Analogues of pterostilbene amino acids with carbonates for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Abstract

A series of novel analogs of water-soluble amino acids of pterostilbene with carbonates were synthesized, which showed activity in the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH).

Description

Invention Field

[0001] This invention relates to novel analogs of pterostilbene amino acids containing carbonates for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Background of the Invention

[0003] Nonalcoholic fatty liver disease (NAFLD) consists of a series of histological changes in which simple fatty infiltration originates in the liver, also known as nonalcoholic fatty liver disease (1). Nonalcoholic steatohepatitis (NASH) is a severe and progressive form of NAFLD. It can progress to fibrotic cirrhosis, liver failure, and hepatocellular carcinoma (HCC) and can rapidly transform into a major cancer for advanced liver disease or liver transplantation (2,3). NAFLD is the most prevalent chronic liver disease and affects one-quarter of the adult population worldwide (4).

[0004] According to current estimates, the combined prevalence of NASH among the adult population diagnosed with it in Japan, the United Kingdom, France, Germany, Italy, and Spain will reach 18 million by 2027. Lifestyle interventions, such as dietary calorie restriction and exercise, are currently the basic treatments for NASH, but they are difficult to modify and maintain, not to mention they do not meet the urgent need for medicine (2).

[0005] Although several clinical trials (5-7) exist for NASH drug candidates in development, no drug for the treatment of NASH has yet been approved by the US FDA. Among the candidates in clinical trials, obeticholic acid (Ocaliva), known primarily as a treatment for biliary cholangitis, is currently the only Phase III clinical trial candidate showing positive results in inhibiting NASH, and a New Drug Application (NDA) has been submitted to the US NDA (8,9). In conclusion, developing new, safe, and effective drugs for the treatment or prevention of NASH / NAFLD is a top priority.

[0006] Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a naturally occurring phytochemical compound found primarily in the wood of blueberries, grapes, and various other trees (10-12). Pterostilbene is known to have various advantages in the prevention and treatment of certain diseases, including cancer, dyslipidemia, diabetes, and cognitive decline (10,11,13).

[0007] Recently, pterostilbene has been reported to reduce hepatic steatosis and modify the hepatic fatty acid profile in obese rats (14,15). Results from animal and human studies using pterostilbene have shown low toxicity and high safety (16). Therefore, it is highly probable that pterostilbene could be developed as a clinical drug for the treatment of NAFLD / NASH. However, pterostilbene has poor water solubility (0.011 mg / mL, www.vcclab.org), which hinders its clinical research. Some medicinal chemists have derived it into water-soluble phosphate derivatives (17). Generally, phenolic phosphates have poor stability and are therefore rarely formulated into oral dosage forms. To date, there is no literature on the oral in vivo efficacy of pterostilbene phosphate. Only intravenous (iv) animal studies have been reported (18). Later, Chavasatyanarayana et al. formulated a pharmaceutical composition containing a therapeutically effective amount of sitagliptin pterostilbene phosphate in crystalline (or amorphous) form (Chavasatyanarayana et al., patent number: WO2014147641). This compound is based on sitagliptin. This patent relates to sitagliptin pterostilbene phosphate, includes a method of preparation and the same pharmaceutical composition, but yielded no in vivo efficacy results.

[0008] Azzolini M et al. synthesized a series of water-soluble derivatives of pterostilbene amino acid carbamates (19), tested their pharmacokinetics and distribution curves, and found increased absorption and decreased metabolism, but did not further test their in vivo efficacy. A possible reason is that the ester bonds of carbamates break down too slowly in vivo to convert the carbamate derivatives into bioactive metabolites (e.g., irinotecan). In addition, Gonzalez-Alfonso JL et al. synthesized a series of novel octa-arm-polyethylene glycol pterostilbene derivatives with good water solubility, but only performed IV methods to test their antitumor activity (20). Kuo et al. synthesized a series of stilbene compounds as inhibitors for squamous cell carcinoma and hepatocellular carcinoma (Kuo Sheng-Chu et al., US Patent 9,266,813B2,2016). Among the synthesized stilbene compounds, some water-soluble pterostilbene compounds are unstable, and some stable pterostilbene compounds are poorly water-soluble. Recently, Jose'L et al. synthesized pterostilbene α-glucoside via enzymatic synthesis. Its water solubility was increased, but there were no reports on its in vivo efficacy (20). Summary of the Invention

[0009] One object of the present invention is to provide a series of new compounds having the following formula or pharmaceutically acceptable salts thereof:

[0010]

[0011] Where n is between 1 and 3;

[0012] m ranges from 2 to 6;

[0013] Q, X, and Y are independently O, S, or NH;

[0014] Ra, Rb, and Rc are independently H, halogen, C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, C3-C6 branched alkoxy, or C1-C6 fluoroalkoxy.

[0015] Rd and Re are independently H, halogen, C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, C3-C6 branched alkoxy, or C1-C6 fluoroalkoxy, or Rd and Re are connected to form a ring structure, such that Where j is 1 to 3.

[0016] Another object of the present invention is to provide novel uses of the compounds of the present invention or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

[0017] Another object of the present invention is to provide a pharmaceutical composition for treating a subject with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, said pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for said treatment.

[0018] The present invention further provides a method for treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject suffering from non-alcoholic fatty liver disease or non-alcoholic steatohepatitis who requires the treatment.

[0019] The present invention also provides an intermediate compound having the following formula for synthesizing the compound of the present invention or a pharmaceutically acceptable salt thereof:

[0020]

[0021] Wherein m, Rc, Rd, and Re are as defined above, and Boc is tert-butoxycarbonyl, provided that Rd is not hydrogen. Preferred embodiments of the invention include (but are not limited to) the features described in the appended claims.

[0022] Brief description of the attached figures

[0023] Figure 1To show photographs of liver samples from five groups of mice (magnification: 200X): sham-operated group (non-MCD diet); MCD diet group; MCD diet + 75 mg / kg compound 5c of the present invention; MCD diet + 100 mg / kg compound 5c; and MCD diet + 150 mg / kg compound 5c, wherein the liver samples were photographed using a phase-contrast microscope by hematoxylin-eosin (H&E) staining.

[0024] Figure 2 The solubility of compound 5c in H2O at 25°C for 24 hours is shown. Invention Details

[0026] According to a preferred embodiment of the present invention, a series of novel water-soluble carbonate-containing pterostilbene amino acid analogs have been synthesized, which have shown activity in the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH). Example

[0027] 1. Chemical Synthesis

[0028] 1-1. Materials and Instruments

[0029] Starting materials, reagents, and solvents were purchased from commercial suppliers (Sigma-Aldrich, Acros, TCI, Alfa, Combi-Blocks, Matrix, and Fischer) and used as is without further purification. 1 H and 13 C-NMR spectra were obtained in the specified solvents on a Varian AS500 500NMR spectrometer or an Agilent Technologies VnmrJ 500NMR spectrometer. Chemical shifts relative to the TMS signal used as an internal standard are expressed in ppm (δ units). Rapid column chromatography was performed on columns packed with Merck silica gel 60 (0.063–0.200 μm). Purification of the compounds or final compounds was performed using reversed-phase high-performance liquid chromatography (RP-HPLC) at 220 or 254 nm with UV detection (Jasco UV-975 detector) on an Inertsil ODS-3C18 (5 μm, 30 mm × 250 mm) column. The mobile phase consisted of H₂O and CH₃CN (elution buffer A, 70% ACN or 80% ACN, isocratic, 42 mL / min flow rate; elution buffer B, gradient, described in detail in the experiments). Electron-bomb mass spectrometry (MS) was used to record data using an API 3200 LC / MS / MS system. Reagent-grade solvents were used, and, when necessary, purified and dried using standard methods. Concentration of the reaction solutions involved rotary evaporation under reduced pressure.

[0030] Synthesis of target compound 5a-10 (1-2)

[0031] 1-2-1. Synthesis of compounds 5a-5s

[0032] The target compounds 5a-5s were synthesized according to Scheme 1. Various amino acids (1a-1s) were reacted with ethanolamine in CH2Cl2 in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), diisopropylethylamine (DIPEA), and N,N-dimethylaminopyridine (DMAP), or in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and DIPEA to obtain the corresponding hydroxyamide derivatives (compounds 2a-2s). The reaction of 2a-2s with p-nitrophenyl chloroformate yielded the corresponding p-nitrophenyl carbonate (3a-3s), which, without further purification, reacted with pterostilbene to obtain the corresponding 4a-4s. Compounds 4a-4s were subsequently deprotected with a solution of 4M HCl in 1,4-dioxane or a solution of trifluoroacetic acid (TFA) and triisopropylsilane (TIPS) in CH2Cl2 to provide target compounds 5a-5s.

[0033] Scheme 1: Synthesis of compounds 5a-5s

[0034]

[0035]

[0036] Reagents and conditions: (a) EDCI, DIPEA, DMAP, CH2Cl2 or HATU, DIPEA, CH2Cl2; (b) NEt3, CH2Cl2; (c) DMAP, ACN, 50℃; (d) 4M HCl in 1,4-dioxane, or TFA, TIPS, CH2Cl2.

[0037] (2-((2-hydroxyethyl)amino)-2-oxoethyl)carbamate tert-butyl ester (2a)

[0038] EDCI (61.7 g, 46.6 mmol) was added to a stirred solution of ethanolamine (3.03 g, 49.6 mmol), Boc-Gly-OH 1a (7.2 g, 41.3 mmol), and DIPEA (16 g, 124 mmol) in CH2Cl2 (80 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed under vacuum, and the residue was purified by column chromatography (n-hexane to EA / n-hexane = 1 / 5 (V / V)) to provide the target product 2a (3.3 g, 37% yield) as a white powder. 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).

[0039] (1-((2-hydroxyethyl)amino)-1-oxopropane-2-yl)tert-butyl carbamate (2b)

[0040] 2b was obtained from Boc-Ala-OH 1b using the same synthetic steps as 2a.

[0041] Yield: 37%. 1 H-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).

[0042] (1-((2-hydroxyethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (2c)

[0043] HATU (2501 mg, 6.6 mmol) was added to a stirred solution of ethanolamine (335 mg, 5.4819 mmol), Boc-Val-OH 1c (1191 mg, 5.5 mmol), and DIPEA (2387 μL, 13.7 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed under vacuum, and the residue was purified by column chromatography (n-hexane to EA / n-hexane = 3 / 1 (V / V)) to provide the target product 2c (1113 mg, 78% yield) as a white powder. 1 H-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).

[0044] (1-((2-hydroxyethyl)amino)-4-methyl-1-oxopentane-2-yl)tert-butyl carbamate (2d)

[0045] 2d was obtained from Boc-Leu-OH 1d using the same synthetic steps as 2a.

[0046] Yield: 70%. 1 H-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).

[0047] (1-((2-hydroxyethyl)amino)-3-methyl-1-oxopentane-2-yl)tert-butyl carbamate (2e)

[0048] 2e was obtained from Boc-Ile-OH 1e using the same synthetic steps as 2a.

