Pyrazole carboxamide compound and use thereof

Abstract

Disclosed in the present invention are a pyrazole carboxamide compound and a use thereof. Specifically, disclosed is the compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention is an IL-17 small molecule modulator, and can be used for treating or preventing IL-17-mediated diseases, such as autoimmune diseases.

Description

A pyrazole carboxamide compound and its application

[0001] This application claims Chinese patent applications filed on November 24, 2024 (2024116962838), January 28, 2025 (2025101287045), April 3, 2025 (2025104241217), May 5, 2025 (2025105813618), and June 29, 2025 (2025). This application claims priority to Chinese patent applications 202510891103X, 2025109728686 (filed July 14, 2025), 2025111299532 (filed August 12, 2025), 2025112366568 (filed August 31, 2025), and 2025114250674 (filed September 30, 2025). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a pyrazole carboxamide compound and its applications. Background Technology

[0003] Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T cells, playing various regulatory roles in the immune system. The IL-17 family consists of six members: IL-17A through IL-17F. IL-17A and IL-17F can form homodimers or heterodimers, and they exhibit different binding specificities when binding to five receptors: IL-17RA through IL-17RE. Studies have found a close link between IL-17AA and autoimmune diseases such as psoriasis and ankylosing spondylitis.

[0004] Psoriasis is a common chronic inflammatory skin disease characterized by itching, bleeding, and pain, often accompanied by erythema and scaling on the skin. Psoriasis is a long-term condition, prone to recurrence, and can even cause disfigurement, placing a heavy psychological burden on patients. Currently, there is no cure for this disease. Previous research has shown that interleukin-17 (IL-17) plays a crucial role in the pathological mechanism of psoriasis, making it one of the main research targets for psoriasis treatment drugs.

[0005] Currently, first-line treatments for moderate to severe psoriasis mainly include methotrexate, acitretin, cyclosporine, adalimumab, and secukinumab. Oral small-molecule drugs targeting IL-17AA have a well-defined mechanism of action, effectively avoiding off-target effects; they also avoid the safety issues associated with other targets (such as TNF, TYK2, and PDE4). Furthermore, small-molecule drugs exhibit better compliance and tolerability than biologics, are superior to large-molecule drugs in disease management, and can reduce the side effects caused by antibody drugs. Therefore, developing new, safer, and more effective small-molecule drugs for moderate to severe psoriasis patients has significant market potential and clinical demand. Summary of the Invention

[0006] The technical problem solved by this invention is the scarcity of oral small molecules targeting IL-17 in existing technologies. Therefore, this invention provides a pyrazole carboxamide compound and its applications. The compound of this invention exhibits superior biological activity in inhibiting IL-17.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof:

[0009] Among them, R 1 for -OR 1-8 C3-C8 cycloalkyl groups, with one or more R 1-9 Substituted C3-C8 cycloalkyl, C2-C6 alkenyl, or with one or more R 1-10 Substituted C2-C6 alkenyl, C2-C6 ynyl group, with one or more R 1-14 Substituted C2-C6 ynyl group, 3-12 membered heterocyclic group, or grouped by one or more R 1-15 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-16 Substituted 5-12-membered heteroaryl, C1-C6 alkyl, or with one or more R 1-17 The substituted C1-C6 alkyl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0010] R 1-1 R 1-2 R 1-3 Each of the following is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with one or more deuterates, halogen, C1-C6 alkoxy, or substituted with one or more R1-1-1 Substituted C1-C6 alkoxy groups, with one or more R 1-1-2 Substituted C1-C6 alkyl groups;

[0011] R 1-1-1 It is a halogen;

[0012] R 1-1-2 It is a C1-C6 alkoxy group;

[0013] R 1-4 It is hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more deuterium groups, C3-C8 cycloalkyl, -OR 1-4-1 Oxidation, oxidation;

[0014] R 1-4-1 It is a C1-C6 alkyl group, with one or more R 1-4-1-1 Substituted C1-C6 alkyl, 3-12 membered heterocyclic groups; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0015] R 1-4-1-1 It is a halogen;

[0016] R 1-5 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 1-5-1 Substituted C1-C6 alkyl groups;

[0017] R 1-5-1 It is a halogen;

[0018] R 1-6 It is hydrogen, C1-C6 alkyl;

[0019] R 1-7 It is hydrogen, C1-C6 alkyl;

[0020] R 1-8 C5-C 12 aryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, with one or more R 1-8-1 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0021] R 1-8-1 It is a C1-C6 alkyl group;

[0022] R 1-9 It is a C1-C6 alkyl group, with one or more R 1-9-1 Substituted C1-C6 alkyl, halogen, deuterated, cyano, hydroxyl;

[0023] R1-9-1 It is a halogen;

[0024] R 1-10 Halogen, C3-C8 cycloalkyl, with one or more R 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl, deuterated, -NR 1-10-3 R 1-10-4 3-12 membered heterocyclic group, surrounded by one or more R 1-10-5 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-10-6 The substituted 5-12 membered heteroaryl and cyano groups; the heteroatoms in the heterocyclic groups and heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3.

[0025] R 1-10-1 Halogenated, C1-C6 alkyl, deuterated;

[0026] R 1-10-2 For deuterated, halogenated, -NR 1-10-2-1 R 1-10-2-2 ;

[0027] R 1-10-2-1 R 1-10-2-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0028] R 1-10-3 R 1-10-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0029] R 1-10-5 It is halogenated or C1-C6 alkyl;

[0030] R 1-10-6 It is halogenated or C1-C6 alkyl;

[0031] R 1-11 R 1-12 R 1-13 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 1-11-1 Substituted C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0032] R 1-11-1 For deuteration and halogenation;

[0033] R 1-14 It is a halogen;

[0034] R 1-15 It is a C1-C6 alkyl group or a halogen.

[0035] R 1-16It is halogenated or C1-C6 alkyl;

[0036] R 1-17 Halogen, -NR 1-17-1 R 1-17-2 C3-C8 cycloalkyl groups;

[0037] R 1-17-1 R 1-17-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0038] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, C3-C 20 cycloalkyl, with one or more R 2-2 Replacement C3-C 20 cycloalkyl;

[0039] R 2-1 It is a C3-C8 cycloalkyl group or a halogen.

[0040] R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2-2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 2-2-8 Substituted C3-C8 cycloalkyl groups The heteroatoms in the heterocyclic group are independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3.

[0041] R 2-2-1 It is a halogen;

[0042] R 2-2-2 It is a halogen;

[0043] R 2-2-3 R 2-2-4 R 2-2-5 Each is independently an H or C1-C6 alkyl group;

[0044] R 2-2-6 It is a C1-C6 alkyl group;

[0045] R 2-2-7It is halogenated or C1-C6 alkyl;

[0046] R 2-2-8 It is a halogen;

[0047] R 2-2-9 R 2-2-10 Each is independently hydrogen, halogen, or C1-C6 alkyl;

[0048] R 3 R 4 R 5 R 6 R 7 Each independently consists of H, halogen, -CR 5-13 R 5-14 R 5- 15 Or it may not exist;

[0049] R 5-0 For H;

[0050] R 5-1 H, C1-C6 alkyl, and formed by one or more R 5-1-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, or substituted with one or more R 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0051] R 5-1-1 It is C1-C6 alkoxy or halogen;

[0052] R 5-1-2 Halogens, C1-C6 alkyl groups;

[0053] R 5-2 It is H, C1-C6 alkyl;

[0054] R 5-3 R 5-4 Each is independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 -(C=O)-R 5-3-3 4-12 membered heterocyclic group, surrounded by one or more R 5-3-4 Substituted 4-12 membered heterocyclic groups, C3-C8 cycloalkyl groups, C1-C6 alkyl groups, and those with one or more R groups 5-3-5 Substituted C1-C6 alkyl groups, -SO2R 5-3-6 The heteroatoms in the heterocyclic group are independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3.

[0055] R 5-3-1 R 5-3-2Each is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, or composed of one or more R groups. 5-3-1-1 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-3-1-2 Substituted 4-12 membered heterocyclic groups, by one or more R 5-3-1-3 The substituted C1-C6 alkyl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0056] R 5-3-1-1 for

[0057] R 5-3-1-1-1 R 5-3-1-1-2 Each is independently hydrogen, halogen, or C1-C6 alkyl;

[0058] R 5-3-1-2 It is halogenated or C1-C6 alkyl;

[0059] R 5-3-1-3 It is a halogen;

[0060] Or R 5-3-1 R 5-3-2 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 5-3-1-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0061] R 5-3-1-1 It is a C1-C6 alkyl group;

[0062] R 5-3-3 It is a C1-C6 alkyl group, with one or more R 5-3-3-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-3-3-2 Substituted 4-12 membered heterocyclic groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-3-3-3 Substituted C3-C8 cycloalkyl, -OR 5-3- 3-4 5-12 aryl groups, surrounded by one or more R groups 5-3-3-5 The substituted C2-C6 alkenyl group; the heteroatoms in the heterocyclic group and heteroaryl group are independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0063] R 5-3-3-1 It is -Si(CH3)3, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen, 4-12 membered heterocyclic group, or surrounded by one or more R groups.5-3-3-1-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0064] R 5-3-3-1-1 It is halogenated or C1-C6 alkyl;

[0065] R 5-3-3-2 It is a C1-C6 alkyl group;

[0066] R 5-3-3-3 It is a halogen;

[0067] R 5-3-3-4 It is a C3-C8 cycloalkyl, C1-C6 alkyl, or formed by one or more R 5-3-3-4-1 Substituted C1-C6 alkyl groups;

[0068] R 5-3-3-4-1 It is a 5-12 membered heteroaryl group; the heteroatom in the heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3.

[0069] R 5-3-3-5 It is a halogen;

[0070] R 5-3-4 It is a C1-C6 alkyl group, with one or more R 5-3-4-1 Substituted C1-C6 alkyl groups;

[0071] R 5-3-4-1 It is a C1-C6 alkoxy group;

[0072] R 5-3-5 -(C=O)-NR 5-3-5-1 R 5-3-5-2 4-12 membered heterocyclic group, surrounded by one or more R 5-3-5-3 Substituted 4-12 membered heterocyclic groups;

[0073] R 5-3-5-1 R 5-3-5-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0074] R 5-3-5-3 For -NR 5-3-5-3-1 R 5-3-5-3-2 ;

[0075] R 5-3-5-3-1 R 5-3-5-3-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0076] R 5-3-6 It is a C1-C6 alkyl group;

[0077] Or R5-3 R 5-4 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 5-4-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0078] R 5-4-1 It is oxo, halogen, C1-C6 alkyl, or formed by one or more R 5-4-1-1 Substituted C1-C6 alkyl groups;

[0079] R 5-4-1-1 It is a halogen;

[0080] R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 5-5-3 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-5-4 Substituted 4-12 membered heterocyclic groups, C2-C6 ynyl groups, or groups with one or more R groups 5-5-5 The substituted C1-C6 alkyl group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0081] R 5-5-1 It can be an oxide, -OH, C1-C6 alkyl, or halogen.

[0082] R 5-5-2 It can be OH, C1-C6 alkyl, or halogen;

[0083] R 5-5-3 For -NR 5-5-3-1 R 5-5-3-2 Halogen, C2-C6 alkynyl, C1-C6 alkyl, with one or more R 5-5-3-3 Substituted C1-C6 alkyl groups, -(C=O)NR 5-5-3-4 R 5-5-3-5 ;

[0084] R 5-5-3-1 R 5-5-3-2 Each is independently H or C1-C6 alkyl;

[0085] R 5-5-3-3 for

[0086] R 5-5-3-3-1 R 5-5-3-3-2 Each is independently H or C1-C6 alkyl;

[0087] R 5-5-3-4 R 5-5-3-5 Each is independently H or C1-C6 alkyl;

[0088] R 5-5-4 It is C2-C6 alkynyl or C1-C6 alkyl;

[0089] R 5-5-5 -SO2NR 5-5-5-1 R 5-5-5-2 C3-C8 cycloalkyl, NR 5-5-5-3 R 5-5-5-4 C1-C6 alkoxy groups;

[0090] R 5-5-5-1 R 5-5-5-2 Each is independently H or C1-C6 alkyl;

[0091] R 5-5-5-3 R 5-5-5-4 Each is independently H or C1-C6 alkyl;

[0092] Or R 5-5 R 5-6 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-6-1 The substituted 4-12 membered heterocyclic group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, and selenium, and the number of heteroatoms is independently 1, 2, or 3.

[0093] R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5- 6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups, -NR 5-6-1-8 R 5-6-1-9 C3-C8 cycloalkyl groups, with one or more R 5-6-1-10 Substituted C3-C8 cycloalkyl groups C1-C6 alkoxy group, 4-12 heterocyclic group, surrounded by one or more R groups 5-6-1-14 Substituted 4-12 heterocyclic groups, hydroxyl groups, and one or more R groups 5-6-1-15 The substituted C1-C6 alkoxy group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, and selenium, and the number of heteroatoms is independently 1, 2, or 3.

[0094] R 5-6-1-1 R 5-6-1-2 Each is independently H or C1-C6 alkyl;

[0095] R 5-6-1-3 It is a C3-C8 cycloalkyl group or a halogen.

[0096] R 5-6-1-4 R 5-6-1-5 H and C1-C6 alkyl groups, each independently;

[0097] R 5-6-1-6 It is a halogen;

[0098] R 5-6-1-7 It is an oxidized, C1-C6 alkyl group;

[0099] R 5-6-1-8 R 5-6-1-9 Each is independently H or C1-C6 alkyl;

[0100] R 5-6-1-10 It is a C1-C6 alkyl group, with one or more R 5-6-1-10-1 Substituted C1-C6 alkyl groups;

[0101] R 5-6-1-10-1 It is a halogen;

[0102] R 5-6-1-11 R 5-6-1-12 Each is independently H, halogen, or C1-C6 alkyl;

[0103] R 5-6-1-13 It is hydrogen, C1-C6 alkyl;

[0104] R 5-6-1-14 It is halogenated or C1-C6 alkyl;

[0105] R 5-6-1-15 It is deuterium, a halogen;

[0106] n1 is 0, 1, or 2;

[0107] R 5-7 It is H, C1-C6 alkyl;

[0108] R 5-8 C1-C6 alkyl, NR5-8-1 R 5-8-2 ;

[0109] R 5-8-1 For H;

[0110] R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ;

[0111] R 5-8-2-1 R 5-8-2-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0112] R 5-9 For H;

[0113] R 5-10 H, 5-14-membered heteroaryl, surrounded by one or more R 5-10-1 The substituted heteroaryl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0114] R 5-10-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-10-1-1 Substituted C1-C6 alkyl groups;

[0115] R 5-10-1-1 It is a halogen;

[0116] Or R 5-9 R 5-10 The C atoms bonded to it together form a carbonyl group;

[0117] R 5-11 For H;

[0118] R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ;

[0119] R 5-12-1 R 5-12-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0120] Or R 5-11 R 5-12 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-11-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0121] R 5-11-1It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-11-1-1 Substituted C1-C6 alkyl groups;

[0122] R 5-11-1-1 It is a halogen;

[0123] R 5-13 For H;

[0124] R 5-14 It is a C1-C6 alkyl group;

[0125] R 5-15 It is a 4-12 membered heterocyclic group, surrounded by one or more R 5-15-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0126] R 5-15-1 It is an oxo- or C1-C6 alkyl group;

[0127] R 8 For H and deuterium;

[0128] n2 is 0, 1, or 2;

[0129] Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N;

[0130] m is 0 or 1.

[0131] Those skilled in the art will understand that, in the compound represented by Formula I, when Y 1 When R is N, 3 It does not exist. When Y 2 When R is N, 7 It does not exist. When Y 3 When R is N, 6 It does not exist. When Y 4 When R is N, 5 It does not exist. When Y 5 When R is N, 4 It does not exist.

[0132] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-5-5 It can also be used for CONR 5-5-5-5 R 5-5-5-6 ;R 5-5-5-5 R 5-5-5-6Each is independently H or C1-C6 alkyl.

[0133] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein the compound represented by Formula I is not any of the following compounds:

[0134] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein the structural formula of Formula I is shown in Formula I-1 or I-2 below:

[0135] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 Y 1 Y 2 Y 3 Y 4 Y 5 The definition is as described above.

[0136] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite are:

[0137] Among them, R 1 for -OR 1-8 C3-C8 cycloalkyl groups, with one or more R 1-9 Substituted C3-C8 cycloalkyl, C2-C6 alkenyl, or with one or more R 1-10 Substituted C2-C6 alkenyl, C2-C6 ynyl group, with one or more R 1-14 Substituted C2-C6 ynyl group, 3-12 membered heterocyclic group, or grouped by one or more R 1-15 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-16Substituted 5-12-membered heteroaryl, C1-C6 alkyl, or with one or more R 1-17 The substituted C1-C6 alkyl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0138] R 1-1 R 1-2 R 1-3 Each is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with one or more deuterium groups;

[0139] R 1-4 It is hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more deuterium groups, C3-C8 cycloalkyl, -OR 1-4-1 Oxidation;

[0140] R 1-4-1 It is a C1-C6 alkyl group, with one or more R 1-4-1-1 Substituted C1-C6 alkyl groups;

[0141] R 1-4-1-1 It is a halogen;

[0142] R 1-5 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 1-5-1 Substituted C1-C6 alkyl groups;

[0143] R 1-5-1 It is a halogen;

[0144] R 1-6 It is hydrogen, C1-C6 alkyl;

[0145] R 1-7 It is hydrogen, C1-C6 alkyl;

[0146] R 1-8 C5-C 12 aryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, with one or more R 1-8-1 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0147] R 1-8-1 It is a C1-C6 alkyl group;

[0148] R 1-9 It is a C1-C6 alkyl group, with one or more R 1-9-1 Substituted C1-C6 alkyl groups, halogens, deuterated groups;

[0149] R 1-9-1 It is a halogen;

[0150] R 1-10 Halogen, C3-C8 cycloalkyl, with one or more R 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl, deuterated, -NR 1-10-3 R 1-10-4 3-12 membered heterocyclic group, surrounded by one or more R 1-10-5 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-10-6 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0151] R 1-10-1 Halogenated, C1-C6 alkyl, deuterated;

[0152] R 1-10-2 For deuterated, halogenated, -NR 1-10-2-1 R 1-10-2-2 ;

[0153] R 1-10-2-1 R 1-10-2-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0154] R 1-10-3 R 1-10-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0155] R 1-10-5 It is halogenated or C1-C6 alkyl;

[0156] R 1-10-6 It is halogenated or C1-C6 alkyl;

[0157] R 1-11 R 1-12 R 1-13 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 1-11-1 Substituted C1-C6 alkyl groups and C3-C8 cycloalkyl groups;

[0158] R 1-11-1 For deuteration and halogenation;

[0159] R 1-14 It is a halogen;

[0160] R 1-15 It is a C1-C6 alkyl group or a halogen.

[0161] R 1-16It is halogenated or C1-C6 alkyl;

[0162] R 1-17 Halogen, -NR 1-17-1 R 1-17-2 ;

[0163] R 1-17-1 R 1-17-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0164] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, C3-C 20 cycloalkyl, with one or more R 2-2 Replacement C3-C 20 cycloalkyl;

[0165] R 2-1 It is a C3-C8 cycloalkyl group or a halogen.

[0166] R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2-2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 2-2-8 The substituted C3-C8 cycloalkyl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0167] R 2-2-1 It is a halogen;

[0168] R 2-2-2 It is a halogen;

[0169] R 2-2-3 R 2-2-4 R 2-2-5 Each is independently an H or C1-C6 alkyl group;

[0170] R 2-2-6 It is a C1-C6 alkyl group;

[0171] R 2-2-7 It is halogenated or C1-C6 alkyl;

[0172] R 2-2-8 It is a halogen;

[0173] R 3 R 4 R 5 R 6 R 7 Each independently consists of H, halogen, -CR 5-13 R 5-14 R 5- 15 Or it may not exist;

[0174] R 5-0 For H;

[0175] R 5-1 H, C1-C6 alkyl, and formed by one or more R 5-1-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, or substituted with one or more R 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0176] R 5-1-1 It is C1-C6 alkoxy or halogen;

[0177] R 5-1-2 Halogens, C1-C6 alkyl groups;

[0178] R 5-2 It is H, C1-C6 alkyl;

[0179] R 5-3 R 5-4 Each is independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 -(C=O)-R 5-3-3 4-12 membered heterocyclic group, surrounded by one or more R 5-3-4 Substituted 4-12 membered heterocyclic groups, C3-C8 cycloalkyl groups, C1-C6 alkyl groups, and those with one or more R groups 5-3-5 Substituted C1-C6 alkyl groups, -SO2R 5-3-6 ;

[0180] Or R 5-3 R 5-4 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 5-4-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0181] R 5-3-1 R 5-3-2Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0182] Or R 5-3-1 R 5-3-2 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 5-3-1-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0183] R 5-3-1-1 It is a C1-C6 alkyl group;

[0184] R 5-3-3 It is a C1-C6 alkyl group, with one or more R 5-3-3-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-3-3-2 Substituted 4-12 membered heterocyclic groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-3-3-3 Substituted C3-C8 cycloalkyl, -OR 5-3- 3-4 5-12 aryl groups, surrounded by one or more R groups 5-3-3-5 The substituted C2-C6 alkenyl group; the heteroatoms in the heterocyclic group and heteroaryl group are independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0185] R 5-3-3-1 -Si(CH3)3, C1-C6 alkoxy, C3-C8 cycloalkyl, halogen;

[0186] R 5-3-3-2 It is a C1-C6 alkyl group;

[0187] R 5-3-3-3 It is a halogen;

[0188] R 5-3-3-4 It is a C3-C8 cycloalkyl, C1-C6 alkyl, or formed by one or more R 5-3-3-4-1 Substituted C1-C6 alkyl groups;

[0189] R 5-3-3-4-1 It is a 5-12 membered heteroaryl group; the heteroatom in the heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3.

[0190] R 5-3-3-5 It is a halogen;

[0191] R 5-3-4 It is a C1-C6 alkyl group, with one or more R 5-3-4-1Substituted C1-C6 alkyl groups;

[0192] R 5-3-4-1 It is a C1-C6 alkoxy group;

[0193] R 5-3-5 -(C=O)-NR 5-3-5-1 R 5-3-5-2 4-12 membered heterocyclic group, surrounded by one or more R 5-3-5-3 Substituted 4-12 membered heterocyclic groups;

[0194] R 5-3-5-1 R 5-3-5-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0195] R 5-3-5-3 For -NR 5-3-5-3-1 R 5-3-5-3-2 ;

[0196] R 5-3-5-3-1 R 5-3-5-3-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0197] R 5-3-6 It is a C1-C6 alkyl group;

[0198] R 5-4-1 It is oxo, halogen, C1-C6 alkyl, or formed by one or more R 5-4-1-1 Substituted C1-C6 alkyl groups;

[0199] R 5-4-1-1 It is a halogen;

[0200] R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 5-5-3 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-5-4 Substituted 4-12 membered heterocyclic groups, C2-C6 ynyl groups, or groups with one or more R groups 5-5-5 The substituted C1-C6 alkyl group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0201] R 5-5-1 It can be an oxide, -OH, C1-C6 alkyl, or halogen.

[0202] R 5-5-2 It can be OH, C1-C6 alkyl, or halogen;

[0203] R 5-5-3 For -NR 5-5-3-1 R 5-5-3-2 Halogen, C2-C6 alkynyl, C1-C6 alkyl, with one or more R 5-5-3-3 Substituted C1-C6 alkyl groups, -(C=O)NR 5-5-3-4 R 5-5-3-5 ;

[0204] R 5-5-3-1 R 5-5-3-2 Each is independently H or C1-C6 alkyl;

[0205] R 5-5-3-3 for

[0206] R 5-5-3-3-1 R 5-5-3-3-2 Each is independently H or C1-C6 alkyl;

[0207] R 5-5-3-4 R 5-5-3-5 Each is independently H or C1-C6 alkyl;

[0208] R 5-5-4 It is C2-C6 alkynyl or C1-C6 alkyl;

[0209] R 5-5-5 -SO2NR 5-5-5-1 R 5-5-5-2 C3-C8 cycloalkyl groups;

[0210] R 5-5-5-1 R 5-5-5-2 Each is independently H or C1-C6 alkyl;

[0211] Or R 5-5 R 5-6 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-6-1 The substituted 4-12 membered heterocyclic group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, and selenium, and the number of heteroatoms is independently 1, 2, or 3.

[0212] R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5-6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups, -NR 5-6-1-8 R 5-6-1-9 C3-C8 cycloalkyl groups, with one or more R 5-6-1-10 Substituted C3-C8 cycloalkyl groups;

[0213] R 5-6-1-1 R 5-6-1-2 Each is independently H or C1-C6 alkyl;

[0214] R 5-6-1-3 It is a C3-C8 cycloalkyl group or a halogen.

[0215] R 5-6-1-4 R 5-6-1-5 H and C1-C6 alkyl groups, each independently;

[0216] R 5-6-1-6 It is a halogen;

[0217] R 5-6-1-7 It is an oxidized, C1-C6 alkyl group;

[0218] R 5-6-1-8 R 5-6-1-9 Each is independently H or C1-C6 alkyl;

[0219] R 5-6-1-10 It is a C1-C6 alkyl group, with one or more R 5-6-1-10-1 Substituted C1-C6 alkyl groups;

[0220] R 5-6-1-10-1 It is a halogen;

[0221] n1 is 0, 1, or 2;

[0222] R 5-7 It is H, C1-C6 alkyl;

[0223] R 5-8 C1-C6 alkyl, NR 5-8-1 R 5-8-2 ;

[0224] R 5-8-1 For H;

[0225] R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ;

[0226] R5-8-2-1 R 5-8-2-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0227] R 5-9 For H;

[0228] R 5-10 H, 5-14-membered heteroaryl, surrounded by one or more R 5-10-1 The substituted heteroaryl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0229] R 5-10-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-10-1-1 Substituted C1-C6 alkyl groups;

[0230] R 5-10-1-1 It is a halogen;

[0231] Or R 5-9 R 5-10 The C atoms bonded to it together form a carbonyl group;

[0232] R 5-11 For H;

[0233] R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ;

[0234] R 5-12-1 R 5-12-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0235] Or R 5-11 R 5-12 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-11-1 Substituted 4-12 membered heterocyclic groups;

[0236] R 5-11-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-11-1-1 Substituted C1-C6 alkyl groups;

[0237] R 5-11-1-1 It is a halogen;

[0238] R 5-13 For H;

[0239] R 5-14 It is a C1-C6 alkyl group;

[0240] R 5-15It is a 4-12 membered heterocyclic group, surrounded by one or more R 5-15-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0241] R 5-15-1 It is an oxo- or C1-C6 alkyl group;

[0242] R 8 For H and deuterium;

[0243] n2 is 0, 1, or 2;

[0244] Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N;

[0245] m is 0 or 1.

[0246] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite are:

[0247] Among them, R 1 for -OR 1-8 C3-C8 cycloalkyl groups, with one or more R 1-9 Substituted C3-C8 cycloalkyl, C2-C6 alkenyl, or with one or more R 1-10 Substituted C2-C6 alkenyl groups;

[0248] R 1-1 R 1-2 R 1-3 Each is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or deuterated C1-C6 alkyl;

[0249] R 1-4 Hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, -OR 1-4-1 Oxidation;

[0250] R 1-4-1 It is a C1-C6 alkyl group, with one or more R 1-4-1-1 Substituted C1-C6 alkyl groups;

[0251] R 1-4-1-1 It is a halogen;

[0252] R 1-5 It is hydrogen, C1-C6 alkyl, and is formed by one or more R1-5-1 Substituted C1-C6 alkyl groups;

[0253] R 1-5-1 It is a halogen;

[0254] R 1-6 It is hydrogen, C1-C6 alkyl;

[0255] R 1-7 It is hydrogen, C1-C6 alkyl;

[0256] R 1-8 C5-C 12 Aryl;

[0257] R 1-9 It is a C1-C6 alkyl group, with one or more R 1-9-1 Substituted C1-C6 alkyl groups;

[0258] R 1-9-1 It is a halogen;

[0259] R 1-10 Halogen, C3-C8 cycloalkyl, C1-C6 alkyl;

[0260] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, C3-C 20 cycloalkyl, with one or more R 2-2 Replacement C3-C 20 cycloalkyl;

[0261] R 2-1 It is a C3-C8 cycloalkyl group;

[0262] R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2-2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 2-2-8 The substituted C3-C8 cycloalkyl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0263] R2-2-1 It is a halogen;

[0264] R 2-2-2 It is a halogen;

[0265] R 2-2-3 R 2-2-4 R 2-2-5 Each is independently an H or C1-C6 alkyl group;

[0266] R 2-2-6 It is a C1-C6 alkyl group;

[0267] R 2-2-7 It is halogenated or C1-C6 alkyl;

[0268] R 2-2-8 It is a halogen;

[0269] R 3 R 4 R 5 R 6 R 7 Each independently consists of H, halogen, -CR 5-13 R 5- 14 R 5-15 Or it may not exist;

[0270] R 5-0 For H;

[0271] R 5-1 H, C1-C6 alkyl, and formed by one or more R 5-1-1 Substituted C1-C6 alkyl groups;

[0272] R 5-1-1 It is C1-C6 alkoxy or halogen;

[0273] R 5-2 It is H, C1-C6 alkyl;

[0274] R 5-3 R 5-4 Each is independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 -(C=O)-R 5-3-3 4-12 membered heterocyclic group, surrounded by one or more R 5-3-4 Substituted 4-12 membered heterocyclic groups; or R 5-3 R 5-4 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 5-4-1The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0275] R 5-3-1 R 5-3-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0276] R 5-3-3 It is a C1-C6 alkyl group, with one or more R 5-3-3-1 Substituted C1-C6 alkyl groups;

[0277] R 5-3-4 It is a C1-C6 alkyl group;

[0278] R 5-3-3-1 It is -Si(CH3)3;

[0279] R 5-4-1 It is oxo, halogen, C1-C6 alkyl, or formed by one or more R 5-4-1-1 Substituted C1-C6 alkyl groups;

[0280] R 5-4-1-1 It is a halogen;

[0281] R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 5-5-3 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-5-4 Substituted 4-12 membered heterocyclic groups, C2-C6 ynyl groups, or groups with one or more R groups 5-5-5 The substituted C1-C6 alkyl group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0282] R 5-5-1 It can be an oxide, -OH, C1-C6 alkyl, or halogen.

[0283] R 5-5-2 It can be OH, C1-C6 alkyl, or halogen;

[0284] R 5-5-3 For -NR 5-5-3-1 R 5-5-3-2Halogen, C2-C6 alkynyl, C1-C6 alkyl, with one or more R 5-5-3-3 Substituted C1-C6 alkyl groups, -(C=O)NR 5-5-3-4 R 5-5-3-5 ;

[0285] R 5-5-3-1 R 5-5-3-2 Each is independently H or C1-C6 alkyl;

[0286] R 5-5-3-3 for

[0287] R 5-5-3-3-1 R 5-5-3-3-2 Each is independently H or C1-C6 alkyl;

[0288] R 5-5-3-4 R 5-5-3-5 Each is independently H or C1-C6 alkyl;

[0289] R 5-5-4 It is C2-C6 alkynyl or C1-C6 alkyl;

[0290] R 5-5-5 -SO2NR 5-5-5-1 R 5-5-5-2 ;

[0291] R 5-5-5-1 R 5-5-5-2 Each is independently H or C1-C6 alkyl;

[0292] Or R 5-5 R 5-6 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-6-1 The substituted 4-12 membered heterocyclic group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, and selenium, and the number of heteroatoms is independently 1, 2, or 3.

[0293] R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5-6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups, -NR5-6-1-8 R 5-6-1-9 C3-C8 cycloalkyl groups, with one or more R 5-6-1-10 Substituted C3-C8 cycloalkyl groups;

[0294] R 5-6-1-1 R 5-6-1-2 Each is independently H or C1-C6 alkyl;

[0295] R 5-6-1-3 It is a C3-C8 cycloalkyl group or a halogen.

[0296] R 5-6-1-4 R 5-6-1-5 H and C1-C6 alkyl groups, each independently;

[0297] R 5-6-1-6 It is a halogen;

[0298] R 5-6-1-7 It is an oxidized, C1-C6 alkyl group;

[0299] R 5-6-1-8 R 5-6-1-9 Each is independently H or C1-C6 alkyl;

[0300] R 5-6-1-10 It is a C1-C6 alkyl group, with one or more R 5-6-1-10-1 Substituted C1-C6 alkyl groups;

[0301] R 5-6-1-10-1 It is a halogen;

[0302] n1 is 0, 1, or 2;

[0303] R 5-7 It is H, C1-C6 alkyl;

[0304] R 5-8 C1-C6 alkyl, NR 5-8-1 R 5-8-2 ;

[0305] R 5-8-1 For H;

[0306] R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ;

[0307] R 5-8-2-1 R 5-8-2-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0308] R 5-9 For H;

[0309] R 5-10H, 5-14-membered heteroaryl, surrounded by one or more R 5-10-1 The substituted heteroaryl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0310] R 5-10-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-10-1-1 Substituted C1-C6 alkyl groups;

[0311] R 5-10-1-1 It is a halogen;

[0312] Or R 5-9 R 5-10 The C atoms bonded to it together form a carbonyl group;

[0313] R 5-11 For H;

[0314] R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ;

[0315] R 5-12-1 R 5-12-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0316] Or R 5-11 R 5-12 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-11-1 Substituted 4-12 membered heterocyclic groups;

[0317] R 5-11-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-11-1-1 Substituted C1-C6 alkyl groups;

[0318] R 5-11-1-1 It is a halogen;

[0319] R 5-13 For H;

[0320] R 5-14 It is a C1-C6 alkyl group;

[0321] R 5-15 It is a 4-12 membered heterocyclic group, surrounded by one or more R 5-15-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0322] R 5-15-1It is an oxo- or C1-C6 alkyl group;

[0323] R 8 For H;

[0324] n2 is 0, 1, or 2;

[0325] Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N;

[0326] m is 0 or 1.

[0327] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite are:

[0328] Among them, R 1 for -OR 1-8 C3-C8 cycloalkyl groups, with one or more R 1-9 Substituted C3-C8 cycloalkyl, C2-C6 alkenyl, or with one or more R 1-10 Substituted C2-C6 alkenyl groups;

[0329] R 1-1 R 1-2 R 1-3 Each is independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0330] R 1-4 Hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C8 cycloalkyl, -OR 1-4-1 Oxidation;

[0331] R 1-4-1 It is a C1-C6 alkyl group, with one or more R 1-4-1-1 Substituted C1-C6 alkyl groups;

[0332] R 1-4-1-1 It is a halogen;

[0333] R 1-5 It is hydrogen, C1-C6 alkyl, and is formed by one or more R 1-5-1 Substituted C1-C6 alkyl groups;

[0334] R 1-5-1 It is a halogen;

[0335] R 1-6 It is hydrogen, C1-C6 alkyl;

[0336] R1-7 It is hydrogen, C1-C6 alkyl;

[0337] R 1-8 C5-C 12 Aryl;

[0338] R 1-9 It is a C1-C6 alkyl group, with one or more R 1-9-1 Substituted C1-C6 alkyl groups;

[0339] R 1-9-1 It is a halogen;

[0340] R 1-10 Halogen, C3-C8 cycloalkyl, C1-C6 alkyl;

[0341] R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, or substituted with one or more R 2-2 Substituted C3-C8 cycloalkyl groups;

[0342] R 2-1 It is a C3-C8 cycloalkyl group;

[0343] R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2-2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 Aryl; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0344] R 2-2-1 It is a halogen;

[0345] R 2-2-2 It is a halogen;

[0346] R 2-2-3 R 2-2-4 R 2-2-5 Each is independently an H or C1-C6 alkyl group;

[0347] R 2-2-6 It is a C1-C6 alkyl group;

[0348] R 2-2-7 It is halogenated or C1-C6 alkyl;

[0349] R 3 R 4 R 5 R 6 R 7 Each independently consists of H, halogen, -CR 5-13 R 5-14 R 5- 15 Or it may not exist;

[0350] R 5-0 For H;

[0351] R 5-1 H, C1-C6 alkyl, and formed by one or more R 5-1-1 Substituted C1-C6 alkyl groups;

[0352] R 5-1-1 It is C1-C6 alkoxy or halogen;

[0353] R 5-2 It is H, C1-C6 alkyl;

[0354] R 5-3 R 5-4 Each is independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 -(C=O)-R 5-3-3 Or R 5-3 R 5- 4 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, which is then bound by one or more R atoms. 5-4-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0355] R 5-3-1 R 5-3-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0356] R 5-3-3 It is a C1-C6 alkyl group, with one or more R 5-3-3-1 Substituted C1-C6 alkyl groups;

[0357] R 5-3-3-1 It is -Si(CH3)3;

[0358] R 5-4-1It is oxo, halogen, C1-C6 alkyl, or formed by one or more R 5-4-1-1 Substituted C1-C6 alkyl groups;

[0359] R 5-4-1-1 It is a halogen;

[0360] R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 Aryl; the heteroatom in the heteroaryl group is independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0361] R 5-5-1 It can be an oxide, -OH, C1-C6 alkyl, or halogen.

[0362] R 5-5-2 It is OH, C1-C6 alkyl, halogen; or R 5-5 R 5-6 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-6-1 The substituted 4-12 membered heterocyclic group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, and selenium, and the number of heteroatoms is independently 1, 2, or 3.

[0363] R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5- 6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups;

[0364] R 5-6-1-1 R 5-6-1-2 Each is independently H or C1-C6 alkyl;

[0365] R 5-6-1-3 It is a C3-C8 cycloalkyl group or a halogen.

[0366] R5-6-1-4 R 5-6-1-5 H and C1-C6 alkyl groups, each independently;

[0367] R 5-6-1-6 It is a halogen;

[0368] R 5-6-1-7 It is an oxidized, C1-C6 alkyl group; n1 is 0, 1 or 2;

[0369] R 5-7 It is H, C1-C6 alkyl;

[0370] R 5-8 C1-C6 alkyl, NR 5-8-1 R 5-8-2 ;

[0371] R 5-8-1 For H;

[0372] R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ;

[0373] R 5-8-2-1 R 5-8-2-2 Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0374] R 5-9 For H;

[0375] R 5-10 H, 5-14-membered heteroaryl, surrounded by one or more R 5-10-1 The substituted heteroaryl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0376] R 5-10-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-10-1-1 Substituted C1-C6 alkyl groups;

[0377] Or R 5-9 R 5-10 The C atoms bonded to it together form a carbonyl group;

[0378] R 5-11 For H;

[0379] R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ;

[0380] R 5-12-1 R 5-12-2Each can be independently H, C1-C6 alkyl, or C3-C8 cycloalkyl;

[0381] Or R 5-11 R 5-12 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-11-1 Substituted 4-12 membered heterocyclic groups;

[0382] R 5-11-1 It is an oxo, C1-C6 alkyl group, or formed by one or more R groups. 5-11-1-1 Substituted C1-C6 alkyl groups;

[0383] R 5-11-1-1 It is a halogen;

[0384] R 5-13 For H;

[0385] R 5-14 It is a C1-C6 alkyl group;

[0386] R 5-15 It is a 4-12 membered heterocyclic group, surrounded by one or more R 5-15-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0387] R 5-15-1 It is an oxo- or C1-C6 alkyl group;

[0388] n2 is 0, 1, or 2;

[0389] Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N;

[0390] m is 0 or 1.

[0391] In one embodiment, a compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 for

[0392] In one embodiment, a compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 2 for

[0393] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 3 R 4 R 5 R 6 R 7 In the middle, the aforementioned The structural formula is as follows:

[0394] Among them, ring A is a 4-12 membered heterocyclic group.

[0395] R 5-6-1 C1-C6 alkyl, C 5- C 12 aryl, oxo, with one or more R 5-6-1-6 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, or substituted with one or more R 5-6-1-10 Substituted C3-C8 cycloalkyl groups;

[0396] R 5-6-1-6 It is a halogen;

[0397] R 5-6-1-10 It is a C1-C6 alkyl group, with one or more R 5-6-1-10-1 Substituted C1-C6 alkyl groups;

[0398] R 5-6-1-10-1 Halogen

[0399] n2 can be 0, 1, 2, or 3.

[0400] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 3 R 4 R 5 R 6 R 7 In the middle, the aforementioned The structural formula is as follows:

[0401] In one embodiment, a compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite R 3 For H; R 4 For H; R 6 For H; R 7 It is a halogen, preferably F; R 5 for -CR 5-13 R5-14 R 5-15 n1 is 1; n2 is 1; Y 1 Y 2 Y 3 Y 4 Y 5 All are C. In one possible solution, n can also be 0.

[0402] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein n1 is 0 or 1, preferably 0; when n1 is 0, R 5 middle for When n1 is 1, R 5 middle

[0403] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite, has the structural formula shown in Formula Ia below:

[0404] Among them, R 1 R 2 R 3 R 4 R 6 R 7 R 8 Y 1 Y 2 Y 3 Y 4 Y 5 R 5-0 R 5-1 R 5-2 R 5-3 R 5-4 R 5-5 R 5-6 The definitions of m and n1 are as described above.

