Polypeptide inhibitor and use thereof

Abstract

Provided are a polypeptide inhibitor and a use thereof. The polypeptide inhibitor is a compound represented by formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof. The polypeptide inhibitor has good inhibitory activity against IL-23R.

Description

Peptide inhibitors and their applications

[0001] This application claims priority to Chinese patent applications 2024119127243 (filed December 23, 2024), 2025104241804 (filed April 4, 2025), 2025111437316 (filed August 14, 2025), and 2025117135095 (filed November 20, 2025). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a novel peptide inhibitor and its applications. Background Technology

[0003] Interleukin-23 (IL-23) plays a crucial role in the pathogenesis of certain autoimmune and inflammatory diseases, including but not limited to psoriasis, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and asthma. IL-23 can signal through its specific receptor, the interleukin-23 receptor (IL-23R), to stimulate effector cell responses such as helper T cells 17 (Th17), thereby leading to the development of related diseases. For example, in psoriasis, IL-23 has been found to be a key factor in its pathogenesis, reportedly leading to persistent chronic inflammation by inducing interleukin-17, regulating memory T cells, and activating macrophages. In intestinal inflammation-related diseases, IL-23 accumulates in the gut and plays a key role in intestinal homeostasis by regulating the balance between tolerance and immunity through its effects on helper T cells 1 (Th1) and Th17.

[0004] Structurally, IL-23, as a heterodimer, contains a unique p19 subunit, which is linked to the p40 subunit of interleukin-12 (IL-12) via a disulfide bond. Therefore, the development of IL-23-targeted inhibitors currently focuses on targeting the p40 subunit, p19 subunit, and IL-23R. For example, Ustekinumab is a marketed drug that binds to the p40 subunit; several antibodies that bind to the p19 subunit of IL-23 have also been approved for marketing, such as Mirikizumab, Risankizumab, Tildrakizumab, and Guselkumab. These drugs are widely used in autoimmune and inflammatory diseases such as psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease, demonstrating excellent therapeutic effects. However, existing marketed therapies are all antibody drugs, requiring injection administration, leading to poor patient compliance with long-term medication, low convenience of administration, and injection irritation. The development of oral drugs in this area is urgently needed.

[0005] Johnson & Johnson's Icotrokinra (JNJ-2113, CAS: 2763602-16-8) inhibits IL-23 binding and signal transduction by specifically binding to IL-23R, without affecting the IL-12 signaling pathway. It is the first selectively blocking oral peptide targeting IL-23R. This drug demonstrated excellent efficacy in a Phase III clinical trial for moderate to severe plaque psoriasis and is expected to be approved for market. Therefore, developing drugs targeting IL-23R is a feasible approach. Summary of the Invention

[0006] This invention provides a compound of Formula I, and its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound:

[0007] in,

[0008] X 1 It is a C1-C6 alkylene group or is composed of one or more X groups. 1-1 Substituted alkylene groups;

[0009] X 2 It is a C1-C6 alkylene group or is composed of one or more X groups. 2-1 Substituted alkylene groups;

[0010] X 1-1 It is a C3-C8 cycloalkyl group;

[0011] Or two X's 1-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group;

[0012] X 2-1 It is a C3-C8 cycloalkyl group;

[0013] Or two X's 2-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group;

[0014] Q is the key for connection, S or -SS-;

[0015] R 1 -(C=O)R 1-1 ,

[0016] R 1-1 It is hydrogen or C1-C 24 alkyl;

[0017] R 1-2 and R 1-3 C1-C independently 12Alkyl, C3-C8 cycloalkyl;

[0018] R 1-4 It is hydrogen or C1-C6 alkyl;

[0019] R 1-5 -C(=O)R 1-5-1 ;

[0020] R 1-5-1 It is a C1-C6 alkyl group;

[0021] R 1-6 It is a C2-C6 alkynyl or C1-C6 alkyl group;

[0022] Y 1-1 For linking bonds or amino acids;

[0023] Y 1-2 For linking bonds or amino acids;

[0024] Y 1-3 For linking bonds or amino acids;

[0025] Y 1-4 For linking bonds or amino acids;

[0026] Y 1-5 For linking bonds or amino acids;

[0027] m 1-1 m 1-2 m 1-3 m 1-5 m 1-6 m 1-7 m 1-8 Each is an independent integer from 1 to 20;

[0028] m 1-4 Integers between 0 and 20;

[0029] n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Each is an independent integer between 0 and 12;

[0030] Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0031] R 2 for

[0032] R3 It is a C1-C6 alkyl or a C3-C8 cycloalkyl;

[0033] R 4 for

[0034] Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ;

[0035] R 4-1-1 R 4-1-2 and R 4-1-3 Each can be either hydrogen or halogen;

[0036] R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0037] R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0038] R 5 -(C=O)R 5-1 ,

[0039] R 5-1 For H or C1-C 24 alkyl;

[0040] R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0041] Y 5-1 For linking bonds or amino acids;

[0042] Y 5-2 For linking bonds or amino acids;

[0043] Y 5-3 For linking bonds or amino acids;

[0044] Y 5-4 For linking bonds or amino acids;

[0045] m 5-1 m 5-2 m 5-3Each is an independent integer from 1 to 20;

[0046] m 5-4 Integers between 0 and 20;

[0047] n 5-1 n 5-2 n 5-3 n 5-4 Each is an independent integer between 0 and 12;

[0048] R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl;

[0049] R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkyl, halogen, -OR 6-1-2 ;

[0050] R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ;

[0051] R 6-1-1-1 and R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0052] R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups;

[0053] R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens or C1-C6 alkyl groups;

[0054] R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or C1-C6 alkyl;

[0055] R 7 for

[0056] R 8 It is hydrogen or C1-C 24 alkyl;

[0057] R 9 For C2-C 12 acetylinyl

[0058] Z 9-1for Where end a and Connection, B end and

[0059] Z 9-2 for Where end a and Connection, B end and

[0060] m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Each is an independent integer from 1 to 20;

[0061] m 9-6 Integers between 0 and 20;

[0062] n 9-1 n 9-2 n 9-3 n 9-5 n 9-6 Each is an independent integer between 0 and 12;

[0063] n 9-4 Integers between 0 and 20;

[0064] Y 9-1 For linking bonds or amino acids;

[0065] Y 9-2 For linking bonds or amino acids;

[0066] Y 9-3 For linking bonds or amino acids;

[0067] R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0068] Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0069] R 8-1 For C2-C 12 acetylinyl C1-C6 alkyl, with one or more R 8-1-2 Substituted C1-C6 alkyl groups

[0070] Z 8-1 for Where end a and Connection, B end and

[0071] Z 8-2 for Where end a and Connection, B end and

[0072] m 8-1 m 8-2 m 8-3 m 8-4 m 8-5 m 8-6 Each is an independent integer from 1 to 20;

[0073] n 8-1 n 8-2 n 8-3 n 8-4 Each is an independent integer between 0 and 12;

[0074] Y 8-1 For linking bonds or amino acids;

[0075] Y 8-2 For linking bonds or amino acids;

[0076] R 8-1-1 For C2-C 12 Alkynyl, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens;

[0077] R 8-1-2 For C6-C 12 aryl, amino, and one or more R 8-1-2-1 Replacement C6-C 12 Aryl, cyano;

[0078] R 8-1-2-1 It is a C1-C6 alkyl group or a halogen.

[0079] R 8-2 Halogen, C1-C6 alkyl, oxo group, or with one or more R groups 8-2-1 Substituted C1-C6 alkyl groups;

[0080] R 8-2-1 It is a halogen;

[0081] R 10hydroxyl group

[0082] m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Each is an independent integer from 1 to 20;

[0083] m 10-6 Integers between 0 and 20;

[0084] n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Each is an independent integer between 0 and 12;

[0085] Y 10-1 For linking bonds or amino acids;

[0086] Y 10-2 For linking bonds or amino acids;

[0087] R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0088] R 11 for

[0089] R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13- 4 ,

[0090] R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ;

[0091] R 13-2-1 It is hydrogen, C1-C6 alkyl;

[0092] R13-2-2 For C2-C 12 alkynyl group;

[0093] R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0094] R 13-3 It is hydrogen, C1-C6 alkyl;

[0095] R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl;

[0096] R 13-5 It is a C1-C6 alkyl group;

[0097] R 13-6 It is a C1-C6 alkyl group;

[0098] R 14 It is hydrogen or C1-C6 alkyl;

[0099] Or R 9 R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0100] m 13-1 Integers from 1 to 6;

[0101] m 13-2 Integers from 1 to 6;

[0102] m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Each is an independent integer from 1 to 20;

[0103] m 12-6 Integers between 0 and 20;

[0104] m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 m 12-16 m 12-17 m 12-18 m12-19 Each is an independent integer from 1 to 20;

[0105] n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 n 12-15 n 12-16 n 12-17 n 12-18 n 12-19 Each is an independent integer between 0 and 12;

[0106] Z 12-1 for Where end a and Connection, B end and connect;

[0107] Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0108] Z 12-3 for Where end a and Connection, B end and connect;

[0109] Y 12-1 For linking bonds or amino acids;

[0110] Y 12-2 For linking bonds or amino acids;

[0111] Y 12-3 For linking bonds or amino acids;

[0112] Y 12-4 For linking bonds or amino acids;

[0113] Y 12-5 For linking bonds or amino acids;

[0114] Y 12-6 For linking bonds or amino acids;

[0115] Y 12-7 It is a linking bond or an amino acid.

[0116] In one embodiment, certain groups in the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0117] In one particular scheme, where,

[0118] X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups; X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups; X 1-1 It is a C3-C8 cycloalkyl group; or two X groups. 1-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group; X 2-1 It is a C3-C8 cycloalkyl group;

[0119] Or two X's 2-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group;

[0120] Q is the key for connection, S or -SS-;

[0121] R 1 -(C=O)R 1-1 ,

[0122] R 1-1 Hydrogen, C1-C 24 alkyl;

[0123] R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0124] R 1-4 It is hydrogen, C1-C6 alkyl;

[0125] R 1-5 -C(=O)R 1-5-1 ;

[0126] R 1-5-1 It is a C1-C6 alkyl group;

[0127] R 1-6 It is C2-C6 alkynyl or C1-C6 alkyl;

[0128] Y 1-1 For linking bonds or amino acids;

[0129] Y 1-2 For linking bonds or amino acids;

[0130] Y 1-3 For linking bonds or amino acids;

[0131] Y 1-4 For linking bonds or amino acids;

[0132] Y 1-5 For linking bonds or amino acids

[0133] m 1-1 m 1-2 m 1-3 m 1-5 m 1-6 m 1-7 m 1-8 Integers between 1 and 20;

[0134] m 1-4 Integers between 0 and 20;

[0135] n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Integers between 0 and 12;

[0136] Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0137] R 2 for

[0138] R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl;

[0139] R 4 for

[0140] Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ;

[0141] R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen;

[0142] R 4-2 R4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0143] R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0144] R 5 -(C=O)R 5-1 ,

[0145] R 5-1 For H, C1-C 24 alkyl;

[0146] R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0147] Y 5-1 For linking bonds or amino acids;

[0148] Y 5-2 For linking bonds or amino acids;

[0149] Y 5-3 For linking bonds or amino acids;

[0150] Y 5-4 For linking bonds or amino acids;

[0151] m 5-1 m 5-2 m 5-3 Integers between 1 and 20;

[0152] m 5-4 Integers between 0 and 20;

[0153] n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12;

[0154] R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl;

[0155] R 6-1It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy

[0156] radical, halogen, -OR 6-1-2 ;

[0157] R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ;

[0158] R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0159] R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups;

[0160] R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens, C1-C6 alkyl groups;

[0161] R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0162] R 7 for

[0163] R 8 Hydrogen, C1-C 24 alkyl;

[0164] R 9 For C2-C 12 acetylinyl

[0165] Z 9-1 for Where end a and Connection, B end and

[0166] Z 9-2 for Where end a and Connection, B end and

[0167] m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20;

[0168] m9-6 Integers between 0 and 20;

[0169] n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12;

[0170] Y 9-1 For linking bonds or amino acids;

[0171] Y 9-2 For linking bonds or amino acids;

[0172] Y 9-3 For linking bonds or amino acids;

[0173] R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0174] Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0175] R 8-1 For C2-C 12 acetylinyl C1-C6 alkyl, with one or more R 8-1-2 Substituted C1-C6 alkyl groups Z 8-1 for Where end a and Connection, B end and

[0176] Z 8-2 for Where end a and Connection, B end and

[0177] m 8-1 m 8-2 m 8-3 m 8-4 m8-5 m 8-6 Integers between 1 and 20;

[0178] n 8-1 n 8-2 n 8-3 Integers between 0 and 12;

[0179] Y 8-1 For linking bonds or amino acids;

[0180] Y 8-2 For linking bonds or amino acids;

[0181] R 8-1-1 For C2-C 12 alkynyl group;

[0182] R 8-1-2 For C6-C 12 aryl, with one or more R 8-1-2-1 Replacement C6-C 12 Aryl, cyano;

[0183] R 8-1-2-1 C1-C6 alkyl, halogen; R 8-2 Halogen, C1-C6 alkyl, or with one or more R 8-2-1 Substituted C1-C6 alkyl groups;

[0184] R 8-2-1 It is a halogen;

[0185] R 10 hydroxyl group

[0186] m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20;

[0187] m 10-6 Integers between 0 and 20;

[0188] n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12;

[0189] Y 10-1 For linking bonds or amino acids;

[0190] Y 10-2 For linking bonds or amino acids;

[0191] R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0192] R 11 for

[0193] R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13- 4 ,

[0194] R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ;

[0195] R 13-2-1 It is hydrogen, C1-C6 alkyl;

[0196] R 13-2-2 For C2-C 12 alkynyl group;

[0197] R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0198] R 13-3 It is hydrogen, C1-C6 alkyl;

[0199] R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl;

[0200] R 13-5 It is a C1-C6 alkyl group;

[0201] R 13-6 It is a C1-C6 alkyl group;

[0202] R 14 It is hydrogen;

[0203] Or R 9R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0204] m 13-1 Integers from 1 to 6;

[0205] m 13-2 Integers from 1 to 6;

[0206] m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20;

[0207] m 12-6 Integers between 0 and 20;

[0208] m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 m 12-16 m 12-17 m 12-18 m 12-19 Integers between 1 and 20;

[0209] n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 n 12-15 n 12-16 n 12-17 n 12-18 n 12-19 Integers between 0 and 12;

[0210] Z 12-1 for Where end a and Connection, B end and connect;

[0211] Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0212] Z 12-3 for Where end a and Connection, B end and connect;

[0213] Y 12-1 For linking bonds or amino acids;

[0214] Y 12-2 For linking bonds or amino acids;

[0215] Y 12-3 For linking bonds or amino acids;

[0216] Y 12-4 For linking bonds or amino acids;

[0217] Y 12-5 For linking bonds or amino acids;

[0218] Y 12-6 For linking bonds or amino acids;

[0219] Y 12-7 It is a linking bond or an amino acid.

[0220] In one possible solution, n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 n is an integer between 0 and 12. 8-1 n 8-2 n 8-3 It is an integer between 0 and 12.

[0221] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound:

[0222] in,

[0223] X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups;

[0224] X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups;

[0225] X 1-1 It is a C3-C8 cycloalkyl group;

[0226] Or two X's 1-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group;

[0227] X 2-1 It is a C3-C8 cycloalkyl group;

[0228] Or two X's 2-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group;

[0229] Q is the key for connection, S or -SS-;

[0230] R 1 -(C=O)R 1-1 ,

[0231] R 1-1 Hydrogen, C1-C 24 alkyl;

[0232] R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0233] R 1-4 It is hydrogen, C1-C6 alkyl;

[0234] R 1-5 -C(=O)R 1-5-1 ;

[0235] R 1-5-1 It is a C1-C6 alkyl group;

[0236] R 1-6 It is C2-C6 alkynyl or C1-C6 alkyl;

[0237] Y 1-1 For linking bonds or amino acids;

[0238] Y 1-2 For linking bonds or amino acids;

[0239] Y 1-3 For linking bonds or amino acids;

[0240] Y 1-4 For linking bonds or amino acids;

[0241] Y 1-5 For linking bonds or amino acids

[0242] m 1-1 m 1-2 m 1-3 m 1-5 m 1-6 m 1-7 m 1-8 Integers between 1 and 20;

[0243] m 1-4 Integers between 0 and 20;

[0244] n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Integers between 0 and 12;

[0245] Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0246] R 2 for

[0247] R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl;

[0248] R 4 for

[0249] Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ;

[0250] R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen;

[0251] R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0252] R 4-6 R 4-7 R 4-8 R 4-9 R 4-10Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0253] R 5 -(C=O)R 5-1 ,

[0254] R 5-1 For H, C1-C 24 alkyl;

[0255] R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0256] Y 5-1 For linking bonds or amino acids;

[0257] Y 5-2 For linking bonds or amino acids;

[0258] Y 5-3 For linking bonds or amino acids;

[0259] Y 5-4 For linking bonds or amino acids;

[0260] m 5-1 m 5-2 m 5-3 Integers between 1 and 20;

[0261] m 5-4 Integers between 0 and 20;

[0262] n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12;

[0263] R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl;

[0264] R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy

[0265] radical, halogen, -OR 6-1-2 ;

[0266] R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ;

[0267] R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0268] R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups;

[0269] R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens, C1-C6 alkyl groups;

[0270] R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0271] R 7 for

[0272] R 8 Hydrogen, C1-C 24 alkyl;

[0273] R 9 For C2-C 12 acetylinyl

[0274] Z 9-1 for Where end a and Connection, B end and

[0275] Z 9-2 for Where end a and Connection, B end and

[0276] m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20;

[0277] m 9-6 Integers between 0 and 20;

[0278] n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12;

[0279] Y9-1 For linking bonds or amino acids;

[0280] Y 9-2 For linking bonds or amino acids;

[0281] Y 9-3 For linking bonds or amino acids;

[0282] R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0283] Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0284] R 8-1 For C2-C 12 acetylinyl

[0285] Z 8-1 for Where end a and Connection, B end and

[0286] m 8-1 m 8-2 m 8-3 Integers between 1 and 20;

[0287] n 8-1 n 8-2 n 8-3 Integers between 0 and 12;

[0288] Y 8-1 For linking bonds or amino acids;

[0289] Y 8-1-1 For C2-C 12 alkynyl group;

[0290] R 8-2 It is halogenated or C1-C6 alkyl;

[0291] R 10 hydroxyl group

[0292] m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20;

[0293] m 10-6 Integers between 0 and 20;

[0294] n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12;

[0295] Y 10-1 For linking bonds or amino acids;

[0296] Y 10-2 For linking bonds or amino acids;

[0297] R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0298] R 11 for

[0299] R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13- 4 ,

[0300] R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ;

[0301] R 13-2-1 It is hydrogen, C1-C6 alkyl;

[0302] R 13-2-2 For C2-C 12 alkynyl group;

[0303] R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0304] R 13-3 It is hydrogen, C1-C6 alkyl;

[0305] R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl;

[0306] R 13-5 It is a C1-C6 alkyl group;

[0307] R 13-6 It is a C1-C6 alkyl group;

[0308] R 14 It is hydrogen;

[0309] Or R 9 R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0310] m 13-1 Integers from 1 to 6;

[0311] m 13-2 Integers from 1 to 6;

[0312] m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20;

[0313] m 12-6 Integers between 0 and 20;

[0314] m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 m 12-16 m 12-17 m 12-18 m 12-19 Integers between 1 and 20;

[0315] n 12-1 n12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 n 12-15 n 12-16 n 12-17 n 12-18 n 12-19 Integers between 0 and 12;

[0316] Z 12-1 for Where end a and Connection, B end and connect;

[0317] Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0318] Z 12-3 for Where end a and Connection, B end and connect;

[0319] Y 12-1 For linking bonds or amino acids;

[0320] Y 12-2 For linking bonds or amino acids;

[0321] Y 12-3 For linking bonds or amino acids;

[0322] Y 12-4 For linking bonds or amino acids;

[0323] Y 12-5 For linking bonds or amino acids;

[0324] Y 12-6 For linking bonds or amino acids;

[0325] Y 12-7 It is a linking bond or an amino acid.

