Amphiphilic quaternary ammonium salt type magnoflorine analogues, their preparation methods and antibacterial applications

Abstract

The present invention discloses a series of novel amphiphilic quaternary ammonium salt magnoflorine analogues, their preparation methods and antibacterial applications. This series of compounds uses magnoflorine analogues as substrates, and hydrophilic quaternary ammonium salt fragments are introduced onto the phenolic hydroxyl groups through nucleophilic substitution reactions, thereby preparing a series of amphiphilic quaternary ammonium salt magnoflorine analogues, and their structural general formula is as follows. Compared with the existing magnoflorine analogues, the amphiphilic quaternary ammonium salt magnoflorine analogues prepared in the present invention have excellent antibacterial effects, especially have good antibacterial effects on Staphylococcus aureus ATCC 29213 and various methicillin-resistant Staphylococcus aureus (MRSA). At the same time, their water solubility is improved, their biological toxicity is reduced, and they have a high yield, and are expected to be further developed into semi-synthetic antibacterial drugs in clinical practice.

Description

Technical Field

[0001] The present invention belongs to the technical field of magnoflorine analogs, and particularly relates to amphiphilic quaternary ammonium salt-type magnoflorine analogs, a preparation method thereof, and an antibacterial application thereof. Background Art

[0002] Magnoflorine belongs to natural lignin compounds and is formed by the polymerization of two molecules of phenylpropanoid derivatives (i.e., C6-C3 monomers). It was first isolated from the bark of Illicium verum by Kouno I et al. in 1994. At the same time, this type of compound is also a diaryl ether-type neolignin and can be formed in nature through the C-O coupling of phenyl radicals (Kouno I, et al. A new triphenyl type neolignan and a biphenyl neolignan from the bark of Illicium simonsii. Chemical and Pharmaceutical Bulletin, 1994, 42(1): 112 - 114.). In 2002, Panda A K et al. first synthesized a suitable diaryl ether through the mutual conversion of required functional groups (Panda AK, et al. A convenient synthesis of an unsymmetrical biphenyl ether and its elaboration for the synthesis of Illicium neolignan - isomagnolone. 2002, 41B, 181 - 183.). During the exploration of the total synthesis of magnoflorine by the research group of the inventors of the present application, magnoflorine analogs, that is, isomers of magnoflorine with ortho-substituted propenyl groups, were discovered.

[0003] As a lignin compound, magnoflorine has a wide range of biological activities. As a phytoestrogen, it can scavenge free radicals in the body, play an antioxidant role, and at the same time has antifungal and immunosuppressive activities. In terms of antibacterial activity, although magnoflorine shows certain antibacterial activity, the effect is poor, and it has disadvantages such as poor water solubility and high toxicity. Summary of the Invention

[0004] Object of the Invention: Aiming at the problems of low antibacterial activity and poor water solubility of magnoflorine and its analogs, the present invention provides an amphiphilic quaternary ammonium salt-type magnoflorine analog, a preparation method thereof, and an antibacterial application thereof. The amphiphilic quaternary ammonium salt-type magnoflorine analog solves the problems of poor water solubility and high toxicity of the original compound and has good clinical application prospects.

[0005] Technical solution: To achieve the above-mentioned invention object, the technical solution adopted by the present invention is as follows:

[0006] An amphiphilic quaternary ammonium salt type magnoflorine analogue, the structure of which is shown as follows:

[0007]

[0008] wherein, n = 2, 3 or 4, and R is or azacyclic amine, wherein, R 1 and R 2 are independently selected from H or C1-C8 alkyl.

[0009] Preferably, the R 1 and R 2 are independently selected from H or C2-C6 alkyl; the azacyclic amine is selected from five-membered or six-membered azacyclic amine.

[0010] Preferably, when R is , n, R 1 and R 2 are respectively:

[0011] (1) n = 2, R 1 = H, R 2 = -CH 2 CH 3 (2) n = 2, R 1 = H, R 2 = -(CH 2 ) 2 CH 3

[0012] (3) n = 2, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (4) n = 2, R 1 = H, R 2 = -(CH 2 ) 4 CH 3

[0013] (5) n = 2, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (6) n = 2, R 1 = R 2 = -CH 2 CH 3

[0014] (7) n = 2, R1 = R 2 = -(CH 2 ) 2 CH 3 (8) n = 2, R 1 = R 2 = -(CH 2 ) 3 CH 3

[0015] (9) n = 3, R 1 = H, R 2 = -CH 2 CH 3 (10) n = 3, R 1 = H, R 2 = -(CH 2 ) 2 CH 3

[0016] (11) n = 3, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (12) n = 3, R 1 = H, R 2 = -(CH 2 ) 4 CH 3

[0017] (13) n = 3, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (14) n = 3, R 1 = R 2 = -CH 2 CH 3

[0018] (15) n = 3, R 1 = R 2 = -(CH 2 ) 2 CH 3 (16) n = 3, R 1 = R 2 = -(CH 2 ) 3 CH 3

[0019] (17) n = 4, R 1 = H, R 2 = -CH 2 CH3 (18) n = 4, R 1 = H, R 2 = -(CH 2 ) 2 CH 3

[0020] (19) n = 4, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (20) n = 4, R 1 = H, R 2 = -(CH 2 ) 4 CH 3

[0021] (21) n = 4, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (22) n = 4, R 1 = R 2 = -CH 2 CH 3

[0022] (23) n = 4, R 1 = R 2 = -(CH 2 ) 2 CH 3 (24) n = 4, R 1 = R 2 = -CH 2 CH 3 。

[0023] Preferably, when R is aza cyclic amine, n and R are respectively:

[0024] (25) n = 2, (26) n = 2,

[0025] (27) n = 3, (28) n = 3,

[0026] (29) n = 4, (30) n = 3,

[0027] The above selections represent the tabular compounds 1 - 30 in the following examples.

[0028] The preparation method of the amphiphilic quaternary ammonium salt type magnoflorine analogs includes using magnoflorine analogs as substrates, introducing bromoalkanes on their phenolic hydroxyl groups to synthesize intermediate a, and then undergoing a substitution reaction with intermediate b to generate a series of quaternary ammonium salt type magnoflorine analogs:

[0029]

[0030] Among them, R and n are as described above.

[0031] Preferably, the molar ratio of intermediate a to intermediate b is 1:2 - 1:4, the reaction temperature of the substitution reaction is 70 - 90 °C, and the reaction solvent is preferably anhydrous ethanol.

[0032] Preferably, the preparation method of intermediate a is as follows: Magnoflorine analogs and dibromoalkanes undergo a substitution reaction under alkaline conditions to generate intermediate a;

[0033]

[0034] Among them, n = 2, 3 or 4.

[0035] More preferably, the base in the alkaline conditions is K 2 CO 3 ; the molar ratio of magnoflorine analogs to the base is 1:1.5 - 1:3, the molar ratio of magnoflorine analogs to dibromoalkanes is 1:2 - 1:4, the reaction temperature is 45 - 60 °C, and the reaction solvent is acetone.

[0036] Preferably, the preparation method of intermediate b is as follows: Under alkaline conditions, various amines RH react with bromoacetyl bromide to undergo a substitution reaction to generate bromoacetamide, and then under alkaline conditions, bromoacetamide continues to react with dimethylamine to undergo a substitution reaction to generate intermediate b:

[0037]

[0038] Among them, R is as described above.

[0039] More preferably, the preparation method of intermediate b is as follows:

[0040]

[0041] Among them, R 1 and R 2 are as described above.

[0042] More preferably, the molar ratio of various amines RH with different carbon chain lengths to bromoacetyl bromide is 1:1.5 - 1:3, and the base used in the reaction is K 2 CO 3, the reaction temperature is from 0 °C to room temperature, and the reaction lasts for 2 - 8 h. The reaction solvent is anhydrous dichloromethane; the molar ratio of bromoamide to dimethylamine in the reaction is 1:1.5 - 1:3, the reaction temperature is room temperature, and the reaction solvent is acetone.

[0043] Finally, the present invention provides the application of the amphiphilic quaternary ammonium salt type magnoflorine analogues in antibacterial drugs. Preferably, it is applied in the preparation against Staphylococcus aureus ATCC 29213 and MRSA clinical strains.

[0044] The compounds of the present invention are quaternary ammonium salt type derivatives designed by simulating antibacterial peptides and targeting bacterial cell membranes. Evaluation of the antibacterial activity of all target compounds found that they have strong antibacterial activity against Staphylococcus aureus ATCC 29213 and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA), and the antibacterial value is much higher than that of their parent compound magnoflorine analogues, and is comparable to the positive control vancomycin. Toxicity evaluation found that the safety of the amphiphilic quaternary ammonium salt magnoflorine analogues is also much higher than that of their parent compounds, and they have good stability and water solubility. Therefore, these compounds have broad clinical application prospects.

[0045] Technical effect: Compared with the existing magnoflorine analogues, the amphiphilic quaternary ammonium salt magnoflorine analogues prepared in the present invention have excellent antibacterial effects, especially have good antibacterial effects against Staphylococcus aureus ATCC 29213 and various methicillin-resistant Staphylococcus aureus (MRSA). At the same time, it improves water solubility, reduces biological toxicity, and has a high yield, and is expected to be further developed into a semi-synthetic antibacterial drug in clinical practice. Description of the Drawings

[0046] Figure 1 It is the dynamic bactericidal curves of drugs 5 (III5) and 13 (III15).

[0047] Figure 2 It is the cytotoxicity of drugs 5 (III5) and 13 (III15).

[0048] Figure 3 It is the blood routine and blood biochemical indexes in vivo of drugs 5 (III5) and 13 (III15).

[0049] Figure 4 It is the change of the bacterial load in the active organs in vivo of drugs 5 (III5) and 13 (III15).

[0050] Figure 5 It is the 1H-NMR spectrum of compound 5 (HEH-102).

[0051] Figure 6 13C-NMR spectrum of compound 5 (HEH-102).

[0052] Figure 7 1H-NMR spectrum of compound 13 (HEH-104).

[0053] Figure 8 13C-NMR spectrum of compound 13 (HEH-104). Detailed implementation manners

[0054] The present invention will be further elaborated in detail through examples below.

[0055] Example 1 Preparation of intermediate a

[0056] Weigh an appropriate amount of magnoflorine analogue (1 mmol) and potassium carbonate (4.5 mmol) and place them in a 25 mL round-bottom flask. After adding 3 mL of acetone to dissolve them, add 1,2-dibromoethane / 1,3-dibromopropane / 1,4-dibromobutane (3 mmol). Heat and stir at 50 °C. Detect by thin-layer chromatography (TLC) until the reaction ends. Extract with ethyl acetate (3 × 30 mL), combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain intermediate a.

