Cinnamylursodeoxycholic acid compounds, their preparation methods, pharmaceutical compositions and applications

Abstract

This invention discloses a cinnamylursodeoxycholic acid compound, its preparation method, pharmaceutical composition, and applications. The compound has the structure of Formula 1 or Formula 2, and also includes its stereoisomers, geometric isomers, tautomers, deuterated compounds, pharmaceutically acceptable salts, or mixtures thereof. This class of compounds exhibits highly efficient inhibitory activity against inflammatory cells and significantly inhibits NO production, while also possessing low cytotoxicity, making it suitable for preparation as an anti-inflammatory drug. Furthermore, the preparation method for this class of compounds is simple and facilitates structural expansion.

Description

TECHNICAL FIELD

[0001] The present application relates to a cinnamoyl ursodeoxycholic acid compound and a preparation method, a pharmaceutical composition and an application thereof, in particular to a cinnamoyl ursodeoxycholic acid compound with anti-inflammatory activity and a preparation method, a pharmaceutical composition and an application thereof. BACKGROUND

[0002] Ursodeoxycholic acid (UDCA) is a hydrophilic and less toxic bile acid, its chemical name is 3α, 7β-dihydroxy-5β-cholestane-24-acid, which has the following structure:

[0003]

[0004] The steroidal compound composed of 3 six-membered rings, 1 five-membered ring and 1 fatty side chain with 24 carbon atoms is composed of a steroidal skeleton and a fatty side chain. As can be seen from the stereoscopic configuration diagram, the A ring and the B ring of the steroidal skeleton are cis-fused, the B ring and the C ring are trans-fused, the C ring and the D ring are trans-fused, the 3-hydroxyl group is in the alpha position, and the 7-hydroxyl group is in the beta position. Therefore, the molecule has hydrophilicity and lipophilicity. Because UDCA molecule contains hydroxyl and carboxyl functional groups, it has a wide range of biological activities and potential medicinal value. Although UDCA has anti-inflammatory activity, its activity intensity and bioavailability limit its further application and development. SUMMARY

[0005] The first object of the present application is to provide a cinnamoyl ursodeoxycholic acid compound, the second object is to provide a preparation method of the compound, the third object is to provide a pharmaceutical composition comprising the compound, and the fourth object is to provide an application of the compound and the pharmaceutical composition thereof.

[0006] Technical scheme: The cinnamoyl ursodeoxycholic acid compound of the present application has the structure of formula 1 or formula 2, and also comprises stereoisomers, geometric isomers, tautomers, deuterium compounds, pharmaceutically acceptable salts or mixtures thereof:

[0007]

[0008] Among them:

[0009] R is selected from

[0010]

[0011] R1, R2, R3, R4, R5, R6are each independently selected from H, hydroxy, cyano, amino, halogen, nitro, C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkoxy, thiol, C1-C6alkoxy, C1-C6alkylamino, 6-12 membered aryl, 6-12 membered aryl substituted C1-C6alkyl, 5-7 membered heteroaryl containing 1-3 N, O, S, 5-7 membered heteroaryl containing 1-3 N, O, S substituted C1-C6alkyl, 3-7 membered heterocyclyl containing 1-2 N, O, S, 3-7 membered heterocyclyl containing 1-2 N, O, S substituted C1-C6alkyl, 3-7 membered cycloalkyl containing 0-3 double bonds or 3-7 membered cycloalkyl containing 0-3 double bonds substituted C1-C6alkyl or R3, R2and the carbon atom to which they are attached form a 5-7 membered heterocyclic ring containing 1-2 N, O or R3, R4and the carbon atom to which they are attached form a 5-7 membered heterocyclic ring containing 1-2 N, O or R3, R2and the carbon atom to which they are attached form a 4-6 membered aromatic ring or R3, R4and the carbon atom to which they are attached form a 4-6 membered aromatic ring;

[0012] R7, R8are each independently selected from H, C1-C6haloalkyl, C1-C6alkyl, 3-7 membered cycloalkyl containing 0-3 double bonds, 6-12 membered aryl substituted C1-C6alkyl, 6-12 membered aryl or C1-C6alkylacyl.

[0013] R1, R2, R3, R4, R5, R6are each independently selected from H, hydroxy, cyano, amino, halogen, nitro, C1-C4alkyl, C1-C4haloalkyl, C1-C4haloalkoxy, thiol, C1-C4alkoxy, C1-C4alkylamino, phenyl, naphthyl, phenyl or naphthyl substituted C1-C4alkyl, 5-6 membered heteroaryl containing 1-3 N, O, S, 5-6 membered heteroaryl containing 1-3 N, O, S substituted C1-C4alkyl, 3-6 membered heterocyclyl containing 1-2 N, O, S, 3-6 membered heterocyclyl containing 1-2 N, O, S substituted C1-C4alkyl, 3-6 membered cycloalkyl containing 0-2 double bonds or 3-6 membered cycloalkyl containing 0-2 double bonds substituted C1-C4alkyl or R3, R2and the carbon atom to which they are attached form a 5-6 membered heterocyclic ring containing 1-2 N, O or R3, R4and the carbon atom to which they are attached form a 5-6 membered heterocyclic ring containing 1-2 N, O or R3, R2and the carbon atom to which they are attached form a 4-6 membered aromatic ring or R3, R4and the carbon atom to which they are attached form a 4-6 membered aromatic ring;

[0014] R7, R8are each independently selected from H, C1-C4haloalkyl, C1-C4alkyl, 3-6 membered cycloalkyl containing 0-2 double bonds, 6-12 membered aryl substituted C1-C4alkyl, 6-12 membered aryl or C1-C4alkylacyl.

[0015] Preferably, R1, R2, R3, R4, R5, R6are each independently selected from H, hydroxy, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4haloalkoxy, C1-C4alkoxy or R3, R2form with the carbon atom to which they are attached a 5-6 membered heterocyclic ring containing 2 O or R3, R4form with the carbon atom to which they are attached a 5-6 membered heterocyclic ring containing 2 O or R3, R2form with the carbon atom to which they are attached a 6 membered aromatic ring or R3, R4form with the carbon atom to which they are attached a 6 membered aromatic ring;

[0016] R7, R8are each independently selected from H, C1-C4alkyl or C1-C4alkyl acyl.

[0017] Preferably, R1, R2, R3, R4, R5, R6are each independently selected from H, hydroxy, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy or R3, R2form with the carbon atom to which they are attached a 5 membered heterocyclic ring containing 2 O or R3, R4form with the carbon atom to which they are attached a 5 membered heterocyclic ring containing 2 O or R3, R2form with the carbon atom to which they are attached a 6 membered aromatic ring or R3, R4form with the carbon atom to which they are attached a 6 membered aromatic ring;

[0018] R7, R8are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, acetyl, propionyl, butyryl or isopropyl formyl.

[0019] Preferably, R1, R2, R3, R4, R5, R6are each independently selected from H, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, trifluoromethoxy, methoxy or R3, R2form with the carbon atom to which they are attached a 5 membered heterocyclic ring containing 2 O or R3, R4form with the carbon atom to which they are attached a 5 membered heterocyclic ring containing 2 O or R3, R2form with the carbon atom to which they are attached a 6 membered aromatic ring or R3, R4form with the carbon atom to which they are attached a 6 membered aromatic ring;

[0020] R7, R8are each independently selected from H, methyl or acetyl.

[0021] In particular, when R1, R2, R3, R4, R5, R6are each independently selected from fluorine, chlorine, methoxy, the number can be 1, 2, 3; when monosubstituted, the substitution position is ortho, meta, para position of the connected phenyl ring; when disubstituted, the substitution position is ortho+para, meta+para, meta+meta; when trisubstituted, the substitution position is ortho+para+ortho.

[0022] More preferably, any one of the following compounds:

[0023]

[0024] The present application is directed to structural modification and transformation of ursodeoxycholic acid to design drug molecules with good anti-inflammatory activity and lower toxicity.

[0025] Further, the compound forms a pharmaceutically acceptable salt thereof with any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.

[0026] The preparation method of the compound of the present application is as follows:

[0027] (1) When the target compound structure is formula 1, the compound of formula 3 is subjected to acylation reaction to obtain the compound of formula 4, which is catalyzed by HATU and DIEA; then the compound of formula 4 is subjected to isomerization to obtain the compound of formula 5:

[0028]

[0029] Among them, formula 4 has the following structural fragment:

[0030]

[0031] (2) When the target compound structure is formula 2, the compound of formula 4 is subjected to dehydrogenation reaction to obtain the compound of formula 6, or the compound of formula 4 is subjected to acylation reaction to obtain the compound of formula 7, or the compound of formula 4 is subjected to alkylation reaction to obtain the compound of formula 8:

[0032]

[0033] Among them, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above.

[0034] The corresponding acid is salted with the target compound of formula 1 or formula 2 prepared by the above method to obtain the pharmaceutically acceptable salt of the compound.

[0035] Specifically, the synthesis route of the target compound is as follows:

[0036] The carboxyl group at position 24 of ursodeoxycholic acid reacts with piperazine to form amide intermediate 1, and then intermediate 1 reacts with substituted cinnamic acid to obtain target compounds 2a-2x through amide condensation reaction. The synthesis of compounds 2w and 2x is obtained by condensation reaction of intermediate 1 with 3-(1-naphthyl) acrylic acid and 3-phenylpropionic acid, respectively. On the basis of 2r, 2s and 2u, cis products 3a-3d are obtained by photochemical reaction.

[0037] The synthesis route of 4a-4c is as follows:

[0038] Dess-Martin oxidation of compound 2m with Dess-Martin periodinane to generate a double carbonyl product 4a; acetylation of compound 2m with an acid anhydride to obtain compound 4b; and reaction of compound 2m with methyl iodide to obtain compound 4c.

