Manufacturing and applications of interleukin-23 receptor peptide inhibitors

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, stereoisomers or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions containing the same, and uses of the peptide inhibitors in the treatment or prevention of diseases or disorders, including inflammatory bowel disease, Crohn's disease, and psoriasis.

Description

[Technical Field]

[0001] The present invention relates to a novel peptide inhibitor of the interleukin-23 receptor and its use in the treatment or prevention of various diseases and disorders, the diseases and disorders including inflammatory bowel disease, Crohn's disease, and psoriasis. [Background technology]

[0002] Interleukin-23 (IL-23) cytokines are thought to play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). Model studies in acute and chronic IBD mice have shown that IL-23R and downstream effector cytokines play major roles in disease pathogenesis. IL-23R is expressed on various adaptive and intrinsic immune cells, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and intrinsic lymphocytes, which are abundant in the gut. On the intestinal mucosal surface, elevated IL-23R gene expression and protein levels have been found in IBD patients. Studies suggest that IL-23 mediates this role by promoting the development of pathogenic CD4+ T cell populations that produce IL-6, IL-17, and tumor necrosis factor (TNF).

[0003] The produced IL-23 is abundant in the gut and plays a crucial role in regulating the balance between resistance and immunity through T cell-dependent and T cell-independent colitis pathways by acting on helper T cell 1 (Th1) and Th17-related cytokines and inhibiting the regulatory T cell response in the gut (which is favorable to inflammation). Furthermore, IL-23 receptor (IL-23R) polymorphism has already been linked to susceptibility to inflammatory bowel disease (IBD), and its important role in the steady state of the gut has been established.

[0004] Psoriasis is a chronic skin disease affecting 2% to 3% of the population, and it has been shown to be mediated by the body's T-cell inflammatory response mechanism. IL-23 is one of several interleukins and is thought to play a crucial role in the pathogenesis of psoriasis, maintaining chronic autoimmune inflammation through the induction of interleukin-17, regulation of memory T cells, and activation of macrophages. IL-23 and IL-23R expression are increased in the tissues of psoriasis patients, and antibodies that neutralize IL-23 have been shown to exhibit IL-23-dependent inhibition of psoriasis progression in animal models of psoriasis.

[0005] IL-23 is a heterodimer consisting of a unique p19 subunit and the p40 subunit of IL-12, and it is a cytokine that develops helper T cell 1 (TH1) cells involved in interferon-γ (IFN-γ) production. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic characteristics. For example, IL-12-deficient animals are susceptible to inflammatory autoimmune diseases, while IL-23-deficient animals are resistant, which is thought to be due to a reduction in the number of CD4+ T cells that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 binds to IL-23R, which is a heterodimer receptor consisting of IL-12Rβ1 and IL-23R subunits. The binding of IL-23 to IL-23R activates the Jak-stat signaling molecules Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5. Activation of Stat4 is substantially weak, and it forms a DNA-binding Stat complex different from that of IL-12 in response to IL-23. IL-23R constitutively binds to Jak2 and binds to Stat3 in a ligand-dependent manner. Compared to IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0006] Therapeutic moieties that inhibit the IL-23 pathway have been identified and are used to treat IL-23-related diseases. Large numbers of antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab (a humanized antibody that binds to IL-23), which has been approved for use in the treatment of psoriasis. Recently, polypeptide inhibitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R have been identified. Clinical trials of Crohn's disease or psoriasis using ustekinumab and briakinumab (which targets the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which targets the unique p19 subunit of IL-23) have highlighted the potential of blocking IL-23 signaling in the treatment of human inflammatory diseases. While these findings are promising, identifying stable and selective agents that preferentially target the IL-23 pathway in the gut remains challenging, and such agents could be used to treat colitis (including Crohn's disease, ulcerative colitis, and related disorders).

[0007] Therefore, there is still a need in this field for new therapies targeting the IL-23 pathway, which can be used for the treatment and prevention of IL-23-related diseases, including autoimmune diseases. Furthermore, compounds and methods that specifically target IL-23R from the lumen side can provide therapeutic benefits to IBD patients. This invention addresses these needs by providing a novel peptide inhibitor that binds to IL-23R, inhibits binding to and signaling of IL-23, and is suitable for oral administration. [Overview of the Initiative] [Means for solving the problem]

[0008] The present invention discloses novel peptide inhibitors of the interleukin-23 receptor, stereoisomers or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions containing the same, and the uses of the peptide inhibitors in the treatment or prevention of diseases or disorders, including inflammatory bowel disease, Crohn's disease, and psoriasis.

[0009] The peptide compounds of the present invention possess protein stability, are stable against plasma proteases, epithelial proteases, gastrointestinal proteases, pulmonary surface proteases, intracellular proteases, etc., have specific targeting properties for IL-23, have a long plasma half-life, and exhibit good pharmacokinetic and pharmacodynamic properties.

[0010] The present invention relates to a cyclic peptide compound, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or dimer thereof, wherein the peptide compound has the amino acid sequence of formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (IV), formula (IV-1), and formula (V). [ka] As an option, the peptide compound is a dimer compound, and the dimer compound is formed by linking the peptide compound and the amino acid residues in the peptide compound via a polyethylene glycol chain, and the polyethylene glycol chain is [ka] And, n is selected from any integer between 0 and 99. As an option, the peptide compound may be optionally conjugated with a modifying group at position Xa1 or position Xa5. Alternatively, the peptide compound may be optionally conjugated with a modifying group at position Xa1, position Xa5, or position Xa7. In some embodiments, the modifying group is [ka] And p is selected from any integer between 0 and 50, and q is selected from any integer between 0 and 50. In some embodiments, the modifying group is [ka] And p is selected from any integer between 0 and 50, and q is selected from any integer between 0 and 50. In some embodiments, the modifying group is [ka] Here, p is selected from any integer between 0 and 5, and q is selected from any integer between 0 and 5. In some embodiments, the modifying group is [ka] And, In some embodiments, p is 1 and q is 2. Here, Xa1 and Xa6 are independently selected from Pen, Pcn, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, and Glu, and the residues between Xa1 and Xa6 either form a peptide ring by reaction or form a cyclic peptide via L1. In some embodiments, Xa1 and Xa6 are independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, and Glu, and the residues between Xa1 and Xa6 form a peptide ring through reaction. In some embodiments, Xa1 and Xa6 are independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), and Val(2-ethene), and the residues between Xa1 and Xa6 form a peptide ring through reaction. Here, the residues between Xa1 and Xa6 preferably form a peptide ring through a condensation reaction, an RCM ring-closing reaction, etc. In some embodiments, Xa1, Xa6 are selected from Pen, In some embodiments, Xa1 and Xa6 are independently selected from Asn or Ala(3-amino), In some embodiments, Xa1 is selected from Asn, and Xa6 is selected from Ala(3-amino). In some embodiments, Xa1 and Xa6 are independently selected from Ala(2-ethyne) or Ala(3-azido), In some embodiments, Xa1 is selected from Ala(3-azido) and Xa6 is selected from Ala(2-ethyne), In some embodiments, Xa1 and Xa6 are selected from Val(2-ethene), In some embodiments, Xa1, Xa6 are selected from Ala(2-ethene), In some embodiments, Xa1 and Xa6 are independently selected from Asp or Ala(3-amino), In some embodiments, Xa1 and Xa6 are selected from 2,4-diaminobutyric acid. In some embodiments, Xa1 and Xa6 are independently selected from 2,4-diaminobutyric acid or Asp, In some embodiments, Xa1 and Xa6 are independently selected from Ser or Ala(3-amino), In some embodiments, Xa1 and Xa6 are independently selected from 2,4-diaminobutyric acid or Ser. In some embodiments, Xa1 and Xa6 are selected from Ala(3-amino). In some embodiments, Xa1 and Xa6 are independently selected from Cys or Asp. In some embodiments, Xa1 and Xa6 are independently selected from Glu or Ala(3-amino), In some embodiments, Xa1 and Xa6 are independently selected from Hcys or Asp. In some embodiments, the residues Xa1 and Xa6 react [ka] This forms a structure, In some embodiments, the residues Xa1 and Xa6 react [ka] This forms a structure, In some embodiments, the residues Xa1 and Xa6 react [ka] This forms a structure, Here, [ka] The terminal is the Xa1 terminal, and Xa1 and Xa2 are, [ka] Linked via position, the NH2 terminus is linked to the protecting group, or [ka] The terminal is the Xa1 terminal, and Xa1 and Xa2 are, [ka] Linked via position, the NH2 terminus conjugates with the modifying group, In some embodiments, the modifying group conjugates with the NH2 terminus, [ka] Selected from, In some embodiments, the modifying group conjugates with the NH2 terminus,

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[0011] As a more specific first technical example of the present invention, the present invention provides a cyclic peptide compound, its stereoisomer or a pharmaceutically acceptable salt or solvate or dimer thereof, wherein the peptide compound has the amino acid sequence of formula (I), [ka] Here, Xa1 and Xa6 are independently selected from Pen, Pcn, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, and Glu, and the residues of Xa1 and Xa6 either form a peptide ring by reaction or form a cyclic peptide via L1, and in some embodiments, Xa1 and Xa6 are independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, and Glu, and the residues of Xa1 and Xa6 either form a peptide ring by reaction, Xa2 is selected from Asn, His, or analogues of Asn, His, Xa3 is selected from Thr or an analogue of Thr. Xa4 is selected from Trp or an analogue of Trp, Xa5 is selected from Lys, Gln, Arg, Cit, or analogues of Lys, Gln, Cit, Arg. Xa7 is selected from Phe or an analogue of Phe, Xa8 is selected from Phe, Trp, 2-Nal, or analogues of Phe, Trp, 2-Nal. Xa9 is selected from Thp or an analogue of Thp. Xa 10 It is selected from Glu, Cys, or analogs of Glu, Cys, Xa 11 It is selected from Asn, Lys, or analogues of Asn, Lys, Xa 12 is selected from 3-Pal, Phe, Asp, or analogues of 3-Pal, Phe, Asp, Xa 13 It is selected from Sarc or an analogue of Sarc, The options are Xa1, Xa2, Xa3, Xa4, Xa5, Xa7, Xa8, Xa9, Xa 10 Xa 11 Xa 12 Xa 13 Any amino acid residue in can form one or more peptide rings by direct condensation or by linking via L1. L1 is W1-R L -Selected from W2, R L is a bond, C 1-6 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, 3-6 membered cycloalkyl group, 4-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, 6-10 membered aryl group, -(OCH2CH2) a -Selected from, the alkylene group, alkenylene group, alkylylene group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, aryl group may optionally consist of 1 to 4 R L1 It is further replaced by, in some embodiments, R L is a bond, C 1-6 Alkylene group, C 2-4 Alkenylene group, C 2-4 The alkylene group, alkenylene group, 3-6 membered cycloalkyl group, 4-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, and 6-10 membered aryl group are selected, and the alkylene group, alkenylene group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and aryl group can optionally have 1 to 4 R L1 It is further replaced by, a is selected from any integer between 0 and 10. R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4Alkoxy group, 3-6 membered cycloalkyl group, COOH, NH2, -NH-C(=O)-C 1-4 Selected from alkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1 to 4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are joined together. 1-6 Alkylene group, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 The alkylene group is selected from CO-, -C(=O)O-, or -OC(=O)-, and one or more -CH2- groups in the alkylene group are optionally -O-, -S-, or -NR W1 Substituted with 1 to 4 groups selected from - or -CO-, the alkylene group is optionally a halogen, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, R W1 H, C 1-4 Selected from alkyl groups and halogens, Furthermore, the peptide compound is optionally linked to a protecting group, The protecting group is selected from Ac, glutaryl group, succinyl group, NH2, or OH. As options, polypeptides have reactive groups Xa1, Xa6, Xa 10 A polypeptide ring containing at least two rings is formed, separated by covalent bonds formed by a molecular scaffold. As an option, the peptide compound may be optionally conjugated with a modifying group at position Xa1 or position Xa5, or as an option, the peptide compound may be optionally conjugated with a modifying group at position Xa1, position Xa5 or position Xa7. As a condition, the peptide compound is not selected from the structure (Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2), and a disulfide bond is formed between the Pen and Pen atoms.

[0012] Furthermore, the peptide compound has the amino acid sequence of formula (I), [ka] Here, Xa1 and Xa6 are independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, and Glu, and the residues between Xa1 and Xa6 form a peptide ring through reaction. Xa2 is selected from Asn, His, or analogues of Asn and His. Xa3 is selected from Thr or an analogue of Thr. Xa4 is selected from Trp or an analogue of Trp, Xa5 is selected from Lys, Gln, Arg, Cit, or analogues of Lys, Gln, Cit, Arg, and in some embodiments, Xa5 is selected from Lys, Gln, Arg, or analogues of Lys, Gln, Arg, Xa7 is selected from Phe or an analogue of Phe, Xa8 is selected from Phe, Trp, 2-Nal, or analogues of Phe, Trp, 2-Nal. Xa9 is selected from Thp or an analogue of Thp. Xa 10 It is selected from Glu, Cys, or analogs of Glu, Cys, Xa 11 It is selected from Asn, Lys, or analogues of Asn, Lys, Xa 12is selected from 3-Pal, Phe, Asp, or analogues of 3-Pal, Phe, Asp, Xa 13 It is selected from Sarc or an analogue of Sarc, The options are Xa1, Xa2, Xa3, Xa4, Xa5, Xa7, Xa8, Xa9, Xa 10 Xa 11 Xa 12 Xa 13 Any amino acid residue in can form one or more peptide rings by direct condensation or by linking via L1, and in some embodiments, Xa1, Xa2, Xa3, Xa4, Xa5, Xa7, Xa8, Xa9, Xa 10 Xa 11 Xa 12 Xa 13 Any amino acid residue in can form one or more peptide rings by being bonded via L1. L1 is W1-R L -Selected from W2, R L is a bond, C 1-6 Alkylene group, C 2-4 Alkenylene group, C 2-4 The alkylene group, alkenylene group, 3-6 membered cycloalkyl group, 4-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, and 6-10 membered aryl group are selected, and the alkylene group, alkenylene group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and aryl group can optionally have 1 to 4 R L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Alkoxy group, 3-6 membered cycloalkyl group, COOH, NH2, -NH-C(=O)-C 1-4 Selected from alkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1 to 4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are joined together.1-6 Alkylene group, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 The alkylene group is selected from CO-, -C(=O)O-, or -OC(=O)-, and one or more -CH2- groups in the alkylene group are optionally -O-, -S-, or -NR W1 Substituted with 1 to 4 groups selected from - or -CO-, the alkylene group is optionally a halogen, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, R W1 H, C 1-4 Selected from alkyl groups and halogens, Furthermore, the peptide compound is optionally linked to a protecting group, The protecting group is selected from Ac, glutaryl group, succinyl group, NH2, or OH. As options, polypeptides have reactive groups Xa1, Xa6, Xa 10 A polypeptide ring containing at least two rings is formed, separated by covalent bonds formed by a molecular scaffold. As a condition, the peptide compound is not selected from the structure (Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2), and a disulfide bond is formed between the Pen and Pen atoms.

[0013] Furthermore, the peptide compound has the amino acid sequence of formula (I), [ka] Here, Xa1 and Xa6 are independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, and Glu, and the residues between Xa1 and Xa6 form a peptide ring through reaction. Xa2 is selected from Asn, His, or analogues of Asn and His. Xa3 is selected from Thr or an analogue of Thr. Xa4 is selected from Trp or an analogue of Trp, Xa5 is selected from Lys, Gln, Arg, or analogues of Lys, Gln, and Arg. Xa7 is selected from Phe or an analogue of Phe, Xa8 is selected from Phe, Trp, 2-Nal or analogues of Phe, Trp and 2-Nal. Xa9 is selected from Thp or an analogue of Thp. Xa 10 It is selected from Glu, Cys, or analogs of Glu and Cys, Xa 11 It is selected from Asn, Lys, or analogues of Asn and Lys, Xa 12 It is selected from 3-Pal, Phe, Asp or analogs of 3-Pal, Phe and Asp, Xa 13 It is selected from Sarc or an analogue of Sarc, The options are Xa1, Xa2, Xa3, Xa4, Xa5, Xa7, Xa8, Xa9, Xa 10 Xa 11 Xa 12 Xa 13 Any amino acid residue in can form one or more peptide rings by being bonded via L1. L1 is W1-R L -Selected from W2, R L is a bond, C 1-6 Alkylene group, C 2-4 Alkenylene group, C2-4 The alkylene group, alkenylene group, 3-6 membered cycloalkyl group, 4-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, and 6-10 membered aryl group are selected, and the alkylene group, alkenylene group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and aryl group can optionally have 1 to 4 R L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Alkoxy group, 3-6 membered cycloalkyl group, COOH, NH2, -NH-C(=O)-C 1-4 Selected from alkyl groups, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1 to 4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are joined together. 1-6 Alkylene group, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 The alkylene group is selected from CO-, -C(=O)O-, or -OC(=O)-, and one or more -CH2- groups in the alkylene group are optionally -O-, -S-, or -NR W1 Substituted with 1 to 4 groups selected from - or -CO-, the alkylene group is optionally a halogen, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, R W1 H, C 1-4 Selected from alkyl groups and halogens, Furthermore, the peptide compound is optionally linked to a protecting group, The protecting group is selected from Ac, glutaryl group, succinyl group, NH2, or OH. As a condition, the peptide compound is not selected from the structure (Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2), and a disulfide bond is formed between the Pen and Pen atoms.

