Peptide inhibitors of interleukin-23 receptor and uses thereof

Abstract

The present invention relates to a peptide inhibitor of an interleukin-23 receptor and a use thereof. In particular, the present invention relates to peptide inhibitors of the interleukin-23 receptor, stereoisomers or pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions thereof, and uses of the peptide inhibitors in the treatment or prevention of diseases or conditions including inflammatory bowel disease, Crohn's disease and psoriasis.

Description

Technical Field

[0001] This disclosure relates to novel peptide inhibitors of the interleukin-23 receptor and their use in treating or preventing a variety of diseases and conditions, including inflammatory bowel disease, Crohn's disease, and psoriasis. Background Technology

[0002] Interleukin-23 (IL-23) cytokines are believed to play a decisive role in the pathogenesis of autoimmune diseases such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD). Studies in mouse models of acute and chronic IBD have shown that IL-23R and downstream effector cytokines play a major role in disease pathogenesis. IL-23R is expressed on a variety of adaptive and innate immune cells, including Th17 cells, γδT cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphocytes, which are abundant in the intestine. Elevated IL-23R gene expression and protein levels have been found on the intestinal mucosal surface in IBD patients. It is believed 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 accumulates in the gut, playing a crucial role in regulating the balance between tolerance and immunity through both T-cell-dependent and T-cell-independent enteritis pathways. This is achieved by acting on helper T cell 1 (Th1) and Th17-related cytokines and by inhibiting regulatory T cell responses in the gut (which are pro-inflammatory). Furthermore, the polymorphism of the IL-23 receptor (IL-23R) has been associated with susceptibility to inflammatory bowel disease (IBD), further establishing the critical role of the IL-23 pathway in intestinal homeostasis.

[0004] Psoriasis is a chronic skin disease affecting 2% to 3% of the general population, and it has been shown to be mediated by a T-cell inflammatory response mechanism. IL-23, one of several interleukins, is considered to play a key role in the pathogenesis of psoriasis, and is believed to maintain chronic autoimmune inflammation by inducing interleukin-17, regulating memory T cells, and activating macrophages. Increased expression of IL-23 and IL-23R has been shown in psoriasis patient tissues, and antibodies neutralizing IL-23 have demonstrated IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0005] IL-23 is a heterodimer composed of a unique p19 subunit and the p40 subunit of IL-12. It is a developmental cytokine of helper T cell 1 (TH1) involved in the production of interferon-γ (IFN-γ). Although both IL-23 and IL-12 contain a p40 subunit, they have different phenotypic properties. For example, IL-12-deficient animals are susceptible to inflammatory autoimmune diseases, while IL-23-deficient animals are resistant, presumably due to a reduced number of CD4+ T cells producing IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. IL-23 binds to IL-23R, a heterodimer receptor composed of the IL-12Rβ1 and IL-23R subunits. The binding of IL-23 to IL-23R activates Jak-stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, although the activation of Stat4 is substantially weaker and it forms a different DNA-binding Stat complex in response to IL-23 compared to IL-12. 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 components that inhibit the IL-23 pathway have been identified for the treatment of IL-23-related diseases. Numerous antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab (a humanized antibody that binds to IL-23), which is already approved for the treatment of psoriasis. Recently, peptide inhibitors that bind to and inhibit the binding of IL-23 to IL-23R have been identified. Clinical trials of ustekinumab and briakinumab (which target the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL-23) in Crohn's disease or psoriasis highlight 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 for the treatment of enteritis, including Crohn's disease, ulcerative colitis, and related conditions, remains challenging.

[0007] Therefore, there remains a need in the art for novel therapies targeting the IL-23 pathway, which can be used to treat and prevent IL-23-related diseases, including those related to autoimmunity. Furthermore, compounds and methods that specifically target IL-23R from the intestinal lumen could provide therapeutic benefits to patients with IBD. This invention addresses these needs by providing novel peptide inhibitors that bind to IL-23R to inhibit IL-23 binding and signal transduction and are suitable for oral administration. Summary of the Invention

[0008] This invention discloses a cyclic peptide inhibitor of the interleukin-23 receptor, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition containing them, and the use of said cyclic peptide inhibitor in the treatment or prevention of diseases including inflammatory bowel disease, Crohn's disease and psoriasis.

[0009] The cyclic peptide compounds of the present invention exhibit protein stability, are stable against plasma proteases, epithelial proteases, gastric and intestinal proteases, lung surface proteases, and intracellular proteases, have specific targeting of IL-23, have a long plasma half-life, and possess good pharmacokinetic and pharmacodynamic characteristics.

[0010] This invention relates to a cyclic peptide compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the peptide compound has an amino acid sequence of formula (I):

[0011] Xa1-HT-Xa4-Xa5-[Pen]-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-Xa 13 (I)(SEQ ID NO: 1)

[0012] in,

[0013] Xa1 is Pen;

[0014] Xa4 is Trp(7-methyl) or Trp(7-cyclopropyl);

[0015] Xa5 is either Lys or Gln;

[0016] Xa7 is

[0017] Xa9 is Thrp or

[0018] Xa 13 It is either Sarc or does not exist;

[0019] The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound is optionally linked to a protecting group;

[0020] At least one amino acid in the cyclic peptide compound is quaternized and / or conjugated with a modifying group, wherein the modifying group comprises a PEG linker or a quaternary ammonium group;

[0021] Alternatively, the cyclic peptide compound Xa1 is linked to the glutamic acid side chain in the sequence of formula (I) to form a ring via a modifying group, wherein the modifying group comprises a PEG linker;

[0022] The conditions are:

[0023] (1) When Xa4 is Trp(7-cyclopropyl), Xa5 is Gln, and Xa9 is... Furthermore, when the modifying group is attached only at Xa1, the modifying group is not:

[0024] (2) When Xa4 is Trp(7-cyclopropyl), Xa5 is Lys, and Xa9 is... When, and only at Xa5, the modifying group is attached, the modifying group is not:

[0025] In some embodiments, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 At least one of the following is conjugated to -LR: 3-Pal or T, wherein L contains a PEG linker, and R is hydrogen, hydroxyl, C 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30 heterofatty acids;

[0026] In some embodiments, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 Or at least one conjugation of -LR in 3-Pal, wherein L contains a PEG linker, and R is hydrogen, hydroxyl, or C. 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30 heterofatty acids;

[0027] In some embodiments, the cyclic peptide compound is conjugated with -LR at at least one of Xa1, Xa5, Xa7, E, or Sarc, wherein the L comprises a PEG linker, and R is hydrogen, hydroxyl, or C. 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C1-30 heterofatty acids;

[0028] In some embodiments, the cyclic peptide compound is conjugated with -LR at at least one of Xa1, Xa5, or Xa7, wherein the L comprises a PEG linker and R is hydrogen, hydroxyl, or C. 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30 heterofatty acids;

[0029] In some embodiments, the cyclic peptide compound Xa1 forms a ring with the glutamate side chain in the sequence of formula (I) via a -L-link;

[0030] In some embodiments, the PEG connector is p is 0-50, q is 1-50;

[0031] In some embodiments, R is hydrogen, hydroxyl, C 1-3 Alkyl, -COC 1-3 Alkyl, -CO halogenated C 1-3 Alkyl, C 1-24 Fatty acids or C 1-24 heterofatty acids;

[0032] In some implementations, the C 1-30 Fatty acids or C 1-30 The following are heterofatty acids: Where n is 1-15;

[0033] In some implementations, the C 1-20 Fatty acids or C 1-20 The following are heterofatty acids: Where n is 1-15;

[0034] In some implementations, the C 1-24 Fatty acids or C 1-24 The following are heterofatty acids: Where n is 2-15;

[0035] In some implementations, the C 1-24 Fatty acids or C 1-24 The following are heterofatty acids: Where n is 4-12;

[0036] In some implementations, the C 1-30 Fatty acids or C 1-30 The following are heterofatty acids:

[0037] In some implementations, the C 1-24 Fatty acids or C 1-24 The following are heterofatty acids:

[0038]

[0039] In some implementations, L is -L1-L2-L3-, where L2 is p is 0-50, q is 1-50; L1 and L3 are each independently a bond, One or more combinations thereof, where m is 0-5, and in some embodiments, m is 1-5;

[0040] In some implementations, L2 is p is 0-10, q is 1-5;

[0041] In some implementations, L2 is p is 1-6, q is 1-4;

[0042] In some implementations, L2 is p = 1-3, q = 1-2;

[0043] In some implementations, L2 is

[0044] In some implementations, L1 and L3 are each independently a key, One or more combinations thereof;

[0045] In some implementations, L1 is a key,

[0046] One or more combinations thereof;

[0047] In some implementations, L3 is One or more combinations thereof; in some embodiments, L3 is

[0048] In some implementations, L is:

[0049] p = 1-3, q = 1-2, m = 1-2;

[0050] In some implementations, L is:

[0051]

[0052] p = 1-3, q = 1-2;

[0053] In some implementations, L is:

[0054]

[0055]

[0056] In some implementations, L is:

[0057] In some embodiments, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 At least one of 3-Pal or T is quaternized and / or conjugated with a modifying group, said modifying group comprising quaternary ammonium;

[0058] In some embodiments, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 At least one of 3-Pal is quaternized and / or conjugated with a modifying group, the modifying group comprising a quaternary ammonium;

[0059] In some embodiments, the cyclic peptide compound is quaternized and / or conjugated with a modifying group at least at one of Xa1, Xa5, Xa7, E, or Sarc, the modifying group comprising a quaternary ammonium group;

[0060] In some embodiments, the cyclic peptide compound is quaternized and / or conjugated with a modifying group at at least one of Xa1, Xa5, or Xa7, the modifying group comprising a quaternary ammonium group.

[0061] The present invention also relates to a peptide dimer compound, its stereoisomer or its pharmaceutically acceptable salt, wherein two cyclic peptide compounds are linked together via one or more linkers selected from diethylene glycol, iminodiacetic acid (IDA), β-Ala-iminodiacetic acid (β-Ala-IDA) or polyethylene glycol to form a peptide dimer, said cyclic peptide compound having an amino acid sequence as shown in formula (I).

[0062] In some embodiments, the two cyclic peptide compounds are linked via polyethylene glycol to form a peptide dimer;

[0063] In some embodiments, the two cyclic peptide compounds are via The peptide dimers are linked together, with t ranging from 0 to 99.

[0064] In some embodiments, the two cyclic peptide compounds are via The peptide dimers are formed by linking, with t ranging from 0 to 10.

