Polypeptide compound and use thereof

Abstract

Disclosed are a polypeptide compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a composition comprising same, and a use thereof. c[X4-X5-X6-X7-X8-X9]-X10-X11-X12-X13-X14-X15-X16 (I)

Description

Polypeptide compound and application thereof

[0001] This application claims priority to Chinese Patent Application No. 2024113842923, filed on September 30, 2024, and Chinese Patent Application No. 2024114744631, filed on October 22, 2024. This application incorporates the entirety of the above-mentioned Chinese Patent Applications. TECHNICAL FIELD

[0002] The present application relates to a polypeptide compound and application thereof. BACKGROUND

[0003] Interleukin-23 (IL-23) is a heterodimeric hematopoietic cytokine composed of two subunits, p40 and p19, which shares the p40 subunit with IL-12 and is linked by a disulfide bond. The IL-23 receptor is composed of two subunits, the IL-12 receptor beta 1 subunit (IL-12Rβ1) and the IL-23 receptor (IL-23R); IL-23R is a unique subunit of the IL-23 pathway and interacts with the IL-23 p19 subunit. The IL-23R protein contains an extracellular region, a single transmembrane region, and a cytoplasmic region with 252 amino acids. Its extracellular region is different from the three membrane fibrous protein connections of other hematopoietic factor receptor superfamily members, but is composed of a signal sequence, an N-terminal immunoglobulin-like domain, and two cytokine receptor regions.

[0004] IL-23 is a cytokine with multiple biological functions, which can act on various cells, promote the secretion of cytokines, and produce corresponding cellular effects. IL-23 can act on human memory T cells and promote their strong proliferation. IL-23 can induce T cells to produce various cytokines such as IFN-g, IL-17, IL-10, etc. In addition to directly acting on T cells, IL-23 can also activate and regulate T cell-dependent immune responses through DC. The secretion of IL-17 can be regulated by regulating neutrophils to control the production of granulocytes.

[0005] IL-23 provides the necessary conditions for Th17 cell generation and survival. Th17 is a recently discovered CD4+ T cell subset different from Th1 and Th2 cells, which highly expresses IL-17, and also produces IL-6 and TNF-α. IL-17 is an inflammatory cytokine, and its main biological function is to promote inflammatory response, which is closely related to autoimmune diseases such as rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, and transplant rejection. Th17 cells mediate the occurrence and development of inflammatory response, autoimmune diseases, tumors, and transplant rejection. The differentiation and function of Th17 cell subsets are regulated by Th1 and Th2 cytokines. Studies have shown that IL-23 stimulates the expansion and maintenance of TH17, so IL-23R is a key factor for TH17 cell subsets. The pathogenicity of IL23-IL23R-TH17-IL17 axis in autoimmune diseases has also been confirmed.

[0006] The total size of autoimmune disease drugs in the world is more than 100 billion US dollars. According to the estimate of Frost & Sullivan, it is expected to reach 176.7 billion US dollars by 2030. In comparison, the total size of the global anti-tumor drug market in 2023 was 239.8 billion US dollars. In terms of market size, autoimmune diseases have the potential to become the next big market after tumor drugs. Autoimmune diseases are difficult to completely cure, and the efficacy of traditional therapies is limited. The causes of most autoimmune diseases are not completely clear, and the onset and remission of the disease often alternate, making it difficult to cure autoimmune diseases using current treatment methods. Traditional treatment methods have limited efficacy for patients with severe disease, and have significant side effects in long-term use. In comparison, targeted drugs can selectively inhibit the immune system, thereby appropriately reducing the occurrence of side effects and acting faster. Current autoimmune field targeted drugs are mostly biological agents represented by antibodies, and injection is the main administration method. For chronic diseases such as autoimmune diseases, oral preparations are more convenient to use, and can bring better patient compliance and drug accessibility. However, the efficacy of current oral small molecule drugs for autoimmune diseases is not as good as that of biological agents, and the side effects are large, so the patient's oral drug selection is very limited, and there is an urgent need for oral autoimmune drugs with better efficacy and fewer side effects. SUMMARY

[0007] The present application provides a polypeptide compound and its application in order to solve the problem of poor pharmacokinetic properties of autoimmune disease drugs in the prior art. The present application provides oral polypeptide molecules that specifically block the IL-23 signaling pathway by blocking IL-23R, compositions comprising these molecules, methods of screening these molecules, and methods of using these molecules to treat various autoimmune diseases. These molecules have strong biological activity and good pharmacokinetic properties, and show good efficacy in animal efficacy.

[0008] The present application provides a polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

[0009] c[X4-X5-X6-X7-X8-X9]-X10-X11-X12-X13-X14-X15-X16

[0010] (I)

[0011] wherein X6, X7, X9, X11, X13, X14and X15are any amino acid residue;

[0012] c[] in c[X4-X5-X6-X7-X8-X9] indicates that X4and X9are connected to form a ring;

[0013] X4is or any amino acid residue;

[0014] X 4a is -CH2-, -O-, -S-, or -N(R 4c )-;

[0015] R 4a , R 4b , and R 4c are independently H or C 1-6 alkyl; or R 4a , R 4b and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0016] X5is absent or any amino acid residue;

[0017] X8is or any amino acid residue;

[0018] X10is connected to X11;

[0019] Ring A is C 6-10 arylene, C 5-10 cycloalkenylene, 5-10 membered heteroarylene, or 5-10 membered heterocycloalkenylene;

[0020] R 10a is halogen, -SF5, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, -CON(C 1-6 alkyl)2, -L-Z 1 , C 10a-1 alkyl substituted with one or more R 1-6 , or C 10a-2 alkyl substituted with one or more R 1-6alkoxy;

[0021] R 10a-1 and R 10a-2 independently -NH2, -OH, or halogen;

[0022] R 10b is H or C 1-6 alkyl;

[0023] X12is or any amino acid residue;

[0024] X16is -L-Z 1 or any amino acid residue;

[0025] X4, X5, X8, X12, X13, or X16is any amino acid residue, X4, X5, X8, X12, X13, and X16are optionally amino acid residues substituted with -L-Z 1 ;

[0026] L is independently a bond or a linking unit;

[0027] Z 1 is independently

[0028] Z 1a , Z 1b , and Z 1c are independently H or C 1-6 alkyl;

[0029] Alternatively, Z 1a , Z 1b together with the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkyl substituted with one or more Z 1a-1 ;

[0030] Z 1a-1 is halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0031] provided that at least one of X4, X5, X8, X10, X12, X13, and X16comprises -Z 1 ;

[0032] when the compound of formula (I) contains a cationic fragment, the anion is acetate, trifluoroacetate, chloride, bromide, adipate, benzoate, besylate, citrate, decanoate, lactate, maleate, mesylate, propionate, oxalate, succinate, sulfate, or tartrate; the cation and anion are equal in charge number;

[0033] n1, n2, n3, n4, n5 and n6 are independently 0, 1, 2, 3, 4, 5 or 6;

[0034] In the 4-10 membered heterocycloalkyl, 5-10 membered heteroarylene and 5-10 membered heterocycloalkenylene, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0035] The present application provides a polypeptide compound as shown in formula (I), or a pharmaceutically acceptable salt thereof,

[0036] c[X4-X5-X6-X7-X8-X9]-X10-X11-X12-X13-X14-X15-X16

[0037] (I)

[0038] wherein X6, X7, X9, X11, X13, X14 and X15 are any amino acid residue;

[0039] “c[]” in c[X4-X5-X6-X7-X8-X9] indicates that X4 and X9 are connected to form a ring;

[0040] X4 is or any amino acid residue;

[0041] X 4a is -CH2-, -O-, -S- or -N(R 4c )-;

[0042] R 4a , R 4b and R 4c are independently H or C 1-6 alkyl; or R 4a , R 4b and R 3-8 together with the carbon atom to which they are attached form a C 6-10 cycloalkyl;

[0043] X5 is absent or any amino acid residue;

[0044] X8 is or any amino acid residue;

[0045] X10 is connected to X11;

[0046] Ring A is C 6-10 arylene, C 5-10 cycloalkenylene, 5-10 membered heteroarylene or 5-10 membered heterocycloalkenylene;

[0047] R 10a is halogen, -SF5, oxo, C 1-6 alkyl, C1-6 alkoxy, C 3-8 cycloalkyl, -L-Z 1 substituted C 10a-1 alkyl, or C 1-6 alkyl substituted by one or more R 10a-2 substituted C 1-6 alkoxy;

[0048] R 10a-1 and R 10a-2 are independently -NH2, -OH, or halogen;

[0049] R 10b is H or C 1-6 alkyl;

[0050] X12is or any amino acid residue;

[0051] X16is -L-Z 1 or any amino acid residue;

[0052] X4, X5, X8, X12, X13, or X16is any amino acid residue, X4, X5, X8, X12, X13, and X16are optionally amino acid residues substituted by -L-Z 1 ;

[0053] L is independently a bond or a linking unit;

[0054] Z 1 is independently

[0055] Z 1a , Z 1b , and Z 1c are independently H or C 1-6 alkyl;

[0056] Alternatively, Z 1a , Z 1b and the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkyl substituted by one or more Z 1a-1 ;

[0057] Z 1a-1 is halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0058] with the proviso that at least one of X4, X5, X8, X10, X12, X13, and X16comprises -Z 1 structure;

[0059] When the compound as shown in formula (I) contains a cationic fragment, the anion is acetate, trifluoroacetate, chloride, bromide, adipate, benzoate, besylate, citrate, decanoate, lactate, maleate, mesylate, propionate, oxalate, succinate, sulfate, or tartrate; the cation and the anion have equal charge number;

[0060] n1, n2, n3, n4, n5, and n6 are independently 0, 1, 2, 3, 4, 5, or 6;

[0061] In the 4-10 membered heterocycloalkyl, 5-10 membered heteroarylene, and 5-10 membered heterocycloalkenylene, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0062] In the present application, the amino acid residue includes a natural amino acid residue and a non-natural amino acid residue, and contains a carbonyl group and a nitrogen-containing group.

[0063] In some embodiments, when the compound as shown in formula (I) contains a cationic fragment, the anion is formate, carbonate, bicarbonate, hydroxide, iodide, or an internal salt formed by the carboxylate of the compound itself.

[0064] In some embodiments, when the compound as shown in formula (I) contains a cationic fragment, the anion is acetate; the cation and the anion have equal charge number.

[0065] In some embodiments of the present application, in L, the linking unit is a combination of one or more selected from the group consisting of C 1-6 alkylene, -C(=O)-, -NR La -, -C(=O)NR Lb -, -NR Lc C(=O)-, -C(=O)O-, -O-, -S-, or -(CH2CH2O)-;

[0066] R La , R Lb , and R Lc are independently H or C 1-6 alkyl.

[0067] In some embodiments of the present application, L is a chemical bond, -C(=O)-, , or -NH-.

[0068] In some embodiments of the present application, Z 1 is n4, n5, and n6 are independently 1, 2, 3, 4, 5, or 6.

[0069] In some embodiments of the present application, Z1 For

[0070] In some embodiments of the application, X4is is attached to X5at the carbonyl end;

[0071] X 4a , X 4b and X 4c are independently -CH2-, -O-, -S-, or -N(R 4c )-;

[0072] R 4a , R 4b , R 4c , R 4d , R 4e , R 4g and R 4h are independently H or C 1-6 alkyl; or R 4a , R 4b and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0073] R 4i is C 1-6 alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, or C 3-8 cycloalkyl substituted with one or more halogens;

[0074] R 4f is -L 4 -Z 41 ; L 4 is as defined above for L, and Z 41 is as defined above for Z. 1

[0075] In some embodiments of the application, X4is is attached to X5at the carbonyl end;

[0076] R 4f is -L 4 -Z 41 ; L 4 is as defined above for L, and Z 41 is as defined above for Z. 1

[0077] In some embodiments of the application, L 4 is -C(=O)-. ​​

[0078] In some embodiments of the application, X4is the carbonyl end is attached to X5.

[0079] In some embodiments of the application, X5is the carbonyl end is attached to X6;

[0080] R 5a is -L 5 -Z 51 ; L 5 is as defined above for L, and Z 51 is as defined above for Z 1 ;

[0081] p1is 0, 1, 2, 3, 4, 5, or 6.

[0082] In some embodiments of the application, X5is the carbonyl end is attached to X6.

[0083] In some embodiments of the application, X6, X7, X11, X14, and X15are independently

[0084] R a is H or C 1-6 alkyl;

[0085] Rwis -(CH2) p1 -R b-1 ;

[0086] Alternatively, R a , R b and the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C b-2 cycloalkyl substituted with one or more R 3-8 cycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R b-3 ;

[0087] R b-1 is -OH, -CO2H, -CON(R b-4 R b-5 ), -N(R b-6 )C(=O)R b-7 , C 1-6 alkyl, haloC 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, C 1-6alkyl, C b-8 substituted C 6-10 aryl, C b-9 substituted 5-10 membered heteroaryl, C b-10 substituted 4-10 membered heterocycloalkyl, or C b-11 substituted 5-10 membered heterocycloalkenyl;

[0088] R b-4 , R b-5 , and R b-6 are independently H or C 1-6 alkyl;

[0089] R b-7 is C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0090] R b-2 , R b-3 , R b-8 , R b-9 , R b-10 , and R b-11 are independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 haloalkyl, C 3- 8cycloalkyl, -NR b-9a R b-9b or C b-9c substituted C 1-6 alkyl; R b-9a , and R b-9b are independently H or C 1-6 alkyl; R b-9c is independently -CO2H, -CONH2, or -CO2C 1-6 alkyl;

[0091] p1 is 0, 1, 2, 3, 4, 5, or 6;

[0092] In the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl, the heteroatoms are one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0093] In some embodiments of the application, R b-1 is 5-10 membered heterocycloalkenyl or 5-10 membered heterocycloalkenyl substituted with one or more R b-10 ; R b-2 , R b-3 , R b-8 , R b-9 , and R b-10 are independently -NR b-9a R b-9b or Cb-9c substituted C 1-6 alkyl;

[0094] R b-11 independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, -NR b-9a R b-9b or substituted with one or more R b-9c substituted C 1-6 alkyl; R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c are independently -CO2H, -CONH2, or -CO2C 1-6 alkyl;

[0095] R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c are independently -CO2H, -CONH2, or -CO2C 1-6 alkyl.

[0096] In some embodiments of the application, X6, X7, X11, X14, and X15 are independently

[0097] R a is H or C 1-6 alkyl;

[0098] R b is -(CH2) p1 -R b-1 ;

[0099] Alternatively, R a , R b and the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, substituted C b-2 cycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R 3-8 cycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R b-3 ;

[0100] R b-1 is -OH, -CO2H, -CON(R b-4 R b-5 ), -N(R b-6 )C(=0)R b-7 , C 1-6 alkyl, haloC 1-6 alkyl, C 6-10aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 1-6 alkyl, C b-8 substituted C 6- 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C b-9 substituted 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl; b-10

[0101] R b-4 , R b-5 , and R b-6 are independently H or C 1-6 alkyl;

[0102] R b-7 is C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0103] R b-2 , R b-3 , R b-8 , R b-9 and R b-10 are independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl;

[0104] p1 is 0, 1, 2, 3, 4, 5 or 6;

[0105] in the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0106] In some embodiments of the present application, X6 is carbonyl end to X7.

[0107] In some embodiments of the present application, X7 is carbonyl end to X8.

[0108] In some embodiments of the present application, X8 is or is substituted with -L 8 -Z 81 substituted amino acid residue; L 8 Z is defined as above. 81 Z is defined as above. 1

[0109] In some embodiments of the present application, X8 is carbonyl end to X9.

[0110] ​​In some embodiments of the application, X8is The carbonyl end is connected to X9.

[0111] In some embodiments of the application, X9is The a end is connected to X10and the b end is connected to X4; R 9a is H; R 9b is

[0112] X 9a is -CH2-, -0-, -S-, or -N(R 9b-3 )-;

[0113] R 9b-1 , R 9b-2 , and R 9b-3 are independently H or C 1-6 alkyl;

[0114] Alternatively, R 9a , R 9b and the carbon atom to which they are attached form a 4-10 membered heterocycloalkylene;

[0115] q2 is 0, 1, 2, 3, or 4;

[0116] In the 4-10 membered heterocycloalkylene, the heteroatoms are one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

[0117] In some embodiments of the application, X9is The a end is connected to X10and the b end is connected to X4.

[0118] In some embodiments of the application, X10is The a end is connected to X11; ring E is 5-6 membered heterocycloalkenylene or 5-6 membered heteroaryl; R 10a , R 10b , n2, and n3 are as defined above.

[0119] In some embodiments of the application, X10is The a end is connected to X11; Q1is -0-, -S-, or -NH-; s1and s3 are independently 1 or 2; s2 is 0, 1, or 2; R 10a are as defined above.

[0120] In some embodiments of the application, X10is The a end is connected to X11;

[0121] L10 Z is as defined above for L 101 Z is as defined above 1 .

[0122] In some embodiments of the application, X10is * end is connected to X11;

[0123] L 10 Z is as defined above for L 101 Z is as defined above 1 .

[0124] In some embodiments of the application, X10is * end is connected to X11.

[0125] In some embodiments of the application, X10is * end is connected to X11.

[0126] In some embodiments of the application, X11is * end is connected to X12.

[0127] In some embodiments of the application, X12is * end is connected to X13;

[0128] R 12a is H or C 1-6 alkyl;

[0129] R 12b is C 1-6 alkyl or -L 12 -Z 121 ;

[0130] Alternatively, R 12a , R 12b and the carbon atom to which they are attached form a 4-10 membered heterocycloalkyl or

[0131] p2 is 0, 1, 2, 3, 4, 5 or 6;

[0132] in the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0133] L 12 Z is as defined above for L 121 Z is as defined above 1 .

[0134] In some embodiments of the application, X12is the carbonyl terminus is attached to X13.

[0135] In some embodiments of the application, X13is the carbonyl terminus is attached to X14.

[0136] R 13a is -L 13 -Z 131 ; L 13 is as defined above for L, Z 131 is as defined above for Z 1 .

[0137] In some embodiments of the application, X13is the carbonyl terminus is attached to X14.

[0138] In some embodiments of the application, X14is the carbonyl terminus is attached to X15.

[0139] In some embodiments of the application, X15is the carbonyl terminus is attached to X16; ring B is a 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 R b-9 ; R b-9 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR b-9a R b-9b , or C b-9c alkyl substituted with one or more R 1-6 ; R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c is independently -CO2H, -CONH2, or -CO2C 1-6 alkyl.

[0140] In some embodiments of the application, X15is the carbonyl terminus is attached to X16; T 1 and T 4 are independently -NH-, -NR b-9 -, -O-, or -S-; T 2 , T 3 , T 5 , and T 6 are independently N, CH, or CR b-9 ; R b-9 is independently C 1-6 alkyl, -NR b-9a Rb-9b or C1-C6alkyl substituted with one or more R b-9c ; R 1-6 ; R b-9a and R b-9b are independently H or C 1-6 ; R b-9c are independently -CO2H, -CONH2, or -CO2C 1-6 alkyl.

[0141] In some embodiments of the application, X15is In some embodiments of the application, X15is

[0142] In some embodiments of the application, X15is In some embodiments of the application, X15is

[0143] In some embodiments of the application, X16is -L 16 -Z 161 or

[0144] R 16a -L 16 -Z 161 ;

[0145] L 16 , Z 161 , and Z 1 are as defined above.

[0146] In some embodiments of the application, X16is

[0147] In some embodiments, X16is

[0148] In some embodiments of the application, X10is In some embodiments of the application, X10is 1 structure.

[0149] In some embodiments of the application, X10is In some embodiments of the application, X10is In some embodiments of the application, X10is 1 structure.

[0150] In some embodiments of the present application, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1):

[0151] wherein X4, X5, X10, X12, X13, X14and X16are defined as in any of the embodiments of the present application.

[0152] In some embodiments of the present application, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1a):

[0153] wherein Z 41 is

[0154] X5, X10, X12, X13, X14, X16, n4, n5, n6, Z 1a , Z 1b and Z 1c are defined as in any of the embodiments of the present application.

[0155] In some embodiments of the present application, in the compound as shown in formula (I-1a), Z41is

[0156] In some embodiments of the present application, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1b):

[0157] wherein X16is -L 16 -Z 161 or R 16a is -L 16 _Z 161 ;

[0158] X5, X10, X13, L 16 and Z 161 are defined as in any of the embodiments of the present application.

[0159] In some embodiments of the present application, in the compound as shown in formula (I-1b), X16is

[0160] In some embodiments of the present application, in the compound as shown in formula (I-1), formula (I-1a) and formula (I-1b), X10is independently * is connected with X11; preferably * is connected with X11.

[0161] In some embodiments of the application, in the compounds of formula (I-1), (I-1a) and (I-1b), X5is independently is attached to X6.

[0162] In some embodiments of the application, the polypeptide compound of formula (I) is a compound of formula (I-1c):

[0163] Ring A is C 6-10 arylene or 5-10 membered heteroarylene; R

[0164] R 10a halo, -SF5, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 10a-1 substituted C 1- 6alkyl, or C 10a-2 substituted C 1-6 alkoxy; preferably oxo;

[0165] n31is 0, 1, 2, 3 or 4;

[0166] X5and Z 1 as defined in any aspect of the application.

[0167] In some embodiments of the application, is

[0168] In some embodiments of the application, the polypeptide compound of formula (I) is a compound of formula (I-2):

[0169] Ring A is C 6-10 arylene, 5-10 membered heteroarylene or 5-10 membered heterocarylene; R 10a halo, -SF5, oxo, C 1-6 alkyl, C 1-6 alkoxy, -CON(C 1-6 alkyl)2, -L-Z 1 or C 1-6 alkoxy substituted with one or more -NH2;

[0170] L is a bond; Z 1 is

[0171] X5is is attached to X6; R 5a is -L 5-Z 51 ; p1 is 0, 1, 2, 3, 4, 5, or 6;

[0172] L 5 is a direct bond; Z 51 is

[0173] R 4 is -CH3 or -L 4 -Z 41 ;

[0174] L 4 is a direct bond; Z 41 is

[0175] X16 is -L 16 -Z 161 or

[0176] R 16a is -L 16 -Z 161 ; L 16 is independently -NH- or Z 161 is

[0177] Z 1a , Z 1b , and Z 1c are independently H or C 1-6 alkyl; alternatively, Z 1a , Z 1b , and the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl;

[0178] n4, n5, and n6 are independently 0, 1, 2, 3, 4, 5, or 6;

[0179] Ring B is 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 R b-9 ; R b-9 is independently halogen, C 1- 6alkyl, C 1-6 haloalkyl, -NR b-9a R b-9b , or C b-9c alkyl substituted with one or more R 1-6 ; R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c is independently -CO2H, -CONH2, or -CO2C 1-6 alkyl;

[0180] X12, X13, and X14 are as described in any of the aspects of the application.

[0181] In some embodiments of the application, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-3):

[0182] wherein X10 is * is connected to X11; s1 and s3 are independently 1 or 2; s2 is 0, 1 or 2; R 10a is C 1-6 alkyl or -L-Z 1 ; L is a chemical bond; Z 1 is

[0183] X5 is * is connected to X6; R 5a is -L 5 -Z 51 ; p1 is 0, 1, 2, 3, 4, 5 or 6;

[0184] L 5 is a chemical bond; Z 51 is

[0185] R 4 is -CH3 or -L 4 -Z 41 ;

[0186] L 4 is a chemical bond; Z 41 is

[0187] X16 is -L 16 -Z 161 or

[0188] R 16a is -L 16 -Z 161 ; L 16 is independently -NH- or Z 161 is independently R 16a is

[0189] Z 1a , Z 1b , and Z 1c are independently H or C 1-6 alkyl; or, Z1a Z 1b Together with the nitrogen atom it is attached to, it forms a 4-10 membered heterocyclic alkyl group;

[0190] n4, n5, and n6 are independently 0, 1, 2, 3, 4, 5, or 6;

[0191] Ring B is a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally surrounded by 1, 2 or 3 R groups. b-9 Replace; R b-9 Independent of halogen, C 1- 6-alkyl, C 1-6 Halogenated alkyl groups, -NR b-9a R b-9b Or by one or more R b-9c Replacement C 1-6 Alkyl; R b-9a and R b-9b Independently H or C 1-6 Alkyl; R b-9c Independently -CO2H, -CONH2, or -CO2C 1-6 alkyl;

[0192] X12 is The carbonyl end is connected to X13;

[0193] X13 is The carbonyl end is connected to X14;

[0194] X14 is The carbonyl end is connected to X15.

[0195] In some embodiments of the present invention, the polypeptide compound represented by formula (I) is any one of the compounds in Table A below:

[0196] Table A

[0197] In some embodiments, when the compounds in Table A contain a cationic fragment, the anion is acetate.

[0198] This invention provides a polypeptide compound as shown in formula (II) or a pharmaceutically acceptable salt thereof.