[0014] Furthermore, the peptide compound has the amino acid sequence of formula (I), [ka] Here, Xa1 and Xa6 are independently selected from Pen, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), and Val(2-ethene), and the residues between Xa1 and Xa6 form a peptide ring through reaction. Xa2 is selected from Asn, His, or analogues of Asn and His. Xa3 is selected from Thr or an analogue of Thr. Xa4 is selected from Trp or an analogue of Trp, Xa5 is selected from Lys or an analogue of Lys, Xa7 is selected from Phe or an analogue of Phe, Xa8 is selected from Phe, Trp, 2-Nal or analogues of Phe, Trp and 2-Nal. Xa9 is selected from Thp or an analogue of Thp. Xa 10 It is selected from Glu or an analogue of Glu, Xa 11 It is selected from Asn, Lys, or analogues of Asn and Lys, Xa 12 It is selected from 3-Pal, Phe, Asp or analogs of 3-Pal, Phe and Asp, Xa 13 It is selected from Sarc or an analogue of Sarc, The options are Xa2, Xa3, Xa4, Xa5, Xa7, Xa8, Xa9, Xa10 Xa 11 Xa 12 Xa 13 Any amino acid residue in the compound forms a peptide ring by binding via L1. L1 is W1-R L -Selected from W2, R L is a bond, C 1-6 Alkylene group, C 2-4 Alkenylene group, C 2-4 The alkylene group, alkenylene group, 3-6 membered cycloalkyl group, 4-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, and 6-10 membered aryl group are selected, and the alkylene group, alkenylene group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and aryl group can optionally have 1 to 4 R L1 It is further replaced by, R L1 These are, independently, halogen, =O, and C. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 1-4 Selected from alkoxy groups, 3-6 membered cycloalkyl groups, COOH, and NH2, the alkyl group, alkoxy group, and cycloalkyl group are optionally further substituted with 1-4 substituents selected from halogens, CN, OH, and NH2. W1 and W2 are independent of each other, and are joined together. 1-6 Alkylene group, -O-, -S-, -NR W1 -, -CONR W1 -, -NR W1 The alkylene group is selected from CO-, -C(=O)O-, or -OC(=O)-, and one or more -CH2- groups in the alkylene group are optionally -O-, -S-, or -NR W1 Substituted with 1 to 4 groups selected from - or -CO-, the alkylene group is optionally a halogen, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, R W1 H, C 1-4 Selected from alkyl groups and halogens, Furthermore, the peptide compound is optionally linked to a protecting group, The protecting group is selected from Ac, glutaryl group, succinyl group, NH2, or OH. As a condition, the peptide compound is not selected from the structure (Ac)Pen-Asn-Thr-Trp(CH3)-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH2), and a disulfide bond is formed between the Pen and Pen atoms.

[0015] A more specific second technical example of the present invention is the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the peptide compound has the amino acid sequence of formula (II) and formula (II-1). [ka] Here, the residues Xa1 and Xa6 form a peptide ring through a reaction, or the residues Xa1 and Xa6 are linked via L1 to form a peptide ring. The definitions of other bases are consistent with any of the above technical proposals.

[0016] Furthermore, the peptide compound has the amino acid sequence of formula (II-1), [ka] Here, the residues between Xa1 and Xa6 form a peptide ring through a reaction. The definitions of other bases are consistent with any of the above technical proposals.

[0017] A third, more specific technical proposal of the present invention is the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the peptide compound has the amino acid sequence of formula (III) and formula (III-1). [ka] Here, the residues Xa1 and Xa6 form a peptide ring through a reaction, or the residues Xa1 and Xa6 are linked via L1 to form a peptide ring. Furthermore, the residues of Trp(R1) and Xa5 either condense directly or are linked via L1 to form a peptide ring. Alternatively, the residues of Trp(CH3) and Lys(Ac) may condense directly or be linked via L1 to form a peptide ring. Or Xa1, Xa6, Xa 10 The molecular scaffold forms a bicyclic peptide, R1 is H, C 1-4 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups and 4- to 8-membered heterocycloalkyl groups, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with halogens, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, Furthermore, the peptide compound has the amino acid sequences of formula (III) and formula (III-1), [ka] Here, the residues between Xa1 and Xa6 form a peptide ring through a reaction. Furthermore, the residues of Trp(R1) and Xa5 are linked via L1 to form a peptide ring. Alternatively, the residues of Trp(CH3) and Lys(Ac) are linked via L1 to form a peptide ring. Or Xa1, Xa6, Xa 10 The molecular scaffold forms a bicyclic peptide, R1 is H, C 1-4 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups and 4- to 8-membered heterocycloalkyl groups, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with halogens, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, The definitions of other bases are consistent with any of the above technical proposals.

[0018] Furthermore, the peptide compound has the amino acid sequence of formula (III-1), [ka] Here, the residues between Xa1 and Xa6 form a peptide ring through a reaction. Furthermore, the residues of Trp(R1) and Xa5 are linked via L1 to form a peptide ring. Alternatively, the residues of Trp(CH3) and Lys(Ac) are linked via L1 to form a peptide ring. R1 is H, C 1-4 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups and 4- to 8-membered heterocycloalkyl groups, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with halogens, =O, C 1-4 Alkyl, halo C 1-4 Further substituted with 1 to 4 substituents selected from alkyl groups, CN, OH, and NH2, The definitions of other bases are consistent with any of the above technical proposals.

[0019] Furthermore, the peptide compound has the amino acid sequence of formula (III-1), [ka] Here, the residues between Xa1 and Xa6 form a peptide ring through a reaction. Furthermore, the residues of Trp(CH3) and Lys(Ac) are linked via L1 to form a peptide ring. The definitions of other bases are consistent with any of the above technical proposals.

[0020] A fourth, more specific technical proposal of the present invention, is a peptide compound, its stereoisomer, or a pharmaceutically acceptable salt or solvate or dimer thereof, wherein the peptide compound has the amino acid sequence of formula (IV), formula (IV-1), or formula (V). [ka] Here, the residues Xa1 and Xa6 form a peptide ring through a reaction, or the residues Xa1 and Xa6 are linked via L1 to form a peptide ring. Protecting groups are present at the N-terminus and C-terminus, or they are not. Alternatively, the N-terminus is conjugated with a modifying group, 2-Nal and Xa 12 The residues are linked via L1 to form a peptide ring, and / or Xa9 and Xa 12 The residues are linked via L1 to form a peptide ring, and / or The residues of Lys(Ac) and Xa7 are linked via L1 to form a peptide ring, and / or Xa7 and Xa 11 The residues are linked via L1 to form a peptide ring, and / or The residues of 2-Nal and Glu are linked via L1 to form a peptide ring, and / or The residues of Xa1 and Glu are linked via L1 to form a peptide ring, and / or Xa1 and Xa 11 The residues are linked via L1 to form a peptide ring, and / or Xa1 and Xa 10 The residues are linked via L1 to form a peptide ring, and / or The residues of 2-Nal and Sarc are linked via L1 to form a peptide ring, and / or The residues between Xa9 and Sarc are linked via L1 to form a peptide ring, and / or Xa 11 The residues of and Sarc are linked via L1 to form a peptide ring, and / or The residues of Xa1, Sarc and Glu are linked via L1 to form a peptide ring, and / or Or Xa1, Xa6, Xa 10 The molecular scaffold forms a bicyclic peptide, R1 is C 1-2A alkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group are selected from alkyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups are further optionally substituted with 1 to 4 substituents selected from F, Cl, Br, =O, methyl group, ethyl group, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2F, -CHF2, -CF3, CN, OH, and NH2. The conditions for this are: (1) When the N-terminal Xa1 is bonded to another amino acid residue via L1, there is no N-terminal protecting group. (2) When the C-terminal Sarc is linked to another amino acid residue via L1, there is no C-terminal protecting group. The definitions of other bases are consistent with any of the above technical proposals.

[0021] Furthermore, the peptide compound has the amino acid sequences of formula (IV) and formula (IV-1), [ka] Here, the residues between Xa1 and Xa6 form a peptide ring through a reaction. Protecting groups are present or absent at the N-terminus and C-terminus, and 2-Nal and Xa 12 The residues are linked via L1 to form a peptide ring, and / or Xa9 and Xa 12 The residues are linked via L1 to form a peptide ring, and / or The residues of Lys(Ac) and Xa7 are linked via L1 to form a peptide ring, and / or Xa7 and Xa 11 The residues are linked via L1 to form a peptide ring, and / or The residues of 2-Nal and Glu are linked via L1 to form a peptide ring, and / or The residues of Xa1 and Glu are linked via L1 to form a peptide ring, and / or Xa1 and Xa 11 The residues are linked via L1 to form a peptide ring, and / or Xa1 and Xa 10 The residues are linked via L1 to form a peptide ring, and / or The residues of 2-Nal and Sarc are linked via L1 to form a peptide ring, and / or The residues between Xa9 and Sarc are linked via L1 to form a peptide ring, and / or Xa 11 The residues of and Sarc are linked via L1 to form a peptide ring, and / or The residues of Xa1, Sarc, and Glu are linked via L1 to form a peptide ring. R1 is C 1-2 A alkyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group are selected from alkyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups are further optionally substituted with 1 to 4 substituents selected from F, Cl, Br, =O, methyl group, ethyl group, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2F, -CHF2, -CF3, CN, OH, and NH2. The conditions for this are: (1) When the N-terminal Xa1 is bonded to another amino acid residue via L1, there is no N-terminal protecting group. (2) When the C-terminal Sarc is linked to another amino acid residue via L1, there is no C-terminal protecting group. The definitions of other bases are consistent with any of the above technical proposals.

[0022] Furthermore, the peptide compound has the amino acid sequence of formula (IV-1), [ka] Here, the residues between Xa1 and Xa6 form a peptide ring through a reaction. Protecting groups are present at the N-terminus and C-terminus, or they are not. 2-Nal and Xa 12 The residues are linked via L1 to form a peptide ring, and / or Xa9 and Xa 12The residues are linked via L1 to form a peptide ring, and / or The residues of Lys(Ac) and Xa7 are linked via L1 to form a peptide ring, and / or Xa7 and Xa 11 The residues are linked via L1 to form a peptide ring, and / or The residues of 2-Nal and Glu are linked via L1 to form a peptide ring, and / or The residues of Xa1 and Glu are linked via L1 to form a peptide ring, and / or Xa1 and Xa 11 The residues are linked via L1 to form a peptide ring, and / or The residues of 2-Nal and Sarc are linked via L1 to form a peptide ring, and / or The residues between Xa9 and Sarc are linked via L1 to form a peptide ring, and / or Xa 11 The residues of and Sarc are linked via L1 to form a peptide ring, and / or The residues of Xa1, Sarc, and Glu are linked via L1 to form a peptide ring. The conditions for this are: (1) When the N-terminal Xa1 is bonded to another amino acid residue via L1, there is no N-terminal protecting group. (2) When the C-terminal Sarc is linked to another amino acid residue via L1, there is no C-terminal protecting group. The definitions of other bases are consistent with any of the above technical proposals. A fifth, more specific technical example of the present invention is the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein, Between the residues of Xa1 and Xa6, a peptide ring is formed by reaction, or a cyclic peptide is formed via L1, and between Xa4 and Xa5, Xa1 and Xa 10 , Xa8 and Xa 10 , Xa8 and Xa 12 , Xa8 and Xa 13 , Xa9 and Xa 13 Xa5 and Xa7, Xa 11 and Xa 13, Xa1 and Xa 11 , Xa7 and Xa 11 One or two sets of residues either condense directly or are linked via L1 to form a peptide ring. Or Xa1, Xa6, Xa 10 The molecular scaffold forms a bicyclic peptide, The definitions of other bases are consistent with any of the above technical proposals.

[0023] Furthermore, the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the residues between Xa1 and Xa6 form a peptide ring by reaction, and Xa4 and Xa5, Xa1 and Xa 10 , Xa8 and Xa 10 , Xa8 and Xa 12 , Xa8 and Xa 13 , Xa9 and Xa 13 Xa5 and Xa7, Xa 11 and Xa 13 , Xa1 and Xa 11 , Xa7 and Xa 11 One or two sets of residues either condense directly or are linked via L1 to form a peptide ring. Or Xa1, Xa6, Xa 10 The molecular scaffold forms a bicyclic peptide, The definitions of other bases are consistent with any of the above technical proposals.

[0024] A sixth, more specific technical proposal of the present invention, the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the peptide compound and the amino acid residues in the peptide compound are linked via a polyethylene glycol chain to form a dimer compound, and the polyethylene glycol chain is [ka] And, n is selected from any integer between 0 and 99. The definitions of other groups are consistent with any of the above technical proposals. A more specific seventh technical proposal of the present invention is the peptide compound, its stereoisomer or its pharmaceutically acceptable salt or solvate or dimer, wherein the modifying group is [ka] where p is selected from any integer between 0 and 50, q is selected from any integer between 0 and 50, and in some embodiments, the modifying group is [ka] And p is selected from any integer between 0 and 50, and q is selected from any integer between 0 and 50. The definitions of other bases are consistent with any of the above technical proposals.

[0025] Furthermore, the modifying group here is [ka] And p is selected from any integer between 0 and 5, and q is selected from any integer between 0 and 5. The definitions of other bases are consistent with any of the above technical proposals.

[0026] Furthermore, the modifying group here is [ka] And, The definitions of other bases are consistent with any of the above technical proposals.

[0027] A more specific eighth technical proposal of the present invention is the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein, The residues Xa1 and Xa6 are formed by the reaction [ka] This forms a structure, Here, [ka] The terminal is the Xa1 terminal, and Xa1 and Xa2 are, [ka] The NH2 terminus is linked via a protective group, or [ka] The terminal is the Xa1 terminal, and Xa1 and Xa2 are, [ka] Linked via position, the NH2 terminus is linked to a protecting group or the NH2 terminus is conjugated to a modifying group. Xa2 is selected from Asn, His, or an analogue of His, and the analogue of His is [ka] Selected from, or analogues of His, [ka] Selected from, or analogues of His, [ka] Selected from, Xa3 is selected from Thr, Xa4 is selected from analogs of Trp, and the analogs of Trp are [ka] Selected from, Xa5 is selected from Lys, Gln, Arg, Cit, or analogues of Arg, Lys, and the analogues of Arg, Lys are [ka] Selected from, Alternatively, the Xa5 residue can be conjugated with a modifying group. Xa7 is selected from Phe or an analogue of Phe, and the analogue of Phe is [ka] Selected from, Alternatively, the Xa7 residue can be conjugated with a modifying group. Xa8 is selected from Phe, Trp, 2-Nal, or analogs of Phe, Trp and 2-Nal, and the analogs of Phe, Trp and 2-Nal are [ka] Selected from, or [ka] Selected from, Xa9 is selected from Thp or an analogue of Thp, and the analogue of Thp is [ka] Selected from, Xa 10 It is selected from Glu or Cys, Xa 11 This is selected from Asn or Lys. Xa 12 It is selected from 3-Pal or Phe, The aforementioned molecular scaffold is, [ka] Selected from, or [ka] Selected from, The definitions of other bases are consistent with any of the above technical proposals.

[0028] Furthermore, the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the residues Xa1 and Xa6 are formed by the reaction [ka] This forms a structure, Here, [ka] The terminal is the Xa1 terminal, and Xa1 and Xa2 are, [ka] Linked via position, the NH2 terminus is linked to the protecting group, Xa2 is selected from Asn, His, or an analogue of His, where the analogue of His is [ka] Selected from, Xa4 is selected from analogs of Trp, and the analogs of Trp are [ka] Selected from, Xa5 is selected from Lys, Gln, Arg, or an analogue of Arg, and the analogue of Arg is [ka] Selected from, Xa7 is selected from Phe or an analogue of Phe, and the analogue of Phe is [ka] Selected from, Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal, and the analogs of Phe, Trp and 2-Nal are [ka] Selected from, Xa9 is selected from Thp or an analogue of Thp, and the analogue of Thp is [ka] Selected from, Xa 10 It is selected from Glu or Cys, Xa 11 This is selected from Asn or Lys. Xa 12 It is selected from 3-Pal or Phe, The aforementioned molecular scaffold is, [ka] Selected from, The definitions of other bases are consistent with any of the above technical proposals.

[0029] Furthermore, the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein, The residues Xa1 and Xa6 are formed by the reaction [ka] This structure is formed, or the residues Xa1 and Xa6 react to the reaction. [ka] This structure is formed, or the residues Xa1 and Xa6 react to the reaction. [ka] This forms a structure, Here, [ka] The terminal is the Xa1 terminal, and Xa1 and Xa2 are, [ka] Linked via position, the NH2 terminus is linked to the protecting group, Xa2 is selected from Asn, His, or an analogue of His, where the analogue of His is [ka] Selected from, Xa4 is selected from analogs of Trp, and the analogs of Trp are [ka] Selected from, Xa5 is selected from Lys, Gln, Arg, or an analogue of Arg, and the analogue of Arg is [ka] Selected from, Xa7 is selected from Phe or an analogue of Phe, and the analogue of Phe is [ka] Selected from, in some embodiments, Xa7 is selected from Phe or an analogue of Phe, the analogue of Phe is [ka] Selected from, Xa8 is selected from Phe, Trp, 2-Nal or analogs of Phe, Trp and 2-Nal, and the analogs of Phe, Trp and 2-Nal are [ka] Selected from, or analogues of the Trp, [ka] Selected from, Xa9 is selected from Thp or an analogue of Thp, and the analogue of Thp is [ka] Selected from, Xa 10 It is selected from Glu or Cys, Xa 11 This is selected from Asn or Lys. Xa 12 It is selected from 3-Pal or Phe, The definitions of other bases are consistent with any of the above technical proposals.

[0030] A ninth more specific technical proposal of the present invention is the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the molecular scaffold is [ka] Selected from, in some embodiments, the molecular scaffold is [ka] Selected from, The definitions of other bases are consistent with any of the above technical proposals.