[0065] The present invention also relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has an amino acid sequence of formula (II-1), (II-2), (II-3), (II-4):

[0066] Pen-HT-[Trp(7-methyl)]-Gln-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-1)(SEQ ID NO: 2)

[0067] Pen-HT-[Trp(7-methyl)]-Lys-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-2)(SEQ ID NO: 3)

[0068] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-3)(SEQ ID NO: 4)

[0069] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-[Sarc] (II-4)(SEQ ID NO: 5)

[0070] Xa1 and Xa6 are Pen or Furthermore, Xa1 and Xa6 are not both Pen;

[0071] Xa7 is

[0072] Xa9 is

[0073] The cyclic peptide compound is cyclized via Pen-Pen or Xa1-Xa6 disulfide bonds;

[0074] Alternatively, the terminal amino group of the side chain of amino acids Pen, Gln, Lys, or Xa7 or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, amino acid, or α-hydroxyisobutyric acid.

[0075] The cyclic peptide compound is optionally linked to a protecting group;

[0076] The condition is that the cyclic peptide compound is not...

[0077] In some embodiments, the protecting group is a hydroxyl group, NH2, or C. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, Gly, Ser;

[0078] In some embodiments, the protecting group is a hydroxyl group, NH2, or C. 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2、-COC 1-3 Alkyl or -CO halogenated C 1-3 alkyl;

[0079] In some embodiments, the protecting group is a hydroxyl group, NH2, methyl group, -N(CH3)2, -COCH3, or -COCF3;

[0080] In some embodiments, the protecting group is an amino protecting group, selected from acetyl groups;

[0081] In some embodiments, the terminal amino group of the side chain of amino acids Pen, Gln, Lys, Xa7, or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, serine, or α-hydroxyisobutyric acid.

[0082] In some embodiments, the terminal amino group of the side chain of amino acids Pen, Gln, Lys, or Xa7 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, or serine.

[0083] In some implementations, n is 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0084] In some implementations, p is 1, 2, 3, 4, 5, or 6;

[0085] In some implementations, q is 1, 2, 3, or 4;

[0086] In some implementations, m is 0, 1, 2, 3, 4, or 5;

[0087] In some implementations, m is 0, 1, or 2;

[0088] In some implementations, m is 1, 2, 3, 4, or 5;

[0089] In some implementations, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0090] Specifically, the first embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has the amino acid sequence of formula (I):

[0091] Xa1-HT-Xa4-Xa5-[Pen]-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-Xa 13 (I)(SEQ ID NO: 1)

[0092] in:

[0093] Xa1 is Pen;

[0094] Xa4 is Trp(7-methyl) or Trp(7-cyclopropyl);

[0095] Xa5 is either Gln or Lys;

[0096] Xa7 is

[0097] Xa9 is Thrp or

[0098] Xa 13 It is either Sarc or does not exist;

[0099] The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound is optionally linked to a protecting group;

[0100] At least one amino acid in the cyclic peptide compound is quaternized and / or conjugated with a modifying group, wherein the modifying group comprises a PEG linker or a quaternary ammonium group;

[0101] Alternatively, the cyclic peptide compound Xa1 is linked to the glutamic acid side chain in the sequence of formula (I) to form a ring via a modifying group, wherein the modifying group comprises a PEG linker;

[0102] The conditions are:

[0103] (1) When Xa4 is Trp(7-cyclopropyl), Xa5 is Gln, and Xa9 is... Furthermore, when the modifying group is attached only at Xa1, the modifying group is not:

[0104] (2) When Xa4 is Trp(7-cyclopropyl), Xa5 is Lys, and Xa9 is... When, and only at Xa5, the modifying group is attached, the modifying group is not:

[0105] The second specific embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has the amino acid sequence of formula (I):

[0106] Xa1-HT-Xa4-Xa5-[Pen]-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-[Sarc](I) (SEQ ID NO: 1)

[0107] in:

[0108] Xa1 is Pen;

[0109] Xa4 is Trp(7-methyl) or Trp(7-cyclopropyl);

[0110] Xa5 is either Gln or Lys;

[0111] Xa7 is

[0112] Xa9 is Thrp or

[0113] The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound is optionally linked to a protecting group;

[0114] At least one amino acid in the cyclic peptide compound is quaternized and / or conjugated with a modifying group, wherein the modifying group comprises a PEG linker or a quaternary ammonium group;

[0115] Alternatively, the cyclic peptide compound Xa1 is linked to the glutamic acid side chain in the sequence of formula (I) to form a ring via a modifying group, wherein the modifying group comprises a PEG linker;

[0116] The conditions are:

[0117] (1) When Xa4 is Trp(7-cyclopropyl), Xa5 is Gln, and Xa9 is... Furthermore, when the modifying group is attached only at Xa1, the modifying group is not:

[0118] (2) When Xa4 is Trp(7-cyclopropyl), Xa5 is Lys, and Xa9 is... When, and only at Xa5, the modifying group is attached, the modifying group is not:

[0119] Specifically, in the third embodiment, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 At least one of the following is conjugated to -LR: 3-Pal or T, wherein L contains a PEG linker, and R is hydrogen, hydroxyl, C 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30 Mixed fatty acids; alternatively, the cyclic peptide compound Xa1 forms a ring with the glutamic acid side chain in the sequence of formula (I) via a -L-link.

[0120] Specifically, in the fourth embodiment, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 Or at least one conjugation of -LR in 3-Pal, wherein L contains a PEG linker, and R is hydrogen, hydroxyl, or C. 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30 Mixed fatty acids; alternatively, the cyclic peptide compound Xa1 forms a ring with the glutamic acid side chain in the sequence of formula (I) via a -L-link.

[0121] In a specific fifth embodiment, the cyclic peptide compound is conjugated with -LR at least once in Xa1, Xa5, Xa7, E, or Sarc, wherein L comprises a PEG linker, and R is hydrogen, hydroxyl, or C. 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30 Mixed fatty acids; alternatively, the cyclic peptide compound Xa1 forms a ring with the glutamic acid side chain in the sequence of formula (I) via a -L-link.

[0122] In a specific sixth embodiment, the cyclic peptide compound is conjugated with -LR at least once in Xa1, Xa5, or Xa7, wherein L comprises a PEG linker, and R is hydrogen, hydroxyl, or C. 1-6 Alkyl, -COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, C 1-30 Fatty acids or C 1-30Mixed fatty acids; alternatively, the cyclic peptide compound Xa1 forms a ring with the glutamic acid side chain in the sequence of formula (I) via a -L-link.

[0123] Specifically, in the seventh implementation scheme, wherein C 1-30 Fatty acids or C 1-30 The following are heterofatty acids: Where n is between 1 and 15.

[0124] Specifically, in the eighth implementation scheme, wherein C 1-24 Fatty acids or C 1-24 The following are heterofatty acids: Where n is 2-15.

[0125] Specifically, in the ninth implementation scheme, L stands for -L1-L2-L3-, where L2 is... p is 0-50, q is 1-50; L1 and L3 are each independent bonds. One or more combinations of these, where m is 0-5;

[0126] The preferred value for L is: p = 1-3, q = 1-2, m = 1-2.

[0127] In the specific tenth implementation scheme, L stands for -L1-L2-L3-, where L2 is... p is 0-50, q is 1-50; L1 and L3 are each independently a bond, One or more combinations of these, where m is 0-5;

[0128] In some implementations, L is:

[0129] p is 1-3, q is 1-2.

[0130] Specifically, in the eleventh implementation scheme, L stands for -L1-L2-L3-, where L2 is... p is 0-50, q is 1-50; L1 and L3 are each independently a bond, One or more combinations of these, where m is 0-5;

[0131] In some implementations, L is:

[0132] p is 1-3, q is 1-2.

[0133] Specifically, in the twelfth embodiment, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 At least one of 3-Pal or T is quaternized and / or conjugated with a modifying group, said modifying group comprising quaternary ammonium.

[0134] Specifically, in the thirteenth embodiment, the cyclic peptide compound is in Xa1, Xa5, Xa7, E, Xa 13 At least one of 3-Pal is quaternized and / or conjugated with a modifying group, the modifying group comprising a quaternary ammonium.

[0135] In the fourteenth embodiment, the cyclic peptide compound is quaternized and / or conjugated with a modifying group at least at one of Xa1, Xa5, Xa7, E, or Sarc, the modifying group comprising a quaternary ammonium group.

[0136] In the specific fifteenth embodiment, the cyclic peptide compound is quaternized and / or conjugated with a modifying group at least at one of Xa1, Xa5, or Xa7, the modifying group comprising a quaternary ammonium.

[0137] The sixteenth specific embodiment relates to a peptide dimer compound, its stereoisomer or its pharmaceutically acceptable salt, wherein two cyclic peptide compounds are linked together via one or more linkers selected from diethylene glycol, iminodiacetic acid (IDA), β-Ala-iminodiacetic acid (β-Ala-IDA) or polyethylene glycol to form a peptide dimer, said cyclic peptide compound having an amino acid sequence of formula (I) as described in any of the preceding embodiments.

[0138] The seventeenth specific embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has an amino acid sequence of formula (II-1), (II-2), (II-3), (II-4):

[0139] Pen-HT-[Trp(7-methyl)]-Gln-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-1)(SEQ ID NO: 2)

[0140] Pen-HT-[Trp(7-methyl)]-Lys-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-2)(SEQ ID NO: 3)

[0141] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-3)(SEQ ID NO: 4)

[0142] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-[Sarc] (II-4)(SEQ ID NO: 5)

[0143] Xa1 and Xa6 are Pen or Furthermore, Xa1 and Xa6 are not both Pen;

[0144] Xa7 is

[0145] Xa9 is

[0146] The cyclic peptide compound is cyclized via Pen-Pen or Xa1-Xa6 disulfide bonds;

[0147] Alternatively, the terminal amino group of the side chain of amino acids Pen, Gln, Lys, Xa7, or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, amino acid, or α-hydroxyisobutyric acid.

[0148] The cyclic peptide compound is optionally linked to a protecting group;

[0149] The condition is that the cyclic peptide compound is not...

[0150] Specifically, the eighteenth embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has an amino acid sequence of formula (II-1), (II-2):

[0151] Pen-HT-[Trp(7-methyl)]-Gln-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-1)(SEQ ID NO: 2)

[0152] Pen-HT-[Trp(7-methyl)]-Lys-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-2)(SEQ ID NO: 3)

[0153] Xa7 is

[0154] The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound is optionally linked to a protecting group;

[0155] Alternatively, the terminal amino groups of the side chains of amino acids Pen, Gln, Lys, and Xa7 are condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, and amino acids.

[0156] The condition is that the cyclic peptide compound is not...

[0157] Specifically, the nineteenth embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has an amino acid sequence of formula (II-1), (II-2):

[0158] Pen-HT-[Trp(7-methyl)]-Gln-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-1)(SEQ ID NO: 2)

[0159] Pen-HT-[Trp(7-methyl)]-Lys-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-2)(SEQ ID NO: 3)

[0160] Xa7 is

[0161] The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound is optionally linked to a protecting group;

[0162] Alternatively, the terminal amino groups of the side chains of amino acids Pen, Gln, and Lys are condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, and amino acids.

[0163] The condition is that the cyclic peptide compound is not...