[0326] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein the compound of Formula I has a structure represented by Formula IA:

[0327] in,

[0328] X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups;

[0329] X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups;

[0330] X 1-1 It is a C3-C8 cycloalkyl group;

[0331] X 2-1 It is a C3-C8 cycloalkyl group;

[0332] Q is the key for connection, S or -SS-;

[0333] R 1 -(C=O)R 1-1 ,

[0334] R 1-1 Hydrogen, C1-C 24 alkyl;

[0335] R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0336] Y 1-1 For linking bonds or amino acids;

[0337] Y 1-2 For linking bonds or amino acids;

[0338] Y 1-3 For linking bonds or amino acids;

[0339] Y 1-4 For linking bonds or amino acids;

[0340] Y 1-5 For linking bonds or amino acids

[0341] m 1-1 m 1-2 m 1-3 m 1-5 m1-6 m 1-7 Integers between 1 and 20;

[0342] m 1-4 Integers between 0 and 20;

[0343] n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Integers between 0 and 12;

[0344] Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0345] R 2 for

[0346] R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl;

[0347] R 4 for

[0348] Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ;

[0349] R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen;

[0350] R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0351] R 5 -(C=O)R 5-1 ,

[0352] R 5-1 For H, C1-C 24 alkyl;

[0353] R 5-2 R 5-3 C1-C independently12 Alkyl, C3-C8 cycloalkyl;

[0354] Y 5-1 For linking bonds or amino acids;

[0355] Y 5-2 For linking bonds or amino acids;

[0356] Y 5-3 For linking bonds or amino acids;

[0357] Y 5-4 For linking bonds or amino acids;

[0358] m 5-1 m 5-2 m 5-3 Integers between 1 and 20;

[0359] m 5-4 Integers between 0 and 20;

[0360] n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12;

[0361] R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl;

[0362] R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy

[0363] radical, halogen, -OR 6-1-2 ;

[0364] R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ;

[0365] R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0366] R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups;

[0367] R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens, C1-C6 alkyl groups;

[0368] R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0369] R 7 for

[0370] R 8 Hydrogen, C1-C 24 alkyl;

[0371] R 9 For C2-C 12 acetylinyl

[0372] Z 9-1 for Where end a and Connection, B end and

[0373] Z 9-2 for Where end a and Connection, B end and

[0374] m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20;

[0375] m 9-6 Integers between 0 and 20;

[0376] n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12;

[0377] Y 9-1 For linking bonds or amino acids;

[0378] Y 9-2 For linking bonds or amino acids;

[0379] Y 9-3 For linking bonds or amino acids;

[0380] R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0381] Or R 8 R9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0382] R 8-1 For C2-C 12 acetylinyl

[0383] Z 8-1 for Where end a and Connection, B end and

[0384] m 8-1 m 8-2 m 8-3 Integers between 1 and 20;

[0385] n 8-1 n 8-2 n 8-3 Integers between 0 and 12;

[0386] Y 8-1 For linking bonds or amino acids;

[0387] Y 8-1-1 For C2-C 12 alkynyl group;

[0388] R 8-2 It is halogenated or C1-C6 alkyl;

[0389] R 10 hydroxyl group

[0390] m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20;

[0391] m 10-6 Integers between 0 and 20;

[0392] n 10-1 n 10-2 n 10-3 n 10-4 n 10-5Integers between 0 and 12;

[0393] Y 10-1 For linking bonds or amino acids;

[0394] Y 10-2 For linking bonds or amino acids;

[0395] R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0396] R 11 for

[0397] R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13- 4 ,

[0398] R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ;

[0399] R 13-2-1 It is hydrogen, C1-C6 alkyl;

[0400] R 13-2-2 For C2-C 12 alkynyl group;

[0401] R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0402] R 13-3 It is hydrogen, C1-C6 alkyl;

[0403] R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl;

[0404] m 13-1 Integers from 1 to 6;

[0405] m13-2 Integers from 1 to 6;

[0406] m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20;

[0407] m 12-6 Integers between 0 and 20;

[0408] m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 Integers between 1 and 20;

[0409] n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 Integers between 0 and 12;

[0410] Z 12-1 for Where end a and Connection, B end and connect;

[0411] Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect;

[0412] Z 12-3 for Where end a and Connection, B end and connect;

[0413] Y 12-1 For linking bonds or amino acids;

[0414] Y 12-2 For linking bonds or amino acids;

[0415] Y12-3 For linking bonds or amino acids;

[0416] Y 12-4 For linking bonds or amino acids;

[0417] Y 12-5 For linking bonds or amino acids;

[0418] Y 12-6 It is a linking bond or an amino acid.

[0419] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound:

[0420] in,

[0421] X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups;

[0422] X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups;

[0423] X 1-1 It is a C3-C8 cycloalkyl group;

[0424] X 2-1 It is a C3-C8 cycloalkyl group;

[0425] Q is the key for connection, S or -SS-;

[0426] R 1 -(C=O)R 1-1 ,

[0427] R 1-1 Hydrogen, C1-C 24 alkyl;

[0428] R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0429] Y 1-1 For linking bonds or amino acids;

[0430] Y 1-2 For linking bonds or amino acids;

[0431] Y 1-3 For linking bonds or amino acids;

[0432] Y1-4 For linking bonds or amino acids;

[0433] m 1-1 m 1-2 m 1-3 Integers between 1 and 20;

[0434] m 1-4 Integers between 0 and 20;

[0435] n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 Integers between 0 and 12;

[0436] R 2 for

[0437] R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl;

[0438] R 4 for

[0439] Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ;

[0440] R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen;

[0441] R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0442] R 5 -(C=O)R 5-1 ,

[0443] R 5-1 For H, C1-C 24 alkyl;

[0444] R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl;

[0445] Y 5-1 For linking bonds or amino acids;

[0446] Y 5-2 For linking bonds or amino acids;

[0447] Y 5-3 For linking bonds or amino acids;

[0448] Y 5-4 For linking bonds or amino acids;

[0449] m 5-1 m 5-2 m 5-3 Integers between 1 and 20;

[0450] m 5-4 Integers between 0 and 20;

[0451] n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12;

[0452] R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl;

[0453] R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy

[0454] Roots, halogens;

[0455] R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ;

[0456] R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0457] R 7 for

[0458] R 8 Hydrogen, C1-C 24 alkyl;

[0459] R 9 For C2-C 12 acetylinyl

[0460] Z 9-1 for Where end a and Connection, B end and

[0461] Z 9-2 for Where end a and Connection, B end and

[0462] m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20;

[0463] m 9-6 Integers between 0 and 20;

[0464] n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12;

[0465] Y 9-1 For linking bonds or amino acids;

[0466] Y 9-2 For linking bonds or amino acids;

[0467] Y 9-3 For linking bonds or amino acids;

[0468] R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0469] Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0470] R 8-1 For C2-C 12 acetylinyl

[0471] Z 8-1 for Where end a and Connection, B end and

[0472] m8-1 m 8-2 m 8-3 Integers between 1 and 20;

[0473] n 8-1 n 8-2 n 8-3 Integers between 0 and 12;

[0474] Y 8-1 For linking bonds or amino acids;

[0475] R 10 hydroxyl group

[0476] m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20;

[0477] m 10-6 Integers between 0 and 20;

[0478] n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12;

[0479] Y 10-1 For linking bonds or amino acids;

[0480] Y 10-2 For linking bonds or amino acids;

[0481] R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl;

[0482] R 11 for

[0483] R 12 R 13 Each is independently H, C1-C6 alkyl,

[0484] m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20;

[0485] m12-6 Integers between 0 and 20;

[0486] n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 Integers between 0 and 12;

[0487] Y 12-1 For linking bonds or amino acids;

[0488] Y 12-2 For linking bonds or amino acids;

[0489] Y 12-3 It is a linking bond or an amino acid.

[0490] In one of the schemes, R 2 for For example, R 2 for Preferred

[0491] In one embodiment, the compound represented by Formula I is the compound represented by Formula A;

[0492] Among them, R 1 R 4 R 6 R 8 R 9 and R 13 As described in any embodiment of the present invention.

[0493] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound satisfies any of the following conditions (e.g., 1, 2, 3, or 4):

[0494] (1)R 1 for

[0495] (2)R 4 for

[0496] (3)R 6 For 0, 1, 2 or 3 (e.g. 0) R 6-1 Replaced by:

[0497] (4)R 8 For hydrogen, R 9 For C2-C 12 acetylinyl or

[0498] Or, R 8 R 9 Together with the C atoms it is attached to, they form:

[0499] Or, R 8 R 9 Together with the C atoms it is attached to, they form C3-C. 12 Cycloalkyl (e.g., cyclohexyl), by one or more R 8-2 Replacement C3-C 12 Cycloalkyl groups (e.g., cyclobutyl), the C3-C 12 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclohexyl,

[0500] (5)R 13 For: -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 R 13-1 For H, R 13-2 For -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ;

[0501] (Preferred R) 8 R 9 Together with the C atoms it is attached to, they form C3-C. 12 Cycloalkyl (e.g., cyclohexyl), by one or more R 8-2 Substituted cyclopropyl or by one or more R 8-2 Substituted cyclobutyl, or, R 8 R 9 Together with the C atom it is attached to, they form an oxacyclopentane.

[0502] In one embodiment, the compound represented by Formula I is the compound represented by Formula A1;

[0503] Among them, R 8 R 9 and R 13 As described in any embodiment of the present invention.

[0504] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound satisfies one or more of the following conditions (e.g., one or two):

[0505] (1)R 8 For hydrogen, R 9 for

[0506] Or, R 8 R 9 Together with the C atoms it is attached to, they form: (preferred) )

[0507] R 8-1 for

[0508] (2)R 13 for:

[0509] In one of the schemes,

[0510] X 1 It is a C1-C6 alkylene group;

[0511] X 2 It is a C1-C6 alkylene group;

[0512] Q is -SS-;

[0513] R 1 -(C=O)R 1-1 or

[0514] R 1-1 For C1-C 24 alkyl;

[0515] R 1-4 It is hydrogen;

[0516] R 1-5 -C(=O)R 1-5-1 ;

[0517] R 1-5-1 It is a C1-C6 alkyl group;

[0518] R 1-6 It is a C2-C6 acetylene group;

[0519] m 1-8 Integers between 1 and 20;

[0520] R 2 for

[0521] R 3 It is a C1-C6 alkyl group;

[0522] R 4 for

[0523] Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ;

[0524] R 4-1-1 R 4-1-2 and R 4-1-3 Each can be either hydrogen or halogen;

[0525] R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen or C1-C6 alkyl;

[0526] R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 Each is independently hydrogen;

[0527] R 5 -(C=O)R 5-1 ;

[0528] R 5-1 For C1-C 24 alkyl;

[0529] R 6 For one or more R 6-1 Replacement C5-C 12 Aryl;

[0530] R 6-1 For one or more R 6-1-1 Substituted C1-C6 alkoxy groups;

[0531] R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ;

[0532] R 6-1-1-1 and R 6-1-1-2 Each is independently hydrogen;

[0533] R 7 for

[0534] R 8 It is hydrogen;

[0535] R 9 For C2-C 12 acetylinyl or

[0536] Z9-1 for Where end a and Connection, B end and

[0537] m 9-1 and m 9-2 Integers between 1 and 20;

[0538] n 9-1 n 9-2 and n 9-3 Integers between 0 and 12;

[0539] n 9-4 Integers between 0 and 20;

[0540] Y 9-1 It consists of amino acids;

[0541] Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0542] R 8-1 For C2-C 12 acetylinyl by one or more R 8-1-2 Substituted C1-C6 alkyl groups Z 8-1 for Where end a and Connection, B end and

[0543] Z 8-2 for Where end a and Connection, B end and

[0544] m 8-1 m 8-2 m 8-3 m 8-4 m 8-5 m 8-6 Integers between 1 and 20;

[0545] n 8-1 n 8-2 n8-3 n 8-4 Integers between 0 and 12;

[0546] Y 8-1 It consists of amino acids;

[0547] Y 8-2 It consists of amino acids;

[0548] R 8-1-1 For C2-C 12 Alkyne or C1-C6 alkyl group substituted with one or more halogens;

[0549] R 8-1-2 For C6-C 12 Aryl or cyano;

[0550] R 8-2 Halogen or by one or more R 8-2-1 Substituted C1-C6 alkyl groups;

[0551] R 8-2-1 It is a halogen;

[0552] R 10 hydroxyl

[0553] R 11 for

[0554] R 12 It is a C1-C6 alkyl group;

[0555] R 13 -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 ,

[0556] R 13-1 R 13-2 Each is independently hydrogen or -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ;

[0557] R 13-2-1 It is hydrogen;

[0558] R 13-2-2 For C2-C 12 alkynyl group;

[0559] R 13-2-3 and R 13-2-4 Each is independently hydrogen;

[0560] R 13-6It is a C1-C6 alkyl group;

[0561] R 14 It is hydrogen;

[0562] Or R 9 R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3;

[0563] m 13-1 Integers from 1 to 6;

[0564] m 12-1 m 12-2 Integers between 1 and 20;

[0565] m 12-18 m 12-19 Integers between 1 and 20;

[0566] n 12-1 n 12-2 n 12-3 n 12-18 and n 12-19 Integers between 0 and 12;

[0567] Z 12-1 for Where end a and Connection, B end and connect;

[0568] Y 12-1 It is an amino acid.

[0569] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 9 For C2-C 12 Alkyne group.

[0570] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 9 For C2-C 12 Alkyne group.

[0571] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 9 for

[0572] Z9-1 Y 9-1 m 9-1 m 9-2 n 9-1 n 9-2 n 9-3 and n 9-4 The definition is as stated in any of the above items.

[0573] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, wherein R 8-1 For C2-C 12 Alkyne group.

[0574] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, wherein R 8-1 for

[0575] Among them, Z 8-1 Y 8-1 m 8-1 m 8-2 m 8-3 n 8-1 n 8-2 n 8-3 The definition is as stated in any of the above items.

[0576] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0577] for

[0578] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y 1-5 Y 5-2 Y 5-3 Y5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 8-2 Y 10- 1 Y 10-2 Y 10-3 Y 12-1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 Y 12-7 and Y 12-8 In the text, the amino acid mentioned is glutamic acid, with the structural formula as follows: Where end a is connected to -NH-, and end b is connected to... connect.

[0579] In one of the schemes, for

[0580] In one particular scheme, Q is -SS-.

[0581] In one of the schemes, Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y 1-5 Y 5-2 Y 5-3 Y 5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 8-2 Y 10-1 Y 10-2 Y 10-3 Y 12-1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 Y 12-7 and Y 12-8 The amino acid is, for example, a glutamic acid residue. Where end a is connected to -NH-, and end b is connected to... connect.

[0582] In one of the schemes, R 1 -(C=O)R 1-1 , For example, -(C=O)R1-1 or Preferably -(C=O)R 1-1 .

[0583] In one scheme, m 1-5 and m 1-6 Independently an integer from 1 to 6, such as 2 or 4.

[0584] In a certain scheme, n 1-6 n 1-7 and n 1-8 Independently positive numbers from 1 to 4, such as 2.

[0585] In one scheme, m 1-7 Independently an integer between 10 and 18, such as 16.

[0586] In one of the schemes, R 1-1 It is a C1-C6 alkyl group, such as methyl.

[0587] In one of the schemes, R 1-4 It is hydrogen.

[0588] In one of the schemes, R 1-6 It is a C2-C6 alkynyl group, such as ethynyl.

[0589] In one scheme, m 1-8 It is an integer from 1 to 6, for example, 4.

[0590] In one of the schemes, R 2 for

[0591] In one of the schemes, R 2 for Preferred

[0592] In one of the schemes, R 3 It is a C1-C6 alkyl group, such as methyl.

[0593] In one of the schemes, R 4-3 R 4-4 and R 4-5 For hydrogen, R 4-2 It is a C1-C6 alkyl group, such as methyl.

[0594] In one of the schemes, R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 It is hydrogen.

[0595] In one of the schemes, R 5 -(C=O)R 5-1 .

[0596] In one of the schemes, R 5-1 It is a C1-C6 alkyl group, such as methyl.

[0597] In one of the schemes, R 6 For one or more R 6-1 Replacement C5-C 12 Aryl.

[0598] In one of the schemes, R 6-1 It is a C1-C6 alkyl group or is composed of one or more R groups. 6-1-1 Substituted C1-C6 alkoxy groups, such as C1-C6 alkoxy groups substituted with one or more amino groups.

[0599] In one of the schemes, R 6-1-1-1 and R 6-1-1-2 It is hydrogen.

[0600] In one of the schemes, R 7 for

[0601] In one of the schemes, R 8 It is hydrogen or a C1-C6 alkyl group, such as hydrogen.

[0602] In one of the schemes, R 9 For C2-C 12 acetylinyl or

[0603] In one scheme, m 9-1 and m 9-2 Independently an integer from 1 to 6, such as 2 or 1.

[0604] In a certain scheme, n 9-1 n 9-2 and n 9-3 Independently positive numbers from 1 to 4, such as 2.

[0605] In one scheme, m 9-4 Independently an integer between 10 and 18, such as 16.

[0606] In one of the schemes, R 8 R 9 Together with the C atoms it is attached to, they form

[0607] In one of the schemes, R 8 R 9 Together with the C atoms attached to it, they form unsubstituted or R atoms. 8-2 Substituted with: cyclopropyl, cyclobutyl, cyclohexyl

[0608] In one of the schemes, R 8-1 For C2-C 12 acetylinyl C1-C6 alkyl, with one or more R 8-1-2 Substituted C1-C6 alkyl groups

[0609] In one scheme, m 8-1 m 8-2 m 8-4 and m 8-5 Independently an integer from 1 to 6, such as 1 or 2.

[0610] In a certain scheme, n 8-1 n 8-2 n 8-3 and n 8-4 Independently positive numbers from 1 to 4, such as 2.

[0611] In one scheme, m 8-4 and m 8-6 Independently an integer between 10 and 18, such as 16.

[0612] In one of the schemes, R 8-1-1 It is a C2-C6 alkynyl group, such as ethynyl or

[0613] In one of the schemes, R 8-1-2 For C6-C 12 Aryl or cyano.

[0614] In one of the schemes, R 8-2 Halogen or by one or more R 8-2-1 Substituted C1-C6 alkyl groups.

[0615] In one of the schemes, R 10 It is a hydroxyl group.

[0616] In one of the schemes, R 11 for

[0617] In one of the schemes, R 12 It is a C1-C6 alkyl group, such as methyl.

[0618] In one of the schemes, R 13 C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 ,

[0619] In one scheme, m 13-1It is an integer between 1 and 4, for example, 1.

[0620] In one scheme, m 13-2 It is an integer between 1 and 4, for example, 1.

[0621] In one scheme, m 12-1 m 12-3 m 12-5 m 12-7 m 12-8 m 12-10 m 12-11 m 12-13 m 12-14 m 12-16 m 12-18 It is an integer between 1 and 4, for example, 2.

[0622] In one scheme, m 12-2 m 12-4 m 12-6 m 12-9 m 12-12 m 12-15 m 12-17 m 12-19 It is an integer between 0 and 20, such as an integer between 10 and 18, preferably 14 or 16 (e.g., 14).

[0623] In a certain scheme, n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 n 12-15 n 12-16 n 12-17 n 12-18 n 12-19 It is an integer between 1 and 6, for example, 2.

[0624] In one of the schemes, R 13-1 R 13-2 Each is independently hydrogen or -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 .

[0625] In one of the schemes, R 13-2-1 It is hydrogen.

[0626] In one of the schemes, R 13-2-3 and R 13-2-4 It is hydrogen.

[0627] In one of the schemes, R 13-3 It is hydrogen.

[0628] In one of the schemes, R 13-4 For C2-C 12 Alkyne group, such as ethynyl group.

[0629] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0630] R 12 It is hydrogen or C1-C6 alkyl;

[0631] R 13 -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 ;

[0632] m 13-1 Integers from 1 to 6;

[0633] R 13-1 R 13-2 Each is independently hydrogen or C1-C6 alkyl.

[0634] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 13 In the context, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 It is -CH2-(C=O)-NH2.

[0635] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 12 In this context, the C1-C6 alkyl group is methyl.

[0636] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0637] R 12 It is hydrogen or C1-C6 alkyl;

[0638] R 13 for

[0639] m12-1 m 12-2 Integers between 1 and 20;

[0640] n 12-1 n 12-2 n 12-3 Integers between 0 and 12;

[0641] Y 12-1 In this context, the amino acid mentioned is glutamic acid.

[0642] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0643] R 12 In this context, the C1-C6 alkyl group is methyl;

[0644] R 13 In the middle, the aforementioned for

[0645] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0646] R 8 R 9 Together with the C atoms it is attached to, they form C3-C. 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 cycloalkyl;

[0647] The C3-C mentioned 12 The cycloalkyl group is a C4-C6 cycloalkyl group;

[0648] The R mentioned 8-2 As defined above, it is preferably a halogen.

[0649] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0650] R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0651] R 8-1 for

[0652] Z 8-2 Y 8-2 m 8-4 m 8-5 m 8-6 n 8-4 The definition is as described above.

