Group of cyclic alkaline lipopeptide compounds as well as preparation method and application thereof

Abstract

The invention relates to a cyclic alkaline lipopeptide compound as well as a preparation method and application thereof. Wherein the compound has a structure as shown in a general formula I, and AA represents amino acid. The preparation method of the cyclic lipopeptide compound comprises the following steps: (1) carrying out a reaction on a protected basic amino acid Fmoc-AA-OP side chain free amino group and halogenated resin to obtain Fmoc-AA-OP-resin; (2) coupling Fmoc-AA-OP-resin one by one to obtain linear polypeptide-resin; (3) selectively removing a protecting group from the linear polypeptide-resin, and performing solid-phase cyclization to obtain cyclic polypeptide-resin; (4) performing acidolysis and diethyl ether precipitation on the cyclic polypeptide-resin to obtain a cyclic polypeptide crude product; and (5) carrying out purification and / or salt conversion and freeze-drying on the cyclic polypeptide crude product to obtain a cyclic polypeptide pure product. The cyclic lipopeptide compound can be used for preparing the antibacterial medicine, and particularly can be used for preparing the antibacterial medicine with improved antibacterial activity and reduced renal toxicity, including preparing the antibacterial medicine for resisting carbapenem-resistant super bacteria. R < 0-CO >-AA < 1->-AA < 2->-D / L-AA < 3->-ring (4-10) [Dab4-AA < 5->-D / L-AA < 6->-AA < 7->-AA < 8->-AA < 9->] I is shown in the specification.

Description

Technical Field

[0001] The present invention relates to a cyclic basic lipopeptide compound and a preparation method thereof, and also relates to the use of the inventive compound in the preparation of antibacterial drugs, in particular, the use of the inventive compound in the preparation of antibacterial drugs with improved antibacterial activity and reduced nephrotoxicity, including the use of the inventive compound in the preparation of broad-spectrum antibacterial drugs against carbapenem-resistant "super bacteria" and Pseudomonas aeruginosa, as well as a pharmaceutical composition containing the compound as an active ingredient and the use thereof, and belongs to the field of biomedicine. Background Art

[0002] The cyclic alkaline lipopeptide antibiotic polymyxin was first reported in 1947. It is a series of cationic antimicrobial peptides produced by Bacillus polymyxa. It has different types of structures such as A, B, C, D, E, F, K, M, P, S and T, and a molecular weight of about 1200D. The common structural characteristics of polymyxin antibiotics are that they are composed of three parts: a cyclic heptapeptide, a linear tripeptide, and a side chain acyl group connected to the linear tripeptide. They have similar antibacterial spectra and produce bactericidal effects by destroying the cell membrane of Gram-negative bacteria, causing the leakage of cell contents.

[0003] The cyclic alkaline lipopeptide antibiotic polymyxin has been used in clinical practice since the 1950s. It has a narrow antibacterial spectrum and is only effective against Gram-negative bacteria. It also has certain nephrotoxicity. In particular, the emergence of new broad-spectrum antibacterial drugs such as third-generation cephalosporins and carbapenems has led to a gradual reduction in its clinical use. In recent years, with the continuous emergence of multidrug-resistant Gram-negative bacteria, especially the increasing number of carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, polymyxin has become the last line of defense for the treatment of carbapenem-resistant Gram-negative bacteria infections. Therefore, polymyxin has regained clinical attention.

[0004] At present, polymyxin B and colistin (polymyxin E) are used clinically, both of which are multi-component mixtures obtained by bacterial fermentation. The polymyxins currently used clinically have complex compositions and severe nephrotoxicity, which limits their clinical use. Therefore, it is particularly urgent to design and synthesize cyclic antimicrobial lipopeptides with high antibacterial activity and low nephrotoxicity.

[0005] The chemical preparation methods of polymyxin B reported in the literature include solid phase condensation and liquid phase cyclization strategies. Liquid phase cyclization requires a large amount of solvent, the product is not easy to separate and purify, the yield is less than 20%, and the yield is even lower in the actual synthesis process. The literature (deVisser PC, Kriek NM, van Hooft PA, et al. Solid-phase synthes is of polymyxinB1 and analogues via a safety-catch approach. J Pept Res, 2003, 61 (6): 298-306) uses Kenner's safety catch method solid phase condensation and solid phase cyclization to synthesize polymyxin B1, but the total yield is 1.5%. The literature (Wei-Liang Xu, A-Long Cui, Xin-Xin Hu, et al. A new strategy for total solid-phase synthesis of polymyxins. Tetrahedron Letters, 2015, 56 (33): 4796-4799.) uses solid phase condensation and solid phase cyclization to synthesize polymyxin B2 and E2, with a yield of about 25%. WO2013156977A1 ​​reports a method for solid phase synthesis of insulin by connecting the side chain amino group of lysine to a resin. The present invention connects the side chain amino group of a protected basic amino acid Fmoc-AA-OP similar to that of lysine to a resin, and uses solid phase condensation and solid phase cyclization to synthesize polymyxin derivatives. This method avoids a large amount of solvent produced by liquid phase cyclization, is green and environmentally friendly, has high purity of crude polypeptide, is easy to separate and purify, and has a total yield of more than 30%.

[0006] Regarding the preparation of cyclic basic lipopeptide compounds, the present invention prepares for the first time new derivatives that increase or decrease the hydrophobicity of the side chain acyl chain (changing R0-CO-) by changing the length and volume of the side chain acyl chain, new derivatives that replace the amino acids at positions 1 and / or 3 and / or 5 and / or 8 and / or 9 (changing AA1, AA3, AA5, AA8, AA9) with basic amino acids or polar amino acids, new derivatives that replace the amino acids at positions 6 and / or 7 (changing AA6, AA7) with hydrophobic amino acids or polar amino acids, and derivatives that introduce strong polar groups such as sulfomethyl groups into the amino acid residues at positions 1, 2, 3, 5, 6, 7, 8, 9, and 10. By changing the basic amino acids or hydrophobicity of the polymyxin molecule, the antibacterial activity is improved and the nephrotoxicity is reduced.

[0007] Regarding the biological functions of cyclic lipopeptide derivatives, the present invention studied the antibacterial activity and nephrotoxicity of cyclic lipopeptide derivatives. Compared with the positive control, some cyclic lipopeptide derivatives had improved antibacterial activity against Gram-negative bacteria and reduced nephrotoxicity. In particular, the compounds of the invention had an antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa. - It has broad-spectrum antibacterial activity. Summary of the invention

[0008] The purpose of the present invention is to provide a cyclic basic lipopeptide compound and a preparation method thereof, in particular a preparation method of a cyclic lipopeptide compound synthesized by solid phase condensation and solid phase cyclization. The compound of the present invention has a significant antibacterial effect, in particular, its use in antibacterial drugs against carbapenem-resistant "super bacteria".

[0009] In order to achieve the above object, the present invention adopts the following technical solutions:

[0010] The present invention provides a polymyxin compound or a pharmaceutically acceptable salt thereof, the structure of which is shown in general formula I:

[0011] R0-CO-AA1-AA2-D / L-AA3-ring(4-10)[Dab4-AA5-D / L-AA6-AA7-AA8-AA9-AA 10 ]

[0012] Ⅰ

[0013] Specifically, the present invention provides the polymyxin compounds or pharmaceutically acceptable salts thereof according to the following embodiments.

[0014] A cyclic basic lipopeptide compound having a structure as shown in general formula I or a pharmaceutically acceptable salt thereof, wherein the compound consists of three parts: a cyclic heptapeptide, a linear tripeptide and a side chain acyl chain (i.e., R0-CO-) connected to the linear tripeptide, AA represents an amino acid, wherein the carboxyl group of R0-COOH condenses with the α-amino group of AA1 to form an amide bond, the carboxyl group of AA1 condenses with the α-amino group of AA2 to form an amide bond, the carboxyl group of AA2 condenses with the α-amino group of AA3 to form an amide bond, the carboxyl group of AA3 condenses with the α-amino group of Dab4 to form an amide bond, the carboxyl group of Dab4 condenses with the α-amino group of AA5 to form an amide bond, the carboxyl group of AA5 condenses with the α-amino group of AA6 to form an amide bond, the carboxyl group of AA6 condenses with the α-amino group of AA7 to form an amide bond, the carboxyl group of AA7 condenses with the α-amino group of AA8 to form an amide bond, the carboxyl group of AA8 condenses with the α-amino group of AA9 to form an amide bond, the carboxyl group of AA9 condenses with the α-amino group of AA1 to form an amide bond, 10 The α-amino groups of 10 The carboxyl group of Dab4 condenses with the γ-amino group of Dab4 to form an amide bond.

[0015] R0-CO-AA1-AA2-D / L-AA3-ring(4-10)[Dab4-AA5-D / L-AA6-AA7-AA8-AA9-AA 10 ]

[0016] Ⅰ

[0017] Where:

[0018] R0 is selected from the group consisting of: (C6-C 11 )-straight chain alkyl, (C7-C 12 )-branched alkyl;

[0019] AA1 and AA3 are independently selected from the group consisting of Ser (serine), Ser (CH2SO3H) (2-amino-3-sulfomethyloxypropionic acid), Dap (2,3-diaminopropionic acid), Dap (CH2SO3H) (2-amino-3-sulfomethylaminopropionic acid), Dab (2,4-diaminobutyric acid), Dab (CH2SO3H) (2-amino-4-sulfomethylaminobutyric acid), Orn (ornithine), Lys (lysine); the configuration of the amino acid at position 1 is L-type, and the configuration of the amino acid at position 3 is D or L-type;

[0020] AA2 and AA 10 Independently selected from the group consisting of: Thr (threonine), Thr (CH2SO3H) (2-amino-3-sulfomethoxybutyric acid); the configuration of amino acids at positions 2 and 10 is L-type;

[0021] The conformation of Dab4 is L-type;

[0022] AA5, AA8 and AA9 are independently selected from the group consisting of: Dap (2,3-diaminopropionic acid), Dap (CH2SO3H) (2-amino-3-sulfomethylaminopropionic acid), Dab (2,4-diaminobutyric acid), Dab (CH2SO3H) (2-amino-4-sulfomethylaminobutyric acid), Orn (ornithine); the configuration of amino acids at positions 5, 8 and 9 is L-type;

[0023] AA6 and AA7 are independently selected from the group consisting of: Phe (phenylalanine), Phe (4-CH2SO3) (4-sulfomethylphenylalanine), Leu (leucine), Thr (threonine), Thr (CH2SO3H) (2-amino-3-sulfomethyloxybutyric acid); the configuration of the amino acid at position 6 is D or L, and the configuration of the amino acid at position 7 is L;

[0024] The straight chain alkyl group may be hexyl, heptyl, octyl or nonyl; the branched chain alkyl group may be 5-methylhexyl, 5-methylheptyl, 6-methylheptyl, 6-methyloctyl, such as (S)-5-methylheptyl.

