Novel modified side chain, and preparation method therefor and use thereof

Abstract

Provided are a novel modified side chain, and a preparation method therefor and a use thereof. In particular, provided are a modified side chain as represented by general formula (I), and a preparation method therefor, a pharmaceutical composition containing same, and a use thereof in the preparation of drugs for treating cancer, infections, neuropsychiatric diseases, cardiovascular diseases, endocrine diseases, and immune-related diseases.

Description

Novel modified side chains, methods of making and uses thereof TECHNICAL FIELD

[0001] The present invention relates to a novel modified side chain, methods of making and uses thereof. In particular, the present invention relates to a modified side chain comprising a general formula (I) and methods of making thereof, and pharmaceutical compositions comprising said side chain and uses of said side chain or pharmaceutical compositions. BACKGROUND

[0002] Polypeptide drugs are drug molecules composed of short chains of amino acids, typically consisting of 2 to 50 amino acid residues, with a molecular size between small molecule compound drugs and large molecule protein drugs. Compared with small molecule compound drugs, polypeptide drugs often have higher activity and stronger selectivity, while being relatively safe and well tolerated. Compared with protein drugs, polypeptide drugs have the advantages of low immunogenicity, lower toxicity and side effects, and lower production cost; at the same time, some polypeptide drugs can also pass through the cell membrane and specifically bind to intracellular targets, which has an incomparable advantage over antibody drugs.

[0003] Some common polypeptide drugs include insulin, growth hormone releasing hormone analogs, somatostatin analogs, peptide anti-tumor drugs, and peptide neuromodulators, etc. In addition, there are many ongoing researches to develop new polypeptide drugs to treat various diseases such as cancer, metabolic diseases, autoimmune diseases and nervous system diseases, etc. In general, polypeptide drugs have a wide range of therapeutic applications and have shown great potential in the field of biological medicine.

[0004] At present, more than 7000 naturally occurring peptides have been identified, which usually play a crucial role in human physiology, including as hormones, neurotransmitters, growth factors, ion channel ligands or anti-infective agents. However, naturally occurring peptides are not directly suitable for use as therapeutic drugs due to their inherent weaknesses, including poor chemical and physical stability and short circulating plasma half-life, etc. The problem of short half-life can be solved by modifying the amino acid sequence (such as introducing non-natural amino acids) or covalently linking side chains such as medium-chain fatty acids or polyethylene glycol.

[0005] Modifying the site of easily degradable amino acids in the polypeptide sequence can increase drug stability and reduce degradation by proteases. At the same time, by covalently linking a fatty chain or a polyethylene glycol side chain to the polypeptide sequence, the molecular weight of the polypeptide can be increased, the binding to albumin can be increased, the kidney clearance problem can be overcome, the plasma circulation time can be prolonged, and the half-life can be improved. In recent years, the GLP-1R agonist drug semaglutide has been marketed, which connects octadecanedioic acid to the 26th lysine of the peptide segment through a glutamic acid and two 8-amino-3,6-dioxoctanoic acid moieties, thereby reducing the kidney clearance of the polypeptide, greatly prolonging the half-life of the drug, achieving subcutaneous injection once a week, and reducing the frequency of drug administration for patients.

[0006] However, the modification of the polypeptide sequence with a fatty chain or a polyethylene glycol side chain may result in an excessively high plasma protein binding rate, leading to an excessively low free drug concentration and potential problems such as reduced drug efficacy or the need to increase the dosage of the polypeptide drug. Therefore, it is necessary to develop new types of polypeptide modification side chains that can improve drug stability and metabolic half-life while improving drug efficacy or reducing the dosage. SUMMARY

[0007] The present application aims to provide a side chain represented by general formula (I) comprising a structure represented by formula (I):

[0008] wherein: R1 is selected from -C(O)OR 1a or -P(O)OR 1a OR 1b ; R2 is selected from -C(O)OR 2a or -P(O)OR 2a OR 2b ; R3 is selected from -C(O)OR 3a or -P(O)OR 3a OR 3b ;

[0009] R4 is absent,

[0010] R 1a , R 2a or R 3a are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy;

[0011] R 1b , R 2b or R 3b are each independently selected from hydrogen, C 1-6 alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0012] R a Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0013] R b Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0014] R c Selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0015] R d Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0016] R e Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0017] R f Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0018] X is selected from -CH2- or -0-; n1 is selected from 0 or 1 ; n2 is selected from an integer between 1 and 30; n3 is selected from 0, 1, 2, 3 or 4; n4 is selected from 0 or 1 ; n5 is selected from 0, 1, 2, 3 or 4; n6 is selected from 0, 1, 2 or 3; n7 is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1, 2 or 3; n9 is selected from 0 or 1 ; m1 is selected from an integer between 0 and 19; m2 is selected from an integer between 0 and 19; m3 is selected from an integer between 0 and 19; m4 is selected from an integer between 0 and 19; m5 is selected from an integer between 0 and 19; preferably, n6 and n8 are not simultaneously 0.

[0019] In a preferred embodiment of the application, said side chain comprises a structure according to formula (II):

[0020] In a preferred embodiment of the application, said side chain comprises a structure according to formula (III):

[0021] In a preferred embodiment of the application, said side chain comprises a structure according to formula (IV):

[0022] In a preferred embodiment of the application, said side chain comprises a structure according to formula (I-A):

[0023] In a preferred embodiment of the application, said side chain comprises a structure according to formula (I-B):

[0024] wherein: R1, R2, R3 are not simultaneously carboxylic acid or carboxylic acid derivative;

[0025] Preferably:

[0026] R1 is selected from -C(0)OR 1a , R2 is selected from -P(0)OR 2a , R3 is selected from -C(0)OR 3a OR 3b ;

[0027] R1 is selected from -C(0)OR 1a , R2 is selected from -P(0)OR 2a OR 2b , R3 is selected from -C(0)OR 3a ;

[0028] R1 is selected from -C(0)OR 1a , R2 is selected from -P(0)OR 2a OR 2b , R3 is selected from -P(0)OR 3a OR 3b ;

[0029] R1is selected from -P(O)OR 1a OR 1b R2is selected from -C(O)OR 2a R3is selected from -C(O)OR 3a ;

[0030] R1is selected from -P(O)OR 1a OR 1b R2is selected from -C(O)OR 2a R3is selected from -P(O)OR 3a OR 3b ;

[0031] R1is selected from -P(O)OR 1a OR 1b R2is selected from -P(O)OR 2a OR 2b R3is selected from -C(O)OR 3a ; or

[0032] R1is selected from -P(O)OR 1a OR 1b R2is selected from -P(O)OR 2a OR 2b R3is selected from -P(O)OR 3a OR 3b .

[0033] In preferred embodiments of the application, the side chain comprises a structure according to Formula (I-C):

[0034] In preferred embodiments of the application, the side chain comprises a structure according to Formula (II-A):

[0035] In preferred embodiments of the application, the side chain comprises a structure according to Formula (II-B):

[0036] In preferred embodiments of the application, the side chain comprises a structure according to Formula (II-C):

[0037] In preferred embodiments of the application, the side chain comprises a structure according to Formula (III-A):

[0038] In preferred embodiments of the application, the side chain comprises a structure according to Formula (III-B):

[0039] In preferred embodiments of the application, the side chain comprises a structure according to Formula (III-C):

[0040] In preferred embodiments of the application, the side chain comprises a structure according to Formula (IV-A):

[0041] In preferred embodiments of the application, the side chain comprises a structure according to Formula (IV-B):

[0042] In preferred embodiments of the application, the side chain comprises a structure according to Formula (IV-C):

[0043] In preferred embodiments of the application, R1is -C(O)OR 1a .

[0044] In preferred embodiments of the application, R1is -P(O)OR 1a OR 1b .

[0045] In preferred embodiments of the application, R2is -C(O)OR 2a .

[0046] In preferred embodiments of the application, R2is -P(O)OR 2a OR 2b .

[0047] In preferred embodiments of the application, R3is -C(O)OR 3a .

[0048] In preferred embodiments of the application, R3is -P(O)OR 3a OR 3b .

[0049] In preferred embodiments of the application, R4is absent.

[0050] In preferred embodiments of the application, R4is

[0051] In preferred embodiments of the application, R4is

[0052] In preferred embodiments of the application, R 1a is selected from hydrogen, C 1-6 1-6alkyl, C 1-6 1-6haloalkyl, C 1-6 1-6hydroxyalkyl, C 1-6alkyl, C 1-6 haloalkyl; preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0053] In a preferred embodiment of the application, said R 2a is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0054] In a preferred embodiment of the application, said R 3a is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0055] In a preferred embodiment of the application, said R 1b is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0056] In a preferred embodiment of the application, said R 2b is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C1-6 alkyl, C 1-6 haloalkyl; preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0057] In a preferred embodiment of the application, said R 3b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0058] In a preferred embodiment of the application, said R a is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1- 6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably from the group consisting of hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0059] In a preferred embodiment of the application, said R b is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1- 6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably from the group consisting of hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen.

[0060] In a preferred embodiment of the application, said R c is selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6alkyl, C 1- 6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydroxy.

[0061] In a preferred embodiment of the present application, said R d is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen or methyl.

[0062] In a preferred embodiment of the present application, said R e is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen or methyl.

[0063] In a preferred embodiment of the present application, said R f is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; more preferably hydrogen or methyl.

[0064] In preferred embodiments of the application, X is -CH2-. In preferred embodiments of the application, X is -O-. In preferred embodiments of the application, n1 is selected from 0 or 1.

[0065] In preferred embodiments of the application, n2 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30; preferably from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 26; more preferably from 6, 8, 10 or 12.

[0066] In preferred embodiments of the application, n3 is selected from 0, 1, 2, 3 or 4.

[0067] In preferred embodiments of the application, n4 is selected from 0 or 1.

[0068] In preferred embodiments of the application, n5 is selected from 0, 1, 2, 3 or 4.

[0069] In preferred embodiments of the application, n6 is selected from 0, 1, 2 or 3; preferably 1, 2 or 3.

[0070] In preferred embodiments of the application, n7 is selected from 0, 1, 2, 3 or 4.

[0071] In preferred embodiments of the application, n8 is selected from 0, 1, 2 or 3.

[0072] In preferred embodiments of the application, n9 is selected from 0 or 1.

[0073] In preferred embodiments of the application, m1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; preferably 1.

[0074] In preferred embodiments of the application, m2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; preferably 1.

[0075] In preferred embodiments of the application, m3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; preferably 1.

[0076] In preferred embodiments of the application, m4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; preferably 1.

[0077] In preferred embodiments of the application, m5 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; preferably 1.

[0078] In preferred embodiments of the application, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26; n3 is 2; n4 is 0; n5 is 0; n6 is 1; n7 is 0; n8 is 0; m1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; m3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0079] In preferred embodiments of the application, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26; n3 is 0, 1, 2, 3, or 4; n4 is 0; n5 is 0; n6 is 1; n7 is 0; n8 is 0; m1 is 1; m3 is 1.

[0080] In preferred embodiments of the application, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26; n3 is 2; n4 is 0; n5 is 0; n6 is 1, 2, or 3; n7 is 0; n8 is 0; m1 is 1; m3 is 1.

[0081] In preferred embodiments of the application, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26; n3 is 0, 1, or 2; n4 is 0; n5 is 0; n6 is 1; n7 is 1 or 2; n8 is 0 or 1; m1 is 1; m3 is 1; m4 is 1; m5 is 1.

[0082] In preferred embodiments of the application, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26; n3 is 1 or 2; n4 is 1; n5 is 0 or 1; n6 is 1; n7 is 0; n8 is 0; m1 is 1; m2 is 1; m3 is 1.

[0083] In preferred embodiments of the application, nl is 0; n2 is selected from 6, 8, 10 or 12; n3 is 2; n4 is 0; n5 is 0; n6 is 1; n7 is 0; n8 is 0; ml is 1; and m3 is 1.

[0084] In preferred embodiments of the application, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are hydrogen.

[0085] In preferred embodiments of the application, the side chain comprises a structure according to formula (II-A-1), (II-A-2), (II-A-3) or (II-A-4):

[0086] In preferred embodiments of the application, the side chain comprises a structure according to formula (III-A-1), (III-A-2), (III-A-3) or (III-A-4):

[0087] In preferred embodiments of the application, the side chain comprises a structure according to formula (IV-A-1), (IV-A-2), (IV-A-3) or (IV-A-4):

[0088] The present application further relates to a method for preparing the above-mentioned side chain, characterized in that the method comprises the following steps:

[0089] Method I: raw material A is condensed with INT-1 in the presence of a condensing agent, and then ester hydrolysis is performed to obtain the product according to formula (I-1), wherein the raw material A, INT-1 and (I-1) are as follows:

[0090] Method II: raw material B is condensed with INT-2 in the presence of a condensing agent, and then ester hydrolysis is performed to obtain the product according to formula (I-2), wherein the raw material B, INT-2 and (I-2) are as follows:

[0091] wherein Pg is an amino protecting group selected from allyloxycarbonyl, trifluoroacetyl, tert-butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, piperonyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably 9-fluorenylmethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl;

[0092] R 1a-C(O)O-t-Bu or -P(O)OR 1a O-t-Bu;

[0093] R 2a -C(O)O-t-Bu or -P(O)OR 2a O-t-Bu;

[0094] R 3a -C(O)O-t-Bu or -P(O)OR 3a O-t-Bu;

[0095] R a , R b , R c , R e , R d , X, n1, n2, n3, n4, n5, n6, n7or n8are as defined in claim 1.