[0164] The twentieth embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has an amino acid sequence of formula (II-1), (II-3), (II-4):

[0165] Pen-HT-[Trp(7-methyl)]-Gln-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-1)(SEQ ID NO: 2)

[0166] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-3)(SEQ ID NO: 4)

[0167] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-[Sarc] (II-4)(SEQ ID NO: 5)

[0168] Xa1 and Xa6 are each independently selected from Pen or Furthermore, Xa1 and Xa6 are not both Pen; in some implementations, Xa1 and Xa6 are Pen,

[0169] Xa7 is

[0170] Xa9 is

[0171] The cyclic peptide compound is cyclized via Pen-Pen or Xa1-Xa6 disulfide bonds;

[0172] The terminal amino group of the side chain of amino acid Pen, Gln, Lys, Xa7, or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, amino acid, or α-hydroxyisobutyric acid; in some embodiments, the terminal amino group of the side chain of amino acid Pen, Lys, Xa7, or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, amino acid, or α-hydroxyisobutyric acid.

[0173] Alternatively, the cyclic peptide compound Xa1 is linked to the glutamic acid side chain in the sequences of formulas (II-3) and (II-4) via a PEG linker to form a ring;

[0174] The cyclic peptide compound is optionally linked to a protecting group.

[0175] Furthermore, the present invention relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has an amino acid sequence of formula (II-3), (II-4):

[0176] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-3)(SEQ ID NO: 4)

[0177] Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-[Sarc] (II-4)(SEQ ID NO: 5)

[0178] Xa1 and Xa6 are each independently selected from Pen or Furthermore, Xa1 and Xa6 are not both Pen; in some implementations, Xa1 and Xa6 are Pen,

[0179] Xa7 is

[0180] Xa9 is

[0181] The cyclic peptide compounds Xa1-Xa6 form disulfide cyclization;

[0182] The amino group at the terminal side chain of amino acid Pen, Lys, Xa7, or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, amino acid, or α-hydroxyisobutyric acid; in some embodiments, the amino group at the terminal side chain of amino acid Pen or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, or α-hydroxyisobutyric acid; in some embodiments, the amino group at the terminal side chain of amino acid Pen or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, or 2-methyllactic acid.

[0183] The cyclic peptide compound is optionally linked to a protecting group; in some embodiments, the protecting group is selected from hydroxyl, NH2, C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, Gly, Ser; in some embodiments, the protecting group of the carboxyl group is selected from amino groups, and the protecting group of the amino group is -COC. 1-3 Alkyl group; in some embodiments, the protecting group of the carboxyl group is selected from amino groups, and the protecting group of the amino group is an acetyl group.

[0184] Specifically, the twenty-first embodiment relates to a cyclic peptide compound as described in the twenty-tenth embodiment, its stereoisomer, or its pharmaceutically acceptable salt, wherein the protecting group is selected from hydroxyl, NH2, C... 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, Gly, Ser.

[0185] Specifically, in the twenty-second embodiment, a cyclic peptide compound as described in the twenty-first or twenty-first embodiment, its stereoisomer, or its pharmaceutically acceptable salt, wherein the PEG linker is... p is 0-50, q is 1-50; in some implementations, p is 1-10, q is 1-10; in some implementations, p is 1-5, q is 1-3; in some implementations, p is 3, q ​​is 1.

[0186] Specifically, the twenty-third embodiment relates to a cyclic peptide compound, its stereoisomer or its pharmaceutically acceptable salt, wherein the cyclic peptide compound has the amino acid sequence of formula (II-2):

[0187] Xa1-HT-[Trp(7-methyl)]-Lys-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-2)(SEQ ID NO: 3)

[0188] Xa1 is Pen;

[0189] Xa7 is

[0190] The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound Xa1 is linked to the glutamic acid side chain in the (II-2) sequence via a PEG linker to form a ring; in some embodiments, the PEG linker is... p is 0-50, q is 1-50; in some implementations, p is 1-10, q is 1-10; in some implementations, p is 1-5, q is 1-3; in some implementations, p is 3, q ​​is 1.

[0191] In the specific twenty-fourth embodiment, the compound is selected from one of the structures in Table 1 below:

[0192] Table 1:

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] The present invention also relates to a pharmaceutical composition comprising the peptide compound or a pharmaceutically acceptable salt thereof described in any of the foregoing technical solutions, and a pharmaceutically acceptable carrier and / or excipient.

[0200] The present invention also relates to an application of the peptide compound or its pharmaceutically acceptable salt, or the pharmaceutical composition described in any of the foregoing technical solutions, in the preparation of a medicament for the prevention and treatment of diseases or conditions in which IL-23 is overexpressed in diseased tissues of a subject.

[0201] Furthermore, the diseases or conditions that overexpress IL-23 include inflammatory bowel disease, Crohn's disease, and psoriasis.

[0202] The present invention also relates to a pharmaceutical composition or pharmaceutical formulation comprising 1-1500 mg of the peptide compound or a pharmaceutically acceptable salt thereof as described in any of the foregoing technical solutions, and a pharmaceutically acceptable carrier and / or excipient.

[0203] The present invention also relates to a method for treating diseases in mammals or humans, the method comprising administering to a subject a therapeutically effective amount of the peptide compound or a pharmaceutically acceptable salt thereof described in any of the foregoing technical solutions, preferably 1-1500 mg, wherein the disease is preferably inflammatory bowel disease, Crohn's disease, or psoriasis.

[0204] The present invention also provides a composition or pharmaceutical formulation comprising the peptide compound or a pharmaceutically acceptable salt thereof as described in any of the foregoing embodiments, and a pharmaceutically acceptable carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (unit dosage is also referred to as a “dosage strength”).

[0205] Furthermore, the compositions or pharmaceutical preparations of the present invention contain 1-1500 mg of the peptide compound or a pharmaceutically acceptable salt thereof described in any of the foregoing schemes, as well as a pharmaceutically acceptable carrier and / or excipients.

[0206] The present invention also provides the use of the peptide compound or a pharmaceutically acceptable salt thereof described in any of the foregoing embodiments in the preparation of a medicament for the prevention and treatment of diseases or conditions in which IL-23 is overexpressed in diseased tissues of a subject. Further, the diseases or conditions in which IL-23 is overexpressed include inflammatory bowel disease, Crohn's disease, and psoriasis.

[0207] The present invention also provides a method for treating diseases in mammals or humans, the method comprising administering to a subject a therapeutically effective amount of the peptide compound or a pharmaceutically acceptable salt thereof as described in any of the foregoing embodiments, wherein the disease is preferably inflammatory bowel disease, Crohn's disease, and psoriasis, and the therapeutically effective amount is preferably 1-1500 mg. In some embodiments, the mammals described in the present invention do not include humans.

[0208] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application or a pharmaceutically acceptable salt thereof required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 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, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 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;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, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0209] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of the peptide compound of the present invention or a pharmaceutically acceptable salt thereof;

[0210] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the peptide compound of the invention or a pharmaceutically acceptable salt thereof, along with a carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 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, 23 mg, etc. The peptide compounds of the present invention or pharmaceutically acceptable salts thereof are present in the following amounts: 0 mg, 240 mg, 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.

[0211] A method for treating a disease in mammals or humans, 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, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being inflammatory bowel disease, Crohn's disease, and psoriasis.

[0212] A method for treating a disease in mammals or humans. The method comprises administering a pharmaceutically acceptable peptide compound of the present invention or a pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier and / or excipient, to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 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, 100-1000 mg / day, etc. The daily dose may be 1 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, or 200-400 mg / day. In some embodiments, the daily dose may include, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, or 1500 mg / day.

[0213] This invention relates to a kit that may comprise a single-dose or multi-dose composition containing a peptide compound of the invention or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is the same as that in the pharmaceutical composition described above.

[0214] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0215] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0216] the term

[0217] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature used in conjunction with the chemical, molecular biological, cell and cancer biological, immunological, microbiological, pharmacological, and protein and nucleic acid chemistry described herein, as well as the techniques used in these fields, are well known and commonly used in the art. In case of any discrepancy, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0218] As used herein, the following terms have the meanings assigned to them unless otherwise stated.

[0219] Throughout this specification, the word “comprising” or variations thereof such as “containing” or “including” should be understood to mean that the said integer (or component) or group of integers (or components) is included, but does not exclude the possibility that any other integers (or components) or group of integers (or components) may be included further.

[0220] In a broad sense, a peptide is a sequence of two or more amino acids linked together by peptide bonds. It should be understood that the term does not imply a polymer of amino acids 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.

[0221] The peptides provided by the present invention may contain at least 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity. Therefore, the polypeptide provided by the present invention comprises having at least 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity with the sequence of formula (I).

[0222] "Sequence identity," "identity percentage," "homology percentage," or, for example, "50% identical to...", refers to the degree of sequence similarity based on nucleotide to nucleotide or amino acid to amino acid within a comparison window. Therefore, the "sequence identity percentage" can be calculated as follows: comparing two best-aligned sequences within a comparison window, determining the number of identical nucleic acid bases (e.g., A, T, C, G, I) or identical amino acid residues (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) in both sequences to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to obtain the sequence identity percentage. Sequence similarity or sequence identity (the terms are used interchangeably herein) between sequences can be calculated as follows. To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., for optimal alignment, vacancies can be introduced into one or both of the first and second amino acid or nucleic acid sequences; while for comparison purposes, non-homologous sequences can be ignored). In some embodiments, the length of the reference sequence for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position.

[0223] The percentage of identity between two sequences is a function of the number of common positions in the sequences (taking into account the number of gaps that must be introduced for optimal alignment of the two sequences and the length of each gap).

[0224] It should be understood that the peptide sequences disclosed herein are shown from left to right, with the left end of the sequence representing the N-terminus of the peptide and the right end representing the C-terminus. The sequences disclosed herein are those incorporating a "Hy-" portion at the amino terminus (N-terminus) and a "-OH" or "-NH2" portion at the carboxyl terminus (C-terminus). In such cases, and unless otherwise stated, the "Hy-" portion at the N-terminus of the discussed sequence represents a hydrogen atom, corresponding to the presence of a free primary or secondary amino group at the N-terminus, while the "-OH" or "NH2" portion at the C-terminus represents a hydroxyl or amino group, respectively, corresponding to the presence of an amide (CONH2) group at the C-terminus. In the sequences of this invention, the C-terminal "-OH" portion may replace the C-terminal "-NH2" portion, and vice versa.