[0199] c[×19-X20-X21-X22-X23-X24]-X25-X26-X27-X28-X29-X30-X31

[0200] (II)

[0201] In c[X19-X20-X21-X22-X23-X24], “c[]” indicates that X19 and X24 are connected in a ring;

[0202] X19 is The carbonyl end is connected to X20;

[0203] X 19a X 19b and X 19c Independently for -C(R) 19a-1 R 19a-2 -, -O-, -S- or -N(R) 19a-3 )-;

[0204] R 19a R 19b R 19c R 19d R 19a-1 R 19a-2 and R 19a-3 Independently H or C 1-6 Alkyl; or R 19a R 19b Together with the carbon atoms it is attached to, they form C 3-8 cycloalkyl; or R 19c R 19d Together with the carbon atoms it is attached to, they form C 3-8 cycloalkyl;

[0205] R 19e C 1-6 Alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more halogens 3-8 cycloalkyl;

[0206] m1 is 0, 1, 2, 3, 4, 5 or 6;

[0207] X24is c-terminal to X25and d-terminal to X19; R 24a is H; R 24b is

[0208] X 24a is -CH2-, -0-, -S-, or -N(R 24b-3 )-;

[0209] R 24b-1 , R 24b-2 , and R 24b-3 are independently H or C 1-6 alkyl;

[0210] Alternatively, R 24a , R 24b , and the carbon atom to which they are attached form a 4-10 membered heterocycloalkylene;

[0211] m2 is 0, 1, 2, 3, or 4;

[0212] X20is absent or

[0213] X23is

[0214] X21, X22, X25, X26, X27, X28, X29, and X30are independently

[0215] X a is -0-, -S-, or -N(R e )-; R c , and R e are independently H or C 1-6 alkyl;

[0216] R d is -(CH2) q1 -R d-1 ;

[0217] Alternatively, R c , R d , and the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C d-2 cycloalkyl substituted with one or more R 3-8 , or 4-10 membered heterocycloalkyl substituted with one or more R d-3 ;

[0218] R d-1 is -OH, -C02H, -CON(R d-4R d-5 ), -N(R d-6 )C(=O)R d-7 , -COR d-8 , C 1-6 alkyl, haloC 1-6 alkyl, C 6- 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, C 1-6 alkyl substituted with one or more R d-9 , C 6-10 aryl substituted with one or more R d-10 , 5-10 membered heteroaryl substituted with one or more R d-11 , 4-10 membered heterocycloalkyl substituted with one or more R d-12 , 5-10 membered cycloalkenyl substituted with one or more R d- , or 5-10 membered heterocycloalkenyl substituted with one or more R 13 ;

[0219] R d-4 , R d-5 , and R d-6 are independently H or C 1-6 alkyl;

[0220] R d-7 , and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0221] R d-2 , R d-3 , R d-9 , R d-10 , R d-11 , R d-12 , and R d-13 are independently halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, C 3-8 cycloalkyl, -NR d-10a R d-10b , C 1-6 alkoxy substituted with amino, or C d-10c alkyl substituted with one or more R 1-6 ;

[0222] R d-10a , and R d-10b are independently H or C 1-6 alkyl; R d-10c is independently -CO2H, -CONH2, or -CO2C1-6 alkyl;

[0223] q1 is 0, 1, 2, 3, 4, 5, or 6;

[0224] X31 is

[0225] R 31 For -NR 31a R 31b -OH, C 1-6 Alkyl, C 1-6 Alkoxy, 4-10 membered heterocyclic alkyl, with one or more R 31c Substituted 4-10 membered heterocyclic alkyl groups;

[0226] R 31a and R 31b Independently H or C 1-6 alkyl;

[0227] R 31c Independently for C 1-6 Alkyl, halogen, or oxo group (=O);

[0228] In the 4-10 membered heterocyclic alkyl and 5-10 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0229] This invention provides a polypeptide compound as shown in formula (II) or a pharmaceutically acceptable salt thereof.

[0230] c[×19-X20-X21-X22-X23-X24]-X25-X26-X27-X28-X29-X30-X31

[0231] (II)

[0232] In c[X19-X20-X21-X22-X23-X24], “c[]” indicates that X19 and X24 are connected in a ring;

[0233] X19 is The carbonyl end is connected to X20;

[0234] X 19a X 19b and X 19c Independently for -C(R) 19a-1 R 19a-2 -, -O-, -S- or -N(R) 19a-3 )-;

[0235] R 19a R 19b R 19cR 19d R 19a-1 R 19a-2 and R 19a-3 are independently H or C 1-6 alkyl; or R 19a , R 19b and the carbon atom to which they are attached form a C 3-8 cycloalkyl; or R 19c , R 19d and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0236] R 19e is C 1-6 alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogen, or C 3-8 cycloalkyl substituted with one or more halogen;

[0237] m1 is 0, 1, 2, 3, 4, 5 or 6;

[0238] X24 is the C-terminus is connected to X25 and the D-terminus is connected to X19; R 24a is H; R 24b is

[0239] X 24a is -CH2-, -O-, -S- or -N(R 24b-3 )-;

[0240] R 24b-1 , R 24b-2 and R 24b-3 are independently H or C 1-6 alkyl;

[0241] or R 24a , R 24b and the carbon atom to which they are attached form a 4-10 membered heterocycloalkylene;

[0242] m2 is 0, 1, 2, 3 or 4;

[0243] X20 is absent or

[0244] X23 is

[0245] X21, X22, X25, X26, X27, X28, X29 and X30 are independently

[0246] Xa -O-, -S-, or -N(R e )-; R c and R e are independently H or C 1-6 alkyl;

[0247] R d is -(CH2) q1 -R d-1 ;

[0248] Alternatively, R c , R d and the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C d-2 cycloalkyl substituted with one or more R 3-8 , or 4-10 membered heterocycloalkyl substituted with one or more R d-3 ;

[0249] R d-1 is -OH, -CO2H, -CON(R d-4 R d-5 ), -N(R d-6 )C(=O)R d-7 , -COR d-8 , C 1-6 alkyl, haloC 1-6 alkyl, C 6- 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 1-6 alkyl substituted with one or more hydroxyl groups, C d-9 aryl substituted with one or more R 6-10 , 5-10 membered heteroaryl substituted with one or more R d-10 , or 4-10 membered heterocycloalkyl substituted with one or more R d-11 ;

[0250] R d-4 , R d-5 , and R d-6 are independently H or C 1-6 alkyl;

[0251] R d-7 , and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0252] R d-2 , R d-3 , R d-9 , R d-10 , and R d-11 are independently halogen, oxo (=O), C1-6 Alkyl, C 1-6 Alkoxy, -SF5, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, or C substituted with amino 1-6 Alkoxy;

[0253] q1 is 0, 1, 2, 3, 4, 5, or 6;

[0254] X31 is

[0255] R 31 For -NR 31a R 31b -OH, C 1-6 Alkyl, C 1-6 Alkoxy, 4-10 membered heterocyclic alkyl, with one or more R 31c Substituted 4-10 membered heterocyclic alkyl groups;

[0256] R 31a and R 31b Independently H or C 1-6 alkyl;

[0257] R 31c Independently for C 1-6 Alkyl, halogen, or oxo group (=O);

[0258] In the 4-10 membered heterocyclic alkyl and 5-10 membered heteroaryl groups, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0259] In some embodiments of the present invention, X19 is... The carbonyl end is connected to X20;

[0260] X 19a It can be -CH2-, -O-, or -S-;

[0261] R 19a and R 19b Independently H or C 1-6 alkyl;

[0262] m1 is 1, 2, or 3;

[0263] R 19e C 1-6 Alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more halogens 3-8 Cycloalkyl.

[0264] In some embodiments of the application, X19is the carbonyl end is attached to X20.

[0265] In some embodiments of the application, X20is absent or the carbonyl end is attached to X21;

[0266] R c is H;

[0267] R d is -(CH2) q1 -R d-1 ;

[0268] Alternatively, R c , R d and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0269] R d-1 is -CONH2, -NHC(=0)R d-7 , -COR d-8 , C 1-6 alkyl, 4-10 membered heterocycloalkyl, C 1-6 alkyl substituted with one or more R d-11 ;

[0270] R d-7 and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0271] R d-11 is oxo (=0);

[0272] q1 is 0, 1, 2, 3, 4, 5, or 6.

[0273] In some embodiments of the application, X20is absent, the carbonyl end is attached to X21.

[0274] In some embodiments of the application, X21is the carbonyl end is attached to X22.

[0275] In some embodiments of the application, X22is the carbonyl end is attached to X23; R d-1 is 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R d-10 ; d-10for C 1-6 alkyl or C 1-6 haloalkyl.

[0276] In some embodiments of the application, X22is carbonyl end is attached to X23.

[0277] In some embodiments of the application, X23is carbonyl end is attached to X24;

[0278] R c is H or C 1-6 alkyl;

[0279] R d is -(CH2) q1 -R d-1 ;

[0280] Alternatively, R c , R d and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0281] R d-1 is -NHC(=O)R d-7 , -COR d-8 , C 1-6 alkyl, 4-10 membered heterocycloalkyl, C 1-6 alkyl substituted with one or more R d-11 ;

[0282] R d-7 and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0283] R d-11 is independently halogen or oxo (=O);

[0284] q1 is 0, 1, 2, 3, 4, 5 or 6.

[0285] In some embodiments of the application, X23is carbonyl end is attached to X24.

[0286] In some embodiments of the application, X24is carbonyl end is attached to X19; R 24a is H; R 24b is

[0287] X 24a It can be -CH2-, -O-, or -S-;

[0288] R 24b-1 and R 24b-2 Independently H or C 1-6 alkyl;

[0289] Or, R 24a R 24b Together with the carbon atoms attached thereto, they form 4-10 membered heterocyclic alkyl groups;

[0290] m2 can be 0, 1, 2, 3 or 4.

[0291] In some embodiments of the present invention, X24 is... The c-end connects to X25, and the d-end connects to X19.

[0292] In some embodiments of the present invention, X25 is... The carbonyl end is connected to X26;

[0293] R d-1 C 6-10 aryl, 4-10 membered heterocyclic alkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocyclic alkenyl, with one or more R d-9 Replacement C 6-10 aryl, with one or more R d-11 Substituted 4-10 membered heterocyclic alkyl groups, with one or more R d-12 Substituted 5-10 membered cycloalkenyl groups, or one or more R groups d-13 Substituted 5-10 membered heterocyclic alkenyl groups;

[0294] R d-9 R d-11 R d-12 and R d-13 Independently halogen, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, -SF5, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, or C substituted with amino 1-6 Alkyl group.

[0295] In some embodiments of the present invention, R d-1 It is a 5-10 membered cycloalkenyl group, a 5-10 membered heterocyclic alkenyl group, or a compound with one or more R groups. d-12 Substituted 5-10 membered cycloalkenyl groups, or one or more R groups d-13 Substituted 5-10 membered heterocyclic alkenyl groups;

[0296] R d-12 and R d-13independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-6 alkoxy.

[0297] In some embodiments of the application, X25is the carbonyl end is attached to X26;

[0298] R d-1 is C 6-10 aryl, 4-10 membered heterocycloalkyl, C d-9 substituted C 6-10 aryl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11 ;

[0299] R d-9 and R d-11 independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-6 alkoxy.

[0300] In some embodiments of the application, X25is the carbonyl end is attached to X26; s4and s6are independently 0, 1 or 2; s5and s7are independently 1 or 2; R d-9 and R d-13 are as defined above.

[0301] In some embodiments of the application, X25is the carbonyl end is attached to X26.

[0302] In some embodiments of the application, X25is the carbonyl end is attached to X26.

[0303] In some embodiments of the application, X26is the carbonyl end is attached to X27.

[0304] In some embodiments of the application, X27is the carbonyl end is attached to X28; X a is -0-, -S- or -NH-;

[0305] R c , Rd together with the carbon atom to which they are attached form C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, substituted C d-2 substituted C 3- 8cycloalkyl, or substituted 4-10 membered heterocycloalkyl; d-3 substituted 4-10 membered heterocycloalkyl;

[0306] R d-2 and R d-3 are independently halogen.

[0307] In some embodiments of the application, X27is carbonyl end to X28.

[0308] In some embodiments of the application, X28is carbonyl end to X29; R c is H or C 1-6 alkyl;

[0309] R d is -(CH2) q1 -R d-1 ;

[0310] Alternatively, R c , R d together with the carbon atom to which they are attached form C 3-8 cycloalkyl;

[0311] R d-1 is -CO2H, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more hydroxyl;

[0312] q1 is 0, 1, 2, 3, 4, 5, or 6.

[0313] In some embodiments of the application, X28is carbonyl end to X29.

[0314] In some embodiments of the application, X29is carbonyl end to X30; R d is -(CH2) q1 -R d-1 ;

[0315] R d-1 is -OH, -CONH2, C 1-6 alkyl, haloC 1-6 alkyl, 4-10 membered heterocycloalkyl, or substituted 4-10 membered heterocycloalkyl; d-11 substituted 4-10 membered heterocycloalkyl;

[0316] Rd-11 Independently halogen, oxo group (=O) or C 1-6 alkyl;

[0317] q1 can be 0, 1, 2, 3, 4, 5 or 6.

[0318] In some embodiments of the present invention, X29 is... The carbonyl end is connected to X30.

[0319] In some embodiments of the present invention, X30 is... The carbonyl end is connected to X31; R d-1 C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl, with one or more R d-9 Replacement C 6-10 aryl, with one or more R d-10 Substituted 5-10 heteroaryl groups, or one or more R groups d-13 Substituted 5-10 membered heterocyclic alkenyl groups;

[0320] R d-9 R d-10 and R d-13 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR d-10a R d-10b Or by one or more R d-10c Replacement C 1-6 Alkyl; R d-10a and R d-10b Independently H or C 1-6 Alkyl; R d-10c Independently -CO2H, -CONH2, or -CO2C 1-6 alkyl.

[0321] In some embodiments of the present invention, R d-9 R d-10 and R d-13 Halogens are independent of each other.

[0322] In some embodiments of the present invention, X30 is... The carbonyl end is connected to X31; ring B is independently a 5-6 membered heteroaryl group, which is optionally surrounded by 1, 2 or 3 R groups. d-10 Replace; R d-9 and R d-10 Independent of halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -NR d-10a R d-10bor one or more R d-10c substituted C 1-6 alkyl; R d-10a and R d-10b independently H or C 1-6 alkyl; R d-10c independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; s8, s9, and s10 are independently 1, 2, or 3;

[0323] R d-9 and R d-10 are independently halogen.

[0324] In some embodiments of the application, X30 is carbonyl end to X31; R d-1 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C d-9 substituted C 6-10 aryl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11

[0325] R d-9 and R d-11 are independently halogen or C 1-6 alkyl.

[0326] In some embodiments of the application, X30 is carbonyl end to X31.

[0327] In some embodiments of the application, X30 is carbonyl end to X31.

[0328] In some embodiments of the application, X31 is

[0329] R 31 -NH2, -OH, -OCH3,

[0330] In some embodiments of the application, X31 is

[0331] In some embodiments of the application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-1):

[0332] X19 is carbonyl end to the amino group above; ​

[0333] X 19a is -CH2-, -O- or -S-;

[0334] R 19a and R 19b are independently H or C 1-6 alkyl;

[0335] m1 is 1, 2 or 3;

[0336] R 19e is C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl, or C 3-8 alkyl substituted by one or more halogen;

[0337] m1 is 1, 2 or 3.

[0338] In some embodiments of the present application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-2):

[0339] X 24a is -CH2- or -O-;

[0340] m2 is 0, 1, 2, 3 or 4;

[0341] X19, X20, X28 and X31 are defined as in any of the embodiments of the present application.

[0342] In some embodiments of the present application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-3):

[0343] X20 is connected to the amino group above;

[0344] R c is H;

[0345] R d is -(CH2) q1 -R d-1 ;

[0346] or, R c , R d and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0347] R d-1 is -NHC(=O)R d-7 , -COR d-8 , 4-10 membered heterocycloalkyl, C1-6 alkyl, C 1-6 alkyl, or C d-11 substituted 4-10 membered heterocycloalkyl;

[0348] R d-7 and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0349] R d-11 is oxo (=0);

[0350] q1 is 0, 1, 2, 3, 4, 5, or 6.

[0351] In some embodiments of the application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-4):

[0352] X23 is carbonyl group is connected to the left amino group;

[0353] R c is H or C 1-6 alkyl;

[0354] R d is -(CH2) q1 -R d-1 ;

[0355] Alternatively, R c , R d and the carbon atom to which they are attached form a C 3-8 cycloalkyl;

[0356] R d-1 is -COR d-8 , C 1-6 alkyl, 4-10 membered heterocycloalkyl, C 1-6 alkyl, or C d-11 substituted 4-10 membered heterocycloalkyl;

[0357] R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl;

[0358] R d-11 are independently halogen or oxo (=0);

[0359] q1 is 0, 1, 2, 3, 4, 5, or 6.

[0360] In some embodiments of the present application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-5):

[0361] X25 is the carbonyl end is connected to the left amino group;

[0362] R d-1 is C 6-10 aryl, 4-10 membered heterocycloalkyl, C d-9 substituted C 6-10 aryl, or 4-10 membered heterocycloalkyl substituted by one or more R d-11 ;

[0363] R d-9 and R d-11 are independently halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, or C 3-8 cycloalkyl;

[0364] In the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0365] In some embodiments of the present application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-6):

[0366] X31 is

[0367] R 31 is -OH, C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocycloalkyl, C 31c substituted 4-10 membered heterocycloalkyl;

[0368] R 31c is independently C 1-6 alkyl, halogen or oxo (=O);

[0369] In the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0370] X20, X23 and X28 are as defined above.

[0371] In some embodiments of the present application, in the compound as shown in formula (II-6), X31 is

[0372] In some embodiments of the present application, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-7):

[0373] X30is carbonyl group is connected with the right nitrogen atom; R d-1 is 4-10 membered heterocycloalkyl, C d-9 aryl, or 4-10 membered heterocycloalkyl substituted with one or more R 6-10 ; d-11 ;

[0374] R d-9 and R d-11 are independently halogen or C 1-6 alkyl;

[0375] In the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0376] In some embodiments of the present application, the polypeptide compound as shown in formula (II) is any one of the following compounds in Table B:

[0377] Table B

[0378] The present application provides a pharmaceutical composition comprising the polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described above, or the polypeptide compound as shown in formula (II) or a pharmaceutically acceptable salt thereof as described above, and at least one pharmaceutical excipient.

[0379] The present application also provides use of the polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof as described above, or the polypeptide compound as shown in formula (II) or a pharmaceutically acceptable salt thereof as described above in the preparation of a medicament for preventing and / or treating an interleukin-23 related disease; the interleukin-23 related disease is preferably an autoimmune disease, such as psoriasis, arthritis or inflammatory bowel disease.

[0380] Definitions of terms

[0381] Unless otherwise specified, the terms used in the present application have the following meanings:

[0382] In the present application, the amino acid residues include natural amino acid residues and unnatural amino acid residues; the natural amino acids refer to 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);

[0383] The unnatural amino acids refer to amino acids that are not naturally encoded or found in the genetic code of any organism, which can be a purely synthetic compound. In addition, in the present application, the amino acid residues also include C-terminal carboxyl, N-terminal amino and / or side chain functional groups of natural amino acids or unnatural amino acids being chemically modified.

[0384] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0385] The term "alkyl" refers to a straight chain or branched alkyl group having the specified number of carbon atoms (e.g. C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0386] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, e.g. an alkyl group substituted with one, two, three or four halogens.

[0387] The term "alkoxy" refers to the group RX -O-, wherein R X is alkyl as defined above.

[0388] In the present application, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain radical having at least one double bond, consisting solely of carbon and hydrogen atoms, having, for example, 2 to 6 (preferably 2 to 4) carbon atoms, and being attached to the rest of the molecule by a single bond, including, for example, but not limited to, ethenyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl, or pent-1,4-dienyl, and the like.

[0389] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain radical having at least one triple bond, consisting solely of carbon and hydrogen atoms, having, for example, 2 to 6 (preferably 2 to 4) carbon atoms, and being attached to the rest of the molecule by a single bond, including, for example, but not limited to, ethynyl, 1-propynyl, n-propargyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, or pent-1,4-diynyl, and the like.

[0390] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same atom, for example, methylene (-(CH2-)) becomes carbonyl (-C(=O)-) upon oxo substitution.

[0391] The term "cycloalkyl" refers to a saturated monocyclic ring radical consisting solely of carbon and having the specified number of carbon atoms (e.g., C3-C8). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0392] The term "cycloalkenyl" refers to a monocyclic ring radical having at least one carbon-carbon sp 2 partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more ring bridged, fused (or catenated), or spiro ring systems) nonaromatic carbocyclic substituent having the specified number of carbon ring atoms (e.g., C7-C 15 cycloalkenyl, C7-C 10 cycloalkenyl, C8-C9cycloalkenyl, C3-C 12 cycloalkenyl, C3-C 10 cycloalkenyl, or C5-C6cycloalkenyl). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl.

[0393] In the present application, the term "heterocycloalkenyl" refers to a cyclic, unsaturated radical having the specified number of ring atoms (e.g., 3-10 membered, 3-6 membered, or 8-10 membered), the specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), the specified kind of heteroatoms (one, two, or more of N, O, and S); having one or more (e.g., 1, 2, or 3) sp 2Double bonds, which are monocyclic or polycyclic (e.g., bridged rings, fused rings, or spirocyclic systems of bicyclic, tricyclic, or more rings), are not aromatic. Heterocyclic alkenyl groups are attached to the rest of the molecule via carbon atoms or heteroatoms.

[0394] The term "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic, bridged, or spirocyclic, and each ring is saturated. Heterocyclic alkyl groups include, but are not limited to, aza-butanediol, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl.

[0395] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6 to C5). 10 An aryl group is a cyclic group consisting solely of carbon atoms, which may be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). An aryl group is linked to other segments of the molecule via an aromatic or non-aromatic ring. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0396] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). Heteroaryl groups are linked to other segments of a molecule via aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and indoleyl groups.

[0397] As used in this invention, the terms "cycloalkylene", "heterocycloalkylene", "arylene", and "heteroaryl" refer to a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group in which one hydrogen atom is further substituted, as defined above.

[0398] The "-" at the end of a group indicates that the group is connected to other segments in the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0399] In structural fragments This refers to the connection between this structural segment and other segments in the molecule through this site. Unless otherwise specified, use wedge-shaped solid lines. and wedge-shaped dashed key This indicates the absolute configuration of a stereocenter. When the compound is chiral, it is either the R configuration or the S configuration.

[0400] The term "multiple" refers to 2, 3, 4, or 5.

[0401] When any variable (e.g., a group R 10a-4 ) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other occurrence. 10a-4 For example, a C 1-6 alkyl group can be substituted with 3 R 1-6 groups, and the 3 R 10a-4 groups are defined independently of one another. 10a-4

[0402] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is produced by reaction of the compound with a pharmaceutically acceptable (relatively non-toxic, biologically compatible) acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the freely-forming compound with a sufficient amount of the appropriate base to produce the salt. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, ammonium, and quaternary ammonium salts. When a compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the freely-forming compound with a sufficient amount of the appropriate acid to produce the salt. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, methanesulfonate, and the like.

[0403] The term "pharmaceutically acceptable excipient" refers to an excipient that is useful in preparing a pharmaceutical composition given the other components of the composition, and that does not destroy the pharmacological activity of the active compound when present in an amount effective for achieving its intended purpose.

[0404] The term "treatment" refers to any one of: (1) alleviating one or more of the biological manifestations of a disease; (2) interfering with one or more points in the biological cascade leading to the disease; (3) slowing the development of one or more of the biological manifestations of a disease.

[0405] The term "prevention" refers to reducing the risk of developing a disease.

[0406] The term "patient" refers to any animal, preferably a mammal, most preferably a human, who has been or will be the object of treatment. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0407] The above preferred conditions can be combined in any way, to obtain the preferred embodiments of the present application.

[0408] The reagents and materials used in the present application are commercially available.

[0409] The positive progress effect of the present application is that the present application provides polypeptide compounds that specifically block the IL-23 signaling pathway, and these molecules have very strong biological activity, good pharmacokinetic properties, or good pharmacodynamic effects in animals. ​DETAILED DESCRIPTION

[0410] The application is further illustrated by the following examples, but the application is not limited to the scope thereof. The experimental methods in the following examples, unless otherwise specified, are carried out according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0411] For the sake of clarity, the application is further illustrated by the examples, but the examples do not limit the scope of the application. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments described herein without departing from the spirit and scope of the application. All reagents used in the application are commercially available and used without further purification.

[0412] The compounds of the application can be prepared by a person skilled in the art of organic synthesis with reference to the routes or methods of the following examples, and the resulting compounds can be characterized by known instruments or methods, including but not limited to mass spectrometry, nuclear magnetic resonance, etc.