[0096] The condensing agent is selected from EDC, DIC, DCC, HATU, HBTU, HCTU, PyBop, DEPBT, TCFH, NMI, HOBT or Oxama.

[0097] In a preferred embodiment of the present application, the I-1 or I-2 can further condense with a starting material C under the action of a condensing agent to obtain a product represented by (I-3) after removing Pg, wherein the starting material C and (I-3) are as follows:

[0098] The present application further relates to a medicament comprising a polypeptide or protein modified by any of the side chains described; preferably, the protein is an antibody;

[0099] The polypeptide or antibody is an il-23 polypeptide antagonist, or a selective blocker of IL-23 receptor inhibitor, GLP1R / GIPR / GCGR single, double or triple agonist, or a C5 complement inhibitor;

[0100] Preferably, the il-23 inhibitor is an il-23 cyclic peptide inhibitor; more preferably, an oral cyclic peptide inhibitor; most preferably, APG-2309 and the following specific polypeptides or antibodies 1-25:

[0101] The GLP1R / GIPR / GCGR single, double or triple agonist is selected from the group consisting of maralixibat, BGM0504, HDM1005, tirzepatide, orforglipron, cagrisema, DR10624, UBT251, HM-15211, HM15275, retatrutide, efimosfermin, benaglutide, lixisenatide, exenatide, tirzepatide, insulinotropin, betatropin, TH-0318, MKC-253, LY-307161, utreglutide, BPI-3016, LY-548806, BIM-51077, GZR-18, XW-003, XW-004, GLP-1(7-37), CJC-1131, NN-9904, BMS-686117, DA-CH-5, NPM-115, HRS-4729, ZX2021, HZ010, MWN109, DYX116, HEC-007 and the following specific polypeptides 27-31.

[0102] The C5 complement inhibitor is selected from the group consisting of Zilucoplan, ALXN1720, Danicopan, Ravulizumab, Eculizumab and the following specific polypeptide 26.

[0103] The exemplary polypeptide compound according to the present application is an embodiment.

[0104] The present application further relates to a pharmaceutical preparation, wherein the drug of the pharmaceutical preparation comprises the side chain according to the present application.

[0105] The pharmaceutical preparation according to the present application is characterized in that the pharmaceutical preparation is an oral preparation or an injection preparation, wherein the oral preparation is selected from the group consisting of tablets, capsules, granules, oral liquids, pills or powders, and the injection preparation is selected from the group consisting of solution-type injection, suspension-type injection, emulsion-type injection, powder injection, liposome injection, microsphere injection and nanoparticle injection.

[0106] The side chain, the pharmaceutical preparation and the pharmaceutical composition according to the present application are characterized in that the side chain, the pharmaceutical preparation and the pharmaceutical composition can be applied to the target IL-23R, C5, GIPR / GLP1R or GLP1R / GIPR / GCGR.

[0107] A pharmaceutical composition comprising a therapeutically effective amount of a polypeptide drug comprising the side chain of the present application and a pharmaceutically acceptable carrier, diluent or excipient.

[0108] The present application further relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned drug or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0109] The present application further relates to the use of the above-mentioned drug or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the manufacture of a medicament for targeting IL-23R, C5, GIPR / GLP1R or GLP1R / GIPR / GCGR.

[0110] The present application further relates to the use of the above-mentioned side chain, drug or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, or the formulation thereof, in the manufacture of a medicament for treating or preventing cancer, infection, psychiatric, cardiovascular, endocrine and immune diseases; preferably, the diseases are inflammatory, autoimmune diseases and cancer, preferably inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schdede-Douglas syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes disease drugs; preferably inflammatory bowel disease (IBD), rheumatoid arthritis or psoriasis; or, the diseases are complement-related diseases, preferably recurrent severe infections, systemic lupus erythematosus, kidney disease, age-related macular edema, paroxysmal nocturnal hemoglobinuria, vascular edema, myasthenia gravis, inflammatory diseases, traumatic diseases, injury diseases, autoimmune diseases, vascular diseases, neurological diseases, eye diseases and atypical hemolytic uremic syndrome; or, the diseases are non-insulin-dependent diabetes, insulin-dependent diabetes or obesity; or, the diseases are metabolic disorder-related diseases, preferably diabetes or diabetes-related conditions, obesity or obesity-related conditions, non-alcoholic steatohepatitis.

[0111] In some embodiments of the present application, the pharmaceutical composition comprises the compound, its stereoisomer or its pharmaceutically acceptable salt in an amount of 0.1% to 95% by weight of the free base, preferably 90%, 85%, 80%, 75%, 70%, 60%, 50%.

[0112] In some embodiments of the present application, the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a liquid preparation or an injection, preferably further comprising a filler, optionally further comprising a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0113] The present application also provides a method of treating a disease condition using the polypeptide and its derivatives, or its pharmaceutically acceptable salt, or the pharmaceutical composition of the present application, which disease condition includes but is not limited to a condition associated with IL-23R, C5, GIPR / GLP1R or GLP1R / GIPR / GCGR.

[0114] The present application also relates to a method of treating a metabolic disorder-related condition in a mammal, comprising administering to the mammal a therapeutically effective amount of the polypeptide and its derivatives, or its pharmaceutically acceptable salt, of the present application.

[0115] The polypeptide drug and its derivatives, or its pharmaceutically acceptable salt, or the pharmaceutical composition, or its formulation form (such as oral or injection) of the present application is used for preparing a medicament for treating an immunological disease, a metabolic disease, a complement-related disease / condition, non-insulin dependent diabetes, insulin dependent diabetes or an obesity-related disease / condition.

[0116] In some embodiments, the present method is directed to the treatment of diseases such as cancer, infections, neuropsychiatric, cardiovascular, endocrine and immune disorders; preferably, the disease is an inflammatory, autoimmune disease and cancer, preferably inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with congenital immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schindler-Kanzaki syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes disease drugs; preferably inflammatory bowel disease (IBD), rheumatoid arthritis or psoriasis; or, the disease is a complement-associated disease, preferably recurrent severe infections, systemic lupus erythematosus, kidney disease, age-related macular edema, paroxysmal nocturnal hemoglobinuria, vascular edema, myasthenia gravis, inflammatory disease, traumatic disease, injury disease, autoimmune disease, vascular disease, neurological disease, ocular disease and atypical hemolytic uremic syndrome; or, the disease is non-insulin-dependent diabetes, insulin-dependent diabetes or obesity; or, the disease is a metabolic disorder-associated disease, preferably diabetes or diabetes-related disorder, obesity or obesity-related disorder, nonalcoholic steatohepatitis.

[0117] Detailed description of the invention

[0118] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0119] The amino acid sequences of the present invention contain the standard one-letter or three-letter codes for the twenty amino acids, and all amino acid residues in the present invention are preferably in the L-form, unless explicitly stated otherwise. In addition, Aib is alpha aminoisobutyric acid, D-Ala is D-form of alanine

[0120] "Natural amino acids" refer to the 20 conventional amino acids (i.e., alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y).

[0121] "Non-natural amino acids" refer to amino acids that are not naturally encoded or found in the genetic code of any organism. They can be, for example, purely synthetic compounds. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, gamma-carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminoheptanedioic acid, t-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2'-diaminoheptanedioic acid, 2,3-diaminopropionic acid (Dab), N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine (Orn), D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid, and thioproline. In addition, C-terminal carboxyl groups, N-terminal amino groups, and / or side chain functional groups of natural amino acids or non-natural amino acids are chemically modified.

[0122] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl being preferred.

[0123] The phrases "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used in the same sense and are intended to express that X can be any one of A, B, or C, or any combination thereof.

[0124] The term "modification" of an amino acid as used herein refers to substitution, addition, or deletion of an amino acid, including substitution or addition of any of the 20 naturally occurring amino acids.

[0125] The term "substitution" of an amino acid as used herein refers to the replacement of one amino acid residue with a different amino acid residue.

[0126] The term "polyethylene glycol" or "PEG" refers to a mixture of condensation products of ethylene oxide and water, existing in linear or branched form, having the general formula H(OCH2CH2)nOH, wherein n is minimally equal to 9. Unless otherwise specified, this term includes polymers of polyethylene glycol having an average total molecular weight selected from the range of 5,000 to 40,000 Daltons. n OH, wherein n is minimally equal to 9. Unless otherwise specified, this term includes polymers of polyethylene glycol having an average total molecular weight selected from the range of 5,000 to 40,000 Daltons.

[0127] The term "polyethylene glycol" or "PEG" used with a numerical suffix refers to the approximate average molecular weight of the PEG. For example, PEG-5000 refers to a polyethylene glycol having an average molecular weight of approximately 5,000 Daltons.

[0128] The term "PEGylation" or similar terms refers to the modification of a compound from its native state by attaching a PEG chain to the peptide.

[0129] The term "PEGylated peptide" refers to a peptide having a PEG chain covalently bound to the peptide.

[0130] The term "fatty acid" refers to a carboxylic acid having a long aliphatic tail (chain) which can be saturated or unsaturated; in the present invention, a fatty acid is a carboxylic acid having a C4-C30 straight chain or branched aliphatic group.

[0131] The general definition of "polypeptide" or "peptide" as used herein includes peptides having modified amino termini and carboxy termini. For example, a chain of amino acids comprising an amide group in place of the terminal carboxylic acid is included within the designation of an amino acid sequence of a naturally occurring amino acid.

[0132] The polypeptides of the present invention can include amino acids having amide bond hydrogen moieties replaced with methyl (N-methylation) or other alkyl groups, chemical groups or chemical linkages that are resistant to chemical or enzymatic treatment, N-terminal and C-terminal modifications.

[0133] Some polypeptides of the application can be cyclic. Cyclic polypeptides include any polypeptide having one or more cyclic features such as loops, bridging moieties, and / or internal linkages as part of its structure. As used herein, the term "bridging moiety" refers to one or more components of a bridge formed between two adjacent or non-adjacent amino acids, non-natural amino acids, or non-amino acids in a polypeptide. Bridging moieties can be of any size or composition. In some embodiments, a bridging moiety can comprise one or more chemical bonds between two adjacent or non-adjacent amino acids, non-natural amino acids, non-amino acid residues, or a combination thereof. In some embodiments, such chemical bonds can be between one or more functional groups on adjacent or non-adjacent amino acids, non-natural amino acids, non-amino acid residues, or a combination thereof. Bridging moieties can comprise one or more features including, but not limited to, amide bonds (lactams), disulfide bonds, thioether bonds, aromatic rings, triazole rings, hydrocarbon chains, and -COCH2-N-CH2CO- (where N is a substituted or unsubstituted -NH-). In some embodiments, a bridging moiety comprises an amide bond between an amine functional group and a carboxylic acid functional group, each present in an amino acid, non-natural amino acid, or non-amino acid residue side chain. In some embodiments, the amine or carboxylic acid functional group is part of a non-amino acid residue or non-natural amino acid residue. In some cases, a bridging moiety can comprise a bond formed between residues including, but not limited to, lysine and aspartic acid. Bridging moieties can be formed using olefin metathesis via a cyclization reaction. In some embodiments, a bridging moiety comprises a disulfide bond formed between two thiol-containing residues, including but not limited to cysteine. In some embodiments, a bridging moiety comprises one or more thioether bonds. Such thioether bonds can include those found in cycloalkyl sulfide compounds. These bonds are formed during a chemical cyclization reaction between a chloroacetic N-terminal modification group and a cysteine residue. In some cases, a bridging moiety comprises one or more triazole rings. In some cases, a bridging moiety comprises a -COCH2-N-CH2CO- structure (where N is a substituted or unsubstituted -NH-), "substituted" as defined below, and in addition N can also be substituted with a side chain as shown by Y2. In some embodiments, a bridging moiety comprises a non-protein or non-polypeptide based moiety including, but not limited to, a cyclic ring including, but not limited to, an aromatic ring structure (e.g., a xylyl group). Such bridging moieties can be introduced by reaction with a reagent containing multiple reactive halogens including, but not limited to, poly(bromomethyl)benzene, poly(bromomethyl)pyridine, poly(bromomethyl)alkylbenzene, and / or (E)-1,4-dibromo-but-2-ene.