[0039]

[0040] The pharmaceutical composition of the present application comprises the compound and a pharmaceutically acceptable carrier, and can be prepared into a pharmaceutical preparation such as a tablet, a capsule, a syrup, a suspension, an injection, etc. by adding a flavoring agent, a sweetening agent, a liquid / solid filler, a diluent, and the like.

[0041] The compound and the pharmaceutical composition thereof of the present application are applied to the preparation of a drug for treating inflammation, and are particularly applied to the inhibition or treatment of inflammation in the digestive tract (colon cancer, rectal cancer, colon tumor, rectal tumor, colon cancer, rectal cancer, ulcerative colitis, polypoid adenoma, familial polyposis, etc.), inflammation in the liver (liver disease, serum biochemical properties of liver function, bile flow, bile secretion of phospholipid or cholesterol, etc.), inflammatory skin disease or severe pruritus (atopic dermatitis, acne, psoriasis, urticaria, inflammatory skin disease, seborrheic dermatitis, contact dermatitis, etc.), acute inflammation of the gallbladder or biliary tract, chronic inflammation of the kidney, and the like.

[0042] Advantages: Compared with the prior art, the present application has the following remarkable advantages:

[0043] The compound has a high inhibitory effect on inflammatory cells (IC 50 value reaching the level of ten micromolar concentration) and significantly inhibits the generation of NO (P<0.01), while having low cytotoxicity, and can be prepared into an anti-inflammatory drug; and the compound is simple to prepare and easy to structurally expand. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 Effect of the compound on the activity of RAW264.7 cells;

[0045] Figure 2 Effect of the compound on the amount of NO generated by LPS-induced RAW264.7 cells;

[0046] Figure 3 IC 50 value of the compound on LPS-induced RAW264.7 cells. DETAILED DESCRIPTION

[0047] The technical solutions of the present application are further described below in combination with examples.

[0048] The materials used in the present application are commercially available, unless otherwise specified.

[0049] Example 1: Preparation of compound 2a

[0050] 1. Preparation of compound 1

[0051] Piperazine (655.3 mg, 7.62 mmol) was dissolved in dichloromethane (40 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.448 g, 3.81 mmol) was added, ursodeoxycholic acid (1.0 g, 2.54 mmol) was added, and finally N,N-diisopropylethylamine (983 mg, 7.62 mmol) was added. After the addition was completed, the reaction was allowed to proceed at room temperature for 4 h. TLC monitoring showed that the reaction was complete, and the reaction was stopped. Water (100 mL) was added, and dichloromethane (60 mL x 3) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane-methanol = 10:1 (V / V) as the eluent. Finally, white compound 1 was obtained in a yield of 90.1%.

[0052] Yield: 90.1%. mp: 121.1-122.8℃; 1 H NMR (600 MHz, CD3OD) δ 3.67-3.53 (m, 4H), 3.52-3.44 (m, 2H), 2.97-2.86 (m, 2H), 2.85-2.75 (m, 2H), 2.45 (ddd, J = 14.7 Hz, 10.9 Hz, 5.2 Hz, 1H), 2.31 (ddd, J = 14.7 Hz, 10.6 Hz, 5.8 Hz, 1H), 2.05 (ddd, J = 12.6 Hz, 3.7 Hz, 2.8 Hz, 1H), 1.95-1.72 (m, 5H), 1.66-1.53 (m, 4H), 1.52-1.42 (m, 6H), 1.38-1.17 (m, 6H), 1.16-1.10 (m, 1H), 1.04 (td, J = 14.2 Hz, 2.9 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H); 13C NMR (150 MHz, CD3OD) δ 174.1, 72.1, 71.9, 57.5, 56.5, 47.1, 46.4, 46.0, 44.8, 44.5, 44.0, 42.7, 41.5, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.1, 31.0, 29.8, 28.0, 23.9, 22.4, 19.1, 12.6;

[0053] HRMS m / z calcd for C 28 H 49 N2O3[M+H] + : 461.3743; found: 461.3743.

[0054] 2, Preparation of compound 2a

[0055] Compound 1 (100 mg, 0.217 mmol) was dissolved in dichloromethane (5 ml), trans-cinnamic acid (35 mg, 0.239 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91 mg, 0.239 mmol) were added, and finally N,N-diisopropylethylamine (60 mg, 0.434 mmol) was added. After completion of the reaction, water (50 mL) was added, and dichloromethane (50 mL x 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography with dichloromethane-methanol = 30:1 (V / V) as the eluent. Compound 2a was obtained in a yield of 85.9%.

[0056] Yield: 85.9%. mp: 117.4-119.2 °C;1H NMR (600 MHz, CD3OD) δ 7.68-7.63 (m, 2H), 7.61 (d, J = 15.4 Hz, 1H), 7.44-7.35 (m, 3H), 7.18 (d, J = 15.4 Hz, 1H), 3.87-3.59 (m, 8H), 3.54-3.44 (m, 2H), 2.50 (ddd, J = 14.7 Hz, 11.0 Hz, 5.1 Hz, 1H), 2.35 (ddd, J = 14.6 Hz, 10.4 Hz, 5.6 Hz, 1H), 2.05 (ddd, J = 12.5 Hz, 3.5 Hz, 2.6 Hz, 1H), 1.96-1.74 (m, 5H), 1.66-1.53 (m, 4H), 1.52-1.41 (m, 6H), 1.39-1.17 (m, 6H), 1.16-1.10 (m, 1H), 1.04 (td, J = 14.2 Hz, 2.9 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H); 13 C NMR (150 MHz, CD3OD) δ 175.0, 168.0, 144.7, 136.4, 131.1, 130.0, 129.1, 118.0, 72.1, 71.9, 57.5, 56.5, 47.0, 46.9, 46.5, 44.8, 44.5, 44.0, 43.5, 43.0, 42.5, 41.6, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 30.8, 29.8, 28.0, 23.9, 22.4, 19.1, 12.7;

[0057] HRMS m / z calcd for C 37 H 55 N2O4[M+H] + :591.4162; found: 591.4163.

[0058] Example 2: Preparation of compound 2b

[0059] Using trans-2,4-difluorocinnamic acid as starting material, the same procedure as the synthesis of compound 2a was followed to give compound 2b in 84.6% yield.

[0060] Yield: 84.6%. mp: 128.9-130.7 °C; 1H NMR (600 MHz, CD3OD) δ 7.89-7.79 (m, 1H), 7.71 (d, J = 15.6 Hz, 1H), 7.21 (d, J = 15.6 Hz, 1H), 7.07-6.99 (m, 2H), 3.86-3.58 (m, 8H), 3.55-3.41 (m, 2H), 2.49 (ddd, J = 14.7 Hz, 11.0 Hz, 5.0 Hz, 1H), 2.35 (ddd, J = 14.7 Hz, 10.3 Hz, 5.7 Hz, 1H), 2.04 (ddd, J = 12.4 Hz, 3.4 Hz, 2.6 Hz, 1H), 1.95-1.72 (m, 5H), 1.67-1.53 (m, 4H), 1.52-1.40 (m, 6H), 1.38-1.16 (m, 6H), 1.15-1.08 (m, 1H), 1.03 (td, J = 14.2 Hz, 2.7 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.96 (s, 3H), 0.71 (s, 3H); 13 C NMR (150 MHz, CD3OD) δ 174.9, 174.8, 167.4, 165.2 (dd, J = 251.8 Hz, 12.3 Hz), 162.7 (dd, J = 254.0 Hz, 12.1 Hz), 135.4, 131.3, 120.8 (dd, J = 11.9 Hz, 3.9 Hz), 120.2, 120.1, 113.2 (dd, J = 21.9 Hz, 3.6 Hz), 105.3 (t, J = 26.1 Hz), 72.1, 71.9, 57.5, 56.4, 46.9, 46.8, 46.5, 46.4, 44.8, 44.5, 44.0, 43.5, 43.1, 43.0, 42.4, 41.5, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 29.8, 28.0, 24.0, 22.4, 19.2, 12.7;

[0061] HRMS m / z calcd for C 37 H 53 F2N2O4[M+H] + :627.3973; found: 627.3976.

[0062] Example 3: Preparation of compound 2c

[0063] Using trans-3,4-difluorocinnamic acid as starting material, the same procedure as the synthesis of compound 2a was followed to give compound 2c in 51.5% yield.

[0064] Yield:51.5%.mp:129.8-137.0℃; 1 H NMR(600MHz,CD3OD)δ7.68(ddd,J=

[0065] 10.8Hz,7.7Hz,1.2Hz,1H),7.53(d,J=15.4Hz,1H),7.44(ddd,J=6.3Hz,3.8Hz,1.9Hz,1H),7.30(ddd,J=10.1Hz,8.6Hz,8.5Hz,1H),7.18(d,J=15.4Hz,1H),3.85-3.59(m,8H),3.54-3.43(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.0Hz,1H),2.35(ddd,J=14.7Hz,10.6Hz,5.6Hz,1H),2.04(ddd,J=12.5Hz,3.5Hz,2.8Hz,1H),1.94-1.74(m,5H),1.66-1.53(m,4H),1.52-1.41(m,6H),1.38-1.17(m,6H),1.16-1.09(m,1H),1.03(td,J=14.2Hz,2.8Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.72(s,3H); 13 C NMR(150MHz,CD3OD)δ175.0,174.9,167.4,152.4(dd,J=250.8Hz,J=13.0Hz),151.8(dd,J=246.8Hz,J=13.1Hz),142.2,134.2(dd,J=5.3Hz,J=4.4Hz),126.5(dd,J=6.2Hz,J=3.2Hz),119.6,119.5,118.8(d,J=17.7Hz),117.3(dd,J=17.9Hz,J=5.7Hz),72.1,71.9,57.5,56.5,54.8,47.0,46.9,46.5,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.1,12.7;

[0066] HRMS m / z calcd for C 37 H 53 F2N2O4[M+H] +:627.3973; found:627.3974.