[0025] Specifically, in the present invention, the antimicrobial lipopeptide compound is selected from the following compounds 1 to 120:

[0026] (1) (S)-6-Methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0027] (2) 6-Methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0028] (3) Octanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0029] (4) Heptanoyl-Dab-Thr-D-Dap-Cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0030] (5) Nonanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0031] (6) (S)-6-Methyloctanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0032] (7) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0033] (8) Octanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0034] (9) Heptanoyl-Dab-Thr-Dap-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0035] (10) Nonanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0036] (11) (S)-6-Methyloctanoyl-Dab-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0037] (12) 6-Methylheptanoyl-Dab-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0038] (13) Octanoyl-Dab-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0039] (14) Heptanoyl-Dab-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0040] (15) Nonanoyl-Dab-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0041] (16) (S)-6-Methyloctanoyl-Dab-Thr-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0042] (17) 6-Methylheptanoyl-Dab-Thr-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0043] (18) Octanoyl-Dab-Thr-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0044] (19) Heptanoyl-Dab-Thr-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0045] (20) Nonanoyl-Dab-Thr-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0046] (21) (S)-6-Methyloctanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0047] (22) 6-Methylheptanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0048] (23) Octanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0049] (24) Heptanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0050] (25) Nonanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0051] (26) (S)-6-Methyloctanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0052] (27) 6-Methylheptanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0053] (28) Octanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0054] (29) Heptanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0055] (30) Nonanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0056] (31) (S)-6-Methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0057] (32) 6-Methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0058] (33) Octanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0059] (34) Heptanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0060] (35) Nonanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0061] (36) (S)-6-Methyloctanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0062] (37) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0063] (38) Octanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0064] (39) Heptanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0065] (40) Nonanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0066] (41) (S)-6-Methyloctanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0067] (42) 6-Methylheptanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0068] (43) Octanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0069] (44) Heptanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0070] (45) Nonanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0071] (46) (S)-6-Methyloctanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0072] (47) 6-Methylheptanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0073] (48) Octanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0074] (49) Heptanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0075] (50) Nonanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0076] (51) (S)-6-Methyloctanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0077] (52) 6-Methylheptanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0078] (53) Octanoyl-Dap-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0079] (54) Heptanoyl-Dap-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0080] (55) Nonanoyl-Dap-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0081] (56) (S)-6-Methyloctanoyl-Orn-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0082] (57) 6-Methylheptanoyl-Orn-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0083] (58) Octanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0084] (59) Heptanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0085] (60) Nonanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0086] (61) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]

[0087] (62) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]

[0088] (63) Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]

[0089] (64) Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]

[0090] (65) Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]

[0091] (66) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]

[0092] (67) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]

[0093] (68) Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]

[0094] (69) Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]

[0095] (70) Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]

[0096] (71) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]

[0097] (72) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]

[0098] (73) Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]

[0099] (74) Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]

[0100] (75) Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]

[0101] (76) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]

[0102] (77) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]

[0103] (78) Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]

[0104] (79) Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]

[0105] (80) Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]

[0106] (81)(S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]

[0107] (82) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]

[0108] (83) Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]

[0109] (84) Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]

[0110] (85) Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]

[0111] (86) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]

[0112] (87) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]

[0113] (88) Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]

[0114] (89) Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]

[0115] (90) Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]

[0116] (91)(S)-6-Methyloctanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0117] (92) 6-Methylheptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0118] (93) Octanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0119] (94) Heptanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0120] (95) Nonanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]

[0121] (96) (S)-6-Methyloctanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]

[0122] (97) 6-Methylheptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]

[0123] (98) Octanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]

[0124] (99) Heptanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]

[0125] (100) Nonanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]

[0126] (101)(S)-6-Methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-Phe-Thr-Dab-Dab-Thr]

[0127] (102) 6-Methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-Phe-Thr-Dab-Dab-Thr]

[0128] (103) 6-Methylheptanoyl-Dab-Thr-D-Ser(CH2SO3H)-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0129] (104) 6-Methylheptanoyl-Dab-Thr(CH2SO3H)-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0130] (105) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr(CH2SO3H)-Dab-Dab-Thr]

[0131] (106) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr(CH2SO3H)]

[0132] (107) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe(4-CH2SO3H)-Thr-Dab-Dab-Thr]

[0133] (108) 6-Methylheptanoyl-Dab(CH2SO3H)-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0134] (109) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab(CH2SO3H)-D-Phe-Thr-Dab-Dab-Thr]

[0135] (110) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab(CH2SO3H)-Dab-Thr]

[0136] (111) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab(CH2SO3H)-Thr]

[0137] (112) 6-Methylheptanoyl-Dab-Thr-Dap(CH2SO3H)-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0138] (113) 6-Methylheptanoyl-Dab-Thr(CH2SO3H)-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0139] (114) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr(CH2SO3H)-Dab-Dab-Thr]

[0140] (115) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr(CH2SO3H)]

[0141] (116) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe(4-CH2SO3H)-Thr-Dab-Dab-Thr]

[0142] (117) 6-Methylheptanoyl-Dab(CH2SO3H)-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]

[0143] (118) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab(CH2SO3H)-D-Phe-Thr-Dab-Dab-Thr]

[0144] (119) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab(CH2SO3H)-Dab-Thr]

[0145] (120) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab(CH2SO3H)-Thr].

[0146] The term "ring (4-10)" refers to connecting the carboxyl group of the amino acid at position 10 to the side chain amino group of the basic amino acid at position 4 through an amide bond to form a heptapeptide ring, the structure of which is shown in general formula I.

[0147] Among them, the configuration of D-amino acid is represented by D. When the configuration is not mentioned, it can be understood that the amino acid configuration is L. Dab represents 2,4-diaminobutyric acid, Orn represents 2,5-diaminopentanoic acid, and Dap represents 2,3-diaminopropionic acid.

[0148] The cyclic basic lipopeptide compound or its pharmaceutically acceptable salt described in the present invention, the pharmaceutically acceptable salt of the compound of general formula I includes a salt formed by the compound of general formula I and an acid, wherein the acid is selected from the following group consisting of: an inorganic acid or an organic acid, wherein the inorganic acid is preferably perchloric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; the organic acid is preferably acetic acid, trifluoroacetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid or p-toluenesulfonic acid.

[0149] The present invention also provides a method for solid phase synthesis of a cyclic lipopeptide compound or a pharmaceutically acceptable salt thereof. The method prepares a polymyxin compound or a pharmaceutically acceptable salt thereof by solid phase condensation and solid phase cyclization, comprising the following steps:

[0150] (1) The protected free amino group of the side chain of the basic amino acid Fmoc-AA-OP is reacted with a halogenated resin to obtain Fmoc-AA-OP-resin; wherein P is a carboxyl protecting group, for example, allyl (Allyl) or benzyl (Bn); when Fmoc-AA-OP is Fmoc-Dab-OP, its structure is shown in Formula II; when Fmoc-AA-OP is Fmoc-Dap-OP, its structure is shown in Formula III; when Fmoc-AA-OP is Fmoc-Orn-OP, its structure is shown in Formula IV.

[0151]

[0152] (2) Fmoc-AA-OP-resin is coupled one by one to obtain linear peptide-resin;

[0153] (3) selectively removing the protecting group from the linear peptide-resin and performing solid phase cyclization to obtain the cyclic peptide-resin;

[0154] (4) Acid hydrolysis of the cyclic polypeptide-resin to obtain a crude cyclic polypeptide;

[0155] (5) The crude cyclic polypeptide is purified and / or converted to salt, and then freeze-dried to obtain a pure cyclic polypeptide.

[0156] Regarding step (1):

[0157] The halogenated resin described in step (1) is selected from: trityl chloride resin, 4-methyltrityl chloride resin, 4-methoxytrityl chloride resin, 2-chlorotrityl chloride resin, bromo-(4-methylphenyl)-methyl resin or bromo-(4-methoxyphenyl)-methyl resin, for example, the resin is one or more of 2-chlorotrityl chloride resin.

[0158] The degree of substitution of the halogenated resin is 0.1-1.6 mmol / g, preferably, the degree of substitution is 0.5-1.0 mmol / g.

[0159] The amount of each Fmoc-protected amino acid used is 1.2-6 times the total molar number of the resin fed, preferably 2.0-4.0 times.

[0160] The base is selected from at least one of N,N-diisopropylethylamine (DIEA), triethylamine (TEA), and pyridine, preferably DIEA; the molar amount of the base is 1.5-3 times the molar amount of the Fmoc-protected amino acid, preferably, 2 times the molar amount of the Fmoc-protected amino acid.

[0161] The substitution reaction time is 1-12 h, preferably 2-3 h.

[0162] Regarding step (2):

[0163] The reagent for removing the α-amino Fmoc protecting group in step (2) includes but is not limited to a solution of piperidine (PIP) in DMF, with a concentration of 10-30%. The solution of PIP in DMF is preferably 20%. The amount of the deprotecting reagent used is 5-15 mL per gram of the resin, preferably 10 mL per gram of the resin. The deprotection reaction time is 10-60 min, preferably 10-20 min. The reagent for removing the amino ivDde or Dde protecting group of the side chain of the 4-amino acid includes but is not limited to a solution of hydrazine hydrate in DMF, with a concentration of 1-10%. The solution of hydrazine hydrate in DMF is preferably 2%. The amount of the deprotecting reagent used is 5-15 mL per gram of the resin, preferably 10 mL per gram of the resin. The deprotection reaction time is 30-100 min, preferably 30-60 min.

[0164] In the coupling reaction, the coupling agent is selected from: at least one of N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), preferably 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU).

[0165] The molar amount of the coupling agent is 1.2-6 times the total molar amount of the feed resin, preferably 2.0-4.0 times.