[0134] The term "antibody" refers to an immunoglobulin, which is a four polypeptide chain structure connected by interchain disulfide bonds, consisting of two heavy chains and two light chains. According to the difference in the amino acid composition and the arrangement order of the constant region of the heavy chain of immunoglobulin, the immunoglobulin can be divided into five types, or called isotypes of immunoglobulin, namely IgM, IgD, IgG, IgA and IgE, and the corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain, respectively. The same type of Ig can be divided into different subtypes according to the difference in the amino acid composition of the hinge region and the number and position of the heavy chain disulfide bond, such as IgG can be divided into IgG1, IgG2, IgG3 and IgG4. The light chain is divided into κ chain or λ chain through the constant region. Each type of Ig in the five types of Ig can have κ chain or λ chain. The antibodies of the present disclosure include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies. The antibodies described in the present disclosure are preferably specific antibodies against cell surface antigens on target cells, and non-limiting examples are one or more of the following antibodies: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD44 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD105 antibody, anti-CEA antibody, anti-A33 antibody, anti-Cripto antibody, anti-EphA2 antibody, anti-G250 antibody, anti-MUC1 antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody or anti-Mesothelin antibody; exemplary examples are Trastuzumab (Trastuzumab, trade name Herceptin), Pertuzumab (also known as 2C4, trade name Perjeta), Nimotuzumab (trade name Tyvyt), Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab, Brentuximab, Gemtuzumab, Bivatuzumab, Lorvotuzumab, cBR96 and Glematumamab.

[0135] Any hydrogen atom in the compounds of the embodiments described in the present disclosure can be replaced by its isotope deuterium.

[0136] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclic group optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

[0137] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible (experimentally or theoretically) by a person skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0138] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The goal of a pharmaceutical composition is to facilitate administration to an organism and to facilitate absorption of the active ingredient(s) thereby facilitating biological activity.

[0139] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in a mammal and possess the desirable biological activity.

[0140] " " indicates that the bond can be in the R or S configuration, for example,

[0141] "THF" refers to tetrahydrofuran. "MeOH" refers to methanol. "DMF" refers to N,N-dimethylformamide.

[0142] "DCM" refers to dichloromethane. "TFA" refers to trifluoroacetic acid. "TEA" refers to triethylamine.

[0143] "DIEA" refers to N,N-diisopropylethylamine.

[0144] "HATU" refers to 2-(7-oxabenzo[l]triazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0145] "HCTU" refers to 6-chlorobenzotriazol-l, 1,3,3-tetramethyluronium hexafluorophosphate.

[0146] "IPA" refers to isopropyl alcohol. "TIS" refers to triisopropylsilane. "DTT" refers to dithiothreitol.

[0147] "HFIP" refers to hexafluoroisopropanol.​​

[0148] Other terms: DETAILED DESCRIPTION

[0149] In order to explain the present application in more detail, the following specific embodiments are provided, but the scope of the present application is not limited to the following embodiments.

[0150] The present application is further described in conjunction with the following examples, but the scope of the present application is not limited to the following examples.

[0151] The side chain structure of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The NMR determination is performed using a Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or deuterium water (D2O), and the internal standard (if any) is tetramethylsilane (TMS).

[0152] The determination of liquid chromatography-mass spectrometry LC-MS uses electrospray ion chromatography: Thermo.Scientific-LTQ-XL, and the determination of HPLC uses an Agilent 1260 high-pressure liquid chromatograph (Phenomenex Gemini C18, 4.6x150mm, 5μm chromatographic column). The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of TLC is 0.15mm-0.20mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0153] The starting materials in the embodiments of the present application are known and can be purchased on the market, or can be synthesized by using or according to the methods known in the art.

[0154] Unless otherwise specified, all reactions of the present application are carried out under continuous stirring, in a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature is in units of degrees Celsius.

[0155] Synthesis of side chain

[0156] Side chain L1

[0157] First step: Weigh 2-CTC Resin (346.4 g, Substitution 1.5 mmol / g) into the solid phase reactor, add anhydrous DCM (2 L), and swell for 30 minutes with nitrogen bubbling. Then, dry it. Weigh L1-P1 (100 g, 259.7 mmol) and DIEA (180.5 mL, 1.04 mol) into anhydrous DCM (2 L), and add them into the solid phase reactor. Bubble with nitrogen for 5 hours, and dry it. Then, add a mixture of DIEA (180.5 mL, 1.04 mol) in MeOH / DCM (1:4, 2 L), and bubble for 1.5 hours. Dry it. Wash it with DMF (2 L) and IPA (2 L) alternately for two times (bubble with nitrogen for 10 minutes), and then wash it with DMF (2 L) for three times. Dry it to obtain L1-1, which is directly used in the next step.

[0158] Second step: Add 20% piperidine / DMF solution (2 L*2) and bubble for 5 minutes, respectively. After 20 minutes, dry it. Wash the resin with DMF (2 L) for two times (bubble with nitrogen for 10 minutes), and then dry it to obtain L1-2, which shows deep blue in ninhydrin test.

[0159] Third step: Weigh L1-P1 (150 g, 389.6 mmol), HATU (148.05 g, 389.6 mmol), and DIEA (180.5 mL, 1.04 mol) into DMF (2 L), and add them into the solid phase reactor. Bubble with nitrogen for 2 hours, and dry it. Ninhydrin test shows light yellow. Wash it with DMF (2 L) and IPA (2 L) alternately for two times (bubble with nitrogen for 10 minutes), and then wash it with DMF (2 L) for three times. Dry it to obtain L1-3, which is directly used in the next step.

[0160] Fourth step: Add 20% piperidine / DMF solution (2 L*2) and bubble for 5 minutes, respectively. After 20 minutes, dry it. Wash the resin with DMF (2 L) for two times (bubble with nitrogen for 10 minutes), and then dry it to obtain L1-4, which shows deep blue in ninhydrin test.

[0161] Fifth step: Weigh L1-P2 (165.58 g, 389.6 mmol), HATU (148.05 g, 389.6 mmol), and DIEA (180.5 mL, 1.04 mol) into DMF (2 L), and add them into the solid phase reactor. Bubble with nitrogen for 2 hours, and dry it. Ninhydrin test shows light yellow. Wash it with DMF (2 L) and IPA (2 L) alternately for two times (bubble with nitrogen for 10 minutes), and then wash it with DMF (2 L) for three times. Dry it to obtain L1-5, which is directly used in the next step.

[0162] Step 6: Add 20% piperidine / DMF solution (2 L*2) for 5 min each, and dry under vacuum for 20 min; wash the resin with DMF (2 L) for 2 times (nitrogen bubbling for 10 min), and dry under vacuum to get L1-6, which shows deep blue color in ninhydrin test.

[0163] Step 7: Weigh L1-P3 (133.25 g, 389.6 mmol), HATU (148.05 g, 389.6 mmol) and DIEA (180.5 mL, 1.04 mol) into DMF (2 L), and add into the solid phase reactor, nitrogen bubbling for 2 hours, dry under vacuum, ninhydrin test shows light yellow; wash with DMF (2 L) and IPA (2 L) alternately for 2 times (nitrogen bubbling for 10 min), and then wash with DMF (2 L) for 3 times, dry under vacuum to get L1-7.

[0164] Step 8: Wash with isopropyl ether (2 L*4) for 10 min each, and dry under vacuum, and then dry under nitrogen. Then transfer the resin into a 5 L three-necked flask, and add 20% hexafluoroisopropanol / DCM solution (2 L), and stir overnight at room temperature. Filter under suction, and then stir the resin again with 20% hexafluoroisopropanol / DCM solution (2 L) for 3 hours, filter under suction, and combine the filtrates, and concentrate the residue to give compound L1-8 (132 g). LC / MS: [M+H] + = 818.6.

[0165] 1 H NMR (400 MHz, CD3OD) δ 4.26 (dd, 1H), 4.15 (s, 2H), 4.03 (s, 2H), 3.74-3.70 (m, 4H), 3.69-3.66 (m, 4H), 3.62-3.56 (m, 4H), 3.47 (t, 2H), 3.40 (t, 2H), 2.37-2.18 (m, 6H), 2.17-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.69-1.55 (m, 4H), 1.47 (d, 18H), 1.32 (s, 20H).

[0166] Step 9: Add DIEA (47.40 g, 366.73 mmol) and HATU (35.97 g, 94.61 mmol) into a solution of compound L1-9 (60 g, 73.35 mmol) in ACN (600 mL) at 0 °C, and then add compound L1-P4 (23.18 g, 88.01 mmol), and stir for 1 hour at 0 °C. Concentrate the reaction solution under reduced pressure, dilute with water, and extract with ethyl acetate for 2 times, dry the organic phase, filter, and concentrate to give compound L1-9 (95.3 g, crude). LC / MS: [M] += 1062.

[0167] Step 10: To a solution of compound L1-9 (15 g, 14.12 mmol) in THF (100 mL) was added a solution of LiOH (1.78 g, 42.37 mmol) in water (50 mL) at 0 °C and stirred at 0 °C for 1 h. The reaction was concentrated and the residue was adjusted to pH 7 with 2N HC1 solution and purified by reverse phase C18 column chromatography (5% - 40%, 40% - 70%, ACN / 0.03% TFA / water) to give side chain L1 (10.09 g, TFA salt). LC / MS: [M] + = 1048.7.

[0168] 1 H NMR (400 MHz, CD3OD) δ 4.25 (dd, 1H), 4.04 (s, 2H), 4.01 (s, 2H), 3.95 (s, 2H), 3.74 (t, 4H), 3.72 - 3.63 (m, 14H), 3.62 - 3.54 (m, 6H), 3.47 (t, 2H), 3.39 (d, 2H), 3.23 (s, 6H), 2.55 (t, 2H), 2.32 - 2.19 (m, 6H), 2.15 - 2.06 (m, 1H), 1.90 (dd, 1H), 1.69 - 1.51 (m, 4H), 1.46 (d, 18H), 1.30 (s, 20H).

[0169] The following side chain was prepared according to the procedure for the synthesis of side chain L1:

[0170] Side chain L2

[0171] LC / MS: [M] + = 1104.6.

[0172] 1 H NMR (400 MHz, CD3OD) δ 4.26 (dd, 1H), 4.04 (d, 4H), 3.97 (d, 2H), 3.80 - 3.73 (m, 4H), 3.73 - 3.54 (m, 20H), 3.48 (t, 2H), 3.42 - 3.35 (m, 2H), 3.24 (s, 6H), 2.57 (t, 2H), 2.34 - 2.19 (m, 6H), 2.18 - 2.07 (m, 1H), 1.92 (ddd, 1H), 1.68 - 1.55 (m, 4H), 1.47 (d, 18H), 1.31 (s, 28H).

[0173] Side chain L3

[0174] LC / MS: [M] + = 959.6.

[0175] 1 H NMR (400 MHz, CD3OD) δ 4.27 (s, 1H), 4.06 (s, 2H), 3.97 (s, 2H), 3.83 - 3.63 (m, 14H), 3.62 - 3.53 (m, 4H), 3.40 (td, 2H), 3.24 (s, 6H), 2.57 (t, 2H), 2.36 - 2.19 (m, 6H), 2.19 - 2.06 (m, 1H), 1.91 (ddd, 1H), 1.69 - 1.54 (m, 4H), 1.47 (d, 18H), 1.31 (s, 28H).

[0176] Side chain L4

[0177] LC / MS: [M] + = 1077.2.

[0178] 1 H NMR (400 MHz, CD3OD) δ 4.27 (dd, 1H), 4.06 (s, 2H), 4.03 (s, 2H), 3.97 (s, 2H), 3.76 (t, 4H), 3.73 - 3.64 (m, 14H), 3.63 - 3.55 (m, 6H), 3.48 (t, 2H), 3.42 - 3.37 (m, 2H), 3.24 (s, 6H), 2.57 (t, 2H), 2.35 - 2.20 (m, 6H), 2.19 - 2.06 (m, 1H), 1.98 - 1.82 (m, 1H), 1.69 - 1.54 (m, 4H), 1.48 (d, 18H), 1.31 (s, 24H).

[0179] Side chain L5

[0180] LC / MS: [(M] + = 759.24

[0181] 1 H NMR (400 MHz, CD3OD) δ 4.29 (dd, 1H), 3.96 (s, 2H), 3.76 (t, 2H), 3.73 - 3.67 (m, 3H), 3.67 - 3.59 (m, 5H), 3.52 (t, 2H), 3.22 (s, 6H), 2.57 (t, 2H), 2.34 (t, 2H), 2.29 - 2.14 (m, 5H), 1.89 (ddt,, 1H), 1.60 (dd, 4H), 1.48 (d, 18H), 1.33 (d, 20H).

[0182] Side chain L6

[0183] LC / MS: [(M+H) / 2] = 625.06 +

[0184] 1 H NMR (400 MHz, CD3OD) δ 4.33 - 4.19 (m, 1H), 4.04 (d, 6H), 3.97 (d, 2H), 3.76 (t, 4H), 3.73 - 3.64 (m, 18H), 3.64 - 3.55 (m, 8H), 3.49 (t, 4H), 3.40 (d, 2H), 3.24 (s, 6H), 2.57 (t, 2H), 2.31 (t, 2H), 2.28 - 2.19 (m, 4H), 2.18 - 2.08 (m, 1H), 1.97 - 1.86 (m, 1H), 1.66 - 1.54 (m, 4H), 1.48 (d, 18H), 1.31 (s, 28H).