[0405] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof is characterized by having a structural formula as shown in Formula Ia-1:

[0406] Where t-1 is 0, 1, 2, 3, 4, 5, 6 or 7;

[0407] R 1 R 2 R 3 R4 R 6 R 7 R 8 Y 1 Y 2 Y 3 Y 4 Y 5 R 5-0 R 5-1 R 5-2 R 5-3 R 5-4 R 5-5 R 5-6 R 5- 6-1 The definitions of m and n1 are as described above.

[0408] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein...

[0409] for

[0410] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, wherein its structural formula is shown in Formula Ib below:

[0411] Among them, R 1-10-a It is halogenated or C1-C6 alkyl;

[0412] R 1-10-b R 1-10-c Each is independently hydrogen, halogenated, deuterated, C3-C8 cycloalkyl, or oxidized by one or more R groups. 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl groups, 3-12 membered heterocyclic groups, -NR 1-10-3 R 1-10-4 , by one or more R 1-10-5 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-10-6 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0413] R 1-10-1 Halogenated, C1-C6 alkyl, deuterated;

[0414] R 1-10-2For deuterated, halogenated, -NR 1-10-2-1 R 1-10-2-2 ;

[0415] R 1-10-2-1 R 1-10-2-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0416] R 1-10-3 R 1-10-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0417] R 1-10-5 It is halogenated or C1-C6 alkyl;

[0418] R 1-10-6 It is halogenated or C1-C6 alkyl;

[0419] Among them, R 2 R 3 R 4 R 6 R 7 R 8 Y 1 Y 2 Y 3 Y 4 Y 5 The definitions of m are as described above.

[0420] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, wherein its structural formula is shown in Formula Ib-1 below:

[0421] Among them, R 1-10-a It is halogen, C1-C6 alkyl, or cyano;

[0422] R 1-10-b R 1-10-c Each is independently hydrogen, halogenated, deuterated, C3-C8 cycloalkyl, or oxidized by one or more R groups. 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl groups, 3-12 membered heterocyclic groups, -NR 1-10-3 R 1-10-4 , by one or more R 1-10-5 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-10-6 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3;

[0423] R 1-10-1 Halogenated, C1-C6 alkyl, deuterated;

[0424] R 1-10-2 For deuterated, halogenated, -NR 1-10-2-1 R 1-10-2-2 ;

[0425] R 1-10-2-1 R 1-10-2-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0426] R 1-10-3 R 1-10-4 Each is independently hydrogen or a C1-C6 alkyl group;

[0427] R 1-10-5 It is halogenated or C1-C6 alkyl;

[0428] R 1-10-6 It is halogenated or C1-C6 alkyl;

[0429] Among them, R 2 R 3 R 4 R 6 R 7 R 8 Y 1 Y 2 Y 3 Y 4 Y 5 R 5-0 R 5-1 R 5-2 R 5-3 R 5-4 R 5-5 R 5-6 The definitions of m and n1 are as described above.

[0430] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 For vinyl or the one or more R 1-10 Substituted vinyl.

[0431] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1-10 It is a halogen; preferably F.

[0432] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-5 R 5-6 The N atoms connected to it together form a 7-membered spiroheterocyclic group or are bonded by one or more R atoms. 5-6-1 Substituted 7-membered spiroheterocyclic group.

[0433] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-6-1 It is a halogen; preferably F.

[0434] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-3 and R 5-4 H and -(C=O)-NR respectively 5-3-1 R 5-3-2 .

[0435] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-3-1 and R 5-3-2 They are C1-C6 alkyl and C3-C8 cycloalkyl, respectively.

[0436] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 For vinyl or the one or more R 1-10 Substituted vinyl. R 1-10 It is a halogen. R 5-5 R 5-6 The N atoms connected to it together form a 7-membered spiroheterocyclic group or are bonded by one or more R atoms. 5-6-1 Substituted 7-membered spiroheterocyclic group. R 5-6-1 It is a halogen. R 5-3 and R 5-4 H and -(C=O)-NR respectively 5-3-1 R 5-3-2 R 5-3-1 and R 5-3-2 They are C1-C6 alkyl and C3-C8 cycloalkyl, respectively.

[0437] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 for

[0438] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-5 R 5-6 Together with the N atoms connected to it, they form

[0439] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-3 and R 5-4 H and -(C=O)-NR respectively 5-3-1 R 5-3-2 .

[0440] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-3-1 and R 5-3-2 They are methyl and cyclopropyl, respectively.

[0441] In one embodiment, the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 for R 5-5 R 5-6 Together with the N atoms connected to it, they form R 5-3 and R 5-4 H and -(C=O)-NR respectively 5-3-1 R 5-3-2 R 5-3-1 and R 5-3-2 They are methyl and cyclopropyl, respectively.

[0442] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, satisfies one or more of the following conditions:

[0443] (1)R 2-2-1 R 2-2-2 R 2-2-7 R 3R 4 R 5 R 6 R 7 R 5-1-1 R 5-4-1 R 5-4-1-1 R 5-5-1 R 5-11-1-1 R 2-2-8 R 5-5-3 R 5-6-1-10-1 R 5-10-1-1 R 1-9 R 1-10-1 R 1-10-2 R 1-10-5 R 1-10-6 R 1-14 R 1-15 R 1-16 R 1-17 R 5-1-2 R 2- 1 R 5-3-3-1 R 5-3-3-3 R 5-3-3-5 R 5-6-1-14 R 1-1 R 1-2 R 1-3 R 1-1-1 R 5-6-1-15 R 1-4-1-1 R 1-5-1 In this context, the halogen is independently F, Cl, Br, or I; preferably F;

[0444] (2)R 1-1 R 1-2 R 1-3 R 1-4 R 2 R 2-2-6 R 2-2-7 R 5-1 R 5-2 R 5-3-1 R 5-3-2 R 5-3-3 R 5-4-1 R 5-5 R 5-6 R 5-5-1 R 5-5-2 R 5-6-1 R 5-6-1-1 R 5-6-1-2 R 5-7 R 5-8 R 5-8-2-1 R 5-8-2-2 R 5-10-1 R 5-12-1 R 5-12-2 R5-11-1 R 5-3-4 R 5-5-3 R 5-5-4 R 5-5-5-1 R 5-5-5-2 R 5-5-3-1 R 5-5-3-2 R 5-5-3-3-1 R 5-5-3-3-2 R 5-5-3-4 R 5-5-3-5 R 5-5-4 R 5-6-1-8 R 5-6-1-9 R 5-6-1-10 R 1 R 1-8-1 R 1-10-1 R 1-10-2-1 R 1-10-2-2 R 1-10-3 R 1-10-4 R 1-10-5 R 1-10-6 R 1- 11 R 1-12 R 1-13 R 1-15 R 1-16 R 1-17-1 R 1-17-2 R 5-1-2 R 5-3 R 5-4 R 5-3-1-1 R 5-3-3-2 R 5-3-3-4 R 5-3-5- 1 R 5-3-5-2 R 5-3-5-3-1 R 5-3-5-3-2 R 5-3-6 R 5-6-1-14 In the above, the C1-C6 alkyl group, the C1-C6 alkyl group substituted with one or more substituents, wherein the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0445] (3)R 2-2 R 5-3-3 R 1 R 5-6-1 In this context, the alkenyl group of C2-C6 is vinyl or propenyl;

[0446] (4)R 1-1 R 1-2 R 1-3 R 1-4 R 2 R 2-1 R 5-3-1R 5-3-2 R 5-8-2-1 R 5-8-2-2 R 5-12-1 R 5-12-2 R 5-5 R 5- 6 R 5-6-1 R 1-8 R 1-11 R 1-12 R 1-13 R 5-1 R 1-10 R 5-1 R 5-3 R 5-4 R 5-3-3 R 5-3-3-1 R 5-3-3-4 R 5-5-5 R 1-17 In the context, the C3-C8 cycloalkyl group, with one or more R 4-1 The C3-C8 cycloalkyl group substituted is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, preferably cyclopropane;

[0447] (5)R 2-2 R 5-3 R 5-4 In the context of the 4-12 membered heterocyclic group and one or more R groups, 2-2-6 The substituted 4-12 membered heterocyclic groups are either monocyclic heterocyclic groups or independently 5, 6, or 7 membered heterocyclic groups;

[0448] (6)R 5-3 R 5-4 In the 4-12 membered heterocyclic group formed by the N atom connected thereto, the 4-12 membered heterocyclic group and the one or more R atoms 5-4-1 In the substituted 4-12 membered heterocyclic groups, the 4-12 membered heterocyclic alkyl group is a monocyclic heterocyclic group, which is independently a 5, 6 or 7 membered heterocyclic alkyl group;

[0449] (7)R 5-5 R 5-6 The N atoms connected to it together form the 4-12 membered heterocyclic group described in the 4-12 membered heterocyclic group, which is affected by one or more R atoms. 5-6-1 The substituted 4-12 membered heterocyclic group is either a 5-7 membered monocyclic heterocyclic group or a 7-12 membered spirocyclic heterocyclic group;

[0450] (8)R 5-11 R 5-12 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-11-1The 4-12-membered heterocyclic group mentioned in the substituted 4-12-membered heterocyclic group is a 5-7-membered monocyclic heterocyclic group;

[0451] (9)R 5-5 R 5-6 In the context, the 5-14 membered heteroaryl group and one or more R groups 5-5-1 In the substituted 5-14 membered heteroaryl group, 5-14 is a 5-6 membered monocyclic heteroaryl group;

[0452] (10)R 5-5 R 5-6 In the context of C5-C 12 aryl aryl and one or more of the R 5-5-2 Replacement C5-C 12 C5-C in aryl 12 The aryl group is C7-C. 12 Fused polycyclic aryl groups;

[0453] (11)R 1 R 5-5 R 5-6 R 5-5-3 R 5-5-4 In this context, the C2-C6 ynyl group refers to ethynyl or propynyl.

[0454] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 2-2-1 R 2-2-2 R 2-2-7 R 3 R 4 R 5 R 6 R 7 R 5-1-1 R 5-4 - 1 R 5-4-1-1 R 5-5-1 R 5-11-1-1 R 2-2-8 R 5-5-3 R 5-6-1-10-1 R 5-10-1-1 R 1-9 R 1-10-1 R 1-10-2 R 1-10-5 R 1-10-6 R 1- 14 R 1-15 R 1-16 R 1-17 R 5-1-2 R 2-1 R 5-3-3-1R 5-3-3-3 R 5-3-3-5 R 2-2-9 R 2-2-10 R 5-3-1-1-1 R 5-3-1-1-2 R 5-3-1- 2 R 5-3-3-1-1 R 5-6-1-11 R 5-6-1-12 R 5-6-1-14 R 1-1 R 1-2 R 1-3 R 1-1-1 R 5-6-1-15 In this context, the halogen is independently F, Cl, Br, or I; preferably F.

[0455] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1-1 R 1-2 R 1-3 R 1-4 R 2 R 2-2-6 R 2-2-7 R 5-1 R 5-2 R 5-3 - 1 R 5-3-2 R 5-3-3 R 5-4-1 R 5-5 R 5-6 R 5-5-1 R 5-5-2 R 5-6-1 R 5-6-1-1 R 5-6-1-2 R 5-7 R 5-8 R 5-8-2-1 R 5-8-2-2 R 5- 10-1 R 5-12-1 R 5-12-2 R 5-11-1 R 5-3-4 R 5-5-3 R 5-5-4 R 5-5-5-1 R 5-5-5-2 R 5-5-3-1 R 5-5-3-2 R 5-5-3-3-1 R 5-5- 3-3-2 R 5-5-3-4 R 5-5-3-5 R 5-5-4R 5-6-1-8 R 5-6-1-9 R 5-6-1-10 R 1 R 1-8-1 R 1-10-1 R 1-10-2-1 R 1-10-2-2 R 1-10- 3 R 1-10-4 R 1-10-5 R 1-10-6 R 1-11 R 1-12 R 1-13 R 1-15 R 1-16 R 1-17-1 R 1-17-2 R 5-1-2 R 5-3 R 5-4 R 5-3-1-1 R 5-3-3-2 R 5-3-3-4 R 5-3-5-1 R 5-3-5-2 R 5-3-5-3-1 R 5-3-5-3-2 R 5-3-6 R 2-2-9 R 2-2-10 R 5-3-1-1-1 R 5-3-1-1- 2 R 5-3-1-2 R 5-3-3-1-1 R 5-6-1-11 R 5-6-1-12 R 5-6-1-14 In the C1-C6 alkyl group, the C1-C6 alkyl group that has been substituted by one or more alkyl groups, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0456] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 2-2 R 5-3-3 R 1 R 5-6-1 In this context, the C2-C6 alkenyl groups are vinyl or propenyl.

[0457] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1-1 R 1-2 R 1-3 R 1-4 R2 R 2-1 R 5-3-1 R 5-3-2 R 5-8-2-1 R 5-8-2-2 R 5-12-1 R 5-12-2 R 5-5 R 5-6 R 5-6-1 R 1-8 R 1-11 R 1-12 R 1-13 R 5-1 R 1-10 R 5-1 R 5-3 R 5-4 R 5- 3-3 R 5-3-3-1 R 5-3-3-4 R 5-5-5 R 1-17 In the context, the C3-C8 cycloalkyl group, with one or more R 4-1 The substituted C3-C8 cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane, preferably cyclopropane.

[0458] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 2-2 R 5-3 R 5-4 In the context of the 4-12 membered heterocyclic group and one or more R groups, 2-2-6 The substituted 4-12-membered heterocyclic groups are either monocyclic heterocyclic groups or independently 5, 6, or 7-membered heterocyclic groups.

[0459] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-3 R 5-4 In the 4-12 membered heterocyclic group formed by the N atom connected thereto, the 4-12 membered heterocyclic group and the one or more R atoms 5-4-1 In the substituted 4-12 membered heterocyclic groups, the 4-12 membered heterocyclic alkyl group is a monocyclic heterocyclic group, which is independently a 5, 6 or 7 membered heterocyclic alkyl group.

[0460] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-5R 5-6 The N atoms connected to it together form the 4-12 membered heterocyclic group described in the 4-12 membered heterocyclic group, which is affected by one or more R atoms. 5-6-1 The substituted 4-12 membered heterocyclic groups are either 5-7 membered monocyclic heterocyclic groups or 7-12 membered spirocyclic heterocyclic groups.

[0461] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-11 R 5-12 The N atoms connected to it together form a 4-12 membered heterocyclic group, which is then bonded by one or more R atoms. 5-11-1 The 4-12-membered heterocyclic group mentioned in the replaced 4-12-membered heterocyclic group is a 5-7-membered monocyclic heterocyclic group.

[0462] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-5 R 5-6 In the context, the 5-14 membered heteroaryl group and one or more R groups 5-5-1 In the substituted 5-14 membered heteroaryl group, 5-14 is a 5-6 membered monocyclic heteroaryl group.

[0463] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-5 R 5-6 In the context of C5-C 12 aryl aryl and one or more of the R 5-5-2 Replacement C5-C 12 C5-C in aryl 12 The aryl group is C7-C. 12 Fused polycyclic aryl groups.

[0464] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 R 5-5 R 5-6 R 5-5-3 R 5-5-4 In this context, the C2-C6 ynyl group refers to ethynyl or propynyl.

[0465] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1-8 R2-2 R 5-5 R 5-6 R 5-6-1 In the context of C5-C 12 Aryl groups and the C5-C groups substituted with one or more substituents. 12 The aryl group is independently C6-C 12 Aryl group, preferably C6-C 10 Aryl.

[0466] In one embodiment, the pharmaceutically acceptable salt of Formula I or thereof, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, satisfies one or more of the following conditions:

[0467] (1)R 1 for

[0468] (2)R 2 for

[0469] (3)R 3 For H and F;

[0470] (4)R 4 For H;

[0471] (5)R 6 For H;

[0472] (6)R 7 For H and F;

[0473] (7)R 5 for

[0474] (8)R 5 for

[0475] (9)R 5-0 For H;

[0476] (10)R 5-1 -CH3,

[0477] (11)R 5-2 For H;

[0478] (12) n1 is 0 or 1;

[0479] (13) n2 is 0 or 1;

[0480] (14) for

[0481] (15) for

[0482] (16)R 5-7 For H, -CH3;

[0483] (17)R 5-8 -CH3,

[0484] (18)R 5-9 For H;

[0485] (19)R 5-10 For H,

[0486] (20) for

[0487] (21)Y 1 Y 2 Y 3 Y 4 Y 5 All are C.

[0488] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 It can also be used for

[0489] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5It can also be used for

[0490] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, satisfies one or more of the following conditions:

[0491] (1)R 1 for -CF3、

[0492] (2)R 2 for

[0493] (3)R 5 for

[0494] (4) m is 0 or 1;

[0495] (5)R 3 It is H or a halogen, preferably H or F;

[0496] (6)R 4 For H;

[0497] (7)R 6 For H;

[0498] (8)R 7 For H;

[0499] (9)R 8 For H;

[0500] (10)Y 1 It is C or N; preferably, Y 1 The answer is C;

[0501] (11)Y 2 The answer is C;

[0502] (12)Y 3 The answer is C;

[0503] (13)Y 4 The answer is C;

[0504] (14)Y 5 The answer is C;

[0505] Preferably, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite satisfies the above condition (3).

[0506] More preferably, the compound of Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite, satisfies the above conditions (1), (2) and (3);

[0507] Ideally, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite satisfies the above conditions (1)-(14).

[0508] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, satisfies one or more of the following conditions:

[0509] (1)R 1 for -CF3、

[0510] (2)R 2 for

[0511] (3)R 5 for

[0512] (4) m is 0 or 1;

[0513] (5)R 3 It is H or a halogen, preferably H or F;

[0514] (6)R 4 For H;

[0515] (7)R 6 For H;

[0516] (8)R 7 For H;

[0517] (9)R 8 For H;

[0518] (10)Y 1 It is C or N; preferably, Y 1 The answer is C;

[0519] (11)Y 2 The answer is C;

[0520] (12)Y 3 The answer is C;

[0521] (13)Y 4 The answer is C;

[0522] (14)Y 5 The answer is C;

[0523] Preferably, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite satisfies the above condition (3).

[0524] More preferably, the compound of Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite, satisfies the above conditions (1), (2) and (3);

[0525] Ideally, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite satisfies the above conditions (1)-(14).

[0526] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, satisfies one or more of the following conditions:

[0527] (1)R 1 for -CF3、

[0528] (2)R 2 for

[0529] (3)R 5 for

[0530] (4) m is 0 or 1;

[0531] (5)R 3 It is H or a halogen, preferably H or F;

[0532] (6)R 4 For H;

[0533] (7)R 6 For H;

[0534] (8)R 7 For H;

[0535] (9)R 8 For H;

[0536] (10)Y 1 For C or N; preferred, Y 1 The answer is C;

[0537] (11)Y 2 The answer is C;

[0538] (12)Y 3 The answer is C;

[0539] (13)Y 4 The answer is C;

[0540] (14)Y 5 The answer is C;

[0541] Preferably, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite satisfies the above condition (3).

[0542] More preferably, the compound of Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite, satisfies the above conditions (1), (2) and (3);

[0543] Ideally, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite satisfies the above conditions (1)-(14).

[0544] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 1 for

[0545] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R1 for

[0546] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 2 for

[0547] ;

[0548] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 3 For H and F.

[0549] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 4 For H.

[0550] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 6 For H.

[0551] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 7 For H and F.

[0552] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5 for

[0553] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5 For

[0554] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5 for

[0555] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-0 For H.

[0556] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-1 -CH3,

[0557] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-2 For H.

[0558] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite, wherein n1 is 0 or 1.

[0559] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite, wherein n2 is 0 or 1.

[0560] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein, for

[0561] -NHCH3、

[0562] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein, for

[0563] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein, for

[0564] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein, for

[0565] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-7 It is H, -CH3.

[0566] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-8 -CH3,

[0567] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-9 For H.

[0568] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein R 5-10 For H,

[0569] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein, for

[0570] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein Y 1 For C or N, Y 2 Y 3 Y 4 Y 5 All are C.

[0571] In one embodiment, the compound represented by Formula I or its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, wherein Y 1 Y 2 Y 3 Y 4 Y 5 All are C.

[0572] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula I is any of the following compounds:

[0573] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula I is any of the following compounds:

[0574] The present invention also provides a pharmaceutical composition comprising: (1) a compound of formula I or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof or a metabolite thereof, and (2) a pharmaceutically acceptable excipient.

[0575] The present invention also provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing IL-17-mediated diseases or conditions. In the stated use, the IL-17-mediated diseases or conditions are selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, spondyloarthritis, and non-infectious uveitis.

[0576] In the aforementioned uses, the psoriasis refers to plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, or palmoplantar psoriasis.

[0577] Unless otherwise specified, the terms used in this invention have the following meanings:

[0578] 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.

[0579] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0580] 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.

[0581] 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.

[0582] 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.

[0583] The term "metabolites" refers to intermediate and final metabolites in metabolism.

[0584] The term "isotopic compound" refers to a compound in which one or more atoms exist in their non-natural abundance form. For example, the non-natural abundance of hydrogen atoms means that approximately 95% of them are deuterium.

[0585] 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.

[0586] 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.

[0587] 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.

[0588] “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.

[0589] The "prevention" mentioned in this invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0590] The expression "a group substituted by one or more substituents" means that one or more hydrogen atoms in that group are independently replaced by that substituent. When multiple substituents appear simultaneously, unless otherwise specified, their definitions are independent and do not affect each other. Therefore, if a group is substituted by one, two, or three R groups... 1 Group substitution, meaning that the group can be replaced by up to 3 R groups. 1 Replace, the position R 1 Definition and other positions R 1 The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0591] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0592] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0593] 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, n-hexyl, etc.

[0594] 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). 20 Alkylenes. 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.

[0595] The term "alkenyl" refers to a straight-chain or branched olefin having a specified number of carbon atoms (e.g., C2-C6) containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds can be internal or terminal. Examples of alkenes include vinyl, allyl, methyl vinyl, etc.

[0596] The term "alkoxy group" refers to the group -OR X R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0597] 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).

[0598] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0599] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0600] 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). 10 Spirocycloalkyl). 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:

[0601] 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). 10The 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:

[0602] 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). 12 Bridged 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:

[0603] 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). Non-limiting examples of the monocyclic heterocyclic group include:

[0604] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0605] 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:

[0606] 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 ...

[0607] 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:

[0608] 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:

[0609] 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:

[0610] In this invention, R 5-4-1 The oxygen substitution mentioned herein is a divalent group with the formula =O, such as a heterocyclic group. When the substituent is oxy, it can be...

[0611] In this invention, R 5-5-1 The oxidation mentioned refers to the oxidation of the heteroatom on the heteroaryl group, for example... When the substituent is oxidized, it can be used as...

[0612] 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.

[0613] The reagents and raw materials used in this invention are all commercially available.

[0614] The positive and progressive effects of the present invention are that the compounds of the present invention have one or more of the following effects: (1) better inhibition of IL-17 bioactivity; (2) better pharmacokinetic properties; (3) better oral bioavailability; (4) reduction of inflammation (especially arthritis). Attached Figure Description

[0615] Figure 1 is a graph showing the change in ankle joint thickness over time in rats in Example 4. Detailed Implementation

[0616] 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.

[0617] Example 1: Compound I-1

[0618] first step:

[0619] 3-(1,3-dioxoisoindol-2-yl)-2,2-difluoropropyltrifluoromethanesulfonate (0.34 g, 0.9 mmol), compound 1-1 (0.19 g, 0.33 mmol, prepared according to WO 2023164057), and N,N-diisopropylethylamine (1 mL) were added to 10 mL of acetonitrile and stirred at 70 °C for 48 h. The reaction solution was concentrated and passed through a column (methanol:dichloromethane = 0-20%) to give a white solid, compound 1-2 (0.24 g, 0.30 mmol, 91%). LC-MS: m / z: (M+H) + =805.4.

[0620] Step Two:

[0621] Compounds 1-2 (0.3 g, 0.37 mmol) were added to 15 mL of ethanol, followed by 1.5 mL of 30% hydrazine hydrate. The mixture was stirred overnight at room temperature. The reaction solution was concentrated and purified by reverse-phase column chromatography (methanol:water = 0-100%) to give a white solid, compound 1-3 (0.24 mg, 0.36 mmol, 95%). LC-MS: m / z: (M+H) + =675.4.

[0622] Step 3:

[0623] Compounds 1-3 (0.21 g, 0.31 mmol) and N,N'-carbonyldiimidazole (0.31 g, 1.92 mmol) were added to 10 mL of tetrahydrofuran and stirred overnight at 60 °C. The reaction solution was concentrated and passed through a column (methanol:dichloromethane = 0-20%), followed by high-performance liquid chromatography (HPLC) to prepare a white solid compound I-1 (140 mg, 0.20 mmol, 64%). LC-MS: m / z: (M+H) + =700.4.

[0624] 1 H NMR(400MHz,MeOD)δ8.39(s,1H),7.91–7.81(m,1H),7.53(d,J=2.1Hz,1H),7.25–7.10(m,2 H),6.87(t,J=1.9Hz,1H),5.47(dd,J=16.3,11.2Hz,1H),4.98(dd,J=7.1,4.4Hz,1H),4.56 (q,J=7.1Hz,2H),4.23–3.72(m,4H),3.71–3.54(m,2H),3.42(ddd,J=10.9,7.1,3.5Hz,1H) ,3.21–2.46(m,3H),2.43–2.11(m,4H),1.76–1.23(m,7H),1.08–0.77(m,6H),0.42(m,8H).

[0625] Example 2: Compound I-2

[0626] first step:

[0627] To a solution of compound 2-1 (synthesis reference WO2024208228, 50 mg, 0.08 mmol) and 4,4-dimethyl-1,4-azasilane hydrochloride (14.80 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL), HATU (46.39 mg, 0.12 mmol) and triethylamine (24.59 mg, 0.24 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-2 (22 mg, 0.03 mmol, 37.23%) as a white solid. LC-MS: 729.7 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.95–7.86(m,1H),7.51(d,J=2.1Hz,1H),7.20–7.10(m,2H),6.89(d,J=2.1Hz,1H) ,4.96-4.88(m,1H),4.66–4.51(m,3H),3.84–3.68(m,2H),3.53–3.36(m,2H),3.29-3.20(m,1H),2.91( s,3H),2.64–2.49(m,3H),2.14–1.97(m,2H),1.95-1.82(m,3H),1.43-1.34(m,6H),1.33–1.18(m,2H), 1.00–0.90(m,2H),0.81–0.63(m,4H),0.52-0.42(m,1H),0.30-0.20(m,1H),0.04(s,3H),-0.08(s,3H).

[0628] Example 3: Compound I-3

[0629] first step:

[0630] To a solution of compound 2-1 (50 mg, 0.08 mmol) and 2-amino-N-methylacetamide (7.84 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL), HATU (46.39 mg, 0.12 mmol) and triethylamine (24.59 mg, 0.24 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-3 (27 mg, 0.04 mmol, 48.39%) as a pale yellow solid. LC-MS: 689.2 [M+1] +.1HNMR(400MHz,MeOD)δ7.83(t,J=8.2Hz,1H),7.51(d,J=2.1Hz,1H),7.24–7.07(m,2H),6.89(d,J= 2.1Hz,1H),4.65-4.51(m,3H),4.33(d,J=7.8Hz,1H),3.76(d,J=16.8Hz,1H),3.59(d,J=16.8Hz,1H) ,3.32–3.25(m,1H),2.88(s,3H),2.70(s,3H),2.64–2.49(m,3H),2.14–1.98(m,2H),1.96-1.83(m, 3H),1.45-1.35(m,6H),1.33–1.19(m,2H),0.97–0.83(m,2H),0.82-0.74(m,1H),0.70–0.60(m,1H).

[0631] Example 4: Compound I-4

[0632] Step 1:

[0633] To a solution of compound 4-1 (380.00 mg, 1.11 mmol) and methylamine hydrochloride (112.40 mg, 1.66 mmol) in N,N-dimethylformamide (5.00 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (633.10 mg, 1.66 mmol) and triethylamine (337.00 mg, 3.33 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 4-2 (350.00 mg, 0.98 mmol, 88.72%) as a pale yellow solid. LC-MS: 300.0 [M-56+1] + .

[0634] Step Two:

[0635] Palladium on carbon (50.00 mg) was added to a methanol (30.00 mL) solution of compound 4-2 (350.00 mg, 0.98 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was evaporated to dryness to give a pale yellow solid, compound 4-3 (280.00 mg, 0.86 mmol, 87.36%). LC-MS: 270.1 [M-56+1] + .

[0636] Step 3:

[0637] Sodium bicarbonate (209.18 mg, 2.49 mmol) was added to a tetrahydrofuran (10.00 mL) solution of compound 4-3 (270.00 mg, 0.83 mmol) and fluorenyl chloroformate (322.08 mg, 1.24 mmol). The reaction mixture was stirred at 60 °C under argon protection for 3 hours. The mixture was filtered, and the filtrate was concentrated to obtain a residue, which was purified by column chromatography to give a pale yellow solid, compound 4-4 (335.00 mg, 0.61 mmol, 73.70%). LC-MS: 603.8 [M+1] + .

[0638] Step Four:

[0639] Compound 4-4 (335.00 mg, 0.61 mmol) was added to methanol hydrochloride (12.00 mmol, 3.00 mL), and the reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried, and concentrated to give a yellow solid, compound 4-5 (270 mg, 0.60 mmol, 98.58%). LC-MS: 448.3 [M+1] + .

[0640] Step 5:

[0641] N,N-diisopropylethylamine (86.59 mg, 0.67 mmol) was added to a solution of compounds 4-5 (150.00 mg, 0.34 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (225.07 mg, 0.60 mmol) in acetonitrile (10.00 mL). The reaction mixture was stirred overnight at 50 °C under argon protection. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 4-6 (135.00 mg, 0.20 mmol, 60.09%). LC-MS: 671.3 [M+1] + .

[0642] Step Six:

[0643] Hydrazine hydrate (30.19 mg, 0.60 mmol) was added to a 3.00 mL ethanol solution of compounds 4-6 (135.00 mg, 0.20 mmol). The reaction mixture was stirred at 60 °C under argon protection for 2 hours. The reaction mixture was diluted with water and concentrated to obtain a residue, which was purified by column chromatography to give a pale yellow solid compound 4-7 (80.00 mg, 0.15 mmol, 73.63%). LC-MS: 541.2 [M+1]+ .

[0644] Step Seven:

[0645] N,N'-carbonyldiimidazole (72.00 mg, 0.44 mmol) was added to a tetrahydrofuran (5.00 mL) solution of compounds 4-7 (80.00 mg, 0.15 mmol). The reaction mixture was stirred at 60 °C under argon protection for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 4-8 (42.00 mg, 0.074 mmol, 50.06%). LC-MS: 567.7 [M+1] + .

[0646] Step 8:

[0647] To a solution of compounds 4-8 (42.00 mg, 0.07 mmol) in N,N-dimethylformamide (2.00 mL), piperidine (12.60 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compounds 4-9 (22.00 mg, 0.064 mmol, 86.34%) as a white solid. LC-MS: 344.8 [M+1] + .

[0648] Step Nine:

[0649] To a solution of compound 4-9 (22.00 mg, 0.06 mmol) and (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropylpropionic acid (34.48 mg, 0.13 mmol) in pyridine (3.00 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61.34 mg, 0.32 mmol) was added. The reaction mixture was stirred overnight at room temperature under argon protection. Pyridine was removed by vacuum distillation, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 4-10 (28.00 mg, 0.047 mmol, 73.49%) as a pale yellow solid. LC-MS: 540.8 [M-56+1] + .

[0650] Step 10:

[0651] Compound 4-10 (28 mg, 0.047 mmol) was added to a 2.00 mL (8 mmol) solution of hydrochloric acid and methanol, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give a yellow solid, compound 4-11 (22.00 mg, 0.044 mmol, 94.42%). LC-MS: 495.8 [M+1] + .

[0652] Step Eleven:

[0653] To a solution of 2-isopropylpyrazole-3-carboxylic acid (8.79 mg, 0.06 mmol) and compound 4-11 (22.00 mg, 0.044 mmol) in N,N-dimethylformamide (2.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (25.10 mg, 0.07 mmol) and triethylamine (8.90 mg, 0.09 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain a residue, which was purified by preparative separation to give a pale yellow solid, compound I-4 (8.00 mg, 0.013 mmol, 28.78%). LC-MS: 631.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.84(t,J=8.0Hz,1H),7.54(d,J=2.0Hz,1H),7.17-7.08(m,2H),6 .81(d,J=2.0Hz,1H),5.48-5.35(m,1H),4.99(d,J=7.2Hz,1H),4.96-4.88(m,1H),4.02 -3.90(m,1H),3.86-3.75(m,1H),3.66-3.55(m,2H),3.39-3.33(m,1H),2.45(d,J=4.0H z,3H),1.53-1.43(m,6H),1.24(d,J=7.2Hz,3H),0.98-0.75(m,3H),0.62-0.20(m,8H).

[0654] Example 5: Compound I-5

[0655] Step 1:

[0656] Compound 2-1 (20 mg, 0.03 mmol) and N1,N1-dimethylbicyclo[1.1.1]pentane-1,3-diamine dihydrochloride (7.57 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (20 mg, 0.13 mmol) and HATU (20 mg, 0.04 mmol) were added, and the reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to give a white solid compound I-5 (14.28 mg, 0.02 mmol, 61.40%). LC-MS: 727.3 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),8.53(d,J=8.2Hz,1H),8.41(s,1H),7.70(t,J=8.3Hz,1H),7.49(d,J=2.0Hz,1H),7.08 (dd,J=12.2,1.4Hz,1H),7.04–6.98(m,2H),5.92(d,J=9.1Hz,1H),4.62(t,J=8.3Hz,1H),4.47(q,J=7.1Hz,2H),4.29(dd,J= 9.0,6.8Hz,1H),3.07(dd,J=13.9,6.9Hz,1H),2.71(s,3H),2.51–2.47(m,2H),2.42(s,2H),2.06(s,6H),2.01(d,J=8.7Hz, 1H),1.95–1.64(m,10H),1.29(t,J=7.1Hz,3H),1.23–1.08(m,4H),0.87–0.75(m,2H),0.70–0.63(m,1H),0.62–0.53(m,1H).

[0657] Example 6: Compound I-6

[0658] Step 1:

[0659] Compound 2-1 (10 mg, 0.015 mmol) and 3-ethyloxetane-3-amine hydrochloride (3.0 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and N,N-diisopropylethylamine (20 mg, 0.13 mmol) and HATU (10 mg, 0.02 mmol) were added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to give a white solid compound I-6 (4.5 mg, 0.006 mmol, 40.0%). LC-MS: 698.3 [M + H] + . 1 H NMR (400MHz, MeOD) δ7.83(t,J=8.3Hz,1H),7.52(d,J=2.1Hz,1H),7.13(t,J=8.8Hz,2H),6.89(d,J=2.1Hz,1H),5.36(t,J=8.8Hz 1H),4.69-4.57(m,3H),4.57-4.49(m,3H),4.43(d,J=8.4Hz,1H),3.23-3.14(m,1H),2.97(s,1H),2.89(s,3H),2.64-2.50(m,3H),2.2 2(t,J=7.6Hz,1H),2.11-2.00(m,3H),1.96-1.82(m,3H),1.70-1.60(m,1H),1.42-1.36(m,4H),0.94-0.89(m,3H),0.78-0.64(m,2H).

[0660] Example 7: Compound I-7, Compound I-8

[0661] Step 1:

[0662] Compound 2-1 (20 mg, 0.03 mmol) and tert-butyl (4-methylpiperidin-4-yl)carbamate (8.29 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (8.26 mg, 0.06 mmol) and T3P (10 mg, 50% in EA, 0.04 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid compound 7-1 (25 mg, 0.03 mmol, 95.79%). LC-MS: 814.7 [M + H]+ .

[0663] Step Two:

[0664] Compound 2-1 (25 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and dioxane hydrochloride solution (2 mL, 4 M, 8 mmol) was added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated, and the crude product was prepared by preparative HPLC to obtain a white solid compound I-7 (7.43 mg, 0.01 mmol, 33.53%). LC-MS: 715.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ8.57(s,1H),7.82(t,J=8.2Hz,1H),7.54–7.48(m,1H),7.25–7.08(m,2H),6.9 1(dd,J=11.0,2.1Hz,1H),4.65–4.47(m,3H),3.97(d,J=14.0Hz,1H),3.66-3.56(m,2H),3.31–3.07 (m,3H),3.06–2.94(m,1H),2.90(s,3H),2.61(ddd,J=15.9,8.0,4.3Hz,3H),2.07–2.02(m,5H),1. 64–1.47(m,2H),1.46–1.14(m,10H),1.13(s,2H),0.94(dd,J=13.2,6.8Hz,2H),0.80–0.65(m,2H).

[0665] Step 3:

[0666] Compound I-7 (22 mg, 0.03 mmol) and an aqueous formaldehyde solution (93 mg, 30%, 3.1 mmol) were dissolved in methanol (2 mL). Triethylamine (20 mg, 0.16 mmol), sodium cyanoborohydride (5.8 mg, 0.09 mmol), and acetic acid (4.38 mg, 0.07 mmol) were added, and the reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to preparative HPLC to obtain a white solid compound I-8 (9.48 mg, 0.01 mmol, 41.1%). LC-MS: 743.2 [M+H] + . 1H NMR (400MHz, MeOD) δ8.57(s,1H),7.85(t,J=8.2Hz,1H),7.73(s,1H),7.52(dd,J=4.0,2.1Hz,1H),7.23–7.09(m,2H),6.91(dd,J=11.1,2.0H z,1H),6.31(d,J=9.0Hz,1H),4.57(dt,J=14.3,7.7Hz,3H),3.91(s,1H),3.56(s,2H),3.28–2.95(m,2H),2.90(s,3H),2.66–2.51(m,3H),2.2 5(s,3H),2.05(s,1H),1.92(d,J=9.7Hz,2H),1.56(d,J=24.6Hz,1H),1.44–1.37(m,3H),1.27(dd,J=24.4,10.9Hz,3H),1.04(d,J=38.2Hz,1H ),0.95(s,2H),0.85(s,2H),0.76(s,2H).1.29(t,J=7.1Hz,3H),1.23– 1.08(m,4H),0.87–0.75(m,2H),0.70–0.63(m,1H),0.62–0.53(m,1H).

[0667] Example 8: Compound I-9

[0668] Step 1:

[0669] At -50°C, 2-difluoromethanesulfonylpyridine (1.02 g, 5.27 mmol) and compound 9-1 (1.25 g, 6.27 mmol) in N,N-dimethylformamide (15.00 mL) were added to a solution of potassium tert-butoxide (1.06 g, 9.41 mmol) and N,N-dimethylformamide (10 mL). The reaction mixture was stirred at this temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (4 mL) and 3N hydrochloric acid (9 mL) were added sequentially, and the reaction mixture was allowed to rise naturally to room temperature. The reaction mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with saturated brine, dried, and concentrated to give a yellow oily substance. Purification by column chromatography gave a white solid compound 9-2 (600.00 mg, 2.57 mmol, 41.00%). LC-MS: 178.2 [M-56+1] + .

[0670] Step Two:

[0671] To a solution of sodium iodide (98.63 mg, 0.66 mmol) and compound 9-2 (300.00 mg, 1.29 mmol) in tetrahydrofuran (10.00 mL), trifluoromethyltrimethylsilane (914.35 mg, 6.43 mmol) was added, and the reaction mixture was refluxed overnight under argon protection. The reaction mixture was diluted with ethyl acetate, washed with water, sodium sulfite solution, and saturated brine, dried, concentrated, and purified by column chromatography to give a colorless liquid compound 9-3 (210 mg, 0.74 mmol, 57.65%). LC-MS: 228.1 [M-56+1] + .

[0672] Step 3:

[0673] Dioxane hydrochloride (2.00 mL, 8.00 mmol) was added to compound 9-3 (210.00 mg, 0.74 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give compound 9-4 (135 mg, 0.74 mmol, 99.48%) as a white solid. LC-MS: 184.1 [M+1] +.

[0674] Step Four:

[0675] HATU (46.01 mg, 0.12 mmol) and triethylamine (24.59 mg, 0.24 mmol) were added to a solution of compound 2-1 (50 mg, 0.08 mmol) and compound 9-4 (19.2 mg, 0.11 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-9 (38 mg, 0.048 mmol, 59.85%) as a white solid. LC-MS: 784.4 [M+1] + . 1H NMR (400MHz, MeOD) δ7.85-7.77(m,1H),7.51(d,J=2.1Hz,1H),7.21-7.12(m,2H),6.88(d,J=2.1 Hz,1H),4.91-4.85(m,1H),4.65-4.51(m,3H),3.65-3.56(m,1H),3.46-3.40(m,2H),3.32-3.26( m,1H),3.23-3.13(m,1H),2.90(s,3H),2.66-2.49(m,3H),2.12-1.97(m,2H),1.95-1.84(m,3H) ,1.75-1.65(m,2H),1.43-1.37(m,6H),1.36-1.12(m,4H),0.98-0.90(m,2H),0.78-0.72(m,2H).