[0049] Yield: 64%. 1 H-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).

[0050] (1-((2-hydroxyethyl)amino)-4-(methylthio)-1-oxobutane-2-yl)tert-butyl carbamate (2f)

[0051] 2f was obtained from Boc-Met-OH 1f using the same synthetic steps as 2c.

[0052] Yield: 32%. 1 H-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).

[0053] (3-(tert-butoxy)-1-((2-hydroxyethyl)amino)-1-oxopropane-2-yl)tert-butyl carbamate (2g)

[0054] 2g were obtained from 1g of Boc-Ser(tBu)-OH using the same synthetic steps as 2a.

[0055] Yield: 41%. 1 H-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).

[0056] (3-(tert-butoxy)-1-((2-hydroxyethyl)amino)-1-oxobutane-2-yl)carbamate tert-butyl ester (2h)

[0057] 2h was obtained from Boc-Thr(tBu)-OH 1h using the same synthetic steps as 2a.

[0058] Yield: 24%. 1 H-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).

[0059] (1-((2-hydroxyethyl)amino)-1-oxo-3-(triphenylmethylthio)propane-2-yl)tert-butyl carbamate (2i)

[0060] 2i was obtained from Boc-Cys(Trt)-OH 1i using the same synthetic steps as 2c.

[0061] Yield: 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).

[0062] (1-((2-hydroxyethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (2j)

[0063] 2j was obtained from Boc-Phe-OH 1j using the same synthetic steps as 2c.

[0064] Yield: 88%. 1 H-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).

[0065] (3-(4-(tert-butoxy)phenyl)-1-((2-hydroxyethyl)amino)-1-oxopropane-2-yl)carbamate tert-butyl ester (2k)

[0066] 2k was obtained from Boc-Tyr(tBu)-OH 1k using the same synthetic steps as 2c.

[0067] Yield: 34%. 1 H-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).

[0068] 3-(2-((tert-butoxycarbonyl)amino)-3-((2-hydroxyethyl)amino)-3-oxopropyl)-1H-indole-1-carboxylic acid tert-butyl ester (2l)

[0069] 2l was obtained from Boc-Trp(Boc)-OH 1l using the same synthetic steps as 2a.

[0070] Yield: 35%. 1 H-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).

[0071] (1-((2-hydroxyethyl)amino)-1-oxo-3-(1-triphenylmethyl-1H-imidazol-2-yl)propane-2-yl)tert-butyl carbamate (2m)

[0072] 2m was obtained from Boc-His(Trt)-OH 1m using the same synthetic steps as 2c.

[0073] Yield: 67%. 1 H-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).

[0074] (6-((2-hydroxyethyl)amino)-6-oxohexane-1,5-diyl)dicarbamate di-tert-butyl ester (2n)

[0075] 2n was obtained from Boc-Lys(Boc)-OH 1n using the same synthetic steps as 2c.

[0076] Yield: 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), 3.41-3.4 0(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).

[0077] (1-((2-hydroxyethyl)amino)-1-oxo-5-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidinyl)pentan-2-yl)tert-butyl carbamate (2o)

[0078] 2o was obtained from Boc-Arg(Pbf)-OH 1o using the same synthetic steps as 2a.

[0079] Yield: 50%. 1 H-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).

[0080] (1-((2-hydroxyethyl)amino)-1,4-dioxo-4-(triphenylmethylamino)butane-2-yl)tert-butyl carbamate (2p)

[0081] 2p was obtained from Boc-Asn(Trt)-OH 1p using the same synthetic steps as 2a.

[0082] Yield: 37%. 1 H-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).

[0083] (1-((2-hydroxyethyl)amino)-1,5-dioxo-5-(triphenylmethylamino)pentan-2-yl)carbamate tert-butyl ester (2q)

[0084] 2q was obtained from Boc-Gln(Trt)-OH 1q using the same synthetic steps as 2c.

[0085] Yield: 51%. 1 H-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).

[0086] 3-((tert-butoxycarbonyl)amino)-4-((2-hydroxyethyl)amino)-4-oxobutyric acid tert-butyl ester (2r)

[0087] 2r was obtained from Boc-Asp(tBu)-OH 1r using the same synthetic steps as 2a.

[0088] Yield: 37%. 1 H-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).

[0089] 4-((tert-butoxycarbonyl)amino)-5-((2-hydroxyethyl)amino)-5-oxovalerate tert-butyl ester (2S)

[0090] 2s was obtained from Boc-Glu(tBu)-OH 1s using the same synthetic steps as 2a.

[0091] Yield: 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).

[0092] Synthesis of (E)-(2-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-2-oxoethyl)carbamate tert-butyl ester (4a)

[0093] Triethylamine (3.22 mL, 23.1 mmol) was added to a stirred solution of compound 2a (2.02 g, 9.3 mmol) in anhydrous CH2Cl2 (15 mL), followed by dropwise addition of a solution of 4-nitrophenyl chloroformate (1.96 g, 9.7 mmol in 10 mL CH2Cl2) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature. The mixture was stirred at room temperature for an additional 4 hours. After the reaction was complete (confirmed by TLC), the solvent was removed by evaporation. The crude intermediate was mixed with pterostilbene (2.50 g, 9.8 mmol) and DMAP (2.27 g, 18.6 mmol) in ACN (20 mL). The resulting mixture was heated to 50 °C for 1 hour. After the reaction, the solvent was removed under vacuum. The residue was transferred to EA and washed with saturated citric acid solution. The organic layer was collected, dried over Na2SO4, and then evaporated. The residue was purified by column chromatography (silica gel, 0 to 25% EtOAc / n-hexane) to provide a crude product, which was further purified by preparative HPLC (70% ACN, 30% H2O) to provide target compound 4a (2.22 g, 48% yield) as a white powder. 1 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). Mass observation [M-Boc+H] + =402.2; [M+H] + =502.2,[M+Na]+ =524.2,[2M+H] + =902.4.

[0094] Intermediate 4b-4s is synthesized using a similar synthesis procedure as that used for 4a.

[0095] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxopropane-2-yl)tert-butyl carbamate (4b)

[0096] 4b is obtained from 2b using the same synthesis steps as 4a.

[0097] Yield: 56%. 1 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). Mass observation [M-Boc+H] + =416.2; [M+H] + =516.3, [M+Na] + =538.3.

[0098] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (4c)

[0099] 4c is obtained from 2c using the same synthesis steps as 4a.

[0100] Yield: 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 = 5.0 Hz, 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 = 6.5 Hz, 3H). Mass observation [M–Boc+H] + =444.1; [M+Na] + =566.1.

[0101] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-methyl-1-oxopentane-2-yl)tert-butyl carbamate (4d)

[0102] 4d was obtained from 2d using the same synthesis steps as 4a.

[0103] Yield: 32%. 1 H-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 = 5.0 Hz, 2H), 4.11 (s, 1H), 3.84 (s, 6H), 3.64 (dd, J = 5.0, 10.5 Hz, 2H), 1.73–1.66 (m, 2H), 1.51–1.47 (m, 1H), 1.45 (s, 9H), 0.96–0.94 (m, 6H). Mass observation [M–Boc+H] + =457.3; [M – Boc + Na] + =479.2; [M+Na] + =579.3; [2M+Na] + =1135.5.

[0104] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxopentane-2-yl)tert-butyl carbamate (4e)

[0105] 4e is obtained from 2e using the same synthesis steps as 4a.

[0106] Yield: 27%. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 7.51 (d, J = 8.0Hz, 2H), 7.17 (d, J = 9.0Hz, 2H), 7.06 (d, J = 1 6.5Hz,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 = 5.0 Hz, 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). Mass observation [M–Boc+H] + =457.3; [M+Na] + =579.3; [2M+H] + =1135.5.

[0107] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-(methylthio)-1-oxobutane-2-yl)tert-butyl carbamate (4f)

[0108] 4f is obtained from 2f using the same synthesis steps as 4a.

[0109] Yield: 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 = 1 6.5Hz,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 = 5.0 Hz, 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). Mass observation [M – Boc + H] + =476.2; [M+H] + =576.3; [M+Na] + =598.3.

[0110] (E)-(3-(tert-butoxy)-1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxopropane-2-yl)tert-butyl carbamate (4g)

[0111] 4g was obtained from 2g using the same synthesis steps as 4a.

[0112] Yield: 46%. 1 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). Mass observation [M–Boc–tBu+H] + =432.3; [M+H] + =588.5; [M+Na] + =610.4; [2M+H] + =1174.8; [2M+Na] + =1196.9.

[0113] (E)-(3-(tert-butoxy)-1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxobutane-2-yl)tert-butyl carbamate (4h)

[0114] 4h was obtained from 2h using the same synthesis steps as 4a.

[0115] Yield: 48%. 1 H-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 5.5 Hz, 1H), 5.64 (d, J = 5.0 Hz, 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 = 6.0 Hz, 3H). Mass observation [M–Boc–tBu+H] + =446.2; [M+H] + =602.5; [M+Na] + =624.4; [2M+H] + =1202.9; [2M+Na] + =1224.9.

[0116] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-(triphenylmethylthio)propane-2-yl)tert-butyl carbamate (4i)

[0117] 4i was obtained from 2i using the same synthesis steps as 4a.

[0118] Yield: 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),6.6 6 (d, J = 2.5 Hz, 2H), 6.41 (t, J = 2.0 Hz, 1H), 6.40 (s, 1H), 4.79 (s, 1H), 4.28 (t, J = 5.0 Hz, 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), mass observation [M+H] + =789.3; [M+Na] + =811.3.

[0119] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (4j)

[0120] 4j is obtained from 2j using the same synthesis steps as 4a.

[0121] Yield: 46%. 1 H-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). Mass observation value [M–Boc+H] + =492.2; [M+H] + =592.4; [M+Na] + =614.3.

[0122] (E)-(3-(4-(tert-butoxy)phenyl)-1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxopropane-2-yl)tert-butyl carbamate (4k)

[0123] 4k was obtained from 2k using the same synthesis steps as 4a.

[0124] Yield: 39%. 1 H-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). Mass observation value [M–Boc–tBu+H] + =508.2; [M – Boc + H] + =564.3; [M+H] + =664.4, [M+Na] + =686.4; [M+K] + =702.4.

[0125] (E)-3-(2-((tert-butoxycarbonyl)amino)-3-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-oxopropyl)-1H-indole-1-carboxylic acid tert-butyl ester (4l)

[0126] 4l was obtained from 2l using the same synthesis steps as 4a.

[0127] Yield: 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). Mass observation value [M-2Boc+H] + =530.2; [M – Boc + H] + =630.2; [M+H] + =730.2; [2M+H] + =1459.5.

[0128] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-(1-triphenylmethyl-1H-imidazol-2-yl)propane-2-yl)tert-butyl carbamate (4m)

[0129] 4m was obtained from 2m using the same synthesis steps as 4a.