[0067] Example 4: Preparation of compound 2d

[0068] Starting with trans-3,5-difluorocinnamic acid, compound 2d was obtained by following the same synthetic method as compound 2a, with a yield of 80.8%.

[0069] Yield:80.8%.mp:128.4-130.3℃; 1 H NMR (600MHz, CD3OD) δ7.53 (d, J=

[0070] 15.4Hz, 1H), 7.31 (dd, J=6.5Hz, 1.8Hz, 2H), 7.27 (dd, J=15.4Hz, 6.5Hz, 1H), 6.99 (tt, J=8.9Hz, 1.8Hz, 1H), 3.8 6-3.58(m,8H),3.55-3.43(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.1Hz,1H),2.35(ddd,J=14.7Hz,10.5Hz,5.6Hz ,1H),2.05(ddd,J=12.5Hz,3.9Hz,2.8Hz,1H),1.96-1.74(m,5H),1.66-1.53(m,4H),1.52-1.41(m,6H),1.39-1 .17(m,6H),1.16-1.09(m,1H),1.03(td,J=14.2Hz,2.9Hz,1H),1.01(d,J=6.5Hz,3H),0.97(s,3H),0.72(s,3H); 13 C NMR (150MHz, CD3OD) δ175.0, 174.9, 167.2, 164.7 (dd, J = 247.3Hz, 13.0Hz), 141.9, 140.2 (t,J=9.8Hz),121.4,121.3,111.8(dd,J=21.1Hz,4.9Hz),105.7(t,J=25.9Hz),72.1,71 .9,57.5,56.5,47.0,46.9,46.5,46.5,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.6,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7;

[0071] HRMS m / z calcd for C37 H 53 F2N2O4[M+H] + :627.3973;found:627.3971

[0072] Example 5: Preparation of compound 2e

[0073] Using trans-3,4,5-trifluorocinnamic acid as starting material, the same procedure as the synthesis of compound 2a was followed to give compound 2e in 71.4% yield.

[0074] Yield:71.4%.mp:131.5-133.4℃; 1 H NMR(600MHz,CD3OD)δ7.50(t,J=7.6

[0075] Hz,2H),7.48(d,J=15.4Hz,1H),7.22(dd,J=15.4Hz,5.7Hz,1H),3.86-3.58(m,8H),3.54-3.43(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.0Hz,1H),2.35(ddd,J=14.7Hz,10.3Hz,5.9Hz,1H),2.04(ddd,J=12.5Hz,3.3Hz,2.4Hz,1H),1.96-1.73(m,5H),1.67-1.53(m,4H),1.52-1.41(m,6H),1.38-1.16(m,6H),1.15-1.09(m,1H),1.03(td,J=14.2Hz,2.7Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.72(s,3H); 13 C NMR(150MHz,CD3OD)δ175.0,174.9,167.0,167.0,152.6(ddd,J=248.3Hz,10.1Hz,3.5Hz),141.5(dt,J=253.8Hz,15.6Hz),141.2,133.4(td,J=7.9Hz,4.3Hz),121.1,121.0,113.3(dd,J=17.6Hz,3.3Hz),72.1,71.9,57.5,56.5,47.0,46.9,46.5,46.4,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.2,31.0,29.8,28.0,24.0,22.4,19.1,12.7;

[0076] HRMS m / z calcd for C 37 H 52 F3N2O4[M+H] + :645.3879;found:645.3877.

[0077] Example 6: Preparation of compound 2f

[0078] Using trans-2-chlorocinnamic acid as starting material, the same procedure as the synthesis of compound 2a was followed to give compound 2f in yield of 70.0%.

[0079] Yield:70.0%.mp:118.4-120.3℃; 1 H NMR(600MHz,CD3OD)δ8.03(d,J=

[0080] 15.4Hz,1H),7.91-7.84(m,1H),7.50-7.42(m,1H),7.40-7.31(m,2H),7.20(d,J=15.4Hz,1H),3.86-3.59(m,8H),3.53-3.43(m,2H),2.49(ddd,J=14.3Hz,10.5Hz,4.9Hz,1H),2.35(ddd,J=14.3Hz,10.1Hz,5.3Hz,1H),2.03(ddd,J=12.4Hz,3.8Hz,2.6Hz,1H),1.95-1.73(m,5H),1.66-1.52(m,4H),1.51-1.39(m,6H),1.37-1.15(m,6H),1.14-1.08(m,1H),1.03(td,J=14.2Hz,2.7Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 CNMR(150MHz,CD3OD)δ174.9,174.9,167.3,139.9,135.7,134.4,132.1,131.1,129.0,128.5,121.0,120.9,72.1,71.9,57.5,56.4,47.0,46.9,46.5,46.4,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0081] HRMS m / z calcd for C 37 H 54 ClN2O4[M+H] + :625.3772;found:625.3770.

[0082] Example 7: Preparation of compound 2g

[0083] Compound 2g was obtained by using trans-3-chlorocinnamic acid as starting material, following the synthetic procedure of compound 2a, in yield of 73.7%.

[0084] Yield:73.7%.mp:126.0-127.7℃; 1 H NMR (600 MHz, CD3OD) δ 7.71 (s, 1H), 7.59-7.51 (m, 2H), 7.41-7.36 (m, 2H), 7.23 (d, J = 15.3 Hz, 1H), 3.87-3.57 (m, 8H), 3.54-3.42 (m, 2H), 2.49 (ddd, J = 14.7 Hz, 11.0 Hz, 5.1 Hz, 1H), 2.34 (ddd, J = 14.6 Hz, 10.3 Hz, 5.4 Hz, 1H), 2.04 (ddd, J = 12.5 Hz, 3.7 Hz, 2.8 Hz, 1H), 1.95-1.73 (m, 5H), 1.67-1.52 (m, 4H), 1.52-1.41 (m, 6H), 1.37-1.15 (m, 6H), 1.14-1.08 (m, 1H), 1.03 (td, J = 14.2 Hz, 2.9 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.96 (s, 3H), 0.71 (s, 3H); 13 CNMR (150 MHz, CD3OD) δ 174.9, 174.9, 167.5, 142.9, 142.8, 138.5, 135.9, 131.5, 130.8, 128.7, 128.6, 127.7, 119.9, 119.8, 72.1, 71.9, 57.5, 56.4, 47.0, 46.9, 46.5, 46.5, 44.8, 44.5, 44.0, 43.5, 43.1, 43.0, 42.4, 41.5, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.2, 31.0, 29.8, 28.0, 24.0, 22.4, 19.2, 12.7;

[0085] HRMS m / z calcd for C 37 H 54ClN2O4[M+H] + :625.3772; found:625.3771.

[0086] Example 8: Preparation of compound 2h

[0087] Starting with trans-4-chlorocinnamic acid, compound 2h was obtained by following the same synthetic method as compound 2a, with a yield of 62.6%.

[0088] Yield:62.6%.mp:127.6-129.2℃; 1 H NMR (600MHz, CD3OD) δ7.63 (d, J=

[0089] 8.5Hz,2H),7.57(d,J=15.4Hz,1H),7.40(d,J=8.5Hz,2H),7.18(d,J=15.4Hz,1H),3.85-3.58(m,8H),3.5 4-3.43(m,2H),2.49(ddd,J=14.5Hz,11.0Hz,5.0Hz,1H),2.34(ddd,J=14.7Hz,10.6Hz,5.6Hz,1H),2.03( ddd,J=12.5Hz,3.3Hz,2.6Hz,1H),1.94-1.73(m,5H),1.66-1.52(m,4H),1.51-1.40(m,6H),1.37-1.15(m ,6H),1.15-1.08(m,1H),1.02(td,J=14.2Hz,2.8Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 C NMR (150MHz, CD3OD) δ174.9,174.8,167.6,143.1,136.7,135.2,130.6,130.1,118.9,118.8,72.1,71.9,57.4,56.4,47.0,46.8,46.5,4 4.8,44.4,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0090] HRMS m / z calcd for C 37 H 54 ClN2O4[M+H] + :625.3772; found:625.3773.

[0091] Example 9: Preparation of compound 2i

[0092] Starting with trans-3,4-dichlorocinnamic acid, compound 2i was obtained by following the same synthetic method as compound 2a, with a yield of 72.0%.

[0093] Yield:72.0%.mp:136.5-138.2℃; 1 H NMR (600MHz, CD3OD) δ7.88 (d, J=

[0094] 1.6Hz,1H),7.58(dd,J=8.4Hz,1.4Hz,1H),7.55(d,J=8.4Hz,1H),7.52(d,J=15.4Hz,1H),7.25(d,J=15.4Hz,1H) ,3.85-3.59(m,8H),3.53-3.44(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.0Hz,1H),2.35(ddd,J=14.7Hz,10.0Hz,5. 6Hz,1H),2.05(ddd,J=12.7Hz,3.3Hz,2.2Hz,1H),1.95-1.74(m,5H),1.66-1.53(m,4H),1.52-1.42(m,6H),1.38- 1.17(m,6H),1.16-1.09(m,1H),1.03(td,J=14.2Hz,2.9Hz,1H),1.01(d,J=6.5Hz,3H),0.97(s,3H),0.72(s,3H); 13 C NMR (150MHz, CD3OD) δ175.0,174.9,167.3,141.7,141.7,137.1,134.4,134. 0,132.0,130.7,130.7,128.8,120.5,120.4,72.1,71.9,57.5,56.5,47.0,4 6.9,46.5,46.5,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7;

[0095] HRMS m / z calcd for C 37 H 53 Cl2N2O4[M+H] +:659.3382; found:659.3380.

