Pyrazole formamide compound and application thereof

Abstract

The invention discloses a pyrazolecarboxamide compound and application of the pyrazolecarboxamide compound. Specifically, the invention discloses a compound shown as a formula I or a pharmaceutically acceptable salt thereof. The compounds of the present invention are IL-17 small molecule modulators, and can be used for the treatment or prevention of IL-17 mediated diseases, such as autoimmune diseases.

Description

[0001] This application claims priority to Chinese patent application CN2024107354161, filed June 6, 2024; Chinese patent application CN2024112970290, filed September 15, 2024; and Chinese patent application CN2025101265296, filed January 27, 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]

[0010] Among them, R 12 for

[0011] R 1 R 2 R 3 R 12-1 Each is independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group;

[0012] R 12-2 R 12-3 R 12-4 and R 12-5 Independently, it is H, deuterium, halogen, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, CN, or 3-8 membered heterocyclic alkyl; the heteroatom in the 3-8 membered heterocyclic alkyl is independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0013] m1 and m2 are independently 1, 2 or 3;

[0014] R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4-2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups, or

[0015] R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group;

[0016] R 4-4Independently, it is a C3–C8 cycloalkyl group;

[0017] R 4a and R 4b It is independently a halogen or a C1-C6 alkyl group;

[0018] R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, -NR 5-4 R 5-5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0019] R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0020] R 5-1-1 R 5-1-2 Halogens are independent of each other;

[0021] R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups;

[0022] R 5-2-1 R 5-2-2 Halogens are independent of each other;

[0023] R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens;

[0024] R 5-3-1 It is a halogen;

[0025] R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups

[0026] R 5-4-1 Halogens and hydroxyl groups;

[0027] R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups;

[0028] R 5-4-2-1 Halogens and hydroxyl groups;

[0029] R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , -NR 5-6-6 R 5-6-7 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0030] R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5 -6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0031] R 5-6-1-1 It is a halogen;

[0032] R 5-6-1-2 Hydroxyl group, -COOH;

[0033] R 5-6-1-3 It consists of C1 to C6 alkyl, oxo, and hydroxyl groups;

[0034] R5-6-1-4 For oxygenation;

[0035] R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl.

[0036] R 5-6-4 It is hydrogen or a C1-C6 alkyl group;

[0037] R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0038] R 5-6-5-1 It is a C1 to C6 alkyl group, and is bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups, -NR 5-6-5-1-2 R 5 -6-5-1-3 -COOH;

[0039] R 5-6-5-1-1 It is a hydroxyl group;

[0040] R 5-6-5-1-2 R 5-6-5-1-3 It is an H, C1-C6 alkyl group;

[0041] R 5-6-6 R 5-6-7 It is an H, C1-C6 alkyl group;

[0042] R 13 For H,

[0043] R 9 For -NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0044] R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ;

[0045] R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups;

[0046] R 9-1-1-1 It is a halogen;

[0047] R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups;

[0048] R 9-3-1 It is a halogen;

[0049] R 9-7 Independently for -CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, -COOH, -COOR 9-7-4 5-12 yuan heteroaryl, surrounded by one or more R 9-7-5 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 9-7-5 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0050] R 9-7-1 R 9-7-2Each of the following is independently hydrogen, C1-C6 alkyl, 5-12-membered heteroaryl, or 4-8-membered heterocyclic alkyl; the heteroatoms in the 5-12-membered heteroaryl and 4-8-membered heterocyclic alkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0051] R 9-7-3 Independently oxidized or halogenated;

[0052] R 9-7-4 It is an alkyl group of C1 to C6;

[0053] R 9-7-5 For oxygenation;

[0054] R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 Substituted C1–C6 alkyl groups, C1–C6 alkoxy groups, halogens, C3–C8 cycloalkyl groups, C3–C8 heterocycloalkyl groups, -CONR 10-2 RR 10-3 The heteroatoms in the C3-C8 heterocyclic alkyl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0055] R 10-1 It is a halogen, a C1-C6 alkoxy group, a 5-6 membered heterocyclic alkyl group, or a 5-6 membered heterocyclic alkyl group substituted with one or more C1-C6 alkyl groups;

[0056] R 10-2 R 10-3 Each is independently an H, C1-C6 alkyl group;

[0057] Or, R 10-2 R 10-3 Together with the carbon atom attached thereto, they form a 5-6 membered heterocyclic alkyl group or are bounded by one or more R atoms. 10a Substituted 5-6 membered heterocyclic alkyl groups;

[0058] R 10a It is independently a C1 to C6 alkyl group;

[0059] Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N;

[0060] It can be a single bond or a double bond.

[0061] 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:

[0062]

[0063] Among them, R 12 for

[0064] R 1 R 2 R 3 R 12-1 Each is independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group;

[0065] R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4-2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups, or

[0066] R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group;

[0067] R 4-4 Independently, it is a C3–C8 cycloalkyl group;

[0068] R 4a and R 4b It is independently a halogen or a C1-C6 alkyl group;

[0069] R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5-5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0070] R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0071] R 5-1-1 R 5-1-2 Halogens are independent of each other;

[0072] R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups;

[0073] R 5-2-1 R 5-2-2 Halogens are independent of each other;

[0074] R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens;

[0075] R 5-3-1 It is a halogen;

[0076] R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups

[0077] R 5-4-1 Halogens and hydroxyl groups;

[0078] R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups;

[0079] R 5-4-2-1 Halogens and hydroxyl groups;

[0080] R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , -NR 5-6-6 R 5-6-7 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0081] R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5 -6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0082] R 5-6-1-1 It is a halogen;

[0083] R 5-6-1-2 Hydroxyl group, -COOH;

[0084] R 5-6-1-3 It consists of C1 to C6 alkyl, oxo, and hydroxyl groups;

[0085] R 5-6-1-4 For oxygenation;

[0086] R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl.

[0087] R 5-6-4 It is hydrogen or a C1-C6 alkyl group;

[0088] R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0089] R 5-6-5-1 It is a C1 to C6 alkyl group, and is bonded by one or more R 5-6-5-1-1Substituted C1-C6 alkyl groups, -NR 5-6-5-1-2 R 5 -6-5-1-3 -COOH;

[0090] R 5-6-5-1-1 It is a hydroxyl group;

[0091] R 5-6-5-1-2 R 5-6-5-1-3 It is an H, C1-C6 alkyl group;

[0092] R 5-6-6 R 5-6-7 It is an H, C1-C6 alkyl group;

[0093] R 13 For H,

[0094] R 9 For -NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0095] R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ;R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups;

[0096] R 9-1-1-1 It is a halogen;

[0097] R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups;

[0098] R 9-3-1 It is a halogen;

[0099] R 9-7 Independent for CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, -COOH, -COOR 9-7-4 5-12 yuan heteroaryl, surrounded by one or more R 9-7-5 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 9-7-5 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0100] R 9-7-1 R 9-7-2 Each of the following is independently hydrogen, C1-C6 alkyl, 5-12-membered heteroaryl, or 4-8-membered heterocyclic alkyl; the heteroatoms in the 5-12-membered heteroaryl and 4-8-membered heterocyclic alkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0101] R 9-7-3 Independently oxidized or halogenated;

[0102] R 9-7-4 It is an alkyl group of C1 to C6;

[0103] R 9-7-5 For oxygenation;

[0104] R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 Substituted C1–C6 alkyl groups, C1–C6 alkoxy groups, halogens, C3–C8 cycloalkyl groups, C3–C8 heterocycloalkyl groups, -CONR 10-2 RR 10-3The heteroatoms in the C3-C8 heterocyclic alkyl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0105] R 10-1 It is a halogen, a C1-C6 alkoxy group, a 5-6 membered heterocyclic alkyl group, or a 5-6 membered heterocyclic alkyl group substituted with one or more C1-C6 alkyl groups; R 10-2 R 10-3 Each is independently an H, C1-C6 alkyl group;

[0106] Or, R 10-2 R 10-3 Together with the carbon atom attached thereto, they form a 5-6 membered heterocyclic alkyl group or are bounded by one or more R atoms. 10a Substituted 5-6 membered heterocyclic alkyl groups;

[0107] R 10a It is independently a C1 to C6 alkyl group;

[0108] Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N;

[0109] It can be a single bond or a double bond.

[0110] In one particular scheme, the compound represented by Formula I is shown as Formula I-1:

[0111]

[0112] Among them, R 12 for

[0113] R 1 R 2 R 3 R 12-1 Each is independently hydrogen or a C1-C6 alkyl or a C3-C8 cycloalkyl;

[0114] R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4-2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups;

[0115] R 4-1R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group;

[0116] R 4-4 Independently, it is a C3–C8 cycloalkyl group;

[0117] R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5-5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0118] R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0119] R 5-1-1 R 5-1-2 Halogens are independent of each other;

[0120] R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups;

[0121] R 5-2-1 R 5-2-2 Halogens are independent of each other;

[0122] R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens;

[0123] R 5-3-1 It is a halogen;

[0124] R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1Substituted C1-C6 alkyl groups

[0125] R 5-4-1 Halogens and hydroxyl groups;

[0126] R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups;

[0127] R 5-4-2-1 Halogens and hydroxyl groups;

[0128] R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , -NR 5-6-6 R 5-6-7 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0129] R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5 -6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0130] R 5-6-1-1 It is a halogen;

[0131] R 5-6-1-2 Hydroxyl group, -COOH;

[0132] R 5-6-1-3 It consists of C1 to C6 alkyl, oxo, and hydroxyl groups;

[0133] R 5-6-1-4 For oxygenation;

[0134] R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl.

[0135] R 5-6-4 It is hydrogen or a C1-C6 alkyl group;

[0136] R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0137] R 5-6-5-1 It is a C1 to C6 alkyl group, bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups, -NR 5-6-5-1-2 R 5 -6-5-1-3 -COOH;

[0138] R 5-6-5-1-1 It is a hydroxyl group;

[0139] R 5-6-5-1-2 R 5-6-5-1-3 It is an H, C1-C6 alkyl group;

[0140] R 5-6-6 R 5-6-7 It is an H, C1-C6 alkyl group;

[0141] R 13 For H,

[0142] R 9 For -NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0143] R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ;

[0144] R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups;

[0145] R 9-1-1-1 It is a halogen;

[0146] R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups;

[0147] R 9-3-1 It is a halogen;

[0148] R 9-7 Independent for CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, -COOH, -COOR 9-7-4 5-12 yuan heteroaryl, surrounded by one or more R 9-7-5 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 9-7-5 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0149] R 9-7-1 R 9-7-2Each of the following is independently hydrogen, C1-C6 alkyl, 5-12-membered heteroaryl, or 4-8-membered heterocyclic alkyl; the heteroatoms in the 5-12-membered heteroaryl and 4-8-membered heterocyclic alkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0150] R 9-7-3 Independently oxidized or halogenated;

[0151] R 9-7-4 It is an alkyl group of C1 to C6;

[0152] R 9-7-5 For oxygenation;

[0153] R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 Substituted C1–C6 alkyl groups, C1–C6 alkoxy groups, halogens, C3–C8 cycloalkyl groups, C3–C8 heterocycloalkyl groups, -CONR 10-2 RR 10-3 The heteroatoms in the C3-C8 heterocyclic alkyl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0154] R 10-1 It is a halogen or a C1-C6 alkoxy group;

[0155] R 10-2 R 10-3 Each is independently an H, C1-C6 alkyl group;

[0156] Y1, Y2, Y3, Y4, and Y5 are each independently C or N.

[0157] In one embodiment, the present invention provides 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, the structural formula of which is shown in Formula IA below:

[0158]

[0159] Among them, R 1 R 2 R 3 Each is independently hydrogen or a C1-C6 alkyl or a C3-C8 cycloalkyl;

[0160] R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4-2Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups;

[0161] R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group;

[0162] R 4-4 Independently, it is a C3–C8 cycloalkyl group;

[0163] R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5-5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0164] R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0165] R 5-1-1 R 5-1-2 Halogens are independent of each other; R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups;

[0166] R 5-2-1 R 5-2-2 Halogens are independent of each other;

[0167] R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens;

[0168] R5-3-1 It is a halogen;

[0169] R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups

[0170] R 5-4-1 Halogens and hydroxyl groups;

[0171] R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups;

[0172] R 5-4-2-1 Halogens and hydroxyl groups;

[0173] R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0174] R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5 -6-1-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-1-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0175] R 5-6-1-1 It is a halogen;

[0176] R 5-6-1-2 It is a hydroxyl group;

[0177] R 5-6-1-3 It is a C1 to C6 alkyl or oxoalkyl group;

[0178] R 5-6-3It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl.

[0179] R 5-6-4 It is hydrogen or a C1-C6 alkyl group;

[0180] R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0181] R 5-6-5-1 It is a C1 to C6 alkyl group, and is bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups;

[0182] R 5-6-5-1-1 It is a hydroxyl group;

[0183] R 9 For NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0184] R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ;

[0185] R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups;

[0186] R 9-1-1-1 It is a halogen;

[0187] R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups;

[0188] R 9-3-1 It is a halogen;

[0189] R 9-7 Independent for CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-7-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0190] R 9-7-1 R 9-7-2 Each is independently hydrogen or a C1-C6 alkyl group;

[0191] R 9-7-3 Independently oxidized or halogenated;

[0192] R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 The substituted C1-C6 alkyl, C1-C6 alkoxy, halogen, C3-C8 cycloalkyl, and C3-C8 heterocycloalkyl; wherein the heteroatom in the C3-C8 heterocycloalkyl is independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0193] R 10-1 It is a halogen or a C1-C6 alkoxy group.

[0194] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof:

[0195] Among them, R 1 R 2 R 3 Each is independently hydrogen or a C1-C6 alkyl group;

[0196] R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4-2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12 heteroaryl groups;

[0197] R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group;

[0198] R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5-5 4-8 membered heterocyclic alkyl groups, with one or more R 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3.

[0199] R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups;

[0200] R 5-1-1 R 5-1-2 Halogens are independent of each other;

[0201] R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups;

[0202] R 5-2-1 R 5-2-2 Halogens are independent of each other;

[0203] R 5-3It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens;

[0204] R 5-3-1 It is a halogen;

[0205] R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups

[0206] R 5-4-1 Halogens and hydroxyl groups;

[0207] R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups;

[0208] R 5-4-2-1 Halogens and hydroxyl groups;

[0209] R 9 For NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9 -4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0210] R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ;

[0211] R9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups;

[0212] R 9-1-1-1 It is a halogen;

[0213] R 9-3 R 9-4 R 9-5 R 9-6 It is independently an oxo, thio, halogenated or C1-C6 alkyl group;

[0214] R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 The substituted C1-C6 alkyl, C1-C6 alkoxy, halogen, C3-C8 cycloalkyl, and C3-C8 heterocycloalkyl; wherein the heteroatom in the C3-C8 heterocycloalkyl is independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0215] R 10-1 It is a halogen or a C1-C6 alkoxy group.

[0216] In one embodiment, the compound represented by Formula I is shown as Formula IA-1 and Formula IA-2:

[0217]

[0218] Where L is

[0219] R 9A It is a halogen, a C1-C6 alkyl group, an oxoalkyl group, or a C1-C6 haloalkyl group;

[0220] s can be 0, 1, 2, 3, or 4;

[0221] It is a 4-8 membered heterocyclic alkyl, a 4-12 membered heteroaryl, a 7-12 membered heterocyclic alkyl or a 7-12 membered heterocyclic alkyl;

[0222] Other groups are defined as described in any embodiment of the present invention;

[0223] For example, compounds of formula IA-1 are shown as IA-1a:

[0224]

[0225] Compounds of formula IA-2 are shown as IA-2a:

[0226]

[0227] R 9A It is a halogen, a C1-C6 alkyl group, an oxoalkyl group, or a C1-C6 haloalkyl group;

[0228] s can be 0, 1, 2, 3, or 4;

[0229] Other groups are defined as described in any embodiment of the present invention;

[0230] For example, compounds such as IA-2a are shown as IA-2a-1 or IA-2a-2:

[0231]

[0232] The definitions of other groups are as described in any embodiment of this invention.

[0233] In one embodiment, the compound represented by Formula I is shown in Formula IB:

[0234]

[0235] q is 0, 1, or 2;

[0236] p is 0, 1, or 2;

[0237] Other groups are defined as described in any embodiment of the present invention;

[0238] For example, the compound represented by formula IB is the same as that represented by formula IB-1:

[0239]

[0240] Other groups are defined as described in any embodiment of the present invention;

[0241] For example, compounds represented by formula IB-1 are shown as formula IB-1-1 or IB-1-2:

[0242]

[0243] The definitions of other groups are as described in any embodiment of this invention.

[0244] In one particular scheme, R 5-6 for

[0245]

[0246] In one particular scheme, R 9-7 for

[0247] In one of the solutions, for

[0248] 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 is a C1 to C6 alkyl group, preferably isopropyl.

[0249] In one embodiment, a compound or a pharmaceutically acceptable salt thereof, as shown in Formula I, wherein R 4 It is cyclohexane or cyclooctane, preferably cyclohexane.

[0250] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, wherein R 6 It is a halogen, preferably F.

[0251] 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 10 It is a C1 to C6 alkyl group, preferably methyl.

[0252] 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 the 4-8 membered heterocyclic alkyl group is surrounded by one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 The heteroatoms in the substituted 4-8-membered heteroaryl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2 or 3.

[0253] 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 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently nitrogen or oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0254] 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:

[0255] (1)R 1 It is a C1-C6 alkyl group or a C3-C8 cycloalkyl group;

[0256] (2)R 4 R 1 R 4-4 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;

[0257] (3)R 6 It is a halogen;

[0258] (4)R 9 In the context, the 4-8 membered heterocyclic alkyl group and one or more R 9-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is independently a 5-, 6-, or 7-membered heterocyclic alkyl group;

[0259] (5)R 9 In the context, the 4-8 membered heterocyclic alkyl group and one or more R 9-3 In the substituted 4-8 membered heterocyclic alkyl groups, the heteroatoms are independently N or O, and the number is 2;

[0260] (6)R 9 In the context, the 4-8 membered heteroaryl group and one or more R groups 9-4 In the substituted 4-8 heteroaryl group, the 4-8 heteroaryl group is independently a 5- or 6-heteroaryl group;

[0261] (7)R 9 In the context, the 4-8 membered heteroaryl group and one or more R groups 9-4 In the substituted 4-8 membered heteroaryl groups, the heteroatoms are independently N or O, and the number is 3;

[0262] (8)R 9 In the context, the 7-12 membered spirochetal alkyl group, surrounded by one or more R 9-5 The substituted 7-12 spirochetal alkyl groups are independently 8-membered spirochetal alkyl groups or 9-membered spirochetal alkyl groups;

[0263] (9)R 9 In the context, the 7-12 membered spirochetal alkyl group, surrounded by one or more R 9-5The heteroatoms in the substituted 7-12 membered spiroheterocyclic alkyl groups are independently N or O, and the number is 2 or 3;

[0264] (10)R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 In the substituted 7-12-membered heterocyclic alkyl groups, the 7-12-membered heterocyclic alkyl group is independently an 8-membered heterocyclic alkyl group;

[0265] (11)R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 The heteroatoms in the substituted 7-12 membered heterocyclic alkyl groups are independently N or O, and the number is 2 or 3;

[0266] (12)R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 The 7-12 fused heterocyclic alkyl group is a heterocyclic aryl group, preferably a 10- or 11-membered heterocyclic alkyl group;

[0267] (13)R 10 It is hydrogen;

[0268] (14)R 11 It is an alkyl group of C1 to C6;

[0269] (15)R 12 It is an alkyl group of C1 to C6;

[0270] (16)R 13 For H;

[0271] (17)R 1 R 2 R 3 R 4-1 R 4-2 R 4-3 R 5-1 R 5-2 R 5-3 R 5-4 R 5-5 R 5-4-2 R 5-6-1 R 5-6-2 R 5-6- 3. R 9 -1 R 9-2 R 9-1-1 R 9-1-2 R 9-3 R 9-4 R 9-5 R 9-6 R 10 R11 R 4 In the above, the C1-C6 alkyl group and the C1-C6 alkyl group that has been substituted by one or more are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0272] (18)R 4-1 R 4-2 R 4-3 R 5 R 6 R 7 R 8 R 5-3 R 5-1-1 R 5-1-2 R 5-2-1 R 5-2-2 R 5-3-1 R 5-4-1 R 5-4-2-1 R 5-6-3 R 9-1-1-1 R 9-3 R 9-4 R 9-5 R 9-6 R 10 R 11 R 10-1 In this context, the halogen is independently F, Cl, Br, or I;

[0273] (19)R 5 R 6 R 7 R 8 In this context, the 4-8 membered heterocyclic alkyl group, surrounded by one or more R 5-3 The heteroatom in the substituted 4-8 membered heterocyclic alkyl groups is nitrogen;

[0274] (20)R 5 R 6 R 7 R 8 In this context, the 4-8 membered heterocyclic alkyl group, surrounded by one or more R 5-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is a 5-membered ring or a 6-membered ring;

[0275] (21)R 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is a 5-membered ring or a 6-membered ring;

[0276] (22)R 5-6The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are nitrogen or oxygen, and the number of heteroatoms is 1 or 2.

[0277] (23)R 5-6-1 R 5-6-2 The 5-12 member heteroaryl group, surrounded by one or more R 5-6-1-4 In the substituted 5-12 heteroaryl group, the 5-12 heteroaryl group is a 5-membered heteroaryl group;

[0278] (24)R 9-7 R 9-7-1 R 9-7-2 In the middle, 5-12 member heteroaryl, surrounded by one or more R 9-7-5 In the substituted 5-12 heteroaryl group, the 5-12 heteroaryl group is either a 5-membered heteroaryl group or a 6-membered heteroaryl group;

[0279] (25)R 9-7-1 R 9-7-2 The 4-8 membered heterocyclic alkyl group is a 5-membered or 6-membered heterocyclic alkyl group;

[0280] (26)R 5-6-1 R 5-6-2 The 5-12 membered heteroaryl group, surrounded by one or more R 5-6-1-4 In the substituted 5-12 membered heteroaryl groups, the heteroatoms are nitrogen or oxygen, and the number is 1, 2 or 3;

[0281] (27)R 9-7 R 9-7-1 R 9-7-2 In the middle, 5-12 member heteroaryl, surrounded by one or more R 9-7-5 In the substituted 5-12 membered heteroaryl groups, the heteroatoms are nitrogen or oxygen, and the number is 1, 2 or 3;

[0282] (28)R 9-7-1 R 9-7-2 In 4-8 membered heterocyclic alkyl groups, the heteroatom is nitrogen or oxygen, and the number is 1 or 2;

[0283] (29)R 9-7-1 R 9-7-2 In 4-8 membered heterocyclic alkyl groups, the heteroatom is nitrogen or oxygen, and the number is 1 or 2.

[0284] In one particular scheme, R 1 It is a C1-C6 alkyl group or a C3-C8 cycloalkyl group;

[0285] In one particular scheme, R4 R 1 R 4-4 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.

[0286] In one particular scheme, R 6 It is a halogen.

[0287] In one particular scheme, R 9 In the context, the 4-8 membered heterocyclic alkyl group and one or more R 9-3 The substituted 4-8 membered heterocyclic alkyl groups are independently 5, 6, or 7 membered heterocyclic alkyl groups.

[0288] In one particular scheme, R 9 In the context, the 4-8 membered heterocyclic alkyl group and one or more R 9-3 The substituted 4-8 membered heterocyclic alkyl groups have two heteroatoms, which are either N or O.

[0289] In one particular scheme, R 9 In the context, the 4-8 membered heteroaryl group and one or more R groups 9-4 In the substituted 4-8 heteroaryl group, the 4-8 heteroaryl group is independently a 5- or 6-heteroaryl group.

[0290] In one particular scheme, R 9 In the context, the 4-8 membered heteroaryl group and one or more R groups 9-4 In the substituted 4-8 membered heteroaryl groups, the heteroatoms are independently N or O, and the number is 3.

[0291] In one particular scheme, R 9 In the context, the 7-12 membered spirochetal alkyl group, surrounded by one or more R 9-5 The substituted 7-12 spirochetal alkyl groups are independently 8-membered spirochetal alkyl groups or 9-membered spirochetal alkyl groups.

[0292] In one particular scheme, R 9 In the context, the 7-12 membered spirochetal alkyl group, surrounded by one or more R 9-5 The heteroatoms in the substituted 7-12 membered spiroheterocyclic alkyl groups are independently N or O, and the number is 2 or 3.

[0293] In one particular scheme, R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 In the substituted 7-12 fused heterocyclic alkyl groups, the 7-12 fused heterocyclic alkyl group is independently an 8-membered heterocyclic alkyl group.

[0294] In one particular scheme, R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 The heteroatoms in the substituted 7-12 membered heterocyclic alkyl groups are independently N or O, and the number is 2 or 3.

[0295] In one particular scheme, R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 The substituted 7-12 fused heterocyclic alkyl group is a heterocyclic aryl group, preferably a 10- or 11-membered heterocyclic alkyl group.

[0296] In one particular scheme, R 10 It is hydrogen.

[0297] In one particular scheme, R 11 It is an alkyl group of C1 to C6.

[0298] In one particular scheme, R 12 It is an alkyl group of C1 to C6;

[0299] In one particular scheme, R 13 For H.

[0300] In one particular scheme, R 1 R 2 R 3 R 4-1 R 4-2 R 4-3 R 5-1 R 5-2 R 5-3 R 5-4 R 5-5 R 5-4-2 R 5-6-1 R 5-6-2 R 5-6-3 R 9-1 R 9-2 R 9-1-1 R 9-1-2 R 9-3 R 9-4 R 9-5 R 9-6 R 10 R 11 R 4 In the above, the C1 to C6 alkyl groups, and the C1 to C6 alkyl groups that are substituted by one or more, wherein the C1 to C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0301] In one particular scheme, R 4-1R 4-2 R 4-3 R 5 R 6 R 7 R 8 R 5-3 R 5-1-1 R 5-1-2 R 5-2-1 R 5-2-2 R 5-3-1 R 5 -4-1 R 5-4-2-1 R 5-6-3 R 9-1-1-1 R 9-3 R 9-4 R 9-5 R 9-6 R 10 R 11 R 10-1 In this context, the halogen is independently F, Cl, Br, or I.

[0302] In one particular scheme, R 5 R 6 R 7 R 8 In this context, the 4-8 membered heterocyclic alkyl group, surrounded by one or more R 5-3 The heteroatom in the substituted 4-8 membered heterocyclic alkyl group is nitrogen.

[0303] In one particular scheme, R 5 R 6 R 7 R 8 In this context, the 4-8 membered heterocyclic alkyl group, surrounded by one or more R 5-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is a 5-membered ring or a 6-membered ring.

[0304] In one particular scheme, R 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is a 5-membered ring or a 6-membered ring.

[0305] In one particular scheme, R 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are nitrogen or oxygen, and the number is 1 or 2.

[0306] In one particular scheme, R 5-6-1 R 5-6-2 The 5-12 membered heteroaryl group, surrounded by one or more R 5-6-1-4 In the substituted 5-12 heteroaryl group, the 5-12 heteroaryl group is a 5-membered heteroaryl group.

[0307] In one particular scheme, R 9-7 R 9-7-1 R 9-7-2 In the middle, 5-12 member heteroaryl, surrounded by one or more R 9-7-5 In the substituted 5-12 heteroaryl group, the 5-12 heteroaryl group is either a 5-membered heteroaryl group or a 6-membered heteroaryl group.

[0308] In one particular scheme, R 9-7-1 R 9-7-2 The 4-8 membered heterocyclic alkyl group is either a 5-membered or a 6-membered heterocyclic alkyl group.

[0309] In one particular scheme, R 5-6-1 R 5-6-2 The 5-12 membered heteroaryl group, surrounded by one or more R 5-6-1-4 In the substituted 5-12-membered heteroaryl groups, the heteroatoms are nitrogen or oxygen, and the number is 1, 2 or 3.

[0310] In one particular scheme, R 9-7 R 9-7-1 R 9-7-2 In the middle, 5-12 member heteroaryl, surrounded by one or more R 9-7-5 In the substituted 5-12-membered heteroaryl groups, the heteroatoms are nitrogen or oxygen, and the number is 1, 2 or 3.

[0311] In one particular scheme, R 9-7-1 R 9-7-2 In 4-8 membered heterocyclic alkyl groups, the heteroatom is nitrogen or oxygen, and the number is 1 or 2.

[0312] In one particular scheme, R 9-7-1 R 9-7-2 In 4-8 membered heterocyclic alkyl groups, the heteroatom is nitrogen or oxygen, and the number is 1 or 2.

[0313] 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:

[0314] (1)R 1 It is isopropyl or cyclopentyl;

[0315] (2)R 2 For H;

[0316] (3)R 3 For H;

[0317] (4)R 4 For cyclohexyl,

[0318] (5)R 5 For H, For example, R 5 For H;

[0319] (6)R 6 It is F, H, or does not exist; for example, R. 6 For F or H;

[0320] (7)R 7 It is H, F, or does not exist; for example, R. 7 For F or H;

[0321] (8)R 8 For H,

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] (10)R 9-1 For H;

[0328] (11)R 9-2 For -CONR 9-1-1 R 9-1-2 ;

[0329] (12)R 9-1-1 For H;

[0330] (13)R 9-1-2 For one or more R 9-1-1-1 Substituted C1-C6 alkyl groups;

[0331] (14)R 9-1-1-1 For F;

[0332] (15)R 9-3 For oxygenation;

[0333] (16)R10 For hydrogen, methyl, or For example, hydrogen or methyl; for example, R 10 It is hydrogen;

[0334] (17)R 11 H, methyl, ethyl, isopropyl, For example, H, methyl, ethyl, isopropyl,

[0335] (18)R 5-6 for

[0336] (19)R 12 for For example, For example, R 12 for

[0337] (20)R 12-1 It is methyl;

[0338] (21)R 13 For H,

[0339]

[0340]

[0341]

[0342] (22)Y 1 Y 2 Y 3 Y 4 Y 5 All are C;

[0343] (23)Y 1 For N, Y 2 Y 3 Y 4 Y 5 All are C;

[0344] (24)Y 5 For N, Y 2 Y 3 Y 4 Y 1 All are C;

[0345] (25)Y 2 For N, Y 1 Y 3 Y 4 Y 1All are C.

[0346] In one of the schemes, R 12-2 R 12-3 and R 12-4 It is independently H, halogen, or C3–C8 cycloalkyl; for example, H, F, or cyclopropyl.

[0347] In one of the schemes, R 12-5 It is a halogen; for example, F.

[0348] In one scheme, m1 is 1.

[0349] In one particular scheme, m2 is 1.

[0350] In one of the schemes, R 1 It is isopropyl or cyclopentyl.

[0351] In one of the schemes, R 2 For H.

[0352] In one of the schemes, R 3 For H.

[0353] In one of the schemes, R 4 For cyclohexyl,

[0354] In one of the schemes, R 5 For H,

[0355] In one of the schemes, R 6 It is F, H, or does not exist.

[0356] In one of the schemes, R 7 It is H, F, or does not exist.

[0357] In one of the schemes, R 8 For H,

[0358]

[0359]

[0360]

[0361] In one of the schemes, R 9 for

[0362]

[0363]

[0364] In one of the schemes, R 9-1 For H.

[0365] In one of the schemes, R 9-2 For -CONR 9-1-1 R 9-1-2 .

[0366] In one of the schemes, R 9-1-1 For H.

[0367] In one of the schemes, R 9-1-2 For one or more R 9-1-1-1 Substituted C1 to C6 alkyl groups.

[0368] In one of the schemes, R 9-1-1-1 It is F.

[0369] In one of the schemes, R 9-3 It is oxygenated.

[0370] In one of the schemes, R 10 For hydrogen, methyl, or For example, hydrogen or methyl; for example, R 10 for.

[0371] In one of the schemes, R 11 H, methyl, ethyl, isopropyl, For example, H, methyl, ethyl, isopropyl,

[0372] In one of the schemes, R 5-6 for

[0373] In one of the schemes, R 12 for For example, For example

[0374] In one of the schemes, R 12-1 It is a methyl group.

[0375] In one of the schemes, R 13 For H,

[0376]

[0377] In one of the schemes, Y 1 Y 2 Y 3 Y 4 Y5 All are C.

[0378] In one of the schemes, Y 1 For N, Y 2 Y 3 Y 4 Y 5 All are C.

[0379] In one of the schemes, Y 5 For N, Y 2 Y 3 Y 4 Y 1 All are C.

[0380] In one of the schemes, Y 2 For N, Y 1 Y 3 Y 4 Y 1 All are C.