[0676] Example 9: Compound I-10

[0677] Step 1:

[0678] In a 100 mL round-bottom flask, HATU (20 mg, 0.05 mmol) and triethylamine (45 mg, 0.44 mmol) were added sequentially to a 10 mL solution of compound 2-1 (25 mg, 0.04 mmol) in dichloromethane. The reaction mixture was then stirred at room temperature for 0.5 hours. Compound 10-1 (7 mg, 0.05 mmol) was then added to the reaction mixture in one step, and the mixture was stirred at room temperature for 16 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0). ～ 1:1; Dichloromethane: Methanol = 1:0 ～ The target compound I-10 (55 mg, 0.091 mmol) was obtained as a white solid (20:1). LC-MS: 719.7 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.96(d,J=16.8Hz,1H),8.53(t,J=8.8Hz,1H),7.92-7.65(m,1H),7.49(s,1H),7.17(t,J=12.4 Hz,1H),7.12–7.04(m,1H),7.02(t,J=2.8Hz,1H),6.18(d,J=8.8Hz,1H),4.71-4.57(m,1H),4.47(q,J=7.6Hz,2H),4.35 -4.18(m,2H),3.94-3.85(m,1H),3.83-3.71(m,1H),3.70–3.58(m,1H),3.23–3.08(m,1H),2.75(s,3H),2.46-3.36(m, 2H),2.10-1.95(m,1H),1.94-1.72(m,4H),1.71-1.48(m,2H),1.36-1.07(m,9H),0.93–0.74(m,2H),0.69-0.53(m,2H).

[0679] Example 10: Compound I-11

[0680] Step 1:

[0681] HATU (68 mg, 0.179 mmol), 4-aminopyridine (17 mg, 0.181 mmol), and triethylamine (35 mg, 0.346 mmol) were added to a solution of compound 2-1 (100 mg, 0.162 mmol) in N,N-dimethylformamide (2 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, 8 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with saturated brine (7 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to give a grayish-white powder, compound I-11 (105 mg, 0.15 mmol, 93.3%). LC-MS: 695.4 [M + H] + . 1H NMR (400MHz, CD3OD) δ8.32(d,J=6.0Hz,2H),8.00(s,1H),7.76(t,J=8.4Hz,1H),7.51(d, J=2.0Hz,1H),7.48(m,1H),7.15(m,2H),6.89(d,J=2.0Hz,1H),6.34(d,J=8.4Hz,1H),4.6 4–4.45(m,4H),3.29(m,1H),3.01(s,3H),2.88(m,4H),2.64(m,1H),2.53(m,2H),2.01(m ,2H),1.85(m,2H),1.44–1.35(m,6H),1.31–1.18(m,2H),0.94(m,2H),0.84–0.67(m,2H).

[0682] Example 11: Compound I-12

[0683] Step 1:

[0684] HATU (14 mg, 0.0368 mmol), compound 12-1 (6 mg, 0.0327 mmol), and triethylamine (7 mg, 0.0692 mmol) were added to a solution of compound 2-1 (20 mg, 0.0323 mmol) in N,N-dimethylformamide (1 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, water (6 mL) was added, followed by extraction with ethyl acetate (8 mL x 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder, compound I-12 (10 mg, 0.013 mmol, 41.8%). LC-MS: 748.4 [M + H] + . 1 H NMR(400MHz,CD3OD)δ7.83(m,1H),7.52(t,J=2.0Hz,1H),7.15(m,2H),6.90(m,1H ),6.31(d,J=8.8Hz,1H),4.66–4.49(m,3H),3.52(m,2H),3.38(m,1H),3.24–3.11( m,2H),2.91(s,3H),2.62(m,1H),2.55(m,2H),2.05(m,3H),1.91(m,3H),1.65–1. 47(m,2H),1.39(m,6H),1.25(m,2H),1.18–1.02(m,3H),0.93(m,3H),0.76(m,2H).

[0685] Example 12: Compound I-13

[0686] Step 1:

[0687] Compound 2-1 (25 mg, 0.04 mmol) was dissolved in 2 mL of N,N-dimethylformamide. HATU (17 mg, 0.044 mmol) and DIPEA (21 mg, 0.16 mmol) were added sequentially to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Compound 13-1 (5 mg, 0.044 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated and purified by column chromatography, eluting with pure ethyl acetate to give a white solid, compound I-13 (12 mg, 0.018 mmol, 44.4%). LC-MS: 675.7 (M+H) + . 1 H NMR: (400MHz, CD3OD-d4) δ7.77(t,J=8.1Hz,1H),7.49(d,J=2.0Hz,1H),7.16-7.05(m,2H),6.87(d,J=2.0Hz ,1H),4.63-4.48(m,4H),3.63-3.57(m,1H),3.22-3.18(m,1H),2.84(s,3H),2.62-2.50(m,3H),2.32(s,1H), 2.21-2.17(m,1H),2.11-2.04(m,1H),2.00-1.95(m,1H),1.94-1.79(m,3H),1.66-1.51(m,1H),1.37(t,J=7. 1Hz, 3H), 1.30 (d, J = 5.4Hz, 3H), 1.11-1.00 (m, 1H), 0.92-0.83 (m, 3H), 0.76-0.69 (m, 1H), 0.68-0.59 (m, 1H).

[0688] Example 13: Compound I-14

[0689] Step 1:

[0690] Compound 2-1 (20 mg, 0.03 mmol) and compound 14-1 (4.34 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (13 mg, 0.10 mmol) and T3P (30 mg, 50% ethyl acetate solution, 0.05 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to give a white solid compound I-14 (14.46 mg, 0.02 mmol, 63.21%). LC-MS: 715.2 [M + H] + .1H NMR(400MHz,MeOD)δ7.85-7.72(m,1H),7.51(dd,J=2.0,1.2Hz,1H),7.23–7.10(m,2H),6.89(t,J=1.8Hz ,1H),6.34–6.24(m,1H),4.57-4.53(m,4H),3.84–3.80(m,1H),3.66–3.49(m,1H),3.27-3.14(m,2H),3.0 9–2.97(m,1H),2.90(d,J=2.3Hz,3H),2.89–2.76(m,1H),2.66–2.52(m,3H),2.40–2.15(m,6H),2.12–1.8 6(m,6H),1.77–1.53(m,1H),1.43-1.38(m,6H),1.34-1.21(m,2H),0.95-0.93(m,2H),0.80–0.70(m,2H).

[0691] Example 14: Compound I-15

[0692] Step 1:

[0693] HATU (14 mg, 0.0368 mmol), compound 15-1 (5 mg, 0.0374 mmol), and triethylamine (7 mg, 0.0692 mmol) were added to a solution of compound 2-1 (20 mg, 0.0323 mmol) in N,N-dimethylformamide (1 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, water (6 mL) was added, followed by extraction with ethyl acetate (8 mL x 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder, compound I-15 (10 mg, 0.014 mmol, 44.3%). LC-MS: 698.5 (M+H)+ . 1 H NMR (400MHz, CD3OD) δ7.80(t,J=8.8Hz,1H),7.52(d,J=2.0Hz,1H),7.24–7.06(m,2H),6.91(d,J=2. 0Hz,1H),6.24(d,J=8.8Hz,1H),4.62(m,1H),4.56(q,J=7.2Hz,2H),4.23–4.11(m,1H),3.98(m,1H) ,3.20–3.03(m,2H),2.91(s,3H),2.63(m,2H),2.55(m,2H),2.20(m,2H),2.05(m,2H),2.03–1.84(m ,4H),1.76(m,2H),1.61(m,2H),4.56(t,J=7.2Hz,3H),1.36–1.23(m,6H),0.94(m,2H),0.76(m,2H).

[0694] Example 15: Compounds I-16-A and I-16-B

[0695] Step 1:

[0696] Compound 2-1 (20 mg, 0.03 mmol) and compound 16-1 (7.71 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (20 mg, 0.13 mmol) and T3P (30 mg, 0.05 mmol) were added. The reaction solution was stirred at 20 °C for 16 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by SFC preparation.

[0697] White solid compound I-16-A (2.30 mg, 0.003 mmol, 9.51%), LC-MS: 748.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.78(t,J=8.2Hz,1H),7.51(d,J=2.0Hz,1H),7.15(t,J=8.3Hz,2H),6.88( d,J=2.1Hz,1H),6.28(d,J=9.2Hz,1H),4.99(t,J=9.7Hz,1H),4.59-4.52(m,3H),3.73(t,J=12.8H z,2H),3.27–3.05(m,3H),2.91(d,J=3.0Hz,3H),2.65–2.46(m,3H),2.15–1.98(m,2H),1.90-1.77 (m,3H),1.70-1.65(m,1H),1.59–1.46(m,2H),1.45–1.17(m,9H),1.00–0.84(m,4H),0.75(s,2H).

[0698] White solid compound I-16-B (2.23 mg, 0.003 mmol, 9.25%). LC-MS: 748.2 [M+H] + . 1 H NMR (400MHz, MeOD) δ7.87(t,J=8.3Hz,1H),7.51(d,J=2.1Hz,1H),7.18–7.02(m,2H),6.89(d,J=2.0Hz,1H),6.29( t,J=11.5Hz,1H),4.98(t,J=9.2Hz,1H),4.62(t,J=7.9Hz,1H),4.55(q,J=7.1Hz,2H),3.62(d,J=13.5Hz,1H),3.5 6–3.43(m,1H),3.31–3.23(m,1H),3.21–2.98(m,2H),2.90(d,J=4.8Hz,3H),2.62-2.59(m,3H),2.13–1.97(m,2H) ,1.90-1.86(m,3H),1.65-1.48(m,3H),1.43-1.21(m,9H),1.12-0.98(m,2H),0.94(d,J=4.4Hz,2H),0.74(s,2H).

[0699] Example 16: Compound I-17

[0700] Step 1:

[0701] To a solution of compound 2-1 (20 mg, 0.03 mmol) and propargylamine (3.52 mg, 0.06 mmol) in N,N-dimethylformamide (3 mL), HATU (18.25 mg, 0.05 mmol) and triethylamine (9.71 mg, 0.10 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-17 (16 mg, 0.024 mmol, 76.19%) as a white solid. LC-MS: 656.4 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.81(t,J=8.2Hz,1H),7.51(d,J=2.1Hz,1H),7.17-7.04(m,2H) ,6.89(d,J=2.1Hz,1H),4.63-4.51(m,3H),4.42(d,J=8.0Hz,1H),3.88-3.73(m,2H) ,3.28-3.18(m,1H),2.87(s,3H),2.69-2.45(m,4H),2.13-1.98(m,2H),1.97-1.83( m,3H),1.42-1.34(m,6H),1.31-1.19(m,2H),0.96-0.86(m,2H),0.78-0.63(m,2H).

[0702] Example 17: Compound I-18

[0703] Step 1:

[0704] Compound 2-1 (20 mg, 0.03 mmol) and (3-amino-2,2-difluorobicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (8.9 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (12.9 mg, 0.1 mmol) and T3P (30 mg, 50% in EA, 0.05 mmol) were added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, compound 18-1 (20 mg, 74.1%). MS (ESI, m / z): 834.7 [M+H] + .

[0705] Step Two:

[0706] Compound 18-1 (20 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and a solution of dioxane hydrochloride (2 mL, 4 M, 8 mmol) was added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated to give a white solid compound 18-2 (17.6 mg, 100%). MS (ESI, m / z): 734.7 [M+H] + .

[0707] Step 3:

[0708] Compound 18-2 (17.6 mg, 0.02 mmol) and an aqueous formaldehyde solution (72 mg, 30%, 2.4 mmol) were dissolved in methanol (2 mL). Triethylamine (12 mg, 0.12 mmol), sodium cyanoborohydride (4.52 mg, 0.07 mmol), and acetic acid (3.42 mg, 0.06 mmol) were added, and the reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to preparative HPLC to obtain a white solid compound I-18 (10.25 mg, 55.99%). MS (ESI, m / z): 763.2 [M+H] + . 1 H NMR (400MHz, MeOD) δ7.82(t,J=8.2Hz,1H),7.73(t,J=8.2Hz,1H),7.51(d,J=2.1Hz,1H),7.43–7.39(m,1H),7.12–7 .04(m,2H),6.89(d,J=2.1Hz,1H),4.62(d,J=8.5Hz,1H),4.55(dd,J=14.5,7.3Hz,2H),4.33(d,J=8.7Hz,1H),3.15 –3.09(m,1H),2.89(s,3H),2.63–2.50(m,3H),2.31(s,6H),2.19(d,J=10.1Hz,1H),2.13–1.98(m,3H),1.90(s,3H) ,1.75(d,J=15.9Hz,2H),1.40-1.33(m,5H),1.30-1.23(m,3H),0.92(d,J=6.2Hz,2H),0.75(dd,J=12.5,7.8Hz,2H).

[0709] Example 18: Compound I-19

[0710] Step 1:

[0711] Compound 2-1 (30 mg, 0.05 mmol), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (8.17 mg, 0.06 mmol), HATU (30 mg, 0.07 mmol), and DIPEA (10 mg, 0.10 mmol) were dispersed in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by separation and HPLC using a GF254 preparative chromatography plate (methanol:dichloromethane = 10%) to give a white solid compound I-19 (4 mg, 12%). LC-MS: 720.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.34–8.05(m,2H),7.48(d,J=1.8Hz,1H),7.15–6.89(m,3H),6.65(d,J=1.8Hz,1H),5.94–5.75(m,1H),4 .78–4.47(m,4H),4.09(dd,J=35.6,9.5Hz,1H),3.97–3.62(m,1H),3.49(d,J=9.0Hz,2H),3.32(dd,J=41.0,11.5Hz,1H),3.20– 3.02(m,1H),2.89(d,J=2.8Hz,3H),2.82(s,2H),2.52(dd,J=9.8,3.2Hz,3H),2.17(dd,J=14.0,10.3Hz,2H),2.12–2.02(m,1H ),1.94(t,J=13.6Hz,2H),1.80(s,2H),1.44(t,J=7.1Hz,3H),1.36(d,J=7.0Hz,2H),0.89(d,J=2.6Hz,2H),0.81–0.68(m,2H).

[0712] Example 19: Compound I-20

[0713] Step 1:

[0714] Compound 4-1 (100 mg, 0.29 mmol) and N-methylpiperazine (40 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (110 mg, 0.88 mmol) and T3P (370 mg, 50% ethyl acetate solution, 0.58 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (methanol / dichloromethane = 0-10%) to give a white solid compound 20-1 (120 mg, 96.82%). MS (ESI, m / z): 424.8 [M+H] + .

[0715] Step Two:

[0716] Compound 20-1 (170 mg, 0.4 mmol) was dissolved in a hydrochloric acid-methanol solution (4 M, 2 mL, 8 mmol). The reaction solution was stirred at 20 °C for 1 hour, and then concentrated to give a white solid compound 20-2 (129 mg, 99.43%). MS (ESI, m / z): 324.9 [M+H] + .

[0717] Step 3:

[0718] Compound 20-2 (150 mg, 0.46 mmol) and N-methyl-4-piperidinone (105 mg, 0.93 mmol) were dissolved in dimethyl sulfoxide (3 mL), and triethylamine (233 mg, 2.31 mmol), sodium cyanoborohydride (87 mg, 1.39 mmol), and acetic acid (66 mg, 1.10 mmol) were added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was purified by reverse-phase preparative column chromatography (methanol / water = 0-95%) to give a yellow solid compound 20-3 (50 mg, 25.68%). MS (ESI, m / z): 421.9 [M+H] + .

[0719] Step Four:

[0720] Compound 20-3 (50 mg, 0.12 mmol) was dissolved in isopropanol (5 mL), and 10% wetted palladium on carbon (45 mg) was added. The reaction mixture was stirred at room temperature under hydrogen (15 psi) for 16 hours. The reaction mixture was filtered and concentrated to give a white solid, compound 20-4 (46 mg, 96.57%). MS (ESI, m / z): 391.9 [M+H] + .

[0721] Step 5:

[0722] Compound 20-4 (45 mg, 0.12 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-2-(4-(difluoromethylene)cyclohexyl)acetic acid (40 mg, 0.14 mmol) were dissolved in pyridine (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.58 mmol) was added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (dichloromethane / methanol = 10 / 1) to give white compound 20-5 (10 mg, 12.80%). MS (ESI, m / z): 678.8 [M+H] + .

[0723] Step Six:

[0724] Compound 20-5 (10 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and dioxane hydrochloride solution (4 M, 2 mL, 8 mmol) was added at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour, and then concentrated to give a white solid compound 20-6 (8.68 mg, 100%). MS (ESI, m / z): 578.9 [M+H] + .

[0725] Step Seven:

[0726] Compound 20-6 (8.68 mg, 0.02 mmol) and 1-isopropyl-1H-pyrazole-5-carboxylic acid (2.77 mg, 0.02 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (5.8 mg, 0.04 mmol) and HATU (8.75 mg, 0.02 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative HPLC to obtain compound 1-20 (2.63 mg, 24.53%) as a white solid. MS (ESI, m / z): 715.3 [M+H] + . 1H NMR(400MHz,MeOD)δ8.40(s,2H),7.78(t,J=8.1Hz,1H),7.53(s,1H),7.18(d,J=11.9Hz,1H),7.12 (d,J=8.6Hz,1H),6.82(s,1H),5.42(dd,J=13.3,6.7Hz,1H),4.59(d,J=8.3Hz,1H),3.75(d,J=8.1 Hz,2H),3.47(d,J=25.7Hz,4H),3.05(s,2H),2.90(s,1H),2.82(s,3H),2.57-2.46(m,5H),2.28(d ,J=15.5Hz,3H),2.11-1.79(m,11H),1.52–1.44(m,6H),1.42(d,J=6.9Hz,3H),1.37–1.17(m,3H).

[0727] Example 20: Compound I-21

[0728] Step 1:

[0729] HATU (14 mg, 0.0368 mmol), 2-trifluoromethyl-morpholine hydrochloride (7 mg, 0.0374 mmol), and triethylamine (7 mg, 0.0692 mmol) were added to a solution of compound 2-1 (20 mg, 0.0323 mmol) in N,N-dimethylformamide (1 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give a grayish-white powder of the formate of compound I-21 (10 mg, 0.013 mmol, 41.4%). LC-MS: M / Z = 756.4 (M + H) + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 0.78H) (formic acid), 7.92–7.68 (m, 1H), 7.52 (d, J = 2.0Hz, 1H), 7.18 (m, 2H), 6.89 (m, 1H), 6.36 (m, 1H), 4.80 (m, 2H), 2.03 (m, 3H), 1.45 (m, 2H), 1.39 (m, 3H), 1.35–1.19 (m, 3H), 0.95 (m, 2H), 0.76 (m, 2H).

[0730] Example 21: Compound I-22

[0731] Step 1:

[0732] In a 100 mL round-bottom three-necked flask placed in an ice-water bath, NaH (60%, 106 mg, 2.65 mmol) was added dropwise to an anhydrous tetrahydrofuran solution (10 mL) of compound 22-1 (250 mg, 2.21 mmol), and the mixture was stirred for 15 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (405 mg, 2.43 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The consumption of the starting material was monitored by LC-MS. The reaction mixture was placed in an ice-water bath, and a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The combined extracts were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–3:1) to give compound 22-2 (420 mg, 1.96 mmol, 78.2%) as a white solid. LC-MS: m / z = 114.2 [M-SEM+H] + .

[0733] Step Two:

[0734] In a 100 mL round-bottom flask, palladium on carbon (10%, 12 mg) was added to 20 mL of methanol containing compound 22-2 (120 mg, 0.49 mmol). The reaction mixture was then placed under a hydrogen atmosphere and stirred at room temperature for 2 hours. The starting materials were monitored by LC-MS until consumed. Ethyl acetate was added dropwise to dilute the reaction mixture, which was then filtered through diatomaceous earth. The resulting filtrate was concentrated under reduced pressure, yielding a white solid, compound 22-3 (120 mg, 0.49 mmol), which was used directly in the next step without purification. LC-MS: m / z = 214.2 [M+H] + .

[0735] Step 3:

[0736] In a 100 mL round-bottom flask, HATU (37 mg, 0.097 mmol) and triethylamine (15 mg, 0.13 mmol) were added sequentially to a 5 mL solution of N,N-dimethylformamide containing compound 2-1 (40 mg, 0.065 mmol). The reaction mixture was then stirred at room temperature for 0.5 hours. Compound 22-3 (18 mg, 0.084 mmol) was added to the reaction mixture in one step, and the mixture was stirred at room temperature for 16 hours. The consumption of the starting materials was monitored by LC-MS. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to obtain a white solid compound 22-4 (50 mg, 0.061 mmol, 94.7%). LC-MS: m / z = 814.5 [M+H] + .

[0737] Step Four:

[0738] In a 100 mL round-bottom flask, tetrabutylammonium fluoride solution (1 M, 0.12 mL, 0.12 mmol) was added to 15 mL of anhydrous tetrahydrofuran solution of compound 22-4 (50 mg, 0.061 mmol). The reaction mixture was then heated to reflux and stirred for 3 hours. LC-MS monitoring showed that the starting material was completely consumed. The reaction mixture was then reduced under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 1:0). ～ 1:1; Dichloromethane: Methanol = 1:0 ～ The reaction was carried out at a ratio of 20:1, yielding a white solid compound I-22 (20 mg, 0.029 mmol, 50.0%). LC-MS: m / z = 684.4 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ7.85-7.74(m,1H),7.71–7.63(m,1H),7.62-7.54(m, 1H),7.53-7.46(m,1H),7.30–7.10(m,2H),6.90-6.86(m,1H),4.95-4.86(m,1H), 4.69–4.49(m,4H),2.88(s,2H),2.80(s,1H),2.65–2.42(m,3H),2.17-1.82(m,5H ),1.42–1.35(m,6H),1.34–1.18(m,3H),0.92(d,J=6.5Hz,1H),0.83–0.61(m,2H).

[0739] Example 22: Compound I-23

[0740] Step 1:

[0741] HATU (1.2 g, 3.214 mmol), 4,4-dimethyl-1,4-azasilane hydrochloride (533 mg, 3.216 mmol), and triethylamine (621 mg, 6.137 mmol) were added to a solution of N,N-dimethylformamide (10 mL) containing compound 23-1 (1.0 g, 2.921 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, 40 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to give a brown powder of formate of compound 23-2 (1.38 g, 3.05 mmol, 99.9%). LC-MS: M / Z = 454.3 (M+H). + .

[0742] Step Two:

[0743] 8 mL of 4 M dioxane hydrochloride solution was added to compound 23-2 (579 mg, 1.276 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure to give compound 23-3 (492 mg, 1.40 mmol, 98.9%) as a grayish-white powder. LC-MS: M / Z = 354.2 (M+H) + .

[0744] Step 3:

[0745] Triphosgene (58 mg, 0.195 mmol) was added to a 2 mL solution of dichloromethane containing compound 23-3 (120 mg, 0.308 mmol) and N,N-diisopropylethylamine (163 mg, 1.261 mmol). The mixture was stirred at 0 °C under argon for 10 minutes. A 2 mL solution of dichloromethane containing N-methylcyclopropylamine hydrochloride (100 mg, 0.930 mmol) and N,N-diisopropylethylamine (163 mg, 1.261 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at room temperature for 2 hours, and the reaction was monitored for completion by LC-MS. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (8 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 4 / 1 to 2 / 1) to give a yellow viscous compound 23-4 (109 mg, 0.24 mmol, 78.5%). LC-MS: M / Z = 450.8 (M+H) + .

[0746] Step Four:

[0747] 10% Pd / C (100 mg) was added to a solution of compound 23-4 (900 mg, 1.997 mmol) in 10 mL of ethyl acetate. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LC-MS until complete. The mixture was filtered, and the filter cake was washed successively with ethyl acetate (10 mL) and methanol (10 mL). The combined filtrates were concentrated under reduced pressure to give a brown, viscous compound 23-5 (838 mg, 2.00 mmol, 99.8%). LC-MS: M / Z = 421.3 (M+H) + .

[0748] Step 5:

[0749] EDCI (491 mg, 2.561 mmol), compound 23-6 (430 mg, 1.408 mmol), and pyridine (5 mL) were added to compound 23-5 (538 mg, 1.279 mmol), and the mixture was reacted overnight at room temperature. After the reaction was complete, pyridine was removed by rotary evaporation under reduced pressure, and 15 mL of water was added. The mixture was extracted with ethyl acetate (15 mL * 2), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1 to 1 / 1) to give a grayish-white powder, compound 23-7 (588 mg, 0.83 mmol, 64.9%). LC-MS: M / Z = 708.5 (M + H) + .

[0750] Step Six:

[0751] Zinc bromide (200 mg, 0.888 mmol) was added to a solution of dichloromethane (2 mL) containing compound 23-7 (150 mg, 0.212 mmol). The mixture was reacted at 30 °C for 4 hours. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a grayish-white powder of compound 23-8 (128 mg, 0.21 mmol, 99.3%). LC-MS: M / Z = 608.4 (M + H) + .

[0752] Step Seven:

[0753] HATU (15 mg, 0.0394 mmol), compound 23-9 (5 mg, 0.0384 mmol), and triethylamine (8 mg, 0.0791 mmol) were added to a solution of N,N-dimethylformamide (1 mL) containing compound 23-8 (20 mg, 0.0329 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder, formate of compound I-23 (12 mg, 0.016 mmol, 50.5%). LC-MS: M / Z = 719.7 (M + H) + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 0.73H) (formic acid), 7.90 (t, J = 8.0Hz, 1H), 7.15 (m, 2H), 5.33–5.23 (m, 1H), 4.94 (m, 1H), 4.59 (d, J = 7.6Hz, 1H), 3.82–3.67 (m, 2H), 3.53–3.37 (m, 2H), 3.29–3.17 (m, 1H), 2.91 (s, 3H), 2.61 (m ,2H),2.53(m,2H),2.09–1.96(m,2H),1.89(m,4H),1.45(s,1H),1.37(d,J=7.2Hz,1H),1.32–1.13(m,4H) ,0.94(m,4H),0.75(m,2H),0.71–0.62(m,2H),0.51(m,2H),0.31–0.18(m,1H),0.05(s,3H),-0.06(s,3H).

[0754] Example 23: Compound I-24

[0755] Step 1:

[0756] HATU (15 mg, 0.0394 mmol), compound 24-1 (prepared according to patent WO 2024235205, 6 mg, 0.0413 mmol), and triethylamine (7 mg, 0.0692 mmol) were added to a solution of N,N-dimethylformamide (1 mL) containing compound 23-8 (20 mg, 0.0329 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder of formate of compound I-24 (12 mg, 0.016 mmol, 49.6%). LC-MS: M / Z = 734.8 (M + H) + . 1 H NMR (400MHz, CD3OD) δ8.52(s,2H)(formic acid),7.90(t,J=8.0Hz,1H),7.51(d,J=2.0Hz,1H),7.22–7.06(m,2H),6.88(d,J=2.0Hz ,1H),6.26(d,J=9.2Hz,1H),4.94(q,J=7.2Hz,1H),4.62(d,J=8.4Hz,1H),3.84–3.62(m,2H),3.53–3.37(m,2H),3.23(m, 1H),2.91(s,3H),2.65–2.57(m,1H),2.54(m,2H),2.13–1.98(m,2H),2.01–1.78(m,2H),1.37(d,J=7.2Hz,3H),1.35–1.1 9(m,4H),0.93(m,2H),0.73(m,2H),0.73–0.61(m,2H),0.53–0.41(m,1H),0.31–0.19(m,1H),0.04(s,3H),-0.08(s,3H).

[0757] Example 24: Compounds I-25-A, I-25-B, I-25-C

[0758] Step 1:

[0759] Sodium borohydride (0.847 g, 22.9 mmol) was added to a methanol (10.0 mL) solution of compound 25-1 (prepared according to WO 201008929, 3.8 g, 22.9 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography to give a yellow liquid compound 25-2 (3.8 g, 22.8 mmol, 45%). LC-MS: 169.1 [M+1] + .

[0760] Step Two:

[0761] Dichloromethane (10.0 mL), triphenylphosphine (5.58 g, 21.3 mmol), and carbon tetrabromide (7.05 g, 21.3 mmol) were added to compound 25-2 (3.6 g, 21.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography to give compound 25-3 (4.0 g, 17.4 mmol, 81%) as a white solid. LC-MS: 231.0 [M+1] + .

[0762] Step 3:

[0763] To a DMF (10.0 mL) of compound 25-3 (2.8 g, 12.2 mmol), (S)-(O-(N-benzylproline)aminoI(phenyl)N,N,N-nickel (6.07 g, 12.2 mmol) and sodium hydroxide (0.6 g, 15.0 mL) were added, and the reaction mixture was stirred at -25 °C for 3 hours. Water was then added, and the organic phase was extracted with ethyl acetate (100 mL x 3). The residue was concentrated, and 10.0 mL of 4.0 N dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. After washing with ethyl acetate (100 mL x 3), di-tert-butyl dicarbonate (5.72 g, 20.0 mmol) and sodium bicarbonate (8.4 g, 0.1 mol) were added to the aqueous phase, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL x 3). 3) Column chromatography yielded a yellow liquid compound 25-4 (2.0 g, 6.2 mmol, 52%). LC-MS: 326.1 [M+1] + .

[0764] Step Four:

[0765] Hydrogen chloride-methanol (10.0 mL) was added to a solution of compound 25-4 (1.0 g, 3.1 mmol) in ethanol (10.0 mL), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the residue was concentrated and purified by column chromatography to give a yellow liquid compound 25-5 (1.1 g, 4.3 mmol, 69.0%). LC-MS: 254.1 [M+1] + .

[0766] Step 5:

[0767] A solution of compound 25-5 (1.1 g, 4.3 mmol) in dichloromethane (10.0 mL) was added with triphosgene (1.28 g, 4.3 mmol) and triethylamine (8.0 mL), and stirred at room temperature for 1 hour. Then, N-methylcyclopropylamine hydrochloride (1.07 g, 10.0 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, concentrated, and palladium / carbon (0.1 g) and isopropanol (2.0 mL) were added, followed by purging with hydrogen three times. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the product was purified by column chromatography to give a yellow liquid compound 25-6 (400 mg, 1.24 mmol, 29%). LC-MS: 321.2 [M+1] + .

[0768] Step Six:

[0769] To a solution of pyridine (5.0 mL) containing 400 mg (1.24 mmol) of compound 25-6, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg, 1.25 mmol) and compound 23-6 (381 mg, 1.25 mmol) were added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated to give a yellow liquid compound 25-7 (350 mg, 0.58 mmol, 46%). LC-MS: 608.3 [M+1] + .

[0770] Step Seven:

[0771] Compound 25-7 (200 mg, 0.33 mmol) was added to ethyl hydrogen chloride (4.0 N, 10.0 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated to give a yellow liquid compound 25-8 (150 mg, 0.30 mmol, 90%). LC-MS: 508.3 [M+1] + .

[0772] Step 8:

[0773] To a DMF (2.0 mL) solution of compound 25-8 (150 mg, 0.30 mmol), (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (200 mg, 0.51 mmol), triethylamine (1.0 mL), and 1-ethyl-1H-pyrazole-5-carboxylic acid (73 mg, 0.52 mmol) were added. The mixture was purged three times with nitrogen, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the residue was concentrated and purified by column chromatography to give a white solid compound 25-9 (100 mg, 0.16 mmol, 54%). LC-MS: 630.3 [M+1] + .

[0774] Step Nine:

[0775] A solution of compound 25-9 (50 mg, 0.11 mmol) in tetrahydrofuran (5.0 mL) was added to an aqueous solution of lithium hydroxide (4.0 N, 1.0 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH was adjusted to approximately 5-6 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate to give a yellow solid, compound 25-10 (60.0 mg, 0.010 mmol, 62%). LC-MS: 602.3 [M+1] + .

[0776] Step 10:

[0777] To a solution of compound 25-10 (60 mg, 0.10 mmol) in pyridine (2.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N-methylpiperazine (0.1 mL) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the product was purified to obtain:

[0778] Compound I-25-A (7.0 mg, 0.010 mmol, 10.2%), LC-MS: 684.2 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.63(s,1H),8.20(s,1H),8.10(d,J=8.0Hz,1H),7.64(d,J=8.4Hz,1H),7.50(s,1H),6.85(s, 1H),6.68(s,1H),6.04(d,J=9.0Hz,1H),5.45-5.30(m,1H),5.05-4.93(m,1H),4.73-4.65(m,1H),4.61(q,J=7.2Hz, 2H),3.60-3.40(m,3H),3.30-3.12(m,2H),3.07(q,J=7.2Hz,3H),2.91(s,3H),2.58-2.50(m,3H),2.40-2.28(m,2H) ,2.26-2.20(m,4H),2.15-2.02(m,4H),1.98-1.90(m,3H),1.87-1.75(m,3H),0.90-0.88(m,2H),0.80-0.76(m,2H).

[0779] Compound I-25-B (15.1 mg, 0.022 mmol, 22.1%), LC-MS: 684.2 [M+1] + , 1 H NMR (400MHz, CDCl3) δ9.00-8.80(m,1H),8.24-8.11(m,2H),7.73-7.58(m,1H),7.49(s,1H),7.10-6.88(m,1H),6.69 (d,J=6.4Hz,1H),6.61-5.90(m,1H),5.60-5.30(m,1H),5.25-4.90(m,1H),4.75-4.70(m,1H),4.61(q,J=7.2Hz,2H), 3.89-3.33(m,4H),3.30-3.20(m,1H),3.06(q,J=7.2Hz,2H),2.90-2.80(m,3H),2.60-2.45(m,5H),2.43-2.27(m,3H ),2.25-2.15(m,3H),2.12-2.00(m,3H),1.98-1.70(m,5H),1.70-1.62(m,1H),0.95-0.88(m,2H),0.80-0.73(m,2H).

[0780] Compound I-25-C (8.3 mg, 0.012 mmol, yield 12.2%), LC-MS: 684.2 [M+1]+. 1H NMR(400MHz, CDCl3)δ8.68(s,1H),8.30-7.94(m,2H),7.80-7.60(m,1H),7.50(s,1H),6.90-6 .60(m,1H),6.05-5.87(m,1H),5.65-5.30(m,1H),5.10-4.90(m,1H),4.70–4.55(m,3H),3.88 -3.60(m,3H),3.65-3.55(m,3H),3.30-3.00(m,2H),2.95-2.90(m,3H),2.60-2.40(m,6H),2. 30-2.10(m,3H),1.95-1.75(m,5H),1.50-1.40(m,6H),0.94-0.86(m,2H),0.74-0.50(m,2H).

[0781] Example 25: Compound I-26

[0782] HATU (14 mg, 0.0368 mmol), 7,7-difluoro-3-azabicyclo[4.1.0]heptane hydrochloride (7 mg, 0.0374 mmol), and triethylamine (7 mg, 0.0692 mmol) were added to a solution of compound 2-1 (20 mg, 0.0323 mmol) in N,N-dimethylformamide (1 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give a grayish-white powder of compound I-26 formate (10 mg, 0.137 mmol, 42.6%). LC-MS: M / Z = 734.5 (M + H) + . 1 H NMR (400MHz, CD3OD) δ8.50 (s, 1H) (formic acid), 7.87–7.72 (m, 1H), 7.51 (d, J = 1.6Hz, 1H), 7.22–7.05(m,2H),6.89(d,J=1.6Hz,1H),4.60(m,1H),4.55(q,J=7.2Hz,2H),3.5 0(m,2H),3.15(m,2H),2.91(s,3H),2.66–2.48(m,4H),2.02(m,4H),1.90(m,4H), 1.64(m,3H),1.40(t,J=7.2Hz,3H),1.37–1.23(m,6H),0.94(m,2H),0.75(m,2H).

[0783] Example 26: Compound I-27

[0784] Step 1:

[0785] Triethylamine (35.82 mg, 0.35 mmol) and HATU (67.30 mg, 0.18 mmol) were added to a solution of compound 27-1 (prepared according to the method of compound 30-2, 70.00 mg, 0.12 mmol) and 1-ethyl-1H-pyrazole-5-carboxylic acid (18.22 mg, 0.13 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-27 (10 mg, 0.015 mmol, 12.49%) as a white solid. LC-MS (ESI, m / z): 678.7 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.87 (dt, J=64.2, 8.1Hz, 1H), 7.51 (d, J=1.6Hz, 1H), 7.20–7. 02(m,2H),6.89(s,1H),4.73–4.49(m,4H),4.16–4.04(m,1H),3.79-3.73(m,1H), 3.65-3.56(m,1H),3.48-3.35(m,1H),3.23–3.10(m,1H),2.58-2.48(m,2H),2.41 –2.19(m,4H),2.08–1.85(m,5H),1.42–1.31(m,8H),1.15(td,J=7.6,2.1Hz,3H).

[0786] Example 27: Compound I-28

[0787] Step 1:

[0788] Compound 23-8 (50 mg, 0.08 mmol) and sodium bicarbonate (69 mg, 0.82 mmol) were dissolved in acetonitrile (2 mL), and p-nitrophenyl chloroformate (19 mg, 0.1 mmol) was added. The reaction mixture was stirred at 10 °C for 20 min. Tert-butyl hydrazide formate (42 mg, 0.32 mmol) was added, and the reaction mixture was stirred at 120 °C for 10 min. The reaction mixture was filtered, concentrated, and the crude product was purified by preparative plate chromatography (dichloromethane / methanol = 10:1) to give compound 28-1 (30 mg, 47.76%) as a white solid. LC-MS (ESI, m / z): 765.8 [M+H] + .

[0789] Step Two:

[0790] Compound 28-1 (20 mg, 0.03 mmol) was dissolved in methanol (2 mL), and ethyl acetate hydrochloride solution (4 M, 8 mL, 32 mmol) was added. The reaction mixture was stirred at 10 °C for 1 hour, and then concentrated to give a white solid, compound 28-2 (17.3 mg, 99.93%). LC-MS (ESI, m / z): 665.8 [M+H] + .

[0791] Step 3:

[0792] Compound 28-2 (17.3 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (10 mg, 0.08 mmol) and acetic anhydride (3.47 mg, 0.03 mmol) were added at 0 °C, and the reaction mixture was stirred at 10 °C for 10 minutes. The reaction mixture was concentrated to give a white solid, compound 28-3 (18.4 mg, 100%), which was used directly in the next step without purification. LC-MS (ESI, m / z): 707.8 [M+H] + .

[0793] Step Four:

[0794] Compound 28-3 (15 mg, 0.021 mmol) was dissolved in tetrahydrofuran (3 mL), and N,N-diisopropylethylamine (27 mg, 0.21 mmol) and phosphorus oxychloride (32 mg, 0.21 mmol) were added. The reaction mixture was stirred at 80 °C for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to give a white solid compound I-28 (1.88 mg, 12.98%). LC-MS (ESI, m / z): 690.2 [M+H] + . 1H NMR(400MHz,MeOD)δ7.88(t,J=8.1Hz,1H),7.18–7.10(m,2H),6.25(d,J=9.4Hz,1H),4.96-4.94(m,1H) ,4.21(d,J=6.9Hz,1H),3.75-3.68(m,3H),3.51–3.40(m,2H),3.27–3.21(m,1H),2.91(s,3H),2.65–2.4 8(m,4H),2.38(s,3H),2.01-1.99(m,2H),1.95-1.88(m,3H),1.36(d,J=7.1Hz,3H),1.31-1.26(m,1H), 0.98–0.90(m,2H),0.74-0.65(m,4H),0.51-0.45(m,1H),0.28-0.23(m,1H),0.05(s,3H),-0.09(s,3H).

[0795] Example 28: Compound I-29

[0796] Step 1:

[0797] HATU (15 mg, 0.0394 mmol), compound 29-1 (6 mg, 0.0413 mmol), and triethylamine (8 mg, 0.0791 mmol) were added to a solution of N,N-dimethylformamide (1 mL) containing compound 23-8 (20 mg, 0.0329 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder, formate of compound I-29 (12 mg, 49.4%). LC-MS (ESI, m / z) = 737.4 (M + H). + . 1¹H NMR (400MHz, CD₃OD) δ 8.51 (s, 0.67H) (formic acid), 7.89 (t, J = 8.0Hz, 1H), 7.15 (m, 2H), 6.26 (d, J = 9.6Hz, 1H), 4.95 (m, 1H), 4.71 (d, J = 7.6Hz, 1H), 3.80–3.64 (m, 2H), 3.47 (m, 2H), 3.28–3.18 (m, 1H), 2.91 (s, 3H), 2.66 –2.57(m,1H),2.54(m,2H),2.14–1.97(m,2H),1.90(m,3H),1.37(d,J=7.2Hz,3H),1.35–1.17(m,4H),1 .00–0.87(m,2H),0.74(m,1H),0.69(m,2H),0.48(m,1H),0.34–0.22(m,1H),0.05(s,3H),-0.06(s,3H).

[0798] Example 29: Compound I-30

[0799] Step 1:

[0800] Under ice bath conditions, N,N-diisopropylethylamine (702.55 mg, 5.44 mmol) and propionyl chloride (377.20 mg, 4.08 mmol) were added to a solution of compound 23-3 (530.00 mg, 1.36 mmol) in dichloromethane (20.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 30-1 (496 mg, 1.21 mmol, 89.11%). LC-MS (ESI, m / z): 410.2 [M+1] + .

[0801] Step Two:

[0802] Palladium on carbon (100.00 mg) was added to a methanol (20.00 mL) solution of compound 30-1 (496.00 mg, 1.21 mmol), and the reaction mixture was stirred under hydrogen protection for 1 hour. The palladium on carbon was filtered off, and the filtrate was evaporated to dryness to give a yellow solid, compound 30-2 (450 mg, 1.19 mmol, 97.91%). LC-MS (ESI, m / z): 380.3 [M+1] + .