[0130] Yield: 62%. 1 H-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 = 8.5H z,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=2.5H z, 2H), 6.41 (t, J = 2.5 Hz, 1H), 5.69 (d, J = 8.0 Hz, 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). Mass observation [M+H]+ =832.4.

[0131] (6-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-6-oxohexane-1,5-diyl)(E)-dicarboxylic acid di-tert-butyl ester (4n)

[0132] 4n is obtained from 2n using the same synthesis steps as 4a.

[0133] Yield: 39%. 1 H-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(b rs,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). Mass observation value [M-2Boc+H] + =473.0; [M-Boc+H] + =573.4; [M+H] + =673.4, [M+Na] + =695.4, [M+K] + =711.4.

[0134] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-5-(3-(((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidinyl)pentan-2-yl)tert-butyl carbamate (4o)

[0135] 4o was obtained from 2o using the same synthetic steps as 4a.

[0136] Yield: 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). Mass observation value [M+H] + =852.3.

[0137] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1,4-dioxo-4-(triphenylmethylamino)butane-2-yl)tert-butyl carbamate (4p)

[0138] 4p is obtained from 2p using the same synthesis steps as 4a.

[0139] Yield: 28%. 1 H-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 = 2.0 Hz, 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). Mass observation [M+H] + =799.5.

[0140] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1,5-dioxo-5-(triphenylmethylamino)pentan-2-yl)tert-butyl carbamate (4q)

[0141] 4q is obtained from 2q using the same synthesis steps as 4a.

[0142] Yield: 27%. 1 H-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), 7.0 5(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). Mass observation value [M+H] + =814.3.

[0143] (E)-3-((tert-butoxycarbonyl)amino)-4-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-oxobutyric acid tert-butyl ester (4r)

[0144] 4r is obtained from 2r using the same synthesis steps as 4a.

[0145] Yield: 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(b rs,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). Mass observation value [M-Boc-tBu+H] + =460.1; [M+H] + =616.3; [M+Na] + =638.3.

[0146] (E)-4-((tert-butoxycarbonyl)amino)-5-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-5-oxovalerate tert-butyl ester (4S)

[0147] 4s is obtained from 2s using the same synthesis steps as 4a.

[0148] Yield: 55%. 1 H-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, 1 H),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 = 5.5 Hz, 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). Mass observation [M – Boc – OtBu + H] + =456.1,[M–Boc–tBu+H] + =474.0; [M+H] + =630.4; [M+Na] +=652.3.

[0149] (E)-2-(2-aminoacetamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5a)

[0150] A solution of 4M HCl in 1,4-dioxane (7.25 mL) was added to a stirred solution of compound 4a (726 mg, 1.5 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was then evaporated and purified by preparative HPLC (TFA as buffer, detailed gradient elution, see information below). The aqueous solution was then treated with a few drops of concentrated HCl and lyophilized to provide compound 5a (602 mg, 95% yield) as a white solid. 1 H-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); 13 C-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; Mass observation [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.

[0151] Column: Inertsil ODS-3C18, 5um, 30*250mm

[0152] Flow rate: 38 ml / min

[0153] Solvent A: 10% ACN in H2O + 0.1% TFA

[0154] Solvent B: 90% ACN in H2O + 0.1% TFA

[0155] gradient:

[0156] Time (min) Flow rate (ml / min) ％A ％B 0 38 100 0 20 38 0 100 24 38 0 100 28 38 100 0 30 38 100 0

[0157] (E)-2-(2-aminopropionamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5b)

[0158] 5b is obtained from 4b using the same synthesis steps as 5a.

[0159] Yield: 98%. 1 H-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 = 2.0H z,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); 13 C-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; Mass observation [M-HCl+H] + = 416.2; [M–HCl+Na] + =438.2; [2M-HCl+H] + =830.5; [2M–2HCl+Na] + =852.4.

[0160] E-(2-amino-3-methylbutamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5c)

[0161] 5c was obtained from 4c using the same synthesis steps as 5a.

[0162] Yield: 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); 13 C-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; Mass observation [M-HCl+H] + =444.1; [M-HCl+Na] + =466.1.

[0163] (E)-2-(2-amino-4-methylpentamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5d)

[0164] 5d was obtained from 4d using the same synthesis steps as 5a.

[0165] Yield: 95%. 1 H-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),3.7 2-3.67(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; Mass observation [M-HCl+H] + =457.2; [2M-2HCl+H] + =913.3.

[0166] (E)-2-(2-amino-3-methylpentamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5e)

[0167] 5e is obtained from 4e using the same synthesis steps as 5a.

[0168] Yield: 98%. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =457.2; [2M-2HCl+H] + =913.3.

[0169] E-(2-amino-4-(methylthio)butamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5f)

[0170] 5f was obtained from 4f using the same synthesis steps as 5a.

[0171] Yield: 85%. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =476.2; [M-HCl+Na] + =498.2; [2M-HCl+H] + =950.4.

[0172] (E)-2-(2-amino-3-hydroxypropamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5g)

[0173] 5g was obtained from 4g using the same synthesis steps as 5a.

[0174] Yield: 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); 13 C-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; Mass observation [M-HCl+H] + =431.2; [2M-2HCl+H] + =861.2.

[0175] (E)-2-(2-amino-3-hydroxybutamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5h)

[0176] 5h was obtained from 4h using the same synthesis steps as 5a.

[0177] Yield: 74%. 1 H-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 = 2.0H z,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; Mass observation [M-HCl+H] + =445.2; [2M-2HCl+H] + =889.2.

[0178] E-(2-amino-3-mercaptopropamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5i)

[0179] TFA (14.9 mL) and triisopropylsilane (TIPS, 790 μL, 3.9 mmol) were added to a stirred solution of compound 4i (760 mg, 1.0 mmol) in DCM (15 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was then evaporated and purified by preparative HPLC (TFA as buffer, detailed gradient elution, see information below). The aqueous solution was then treated with a few drops of concentrated HCl and lyophilized to provide compound 5i (354 mg, 76%) as a white solid. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =448.2; [M-HCl+Na]+ =470.2; [2M-2HCl+H] + =894.4.

[0180] Column: Inertsil ODS-3C18, 5um, 30*250mm

[0181] Flow rate: 38 mL / min

[0182] Solvent A: 10% ACN in H2O + 0.1% TFA

[0183] Solvent B: 90% ACN in H2O + 0.1% TFA

[0184] gradient:

[0185] Time (min) Flow rate (ml / min) ％A ％B 0 38 100 0 20 38 0 100 24 38 0 100 28 38 100 0 30 38 100 0

[0186] E-(2-amino-3-phenylpropamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5j)

[0187] 5j was obtained from 4j using the same synthesis steps as 5a.

[0188] Yield: 90%. 1 H-NMR (CD3OD, 500MHz), δ (ppm): 7.58 (d, J = 8.5Hz, 2H), 7.38-7.35 (m, 2H), 7.31-7.29 (m, 3 H),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); 13 C-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; Mass observation [M-HCl+H] +=491.3; [M-HCl+Na] + =513.2.

[0189] E-(2-amino-3-(4-hydroxyphenyl)propamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5k)

[0190] 5k was obtained from 4k using the same synthesis steps as 5a.

[0191] Yield: 84%. 1 H-NMR (CD3OD, 500MHz), δ (ppm): 7.57 (d, J = 8.5Hz, 2H), 7.18 (d, J = 8.5Hz, 2H), 7.14 (d, J = 1 6.5Hz,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); 13 C-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; Mass observation [M-HCl+H] + =507.2; [2M–2HCl+H] + =1013.2.

[0192] E-(2-amino-3-(1H-indol-3-yl)propamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5l)

[0193] 5l was obtained from 4l using the same synthesis steps as 5a.

[0194] Yield: 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); 13 C-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; Mass observation [M-HCl+H] + =530.3; [2M–2HCl+H] + =1059.4.

[0195] E-(2-amino-3-(1H-imidazol-2-yl)propamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester dihydrochloride (5m)

[0196] 5m was obtained from 4m using the same synthesis steps as 5a.

[0197] Yield: 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); 13 C-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; Mass observation [M-HCl+H] + =482.2; [M-HCl+Na] + =504.1; [2M–2HCl+H] + =962.3.

[0198] (E)-2-(2,6-diaminohexanoyl)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester dihydrochloride (5n)

[0199] 5n is obtained from 4n using the same synthesis steps as 5a.

[0200] Yield: 78%. 1 H-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,1 H),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);13 C-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; Mass observation [M-2HCl+H] + =472.2.

[0201] E-(2-amino-5-guanidinopentamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester dihydrochloride (5o)

[0202] 5o was obtained from 4o using the same synthesis steps as 5i.

[0203] Yield: 64%. 1 H-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); 13 C-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; Mass observation [M-2HCl+H] + =500.1.

[0204] E-(2,4-diamino-4-oxobutamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5p)

[0205] 5p is obtained from 4p using the same synthesis steps as 5i.

[0206] Yield: 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); 13 C-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; Mass observation [M-HCl+H] + =459.2; [M-HCl+Na] + =481.1; [2M–2HCl+H] + =916.4.

[0207] (E)-2-(2,5-diamino-5-oxopentanamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5q)

[0208] 5q is obtained from 4q using the same synthesis steps as 5i.

[0209] Yield: 62%. 1 H-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; Mass observation [M-HCl+H] + =473.3; [M-HCl+Na] + =495.3; [2M–2HCl+H] + =944.6.

[0210] (E)-3-amino-4-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-4-oxobutyrate (5r)

[0211] 5r is obtained from 4r using the same synthesis steps as 5a.

[0212] Yield: 82%. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =459.1; [2M–2HCl+H] + =917.2.

[0213] (E)-4-amino-5-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-5-oxovalerate (5S)

[0214] 5s was obtained from 4s using the same synthesis steps as 5a.

[0215] Yield: 88%. 1 H-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,1 H),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); 13 C-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; Mass observation [M-HCl+H] + =473.0.

[0216] 1-2-2. Synthesis of target compound 5t

[0217] Compound 5t was synthesized according to Scheme 2, which is similar to Scheme 1.

[0218] Scheme 2: Synthesis of compound 5t

[0219]

[0220] Reagents and conditions: (a) HATU, DIPEA, CH2Cl2, 41%; (b) NEt3, CH2Cl2, 0℃; (c) DMAP, ACN, 50℃, 57%; (d) 4M HCl in 1,4-dioxane, CH2Cl2, 92%.

[0221] E-(3,5-dimethoxystyryl)phenyl carbonate (2-(pyrrolidine-2-carboxamido)ethyl) ester hydrochloride (5t)

[0222] Compound 5t was obtained from 1t using a synthetic procedure similar to that of 5a.

[0223] White powder. 92% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + = 442.0; [M-HCl+Na] + =464.1; [2M - 2HCl + H] + =882.4; [2M-2HCl+Na] + =904.4.

[0224] 1-2-3. Synthesis of the target compound 5u

[0225] Compound 5u was synthesized according to Scheme 3, which is similar to Scheme 1.