[0057] Example 2 Preparation of intermediate b

[0058] Weigh the corresponding amine (1 mmol) in a 50 mL round-bottom flask. After adding 2 mL of anhydrous dichloromethane to dissolve it, add potassium carbonate (1.5 mmol). At 0 °C, slowly drop bromoacetyl bromide (1.5 mmol) into the reaction solution, continue the reaction for half an hour, and then transfer it to room temperature for reaction. Detect by thin-layer chromatography (TLC) until the reaction ends. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain the corresponding bromoacetamide.

[0059] Weigh dimethylamine (1.5 mmol) and the corresponding bromoacetamide (1 mmol) and place them in a 25 mL round-bottom flask. Add 3 mL of acetone to dissolve them, add an appropriate amount of potassium carbonate (1.5 mmol), and react at room temperature. Detect by thin-layer chromatography (TLC) until the reaction ends. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain intermediate c.

[0060] Example 3 Compound 1

[0061] Weigh intermediate a (1 mmol) and intermediate c (3 mmol) in a 25 mL round-bottom flask. After adding 2 mL of anhydrous ethanol to dissolve them, stir and react at 78 °C. Detect by thin-layer chromatography (TLC) until the reaction ends. Separate by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain the pure target compound.

[0062] The physical and chemical properties of Compound 1 are as follows:

[0063] 1), Pale yellow liquid;

[0064] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0065] Using DMSO as the solvent, the attribution of each peak is: Yield: 31.2%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 8.55 (t, J = 5.4 Hz, 1H, -NH-), 7.90 (d, J = 9.0 Hz, -Ph), 7.26 (t, J = 7.8 Hz, 1H, -Ph), 7.14 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.99 (dd, J = 9.0, 1.2 Hz, 1H, -Ph), 6.84 (d, J = 9 Hz, 2H, -Ph), 5.79 - 5.83 (m, 1H, -CH=CH 2 ), 4.94 - 4.97 (m, 2H, -CH=CH 2 ), 4.43 - 4.45 (m, 2H, -CH 2 -), 3.95 (s, 2H, -CH 2 -), 3.80 - 3.82 (m, 2H, -CH 2 -), 3.22 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.06 - 3.08 (m, 2H, -CH 2 -), 2.94 (dd, J = 14.4, 7.2 Hz, 8H, -CH 2 -, N-CH 3 ), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 1.00 (t, J = 7.2 Hz, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.2, 162.9, 161.7, 150.3, 140.1, 136.3, 134.5, 131.1, 130.6, 126.8, 123.4, 115.0, 112.8, 63.6, 63.4, 62.6, 51.8, 39.9, 34.0, 33.9, 31.3, 14.5, 8.6. HRMS (ESI) C 26 H 35 BrN2 O 4 [M-Br] + calcd = 439.2591; found = 439.2557.

[0066] Compound 2 of Example 4

[0067] Compound 2 was synthesized by the method described in Example 3, and the physical and chemical properties of Compound 2 are as follows:

[0068] 1), yellow liquid;

[0069] 2), the nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 400 MHz) characteristics

[0070] Using DMSO as the solvent, the attribution of each peak is: Yield: 61.5%, yellow liquid, 1 H NMR (400 MHz DMSO-d6) δ: 8.55 - 8.58 (m, 1H, -NH-), 7.89 (d, J = 8.8 Hz, 2H, -Ph), 7.26 (t, J = 8.0 Hz, 1H, -Ph), 7.14 (d, J = 7.2 Hz, 1H, -Ph), 7.69 (d, J = 4.8 Hz, 1H, -Ph), 6.84 (d, J = 8.8 Hz, 2H, -Ph), 5.78 - 5.84 (m, 1H, -CH=CH 2 ), 4.94 - 4.98 (m, 2H, -CH=CH 2 ), 4.45 (s, 2H, -CH 2 -), 3.99 (s, 2H, -CH 2 -), 3.82 (s, 2H, -CH 2 -), 3.22 (d, J = 6.8 Hz, 2H, -CH 2 -), 3.00 - 3.03 (m, 4H, -CH 2 -), 2.96 (s, 6H, N-CH 3 ), 1.38 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.81 - 0.85 (m, 3H, -CH 3 ); 13 C NMR (100 MHz DMSO-d 6)δ: 198.7, 162.6, 161.2, 149.8, 139.6, 135.8, 134.0, 130.6, 130.1, 126.3, 122.9, 116.3, 114.4, 112.3, 63.1, 62.9, 62.1, 51.3, 33.4, 30.8, 21.8, 11.3, 8.1. HRMS(ESI) C 27 H 37 BrN 2 O 4 [M - Br] + calcd = 453.2748; found = 453.2702.

[0071] Compound 3 of Example 5

[0072] Compound 3 was synthesized by the method described in Example 3. The physicochemical properties of Compound 3 are as follows:

[0073] 1), Pale yellow liquid;

[0074] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0075] Using DMSO as the solvent, the attribution of each peak is: Yield: 33.0%, pale yellow liquid, 1 H NMR (600 MHz DMSO - d 6 )δ: 8.54 (t, J = 5.4 Hz, 1H, -NH-), 8.45 (d, J = 5.4 Hz, 2H, -Ph), 7.26 - 7.29 (m, 1H, -Ph), 7.13 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.99 (dd, J = 7.8, 7.2 Hz, 1H, -Ph), 6.84 (d, J = 9.0 Hz, 2H, -Ph), 5.78 - 5.83 (m, 1H, -CH=CH 2 ), 4.94 - 4.97 (m, 2H, -CH=CH 2 ), 4.42 - 4.44 (m, 2H, -CH 2 -), 3.93 (s, 2H, -CH 2 -), 3.80 (t, J = 4.2 Hz, 2H, -CH 2 -), 3.22 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.02 (dd, J = 12.6, 6.0 Hz, 2H, -CH 2 -), 2.95 (d, J = 7.2 Hz, 2H, -CH 2-), 2.95 (s, 6H, N-CH 3 ), 1.35 - 1.38 (m, 2H, -CH 2 -), 1.24 - 1.28 (m, 2H, -CH 2 -), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.84 (t, J = 7.2 Hz, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.2, 163.0, 161.7, 150.3, 140.1, 136.3, 134.5, 131.1, 130.6, 126.8, 123.4, 116.8, 114.9, 112.8, 63.6, 63.4, 62.6, 51.9, 38.7, 33.9, 31.3, 31.0, 19.9, 14.0, 8.6. HRMS (ESI) C 28 H 39 BrN 2 O 4 [M - Br] + calcd = 467.2904; found = 467.2859.

[0076] Example 6 Compound 4

[0077] Compound 4 was synthesized by the method described in Example 3. The physicochemical properties of Compound 4 are as follows:

[0078] 1), yellow liquid;

[0079] 2), the nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0080] Using DMSO as the solvent, the attribution of each peak is: Yield: 68.1%, yellow solid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 8.42 (t, J = 5.4 Hz, 1H, -NH-), 7.89 (d, J = 9.0 Hz, 2H, -Ph), 7.26 - 7.29 (m, 1H, -Ph), 7.13 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.99 (dd, J = 7.8, 7.2 Hz, 1H, -Ph), 6.84 (d, J = 8.4 Hz, 2H, -Ph), 5.78 - 5.83 (m, 1H, -CH = CH 2 ), 4.94 - 4.97 (m, 2H, -CH = CH 2), 4.42 (t, J = 4.2 Hz, 2H, -CH 2 -), 3.92 (s, 2H, -CH 2 -), 3.79 - 3.81 (m, 2H, -CH 2 -), 3.22 (d, J = 6.6 Hz, -CH 2 -), 3.02 - 3.05 (m, 2H, -CH 2 -), 2.95 (t, J = 7.2 Hz, 2H, -CH 2 -), 2.94 (s, 6H, N-CH 3 ), 1.37 (t, J = 7.2 Hz, 2H, -CH 2 -), 1.21 - 1.26 (m, 4H.–CH 2 -), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.84 - 0.86 (m, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.2, 163.0, 161.7, 150.3, 140.1, 136.3, 134.5, 131.7, 130.6, 126.8, 123.4, 116.8, 114.9, 112.8, 63.6, 63.4, 62.6, 51.9, 39.0, 33.9, 31.3, 28.9, 28.6, 22.1, 14.3, 8.6. HRMS (ESI) C 29 H 41 BrN 2 O 4 [M - Br] + calcd = 481.3061; found = 481.3013.

[0081] Example 7 Compound 5

[0082] Compound 5 was synthesized by the method described in Example 3. The physicochemical properties of Compound 5 are as follows:

[0083] 1), Pale yellow liquid;

[0084] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0085] Using DMSO as the solvent, the attribution of each peak is: Yield: 48.3%, pale yellow solid, 1 H NMR (600 MHz DMSO-d 6) δ: 8.52 (t, J = 5.4 Hz, 1H, -NH-), 7.89 (d, J = 8.4 Hz, 2H, -Ph), 7.25 (t, J = 7.8 Hz, 1H, -Ph), 7.12 - 7.14 (m, 1H, -Ph), 6.98 - 6.99 (m, 1H, -Ph), 6.83 (d, J = 9.0 Hz, 2H, -Ph), 5.77 - 5.82 (m, 1H, -CH=CH 2 ), 4.93 - 4.96 (m, 2H, -CH=CH 2 ), 4.41 - 4.43 (m, 2H, -CH 2 -), 3.93 (s, 2H, -CH 2 -), 3.79 (t, J = 4.2 Hz, 2H, -CH 2 -), 3.21 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.00 - 3.04 (m, 2H, -CH 2 -), 2.94 - 2.97 (m, 2H, -CH 2 -), 2.96 (d, J = 7.2 Hz, 2H, -CH 2 -), 2.94 (s, 6H, N-CH 3 ), 1.36 (t, J = 6.6 Hz, 2H, -CH 2 -), 1.21 (d, J = 5.4 Hz, 6H, -CH 2 -), 1.03 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.82 - 0.85 (m, 3H, -CH 3 ); 13 C NMR (150 MHz, DMSO-d 6 ) δ: 199.3, 163.0, 161.7, 150.3, 140.1, 136.2, 134.5, 131.1, 130.6, 126.8, 123.4, 116.8, 114.9, 112.8, 63.6, 63.4, 62.6, 51.9, 39.1, 33.9, 31.3, 31.2, 28.8, 26.4, 22.4, 14.3, 8.6 HRMS (ESI) C 30 H 43 BrN 2 O 4 [M - Br] + calcd = 495.3217;found = 495.3167.