[0653] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0654] R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0655] The 4-12 member heterocyclic group is preferably a 6-membered heterocyclic group. Where end a and R 8-1 Connected;

[0656] The R mentioned 8-1 for Among them, Z 8-2 Y 8-2 m 8-4 m 8- 5. m 8-6 n 8-4 The definition is as described in claim 1; preferably...

[0657] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0658] R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3;

[0659] The 4-12 member heterocyclic group is preferably a 6-membered heterocyclic group. Where end a and R 8-1 Connected;

[0660] The R mentioned 8-1 Among them, Z 8-1 Y 8-1 m8-1 m 8-2 m 8-3 n 8-1 n 8-2 n 8-3 The definition is as described above, preferably

[0661] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein,

[0662] R 8 It is hydrogen;

[0663] R 9 for

[0664] Among them, Z 9-1 Y 9-1 m 9-1 m 9-2 n 9-1 n 9-2 n 9-3 and n 9-4 The definition is as described above;

[0665] Preferred

[0666] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 6 In the context of C5-C 12 The aryl group is C6-C. 12 Aryl, preferably phenyl.

[0667] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, solvate, prodrug, metabolite, or isotope, wherein R 1 Methyl, -(C=O)CH3,

[0668] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 2 for

[0669] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 3 It can be methyl, ethyl, propyl, isopropyl, or cyclopropyl.

[0670] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 4 for

[0671] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 5 for

[0672] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 6 for Where p is an integer from 1 to 8.

[0673] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 7 for

[0674] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 8 It can be hydrogen or methyl.

[0675] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 9 for

[0676] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein, for

[0677] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 10 It is a hydroxyl group.

[0678] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 11 for

[0679] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 12 It is H or methyl.

[0680] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, R 13 For H,

[0681] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein, for

[0682] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y 5-1 Y 5-2 Y 5-3 Y 5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 10-1 Y 10- 2 Y 12-1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 for Where end a is connected to -NH-, and end b is connected to... connect.

[0683] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, solvate, prodrug, metabolite, or isotope, wherein R 1-1 R 3 R 4-2 R 4-3 R 4-4 R 4-5 R 5-1 R 6-1-1-1 R 6-1-1-2 R8 R 12 R 13 R 6-1-2-1 R 6-1-2-1-1 R 6-1-2- 1-2 R 8-2 R 13-1 R 13-2 R 13-2-1 R 13-2-3 R 13-2-4 R 13-3 R 13-4 R 8-1 R 8-1-1 R 8-1-2-1 In the C1-C6 alkyl group and the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0684] In one embodiment, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0685] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein X 1 X 2 In the C1-C6 alkylene and the substituted C1-C6 alkylene, the C1-C6 alkylene is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-; preferably -C(CH3)2-.

[0686] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 4-1-1 R 4-1-2 R 4-1-3 R 6-1 R 8-2 R 6-1-2-1 R 8-2 R 8-1-2-1 R 8-2-1 In this context, the halogen is independently F, Cl, Br, or I, for example, F.

[0687] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein X1-1 X 2-1 R 3 R 4-2 R 4-3 R 4-4 R 4-5 R 8 R 9 In the C3-C8 cycloalkyl group formed together with the C atom attached thereto, or in the case of a substituted C3-C8 cycloalkyl group, the C3-C8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, preferably cyclopropyl.

[0688] In one embodiment, the C3-C8 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl.

[0689] In one scheme, the C1-C 24 Alkyl and C1-C 12 Alkyl groups are independently C1-C6 alkyl groups, such as methyl.

[0690] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 9 R 8-1 R 8-1-1 R 13-1 R 13-2 R 13-2-2 R 13-4 In the context of C2-C 12 The alkynyl group is either ethynyl or propynyl.

[0691] In one scheme, the C2-C 12 The alkynyl group is independently a C2-C6 alkynyl group.

[0692] In one embodiment, the C2-C6 ynyl group is independently... q can be 0, 1, 2 or 3, for example 0 or 1.

[0693] In one embodiment, the C5-C 12 The aryl group is independently phenyl or benzo[3-C8]cycloalkyl (e.g., benzo[3-C6]cycloalkyl), such as phenyl or Phenyl is preferred.

[0694] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y5-1 Y 5-2 Y 5-3 Y 5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 10-1 Y 10- 2 Y 12-1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 Y 8-2 In this context, the amino acid is a natural amino acid, preferably glutamic acid.

[0695] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 In the substituted 4-12 member heterocyclic group, the 4-12 member heterocyclic group is a 6 member heterocyclic group.

[0696] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 In the substituted 4-12 membered heterocyclic group, the heteroatom in the 4-12 membered heterocyclic group is an oxygen atom.

[0697] In one embodiment, the 4-12 membered heterocyclic group is a 4-6 membered heterocyclic alkyl group containing one nitrogen atom, for example...

[0698] In one scheme, the C3-C 12 Cycloalkyl groups are monocyclic C 3-8 cycloalkyl or spirocyclic C 6-12 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclohexyl,

[0699] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, wherein, in 1, the compound represented by Formula I or its pharmaceutically acceptable salt, and the compound represented by Formula I is any one of the following compounds:

[0700] The present invention also provides a pharmaceutical composition comprising:

[0701] The pharmaceutical composition of any of the compounds represented by Formula I, or a pharmaceutically acceptable salt thereof, or a deuterated thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug thereof, or a metabolite thereof, preferably further comprises a pharmaceutically acceptable excipient.

[0702] The present invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by IL-23 / IL-23R.

[0703] The diseases or conditions mediated by IL-23 / IL-23R are selected from those treated with inflammatory, autoimmune, and cancer-related conditions, such as inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical stomatitis), enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radiotherapy or chemotherapy, colitis associated with congenital immune disorders such as leukopenia-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Praque syndrome, Scherdick-Donnell syndrome, and Weil-O. Use in medications for: Ischemia syndrome, colitis following rectocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome (IBS), multiple sclerosis (MS), psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus (SLE), or diabetes; preferably for inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis.

[0704] The present invention provides a method for preparing a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof, comprising the following steps: in a solvent, subjecting a compound of Formula Ia to a cyclization reaction to obtain a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof.

[0705] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 X1, X2 and Q are defined as in any embodiment of the present invention.

[0706] The cyclization reaction can be carried out in the presence of an alcoholic reagent of iodine, such as an alcoholic reagent of iodine.

[0707] This invention provides a compound of formula Ia or a pharmaceutically acceptable salt thereof.

[0708] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 X1, X2 and Q are defined as in any embodiment of the present invention.

[0709] For example, the compound represented by formula Ia is any of the following compounds:

[0710] Unless otherwise defined herein, the scientific and technical terms used in this patent application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the nomenclature and techniques described herein in conjunction with those of chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry are nomenclature and techniques well known and commonly used in the art.

[0711] As used herein, unless otherwise specified, the following terms have their respective meanings.

[0712] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0713] The terms “patient,” “subject,” and “individual” are used interchangeably and refer to humans or non-human animals. These terms include mammals such as humans, primates, livestock (e.g., bovines, suidae), companion animals (e.g., canines, felines), and rodents (e.g., mice and rats).

[0714] As used herein, the term "peptide" broadly refers to a sequence of two or more amino acids linked together by peptide bonds. It should be understood that this term does not imply a specific length of an amino acid polymer, nor is it intended to suggest or distinguish between polypeptides produced using recombinant techniques, chemical or enzymatic synthesis, or naturally occurring polypeptides. The term peptide includes cyclic peptides.

[0715] As used in this article, the oxo group refers to =O; for example, R 8-2 It is an oxo group, which is formed by one or more R groups. 8-2 Replacement C3-C 12 cycloalkyl is

[0716] As is conventionally understood by those skilled in the art, the peptide sequences disclosed herein are shown from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide.

[0717] The sequences disclosed herein are sequences incorporating a "-OH" or "-NH2" portion at the carboxyl terminus (C-terminus). In such cases, and unless otherwise stated, the "-OH" or "-NH2" portion at the C-terminus of the sequence indicates a hydroxyl or amino group corresponding to a carboxylic acid (COOH) or amide (CONH2) group present at the C-terminus, respectively. In each sequence of the invention, the C-terminal "-OH" portion may replace the C-terminal "-NH2" portion, and vice versa.

[0718] Those skilled in the art will understand that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain can be modified when it forms an intramolecular bridge with another amino acid side chain; for instance, one or more hydrogen atoms may be removed or replaced by bonds.

[0719] As used herein, the term "amino acid" or "any amino acid" refers to any and all amino acids, including naturally occurring amino acids (e.g., α-amino acids), non-natural amino acids, modified amino acids, and non-natural amino acids. This includes both D-amino acids and L-amino acids. Natural amino acids include those found in nature, such as the 23 amino acids that combine into peptide chains to form the building blocks of numerous proteins. These stereoisomers are primarily L-stereomers, but some D-amino acids are found in bacterial envelopes and some antibiotics. Twenty "standard" natural amino acids are listed in the table above. "Non-standard" natural amino acids are pyrrolidine (found in methane-producing organisms and other eukaryotes), selenocysteine ​​(found in many non-eukaryotes and most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria, and chloroplasts). "Non-natural" or "non-natural" amino acids are non-protein amino acids that are naturally occurring or chemically synthesized (i.e., amino acids not naturally encoded or found in the genetic code). More than 140 non-natural amino acids are known, and there may be thousands of combinations. Examples of “non-natural” amino acids include β-amino acids (β3 and β2), high-molecular-weight amino acids, proline derivatives and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, cyclic-substituted phenylalanine and tyrosine derivatives, linear nucleoamino acids, diamino acids, D-diamino acids, α-methyl amino acids, and N-methyl amino acids. Non-natural or non-natural amino acids also include modified amino acids. “Modified” amino acids include amino acids that have been chemically modified to include groups or chemical moieties that are not naturally present on the amino acid (e.g., natural amino acids). According to some embodiments, peptide inhibitors contain an intramolecular bond between two amino acid residues present in the peptide inhibitor. It should be understood that the amino acid residues forming the bond will be slightly altered when bonded to each other compared to when they are not bonded to each other. References to specific amino acids are intended to cover amino acids in both their unbonded and bonded states.

[0720] Primarily, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions proposed by the IUPAC Committee on the Nomenclature of Organic Chemistry and the IUPAC-IUB Committee on the Nomenclature of Biochemicals, as stated in the α-amino acid nomenclature (Recommendations, 1974; Biochemistry, 14(2), 1975). Some abbreviations used to describe this invention are defined in Table 1 below.

[0721] Table 1. Abbreviations for relevant amino acids and chemical components (unless all Ls specify, this applies to amino acid derivatives).

[0722] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0723] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0724] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0725] The term "pharmaceutical excipients" can refer to those excipients widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0726] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0727] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0728] "Absorption enhancer" refers to a component that improves or promotes the mucosal absorption of a drug in the gastrointestinal tract, such as a permeation enhancer or intestinal permeation enhancer. As conventionally understood in the art, a permeation enhancer (PE) is an agent designed to improve the oral delivery of a therapeutic drug with poor bioavailability. PE can increase the intercellular or transcellular pathways of the drug.

[0729] Drug excipients that can increase permeability are known as "absorption-modifying excipients" (AMEs). AMEs can be used in oral compositions, for example as wetting agents (sodium lauryl sulfate), antioxidants (e.g., EDTA), and emulsifiers (e.g., polyethylene glycol glyceride), and can be included in compositions, particularly as PEs, to improve bioavailability. PEs can be classified according to how they alter barrier integrity via paracellular or transcellular pathways.

[0730] "Intestinal permeability enhancer (IPE)" refers to a component that improves the bioavailability of a component. Suitable representative IPEs for use in this invention include, but are not limited to, various surfactants, fatty acids, medium-chain glycerides, steroidal detergents, acylcarnitines and alkylcholine, N-acetylated α-amino acids and N-acetylated non-α-amino acids, as well as deacetylated chitosans and other mucosal adhesion polymers. For example, a suitable IPE for use in this invention may be sodium decanoate.

[0731] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[0732] The "prevention" mentioned in this invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0733] The expression "a group substituted by one or more substituents" means that one or more hydrogen atoms in a group are independently replaced by that substituent. When multiple substituents are present, unless otherwise specified, their definitions are independent and do not affect each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0734] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0735] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0736] The term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Furthermore, "alkyl" should include "cycloalkyl" structures.

[0737] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C1-C2). 20Alkylenes. The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C1-C1). 12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C1-C6 alkylenes). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0738] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds with a specified number of carbon atoms (e.g., C2-C6, C2-C4 alkynyl). These carbon-carbon triple bonds can be internal or terminal, such as ethynyl or propynyl with the triple bond internal. Or a propynyl group at the end of the triple bond

[0739] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic carbocyclic ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C3-C). 20 Cycloalkyl groups. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., C3-C4). 12 Cycloalkyl, more preferably cycloalkyl having 3 to 8 ring atoms (i.e., C3-C8 cycloalkyl), and most preferably cycloalkyl having 3 to 6 ring atoms (i.e., C3-C6 cycloalkyl).

[0740] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0741] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0742] The term "spirocycloalkyl" refers to a polycyclic system in which the rings share a single carbon atom (called the spiro atom), and the rings may contain one or more double bonds. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C5 to C6). 20 Spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C6-C). 14 Spirocycloalkyl, more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C7-C14). 10Spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5 or 7 / 6 monospirocycloalkyl. Non-limiting examples include:

[0743] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. It is a fusion of a monocyclic cycloalkyl group with one or more other monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C5-C). 20 The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., C6 to C7). 14 fused cycloalkyl groups, more preferably fused cycloalkyl groups having 7 to 10 ring atoms (i.e., C7 to C14). 10 The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.), preferably bicyclic fused cyclic alkyl groups or tricyclic fused cyclic alkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cyclic alkyl groups. Non-limiting examples include:

[0744] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon system in which two non-directly bonded carbon atoms are shared between the rings. The ring may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C5-C). 20 Bridged cycloalkyl group). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., C6 to C5). 14 Bridged cycloalkyl groups, more preferably bridged cycloalkyl groups having 7 to 12 carbon atoms (C7-C4). 12Bridged cycloalkyl groups). The bridged cycloalkyl groups include bicyclic bridged cycloalkyl groups and polycyclic bridged cycloalkyl groups (such as tricyclic bridged cycloalkyl groups, tetracyclic bridged cycloalkyl groups, etc.), preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples include:

[0745] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3-20 membered heterocyclic group). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3-12 membered heterocyclic group); more preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3-8 membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3-6 membered heterocyclic group), a heterocyclic group having 4 to 6 ring atoms (i.e., a 4-6 membered heterocyclic group), or a heterocyclic group having 5 to 7 ring atoms (i.e., a 5-7 membered heterocyclic group); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5 or 6 membered heterocyclic group).

[0746] Non-limiting examples of the monocyclic heterocyclic group include:

[0747] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0748] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheterocyclic groups). The spiroheterocyclic group is preferably a spiroheterocyclic group with 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocyclic groups), and more preferably a spiroheterocyclic group with 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocyclic groups). The spiroheterocyclic group includes monospirocyclic and multispirocyclic groups (such as bispirocyclic groups), preferably monospirocyclic or bispirocyclic, and more preferably ternary / quadrivalent, ternary / pentarivalent, ternary / hexavalent, quadrivalent / quadrivalent, quadrivalent / pentarivalent, quadrivalent / pentarivalent, quadrivalent / pentarivalent, quadrivalent / pentarivalent, pentari ... or pentarivalent / pentarivalent monospirocyclic groups. Non-limiting examples include:

[0749] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur. This system is formed by the fusion of a monocyclic heterocyclic group with one or more monocyclic heterocyclic groups, or by the fusion of a monocyclic heterocyclic group with one or more cycloalkyl, aryl, or heteroaryl groups. The bonding point is located on the monocyclic heterocyclic group, and the system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclic group). The fused heterocyclic group is preferably a fused heterocyclic group with 6 to 14 ring atoms (i.e., a 6-14-membered fused heterocyclic group), more preferably a fused heterocyclic group with 6 to 10 ring atoms (i.e., a 6-10-membered fused heterocyclic group), and more preferably a 6- or 7-membered fused heterocyclic group. The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic or tricyclic fused heterocyclic groups, more preferably ternary / quadricyclic, ternary / pentaricyclic, ternary / hexacyclic, quadricyclic / quadricyclic, quadricyclic / pentaricyclic, quadricyclic / pentaricyclic, pentari ...

[0750] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly connected atoms are shared between the rings. The rings may contain one or more double bonds, and the rings contain at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur. The system has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group with 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), more preferably a bridged heterocyclic group with 6 to 10 ring atoms (i.e., 6 to 10-membered bridged heterocyclic groups), and more preferably a 6-, 7-, or 8-membered bridged heterocyclic group. Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), with bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups being preferred. Non-limiting examples include:

[0751] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered aryl). The aryl is preferably an aryl having 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). The monocyclic aryl is, for example, phenyl. Non-limiting examples of the polycyclic aryl include naphthyl, anthraceneyl, phenanthrene, etc. The polycyclic aryl also includes fusion of phenyl, naphthyl with one or more heterocyclic or cycloalkyl groups (i.e., fused polycyclic aryl), wherein the bonding point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0752] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, wherein the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5 to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., 5 or 6-membered heteroaryl) or a heteroaryl having 9 or 10 ring atoms (i.e., 9 or 10-membered heteroaryl). The polycyclic aryl group further includes fusion of a monocyclic heteroaryl group with one or more heterocyclic groups or cycloalkyl groups (i.e., fused polycyclic heteroaryl groups), wherein the bonding point is on the monocyclic heteroaryl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including:

[0753] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0754] The term "prodrug" refers to a compound obtained by chemically modifying a drug, which has no or low activity in vitro, but releases an active drug in vivo through enzymatic or non-enzymatic conversion to exert its pharmacological effect.

[0755] The term "metabolites" refers to intermediate and final metabolites in metabolism.

[0756] The term "isotopic compound" refers to a compound in which one or more atoms can exist in their non-natural abundance form. Taking hydrogen atoms as an example, their non-natural abundance form means that approximately 95% of them are deuterium.

[0757] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0758] The reagents and raw materials used in this invention are all commercially available.

[0759] The positive and progressive effects of this invention are that the compounds of this invention have better inhibitory activity against IL-23R. Detailed Implementation

[0760] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0761] Example:

[0762] In certain embodiments of methods for treating related diseases, peptide inhibitors comprise or are any of the amino acid sequences listed below; or a pharmaceutically acceptable salt thereof;

[0763] The peptides of this invention are condensed using DIC (N,N'-diisopropylcarbodiimide) and HOAT (N-hydroxy-7-azabenzotriazole). Rink amide MBHA resin (100 to 200 mesh, 0.702 mmol / g) is used for peptides with C-terminal amides. CTC resin (100 to 200 mesh, 0.702 mmol / g) is used for polypeptide fragment synthesis. The peptide inhibitors of this invention are identified based on medical chemistry optimization and / or phage presentation, and are screened to identify compounds with excellent binding and / or inhibitory properties.

[0764] Detection method:

[0765] The structure of the compound was determined by mass spectrometry (MS).

[0766] MS determination was performed using (Agilent 6125B (ESI) and Agilent 6125B (APCI)).

[0767] The HPLC determination was performed using a Waters 2998PDA high-performance liquid chromatograph (BioSuite). TM C18 PA-B, 4.6×150mm, 3.5μm).

[0768] In this embodiment, IM (Intermediate) is synonymous with intermediate, that is, intermediate 1 is synonymous with IM 1. Cpd (Compound) is synonymous with compound, that is, compound 1 is synonymous with Cpd 1.

[0769] Preparation Example 1: Preparation of Intermediate 1

[0770] Step 1: Compound 1a (5.0 g, 20.46 mmol) was dissolved in THF (100 mL), cooled to 0 °C in an ice-water bath, and NaH (1.64 g, 40.93 mmol) was added in portions. After reacting for 1.5 hours in an ice-water bath, bromopropyne (4.87 g, 40.93 mmol) was added, and the reaction was continued for another 4 hours in an ice-water bath. The reaction was quenched by adding trifluoroacetic acid (2 mL) in an ice-water bath, and the mixture was concentrated under reduced pressure to dryness. The LCMS m / z of the main product 1b was 283.1 [M+H]. + Without further purification, proceed directly to the next reaction.

[0771] Step 2: Add 100 mL of dichloromethane to the reaction system, and then add 10 mL of trifluoroacetic acid dropwise. Let the reaction proceed overnight at room temperature. After the reaction of starting material 1b is complete, monitor by TLC and then evaporate to dryness. Do not process it further and use it directly in the next reaction.