[0413] The following abbreviations are used in the application:

[0414] DCM stands for dichloromethane; DCE stands for dichloroethane; PE stands for petroleum ether; Dioxane or 1,4-dioxane stands for dioxane; DMF stands for dimethylformamide; DMSO stands for dimethyl sulfoxide; EA or EtOAc stands for ethyl acetate; MeCN or ACN stands for acetonitrile; MeOH stands for methanol; HFIP stands for hexafluoroisopropanol; MTBE stands for methyl tert-butyl ether; DMA or DMAC stands for N,N-dimethylacetamide; H2O stands for water; Pip stands for piperidine; HATU stands for (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOAT stands for N-hydroxy-7-azabenzotriazole; HOBT stands for 1-hydroxybenzotriazole; DIPEA or DIEA stands for N,N-diisopropylethylamine; NaH stands for sodium hydride; NaBH4 stands for sodium borohydride; Na2CO3 stands for sodium carbonate; NaCl stands for sodium chloride; NaHCO3 stands for sodium bicarbonate; NaOH stands for sodium hydroxide; Na2SO4 stands for sodium sulfate; NBS stands for N-bromosuccinimide; K2CO3 stands for potassium carbonate; Cs2CO3 stands for cesium carbonate; AcOH stands for acetic acid; Ac2O stands for acetic anhydride; HCl stands for hydrochloric acid; TFA stands for trifluoroacetic acid; Tis stands for triisopropylsilane; EDT stands for 1,2-ethanedithiol; NH4I stands for ammonium iodide; I2 stands for iodine; Oxyma stands for 2-oxymethyl oxime acetic acid ethyl ester; DIC stands for N,N'-diisopropylcarbodiimide; PhSiH3 stands for phenylsilane; 1,3-Dimethylbarbituric acid stands for 1,3-dimethylbarbituric acid; Pd(PPh4)3 stands for tetrakis(triphenylphosphine)palladium; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; DCC stands for dicyclohexylcarbodiimide; TMAD stands for azodicarbonamide; Q-phos stands for 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; TBSCl stands for tert-butyldimethylsilyl chloride; HOSU stands for N-hydroxysuccinimide; Me3SnOH stands for trimethyltin hydroxide; MeI stands for methyl iodide; KI stands for potassium iodide; K2CO3 stands for potassium carbonate; DMAP 4-dimethylaminopyridine; TsCl stands for p-toluenesulfonyl chloride; NiBr2 stands for nickel bromide; NiBr2.3H20 represents nickel bromide trihydrate; DME NiCl2 represents nickel (II) chloride ethylene glycol dimethyl ether complex; Mn represents manganese; Dtbbpy 4,4'-di-tert-butyl-2,2'-bipyridine; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; Pd / C represents palladium on carbon catalyst; FmocOSu represents 9-fluorenylmethyl N-succinimidyl carbonate; FmocCl represents 9-fluorenylmethyl chloroformate; DBU represents 1,8-diazabicyclo[5,4,0]undec-7-ene; DME NiCl2 represents nickel chloride dimethoxyethane; Mn represents manganese powder; Zn represents zinc powder; dtbpy represents 4,4'-di-tert-butyl-2,2'-bipyridine; NiBr represents nickel bromide; TPP represents triphenylphosphine; (2,2'-Bipyridine)NiCl2 represents (2,2'-bipyridine)nickel dichloride; DEA represents diethylamine; TSTU represents 2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate; Fmoc represents 9-fluorenylmethyloxycarbonyl; Trt represents trityl; Boc represents tert-butoxycarbonyl. t Bu represents tert-butyl; Ac represents acetyl; Me represents methyl; All represents allyl; Dde represents 1-(4,4-dimethyl-2,6-dioxocyclohexyl-1-ylidene)ethyl; TIS represents triisopropylsilane; 3-MPA represents 3-mercaptopropionic acid.

[0415] h represents hour(s); min represents minute(s); mg represents milligram(s); mL represents milliliter(s); M represents mol; mmol represents millimole(s); g represents gram(s); v or V represents volume; %wt represents weight percent; N2 represents nitrogen; HPLC represents high performance liquid chromatography; d represents doublet; br represents broad; brs represents broad singlet; m represents multiplet; °C represents degrees Celsius; CD3OD represents deuterated methanol; CDCl3 represents deuterated chloroform; DMSO-d6 represents deuterated dimethyl sulfoxide; D2O represents deuterated water; LC-MS represents liquid chromatography-mass spectrometry; ESI represents electrospray ionization; m / z represents mass to charge ratio.

[0416] List of Amino Acids:

[0417] List of Fragments

[0418] Example 1: Intermediate Synthesis:

[0419] Intermediate AA1

[0420] Compound AA1-1 (5 g, 22.12 mmol) was dissolved in DMAC (70 mL), NaH (1.06 g, 26.54 mmol, 60% purity) was added at 0 °C; the system was stirred at 0 °C for 0.5 h. Mel (4.71 g, 33.18 mmol) was added dropwise at 0 °C. The system was warmed to room temperature (25 °C) and stirred for 2 h. Water was added to the system, the pH was adjusted to 6 with 2N dilute hydrochloric acid, and it was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 25%) to give compound AA1-2. MS m / z (ESI): 239.9 [M+H] + .

[0421] Compound AA1-2 (4.35 g, 18.12 mmol) was dissolved in DMA (50 mL), DME NiCl2 (398.08 mg, 1.81 mmol), Mn (4.98 g, 90.59 mmol), compound AA1-3 (12.26 g, 27.18 mmol), and pyridine-2-carboxamidine (856.61 mg, 5.44 mmol) were added. The system was warmed to 60 °C and stirred for 2 h under N2. The system was poured into ice water and stirred until uniform, then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to give compound AA1-4. MS m / z (ESI): 485.3 [M+H] + .

[0422] Compound AA1-4 (2 g, 4.13 mmol) was dissolved in DCE (20 mL), and trimethyltin hydroxide (2.99 g, 16.51 mmol) was added. The system was warmed to 65 °C and stirred for 12 h under N2. The system was concentrated to give a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to give compound AA1. MS m / z (ESI): 471.1 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 7.4 Hz, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.59-7.47 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.26 (q, J = 7.1 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.89-6.84 (m, 1H), 4.28-4.24 (m, 1H), 4.14-4.03 (m, 3H), 3.18-3.12 (m, 1H), 3.02-2.87 (m, 5H), 2.79-2.66 (m, 3H).

[0423] intermediates AA3, AA4, AA6, AA7, AA10, AA17, AA26, AA27, AA29, AA43

[0424] Intermediates AA3, AA4, AA6, AA26, AA27, AA29 were synthesized following the procedure of intermediate AA1 starting from the corresponding starting materials.

[0425] AA3: MS m / z (ESI): 443.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 2.8 Hz, 2H), 7.55 (m, 1H), 7.38 (m, 4H), 6.94 (m, 2H), 6.37 (d, J = 4.8 Hz, 1H), 4.25 (m, 4H), 3.14 (t, J = 10.8 Hz, 2H), 2.98 (m, 1H), 2.75 (m, 3H), 2.98 (s, 3H).

[0426] AA4: MS m / z (ESI): 428.0 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6) δ 7.94-7.87 (m, 2H), 7.68-7.63 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32-7.25 (m, 2H), 7.08-6.97 (m, 3H), 4.28-4.00 (m, 4H), 3.09-2.81 (m, 2H), 2.75 (q, J = 6.8 Hz, 4H), 1.96-1.89 (m, 2H)

[0427] AA6: MS m / z (ESI): 536.2 [M+Na] + ; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.71 (t, J = 7.2 Hz, 2H), 7.58 (t, J = 4.8 Hz, 2H), 7.50 - 7.35 (m, 5H), 7.30 - 7.20 (m, 2H), 4.21 - 4.12 (m, 4H), 3.18 - 3.08 (m, 1H), 2.95 - 2.85 (m, 1H).

[0428] AA7: MS m / z (ESI): 442.2 [M+H] + ;

[0429] AA10: MS m / z (ESI): 407.2 [M+H] + ;

[0430] AA17: MS m / z (ESI): 457.0 [M+H] + ;

[0431] AA26: MS m / z (ESI): 526.6 [M+H] + .

[0432] AA27: MS m / z (ESI): 428.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 4.8 Hz, 3H), 7.61 (d, J = 6.4 Hz, 2H), 7.41 (d, J = 6.4 Hz, 3H), 7.21 (m, 2H), 6.71 (d, J = 6.4 Hz, 2H), 6.48 (s, 1H), 4.12 (m, 4H), 3.12 (dd, J = 6.8 Hz, J = 7.6 Hz, 1H), 2.98 (dd, J = 4.8 Hz, J = 5.2 Hz, 1H).

[0433] AA29: MS m / z (ESI): 466.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.80 (m, 4H), 7.71 - 7.65 (m, 2H), 7.65 - 7.55 (m, 2H), 7.45 - 7.35 (m, 2H), 7.35 - 7.15 (m, 4H), 4.35 - 3.95 (m, 4H), 3.25 - 3.15 (m, 1H), 3.05 - 2.95 (m, 1H).

[0434] AA43: MS m / z (ESI): 514.2 [M+H] + ;

[0435] Intermediate AA2

[0436] NiBr2(892.42 mg, 3.77 mmol) and dtbpy (1.01 g, 3.77 mmol) were dissolved in DMA (30 mL). The system was stirred at room temperature (25 °C) for 1 h under N2condition. To this, compound AA2-1 (4.87 g, 21.56 mmol), AA2-2 (6 g, 10.78 mmol) and Zn (3.17 g, 48.51 mmol) were added. The system was stirred at 40 °C for 2 h under N2condition. To the system, water was added and extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 50%) to give compound AA2-3. MS m / z (ESI): 513.4 [M+H] + .

[0437] Compound AA2-3 (1 g, 1.95 mmol) was dissolved in DCM (8 mL) and TFA (8 mL) was added thereto. The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give a crude product. The crude product was purified by column chromatography (tetrahydrofuran / petroleum ether (v / v) = 50%) to give compound AA2. MS m / z (ESI): 457.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.89-7.78 (m, 3H), 7.64-7.55 (m, 3H), 7.45-7.37 (m, 4H), 7.31-7.24 (m, 2H), 4.41-4.13 (m, 6H), 3.22-2.94 (m, 5H).

[0438] Intermediate AA8

[0439] Compound AA1-3 (5.96 g, 13.20 mmol), zinc powder (2.59 g, 39.61 mmol) and iodine (837.69 mg, 3.3 mmol) were mixed and dissolved in DMF (30 mL); the system was warmed to 50 °C under N2for 0.5 h to obtain a zinc reagent solution. Compound AA8-1 (1.4 g, 6.60 mmol) was dissolved in DMF (10 mL), Sphos (277.25 mg, 660.11 mmol), Pd2(dba)3(604.00 mg, 660.11 mmol) were added thereto under N2, and the system was warmed to 50 °C under N2for 0.5 h; the supernatant of the zinc reagent solution was added thereto, and the system was stirred at 50 °C for 16 h under N2. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to obtain compound AA8-2. MS m / z (ESI): 457.3 [M+H] + .

[0440] Compound AA8-2 (1.2 g, 2.63 mmol) was dissolved in dichloroethane (100 mL), and trimethyltin hydroxide (1.43 g, 7.89 mmol) was added thereto. The system was warmed to 65 °C under N2and stirred for 16 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to obtain compound AA8. MS m / z (ESI): 443.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.23 (s, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 4.8 Hz, 2H), 7.48 (t, J = 12.8 Hz, 2H), 7.39 (t, J = 9.6 Hz, 3H), 4.27 (m, 4H), 3.11 (m, 1H), 2.86 (m, 1H), 2.67 (t, J = 12.8 Hz, 2H), 2.56 (m, 2H), 1.72 (m, 4H).

[0441] Intermediate AA17

[0442] Intermediate AA17 was synthesized according to the procedures of Intermediate AA8 starting from the corresponding starting materials.

[0443] AA17: MS m / z (ESI): 457.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 2.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 3H), 7.39 (dt, J = 5.6 Hz, 2H), 6.89 (m, 3H), 4.25 (m, 4H), 2.98 (d, J = 7.6 Hz, 2H), 2.75 (m, 3H), 2.65 (m, 3H), 2.33 (s, 3H).

[0444] Intermediate AA9

[0445] NiBr2.3H2O (0.88 g, 3.24 mmol) and Dtbbpy (0.87 g, 3.24 mmol) were dissolved in DMA (60 mL), to which was added compound AA2-2 (6.00 g, 10.8 mmol), zinc powder (3.54 g, 54.1 mmol) and compound AA9-1 (120.4 mg, 0.540 mmol). The system was stirred at room temperature (25 °C) for 12 h under N2. The system was filtered with celite, and the organic phase was washed with ethyl acetate (200 mL), and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to give compound AA9-2. MS m / z (ESI): 519.2 [M+Na] + .

[0446] Compound AA9-2 (1.70 g, 3.43 mmol) was dissolved in DCM (30 mL), to which was added TFA (5 mL). The system was stirred at room temperature (25 °C) for 12 h under N2. The system was concentrated to give a crude product, which was purified by column chromatography (methanol / dichloromethane (v / v) = 10%) to give compound AA9. MS m / z (ESI): 441.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.34-7.24 (m, 2H), 4.30-4.11 (m, 4H), 3.16 (dd, J = 14.0, 4.4 Hz, 1H), 2.97-2.85 (m, 1H).

[0447] Intermediate AA10

[0448] Intermediate AA10 was synthesized according to the procedures described for Intermediate AA9, starting from the corresponding starting materials.

[0449] AA10: MS m / z (ESI): 407.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.12 (s, 1H), 7.93-7.81 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 7.2, 3.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.34-7.25 (m, 2H), 7.12-7.05 (m, 1H), 4.26-4.01 (m, 4H), 3.13 (dd, J = 14.0, 4.4 Hz, 1H), 2.93-2.85 (m, 1H).

[0450] Intermediate AA11

[0451] Compound AA11-1 (660 mg, 1.31 mmol) was dissolved in acetonitrile (10 mL), to which 85% phosphoric acid (7.6 g, 65.5 mmol) was added. The system was warmed to 65 °C for 2.5 h. The system was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water (0.05% trifluoroacetic acid) = 0-50%) to give intermediate AA11-2. MS m / z (ESI): 447.0 [M+H] + .

[0452] Compound AA11-2 (340 mg, 0.76 mmol) was dissolved in N,N-dimethylformamide (34 mL), to which N,N-diisopropylethylamine (147 mg, 1.14 mmol) and Cat's reagent (438 mg, 0.99 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h. Water (100 mL) was added to the system, which was extracted with ethyl acetate twice (150 mL x 2), the organic phases were combined, washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to give compound AA11-3. MS m / z (ESI): 429.2 [M+H] + .

[0453] Compound AA11-3 (240 mg, 0.56 mmol) was dissolved in methanol (5 mL), to which was added 20% palladium hydroxide on carbon (39 mg, 0.056 mmol) and two drops of 12 N hydrochloric acid. The system was stirred at room temperature (25 °C) under H2atmosphere for 4 h. The system was filtered, and the filtrate was concentrated to give compound AA11-4, which was used in the next step without further purification. MS m / z (ESI): 159.1 [M+H] + .

[0454] The crude compound AA11-4 (0.56 mmol) was dissolved in a mixture of tetrahydrofuran / water (1 / 1, v / v) (6 mL), to which was added 9-fluorenylmethyl-N-succinimidyl carbonate (226 mg, 0.67 mmol) and sodium bicarbonate (141 mg, 1.68 mmol) respectively. The system was stirred at room temperature (25 °C) for 4 h. To the system was added 10% aqueous citric acid solution to adjust pH to 5, and it was extracted with ethyl acetate twice (50 mL x 2). The organic phase was combined, washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water (0.05% trifluoroacetic acid) = 0-60%) to give compound AA11. MS m / z (ESI): 381.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.85-7.59 (m, 4H), 7.48-7.39 (m, 2H), 7.38-7.29 (m, 2H), 4.62-4.38 (m, 1H), 4.33-4.13 (m, 3H), 3.25-3.12 (m, 2H), 2.93-2.81 (m, 1H), 2.18-1.92 (m, 2H).

[0455] Intermediate AA13

[0456] Compound AA13-1 (5 g, 20.2 mmol), compound AA13-2 (2.9 g, 20.2 mmol) and 4-dimethylaminopyridine (3.2 g, 26.3 mmol) were dissolved in dichloromethane (40 mL), and N, N'-dicyclohexylcarbodiimide (5.4 g, 26.3 mmol) was slowly added thereto at 0 °C. The system was warmed to room temperature (25 °C) and stirred for 4 h. The system was filtered, the filtrate was adjusted to pH 5 with 10% aqueous citric acid solution, extracted with ethyl acetate twice (150 mL x 2), the combined organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was dissolved in toluene (40 mL), and benzyl alcohol (2.8 g, 26.3 mmol) was added thereto. The system was warmed to 85 °C and stirred for 3 h. The system was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 25%) to give compound AA13-3. MS m / z (ESI): 402.1 [M+Na] + .

[0457] Compound AA13-3 (5 g, 13.2 mmol) was dissolved in methanol (25 mL), and 10% palladium on carbon (500 mg) was added thereto, followed by the slow dropwise addition of triethylsilane (15.3 g, 132 mmol). The system was stirred at room temperature (25 °C) for 1 h, and then warmed to 70 °C and stirred for 2 h. The system was filtered, the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-40%) to give compound AA13-4. MS m / z (ESI): 286.0 [M+Na] + .

[0458] Compound AA13-4 (3 g, 12.2 mmol) was dissolved in dichloromethane (30 mL), and diethylaminosulfur trifluoride (5.9 g, 36.6 mmol) was added thereto under N2. The system was stirred at room temperature (25 °C) for 48 h. The system was quenched by adding saturated aqueous sodium bicarbonate solution thereto, and then triethylsilane (15.3 g, 132 mmol) was slowly added dropwise thereto, and the system was stirred at room temperature (25 °C) for 16 h, and then warmed to 70 °C and stirred for 2 h. The system was filtered, the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to give compound AA13-5. MS m / z (ESI): 290.1 [M+Na] + .

[0459] Compound AA13-5 (1.5 g, 5.6 mmol) was dissolved in dichloromethane (10 mL), to which trifluoroacetic acid (5 mL) was added. The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give compound AA13-6, which was used in the next step without further purification. MS m / z (ESI): 168.1 [M+H] + .

[0460] Compound AA13-6 (5.6 mmol) was dissolved in a mixture solvent of acetonitrile / water (2 / 1, v / v) (18 mL), to which 9-fluorenylmethyl-N-succinimidyl carbonate (2.83 g, 8.4 mmol) and sodium bicarbonate (2.35 g, 28 mmol) were added respectively. The system was stirred at room temperature (25 °C) for 2 h. The pH of the system was adjusted to 5 with 10% aqueous citric acid solution, which was extracted with ethyl acetate twice (100 mL x 2), the combined organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to give compound AA13-7. MS m / z (ESI): 390.2 [M+H] + .

[0461] Compound AA13-7 (2 g, 5.1 mmol) was dissolved in dichloroethane (15 mL), to which trimethyltin hydroxide (2.8 g, 15.3 mmol) was added. The system was warmed to 85 °C and stirred for 2 h. The system was filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse phase medium pressure column chromatography (acetonitrile / water (0.05% trifluoroacetic acid) = 0-55%) to give compound AA13. MS m / z (ESI): 398.1 [M+Na] + . 1 H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 8.01-7.58 (m, 5H), 7.44 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 4.50-3.95 (m, 4H), 2.49-2.13 (m, 2H), 1.75-1.47 (m, 3H).

[0462] Intermediate AA16

[0463] Compound Fmoc-2-Nal-OH (3 g, 13.94 mmol) was dissolved in dichloromethane (50 mL), to which DCC (5.75 g, 27.87 mmol) and HOSu (4.81 g, 41.81 mmol) were added. The system was stirred at room temperature (25 °C) for 16 h under N2condition. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 20%) to obtain compound AA16-1. MS m / z (ESI): 557.3 [M+Na] + .

[0464] Compound AA16-1 (5.49 g, 10.26 mmol) was dissolved in DMF (100 ml), to which compound AA16-2 (1 g, 6.84 mmol) and DIEA (2.65 g, 20.53 mmol) were added under N2condition. The system was stirred at room temperature (25 °C) for 16 h under N2condition. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to obtain compound AA16. MS m / z (ESI): 588.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) d 8.05 (d, J = 8.8 Hz, 1H), 7.92-7.80 (m, 6H), 7.59 (dd, J = 7.6 Hz, 7.2 Hz, 2H), 7.51-7.45 (m, 3H), 7.41-7.35 (m, 2H), 7.25-7.15 (m, 2H), 4.52-4.41 (m, 1H), 4.20-4.10 (m, 3H), 3.70-3.60 (m, 2H), 3.60-3.40 (m, 2H), 3.32 (dd, J = 14.4 Hz, 4.4 Hz, 1H), 3.08 (dd, J = 11.2 Hz, 10.8 Hz, 1H), 1.80-2.01 (m, 4H).

[0465] Intermediate AA19

[0466] Compound AA19-1 (4.5 g, 14.9 mmol) and methyl 4-bromobutyrate (1.34 g, 7.45 mmol) were dissolved in acetonitrile (30 mL). After the system was stirred at room temperature (25 °C) for 2.5 h, it was warmed to 80 °C and stirred for 16 h. The system was concentrated to give a crude product, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 0-5%) to give compound AA19-2. MS m / z (ESI): 371.4 [M+H] + .

[0467] Compound AA19-2 (2.7 g, 7.3 mmol) was dissolved in dichloromethane (10 mL), and 4M HCl dioxane solution (5.5 mL, 21.9 mmol) was added thereto. The system was stirred at room temperature (25 °C) for 2.5 h. The system was concentrated to give compound AA19-3, which was directly used in the next reaction without further purification. MS m / z (ESI): 215.2 [M+H] + .

[0468] The crude compound AA19-3 (7.3 mmol) was dissolved in a mixed solvent of acetonitrile / water (1 / 1, v / v) (20 mL), and 9-fluorenylmethyl N-succinimidyl carbonate (3.2 g, 9.5 mmol) and sodium bicarbonate (3.1 g, 36.5 mmol) were added thereto, respectively. The system was stirred at room temperature (25 °C) for 4 h. The pH of the system was adjusted to 5 with 10% citric acid aqueous solution, and it was extracted with ethyl acetate twice (150 mL x 2), and the combined organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water (0.05% trifluoroacetic acid) = 0-65%) to give intermediate AA19. MS m / z (ESI): 437.4 [M] + . 1 H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.73 (d, J = 7.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (td, J = 7.5, 1.1 Hz, 2H), 7.33 (td, J = 7.5, 1.2 Hz, 2H), 4.34-4.17 (m, 3H), 3.97-3.85 (m, 1H), 3.29 (t, J = 7.1 Hz, 2H), 3.15 (t, J = 7.0 Hz, 2H), 2.18 (t, J = 8.0 Hz, 2H), 1.88 (p, J = 7.7 Hz, 2H), 1.77-1.54 (m, 2H), 1.51-1.36 (m, 2H), 1.33-1.20 (m, 2H).

[0469] Intermediate AA21

[0470] Compound AA21-1 (1 g, 11.98 mmol) was dissolved in 4 M HC1 in dioxane (50 mL). The system was stirred at room temperature (25 °C) for 2 hours. The system was concentrated to obtain compound AA21-2, which was directly used in the next reaction without further purification.

[0471] The crude compound AA21-2 (1.00 g) was dissolved in dioxane (10 mL) and water (2 mL), to which FmocOSu (1.10 g, 3.26 mmol) and sodium carbonate (1.41 g, 10.86 mmol) were added. The system was warmed to 65 °C and stirred for 16 h under N2condition. The system was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound AA21-3.

[0472] Compound AA21-3 (654.00 mg, 1.00 mmol) was dissolved in dichloroethane (100 ml), to which trimethyltin hydroxide (1.33 g, 7.34 mmol) was added. The system was warmed to 65 °C and stirred for 16 h under N2condition. The system was concentrated to obtain a crude product, which was purified by column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound AA21. MS m / z (ESI): 395.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 4.8 Hz, 3H), 7.58 (m, 1H), 7.48 (t, J = 12.8 Hz, 2H), 7.39 (t, J = 9.6 Hz, 2H), 4.27 (m, 3H), 4.11 (m, 1H), 3.25 (m, 2H), 2.13 (m, 1H), 1.98 (m, 2H), 1.56 (m, 2H).

[0473] Intermediate AA22

[0474] Compound A22-1 (3 g, 24.98 mmol) was dissolved in DMF (50 mL), to which TBSCl (4.52 g, 29.97 mmol) and imidazole (1.70 g, 24.98 mmol) were added. The system was stirred at room temperature (25 °C) for 2 hours under N2condition. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 20%) to obtain compound AA22-2. MS m / z (ESI): 256.7 [M+Na] + .

[0475] Compound AA22-2 (2.6 g, 11.09 mmol) was dissolved in dichloroethane (50 mL), to which trimethyltin hydroxide (865.94 mg, 22.18 mmol) was added. The system was stirred at room temperature (25 °C) for 2 hours under N2condition. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 20%) to obtain compound AA22-3. MS m / z (ESI): 220.9 [M+H] + .