[0031] A more specific tenth technical example of the present invention is the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein, L1 is a bond, vinyl group, propenyl group, butenyl group, -O-(CH2) r -O-(CH2) r -NH-C(=O)-, -O-(CH2) r -O-(CH2) r -, -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -NH-C(=O)-, -NH-C(=O)-, -C(=O)-(CH2)r -O-(CH2) r -, -O-(CH2) r -NH-C(=O)-(CH2) r -,-(CH2) r -O-(CH2) r -, -O-(CH2) r -NH-, C 1-6 Alkylene group, -C(=O)-, -C(=O)-(CH2) r -NH-, [ka] -(CH2) r -O-(CH2) r -NH-, -O-(CH2) r -O-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -NH-, -(CH2) r -NH-C(=O)-(CH2) r -, -C(=O)-(CH2)-(OCH2CH2) a Selected from -NH-, Furthermore, L1 consists of a bond, a vinyl group, a propenyl group, a butenyl group, and -O-(CH2) r -O-(CH2) r -NH-C(=O)-, -O-(CH2) r -O-(CH2) r -, -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -NH-C(=O)-, -NH-C(=O)-, -C(=O)-(CH2)r -O-(CH2) r -, -O-(CH2) r -NH-C(=O)-(CH2) r -,-(CH2) r -O-(CH2) r -, -O-(CH2) r -NH-, C 1-2 Alkylene group, -C(=O)-, -C(=O)-(CH2) r -NH-, [ka] -(CH2) r -O-(CH2) r -NH-, -O-(CH2) r -O-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r Selected from -NH-, Furthermore, L1 consists of a bond, a vinyl group, a propenyl group, a butenyl group, and -O-(CH2) r -O-(CH2) r -NH-C(=O)-, -O-(CH2) r -O-(CH2) r -, -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -NH-C(=O)-, -NH-C(=O)-, -C(=O)-(CH2) r -O-(CH2) r -, -O-(CH2) r -NH-C(=O)-(CH2) r -,-(CH2)r -O-(CH2) r -, -O-(CH2) r -NH-, C 1-2 Alkylene group, -C(=O)-, -C(=O)-(CH2) r -NH-, [ka] Selected from, or -(CH2) r -O-(CH2) r -NH-, -O-(CH2) r -O-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -(CH2) r Selected from -NH-, Furthermore, the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, where L1 is a bond, vinyl group, propenyl group, butenyl group, -O-(CH2) r -O-(CH2) r -NH-C(=O)-, -O-(CH2) r -O-(CH2) r -, -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -, -C(=O)-(CH2) r -O-(CH2) r -O-(CH2) r -NH-, -C(=O)-(CH2) r -O-(CH2) r -NH-C(=O)-, -NH-C(=O)-, -C(=O)-(CH2) r -O-(CH2) r -, -O-(CH2) r -NH-C(=O)-(CH2) r -,-(CH2) r -O-(CH2) r -, -O-(CH2) r -NH-, C 1-2Alkylene group, -C(=O)-(CH2) r -NH-, [ka] Selected from, or L1 is, [ka] Selected from, r is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. a is selected from 3, 4, 5, or 6. The definitions of other bases are consistent with any of the above technical proposals.

[0032] As a more specific eleventh technical proposal of the present invention, the peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein the peptide compound is selected from one of the structures in Table 1 below. Table 1: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0033] The present invention further relates to a pharmaceutical composition comprising a peptide compound or a pharmaceutically acceptable salt thereof as described in any one of the first to eleventh technical proposals described above, and a pharmaceutically acceptable carrier and / or excipient.

[0034] The present invention further relates to the application of a peptide compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, described in any one of the above-described technical proposals 1 to 11, in the manufacture of a pharmaceutical product for preventing and treating a disease or disorder in which IL-23 is overexpressed in the diseased tissue of a subject.

[0035] Furthermore, the aforementioned diseases or disorders that overexpress IL-23 include inflammatory bowel disease, Crohn's disease, and psoriasis.

[0036] The present invention further relates to a pharmaceutical composition or pharmaceutical preparation, the pharmaceutical composition or pharmaceutical preparation comprising 1 to 1500 mg of a peptide compound described in any one of the above 1 to 11 technical proposals or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0037] The present invention further relates to a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a peptide compound or a pharmaceutically acceptable salt thereof described in any one of the above 1 to 11 technical proposals, the therapeutically effective amount being preferably 1 to 1500 mg, and the disease being preferably inflammatory bowel disease, Crohn's disease, and psoriasis.

[0038] The present invention further provides compositions or pharmaceutical formulations comprising a peptide compound or a pharmaceutically acceptable salt thereof as described in any one of the above-described technical proposals, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit formulation (a unit formulation is also called a “formulation specification”).

[0039] Furthermore, the present invention provides a composition or pharmaceutical preparation comprising 1 to 1500 mg of any one of the aforementioned technical proposals, a peptide compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0040] The present invention further provides applications of the peptide compounds described in any one of the above-described technical proposals, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the prevention and treatment of diseases or disorders that overexpress IL-23 in the diseased tissue of a subject. Furthermore, the diseases or disorders that overexpress IL-23 include inflammatory bowel disease, Crohn's disease, and psoriasis.

[0041] The present invention further provides a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of any one of the aforementioned technical proposals, the peptide compound or a pharmaceutically acceptable salt thereof, the disease being preferably inflammatory bowel disease, Crohn's disease, and psoriasis, and preferably the therapeutically effective amount being 1 to 1500 mg. In some embodiments, the mammal described in the present invention does not include humans.

[0042] The “effective dose” or “therapeutic effective dose” as described in this application comprises administering a sufficient amount of the compound disclosed herein that alleviates, to some extent, one or more symptoms of the disease or disorder being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, the “effective dose” for therapeutic use is the amount of a composition containing the peptide compound disclosed herein or a pharmaceutically acceptable salt thereof, necessary to provide a clinically significant reduction of disease symptoms. Examples of therapeutically effective doses include 1-1500mg, 1-1400mg, 1-1300mg, 1-1200mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 1-500mg, 1-400mg, 1-300mg, 1-250mg, 1-200mg, 1-150mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, and 1-20mg. g, 5~1500mg, 5~1000mg, 5~900mg, 5~800mg, 5~700mg, 5~600mg, 5~500mg, 5~400mg, 5~300mg, 5~250mg, 5~200mg, 5~1 50mg, 5~125mg, 5~100mg, 5~90mg, 5~70mg, 5~80mg, 5~60mg, 5~50mg, 5~40mg, 5~30mg, 5~25mg, 5~20mg, 10~1500mg, 10 ~1000mg, 10~900mg, 10~800mg, 10~700mg, 10~600mg, 10~500mg, 10~450mg, 10~400mg, 10~300mg, 10~250mg, 10~200 mg, 10~150mg, 10~125mg, 10~100mg, 10~90mg, 10~80mg, 10~70mg, 10~60mg, 10~50mg, 10~40mg, 10~30mg, 10~20mg, 20 ~1500mg, 20~1000mg, 20~900mg, 20~800mg, 20~700mg, 20~600mg, 20~500mg, 20~400mg, 20~350mg, 20~300mg, 20~25 0mg, 20~200mg, 20~150mg, 20~125mg, 20~100mg, 20~90mg, 20~80mg, 20~70mg, 20~60mg, 20~50mg, 20~40mg, 20~30mg,This includes, but is not limited to, 50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 50-100mg, 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, and 100-200mg. In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the peptide compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of the peptide compound described in the present invention or a pharmaceutically acceptable salt thereof, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit formulation (the amount of the active ingredient in the unit formulation is also called the "formulation specification"). In some embodied forms, the pharmaceutical composition is available in doses of 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, This includes, but is not limited to, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg of the peptide compounds of the present invention or pharmaceutically acceptable salts thereof.

[0043] A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of the peptide compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably inflammatory bowel disease, Crohn's disease, and psoriasis.

[0044] A method for treating a disease in a mammal or a human, the method comprising administering to a subject a daily dose of a peptide compound of the present invention which is a pharmaceutical product or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, the daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose is 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 1 This includes, but is not limited to, daily doses of 00-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. In some embodiments, the daily dose is 1 mg / day. This includes, but is not limited to, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, and 1500mg / day.

[0045] The present invention relates to a kit, which may comprise a composition in the form of a single dose or multiple doses, the kit comprising the peptide compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or its stereoisomer or pharmaceutically acceptable salt is the same as the amount in the pharmaceutical composition.

[0046] In the present invention, the amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt is, in each case, calculated in terms of the form of the free base.

[0047] "Formulation specifications" refer to the weight of the active ingredient contained in one unit formulation, one tablet formulation, or any other unit formulation.

[0048] term Unless otherwise specified in this invention, the terms used in this invention have the following meanings.

[0049] In the present invention, "peptide" broadly refers to a sequence in which two or more amino acids are linked via peptide bonds. It should be understood that this term does not imply an amino acid polymer of a specific length, nor is it intended to imply or distinguish whether a polypeptide is produced using recombinant technology, chemical synthesis, or enzymatic synthesis, or whether it is naturally occurring.

[0050] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogens in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogens in the groups and compounds described in the present invention may be optionally further substituted with one or more corresponding isotopes, where the isotope of carbon is, 12 C and, 13 C and, 14 It contains C, and its isotopes include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and its isotopes include 16 O and, 17 O and, 18 It contains O, and the sulfur isotopes are 32 S and, 33 S and, 34 S and, 36 It contains S, and the isotopes of nitrogen are 14 N and 15 It contains N, and the isotopes of fluorine are 19 It is F, and the isotope of chlorine is, 35 Cl and37 It contains Cl, and the isotope of bromine is, 79 Br and 81 The compounds disclosed herein may be prepared by standard methods known in the art.

[0051] The term "dimer" as used in this invention broadly refers to a peptide containing two or more monomer subunits. Some dimers contain two DRPs. The dimers of this invention include homodimers and heterodimers. The monomer subunits of a dimer may be linked at their C-terminus or N-terminus, or via internal amino acid residues. Each monomer subunit of a dimer may be linked via the same site, or each may be linked via different sites (e.g., C-terminus, N-terminus, or internal site).

[0052] As used herein, the terms "cyclization" or "peptide ring" refer to such a reaction, in which a portion of the polypeptide molecule is linked to another portion of the polypeptide molecule to form a closed ring, or a portion of the polypeptide molecule is linked to several other portions of the polypeptide molecule to form multiple closed rings, for example, via disulfide bridges or other similar bonds or linkers.

[0053] In the invention, "Ac" refers to an "acetyl group". The terms “derivative” or “analog” as used herein refer to products derived by the substitution of a hydrogen atom or group of atoms in a compound with another atom or group of atoms. It should be understood that amino acid analogs of peptide compounds as defined herein fall within the scope of the present invention. Examples of such appropriately modified amino acid derivatives include N-terminal and / or C-terminal modifications, substitution of one or more amino acid residues with one or more unnatural amino acid residues (e.g., substitution of one or more polar amino acid residues with one or more isosteres or isoelectron amino acids, substitution of one or more nonpolar amino acid residues with other unnatural isosteres or isoelectron amino acids), addition of spacer groups, substitution of one or more oxidation-resistant amino acid residues with one or more oxidation-sensitive amino acid residues, substitution of one or more amino acid residues with alanine, substitution of one or more L-amino acid residues with one or more D-amino acid residues, N-alkylation of one or more amide bonds in bicyclic peptide ligands, and surrogate bonding. This includes one or more modifications selected from those which involve substituting one or more peptide bonds with a bond, modifying the length of the peptide skeleton, substituting or replacing hydrogen atoms on the α-carbon of one or more amino acid residues with another chemical group, functionalizing amino acids such as glycine, thiol, carboxylic acid, and phenol reactive reagents, introducing or substituting amino acids to introduce orthogonal reactivity suitable for functionalization, for example, amino acids having azide or alkyne groups may be functionalized at the alkyne or azide moiety.

[0054] Unless otherwise specified, all amino acids are used in their L-stereoconfiguration.

[0055] For some commonly encountered amino acid names and their three-letter and one-letter abbreviations, please refer to the table below.

[0056] [Table 1]

[0057] 2-Nal:

change

change

change

change

change

change

change

change

change

change

change

[0058] "Pharmaceutical composition" means one or more of the compounds herein or their stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, or mixtures with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and / or excipients.

[0059] A "carrier" refers to a system that does not cause significant irritation to the living body, does not cause the loss of the biological activity and properties of the administered compound, alters the method of drug administration to the human body and its distribution within the body, controls the rate of drug release, and delivers the drug to the target organ. Non-limited examples include microcapsules and microspheres, nanoparticles, and liposomes.

[0060] "Excipients" are substances that are not therapeutic agents themselves, but are added to pharmaceutical compositions as diluents, excipients, adhesives and / or mediators to improve their treatment and preservation properties, or to allow or facilitate the formation of a dosage form for administration. As is known to those skilled in the art, medicinal excipients can provide a variety of functions and may be described as wetting agents, buffers, suspension aids, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners. Examples of medicinal excipients include: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., sodium cross-linked carboxymethylcellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa (9) Fat, suppository wax, (10) Oils, such as peanut oil, cottonseed oil, safflower oil, goa oil, olive oil, corn oil and soybean oil, (11) Glycols, such as propylene glycol, (12) Polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol, (13) Esters, such as ethyl oleate and ethyl laurate, (14) Agar, (15) Buffers, such as magnesium hydroxide and aluminum hydroxide, (16) Alginic acid, (17) Water for endotoxin testing, (18) Isotonic saline solution, (19) Ringer's solution, (20) Ethanol, (21) pH buffer solution, (22) Polyesters, polycarbonates and / or polyanhydrides, and (23) Other non-toxic and suitable substances used in pharmaceutical formulations, but not limited to these. [Modes for carrying out the invention]

[0061] The present invention will be described in detail below with reference to examples. Unless specific conditions are specified in the examples, the experiments were carried out according to general experimental methods. The examples given are for the purpose of better illustrating the present invention, and it should be understood that the present invention is not limited to the examples given. Non-essential improvements and adjustments made to the embodiments by those skilled in the art based on the above description of the invention are still within the scope of protection of the present invention.

[0062] Detection method The structure of a compound is determined by mass spectrometry (MS).

[0063] MS measurements were performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM). Explanation of abbreviations: DCM: Dichloromethane DMF: N,N-dimethylformamide DIEA: N,N-diisopropylethylamine MeOH: methanol TFA: Trifluoroacetic acid DMSO: Dimethyl sulfoxide DIC: N,N'-Diisopropylcarbodiimide HOBT: 1-hydroxybenzotriazole HOAT: N-hydroxy-7-azabenzotriazole Intermediate 1: [ka]

[0064] Step 1: Sodium nitrite (42.14 g, 610.7 mmol) was added to DMF (300 mL) and water (400 mL), the mixture was purged with nitrogen gas, and hydrochloric acid (2 mol / L, 103 mL) was added dropwise at 0°C. Compound 1a (10 g, 76.3 mmol) was dissolved in DMF (300 mL) and added dropwise to the reaction solution within 2 hours. The reaction was allowed to proceed to room temperature, stirred overnight, and the completion of raw material consumption was detected by spot plate. Water (2 L) was added, and the mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, spin-dried, and separated and purified by silica gel chromatography column (EA:PE = 5:1) to obtain compound 1b (7.4 g, 60.6%). LC-MS (ESI): m / z = 161.0 [M+H] + .

[0065] Step 2: Compound 1b (7.4 g, 45.9 mmol) was dissolved in dichloromethane (100 mL), triethylamine (7 g, 68.9 mmol) and di-tert-butyl dicarbonate (12 g, 55.2 mmol) were added, and the mixture was stirred while it was allowed to react overnight. Then, dichloromethane (100 mL) was added to dilute the mixture, and it was washed three times with water (100 mL). The organic phase was then concentrated to obtain compound 1c (10 g, 83.2%). LC-MS (ESI): m / z = 261.0 [M+H] + .

[0066] Step 3: Dissolve (±)benzyloxycarbonyl-α-phosphonoglycine trimethyl (14 g, 42.3 mmol) in dichloromethane (100 mL), purge with nitrogen gas, add DBU (6.43 g, 42.3 mmol), stir for 30 min, then dissolve compound 1c (10 g, 38.4 mmol) in dichloromethane (100 mL), add dropwise to the reaction, continue stirring overnight, dilute the reaction mixture with dichloromethane (100 mL), wash with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and spin dry. Separation and purification by silica gel chromatography column (EA:PE = 3:1) yielded compound 1d (12 g, 67.1%). LC-MS (ESI): m / z = 466.2[M+H] + .

[0067] Step 4: Compound 1d (5 g, 10.74 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), and (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphanbenzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.5 g, 0.69 mmol) was added. The mixture was then autoclaved and filled with hydrogen gas until the pressure reached approximately 4.0 bar, stirred at room temperature for 3 hours, filtered to remove the solid, and the reaction solution was concentrated to obtain compound 1e (5 g, 99.8%). LC-MS (ESI): m / z = 468.2[M+H] + .

[0068] Step 5: Compound 1e (5 g, 10.69 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), palladium carbon (10%, 1 g) was added, the mixture was stirred overnight in a hydrogen gas environment, and the solid was removed by filtration. The reaction solution was then spin-dried to obtain compound 1f (3.2 g, 89.7%). LC-MS (ESI): m / z = 334.2[M+H] + .

[0069] Step 6: Add compound 1f (3.2 g, 9.60 mmol) to dichloromethane (30 mL), add trifluoroacetic acid (10 mL) dropwise, stir the reaction at room temperature for 2 hours, monitor the completion of raw material consumption by LC-MS, and directly spin-dry to obtain 1 g of crude compound, which was used directly in the next step without purification. LC-MS (ESI): m / z = 234.1 [M+H] + .

[0070] Step 7: Dissolve 1 g of compound (2.2 g, 9.43 mmol) in tetrahydrofuran (20 mL), add lithium hydroxide monohydrate (1.58 g, 37.7 mmol) and water (20 mL), stir the reaction overnight at room temperature, extract impurities with ethyl acetate (10 mL x 3), adjust the aqueous phase pH to neutral with dilute hydrochloric acid (1 N), precipitate the product, filter and dry to obtain compound 1h (2 g, 96.7%). LC-MS (ESI): m / z = 220.1 [M+H] + .

[0071] Step 8: Compound 1h (2 g, 9.12 mmol) was dissolved in a mixed solution of acetonitrile (20 mL) and water (20 mL), sodium bicarbonate (3.83 g, 45.6 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (4.6 g, 13.7 mmol) were added, and the reaction was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to neutral, and the mixture was concentrated under vacuum at 40°C, spin-dried to remove most of the acetonitrile, filtered, and the solid was collected to obtain the crude product. The product was separated and purified by silica gel chromatography column (DCM:MeOH = 10:1) to obtain intermediate 1 (2.5 g, 62.1%).