[0772] Step 3: Add 60 mL of water and 60 mL of tetrahydrofuran sequentially to the reaction system. Add 4.25 g of sodium bicarbonate to the system under an ice-water bath. Dissolve Fmoc-Osu (7.89 g) in 60 mL of tetrahydrofuran and add it dropwise to the reaction system under an ice-water bath. Stir overnight at room temperature. After the reaction is complete, adjust the pH to approximately 4-5 with hydrochloric acid. Elute the organic phase by rotary evaporation and freeze-dry directly. Separate the crude product by column chromatography (DCM:MeOH (10:1)) to obtain an oily intermediate 1 (IM-1) (2.9 g), LCMS m / z = 405.2 [M+H]. + .

[0773] Preparation Example 2: Preparation of Intermediate 2

[0774] Step 1: Compound 2a (1.0 g, 1.06 mmol) and compound 2b (0.18 g, 1.06 mmol) were dissolved in 30 mL of anhydrous tetrahydrofuran, heated to 40 °C, and stirred overnight. After the reaction was complete as monitored by TLC, the solvent was evaporated, and the crude product was separated by column chromatography to obtain DCM:MeOH (30:1), yielding a colorless oily intermediate 2 (IM-1) (1.0 g). 1 H NMR (400MHz, Chloroform-d) δ4.20 (s, 2H), 4.01 (d, J = 13.9Hz, 4H), 3.79 (s, 2 H),3.69-3.30(m,30H),2.24-2.17(m,5H),1.44(s,18H),1.29-1.20(m,30H).

[0775] Preparation Example 3: Preparation of Intermediate 13-1

[0776] first step:

[0777] 2,2-Difluorospiro[3.5]non-7-one (600 mg, 3.44 mmol) was dissolved in methanol (5 mL) at 0 °C. Ammonia-methanol solution (7 M, 6 mL) was added to the solution, and the mixture was stirred at 0 °C for 3 hours. Then, trimethylcyanosyl silane (360 mg) was added dropwise. After the addition was complete, the mixture was gradually brought to room temperature and stirred for 1.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a light brown oil. Upon slurrying with petroleum ether at 0 °C, a white solid precipitated. After filtration and drying, a white product 13-1-a (540 mg, yield 78%) was obtained. LC-MS: 201.2 [M+H] + .

[0778] Step Two:

[0779] 13-1-a (540 mg, 2.70 mmol) was dissolved in a mixed solution of tetrahydrofuran and water (v / v = 1:1, 10 mL), and anhydrous sodium carbonate (343 mg, 3.24 mmol) was added. Fmoc-Cl (733 mg, 2.83 mmol) was dissolved in tetrahydrofuran (20 mL) and slowly added dropwise to the reaction solution at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, slurried with water, and filtered to obtain a white solid. The obtained solid was then slurried with petroleum ether and filtered to obtain a white solid 13-1-b (790 mg, yield 69.0%). LC-MS: 423.4 [M+H] + .

[0780] Step 3:

[0781] 13-1-b (790 mg, 1.87 mmol) was dissolved in dioxane hydrochloride solution (4 M, 6 mL), followed by the addition of concentrated hydrochloric acid (6 mL). The reaction mixture was stirred at 90 °C for 24 h. After the reaction was complete, the solution was concentrated under reduced pressure, and a white solid precipitated upon addition of water. The white solid was filtered and dried to obtain the product, a white powder intermediate 13-1 (690 mg, yield 83.6%), LC-MS: 442.4 [M+H]. + . 1H NMR (400MHz, DMSO) δ8.02(s,1H),7.90(d,J=7.5Hz,2H),7.72(d,J=7.5Hz,2H),7.43(t,J=7.4Hz,2H),7.35(td,J=7.4,1.0Hz,2H) ,4.42(d,J=6.4Hz,2H),4.25(t,J=6.6Hz,1H),2.37(dd,J=22.1,12.5Hz,4H),2.22–1.93(m,2H),1.80–1.51(m,4H),1.24(s,2H).

[0782] Preparation Example 4: Synthesis of Intermediate 4

[0783] Compound 4a (2.0 g, 10.52 mmol, CAS: 140681-41-0, purchased from Jiangsu Aikon Biomedical R&D Co., Ltd.) was weighed and dissolved in 100 mL of methanol. Acetyl-L-lysine (2.13 g, 12.62 mmol) was then added, and the mixture was stirred overnight at 25 °C. LC-MS showed the reaction was complete. The reaction solution was concentrated to obtain a white crude solid. The crude solid was passed through a silica gel column (eluted with DCM:MeOH = 10:1), finally yielding 1.6 g of a white solid, yield: 63.3%. LC-MS: 240.9 [M+H] + .

[0784] 1 H NMR (400MHz, DMSO) δ12.48(s,1H),8.69(t,J=5.5Hz,1H),8.07(d,J=7.7Hz,1H),4.15–4.10(m,1H),4.09(s,1H),3.05(dd,J=12.9,6 .8Hz,2H),1.84(s,3H),1.66(td,J=13.4,8.7Hz,1H),1.54(dt,J=13.9,8.8Hz,1H),1.38(dd,J=13.5,7.4Hz,2H),1.33–1.18(m,2H).

[0785] Preparation Example 5: Synthesis of Intermediates 5-1 and 5-2

[0786] Synthesis of intermediate 5-1:

[0787] Weigh (R)-3-aminotetrahydrofuran-3-carboxylic acid (CAS: 1315053-78-1, 0.06 g, 0.50 mmol, 1.00 eq), add acetonitrile (2.00 ml) and water (2.00 ml), stir to dissolve, add sodium bicarbonate (125.01 mg, 1.49 mmol, 3.00 eq), stir to react, then add 9-fluorenylmethyl-N-succinimide carbonate (184.18 mg, 0.55 mmol, 1.10 eq), stir to react overnight. LCMS showed that the reaction was complete. Adjust the pH to 3-4 with dilute hydrochloric acid, remove most of the acetonitrile by rotary evaporation, filter and collect the solid to obtain the crude product. The crude product was passed through a silica gel column (eluted with DCM:MeOH = 10:1) to give a white solid intermediate Fmoc-(R)-3-aminotetrahydrofuran-3-carboxylic acid 5-1 (120 mg, supercritical fluid chromatography conditions: SA column, 5 μm, 20*150 mm, 20% methanol modifier, flow rate 50 mL / min, retention time 5.87 min). LCMS m / z = [M+H] + . 1 H NMR (400MHz, DMSO) δ7.97(s,1H),7.89(d,J=7.5Hz,2H),7.72(d,J=7.4Hz,2H),7.42(t,J=7.4Hz,2H),7.33(t,J=7.4Hz,2 H),4.35–4.27(m,2H),4.27–4.16(m,1H),4.01(d,J=9.1Hz,1H),3.80(ddd,J=23.6,16.4,8.6Hz,3H),2.35–2.13(m,2H).

[0788] Synthesis of intermediate 5-2:

[0789] Weigh (S)-3-aminotetrahydrofuran-3-carboxylic acid (CAS: 1315052-80-2, 131 mg, 0.969 mmol), add acetonitrile (5 mL) and water (5 mL), stir to dissolve, add NaHCO3 (246.68 mg, 2.907 mmol), stir to react, then add Fmoc-OSu (363.23 mg, 1.066 mmol), stir to react overnight. LCMS showed that the reaction was complete. Adjust the pH to 3-4 with dilute hydrochloric acid, remove most of the acetonitrile by rotary evaporation, filter and collect the solid to obtain the crude product. The crude product was passed through a silica gel column (eluted with DCM:MeOH = 10:1) to give a white solid intermediate 5-2 of Fmoc-(S)-3-aminotetrahydrofuran-3-carboxylic acid (210 mg, supercritical fluid chromatography conditions: SA column, 5 μm, 20*150 mm, 20% methanol modifier, flow rate 50 mL / min, retention time 7.66 min). LCMS m / z = 353.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.97(s,1H),7.89(d,J=7.5Hz,2H),7.72(d,J=7.4Hz,2H),7.42(t,J=7.4Hz,2H),7.33(t,J=7.3Hz,2 H),4.36–4.27(m,2H),4.27–4.18(m,1H),4.01(d,J=9.1Hz,1H),3.80(ddd,J=23.3,16.5,8.5Hz,3H),2.34–2.13(m,2H).

[0790] Splitting intermediates 5-1 and 5-2:

[0791] Fmoc-3-aminotetrahydrofuran-3-carboxylic acid (CAS: 1132879-21-0, 10 g) was subjected to preparative separation by supercritical fluid chromatography (SCLC). An SA column (5 μm, 20 x 150 mm) was used with 20% methanol as the modifier. The flow rate was 50 mL / min. The fraction with a retention time of 5.87 min was collected, concentrated, and lyophilized to obtain a white solid intermediate 5-1 (4.96 g, SFC purity: 100%). LCMS m / z = 354.0 [M+H] + The fraction with a retention time of 7.66 min was collected, concentrated, and lyophilized to obtain intermediate 5-2 (4.92 g, SFC purity: 98.3%), LCMS m / z = 354.0 [M+H]. + .

[0792] Preparation Example 6: Synthesis of Intermediate 6

[0793] At room temperature, bromoacetonitrile (0.57 mL, 8.20 mmol) was added to a mixture of acetonitrile solution (30 mL) of compound 4-(Fmoc-amino)-4-piperidinecarboxylate (6a, 2.00 g, 5.46 mmol) and saturated sodium bicarbonate solution (15 mL), and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until complete. The acetonitrile in the solution was removed by vacuum dilution, and the pH was adjusted to 7-8 with 1 N hydrochloric acid. A large amount of white solid precipitated. After filtration, the filter cake was washed with water and dried to give intermediate 6 (1.80 g, yield 80.94%), a white solid product. LC-MS: 406.2 [M+H] + .

[0794] 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),7.90(d,J=7.6Hz,2H),7.74(d,J=7.4Hz,2H),7.67(s,1H),7.43(t,J=7.2Hz,2H),7.35(t,J=7 .4Hz,2H),4.26(s,3H),3.74(s,2H),2.61(d,J=11.0Hz,2H),2.47(d,J=12.2Hz,2H),2.05(t,J=11.8Hz,2H),1.91(t,J=11.4Hz,2H).

[0795] Preparation Example 7: Synthesis of Intermediate 7

[0796] Step 1: Weigh compound 7a (950.00 mg, 3.78 mmol), add dioxane hydrochloride (10.00 mL), and stir to dissolve. React at 23°C overnight with stirring. TLC showed the reaction was complete. Concentrate the reaction solution to obtain a yellow solid product, compound 7b (708 mg, yield: 99.83%). LC-MS: 152.1 [M+H] + .

[0797] Step 2: Weigh compound 7b (0.71 g, 3.78 mmol), add acetonitrile (20.00 mL) and water (20.00 mL), stir to dissolve, add sodium bicarbonate (1.59 g, 0.02 mol), stir to react, then add 9-fluorenylmethyl-N-succinimide carbonate (1.40 g, 4.15 mmol), stir to react overnight. LC-MS showed the reaction was complete. Adjust pH to 3 with dilute hydrochloric acid, remove most of the acetonitrile by rotary evaporation, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash once with saturated brine, and concentrate to obtain the crude product. Elute the crude product onto a silica gel column (using PE:EA = 10:1-2:1), finally giving the white solid intermediate 7 (1.32 g, yield: 93.66%). LC-MS: 396.0 [M + Na] + .

[0798] 1 H NMR (400MHz, DMSO) δ13.14(s,1H),8.19(s,1H),7.89(d,J=7.5Hz,2H),7.70(d,J=7.1Hz,2H),7.42(t,J=7.4Hz,2H),7.33(t,J=7.2Hz,2H) ,5.94(td,J=55.8,7.4Hz,1H),4.35–4.25(m,2H),4.22(dd,J=12.8,6.1Hz,1H),1.91-1.99(m,1H),1.69-1.73(m,1H),1.44–1.37(m,1H).

[0799] Preparation Example 8: Synthesis of Intermediate 8

[0800] Step 1: At 0°C, DIPEA (369.50 mg, 2.86 mmol), HATU (217.42 mg, 0.57 mmol), and 8a (CAS: 148088-78-2, 158.88 mg, 0.71 mmol) were added sequentially to a 15 mL solution of acetonitrile containing compound 2a (500.00 mg, 0.48 mmol). The solution was then stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (2%–70%, CH3CN / 0.03% TFA / water) to give compound 8b (650.00 mg, yellow oil, TFA salt), purity: 80%, yield: 87.05%. LC / MS: [M] + =1252.6.

[0801] Step 2: Add 10% Pd / C (110.36 mg) to a 20 mL isopropanol solution of compound 8b (650 mg, 0.52 mmol) at room temperature, and stir the reaction at room temperature under hydrogen atmosphere (1 atm) for 5 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to obtain the final compound intermediate 8,(S)-25-(tert-butoxycarbonyl)-N,N,44,44-tetramethyl-N-(5-methyl-6-oxo-9,12-dioxa-2,5-diazatetradecane-14-yl)-4,13,22,27,42-pentoxy-6,9,15,18,43-pentoxy-3,12,21,21,21,26-tetraazapentadecan-1-amine (370 mg, yellow oil, TFA salt). Purity: 99.46%, Yield: 63.39%. LC / MS: [M] + =1118.5.

[0802] 1 HNMR (400MHz, CD4OD): δ4.23-4.26 (m, 1H), 4.05 (t, j = 6.2Hz, 4H), 3.95 (brs, 2H), 3.66-3.79(m,20H),3.54-3.61(m,6H),3.45-3.47(m,2H),3.36-3.39(m,2H),3.20 -3.23(m,8H),3.10(s,3H),2.68-2.73(m,5H),2.18-2.31(m,6H),2.08-2.13(m,1 H),1.86-1.92(m,1H),1.54-1.66(m,4H),1.44-1.46(m,18H),1.29-1.38(m,20H).

[0803] Intermediate 9:

[0804] Step 1: At 0°C, DIEA (2.17 g, 16.80 mmol), HATU (1.28 g, 3.36 mmol), and 8a (0.75 g, 4.05 mmol) were added sequentially to a 30 mL solution of acetonitrile containing compound 9a (CAS: 1118767-16-0, 2.40 g, 2.80 mmol). The solution was then stirred at 0°C for 6 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase column chromatography (2%–70%, CH3CN / 0.03% TFA / water) to give compound 9b (2.00 g, yellow oil, TFA salt), purity: 90%, yield: 60.71%. LC / MS: [M+H] + =1050.4

[0805] Step 2: 10% Pd / C (0.18 g) was added to a tetrahydrofuran (60 mL) solution of compound 9b (1.80 g, 1.70 mmol) at room temperature. The reaction was carried out under hydrogen atmosphere (1 atm) at room temperature with stirring for 24 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography to obtain intermediate 9,(S)-27-(tert-butoxycarbonyl)-5-methyl-6,15,24,29-tetraoxo-8,11,17,20-tetraoxo-2,5,14,23,28-pentazahexacarbontetraenoic acid tert-butyl ester (0.82 g, yellow oil, TFA salt) with a purity of 95.17% and a yield of 52.94%. LC / MS: [M+H] + =916.4

[0806] 1 HNMR (400MHz, CDCl3): δ9.25 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.75 (d, j = 3.8Hz, 1H), 4.39(s,1H),4.25(s,2H),4.03(s,2H),3.58-3.73(m,14H),3.42-3.51(m,4H),3.22-3. 25(m,2H),3.00(s,3H),2.74(s,3H),2.30-2.37(m,2H),2.18-2.25(m,4H),2.10-2.14 (m,1H),1.94-1.97(m,1H),1.57-1.60(m,4H),1.44-1.46(m,18H),1.25-1.27(m,24H).

[0807] Intermediate 10:

[0808] Step 1: At room temperature, 4-(Fmoc-amino)-4-piperidine carboxylate (2.00 g, 5.46 mmol) was dissolved in pyridine solution (20 mL). 4-Dimethylaminopyridine (0.13 g, 1.09 mmol) and trifluoroacetic anhydride (1.72 g, 8.19 mmol) were added to this solution, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS until complete. The solution was concentrated under reduced pressure and evaporated to dryness. It was then dissolved in ethyl acetate, washed several times with 1N hydrochloric acid, dried over anhydrous sodium sulfate, and evaporated to dryness. Using a Biotage instrument, a 40 g normal-phase silica gel column was used as the elution medium, with an ethyl acetate / petroleum ether gradient from 0-60%. The collected product was evaporated to dryness to give a colorless oily intermediate 10 (1.8 g, yield 70.97%). LC-MS: 485.2 [M+H] + .

[0809] 1 H NMR (400MHz, DMSO-d6) δ12.74 (s, 1H), 7.91 (d, J = 7.6Hz, 2H), 7.88 (s, 1H), 7.7 4(d,J=7.4Hz,2H),7.43(t,J=7.4Hz,2H),7.35(td,J=7.4,1.0Hz,2H),4.33(d, J=6.8Hz,2H),4.25(t,J=6.6Hz,1H),3.70(d,J=12.0Hz,1H),3.41(t,J=12.2Hz ,,2H),3.17(t,J=12.2Hz,1H),2.10(t,J=15.8Hz,2H),1.90(t,J=17.8Hz,2H).

[0810] Intermediate 11:

[0811] first step:

[0812] At room temperature, N,N-diisopropylethylamine (2.81 g, 21.83 mmol) and 2-(tert-butoxycarbonyl-amino)bromoethane (2.45 g, 10.91 mmol) were added to a mixed solution of compound 24-(Fmoc-amino)-4-piperidinecarboxylate (2.00 g, 5.46 mmol) in water (10 mL) and methanol (20 mL). The temperature was raised to 80 °C and the mixture was stirred for 16 hours. The reaction was monitored by LC-MS until completion. The reaction solution was directly evaporated to dryness to obtain the crude product 11b (1.57 g, 100% yield). LC-MS: 303.2 [M+H] + .

[0813] Step Two:

[0814] 11b (1.57 g, 5.46 mmol) was dissolved in a mixture of tetrahydrofuran and water (v / v = 2:1, 30 mL), and anhydrous sodium carbonate (2.31 g, 21.88 mmol) and 9-fluorenylmethyl-N-succinimide carbonate (4.61 g, 13.66 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete as monitored by LC-MS, the solvent was evaporated to dryness, dissolved in water, and the pH was adjusted to 6-7 with 1N hydrochloric acid. The mixture was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column-sected. Using a silica gel column with an EA / PE ratio of 0-100% as the eluent, a white solid intermediate 11 (1.27 mg, yield 45.61%) was obtained. LC-MS: 510.4 [M+H] + .

[0815] 1H NMR (400MHz, DMSO-d6) δ12.40(s,1H),7.91(d,J=7.6Hz,2H),7.74(d,J=7.4Hz,2H),7.64(d,J=7.6Hz,1H),7.52(s,1H),7.42(t,J=7.4Hz,2 H),7.35(t,J=7.4Hz,2H),4.33–4.26(m,4H),4.24(d,J=6.6Hz,1H),3.51–3.43(m,3H),3.17–3.05(m,3H),2.06–2.01(m,4H),1.39(s,9H).

[0816] Example 1: Synthesis of Compound 1

[0817] Step 1: The synthesis of 1B was carried out using the Fmoc chemical solid-phase synthesis method for peptides, as follows:

[0818] 1. Add 1.0 g of Rink amide MBHA resin (100 to 200 mesh, 0.702 mmol / g) to the polypeptide solid-phase synthesis tube and swell with 10 mL of DCM for 30 minutes.

[0819] 2. First, treat the resin with 10 mL of 20% 4-methylpiperidine / DMF (for Fmoc deprotection) for 5 minutes. Then, filter the resin and wash it once with DMF (10 mL), and then treat the resin again with 10 mL of 20% 4-methylpiperidine / DMF for 15-30 minutes.

[0820] 3. Drain the solvent and rinse five times with DMF (10 mL).

[0821] 4. Dissolve Fmoc-Sar-OH (3.6 equivalents, 0.8 g) and HOAt (3.6 equivalents, 0.25 g) together in 10 mL of DMF. Pre-activate the acid by adding DIC (3.1 equivalents, 0.33 mL) under shaking for 15 minutes, then add it to the deprotected resin.

[0822] 4. Subsequently, after approximately 15 minutes of coupling, DIC (2.1 equivalents, 0.22 mL) was added. The progress of the coupling reaction was monitored using a colorimetric Kaiser assay. Once the reaction was deemed complete, the resin was dried and washed three times with DMF.

[0823] 5. Next, treat the resin with 10 mL of 20% 4-methylpiperidine / DMF (for Fmoc deprotection) for 5 minutes. Then, dry the resin and wash it once with DMF (10 mL), and then treat the resin with 10 mL of 20% 4-methylpiperidine / DMF for 15-30 minutes.

[0824] 6. Drain the solvent and rinse five times with DMF (10 mL).