[0381] In one embodiment, the compound represented by Formula I, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, wherein the compound represented by Formula I is any one of the following compounds:

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400] A compound of Formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, characterized in that the pharmaceutically acceptable salt of the compound of Formula I is any one of the following compounds:

[0401]

[0402] In one embodiment, the compound represented by Formula I has any of the following structures:

[0403] Under the following conditions The compounds with retention times of 7.682 min or 7.766 min correspond to these compounds;

[0404] Agilent Technologies HPLC 1260, test conditions as follows:

[0405] Detector: DAD

[0406] Mobile phase:

[0407] A: Water containing 0.1% formic acid; B: Acetonitrile containing 0.1% formic acid;

[0408] Column: Agilent EC-C18, 3.0 × 150 mm, 2.7 μm

[0409] Gradient method:

[0410] Time (min) A(％) B(％) Flow rate (mL / min) 0.00 90.0 10.0 0.500 6.00 5.0 95.0 9.00 5.0 95.0 ;

[0411] Under the following conditions The compounds with retention times of 10.03 min or 10.45 min; Waters preparative liquid phase (column Prep C18 5μm OBD TM (30*150mm), mobile phase: A%: water (containing 1% FA): 55%, B%: ACN (containing 1% FA): 45%, 37mL / min;

[0412] Under the following conditions The compounds with retention times of 8.22 min or 8.60 min were identified; Waters preparative liquid chromatography (column) Prep C18 5μm OBD TM (30*150mm), mobile phase: A%: water (containing 1% FA): 50%, B%: ACN (containing 1% FA): 50%, 37mL / min;

[0413] Under the following conditions The compounds with retention times of 5.4 min or 12.3 min correspond to the following: (Waters SFC 150) (column DAICEL CHIRALPAK AD-H (250 mm * 19 mm, 5 μm), mobile phase: [CO2]; B%: 30%–30% methanol, 50 mL / min).

[0414] The present invention also provides a pharmaceutical composition comprising:

[0415] (1) A compound of formula I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, and

[0416] (2) Pharmaceutically acceptable excipients.

[0417] 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 or a metabolite thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing diseases or conditions mediated by IL-17.

[0418] In the described uses, the IL-17-mediated diseases or conditions are selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, spondyloarthritis, and non-infectious uveitis.

[0419] In the aforementioned uses, the psoriasis refers to plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, or palmoplantar psoriasis.

[0420] Unless otherwise specified, the terms used in this invention have the following meanings:

[0421] 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.

[0422] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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.

[0427] “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.

[0428] The "prevention" mentioned in this invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0429] The expression "a group substituted by one or more substituents" means that one or more hydrogen atoms in the group are independently substituted by the substituent. When multiple substituents are present, unless otherwise specified, their definitions are independent and do not affect each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0430] The term "multiple" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0431] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0432] 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.

[0433] The term "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 4-8), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatom (1, 2 or 3 of N, O and S), and each ring is saturated.

[0434] Heterocyclic alkyl groups, for example, wait.

[0435] The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing one, two, or three 5-6 membered aromatic monocyclic rings independently selected from nitrogen, oxygen, and sulfur, for example... wait.

[0436] The term "cycloalkyl" refers to a non-aromatic, saturated monovalent cyclic hydrocarbon group having a specified number (e.g., C3 to C8) of ring carbon atoms. It is a monocyclic group, and examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0437] The term "spiroheterocycle" refers to a polycyclic heterocyclic group consisting of a specified number (e.g., 7-12) of monocyclic rings sharing a single atom (called a spiro atom), for example: The “spiroheterocycle” is defined as having at least one heterocycle, wherein the heteroatom is selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally substituted with oxygen (i.e. forming sulfoxide or sulfone), and the remaining ring atoms are carbon.

[0438] The term "heterocyclic ring" refers to a ring having a specified number (e.g., 7-12 atoms) containing two or more rings, at least one of which is a heterocyclic ring, and these rings are connected by sharing two atoms. For example, they can be heterocyclic rings or heterocyclic rings. For example, it could be a heterocyclic aryl group:

[0439] Oxygen is replaced by a divalent group with the formula =O; sulfur is replaced by a divalent group with the formula =S; nitrogen is replaced by a divalent group with the formula =NH.

[0440] 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.

[0441] The reagents and raw materials used in this invention are all commercially available.

[0442] The positive and progressive effects of this invention are that the compounds of this invention have better biological activity in inhibiting IL-17. Detailed Implementation

[0443] 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.

[0444] In Example 25 below, the high-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1260, and the test conditions were as follows:

[0445] Detector: DAD

[0446] Mobile phase:

[0447] A: Water containing 0.1% formic acid; B: Acetonitrile containing 0.1% formic acid;

[0448] Column: Agilent EC-C18, 3.0 × 150 mm, 2.7 μm

[0449] Gradient method:

[0450] Time (min) A(％) B(％) Flow (mL / min) 0.00 90.0 10.0 0.500 6.00 5.0 95.0 9.00 5.0 95.0

[0451] Example 1: Compound I-1

[0452]

[0453] Step 1:

[0454]

[0455] Boc-L-cyclohexylglycine (7.31 g, 28.404 mmol), HATU (16.20 g, 42.606 mmol), and DMF (60 mL) were added sequentially to a dry 250 mL three-necked flask. Compound 1-1 (prepared according to reference WO2023283453, 6 g, 28.404 mmol) and DIEA (11.01 g, 85.212 mmol) were slowly added to the above solution at room temperature. The reaction mixture was vigorously stirred at room temperature for 16 hours. After the reaction was complete as monitored by liquid chromatography-mass spectrometry, the reaction mixture was quenched with ice water (100 mL), then extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 1-2 (7.3 g, 57% yield) as a white solid. LC-MS:[M+1] + =451.20.

[0456] Step Two:

[0457]

[0458] Compounds 1-2 (7.3 g, 16.202 mmol) and DCM (73 mL) were added sequentially to a dry 250 mL three-necked flask. Trifluoroacetic acid (18 mL) was slowly added dropwise to the solution at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LC-MS, the pH was adjusted to 8 with a saturated aqueous solution of NaHCO3 at 0 °C, followed by extraction with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow oily compound 1-3 (6.1 g, crude). LC-MS: [M+1] + =351.15.

[0459] Step 3:

[0460]

[0461] To a dry 250 mL three-necked flask, 1-isopropylpyrazole-5-carboxylic acid (2.95 g, 19.148 mmol), HTAU (9.93 g, 26.111 mmol), and DMF (60 mL) were added sequentially. Compounds 1-3 (6.1 g, 17.407 mmol) and DIEA (6.75 g, 52.221 mmol) were slowly added to the above solution at room temperature. The reaction mixture was vigorously stirred at room temperature for 16 hours. After the reaction was complete as monitored by LC-MS, the reaction mixture was quenched with ice water (100 mL), then extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (50 mL x 3) and dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 1-4 (6.8 g, 80% yield) as a white solid. LC-MS: [M+1] + =487.25.

[0462] Step Four:

[0463]

[0464] Compounds 1-4 (6.1 g, 12.536 mmol), LiOH·H₂O (1.05 g, 25.072 mmol), water (30 mL), and anhydrous ethanol (30 mL) were added sequentially to a dry 250 mL three-necked flask. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete as monitored by LC-MS, the pH was adjusted to 2 with 2 M HCl at 0 °C. The reaction mixture was allowed to stand for 10 minutes, then filtered, and the filter cake was collected. The collected filter cake was dried to give compound 1-5 (5.6 g, 97% yield) as a white solid. LC-MS: [M+1] + =459.30, 1H NMR (400MHz, DMSO-d6) δ12.42(s,1H),9.92(s,1H),8.46(d,J=8.2Hz,1H),7.71(m,1H),7.49(d,J=1.8Hz,1H),7.17(d,J=11.8Hz,1H),7.08(d ,J=8.4Hz,1H),6.94(d,J=1.9Hz,1H),5.39(m,1H),4.53(m,1H),3.68(m,1H),1.83(m,2H),1.67(d,J=34.9Hz,4H),1.36(m,9H),1.11(m,5H). 19 F NMR (377MHz, DMSO) δ-123.53.

[0465] Step 5:

[0466]

[0467] A solution of compounds 1-5 (120 mg, 0.2617 mmol) in toluene (10 mL) was added to DPPA (110 mg, 0.39971 mmol) and triethylamine (60 mg, 0.5929 mmol). The reaction mixture was stirred at 120 °C under argon protection for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and dissolved in acetonitrile (8 mL), and 2,2,2-trifluoroethylamine (52 mg, 0.5249 mmol) and triethylamine (60 mg, 0.59294 mmol) were added. The reaction mixture was stirred at room temperature 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 compound I-1 (55 mg, 0.09917 mmol, yield 37.89%) as a white solid. LC-MS: 555.3 [M+1] + , 1 H NMR (400MHz, MeOD) δ7.78(t,J=8.2Hz,1H),7.51(d,J=1.6Hz,1H),7.21–7.05(m,2H),6.81(d,J=1.6Hz,1H),5.49–5.32(m, 1H),4.86-4.80(m,1H),4.58(d,J=8.2Hz,1H),3.96–3.68(m,2H),2.01–1.67(m,6H),1.50-1.40(m,9H),1.38–1.10(m,5H).

[0468] Example 2: Compound I-2

[0469]

[0470] Step 1:

[0471] In a 100 mL round-bottom three-necked flask, triethylamine (200 mg, 1.98 mmol) and diphenyl azide phosphate (600 mg, 2.18 mmol) were added sequentially to a 25 mL toluene solution (600 mg, 1.31 mmol) of compound 1-5. The reaction mixture was placed under argon protection, heated to reflux, and stirred for 2 hours, then cooled to room temperature. LC-MS monitoring showed that the starting material had been consumed. Tetrahydrofuran (10 mL) and sodium hydroxide aqueous solution (10 mL, 2.0 mmol / mL) were added sequentially, and the reaction mixture was stirred for 16 hours. LC-MS analysis showed that the target compound had been synthesized. The reaction mixture was diluted with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 1:0-20:1) to obtain a white solid compound 2-1 (330 mg, 0.70 mmol). LC-MS: 413.2 [M-NH2+1] + .

[0472] Step Two:

[0473] [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (prepared according to WO2010011959, 280 mg, 0.7503 mmol) and compound 2-1 (130 mg, 0.3027 mmol) in acetonitrile (5 mL) were reacted with N,N-diisopropylethylamine (110 mg, 0.85159 mmol). 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 compound 2-2 as a yellow solid (110 mg, 0.1685 mmol, yield 55.68%). LC-MS: 327.2 [M / 2+1] +

[0474] Step 3:

[0475] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 2-2 (110 mg, 0.1685 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 2-3 (85 mg, 0.1626 mmol, yield 96.51%). LC-MS: 523.3 [M+1] +

[0476] Step Four:

[0477] CDI (80 mg, 0.49337 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 2-3 (85 mg, 0.1626 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 compound I-2 (75 mg, 0.1367 mmol, yield 84.05%) as a white solid. LC-MS: 549.3 [M+1] +1 H NMR (400MHz, MeOD) δ7.91-7.83(m,1H),7.52(d,J=2.0Hz,1H),7.24–7.13(m,2H),6.81(d,J=2.0Hz,1H),5.70(q,J=7.2Hz,1H),5.57–5.25(m,1H) ,4.57(d,J=8.4Hz,1H),3.66–3.46(m,3H),3.22-3.09(m,1H),2.03–1.68 (m,6H),1.54(d,J=7.2Hz,3H),1.46(t,J=6.4Hz,6H),1.42–1.12(m,5H).

[0478] Example 3: Compound I-3

[0479]

[0480] Step 1:

[0481] A solution of compounds 1-5 (400 mg, 0.8724 mmol) and ammonium chloride (465 mg, 8.693 mmol) in N,N-dimethylformamide (10 mL) was reacted with HATU (500 mg, 1.3150 mmol) and N,N-diisopropylethylamine (335 mg, 2.5927 mmol). 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 saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 3-1 as a white solid (360 mg, 0.7869 mmol, yield 90.20%). LC-MS: 458.3 [M+1] +

[0482] Step Two:

[0483] At 0 °C, triethylamine (80 mg, 0.79059 mmol) and trifluoroacetic anhydride (251 mg, 1.1950 mmol) were added to a tetrahydrofuran (20 mL) solution of compound 3-1 (360 mg, 0.7869 mmol). The reaction mixture was stirred at 0 °C for half an hour. The reaction was quenched with ice 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 3-2 (320 mg, 0.7281 mmol, yield 92.53%) as a white solid. LC-MS: 440.2 [M+1] +

[0484] Step 3:

[0485] Sodium carbonate (766 mg, 7.2271 mmol) was added to an ethanol (20 mL) solution of compound 3-2 (320 mg, 0.7281 mmol) and hydroxylamine hydrochloride (250 mg, 3.598 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 3-3 (340 mg, 0.7194 mmol, yield 98.81%). LC-MS: 473.3 [M+1] +

[0486] Step Four:

[0487] At 0 °C, triethylamine (85 mg, 0.84000 mmol) and phenyl chloroformate (66 mg, 0.42154 mmol) were added to a solution of compound 3-3 (200 mg, 0.4232 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, redissolved in toluene (10 mL), refluxed overnight, concentrated, and purified by column chromatography to give a white solid, compound I-3 (105 mg, 0.2106 mmol, yield 49.76%). LC-MS: 499.2 [M+1] + , 1 H NMR(400MHz,MeOD)δ7.87(t,J=8.0Hz,1H),7.52(d,J=2.0Hz,1H),7.23–7.09(m,2H),6.81(d,J=2.0Hz,1H),5.50–5.31(m,1H),4 .57(d,J=8.3Hz,1H),4.11(q,J=7.2Hz,1H),2.02–1.67(m,6H),1.60(d,J=7.2Hz,3H),1.46(t,J=6.6Hz,6H),1.41–1.10(m,5H).

[0488] Example 4: Compound I-4

[0489]

[0490] Step 1:

[0491] Sodium carbonate (51 mg, 0.48 mmol) was added to a solution of ethyl 2-(1,3-dioxoisoindoline-2-yl)trifluoromethanesulfonate (103 mg, 0.32 mmol) and compound 2-1 (70 mg, 0.16 mmol) in dichloromethane (5 mL). The reaction mixture was stirred overnight at room temperature 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 4-1 (50 mg, 0.8 mmol, 50% yield). LC-MS: 603.3 [M+1] +

[0492] Step Two:

[0493] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 4-1 (50 mg, 0.08 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 4-2 (20 mg, 0.04 mmol, yield 50%). LC-MS: 473.3 [M+1] +

[0494] Step 3:

[0495] CDI (19 mg, 0.12 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 4-2 (20 mg, 0.04 mmol), and 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 compound I-4 (6 mg, 0.012 mmol, yield 30%) as a white solid. LC-MS: 499.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.84(t,J=8.3Hz,1H),7.52(d,J=2.0Hz,1H),7.31–7.07 (m,2H),6.81(d,J=2.0Hz,1H),5.45–5.34(m,1H),5.13(q,J=7.2Hz,1H),4.5 6(d,J=8.3Hz,2H),3.55–3.36(m,2H),3.11(dd,J=15.7,8.6Hz,1H),2.12–1. 68(m,6H),1.57(t,J=18.1Hz,3H),1.47(t,J=6.2Hz,6H),1.32–1.15(m,5H).

[0496] Example 5: Compound I-5

[0497]

[0498] Step 1:

[0499] Potassium carbonate (159 mg, 0.69 mmol) was added to a solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (112 mg, 0.46 mmol) and compound 5-1 (140 mg, 0.33 mmol) in acetonitrile (5 mL). The reaction mixture was stirred overnight at 80 °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 5-1 (126 mg, 0.21 mmol, yield 65%). LC-MS: 588.4 [M+1] +

[0500] Step Two:

[0501] 1 M HCl (1 mL) was added to a methanol (5 mL) solution of compound 5-1 (126 mg, 0.21 mmol), and the reaction mixture was stirred overnight at room temperature 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 5-2 (100 mg, 0.21 mmol, 100% yield). LC-MS: 474.3 [M+1] +

[0502] Step 3:

[0503] CDI (68 mg, 0.42 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 5-2 (100 mg, 0.21 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 compound I-5 as a white solid (93 mg, 0.19 mmol, yield 89%). LC-MS: 500.3 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ9.96(s,1H),8.46(d,J=8.2Hz,1H),7.93–7.74(m,1H),7.50(d,J=2.0Hz,1H),7.24(dd,J= 11.9,2.0Hz,1H),7.14(dd,J=8.3,2.0Hz,1H),6.94(d,J=2.0Hz,1H),5.58–5.36(m,1H),4.94(q,J=7.1Hz,1H),4. 55(t,J=8.4Hz,1H),4.37–4.16(m,2H),3.69–3.52(m,1H),3.28–3.16(m,1H),2.00(p,J=7.0,6.5Hz,1H),1.84(dd ,J=18.4,12.6Hz,2H),1.73(s,2H),1.64(s,2H),1.50(d,J=7.2Hz,3H),1.37(dd,J=8.5,6.6Hz,6H),1.24(s,4H).

[0504] Example 6: Compound I-6

[0505]

[0506] Step 1:

[0507] 2-(ethylene oxide-2-ylmethyl)isoindoline-1,3-dione (426 mg, 2.1 mmol) and compound 2-1 (300 mg, 0.7 mmol) were dissolved in isopropanol (10 mL). The reaction mixture was refluxed and stirred overnight 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 compound 6-1 (200 mg, 0.32 mmol, yield 45%) as a yellow solid. LC-MS: 633.3 [M+1] + .

[0508] Step Two:

[0509] A solution of compound 6-1 (30 mg, 0.05 mmol) in ethanol (3 mL) was reacted with hydrazine hydrate (0.5 mL), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 6-2 (15 mg, 0.03 mmol, yield 63%). LC-MS: 503.3 [M+1] + .

[0510] Step 3:

[0511] CDI (30 mg, 0.18 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 6-2 (50 mg, 0.1 mmol), and 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 compound I-6 (10 mg, 0.02 mmol, yield 19%) as a white solid. LC-MS: 529.3 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.89(td,J=8.1,2.7Hz,1H),7.53(d,J=2.0Hz,1H),7.30(dd,J=11.6,1.6Hz,1H),7. 23(d,J=8.4Hz,1H),6.81(d,J=2.0Hz,1H),5.47–5.28(m,1H),4.86–4.73(m,1H),4.56(d,J=8.4Hz,1H),4 .09(p,J=6.6Hz,1H),3.65(tt,J=10.5,5.3Hz,1H),3.28–3.18(m,1H),3.02–2.92(m,1H),2.90–2.74(m, 1H),1.98–1.70(m,5H),1.51(dd,J=6.7,2.4Hz,3H),1.46(t,J=6.3Hz,6H),1.33(dd,J=12.0,4.5Hz,6H).

[0512] Example 7: Compound I-7

[0513]

[0514] Step 1:

[0515] In a 100 mL round-bottom flask, potassium carbonate (850 mg, 6.16 mmol) and benzyl bromide (528 mg, 3.09 mmol) were added sequentially to a 25 mL acetonitrile solution of 2,2,3,3-tetrafluoro-1,4-butanediol compound 7-1 (500 mg, 3.08 mmol). The reaction mixture was placed under argon protection, heated to reflux, and stirred for 16 hours, then cooled to room temperature. TLC (petroleum ether: ethyl acetate = 4:1) showed that the starting material had been completely consumed. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0–3:1) to give the target compound 7-2 (750 mg, 2.97 mmol) as a colorless oil. 1H NMR (400MHz, Chloroform-d) δ7.44–7.33(m,5H),4.70(s,2H),4.09-3.97(m,2H),3.93(tt,J=13.2,1.6Hz,2H),2.52(t,J=7.6Hz,1H).

[0516] Step Two:

[0517] In a 100 mL round-bottom flask, pyridine (470 mg, 5.94 mmol) was added to a 25 mL solution of 4-(benzyloxy)-2,2,3,3-tetrafluorobut-1-ol (compound 7-2, 750 mg, 2.97 mmol) in dichloromethane. The flask was then placed in an ice-water bath and cooled to 0 °C, with stirring for 10 minutes. Trifluoromethanesulfonic anhydride (840 mg, 2.97 mmol) was then added dropwise to the reaction mixture. The reaction mixture was slowly heated to room temperature and stirred for 3 hours. TLC (petroleum ether:ethyl acetate = 4:1) showed that the starting material had been completely consumed. Ice water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. 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 to 4:1) to give the target compound 7-3 (1.04 g, 2.71 mmol) as a colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.45–7.31(m,5H),4.88(t,J=14.0Hz,2H),4.67(s,2H),3.90(tt,J=12.8,2.0Hz,2H).

[0518] Step 3:

[0519] In a 100 mL round-bottom flask, potassium phthalimide (1 g, 5.40 mmol) was added to a 15 mL solution of compound 7-3 (1.04 g, 2.71 mmol) in N,N-dimethylformamide. The mixture was then heated to 85 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and the starting material was monitored by LC-MS until consumed. 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–3:1) to give the target compound 7-4 (0.8 g, 2.0 mmol) as a white solid. LC-MS: 381.8 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.94(dd,J=5.5,3.0Hz,2H),7.79(dd,J=5.5,3.0Hz,2H) ,7.45–7.31(m,6H),4.72(s,2H),4.41(t,J=16.1Hz,2H),3.97(tt,J=13.7,1.7Hz,2H).

[0520] Step Four:

[0521] In a 100 mL round-bottom three-necked flask, a 5 mL solution of compound 7-4 (0.2 g, 0.52 mmol) in dichloromethane was placed under an argon atmosphere and cooled to -78 °C. A 1 M solution of boron trichloride in dichloromethane (1.5 mL, 1.5 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred for 15 minutes, then slowly heated to room temperature and stirred for 3 hours. LC-MS monitoring showed that the starting material was completely consumed. The three-necked flask was placed in an ice-water bath, and a saturated sodium bicarbonate solution was added to the reaction mixture 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 = 1:0–1:1) to give the target compound 7-5 (0.143 g, 0.49 mmol) as a white solid. LC-MS: 291.8 [M+H] + .

[0522] Step 5:

[0523] In a 100 mL round-bottom three-necked flask, a dichloromethane solution of compound 7-5 (0.143 g, 0.49 mmol) was added, and the mixture was placed in an ice-water bath and cooled to 0 °C. Pyridine (80 mg, 1.01 mmol) was added dropwise to the reaction solution, and the mixture was stirred for 15 minutes. Then, trifluoromethanesulfonic anhydride (139 mg, 0.49 mmol) was added dropwise. The reaction solution was heated to room temperature and stirred for 2 hours. LC-MS monitoring showed that the starting material was completely consumed. The three-necked flask was placed in an ice-water bath, and water was added to the reaction solution 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 to 1:1) to give the target compound 7-6 (0.18 g, 0.425 mmol) as a white solid. LC-MS: 423.6 [M+H] + .

[0524] Step Six:

[0525] In a 100 mL round-bottom flask, triethylamine (100 mg, 0.99 mmol) and compound 1-5 (140 mg, 0.49 mmol) were added sequentially to an acetonitrile solution of compound 7-6 (0.143 g, 0.49 mmol). The reaction mixture was then placed under an argon atmosphere, heated to reflux, and stirred for 16 hours. LC-MS monitoring showed that most of the starting material had been converted to the target product. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 7-7 (80 mg, 0.11 mmol) as a white solid. LC-MS: 351.9 [M / 2+H] + .

[0526] Step Seven:

[0527] In a 100 mL round-bottom flask, hydrazine hydrate (50%, 40 mg, 0.4 mmol) was added to an ethanol solution of compound 7-7 (80 mg, 0.11 mmol), and the mixture was heated to 50 °C and stirred for 2 hours. LC-MS monitoring showed that the starting material had been converted to the target product. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oily crude product 7-8 (60 mg, 0.105 mmol). The crude product obtained did not require further purification and was used directly in the next reaction. LC-MS: 572.8 [M+H] + .

[0528] Step 8:

[0529] In a 100 mL round-bottom flask, triethylamine (30 mg, 0.29 mmol) and phenyl p-nitrochloroformate (25 mg, 0.124 mmol) were added sequentially to an anhydrous acetonitrile solution of compound 7-8 (60 mg, 0.105 mmol), and the mixture was stirred at room temperature for 3 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to give the target compound I-7 (8 mg, 0.0133 mmol) as a white solid. LC-MS: 598.8 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ7.88(t,J=8.2Hz,1H),7.52(d,J=2.0Hz,1H),7.35–7.23(m ,2H),6.80(d,J=2.0Hz,1H),5.44–5.30(m,2H),4.59–4.56(m,1H),3.44(dt,J=33.0,12 .2Hz,4H),1.94(t,J=11.0Hz,2H),1.83(d,J=11.2Hz,3H),1.73(d,J=12.2Hz,1H),1.58 (d,J=7.1Hz,3H),1.46(t,J=6.4Hz,6H),1.35(dd,J=9.8,3.5Hz,2H),1.29–1.14(m,3H).

[0530] Example 8: Compound I-8

[0531]

[0532] Step 1:

[0533] 4-(1,3-dioxoisoindol-2-yl)pentanal (226 mg, 0.98 mmol) and compound 2-1 (214 mg, 0.5 mmol) were dissolved in methanol (5 mL). The reaction mixture was stirred at room temperature for one hour, then sodium cyanoborohydride (126 mg, 2.0 mmol) was added, and the mixture was stirred overnight. 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 compound 8-1 (300 mg, 0.47 mmol, 96% yield) as a white solid. LC-MS: 645.4 [M+1] + .

[0534] Step Two:

[0535] Hydrazine hydrate (0.5 mL) was added to a 6 mL ethanol solution of compound 8-1 (400 mg, 0.62 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 8-2 (200 mg, 0.38 mmol, yield 63%). LC-MS: 515.4 [M+1] + .

[0536] Step 3:

[0537] CDI (63 mg, 0.38 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 8-2 (100 mg, 0.19 mmol), and 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 compound I-8 (20 mg, 0.04 mmol, yield 19%) as a white solid. LC-MS: [M+1] + 541.3. 1 H NMR (400MHz, MeOD) δ7.82 (ddd, J=13.9, 13.4, 4.9Hz, 1H), 7.52 (d, J=1.9Hz, 1H) ,7.34–7.10(m,2H),6.81(d,J=1.9Hz,1H),5.48–5.30(m,2H),4.57(d,J=8.3Hz ,1H),3.26–3.04(m,1H),3.01–2.79(m,1H),2.04(d,J=8.4Hz,3H),1.99–1.58( m,7H),1.54(d,J=6.9Hz,3H),1.46(dd,J=13.1,6.9Hz,6H),1.41–1.12(m,9H).

[0538] Example 9: Compound I-9

[0539]

[0540] Step 1:

[0541] Tert-butyl (2-(2-bromoethyl)phenyl)carbamate (100 mg, 0.33 mmol) and compound 2-1 (143 mg, 0.33 mmol) were dissolved in DMF (8 mL), and a reaction solution of pyridine (52 mg, 0.65 mmol) was added. The mixture was stirred in a microwave-safe solution at 80 °C for 2 hours. The reaction solution 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 a residue, which was purified by column chromatography to give a white solid 9-1 (100 mg, 0.15 mmol, yield 46%). LC-MS: 649.4 [M+1] + .

[0542] Step Two:

[0543] TFA (0.1 mL) was added to a dichloromethane (5 mL) solution of compound 9-1 (80 mg, 0.12 mmol), 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 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give compound 9-2 (60 mg, 0.11 mmol, yield 89%) as a yellow solid. LC-MS: 549.3 [M+1] + .

[0544] Step 3:

[0545] To a solution of compound 9-2 (46 mg, 0.08 mmol) in acetonitrile (5 mL), 4-nitrophenyl chloroformate (20 mg, 0.09 mmol) and triethylamine (10 mg, 0.09 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 2). 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-9 (20 mg, 0.03 mmol, yield 42%) as a white solid. LC-MS: 575.3 [M+1] + . 1 HNMR(400MHz,MeOD)δ7.88(t,J=8.3Hz,1H),7.52(d,J=2.0Hz,1H),7.24(t,J=9.1Hz,2H),7.1 0(t,J=7.7Hz,1H),6.99(dd,J=20.7,7.4Hz,2H),6.88(t,J=7.4Hz,1H),6.81(d,J=2.0Hz,1H) ,5.75(q,J=7.0Hz,1H),5.46–5.24(m,1H),4.57(d,J=8.3Hz,1H),3.32–3.19(m,2H),2.94–2. 69(m,2H),2.01–1.67(m,5H),1.59(d,J=7.1Hz,3H),1.46(t,J=6.3Hz,6H),1.34–1.11(m,6H).

[0546] Example 10: Compound I-10

[0547]

[0548] Step 1:

[0549] To a DMF (10 mL) solution of compounds 1-5 (900 mg, 1.96 mmol), N,O-dimethylhydroxylamine (230 mg, 3.77 mmol), HATU (1.1 g, 2.9 mmol), and DIPEA (509 mg, 3.94 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 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give compound 10-1 (900 mg, 1.8 mmol, 92% yield) as a white solid. LC-MS: 502.3 [M+1] + .

[0550] Step Two:

[0551] DIBAL (2.4 mL, 2.4 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 10⁻¹ (400 mg, 0.80 mmol). The reaction mixture was stirred at -78 °C under argon protection for 2 hours. The reaction was quenched with Na₂SO₄·10H₂O and filtered. The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a colorless oily compound 10⁻² (220 mg, 0.50 mmol, yield 62%). LC-MS: 515.4 [M+1] + .

[0552] Step 3:

[0553] In a 100 mL round-bottom flask, dimethyl 1-diazo-2-oxopropyl phosphonate (65 mg, 0.339 mmol) and potassium carbonate (63 mg, 0.46 mmol) were added to a 15 mL methanol solution (100 mg, 0.226 mmol) of compound 10⁻². The reaction mixture was placed under argon protection and stirred at room temperature for 16 hours. TLC (petroleum ether: ethyl acetate = 4:1) monitoring showed that the starting material had been consumed. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0–2:1) to give a colorless oily compound 10⁻³ (75 mg, 0.17 mmol). LC-MS: 438.9 [M+H] + .

[0554] Step Four:

[0555] In a 100 mL round-bottom flask, 2-azido-1,1,1-trifluoroethane (32 mg, 0.255 mmol), copper sulfate (4 mg), sodium vitamin C (75 mg, 0.375 mmol), water (0.3 mL), and tert-butanol (0.125 mL) were added sequentially to a 10 mL solution of compound 10-3 (75 mg, 0.17 mmol) in N,N-dimethylformamide. The reaction mixture was heated to 50 °C and stirred for 16 hours. After cooling to room temperature, LC-MS monitoring showed that the starting material had been completely consumed. 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1) to give compound I-10 (58.83 mg, 0.104 mmol) as a brown solid. LC-MS: 563.8 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.90 (s, 1H), 7.76 (t, J = 8.3Hz, 1H), 7.52 (d, J = 2.1Hz, 1H) ,7.15–7.08(m,2H),6.80(d,J=2.1Hz,1H),5.39(p,J=6.7Hz,1H),5.26(q,J=8.7Hz,2H ),4.55(d,J=8.4Hz,1H),4.33(q,J=7.2Hz,1H),1.92(d,J=11.8Hz,2H),1.82(d,J=11. 1Hz, 3H), 1.69 (d, J = 7.3Hz, 4H), 1.46 (t, J = 6.3Hz, 6H), 1.30 (dt, J = 24.6, 12.4Hz, 5H).

[0556] Example 11: Compound I-11

[0557]

[0558] Step 1:

[0559] To a DMF (5 mL) solution of compounds 1-5 (400 mg, 0.87 mmol), trifluoroethylamine (104 mg, 1.0 mmol), HATU (662 mg, 1.74 mmol), and DIPEA (337 mg, 2.61 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 2). The combined organic layers were washed with saturated brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 11-1 (400 mg, 0.74 mmol, 85% yield) as a white solid. LC-MS: 540.3 [M+1] + .

[0560] Step Two:

[0561] Triphenylphosphine (292 mg, 1.11 mmol) and two drops of carbon tetrachloride were added to a 10 mL solution of compound 11-1 (200 mg, 0.37 mmol) in acetonitrile. The reaction mixture was stirred at 85 °C under argon protection for 2 hours. The reaction mixture was cooled to room temperature, and then TMSN3 (128 mg, 1.11 mmol) was added. The reaction mixture was stirred overnight at 85 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give compound I-11 (10 mg, 0.01 mmol, yield 5%) as a white solid. LC-MS: 565.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.71(td,J=7.8,2.9Hz,1H),7.58–7.26(m,3H),6.68(dd, J=5.6,2.0Hz,1H),5.35–5.17(m,1H),5.06(dd,J=9.7,4.5Hz,1H),4.09–3.78 (m,3H),2.31–2.15(m,1H),2.11–1.89(m,1H),1.77(d,J=7.3Hz,1H),1.69(d, J=9.1Hz,2H),1.53(t,J=6.9Hz,3H),1.41(d,J=6.7Hz,6H),1.32–0.87(m,6H).

[0562] Example 12: Compound I-12

[0563]

[0564] To a solution of compound 3-3 (80 mg, 0.1693 mmol) in trimethyl orthoformate (1 mL), 10 mg of trifluoroacetic acid was added, and the reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography to give a white solid compound I-12 (65 mg, 0.1347 mmol, yield 79.57%). LC-MS: 483.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ9.15(s,1H),7.80(t,J=8.2Hz,1H),7.52(d,J=2.0Hz,1H),7.24–7.10(m,2H),6.80(d,J=2.0Hz,1H),5.48–5.33(m ,1H),4.56(d,J=8.2Hz,1H),4.40(q,J=7.2Hz,1H),2.01–1.71(m,5H),1.70(d,J=7.2Hz,3H),1.46(t,J=6.4Hz,6H),1.40–1.10(m,6H).

