g、5d、5e、5j、5m、5p、6a、6b處理，防止MCD膳食-誘發的脂肪肝炎而具有減低的脂肪變性、炎症、腫脹及纖維化。(表1)。
AST及ALT的血清濃度為肝臟損傷的標記。如示於表2，相較於餵食正常膳食的小鼠，餵食MCD膳食的小鼠中的AST及ALT的血清濃度顯著地增加。化合物5c、5a、5b、5f、5h、5d、5m及5p以劑量依賴形式顯著地抑制AST及ALT的血清濃度。
丙胺酸轉胺酶(ALT)；天冬胺酸轉胺酶(AST)；甲硫胺酸及膽鹼缺陷膳食(MCD)；***p<0.001對於MDC群
化合物5c係最為確證且選擇用於進一步評估。進行組織學研究以測定化合物5c於藉由MCD膳食所誘發的肝的脂肪變性的發展的功效。MCD膳食餵食誘發顯著的肝的脂肪變性、肝細胞損傷及炎性細胞浸潤、腫脹及纖維化。化合物5c處理防止，防止MCD膳食-誘發的脂肪肝炎而具有減低的脂肪變性、炎症、腫脹及纖維化。(圖1，表3)。
AST及ALT的血清濃度為肝臟損傷的標記。如示於表4，相較於餵食正常膳食的小鼠，餵食MCD膳食的小鼠中AST及ALT的血清濃度顯著地增加。化合物5c以劑量/依賴形式顯著地抑制AST及ALT的血清濃度。
丙胺酸轉胺酶(ALT)；天冬胺酸轉胺酶(AST)；甲硫胺酸及膽鹼缺陷膳食(MCD)；***p<0.001對於對照群。###p<0.001對於MCD群。
3.目標化合物的安定性及溶解性
3-1.化合物5a、5c、5m、5v、5w、6a及6b於pH=1.2的安定性
化合物5a、5c、5m、5v、5w、6a及6b於PH 1.2溶液(無酵素的USP胃液)的活體外安定性
3-1-1.材料及方法
材料：本發明的目標化合物5a、5c、5m、5v、5w、6a及6b。
試劑：pH=1.2溶液NaCl 2.0g係溶解於H2O 800mL且添加濃HCl 7.0mL。攪拌混合物且以2N的NaON及2N的濃HCl調整至pH1.2後以H2O to 1000mL稀釋。
活體外試驗：化合物5a、5c、5m、5v、5w、6a及6b係分別地與pH 1.2溶液於37℃培育6小時。樣品收集：於0、0.17、0.5、1、2、4及6小時，由培育混合物分取100mL且置入含有100μL的冰冷乙腈以及1μm內標準的離心管而於該處終止反應。樣品於15000rpm離心10分鐘，且將上清注射置HPLC系統。
HPLC方法：HPLC：Waters 1525 Binary HPLC Pump；Waters 2707 Autosampler；Waters 2487 Dual λ Absorbance Detector；管柱：XBridge Shield RP18,5μm，4.6x50mm管柱；UV Detector：305nm；溫度：室溫；運行時間：15.0分鐘；移動相：A：0.1%FA於H2O；B：乙腈。
HPLC移動相梯度：
化合物5a、5c、5m、5v、5w、6a及6h的滯留時間(RT)：
3-1-2.結果及討論
測試化合物的量級係比較於表5。結果顯示該等測試化合物為相對安定於pH=1.2溶液。6小時培育後，多於90%的化合物5a、5c、5m、5w、6a及6b殘留在pH=1.2溶液。然而，僅有84.8%的化合物5v殘留。
總結，活體外研究顯展現該等目標化合物針對胃液(無酵素)為相對安定。胃觀察到時間-依賴性降解。
3-2.化合物5c於H
2
O的溶解度
3-2-1.材料及方法
化合物5c濃度係設定40mg/mL於H2O中。超音波及渦旋30分鐘後，分別地，管於25℃靜置。在取樣時間點(1、3、6及24小時)，管於15,000rpm離心10分鐘，收集上清且合適地以乙腈稀釋。樣品藉由HPLC定量。
HPLC方法：管柱：XBridge Shield RP18，5μm，4.6x50mm；UV Detector：305nm；溫度：室溫；注射體積：10μL；運行時間：15.0分鐘；移動相：A：0.1% FA於H2O；B：乙腈
HPLC移動相梯度：
3-2-2.結果與討論
如表6及圖2所示，化合物5c於H2O中於25℃ 24小時後的溶解度係高於34mg/mL。根據US藥典的準則，化合物5c可稱為水可溶物質。
4.結論
本發明中，合成一系列的水可溶之帶有碳酸第三丁基酯的紫檀芪胺基酸的新穎類似物。該等化合物係安定於pH=1.2(胃液(無酵素)的pH值)且經檢查其抗-NASAH活性。多數的所合成化合物顯示抗-NASH/NAFLD活性(如示於表1.2)。其等之中，化合物5c最有希望且選擇用於進一步評估。結果指示化合物5c(代表性化合物)顯示顯著的抗-NASH/NAFLD活性(圖1，表3及表4)。
本發明之帶有碳酸酯的紫檀芪胺基酸類似物的新系列化學結構為水可溶、安定且生物有效於活體內用於治療NAFLD/NASH，且因此具有潛力開發作為治療NAFLD/NASH的新藥物。
縮寫列單
Claims (15)
- 一種具下式之化合物或其醫藥可接受鹽，
，其中j為1至3。
- 如請求項1之化合物或其醫藥可接受鹽，其中Q為O；X為O；以及Y為NH。
- 如請求項1之化合物或其醫藥可接受鹽，其中Q為O；X為O；以及Y為O。
- 如請求項1之化合物或其醫藥可接受鹽，其中Q為O；X為NH；以及Y為O。
- 如請求項1之化合物或其醫藥可接受鹽，其中Q為O；X為S；以及Y為NH。
- 如請求項1至5中任一項之化合物或其醫藥可接受鹽，其中，m為2；以及n為1或2。
- 如請求項1至5中任一項之化合物或其醫藥可接受鹽，其中，Ra及Rb為甲氧基。
- 如請求項7之化合物或其醫藥可接受鹽，其中Ra及Rb為3,5-二甲氧基。
- 如請求項1至5中任一項之化合物或其醫藥可接受鹽，其中，Rd為C3-C6支鏈烷基。
- 如請求項9之化合物或其醫藥可接受鹽，其中Rd為異丙基。
- 如請求項1至5中任一項之化合物或其醫藥可接受鹽，其中，Rd及Re係鏈結以形成環結構，使得，其中j為1。
- 如請求項1至5中任一項之化合物或其醫藥可接受鹽，其中，該醫藥可接受鹽為鹽酸鹽或菸鹼酸鹽。
- 一種於個體用以治療非酒精性脂肪肝疾病的醫藥組成物，包含對該治療的治療有效量的如請求項1至12之化合物或其醫藥可接受鹽。
- 一種於個體用以治療非酒精性脂肪肝炎的醫藥組成物，包含對該治療的治療有效量的如請求項1至12之化合物或其醫藥可接受鹽。
- 一種有用於如請求項1至12之化合物或其醫藥可接受鹽的合成的中間體化合物，其具有下式：
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