[0226] Scheme 3: Synthesis of compound 5u

[0227]

[0228] Reagents and conditions: (a) EDCI, DIPEA, CH2Cl2, 45%; (b) NEt3, CH2Cl2, 0℃; (c) DMAP, ACN, 50℃, 33%; (d) 4M HCl in dioxane, CH2Cl2, 90%.

[0229] (E)-3-(2-amino-3-methylbutamido)propyl carbonate (4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (5u)

[0230] Compound 5u was obtained from 1c and 3-aminopropane-1-ol using a synthetic procedure similar to that of 5a.

[0231] White powder. 90% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =457.3; [M-HCl+Na] + =479.2; [2M-2HCl+Na] + =935.4.

[0232] 1-2-4. Synthesis of target compounds 5v and 5w

[0233] As shown in Scheme 4, compounds 5a or 5c are neutralized with sodium carbonate and then treated with nicotinic acid to obtain the corresponding nicotinic acid salts 5v and 5w.

[0234] Scheme 4: Synthesis of compounds 5v and 5w

[0235]

[0236] Reagents and conditions: (a) 1. K2CO3, H2O, CH2Cl2, 1 hour; 2. Nicotinic acid, ethanol, 3 hours.

[0237] E-(2-aminoacetamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) nicotinate (5v)

[0238] A solution of K₂CO₃ (0.182 g, 1.3 mmol) in H₂O (0.4 mL) was added to a stirred solution of compound 5a (0.42 g, 1.0 mmol) in CH₂Cl₂ (20 mL), and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum to obtain free ammonia, which was dissolved in 10 mL of ethanol and nicotinic acid (0.145 g, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and the crude product was recrystallized from ethanol and anhydrous diethyl ether to obtain compound 5v as a white powder (0.39 g, 78% yield). 1 H-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),4.3 3(t,J=5.0Hz,2H),3.81(s,6H),3.68-3.66(m,2H),3.61(t,J=5.0Hz,2H).

[0239] E-(2-amino-3-methylbutamido)ethyl carbonate (4-(3,5-dimethoxystyryl)phenyl) nicotinate (5w)

[0240] 5w is obtained from 5c using the same synthesis steps as 5v.

[0241] White powder. Yield: 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).

[0242] 1-2-5. Synthesis of target compounds 6a-6h

[0243] Compounds 6a-6h were synthesized according to scheme 5. As shown, the starting 4-hydroxybenzaldehyde (11a-11b) was treated with imidazole and TIPS to form the corresponding silyl ethers (12a-12b), which were then reduced with NaBH4 to obtain the corresponding carbonates (13a-13b). Compounds 13a-13b were treated with triethyl phosphite and ZnI2 to provide the corresponding phosphonates (14a-14b). Compounds 14a-14b were coupled with commercially available aldehydes (15a-15d) to produce the corresponding 16a-16d, which were subsequently treated with a THF solution of Bu4NF to obtain the desired compounds 17a-17d. On the other hand, compounds 2a, 2c, and 2j were reacted with p-nitrophenyl chloroformate to produce the corresponding 18a, 18c, and 18j, which were reacted with 17a-17d in the presence of DMAP without further purification to obtain the corresponding carbonates 19a-19h. 19a-19h were subsequently deprotected with a solution of 4M HCl in 1,4-dioxane to provide target compounds 6a-6h.

[0244] Scheme 5: Synthesis of compounds 6a-6h

[0245]

[0246] Reagents and conditions: (a) Imidazole, TIPSCl, CH2Cl2, 16 h; (b) NaBH4, THF, MeOH, 0 °C, 1 h; (c) ZnI2, triethyl phosphite, THF, 80 °C, 16 h; (d) t-BuOK, THF, 0 °C, 3 h; (e) 1.0 M Bu4NF in THF; (f) NEt3, CH2Cl2, 0 °C; (g) DMAP, ACN, 50 °C; (h) 4 M HCl in 1,4-dioxane, CH2Cl2.

[0247] 4-((triisopropylsilyl)oxy)benzaldehyde (12a)

[0248] Imidazole (41.8 g, 614.7 mmol) was added to a solution of 4-hydroxybenzaldehyde 11a (50 g, 409.8 mmol) in DCM (500 mL), followed by the dropwise addition of TIPSCl (86.5 g, 450.8 mmol). The mixture was stirred for 16 hours and then poured into ice / water for extraction with DCM. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / petroleum ether = 1 / 50) to obtain compound 12a (95 g, 99%) as a yellow oil. 1 H-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).

[0249] 3-Methoxy-4-((triisopropylsilyl)oxy)benzaldehyde (12b)

[0250] 12b was obtained from 11b using the same synthetic steps as 12a.

[0251] Yellow oil. 98% yield. 1 H-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).

[0252] (4-((triisopropylsilyl)oxy)phenyl)methanol(13a)

[0253] NaBH4 (27.3 g, 719.4 mmol) was added to a solution of compound 12a (100 g, 359.7 mmol) in MeOH / THF (1:1, 1 L) at 0 °C and stirred for 1 hour. The reaction mixture was poured into ice / water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / petroleum ether = 1 / 20) to obtain compound 13a (88 g, 99% yield) as a yellow oil. 1 H-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).

[0254] (3-Methoxy-4-((triisopropylsilyl)oxy)phenyl)methanol(13b)

[0255] 13b was obtained from 12b using the same synthetic steps as 13a.

[0256] Yellow oil. 95% yield. 1 H-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).

[0257] (4-((triisopropylsilyl)oxy)benzyl)phosphonate diethyl ester (14a)

[0258] ZnI₂ (145.3 g, 455.4 mmol) and triethyl phosphite (100.8 g, 607.2 mmol) were added to a solution of compound 13a (85 g, 303.6 mmol) in THF (850 mL). The mixture was refluxed for 16 hours and then evaporated. The residue was extracted with 2N NaOH (500 mL) and diethyl ether. The organic layer was washed with brine, dried over Na₂SO₄, and then evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / petroleum ether = 1 / 30) to obtain compound 14a (90 g, 75% yield) as a yellow oil. 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).

[0259] (3-Methoxy-4-((triisopropylsilyl)oxy)benzyl)phosphonate diethyl ester (14b)

[0260] 14b was obtained from 13b using the same synthetic steps as 14a.

[0261] Yellow oil. 78% yield. 1 H-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).

[0262] (E)-(4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)triisopropylsilane(16a)

[0263] Compound 15a (3.0 g, 17.5 mmol) and t-BuOK (4.1 g, 36.7 mmol) were added to a solution of compound 14a (7.0 g, 17.5 mmol) in THF (175 mL) at 0 °C, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was poured into ice / water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 8) to give compound 16a (5.6 g, 76% yield) as a white solid. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 7.37 (d, J = 8.0Hz, 2H), 7.03 (d, J = 16.5Hz, 1H), 6.91-6.8 6(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).

[0264] (E)-(4-(3,5-diethoxystyryl)phenoxy)triisopropylsilane(16b)

[0265] 16b was obtained from 14b and 15b using the same synthetic steps as 16a.

[0266] White powder. 75% yield. 1 H-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), 6.6 3(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).

[0267] (E)-(4-(3,5-dimethoxystyryl)-2-methoxyphenoxy)triisopropylsilane(16c)

[0268] 16c was obtained from 14c and 15c using the same synthetic steps as 16a.

[0269] White solid. 78% yield. 1 H-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).

[0270] (E)-(4-(3,5-dimethoxystyryl)-2-methoxyphenoxy)triisopropylsilane (16d)

[0271] 16d was obtained from 14d and 15d using the same synthetic steps as 16a.

[0272] Pale yellow solid. 77% yield. 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).

[0273] (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenol(17a)

[0274] Compound 16a (0.80 g, 1.9 mmol) was stirred for 2 hours at room temperature under a nitrogen atmosphere in anhydrous THF (15 mL) and a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.50 mL, 2.5 mmol). The reaction mixture was diluted with EtOAc and the organic layer was washed with water. The organic layer was dried over Na2SO4 and evaporated, and the residue was purified by column chromatography on silica gel (elution solvent: ethyl acetate / n-hexane = 1 / 8) to obtain product 17a (0.46 g, 91% yield) as a white powder. 1 H-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).

[0275] (E)-4-(3,5-diethoxystyryl)phenol (17b)

[0276] 17b was obtained from 16b using the same synthetic steps as 17a.

[0277] White powder. 1 H-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).

[0278] (E)-4-(3,5-dimethoxystyryl)-2-methoxyphenol (17c)

[0279] 17c was obtained from 16c using the same synthetic steps as 17a.

[0280] White powder. 1 H-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).

[0281] 4-((1E,3E)-4-(3,5-dimethoxyphenyl)but-1,3-dien-1-yl)phenol (17d)

[0282] 17d was obtained from 16d using the same synthetic steps as 17a.

[0283] White powder. 1 H-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).

[0284] (E)-(2-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)oxy)ethyl)amino)-2-oxoethyl)tert-butyl carbamate (19a)

[0285] Triethylamine (2.15 mL, 15.4 mmol) was added to a stirred solution of compound 2a (1.12 g, 5.1 mmol) in anhydrous CH2Cl2 (15 mL), followed by dropwise addition of a solution of 4-nitrophenyl chloroformate (1.15 g, 5.7 mmol in 10 mL CH2Cl2) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature. The mixture was stirred at room temperature for an additional 4 h. After the reaction was complete (confirmed by TLC), the solvent was removed by evaporation. The crude intermediate was mixed with pterostilbene derivative 17a (1.41 g, 5.4 mmol) and DMAP (1.26 g, 10.3 mmol) in ACN (30 mL). The resulting mixture was heated to 50 °C for 1 h. After the reaction, the solvent was removed under vacuum to obtain a crude residue, which was purified by column chromatography (EA / n-hexane = 1 / 5 (V / V)) to provide the crude product. The crude product was purified by preparative HPLC (70% ACN, 30% H2O) to provide target compound 19a (0.99 g, 38% yield) as a white powder. 1 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, 2H), 1.46 (s, 9H). Mass observation [M–Boc+H] + =408.3; [M+H] + =508.4; [M+Na] + =530.4, [2M+H] + =914.6.

[0286] (E)-(2-((2-(((4-(3,5-diethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-2-oxoethyl)tert-butyl carbamate (19b)

[0287] 19b was obtained from 2a and 17b using the same synthetic steps as 19a.

[0288] White powder. 45% yield. 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 = 2.0 Hz, 1H), 5.12 (brs, NH), 4.35 (t, J = 5.5 Hz, 2H), 4.06 (q, J = 7.0 Hz, 4H), 3.83 (d, J = 5.5 Hz, 2H), 3.66 (q, J = 5.5 Hz, 2H), 1.46 (s, 9H), 1.43 (t, J = 7.0 Hz, 6H). Mass observation [M – Boc + H] + =430.3; [M+H] + =530.3; [M+Na] + =552.2,[2M+H] + =1058.6,[2M+Na] + =1080.6.