[0225] The term "protecting group" refers to the protecting group at the free amino and / or carboxyl terminus of an amino acid residue in a polypeptide. Preferred protecting groups include, but are not limited to, acetyl, amide, alkyl groups of 3-20 carbon atoms, Fmoc, t-boc, 9-fluorenacetyl, 1-fluorencarboxyl, 9-fluorencarboxyl, 9-fluorenone-1-carboxyl, benzyloxycarbonyl, xanthonyl (Xan), triphenylmethyl (Trt), 4-methyltriphenylmethyl (Mtt), 4-methoxytriphenylmethyl (Mmt), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), 1,3,5-trimethylbenzene-2-sulfonyl (Mts), 4,4-dimethoxydiphenylmethyl (Mbh), toluenesulfonyl (Tos), and 2,2,5,7,8-pentamethylbenzodihydropyran (chroman)-6-sulfonyl (Pmc). 4-Methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO), benzyl (Bzl), benzoyl (Bz), 3-nitro-2-pyridinesulfonyl (sulphenyl)(Npys), 1-(4,4-dimentyl-2,6-diazocyclohexyl)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), benzyloxymethyl (Bom), t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-butyl (tBu), acetyl (Ac), benzoyl, benzyloxycarbonyl, propyl, butyl, pentyl, hexyl and trifluoroacetyl (TFA). In some embodiments, the polypeptide of the present invention contains a protecting group coupled to the amino terminus, said amino-terminal protecting group being C 1-6 Alkyl, -COC 1-6 Alkyl or -CO halogenated C 1-6Alkyl group. In some embodiments, the polypeptide of the present invention contains a protecting group coupled to a carboxyl terminus, said carboxyl terminus being NH2 or -NHC. 1-3 Alkyl, -N(C) 1-3 Alkyl)2.

[0226] The term "NH2" may refer to a free amino group present at the amino terminus of a peptide. The term "OH" as used herein may refer to a free carboxyl group present at the carboxyl terminus of a peptide. Additionally, the term "Ac" as used herein refers to acetyl protection formed by acylation of the C-terminus or N-terminus of the peptide. In some peptides shown herein, NH2 at the C-terminus indicates an amino group.

[0227] The term "quaternary ammonium" is used in its common sense in the art. For example, a quaternary ammonium is a substituent containing one or more permanently positively charged nitrogen atoms. A non-limiting example of a quaternary ammonium can be a moiety having four organic substituents on a nitrogen atom, typically described by the formula NR4+X-, where R is any chemically permissible substituent, including acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds, and X is a suitable counterion (or anion), a negatively charged group associated with the positively charged quaternary ammonium to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F, Cl, Br, I), NO3-, ClO4-, OH-, H2PO4-, HSO4-, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic-5-sulfonate, ethane-1-sulfonic-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.). "Quaternization" refers to the reaction with the aforementioned R groups to form quaternary ammonium compounds. It should be understood that quaternization of amino acids in the cyclic peptide compounds of this invention means that the NH2 residue on the amino acid residue can be quaternized.

[0228] "Fatty acid" refers to a long aliphatic hydrocarbon chain that is fully saturated or contains one or more unsaturated units, and is either straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, and has a carboxyl group at at least one end. The fatty acid preferably has 1 to 30 carbon atoms, i.e., "C". 1-30 "Fatty acids", preferably having 1 to 24 carbon atoms (i.e., C64) 1-24 Fatty acids), more preferably having 1 to 22 carbon atoms (i.e., C64-22 carbon atoms). 1-22Fatty acids). Non-limiting examples include: lauric acid, myristic acid, hard fatty acids, soft fatty acids, arachidic acid, horny acid, palmitic acid, oleic acid, isoleic acid, nervonic acid, linoleic acid, α-linolenic acid, γ-linolenic acid, arachidonic acid, EPA, DPA, DHA, sebacic acid, C12 diacid, C14 diacid, C16 diacid, C18 diacid, C20 diacid, etc. "Heterofatty acids" refer to fatty acids having at least one heteroatom, that is, one or more carbon atoms in a fatty acid are surrounded by at least one heteroatom (e.g., nitrogen, oxygen, P(O)). m and S(O) n (where m and n are integers from 0 to 2) are replaced by heteroatoms, and non-limiting examples include: 9-hydroxynonanoic acid.

[0229] Exemplary C 1-24 Fatty acids or C 1-24 heterofatty acids

[0230]

[0231]

[0232] "Polyethylene glycol" or "PEG" is a polyether compound with the general formula H-(O-CH2-CH2)n-OH. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on their molecular weight, but PEG tends to refer to oligomers and polymers with a molecular weight less than 20,000 Da. In some embodiments, PEG with a molecular weight of 50 to 2,000 or 100 to 500 is used. Different forms of PEG can also be used, depending on the initiator used in the polymerization process—common initiators are monofunctional methyl ether PEG or methoxylated poly(ethylene glycol) (abbreviated as mPEG). In some embodiments, PEG is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In some embodiments, the PEG connector is...

[0233] The term "carboxyl group" refers to -COOH, and "Ac" refers to "acetyl group".

[0234] The term "connector" broadly refers to a chemical structure that can link or combine two peptide monomer subunits to form a dimer.

[0235] The term "dimer" broadly refers to a peptide containing two or more monomeric subunits. Some dimers contain two DRPs. The dimers of this invention include homodimers and heterodimers. The monomeric subunits of the dimer may be linked at their C-terminus or N-terminus, or they may be linked via internal amino acid residues. The monomeric subunits of the dimer may be linked through the same site, or each may be linked through different sites (e.g., C-terminus, N-terminus, or internal sites).

[0236] The term "cyclization" or "forming a peptide ring" refers to a reaction in which a portion of a polypeptide molecule links with another portion of the polypeptide molecule to form a closed ring, or a portion of a polypeptide molecule links with several other portions of the polypeptide molecule to form multiple closed rings, such as by forming a disulfide bridge or other similar bond, or by linker linkage.

[0237] "Derivative" or "analyte" refers to a product derived from a compound by replacing a hydrogen atom or group of atoms with another atom or group of atoms. It should be understood that amino acid analogs of peptide compounds as defined herein are within the scope of this invention. Examples of such suitable modified amino acid derivatives include one or more modifications selected from: N-terminal and / or C-terminal modifications; replacement of one or more amino acid residues with one or more non-natural amino acid residues (e.g., replacement of one or more polar amino acid residues with one or more isosteric or isoelectronic amino acids; replacement of one or more non-polar amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of a spacer group; replacement of one or more oxidatively resistant amino acid residues with one or more oxidatively resistant amino acid residues; replacement of one or more amino acid residues with alanine, or replacement 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 a bicyclic peptide ligand; replacement of surrogate bonds. Replace one or more peptide bonds with another chemical group; modify the length of the peptide backbone; replace or substitute the hydrogen on the α carbon of one or more amino acid residues with another chemical group; modify amino acids such as glycine, alanine, phenylalanine, cysteine, lysine, glutamic acid / aspartic acid, and tyrosine with suitable amine, thiol, carboxylic acid, and phenolic reactive reagents to functionalize the amino acids; and introduce or replace amino acids to introduce orthogonal reactivity suitable for functionalization, for example, amino acids carrying azide or alkyne groups are respectively allowed to be functionalized with the alkyne or azide-carrying portions.

[0238] In the specific chemical structure of this invention, * indicates that the atom has a single optical configuration, such as R or S configuration.

[0239] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly or conventionally understood by one of ordinary skill in the art. In chemistry, dashes before or at the end of chemical groups are for convenience; chemical groups may or may not be described with one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in a structure indicate the attachment point of a group. Dashed lines indicate optional bonds. Unless chemically or structurally required, the order in which chemical groups are written or the connection point of a chemical group to the rest of the molecule does not indicate or imply directionality. For example, the group “-SO2CH2-” is equivalent to “-CH2SO2-” and can be attached in either direction. Similarly, the “arylalkyl” group may, for example, be attached to the rest of the molecule at the aryl or alkyl portion of the group. “Cu-v” or (Cu-Cv) indicates that the following groups have u to v carbon atoms. For example, “C…” 1-6 Both "alkyl" and "C1-C6 alkyl" indicate that an alkyl group has 1 to 6 carbon atoms.

[0240] Throughout this specification, unless naturally occurring amino acids are referred to by their full names (e.g., alanine, arginine, etc.), they are designated by conventional three-letter or one-letter abbreviations (e.g., Ala or A for alanine; Arg or R for arginine, etc.). Unless otherwise stated, the three-letter and one-letter abbreviations for amino acids refer to the L-isomers of the amino acid under discussion. The term "L-amino acid" as used herein refers to the "L" isomer of the peptide, and conversely, the term "D-amino acid" refers to the "D" isomer of the peptide (e.g., Dasp, (D)Asp, or D-Asp; Dphe, (D)Phe, or D-Phe). The amino acid residues in the D isomers may substitute for any L-amino acid residue, provided that the peptide retains the desired function. When referred to using one-letter abbreviations, D-amino acids may be conventionally represented by lowercase letters.

[0241] In the case of uncommon or non-naturally occurring amino acids, unless they are mentioned by their full names (e.g., sarcosine, ornithine, etc.), their residues are usually represented by common three- or four-character codes, including Sar or Sarc (sarcosine, i.e., N-methylglycine), Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutyric acid), Dapa (2,3-diaminopropionic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidine-3-carboxylic acid), 8Ado (8-amino-3,6-dioxanoic acid), Abu (2-aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenylalanine), and Bip (β,β-diphenylalanine), as well as Ida (iminodiacetic acid).

[0242] Unless otherwise specified, all amino acids are used in the L-configuration.

[0243] The following table lists some common amino acid names and their three-letter and single-letter abbreviations:

[0244]

[0245]

[0246] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0247] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0248] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0249] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0250] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0251] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0252] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0253] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0254] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0255] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0256] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0257] In the examples, the asterisk (*) in the chemical structure indicates a single configuration R or S.

[0258] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Detailed Implementation

[0259] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0260] Detection method: The structure of the compound was determined by mass spectrometry (MS).

[0261] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0262] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0263] 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.

[0264] Example

[0265] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0266] Intermediate 1:

[0267]

[0268] Step 1: Compound 1a (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 above reaction solution. The mixture was cooled to 0 °C. After 5 min, 1,1-dichlorodimethyl ether (9.4 g, 81.51 mmol) was added dropwise, and the mixture was stirred at 0 °C for 3 h. After the reaction was completed, 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 subjected to column chromatography (EA:PE = 1:4) to obtain compound 1b (5.58 g, 46.3%).

[0269] LC-MS (ESI): m / z = 163.2 [M+H] + .

[0270] Step 2: Compound 1b (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 h. After the reaction was complete, 100 mL of water was added, and the reaction solution was extracted three times with ethyl acetate (50 mL × 3). The solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (EA:PE = 4:1) to obtain compound 1c (4.9 g, 87%).

[0271] LC-MS (ESI): m / z = 306.1 [M+H] + .

[0272] Step 3: Trimethyl benzyloxycarbonyl-α-phosphonoglycine (6.2 g, 18.74 mmol) was dissolved in dichloromethane (100 mL), purged with nitrogen, and DBU (3.1 g, 20.31 mmol) was added and stirred for 30 min. Then, compound 1c (4.8 g, 15.62 mmol) dissolved in dichloromethane (100 mL) was added dropwise to the reaction mixture, and the mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 5% citric acid aqueous solution (100 mL) and saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Compound 1d (6.1 g, 76.2%) was purified by silica gel column chromatography (EA:PE = 3:1).