[0086] Example 8 Compound 6

[0087] Compound 6 was synthesized using the method described in Example 3. The physicochemical properties of Compound 6 are as follows:

[0088] 1) Pale yellow liquid;

[0089] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) are as follows:

[0090] Using DMSO as the solvent, the attribution of each peak is: Yield: 86.0%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 7.91 (d, J = 9.0 Hz, 2H, -Ph), 7.26 (t, J = 7.8 Hz, 1H, -Ph), 7.15 - 7.16 (m, 1H, -Ph), 6.99 (d, J = 7.2 Hz, 1H, -Ph), 6.85 (d, J = 8.4 Hz, 2H, -Ph), 5.78 - 5.83 (m, 1H, -CH=CH 2 ), 4.43 (t, J = 4.2 Hz, 2H, -CH 2 -), 4.39 (s, 2H, -CH 2 -), 3.91 (d, J = 4.2 Hz, 2H, -CH 2 -), 3.20 - 3.26 (m, 6H, -CH 2 -), 3.02 (s, 6H, N-CH 3 ), 2.95 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.05 - 1.09 (m, 6H, -CH 3 ), 0.99 (t, J = 7.2 Hz, 3H, -CH 3 ); 13 C NMR (100 MHz DMSO-d 6 ) δ: 199.2, 162.8, 161.7, 150.4, 140.2, 136.3, 134.5, 131.1, 130.7, 126.8, 123.4, 116.8, 115.0, 112.9, 63.0, 62.7, 61.6, 52.0, 41.4, 33.9, 31.4, 14.1, 8.6. HRMS (ESI) C 28 H 39 BrN 2 O 4 [M - Br] + calcd = 467.2904; found = 467.2857.

[0091] Example 9 Compound 7

[0092] Compound 7 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 7 are as follows:

[0093] 1) Yellow liquid;

[0094] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 400 MHz) are as follows:

[0095] Using DMSO as the solvent, the attribution of each peak is: Yield: 47.7%, pale yellow liquid, 1 H NMR (400 MHz DMSO-d 6 ) δ: 7.91 (d, J = 8.8, 2H, -Ph), 7.25 (t, J = 8.0 Hz, 1H, -Ph), 7.15 (d, J = 7.2 Hz, 1H, -Ph), 6.98 (d, J = 7.6 Hz, 1H, -Ph), 6.84 (d, J = 8.8 Hz, 2H, -Ph), 5.77 - 5.84 (m, 1H, -CH=CH 2 ), 4.93 - 4.97 (m, 2H, -CH=CH 2 ), 4.44 - 4.47 (m, 2H, -CH=CH 2 ), 3.93 (s, 2H, -CH 2 -), 3.21 (d, J = 6.4 Hz, 2H, -CH 2 -), 3.15 - 3.19 (m, 2H, -CH 2 -), 3.09 - 3.13 (m, 2H, -CH 2 -), 3.00 (s, 6H, N-CH 3 ), 2.94 - 3.00 (m, 2H, -CH 2 -), 1.43 - 1.51 (m, 4H, -CH 2 -), 1.04 - 1.07 (m, 3H, -CH 3 ), 0.77 - 0.84 (m, 3H, -CH 3 ); 13 C NMR (100 MHz DMSO-d 6)δ: 198.7, 162.8, 161.2, 149.9, 139.7, 135.8, 134.0, 130.6, 130.1, 126.3, 122.9, 116.3, 114.5, 112.5, 62.4, 62.3, 61.1, 51.5, 48.1, 47.0, 33.4, 30.9, 21.2, 20.2, 11.0, 10.8, 8.1. HRMS(ESI) C 30 H 43 BrN 2 O 4 [M - Br] + calcd = 495.3217; found = 495.3162.

[0096] Compound 8 of Example 10

[0097] Compound 8 was synthesized by the method described in Example 3. The physicochemical properties of Compound 8 are as follows:

[0098] 1), Pale yellow liquid;

[0099] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0100] Using DMSO as the solvent, the attribution of each peak is: Yield: 28.1%, pale yellow liquid, 1 H NMR (600 MHz DMSO - d 6 )δ: 7.92 (d, J = 9.0 Hz, 1H, -NH-), 7.27 (t, J = 7.8 Hz, 2H, -Ph), 7.15 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.99 - 7.01 (m, 1H, -Ph), 6.85 (d, J = 8.4 Hz, 2H, -Ph), 5.79 - 5.83 (m, 1H, -CH = CH 2 ), 4.95 - 4.98 (m, 2H, -CH = CH 2 ), 4.42 - 4.44 (m, 2H, -CH 2 -), 4.37 (s, 2H, -CH 2 -), 3.89 - 3.91 (m, 2H, -CH 2 -), 3.27 (t, J = 7.8 Hz, 2H, -CH 2 -), 3.19 - 3.21 (m, 4H, -CH 2 -), 3.11 (t, J = 7.8 Hz, 2H, -CH 2 -), 3.02 (s, 6H, N - CH3 ), 2.96 (dd, J=14.4, 7.2 Hz, 2H, -CH 2 -), 1.41 - 1.45 (m, 4H, -CH 2 -), 1.22 - 1.24 (m, 4H, -CH 2 -), 1.05 (t, J=7.2 Hz, 3H, -CH 3 ), 0.86 - 0.88 (m, 6H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 198.1, 162.0, 160.6, 149.3, 139.2, 135.2, 133.4, 130.1, 129.6, 125.7, 122.3, 115.8, 113.9, 111.9, 61.9, 61.7, 60.4, 51.0, 44.3, 32.8, 30.3, 29.4, 28.4, 18.9, 13.0, 7.5. HRMS (ESI) C 32 H 47 BrN 2 O 4 [M - Br] + calcd=523.3530;found=523.3474.

[0101] Example 11 Compound 9

[0102] Compound 9 was synthesized by the method described in Example 3. The physicochemical properties of Compound 9 are as follows:

[0103] 1), Pale yellow liquid;

[0104] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0105] Using DMSO as the solvent, the attribution of each peak is: Yield: 62.9%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 8.66 (s, 1H, -NH-), 7.94 (d, J=8.4 Hz, 2H, -Ph), 7.22 (t, J=7.8 Hz, 1H, -Ph), 7.08 (dd, J=7.8, 1.2 Hz, 1H, -Ph), 6.95 (dd, J=7.8, 1.2 Hz, 1H, -Ph), 6.86 (d, J=9.0 Hz, 2H, -Ph), 5.80 - 5.85 (m, 1H, -CH=CH 2), 4.95 - 4.98 (m, 2H, -CH=CH 2 ), 3.98 - 4.00 (m, 2H, -CH 2 -), 3.93 (s, 2H, -CH 2 -), 3.25 (d, J=6.6Hz, 2H, -CH 2 -), 3.18 (t, J=8.4Hz, 2H, -CH 2 -), 3.09 (dd, J=7.2, 5.4Hz, 2H, -CH 2 -), 3.01 (s, 6H, N-CH 3 ), 2.97 (d, J=7.2Hz, -CH 2 -), 1.95 (d, J=4.8Hz, -CH 2 -), 1.05 (t, J=7.2Hz, 3H, -CH 3 ), 1.01 (t, J=7.2Hz, 3H, -CH 3 ); 13 C NMR (150MHz DMSO-d 6 ) δ: 199.3, 162.9, 162.0, 150.9, 140.5, 136.4, 134.3, 131.1, 130.7, 126.7, 123.0, 116.7, 115.1, 113.0, 65.8, 62.5, 62.1, 51.6, 45.9, 39.9, 34.0, 31.3, 22.6, 14.6, 8.6. HRMS (ESI) C 27 H 37 BrN 2 O 4 [M - Br] + calcd=453.2748;found=453.2693.

[0106] Example 12 Compound 10

[0107] Compound 10 was synthesized by the method described in Example 3. The physicochemical properties of Compound 10 are as follows:

[0108] 1), Brown liquid;

[0109] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600MHz) characteristics:

[0110] Using DMSO as the solvent, the attribution of each peak is: Yield: 45.8%, brown liquid, 1 H NMR (600MHz DMSO-d 6)δ: 8.87 (t, J = 5.4 Hz, 1H, -NH-), 7.93 (d, J = 9.0 Hz, 2H, -Ph), 7.21 - 7.24 (m, 1H, -Ph), 7.07 (dd, J = 8.4, 1.2 Hz, 1H, -Ph), 6.94 (dd, J = 7.8, 1.2 Hz, 1H, -Ph), 6.86 (d, J = 9.0 Hz, 2H, -Ph), 5.80 - 5.84 (m, 1H, -CH=CH 2 ), 4.95 - 4.97 (m, 2H, -CH=CH 2 ), 3.97 - 3.99 (m, 4H, -CH 2 -), 3.24 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.15 - 3.18 (m, 2H, -CH 2 -), 3.00 (s, 6H, N-CH 3 ), 2.95 (t, J = 7.2 Hz, 2H, -CH 2 -), 1.94 - 1.97 (m, 2H, -CH2-), 1.39 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.82 - 0.85 (m, 3H, -CH 3 ); 13 C NMR (150 MHz, DMSO-d 6 ) δ: 199.3, 163.1, 162.0, 150.8, 140.5, 136.4, 134.2, 131.1, 130.7, 126.7, 123.0, 116.7, 115.1, 113.0, 65.8, 62.5, 62.2, 51.6, 34.0, 31.3, 22.7, 22.3, 11.8, 8.6. HRMS (ESI) C 28 H 39 BrN 2 O 4 [M - Br] + calcd = 467.2904;found = 467.2848.

[0111] Example 13 Compound 11

[0112] Compound 11 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 11 are as follows:

[0113] 1), white solid;

[0114] 2), the nuclear magnetic resonance spectrum of this compound (1 Characteristic of \(^1H\) NMR (400 MHz):

[0115] Using DMSO as the solvent, the assignments of each peak are as follows: Yield: 72.4%, white solid, 1 \(^1H\) NMR (400 MHz, DMSO-\(d_6\)) 6 ) \(\delta\): 8.59 (t, \(J = 5.2\) Hz, 1H, -NH-), 7.93 (d, \(J = 8.8\) Hz, 2H, -Ph), 7.21 (t, \(J = 8.0\) Hz, 1H, -Ph), 7.07 (d, \(J = 7.2\) Hz, 1H, -Ph), 6.94 (d, \(J = 7.6\) Hz, 1H, -Ph), 6.85 (d, \(J = 8.8\) Hz, 2H, -Ph), 5.79 - 5.85 (m, 1H, -CH=CH 2 ), 4.94 - 4.98 (m, 2H, -CH=CH 2 ), 3.95 - 4.00 (m, 2H, -CH 2 -), 3.24 (d, \(J = 6.4\) Hz, 2H, -CH 2 -), 3.17 - 3.20 (m, 2H, -CH 2 -), 3.06 - 3.09 (m, 2H, -CH 2 -), 3.01 (s, 6H, N-CH 3 ), 2.95 (t, \(J = 7.2\) Hz, 2H, -CH 2 -), 1.35 - 1.42 (m, 2H, -CH 2 -), 1.24 - 1.29 (m, 2H, -CH 2 -), 1.04 (t, \(J = 7.2\) Hz, 3H, -CH 3 ), 0.83 - 0.87 (m, 3H, -CH 3 ); 13 \(^{13}C\) NMR (100 MHz, DMSO-\(d_6\)) 6 ) \(\delta\): 198.8, 162.5, 161.5, 150.3, 140.1, 135.9, 133.7, 130.6, 130.2, 126.2, 122.5, 116.2, 114.6, 112.5, 65.3, 62.0, 61.7, 51.2, 38.2, 33.5, 30.8, 30.5, 22.2, 19.4, 13.5, 8.1. HRMS (ESI) \(C\) 29 \(_nH\) 41 \(_mBrN\) 2 \(_pO\) 4 [M - Br] + calcd = 481.3061; found = 481.3004.