[0185] Side chain L7

[0186] First step: To a solution of compound L7-1 (CAS: 1118767-16-0, 4.0 g, 4.73 mmol) in CH3CN (45 mL) was added DIEA (3.67 g, 28.37 mmol), HATU (2.16 g, 5.67 mmol) and 2-amino-N-(2-(2-(3-methoxy-3-oxopropoxy)ethoxy)ethyl)-N,N-dimethylethan-1-aminium hydrochloride (2.13 g, 7.09 mmol) sequentially at 0 °C, then the solution was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure, the residue was purified by reverse column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound L7-2 (as TFA salt, 3.05 g), yield: 53.6%. LC / MS: [M] + = 1090.8.

[0187] ​​Second Step: To a solution of compound L7-2 (2.4 g, 1.99 mmol) in THF (24 mL) was added LiOH aqueous solution (143 mg, 5.97 mmol, 12 mL) at 0 °C, and the reaction was allowed to proceed at this temperature for 1 h. The reaction was concentrated to remove THF, and 1 N HC1 was added dropwise to the residue to adjust pH = 7. The mixture was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound L7-3 (as TFA salt, 1.1 g) in 46.4% yield. LC / MS: [M] + = 1076.7.

[0188] Third Step: To a solution of compound L7-3 (0.8 g, 0.67 mmol) in CH3CN (12 mL) was added DIEA (521 mg, 4.03 mmol), HATU (306 mg, 0.81 mmol) and N-Cbz-N-methylethylenediamine (hydrochloride, 245 mg, 1.01 mmol) sequentially at 0 °C, and the solution was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound L7-4 (as TFA salt, 870 mg) in 93.8% yield. LC / MS: [(M+H) / 2] + = 632.9.

[0189] Fourth Step: To a solution of compound L7-4 (650 mg, 0.56 mmol) in THF (20 mL) was added 10% Pd / C (65 mg), and the reaction was stirred at room temperature under a hydrogen atmosphere (1.5 atm) for 16 h. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound side chain L7 (as TFA salt, 570 mg) in 97.1% yield. LC / MS: [M] + = 1132.8.

[0190] Side chain L8

[0191] First Step: To a solution of compound L8-1 (50 g, 0.19 mol) in DMF (350 mL) was added NaHC03(79.8 g, 0.95 mol) and Mel (80.9 g, 0.57 mol) at room temperature. The mixture was stirred at 30 °C for 16 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2S04, filtered and the filtrate was concentrated to give compound L8-2 (55 g), which was used directly in the next step. LC / MS: [M+H] + -100 = 178.0.

[0192] Second Step: Compound L8-2 (10 g, 36.06 mmol) was dissolved in TFA / DCM (v:v = 1:2, 100 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to give compound L8-3 (10 g), which was used directly in the next step. LC / MS: [M+H] + = 178.1.

[0193] Third Step: To a solution of compound L8-1 (9.5 g, 36 mmol) in CH3CN (250 mL) was added compound L8-3 (6.4 g, 36 mmol), DIEA (23.3 g, 180 mmol) and HATU (13.6 g, 36 mmol) at 0 °C. The reaction was stirred at room temperature for 1 hour, diluted with water and extracted with ethyl acetate for three times. The combined organic layers were washed with saturated brine, dried over Na2S04, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0% - 5%, MeOH / DCM) to give compound L8-4 (15 g), yield: 98.7%. LC / MS: [M+H] + -100 = 323.2.

[0194] Fourth Step: Compound L8-4 (9.1 g, 21.54 mmol) was dissolved in HC1 / dioxane (4 N, 100 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to give compound L8-5 (7 g), which was used directly in the next step. LC / MS: [M+H] + = 323.4.

[0195] Step 5: To a solution of (S)-4-(((benzyloxy)carbonyl)amino)-5-(tert- butoxy)-5-oxopentanoic acid (7.2 g, 21.34 mmol) in CH3CN (80 mL) was added compound L8-5 (6.88 g, 21.34 mmol), DIEA (13.79 g, 106.71 mmol) and HATU (8.05 g, 21.34 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. The mixture was diluted with brine and extracted with EtOAc three times. The combined organic layers were washed with saturated brine, dried over Na2SO4and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0% - 5% MeOH / DCM) to give compound L8-6 (7 g) in 51.1% yield. LC / MS: [M+H] = 642.6. +

[0196] Step 6: To a solution of compound L8-6 (7 g, 10.91 mmol) in THF (150 mL) was added 10% Pd / C (700 mg) at room temperature. The mixture was stirred at room temperature under hydrogen atmosphere (1.5 atm) for 16 h. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give compound L8-7 (5.07 g) in 91.6% yield. LC / MS: [M+H] = 508.4. +

[0197] Step 7: To a solution of hexadecanedioic acid mono-tert-butyl ester (4.45 g, 12.99 mmol) in CH3CN (80 mL) was added compound L8-7 (5.07 g, 10 mmol), DIEA (6.45 g, 50 mmol) and HATU (4.45 g, 13 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h, diluted with brine and extracted with EtOAc three times. The combined organic layers were washed with saturated brine, dried over Na2SO4and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0% - 5% MeOH / DCM) to give compound L8-8 (7.7 g) in 92.6% yield. LC / MS: [M+H] = 832.7; +

[0198] 1 ​​​H NMR (400 MHz, CD3OD) δ 4.24 (dd, J = 9.1, 5.1 Hz, 1H), 4.16 (s, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 3.69 (dt, J = 5.3, 2.7 Hz, 4H), 3.66 - 3.62 (m, 4H), 3.56 (dt, J = 8.4, 5.5 Hz, 4H), 3.44 (t, J = 5.4 Hz, 2H), 3.37 (t, J = 5.5 Hz, 2H), 2.29 (t, J = 7.7 Hz, 2H), 2.25 - 2.16 (m, 4H), 2.10 (qd, J = 7.6, 5.3 Hz, 1H), 1.89 (dt, J = 16.5, 7.5 Hz, 1H), 1.64 - 1.52 (m, 4H), 1.45 (d, J = 9.1 Hz, 18H), 1.29 (s, 20H).

[0199] Step 8: To a solution of compound L8-8 (4 g, 4.81 mmol) in THF (40 mL) was added a solution of LiOH (0.23 g, 9.61 mmol) in water (10 mL) at 0 °C and the reaction was allowed to proceed at this temperature for 1 h. To the reaction was added 1 N HC1 to adjust pH = 4 and the aqueous phase was extracted with EtOAc for three times. The combined organic layers were washed with saturated brine, dried over Na2S04and filtered. The filtrate was concentrated under reduced pressure to give compound L8-9 (4 g) which was used directly in the next step. LC / MS: [M+H] + = 818.7.

[0200] Step 9: To a solution of compound L8-9 (3.5 g, 4.28 mmol) in CH3CN (40 mL) was added DIEA (3.32 g, 25.67 mmol), HATU (1.94 g, 5.13 mmol) and 2-amino-N-(2-(2-(3-methoxy-3-oxopropoxy)ethoxy)ethyl)-N,N-dimethylethan-1-aminium hydrochloride (1.92 g, 6.42 mmol) sequentially at 0 °C and the solution was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound L8-10 (as TFA salt, 2.16 g) in 43.7% yield. LC / MS: [M] + = 1062.8.

[0201] Tenth step: To a solution of compound L8-10 (2 g, 1.88 mmol) in THF (20 mL) was added LiOH aqueous solution (135 mg, 5.64 mmol, 10 mL) at 0 °C and the reaction was allowed to proceed at this temperature for 1 h. The reaction was concentrated to remove THF and 1 N HC1 was added dropwise to the residue to adjust pH = 7. The mixture was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound L8-11 (as TFA salt, 0.7 g) in 35.5% yield. LC / MS: [M] + = 1048.8.

[0202] Eleventh step: To a solution of compound L8-11 (0.7 g, 0.67 mmol) in CH3CN (10 mL) was added DIEA (517 mg, 4.0 mmol), HATU (302 mg, 0.8 mmol) and 2-amino-N-(2-(2-(3-methoxy-3-oxopropoxy)ethoxy)ethyl)-N,N-dimethylethan-1-aminium hydrochloride (208 mg, 1.0 mmol) sequentially at 0 °C and the solution was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound L8-12 (as TFA salt, 820 mg) in 99.2% yield. LC / MS: [(M+H) / 2] + = 620.4.

[0203] Twelfth step: To a solution of compound L8-12 (700 mg, 0.56 mmol) in THF (20 mL) was added 10% Pd / C (70 mg) at room temperature and the reaction was stirred under hydrogen atmosphere (1.5 atm) at room temperature for 16 h. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (5% - 40%, 40% - 70%, CH3CN / 0.03% TFA / water) to give compound side chain L8 (as TFA salt, 600 mg) in 95.1% yield. LC / MS: [M] + = 1104.7.

[0204] 1H NMR (400 MHz, CD3OD) δ 4.24 (dd, J = 9.2, 5.2 Hz, 1H), 4.02 (d, J = 14.0 Hz, 4H), 3.94 (s, 2H), 3.74 (q, J = 6.1 Hz, 4H), 3.71 - 3.63 (m, 14H), 3.61 - 3.54 (m, 6H), 3.48 (dt, J = 10.6, 5.6 Hz, 4H), 3.40 - 3.35 (m, 2H), 3.22 (s, 6H), 3.13 (t, J = 5.8 Hz, 2H), 2.73 (s, 3H), 2.51 (t, J = 6.2 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 2.26 - 2.17 (m, 4H), 2.11 (ddd, J = 15.6, 10.3, 6.6 Hz, 1H), 1.95 - 1.82 (m, 1H), 1.59 (dt, J = 22.3, 7.1 Hz, 4H), 1.45 (d, J = 9.0 Hz, 18H), 1.29 (s, 20H).

[0205] Side chain L9

[0206] Side chain L9 was prepared according to the synthesis of side chain L1-L8. LC / MS: [M] + = 1160.8.

[0207] Side chain L45

[0208] Side chain L45 can be prepared according to WO 2023 / 141044 and the synthesis of side chain L1.

[0209] Side chain L45 can be prepared from L1-6 according to the synthesis of side chain L1 by replacing starting material L1-P3 with 19-(bis(benzyloxy)phosphoryl)nonadecanoic acid (CAS: 2807449-20-1).

[0210] LC / MS: [(M+H) / 2] + = 632.9.

[0211] Side chain list

[0212] The preparation of side chains was performed according to the above preparation methods:

[0213] Preparation of exemplary polypeptide molecules

[0214] Polypeptide molecule P7

[0215] Polypeptide molecule P7 can be prepared by following the synthetic procedure for compound number 74 in patent WO2020 / 207477, replacing the side chain therein with side chain L2. LC / MS: [M-4H] 4- = 1311.9.

[0216] Polypeptide molecule P8

[0217] Polypeptide molecule P8 can be prepared by following the synthetic procedure for compound number 74 in patent WO2020 / 207477, replacing the side chain therein with side chain L6. LC / MS: [M-4H] 4- = 1348.9.

[0218] Polypeptide molecule P11

[0219] 3.1.1 Synthesis of resin peptide 1a: Refer to the synthetic procedure for resin peptide of compound number 74 in patent WO2020 / 207477, replacing Fmoc-Lys-L-(Mtt)-OH with Fmoc-L-Lys(Alloc)-OH to prepare resin peptide 1a;

[0220] 3.1.2 Side chain coupling

[0221] Side chain coupling charge table

[0222] 1) Wash: To the reaction tube containing resin peptide 1a, add 15 mL DCM, bubble nitrogen and stir for 2-3 minutes, and then drain. Repeat this step once more.

[0223] 2) Remove Alloc protecting group: Weigh morpholine (0.6 g) and Pd(PPh3)4(0.15 g) into 15 mL DCM, add to the reaction tube, bubble nitrogen and stir for 20-25 minutes, and then drain. Repeat this step twice.

[0224] 3) Remove Alloc protecting group wash: Add 15 mL DCM, bubble nitrogen and stir for 2-3 minutes, and then drain. Repeat this step twice. Add 15 mL DMF, bubble nitrogen and stir for 2-3 minutes, and then drain. Repeat this step twice. Ninhydrin test should be blue.

[0225] 4) Dissolve side chain L1 (2.05 g) and HCTU (0.8 g) in 15 mL DMF, then add DIEA (0.5 g), and then add to the reaction tube after stirring the mixture.

[0226] 5) Coupling reaction: nitrogen bubbling and stirring for 5 hours, ninhydrin test, no blue result, resin peptide 1b was obtained.