[0825] 7. Dissolve the next Fmoc-protected amino acid in 10 mL of DMF along with HOAt (3.6 equivalents). Pre-activate the acid by adding DIC (3.1 equivalents) under shaking for 15 minutes, then add it to the deprotected resin and bubble it under nitrogen.

[0826] 8. Subsequently, after approximately 15 minutes of coupling, DIC (2.1 equivalents, 0.22 mL) was added. The progress of the coupling reaction was monitored using a colorimetric Kaiser assay. Once the reaction was deemed complete, the resin was dried and washed three times with DMF.

[0827] 9. Repeat steps 5-8 of the next amino acid coupling.

[0828] 10. After all amino acids have been coupled in sequence, treat the resin with 10 mL of 20% 4-methylpiperidine / DMF (for Fmoc deprotection) for 5 minutes. Then, dry the resin and wash it once with DMF (10 mL), and treat the resin again with 10 mL of 20% 4-methylpiperidine / DMF for 15-30 minutes to complete the deprotection of the Fmoc groups at the resin ends.

[0829] 11. Determine whether acetyl capping is required based on the specific structure. The capping procedure is as follows: Add 10 mL of capping reagent (THF / acetic anhydride / pyridine, 80:10:10) to the resin with determinated Fmoc, bubble under nitrogen for 30 minutes, and then dry. If acetyl capping is not required, proceed directly to step 12.

[0830] 12. In the final step, the resin was washed three times with DMF, followed by three washes each with MeOH and DCM, respectively. It was then dried under vacuum to obtain peptide resin 1B (5.0 g), which was used directly in the next reaction.

[0831] The reactants used to synthesize compound 1 are shown in Table 2 below, and participate in the reaction in sequence according to their serial numbers:

[0832] Table 2

[0833] Step 2: TFA lysis and peptide precipitation:

[0834] Prepare 50 mL of TFA lysis mixture (90 / 5 / 2.5 / 2.5: TFA / water / Tip / DODT). Add 50 mL of the lysis mixture to peptide resin 1B (5.0 g) and shake at room temperature for 2.5 hours. Filter the resin to obtain a filtrate, and slowly add the filtrate to 300 mL of methyl tert-butyl ether (keeping the temperature of the methyl tert-butyl ether below 0°C as much as possible). A white flocculent precipitate will form. Centrifuge (5 min at 3500 rpm) to obtain a white precipitate, wash three times with methyl tert-butyl ether, and vacuum dry to obtain a white solid crude peptide 1C (1.5 g), which is used directly in the next reaction without further processing.

[0835] Step 3: Disulfide oxidation (cyclization)

[0836] Dissolve 100 mg of crude peptide 1C in 100 mL of 20% acetonitrile / water. Stir at room temperature until the system becomes clear. Slowly add a saturated methanol solution of iodine to the reaction system until the system remains pale yellow and does not fade. After standing for 5 minutes, quench with a small amount of sodium ascorbate.

[0837] Step 4: RP-HPLC purification

[0838] RP-HPLC was performed immediately after the oxidation of iodine. 100 mL of the quenched oxidized peptide from the third step was filtered through a 0.45 μm filter to obtain the sample solution. Separation method: 1. Instrument: Waters Pre 150 preparative HPLC; Column: Phenomenex, Luna, C18(2), 250 × 21.2 mm. 2. Preparative chromatographic conditions: a. Composition of mobile phases A and B: A was 0.1% trifluoroacetic acid / water, B was 0.1% trifluoroacetic acid / acetonitrile; b. Gradient elution: mobile phase content 25%-45%, flow rate 14 mL / min, elution time 60 min. The purified peptide TFA salt was obtained by lyophilization and prepared for relative ion exchange.

[0839] Step 5: Relative ion exchange to form acetate

[0840] The same preparative RP-HPLC column was equilibrated at 14 mL / min with MPA containing 5% MPB (MPA = 0.3% AcOH / water, MPB = 0.3% AcOH / ACN, MPC = 0.5M NH4OAc / water). The purified peptide TFA salt was dissolved in 50 / 50 ACN / water and diluted to 15% ACN. The solution was loaded onto the equilibration column at 14 mL / min, and the solvent tip was dissociated. The loaded peptide was washed with 5% MPB / MPA for 5 min. The loaded peptide was then washed with 5% MPB / MPC for 40 min, and the relative ions were exchanged to acetate at 14 mL / min. The loaded peptide was washed with 5% MPB / MPA at 14 mL / min for 10 min to remove all NH4OAc. Finally, the peptide was dissociated with a gradient of 5-70% MPB / MPA (total elution time 60 min) and collected in solution. Lyophilization gave compound 1 (50 mg, 99% purity). LCMS m / z = 622.8[(M+2H) / 3] + 933.5[(M+H) / 2] + .

[0841] Example 2: Synthesis of Compound 2

[0842] Table 3

[0843] Using the raw materials listed in Table 3 above, compound 2 (50 mg, 98% purity) was obtained using the method described for compound 1. LCMS m / z = 645.8 [(M+2H) / 3] + 967.9[(M+H) / 2] + .

[0844] Example 3: Synthesis of Compound 3

[0845] Table 4

[0846] Using the raw materials listed in Material Table 4 above, Compound 3 (50 mg, 99% purity) was obtained using the method described for Compound 1. LCMS m / z = 622.8 [(M+2H) / 3] + 933.5[(M+H) / 2] + .

[0847] Example 4: Synthesis of Compound 4

[0848] first step:

[0849] Under nitrogen protection, compound 1 (100 mg, 0.054 mmol), intermediate 2 (54 mg, 0.054 mmol), sodium ascorbate (21.2 mg, 0.108 mmol), and copper tetraacetonitrile hexafluorophosphate (5 mg, 0.014 mmol) were dissolved in 10 mL of a mixed solvent (20% tert-butanol / water) and stirred overnight at room temperature. After the reaction was complete, the organic phase was evaporated, and the aqueous phase was lyophilized before direct preparative HPLC separation. Chromatographic conditions: a. Mobile phase A and B composition: A was 0.1% trifluoroacetic acid / water, and B was 0.1% trifluoroacetic acid / acetonitrile; b. Gradient elution: mobile phase content 35%-65%, flow rate 14 mL / min, elution time 60 min. Lyophilization yielded intermediate 4A (100 mg). LCMS m / z = 956.7 [(M+2H) / 3] + 1434.4[(M+H) / 2] + .

[0850] Step Two:

[0851] 100 mg of intermediate 4A was dissolved in 10 mL of 10% trifluoroacetic acid / dichloromethane and reacted overnight at room temperature with stirring. After the reaction was complete, the solvent was evaporated, and the mixture was directly subjected to preparative liquid chromatography. Chromatographic conditions: a. Mobile phase A and B composition: A was 0.1% trifluoroacetic acid / water, and B was 0.1% trifluoroacetic acid / acetonitrile; b. Gradient elution: mobile phase content 35%-65%, flow rate 14 mL / min, elution time 60 min. The purified peptide TFA salt was obtained by lyophilization and prepared for relative ion exchange.

[0852] Step 3: Relative ion exchange to form acetate

[0853] The same preparative RP-HPLC column was equilibrated at 14 mL / min with MPA containing 5% MPB (MPA = 0.3% AcOH / water, MPB = 0.3% AcOH / ACN, MPC = 0.5M NH4OAc / water). The purified peptide TFA salt was dissolved in 50 / 50 ACN / water and diluted to 15% ACN. The solution was loaded onto the equilibration column at 14 mL / min, and the solvent tip was dissociated. The loaded peptide was washed with 5% MPB / MPA for 5 min. The loaded peptide was then washed with 5% MPB / MPC for 40 min, and the relative ions were exchanged to acetate at 14 mL / min. The loaded peptide was washed with 5% MPB / MPA at 14 mL / min for 10 min to remove all NH4OAc. Finally, the peptide was dissociated with a gradient of 5-70% MPB / MPA (total elution time 60 min) and collected in solution. Lyophilization gave intermediate 4A (60 mg, 95% purity). LCMS m / z = 919.3[(M+2H) / 3] + 1378.9[(M+H) / 2] +.

[0854] Example 5: Synthesis of Compound 5

[0855] Compound 5 (50 mg, 97% purity) was obtained from compound 2 using the same synthetic method as compound 4. LCMS m / z = 942.3 [M / 3+H] + 1412.9 [M / 2+H] + .

[0856] Example 6: Synthesis of Compound 6

[0857] Compound 6 (50 mg, 95% purity) was obtained from compound 3 using the same synthetic method as compound 4. LCMS m / z = 919.3 [(M+2H) / 3] + 1378.9[(M+H) / 2] + .

[0858] Example 7: Synthesis of Compound 7

[0859] Table 5

[0860] Using material 5 from the above-mentioned material list as raw material, compound 7 (40 mg, 95% purity) was obtained using the method described in Compound 1. LCMS m / z = 979.5[(M+H) / 2] + .

[0861] Example 8: Synthesis of Compound 8

[0862] Table 6

[0863] Using the raw materials listed in Material Table 6 above, Compound 8 (55 mg, 99% purity) was obtained using the method described in Compound 1. LCMS m / z = 986.4 [(M+H) / 2] + .

[0864] Example 9: Synthesis of Compound 9

[0865] Table 7

[0866] Using the raw materials listed in Material List 7 above, including Fmoc-Ac6c-OH (CAS: 162648-54-6) purchased from Shanghai Haohong Biomedical Technology Co., Ltd., compound 9 (46 mg, 99% purity) was obtained using the method described in Compound 1. LCMS m / z = 947.9 [(M+H) / 2] + .

[0867] Example 10: Synthesis of Compound 10

[0868] Table 8

[0869] Using the raw materials listed in Table 8 above, 3-(Fmoc-amino)tetrahydro-3-furan carboxylic acid (CAS: 1132879-21-0) was purchased from Suzhou Aimaite Biotechnology Co., Ltd. Compound 10 (46 mg, 98% purity) was obtained using the method described in Compound 1. LCMS m / z = 941.9 [(M+H) / 2] + .

[0870] Example 11: Synthesis of Compound 11

[0871] Table 9

[0872] Using the raw materials listed in Table 9 above, 3-(Fmoc-amino)-3-oxetaneic acid (CAS: 1380327-56-9) was purchased from Suzhou Aimaite Biotechnology Co., Ltd., and compound 11 (42 mg, 95% purity) was obtained using the method described in Compound 1. LCMS m / z = 934.9 [(M+H) / 2] + .

[0873] Example 12: Synthesis of Compound 12

[0874] Table 10

[0875] Using the raw materials listed in Material List 10 above, Fmoc-3,3-difluoro-cyclobutane-1-carboxylic acid (CAS: 1936532-04-5) was purchased from Nanjing Yaoshi Technology Co., Ltd., and Compound 12 (46 mg, purity 94%) was obtained using the method described in Compound 1. LCMS m / z = 951.5[(M+H) / 2] + .

[0876] Example 13: Synthesis of Compound 13

[0877] Table 11

[0878] Using the raw materials listed in Material List 11 above, Compound 13 (44 mg, 96% purity) was obtained using the method described in Compound 1. LCMS m / z = 986.2[(M+H) / 2] + .

[0879] Example 14: Synthesis of Compound 14

[0880] Table 12

[0881] Using the raw materials listed in Material List 12 above, intermediate 14-1 was prepared according to reference (WO2024227437A1, intermediate 3), and compound 14 (54 mg, 99% purity) was obtained using the method described in Compound 1. LCMS m / z = 952.9 [(M+H) / 2] + .

[0882] Example 15: Synthesis of Compound 15

[0883] Table 13

[0884] Using the raw materials listed in Material List 13 above, Fmoc-ThpGly-OH (CAS: 285996-72-7) was purchased from Shanghai Jier Peptide Co., Ltd., and Compound 15 (25 mg, 96% purity) was obtained using the method described in Compound 1. LCMS m / z = 997.2[(M+H) / 2] + .

[0885] Example 16: Synthesis of Compound 16

[0886] Table 14

[0887] Using the raw materials listed in Material List 14 above, Compound 16 (32 mg, 96% purity) was obtained using the method described in Compound 1. LCMS m / z = 997.3[(M+H) / 2] + .

[0888] Example 17: Synthesis of Compound 17

[0889] Table 15

[0890] Using the raw materials listed in Material Table 15 above, Fmoc-spiro[2.5]octane-OH (CAS: 1997996-67-4) was purchased from Duchuang (Shanghai) Pharmaceutical Technology Co., Ltd., and Compound 17 (33 mg, purity 97%) was obtained using the method described in Compound 1. LCMS m / z = 961.5[(M+H) / 2] + .

[0891] Example 18: Synthesis of Compound 18

[0892] Table 16

[0893] Using the raw materials listed in Material List 16 above, Compound 18 (25 mg, 98% purity) was obtained using the method described in Compound 1. LCMS m / z = 1039.4 [(M+H) / 2] + .

[0894] Example 19: Synthesis of Compound 19

[0895] Table 17

[0896] Using the raw materials listed in Material List 17 above, Fmoc-1-aminocyclopropanecarboxylic acid (CAS: 126705-22-4) was purchased from Shanghai Haohong Biomedical Technology Co., Ltd., and Compound 19 (30 mg, 95% purity) was obtained using the method described in Compound 1. LCMS m / z = 928.2 [(M+H) / 2] + .

[0897] Example 20: Synthesis of Compound 20

[0898] Table 18

[0899] Using the raw materials listed in Material List 18 above, including Fmoc-1-amino-1-cyclobutanecarboxylic acid (CAS: 885951-77-9) purchased from Shanghai Haohong Biomedical Technology Co., Ltd., compound 20 (24 mg, purity 96%) was obtained using the method described in Compound 1. LCMS m / z = 624.0 [M / 3+H] + .

[0900] Example 21: Synthesis of Compound 21

[0901] Table 19

[0902] Using material 19 from the above-mentioned material list as raw material, compound 21 (23 mg, 94% purity) was obtained using the method of compound 1. LCMS m / z = 623.9 [M / 3+H] + .

[0903] Example 22: Synthesis of Compound 22

[0904] Table 20

[0905] Using material 20 from the above-mentioned material list as raw material, Fmoc-L-3-Benzothienylalanine (CAS: 885951-77-9) was purchased from Shanghai Haohong Biomedical Technology Co., Ltd., and compound 22 (16 mg, purity 95%) was obtained using the method of compound 1. LCMS m / z = 951.0 [(M+H) / 2] + .

[0906] Example 23: Synthesis of Compound 23

[0907] Table 21

[0908] Using material 21 from the above-mentioned material list as raw material, compound 23 (19 mg, purity 96%) was obtained using the method of compound 1. LCMS m / z = 942.7[(M+H) / 2] + .

[0909] Example 24: Synthesis of Compound 24

[0910] Table 22

[0911] Using material 22 from the above-mentioned material list as raw material, compound 24 (80 mg, 95% purity) was obtained using the method of compound 1. LCMS m / z = 942.7[(M+H) / 2] + .

[0912] Example 25: Synthesis of Compound 25

[0913] first step:

[0914] Weigh 1 g of 2-CTC resin (degree of substitution = 1.2 mmol / g) and 234 mg of Fmoc-3Pal-OH, add them to a multi-solid phase synthesis reactor, add 10 mL of DCM, then add 1.8 mL of DIEA and purge the reactor with nitrogen for 2 hours. Then add 1.2 mL of methanol to the reactor and continue purging with nitrogen for 30 min. After that, filter the reaction solution, add DMF and wash 5 times, 1 min each time, then filter the reaction solution again.

[0915] Add 15 mL of 20% 4-methylpiperidine / DMF solution to the reactor, purge with nitrogen for 20 min to remove the Fmoc protecting group, filter to remove the reaction solution, add DMF to wash 5 times, 1 min each time, and filter to remove the reaction solution.

[0916] Weigh out 1078 mg (3.0 eq) of Fmoc-Asn(Trt)-OH and 385 mg (4.5 eq) of Oxyma, dissolve them in 15 mL of DMF, add 0.38 mL (3.9 eq) of DIC and pre-activate for 15 min, then add to a solid-phase reactor. React under nitrogen purging for 15 min, then add another portion of DIC (0.2 mL (2.6 eq) and continue the reaction. Monitor the reaction using the Kaiser colorimetric method. Stop the reaction when the resin in the ninhydrin solution becomes colorless. Filter to remove the reaction solution, wash five times with DMF for 1 min each time, and filter to remove the reaction solution.

[0917] Repeat steps 2 and 3 until all amino acids are linked together.

[0918] After the last amino acid was ligated, the Fmoc protecting group was removed and the resin was washed five times with DMF. DMF (15 mL), DIEA (2.5 mL, 6.0 eq), and acetic anhydride (2.5 mL, 5.0 eq) were added to the solid-phase reactor, and the reaction was carried out under nitrogen purging for 10 min. The resin was colorless as determined by ninhydrin. The reaction solution was removed by filtration, and the resin was washed five times with DMF for 1 min each time. The reaction solution was then removed by filtration.

[0919] Step Two:

[0920] Methanol (20 mL) was added to shrink the resin, 3 min each time, and the methanol was removed by filtration. Then, methyl ether (20 mL) was added to wash the resin three times, the methyl ether was removed by filtration, and the resin was dried under nitrogen. 20 mL of 20% HFIP / DCM solution was added to the reactor, and the reaction was carried out under nitrogen for 30 min to cleave the peptide from the resin. This reaction was repeated three times, and all filtrates were collected. The filtrate was concentrated to dryness under reduced pressure, then DCM was added for dispersion, and the concentration was further reduced to dryness under reduced pressure. 100 mL of acetonitrile / water solution was added, and the solid was completely dispersed by sonication. The solution was then lyophilized to obtain 25-2. LCMS m / z = 1000.2[(M+2H) / 3] + .

[0921] The reactants used to synthesize compound 25-2 are shown in Table 23 below, and participate in the reaction in order of their serial numbers:

[0922] Table 23

[0923] Step 3:

[0924] Weigh 200 mg of polypeptide 25-2 with a side-chain protecting group, add 1.5 mL of DMF, 32 mg of DIEA (3.0 eq), and side chain 1 (77 mg, 1.0 eq, prepared according to the preparation of intermediate A in WO2024114762A1, labeled L1 in the reaction formula). Then slowly add 27 mg of HATU in 0.5 mL of DMF solution. Stir the reaction at room temperature for 3 h and monitor the reaction using LC-MS. After the reaction is complete, remove the DMF using an oil pump to obtain compound 25-3.

[0925] Step 4:

[0926] Prepare 10 mL of cutting solution according to the ratio of TFA / Tips / H2O / Mpr = 90:2.5:2.5:5. Add the cutting solution to 25-3, shake and react for 2.5 h, then filter. Add the filtrate to 10 times its volume of methyl ether and centrifuge. Wash the resulting white precipitate three times with methyl ether, and then dry under vacuum for 2 h to obtain compound 25-4.

[0927] Step 5:

[0928] Compound 25-4 was dissolved in 40 mL of water and 10 mL of acetonitrile. Then, 0.1 mol / L iodine-methanol solution was slowly added dropwise until the solution turned bright yellow. After stirring for five minutes and observing that the yellow color had not disappeared, 0.1 mol / L L-ascorbic acid solution was added dropwise until the yellow color just disappeared and there was no further change after stirring for two minutes. The sample was then freeze-dried directly to obtain crude peptide 25.

[0929] Compound 25 was dissolved in 5 mL of 40% acetonitrile solution and purified by liquid chromatography. Separation method: 1. Instrument: Waters 2707 preparative liquid chromatograph; 2. Column: XBridge BEH C18 OBD Prep Column, 130A, 5µm, 30mm × 150mm, 1 / pk; 3. Mobile phase A: 0.1% TFA aqueous solution, B: acetonitrile, flow rate: 20 mL / min; 4. Gradient elution: mobile phase content 20%-45%. The sample was collected and lyophilized to obtain the product, white solid 25 (24 mg, purity: 99%). LCMS m / z = 698.4 [M / 4 + H] + .

[0930] Example 26: Synthesis of Compound 26

[0931] Table 24

[0932] Using the materials listed in Bill of Materials 24 and side chain 1 as raw materials, compound 26 (43 mg, 95% purity) was obtained using the method described for compound 25. LCMS m / z = 698.3 [M / 4 + H] + .

[0933] Example 27: Synthesis of Compound 27

[0934] Table 25

[0935] Using material 25 and side chain 1 as raw materials, compound 27 (35 mg, 98% purity) was obtained using the method described for compound 25. LCMS m / z = 937.1 [M / 3+H] + .

[0936] Example 28: Synthesis of Compound 28

[0937] Table 26

[0938] Using the materials listed in Bill of Materials 26 and side chain 1 as raw materials, compound 28 (75 mg, 95% purity) was obtained using the method described for compound 25. LCMS m / z = 934.6 [M / 3+H] + .