[0116] Example 14 Compound 12

[0117] Compound 12 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 12 are as follows:

[0118] 1) Yellow liquid;

[0119] 2) The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 400 MHz) characteristics:

[0120] Using DMSO as the solvent, the attribution of each peak is: Yield: 55.5%, yellow liquid, 1 H NMR (400 MHz DMSO-d 6 ) δ: 8.61 (d, J = 5.2 Hz, 1H, -NH-), 7.93 (d, J = 8.8 Hz, 2H, -Ph), 7.21 (t, J = 8.0 Hz, 1H, -Ph), 7.07 - 7.09 (m, 1H, -Ph), 6.94 - 6.99 (m, 1H, -Ph), 6.85 (d, J = 9.2 Hz, 2H, -Ph), 5.79 - 5.85 (m, 1H, -CH=CH 2 ), 4.94 - 4.98 (m, 2H, -CH=CH 2 ), 3.95 - 4.00 (m, 4H, -CH 2 -), 3.24 (d, J = 6.8 Hz, 2H, -CH 2 -), 3.12 (s, 2H, -CH 2 -), 3.05 (d, J = 6.0 Hz, 2H, -CH 2 -), 3.00 (s, 6H, N-CH 3 ), 2.95 - 2.98 (m, 2H, -CH 2 -), 1.93 - 1.97 (m, 2H, -CH 2 -), 1.38 (t, J = 6.8 Hz, 2H, -CH 2 -), 1.03 - 1.06 (m, 4H, -CH 2 -), 0.82 - 0.86 (m, 3H, -CH 3 ); 13 C NMR (100 MHz DMSO-d 6)δ: 198.8, 169.2, 162.5, 150.3, 148.0, 140.8, 135.9, 133.8, 130.2, 126.2, 122.5, 116.2, 114.6, 112.5, 65.2, 62.7, 61.9, 51.2, 38.0, 30.8, 28.4, 28.1, 22.1, 21.6, 13.8, 8.1. HRMS(ESI) C 30 H 43 BrN 2 O 4 [M - Br] + calcd = 495.3217; found = 495.3158.

[0121] Example 15 Compound 13

[0122] Compound 13 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 13 are as follows:

[0123] 1). Brown liquid.

[0124] 3). The NMR spectrum of this compound ( 1 H NMR, 400 MHz) characteristics:

[0125] Using DMSO as the solvent, the assignment of each peak: Yield: 45.6%, brown liquid, 1 H NMR (400 MHz DMSO - d 6 )δ: 8.73 - 8.76 (m, 1H, -NH-), 7.93 (d, J = 8.8 Hz, 2H, -Ph), 7.20 (t, J = 8.0 Hz, 1H, -Ph), 7.07 - 7.09 (m, 1H, -Ph), 6.94 (d, J = 7.6 Hz, 1H, -Ph), 6.85 (d, J = 9.2 Hz, 2H, -Ph), 5.78 - 5.85 (m, 1H, -CH=CH 2 ), 4.94 - 4.98 (m, 2H, -CH=CH 2 ), 3.98 (s, 4H, -CH 2 -), 3.24 (d, J = 6.4 Hz, 2H, -CH 2 -), 3.15 - 3.19 (m, 2H, -CH 2 -), 3.05 - 3.08 (m, 2H, -CH 2 -), 3.01 (s, 6H, N - CH 3 ), 2.95 (d, J = 6.8 Hz, 2H, -CH 2 -), 1.93 - 1.97 (m, 2H, -CH2 -), 1.37 (d, J = 6.8 Hz, 2H, -CH 2 -), 1.22 (s, 6H, -CH 2 -), 1.03 - 1.07 (m, 3H, -CH 3 ), 0.81 - 0.84 (m, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 198.7, 169.2, 162.5, 161.5, 150.3, 140.1, 135.9, 133.7, 130.6, 130.1, 126.2, 122.5, 116.2, 114.6, 112.5, 65.3, 62.8, 61.9, 61.7, 51.2, 45.4, 40.1, 38.0, 33.5, 30.9, 30.8, 29.1, 28.4, 25.9, 21.9, 13.8, 8.1. HRMS (ESI) C 31 H 45 BrN 2 O 4 [M - Br]+ calcd = 509.3374; found = 509.3314.

[0126] Example 16 Compound 14

[0127] Compound 14 was synthesized by the method described in Example 3. The physicochemical properties of Compound 14 are as follows:

[0128] 1), Pale yellow liquid;

[0129] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0130] Using DMSO as the solvent, the attribution of each peak: Yield: 57.3%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 7.94 (d, J = 9.0 Hz, 2H, -Ph), 7.22 - 7.25 (m, 1H, -Ph), 7.07 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.96 - 6.97 (m, 1H, -Ph), 6.87 (d, J = 9.0 Hz, 2H, -Ph), 5.80 - 5.85 (m, 1H, -CH=CH 2 ), 4.95 - 4.98 (m, 2H, -CH=CH 2 ), 4.31 (s, 2H, -CH 2-), 3.98 - 4.00 (m, 2H, -CH 2 -), 3.32 - 3.35 (m, 2H, -CH 2 -), 3.24 - 3.27 (m, 4H, -CH 2 -), 3.06 (s, 6H, N-CH 3 ), 2.96 (dd, J=14.4, 7.2 Hz, 2H, -CH 2 -), 1.90 (d, J=4.8 Hz, -CH 2 -), 1.09 - 1.11 (m, 3H, -CH 3 ), 1.05 (t, J=7.2 Hz, 3H, -CH 3 ), 1.00 (t, J=7.2 Hz, 3H, -CH 3) ; 13 C NMR (150 MHz DMSO-d 6 ) δ: 198.8, 162.2, 161.5, 150.4, 140.0, 135.9, 133.8, 130.6, 130.1, 126.2, 122.5, 116.2, 114.6, 112.5, 65.3, 61.5, 59.5, 49.9, 39.4, 33.5, 30.8, 22.2, 12.6, 8.1. HRMS (ESI) C 29 H 41 BrN 2 O 4 [M - Br] + calcd=481.3061; found=481.3005.

[0131] Example 17 Compound 15

[0132] Compound 15 was synthesized by the method described in Example 3. The physicochemical properties of Compound 15 are as follows:

[0133] 1), Pale yellow liquid;

[0134] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 400 MHz) characteristics:

[0135] Using DMSO as the solvent, the attribution of each peak: Yield: 44.5%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6) δ 7.94 (d, J = 9.0 Hz, 2H, -Ph), 7.22 - 7.24 (m, 1H, -Ph), 7.07 - 7.08 (m, 1H, -Ph), 6.95 (d, J = 6.6 Hz, 1H, -Ph), 6.86 (d, J = 9.0 Hz, 2H, -Ph), 5.80 - 5.85 (m, 1H, -CH=CH 2 ), 4.95 - 4.98 (m, 2H, -CH=CH 2 ), 4.35 (s, 2H, -CH 2 -), 3.97 - 3.99 (m, 2H, -CH 2 -), 3.23 - 3.26 (m, 4H, -CH 2 -), 3.18 - 3.19 (m, 2H, -CH 2 -), 3.12 - 3.15 (m, 2H, -CH 2 -), 3.06 (s, 6H, N-CH 3 ), 2.96 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.88 - 1.91 (m, 2H, -CH 2 -), 1.44 - 1.52 (m, 4H, -CH 2 -), 1.05 - 1.07 (m, 3H, -CH 3 ), 0.83 - 0.86 (m, 3H, -CH 3 ); 13 C NMR (150 MHz, DMSO-d 6 ) δ: 199.2, 163.3, 162.0, 150.9, 140.6, 134.3, 131.1, 130.6, 126.7, 123.0, 116.7, 115.1, 113.0, 65.8, 61.8, 59.9, 52.0, 48.7, 48.5, 34.0, 31.3, 21.7, 20.8, 20.7, 11.8, 8.6. HRMS (ESI) C 31 H 45 BrN 2 O 4 [M - Br] + calcd = 509.3374;found = 509.3311.

[0136] Example 18 Compound 16

[0137] Compound 16 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 16 are as follows:

[0138] 1), Brown liquid;

[0139] 2), the nuclear magnetic resonance spectrum of the compound ( 1 H NMR, 600 MHz) characteristics:

[0140] Using DMSO as the solvent, the attribution of each peak: Yield: 37.0%, green liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ 9.32 (d, J = 9.9 Hz, 2H, -Ph), 7.21 - 7.23 (m, 1H, -Ph), 7.06 - 7.07 (m, 1H, -Ph), 6.94 - 6.95 (m, 1H, -Ph), 6.85 (d, J = 9.0 HZ, 2H, -Ph), 5.79 - 5.83 (m, 1H, -CH=CH 2 ), 4.94 - 4.97 (m, 2H, -CH=CH 2 ), 4.32 (s, 1H, -CH 2 -), 3.97 - 3.98 (m, 2H, -CH 2 -), 3.34 (d, J = 3.0 Hz, 2H, -CH 2 -), 3.21 - 3.23 (m, 4H, -CH 2 -), 3.15 - 3.16 (m, 2H, -CH 2 -), 2.98 (s, 6H, N-CH 3 ), 2.95 (t, J = 72 Hz, 2H, -CH 2 -), 1.87 - 1.89 (m, 2H, -CH 2 -), 1.45 - 1.47 (m, 2H, -CH 2 -), 1.39 - 1.42 (m, 2H, -CH 2 -), 1.22 - 1.24 (m, 2H, -CH 2 -), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.85 - 0.89 (m, 6H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.3, 163.1, 162.0, 150.9, 140.5, 136.4, 134.3, 131.0, 130.6, 126.7, 123.0, 116.7, 115.1, 113.0, 65.8, 61.8, 59.9, 52.0, 46.8, 45.5, 34.0, 31.3, 30.5, 29.5, 22.7, 20.0, 14.1, 8.6. HRMS (ESI) C33 H 49 BrN 2 O 4 [M - Br] + calcd = 537.3687; found = 537.3623.