[0072] LC-MS (ESI): m / z = 442.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 12.81 (s,1H),7.87 (d,2H),7.68 - 7.57 (m,3H),7.54 - 7.43 (m,1H),7.42 - 7.35 (m,2H),7.32 - 7.22 (m,2H),7.06 (d,1H),6.99 - 6.90 (m,1H),4.44 - 4.34 (m,1H),4.21 - 3.93 (m,3H),3.43 - 3.25 (m,2H),2.47 (s,3H). Intermediate 2: [ka]

[0073] Step 1: Compound 2a (10.0 g, 75.65 mmol) was dissolved in dichloromethane (100 mL), and SnCl4 (23.7 g, 90.78 mmol) was added dropwise to the reaction mixture, and the temperature was lowered to 0°C. After 5 minutes, 1,1-dichlorodimethyl ether (9.6 g, 83.22 mmol) was added dropwise, and the mixture was stirred at 0°C for 3 hours. After the reaction was complete, 200 mL of water was added to the reaction system, and the resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 2b (4.1 g, 33.8%) was obtained by column chromatography (EA:PE = 1:50). LC-MS (ESI): m / z = 161.1[M+H] + .

[0074] Step 2: (±)benzyloxycarbonyl-α-phosphonoglycine trimethyl (9.9 g, 29.93 mmol) was dissolved in dichloromethane (100 mL), purged with nitrogen gas, and then DBU (4.9 g, 32.42 mmol) was added. The mixture was stirred for 30 minutes, and then compound 2b (4.0 g, 24.94 mmol) was dissolved in dichloromethane (100 mL) and added dropwise to the reaction. The mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (100 mL), washed with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was separated and purified by silica gel chromatography column (EA:PE = 5:1) to obtain compound 2c (6.1 g, 66.9%). LC-MS (ESI): m / z = 366.2[M+H] + .

[0075] Step 3: Compound 2c (6.0 g, 16.42 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL). (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphanbenzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.6 g, 0.84 mmol) was added, and the mixture was autoclaved with hydrogen gas until the pressure reached approximately 4.0 bar. The mixture was stirred at room temperature for 3 hours, filtered to remove the solid, and the reaction solution was concentrated to obtain compound 2d (5.9 g, 98%). LC-MS (ESI): m / z = 368.2[M+H] + .

[0076] Step 4: Compound 2d (5.9 g, 9.08 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), palladium carbon (10%, 1 g) was added, the mixture was stirred overnight in a hydrogen gas environment, and the solid was removed by filtration. The reaction solution was then spin-dried to obtain compound 2e (3.5 g, 93.4%). LC-MS (ESI): m / z = 234.1 [M+H] + .

[0077] Step 5: Compound 2e (3.5 g, 15.00 mmol) was dissolved in tetrahydrofuran (35 mL), lithium hydroxide monohydrate (1.4 g, 59.71 mmol) and water (25 mL) were added, and the reaction was stirred overnight at room temperature. Impurities were extracted with ethyl acetate (20 mL x 3), and the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (1 N). The product was precipitated, filtered, and dried to obtain compound 2f (2.8 g, 85.1%). LC-MS (ESI): m / z = 220.1 [M+H] + .

[0078] Step 6: Compound 2f (2.7 g, 12.31 mmol) was dissolved in a mixed solution of acetonitrile (25 mL) and water (25 mL), sodium bicarbonate (10.3 g, 123.10 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (5.0 g, 14.77 mmol) were added, and the reaction was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to neutral, and the mixture was concentrated under vacuum at 40°C, spin-dried to remove most of the acetonitrile, filtered, and the solid was collected to obtain the crude product. The product was separated and purified by silica gel chromatography column (DCM:MeOH = 12:1) to obtain intermediate 2 (1.3 g, 23.9%).

[0079] LC-MS (ESI): m / z = 442.2[M+H] + . 1 H NMR (400MHz,MeOD) δ 7.77 (d,2H),7.60 - 7.48 (m,2H),7.37 (t,2H),7.26 (q,2H),6.94 - 6.78 (m,3H),4.46 - 4.21 (m,2H),4.14 (dt,2H),3.13 (dd,1H),2.86 (dd,1H),2.67 (s,4H),1.71 (s,4H). Intermediate 3: [ka]

[0080] Step 1: Compound 3a (10.0 g, 73.43 mmol) was dissolved in dichloromethane (100 mL), and TiCl4 (25.5 g, 134.38 mmol) was added dropwise to the reaction mixture, and the temperature was lowered to 0°C. After 5 minutes, 1,1-dichlorodimethyl ether (9.4 g, 81.51 mmol) was added dropwise, and the mixture was stirred at 0°C for 3 hours. After the reaction was complete, 200 mL of water was added to the reaction system, and the resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 3b (5.58 g, 46.3%) was obtained by column chromatography (EA:PE = 1:4). LC-MS (ESI): m / z = 163.2[M+H]+ .

[0081] Step 2: Compound 3b (3.0 g, 18.27 mmol), tert-butyl (2-bromoethyl)carbamate (4.9 g, 21.91 mmol), potassium carbonate (5.1 g, 36.54 mmol), and sodium iodide (0.8 g, 5.47 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at 25°C for 16 hours. After the reaction was complete, 100 mL of water was added, the reaction mixture was extracted three times with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 3c (4.9 g, 87%) was obtained by column chromatography (EA:PE = 4:1). LC-MS (ESI): m / z = 306.1[M+H] + .

[0082] Step 3: Dissolve (±)benzyloxycarbonyl-α-phosphonoglycine trimethyl (6.2 g, 18.74 mmol) in dichloromethane (100 mL), purge with nitrogen gas, add DBU (3.1 g, 20.31 mmol), stir for 30 min, then dissolve compound 3c (4.8 g, 15.62 mmol) in dichloromethane (100 mL), add dropwise to the reaction, stir overnight, dilute the reaction mixture with dichloromethane (100 mL), wash with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and spin dry. Separation and purification by silica gel chromatography column (EA:PE=3:1) yielded compound 3d (6.1 g, 76.2%). LC-MS (ESI): m / z = 511.1[M+H] + .

[0083] Step 4: Compound 3d (6.0 g, 11.71 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL). (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphanbenzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.6 g, 0.83 mmol) was added, and the mixture was autoclaved with hydrogen gas until the pressure reached approximately 4.0 bar. The mixture was stirred at room temperature for 3 hours, filtered to remove the solid, and the reaction solution was concentrated to obtain compound 3e (5.9 g, 98%). LC-MS (ESI): m / z = 513.2[M+H] + .

[0084] Step 5: Compound 3e (5.9 g, 11.46 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), palladium carbon (10%, 1 g) was added, the mixture was stirred overnight in a hydrogen gas environment, and the solid was removed by filtration. The reaction solution was then spin-dried to obtain compound 3f (3.7 g, 84.5%). LC-MS (ESI): m / z = 379.4[M+H] + .

[0085] Step 6: Compound 3f (3.7g, 9.72 mmol) was dissolved in tetrahydrofuran (25 mL), lithium hydroxide monohydrate (1.2 g, 48.6 mmol) and water (25 mL) were added, and the reaction was stirred overnight at room temperature. Impurities were extracted with ethyl acetate (15 mL x 3), and the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (1 N). The product was precipitated, filtered, and dried to obtain compound 3 g (3.2 g, 89.8%). LC-MS (ESI): m / z = 365.2[M+H] + .

[0086] Step 7: 3 g of compound (2.7 g, 7.41 mmol) was dissolved in a mixed solution of acetonitrile (25 mL) and water (25 mL). Sodium bicarbonate (6.2 g, 74.16 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (3.3 g, 9.63 mmol) were added, and the reaction was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to neutral, and the mixture was concentrated under vacuum at 40°C. The mixture was then spin-dried to remove most of the acetonitrile, filtered, and the solid was collected to obtain the crude product. The product was separated and purified by silica gel chromatography column (DCM:MeOH = 10:1) to obtain intermediate 3 (2.7 g, 62.1%).

[0087] LC-MS (ESI): m / z = 587.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 12.65 (s,1H),7.88 (d,2H),7.67 (s,2H),7.41 (d,2H),7.36 - 7.24 (m,2H),7.03 - 6.88 (m,2H),6.65 (d,1H),4.26 - 4.09 (m,4H),3.91 (s,2H),3.28 (s,2H),2.99 (d,1H),2.90 - 2.68(m,5H),2.51 (s,1H),1.98 (s,2H),1.39 (s,9H). Intermediate 4: [ka]

[0088] Step 1: Compound 4a (2.0 g, 14.09 mmol) and N-(tert-butoxycarbonyl)ethanolamine (4.5 g, 28.18 mmol) were dissolved in N,N-dimethylacetamide (20 mL), potassium carbonate (3.9 g, 28.18 mmol) was added, and the mixture was stirred at 80°C under microwave conditions for 2 hours. After the reaction was complete, 20 mL of water was added to the reaction system, and the resulting solution was extracted three times with ethyl acetate (40 × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 4b (0.9 g, 24.0%) was obtained by column chromatography (PE:PE = 4:1). LC-MS (ESI): m / z = 267.2[M+H] + .

[0089] Step 2: (±)benzyloxycarbonyl-α-phosphonoglycine trimethyl (6.1 g, 18.47 mmol) was dissolved in dichloromethane (100 mL), purged with nitrogen gas, and then DBU (3.1 g, 20.02 mmol) was added. The mixture was stirred for 30 minutes, and compound 4b (4.1 g, 15.40 mmol) was dissolved in dichloromethane (100 mL) and added dropwise during the reaction. The mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (100 mL), washed with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was separated and purified by silica gel chromatography column (EA:PE = 3:1) to obtain compound 4c (4.5 g, 62.0%). LC-MS (ESI): m / z = 472.2[M+H] + .

[0090] Step 3: Compound 4c (4.4 g, 9.33 mmol) was dissolved in a mixed solution of methanol (40 mL) and dichloromethane (20 mL), and (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphanbenzene(cyclooctadiene)trifluoromethanesulfonate rhodium (0.6 g, 0.83 mmol) was added. The mixture was then autoclaved and filled with hydrogen gas until the pressure reached approximately 4.0 bar, stirred at room temperature for 3 hours, filtered to remove the solid, and the reaction solution was concentrated to obtain compound 4d (4.3 g, 97%). LC-MS (ESI): m / z = 474.2 [M + H] + .

[0091] Step 4: Compound 4d (4.3 g, 9.08 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), palladium carbon (10%, 1 g) was added, the mixture was stirred overnight in a hydrogen gas environment, and the solid was removed by filtration. The reaction solution was then spin-dried to obtain compound 4e (2.9 g, 94.1%). LC-MS (ESI): m / z = 340.3 [M+H] + .

[0092] Step 5: Compound 4e (3.0 g, 8.84 mmol) was dissolved in tetrahydrofuran (25 mL), lithium hydroxide monohydrate (0.9 g, 37.6 mmol) and water (25 mL) were added, and the reaction was stirred overnight at room temperature. Impurities were extracted with ethyl acetate (20 mL x 3), and the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (1 N). The product was precipitated, filtered, and dried to obtain compound 4f (2.4 g, 83.4%). LC-MS (ESI): m / z = 326.2[M+H] + .

[0093] Step 6: Compound 4f (2.4 g, 7.38 mmol) was dissolved in a mixed solution of acetonitrile (20 mL) and water (20 mL), sodium bicarbonate (6.2 g, 73.8 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (3.2 g, 9.59 mmol) were added, and the reaction was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to neutral, and the mixture was concentrated under vacuum at 40°C, spin-dried to remove most of the acetonitrile, filtered, and the solid was collected to obtain the crude product. The product was separated and purified by silica gel chromatography column (DCM:MeOH = 10:1) to obtain intermediate 4 (1.9 g, 47.0%).

[0094] LC-MS (ESI): m / z = 548.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 12.80 (s,1H),8.02 (d,1H),7.88 (d,2H),7.73 (d,1H),7.66 - 7.58 (m,3H),7.41 (t,2H),7.30 (dd,2H),6.93 (s,1H),6.70 (d,1H),4.24 - 4.09 (m,6H),3.26 (q,2H),3.02 (dd,1H),2.87 - 2.75 (m,1H),1.37 (s,9H). Intermediate 5: [ka]

[0095] Step 1: A known compound 5a (5 g, 0.043 mol) was added to trifluoroethanol (50 mL), and then tert-butylisocyanide (7.15 g, 0.086 mol) and ammonium acetate (13.3 g, 0.172 mol) were added, and the 3d reaction was carried out at room temperature. Complete reaction was shown by TLC, the reaction mixture was concentrated to dry, and purified by C18 reversed-phase column. The compositions of mobile phases A and B were determined to be acetonitrile for mobile phase A and water (containing 0.1% TFA) for mobile phase B, and the mixture was separated and purified by (A / B = 35 / 65) to obtain compound 5b (9.5 g, yield: 85%). LCMS m / z=259.2[M+1] + .

[0096] Step 2: Compound 5b (7.5 g, 0.029 mol) was added to 6N HCl (75 mL) and reacted overnight at 100°C. Complete reaction of the starting materials was shown by LC-MS. The mixture was concentrated to dry and purified by C18 reversed-phase column chromatography. The mobile phases A and B were separated by (A / B = 5 / 95), with mobile phase A being acetonitrile and mobile phase B being water (containing 0.1% TFA), and the mixture was purified to obtain compound 5c (4.6 g, yield: 98%). LCMS m / z=162.1[M+1] + .

[0097] Step 3: Compound 5c (4.6 g, 0.028 mol) was added to acetonitrile (46 mL) and water (46 mL), and then 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-Osu) (10.5 g, 0.03 mol) and sodium bicarbonate (24.4 g, 0.28 mol) were added, and the mixture was reacted overnight at room temperature. The complete reaction was monitored by LC-MS, the pH was adjusted to 5-6 with 1N HCl, the mixture was concentrated to remove acetonitrile, ethyl acetate (200 mL) was added for extraction, the ethyl acetate phase was concentrated to dry, and the mixture was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 5d (6.3 g, yield: 58%). LCMS m / z=384.2[M+1] + .

[0098] Step 4: Compound 5d (5.0 g, 0.013 mol) was added to dichloromethane (50 mL), and then methachloroperbenzoic acid 85% (m-CPBA) (7.9 g, 0.039 mol) was added little by little, and the mixture was reacted overnight at room temperature. The complete reaction was monitored by LC-MS, the reaction (100 mL) was quenched with sodium thiosulfate solution, stirred for 30 min, and ethyl acetate (200 mL) was added for extraction. The ethyl acetate phase was concentrated to dry. The mixture was separated and purified using a liquid preparative column (liquid preparative conditions: C18 reversed-phase preparative column, mobile phase: deionized water containing 0.1% trifluoroacetic acid (A), acetonitrile containing 0.1% trifluoroacetic acid (B), gradient elution, B content = 5%~70%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 °C, retention time: 8.54 min) to obtain intermediate 5 (3.5 g, yield: 64%).

[0099] 1 H NMR (400MHz,CDCl3) δ 7.78-7.76 (d,2H),7.60-7.58 (d,2H),7.43-7.40 (t,2H),7.34-7.31 (t,2H),4.52-4.51 (d,2H),4.22-4.19 (t,1H),3.03 (s,4H),2.60-2.50 (m,4H). LCMS m / z = 433.1[M+H2O] + . Intermediate 6: [ka]

[0100] Step 1: Compound 6a (10.0 g, 51.28 mmol), cyclopropylboronic acid (8.8 g, 102.56 mmol), and cesium carbonate (50.46 g, 153.84 mmol) were added to dioxane (200 mL) and water (40 mL). 1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (3.8 g, 5.13 mmol) was added, the mixture was purged with nitrogen gas, and the reaction was allowed to proceed overnight at 80°C. After concentration, the mixture was separated and purified by silica gel chromatography column (EA:PE=5:2) to obtain compound 6b (7.0 g, 86.9%). LC-MS (ESI): m / z = 158.1 [M+H] + .

[0101] Step 2: DMF (6.5 g, 89.18 mmol) was added dropwise to phosphorus oxychloride (70 mL) under conditions of 0°C. After 10 minutes, compound 6b (7.0 g, 44.59 mmol) was dissolved in phosphorus oxychloride (30 mL) under conditions of 0°C. The mixture was reacted at room temperature for 1 hour, neutralized to pH 7-8 with saturated sodium bicarbonate under an ice bath, extracted with dichloromethane (100 mL x 3), the organic phases were combined, spin-dried, concentrated, and then separated and purified by silica gel chromatography column (EA:PE = 5:2) to obtain compound 6c (4.5 g, 54.5%). LC-MS (ESI): m / z = 186.2[M+H] + .

[0102] Step 3: Compound 6c (4.5 g, 24.32 mmol) was dissolved in acetonitrile (50 mL), di-tert-butyl dicarbonate (10.6 g, 48.64 mmol) was added, and then 4-dimethylaminopyridine (3.6 g, 29.18 mmol) was added. The mixture was reacted at room temperature for 2 hours, extracted with dichloromethane (100 mL x 3), the organic phases were combined, spin-dried, concentrated, and then separated and purified by silica gel chromatography column (EA:PE = 5:1) to obtain compound 6d (6.0, 86.9%). LC-MS (ESI): m / z=230.2[M-56+H] + .

[0103] Step 4: Dissolve (±)benzyloxycarbonyl-α-phosphonoglycine trimethyl (7.0 g, 21.05 mmol) in dichloromethane (100 mL), purge with nitrogen gas, add DBU (6.43 g, 42.3 mmol), stir for 30 min, then dissolve compound 6d (6.0 g, 21.05 mmol) in dichloromethane (100 mL), add dropwise to the reaction, continue stirring overnight, dilute the reaction mixture with dichloromethane (100 mL), wash with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and spin dry. Separation and purification by silica gel chromatography column (EA:PE=3:1) yielded compound 6e (5.7 g, 55.3%). LC-MS (ESI): m / z = 491.3[M+H] + .

[0104] Step 5: Compound 6e (5.7 g, 11.6 mmol) was dissolved in methanol (50 mL), and (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanephosphanbenzene(cyclooctadiene)trifluoromethanesulfonate rhodium (420 mg, 0.58 mmol) was added. The mixture was then autoclaved with hydrogen gas until the pressure reached approximately 2.5 MPa, stirred overnight at room temperature, filtered to remove the solid, and the reaction solution was concentrated to obtain compound 6f (5.7 g, 99.9%). LC-MS (ESI): m / z = 493.2 [M + H] + .

[0105] Step 6: Compound 6f (3.0 g, 6.1 mmol) was dissolved in dichloromethane (50 mL), triethylamine (3.1 g, 30.5 mmol) was added in an ice bath, and then iodotrimethylsilane (6.1 g, 30.5 mmol) was added. The mixture was stirred at room temperature for 16 hours, concentrated at room temperature, and then methanol (5 mL) was added to quench the reaction. The compound was separated and purified using a C18 reversed-phase column (water containing 0.5% TFA:acetonitrile = 3:10) to obtain compound 6 g (1.5 g, 95.5%). LC-MS (ESI): m / z = 259.1 [M+H] + .