[0565] Example 13: Compound I-13

[0566]

[0567] To a toluene (10 mL) solution of compounds 1-5 (200 mg, 0.4362 mmol), diphenyl azidophosphate (180 mg, 0.65407 mmol) and triethylamine (90 mg, 0.88942 mmol) were added, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated and dissolved in dichloromethane (10 mL), and methyl 2-amino-2-methylpropionate (80 mg, 0.68289 mmol) and N,N-diisopropylethylamine (78 mg, 0.60367 mmol) were added to the above solution and stirred overnight at room temperature. DBU (95 mg, 0.625 mmol) was added, and the mixture was stirred at 50 °C for 5 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried, concentrated, and purified by column chromatography to give a white solid compound I-13 (35 mg, 0.06474 mmol, yield 14.84%). LC-MS: 540.9 [M+1] + . 1H NMR (400MHz, MeOD) δ7.83(t,J=8.4Hz,1H),7.52(d,J=2.0Hz,1H),7.27(d,J=12.0Hz,1H),7.19(d,J=8.4Hz,1H),6.80(d,J=2.0Hz ,1H),5.45-5.34(m,1H),5.32-5.23(m,1H),4.57(d,J=8.4Hz,1H),2.02–1.65(m,9H),1.46(t,J=6.4Hz,6H),1.41–1.10(m,11H).

[0568] Example 14: Compound I-14

[0569]

[0570] To a toluene (10 mL) solution of compounds 1-5 (200 mg, 0.4362 mmol), diphenyl azidophosphate (180 mg, 0.65407 mmol) and triethylamine (90 mg, 0.88942 mmol) were added, and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated and dissolved in dichloromethane (10 mL), and methyl 1-amino-1-cyclopentanecarbamate (80 mg, 0.55874 mmol) and N,N-diisopropylethylamine (78 mg, 0.60367 mmol) were added to the above solution and stirred overnight at room temperature. DBU (95 mg, 0.625 mmol) was added, and the mixture was stirred at 50 °C for 5 hours. The reaction was quenched with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine, dried, concentrated, and purified by column chromatography to give a white solid compound I-14 (42 mg, 0.07411 mmol, yield 16.99%). LC-MS: 566.8 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.83(t,J=8.2Hz,1H),7.52(d,J=2.0Hz,1H),7.29-7.23(m,1H),7.22-7.17(m,1H),6.80(d,J=2.0Hz,1H),5.46–5. 34(m,1H),5.28(q,J=7.2Hz,1H),4.57(d,J=8.4Hz,1H),2.18–1.51(m,10H)1.50–1.62(m,7H),1.46(t,J=6.4Hz,6H),1.41–1.09(m,5H).

[0571] Example 15: Compound I-15

[0572]

[0573] Step 1:

[0574] In a 100 mL round-bottom flask, a 10 mL solution of compound 15-1 (50 mg, 0.23 mmol) in dichloromethane was added to a solution of Dys-Martin oxidant (160 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 4:1) showed that the starting material had been completely consumed. Water was added to quench the reaction mixture, and the mixture was extracted 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 a colorless oily target compound 15-2 (38 mg, 0.176 mmol). LC-MS: 159.9 [M+H] + .

[0575] Step Two:

[0576] In a 100 mL round-bottom flask, compound 2-1 (76 mg, 0.18 mmol) was added to a 15 mL solution of compound 15-2 (38 mg, 0.176 mmol) in dichloromethane, followed by the addition of glacial acetic acid (2 mg) as a catalyst. The reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetylborohydride (118 mg, 0.53 mmol) was added, and the reaction was continued for 16 hours. LC-MS monitoring showed that the starting material had been completely consumed. Water was added to quench the reaction mixture, 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1) to give compound 15-3 (80 mg, 0.127 mmol) as a white solid. LC-MS: 628.8 [M+H] + .

[0577] Step 3:

[0578] In a 100 mL round-bottom flask, a solution of ethyl hydrogen chloride (1 M, 0.2 mL, 0.2 mmol) in dichloromethane was added to 10 mL of a solution of compound 15-3 (130 mg, 0.206 mmol). The mixture was stirred at room temperature for 5 hours until the reactants were consumed. Petroleum ether (20 mL) was added dropwise to quench the reaction. The mixture was filtered, and the filter cake was washed with petroleum ether to give a white solid, compound 15-4 (100 mg, 0.17 mmol). LC-MS: 528.9 [M+H] + .

[0579] Step Four:

[0580] In a 100 mL round-bottom flask placed in an ice-water bath, triethylamine (50 mg, 0.494 mmol) and phenyl p-nitrochloroformate (50 mg, 0.248 mmol) were added sequentially to a 10 mL acetonitrile solution (80 mg, 0.14 mmol) of compound 15-4. The mixture was then slowly heated to room temperature and stirred for 3 hours until LC-MS monitoring showed that the starting material had been completely consumed. 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 to 1:1) to give the target compound I-15 (50 mg, 0.09 mmol) as a white solid. LC-MS: 554.8 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.86(td,J=8.3,2.0Hz,1H),7.52(d,J=2.1Hz,1H),7.17(tdd,J=8.9,6.0,2.0Hz,2H) ,6.80(d,J=2.1Hz,1H),5.39(p,J=6.6Hz,1H),5.15(q,J=7.0Hz,1H),4.59–4.54(m,2H),3.98–3.79(m,2H),3.72– 3.64(m,1H),3.62–3.51(m,1H),3.49(d,J=9.3Hz,1H),3.09(dd,J=9.3,2.6Hz,1H),2.14–1.89(m,4H),1.83(d,J= 11.0Hz, 3H), 1.73 (d, J=11.7Hz, 1H), 1.55 (dd, J=7.2, 4.5Hz, 3H), 1.47 (dd, J=6.7, 5.7Hz, 6H), 1.38–1.27 (m, 4H).

[0581] Example 16: Compound I-16

[0582]

[0583] Sulfonamide (65 mg, 0.6763 mmol) was added to a pyridine (5 mL) solution of compound 2-3 (117 mg, 0.2239 mmol), and the reaction mixture was stirred overnight at 100 °C under argon protection. The solvent was evaporated, 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 compound I-16 (25 mg, 0.04276 mmol, yield 19.10%) as a white solid. LC-MS: 585.1 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.90(t,J=8.4Hz,1H),7.53(d,J=2.0Hz,1H),7.36-7.22(m,2H),6.81(d,J=2.0Hz,1H),5.46-5.35(m,1H),5.17 -5.09(m,1H),4.56(d,J=8.4Hz,1H),3.76-3.48(m,3H),3.18–3.08(m,1H),2.0 5–1.67(m,6H),1.59(d,J=7.2Hz,3H),1.47(t,J=6.4Hz,6H),1.43–1.10(m,5H).

[0584] Example 17: Compound I-17

[0585]

[0586] Cyanogen bromide (25 mg, 0.23603 mmol) was added to a toluene (5 mL) solution of compound 2-3 (120 mg, 0.2296 mmol), and the reaction mixture was stirred for 2 hours at room temperature 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 compound I-17 (20 mg, 0.03652 mmol, yield 15.91%) as a white solid. LC-MS: 548.3 [M+1] + . 1H NMR (400MHz, MeOD) δ7.78(t,J=8.0Hz,1H),7.52(d,J=1.8Hz,1H),7.25-7.12(m,2H),6.81(d,J=1.8Hz,1H),5.46-5.35(m,1H),4.57 (d,J=8.0Hz,1H),3.86-3.79(m,1H),3.56-3.35(m,2H),2.95-2.73(m,2H),2.03-1.66(m,6H),1.52-1.41(m,6H),1.41–1.12(m,8H).

[0587] Example 18: Compound I-18

[0588]

[0589] Step 1:

[0590] A solution of 4-(N-tert-butoxycarbonylamino)-1-butanol compound 18-1 (300 mg, 1.5852 mmol) in dichloromethane (5 mL) was added with Dys-Martin oxidant (1.3 g, 3.1 mmol). The reaction mixture was stirred for 2 hours at room temperature 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a colorless oily compound 18-2 (150 mg, 0.80111 mmol, yield 50.54%). LC-MS: 114.0 [M-56+1] + .

[0591] Step Two:

[0592] Sodium triacetoxyborohydride (300 mg, 1.4155 mmol) was added to a methanol (10 mL) solution of compound 2-1 (200 mg, 0.4657 mmol) and compound 18-2 (150 mg, 0.80111 mmol). The reaction mixture was stirred overnight at room temperature 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 compound 18-3 (105 mg, 0.1748 mmol, yield 37.53%) as a yellow solid. LC-MS: 600.9 [M+1] + .

[0593] Step 3:

[0594] A solution of compound 18-3 (105 mg, 0.1748 mmol) in dichloromethane (1 mL) was added with 1 mL of trifluoroacetic acid. The reaction mixture was stirred for 2 hours at room temperature under argon protection. The reaction mixture was concentrated, extracted with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 18-4 (65 mg, 0.1298 mmol, yield 74.30%). LC-MS: 501.2 [M+1] + .

[0595] Step Four:

[0596] N,N'-carbonyldiimidazole (47 mg, 0.28986 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 18-4 (50 mg, 0.09988 mmol), and 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 compound I-18 as a white solid (1.73 mg, 0.00329 mmol, yield 3.29%). LC-MS: 264.0 [M / 2+1] + . 1 H NMR (400MHz, MeOD) δ7.85(t,J=8.4Hz,1H),7.53(d,J=2.0Hz,1H),7.27-7.19(m,2H),6.81(d,J=2.0Hz,1H),5.44–5.34(m,2H),4.56(d ,J=8.4Hz,1H),3.17–2.96(m,4H),2.26–2.18(m,1H),2.08–1.61(m,8H),1.54(d,J=7.0Hz,3H),1.50–1.42(m,6H),1.31–1.13(m,6H).

[0597] Example 19: Compound I-19

[0598]

[0599] A sulfonamide (59 mg, 0.6139 mmol) was added to a pyridine (5 mL) solution of compound 18-4 (105 mg, 0.2097 mmol), and the reaction mixture was stirred at 100 °C under argon protection for 5 hours. The solvent was evaporated, 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 white solid compound I-19 (35 mg, 0.06402 mmol, yield 30.52%). LC-MS: 563.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.89(t,J=8.2Hz,1H),7.52(d,J=2.0Hz,1H),7.37-7.26(m,2H),6.81(d,J=2.0Hz,1H),5.46-5.33(m,1H), 5.16(q,J=7.2Hz,1H),4.58(d,J=8.4Hz,1H),3.19-3.08(m,4H),2.04–1.50(m,12H),1.46(t,J=6.4Hz,6H),1.41–1.09(m,6H).

[0600] Example 20: Compound I-20

[0601]

[0602] Step 1:

[0603] To a solution of compound 20-1 (prepared according to the method for compound 2-1, 150 mg, 0.3610 mmol), [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (prepared according to WO2010011959, 279 mg, 0.722 mmol) in acetonitrile (5 mL), N,N-diisopropylethylamine (100 mg, 0.77417 mmol) was added. The reaction mixture was stirred at 50 °C under argon protection for 5 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 compound 20-2 as a yellow solid (110 mg, 0.1722 mmol, yield 47.71%). LC-MS: 639.3 [M+1] + .

[0604] Step Two:

[0605] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 20-2 (110 mg, 0.1722 mmol), and the reaction mixture was stirred at 50 °C under argon protection for 1 hour. 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 20-3 (70 mg, 0.1376 mmol, yield 79.91%). LC-MS: 509.3 [M+1] + .

[0606] Step 3:

[0607] N,N'-carbonyldiimidazole (65 mg, 0.40086 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 20-3 (70 mg, 0.1376 mmol), and 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 compound I-20 (50 mg, 0.09353 mmol, yield 67.95%) as a white solid. LC-MS: 535.1 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.84(t,J=8.0Hz,1H),7.52(d,J=2.0Hz,1H),7.18-7.09(m,2H),6.80(d,J=2.0Hz,1H),5.47–5.32(m ,1H),4.57(d,J=8.2Hz,1H),4.53(s,2H),3.64-3.53(m,4H),2.02–1.64(m,6H),1.46(t,J=6.4Hz,6H),1.35–1.13(m,5H).

[0608] Example 21: Compound I-21

[0609]

[0610] Step 1:

[0611] Potassium carbonate (159 mg, 0.69 mmol) was added to a 5 mL solution of acetonitrile containing compound 21-1 (123 mg, 0.46 mmol) and compound 2-1 (140 mg, 0.33 mmol). The reaction mixture was stirred overnight at 80 °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 compound 21-2 (126 mg, 0.21 mmol, yield 65%) as a yellow solid. LC-MS: 617.3 [M+1] + .

[0612] Step Two:

[0613] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 21-2 (50 mg, 0.08 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 21-3 (20 mg, 0.04 mmol, yield 50%). LC-MS: 487.3 [M+1] + .

[0614] Step 3:

[0615] CDI (19 mg, 0.12 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 21-3 (20 mg, 0.04 mmol), and 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 compound I-21 (6 mg, 0.012 mmol, yield 30%) as a white solid. LC-MS: 513.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.85(s,1H),7.53(d,J=1.9Hz,1H),7.27–7.01(m,2H),6 .81(d,J=2.0Hz,1H),5.74(q,J=7.2Hz,1H),5.39(td,J=13.1,6.4Hz,1H),4.5 6(d,J=8.4Hz,1H),3.28–3.17(m,2H),3.02(s,1H),2.93–2.79(m,1H),2.02– 1.69(m,7H),1.53(d,J=7.1Hz,3H),1.47(t,J=6.1Hz,6H),1.36–1.10(m,6H).

[0616] Example 22: Compound I-22

[0617]

[0618] Step 1:

[0619] Triethylamine (510 mg, 5.0400 mmol) was added to a 20 mL solution of compound 22-1 (500 mg, 4.9432 mmol) and phthalic anhydride (735 mg, 4.9622 mmol) in toluene. The reaction mixture was stirred at 130 °C under argon protection for 3 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 compound 22-2 (850 mg, 3.676 mmol, yield 74.37%) as a white solid. LC-MS: 214.1 [M-H2O+1] + .

[0620] Step Two:

[0621] A solution of compound 22-2 (200 mg, 0.8651 mmol) in dichloromethane (5 mL) was added with Dys-Martin oxidant (729 mg, 1.7188 mmol), and the reaction mixture was stirred for 2 hours at room temperature 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give compound 22-3 (190 mg, 0.8290 mmol, yield 95.83%) as a white solid. LC-MS: 230.1 [M+1] + .

[0622] Step 3:

[0623] Sodium cyanoborohydride (70 mg, 1.114 mmol) was added to a methanol (5 mL) solution of compound 2-1 (130 mg, 0.3027 mmol) and compound 22-3 (100 mg, 0.4363 mmol). The reaction mixture was stirred for 2 hours at room temperature 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 compound 22-4 (110 mg, 0.1711 mmol, yield 56.54%) as a yellow solid. LC-MS: 643.4 [M+1] + .

[0624] Step Four:

[0625] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 22-4 (110 mg, 0.1711 mmol), and the reaction mixture was stirred at 50 °C under argon protection for 1 hour. 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 22-5 (75 mg, 0.1463 mmol, yield 85.48%). LC-MS: 513.9 [M+1] + .

[0626] Step 5:

[0627] N,N'-carbonyldiimidazole (72 mg, 0.44403 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 22-5 (75 mg, 0.1463 mmol), and 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 compound I-22 (55 mg, 0.1021 mmol, yield 69.79%) as a white solid. LC-MS: 538.9 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.84(t,J=8.4Hz,1H),7.52(d,J=1.6Hz,1H),7.21–7.11(m,2H ),6.81(d,J=1.6Hz,1H),5.74(q,J=6.8Hz,1H),5.46-5.36(m,1H),4.62-4.55(m,1 H),3.24-3.08(m,2H),2.89(d,J=11.6Hz,1H),2.46(d,J=12.0Hz,1H),2.02–1.69( m,6H),1.55–1.41(m,9H),1.39–1.10(m,5H),0.62-0.51(m,3H),0.32-0.23(m,1H).

[0628] Example 23: Compound I-23

[0629]

[0630] Step 1:

[0631] A solution of compound 23-1 (140 mg, 0.69562 mmol) in dichloromethane (5 mL) was added with Dys-Martin oxidant (595 mg, 1.4028 mmol), and the reaction mixture was stirred for 2 hours at room temperature 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a colorless oily compound 23-2 (120 mg, 0.60226 mmol, yield 86.58%). LC-MS: 144.1 [M-56+1] + .

[0632] Step Two:

[0633] Sodium cyanoborohydride (70 mg, 1.114 mmol) was added to a methanol (5 mL) solution of compound 2-1 (130 mg, 0.3027 mmol) and compound 23-2 (120 mg, 0.60226 mmol). The reaction mixture was stirred for 2 hours at room temperature 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 compound 23-3 (115 mg, 0.1877 mmol, yield 62.00%) as a yellow solid. LC-MS: 612.9 [M+1] + .

[0634] Step 3:

[0635] A solution of compound 23-3 (115 mg, 0.1877 mmol) in dichloromethane (1 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred for 2 hours at room temperature under argon protection. The reaction mixture was concentrated, extracted with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 23-4 (81 mg, 0.1580 mmol, yield 84.19%). LC-MS: 513.9 [M+1] + .

[0636] Step Four:

[0637] N,N'-carbonyldiimidazole (75 mg, 0.46253 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 23-4 (81 mg, 0.1580 mmol), and 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 compound I-23 (52 mg, 0.09653 mmol, yield 61.10%) as a white solid. LC-MS: 538.9 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.86(t,J=8.4Hz,1H),7.53(d,J=2.0Hz,1H),7.23–7.11(m,2 H),6.81(d,J=2.0Hz,1H),5.76(q,J=7.0Hz,1H),5.45-5.35(m,1H),4.57(d,J=8.4 Hz,1H),3.31–3.27(m,1H),3.01–2.89(m,1H),1.99–1.60(m,7H),1.55(d,J=7.2Hz ,3H),1.51–1.43(m,6H),1.42–1.11(m,6H),0.83–0.69(m,2H),0.69–0.54(m,2H).

[0638] Example 24: Compound I-24

[0639]

[0640] Step 1:

[0641] Triethylamine (363 mg, 3.5873 mmol) was added to a toluene (10 mL) solution of compound 24-1 (370 mg, 3.5867 mmol) and phthalic anhydride (530 mg, 3.5782 mmol). The reaction mixture was stirred overnight at 130 °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 compound 24-2 (620 mg, 2.658 mmol, yield 74.09%) as a white solid. LC-MS: 234.1 [M+1] + .

[0642] Step Two:

[0643] A solution of compound 24-2 (400 mg, 1.715 mmol) in dichloromethane (10 mL) was added with Dys-Martin oxidant (1.45 g, 3.42 mmol), and the reaction mixture was stirred for 2 hours at room temperature 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give compound 24-3 (320 mg, 1.384 mmol, yield 80.73%) as a white solid. LC-MS: 232.1 [M+1] + .

[0644] Step 3:

[0645] Sodium cyanoborohydride (180 mg, 2.864 mmol) was added to a dichloromethane (10 mL) solution of compound 2-1 (250 mg, 0.5821 mmol) and compound 24-3 (320 mg, 1.384 mmol). The reaction mixture was stirred overnight at room temperature 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 compound 24-4 as a yellow solid (130 mg, 0.2016 mmol, yield 34.64%). LC-MS: 645.2 [M+1] + .

[0646] Step Four:

[0647] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 24-4 (130 mg, 0.2016 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 24-5 (51 mg, 0.09909 mmol, yield 49.15%). LC-MS: 258.2 [M / 2+1] + .

[0648] Step 5:

[0649] N,N'-carbonyldiimidazole (50 mg, 0.30836 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 24-5 (51 mg, 0.09909 mmol), and 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 compound I-24 (31 mg, 0.05733 mmol, yield 57.86%) as a white solid. LC-MS: 540.9 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.89-7.83(m,1H),7.51(d,J=2.0Hz,1H),7.22–7.13(m,2H),6.81(d,J=2.0Hz,1H),5.75(q,J=7.2Hz,1H),5.46-5.34(m,1H), 4.63-4.56(m,1H),2.98-2.83(m,3H),2.50(d,J=11.7Hz,1H),2.02–1.67 (m,6H),1.54–1.42(m,9H),1.40–1.10(m,5H),0.99(s,3H),0.85(s,3H).

[0650] Example 25: Compound I-25

[0651]

[0652] Step 1:

[0653] Triethylamine (360 mg, 3.5577 mmol) was added to a toluene (20 mL) solution of compound 25-1 (500 mg, 3.4938 mmol) and phthalic anhydride (517 mg, 3.4904 mmol). The reaction mixture was stirred at 130 °C under argon protection for 5 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 compound 25-2 (780 mg, 2.8549 mmol, yield 81.71%) as a white solid. LC-MS: 273.8 [M+1] + .

[0654] Step Two:

[0655] N,N-diisopropylethylamine (380 mg, 2.9419 mmol) was added to a solution of compound 25-2 (400 mg, 1.4641 mmol) and trifluoromethanesulfonic anhydride (648 mg, 2.2969 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 0 °C under argon protection for 3 hours. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give compound 25-3 (425 mg, 1.049 mmol, yield 71.62%) as a white solid. LC-MS: 406.1 [M+1] + .

[0656] Step 3:

[0657] N,N-diisopropylethylamine (129 mg, 0.99868 mmol) was added to an acetonitrile (15 mL, 100 mass%) solution of compound 25-3 (425 mg, 1.049 mmol) and compound 2-1 (300 mg, 0.6985 mmol). The reaction mixture was stirred at 50 °C under argon protection for 6 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 25-4 (186 mg, 0.2717 mmol, yield 38.89%). LC-MS: 685.2 [M+1] + .

[0658] Step Four:

[0659] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 25-4 (186 mg, 0.2717 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 25-5 (130 mg, 0.2344 mmol, yield 86.29%). LC-MS: 278.2 [M / 2+1] + .

[0660] Step 5:

[0661] N,N'-carbonyldiimidazole (112 mg, 0.69072 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 25-5 (130 mg, 0.2344 mmol), and 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 white solid compound I-25-a (34 mg, 0.05856 mmol, yield 24.98%). LC-MS: 580.8 [M+1] + HPLC: Retention time: 7.682 min. 1 H NMR (400MHz, MeOD) δ7.92-7.83(m,1H),7.52(d,J=2.0Hz,1H),7.24–7.13(m,2H),6.81(d,J=2.0Hz,1H),5.76(q,J=7.0Hz,1H),5.47-5.33(m,1H ),4.58(d,J=8.0Hz,1H),3.55–3.35(m,3H),3.01–2.85(m,2H),2.04–1. 67(m,6H),1.54(d,J=7.2Hz,3H),1.49-1.42(m,6H),1.42–1.10(m,5H).

[0662] White solid compound I-25-b (32 mg, 0.05512 mmol, yield 23.51%) LC-MS: 580.8 [M+1] + HPLC: Retention time: 7.766 min. 1 H NMR(400MHz,MeOD)δ7.93-7.84(m,1H),7.52(d,J=2.0Hz,1H),7.24-7.14(m,2H), 6.81(d,J=2.0Hz,1H),5.76(q,J=7.0Hz,1H),5.46–5.33(m,1H),4.57(d,J=8.0Hz ,1H),3.53-3.45(m,1H),3.43–3.34(m,2H),3.13-3.04(m,1H),2.90–2.75(m,1H) ,2.05–1.67(m,6H),1.54(d,J=7.2Hz,3H),1.51-1.43(m,6H),1.42–1.11(m,5H).

[0663] Example 26: Compound I-26

[0664]

[0665] Step 1:

[0666] In a 100 mL round-bottom flask, compound 26-1 (60 mg, 0.39 mmol) and glacial acetic acid (5 mg) were added to a 15 mL solution of compound 2-1 (150 mg, 0.349 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (150 mg, 0.69 mmol) was added, and the reaction was stirred for another 16 hours. Water was then added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined extracts were washed successively with water and saturated brine. The extracts were 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) to give the target compound 26-2 (150 mg, 0.26 mmol) as a white solid. LC-MS: 564.8 [M+H] + .

[0667] Step Two:

[0668] In a 100 mL round-bottom flask, wet palladium on carbon (10%, 10 mg) was added to a methanol solution (10 mL) of compound 26-2 (90 mg, 0.16 mmol). The reaction mixture was then stirred under a hydrogen atmosphere for 2 hours until the reactants were consumed. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain the colorless oily target product compound 26-3 (85 mg, 0.15 mmol). LC-MS: 534.8 [M+H] + .

[0669] Step 3:

[0670] In a 100 mL round-bottom flask, triethylamine (100 mg, 0.988 mmol) and phenyl p-nitrochloroformate (66 mg, 0.32 mmol) were added sequentially to a 10 mL acetonitrile solution of compound 26-3 (85 mg, 0.15 mmol). The mixture was then stirred at room temperature for 3 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to give the target compound I-26 (40 mg, 0.071 mmol) as a white solid. LC-MS: 560.8 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ7.85(t,J=8.0Hz,1H),7.52(d,J=2.0Hz,1H),7.25–7.19(m,2H),7. 18-7.12(m,1H),7.02–6.98(m,1H),6.90(td,J=7.6,1.2Hz,1H),6.84–6.78(m,2H),5.82(q,J=7 .2Hz,1H),5.39(hept,J=6.4Hz,1H),4.57(d,J=8.0Hz,1H),4.38(d,J=14.4Hz,1H),3.95(d,J=1 4.4Hz,1H),2.01-1.65(m,6H),1.62(d,J=7.2Hz,3H),1.46(t,J=6.8Hz,6H),1.40–1.10(m,5H).

[0671] Example 27: Compound I-27

[0672]

[0673] Step 1:

[0674] In a 100 mL round-bottom flask, N,N-diisopropylethylamine (66 mg, 0.51 mmol) and 3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyltrifluoromethanesulfonate (106 mg, 0.284 mmol) were added sequentially to an acetonitrile solution of compound 27-1 (prepared according to compound 2-1). The reaction solution was heated to reflux and stirred for 48 hours. LC-MS monitoring showed that the starting material had been converted into the target product. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solid was 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 = 10:1 to 1:1) to obtain a colorless oily target compound 27-2 (80 mg, 0.116 mmol). LCMS: 689.3 [M+H] + .

[0675] Step Two:

[0676] In a 100 mL round-bottom flask, hydrazine hydrate (50%, 30 mg, 0.468 mmol) was added to an ethanol solution of compound 27-2 (77 mg, 0.11 mmol). The reaction mixture was heated to 50 °C and stirred for 2 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid crude product (60 mg, 0.1 mmol). The crude product 27-3 obtained did not require further purification and was used directly in the next reaction. LC-MS: 558.8 [M+H] + .

[0677] Step 3:

[0678] In a 100 mL round-bottom flask, N,N'-carbonyldiimidazole (55 mg, 0.34 mmol) was added to a tetrahydrofuran solution of crude product 27-3 (60 mg, 0.1074 mmol), and the mixture was heated to 60 °C and stirred for 3 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to give the target compound I-27 (50 mg, 0.085 mmol) as a white solid. LC-MS: 585.3 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ7.88(t,J=8.0Hz,1H),7.53(d,J=2.0Hz,1H),7.27–7.15(m,2H),6.82(d,J=2.0Hz,1H),5.70(q,J=7.2 Hz,1H),5.41(p,J=6.8Hz,1H),4.66(d,J=8.8Hz,1H),3.64–3.47(m,3H),3.22-3.08(m,1H),2.21–1.73(m,7H),1.65–1.43(m,11H).

[0679] Example 28: Compound I-28

[0680]

[0681] Step 1:

[0682] To a toluene (10 mL) solution of compound 28-1 (prepared according to the method of compound 2-1, 300 mg, 0.6348 mmol), diphenyl azidophosphate (275 mg, 0.99927 mmol) and triethylamine (120 mg, 1.1859 mmol) were added. The reaction mixture was stirred at 100 °C under argon protection for 2 hours. After cooling to room temperature, sodium hydroxide (5 mL, 10 mmol, 2 mmol / mL) and tetrahydrofuran (5 mL) were added. The reaction mixture was stirred overnight under argon protection at room temperature. 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 compound 28-2 as a white solid (202 mg, 0.4554 mmol, yield 71.74%). LC-MS: 426.9 [M-NH2] + .

[0683] Step Two:

[0684] To a solution of compound 28-2 (202 mg, 0.4554 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (240 mg, 0.6431 mmol) in acetonitrile (10 mL), N,N-diisopropylethylamine (115 mg, 0.89030 mmol) was added. 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 compound 28-3 (210 mg, 0.3150 mmol, yield 69.17%) as a yellow solid. LC-MS: 334.2 [M / 2+1] + .

[0685] Step 3:

[0686] Hydrazine hydrate (0.5 mL) was added to a 3 mL ethanol solution of compound 28-3 (210 mg, 0.3150 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 28-4 (135 mg, 0.2516 mmol, yield 79.87%). LC-MS: 269.0 [M / 2+1] + .

[0687] Step Four:

[0688] N,N'-carbonyldiimidazole (80 mg, 0.49337 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 28-4 (135 mg, 0.2516 mmol), and 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 compound I-28 (51 mg, 0.09065 mmol, yield 36.03%) as a white solid. LC-MS: 562.8 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.91–7.74(m,1H),7.51(d,J=2.0Hz,1H),7.23–7.12(m,2H),6.79(d,J=2.0Hz,1H),5.70(q,J=7.2Hz,1H),5.45- 5.34(m,1H),4.67(d,J=8.0Hz,1H),3.67–3.45(m,3H),3.19-3.08(m,1H),2.25-2.14(m,1H),1.92–1.50(m,9H),1.49-1.41(m,12H).

[0689] Example 29: Compound I-29

[0690]

[0691] Step 1:

[0692] To a solution of compound 29-1 (5.0 g, 16 mmol) and methylamine hydrochloride (2.1 g, 31 mmol) in N,N-dimethylformamide (50 mL), HATU (9.15 g, 24.1 mmol) and N,N-diisopropylethylamine (6.19 g, 47.9 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 (150 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 a yellow oily compound 29-2 (4.55 g, 14.1 mmol, yield 87%). LC-MS: 224.1 [M-100+1] + .

[0693] Step Two:

[0694] Trifluoroacetic acid (2 mL) was added to a solution of compound 29-2 (4.55 g, 14.1 mmol) in dichloromethane (20 mL), and the reaction mixture was stirred at 50 °C under argon protection for 2 hours. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (150 mL x 3), and the organic layers were combined. The mixture was washed with saturated brine (50 mL), and the combined organic phases were dried and concentrated to obtain the crude product. The crude product was purified by column chromatography to give a yellow solid compound 29-3 (2.58 g, 11.6 mmol, yield 82.1%). LC-MS: 224.1 [M+1] + .

[0695] Step 3:

[0696] N,N-diisopropylethylamine (1.29 g, 9.99 mmol) was added to a solution of compound 29-3 (1.1 g, 4.9 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (1.9 g, 5.1 mmol) in acetonitrile (15 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 compound 29-4 (580 mg, 1.299 mmol, yield 26%) as a yellow solid. LC-MS: 447.0 [M+1] + .

[0697] Step Four:

[0698] Hydrazine hydrate (1 mL) was added to a 5 mL ethanol solution of compound 29-4 (580 mg, 1.299 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 29-5 (300 mg, 0.9485 mmol, yield 73.00%). LC-MS: 317.1 [M+1] + .

[0699] Step 5:

[0700] N,N'-carbonyldiimidazole (458 mg, 2.8245 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 29-5 (300 mg, 0.9485 mmol), and 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 compound 29-6 (278 mg, 0.8122 mmol, yield 85.63%) as a yellow solid. LC-MS: 342.8 [M+1] + .

[0701] Step Six:

[0702] Pd / C (30 mg) was added to a methanol (30 mL) solution of compound 29-6 (278 mg, 0.8122 mmol), and the reaction mixture was stirred for 2 hours under hydrogen protection. The reaction mixture was filtered and concentrated to give a white solid compound 29-7 (250 mg, 0.8005 mmol, yield 98.57%). LC-MS: 312.9 [M+1] + .

[0703] Step Seven:

[0704] To a solution of compound 29-7 (250 mg, 0.8005 mmol) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic acid (257 mg, 0.9988 mmol) in N,N-dimethylformamide (5 mL), HATU (500 mg, 1.3150 mmol) and triethylamine (202 mg, 1.9962 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 29-8 (352 mg, 0.6381 mmol, yield 79.72%) as a yellow solid. LC-MS: 552.3 [M+1] + .

[0705] Step 8:

[0706] A solution of compound 29-8 (352 mg, 0.6381 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 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 obtain the residue, which was purified by column chromatography to give a yellow solid, compound 29-9 (288 mg, 0.6379 mmol, yield 99.96%). LC-MS: 452.3 [M+1] +.