[0141] Example 19 Compound 17

[0142] Compound 17 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 17 are as follows:

[0143] 1), Orange liquid;

[0144] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0145] Using DMSO as the solvent, the attribution of each peak: Yield: 37.8%, orange solid, 1 H NMR (600 MHz DMSO - d 6 ) δ: 8.86 (t, J = 5.2 Hz, 1H, -NH-), 7.93 (d, J = 9.0 Hz, 2H, -Ph), 7.21 - 7.24 (m, 2H, -Ph), 7.06 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.92 (dd, J = 7.8, 6.6 Hz, 1H, -Ph), 6.86 (d, J = 9.0 Hz, 2H, -Ph), 5.79 - 5.84 (m, 1H, -CH=CH 2 ), 4.95 - 4.97 (m, 2H, -CH=CH 2 ), 3.94 - 3.97 (m, 2H, -CH 2 -), 3.41 - 3.43 (m, 2H, -CH2-), 3.23 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.09 (s, 2H, -CH 2 -), 3.01 (s, 6H, N - CH 3 ), 2.96 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.48 - 1.52 (m, 4H, -CH 2 -), 1.06 - 1.07 (m, 3H, -CH 3 ), 1.02 - 1.05 (m, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO - d 6)δ: 199.2, 163.0, 162.0, 151.3, 140.5, 136.4, 134.2, 130.6, 126.7, 122.6, 116.7, 116.2, 115.0, 112.8, 67.7, 64.5, 62.4, 51.2, 45.9, 34.0, 34.0, 25.9, 19.1, 14.6, 8.6. HRMS(ESI) C 28 H 39 BrN 2 O 4 [M - Br] + calcd = 467.2904; found = 467.2849.

[0146] Example 20 Compound 18

[0147] Compound 18 was synthesized by the method described in Example 3. The physicochemical properties of Compound 18 are as follows:

[0148] 1), Pale yellow liquid;

[0149] 2), The NMR spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0150] Using DMSO as the solvent, the attribution of each peak: Yield: 41.6%, pale yellow liquid, 1 H NMR (600 MHz DMSO - d 6 )δ: 8.65 (t, J = 5.4 Hz, 1H, -NH-), 7.92 (d, J = 9.0 Hz, 2H, -Ph), 7.20 - 7.23 (m, 1H, -Ph), 7.05 (dd, J = 8.4, 1.2 Hz, 1H, -Ph), 6.91 (dd, J = 7.8, 0.6 Hz, 1H, -Ph), 6.85 (d, J = 9.0 Hz, 2H, -Ph), 5.78 - 5.83 (m, 1H, -CH = CH 2 ), 4.94 - 4.96 (m, 2H, -CH = CH 2 ), 3.93 - 3.96 (m, 4H, -CH 2 -), 3.33 - 3.36 (m, 2H, -CH 2 -), 3.22 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.03 - 3.06 (m, 2H, -CH 2 -), 3.00 (s, 6H, N - CH 3 ), 2.94 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2-), 1.47 - 1.49 (m, 4H, -CH 2 -), 1.40 - 1.44 (m, 2H, -CH 2 -), 1.04 (t, J=7.2 Hz, 3H, -CH 3 ), 0.82 (t, J=7.2 Hz, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO - d 6 ) δ: 198.8, 162.7, 161.5, 150.8, 140.0, 135.9, 133.7, 130.4, 130.1, 126.2, 122.1, 116.2, 114.5, 112.3, 67.2, 64.0, 61.9, 50.7, 40.3, 39.4, 33.5, 30.8, 25.4, 21.8, 18.6, 11.3, 8.1. HRMS (ESI) C2 9 H 41 BrN 2 O 4 [M - Br] + calcd=481.3061; found=481.3002.

[0151] Example 21 Compound 19

[0152] Compound 19 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 19 are as follows:

[0153] 1), Pale yellow liquid;

[0154] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0155] Using DMSO as the solvent, the attribution of each peak: Yield: 15.4%, pale yellow liquid, 1 H NMR (600 MHz DMSO - d 6 ) δ: 8.68 - 8.69 (m, 1H, -NH-), 7.93 (d, J=9.0 Hz, 2H, -Ph), 7.21 - 7.24 (m, 1H, -Ph), 7.06 (dd, J=7.2, 8.4 Hz, 1H, -Ph), 6.93 (dd, J=7.8, 1.2 Hz, 1H, -Ph), 6.85 (d, J=9.0 Hz, 2H, -Ph), 5.79 - 5.84 (m, 1H, -CH=CH 2 ), 4.95 - 4.97 (m, 2H, -CH=CH 2), 3.95 (s, 4H, -CH 2 -), 3.23 (d, J=6.6 Hz, 2H, -CH 2 -), 3.05 - 3.09 (m, 4H, -CH 2 -), 3.00 (s, 6H, N-CH 3 ), 2.95 (t, J=7.2 Hz, 2H, -CH 2 -), 1.48 - 1.50 (m, 4H, -CH 2 -), 1.39 - 1.41 (m, 2H, -CH 2 -), 1.26 - 1.29 (m, 2H, -CH 2 -), 1.18 - 1.20 (m, 2H, -CH 2 -), 1.05 (t, J=7.2 Hz, 3H, -CH 3 ), 0.85 - 0.78 (m, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.2, 163.2, 151.3, 140.5, 136.4, 134.2, 130.6, 126.7, 122.6, 116.7, 115.0, 112.7, 67.7, 64.5, 62.4, 51.2, 38.7, 34.0, 31.3, 31.1, 25.9, 19.9, 19.1, 14.0, 8.6. HRMS (ESI) C 30 H 40 BrN 2 O 4 [M - Br] + calcd=495.3217;found=495.3155.

[0156] Example 22 Compound 20

[0157] Compound 20 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 20 are as follows:

[0158] 1), Pale yellow liquid;

[0159] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0160] Using DMSO as the solvent, the attribution of each peak: Yield: 28.9%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6) δ: 8.57 - 8.59 (m, 1H, -NH-), 7.92 (d, J = 9.0 Hz, 1H, 2H, -Ph), 7.21 (t, J = 7.8 Hz, 1H, -Ph), 7.05 (dd, J = 8.4, 1.2 Hz, 1H, -Ph), 6.92 (d, J = 7.8 Hz, 1H, -Ph), 6.84 (d, J = 9.0 Hz, 2H, -Ph), 5.78 - 5.83 (m, 1H, -CH=CH 2 ), 4.94 - 4.96 (m, 2H, -CH=CH 2 ), 3.91 - 3.95 (m, 2H, -CH 2 -), 3.31 - 3.34 (m, 2H, -CH 2 -), 3.22 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.07 (dd, J = 5.4 Hz, 2H, -CH 2 -), 2.99 (s, 6H, N-CH 3 ), 2.94 (t, J = 7.2 Hz, 2H, -CH 2 -), 1.47 (d, J = 6.0 Hz, 4H, -CH 2 -), 1.37 - 1.41 (m, 2H, -CH 2 -), 1.23 - 1.25 (m, 4H, -CH 2 -), 1.04 (t, J = 7.2 Hz, 3H, -CH 3 ), 0.83 - 0.85 (m, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.3, 163.1, 162.0, 151.3, 140.4, 136.4, 134.2, 126.7, 122.6, 116.7, 115.0, 112.7, 67.7, 64.4, 62.4, 51.2, 39.0, 34.0, 31.3, 28.9, 26.4, 25.9, 22.4, 19.1, 14.3, 8.6. HRMS (ESI) C 31 H 45 BrN 2 O 4 [M - Br] + calcd = 509.3374;found = 509.3338.

[0161] Example 23 Compound 21

[0162] Compound 21 was synthesized by the method described in Example 3. The physicochemical properties of Compound 21 are as follows:

[0163] 1), white solid;

[0164] 3), the nuclear magnetic resonance spectrum of the compound ( 1 H NMR, 600 MHz) characteristics:

[0165] Using DMSO as the solvent, the assignment of each peak: Yield: 68.9%, white solid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 8.7 (t, J = 5.4 Hz, 1H, -NH-), 7.92 (d, J = 8.4 Hz, 2H, -Ph), 7.05 - 7.07 (m, 1H, -Ph), 6.91 (dd, J = 7.8, 0.6 Hz, 1H, -Ph), 6.84 (d, J = 9.0 Hz, 2H, -Ph), 5.78 - 5.82 (m, 1H, -CH=CH 2 ), 4.93 - 4.96 (m, 2H, -CH=CH 2 ), 3.98 (s, 2H, -CH 2 -), 3.93 - 3.95 (m, 2H, -CH 2 -), 3.40 - 3.67 (m, 2H, -CH 2 -), 3.22 (d, J = 6.6 Hz, 2H, -CH 2 -), 3.05 - 3.07 (m, 2H, -CH 2 -), 3.01 (s, 6H, N-CH 3 ), 2.94 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.47 - 1.52 (m, 4H, -CH 2 -), 1.39 - 1.42 (m, 2H, -CH 2 -), 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.3, 163.2, 162.0, 151.3, 140.4, 136.4, 134.1, 130.9, 130.6, 126.7, 122.6, 116.7, 115.0, 112.8, 67.7, 64.4, 62.4, 51.2, 45.9, 39.0, 34.0, 31.3, 28.9, 28.6, 25.9, 22.1, 19.1, 14.3, 8.9, 8.6. HRMS (ESI) C 32 H 47 BrN 2 O 4 [M - Br]+ calcd = 523.3530; found = 523.3497.

[0166] Example 24 Compound 22

[0167] Compound 22 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 22 are as follows:

[0168] 1), Pale yellow liquid;

[0169] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0170] Using DMSO as the solvent, the attribution of each peak: Yield: 28.1%, pale green liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 7.92 (d, J = 8.8 Hz, 2H, -Ph), 7.20 - 7.24 (m, 1H, -Ph), 7.05 - 7.07 (m, 1H, -Ph), 6.91 (d, J = 7.6 Hz, 1H, -Ph), 6.84 (d, J = 8.8 Hz, 2H, -Ph), 5.77 - 5.84 (m, 1H, -CH=CH 2 ), 4.93 - 4.97 (m, 2H, -CH=CH 2 ), 4.37 (s, 2H, -CH 2 -), 3.93 - 3.96 (m, 2H, -CH 2 -), 3.45 - 3.49 (m, 2H, -CH 2 -), 3.24 - 3.28 (m, 6H, -CH 2 -), 3.06 (s, 6H, N-CH 3 ), 2.94 (t, J = 10.8 Hz, 2H, -CH 2 -), 1.47 (s, 4H, -CH 2 -), 1.10 - 1.13 (m, 3H, -CH 3 ), 1.02 - 1.06 (m, 3H, -CH 3 ); 1313C NMR (150 MHz, DMSO-d6) δ: 198.8, 162.4, 161.5, 150.8, 140.0, 135.9, 133.6, 130.4, 130.1, 126.2, 122.1, 116.2, 114.5, 112.3, 67.2, 63.5, 60.0, 50.7, 40.9, 33.5, 30.8, 25.5, 18.6, 13.7, 12.6, 8.1. HRMS (ESI) C 30 H4 3 BrN 2 O 4 [M - Br] + calcd = 495.3217; found = 495.3154.