[0106] Step 7: 6 g (1.5 g, 5.8 mmol) of the compound was dissolved in tetrahydrofuran (20 mL), lithium hydroxide monohydrate (1.58 g, 37.7 mmol) and water (20 mL) were added, the reaction was stirred at room temperature for 2 hours, and the pH of the aqueous phase was adjusted to neutral with dilute hydrochloric acid (1 N), and the next step was carried out directly. LC-MS (ESI): m / z = 245.1 [M+H] + .

[0107] Step 8: Sodium bicarbonate (4.9 g, 58.0 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (2.9 g, 8.7 mmol) were added to the reaction mixture obtained in the previous step, and the reaction was stirred overnight at room temperature. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to 5-6, the mixture was concentrated under vacuum at 40°C, and the mixture was spin-dried to remove most of the acetonitrile. The mixture was extracted with dichloromethane (100 mL x 3), the organic phases were combined, and the mixture was spin-dried. The mixture was separated and purified by silica gel chromatography column (DCM:MeOH = 10:1) to obtain intermediate 6 (1.2 g, 2-step yield 44.4%).

[0108] LC-MS (ESI): m / z = 467.2[M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 10.83 (s,1H),7.89 - 7.85 (m,2H),7.63 (d,2H),7.42 - 7.34 (m,3H),7.32 - 7.24 (m,2H),7.16 - 6.98 (m,2H),6.88 - 6.80 (m,1H),6.60 (d,1H),4.22 - 4.14 (m,3H),4.11 - 4.05 (m,1H),3.26 - 3.19 (m,1H),3.07 - 2.98 (m,1H),2.25 - 2.15 (m,1H),1.00 - 0.92 (m,2H),0.72 - 0.62 (m, 2H). Intermediate 7 and Intermediate 8: [ka]

[0109] Step 1: Known compound 7a (20 g, 0.09 mol) was added to methanol (46 mL) and tetrahydrofuran (460 mL), and then sodium hydroxide (3.6 g, 0.09 mol) was added, and the mixture was reacted at room temperature for 18 hours. Complete reaction of the starting materials was shown by LC-MS, the reaction mixture was concentrated to dry, diluted with water (300 mL), the pH was adjusted to 5-6 with 1N HCl, ethyl acetate (300 mL) was added for extraction, the ethyl acetate phase was concentrated to dry, and purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 7b (17.8 g, yield: 95%). LCMS m / z=207.1[M+1] + .

[0110] Step 2: Compound 7b (17.8 g, 0.086 mol) was added to tetrahydrofuran (1 L), cooled to 0°C, and borane dimethyl sulfide solution (10 mol / L, 10 mL) was added dropwise. After the addition was complete, the mixture was allowed to react for 2 hours, and complete reaction of the starting materials was shown by LC-MS. Excess borane was quenched by adding methanol (30 mL) dropwise, the mixture was concentrated to dry, and ethyl acetate (500 mL) and water (500 mL) were added for extraction. The ethyl acetate phase was concentrated to dry and purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 7c (15 g, yield: 91%). LCMS m / z=215.2[M+23] + .

[0111] Step 3: Add pyridine (27.84 g, 0.352 mol) to dichloromethane (800 mL), reduce the temperature to -20°C, add trifluoromethanesulfonic anhydride (94.8 g, 0.336 mol) dropwise, and after the dropwise addition is complete, add 2-bromoethanol (40 g, 0.32 mol) to the system, stir at -20°C for 30 minutes, concentrate at a low temperature of 30°C to remove dichloromethane, dissolve the residue with MTBE, filter, concentrate the mother liquor at a low temperature of 25°C until dry, add a portion (59.2 g, 0.231 mol) to a toluene solution (440 mL) of 7c (14.8 g, 0.077 mol), add DIEA (29.6 g, 0.231 mol), and after the addition is complete, stir overnight at 90°C, and complete reaction of the starting materials was shown by TLC. The mixture was concentrated to dry, extracted with ethyl acetate (500 mL) and water (500 mL), concentrated to dry the ethyl acetate phase, and purified by column chromatography (PE:EA = 2:1) to obtain compound 7d (21.6 g, yield: 94%).

[0112] Step 4: Compound 7d (21.6 g, 0.072 mol) was added to tetrahydrofuran (430 mL), and lithium aluminum hydride (5.47 g, 0.144 mol) was added little by little. The mixture was allowed to react at room temperature for 2 hours, and the complete reaction was monitored by TLC. 5.5 mL of water was slowly added dropwise, followed by 5.5 mL of 15% sodium hydroxide solution, and finally 16.5 mL of water was added dropwise. Anhydrous sodium sulfate was added, the mixture was stirred for 30 minutes, filtered, and the mother liquor was concentrated to dry to obtain 7e (15.9 g, yield: 81%). LCMS m / z=271.2[M+1] + .

[0113] Step 5: Compound 7e (12.5 g, 0.046 mol) was added to aqueous ammonia (250 mL) and reacted at room temperature for 18 hours. The reaction was monitored by TLC to ensure that the starting materials were not completely reacted. The mixture was directly concentrated to dry to obtain crude product 7f, which was used in the next step. LCMS m / z=208.2[M+1] + .

[0114] Step 6: The crude compound 7f was added to acetonitrile (120 mL) and water (120 mL), then di-tert-butyl dicarbonate (10.0 g, 0.046 mol) and sodium carbonate (9.75 g, 0.092 mol) were added, the mixture was stirred at room temperature for 18 hours, concentrated to remove acetonitrile, extracted with ethyl acetate (200 mL), concentrated to dry, and purified by column chromatography (PE:EA = 1:1) to obtain 7 g of compound (5.4 g, yield: 38%). LCMS m / z=252.2[M+1-56] + .

[0115] Step 7: 7 g (5.4 g, 0.017 mol) of the compound was added to dichloromethane (54 mL), cooled to 0°C, carbon tetrabromide (9.7 g, 0.28 mol) and triphenylphosphine (7.7 g, 0.28 mol) were added, and the mixture was reacted at room temperature for 18 hours. The complete reaction was monitored by LC-MS. The mixture was concentrated to dry and purified by column chromatography (PE:EA = 2:1) to obtain 7 H (2.4 g, yield: 35%). LCMS m / z=314.2[M+1-56] + .

[0116] Step 8: Compound 7h (2.4 g, 0.006 mol) was added to DMF (24 mL), and then diphenylmethyleneglycine methyl ester (3.15 g, 0.012 mol) and potassium tert-butoxide (1.74 g, 0.015 mol) were added. The mixture was reacted at room temperature for 18 hours, and LC-MS was used to monitor that the starting materials had not completely reacted. Ethyl acetate (100 mL) and water (100 mL) were added for extraction. The ethyl acetate phase was backwashed twice with water, concentrated to dry, and purified by column chromatography (PE:EA = 1:1) to obtain 7i (1.8 g, yield: 51%). LCMS m / z=543.2[M+1] + .

[0117] Step 9: Compound 7i (1.8 g, 3.3 mmol) was added to tetrahydrofuran (32 mL), followed by 1N HCl (16 mL), and the mixture was reacted at room temperature for 1 hour. The complete reaction of the starting materials was monitored by LC-MS. The pH was adjusted to 8-9 with aqueous sodium carbonate solution, and ethyl acetate (100 mL) and water (50 mL) were added for extraction. The ethyl acetate phase was concentrated to dry and purified by column chromatography (DCM:MeOH = 10:1) to obtain 7j (1.25 g, yield: 100%). LCMS m / z=323.2[M+1-56] + .

[0118] Step 10: Compound 7j (1.25 g, 3.3 mmol) was added to methanol (13 mL) and water (4 mL), then lithium hydroxide (554 mg, 13.2 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 hours. The complete reaction of the starting materials was monitored by LC-MS. The reaction mixture was used directly in the next step. LCMS m / z=309.2[M+1-56] + .

[0119] Step 11: The reaction mixture from the previous step was adjusted to pH 5-6 with 1N HCl, then to pH 8-9 with aqueous sodium bicarbonate solution, and then 9-fluorenylmethyl-N-succinimidyl carbonate (1.3 g, 3.96 mmol) and sodium bicarbonate (2.77 g, 33 mmol) were added. The mixture was stirred at room temperature for 2 hours, and complete reaction of the starting materials was shown by LC-MS. The pH was adjusted to 7 with 1N HCl, and ethyl acetate (100 mL) and water (100 mL) were added for extraction. The ethyl acetate phase was concentrated to dry and purified by column chromatography (DCM:MeOH = 10:1) to obtain 1.8 g of racemic mixture. The racemic mixture was chiral-cleared. Instrument: SFC Prep 150 AP, chromatographic column: Daicel AD-H (19 mm × 250 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: methanol, isocratic elution, mobile phase B content 25%, flow rate 40 ml / min. Intermediate 7(P1) (730 mg, yield: 38%) was obtained at 4.1 min, and intermediate 8(P2) (750 mg, yield: 39%) was obtained at 4.6 min.

[0120] Intermediate 7 1 H NMR (400MHz,CDCl3) δ 7.77 - 7.75 (d,2H),7.60 - 7.57 (t,2H),7.41 - 7.37 (t,2H),7.32 - 7.29 (t,2H),4.49 - 4.41 (m,3H),4.23 - 4.20 (t,1H),3.73 -3.68 (m,6H),3.59 - 3.55 (m,2H),3.51 - 3.49 (m,2H),3.31 - 3.27 (m,2H),2.22 - 2.04 (m,2H),1.45 (s,9H). LCMS m / z=487.2[M+1-100] + .

[0121] Intermediate 8 1H NMR (400MHz,CDCl3) δ 7.75 - 7.73 (d,2H),7.59 - 7.56 (t,2H),7.39 - 7.36 (t,2H),7.30 - 7.27 (t,2H),4.47 - 4.39 (m,3H),4.22 - 4.19 (t,1H),3.70 - 3.64 (m,6H),3.57 - 3.53 (m,2H),3.51 - 3.49 (m,2H),3.31 - 3.27 (m,2H),2.20 - 2.03 (m,2H),1.44 (s,9H). LCMS m / z=487.2[M+1-100] + . Intermediate 9 and Intermediate 10: [ka]

[0122] Step 1: Compound 9a (10.4 g, 70.5 mmol) was dissolved in tetrahydrofuran (200 mL), purged with nitrogen gas, and tetraisopropyl titanate (4 ml, 13.6 mmol) was added at zero degrees Celsius. Ethyl magnesium bromide (58.67 ml, 176 mmol) was added dropwise, the mixture was heated to room temperature, and the reaction was allowed to proceed overnight. After the reaction was complete, water was added at zero degrees Celsius to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, spin-dried, and concentrated. The mixture was then separated and purified by silica gel chromatography column (EA:PE = 1:5) to obtain compound 9b (7.0 g, 71%). 1 H NMR (400MHz,CDCl3) δ=4.68 (t,1H),3.47 (s,1H),3.39 (s,6H),1.88 (d,2H),0.77 (t,2H),0.45 (t,2H).

[0123] Step 2: Compound 9b (7.0 g, 47.95 mmol) was dissolved in dichloromethane (50 ml), triethylamine (14.53 g, 143.85 mmol) was added, and the mixture was added dropwise to methanesulfonyl chloride (6.59 g, 57.54 mmol) at zero degrees Celsius. The mixture was reacted at room temperature for 1 hour, quenched with water under an ice bath, extracted with dichloromethane, the organic phases were combined, spin-dried, and concentrated to obtain the crude compound 9c. 1 H NMR (400MHz,CDCl3) δ=4.69 (t,1H),3.37 (s,6H),3.01 (s,3H),2.15 (d,2H),1.30-1.26 (m,2H),0.81 (d,2H).

[0124] Step 3: The crude compound 9c from the previous step was dissolved in tetrahydrofuran / water (60 mL / 30 mL), potassium peroxymonosulfonate (24.91 g, 71.93 mmol) was added at zero degrees Celsius, and the mixture was reacted overnight at room temperature. The mixture was extracted with ethyl acetate, the organic phases were combined, and the mixture was spin-dried. Recrystallization with methyl tert-butyl ether yielded compound 9d (4.8 g, 2-step yield 52%). LC-MS (ESI): m / z = 195.1 [M+H] + .

[0125] Step 4: Add compound 9d (7.0 g, 36.08 mmol) to 1,2-dichloroethane (200 mL), purge with nitrogen gas, add thionyl chloride (3.26 ml, 45 mmol), reflux for 1 hour, cool to room temperature, add NCS (7.2 g, 54.12 mmol) and 10 drops of 4 M hydrogen chloride-1,4-dioxane, reflux overnight, cool to room temperature, add methanol (25 ml), continue reacting for 1 hour, concentrate directly after reaction is complete and spin dry, add chloroform at zero degrees, filter, collect the liquid, concentrate to obtain crude compound 9e. LC-MS (ESI): m / z = 243.1 [M+H] +

[0126] Step 5: The crude compound 9e was dissolved in dichloromethane (20 mL), triethylamine (5.47 g, 54.12 mmol) was added at zero degrees Celsius, and the mixture was stirred at the same temperature for 3 hours. Water was added to quench the mixture, and the compound was extracted with dichloromethane. The organic phases were combined and concentrated, and the mixture was separated and purified by silica gel chromatography column (EA:PE = 1:5) to obtain compound 9f (3.5 g, 2-step yield 66%). LC-MS (ESI): m / z = 147.1 [M+H] +

[0127] Step 6: Compound 9f (3.0 g, 20.55 mmol) was dissolved in acetonitrile (50 mL), sodium bicarbonate (17.26 g, 205.5 mmol) was added, and then thioacetamide (1.54 g, 20.55 mmol) was added. The mixture was stirred at 80°C for 5 hours, filtered, concentrated, and separated and purified by silica gel chromatography column (EA:PE = 1:1) to obtain compound 9 g (3 g, 79%). LC-MS (ESI): m / z = 186.2[M+H] + .

[0128] Step 7: Place 9 g of compound (1 g, 5.38 mmol) in a 50 ml round-bottom flask, add 10 mL of 3 M hydrochloric acid solution, and stir at 100°C for 5 hours. After the reaction is complete, extract with methyl tert-butyl ether, and concentrate the aqueous phase directly to obtain compound 9h hydrochloride. LC-MS (ESI): m / z = 148.2[M+H] + .

[0129] Step 8: Compound 9h (1 g, 6.8 mmol) was placed in a 50 ml round-bottom flask, trifluoroacetic acid (5 ml) and triphenylmethanol (2.12 g, 8.16 mmol) were added, the mixture was stirred at room temperature for 10 minutes, and then spin-dried to obtain the target compound 9i, and the next step was carried out directly. LC-MS (ESI): m / z = 388.5 [MH] + .

[0130] Step 8: The crude compound 9i from the previous step was dissolved in acetonitrile and water (50 ml / 10 ml), sodium bicarbonate (5.7 g, 68 mmol) and 9-fluorenylmethyl-N-succinimidyl carbonate (3.44 g, 10.2 mmol) were added, the mixture was stirred at room temperature for 3 hours, filtered, saturated saline solution (30 ml) was added, extracted with ethyl acetate, the organic phases were combined and concentrated, separated and purified by silica gel chromatography column (DCM:MeOH = 10:1) to obtain 2.2 g of racemic mixture, with a two-step yield of 43%. The racemic mixture was chiralized. Instrument: SFC Prep 150 AP, chromatographic column: Daicel AD-H (19 mm × 250 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: methanol, isocratic elution, mobile phase B content 25%, flow rate 40 ml / min. Intermediate 9 (P1) (890 mg) was obtained in 3.8 min, and intermediate 10 (P2) (910 mg) was obtained in 4.2 min.

[0131] Intermediate 9: 1 H NMR (400MHz,CDCl3) δ=7.78 (d,2H),7.61 - 7.49 (m,8H),7.42 - 7.39 (m,2H),7.34 - 7.30 (m,2H),7.28 - 7.22 (m,6H),7.22 - 7.14 (m,3H),5.00 (d,1H),4.34 (d,2H),4.19 (t,1H),3.88 (d,1H),1.06 - 0.92 (m,1H),0.85 - 0.75 (m,1H),0.75 - 0.63 (m,1H),0.28 - 0.19 (m,1H). Intermediate 10: 1H NMR (400MHz,CDCl3) δ=7.77 (d,2H),7.59 - 7.54 (m,8H),7.42 - 7.39 (m,2H),7.33 - 7.30 (m,2H),7.26 - 7.22 (m,6H),7.21 - 7.13 (m,3H),5.00 (d,1H),4.34 (d,2H),4.19 (t,1H),3.89 (d,1H),1.02 - 0.97 (m,1H),0.86 - 0.74 (m,1H),0.73 - 0.62 (m,1H),0.26 - 0.20 (m,1H). Intermediate 11: [ka]

[0132] Step 1: Compound 11a (20.0 g, 59.6 mmol) was dissolved in ethyl acetate (150 mL), cyclohexane (75 mL) and tert-butyltrichloroacetimidate (32.5 g, 149 mmol) were added at room temperature, the temperature was raised to 30 °C, and the reaction was carried out for 48 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (EA:PE = 10:90) to obtain compound 11b (23.2 g, 99.4%). 1 H NMR (400MHz,Chloroform-d) δ 7.76 (d,2H),7.61 (d,2H),7.39 (t,2H),7.31 (t,2H),5.67 (d,1H),4.40 (ddd,3H),4.24 (t,1H),2.76 (t,2H),2.04 (d,1H),1.50 (s,9H).

[0133] Step 2: Compound 11b (10.0 g, 25.5 mmol) was dissolved in dry N,N-dimethylformamide (200 ml), silver nitrate (434 mg, 2.55 mmol) and N-bromosuccinimide (5.46 g, 30.7 mmol) were added, and the mixture was allowed to react overnight at room temperature. After the reaction was complete, water (500 mL) was added to quench the mixture, and it was extracted with ethyl acetate (200 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product was then purified by silica gel column chromatography (EA:PE = 10:90) to obtain 11c (10.5 g, 87.4%). LC-MS (ESI): m / z = 470.1 [M+H] + .