[0096] Example 10: Preparation of compound 2j

[0097] Starting with trans-4-trifluoromethylcinnamic acid, compound 2j was obtained by following the same synthetic method as compound 2a, with a yield of 83.9%.

[0098] Yield:83.9%.mp:132.9-134.5℃; 1 H NMR (600MHz, CD3OD) δ7.83 (d, J=

[0099] 8.2Hz,2H),7.69(d,J=8.2Hz,2H),7.64(d,J=15.4Hz,1H),7.32(d,J=15.4Hz,1H),3.87-3.60(m,8H),3.5 3-3.43(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.0Hz,1H),2.35(ddd,J=14.7Hz,10.2Hz,5.5Hz,1H),2.04( ddd,J=12.5Hz,3.5Hz,2.8Hz,1H),1.95-1.74(m,5H),1.65-1.53(m,4H),1.52-1.41(m,6H),1.38-1.16(m ,6H),1.15-1.09(m,1H),1.02(td,J=14.2Hz,2.7Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 C NMR(150MHz,CD3OD)δ174.9,174.9,167.3,142.6,142.5,140.2,132.2(q,J=32.6Hz) ,129.6,126.8(q,J=3.6Hz),125.5(q,J=270.9Hz),121.1,121.0,72.1,71.9,57.5,56 .4,47.0,46.9,46.5,46.4,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0100] HRMS m / z calcd for C 38 H 54 F3N2O4[M+H]+ : 659.4036; found: 659.4035.

[0101] Example 11: Preparation of compound 2k

[0102] Using trans-3-trifluoromethoxycinnamic acid as starting material, the same procedure as the synthesis of compound 2a was followed to give compound 2k in yield: 61.5%.

[0103] Yield: 61.5%. mp: 116-118.1 °C; 1 H NMR (600 MHz, CD3OD) δ 7.64 (d, J = 7.7

[0104] Hz, 1H), 7.62-7.57 (m, 2H), 7.50 (dd, J = 8.0 Hz, 7.9 Hz, 1H), 7.33-7.24 (m, 2H), 3.86-3.59 (m, 8H), 3.53-3.43 (m, 2H), 2.49 (ddd, J = 14.7 Hz, 11.1 Hz, 5.0 Hz, 1H), 2.35 (ddd, J = 14.7 Hz, 10.1 Hz, 5.1 Hz, 1H), 2.04 (ddd, J = 12.7 Hz, 3.7 Hz, 2.4 Hz, 1H), 1.95-1.74 (m, 5H), 1.65-1.53 (m, 4H), 1.52-1.42 (m, 6H), 1.36-1.16 (m, 6H), 1.15-1.10 (m, 1H), 1.03 (td, J = 14.2 Hz, 2.8 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.96 (s, 3H), 0.72 (s, 3H); 13 C NMR (150 MHz, CD3OD) δ 175.0, 174.9, 167.4, 151.0, 150.9, 142.7, 142.6, 138.9, 131.7, 128.1, 123.2, 121.9 (q, J = 255.6 Hz), 121.4, 121.4, 120.3, 120.2, 72.1, 71.9, 57.5, 56.5, 47.0, 46.9, 46.5, 46.5, 44.8, 44.5, 44.0, 43.5, 43.1, 43.0, 42.4, 41.5, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 29.8, 28.0, 24.0, 22.4, 19.2, 12.7;

[0105] HRMS m / z calcd for C 38 H 54F3N2O5[M+H] + :675.3985; found:675.3987.

[0106] Example 12: Preparation of compound 2l

[0107] Starting with trans-4-trifluoromethoxycinnamic acid, compound 2l was obtained by following the same synthetic method as compound 2a, with a yield of 82.0%.

[0108] Yield:82.0%.mp:125.2-126.9℃; 1 H NMR (600MHz, CD3OD) δ7.75 (d, J=

[0109] 8.7Hz,2H),7.61(d,J=15.4Hz,1H),7.30(d,J=8.3Hz,2H),7.21(d,J=15.4Hz,1H),3.86-3.59(m,8H),3.5 3-3.43(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.1Hz,1H),2.35(ddd,J=14.7Hz,10.3Hz,5.5Hz,1H),2.04( ddd,J=12.5Hz,3.7Hz,2.9Hz,1H),1.96-1.73(m,5H),1.67-1.53(m,4H),1.52-1.41(m,6H),1.38-1.16(m ,6H),1.15-1.09(m,1H),1.02(td,J=14.2Hz,2.8Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 C NMR (150MHz, CD3OD) δ174.9,174.8,167.5,151.3,142.8,135.5,130.9,122 .3,121.8(q,J=256.2Hz),119.4,119.3,72.1,71.9,57.5,56.4,47.0,46.9 ,46.5,46.5,44.8,44.5,44.0,43.5,43.1,43.0,42.4,41.5,40.7,38.6,38 .0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0110] HRMS m / z calcd for C 38 H 54 F3N2O5[M+H] +:675.3985; found:675.3987.

[0111] Example 13: Preparation of compound 2m

[0112] Starting with trans-4-methylcinnamic acid, compound 2m was obtained by following the same synthetic method as compound 2a, with a yield of 76.3%.

[0113] Yield:76.3%.mp:121.0-123.0℃; 1 H NMR (600MHz, CD3OD) δ7.58 (d, J=

[0114] 15.4Hz,1H),7.53(d,J=8.1Hz,2H),7.22(d,J=8.1Hz,2H),7.11(d,J=15.4Hz,1H),3.85-3.58(m,8H ),3.54-3.43(m,2H),2.50(ddd,J=14.7Hz,11.0Hz,5.1Hz,1H),2.39-2.31(m,4H),2.05(ddd,J=12.5 Hz,3.0Hz,2.6Hz,1H),1.95-1.74(m,5H),1.65-1.53(m,4H),1.52-1.41(m,6H),1.38-1.17(m,6H), 1.16-1.09(m,1H),1.03(td,J=14.2Hz,2.9Hz,1H),1.01(d,J=6.5Hz,3H),0.97(s,3H),0.72(s,3H); 13 C NMR (150MHz, CD3OD) δ175.0,168.1,144.8,141.6,133.7,130.6,129.2,116.8,72.1,71.9,57.5,56.5,47.0,46.9,46.5,44.8,44 .5,44.0,43.5,43.0,42.5,41.6,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,23.9,22.4,21.5,19.1,12.7;

[0115] HRMS m / z calcd for C 38 H 57 N₂O₄[M+H] + :605.4318; found:605.4317.

[0116] Example 14: Preparation of compound 2n

[0117] Using trans-4-methoxycinnamic acid as starting material, the synthetic procedure of compound 2a was followed to give compound 2n in yield of 81.7%.

[0118] Yield:81.7%.mp:124.2-125.6℃; 1 H NMR (600 MHz, CD3OD) δ 7.62-7.54 (m, 3H), 7.02 (d, J = 15.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.82-3.58 (m, 8H), 3.54-3.44 (m, 2H), 2.50 (ddd, J = 14.7 Hz, 11.0 Hz, 5.1 Hz, 1H), 2.35 (ddd, J = 14.5 Hz, 10.6 Hz, 5.7 Hz, 1H), 2.05 (ddd, J = 12.5 Hz, 3.5 Hz, 2.6 Hz, 1H), 1.95-1.74 (m, 5H), 1.66-1.53 (m, 4H), 1.52-1.42 (m, 6H), 1.38-1.17 (m, 6H), 1.16-1.10 (m, 1H), 1.03 (td, J = 14.2 Hz, 2.8 Hz, 1H), 1.01 (d, J = 6.5 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H); 13 C NMR (150 MHz, CD3OD) δ 175.0, 168.3, 162.8, 144.6, 130.8, 129.0, 115.3, 115.1, 72.1, 71.9, 57.5, 56.5, 55.8, 47.0, 46.8, 46.5, 46.5, 44.8, 44.5, 44.0, 43.5, 43.0, 42.5, 41.6, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 29.8, 28.0, 23.9, 22.4, 19.1, 12.7;

[0119] HRMS m / z calcd for C 38 H 57 N2O5[M+H] + :621.4267;found:621.4268.

[0120] Example 15: Preparation of compound 2o

[0121] Using trans-2-hydroxycinnamic acid as starting material, the synthetic procedure of compound 2a was followed to give compound 2o in yield of 72.9%.

[0122] Yield:72.9%.mp:153.8-155.7℃; 1 H NMR (600MHz, CD3OD) δ7.92 (d, J=

[0123] 15.6Hz,1H),7.55(dd,J=8.1Hz,1.2Hz,1H),7.23-7.16(m,2H),6.87-6.82(m,2H),3.82-3.59(m,8H),3.5 4-3.43(m,2H),2.49(ddd,J=14.7Hz,11.0Hz,5.0Hz,1H),2.35(ddd,J=14.7Hz,10.6Hz,5.6Hz,1H),2.05( ddd,J=12.5Hz,3.2Hz,2.2Hz,1H),1.95-1.74(m,5H),1.66-1.53(m,4H),1.52-1.41(m,6H),1.38-1.16(m ,6H),1.15-1.09(m,1H),1.03(td,J=14.2Hz,2.9Hz,1H),1.00(d,J=6.5Hz,3H),0.97(s,3H),0.72(s,3H); 13 C NMR (150MHz, CD3OD) δ175.0,168.8,158.1,140.8,132.2,130.1,123.2,120.7,120.7,117.4,117.3,116.9,72.1,71.9,57.5,56.4,46.9,46.5, 44.8,44.5,44.0,43.4,43.0,42.5,41.5,40.7,38.6,38.0,37.0,36.1, 35.2,32.8,31.2,31.0,29.8,28.0,23.9,22.4,19.1,19.1,12.7,12.7;

[0124] HRMS m / z calcd for C 37 H 55 N₂O₅[M+H] + :607.4111; found:607.4111.