[0166] The activator is selected from at least one of 1-hydroxybenzotriazole (HOBT), 6-chloro-1-hydroxybenzotriazole (Cl-HOBT), and 1-hydroxy-7-azobenzotriazole (HOAT), and preferably 1-hydroxybenzotriazole (HOBT).

[0167] The molar amount of the activator is 1.2-6 times, preferably 2.0-4.0 times, the total molar amount of the feed resin.

[0168] The coupling reaction time is 60-300 min, preferably 60-120 min.

[0169] Part of the coupling agent needs to be added with a catalyst in the coupling reaction. The catalyst is an organic base selected from: N,N-diisopropylethylamine (DIEA), triethylamine (TEA), N-methylmorpholine (NMM), preferably N,N-diisopropylethylamine (DIEA).

[0170] The solvent is an aprotic polar solvent selected from dimethylformamide (DMF) or N-methylpyrrolidone (NMP) or a mixture thereof, preferably DMF.

[0171] About step (3)

[0172] The reagent for removing the carboxyl allyl protecting group in step (3) is a solution of tetrakis(triphenylphosphine)palladium / phenylsilane in DCM and DMF (a mixed solution with a volume ratio of DCM:DMF of 5:5). The molar amount of tetrakis(triphenylphosphine)palladium is 0.1-2 times the total mole number of the feed resin, preferably 0.1-0.3 times. The molar amount of phenylsilane is 2-10 times the total mole number of the feed resin, preferably 3-7 times. The amount of the deprotection reagent used is 10-30mL per gram of feed resin, preferably 20mL per gram of feed resin. The deprotection reaction time is 60-300min, preferably 60-120min. The reagent for removing the carboxyl benzyl protecting group is H2, 10% Pd / C ethanol solution, and the molar amount of 10% Pd / C is 0.1-2 times the total mole number of the feed resin, preferably 0.1-0.3 times. The deprotection reaction time is 30-100 min, preferably 30-60 min.

[0173] The solid phase cyclization coupling agent is selected from the group consisting of: (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxy)tris-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP), benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP), preferably, (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxy)tris-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP).

[0174] The molar amount of the coupling agent is 1.2-6 times the total molar amount of the feed resin, preferably 2.0-4.0 times.

[0175] The activator is selected from the group consisting of 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azobenzotriazole (HOAT), and preferably, 1-hydroxy-7-azobenzotriazole (HOAT).

[0176] The molar amount of the activator is 1.2-6 times, preferably 2.0-4.0 times, the total molar amount of the feed resin.

[0177] The cyclization reaction time is 1-20 h, preferably 1-3 h.

[0178] The catalyst is an organic base selected from the group consisting of: N,N-diisopropylethylamine (DIEA), triethylamine (TEA), N-methylmorpholine (NMM), preferably, N-methylmorpholine (NMM).

[0179] The solvent is an aprotic polar solvent selected from the group consisting of dimethylformamide (DMF) or N-methylpyrrolidone (NMP) or a mixture thereof, preferably DMF.

[0180] Regarding step (4):

[0181] In step (4), the acidolysis solution contains hydrofluoric acid (HF) or trifluoroacetic acid (TFA), preferably trifluoroacetic acid.

[0182] The amount of the acidolysis solution is 5-30 mL per gram of the resin, preferably 10 mL per gram of the resin. The acidolysis solution comprises trifluoroacetic acid and a side chain protecting group removing agent.

[0183] The concentration of trifluoroacetic acid is 80%-95%, and the rest is the side chain protecting group removing agent.

[0184] The side chain protecting group removing agent is selected from the group consisting of thioanisole, triisopropylsilane, phenol, water, and 1,2-ethanedithiol, preferably water.

[0185] The acid hydrolysis time is 60-300 min, preferably 100-120 min.

[0186] The acid hydrolyzate containing the polypeptide after acid hydrolysis was added to cold ether (the volume ratio of the acid hydrolyzate to cold ether was 1:20) to precipitate the peptide, centrifuge, and dry to obtain the crude peptide.

[0187] Regarding step (5):

[0188] In step (5), the crude peptide is dissolved in water, filtered through a 0.22 μm filter membrane, and purified by preparative high performance liquid chromatography, using mobile phase A 0.1% TFA / water solution, mobile phase B 0.1% TFA / acetonitrile solution, gradient elution, detection wavelength 214 nm, and the product is dried by freeze drying. The final purity that can be achieved by this method is greater than 95%, preferably, greater than 99%.

[0189] Specifically, the preparation method of the present invention comprises the following steps:

[0190] In step (1), the preparation of Fmoc-AA-OP-resin is performed, for example, as follows: the halogenated resin is added to a polypeptide solid phase synthesis tube, DCM is added to swell it, and after swelling is completed, it is washed three times with DMF and three times with DCM. The protected starting amino acids Fmoc-AA-OP and DIEA are dissolved in DCM and added to the polypeptide synthesis tube, reacted at room temperature for 2 hours, the reaction solution is removed by vacuum, and the resin is washed three times with DMF and three times with DCM to obtain Fmoc-AA-OP-resin.

[0191] In step (2), the coupling synthesis method comprises: treating the Fmoc-AA-OP-resin obtained in step (1) with 20% piperidine / DMF (twice, 10 minutes each time) to remove the α-amino Fmoc protecting group, washing with DMF three times, washing with DCM three times, dissolving the amino acid or side chain carboxylic acid (R0-COOH), HCTU and HOBT with DMF and adding them to a polypeptide synthesis tube, reacting at room temperature for 120 minutes, removing the reaction solution in vacuo, washing with DMF three times, and washing with DCM three times. The ivDde or Dde protecting group of the amino group of the amino acid at position 4 is removed by using a 2% hydrazine hydrate / DMF solution (30 min), the amino acid is washed three times with DMF and three times with DCM, the carboxyl group of the amino acid at position 10 is coupled to the amino group of the amino acid at position 4, and a linear fully protected polypeptide-resin is obtained; or the amino acid at position 7 is coupled one by one to the amino acid at position 1, and then the side chain carboxyl group is coupled to the protected polypeptide-resin; the ivDde or Dde protecting group of the amino group of the amino acid at position 4 is removed by using a 2% hydrazine hydrate / DMF solution, the amino acid is washed three times with DMF and three times with DCM, the carboxyl group of the amino acid at position 10 is coupled to the amino group of the amino acid at position 4, and then the carboxyl group of the amino acid at position 9 is coupled to the α-amino group of the amino acid at position 10, and a linear fully protected polypeptide-resin is obtained.

[0192] In step (3), the specific method of selectively removing the protecting group and solid phase cyclization is, for example, as follows: the linear fully protected peptide-resin in step (2) is treated with 20% piperidine / DMF (twice, 10 minutes each time) to remove the α-amino Fmoc protecting group, washed three times with DMF and three times with DCM to form a free amino group; the carboxyl allyl protecting group is removed with a solution of tetrakis(triphenylphosphine)palladium / phenylsilane in DCM and DMF (a mixed solution of DCM:DMF with a volume ratio of 5:5) (120 minutes) to form a free carboxyl group. PyAOP and HOAT are dissolved in DMF and then added to NMM, added to the peptide synthesis tube, reacted at room temperature for 3 hours, the reaction solution was removed by vacuum, washed three times with DMF and three times with DCM to obtain a cyclic fully protected peptide-resin.

[0193] In step (4), the specific method for obtaining the crude cyclic basic polypeptide by acid hydrolysis is, for example, as follows: add the acid hydrolysis solution (TFA:H2O volume ratio is 95:5) to the polypeptide synthesis tube, react at room temperature for 120 minutes, add the acid hydrolysis solution to cold ether (TFA lysis solution and cold ether ratio is 1:20) to precipitate the peptide, centrifuge, and dry to obtain the crude peptide.

[0194] In step (5), the specific method of crude product purification, salt conversion and freeze-drying is as follows: the crude product is dissolved in water, filtered with a 0.22 μm filter membrane for later use, and subjected to preparative high performance liquid chromatography, the chromatographic filler is 10 μm reverse phase C18, the mobile phase A is 0.1% TFA / water solution, the mobile phase B is 0.1% TFA / acetonitrile solution, the flow rate of the 22 mm×250 mm chromatographic column is 10 mL / min, the detection wavelength is 215 nm, a gradient system is used for elution, and cyclic injection purification is performed. The crude product solution is loaded on the chromatographic column, the mobile phase elution is started, the fractions corresponding to the main peak of the chromatogram are collected, the acetonitrile is evaporated from the fractions, and the polymyxin compound aqueous solution is obtained, and the product is freeze-dried to obtain the product.

[0195] The final purity that can be achieved by this method is greater than 95.0%, preferably greater than 99.0%. The yield calculated on the resin is greater than 30.0%.

[0196] The present invention prepares new compounds with changed basic amino acids or hydrophobicity of cyclic lipopeptide molecules. The compounds of the present invention are easy to prepare according to the chemical synthesis method, while the polymyxin B and colistin (polymyxin E) used clinically are multi-component mixtures obtained by bacterial fermentation methods.

[0197] Table 1 Structures of some inventive compounds

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205] Another object of the present invention is to provide the use of the cyclic basic lipopeptide compound having the structure shown in general formula I or its pharmaceutically acceptable salt in the preparation of antibacterial drugs.

[0206] Among them, the antibacterial is an antibacterial agent against Gram-negative bacteria. Gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Salmonella, Moraxella, Helicobacter, Legionella, Haemophilus influenzae, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Morganella morganii, Providentiarettgeri, Proteus vulgaris, Proteus mirabilis, Stenotrophomonas maltophilia, ia), Citrobacterfreundii, etc.

[0207] Gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumanii.

[0208] The present invention also provides a cyclic lipopeptide compound or a pharmaceutically acceptable salt thereof having higher antibacterial activity and lower renal cell toxicity than clinically used polymyxin B and colistin (polymyxin E). The renal cell is selected from the group consisting of: human renal tubular epithelial cells (HK-2 cells), human embryonic renal epithelial cells (HEK293 cells), African green monkey kidney cells (Vero cells), canine kidney cells (MDCK cells), for example, human renal tubular epithelial cells (HK-2 cells).

[0209] The present invention also provides an antibacterial drug composition, which comprises a therapeutically effective amount of a cyclic basic lipopeptide compound having a structure shown in general formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The compound itself or a mixture with a pharmaceutical excipient, a diluent, etc. can be orally administered in the form of tablets, capsules, granules, powders or syrups, or non-orally administered in the form of injections, sprays, aerosols, ointments or eye drops.