[0134] Step 3: Compound 11d (9.00 g, 55.8 mmol) was dissolved in dichloromethane (400 ml) at 0°C, and imidazole (4.94 g, 72.6 mmol), iodine (18.4 g, 72.6 mmol), and triphenylphosphine (19.0 g, 72.6 mmol) were added. After the addition of these, the temperature was raised to room temperature and the mixture was allowed to react overnight. After the reaction was complete, saturated sodium thiosulfate aqueous solution (100 mL) and water (500 mL) were added to quench the mixture. The mixture was extracted with ethyl acetate (200 mL x 5), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product was then purified by silica gel column chromatography (EA:PE = 50:50) to obtain 11e (8.90 g, 63.6%). LC-MS (ESI): m / z = 272.0 [M+H] + .

[0135] Step 4: Zinc powder (2.43 g, 37.2 mmol) and iodine (94.5 mg, 0.372 mmol) were added to a round-bottom flask, heated with a heat gun for 5 minutes under nitrogen gas protection, cooled to room temperature, protected with nitrogen gas three times, cooled to 0°C, and then compound 11e (3.17 g, 11.7 mmol) in DMF (50 mL) solution was added by injection, the mixture was heated to room temperature, and allowed to stand for approximately 2 hours. Cuprous cyanide (950 mg, 10.6 mmol) and lithium chloride (900 mg, 21.2 mmol) were added to a round-bottom flask, the mixture was heated to 150°C under nitrogen gas protection and reacted for 2 hours, then cooled to room temperature, 10 mL of DMF was added by injection, and the mixture was stirred for 10 minutes. After cooling to -15°C, a DMF solution of compound 11e activated with zinc powder was added by injection, and after 5 minutes, a DMF solution of compound 11c (5.00 g, 10.6 mmol) was added by injection, and the mixture was then heated to room temperature and stirred overnight. After the reaction was complete, water (500 mL) was added to quench the mixture, and it was extracted with ethyl acetate (200 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was purified by silica gel column chromatography (EA:PE = 70:30) to obtain 11f (3.47 g, 61.1%). LC-MS (ESI): m / z = 535.3 [M + H] + .

[0136] Step 5: Compound 11f (3.47 g, 6.49 mmol) was dissolved in ethyl acetate (200 ml), Pd / C (2.0 g) was added, and a hydrogen gas balloon was inserted. The mixture was then reacted overnight at room temperature. After monitoring the disappearance of the starting materials by TLC, the solid was removed by direct filtration, washed with ethyl acetate, and the organic phases were combined. The mixture was then directly concentrated to obtain a crude product of compound 11 g (3.21 g). LC-MS (ESI): m / z = 539.3 [M+H] + .

[0137] Step 6: 11 g (3.21 g) of the crude compound was dissolved in 1,2-dichloroethane (200 mL), trimethyltin hydroxide (4.31 g, 23.8 mmol) was added, and the temperature was raised to 70°C and the reaction was allowed to proceed overnight. After the reaction was complete, the temperature was lowered to room temperature, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography column (DCM:MeOH = 80:20) to obtain compound 11h (2.90 g, 2-step yield 85.2%). LC-MS (ESI): m / z = 525.3[M+H] + .

[0138] Step 7: Compound 11h (2.90 g, 5.53 mmol) was dissolved in dry N,N-dimethylformamide (150 ml), sodium carbonate (2.34 g, 22.1 mmol) and 3-bromopropene (2.01 g, 16.6 mmol) were added, and the mixture was allowed to react at room temperature for 3 days after the additions were complete. After the reaction was complete, water (500 mL) was added to quench the mixture, and it was extracted with ethyl acetate (200 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained. The crude product was then purified by silica gel column chromatography (EA:PE = 70:30) to obtain 11i (2.41 g, 77.2%). LC-MS (ESI): m / z = 565.3 [M + H] + .

[0139] Step 8: Compound 11i (2.41 g, 4.27 mmol) was dissolved in a mixed solvent of dichloromethane (50 ml) and trifluoroacetic acid (50 ml) and reacted at room temperature. After monitoring the completion of the reaction by TLC, the mixture was directly concentrated under reduced pressure, and the resulting crude product was redissolved in dichloromethane (100 ml). The pH was adjusted to approximately 7 with saturated sodium bicarbonate aqueous solution, water was added, and the mixture was extracted with dichloromethane (100 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Further beating with dichloromethane yielded intermediate 11 (1.69 g, 77.9%).

[0140] 1H NMR (400MHz,Methanol-d4) δ 7.79 (d,2H),7.67 (t,2H),7.39 (t,2H),7.31 (td,2H),6.01 - 5.88 (m,1H),5.33 (dq,1H),5.22 (dq,1H),4.62 (dq,2H),4.42 - 4.33 (m,3H),4.23 (t,1H),4.13 (dd,1H),3.26 - 3.19 (m,1H),1.98 (s,3H),1.89 - 1.77 (m,2H),1.75 - 1.62 (m,2H),1.46 - 1.37 (m,4H). LC-MS (ESI): m / z = 509.2[M+H] + . Example 1: [ka]

[0141] Step 1: The synthesis of 1B was performed using the standard Fmoc chemical method.

[0142] 1. Rink Amide MBHA Resin (1 mmol, 1.4 g, sub: 0.7 mmol / g) and dichloromethane solvent were added to the reactor, allowed to swell for 30 minutes, then 20% piperidine / DMF was added and mixed for 30 minutes.

[0143] 2. It was dried by vacuuming and rinsed five times with DMF.

[0144] 3. Add the Fmoc-Sar-OH protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen gas for 1.5 hours, and monitor the reaction with ninhydrin.

[0145] 4. It was dried by vacuuming and rinsed three times with DMF.

[0146] 5. Add 20% piperidine / DMF and mix for 30 minutes.

[0147] 6. It was dried by vacuuming and rinsed five times with DMF.

[0148] 7. Add the Fmoc-protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen gas for 1.5 hours, and monitor the reaction with ninhydrin.

[0149] 8. Suction-dried and rinsed three times with DMF.

[0150] 9. Steps 5-8 were repeated in the next amino acid coupling.

[0151] 10. In the final step, the mixture was rinsed twice with MeOH, once with DCM, twice with MeOH, and then vacuum dried to obtain peptide resin 1B (6.5g), which was used directly in the reaction of the next step.

[0152] [Table 2]

[0153] Step 2: Add 60 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask and stir uniformly. Then add peptide resin 1B (6.5 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether was preheated to 0°C), precipitate a white cotton-like substance, and centrifuge (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether and vacuum dry to obtain pseudo-white solid crude peptide 1C (2.4 g), which was used directly in the reaction of the next step. LCMS m / z = 627.6[M / 3 + H] + ,940.9[M / 2+H] +

[0154] Step 3: Add water (750 ml), acetonitrile (250 ml), and 1C (2 g, 1.06 mmol) in order to a 2 L reaction flask, and stir uniformly. Then, slowly add iodine / acetonitrile solution (0.1 mol / L) dropwise until the reaction mixture turns pale yellow, add ascorbic acid to quench, and purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative solution, chromatography column: SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 16 min. Compound 1 (400 mg, 99% purity) was obtained by freeze-drying.

[0155] LCMS m / z = 626.9[M / 3 + H] + ,939.9[M / 2+H] + Example 2: [ka]

[0156] Step 1: The synthesis of 2B was performed using standard Fmoc chemical methods.

[0157] 1. Rink Amide MBHA Resin (1 mmol, 1.4 g, sub: 0.7 mmol / g) and dichloromethane solvent were added to the reactor, allowed to swell for 30 minutes, then 20% piperidine / DMF was added and mixed for 30 minutes.

[0158] 2. It was dried by vacuuming and rinsed five times with DMF.

[0159] 3. Add the Fmoc-Sar-OH protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen gas for 1.5 hours, and monitor the reaction with ninhydrin.

[0160] 4. It was dried by vacuuming and rinsed three times with DMF.

[0161] 5. Add 20% piperidine / DMF and mix for 30 minutes.

[0162] 6. It was dried by vacuuming and rinsed five times with DMF.

[0163] 7. Add the Fmoc-protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen gas for 1.5 hours, and monitor the reaction with ninhydrin.

[0164] 8. Suction-dried and rinsed three times with DMF.

[0165] 9. Steps 5-8 were repeated in the next amino acid coupling.

[0166] 10. In the final step, the mixture was rinsed twice with MeOH, once with DCM, twice with MeOH, and then vacuum dried to obtain peptide resin 2B (6.3g), which was used directly in the reaction of the next step.

[0167] [Table 3]

[0168] Step 2: Add 60 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask and stir uniformly. Then add peptide resin 2B (6.3 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether was preheated to 0°C), precipitate a white cotton-like substance, and centrifuge (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether and vacuum dry to obtain pseudo-white solid crude peptide 2C (2.5 g), which was used directly in the reaction of the next step. LCMS m / z = 637.3[M / 3 + H]+ ,955.4[M / 2+H] +

[0169] Step 3: Add water (750 ml), acetonitrile (250 ml), and 2C (2 g, 1.06 mmol) in order to a 2 L reaction flask, stir uniformly, then slowly add iodine / acetonitrile solution (0.1 mol / L) dropwise until the reaction mixture turns pale yellow, add ascorbic acid to quench, and purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative solution, chromatography column: SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 16 min. Compound 2 (410 mg, 99% purity) was obtained by freeze-drying.

[0170] LCMS m / z = 636.6[M / 3 + H] + ,954.4[M / 2+H] + Example 3: [ka]

[0171] [Table 4]

[0172] Using the materials listed above as raw materials, compound 3 (50 mg, 95% purity) was obtained using the synthesis method for compound 1. LCMS m / z = 961.0[M / 2+H] + Example 4: [ka]

[0173] [Table 5]

[0174] Using the materials listed above as raw materials, compound 4 (50 mg, 99% purity) was obtained using the method for compound 1.

[0175] LCMS m / z = 961.5[M / 2+H] + . Example 5: [ka]

[0176] [Table 6]

[0177] Using the materials listed above as raw materials, compound 5 (50 mg, 95% purity) was obtained using the method for compound 1.

[0178] LCMS m / z = 950.3[M / 2+H] + . Example 6: [ka]

[0179] [Table 7]

[0180] Using the materials listed above as raw materials, compound 6 (50 mg, purity 94%) was obtained using the method for compound 1.

[0181] LCMS m / z = 963.4[M / 2+H] + . Example 7: [ka]

[0182] Step 1: The synthesis of 7B was carried out using the standard Fmoc chemical method.

[0183] 1. Rink Amide MBHA Resin (1 mmol, 1.4 g, sub: 0.7 mmol / g) and dichloromethane solvent were added to the reactor, allowed to swell for 30 minutes, then 20% piperidine / DMF was added and mixed for 30 minutes.

[0184] 2. It was dried by vacuuming and rinsed five times with DMF.

[0185] 3. Add the Fmoc-Sar-OH protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen gas for 1.5 hours, and monitor the reaction with ninhydrin.

[0186] 4. It was dried by vacuuming and rinsed three times with DMF.

[0187] 5. Add 20% piperidine / DMF and mix for 30 minutes.

[0188] 6. It was dried by vacuuming and rinsed five times with DMF.

[0189] 7. Add the Fmoc-protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen gas for 1.5 hours, and monitor the reaction with ninhydrin.

[0190] 8. Suction-dried and rinsed three times with DMF.

[0191] 9. Steps 5-8 were repeated in the next amino acid coupling.

[0192] 10. In the final step, the mixture was rinsed twice with MeOH, once with DCM, twice with MeOH, and then vacuum dried to obtain peptide resin 7B (6g), which was used directly in the reaction of the next step.

[0193] [Table 8]

[0194] Step 2: Add 50 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask and stir uniformly. Then add peptide resin 7B (6 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 300 ml of methyl tert-butyl ether (methyl tert-butyl ether was preheated to 0°C), precipitate a white cotton-like substance, and centrifuge (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether and vacuum dry to obtain pseudo-white solid crude peptide 7C (2.2 g), which was used directly in the reaction of the next step. LCMS m / z = 655.2[M / 3 + H] + ,982.1[M / 2+H] +

[0195] Step 3: Add water (750 ml), acetonitrile (250 ml), and 7C (2 g, 1.02 mmol) in order to a 2 L reaction flask, stir uniformly, then slowly add iodine / acetonitrile solution (0.1 mol / L) dropwise until the reaction mixture turns pale yellow, add ascorbic acid to quench, and purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative solution, chromatography column: SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 16 min. Compound 7 (50 mg, 98% purity) was obtained.

[0196] LCMS m / z = 981.0[M / 2+H] + . Example 8: [ka]

[0197] [Table 9]

[0198] Using the materials listed above as raw materials, compound 8 (50 mg, 99% purity) was obtained using the method for compound 1.

[0199] LCMS m / z = 950.3[M / 2+H] + . Example 9: [ka]

[0200] [Table 10]

[0201] Using the materials listed above as raw materials, compound 9 (25 mg, purity 97%) was obtained using the method for compound 1.

[0202] LCMS m / z = 973.6[M / 2+H] + . Example 10 [ka]

[0203] [Table 11]

[0204] Step 1: Using the materials listed above as raw materials, compound 10B was obtained using the method for compound 1.

[0205] Step 2: Add 30 ml of dichloromethane to a solid-phase synthesis reactor, then add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in order. Bubble with nitrogen gas and allow to react for 8 hours. Wash the resin 5 times with dichloromethane, 5 times with N,N-dimethylformamide, wash for 15 min + 15 min with a 0.5% sodium diethyldithiocarbamate solution in N,N-dimethylformamide, and then wash three more times with N,N-dimethylformamide to obtain peptide resin 10C.

[0206] Step 3: Add the 2% hydrazine hydrate N,N-dimethylformamide solution to the reactor and react for 30 min + 30 min. Wash five times with N,N-dimethylformamide solution to obtain peptide resin 10D.

[0207] Step 4: Add N-methylpyrrolidone (20 ml), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) to a solid-phase synthesis reactor and react at room temperature for 16 hours. Monitor for colorlessness using ninhydrin, suction dry the solvent, wash the resin three times with N,N-dimethylformamide, wash the resin twice with methanol, wash the resin once with dichloromethane, wash the resin twice with methanol, and suction dry the resin to obtain peptide resin 10E (5.2 g).

[0208] Step 5: Add 60 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask and stir uniformly. Then add peptide resin 10E (5.2 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate. Add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether preheated to 0°C) to precipitate a white, cotton-like substance, and centrifuge (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether and vacuum dry to obtain pseudo-white solid crude peptide compound 10 (1.8 g), which was purified by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative liquid, chromatography column: SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 17 min. Lyophilization yielded 10 units of white solid compound (25 mg, purity 91.9%).

[0209] LCMS m / z = 1821.3[M+H] + . Example 11: [ka]

[0210] [Table 12]

[0211] Step 1: Using the materials listed above as raw materials, compound 11B was obtained using the method for compound 1.

[0212] Step 2: Add 30 ml of dichloromethane to a solid-phase synthesis reactor, then add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in order. Bubble with nitrogen gas and allow to react for 8 hours. Wash the resin 5 times with dichloromethane, 5 times with N,N-dimethylformamide, wash for 15 min + 15 min with a 0.5% sodium diethyldithiocarbamate solution in N,N-dimethylformamide, and then wash three more times with N,N-dimethylformamide to obtain peptide resin 11C.

[0213] Step 3: Add a 20% piperidine N,N-dimethylformamide solution to the reactor and allow to react for 30 minutes. Wash five times with N,N-dimethylformamide solution to obtain peptide resin 11D.

[0214] Step 4: Add N-methylpyrrolidone (20 ml), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) to a solid-phase synthesis reactor and allow to react at room temperature for 16 hours. Monitor for colorlessness using ninhydrin, suction dry the solvent, wash the resin three times with N,N-dimethylformamide, wash the resin twice with methanol, wash the resin once with dichloromethane, wash the resin twice with methanol, and suction dry the resin to obtain peptide resin 11E.

[0215] Step 5: Add 50 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask and stir uniformly. Then add peptide resin 11E (5 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate. Add the filtrate to 500 ml of methyl tert-butyl ether (methyl tert-butyl ether was preheated to 0°C) to precipitate a white, cotton-like substance, which was then centrifuged (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether and vacuum dry to obtain pseudo-white solid crude peptide 11F (1.5 g).

[0216] Step 6: Add water (1050 ml), acetonitrile (450 ml), and 11F (1.5 g, 0.76 mmol) in order to a 2 L reaction flask, stir uniformly, then slowly add iodine / acetonitrile solution (0.1 mol / L) dropwise until the reaction mixture turns pale yellow, add ascorbic acid to quench, and purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative solution, chromatography column SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 16 min. The compound was freeze-dried to obtain a white solid compound 11 (28 mg, 99% purity).

[0217] LCMS m / z = 987.5[M / 2+H] + 658.8 [M / 3+H] + . Example 12: [ka]

[0218] [Table 13]

[0219] Using the materials listed above as raw materials, compound 12 (300 mg, 98% purity) was obtained using the method for compound 1.

[0220] LCMS m / z = 967.5[M / 2+H] + 645.5 [M / 3+H] + . Example 13: [ka]

[0221] [Table 14]

[0222] Using the materials listed above as raw materials, compound 13 (350 mg, purity 98%) was obtained using the method for compound 1.

[0223] LCMS m / z = 953.1[M / 2 + H] + 635.9 [M / 3+H] + . Example 14: [ka]

[0224] [Table 15]

[0225] Using the materials listed above as raw materials, compound 14 (8 mg, 95% purity) was obtained using the synthesis method for compound 1.

[0226] LCMS m / z = 963.4[M / 2+H] + 642.7 [M / 3+H] + . Example 15: [ka]

[0227] [Table 16]

[0228] Using the materials listed above as raw materials, compound 15 (130 mg, purity 98%) was obtained using the method for compound 1.

[0229] LCMS m / z = 984.2[M / 2+H] + ,656.3[M / 3+H] + . Example 16: [ka]

[0230] [Table 17]

[0231] Using the materials listed above as raw materials, compound 16 (400 mg, purity 94%) was obtained using the method for compound 1.