[0125] Example 16: Preparation of compound 2p

[0126] Starting with trans-3-hydroxycinnamic acid, and following the same synthetic method as compound 2a, compound 2p was obtained in 48.6% yield.

[0127] Yield:48.6%.mp:156.1-157.9℃; 1H NMR (600MHz, CD3OD) δ7.53 (d, J=

[0128] 15.4Hz,1H),7.21(t,J=7.9Hz,1H),7.11(d,J=7.9Hz,1H),7.09(d,J=15.4Hz,1H),7.02(dd,J=2.0Hz,1.8Hz,1H),6.82(d d,J=8.1Hz,1.8Hz,1H),3.84-3.58(m,8H),3.54-3.44(m,2H),2.49(ddd,J=14.6Hz,11.0Hz,5.1Hz,1H),2.35(ddd,J=14. 4Hz,10.6Hz,5.6Hz,1H),2.05(ddd,J=12.5Hz,2.9Hz,2.4Hz,1H),1.95-1.73(m,5H),1.66-1.53(m,4H),1.52-1.41(m,6H ),1.39-1.16(m,6H),1.15-1.09(m,1H),1.03(td,J=14.4Hz,2.9Hz,1H),1.00(d,J=6.5Hz,3H),0.97(s,3H),0.72(s,3H); 13 C NMR (150MHz, CD3OD) δ175.0,168.0,159.0,144.9,137.7,130.9,120.5,118.1,117.9,117.8,115.5,72.1,71.9,57.5,56.5,47.0,46.9, 46.5,44.8,44.5,44.0,43.5,43.0,42.4,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,23.9,22.4,19.1,12.7;

[0129] HRMS m / z calcd for C 37 H 55 N₂O₅[M+H] + :607.4111; found:607.4111.

[0130] Example 17: Preparation of compound 2q

[0131] Starting with trans-4-hydroxycinnamic acid, compound 2q was obtained by following the same synthetic method as compound 2a, with a yield of 53.2%.

[0132] Yield:53.2%.mp:156.2-158.2℃; 1H NMR (600MHz, CD3OD) δ7.55 (d, J=

[0133] 15.3Hz,1H),7.50(d,J=8.6Hz,2H),6.96(d,J=15.3Hz,1H),6.81(d,J=8.6Hz,2H),3.82-3.56(m,8H),3.5 2-3.42(m,2H),2.48(ddd,J=14.7Hz,11.0Hz,5.1Hz,1H),2.33(ddd,J=14.6Hz,10.6Hz,5.6Hz,1H),2.03( ddd,J=12.5Hz,3.4Hz,2.6Hz,1H),1.94-1.73(m,5H),1.65-1.52(m,4H),1.51-1.40(m,6H),1.36-1.15(m ,6H),1.14-1.07(m,1H),1.03(td,J=14.2Hz,2.8Hz,1H),0.99(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 C NMR (150MHz, CD3OD) δ174.9,168.4,160.8,145.0,131.1,131.0,127.8,116.7,114.2,72.1,71.9,57.4,56.4,47.0,46.8,46.5,46.4 ,44.8,44.4,44.0,43.4,43.0,42.5,41.5,40.7,38.6,38.0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0134] HRMS m / z calcd for C 37 H 55 N₂O₅[M+H] + :607.4111; found:607.4112.

[0135] Example 18: Preparation of compound 2r

[0136] Starting with trans-3-methoxy-4-hydroxycinnamic acid, compound 2r was obtained by following the same synthetic method as compound 2a, with a yield of 65.4%.

[0137] Yield:65.4%.mp:141.4-143.2℃; 1 H NMR (600MHz, CD3OD) δ7.55 (d, J=

[0138] 15.3Hz,1H),7.26(s,1H),7.09(d,J=7.9Hz,1H),7.00(d,J=15.3Hz,1H),6.81(d,J=8.2Hz,1H),3.90(s,3H),3. 86-3.56(m,8H),3.53-3.42(m,2H),2.48(ddd,J=14.7Hz,11.0Hz,5.1Hz,1H),2.33(ddd,J=14.5Hz,10.5Hz,5.6H z,1H),2.03(ddd,J=12.7Hz,3.5Hz,2.4Hz,1H),1.94-1.73(m,5H),1.66-1.52(m,4H),1.51-1.39(m,6H),1.37-1 .15(m,6H),1.14-1.08(m,1H),1.02(td,J=14.2Hz,2.8Hz,1H),0.99(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 C NMR(150MHz,CD3OD)δ175.0,168.4,150.1,149.3,145.4,128.4,124.0,1 23.9,116.4,114.4,111.7,111.6,72.1,71.9,57.4,56.5,56.4,47.0,46 .8,46.5,46.4,44.8,44.5,44.0,43.5,43.0,42.5,41.5,40.7,38.6,38. 0,37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0139] HRMS m / z calcd for C 38 H 57 N₂O₆[M+H] + :637.4217; found:637.4218.

[0140] Example 19: Preparation of compound 2s

[0141] Starting with trans-3,4-(methylenedioxy)cinnamic acid, compound 2s was obtained by following the same synthetic method as compound 2a, with a yield of 79.8%.

[0142] Yield:79.8%.mp:132,4-134.2℃; 1 H NMR (600MHz, CD3OD) δ7.53 (d, J=

[0143] 15.3Hz,1H),7.26(s,1H),7.08(dd,J=8.3Hz,1.6Hz,1H),7.00(d,J=15.3Hz,1H),6.84(d,J=8.1Hz,1H),6.00(s,2 H),3.84-3.57(m,8H),3.54-3.43(m,2H),2.49(ddd,J=14.7Hz,10.9Hz,5.1Hz,1H),2.34(ddd,J=14.5Hz,10.6Hz,5 .6Hz,1H),2.04(ddd,J=12.7Hz,3.3Hz,2.4Hz,1H),1.94-1.73(m,5H),1.66-1.52(m,4H),1.51-1.40(m,6H),1.38 -1.15(m,6H),1.14-1.08(m,1H),1.03(td,J=14.2Hz,2.9Hz,1H),1.00(d,J=6.5Hz,3H),0.96(s,3H),0.71(s,3H); 13 C NMR (150MHz, CD3OD) δ174.9,174.9,168.1,150.9,149.9,144.6,130.8,125.7,115.7,109.4,107.4,103.0,72.1,71.9,57.5,56.4,47.0,46.8, 46.5,46.5,44.8,44.5,44.0,43.5,43.0,42.5,41.5,40.7,38.6,38.0, 37.0,36.1,35.2,32.8,31.2,31.0,29.8,28.0,24.0,22.4,19.2,12.7;

[0144] HRMS m / z calcd for C 38 H 55 N₂O₆[M+H] + :635.4060; found:635.4061

[0145] Example 20: Preparation of compound 2t

[0146] Starting with trans-3,5-dimethoxy-4-hydroxycinnamic acid, compound 2t was obtained by following the same synthetic method as compound 2a, with a yield of 62.2%.

[0147] Yield:62.2%.mp:150.3-151.7℃; 1 H NMR (600MHz, CD3OD) δ7.53 (d, J=

[0148] 15.3 Hz, 1 H), 7.04 (d, J = 15.3 Hz, 1 H), 6.96 (s, 2 H), 3.88 (s, 6 H), 3.86-3.58 (m, 8 H), 3.53-3.43 (m, 2 H), 2.48 (ddd, J = 14.5 Hz, 11.2 Hz, 5.0 Hz, 1 H), 2.33 (ddd, J = 14.4 Hz, 10.8 Hz, 5.1 Hz, 1 H), 2.03 (ddd, J = 12.4 Hz, 3.4 Hz, 2.6 Hz, 1 H), 1.95-1.71 (m, 5 H), 1.67-1.52 (m, 4 H), 1.51-1.39 (m, 6 H), 1.38-1.15 (m, 6 H), 1.14-1.07 (m, 1 H), 1.02 (td, J = 14.2 Hz, 2.9 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3 H), 0.96 (s, 3 H), 0.71 (s, 3 H); 13 CNMR (150 MHz, CD3OD) δ 175.0, 168.3, 149.4, 145.6, 139.1, 127.3, 114.9, 106.8, 72.1, 71.9, 57.4, 56.8, 56.4, 47.1, 46.8, 46.5, 46.4, 44.8, 44.5, 44.0, 43.5, 43.1, 42.5, 41.5, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 29.8, 28.0, 24.0, 22.4, 19.1, 12.7;

[0149] HRMS m / z calcd for C 39 H 59 N2O7[M+H] + :667.4322; found: 667.4321.

[0150] Example 21: Preparation of compound 2u

[0151] Using trans-3,4,5-trimethoxycinnamic acid as the starting material, the synthesis method of compound 2a was operated to obtain compound 2u in yield of 74.4%.