[0210] The above-mentioned preparations can be prepared by conventional pharmaceutical methods. Examples of usable pharmaceutical excipients and diluents include excipients (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose calcium, hydroxymethyl cellulose sodium; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate, phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.); binders (e.g., gelatin, polyvinyl pyrrolidone and polyethylene glycol); disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose, polyvinyl pyrrolidone); lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.); flavoring agents (e.g., commonly used sweeteners, sour agents and flavors, etc.); diluents and injection solvents (e.g., water, ethanol and glycerol, etc.).

[0211] Synthesis route: Taking the synthesis route of compound 1 as an example, the remaining compounds were synthesized using a similar route. The reaction conditions of the remaining compounds were the same as those of compound 1, except that the starting amino acid Fmoc-AA-OP and the types and order of the amino acids and fatty acids added during the coupling reaction were different.

[0212]

[0213] P stands for: Allyl

[0214] P1 represents: tert-butyloxycarbonyl (Boc)

[0215] P2 represents: 1-(4,4-dimethyl-2,6-dioxacyclohexane-1-ylidene)-ethyl (Dde), 1-(4,4-dimethyl-2,6-dioxacyclohexane-1-ylidene)-3-methylbutyl (ivDde)

[0216] P3 represents: tert-butyl (tBu)

[0217] Fmoc stands for: 9-fluorenylmethoxycarbonyl

[0218] Compared with existing compounds or synthesis methods, the method of the present invention is convenient, fast, green and environmentally friendly, has high purity of crude polypeptide, is easy to separate and purify, and has a total yield of up to 40%. DETAILED DESCRIPTION

[0219] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0220] Example 1: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 1)

[0221] The order in which the protected amino acids and side chain carboxylic acids are added to the reaction in the synthetic route is: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0222] Take 2-Cl-Trt resin (0.5 mmol, degree of substitution = 0.5 mmol / g) and add it to the peptide solid phase synthesis tube, and prepare (S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] according to the method shown in the synthetic route.

[0223] 530 mg of crude peptide was obtained with a yield of 90.0%. The crude peptide was dissolved in water, filtered with a 0.22 μm filter membrane for later use, and purified by preparative high performance liquid chromatography, the chromatographic filler was 10 μm reverse phase C18, mobile phase A was 0.1% TFA / water solution, mobile phase B was 0.1% TFA / acetonitrile solution, 22 mm × 250 mm chromatographic column, mobile phase flow rate was 8 mL / min, detection wavelength was 214 nm, gradient system elution was adopted, cyclic injection purification was adopted, the crude product solution was loaded on the chromatographic column, mobile phase elution was started, the fraction corresponding to the main peak of the chromatogram was collected and the acetonitrile was evaporated to obtain the compound 1 aqueous solution, and the product was freeze-dried to obtain the product.

[0224] The yield was 238 mg, which was 40.8% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] +).

[0225] Example 2: Preparation of 6-methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 2)

[0226] Compound 2 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0227] The yield was 240 mg, which was 41.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0228] Example 3: Preparation of Octanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 3)

[0229] Compound 3 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0230] The yield was 235 mg, which was 40.4% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0231] Example 4: Preparation of Heptanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 4)

[0232] Compound 4 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0233] The yield was 230 mg, which was 40.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1149.7 ([M+H] + ).

[0234] Example 5: Preparation of Nonanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 5)

[0235] Compound 5 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0236] The yield was 250 mg, which was 42.4% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0237] Example 6: Preparation of (S)-6-methyloctanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 6)

[0238] Compound 6 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0239] The yield was 240 mg, which was 40.8% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0240] Example 7: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 7)

[0241] Compound 7 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0242] The yield was 242 mg, which was 41.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0243] Example 8: Preparation of Octanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 8)

[0244] Compound 8 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0245] The yield was 238 mg, which was 40.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0246] Example 9: Preparation of Heptanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 9)

[0247] Compound 9 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0248] The yield was 235 mg, which was 40.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1149.7 ([M+H] + ).

[0249] Example 10: Preparation of Nonanoyl-Dab-Thr-Dap-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 10)

[0250] Compound 10 was prepared under the same reaction conditions and purification method as compound 1. In the synthetic route, the order in which the protected amino acids and side chain carboxylic acids were added to the reaction was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0251] The yield was 251 mg, which was 42.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0252] Example 11: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 11)

[0253] Compound 11 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0254] The yield was 248 mg, which was 41.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0255] Example 12: Preparation of 6-methylheptanoyl-Dab-Thr-D-Dab-cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 12)

[0256] Compound 12 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0257] The yield was 240 mg, which was 40.8% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0258] Example 13: Preparation of Octanoyl-Dab-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 13)

[0259] Compound 13 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0260] The yield was 235 mg, which was 39.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0261] Example 14: Preparation of Heptanoyl-Dab-Thr-D-Dab-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 14)

[0262] Compound 14 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0263] The yield was 235 mg, which was 40.4% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0264] Example 15: Preparation of Nonanoyl-Dab-Thr-D-Dab-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 15)

[0265] Compound 15 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0266] The yield was 250 mg, which was 42.0% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0267] Example 16: Preparation of (S)-6-methyloctanoyl-Dab-Thr-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 16)

[0268] Compound 16 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0269] The yield was 245 mg, which was 41.1% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0270] Example 17: Preparation of 6-methylheptanoyl-Dab-Thr-Dab-cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 17)

[0271] Compound 17 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0272] The yield was 245 mg, which was 41.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0273] Example 18: Preparation of Octanoyl-Dab-Thr-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 18)

[0274] Compound 18 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0275] The yield was 241 mg, which was 40.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0276] Example 19: Preparation of Heptanoyl-Dab-Thr-Dab-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 19)

[0277] Compound 19 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0278] The yield was 238 mg, which was 40.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0279] Example 20: Preparation of Nonanoyl-Dab-Thr-Dab-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 20)

[0280] Compound 20 was prepared under the same reaction conditions and purification method as compound 1. In the synthetic route, the order of adding protected amino acids and side chain carboxylic acids to the reaction was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0281] The yield was 254 mg, which was 42.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0282] Example 21: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 21)

[0283] Compound 21 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0284] The yield was 251 mg, which was 41.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1205.7 ([M+H] + ).

[0285] Example 22: Preparation of 6-methylheptanoyl-Dab-Thr-D-Orn-cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 22)

[0286] Compound 22 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0287] The yield was 243 mg, which was 40.8% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0288] Example 23: Preparation of Octanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 23)

[0289] Compound 23 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0290] The yield was 239 mg, which was 40.1% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0291] Example 24: Preparation of Heptanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 24)

[0292] Compound 24 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0293] The yield was 238 mg, which was 40.4% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0294] Example 25: Preparation of Nonanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 25)

[0295] Compound 25 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0296] The yield was 253 mg, which was 42.0% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1205.7 ([M+H] + ).

[0297] Example 26: Preparation of (S)-6-methyloctanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 26)

[0298] Compound 26 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0299] The yield was 248 mg, which was 41.1% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1205.7 ([M+H] + ).

[0300] Example 27: Preparation of 6-methylheptanoyl-Dab-Thr-Orn-cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 27)

[0301] Compound 27 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0302] The yield was 245 mg, which was 41.1% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0303] Example 28: Preparation of Octanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 28)

[0304] Compound 28 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0305] The yield was 244 mg, which was 40.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1191.7 ([M+H] + ).

[0306] Example 29: Preparation of Heptanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 29)

[0307] Compound 29 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0308] The yield was 240 mg, which was 40.8% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0309] Example 30: Preparation of Nonanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 30)

[0310] Compound 30 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0311] The yield was 258 mg, which was 42.8% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1205.7 ([M+H] + ).

[0312] Example 31: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 31)

[0313] Compound 31 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0314] The yield was 241 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0315] Example 32: Preparation of 6-methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 32)

[0316] Compound 32 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0317] The yield was 245 mg, which was 41.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1175.7 ([M+H] + ).

[0318] Example 33: Preparation of Octanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 33)

[0319] Compound 33 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0320] The yield was 238 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1175.7 ([M+H] + ).

[0321] Example 34: Preparation of Heptanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 34)

[0322] Compound 34 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0323] The yield was 235 mg, which was 40.4% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1161.7 ([M+H] + ).

[0324] Example 35: Preparation of Nonanoyl-Dab-Thr-D-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 35)

[0325] Compound 35 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0326] The yield was 254 mg, which was 42.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0327] Example 36: Preparation of (S)-6-methyloctanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 36)

[0328] Compound 36 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0329] The yield was 245 mg, which was 41.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0330] Example 37: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 37)

[0331] Compound 37 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0332] The yield was 245 mg, which was 41.6% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1175.7 ([M+H] + ).

[0333] Example 38: Preparation of Octanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 38)

[0334] Compound 38 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0335] The yield was 235 mg, which was 40.0% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1175.7 ([M+H] + ).

[0336] Example 39: Preparation of Heptanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 39)

[0337] Compound 39 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0338] The yield was 235 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1161.7 ([M+H] + ).

[0339] Example 40: Preparation of Nonanoyl-Dab-Thr-Dap-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 40)

[0340] Compound 40 was prepared under the same reaction conditions and purification method as compound 1. In the synthetic route, the order in which the protected amino acids and side chain carboxylic acids were added to the reaction was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0341] The yield was 250 mg, which was 42.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0342] Example 41: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 41)

[0343] Compound 41 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0344] The yield was 254 mg, which was 41.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1217.7 ([M+H] + ).

[0345] Example 42: Preparation of 6-methylheptanoyl-Dab-Thr-D-Orn-cyclo (4-10) [Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 42)

[0346] Compound 42 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0347] The yield was 245 mg, which was 40.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1203.7 ([M+H] + ).

[0348] Example 43: Preparation of Octanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 43)

[0349] Compound 43 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0350] The yield was 244 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1203.7 ([M+H] + ).

[0351] Example 44: Preparation of Heptanoyl-Dab-Thr-D-Orn-Cycle (4-10) [Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 44)

[0352] Compound 44 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0353] The yield was 239 mg, which was 40.2% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0354] Example 45: Preparation of Nonanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 45)

[0355] Compound 45 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0356] The yield was 255 mg, which was 41.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1205.7 ([M+H] + ).