[0273] LC-MS(ESI): m / z = 511.1 [M+H] + .

[0274] Step 4: Compound 1d (6.0 g, 11.71 mmol) was dissolved in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), and (+)-1,2-bis(2S,5S)-2,5-diethylcyclobutanphosphine (cyclooctadiene) rhodium trifluoromethanesulfonate (0.6 g, 0.83 mmol) was added. The autoclave was filled with hydrogen gas to a pressure of about 4.0 bar, stirred at room temperature for 3 h, the solid was filtered off, and the reaction solution was concentrated to obtain compound 1e (5.9 g, 98%).

[0275] LC-MS (ESI): m / z = 513.2 [M+H] + .

[0276] Step 5: Dissolve compound 1e (5.9 g, 11.46 mmol) in a mixed solution of methanol (50 mL) and dichloromethane (20 mL), add palladium on carbon (10%, 1 g), stir overnight under hydrogen atmosphere, then filter off the solid, and evaporate the reaction solution to dryness to obtain compound 1f (3.7 g, 84.5%).

[0277] LC-MS (ESI): m / z = 379.4 [M+H] + .

[0278] Step 6: Compound 1f (3.7g, 9.72mmol) was dissolved in tetrahydrofuran (25mL), and lithium hydroxide monohydrate (1.2g, 48.6mmol) and water (25mL) were added. The reaction was stirred overnight at room temperature. Impurities were extracted with ethyl acetate (15mL x 3). The pH of the aqueous phase was then adjusted to neutral with dilute hydrochloric acid (1N). The product precipitated, filtered, and dried to give compound 1g (3.2g, 89.8%).

[0279] LC-MS (ESI): m / z = 365.2 [M+H] + .

[0280] Step 7: Dissolve 1 g (2.7 g, 7.41 mmol) of the compound in a mixed solution of acetonitrile (25 mL) and water (25 mL), add sodium bicarbonate (6.2 g, 74.16 mmol) and 9-fluorenylmethyl-N-succinimide carbonate (3.3 g, 9.63 mmol), and stir the reaction overnight at room temperature. After the reaction is complete, add dilute hydrochloric acid to adjust the pH to neutral. Concentrate under vacuum at 40 °C to remove most of the acetonitrile, filter and collect the solid to obtain the crude product, and separate and purify it using silica gel column chromatography (DCM:MeOH = 10:1) to obtain intermediate 1 (2.7 g, 62.1%).

[0281] LC-MS (ESI): m / z = 587.2 [M+H] + .

[0282] 1 H NMR (400MHz, DMSO-d6) δ12.65(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).

[0283] Intermediate 4:

[0284]

[0285] Step 1: A dichloromethane solution (50 mL) of intermediate 1 (35.0 g, 71.93 mmol) was added to a mixed solution of dichloromethane (100 mL) and trifluoroacetic acid (50 mL), and stirred at room temperature for 1 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude intermediate 4a (35.83 g, 100%).

[0286] LC-MS (ESI): m / z = 487.2 [M+H] + .

[0287] Step 2: Intermediate 4a (26.8 g, 55.08 mmol) and 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (40.2 g, 220.32 mmol) were added to a mixed solution of tetrahydrofuran (210 mL) and glacial acetic acid (42 mL), and stirred at 95 °C for 16 h. After the reaction was completed, the solution was concentrated under reduced pressure and purified by reverse-phase column chromatography (ACN:H2O = 3:2) to obtain intermediate 4 (11.2 g, 45.9%).

[0288] LC-MS (ESI): m / z = 651.3 [M+H] + .

[0289] 1HNMR(400MHz,DMSO-d6)δ13.46–13.43(m,1H),12.64(s,1H),7.88–7.86(d,2H), 7.68–7.64(m,3H),7.43–7.38(m,2H),7.33–7.27(m,2H),7.01–6.99(m,1H),6.6 9–6.67 (d, 1H), 4.22–4.20 (m, 2H), 4.09–4.03 (m, 4H), 3.82–3.80 (m, 4H), 3.02–2.97 (m, 1H), 2.84–2.79 (m, 5H), 2.53 (s, 3H), 2.27 (s, 4H), 0.94 (s, 6H). Intermediates 15 and 16:

[0290]

[0291] Step 1: Compound 15a (10.4 g, 70.5 mmol) was dissolved in tetrahydrofuran (200 mL), purged with nitrogen, and then tetraisopropyl titanate (4 mL, 13.6 mmol) and ethyl magnesium bromide (58.67 mL, 176 mmol) were added at 0°C. The mixture was heated to room temperature and reacted overnight. After the reaction was completed, the mixture was quenched with water at 0°C, extracted with ethyl acetate, and the organic phases were combined and evaporated to dryness. The mixture was concentrated and purified by silica gel column chromatography (EA:PE = 1:5) to obtain compound 15b (7.0 g, 71%).

[0292] 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).

[0293] Step 2: Compound 15b (7.0 g, 47.95 mmol) was dissolved in dichloromethane (50 ml), triethylamine (14.53 g, 143.85 mmol) was added, and methanesulfonyl chloride (6.59 g, 57.54 mmol) was added dropwise at 0 degrees Celsius. The reaction was carried out at room temperature for 1 h, quenched with water in an ice bath, extracted with dichloromethane, the organic phases were combined and evaporated to dryness, and concentrated to obtain crude compound 15c.

[0294] 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).

[0295] Step 3: The crude compound 15c from the previous step was dissolved in tetrahydrofuran / water (60mL / 30mL), and potassium peroxymonosulfonate (24.91g, 71.93mmol) was added at 0°C. The reaction was carried out overnight at room temperature, extracted with ethyl acetate, and the organic phases were combined and evaporated to dryness. The mixture was recrystallized from methyl tert-butyl ether to give compound 15d (4.8g, 52% yield in both steps).

[0296] LC-MS (ESI): m / z = 195.1 [M+H] + .

[0297] Step 4: Compound 15d (7.0 g, 36.08 mmol) was dissolved in 1,2-dichloroethane (200 mL), purged with nitrogen, and thionyl chloride (3.26 mL, 45 mmol) was added and refluxed for 1 hour. After cooling to room temperature, NCS (7.2 g, 54.12 mmol) and 10 drops of 4M hydrogen chloride-1,4-dioxane were added, and the mixture was refluxed overnight. After cooling to room temperature, methanol (25 mL) was added, and the reaction was continued for 1 hour. After the reaction was completed, the mixture was concentrated and evaporated to dryness. Chloroform was added at 0°C, the liquid was collected by filtration, and concentrated to obtain crude compound 15e.

[0298] LC-MS (ESI): m / z = 243.1 [M+H] +

[0299] Step 5: The crude compound 15e was dissolved in dichloromethane (20 mL), and triethylamine (5.47 g, 54.12 mmol) was added at 0°C. The mixture was stirred for 3 h at this temperature, quenched with water, extracted with dichloromethane, and the organic phases were combined and concentrated. The mixture was then purified by silica gel column chromatography (EA:PE = 1:5) to obtain compound 15f (3.5 g, two-step yield 66%).

[0300] LC-MS (ESI): m / z = 147.1 [M+H] +

[0301] Step 6: Dissolve compound 15f (3.0 g, 20.55 mmol) in acetonitrile (50 mL), add sodium bicarbonate (17.26 g, 205.5 mmol), then add thioacetamide (1.54 g, 20.55 mmol), stir at 80 °C for 5 h, filter and concentrate, and separate and purify by silica gel column chromatography (EA:PE = 1:1) to obtain compound 15g (3 g, 79%).

[0302] LC-MS (ESI): m / z = 186.2 [M+H] + .

[0303] Step 7: Place 15g (1g, 5.38mmol) of compound into a 50ml round-bottom flask, add 10mL of 3M hydrochloric acid solution, stir at 100℃ for 5h, and after the reaction is complete, extract with methyl tert-butyl ether and concentrate directly in aqueous phase to obtain compound 15h hydrochloride.

[0304] LC-MS (ESI): m / z = 148.2 [M+H] + .

[0305] Step 8: Place compound 15h (1g, 6.8mmol) in a 50ml round-bottom flask, add trifluoroacetic acid (5ml) and triphenylmethanol (2.12g, 8.16mmol), stir for 10min at room temperature, and evaporate to dryness to obtain target compound 15i for the next step.

[0306] LC-MS (ESI): m / z = 388.5 [MH] + .

[0307] Step 9: Dissolve the crude compound 15i from the previous step in acetonitrile and water (50 ml / 10 ml), add sodium bicarbonate (5.7 g, 68 mmol) and 9-fluorenylmethyl-N-succinimide carbonate (3.44 g, 10.2 mmol), stir at room temperature for 3 h, filter, add saturated brine (30 ml), extract with ethyl acetate, combine the organic phases and concentrate, separate and purify using a silica gel column (DCM:MeOH = 10:1) to obtain 2.2 g of the racemic mixture. Two-step yield: 43%. The racemic mixture was chirally resolved: Instrument: SFC Prep 150AP; 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 chromatographic conditions: Mobile phase A and B composition: Mobile phase A: CO2; Mobile phase B: methanol; isocratic elution, mobile phase B content 25%; flow rate 40 ml / min. Intermediate 15 (P1) (890 mg) was obtained in 3.8 min and intermediate 16 (P2) (910 mg) was obtained in 4.2 min.

[0308] 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).

[0309] Intermediate 17:

[0310]

[0311] Step 1: Compound 17a (5 g, 0.043 mol) was added to trifluoroethanol (50 mL), followed by tert-butyl isocyanate (7.15 g, 0.086 mol) and ammonium acetate (13.3 g, 0.172 mol). The reaction was allowed to proceed at room temperature for 3 days. TLC showed that the reaction was complete. The reaction solution was concentrated to dryness and purified by a C18 reversed-phase column. The composition of mobile phases A and B was: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% TFA), (A / B = 35 / 65). Compound 17b (9.5 g, yield: 85%) was obtained after separation and purification.

[0312] LCMSm / z = 259.2 [M+1] + .

[0313] Step 2: Compound 17b (7.5 g, 0.029 mol) was added to 6N HCl (75 mL) and reacted overnight at 100 °C. LCMS showed that the reaction of the starting material was complete. The solution was concentrated to dryness and purified by C18 reversed-phase column chromatography. The composition of mobile phases A and B was: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% TFA), (A / B = 5 / 95). Compound 17c (4.6 g, yield: 98%) was obtained after separation and purification.

[0314] LCMSm / z = 162.1[M+1] + .