[0152] Yield: 74.4%. mp: 128.0-129.7 °C; 1 H NMR (600 MHz, CD3OD) δ 7.54 (d, J = 15.3 Hz, 1 H)

[0153] 15.3 Hz, 1 H), 7.13 (d, J = 15.1 Hz, 1 H), 6.97 (s, 2 H), 3.88 (s, 6 H), 3.87-3.59 (m, 11 H), 3.53-3.43 (m, 2 H), 2.49 (ddd, J = 14.5 Hz, 11.0 Hz, 5.0 Hz, 1 H), 2.35 (ddd, J = 14.5 Hz, 10.5 Hz, 5.5 Hz, 1 H), 2.04 (ddd, J = 12.5 Hz, 3.5 Hz, 2.6 Hz, 1 H), 1.95-1.73 (m, 5 H), 1.66-1.53 (m, 4 H), 1.52-1.41 (m, 6 H), 1.38-1.16 (m, 6 H), 1.15-1.08 (m, 1 H), 1.03 (td, J = 14.2 Hz, 2.9 Hz, 1 H), 1.00 (d, J = 6.5 Hz, 3 H), 0.96 (s, 3 H), 0.71 (s, 3 H); 13 CNMR (150 MHz, CD3OD) δ 175.0, 168.0, 154.8, 144.9, 140.8, 132.3, 117.3, 117.2, 106.6, 72.1, 71.9, 61.2, 57.5, 56.7, 56.4, 47.1, 46.8, 46.5, 46.4, 44.8, 44.5, 44.0, 43.5, 43.1, 42.5, 41.5, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 29.8, 28.0, 24.0, 22.4, 19.2, 12.7;

[0154] HRMS m / z calcd for C 40 H 61 N2O7[M+H] + :681.4479; found: 681.4477.

[0155] Example 22: Preparation of compound 2v

[0156] Compound 2v was obtained in yield of 58.0% by using trans-a-methyl cinnamic acid as starting material and following the same procedure as for the synthesis of compound 2a.

[0157] Yield:58.0% mp:113.4-115.1 °C; 1H NMR (600 MHz, CD3OD) δ 7.43 - 7.36 (m, 4H), 7.34 - 7.26 (m, 1H), 6.62 (t, J = 1.5 Hz, 1H), 3.73 - 3.61 (m, 8H), 3.53 - 3.44 (m, 2H), 2.50 (ddd, J = 14.5 Hz, 10.9 Hz, 5.0 Hz, 1H), 2.35 (ddd, J = 14.8 Hz, 10.6 Hz, 5.6 Hz, 1H), 2.09 (d, J = 1.5 Hz, 3H), 2.05 (ddd, J = 12.5 Hz, 3.7 Hz, 2.4 Hz, 1H), 1.95 - 1.74 (m, 5H), 1.65 - 1.53 (m, 4H), 1.52 - 1.42 (m, 6H), 1.37 - 1.17 (m, 6H), 1.16 - 1.10 (m, 1H), 1.03 (td, J = 14.2 Hz, 3.0 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H); 13 C NMR (150 MHz, CD3OD) δ 175.0, 174.8, 137.0, 133.4, 131.7, 130.2, 129.5, 128.8, 72.1, 71.9, 57.5, 56.5, 44.8, 44.5, 44.0, 41.6, 40.7, 38.6, 38.0, 37.0, 36.1, 35.2, 32.8, 31.2, 31.0, 29.8, 28.0, 23.9, 22.4, 19.1, 16.2, 12.7;

[0158] HRMS m / z calcd for C 38 H 57 N2O4[M+H] + :605.4318;found:605.4318.

[0159] Example 23: Preparation of compound 2w

[0160] Compound 2w was obtained by using 3-(1-naphthyl) acrylic acid as starting material, following the synthetic procedure of compound 2a in 53.9% yield.

[0161] Yield:53.9%.mp:136.5-137.9℃; 1 H NMR (600 MHz, CD3OD) δ 8.48 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 7.32 - 7.28 (m, 1H), 7.26 - 7.22 (m, 1H), 7.20 - 7.16 (m, 1H), 6.64 (t, J = 1.5 Hz, 1H), 3.73 - 3.62 (m, 8H), 3.53 - 3.44 (m, 2H), 2.50 (ddd, J = 14.5 Hz, 10.9 Hz, 5.0 Hz, 1H), 2.35 (ddd, J = 14.8 Hz, 10.6 Hz, 5.6 Hz, 1H), 2.09 (d, J = 1.5 Hz, 3H), 2.05 (ddd, J = 12.5 Hz, 3.7 Hz, 2.4 Hz, 1H), 1.95 - 1.74 (m, 5H), 1.65 - 1.53 (m, 4H), 1.52 - 1.42 (m, 6H), 1.37 - 1.17 (m, 6H), 1.16 - 1.10 (m, 1H), 1.03 (td, J = 14.2 Hz, 3.0 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H);

[0162] 15.1 Hz, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.94-7.86 (m, 3 H), 7.56 (ddd, J = 8.5 Hz, 6.8 Hz, 1.0 Hz, 1 H), 7.54-7.47 (m, 2 H), 7.20 (d, J = 15.1 Hz, 1 H), 3.84-3.54 (m, 8 H), 3.52-3.40 (m, 2 H), 2.44 (ddd, J = 14.6 Hz, 10.6 Hz, 4.5 Hz, 1 H), 2.29 (ddd, J = 14.6 Hz, 10.6 Hz, 5.7 Hz, 1 H), 1.96 (ddd, J = 11.6 Hz, 3.9 Hz, 2.8 Hz, 1 H), 1.90-1.68 (m, 5 H), 1.66-1.51 (m, 4 H), 1.47-1.35 (m, 6 H), 1.32-1.21 (m, 4 H), 1.17-1.05 (m, 2 H), 1.04-0.97 (m, 2 H), 0.95 (d, J = 6.4 Hz, 3 H), 0.92 (s, 3 H), 0.66 (s, 3 H); 13 C NMR (150 MHz, CD3OD) δ 174.8, 174.8, 167.7, 141.3, 135.2, 133.4, 132.8, 131.4, 129.9, 128.0, 127.3, 126.7, 126.0, 124.2, 120.6, 120.5, 72.1, 71.8, 57.3, 56.3, 46.9, 46.9, 46.5, 46.4, 44.7, 44.4, 43.9, 43.5, 43.1, 42.9, 42.4, 41.4, 40.6, 38.6, 38.0, 37.0, 36.1, 35.1, 32.7, 31.3, 31.2, 31.0, 29.8, 28.0, 24.0, 22.3, 19.2, 12.7;

[0163] HRMS m / z calcd for C 41 H 57 N2O4[M+H] + :641.4318; found: 641.4317.

[0164] Example 24: Preparation of compound 2x

[0165] Compound 2x was obtained by using trans-3-phenylpropionic acid as starting material, following the synthetic procedure of compound 2a in 54.4% yield.

[0166] Yield: 54.4%. mp: 103.4-105.3 °C; 1H NMR (600 MHz, CD3OD) δ 7.31 - 7.26 (m, 2H), 7.25 - 7.21 (m, 2H), 7.21 - 7.15 (m, 1H), 3.63 - 3.58 (m, 1H), 3.57 - 3.43 (m, 6H), 3.42 - 3.32 (m, 3H), 2.93 (t, J = 7.4 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 2.48 - 2.38 (m, 1H), 2.34 - 2.23 (m, 1H), 2.04 (ddd, J = 12.5 Hz, 2.4 Hz, 2.0 Hz, 1H), 1.96 - 1.78 (m, 4H), 1.77 - 1.68 (m, 1H), 1.67 - 1.53 (m, 4H), 1.52 - 1.40 (m, 6H), 1.35 - 1.16 (m, 6H), 1.15 - 1.08 (m, 1H), 1.03 (td, J = 14.1 Hz, 2.6 Hz, 1H), 1.01 - 0.97 (m, 3H), 0.97 (s, 3H), 0.72 (s, 3H); 13 CNMR (150 MHz, CD3OD) δ 174.8, 174.7, 173.5, 173.4, 142.2, 142.1, 129.6, 129.6, 129.5, 127.3, 72.1, 71.9, 57.5, 56.4, 46.8, 46.6, 46.4, 46.4, 44.8, 44.4, 44.0, 42.9, 42.6, 42.4, 42.3, 41.5, 40.7, 38.6, 38.0, 36.9, 36.1, 35.6, 35.5, 35.2, 32.7, 32.7, 31.2, 31.1, 31.0, 29.8, 28.0, 24.0, 22.4, 19.1, 12.7;

[0167] HRMS m / z calcd for C 37 H 57 N2O4[M+H] + :593.4318; found: 591.4318.

[0168] The structures of 2a-2x are shown below:

[0169]

[0170] Example 25: Preparation of compound 3a

[0171] Compound 2r (20 mg, 0.031 mmol) was dissolved in dichloromethane (1 mL) and irradiated under mercury lamp for 10 h. TLC monitored the reaction was complete, the reaction was stopped, concentrated in vacuum, purified by preparative thin layer chromatography, eluent: ethyl acetate-methanol = 7:1 (V / V, containing 1% ammonia water), compound 3a was obtained, yield: 94.6%.