[0171] Example 25 Compound 23

[0172] Compound 23 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 23 are as follows:

[0173] 1), Brown liquid;

[0174] 2), The nuclear magnetic resonance spectrum of this compound ( 1 1H NMR, 600 MHz) characteristics:

[0175] Using DMSO as the solvent, the attribution of each peak: Yield: 71.3%, brown liquid, 1 1H NMR (600 MHz, DMSO-d 6 ) δ: 7.92 (d, J = 9.0 Hz, 2H, -Ph), 7.21 - 7.24 (m, 1H, -Ph), 7.06 - 7.07 (m, 1H, -Ph), 6.93 - 6.94 (m, 1H, -Ph), 6.85 (d, J = 9.0 Hz, 2H, -Ph), 5.79 - 5.84 (m, 1H, -CH=CH 2 ), 4.95 - 4.98 (m, 2H, -CH=CH 2 ), 4.32 (s, 2H, -CH 2 -), 3.94 (s, 2H, -CH 2 -), 3.44 - 3.47 (m, 2H, -CH 2 -), 3.23 (d, J = 5.4 Hz, 4H, -CH 2 -), 3.14 (t, J = 7.8 Hz, 2H, -CH 2 -), 2.99 (s, 6H, N-CH 3 ), 2.96 (t, J = 7.2 Hz, 2H, -CH 2-), 1.45 - 1.53 (m, 8H, -CH 2 -), 1.05 (t, J=7.2 Hz, 3H, -CH 3 ), 0.85 - 0.87 (m, 6H, -CH 3 ); 13 C NMR (150 MHz DMSO - d 6 ) δ: 199.2, 163.4, 162.1, 151.3, 140.5, 136.4, 134.2, 131.0, 130.6, 126.7, 122.6, 116.7, 115.0, 112.8, 67.6, 63.9, 60.4, 51.4, 48.6, 47.5, 34.0, 31.3, 26.0, 21.7, 20.7, 19.1, 11.5, 11.4, 8.6. HRMS (ESI) C 32 H 47 BrN 2 O 4 [M - Br] + calcd=523.3530; found=523.3462.

[0176] Example 26 Compound 24

[0177] Compound 24 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 24 are as follows:

[0178] 1), Pale yellow liquid;

[0179] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0180] Using DMSO as the solvent, the assignment of each peak: Yield: 68.2%, pale yellow liquid, 1 H NMR (600 MHz DMSO - d 6 ) δ: 7.93 (d, J=9.0 Hz, 2H, -Ph), 7.21 - 7.24 (m, 1H, -Ph), 7.06 (dd, J=8.4, 1.2 Hz, 1H, -Ph), 6.92 (dd, J=7.8, 1.2 Hz, 1H, -Ph), 6.85 (d, J=9.0 Hz, 2H, -Ph), 5.79 - 5.84 (m, 1H, -CH=CH 2 ), 4.95 - 4.98 (m, 2H, -CH=CH 2 ), 4.36 (s, 2H, -CH 2 -), 3.94 - 3.96 (m, 2H, -CH 2-), 3.46 - 3.49 (m, 2H, -CH 2 -), 3.24 (d, J = 1.8 Hz, 4H, -CH 2 -), 3.18 - 3.20 (m, 2H, -CH 2 -), 3.07 (s, 6H, N-CH 3 ), 2.96 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.43 - 1.51 (m, 8H, -CH 2 -), 1.21 - 1.30 (m, 7H, -CH 2 -, -CH 3 ), 0.90 - 0.92 (m, 3H, -CH 3 ), 0.85 - 0.88 (m, 3H, -CH 3 ); 13 C NMR (150 MHz DMSO-d 6 ) δ: 199.3, 163.3, 162.1, 151.3, 140.5, 136.4, 134.1, 130.9, 130.6, 126.7, 122.6, 116.7, 115.0, 112.8, 67.7, 63.9, 60.4, 51.3, 45.6, 44.8, 39.9, 34.0, 31.3, 30.6, 29.5, 26.0, 19.9, 14.1, 8.6. HRMS (ESI) C 34 H 51 BrN 2 O 4 [M - Br] + calcd = 551.3843; found = 551.3773.

[0181] Example 27 Compound 25

[0182] Compound 25 was synthesized by the method described in Example 3. The physicochemical properties of Compound 25 are as follows:

[0183] 1), Orange liquid;

[0184] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0185] Using DMSO as the solvent, the attribution of each peak is: Yield: 35.8%, orange liquid, 1 H NMR (600 MHz DMSO-d 6) δ: 7.98 (d, J = 8.4 Hz, 2H, -Ph), 7.14 (t, J = 7.8 Hz, 1H, -Ph), 7.12 (d, J = 6.0 Hz, 1H, -Ph), 7.03 - 7.04 (m, 1H, -Ph), 6.98 (d, 2H, -Ph), 5.97 - 6.01 (m, 1H, -CH=CH 2 ), 5.07 - 5.10 (m, 2H, -CH=CH 2 ), 4.49 (s, 2H, -CH 2 -), 3.92 - 3.94 (m, 2H, -CH 2 -), 3.57 - 3.59 (m, 8H, -CH 2 -), 3.56 (s, 4H, -CH 2 -), 3.17 (s, 6H, N-CH 3 ), 2.97 - 3.00 (m, 2H, -CH 2 -), 1.06 (t, J = 7.2 Hz, 3H, -CH 3 ); 13 C NMR (150 MHz, DMSO-d 6 ) δ: 199.2, 168.3, 162.5, 161.7, 150.4, 140.2, 136.3, 134.5, 130.7, 126.8, 123.4, 116.8, 115.0, 112.9, 66.8, 62.1, 52.2, 46.1, 45.5, 42.0, 33.9, 31.3, 8.6. HRMS (ESI) C 28 H 37 BrN 2 O 5 [M - Br] + calcd = 481.2697;found = 481.2662.

[0186] Example 28 Compound 26

[0187] Compound 26 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 26 are as follows:

[0188] 1), Pale yellow liquid;

[0189] 2), The NMR spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0190] Using DMSO as the solvent, the attribution of each peak is: Yield: 41.3%, pale yellow liquid, 11H NMR (600 MHz, DMSO-d6) δ: 7.93 (d, J = 9.0 Hz, 2H, -Ph), 7.26 (t, J = 7.8 Hz, 1H, -Ph), 7.14 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.99 (dd, J = 7.8, 7.2 Hz, 1H, -Ph), 6.85 (d, J = 9.0 Hz, 2H, -Ph), 5.75 - 5.83 (m, 1H, -CH=CH 2 ), 4.94 - 4.97 (m, 2H, -CH=CH 2 ), 4.41 (t, J = 4.2 Hz, 2H, -CH 2 -), 4.26 (s, 2H, -CH 2 -), 3.93 (t, J = 4.2 Hz, 2H, -CH 2 -), 3.52 (dd, J = 12.0, 6.0 Hz, 2H, -CH 2 -), 3.45 - 3.48 (m, 2H, -CH 2 -), 3.33 (s, 6H, N-CH 3 ), 3.22 (d, J = 7.2 Hz, 2H, -CH2-), 2.96 (dd, J = 14.4, 7.2 Hz, 2H, -CH 2 -), 1.81 - 1.89 (m, 2H, -CH 2 -), 1.76 (t, J = 7.2 Hz, 2H, -CH 2 -), 1.063 (t, J = 7.2 Hz, 3H, -CH 3 ); 13 13C NMR (150 MHz, DMSO-d6) δ: 199.2, 162.2, 161.7, 150.4, 140.1, 136.3, 134.5, 131.2, 126.8, 123.4, 116.8, 114.9, 112.9, 64.6, 63.2, 59.3, 58.6, 46.2, 45.6, 33.9, 31.3, 21.5, 8.6. HRMS (ESI) C 28 H 37 BrN 2 O 4 [M - Br] + calcd = 465.2748; found = 465.2724.

[0191] Example 29 Compound 27

[0192] Compound 27 was synthesized by the method described in Example 3. The physicochemical properties of Compound 27 are as follows:

[0193] 1), Pale yellow liquid;

[0194] 2), The nuclear magnetic resonance spectrum of the compound ( 1 H NMR, 600 MHz) characteristics:

[0195] Using DMSO as the solvent, the assignment of each peak: Yield: 37.1%, pale yellow liquid, 1 H NMR (600 MHz DMSO-d 6 ) δ: 7.94 (d, J = 9.0 Hz, 2H, -Ph), 7.25 (m, 1H, -Ph), 7.08 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.98 (d, J = 8.4 Hz, 1H, -Ph), 6.87 (d, J = 8.4 Hz, 2H, -Ph), 5.80 - 5.85 (m, 1H, -CH=CH 2 ), 4.95 - 4.98 (m, 2H, -CH=CH 2 ), 4.39 (s, 2H, -CH 2 -), 3.97 (t, J = 6.0 Hz, 2H, -CH 2 -), 3.41 - 3.44 (m, 8H, -CH 2 -), 3.28 (s, 2H, -CH 2 -), 3.25 (d, J = 6.6 Hz, -CH 2 -), 3.04 (s, 6H, N-CH 3 ), 2.97 - 3.00 (m, 2H, -CH 2 -), 1.90 - 1.95 (m, 2H, -CH 2 -), 1.06 - 1.07 (m, 3H, -CH 3 ); 13 CNMR (150 MHz DMSO-d 6 ) δ: 199.3, 162.0, 148.6, 140.5, 136.4, 134.3, 130.6, 126.7, 116.7, 116.3, 115.1, 113.0, 70.5, 66.6, 62.0, 60.3, 51.8, 45.4, 34.0, 31.3, 22.7, 8.6. HRMS (ESI) C 29 H 39 BrN 2 O 5 [M - Br] + calcd = 495.2853; found = 495.2797.