[0289] (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (19c)

[0290] 19c was obtained from 2c and 17a using the same synthetic steps as 19a.

[0291] White powder. 42% yield. 1 H-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(b rs,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). Mass observation [M–Boc+H] + =450.2; [M+H] + =550.4; [M+Na] + =572.4.

[0292] (E)-(1-((2-(((4-(3,5-diethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (19d)

[0293] 19d was obtained from 2c and 17b using the same synthetic steps as 19a.

[0294] White powder. 41% yield. 1 H-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 = 5.5 Hz, 2H), 4.05 (q, J = 7.0 Hz, 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 = 7.0 Hz, 6H), 0.98 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H). Mass observation [M–Boc+H] + =472.3; [M+H] + =572.4; [M+Na] + =594.4; [2M+H] + =1142.8; [2M+Na] + =1164.9.

[0295] (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (19e)

[0296] 19e was obtained from 2j and 17a using the same synthetic steps as 19a.

[0297] White powder. 47% yield. 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 = 2.0 Hz, 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). Mass observation [M–Boc+H] + =498.3; [M+Na] + =620.4; [2M+H] + =1194.9; [2M+Na] + =1216.9.

[0298] (E)-(1-((2-(((4-(3,5-diethoxystyryl)phenoxy)carbonyl)oxy)ethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (19f)

[0299] 19f was obtained from 2j and 17b using the same synthetic steps as 19a.

[0300] White powder. 47% yield. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 7.51 (d, J = 9.0 Hz, 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). Mass observation value [M–Boc+H] + =519.2; [M+H]+ =619.2; [M+Na] + =641.2; [2M+Na] + =1259.5.

[0301] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)-2-methoxyphenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (19g)

[0302] 19g was obtained from 2c and 17c using the same synthetic steps as 19a.

[0303] White powder. 37% yield. 1 ¹H-NMR (CDCl₃, 500MHz), δ (ppm): 7.11–7.08 (m, 3H), 7.05 (d, J = 16.0 Hz, 1H), 6.98 (d, J = 16.0 Hz, 1H), 6.67 (s, 2H), 6.41 (s, 1H), 6.37 (brs, NH), 5.04 (brs, NH), 4.34 (t, J = 5.5 Hz, 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 = 7.0 Hz, 3H), 0.92 (d, J = 7.0 Hz, 3H). Mass observation [M–Boc+H] + =474.3; [M+H] + =574.4; [M+Na] + =596.4.

[0304] (1-((2-(((4-((1E,3E)-4-(3,5-dimethoxyphenyl)but-1,3-dien-1-yl)phenoxy)carbonyl)oxy)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (19h)

[0305] 19h was obtained from 2c and 17d using the same synthetic steps as 19a.

[0306] White powder. 35% yield. 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). Mass observation [M–Boc+H] + =470.0; [M+H] + =570.3; [M+Na] + =592.3.

[0307] (E)-2-(2-aminoacetamido)ethyl carbonate (4-(3,5-bis(methoxy-d3)styryl-d6)phenyl) ester hydrochloride (6a)

[0308] A solution of 4M HCl in 1,4-dioxane (6.3 mL) was added to a stirred solution of compound 19a (639 mg, 1.3 mmol) in DCM (20 mL) and stirred at room temperature for 3 hours. The reaction solution was then evaporated and purified by preparative HPLC (TFA as buffer, detailed gradient elution, see information below). The aqueous solution was then treated with a few drops of concentrated HCl and lyophilized to provide compound 6a (491 mg, 92% yield) as a white solid. 1 H-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; Mass observation [M-HCl+H] + =408.3; [M-HCl+Na] + =430.2; [2M-2HCl+H] + =814.5; [2M–2HCl+Na] + =836.5.

[0309] Column: Inertsil ODS-3C18, 5um, 30*250mm

[0310] Flow rate: 38 ml / min

[0311] Solvent A: 10% ACN in H2O + 0.1% TFA

[0312] Solvent B: 90% ACN in H2O + 0.1% TFA

[0313] gradient:

[0314] Time (min) Flow rate (ml / min) ％A ％B 0 38 100 0 20 38 0 100 24 38 0 100 28 38 100 0 30 38 100 0

[0315] The final compounds 6b-6h were prepared using the experimental steps described in 6a, with some non-critical changes.

[0316] (E)-2-(2-aminoacetamido)ethyl carbonate (4-(3,5-diethoxystyryl)phenyl) ester hydrochloride (6b)

[0317] 6b was obtained from 19b using the same synthesis steps as 6a.

[0318] White solid. 95% yield. 1 H-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; Mass observation [M-HCl+H] + =430.3; [M-HCl+Na] + =452.2; [2M-2HCl+H] + =858.5; [2M–2HCl+Na] + =880.5.

[0319] (E)-2-(2-amino-3-methylbutamido)ethyl carbonate (4-(3,5-bis(methoxy-d3)styryl-d6)phenyl) ester hydrochloride (6c)

[0320] 6c was obtained from 19c using the same synthetic steps as 6a.

[0321] White solid. 89% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =449.3; [M-HCl+Na] + =471.3; [2M–2HCl+Na] + =919.4.

[0322] E-(2-amino-3-methylbutamido)ethyl carbonate (4-(3,5-diethoxystyryl)phenyl) ester hydrochloride (6d)

[0323] 6d was obtained from 19d using the same synthesis steps as 6a.

[0324] White solid. 93% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =472.3; [M-HCl+Na] + =494.3; [2M–2HCl+H] + = 942.6; [2M–2HCl+Na] + =964.6.

[0325] (E)-2-(2-amino-3-phenylpropamido)ethyl carbonate (4-(3,5-bis(methoxy-d3)styryl-d6)phenyl) ester hydrochloride (6e)

[0326] 6e was obtained from 19e using the same synthetic steps as 6a.

[0327] White solid. 90% yield. 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); 13 C-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; Mass observation [M-HCl+H] + =498.2; [M-HCl+Na] + =520.4; [2M–2HCl+H] + =994.6.

[0328] (E)-2-(2-amino-3-phenylpropamido)ethyl carbonate (4-(3,5-diethoxystyryl)phenyl) ester hydrochloride (6f)

[0329] 6f was obtained from 19f using the same synthesis steps as 6a.

[0330] White solid. 92% yield. 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),3.48-3.4 3(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); 13 C-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; Mass observation [M-HCl+H] + =519.2; [2M–2HCl+H] + =1037.4.

[0331] E-(2-amino-3-methylbutamido)ethyl carbonate (4-(3,5-dimethoxystyryl)-2-methoxyphenyl) ester hydrochloride (6g)

[0332] 6g was obtained from 19g using the same synthesis steps as 6a.

[0333] White solid. 85% yield. 1 H-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; Mass observation [M-HCl+H] + =474.2; [M-HCl+Na] + =496.2; [2M–2HCl+H] + = 946.5; [2M - 2HCl + Na] + =968.5.

[0334] 2-(2-amino-3-methylbutamido)ethyl carbonate (4-((1E,3E)-4-(3,5-dimethoxyphenyl)but-1,3-dien-1-yl)phenyl) ester hydrochloride (6h)

[0335] 6h was obtained from 19h using the same synthesis steps as 6a.

[0336] White solid. 80% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =469.0; [M-HCl+Na] + =491.1; [2M–2HCl+H] +=937.0.

[0337] 1-2-6. Synthesis of target compounds 7a-7f

[0338] Compounds 7a-7f were synthesized according to scheme 6. As shown, N-(2-aminoethyl)carbamate benzyl ester hydrochloride was reacted with N-Boc-amino acids (compounds 1a, 1c, and 1j) in the presence of EDCI and DMAP to obtain the corresponding amide derivatives (compounds 20a-20c). Compounds 20a-20c were hydrogenated with Pd / C to provide the corresponding compounds 21a-21c. On the other hand, pterostilbene or 17a was treated with triphosgene in the presence of NEt3 to provide the corresponding 22a-22b, which were reacted with compounds 21a-21c without further purification to obtain the corresponding 23a-23f. 23a-23f were subsequently deprotected with a solution of 4M HCl in 1,4-dioxane to provide the target compounds 7a-7f.

[0339] Scheme 6: Synthesis of compounds 7a-7f

[0340]

[0341] Reagents and conditions: (a) EDCI, DIPEA, CH2Cl2, RT, 12 h; (b) 10% Pd / C, MeOH, RT, 12 h; (c) Triethylamine, 0 °C to RT, 1.5 h; (d) Trimethylamine, RT, 1.5 h; (e) 4 M HCl in 1,4-dioxane.

[0342] (2-(2-((tert-butoxycarbonyl)amino)acetamido)ethyl)benzyl carbamate (20a)

[0343] EDCI (8.6 g, 45.0 mmol) was added to a stirred solution of (2-aminoethyl)carbamate benzyl HCl (8.5 g, 36.8 mmol), Boc-Gly-OH1a (5.3 g, 30.4 mmol), and DIPEA (9.5 g, 73.6 mmol) in CH2Cl2 (80 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (n-hexane to EA / n-hexane = 1 / 5 (V / V)) to provide the target product 20a (8.0 g, 74% yield) as a white powder. 1 H-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).

[0344] (2-(2-((tert-butoxycarbonyl)amino)-3-methylbutamido)ethyl)carbamate benzyl ester (20b)

[0345] 20b was obtained from 1c using the same synthesis steps as 20a.

[0346] White powder. 41% yield. 1 H-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).

[0347] (2-(2-((tert-butoxycarbonyl)amino)-3-phenylpropamido)ethyl)benzyl carbamate (20c)

[0348] 20c was obtained from 1j using the same synthesis steps as 20a.

[0349] White powder. 48% yield. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 7.36-7.18 (m, 11H), 6.18 (brs, NH), 5.07 (s, 2H), 5.0 4(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).

[0350] (2-((2-aminoethyl)amino)-2-oxoethyl)carbamate tert-butyl ester (21a)

[0351] Compound 20a (4.0 g, 11.4 mm) was dissolved in MeOH (50 mL) and treated with 10% Pd / C (0.6 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered through diatomaceous earth. The solvent of the filtrate was evaporated and the residue was purified by column chromatography (CH2Cl2 / methanol = 1 / 19 (V / V)) to provide compound 21a (2.35 g, 95%) as a white powder. 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).

[0352] (1-((2-aminoethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (21b)

[0353] 21b was obtained from 20b using the same synthetic steps as 21a.

[0354] White powder. 95% yield. 1 H-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).

[0355] (1-((2-aminoethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (21c)

[0356] 21c was obtained from 20c using the same synthetic steps as 21a.

[0357] White powder. 95% yield. 1 H-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).