[0357] Example 46: Preparation of (S)-6-methyloctanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 46)

[0358] Compound 46 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0359] The yield was 248 mg, which was 40.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1217.7 ([M+H] + ).

[0360] Example 47: Preparation of 6-methylheptanoyl-Dab-Thr-Orn-cyclo (4-10) [Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 47)

[0361] Compound 47 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0362] The yield was 241 mg, which was 40.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1203.7 ([M+H] + ).

[0363] Example 48: Preparation of Octanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 48)

[0364] Compound 48 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0365] The yield was 245 mg, which was 40.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1203.7 ([M+H] + ).

[0366] Example 49: Preparation of Heptanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 49)

[0367] Compound 49 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0368] The yield was 245 mg, which was 41.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0369] Example 50: Preparation of Nonanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 50)

[0370] Compound 50 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0371] The yield was 250 mg, which was 41.0% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1217.7 ([M+H] + ).

[0372] Example 51: Preparation of (S)-6-methyloctanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 51)

[0373] Compound 51 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0374] The yield was 241 mg, which was 41.4% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0375] Example 52: Preparation of 6-methylheptanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 52)

[0376] Compound 52 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0377] The yield was 241 mg, which was 41.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0378] Example 53: Preparation of Octanoyl-Dap-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 53)

[0379] Compound 53 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0380] The yield was 235 mg, which was 40.8% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0381] Example 54: Preparation of Heptanoyl-Dap-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 54)

[0382] Compound 54 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0383] The yield was 235 mg, which was 41.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1136.6 ([M+H] + ).

[0384] Example 55: Preparation of Nonanoyl-Dap-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 55)

[0385] Compound 55 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0386] The yield was 250 mg, which was 42.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0387] Example 56: Preparation of (S)-6-methyloctanoyl-Orn-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 56)

[0388] Compound 56 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Orn(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0389] The yield was 240 mg, which was 40.2% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H]+).

[0390] Example 57: Preparation of 6-methylheptanoyl-Orn-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 57)

[0391] Compound 57 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Orn(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0392] The yield was 240 mg, which was 40.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H]+).

[0393] Example 58: Preparation of Octanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 58)

[0394] Compound 58 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Orn(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0395] The yield was 240 mg, which was 40.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H]+).

[0396] Example 59: Preparation of Heptanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 59)

[0397] Compound 59 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Orn(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0398] The yield was 238 mg, which was 40.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H]+).

[0399] Example 60: Preparation of Nonanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 60)

[0400] Compound 60 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Orn(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0401] The yield was 252 mg, which was 42.3% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H]+).

[0402] Example 61: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr] (Compound 61)

[0403] Compound 61 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dap(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0404] The yield was 241 mg, which was 41.4% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0405] Example 62: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr] (Compound 62)

[0406] Compound 62 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dap(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0407] The yield was 240 mg, which was 41.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0408] Example 63: Preparation of Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr] (Compound 63)

[0409] Compound 63 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dap(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0410] The yield was 230 mg, which was 40.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0411] Example 64: Preparation of Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr] (Compound 64)

[0412] Compound 64 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dap(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0413] The yield was 230 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1136.6 ([M+H] + ).

[0414] Example 65: Preparation of Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr] (Compound 65)

[0415] Compound 65 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dap(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0416] The yield was 250 mg, which was 42.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0417] Example 66: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr] (Compound 66)

[0418] Compound 66 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Orn(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0419] The yield was 240 mg, which was 40.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H] + ).

[0420] Example 67: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr] (Compound 67)

[0421] Compound 67 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Orn(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0422] The yield was 245 mg, which was 41.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H] + ).

[0423] Example 68: Preparation of Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr] (Compound 68)

[0424] Compound 68 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Orn(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0425] The yield was 236 mg, which was 40.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H] + ).

[0426] Example 69: Preparation of Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr] (Compound 69)

[0427] Compound 69 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Orn(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0428] The yield was 235 mg, which was 40.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0429] Example 70: Preparation of Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr] (Compound 70)

[0430] Compound 70 was prepared under the same reaction conditions and purification method as compound 1. In the synthetic route, the order of adding protected amino acids and side chain carboxylic acids to the reaction was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Orn(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0431] The yield was 250 mg, which was 41.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H] + ).

[0432] Example 71: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr] (Compound 71)

[0433] Compound 71 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0434] The yield was 240 mg, which was 41.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0435] Example 72: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr] (Compound 72)

[0436] Compound 72 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0437] The yield was 240 mg, which was 41.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0438] Example 73: Preparation of Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr] (Compound 73)

[0439] Compound 73 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0440] The yield was 231 mg, which was 40.1% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0441] Example 74: Preparation of Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr] (Compound 74)

[0442] Compound 74 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0443] The yield was 231 mg, which was 40.6% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1136.6 ([M+H] + ).

[0444] Example 75: Preparation of Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dap-Dab-Thr] (Compound 75)

[0445] Compound 75 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0446] The yield was 250 mg, which was 42.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0447] Example 76: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr] (Compound 76)

[0448] Compound 76 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0449] The yield was 241 mg, which was 40.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H] + ).

[0450] Example 77: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr] (Compound 77)

[0451] Compound 77 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0452] The yield was 246 mg, which was 41.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H] + ).

[0453] Example 78: Preparation of Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr] (Compound 78)

[0454] Compound 78 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0455] The yield was 238 mg, which was 40.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H] + ).

[0456] Example 79: Preparation of Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Orn-Dab-Thr] (Compound 79)

[0457] Compound 79 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0458] The yield was 236 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0459] Example 80: Preparation of Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Orn-Dab-Thr] (Compound 80)

[0460] Compound 80 was prepared under the same reaction conditions and purification method as compound 1. In the synthetic route, the order of adding protected amino acids and side chain carboxylic acids to the reaction was: Fmoc-Dab-OAllyl, Fmoc-Orn(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0461] The yield was 251 mg, which was 42.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H] + ).

[0462] Example 81: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr] (Compound 81)

[0463] Compound 81 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dap-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0464] The yield was 241 mg, which was 41.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0465] Example 82: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr] (Compound 82)

[0466] Compound 82 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dap-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0467] The yield was 240 mg, which was 41.9% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0468] Example 83: Preparation of Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr] (Compound 83)

[0469] Compound 83 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dap-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0470] The yield was 232 mg, which was 40.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1150.6 ([M+H] + ).

[0471] Example 84: Preparation of Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr] (Compound 84)

[0472] Compound 84 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dap-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0473] The yield was 231 mg, which was 40.6% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1136.6 ([M+H] + ).

[0474] Example 85: Preparation of Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr] (Compound 85)

[0475] Compound 85 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dap-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0476] The yield was 249 mg, which was 42.7% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0477] Example 86: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr] (Compound 86)

[0478] Compound 86 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Orn-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0479] The yield was 240 mg, which was 40.1% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H] + ).

[0480] Example 87: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr] (Compound 87)

[0481] Compound 87 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Orn-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0482] The yield was 245 mg, which was 41.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H] + ).

[0483] Example 88: Preparation of Octanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr] (Compound 88)

[0484] Compound 88 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Orn-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0485] The yield was 237 mg, which was 40.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1178.7 ([M+H] + ).

[0486] Example 89: Preparation of Heptanoyl-Dab-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr] (Compound 89)

[0487] Compound 89 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Orn-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0488] The yield was 235 mg, which was 40.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1164.7 ([M+H] + ).

[0489] Example 90: Preparation of Nonanoyl-Dab-Thr-D-Ser-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Orn-Thr] (Compound 90)

[0490] Compound 90 was prepared under the same reaction conditions and purification method as compound 1. In the synthetic route, the order of adding protected amino acids and side chain carboxylic acids to the reaction was: Fmoc-Orn-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0491] The yield was 251 mg, which was 42.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1192.7 ([M+H] + ).

[0492] Example 91: Preparation of (S)-6-methyloctanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 91)

[0493] Compound 91 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0494] The yield was 241 mg, which was 40.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0495] Example 92: Preparation of 6-methylheptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 92)

[0496] Compound 92 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0497] The yield was 241 mg, which was 41.0% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1175.7 ([M+H] + ).

[0498] Example 93: Preparation of Octanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 93)

[0499] Compound 93 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0500] The yield was 240 mg, which was 40.8% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1175.7 ([M+H] + ).

[0501] Example 94: Preparation of Heptanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 94)

[0502] Compound 94 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0503] The yield was 240 mg, which was 41.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1161.7 ([M+H] + ).

[0504] Example 95: Preparation of Nonanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 95)

[0505] Compound 95 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0506] The yield was 240 mg, which was 40.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1189.7 ([M+H] + ).

[0507] Example 96: Preparation of (S)-6-methyloctanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr] (Compound 96)

[0508] Compound 96 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0509] The yield was 240 mg, which was 41.5% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1155.7 ([M+H] + ).

[0510] Example 97: Preparation of 6-methylheptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr] (Compound 97)

[0511] Compound 97 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0512] The yield was 240 mg, which was 42.0% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1141.7 ([M+H] + ).

[0513] Example 98: Preparation of Octanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr] (Compound 98)

[0514] Compound 98 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, octanoic acid, and Fmoc-Thr(tBu)-OH.

[0515] The yield was 241 mg, which was 42.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1141.7 ([M+H] + ).

[0516] Example 99: Preparation of Heptanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr] (Compound 99)

[0517] Compound 99 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, heptanoic acid, and Fmoc-Thr(tBu)-OH.

[0518] The yield was 230 mg, which was 40.8% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1127.7 ([M+H] + ).

[0519] Example 100: Preparation of Nonanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr] (Compound 100)

[0520] Compound 100 was prepared under the same reaction conditions and purification method as compound 1. The order of adding protected amino acids and side chain carboxylic acids to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Leu-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dap(Boc)-OH, nonanoic acid, and Fmoc-Thr(tBu)-OH.

[0521] The yield was 235 mg, which was 40.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1155.7 ([M+H] + ).

[0522] Example 101: Preparation of (S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-Phe-Thr-Dab-Dab-Thr] (Compound 101)

[0523] Compound 101 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, (S)-6-methyloctanoic acid, and Fmoc-Thr(tBu)-OH.

[0524] The yield was 240 mg, which was 40.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1177.7 ([M+H] + ).

[0525] Example 102: Preparation of 6-methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-Phe-Thr-Dab-Dab-Thr] (Compound 102)

[0526] Compound 102 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0527] The yield was 240 mg, which was 41.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1163.7 ([M+H] + ).