[0803] Step 3:

[0804] To a pyridine (10.00 mL) solution of compound 30-2 (450.00 mg, 1.19 mmol) and compound 23-6 (398.44 mg, 1.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.14 g, 5.93 mmol) was added. The reaction mixture was stirred overnight at room temperature under argon protection. Pyridine was removed by vacuum distillation, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 30-3 (702 mg, 1.05 mmol, 88.76%) as a pale yellow solid. LC-MS (ESI, m / z): 667.4 [M+1] + .

[0805] Step Four:

[0806] Hydrochloric acid (8.00 mL, 32.00 mmol) was added to a solution of compound 30-3 (702.00 mg, 1.05 mmol) in dichloromethane (2.00 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated to give a pale yellow solid, compound 30-4 (620 mg, 1.03 mmol, 97.88%). LC-MS (ESI, m / z): 567.4 [M-HCl+1] + .

[0807] Step 5:

[0808] Triethylamine (25.20 mg, 0.25 mmol) and HATU (47.15 mg, 0.124 mmol) were added to a solution of compound 30-4 (50.00 mg, 0.08 mmol) and compound 30-5 (13.21 mg, 0.09 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-30 (21 mg, 0.03 mmol, 36.46%) as a white solid. LC-MS (ESI, m / z): 694.5 [M+1] + . 1H NMR(400MHz,MeOD)δ7.90(t,J=8.1Hz,1H),7.51(d,J=2.1Hz,1H),7.18-7.11(m,2H),6.88(d,J=2.1Hz, 1H),5.02(d,J=10.2Hz,1H),4.62(d,J=8.4Hz,1H),3.87-3.76(m,2H),3.45–3.37(m,1H),3.31–3.20(m, 2H),2.62–2.47(m,2H),2.35–2.19(m,2H),2.12–1.83(m,5H),1.37-1.28(m,3H),1.30–1.19(m,2H),1.1 6(t,J=7.6Hz,3H),0.75–0.58(m,2H),0.47-0.37(m,1H),0.32-0.23(m,1H),0.04(s,3H),-0.11(s,3H).

[0809] Example 30: Compound I-31

[0810] Step 1:

[0811] Triethylamine (25.20 mg, 0.25 mmol) and HATU (47.15 mg, 0.124 mmol) were added to a solution of compound 30-4 (50.00 mg, 0.08 mmol) and compound 31-1 (13.21 mg, 0.09 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-31 (14 mg, 0.02 mmol, 24.22%) as a white solid. LC-MS (ESI, m / z): 696.2 [M+1] + . 1H NMR(400MHz,MeOD)δ7.94-7.96(m,1H),7.19-7.12(m,2H),5.02(d,J=10.2Hz,1H),4.71(d, J=7.9Hz,1H),3.87-3.75(m,2H),3.47–3.38(m,1H),3.31–3.20(m,2H),2.58-2.49(m,2H),2 .35-2.21(m,2H),2.13-1.99(m,2H),1.97-1.80(m,3H),1.34-1.21(m,5H),1.16(t,J=7.6H z,3H),0.73–0.61(m,2H),0.48-0.37(m,1H),0.33-0.24(m,1H),0.05(s,3H),-0.09(s,3H).

[0812] Example 31: Compound I-32

[0813] Step 1:

[0814] N,N-diisopropylethylamine (38.38 mg, 0.30 mmol) and HATU (56.28 mg, 148.00 μmol) were added to a solution of compound 30-4 (60.00 mg, 0.10 mmol) and compound 32-1 (10.81 mg, 0.12 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-32 (12 mg, 0.019 mmol, 18.98%) as a white solid. LC-MS (ESI, m / z): 638.8 [M+1] + . 1H NMR(400MHz,MeOD)δ7.88(t,J=8.2Hz,1H),7.18-7.10(m,2H),5.64(dd,J=46.7,3.4Hz,1H),5.26(dd ,J=15.2,3.5Hz,1H),5.06-4.97(m,1H),4.58(d,J=8.3Hz,1H),3.90–3.74(m,2H),3.48–3.37(m,1H), 3.31-3.20(m,2H),2.57-2.47(m,2H),2.32-2.21(m,2H),2.11–1.82(m,5H),1.36–1.24(m,5H),1.16( t,J=7.6Hz,3H),0.71–0.58(m,2H),0.47-0.37(m,1H),0.32-0.22(m,1H),0.05(s,3H),-0.10(s,3H).

[0815] Example 32: Compound I-33

[0816] Step 1:

[0817] Under ice bath conditions, N,N-diisopropylethylamine (135.70 mg, 1.05 mmol) and phosphorus oxychloride (161.00 mg, 1.05 mmol) were added to a tetrahydrofuran (3.00 mL) solution of compound 33-1 (70.00 mg, 0.11 mmol, prepared according to the method for compound I-28). The reaction mixture was refluxed for 1 hour. The reaction was quenched with sodium bicarbonate solution, extracted with dichloromethane, dried, and concentrated to give a pale yellow solid. Further purification and separation yielded a pale yellow solid, compound I-33 (10.50 mg, 0.016 mmol, 15.41%). LC-MS (ESI, m / z): 648.8 [M+1] + . 1H NMR(400MHz,MeOD)δ7.93–7.79(m,1H),7.23–7.02(m,2H),5.06-4.97(m,1H),4.58-4.40 (m,1H),3.87-3.72(m,2H),3.49–3.38(m,1H),3.29-3.22(m,2H),2.58-2.46(m,2H),2.3 9-2.15(m,5H),2.08–1.76(m,5H),1.38-1.28(m,5H),1.16(t,J=7.6Hz,3H),0.74–0.57( m,2H),0.48-0.37(m,1H),0.34–0.21(m,1H),0.06-0.01(m,3H),-0.10(d,J=17.1Hz,3H).

[0818] Example 33: Compound I-34

[0819] Step 1:

[0820] HATU (855 mg, 2.249 mmol), compound 12-1 (413 mg, 2.249 mmol), and triethylamine (435 mg, 4.299 mmol) were added to an 8 mL solution of N,N-dimethylformamide containing compound 4-1 (700 mg, 2.045 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5 / 1 to 2 / 1, V / V) to give a yellow powder, compound 34-1 (962 mg, 99.8%). LC-MS (ESI, m / z) = 416.2 (M-56+H).

[0821] Step Two:

[0822] A 4M hydrogen chloride / ethyl acetate solution (6 mL) was added to a methanol solution (8 mL) containing compound 34-1 (962 mg, 2.040 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (5 mL) was added to the residue. The mixture was stirred for 5 minutes, and then 10 mL of water was added. Extraction was performed with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a grayish-white powder, compound 34-2 (757 mg, 99.9%). LC-MS (ESI, m / z) = 372.2 (M+H) + .

[0823] Step 3:

[0824] Triphosgene (364 mg, 1.227 mmol) was added to an 8 mL solution of dichloromethane containing compound 34-2 (757 mg, 2.038 mmol) and N,N-diisopropylethylamine (536 mg, 4.147 mmol). The mixture was stirred at room temperature for 10 minutes. A 4 mL solution of dichloromethane containing N-methylcyclopropylamine hydrochloride (657 mg, 6.107 mmol) and N,N-diisopropylethylamine (1.072 g, 8.294 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at room temperature for 1 hour, and the reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure. 20 mL of water was added to the residue, and the mixture was extracted twice with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1 to 0 / 1, V / V) to give a yellow viscous compound 34-3 (900 mg, 94.2%). LC-MS (ESI, m / z) = 469.3 (M+H). + .

[0825] Step Four:

[0826] Iron powder (540 mg, 9.670 mmol) and ammonium chloride (308 mg, 5.758 mmol) were added to a 4:1 ethanol / water solution (12 mL) containing compound 34-3 (900 mg, 1.921 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete as monitored by LC-MS, the reaction system was cooled to room temperature, filtered, and the filter cake was washed successively with methanol and dichloromethane. The combined filtrate was concentrated under reduced pressure, and 20 mL of water and 40 mL of ethyl acetate were added to the residue for extraction. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a grayish-white powder of compound 34-4 (840 mg, 99.7%). LC-MS (ESI, m / z) = 439.3 (M+H) + .

[0827] Step 5:

[0828] EDCI (18 mg, 0.0939 mmol), compound 23-6 (15 mg, 0.0491 mmol), and pyridine (1 mL) were added to compound 34-4 (20 mg, 0.0456 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and 6 mL of water was added to the residue. Extraction was performed with ethyl acetate (6 mL x 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1 to 1 / 1, V / V) to give compound 34-5 (23 mg, 68.9%) as a white powder. LC-MS (ESI, m / z) = 725.8 (M+H) + .

[0829] Step Six:

[0830] Zinc bromide (35 mg, 0.155 mmol) was added to a solution of dichloromethane (2 mL) containing compound 34-5 (23 mg, 0.0320 mmol). The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure. 5 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (6 mL x 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a grayish-white powder, compound 34-6 (18 mg, 90.0%). LC-MS (ESI, m / z) = 626.4 (M+H) + .

[0831] Step Seven:

[0832] HATU (12 mg, 0.0316 mmol), 1-fluorocyclopropanecarboxylic acid (3 mg, 0.0288 mmol), and triethylamine (6 mg, 0.0593 mmol) were added to a solution of N,N-dimethylformamide (1 mL) containing compound 34-6 (16 mg, 0.0256 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder, compound I-34 formate (10 mg, 54.0%). LC-MS (ESI, m / z) = 711.7 (M+H) + . 1H NMR(400MHz,CD3OD)δ8.52(s,4H)(formic acid),7.89–7.75(m,1H),7.16(m,2H),6.30(d, J=9.2Hz,1H),4.93(m,1H),4.58(m,2H),3.51(m,2H),3.18(m,2H),2.91(s,3H),2 .66–2.58(m,1H),2.53(m,2H),2.22(m,1H),2.02(m,2H),1.98–1.81(m,3H),1.5 7(m,2H),1.40(m,4H),1.37–1.26(m,6H),1.13(m,2H),0.93(m,2H),0.77(m,2H).

[0833] Example 34: Compound I-35

[0834] Step 1:

[0835] To a pyridine (3.00 mL) solution of compound 34-4 (50.00 mg, 0.11 mmol) and compound 35-1 (35.20 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (109.27 mg, 0.57 mmol) was added. The reaction mixture was stirred overnight at room temperature under argon protection. Pyridine was removed by vacuum distillation, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 35-2 (40 mg, 0.056 mmol, 49.14%) as a pale yellow solid. LC-MS (ESI, m / z): 713.8 [M+1] + .

[0836] Step Two:

[0837] Zinc bromide (126.10 mg, 0.56 mmol) was added to a solution of compound 35-2 (40.00 mg, 0.06 mmol) in dichloromethane (1.00 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine and concentrated to give a yellow solid, compound 35-3 (32 mg, 0.052 mmol, 93.02%). LC-MS (ESI, m / z): 614.4 [M+1] + .

[0838] Step 3:

[0839] Triethylamine (7.89 mg, 0.08 mmol) and HATU (14.83 mg, 0.03 mmol) were added to a solution of compound 35-3 (16.00 mg, 0.03 mmol) and 1-fluorocyclopropane-1-carboxylic acid (3.23 mg, 0.03 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-35 (10 mg, 0.014 mmol, 54.95%) as a white solid. LC-MS (ESI, m / z): 700.2 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.89-7.73(m,1H),7.22-7.12(m,2H),4.97-4.88(m,1H),4. 65-4.55(m,1H),3.59-3.52(m,1H),3.46–3.36(m,2H),3.22-3.13(m,1H),2.91(s ,3H),2.65–2.59(m,1H),2.26–1.63(m,8H),1.60–1.41(m,4H),1.40(d,J=7.0Hz, 3H),1.39-1.28(m,5H),1.17-1.05(m,2H),0.98-0.90(m,3H),0.79-0.72(m,2H).

[0840] Example 35: Compound I-36

[0841] Step 1:

[0842] Compound 34-4 (40 mg, 0.09 mmol) and compound 36-1 (20 mg, 0.09 mmol) were dissolved in pyridine (1 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.46 mmol) was added. The reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-100%) to give compound 36-1 (62 mg, 98.73%) as a white solid. LC-MS (ESI, m / z): 689.8 [M+H] + .

[0843] Step Two:

[0844] Compound 36-1 (62 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), and zinc bromide (0.4 g, 1.80 mmol) was added. The reaction mixture was stirred at 20 °C for 5 hours. The mixture was diluted with ethyl acetate (30 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, a white solid compound 36-2 (50 mg, 94.16%). LC-MS (ESI, m / z): 589.8 [M+H] + .

[0845] Step 3:

[0846] Compound 36-2 (25 mg, 0.04 mmol) and 1-fluorocyclopropane-1-carboxylic acid (4.79 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (16 mg, 0.13 mmol) and HATU (20 mg, 0.16 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to give a white solid compound I-36 (2.10 mg, 7.40%). LC-MS (ESI, m / z): 676.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.92–7.82(m,1H),7.16(dd,J=13.2,4.7Hz,2H),6.29(d,J=9.0Hz,1H),4 .98–4.87(m,2H),3.60–3.37(m,3H),3.23–3.13(m,1H),2.91(s,3H),2.67–2.57(m,1H),1.60 –1.49(m,1H),1.48–1.21(m,9H),1.18–0.99(m,3H),1.05-1.93(m,2H),0.99-0.784(m,2H),0 .79–0.72(m,3H),0.59-0.52(m,3H),0.49-0.43(m,1H),0.42-0.35(m,1H),0.33–0.18(m,3H).

[0847] Example 36: Compound I-37

[0848] Step 1:

[0849] Compound 34-6 (40 mg, 0.06 mmol) and 2-fluoropropionic-2-enoic acid (6.3 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (25 mg, 0.19 mmol) and HATU (40 mg, 0.1 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was obtained by preparative HPLC as a white solid compound I-37 (6.27 mg, 14.03%). LC-MS (ESI, m / z): 698.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.87-7.74(m,1H),7.23–7.07(m,2H),6.30(d,J=9.0Hz,1H),5.71-5.58(m,1H),5.29-5 .24(m,1H),4.95-4.90(m,1H),4.59-4.54(m,1H),3.61–3.51(m,1H),3.48–3.36(m,2H),3.31–3.09(m,2H), 2.91(s,3H),2.63-2.60(m,1H),2.53(d,J=13.2Hz,2H),2.05-2.02(m,1H),2.00–1.76(m,4H),1.54-1.50(m ,1H),1.46–1.32(m,4H),1.32–1.19(m,2H),1.18–1.00(m,3H),0.95(t,J=6.6Hz,2H),0.77(d,J=2.4Hz,2H).

[0850] Example 37: Compound I-38

[0851] Step 1:

[0852] Compound 35-3 (0.02 g, 0.02 mmol, 1.00 eq), 2-fluoropropionic-2-enoic acid (3.00 mg, 0.03 mmol, 1.38 eq), and N,N-diisopropylethylamine (0.01 g, 0.08 mmol, 3.25 eq) were dissolved in N,N-dimethylformamide (1.5 mL), and HATU (0.01 g, 0.04 mmol, 1.54 eq) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, extracted with ethyl acetate (15 mL x 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-38 (11.00 mg, 66.84%) as a white solid. LC-MS (ESI, m / z): 685.7 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.97(d,J=4.0Hz,1H),8.49(dd,J=18.8,8.4Hz,1H),7.71(dt,J=26.8,8.4Hz,1H),7.12 (dt,J=15.2,8.8Hz,2H),6.17(d,J=6.4Hz,1H),5.61(dd,J=47.6,3.6Hz,1H),5.33(d,J=15.6Hz,1H),4.82( t,J=8.8Hz,1H),4.62-4.54(m,1H),3.57–3.32(m,3H),3.26–3.07(m,2H),2.75(s,3H),2.57–2.52(m,2H),2 .06-1.99(m,3H),1.91–1.59(m,4H),1.46-1.43(m,2H),1.37–0.97(m,8H),0.89-0.80(m,2H),0.64(s,2H).

[0853] Example 38: Compound I-39

[0854] Step 1:

[0855] In a 100 mL round-bottom flask, HATU (24 mg, 0.063 mmol) and triethylamine (8.5 mg, 0.084 mmol) were added sequentially to a 5 mL solution of N,N-dimethylformamide containing compound 36-2 (25 mg, 0.042 mmol). The reaction mixture was then stirred at room temperature for 10 minutes. 2-fluoroacrylic acid (4.6 mg, 0.058 mmol) was added to the reaction mixture in one step, and the mixture was stirred at room temperature for 16 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to obtain the target compound I-39 (10 mg, 0.015 mmol) as a white solid. LC-MS (ESI, m / z): 662.2 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.91-7.799(m,1H),7.21–7.09(m,2H),6.29(d,J= 8.8Hz,1H),5.66(dd,J=47.2,3.6Hz,1H),5.28(dt,J=15.2,3.6Hz,1H),4.98-4. 88(m,2H),3.60–3.35(m,3H),3.32-3.26(m,1H),3.24-3.11(m,1H),2.91(s,3H) ),2.67-2.57(m,1H),1.59–1.21(m,6H),1.19–0.69(m,10H),0.61–0.17(m,8H).

[0856] Example 39: Compound I-40

[0857] Step 1:

[0858] In a 100 mL round-bottom flask, HATU (30 mg, 0.07 mmol) and triethylamine (10 mg, 0.14 mmol) were added sequentially to a 5 mL solution of N,N-dimethylformamide containing compound 34-6 (30 mg, 0.05 mmol). The reaction mixture was then stirred at room temperature for 10 minutes. 2,2-Difluorocyclopropane-1-carboxylic acid (8.2 mg, 0.07 mmol) was added to the reaction mixture in one step, and the mixture was stirred at room temperature for 16 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to give a white solid compound I-40 (8 mg, 0.011 mmol). LC-MS (ESI, m / z): 729.7 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.80 (dq, J=40.0, 8.3Hz, 1H), 7.15 (t, J=12.4Hz, 2H), 6.30 (d, J= 8.9Hz,1H),4.95(d,J=9.2Hz,1H),4.66–4.43(m,3H),3.52(d,J=16.7Hz,1H),3.17(d,J=9.6Hz ,1H),2.91(s,3H),2.75–2.58(m,2H),2.53(d,J=14.0Hz,2H),2.10–1.68(m,8H),1.51(s,1H), 1.47–1.19(m,8H),1.11(dt,J=29.5,8.1Hz,3H),0.94(d,J=7.0Hz,3H),0.76(t,J=3.1Hz,2H).

[0859] Example 40: Compound I-41

[0860] Step 1:

[0861] Compounds 34-6 (0.03 g, 0.05 mmol, 1.00 eq), 3,3-difluorocyclobutane-1-carboxylic acid (8.71 mg, 0.06 mmol, 1.33 eq), and N,N-diisopropylethylamine (0.02 g, 0.15 mmol, 3.06 eq) were dissolved in N,N-dimethylformamide (1 mL), and HATU (0.03 g, 0.07 mmol, 1.54 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (20 mL x 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-41 (22.00 mg, 61.62%) as a white solid. LC-MS (ESI, m / z): 744.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.87 (s, 1H), 8.27-8.24 (m, 1H), 7.70 (dt, J = 30.0, 8.4Hz, 1H), 7.11 (d t,J=15.6,9.6Hz,2H),6.17(d,J=6.4Hz,1H),4.82(t,J=8.8Hz,1H),4.60-4.53(m,1H),3.5 9–3.34(m,3H),3.25–2.97(m,3H),2.83–2.62(m,6H),2.56-2.54(m,2H),2.42-2.38(m,2H) ,1.79-1.69(m,5H),1.51-1.31(m,3H),1.27–0.94(m,8H),0.94–0.75(m,2H),0.64(s,2H).

[0862] Example 41: Compound I-42

[0863] Step 1:

[0864] Triethylamine (9.71 mg, 0.10 mmol) and HATU (18.25 mg, 0.048 mmol) were added to a solution of compound 34-6 (20.00 mg, 0.03 mmol) and cyclopentanecarboxylic acid (4 mg, 0.03 mmol) in N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-42 (7 mg, 0.0097 mmol, 30.30%) as a white solid. LC-MS (ESI, m / z): 721.8 [M+1] + .1 H NMR(400MHz,MeOD)δ7.89-7.73(m,1H),7.19-7.09(m,2H),6.29(d,J=9.0Hz,1H),5.02–4.90(m,1H) ,4.53–4.40(m,1H),3.60–3.42(m,2H),3.41-3.35(m,2H),3.22-3.13(m,1H),2.91(s,3H),2.82–2.7 3(m,1H),2.66–2.58(m,1H),2.57-2.46(m,2H),1.99-1.82(m,6H),1.79-1.70(m,4H),1.68-1.58(m, 2H),1.57–1.49(m,1H),1.47–1.34(m,5H),1.30–1.05(m,5H),1.03–0.87(m,3H),0.79-0.72(m,2H).

[0865] Example 42: Compound I-43

[0866] Step 1:

[0867] Compound 34-6 (8 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (18 mg, 0.14 mmol) and HATU (30 mg, 0.07 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative HPLC to obtain a white solid compound I-43 (2.02 mg, 5.7%). LC-MS (ESI, m / z): 738.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.87-7.74(m,1H),7.18-7.12(m,2H),6.30(d,J=9.0Hz,1H) ,4.95-4.90(m,1H),4.51–4.43(m,1H),4.05–3.92(m,2H),3.59–3.36(m,5H),3.1 9-3.15(m,2H),2.91(s,3H),2.68–2.46(m,4H),1.99–1.65(m,8H),1.59–1.50(m, 1H),1.41-1.38(m,4H),1.32-1.06(m,5H),0.97-0.93(m,3H),0.78-0.74(m,2H).

[0868] Example 43: Compound I-44

[0869] Step 1:

[0870] To a solution of compound 44-1 (249.96 mg, 2.90 mmol) and p-nitrophenyl chloroformate (701.72 mg, 3.48 mmol) in tetrahydrofuran (5.00 mL), pyridine (918.19 mg, 11.61 mmol) and 4-dimethylaminopyridine (35.40 mg, 0.29 mmol) were added, and the reaction mixture was stirred at 30 °C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give a colorless oily compound 44-2 (510 mg, 2.03 mmol, 69.95%). 1 H NMR (400MHz, CDCl3) δ8.36–8.24(m,2H),7.46–7.35(m,2H),5.28-5.22(m,1H),2.03–1.77(m,6H),1.76–1.63(m,2H).

[0871] Step Two:

[0872] N,N-diisopropylethylamine (12.41 mg, 0.10 mmol) was added to a solution of compound 34-6 (20.00 mg, 0.03 mmol) and compound 44-2 (16.10 mg, 0.06 mmol) in N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at 60 °C for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-44 (16 mg, 0.022 mmol, 67.80%) as a white solid. LC-MS (ESI, m / z): 737.7 [M+1] + . 1H NMR(400MHz,MeOD)δ7.89-7.73(m,1H),7.21-7.10(m,2H),6.30(d,J=9.0Hz,1H),5.13-5.0 4(m,1H),4.96-4.88(m,1H),4.25-4.15(m,1H),3.61-3.35(m,4H),3.22-3.14(m,1H),2.91( s,3H),2.67–2.59(m,1H),2.57-2.47(m,2H),1.98-1.80(m,6H),1.79-1.68(m,4H),1.67-1 .49(m,3H),1.41(d,J=7.0Hz,3H),1.39-1.05(m,7H),0.99-0.88(m,3H),0.79-0.72(m,2H).

[0873] Example 44: Compound I-45

[0874] Step 1:

[0875] In an anhydrous and oxygen-free environment, compound 2-1 (100 mg, 0.16 mmol, 1.0 eq), NH4Cl (21.7 mg, 0.4 mmol, 2.5 eq), HATU (154 mg, 0.4 mmol, 2.5 eq), DIPEA (50 mg, 0.4 mmol, 2.5 eq), and DMF (5 mL) were added sequentially to the system. The reaction mixture was stirred at room temperature for 6.0 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 45-1 (99 mg, 99%) as a white solid. LC-MS (ESI, m / z): 618.4 [M+H] + .

[0876] Step Two:

[0877] In an ice bath, trifluoroacetic anhydride (217.59 mg, 1.04 mmol) was added to a tetrahydrofuran (15.00 mL) solution of compound 45-1 (160.00 mg, 0.26 mmol), and the reaction mixture was stirred at 0 °C for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 45-2 (130 mg, 0.22 mmol, 83.71%) as a white solid. LC-MS (ESI, m / z): 599.8 [M+1] + .

[0878] Step 3:

[0879] Sodium carbonate (211.98 mg, 2.00 mmol) was added to an ethanol (5.00 mL) solution of compound 45-2 (120.00 mg, 0.20 mmol) and hydroxylamine hydrochloride (69.50 mg, 1.00 mmol). The reaction mixture was stirred at 90 °C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to give a white solid, compound 45-3 (122 mg, 0.19 mmol, 96.44%). LC-MS (ESI, m / z): 632.8 [M+1] + .

[0880] Step Four:

[0881] Triethylamine (37.44 mg, 0.37 mmol) and phenyl chloroformate (43.97 mg, 0.28 mmol) were added to a solution of compound 45-3 (117.00 mg, 0.19 mmol) in dichloromethane (5.00 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour under argon protection. The solvent was evaporated to dryness, and toluene (5.00 mL) was added. The reaction mixture was refluxed and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give a pale yellow solid compound I-45 (10 mg, 0.015 mmol, 8.21%). LC-MS (ESI, m / z): 659.1 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.76(t,J=8.1Hz,1H),7.46(d,J=2.0Hz,1H),7.14-7.03(m ,2H),6.84(d,J=2.0Hz,1H),4.92–4.86(m,1H),4.57(d,J=8.3Hz,1H),4.50(q,J =7.1Hz,2H),3.39–3.32(m,1H),2.85(s,2H),2.61–2.44(m,3H),2.06–1.94(m,2 H),1.93-1.78(m,3H),1.38–1.16(m,8H),0.93–0.82(m,2H),0.76–0.63(m,2H).

[0882] Example 45: Compound I-46

[0883] Step 1:

[0884] HATU (11 mg, 0.0289 mmol), compound 46-1 (4 mg, 0.0296 mmol), and triethylamine (8 mg, 0.0791 mmol) were added to a solution of compound 2-1 (14 mg, 0.0226 mmol) in N,N-dimethylformamide (1 mL). The mixture was reacted overnight at room temperature. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (8 mL * 2). The combined organic phases were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a grayish-white powder, formate of compound I-46 (8 mg, 47.3%). LC-MS (ESI, m / z) = 735.7 (M + H). + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.49 (s, 0.52H) (formic acid), 7.88 (m, 1H), 7.51 (s, 1H), 7.18 (m, 2H), 6.89 (s, 1H), 6.34 (d, J = 8.0Hz, 1H), 4.63 (d, J = 8.0Hz, 1H), 4.55 (q, J = 7.2Hz, 2H), 3.92 (m, 2H) ),3.77(m,2H),3.23(m,2H),3.08(m,2H),2.90(s,3H),2.75(m,2H),2.63–2.42(m,4H), 2.02(m,2H),1.92(m,2H),1.42(t,J=7.2Hz,3H),1.33(m,5H),0.95(m,2H),0.76(m,2H).

[0885] Example 46: Compound I-47

[0886] Step 1:

[0887] Add sodium methoxide methanol solution (5.4M, 0.63mL, 2.92mmol) and methanol (5mL) to a dry 100mL three-necked flask. Place the flask in an ice-salt bath and cool to -5°C. Then, slowly add 2mL of pre-cooled hydroxylamine-O-sulfonic acid (compound 47-2, 300mg, 2.65mmol) methanol solution to the reaction mixture, while maintaining the temperature inside the flask between -5°C and 0°C. Slowly heat the reaction mixture to room temperature and stir for 16 hours.

[0888] The reaction solution was filtered, and the filter cake was washed with methanol. The resulting filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was slurried with acetonitrile (10 mL) to give a white solid compound 47-3 (200 mg, 0.99 mmol). The obtained product was used directly in the next reaction without further purification.1 H NMR (400MHz, Methanol-d4) δ3.68-3.54(m,2H),3.36-3.25(m,2H),2.57-2.34(m,2H),2.24-2.06(m,2H).

[0889] Step Two:

[0890] In a 100 mL round-bottom flask, HATU (30 mg, 0.063 mmol) and triethylamine (17 mg, 0.17 mmol) were added sequentially to a 5 mL solution of N,N-dimethylformamide containing compound 2-1 (30 mg, 0.046 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. Compound 47-3 (12.48 mg, 0.06 mmol) was added to the reaction mixture all at once, and the mixture was stirred at room temperature for 16 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to obtain a white solid, compound I-47 (10 mg, 0.015 mmol). LC-MS(ESI, m / z) = 703.7 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.52(s,1H),7.77(t,J=8.0Hz,1H),7.51(d,J=2.0Hz,1H),7. 16–7.02(m,2H),6.89(d,J=2.0Hz,1H),4.61(d,J=8.4Hz,1H),4.59-4.51(m,2H),4.51–4.4 4(m,1H),3.30–3.07(m,3H),3.03-2.94(m,1H),2.92-2.82(m,3H),2.65–2.47(m,4H),2.13 -1.97(m,5H),1.97-1.82(m,4H),1.43–1.20(m,9H),0.96-0.85(m,2H),0.80–0.68(m,2H).

[0891] Example 47: Compound I-48-A

[0892] Step 1:

[0893] N,N-diisopropylethylamine (19.77 mg, 0.15 mmol) was added to a solution of compound 36-2 (30.00 mg, 0.05 mmol) and compound 48-A-1 (25.80 mg, 0.10 mmol, prepared according to the method for compound 44-2) in N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at 60 °C for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-48-A (11.0 mg, 0.0156 mmol, 30.64%) as a white solid. LC-MS (ESI, m / z): 704.4 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.92-7.80(m,1H),7.19-7.11(m,2H),5.29-5.23(m,1H),4.97-4 .89(m,1H),4.56-4.47(m,1H),4.02-3.79(m,4H),3.53-3.35(m,3H),3.21-3.14(m,1 H),2.91(s,3H),2.65-2.59(m,1H),2.26-2.17(m,1H),2.10-2.02(m,1H),1.56-1.29 (m,7H),1.18-0.83(m,7H),0.80-0.71(m,2H),0.71-0.39(m,5H),0.35-0.17(m,4H).

[0894] Example 48: Compound I-48-B

[0895] Step 1:

[0896] N,N-diisopropylethylamine (19.77 mg, 0.15 mmol) was added to a solution of compound 36-2 (30.00 mg, 0.05 mmol) and compound 48-B-1 (25.80 mg, 0.10 mmol) in N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at 60 °C for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give a white solid compound I-48-B (12 mg, 0.017 mmol, 33.43%). LC-MS (ESI, m / z): 704.4 [M+1] + . 1H NMR(400MHz,MeOD)δ7.92-7.80(m,1H),7.22-7.02(m,2H),5.28-5.23(m,1H),4.99-4.91( m,1H),4.57-4.49(m,1H),4.06-3.76(m,4H),3.53-3.35(m,3H),3.21-3.13(m,1H),2.91( s,3H),2.65-2.57(m,1H),2.26-2.15(m,1H),2.12-2.04(m,1H),1.57-1.30(m,7H),1.18- 0.81(m,7H),0.80-0.71(m,2H),0.69-0.53(m,2H),0.53-0.36(m,3H),0.35-0.15(m,4H).

[0897] Example 49: Compound I-49

[0898] Step 1:

[0899] Triethylamine (14.57 mg, 0.14 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethylurea hexafluorophosphate (27.38 mg, 0.072 mmol) were added to a solution of compound 34-6 (30.00 mg, 0.05 mmol) and (2E)-3-cyclopropyl-2-fluoropropionic acid (7.55 mg, 0.06 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-49 (11 mg, 0.015 mmol, 31.07%) as a white solid. LC-MS (ESI, m / z): 738.1 [M+1] + . 1H NMR(400MHz,MeOD)δ7.89-7.75(m,1H),7.22-7.10(m,2H),5.35-5.23(m,1H),4.96-4.87(m,1H), 4.62-4.52(m,1H),3.65-3.41(m,2H),3.41-3.36(m,1H),3.29-3.13(m,2H),2.91(s,3H),2.69-2 .59(m,2H),2.58-2.48(m,2H),2.08-1.96(m,2H),1.95-1.82(m,3H),1.55-1.47(m,1H),1.41(dd ,J=7.0,1.6Hz,3H),1.36-1.04(m,7H),0.98-0.89(m,4H),0.81-0.71(m,2H),0.55-0.45(m,2H).

[0900] Example 50: Compound I-50

[0901] Step 1:

[0902] The preparation of compound I-39 yielded the following:

[0903] Compound I-50 was found as a grayish-white powder (10 mg, 0.014 mmol, 42.0%). LC-MS (ESI, m / z): 701.8 M+1 + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.51 (s, 0.2H) (formic acid), 7.87 (m, 1H), 7.23–7.05 (m, 2H), 5.31 (m, 1H), 3.63–3.39 (m, 2H), 3.41–3.34 (m, 2H), 3.30 (m, 1H), 3.18 (m, 1H), 2.91 (s, 3H), 2.72–2.54 (m ,2H),1.52(m,2H),1.48-1.35(m,4H),1.33(m,2H),1.20-0.99(m,3H),1.01-0.88(m,4H), 0.89-0.78(m,2H),0.80-0.69(m,3H),0.59-0.50(m,4H),0.42(m,2H),0.38-0.18(m,4H).

[0904] Example 51: Compound I-51

[0905] Step 1:

[0906] Compound 36-2 (25 mg, 0.04 mmol) and compound 51-1 (4.6 mg, 0.05 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (16 mg, 0.13 mmol) and HATU (20 mg, 0.02 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to preparative HPLC to obtain a white solid compound I-51 (7.5 mg, 0.011 mmol, 26.58%). LC-MS (ESI, m / z): 672.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.92-7.88(m,1H),7.18-7.13(m,2H),6.31(d,J=9.0Hz,1H) ,5.66(qd,J=7.0,5.5Hz,1H),4.98-4.93(m,1H),4.89-4.83(m,1H),3.44-3.32(m 4H),3.21-3.13(m,1H),2.91(s,3H),2.63-2.61(m,1H),1.95(d,J=0.9Hz,3H),1.85-1.69(m,3H),1.56-1.49(m,6H), 1.40-1.38(m,3H),0.95-0.88(m,4H),0.80-0.66(m,3H),0.57(d,J=4.3Hz,1H),0.52-0.37(m,3H),0.36-0.18(m,4H).

[0907] Example 52: Compound I-52

[0908] Step 1:

[0909] The compound I-51 was prepared using the same method as that used for compound I-51.

[0910] White solid compound I-52 (15 mg, 0.022 mmol, 43.7%). LC-MS (ESI, m / z): 672.2 [M+H] + . 1HNMR(400MHz,MeOD)δ7.93-7.83(m,1H)7.19-7.10(m,2H),6.54-6.46(m,1H),6.31(d,J=8.8Hz,1H),4.97-4.91(m,1H),4.85(dd,J=9.2,6.8Hz 1H),3.59-3.36(m 3H),3.32-3.28(m,1H),3.23-3.11(m,1H),2.90(s,3H),2.66-2.57(m,1H),1.91(s, 3H),1.82(d,J=6.8H,3H),1.59-1.20(m,6H),1.19-0.68(m,10H),0.59-0.15(m,8H).

[0911] Example 53: Compound I-53

[0912] Step 1:

[0913] Triethylamine (12.75 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (23.96 mg, 0.063 mmol) were added to a solution of compound 36-2 (25.00 mg, 0.04 mmol) and compound 53-1 (4.20 mg, 0.05 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-53 (4 mg, 0.0061 mmol, 14.55%) as a white solid. LC-MS (ESI, m / z): 656.2 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.92-7.82(m,1H),7.19-7.10(m,2H),4.96-4.91(m,1H),4. 89-4.81(m,1H),3.59-3.42(m,2H),3.39-3.33(m,2H),3.21-3.14(m,1H),2.91( s,3H),2.66-2.57(m,1H),2.09-1.99(m,3H),1.58-1.22(m,8H),1.18-1.05(m,2 H),1.01-0.73(m,6H),0.73-0.62(m,1H),0.61-0.34(m,4H),0.33-0.21(m,3H).

[0914] Example 54: Compound I-54

[0915] Step 1:

[0916] Compound 54-1 (1.18 g, 5.88 mmol) and compound 54-2 (500 mg, 4.9 mmol) were dissolved in tetrahydrofuran (15 mL), and pyridine (1.93 g, 24.48 mmol) and DMAP (60 mg, 0.49 mmol) were added. The reaction mixture was stirred at 10 °C for 16 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 54-3 (900 mg, 68.79%) as a white solid. LC-MS (ESI, m / z): 289.8 [M + Na] + .

[0917] Step Two:

[0918] Compound 54-3 (33 mg, 1.25 mmol) and compound 36-2 (25 mg, 0.042 mmol) were dissolved in N,N-dimethylformamide (2 mL), and triethylamine (8 mg, 0.08 mmol) was added. The reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative HPLC to obtain compound I-54 (6.09 mg, 0.012 mmol, 9.58%) as a white solid. LC-MS (ESI, m / z): 717.4 [M+H] + . 1 H NMR (400MHz, MeOD) δ7.88(dt,J=15.7,8.0Hz,1H),7.15(t,J=9.8Hz,2H),6.31(d,J=8.9Hz,1H),4.96 -4.94(m,1H),4.88-4.79(m,1H),4.53(t,J=6.2Hz,1H),3.96-3.93m,2H), 3.62-3.36(m,5H),3.22-3.12(m,1H),2.91(s,3H),2.67-2.58(m,1H),1.9 9-1.96(m,2H),1.71-1.67(m,2H),1.58-1.22(m,6H),1.20-1.00(m,3H),0 .97-0.85(m,4H),0.77-0.76(m,2H),0.69-0.37(m,4H),0.29-0.25(m,4H).

[0919] Example 55: Compound I-55

[0920] Step 1:

[0921] In a 100 mL round-bottom flask, HATU (24.5 mg, 0.043 mmol) and triethylamine (8.7 mg, 0.086 mmol) were added sequentially to a 3 mL solution of N,N-dimethylformamide containing compound 55-1 (8.5 mg, 0.055 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. Compound 36-2 (25 mg, 0.043 mmol) was added to the reaction mixture in one go, and the mixture was stirred at room temperature for 3 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0). ～ 1:1; Dichloromethane: Methanol = 1:0 ～ The reaction was carried out at a 1:1 ratio to obtain a white solid compound I-55 (40 mg, 0.015 mmol, 49.2%). LC-MS (ESI, m / z): 726.2 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.92-7.80(m,1H),7.19-7.10(m,2H),6.30(d,J=8.8H z,1H),4.98-4.90(m,1H),4.87-4.84(m,1H),3.63-3.35(m,4H),3.23-3.12(m,1H), 2.91(s,3H),2.66-2.58(m,1H),1.57-1.48(m,1H),1.44-1.37(m,5H),1.35-1.27( m,3H),1.18-1.10(m,3H),0.98-0.91(m,2H),0.88-0.68(m,5H),0.61-0.19(m,9H).

[0922] Example 56: Compound I-56

[0923] Step 1:

[0924] Compound 36-2 (30 mg, 0.05 mmol, 1.00 eq), compound 56-1 (7.00 mg, 0.06 mmol, 1.24 eq), and N,N-diisopropylethylamine (20 mg, 0.16 mmol, 3.04 eq) were dissolved in N,N-dimethylformamide (1.5 mL), and HATU (30 mg, 0.08 mmol, 1.55 eq) was added. The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with water, extracted with ethyl acetate (15 mL x 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-56 (10.00 mg, 0.015 mmol, 28.72%) as a white solid. LC-MS (ESI, m / z): 682.8 [M+H] + . 1 H NMR(400MHz,DMSO)δ9.92(s,1H),7.89-7.66(m,2H),7.24-7.02(m,2H),6.17(dd,J =9.2,3.2Hz,1H),4.90-4.72(m,2H),3.50-3.42(m,2H),3.33-3.27(m,2H),3.27-3. 06(m,2H),2.75(s,3H),2.56-2.50(m,1H),1.70-1.54(m,3H),1.53-1.38(m,2H),1 .35-1.25(m,4H),1.21-1.00(m,3H),0.85(t,J=7.6Hz,2H),0.77-0.71(m,3H),0.66 -0.63(m,2H),0.45-0.38(m,3H),0.33-0.16(m,4H),0.16-0.07(m,1H).

[0925] Example 57: Compound I-57-A, Compound I-57-B

[0926] Step 1:

[0927] In a dry 100 mL three-necked flask, sodium hydride (60%, 31 mg, 0.77 mmol) was added, followed by 10 mL of dry tetrahydrofuran. The reaction flask was placed under an argon atmosphere and cooled to 0 °C using an ice-water bath. Then, 3 mL of an anhydrous tetrahydrofuran solution of compound 57-2 (100 mg, 0.39 mmol) was slowly added dropwise to this solution. The reaction mixture was stirred at 0 °C for 1 hour. Next, compound 57-1 (28.6 mg, 0.41 mmol) was added dropwise to the same three-necked flask while maintaining the solution temperature below 5 °C. After the addition was complete, the reaction mixture was stirred in an ice-water bath for another 1 hour. TLC (PE:EA = 3:1) monitoring showed that the starting materials had reacted completely. Saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, followed by dilution with water and extraction three times with ethyl acetate solution. The combined extracts were then washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 1:1) to give the target compound 57-3 (60 mg, 0.34 mmol) as a colorless oil. 1 H NMR(400MHz,Chloroform-d)δ6.47(d,J=10.4Hz,1H),4.39-4.23(m,3H),1.36-1.32 (m,3H),1.14-1.06(m,2H),1.06-0.99(m,1H),0.79-0.72(m,2H),0.65-0.59(m,1H).