[0172] Yield: 94.6%. mp: 113.5-115.2 °C; 1 H NMR (600 MHz, CD3OD): ~50:50 mixture of rotamers, * indicates amide rotamer δ 6.97 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.2 Hz, 1.9 Hz, 1H), 6.78 (d, J = 8.2 Hz, 0.5H), *6.77 (d, J = 8.2 Hz, 0.5H), 6.71 (d, J = 12.3 Hz, 1H), 5.93 (d, J = 12.3 Hz, 1H), 3.83 (s, 1.5H), *3.82 (s, 1.5H), 3.73-3.67 (m, 1H), 3.66-3.60 (m, 1H), 3.58-3.44 (m, 5H), 3.43-3.37 (m, 1H), 3.23-3.15 (m, 2H), 2.45 (ddd, J = 14.7 Hz, 10.8 Hz, 5.1 Hz, 0.5H), *2.36 (ddd, J = 14.7 Hz, 10.8 Hz, 5.1 Hz, 0.5H), 2.30 (ddd, J = 14.7 Hz, 10.6 Hz, 5.9 Hz, 0.5H), *2.22 (ddd, J = 14.7 Hz, 10.6 Hz, 5.9 Hz, 0.5H), 2.04 (ddd, J = 12.4 Hz, 3.6 Hz, 2.9 Hz, 0.5H), *2.02 (ddd, J = 12.4 Hz, 3.6 Hz, 2.9 Hz, 0.5H), 1.94-1.77 (m, 4H), 1.75-1.54 (m, 5H), 1.51-1.39 (m, 6H), 1.34-1.16 (m, 6H), 1.14-1.06 (m, 1H), 1.03 (td, J = 14.2 Hz, 2.8 Hz, 1H), 0.98 (d, J = 6.5 Hz, 1.5H), 0.97 (s, 3H), *0.94 (d, J = 6.5 Hz, 1.5H), 0.71 (s, 1.5H), *0.69 (s, 1.5H); 13CNMR (150 MHz, CD3OD) δ 174.9, 174.8, 170.7, 170.7, 149.0, 149.0, 148.7, 148.7, 135.9, 135.7, 128.6, 128.6, 123.2, 123.1, 120.7, 116.4, 116.3, 112.6, 112.5, 72.1, 71.9, 57.5, 57.4, 56.4, 56.4, 56.3, 47.5, 47.2, 46.5, 46.1, 44.8, 44.8, 44.4, 44.0, 42.6, 42.5, 42.2, 41.8, 41.5, 41.5, 40.7, 38.6, 38.0, 37.0, 36.9, 36.1, 35.2, 32.7, 31.1, 31.1, 31.0, 29.8, 29.7, 28.0, 23.9, 22.4, 19.1, 19.1, 12.6;

[0173] HRMS m / z calcd for C 38 H 57 N2O6[M+H] + :637.4217; found: 637.4213.

[0174] Example 26: Preparation of compound 3b

[0175] Compound 3b was obtained from compound 2s as starting material, following the synthetic procedure of compound 3a, in a yield of 95.3%.

[0176] Yield: 95.3%. mp: 122.5-123.8 °C; 1H NMR (600 MHz, CD3OD): ~50:50 mixture of rotamers, * indicates amide rotamer δ 6.89 (d, J = 1.3 Hz, 1H), 6.88 (dd, J = 7.9 Hz, 1.3 Hz, 1H), 6.83 (d, J = 7.9 Hz, 0.5H), *6.82 (d, J = 7.9 Hz, 0.5H), 6.70 (d, J = 12.5 Hz, 1H), 5.99 (d, J = 12.5 Hz, 1H), 5.97 (s, 2H), 3.73-3.67 (m, 1H), 3.66-3.60 (m, 1H), 3.59-3.44 (m, 5H), 3.43-3.39 (m, 1H), 3.28-3.21 (m, 2H), 2.46 (ddd, J = 14.7 Hz, 10.7 Hz, 5.0 Hz, 0.5H), *2.38 (ddd, J = 14.7 Hz, 10.7 Hz, 5.0 Hz, 0.5H), 2.32 (ddd, J = 14.7 Hz, 10.2 Hz, 5.8 Hz, 0.5H), *2.25 (ddd, J = 14.7 Hz, 10.2 Hz, 5.8 Hz, 0.5H), 2.05 (ddd, J = 12.4 Hz, 3.7 Hz, 2.5 Hz, 0.5H), *2.02 (ddd, J = 12.4 Hz, 3.7 Hz, 2.5 Hz, 0.5H), 1.94-1.78 (m, 4H), 1.76-1.54 (m, 5H), 1.51-1.41 (m, 6H), 1.35-1.17 (m, 6H), 1.15-1.07 (m, 1H), 1.03 (td, J = 14.5 Hz, 2.3 Hz, 1H), 0.99 (d, J = 6.5 Hz, 1.5H), 0.97 (s, 3H), *0.95 (d, J = 6.5 Hz, 1.5H), 0.71 (s, 1.5H), *0.70 (s, 1.5H); 13CNMR (150 MHz, CD3OD) δ 174.9, 170.2, 170.2, 149.6, 149.5, 135.3, 135.2, 130.9, 124.4, 121.7, 121.7, 109.4, 109.4, 108.9, 108.9, 102.9, 102.9, 72.1, 71.9, 57.5, 56.4, 56.4, 47.6, 47.2, 46.5, 46.0, 44.8, 44.8, 44.5, 44.0, 42.6, 42.5, 42.1, 41.9, 41.5, 40.7, 38.6, 38.0, 36.9, 36.1, 35.2, 32.7, 31.1, 31.1, 31.0, 29.8, 28.0, 23.9, 22.4, 19.1, 19.1, 12.6;

[0177] HRMS m / z calcd for C 38 H 55 N2O6[M+H] + :635.4060; found: 635.4059.

[0178] Example 27: Preparation of compound 3c

[0179] Compound 3c was obtained from compound 2u following the procedure for the synthesis of compound 3a in 91.6% yield.

[0180] Yield: 91.6%. mp: 116.8-117.5 °C; ~50:50 mixture of rotamers, * indicates amide rotamer δ 6.76 (d, J = 12.4 Hz, 0.5H), * 6.75 (d, J = 12.4 Hz, 0.5H), 6.70 (s, 2H), 6.07 (d, J = 12.4 Hz, IH), 3.81 (s, 6H), 3.75 (s, 1.5H), *3.75 (s, 1.5H), 3.71-3.67 (m, IH), 3.66-3.61 (m, IH), 3.55-3.44 (m, 5H), 3.43-3.38 (m, IH), 3.24-3.16 (m, 2H), 2.44 (ddd, J = 14.7 Hz, 11.1 Hz, 5.1 Hz, 0.5H), *2.37 (ddd, J = 14.7 Hz, 11.1 Hz, 5.1 Hz, 0.5H), 2.30 (ddd, J = 14.7 Hz, 10.5 Hz, 5.9 Hz, 0.5H), *2.23 (ddd, J = 14.7 Hz, 10.5 Hz, 5.9 Hz, 0.5H), 2.03 (ddd, J = 12.5 Hz, 3.7 Hz, 2.9 Hz, 0.5H), *2.01 (ddd, J = 12.5 Hz, 3.7 Hz, 2.9 Hz, 0.5H), 1.93-1.78 (m, 4H), 1.72-1.53 (m, 5H), 1.52-1.38 (m, 6H), 1.35-1.15 (m, 6H), 1.13-1.06 (m, IH), 1.03 (td, J = 14.2 Hz, 2.8 Hz, IH), 0.97 (d, J = 6.5 Hz, 1.5H), 0.96 (s, 3H), *0.94 (d, J = 6.5 Hz, 1.5H), 0.70 (s, 1.5H), *0.69 (s, 1.5H); 13CNMR (150 MHz, CD3OD) δ 174.9, 174.9, 170.3, 170.3, 154.6, 154.6, 139.6, 135.5, 135.4, 132.7, 132.7, 123.1, 106.6, 106.6, 72.1, 71.9, 61.2, 61.2, 57.4, 57.4, 56.6, 56.4, 56.3, 47.5, 47.1, 46.6, 46.1, 44.8, 44.8, 44.4, 44.0, 42.6, 42.1, 41.9, 41.5, 41.5, 40.7, 38.6, 38.0, 37.0, 36.9, 36.1, 35.2, 32.7, 31.1, 31.1, 31.0, 29.8, 28.0, 24.0, 22.4, 19.1, 19.1, 12.7, 12.6;

[0181] HRMS m / z calcd for C 40 H 61 N2O7[M+H] + :681.4479;found:681.4474.

[0182] The structures of 3a-3c are shown below:

[0183]

[0184] Example 28: Preparation of compound 4a

[0185] Compound 2m (100 mg, 0.165 mmol) was dissolved in dichloromethane (4 mL), and Dess-Martin reagent (140 mg, 0.331 mmol) was added. After the addition was completed, the reaction was allowed to proceed at room temperature for 5 h. TLC monitoring showed that the reaction was complete, and the reaction was stopped. Saturated sodium bicarbonate solution (50 mL) was added, and dichloromethane (40 mL x 3) was used to extract the mixture. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed by silica gel column chromatography using dichloromethane-methanol (50:1, V / V) as the eluent to obtain compound 4a in a yield of 80.7%.

[0186] Yield:80.7%.mp:134.7-136.6℃; 1 H NMR (600 MHz, CDCl3) δ 7.67 (d, J = 15.4

[0187] Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 15.4 Hz, 1H), 3.81-3.59 (m, 6H), 3.56-3.47 (m, 2H), 2.87 (dd, J = 12.7 Hz, 5.7 Hz, 1H), 2.49 (t, J = 11.3 Hz, 1H), 2.40 (ddd, J = 14.8 Hz, 10.7 Hz, 5.0 Hz, 1H), 2.36 (s, 3H), 2.30-2.14 (m, 7H), 2.10-2.01 (m, 2H), 2.00-1.92 (m, 2H), 1.88 (td, J = 12.1 Hz, 4.3 Hz, 1H), 1.84-1.75 (m, 2H), 1.67-1.42 (m, 5H), 1.41-1.30 (m, 2H), 1.29 (s, 3H), 1.22-1.10 (m, 2H), 0.96 (d, J = 6.5 Hz, 3H), 0.69 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 211.4, 210.4, 172.4, 166.0, 143.8, 140.4, 132.3, 129.7, 127.9, 115.3, 54.9, 49.6, 48.9, 47.9, 45.6, 45.5, 45.1, 43.0, 42.9, 42.8, 42.2, 41.7, 38.9, 36.9, 35.5, 31.4, 30.3, 28.5, 24.9, 22.5, 22.2, 21.6, 18.7, 12.2;

[0188] HRMS m / z calcd for C 38 H 53 N2O4[M+H] + :601.4005; found: 601.4007.