[0528] Example 103: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser(CH2SO3H)-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 103)

[0529] Compound 103 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(CH2SO3H)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0530] The yield was 240 mg, which was 38.1% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0531] Example 104: Preparation of 6-methylheptanoyl-Dab-Thr(CH2SO3H)-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 104)

[0532] Compound 104 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(CH2SO3H)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0533] The yield was 245 mg, which was 38.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0534] Example 105: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr(CH2SO3H)-Dab-Dab-Thr] (Compound 105)

[0535] Compound 105 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(CH2SO3H)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0536] The yield was 248 mg, which was 39.4% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0537] Example 106: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr(CH2SO3H)] (Compound 106)

[0538] Compound 106 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(CH2SO3H)-OH.

[0539] The yield was 250 mg, which was 39.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0540] Example 107: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe(4-CH2SO3H)-Thr-Dab-Dab-Thr] (Compound 107)

[0541] Compound 107 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe(4-CH2SO3H)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0542] The yield was 260 mg, which was 41.3% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] +).

[0543] Example 108: Preparation of 6-methylheptanoyl-Dab(CH2SO3H)-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 108)

[0544] Compound 108 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(CH2SO3H)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0545] The yield was 245 mg, which was 38.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0546] Example 109: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab(CH2SO3H)-D-Phe-Thr-Dab-Dab-Thr] (Compound 109)

[0547] Compound 109 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(CH2SO3H)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0548] The yield was 248 mg, which was 39.4% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H]+ ).

[0549] Example 110: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab(CH2SO3H)-Dab-Thr] (Compound 110)

[0550] Compound 110 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(CH2SO3)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0551] The yield was 250 mg, which was 39.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0552] Example 111: Preparation of 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab(CH2SO3H)-Thr] (Compound 111)

[0553] Compound 111 was prepared using reaction conditions and purification methods similar to those of compound 1. In the synthetic route, the protected amino acids and side chain carboxylic acids were added in the following order: Fmoc-Dab-OAllyl, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, Fmoc-Thr(tBu)-OH, and Fmoc-Dab(CH2SO3H)-OH.

[0554] The yield was 260 mg, which was 41.3% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1258.6 ([M+H] + ).

[0555] Example 112: Preparation of 6-methylheptanoyl-Dab-Thr-Dap(CH2SO3H)-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 112)

[0556] Compound 112 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(CH2SO3H)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0557] The yield was 240 mg, which was 38.2% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0558] Example 113: Preparation of 6-methylheptanoyl-Dab-Thr(CH2SO3H)-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 113)

[0559] Compound 113 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(CH2SO3H)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0560] The yield was 245 mg, which was 38.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0561] Example 114: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr(CH2SO3H)-Dab-Dab-Thr] (Compound 114)

[0562] Compound 114 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(CH2SO3H)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0563] The yield was 248 mg, which was 39.4% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0564] Example 115: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr(CH2SO3H)] (Compound 115)

[0565] Compound 115 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(CH2SO3H)-OH.

[0566] The yield was 250 mg, which was 39.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0567] Example 116: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe(4-CH2SO3H)-Thr-Dab-Dab-Thr] (Compound 116)

[0568] Compound 116 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe(4-CH2SO3H)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0569] The yield was 260 mg, which was 41.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0570] Example 117: Preparation of 6-methylheptanoyl-Dab(CH2SO3H)-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr] (Compound 117)

[0571] Compound 117 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(CH2SO3H)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0572] The yield was 245 mg, which was 38.9% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0573] Example 118: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab(CH2SO3H)-D-Phe-Thr-Dab-Dab-Thr] (Compound 118)

[0574] Compound 118 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(CH2SO3H)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0575] The yield was 248 mg, which was 39.4% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0576] Example 119: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab(CH2SO3H)-Dab-Thr] (Compound 119)

[0577] Compound 119 was prepared under the same reaction conditions and purification method as compound 1. The order in which the protected amino acids and side chain carboxylic acids were added to the reaction in the synthetic route was: Fmoc-Dab-OAllyl, Fmoc-Dab(CH2SO3)-OH, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, and Fmoc-Thr(tBu)-OH.

[0578] The yield was 250 mg, which was 39.7% based on 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0579] Example 120: Preparation of 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab(CH2SO3H)-Thr] (Compound 120)

[0580] Compound 120 was prepared using reaction conditions and purification methods similar to those of compound 1. In the synthetic route, the protected amino acids and side chain carboxylic acids were added in the following order: Fmoc-Dab-OAllyl, Fmoc-Thr(tBu)-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dap(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methylheptanoic acid, Fmoc-Thr(tBu)-OH, and Fmoc-Dab(CH2SO3H)-OH.

[0581] The yield was 260 mg, which was 41.3% based on the 0.5 mmol of 2-Cl-Trt resin. Characterization of the purified peptide: Purity (by area integration of HPLC spectrum)>99.0%; ESI: m / z=1257.7 ([M+H] + ).

[0582] Experimental Example 1: Antibacterial Activity Experiment

[0583] The minimum inhibitory concentration (MIC) was determined by the broth microdilution method according to the CLSI recommended method.

[0584] Weigh appropriate amounts of the cyclic lipopeptide compounds and reference substances prepared in Examples 1-120, dissolve the samples with sterile pure water, take an appropriate amount of the mother solution and dilute it tenfold to 0.256 mg / mL with sterile MH broth, dispense half of the volume of the solution into a 96-well loading tank, and dilute the other half of the volume of the solution twice with sterile MH broth and add it to a deep-well loading tank. Repeat the above steps to make the drug concentrations in the loading tank 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, and 0.06 mg / L, respectively, and prepare them for immediate use. Select several colonies from the agar plates cultured for 18-24 hours and directly prepare a bacterial suspension in sterile physiological saline, adjusting the concentration of the bacterial suspension to 0.5 McFarland units. Dilute the corrected bacterial solution with MH broth to (4-8)×10 5 CFU / mL, freshly prepared and used. 100 μL of the above-mentioned compounds of the present invention (e.g., compounds prepared in the examples) and reference solutions of different concentrations were respectively pipetted into the 1st to 12th wells of a sterile 96-well polystyrene plate, and 100 μL of the above-mentioned inoculum was added to each well. The final concentrations of the samples in the wells were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03 mg / L, respectively, and the final inoculum concentrations were all (2-4)×10 5 CFU / mL. A growth control well is set up, containing 100μL inoculum and 100μL sterile MH broth. The test substance and inoculum in each well are mixed and sealed. The 96-well plate with the inoculation is placed in a 35-37℃ incubator for 16-20h. After the incubation, the growth of bacteria in each well is observed, and the minimum inhibitory concentration (MIC) is the lowest drug concentration that completely inhibits bacterial growth in the well.

[0585] The strains used in the antibacterial activity experiments were from the American Type Culture Collection (ATCC) and clinical isolates.

[0586] The strains used for the antibacterial activity experiments included Escherichia coli ATCC BAA-2523, ATCC BAA-2340 (KPC), Klebsiella pneumoniae KPN+19-15, ATCC BAA-1705 (KPC), Pseudomonas aeruginosa PAE19-3, ATCC27853, and Acinetobacter baumannii ABA19-1, NCTC13304 (OXA-27).

[0587] Test product: a cyclic lipopeptide compound prepared according to the technical scheme of the present invention;

[0588] Reference substance: polymyxin B.

[0589] result:

[0590] The negative bacterial activity of the cyclic polypeptide compound of the present invention is shown in Table 2.

[0591] Table 2 Gram-negative bacteria activity of the inventive compounds (MIC, unit μg / mL)

[0592]

[0593]

[0594]

[0595]

[0596] Experimental Example 2: Nephrotoxicity Experiment

[0597] The CCK-8 method was used to detect HK-2 cell cytotoxicity in vitro.

[0598] The culture medium of human kidney HK-2 cells is RPMI-1640 complete medium (Invitrogen) containing 10% FBS (Gibco), and the cryopreservation medium is 90% FBS + 10% DMSO, which is stored in liquid nitrogen for a long time; culture in a humidified sterile incubator at 37°C containing 5% CO2, and digest and subculture when the cell density grows to 70%-80%. Weigh the cyclic lipopeptide compound prepared in Example 1-120, dissolve it in sterile water to 1 mg / mL of the mother solution, and prepare the drug-containing culture medium, the final concentration is 500, 250, 200, 100, 50, 25, 12.5 μg / mL. 5×10 4 / ml cells, spread in a 96-well plate, 100μL cell suspension in each well, replace the drug-containing culture medium after stable culture for 24h, and culture in an incubator for 72h. Gently aspirate the culture medium, add 100μL of blank culture medium containing 10% CCK-8, incubate in an incubator for 3h, and use a BIOTEK plate reader to measure the OD 450nm value. The experiment was repeated three times, and each time polymyxin B was set as the positive drug and the blank treatment group without drug was used as the control. Calculate the cell survival rate (%) = (OD drug group-OD zero) / (OD drug-free-OD zero)*100%, and use Log regression to calculate IC 50 value.

[0599] The cells used in the renal cell toxicity experiment were from ATCC (American Type Culture Collection) in the United States. The Cell Counting Kit-8 (CCK-8) kit used in the renal cell toxicity experiment was from Beyotime Biotechnology.

[0600] Test product: antimicrobial lipopeptide compound prepared according to the technical scheme of the present invention;

[0601] Reference substance: polymyxin B.

[0602] result:

[0603] The renal cell toxicity results of some cyclic polypeptide compounds of the present invention are shown in Table 3.

[0604] Table 3 Human renal cell toxicity (IC 50 , unit μg / mL)

[0605]

[0606]

[0607]

[0608]

[0609] Experimental Example 3: Acute toxicity test of compounds 2 and 7 in healthy mice

[0610] Healthy 5-6 week old ICR mice were selected, 5-10 mice per group, and the drug was administered by a single tail vein injection. The administration volume was 20 mL / kg. After the drug dose concentrations at which 100% of mice died and no death occurred after a single intravenous injection of mice were determined in the preliminary test, 4-5 dose groups were set within this dose range, and the interval between dose groups was 1:0.5-1:0.8. The death of animals within 7 days after administration was recorded, and the Bliss method was used to calculate the median lethal dose (LD50) of the test article based on the mortality rate of each group of experimental animals. 50 ), which is the dose that causes death in 50% of the tested animals.