[0227] 3.1.3 Cleavage

[0228] Cleavage feed table

[0229] 1) Preparation of cleavage reagent: TFA (74 mL), DTT (2 g), TIS (2 mL) and purified water (2 mL) were added to the reaction bottle, and the mixture was cooled to 5-15°C by stirring.

[0230] 2) Resin peptide 1b was added to the reaction bottle, and the reaction was stirred for 3.5-4 hours.

[0231] 3) Filtration, filter cake was eluted with TFA; the filtrate was added to 0.8 L of isopropyl ether, stirred for 10 minutes, and then filtered after standing for 20 minutes; the filter cake was washed with isopropyl ether for 3 times, and vacuum dried.

[0232] 3.1.4 Purification

[0233] Purification chromatography conditions

[0234] The crude product was completely dissolved in 50% acetonitrile aqueous solution, diluted with water to one time (concentration about 10 mg / mL), and stirred at 40°C for 2 hours in a water bath. The solution was filtered with a 0.45 μm filter membrane, and the target component was collected with a sample injection volume of 60 mL. The acetonitrile was removed by concentration under reduced pressure, and freeze-drying was performed to obtain compound P11 (0.305 g), with a yield of 9% and a purity of 92.6%. LC / MS: [M-4H] 4- = 1298.3.

[0235] The polypeptide compound examples P12-16 of the application were synthesized by using the experimental scheme of P11, as shown in the following table 1:

[0236] Polypeptide molecule P9

[0237] cyclo(1,6) Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-7-azaTrp-E-Y-P-Chg-K(-NEG-OEG-OEG-γGlu-C20 diacid)

[0238] The polypeptide molecule P9 can be prepared by replacing the side chain in the reference preparation method (Amino Acids (2021) 53:143-147) with the side chain L2. LC / MS: [(M+2H) / 3] + = 1014.2.

[0239] Polypeptide molecule P17

[0240] cyclo(1,6) Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-7-azaTrp-E-Y-P-Chg-K(-NEG-OEG-OEG- γGlu-C16 diacid)

[0241] 3.2.1 Synthesis of the peptide chain sequence: The peptide chain synthesis of the peptide chain sequence cyclo(1,6) Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-7-azaTrp-E-Y-P-Chg-K according to the present example was synthesized from the carboxyl terminus to the amino terminus using the Fmoc-based solid phase synthesis method with Wang resin standard procedure, with HBTU / DIPEA (3 mmol / 6 mmol) as the condensation reagent, and 20% piperidine / DMF for Fmoc group removal. The 15 amino acid building blocks (1 mmol) used in the solid phase synthesis in order were: Fmoc-Lysine(Dde)-OH, Fmoc-L-cyclohexylglycine-OH, Fmoc-Pro-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-7-azaTrp-OH, Fmoc-Tyr(tBu)-OH, Fmoc-L-t-butyl-glycine-OH, Fmoc-N-Me-Asp(OtBu)-OH, Fmoc-Asp(O-2-PhiPr)-OH, Fmoc-Phe-OH, Fmoc-Arg(Boc)2-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, and Fmoc-Lys(Mtt)-OH, to give resin peptide 17a.

[0242] 3.2.2 Amide bond formation at position 1 and 6: Removal of the Mtt protecting group of the Lys at position 1 and the O-2-PhiPr protecting group of the Asp at position 6 for amide bond formation was carried out using 1% TFA in dichloromethane, followed by repeated condensation of the amino acid building blocks to give resin peptide 17b.

[0243] 3.2.3 Acetic anhydride capping: After removal of the Fmoc group at the amino terminus using 20% piperidine / DMF, capping was carried out by the addition of acetic anhydride (5 mmol) and DIPEA (6 mmol) to give resin peptide 17c.

[0244] 3.2.4 Side chain coupling: after removal of the Dde protecting group of Lys at position 15 using 5% hydrazine hydrate in DMF, the side chain L1 (3 mmol) and HCTU (3 mmol) were dissolved in DMF, and DIPEA (6 mmol) was added to the reaction to obtain the resin peptide 17d.

[0245] 3.2.5 Cleavage of resin peptide 17d: after washing the resin peptide 17d with DMF, DCM for 3 times, vacuum drying, and then adding freshly prepared cleavage solution (TFA / TIPS / H2O = 95:2.5:2.5) at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, and a large amount of ice was added to the isopropyl ether to precipitate the solid, and the crude peptide 17e was obtained by filtration.

[0246] 3.2.6 Purification of crude peptide 17e: the crude peptide 17e was dissolved in a mixture of 20% acetonitrile / water (containing 0.1% TFA), filtered through a 0.22 μm membrane, and separated by a WATERS Prep-150 LC reverse phase high performance liquid chromatography system, with buffer A (0.1% TFA, 10% acetonitrile, aqueous solution) and B (0.1% TFA, 90% acetonitrile, aqueous solution). The chromatographic column was X-SELECT OBD C-18 reverse phase chromatographic column, and the detection wavelength of the chromatograph was set to 220 nm during the purification process, and the flow rate was 20 mL / min. The target component was collected, acetonitrile was removed by vacuum concentration, freeze-dried to obtain the target product (0.30 g), yield: 10%, purity: 94.7%. LC / MS: [(M+2H) / 3] + = 995.8.

[0247] Polypeptide molecule P22

[0248] cyclo(1,6) Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-7-azaTrp-E-Y-P-Chg-K(-NEG-OEG-OEG-γGlu-C18 diacid)

[0249] Reference P17 was prepared according to the preparation method, wherein the side chain L1 in the side chain coupling was replaced by the side chain L4 to obtain P22 (0.19 g), total yield: 6.3%, purity: 93.7%. LC / MS: [(M+2H) / 3] + = 1004.9. Polypeptide molecule P10.

[0250] H-Aib-H-G-T-F-T-S-D-Y-S-I-L-L-E-K(-NEG-OEG-OEG-γGlu-C20 diacid)-K-A-A-Q-E-F-V-E-W-L-L-A-G-G-P-S-S-G-A-P-P-P-S-NH2

[0251] 1. Coupling of Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin: Weigh Rink Amide-AM Resin (1 mmol) into a reactor, add DMF (20 mL) to the reactor and nitrogen bubble to swell for 0.5 hour, then dry. Add 20% piperidine / DMF (20 mL) to the reactor, nitrogen bubble for 5 minutes, then dry. Add 20% piperidine / DMF (20 mL) to the reactor, nitrogen bubble for 20 minutes, then dry. Wash with DMF (20 mL) for 4 times, 2 minutes each time, then dry. Ninhydrin test, resin is blue. Weigh Fmoc-Ser(tBu)-OH (3.0 eq), HOBt (3.0 eq), DIC (3.0 eq) into DMF (20 mL), mix well and add to the reactor, nitrogen bubble to react for 2 hours. Ninhydrin test, resin is not blue. Wash with DMF, isopropyl alcohol, DMF, isopropyl alcohol, DMF, DMF, DMF in turn.

[0252] 2. Coupling of peptide chain sequence: Coupling was performed according to the peptide chain sequence of the compound, the peptide chain sequence from N-terminal to C-terminal was (H-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile- a-Me-cpAla-Leu-Glu-Lys-Lys-Ala-Ala-Gln-Glu-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2), and the solid-phase synthesis was performed in the order from C-terminal to N-terminal. The amount of the protecting amino acid and the condensation reagent and the condensation method were the same as those for coupling Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin. The protecting amino acids used in the synthesis process were Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-His(Trt)-Gly-OH, Boc-His(Trt)-Aib-OH, respectively. The coupling of the protecting amino acid and the Fmoc deprotection were repeated to complete the straight-chain resin peptide.

[0253] 3. Removal of Alloc protecting group from linear resin peptide: To the reactor, DCM (20 mL) was added, nitrogen was bubbled for 2 minutes, and then the solution was drained. This step was repeated once more. Morpholine (10 eq) and Pd(PPh3)4(0.2 eq) were dissolved in DCM (20 mL) and added to the reactor, nitrogen was bubbled for 20 minutes, and then the solution was drained. This step was repeated twice. DCM (20 mL) was added and washed for 2 minutes each time, and then the solution was drained. DMF (20 mL) was added and washed for 2 minutes each time, and then the solution was drained. Ninhydrin test, resin was blue.

[0254] 4. Side chain coupling: Side chain L2 (3.0 eq), HCTU (3.0 eq), and DIEA (6.0 eq) were weighed into DMF (20 mL), mixed, and then added to the reactor, nitrogen was bubbled for 4 hours. Ninhydrin test, resin did not turn blue. The resin was washed with DMF, isopropanol, DMF, isopropanol, DMF, DMF, and DMF, in that order.

[0255] 5. Cleavage of resin peptide: 50 mL of cleavage solution was prepared according to the ratio of TFA: DTT: Tis: H2O = 92.5: 2.5: 2.5: 2.5. The resin peptide was added to the cleavage solution, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solution was filtered, and the filtrate was eluted into isopropyl ether (500 mL), filtered, and the crude peptide was obtained.

[0256] 6. Purification of crude peptide: The crude peptide was dissolved in 20% acetonitrile / water solution, filtered through a 0.45 um membrane, and then separated by a reverse phase high performance liquid chromatography system, with buffer A (0.1% trifluoroacetic acid in water) and buffer B (acetonitrile). The chromatographic column was a C18 reverse phase chromatographic column, the detection wavelength of the chromatograph was set to 220 nm during the purification process, and the flow rate was 70 mL / min. The target component was collected, concentrated after reverse phase column, and then concentrated and lyophilized. The sample was determined for purity by HPLC, which was 90.1%; LC / MS (ESI): [(M+4H) / 5] = 1017.80, and the molecular weight of the compound was determined by mass spectrometry to be 5085.9. +

[0257] Polypeptide molecule P18

[0258] H-Aib-H-G-T-F-T-S-D-Y-S-I-Achx-L-E-K(-NEG-OEG-OEG-γGlu-C20 diacid)-K-A-A-Q-E-F-V-E-W-L-L-A-G-G-P-S-S-G-A-P-P-P-S-NH2

[0259] ​3.2.1.1 Coupling of Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin: Weigh Rink Amide-AM Resin (1 mmol) into a reactor, add DMF (20 mL) to the reactor and nitrogen bubbling to swell for 0.5 hour, and then dry the solvent. Add 20% piperidine / DMF (20 mL) to the reactor, and nitrogen bubbling for 5 minutes, and then dry the solvent. Add 20% piperidine / DMF (20 mL) to the reactor, and nitrogen bubbling for 20 minutes, and then dry the solvent. Add DMF (20 mL) to wash for 4 times, 2 minutes each time, and then dry the solvent. Ninhydrin test, the resin is blue. Weigh Fmoc-Ser(tBu)-OH (3.0 eq), HOBt (3.0 eq), DIC (3.0 eq) into DMF (20 mL), and then add to the reactor after mixing, and then nitrogen bubbling for 3 hours. Ninhydrin test, the resin is not blue. Dry the reaction solution, and then wash with DMF, isopropyl alcohol, DMF, isopropyl alcohol, DMF, DMF, and DMF, respectively.

[0260] 3.2.1.2 Coupling of peptide chain sequence: Coupling was performed according to the peptide chain sequence of the compound, the peptide chain sequence from N-terminus to C-terminus was (H-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Achx-Leu-Glu-Lys-Lys-Ala-Ala-Gln-Glu-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2), the solid phase synthesis was performed in the order from C-terminus to N-terminus, the amount of the protected amino acid and the condensation reagent and the condensation method thereof were the same as those of coupling Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin, and the protected amino acids used in the synthesis process were Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Achx-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-His(Trt)-Gly-OH, Boc-His(Trt)-Aib-OH, respectively. The coupling of Fmoc deprotection and protected amino acid was repeated to complete the straight chain resin peptide.

[0261] 3.2.1.3 Removal of Alloc protecting group from linear resin peptide: To the reactor, DCM (20 mL) was added, and nitrogen was bubbled for 5 minutes. The solvent was removed by suction. This step was repeated once more. Morpholine (10 eq) and Pd(PPh3)4(0.2 eq) were dissolved in DCM (20 mL) and added to the reactor. Nitrogen was bubbled for 20 minutes. The reaction was removed by suction. This step was repeated twice. DCM (20 mL) was added and washed for 3 times, 2 minutes each time. The solvent was removed by suction. DMF (20 mL) was added and washed for 3 times, 2 minutes each time. The solvent was removed by suction. Ninhydrin test, resin was blue.

[0262] 3.2.1.4 Side chain coupling: Side chain L2 (3.0 eq), HCTU (3.0 eq), and DIEA (6.0 eq) were weighed into DMF (20 mL) and added to the reactor. After mixing, nitrogen was bubbled for 24 hours. Ninhydrin test, resin did not turn blue. The reaction was removed by suction and washed with DMF, isopropanol, DMF, isopropanol, DMF, DMF, and DMF, in that order.