[0189] Example 29: Preparation of compound 4b

[0190] Compound 2m (100 mg, 0.165 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of DMAP (10 mg, 0.083 mmol) and acetic anhydride (61 mg, 0.595 mmol), and the mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. TLC monitoring showed that the reaction was complete. The reaction was quenched with 1 mol / L hydrochloric acid, followed by the addition of saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was extracted with dichloromethane (40 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: dichloromethane-methanol = 100:1 (V / V)) to obtain compound 4b in a yield of 81.9%.

[0191] Yield: 81.9%. mp: 117.7-113.2 °C; 1 H NMR (600 MHz, CDC13) δ 7.67 (d, J = 15.4

[0192] Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 15.4 Hz, 1H), 4.75 (ddd, J = 10.9 Hz, 10.7 Hz, 5.2 Hz, 1H), 4.65 (ddd, J = 16.5 Hz, 10.8 Hz, 4.9 Hz, 1H), 3.79 - 3.58 (m, 6H), 3.56 - 3.45 (m, 2H), 2.39 (ddd, J = 14.8 Hz, 10.9 Hz, 5.0 Hz, 1H), 2.36 (s, 3H), 2.24 (ddd, J = 14.6 Hz, 10.2 Hz, 5.7 Hz, 1H), 2.01 (s, 3H), 1.97 (s, 3H), 1.84 - 1.65 (m, 8H), 1.61 (ddd, J = 12.9 Hz, 5.2 Hz, 2.0 Hz, 1H), 1.57 - 1.49 (m, 2H), 1.48 - 1.11 (m, 11H), 1.10 - 1.01 (m, 2H), 0.96 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.67 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 172.5, 170.7, 170.7, 166.0, 143.8, 140.3, 132.3, 129.7, 127.9, 115.3, 73.6, 55.3, 55.1, 45.6, 45.5, 43.7, 42.2, 42.1, 41.7, 40.0, 40.0, 39.4, 35.6, 34.6, 34.0, 32.9, 31.4, 30.3, 28.6, 26.4, 25.7, 23.3, 21.9, 21.5, 21.5, 21.3, 18.7, 12.2;

[0193] HRMS m / z calcd for C 42 H 61 N2O6[M+H] + : 689.4530; found: 689.4526.

[0194] Example 30: Preparation of compound 4c

[0195] Compound 2m (100 mg, 0.165 mmol) was dissolved in tetrahydrofuran (4 mL), sodium cyanide (300 mg, 7.5 mmol) was added slowly at 0 °C and stirred for 15 min, then methyl iodide (200 mg, 1.41 mmol) was added, after the addition was completed, it was reacted at room temperature for 30 h. TLC monitoring reaction was complete, saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate (40 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography, eluent: dichloromethane-methanol = 50:1 (V / V), to obtain compound 4c, yield: 37.2%.

[0196] Yield: 37.2%. mp: 106.8-108.6 °C; 1H NMR (600 MHz, CD3OD) δ 7.59 (d, J = 15.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 15.4 Hz, 1H), 3.86-3.58 (m, 8H), 3.34 (s, 3H), 3.24 (s, 3H), 3.16 (ddd, J = 16.2 Hz, 10.6 Hz, 4.5 Hz, 1H), 3.08-3.01 (m, 1H), 2.49 (ddd, J = 14.7 Hz, 11.0 Hz, 5.0 Hz, 1H), 2.36 (s, 3H), 2.36-2.29 (m, 1H), 2.03 (ddd, J = 12.8 Hz, 4.0 Hz, 2.9 Hz, 1H), 1.92-1.81 (m, 3H), 1.80-1.73 (m, 3H), 1.72-1.59 (m, 2H), 1.49-1.40 (m, 7H), 1.29-1.15 (m, 6H), 1.14-1.09 (m, 1H), 1.03 (td, J = 14.3 Hz, 3.0 Hz, 1H), 1.00 (d, J = 6.5 Hz, 3H), 0.95 (s, 3H), 0.70 (s, 3H); 13C NMR (150 MHz, CD3OD) δ 174.9, 168.1, 144.8, 141.6, 133.7, 130.6, 129.2, 116.8, 81.8, 81.6, 57.4, 56.5, 55.9, 55.7, 47.0, 46.8, 46.5, 44.8, 43.5, 43.0, 42.6, 42.5, 41.5, 40.7, 37.0, 35.8, 35.4, 34.7, 33.1, 32.8, 31.2, 30.8, 29.7, 27.7, 27.5, 23.9, 22.5, 21.5, 19.1, 12.7;

[0197] HRMS m / z calcd for C40 H 61 N2O4[M+H] + :633.4631; found:633.4634.

[0198] The structures of 4a-4c are shown below:

[0199]

[0200] Example 31: Study on Anti-inflammatory Activity of Compounds on LPS-induced RAW264.7 Cells

[0201] 1. Effect on RAW264.7 Cell Viability

[0202] Logarithmic growth phase RAW264.7 cells were prepared into a single cell suspension (2 x 10 6 cells / mL), 100 μL / well was inoculated in a 96-well plate, 100 μL of compound was added to make the final concentration 20 μmol / L, and an equal volume of DMSO-containing complete medium was added as a normal control. After incubation in an incubator for 24 h, 20 μL of CCK-8 was added to each well, and the cells were incubated in the incubator for 1 h. The absorbance value of each well was measured at a wavelength of 540 nm. Cell viability (%) = (drug group-blank group) / (control group-blank group) x 100%. Data are shown in Table 1. Figure 1 .

[0203] Figure 1 In the experiment, RAW264.7 cells were inoculated in a 96-well plate and treated with the indicated concentrations of compounds for 24 h. Cell viability was determined by CCK-8 method. Data are expressed as the mean ± standard deviation of three independent experiments. *P < 0.05, **P < 0.01 compared with the control group.

[0204] The results showed that, at a concentration of 20 μmol / L, compounds 2b, 2e, 2l, 2t and 4a had obvious cytotoxicity, and other compounds had no cytotoxicity or only showed weak cytotoxicity.

[0205] 2. Effect on LPS-induced NO Content in RAW264.7 Cells

[0206] The experimental groups were set up as a normal control group (an equal volume of DMSO-containing complete medium), an LPS (10 ng / mL) model group, a drug group (20 μmol / L) administration group, and dexamethasone (DEX, 10 μmol / L) as a positive control. RAW264.7 cells were inoculated in a 96-well plate at a concentration of 2 x 10 6The cells were seeded in 96-well plates at a density of 2 x 105cells / mL, then DEX, drug groups and LPS were added. After 24 h incubation in a CO2cell incubator, 50 μL of cell culture supernatant was taken into a new 96-well plate, and 50 μL of Griess I and Griess II were added respectively. The mixture was shaken on a shaker for 10 min to allow it to react fully, and the absorbance of each well was measured at 540 nm. The specific data are shown below Figure 2 and Figure 3 .

[0207] Figure 2 In the above formula, RAW264.7 cells were treated with synthetic compound (10 μM) and LPS (10 ng / mL) for 24 h, and the DEX group (10 μM) was used as a positive control. The data are expressed as the mean ± standard deviation of three independent experiments. Compared with the normal control group, ## P < 0.01; compared with the LPS model group, *P < 0.05, **P < 0.01.

[0208] Figure 3 Compared with the normal control group, ## P < 0.01; compared with the LPS model group, *P < 0.05, **P < 0.01.

[0209] The experimental results show that at a concentration of 10 μM, most of the derivatives exhibit significant inhibitory effects (inhibition rate greater than 50%), and the inhibitory effect is stronger than that of the parent compound ursodeoxycholic acid. Among them, the IC 50 values of compounds 2a, 2h, 2k, 2m and 2u are between 7.77 and 9.19 μM.

Claims

1. A cinnamoyl ursodeoxycholic acid compound, characterized by, The compound is selected from any one of the following compounds, also including stereoisomers, pharmaceutically acceptable salts thereof:

2. The cinnamoyl ursodeoxycholic acid compound according to claim 1, characterized by, The pharmaceutically acceptable salt is a salt of the compound with any one of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid.

3. A preparation method of the cinnamoyl ursodeoxycholic acid compound according to claim 1, characterized in that, (1) Method I: a compound of formula 4 is prepared by acylation reaction of a compound of formula 3, and a compound of formula 5 is prepared by isomerization of the compound of formula 4: (2) Method II: a compound of formula 7 is prepared by acylation reaction of a compound of formula 4, or a compound of formula 8 is prepared by alkylation reaction of a compound of formula 4: wherein R1, R2, R3, R4, R5, R6, R7 and R8 are defined as substituents at corresponding positions in the structure of the compound according to claim 1; The corresponding acid is salted with the target compound of formula 4, formula 5, formula 7 or formula 8 prepared by the above method to obtain the pharmaceutically acceptable salt of the compound.

4. A pharmaceutical composition, characterized by, The cinnamoyl ursodeoxycholic acid compound according to any one of claims 1-2 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein, The preparation forms are selected from tablets, capsules, syrups, suspensions, injections.

6. Use of the cinnamoyl ursodeoxycholic acid compound according to any one of claims 1-2 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating inflammation.

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