[0928] Step Two:

[0929] In a 100 mL round-bottom flask, lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added to a tetrahydrofuran / water solution (10 mL / 3 mL) of compound 57-3 (60 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 3 hours, and LC-MS monitoring showed that the starting material was completely consumed. The reaction mixture was placed in an ice-water bath, and dilute hydrochloric acid (1 M) was added dropwise to adjust the pH of the solution to 3–4. The mixture was extracted three times with ethyl acetate. The combined extracts were then washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid crude product, compound 57-4 (45 mg, 0.31 mmol). The crude product was used directly in the next reaction without further purification. LC-MS (ESI, m / z): 145.1 [MH] - .

[0930] Step 3:

[0931] In a 100 mL round-bottom flask, HATU (125 mg, 0.33 mmol) and triethylamine (45 mg, 0.44 mmol) were added sequentially to a 3 mL solution of N,N-dimethylformamide containing compound 57-4 (36 mg, 0.266 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. Compound 36-2 (130 mg, 0.22 mmol) was added to the reaction mixture in one step, and the mixture was stirred at room temperature for 16 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–15:1) to obtain a white solid product. The white solid product was resolved by chiral preparation to obtain:

[0932] Compound I-57-A (peak 1: 4.007 mins, 10 mg, 0.014 mmol, 5%), LC-MS (ESI, m / z): 718.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ7.93-7.81(m,1H),7.20-7.10(m,2H),5.70(dd ,J=10.8,3.2Hz,1H),4.97-4.86(m,2H),3.61-3.41(m,2H),3.41-3.35(m,1H ),3.32-3.26(m,1H),3.23-3.12(m,1H),2.91(s,3H),2.69-2.57(m,2H),1. 56-1.48(m,1H),1.46-1.32(m,5H),1.17-0.75(m,12H),0.64-0.21(m,10H). 11H NMR (400 MHz, Chloroform-d) δ 8.31 - 8.18 (m, 1H), 8.09 - 8.00 (m, 1H), 7.64 - 7.56 (m, 1H), 7.10 - 7.00 (m, 2H), 6.02 - 5.94 (m, 1H), 5.69 - 5.62 (m, 1H), 5.02 - 4.92 (m, 1H), 4.78 - 4.68 (m, 1H), 3.71 - 3.56 (m, 1H), 3.53 - 3.07 (m, 4H), 3.04 - 2.94 (m, 1H), 2.92 (s, 3H), 2.60 - 2.50 (m, 1H), 1.49 - 1.31 (m, 5H), 1.21 - 0.72 (m, 13H), 0.70 - 0.45 (m, 6H), 0.43 - 0.33 (m, 2H), 0.30 - 0.22 (m, 2H).

[0933] Compound I-57-B (peak2: 5.864 mins, 10 mg, 0.014 mmol, 5%). LC-MS (ESI, m / z): 718.2 [M+H] + . 1 1H NMR (400 MHz, Methanol-d4) δ 7.92 - 7.78 (m, 1H), 7.21 - 7.09 (m, 2H), 6.54 - 6.40 (m, 1H), 6.29 (d, J = 8.8 Hz, 1H), 4.98 - 4.86 (m, 2H), 3.60 - 3.35 (m, 4H), 3.24 - 3.10 (m, 1H), 2.91 (s, 3H), 2.66 - 2.56 (m, 1H), 2.01 - 1.89 (m, 1H), 1.58 - 1.37 (m, 5H), 1.18 - 1.05 (m, 4H), 1.00 - 0.91 (m, 2H), 0.88 - 0.71 (m, 7H), 0.62 - 0.19 (m, 9H). 1H NMR(400MHz,Chloroform-d)δ8.30-8.15(m,1H),8.09-7.99(m,1H),7.67-7.56(m,1H),7.13-6.98( m,2H),6.56(d,J=10.4Hz,1H),5.96(t,J=10.0Hz,1H),4.97(t,J=9.2Hz,1H),4.79-4.66(m,1H),3.7 2-3.57(m,1H),3.52-3.06(m,4H),2.92(s,3H),2.59-2.49(m,1H),2.00-1.83(m,1H),1.55-1.33(m, 6H),1.17-0.85(m,9H),0.82-0.72(m,5H),0.70-0.47(m,4H),0.45-0.32(m,2H),0.31-0.19(m,2H).

[0934] Example 58: Compound I-58-A, Compound I-58-B

[0935] Step 1:

[0936] Sodium hydroxide (60% in mineral oil) (0.36 g, 8.95 mmol, 1.20 eq) was added to dry tetrahydrofuran (8.00 mL), followed by the dropwise addition of a tetrahydrofuran solution (3 mL) of compound 58-1 (1.99 g, 8.22 mmol, 1.10 eq) and a tetrahydrofuran solution (1 mL) of compound 58-2 (0.80 g, 7.47 mmol, 1.00 eq) at 0 °C. After 15 minutes, the reaction mixture was allowed to react at room temperature for 4 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (60 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative HPLC to give compounds 58-3-A (E, 368.00 mg, 1.89 mmol, 25.24%) and 58-3-B (Z, 118.00 mg, 0.61 mmol, 8%). LC-MS (ESI, m / z): 196.1 [M+H] + .

[0937] Step Two:

[0938] Compound 58-3-B (0.12 g, 0.60 mmol, 1.00 eq) was dissolved in tetrahydrofuran (3.00 mL) and water (0.30 mL), and lithium hydroxide monohydrate (0.10 g, 2.43 mmol, 4.01 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized to pH 6-7 with 1 M HCl, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a white solid compound 58-4-B (20.00 mg, 0.12 mmol, 19.78%). LC-MS (ESI, m / z): 167.9 [M+H] + .

[0939] Step 3:

[0940] Compound 36-2 (0.03 g, 0.05 mmol, 1.00 eq), compound 58-4-B (0.02 g, 0.10 mmol, 2.00 eq), and N,N-diisopropylethylamine (0.02 g, 0.16 mmol, 3.04 eq) were dissolved in N,N-dimethylformamide (1.5 mL), and HATU (0.03 g, 0.08 mmol, 1.55 eq) was added. The reaction mixture was stirred at room temperature for 20 minutes, diluted with water, and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-58-B (9 mg, 0.012 mmol, 24%) as a white solid. LC-MS (ESI, m / z): 739.2 [M+H] + . 1H NMR (400MHz, DMSO) δ9.96 (s, 1H), 8.67 (d, J = 4.4Hz, 1H), 8.51 (t, J = 9.6Hz, 1H), 7.9 7-7.87(m,1H),7.81-7.75(m,2H),7.39(dd,J=6.8,4.8Hz,1H),7.12(dt,J=14.8,8. 4Hz,2H),6.97(d,J=36Hz,1H),6.24-6.10(m,1H),5.02-4.90(m,1H),4.83(t,J=8.8 Hz,1H),3.55-3.35(m,3H),3.22-3.14(m,2H),2.72(s,3H),2.58-2.52(m,1H),1.57 -1.32(m,2H),1.26(d,J=7.2Hz,4H),1.21-1.10(m,3H),0.89-0.82(m,5H), 0.66-0.63(m,2H),0.48-0.45(m,1H),0.39-0.33(m,3H),0.26-0.16(m,4H).

[0941] Step Four:

[0942] Compound 36-2 (0.03 g, 0.05 mmol, 1.00 eq), compound 58-4-A (0.02 g, 0.11 mmol, 2.12 eq, obtained by scale-up preparation of compound 58-4-B), and N,N-diisopropylethylamine (0.02 g, 0.16 mmol, 3.04 eq) were dissolved in N,N-dimethylformamide (1.50 mL), and HATU (0.03 g, 0.08 mmol, 1.55 eq) was added. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water, extracted with ethyl acetate (15 mL x 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC, lyophilized, and given as a white solid I-58-A (8.0 mg, 0.01 mmol, 21%). LC-MS (ESI, m / z): 739.2 [M+H] + . 1H NMR (400MHz, DMSO) δ12.39(d,J=8.4Hz,1H),9.91(s,1H),8.59(d,J=4.4Hz,1H),7.96(t,J=7.6Hz,1H),7.81-7. 57(m,2H),7.47-7.45(m,1H),7.23-6.98(m,3H),6.16(d,J=8.8Hz,1H),5.06-5.02(m,1H),4.85-4.80(m,1H),3 .44-3.39(m,3H),3.28-3.07(m,2H),2.75(s,3H),2.55-2.53(m,1H),1.51-1.39(m,2H),1.27-1.25(m,4H),1.2 1-1.09(m,3H),0.95-0.74(m,4H),0.74-0.55(m,3H),0.53-0.31(m,3H),0.23-0.18(m,4H),0.10-0.06(m,1H).

[0943] Example 59: Compound I-59

[0944] Step 1:

[0945] Compound 58-1 (2.50 g, 10.32 mmol, 1.00 eq) was dissolved in dichloromethane (25.00 mL), and DBU (7.85 g, 51.62 mmol, 5.00 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. Then, compound 59-1 (2.62 g, 15.46 mmol, 1.50 eq) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with ammonium chloride aqueous solution, and extracted with dichloromethane (60 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain a crude product, which was then purified by preparative HPLC to obtain a yellow oily compound 59-2 (650.00 mg, 3.71 mmol, 35.94%). LC-MS (ESI, m / z): 176.2 [M+H] + .

[0946] Step Two:

[0947] Compound 59-2 (0.63 g, 3.60 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.00 mL) and water (1.00 mL). Lithium hydroxide monohydrate (0.61 g, 14.43 mmol, 4.01 eq) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized to pH 6 with 1 N hydrochloric acid, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a colorless oily compound 59-3 (200.00 mg, 1.36 mmol, 37.73%). LC-MS (ESI, m / z): 148.1 [M+H] + .

[0948] Step 3:

[0949] Compound 36-2 (0.03 g, 0.05 mmol, 1.00 eq), compound 59-3 (0.02 g, 0.10 mmol, 2.00 eq), and N,N-diisopropylethylamine (0.02 g, 0.16 mmol, 3.04 eq) were dissolved in N,N-dimethylformamide (2.00 mL), and HATU (0.03 g, 0.08 mmol, 1.55 eq) was added. The reaction mixture was stirred at room temperature for 15 min, diluted with water, and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC and lyophilized to give compound I-59 (40.00 mg, 0.056 mmol, 41.00%) as a white solid. LC-MS (ESI, m / z): 718.8 [M+H] + . 1 H NMR(400MHz,MeOD)δ7.90-7.82(m,1H),7.18 -7.13(m,2H),6.29(d,J=9.2Hz,1H),6.18(dt,J=36.0,7.6Hz,1H),5.00-4.89(m,2H),3.62-3.43( m,2H),3.41-3.36(m,2H),3.27(dd,J=7.6,2.4Hz,2H),3.25-3.11(m,2H),2.91(s,3H),2.63-2.59 (m,1H),2.33(s,6H),1.54-1.51(m,1H),1.40(d,J=7.2Hz,3H),1.39-1.21(m,2H),1.19-0.99(m,3 H),0.97-0.93(m,2H),0.88-0.79(m,2H),0.77-0.75(m,3H),0.62-0.38(m,4H),0.38-0.17(m,4H).

[0950] Example 60: Compound I-60

[0951] Step 1:

[0952] Compound 60-2 (935 mg, 3.92 mmol, 1.00 eq) was dissolved in tetrahydrofuran (8.00 mL) at 0 °C. Sodium hydroxide (in 60% mineral oil) (171 mg, 7.12 mmol, 1.82 eq) was added under an ice-water bath, followed by dropwise addition of a tetrahydrofuran solution of compound 60-1 (250 mg, 3.57 mmol, 0.91 eq). The reaction mixture was stirred under an ice-water bath for 20 minutes, then brought to room temperature and stirred for 4 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give a colorless liquid compound 60-3 (435.00 mg, 2.82 mmol, 71.90%). LC-MS (ESI, m / z): 155.1 [M+H] + .

[0953] Step Two:

[0954] Compound 60-3 (0.13 g, 0.84 mmol, 1.00 eq) was dissolved in 1,4-dioxane (2.0 mL) and water (2.00 mL), and potassium hydroxide (0.20 g, 3.65 mmol, 4.33 eq) was added. The reaction mixture was stirred at 60 °C for 2 hours. The pH was adjusted to 2 with 1 M hydrochloric acid, resulting in the precipitation of a white precipitate. The precipitate was filtered, washed with water, and then dried under vacuum to give a white solid, compound 60-4 (60.00 mg, 0.48 mmol, 56.42%). LC-MS (ESI, m / z): 126.9 [M+H] + .

[0955] Step 3:

[0956] Compound 36-2 (30 mg, 0.05 mmol, 1.00 eq), compound 60-4 (10.00 mg, 0.08 mmol, 1.55 eq), and N,N-diisopropylethylamine (20 mg, 0.16 mmol, 3.04 eq) were dissolved in N,N-dimethylformamide (1.5 mL), and HATU (30 mg, 0.08 mmol, 1.55 eq) was added. The reaction mixture was stirred at room temperature for 20 minutes. The solution was diluted with water, extracted with ethyl acetate (15 mL x 3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-60 (12.00 mg, 0.017 mmol, 33.72%) as a white solid. LC-MS (ESI, m / z): 698.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.78 (s, 1H), 7.77 (q, J = 8.4Hz, 1H), 7.51-7.39 (m, 1H), 7.11 (dt, J = 15.6, 8. 8Hz,2H),6.21-6.08(m,1H),5.76(d,J=10.4Hz,1H),4.82-4.77(m,2H),3.45-3.33(m,2H),3.30- 3.04(m,3H),2.75(s,3H),2.54-2.51(m,1H),1.90(s,3H),1.65-1.60(m,1H),1.53-1.32(m,2H) ,1.32-1.01(m,7H),0.88-0.75(m,6H),0.70-0.64(m,3H),0.54-0.52(m,2H),0.48-0.07(m,8H).

[0957] Example 61: Compound I-61

[0958] Step 1:

[0959] A methanol solution (3.00 mL) of compound 4-1 (800.00 mg, 2.34 mmol) was dissolved in methanol hydrochloric acid (6.00 mL, 24 mmol), and the reaction mixture was stirred overnight at 70 °C under argon protection. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution (25 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to give a yellow solid, compound 61-1 (522 mg, 2.04 mmol, 87.17%). LC-MS (ESI, m / z): 257.1 [M+1] + .

[0960] Step Two:

[0961] Triphosgene (302.37 mg, 1.02 mmol) and N,N-diisopropylethylamine (789.80 mg, 6.11 mmol) were added to a dichloromethane (10.00 mL) solution of compound 61-1 (522.00 mg, 2.04 mmol). The reaction mixture was stirred for 15 minutes under argon protection at 0 °C. A dichloromethane solution of N-methylcyclopropylamine hydrochloride (438.30 mg, 4.07 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 61-2 (640 mg, 1.81 mmol, 88.91%). LC-MS (ESI, m / z): 354.2 [M+1] + .

[0962] Step 3:

[0963] Palladium / carbon (100.00 mg) was added to a 30.00 mL solution of compound 61-2 (640.00 mg, 1.81 mmol) in ethyl acetate. The reaction mixture was stirred for 2 hours under hydrogen protection. The palladium on carbon was filtered off, and the filtrate was evaporated to dryness to give a yellow solid, compound 61-3 (510 mg, 1.58 mmol, 87.09%). LC-MS (ESI, m / z): 324.1 [M+1] + .

[0964] Step Four:

[0965] To a pyridine (10.00 mL) solution of compound 36-1 (446.03 mg, 1.66 mmol) and compound 61-3 (510.00 mg, 1.58 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (906.90 mg, 4.73 mmol) was added. The reaction mixture was stirred overnight at room temperature under argon protection. Pyridine was removed by vacuum distillation, the reaction mixture was diluted with water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 61-4 (620 mg, 1.08 mmol, 68.41%) as a pale yellow solid. LC-MS (ESI, m / z): 575.4 [M+1] + .

[0966] Step 5:

[0967] Trifluoroacetic acid (1.00 mL) was added to a solution of compound 61-4 (610.00 mg, 1.06 mmol) in dichloromethane (5.00 mL), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to give a pale yellow solid, compound 61-5 (501 mg, 1.056 mmol, 99.50%). LC-MS (ESI, m / z): 474.9 [M+1] + .

[0968] Step Six:

[0969] Triethylamine (317.23 mg, 3.14 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (595.84 mg, 1.57 mmol) were added to a solution of compound 61-5 (496.00 mg, 1.04 mmol) and 2-fluoropropionic acid (98.80 mg, 1.10 mmol) in N,N-dimethylformamide (5.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 61-6 (565 mg, 1.03 mmol, 98.91%) as a yellow solid. LC-MS (ESI, m / z): 547.3 [M+1] + .

[0970] Step Seven:

[0971] Lithium hydroxide (3.00 mL, 6.00 mmol) was added to a solution of compound 61-6 (560.00 mg, 1.02 mmol) in tetrahydrofuran (3.00 mL) and methanol (3.00 mL). The reaction mixture was stirred at room temperature for 2 hours under argon protection. The pH was adjusted to approximately 4 with hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and dried and concentrated to give a yellow solid, compound 61-7 (545 mg, 1.02 mmol, 99.93%). LC-MS (ESI, m / z): 532.8 [M+1] + .

[0972] Step 8:

[0973] Triethylamine (17.00 mg, 0.17 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (31.94 mg, 0.084 mmol) were added to a solution of compound 61-7 (30.00 mg, 0.06 mmol) and methylamine hydrochloride (4.19 mg, 0.06 mmol) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-61 (3 mg, 0.0055 mmol, 9.8%) as a white solid. LC-MS (ESI, m / z): 545.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.83(t,J=8.1Hz,1H),7.15-7.05(m,2H),6.15(d,J=8.7Hz,1H), 5.66(dd,J=47.0,3.5Hz,1H),5.29(dd,J=15.3,3.5Hz,1H),4.96-4.88(m,1H),4.42-4 .33(m,1H),3.26-3.13(m,1H),2.88(s,3H),2.64-2.56(m,1H),2.56(s,3H),1.39-1.2 8(m,4H),0.92-0.75(m,5H),0.69-0.63(m,1H),0.60-0.40(m,4H),0.37-0.20(m,4H).

[0974] Example 62: Compound I-62

[0975] Compound I-62 (5 mg, 0.0081 mmol, 14.53%) was obtained as a white solid using the same method as compound I-61. LC-MS (ESI, m / z): 614.8 [M+1] + . 1H NMR(400MHz,MeOD)δ7.84-7.76(m,1H),7.22-7.15(m,1H),7.14-7.08(m,1H),5.65(dd,J=47.1,3.5Hz,1 H),5.28(dd,J=15.3,3.5Hz,1H),4.94-4.87(m,1H),4.85-4.80(m,1H),3.67-3.55(m,1H),3.52-3.44(m ,2H),3.23-3.12(m,2H),2.90(s,3H),2.69-2.57(m,3H),2.36(s,3H),2.25-2.18(m,1H),1.97-1.88(m, 1H), 1.42 (d, J = 7.0Hz, 3H), 1.36-1.29 (m, 1H), 0.97-0.75 (m, 6H), 0.61-0.41 (m, 4H), 0.40-0.23 (m, 4H).

[0976] Example 63: Compound I-63

[0977] Compound I-63 (5 mg, 0.0077 mmol, 13.77%) was obtained as a white solid using the same method as compound I-61. LC-MS (ESI, m / z): 647.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.87(t,J=8.3Hz,1H),7.21-7.08(m,2H),6.29(d,J=9.0Hz,1H),5.66(dd,J=47.0,3.5Hz,1 H),5.28(dd,J=15.3,3.5Hz,1H),4.95-4.88(m,2H),3.59-3.51(m,1H),3.39-3.34(m,2H),3.28-3.13(m,2H),2. 90(s,3H),2.66-2.58(m,1H),2.17-2.03(m,2H),1.82-1.73(m,1H),1.58-1.49(m,1H),1.41(d,J=7.0Hz,3H),1. 38-1.28(m,1H),0.99-0.89(m,2H),0.87-0.71(m,4H),0.59-0.43(m,3H),0.42-0.23(m,4H),0.22-0.15(m,1H).

[0978] Example 64: Compound I-64

[0979] Following the preparation method of compound I-61, compound I-64 (4 mg, 0.0062 mmol, 10.99%) was obtained as a white solid. LC-MS (ESI, m / z): 650.3 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.92-7.84(m,1H),7.22-7.10(m,2H),6.33(d,J=8.4Hz,1H),5.66(dd,J=47.0,3.5Hz,1H), 5.28(dd,J=15.3,3.5Hz,1H),4.95-4.88(m,2H),4.06-3.95(m,2H),3.71-3.58(m,2H),3.27-3.18(m,1H),3.17 -3.10(m,1H),3.06-2.98(m,1H),2.90(s,3H),2.80-2.73(m,1H),2.66-2.59(m,1H),2.56-2.47(m,1H),1.43(d ,J=7.0Hz,3H),1.37-1.30(m,1H),0.99-0.90(m,2H),0.86-0.75(m,4H),0.60-0.40(m,4H),0.39-0.21(m,4H).

[0980] Example 65: Compound I-65

[0981] Compound I-65 (5 mg, 0.0082 mmol, 14.66%) was obtained as a white solid using the same method as compound I-61. LC-MS (ESI, m / z): 608.8 [M+1] + . 1H NMR(400MHz,MeOD)δ8.37-8.28(m,2H),7.82(t,J=8.3Hz,1H),7.52-7.45(m,2H),7.22-7.09(m,2H),6 .32(d,J=8.6Hz,1H),5.65(dd,J=47.0,3.5Hz,1H),5.28(dd,J=15.3,3.5Hz,1H),4.94-4.87(m,1H),4. 55-4.50(m,1H),3.32-3.22(m,1H),2.89(s,3H),2.68-2.60(m,1H),1.43(d,J=7.0Hz,3H),1.36-1.30( m,1H),0.97-0.90(m,2H),0.82-0.71(m,4H),0.56-0.40(m,3H),0.35-0.21(m,4H),0.18-0.12(m,1H).

[0982] Example 66: Compound I-66

[0983] Following the preparation method of compound I-61, compound I-66 (10.00 mg, 0.016 mmol, 28.18%) was obtained as a white solid. LC-MS (ESI, m / z): 633.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.95(d,J=10.4Hz,1H),8.30(t,J=8.0Hz,1H),7.81(dt,J=25.2,8.2Hz,1H),7.18-7.07(m ,2H),6.16(dd,J=8.8,3.6Hz,1H),5.63(dd,J=48.0,3.6Hz,1H),5.35-5.30(m,1H),4.96-4.85(m,1H),4.40-4 .21(m,2H),3.94-3.75(m,2H),3.66-3.62(m,1H),3.18-3.13(m,1H),2.75(s,3H),2.54-2.50(m,1H),1.72-1. 55(m,2H),1.27(d,J=6.8Hz,3H),0.93-0.67(m,5H),0.66-0.53(m,2H),0.47-0.44(m,1H),0.41-0.06(m,7H).

[0984] Example 67: Compound I-67

[0985] Compound I-67 (10 mg, 0.017 mmol, 29.7%) was obtained as a white solid, prepared according to the method used for compound I-61. LC-MS (ESI, m / z): 602.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.86(t,J=8.3Hz,1H),7.20-7.10(m,2H),6.30(d,J=8.9Hz,1H),5.67(dd,J=47.0,3.5Hz,1H), 5.29(dd,J=15.3,3.5Hz,1H),4.93(d,J=6.7Hz,1H),4.88-4.83(m,1H),3.58-3.37(m,4H),3.31-3.11(m,4H),2.99 -2.87(m,4H),2.67-2.57(m,1H),1.41(d,J=7.0Hz,3H),0.98-0.91(m,2H),0.88-0.75(m,4H),0.41-0.57(m,4H),0.22-0.35(m,4H).

[0986] Example 68: Compound I-68

[0987] Following the preparation method of compound I-61, compound I-68 (12.00 mg, 0.021 mmol, 36.59%) was obtained as a white solid. LC-MS (ESI, m / z): 586.2 [M+H] + . 1H NMR (400MHz, DMSO) δ9.89(s,1H),8.28(d,J=8.8Hz,1H),8.01(t,J=5.6Hz,1H),7.72(t,J=8.4Hz,1H),7.17-7.00(m,2H),5 .95(d,J=9.2Hz,1H),5.63(dd,J=48.0,3.6Hz,1H),5.33(dd,J=15.6,3.6Hz,1H),4.92-4.84(m,1H),4.41-4.37(m,1H),3. 17-3.09(m,1H),2.92-2.88(m,1H),2.82-2.74(m,1H),2.73(s,3H),2.50-2.45(m,1H),1.21(d,J=7.2Hz,3H),0.92-0.72( m,5H),0.72-0.60(m,2H),0.58-0.55(m,1H),0.51-0.42(m,1H),0.42-0.22(m,6H),0.22-0.08(m,3H),0.05-0.02(m,2H).

[0988] Example 69: Compound I-69

[0989] Compound I-69 (25 mg, 0.039 mmol, 51.9%) was obtained as a white solid, prepared according to the method used for compound I-61. LC-MS (ESI, m / z): 642.2 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.77(t,J=8.2Hz,1H),7.19-7.07(m,2H),6.27(d,J=9.0Hz,1H),5.65(dd,J=47.1,3.5Hz,1H),5 .28(dd,J=15.3,3.5Hz,1H),4.90(dd,J=12.8,6.1Hz,2H),4.44-4.35(m,2H),4.26(dd,J=14.0,6.0Hz,2H),3.51(ddd ,J=13.3,6.4,3.9Hz,1H),3.19(dddd,J=22.5,15.4,9.1,4.5Hz,4H),2.90(s,3H),2.66-2.54(m,1H),1.81-1.70(m, 2H),1.47-1.35(m,4H),1.11(ddd,J=13.0,8.6,4.2Hz,1H),0.99-0.90(m,2H),0.89-0.71(m,5H),0.62-0.17(m,8H).

[0990] Example 70: Compound I-70

[0991] According to the preparation method of compound I-61:

[0992] A white solid compound, I-70 (15 mg, 0.023 mmol; 42.27%), was obtained. LC-MS (ESI, m / z): 634.1 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.89(dt,J=39.2,8.4Hz,1H),7.19-7.05(m,2H),6.31-6.18(m,1H),5.6 6(dd,J=47.2,3.6Hz,1H),5.32-5.25(m,1H),4.96-4.90(m,1H),4.66-4.51(m,1H),4.10-4.00(m,1H ),3.83-3.62(m,1H),3.44(d,J=12.0Hz,1H),3.25-3.13(m,1H),2.90(d,J=3.6Hz,3H),2.65-2.56(m ,1H),2.43-2.24(m,2H),1.43-1.35(m,3H),1.00-0.89(m,2H),0.87-0.75(m,4H),0.61-0.16(m,9H).

[0993] Example 71: Compound I-71

[0994] Formate of compound I-71 (15 mg, 0.023 mmol, 41.8%) was obtained as a white solid, following the preparation method for compound I-61. LC-MS (ESI, m / z): 641.5 [M+H] + . 1¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 1.5H) (formic acid), 7.83 (t, J = 8.0Hz, 1H), 7.08 (m, 2H), 5.66 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.29 (dd, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 4.96–4.90 (m, 2H), 4.61 (s, 1H), 4.32–4.24 (m, 1H). H),3.15-3.04(m,1H),2.89(s,3H),2.64-2.56(m,1H),2.19(s,6H),1.89(m,2H),1.88(d,J=4.8Hz, 3H),1.40-1.27(m,5H),0.96-0.89(m,2H),0.90-0.66(m,5H),0.61-0.37(m,4H),0.37-0.21(m,3H).

[0995] Example 72: Compound I-72

[0996] Formate of compound I-72 (10 mg, 0.016 mmol, 31.5%) was obtained as a white solid, following the preparation method of compound I-61. LC-MS (ESI, m / z): 647.8 (M+H) + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.57 (s, 2H) (formic acid), 7.88 (t, J = 8.0Hz, 1H), 7.15 (m, 2H), 5.66 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.28 (dd, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 4.62 (s, 1H), 4.33–4.17 (m, 2H), 3.93 (m, 1H), 3.63 (m, 1H), 3 .51(m,1H),3.12(m,2H),2.90(s,3H),2.68(m,2H),2.63(m,1H),2.47(m,2H),1.41(d,J=7.2Hz,3H),1.3 1(m,4H),0.99-0.89(m,2H),0.89-0.68(m,4H),0.60-0.48(m,2H),0.46-0.33(m,2H),0.34-0.21(m,2H).

[0997] Example 73: Compound I-73

[0998] Formate of compound I-73 (23 mg, 0.038 mmol, 72.0%) was obtained as a white solid, following the preparation method of compound I-61. LC-MS (ESI, m / z): 602.8 (M+H) + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.50 (s, 2H) (formic acid), 7.81 (t, J = 8.0Hz, 1H), 7.14 (m, 2H), 6.23 (d, J = 7.6Hz, 1H), 5.66 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.29 (dd, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 4.33–4.17 (m, 1H),3.30-3.16(m,2H),2.89(s,3H),2.87-2.80(m,2H),2.75(s,6H),2.66-2.52(m,4H),1.40 (d,J=7.2Hz,3H),1.36-1.29(m,2H),1.00-0.67(m,6H),0.69-0.44(m,4H),0.43-0.19(m,4H)

[0999] Example 74: Compound I-74

[1000] Compound I-74 (11.0 mg, 0.017 mmol, 61.4%) was obtained as a white solid, prepared according to the method used for compound I-61. LC-MS (ESI, m / z): 639.8 (M+H) + . 1 H NMR (400MHz, CD3OD) δ7.94(t,J=8.0Hz,1H),7.16(m,2H),6.25(d,J=8.8Hz,1H),5.66(dd,J1=46.8Hz,J2=3.2Hz ,1H),5.28(dd,J1=15.2Hz,J2=3.2Hz,1H),4.94(d,J=7.2Hz,1H),4.39-4.22(m,1H),3.83(d,J=8.4Hz,1H),3.4 6(d,J=10.0Hz,1H),3.17(d,J=10.0Hz,1H),3.10(m,2H),2.91(s,3H),2.66-2.56(m,1H),1.53(m,2H),1.40(d, J=7.2Hz,3H),1.32(m,6H),1.16(m,2H),0.94(m,2H),0.87-0.72(m,5H),0.60-0.39(m,4H),0.39-0.21(m,4H).

[1001] Example 75: Compound I-75

[1002] The formate salt of compound I-75 was obtained by referring to the preparation method of compound I-61.

[1003] White solid (6 mg, 0.00954 mmol, 17.0%). LC-MS (ESI, m / z): 628.8 [M+1] + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.48 (s, 1.5H) (formic acid), 7.91–7.66 (m, 1H), 7.18 (m, 2H), 6.43–6.22 (m, 1H), 5.67 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.29 (dd, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 4.71–4.43 (m, 4H), 4.12 (m ,1H),3.54(s,1H),3.19(m,2H),2.91(s,3H),2.63(m,1H),2.43(m,2H),2.35(m,2H),2.03(s,2H) ,1.44(m,2H),1.33(m,2H),1.26(m,2H),1.00–0.71(m,6H),0.60–0.44(m,4H),0.46–0.10(m,4H).

[1004] Example 76: Compound I-76

[1005] Step 1:

[1006] A 2M solution (trimethylsilane), diazomethane, and hexane (5 mL) was added to a methanol solution (10 mL) containing compound 4-1 (800 mg, 2.337 mmol). The mixture was stirred at 0 °C for 1 hour. After the reaction was complete as monitored by LC-MS, 5 mL of saturated ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 5 / 1–4 / 1, V / V) to give a yellow, viscous compound 76-1 (826 mg, 2.32 mmol, 99.2%). LC-MS (ESI, m / z): 257.2 (M-100+H). + .

[1007] Step Two:

[1008] 10% Pd / C (100 mg) was added to a methanol (10 mL) solution containing compound 76-1 (826 mg, 2.318 mmol). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LC-MS until completion. The reaction solution was filtered, and the filter cake was washed successively with methanol and dichloromethane. The combined filtrates were concentrated under reduced pressure to give a brown, viscous compound 76-2 (756 mg, 2.318 mmol, 99.9%). LC-MS (ESI, m / z): 227.1 (M-100+H) + .

[1009] Step 3:

[1010] EDCI (666 mg, 3.474 mmol), pyridine (10 mL), and compound 76-2 (800 mg, 2.637 mmol) were added to (S)-2-((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropionic acid (756 mg, 2.316 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure. 10 mL of saturated sodium bicarbonate solution and 10 mL of water were added to the residue, and the mixture was stirred for ten minutes. The mixture was filtered, the filtrate was washed with water, and the filter cake was concentrated under reduced pressure to obtain a grayish-white powder, compound 76-3 (1416 mg, 2.32 mmol, 99.9%). LC-MS (ESI, m / z): 511.8 (M-100+H). + .

[1011] Step Four:

[1012] 10% Pd / C (150 mg), methanol (30 mL), and dichloromethane (30 mL) were added to compound 76-3 (1400 mg, 2.289 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LC-MS until completion. The reaction solution was filtered, and the filter cake was washed successively with methanol and dichloromethane. The combined filtrates were concentrated under reduced pressure to obtain a grayish-white powder, compound 76-4 (1090 mg, 2.28 mmol, 99.7%). LC-MS (ESI, m / z): 421.8 (M-56+H) + .

[1013] Step 5:

[1014] HATU (946 mg, 2.488 mmol), 2-fluoroacrylic acid (224 mg, 2.488 mmol), and triethylamine (485 mg, 4.792 mmol) were added to a solution of N,N-dimethylformamide (12 mL) containing compound 76-4 (1090 mg, 2.282 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 40 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1 to 1 / 1, V / V) to give compound 76-5 (1217 mg, 2.21 mmol, 97.0%) as a grayish-white powder. LC-MS (ESI, m / z): 449.8 (M-100+H) + .

[1015] Step Six:

[1016] Lithium hydroxide monohydrate (330 mg, 7.865 mmol) was added to a solution of tetrahydrofuran (10 mL) and water (10 mL) containing compound 76-5 (1217 mg, 2.214 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure, and 20 mL of water was added to the residue. The pH of the mixture was adjusted to 4-5 with 2M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL * 2), and the combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a grayish-white powder of compound 76-6 (1112 mg, 2.07 mmol, 93.8%). LC-MS (ESI, m / z): 436.3 (M-100+H) + .

[1017] Step Seven:

[1018] HATU (1000 mg, 2.630 mmol), compound 12-1 (460 mg, 2.505 mmol), and triethylamine (550 mg, 5.435 mmol) were added to a solution of N,N-dimethylformamide (12 mL) containing compound 76-6 (1112 mg, 2.399 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 40 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1 to 1 / 1, V / V) to give compound 76-7 (1360 mg, 2.05 mmol, 85.3%) as a grayish-white powder. LC-MS (ESI, m / z): 564.8 (M-100+H) + .

[1019] Step 8:

[1020] A solution of 4M HCl in ethyl acetate (12 mL) and methanol (4 mL) were added to compound 76-7 (1360 mg, 2.046 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 76-8 (1200 mg, 2.13 mmol, 92.0%) as a brown powder. LC-MS (ESI, m / z): 564.8 (M+H) + .

[1021] Step Nine:

[1022] HATU (12 mg, 0.0316 mmol), 2-methoxyacetic acid (4 mg, 0.0444 mmol), and triethylamine (6 mg, 0.0593 mmol) were added to a solution of N,N-dimethylformamide (1 mL) containing compound 76-8 (16 mg, 0.0283 mmol). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 6 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-76 (10 mg, 0.016 mmol, 56.2%) as a white powder. LC-MS (ESI, m / z): 637.4 (M+H) + . 1H NMR (400MHz, CD3OD) δ7.87(m,1H),7.15(m,2H),5.66(dd,J1=46.8Hz,J2=3.2Hz,1H),5.28(d t, J1=15.2Hz, J2=3.2Hz,1H),5.11(m,1H),4.97-4.90(m,2H),3.97(m,2H),3.51(m,1H),3.46 (s,3H),3.41(m,2H),3.29-3.17(m,1H),1.51(m,2H),1.36(d,J=6.8Hz,3H),1.31(m,2H),1. 18-1.04(m,2H),0.95-0.63(m,3H),0.62-0.48(m,2H),0.47-0.33(m,2H),0.40-0.11(m,4H).

[1023] Example 77: Compound I-77

[1024] I-76 was prepared as a white solid (10 mg, 0.015 mmol, 55.3%) according to the method described for compound I-76. LC-MS (ESI, m / z): 647.4 (M+H) + . 1 H NMR (400MHz, CD3OD) δ7.86(m,1H),7.15(m,2H),5.66(dd,J1=46.8Hz,J2=3.2Hz,1H),5.28( dt,J1=15.2Hz,J2=3.2Hz,1H),5.06(m,1H),4.93(m,2H),3.48(m,2H),3.47-3.36(m,2H),3 .30-3.09(m,2H),2.18(m,2H),1.62-1.41(m,2H),1.37(d,J=7.2Hz,3H),1.32(m,1H),1.15 (m,2H),1.10-1.01(m,2H),0.92-0.68(m,3H),0.60-0.46(m,4H),0.38(m,3H),0.26(m,4H).

[1025] Example 78: Compound I-78

[1026] Formate of compound I-78 (10 mg, 32.3%, 0.015 mmol), a white solid, was obtained using the same method as compound I-76. LC-MS (ESI, m / z): 660.7 (M+H) + . 1¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 0.8H) (formic acid), 7.88 (m, 1H), 7.18 (m, 2H), 5.66 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.28 (dt, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 5.05 (m, 1H), 3.50 (m, 1H), 3.40 (m ,2H),2.68(s,1H),2.24-2.02(m,1H),1.51(m,2H),1.38(d,J=7.2Hz,3H),1.33(m,2H),1 .29-0.92(m,4H),0.79(m,4H),0.61-0.47(m,2H),0.49-0.35(m,2H),0.35-0.16(m,3H).

[1027] Example 79: Compound I-79

[1028] Compound I-79 (10 mg, 0.015 mmol, 44.05%) was obtained as a white solid using the same method as compound I-76. LC-MS (ESI, m / z): 648.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.91-7.81(m,1H),7.19-7.11(m,2H),5.66(dd,J=47.0,3.4Hz ,1H),5.28(dt,J=15.3,3.4Hz,1H),5.11-5.03(m,1H),4.96-4.88(m,1H),4.85-4.7 3(m,4H),3.97-3.87(m,1H),3.55-3.38(m,3H),3.30-3.15(m,2H),1.59-1.42(m,2 H),1.35(d,J=7.0Hz,3H),1.31-1.04(m,4H),0.89-0.72(m,3H),0.59-0.19(m,8H).

[1029] Example 80: Compound I-80

[1030] Compound I-80 (9 mg, 0.014 mmol, 40.36%) was obtained as a white solid using the same method as compound I-76. LC-MS (ESI, m / z): 636.8 [M+1] + . 1H NMR(400MHz,MeOD)δ7.93-7.83(m,1H),7.22-7.13(m,2H),5.76-5.67(m,1H), 5.63-5.55(m,1H),5.34-5.28(m,1H),5.28-5.22(m,1H),5.14-5.07(m,1H),4 .96-4.89(m,1H),3.60-3.35(m,4H),3.32-3.26(m,1H),1.58-1.41(m,2H),1. 38(d,J=6.9Hz,3H),1.32-1.02(m,4H),0.89-0.71(m,3H),0.63-0.13(m,8H).

[1031] Example 81: Compound I-81

[1032] Compound I-81 (4 mg, 0.0064 mmol, 18.43%) was obtained as a white solid using the same method as compound I-76. LC-MS (ESI, m / z): 620.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.91-7.81(m,1H),7.19-7.10(m,2H),5.66(dd,J=47.0,3.3Hz,1H), 5.29(dt,J=15.3,3.3Hz,1H),5.07-4.98(m,1H),4.96-4.89(m,1H),3.53-3.38(m,3H),3 .30-3.15(m,2H),2.37-2.24(m,2H),1.58-1.40(m,2H),1.36(d,J=6.9Hz,3H),1.34-1.2 3(m,2H),1.16(t,J=7.6Hz,3H),1.13-1.01(m,2H),0.89-0.72(m,3H),0.61-0.20(m,8H).

[1033] Example 82: Compound I-82

[1034] Compound I-82 (1.5 mg, 0.002 mmol, 4.47%) was obtained as a white solid, following the preparation method of compound I-76. LC-MS (ESI, m / z): 633.2 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ7.94-7.80(m,1H),7.23-7.11(m,2H),5.77(s,1H),5.66(dd,J=47.2,3.6Hz,1H),5.47(s,1H),5.29(dt,J=15.2,3.6Hz,1 H),5.12-5.05(m,1H),4.98-4.91(m,2H),3.57-3.37(m,4H),1.99(s,3H),1 .61-1.35(m,5H),1.34-0.96(m,4H),0.92-0.71(m,3H),0.60-0.16(m,8H).