[0358] (E)-(2-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl)amino)-2-oxoethyl)tert-butyl carbamate (23a)

[0359] A solution of pterostilbene (1.41 g, 5.51 mmol) and triphosgene (0.54 g, 1.82 mmol) in anhydrous CH2Cl2 (15 mL) was added dropwise to the intermediate solution at 0 °C with triethylamine (1.36 g, 13.4 mmol). The reaction mixture was stirred at 0 °C for 30 min and then warmed to room temperature to provide a solution of intermediate 22a. A solution of compound 21a (1.17 g, 5.9 mmol) and triethylamine (1.36 g, 13.4 mmol) in anhydrous CH2Cl2 (15 mL) was added dropwise to the intermediate 22a solution. The resulting mixture was stirred for an additional 1.5 h. After the reaction, the solvent was removed under vacuum and the residue was transferred to EA and washed with saturated citric acid solution. The organic layer was collected, dried over Na2SO4, and then evaporated. The residue was purified by column chromatography (silica gel, 0 to 67% EtOAc / n-hexane) to provide the crude product. The crude product was purified by preparative HPLC (70% ACN, 30% H2O) to provide target compound 23a (0.86 g, 32% yield, two steps) as a white powder. 1 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). Mass observation [M+Na] + =522.0,[2M+Na] + =1021.3.

[0360] (E)-(2-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)amino)ethyl)amino)-2-oxoethyl)tert-butyl carbamate (23b)

[0361] 23b was obtained from 21a and 22b using the same synthetic steps as 23a.

[0362] White powder. 27% yield. 1¹H-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). Mass observation [M+Na] + =528.2,[2M+Na] + =1033.4.

[0363] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (23c)

[0364] 23c was obtained from 21b and 22a using the same synthetic steps as 23a.

[0365] White powder. 18% yield. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 7.48 (d, J = 8.5Hz, 2H), 7.10 (d, J = 8.5Hz, 2H), 7.05 (d, J = 1 6.0Hz,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). Mass observation value [M–Boc+H] + =443.3; [M+H] + =543.4; [M+Na] + =565.3.

[0366] (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)amino)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (23d)

[0367] 23d was obtained from 21b and 22b using the same synthesis steps as 23a.

[0368] White powder. 28% yield. 1 H-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). Mass observation [M+Na] + =570.3,[2M+Na] + =1117.6.

[0369] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (23e)

[0370] 23e was obtained from 21c and 22a using the same synthetic steps as 23a.

[0371] White powder. 27% yield. 1 H-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 = 2.0 Hz, 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). Mass observation [M-Boc+H] + =491.0; [M+H] +=591.4; [M+Na] + =613.3.

[0372] (E)-(1-((2-(((4-(3,5-bis(methoxy-d3)styryl-d6)phenoxy)carbonyl)amino)ethyl)amino)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (23f)

[0373] 23f was obtained from 21c and 22b using the same synthetic steps as 23a.

[0374] White powder. 30% yield. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 7.48 (d, J = 8.5Hz, 2H), 7.34-7.27 (m, 3H), 7.25-7.22 (m, 2 H),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). Mass observation value [M-Boc+H] + =497.3; [M+H] + =597.4; [M+Na] + =619.5; [2M+H] + =1192.9; [2M+Na] + =1214.8.

[0375] (2-(2-aminoacetamido)ethyl)carbamic acid (E)-4-(3,5-dimethoxystyryl)phenyl ester hydrochloride (7a)

[0376] A solution of 4M HCl in 1,4-dioxane (7.60 mL) was added to a stirred solution of compound 23a (760 mg, 1.5 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated and purified by preparative HPLC (TFA as buffer, detailed gradient elution, see information below). The aqueous fraction was then treated with a few drops of concentrated HCl and lyophilized to provide compound 7a (614 mg, 93% yield) as a white solid. 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); 13 C-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; Mass observation [M-HCl+H] + =400.2; [2M-2HCl+H] + =799.3.

[0377] Column: Inertsil ODS-3C18, 5um, 30*250mm

[0378] Flow rate: 38 ml / min

[0379] Solvent A: 10% ACN in H2O + 0.1% TFA

[0380] Solvent B: 90% ACN in H2O + 0.1% TFA

[0381] gradient:

[0382] Time (min) Flow rate (ml / min) ％A ％B 0 38 100 0 20 38 0 100 24 38 0 100 28 38 100 0 30 38 100 0

[0383] (2-(2-aminoacetamido)ethyl)carbamic acid (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenyl ester hydrochloride (7b)

[0384] 7b was obtained from 23b using the same synthesis steps as 7a.

[0385] White solid. 95% yield. 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); 13 C-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; Mass observation [M-HCl+H] + =406.3; [2M - 2HCl + H] + =811.3.

[0386] (2-(2-amino-3-methylbutyramido)ethyl)carbamic acid (E)-4-(3,5-dimethoxystyryl)phenyl ester hydrochloride (7c)

[0387] 7c was obtained from 23c using the same synthesis steps as 7a.

[0388] White solid. 92% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H]+ = 443.0; [M–HCl+Na] + =465.2; [2M-2HCl+H] + =884.5; [2M–2HCl+Na] + =906.5.

[0389] (2-(2-amino-3-methylbutyramido)ethyl)carbamate (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenyl ester hydrochloride (7d)

[0390] 7d was obtained from 23d using the same synthesis steps as 7a.

[0391] White solid. 93% yield. 1 H-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); 13 C-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; Mass observation [M-HCl+H] + =448.3; [M–HCl+Na] + =470.2; [2M–2HCl+Na] + =1149.5.

[0392] (2-(2-amino-3-phenylpropamido)ethyl)carbamic acid (E)-4-(3,5-dimethoxystyryl)phenyl ester hydrochloride (7e)

[0393] 7e was obtained from 23e using the same synthetic steps as 7a.

[0394] White solid. 90% yield. 1H-NMR (CD3OD, 500MHz), δ (ppm): 7.53 (d, J = 8.5Hz, 2H), 7.41-7.31 (m, 2H), 7.3 3-7.29(m,3H),7.13(d,J=17.0Hz,1H),7.09(d,J=8.5Hz,2H),7.04(d,J=17.0 Hz,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); 13 C-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; Mass observation [M-HCl+H] + =491.2; [M-HCl+Na] + =513.3; [2M–2HCl+H] + =980.5.

[0395] (2-(2-amino-3-phenylpropamido)ethyl)carbamic acid (E)-4-(3,5-bis(methoxy-d3)styryl-d6)phenyl ester hydrochloride (7f)

[0396] 7f was obtained from 23f using the same synthesis steps as 7a.

[0397] White solid. 96% yield. 1 H-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; Mass observation [M-HCl+H] + =496.3; [2M–2HCl+H] + =991.4.

[0398] 1-2-7. Synthesis of target compound 8

[0399] Scheme 7 describes the synthesis of compound 8. As shown, 2-hydroxyethyl acetate reacted with tert-butylchlorodiphenylsilane (TPDPS-Cl) in the presence of NEt3 and DMAP to provide compound 24, which was further deacetylated with sodium methoxy (NaOMe) to obtain compound 25. Compound 25 was coupled with Boc-Val-OH(1c) in the presence of EDCI and DMAP to obtain compound 26, which was then deprotected with TBAF to obtain hydroxy compound 27. Compound 27 was reacted with p-nitrophenyl chloroformate to obtain the corresponding compound 28, which was reacted with pterostilbene without further purification to obtain the desired carbonate 29, which was then deprotected with the Boc group to provide target compound 8.

[0400] Scheme 7: Synthesis of Compound 8

[0401]

[0402] Reagents and conditions: (a) TBDPS-Cl, trimethylamine, DMAP, CH2Cl2, 12 h; (b) 5.4 M NaOMe in MeOH, MeOH, 2 h; (c) Boc-Val-OH 1c, EDCI, triethylamine, DMAP, CH2Cl2, 12 h; (d) 1.0 M TBAF in THF, THF, 1 h, 72%; (e) triethylamine, CH2Cl2, 0 °C; (f) DMAP, ACN, 50 °C; (g) 4 M HCl in 1,4-dioxane, 3 h.

[0403] 2-((tert-butyldiphenylsilyl)oxy)ethyl acetate (24)

[0404] tert-butylchlorodiphenylsilane (TBDPS-Cl) (8.65 g, 31.5 mmol), Et3N (4.6 mL, 33.0 mmol), and DMAP (110 mg, 0.9 mmol) were added to a stirred solution of 2-hydroxyethyl acetate (3.12 g, 30.0 mmol) in CH2Cl2 (25 mL), and the mixture was stirred at room temperature until the starting material was completely consumed (12 h). The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with water (25 mL). The organic layer was dried (Na2SO4), filtered, and evaporated. The residue was subjected to rapid chromatography (silica gel, 0 to 2% EtOAc / n-hexane) to provide compound 24 as a colorless oil (4.59 g, 43% yield). 1 H-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).

[0405] 2-((tert-butyldiphenylsilyl)oxy)ethanol (25)

[0406] A solution of 5.4 M sodium methoxide in MeOH (4.96 mL, 26.8 mmol) was added dropwise to a stirred solution of compound 24 (4589 mg, 13.4 mmol) in MeOH (100 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum, and the residue was subjected to rapid chromatography (silica gel, 0 to 17% EtOAc / n-hexane) to provide compound 25 as a colorless oil (4.00 g, 99% yield). 1 H-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).

[0407] 2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid 2-((tert-butyldiphenylsilyl)oxy)ethyl ester (26)

[0408] EDCI (2198 mg, 11.5 mmol) and DMAP (350 mg, 2.9 mmol) were added to a stirred solution of compound 25 (2871 mg, 9.6 mmol), Boc-Val-OH 1c (2076 mg, 9.6 mmol), and NET3 (1598 μL, 11.5 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed under vacuum, and the residue was purified by column chromatography (silica gel, 0 to 5% of EtOAc / n-hexane) to provide the target product 26 (2719 mg, 57% yield) as a white powder. 1 H-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, 3 H),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).

[0409] 2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid 2-hydroxyethyl ester (27)

[0410] A solution of 1.0 M TBAF in THF (10.88 mL, 10.9 mmol) was added dropwise to a stirred solution of compound 26 (2719 mg, 5.4 mmol) in THF (25 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was removed under vacuum, and the residue was purified by column chromatography (silica gel, 0 to 30% EtOAc / n-hexane) to provide the target product 27 (1022 mg, 72% yield) as a pale yellow oil. 1 H-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).

[0411] 2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl ester (29)

[0412] Triethylamine (1363 μL, 9.8 mmol) was added to a stirred solution of compound 27 (1022 mg, 3.9 mmol) in anhydrous CH₂Cl₂ (20 mL), followed by the dropwise addition of a solution of 4-nitrophenyl chloroformate (867 mg, 4.3 mmol) in 30 mL CH₂Cl₂ at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then warmed to room temperature. After stirring at room temperature for another 4 hours, the solvent was removed under vacuum to obtain crude intermediate 28, which was mixed with pterostilbene (1002 mg, 3.9 mmol) and DMAP (956 mg, 7.8 mmol) in ACN (30 mL). The resulting mixture was heated to 50 °C for 1 h. After the reaction, the solvent was removed under vacuum, and the residue was transferred to EA and washed with saturated citric acid solution. The organic layer was collected, dried over Na₂SO₄, and evaporated. The residue was purified by column chromatography (silica gel, 0 to 33% EtOAc / n-hexane) to provide the crude product. The crude product was purified by preparative HPLC (80% ACN, 20% H2O) to provide compound 29 (600 mg, 28% yield, two steps) as a white powder. 1 H-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,N H, 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 = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H). Mass observation [M–Boc+H] + =445.1; [M+H] + =545.1, [M+Na] + =567.1.