[0476] Compound A22-3 (1.5 g, 6.81 mmol) was dissolved in DMF (30 ml), to which DIEA (2.64 g, 20.42 mmol), HATU (3.88 g, 10.21 mmol) and compound Fmoc-7-Me-Trp-OH (3.00 g, 6.81 mmol) were added. The system was stirred at room temperature (25 °C) for 16 h under N2condition. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to obtain compound AA22. MS m / z (ESI): 643.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.81-10.71 (m, 1H), 7.85-7.75 (m, 3H), 7.63 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 7.6 Hz, 7.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.85-6.80 (m, 2H), 4.75 (d, J = 7.2 Hz, 1H), 4.31-4.21 (m, 1H), 4.21-3.88 (m, 5H), 3.52-3.41 (m, 1H), 2.95-2.85 (m, 1H), 2.38 (s, 3H), 0.82 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H).

[0477] Intermediate AA23

[0478] Compound AA23-1 (10 g, 24.30 mmol) was dissolved in DMF (100 mL), to which HATU (13.85 g, 36.46 mmol), DIEA (9.42 g, 72.91 mmol) and pyrrolidine (1.73 g, 24.30 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h. The system was added with water (500 mL) and extracted with ethyl acetate for three times (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound AA23-2. MS m / z (ESI): 465.3 [M+H] + .

[0479] Compound AA23-2 (10 g, 21.53 mmol) was dissolved in DCM (50 mL), to which TFA (50 mL) was added. The system was stirred at room temperature (25 °C) for 1 h. The system was concentrated to obtain a crude product, which was purified by C18 reverse phase medium pressure column chromatography (acetonitrile / water = 0-50%) to obtain compound AA23. MS m / z (ESI): 409.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H), 7.44-7.31 (m, 4H), 6.79 (d, J = 7.2 Hz, 1H), 4.26-4.22 (m, 3H), 4.06-4.01 (m, 1H), 3.25 (t, J = 6.4 Hz, 4H), 2.64-2.63 (m, 2H), 1.85-1.71 (m, 4H).

[0480] Intermediate AA20

[0481] Intermediate AA20 was synthesized according to the procedures described for Intermediate AA23 starting from the corresponding starting materials.

[0482] AA20: MS m / z (ESI): 423.2 [M+H] + ;

[0483] Intermediate AA24

[0484] Compound AA24-1 (1 g, 2.71 mmol) was dissolved in DMF (10 mL), to which azetidine (185.49 mg, 3.25 mmol), HATU (1.24 g, 3.25 mmol), DIPEA (1.05 g, 8.12 mmol) were added. The system was stirred at room temperature (25 °C) for 2 hours. Water (20 mL) was added to the system, which was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography to obtain compound AA24-2. MS m / z (ESI): 409.3 [M+H] + .

[0485] Compound AA24-2 (700 mg, 1.71 mmol) was dissolved in DCE (10 mL), and Me3SnOH (929.68 mg, 5.14 mmol) was added. The system was warmed to 60 °C and stirred for 16 h. Water (20 mL) was added to the system, which was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to obtain compound AA24. MS m / z (ESI): 395.3 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.89 (d, J = 7.4 Hz, 2H), 7.75-7.69 (m, 3H), 7.42 (t, J = 7.4 Hz, 2H), 7.35-7.31 (m, 2H), 4.41-4.28 (m, 3H), 4.21 (t, J = 6.6 Hz, 1H), 4.10 (t, J = 8.0 Hz, 2H), 3.82 (t, J = 7.6 Hz, 2H), 2.73-2.63 (m, 1H), 2.47-2.39 (m, 1H), 2.20-2.12 (m, 2H).

[0486] Intermediate AA28

[0487] Compound AA28-1 (3 g, 6.43 mmol) was dissolved in DMF (50 mL), to which was added Mel (1.83 g, 12.86 mmol) and potassium carbonate (1.77 g, 12.86 mmol). The system was stirred at room temperature (25 °C) for 2 h under N2. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 20%) to obtain compound AA28-2. MS m / z (ESI): 503.9 [M+K] + .

[0488] Compound AA28-2 (2.5 g, 5.20 mmol) was dissolved in hydrochloric acid dioxane (50 mL). The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to obtain compound AA28-3, which was directly used in the next step without further purification. MS m / z (ESI): 380.9 [M+H] + .

[0489] Compound AA28-3 (1.5 g, 3.94 mmol) was dissolved in DMF (50 mL), to which was added Mel (2.24 g, 15.77 mmol) and potassium carbonate (1.09 g, 7.89 mmol). The system was stirred at room temperature (25 °C) for 2 h under N2. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 20%) to obtain compound AA28-4. MS m / z (ESI): 409.0 [M] + .

[0490] Compound AA28-4 (1.2 g, 2.93 mmol) was dissolved in dichloroethane (30 mL), to which was added trimethyltin hydroxide (1.33 g, 8.93 mmol). The system was stirred at 50 °C for 16 h under N2. The reaction solution was poured into ice water and stirred uniformly, extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to obtain compound AA28. MS m / z (ESI): 394.9 [M] + ; 1H-NMR (400 MHz, D20) δ 7.72 (d, J = 7.4 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.33-7.22 (m, 4H), 4.65 (s, 2H), 4.57-4.52 (m, 1H), 4.09 (s, 1H), 3.11 (s, 2H), 2.87-2.72 (m, 8H), 2.09-1.72 (m, 4H).

[0491] Intermediate AA30

[0492] Compound AA30-1 (10.0 g, 46.4 mmol) was dissolved in DCM (1.2 L), and 1,2-benzenedimethanol (36.6 g, 264 mmol) and DMAP (0.57 g, 4.65 mmol) were added at 0 °C. After the addition was completed, EDCI (11.6 g, 60.4 mmol) was added. The system was slowly warmed to room temperature (25 °C) and stirred for 5 h. The system was concentrated, and water (50 mL) and dichloromethane (150 mL) were added to separate the phases, and the aqueous phase was extracted twice more with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to obtain compound AA30-2. MS m / z (ESI): 358.4 [M+Na] + .

[0493] Compound AA30-2 (13.1 g, 39.1 mmol) was dissolved in 4 M HCl dioxane solution (97.6 mL) at 0 °C. The system was stirred at 0 °C for 1 h. The system was concentrated to obtain compound AA30-3, which was used directly in the next reaction without further purification. MS m / z (ESI): 236.4 [M+H] + .

[0494] Compound AA30-3 (9.19 g, 39.1 mmol) was dissolved in DCM (150 mL), and TEA (13 mL, 93.7 mmol) was added at 0 °C. After the addition was completed, acetyl chloride (3.3 mL, 46.8 mmol) was added dropwise. The system was warmed to room temperature (25 °C) and stirred for 12 h. The system was added with water (50 mL) and dichloromethane (100 mL) to separate the phases, and the aqueous phase was extracted twice more with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water = 0-15%) to obtain compound AA30-4. MS m / z (ESI): 300.1 [M+Na] + .

[0495] Compound AA30-4 (3.00 g, 10.8 mmol) was dissolved in DCM (100 mL), to which [(4-nitrophenyl)oxy]acetic acid 4-nitrophenyl ester (4.94 g, 16.2 mmol) and DIEA (3.60 mL, 21.6 mmol) were added. The system was stirred at room temperature (25 °C) for 12 h under N2condition. The system was quenched by 10% aqueous citric acid solution (250 mL), extracted with dichloromethane (150 mL), and the aqueous phase was extracted with dichloromethane twice (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-57%) to give compound AA30-5. MS m / z (ESI): 443.2 [M+H] + .

[0496] Fmoc-alpha-allyl-L-alanine (10.0 g, 29.6 mmol) was dissolved in EA (200 mL), to which a solution of tert-butyl 2,2,2-trichloroacetimidate (1.62 g, 7.41 mmol) in cyclohexane (20 mL) was added. The system was stirred at room temperature (25 °C) for 72 h. The system was concentrated, partitioned with water (100 mL) and ethyl acetate (300 mL), and the aqueous phase was extracted with ethyl acetate twice (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-8%) to give compound AA30-12. MS m / z (ESI): 416.2 [M+Na] + .

[0497] A solution of diethylamine (11.1 mL, 107 mmol) in DMF (77.9 mL) was added dropwise to compound AA30-12 (10.6 g, 26.9 mmol) at 0 °C. The system was warmed to room temperature (25 °C) and stirred for 1 h. The system was concentrated to give compound AA30-6, which was used directly in the next reaction without further purification. MS m / z (ESI): 194.2 [M+Na] + .

[0498] Compound AA30-6 (4.85 g, 28.3 mmol) was dissolved in DMF (25 mL), to which DIEA (3.50 mL, 21.4 mmol) was added at 0 °C. After addition, compound AA30-5 (3.80 g, 8.59 mmol) was added dropwise. The system was stirred at room temperature (25 °C) for 3 h. The system was directly purified by C18 reverse-phase medium pressure column chromatography (acetonitrile / water = 0-49%) to give compound AA30-7. MS m / z (ESU): 475.2 [M+H]+ .

[0499] Compound AA30-7 (77.0 mg, 0.16 mmol) was dissolved in DCE (32.6 mL), to which Grubbs second generation catalyst (13.7 mg, 0.016 mmol) was added. The system was warmed to 85 °C and stirred for 24 h. The system was filtered, and the filtrate was directly purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water = 0-48%) to give compound AA30-8. MS m / z (ESI): 447.4 [M+H] + .

[0500] Compound AA30-8 (35.0 mg, 0.078 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), to which 5% Pd / C (16.7 mg) was added. The system was stirred under H2at room temperature (25 °C) for 3 h. The system was filtered, and the filtrate was concentrated to give compound AA30-9, which was used directly in the next reaction without further purification. MS m / z (ESI): 303.4 [M+H] + .

[0501] Compound AA30-9 (30.0 mg, 0.10 mmol) was dissolved in THF (2.5 mL) and water (1 mL), to which sodium carbonate (18.5 mg, 0.22 mmol) and 9-fluorenylmethyl chloroformate (28.4 mg, 0.11 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h. To the system was added 1 M aqueous HCl (3 mL) to quench, which was extracted with ethyl acetate three times (10 mL x 3). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound AA30-10, which was used directly in the next reaction without further purification. MS m / z (ESI): 547.3 [M+Na] + .

[0502] Compound AA30-10 (52.2 mg, 0.10 mmol) was dissolved in DMF (2 mL), to which sodium carbonate (16.8 mg, 0.20 mmol) and 3-bromopropene (60.5 mg, 0.50 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h. The system was directly purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water = 0-65%) to give compound AA30-11. MS m / z (ESI): 565.4 [M+H] + .

[0503] To compound AA30-11 (2.00 g, 3.54 mmol) was added TFA (8.1 mL) in DCM (1.5 mL) slowly at 0 °C. The system was warmed to room temperature (25 °C) and stirred for 1 h. The system was directly purified by C18 reverse phase medium pressure column chromatography (acetonitrile / water = 0-55%) to give compound AA30. MS m / z (ESI): 509.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 5.97-5.81 (m, 1H), 5.30 (dd, J = 17.2, 1.6 Hz, 1H), 5.20 (dd, J = 10.6, 1.2 Hz, 1H), 4.59-4.53 (m, 2H), 4.32-4.17 (m, 4H), 3.96-3.86 (m, 1H), 1.85 (s, 3H), 1.71-1.54 (m, 4H), 1.36-1.25 (m, 4H).

[0504] Intermediate AA31

[0505] Fmoc-alpha-allyl-L-alanine (10 g, 29.64 mmol) was dissolved in acetone (200 mL), to which was added Mel (10.52 g, 74.10 mmol), K2CO3(10.24 g, 74.10 mmol). The system was stirred at room temperature (25 °C) for 16 h. Water (300 mL) was added to the system, which was extracted with ethyl acetate three times (150 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to give compound AA31-1. MS m / z (ESI): 374.2 [M+Na] + .

[0506] Compound AA31-1 (4.5 g, 12.81 mmol) was dissolved in DCM (50 mL), tert-butyl 1-buten-4-ate (3.64 g, 25.61 mmol) and Grubbs second generation catalyst (543.60 mg, 640.31 μmol) were added. The system was stirred at room temperature (25 °C) for 3 h. Water (50 mL) was added to the system, which was extracted with dichloromethane twice (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to give compound AA31-3. MS m / z (ESI): 488.3 [M+Na] + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 7.4 Hz, 2H), 7.79-7.76 (m, 1H), 7.68 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.60-5.44 (m, 2H), 4.35-4.18 (m, 3H), 4.10-4.00 (m, 1H), 3.63-3.53 (m, 3H), 3.02-2.90 (m, 2H), 2.45-2.23 (m, 2H), 1.41-1.30 (m, 9H).

[0507] Compound AA31-3 (1.6 g, 3.44 mmol) was dissolved in MeOH (20 mL), and 10% Pd / C (210 mg) was added thereto. The system was stirred at room temperature (25 °C) for 16 h under H2conditions. The system was filtered, and the filtrate was concentrated to give compound AA31-4, which was used directly in the next reaction without further purification. MS m / z (ESI): 490.2 [M+Na] + .

[0508] Compound AA31-4 (1.4 g, 2.99 mmol) was dissolved in DCM (20 mL), and TFA (5 mL) was added thereto. The system was stirred at room temperature (25 °C) for 2 h. Water (20 mL) was added to the system, which was extracted with dichloromethane three times (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound AA31-5. MS m / z (ESI): 412.1 [M+H] + .

[0509] Compound AA31-5 (1.2 g, 2.92 mmol) was dissolved in MeCN (20 mL), to which was added 3-bromopropene (423.40 mg, 3.50 mmol) and K2CO3 (806.16 mg, 5.83 mmol). The system was stirred at room temperature (25 °C) for 16 h. The system was filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to give compound AA31-6. MS m / z (ESI): 452.0 [M+H] + .

[0510] Compound AA31-6 (900 mg, 1.99 mmol) was dissolved in DCE (15 mL), to which was added Me3SnOH (1.08 g, 5.98 mmol). The system was warmed to 60 °C and stirred for 3 h. Water (20 mL) was added to the system, which was extracted with dichloromethane three times (15 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound AA31. MS m / z (ESI): 438.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.4 Hz, 2H), 7.73 (d, J = 7.4 Hz, 2H), 7.64 (s, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 5.90 (m, 1H), 5.30-5.18 (m, 2H), 4.53 (d, J = 5.2 Hz, 2H), 4.27-4.22 (m, 3H), 3.91 (s, 1H), 2.33 (t, J = 7.1 Hz, 2H), 1.68-1.50 (m, 4H), 1.28 (d, J = 39.0 Hz, 2H).

[0511] Intermediate AA5, AA32

[0512] Intermediate AA5, AA32 was synthesized according to the procedures of Intermediate AA31 starting from the corresponding starting materials.

[0513] AA5: MS m / z (ESI): 452.2 [M+H] + .

[0514] AA32: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 5.90 (m, 1H), 5.24 (dd, J = 17.2 Hz, J = 10.8 Hz, 2H), 4.52 (d, J = 5.2 Hz, 2H), 4.25 (m, 3H), 3.90 (m, 1H), 2.30 (t, J = 7.6 Hz, 2H), 1.58 (m, 4H), 1.28 (m, 6H).

[0515] Intermediate AA33

[0516] Compound AA33-1 (10 g, 29.12 mmol) was dissolved in THF (50 mL) and water (50 mL), and lithium hydroxide monohydrate (3.67 g, 87.36 mmol) was added thereto. The system was stirred at room temperature (25 °C) for 2 h. The pH of the system was adjusted to 3 with 1M HC1, and extracted with ethyl acetate three times (50 mL x 3), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound AA33-2, which was used directly in the next reaction without further purification.

[0517] Compound AA33-2 (8 g, 24.29 mmol) and 2-(trimethylsilyl)ethanol (3.45 g, 29.14 mmol) were dissolved in DMF (100 mL), and TEA (7.37 g, 72.86 mmol), HATU (13.93 g, 36.65 mmol) were added thereto. The system was stirred at room temperature (25 °C) for 2 h. Water (150 mL) was added to the system, and extracted with ethyl acetate three times (100 mL x 3), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound AA33-3.

[0518] Compound AA33-3 (2.00 g, 4.65 mmol) was dissolved in DCM (10 mL) and MeOH (10 mL), to which TFA (5 mL) was added. The system was stirred at room temperature (25 °C) for 2 h. The pH of the system was adjusted to 10 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane for three times (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was dissolved in dioxane (20 mL) and H2O (20 mL), to which sodium bicarbonate (1.17 g, 13.95 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (1.88 g, 5.58 mmol) were added. The system was stirred at room temperature (25 °C) for 16 h. Water (20 mL) was added to the system, extracted with ethyl acetate for three times (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-30%) to give compound AA33-5. MS m / z (ESI): 432.2 [M+Na] + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.4 Hz, 2H), 7.63 (dd, J = 7.3, 4.4 Hz, 2H), 7.44-7.31 (m, 4H), 4.46 (m, 1H), 4.33-4.25 (m, 2H), 4.16-4.11 (m, 2H), 3.15 (m, 1H), 2.50 (m, 1H), 2.41 (m, 1H), 0.96-0.91 (m, 2H), -0.00 (s, 9H).

[0519] Compound AA33-5 (1.8 g, 4.40 mmol) was dissolved in DCM (30 mL), to which 4-hydroxybutyric acid allyl ester (760.35 mg, 5.27 mmol) was added, and after the addition was completed, boron trifluoride etherate (389.86 mg, 1.32 mmol, 48% content) was added at 0 °C. The system was stirred at room temperature (25 °C) for 1 h. The pH of the system was adjusted to 9 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane for three times (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography to give compound AA33-6. MS m / z (ESI): 576.2 [M+Na] + .

[0520] Compound AA33-6 (800 mg, 1.44 mmol) was dissolved in DCM (4 mL), to which TFA (4 mL) was added. The system was stirred at room temperature (25 °C) for 2 h. Water (20 mL) was added to the system, which was extracted with dichloromethane for three times (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to give compound AA33. MS m / z (ESI): 454.0 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.78-7.72 (d, J = 14.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 5.88 (m, 1H), 5.28-5.16 (m, 2H), 4.51 (d, J = 5.5 Hz, 2H), 4.27-4.16 (m, 4H), 3.65-3.57 (m, 2H), 3.45-3.39 (m, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1.77-1.70 (m, 2H). LC-MS [M+H] + = 454.0.

[0521] Intermediate AA34

[0522] Fmoc-Pen(Trt)-OH (2 g, 3.26 mmol) was dissolved in DCM (40 mL), to which tert-butyl 2,2,2-trichloroacetimidate (2.14 g, 9.78 mmol) was added. The system was stirred at room temperature (25 °C) for 16 h. Water (30 mL) was added to the system, which was extracted with dichloromethane for three times (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to give compound AA34-1. MS m / z (ESI): 692.3 [M+Na] + .

[0523] Compound AA34-1 (2 g, 2.99 mmol) was dissolved in DCM (30 mL), to which Tis (4.73 g, 29.86 mmol) and TFA (1.70 g, 14.93 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h. Water (20 mL) was added to the system, which was extracted with dichloromethane for three times (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound AA34-2. MS m / z (ESI): 450.2 [M+Na] + .

[0524] Allyl 4-hydroxybutanoate (500 mg, 3.47 mmol) was dissolved in THF (10 mL), to which triphenylphosphine (1.09 g, 4.16 mmol) and NBS (740.74 mg, 4.16 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h. Water (20 mL) was added to the system, which was extracted with ethyl acetate for three times (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was washed with petroleum ether, filtered, and the filtrate was concentrated to obtain allyl 4-bromobutanoate, which was directly used in the next reaction without further purification. 1 H-NMR (400 MHz, CDC13) δ 6.01-5.85 (m, 1H), 5.38-5.20 (m, 2H), 4.64-4.55 (m, 2H), 3.53-3.42 (m, 2H), 2.62-2.49 (m, 2H), 2.25-2.14 (m, 2H).

[0525] Allyl 4-bromobutanoate (1 g, 4.83 mmol) was dissolved in DMF (30 mL), to which compound AA34-2 (2.27 g, 5.31 mmol) and DIPEA (1.25 g, 9.66 mmol) were added. The system was warmed to 50 °C and stirred for 6 h. Water (30 mL) was added to the system, which was extracted with ethyl acetate for three times (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound AA34-3, which was directly used in the next reaction without further purification. MS m / z (ESI): 332.2 [M+H] + .

[0526] Compound AA34-3 (2.2 g, 2.99 mmol) was dissolved in dioxane (20 mL) and water (20 mL), to which FmocOSu (1.21 g, 3.58 mmol) and NaHCO3(52.71 mg, 8.96 mmol) were added. The system was stirred at room temperature (25 °C) for 16 h. Water (20 mL) was added to the system, which was extracted with dichloromethane three times (20 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to obtain compound AA34-4. MS m / z (ESI): 576.3 [M+Na] + .

[0527] Compound AA34-4 (700 mg, 1.26 mmol) was dissolved in DCM (10 mL), to which TFA (2 mL) was added. The system was stirred at room temperature (25 °C) for 3 h. Water (10 mL) was added to the system, which was extracted with dichloromethane three times (15 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound AA34. MS m / z (ESI): 498.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.7 Hz, 2H), 7.74-7.70 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 5.84 (m, 1H), 5.25-5.12 (m, 2H), 4.47 (d, J = 6.6 Hz, 2H), 4.28-4.14 (m, 4H), 2.48-2.59 (m, 2H), 2.38 (t, J = 7.3 Hz, 2H), 1.73-1.66 (m, 2H), 1.32 (s, 3H), 1.25 (s, 3H).

[0528] Intermediate AA35

[0529] Compound AA35-1 (600 mg, 3.71 mmol) was dissolved in DCE (20 mL), to which Me3SnOH (2.01 g, 11.14 mmol) was added. The system was warmed to 60 °C and stirred for 2 h. The system was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound AA35-2. MS m / z (ESI): 148.0 [M+H] + .

[0530] Compound AA35-2 (300 mg, 2.03 mmol) was dissolved in DMF (15 mL), to which was added 3-bromopropene (295.23 mg, 2.44 mmol), K2CO3(562.13 mg, 4.07 mmol). The system was warmed to 50 °C and stirred for 3 h. Water (20 mL) was added to the system, which was extracted with ethyl acetate three times (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-30%) to obtain compound AA35-3. MS m / z (ESI): 188.1 [M+H] + .

[0531] Compound AA35-3 (200 mg, 1.07 mmol) was dissolved in EtOH (3 mL), to which was added thiourea (121.74 mg, 1.60 mmol). The system was warmed to 80 °C and stirred for 2 h. Water (15 mL) was added to the system, which was extracted with ethyl acetate three times (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound AA35-4, which was used directly in the next reaction without further purification. MS m / z (ESI): 186.0 [M+H] + .

[0532] Compound AA35-5 (5 g, 11.94 mmol, HC1 salt) was dissolved in ACN (24 mL), water (16 mL), and acetic acid (4 mL), to which was added dropwise a sodium nitrite aqueous solution (1.24 g, 17.90 mmol) at 0 °C. The system was stirred at room temperature (25 °C) for 2 h, and then the system was warmed to 70 °C and stirred for 2 h. Water (50 mL) was added to the system, which was extracted with ethyl acetate three times (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound AA35-6. MS m / z (ESI): 384.0 [M+H] + .

[0533] Compound AA35-6 (1 g, 2.61 mmol) was dissolved in DCM (20 mL), TEA (527.80 mg, 5.22 mmol) was added, and methylsulfonyl chloride (358.50 mg, 3.13 mmol) was added dropwise at 0 °C. The system was stirred at room temperature (25 °C) for 1 h. Water (30 mL) was added to the system, which was extracted with dichloromethane three times (20 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound AA35-7, which was used directly in the next step without further purification. MS m / z (ESI): 462.2 [M+H] + .

[0534] Compound AA35-7 (1 g, 2.17 mmol) was dissolved in DCE (20 mL), and Me3SnOH (1.18 g, 6.50 mmol) was added. The system was warmed to 70 °C and stirred for 4 h. Water (20 mL) was added to the system, which was extracted with dichloromethane three times (20 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound AA35-8. MS m / z (ESI): 448.1 [M+H] + .

[0535] Compound AA35-8 (700 mg, 1.56 mmol) and compound AA35-4 (318.67 mg, 1.72 mmol) were dissolved in DMF (10 mL), and DIPEA (404.33 mg, 3.13 mmol) was added. The system was warmed to 50 °C and stirred for 16 h. Water (30 mL) was added to the system, which was extracted with ethyl acetate three times (20 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-10%) to obtain compound AA35. MS m / z (ESI): 537.2 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.71 (d, J = 6.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 6.02-5.92 (m, 1H), 5.40-5.24 (m, 2H), 4.77-4.73 (m, 2H), 4.31-4.19 (m, 3H), 3.91 (m, 1H), 3.26-3.21 (m, 2H), 1.78-1.57 (m, 4H), 1.50-1.43 (m, 2H).

[0536] Intermediate AA36

[0537] Compound AA36-1 (1 g, 4.34 mmol) was dissolved in DCM (20 mL), DIPEA (1.40 g, 10.86 mmol, 1.8 mL) and FmocCl (1.24 g, 4.78 mmol) were added at 15 °C. The mixture was stirred at 15 °C for 1 h under N2. The mixture was concentrated to give a crude product, which was purified by column chromatography (tetrahydrofuran / petroleum ether (v / v) = 5-18%) to give compound AA36-2. MS m / z (ESI): 475.3 [M+Na] + .