[1035] Example 83: Compound I-83

[1036] Compound I-83 (6 mg, 0.0088 mmol; 16.6%) was obtained as a white solid, prepared according to the method used for compound I-76. LC-MS (ESI, m / z): 677.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ9.24(d,0J 9.24(d,0MHz,Chlor-8.18(m,2H),7.98-7.86(m,1H),7.39-7.30(m,1H),7.18-7.06(m,2H),5.82-5.64(m,1H ),5.37-5.28(m,1H),5.26-5.17(m,1H),4.83-4.73(m,1H),3.77-3.60(m,1H),3.56-3.09(m,4H),1.45(d,oJ 3.09(m,4H),1.45-1.13(m,3H),1.13-0.94(m,2H),0.93-0.74(m,3H),0.72-0.48(m,4H),0.44-0.19(m,4H). 1 H NMR(400MHz,Methanol-d4)δ9.56(d,0J 9.56(d,0MHz,Meth-7.83(m,1H),7.30-7.17(m,2H),5.76-5.57(m,1H),5.40-5.24(m,2H),4. 96-4.92(m,1H),3.63-3.38(m,5H),1.65-1.01(m,10H),0.93-0.70(m,3H),0.59-0.20(m,8H).

[1037] Example 84: Compound I-84

[1038] Compound I-84 (11 mg, 0.017 mmol, 36.9%) was obtained as a white solid, prepared according to the method used for compound I-76. LC-MS (ESI, m / z): 651.1 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.92-7.81(m,1H),7.23-7.12(m,2H),5.66(dd,J=47.2,3.6Hz,1H),5.28(dt,J=15.2,3.2Hz,1H),5.15-5.08(m ,1H),4.96-4.88(m,2H),3.57-3.36(m,4H),1.57-1.48(m,1H),1.48- 1.25(m,9H),1.20-1.00(m,3H),0.89-0.72(m,3H),0.58-0.19(m,8H).

[1039] Example 85: Compound I-85

[1040] Compound I-85 (10.00 mg, 0.015 mmol, 28.73%) was obtained as a white solid, prepared according to the method used for compound I-76. LC-MS (ESI, m / z): 656.7 [M+H] + . 1 H NMR(400MHz,DMSO)δ9.94(s,1H),9.16-9.00(m,1H),8.38-8.19(m,1H),7.81-7.74(m,1H),7.21-7 .07(m,2H),5.62(dd,J=48.0,3.6Hz,1H),5.33(dt,J=15.6,3.2Hz,1H),4.96-4.86(m,7.9Hz,2H), 3.46-3.43(m,3H),3.30-3.14(m,2H),1.77(t,J=19.6Hz,3H),1.49-1.37(m,2H),1.25-1.20(m,4H ),1.16-1.07(m,3H),0.91-0.64(m,3H),0.54-0.35(m,2H),0.35-0.27(m,2H),0.20-0.11(m,4H).

[1041] Example 86: Compound I-86

[1042] Following the preparation method for compound I-76, compound I-86 (8.00 mg, 0.012 mmol, 23.20%) was obtained as a white solid. LC-MS (ESI, m / z): 650.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.93 (s, 1H), 8.28 (t, J = 10.0Hz, 1H), 8.01 (dd, J = 8.8, 3.6Hz, 1H), 7.77 (dd, J = 19.2, 8 .4Hz,1H),7.19-7.06(m,2H),5.62(dd,J=48.0,3.6Hz,1H),5.37-5.28(m,1H),4.99(t,J=8.8Hz,1H),4.9 1-4.86(m,1H),3.76(q,J=6.8Hz,1H),3.50-3.46(m,2H),3.41-3.37(m,2H),3.22-3.17(m,5H),1.58-1.2 5(m,3H),1.23-1.17(m,8H),0.84-0.72(m,3H),0.45-0.36(m,2H),0.33-0.28(m,2H),0.26-0.05(m,4H).

[1043] Example 87: Compound I-87

[1044] Compound I-87 (9.00 mg, 0.014 mmol, 26.10%) was obtained as a white solid using the same method as compound I-76. LC-MS (ESI, m / z): 650.8 [M+H] +1 H NMR (400MHz, DMSO) δ9.93(s,1H),8.28(t,J=10.0Hz,1H),8.16(t,J=8.4Hz,1H),7.76(dd,J=20.0,8 .4Hz,1H),7.19-7.06(m,2H),5.62(dd,J=48.0,3.6Hz,1H),5.33(d,J=15.6Hz,1H),5.01-4.83(m,2 H),3.81(q,J=6.8Hz,1H),3.49-3.45(m,2H),3.42-3.33(m,2H),3.28-3.19(m,5H),1.59-1.25(m,3 H),1.23-1.16(m,8H),0.83-0.75(m,3H),0.45-0.36(m,2H),0.33-0.29(m,2H),0.23-0.12(m,4H).

[1045] Example 88: Compound I-88

[1046] Compound I-88 (9.00 mg, 0.015 mmol, 26.75%) was obtained as a white solid, prepared according to the method used for compound I-76. LC-MS (ESI, m / z): 635.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.92 (s, 1H), 8.31-8.24 (m, 2H), 7.79-7.72 (m, 1H), 7.15-7.05 (m, 2H), 5.62 (dd, J=48.0, 3.6Hz, 1 H),5.39-5.28(m,1H),4.95-4.86(m,2H),3.56-3.40(m,2H),3.39-3.36(m,1H),3.28-3.11(m,2H),2.52-2.48(m,1H), 1.47-1.43(m,1H),1.38-1.35(m,1H),1.28-1.24(m,1H),1.22-1.15(m,6H),1.02(d,J=6.8Hz,3H),0.97(d,J=6.8Hz,3 H),0.88-0.68(m,3H),0.46-0.43(m,1H),0.38-0.34(m,1H),0.33-0.28(m,2H),0.23-0.20(m,3H),0.15-0.06(m,1H).

[1047] Example 89: Compound I-89

[1048] Compound I-89 (10.00 mg, 0.015 mmol, 28.56%) was obtained as a white solid, prepared according to the method used for compound I-76. LC-MS (ESI, m / z): 660.8 [M+H] + . 1H NMR (400MHz, DMSO) δ9.91 (s, 1H), 8.27 (t, J = 8.8Hz, 1H), 8.21-8.14 (m, 1H), 7.78-7.71 (m, 1H), 7.20-7. 00(m,2H),5.62(dd,J=48.0,3.6Hz,1H),5.34-5.31(m,1H),5.00-4.94(m,1H),4.91-4.85(m,1H),3.55 -3.37(m,3H),3.27-3.07(m,2H),1.72-1.64(m,1H),1.54-1.41(m,2H),1.34-1.11(m,7H),1.09-1.04( m,3H),0.92-0.67(m,4H),0.46-0.43(m,2H),0.39-0.26(m,4H),0.21-0.19(m,3H),0.07-0.05(m,2H).

[1049] Example 90: Compound I-90

[1050] Step 1:

[1051] Triphosgene (5 mg, 0.0168 mmol) was added to a 1 mL solution of dichloromethane containing compound 76-8 (15 mg, 0.0266 mmol) and N,N-diisopropylethylamine (10 mg, 0.0774 mmol). The mixture was stirred at room temperature for 10 minutes. A 1 mL solution of dichloromethane containing tetrahydropyrrole (compound 90-1, 6 mg, 0.0844 mmol) and N,N-diisopropylethylamine (10 mg, 0.0774 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored for completion by LC-MS. The reaction solution was concentrated under reduced pressure. 6 mL of water was added to the residue, and the mixture was extracted twice with ethyl acetate (6 mL * 2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give a white powder, formate of compound I-90 (9 mg, 0.014 mmol, 50.4%). LC-MS (ESI, m / z): 662.2 (M+H) + . 1¹H NMR (400MHz, CD₃OD) δ 8.53 (s, 1H) (formic acid), 7.85 (m, 1H), 7.14 (m, 2H), 5.66 (dd, J₁ = 46.8 Hz, J₂ = 3.2 Hz, 1H), 5.28 (dt, J₁ = 15.2 Hz, J₂ = 3.2 Hz, 1H), 4.94 (m, 2H), 3.61–3.42 (m, 2H), 3.38 ( m,4H),3.28-3.10(m,2H),1.95(m,4H),1.51(m,2H),1.40(d,J=7.2Hz,3H),1.31(m,2H), 1.20-0.94(m,3H),0.90-0.69(m,3H),0.52(m,2H),0.46-0.32(m,2H),0.39-0.14(m,4H).

[1052] Example 91: Compound I-91

[1053] According to the preparation method of compound I-61:

[1054] White solid compound (5 mg, 0.008 mmol, 14.66%). LC-MS (ESI, m / z): 608.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ8.37-8.28(m,2H),7.82(t,J=8.3Hz,1H),7.52-7.45(m,2H),7.22–7.09(m,2H),6 .32(d,J=8.6Hz,1H),5.65(dd,J=47.0,3.5Hz,1H),5.28(dd,J=15.3,3.5Hz,1H),4.94-4.87(m,1H),4. 55-4.50(m,1H),3.32-3.22(m,1H),2.89(s,3H),2.68-2.60(m,1H),1.43(d,J=7.0Hz,3H),1.36–1.30( m,1H),0.97–0.90(m,2H),0.82–0.71(m,4H),0.56–0.40(m,3H),0.35-0.21(m,4H),0.18–0.12(m,1H).

[1055] Example 92: Compound I-92

[1056] According to the preparation method of compound I-61:

[1057] White solid compound I-92 (30 mg, 0.045 mmol, 80.23%). LC-MS (ESI, m / z): 667.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ8.01-7.75(m,1H),7.23–7.02(m,2H),6.39–6.21(m,1H),5.74-5.57(m,1H), 5.33-5.23(m,1H),4.99-4.88(m,2H),4.49-4.38(m,1H),4.14-4.00(m,1H),3.23–3.11(m,1H),3 .05–2.92(m,1H),2.91(d,J=3.7Hz,3H),2.66-2.57(m,1H),2.55-2.45(m,1H),2.42-2.20(m,1H) ,1.84–1.62(m,2H),1.57–1.42(m,1H),1.43-1.36(m,3H),0.98–0.72(m,7H),0.59–0.18(m,8H).

[1058] Example 93: Compound I-93

[1059] The preparation method of compound I-76 yielded the following:

[1060] White solid compound I-93 (12 mg, 0.017 mmol, 34.89%). LC-MS (ESI, m / z): 687.8 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.91-7.81(m,1H),7.19-7.10(m,2H),5.91(d,J=9.3Hz,1H),5.66(dd,J=4 7.1,3.4Hz,1H),5.28(dt,J=15.3,3.5Hz,1H),4.96–4.92(m,1H),4.88–4.79(m,1H),3.63–3.3 4(m,4H),3.18-3.12(m,1H),2.88(s,3H),2.49(s,1H),2.25–2.15(m,5H),1.57–1.41(m,2H),1 .40-1.35(m,3H),1.36–1.22(m,2H),1.18–0.97(m,3H),0.89–0.71(m,3H),0.61–0.19(m,8H).

[1061] Example 94: Compound I-94

[1062] According to the preparation method of compound I-61:

[1063] White solid compound I-94 (20 mg, 0.032 mmol, 56.89%). LC-MS (ESI, m / z): 628.4 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.82(t,J=8.2Hz,1H),7.21-7.11(m,2H),6.30(d,J=8.8Hz,1H),5.66(dd,J=47.1,3.4Hz,1H),5. 28(dd,J=15.3,3.3Hz,1H),4.96-4.88(m,1H),4.63–4.51(m,2H),4.51–4.43(m,1H),4.37-3.83(m,1H),4.28-4.20(m ,1H),3.76–3.56(m,1H),3.44–3.36(m,1H),3.19–3.01(m,2H),2.94-2.88(m,3H),2.86-2.77(m,1H),2.66-2.58(m,1 H),2.09-1.96(m,2H),1.54–1.37(m,3H),0.98-0.90(m,2H),0.85-0.75(m,5H),0.62–0.38(m,4H),0.37–0.16(m,4H).

[1064] Example 95: Compound I-95

[1065] According to the preparation method of compound I-61:

[1066] White solid compound I-95 (6 mg, 0.0094 mmol, 16.72%). LC-MS (ESI, m / z): 640.8 [M+1] + . 1H NMR(400MHz,MeOD)δ7.90-7.80(m,1H),7.21–7.08(m,2H),5.74-5.58(m,1H),5.31–5.25(m ,1H),4.92(d,J=7.0Hz,1H),4.58–4.51(m,1H),3.71-3.63(m,1H),3.43–3.34(m,1H),3.26– 3.10(m,4H),3.09–2.92(m,2H),2.90(s,3H),2.84-2.76(m,1H),2.65-2.58(m,1H),2.30(d, J=10.1Hz,3H),1.94–1.74(m,2H),1.46-1.39(m,3H),0.97–0.72(m,7H),0.60–0.20(m,8H).

[1067] Example 96: Compound I-96

[1068] According to the preparation method of compound I-61:

[1069] Formate of white solid compound I-96 (11 mg, 0.018 mmol, 32.11%). LC-MS (ESI, m / z): 611.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ8.10(d,J=8.6Hz,1H),7.90–7.79(m,1H),7.19-7.11(m,2H),5.67(dd,J=47.0,3.4H z,1H),5.29(dd,J=15.3,3.4Hz,1H),4.97–4.92(m,1H),4.17(d,J=10.3Hz,1H),3.98-3.93(m,1H),3.41 –3.34(m,1H),3.16-3.06(m,1H),3.00–2.76(m,4H),2.71–2.53(m,2H),2.21-2.13(m,1H),2.05–1.90(m ,2H),1.86–1.69(m,2H),1.67–1.55(m,1H),1.40(d,J=7.0Hz,3H),1.04–0.67(m,7H),0.66–0.19(m,8H).

[1070] Example 97: Compound I-97

[1071] The preparation method of compound 76 yielded the following:

[1072] White solid compound I-97 (16 mg, 0.024 mmol, 47.22%). LC-MS (ESI, m / z): 677.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.89-7.81(m,1H),7.17-7.10(m,2H),5.66(dd,J=47.1,3.4Hz,1H), 5.32–5.19(m,2H),4.96–4.91(m,1H),4.86–4.79(m,3H),4.78-4.71(m,2H),3.60–3.38( m,2H),3.39–3.35(m,1H),3.30–3.16(m,2H),3.10(s,3H),1.55-1.45(m,2H),1.39(d,J= 6.9Hz,3H),1.28-1.18(m,1H),1.15-1.00(m,3H),0.90–0.71(m,3H),0.62–0.17(m,8H).

[1073] Example 98: Compound I-98

[1074] The preparation method of compound I-98 yielded the following:

[1075] White solid compound I-98 (7 mg, 0.011 mmol, 19.27%). LC-MS (ESI, m / z): 648.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.92-7.77(m,1H),7.24–7.09(m,2H),5.74-5.59(m,1H),5.32 -5.25(m,1H),4.94–4.90(m,1H),4.87-4.81(m,1H),4.39-4.19(m,1H),4.03–3.73 (m,2H),3.61–3.45(m,1H),3.42-3.35(m,1H),3.32-3.06(m,4H),2.94-2.85(m,3H ),2.68-2.60(m,1H),1.44(d,J=7.0Hz,3H),0.99-0.74(m,7H),0.62–0.17(m,8H).

[1076] Example 99: Compound I-99

[1077] Step 1:

[1078] To a pyridine (5.00 mL) solution of compound 35-1 (99.73 mg, 0.34 mmol, 1.10 eq) and compound 61-3 (100.00 mg, 0.31 mmol, 1.00 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (177.71 mg, 0.93 mmol, 3.00 eq) was added. The reaction mixture was stirred overnight at room temperature under argon protection. Pyridine was removed by vacuum distillation, the reaction mixture was diluted with water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 99-1 (160.00 mg, 0.27 mmol, 86.49%) as a pale yellow solid. LC-MS (ESI, m / z): 599.4 [M+H] + .

[1079] Step Two:

[1080] Trifluoroacetic acid (1.00 mL) was added to a solution of compound 99-1 (160.00 mg, 0.27 mmol, 1.00 eq) in dichloromethane (5.00 mL). The reaction mixture was stirred at room temperature for 2 hours under argon protection. The solvent was removed under reduced pressure, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried, and concentrated to give a pale yellow solid, compound 99-2 (130.00 mg, 0.26 mmol, 97.66%). LC-MS (ESI, m / z): 499.1 [M+H] + .

[1081] Step 3:

[1082] Triethylamine (79.23 mg, 0.78 mmol, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (149.05 mg, 0.39 mmol, 1.50 eq) were added to a solution of compound 99-2 (130.00 mg, 0.26 mmol, 1.00 eq) and compound 99-3 (37.34 mg, 0.29 mmol, 1.10 eq) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 99-4 (152.00 mg, 0.25 mmol, 95.37%) as a yellow solid. LC-MS (ESI, m / z): 611.1 [M+H] + .

[1083] Step Four:

[1084] Lithium hydroxide (2.00 mL, 4 mmol) was added to a solution of compound 99-4 (152.00 mg, 0.25 mmol, 1.00 eq) in tetrahydrofuran (2.00 mL) and methanol (2.00 mL). The reaction mixture was stirred at room temperature for 2 hours under argon protection. The pH was adjusted to approximately 4 with hydrochloric acid, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and dried and concentrated to give a yellow solid, compound 99-5 (146.00 mg, 0.24 mmol, 98.28%). LC-MS (ESI, m / z): 596.8 [M+H] + .

[1085] Step 5:

[1086] Triethylamine (35.52 mg, 0.35 mmol, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (66.54 mg, 0.175.00 mmol, 1.50 eq) were added to a solution of compound 99-5 (70.00 mg, 0.12 mmol, 1.00 eq) and compound 12-1 (23.69 mg, 0.13 mmol, 1.10 eq) in N,N-dimethylformamide (2.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-99 (40.00 mg, 0.055 mmol, 47.11%) as a white solid. LC-MS (ESI, m / z): 726.1 [M+H] + . 1H NMR(400MHz, DMSO)δ9.97(d,J=6.2Hz,1H),8.11(dd,J=20.4,7.6Hz,1H),7.80-7.65(m,1H),7.21-7.03(m,2H),6.1 8(dd,J=8.9,2.7Hz,1H),5.35(dd,J=23.1,10.8Hz,1H),4.82(t,J=8.8Hz,1H),4.64–4.53(m,1H),3.55-3.36(m,3H ),3.25-3.10(m,2H),2.75(s,3H),2.62–2.52(m,2H),2.13-1.92(m,3H),1.91–1.59(m,4H),1.55-1.27(m,4H),1.2 5(d,J=6.9Hz,3H),1.24–1.13(m,3H),1.12-1.00(m,1H),0.97–0.71(m,4H),0.69-0.59(m,2H),0.55-0.42(m,2H).

[1087] Example 100: Compound I-100

[1088] Step 1:

[1089] To a pyridine (5.00 mL) solution of compound 34-4 (150.00 mg, 0.34 mmol, 1.00 eq) and compound 100-1 (97.42 mg, 0.36 mmol, 1.05 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (196.68 mg, 1.03 mmol, 3.00 eq) was added. The reaction mixture was stirred overnight at room temperature under argon protection. Pyridine was removed by vacuum distillation, the reaction mixture was diluted with water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 100-2 (200.00 mg, 0.29 mmol, 84.53%) as a pale yellow solid. LC-MS (ESI, m / z): 692.2 [M+H] + .

[1090] Step Two:

[1091] Zinc bromide (619.30 mg, 2.75 mmol, 10.00 eq) was added to a solution of compound 100-2 (190.26 mg, 0.28 mmol, 1.00 eq) in dichloromethane (5.00 mL), and the reaction mixture was stirred overnight at 45 °C. The reaction was quenched with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine and concentrated to give a yellow solid, compound 100-3 (150.00 mg, 0.25 mmol, 92.18%). LC-MS (ESI, m / z): 592.4 [M+H] + .

[1092] Step 3:

[1093] To a solution of compound 100-3 (60.00 mg, 0.10 mmol, 1.00 eq) and 2-fluoroacrylic acid (10.00 mg, 0.11 mmol, 1.10 eq) in N,N-dimethylformamide (2.00 mL), triethylamine (30.66 mg, 0.30 mmol, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (57.42 mg, 0.15 mmol, 1.50 eq) were added. The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give compound I-100 (42.00 mg, 0.063 mmol, 62.65%) as a white solid. LC-MS (ESI, m / z): 663.8 [M+H] + . 1 H NMR(400MHz, DMSO)δ9.89(s,1H),8.35(dd,J=21.7,8.1Hz,1H),7.74-7.62(m,1H),7.16(dd,J=11.9,5.1Hz,1 H),7.06(d,J=6.6Hz,1H),6.17(dd,J=8.9,3.1Hz,1H),5.61(dd,J=48.0,3.5Hz,1H),5.31(d,J=14.5Hz,1H), 4.82(t,J=8.2Hz,1H),4.46(dd,J=19.7,8.4Hz,1H),3.53-3.38(m,2H),3.32–3.10(m,3H),2.75(s,3H),2.58 -2.50(m,1H),1.93–1.53(m,5H),1.53–1.32(m,2H),1.37–1.07(m,9H),1.09–0.74(m,8H),0.68-0.58(m,2H).

[1094] Example 101: Compound 101

[1095] The preparation method of compound I-100 yielded the following:

[1096] White solid compound I-101 (64 mg, 0.091 mmol, 67.36%). LC-MS (ESI, m / z): 704.2 [M+1] + . 1 H NMR(400MHz, DMSO)δ9.87(s,1H),7.95(dd,J=21.0,7.9Hz,1H),7.78-7.65(m,1H),7.16(dd,J=12.1,4.6Hz,1 H),7.06(d,J=6.6Hz,1H),6.18(dd,J=8.9,3.0Hz,1H),5.34(dd,J=23.2,10.8Hz,1H),4.87-4.78(m,1H),4.53 -4.42(m,1H),3.55-3.35(m,3H),3.28–3.06(m,2H),2.75(s,3H),2.66–2.52(m,2H),1.91–1.53(m,5H),1.53 –1.31(m,2H),1.37–1.06(m,9H),1.09-0.94(m,2H),0.93–0.77(m,8H),0.68-0.58(m,2H),0.54–0.42(m,2H).

[1097] Example 102: Compound I-102

[1098] According to the preparation method of compound I-61:

[1099] White solid compound I-102 (25 mg, 0.038 mmol, 67.46%). LC-MS (ESI, m / z): 662.2 [M+1] + . 1H NMR(400MHz,MeOD)δ7.90(t,J=8.2Hz,1H),7.21-7.10(m,2H),6.26(d,J=8.7Hz,1H),5.66(dd,J=47.0,3.4Hz, 1H),5.33–5.24(m,1H),4.96-4.89(m,1H),4.33–4.22(m,1H),4.13(dd,J=25.4,8.9Hz,1H),3.77(dd,J=21.9,1 0.3Hz,1H),3.53–3.34(m,2H),3.17-3.05(m,1H),2.91(s,3H),2.65-2.57(m,1H),2.29–2.19(m,1H),2.17–1. 83(m,4H),1.73–1.56(m,1H),1.39(t,J=12.9Hz,3H),1.10–0.64(m,7H),0.63–0.40(m,4H),0.39-0.19(m,4H).

[1100] Example 103: Compound I-103

[1101] The preparation method of compound I-76 yielded the following:

[1102] White solid compound I-76 (51 mg, 0.076 mmol, 56.83%). LC-MS (ESI, m / z): 674.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.91-7.80(m,1H),7.20-7.11(m,2H),5.66(dd,J=47.0,3.4Hz,1H ),5.28(dt,J=15.3,3.2Hz,1H),5.13–5.06(m,1H),4.97-4.90(m,1H),3.64-3.35(m,4H ),3.29–3.20(m,1H),1.84–1.63(m,2H),1.55–1.43(m,2H),1.42-1.31(m,4H),1.30–1. 01(m,4H),1.00–0.87(m,4H),0.86–0.69(m,3H),0.67–0.37(m,6H),0.36-0.11(m,6H).

[1103] Example 104: Compound I-104

[1104] The preparation method of compound I-76 yielded the following:

[1105] White solid compound I-104 formate (16 mg, 0.022 mmol, 34.77%). LC-MS (ESI, m / z): 687.2 [M-HCOOH+1] + . 1 H NMR(400MHz,MeOD)δ8.19-8.11(m,1H),7.90-7.80(m,1H),7.19-7.11(m,2H),5.66(dd,J= 47.0,3.3Hz,1H),5.33-5.24(m,1H),5.14–5.07(m,1H),4.96-4.90(m,1H),3.63–3.37(m, 4H),3.27–3.20(m,1H),1.63-1.41(m,2H),1.37(d,J=7.0Hz,3H),1.35-1.19(m,2H),1.18 -1.04(m,4H),1.02-0.94(m,1H),0.89–0.72(m,3H),0.68–0.37(m,8H),0.36-0.15(m,8H).

[1106] Example 105: Compound I-105

[1107] According to the preparation method of compound I-61:

[1108] White solid compound I-105 (90 mg, 0.14 mmol, 74.02%). LC-MS (ESI, m / z): 647.2 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.93–7.79(m,1H),7.24–7.04(m,2H),6.36-6.26(m,1H),5. 75-5.57(m,1H),5.33-5.24(m,1H),4.96-4.92(m,1H),4.91-4.88(m,1H),4.57–4 .03(m,4H),3.99–3.76(m,1H),3.23-2.96(m,2H),2.90(s,3H),2.81–2.55(m,3H) ,2.49–2.09(m,4H),1.40(t,J=8.2Hz,3H),1.11–0.68(m,7H),0.61-0.19(m,8H).

[1109] Example 106: Compound I-106

[1110] According to the preparation method of compound I-61:

[1111] White solid compound I-106 (20 mg, 0.029 mmol, 22.36%). LC-MS (ESI, m / z): 683.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.03–9.90(m,1H),8.28(d,J=8.7Hz,1H),7.83–7.70(m,1H),7.21-6.98(m, 2H),6.27–6.11(m,1H),5.71-5.52(m,1H),5.37-5.27(m,1H),4.93-4.87(m,1H),4.86-4.68(m,1 H),3.92–3.41(m,4H),3.24–3.04(m,2H),2.99-2.85(m,1H),2.79-2.71(m,3H),2.71–2.53(m,2H ),2.42-2.13(m,3H),1.32-1.15(m,3H),0.93-0.70(m,5H),0.69-0.52(m,2H),0.53–0.01(m,8H).

[1112] Example 107: Compound I-107

[1113] According to the preparation method of compound I-61:

[1114] White solid compound I-107 (61 mg, 0.09 mmol, 40.12%). LC-MS (ESI, m / z): 676.2 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.97 (s, 1H), 8.30 (d, J = 8.7Hz, 1H), 7.79 (t, J = 8.1Hz, 1H), 7.16–7.05 (m, 2H ),6.11(d,J=8.8Hz,1H),5.61(dd,J=48.0,3.2Hz,1H),5.32(dd,J=15.6,3.2Hz,1H),4.95-4.84( m,1H),4.24-4.14(m,1H),3.83-3.75(m,1H),3.18–2.96(m,4H),2.75(s,3H),2.56-2.52(m,1H) ,1.85-1.58(m,5H),1.34–1.19(m,6H),0.91-0.70(m,5H),0.66-0.48(m,2H),0.48–0.11(m,8H).

[1115] Example 108: Compound I-108

[1116] Step 1:

[1117] At -50°C, difluoromethyl (2-pyridyl) sulfone (138.70 mg, 0.72 mmol, 1.00 eq) and compound 108-1 (250.00 mg, 0.72 mmol, 1.00 eq) in N,N-dimethylformamide (10.00 mL) were added to a solution of potassium tert-butoxide (122.20 mg, 1.09 mmol, 1.52 eq) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at this temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (2 mL) and 3N hydrochloric acid (4 mL) were added sequentially, and the reaction mixture was then allowed to rise naturally to room temperature. The reaction mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with saturated brine, dried, and concentrated to give a yellow oily substance. The yellow oily substance, compound 108-2 (210.00 mg, 0.55 mmol, 76.48%), was purified by column chromatography. LC-MS(ESI,m / z):282.9[M-100+H] + .

[1118] Step Two:

[1119] Ethyl acetate (2.00 mL, 8.00 mmol, 14.57 eq) was added to a 2.00 mL solution of compound 108-2 (210.00 mg, 0.55 mmol, 1.00 eq) in ethyl acetate (2.00 mL, 8.00 mmol, 14.57 eq). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give a yellow solid, compound 108-3 (150.00 mg, 0.53 mmol, 96.79%). LC-MS (ESI, m / z): 283.1 [M+H] + .

[1120] Step 3:

[1121] Formaldehyde (79.72 mg, 2.66 mmol, 5.00 eq) was added to a solution of compound 108-3 (150.00 mg, 0.53 mmol, 1.00 eq) in dichloromethane (5.00 mL), and the reaction mixture was stirred at room temperature for 0.5 h under argon protection. Sodium borohydride acetate (562.70 mg, 2.66 mmol, 5.00 eq) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried, and concentrated to give a yellow oily compound 108-4 (152.00 mg, 0.51 mmol, 96.60%). LC-MS (ESI, m / z): 296.6 [M+H] + .

[1122] Step Four:

[1123] Iodotrimethylsilane (297.73 mg, 1.49 mmol, 3.00 eq) was added to a solution of compound 108-4 (146.97 mg, 0.50 mmol, 1.00 eq) in dichloromethane (5.00 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 3 hours. LC-MS showed the formation of a product, which was concentrated to give a yellow solid compound 108-5 (78.00 mg, 0.48 mmol, 96.96%). LC-MS (ESI, m / z): 163.1 [M+H] + .

[1124] Step 5:

[1125] Triethylamine (39.77 mg, 0.39 mmol, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (77.19 mg, 0.203 mmol, 1.55 eq) were added to a solution of compounds 61-7 (70.00 mg, 0.131 mmol, 1.00 eq) and 108-5 (23.39 mg, 0.14 mmol, 1.10 eq) in N,N-dimethylformamide (3.00 mL). The reaction mixture was stirred at room temperature for 1 hour under argon protection. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by preparative separation to give the formate salt of compound I-108 (42.00 mg, 0.062 mmol, 47.37%) as a white solid. LC-MS(ESI,m / z): 677.2[M-HCOOH+H] + . 1H NMR (400MHz, DMSO) δ9.94 (s, 1H), 8.37-8.24 (m, 2H), 7.83-7.73 (m, 1H), 7.18-7.04 (m, 2H), 6.20 (dd, J = 24 .2,9.1Hz,1H),5.62(dd,J=48.1,3.5Hz,1H),5.37–5.28(m,1H),4.95–4.85(m,1H),4.70(t,J=9.4Hz,1H) ,4.22-3.85(m,3H),3.27-3.18(m,1H),3.09–2.86(m,3H),2.76(s,3H),2.49–2.44(m,1H),2.11(d,J=14. 9Hz,3H),2.07–1.95(m,2H),1.32-1.23(m,3H),0.93–0.69(m,5H),0.68-0.57(m,2H),0.50–0.03(m,8H).

[1126] Example 109: Compound I-109

[1127] According to the preparation method of compound I-61:

[1128] White solid compound I-109 (52 mg, 0.077 mmol, 51.30%). LC-MS (ESI, m / z): 676.4 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.98-9.91(m,1H),8.33–8.22(m,1H),7.83-7.70(m,1H),7.19–7.04(m,2H),6.1 8-6.11(m,1H),5.62(dt,J=48.0,3.2Hz,1H),5.32(dd,J=15.7,3.3Hz,1H),4.95-4.84(m,1H),4.49–4 .38(m,1H),3.76–3.55(m,1H),3.18-3.82(m,4H),2.80–2.71(m,3H),2.19–1.62(m,7H),1.59-1.45(m ,1H),1.35-1.25(m,3H),1.12–0.97(m,1H),0.90-0.70(m,5H),0.68-0.58(m,2H),0.48–0.10(m,8H).

[1129] Example 110: Compound I-110

[1130] Step 1:

[1131] Compound 110-1 (100 mg, 0.47 mmol, 1.00 eq) and N,N-diisopropylethylamine (152 mg, 1.18 mmol, 2.50 eq) were dissolved in ethanol (2.00 mL), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (131 mg, 0.56 mmol, 1.20 eq) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 110-2 (104 mg, yield 75.02%) as a colorless oil. LC-MS (ESI, m / z): 294.9 [M+H] + .

[1132] Step Two:

[1133] Compound 110-2 (104 mg, 0.35 mmol, 1.00 eq) was dissolved in dichloromethane (2.00 mL), and 4 M ethyl acetate hydrochloride solution (2.00 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 110-3 (82.00 mg, 100% yield) as a white solid. LC-MS (ESI, m / z): 194.9 [M+H] + .

[1134] Step 3:

[1135] Compound 61-7 (65 mg, 0.12 mmol, 1.00 eq), compound 110-3 (40 mg, 0.17 mmol, 1.42 eq), and N,N-diisopropylethylamine (48 mg, 0.37 mmol, 3.06 eq) were added to N,N-dimethylformamide (2.00 mL), followed by HATU (70 mg, 0.18 mmol, 1.50 eq). The reaction mixture was stirred at room temperature for 20 minutes, diluted with water, and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and lyophilized to give compound I-110 (66.00 mg, 76.33% yield) as a white solid. LC-MS (ESI, m / z): 709.2 [M+H] + . 1H NMR (400MHz, DMSO) δ9.92(s,1H),8.28(t,J=8.4Hz,1H),7.81–7.73(m,1H),7.16–7.03(m,2H),6.11(dd,J=17.6,9.2Hz,1H),5.63(dd, J=48.0,3.6Hz,1H),5.33(dd,J=15.6,3.6Hz,1H),4.92–4.87(m,1H),4.81–4.66(m,1H),3.95(d,J=12.0Hz,1H),3.74(d,J=12.0Hz,1H) ,3.66–3.51(m,1H),3.24–3.08(m,3H),3.08–2.94(m,2H),2.79–2.72(m,3H),2.72–2.67(m,1H),2.58–2.53(m,1H),2.44–2.31(m,1H) ,1.71-1.68(m,1H),1.60–1.58(m,1H),1.32–1.16(m,4H),0.91–0.71(m,5H),0.64–0.60(m,2H),0.52–0.28(m,4H),0.27–0.06(m,4H).

[1136] Example 111: Compound I-111

[1137] Step 1:

[1138] Compound 76-8 (35 mg, 0.06 mmol, 1.00 eq), 3,3,3-trifluoro-2-methylpropionic acid (12 mg, 0.08 mmol, 1.35 eq), and N,N-diisopropylethylamine (29 mg, 0.22 mmol, 3.63 eq) were added to N,N-dimethylformamide (1.50 mL), followed by HATU (32 mg, 0.08 mmol, 1.35 eq). The reaction mixture was reacted at room temperature for 20 minutes, diluted with water, and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-111 (15.00 mg, yield 35.13%) as a white solid. LC-MS (ESI, m / z): 688.7 [M+H] + . 1H NMR(400MHz,MeOD)δ8.81-8.72(m,1H),8.10-8.08(m,1H),7.90–7.83(m,1H),7.18–7. 13(m,2H),5.66(dd,J=47.0,3.6Hz,1H),5.28(dt,J=15.2,3.2Hz,1H),5.15–4.99(m,1H ),4.95–4.91(m,1H),3.51–3.33(m,4H),3.30–3.10(m,2H),1.63–1.42(m,2H),1.42–1. 29(m,6H),1.23–1.04(m,4H),0.83–0.74(m,3H),0.65–0.38(m,4H),0.38–0.10(m,4H).

[1139] Example 112: Compound I-112

[1140] Step 1:

[1141] Compound 61-7 (30 mg, 0.06 mmol, 1.00 eq), 1-(3-oxacyclobutyl)piperazine (12 mg, 0.08 mmol, 1.50 eq), and N,N-diisopropylethylamine (22 mg, 0.17 mmol, 3.05 eq) were added to N,N-dimethylformamide (1.50 mL), followed by HATU (32 mg, 0.08 mmol, 1.50 eq). The reaction mixture was stirred at room temperature for 20 minutes, diluted with water, and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-112 (20.00 mg, yield 54.38%) as a white solid. LC-MS (ESI, m / z): 656.8 [M+H] + . 1H NMR(400MHz,MeOD)δ7.82(t,J=8.0Hz,1H),7.24–7.07(m,2H),6.31(d,J=8.8Hz,1H),5.69(dd,J=47.1,3.6Hz,1H),5 .29(dd,J=15.2,3.6Hz,1H),4.92–4.84(m,1H),4.65–4.59(m,2H)4.52–4.44(m,2H),3.70–3.65(m,1H),3.50–3.40(m ,2H),3.18–3.12(m,2H),2.90(s,3H),2.62–2.59(m,1H),2.41–2.36(m,2H),1.85–1.80(m,1H),1.50–1.48(m,1H),1 .41(d,J=7.2Hz,3H),0.96–0.93(m,2H),0.92–0.78(m,3H),0.78–0.75(m,2H),0.64–0.42(m,4H),0.39–0.25(m,4H).

[1142] Example 113: Compound I-113

[1143] Step 1:

[1144] Compound 61-7 (30 mg, 0.06 mmol, 1.00 eq), 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (17 mg, 0.11 mmol, 1.88 eq), and N,N-diisopropylethylamine (22 mg, 0.17 mmol, 3.05 eq) were added to N,N-dimethylformamide (1.50 mL), followed by HATU (32 mg, 0.08 mmol, 1.50 eq). The reaction mixture was stirred at room temperature for 20 minutes, diluted with water, and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-113 (20.00 mg, yield 55.74%) as a white solid. LC-MS (ESI, m / z): 640.8 [M+H] + . 1H NMR (400MHz, DMSO) δ9.93(d,J=4.4Hz,1H),8.29(d,J=8.5Hz,1H),8.15(s,1H),7.81–7.74(m,1H),7.17–7.09(m,1H),7.00(d,J =8.0Hz,1H),6.17–6.10(m,1H),5.63(dd,J=48.0,3.6Hz,1H),5.33(dd,J=15.7,3.6Hz,1H),4.91–4.88(m,1H),4.76–4.71(m,1H ),3.96–3.93(m,1H),3.75–3.68(m,1H),3.25–2.99(m,4H),2.75(d,J=9.2Hz,3H),2.70–2.60(m,1H),2.42–2.33(m,1H),2.22- 2.18(m,3H),1.83–1.79(m,1H),1.70-1.65(m,1H),1.35–1.12(m,4H),0.98–0.73(m,5H),0.64–0.60(m,3H),0.51–0.05(m,8H).

[1145] Example 114: Compound I-114

[1146] Step 1:

[1147] N-Benzyl-N,N-bis(2-chloroethyl)amine hydrochloride (150 mg, 0.56 mmol, 1.00 eq) and 1-trifluoromethylcyclopropylamine hydrochloride (91 mg, 0.56 mmol, 1.01 eq) were added to N,N-diisopropylethylamine (1.00 mL), and the reaction mixture was reacted at 120 °C for 2 days. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate (40 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give a colorless oily compound 114-1 (60.00 mg, yield 37.82%). LC-MS (ESI, m / z): 284.9 [M+H] + .

[1148] Step Two:

[1149] Compound 114-1 (70 mg, 0.25 mmol, 1.00 eq) was dissolved in anhydrous ethanol (5.00 mL), 5% wet palladium on carbon (40 mg) was added, and 2 drops of concentrated hydrochloric acid were added dropwise. The reaction solution was reacted at room temperature for 16 hours under the protection of a hydrogen balloon. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to give compound 114-2 (47.00 mg, yield 98.38%) as a yellow solid. LC-MS (ESI, m / z): 194.9 [M+H] + .

[1150] Step 3:

[1151] Compound 61-7 (65 mg, 0.12 mmol, 1.00 eq), compound 114-2 (30 mg, 0.15 mmol, 1.26 eq), and N,N-diisopropylethylamine (48 mg, 0.37 mmol, 3.05 eq) were added to N,N-dimethylformamide (2.50 mL), followed by HATU (70 mg, 0.18 mmol, 1.50 eq). The reaction mixture was reacted at room temperature for 20 minutes. The mixture was diluted with water, extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and lyophilized to give compound I-114 (70.00 mg, 80.95% yield) as a white solid. LC-MS (ESI, m / z): 709.2 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.91(s,1H),8.26(d,J=9.2Hz,1H),7.79(t,J=8.4Hz,1H),7.15(dd,J=12.3,1.6Hz,1H),7.04(d,J=8.4Hz,1H) ,6.16(d,J=9.2Hz,1H),5.61(dd,J=48.0,3.5Hz,1H),5.32(dd,J=15.7,3.5Hz,1H),4.96–4.87(m,1H),4.79(t,J=8.8Hz,1H),3.32 –3.28(m,1H),3.18–3.09(m,4H),2.75(s,3H),2.62–2.60(m,2H),2.56–2.50(m,1H),2.41–2.38(m,1H),2.33–2.28(m,1H),1.25(d ,J=7.2Hz,3H),0.93–0.92(m,2H),0.86–0.84(m,5H),0.82–0.73(m,2H),0.67–0.55(m,2H),0.49–0.27(m,4H),0.26–0.05(m,4H).

[1152] Example 115: Compound I-115

[1153] Step 1:

[1154] Compound 76-8 (50 mg, 0.09 mmol, 1.00 eq), 2-Boc-aminoacetaldehyde (15 mg, 0.09 mmol, 1.06 eq), and N,N-diisopropylethylamine (31 mg, 0.24 mmol, 2.64 eq) were added to dichloromethane (2.50 mL), followed by two drops of acetic acid. The reaction mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (85 mg, 0.40 mmol, 4.49 eq) was added. The mixture was stirred overnight, the reaction was quenched with water, and extracted with dichloromethane (30 mL x 3). The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 115-1 (62.00 mg, 99% yield) as a colorless oil. LC-MS (ESI, m / z): 707.8 [M+H] + .