[0707] Step Nine:

[0708] To a solution of compound 29-9 (288 mg, 0.6379 mmol) and 2-isopropylpyrazole-3-carboxylic acid (120 mg, 0.77836 mmol) in N,N-dimethylformamide (5 mL), HATU (500 mg, 1.3150 mmol) and triethylamine (128 mg, 1.2649 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-29 (255 mg, 0.4339 mmol, yield 68.02%) as a white solid. LC-MS: 588.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.55–7.44(m,3H),7.28–7.18(m,1H),7.04(d,J=7.6Hz,1H ),6.81(d,J=2.0Hz,1H),5.49–5.29(m,1H),5.03(t,J=8.0Hz,1H),4.52(d,J=8. 4Hz,1H),3.84–3.66(m,2H),3.55–3.37(m,2H),3.28–3.19(m,1H),2.98-2.89(m ,1H),2.69(s,3H),2.01–1.63(m,6H),1.43(t,J=6.8Hz,6H),1.38–1.09(m,5H).

[0709] Example 30: Compound I-30

[0710]

[0711] Step 1:

[0712] To a solution of compound 30-1 (5.0 g, 16 mmol) and methylamine hydrochloride (2.16 g, 31 mmol) in N,N-dimethylformamide (50 mL), HATU (9.15 g, 24.1 mmol) and N,N-diisopropylethylamine (6.19 g, 47.9 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 a yellow oily compound 30-2 (3.4 g, 11 mmol, yield 65%). LC-MS: 223.9 [M-100+1] + .

[0713] Step Two:

[0714] Trifluoroacetic acid (2 mL) was added to a solution of compound 30-2 (3.4 g, 11 mmol) in dichloromethane (20 mL), and the reaction mixture was stirred at 50 °C under argon protection for 2 hours. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 30-3 (2.1 g, 9.4 mmol, yield 89%). LC-MS: 224.1 [M+1] + .

[0715] Step 3:

[0716] To a solution of compound 30-3 (1.5 g, 6.7 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (2.5 g, 6.7 mmol) in acetonitrile (15 mL), N,N-diisopropylethylamine (1.73 g, 13.4 mmol) was added. 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 compound 30-4 (1.02 g, 2.28 mmol, yield 34%) as a yellow solid. LC-MS: 447.0 [M+1] + .

[0717] Step Four:

[0718] Hydrazine hydrate (1.5 mL) was added to a 5 mL ethanol solution of compound 30-4 (1.02 g, 2.28 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 30-5 (708 mg, 2.238 mmol, yield 98.0%). LC-MS: 317.2 [M+1] + .

[0719] Step 5:

[0720] To a solution of compound 30-5 (708 mg, 2.238 mmol) in tetrahydrofuran (15 mL), N,N'-carbonyldiimidazole (1.08 g, 6.66 mmol) was added, and 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 30-6 (550 mg, 1.607 mmol, yield 71.78%). LC-MS: 343.1 [M+1] + .

[0721] Step Six:

[0722] Pd / C (70 mg) was added to a methanol (30 mL) solution of compound 30-6 (550 mg, 1.607 mmol), and the reaction mixture was stirred overnight under hydrogen protection. The reaction mixture was filtered and concentrated to give a white solid, compound 30-7 (480 mg, 1.537 mmol, yield 95.66%). LC-MS: 312.9 [M+1] + .

[0723] Step Seven:

[0724] To a solution of compound 30-7 (150 mg, 0.4803 mmol) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic acid (140 mg, 0.5441 mmol) in N,N-dimethylformamide (5 mL), HATU (300 mg, 0.7890 mmol) and triethylamine (101 mg, 0.99812 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 30-8 (160 mg, 0.2901 mmol, yield 60.39%) as a yellow solid. LC-MS: 551.8 [M+1] + .

[0725] Step 8:

[0726] A solution of compound 30-8 (160 mg, 0.2901 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 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 obtain the residue, which was purified by column chromatography to give a yellow solid, compound 30-9 (130 mg, 0.2879 mmol, yield 99.26%). LC-MS: 451.8 [M+1] + .

[0727] Step Nine:

[0728] To a solution of compound 30-9 (130 mg, 0.2879 mmol) and 2-isopropylpyrazole-3-carboxylic acid (45 mg, 0.29189 mmol) in N,N-dimethylformamide (5 mL), HATU (190 mg, 0.49970 mmol) and triethylamine (60 mg, 0.59294 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-30 (152 mg, 0.2586 mmol, yield 89.83%) as a white solid. LC-MS: 587.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.54-7.45(m,3H),7.27-7.20(m,1H),7.03(d,J=7.6Hz,1H ),6.81(d,J=2.0Hz,1H),5.45-5.33(m,1H),5.03(t,J=8.0Hz,1H),4.52(d,J=8. 4Hz,1H),3.84–3.66(m,2H),3.56–3.38(m,2H),3.28-3.19(m,1H),2.98-2.89(m ,1H),2.69(s,3H),2.03–1.66(m,6H),1.43(t,J=7.2Hz,6H),1.38–1.13(m,5H).

[0729] Example 31: Compound I-31-A, Compound I-31-B

[0730]

[0731] Step 1:

[0732] At room temperature, lithium hydroxide monohydrate (149 mg, 3.55 mmol) was added to a solution of compound 1-2 (798 mg, 1.77 mmol) in water (2 mL) and MeOH (1 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, 1 M HCl was added to adjust the pH of the reaction mixture to 3-4, and the aqueous phase was extracted three times with EtOAc. The organic phase was dried over Na2SO4 and concentrated to give a colorless oily compound 31-1 (730 mg, 1.73 mmol, 98% yield). LC-MS: [M-Boc+1] + 367.8.

[0733] Step Two:

[0734] Under argon protection, DPPA (974 mg, 3.54 mmol) and Et3N (358 mg, 3.54 mmol) were added to a toluene (30 mL) solution of compound 31-1 (730 mg, 1.728 mmol). The reaction mixture was stirred at 120 °C for 2 hours, then cooled to room temperature. 2 M NaOH (5 mL) and THF (5 mL) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily compound 31-2 (432 mg, 1.10 mmol, yield 64%). LC-MS: [M+1] + 394.0.

[0735] Step 3:

[0736] At room temperature, [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyl]trifluoromethanesulfonate (448 mg, 1.20 mmol) and DIEA (258 mg, 2.00 mmol) were added to a 5 mL acetonitrile solution (400 mg, 1.01 mmol) of compound 31-2. The reaction mixture was stirred overnight at 50 °C. The reaction mixture was concentrated and purified by column chromatography to give a colorless oily compound 31-3 (290 mg, 0.47 mmol, yield 46%). LC-MS: [M+1] + 617.3.

[0737] Step Four:

[0738] At room temperature, hydrazine hydrate (0.5 mL) was added to a 5 mL solution of compound 31-3 (270 mg, 0.44 mmol) in ethanol. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was concentrated and purified by column chromatography to give a colorless oily compound 31-4 (210 mg, 0.43 mmol, 99% yield). LC-MS: [M+1] + 487.9.

[0739] Step 5:

[0740] At room temperature, CDI (126 mg, 0.78 mmol) was added to a THF (5 mL) solution of compound 31-4 (190 mg, 0.39 mmol). The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography to give compound 31-5 (86 mg, 0.17 mmol, yield 43%) as a white powder. LC-MS: [M-Boc+1] + 412.9.

[0741] Step Six:

[0742] TFA (0.5 mL) was added to a solution of compound 31-5 (66 mg, 0.13 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give a yellow oily compound 31-6 (49 mg, 0.12 mmol, yield 92%). LC-MS: [M+1] + 412.8.

[0743] Step Seven:

[0744] At room temperature, HATU (87 mg, 0.23 mmol) and DIPEA (47 mg, 0.36 mmol) were added to a DMF (2 mL) solution of compound 31-6 (20 mg, 0.05 mmol) and 2-cyclopentylpyrazole-3-carboxylic acid (26 mg, 0.14 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a white powder crude product (20 mg, 0.03 mmol, yield 72%). The crude product was resolved under the following conditions: Waters Preparative Liquid Chromatography (column...) Prep C18 5μm OBD TM (30*150mm), mobile phase: A%: Water (containing 1% FA): 55%, B%: ACN (containing 1% FA): 45%, 37 mL / min, to obtain compound I-31-A, with peak times of 10.03 min. LC-MS: [M+1] + 574.8. 1 HNMR(400MHz,MeOD)δ7.87-7.83(m,1H),7.74-7.67(m,1H),7.20-7.17(m,1H),6.75(d,J=2.0Hz,1H),6 .44(d,J=2.4Hz,1H),5.72–5.67(m,1H),4.80-4.71(m,2H),4.67(d,J=4.0Hz,1H),3.59–3.52(m,2H),3 20–3.11 (m, 1H), 2.24–2.15 (m, 3H), 2.10–2.01 (m, 3H), 1.95–1.88 (m, 3H), 1.84–1.81 (m, 2H), 1.78–1.70 (m, 3H), 1.54 (d, J = 8.0 Hz, 3H), 1.36–1.31 (m, 2H), 1.27–1.19 (m, 3H). Compound I-31-B, elution time 10.45 min. LC-MS: [M+1] +574.8. 1 H NMR(400MHz,MeOD)δ7.87-7.83(m,1H),7.73-7.67(m,1H),7.20-7.17(m,1H),6.75(d,J=2.0Hz ,1H),6.44(d,J=2.4Hz,1H),5.72–5.67(m,1H),4.80-4.71(m,2H),4.67(d,J=4.0Hz,1H),3.59 –3.52(m,2H),3.20-3.11(m,1H),2.24–2.14(m,3H),2.09–2.02(m,3H),1.98–1.88(m,3H),1.8 4–1.79(m,2H),1.77–1.74(m,3H),1.54(d,J=8.0Hz,3H),1.36–1.31(m,2H),1.24–1.19(m,3H).

[0745] Example 32: Compound I-32

[0746]

[0747] Step 1:

[0748] At room temperature, HATU (87 mg, 0.23 mmol) and DIPEA (47 mg, 0.36 mmol) were added to a DMF (2 mL) solution of compound 31-6 (29 mg, 0.07 mmol) and 1-cyclopentylpyrazole-3-carboxylic acid (25 mg, 0.14 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give compound I-32 (20 mg, 0.03 mmol, 50% yield) as a white powder. LC-MS: [M+1] + 574.8. 1HNMR(400MHz,MeOD)δ7.89-7.83(m,1H),7.50(d,J=2.0Hz,1H),7.28–7.13(m,2H),6.80- 6.75(m,1H),5.72-5.67(m,1H),5.54-5.46(m,1H),4.68-4.56(m,1H),3.66–3.46(m,3H) ,3.19-3.11(m,1H),2.23-2.19(m,1H),2.14–2.01(m,3H),1.94-1.91(m,4H),1.84-1.76 (m,3H),1.74–1.67(m,2H),1.54(d,J=8.0Hz,3H),1.35–1.31(m,3H).1.28–1.16(m,3H).

[0749] Example 33: Compounds I-33A, I-33B

[0750]

[0751] Step 1:

[0752] Compound 33-1 (18.00 g, 106.44 mmol), (R)-tert-butylsulfonylimide (19.35 g, 159.66 mmol), cesium carbonate (69.39 g, 212.88 mmol), and dichloromethane (720 mL) were added to a 1 L three-necked flask. The mixture was heated to reflux and reacted overnight. After the reaction was complete as detected by LC-MS, the reaction was quenched with water (100 mL), extracted with dichloromethane (100 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product, compound 33-2 (28.68 g, 105.33 mmol), a brownish-red solid. LC-MS: 273.2 [M+1] + .

[0753] Step Two:

[0754] Compound 33-2 (28.68 g, 105.33 mmol), iron powder (29.42 g, 526.64 mmol), ammonium chloride (45.02 g, 842.64 mmol), ethanol (430 mL), and water (430 mL) were added to a 1 L three-necked flask. The mixture was heated to reflux and reacted overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth, evaporated to dryness, extracted with ethyl acetate (200 mL x 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give the crude product, compound 33-3 (20.00 g, 82.54 mmol), a brownish-red solid. LC-MS: 243.1 [M+1] + .

[0755] Step 3:

[0756] Compound 33-3 (20.00 g, 82.54 mmol), di-tert-butyl dicarbonate (54.00 g, 247.62 mmol), DMAP (1.01 g, 8.25 mmol), and tetrahydrofuran (500 mL) were added to a 1 L three-necked flask. The mixture was heated to reflux and reacted overnight. After the reaction was complete, the mixture was extracted with water (100 mL) and ethyl acetate (200 mL x 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column separation (PE:EA = 20:1) yielded a brownish-red solid compound 33-4 (22.27 g, 65.11 mmol). LC-MS: 287.1 [M-56+1] + .

[0757] Step Four:

[0758] Under nitrogen protection, compound 33-4 (5.00 g, 14.60 mmol) and THF (50 mL) were added sequentially to a 100 mL three-necked flask at 0 °C. Ethyl magnesium bromide (15 mL, 3 M) was then added dropwise to the system. After 30 mins, the mixture was brought to room temperature and reacted overnight. LC-MS was monitored until the reaction was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a brownish-yellow oily compound 33-5 (4.48 g, 12 mmol). LC-MS: 373.2 [M+1] + .

[0759] Step 5:

[0760] Under nitrogen protection, compound 33-5 (4.48 g, 12 mmol), I2 (4.0 g, 15.76 mmol), THF (117 mL), and H2O (23 mL) were added sequentially to a 500 mL three-necked flask, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with water (200 mL) and ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to column chromatography (DCM:MeOH = 15:1) to give a yellow oily compound 33-6 (2.72 g, 10.1 mmol). LC-MS: 252.2 [M-NH2+1] + .

[0761] Step Six:

[0762] At room temperature, tert-butyl N-(2-oxocyclopentyl)carbamate (450 mg, 2.26 mmol) and one drop of glacial acetic acid were added to a MeOH solution of compound 33-6 (500 mg, 1.86 mmol) in 5 mL of MeOH. The reaction was stirred at room temperature for 1 h. Then, NaBH3CN (600 mg, 9.55 mmol) was added at room temperature, and the reaction was stirred for another 1 h at room temperature. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and concentrated to give the residue, which was purified by column chromatography to give a colored oily compound 33-7 (500 mg, 1.11 mmol, yield 59%). LC-MS: [M+1] + 452.0.

[0763] Step Seven:

[0764] TFA (0.5 mL) was added to a 10 mL solution of CH₂Cl₂ containing 450 mg (1.00 mmol) of compound 33-7 at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give a yellow oily compound 33-8 (200 mg, 0.80 mmol, 80% yield). LC-MS: [M+1] + 252.0.

[0765] Step 8:

[0766] At room temperature, CDI (230 mg, 1.42 mmol) was added to a THF (5 mL) solution of compound 33-8 (180 mg, 0.72 mmol). The reaction was stirred at 50 °C for 2 hours. The reaction solution was concentrated and purified by column chromatography to give a colorless oily compound 33-9 (150 mg, 0.54 mmol, yield 76%). LC-MS: [M+1] + 277.9.

[0767] Step Nine:

[0768] At room temperature, EDCI (518 mg, 2.70 mmol) was added to a pyridine (5 mL) solution of compound 33-9 (130 mg, 0.47 mmol) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic acid (167 mg, 0.65 mmol). The reaction was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with EtOAc (100 mL x 3). The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give compound 33-10 (115 mg, 0.22 mmol, yield 47%) as a colorless oil. LC-MS: [M-Boc+1] + 460.8.

[0769] Step 10:

[0770] TFA (0.5 mL) was added to a 5 mL solution of compound 33-10 (90 mg, 0.17 mmol) in CH₂Cl₂ at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give a yellow oily compound 33-11 (60 mg, 0.14 mmol, 83% yield). LC-MS: [M+1] + 416.9.

[0771] Step Eleven:

[0772] At room temperature, HATU (60 mg, 0.16 mmol) and DIPEA (30 mg, 0.23 mmol) were added to a DMF (2 mL) solution of compound 33-11 (40 mg, 0.10 mmol) and 2-isopropylpyrazole-3-carboxylic acid (20 mg, 0.13 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with EtOAc and washed three times with water. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily crude product (20 mg, 0.04 mmol, yield 38%). The crude product was further purified by Waters preparative HPLC. Prep C18 5μm OBD TM (30*150mm), mobile phase: A%: Water (containing 1% FA): 50%, B%: ACN (containing 1% FA): 50%, 37mL / min, separation conditions obtained:

[0773] Compound I-33-A elutes at 8.22 min. LC-MS: [M+1] + 552.9. 1H NMR(400MHz,MeOD)δ7.85(t,J=8.0Hz,1H),7.52(d,J=2.0Hz,1H),7.24-7.17(m,2H),6.80(d,J=2.0Hz,1H), 5.43-5.35(m,2H),4.80-4.74(m,1H),3.96–3.94(m,1H),3.84-3.82(m,1H),2.23–2.19(m,1H),2.09-2.03(m ,2H),2.01-1.95(m,1H),1.94-1.92(m,2H),1.84-1.82(m,2H),1.74-1.67(m,2H),1.65-1.60(m,3H),1.59- 1.50(m,1H),1.48-1.45(m,3H),1.36-1.31(m,6H),1.27-1.17(m,2H),1.02-0.99(m,2H),0.94-0.90(m,1H).

[0774] The elution time of compound I-33-B was 8.60 min. LC-MS: [M+1] + 552.9. 1 H NMR (400MHz, MeOD) δ7.84(t,J=8.4Hz,1H),7.52(d,J=2.0Hz,1H),7.28-7.16(m,2H),6.80(d,J=2.0H z,1H),5.51–5.26(m,2H),4.78-4.66(m,1H),4.18-4.10(m,1H),3.94-3.84(m,1H),2.33–2.13(m,2H ),2.13–2.00(m,2H),1.94(s,1H),1.82(s,1H),1.78–1.69(m,1H),1.63-1.54(m,2H),1.53–1.43(m, 3H),1.42-1.36(m,5H),1.35-1.31(m,6H),1.29–1.14(m,2H),1.02-0.97(m,1H),0.94-0.90(m,2H).

[0775] Example 34: Compounds I-34-A, I-34-B, I-34-C, I-34-D

[0776]

[0777] Step 1:

[0778] In a 100 mL three-necked flask under argon protection, a borane tetrahydrofuran solution (1.0 mmol / mL, 1.8 mL, 1.8 mmol) was slowly added dropwise to a 0.2 mL anhydrous tetrahydrofuran solution of compound 34-1 (100 mg, 0.349 mmol). The reaction mixture was then heated to 70 °C and stirred for 16 hours. After cooling to room temperature, LC-MS monitoring showed that the starting material had been completely consumed. The reaction mixture was then cooled in an ice-water bath, and methanol was added dropwise to quench the reaction. The mixture was then heated to reflux and stirred for 30 minutes, then cooled to room temperature and concentrated under reduced pressure to obtain the crude product compound 34-2 (90 mg, 0.63 mmol). The crude product did not require further purification and was used directly in the next reaction. LC-MS: 144.0 [M+1] + .

[0779] Step Two:

[0780] In a 100 mL round-bottom flask, triethylamine (65 mg, 0.64 mmol) and phthalic anhydride (90 mg, 0.6 mmol) were added sequentially to a 15 mL toluene solution of compound 34-2 (85 mg, 0.6 mmol). The mixture was heated to reflux and stirred for 3 hours until the starting material was consumed. The reaction solution was cooled to room temperature, quenched with water, and 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 = 1:0–1:1) to give a colorless oily compound 34-3 (85 mg, 0.15 mmol). LC-MS: 273.8 [M+1] + .

[0781] Step 3:

[0782] In a 100 mL three-necked flask, 209 mg of Dysmart oxidant was added sequentially to a 10 mL solution of compound 34-3 (85 mg, 0.15 mmol) in dichloromethane, and the mixture was stirred at room temperature for 2 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 = 1:0–1:1) to give a white solid compound 34-4 (90 mg, 0.33 mmol). LC-MS: 271.8 [M+1] + .

[0783] Step Four:

[0784] In a 100 mL round-bottom flask, compound 2-1 (90 mg, 0.21 mmol) was added to a dichloromethane solution of compound 34-4 (90 mg, 0.33 mmol), and the mixture was stirred at room temperature for 2 hours. Then, sodium triacetylborohydride (145 mg, 0.68 mmol) was added in portions to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. 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 to obtain the crude product. The crude product was purified by column chromatography to give a colorless oily compound 34-5 (110 mg, 0.16 mmol). LC-MS: 684.7 [M+1] + .

[0785] Step 5:

[0786] In a 100 mL round-bottom flask, hydrazine hydrate (80%, 30 mg) was added dropwise to a 15 mL ethanol solution of compound 34-5 (110 mg, 0.16 mmol). The mixture was then heated to reflux and stirred for 3 hours. After cooling to room temperature, the solution was concentrated under reduced pressure, water was added, 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 to obtain the crude product. The crude product was purified by column chromatography to give a white solid, compound 34-6 (60 mg, 0.108 mmol). LC-MS: 554.8 [M+1] + .

[0787] Step Six:

[0788] In a 100 mL round-bottom flask, triethylamine (40 mg, 0.40 mmol) and phenyl p-nitrochloroformate (36 mg, 0.18 mmol) were added dropwise to a solution of compound 34-6 (60 mg, 0.16 mmol) in dichloromethane (15 mL). The mixture was stirred at room temperature for 3 hours until the reactants were consumed. Water was added to quench the reaction mixture, and the solution 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 to obtain the target product as a white solid. Compounds I-34-A, I-34-B, I-34-C, and I-34-D were prepared by chiral resolution.

[0789] Compound I-34-A (6 mg), LC-MS: 580.8 [M+1] + RT = 2.437 mins. 11H NMR (400 MHz, Methanol-d4) δ 7.86 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.17 - 7.13 (m, 1H), 7.13 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 5.75 (q, J = 7.2 Hz, 1H), 5.39 (p, J = 6.4 Hz, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.08 – 3.98 (m, 1H), 3.26 – 3.17 (m, 1H), 2.93 - 2.82 (m, 1H), 2.16 – 1.88 (m, 4H), 1.87 - 1.77 (m, 3H), 1.76 - 1.67 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.47 (t, J = 6.0 Hz, 6H), 1.41 – 1.13 (m, 5H).

[0790] Compound I-34-B (4 mg), LC-MS: 580.8 [M+1] + . RT = 2.677 mins. 1 1H NMR (400 MHz, Methanol-d4) δ 7.86 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.21 – 7.14 (m, 2H), 6.80 (d, J = 2.0 Hz, 1H), 5.76 (q, J = 6.8 Hz, 1H), 5.40 (p, J = 6.8 Hz, 1H), 4.56 (d, J = 8.4 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.30 - 3.22 (m, 1H), 2.97 - 2.87 (m, 1H), 2.13 - 2.04 (m, 1H), 2.02 - 1.88 (m, 3H), 1.87 - 1.77 (m, 3H), 1.76 - 1.68 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.50 - 1.43 (m, 6H), 1.41 – 1.12 (m, 5H).

[0791] Compound I-34-C (2 mg), LC-MS: 581.2 [M+1] + . RT = 9.162 mins. 11H NMR (400 MHz, Methanol-d4) δ 7.86 (t, J = 8.2 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.12 (s, 1H), 6.80 (d, J = 2.1 Hz, 1H), 5.78 - 5.71 (m, 1H), 5.42–5.37 (m, 1H), 4.56 (d, J = 8.0 Hz, 1H), 4.09–4.00 (m, 1H), 3.26 - 3.17 (m, 1H), 2.90 - 2.84 (m, 1H), 2.10–1.90 (m, 6H), 1.87 - 1.78 (m, 3H), 1.77 - 1.69 (m, 1H), 1.65 - 1.57 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.47 (t, J = 6.4 Hz, 6H), 1.21 - 1.15 (m, 2H).

[0792] Compound I-34-D (3 mg was obtained), LC-MS: 581.1 [M+1] + . RT = 9.257 mins. 1 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.86 (t, J = 8.3 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 10.4, 5.8 Hz, 2H), 6.81 (d, J = 2.0 Hz, 1H), 5.76 (q, J = 7.1 Hz, 1H), 5.47–5.34 (m, 2H), 4.56 (d, J = 8.3 Hz, 1H), 4.02 (s, 1H), 2.92 (d, J = 12.8 Hz, 1H), 2.13–1.89 (m, 4H), 1.82 (d, J = 10.5 Hz, 3H), 1.73 (d, J = 11.9 Hz, 1H), 1.62 (s, 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.47 (dd, J = 6.7, 5.7 Hz, 6H), 1.27–1.13 (m, 3H).

[0793] Example 35:

[0794]

[0795] Step 1:

[0796] At -78°C, a solution of compound 35-1 (10.96 g, 40.0 mmol) in tetrahydrofuran (50.0 mL) was added and stirred for 3 hours, followed by the addition of iodomethane (5.64 g, 40.0 mmol) and stirring for another 3 hours. LC-MS was performed until the reaction was complete. The mixture was then brought to room temperature, quenched with water, and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography as a yellow liquid, yielding compound 35-2 (10.33 g, 0.29 mmol, 89.4% yield). LC-MS: 289.7 [M+1] + .

[0797] Step Two:

[0798] In a 100 mL round-bottom flask, tert-butyl carbamate (0.97 g, 8.3 mmol), cesium carbonate (3.38 g, 10.4 mmol), Pd2(dba)3 (0.63 g, 0.69 mmol), and X-PhOS (0.33 g, 0.69 mmol) were added sequentially to a 50 mL toluene solution of compound 35-2 (2.0 g, 6.9 mmol). The reaction mixture was placed under argon protection, heated to reflux, and stirred for 16 hours. LC-MS monitoring showed that the starting material had been consumed. Water was added to quench the reaction mixture, 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–2:1) to give the target compound 35-3 (2.0 g, 6.15 mmol) as a brown oil. LC-MS: 269.9 [M- t Bu+1] + .

[0799] Step 3:

[0800] In a 100 mL round-bottom flask, ethyl hydrochloride solution (1.0 mmol / mL, 5 mL, 5 mmol) was slowly added dropwise to a 25 mL solution of compound 35-3 (1.1 g, 3.4 mmol) in dichloromethane, which was placed in an ice-water bath. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. TLC (petroleum ether: ethyl acetate = 4:1) showed that the starting material had been completely consumed. Petroleum ether (30 mL) was added dropwise to the reaction mixture, followed by filtration. The filter cake was washed with petroleum ether and dried. A brown solid crude product, compound 35-4 (850 mg, 3.24 mmol), was obtained. The crude product was used directly in the next reaction without further purification. LC-MS: 226.2 [M+1] + .

[0801] Step Four:

[0802] In a 100 mL round-bottom flask, ethyl 2-(4-amino-3-fluorophenyl)-2-methylpropionate hydrochloride (0.9 g, 3.0 mmol), triethylamine (0.87 g, 8.6 mmol), and HATU (1.96 g, 5.15 mmol) were added sequentially to a 20 mL solution of N,N-dimethylformamide containing compound 35-4 (1.06 g, 4.12 mmol). The reaction mixture was then placed at room temperature and stirred for 16 hours. LC-MS was used to monitor the consumption 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1) to give the target compound 35-5 (1.2 g, 2.6 mmol) as a brown oil. LC-MS: 408.8 [M-] t Bu+1] + .

[0803] Step 5:

[0804] In a 100 mL round-bottom flask, a solution of ethyl hydrochloride (1.0 mmol / mL, 5 mL, 5 mmol) was slowly added dropwise to a 25 mL solution of compound 35-5 (1.1 g, 2.43 mmol) in dichloromethane, which was placed in an ice-water bath. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. TLC (petroleum ether:ethyl acetate = 4:1) showed that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a crude product, compound 35-6 (950 mg, 2.4 mmol), as a brown solid. The crude product was used directly in the next reaction without further purification. LCMS: 364.9 [M+1] + .

[0805] Step Six:

[0806] In a 100 mL round-bottom flask, compound 35-6 (0.4 g, 0.99 mmol), triethylamine (0.25 g, 2.51 mmol), and HATU (0.57 g, 1.5 mmol) were added sequentially to a 15 mL solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.185 g, 1.2 mmol) in N,N-dimethylformamide. The reaction mixture was then placed at room temperature and stirred for 16 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1) to give the target compound 35-7 (0.62 g, 1.28 mmol) as a brown oil. LC-MS: 500.8 [M+1] + .

[0807] Step Seven:

[0808] Sodium hydroxide (60 mg, 1.5 mmol) was added to a tetrahydrofuran / water solution (10 mL / 2 mL) of compound 35-7 (0.5 g, 0.99 mmol). The reaction mixture was stirred for 5 hours. LC-MS monitoring showed that the starting material was completely consumed. The flask was placed in an ice-water bath, and dilute hydrochloric acid was added dropwise to quench the reaction and adjust the pH of the reaction solution to 3–4. The mixture was then 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 give a brown, oily crude product, compound 35-8 (0.4 g, 0.84 mmol). LC-MS: 472.8 [M+1] + .

[0809] Step 8:

[0810] In a 100 mL round-bottom flask, triethylamine (92 mg, 0.91 mmol) and diphenyl azide phosphate (DPPA) (272 mg, 1.11 mmol) were added sequentially to a 20 mL anhydrous toluene solution of compound 35-8 (0.3 g, 0.63 mmol). The reaction mixture was then placed under an argon atmosphere and heated to reflux with stirring for 3 hours. The reaction mixture was then cooled to room temperature, and 1,4-dioxane (2 mL) and dioxane chloride solution (4 M, 1 mL) were added sequentially. The mixture was heated to 50 °C and stirred for 16 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction mixture was cooled in an ice-water bath, and the pH was adjusted to 12-14 by adding saturated sodium hydroxide solution. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The extract was 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 = 1:0–10:1) to give a white solid compound 35-9 (260 mg, 0.58 mmol). LC-MS: 426.9 [M-NH2+1] + .

[0811] Step Nine:

[0812] In a 100 mL round-bottom flask, N,N-diisopropylethylamine (150 mg, 1.16 mmol) and 3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyltrifluoromethanesulfonate (219 mg, 0.58 mmol) were added sequentially to a 20 mL acetonitrile solution of compound 35-9 (260 mg, 0.58 mmol). The reaction mixture was heated to reflux and stirred for 36 hours. LC-MS monitoring showed that the starting material had been converted into the target product. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 obtain the brown oily target product compound 35-10 (180 mg, 0.27 mmol), which was directly used in the next reaction. LC-MS: 333.9 [M / 2+1] + .

[0813] Step 10:

[0814] In a 100 mL round-bottom flask, hydrazine hydrate (50%, 30 mg, 0.29 mmol) was added sequentially to an anhydrous ethanol solution of compound 35-10 (140 mg, 0.21 mmol). The mixture was then heated to reflux and stirred for 3 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in water. The solution was extracted three times with ethyl acetate, and the combined extracts were washed successively with water and saturated brine. The extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, a white solid compound 35-11 (130 mg, 0.23 mmol). LC-MS: 269.0 [M / 2+H] + .

[0815] Step Eleven:

[0816] In a 100 mL round-bottom flask, triethylamine (65 mg, 0.64 mmol) and phenyl p-nitrochloroformate (45 mg, 0.22 mmol) were added sequentially to an anhydrous acetonitrile solution of compound 35-11 (110 mg, 0.205 mmol), and the mixture was stirred at room temperature for 3 hours. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was 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 = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to obtain the crude product. The crude product was further prepared to give a white solid compound I-35 (70 mg, 0.12 mmol). LC-MS: 563.2 [M+H] + . 1 HNMR (400MHz, Methanol-d4) δ7.77(t,J=8.4Hz,1H),7.52(d,J=2.0Hz,1H),7.20–7.17(m,1H),7.16-7.13(m,1H),6.81(d,J=2.0Hz,1H),5.40(hept,J=6 .8Hz,1H),4.56(d,J=8.4Hz,1H),3.87–3.74(m,2H),3.62–3.51(m,2H),2.0 1–1.70(m,6H),1.67(s,6H),1.46(dd,J=6.7,5.6Hz,6H),1.41–1.10(m,5H).

[0817] Example 36: Compound I-36

[0818]

[0819] Step 1:

[0820] Butyllithium (20 mL, 32 mmol) was added to a tetrahydrofuran (50 mL) solution of acetonitrile (1.31 g, 31.9 mmol) at -78 °C. The reaction mixture was stirred for 0.5 hours under argon protection, followed by the addition of compound 36-1 (4.5 g, 16 mmol). Stirring continued for 2 hours until the reaction was complete. The reaction was quenched with saturated ammonium chloride solution 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 compound 36-2 (3.24 g, 12 mmol, 73% yield) as a white solid. LC-MS: 270.0 [M+1] + .

[0821] Step Two:

[0822] Triethylamine (1.01 g, 9.98 mmol) was added to an ethanol (10 mL) solution of compound 36-2 (850 mg, 3.1470 mmol) and tert-butylhydrazine hydrochloride (1.24 g, 9.95 mmol). The reaction mixture was microwaved at 100 °C under argon protection for 2 hours. The solvent was removed by vacuum distillation, 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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 36-3 (680 mg, 2.00 mmol, yield 63.52%). LC-MS: 339.8, 341.8 [M+1] + .

[0823] Step 3:

[0824] Sodium bicarbonate (504 mg, 5.999 mmol) was added to a 10 mL solution of compound 36-3 (680 mg, 1.999 mmol) and benzyl chloroformate (681 mg, 3.9920 mmol) in acetonitrile. The reaction mixture was stirred overnight at room temperature under argon protection. The mixture was filtered, and the filtrate was concentrated to obtain a residue, which was purified by column chromatography to give compound 36-4 (780 mg, 1.64 mmol, yield 82.26%) as a white solid. LC-MS: 473.7, 475.7 [M+1] + .