[0611] There were no abnormalities in the mice in the vehicle control group after a single tail vein injection of the vehicle.

[0612] The mortality rates of compound 2 injected into the caudal vein at a dose of 30, 24, 19.2, and 15.36 mg / kg were 100% (3 / 3), 62.5% (5 / 8), 25% (2 / 8), and 0% (0 / 8), respectively. 50 The mortality rate of compound 7 injected into the tail vein at a dose of 30, 24, 19.2, and 15.36 mg / kg was 100% (3 / 3), 25% (2 / 8), 12.5% ​​(1 / 8), and 0% (0 / 8), respectively. 50 It is 24.43 mg / kg (95% confidence limit: 21.78-27.59).

[0613] Experimental Example 4: In vivo antibacterial experiment of compound 7

[0614] Pseudomonas aeruginosa ATCC27853 was selected for in vivo antibacterial activity testing.

[0615] The test bacteria were inoculated onto the corresponding nutrient agar plate one day before infection and cultured overnight. On the day of infection, single colonies were picked from the plate and added to sterile physiological saline and mixed to obtain the original bacterial solution. The bacterial solution was then prepared with 5% dry yeast powder to the required concentration and used immediately after preparation.

[0616] Healthy ICR mice were randomly divided into groups, with 5 mice in each group, half male and half female. The above-mentioned bacterial solutions of different dilution concentrations were injected intraperitoneally into the mice, with each mouse injected with 0.5mL / 20g of bacterial solution. The mice were observed for 7 days after infection, and the number of deaths of mice was recorded. The lowest bacterial dose that caused 100% death of mice was taken as the minimum lethal bacterial dose, which was used as the infection bacterial dose for the in vivo protection test.

[0617] The drug was administered by tail vein injection, and the frequency of administration was once at 2h, 8h, 24h, and 30h after infection, for a total of 4 times. The administration volume was 20mL / kg. The drug solution was prepared by preparing compound 7 and control drugs polymyxin B and meropenem with physiological saline to the required concentration solution for tail vein injection, which was prepared and used immediately.

[0618] In the preliminary test, after determining the drug dosage concentrations at which 100% of mice died or no mice died after being infected with the test bacteria, 4-5 dosage groups were set within this dosage range, and the ratio between dosage groups was 1:0.5-1:0.8.

[0619] Mice were randomly divided into groups according to body weight, with 8 mice in each group, half male and half female. The experimental bacterial solution was intraperitoneally infected, and each mouse was injected with 0.5mL / 20g of bacterial solution. The drug was injected into the tail vein 2h, 8h, 24h, and 30h after infection. The blank control group was not infected with bacterial solution, but only given an equal volume of solvent. The administration volume was 20mL / kg. The number of mouse deaths was observed and recorded for 7 consecutive days. The median effective dose (ED) was calculated according to the Bliss method based on the number of mouse deaths. 50 The data were analyzed statistically with 95% confidence limits.

[0620] The minimum lethal concentration of Pseudomonas aeruginosa ATCC27853 for intraperitoneal infection of mice is 4.2×10 2 CFU / mL, this bacterial count is used as the infectious bacterial count for the formal test.

[0621] The number of MLD bacteria inoculated intraperitoneally in the infected control group mice (4.0×10 2Infection symptoms began to appear 3-4 hours after exposure to 5% (CFU / mL) Pseudomonas aeruginosa ATCC27853 bacterial liquid. All 8 animals died within 48 hours (8 / 8), with a mortality rate of 100%.

[0622] Polymyxin B was administered twice a day for 2 days. At the end of the observation period, the mortality rates of animals in the 2 mg / kg and 1.4 mg / kg dosage groups were 62.5% and 87.5%, respectively, and the mortality rates of the 1.0 mg / kg and 0.7 mg / kg dosage groups were both 100%.

[0623] Meropenem was administered twice a day for 2 days. At the end of the observation period, the mortality rate of the 20 mg / kg group was 0% (0 / 8); the mortality rates of the 10 mg / kg, 5 mg / kg, and 2.5 mg / kg groups were 37.5%, 62.5%, and 100%, respectively. The ED5 and ED 50 , ED 95 The values ​​were 2.91 mg / kg, 7.07 mg / kg, and 17.19 mg / kg respectively.

[0624] Compound 7 was administered twice a day for 2 days. At the end of the observation period, the mortality rate of the 10 mg / kg group was 0% (0 / 8); the mortality rates of the 7 mg / kg, 4.9 mg / kg, and 3.4 mg / kg groups were 37.5%, 87.5%, and 100%, respectively. The ED5, ED 50 , ED 95 The values ​​were 4.54 mg / kg, 6.38 mg / kg and 8.96 mg / kg respectively.

[0625] Due to space limitation, only part of the experiments are recorded in the specification, and other compounds of the present invention also have the same or similar therapeutic effects.

[0626] In summary, some of the polymyxin compounds prepared by the present invention have low nephrotoxicity, low acute toxicity, and high in vitro and in vivo antibacterial activity, and are entirely likely to become a new class of clinical antibiotics.

Claims

1. A cyclic basic lipopeptide compound having a structure as shown in general formula I or a pharmaceutically acceptable salt thereof, wherein the compound consists of three parts: a cyclic heptapeptide, a linear tripeptide and a side chain acyl chain (i.e., R0-CO-) connected to the linear tripeptide, AA represents an amino acid, wherein the carboxyl group of R0-COOH condenses with the α-amino group of AA1 to form an amide bond, the carboxyl group of AA1 condenses with the α-amino group of AA2 to form an amide bond, the carboxyl group of AA2 condenses with the α-amino group of AA3 to form an amide bond, the carboxyl group of AA3 condenses with the α-amino group of Dab4 to form an amide bond, the carboxyl group of Dab4 condenses with the α-amino group of AA5 to form an amide bond, the carboxyl group of AA5 condenses with the α-amino group of AA6 to form an amide bond, the carboxyl group of AA6 condenses with the α-amino group of AA7 to form an amide bond, the carboxyl group of AA7 condenses with the α-amino group of AA8 to form an amide bond, the carboxyl group of AA8 condenses with the α-amino group of AA9 to form an amide bond, the carboxyl group of AA9 condenses with the α-amino group of AA1 10 The α-amino groups of 10 The carboxyl group of Dab4 condenses with the γ-amino group of Dab4 to form an amide bond. R0-CO-AA1-AA2-D / L-AA3-cyclo(4-10)[Dab4-AA5-D / L-AA6-AA7-AA8-AA9-AA 10 ​ Ⅰ Where: R0 is selected from the group consisting of: (C6-C 11 )-straight chain alkyl, (C7-C 12 )-branched alkyl; AA1 and AA3 are independently selected from the group consisting of Ser (serine), Ser (CH2SO3H) (2-amino-3-sulfomethyloxypropionic acid), Dap (2,3-diaminopropionic acid), Dap (CH2SO3H) (2-amino-3-sulfomethylaminopropionic acid), Dab (2,4-diaminobutyric acid), Dab (CH2SO3H) (2-amino-4-sulfomethylaminobutyric acid), Orn (ornithine), Lys (lysine); the configuration of the amino acid at position 1 is L-type, and the configuration of the amino acid at position 3 is D or L-type; AA2 and AA 10 Independently selected from the group consisting of: Thr (threonine), Thr (CH2SO3H) (2-amino-3-sulfomethoxybutyric acid); the configuration of amino acids at positions 2 and 10 is L-type; The conformation of Dab4 is L-type; AA5, AA8 and AA9 are independently selected from the group consisting of: Dap (2,3-diaminopropionic acid), Dap (CH2SO3H) (2-amino-3-sulfomethylaminopropionic acid), Dab (2,4-diaminobutyric acid), Dab (CH2SO3H) (2-amino-4-sulfomethylaminobutyric acid), Orn (ornithine); the configuration of amino acids at positions 5, 8 and 9 is L-type; AA6 and AA7 are independently selected from the group consisting of: Phe (phenylalanine), Phe (4-CH2SO3) (4-sulfomethylphenylalanine), Leu (leucine), Thr (threonine), Thr (CH2SO3H) (2-amino-3-sulfomethyloxybutyric acid); the configuration of the amino acid at position 6 is D or L, and the configuration of the amino acid at position 7 is L; The straight-chain alkyl group may be hexyl, heptyl, octyl or nonyl; the branched-chain alkyl group may be 5-methylhexyl, 5-methylheptyl, 6-methylheptyl, 6-methyloctyl, preferably (S)-5-methylheptyl.