[0263] 3.2.1.5 Cleavage of resin peptide: 40 mL of cleavage solution was prepared according to the ratio of TFA:DTT:Tis:H2O = 92.5:2.5:2.5:2.5. The resin peptide was added to the cleavage solution and stirred at room temperature for 2 hours. After the reaction was completed, it was filtered and the filtrate was eluted into isopropyl ether (400 mL). The filtrate was filtered to obtain the crude peptide.

[0264] 3.2.1.7 Purification of crude peptide: The crude peptide was dissolved in 20% acetonitrile / water solution and filtered through a 0.45 um membrane. The purified mobile phase was A (0.1% trifluoroacetic acid in water) and B (acetonitrile). The chromatographic column was a C18 reverse phase chromatographic column. The detection wavelength of the chromatograph was set to 220 nm during the purification process, and the flow rate was 70 mL / min. The target component was collected, concentrated by reverse phase column, and freeze-dried. The sample was determined by HPLC to have a purity of 95.7%. LC / MS (ESI): [(M+3H) / 4] = 1275.00, [(M+4H) / 5] = 1020.20, which is consistent with the molecular weight of the compound 5097.9. + +

[0265] Polypeptide molecule P19

[0266] H-Aib-H-G-T-F-T-S-D-Y-S-I-α-Me-cpA-L-E-K(-NEG-OEG-OEG-γGlu-C20 diacid)-K-A-A-Q-E-F-V-E-W-L-L-A-G-G-P-S-S-G-A-P-P-P-S-NH2 ​​

[0267] 3.2.2.1 Coupling of Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin: Weigh Rink Amide-AM Resin (1 mmol) into a reactor, add DMF (20 mL) to the reactor and nitrogen bubble to swell for 0.5 hour, then dry. Add 20% piperidine / DMF (20 mL) to the reactor, nitrogen bubble for 5 minutes, then dry. Add 20% piperidine / DMF (20 mL) to the reactor, nitrogen bubble for 20 minutes, then dry. Wash with DMF (20 mL) for 4 times, 2 minutes each time, then dry. Ninhydrin test, resin is blue. Weigh Fmoc-Ser(tBu)-OH (3.0 eq), HOBt (3.0 eq), DIC (3.0 eq) into DMF (20 mL), mix well and add to the reactor, nitrogen bubble to react for 2 hours. Ninhydrin test, resin is not blue. Wash with DMF, isopropanol, DMF, isopropanol, DMF, DMF, DMF in turn.

[0268] 3.2.2.2 Coupling of peptide chain sequence: Coupling was performed according to the peptide chain sequence of the compound, the peptide chain sequence from N-terminus to C-terminus was (H-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile- a-Me-cpAla-Leu-Glu-Lys-Lys-Ala-Ala-Gln-Glu-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2), the solid-phase synthesis was performed in the order of C-terminus to N-terminus, the amount of the protected amino acid and the condensation reagent and the condensation method were the same as those of coupling Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin, and the protected amino acids used in the synthesis process were Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-a-Me-cpAla-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-His(Trt)-Gly-OH, Boc-His(Trt)-Aib-OH, respectively. The coupling of Fmoc deprotection and protected amino acid was repeated to complete the straight-chain resin peptide.

[0269] 3.2.2.3 Removal of Alloc protecting group from linear resin peptide: To the reactor, DCM (20 mL) was added, nitrogen was bubbled for 2 minutes, and then the solution was drained. This step was repeated once more. Morpholine (10 eq) and Pd(PPh3)4(0.2 eq) were dissolved in DCM (20 mL) and added to the reactor, nitrogen was bubbled for 20 minutes, and then the solution was drained. This step was repeated twice. DCM (20 mL) was added and washed for 2 minutes each time, and then the solution was drained. DMF (20 mL) was added and washed for 2 minutes each time, and then the solution was drained. Ninhydrin test, resin was blue.

[0270] 3.2.2.4 Side chain coupling: The side chain L2 (3.0 eq), HCTU (3.0 eq), and DIEA (6.0 eq) were weighed into DMF (20 mL), mixed, and then added to the reactor, nitrogen was bubbled for 4 hours. Ninhydrin test, resin did not turn blue. The resin was washed with DMF, isopropanol, DMF, isopropanol, DMF, DMF, and DMF, in that order.

[0271] 3.2.2.5 Cleavage of resin peptide: A 50 mL cleavage solution was prepared according to the ratio of TFA:DTT:Tis:H2O = 92.5:2.5:2.5:2.5. The resin peptide was added to the cleavage solution, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solution was filtered, and the filtrate was eluted into isopropyl ether (500 mL), filtered, and the crude peptide was obtained.

[0272] 3.2.2.6 Purification of crude peptide: The crude peptide was dissolved in 20% acetonitrile / water solution, filtered through a 0.45 um membrane, and then separated using a reverse phase high performance liquid chromatography system, with buffer A (0.1% trifluoroacetic acid in water) and buffer B (acetonitrile). The chromatographic column was a C18 reverse phase chromatographic column, the detection wavelength of the chromatograph was set to 220 nm during the purification process, and the flow rate was 70 mL / min. The target component was collected, concentrated after passing through the reverse phase column, and then freeze-dried. The sample was determined for purity by HPLC, which was 90%; LC / MS (ESI): [(M+3H) / 4] + = 1275.00, [(M+4H) / 5] + = 1020.20, which was consistent with the molecular weight of the compound 5097.9.

[0273] P20 can be synthesized according to the experimental scheme of the above examples.

[0274] Polypeptide molecule P21

[0275] cyclo(17,21)H-Aib-H-G-T-F-T-S-D-Y-S-I-α-Me-L-L-E-K-K-A-A-Q-K(-COCH2N(- NEG-OEG-OEG-γGlu-C20 diacid)-CH2CO)-F-V-E-W-L-L-A-G-G-P-S-S-G-A-P-P-P-S- NH2

[0276] First step Fmoc-Ser(tBu)-OH coupling with Rink Amide-AM Resin: Weigh Rink Amide-AM Resin (1 mmol) into the reactor, add DMF (20 mL) to the reactor and nitrogen bubbling to swell for 0.5 hours, and then dry the solvent. Add 20% piperidine / DMF (20 mL) to the reactor, and nitrogen bubbling for 5 minutes, and then dry the solvent. Add 20% piperidine / DMF (20 mL) to the reactor, and nitrogen bubbling for 20 minutes, and then dry the solvent. Add DMF (20 mL) to wash for 4 times, 2 minutes each time, and then dry the solvent. Ninhydrin test, the resin is blue. Weigh Fmoc-Ser(tBu)-OH (3.0 eq), HOBt (3.0 eq), DIC (3.0 eq) into DMF (20 mL), and then mix well and add to the reactor, and then nitrogen bubbling for 3 hours. Ninhydrin test, the resin does not change blue. Dry the reaction solution, and then wash with DMF, isopropyl alcohol, DMF, isopropyl alcohol, DMF, DMF, and DMF in sequence.

[0277] The second step of coupling the peptide chain sequence: according to the coupling of the compound peptide chain sequence, the peptide chain sequence is (H-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-α-Me-Leu-Leu-Glu-Lys-Lys-Ala-Ala-Gln-Lys-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2) from N terminal to C terminal. The solid phase synthesis is synthesized in the order from C terminal to N terminal. The amount of the protective amino acid and the condensation reagent and the condensation method are the same as those of the coupling of Fmoc-Ser(tBu)-OH to Rink Amide-AM Resin. The protective amino acids used in the synthesis process are Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-α-Me-Leu-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Lys(Alloc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-His(Trt)-Gly-OH, Boc-His(Trt)-Aib-OH, respectively. The coupling of the Fmoc deprotection and the protective amino acid is repeated to complete the straight chain resin peptide.

[0278] Third step: remove Fmoc protecting group: add 20% piperidine / DMF (20 mL) to the reactor, nitrogen bubbling for 5 minutes, dry the solvent. Add 20% piperidine / DMF (20 mL) to the reactor, nitrogen bubbling for 20 minutes, dry the solvent. Add DMF (20 mL) to wash 4 times, 2 minutes each time, dry the solvent. Ninhydrin test, resin blue.

[0279] Fourth step: side chain coupling: weigh side chain L2 (3.0 eq), HCTU (3.0 eq), DIEA (6.0 eq) into DMF (20 mL), mix well and add to the reactor, nitrogen bubbling for 24 hours. Ninhydrin test, resin unchanged blue. Dry the reaction solution, wash with DMF, isopropyl alcohol, DMF, isopropyl alcohol, DMF, DMF, DMF in turn.

[0280] Fifth step: remove Alloc protecting group: add DCM (20 mL) to the reactor, nitrogen bubbling for 5 minutes, dry the solvent. Repeat this step once. Weigh morpholine (10 eq), Pd(PPh3)4(0.2 eq) into DCM (20 mL), add to the reactor, nitrogen bubbling for 20 minutes, dry the reaction solution. Repeat this step twice. Add DCM (20 mL) to wash 3 times, 2 minutes each time, dry the solvent. Add DMF (20 mL) to wash 3 times, 2 minutes each time, dry the solvent.

[0281] Sixth step: remove ivDde protecting group of linear resin peptide: add 3% hydrazine hydrate / DMF (20 mL) to the reactor, nitrogen bubbling for 10 minutes, dry the reaction solution. Repeat this step twice. Add DMF (20 mL) to wash 4 times, 2 minutes each time, dry the solvent. Ninhydrin test, resin blue.

[0282] Seventh step: close the amide ring: weigh HATU (3.0 eq), HOBt (3.0 eq) DIEA (6.0 eq) into DMF (20 mL), mix well and add to the reactor, nitrogen bubbling for 4 hours. Ninhydrin test, resin unchanged blue. Dry the reaction solution, wash with DMF, isopropyl alcohol, DMF, isopropyl alcohol, DMF, DMF, DMF in turn.

[0283] Eighth step: cleavage of resin peptide: prepare 40 mL cleavage solution according to the ratio of TFA: DTT: Tis: H2O = 92.5: 2.5: 2.5: 2.5. Add the resin peptide to the cleavage solution, stir at room temperature for 2 hours. After the reaction is completed, filter, and the filtrate is eluted into isopropyl ether (400 mL), filter to obtain the crude peptide.

[0284] Step 9: Purification of the crude peptide: The crude peptide was dissolved in 20% acetonitrile / water solution, filtered through 0.45 um membrane and separated by reverse phase high performance liquid chromatography system, the mobile phase was A (0.1% trifluoroacetic acid in water) and B (acetonitrile). The C18 reverse phase column was used, the detection wavelength of the chromatograph was set at 220 nm, and the flow rate was 70 mL / min. The target component was collected, concentrated after reverse phase column, and the product was obtained by concentration and lyophilization. The sample was determined by HPLC to have a purity of 94.0%; LC / MS (ESI): [(M+3H) / 4] = 1299.50, which is consistent with the molecular weight of the compound 5196.0. +

[0285] Biological test evaluation

[0286] The following test examples further illustrate the application, but are not meant to limit the scope of the application.

[0287] Test Example 1: Experiment of the compound of the present application blocking hIL23-activated STAT3 phosphorylation in DB cells

[0288] 1.1 Purpose of the experiment: determination of the inhibitory activity of the compound of the present application on hIL23-activated STAT3 phosphorylation in DB cells

[0289] 1.2 Experimental instruments and reagents

[0290] 1.2.1 Instruments

[0291] 1.2.2 Reagents

[0292] 1.3 Experimental method: the above-mentioned compound was added to DB (ATCC Cat# CRL-2289) cells to inhibit the signal transduction of rhIL-23 cytokine. The compound screening was carried out in the form of a multi-well plate (suitable for ELISA assay), usually using rhIL-23 (0.5 nM, R&D SYSTEMS) to stimulate 6.25 x 10 6 cells / mL of DB cells in RPMI medium (Invitrogen) containing 10% FBS, and after half an hour, 50 μL of 2x lysis solution (CST) was used to lyse on ice. The lysis was used to determine the p-STAT3 content by PathScan Phospho-Stat3 (Tyr705) Sandwich ELISA Kit (CST Cat# 7300C), and the activity of the compound of the present application in blocking the signal transduction of rhIL23 on DB cells was calculated.

[0293] 1.4 Experimental data processing method: the inhibition rate was calculated as follows:​

[0294] Inhibition % = (Ave_H-Sample) / (Ave_H-Ave_L) x 100

[0295] H = Ave(DMSO); L = Ave(Guselkumab) Calculate IC of compound 50 Values: Non-linear regression fit of ELISA experimental results data with log(inhibitor) vs. response - Variable slope (four parameters) in Graphpad, fit curve and derive IC 50 Values.

[0296] Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0297] X: log of inhibitor concentration; Y: % Inhibition

[0298] 1.5 Experimental Conclusion: The compounds of the preferred embodiments of the present application showed excellent inhibitory activity in the hIL23 activated STAT3 phosphorylation inhibition test.

[0299] Test Example 2: Assay of the ability of the compounds of the present application to stimulate the production of cAMP by human GLP1R, GIPR, GCGR stable cell lines in the presence of 100% human plasma

[0300] 2.1 Purpose of Experiment: The purpose of this test example is to test the ability of the compounds to stimulate the production of cAMP by human GLP-1R, GIPR, GCGR stable cell lines.