[1155] Step Two:

[1156] Compound 115-1 (94 mg, 0.13 mmol, 1.00 eq) was dissolved in dichloromethane (2.00 mL) and 4 M ethyl hydrochloride solution (2.00 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 115-2 (85.00 mg, 100% yield) as a white waxy solid. LC-MS (ESI, m / z): 607.8 [M+H] + .

[1157] Step 3:

[1158] Compound 115-2 (79 mg, 0.12 mmol, 1.00 eq) and triethylamine (35 mg, 0.35 mmol, 2.82 eq) were added to tetrahydrofuran (5.00 mL), followed by CDI (57 mg, 0.35 mmol, 2.86 eq). The reaction mixture was reacted at 60 °C for 1 hour. The reaction was quenched with water, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and lyophilized to give compound I-115 (30.00 mg, yield 38.49%) as a white solid. LC-MS (ESI, m / z): 634.2 [M+H] + . 1H NMR(400MHz,MeOD)δ7.84(q,J=8.0Hz,1H),7.19–7.15(m,2H),5.66(dd,J=47.0,3.6Hz,1 H),5.36–5.23(m,1H),4.99(dd,J=11.2,4.8Hz,1H),4.92(t,J=6.8Hz,1H),3.66–3.59(m ,2H),3.59–3.41(m,5H),3.32–3.25(m,2H),1.52–1.48(m,1H),1.45–1.35(m,1H),1.31– 1.23(m,5H),1.15–1.06(m,2H),0.89–0.70(m,3H),0.62–0.38(m,4H),0.37–0.15(m,4H).

[1159] Example 116: Compound I-116

[1160] Step 1:

[1161] Triethylamine (12.5 g, 0.12 mmol) was added to a solution of compound 116-1 (3.05 g, 0.03 mmol) in dichloromethane (40 mL) under ice bath conditions, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with water (2 x 20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, a white solid compound 116-2 (5.5 g, 21.3 mmol, yield 71%). 1 H NMR (400MHz, DMSO) δ4.15 (s, 4H), 3.20 (s, 6H), 0.78 (s, 4H).

[1162] Step Two:

[1163] Compound 116-2 (0.78 g, 3 mmol), potassium carbonate (1.3 g, 9.42 mmol), and compound 116-3 (0.22 g, 3.01 mmol) were added to an acetonitrile (30 mL) solution and refluxed with stirring overnight. The solution was filtered, concentrated, and then column-sected (7 mol / L ammonia-methanol:dichloromethane = 0-50%) to give a colorless oily compound 116-4 (0.15 g, 1.07 mmol, yield 35%). LC-MS (ESI, m / z): 141 [M+1] + .

[1164] Step 3:

[1165] Compound 116-4 (35 mg, 0.25 mmol), compound 61-7 (40 mg, 0.075 mmol), HATU (50 mg, 0.14 mmol), and N,N-diisopropylethylamine (50 mg, 0.41 mmol) were added to 5 mL of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by thin-layer chromatography to give compound I-116 (17 mg, 0.026 mmol, yield 34.6%) as a white solid. LC-MS (ESI, m / z): 655.4 [M+1] + . 1 H NMR (400MHz, MeOD) δ8.55(s,1H),7.92–7.80(m,1H),7.16(dt,J=17.5,10.2Hz,2H),6.29(d,J=8.7Hz,1H),5.65(dd,J= 47.1,3.4Hz,1H),5.28(dd,J=15.3,3.4Hz,1H),4.92(m,1H),4.85–4.70(m,1H),3.76(m,1H),3.58(m,1H),3.43(m,1H), 3.27–3.05(m,2H),2.91(d,J=2.1Hz,3H),2.88–2.77(m,1H),2.62(dd,J=5.9,2.5Hz,1H),2.50(t,J=13.4Hz,1H),2.43 –2.17(m,5H),1.41(dd,J=6.9,2.6Hz,3H),1.02–0.89(m,2H),0.89–0.68(m,6H),0.68–0.41(m,7H),0.40–0.22(m,4H).

[1166] Example 117: Compound I-117

[1167] Step 1:

[1168] Under ice bath conditions, a 1 mol / L solution of lithium aluminum hydride in tetrahydrofuran (63 mL, 63.0 mmol) was added to a 30 mL solution of tetrahydrofuran (30 mL) under ice bath conditions, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched by the slow addition of sodium sulfate decahydrate under ice bath conditions. After filtration and concentration, a colorless oily compound 117-2 (2.4 g, 26.7 mmol, yield 66%) was obtained. 1H NMR (400MHz, CDCl3) δ3.85 (d, J = 22.0Hz, 2H), 1.11 (m, 2H), 0.77–0.66 (m, 2H).

[1169] Step Two:

[1170] Pyridinium chlorochromate (3.11 g, 14.43 mmol) and silica gel (10 g) were added to a solution of compound 117-2 (1.3 g, 14.43 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 3 hours. Then, pyridinium chlorochromate (1.58 g, 7.33 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Then, pyridinium chlorochromate (1.58 g, 7.33 mmol) was added again, and the mixture was stirred overnight at room temperature. The reaction mixture was then added to 40 mL of dichloromethane and filtered through silica gel to obtain the crude product compound 117-3, which was used directly in the next step.

[1171] Step 3:

[1172] DBU (6.5 g, 42.76 mmol) was added to a solution of compound 117-4 (2 g, 8.26 mmol) in dichloromethane (15 mL), and the mixture was stirred at 0 °C for 0.5 h. Then, compound 117-3 (the product solution from step two) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with water (2 x 20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a colorless liquid compound 117-5 (1.3 g, 7.38 mmol, yield 89.3%). 1 H NMR (400MHz, CDCl3) δ6.40 (dd, J=32.7, 18.2Hz, 0.65H), 6.14 (dd, J=18.7, 10.9Hz, 0.35H), 4.33(dq,J=18.7,7.1Hz,2H),1.48–1.31(m,5H),1.23–1.14(m,1.3H),1.00–0.90(m,0.7H).

[1173] Step Four:

[1174] Potassium hydroxide (0.62 g, 10.98 mmol) was dissolved in 2 mL of water and added to an ethanol solution of compound 117-5 (0.4 g, 2.27 mmol). The mixture was stirred overnight at room temperature. The pH of the solution was adjusted to acidic (pH = 4-6) with 1 mol / L hydrochloric acid. The solution was concentrated and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, a colorless oily compound 11-6 (0.2 g, 1.35 mmol, yield 59.4%), which was used directly in the next step. LC-MS (ESI, m / z): 149 [M+1] + .

[1175] Step 5:

[1176] Compound 111-6 (60 mg, 0.4 mmol), compound 36-2 (120 mg, 0.2 mmol), HATU (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (80 mg, 0.62 mmol) were added to 5 mL of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by thin-layer chromatography. Chiral resolution gave compound I-117-A (20 mg, 0.028 mmol, yield 12.3%) as a white solid. LC-MS (ESI, m / z): 720.3 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.87(dt,J=14.8,8.3Hz,1H),7.15(dd,J=14.0,6.1Hz,2H),6.30(d,J=9.0Hz,1H),6.10(ddd,J=21.2,1 2.7,3.2Hz,1H),4.98–4.89(m,2H),3.60–3.35(m,3H),3.23–3.13(m,1H),2.91(s,3H),2.67–2.57(m,1H),1.57–1.49(m,1H ), 1.40 (dd, J = 7.0, 1.9 Hz, 3H), 1.36–1.30 (m, 3H), 1.27 (s, 1H), 1.18–0.91 (m, 7H), 0.85 (ddd, J = 12.4, 8.2, 4.3 Hz, 2H), 0.80–0.73 (m, 3H), 0.61–0.38 (m, 4H), 0.37–0.19 (m, 4H) and compound I-117-B (50 mg, 0.07 mmol, yield 32.2%), LC-MS (ESI, m / z): 720.3 [M+1] + . 1H NMR(400MHz,MeOD)δ7.87(dt,J=13.9,8.5Hz,1H),7.15(dd,J=14.2,6.6Hz,2H),6.36–6.1 4(m,2H),4.97–4.90(m,2H),3.61–3.37(m,3H),3.18(ddd,J=10.1,6.9,3.6Hz,1H),2.91( s,3H),2.69–2.55(m,1H),1.58–1.25(m,8H),1.11(dq,J=16.9,8.2Hz,5H),0.96(dd,J=15 .2,8.2Hz,2H),0.89–0.72(m,5H),0.62–0.39(m,4H),0.29(qdd,J=13.3,10.3,6.0Hz,4H).

[1177] Example 118: Compound I-118

[1178] According to the preparation method of compound I-61:

[1179] White solid compound I-118 (58 mg, 0.0926 mmol, 43.9%). LC-MS (ESI, m / z): 627.5 [M+1] + . 1 H NMR (400MHz, CD3OD) δ7.79(m,1H),7.26–7.04(m,2H),6.34(m,1H),5.67(dt, J1=46.8Hz, J2=3.6Hz, 1H),5.29(dt,J1=15.2Hz,J2=3.2Hz,1H),4.63(m,1H),4.36(m,1H),3.75(m,1H),3.29(m,1H),3.17 –2.99(m,1H),2.91(s,3H),2.88–2.74(m,1H),2.64(s,3H),2.36(s,1H),2.06–1.77(m,2H),1.43(t ,J=7.2Hz,3H),1.39–1.22(m,2H),1.03–0.88(m,2H),0.91–0.65(m,5H),0.52(m,4H),0.31(m,4H).

[1180] Example 119: Compound I-119

[1181] According to the preparation method of compound I-61:

[1182] White solid compound I-119 (36 mg, 0.0575 mmol, 43.9%). LC-MS (ESI, m / z): 627.5 [M+1] + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.50 (s, 1H) (formic acid), 7.79 (m, 1H), 7.26–7.04 (m, 2H), 6.34 (m, 1H), 5.67 (dt, J₁ = 46.8 Hz, J₂ = 3.6 Hz, 1H), 5.29 (dt, J₁ = 15.2 Hz, J₂ = 3.2 Hz, 1H), 4.63 (m, 1H), 4.36 (m, 1H), 3.86 (m, 1H), 3.50 (m, 1H),3.26–3.15(m,1H),3.02(t,J=10.3Hz,1H),2.90(s,3H),2.78(m,1H),2.65(s,3H),2.35(s,1H),2.1 8–1.87(m,2H),1.44(t,J=7.2Hz,3H),1.32(m,2H),0.94(m,2H),0.78(m,5H),0.53(m,4H),0.31(m,4H).

[1183] Example 120: Compound I-120

[1184] According to the preparation method of compound I-61:

[1185] White solid compound I-120 (65 mg, 0.100 mmol, 80.9%). LC-MS (ESI, m / z): 647.8 [M+1] + . 1 H NMR (400MHz, CD3OD) δ7.97-7.91(m,1H),7.27–7.03(m,2H),6.36-6.32(m,1H),5.66(dd,J1=46.8Hz,J2= 3.2Hz,1H),5.29(dd,J1=15.2Hz,J2=3.2Hz,1H),4.94(d,J=6.8Hz,1H),4.60(s,1H),4.56–4.43(m,1H), 3.83-3.74(m,1H),3.53-3.37(m,1H),3.22-3.10(m,2H),2.91(s,3H),2.71–2.54(m,1H),1.44(t,J=7.2 Hz,3H),1.38–1.26(m,2H),0.99-0.89(m,4H),0.86-0.72(m,6H),0.60–0.38(m,5H),0.37–0.18(m,4H).

[1186] 1 H NMR(400MHz, DMSO-d6)δ9.94(s,1H),8.28(d,J=8.8Hz,1H),7.87-7.78(m,1H),7.25–7.04(m,2H), 6.26(dd,J=20.8,8.4Hz,1H),5.63(dd,J=48.0,3.6Hz,1H),5.32(dd,J=16.0,3.6Hz,1H),4.97-4.8 7(m,1H),4.49–4.32(m,1H),4.23–3.36(m,3H),3.27–2.97(m,2H),2.76(d,J=4.8Hz,3H),2.59-2.5 2(m,1H),1.38-1.27(m,3H),0.95–0.68(m,8H),0.67–0.50(m,3H),0.46(m,1H),0.40–0.10(m,7H).

[1187] Example 121: Compound I-121

[1188] According to the preparation method of compound I-111, the following was obtained:

[1189] White solid compound I-121 (28 mg, 0.0414 mmol, 45.2%). LC-MS (ESI, m / z): 677.8 [M+1] + . 1 H NMR (400MHz, CDCl3) δ8.33–8.05(m,1H),7.96(d,J=12.0Hz,1H),7.34(m,1H),7.02(m ,1H),6.39(m,1H),5.74(d,J=46.8Hz,1H),5.22(m,1H),5.07(m,1H),4.88–4.71(m,2 H),4.45(m,2H),3.66–3.44(m,2H),3.27–2.96(m,4H),2.73(m,1H),1.47(m,3H),1.3 1(t,J=7.2Hz,3H),1.15(m,4H),0.84(m,4H),0.57(m,4H),0.36(m,2H),0.24(m,2H).

[1190] Example 122: Compound I-122

[1191] The preparation method of compound I-61 yielded the following:

[1192] White solid compound I-122 (28 mg, 0.0423 mmol, 46.8%). LC-MS (ESI, m / z): 662.4 [M+1] + . 1 H NMR (400MHz, CD3OD) δ7.91 (t, J=8.0Hz, 1H), 7.19–7.04 (m, 2H), 5.66 (dd, J1=46.8Hz, J2=3. 2Hz,1H),5.29(dd,J1=15.2Hz,J2=3.2Hz,1H),5.02–4.92(m,2H),4.60(s,1H),3.58(m,1H), 3.41(m,1H),3.20–2.98(m,2H),2.91(s,3H),2.61(m,1H),1.67–1.47(m,3H),1.37(d,J=7.2 Hz,3H),1.33(m,2H),1.13–0.89(m,4H),0.77(m,5H),0.59–0.39(m,4H),0.37–0.19(m,4H).

[1193] Example 123: Compound I-123

[1194] The preparation method of compound I-61 yielded the following:

[1195] White solid compound I-123 (29 mg, 0.0438 mmol, 46.8%). LC-MS (ESI, m / z): 662.4 [M+1] + . 1 H NMR (400MHz, CD3OD) δ7.80 (t, J=8.0Hz, 1H), 7.24–7.04 (m, 2H), 5.66 (dd, J1=46.8Hz, J2= 3.2Hz,1H),5.28(dd,J1=15.2Hz,J2=3.2Hz,1H),4.99(m,1H),4.92(m,1H),4.60(s,1H),3 .71(m,2H),3.28–3.05(m,2H),2.91(s,3H),2.61(m,1H),1.70(m,1H),1.51(m,2H),1.39 (d,J=7.2Hz,3H),1.35(m,2H),0.94(m,4H),0.80(m,5H),0.62–0.38(m,4H),0.30(m,4H).

[1196] Example 124: Compound I-124

[1197] The preparation method of compound I-56 yielded the following:

[1198] White solid compound I-124 (28 mg, 0.0393 mmol, 66.7%). LC-MS (ESI, m / z): 711.8 [M+1] + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.50 (s, 0.6H) (formic acid), 7.92 (m, 1H), 7.15 (m, 2H), 6.30 (d, J = 8.8Hz, 1H), 4.95 (m, 2H), 4.60 (s, 1H), 3.52 (m, 1H), 3.39 (m, 2H), 3.24–3.13 (m, 1H), 2.91 (s, 3H), 2.62 (m, 1H) 1.48(m,2H),1.40(dd,J1=7.2Hz,J2=2.0Hz,3H),1.38–1.26(m,2H),1.20–1.03(m,6H),0.94(m ,2H),0.92–0.79(m,2H),0.80–0.68(m,3H),0.66–0.51(m,3H),0.50–0.38(m,4H),0.29(m,8H).

[1199] Example 125: Compound I-125

[1200] The preparation method of compound I-61 yielded the following:

[1201] White solid compound I-125 (24 mg, 0.0395 mmol, 80.6%). LC-MS (ESI, m / z): 607.8 [M+1] + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.52 (s, 0.3H) (formic acid), 7.93 (t, J = 8.0Hz, 1H), 7.15 (m, 2H), 5.66 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.29 (dd, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 4.94 (d, J = 6.8Hz, 1H), 4.65 (m, 1H) ),4.35–4.16(m,2H),3.93(m,2H),3.18(m,1H),2.90(s,3H),2.66–2.56(m,1H),1.40(d,J=6. 8Hz,3H),1.31(m,1H),0.99–0.87(m,2H),0.90–0.68(m,5H),0.60–0.37(m,4H),0.29(m,4H).

[1202] Example 126: Compound I-126

[1203] The preparation method of compound I-61 yielded the following:

[1204] White solid compound I-126 (8 mg, 0.0128 mmol, 28.4%). LC-MS (ESI, m / z): 625.8 [M+1] + . 1 ¹H NMR (400MHz, CD₃OD) δ 8.49 (s, 3H) (formic acid), 7.94 (t, J = 8.0Hz, 1H), 7.21–7.06 (m, 2H), 5.66 (dd, J₁ = 46.8Hz, J₂ = 3.2Hz, 1H), 5.29 (dd, J₁ = 15.2Hz, J₂ = 3.2Hz, 1H), 4.94 (d, J = 6.8Hz, 1H), 4.61 (s, 1H), 4.30 (d, J = 10.4Hz, 1H), 4.01 (d, J = 8.4Hz, 1H), 3.81 (s ,1H),3.67(d,J=10.4Hz,1H),3.39–3.28(m,2H),3.11(m,2H),2.91(s,3H),2.65–2.56(m,1H),1.82–1.63(m,3H),1.53(m, 4H),1.39(d,J=6.8Hz,3H),1.37–1.22(m,3H),0.99–0.88(m,2H),0.87–0.71(m,4H),0.60–0.43(m,3H),0.44–0.21(m,4H).

[1205] Example 127: Compound I-127

[1206] The preparation method of compound I-61 yielded the following:

[1207] White solid compound I-127 (8 mg, 0.0136 mmol, 28.9%). LC-MS (ESI, m / z): 589.8 [M+1] + . 1H NMR (400MHz, CD3OD) δ7.85 (t, J=8.0Hz, 1H), 7.20–7.01 (m, 2H), 5.66 (dd, J1=46.8Hz, J2=3.2Hz, 1H),5.28(dd,J1=15.2Hz,J2=3.2Hz,1H),4.92(d,J=6.4Hz,1H),4.42(d,J=8.4Hz,1H),3.28(m,1 H),3.25(s,3H),3.23–3.16(m,1H),3.17–3.08(m,2H),2.88(s,3H),2.64–2.51(m,1H),1.35(d,J =6.8Hz,3H),1.33(m,2H),0.90(m,3H),0.84–0.63(m,4H),0.63–0.38(m,4H),0.40–0.17(m,4H).

[1208] Example 128: Compound I-128

[1209] The preparation method of compound I-61 yielded the following:

[1210] White solid compound I-128 (11 mg, 0.0172 mmol, 61.4%). LC-MS (ESI, m / z): 639.8 [M+1] + M / Z = 639.8(M+H) + . 1 H NMR (400MHz, CD3OD) δ7.94(t,J=8.0Hz,1H),7.16(m,2H),6.25(d,J=8.8Hz,1H),5.66(dd,J1=46.8Hz,J2=3.2Hz ,1H),5.28(dd,J1=15.2Hz,J2=3.2Hz,1H),4.94(d,J=7.2Hz,1H),4.39–4.22(m,1H),3.83(d,J=8.4Hz,1H),3.4 6(d,J=10.0Hz,1H),3.17(d,J=10.0Hz,1H),3.10(m,2H),2.91(s,3H),2.66–2.56(m,1H),1.53(m,2H),1.40(d, J=7.2Hz,3H),1.32(m,6H),1.16(m,2H),0.94(m,2H),0.87–0.72(m,5H),0.60–0.39(m,4H),0.39–0.21(m,4H).

[1211] Example 129: Compound I-129

[1212] Step 1:

[1213] Compound 61-7 (30 mg, 0.06 mmol, 1.00 eq), 2,2-difluoro-7-aza[3.5]nonane hydrochloride (17 mg, 0.09 mmol, 1.54 eq), and N,N-diisopropylethylamine (22 mmol, 0.17 mmol, 3.05 eq) were dissolved in N,N-dimethylformamide (2.00 mL), and HATU (32 mg, 0.08 mmol, 1.50 eq) was added. The reaction mixture was stirred at room temperature for 20 minutes, diluted with water, extracted with ethyl acetate (15 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give compound I-129 (20.00 mg, yield 52.85%) as a white solid. LC-MS (ESI, m / z): 676.1 [M+H] + 1 H NMR(400MHz,MeOD)δ7.82(t,J=8.0Hz,1H),7.21–7.07(m,2H),6.28(d,J=9.0Hz,1H),5.66(dd,J=47.2,3.6Hz,1 H),5.28(dd,J=15.2,3.6Hz,1H),4.93–4.90(m,2H),3.60–3.47(m,1H),3.31–3.22(m,2H),3.20–3.11(m,2H),2 .90(s,3H),2.68–2.56(m,1H),2.30(t,J=16.0Hz,2H),2.19(td,J=12.8,4.0Hz,2H),1.57–1.44(m,2H),1.40(d ,J=7.2Hz,3H),1.32–1.21(m,1H),0.96–0.91(m,3H),0.89–0.67(m,5H),0.62–0.40(m,4H),0.39–0.18(m,4H).

[1214] Example 103: Compound I-130

[1215] The preparation method of compound I-61 yielded the following:

[1216] White solid compound I-130 (25 mg, 0.038 mmol, yield 67%). LC-MS (ESI, m / z): 662.3 [M+1] + . 1H NMR(400MHz,MeOD)δ7.85(q,J=8.1Hz,1H),7.22–7.10(m,2H),6.29(d,J=8.8Hz,1H),5.66(dd,J=47.0,3.4Hz,1H),5. 28(dd,J=15.3,3.4Hz,1H),4.92(d,J=6.5Hz,1H),4.64–4.47(m,1H),3.78–3.60(m,1H),3.43–3.28(m,1H),3.13(m,2H ),2.94–2.82(m,4H),2.66–2.59(m,1H),2.48(m,2H),2.19(dt,J=25.9,13.3Hz,2H),1.98–1.65(m,2H),1.43(dd,J=7 .0,2.0Hz,3H),0.95(dd,J=8.9,4.4Hz,2H),0.79(ddd,J=11.7,7.7,3.5Hz,5H),0.60–0.38(m,4H),0.38–0.19(m,4H).

[1217] Example 131: Compound I-131

[1218] The preparation method of compound I-61 yielded the following:

[1219] White solid compound I-131 (3 mg, 0.0046 mmol, yield 8.3%). LC-MS (ESI, m / z): 648.7 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.90(ddd,J=27.1,16.5,8.2Hz,1H),7.23–7.08(m,2H),6.31(d,J=8.7Hz,1H ),5.66(dd,J=47.0,3.4Hz,1H),5.34–5.23(m,1H),4.93(dd,J=14.2,6.7Hz,1H),4.57(dt,J=19.1 ,9.3Hz,1H),3.88–3.35(m,2H),3.24–3.09(m,2H),3.03–2.85(m,4H),2.63(dt,J=6.6,3.1Hz,1H ),2.10–1.58(m,2H),1.46–1.23(m,5H),1.00–0.90(m,2H),0.89–0.72(m,5H),0.60–0.20(m,8H).

[1220] Example 132: Compound I-132

[1221] The preparation method of compound I-61 yielded the following:

[1222] White solid compound I-132 (25 mg, 0.04 mmol, yield 71.8%). LC-MS (ESI, m / z): 622.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.88(td,J=8.0,1.5Hz,1H),7.24–7.08(m,2H),6.33(dd,J=8.6,2.4Hz, 1H),5.66(dd,J=47.0,3.4Hz,1H),5.29(dd,J=15.3,3.5Hz,1H),4.93(d,J=6.8Hz,1H),4.66 –4.37(m,1H),4.09–3.81(m,1H),3.74–3.48(m,1H),3.41–3.07(m,3H),2.90(s,3H),2.68–2 .58(m,1H),2.41–1.99(m,2H),1.44(d,J=7.0Hz,3H),1.01–0.72(m,7H),0.61–0.19(m,8H).

[1223] Example 133: Compound I-133

[1224] The preparation method of compound I-56 yielded the following:

[1225] White solid compound I-133 (13 mg, 0.0192 mmol, 41.7%). LC-MS (ESI, m / z): 677.7 [M+1] + . 1 H NMR(400MHz,CD3OD)δ7.86(m,1H),7.16(m,2H),6.50(s,1H),5.96(m,1H),4 .92(m,1H),4.60(s,2H),3.50(m,2H),3.43–3.35(m,2H),3.18(m,2H),2.91( s,3H),2.62(m,1H),1.53(m,2H),1.41(d,J=7.2Hz,3H),1.33(m,2H),1.20–0 .99(m,3H),0.95(m,2H),0.80(m,5H),0.63–0.38(m,4H),0.39–0.17(m,4H).

[1226] Example 134: Compound I-134

[1227] Step 1:

[1228] In a 100 mL round-bottom flask, triethylamine (23 mg, 0.224 mmol) and HATU (56 mg, 0.146 mmol) were added sequentially to a 5 mL solution of compound 76-6 (60 mg, 0.112 mmol) in dichloromethane. The reaction mixture was then stirred at room temperature for 20 minutes. Next, intermediate compound 134-1 (23 mg, 0.134 mmol) was added to the reaction mixture, and the mixture was stirred for another 2 hours. LC-MS was used to monitor the depletion of the starting materials. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 134-2 (55 mg, 0.084 mmol, 75.5%) as a white solid. LC-MS (ESI, m / z): 650.2 [M+H] + .

[1229] Step Two:

[1230] In a 100 mL round-bottom flask, ethyl hydrogen chloride solution (4 M, 0.1 mL, 0.4 mmol) was added sequentially to a 5 mL solution of compound 134-2 (50 mg, 0.077 mmol) in dichloromethane. The reaction mixture was then stirred at room temperature for 2 hours. The starting material was monitored by LC-MS until complete consumption. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next reaction without further purification. Compound 134-3 (45 mg, 0.075 mmol, 99.7%) was obtained as a white solid. LC-MS (ESI, m / z): 550.1 [M+H] + .

[1231] Step 3:

[1232] In a 100 mL round-bottom flask, triethylamine (23 mg, 0.224 mmol) and HATU (56 mg, 0.146 mmol) were added sequentially to a 5 mL solution of compound 134-3 (45 mg, 0.077 mmol) in dichloromethane. The reaction mixture was then stirred at room temperature for 20 minutes. Methoxyacetic acid (8.23 mg, 0.092 mmol) was then added to the reaction mixture, and the mixture was stirred for another 2 hours. LC-MS was used to monitor the depletion of the starting materials. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give a white solid compound I-134 (16 mg, 0.026 mmol, 33.4%). LC-MS (ESI, m / z): 622.2 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.92–7.79(m,1H),7.27–7.06(m,2H),5.75-5.55(m,1H),5.34-5.23(m,1H),5.14-5.03(m,1H),4.96-4.89(m,2H),4.64 –3.74(m,5H),3.53-3.43(m,3H),3.30–2.89(m,2H),2.88–2.37(m,2H),2. 35–1.97(m,4H),1.44–1.23(m,4H),0.93-0.71(m,3H),0.61–0.09(m,8H).

[1233] Example 135: Compound I-135

[1234] The preparation method of compound I-134 yielded the following:

[1235] Compound I-135 (18.59 mg, 0.03 mmol, 36.1%) was a white solid. LC-MS (ESI, m / z): 606.2 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ7.88-7.80(m,1H),7.22–7.06(m,2H),5.75-5.56(m,1H),5.3 3-5.23(m,1H),5.03–4.88(m,3H),4.61–4.22(m,2H),4.21–4.01(m,1H),3.98–3.82(m,1H ),3.26–3.12(m,1H),2.89–2.42(m,2H),2.37–2.20(m,4H),2.16(d,J=10.0Hz,2H),1.43- 1.25(m,4H),1.20-1.09(m,3H),0.88–0.71(m,3H),0.61–0.39(m,4H),0.38–0.20(m,4H).

[1236] Example 136: Compound I-136

[1237] The preparation method of compound I-134 yielded the following:

[1238] Compound I-136 (26 mg, 0.04 mmol, 47.3%) was a white solid. LC-MS (ESI, m / z): 646.2 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.89-7.78(m,1H),7.24–7.05(m,2H),5.74-5.57(m,1H),5.32-5.23( m,1H),5.10–4.97(m,1H),4.95-4.89(m,1H),4.68–3.81(m,4H),3.30–2.83(m,2H),2.79–2.47(m,2 H),2.32(d,J=2.4Hz,1H),2.29–2.04(m,3H),1.80-1.57(m,2H),1.43-1.30(m,3H),1.28–1.17(m,3 H),1.02-0.89(m,1H),0.87-0.72(m,3H),0.64–0.40(m,6H),0.39–0.23(m,5H),0.21-0.10(m,1H).

[1239] Example 137: Compound I-137

[1240] Step 1:

[1241] In a 100 mL round-bottom flask, N,N-diisopropylethylamine (15 mg, 0.14 mmol) was added sequentially to a 3 mL solution of compound 36-2 (40 mg, 0.068 mmol) in dichloromethane. The reaction mixture was then cooled in an ice-water bath and stirred for 20 minutes. Trifluoroacetic anhydride (18.5 mg, 0.088 mmol) was then added to the reaction mixture all at once. The reaction mixture was slowly heated to room temperature and stirred for 2 hours. LC-MS was used to monitor the consumption of the starting materials. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography and separated by preparative column chromatography to obtain compound I-137 (9 mg, 0.013 mmol, 17.37%) as a white solid. LC-MS (ESI, m / z): 686.2 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ7.98-7.83(m,1H),7.21–7.09(m,2H),6.30(d,J=8.8Hz,1H),4.98–4.89(m ,2H),3.60–3.36(m,3H),3.23–3.13(m,1H),2.91(s,3H),2.66-2.58(m,1H),1.58–1.48(m,1H),1.41(d ,J=7.2Hz,3H),1.37-1.32(m,1H),1.30-1.21(m,1H),1.17–1.00(m,3H),0.99-0.91(m,2H),0.86-0.79 (m,2H),0.78-0.72(m,3H),0.60-0.52(m,1H),0.51-0.43(m,2H),0.42-0.33(m,2H),0.32-0.19(m,3H).

[1242] Example 138: Compound I-138

[1243] Step 1:

[1244] In a 100 mL round-bottom flask, DIPEA (30 mg, 0.225 mmol) and HATU (43 mg, 0.11 mmol) were added sequentially to a 3 mL solution of N,N-dimethylformamide containing compound 61-7 (40 mg, 0.075 mmol). The reaction mixture was stirred for 20 minutes. Then, 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (19.2 mg, 0.09 mmol) was added to the reaction mixture all at once. The reaction mixture was stirred at room temperature for 2 hours. The consumption of the starting material was monitored by LC-MS. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain a white solid formate of compound I-138 (25 mg, 0.038 mmol, 50.9%). LC-MS (ESI, m / z): 655.2 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.50 (br, 3H) (formic acid), 7.68 (t, J = 8.0Hz, 1H), 7.19 (dd, J = 12.0, 2.0Hz, 1H) ,7.09(dd,J=8.4,2.0Hz,1H),6.31(d,J=8.8Hz,1H),5.73-5.28(m,1H),3.90(s,2H),3.80–3.71(m,3 H),3.25–3.13(m,4H),3.08–2.97(m,2H),2.90(s,3H),2.87(s,3H),2.65-2.56(m,3H),1.78-1.68( m,3H),1.44-1.39(m,4H),1.0-0.9(m,3H),0.77-0.72(m,4H),0.60–0.44(m,3H),0.40–0.25(m,3H).

[1245] Example 139: Compound I-139

[1246] The preparation method of compound I-138 yielded the following:

[1247] Formate of compound I-139 (22 m...

Claims

1. A compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof: ###0001### Formula I ​ wherein R 1 For -OR 1-8 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 1-9 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 1-10 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R C2-C6 ynyl group, with one or more R 1-14 Substituted C2-C6 ynyl group, 3-12 membered heterocyclic group, or grouped by one or more R 1-15 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-16 Substituted 5-12-membered heteroaryl, C1-C6 alkyl, or substituted with one or more R 1-17 The substituted C1-C6 alkyl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 1-1 R 1-2 R 1-3 Each of the following is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with one or more deuterates, halogen, C1-C6 alkoxy, or substituted with one or more R 1-1-1 Substituted C1-C6 alkoxy groups, with one or more R 1-1-2 Substituted C1-C6 alkyl groups; R 1-1-1 R is halogen; R 1-1-2 is Ci-C6-alkoxy; R 1-4 is hydrogen, C1-C6alkyl, C1-C6alkyl deuterated by one or more deuterium, C3-C8cycloalkyl, -OR 1-4-1 , oxidized or oxo; R 1-4-1 C1-C6alkyl, C1-C6alkyl substituted with one or more R 1-4-1-1 C1-C6alkyl, C1-C6alkyl substituted with one or more R substituted C1-C6alkyl or 3-12 membered heterocyclyl; the heteroatoms in the heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms each independently being 1, 2, or 3; R 1-4-1-1 is halogen; R 1-5 is hydrogen, Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 1-5-1 substituents; R 1-5-1 is halogen; R 1-6 is hydrogen or CrC6alkyl; R 1-7 is hydrogen or CrC6alkyl; R 1-8 C5-C 12 aryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, or compounded by one or more R 1-8-1 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 1-8-1 Ci-C6-alkyl; R 1-9 C1-C6alkyl, C1-C6alkoxy, halo, deuterated, cyano, or hydroxyl; each R 1-9-1 substituted C1-C6alkyl, halo, deuterated, cyano, or hydroxyl; R 1-9-1 is halogen; R 1-10 Halogen, C3-C8 cycloalkyl, with one or more R 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl, deuterated, -NR 1-10-3 R 1-10-4 3-12 membered heterocyclic group, surrounded by one or more R 1-10-5 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and groups with one or more R groups 1-10-6 The substituted 5-12-membered heteroaryl or cyano group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3. R 1-10-1 halogen, Ci-C6alkyl, or deuterated; R 1-10-2 is deuterium, halogen or -NR 1-10-2-1 R 1-10-2-2 ; R 1-10-2-1 , R 1-10-2-2 each independently is hydrogen or Ci-C6alkyl; R 1-10-3 , R 1-10-4 each independently is hydrogen or Ci-C6alkyl; R 1-10-5 halogen or Ci-C6alkyl; R 1-10-6 R is halo or Ci-C6alkyl; R 1-11 , R 1-12 , R 1-13 each independently is hydrogen, Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 1-11-1 , C3-C8-cycloalkyl; R 1-11-1 is deuterium or halogen; R 1-14 is halogen; R 1-15 Ci-C6-alkyl or halogen; R 1-16 halogen or Ci-C6alkyl; R 1-17 R is halogen, -NR 1-17-1 R 1-17-2 or C3-C8cycloalkyl; R 1-17-1 , R 1-17-2 each independently is hydrogen or Ci-C6alkyl; R 2 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 2-1 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 20 C3-C7-cycloalkyl or C3-C7-cycloalkyl substituted by one or more R 2-2 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 20 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R R 2-1 C3-C8cycloalkyl or halogen; R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2- 2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 2-2-8 Substituted C3-C8 cycloalkyl, or the heteroatoms in the heterocyclyl group are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3; R 2-2-1 R is halogen; R 2-2-2 is halogen; R 2-2-3 , R 2-2-4 , R 2-2-5 each independently is H or C1-C6alkyl; R 2-2-6 Ci-C6-alkyl; R 2-2-7 halogen or Ci-C6alkyl; R 2-2-8 is halogen; R 2-2-9 , R 2-2-10 each independently is hydrogen, halogen or Ci-C6-alkyl; R 3 , R 4 , R 5 , R 6 , R 7 each independently H, halogen, -CR 5-13 R 5- 14 R 5-15 or nothing; R 5-0 is H; R 5-1 H, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with one or more R 5-1-1 substituents; or R1and R2together with the carbon atom to which they are attached form a C3-C8 cycloalkyl ring; 5- 1-2 substituents; or R1and R2together with the carbon atom to which they are attached form a C3-C8 cycloalkyl ring; R 5-1-1 is Ci-C6alkoxy or halogen; R 5-1-2 halogen or Ci-C6alkyl; R 5-2 is H or C1-C6alkyl; R 5-3 , R 5-4 each independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 -(C=O)-R 5-3-3 , 4-12 membered heterocyclyl, 4-12 membered heterocyclyl substituted with one or more R 5-3-4 , C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkyl substituted with one or more R 5-3-5 , or -SO2R 5-3-6 ; the heteroatoms in the heterocyclyl groups are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 for each heteroatom. R 5-3-1 , R 5-3-2 each independently H, C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with one or more R 5-3-1-1 , 4-12 membered heterocyclyl, 4-12 membered heterocyclyl substituted with one or more R 5-3-1-2 , or C1-C6alkyl substituted with one or more R 5-3-1-3 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3; R 5-3-1-1 for R 5-3-1-1-1 , R 5-3-1-1-2 each independently is hydrogen, halogen or Ci-C6-alkyl; R 5-3-1-2 R is halo or Ci-C6alkyl; R 5-3-1-3 R is halogen; or R 5-3-1 , R 5-3-2 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-3-1-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 at each occurrence; R 5-3-1-1 Ci-C6-alkyl; R 5-3-3 C1-C6alkyl, C1-C6alkyl substituted with one or more R 5-3-3-1 C2-C6alkenyl, 4-12 membered heterocyclyl, 4-12 membered heterocyclyl substituted with one or more R 5-3-3-2 C2-C6alkenyl, 4-12 membered heterocyclyl, 4-12 membered heterocyclyl substituted with one or more R 5-3-3-3 C3-C8cycloalkyl, C3-C8cycloalkyl substituted with one or more R 5- 3-3-4 5-12 membered heteroaryl, or C2-C6alkenyl substituted with one or more R 5-3-3-5 C2-C6alkenyl; the heteroatoms in said heterocyclyl, heteroaryl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms each independently is 1, 2, or 3; R 5-3-3-1 -Si(CH3)3, C1-C6alkoxy, C3-C8cycloalkyl, halogen, 4-12 membered heterocyclyl, or substituted 4-12 membered heterocyclyl; wherein the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms each independently is 1, 2, or 3; 5-3-3-1- 1 -Si(CH3)3, C1-C6alkoxy, C3-C8cycloalkyl, halogen, 4-12 membered heterocyclyl, or substituted 4-12 membered heterocyclyl; wherein the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms each independently is 1, 2, or 3; R 5-3-3-1-1 halogen or Ci-C6alkyl; R 5-3-3-2 Ci-C6-alkyl; R 5-3-3-3 R is halogen; R 5-3-3-4 C3-C8cycloalkyl, C1-C6alkyl, or C1-C6alkyl substituted with one or more R 5-3-3-4-1 substituted C1-C6alkyl; R 5-3-3-4-1 is 5-12 membered heteroaryl; the heteroatom in the heteroaryl is independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms is independently 1, 2, or 3; R 5-3-3-5 R is halogen; R 5-3-4 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 5-3-4-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 5-3-4-1 is Ci-C6-alkoxy; R 5-3-5 -(C=O)-NR 5-3-5-1 R 5-3-5-2 , 4-12 membered heterocyclyl, or 4-12 membered heterocyclyl substituted with one or more R 5-3-5-3 R R 5-3-5-1 , R 5-3-5-2 each independently is hydrogen or Ci-C6alkyl; R 5-3-5-3 -NR 5-3-5-3-1 R 5-3-5-3-2 ; R 5-3-5-3-1 , R 5-3-5-3-2 each independently is hydrogen or Ci-C6alkyl; R 5-3-6 Ci-C6-alkyl; or R 5-3 , R 5-4 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-4-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 at each occurrence; R 5-4-1 is oxo, halogen, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 5-4-1-1 substituted with one or more R R 5-4-1-1 R is halogen; R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 5-5-3 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-5-4 Substituted 4-12 membered heterocyclic groups, C2-C6 alkynyl groups, or groups with one or more R groups 5-5-5 The substituted C1-C6 alkyl group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; R 5-5-1 is oxo, -OH, C1-C6alkyl, or halo; R 5-5-2 OH, C1-C6 alkyl, or halogen; R 5-5-3 -NR 5-5-3-1 R 5-5-3-2 halogen, C2-C6alkynyl, C1-C6alkyl, C1-C6alkyl substituted by one or more R 5-5-3-3 halogen, C2-C6alkynyl, C1-C6alkyl, C1-C6alkyl substituted by one or more R 5-5-3-4 R 5-5-3-5 ; R 5-5-3-1 , R 5-5-3-2 each independently H or Ci-C6alkyl; R 5-5-3-3 for R 5-5-3-3-1 , R 5-5-3-3-2 each independently H or Ci-C6alkyl; R 5-5-3-4 , R 5-5-3-5 each independently H or Ci-C6alkyl; R 5-5-4 C2-C6alkenyl or Ci-C6alkyl; R 5-5-5 -SO2NR 5-5-5-1 R 5-5-5-2 , C3-C8cycloalkyl, NR 5-5-5-3 R 5-5-5-4 , C1-C6alkoxy, or CONR 5-5-5-5 R 5-5-5-6 ; R 5-5-5-1 , R 5-5-5-2 each independently H or Ci-C6alkyl; R 5-5-5-3 , R 5-5-5-4 each independently H or Ci-C6alkyl; R 5-5-5-5 , R 5-5-5-6 each independently H or Ci-C6alkyl; or R 5-5 , R 5-6 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-6-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, selenium, each independently in a number of 1, 2, or 3; R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5-6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups, -NR 5-6-1-8 R 5-6-1-9 C3-C8 cycloalkyl groups, with one or more R 5-6-1 - 10 Substituted C3-C8 cycloalkyl, C1-C6alkoxy, 4-12heterocyclyl, substituted 4-12heterocyclyl, hydroxy, or substituted hydroxy 5- 6-1-14 substituted 4-12heterocyclyl, hydroxy, or substituted hydroxy 5-6-1-15 substituted C1-C6alkoxy; the heteroatom in the heteroaryl, heterocyclyl is independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, selenium, the number of heteroatoms is independently 1, 2, or 3; R 5-6-1-1 , R 5-6-1-2 each independently H or Ci-C6alkyl; R 5-6-1-3 C3-C8cycloalkyl or halogen; R 5-6-1-4 , R 5-6-1-5 each independently H or Ci-C6alkyl; R 5-6-1-6 halogen; R 5-6-1-7 is oxo or C1-C6alkyl; R 5-6-1-8 , R 5-6-1-9 each independently H or Ci-C6alkyl; R 5-6-1-10 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 5-6-1-10-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 5-6-1-10-1 is halogen; R 5-6-1-11 , R 5-6-1-12 each independently H, halogen, or Ci-C6alkyl; R 5-6-1-13 is hydrogen or CrC6alkyl; R 5-6-1-14 halogen or Ci-C6alkyl; R 5-6-1-15 is deuterium or halogen; n1 is 0, 1, or 2; R 5-7 H or C1-C6 alkyl; R 5-8 is Ci-C6-alkyl or NR 5-8-1 R 5-8-2 ; R 5-8-1 is H; R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ; R 5-8-2-1 , R 5-8-2-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; R 5-9 is H; R 5-10 H, 5-14 membered heteroaryl, or heteroaryl substituted with one or more R 5-10-1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R R 5-10-1 C1-C6alkyl substituted by one or more R 5-10-1-1 C1-C6alkyl substituted by one or more R R 5-10-1-1 R is halogen; or R 5-9 , R 5-10 and the C atom to which they are attached together form a carbonyl group; R 5-11 is H; R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ; R 5-12-1 , R 5-12-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; or R 5-11 , R 5-12 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-11-1 , wherein the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 at each occurrence; R 5-11-1 C1-C6alkyl substituted by one or more R 5-11-1-1 C1-C6alkyl substituted by one or more R R 5-11-1-1 is halogen; R 5-13 is H; R 5-14 Ci-C6-alkyl; R 5-15 is 4-12 membered heterocyclyl, or 4-12 membered heterocyclyl substituted with one or more R 5-15-1 substituted 4-12 membered heterocyclyl; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms each independently being 1, 2, or 3; R 5-15-1 is oxo or C1-C6alkyl; R 8 is H or deuterium; n2 is 0, 1, or 2; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each independently C or N; m is 0 or 1.