[0232] LCMS m / z = 997.4[M / 2 + H] + ,665.2[M / 3+H] + . Example 17: [ka]

[0233] [Table 18]

[0234] Using the materials listed above as raw materials, compound 17 (40 mg, purity 93%) was obtained using the method for compound 1.

[0235] LCMS m / z = 984.0[M / 2+H] + ,656.5[M / 3+H] + . Example 18: [ka]

[0236] [Table 19]

[0237] Using the materials listed above as raw materials, compound 18 (40 mg, purity 94%) was obtained using the method for compound 1.

[0238] LCMS m / z = 984.0[M / 2+H] + ,656.5[M / 3+H] + . Example 19: [ka]

[0239] [Table 20]

[0240] Using the materials listed above as raw materials, compound 19C (1.5g) was obtained using the method for compound 1.

[0241] Step 3: Add water (1050 ml), acetonitrile (450 ml), and 19C (1.5 g, 0.8 mmol) in order to a 3 L reaction flask, stir uniformly, then add 1,3,5-tris(bromomethyl)benzene (0.26 g, 0.8 mmol), adjust the pH to 8 with ammonium bicarbonate, react for 16 hours, and then purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative liquid, chromatography column SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 17 min. Lyophilization was performed to obtain white solid compound 19 (50 mg, purity 97%).

[0242] LCMS m / z = 1001.5[M / 2 + H] + ,667.8[M / 3+H] + . Example 20: [ka]

[0243] [Table 21]

[0244] Using the materials listed above as raw materials, compound 20 (40 mg, purity 96%) was obtained using the method for compound 1.

[0245] LCMS m / z = 890.1[M / 3 + H] + . Example 21: [ka]

[0246] [Table 22]

[0247] Using the materials listed above as raw materials, the compound was synthesized in solid phase up to step 14 using the method for compound 1. Then, Dde was removed with 2% hydrazine hydrate / DMF, and compound 21 (30 mg, purity 97%) was obtained by continuing the synthesis using the method for compound 1.

[0248] LCMS m / z = 904.0[M / 3+H] + . Example 22: [ka]

[0249] [Table 23]

[0250] Using the materials listed above as raw materials, compound 22 (15 mg, purity 87%) was obtained using the method for compound 10.

[0251] LCMS m / z = 908.7[M / 2+H] + . Example 23: [ka]

[0252] [Table 24]

[0253] Using the materials listed above as raw materials, the compound was synthesized in solid phase up to step 14 using the method for compound 1. Then, Dde was removed with 2% hydrazine hydrate / DMF, and compound 23 (25 mg, purity 95%) was obtained by continuing the synthesis using the method for compound 1.

[0254] LCMS m / z = 909.2[M / 2 + H] + . Example 24: [ka]

[0255] [Table 25]

[0256] Using the materials listed above as raw materials, compound 24 (180 mg, purity 96%) was obtained using the method for compound 1.

[0257] LCMS m / z = 996.2[M / 2 + H] + ,664.6[M / 3+H] + . Example 25: [ka]

[0258] [Table 26]

[0259] Step 1: Using the materials listed above as raw materials, compound 25B was obtained using the method for compound 1.

[0260] Step 2: Add 30 ml of dichloromethane to a solid-phase synthesis reactor, then add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in order. Bubble with nitrogen gas and allow to react for 8 hours. Wash the resin 5 times with dichloromethane, 5 times with N,N-dimethylformamide, wash for 15 min + 15 min with a 0.5% sodium diethyldithiocarbamate solution in N,N-dimethylformamide, and then wash three more times with N,N-dimethylformamide to obtain peptide resin 25C.

[0261] Step 3: Add a 20% piperidine N,N-dimethylformamide solution to the reactor and allow to react for 30 minutes. Wash five times with N,N-dimethylformamide solution, wash three times with methanol, and vacuum dry to obtain peptide resin 25D (5g).

[0262] Step 4: Add 50 ml of the dissolution (2% trifluoroacetic acid + 98% dichloromethane) to a 100 ml reaction flask, stir uniformly, then add peptide resin 25D (5 g), stir at room temperature for 0.5 hours, filter the resin to obtain the filtrate, dissolve the peptide resin once more using the above dissolution method, collect the two resulting filtrates, extract and wash twice with water, extract and wash once with saturated saline, dry with anhydrous sodium sulfate, and vacuum dry to obtain compound 25E (2.3 g).

[0263] Step 5: Dichloromethane (1.2 L), compound 25E (2.3 g, 0.68 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) were added to a 2 L flask and reacted at room temperature for 16 hours. Mass analysis showed that the reaction was substantially complete. The mixture was then extracted and washed twice with water, extracted and washed once with saturated saline, dried over anhydrous sodium sulfate, and vacuum dried to obtain compound 25F (2.1 g).

[0264] Step 6: Add 60 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask and stir uniformly. Then add compound 25F (2.1 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate. Add the filtrate to 600 ml of methyl tert-butyl ether (methyl tert-butyl ether was preheated to 0°C) to precipitate a white, cotton-like substance, which was then centrifuged (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether and vacuum dry to obtain a pseudo-white solid crude peptide 25 G (1.2 g).

[0265] Step 7: Add water (1050 ml), acetonitrile (450 ml), and 25 G (1.2 g, 0.6 mmol) in order to a 2 L reaction flask, stir uniformly, then slowly add iodine / acetonitrile solution (0.1 mol / L) dropwise until the reaction mixture turns pale yellow, add ascorbic acid to quench, and purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative liquid, chromatography column SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 16 min. Freeze-drying was performed to obtain 25 units of a white solid (80 mg, 95% purity).

[0266] LCMS m / z = 10¹⁰.⁹[M / ² + H] + 674.3 [M / 3+H] + . Example 26: [ka]

[0267] [Table 27]

[0268] Using the materials listed above as raw materials, compound 26 (50 mg, 98% purity) was obtained using the method for compound 25.

[0269] LCMS m / z = 1003.7[M / 2+H] + ,669.7[M / 3+H] + . Example 27: [ka]

[0270] [Table 28]

[0271] Using the materials listed above as raw materials, compound 27 (65 mg, 99% purity) was obtained using the method for compound 25.

[0272] LCMS m / z = 1003.8[M / 2+H] + . Example 28: [ka]

[0273] [Table 29]

[0274] Using the materials listed above as raw materials, compound 28 (48 mg, purity 95%) was obtained using the method for compound 25.

[0275] LCMS m / z = 988.8[M / 2+H] + . Example 29: [ka]

[0276] [Table 30]

[0277] Using the materials listed above as raw materials, compound 29 (140 mg, 99% purity) was obtained using the method for compound 25.

[0278] LCMS m / z = 1047.9 [M / 2 + H] + . Example 30: [ka]

[0279] [Table 31]

[0280] Using the materials listed above as raw materials, compound 30 (180 mg, purity 92%) was obtained using the method for compound 19.

[0281] LCMS m / z = 1008.5[M / 2+H] + ,672.8[M / 3+H] + . Example 31: [ka]

[0282] [Table 32]

[0283] Using the materials listed above as raw materials, compound 31 (279 mg, purity 94%) was obtained using the method for compound 19.

[0284] LCMS m / z = 1008.4[M / 2 + H] + ,672.9[M / 3+H] + . Example 32: [ka]

[0285] [Table 33]

[0286] Using the materials listed above as raw materials, compound 32 (200 mg, 99%) was obtained using the method for compound 19.

[0287] LCMS m / z = 1126.6[M / 2+H] + ,751.6[M / 3+H] + . Example 33: [ka]

[0288] [Table 34]

[0289] Using the materials listed above as raw materials, compound 33 (190 mg, 97%) was obtained using the method for compound 19.

[0290] LCMS m / z = 1002.9[M / 2+H] + ,669.3[M / 3+H] + . Example 34: [ka]

[0291] [Table 35]

[0292] Using the materials listed above as raw materials, compound 34 (130 mg, purity 94%) was obtained using the method for compound 25.

[0293] LCMS m / z = 1000.0 [M / 2 + H]+ ,667.2[M / 3+H] + . Example 35: [ka]

[0294] [Table 36]

[0295] Using the materials listed above as raw materials, compound 35 (150 mg, purity 94%) was obtained using the method for compound 1.

[0296] LCMS m / z = 1122.3[M / 2+H] + ,748.5[M / 3+H] + . Example 36: [ka]

[0297] [Table 37]

[0298] Using the materials listed above as raw materials, compound 36 (300 mg, purity 96%) was obtained using the method for compound 1.

[0299] LCMS m / z = 805.0[M / 3+H] + . Example 37: [ka]

[0300] [Table 38]

[0301] Using the materials listed above as raw materials, compound 37 (100 mg, 95% purity) was obtained using the synthesis method of compound 1. LCMS m / z = 948.5[M / 2+H] + Example 38: [ka]

[0302] [Table 39]

[0303] Using the materials listed above as raw materials, compound 38 (45 mg, purity 95%) was obtained using the method for compound 25.

[0304] LCMS m / z = 981.7[M / 2+H] + . Example 39: [ka]

[0305] [Table 40]

[0306] Using the materials listed above as raw materials, compound 39 (110 mg, purity 97%) was obtained using the method for compound 1.

[0307] LCMS m / z = 807.5[M / 3+H] + . Example 40: [ka]

[0308] [Table 41]

[0309] Using the materials listed above as raw materials, compound 40 (150 mg, purity 94%) was obtained using the method for compound 1.

[0310] LCMS m / z = 996.4[M / 2+H] + ,664.7[M / 3+H] + . Example 41: [ka]

[0311] [Table 42]

[0312] Using the materials listed above as raw materials, compound 41 (150 mg, purity 97%) was obtained using the method for compound 1.

[0313] LCMS m / z = 996.7[M / 2+H] + ,664.8[M / 3+H] + . Example 42: [ka]

[0314] [Table 43]

[0315] Using the materials listed above as raw materials, compound 42 (35 mg, 98% purity) was obtained using the method for compound 1.

[0316] LCMS m / z = 996.2[M / 2 + H] + ,664.5[M / 3+H] + . Example 43: [ka]

[0317] [Table 44]

[0318] Using the materials listed above as raw materials, compound 43 (95 mg, purity 97%) was obtained using the method for compound 10.

[0319] LCMS m / z = 965.9[M / 2+H] + ,644.4[M / 3+H] + . Example 44 [ka]

[0320] [Table 45]

[0321] Step 1: Using the materials listed above as raw materials, compound 44B was obtained using the method for compound 1.

[0322] Step 2: Add 30 ml of dichloromethane to a solid-phase synthesis reactor, then add phenylsilane (1 g) and tetrakis(triphenylphosphine)palladium (462 mg) in order. Bubble with nitrogen gas and allow to react for 8 hours. Wash the resin 5 times with dichloromethane, 5 times with N,N-dimethylformamide, wash for 15 min + 15 min with a 0.5% sodium diethyldithiocarbamate solution in N,N-dimethylformamide, and then wash three more times with N,N-dimethylformamide to obtain peptide resin 44C.

[0323] Step 3: Add a 20% piperidine solution to N,N-dimethylformamide and allow to react for 30 minutes. Wash five times with N,N-dimethylformamide solution to obtain peptide resin 44D.

[0324] Step 4: Add N-methylpyrrolidone (20 ml), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (417.2 mg, 1.1 mmol), and DIEA (0.19 ml, 1.1 mmol) to a solid-phase synthesis reactor and allow to react at room temperature for 24 hours. Monitor for colorlessness using ninhydrin, suction dry the solvent, wash the resin three times with N,N-dimethylformamide, wash the resin twice with methanol, wash the resin once with dichloromethane, wash the resin twice with methanol, and suction dry the resin to obtain peptide resin 44E / F (5 g).

[0325] Step 5: Add 40 ml of the dissolution (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethanedithiol + 2% water) to a 100 ml reaction flask, stir uniformly, then add peptide resin 44E / F (5 g) and stir at room temperature for 2 hours. Filter the resin to obtain the filtrate, add the filtrate to 300 ml of methyl tert-butyl ether (methyl tert-butyl ether preheated to 0°C), precipitate a white cotton-like substance, and centrifuge (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether, vacuum dry to obtain a pseudo-white solid crude peptide compound 44E / F (1.5 g), and purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative liquid, chromatography column: SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 5 mmol / L ammonium acetate / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min. Lyophilization yielded white solid compounds 44-1 (77 mg, purity 94%, retention time 13.198 min) and 44-2 (44 mg, purity 98%, retention time 14.50 min).

[0326] 44-1, LCMS m / z = 903.8 [M / 2 + H] + ,603.0[M / 3+H] + . 44-2, LCMS m / z = 904.1 [M / 2 + H] + . Example 45: [ka]

[0327] [Table 46]

[0328] Using the materials listed above as raw materials, compound 45C (1.5g) was obtained using the method for compound 1.

[0329] Step 3: Add water (750 ml), acetonitrile (750 ml), and 45C (1.5 g, 0.8 mmol) in order to a 3 L reaction flask, stir uniformly, then add bismuth bromide (0.36 g, 0.8 mmol), adjust the pH to 8 with ammonium bicarbonate, react for 16 hours, and then purify by preparative HPLC. Separation method: 1. Instrument: waters2767 preparative liquid, chromatography column SunFire@PrepC18 (19 mm × 250 mm). 2. Filter the sample through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN, b. Gradient elution: mobile phase content 5%~45%, c. Flow rate: 12 ml / min, d. Elution time: 30 min, retention time: 17 min. The compound was freeze-dried to obtain a white solid compound 45 (57 mg, 90% purity).

[0330] LCMS m / z = 1047.1[M / 2 + H] + ,698.5[M / 3+H] + . Example 46: [ka]

[0331] [Table 47]

[0332] Using the materials listed above as raw materials, compound 46 (105 mg, purity 92%) was obtained using the method for compound 1.

[0333] LCMS m / z = 851.7[M / 3+H] + . Example 47: [ka]

[0334] [Table 48]

[0335] Using the materials listed above as raw materials, compound 47 (320 mg, purity 95%) was synthesized using the method for compound 21.

[0336] LCMS m / z = 818.9[M / 3+H] + ,614.5[M / 4+H] + . Example 48: [ka]

[0337] [Table 49]

[0338] Using the materials listed above as raw materials, compound 48 (200 mg, purity 97%) was obtained using the method for compound 1.

[0339] LCMS m / z = 1049.7[M / 2+H] + ,833.7[M / 3+H] + . Example 49: [ka]

[0340] [Table 50]

[0341] Using the materials listed above as raw materials, compound 49 (220 mg, purity 95%) was synthesized using the method for compound 21.

[0342] LCMS m / z = 1271.0 [M / 2 + H] + ,847.7[M / 3+H] + . Example 50: [ka]

[0343] [Table 51]

[0344] Using the materials listed above as raw materials, compound 50 (100 mg) was obtained using the method for compound 25.

[0345] LCMS m / z = 1046.0 [M / 2 + H] + . Example 51: [ka]

[0346] [Table 52]

[0347] Using the materials listed above as raw materials, compound 51 (75 mg) was obtained using the method for compound 25.

[0348] LCMS m / z = 1046.0 [M / 2 + H] + . Example 52: [ka]

[0349] [Table 53]

[0350] Using the materials listed above as raw materials, compound 52 (400 mg) was obtained using the method for compound 44.

[0351] LCMS m / z = 935.5[M / 2+H] + ,623.9[M / 3+H] + . Example 53: [ka]

[0352] [Table 54]

[0353] Using the materials listed above as raw materials, compound 53 (72 mg) was obtained using the method for compound 25.

[0354] LCMS m / z = 1049.6[M / 2+H] + ,700.2[M / 3+H] + . Example 54: [ka]

[0355] [Table 55]

[0356] Using the materials listed above as raw materials, compound 54 (400 mg) was obtained using the method for compound 1.

[0357] LCMS m / z = 995.0[M / 2+H]+ . Example 55: [ka]

[0358] [Table 56]

[0359] Using the materials listed above as raw materials, compound 55 (410 mg) was obtained using the method for compound 1.

[0360] LCMS m / z = 982.0[M / 2+H] + .

[0361] Biological testing methods 1. IL-23α / IL-12β & IL-23R binding test experiment The inhibitory activity of compounds against IL-23α / IL-12β & IL-23R binding was tested using the TR-FRET method. In reaction buffer PPI ((PerkinElmer, Cat #61DB10RDF), the inhibitory activity of compounds against the protein IL-23α / IL-12β (ACRO, Cat #61DB10RDF) was tested. Solutions of IL-23α / IL-12β (#ILB-H52W5) and IL-23R (ACRO, Cat#ILR-H82F3) were prepared. The final concentrations of IL-23α / IL-12β and IL-23R in the reaction mixture were both 0.3 nM. The initial concentration of the positive reference sample Guselkumab was 30 nM, which was diluted 3-fold to 10 doses. Using acoustic liquid transfer technology (Echo655), 0.1 μL of the diluted positive reference sample in reaction buffer was transferred to a 384-well plate (Grenier, Cat#784075), centrifuged at 1000 rpm for 1 minute, and 2.5 μL of the IL-23α / IL-12β solution was transferred to the 384-well plate, centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes, and 2.5 μL of the IL-23R solution was transferred to the 384-well plate, centrifuged at 1000 rpm for 1 minute, and 5 μL of Streptavidin-Tb The cryptate and Anti 6HIS-d2 detection mixture was transferred to a 384 reaction plate, centrifuged at 1000 rpm for 1 minute, incubated at 25°C for 60 minutes, and finally the HTRF signal (Ratio 665 / 620 nm) was read using a BMG high-throughput drug screening multifunction plate reader. IC was analyzed using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fittings were obtained.

[0362] [Table 57]

[0363] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibited significant inhibitory activity against the binding of IL-23α / IL-12β to IL-23R.