[0825] Step Four:

[0826] To a solution of compound 36-4 (780 mg, 1.644 mmol) and tert-butyl carbamate (281 mg, 2.3988 mmol) in toluene (15 mL), tris(dibenzylacetone)palladium (156 mg, 0.17036 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (81 mg, 0.16991 mmol), and cesium carbonate (1.6 g, 4.9 mmol) were added. The reaction mixture was stirred at 110 °C under argon protection for 5 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, dried, and concentrated to give the residue, which was purified by column chromatography to give a yellow solid compound 36-5 (280 mg, 0.74 mmol, yield 45.23%). LC-MS: 376.9 [M+1] + .

[0827] Step 5:

[0828] Sodium bicarbonate (193 mg, 2.297 mmol) was added to a solution of compound 36-5 (280 mg, 0.7437 mmol) and benzyl chloroformate (255 mg, 1.4948 mmol) in acetonitrile (10 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature under argon protection. The mixture was filtered, and the filtrate was concentrated to obtain a residue, which was purified by column chromatography to give compound 36-6 (350 mg, 0.6855 mmol, yield 92.17%) as a white solid. LC-MS: 511.4 [M+1] + .

[0829] Step Six:

[0830] A solution of compound 36-6 (350 mg, 0.69 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to give a yellow solid, compound 36-7 (215 mg, 0.52 mmol, yield 76.41%). LC-MS: 411.3 [M+1] + .

[0831] Step Seven:

[0832] EDCI (473 mg, 2.467 mmol) was added to a pyridine (5 mL) solution of compound 36-7 (205 mg, 0.50 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (161 mg, 0.60 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, 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 36-8 (223 mg, 0.33 mmol, yield 67.47%) as a yellow solid. LC-MS: 661.8 [M+1] + .

[0833] Step 8:

[0834] A solution of compound 36-8 (223 mg, 0.33 mmol) in dichloromethane (1 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 36-9 (185 mg, 0.33 mmol, yield 97.74%). LC-MS: 561.8 [M+1] + .

[0835] Step Nine:

[0836] To a solution of compound 36-9 (185 mg, 0.33 mmol) and 2-isopropylpyrazole-3-carboxylic acid (60 mg, 0.39 mmol) in N,N-dimethylformamide (5 mL), HATU (186 mg, 0.49 mmol) and triethylamine (65 mg, 0.64 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 36-10 (221 mg, 0.32 mmol, yield 96.16%) as a yellow solid. LC-MS: 697.8 [M+1] + .

[0837] Step 10:

[0838] Compound 36-10 (221 mg, 0.32 mmol) was added to formic acid (5 mL), and the reaction mixture was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 36-11 (180 mg, 0.28 mmol, yield 88.57%). LC-MS: 641.8 [M+1] + .

[0839] Step Eleven:

[0840] Pd / C (50 mg) was added to a methanol (30 mL) solution of compound 36-11 (180 mg, 0.28 mmol), and the reaction mixture was stirred for 2 hours under hydrogen protection. The reaction mixture was filtered and concentrated to obtain a residue, which was purified by column chromatography to give a yellow solid compound I-36 (100 mg, 0.20 mmol, yield 70.23%). LC-MS: 508.3 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.84-7.77(m,1H),7.53(d,J=2.0Hz,1H),7.15–7.01(m,2H),6.80(d,J=2.0Hz,1H),5.49(s,1H),5.47–5.35(m,1H),5.00( d,J=7.2Hz,1H),4.07(q,J=7.2Hz,1H),1.57(d,J=7.2Hz,3H),1.47(t,J=6.4Hz,6H),0.98–0.76(m,3H),0.61–0.34(m,5H),0.33-0.21(m,3H).

[0841] Example 37: Compound I-37-A, Compound I-34-B

[0842]

[0843] Step 1:

[0844] In a 100 mL round-bottom flask, (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (550 mg, 2.05 mmol), triethylamine (270 mg, 2.66 mmol), and HATU (863 mg, 2.27 mmol) were added sequentially to a 25 mL solution of N,N-dimethylformamide containing compound 37-1 (400 mg, 2.05 mmol). The reaction mixture was placed under argon protection and stirred at room temperature for 16 hours until the reactants were completely consumed and converted to the target product. Water was added to quench the reaction mixture, 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–2:1) to obtain the target compound 37-2 (700 mg, 1.51 mmol) as a white solid. LC-MS: 406.8 [M+1] + .

[0845] Step Two:

[0846] In a 100 mL round-bottom flask, ethyl hydrochloride solution (1.0 mmol / mL, 3.5 mL, 3.5 mmol) was slowly added dropwise to a 25 mL solution of compound 37-2 (700 mg, 1.51 mmol) in dichloromethane, which was placed in an ice-water bath. The reaction mixture was slowly heated to room temperature and stirred for 5 hours. TLC (petroleum ether:ethyl acetate = 4:1) showed that the starting material had been completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a white solid crude product, compound 37-3 (566 mg, 1.47 mmol). The crude product was used directly in the next reaction without further purification. LC-MS: 348.9 [M+1] + .

[0847] Step 3:

[0848] In a 100 mL round-bottom flask, compound 37-3 (0.57 g, 1.47 mmol), triethylamine (0.375 g, 3.7 mmol), and HATU (0.84 g, 2.20 mmol) were added sequentially to a 15 mL solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.27 g, 1.76 mmol) in N,N-dimethylformamide. The reaction mixture was then placed at room temperature and stirred for 16 hours. After the starting material was consumed as monitored by LC-MS, 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 to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to give a brown oily compound 37-4 (0.62 g, 1.28 mmol). LC-MS: 484.8 [M+1] + .

[0849] Step Four:

[0850] In a 100 mL single-necked flask, lithium hydroxide monohydrate (120 mg, 2.86 mmol) was added to a tetrahydrofuran / water solution (10 mL / 2 mL) of compound 37-4 (0.62 g, 1.28 mmol). The reaction mixture was stirred for 5 hours. After LC-MS monitoring showed that the starting material was consumed, the flask was placed in an ice-water bath, and dilute hydrochloric acid was added dropwise to quench the reaction and adjust the pH of the reaction solution to 3–4. The mixture was then 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 give a white solid crude product, compound 37-5 (0.55 g, 1.17 mmol). LC-MS: 470.8 [M+1] + .

[0851] Step 5:

[0852] In a 100 mL round-bottom flask, triethylamine (355 mg, 3.51 mmol), HATU (667 mg, 1.75 mmol), and ammonium chloride (94 mg, 1.75 mmol) were added sequentially to a 10 mL solution of N,N-dimethylformamide containing compound 37-5 (0.55 g, 1.17 mmol). The reaction mixture was kept at room temperature and stirred for 16 hours. After LC-MS monitoring showed that the starting material was consumed, the reaction mixture was placed in an ice-water bath, and water was added to quench the reaction. 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 to 1:1) to give compound 37-6 (0.23 g, 0.49 mmol) as a white solid. LC-MS: 469.8 [M+1] + .

[0853] Step Six:

[0854] In a 100 mL round-bottom flask, bis(trifluoroacetoxy)iodobenzene (240 mg, 0.56 mmol) was added to an acetonitrile / water solution (10 mL / 10 mL) containing 0.22 g (0.47 mmol) of compound 37-6. The reaction mixture was stirred at room temperature for 16 hours. After LC-MS monitoring showed that most of the starting material had been converted to the target product, the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in an aqueous solution, and the pH of the solution was adjusted to 12-14 by adding sodium hydroxide solution (1.0 mmol / mL). The solution was extracted three times with ethyl acetate, and the combined extracts were 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 37-7 (200 mg, 0.45 mmol). LC-MS: 424.8 [M-NH2+1] + .

[0855] Step Seven:

[0856] In a 100 mL round-bottom flask, N,N-diisopropylethylamine (132 mg, 1.02 mmol) and 3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyltrifluoromethanesulfonate (190 mg, 0.51 mmol) were added sequentially to a 20 mL acetonitrile solution of compound 37-7 (200 mg, 0.45 mmol). The reaction mixture was heated to reflux and stirred for 36 hours. After LC-MS monitoring showed that the starting material had been converted into the target product, the reaction mixture was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate solution, 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 a brown oily compound 37-8 (140 mg, 0.21 mmol). LC-MS: 332.9 [M / 2+1] + .

[0857] Step 8:

[0858] In a 100 mL round-bottom flask, hydrazine hydrate (50%, 30 mg, 0.29 mmol) was added sequentially to an anhydrous ethanol solution of compound 37-8 (167 mg, 0.25 mmol). The mixture was then heated to reflux and stirred for 3 hours. After LC-MS monitoring showed that the starting material had been completely consumed, the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in water and 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 give a white solid crude product, compound 37-9 (130 mg, 0.23 mmol). LC-MS: 534.8 [M+1] + .

[0859] Step Nine:

[0860] In a 100 mL round-bottom flask, triethylamine (60 mg, 0.59 mmol) and phenyl p-nitrochloroformate (80 mg, 0.40 mmol) were added sequentially to an anhydrous acetonitrile solution of compound 37-9 (130 mg, 0.105 mmol), and the mixture was stirred at room temperature for 3 hours. After LC-MS monitoring showed that the starting material had been completely consumed, the reaction solution was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate solution, 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 = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to obtain the racemic compound. The obtained racemic compound was chirally resolved by SFC (Waters SFC 150) (column DAICEL CHIRALPAK AD-H (250mm*19mm, 5um), mobile phase: [CO2]; B%: 30%~30% methanol, 50mL / min).

[0861] A white solid compound, I-37-A, was obtained with a peak elution time of 5.4 mins and an LC-MS concentration of 561.2 [M+1]. + . 1 H NMR(400MHz, Methanol-d4)δ7.94(t,J=8.0Hz,1H),7.54(d,J=2.0Hz,1H),7.22–7.1 8(m,1H),7.18-7.16(m,1H),6.80(d,J=2.0Hz,1H),5.70(q,J=6.8Hz,1H),5.42(hep t,J=6.8Hz,1H),5.00(d,J=6.8Hz,1H),3.64-3.46(m,3H),3.23-3.10(m,1H),1.54( d,J=7.2Hz,3H),1.48(dd,J=6.7,5.5Hz,6H),0.98–0.77(m,3H),0.63–0.22(m,8H).

[0862] A white solid compound, I-37-B, was obtained with an elution time of 12.3 mins and an LC-MS concentration of 561.2 [M+1]. + . 1H NMR(400MHz, Methanol-d4)δ7.94(t,J=8.4Hz,1H),7.54(d,J=2.0Hz,1H),7.22-7 .19(m,1H),7.18(s,1H),6.80(d,J=2.0Hz,1H),5.70(q,J=7.2Hz,1H),5.42(hept, J=6.8Hz,1H),5.00(d,J=6.8Hz,1H),3.64–3.47(m,3H),3.23-3.10(m,1H),1.54(d ,J=7.2Hz,3H),1.48(dd,J=6.7,5.5Hz,6H),0.97-0.77(m,3H),0.62–0.22(m,8H).

[0863] Example 38: Compound I-38

[0864]

[0865] Step 1:

[0866] In a 100 mL round-bottom flask, 4-(1,3-dioxoisoindol-2-yl)butyraldehyde (1.2 g, 5.53 mmol) and NaHB(OAc)3 (1.4 g, 6.60 mmol) were added sequentially to a 20 mL solution of compound 29-3 (1.0 g, 4.48 mmol) in DCM. The mixture was stirred at room temperature for 6 hours. After LC-MS monitoring showed that the starting material had been converted to the target product, the reaction was quenched with saturated ammonium chloride (10 mL), extracted with DCM (50 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1 to 5:1) to give a white solid compound 38-1 (950 mg, 2.24 mmol). LC-MS: 425.1 [M+1] + .

[0867] Step Two:

[0868] In a 100 mL round-bottom flask, hydrazine hydrate (50%, 300 mg, 2.9 mmol) was added to a 40 mL MeOH solution of compound 38-1 (950 mg, 2.24 mmol), and the mixture was refluxed for 3 hours. After LC-MS monitoring showed that the starting material had been converted to the target product, the mixture was concentrated and evaporated to dryness, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white solid compound 38-2 (400 mg, 1.36 mmol). LC-MS: 295.1 [M+1] + .

[0869] Step 3:

[0870] In a 100 mL round-bottom flask, triethylamine (275 mg, 2.72 mmol) and phenyl p-nitrochloroformate (412 mg, 2.04 mmol) were added sequentially to an anhydrous acetonitrile solution of compound 38-2 (400 mg, 1.36 mmol), and the mixture was stirred at room temperature for 6 hours. After LC-MS monitoring showed that the starting material had been completely consumed, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white solid compound 38-3 (340 mg, 1.06 mmol). LC-MS: 321.1 [M+1] + .

[0871] Step Four:

[0872] In a 100 mL round-bottom flask, Pd / C (50 mg, 10%) was added to a MeOH solution of compound 38-3 (340 mg, 1.06 mmol) in 15 mL. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a white solid crude product, compound 38-4 (320 mg), which required no further purification. LC-MS: 290.9 [M+1] + .

[0873] Step 5:

[0874] In a 100 mL round-bottom flask, (S)-2-((tert-butyloxycarbonyl)amino)-2-cyclohexylacetic acid (339 mg, 1.32 mmol), triethylamine (278 mg, 2.75 mmol), and HATU (836 mg, 2.20 mmol) were added sequentially to a 15 mL solution of compound 38-4 (320 mg, 1.10 mmol) in N,N-dimethylformamide. The reaction mixture was placed under argon protection and stirred at room temperature for 12 hours until the starting material was completely consumed and converted to the target product. Extraction was performed with ethyl acetate (50 mL × 3), washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white solid compound 38-5 (300 mg, 0.57 mmol). LC-MS: 530.2 [M+1] + .

[0875] Step Six:

[0876] In a 50 mL round-bottom flask, TMSI (24 mg, 0.12 mmol) was added sequentially to 5 mL of DCM containing compound 38-5 (32 mg, 0.06 mmol). Under argon protection, the mixture was stirred at room temperature for 2 hours until the starting material was completely consumed and converted to the target product. The crude product was concentrated and purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white solid, compound 38-6 (20 mg, 0.05 mmol). LC-MS: 430.2 [M+1] + .

[0877] Step Seven:

[0878] In a 50 mL round-bottom flask, compound 38-6 (20 mg, 0.05 mmol), triethylamine (38 mg, 0.38 mmol), and HATU (38 mg, 0.1 mmol) were added sequentially to a 5 mL solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (15.4 mg, 0.1 mmol) in N,N-dimethylformamide. The reaction mixture was then placed at room temperature and stirred for 12 hours. The reactants were monitored by LC-MS until consumption was complete, and the mixture was concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white compound I-38 (8 mg, 0.01 mmol). LC-MS: 566.4 [M+1] + . 1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.49(s,2H),7.22(s,2H),7.00(s,1H), 6.83(s,1H),6.60(s,1H),5.52–5.38(m,1H),4.88–4.69(m,2H),4.52(s,1H),3.28 (s,2H),2.93(s,3H),2.75(s,3H),2.05–1.90(m,2H),1.89–1.73(m,4H),1.72–1.5 4(m,4H),1.48(d,J=6.5Hz,3H),1.46–1.40(m,4H),1.25(s,3H),1.22–1.08(m,3H).

[0879] Example 39: Compound I-39

[0880]

[0881] Step 1:

[0882] Compound 39-1 (20 g, 64.45 mmol), methylamine hydrochloride (4.80 g, 71.1 mmol), HATU (29.41 g, 77.35 mmol), DIPEA (25.00 g, 193.4 mmol), and DMF (200 mL) were added sequentially to a 500 mL three-necked flask and stirred overnight at room temperature. After the reaction was complete, the reaction solution was slowly added dropwise to 2 L of water, stirred for 4 h, filtered, and the filter cake was washed with 100–200 mL of water. The solid was transferred to a round-bottom flask and evaporated to dryness to obtain a brown solid compound 39-2 (19.10 g, 59.08 mmol). LC-MS: 224.1 [M+1] + .

[0883] Step Two:

[0884] Compound 39-2 (20 g, 61.86 mmol) and 100 mL of 4 M HCl and 1,4-dioxane were added to a 250 mL three-necked flask and stirred overnight at room temperature. The reaction was detected by LC-MS. After the reaction was complete, the solution was evaporated to dryness under reduced pressure to give a pink solid, compound 39-3 (10 g, 44.797 mmol). LC-MS: 224.1 [M+1] + .

[0885] Step 3:

[0886] Under argon protection, compound 39-3 (1.50 g, 6.73 mmol), [3-(1,3-dioxoisoindol-2-yl)-2,2-difluoropropyl]trifluoromethanesulfonate (3.00 g, 8.04 mmol), potassium carbonate (3.18 g, 23.0 mmol), and acetonitrile (50 mL) were added sequentially to a 100 mL three-necked flask. The mixture was heated to reflux and reacted overnight. LC-MS analysis was performed. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography (PE:EA = 1:5) gave a yellow oily compound 39-4 (1.62 g, 3.63 mmol, 47.4%). LC-MS: 447.0 [M+1] + .

[0887] Step Four:

[0888] Hydrazine hydrate (2 mL) was added to an ethanol (10 mL) solution of compound 39-4 (1.3 g, 2.9 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 39-5 (820 mg, 2.592 mmol, yield 89%). LC-MS: 316.9 [M+1] + .

[0889] Step 5:

[0890] N,N'-carbonyldiimidazole (1.26 g, 7.77 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 39-5 (820 mg, 2.592 mmol), and 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 39-6 (697 mg, 2.036 mmol, yield 78.54%). LC-MS: 343.1 [M+1] + .

[0891] Step Six:

[0892] Pd / C (70 mg) was added to a methanol (30 mL) solution of compound 39-6 (697 mg, 2.036 mmol), and the reaction mixture was stirred for 2 hours under hydrogen protection. The reaction mixture was filtered and concentrated to give a white solid compound 39-7 (502 mg, 1.607 mmol, yield 78.94%). LC-MS: 313.1 [M+1] + .

[0893] Step Seven:

[0894] To a solution of compound 39-7 (250 mg, 0.8005 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (269 mg, 0.9989 mmol) in N,N-dimethylformamide (5 mL), HATU (500 mg, 1.3150 mmol) and triethylamine (202 mg, 1.9962 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 39-8 (350 mg, 0.6210 mmol, yield 77.58%) as a yellow solid. LC-MS: 563.8 [M+1] + .

[0895] Step 8:

[0896] A solution of compound 39-8 (350 mg, 0.6210 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 39-9 (170 mg, 0.3668 mmol, yield 59.06%). LC-MS: 463.8 [M+1] + .

[0897] Step Nine:

[0898] To a solution of compound 39-9 (170 mg, 0.3668 mmol) and 2-isopropylpyrazole-3-carboxylic acid (70 mg, 0.45404 mmol) in N,N-dimethylformamide (5 mL), HATU (210 mg, 0.55230 mmol) and triethylamine (90 mg, 0.88942 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 a residue, which was purified by column chromatography to give compound I-39 as a white solid (115 mg, 0.1918 mmol, yield 52.28%). LC-MS: 600.2 [M+1] + . 1H NMR(400MHz,MeOD)δ7.61-7.48(m,3H),7.28-7.22(m,2H),6.80(d,J=2.0Hz,1H ),5.47-5.35(m,1H),5.05(t,J=8.0Hz,1H),4.93-4.88(m,1H),3.84–3.64(m,2 H),3.56–3.37(m,2H),3.23(dd,J=14.2,7.3Hz,1H),2.95(dd,J=14.2,8.9Hz,1 H),2.73-2.67(m,3H),1.51-1.42(m,6H),0.97–0.71(m,3H),0.59–0.19(m,8H).

[0899] Example 40: Compound I-40

[0900]

[0901] According to Example 39, compound I-40 (55 mg, 0.091 mmol) was obtained as a white solid. LC-MS: 600.2 [M+1] + . 1 H NMR (400MHz, Methanol-d4) δ7.57-7.51(m,3H),7.29-7.22(m,2H),6.80(d,J= 2.0Hz,1H),5.41(p,J=6.8Hz,1H),5.04(t,J=8.0Hz,1H),4.87(s,1H),3.83–3. 64(m,2H),3.56–3.39(m,2H),3.27–3.20(m,1H),3.00-2.90(m,1H),2.70(s,3H ),1.51-1.44(m,6H),0.93–0.72(m,3H),0.60–0.42(m,3H),0.42-0.20(m,5H). 1HNMR(400MHz,DMSO-d6)δ10.10(s,1H),8.42(d,J=8.8Hz,1H),7.91-7.83(m,1H),7.53-7.47(m,3H),7.20-7.13(m,2 H),6.93(d,J=2.0Hz,1H),6.75(br,1H),5.42(p,J=6.8Hz,1H),5.02-4.94(m,1H),4.79(t,J=8.0Hz,1H),3.85-3.58 (m,2H),3.50-3.36(m,1H),3.33-3.26(m,1H),3.11-2.99(m,1H),2.88-2.77(m,1H),2.56(d,J=4.4Hz,3H),1.37(dd ,J=13.0,6.6Hz,6H),0.91–0.68(m,3H),0.50-0.41(m,1H),0.40–0.26(m,3H),0.25-0.14(m,3H),0.13-0.05(m,1H).

[0902] Example 41: Compound I-41

[0903]

[0904] Step 1:

[0905] To a solution of compound 41-1 (2.0 g, 6.2 mmol) and methylamine hydrochloride (628 mg, 9.301 mmol) in N,N-dimethylformamide (20 mL), HATU (3.54 g, 9.31 mmol) and N,N-diisopropylethylamine (1.61 g, 12.5 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 a yellow oily compound 41-2 (1.64 g, 4.86 mmol, yield 79%). LC-MS: 238.1 [M-100+1] + .

[0906] Step Two:

[0907] Trifluoroacetic acid (2 mL) was added to a dichloromethane (2 mL) solution of compound 41-2 (1.64 g, 4.86 mmol), and the reaction mixture was stirred at 50 °C under argon protection for 2 hours. The solvent was removed under reduced pressure, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 41-3 (1.07 g, 4.51 mmol, yield 92.8%). LC-MS: 237.9 [M+1] + .

[0908] Step 3:

[0909] To a solution of compound 41-3 (1.07 g, 4.51 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (2.2 g, 5.9 mmol) in acetonitrile (20 mL), N,N-diisopropylethylamine (1.17 g, 9.06 mmol) was added. The reaction mixture was stirred for 3 days 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 compound 41-4 (1.78 g, 3.87 mmol, yield 85.7%) as a yellow solid. LC-MS: 460.8 [M+1] + .

[0910] Step Four:

[0911] Hydrazine hydrate (2 mL) was added to a 5 mL ethanol solution of compound 41-4 (1.78 g, 3.87 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 41-5 (1.24 g, 3.75 mmol, yield 97.1%). LC-MS: 331.1 [M+1] + .

[0912] Step 5:

[0913] N,N'-carbonyldiimidazole (1.75 g, 10.8 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 41-5 (1.24 g, 3.75 mmol), and 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 41-6 (1.2 g, 3.4 mmol, 90% yield). LC-MS: 356.8 [M+1] + .

[0914] Step Six:

[0915] Pd / C (120 mg) was added to a methanol (50 mL) solution of compound 41-6 (1.2 g, 3.4 mmol), and the reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a white solid, compound 41-7 (1.1 g, 3.4 mmol, 100% yield). LC-MS: 326.9 [M+1] + .

[0916] Step Seven:

[0917] To a solution of compound 41-7 (350 mg, 1.073 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (318 mg, 1.181 mmol) in N,N-dimethylformamide (5 mL), HATU (577 mg, 1.5175 mmol) and triethylamine (217 mg, 2.1445 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 a residue, which was purified by column chromatography to give a yellow solid compound 41-8 (380 mg, 0.6578 mmol, yield 61.32%). LC-MS: 577.8 [M+1] + .

[0918] Step 8:

[0919] A solution of compound 41-8 (380 mg, 0.6578 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 41-9 (175 mg, 0.3664 mmol, yield 55.70%). LC-MS: 477.9 [M+1] + .

[0920] Step Nine:

[0921] To a solution of compound 41-9 (175 mg, 0.3664 mmol) and 2-isopropylpyrazole-3-carboxylic acid (70 mg, 0.45404 mmol) in N,N-dimethylformamide (5 mL), HATU (206 mg, 0.54178 mmol) and triethylamine (73 mg, 0.72142 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-41 (66 mg, 0.1075 mmol, yield 29.35%) as a white solid. LC-MS: 614.4 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.60–7.50(m,3H),7.27-7.23(m,2H),6.81(d,J=2.0Hz,1 H),5.48–5.35(m,1H),4.91-4.86(m,1H),4.61-4.50(m,1H),3.58-3.46(m,1H) ,3.43-3.32(m,3H),3.08–2.95(m,1H),2.88-2.81(m,1H),2.75–2.60(m,4H),2 .49-2.42(m,1H),1.47(t,J=6.5Hz,6H),0.97–0.72(m,3H),0.62–0.18(m,8H).

[0922] Example 42: Compound I-42

[0923]

[0924] Step 1:

[0925] To a solution of compound 42-1 (1.2 g, 5.4 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (2.1 g, 5.6 mmol) in acetonitrile (20 mL), N,N-diisopropylethylamine (1.40 g, 10.8 mmol) was added. 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 a residue, which was purified by column chromatography to give a yellow solid, compound 42-2 (1.2 g, 2.7 mmol, 50% yield). LC-MS: 446.8 [M+1] + .

[0926] Step Two:

[0927] Hydrazine hydrate (2 mL) was added to a 10 mL ethanol solution of compound 42-2 (1.2 g, 2.7 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 42-3 (780 mg, 2.466 mmol, yield 92%). LC-MS: 316.8 [M+1] + .

[0928] Step 3:

[0929] N,N'-carbonyldiimidazole (1.21 g, 7.46 mmol) was added to a tetrahydrofuran (15 mL) solution of compound 42-3 (780 mg, 2.466 mmol), and 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 42-4 (720 mg, 2.103 mmol, yield 85.30%). LC-MS: 342.8 [M+1] + .

[0930] Step Four:

[0931] Pd / C (80 mg) was added to a methanol (30 mL) solution of compound 42-4 (720 mg, 2.103 mmol), and the reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a white solid compound 42-5 (652 mg, 2.088 mmol, yield 99.25%). LC-MS: 312.9 [M+1] + .

[0932] Step 5:

[0933] To a solution of compound 42-5 (250 mg, 0.8005 mmol) and (S)-2-((tert-butyloxycarbonyl)amino)-3,3-dicyclopropylpropionic acid (238 mg, 0.8838 mmol) in N,N-dimethylformamide (5 mL), HATU (460 mg, 1.2098 mmol) and triethylamine (202 mg, 1.9962 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 42-6 (311 mg, 0.5518 mmol, yield 68.93%) as a yellow solid. LC-MS: 563.8 [M+1] + .

[0934] Step Six:

[0935] A solution of compound 42-6 (311 mg, 0.5518 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, 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 obtain the residue, which was purified by column chromatography to give a yellow solid, compound 42-7 (190 mg, 0.4099 mmol, yield 74.29%). LC-MS: 463.8 [M+1] + .

[0936] Step Seven:

[0937] To a solution of compound 42-7 (190 mg, 0.4099 mmol) and 2-isopropylpyrazole-3-carboxylic acid (77 mg, 0.49945 mmol) in N,N-dimethylformamide (5 mL), HATU (240 mg, 0.63120 mmol) and triethylamine (81 mg, 0.80047 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-42 (110 mg, 0.1834 mmol, yield 44.75%) as a white solid. LC-MS: 600.4 [M+1] + . 1H NMR (400MHz, MeOD) δ7.55-7.46(m,3H),7.26(t,J=7.8Hz,1H),7.05(d,J=7.6Hz,1H),6.80( d,J=2.0Hz,1H),5.48-5.35(m,1H),5.08-5.00(m,1H),4.91(d,J=7.5Hz,1H),3.84–3.64(m ,2H),3.55–3.38(m,2H),3.29-3.21(m,1H),3.02–2.92(m,1H),2.71(d,J=3.8Hz,3H),1.51 -1.42(m,6H),0.96–0.74(m,3H),0.60–0.44(m,3H),0.44–0.34(m,2H),0.34–0.19(m,3H).

[0938] Example 43: Compound I-43

[0939]

[0940] The experimental procedure was followed as described in Example 42, yielding a white solid compound I-43 (35 mg, 0.056 mmol). LC-MS: m / z 625.8 [M+1] + . 1 H NMR(400MHz, Methanol-d4)δ7.54(d,J=2.4Hz,1H),7.52–7.46(m,2H),7.27(t,J=7.8Hz,1H),7.0 8–7.02(m,1H),6.80(d,J=2.0Hz,1H),5.42(p,J=6.4Hz,1H),5.00(t,J=8.4Hz,1H),3.92–3.67(m, 2H),3.54-3.40(m,2H),3.27-3.17(m,1H),2.99-2.90(m,1H),2.60(tt,J=7.2,4.0Hz,1H),1.47(d d,J=6.4,5.2Hz,6H),0.95–0.75(m,3H),0.72–0.62(m,2H),0.59–0.33(m,7H),0.33–0.22(m,4H).

[0941] Example 44: Compound I-44

[0942]

[0943] Step 1:

[0944] At room temperature, NaBH3CN (580 mg, 9.21 mmol) was added to a DCM (25 mL) solution of compound 33-1 (2.0 g, 7.46 mmol) and 4-(1,3-dioxoisoindol-2-yl)butyraldehyde (2.0 g, 9.21 mmol). The reaction was stirred at room temperature for 1 h, and the reaction was detected as complete by LC-MS. The reaction was quenched with saturated NH4Cl (20 mL), extracted with DCM (50 mL x 3), washed with saturated brine and ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a colorless oily compound 44-1 (1.8 g, 3.83 mmol). LC-MS: [M+1] + 471.8.

[0945] Step Two:

[0946] At room temperature, water and hydrazine (342 mg, 3.42 mmol, 50%) were added to a 20 mL solution of compound 44-1 (0.8 g, 1.71 mmol) in MeOH. The mixture was heated to reflux and stirred for 2 h. The reaction was confirmed by LC-MS. The crude product was concentrated and purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a colorless oily compound 44-2 (500 mg, 0.15 mmol). LC-MS: [M+1] + 340.1.

[0947] Step 3:

[0948] In a 100 mL round-bottom flask, triethylamine (298 mg, 2.95 mmol) and phenyl p-nitrochloroformate (476 mg, 2.36 mmol) were added sequentially to an anhydrous acetonitrile solution of compound 44-2 (400 mg, 1.18 mmol), and the mixture was stirred at room temperature for 6 hours. After LC-MS monitoring showed that the starting material had been completely consumed, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white solid compound 44-3 (460 mg, 1.26 mmol). LC-MS: 366.2 [M+1] + .

[0949] Step Four:

[0950] In a 50 mL round-bottom flask, TMSI (504 mg, 2.52 mmol) was added sequentially to 5 mL of DCM containing compound 44-3 (340 mg, 1.26 mmol). Under argon protection, the mixture was stirred at room temperature for 2 hours until the starting material was completely consumed and converted to the target product. The crude product was concentrated and purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a yellow oily compound 44-4 (220 mg, 0.83 mmol). LC-MS: 266.1 [M+1] + .

[0951] Step 5:

[0952] In a 100 mL round-bottom flask, (S)-2-((tert-butyloxycarbonyl)amino)-2-cyclohexylacetic acid (335 mg, 1.30 mmol), triethylamine (220 mg, 2.18 mmol), and HATU (661 mg, 1.74 mmol) were added sequentially to a 15 mL solution of N,N-dimethylformamide containing compound 44-4 (230 mg, 0.87 mmol). The reaction mixture was placed under argon protection and stirred at room temperature for 12 hours until the starting material was completely consumed and converted to the target product. Extraction was performed with ethyl acetate (50 mL × 3), washing with saturated brine (10 mL), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a yellow oily compound 44-5 (380 mg, 0.75 mmol). LC-MS: 449.1 [M-56+1] + .

[0953] Step Six:

[0954] In a 50 mL round-bottom flask, TMSI (160 mg, 0.8 mmol) was added sequentially to 10 mL of DCM containing compound 44-5 (200 mg, 0.40 mmol). Under argon protection, the mixture was stirred at room temperature for 2 hours until the starting material was consumed. The crude product was concentrated and purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a yellow oily compound 44-6 (100 mg, 0.5 mmol). LC-MS: 405.1 [M+1] + .