[0301] 2.2 Experimental Instruments: Microplate reader (BioTek Synergy H1), Pipettor (Eppendorf & Rainin), IDOT non-contact microdispensing system (Dispendix)

[0302] 2.3 Experimental Reagents: DMEM / F12 medium purchased from Gibco, item number 11330032, 384-well plate purchased from Perkin Elmer, item number 6007299, IBMX purchased from Sigma, item number I7018, Cisbio cAMP-Gs Dynamic kit purchased from Cisbio, item number 62AM4PEC, 96-well plate purchased from Corning, item number 3610

[0303] 2.4 Experimental method: CHO-K1 / hGLP-1R, CHO-K1 / hGIPR, CHO-K1 / hGCGR stable cell lines were trypsinized and centrifuged, resuspended with DMEM / F12 (Gibco Cat#11330032) complete medium, counted, and plated at 7500 cells / 100 μL / well in 96-well cell plates, and incubated at 37°C, 5% CO2 incubator overnight. The next day, the cell plates were taken out, the supernatant was discarded, and the cells were washed once with serum-free DMEM / F12, then 100% human plasma solution containing 500 μM IBMX (Sigma Cat#I7018) was added, 100 μL per well. 1 μL / well of DMSO gradient-diluted polypeptide sample (10 μM or 1 μM starting, 3-fold dilution, 12 concentrations) was added using an IDOT dispenser, and incubated at 37°C for 30 minutes. Detection was performed using the cAMP detection kit Cisbio cAMP-Gs Dynamic kit (Cisbio Cat#62AM4PEC), the cell plates were taken out, the supernatant was discarded, and the cells were washed once with PBS, then cAMP Lysis & Detection Buffer in the kit was added as lysis solution, 50 μL per well, and the cells were shaken and lysed at room temperature for 5 minutes. 10 μL of cell supernatant lysate was taken from each well and added to a 384-well plate, 5 μL / well of cAMP-d2 solution diluted 20 times with lysis solution was added, and 5 μL / well of Anti-cAMP-Eu 3+ -Cryptate solution, shake for 10 seconds, mix well, and incubate at room temperature for 1 hour in the dark.

[0304] 2.5 Experimental data processing method: Calculate the signal ratio (665 nm / 620 nm*10,000), and use the four-parameter equation to perform nonlinear fitting of the signal ratio and sample concentration in GraphPad Prism 9 to obtain the EC 50 value.

[0305] 2.6 Experimental conclusion: Through the above scheme, it is concluded that the compound of the present application shows good agonistic activity in the CHO-K1 / hGLP1R, CHO-K1 / hGIPR, CHO-K1 / hGCGR cell agonistic activity test after stimulating the CHO-K1 / hGLP1R, CHO-K1 / hGIPR, CHO-K1 / hGCGR stable cell line for 30 minutes in 100% human plasma.

[0306] Test Example 3: Determination of the inhibitory activity of the test compound on C5a

[0307] 1. Experimental purpose: Test the target inhibitory activity of polypeptide samples on C5.

[0308] 2. Experimental procedure

[0309] 1) Coating IgM reaction plate / C5a detection plate, 4 degrees overnight.

[0310] 2) Polypeptide serum co-incubation: prepare polypeptide gradient dilution, dilute serum with GVB buffer to several different gradient concentrations, and mix polypeptide dilution with different concentrations of serum as experimental group, at this time the final concentration of serum is between 2% to 50%, and place in a 37 degree incubator for 15 min.

[0311] 3) Remove the coating solution from the coated IgM reaction plate, add 300 μL of wash buffer to each well and wash the plate 3 times.

[0312] 4) Take the incubated polypeptide serum mixture and controls and add them to the reaction plate, incubate at 37 degrees for 30 min, and use IgM to activate the complement classical pathway for reaction.

[0313] 5) Perform ELISA detection on the C5a-coating plate, transfer 100 μL of polypeptide / serum mixture and controls from the IgM reaction plate to the detection plate, and finally perform plate reading on the enzyme marker at 450 nm.

[0314] 3. Data analysis and results

[0315] Inhibition rate % = [(positive control well average - sample well value) / (positive control well average - negative control well average)] x 100, where the positive control well is a polypeptide-free reaction well and the negative control well is a reaction well without serum. Curve fitting: use log(inhibitor) vs. response - Variable slope(four parameters) in GraphPad Prism 6 to analyze the fitting equation of compound concentration and corresponding inhibition rate, fit the curve and obtain the IC 50 value of the compound.

[0316] The fitting calculation equation is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0317] 4. Experimental conclusion: In some embodiments, the IC 50 of the compound of the present application for C5 inhibition is less than 200 nM; preferably the IC 50 of the compound for C5 inhibition is less than 20 nM; and even more preferably the IC 50less than 10 nM. The polypeptides of the present application have a significant inhibitory effect on C5a, i.e., the activation of the C5 protein is impeded.

[0318] Test Example 4: SD Rat Pharmacokinetic Determination

[0319] 1. Purpose of the Study: To study the pharmacokinetic behavior of the compound of the present application in the plasma of rats after intravenous administration at a dose of 1 mg / kg.

[0320] 2. Test Plan

[0321] 2.1 Test Drug: The compound of the present application, self-made.

[0322] 2.2 Test Animals: SD rats, 3 per example, male, Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., Animal Production License No.: SCXK(Zhe)2024-0001.

[0323] 2.3 Drug Preparation: Intravenous administration drug preparation: PBS

[0324] The compound of the example was weighed, PBS was added according to the volume, and it was vortexed until it was completely dissolved. It was filtered through a 0.22 um filter to obtain a colorless transparent clear solution with a concentration of 0.2 mg / mL.

[0325] 2.4 Administration: SD rats, male; after fasting overnight, i.v. at a dose of 1 mg / kg, with a drug volume of 5 mL / kg.

[0326] 2.5 Sample Collection: Before and after administration of the rats at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 h, 0.2 mL of blood was collected from the jugular vein and placed in an EDTA-K2 test tube. The plasma was separated by centrifugation at 4°C at 4000 x g for 5 min and stored at -80°C.

[0327] 2.6 Sample Treatment:

[0328] 1) 40 uL of the plasma sample was added to 160 uL of acetonitrile for precipitation, and after mixing, it was centrifuged at 3500 x g for 5-20 min.

[0329] 2) 100 uL of the supernatant after treatment was taken for LC / MS / MS analysis of the concentration of the test compound.

[0330] 2.7 Liquid Chromatography Analysis

[0331] • Liquid Chromatography Conditions: Shimadzu LC-20AD pump

[0332] • Mass Spectrometry Conditions: AB Sciex API 4000 mass spectrometer

[0333] • Column: phenomenex Gemini 5um C18 50x4.6mm

[0334] • Mobile phase: A liquid is 0.1% formic acid aqueous solution, B liquid is acetonitrile

[0335] • Flow rate: 0.8 mL / min

[0336] • Elution time: 0-4.0 minutes, eluent as follows:

[0337] 3. Test results and analysis

[0338] The main pharmacokinetic parameters were calculated by WinNonlin 8.2, and the results of rat pharmacokinetic experiments are shown in the following table:

[0339] 4. Experimental conclusion: The data show that the preferred embodiment compound of the application has higher exposure, longer half-life and lower clearance in the rat pharmacokinetic evaluation experiment.

[0340] Test Example 5: SD rat pharmacokinetic determination

[0341] 1. Purpose of the study: SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the application in rat plasma after intravenous injection at a dose of 1 mg / kg.

[0342] 2. Test scheme

[0343] 2.1 Test drug: The compound of the example of the application was self-made.

[0344] 2.2 Test animals: 3 SD rats per example, male, Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd., Animal Production License No.: SCXK(Zhe)2024-0001.

[0345] 2.3 Drug preparation: Intravenous drug preparation: PBS

[0346] The compound of the example was weighed and added to PBS according to the volume, and vortexed to completely dissolve it to obtain a colorless transparent clear solution with a concentration of 0.2 mg / mL.

[0347] 2.4 Administration: SD rats, male; after fasting overnight, i.v. at a dose of 1 mg / kg, with a drug volume of 5 mL / kg.

[0348] 2.5 Sample collection: 0.2 mL blood was collected from the rats before and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48 h after administration from the jugular vein, and placed in EDTA-K2 test tubes. The plasma was separated by centrifugation at 4000 x g for 5 min at 4°C, and stored at -80°C.

[0349] 2.6 Sample processing: 55 μL of the plasma sample was vortexed with 3 μL of 5% trichloroacetic acid (TCA) aqueous solution, and then 200 μL of an internal standard-containing acetonitrile / methanol solution (v:v = 1:1) was vortexed to precipitate the protein. After centrifugation at 4000 rpm for 15 min at 4°C, the supernatant was diluted with pure water by 3 times.

[0350] The diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0351] 2.7 Liquid chromatography analysis

[0352] Liquid chromatography system: Shimadzu LC-40DXS pump Mass spectrometry system: AB Sciex API mass spectrometer

[0353] Chromatographic column type: Raptor Biphenyl Flow rate: 0.6 mL / min

[0354] Mobile phase: A liquid is 0.1% formic acid aqueous solution, and B liquid is 0.1% formic acid acetonitrile

[0355] Elution gradient:

[0356] 3. Test results and analysis

[0357] The main pharmacokinetic parameters were calculated using WinNonlin 8.2, and the results of the rat pharmacokinetic experiment are shown in the following table:

[0358] 4. Experimental conclusion: The data show that the compound of the present application has the remarkable effects of high exposure, long half-life and low clearance in the rat pharmacokinetic evaluation experiment.

[0359] Test Example 6: Determination of the ability of the compound of the present application to stimulate the production of cAMP by human GLP1R, GIPR and GCGR stable cell lines under 0.1% casein conditions

[0360] 1. Purpose of the experiment: The purpose of this test example is to test the ability of the compound to generate cAMP after activating the cell surface human GLP-1R and GIPR.

[0361] 2. Experimental method: CHO-K1 / hGLP-1R and CHO-K1 / hGIPR stable cell lines were trypsinized and centrifuged, resuspended with DMEM / F12 (Gibco Cat#11330032) complete medium, counted, and plated at 7500 cells / 100 μL / well in 96-well cell plates, and incubated at 37°C, 5% CO2 incubator overnight. The next day, the cell plates were taken out, the supernatant was discarded, and the cells were washed once with serum-free DMEM / F12, and then 100 μL / well of DMEM / F12 medium containing 500 μM IBMX (Sigma Cat#I7018) and 0.1% casein (Sigma Cat#C4765) was added. 1 μL / well of polypeptide sample (1 nM starting, 3-fold dilution, 12 concentrations) diluted with DMSO was added using an IDOT dispenser, and incubated at 37°C for 30 minutes. Detection was performed using the cAMP detection kit Cisbio cAMP-Gs Dynamic kit (Cisbio Cat#62AM4PEC), the cell plates were taken out, the supernatant was discarded, and the cells were washed once with PBS, and 50 μL / well of cAMP Lysis & Detection Buffer in the kit was added as a lysis solution, and the cells were shaken at room temperature for 5 minutes. 10 μL of cell supernatant lysis solution was taken from each well and added to a 384-well plate, 5 μL / well of cAMP-d2 solution diluted 20 times with lysis solution was added, and 5 μL / well of Anti-cAMP-Eu Cryptate solution diluted 20 times with lysis solution was added. The solution was shaken for 10 seconds and mixed, and incubated at room temperature for 1 hour in the dark. 3+ -Cryptate solution, shaken for 10 seconds and mixed, and incubated at room temperature for 1 hour in the dark.

[0362] 3. Experimental data processing method: Calculate the signal ratio (665 nm / 620 nm*10,000), and use the four-parameter equation to perform nonlinear fitting of the signal ratio and sample concentration in GraphPad Prism 9 to obtain the EC 50 value.

[0363] 4. Experimental data and conclusion: Through the above scheme, it is found that the compound of the present application shows good agonistic activity in the CHO-K1 / hGLP1R, CHO-K1 / hGIPR, and CHO-K1 / hGCGR cell agonistic activity test after stimulating the CHO-K1 / hGLP1R, CHO-K1 / hGIPR, and CHO-K1 / hGCGR stable cell lines for 30 minutes under the condition of 0.1% casein.

[0364] Test Example 7: Stability of the compound of the present application in plasma

[0365] 1. Research purposes: to study the stability of the compounds in this embodiment in mouse, rat, beagle dog, cynomolgus monkey, and human plasma.

[0366] 2. Experimental reagents: compounds of the present application (self-made), methanol (Merck), acetonitrile (Merck), DMSO (Sigma), Propantheline (Sigma Lot 1571001), Mevinolin (Sigma Lot 1370600).