[0315] Step 3: Compound 17c (4.6 g, 0.028 mol) was added to acetonitrile (46 mL) and water (46 mL), followed by 9-fluorenylmethyl-N-succinimide carbonate (Fmoc-Osu) (10.5 g, 0.03 mol) and sodium bicarbonate (24.4 g, 0.28 mol). The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS until complete. The pH was adjusted to 5-6 with 1N HCl, the acetonitrile was removed by concentration, and the mixture was extracted with ethyl acetate (200 mL). The ethyl acetate phase was concentrated to dryness and purified by column chromatography (DCM:MeOH = 10:1) to give compound 17d (6.3 g, yield: 58%).

[0316] LCMSm / z = 384.2[M+1] + .

[0317] Step 4: Compound 17d (5.0 g, 0.013 mol) was added to dichloromethane (50 mL), followed by the addition of 85% m-chloroperoxybenzoic acid (m-CPBA) (7.9 g, 0.039 mol) in portions. The reaction was allowed to proceed overnight at room temperature. LC-MS was used to monitor the reaction until complete. The reaction was quenched with sodium thiosulfate solution (100 mL), stirred for 30 min, and extracted with ethyl acetate (200 mL). The ethyl acetate phase was concentrated to dryness. The mixture was then purified by preparative liquid chromatography (preparative liquid chromatography conditions: C18 reversed-phase column, mobile phase: deionized water (A) containing 0.1% trifluoroacetic acid, acetonitrile (B) containing 0.1% trifluoroacetic acid, gradient elution, B content = 5%–70%, elution time 15 min, flow rate 12 mL / min, column temperature: 30℃, retention time: 8.54 min) to obtain intermediate 17 (3.5 g, yield: 64%).

[0318] 1 H NMR(400MHz, CDCl3)δ7.78–7.76(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).

[0319] LCMSm / z = 433.1 [M + H₂O] + .

[0320] Example 30

[0321]

[0322]

[0323]

[0324] Step 1: The synthesis of 30B employs standard Fmoc chemical methods:

[0325] 1. Add Sieber Resin (1 mmol, 1.4 g, sub: 0.7 mmol / g) and dichloromethane solvent to the reactor, allow it to swell for 30 min, then dry it under vacuum and add 20% piperidine / DMF, mix for 30 min.

[0326] 2. Drain and rinse five times with DMF.

[0327] 3. Add the Fmoc-Sar-OH protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen for 1.5 hours, and monitor the reaction with ninhydrin.

[0328] 4. Drain and rinse three times with DMF.

[0329] 5. Add 20% piperidine / DMF and mix for 30 minutes.

[0330] 6. Drain and rinse five times with DMF.

[0331] 7. Add the Fmoc-protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen for 1.5 hours, and monitor the reaction with ninhydrin.

[0332] 8. Drain and rinse three times with DMF.

[0333] 9. Repeat steps 5-8 of the next amino acid coupling.

[0334] Step 2: Add 30 ml of dichloromethane to the solid-phase synthesis reactor, then add 1 g of phenylsilane and 462 mg of tetra(triphenylphosphine)palladium in sequence. React under nitrogen for 8 hours. Wash the resin 5 times with dichloromethane, 5 times with N,N-dimethylformamide, and 15 min + 15 min with a 0.5% sodium diethyldithiocarbamate solution in N,N-dimethylformamide. Then wash three more times with N,N-dimethylformamide to obtain peptide resin 30C.

[0335] Step 3: Add a 20% piperidine N,N-dimethylformamide solution to the reactor and react for 30 min. Wash 5 times with N,N-dimethylformamide solution and 3 times with methanol. Dry under vacuum to obtain peptide resin 30D (3g).

[0336] Step 4: Add 50 ml of lysis buffer (2% trifluoroacetic acid + 98% dichloromethane) to a 100 ml reaction flask, stir well, then add peptide resin 30D (3 g), stir at room temperature for 0.5 hours, filter the resin to obtain filtrate, lyse the peptide resin again using the above lysis method, collect the filtrates obtained from the two lysis processes, wash twice with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and vacuum dry to obtain compound 30E (1.2 g).

[0337] Step 5: Dichloromethane (600 mL), compound 30E (1.2 g, 0.36 mmol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (166 mg, 0.44 mmol), and DIEA (0.13 mL, 0.72 mmol) were added to a 1 L flask. The mixture was reacted at room temperature for 16 h. MS showed that the reaction was basically complete. The mixture was washed twice with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate and dried under vacuum to obtain compound 30F (1.2 g).

[0338] Step 6: Add 30 ml of lysis buffer (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethylenedithiol + 2%) to a 100 ml reaction flask.

[0339] Add water), stir well, then add compound 30F (1.2 g), and stir at room temperature for 2 hours. Filter through resin to obtain a filtrate, which is then added to 300 ml of methyl tert-butyl ether (pre-cooled to 0°C). A white flocculent precipitate forms, which is then centrifuged (3 min at 3000 rpm). The white precipitate is washed three times with methyl tert-butyl ether and dried under vacuum to obtain a white solid crude peptide 30 G (1.2 g).

[0340] Step 7: In a 2L reaction flask, add water (840ml), acetonitrile (360ml), and 30g (1.2g, 0.56mmol) sequentially. After stirring evenly, slowly add iodine / acetonitrile solution (0.1mol / L) until the reaction solution turns pale yellow. Quench with ascorbic acid and perform HPLC purification. Separation method: 1. Instruments: Waters 2767 preparative HPLC; column: SunFire@PrepC18 (19mm×250mm). 2. Filter the sample through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml / min; d. Elution time: 30min, retention time: 16min. Lyophilization yielded compound 30 (20mg, purity 99%).

[0341] LCMSm / z = 1067.8 [M / 2 + H] + 712.3 [M / 3+H] + .

[0342] Example 34:

[0343]

[0344]

[0345] Using the above-mentioned material list as raw materials, compound 34 (20 mg, 99% purity) was obtained by the method of compound 30.

[0346] LCMSm / z = 1024.1 [M / 2 + H] + 683.0 [M / 3+H] + .

[0347] Example 36:

[0348]

[0349] Step 1: The synthesis of 36B employs standard Fmoc chemical methods:

[0350] 1. Add Rink Amide MBHA Resin (1 mmol, 1.4 g, sub: 0.7 mmol / g) and dichloromethane solvent to the reactor, allow it to swell for 30 min, add 20% piperidine / DMF, and mix for 30 min.

[0351] 2. Drain and rinse five times with DMF.

[0352] 3. Add the Fmoc-Sar-OH protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen for 1.5 hours, and monitor the reaction with ninhydrin.

[0353] 4. Drain and rinse three times with DMF.

[0354] 5. Add 20% piperidine / DMF and mix for 30 minutes.

[0355] 6. Drain and rinse five times with DMF.

[0356] 7. Add the Fmoc-protected amino acid solution, mix for 30 seconds, then add the coupling reagent, bubble with nitrogen for 1.5 hours, and monitor the reaction with ninhydrin.

[0357] 8. Drain and rinse three times with DMF.

[0358] 9. Repeat steps 5-8 of the next amino acid coupling.

[0359] 10. In the final step, the resin was washed twice with MeOH, once with DCM, and twice with MeOH. After vacuum drying, peptide resin 36B was obtained and used directly in the next reaction.

[0360]

[0361]

[0362] Step 2: Add 50 ml of lysis buffer (91% trifluoroacetic acid + 4% triisopropylsilane + 3% 1,2-ethylenedithiol + 2% water) to a 100 ml reaction flask, stir well, then add peptide resin 36B 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 (pre-cooled to 0°C), a white flocculent precipitate will form, centrifuge (3 min at 3000 rpm). Wash the white precipitate three times with methyl tert-butyl ether, and vacuum dry to obtain a white solid crude peptide 36C, which can be used directly in the next reaction.

[0363] Step 3: In a 2L reaction flask, add water (750ml), acetonitrile (250ml), and 36C (2g) sequentially. After stirring evenly, slowly add iodine / acetonitrile solution (0.1mol / L) until the reaction solution turns pale yellow. Quench with ascorbic acid and perform HPLC purification. Separation method: 1. Instrument: Waters 2767 preparative HPLC; Column: SunFire@PrepC18 (19mm×250mm). 2. Filter the sample through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: A: 0.1% trifluoroacetic acid / H2O, B: CH3CN; b. Gradient elution: mobile phase content 5%-45%; c. Flow rate: 12ml / min; d. Elution time: 30min. Lyophilization yielded compound 36 (320mg, purity 98%).

[0364] LCMSm / z = 980.4 [M / 2 + H] + .

[0365] Example 37:

[0366]

[0367] Serial Number raw material Coupling reagents 1 Fmoc-Sar-OH (3.0 eq.) DIC(3eq.) and HOBT(3eq.) 2 Fmoc-3Pal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 3 Fmoc-Asn(Trt)-OH(3.0eq.) DIC(3eq.) and HOBT(3eq.) 4 Fmoc-Glu(OtBu)-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 5 Fmoc-ThpGly-OH(2.0 eq.) DIC(2eq.) and HOBT(2eq.) 6 Fmoc-2-Nal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 7 Intermediate 1 (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 8 Fmoc-Pen(Trt)-OH(2.0 eq.) DIC(2eq.) and HOAT(2eq.) 9 Fmoc-Lys(Ac)-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 10 Fmoc-7MeTrp-OH (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 11 Fmoc-Thr(tBu)-OH(3.0 eq.) DIC(3eq.) and HABT(3eq.) 12 Fmoc-His(Trt)-OH(3.0eq.) DIC(3eq.) and HOBT(3eq.) 13 Intermediate 15 (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 14 2-Methyl-2-hydroxypropionic acid (3.0 eq.) DIC(3eq.) and HOBT(3eq.)

[0368] Using the above-mentioned material list as raw materials, compound 37 (350 mg, purity 98%) was synthesized using the method of compound 36.

[0369] LCMSm / z = 1002.6[M / 2 + H] + .

[0370] Example 38:

[0371]

[0372] Serial Number raw material Coupling reagents 1 Fmoc-Sar-OH (3.0 eq.) DIC(3eq.) and HOBT(3eq.) 2 Fmoc-3Pal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 3 Fmoc-Asn(Trt)-OH(3.0eq.) DIC(3eq.) and HOBT(3eq.) 4 Fmoc-Glu(OtBu)-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 5 Fmoc-ThpGly-OH(2.0 eq.) DIC(2eq.) and HOBT(2eq.) 6 Fmoc-2-Nal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 7 Intermediate 1 (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 8 Intermediate 15 (2.0 eq.) DIC(2eq.) and HOAT(2eq.) 9 Fmoc-Lys(Ac)-OH(3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 10 Fmoc-7MeTrp-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 11 Fmoc-Thr(tBu)-OH (3.0 eq.) DIC (3 eq.) and HABT (3 eq.) 12 Fmoc-His(Trt)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 13 Fmoc-Pen(Trt)-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 14 Acetic anhydride Ac2O (5%) and DIPEA (5%) 20 ml

[0373] Using the above-mentioned material list as raw materials, compound 38 (500 mg, purity 98%) was synthesized using the method of compound 36.

[0374] LCMSm / z = 980.4 [M / 2 + H] + .