[0955] Step Seven:

[0956] In a 50 mL round-bottom flask, compound 44-6 (77 mg, 0.19 mmol), triethylamine (66 mg, 0.65 mmol), and HATU (198 mg, 0.52 mmol) were added sequentially to a 5 mL solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (40 mg, 0.26 mmol) in N,N-dimethylformamide. The reaction mixture was then placed at room temperature and stirred for 12 hours. The reactants were monitored by LC-MS until consumption was complete, and the mixture was concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1–5:1) to give a white compound I-44 (33 mg, 0.06 mmol). LC-MS: 541.2 [M+1] + . 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),8.03(d,J=12.4Hz,1H),7.49(d,J=1.9Hz,1H),7.17(s,1H), 6.74(dd,J=8.6,4.4Hz,1H),6.58(d,J=2.0Hz,1H),5.52–5.40(m,1H),5.37–5.32(m,1H),4.63–4.51(m, 1H),3.16(s,2H),2.93(s,1H),2.22(t,J=7.6Hz,1H),2.08–1.92(m,3H),1.89–1.75(m,3H),1.73–1.58( m,3H),1.50(d,J=6.6Hz,3H),1.46(d,J=6.6Hz,3H),1.35–1.27(m,4H),1.21–1.10(m,3H),1.02(s,3H).

[0957] Example 45: Compound I-45, Compound I-46

[0958]

[0959] Step 1:

[0960] To a solution of compound 45-1 (3.5 g, 13 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (7.8 g, 21 mmol) in acetonitrile (60 mL), N,N-diisopropylethylamine (3.36 g, 26 mmol) was added. The reaction mixture was stirred for 3 days 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 compound 45-2 (3.09 g, 6.91 mmol, yield 51%) as a yellow solid. LC-MS: 448.0 [M+1]+ .

[0961] Step Two:

[0962] Hydrazine hydrate (2 mL) was added to a 5 mL ethanol solution of compound 45-2 (3.09 g, 6.91 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 45-3 (1.67 g, 5.26 mmol, yield 76.2%). LC-MS: 318.1 [M+1] + .

[0963] Step 3:

[0964] N,N'-carbonyldiimidazole (2.43 g, 15.0 mmol) was added to a tetrahydrofuran (30 mL) solution of compound 45-3 (1.67 g, 5.26 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 45-4 (1.71 g, 4.98 mmol, yield 94.6%). LC-MS: 344.0 [M+1] + .

[0965] Step Four:

[0966] Pd / C (200 mg) was added to a methanol (50 mL) solution of compound 45-4 (1.71 g, 4.98 mmol), and the reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a white solid compound 45-5 (1.54 g, 4.92 mmol, yield 98.80%). LC-MS: 314.1 [M+1] + .

[0967] Step 5:

[0968] To a solution of compound 45-5 (1.54 g, 4.92 mmol) in N,N-dimethylformamide (15 mL), HATU (2.81 mg, 7.39 mmol) and triethylamine (1.24 g, 12.3 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 45-6 (2.11 g, 3.74 mmol, yield 76.0%) as a yellow solid. LC-MS: 565.1 [M+1] + .

[0969] Step Six:

[0970] To a solution of compound 45-6 (2.11 g, 3.74 mmol) in dichloromethane (2 mL), 2 mL of trifluoroacetic acid was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, 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 obtain the residue, which was purified by column chromatography to give a yellow solid, compound 45-7 (1.63 g, 3.51 mmol, yield 93.9%). LC-MS: 465.1 [M+1] + .

[0971] Step Seven:

[0972] To a solution of compound 45-7 (1.63 g, 3.51 mmol) and 2-isopropylpyrazole-3-carboxylic acid (600 mg, 3.8918 mmol) in N,N-dimethylformamide (15 mL), HATU (2 g, 5.2600 mmol) and triethylamine (1.06 g, 10.5 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 I-45 (1.72 g, 2.86 mmol, yield 81.6%) as a white solid. LC-MS: 601.3 [M+1] + . 1 HNMR(400MHz,MeOD)δ7.56-7.48(m,3H),7.28(t,J=7.8Hz,1H),7.05(d,J=7.6Hz,1H) ,6.80(d,J=2.0Hz,1H),5.48-5.36(m,1H),4.91(d,J=7.5Hz,1H),4.86-4.79(m,1H), 3.75(s,3H),3.70-3.56(m,1H),3.51-3.37(m,3H),3.36-3.29(m,1H),3.18-3.09(m, 1H), 1.46 (t, J = 6.5Hz, 6H), 0.98-0.74 (m, 3H), 0.62-0.34 (m, 5H), 0.33-0.19 (m, 3H).

[0973] Step 8:

[0974] Trimethyltin hydroxide (2.49 g, 13.8 mmol) was added to a solution of compound I-45 (1.65 g, 2.75 mmol) in 1,2-dichloroethane (30 mL), and the reaction mixture was stirred overnight at 80 °C under argon protection. The reaction was quenched with 5% hydrochloric acid after cooling to room temperature and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-46 (908 mg, 1.548 mmol, yield 56.4%) as a white solid. LC-MS: 587.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.57-7.47(m,2H),7.46-7.39(m,1H),7.23(t,J=7.8Hz,1H) ,7.04(d,J=7.4Hz,1H),6.87-6.82(m,1H),5.46-5.37(m,1H),4.95(d,J=6.8Hz, 1H),4.88-4.84(m,1H),3.69-3.52(m,2H),3.51-3.34(m,3H),3.09-2.91(m,1H) ,1.44(t,J=6.3Hz,6H),0.99-0.78(m,3H),0.61-0.34(m,5H),0.34-0.19(m,3H).

[0975] Example 46: Compound I-47

[0976]

[0977] Step 1:

[0978] Sodium hydroxide (2 mL, 2 mmol / mL, 4 mmol) was added to a solution of compound I-45 (70 mg, 0.1165 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain the residue, which was purified by column chromatography to give compound I-47 (69 mg, 0.1134 mmol, yield 97.29%) as a white solid. LC-MS: 587.3 [M-23+2] + . 1H NMR(400MHz,DMSO)δ10.32(brs,1H),8.95-8.61(m,1H),7.66-7.40(m,2H), 7.38-7.27(m,1H),7.17-7.06(m,1H),7.02-6.78(m,2H),6.45-6.20(m,1H), 5.61-5.35(m,1H),4.82-4.62(m,2H),4.03-3.87(m,1H),3.39-3.16(m,4H), 2.75-2.60(m,1H),1.45-1.30(m,6H),1.02-0.68(m,3H),0.55-0.05(m,8H).

[0979] Example 47: Compound I-48

[0980]

[0981] Step 1:

[0982] To a solution of compound I-46 (50 mg, 0.08524 mmol) and 1-methylpiperidin-4-amine (12 mg, 0.10509 mmol) in N,N-dimethylformamide (3 mL), HATU (49 mg, 0.12887 mmol) and triethylamine (20 mg, 0.19765 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 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give I-48 (31 mg, 0.04540 mmol, yield 53.26%) as a white solid. LC-MS: 683.5 [M+1] + . 1H NMR (400MHz, MeOD) δ7.54(d,J=2.0Hz,1H),7.53-7.47(m,2H),7.33-7.25(m,1H),7.07(d,J=7.6Hz,1H),6.81(d,J=2. 0Hz,1H),5.48-5.38(m,1H),5.05(t,J=8.1Hz,1H),4.94-4.85(m,1H),3.95–3.70(m,2H),3.69-3.61(m,1H),3.56-3. 42(m,2H),3.27-3.18(m,1H),2.97-2.89(m,1H),2.88-2.71(m,2H),2.30(s,3H),2.28-2.13(m,2H),1.88-1.82(m,1H ),1.77-1.66(m,1H),1.48-1.44(m,6H),1.58–1.28(m,2H),0.96–0.73(m,3H),0.62–0.33(m,5H),0.33–0.21(m,3H).

[0983] Example 48: Compound I-49

[0984]

[0985] Step 1:

[0986] To a solution of compound I-46 (55 mg, 0.09376 mmol) and 2-aminocyclopentanol (12 mg, 0.11864 mmol) in N,N-dimethylformamide (3 mL), HATU (57 mg, 0.14991 mmol) and triethylamine (20 mg, 0.19765 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 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-49 (45 mg, 0.06718 mmol, yield 71.66%) as a white solid. LC-MS: 670.4 [M+1] + . 1H NMR(400MHz,MeOD)δ7.54(d,J=2.0Hz,1H),7.53-7.46(m,2H),7.34-7.23(m,1H),7.11- 7.02(m,1H),6.81(d,J=2.0Hz,1H),5.48-5.37(m,1H),5.12-5.03(m,1H),4.93-4.89(m, 1H),3.97-3.68(m,4H),3.57-3.40(m,2H),3.29-3.19(m,1H),2.99-2.89(m,1H),1.51-1 .44(m,6H),2.13-1.22(m,6H),0.97-0.72(m,3H),0.62-0.34(m,5H),0.33-0.21(m,3H).

[0987] Example 49: Compound I-50

[0988]

[0989] Step 1:

[0990] To a solution of compound I-46 (50 mg, 0.08524 mmol) and ammonium chloride (45 mg, 0.8413 mmol) in N,N-dimethylformamide (3 mL), HATU (49 mg, 0.12887 mmol) and N,N-diisopropylethylamine (20 mg, 0.15479 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The residue was purified by column chromatography to give a white solid compound I-50 (35 mg, 0.05977 mmol, yield 70.12%). LC-MS: 586.3 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.54(d,J=2.0Hz,1H),7.53-7.46(m,2H),7.28(t,J=7.8Hz, 1H),7.08(d,J=7.7Hz,1H),6.81(d,J=2.0Hz,1H),5.48-5.37(m,1H),5.13-5.06 (m,1H),4.92-4.86(m,1H),3.79-3.63(m,2H),3.56-3.37(m,2H),3.32-3.24(m, 1H),3.04-2.96(m,1H),1.52-1.43(m,6H),0.95-0.72(m,3H),0.62-0.21(m,8H).

[0991] Example 50: Compound I-51

[0992]

[0993] Step 1:

[0994] In a 100 mL round-bottom flask, N,N-diisopropylethylamine (14 mg, 0.108 mmol) and HATU (38 mg, 0.099 mmol) were added sequentially to a 15 mL solution of compound pentoxide I-46 (50 mg, 0.083 mmol) in dichloromethane. The reaction mixture was then stirred at room temperature for 0.5 hours. Then, (S)-morpholino-2-ylmethanol (11 mg, 0.091 mmol) was added to the reaction mixture in a single batch, 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 dichloromethane. 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 the target compound I-51 (45 mg, 0.058 mmol) as a white solid. LC-MS: 686.4 [M+1] + . 1 H NMR (400MHz, Methanol-d4) δ7.57–7.45(m,3H),7.33-7.23(m,1H),7.11-7.03(m,1H),6.81( d,J=2.0Hz,1H),5.60-5.51(m,1H),5.42(p,J=6.4Hz,1H),4.40-4.25(m,1H),4.10-3.88(m,1 H),3.89–3.64(m,3H),3.61–3.40(m,5H),3.30–3.07(m,2H),3.01–2.51(m,4H),1.48(dd,J= 6.4,4.0Hz,6H),0.96–0.71(m,3H),0.63–0.45(m,3H),0.44-0.34(m,2H),0.34-0.21(m,3H).

[0995] Example 51: Compound I-52

[0996]

[0997] Referring to Example 50, a white solid compound I-52 was obtained. LC-MS: 686.4 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ7.57–7.45(m,3H),7.33-7.23(m,1H),7.11-7.03(m,1H),6.81( d,J=2.0Hz,1H),5.60-5.51(m,1H),5.42(p,J=6.4Hz,1H),4.40-4.25(m,1H),4.10-3.88(m,1 H),3.89–3.64(m,3H),3.61–3.40(m,5H),3.30–3.07(m,2H),3.01–2.51(m,4H),1.48(dd,J= 6.4,4.0Hz,6H),0.96–0.71(m,3H),0.63–0.45(m,3H),0.44-0.34(m,2H),0.34-0.21(m,3H).

[0998] Example 52: Compound I-53

[0999]

[1000] Step 1:

[1001] Triethylamine (10.2 mg, 0.1 mmol), N-methylpiperazine (10.1 mg, 0.1 mmol), and HATU (38.0 mg, 0.1 mmol) were added to a solution of compound I-46 (58.7 mg, 0.1 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-53 (20 mg, 0.03 mmol, yield 30.0%) as a white solid. LC-MS: 669.2 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 7.51 (s, 1H), 7.46 (d, J = 7.2Hz, 1H), 7.36 (s, 1H), 7.32-7.28 (m, 1H), 7.21 (t,J=7.6Hz,1H),7.01(d,J=7.6Hz,1H),6.63(s,1H),5.61-5.49(m,2H),5.47-5.37(m,1H),4.92(s,1H),4. 09(s,1H),3.76-3.50(m,6H),3.46-3.37(m,1H),3.31-3.12(m,1H),2.95-2.87(m,1H),2.40-2.25(m,3H),2 .24(s,3H),2.20-2.05(m,1H),1.52-1.41(m,6H),0.95-0.90(m,3H),0.65-0.45(m,4H),0.39-0.22(m,4H).

[1002] Example 53: Compound I-54

[1003]

[1004] Step 1:

[1005] Triethylamine (10.2 mg, 0.1 mmol), 3-aminotetrahydrothiophene 1,1-dioxide (13.5 mg, 0.1 mmol), and HATU (38.0 mg, 0.1 mmol) were added to a solution of compound I-46 (58.7 mg, 0.1 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-54 (20 mg, 0.29 mmol, yield 29.0%) as a white solid. LC-MS: 704.2 [M+1] + . 1H NMR (400MHz, CDCl3) δ9.10-8.99(m,1H),7.95-7.76(m,1H),7.50(s,1H),7.43(t,J=9.2Hz,1H),7.37-3.32(m,1H),7.31-7.27(m,1H), 7.19-7.12(m,1H),6.94-6.84(m,1H),6.67-6.63(m,1H),5.96-5.90(m,1H),5.48-5.32(m,1H),5.07(t,J=7.6Hz,1H),5.02-4.90(m,1H ),4.67-4.52(m,1H),3.85-3.70(m,1H),3.67-3.55(m,1H),3.54-3.40(m,2H),3.35-3.23(m,1H),3.21-3.11(m,1H),3.08-2.96(m,2H ),2.91-2.81(m,1H),2.44-2.25(m,1H),2.25-1.97(m,1H),1.4-1.39(m,6H),0.93-0.79(m,3H),0.61-0.42(m,4H),0.41-0.19(m,4H).

[1006] Example 54: Compound I-55

[1007]

[1008] Step 1:

[1009] Triethylamine (10.2 mg, 0.1 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (20.0 mg, 0.1 mmol), and HATU (38.0 mg, 0.1 mmol) were added to a solution of compound I-46 (58.7 mg, 0.1 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 55-1 (69 mg, 0.09 mmol, yield 90.0%) as a white solid. LC-MS: 769.4 [M+1] + .

[1010] Step Two:

[1011] A solution of compound 55-1 (69.0 mg, 0.9 mmol) in dichloromethane (1.0 mL) was added with 1.0 mL of trifluoroacetic acid, and the reaction was allowed to proceed for 3 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography to give a white solid compound I-55 (15 mg, 0.02 mmol, yield 25.0%). LC-MS: 669.2 [M+1] + . 1 H NMR (400MHz, CD3OD) δ8.57(s,1H),7.57-7.51(m,2H),7.47(d,J=8.0Hz,1H),7.29(t,J=8.0Hz,1H),7.07(d,J =7.6Hz,1H),6.85-6.79(m,1H),5.52-5.27(m,1H),5.04(t,J=8.0Hz,1H),3.97-3.69(m,3H),3.50(t,J=12.4 Hz,2H),3.28-3.17(m,3H),3.10-2.91(m,3H),2.10-2.00(m,1H),1.98-1.84(m,1H),1.72-1.60(m,1H),1.58 -1.51(m,1H),1.50-1.45(m,6H),1.04-0.68(m,4H),0.61-0.44(m,3H),0.44-0.34(m,2H),0.33-0.19(m,3H).

[1012] Example 55: Compound I-56

[1013]

[1014] Step 1:

[1015] A solution of 1,4-dioxane hydrochloride (1.0 mL) was added to a solid of compound I-55 (5 mg, 0.007 mmol), and the mixture was stirred at room temperature for one hour. After the reaction was complete, the solution was concentrated to give a yellow solid of compound I-56 (5 mg, 0.03 mmol, yield 100.0%). LC-MS: 669.2 [M-HCl+1] + . 1H NMR(400MHz,CD3OD)δ7.59(s,1H),7.56-7.43(m,2H),7.27(s,1H),7.05(s,1H),6 .83(s,1H),5.52-5.28(m,2H),4.00-3.75(m,3H),3.3.60-3.47(m,2H),3.27-3.1 5(m,3H),3.10-2.90(m,3H),2.00-1.85(m,2H),1.75-1.55(m,2H),1.50-1.40(m, 6H),1.40-1.25(m,5H),0.95-0.75(m,3H),0.60-0.40(m,3H),0.38-0.20(m,5H).

[1016] Example 56: Compound I-57

[1017]

[1018] Step 1:

[1019] At room temperature, HATU (76 mg, 0.20 mmol) and DIPEA (47 mg, 0.36 mmol) were added to a DMF (2 mL) solution of compound I-46 (50 mg, 0.09 mmol) and trifluoroethylamine (18 mg, 0.18 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a white powder of compound I-57 (20 mg, 0.03 mmol, yield 35%). LC-MS: [M+1] + 668.7. 1 H NMR (400MHz, MeOD) δ7.63–7.41(m,3H),7.28(m,1H),7.07(d,J=7.6Hz,1H),6.81(d,J=2.0Hz,1 H),5.45-5.35(m,2H),5.16-5.12(m,1H),4.00–3.86(m,2H),3.76-3.70(m,2H),3.47–3.43(m, 2H),3.31–3.24(m,1H),3.02-2.97(m,1H),1.49-1.46(m,6H),1.31(s,2H),0.92-0.84(m,2H), 0.80-0.74(m,1H),0.57-0.55(m,1H),0.51–0.44(m,1H),0.44–0.31(m,2H),0.31–0.23(m,2H).

[1020] Example 57: Compound I-58

[1021]

[1022] Step 1:

[1023] Compound 37-1 (0.5 g, 2 mmol), (2S)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropionic acid (0.73 g, 2.7 mmol, 100 mass%), EDCI (0.68 g, 3.5 mmol), and Py (10 mL) were added to a 100 mL round-bottom flask and stirred at room temperature for 6 hours. The reaction was monitored by LC-MS until complete. The solution was concentrated, diluted with water, and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a yellow oily compound 58-1 (1.08 g, 2.32 mmol). LC-MS: 409.3 [M+1] + .

[1024] Step Two:

[1025] Compound 58-1 (1.03 g, 2.22 mmol) and HCl-1,4-dioxane (20 mL, 100 mass%) were added to a 100 mL round-bottom flask and stirred at room temperature for 6.0 h. The reaction was monitored by LC-MS until complete, and the mixture was evaporated to dryness to give a yellow solid, compound 58-2 (0.75 g, 2.1 mmol). LC-MS: 365.2 [M+1] + .

[1026] Step 3:

[1027] Compound 58-2 (0.92 g, 2.5 mmol, 100 mass%), isopropylpyrazole-3-carboxylic acid (0.42 g, 2.7 mmol, 100 mass%), HATU (1.16 g, 3.05 mmol, 100 mass%), DIPEA (0.66 g, 5.1 mmol, 100 mass%), and DMF (10 mL) were added to a 100 mL round-bottom flask and stirred at room temperature for 6.0 h. The reaction was monitored by LC-MS until complete. The reaction mixture was then added dropwise to water, resulting in the precipitation of a solid. After stirring for 2 h, the mixture was filtered, washed with water, and dried to obtain a yellow solid, compound 58-3 (1.2 g). LC-MS: 50 1.3 [M+1] + .

[1028] Step Four:

[1029] Compound 58-3 (1.2 g, 2.4 mmol), LiOH (0.85 g, 100 mass%), H₂O (10 g, 555.09 mmol), and MeOH (10 mL, 100 mass%) were added to a 100 mL round-bottom flask and stirred at room temperature for 6.0 h. The reaction was monitored by LC-MS until complete. The mixture was evaporated to dryness, extracted twice with ethyl acetate, and the organic phases were combined, washed with water and salt, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM / MeOH = 20:1) to give a white solid compound 58-4 (0.62 g, 1.3 mmol). LC-MS: 373.3 [M+1] + .

[1030] Step 5:

[1031] Compound 58-4 (420 mg, 0.89 mmol), DPPA (0.41 g, 1.5 mmol), toluene (16 mL), and TEA (0.14 g) were added to a 100 mL round-bottom flask. The mixture was heated under nitrogen protection for 2 h. TLC was used to confirm the reaction was complete. THF (8 mL) and NaOH (1.0 mL, 2N) were added to the system, and the mixture was stirred overnight at room temperature until complete. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and salt, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (DCM / MeOH = 20:1) to give a white solid, compound 58-5 (0.15 g, 0.34 mmol). LC-MS: 427 [M+1] + .

[1032] Step Six:

[1033] Compound 58-5 (100 mg, 0.23 mmol), [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (88 mg, 0.24 mmol), DIPEA (89 mg, 0.69 mmol), and acetonitrile (10 mL) were added to a 100 mL round-bottom flask. The mixture was heated to reflux under an argon atmosphere and stirred for three days until the reaction was complete as detected by LC-MS. The reaction solution was evaporated to dryness, extracted with ethyl acetate, and the organic phases were combined, washed with water and salt, dried over anhydrous sodium sulfate, and evaporated to dryness to give a yellow oily compound 58-6 (100 mg, 0.15 mmol). LC-MS: 666.8 [M+1] + .

[1034] Step Seven:

[1035] Compound 58-6 (80 mg, 0.12 mmol), NH₂-NH₂.H₂O (0.4 mL), and MeOH (10 mL) were added to a 100 mL round-bottom flask and stirred overnight. After confirming the reaction was complete by LC-MS, the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness, and separated by column chromatography (DCM / MeOH = 10:1) to give a yellow oily compound 58-7 (60 mg, 0.112 mmol). LC-MS: 537.8 [M+H] + .

[1036] Step 8:

[1037] Compound 58-7 (50 mg, 0.09 mmol), phenyl p-nitrochloroformate (61 mg, 0.30 mmol), DIPEA (58 mg, 0.45 mmol), and acetonitrile (5 mL) were added to a 100 mL round-bottom flask and stirred overnight at room temperature. After confirming the reaction was complete by LC-MS, the solvent was evaporated to dryness, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water and salt, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography (DCM:MeOH = 20:1) yielded a pale red solid, compound I-58 (14 mg, 0.025 mmol). LC-MS: 563.2 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.87(t,J=8.3Hz,1H),7.53(d,J=2.0Hz,1H),7.23–7.11(m,2H),6.81(d ,J=2.0Hz,1H),5.70(q,J=6.6Hz,1H),5.47–5.36(m,1H),3.61–3.50(m,3H),3.15(dd,J=22.1 ,12.9Hz,1H),2.21(t,J=7.6Hz,1H),2.06(s,1H),1.83–1.79(m,2H),1.54(d,J=7.1Hz,3H),1 .47(dd,J=6.6,4.3Hz,7H),1.33(d,J=18.2Hz,6H),1.12–0.99(m,2H),0.92(t,J=6.9Hz,1H).

[1038] Example 58: Compound I-59

[1039]

[1040] At room temperature, HATU (76 mg, 0.20 mmol) and DIPEA (39 mg, 0.30 mmol) were added to a DMF (5 mL) solution of compound I-46 (50 mg, 0.09 mmol) and N,N-dimethylpyrrolidone-3-amine (23 mg, 0.20 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give compound I-59 (15 mg, 0.02 mmol, yield 26%) as a white powder. LC-MS: 682.8 [M+1] + . 1 HNMR(400MHz,MeOD)δ7.54-7.49(m,3H),7.30(s,1H),7.09(s,1H),6.82(s,1H ),5.43-5.31(m,2H),4.12–3.74(m,3H),3.74–3.47(m,3H),3.39(s,2H),3.23 (s,2H),3.04-2.95(m,2H),2.81–2.37(m,6H),2.21(s,1H),2.03-1.91(m,1H) ,1.48-1.32(m,6H),0.91-0.80(m,3H),0.57-0.50(m,3H),0.38-0.30(m,5H).

[1041] Example 59: Compound I-60

[1042]

[1043] Step 1:

[1044] At room temperature, HATU (38 mg, 0.10 mmol) and DIPEA (19 mg, 0.15 mmol) were added to a DMF (5 mL) solution of compound I-46 (30 mg, 0.05 mmol) and methyl 3-aminocyclohexanecarboxylate (10 mg, 0.06 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily compound 60-1 (36 mg, 0.05 mmol, yield 97%). LC-MS: 725.7 [M+1] + .

[1045] Step Two:

[1046] Lithium hydroxide (2 mg, 0.05 mmol) was added to a solution of compound 60-1 (18 mg, 0.02 mmol) in THF (2 mL), water (1 mL), and MeOH (0.5 mL). The reaction mixture was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 3–4. The mixture was extracted three times with EtOAc, the organic phase was dried over Na₂SO₄, and concentrated to give a colorless oily compound I-60 (15 mg, 0.02 mmol, 85% yield). LC-MS: 711.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.56(d,J=2.0Hz,1H),7.52-7.46(m,2H),7.30-7.26(m,1H),7.07(d,J=7.6Hz,1H),6.82(s,1H),5.51–5.34(m,1H),5.17–4.98 (m,1H),4.05-3.85(m,1H),3.84–3.75(m,1H),3.74-3.56(m,1H),3.55-3 .40(m,2H),3.26-3.21(m,1H),3.03-2.91(m,1H),2.59-2.48(m,1H),2.42 –2.23(m,1H),2.16–1.97(m,1H),1.84-1.73(m,1H),1.70-1.60(m,1H),1 .65(s,1H),1.59-1.53(m,1H),1.52–1.40(m,6H),1.39–1.29(m,2H),1.27 -1.20(m,1H),1.18–0.99(m,1H),0.92-0.84(m,2H),0.81-0.74(m,1H),0. 62–0.52(m,1H),0.52–0.44(m,1H),0.44-0.35(m,2H),0.31-0.23(m,3H).

[1047] Example 60: Compound I-61

[1048]

[1049] Step 1:

[1050] At room temperature, HATU (129 mg, 0.34 mmol) and DIPEA (66 mg, 0.51 mmol) were added to a DMF (5 mL) solution of compound I-46 (100 mg, 0.17 mmol) and methyl piperazine carboxylate (83 mg, 0.34 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily compound 61-1 (130 mg, 0.16 mmol, yield 94%). LC-MS: 812.7 [M+1] + .

[1051] Step Two:

[1052] A solution of compound 61-1 (130 mg, 0.16 mmol) in dichloromethane (5 mL) was added to trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for one hour. The reaction mixture was concentrated to give a colorless oily compound 61-2 (100 mg, 0.14 mmol, yield 88%). LC-MS: 713.4 [M+1] + .

[1053] Step 3:

[1054] Lithium hydroxide (6 mg, 0.14 mmol) was added to a solution of compound 61-2 (50 mg, 0.07 mmol) in THF (2 mL), water (1 mL), and MeOH (0.5 mL). The reaction mixture was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 3–4. The mixture was extracted three times with EtOAc. The organic phase was dried over Na₂SO₄ and concentrated to give a colorless oily compound I-61 (20 mg, 0.03 mmol, yield 41%). LC-MS: 699.2 [M+1] + . 1H NMR (400MHz, MeOD) δ7.66–7.39(m,3H),7.29(d,J=7.6Hz,1H),7.11(s,1H),6.82(d,J=1 .6Hz,1H),5.68-5.53(m,1H),5.45-5.36(m,1H),4.45-4.21(m,1H),4.07(s,1H),3.97–3 .62(m,3H),3.53-3.51(m,3H),3.38(s,1H),3.25-3.15(m,2H),3.00-2.97(m,3H),2.40 (s,1H),1.47(d,J=6.4Hz,6H),1.02–0.71(m,3H),0.56-0.49(m,3H),0.43–0.21(m,4H).

[1055] Example 61: Compound I-62

[1056]

[1057] Synthesize reference compound I-59. LC-MS: 685.7 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.67–7.40(m,3H),7.27(d,J=8.4Hz,1H),7.07(d,J=7.6Hz,1H),6.81(d,J=2.0Hz,1H),5.50–5.34 (m,1H),5.10-5.06(m,1H),4.60(s,1H),3.99–3.82(m,2H),3.82–3.65(m,3H),3.59–3.43(m,2H),3.41-3.36(m,2H),3 .29-3.23(m,1H),3.14-3.12(m,1H),2.97-2.91(m,1H),1.80-1.67(m,1H),1.47(dd,J=6.4,4.8Hz,6H),1.36-1.31(m, 1H),0.96–0.82(m,2H),0.82–0.74(m,1H),0.61–0.53(m,1H),0.53–0.44(m,2H),0.44–0.34(m,2H),0.34–0.21(m,3H).

[1058] Example 62: Compound I-63

[1059]

[1060] Synthesize reference compound I-62. LC-MS: 685.7 [M+1] + .1 H NMR (400MHz, MeOD) δ7.60–7.47(m,3H),7.31-7.27(m,1H),7.08(d,J=7.6Hz,1H),6.81(d,J=2.0Hz,1H),5.46-5.35(m ,1H),5.09-5.04(m,1H),4.91-4.89(m,2H),3.95-3.88(m,1H),3.85-3.80(m,2H),3.79–3.68(m,2H),3.53(d,J=12Hz ,1H),3.49-3.40(m,2H),3.30-3.24(m,1H),3.01-2.96(m,1H),1.85-1.75(m,1H),1.55–1.37(m,6H),1.36-1.31(m,2 H),0.99–0.82(m,2H),0.81-0.74(m,1H),0.61–0.53(m,1H),0.54–0.44(m,2H),0.44–0.34(m,2H),0.33-0.24(m,3H).

[1061] Example 63: Compound I-64

[1062]

[1063] Synthesize reference compound I-59. LC-MS: 652.7 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.65(s,1H),7.64–7.53(m,2H),7.53–7.46(m,1H),7.29(t,J=8.0Hz,1H),7.19–7 .03(m,2H),6.81(d,J=2.0Hz,1H),5.46–5.35(m,1H),5.24(s,1H),3.85-3.75(m,2H),3.52-3.43(m,2 H),3.39–3.35(m,1H),3.15-3.05(m,1H),2.95-2.90(m,1H),1.47(dd,J=6.8,5.2Hz,6H),0.92-0.83( m,2H),0.82–0.72(m,1H),0.60–0.53(m,1H),0.52-0.43(m,2H),0.42–0.33(m,2H),0.32-0.22(m,3H).

[1064] Example 64: Compound I-65

[1065]

[1066] Step 1:

[1067] At room temperature, EDCI (96 mg, 0.50 mmol) was added to a pyridine (5 mL) solution of compound I-46 (50 mg, 0.09 mmol) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-amine (20 mg, 0.09 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give compound 65-1 as a colorless oil (45 mg, 0.06 mmol, yield 67%). LC-MS: 783.4 [M+1] + .

[1068] Step Two:

[1069] To a solution of compound 65-1 (30 mg, 0.04 mmol) in tetrahydrofuran (5 mL), 0.5 mL of TBAF was added. The reaction mixture was stirred at 75 °C for three hours. The reaction mixture was concentrated and purified by column chromatography to give a white powder of compound I-65 (20 mg, 0.03 mmol, yield 80%). LC-MS: 652.8 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.72(s,1H),7.61(s,1H),7.54(d,J=2.0Hz,1H),7.46(s,1H),7.29(t,J=8.0Hz,1H), 7.11(d,J=7.2Hz,1H),6.81(d,J=2.0Hz,1H),5.42-5.33(m,1H),5.32-5.27(m,1H),4.90(d,J=7.6Hz,1H) ,3.87-3.76(m,2H),3.52-3.43(m,2H),3.41-3.36(m,1H),3.17–3.03(m,1H),1.49-1.36(m,6H),0.95–0. 87(m,1H),0.87–0.73(m,2H),0.59–0.52(m,1H),0.52–0.41(m,2H),0.40-0.34(m,2H),0.29-0.23(m,3H).

[1070] Example 65: Compound I-66

[1071]

[1072] Synthesize reference compound I-59. LC-MS: 679.3 [M+1] + .1 H NMR(400MHz,MeOD)δ8.38(d,J=6.4Hz,1H),7.52-7.47(m,3H),7.34–7.22(m,1H),7.11(d,J= 4.4Hz,2H),6.80(d,J=5.2Hz,1H),6.44–6.27(m,1H),5.47–5.34(m,1H),5.10(s,1H),3.72- 3.69(m,1H),3.62–3.35(m,4H),3.17–3.07(m,1H),3.0-2.83(m,1H),1.51–1.33(m,6H),0.9 5-0.87(m,1H),0.86–0.70(m,2H),0.61–0.41(m,3H),0.41–0.31(m,2H),0.31–0.15(m,3H).

[1073] Example 66: Compound I-67

[1074]

[1075] Step 1:

[1076] At room temperature, EDCI (32 mg, 0.17 mmol) was added to a pyridine (5 mL) solution of compound I-46 (50 mg, 0.09 mmol) and 1-(2-trimethylsilylethoxymethyl)pyrazole-3-amine (20 mg, 0.09 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with EtOAc. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give a colorless oily compound 67-1 (40 mg, 0.05 mmol, yield 67%), LC-MS: 781.7 [M+1]. + .