[0538] Compound AA36-2 (1.6 g, 3.54 mmol) was dissolved in DCE (25 mL), Me3SnOH (1.92 g, 10.61 mmol) was added. The mixture was stirred at 65 °C for 16 h under N2. The mixture was concentrated to give a crude product, which was diluted with saturated ammonium chloride (15 mL), the aqueous phase was extracted with ethyl acetate for three times (15 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (methanol / dichloromethane (v / v) = 2-12%) to give compound AA36-3. MS m / z (ESI): 460.8 [M+Na] + .

[0539] Compound AA36-3 (600 mg, 1.37 mmol) was dissolved in HFIP (8 mL), TFA (935.98 mg, 8.21 mmol) was added. The mixture was stirred at 12 °C for 12 h under N2. DIEA (882.61 mg, 6.84 mmol, 1.1 mL) was added to the mixture, and compound AA36-4 was obtained by concentration. It was used in the next step without further purification. MS m / z (ESI): 339.0 [M+H]+ .

[0540] Dissolve oxalyl chloride (880.40 mg, 6.94 mmol) in THF (6 mL), slowly add DMSO (812.94 mg, 10.40 mmol) in THF (0.5 mL) dropwise at -65 °C, stir the mixture at -65 °C for 0.5 h; slowly add compound AA36-5 (500 mg, 3.47 mmol) in THF (0.5 mL) dropwise at -65 °C, stir the mixture at -65 °C for 0.5 h; add TEA (2.11 g, 20.81 mmol, 2.90 mL) to the mixture, after 10 min, warm the mixture to 10 °C in 30 min. Add water (10 mL) to the mixture, extract with ethyl acetate for three times (12 mL x 3). Combine the organic phase, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to give compound AA36-6, which is used in the next step without further purification.

[0541] Dissolve compound AA36-4 (0.5 g, 1.48 mmol) and compound AA36-6 (336.10 mg, 2.36 mmol) in methanol (15 mL), add sodium cyanoborohydride (278.59 mg, 4.43 mmol) to the mixture. Stir the mixture at 12 °C for 12 h. Add saturated ammonium chloride (15 mL) to the mixture, extract with ethyl acetate for three times (12 mL x 3). Combine the organic phase, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to give a crude product, which is purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 1-3%) and then by C18 reverse phase medium pressure column chromatography to give compound AA36. MS m / z (ESI): 465.3 [M+H] + .

[0542] Intermediate AA38

[0543] Dissolve Fmoc-Asp(O t Bu)-OH (3.5 g, 8.51 mmol) in THF (30 mL), add DIPEA (2.20 g, 17.01 mmol) and TSTU (2.56 g, 8.51 mmol) to the mixture. Stir the mixture at room temperature (25 °C) for 16 h. Add water (30 mL) to the mixture, extract with ethyl acetate for three times (30 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to give compound AA38-1, which is used in the next step without further purification. MS m / z (ESI): 530.8 [M+Na] + .

[0544] Fmoc-3-Pal-OH (4 g, 10.30 mmol) was dissolved in DMF (50 mL), to which was added compound AA38-2 (2.24 g, 12.36 mmol, HC1 salt), HATU (5.90 g, 15.45 mmol) and DIPEA (3.99 g, 30.89 mmol). The system was stirred at room temperature (25 °C) for 2 h. Water (50 mL) was added to the system, which was extracted with ethyl acetate three times (50 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 0-60%) to obtain compound AA38-3. MS m / z (ESI): 515.9 [M+H] + .

[0545] Compound AA38-3 (5 g, 9.70 mmol) was dissolved in DCM (15 mL), to which was added TFA (15 mL). The system was stirred at room temperature (25 °C) for 16 h. The system was concentrated to obtain a crude product, which was purified by C18 reverse phase medium pressure column chromatography (acetonitrile / water = 0-50%) to obtain compound AA38-4. MS m / z (ESI): 459.9 [M+H] + .

[0546] Compound AA38-4 (4 g, 8.71 mmol) was dissolved in DEA (20 mL) and ACN (20 mL). The system was stirred at room temperature (25 °C) for 1 h. The system was concentrated to obtain compound AA38-5, which was directly used in the next reaction without further purification. MS m / z (ESI): 238.2 [M+H] + .

[0547] Compound AA38-5 (2 g, 8.43 mmol) was dissolved in THF (30 mL), to which was added compound A38-1 (4.29 g, 8.43 mmol) and DIPEA (2.18 g, 16.86 mmol). The system was stirred at room temperature (25 °C) for 2 h. Water (30 mL) was added to the system, which was extracted with ethyl acetate three times (30 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium pressure column chromatography (methanol / dichloromethane (v / v) = 0-20%) to obtain compound AA38-6. MS m / z (ESI): 630.9 [M+H] + .

[0548] Compound AA38-6 (4 g, 6.34 mmol) was dissolved in DMF (50 mL), to which allyl bromide (843.99 mg, 6.98 mmol) and K2CO3 (1.75 g, 12.68 mmol) were added. The system was stirred at room temperature (25 °C) for 16 h. Water (50 mL) was added to the system, which was extracted with ethyl acetate three times (30 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 0-50%) to obtain compound AA38-7. MS m / z (ESI): 671.5 [M+H] + .

[0549] Compound AA38-7 (2.8 g, 4.17 mmol) was dissolved in DCM (10 mL) and TFA (10 mL). The system was stirred at room temperature (25 °C) for 16 h. The system was concentrated to obtain a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water = 0-50%) to obtain compound AA38. MS m / z (ESI): 615.3 [M+H] + .

[0550] Intermediate AA39

[0551] Compound AA1-1 (2 g, 8.85 mmol) was dissolved in DMF (30 mL), to which NaH (386.01 mg, 10.62 mmol, 66% purity) was added, and the system was stirred at room temperature (25 °C) for 30 min. Compound AA39-1 (2.84 g, 10.62 mmol) was then added to the system, which was stirred at room temperature (25 °C) for 16 h. The system was quenched with water (50 mL) and extracted with ethyl acetate three times (30 mL x 3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 0-30%) to obtain compound AA39-2. MS m / z (ESI): 411.9 [M+H] + .

[0552] Zn (2.85 g, 43.64 mmol) was dissolved in DMF (30 mL), one particle of iodine was added, the system was stirred at room temperature (25 °C) for 5 min, and a solution of compound AA1-3 (6.56 g, 14.55 mmol) in DMF (40 mL) was added dropwise. The system was stirred at room temperature (25 °C) for 2 h. Compound AA39-2 (3 g, 7.27 mmol) was dissolved in DMF (30 mL), Pd2dba3 (333.04 mg, 363.69 μmol) and Q-phos (516.96 mg, 727.39 μmol) were added. Under nitrogen protection, the system was stirred at room temperature for 30 min, and then the above system was added. The system was warmed to 80 °C and stirred for 16 h. The system was filtered through diatomite, the filtrate was added with water (150 mL), and extracted with ethyl acetate three times (100 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (tetrahydrofuran / petroleum ether (v / v) = 0-50%) to give compound AA39-3. 1 H-NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 8.2 Hz, 2H), 7.39 (m, 2H), 7.30-7.19 (m, 3H), 7.14 (s, 1H), 4.33-4.12 (m, 4H), 3.62-3.56 (m, 5H), 3.46-3.41 (m, 4H), 3.16-2.80 (m, 4H), 1.57-1.40 (m, 4H), 0.83 (s, 9H), 0.00 (s, 6H).

[0553] Compound AA39-3 (1.7 g, 2.59 mmol) was dissolved in DCE (20 mL), and trimethyltin hydroxide (1.40 g, 7.76 mmol) was added. The system was warmed to 65 °C and stirred for 16 h under N2. The system was concentrated to give a crude product, which was purified by column chromatography (tetrahydrofuran / petroleum ether (v / v) = 0-50%) to give compound AA39. MS m / z (ESI): 643.4 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H) 7.86 (d, J = 7.4 Hz, 2H), 7.76 (dd, J = 11.2, 8.2 Hz, 2H), 7.60 (dd, J = 10.2, 7.8 Hz, 2H), 7.38 (dd, J = 12.4, 7.2 Hz, 2H), 7.30-7.16 (m, 4H), 4.22-4.11 (m, 4H), 3.60 (m, 2H), 3.43 (m, 4H), 3.12-2.82 (m, 4H), 1.57-1.38 (m, 4H), 0.83 (s, 9H), 0.00 (s, 6H).

[0554] Intermediate AA52

[0555] Intermediate AA52 was synthesized according to the procedures described for Intermediate AA39, starting from the corresponding starting materials.

[0556] AA52: MS m / z (ESI): 629.3 [M+H] + ;

[0557] Intermediate AA40

[0558] Compound AA40-1 (6.82 g, 16.34 mmol) was dissolved in THF (50 mL), to which was added compound AA40-2 (3 g, 13.61 mmol), TMAD (4.68 g, 27.23 mmol) and triphenylphosphine (7.14 g, 27.23 mmol). The system was stirred at room temperature (25 °C) for 2 h under N2. The reaction solution was poured into ice water and stirred well, extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (methanol / dichloromethane (v / v) = 20%) to give compound AA40-3. MS m / z (ESI): 620.3 [M+H] + .

[0559] Compound AA40-3 (3 g, 6.03 mmol) was dissolved in dichloroethane (50 mL), to which was added trimethyltin hydroxide (1.09 g, 6.03 mmol). The system was stirred at 60 °C for 16 h under N2. The reaction solution was poured into ice water and stirred well, extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (methanol / dichloromethane (v / v) = 10%) to give compound AA40. MS m / z (ESI): 606.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 6.8 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.31 - 7.20 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.22 - 4.08 (m, 3H), 4.06 - 3.93 (m, 3H), 3.70 - 3.62 (m, 4H), 3.46 (t, J = 5.6 Hz, 2H), 2.98 (dd, J = 14.0 Hz, 4.4 Hz, 1H), 2.77 (dd, J = 13.6 Hz, 9.6 Hz, 1H), 0.82 (s, 9H), 0.00 (s, 6H).

[0560] Intermediate AA41

[0561] Intermediate AA41 was synthesized according to the procedures described for Intermediate AA40, starting from the corresponding starting materials.

[0562] AA41: MS m / z (ESI): 604.5 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.2 Hz, 2H), 7.71 - 7.61 (m, 3H), 7.41 - 7.35 (m, 2H), 7.33 - 7.25 (m, 2H), 7.13 (d, J = 7.6 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 4.21 - 4.01 (m, 4H), 3.82 (t, J = 11.2 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.01 - 2.95 (m, 1H), 2.85 - 2.71 (m, 1H), 1.71 - 1.62 (m, 2H), 1.52 - 1.35 (m, 4H), 0.85 (s, 9H), 0.08 (s, 6H).

[0563] Intermediate AA42

[0564] Compound AA42-1 (4.5 g, 9.33 mmol) was dissolved in MeOH (25 mL) and toluene (25 mL), and diazomethane (2 M, 14 mL) was added dropwise at 0 °C. The system was warmed to room temperature (25 °C) and stirred for 16 h. The system was concentrated to give compound AA42-2, which was used directly in the next step without further purification. MS m / z (ESI): 519.0 [M+Na] + .

[0565] Compound AA42-2 (4.5 g, 9.06 mmol) was dissolved in 4M HCl in dioxane (30 mL). The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give compound AA42-3, which was used in the next step without further purification. MS m / z (ESI): 397.3 [M+Na] + .

[0566] Compound AA42-3 (4 g, 10.09 mmol) was dissolved in ACN (18 mL), water (12 mL), AcOH (3 mL), and a solution of sodium nitrite (1.04 g, 15.13 mmol) in water was added at 0 °C. The system was stirred at room temperature (25 °C) for 16 h. Water (50 mL) was added to the system, and it was extracted with ethyl acetate three times (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 0-30%) to give compound AA42-4. MS m / z (ESI): 398.2 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H), 7.65 (s, 1H), 7.36 (dt, J = 33.2, 7.4 Hz, 4H), 4.40-4.35 (m, 1H), 4.29-4.17 (m, 3H), 3.56-3.48 (m, 3H), 3.36 (m, 2H), 1.80-1.61 (m, 2H), 1.37-1.30 (m, 5H), 1.19 (m, 2H).

[0567] Compound AA42-4 (1.2 g, 3.02 mmol) was dissolved in DMF (20 mL), and TBSCl (546.06 mg, 3.62 mmol) and imidazole (616.60 mg, 9.06 mmol) were added thereto. The system was stirred at room temperature (25 °C) for 16 h. Water (50 mL) was added to the system, and it was extracted with ethyl acetate three times (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound AA42-5, which was used in the next step without further purification. MS m / z (ESI): 512.4 [M+H] + .

[0568] Compound AA42-5 (800 mg, 1.56 mmol) was dissolved in THF (5 mL) and water (5 mL), to which was added lithium hydroxide monohydrate (196.81 mg, 4.69 mmol). The system was warmed to 50 °C and stirred for 2 h. The pH of the system was adjusted to 7 with 1 N dilute hydrochloric acid, to which was added dioxane (10 mL), water (10 mL), 9-fluorenylmethyl-N-succinimidyl carbonate (631.90 mg, 1.87 mmol) and NaHC03(393.41 mg, 4.68 mmol). The system was stirred at room temperature (25 °C) for 16 h. Water (20 mL) was added to the system, which was extracted with ethyl acetate three times (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography to give compound AA42. MS m / z (ESI): 498.3 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.70 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 4.24-4.17 (m, 3H), 3.54 (t, J = 6.0 Hz, 2H), 1.86-1.74 (m, 2H), 1.47-1.36 (m, 2H), 1.31-1.22 (m, 5H), 0.83 (s, 9H), -0.00 (s, 6H).

[0569] Intermediate AA37

[0570] Intermediate AA37 was synthesized according to the procedures of Intermediate AA42 starting from the corresponding starting material.

[0571] AA37: MS m / z (ESI): 484.2 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.62 (s, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 4.29-4.18 (m, 3H), 3.91 (s, 1H), 3.55 (t, J = 6.0 Hz, 2H), 1.75-1.53 (m, 2H), 1.47-1.32 (m, 4H), 0.83 (s, 9H), 0.00 (s, 6H).

[0572] Intermediate AA44

[0573] Compound AA44-1 (5 g, 25.3 mmol) was dissolved in DMF (50 mL), and sodium hydride (1.2 g, 30.2 mmol) was added at 0 °C; the system was stirred at 0 °C for 0.5 h. SEMCl (4.13 g, 27.7 mmol) was added at 0 °C. The system was stirred at room temperature (25 °C) for 1 h. Water (1500 mL) was added to the system, which was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 30%) to obtain compound AA44-2. MS m / z (ESI): 328.3 [M+H] + .

[0574] Activated zinc powder (0.7 g, 10.6 mmol) was added to DMF (5 mL), and iodine (0.077 g, 0.3 mmol) was added under nitrogen; the system was stirred at room temperature (25 °C) for 0.5 h. The system was added to a DMF (10 mL) solution of AA1-3 (2.06 g, 4.6 mmol); the system was stirred at room temperature (25 °C) for 0.5 h, and the supernatant A was taken. AA44-2 (1 g, 3 mmol), tris(dibenzylideneacetone)dipalladium (0.28 g, 0.3 mmol), and tricyclohexylphosphine (0.17 g, 0.6 mmol) were added to DMF (10 mL) under nitrogen, and the supernatant A was added thereto; the system was warmed to 80 °C and stirred for 4 h. Water (200 mL) was added to the system, which was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 25%) to obtain compound AA44-3. MS m / z (ESI): 573.5 [M+H] + .

[0575] Compound AA44-3 (1.5 g, 2.6 mmol) was dissolved in THF (12 mL) and H2O (3 mL), and lithium hydroxide (0.15 g, 5.2 mmol) was added thereto at 0 °C. The system was stirred for 1 h under an ice bath. Water (20 mL) was added to the system, which was adjusted to neutral with 1 mol / L aqueous hydrochloric acid solution, and extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 7%) to obtain compound AA44. MS m / z (ESI): 559.5 [M+H] + .

[0576] Starting from the corresponding starting materials, intermediates AA46, AA47, AA48, AA49, AA50 and AA51 were synthesized according to the procedure described for intermediate AA44.

[0577] AA46: MS m / z (ESI): 543.4 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.77-7.69 (m, 2H), 7.52 (t, J = 5.6 Hz, 2H), 7.28-7.15 (m, 4H), 5.63-5.47 (m, 2H), 4.13-3.97 (m, 3H), 3.79-3.69 (m, 1H), 3.04 (s, 1H), 2.93-2.88 (m, 1H), 1.23 (s, 9H).

[0578] AA47: MS m / z (ESI): 558.6 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.38-8.31 (m, 2H), 7.93 (q, J = 7.6 Hz, 3H), 7.64 (d, J = 7.2 Hz, 2H), 7.49-7.27 (m, 4H), 7.10 (d, J = 2.8 Hz, 1H), 5.84 (s, 2H), 4.52-4.46 (m, 1H), 4.27-4.11 (m, 3H), 3.60-3.49 (m, 4H), 0.89-0.80 (m, 2H), -0.07 (s, 9H).

[0579] AA48: MS m / z (ESI): 443.2 [M+H] + .

[0580] AA49: MS m / z (ESI): 446.2 [M+H] + .

[0581] AA50: MS m / z (ESI): 486.2 [M+H] + .

[0582] AA51: MS m / z (ESI): 674.2 [M+H] + .

[0583] Intermediate AA45

[0584] Compound AA45-1 (10 g, 52.85 mmol) was dissolved in DMF (100 mL), potassium carbonate (14.61 g, 105.70 mmol) and allyl bromide (8.31 g, 68.71 mmol) were added thereto; the system was stirred at room temperature (25 °C) for 2 h. Water (200 mL) was added to the system, which was extracted with ethyl acetate (200 mL x 3). After the organic phase was washed with saturated brine (300 mL x 2), it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 5%) to give compound AA45-2. MS m / z (ESI): 252.2 [M+Na] + .

[0585] Compound AA45-2 (11 g, 47.98 mmol) was dissolved in a hydrochloric acid dioxane solution (120 mL); the system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give compound AA45-3, which was directly used in the next step without further purification. MS m / z (ESI): 130.3 [M+1] + .

[0586] Compound AA44 (20 g, 35.80 mmol) was dissolved in DMF (100 mL), potassium carbonate (9.9 g, 71.60 mmol) and allyl bromide (5.64 g, 46.54 mmol) were added thereto; the system was stirred at room temperature (25 °C) for 2 h. Water (300 mL) was added to the system, which was extracted with ethyl acetate (300 mL x 3). After the organic phase was washed with saturated brine (300 mL x 2), it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 30%) to give compound AA45-4. MS m / z (ESI): 599.6 [M+H] + .

[0587] Compound AA45-4 (13 g, 21.71 mmol) and DEA (6.67 g, 1.19 mol, 75 mL) were dissolved in ACN (75 mL); the system was stirred at room temperature (25 °C) for 1 h. The system was concentrated to give a crude product, which was purified by medium pressure column chromatography (petroleum ether / tetrahydrofuran (v / v) = 33%) to give compound AA45-5.

[0588] Compound AA45-5 (7.75 g, 20.58 mmol) and Fmoc-Asp(OtBu)-OH (8.47 g, 20.58 mmol) were dissolved in DMF (100 mL), and HATU (11.73 g, 30.87 mmol) and DIPEA (7.98 g, 61.75 mmol) were added thereto; the system was stirred at room temperature (25 °C) for 1 h. Water (300 mL) was added to the system, and extraction was performed with ethyl acetate (300 mL x 3). The organic phase was combined, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 35%) to obtain compound AA45-6. MS m / z (ESI): 770.6 [M+H] + .

[0589] Compound AA45-6 (14 g, 18.18 mmol) and tetrakis(triphenylphosphine)palladium (1.68 g, 1.45 mmol) were dissolved in dichloromethane (150 mL), and phenylsilane (15.74 g, 145.46 mmol) was added thereto under nitrogen; the system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 65%) to obtain compound AA45-7. MS m / z (ESI): 730.4 [M+H] + .

[0590] Compound AA45-7 (14.00 g, 14.39 mmol) and compound AA45-3 (2.85 g, 17.28 mmol) were dissolved in DMF (100 mL), and HATU (8.20 g, 21.58 mmol) and DIPEA (5.57 g, 43.2 mmol) were added thereto; the system was stirred at room temperature (25 °C) for 1 h. Water (300 mL) was added to the system, and extraction was performed with ethyl acetate (300 mL x 3). The organic phase was combined, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by medium-pressure column chromatography (tetrahydrofuran / petroleum ether (v / v) = 30%) to obtain compound AA45-8. MS m / z (ESI): 841.6 [M+H] + .

[0591] Compound AA45-8 (10.00 g, 10.30 mmol) was dissolved in dichloromethane (150 mL), to which zinc bromide (18.54 g, 82.40 mmol) was added; the system was stirred at room temperature (25 °C) for 1 h. The system was quenched by adding sodium bicarbonate aqueous solution (500 mL), the system was filtered and the aqueous phase was extracted with dichloromethane (300 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (water: acetonitrile = 3:2) to give intermediate AA45. MS m / z (ESI): 785.7 [M+H] + .

[0592] Intermediate L2

[0593] Compound L2-1 (5 g, 20.6 mmol) was dissolved in THF (50 mL), to which NBS (13.3 g, 40.11 mmol) and TPP (10.52 g, 40.11 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h under nitrogen. The system was poured into ice water and stirred uniformly, and then extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by medium-pressure column chromatography (ethyl acetate / petroleum ether (v / v) = 20%) to give compound L2-2. MS m / z (ESI): 352.7 [M+H+ACN] + .

[0594] Compound L2-2 (4 g, 12.81 mmol) was dissolved in acetonitrile (50 mL), to which trimethylamine (20 mL) was added. The system was stirred at 50 °C for 16 h under nitrogen. The system was concentrated to give compound L2-3, which was used directly in the next reaction without further purification. MS m / z (ESI): 291.0 [M] + .

[0595] Compound L2-3 (4.0 g) was dissolved in DCM (50 ml), to which TFA (20 mL) was added. The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (water = 100%) to give intermediate L2. MS m / z (ESI): 191.1 [M] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (br s, 2H), 3.85-3.80 (m, 2H), 3.60-3.57 (m, 6H), 3.54-3.50 (m, 2H), 3.10 (s, 9H), 2.94 (s, 2H).

[0596] Intermediate L8

[0597] Intermediate L8 was synthesized according to the procedures described for Intermediate L2 starting from the corresponding starting materials.

[0598] L8: MS m / z (ESI): 147.2 [M] + .

[0599] Intermediate L3

[0600] Compound L3-1 (2.5 g, 13.14 mmol) was dissolved in THF (50 mL), to which carbon tetrabromide (8.72 g, 26.28 mmol) and triphenyl phosphine (6.89 g, 26.28 mmol) were added. The system was stirred at room temperature (25 °C) for 2 h under N2. The system was poured into ice water and stirred well, then extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound L3-2, which was used in the next step without further purification. MS m / z (ESI): 253.2 [M+H] + .

[0601] Compound L3-2 (3 g, 11.85 mmol) was dissolved in acetonitrile (50 mL), to which trimethylamine was added. The system was stirred at 50 °C for 16 h under N2. The system was concentrated to give compound L3-3, which was used in the next step without further purification. MS m / z (ESI): 232.2 [M] + .

[0602] Compound L3-3 (2.5 g, crude) was dissolved in 4M HCl dioxane (50 mL). The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give a crude product, which was purified by C18 reverse phase medium pressure column chromatography (acetonitrile / water = 100%) to give intermediate L3. MS m / z (ESI): 176.1 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ 3.81 (m, 2H), 3.65 (t, J = 2.8 Hz, 2H), 3.51 (t, J = 4.8 Hz, 2H), 3.12 (s, 9H), 2.51 (m, 2H).

[0603] Intermediate L1, L4

[0604] Intermediate L1, L4 was synthesized according to the procedures described for Intermediate L3 starting from the corresponding starting materials.

[0605] L1: MS m / z (ESI): 236.2 [M] + ;

[0606] L4:1 H-NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 3.28 (m, 2H), 3.05 (s, 9H), 2.20 (t, J = 7.4 Hz, 2H), 1.70-1.64 (m, 2H), 1.53-1.46 (m, 2H), 1.29 (s, 8H).

[0607] Intermediate L5

[0608] Compound L5-1 (7 g, 34.95 mmol) was dissolved in DMF (100 mL), to which K2CO3 (14.49 g, 104.85 mmol) and Mel (9.92 g, 69.90 mmol) were added. The system was warmed to 50 °C and stirred for 12 h. The system was filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water = 5%) to give compound L5-2. MS m / z (ESI): 215.2 [M] + .

[0609] Compound L5-2 (4 g, 18.58 mmol) was dissolved in 6 M hydrochloric acid (80 mL). The system was stirred at room temperature (25 °C) for 12 h. The system was concentrated to give compound L5-3, which was used directly in the next reaction without further purification. MS m / z (ESI): 115.2 [M] + .