[0196] Example 30 Compound 28

[0197] Compound 28 was synthesized by the method described in Example 3. The physicochemical properties of Compound 28 are as follows:

[0198] 1) Brown liquid;

[0199] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) are as follows:

[0200] Using DMSO as the solvent, the assignment of each peak is as follows: Yield: 34.2%, brown liquid, 1 H NMR (600 MHz, DMSO-d 6 ) δ: 7.95 (d, J = 9.0 Hz, 2H, -Ph), 7.22 (t, J = 7.8 Hz, 1H, -Ph), 7.06 - 7.07 (m, 1H, -Ph), 6.95 - 6.96 (m, 1H, -Ph), 6.86 (d, J = 9.0 Hz, 2H, -Ph), 4.95 - 4.97 (m, 1H, -CH=CH 2 ), 4.95 - 4.97 (m, 2H, -CH=CH 2 ), 4.25 (s, 2H, -CH 2 -), 3.97 - 3.99 (m, 2H, -CH 2 -), 3.57 - 3.61 (m, 2H, -CH 2 -), 3.32 (s, 6H, N-CH 3 ), 3.27 - 3.30 (m, 4H, -CH 2 -), 3.24 - 3.25 (m, 2H, -CH 2 -), 2.96 (dd, J = 14.4, 7.2 Hz, 2H, -Ph), 1.99 - 2.01 (m, 2H, -CH 2 -), 1.86 (t, J = 6.6 Hz, 2H, -CH 2 -), 1.74 - 1.76 (m, 2H, -CH 2 -), 1.05 (t, J = 7.2 Hz, 3H, -CH 3 ); 13 C NMR (150 MHz, DMSO-d 6) δ: 199.3, 162.2, 161.9, 150.9, 140.3, 136.4, 134.2, 131.0, 130.6, 126.7, 123.0, 112.8, 65.7, 64.3, 58.2, 46.2, 46.0, 45.7, 34.0, 31.3, 23.9, 21.8, 8.7. HRMS(ESI) C 29 H 39 BrN 2 O 4 [M - Br] + calcd = 479.2904; found = 479.2853.

[0201] Example 31 Compound 29

[0202] Compound 29 was synthesized by the method described in Example 3. The physicochemical properties of Compound 29 are as follows:

[0203] 1), Pale yellow liquid;

[0204] 2), The nuclear magnetic resonance spectrum of this compound ( 1 H NMR, 600 MHz) characteristics:

[0205] Using DMSO as the solvent, the assignment of each peak: Yield: 40.3%, pale yellow liquid, 1 H NMR (600 MHz DMSO - d 6 ) δ: 7.92 (d, J = 9.0 Hz, 2H, -Ph), 7.22 - 7.24 (m, 1H, -Ph), 7.06 (dd, J = 8.4, 7.2 Hz, 1H, -Ph), 6.93 (dd, J = 7.8, 6.6 Hz, 1H, -Ph), 6.86 (d, J = 9.0 Hz, 2H, -Ph), 5.79 - 5.84 (m, 1H, -CH=CH 2 ), 4.95 - 4.87 (m, 2H, -CH=CH 2 ), 4.35 (s, 2H, -CH 2 -), 3.95 - 3.96 (m, 2H, -CH 2 -), 3.41 - 3.45 (m, 8H, -CH 2 -), 3.23 (d, J = 6.6 Hz, -CH 2 -), 3.03 (s, 6H, N - CH 3 ), 1.46 - 1.52 (m, 4H, -CH 2 -), 1.05 (t, J = 7.2 Hz, 3H, -CH 3 ); 1313C NMR(150MHz DMSO-d 6 ) δ: 199.3, 167.9, 162.6, 162.0, 151.3, 140.5, 136.4, 134.2, 126.7, 122.6, 116.7, 112.7, 67.6, 66.2, 66.1, 51.3, 46.0, 34.0, 31.3, 25.9, 19.1, 8.6. HRMS(ESI) C 30 H 41 BrN 2 O 5 [M - Br] + calcd = 509.3010; found = 509.2943.

[0206] Example 32 Compound 30

[0207] Compound 30 was synthesized by the method described in Example 3. The physical and chemical properties of Compound 30 are as follows:

[0208] 1), Pale yellow liquid;

[0209] 2), The nuclear magnetic resonance spectrum of this compound ( 1 1H NMR, 600 MHz) characteristics:

[0210] Using DMSO as the solvent, the assignment of each peak: Yield: 41.6%, pale yellow liquid, 1 1H NMR(600 MHz DMSO-d 6 ) δ: 7.93 (d, J = 9.0 Hz, 2H, -Ph), 7.21 (t, J = 7.8 Hz, 1H, -Ph), 7.05 (d, J = 8.4, 7.2 Hz, 1H, -Ph), 6.92 - 6.94 (m, 1H, -Ph), 6.85 (d, J = 9.0 Hz, 2H, -Ph), 5.79 - 5.83 (m, 1H, -CH=CH 2 ), 4.94 - 4.98 (m, 2H, -CH=CH 2 ), 4.22 (s, 2H, -CH 2 -), 3.93 (t, J = 5.4 Hz, -CH 2 -), 3.56 - 3.59 (m, 2H, -CH 2 -), 3.33 (s, 6H, N-CH 3 ), 3.22 (d, J = 6.6 Hz, 2H, -CH 2 -), 2.93 - 3.00 (m, 2H, -CH 2 -), 2.02 - 2.04 (m, 2H, -CH2 -), 1.95 - 1.97 (m, 2H, -CH 2 -), 1.88 - 1.90 (m, 2H, -CH 2 -), 1.74 - 1.78 (m, 2H, -CH 2 -), 1.06 - 1.08 (m, 3H, -CH 3 ); 13 C NMR (150 MHz, DMSO-d 6 ) δ: 199.3, 162.3, 162.0, 151.3, 140.5, 136.4, 134.2, 130.9, 130.6, 126.7, 122.6, 116.7, 115.0, 112.7, 67.6, 64.0, 60.4, 58.3, 46.0, 34.0, 31.3, 25.9, 23.9, 22.0, 8.6. HRMS (ESI) C 30 H 41 BrN 2 O 4 [M - Br] + calcd = 493.3061; found = 493.3012.

[0211] Application Example 1: In Vitro Antibacterial Activity Assay

[0212] 1. Test Bacteria:

[0213] Standard strain of Staphylococcus aureus (Staphylococcus aureus ATCC 29213); Methicillin-resistant Staphylococcus aureus (MRSA).

[0214] 2. Samples and Reagents:

[0215] The samples are: Magnoflorine analogs, Vancomycin, Meropenem, and Compounds 1 - 30 prepared in the examples.

[0216] 3. Test Method:

[0217] According to the standards of the Clinical and Laboratory Standards Institute (CLSI) of the United States, using a 96-well plate, the in vitro antibacterial activities of the magnoflorine analogs, Compounds 1 - 30 of the present invention, and the clinical antibacterial drug vancomycin were tested by the method of serial dilution. The drug concentration of the smallest completely clear well observed with the naked eye was taken as the minimum inhibitory concentration (MIC) value.

[0218] Table 1. In Vitro Bacteriostatic Activities of Amphiphilic Quaternary Ammonium Salt-Type Magnoflorine Analogs 1 - 30 of the Present Invention (μg / mL)

[0219]

[0220]

[0221] Note: YML: Magnoflorine analogues, Van: Vancomycin, MEM: Meropenem, S.a a : Staphylococcus aureus ATCC 29213, E.f b : Enterococcus faecalis, M.l d : Micrococcus luteus, E.c e : Escherichia coli ATCC 29522, S.e f : Salmonella H9812, S.e g : Salmonella 8389.

[0222] It can be seen from Table 1 that the amphiphilic quaternary ammonium salt magnoflorine analogues prepared in the present invention have good antibacterial effects against Gram-positive bacteria. Compared with the parent compound, the antibacterial activities of all amphiphilic quaternary ammonium salt magnoflorine analogues against Gram-positive bacteria have been improved. Among them, the best ones are Compounds 5 and 13, and they also show certain antibacterial activities against Gram-negative bacteria. Their MIC against Staphylococcus aureus reaches 1-2 μg / mL, which is reduced by about 32-64 times. At the same time, the hemolytic toxicity HC of the active compounds 50 has also been greatly improved, reducing the biological toxicity. Therefore, Compounds 5 and 13 have the advantages of high anti-Gram-positive bacterial activity and low biological toxicity.

[0223] Table 2 MIC values of the amphiphilic quaternary ammonium salt type magnoflorine analogues 1-30 of the present invention against 10 clinical isolates of MRSA

[0224]

[0225]

[0226] It can be concluded from Table 2 that the amphiphilic quaternary ammonium salt magnoflorine analogues prepared in the present invention have good antibacterial activities against clinical strains of MRSA. Compounds 4, 5, 8, 11-13, 16, 19, 21, 23, 24 all show better antibacterial activities than the parent compound, and their minimum inhibitory concentrations are all ≤ 32 μg / mL. In particular, the antibacterial effects of Compounds 5 and 13 are the best, approaching that of the positive control drug vancomycin, and they have potential clinical development value.

[0227] Application Example 2: In vitro time-kill kinetic experiment:

[0228] 1. Test bacteria:

[0229] MRSA-16 (clinical isolate)

[0230] 2. Samples and Reagents:

[0231] The samples are vancomycin and Compounds 5 and 13 prepared in the examples.

[0232] Testing Method:

[0233] Staphylococcus aureus ATCC 29213 and MRSA-16 were shaken overnight in a shaker at 225 rpm and 37 °C, then diluted 10,000 times with LB liquid medium, and then cultured at 225 rpm and 37 °C for 2.5 h (early logarithmic growth phase). The test drugs were added, and the drug concentrations were set at 8×, 6×, and 4× MIC respectively. Vancomycin (8× MIC) was used as a positive control, and a blank group without drugs was set. At each time point of 0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 24 h after adding the drugs, 100 μL was taken from each group, centrifuged at 3500 rpm and 4 °C for 3 min, the supernatant was removed, washed three times, resuspended with 100 μL of 1× PBS buffer solution, serially diluted, drop-plated for counting, and three parallel controls were set for each group. They were cultured overnight in a constant temperature incubator at 37 °C, and the colony numbers were counted the next day, with the unit log 10 CFU / mL, plotted, and the results are as Figure 1 shown.

[0234] Figure 1 It is shown that Compounds 5 and 13 have a rapid antibacterial effect against Staphylococcus aureus ATCC 29213 ( Figure 1 A and B) and MRSA-16 ( Figure 1 C and D). Compared with vancomycin, Compounds 5 and 13 can also control the growth of bacteria in a short time and kill them quickly at low concentrations, while vancomycin only effectively inhibits the growth and reproduction of bacteria and does not achieve the purpose of killing bacteria. Therefore, Compounds 5 and 13 are expected to be developed into clinical rapid antibacterial agents.