[0939] Example 29: Synthesis of Compound 29

[0940] Table 27

[0941] Using the materials listed in Bill of Materials 27 and side chain 1 as raw materials, compound 29 (36 mg, 96% purity) was obtained using the method described for compound 25. LCMS m / z = 939.2 [M / 3+H] + .

[0942] Example 30: Synthesis of Compound 30

[0943] Table 28

[0944] Using the materials listed in Bill of Materials 28 and side chain 1 as raw materials, compound 30 (13 mg, 97% purity) was obtained using the method described for compound 25. LCMS m / z = 1446.1 [M / 2 + H] + .

[0945] Example 31: Synthesis of Compound 31

[0946] Table 29

[0947] Using the materials listed in Bill of Materials 29 and side chain 1 as raw materials, compound 31 (11 mg, 96% purity) was obtained using the method described for compound 25. LCMS m / z = 948.2 [M / 3+H] + .

[0948] Example 32: Synthesis of Compound 32

[0949] Table 30

[0950] Using material 30 and side chain 1 from the above-mentioned material list as raw materials, compound 32 (9 mg, 94% purity) was obtained using the method for compound 25. LCMS m / z = 1405.5 [M / 2 + H] + .

[0951] Example 33: Synthesis of Compound 33

[0952] Table 31

[0953] Using the above-mentioned material list 31 and intermediate 9 as raw materials, compound 33 (20 mg, 96% purity) was obtained using the method described for compound 25. LCMS m / z = 874.4 [M / 3+H] + .

[0954] Example 34: Synthesis of Compound 34

[0955] Table 32

[0956] Using material 32 from the above-mentioned material list as the starting material, and employing the method of compound 4, intermediate 2 was replaced with (S)-1-azido-40-(tert-butoxycarbonyl)-37,42-dioxo-3,6,9,12,15,18,21,24,27,30,33-undecoxa-36,41-diazapentanonadecano-59-acid tert-butyl ester (refer to the example in CN119013287A: azide-Peg11-γGlu-FDA18, step 4 synthesis) to obtain compound 34 (30 mg, 95% purity). LCMS m / z = 1467.0 [(M / 2+H)] + .

[0957] Example 35: Synthesis of Compound 35

[0958] Table 33

[0959] Using material 33 and side chain 1 as raw materials, compound 35 (58 mg, 98% purity) was obtained using the method for compound 25. LCMS m / z = 936.2 [M / 3+H] + .

[0960] Example 36: Synthesis of Compound 36

[0961] Table 34

[0962] Using the above-mentioned material list 34 (including 1-(Fmoc-amino)-4,4-DiF-cyclohexanecarboxylic Acid, CAS: 1986905-26-3) and side chain 1 as raw materials, compound 36 (18 mg, 95% purity) was obtained using the method of compound 25. LCMS m / z = 1420.6 [M / 2+H] + .

[0963] Example 37: Synthesis of Compound 37

[0964] Table 35

[0965] Using material 35 and side chain 1 from the above-mentioned material list as raw materials, compound 37 (11 mg, purity 96%) was obtained using the method of compound 25. LCMS m / z = 1423.7 [M / 2 + H] + .

[0966] Example 38: Synthesis of Compound 38

[0967] Table 36

[0968] Using material 36 and side chain 1 as raw materials, compound 38 (15 mg, 95% purity) was obtained using the method described for compound 25. LCMS m / z = 967.1 [M / 3+H] + .

[0969] Example 39: Synthesis of Compound 39

[0970] Table 37

[0971] Using the above-mentioned material list 37 (of which Fmoc-amino-4-onecyclohexylcarboxylic acid, CAS: 285996-74-9) and side chain 1 as raw materials, compound 39 (20 mg, purity 95%) was obtained by the method of compound 25. LCMS m / z = 939.2 [M / 3+H] + .

[0972] Example 40: Synthesis of Compound 40

[0973] Table 38

[0974] Using the materials listed in Bill of Materials 38 and side chain 1 as raw materials, compound 40 (65 mg, 96% purity) was obtained using the method described for compound 25. LCMS m / z = 949.3 [M / 3+H] + .

[0975] Example 1: Inhibition of interleukin-23 binding to its receptor peptide.

[0976] The peptides were tested to identify those that inhibit the binding of IL-23 to human IL-23R and inhibit the functional activity of IL-23 / IL-23R, as described below.

[0977] DB cell IL23R pSTAT3 cell analysis

[0978] Detection of STAT3 phosphorylation level in cells

[0979] Human B-cell lymphoma cells (DB) were centrifuged and resuspended in RPMI-1640 medium containing 10% FBS and 1% PS, adjusting the cell density to 6.25 x 10⁻⁶ cells / year. 6Cells were seeded at a concentration of 1000 mcg / mL in 96-well cell culture plates, with 80 μL of the above cell suspension added to each well. Then, 10 μL of a 10-fold test concentration of peptide was added. The working concentration of the peptide test started from 1 nM and was serially diluted 3-fold with the above culture medium to obtain 10 concentrations. The same volume of culture medium was added to the control group and the blank control group. Each drug concentration constituted one group, with two replicates per group. After pretreatment in an incubator for 1 hour, 10 μL of culture medium containing the cytokine hIL23 was added to each well to bring the final cytokine concentration to 10 ng / mL. The blank control group received the same volume of basal culture medium. The cells were then incubated for 30 minutes. Cells were centrifuged at 1200 rpm for 5 minutes, the supernatant was discarded, and pre-prepared lysis buffer was added. The cells were lysed for 30 minutes. 15 μL of the cell lysis buffer was transferred to a detection plate, and 5 μL of Mix Antibody was added. The plates were incubated at room temperature for 4 hours. The TR-FRET signal was read at 665 / 615 nm using a microplate reader, and the data were analyzed using Graphpad Prism 8 software. (A:﹤0.25nM; B:0.25nM-0.5nM; C:0.5nM-1nM; D:﹥1nM; Table 39)

[0980] Table 39. IC50 of additional exemplary peptides of the present invention 50

[0981] Conclusion: The compounds of the present invention, such as those in the examples, have a significant inhibitory effect on STAT3 phosphorylation in DB cells.

[0982] Test Example 2: Experiment on the competitive binding of the compound of this invention to IL23R with IL23

[0983] 2.1 Experimental Methods

[0984] 0.5 μg / well of Rat IL-23 (Sino Biological) protein was coated into high-adsorption 96-well plates and incubated overnight at 4°C. The plates were washed four times with 300 μL of 0.05% TBST, and then blocked at 37°C for 1.5 h with blocking buffer (2% BSA in TBST). 10x peptide and 10x rat IL-23R (Sino Biological) protein were prepared using 0.5% BSA in TBST. The working concentration of the peptide was serially diluted 3-fold from 1 nM to obtain eight concentrations. The same volume of diluent was added to the control group and the blank control group. The working concentration of rat IL-23R protein was 250 ng / mL. The peptide and rat IL-23R protein were mixed to a 250 μL solution: 200 μL 0.5% BSA in TBST + 25 μL 10x peptide + 25 μL 10x rat IL-23R. The solution was incubated at 37°C for 1 h. Wash the test plate four times with 300 μL of 0.05% TBST. Add 100 μL of the above mixture to each well and incubate at 37°C for 1.5 h. Wash four times with 300 μL of 0.05% TBST. Add HRP (Jackson ImmunoResearch Inc.) antibody and incubate at 37°C for 1 h. Wash four times with 300 μL of 0.05% TBST. Add 100 μL of TMB for color development. Incubate at 37°C for 20 minutes, then add 50 μL of 2N sulfuric acid to stop the incubation. Measure OD450 using a full-wavelength microplate reader (Thermo Fisher, Multiskan Go). Analyze the data using Graphpad Prism8 software. Conclusion: The preferred embodiment of this application exhibits good competitive binding activity.

[0985] Test Example 3: Rat Pharmacokinetic Test

[0986] 3.1 Test Plan

[0987] Intravenous injection group: male, weighing 200-220g, intravenous solvent formulation: PBS (1x), administration volume: 5mL / kg, administration dose: 1mg / kg. At 0.083h, 0.5h, 1h, 3h, 6h, 10h, 24h, 32h, 48h, 56h, 72h, 96h, and 120h after administration, 100μL of blood was collected from the jugular vein of rats and added to tubes containing EDTA-K2 anticoagulant.

[0988] Oral administration group: male, weighing 200-220g, PO solvent formulation: 1% NaClO (PBS), administration volume: 10mL / kg, administration dose: 30mg / kg. Before administration and at 0.25h, 1h, 3h, 6h, 10h, 24h, 32h, 48h, 56h, 72h, 96h, and 120h after administration, 200μL of blood was collected from the jugular vein of rats and added to tubes containing EDTA-K2 anticoagulant.

[0989] The blood sample was centrifuged at 8000 rpm for 7 min, and the plasma was collected and stored at -20℃ in a low-adsorption centrifuge tube for later use.

[0990] Sample pretreatment: Quantitatively pipette 20 μL of sample into a 96-well plate (samples from the intravenous administration group were diluted 10-fold 10 hours prior). Add 200 μL (iv) / 100 μL (po) of acetonitrile containing 3% FA internal standard (verapamil, indomethacin, tolbutamide, 5 ng / mL) to precipitate the protein. Vortex for 10 min, centrifuge at 6000 g and 4 °C for 10 min. After centrifugation, take 40 μL of the supernatant, add 40 μL of reconstitution solution (0.1% FA in H2O) to reconstitute, vortex and centrifuge, and then analyze by LC-MS.

[0991] Preparation of standard curve: Intravenous injection group: 45 μL of blank rat plasma was collected. 5 μL of standard working solution was added to prepare a series of concentrations of 3000, 1000, 300, 100, 30, 10, 5, 2, and 1 ng / mL, and the mixture was vortexed. 250 μL of acetonitrile containing 3% FA internal standard (verapamil, indomethacin, tolbutamide, 5 ng / mL) was added to precipitate the protein. The mixture was vortexed for 10 min, centrifuged at 6000g and 4℃ for 10 min. After centrifugation, 40 μL of the supernatant was collected and reconstituted with 40 μL of reconstitution solution (0.1% FA in H2O). After vortexing and centrifugation, the mixture was analyzed by LC-MS.

[0992] Analytical instruments: Liquid chromatography system: Waters Acquity UPLC system (including binary pump, autosampler, column oven, and degasser); MS / MS system: AB SCIEX 7500 triple quadrupole tandem mass spectrometer, equipped with an electrospray ionization source (ESI).

[0993] The sources of reagents are shown in Table 40:

[0994] Table 40

[0995] The experimental results are shown in Table 41:

[0996] Table 41

[0997] As shown in Table 41, the compounds in this application have good pharmacokinetic properties and high exposure levels.

[0998] The structure of JNJ-2113 (CAS:2763602-16-8) is as follows: Purchased from Nanchang Tanzhen Biotechnology Co., Ltd.

[0999] Positive control B is the compound disclosed in Example 1-16-1 of WO2024 / 114762A1:

[1000] Test Example 4: Mouse Pharmacokinetic Test

[1001] 4.1 Test Plan

[1002] Intravenous injection group: male, weighing 20-22g, intravenous solvent formulation: PBS (1x), administration volume: 10mL / kg, administration dose: 1mg / kg, blood was collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and 30μL of blood was collected from the mandibular vein of mice and added to a tube containing EDTA-K2 anticoagulant;

[1003] Oral administration group: male, weighing 20-22g, PO solvent formulation: 1% NaClO (PBS), administration volume: 20mL / kg, administration dose: 30mg / kg. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. 30μL of blood was collected from the mandibular vein of the mice and added to a tube containing EDTA-K2 anticoagulant.

[1004] The blood sample was centrifuged at 8000 rpm for 5 min, and the plasma was collected in a centrifuge tube and stored at -20℃ for later use.

[1005] Sample pretreatment: Quantitatively pipette 10 μL of sample into a 96-well plate (samples from the intravenous administration group were diluted 10-fold 1 hour prior), add 100 μL of acetonitrile containing 3% FA internal standard (verapamil, indomethacin, tolbutamide, 5 ng / mL) to precipitate protein, vortex for 10 min, centrifuge at 6000 g and 4 °C for 10 min; after centrifugation, take 40 μL of supernatant, add 40 μL of reconstitution solution (0.1% FA in H2O) to reconstitute, vortex and centrifuge, and then analyze by LC-MS.

[1006] Preparation of standard curve: Take 9 μL of blank mouse plasma and add 1 μL of standard curve working solution to prepare a series of concentrations of 3000, 1000, 300, 100, 30, 10, 5, 2, 1 ng / mL & 2400, 80, 5, 3 ng / mL. Vortex to mix, add 100 μL of acetonitrile (verapamil, indomethacin, tolbutamide, 5 ng / mL) containing 3% formic acid as an internal standard to precipitate the protein, vortex for 10 min, and centrifuge at 6000g, 4℃ for 10 min. Take 50 μL of the supernatant and add it to a 96 plate, then add 50 μL of pure water containing 0.1% formic acid to reconstitute.

[1007] Analytical instruments: Liquid chromatography system: Waters Acquity UPLC system (including binary pump, autosampler, column oven, and degasser); MS / MS system: AB SCIEX 7500 triple quadrupole tandem mass spectrometer, equipped with an electrospray ionization source (ESI).

[1008] The sources of the reagents are shown in Table 42:

[1009] Table 42

[1010] The preferred embodiments of this application have good pharmacokinetic properties and high exposure levels.

[1011] Test Example 5: Stability Test of Gastrointestinal Fluids

[1012] 5.1 Experimental Procedure

[1013] Stability of simulated gastric juice (SGF): Simulated gastric juice (SGF) was prepared with deionized water using 0.2% (w / v) sodium chloride, 0.7% (v / v) hydrochloric acid, and 0.32% (w / v) pepsin, and the pH was adjusted to 1.2 ± 0.05. In the experiment, 2 μL of the working solution of the test and control compounds was added to the corresponding wells (T0, T120, T480, T1440, T2880) of a 96-well plate, with n = 2 at each time point. 198 μL of SGF was added (except for T0) to ensure the final solvent ratio did not exceed 1%. Samples were incubated at 37℃ and 600 rpm at each specified time point. After incubation, 400 μL of stop solution was immediately added and thoroughly mixed. Then, 200 μL of the suspension was added to 400 μL of stop solution for remixing. Sample T0 was treated by adding stop solution first, followed by the addition of SGF. All samples were then centrifuged at 4000 rpm and 4℃ for 20 min, and 300 μL of the supernatant was used for LC-MS / MS analysis. The remaining percentage was calculated based on the Analyte / IS peak area ratio at each time point and the peak area ratio at time T0.

[1014] Stability of simulated intestinal fluid (SIF): Simulated intestinal fluid (SIF) was prepared by dissolving 0.68% (w / v) potassium dihydrogen phosphate (KH2PO4) and 1% (w / v) pancreatin in deionized water, and adjusting the pH to 6.8 ± 0.05. In the experiment, 2 μL of the working solution of the test compound was added to wells T0, T120, T480, T1440, and T2520 of a 96-well plate, with n = 2 at each time point. Subsequently, 198 μL of SIF was added to all wells except T0, ensuring the final organic solvent ratio was ≤1%, and the plate was incubated at 37℃ and 600 rpm to the corresponding time point. Immediately after incubation, 400 μL of stop solution was added and mixed thoroughly, and then 200 μL of the suspension was added to another 400 μL of stop solution for remixing. The T0 sample was treated by adding the stop solution first, followed by the SIF. After centrifuging the sample at 4000 rpm and 4℃ for 20 min, 300 μL of the supernatant was taken for LC-MS / MS analysis; the remaining percentage was calculated based on the Analyte / IS peak area ratio at each time point and the peak area ratio at time T0.

[1015] LC-MS / MS Instruments: LC System: Shimadzu LC-40D X3; Mass Spectrometry System: SCIEX Triple Quad 6500+; Autosampler: CTC PAL3-RSI. The preferred embodiment of the present invention exhibits excellent stability in gastrointestinal fluids.

[1016] Test Example 6: Plasma Stability Test

[1017] 6.1 Experimental Procedure

[1018] Use heparinized anticoagulated plasma (Mouse CD-1, Rat SD, Dog Beagle, Monkey) Cynomolgus (all males; Humans were mixed sexes) were used. The procedure was as follows: First, thaw the plasma and centrifuge at 3220g for 5 min to remove visible precipitate. Add 98 μL of plasma to each well of a 96-well plate (set timers: Blank, T0, T2, T4, T8, T24, T48, T72). Add 2 μL of working solution to each well (except Blank) to ensure the final organic solvent content meets the method requirements. Incubate the plate in a 37°C water bath and start the timer. At each time point, add 500 μL of stop solution (methanol containing 0.1% formic acid, with tolbutamide and labetalol as internal standards) to each well and mix thoroughly to terminate the reaction. Centrifuge at 3220g for 20 min. Transfer 150 μL of the supernatant to the corresponding bioanalytical plate, seal the plate, and store at 4°C for LC-MS / MS analysis. Preparation of working solutions: Standards and test compounds were diluted with 10 mM (dissolved in DMSO): 5 μL was diluted with 495 μL of DMSO to prepare a 100 μM (100% DMSO) working solution; Propantheline bromide aqueous solution (10 mM in H2O) was diluted to 100 μM (100% H2O) by equal volume. Control compounds (final concentration all 2 μM): Propantheline bromide, Enalapril maleate, Somatostatin Acetate, Procaine HCl, Bisacodyl

[1019] Quantification and Results Presentation: The peak area ratio (PAR) of the analyzee to the internal standard at each time point was determined by LC-MS / MS. The percentage remaining at each time point (%Remaining = PAR) was calculated using the peak area ratio (PAR) of the analyzee to the internal standard. t / PAR0×100%.

[1020] 6.2 Experimental results are shown in Table 43.

[1021] Table 43

[1022] As shown in Table 43, the preferred embodiments of the present invention exhibit excellent stability in plasma.

[1023] Test Example 7: Liver S9 Stability Test

[1024] 7.1 Experimental Procedure

[1025] The stock solutions of the control compounds 7-Ethoxycoumarin and 7-Hydroxycoumarin were both 10 mM, diluted to 100 μM (MeOH solution); S9 was diluted to 1 mg / mL with 100 mM potassium phosphate buffer (the final concentration of S9 in the final reaction system was approximately 0.5 mg / mL). 100 μL of S9 solution (Blank, T0, T15, T30, T60, T120, T240, and NCF240) was added to each well of a 96-well reaction plate. Except for Blank, 2 μL of the compound working solution was added to each well. All reaction plates were pre-incubated at 37°C for 10 min. Then, 98 μL of 100 mM PB was added to NCF240 (as a cofactor-free control and incubated for 240 min). For the remaining plates (except NCF240), 98 μL of cofactor working solution was added after pre-incubation to initiate the metabolic reaction. (The cofactors included NADP, G6P, G6PDH, UDPGA, PAPS, GSH, and MgCl2, prepared according to intermediate concentrations, resulting in final cofactor concentrations of 1.3 mM NADP, 3.3 mM G6P, 0.4 U / mL G6PDH, 2.5 mM UDPGA, 0.1 mM PAPS, and 5 mM MgCl2). GSH and 3.3 mM MgCl2 were used. The reaction was carried out at 37 °C for specified times (T0, T15, T30, T60, T120, T240). At each endpoint, 600 μL of ice-cold MeOH (4 °C) containing 250 nM tolbutamide and 250 nM labetalol as internal standards was added to terminate the reaction. After shaking the sample for 10 min, it was centrifuged at 3220 g and 4 °C for 20 min. 100 μL of the supernatant was diluted with 300 μL of pure water, shaken to mix, sealed, and incubated at 4 °C for LC-MS / MS analysis. The percentage remaining at each time point (%Remaining = PAR) was calculated using the peak area ratio (PAR) of the analytical / internal standard. t / PAR0×100%.

[1026] 7.2 Experimental results are shown in Table 44.

[1027] Table 44

[1028] The preferred embodiments of the present invention exhibit excellent stability in liver S9.

[1029] Test Example 8: In vivo pharmacodynamic study in an IL23-induced rat otitis model

[1030] 8.1 Experimental Procedure

[1031] 8.1 Experimental Instruments and Reagents

[1032] 8.1.1 Experimental Apparatus

[1033] Analytical balance (Secura225D-1CN, Sartorius), micrometer (MDC-25X, Mitutoyo), anesthesia machine (RM-AS-I, RWD), electronic balance (WT-H10001, Wante).

[1034] 8.1.2 Experimental Reagents

[1035] Rat IL-23 Protein (CT045-R08H, Sino Biological), PBS (10010-23, Gibco), Sodium decanoate (27243001, THBIO), Isoflurane (RP100, Ringpu)

[1036] 8.2 Experimental Methods and Procedures

[1037] 8.2.1 Animal Procurement

[1038] Female SD rats, 6-8 weeks old, were purchased from Shanghai Slack Laboratory Animal Co., Ltd.