[0610] Compound L5-3 (2.8 g, 18.58 mmol) was dissolved in DMF (20 mL), to which compound L5-4 (3 g, 18.58 mmol), KI (867 mg, 5.22 mmol), and K2CO3 (6.02 g, 43.56 mmol) were added in sequence. The system was warmed to 80 °C and stirred for 2 h. The system was filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography (acetonitrile / water = 10%) to give compound L5-5. MS m / z (ESI): 287.2 [M] + .

[0611] Compound L5-5 (300 mg, 1.04 mmol) was dissolved in 6 M hydrochloric acid (6 mL). The system was stirred at room temperature (25 °C) for 12 h. The system was concentrated to give compound L5, which was used directly in the next reaction without further purification. MS m / z (ESI): 231.2 [M] + . 1 H NMR (400 MHz, D2O) δ 3.77-3.64 (m, 12H), 3.43 (t, J = 5.2 Hz, 2H), 3.23 (s, 6H), 2.54 (t, J = 5.6 Hz, 2H).

[0612] Intermediate L6

[0613] Compound L6-1 (9 g, 47.31 mmol) was dissolved in DCM (100 mL), to which TEA (9.57 g, 94.62 mmol), DMAP (577.98 mg, 4.73 mmol) and TsCl (10.82 g, 56.77 mmol) were added. The system was stirred at room temperature (25 °C) for 12 h. Water was added to the system, which was extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 33%) to give compound L5-4.

[0614] Compound L5-4 (6 g, 17.42 mmol) was dissolved in DMF (60 mL), to which morpholine (1.97 g, 22.64 mmol), potassium iodide (867 mg, 5.22 mmol) and K2CO3 (6.02 g, 43.56 mmol) were added. The system was warmed to 80 °C and stirred for 2 h. Water was added to the system, which was extracted with ethyl acetate for three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 100%) to give compound L6-2. MS m / z (ESI): 260.0 [M+H] + .

[0615] Compound L6-2 (2.81 g, 10.84 mmol) was dissolved in DMF (20 mL), to which K2CO3 (4.49 g, 32.51 mmol) and iodomethane (3.08 g, 21.67 mmol) were added in sequence. The system was warmed to 50 °C and stirred for 12 h. The system was filtered, and the filtrate was concentrated to give a crude product, which was purified by C18 reverse phase column chromatography (acetonitrile / water = 18%) to give compound L6-3. MS m / z (ESI): 274.2 [M] + .

[0616] Compound L6-3 (360 mg, 1.31 mmol) was dissolved in 6M hydrochloric acid (6 mL). The system was stirred at room temperature (25 °C) for 12 h. The system was concentrated to give compound L6, which was used directly in the next step without further purification. MS m / z (ESI): 218.1 [M] + . 1 HNMR (400 MHz, D2O) δ 3.91-3.86 (m, 6H), 3.66-3.59 (m, 4H), 3.50-3.34 (m, 4H), 3.12 (s, 3H), 2.51 (t, J = 5.8 Hz, 2H).

[0617] Intermediate L7

[0618] Compound L1 (1.5 g, 6.81 mmol) was dissolved in dichloromethane (50 mL), to which was added dichlorosulfoxide (8.10 g, 68.09 mmol). The system was warmed to 40 °C and stirred for 1 h. The system was concentrated to give a crude product, which was dissolved in dichloromethane and added dropwise to a dichloromethane solution of compound L7-1 (1.08 g, 6.81 mmol). The system was stirred at room temperature (25 °C) for 2 h. The system was concentrated to give a crude product, which was purified by C18 reverse-phase medium-pressure column chromatography to give intermediate L7-2.

[0619] Compound L7-2 (1.20 g, 5.69 mmol) was dissolved in dichloromethane (50 mL), to which was added TFA (20 ml). The system was stirred at room temperature (25 °C) for 2 h under N2. The system was concentrated to give a crude product, which was purified by medium-pressure column chromatography (methanol / dichloromethane (v / v) = 10%) to give compound L7. MS m / z (ESI): 276.1 [M] + .

[0620] Example 2: Polypeptide synthesis

[0621] In the following polypeptide synthesis, Rink amide-MBHAresin was used as the solid support. 2-CTCResin was used as the solid support.

[0622] Synthetic route one:

[0623] Synthesis of polypeptide 1:

[0624] Chemical solid-phase synthesis:

[0625] Synthetic table:

[0626] 1.2 Solid-phase synthesis operation steps:

[0627] 1.2.1 Weigh 1.12 g of Rink amide-MBHAresin (substitution degree 0.268 mmol / g) into the reactor, swell the resin with 10 V of dichloromethane for 30 min, and then wash the resin with 10 V of DMF twice after suction filtration.

[0628] 1.2.2 Add 10V 20% Pip / DMF to the reactor, N2blow for 10 min. After the system is filtered, add 10V 20% Pip / DMF to the reactor, N2blow for 10 min.

[0629] 1.2.3 After the reaction is completed, wash the resin with 10V DMF for 6 times, ninhydrin / tetrachloroquinone detection: positive.

[0630] 1.2.4 Weigh 2.0 eq Fmoc-Sar-OH, 4.0 eq DIEA, 10V DMF into the reactor, then add 1.8 eq HATU, N2blow for 1 h.

[0631] 1.2.5 After the reaction is completed, ninhydrin / tetrachloroquinone detection: negative; after the system is filtered, wash the resin with 10V DMF for 5 times.

[0632] 1.2.6 Repeat the operation of 1.2.2-1.2.5 to sequentially condense amino acids 2-14 according to the synthesis table.

[0633] 1.2.7 Wash the resin with MeOH for 2 times, wash the resin with MTBE for 2 times, and dry the resin into fine sand.

[0634] 1.3 Cleavage cleavage:

[0635] Weigh the peptide resin into a centrifuge tube, add 10V cleavage solution (85% TFA / 2.5% Tis / 5% H2O / 5% EDT / 2.5% anisyl sulfide + NH4I (150 mg / ml)), cleave at room temperature (25°C) for 2.5 h, and filter. At 0°C, add the filtrate to 10V MTBE, and the solid is precipitated, centrifuged, and washed with MTBE twice. Dry the centrifuged solid with N2, and obtain crude peptide 1-2, which is directly used in the next step without further purification.

[0636] 1.4 Disulfide bond cyclization:

[0637] Weigh the crude peptide 1-2 into a reaction bottle, dissolve in 10%-20% ACN / water solution to prepare a solution with a concentration of 0.5 mg / mL-1 mg / mL, and add 0.2 mmol / mL I2 / MeOH solution dropwise until the reaction solution is light yellow. React at room temperature (25°C) for 10-15 min. Add saturated vitamin C sodium aqueous solution dropwise until the reaction solution is light yellow, and purify the system by high-performance preparative liquid chromatography and salt conversion to obtain polypeptide 1.

[0638] Salt conversion conditions:

[0639] High performance prep. The sample after liquid phase purification was diluted and pumped into the column. The mobile phase was 95% C equilibrated for 3 column volumes, then 95% A equilibrated for 3 column volumes, then the gradient above was used for prep. The fractions were lyophilized to give the product.

[0640] MS m / z (ESI): 961.6 [(M+2H) / 2] + ; 641.5 [(M+3H) / 3] + .

[0641] The following polypeptides were synthesized according to the above procedure starting from the corresponding starting materials:

[0642] Synthetic route two:

[0643] Synthesis of polypeptide 48:

[0644] Chemical solid phase synthesis:

[0645] 1.1 Synthesis table:

[0646] 1.2 Solid phase synthesis procedure:

[0647] 1.2.1 Weigh 2-CTC Resin (1.5 g, substitution degree 1.13 mmol / g) into the reactor, swell the resin with 10 V dichloromethane for 30 min, then filter the system, and wash the resin with 10 V DMF for 3 times.

[0648] 1.2.2 Add 1.0 eq Fmoc-Sar-OH, 2.0 eq DIEA, 10 V DCM into the reactor, and blow nitrogen for 3 h. Filter the system, and wash the resin with 10 V DMF for 3 times. Add 10 V 10% methanol / DIEA / dichloromethane (1:2:4) into the reactor, and blow nitrogen for 30 min; filter the system, and wash the resin with 10 V DMF for 6 times.

[0649] 1.2.3 Add 10V 20% Pip / DMF to the reactor, N2 blow for 10 min. After the system is filtered, add 10V 20% Pip / DMF to the reactor, N2 blow for 10 min.

[0650] 1.2.4 After the reaction is completed, wash the resin with 10V DMF for 6 times, ninhydrin / tetrachloroquinone detection: positive.

[0651] 1.2.5 Weigh 2.0 eq Fmoc-3-Pal-OH, 4.0 eq DIEA, 10V DMF into the reactor, then add 1.8 eq HATU, N2 blow for 1 h.

[0652] 1.2.6 After the reaction is completed, ninhydrin / tetrachloroquinone detection: negative; after the system is filtered, wash the resin with 10V DMF for 5 times.

[0653] 1.2.7 Repeat the operation of 1.2.3-1.2.6 to sequentially condense amino acids 3-14 according to the synthesis table.

[0654] 1.2.8 Wash the resin with MeOH for 2 times, wash the resin with MTBE for 2 times, and dry the resin into fine sand.

[0655] 1.3 Soft cleavage:

[0656] Weigh the peptide resin into a centrifuge tube, add 10V cleavage solution (30% HFIP / DCM), and cleave at room temperature (25°C) for 3-4 h, filter, and adjust the pH of the filtrate to 7-8 with DIEA, then concentrate; at 0°C, add 10V MTBE to the system, and solid precipitates, centrifuge, wash the solid with MTBE twice, dry the centrifuged solid with N2, and obtain the crude peptide 48-3, which is directly used in the next step without further purification.

[0657] 1.4 Condensation of piperidine:

[0658] Weigh the crude peptide 48-3 into the reactor, then add 5.0 eq HOAT (dissolved in a small amount of DMF and added to the reactor), add 4.8 eq DIC and DCM to the system, activate at room temperature for 5 min, then add 5.0 eq piperidine, and react the system at room temperature (25°C) for 16 h. Concentrate the system to obtain the crude peptide 48-4, which is directly used in the next step without further purification.

[0659] 1.5 Removal of all protecting groups:

[0660] The crude peptide 48-4 was dissolved in 10 V cleavage solution (85% TFA / 2.5% Tis / 5% H2O / 5% EDT / 2.5% thioanisole + NH4I (150 mg / ml)) and the system was reacted at room temperature (25 °C) for 2.5 h. 10 V MTBE was added to the system at 0 °C and the solid was precipitated. The solid was washed twice with MTBE and the centrifuged solid was dried with N2 to obtain the crude peptide 48-5 which was directly used in the next step without further purification.

[0661] 1.6 disulfide bond cyclization:

[0662] The crude peptide 48-5 was weighed into a reaction bottle and dissolved in 10% to 20% acetonitrile / water solution to prepare a solution with a concentration of 0.5 mg / mL to 1 mg / mL. 0.2 mmol / mL I2 / MeOH solution was added dropwise to the reaction solution until it was light yellow. The system was reacted at room temperature (25 °C) for 10 to 15 min. Saturated vitamin C sodium aqueous solution was added dropwise to the system until the light yellow color of the reaction solution disappeared. The system was purified by high-performance preparative liquid chromatography and salt conversion to obtain the polypeptide 48.

[0663] Salt conversion conditions:

[0664] After dilution, the sample was pumped into the chromatographic column after high-performance preparative liquid chromatography. The mobile phase was 95% C and was equilibrated for 3 column volumes. Then, the mobile phase was 95% A and was equilibrated for 3 column volumes. Then, the above gradient was used for preparation, and the fraction was freeze-dried to obtain the product.

[0665] MS m / z (ESI): 983.7 [(M+2H) / 2] + ; 656.3 [(M+3H) / 3] + .

[0666] The following polypeptides were synthesized according to the above operation steps starting from the corresponding starting materials:

[0667] Synthetic route three:

[0668] Synthesis of polypeptide 61:

[0669] Chemical solid-phase synthesis:

[0670] 1.1 Synthesis table:

[0671] 1.2 Solid phase synthesis procedure:

[0672] 1.2.1 Weigh 1.5 g Rink amide-MBHA resin (0.348 mmol / g) into the reactor, swell the resin with 10 V dichloromethane for 30 min, then filter the system, and wash the resin with 10 V DMF for 2 times.

[0673] 1.2.2 Add 10 V 20% Pip / DMF into the reactor, and blow N2 for 20 min. After filtering the system, add 10 V 20% Pip / DMF into the reactor, and blow N2 for 20 min.

[0674] 1.2.3 After the reaction, wash the resin with 10 V DMF for 6 times, and test with ninhydrin / tetrachloranil: positive.

[0675] 1.2.4 Weigh 2.0 eq Fmoc-Sar-OH, 4.0 eq DIEA, and 10 V DMF into the reactor, and then add 2 eq HATU, and blow N2 for 1 h.

[0676] 1.2.5 After the reaction, test with ninhydrin / tetrachloranil: negative; then filter the system, and wash the resin with 10 V DMF for 5 times.

[0677] 1.2.6 Repeat the procedures of 1.2.2-1.2.5 to sequentially condense amino acids 2-12 according to the synthesis table.

[0678] 1.2.7 Wash the resin with MeOH for 2 times, and with MTBE for 2 times, and then dry the resin into fine sand.

[0679] 1.2.8. Weigh the above resin into the reactor, add 0.5 eq of tetrakis(triphenylphosphine)palladium, 20 eq of phenylsilane, and 20 eq of 1,3-dimethylbarbituric acid, and then add DCM, and blow N2 for 8 h. After the reaction, wash the resin with DMF for 6 times.

[0680] 1.2.9 Add 2 eq HATU and 4 eq DIEA into the reactor, and then add DMF, and blow N2 for 1 h. After the reaction, test with ninhydrin / tetrachloranil: negative; then filter the system, and wash the resin with 10 V DMF for 6 times, and with methanol and MTBE for 2 times each, and then dry the resin into fine sand.

[0681] 1.3 Remove all the protecting groups:

[0682] Weigh the peptide resin into a centrifuge tube, add 10 V cleavage solution (85% TFA / 2.5% Tis / 5% H2O / 5% EDT / 2.5% anisole + NH4I (150 mg / ml)), cleave at room temperature (25 °C) for 2.5 h, filter. At 0 °C, add 10 V MTBE to the filtrate, solid precipitates, centrifuge, wash the solid with MTBE twice, dry the centrifuged solid with N2, obtain the crude peptide, purify by high performance preparative liquid chromatography and convert the salt to obtain the polypeptide 61.

[0683] Salt conversion conditions:

[0684] After high performance preparative liquid chromatography, dilute the sample and pump it into the column, equilibrate with 95% C mobile phase for 3 column volumes, then equilibrate with 95% A mobile phase for 3 column volumes, then use the above gradient for preparation, obtain the fraction, freeze-dry to obtain the product.

[0685] MS m / z (ESI): 875.1 [(M+2H) / 2] + ; 583.8 [(M+3H) / 3] + .

[0686] The following polypeptides are synthesized according to the above operation steps starting from the corresponding starting materials:

[0687] Synthetic route four:

[0688] Synthesis of polypeptide 72:

[0689] Chemical solid-phase synthesis:

[0690] 1.1 Synthesis table:

[0691] 1.2 Solid-phase synthesis operation steps:

[0692] 1.2.1 Weigh 1.12 g of Rink amide-MBHA resin (degree of substitution 0.348 mmol / g) into a reactor, swell the resin with 10 V dichloromethane for 30 min, after suction filtration, wash the resin with 10 V DMF twice.

[0693] 1.2.2 Add 10 V 20% Pip / DMF to the reactor, N2 blow for 10 min. After suction filtration, add 10 V 20% Pip / DMF to the reactor, N2 blow for 10 min.

[0694] 1.2.3 Reaction was completed, the resin was washed with 10V DMF for 6 times, ninhydrin / tetrachlorobenzoquinone test: positive.

[0695] 1.2.4 2.0 eq Fmoc-Sar-OH, 4.0 eq DIEA, 10V DMF were weighed into the reactor, then 1.8 eq HATU was added, N2 was blown for 1 h.

[0696] 1.2.5 Reaction was completed, ninhydrin / tetrachlorobenzoquinone test: negative; after the system was suction filtered, the resin was washed with 10V DMF for 5 times.

[0697] 1.2.6 The operation of 1.2.2-1.2.5 was repeated according to the synthesis table to sequentially condense amino acids 2-12.

[0698] 1.2.7 10V 20% Pip / DMF was added into the reactor, N2 was blown for 10 min. After the system was suction filtered, 10V 20% Pip / DMF was added into the reactor, N2 was blown for 10 min.

[0699] 1.2.8 Reaction was completed, the resin was washed with 10V DMF for 6 times, ninhydrin / tetrachlorobenzoquinone test: positive.

[0700] 1.2.9 2.0 eq Fmoc-Pen(Trt)-OH, 2.5 eq HOAt, 10V DMF were weighed into the reactor, then 2.5 eq DIC was added, N2 was blown for 24 h; the reaction was repeated for 3 times.

[0701] 1.2.10 10V 20% Pip / DMF was added into the reactor, N2 was blown for 10 min. After the system was suction filtered, 10V 20% Pip / DMF was added into the reactor, N2 was blown for 10 min.

[0702] 1.2.11 Reaction was completed, the resin was washed with 10V DMF for 6 times, ninhydrin / tetrachlorobenzoquinone test: positive.

[0703] 1.2.12 2.0 eq intermediate L1, 4.0 eq DIEA, 10V DMF were weighed into the reactor, then 1.8 eq HATU was added, N2 was blown for 1 h.

[0704] 1.2.13 Reaction was completed, ninhydrin / tetrachlorobenzoquinone test: negative; after the system was suction filtered, the resin was washed with 10V DMF for 5 times.

[0705] 1.2.14 The resin was washed with MeOH for 2 times, washed with MTBE for 2 times, and the resin was suctioned to be fine sand.

[0706] 1.3 Cleavage:

[0707] The peptide resin was weighed into a centrifuge tube, 10 V cleavage solution (85% TFA / 2.5% Tis / 5% H2O / 5% EDT / 2.5% thioanisole + NH4I (150 mg / ml)) was added, and the mixture was allowed to cleave at room temperature (25 °C) for 2.5 h, and filtered. The filtrate was added to 10 V MTBE at 0 °C, and the solid was allowed to precipitate, centrifuged, and the solid was washed twice with MTBE. The centrifuged solid was dried with N2, and the crude peptide 72-2 was obtained, which was used directly in the next step without further purification.

[0708] 1.4 Disulfide bond cyclization:

[0709] The crude peptide 72-2 was weighed into a reaction bottle, dissolved in 10%-20% ACN / water solution to make a solution with a concentration of 0.5 mg / mL-1 mg / mL, and 0.2 mmol / mL I2 / MeOH solution was added dropwise until the reaction solution was light yellow. The system was allowed to react at room temperature (25 °C) for 10-15 min. Saturated vitamin C sodium aqueous solution was added dropwise until the light yellow color of the reaction solution disappeared, and the system was purified by high-performance preparative liquid chromatography and salt conversion to obtain the polypeptide 72.

[0710] Salt conversion conditions:

[0711] After high-performance preparative liquid chromatography, the sample was diluted and pumped into the chromatographic column. After equilibration with 95% C for 3 column volumes, the system was equilibrated with 95% A for 3 column volumes, and then prepared using the above gradient to obtain the fraction, which was freeze-dried to obtain the product.

[0712] MS m / z (ESI): 1014.0 [(M+H) / 2] + ; 676.2 [(M+2H) / 3] + .

[0713] The following polypeptides were synthesized according to the above procedures starting from the corresponding starting materials:

[0714] Synthetic route five:

[0715] Synthesis of polypeptide 100: (HCO2-212)

[0716] Chemical solid phase synthesis:

[0717] 1.1 Synthesis table:

[0718] 1.2 Solid phase synthesis operation steps:

[0719] 1.2.1 Weigh 1.46 g of Rink amide-MBHA resin (degree of substitution 0.343 mmol / g) into the reactor, swell the resin with 10 V dichloromethane for 30 min, after the system is filtered, wash the resin with 10 V DMF for 2 times.

[0720] 1.2.2 Add 10 V 20% Pip / DMF into the reactor, N2 blow for 10 min. After the system is filtered, add 10 V 20% Pip / DMF into the reactor, N2 blow for 10 min.

[0721] 1.2.3 After the reaction is completed, wash the resin with 10 V DMF for 6 times, ninhydrin / tetrachlorobenzoquinone detection: positive.

[0722] 1.2.4 Weigh 2.0 eq of Fmoc-Sar-OH, 4.0 eq of DIEA, 10 V DMF into the reactor, and then add 2.0 eq of HATU, N2 blow for 1 h.

[0723] 1.2.5 After the reaction is completed, ninhydrin / tetrachlorobenzoquinone detection: negative; after the system is filtered, wash the resin with 10 V DMF for 5 times.

[0724] 1.2.6 Repeat the operation steps 1.2.2-1.2.5 according to the synthesis table to sequentially condense amino acids 2-12.

[0725] 1.2.7 Add 10 V 20% Pip / DMF into the reactor, N2 blow for 10 min. After the system is filtered, add 10 V 20% Pip / DMF into the reactor, N2 blow for 10 min.

[0726] 1.2.8 After the reaction is completed, wash the resin with 10 V DMF for 6 times, ninhydrin / tetrachlorobenzoquinone detection: positive.

[0727] 1.2.9 Weigh 2.1 eq of Fmoc-Pen(Trt)-OH, 2.1 eq of HOAt, 10 V DMF into the reactor, and then add 1.95 eq of DIC, N2 blow for 24 h; repeat the reaction for 2 times.

[0728] 1.2.10 To the reactor, add 10 V DMF, then 6 mL DIEA and 3 mL Ac2O, and N2 blow for 1 h.

[0729] 1.2.11 Upon completion of the reaction, wash the resin with 10 V DMF for 6 times, and ninhydrin / tetrachloroquinone test: negative.

[0730] 1.2.12 To the reactor, add 10 V 20% Pip / DMF, and N2 blow for 10 min. After suction filtration, add 10 V 20% Pip / DMF to the reactor, and N2 blow for 10 min.

[0731] 1.2.13 Upon completion of the reaction, wash the resin with 10 V DMF for 6 times, and ninhydrin / tetrachloroquinone test: positive.

[0732] 1.2.14 To the reactor, add 2.0 eq of intermediate L1, 4.0 eq of DIEA, 10 V DMF, then 2.0 eq of HATU, and N2 blow for 1 h.

[0733] 1.2.15 Upon completion of the reaction, ninhydrin / tetrachloroquinone test: negative; after suction filtration, wash the resin with 10 V DMF for 5 times.

[0734] 1.2.16 Wash the resin with MeOH for 2 times, and MTBE for 2 times, and suction dry the resin into fine sand.

[0735] 1.3 Trimethylamine

[0736] 1.3.1 To the reactor, add 10 V THF to swell for 30 min, then 20 eq of TBAF (1 M, 10 mL), and N2 blow for 3 h. Upon completion of the reaction, wash the resin with DMF for 3 times, and then with DCM for 3 times.

[0737] 1.3.2 To the reactor, add 10 V DCM, 60 eq of TEA and 30 eq of MsCl, and N2 blow for 3 h. Upon completion of the reaction, wash the resin with DMF for 6 times.

[0738] 1.3.3 Put the peptide resin into a round bottom flask, and add 20 V DMF, 20 eq of trimethylamine and 100 eq of lithium bromide to it, and stir at 60 °C for 3 h. Upon completion of the reaction, wash the resin with water for 3 times, and then with DMF for 6 times.

[0739] 1.3.4 Wash the resin with MeOH for 2 times, and MTBE for 2 times, and suction dry the resin into fine sand.

[0740] 1.4 Cleavage:

[0741] Weigh the crude peptide 100-4 into a centrifuge tube, add 10V cleavage solution (85% TFA / 2.5% Tis / 5% H2O / 5% EDT / 2.5% anisole + NH4I (150 mg / ml)), cleave at room temperature (25 °C) for 2.5 h, filter. At 0 °C, add 10V MTBE to the filtrate, solid precipitates, centrifuge, wash the solid with MTBE twice, dry the centrifuged solid with N2, obtain crude peptide 100-4, which is used directly in the next step without further purification.

[0742] 1.5 disulfide bond cyclization:

[0743] Weigh the crude peptide 100-4 into a reaction bottle, dissolve in 10%-20% ACN / water solution, configure into a solution with a concentration of 0.5 mg / mL-1 mg / mL, add 0.2 mmol / mL I2 / MeOH solution dropwise until the reaction solution is light yellow, the system is reacted at room temperature (25 °C) for 10-15 min. Add saturated vitamin C sodium aqueous solution dropwise until the reaction solution is light yellow, the system is purified by high-performance preparative liquid chromatography and salted to obtain polypeptide 100.

[0744] Salt conversion conditions:

[0745] After high-performance preparative liquid chromatography, the sample is diluted and pumped into the chromatographic column, the mobile phase is 95% C, balanced for 3 column volumes, then balanced with the mobile phase 95% A for 3 column volumes, then prepared using the above gradient, and the fraction is freeze-dried to obtain the product.

[0746] MS m / z (ESI): 1046.3 [M / 2] + ; 698.0 [(M+H) / 3] + .