2. The cyclic basic lipopeptide compound having the structure represented by general formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The cyclic lipopeptide compound is selected from the group consisting of: (1) (S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (2) 6-methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (3) Octanoyl-Dab-Thr-D-Dap-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (4) Heptanoyl-Dab-Thr-D-Dap-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (5) Nonanoyl-Dab-Thr-D-Dap-cyclo (4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (6)(S)-6-methyloctanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (7) 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (8) Octanoyl-Dab-Thr-Dap-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (9) Heptanoyl-Dab-Thr-Dap-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (10) Nonanoyl-Dab-Thr-Dap-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (11) (S)-6-methyloctanoyl-Dab-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (12) 6-methylheptanoyl-Dab-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (13) Octanoyl-Dab-Thr-D-Dab-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (14) Heptanoyl-Dab-Thr-D-Dab-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (15) Nonanoyl-Dab-Thr-D-Dab-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (16) (S)-6-methyloctanoyl-Dab-Thr-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (17) 6-methylheptanoyl-Dab-Thr-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (18) Octanoyl-Dab-Thr-Dab-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (19) Heptanoyl-Dab-Thr-Dab-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (20) Nonanoyl-Dab-Thr-Dab-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (21) (S)-6-Methyloctanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (22) 6-methylheptanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (23) Octanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (24) Heptanoyl-Dab-Thr-D-Orn-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (25) Nonanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (26) (S)-6-Methyloctanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (27) 6-Methylheptanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (28) Octanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (29) Heptanoyl-Dab-Thr-Orn-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (30) Nonanoyl-Dab-Thr-Orn-Cyclo(4-10) [Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (31) (S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (32) 6-methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (33) Octanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (34) Heptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (35) Nonanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (36) (S)-6-methyloctanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (37) 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (38) Octanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (39) Heptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (40) Nonanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (41)(S)-6-Methyloctanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (42) 6-Methylheptanoyl-Dab-Thr-D-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (43) Octanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (44) Heptanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (45) Nonanoyl-Dab-Thr-D-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (46) (S)-6-Methyloctanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (47) 6-Methylheptanoyl-Dab-Thr-Orn-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (48) Octanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (49) Heptanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (50) Nonanoyl-Dab-Thr-Orn-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (51) (S)-6-methyloctanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (52) 6-methylheptanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (53) Octanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (54) Heptanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (55) Nonanoyl-Dap-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (56) (S)-6-Methyloctanoyl-Orn-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (57) 6-methylheptanoyl-Orn-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (58) Octanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (59) Heptanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (60) Nonanoyl-Orn-Thr-D-Ser-Cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (61) (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]; (62) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]; (63) Octanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]; (64) Heptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]; (65) Nonanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dap-D-Phe-Thr-Dab-Dab-Thr]; (66) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]; (67) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]; (68) Octanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]; (69) Heptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]; (70) Nonanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Orn-D-Phe-Thr-Dab-Dab-Thr]; (71) (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]; (72) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]; (73) Octanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]; (74) Heptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]; (75) Nonanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dap-Dab-Thr]; (76) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]; (77) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]; (78) Octanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]; (79) Heptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]; (80) Nonanoyl-Dab-Thr-D-Ser-cyclo(4-10) [Dab-Dab-D-Phe-Thr-Orn-Dab-Thr]; (81) (S)-6-methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]; (82) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]; (83) Octanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]; (84) Heptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]; (85) Nonanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dap-Thr]; (86) (S)-6-Methyloctanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]; (87) 6-Methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]; (88) Octanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]; (89) Heptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]; (90) Nonanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Orn-Thr]; (91)(S)-6-methyloctanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (92) 6-methylheptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (93) Octanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (94) Heptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (95) Nonanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr]; (96) (S)-6-methyloctanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]; (97) 6-methylheptanoyl-Dap-Thr-D-Dab-cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]; (98) Octanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]; (99) Heptanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]; (100) Nonanoyl-Dap-Thr-D-Dab-Cyclo(4-10)[Dab-Dab-D-Leu-Leu-Dab-Dab-Thr]; (101)(S)-6-methyloctanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-Phe-Thr-Dab-Dab-Thr]; (102) 6-Methylheptanoyl-Dab-Thr-D-Dap-cyclo(4-10)[Dab-Dab-Phe-Thr-Dab-Dab-Thr] (103) 6-methylheptanoyl-Dab-Thr-D-Ser(CH2SO3H)-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (104) 6-methylheptanoyl-Dab-Thr(CH2SO3H)-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (105) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr(CH2SO3H)-Dab-Dab-Thr]; (106) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr(CH2SO3H)]; (107) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe(4-CH2SO3H)-Thr-Dab-Dab-Thr]; (108) 6-methylheptanoyl-Dab(CH2SO3H)-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (109) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab(CH2SO3H)-D-Phe-Thr-Dab-Dab-Thr]; (110) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab(CH2SO3H)-Dab-Thr]; (111) 6-methylheptanoyl-Dab-Thr-D-Ser-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab(CH2SO3H)-Thr]; (112) 6-Methylheptanoyl-Dab-Thr-Dap(CH2SO3H)-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (113) 6-Methylheptanoyl-Dab-Thr(CH2SO3H)-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (114) 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr(CH2SO3H)-Dab-Dab-Thr]; (115) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr(CH2SO3H)]; (116) 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe(4-CH2SO3H)-Thr-Dab-Dab-Thr]; (117) 6-methylheptanoyl-Dab(CH2SO3H)-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab-Thr]; (118) 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab(CH2SO3H)-D-Phe-Thr-Dab-Dab-Thr]; (119) 6-methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab(CH2SO3H)-Dab-Thr]; (120) 6-Methylheptanoyl-Dab-Thr-Dap-cyclo(4-10)[Dab-Dab-D-Phe-Thr-Dab-Dab(CH2SO3H)-Thr].

3. The cyclic basic lipopeptide compound having the structure represented by general formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salts of the compound of general formula I include salts formed by the compound of general formula I and an acid, wherein the acid is selected from the group consisting of: an inorganic acid or an organic acid, wherein the inorganic acid is perchloric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; and the organic acid is acetic acid, trifluoroacetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid or p-toluenesulfonic acid.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the cyclic basic lipopeptide compound having the structure shown in general formula I as described in any one of claims 1 to 3 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.

5. Use of the cyclic basic lipopeptide compound having the structure represented by general formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 in the preparation of antibacterial drugs.

6. The use according to claim 5, characterized in that The antibacterial drug is a drug against Gram-negative bacteria.

7. A method for preparing the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: (1) The protected free amino group of the side chain of the basic amino acid Fmoc-AA-OP is reacted with a halogenated resin to obtain Fmoc-AA-OP-resin; wherein P is a carboxyl protecting group selected from: allyl (Allyl) and benzyl (Bn); when Fmoc-AA-OP is Fmoc-Dab-OP, its structure is shown in Formula II; when Fmoc-AA-OP is Fmoc-Dap-OP, its structure is shown in Formula III; when Fmoc-AA-OP is Fmoc-Orn-OP, its structure is shown in Formula IV: (2) Fmoc-AA-OP-resin is coupled one by one to obtain linear peptide-resin; (3) selectively removing the protecting group from the linear peptide-resin and performing solid phase cyclization to obtain the cyclic peptide-resin; (4) Acid hydrolysis of the cyclic polypeptide-resin to obtain a crude cyclic polypeptide; (5) The crude cyclic polypeptide is purified and / or converted to salt, and then freeze-dried to obtain a pure cyclic polypeptide.

8. The method according to claim 7, characterized in that The following steps are involved: (1) Preparation of Fmoc-AA-OP resin: Add the halogenated resin to a peptide solid phase synthesis tube, add DCM to swell, wash with DMF three times, wash with DCM three times after swelling, dissolve the protected starting amino acid Fmoc-AA-OP and the base with DCM and add to the peptide synthesis tube, react at room temperature for 2 h, remove the reaction solution under vacuum, wash the resin with DMF three times, and wash with DCM three times to obtain Fmoc-AA-OP resin; (2) Coupling synthesis method: The Fmoc-AA-OP-resin obtained in step (1) was treated with 20% piperidine / DMF for 10 min each time, for a total of 2 times to remove the α-amino Fmoc protecting group, and then washed with DMF three times and DCM three times. The amino acid or side chain carboxylic acid, DIEA and HCTU were dissolved in DMF and added to the peptide synthesis tube, reacted at room temperature for 120 min, the reaction solution was removed by vacuum, and washed with DMF three times and DCM three times; From the 8th amino acid, one by one is coupled to the 1st amino acid, and then the side chain carboxylic acid is coupled to the protected polypeptide-resin; the ivDde or Dde protecting group of the side chain amino group of the 4th amino acid is removed with a 2% hydrazine hydrate / DMF solution, washed with DMF three times, washed with DCM three times, and the carboxyl group of the 10th amino acid is coupled to the side chain amino group of the 4th amino acid; or from the 7th amino acid, one by one is coupled to the 1st amino acid, and then the side chain carboxylic acid is coupled to the protected polypeptide-resin; the ivDde or Dde protecting group of the side chain amino group of the 4th amino acid is removed with a 2% hydrazine hydrate / DMF solution, washed with DMF three times, washed with DCM three times, and the carboxyl group of the 10th amino acid is coupled to the side chain amino group of the 4th amino acid, and then the carboxyl group of the 9th amino acid is coupled to the α-amino group of the 10th amino acid; (3) Selective removal of protecting groups and solid phase cyclization: The linear fully protected peptide-resin in step (2) is treated with 20% piperidine / DMF for 10 min each time, for a total of 2 times, to remove the α-amino Fmoc protecting group, and then washed with DMF three times and DCM three times to form a free amino group; the carboxyl allyl protecting group is removed with tetrakis(triphenylphosphine)palladium / phenylsilane in a mixed solution of DCM and DMF to form a free carboxyl group; Dissolve PyAOP and HOAT in DMF and add NMM, add to the peptide synthesis tube, react at room temperature for 3 hours, remove the reaction solution in vacuo, wash three times with DMF and three times with DCM to obtain a cyclic fully protected peptide-resin; (4) Crude cyclic basic lipopeptide obtained by acid hydrolysis: add an acid hydrolysis solution with a volume ratio of TFA:H2O of 95:5 to a peptide synthesis tube, react at room temperature for 120 min, add the acid hydrolysis solution to cold ether, the volume ratio of TFA lysis solution to cold ether is 1:20, precipitate the peptide, centrifuge, and dry to obtain a crude product; (5) Purification, salt conversion and freeze-drying of crude product: The crude product was dissolved in water and filtered with a 0.22 μm filter membrane for later use. The crude product was subjected to preparative high performance liquid chromatography. The chromatographic filler was 10 μm reverse phase C18, the mobile phase A was 0.08% TFA / water solution, the mobile phase B was 0.08% TFA / acetonitrile solution, the flow rate of the 22 mm×250 mm chromatographic column was 8 mL / min, the detection wavelength was 214 nm, and the gradient system was used for elution and cyclic injection purification. The crude product solution was loaded on the chromatographic column, and the mobile phase elution was started. The fractions corresponding to the main peak of the chromatogram were collected. The acetonitrile was evaporated from the fractions to obtain a polypeptide aqueous solution, which was freeze-dried to obtain the product.

9. The method according to claim 7 or 8, characterized in that The halogenated resin is selected from the group consisting of trityl chloride resin, 4-methyltrityl chloride resin, 4-methoxytrityl chloride resin, 2-chlorotrityl chloride resin, bromo-(4-methylphenyl)-methyl resin or bromo-(4-methoxyphenyl)-methyl resin, preferably, the resin is 2-chlorotrityl chloride resin.

10. The method according to claim 7 or 8, characterized in that In step (1), the degree of substitution of the halogenated resin is 0.1-1.6 mmol / g, preferably 0.5-1.0 mmol / g; The amount of each Fmoc-protected amino acid is 1.2-6 times the total molar number of the feed resin, preferably 2.0-4.0 times; The base is selected from at least one of N,N-diisopropylethylamine (DIEA), triethylamine (TEA), and pyridine, and the molar amount of the base is 1.5-3 times the molar amount of the Fmoc-protected amino acid. The substitution reaction time is 1-12h.

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