[0235] Application Example 3: In vitro and in vivo safety evaluation experiments of Drugs 5 and 13

[0236] 3.1 Cytotoxicity of Drugs 5 and 13

[0237] 3.1.1 Reagents:

[0238] Drugs 5 and 13

[0239] 3.1.2 Test Cells:

[0240] Cell line LO2

[0241] Testing Method:

[0242] The prepared cell suspension (5×10 4Inoculate 100 μL (100 cells / mL per well) into a 96-well cell culture plate, then add 100 μL of culture medium respectively. Place the 96-well cell culture plate in a cell culture incubator and culture for 24 h. After the cells adhere to the wall, discard the culture medium. Add 200 μL of a series of concentration gradients of the test compounds 5 and 13 (2.5, 5, 10, 20, 40, 80 μg / mL) dissolved in cell culture medium to each well, with the DMSO content per well not exceeding 0.1%. Set three parallel controls for each concentration gradient, and continue to place them in a 37 °C incubator for 24 h. Discard the culture solution, add 100 μL of 5% CCK-8 solution to each well, and return it to the incubator for incubation for 4 h. Measure the OD with an enzyme-linked immunosorbent assay (ELISA) reader 450 , and use Excel to calculate the cell survival rate. The results are as Figure 2 shown

[0243] Figure 2 It shows that drugs 5 (III5) and 13 (III15) have low toxicity to cells LO2. When the drug concentration reaches 80 μg / mL, the cell survival rate still reaches more than 90%. It can be seen that the drug has low cytotoxicity and high safety

[0244] 3.2 In vivo toxicity of drugs 5 and 13

[0245] 3.2.1 Reagents

[0246] Drugs 5 and 13

[0247] 3.2.2 Test animals

[0248] SPF-grade BALA / C mice

[0249] Test method

[0250] SPF-grade BALA / C mice were randomly divided into nine groups: Control (saline), A-1 (injected with drug 5 at a concentration of 10 mg / kg), A-2 (injected with drug 5 at a concentration of 20 mg / kg), A-3 (injected with drug 5 at a concentration of 30 mg / kg), A-4 (injected with drug 5 at a concentration of 50 mg / kg), B-1 (injected with drug 13 at a concentration of 10 mg / kg), B-2 (injected with drug 13 at a concentration of 20 mg / kg), B-3 (injected with drug 13 at a concentration of 30 mg / kg), and B-4 (injected with drug 13 at a concentration of 50 mg / kg), with six mice in each group. The mice in each group were injected with 100 μL of drug 5 or 13 at the corresponding concentration, observed for seven days, and the status and death of the mice in each group were recorded. After seven days, no mouse death was found. Then, 18 mice were randomly divided into three groups: Control, A (injected with drug 5 at a concentration of 50 mg / kg), and B (injected with drug 13 at a concentration of 50 mg / kg), with six mice in each group. The mice in groups A and B were injected with the corresponding concentration of the drug. After 24 h, blood was collected from the eyes to measure its biochemistry and blood routine to evaluate whether drugs 5 and 13 had in vivo toxicity to mice. The results were as Figure 3 shown.

[0251] Figure 3 It was shown that blood samples were analyzed for blood routine and blood biochemistry, and the test items included white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and platelet count (PLT). The statistical results showed that when compound 5 (III5) and 13 (III15) were intraperitoneally injected into BABL / c mice, there was no significant difference in the results of compound 5 and 13 compared with the saline control group. At the same time, we also collected serum for blood biochemistry tests, including albumin (ALB), urea (UREA), and creatinine (CREA). Compared with the saline group, when compound 5 and 13 were intraperitoneally injected into mice, the corresponding indicators of liver and kidney function in mice showed no obvious difference, indicating that compound 5 and 13 had relatively high in vivo safety.

[0252] Application Example 4: In Vivo Anti-MRSA Infection Activity Experiment of Drugs 5 and 13

[0253] 1. Test bacteria:

[0254] MRSA-16 (clinical isolate)

[0255] 2. Samples and reagents:

[0256] The samples were: vancomycin and compounds 5 and 13 prepared in the examples.

[0257] 3. Test animals:

[0258] SPF - level BALA / C mice

[0259] Test method:

[0260] Randomly divide SPF - level BALA / C mice into 5 groups: blank group, Control (only injected with bacterial solution), Group A (injected with bacterial solution and drug 5), Group B (injected with bacterial solution and drug 13), and Group C (injected with bacterial solution and positive control drug vancomycin), with 6 mice in each group. Prepare solutions of compound 5 and 13 at 10 mg / kg and vancomycin at 5 mg / kg for standby. Inject each mouse in the groups other than the blank group with 100 μL of 5×10 8 CFU (median lethal dose) of bacterial solution. One hour after injection, inject 100 μL of the drug into the mice in Groups A, B, and C, and inject 100 μL of PBS into the mice in the blank group. Observe the status of the mice. After three days, dissect them, take their liver, kidney, and spleen, grind the tissue organs, perform plate counting, and read the bacterial load in each organ of the mice at 24 h. The results are as Figure 4 shown.

[0261] Figure 4 The results show that: compared with the mice in the Control group, the bacterial loads in the three organs of the liver, kidney, and spleen of the mice in Groups A, B, and C have all decreased significantly, approximately by 3 log10 values; at the same time, compared with the clinical antibacterial drug vancomycin, the therapeutic effects of 2 - fold doses of drugs 5 and 13 are comparable to that of vancomycin. Therefore, from the perspective of the in - vivo antibacterial activity of compounds 5 and 13, they have good stability in vivo and simultaneously exhibit good bactericidal activity in vitro, and are expected to be developed into clinical antibacterial agents.

Claims

1. Amphiphilic quaternary ammonium salt type magnoflorine analogues, the structure of which is shown as follows: Wherein, n = 2, 3 or 4, and R is wherein R 1 and R 2 are independently selected from H or C1-C8 alkyl; or n and R are respectively: (25) (26) (27) (28) (29) (30) 2. The amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 1, characterized in that, Said R 1 and R 2 are independently selected from H or C2-C6 alkyl.

3. The amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 1, characterized in that, When R is , n, R 1 and R 2 are respectively: (1) n = 2, R 1 = H, R 2 = -CH 2 CH 3 (2) n = 2, R 1 = H, R 2 = -(CH 2 ) 2 CH 3 (3) n = 2, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (4) n = 2, R 1 = H, R 2 = -(CH 2 ) 4 CH 3 (5) n = 2, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (6) n = 2, R 1 = R 2 = -CH 2 CH 3 (7) n = 2, R 1 = R 2 = -(CH 2 ) 2 CH 3 (8) n = 2, R 1 = R 2 = -(CH 2 ) 3 CH 3 (9) n = 3, R 1 = H, R 2 = -CH 2 CH 3 (10) n = 3, R 1 =H, R 2 = -(CH 2 ) 2 CH 3 (11) n = 3, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (12) n = 3, R 1 = H, R 2 = -(CH 2 ) 4 CH 3 (13) n = 3, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (14) n = 3, R 1 = R 2 = -CH 2 CH 3 (15) n = 3, R 1 = R 2 = -(CH 2 ) 2 CH 3 (16) n = 3, R 1 = R 2 = -(CH 2 ) 3 CH 3 (17) n = 4, R 1 = H, R 2 = -CH 2 CH 3 (18) n = 4, R 1 = H, R 2 = -(CH 2 ) 2 CH 3 (19) n = 4, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (20) n = 4, R 1 = H, R 2 = -(CH 2 ) 4 CH 3 (21) n = 4, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (22) n = 4, R 1 = R 2 = -CH 2 CH 3 (23) n = 4, R 1 = R 2 = -(CH 2 ) 2 CH 3 (24) n = 4, R 1 = R 2 = -CH 2 CH 3 .

4. Preparation method of the amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 1, characterized in that, it includes using magnoflorine analogues as a substrate, introducing bromoalkane on its phenolic hydroxyl group to synthesize intermediate a, and then undergoing a substitution reaction with intermediate b to generate a series of quaternary ammonium salt type magnoflorine analogues: Wherein, R and n are the same as those described in claim 1; The structural formula of the magnoflorine analogues is shown as follows:

5. Preparation method of the amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 4, characterized in that, the molar ratio of intermediate a to intermediate b is 1:2 - 1:4, the reaction temperature of the substitution reaction is 70 - 90 °C, and the reaction solvent is ethanol.

6. Preparation method of the amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 4, characterized in that, the preparation method of intermediate a is as follows: reacting magnoflorine analogues with dibromoalkane under alkaline conditions to generate intermediate a; wherein, n = 2, 3 or 4.

7. Preparation method of the amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 6, characterized in that, The base in the alkaline condition is K 2 CO 3 ; the molar ratio of the magnoflorine analog to the base is 1:1.5 - 1:3, the molar ratio of the magnoflorine analog to the dibromoalkane is 1:2 - 1:4, the reaction temperature is 45 - 60 °C, and the reaction solvent is acetone.

8. Preparation method of the amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 4, characterized in that, the preparation method of intermediate b is as follows: under alkaline conditions, amine RH undergoes a substitution reaction with bromoacetyl bromide to generate bromoacetamide, and then under alkaline conditions, bromoacetamide continues to undergo a substitution reaction with dimethylamine to generate intermediate b: Wherein, R is the same as that described in claim 1.

9. Application of the amphiphilic quaternary ammonium salt type magnoflorine analogues according to claim 1 in the preparation of drugs for inhibiting methicillin-resistant Staphylococcus aureus.

10. Application of the amphiphilic quaternary ammonium salt type magnoflorine analogues in the preparation of drugs for inhibiting Staphylococcus aureus ATCC 29213, characterized in that, the structure of the amphiphilic quaternary ammonium salt type magnoflorine analogues is shown as follows: wherein, R is selected from n, R 1 and R 2 are respectively: (1) n = 2, R 1 = H, R 2 = -CH 2 CH 3 (2) n = 2, R 1 = H, R 2 = -(CH 2 ) 2 CH 3 (3) n = 2, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (4) n = 2, R 1 = H, R 2 = -(CH 2 ) 4 CH 3 (5) n = 2, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (6) n = 2, R 1 = R 2 = -CH 2 CH 3 (7) n = 2, R 1 = R 2 = -(CH 2 ) 2 CH 3 (8) n = 2, R 1 = R 2 = -(CH 2 ) 3 CH 3 (9) n = 3, R 1 = H, R 2 = -CH 2 CH 3 (10) n = 3, R 1 =H, R 2 = -(CH 2 ) 2 CH 3 (11) n = 3, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (12) n = 3, R 1 = H, R 2 = -(CH 2 ) 4 CH 3 (13) n = 3, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (14) n = 3, R 1 = R 2 = -CH 2 CH 3 (15) n = 3, R 1 = R 2 = -(CH 2 ) 2 CH 3 (16) n = 3, R 1 = R 2 = -(CH 2 ) 3 CH 3 (18) n = 4, R 1 = H, R 2 = -(CH 2 ) 2 CH 3 (19) n = 4, R 1 = H, R 2 = -(CH 2 ) 3 CH 3 (20) n = 4, R 1 = H, R 2 = -(CH 2 ) 4 CH 3 (21) n = 4, R 1 = H, R 2 = -(CH 2 ) 5 CH 3 (22) n = 4, R 1 = R 2 = -CH 2 CH 3 (23) n = 4, R 1 = R 2 = -(CH 2 ) 2 CH 3 (24) n = 4, R 1 = R 2 = -CH 2 CH 3 Or, n and R are respectively: (25) (26) (27) (28) (29) (30)

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