[0747] The following polypeptides are synthesized according to the above operation steps starting from the corresponding starting materials:

[0748] Synthetic route six:

[0749] Synthesis of polypeptide 106:

[0750] Chemical solid-phase synthesis:

[0751] 1.1 Synthesis table:

[0752] 1.2 Solid-phase synthesis operation steps:

[0753] 1.2.1 Weigh 1.46 g Rink amide-MBHA resin (0.343 mmol / g) into the reactor, swell the resin with 10 V dichloromethane for 30 min, then filter the system, and wash the resin with 10 V DMF for 2 times.

[0754] 1.2.2 Add 10 V 20% Pip / DMF into the reactor, and blow N2 for 10 min. After filtering the system, add 10 V 20% Pip / DMF into the reactor, and blow N2 for 10 min.

[0755] 1.2.3 After the reaction is completed, wash the resin with 10 V DMF for 6 times, and perform ninhydrin / tetrachloroquinone detection: positive.

[0756] 1.2.4 Weigh 2.0 eq of intermediate AA38 and 4.0 eq of DIEA into the reactor, and add 10 V DMF, and then add 2.0 eq of HATU, and blow N2 for 1 h.

[0757] 1.2.5 After the reaction is completed, perform ninhydrin / tetrachloroquinone detection: negative; and then filter the system, and wash the resin with 10 V DMF for 5 times.

[0758] 1.2.6 Repeat the operation of 1.2.2-1.2.5 to sequentially condense amino acids 2-10 according to the synthesis table.

[0759] 1.2.7 Add 10 V 20% Pip / DMF into the reactor, and blow N2 for 10 min. After filtering the system, add 10 V 20% Pip / DMF into the reactor, and blow N2 for 10 min.

[0760] 1.2.8 After the reaction is completed, wash the resin with 10 V DMF for 6 times, and perform ninhydrin / tetrachloroquinone detection: positive.

[0761] 1.2.9 Weigh 2.1 eq of Fmoc-Pen(Trt)-OH and 2.1 eq of HOAt into the reactor, and add 10 V DMF, and then add 1.95 eq of DIC, and blow N2 for 24 h; repeat the reaction for 3 times.

[0762] 1.2.10 Add 10 V 20% Pip / DMF into the reactor, and blow N2 for 10 min. After filtering the system, add 10 V 20% Pip / DMF into the reactor, and blow N2 for 10 min.

[0763] 1.2.11 After the reaction is completed, wash the resin with 10 V DMF for 6 times, and perform ninhydrin / tetrachloroquinone detection: positive.

[0764] 1.2.12 To the reactor, add 10 V of DMF, then add 6 mL of DIEA and 3 mL of Ac2O, and N2 blow for 1 h.

[0765] 1.2.13 Upon completion of the reaction, wash the resin with 10 V of DMF for 6 times, and ninhydrin / tetrachloroquinone test: negative.

[0766] 1.2.14 Weigh the resin into the reactor, add DCM to swell for 30 min, then add 20 eq of phenylsilane, 20 eq of 1,3-dimethylbarbituric acid, and 0.25 eq of tetrakis triphenylphosphine palladium, and N2 blow for 4 h.

[0767] 1.2.15 Upon completion of the reaction, wash the resin with 10 V of DMF for 6 times.

[0768] 1.2.16 To the reactor, add 2.0 eq of intermediate L2, then add 10 V of DMF, 4.0 eq of DIEA, then add 2.0 eq of HATU, and N2 blow for 1 h.

[0769] 1.2.17 Upon completion of the reaction, wash the resin with 10 V of DMF for 6 times.

[0770] 1.2.18 Wash the resin with MeOH for 2 times, then wash the resin with MTBE for 2 times, and dry the resin into fine sand.

[0771] 1.3 Trimethylamine

[0772] 1.3.1 To the reactor, add 10 V of THF to swell for 30 min, then add 20 eq of TBAF (1 M, 10 mL), and N2 blow for 3 h. Upon completion of the reaction, wash the resin with DMF for 3 times, then wash the resin with DCM for 3 times.

[0773] 1.3.2 To the reactor, add 10 V of DCM, 60 eq of TEA, and 30 eq of MsCl, and N2 blow for 3 h. Upon completion of the reaction, wash the resin with DMF for 6 times.

[0774] 1.3.3 Weigh the peptide resin into a round bottom flask, then add 20 V of DMF, 20 eq of trimethylamine, and 100 eq of lithium bromide, and stir at 60 °C for 12 h. Upon completion of the reaction, wash the resin with water for 3 times, then wash the resin with DMF for 6 times.

[0775] 1.3.4 Wash the resin with MeOH for 2 times, then wash the resin with MTBE for 2 times, and dry the resin into fine sand.

[0776] 1.4 Cleavage:

[0777] Weigh the peptide resin into a centrifuge tube, add 10 V cleavage solution (85% TFA / 2.5% Tis / 5% H2O / 5% EDT / 2.5% anisole + NH4I (150 mg / ml)), cleave at room temperature (25 °C) for 2.5 h, filter. Add the filtrate to 10 V MTBE at 0 °C, solid precipitates, centrifuge, wash the solid with MTBE twice, dry the centrifuged solid with N2, obtain the crude peptide 106-5, which is used directly in the next step without further purification.

[0778] 1.5 disulfide bond cyclization:

[0779] Weigh the crude peptide 106-5 into a reaction bottle, dissolve in 10%-20% ACN / water solution, configure into a solution with a concentration of 0.5 mg / mL-1 mg / mL, add 0.2 mmol / mL I2 / MeOH solution dropwise until the reaction solution is light yellow, the system is reacted at room temperature (25 °C) for 10-15 min. Add saturated vitamin C sodium aqueous solution dropwise until the reaction solution is light yellow, the system is purified by high performance preparative liquid chromatography and salt conversion to obtain the polypeptide 106.

[0780] Salt conversion conditions:

[0781] After high performance preparative liquid chromatography, the sample is diluted and pumped into the chromatographic column, the mobile phase is 95% C balanced for 3 column volumes, then balanced with the mobile phase 95% A for 3 column volumes, then prepared using the above gradient to obtain the fraction, which is freeze-dried to obtain the product.

[0782] MS m / z (ESI): 1082.3 [M / 2] + ; 722.0 [(M+H) / 3] + .

[0783] The following polypeptides are synthesized according to the above operation steps starting from the corresponding starting materials:

[0784] Synthetic route seven:

[0785] Synthesis of polypeptide 116:

[0786] Chemical solid-phase synthesis:

[0787] 1.1 Synthesis table:

[0788] 1.2 Solid-phase synthesis operation steps:

[0789] 1.2.1 Weigh 0.5 g of Sieber resin (0.6 mmol / g) into the reactor, swell the resin with 10 V of dichloromethane for 10 min, filter the system, and then wash the resin with 10 V of DMF twice.

[0790] 1.2.2 Add 10 V of 20% Pip / DMF to the reactor, and then blow N2 for 20 min.

[0791] 1.2.3 After the reaction is completed, wash the resin with 10 V of DMF six times, and then perform ninhydrin / tetrachlorobenzoquinone detection: positive.

[0792] 1.2.4 Weigh 3.0 eq of intermediate AA45, 3.0 eq of HATU, 3.0 eq of HOBt, 4.0 eq of DIEA, and 10 V of DMF into the reactor, and then blow N2 for 2 h.

[0793] 1.2.5 After the reaction is completed, perform ninhydrin / tetrachlorobenzoquinone detection: negative; filter the system, and then wash the resin with 10 V of DMF twice.

[0794] 1.2.6 Repeat the procedures of 1.2.2-1.2.5 to sequentially condense amino acids 2-11 according to the synthesis table.

[0795] 1.2.7 Add 10 V of 20% Pip / DMF to the reactor, and then blow N2 for 20 min.

[0796] 1.2.8 After the reaction is completed, wash the resin with 10 V of DMF twice, and then perform ninhydrin / tetrachlorobenzoquinone detection: positive.

[0797] 1.2.9 Add 10 V of DMF to the reactor, and then add 20.0 eq of DIEA and 10.0 eq of Ac2O, and then blow N2 for 1 h.

[0798] 1.2.10 After the reaction is completed, wash the resin with 10 V of DMF twice, and then perform ninhydrin / tetrachlorobenzoquinone detection: negative.

[0799] 1.2.11 Weigh the resin into the reactor, swell for 30 min with 10 V of DCM, add 20 eq of phenylsilane and 0.1 eq of tetrakistriphenylphosphine palladium to the reactor, and then blow N2 for 1 h.

[0800] 1.2.12 After the reaction is completed, wash the resin with 10 V of DMF twice.

[0801] 1.2.13 Add 3.0 eq of intermediate L2 to the reactor, and then add 10 V of DMF, 5.0 eq of DIEA, and then add 3.0 eq of HATU and 3.0 eq of HOBt, and then blow N2 for 2 h.

[0802] 1.2.14 After the reaction is completed, the resin is washed with 10 V of DMF for 2 times.

[0803] 1.2.15 The resin is washed with MeOH for 2 times, and MTBE for 2 times, and the resin is dried into fine sand.

[0804] 1.3 Cleavage:

[0805] The peptide resin is weighed into a centrifuge tube, 10 V of cleavage solution (TFA / 2.5% Tis / 2.5% H2O / 5% 3-MPA) is added, and the mixture is cleaved at room temperature (25°C) for 1.5 h, and filtered. The filtrate is added to 10 V of ether at 0°C, and the solid is precipitated, centrifuged or filtered, and the centrifuged or filtered solid is dissolved in 30% acetonitrile / water, and purified by reverse phase chromatography (C18, 0.05% TFA in H2O / CAN), and the fractions are lyophilized to obtain 116-2.

[0806] 1.4 Disulfide bond cyclization:

[0807] The 116-2 is weighed into a reaction bottle, dissolved in 50% ACN / water solution, and configured into a solution with a concentration of 15 mg / mL, and 1.5 eq of I2 / MeOH solution is added dropwise until the reaction solution is light yellow, and the system is reacted at room temperature (25°C) for 5 min. Saturated vitamin C sodium aqueous solution is added dropwise until the reaction solution is light yellow, and the system is purified by high-performance preparative liquid chromatography and salt conversion to obtain the polypeptide 116.

[0808] Salt conversion conditions:

[0809] After high-performance preparative liquid chromatography, the sample is diluted and pumped into the chromatographic column, and the mobile phase is balanced with 95% C for 3 column volumes, then balanced with 95% A for 3 column volumes, and then prepared using the above gradient to obtain fractions, which are lyophilized to obtain the product.

[0810] MS m / z (ESI): 1061.6 [M+H / 2] + ; 708.2 [(M+2H) / 3] + .

[0811] The following polypeptides are synthesized according to the above operation steps starting from the corresponding starting materials:

[0812] Biological test part:

[0813] Experimental Example 1: PBMC detection of pSTAT3 experiment

[0814] 1. Purpose of the test:

[0815] The inhibitory effect of the compound on the expression of pSTAT3 by PBMC is evaluated by ELISA.

[0816] 2. Related samples:

[0817] Polypeptide compound

[0818] 3. Cells:

[0819] Normal human PBMC cells

[0820] 4. Test process:

[0821] Recover the frozen PBMC, stimulate the PBMC for 3 days using 5 μg / mL coated anti-human CD3 (Thermo, 16-0037-38) and anti-human CD28 (Thermo, 16-0289-85) with a final concentration of 1 μg / mL. Collect the cells, induce again for 2 days under the same conditions, for a total of 5 days. Collect the cells, resuspend the cells using serum-free medium, plant in a 96-well plate, and incubate overnight. Add different concentrations of compounds, incubate in a 37℃ & 5% CO2 incubator for 1 hour, then add human IL-23 (biotechne, A10123091) with a final concentration of 20 ng / mL, and incubate in a 37℃ & 5% CO2 incubator for 30 minutes. Add lysis solution (PhosStop: 10X; cOmplete TM Cocktail 50X; Lysis Buffer 10X; PMSF 100X), and perform cell lysis treatment. Detect pSTAT3 (CST, 7300C) according to the ELISA instructions, read the absorbance value at OD450, and perform IC50 fitting in the non-linear fitting-four parameter formula in GraphPad Prism 8 software.

[0822] 5. Results:

[0823] The experimental results are shown in Table 1 below:

[0824] Table 1

[0825] Conclusion: The compound of the present application has very strong biological activity in the normal human PBMC pSTAT3 inhibition test.

[0826] Experimental Example 2: Exposed polar surface area (EPSA)

[0827] I. Experimental scheme

[0828] Exposed polar surface area (EPSA) is a molecular polarity experimental descriptor obtained by supercritical fluid chromatography (SFC) retention behavior, and the oral absorption of a molecule is generally negatively correlated with the molecular polarity.

[0829] Selection (S)-VAL and (R)-NEA stationary phases are based on the balanced properties of their lipophilicity and polar characteristics, as well as the ability to separate compounds with large differences in polarity. The mobile phase is composed of methanol (with ammonium formate) and carbon dioxide. Under this condition, polar compounds are retained more strongly, and separation based on increasing polarity of the mobile phase is achieved by elution with a low-slope gradient of methanol. The results are normalized using calibration standards, and a linear relationship between retention time (tR) and EPSA value is established. EPSA is in angstroms 2

[0830] While determining the target compound, a linear relationship between retention time and EPSA value is established by analyzing 7 calibration standards (see Materials section for details). The EPSA values of these 7 calibration compounds are defined by G. Goetz by comparing topological polar surface area (TPSA) (ACS Med. Chem. Lett., 2014, 5, 1167-1172). Based on the slope of the linear relationship between the EPSA values of these 7 compounds and their retention times, the EPSA value of the target compound under the same conditions is calculated using the following equation:

[0831] EPSA = a tR + b

[0832] a: slope;

[0833] b: intercept;

[0834] Tr: retention time of the compound being analyzed

[0835] II. Materials

[0836] 1. Instruments:

[0837] Waters Acquity UPC^ supercritical fluid chromatograph;

[0838] 2. Calibration standards

[0839] Table 2

[0840] 3. Reagents

[0841] Table 3

[0842] III. Methods and Procedures

[0843] Instrument: Waters Acquity UPC^ supercritical fluid chromatograph;

[0844] Column: Phenomenex Chirex (S)-VAL and Column:Chromolith SpeedROD®(Part No: 00G-3014-E0), size 250 x 4.6 mm, 5 μm

[0845] Detector:PDA, detection wavelength 220 nm

[0846] Column temperature:40 °C

[0847] Back pressure:140 Bar

[0848] Sample treatment:the sample was dissolved in methanol with a concentration of 1 mg / mL.

[0849] Gradient description:flow rate 4 mL / min, injection volume 5 μL, mobile phase CO2and modifier methanol (containing 20 mmol / L ammonium formate), linear gradient of mobile phase modifier from 5% to 50% in 10 minutes, then linear from 50% to 60% in 1 minute, 60% for 5 minutes, then linearly decreased to 35% in 1 minute, linearly decreased to 5% in the next minute, and kept at 5% until the end of the run.

[0850] The specific elution gradient is shown in Table 4 below.

[0851] Table 4

[0852] The results are shown in Table 5 below.

[0853] Table 5

[0854] Conclusion:It can be seen that compared with the clinical molecule JNJ-2113, the compound of the present application has significantly reduced polar surface area exposure.

[0855] Experimental Example 3: Pharmacokinetic experiment

[0856] This experimental example carried out in vivo pharmacokinetic evaluation on rats through intravenous injection and duodenal intubation administration.

[0857] Experimental method and conditions: male SD rats were respectively given a single dose of 1 mg / Kg (intravenous injection (IV), solvent: PBS) and 10 mg / Kg (duodenal intubation administration (ID), solvent: PBS+100 mg / Kg penetration enhancer NaC10) of the polypeptide compound to be tested, and blood samples were collected from the jugular vein at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, with about 0.2 mL collected for each sample, K2-EDTA anticoagulation, centrifugal separation of plasma for testing. The detection of drug concentration in plasma used liquid chromatography tandem mass spectrometry (LC / MS / MS), and the measured concentration was used to calculate the pharmacokinetic parameters. The results are shown in Table 6 below.

[0858] Table 6 Pharmacokinetics of ID administration (10 mg / Kg)

[0859] Conclusion: Compared with clinical molecule JNJ-2113, the compound of the present application has the advantage of pharmacokinetics in rats in vivo.

[0860] Experimental Example 4: IL23-induced rat otitis model in vivo efficacy experiment

[0861] 1. Experimental purpose

[0862] The purpose of this experiment is to evaluate the efficacy of the compound on human interleukin 23-induced rat psoriasis model.

[0863] 2. Experimental materials

[0864] 2.1 Reagent materials

[0865] hIL-23 (ILB-H52W5, Acrobiosystem), phosphate buffer (pH: 7.2) (Gibco), phosphate buffer (pH: 7.4) (Gibco), penetration enhancer

[0866] 2.2 Instrument equipment

[0867] Electronic balance, electronic scale, centrifuge, ultrasonic cleaner, electronic oscillator, anesthetic machine

[0868] 2.3 Animal information

[0869] Table 7

[0870] Note: All operations on animals in this experimental protocol are approved by the Animal Welfare and Use Management Committee (IACUC).

[0871] 3. Experimental method

[0872] 3.1 Grouping

[0873] After the adaptation period, all rats will be randomly grouped according to body weight.

[0874] 3.2 Model establishment

[0875] Except for the blank control group, the rats in the other groups were injected with 2.5 μg of human interleukin 23 intradermally in the right ear to induce a rat psoriasis model. On day 0, day 1, day 2, and day 3, injection was performed once a day, for a total of 4 times. Single-point injection was performed each time, with an injection volume of 20 μL each time. The blank control group was injected with the same volume of phosphate buffer intradermally in the right ear as a control.

[0876] 3.3 Drug treatment

[0877] All rats were administered with compound or vehicle (model group) from day -1 to day 3, for a total of 5 days. Administration was performed 30 minutes before human interleukin 23 injection. Groups administered twice a day were administered with a 10-hour interval between each administration.

[0878] 3.4 Data processing

[0879] 1) Ear thickness measurement

[0880] All animals were measured for right ear thickness every day, from day -1 to day 4, for a total of 6 times. The ear thickness of each group of animals every day was subtracted from the initial ear thickness (ear thickening), and compared with the model group. The results of the ear thickness on the last day of the experiment, day 4 - day -1, were analyzed graphically using GraphPad Prism. The % inhibition of ear thickening = [1 - (average value of the administered group / average value of the model group)] x 100%.

[0881] 2) PK detection samples (day 3)

[0882] The animal plasma was collected for PK detection (baseline, 0.25 h, 2 h, 6 h, 24 h). The rats were taken about 0.2 mL of whole blood through the jugular vein into a tube containing K2-EDTA as an anticoagulant, and placed on wet ice until centrifugation. The samples will be centrifuged (3200 x g, 4°C, 10 minutes) within 1 hour after collection. The collected plasma samples were stored at -80°C until bioanalysis.

[0883] 4. Experimental endpoint

[0884] On the day of the experimental endpoint (day 4), all rats were euthanized with carbon dioxide. The right ear was collected and weighed after treatment, and then treated with RNA Later overnight. The next day, the supernatant was discarded, and the ear sample was stored at -80°C. The sample was collected for Q-PCR analysis of IL17A relative expression.

[0885] 5. Q-PCR analysis method

[0886] 5.1 Experimental materials

[0887] 5.1.1 Reagents

[0888] TRIzol TM Reagent: Invitrogen, item number: 15596018; PrimeScript RT Reagent Kit with gDNA Eraser (Perfect Real Time): Takara, item number: RR047A; TB Premix Ex Taq TMII (Tli RNaseH Plus): Takara, Cat: RR820A; QPCR primers (see Table 8), Suzhou Genewiz.

[0889] Table 8

[0890] 5.1.2 Instruments

[0891] Tissue grinder: Shanghai Jingxin, Model: Tissuelyser-24L; Spectrophotometer: Thermo Scientific, Model: Nanodrop2000; PCR thermal cycler: Applied Biosystems, Model: 4375305; Fluorescent quantitative PCR instrument, Bio-Rad, Model: CFX384.

[0892] 5.2 PCR detection method

[0893] 5.2.1 RNA extraction

[0894] 1) Add 1 ml of TRIzol lysis solution to each 20-30 mg of tissue, homogenize with a pre-cooled tissue grinder (60 Hz, 1 min, 2 times).

[0895] 2) Incubate for 5 minutes to completely dissociate the nucleoprotein complex, centrifuge at 4°C, 12000 x g for 5 minutes, and transfer the supernatant to a new centrifuge tube.

[0896] 3) Add 0.2 mL of chloroform and mix well, stand at room temperature for 2-5 minutes.

[0897] 4) Centrifuge at 4°C, 12000 x g for 15 minutes. The mixture separates into a lower red phenol-chloroform, an intermediate phase, and a colorless upper aqueous phase. Transfer the aqueous phase containing RNA to a new tube.

[0898] 5) Add 0.5 mL of isopropanol to the aqueous phase, mix gently, and stand at -20°C for 1 hour or overnight.

[0899] 6) Centrifuge at 4°C, 12000 x g for 15 minutes. The total RNA is precipitated at the bottom of the tube as a white gelatinous precipitate. Discard the supernatant.

[0900] 7) Resuspend the precipitate with 1 mL of 75% ethanol. First vortex the sample briefly, then centrifuge at 4°C, 7500 x g for 5 minutes. Discard the supernatant.

[0901] 8) Repeat step 7.

[0902] 9) Vacuum or air dry the RNA pellet for 5-10 minutes.

[0903] 10) 40 μL of RNA precipitate was dissolved in enzyme-free water and stored at -80°C.

[0904] 11) The 260 / 280 ratio was determined using a Nanodrop 2000.

[0905] 5.2.2 Reverse transcription reaction

[0906] Genomic DNA elimination reaction

[0907] 1) The genomic DNA elimination reaction solution was prepared on ice (Table 9).

[0908] 2) The program was set on the PCR machine at 42°C for 2 minutes and 4°C for storage.

[0909] Table 9 Reagents for genomic DNA elimination reaction

[0910] Reverse transcription reaction

[0911] 1) The reverse transcription reaction solution was prepared on ice (Table 10). 10 μL of the reaction from the previous step was added to the prepared solution, which was then mixed gently, and the reverse transcription reaction was immediately performed.

[0912] 2) The program was set on the PCR machine at 37°C for 15 minutes, 85°C for 5 seconds, and 4°C for storage.

[0913] 3) After the reaction was completed, the cDNA was stored at 20°C for long-term storage.

[0914] Table 10 Reagents for reverse transcription reaction

[0915] 5.2.3 QPCR reaction

[0916] 1) The qPCR reaction solution was prepared on ice (Table 11).

[0917] 2) The 384-well plate was loaded into the Real-Time PCR machine, the PCR program was set according to Table 12, and the reaction was immediately performed.

[0918] 3) The expression of the target gene was calculated using the ΔΔCt method

[0919] Table 11 Reagents for QPCR reaction

[0920] Table 12 PCR program

[0921] 6. Data analysis

[0922] Experimental data are expressed as mean ± SEM, and analyzed by One Way ANOVA and Two Way ANOVA methods using GraphPad Prism software (*P<0.05, **P<0.01, ***P<0.001; ****P<0.0001).

[0923] 7. Experimental results

[0924] The ear thickening inhibition rate % and the relative expression amount of IL17A are shown in the following table.

[0925] Conclusion: The preferred compound of the present application can effectively inhibit ear thickening in the IL23-induced rat otitis model in vivo pharmacodynamic experiment; and the inhibition effect on ear thickening is more significant than that of the clinical molecule JNJ-2113 at the same dose.

[0926] The preferred compound of the present application can effectively inhibit the expression of IL17A in the downstream of the signal pathway in the IL23-induced rat otitis model in vivo pharmacodynamic experiment; and the inhibition effect on the expression of IL17A is more significant than that of the clinical molecule JNJ-2113 at the same dose.