[0413] 2-Amino-3-methylbutyric acid (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)oxy)ethyl ester hydrochloride (8)

[0414] A solution of compound 29 (561 mg, 1.0 mmol) and 4 M HCl in 1,4-dioxane (5.16 mL) was added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, the mixture was freeze-dried to obtain the desired product 8 as a white powder (446 mg, 90% yield). 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); 13 C-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; Mass observation [M-HCl+H] + =445.2; [M–HCl+Na] + =467.2; [2M–2HCl+H] + =888.6.

[0415] 1-2-8. Synthesis of target compound 9

[0416] Compound 9 was synthesized according to scheme 8. As shown, the substitution reaction of 2-bromoethanol with sodium azide (NaN3) provides compound 30, which is activated by EDCI and coupled with Boc-Val-OH(1c) to provide ester 31, followed by further hydrogenation of the N3 group to amine 32. Compound 32 is reacted with p-nitrophenyl chloroformate to obtain the corresponding carbamate 33, which is reacted with pterostilbene without further purification to obtain the desired carbamate 34, followed by deprotection of the Boc group to provide amino derivative 9.

[0417] Scheme 8: Synthesis of Compound 9

[0418]

[0419] Reagents and conditions: (a) NaN3, water, 80°C, 24 h; (b) Boc-Val-OH, EDCI, triethylamine, DMAP, CH2Cl2, 12 h; (c) H2, 10% Pd / C, EtOAc, MeOH, 2 h; (d) triethylamine, CH2Cl2, 0°C; (e) DMAP, ACN, 50°C, 1 h; (f) 4M HCl in 1,4-dioxane, 3 h.

[0420] 2-Azide-ethanol (30)

[0421] A solution of 2-bromoethanol (5827 mg, 46.6 mmol) and sodium azide (6062 mg, 93.3 mmol) in water (50 mL) was added to a 100 mL round-bottom flask. The mixture was stirred at 80 °C for 24 hours and then cooled to room temperature. The solution was extracted with ethyl acetate (30 mL x 4), and the organic layer was dried over Na₂SO₄ and filtered. The solvent of the filtrate was evaporated, and the residue was purified by column chromatography (silica gel, 0 to 25% EtOAc / n-hexane) to provide target compound 30 as a pale yellow liquid (3735 mg, 92% yield). 1 H-NMR (CDCl3, 500MHz), δ (ppm): 3.78 (d, J = 4.0Hz, 2H), 3.45 (s, 2H), 1.86 (s, OH, 1H).

[0422] 2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid 2-azidoethyl ester (31)

[0423] EDCI (1805 mg, 9.4 mmol) and DMAP (288 mg, 2.4 mmol) were added to a stirred solution of 2-azidoethanol 30 (683 mg, 7.9 mmol), Boc-Val-OH 1c (1705 mg, 7.9 mmol), and NET3 (1313 μL, 9.4 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed under vacuum, and the residue was purified by column chromatography (silica gel, 0 to 11% EtOAc / n-hexane) to provide the target product 31 (1527 mg, 68% yield) as a white powder. 1 H-NMR (CDCl3, 500MHz), δ (ppm): 4.99 (d, J = 6.5Hz, NH, 1H), 4.31-4.27 (m, 3H), 3.51-3.5 0(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).

[0424] 2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid 2-aminoethyl ester (32)

[0425] 1527 mg of compound 31 was dissolved in 25 mL of methanol and 25 mL of EA, 568 mg of 10% Pd / C was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The Pd / C was filtered off and the mixture was washed with 15 mL of methanol. The solvent was removed under vacuum. The residue was then lyophilized after adding 10 mL of water to yield product 32 as an oil (1319 mg, 95% yield). 1 H-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).

[0426] 2-((tert-butoxycarbonyl)amino)-3-methylbutyric acid (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl ester (34)

[0427] Triethylamine (1966 μL, 14.1 mmol) was added to a stirred solution of compound 32 (1469 mg, 5.6 mmol) in anhydrous CH2Cl2 (30 mL), followed by dropwise addition of a solution of 4-nitrophenyl chloroformate (1251 mg, 6.2 mmol in 30 mL CH2Cl2) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then warmed to room temperature. After stirring at room temperature for an additional 4 hours, the solvent was removed under vacuum to obtain crude intermediate 33, which was mixed with pterostilbene (1446 mg, 5.6 mmol) and DMAP (1379 mg, 11.3 mmol) in ACN (30 mL). The resulting mixture was heated to 50 °C for 1 h. The solvent was evaporated after the reaction. The residue was collected to EA and washed with saturated citric acid solution. The organic layer was collected, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, 0 to 30% EtOAc / n-hexane) to provide the crude product. The crude product was further purified by preparative HPLC (80% ACN, 20% H2O) to provide 34 (320 mg, 11% yield, two steps) as a white powder. 1¹H-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). Mass observation [M–Boc+H] + =444.3; [M+H] + =544.3, [M+Na] + =566.3.

[0428] 2-Amino-3-methylbutyric acid (E)-2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)amino)ethyl ester hydrochloride (9)

[0429] A solution of compound 34 (320 mg, 0.6 mmol) and 4 M HCl in 1,4-dioxane (2.95 mL) was placed in a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, the mixture was freeze-dried to obtain the desired product, compound 9, as a white powder (249 mg, 88%). 1 H-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; Mass observation [M+H] + =444.3; [M+Na] + =466.3.

[0430] 1-2-9. Synthesis of target compound 10

[0431] Scheme 9 describes the synthesis of compound 10. The carboxylic acid of Boc-Val-OH(1c) is activated by N-hydroxysuccinimide (NHS) and dicyclohexylcarbodiimide (DCC) to allow cysteine ​​to undergo amino grouping and yield the desired amide 35. Compound 35 reacts with p-nitrophenyl chloroformate to yield the corresponding p-nitrophenyl thiocarbonate 36, which, without further purification, reacts with pterostilbene to yield the desired thiocarbonate 37. Subsequent deprotection of the Boc group provides target compound 10.

[0432] Scheme 9: Synthesis of Compound 10

[0433]

[0434] Reagents and conditions: (a) 1. NHS, DCC, THF, 24 h; 2. DIPEA, CH2Cl2, 24 h; (b) DIPEA, CH2Cl2, 0 °C; (c) DMAP, ACN, 50 °C, 2 h; (d) 4 M HCl in 1,4-dioxane, CH2Cl2.

[0435] (1-((2-mercaptoethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (35)

[0436] NHS (1.72 g, 15.0 mmol) and DCC (3.1 g, 15.0 mmol) were added to a solution of Boc-Val-OH 1c (3.23 g, 14.9 mmol) in THF (16 mL). The reaction mixture was stirred at room temperature for 24 hours and then filtered. The solvent of the filtrate was evaporated and the residue was transferred to CH2Cl2 (12 mL), then DIPEA (5.7 g, 44.2 mmol) and cysteine ​​hydrochloride (1.23 g, 15.9 mmol) were added and the reaction mixture was stirred for 24 hours. Water (5 mL) was added and the reaction mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with 1N HCl (2 × 10 mL) and brine (10 mL). The organic layer was dried and evaporated with MgSO4, and the residue was purified by column chromatography (silica gel, n-hexane / EtOAc, (4:1, v / v)) to obtain 35 (1.67 g, 41% yield) as a white solid. 1 H-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).

[0437] (E)-(1-((2-(((4-(3,5-dimethoxystyryl)phenoxy)carbonyl)thio)ethyl)amino)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (37)

[0438] DIPEA (1.78 g, 13.8 mmol) was added to a stirred solution of compound 35 (1.26 g, 4.6 mmol) in anhydrous CH2Cl2 (40 mL), followed by the dropwise addition of a solution of 4-nitrophenyl chloroformate (1.02 g, 5.1 mmol) in 10 mL CH2Cl2 at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then warmed to room temperature. After stirring at room temperature for an additional 4 hours, the solvent was removed under vacuum to obtain crude intermediate 36, which was mixed with pterostilbene (1.19 g, 4.7 mmol) and DMAP (1.13 g, 9.3 mmol) in ACN (30 mL). The resulting mixture was heated to 50 °C for 2 h. After the reaction, the solvent was removed under vacuum. The residue was purified by column chromatography (EA / n-hexane = 1 / 5 (V / V)) to provide the crude product. The crude product was further purified by preparative HPLC (80% ACN, 20% H2O) to provide target compound 37 (1.46 g, 56% yield) as a white powder. 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,N H), 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); mass observation [M–Boc+H] + =460.2; [M+H] + =560.3; [M+Na] + =582.3.

[0439] Thiocarbonate (E)-S-(2-(2-amino-3-methylbutamido)ethyl) ester O-(4-(3,5-dimethoxystyryl)phenyl) ester hydrochloride (10)

[0440] A solution of 4M HCl in 1,4-dioxane (7.20 mL) was added to a stirred solution of compound 37 (805 mg, 1.4 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was then evaporated and purified by preparative HPLC (TFA as buffer, detailed gradient elution, see information below). The aqueous solution was then treated with a few drops of concentrated HCl and lyophilized to provide compound 10 (647 mg, 91% yield) as a white solid. 1 H-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; Mass observation [M-HCl+H] + =459.2; [2M-2HCl+H] + =917.3.

[0441] Column: Inertsil ODS-3C18, 5um, 30*250mm

[0442] Flow rate: 38 ml / min

[0443] Solvent A: 10% ACN in H2O + 0.1% TFA

[0444] Solvent B: 90% ACN in H2O + 0.1% TFA

[0445] gradient:

[0446] Time (min) Flow rate (ml / min) ％A ％B 0 38 100 0 20 38 0 100 24 38 0 100 28 38 100 0 30 38 100 0

[0447] 2. In vivo studies of the target compound's anti-NAFLD and anti-NASH effects.

[0448] 2-1. Materials and Methods

[0449] Animals and experimental procedures: Male C57BL / 6 mice, 4 weeks old, were purchased from the Laboratory Animal Center (Taiwan, China) and maintained according to the procedures and guidelines provided by the Institutional Animal Care and Use Committee of the National Health Research Institutes of Taiwan (Taiwan, China). Animals were kept in stainless steel cages at 21±2°C with a 12-hour light / dark cycle and had free access to pelleted food and water. All experiments were conducted under the supervision of the Institutional Animal Care and Use Committee of China Medical University, Taiwan (Taiwan, China), procedure number (CMUIACUC-2020-117).