[1039] 8.2.2 Experimental Procedure

[1040] The experimental animals were acclimatized for one week after arrival. On day -2, the rats were weighed and their ear thickness was measured using a micrometer. Based on the ear thickness and weight data, the rats were randomly assigned to groups. From day -1 to day 3, the animals were administered drugs via gavage according to the experimental design. Rats in the test compound group received the drug once daily at a volume of 10 ml / kg; rats in the JNJ-2113 group received the drug twice daily, with a 7-hour interval, at a volume of 10 ml / kg. From day 0 to day 3, the rats were anesthetized with isoflurane daily. After measuring the ear thickness of the right ear, IL-23 (2ug, 20ul) or 20ul of PBS was injected intradermally into the right ear. On day 4, the ear thickness was measured again, the rats were euthanized, and blood and ear tissue samples were collected for further biochemical analysis.

[1041] 8.3 Data Processing

[1042] The ear thickness of rats in each group was subtracted from their initial ear thickness (day 0) daily and compared with the model group. Ear thickness data from day 4 minus day 0 were statistically analyzed using GraphPad Prism 8.0 software. One-way ANOVA and multiple comparisons test were employed for analysis. *p < 0.05 was considered statistically significant. Ear thickness inhibition rate % = 1 - (mean of the drug treatment group - mean of the PBS group) / (mean of the model group - mean of the PBS group).

[1043] 8.4 Experimental results are shown in Table 45.

[1044] Table 45

[1045] The preferred embodiment of the compound of the present invention, in an IL23-induced rat otitis model, showed a significantly stronger inhibitory effect on ear thickening when administered once daily than that of JNJ-2113 administered twice daily, thus achieving a reduction in the frequency of administration.

[1046] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound thereof: in, X 1 It is a C1-C6 alkylene group or is composed of one or more X groups. 1-1 Substituted alkylene groups; X 2 It is a C1-C6 alkylene group or is composed of one or more X groups. 2-1 Substituted alkylene groups; X 1-1 It is a C3-C8 cycloalkyl group; Or two X's 1-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group; X 2-1 It is a C3-C8 cycloalkyl group; Or two X's 2-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group; Q is the key for connection, S or -SS-; R 1 -(C=O)R 1-1 , R 1-1 It is hydrogen or C1-C 24 alkyl; R 1-2 and R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; R 1-4 It is hydrogen or C1-C6 alkyl; R 1-5 -C(=O)R 1-5-1 ; R 1-5-1 It is a C1-C6 alkyl group; R 1-6 It is a C2-C6 alkynyl or C1-C6 alkyl group; Y 1-1 For linking bonds or amino acids; Y 1-2 For linking bonds or amino acids; Y 1-3 For linking bonds or amino acids; Y 1-4 For linking bonds or amino acids; Y 1-5 For linking bonds or amino acids; m 1-1 m 1-2 m 1-3 m 1-5 m 1-6 m 1-7 m 1-8 Each is an independent integer from 1 to 20; m 1-4 Integers between 0 and 20; n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Each is an independent integer between 0 and 12; Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect; R 2 for R 3 It is a C1-C6 alkyl or a C3-C8 cycloalkyl; R 4 for Among them, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ; R 4-1-1 R 4-1-2 and R 4-1-3 Each can be either hydrogen or halogen; R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 5 -(C=O)R 5-1 , R 5-1 For H or C1-C 24 alkyl; R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 5-1 For linking bonds or amino acids; Y 5-2 For linking bonds or amino acids; Y 5-3 For linking bonds or amino acids; Y 5-4 For linking bonds or amino acids; m 5-1 m 5-2 m 5-3 Each is an independent integer from 1 to 20; m 5-4 Integers between 0 and 20; n 5-1 n 5-2 n 5-3 n 5-4 Each is an independent integer between 0 and 12; R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl; R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkyl, halogen, -OR 6-1-2 ; R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ; R 6-1-1-1 and R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups; R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens or C1-C6 alkyl groups; R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or C1-C6 alkyl; R 7 for R 8 It is hydrogen or C1-C 24 alkyl; R 9 For C2-C 12 acetylinyl Z 9-1 for Where end a and Connection, B end and Z 9-2 for Where end a and Connection, B end and m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Each is an independent integer from 1 to 20; m 9-6 Integers between 0 and 20; n 9-1 n 9-2 n 9-3 n 9-5 n 9-6 Each is an independent integer between 0 and 12; n 9-4 Integers between 0 and 20; Y 9-1 For linking bonds or amino acids; Y 9-2 For linking bonds or amino acids; Y 9-3 For linking bonds or amino acids; R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; R 8-1 For C2-C 12 acetylinyl C1-C6 alkyl, with one or more R 8-1-2 Substituted C1-C6 alkyl groups Z 8-1 for Where end a and Connection, B end and Z 8-2 for Where end a and Connection, B end and m 8-1 m 8-2 m 8-3 m 8-4 m 8-5 m 8-6 Each is an independent integer from 1 to 20; n 8-1 n 8-2 n 8-3 n 8-4 Each is an independent integer between 0 and 12; Y 8-1 For linking bonds or amino acids; Y 8-2 For linking bonds or amino acids; R 8-1-1 For C2-C 12 Alkynyl, C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens; R 8-1-2 For C6-C 12 aryl, amino, and one or more R 8-1-2-1 Replacement C6-C 12 Aryl, cyano; R 8-1-2-1 It is a C1-C6 alkyl group or a halogen. R 8-2 Halogen, C1-C6 alkyl, oxo group, or with one or more R groups 8-2-1 Substituted C1-C6 alkyl groups; R 8-2-1 It is a halogen; R 10 hydroxyl group m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Each is an independent integer from 1 to 20; m 10-6 Each is an independent integer between 0 and 20; n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Each is an independent integer between 0 and 12; Y 10-1 For linking bonds or amino acids; Y 10-2 For linking bonds or amino acids; R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; R 11 for R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13-4 , R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ; R 13-2-1 It is hydrogen, C1-C6 alkyl; R 13-2-2 For C2-C 12 alkynyl group; R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group; R 13-3 It is hydrogen, C1-C6 alkyl; R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl; R 13-5 It is a C1-C6 alkyl group; R 13-6 It is a C1-C6 alkyl group; R 14 It is hydrogen or C1-C6 alkyl; Or R 9 R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3; m 13-1 Each is an independent integer from 1 to 6; m 13-2 Each is an independent integer from 1 to 6; m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Each is an independent integer from 1 to 20; m 12-6 Integers between 0 and 20; m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 m 12-16 m 12-17 m 12-18 m 12-19 Each is an independent integer from 1 to 20; n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 n 12-15 n 12-16 n 12-17 n 12-18 n 12-19 Each is an independent integer between 0 and 12; Z 12-1 for Where end a and Connection, B end and connect; Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect; Z 12-3 for Where end a and Connection, B end and connect; Y 12-1 For linking bonds or amino acids; Y 12-2 For linking bonds or amino acids; Y 12-3 For linking bonds or amino acids; Y 12-4 For linking bonds or amino acids; Y 12-5 For linking bonds or amino acids; Y 12-6 For linking bonds or amino acids; Y 12-7 It is a linking bond or an amino acid.

2. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1)R 1 for (2)R 4 for (3)R 6 For 0, 1, 2 or 3 (e.g. 0) R 6-1 Replaced by: (4)R 8 For hydrogen, R 9 For C2-C 12 acetylinyl or Or, R 8 R 9 Together with the C atoms it is attached to, they form: Or, R 8 R 9 Together with the C atoms it is attached to, they form C3-C. 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 cycloalkyl, the C3-C 12 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclohexyl, (5)R 13 For: -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 R 13-1 For H, R 13-2 For -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2- 4 ; Preferably, in the compound represented by Formula I, R 8 For hydrogen, R 9 for Or, R 8 R 9 Together with the C atoms it is attached to, they form: R 8-1 for Or, R 13 for: Preferred R 8 R 9 Together with the C atoms it is attached to, they form C3-C. 12 cycloalkyl, with one or more R 8-2 Substituted cyclopropyl or by one or more R 8-2 Substituted cyclobutyl, or, R 8 R 9 Together with the C atom it is attached to, they form an oxacyclopentane.

3. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1) for (2) Q is -SS-; (3)Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y 1-5 Y 5-2 Y 5-3 Y 5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 8-2 Y 10-1 Y 10-2 Y 10-3 Y 12-1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 Y 12-7 and Y 12-8 The amino acid is, for example, a glutamic acid residue. Where end a is connected to -NH-, and end b is connected to... connect; (4)R 1 -(C=O)R 1-1 , For example, -(C=O)R 1-1 ; (5)m 1-5 and m 1-6 Independently an integer from 1 to 6, such as 2 or 4; (6)n 1-6 n 1-7 and n 1-8 Positive numbers that are independently between 1 and 4, such as 2; (7)m 1-7 Independently, an integer between 10 and 18, such as 16; (8)R 1-1 It is a C1-C6 alkyl group, such as methyl; (9)R 1-4 It is hydrogen; (10)R 1-6 It is a C2-C6 ynyl group, such as an ethynyl group; (11)m 1-8 Integers between 1 and 6, for example, 4; (12)R 2 for Preferred (13)R 3 It is a C1-C6 alkyl group, such as methyl; (14)R 4-3 R 4-4 and R 4-5 For hydrogen, R 4-2 It is a C1-C6 alkyl group, such as methyl; (15)R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 It is hydrogen; (16)R 5 -(C=O)R 5-1 ; (17)R 5-1 It is a C1-C6 alkyl group, such as methyl; (18)R 6 For one or more R 6-1 Replacement C5-C 12 Aryl; (19)R 6-1 It is a C1-C6 alkyl group or is composed of one or more R groups. 6-1-1 Substituted C1-C6 alkoxy groups, such as C1-C6 alkoxy groups substituted with one or more amino groups; (20)R 6-1-1-1 and R 6-1-1-2 It is hydrogen; (21)R 7 for (22)R 8 It is hydrogen or a C1-C6 alkyl group, such as hydrogen; (23)R 9 For C2-C 12 acetylinyl or (24)m 9-1 and m 9-2 Independently an integer from 1 to 6, such as 2 or 1; (25)n 9-1 n 9-2 and n 9-3 Positive numbers that are independently between 1 and 4, such as 2; (26)m 9-4 Independently, an integer between 10 and 18, such as 16; (27)R 8 R 9 Together with the C atoms it is attached to, they form (28)R 8 R 9 Together with the C atoms attached to it, they form unsubstituted or R atoms. 8-2 Substituted with: cyclopropyl, cyclobutyl, cyclohexyl (29)R 8-1 For C2-C 12 acetylinyl C1-C6 alkyl, with one or more R 8-1-2 Substituted C1-C6 alkyl groups (30)m 8-1 m 8-2 m 8-4 and m 8-5 Independently an integer from 1 to 6, such as 1 or 2; (31)n 8-1 n 8-2 n 8-3 and n 8-4 Positive numbers that are independently between 1 and 4, such as 2; (32)m 8-4 and m 8-6 Independently, an integer between 10 and 18, such as 16; (33)R 8-1-1 It is a C2-C6 alkynyl group, such as ethynyl or (34)R 8-1-2 For C6-C 12 Aryl or cyano; (35)R 8-2 Halogen or by one or more R 8-2-1 Substituted C1-C6 alkyl groups; (36)R 10 It is a hydroxyl group; (37)R 11 for (38)R 12 It is a C1-C6 alkyl group, such as methyl; (39)R 13 C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 , (40)m 13-1 Integers between 1 and 4, for example, 1; (41)m 13-2 Integers between 1 and 4, for example, 1; (42)m 12-1 m 12-3 m 12-5 m 12-7 m 12-8 m 12-10 m 12-11 m 12-13 m 12-14 m 12-16 m 12-18 Independently, it is an integer from 1 to 4, such as 2; (43)m 12-2 m 12-4 m 12-6 m 12-9 m 12-12 m 12-15 m 12-17 m 12-19 Independently an integer between 10 and 18, preferably 14 or 16, for example 14; (44)n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 n 12-15 n 12-16 n 12-17 n 12-18 n 12-19 Independently an integer from 1 to 6, such as 2; (45)R 13-1 R 13-2 Each is independently hydrogen or -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ; (46)R 13-2-1 It is hydrogen; (47)R 13-2-3 and R 13-2-4 It is hydrogen; (48)R 13-3 It is hydrogen; (49)R 13-4 For C2-C 12 Alkyne group, such as ethynyl group.

4. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, characterized in that, It is any of the following schemes: Option 1: X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups; X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups; X 1-1 It is a C3-C8 cycloalkyl group; or two X groups. 1-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group; X 2-1 It is a C3-C8 cycloalkyl group; Or two X's 2-1 It is attached to the same C atom in the alkylene group and together with this C atom forms a C3-C8 cycloalkyl group; Q is the key for connection, S or -SS-; R 1 -(C=O)R 1-1 , R 1-1 Hydrogen, C1-C 24 alkyl; R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; R 1-4 It is hydrogen, C1-C6 alkyl; R 1-5 -C(=O)R 1-5-1 ; R 1-5-1 It is a C1-C6 alkyl group; R 1-6 It is C2-C6 alkynyl or C1-C6 alkyl; Y 1-1 For linking bonds or amino acids; Y 1-2 For linking bonds or amino acids; Y 1-3 For linking bonds or amino acids; Y 1-4 For linking bonds or amino acids; Y 1-5 For linking bonds or amino acids m 1-1 m 1-2 m 1-3 m 1-5 m 1-6 m 1-7 m 1-8 Integers between 1 and 20; m 1-4 Integers between 0 and 20; n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Integers between 0 and 12; Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect; R 2 for R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl; R 4 for in, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ; R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen; R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 5 -(C=O)R 5-1 , R 5-1 For H, C1-C 24 alkyl; R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 5-1 For linking bonds or amino acids; Y 5-2 For linking bonds or amino acids; Y 5-3 For linking bonds or amino acids; Y 5-4 For linking bonds or amino acids; m 5-1 m 5-2 m 5-3 Integers between 1 and 20; m 5-4 Integers between 0 and 20; n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12; R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl; R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkoxy radical, halogen, -OR 6-1-2 ; R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ; R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups; R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens, C1-C6 alkyl groups; R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 7 for R 8 Hydrogen, C1-C 24 alkyl; R 9 For C2-C 12 acetylinyl Z 9-1 for Where end a and Connection, B end and Z 9-2 for Where end a and Connection, B end and m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20; m 9-6 Integers between 0 and 20; n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12; Y 9-1 For linking bonds or amino acids; Y 9-2 For linking bonds or amino acids; Y 9-3 For linking bonds or amino acids; R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; R 8-1 For C2-C 12 acetylinyl C1-C6 alkyl, with one or more R 8-1-2 Substituted C1-C6 alkyl groups Z 8-1 for Where end a and Connection, B end and Z 8-2 for Where end a and Connection, B end and m 8-1 m 8-2 m 8-3 m 8-4 m 8-5 m 8-6 Integers between 1 and 20; n 8-1 n 8-2 n 8-3 Integers between 0 and 12; Y 8-1 For linking bonds or amino acids; Y 8-2 For linking bonds or amino acids; R 8-1-1 For C2-C 12 alkynyl group; R 8-1-2 For C6-C 12 aryl, with one or more R 8-1-2-1 Replacement C6-C 12 Aryl, cyano; R 8-1-2-1 C1-C6 alkyl, halogen; R 8-2 Halogen, C1-C6 alkyl, or with one or more R 8-2-1 Substituted C1-C6 alkyl groups; R 8-2-1 It is a halogen; R 10 hydroxyl group m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20; m 10-6 Integers between 0 and 20; n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12; Y 10-1 For linking bonds or amino acids; Y 10-2 For linking bonds or amino acids; R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; R 11 for R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13-4 , R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ; R 13-2-1 It is hydrogen, C1-C6 alkyl; R 13-2-2 For C2-C 12 alkynyl group; R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group; R 13-3 It is hydrogen, C1-C6 alkyl; R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl; R 13-5 It is a C1-C6 alkyl group; R 13-6 It is a C1-C6 alkyl group; R 14 It is hydrogen; Or R 9 R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3; m 13-1 Integers from 1 to 6; m 13-2 Integers from 1 to 6; m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20; m 12-6 Integers between 0 and 20; m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 m 12-16 m 12-17 m 12-18 m 12-19 Integers between 1 and 20; n 12-1 、n 12-2 、n 12-3 、n 12-4 、n 12-5 、n 12-6 、n 12-7 、n 12-8 、n 12-9 、n 12-10 、n 12-11 、n 12-12 、n 12-13 、n 12-14 、n 12-15 、n 12-16 、n 12-17 、n 12-18 、n 12-19 is an integer from 0 to 12; Z 12-1 for Where end a and Connection, B end and connect; Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect; Z 12-3 for Where end a and Connection, B end and connect; Y 12-1 For linking bonds or amino acids; Y 12-2 For linking bonds or amino acids; Y 12-3 For linking bonds or amino acids; Y 12-4 For linking bonds or amino acids; Y 12-5 For linking bonds or amino acids; Y 12-6 For linking bonds or amino acids; Y 12-7 For linking bonds or amino acids; Option 2: The compound of formula I has the structure shown in formula IA: in, X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups; X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups; X 1-1 It is a C3-C8 cycloalkyl group; X 2-1 It is a C3-C8 cycloalkyl group; Q is the key for connection, S or -SS-; R 1 -(C=O)R 1-1 , R 1-1 For hydrogen, C 1 -C 24 alkyl; R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 1-1 For linking bonds or amino acids; Y 1-2 For linking bonds or amino acids; Y 1-3 For linking bonds or amino acids; Y 1-4 For linking bonds or amino acids; Y 1-5 For linking bonds or amino acids m 1-1 m 1-2 m 1-3 m 1-5 m 1-6 m 1-7 Integers between 1 and 20; m 1-4 Integers between 0 and 20; n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 n 1-6 n 1-7 n 1-8 Integers between 0 and 12; Z 1-1 for Where end a is connected to -(C=O)-, and end b is connected to... connect; R 2 for R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl; R 4 for in, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ; R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen; R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 5 -(C=O)R 5-1 , R 5-1 For H, C1-C 24 alkyl; R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 5-1 For linking bonds or amino acids; Y 5-2 For linking bonds or amino acids; Y 5-3 For linking bonds or amino acids; Y 5-4 For linking bonds or amino acids; m 5-1 m 5-2 m 5-3 Integers between 1 and 20; m 5-4 Integers between 0 and 20; n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12; R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl; R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkyl, halogen, -OR 6-1-2 ; R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ; R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 6-1-2 It is a C3-C8 cycloalkyl group, with one or more R 6-1-2-1 Substituted C3-C8 cycloalkyl groups; R 6-1-2-1 For -NR 6-1-2-1-1 R 6-1-2-1-2 Halogens, C1-C6 alkyl groups; R 6-1-2-1-1 R 6-1-2-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 7 for R 8 Hydrogen, C1-C 24 alkyl; R 9 For C2-C 12 acetylinyl Z 9-1 for Where end a and Connection, B end and Z 9-2 for Where end a and Connection, B end and m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20; m 9-6 Integers between 0 and 20; n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12; Y 9-1 For linking bonds or amino acids; Y 9-2 For linking bonds or amino acids; Y 9-3 For linking bonds or amino acids; R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; R 8-1 For C2-C 12 acetylinyl Z 8-1 for Where end a and Connection, B end and m 8-1 m 8-2 m 8-3 Integers between 1 and 20; n 8-1 n 8-2 n 8-3 Integers between 0 and 12; Y 8-1 For linking bonds or amino acids; Y 8-1-1 For C2-C 12 alkynyl group; R 8-2 It is halogenated or C1-C6 alkyl; R 10 hydroxyl group m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20; m 10-6 Integers between 0 and 20; n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12; Y 10-1 For linking bonds or amino acids; Y 10-2 For linking bonds or amino acids; R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; R 11 for R 12 R 13 Each is independently H, C1-C6 alkyl, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 -(CH2)m 13-2 -NR 13-3 -(C=O)-R 13-4 , R 13-1 R 13-2 Each is independently hydrogen, C1-C6 alkyl, C2-C 12 alkynyl group, -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ; R 13-2-1 It is hydrogen, C1-C6 alkyl; R 13-2-2 For C2-C 12 alkynyl group; R 13-2-3 R 13-2-4 Each is independently hydrogen or a C1-C6 alkyl group; R 13-3 It is hydrogen, C1-C6 alkyl; R 13-4 For C2-C 12 Alkynyl, C1-C6 alkyl; m 13-1 Integers from 1 to 6; m 13-2 Integers from 1 to 6; m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20; m 12-6 Integers between 0 and 20; m 12-7 m 12-8 m 12-9 m 12-10 m 12-11 m 12-12 m 12-13 m 12-14 m 12-15 Integers between 1 and 20; n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 n 12-6 n 12-7 n 12-8 n 12-9 n 12-10 n 12-11 n 12-12 n 12-13 n 12-14 Integers between 0 and 12; Z 12-1 for Where end a and Connection, B end and connect; Z 12-2 for Where end a is connected to -(C=O)-, and end b is connected to... connect; Z 12-3 for Where end a and Connection, B end and connect; Y 12-1 For linking bonds or amino acids; Y 12-2 For linking bonds or amino acids; Y 12-3 For linking bonds or amino acids; Y 12-4 For linking bonds or amino acids; Y 12-5 For linking bonds or amino acids; Y 12-6 For linking bonds or amino acids; Option 3: X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups; X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups; X 1-1 It is a C3-C8 cycloalkyl group; X 2-1 It is a C3-C8 cycloalkyl group; Q is the key for connection, S or -SS-; R 1 -(C=O)R 1-1 , R 1-1 Hydrogen, C1-C 24 alkyl; R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 1-1 For linking bonds or amino acids; Y 1-2 For linking bonds or amino acids; Y 1-3 For linking bonds or amino acids; Y 1-4 For linking bonds or amino acids; m 1-1 m 1-2 m 1-3 Integers between 1 and 20; m 1-4 Integers between 0 and 20; n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 Integers between 0 and 12; R 2 for R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl; R 4 for in, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ; R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen; R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 5 -(C=O)R 5-1 , R 5-1 For H, C1-C 24 alkyl; R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 5-1 For linking bonds or amino acids; Y 5-2 For linking bonds or amino acids; Y 5-3 For linking bonds or amino acids; Y 5-4 For linking bonds or amino acids; m 5-1 m 5-2 m 5-3 Integers between 1 and 20; m 5-4 Integers between 0 and 20; n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12; R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl; R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkyl, halogen; R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ; R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 7 for R 8 Hydrogen, C1-C 24 alkyl; R 9 For C2-C 12 acetylinyl Z 9-1 for Where end a and Connection, B end and Z 9-2 for Where end a and Connection, B end and m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20; m 9-6 Integers between 0 and 20; n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12; Y 9-1 For linking bonds or amino acids; Y 9-2 For linking bonds or amino acids; Y 9-3 For linking bonds or amino acids; R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups; among which, The heteroatoms in the 4-12 membered heterocyclic groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1-3. R 8-1 For C2-C 12 acetylinyl Z 8-1 for Where end a and Connection, B end and m 8-1 m 8-2 m 8-3 Integers between 1 and 20; n 8-1 n 8-2 n 8-3 Integers between 0 and 12; Y 8-1 For linking bonds or amino acids; R 10 hydroxyl group m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20; m 10-6 Integers between 0 and 20; n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12; Y 10-1 For linking bonds or amino acids; Y 10-2 For linking bonds or amino acids; R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; R 11 for R 12 R 13 Each is independently H, C1-C6 alkyl, m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20; m 12-6 Integers between 0 and 20; n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 Integers between 0 and 12; Y 12-1 For linking bonds or amino acids; Y 12-2 For linking bonds or amino acids; Y 12-3 For linking bonds or amino acids; Option 4: X 1 It is a C1-C6 alkylene group, with one or more X atoms 1-1 Substituted alkylene groups; X 2 It is a C1-C6 alkylene group, with one or more X atoms 2-1 Substituted alkylene groups; X 1-1 It is a C3-C8 cycloalkyl group; X 2-1 It is a C3-C8 cycloalkyl group; Q is the key for connection, S or -SS-; R 1 -(C=O)R 1-1 , R 1-1 Hydrogen, C1-C 24 alkyl; R 1-2 R 1-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 1-1 For linking bonds or amino acids; Y 1-2 For linking bonds or amino acids; Y 1-3 For linking bonds or amino acids; Y 1-4 For linking bonds or amino acids; m 1-1 m 1-2 m 1-3 Integers between 1 and 20; m 1-4 Integers between 0 and 20; n 1-1 n 1-2 n 1-3 n 1-4 n 1-5 Integers between 0 and 12; R 2 for R 3 It is C1-C6 alkyl or C3-C8 cycloalkyl; R 4 for in, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ; R 4-1-1 R 4-1-2 R 4-1-3 Each is independently hydrogen or halogen; R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 5 -(C=O)R 5-1 , R 5-1 For H, C1-C 24 alkyl; R 5-2 R 5-3 C1-C independently 12 Alkyl, C3-C8 cycloalkyl; Y 5-1 For linking bonds or amino acids; Y 5-2 For linking bonds or amino acids; Y 5-3 For linking bonds or amino acids; Y 5-4 For linking bonds or amino acids; m 5-1 m 5-2 m 5-3 Integers between 1 and 20; m 5-4 Integers between 0 and 20; n 5-1 n 5-2 n 5-3 n 5-4 Integers between 0 and 12; R 6 C5-C 12 aryl, with one or more R 6-1 Replacement C5-C 12 Aryl; R 6-1 It is a C1-C6 alkoxy group, and is oxidized by one or more R groups. 6-1-1 Substituted C1-C6 alkoxy, C1-C6 alkyl, halogen; R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ; R 6-1-1-1 R 6-1-1-2 Each is independently hydrogen or a C1-C6 alkyl group; R 7 for R 8 Hydrogen, C1-C 24 alkyl; R 9 For C2-C 12 acetylinyl Z 9-1 for Where end a and Connection, B end and Z 9-2 for Where end a and Connection, B end and m 9-1 m 9-2 m 9-3 m 9-4 m 9-5 Integers between 1 and 20; m 9-6 Integers between 0 and 20; n 9-1 n 9-2 n 9-3 n 9-4 n 9-5 n 9-6 Integers between 0 and 12; Y 9-1 For linking bonds or amino acids; Y 9-2 For linking bonds or amino acids; Y 9-3 For linking bonds or amino acids; R 9-1 R 9-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups; among which, The heteroatoms in the 4-12 membered heterocyclic groups are selected from one or more of N, O, and S, and the number of heteroatoms is 1-3. R 8-1 For C2-C 12 acetylinyl Z 8-1 for Where end a and Connection, B end and m 8-1 m 8-2 m 8-3 Integers between 1 and 20; n 8-1 n 8-2 n 8-3 Integers between 0 and 12; Y 8-1 For linking bonds or amino acids; R 10 hydroxyl group m 10-1 m 10-2 m 10-3 m 10-4 m 10-5 Integers between 1 and 20; m 10-6 Integers between 0 and 20; n 10-1 n 10-2 n 10-3 n 10-4 n 10-5 Integers between 0 and 12; Y 10-1 For linking bonds or amino acids; Y 10-2 For linking bonds or amino acids; R 10-1 R 10-2 Each independently is C1-C 12 Alkyl, C3-C8 cycloalkyl; R 11 for R 12 R 13 Each is independently H, C1-C6 alkyl, m 12-1 m 12-2 m 12-3 m 12-4 m 12-5 Integers between 1 and 20; m 12-6 Integers between 0 and 20; n 12-1 n 12-2 n 12-3 n 12-4 n 12-5 Integers between 0 and 12; Y 12-1 For linking bonds or amino acids; Y 12-2 For linking bonds or amino acids; Y 12-3 For linking bonds or amino acids; Option 5: X 1 It is a C1-C6 alkylene group; X 2 It is a C1-C6 alkylene group; Q is -SS-; R 1 -(C=O)R 1-1 or R 1-1 For C1-C 24 alkyl; R 1-4 It is hydrogen; R 1-5 -C(=O)R 1-5-1 ; R 1-5-1 It is a C1-C6 alkyl group; R 1-6 It is a C2-C6 acetylene group; m 1-8 Integers between 1 and 20; R 2 for R 3 It is a C1-C6 alkyl group; R 4 for in, R 4-1 For hydrogen, -SCR 4-1-1 R 4-1-2 R 4-1-3 ; R 4-1-1 R 4-1-2 and R 4-1-3 Each can be either hydrogen or halogen; R 4-2 R 4-3 R 4-4 R 4-5 Each is independently hydrogen or C1-C6 alkyl; R 4-6 R 4-7 R 4-8 R 4-9 R 4-10 Each is independently hydrogen; R 5 -(C=O)R 5-1 ; R 5-1 For C1-C 24 alkyl; R 6 For one or more R 6-1 Replacement C5-C 12 Aryl; R 6-1 For one or more R 6-1-1 Substituted C1-C6 alkoxy groups; R 6-1-1 For NR 6-1-1-1 R 6-1-1-2 ; R 6-1-1-1 and R 6-1-1-2 Each is independently hydrogen; R 7 for R 8 It is hydrogen; R 9 For C2-C 12 acetylinyl or Z 9-1 for Where end a and Connection, B end and m 9-1 and m 9-2 Integers between 1 and 20; n 9-1 n 9-2 and n 9-3 Integers between 0 and 12; n 9-4 Integers between 0 and 20; Y 9-1 It consists of amino acids; Or R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, C3-C 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 Cycloalkyl; the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; R 8-1 For C2-C 12 acetylinyl by one or more R 8-1-2 Substituted C1-C6 alkyl groups Z 8-1 for Where end a and Connection, B end and Z 8-2 for Where end a and Connection, B end and m 8-1 m 8-2 m 8-3 m 8-4 m 8-5 m 8-6 Integers between 1 and 20; n 8-1 n 8-2 n 8-3 n 8-4 Integers between 0 and 12; Y 8-1 It consists of amino acids; Y 8-2 It consists of amino acids; R 8-1-1 For C2-C 12 Alkyne or C1-C6 alkyl group substituted with one or more halogens; R 8-1-2 For C6-C 12 Aryl or cyano; R 8-2 Halogen or by one or more R 8-2-1 Substituted C1-C6 alkyl groups; R 8-2-1 It is a halogen; R 10 hydroxyl R 11 for R 12 It is a C1-C6 alkyl group; R 13 -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 , R 13-1 R 13-2 Each is independently hydrogen or -CR 13-2-1 R 13-2-2 -(C=O)-NR 13-2-3 R 13-2-4 ; R 13-2-1 It is hydrogen; R 13-2-2 For C2-C 12 alkynyl group; R 13-2-3 and R 13-2-4 Each is independently hydrogen; R 13-6 It is a C1-C6 alkyl group; R 14 It is hydrogen; Or R 9 R 9 Connected C atoms, R 14 R 14 The connected N atoms together form a 4-12 membered heterocyclic group; the heteroatoms in the 4-12 membered heterocyclic group are selected from one or more of N, O and S, and the number of heteroatoms is 1-3; m 13-1 Integers from 1 to 6; m 12-1 m 12-2 Integers between 1 and 20; m 12-18 m 12-19 Integers between 1 and 20; n 12-1 n 12-2 n 12-3 n 12-18 and n 12-19 Integers between 0 and 12; Z 12-1 for Where end a and Connection, B end and connect; Y 12-1 It is an amino acid.

5. The compound of formula I as claimed in claim 1, its pharmaceutically acceptable salt, solvate, prodrug, metabolite, or isotopic compound, characterized in that, It satisfies one or more of the following conditions: (1)R 9 For C2-C 12 alkynyl group; Or, R 9 for Among them, Z 9-1 Y 9-1 m 9-1 m 9-2 n 9-1 n 9-2 n 9-3 and n 9-4 The definition is as described in claim 1; Or, R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, wherein R 8-1 For C2-C 12 alkynyl group; Or, R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 Substituted 4-12 membered heterocyclic groups, wherein R 8-1 for Among them, Z 8-1 Y 8-1 m 8-1 m 8-2 m 8-3 n 8-1 n 8-2 n 8-3 The definition is as described in claim 1; Or, R 8 R 9 Together with the C atoms it is attached to, they form C3-C. 12 cycloalkyl, with one or more R 8-2 Replacement C3-C 12 cycloalkyl; The C3-C mentioned 12 The cycloalkyl group is a C4-C6 cycloalkyl group; The R mentioned 8-2 The definition is as described in claim 1, preferably halogen; Or, R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; R 8-1 for Z 8-2 Y 8-2 m 8-4 m 8-5 m 8-6 n 8-4 The definition is as described in claim 1; Or, R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; The 4-12 member heterocyclic group is preferably a 6-membered heterocyclic group. Where end a and R 8-1 Connected; The R mentioned 8-1 for Among them, Z 8-2 Y 8-2 m 8-4 m 8- 5. m 8-6 n 8-4 The definition is as described in claim 1; preferably... Or, R 8 R 9 Together with the C atoms it is attached to, they form a structure consisting of one or more R atoms. 8-1 A substituted 4-12 membered heterocyclic group; wherein the heteroatom in the 4-12 membered heterocyclic group is selected from one or more of N, O, and S, and the number of heteroatoms is 1-3; The 4-12 member heterocyclic group is preferably a 6-membered heterocyclic group. Where end a and R 8-1 Connected; The R mentioned 8-1 for Among them, Z 8-1 Y 8-1 m 8-1 m 8-2 m 8-3 n 8-1 n 8-2 n 8-3 The definition is as described in claim 1, preferably... Or, R 8 It is hydrogen; R 9 for Among them, Z 9-1 Y 9-1 m 9-1 m 9-2 n 9-1 n 9-2 n 9-3 and n 9-4 The definition is as described in claim 1; Preferred (2) for (3)Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y 5-1 Y 5-2 Y 5-3 Y 5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 10-1 Y 10-2 Y 12- 1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 Y 8-2 In the text, the amino acid mentioned is glutamic acid, with the structural formula as follows: Where end a is connected to -NH-, and end b is connected to... connect; (4)R 12 It is hydrogen or C1-C6 alkyl; R 13 -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 ;m 13-1 R is an integer from 1 to 6; 13-1 R 13- 2 Each is independently hydrogen or C1-C6 alkyl; Or, R 13 In the context, -(CH2)m 13-1 -(C=O)-NR 13-1 R 13-2 It is -CH2-(C=O)-NH2; Or, R 12 In this context, the C1-C6 alkyl group is methyl; Or, R 12 It is hydrogen or C1-C6 alkyl, R 13 for m 12-1 m 12-2 Integers between 1 and 20; n 12-1 n 12-2 n 12-3 Integers between 0 and 12; Y 12-1 In this context, the amino acid mentioned is glutamic acid; Or, R 12 In this context, the C1-C6 alkyl group is methyl, and R 13 In the middle, the aforementioned for (5)R 6 In the context of C5-C 12 The aryl group is C6-C. 12 Aryl, preferably phenyl.

6. The compound of formula I or a pharmaceutically acceptable salt thereof, solvate, prodrug, metabolite or isotope compound as described in claim 1, characterized in that, The compound shown in Formula I is the same as the compound shown in Formula A; Among them, R 1 R 4 R 6 R 8 R 9 and R 13 As defined in claim 1; Preferably, the compound represented by Formula I is the compound represented by Formula A1; Among them, R 8 R 9 and R 13 As defined in claim 1.

7. The compound of formula I or a pharmaceutically acceptable salt thereof, solvate, prodrug, metabolite or isotope compound as described in claim 1, characterized in that, It meets one or more of the following conditions: (1)R 1 Methyl, -(C=O)CH3, (2)R 2 for (3)R 3 It can be methyl, ethyl, propyl, isopropyl, or cyclopropyl; (4)R 4 for (5)R 5 for (6)R 6 for Where p is an integer from 1 to 8; (7)R 7 for (8)R 8 It is hydrogen or methyl; (9)R 9 for (10) for (11)R 10 It is a hydroxyl group; (12)R 11 for (13)R 12 H, methyl; (14)R 13 For H, (15)Y 1-1 、Y 1-2 、Y 1-3 、Y 1-4 、Y 5-1 、Y 5-2 、Y 5-3 、Y 5-4 、Y 9-1 、Y 9-2 、Y 9-3 、Y 8-1 、Y 10-1 、Y 10-2 、Y 12- 1 、Y 12-2 、Y 12-3 、Y 12-4 、Y 12-5 、Y 12-6 、Y 8-2 is Where end a is connected to -NH-, and end b is connected to... connect; (16) for 8. The compound of formula I or a pharmaceutically acceptable salt thereof, solvate, prodrug, metabolite or isotope compound as described in claim 1, characterized in that, It meets one or more of the following conditions: (1)R 1-1 R 3 R 4-2 R 4-3 R 4-4 R 4-5 R 5-1 R 6-1-1-1 R 6-1-1-2 R 8 R 12 R 13 R 6-1-2-1 R 6-1-2-1-1 R 6-1-2-1-2 R 8-2 R 13-1 R 13-2 R 13-2-1 R 13-2-3 R 13-2-4 R 13-3 R 13-4 R 8-1 R 8-1-1 R 8-1-2-1 In the C1-C6 alkyl group and the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl; (2)X 1 X 2 In the C1-C6 alkylene and the substituted C1-C6 alkylene, the C1-C6 alkylene is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-; preferably -C(CH3)2-; (3)R 4-1-1 R 4-1-2 R 4-1-3 R 6-1 R 8-2 R 6-1-2-1 R 8-2 R 8-1-2-1 R 8-2-1 In this context, the halogen is independently F, Cl, Br, or I, for example, F; (4)X 1-1 X 2-1 R 3 R 4-2 R 4-3 R 4-4 R 4-5 R 6-1-2 R 8 R 9 In the C3-C8 cycloalkyl or substituted C3-C8 cycloalkyl formed together with the C atoms attached thereto, the C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl and cyclooctyl, preferably cyclopropyl; (5) The C2-C 12 The alkynyl group is independently a C2-C6 alkynyl group, for example, q can be 0, 1, 2 or 3, with q preferably being 0 or 1; (6)Y 1-1 Y 1-2 Y 1-3 Y 1-4 Y 5-1 Y 5-2 Y 5-3 Y 5-4 Y 9-1 Y 9-2 Y 9-3 Y 8-1 Y 10-1 Y 10-2 Y 12- 1 Y 12-2 Y 12-3 Y 12-4 Y 12-5 Y 12-6 Y 8-2 In this context, the amino acid is a natural amino acid, preferably glutamic acid. (7)R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 In the substituted 4-12-membered heterocyclic group, the 4-12-membered heterocyclic group is a 6-membered heterocyclic group; preferably, the 4-12-membered heterocyclic group is a 4-6-membered heterocyclic alkyl group containing one nitrogen atom, for example... (8)R 8 R 9 Together with the C atoms attached thereto, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 8-1 In the substituted 4-12 membered heterocyclic group, the heteroatom in the 4-12 membered heterocyclic group is an oxygen atom; (9) The C1-C 24 Alkyl and C1-C 12 Alkyl groups are independently C1-C6 alkyl groups, such as methyl; (10) The C5-C 12 The aryl group is independently phenyl or benzo[3-C6]cycloalkyl, such as phenyl or (11) The C3-C 12 Cycloalkyl groups are monocyclic C 3-8 cycloalkyl or spirocyclic C 6-12 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclohexyl, 9. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any of the following compounds:

10. A pharmaceutical composition comprising: The pharmaceutical composition comprises, preferably, a pharmaceutically acceptable excipient, a compound of Formula I as described in any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or an isotopic compound thereof, and preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

11. Use in the preparation of a medicament for an IL-23R inhibitor by a compound of Formula I as described in any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug, a metabolite thereof, or an isotopic compound thereof, or a pharmaceutical composition as described in claim 10, particularly for the treatment or prevention of diseases or conditions mediated by IL-23 / IL-23R, such as diseases or conditions mediated by IL-23 / IL-23R selected from those for the treatment of inflammatory, autoimmune, and cancer diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, celiac disease, such as nontropical stomatitis diarrhea, enteropathy associated with seronegative arthropathy, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, and those associated with radiotherapy or chemotherapy. Colitis, colitis associated with congenital immune disorders such as leukopenia-1, chronic granulomatous disease, type 1b glycogen storage disease, Hermansky-Praque syndrome, Scherdick-Donnell syndrome and Weil-O'Sullivan syndrome, pouchitis following rectocele and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholecystitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, irritable bowel syndrome, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, pemphigus vulgaris, organ transplant rejection, Crohn's disease, systemic lupus erythematosus, or diabetes; preferably inflammatory bowel disease, rheumatoid arthritis, or psoriasis.

12. A method for preparing a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof, comprising the following steps: cyclizing a compound of Formula Ia in a solvent to obtain a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or an isotope thereof. in, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 X1, X2 and Q are as defined in any one of claims 1-9.

13. A compound of formula Ia or a pharmaceutically acceptable salt thereof, in, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 X1, X2 and Q are as defined in any one of claims 1-9; For example, the compound represented by formula Ia is any of the following compounds:

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