[1077] Step Two:

[1078] TBAF (0.5 mL) was added to a tetrahydrofuran (5 mL) solution of compound 67-1 (30 mg, 0.04 mmol). The reaction mixture was stirred at 75 °C for three hours. The reaction mixture was concentrated and purified by column chromatography to give a white powder of compound I-67 (20 mg, 0.03 mmol, 80% yield). LC-MS: 651.8 [M+1] + . 1H NMR (400MHz, MeOD) δ7.56-7.53(m,3H),7.50(d,J=8.4Hz,1H),7.28(t,J=8.0Hz,1H),7.11(d,J=7. 6Hz,1H),6.81(d,J=2.0Hz,1H),6.52(s,1H),5.45-5.35(m,2H),5.31–5.23(m,1H),3.90–3.70(m,2 H),3.58–3.42(m,2H),3.38(d,J=7.2Hz,1H),3.09-3.03(m,1H),1.49-1.35(m,6H),0.94-0.83(m,2 H),0.82-0.73(m,1H),0.59–0.51(m,1H),0.50-0.43(m,2H),0.42–0.32(m,2H),0.32–0.17(m,3H).

[1079] Example 67: Compound I-68

[1080]

[1081] Following the preparation method for compound I-3, compound I-68 was obtained as a white solid. LC-MS: [M+1] + 626.8. 1 H NMR (400MHz, MeOD) δ7.66-7.53(m,2H),7.49(d,J=7.6Hz,1H),7.31(t,J=8.0Hz,1H),7.12(d,J=7.6H z,1H),6.81(d,J=2.0Hz,1H),5.60-5.56(m,1H),5.47-5.35(m,1H),4.90(d,J=7.6Hz,1H),3.80-3.6 8(m,1H),3.50-3.44(m,3H),3.41-3.34(m,1H),3.22-3.17(m,1H),1.49-1.36(m,6H),0.92-0.87(m, 1H),0.86-0.73(m,2H),0.62-0.53(m,1H),0.52-0.44(m,2H),0.43-0.33(m,2H),0.32-0.24(m,3H).

[1082] Example 68: Compound I-69

[1083]

[1084] Step 1:

[1085] DBU (3.04 g, 20.0 mmol) was added to a DCM (20 mL) solution of compound 69-1 (2.0 g, 9.9 mmol) and methyl 2-(benzyloxycarbonylamino)-2-dimethoxyphosphonoacetate (4.3 g, 13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purified by column chromatography to give compound 69-2 (2.6 g, 6.1 mmol, 61% yield) as a white powder. LC-MS: 428.3 [M+1] + .

[1086] Step Two:

[1087] Under a hydrogen atmosphere, Pd / C (1 g) was added to a 5 mL solution of compound 69-2 (2 g, 4.7 mmol) in ethyl acetate. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through diatomaceous earth and concentrated to give a colorless oily compound 69-3 (1.2 g, 4.1 mmol, yield 87%). LC-MS: 295.9 [M+1] + .

[1088] Step 3:

[1089] At room temperature, [3-(1,3-dioxoisoindol-2-yl)-2,2-difluoropropyl]trifluoromethanesulfonate (2.8 g, 7.40 mmol) and DIEA (1.4 g, 11 mmol) were added to a solution of compound 69-3 (1.1 g, 3.7 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was concentrated and purified by column chromatography to give compound 69-4 (1.2 g, 2.3 mmol, yield 62%) as a white powder. LC-MS: 518.7 [M+1] + .

[1090] Step Four:

[1091] At room temperature, hydrazine hydrate (0.5 mL) was added to a 20 mL solution of compound 69-4 (1.1 g, 2.1 mmol) in ethanol. The reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was concentrated and purified by column chromatography to give a colorless oily compound 69-5 (600 mg, 1.5 mmol, yield 73%). LC-MS: 388.8 [M+1] + .

[1092] Step 5:

[1093] At room temperature, CDI (420 mg, 2.57 mmol) was added to a THF (10 mL) solution of compound 69-5 (500 mg, 1.29 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated and purified by column chromatography to give compound 69-6 (500 mg, 1.21 mmol, 94% yield) as a white powder. LC-MS: 415.2 [M+1] + .

[1094] Step Six:

[1095] TFA (0.5 mL) was added to a solution of compound 69-6 (470 mg, 1.13 mmol) in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give compound 69-7 (350 mg, 1.11 mmol, 98% yield) as a colorless oil. LC-MS: 315.1 [M+1] + .

[1096] Step Seven:

[1097] At room temperature, EDCI (1.01 g, 5.25 mmol) was added to a pyridine (5 mL) solution of compound 69-7 (330 mg, 1.05 mmol) and (2S)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dicyclopropylpropionic acid (340 mg, 1.27 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed three times with water. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give compound 69-8 (50 mg, 0.08 mmol, yield 8%) as a yellow oil. LC-MS: 566.3 [M+1] + .

[1098] Step 8:

[1099] TFA (0.5 mL) was added to a solution of compound 69-8 (40 mg, 0.07 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a colorless oily compound 69-9 (20 mg, 0.04 mmol, yield 61%). LC-MS: 466.3 [M+1] + .

[1100] Step Nine:

[1101] At room temperature, HATU (0.06 mmol, 20 mg) and DIPEA (0.09 mmol, 10 mg) were added to a DMF (5 mL) solution of compound 69-9 (20 mg, 0.04 mmol) and 1-(propyl-2-yl)-1H-pyrazole-5-carboxylic acid (0.05 mmol, 8 mg). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and washed three times with water. The organic phase was dried over Na2SO4, concentrated, and purified by column chromatography to give compound I-69 (10 mg, 0.02 mmol, yield 39%) as a white powder. LC-MS: 602.3 [M+1] + . 1 H NMR (400MHz, MeOD) δ8.23(d,J=5.2Hz,1H),8.07(s,1H),7.55(d,J=2.0Hz,1H),7.09(d,J=5.2Hz ,1H),6.82(d,J=2.0Hz,1H),5.41-5.37(m,1H),4.96(d,J=6.8Hz,1H),4.62(s,3H),3.77(s,2H) ,3.75–3.64(m,1H),3.55–3.36(m,3H),3.27-3.15(m,1H),1.49-1.35(m,6H),1.05-0.92(m,1H) ,0.91–0.73(m,2H),0.63–0.53(m,1H),0.53–0.41(m,2H),0.42–0.24(m,4H),0.23-0.15(m,1H).

[1102] Example 69: Compound I-70

[1103]

[1104] Step 1:

[1105] Compound 70-1 (3.00 g, 11.8 mmol, synthesized from compound 33-6), [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyl]trifluoromethanesulfonate (6.00 g, 16.1 mmol), K₂CO₃ (4.9 g, 35 mmol), and ACN (120 mL) were added to a 250 mL three-necked flask. The mixture was purged three times with argon gas, heated to reflux, and reacted for 16 h. LC-MS was used to determine the completeness of the reaction. The concentrated solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with water and salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1) to give a yellow oily compound 70-2 (2.01 g, 4.21 mmol, yield 35.7%). LC-MS: 477.8 [M+1]+ .

[1106] Step Two:

[1107] Compound 70-2 (1.86 g, 3.90 mmol), hydrazine hydrate (0.93 g, 19 mmol), and EtOH (50 mL) were added to a 100 mL three-necked flask. The mixture was purged three times with argon gas, heated to reflux, and reacted for 2–3 h. A sample was taken, and the reaction was analyzed by LC-MS until complete. The concentrated solution was diluted with water, separated by reverse-phase column chromatography (methanol:water = 1:1), and concentrated to give a yellow oily compound 70-3 (0.92 g, 2.6 mmol, yield 68%). LC-MS: 347.9 [M+1] + .

[1108] Step 3:

[1109] Compound 70-3 (0.90 g, 2.6 mmol), CDI (839 mg, 5.17 mmol), and THF (50 mL) were added to a 100 mL three-necked flask. The mixture was heated to 50 °C and reacted for 16 h. A sample was taken, and the reaction was analyzed by LC-MS until completion. The concentrated solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with water and salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1) to give a yellow oily compound 70-4 (0.82 g, 2.20 mmol, yield 85%). LC-MS: 318.8 [M+1] + .

[1110] Step Four:

[1111] Compound 70-4 (0.1 g, 0.30 mmol) and HCl / dioxane (1.0 M, 5 mL) were added to a 25 mL three-necked flask. The mixture was stirred for 2 h, and the reaction was monitored by LC-MS until complete. The solution was evaporated to dryness to give a yellow oily compound 70-5 (80 mg, 0.29 mmol, 100% yield). LC-MS: 274.2 [M+1] + .

[1112] Step 5:

[1113] Compound 70-5 (73 mg, 0.27 mmol), (2S)-2-(tert-butylaminocarbonate)-2-phenyl-acetic acid (81 mg, 0.32 mmol), EDCI (104 mg, 0.54 mmol), and Py (10 mL) were added to a 25 mL three-necked flask. After stirring for 2 h, a sample was taken, and the reaction was monitored by LC-MS until complete. The mixture was evaporated to dryness, extracted twice with ethyl acetate, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow oily compound 70-6 (120 mg, 0.24 mmol, yield 88.68%). LC-MS: 545.3 [M+1] + .

[1114] Step Six:

[1115] Compound 70-6 (142 mg, 0.28 mmol) and HCl / dioxane (1.0 M, 10 mL) were added to a 25 mL three-necked flask. After stirring for 2 h, the reaction was monitored by LC-MS until complete. The solution was evaporated to dryness to give a yellow oily compound 70-7 (100 mg, 0.2461 mmol, yield 87.77%). LC-MS: 407.2 [M+1] + .

[1116] Step Seven:

[1117] Compound 70-7 (100 mg, 0.25 mmol), HATU (135 mg, 0.36 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (49 mg, 0.32 mmol), DIPEA (140 mg, 1.08 mmol), and DMF (5 mL) were added to a 25 mL three-necked flask. The mixture was stirred for 16 h, and the reaction was monitored by LC-MS until complete. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (PE:EA = 1:1) to give a white solid, compound I-70 (18.6 mg, 0.03 mmol, yield 13.9%). LC-MS: 543.1 [M+1] + . 1H NMR(400MHz,MeOD)δ7.90(t,J=8.2Hz,1H),7.59(d,J=7.1Hz,2H),7.51(d,J=2 .0Hz,1H),7.48–7.36(m,3H),7.18(s,1H),7.15(d,J=2.8Hz,1H),6.83(d,J=2 .0Hz,1H),5.90(s,1H),5.75–5.63(m,1H),5.47–5.35(m,1H),3.61–3.48(m,3 H),3.37(s,1H),3.18-3.09(m,1H),1.53(d,J=7.1Hz,3H),1.49–1.44(m,5H).

[1118] Example 70: Compound I-71

[1119]

[1120] Step 1:

[1121] Compound 71-1 (0.88 g, 3.1 mmol), [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyl]trifluoromethanesulfonate (0.88 g, 3.1 mmol), K₂CO₃ (41.76 g, 12.7 mmol), and ACN (50 mL) were added to a 250 mL three-necked flask. The mixture was purged three times with argon gas, heated to reflux, and reacted for 16 h. The reaction was then monitored by LC-MS to confirm completion. The concentrated solution was extracted three times with ethyl acetate. The combined organic phases were washed with salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 3:1) to give a yellow oily compound 71-2 (0.88 g, 1.7 mmol, yield 56%). LC-MS: 506.3 [M+1] + .

[1122] Step Two:

[1123] Compound 71-2 (700 mg, 1.39 mmol), hydrazine hydrate (0.277 g, 5.54 mmol), and EtOH (10 mL) were added to a 25 mL three-necked flask. The mixture was purged three times with argon gas, heated to reflux, and reacted for 2–3 h. The reaction was monitored by LC-MS until complete. The concentrated solution was diluted with water, separated by reverse-phase column chromatography (acetonitrile:water = 1:3), and concentrated to give a yellow oily compound 71-3 (360 mg, 0.96 mmol, yield 69.25%). LC-MS: 376.3 [M+1] + .

[1124] Step 3:

[1125] Compound 71-3 (360 mg, 0.96 mmol), CDI (360 mg, 2.22 mmol), and THF (10 mL) were added to a 25 mL three-necked flask. The mixture was heated to 50 °C and reacted for 16 h. The reaction was monitored by LC-MS until completion. The solution was concentrated, extracted three times with ethyl acetate, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1) to give a yellow oily compound 71-4 (300 mg, 0.75 mmol, yield 77.94%). LC-MS: 803.4 [2 M + 1] + .

[1126] Step Four:

[1127] Compound 71-4 (100 mg, 0.25 mmol) and HCl / dioxane (1.0 M, 5 mL) were added to a 25 mL three-necked flask. After stirring for 2 h, the reaction was monitored by LC-MS until complete. The solution was evaporated to dryness to give a yellow oily compound 71-5 (60 mg, 0.20 mmol, yield 79.93%). LC-MS: 603.3 [2 M + 1] + .

[1128] Step 5:

[1129] Compound 71-5 (50 mg, 0.17 mmol), (2S)-2-(tert-butylaminocarbonate)-2-phenyl-acetic acid (50 mg, 0.19 mmol), EDCI (65 mg), and Py (5 mL) were added to a 25 mL three-necked flask. The mixture was stirred for 2 h, and the reaction was monitored by LC-MS until complete. The solution was evaporated to dryness, extracted twice with ethyl acetate, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow oily compound 71-6 (90 mg, 0.16 mmol, yield 98.14%). LC-MS: 453.3 [M+1-Boc] + .

[1130] Step Six:

[1131] Compound 71-6 (80 mg, 0.15 mmol) and HCl / dioxane (1.0 M, 5 mL) were added to a 25 mL three-necked flask. After stirring for 2 h, the reaction was monitored by LC-MS until completion. The solution was evaporated to dryness to give a yellow oily compound 71-7 (60 mg, 0.13 mmol, yield 91.59%). LC-MS: 453.3 [M+1] + .

[1132] Step Seven:

[1133] Compound 71-7 (140 mg, 0.31 mmol), HATU (141 mg, 0.37 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (50 mg, 0.32 mmol), DIPEA (160 mg, 1.18 mmol), and DMF (5 mL) were added to a 25 mL three-necked flask. The mixture was stirred for 16 h, and the reaction was monitored by LC-MS until complete. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (PE:EA = 2:1) to give a white solid, compound I-71 (26 mg, 0.04 mmol, yield 14.27%). LC-MS: 589.2 [M+1] + . 1 H NMR (400MHz, MeOD) δ7.94(t,J=8.0Hz,1H),7.53(s,1H),7.23(t,J=11.7Hz,2H),6.81(s,1H),5.51–5.35(m,1H),5.16–4.99(m,2H),3.70–3 .40(m,3H),3.21(s,1H),2.46(s,1H),1.46(t,J=6.6Hz,6H),1.06(d,J=6.1Hz,3H),0.88(d,J=6.1Hz,6H),0.66–0.36(m,5H),0.29(s,3H).

[1134] Example 71: Compound I-72

[1135]

[1136] Step 1:

[1137] Zinc powder (19.73 g, 301.80 mmol) was added to a three-necked flask, purged three times with nitrogen, and heated to 200 °C under vacuum for 30 min. The mixture was then cooled to room temperature, and this process was repeated three times. At room temperature, 1,2-dibromoethane (0.92 g, 4.9 mmol) dissolved in DMF (20 mL) was added, and the mixture was heated to 90 °C. After reacting for 45 min, the mixture was cooled to room temperature, and TMSCl (0.11 g, 1.0 mmol) was added. The mixture was stirred at room temperature for 1 h, then compound 72-1 (5.35 g, 16.25 mmol) and DMF (35 mL) were added, and the mixture was heated to 35 °C. After reacting for 2.5 h, 2,5-dibromopyridine (5.0 g, 21 mmol) and Pd(PPh3)2Cl2 (0.57 g, 0.80 mmol) were added, and the mixture was heated to 68 °C and stirred for 2.5 h. The reaction was monitored by LC-MS until completion. The solution was filtered, and the filter cake was washed with a small amount of DMF until the dripping solution was colorless. The filtrate was added dropwise to water, followed by 200 mL of MTBE and 200 mL of water. After shaking, the mixture was separated. The aqueous phase was extracted twice with 500 mL of MTBE. The organic phases were combined, washed three times with water and once with salt, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (PE:EA = 4:1) to give a yellow oily compound 72-2 (4.87 g, 18.8 mmol, yield 80.5%). LC-MS: 259.0, 261.0 [M+1-Boc] + .

[1138] Step Two:

[1139] Compound 72-2 (2.00 g, 5.57 mmol) and HCl / dioxane (1.0 M, 40 mL) were added to a 100 mL three-necked flask. After stirring for 16 h, the reaction was monitored by LC-MS until completion. The solution was evaporated to dryness to give a yellow oily compound 72-3 (1.2 g, 4.6 mmol, yield 83%). LC-MS: 259.0, 261.0 [M+1] + .

[1140] Step 3:

[1141] Compound 72-3 (1.60 g, 6.18 mmol), [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoropropyl]trifluoromethanesulfonate (3.60 g, 9.65 mmol), K₂CO₃ (3.60 g, 26.0 mmol), and ACN (10 mL) were added to a 50 mL three-necked flask. The mixture was purged three times with argon gas, heated to reflux, and reacted for 16 h. The reaction was then monitored by LC-MS to confirm completion. The concentrated solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1) to give a yellow oily compound 72-4 (2.14 g, 4.44 mmol, yield 71.9%). LC-MS: 482.0, 480.0 [M+1] + .

[1142] Step Four:

[1143] Compound 72-4 (2.5 g, 5.2 mmol), hydrazine hydrate (1.04 g, 20.78 mmol), and EtOH (75 mL) were added to a 25 mL three-necked flask. The mixture was purged three times with argon gas, heated to reflux, and reacted for 2–3 h. The reaction was monitored by LC-MS until complete. The concentrated solution was diluted with water, separated by reverse-phase column chromatography (acetonitrile:water = 1:5), and concentrated to give a yellow oily compound 72-5 (700 mg, 1.99 mmol, yield 38%). LC-MS: 352.0, 354.0 [M+1] + .

[1144] Step 5:

[1145] Compound 72-5 (0.60 g, 1.7 mmol), CDI (0.55 g, 3.4 mmol), and THF (10 mL) were added to a 25 mL three-necked flask. The mixture was stirred overnight at room temperature and reacted for 16 h. The reaction was monitored by LC-MS until complete. The concentrated solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with water and salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:1) to give a yellow oily compound 72-6 (0.32 g, 0.85 mmol, 50% yield). LC-MS: 378.0, 380.0 [M+1] + .

[1146] Step Six:

[1147] Compound 72-6 (190 mg, 0.50 mmol), benzophenone imine (182 mg, 1.004 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), XantPhos (58 mg, 0.10 mmol), Cs2CO3 (488 mg, 1.50 mmol), and dioxane (8 mL) were added to a 25 mL three-necked flask. The mixture was heated and stirred overnight, and the reaction was monitored by LC-MS until complete. The solution was filtered, concentrated, and extracted three times with ethyl acetate. The organic phases were combined, washed with water and salt, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 10:1) to give a yellow oily compound 72-7 (180 mg, 0.39 mmol, 80% yield). LC-MS: 465.2 [M+1] + .

[1148] Step Seven:

[1149] Compound 72-7 (100 mg, 0.2153 mmol), SOCl2 (2 mL), and MeOH (10 mL) were added to a 10 mL three-necked flask. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by LC-MS until completion. The concentrated solution was extracted three times with ethyl acetate. The combined organic phases were washed with salt, dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase column chromatography (H2O:MeOH = 1:1) to give a yellow oily compound 72-8 (60 mg, 0.1909 mmol, yield 88.67%). LC-MS: 315.0 [M+1] + .

[1150] Step 8:

[1151] Compound 72-8 (80 mg, 0.25 mmol), (2S)-2-(tert-butylaminocarbonate)-2-phenyl-acetic acid (84 mg, 0.31 mmol), EDCI (75 mg, 0.39 mmol), and Py (2 mL) were added to a 25 mL three-necked flask. After stirring for 2 h, the reaction was monitored by LC-MS until complete. The mixture was evaporated to dryness, extracted twice with ethyl acetate, and the organic phases were combined, washed with salt, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography (DCM:MeOH = 10:1) to give a yellow oily compound 72-9 (80 mg, 0.14 mmol, yield 55.57%). LC-MS: 566.1 [M+1] + .

[1152] Step Nine:

[1153] Compound 72-9 (60 mg, 0.11 mmol) and HCl / dioxane (1.0 M, 2 mL) were added to a 25 mL three-necked flask. The mixture was reacted overnight at room temperature, and the reaction was monitored by LC-MS until completion. The solution was evaporated to dryness to give a yellow oily compound 72-10 (40 mg, 0.09 mmol, yield 81%). LC-MS: 466.2 [M+1] + .

[1154] Step 10:

[1155] To a 10 mL round-bottom flask, add compound 72-10 (0.11 mmol, 0.05 g), HATU (0.15 mmol, 0.06 g), DIPEA (0.43 mmol, 0.06 g), 2-isopropylpyrazole-3-carboxylic acid (0.11 mmol, 0.02 g), and DMF (0.11 mmol, 5.00 mL). Stir at room temperature, spot the mixture onto a TLC plate to confirm completion, add water, extract with EA, and perform column chromatography (DCM:MeOH = 10:1) to give a white solid, compound 72-11 (30 mg, 0.05 mmol, yield 59%). LC-MS: 602.0 [M+1] + .

[1156] Step Eleven:

[1157] Compound 72-11 (0.10 mmol, 0.06 g), lithium hydroxide (10.00 mg), methanol (5.00 mL), and water were added to a 25 mL round-bottom flask and stirred at room temperature. The reaction was spotted onto a TLC plate until complete. The pH was adjusted to 2-3 with 1 M hydrochloric acid, and the sample was prepared to give a white solid, compound I-72 (3 mg, 0.005 mmol, yield 5.11%). LC-MS: 588.2 [M+1] + , 1 H NMR(400MHz,MeOD)δ8.75(d,J=3.8Hz,1H),8.06(s,1H),7.54(d,J=1.9Hz,2H),7.35(t,J= 8.2Hz,1H),6.81(d,J=2.0Hz,1H),6.37(d,J=8.6Hz,1H),5.50–5.21(m,4H),4.56(dd,J=9. 7,3.7Hz,3H),2.20(d,J=7.7Hz,1H),2.09–2.01(m,2H),1.62(d,J=7.5Hz,2H),1.24(d,J=6 .4Hz,4H),0.92(t,J=6.8Hz,4H),0.85–0.77(m,2H),0.57–0.45(m,4H),0.43–0.32(m,3H).

[1158] Example 72: Compound I-73

[1159]

[1160] Step 1:

[1161] In a 100 mL three-necked round-bottom flask, methyl magnesium bromide solution (3 M, 3.0 mL, 3.0 mmol) was slowly added dropwise to 15 mL of anhydrous tetrahydrofuran solution of compound 73-1 (475 mg, 0.127 mmol, reference WO2024121427), which was cooled in an ice-water bath. The reaction was stirred for 2 hours until the starting material was consumed. A saturated ammonium chloride solution was then added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined extracts were washed successively with water and saturated brine. The extracts were 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 = 10:0–1:1) to give the target compound 73-2 (310 mg, 0.79 mmol) as a white solid. LC-MS: 389.9 [M+H] + .

[1162] Step Two:

[1163] In a 100 mL round-bottom flask, a 15 mL solution of compound 73-2 (310 mg, 0.79 mmol) in dichloromethane was cooled to 0 °C in an ice-water bath. Then, Dysmart oxidant (513 mg, 1.21 mmol) was added to the reaction solution. The reaction solution was slowly heated to room temperature and stirred for 0.5 hours. LC-MS monitoring showed complete consumption of the starting material. Water was added to quench the reaction solution, and saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7–8. The solution was extracted three times with ethyl acetate, and the combined extracts were washed successively with water and saturated brine. The extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1) to give a colorless oily target compound 73-3 (300 mg, 0.77 mmol). LC-MS: 387.9 [M+H] + .

[1164] Step 3:

[1165] In a 100 mL round-bottom flask, 2,2-difluoropropane-1,3-diamine dihydrochloride (102 mg, 0.56 mmol) was added to a 20 mL isopropanol solution of compound 73-3 (180 mg, 0.46 mmol). The reaction solution was heated to 60 °C under argon protection and stirred for 16 hours. Then, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Methanol (10 mL) was added to the round-bottom flask and stirred until clear. Sodium cyanoborohydride (60 mg, 0.93 mmol) was added to the reaction solution and stirred for 10 minutes. Then, glacial acetic acid (60 mg, 1.02 mmol) was added dropwise. The reaction solution was heated to 40 °C and stirred for another 16 hours. The reaction solution was then cooled to room temperature, and water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the combined extracts were washed successively with water and saturated brine. The extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give a colorless oily compound 73-4 (190 mg, 0.46 mmol). LC-MS: 481.9 [M+H] + .

[1166] Step Four:

[1167] In a 100 mL round-bottom flask, N,N'-carbonyldiimidazole (70 mg, 0.4 mmol) was added sequentially to a 10 mL acetonitrile solution of compound 73-4 (190 mg, 0.4 mmol), and the mixture was stirred at room temperature for 1 hour. LC-MS monitoring showed that the starting material had been completely consumed. The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in ethyl acetate solution. The solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–15:1) to give a white solid compound 73-5 (140 mg, 0.4 mmol). LC-MS: 507.8 [M+H] + .

[1168] Step 5:

[1169] In a 100 mL round-bottom flask, 1 mL of ethyl hydrogen chloride solution (1 M, 1.0 mmol) was added to a 20 mL solution of compound 73-5 (140 mg, 0.4 mmol) in dichloromethane. The reaction mixture was incubated at room temperature and stirred for 2 hours until the starting material was consumed. The reaction mixture was then concentrated under reduced pressure to obtain the crude product compound 73-6, which was used directly in the next reaction without further purification. LC-MS: 408.1 [M+H] + .

[1170] Step Six:

[1171] In a 100 mL round-bottom flask, triethylamine (30 mg, 0.3 mmol) and HATU (50 mg, 0.12 mmol) were added sequentially to a solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (20 mg, 0.13 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was then placed at room temperature and stirred for 0.5 hours. Compound 73-6 (35 mg, 0.07 mmol) was then added to the reaction mixture, 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. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0–1:1; dichloromethane:methanol = 1:0–20:1) to give the target compound I-73 (25 mg, 0.036 mmol) as a white solid. LC-MS: 543.8 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.31(d,J=5.3Hz,1H),8.16(d,J=5.7Hz,1H),7.55(d,J=2.0H z,1H),7.12(d,J=5.3Hz,1H),6.83(d,J=2.1Hz,1H),5.68(d,J=7.4Hz,1H),5.41(p,J=6.7H z,1H),4.96(d,J=6.8Hz,1H),3.60(d,J=8.1Hz,3H),3.31–3.21(m,1H),1.58(d,J=7.1Hz, 3H),1.47(dd,J=6.7,5.5Hz,6H),1.00–0.76(m,3H),0.61–0.43(m,3H),0.42–0.18(m,5H).

[1172] Example 73: Compound I-74

[1173]

[1174] In a 100 mL round-bottom flask, triethylamine (30 mg, 0.26 mmol) and HATU (60 mg, 0.16 mmol) were added sequentially to 5 mL of DMF containing 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (30 mg, 0.2 mmol). The reaction mixture was then stirred at room temperature for 0.5 hours. Compound 73-6 (40 mg, 0.1 mmol) was then added, 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 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 the target compound I-74 (25 mg, 0.036 mmol) as a white solid. LC-MS: 517.8 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.31(d,J=5.2Hz,1H),8.15(d,J=6.0Hz,1H),7.13(d,J=5.2Hz,1H),5.72-5.62(m,1H),5.03(d,J=5.6Hz,1 H),3.68-3.53(m,3H),3.30–3.21(m,1H),2.57(s,3H),1.58(d,J=7.2Hz,3H),0.97-0.81(m,3H),0.64–0.44(m,3H),0.43–0.23(m,5H).

[1175] Example 74: Compound I-75

[1176]

[1177] EDCI (180 mg, 0.9390 mmol) was added to a pyridine (5 mL) solution of compound I-46 (100 mg, 0.1705 mmol) and 1H-imidazol-2-amine (42 mg, 0.5055 mmol), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated, the reaction mixture was diluted with water, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound I-75 (35 mg, 0.05371 mmol, yield 31.50%) as a white solid. LC-MS: 651.8 [M+1] + . 1H NMR(400MHz,MeOD)δ7.62-7.57(m,1H),7.54(d,J=2.0Hz,1H),7.48-7.43(m,1 H),7.33-7.25(m,1H),7.11(d,J=7.7Hz,1H),6.84–6.78(m,3H),5.47-5.37(m, 1H),5.29–5.20(m,1H),4.92-4.88(m,1H),3.92-3.71(m,2H),3.58–3.35(m,3H ),3.13-3.03(m,1H),1.53-1.43(m,6H),0.96–0.72(m,3H),0.62–0.16(m,8H).

[1178] Example 75: Compound I-76

[1179]

[1180] Step 1:

[1181] EDCI (393 mg, 2.05 mmol) was added to a pyridine (5 mL) solution of compound I-46 (300 mg, 0.5114 mmol) and N-methoxymethylamine hydrochloride (98 mg, 1.005 mmol), and the reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated, the reaction mixture was diluted with water, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine and concentrated to obtain the residue, which was purified by column chromatography to give compound 76-1 (302 mg, 0.4796 mmol, yield 93.78%) as a white solid. LC-MS: 630.4 [M+1] + .

[1182] Step Two:

[1183] At -78°C, diisobutylaluminum hydride (1.5 mL, 1.5 mmol) was added to a tetrahydrofuran (5 mL) solution of compound 76-1 (302 mg, 0.4796 mmol), and the mixture was stirred for 3 hours. Anhydrous sodium sulfate was added and stirred for half an hour. The mixture was filtered and concentrated to obtain a residue, which was purified by column chromatography to give a white solid compound 76-2 (270 mg, 0.4732 mmol, yield 98.67%). LC-MS: 570.8 [M+1] + .

[1184] Step 3:

[1185] Sodium cyanoborohydride (125 mg, 1.989 mmol) was added to a methanol (5 mL) solution of compound 76-2 (285 mg, 0.4995 mmol) and methylamine hydrochloride (67 mg, 0.9923 mmol, 100 mass%). The reaction mixture was stirred overnight at room temperature under argon protection. The reaction was quenched 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 compound I-76 (22 mg, 0.03756 mmol, yield 7.5%) as a white solid. LC-MS: 586.4 [M+1] + . 1 H NMR(400MHz,MeOD)δ7.64-7.60(m,1H),7.55(d,J=2.0Hz,1H),7.47-7.42(m,1H),7 .33(t,J=7.8Hz,1H),7.12-7.06(m,1H),6.81(d,J=2.0Hz,1H),5.48-5.38(m,1H), 4.92-4.87(m,1H),4.69-4.61(m,1H),3.64-3.53(m,1H),3.52-3.36(m,4H),3.12- 2.90(m,3H),2.70(s,3H),1.53-1.43(m,6H),0.95-0.74(m,3H),0.61-0.20(m,8H).

[1186] Example 76: Compound I-77

[1187]

[1188] Step 1:

[1189] Butyllithium (19 mL, 30 mmol, 1.6 mmol / mL) was added to a tetrahydrofuran (60 mL) solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (compound 77-2, 5.5 g, 30 mmol) at -78 °C, and the reaction mixture was stirred at -78 °C for 0.5 h. Compound 77-1 (6.0 g, 26 mmol) was added and stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution 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 oily compound 77-3 (1.82 g, 5.39 mmol, yield 21%). LC-MS: 338.2 [M+1] + .

[1190] Step Two:

[1191] Hydrochloric acid (50 mL, 12.5 mmol, 0.25 mmol / mL) was added to a 25 mL solution of compound 77-3 (1.82 g, 5.39 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (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 77-4 (1.0 g, 4.1 mmol, 77% yield). LC-MS: 243.1 [M+1] + .

[1192] Step 3:

[1193] To a solution of compound 77-4 (500 mg, 2.0644 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (1.4 g, 3.8 mmol) in acetonitrile (15 mL), N,N-diisopropylethylamine (520 mg, 4.0257 mmol) was added. 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 compound 77-5 (420 mg, 0.9024 mmol, yield 43.71%) as a yellow solid. LC-MS: 466.0 [M+1] + .

[1194] Step Four:

[1195] Palladium on carbon (40 mg) was added to a methanol (20 mL) solution of compound 77-5 (220 mg, 0.4727 mmol), and the reaction mixture was stirred for 2 hours at room temperature under hydrogen protection. The solution was then filtered and concentrated to give a yellow solid, compound 77-6 (172 mg, 0.3950 mmol, yield 83.57%). LC-MS: 436.2 [M+1] + .

[1196] Step 5:

[1197] Hydrazine hydrate (0.5 mL) was added to a 5 mL ethanol solution of compound 77-6 (172 mg, 0.3950 mmol), and the reaction mixture was stirred at 50 °C under argon protection for 2 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography to give a yellow solid compound 77-7 (100 mg, 0.3275 mmol, yield 83.92%). LC-MS: 306.2 [M+1] + .