[0450] The synthesized target compounds (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5j, 5m, 5p, 5t, 5v, 5w, 6a, 6b, 6g, 7c, 7e) were dissolved in PG / TPSG (1:1). Mice were given an MCD diet for 14 days, followed by PG / TPSG (1:1) as a control, and all compounds were administered orally at 100 mg / kg once daily for 5 weeks for 42 days. Mice were randomly divided into 5 groups and treated as follows: (1) MCD diet + PG / TPSG (2) MCD diet + 100 mg / kg of all compounds. After 28 days, the animals were sacrificed to collect blood for plasma ALT and AST concentrations, and liver samples were used for H&E staining.

[0451] Mice were given an MCD diet for 14 days, followed by oral administration of compound 5c at doses of 75, 100, and 150 mg / kg once daily for 42 days, five times a week. Mice were randomly assigned to five groups and treated as follows: (1) sham-operated group (non-MCD diet); (2) MCD diet; (3) MCD diet + 75 mg / kg compound 5c; (4) MCD diet + 100 mg / kg compound 5c; (5) MCD diet + 150 mg / kg compound 5c. After 28 days, the animals were sacrificed to collect blood for plasma ALT and AST concentrations, and liver samples were used for H&E staining.

[0452] 2-2. Results and Discussion

[0453] Histological studies were conducted to determine the efficacy of all compounds (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5j, 5m, 5p, 5t, 5v, 5w, 6a, 6b, 6g, 7c, 7e) in the development of MCD-induced hepatic steatosis. H&E staining results showed that MCD diet feeding induced significant hepatic steatosis, hepatocellular damage and inflammatory cell infiltration, swelling, and fibrosis. Treatment with compounds 5a, 5b, 5c, 5f, 5t, 6g, 7c, 7e, 5w, 5g, 5d, 5e, 5j, 5m, 5p, 6a, and 6b prevented MCD-induced steatohepatitis by reducing steatosis, inflammation, swelling, and fibrosis (Table 1).

[0454]

[0455]

[0456]

[0457]

[0458] Serum concentrations of AST and ALT are markers of liver injury. As shown in Table 2, serum concentrations of AST and ALT were significantly increased in mice fed an MCD diet compared to mice fed a normal diet. Compounds 5c, 5a, 5b, 5f, 5h, 5d, 5m, and 5p significantly inhibited serum concentrations of AST and ALT in a dose-dependent manner.

[0459] Table 2: Serum AST and ALT parameters from compound-treated NASH mice

[0460]

[0461] Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); Methionine and choline deficient diet (MCD); ***p<0.001 for the MDC group.

[0462] Table 2: Serum AST and ALT parameters from compound-treated NASH mice

[0463]

[0464] Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); Methionine and choline deficient diet (MCD); ***p<0.001 for the MDC group.

[0465] Compound 5c was the most promising and was selected for further evaluation. Histological studies were performed to determine the efficacy of compound 5c in the development of hepatic steatosis induced by the MCD diet. HE staining results showed that MCD diet feeding induced significant hepatic steatosis, hepatocellular damage and inflammatory cell infiltration, swelling and fibrosis. Treatment with compound 5c prevented MCD diet-induced steatohepatitis with reduced steatosis, inflammation, swelling and fibrosis. Figure 1 (Table 3).

[0466]

[0467] Serum concentrations of AST and ALT are markers of liver injury. As shown in Table 4, serum concentrations of AST and ALT were significantly increased in mice fed an MCD diet compared to mice fed a normal diet. Compound 5c significantly inhibited serum concentrations of AST and ALT in a dose-dependent manner.

[0468] Table 4: Serum AST and ALT parameters from NASH mice treated with compound 5c

[0469]

[0470] Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); Methionine and choline deficient diet (MCD); ***p<0.001 for the control group. ###p<0.001 for the MCD group.

[0471] 3. Stability and solubility of the target compound

[0472] 3-1. Stability of compounds 5a, 5c, 5m, 5v, 5w, 6a, and 6b at pH 1.2

[0473] In vitro stability of compounds 5a, 5c, 5m, 5v, 5w, 6a, and 6b in a solution at pH 1.2 (enzyme-free USP gastric juice).

[0474] 3-1-1. Materials and Methods

[0475] Materials: The target compounds of this invention, 5a, 5c, 5m, 5v, 5w, 6a, and 6b.

[0476] Reagents: pH=1.2 solution: Dissolve 2.0g of NaCl in 800mL of H2O and add 7.0mL of concentrated HCl. Stir the mixture and adjust the pH to 1.2 with 2N NaON and 2N concentrated HCl, then dilute to 1000mL with H2O.

[0477] In vitro assays: Compounds 5a, 5c, 5m, 5v, 5w, 6a, and 6b were incubated with pH 1.2 solution at 37°C for 6 hours. Sample collection: At 0, 0.17, 0.5, 1, 2, 4, and 6 hours, 100 mL aliquots of the incubation mixture were transferred to centrifuge tubes containing 100 μL of ice-cold acetonitrile and a 1 μm internal standard to terminate the reaction. The samples were centrifuged at 15,000 rpm for 10 minutes, and the supernatant was injected into the HPLC system.

[0478] HPLC method: HPLC: Waters 1525 binary HPLC pump; Waters 2707 autosampler; Waters 2487 dual λ absorption detector; Column: XBridge Shield RP18, 5μm, 4.6x50mm column; UV detector: 305nm; Temperature: room temperature; Run time: 15.0 min; Mobile phase: A: 0.1% FA in H2O; B: acetonitrile.

[0479] HPLC mobile phase gradient:

[0480] time Flow rate (mL) ％A ％B 0 1 90 10 3 1 90 10 9 1 10 90 12 1 90 10 15 1 90 10

[0481] Note: Mobile phase: A: 0.1% FA in H2O; B: Acetonitrile.

[0482] Retention times (RT) of compounds 5a, 5c, 5m, 5v, 5w, 6a, and 6b:

[0483]

[0484]

[0485] 3-1-2. Results and Discussion

[0486] Table 5 compares the levels of the tested compounds. The results show that these tested compounds are relatively stable in a solution at pH 1.2. After 6 hours of incubation, more than 90% of compounds 5a, 5c, 5m, 5w, 6a, and 6b remained in the solution at pH 1.2. However, only 84.8% of compound 5v remained.

[0487] In summary, in vitro studies showed that these target compounds were relatively stable in gastric juice (without enzymes). No time-dependent degradation was observed.

[0488] Table 5. Time-dependent stability of compounds 5a, 5c, 5m, 5v, 5w, 6a and 6b in solution at pH 1.2

[0489]

[0490] 3-2. Solubility of compound 5c in H2O

[0491] 3-2-1. Materials and Methods

[0492] The concentration of compound 5c in H2O was set at 40 mg / mL. After sonication and vortexing for 30 minutes, the tubes were allowed to stand at 25°C. At sampling time points (1, 3, 6, and 24 hours), the tubes were centrifuged at 15,000 rpm for 10 minutes, the supernatant was collected, and appropriately diluted with acetonitrile. The samples were quantified by HPLC.

[0493] HPLC method: Column: XBridge Shield RP18, 5 μm, 4.6 x 50 mm; UV detector: 305 nm; Temperature: room temperature; Injection volume: 10 μL; Run time: 15.0 min; Mobile phase: A: 0.1% FA in H2O; B: acetonitrile.

[0494] HPLC mobile phase gradient:

[0495] time Flow rate ％A ％B 0 1 90 10 3 1 90 10 9 1 10 90 12 1 90 10 15 1 90 10

[0496] Note: Mobile phase: A: 0.1% FA in H2O; B: Acetonitrile.

[0497] 3-2-2. Results and Discussion

[0498] As shown in Table 6 and Figure 2 As shown, compound 5c exhibits a solubility of over 34 mg / mL in H₂O after 24 hours at 25°C. According to the US Pharmacopoeia, compound 5c can be classified as a water-soluble substance.

[0499] Table 6: Solubility trend of compound 5c in H2O

[0500] 1 hour 3 hours 6 hours 24 hours mg / mL 37 33 33 34

[0501] 4. Conclusion

[0502] In this invention, a series of novel water-soluble carbonate-containing pterostilbene amino acid analogs were synthesized. These compounds were stable at pH 1.2 (the pH of gastric juice (without enzymes)) and their anti-NASH activity was tested. Most of the synthesized compounds showed anti-NASH / NAFLD activity (as shown in Table 1.2). Among them, compound 5c was the most promising and was selected for further evaluation. The results showed that compound 5c (the representative compound) showed significant anti-NASH / NAFLD activity. Figure 1 (Tables 3 and 4).

[0503] The novel series of pterostilbene amino acid analogs of the present invention have a water-soluble, stable chemical structure and are bioeffective for the in vivo treatment of NAFLD / NASH, and therefore have the potential to be developed as new drugs for the treatment of NAFLD / NASH.

[0504] List of abbreviations

[0505]

[0506] References

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Claims

1. A compound having the following formula or a pharmaceutically acceptable salt thereof, Where n is between 1 and 3; m ranges from 2 to 6; Q, X, and Y are independently O, S, or NH; Ra and Rb are independently C1-C6 straight-chain alkoxy or C3-C6 branched-chain alkoxy; Rc is H, C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy; Rd is a C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy, and Re is H, a C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy, or Rd and Re are connected to form a ring structure, such that , where j is 1 to 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are independently C1-C6 straight-chain alkoxy groups.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is O; X is O; and Y is NH.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is O; X is NH and Y is NH.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is O; X is O; and Y is O.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is O; X is NH; and Y is O.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is O; X is S; and Y is NH.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, m is 2; and n is 1 or 2.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, Ra and Rb are methoxy groups.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are 3,5-dimethoxy.

11. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, Rd is a C3-C6 branched alkyl group.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein Rd is isopropyl.

13. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, Rd and Re are connected to form a ring structure, making , where j is 1.

14. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein, The pharmaceutically acceptable salt is hydrochloride or nicotinic acid salt.

15. A pharmaceutical composition for treating a subject with non-alcoholic fatty liver disease, comprising a therapeutically effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof for said treatment. Where n is between 1 and 3; m ranges from 2 to 6; Q, X, and Y are independently O, S, or NH; Ra and Rb are independently C1-C6 straight-chain alkoxy or C3-C6 branched-chain alkoxy; Rc is H, C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy; Rd is a C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy, and Re is H, a C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy, or Rd and Re are connected to form a ring structure, such that , where j is 1 to 3.

16. A pharmaceutical composition for treating non-alcoholic steatohepatitis in a subject, comprising a therapeutically effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof for said treatment. Where n is between 1 and 3; m ranges from 2 to 6; Q, X, and Y are independently O, S, or NH; Ra and Rb are independently C1-C6 straight-chain alkoxy or C3-C6 branched-chain alkoxy; Rc is H, C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy; Rd is a C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy, and Re is H, a C1-C6 straight-chain alkyl, C1-C6 straight-chain alkoxy, C3-C6 branched alkyl, or C3-C6 branched alkoxy, or Rd and Re are connected to form a ring structure, such that , where j is 1 to 3.

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