[0375] Example 39:

[0376]

[0377] Serial number Raw material Coupling reagent 1 Fmoc-Sar-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 2 Fmoc-3Pal-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 3 Fmoc-Asn(Trt)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 4 Fmoc-Glu(OtBu)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 5 Fmoc-ThpGly-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 6 Fmoc-2-Nal-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 7 Intermediate 1 (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 8 Intermediate 15 (2.0 eq.) DIC (2 eq.) and HOAT (2 eq.) 9 Fmoc-Lys(Ac)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 10 Fmoc-7MeTrp-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 11 Fmoc-Thr(tBu)-OH (3.0 eq.) DIC (3 eq.) and HABT (3 eq.) 12 Fmoc-His(Trt)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 13 Fmoc-Pen(Trt)-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 14 2-Methyl-2-hydroxypropanoic acid (3.0 eq.) DIC (aniline) and HOBT (3 eq.)

[0378] Using the above-mentioned material list as raw materials, compound 39 (360 mg, purity 98%) was synthesized using the method of compound 36.

[0379] LCMSm / z = 1002.6[M / 2 + H] + .

[0380] Example 40:

[0381]

[0382] Serial number Raw material Coupling reagent 1 Fmoc-Sar-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 2 Fmoc-3Pal-OH (aniline) DIC (3 eq.) and HOBT (3 eq.) 3 Fmoc-Asn(Trt)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 4 Fmoc-Glu(OtBu)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 5 Intermediate 17 (2.0 eq.) DIC (2 eq.) and HOAT (2 eq.) 6 Fmoc-2-Nal-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 7 Intermediate 1 (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 8 Intermediate 15 (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 9 Fmoc-Lys(Ac)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 10 Fmoc-7MeTrp-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 11 Fmoc-Thr(tBu)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 12 Fmoc-His(Trt)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 13 Fmoc-Pen(Trt)-OH (2. ​ 14 ​ ​

[0383] Using the above-mentioned material list as raw materials, compound 40 (97 mg, purity 99%) was synthesized using the method of compound 36.

[0384] LCMSm / z = 1004.2[M / 2 + H] + .

[0385] Example 41:

[0386]

[0387] ​ ​ ​ 1 ​ ​ 2 ​ ​ 3 ​ ​ 4 ​ ​ 5 ​ ​ 6 ​ ​ 7 ​ ​ 8 ​ ​ 9 ​ ​ 10 ​ ​ 11 ​ ​ 12 ​ ​ 13 Intermediate 15 (2.0 eq.) DIC(2eq.) and HOAT(2eq.) 14 Acetic anhydride Ac2O (5%) and DIPEA (5%) 20ml

[0388] Using the above-mentioned material list as raw materials, compound 41 (137 mg, 100% purity) was synthesized using the method of compound 36.

[0389] LCMSm / z = 1004.2[M / 2 + H] + .

[0390] Example 45:

[0391]

[0392] Serial Number raw material Coupling reagents 1 Fmoc-Sar-OH (3.0 eq.) DIC(3eq.) and HOBT(3eq.) 2 Fmoc-3Pal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 3 Fmoc-Asn(Trt)-OH(3.0eq.) DIC(3eq.) and HOBT(3eq.) 4 Fmoc-Glu(OtBu)-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 5 Fmoc-ThpGly-OH(2.0 eq.) DIC(2eq.) and HOBT(2eq.) 6 Fmoc-2-Nal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 7 Intermediate 1 (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 8 Intermediate 15 (2.0 eq.) DIC(2eq.) and HOAT(2eq.) 9 Fmoc-Lys(Ac)-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 10 Fmoc-7MeTrp-OH (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 11 Fmoc-Thr(tBu)-OH(3.0 eq.) DIC(3eq.) and HABT(3eq.) 12 Fmoc-His(Trt)-OH(3.0eq.) DIC(3eq.) and HOBT(3eq.) 13 Fmoc-Pen(Trt)-OH(2.0 eq.) DIC(2eq.) and HOBT(2eq.) 14 3-Hydroxypropionic acid (3.0 eq.) DIC(3eq.) and HOBT(3eq.)

[0393] Using the above-mentioned material list as raw materials, compound 45 (100 mg, purity 97%) was synthesized using the method of compound 36.

[0394] LCMSm / z = 995.4 [M / 2 + H] + .

[0395] Example 46:

[0396]

[0397] Serial Number raw material Coupling reagents 1 Fmoc-Sar-OH (3.0 eq.) DIC(3eq.) and HOBT(3eq.) 2 Fmoc-3Pal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 3 Fmoc-Asn(Trt)-OH(3.0eq.) DIC(3eq.) and HOBT(3eq.) 4 Fmoc-Glu(OtBu)-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 5 Fmoc-ThpGly-OH(2.0 eq.) DIC(2eq.) and HOBT(2eq.) 6 Fmoc-2-Nal-OH(3.0 eq.) DIC(3eq.) and HOBT(3eq.) 7 Intermediate 1 (2.0 eq.) DIC(2eq.) and HOBT(2eq.) 8 Fmoc-Pen(Trt)-OH (2.0 eq.) DIC (2 eq.) and HOAT (2 eq.) 9 Fmoc-Lys(Ac)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 10 Fmoc-7MeTrp-OH (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 11 Fmoc-Thr(tBu)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 12 Fmoc-His(Trt)-OH (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.) 13 Intermediate 15 (2.0 eq.) DIC (2 eq.) and HOBT (2 eq.) 14 3-Hydroxypropionic acid (3.0 eq.) DIC (3 eq.) and HOBT (3 eq.)

[0398] Using the above-mentioned material list as raw materials, compound 46 (120 mg, purity 92.4%) was synthesized using the method of compound 36.

[0399] LCMSm / z = 995.5 [M / 2 + H] + .

[0400] Example 47:

[0401]

[0402] Serial number Raw material Coupling reagent 1 Fmoc-Sar-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 2 Fmoc-3Pal-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 3 Fmoc-Asn(Trt)-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 4 Fmoc-Glu(OtBu)-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 5 Fmoc-ThpGly-OH (2 eq.) DIC (2 eq.) and HOBT (2 eq.) 6 Fmoc-2-Nal-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 7 Intermediate 4 (2 eq.) DIC (2 eq.) and HOBT (2 eq.) 8 Intermediate 15 (2 eq.) DIC (2 eq.) and HOBT (2 eq.) 9 Fmoc-Lys(Ac)-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 10 Fmoc-7MeTrp-OH (2 eq.) DIC (2 eq.) and HOBT (2 eq.) 11 Fmoc-Thr(tBu)-OH (2 eq.) DIC (2 eq.) and HOBT (2 eq.) 12 Fmoc-His(Trt)-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 13 Fmoc-Pen(Trt)-OH (2 eq.) DIC (2 eq.) and HOBT (2 eq.) 14 Ac2O DIEA 15 2-(tert-butoxy)acetic acid DIC (2 eq.) and HOBT (2 eq.)

[0403] Using the above-mentioned material list as raw materials, compound 47 (35 mg, 99.8%) was synthesized using the method of compound 36.

[0404] LCMSm / z = 1009.5 [M / 2 + H] + .

[0405] Example 48:

[0406]

[0407] Serial number Raw material Coupling reagent 1 Fmoc-Sar-OH (3 eq.) DIC (3 eq.) and HOBT (3 eq.) 2 Fmoc-3Pal-OH (3 eq.) DIC(3eq.) and HOBT(3eq.) 3 Fmoc-Asn(Trt)-OH(3eq.) DIC(3eq.) and HOBT(3eq.) 4 Fmoc-Glu(OtBu)-OH(3eq.) DIC(3eq.) and HOBT(3eq.) 5 Fmoc-ThpGly-OH(2eq.) DIC(2eq.) and HOBT(2eq.) 6 Fmoc-2-Nal-OH(3eq.) DIC(3eq.) and HOBT(3eq.) 7 Intermediate 4 (2eq.) DIC(2eq.) and HOBT(2eq.) 8 Fmoc-Pen(Trt)-OH(2eq.) DIC(2eq.) and HOBT(2eq.) 9 Fmoc-Lys(Ac)-OH(3eq.) DIC(3eq.) and HOBT(3eq.) 10 Fmoc-7MeTrp-OH(2eq.) DIC(2eq.) and HOBT(2eq.) 11 Fmoc-Thr(tBu)-OH(2eq.) DIC(2eq.) and HOBT(2eq.) 12 Fmoc-His(Trt)-OH(3eq.) DIC(3eq.) and HOBT(3eq.) 13 Intermediate 15 (2 eq.) DIC(2eq.) and HOBT(2eq.) 14 Ac2O DIEA 15 3-(tert-butoxy)propanoic acid DIC(2eq.) and HOBT(2eq.)

[0408] Using the above-mentioned materials as raw materials, compound 48 (15 mg, 99.9%) was synthesized using the same method as compound 36. LCMS m / z = 1016.3 [M / 2 + H] + .

[0409] Biological testing evaluation

[0410] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0411] 1. IL-23α / IL-12β & IL-23R binding test experiment

[0412] The inhibition of IL-23α / IL-12β & IL-23R binding by the compounds was tested using the TR-FRET method. Solutions of protein IL-23α / IL-12β (ACRO, Cat#ILB-H52W5) and IL-23R (ACRO, Cat#ILR-H82F3) were prepared in reaction buffer PPI (PerkinElmer, Cat#61DB10RDF). The final concentrations of IL-23α / IL-12β and IL-23R in the reaction mixture were both 0.3 nM. 0.1 μL of the analyte diluted in DMSO was transferred to a 384-well plate (Grenier, Cat#784075) using a nano-pipette system (Echo 655) and centrifuged at 1000 rpm for 1 minute. 2.5 μL of IL-23α / IL-12β solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 minutes. 2.5 μL of IL-23R solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute. 5 μL of the Streptavidin-Tb cryptate (PerkinElmer, Cat#610SATLA) and Anti 6HIS-d2 (PerkinElmer, Cat#61HISDLB) detection mixture was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 minutes. Finally, the HTRF signal (Ratio) was read using a BMG high-throughput drug screening multi-mode microplate reader. (665 / 620nm). The IC50 (half-maximum inhibitory concentration) value of the compound was obtained using the four-parameter nonlinear fitting formula (Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))) in GraphPad Prism software.

[0413] Table 1

[0414] compound <![CDATA[IC 50 (nM)]]> Compound 30 0.062 Compound 34 0.061 Compound 36 0.043 Compound 37 0.041 Compound 38 0.052 Compound 39 0.055 Compound 40 0.055 Compound 41 0.015 Compound 45 0.060 Compound 46 0.033 Compound 47 0.067 Compound 48 0.094

[0415] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the binding of IL-23α / IL-12β and IL-23R.