[1198] Step Six:

[1199] N,N'-carbonyldiimidazole (70 mg, 0.4317 mmol) was added to a tetrahydrofuran (50 mL) solution of compound 77-7 (100 mg, 0.3275 mmol), and 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 77-8 (60 mg, 0.1811 mmol, yield 55.29%). LC-MS: 332.1 [M+1] + .

[1200] Step Seven:

[1201] EDCI (160 mg, 0.8346 mmol) was added to a pyridine (5 mL) solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propionic acid (50 mg, 0.1857 mmol) and compound 77-8 (50 mg, 0.1509 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, 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 77-9 (75 mg, 0.1287 mmol, yield 85.30%) as a white solid. LC-MS: 582.8 [M+1] + .

[1202] Step 8:

[1203] A solution of compound 77-9 (75 mg, 0.1287 mmol) in dichloromethane (2 mL) was added to trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to give a yellow solid, compound 77-10 (62 mg, 0.1285 mmol, yield 99.82%). LC-MS: 483.2 [M+1] + .

[1204] Step Nine:

[1205] To a solution of compound 77-10 (62 mg, 0.1285 mmol) and 2-isopropylpyrazole-3-carboxylic acid (25 mg, 0.16216 mmol) in N,N-dimethylformamide (3 mL), HATU (69 mg, 0.18147 mmol) and triethylamine (25 mg, 0.24706 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-77 (23 mg, 0.03718 mmol, yield 28.94%) as a white solid. LC-MS: 619.3 [M+1] + . 1 HN MR(400MHz,MeOD)δ7.88-7.82(m,1H),7.54(d,J=2.0Hz,1H),7.18-7.08(m,2H ),6.80(d,J=2.0Hz,1H),5.47-5.37(m,1H),4.99(d,J=7.0Hz,1H),4.83-4.76 (m,1H),3.75(s,3H),3.72-3.61(m,1H),3.54-3.41(m,3H),3.35-3.28(m,1H) ,3.19-3.11(m,1H),1.53-1.43(m,6H),0.96-0.78(m,3H),0.60-0.23(m,8H).

[1206] Example 77: Compound I-78

[1207]

[1208] Step 1:

[1209] To a solution of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (40 mg, 0.31228 mmol) and compound 39-9 (138 mg, 0.2977 mmol) in N,N-dimethylformamide (3 mL), HATU (178 mg, 0.46814 mmol) and triethylamine (63 mg, 0.62259 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-78 (70 mg, 0.1220 mmol, yield 40.99%) as a white solid. LC-MS: 574.3 [M+1] + . 1H NMR (400MHz, MeOD) δ7.53(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),5.04(t,J=8.0Hz,1H),4.94(d,J=6.7Hz,1H),3.84–3.63(m,2H) ,3.56–3.36(m,2H),3.30–3.17(m,1H),3.05–2.90(m,1H),2.73-2.68(m,3H),2.56(s,3H),0.98–0.75(m,3H),0.62–0.22(m,8H).

[1210] Example 78: Compound I-79, Compound I-80

[1211]

[1212] Step 1:

[1213] N,N-diisopropylethylamine (4.9 g, 38 mmol) was added to an acetonitrile (80 mL) solution of compound 79-1 (5.0 g, 19 mmol) and [3-(1,3-dioxoisoindoline-2-yl)-2,2-difluoro]trifluoromethanesulfonate (11.3 g, 30.3 mmol). The reaction mixture was stirred at 50 °C under argon protection for 6 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 compound 79-2 (4.4 g, 9.8 mmol, yield 51%) as a yellow solid. LC-MS: 448.1 [M+1] + .

[1214] Step Two:

[1215] Hydrazine hydrate (2 mL) was added to a 15 mL ethanol solution of compound 79-2 (4.4 g, 9.8 mmol), and the reaction mixture was stirred at 50 °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, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid compound 79-3 (2.1 g, 6.6 mmol, yield 67%). LC-MS: 318.1 [M+1] + .

[1216] Step 3:

[1217] N,N'-carbonyldiimidazole (3.21 g, 19.8 mmol) was added to a tetrahydrofuran (30 mL) solution of compound 79-3 (2.1 g, 6.6 mmol), and 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 compound 79-4 (2.18 g, 6.35 mmol, yield 96%) as a yellow solid. LC-MS: 344.1 [M+1] + .

[1218] Step Four:

[1219] Pd / C (220 mg) was added to a methanol (50 mL) solution of compound 79-4 (2.18 g, 6.35 mmol), and the reaction mixture was stirred for 2 hours under hydrogen protection. The reaction mixture was filtered and concentrated to give a white solid compound 79-5 (1.98 g, 6.32 mmol, yield 99.5%). LC-MS: 314.2 [M+1] + .

[1220] Step 5:

[1221] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propionic acid (1.79 g, 6.65 mmol) and compound 79-5 (1.98 g, 6.32 mmol) in N,N-dimethylformamide (25 mL), HATU (3.6 g, 9.47 mmol) and triethylamine (1.28 g, 12.6 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 79-6 (2.52 g, 4.46 mmol, yield 70.6%) as a yellow solid. LC-MS: 564.8 [M+1] + .

[1222] Step Six:

[1223] To a solution of compound 79-6 (2.52 g, 4.46 mmol) in dichloromethane (2 mL), 2 mL of trifluoroacetic acid was added, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine, dried, and concentrated to obtain the residue, which was purified by column chromatography to give a yellow solid, compound 79-7 (2.05 g, 4.41 mmol, yield 98.9%). LC-MS: 465.3 [M+1] + .

[1224] Step Seven:

[1225] To a solution of compound 79-7 (2.17 g, 4.67 mmol) and 2-isopropylpyrazole-3-carboxylic acid (791 mg, 5.1307 mmol) in N,N-...

Claims

1. Compounds of Formula I, their pharmaceutically acceptable salts, their solvates, their stereoisomers, their tautomers, their prodrugs, or their metabolites: in, R 12 for R 1 R 2 R 3 R 12-1 Each is independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group; R 12-2 R 12-3 R 12-4 and R 12-5 Independently, it is H, deuterium, halogen, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, CN, or 3-8 membered heterocyclic alkyl; the heteroatom in the 3-8 membered heterocyclic alkyl is independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2, 3 or 4; m1 and m2 are independently 1, 2 or 3; R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4 -2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups, or R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group; R 4-4 Independently, it is a C3–C8 cycloalkyl group; R 4a and R 4b It is independently a halogen or a C1-C6 alkyl group; R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, -NR 5-4 R 5 -5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups; R 5-1-1 R 5-1-2 Halogens are independent of each other; R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups; R 5-2-1 R 5-2-2 Halogens are independent of each other; R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens; R 5-3-1 It is a halogen; R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups R 5-4-1 Halogens and hydroxyl groups; R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups; R 5-4-2-1 Halogens and hydroxyl groups; R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , -NR 5-6-6 R 5-6-7 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1-1 It is a halogen; R 5-6-1-2 Hydroxyl group, -COOH; R 5-6-1-3 It consists of C1 to C6 alkyl, oxo, and hydroxyl groups; R 5-6-1-4 For oxygenation; R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl. R 5-6-4 It is hydrogen or a C1-C6 alkyl group; R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-5-1 It is a C1 to C6 alkyl group, and is bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups, -NR 5-6-5-1-2 R 5 -6-5-1-3 -COOH; R 5-6-5-1-1 It is a hydroxyl group; R 5-6-5-1-2 R 5-6-5-1-3 It is an H, C1-C6 alkyl group; R 5-6-6 R 5-6-7 It is an H, C1-C6 alkyl group; R 13 For H, R 9 For -NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ; R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups; R 9-1-1-1 It is a halogen; R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups; R 9-3-1 It is a halogen; R 9-7 Independently for -CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, -COOH, -COOR 9-7-4 5-12 yuan heteroaryl, surrounded by one or more R 9-7-5 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 9-7-5 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-1 R 9-7-2 Each of the following is independently hydrogen, C1-C6 alkyl, 5-12-membered heteroaryl, or 4-8-membered heterocyclic alkyl; the heteroatoms in the 5-12-membered heteroaryl and 4-8-membered heterocyclic alkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-3 Independently oxidized or halogenated; R 9-7-4 It is an alkyl group of C1 to C6; R 9-7-5 For oxygenation; R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 Substituted C1–C6 alkyl groups, C1–C6 alkoxy groups, halogens, C3–C8 cycloalkyl groups, C3–C8 heterocycloalkyl groups, -CONR 10-2 RR 10-3 The heteroatoms in the C3-C8 heterocyclic alkyl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4. R 10-1 It is a halogen, a C1-C6 alkoxy group, a 5-6 membered heterocyclic alkyl group, or a 5-6 membered heterocyclic alkyl group substituted with one or more C1-C6 alkyl groups; R 10-2 R 10-3 Each is independently an H, C1-C6 alkyl group; Or, R 10-2 R 10-3 Together with the carbon atom attached thereto, they form a 5-6 membered heterocyclic alkyl group or are bounded by one or more R atoms. 10a Substituted 5-6 membered heterocyclic alkyl groups; R 10a It is independently a C1 to C6 alkyl group; Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N; It can be a single bond or a double bond.

2. The compound of formula I as described in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite: in, R 12 for R 1 R 2 R 3 R 12-1 Each is independently hydrogen, a C1-C6 alkyl group, or a C3-C8 cycloalkyl group; R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4 -2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups, or R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group; R 4-4 Independently, it is a C3–C8 cycloalkyl group; R 4a and R 4b It is independently a halogen or a C1-C6 alkyl group; R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, -NR 5-4 R 5 -5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups; R 5-1-1 R 5-1-2 Halogens are independent of each other; R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups; R 5-2-1 R 5-2-2 Halogens are independent of each other; R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens; R 5-3-1 It is a halogen; R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups R 5-4-1 Halogens and hydroxyl groups; R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups; R 5-4-2-1 Halogens and hydroxyl groups; R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , -NR 5-6-6 R 5-6-7 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1-1 It is a halogen; R 5-6-1-2 Hydroxyl group, -COOH; R 5-6-1-3 It consists of C1 to C6 alkyl, oxo, and hydroxyl groups; R 5-6-1-4 For oxygenation; R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl. R 5-6-4 It is hydrogen or a C1-C6 alkyl group; R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-5-1 It is a C1 to C6 alkyl group, bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups, -NR 5-6-5-1-2 R 5 -6-5-1-3 -COOH; R 5-6-5-1-1 It is a hydroxyl group; R 5-6-5-1-2 R 5-6-5-1-3 It is an H, C1-C6 alkyl group; R 5-6-6 R 5-6-7 It is an H, C1-C6 alkyl group; R 13 For H, R 9 For -NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ; R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups; R 9-1-1-1 It is a halogen; R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups; R 9-3-1 It is a halogen; R 9-7 Independently for -CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, -COOH, -COOR 9-7-4 5-12 yuan heteroaryl, surrounded by one or more R 9-7-5 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 9-7-5 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-1 R 9-7-2 Each of the following is independently hydrogen, C1-C6 alkyl, 5-12-membered heteroaryl, or 4-8-membered heterocyclic alkyl; the heteroatom in the 5-12-membered heteroaryl or 4-8-membered heterocyclic alkyl is independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-3 Independently oxidized or halogenated; R 9-7-4 It is an alkyl group of C1 to C6; R 9-7-5 For oxygenation; R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 Substituted C1–C6 alkyl groups, C1–C6 alkoxy groups, halogens, C3–C8 cycloalkyl groups, C3–C8 heterocycloalkyl groups, -CONR 10-2 RR 10-3 The heteroatoms in the C3-C8 heterocyclic alkyl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4. R 10-1 It is a halogen, a C1-C6 alkoxy group, a 5-6 membered heterocyclic alkyl group, or a 5-6 membered heterocyclic alkyl group substituted with one or more C1-C6 alkyl groups; R 10-2 R 10-3 Each is independently an H, C1-C6 alkyl group; Or, R 10-2 R 10-3 Together with the carbon atom attached thereto, they form a 5-6 membered heterocyclic alkyl group or are bounded by one or more R atoms. 10a Substituted 5-6 membered heterocyclic alkyl groups; R 10a It is independently a C1 to C6 alkyl group; Y 1 Y 2 Y 3 Y 4 Y 5 Each can be independently represented as C or N; It can be a single bond or a double bond.

3. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite: characterized in that, Compounds represented by Formula I are shown in Formula I-1: Among them, R 12 for R 1 R 2 R 3 R 12-1 Each is independently hydrogen or a C1-C6 alkyl or a C3-C8 cycloalkyl; R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4 -2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups; R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group; R 4-4 Independently, it is a C3–C8 cycloalkyl group; R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5-5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups; R 5-1-1 R 5-1-2 Halogens are independent of each other; R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups; R 5-2-1 R 5-2-2 Halogens are independent of each other; R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens; R 5-3-1 It is a halogen; R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, and composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups R 5-4-1 Halogens and hydroxyl groups; R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups; R 5-4-2-1 Halogens and hydroxyl groups; R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , -NR 5-6-6 R 5-6-7 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 5-6-1-4 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1-1 It is a halogen; R 5-6-1-2 Hydroxyl group, -COOH; R 5-6-1-3 It consists of C1 to C6 alkyl, oxo, and hydroxyl groups; R 5-6-1-4 For oxygenation; R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl. R 5-6-4 It is hydrogen or a C1-C6 alkyl group; R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-5-1 It is a C1 to C6 alkyl group, bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups, -NR 5-6-5-1-2 R 5 -6-5-1-3 -COOH; R 5-6-5-1-1 It is a hydroxyl group; R 5-6-5-1-2 R 5-6-5-1-3 It is an H, C1-C6 alkyl group; R 5-6-6 R 5-6-7 It is an H, C1-C6 alkyl group; R 13 For H, R 9 For -NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ; R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups; R 9-1-1-1 It is a halogen; R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups; R 9-3-1 It is a halogen; R 9-7 Independent for CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, -COOH, -COOR 9-7-4 5-12 yuan heteroaryl, surrounded by one or more R 9-7-5 Substituted 5-12-membered heteroaryl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R groups 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups, 5-12 membered heteroaryl groups, and those with one or more R groups 9-7-5 The heteroatoms in the substituted 5-12-membered heteroaryl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-1 R 9-7-2 Each of the following is independently hydrogen, C1-C6 alkyl, 5-12-membered heteroaryl, or 4-8-membered heterocyclic alkyl; the heteroatoms in the 5-12-membered heteroaryl and 4-8-membered heterocyclic alkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-3 Independently oxidized or halogenated; R 9-7-4 It is an alkyl group of C1 to C6; R 9-7-5 For oxygenation; R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 Substituted C1–C6 alkyl groups, C1–C6 alkoxy groups, halogens, C3–C8 cycloalkyl groups, C3–C8 heterocycloalkyl groups, -CONR 10-2 RR 10-3 The heteroatoms in the C3-C8 heterocyclic alkyl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4. R 10-1 It is a halogen or a C1-C6 alkoxy group; R 10-2 R 10-3 Each is independently an H, C1-C6 alkyl group; Y 1 Y 2 Y 3 Y 4 Y 5 Each can be either C or N independently.

4. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, characterized in that, Its structural formula is shown in equation IA below: Among them, R 1 R 2 R 3 Each is independently hydrogen or a C1-C6 alkyl or a C3-C8 cycloalkyl; R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4 -2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12-membered heteroaryl groups, C1-C6 alkyl groups, or groups with one or more R groups 4-4 Substituted C1-C6 alkyl groups; R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group; R 4-4 Independently, it is a C3–C8 cycloalkyl group; R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5-5 C1 to C6 alkyl groups, with one or more R 5-6 Substituted C1-C6 alkyl groups, 4-8 membered heterocyclic alkyl groups, or alkyl groups with one or more R groups 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups; R 5-1-1 R 5-1-2 Halogens are independent of each other; R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups; R 5-2-1 R 5-2-2 Halogens are independent of each other; R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens; R 5-3-1 It is a halogen; R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups R 5-4-1 Halogens and hydroxyl groups; R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups; R 5-4-2-1 Halogens and hydroxyl groups; R 5-6 for 4-8 membered heterocyclic alkyl groups, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, COOR 5-6-4 , The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1 R 5-6-2 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-6-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-6-1-2 Substituted C3-C8 cycloalkyl, 4-8 membered heterocyclic alkyl, or substituted with one or more R 5-6-1-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-1-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-1-1 It is a halogen; R 5-6-1-2 It is a hydroxyl group; R 5-6-1-3 It is a C1 to C6 alkyl or oxoalkyl group; R 5-6-3 It can be oxo, thio, halogen, C1-C6 alkyl, or hydroxyl. R 5-6-4 It is hydrogen or a C1-C6 alkyl group; R 5-6-5 It is a 4-8 membered heterocyclic alkyl group, with one or more R 5-6-5-1 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-6-5-1 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 5-6-5-1 It is a C1 to C6 alkyl group, and is bonded by one or more R 5-6-5-1-1 Substituted C1-C6 alkyl groups; R 5-6-5-1-1 It is a hydroxyl group; R 9 For NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups, C1-C6 alkyl groups, and alkyl groups with one or more R groups 9-7 Substituted C1-C6 alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ; R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups; R 9-1-1-1 It is a halogen; R 9-3 R 9-4 R 9-5 R 9-6 Independently oxo, thio, nitro, halogen, hydroxyl, C1-C6 alkyl, or formed by one or more R 9-3-1 Substituted C1-C6 alkyl groups; R 9-3-1 It is a halogen; R 9-7 Independent for CONR 9-7-1 R 9-7-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-7-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 9-7-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 9-7-1 R 9-7-2 Each is independently hydrogen or a C1-C6 alkyl group; R 9-7-3 Independently oxidized or halogenated; R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 The substituted C1-C6 alkyl, C1-C6 alkoxy, halogen, C3-C8 cycloalkyl, and C3-C8 heterocycloalkyl; wherein the heteroatom in the C3-C8 heterocycloalkyl is independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4. R 10-1 It is a halogen or a C1-C6 alkoxy group.

5. The compound of Formula I as described in any one of claims 1-4, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite, characterized in that: in, R 1 R 2 R 3 Each is independently hydrogen or a C1-C6 alkyl group; R 4 It is a C3-C8 cycloalkyl group, with one or more R 4-1 Substituted C3-C8 cycloalkyl, 6-8 aryl, or with one or more R 4 -2 Substituted aryl, 6-12 membered heteroaryl, with one or more R 4-3 Substituted 6-12 heteroaryl groups; R 4-1 R 4-2 R 4-3 It is independently a halogen or a C1-C6 alkyl group; R 5 R 6 R 7 R 8 Each independently consists of hydrogen, halogen, NR 5-4 R 5 -5 4-8 membered heterocyclic alkyl groups, with one or more R 5-3 Substituted 4-8 membered heterocyclic alkyl groups; the 4-8 membered heterocyclic alkyl groups, substituted with one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3. R 5-1 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-1-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-1-2 Substituted C3-C8 cycloalkyl groups; R 5-1-1 R 5-1-2 Halogens are independent of each other; R 5-2 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-2-1 Substituted C1-C6 alkyl groups, C3-C8 cycloalkyl groups, or groups with one or more R groups 5-2-2 Substituted C3-C8 cycloalkyl groups; R 5-2-1 R 5-2-2 Halogens are independent of each other; R 5-3 It is hydrogen, C1 to C6 alkyl, and is surrounded by one or more R 5-3-1 Substituted C1-C6 alkyl groups and halogens; R 5-3-1 It is a halogen; R 5-4 R 5-5 Independently hydrogen, C1-C6 alkyl, or composed of one or more R 5-4-1 Substituted C1-C6 alkyl groups R 5-4-1 Halogens and hydroxyl groups; R 5-4-2 It is a C1 to C6 alkyl group, and is formed by one or more R 5-4-2-1 Substituted C1-C6 alkyl groups; R 5-4-2-1 Halogens and hydroxyl groups; R 9 For NR 9-1 R 9-2 4-8 membered heterocyclic alkyl groups, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 Substituted 7-12-membered heterocyclic alkyl groups; the 4-8-membered heterocyclic alkyl groups, substituted with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 Substituted 4-8-membered heteroaryl, 7-12-membered spirochetal alkyl, or with one or more R 9-5 Substituted 7-12 spirocycloalkyl, 7-12 fenoxanecycloalkyl, or substituted with one or more R 9-6 The heteroatoms in the substituted 7-12 fused heterocyclic alkyl groups are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4. R 9-1 R 9-2 Each is independently hydrogen, C1-C6 alkyl, or -CONR. 9-1-1 R 9-1-2 ; R 9-1-1 R 9-1-2 Each is independently hydrogen, a C1-C6 alkyl group, or composed of one or more R groups. 9-1-1-1 Substituted C1-C6 alkyl groups; R 9-1-1-1 It is a halogen; R 9-3 R 9-4 R 9-5 R 9-6 It is independently an oxo, thio, halogenated or C1-C6 alkyl group; R 10 R 11 Each is independently hydrogen, C1-C6 alkyl, and composed of one or more R groups. 10-1 The substituted C1-C6 alkyl, C1-C6 alkoxy, halogen, C3-C8 cycloalkyl, and C3-C8 heterocycloalkyl; wherein the heteroatom in the C3-C8 heterocycloalkyl is independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4. R 10-1 It is a halogen or a C1-C6 alkoxy group.

6. The compound of Formula I as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, characterized in that, The compounds represented by Formula I are shown in Formula IA-1 and Formula IA-2: Where L is R 9A It is independently a halogen, a C1-C6 alkyl group, an oxoalkyl group, or a C1-C6 haloalkyl group; s can be 0, 1, 2, 3, or 4; It is a 4-8 membered heterocyclic alkyl, a 4-12 membered heteroaryl, a 7-12 membered heterocyclic alkyl or a 7-12 membered heterocyclic alkyl; The definitions of other groups are as described in any one of claims 1-5; For example, compounds of formula IA-1 are shown as IA-1a: Compounds of formula IA-2 are shown as IA-2a: R 9A Independently, it is a halogen, a C1-C6 alkyl group, an oxoalkyl group, or a C1-C6 haloalkyl group; s is 0, 1, 2, 3, or 4; The definitions of other groups are as described in any one of claims 1-5; For example, compounds such as IA-2a are shown as IA-2a-1 or IA-2a-2: The definitions of other groups are as described in any one of claims 1-5.

7. The compound of Formula I as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, characterized in that, The compound shown in Formula I is shown in Formula IB: q is 0, 1, or 2; p is 0, 1, or 2; The definitions of other groups are as described in any one of claims 1-5; For example, the compound represented by formula IB is the same as that represented by formula IB-1: Formula IB-1 The definitions of other groups are as described in any one of claims 1-5; For example, compounds represented by formula IB-1 are shown as formula IB-1-1 or IB-1-2: The definitions of other groups are as described in any one of claims 1-5.

8. The compound of formula I as claimed in claim 6 or 7, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, characterized in that, It meets one or more of the following conditions: (1)R 5-6 for (2)R 9-7 for (3) 9. The compound of Formula I as claimed in any one of claims 1-5, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 It is a C1 to C6 alkyl group, preferably isopropyl; (2)R 4 It is cyclohexane or cyclooctane, preferably cyclohexane; (3)R 6 It is a halogen, preferably F; (4)R 10 It is an alkyl group of C1 to C6, preferably methyl; (5)R 9 The 4-8 membered heterocyclic alkyl group described herein, with one or more R 9-3 Substituted 4-8 membered heterocyclic alkyl, 4-8 membered heteroaryl, or substituted with one or more R 9-4 The heteroatoms in the substituted 4-8-membered heteroaryl groups are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4. (6)R 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are independently nitrogen or oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4.

10. The compound of Formula I as claimed in any one of claims 1-5, or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug, or metabolite thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 It is a C1-C6 alkyl group or a C3-C8 cycloalkyl group; (2)R 4 R 1 R 4-4 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; (3)R 6 It is a halogen; (4)R 9 In the context, the 4-8 membered heterocyclic alkyl group and one or more R 9-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is independently a 5-, 6-, or 7-membered heterocyclic alkyl group; (5)R 9 In the context, the 4-8 membered heterocyclic alkyl group and one or more R 9-3 In the substituted 4-8 membered heterocyclic alkyl groups, the heteroatoms are independently N or O, and the number is 2; (6)R 9 In the context, the 4-8 membered heteroaryl group and one or more R groups 9-4 In the substituted 4-8 heteroaryl group, the 4-8 heteroaryl group is independently a 5- or 6-heteroaryl group; (7)R 9 In the context, the 4-8 membered heteroaryl group and one or more R groups 9-4 In the substituted 4-8 membered heteroaryl groups, the heteroatoms are independently N or O, and the number is 3; (8)R 9 In the context, the 7-12 membered spirochetal alkyl group, surrounded by one or more R 9-5 The substituted 7-12 spirochetal alkyl groups are independently 8-membered spirochetal alkyl groups or 9-membered spirochetal alkyl groups; (9)R 9 In the context, the 7-12 membered spirochetal alkyl group, surrounded by one or more R 9-5 The heteroatoms in the substituted 7-12 membered spiroheterocyclic alkyl groups are independently N or O, and the number is 2 or 3; (10)R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 In the substituted 7-12-membered heterocyclic alkyl groups, the 7-12-membered heterocyclic alkyl group is independently an 8-membered heterocyclic alkyl group; (11)R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 The heteroatoms in the substituted 7-12 membered heterocyclic alkyl groups are independently N or O, and the number is 2 or 3; (12)R 9 In the context, the 7-12 membered heterocyclic alkyl group, surrounded by one or more R 9-6 The 7-12 fused heterocyclic alkyl group is a heterocyclic aryl group, preferably a 10- or 11-membered heterocyclic alkyl group; (13)R 10 It is hydrogen; (14)R 11 It is an alkyl group of C1 to C6; (15)R 12 It is an alkyl group of C1 to C6; (16)R 13 For H; (17)R 1 R 2 R 3 R 4-1 R 4-2 R 4-3 R 5-1 R 5-2 R 5-3 R 5-4 R 5-5 R 5-4-2 R 5-6-1 R 5-6-2 R 5-6- 3. R 9-1 R 9-2 R 9-1-1 R 9-1-2 R 9-3 R 9-4 R 9-5 R 9-6 R 10 R 11 R 4 R 5-6-6 R 5-6-7 R 12-1 R 5-6-5-1-2 R 5-6-5-1-3 R 10-2 R 10-3 In the above, the C1-C6 alkyl group and the C1-C6 alkyl group that has been substituted by one or more are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. (18)R 4-1 R 4-2 R 4-3 R 5 R 6 R 7 R 8 R 5-3 R 5-1-1 R 5-1-2 R 5-2-1 R 5-2-2 R 5-3-1 R 5-4-1 R 5-4-2-1 R 5 -6-3 R 9-1-1-1 R 9-3 R 9-3-1 R 9-4 R 9-5 R 9-6 R 10 R 11 R 10-1 In this context, the halogen is independently F, Cl, Br, or I; (19)R 5 R 6 R 7 R 8 In this context, the 4-8 membered heterocyclic alkyl group, surrounded by one or more R 5-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are nitrogen or oxygen, and the number of heteroatoms is 1 or 2. (20)R 5 R 6 R 7 R 8 In this context, the 4-8 membered heterocyclic alkyl group, surrounded by one or more R 5-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is a 5-membered ring or a 6-membered ring; (21)R 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 In the substituted 4-8 membered heterocyclic alkyl groups, the 4-8 membered heterocyclic alkyl group is a 5-membered ring or a 6-membered ring; (22)R 5-6 The 4-8 membered heterocyclic alkyl group, with one or more R 5-6-3 Substituted 4-8 membered heterocyclic alkyl groups, wherein the 4-8 membered heterocyclic alkyl group is substituted with one or more R 5-6-3 The heteroatoms in the substituted 4-8 membered heterocyclic alkyl groups are nitrogen or oxygen, and the number of heteroatoms is 1 or 2. (23)R 5-6-1 R 5-6-2 The 5-12 membered heteroaryl group, surrounded by one or more R 5-6-1-4 In the substituted 5-12 heteroaryl group, the 5-12 heteroaryl group is a 5-membered heteroaryl group; (24)R 9-7 R 9-7-1 R 9-7-2 In the middle, 5-12 member heteroaryl, surrounded by one or more R 9-7-5 In the substituted 5-12 heteroaryl group, the 5-12 heteroaryl group is either a 5-membered heteroaryl group or a 6-membered heteroaryl group; (25)R 9-7-1 R 9-7-2 The 4-8 membered heterocyclic alkyl group is a 5-membered or 6-membered heterocyclic alkyl group; (26)R 5-6-1 R 5-6-2 The 5-12 membered heteroaryl group, surrounded by one or more R 5-6-1-4 In the substituted 5-12 membered heteroaryl groups, the heteroatoms are nitrogen or oxygen, and the number is 1, 2 or 3; (27)R 9-7 R 9-7-1 R 9-7-2 In the middle, 5-12 member heteroaryl, surrounded by one or more R 9-7-5 In the substituted 5-12 membered heteroaryl groups, the heteroatoms are nitrogen or oxygen, and the number is 1, 2 or 3; (28)R 9-7-1 R 9-7-2 In 4-8 membered heterocyclic alkyl groups, the heteroatom is nitrogen or oxygen, and the number is 1 or 2; (29)R 9-7-1 R 9-7-2 In 4-8 membered heterocyclic alkyl groups, the heteroatom is nitrogen or oxygen, and the number is 1 or 2.

11. The pharmaceutically acceptable salt of Formula I or thereof, its solvate, its stereoisomer, its tautomer, its prodrug or its metabolite as described in any one of claims 1-5, characterized in that, It meets one or more of the following conditions: (1)R 1 It is isopropyl or cyclopentyl; (2)R 2 For H; (3)R 3 For H; (4)R 4 For cyclohexyl, (5)R 5 For H, For example, R 5 For H; (6)R 6 It is F, H, or does not exist; for example, R. 6 For F or H; (7)R 7 It is H, F, or does not exist; for example, R. 7 For F or H; (8)R 8 For H, (9)R 9 for (10)R 9-1 For H; (11)R 9-2 For -CONR 9-1-1 R 9-1-2 ; (12)R 9-1-1 For H; (13)R 9-1-2 For one or more R 9-1-1-1 Substituted C1-C6 alkyl groups; (14)R 9-1-1-1 For F; (15)R 9-3 For oxygenation; (16)R 10 For hydrogen, methyl, or For example, hydrogen or methyl; another example is R. 10 It is hydrogen; (17)R 11 H, methyl, ethyl, isopropyl, For example, H, methyl, ethyl, isopropyl, (18)R 5-6 for (19)R 12 for For example, For example, R 12 for (20)R 12-1 It is methyl; (21)R 13 For H, (22)Y 1 and Y 2 and Y 3 and Y 4 and Y 5 are all C; (23)Y 1 For N, Y 2 Y 3 Y 4 Y 5 All are C; (24)Y 5 For N, Y 2 Y 3 Y 4 Y 1 All are C; (25)Y 2 For N, Y 1 Y 3 Y 4 Y 1 All are C; (26)R 12-2 R 12-3 and R 12-4 Independently, it is H, halogen, or C3–C8 cycloalkyl; for example, it is H, F, or cyclopropyl. (27)R 12-5 It is a halogen; for example, it is F; (28) m1 is 1; (29) m2 is 1.

12. The compound of formula I as described in claim 11, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 12 for (2)R 4 for (3)R 5-6 for (4)R 9 Or R 9-7 for 13. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any of the following compounds:

14. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite, characterized in that, The pharmaceutically acceptable salt of the compound represented by Formula I is any of the following compounds:

15. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I has any of the following structures: Under the following conditions The compounds with retention times of 7.682 min or 7.766 min correspond to these compounds; Agilent Technologies HPLC 1260, test conditions as follows: Detector: DAD Mobile phase: A: Water containing 0.1% formic acid; B: Acetonitrile containing 0.1% formic acid; Column: Agilent EC-C18, 3.0 × 150 mm, 2.7 μm Gradient method: ； Under the following conditions The compounds with retention times of 10.03 min or 10.45 min; Waters preparative liquid phase (column Prep C18 5μm OBD TM (30*150mm), mobile phase: A%: water (containing 1% FA): 55%, B%: ACN (containing 1% FA): 45%, 37mL / min; Under the following conditions The compounds with retention times of 8.22 min or 8.60 min were identified; Waters preparative liquid chromatography (column) Prep C18 5μm OBD TM (30*150mm), mobile phase: A%: water (containing 1% FA): 50%, B%: ACN (containing 1% FA): 50%, 37mL / min; Under the following conditions The compounds with retention times of 5.4 min or 12.3 min correspond to the following: (Waters SFC 150) (column DAICEL CHIRALPAK AD-H (250 mm * 19 mm, 5 μm), mobile phase: [CO2]; B%: 30%–30% methanol, 50 mL / min).

16. A pharmaceutical composition comprising: (1) The compound of formula I as described in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, its prodrug, or its metabolite thereof, and (2) Pharmaceutically acceptable excipients.

17. Use of a compound of Formula I as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition as claimed in claim 21, in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by IL-17.

18. The use as claimed in claim 17, wherein the IL-17-mediated disease or condition is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, spondyloarthritis, and non-infectious uveitis; for example, the psoriasis is plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, or palmoplantar psoriasis.

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