Claims

1. A polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, c[X4-X5-X6-X7-X8-X9]-X10-X11-X12-X13-X14-X15-X16 (I) wherein, X6, X7, X9, X11, X13, X14 and X15 are any amino acid residue; "c[]" in c[X4-X5-X6-X7-X8-X9] means that X4 and X9 are connected into a ring; X4 is or any amino acid residue; X 4a is -CH2-, -0-, -S-, or -N(R 4c )-; R 4a , R 4b , and R 4c are independently H or C 1-6 alkyl; or R 4a , R 4b and the carbon atom to which they are attached form a C 3-8 cycloalkyl; X5 is absent or any amino acid residue; X8is or any amino acid residue; X10 is * end is connected with X11; A is C 6-10 arylene, C 5-10 cycloalkenylene, 5-10 membered heteroarylene, or 5-10 membered heterocycloalkenylene; R 10a halogen, -SF5, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, -CON(C 1-6 alkyl)2, -L-Z 1 , C 10a-1 alkyl substituted by one or more R 1-6 , or C 10a-2 alkoxy substituted by one or more R 1-6 ; R 10a-1 and R 10a-2 independently -NH2, -OH or halogen; R 10b is H or C 1-6 alkyl; X12 is or any amino acid residue; X16 is -L-Z 1 or any amino acid residue; X4, X5, X8, X12, X13, or X16 is any amino acid residue, X4, X5, X8, X12, X13, and X16 are optionally substituted amino acid residues; and 1 substituted amino acid residues; and L is independently a chemical bond or a linking unit; Z 1 independently Z 1a , Z 1b and Z 1c are independently H or C 1-6 alkyl; or Z 1a , together with the nitrogen atom to which it is attached, forms a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkyl substituted with one or more Z 1b , together with the nitrogen atom to which it is attached, forms a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkyl substituted with one or more Z 1a-1 substituted 4-10 membered heterocycloalk Z 1a-1 halogen, C 1-6 alkyl or C 1-6 alkoxy; with the proviso that at least one of X4, X5, X8, X10, X12, X13and X16comprises -Z 1 structure; when the compound as shown in formula (I) contains a cationic fragment, the anion is acetate, trifluoroacetate, chloride, bromide, adipate, benzoate, benzenesulfonate, citrate, decanoate, lactate, maleate, methanesulfonate, propionate, oxalate, succinate, sulfate or tartrate; the number of charges of the cation and the anion is equal; n1, n2, n3, n4, n5 and n6 are independently 0, 1, 2, 3, 4, 5 or 6; in the 4-10 membered heterocycloalkyl, 5-10 membered heteroarylene and 5-10 membered heterocycloalkylene, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

2. The polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, the polypeptide compound as shown in formula (I) satisfies one or both of the following conditions: (1) In L, the linking unit is a combination of one or more selected from the group consisting of C 1-6 alkylene, -C(=O)-, -NR La -, -C(=O)NR Lb -, -NR Lc C(=O)-, -C(=O)O-, -O-, -S-, or -(CH2CH2O)-; R La , R Lb , and R Lc are independently H or C 1-6 alkyl; (2) Z 1 To n4, n5 and n6 are independently 1, 2, 3, 4, 5 or 6.

3. The polypeptide compound of formula (I) as described in claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, the polypeptide compound as shown in formula (I) satisfies one or both of the following conditions: (1) L is a chemical bond, -C(=0)-, or -NH-; (2) Z 1 To 4. The polypeptide compound of formula (I) as claimed in claim 1, characterized in that, the polypeptide compound as shown in formula (I) satisfies one or more of the following conditions: (1) X4 is carbonyl end is connected with X5; X 4a , X 4b and X 4c are independently -CH2-, -O-, -S-, or -N(R 4c )-; R 4a , R 4b , R 4c , R 4d , R 4e , R 4g and R 4h are independently H or C 1-6 alkyl; or R 4a , R 4b and the carbon atom to which they are attached form a C 3-8 cycloalkyl; R 4i is C 1-6 alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl, or C 3-8 cycloalkyl; R 4f -L 4 -Z 41 ; L 4 Z as defined in any one of claims 1 to 3 41 Z as defined in any one of claims 1 to 3 1 Z as defined in any one of claims 1 to 3 (2) X6, X7, X11, X14and X15are independently R a is H or C 1-6 alkyl; R b -(CH2) p1 -R b-1 ; or R a , R b together with the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C b-2 substituted C 3-8 cycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R b-3 substituted C R b-1 is -OH, -CO2H, -CON(R b-4 )2, -N(R b-5 )C(=O)R b-6 , -OC(=O)R b-7 , C 1-6 1-6 alkyl, haloC 1-6 1-6 alkyl, C 6-10 6 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, C 1-6 1-6 alkyl substituted with one or more hydroxyl, C b-8 6 aryl substituted with one or more R 6-10 , 5-10 membered heteroaryl substituted with one or more R b-9 , 4-10 membered heterocycloalkyl substituted with one or more R b-10 , or 5-10 membered heterocycloalkenyl substituted with one or more R b-11 ; R b-4 , R b-5 , and R b-6 are independently H or C 1-6 alkyl; R b-7 is C 1-6 alkyl or 4-10 membered heterocycloalkyl; R b-2 , R b-3 , R b-8 , R b-9 , R b-10 , and R b-11 are independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 haloalkyl, C 3- 8cycloalkyl, -NR b-9a R b-9b , or C b-9c alkyl substituted with one or more R 1-6 ; R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c is independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; p1 is 0, 1, 2, 3, 4, 5 or 6; in the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; (3) X9 is a is attached to X10 and b is attached to X4; R 9a is H; R 9b is X 9a is -CH2-, -0-, -S-, or -N(R 9b-3 )-; R 9b-1 , R 9b-2 , and R 9b-3 are independently H or C 1-6 alkyl; or R 9a , R 9b together with the carbon atom to which they are attached form a 4-10 membered heterocycloalkylene; q2 is 0, 1, 2, 3 or 4; in the 4-10 membered heterocycloalkyl, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

5. The polypeptide compound of formula (I) as described in claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, the polypeptide compound as shown in formula (I) satisfies one or more of the following conditions: (1) X4 is carbonyl end is connected with X5; R 4f -L 4 -Z 41 ; L 4 Z as defined in any one of claims 1 to 3 41 Z as defined in any one of claims 1 to 3 1 Z as defined in any one of claims 1 to 3 (2) X5 is carbonyl end is connected with X6; R 5a -L 5 -Z 51 ; p1 is 0, 1, 2, 3, 4, 5 or 6; L 5 Z as defined in any one of claims 1 to 3 S1 Z as defined in any one of claims 1 to 3 1 Z as defined in any one of claims 1 to 3 (3) X12 is carbonyl end is connected with X13; R 12a is H or C 1-6 alkyl; R 12b is C 1-6 alkyl or -L 12 -Z 121 ; or R 12a or R 12b together with the carbon atom to which it is attached form a 4-10 membered heterocycloalkyl or p2 is 0, 1, 2, 3, 4, 5 or 6; in the 4-10 membered heterocycloalkyl, the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; L 12 Z as defined in any one of claims 1 to 3 121 Z as defined in any one of claims 1 to 3 1 Z as defined in any one of claims 1 to 3 (4) X13 is carbonyl end is connected to X14; R 13a is -L 13 -Z 131 ; L 13 Z as defined in any one of claims 1 to 3 131 Z as defined in any one of claims 1 to 3 1 Z as defined in any one of claims 1 to 3 (5) X16 is - L 16 - Z 161 or R 16a -L 16 -Z 161 ; L 16 Z as defined in any one of claims 1 to 3 161 Z as defined in any one of claims 1 to 3 1 Z as defined in any one of claims 1 to 3 (6) X8 is or -L 8 -Z 81 substituted amino acid residue, the carbonyl terminus being attached to X9; L 8 Z as defined in any one of claims 1 to 3 for L 81 Z as defined in any one of claims 1 to 3 1 ; (7) X10 is * end connected to X11; ring E is 5-6 membered heterocycloalkenylene or 5-6 membered heteroaryl; preferably * end is connected with X11; L 10 Z as defined in any one of claims 1 to 3 for L 101 Z as defined in any one of claims 1 to 3 1 ; (8) X15 is carbonyl terminus to X16; Ring B is a 5-6 membered heteroaryl, which is optionally substituted with 1, 2, or 3 R b-9 substituents; R b-9 independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR b-9a R b- 9b or C b-9c alkyl substituted with one or more R 1-6 substituents; R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c are independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; preferably is connected to X16; T 1 and T 4 independently -NH-, -NR b-9 -, -O- or -S-; T 2 , T 3 , T 5 and T 6 independently N, CH or CR b-9 ; R b-9 independently C 1-6 alkyl, -NR b-9a R b-9b or C b-9c alkyl substituted by one or more R 1-6 ; R b-9a and R b-9b independently H or C 1-6 alkyl; R b-9c independently -CO2H, -CONH2or -CO2C 1-6 alkyl.

6. The polypeptide compound of formula (I) as claimed in claim 1, characterized in that, the polypeptide compound as shown in formula (I) satisfies one or more of the following conditions: (1) X4 is carbonyl end is connected with X5; (2) X5 is carbonyl end is connected with X6; (3) X6 is carbonyl end is connected with X7; (4) X7 is carbonyl end is connected with X8; (5) X8 is carbonyl end is connected with X9; (6) X9 is a end is connected with X10, and b end is connected with X4; (7) X10 is * end is connected with X11; (8) X11 is carbonyl end is connected with X12; (9) X12 is carbonyl end is connected with X13; (10) X13 is carbonyl end is connected with X14; (11) X14is carbonyl end is connected with X15; (12) X15 is carbonyl end is connected with X16; (13) X16 is 7. The polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein X10 is at least one of X4, X5, X8, X12, X13, and X16 comprises -Z 1 structure; Preferably, X10 is * end connected to X11; X5 is the carbonyl terminus is attached to X6; at least one of X4, X8, X12, X13, and X16 comprises -Z 1 structure.

8. The polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein The polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1): wherein X4, X5, X10, X12, X13, X14and X16are as defined in any one of claims 1-6.

9. The polypeptide compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein The polypeptide compound of Formula (I) satisfies any one of the following: Scheme one, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1a): wherein Z 41 is X5, X10, X12, X13, X14, X16, n4, n5, n6, Z 1a , Z 1b and Z 1c as defined in any one of claims 1-6; Preferably, Z 41 is Scheme two, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1b): wherein X16is -L 16 -Z 161 or R 16a -L 16 -Z 161 ; X5, X10, X13, L 16 and Z 161 as defined in any one of claims 1-6; Preferably, X16 is Scheme three, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-1c): Ring A is C 6-10 arylene or 5-10 membered heterocycloalkenylene; R 10a halogen, -SF5, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, substituted by one or more R 10a-1 substituted C 1- 6alkyl, or C 10a-2 substituted C 1-6 alkoxy; preferably oxo; n31 is 0, 1, 2, 3, or 4; X5and Z 1 as defined in any one of claims 1-6; Preferably, For Scheme Four, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-2): Cyc A is C 6-10 arylene, 5-10 membered heteroarylene, or 5-10 membered heterocycloalkylene; R 10a halo, -SF5, oxo, C 1-6 alkyl, C 1-6 alkoxy, -CON(C 1-6 alkyl)2, -L-Z 1 or C 1-6 alkoxy; L is a chemical bond; Z 1 is X5 is the carbonyl end is attached to X6; R 5a -L 5 -Z 51 ; p1 is 0, 1, 2, 3, 4, 5, or 6; L 5 is a chemical bond; Z 51 is R 4 is -CH3or -L 4 -Z 41 ; L 4 is a chemical bond; Z 41 is X16 is - L 16 - Z 161 or R 16a is -L 16 -Z 161 ; L 16 is independently -NH- or Z 161 for Z 1a , Z 1b and Z 1c are independently H or C 1-6 alkyl; or, Z 1a , Z 1b and the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl group; n4, n5, and n6 are independently 0, 1, 2, 3, 4, 5, or 6; Ring B is a 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 R b-9 substituents; R b-9 independently halogen, C 1- 6alkyl, C 1-6 haloalkyl, -NR b-9a R b-9b or C b-9c 6alkyl optionally substituted with one or more R 1-6 substituents; R b-9a and R b-9b are independently H or C 1-6 alkyl; R b-9c are independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; X12, X13, and X14are as defined in any one of claims 1-6; Scheme five, the polypeptide compound as shown in formula (I) is a compound as shown in formula (I-3): wherein X10is * end is attached to X11; s1and s3are independently 1 or 2; s2is 0, 1 or 2; R 10a is C 1-6 alkyl or -L-Z 1 ; L is a bond; Z 1 is X5 is the carbonyl end is attached to X6; R 5a -L 5 -Z 51 ; p1 is 0, 1, 2, 3, 4, 5, or 6; L 5 is a chemical bond; Z 51 is R 4 is -CH3or -L 4 -Z 41 ; L 4 is a chemical bond; Z 41 is X16 is - L 16 - Z 161 or R 16a is -L 16 -Z 161 ; L 16 is independently -NH- or Z 161 independently Preferably, R 16a is Z 1a , Z 1b and Z 1c are independently H or C 1-6 alkyl; or, Z 1a , Z 1b and the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl group; n4, n5, and n6 are independently 0, 1, 2, 3, 4, 5, or 6; Ring B is a 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 R b-9 substituents; R b-9 independently halogen, C 1- 6alkyl, C 1-6 haloalkyl, -NR b-9a R b-9b or C b-9c 6alkyl optionally substituted with one or more R 1-6 alkyl; R b-9a and R b-9b independently H or C 1-6 alkyl; R b-9c independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; X12 is the carbonyl end is connected to X13; X13 is the carbonyl end is connected to X14; X14 is the carbonyl end is connected to X15.

10. The polypeptide compound of formula (I) as described in claim 9, characterized in that, The polypeptide compound of Formula (I) satisfies one or more of the following: (1) in the compound of formula (I-1), of formula (I- la), or of formula (I- lb), X10is independently * end connected to X11; preferably, X10 is the carbonyl end is connected to X6. (2) in the compound of formula (I-1), of formula (I- la), or of formula (I- lb), X5is independently The polypeptide compound of Formula (I) is any one of the compounds in Table A.

11. The polypeptide compound of formula (I) as claimed in claim 1, characterized in that, 12. A polypeptide compound of Formula (II), or a pharmaceutically acceptable salt thereof, c[X19-X20-X21-X22-X23-X24]-X25-X26-X27-X28-X29-X30-X31 (II) "c[]" in c[X19-X20-X21-X22-X23-X24] means that X19and X24are connected to form a ring; wherein the carbonyl end is connected to X20; X19 is m1 is 0, 1, 2, 3, 4, 5, or 6; X 19a , X 19b and X 19c are independently -C(R 19a-1 R 19a-2 )-, -O-, -S- or -N(R 19a-3 )-; R 19a , R 19b , R 19c , R 19d , R 19a-1 , R 19a-2 and R 19a-3 are independently H or C 1-6 alkyl; or R 19a , R 19b together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; or R 19c , R 19d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R 19e is C 1-6 alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl, or C 3-8 cycloalkyl; m2 is 0, 1, 2, 3, or 4; X24 is C-terminal to X25 and d-terminal to X19; R 24a is H; R 24b is X 24a is -CH2-, -0-, -S-, or -N(R 24b-3 )-; R 24b-1 , R 24b-2 , and R 24b-3 are independently H or C 1-6 alkyl; or R 24a , R 24b together with the carbon atom to which they are attached form a 4-10 membered heterocycloalkylene; q1 is 0, 1, 2, 3, 4, 5, or 6; X20 indicates that it does not exist or X23 is X21, X22, X25, X26, X27, X28, X29, and X30are independently X a is -O-, -S- or -N(R e ); R c and R e are independently H or C 1-6 alkyl; R d -(CH2) q1 -R d-1 ; or R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C d-2 substituted C 3-8 cycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R d-3 substituted C R d-1 is -OH, -CO2H, -CON(R d-4 R d-5 ), -N(R d-6 )C(=O)R d-7 , -COR d-8 , C 1-6 alkyl, haloC 1-6 alkyl, C 6- 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, C 1-6 alkyl substituted with one or more R d-9 , C 6-10 aryl substituted with one or more R d-10 , 5-10 membered heteroaryl substituted with one or more R d-11 , 4-10 membered heterocycloalkyl substituted with one or more R d-12 , 5-10 membered cycloalkenyl substituted with one or more R d- , or 5-10 membered heterocycloalkenyl substituted with one or more R 13 ; R d-4 , R d-5 , and R d-6 are independently H or C 1-6 alkyl; R d-7 and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl; R d-2 , R d-3 , R d-9 , R d-10 and R d-11 are independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, C 3-8 cycloalkyl, -NR d-10a R d-10b , C 1-6 alkoxy substituted by amino, or C d-10c alkyl substituted by one or more R 1-6 ; R d-10a and R d-10b independently H or C 1-6 alkyl; R d-10c independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; in the 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl, the heteroatom is one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. X31 is R 31 -NR 31a R 31b , -OH, C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl substituted with one or more R 31c substituents; R 31a and R 31b are independently H or C 1-6 alkyl; R 31c independently C 1-6 alkyl, halo, or oxo (=0); The polypeptide compound of Formula (II) satisfies one or more of the following:

13. The polypeptide compound of claim 12, having Formula (II): ###0002### or a pharmaceutically acceptable salt thereof. the carbonyl end is connected to X20; (1) X19 is m1 is 1, 2, or 3; X 19a is -CH2-, -O- or -S-; R 19a and R 19b are independently H or C 1-6 alkyl; the carbonyl end is connected to X21; R 19e is C 1-6 alkyl, C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl, or C 3-8 cycloalkyl; (2) X20is absent or q1 is 0, 1, 2, 3, 4, 5, or 6; R c is H; R d -(CH2) q1 -R d-1 ; or R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R d-1 is -CONH2, -NHC(=O)R d-7 , -COR d-8 , C 1-6 alkyl, 4-10 membered heterocycloalkyl, C 1-6 alkyl substituted by one or more R d-11 substituted 4-10 membered heterocycloalkyl; R d-7 and R d-8 are independently C 1-6 alkyl or 4-10 membered heterocycloalkyl; R d-11 is oxo (=0); the carbonyl end is connected to X24; (3) X22 is carbonyl end is attached to X23; R d-1 is 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R d-10 is 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R d-10 is C 1-6 alkyl or C 1-6 haloalkyl; (4) X23 is q1 is 0, 1, 2, 3, 4, 5, or 6; R c is H or C 1-6 alkyl; R d -(CH2) q1 -R d-1 ; or R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R d-1 -NHC(=O)R d-7 -COR d-8 , C 1-6 alkyl, 4-10 membered heterocycloalkyl, C 1-6 alkyl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11 ; R d-7 and R d-8 independently C 1-6 alkyl or 4-10 membered heterocycloalkyl; R d-11 independently halogen or oxo (=0); m2 is 0, 1, 2, 3, or 4; (5) X24 is C-terminal to X25 and d-terminal to X19; R 24a is H; R 24b is X 24a is -CH2-, -O- or -S-; R 24b-1 and R 24b-2 are independently H or C 1-6 alkyl; or R 24a , R 24b together with the carbon atom to which they are attached form a 4-10 membered heterocycloalkylene; the carbonyl end is connected to X26; (6) X25 is q1 is 0, 1, 2, 3, 4, 5, or 6; R d-1 is C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, substituted C d-9 aryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, substituted C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, substituted C d-11 aryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, substituted C d-12 aryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heterocycloalkenyl, substituted C d-13 aryl, 4-10 membered heterocycloalkyl, 5-10 membered cycloalkenyl, 5-10 membered heter R d-9 , R d-11 , R d-12 and R d-13 are independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-6 alkoxy substituted by amino; Preferably, X25 is carbonyl terminus to X26; s4 and s6 are independently 0, 1 or 2; s5 and s7 are independently 1 or 2; R d-9 and R d-13 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl, C 3-8 cycloalkyl, or C 1-6 alkoxy substituted with amino; (7) X27 is the carbonyl end is attached to X28; X a is -0-, -S-, or -NH-; R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, C d-2 substituted C 3- 8cycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R d-3 ; R d-2 and R d-5 independently halogen; (8) X28 is The carbonyl end is connected to X29; R c For H or C 1-6 alkyl; R d -(CH2) q1 -R d-1 ; or R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R d-1 -CO2H, C 1-6 alkyl, or C 1-6 alkyl; q1 is 0, 1, 2, 3, 4, 5, or 6; (9) X29 is carbonyl end is connected to X30; R d is -(CH2) q1 -R d-1 ; R d-1 is -OH, -CONH2, C 1-6 alkyl, haloC 1-6 alkyl, 4-10 membered heterocycloalkyl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11 substituted 4-10 membered heterocycloalkyl; R d-11 independently halogen, oxo (=0) or C 1-6 alkyl; The polypeptide compound of Formula (II) satisfies one or more of the following: (10) X30 is carbonyl end is attached to X31; R d-1 is C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclenyl, C d-9 substituted with one or more R 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclenyl, C d-10 substituted with one or more R d-13 substituted with one or more R R d-9 , R d-10 , and R d-13 are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR d-10a R d-10b , or C d-10c alkyl substituted with one or more R 1-6 ; R d-10a and R d-10b are independently H or C 1-6 alkyl; R d-10c is independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; Preferably, X30 is carbonyl terminus is attached to X31; Ring B is independently 5-6 membered heteroaryl optionally substituted with 1, 2, or 3 R d-10 substituents; R d-9 and R d-10 are independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, -NR d- 10a R d-10b or C d-10c alkyl substituted with one or more R 1-6 substituents; R d-10a and R d-10b are independently H or C 1-6 alkyl; R d-10c is independently -CO2H, -CONH2, or -CO2C 1-6 alkyl; s8, s9, and s10 are independently 1, 2, or 3; (11) X31 is R 31 -NH2, -OH, -OCH3, 14. The polypeptide compound of claim 13, having Formula (II): ###0002### or a pharmaceutically acceptable salt thereof. the carbonyl end is connected to X20; (1) X19 is the carbonyl end is connected to X21; (2) X20 is absent, the carbonyl end is connected to X22; (3) X21 is the carbonyl end is connected to X23; (4) X22 is the carbonyl end is connected to X24; (5) X23 is the carbonyl end is connected to X25, and the carbonyl end is connected to X19; (6) X24 is the carbonyl end is connected to X26; (7) X25 is the carbonyl end is connected to X27; (8) X26 is the carbonyl end is connected to X28; (9) X27 is the carbonyl end is connected to X29; (10) X28 is the carbonyl end is connected to X30; (11) X29 is the carbonyl end is connected to X31; (12) X30 is The polypeptide compound of Formula (II) satisfies any one of the following: (13) X31 is 15. The polypeptide compound of formula (II) as described in any one of claims 12-14, or a pharmaceutically acceptable salt thereof, characterized in that, the carbonyl end is connected to the amino group above; Scheme one, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-1): X19 is m1 is 1, 2, or 3; X 19a is -CH2-, -O- or -S-; R 19a and R 19b are independently H or C 1-6 alkyl; m1 is 1, 2, or 3; R 19e is C 3-8 cycloalkyl, -SO2-C 1-6 alkyl, C 1-6 alkyl, or C 3-8 cycloalkyl; m2 is 0, 1, 2, 3, or 4; Scheme two, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-2): X 24a is -CH2- or -O-; X19, X20, X28, and X31 are as defined in any one of claims 12-14; the carbonyl end is connected to the amino group above; Scheme Three, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-3): X20 is q1 is 0, 1, 2, 3, 4, 5, or 6; R c is H; R d -(CH2) q1 -R d-1 ; or R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R d-1 -NHC(=O)R d-7 -COR d-8 , 4-10 membered heterocycloalkyl, C 1-6 1-6 C alkyl, C 1-6 1-6 C alkyl substituted by one or more R d-11 4-10 membered heterocycloalkyl; R d-7 and R d-8 independently C 1-6 alkyl or 4-10 membered heterocycloalkyl; R d-11 is oxo (=0); the carbonyl end is connected to the amino group on the left; Scheme Four, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-4): X23 is q1 is 0, 1, 2, 3, 4, 5, or 6; R c is H or C 1-6 alkyl; R d -(CH2) q1 -R d-1 ; or R c , R d together with the carbon atom to which they are attached form a C 3-8 cycloalkyl; R d-1 -COR d-8 , C 1-6 alkyl, 4-10 membered heterocycloalkyl, C 1-6 alkyl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11 ; R d-8 independently C 1-6 alkyl or 4-10 membered heterocycloalkyl; R d-11 independently halogen or oxo (=0); the carbonyl end is connected to the amino group on the left; Scheme Five, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-5): X25 is ​ R d-1 is C 6-10 aryl, 4-10 membered heterocycloalkyl, C d-9 substituted with one or more R 6-10 aryl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11 substituted with one or more R R d-9 and R d-11 independently halogen, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, -SF5, C 1-6 haloalkyl or C 3-8 cycloalkyl; In the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Scheme Six, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-6): X31 is R 31 is -OH, C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl substituted with one or more R 31c substituted 4-10 membered heterocycloalkyl; R 31c independently C 1-6 alkyl, halo, or oxo (=0); In the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; X20, X23and X28are as defined in any one of claims 12-14; Preferably, X31 is Scheme Seven, the polypeptide compound as shown in formula (II) is a compound as shown in formula (II-7): X30 is carbonyl end is attached to the right nitrogen atom; R d-1 is 4-10 membered heterocycloalkyl, C d-9 substituted C 6-10 aryl, or 4-10 membered heterocycloalkyl substituted with one or more R d-11 substituted 4-10 membered heterocycloalkyl; R d-9 and R d-11 are independently halogen or C 1-6 alkyl; In the 4-10 membered heterocycloalkyl, the heteroatoms are one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

16. The polypeptide compound of claim 12, having Formula (II): ###0002### or a pharmaceutically acceptable salt thereof. The polypeptide compound of formula (II) is any one of the compounds in Table B.

17. A pharmaceutical composition comprising the polypeptide compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, or the polypeptide compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 12-16, and at least one pharmaceutical excipient.

18. Use of the polypeptide compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, or the polypeptide compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 12-16, for the manufacture of a medicament for the prevention and / or treatment of an interleukin-23 associated disease; preferably an autoimmune disease, such as psoriasis, arthritis or inflammatory bowel disease.

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