[0416] 2. IL-23R reporter gene assay

[0417] The purpose of this experiment was to evaluate the ability of the compound to inhibit the binding of IL23p19 and IL23R in a reporter gene system. HEK-blue IL23 reporter gene cell line (Invivogen, hkb-il23) was cultured in DMEM + 10% FBS + 100 μg / mL Normocin medium. When the cell density reached 80%-90%, it was seeded into 384-well plates at 5000 cells / well and cultured overnight at 37°C and 5% CO2. The stock solution of the compound was then diluted in DMSO, and 40 nmol of the diluted solution was transferred to 384-well culture plates via Echo. The plates were incubated at 37°C and 5% CO2 for 0.5 h. 40 nmol / well of rhIL23 (R&D, 1290-IL) was added to the 384-well cell culture plates, resulting in a final concentration of 1 ng / mL, and incubated at 37°C and 5% CO2 for 24 h. 18 μL of Quanti-Blue was then added. TM The solution was added to a new 384-well plate, and 2 μL / well of 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 ​​were read on a BMG spectrophotometer from 620 to 655 nM. The binding affinity of the compound was evaluated using the following formula, and IC50 was fitted using Graphpad. 50 .

[0418] Inhibition rate calculation formula:

[0419] DMSO control group mean

[0420] Mean value of the group without IL23 stimulation

[0421] IC 50 The calculation formula is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0422] X: Compound concentration

[0423] Y: Compound inhibition rate

[0424] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on the binding of IL23p19 and IL23R.

[0425] 3. IL-23-stimulated pSTAT3 detection assay in PBMCs

[0426] Frozen human PBMCs were thawed and seeded onto plates pre-coated with CD3 antibody, at a density of 1 × 10^6 cells per well. CD28 antibody was then added to the plates, and the cells were incubated at 37°C and 5% CO2 for 5 days. On day 5, after 4 hours of FBS starvation stimulation, cells were seeded onto 96-well plates at a density of 100 K cells per well. The diluted compound was 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 the plates were 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, followed by centrifugation at 1000 rpm for 1 minute. The supernatant was then transferred to 96-well ELISA plates, and pSTAT3 ELISA was performed according to the kit (CST, 7300CA) instructions. The absorbance was read at 450 nM on a PHERAstar FSX (BMG LRBTECH) spectrophotometer. The inhibition rate of the compound was evaluated using the following formula, and IC50 was fitted using Graphpad. 50 .

[0427] Inhibition rate calculation formula:

[0428] DMSO control group mean

[0429] Mean value of the group without IL23 stimulation

[0430] IC 50 The calculation formula is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0431] X: Compound concentration

[0432] Y: Compound inhibition rate.

[0433] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant inhibitory effect on STAT3 phosphorylation.

[0434] 4. Pharmacokinetic assays in mice

[0435] 4.1 Experimental animals: Male Balb / c mice, 20-25g, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0436] 4.2 Experimental Design: On the day of the experiment, Balb / c mice were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0437] Table 2. Dosage Information

[0438]

[0439] Note: Intravenous administration solvent: PBS; Gavage administration solvent: PBS

[0440] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0441] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in mice.

[0442] 5. Rat pharmacokinetic test

[0443] 5.1 Experimental animals: Male SD rats, approximately 220g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0444] 5.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water. They were fed 4 hours after drug administration.

[0445] Table 3. Dosage Information

[0446]

[0447] Note: Intravenous administration solvent: PBS; Gavage administration solvent: PBS

[0448] Blood samples of 0.15 ml were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. Blood collection time points for both the intravenous and gavage groups were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. Brain tissue was collected 24 h after administration. The brain tissue was rinsed with cold physiological saline to remove residual blood, dried, and homogenized. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0449] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in rats.

[0450] 6. Pharmacokinetics of Beagle Dogs

[0451] 6.1 Experimental animals: Male beagle dogs, weighing approximately 8–11 kg, 6 dogs per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[0452] 6.2 Experimental Methods: On the day of the experiment, beagles were randomly grouped according to their body weight. They were fasted for 12–14 hours prior to administration but allowed free access to water. Food was given 4 hours after administration.

[0453] Blood samples (1 ml) were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0454] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in dogs.

[0455] 7. Pharmacokinetics in monkeys

[0456] 7.1 Experimental animals: Male cynomolgus monkeys, 3–5 kg, 3–6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0457] 7.2 Experimental Methods: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14–18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0458] Blood samples of 1.0 mL were collected from venous veins of the extremities before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for the venous group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0459] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

[0460] 8. Plasma stability test

[0461] This experiment used plasma from five species—human, monkey, dog, rat, and mouse—to evaluate the plasma stability of the compounds.

[0462] Plasma samples with a concentration of 1000 ng / mL were prepared and aliquoted into EP tubes at time points of 0 h and 6 h. For the 0 h samples, acetonitrile solution containing the internal standard was added directly, while for the 6 h samples, the solution was added after incubation at 37°C for the corresponding time. The concentration of the analyte in the samples was determined using LC-MS / MS. The residual rate was calculated as the ratio of the peak area of ​​the analyte to the internal standard in the time point samples to the peak area of ​​the sample at time zero.

[0463] 9. Stability test of gastrointestinal fluids

[0464] 9.1. Solution Preparation

[0465] Preparation of dilute hydrochloric acid: Measure 23.4 ml of hydrochloric acid and dilute it with water to 1000 ml.

[0466] Preparation of artificial gastric juice: Take 1.64 ml of dilute hydrochloric acid, add about 80 ml of water and 1 g of pepsin, shake well, and then dilute with water to 100 ml.

[0467] To prepare 0.1 mol / L NaOH: Weigh 0.4 g of NaOH and dissolve it in 100 ml of water.

[0468] Preparation of artificial intestinal fluid: Dissolve 0.68g of potassium dihydrogen phosphate in 50ml of water, and adjust the pH to 6.8 with 0.1mol / L sodium hydroxide solution; dissolve 1g of pancreatic enzyme in an appropriate amount of water, mix the two solutions, and dilute with water to 1000ml to obtain the final solution.

[0469] 9.2. Sample Preparation

[0470] Take approximately 12.5 mg of the sample and dissolve it in a 25 ml volumetric flask. Add artificial gastric fluid (or artificial intestinal fluid) to dissolve and dilute to the mark.

[0471] 9.3. Analytical Methods

[0472] Instrument model: Agilent 1260 Infinity; Mobile phase A: 10 mmol / L K₂HPO₄; Mobile phase B: Acetonitrile; Column: Phenomenex Gemini @ 3um C18 150*4.6mm; Wavelength: 224nm; Column temperature: 30℃; Sample tray temperature: 37℃; Injection time: 35min; Injection volume: 10ul; Injection method: Gradient injection; Gradient method. The gradient mobile phase is shown in the table.

[0473] 9.4. Sampling, Testing and Results

[0474] Sampling and testing: First, test the blank solution (artificial gastric fluid or artificial intestinal fluid), then take the prepared sample (freshly prepared before use) and put it into the injection tray for immediate injection, and then inject the sample once at each time.

[0475] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good stability in artificial gastrointestinal fluids.

[0476] 10. hERG potassium ion channel function test

[0477] Experimental platform: Electrophysiological manual patch-clamp system

[0478] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0479] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -80 mV with a 2-second depolarization voltage to +20 mV, then repolarized to -50 mV, held for 1 second, and then returned to -80 mV. This voltage stimulation was applied every 10 seconds. After confirming that the hERG potassium current was stable (at least 1 minute), the drug delivery process began. Each compound was administered for at least 1 minute at each test concentration, and at least 2 cells were tested for each concentration (n≥2).

[0480] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (the peak hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula:

[0481] Inhibition%=[1–(I / Io)]×100%

[0482] Where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0483] The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation:

[0484] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0485] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom

[0486] Top and Minimum Suppression Percentages are respectively the minimum and maximum suppression percentages.

[0487] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit hERG.

[0488] 11. CYP enzyme inhibition test

[0489] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing. Changes in CYP enzyme activity were measured, IC50 values ​​were calculated, and the inhibitory potential of the test substances against each CYP enzyme isoform was evaluated. Under the test conditions, the incubation concentration ranged from 0 to 30 μM.

[0490] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit CYP enzymes.

[0491] 12. Liver microsomal stability test

[0492] This experiment used liver microsomes from five genera—human, canine, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0493] At 37°C, 1 μM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T1 / 2 was obtained by using the ln value of the drug residue in the incubation system and the incubation time. The intrinsic clearance rate of liver microsomes CLint(mic) and intrinsic clearance rate of liver CLint(Liver) were further calculated.

[0494] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0495] 13. CaCO2 Permeability Test

[0496] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1 °C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0497] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good efflux rates.

Claims

1. A cyclic peptide compound, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide compound has an amino acid sequence of formula (II-3), (II-4): Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-3)(SEQ ID NO: 4) Xa1-HT-[Trp(7-methyl)]-Lys-Xa6-Xa7-[2-Nal]-Xa9-EN-[3-Pal]-[Sarc](II-4)(SEQ ID NO: 5) Xa1 and Xa6 are each independently selected from Pen or Furthermore, Xa1 and Xa6 are not both Pen; Xa7 is Xa9 is The cyclic peptide compounds Xa1-Xa6 form disulfide cyclization; The terminal amino group of the side chain of amino acids Pen, Lys, Xa7 or Xa1 is condensed and linked with α-hydroxyacetic acid, β-hydroxypropionic acid, 2-methyllactic acid, amino acid, or α-hydroxyisobutyric acid. The cyclic peptide compound is optionally linked to a protecting group.

2. The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, The protecting group is selected from hydroxyl, NH2, C. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-COC 1-6 Alkyl, -CO halogenated C 1-6 Alkyl, Gly, Ser.

3. The cyclic peptide compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, The PEG connector is p is 0-50, q is 1-50.

4. A cyclic peptide compound, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide compound has an amino acid sequence of formula (II-2): Xa1-HT-[Trp(7-methyl)]-Lys-[Pen]-Xa7-[2-Nal]-[Thp]-EN-[3-Pal]-[Sarc](II-2)(SEQ ID NO: 3) Xa1 is Pen; Xa7 is The cyclic peptide compound is cyclized via a Pen-Pen disulfide bond, and the cyclic peptide compound Xa1 is linked to the glutamic acid side chain in the (II-2) sequence via a PEG linker to form a ring.

5. The compound according to any one of claims 1-4, its stereoisomer or its pharmaceutically acceptable salt, or characterized in that the compound is selected from the following structures:

6. A pharmaceutical composition comprising the compound of any one of claims 1-5, its stereoisomer or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

7. The pharmaceutical composition according to claim 6, comprising 1-1500 mg of the compound of any one of claims 1-5, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

8. The use of the compound, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition of any one of claims 1-5, in the preparation of a medicament for the prevention and treatment of diseases or conditions in which IL-23 is overexpressed in diseased tissues of a subject.

9. The application according to claim 8, wherein the disease or condition overexpressing IL-23 includes inflammatory bowel disease, Crohn's disease, and psoriasis.

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