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof, wherein The structure of formula I is shown in formula I-1 or I-2 below: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are as defined in claim 1.

3. The compound of Formula I, pharmaceutically acceptable salts thereof, solvates thereof, stereoisomers thereof, tautomers thereof, prodrugs thereof, or metabolites thereof of claim 1, wherein: wherein R 1 for -OR 1-8 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 1-9 C2-C6alkenyl, C2-C6alkenyl substituted by one or more R 1-10 C2-C6alkenyl, C2-C6alkenyl substituted by one or more R C2-C6 ynyl group, with one or more R 1-14 Substituted C2-C6 ynyl group, 3-12 membered heterocyclic group, or grouped by one or more R 1-15 Substituted 3-12-membered heterocyclic groups, 5-12-membered heteroaryl groups, and those with one or more R groups 1-16 Substituted 5-12-membered heteroaryl, C1-C6 alkyl, or substituted with one or more R 1-17 The substituted C1-C6 alkyl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 1-1 , R 1-2 , R 1-3 each independently is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or C1-C6alkyl which is substituted with one or more deuterium; R 1-4 is hydrogen, Ci-C6alkyl, Ci-C6alkyl deuterated in one or more positions, C3-C8cycloalkyl, -OR 1-4-1 , or oxidized; R 1-4-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 1-4-1-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 1-4-1-1 R is halogen; R 1-5 is hydrogen, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 1-5-1 substituents; R 1-5-1 R is halogen; R 1-6 is hydrogen or CrC6alkyl; R 1-7 is hydrogen or CrC6alkyl; R 1-8 C5-C 12 aryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, 5-12 membered heteroaryl, or compounded by one or more R 1-8-1 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 1-8-1 Ci-C6-alkyl; R 1-9 C1-C6alkyl, C1-C6alkoxy, halo, or deuterated; or 1-9-1 C1-C6alkyl substituted by one or more R R 1-9-1 R is halogen; R 1-10 Halogen, C3-C8 cycloalkyl, with one or more R 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl, deuterated, -NR 1-10-3 R 1-10-4 3-12 membered heterocyclic group, surrounded by one or more R 1-10-5 Substituted 3-12-membered heterocyclic group, 5-12-membered heteroaryl group, or grouped by one or more R 1-10-6 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 1-10-1 halogen, Ci-C6alkyl, or deuterated; R 1-10-2 R is H, deuterium, halogen, or -NR 1-10-2-1 R 1-10-2-2 ; R 1-10-2-1 , R 1-10-2-2 each independently is hydrogen or Ci-C6alkyl; R 1-10-3 , R 1-10-4 each independently is hydrogen or Ci-C6alkyl; R 1-10-5 halogen or Ci-C6alkyl; R 1-10-6 halogen or Ci-C6alkyl; R 1-11 , R 1-12 , R 1-13 each independently is hydrogen, Ci-C6alkyl, Ci-C6alkyl substituted with one or more R 1-11-1 , or C3-C8cycloalkyl; R 1-11-1 is deuterium or halogen; R 1-14 R is halogen; R 1-15 Ci-C6-alkyl or halogen; R 1-16 halogen or Ci-C6alkyl; R 1-17 halogen or -NR 1-17-1 R 1-17-2 ; R 1-17-1 , R 1-17-2 each independently is hydrogen or Ci-C6alkyl; R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, C3-C 20 cycloalkyl, or by one or more R 2-2 Replacement C3-C 20 cycloalkyl; R 2-1 C3-C8cycloalkyl, or halogen; R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2 - 2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, or with one or more R 2-2-8 The substituted C3-C8 cycloalkyl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3. R 2-2-1 is halogen; R 2-2-2 R is halogen; R 2-2-3 , R 2-2-4 , R 2-2-5 each independently H or C1-C6alkyl; R 2-2-6 Ci-C6-alkyl; R 2-2-7 halogen or Ci-C6alkyl; R 2-2-8 is halogen; R 3 , R 4 , R 5 , R 6 , R 7 each independently H, halogen, -CR 5-13 R 5- 14 R 5-15 or nothing; R 5-0 is H; R 5-1 H, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with one or more R 5-1-1 substituted with one or more R 5- 1-2 substituted with one or more R R 5-1-1 is Ci-C6alkoxy or halogen; R 5-1-2 halogen or Ci-C6alkyl; R 5-2 H or C1-C6 alkyl; R 5-3 , R 5-4 each independently H, OH, -(C=0)-NR 5-3-1 R 5-3-2 -(C=0)-R 5-3-3 , 4-12 membered heterocyclyl, 4-12 membered heterocyclyl substituted by one or more R 5-3-4 , C3-C8cycloalkyl, C1-C6alkyl, C1-C6alkyl substituted by one or more R 5-3-5 , or -SO2R 5-3-6 ; or R 5-3 , R 5-4 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-4-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 at each occurrence; R 5-3-1 , R 5-3-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; or R 5-3-1 , R 5-3-2 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-3-1-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 at each occurrence; R 5-3-1-1 Ci-C6-alkyl; R 5-3-3 It is a C1-C6 alkyl group, with one or more R 5-3-3-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-3-3-2 Substituted 4-12 membered heterocyclic groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-3-3-3 Substituted C3-C8 cycloalkyl, -OR 5- 3-3-4 5-12 aryl groups, or those containing one or more R groups 5-3-3-5 The substituted C2-C6 alkenyl group; the heteroatoms in the heterocyclic group and heteroaryl group are independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 5-3-3-1 -Si(CH3)3, C1-C6alkoxy, C3-C8cycloalkyl, or halogen; R 5-3-3-2 Ci-C6-alkyl; R 5-3-3-3 is halogen; R 5-3-3-4 C3-C8cycloalkyl, C1-C6alkyl, or C1-C6alkyl substituted by one or more R 5-3-3-4-1 substituted C1-C6alkyl; R 5-3-3-4-1 is 5-12 membered heteroaryl; the heteroatom in the heteroaryl is independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms is independently 1, 2, or 3; R 5-3-3-5 is halogen; R 5-3-4 C1-C6alkyl, or C1-C6alkyl substituted by one or more R 5-3-4-1 substituted C1-C6alkyl; R 5-3-4-1 is Ci-C6-alkoxy; R 5-3-5 -(C=O)-NR 5-3-5-1 R 5-3-5-2 , 4-12 membered heterocyclyl, or 4-12 membered heterocyclyl substituted with one or more R 5-3-5-3 substituents; R 5-3-5-1 , R 5-3-5-2 each independently is hydrogen, or Ci-C6alkyl; R 5-3-5-3 -NR 5-3-5-3-1 R 5-3-5-3-2 ; R 5-3-5-3-1 , R 5-3-5-3-2 each independently is hydrogen, or Ci-C6alkyl; R 5-3-6 Ci-C6-alkyl; R 5-4-1 is oxo, halogen, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 5-4-1-1 substituents; R 5-4-1-1 is halogen; R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 5-5-3 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-5-4 Substituted 4-12 membered heterocyclic groups, C2-C6 alkynyl groups, or groups with one or more R groups 5-5-5 The substituted C1-C6 alkyl group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; R 5-5-1 is oxo, -OH, C1-C6alkyl, or halo; R 5-5-2 OH, C1-C6 alkyl, or halogen; R 5-5-3 -NR 5-5-3-1 R 5-5-3-2 , halogen, C2-C6alkynyl, C1-C6alkyl, C1-C6alkyl substituted by one or more R 5-5-3-3 , -(C=0)NR 5-5-3-4 R 5-5-3-5 ; R 5-5-3-1 , R 5-5-3-2 each independently H or Ci-C6alkyl; R 5-5-3-3 for R 5-5-3-3-1 , R 5-5-3-3-2 each independently H or Ci-C6alkyl; R 5-5-3-4 , R 5-5-3-5 each independently H or Ci-C6alkyl; R 5-5-4 C2-C6alkenyl or Ci-C6alkyl; R 5-5-5 -SO2NR 5-5-5-1 R 5-5-5-2 or C3-C8cycloalkyl; R 5-5-5-1 , R 5-5-5-2 each independently H or Ci-C6alkyl; or R 5-5 , R 5-6 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-6-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, selenium, each independently in a number of 1, 2, or 3; R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5-6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups, -NR 5-6-1-8 R 5-6-1-9 C3-C8 cycloalkyl, or with one or more R 5- 6-1-10 Substituted C3-C8 cycloalkyl groups; R 5-6-1-1 , R 5-6-1-2 each independently H or Ci-C6alkyl; R 5-6-1-3 C3-C8cycloalkyl or halogen; R 5-6-1-4 , R 5-6-1-5 each independently H or Ci-C6alkyl; R 5-6-1-6 R is halogen; R 5-6-1-7 is oxo or C1-C6alkyl; R 5-6-1-8 , R 5-6-1-9 each independently H or Ci-C6alkyl; R 5-6-1-10 C1-C6alkyl or C1-C6alkyl substituted by one or more R 5-6-1-10-1 substituted C1-C6alkyl; R 5-6-1-10-1 is halogen; n1 is 0, 1, or 2; R 5-7 H or C1-C6 alkyl; R 5-8 is Ci-C6alkyl or NR 5-8-1 R 5-8-2 ; R 5-8-1 is H; R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ; R 5-8-2-1 , R 5-8-2-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; R 5-9 is H; R 5-10 H, 5-14 membered heteroaryl, or heteroaryl substituted with one or more R 5-10-1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R R 5-10-1 C1-C6alkyl substituted by one or more R 5-10-1-1 C1-C6alkyl substituted by one or more R R 5-10-1-1 R is halogen; or R 5-9 , R 5-10 and the C atom to which they are attached together form a carbonyl group; R 5-11 is H; R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ; R 5-12-1 , R 5-12-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; or R 5-11 , R 5-12 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-11-1 ; R 5-11-1 C1-C6alkyl substituted by one or more R 5-11-1-1 C1-C6alkyl substituted by one or more R R 5-11-1-1 R is halogen; R 5-13 is H; R 5-14 Ci-C6-alkyl; R 5-15 is 4-12 membered heterocyclyl, or 4-12 membered heterocyclyl substituted with one or more R 5-15-1 substituted 4-12 membered heterocyclyl; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms each independently being 1, 2, or 3; R 5-15-1 is oxo or C1-C6alkyl; R 8 H or deuterium; n2 is 0,1, or 2; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each independently C or N; m is 0 or 1.

4. The compound of Formula I, pharmaceutically acceptable salts thereof, solvates thereof, stereo isomers thereof, tautomers thereof, prodrugs thereof, or metabolites thereof of claim I, wherein, wherein, R 1 for -OR 1-8 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 1-9 substituted C3-C8cycloalkyl, C2-C6alkenyl, or C2-C6alkenyl substituted by one or more R 1-10 substituted C2-C6alkenyl; R 1-1 , R 1-2 , R 1-3 each independently is hydrogen, Ci-C6alkyl, C3-C8cycloalkyl, or deuterated Ci-C6alkyl; R 1-4 is hydrogen, C1-C6alkyl, deuterated C1-C6alkyl, C3-C8cycloalkyl, -OR 1-4-1 , or oxidized; R 1-4-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 1-4-1-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 1-4-1-1 R is halogen; R 1-5 is hydrogen, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 1-5-1 substituents; R 1-5-1 R is halogen; R 1-6 is hydrogen or CrC6alkyl; R 1-7 is hydrogen or CrC6alkyl; R 1-8 is C5-C 12 aryl; R 1-9 Ci-C6-alkyl, or Ci-C6-alkyl substituted by one or more R 1-9-1 Ci-C6-alkyl, or Ci-C6-alkyl substituted by one or more R R 1-9-1 R is halogen; R 1-10 halogen, C3-C8cycloalkyl, or Ci-C6alkyl; R 2 It is a C1-C6 alkyl group, with one or more R 2-1 Substituted C1-C6 alkyl, C3-C 20 cycloalkyl, or by one or more R 2-2 Replacement C3-C 20 cycloalkyl; R 2-1 is C3-C8cycloalkyl; R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2 - 2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, with one or more R 2-2-7 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, or with one or more R 2-2-8 The substituted C3-C8 cycloalkyl group; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3. R 2-2-1 is halogen; R 2-2-2 R is halogen; R 2-2-3 , R 2-2-4 , R 2-2-5 each independently H or Ci-C6alkyl; R 2-2-6 Ci-C6-alkyl; R 2-2-7 halogen or Ci-C6alkyl; R 2-2-8 R is halogen; R 3 , R 4 , R 5 , R 6 , R 7 each independently H, halogen, -CR 5-13 R 5- 14 R 5-15 or nothing; R 5-0 is H; R 5-1 H, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 5-1-1 substituted with one or more R R 5-1-1 is Ci-C6alkoxy or halogen; R 5-2 is H or C1-C6alkyl; R 5-3 , R 5-4 each independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 -(C=O)-R 5-3-3 4-12 membered heterocyclic groups, or those containing one or more R groups 5-3-4 Substituted 4-12 membered heterocyclic groups; or R 5-3 R 5-4 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, or are bound by one or more R atoms. 5-4-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 5-3-1 , R 5-3-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; R 5-3-3 C1-C6alkyl or C1-C6alkyl substituted by one or more R 5-3-3-1 substituted C1-C6alkyl; R 5-3-4 Ci-C6-alkyl; R 5-3-3-1 -Si(CH3)3; R 5-4-1 is oxo, halogen, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 5-4-1-1 substituents; R 5-4-1-1 is halogen; R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, with one or more R 5-5-2 Replacement C5-C 12 aryl, C3-C8 cycloalkyl, with one or more R 5-5-3 Substituted C3-C8 cycloalkyl, 4-12 membered heterocyclic groups, or those with one or more R groups 5-5-4 Substituted 4-12 membered heterocyclic groups, C2-C6 alkynyl groups, or groups with one or more R groups 5-5-5 The substituted C1-C6 alkyl group; the heteroatoms in the heteroaryl and heterocyclic groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; R 5-5-1 is oxo, -OH, C1-C6alkyl, or halo; R 5-5-2 OH, C1-C6 alkyl, or halogen; R 5-5-3 -NR 5-5-3-1 R 5-5-3-2 halogen, C2-C6alkynyl, C1-C6alkyl, C1-C6alkyl substituted by one or more R 5-5-3-3 halogen, C2-C6alkynyl, C1-C6alkyl, C1-C6alkyl substituted by one or more R 5-5-3-4 R 5-5-3-5 ; R 5-5-3-1 , R 5-5-3-2 each independently H or Ci-C6alkyl; R 5-5-3-3 for R 5-5-3-3-1 , R 5-5-3-3-2 each independently H or Ci-C6alkyl; R 5-5-3-4 , R 5-5-3-5 each independently H or Ci-C6alkyl; R 5-5-4 C2-C6alkenyl or Ci-C6alkyl; R 5-5-5 -SO2NR 5-5-5-1 R 5-5-5-2 ; R 5-5-5-1 , R 5-5-5-2 each independently H or Ci-C6alkyl; or R 5-5 , R 5-6 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-6-1 heteroatoms in the heterocyclyl group are independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, selenium, each number of heteroatoms is independently 1, 2, or 3; R 5-6-1 halogen, Ci-C6alkyl, -(C=0)-NR 5-6-1-1 R 5-6-1-2 , C 5- C 12 aryl, oxo, C2-C6alkenyl, C2-C6alkenyl substituted with one or more R 5-6-1-3 halogen, Ci-C6alkyl, -(C=0)-NR 5-6-1-4 R 5-6-1-5 , Ci-C6alkyl substituted with one or more R 5-6-1-6 halogen, Ci-C6alkyl, -(C=0)-NR 5-6-1-7 halogen, Ci-C6alkyl, -(C=0)-NR 5-6-1-8 R 5-6-1-9 , C3-C8cycloalkyl, or C3-C8cycloalkyl substituted with one or more R 5 - 6-1-10 halogen, Ci-C6alkyl, -(C=0)-NR R 5-6-1-1 , R 5-6-1-2 each independently H or Ci-C6alkyl; R 5-6-1-3 C3-C8cycloalkyl or halogen; R 5-6-1-4 , R 5-6-1-5 each independently H or Ci-C6alkyl; R 5-6-1-6 is halogen; R 5-6-1-7 is oxo or C1-C6alkyl; R 5-6-1-8 , R 5-6-1-9 each independently H or Ci-C6alkyl; R 5-6-1-10 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 5-6-1-10-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 5-6-1-10-1 R is halogen; n1 is 0, 1, or 2; R 5-7 H or C1-C6 alkyl; R 5-8 is Ci-C6alkyl or NR 5-8-1 R 5-8-2 ; R 5-8-1 is H; R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ; R 5-8-2-1 , R 5-8-2-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; R 5-9 is H; R 5-10 H, 5-14 membered heteroaryl, or heteroaryl substituted with one or more R 5-10-1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R R 5-10-1 C1-C6alkyl substituted by one or more R 5-10-1-1 C1-C6alkyl substituted by one or more R R 5-10-1-1 R is halogen; or R 5-9 , R 5-10 and the C atom to which they are attached together form a carbonyl group; R 5-11 is H; R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ; R 5-12-1 , R 5-12-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; or R 5-11 , R 5-12 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-11-1 groups; R 5-11-1 C1-C6alkyl substituted by one or more R 5-11-1-1 C1-C6alkyl substituted by one or more R R 5-11-1-1 R is halogen; R 5-13 is H; R 5-14 Ci-C6-alkyl; R 5-15 is 4-12 membered heterocyclyl or 4-12 membered heterocyclyl substituted with one or more R 5-15-1 heteroatoms in the heterocyclyl group are independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms each independently is 1, 2, or 3; R 5-15-1 is oxo or C1-C6alkyl; R 8 is H; n2 is 0, l, or 2; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each independently C or N; m is 0 or 1.

5. The compound of Formula I, pharmaceutically acceptable salts thereof, solvates thereof, ster eoisomers thereof, tautomers thereof, prodrugs thereof, or metabolites thereof of clai m 1, wherein, wherein, R 1 for -OR 1-8 C3-C8cycloalkyl, C3-C8cycloalkyl substituted by one or more R 1-9 substituted C3-C8cycloalkyl, C2-C6alkenyl, or C2-C6alkenyl substituted by one or more R 1-10 substituted C2-C6alkenyl; R 1-1 , R 1-2 , R 1-3 each independently is hydrogen, Ci-C6alkyl, or C3-C8cycloalkyl; R 1-4 is hydrogen, C1-C6alkyl, deuterated C1-C6alkyl, C3-C8cycloalkyl, -OR 1-4-1 , or oxidized; R 1-4-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 1-4-1-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 1-4-1-1 R is halogen; R 1-5 is hydrogen, Ci-C6alkyl, or Ci-C6alkyl substituted with one or more R 1-5-1 substituted with one or more R R 1-5-1 is halogen; R 1-6 is hydrogen or CrC6alkyl; R 1-7 is hydrogen or CrC6alkyl; R 1-8 is C5-C 12 aryl; R 1-9 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 1-9-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 1-9-1 R is halogen; R 1-10 halogen, C3-C8cycloalkyl, or Ci-C6alkyl; R 2 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 2-1 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 2-2 Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R R 2-1 is C3-C8cycloalkyl; R 2-2 Halogen, C1-C6 alkyl, or with one or more R 2-2-1 Substituted C1-C6 alkyl, C2-C6 alkenyl, or with one or more R 2-2 - 2 Substituted C2-C6 alkenyl, -SiR 2-2-3 R 2-2-4 R 2-2-5 4-12 membered heterocyclic group, surrounded by one or more R 2-2-6 Substituted heterocyclic group, C5-C 12 aryl, or with one or more R 2-2-7 Replacement C5-C 12 Aryl; the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 2-2-1 R is halogen; R 2-2-2 R is halogen; R 2-2-3 , R 2-2-4 , R 2-2-5 each independently H or Ci-C6alkyl; R 2-2-6 Ci-C6-alkyl; R 2-2-7 halogen or Ci-C6alkyl; R 3 , R 4 , R 5 , R 6 , R 7 each independently H, halogen, -CR 5-13 R 5- 14 R 5-15 or nothing; R 5-0 is H; R 5-1 It is H, C1-C6 alkyl, or composed of one or more R 5-1-1 Substituted C1-C6 alkyl groups; R 5-1-1 is Ci-C6alkoxy or halogen; R 5-2 H or C1-C6 alkyl; R 5-3 , R 5-4 each independently H, OH, -(C=O)-NR 5-3-1 R 5-3-2 、or -(C=O)-R 5-3-3 Or R 5-3 R 5-4 Together with the N atom it is attached to, they form a 4-12 membered heterocyclic group, or are bound by one or more R atoms. 5-4-1 The substituted 4-12 membered heterocyclic group; wherein the heteroatom in the heterocyclic group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 5-3-1 , R 5-3-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; R 5-3-3 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 5-3-3-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 5-3-3-1 -Si(CH3)3; R 5-4-1 is oxo, halogen, C1-C6alkyl, or C1-C6alkyl substituted by one or more R 5-4-1-1 substituents; R 5-4-1-1 R is halogen; R 5-5 R 5-6 Each is independently H, C1-C6 alkyl, 5-14 heteroaryl, and surrounded by one or more R groups. 5-5-1 Substituted 5-14 heteroaryl, C5-C 12 aryl, or with one or more R 5-5-2 Replacement C5-C 12 Aryl; the heteroatom in the heteroaryl group is independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; R 5-5-1 is oxo, -OH, C1-C6alkyl, or halo; R 5-5-2 OH, C1-C6 alkyl, or halogen; or R 5-5 , R 5-6 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-6-1 ; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, phosphorus, selenium, each independently in a number of 1, 2, or 3; R 5-6-1 Halogen, C1-C6 alkyl, -(C=O)-NR 5-6-1-1 R 5-6-1-2 C 5- C 12 aryl, oxo, C2-C6 alkenyl, with one or more R 5-6-1-3 Substituted C2-C6 alkenyl, -SO2NR 5-6-1-4 R 5-6-1-5 , by one or more R 5-6-1-6 Substituted C1-C6 alkyl, 5-14 heteroaryl, or substituted with one or more R 5-6-1-7 Substituted 5-14 heteroaryl groups; R 5-6-1-1 , R 5-6-1-2 each independently H, or Ci-C6alkyl; R 5-6-1-3 C3-C8cycloalkyl, or halogen; R 5-6-1-4 , R 5-6-1-5 each independently H, or Ci-C6alkyl; R 5-6-1-6 R is halogen; R 5-6-1-7 is oxo or C1-C6alkyl; n1 is 0, 1, or 2; R 5-7 H or C1-C6 alkyl; R 5-8 is Ci-C6alkyl or NR 5-8-1 R 5-8-2 ; R 5-8-1 is H; R 5-8-2 -(C=O)-NR 5-8-2-1 R 5-8-2-2 ; R 5-8-2-1 , R 5-8-2-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; R 5-9 is H; R 5-10 H, 5-14 membered heteroaryl, or heteroaryl substituted with one or more R 5-10-1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R R 5-10-1 C1-C6alkyl substituted by one or more R 5-10-1-1 C1-C6alkyl substituted by one or more R or R 5-9 , R 5-10 and the C atom to which they are attached together form a carbonyl group; R 5-11 is H; R 5-12 -(C=O)-NR 5-12-1 R 5-12-2 ; R 5-12-1 , R 5-12-2 each independently H, C1-C6alkyl, or C3-C8cycloalkyl; or R 5-11 , R 5-12 and the N atom to which they are attached together form a 4-12 membered heterocyclyl, or a 4-12 membered heterocyclyl substituted with one or more R 5-11-1 ; R 5-11-1 C1-C6alkyl substituted by one or more R 5-11-1-1 C1-C6alkyl substituted by one or more R R 5-11-1-1 R is halo; R 5-13 is H; R 5-14 Ci-C6-alkyl; R 5-15 is 4-12 membered heterocyclyl or 4-12 membered heterocyclyl substituted with one or more R 5-15-1 substituted 4-12 membered heterocyclyl; the heteroatoms in said heterocyclyl are independently one or more of nitrogen, oxygen, sulfur, silicon, the number of heteroatoms each independently being 1, 2, or 3; R 5-15-1 is oxo or C1-C6alkyl; n2 is O, 1, or 2; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 each independently C or N; m is 0 or 1.

6. The compound of Formula I, pharmaceutically acceptable salts thereof, solvates thereof, st ereoisomers thereof, tautomers thereof, prodrugs thereof, or metabolites thereof of cla im 1, wherein, R 1 for 7. The compound of Formula I, pharmaceutically acceptable salts thereof, solvates thereof, s ter eoisomers thereof, tautomers thereof, prodrugs thereof, or metabolites thereof o f claim 1, wherein, R 2 for 8. The compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof, wherein, R 3 , R 4 , R 5 , R 6 , R 7 , R The structural formula is as follows: wherein ring A is a 4-12 membered heterocyclyl group, R 5-6-1 C1-C6 alkyl, C 5- C 12 aryl, oxo, C1-C6 alkyl substituted by one or more R 5-6-1-6 C3-C8 cycloalkyl, or C3-C8 cycloalkyl substituted by one or more R 5-6-1-10 substituted C3-C8 cycloalkyl; R 5-6-1-6 R is halogen; R 5-6-1-10 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 5-6-1-10-1 Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R R 5-6-1-10-1 R is halogen; n2 is 0, 1, 2, or 3.

9. The compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof, wherein, R 3 , R 4 , R 5 , R 6 , R 7 , R The structural formula is as follows:

10. The compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate thereof, stereoisomer thereof, tautomer thereof, prodrug thereof, or metabolite thereof of claim 1-5, wherein, R 3 is H; R 4 is H; R 6 is H; R 7 R is halogen, preferably F; R 5 for or -CR 5-13 R 5-14 R 5-15 ; n1 is 1 or 0; n2 is 1; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each C.

11. The compound as shown in formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof according to claim 1, wherein, The structural formula is shown as formula I-a below: wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 5-0 , R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , m, n1 are as defined in claim 1.

12. The compound as shown in formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof according to claim 1, characterized in that, The structural formula is shown as formula I-a-1 below: wherein t-1 is 0, 1, 2, 3, 4, 5, 6, or 7; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 5-0 , R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5-6 , R 5-6-1 , m, n1 are as defined in claim 1.

13. The compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate thereo f, stereoisomer thereof, tautomer thereof, prodrug thereof, or metabolite thereof o f claim 9, wherein: For 14. The compound as shown in formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof according to claim 1, wherein, The structural formula is shown as formula I-b below: wherein R is halogen, C1-C6alkyl, or cyano; 1-10-a halogen, C1-C6alkyl, or cyano; R 1-10-b , R 1-10-c each independently is hydrogen, halogen, deuterium, C3-C8cycloalkyl, C3-C8cycloalkyl substituted with one or more R 1-10-1 , C1-C6alkyl, C1-C6alkyl substituted with one or more R 1-10-2 , 3-12 membered heterocyclyl, -NR 1-10-3 R 1-10-4 , 3-12 membered heterocyclyl substituted with one or more R 1-10-5 , 5-12 membered heteroaryl, or 5-12 membered heteroaryl substituted with one or more R 1-10-6 ; the heteroatoms in the heterocyclyl, heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, silicon, and the number of heteroatoms is independently 1, 2, or 3 each. R 1-10-1 halogen, Ci-C6alkyl, or deuterated; R 1-10-2 R is H, deuterium, halogen, or -NR 1-10-2-1 R 1-10-2-2 ; R 1-10-2-1 , R 1-10-2-2 each independently is hydrogen or Ci-C6alkyl; R 1-10-3 , R 1-10-4 each independently is hydrogen or Ci-C6alkyl; R 1-10-5 halogen or Ci-C6alkyl; R 1-10-6 halogen or C1-C6alkyl; wherein R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , m is as defined in claim 1.

15. The compound as shown in formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof according to claim 1, wherein, The structural formula is shown as formula I-b-1 below: wherein R is halogen, C1-C6alkyl, or cyano; 1-10-a halogen, C1-C6alkyl, or cyano; R 1-10-b R 1-10-c Each is independently hydrogen, halogenated, deuterated, C3-C8 cycloalkyl, or oxidized by one or more R groups. 1-10-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, or substituted with one or more R 1-10-2 Substituted C1-C6 alkyl groups, 3-12 membered heterocyclic groups, -NR 1-10-3 R 1-10-4 , by one or more R 1-10-5 Substituted 3-12-membered heterocyclic group, 5-12-membered heteroaryl group, or grouped by one or more R 1-10-6 The substituted 5-12-membered heteroaryl group; the heteroatom in the heterocyclic group or heteroaryl group is independently one or more of nitrogen, oxygen, sulfur, and silicon, and the number of heteroatoms is independently 1, 2, or 3; R 1-10-1 halogen, Ci-C6alkyl, or deuterated; R 1-10-2 R is deuterium, halogen, or -NR 1-10-2-1 R 1-10-2-2 ; R 1-10-2-1 , R 1-10-2-2 each independently is hydrogen, or Ci-C6alkyl; R 1-10-3 , R 1-10-4 each independently is hydrogen, or Ci-C6alkyl; R 1-10-5 halogen or Ci-C6alkyl; R 1-10-6 halogen or C1-C6alkyl wherein R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , R 5-0 , R 5-1 , R 5-2 , R 5-3 , R 5-4 , R 5-5 , R 5- 6 , m, n1 are as defined in claim 1.

16. The compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof, wherein, satisfies one or more of the following conditions: (1) R 1 is vinyl or said substituted vinyl by one or more R 1-10 ; preferably, R 1 is (2) R 1-10 is halogen; preferably, R 1-10 is F; (3) R 5-5 (3) R 5-6 with the N atom to which they are attached form a 7-membered spiro heterocyclyl or a 7-membered spiro heterocyclyl substituted by one or more R 5-6-1 (3) R 5-5 (3) R 5-6 with the N atom to which they are attached form a 7-membered spiro heterocyclyl or a 7-membered spiro heterocyclyl substituted by one or more R (4) R 5-6-1 halogen; preferably F; (5) R 5-3 and R 5-4 are H and -(C=0)-NR 5-3-1 R 5-3-2 ; (6) R 5-3-1 and R 5-3-2 are independently C1-C6alkyl and C3-C8cycloalkyl; preferably, R 5-3-1 and R 5-3-2 are independently methyl and cyclopropyl.

17. The compound as shown in the formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof according to claim 1 to claim 4, characterized in that, satisfies one or more of the following conditions: (1)R 2-2-1 R 2-2-2 R 2-2-7 R 3 R 4 R 5 R 6 R 7 R 5-1-1 R 5-4-1 R 5-4-1-1 R 5-5-1 R 5-11-1-1 R 2-2-8 R 5-5-3 R 5-6-1-10-1 R 5-10-1-1 R 1-9 R 1-10-1 R 1-10-2 R 1-10-5 R 1-10-6 R 1-14 R 1-15 R 1-16 R 1-17 R 5-1-2 R 2- 1 R 5-3-3-1 R 5-3-3-3 R 5-3-3-5 R 2-2-9 R 2-2-10 R 5-3-1-1-1 R 5-3-1-1-2 R 5-3-1-2 R 5-3-3-1-1 R 5-6-1-11 R 5-6-1-12 R 5- 6-1-14 R 1-1 R 1-2 R 1-3 R 1-1-1 R 5-6-1-15 In this context, the halogen is independently F, Cl, Br, or I; preferably F; (2)R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 2 、R 2-2-6 、R 2-2-7 、R 5-1 、R 5-2 、R 5-3-1 、R 5-3-2 、R 5-3-3 、R 5-4-1 、R 5-5 、R 5- 6 R 5-5-1 、R 5-5-2 、R 5-6-1 R 5-6-1-1 、R 5-6-1-2 、R 5-7 、R 5-8 、R 5-8-2-1 、R 5-8-2-2 、R 5-10-1 、R 5-12-1 、R 5-12-2 、R 5-11-1 、R 5-3- 4 、R 5-5-3 、R 5-5-4 、R 5-5-5-1 、R 5-5-5-2 、R 5-5-3-1 、R 5-5-3-2 、R 5-5-3-3-1 、R 5-5-3-3-2 、R 5-5-3-4 、R 5-5-3-5 、R 5-5-4 、R 5-6-1-8 、R 5-6-1-9 、R 5-6-1-10 、R 1 、R 1-8-1 、R 1-10-1 、R 1-10-2-1 、R 1-10-2-2 、R 1-10-3 、R 1-10-4 、R 1-10-5 、R 1-10-6 、R 1-11 、R 1-12 、R 1-13 、R 1-15 、R 1-16 、R 1-17-1 、R 1-17-2 、R 5-1-2 、R 5-3 、R 5-4 、R 5-3-1-1 、R 5-3-3-2 、R 5-3-3-4 R 5-3-5-1 R 5-3-5-2 R 5-3- 5-3-1 R 5-3-5-3-2 R 5-3-6 R 2-2-9 R 2-2-10 R 5-3-1-1-1 R 5-3-1-1-2 R 5-3-1-2 R 5-3-3-1-1 R 5-6-1-11 R 5-6-1-12 R 5-6-1-14 In this context, the C1-C6 alkyl group, and the C1-C6 alkyl group substituted with one or more substituents, are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. (3) R 2-2 (3) R 5-3-3 (3) R 1 (3) R 5-6-1 Among them, the C2-C6 alkenyl in the C2-C6 alkenyl and the C2-C6 alkenyl in the C2-C6 alkenyl substituted by one or more substituents is independently ethenyl, propenyl; (4)R 1-1 R 1-2 R 1-3 R 1-4 R 2-2 R 2-1 R 5-3-1 R 5-3-2 R 5-8-2-1 R 5-8-2-2 R 5-12-1 R 5-12-2 R 5-5 R 5- 6 R 5-6-1 R 1-8 R 1-11 R 1-12 R 1-13 R 5-1 R 1-10 R 5-1 R 5-3 R 5-4 R 5-3-3 R 5-3-3-1 R 5-3-3-4 R 5-5-5 R 1-17 In the above, the C3-C8 cycloalkyl group, and the C3-C8 cycloalkyl group substituted with one or more substituents, are independently cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, preferably cyclopropane; (5) R 2-2 , R 5-3 , R 5-4 Among them, the 4-12 membered heterocyclyl in the 4-12 membered heterocyclyl and the 4-12 membered heterocyclyl substituted by one or more substituents is independently monocyclic heterocyclyl, preferably 5, 6 or 7 membered heterocyclyl. (6) R 5-3 (6) R 5-4 with the N atom to which it is attached to form a 4-12 membered heterocyclyl, said 4-12 membered heterocyclyl being substituted with one or more R 5-4-1 4-12 membered heterocycloalkyl is independently a monocyclic heterocyclyl, preferably a 5, 6 or 7 membered heterocycloalkyl; (7)R 5-5 (7)R 5-6 with the N atom to which it is attached to form a 4-12 membered heterocyclyl, the 4-12 membered heterocyclyl in said 4-12 membered heterocyclyl substituted with one or more R 5-6-1 membered heterocyclyl is independently a 5-7 membered monocyclic heterocyclyl or a 7-12 membered spiroheterocyclyl; (8)R 5-11 (8)R 5-12 and the N atom to which it is attached to form a 4-12 membered heterocyclyl, 4-12 membered heterocyclyl substituted with one or more R 5-11-1 membered heterocyclyl is independently a 5-7 membered monocyclic heterocyclyl; (9) R 5-5 , R 5-6 Among them, the 5-14 membered heteroaryl and the one or more R 5-5-1 5-14 in the 5-14 membered heteroaryl independently substituted by one or more R (10)R 5-5 R 5-6 In the context of C5-C 12 aryl and one or more of the R 5-5-2 Replacement C5-C 12 C5-C in aryl 12 The aryl group is independently C7-C 12 Fused polycyclic aryl groups; (11) R 1 , R 5-5 , R 5-6 , R 5-5-3 , R 5-5-4 wherein said C2-C6alkynyl is independently ethynyl or propynyl; (12) R 1-8 (12) R 2-2 (12) R 5-5 (12) R 5-6 (12) R 5-6-1 (12) R 12 (12) R 12 (12) R 12 (12) R 10 (12) R 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, solvate thereof, stereoisomer thereof, tautomer thereof, prodrug thereof, or metabolite thereof, wherein, satisfies one or more of conditions: (1) R 1 To -CF3, (2) R 2 For (3) R 3 H or halogen, preferably H or F; (4) R 4 is H; (5) R 6 is H; (6) R 7 H or halogen, preferably H or F, more preferably H; (7) R 5 For (8) R 5-0 is H; (9) R 5-1 is -CH3, (10) R 5-2 is H; (11) n1 is 0 or 1; (12) n2 is 0 or 1; (13) For -NHCH3, (14) For (15) R 5-7 is H or -CH3; (16) R 5-8 is -CH3, (17) R 5-9 is H; (18) R 5-10 is H, (19) For (20) R 8 is hydrogen; (21) Y 1 is C or N, Y 2 , Y 3 , Y 4 , Y 5 are each C; preferably, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each C.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, solvate thereof, stereoisomer thereof, tautomer thereof, prodrug thereof, or metabolite thereof, wherein, satisfies conditions (1), (2), and (7); preferably, it satisfies conditions (1)-(7) and (20)-(21).

20. The compound as shown in formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof according to claim 1, wherein, The compound as shown in Formula I is any one of the following compounds:

21. The compound as shown in formula I or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug or metabolite thereof of claim 1, wherein, The compound as shown in Formula I is any one of the following compounds:

22. A pharmaceutical composition comprising: (1) a compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate thereof, stereo isomer thereof, tautomer thereof, prodrug thereof, or metabolite thereof of any one of claims 1-21, and (2) a pharmaceutically acceptable excipient.

23. Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, solvate thereof, stereoisomer thereof, tautomer thereof, prodrug thereof, or metabolite thereof of any one o f claims 1-21, or a pharmaceutical composition of claim 22, for the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by IL-17.

24. The use of claim 23, wherein the IL-17 mediated disease or disorder is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, spondyloarthritides, and non-infectious uveitis.

25. The use of claim 24, wherein the psoriasis is plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, or palmoplantar psoriasis.

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