[0367] 3. Plasma samples

[0368] 4. Experimental steps

[0369] 1) Solution preparation: prepare 1 mM working solutions of the test compounds in pure water, 1 mM working solutions of the control compounds Melvinolin in DMSO, and 1 mM working solutions of the control compounds Propantheline in acetonitrile. Propantheline is used as a positive control for mouse, dog, monkey and human plasma, and Melvinolin is used as a positive control for rat plasma.

[0370] 2) Stability determination: add 398 μL of plasma to each well of the incubation plate and preheat at 37°C for 15 minutes.

[0371] After preincubation, add 2 μL of the working solution to 398 μL of plasma and mix well. Incubate the reaction sample at 37°C, and the final incubation concentration of the test compound is 5 μM.

[0372] At 0, 1, 2, 4, 6 and 24 hours, respectively, take 50 μL from the reaction sample and add 450 μL of cold methanol containing formic acid (0.1%) and an internal standard to terminate the reaction.

[0373] Vortex all samples for 10 minutes, then centrifuge at 3220 g for 30 minutes to precipitate the protein. Transfer 100 μL of supernatant to a new well plate. According to the LC-MS signal response and peak shape, dilute the supernatant with ultrapure water, and inject for detection.

[0374] 5. Bioanalysis

[0375] 1) Chromatographic conditions

[0376] Liquid chromatography system: Shimadzu LC-40DXS chromatographic column: 3 μm Horizon C18 50*2.1 mm

[0377] Mobile phase: A phase: 0.1% formic acid in water; B phase: 0.1% formic acid in acetonitrile

[0378] Elution gradient:

[0379] 2) Mass spectrometry conditions

[0380] Mass spectrometer: AB Sciex Triple Quad 6500+ Ion source: Electrospray ionization source (ESI)

[0381] Dry gas: N2, temperature 500°C Electrospray voltage: 5500 V

[0382] Detection mode: Positive ion detection Scan mode: Reaction monitoring (MRM) mode

[0383] 6. Experimental results and data processing: Peak area ratio = compound peak area / internal standard peak area

[0384] t hours Compound remaining percentage (%) = peak area ratio t hours / peak area ratio 0 hours x 100

[0385] 7. Experimental conclusion: The preferred embodiment compound of the present application exhibits excellent stability in the plasma of various genera.

Claims

1. A side chain comprising the structure shown in formula (I): wherein: R1is selected from -C(O)OR 1a or -P(O)OR 1a OR 1b ; R2is selected from -C(O)OR 2a or -P(O)OR 2a OR 2b ; R3is selected from -C(O)OR 3a or -P(O)OR 3a OR 3b ; R4 is absent, R 1a , R 2a or R 3a are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R 1b , R 2b , or R 3b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R a selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R b selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R c selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R d selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R e selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; R f selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; X is selected from -CH2- or -O-; n1 is selected from 0 or 1; n2 is selected from an integer from 1 to 30; n3 is selected from 0, 1, 2, 3 or 4; n4 is selected from 0 or 1; n5 is selected from 0, 1, 2, 3 or 4; n6 is selected from 0, 1, 2 or 3; n7 is selected from 0, 1, 2, 3 or 4; n8 is selected from 0, 1, 2 or 3; n9 is selected from 0 or 1; m1 is selected from an integer from 0 to 19; m2 is selected from an integer from 0 to 19; m3 is selected from an integer from 0 to 19; m4 is selected from an integer from 0 to 19; m5 is selected from an integer from 0 to 19; Preferably, n6 and n8 are not both 0.

2. The side chain according to claim 1, wherein said side chain comprises a structure according to formula (II), (III) or (IV):

3. The side chain of claim 1, wherein the side chain comprises a structure represented by Formula (I-A), (I-B), or (I-C): ###00003### (I-A) (I-B) (I-C) wherein: R1, R2, R3 are not simultaneously carboxylic acid or carboxylic acid derivatives; Preferably R1is selected from -C(O)OR 1a R2is selected from -C(O)OR 2a R3is selected from -P(O)OR 3a OR 3b ; R1is selected from -C(O)OR 1a , R2is selected from -P(O)OR 2a OR 2b , R3is selected from -C(O)OR 3a ; R1is selected from -C(O)OR 1a , R2is selected from -P(O)OR 2a OR 2b , R3is selected from -P(O)OR 3a OR 3b ; R1is selected from -P(O)OR 1a OR 1b R2is selected from -C(O)OR 2a R3is selected from -C(O)OR 3a ; R1is selected from -P(O)OR 1a OR 1b R2is selected from -C(O)OR 2a R3is selected from -P(O)OR 3a OR 3b ; R1is selected from -P(O)OR 1a OR 1b R2is selected from -P(O)OR 2a OR 2b R3is selected from -C(O)OR 3a ; or R1is selected from -P(O)OR 1a OR 1b , R2is selected from -P(O)OR 2a OR 2b , R3is selected from -P(O)OR 3a OR 3b ; 4. The sidechain according to claim 1, wherein the sidechain comprises the structure shown in formula (II-A), (II-B) or (II-C):

5. The sidechain according to claim 1, wherein the sidechain comprises the structure shown in formula (III-A), (III-B) or (III-C):

6. The side chain according to claim 1, wherein said side chain comprises a structure according to formula (IV-A), (IV-B) or (IV-C): ###00023### (IV-A) (IV-B) (IV-C) ​ 7. The side chain according to any one of claims 1 to 6, characterized in that, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 26; n3 is 2; n4 is 0; n5 is 0; n6 is 1; n7 is 0; n8 is 0; m1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; m3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; or, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 26; n3 is 0, 1, 2, 3 or 4; n4 is 0; n5 is 0; n6 is 1; n7 is 0; n8 is 0; m1 is 1; m3 is 1; or, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 26; n3 is 2; n4 is 0; n5 is 0; n6 is 1, 2 or 3; n7 is 0; n8 is 0; m1 is 1; m3 is 1; or, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 26; n3 is 0, 1 or 2; n4 is 0; n5 is 0; n6 is 1; n7 is 1 or 2; n8 is 0 or 1; m1 is 1; m3 is 1; m4 is 1; m5 is 1; or, n1 is 0; n2 is selected from 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 26; n3 is 1 or 2; n4 is 1; n5 is 0 or 1; n6 is 1; n7 is 0; n8 is 0; m1 is 1; m2 is 1; m3 is 1; or, n1 is 0; n2 is selected from 6, 8, 10 or 12; n3 is 2; n4 is 0; n5 is 0; n6 is 1; n7 is 0; n8 is 0; m1 is 1; m3 is 1.

8. The side chain according to any one of claims 1 to 7, characterized in that, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b are hydrogen.

9. The side chain according to any one of claims 1 to 8, characterized in that, X is -O-.

10. The side chain according to any one of claims 1-4, 7-9, wherein said side chain comprises a structure according to Formula (II-A-1), (II-A-2), (II-A-3), or (II-A-4): ###00010### (II-A-1) (II-A-2) (II-A-3) (II-A-4) 11. The side chain according to any one of claims 1-3, 5, 7-9, wherein the side chain comprises the structure shown in formula (III-A-1), (III-A-2), (III-A-3), or (III-A-4):

12. The side chain according to any one of claims 1-3, 6-9, wherein said side chain comprises a structure according to Formula (IV-A-1), (IV-A-2), (IV-A-3), or (IV-A-4): ###00025### (IV-A-1) (IV-A-2) (IV-A-3) (IV-A-4) 13. The side chain of any one of claims 1-12, wherein, The R mentioned a Selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy group; preferably hydrogen; and / or, said R b selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; preferably hydrogen; and / or, said R c selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; preferably hydroxyl; and / or, R d selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1- 3haloalkoxy; preferably hydrogen or methyl; and / or, R e selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1- 3haloalkoxy; preferably hydrogen or methyl; and / or, R f selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy or C 1- 3haloalkoxy; preferably hydrogen or methyl.

14. The side chain according to any one of claims 1-13, comprising the following structure:

15. A pharmaceutical preparation, characterized in that, The drug preparation contains the side chain as claimed in claims 1-14 in the drug.

16. The pharmaceutical preparation according to claim 15, characterized in that The drug preparation is an oral preparation or an injection preparation.

17. A process for the preparation of a side chain according to any one of claims 1 to 14, characterized by, The preparation method comprises the following steps: Method I: The starting material A is condensed with INT-1 in the presence of a condensing agent, and then the ester is hydrolyzed to obtain the product represented by (I-1). The starting material A, INT-1 and (I-1) are as follows: Method two: the starting material B is condensed with INT-2 in the presence of a condensing agent, and then the ester is hydrolyzed to obtain the product represented by (I-2), wherein the starting material B, INT-2 and (I-2) are as follows: Optionally, I-1 or I-2 can further undergo condensation reaction with raw material C in the presence of condensing agent, and after removal of Pg, product represented by (I-3) is obtained, wherein the raw material C and (I-3) are as follows: Pg is a protecting group selected from allyloxycarbonyl, trifluoroacetyl, tert- butylsulfinyl 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, piperonyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-toluenesulfonyl, p-methoxybenzyl, formate, acetyl, benzyloxycarbonyl, phthaloyl, tert-butyloxycarbonyl, benzyl or p-methoxyphenyl; preferably 9-fluorenylmethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl; R 1a selected from -C(O)O-t-Bu or -P(O)OR 1a O-t-Bu; R 2a selected from -C(O)O-t-Bu or -P(O)OR 2a O-t-Bu; R 3a selected from -C(O)O-t-Bu or -P(O)OR 3a O-t-Bu; R a , R b , R c , R e , R d , X, n1, n2, n3, n4, n5, n6, n7or n8are as defined in claim 1; The condensing agent is selected from EDC, DIC, DCC, HATU, HBTU, HCTU, PyBop, DEPBT, TCFH, NMI, HOBT or Oxama.

18. A medicament comprising a side chain modified polypeptide or protein according to any one of claims 1-14; preferably the protein is an antibody; the polypeptide or antibody is an IL-23 polypeptide antagonist, or a selective blocker of IL-23 receptor inhibitor, GLP1R / GIPR / GCGR single, dual or triple agonist, C5 complement inhibitor, GIPR / GLP1R; wherein The IL-23 inhibitor is preferably an IL-23 cyclic peptide inhibitor, more preferably an oral cyclic peptide inhibitor; most preferably APG-2309, and the following specific polypeptides or antibodies 1-25: The GLP1R / GIPR / GCGR single, dual or triple agonist is selected from Metrin, BGM0504, HDM1005, Tirzepatide, Orforglipron, Cagrisema, DR10624, UBT251, HM-15211, HM15275, Retatrutide, Efimosfermin, benaglutide, lixisenatide, exenatide, tirzepatide, insulinotropin, Betatropin, TH-0318, MKC-253, LY-307161, utreglutide, BPI-3016, LY-548806, BIM-51077, GZR-18, XW-003, XW-004, GLP-1(7-37), CJC-1131, NN-9904, BMS-686117, DA-CH-5, NPM-115, HRS-4729, ZX2021, HZ010, MWN109, DYX116, HEC-007 and the following specific polypeptides 27-31: wherein the C5 complement inhibitor is selected from Zilucoplan, ALXN1720, Danicopan, Ravulizumab, Eculizumab, and the following specific polypeptides 26. The drug preferably has the following structure:

19. A pharmaceutical composition comprising, A medicament comprising a therapeutically effective amount of a side chain related medicament according to claims 1-14, or a medicament according to claims 21-22, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

20. Use of the side chain according to claims 1-14, or the pharmaceutical preparation according to claims 15-16, or the medicament according to claim 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the manufacture of a medicament for targeting IL-23R, C5, GIPR / GLP1R or GLP1R / GIPR / GCGR.

21. Use of the side chain according to claims 1-14, or the pharmaceutical preparation according to claims 15-16, or the medicament according to claim 18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the manufacture of a medicament for treating or preventing cancer, infection, psychiatric, cardiovascular, metabolic, endocrine and immune diseases; Preferably, the disease is an inflammatory, autoimmune disease and cancer, preferably inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiation therapy or chemotherapy, colitis associated with innate immune disorders such as leukocyte adhesion deficiency-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Pudlak syndrome, Schindler-Kanzaki syndrome and Weber-Christian syndrome, pouchitis following proctocolectomy and ileal pouch-anal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE) or diabetes disease; preferably inflammatory bowel disease (IBD), rheumatoid arthritis or psoriasis; or, the disease is a complement-associated disease, preferably recurrent severe infections, systemic lupus erythematosus, kidney disease, age-related macular edema, paroxysmal nocturnal hemoglobinuria, vascular edema, myasthenia gravis, inflammatory disease, traumatic disease, injury disease, autoimmune disease, vascular disease, neurological disease, ocular disease and atypical hemolytic uremic syndrome; or, the disease is non-insulin-dependent diabetes, insulin-dependent diabetes or obesity; or, the disease is a metabolic disorder-associated disease, preferably diabetes or diabetes-related conditions, obesity or obesity-related conditions, non-alcoholic steatohepatitis.

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