[0364] 2. IL-23R reporter gene experiment The objective of this study was to evaluate the ability of the compound to inhibit the binding of IL23p19 to IL23R in a reporter gene system. The HEK-blue IL23 reporter gene cell line (Invivogen, hkb-il23) was cultured in DMEM + 10% FBS + 100 ug / mL Normocin medium. When the cell density reached 80%–90%, 5000 cells / well were plated into 384-well plates and cultured overnight at 37°C and 5% CO2. The compound stock solution was then diluted in DMSO, and 40 nL of the dilution was transferred to the 384-well culture plate by Echo. It was incubated at 37°C and 5% CO2 for 0.5 hours. 40 nL / well of rhIL23 (R&D, 1290-IL) was added to the 384-well cell culture plate to a final concentration of 1 ng / mL, and incubated at 37°C and 5% CO2 for 24 hours. 18 μL of Quanti-Blue was added. TM The solution was added to a new 384-well plate, and 2 μL / well of the cell culture supernatant was transferred to the 384-well plate prepared in step 6. The plate was incubated at 37°C and 5% CO2 for 1 hour. Absorbance values ​​of 620-655 nM were read using BMG. The binding capacity of the compound was evaluated using the following formula, and IC was measured using Graphpad. 50 I fitted it. Inhibition rate calculation formula:

number

[0365] [Table 58]

[0366] Conclusion: The compounds of the present invention, such as the compounds in the examples, had significant inhibitory activity against the binding of IL23p19 to IL23R.

[0367] 3. IL-23 stimulation-induced pSTAT3 detection test in PBMCs Frozen human PBMCs were thawed and inoculated at a rate of 1 × 10^6 cells per well onto plates pre-coated with CD3 antibody. CD28 antibody was then added to the plates, and the cells were incubated at 37°C and 5% CO2 for 5 days. On the fifth day, after 4 hours of starvation stimulation with FBS, the cells were inoculated into 96-well plates with a cell density of 100K cells per well. Diluted compounds were transferred to 96-well cell culture plates and incubated at 37°C and 5% CO2 for 1 hour. rhIL23 (R&D, 1290-IL) was added to the cell culture plates and incubated at 37°C and 5% CO2 for 30 minutes. Cells in the wells were lysed on ice for 30 minutes with lysis buffer containing 1 × PHOSstop solution, and then centrifuged at 1000 rpm for 1 minute. The supernatant was then transferred to 96-well ELISA plates, and pSTAT3 ELISA detection was performed according to the instructions for the kit (CST, 7300CA). Absorbance values ​​at 450 nM were read using PHERAstar FSX (BMG LRBTECH). The inhibition rate of the compound was evaluated using the following formula, and IC was calculated using Graphpad. 50 I fitted it. Inhibition rate calculation formula:

number

[0368] [Table 59]

[0369] Conclusion: The compounds of the present invention, such as the compounds in the examples, had a significant inhibitory effect on the phosphorylation of STAT3.

[0370] 4. Pharmacokinetic studies in mice 4.1 Test animals: Male Balb / c mice, 20-25g, 18 mice / compound. Purchased from Chengdu Dashuo Laboratory Animals Co., Ltd.

[0371] 4.2 Study Design: On the day of the study, Balb / c mice were randomly divided into groups based on body weight. They were fasted for 12-14 hours without water restriction one day prior to administration, and fed 4 hours after administration.

[0372] [Table 60]

[0373] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood collection times for both the intravenous and intragastric administration groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. Before analysis, all samples were stored at -80°C and quantitative analysis was performed on the samples by LC-MS / MS.

[0374] [Table 61]

[0375] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibited good pharmacokinetic characteristics in vivo in mice. For example, compounds 7, 16, and 24 showed excellent pharmacokinetic characteristics in vivo in mice.

[0376] 5. Plasma stability test This experiment evaluated the plasma stability of compound 7 using plasma from five genera: human, monkey, dog, rat, and mouse.

[0377] Plasma samples with a concentration level of 1000 ng / mL were prepared and dispensed into EP tubes at time points 0h and 6h. The 0h sample was directly treated with acetonitrile solution containing an internal standard, while the 6h sample was left to stand for the appropriate time at 37°C before being treated with acetonitrile solution containing an internal standard. The concentration of the test substance in the samples was detected by LC-MS / MS, and the residual rate was calculated by the peak area ratio of the test substance to the internal standard in the time point samples and the 0h sample.

[0378] Experimental results: Under the test conditions, when the concentration level was 1000 ng / mL, the residual rate of the test compound is as shown in Table 6 below.

[0379] [Table 62]

[0380] 6. Gastrointestinal fluid stability test 1. Solution preparation: 1.1 Dilute hydrochloric acid preparation: Measure out 23.4 ml of hydrochloric acid and dilute it with water to make 1000 ml.

[0381] 1.2 Preparation of artificial gastric juice: Take 1.64 ml of dilute hydrochloric acid, add approximately 80 ml of water and 1 g of pepsin, shake well, and then add water to dilute to 100 ml.

[0382] 1.3 Preparation of 0.1 mol / L NaOH: Weigh 0.4 g of NaOH and dissolve it in 100 ml of water.

[0383] 1.4 Preparation of artificial intestinal fluid: Take 0.68 g of potassium dihydrogen phosphate, add 50 ml of water and dissolve, adjust the pH to 6.8 with 0.1 mol / L sodium hydroxide solution, and take 1 g of pancreatin, add an appropriate amount of water and dissolve, mix the two solutions, and then add water to dilute to 1000 ml.

[0384] 2. Sample preparation Approximately 12.5 mg of the sample was added to a 25 ml volumetric flask, dissolved with artificial gastric fluid (or artificial intestinal fluid), and diluted to the marked line.

[0385] 3. Analysis method Instrument model: Agilent 1260 Infinity, Mobile phase A: 10 mmol / L K2HPO4, Mobile phase B: Acetonitrile, Column: Phenomenex Gemini @ 3µm C18 110Å 150*4.6mm, wavelength: 224nm, column temperature: 30℃, sample tray temperature: 37℃, sample loading time: 35min, sample loading volume: 10µl, sample loading method: gradient loading, gradient method. The gradient mobile phase is as shown in Table 7.

[0386] [Table 63] Sample concentration: 0.5 mg / ml

[0387] 4. Sampling, detection, and results Sampling detection: First, a blank solution (artificial gastric or intestinal fluid) was detected. Then, the prepared sample (freshly prepared immediately before use) was placed in the sample input tray and immediately injected. Further sample injections were then performed at 4.5 hours, 9.5 hours, and 18 hours, respectively.

[0388] The detection results are shown in Table 8.

[0389] [Table 64]

[0390] Conclusion: Compound 7 exhibited stability in artificial gastrointestinal fluid.

Claims

1. A cyclic peptide compound, its stereoisomer, or a pharmaceutically acceptable salt, solvate, or dimer thereof, wherein the peptide compound has the amino acid sequence of formula (I), 【Chemistry 1】 Here, Xa １ and Xa ６ Each of these is independently selected from Pen, Pcn, Asn, Ala, Ala(3-amino), Ala(2-ethyne), Ala(3-azido), Ala(2-ethene), Val(2-ethene), Asp, 2,4-diaminobutyric acid, Ser, Cys, Hcys, Glu, and Xa １ and Xa ６ The residues between them either form a peptide ring through reaction, or L １ Forms a cyclic peptide via, Xa ２ is selected from Asn, His, or analogues of Asn, His, Xa ３ is selected from Thr or an analogue of Thr, Xa ４ is selected from Trp or an analogue of Trp, Xa ５ is selected from Lys, Gln, Arg, Cit, or analogs of Lys, Gln, Cit, Arg, Xa ７ is selected from Phe or an analogue of Phe, Xa ８ is selected from Phe, Trp, 2-Nal, or analogues of Phe, Trp, 2-Nal, Xa ９ It is selected from Thp or an analogue of Thp, Xa １０ is selected from Glu, Cys, or analogues of Glu, Cys, Xa １１ is selected from Asn, Lys, or analogues of Asn, Lys, Xa １２ is selected from 3-Pal, Phe, Asp, or analogues of 3-Pal, Phe, Asp, Xa １３ is selected from Sarc or an analogue of Sarc, As an option, Xa １ , Xa ２ , Xa ３ , Xa ４ , Xa ５ , Xa ７ , Xa ８ , Xa ９ , Xa １０ , Xa １１ , Xa １２ , Xa １３ Any amino acid residue in can be directly condensed or L １ By bonding via this, one or more peptide rings are formed, L １ is, W １ -R Ｌ -W ２ Selected from, R Ｌ C １－６ Alkylene group, C ２－４ Alkenylene group, C ２－４ Alkynylene group, 3-6 membered cycloalkyl group, 4-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, 6-10 membered aryl group, -(OCH ２ CH ２ ) ａ - Selected from, the alkylene group, alkenylene group, alkylylene group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and aryl group optionally have 1 to 4 R Ｌ１ It is further replaced by, a is selected from any integer between 0 and 10, R Ｌ１ These are, independently, halogen, =O, and C. １－４ alkyl group, C ２－４ Alkenyl group, C １－４ Alkoxy group, 3-6 membered cycloalkyl group, COOH, NH ２ , -NH-C(=O)-C １－４ Selected from alkyl groups, the alkyl group, alkoxy group, and cycloalkyl group may optionally be halogen, CN, OH, and NH ２ Further substituted with 1 to 4 substituents selected from, W １ , W ２ Each is independent, combined, C １－６ Alkylene group, -O-, -S-, -NR Ｗ１ -, -CONR Ｗ１ -, -NR Ｗ１ Selected from CO-, -C(=O)O-, or -OC(=O)-, one or more -CH groups in the alkylene group ２ - can be optionally -O-, -S-, or -NR Ｗ１ Substituted with 1 to 4 groups selected from - or -CO-, the alkylene group is optionally a halogen, =O, C １－４ Alkyl, Halo C １－４ Alkyl, CN, OH and NH ２ Further substituted with 1 to 4 substituents selected from, R Ｗ１ H, C １－４ Selected from alkyl groups and halogens, Furthermore, the peptide compound is optionally linked to a protecting group, The protecting groups are Ac, glutaryl group, succinyl group, and NH ２ Or selected from OH, As an option, polypeptides have the reactive group Xa １ , Xa ６ , Xa １０ A polypeptide ring containing at least two rings is formed, separated by covalent bonds formed by a molecular scaffold. As an option, the peptide compound can be optionally selected as Xa １ Position, Xa ５ Position or Xa ７ It conjugates with the modifying group at the position, As a condition, the peptide compound is (Ac)Pen-Asn-Thr-Trp(CH ３ )-Lys(Ac)-Pen-Phe[4-(2-aminoethoxy)]-[2-Nal]-Thp-Glu-Asn-[3-Pal]-Sarc(NH ２ A cyclic peptide compound, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, which is not selected from the structure ) and in which a disulfide bond is formed between Pen and Pen.

2. The peptide compound has the amino acid sequences of formula (II) and formula (II-1), 【Chemistry 2】 Here, Xa １ and Xa ６ The residues between them either form a peptide ring through reaction, or L １ A peptide compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or dimer thereof, which are bonded via a linkage to form a peptide ring.

3. The peptide compound has the amino acid sequences of formula (III) and formula (III-1), 【Transformation 3】 Here, Xa １ and Xa ６ The residues between them either form a peptide ring through reaction, or L １ Forms a cyclic peptide via, And Trp(R １ ) and Xa ５ The residues are either directly condensed or L １ They bond via a linkage to form a peptide ring, or Trp(CH ３ The residues between ) and Lys(Ac) either condense directly or L １ They bond via a linkage to form a peptide ring, or Xa １ , Xa ６ , Xa １０ The molecular scaffold forms a bicyclic peptide, R １ is selected from H, C １－４ alkyl group, C ３－６ cycloalkyl group, 4- to 8-membered heterocycloalkyl group, and the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with 1 to 4 substituents selected from halogen, =O, C １－４ alkyl group, halo C １－４ alkyl group, CN, OH, and NH ２ The peptide compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt or solvate or dimer, which is further substituted with 1 to 4 substituents selected from

4. The peptide compound has the amino acid sequences of formula (IV), formula (IV-1), and formula (V), 【Chemistry 4】 Here, Xa １ and Xa ６ The residues between them either form a peptide ring through reaction, or L １ They bond via a linkage to form a peptide ring, Protecting groups are present or absent at the N-terminus and C-terminus. Alternatively, the N-terminus is conjugated with a modifying group, 2-Na and Xa １２ The space between the residues is L １ They bind via and form a peptide ring, and / or Xa ９ and Xa １２ are linked through L １ to form a peptide ring, and / or Lys(Ac) and Xa ７ The space between the residues is L １ They bind via and form a peptide ring, and / or Xa ７ and Xa １１ The space between the residues is L １ They bind via and form a peptide ring, and / or The space between the 2-Nal and Glu residues is L １ They bind via and form a peptide ring, and / or Xa １ The space between the residues of and Glu is L １ They bind via and form a peptide ring, and / or Xa １ and Xa １１ The space between the residues is L １ They bind via and form a peptide ring, and / or Xa １ and Xa １０ The space between the residues is L １ They bind via and form a peptide ring, and / or The space between the 2-Nal and Sarc residues is L １ They bind via and form a peptide ring, and / or Xa ９ The space between the residues of and Sarc is L １ They bind via and form a peptide ring, and / or Xa １１ The space between the residues of and Sarc is L １ They bind via and form a peptide ring, and / or Xa １ The space between Sarc and Glu residues is L １ They bind via and form a peptide ring, and / or or Xa １ , Xa ６ , Xa １０ The molecular scaffold forms a bicyclic peptide, R １ C １－２ Selected from alkyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups, the alkyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups may optionally be F, Cl, Br, =O, methyl groups, ethyl groups, and -CH ２ CH ２ F, -CH ２ CHF ２ ien-CH ２ CF ３ ien-CH ２ F, -CHF ２ , -CF ３ , CN, OH and NH ２ Further substituted with 1 to 4 substituents selected from, The conditions are: (1) Xa at the N-terminus １ and other amino acid residues L １ When bonded via this, there is no protecting group at the N-terminus. (2) The C-terminal Sarc and the residues of other amino acids are L １ The peptide compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein, when bonded via a C-terminal protecting group, the C-terminal protecting group is absent.

5. Xa １ and Xa ６ The residues between them either form a peptide ring through reaction, or L １ A cyclic peptide is formed via Xa ４ and Xa ５ , Xa １ and Xa １０ , Xa ８ and Xa １０ , Xa ８ and Xa １２ , Xa ８ and Xa １３ , Xa ９ and Xa １３ , Xa ５ and Xa ７ , Xa １１ and Xa １３ , Xa １ and Xa １１ , Xa ７ and Xa １１ One or two pairs of residues are directly condensed, or L １ They bond via a linkage to form a peptide ring, or Xa １ , Xa ６ , Xa １０ The molecular scaffold forms a bicyclic peptide, the peptide compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer.

6. The peptide compound is a dimer compound, and the dimer compound is formed by linking the peptide compound and the amino acid residues in the peptide compound via a polyethylene glycol chain, and the polyethylene glycol chain is 【Transformation 5】 And, n is selected from any integer from 0 to 99, and the peptide compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer.

7. The modifying group is, 【Transformation 6】 The peptide compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, solvate, or dimer, wherein p is selected from any integer between 0 and 50, and q is selected from any integer between 0 and 50.

8. Xa １ and Xa ６ The residues are affected by the reaction. 【Transformation 7】 This forms a structure, Here, 【Transformation 8】 The end is Xa １ It is the terminal, Xa １ and Xa ２ teeth, 【Chemistry 9】 Connected via NH ２ The terminal is ligated to a protecting group or NH ２ The terminal end is conjugated with a modifying group, Xa ２ is selected from Asn, His, or an analogue of His, and the analogue of His is 【Chemistry 10】 Selected from, Xa ３ It is selected from Thr, Xa ４ is selected from analogs of Trp, and the analogs of Trp are 【Chemistry 11】 Selected from, Xa ５ is selected from Lys, Gln, Arg, Cit, or analogs of Arg, Lys, and the analogs of Arg, Lys are 【Chemistry 12】 Selected from, As an option, Xa ５ The residue conjugates with the modifying group, Xa ７ is selected from Phe or an analogue of Phe, and the analogue of Phe is 【Chemistry 13】 Selected from, As an option, Xa ７ The residue conjugates with the modifying group, Xa ８ is selected from Phe, Trp, 2-Nal, or analogs of Phe, Trp and 2-Nal, and the analogs of Phe, Trp and 2-Nal are 【Chemistry 14】 Selected from, Xa ９ is selected from Thp or an analogue of Thp, and the analogue of Thp is 【Chemistry 15】 Selected from, Xa １０ This is selected from Glu or Cys. Xa １１ This is selected from Asn or Lys, Xa １２ It is selected from 3-Pal or Phe, The aforementioned molecular scaffold is, 【Chemistry 16】 A peptide compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or dimer thereof, selected from among.

9. L １ The bond consists of a vinyl group, a propenyl group, a butenyl group, and -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-C(=O)-, -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -, -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-, -C(=O)-(CH ２ ) ｒ -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -, -C(=O)-(CH ２ ) ｒ -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-, -C(=O)-(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-C(=O)-, -NH-C(=O)-, -C(=O)-(CH ２ ) ｒ -O-(CH ２ ) ｒ -, -O-(CH ２ ) ｒ -NH-C(=O)-(CH ２ ) ｒ -, - (CH ２ ) ｒ -O-(CH ２ ) ｒ -, -O-(CH ２ ) ｒ -NH-, C １－６ Alkylene group, -C(=O)-, -C(=O)-(CH ２ ) ｒ -NH-, 【Chemistry 17】 -(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-、-O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-、-(CH ２ ) ｒ -NH-、-C(=O)-(CH ２ ) ｒ -O-(CH ２ ) ｒ -NH-、-(CH ２ ) ｒ -NH-C(=O)-(CH ２ ) ｒ -、-C(=O)-(CH ２ )-(OCH ２ CH ２ ) ａ selected from -NH-、 r is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. a is a peptide compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or dimer thereof, selected from 3, 4, 5, or 6.

10. The peptide compound is selected from one of the structures in Table 1, and is a peptide compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, or dimer thereof.

11. A pharmaceutical composition comprising a peptide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

12. Application of a peptide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a pharmaceutical product for preventing and treating a disease or disorder in which IL-23 is overexpressed in the diseased tissue of a subject.

13. The application according to claim 12, wherein the disease or disorder that overexpresses IL-23 includes inflammatory bowel disease, Crohn's disease, and psoriasis.

14. A pharmaceutical composition or pharmaceutical preparation comprising 1 to 1500 mg of a peptide compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

15. A method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a peptide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably inflammatory bowel disease, Crohn's disease, and psoriasis.

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