Olefin derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to an olefin derivative inhibitor as well as a preparation method and application thereof. In particular, the present invention relates to a compound, a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof as an inhibitor in the treatment of autoimmune diseases.

Description

[0001] This application claims priority to Chinese patent application CN202410607180.3, filed May 15, 2024, and Chinese patent application CN202411166516.3, filed August 22, 2024. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to an olefin derivative inhibitor, its preparation method, and its application. Background Technology

[0003] TNFα is a member of the tumor necrosis factor (TNF) superfamily of proteins. It is a pro-inflammatory cytokine produced by macrophages and monocytes, participating in normal inflammatory and immune responses and driving the expression of other cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6). It possesses pro-inflammatory and immunomodulatory functions and is considered a pleiotropic cytokine. TNFα is expressed as a membrane-bound precursor (mTNF) and requires cleavage by TNFα convertase to release it as a soluble cytokine (sTNF). Both mTNFα and sTNFα are biologically active symmetrical trimeric proteins that signal through two separate tumor necrosis factor receptors, TNFR1 and TNFR2.

[0004] TNFR1 is widely expressed and primarily promotes TNF-induced inflammatory responses, while TNFR2 expression is limited to immune cells and maintains local immune homeostasis. The TNFR1 signaling pathway uses the typical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAP) pathways to transmit pro-inflammatory signals. Conversely, TNFR2 signals via the atypical NF-κB pathway. TNFR2 activation is crucial for Treg cell proliferation, survival, lineage stability, and thymic Treg cell development, and is involved in immune regulation. At physiological concentrations, sTNF activates TNFR1 but not TNFR2, while mTNF can activate both receptors.

[0005] TNFα is associated with the development of chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis, and certain types of juvenile idiopathic arthritis (JIA). RA is a common chronic inflammatory disease with a global prevalence of 0.51%. It is a complex autoimmune disease involving multiple inflammatory mediators that contribute to driving chronic inflammation in the joints, such as TNF, IL-6, and IL-1, as well as immune cells (T cells, B cells, monocytes, and macrophages). Rheumatoid arthritis can lead to cumulative joint damage and irreversible disability, but it can also cause extra-articular manifestations such as rheumatoid nodules, lung involvement, or vasculitis, as well as other systemic comorbidities. Current drug treatment for RA involves symptomatic medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying drugs, known as disease-modified antirheumatic drugs (DMARDs), which consist of small molecules and biologics. Disease-modifying antirheumatic drugs aim to improve patients' signs and symptoms of the disease and restore bodily function by inhibiting the progression of damage to cartilage and bone structures.

[0006] TNF-α inhibitors, such as infliximab, adalimumab, etanercept, golimumab, and pecelizumab, have ushered in a new era of rheumatic immunotherapy and have become one of the most powerful weapons in the treatment of rheumatic and immune diseases, receiving consistent recommendations from authoritative domestic and international guidelines. Anti-TNF-α biologics have been successfully used in the clinical treatment of RA, JIA, PsA, ankylosing spondylitis, psoriasis, and IBD, especially Crohn's disease (CD) and ulcerative colitis (UC). Anti-TNF-α biologics have revolutionized the treatment of RA; despite their significant success, the disease remission rate for RA remains quite low, with only 25% of patients achieving remission. Furthermore, there are reports that after 6 months of anti-TNF-α combined with methotrexate treatment, only 25% of patients achieved low disease activity (LDA). Other limitations of anti-TNF-α biologics include the occurrence of adverse reactions such as opportunistic infections, reactivation of latent tuberculosis, and an increased risk of certain malignancies (such as lymphoma), as well as the immunogenicity of the drug itself leading to the development of anti-drug antibodies (ADA), all of which may limit their efficacy. The high cost and intravenous administration of biologics pose significant obstacles to their widespread clinical use.

[0007] To date, there are no marketed small molecule inhibitors of TNFα, thus there is a high clinical demand for oral TNFα small molecule inhibitors. The aim of this project is to develop highly specific, safe, and effective oral TNFα small molecule inhibitors for the treatment of rheumatic immune diseases.

[0008] There are already patent reports on small molecule inhibitors of TNFα, such as WO2016050975A1, WO2018167176, WO2018197503, and WO2020084008 (Sanofi). Currently, the most advanced is SAR-441566, which is in Phase I clinical trials, while the others are in the preclinical development stage. This invention aims to develop an orally administered small molecule inhibitor of TNFα. Summary of the Invention

[0009] This invention provides a compound as shown in general formula (I) or formulas (A)-(C), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in,

[0012] L1 is selected from CONH;

[0013] M1 is selected from N or CR2;

[0014] Cycloyl G is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl;

[0015] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =CR 1-1 R 1-2 =NR 1-3 =N-OR 1-3 -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 Ra6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 -(CH2) m10 R a10 -(CH2) m14 P(O)R a14 R a15 -O(CH2) m15 P(O)R a14 R a15 or -NH(CH2) m16 P(O)R a14 R a15 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0016] Preferably, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =CR 1-1 R 1-2 =NR 1-3 =N-OR 1-3 -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 Or -(CH2) m10 R a10 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C6-10 One or more substitutions are made from aryl and 5-10 heteroaryl groups; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0017] R 1-1 and R 1-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0018] R 1-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally covered by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0019] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0020] R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0021] R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 ,-(CH2) m10 R a10 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0022] R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0023] Alternatively, two R5 connections can form a C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0024] R 8-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0025] R 8-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0026] R 9-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0027] R 9-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0028] R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R a10 R a14 and R a15 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0029] y is 1, 2, 3, 4 or 5;

[0030] z can be 0, 1, 2, or 3;

[0031] w can be 0, 1, 2, 3, or 4;

[0032] m1, m2, m3, m4, m5, m6, m8, m9, m10, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0033] m7 is selected from 0, 1, or 2.

[0034] The present invention also provides a compound of formula (II), (II-A), (II-B) or (II-C), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0035]

[0036] in,

[0037] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl;

[0038] R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0039] u is 0, 1, 2, 3 or 4; other groups are as shown in general formula (I) or formula (A)-(C).

[0040] The present invention also provides a compound of formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0041]

[0042] in,

[0043] The ring C is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C10. 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl; more preferably 5-6 membered heterocyclic or 5-6 membered heteroaryl;

[0044] R7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0045] v is 0, 1, 2, 3 or 4; other groups are shown in general formula (I).

[0046] This invention provides a compound as shown in general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0047]

[0048] in,

[0049] It can be a single bond or a double bond;

[0050] X1 is selected from NR4 or CR 4-1 R 4-2 ;

[0051] X2, X3, X5, and X6 are each independently selected from N or C;

[0052] X4, X7, X8, and X9 are each independently selected from N or CR3;

[0053] Cycloyl G is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-8Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl;

[0054] Cy1 is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-12 Cycloalkyl, 3-12-membered heterocyclic, 6-14-aryl, or 5-15-membered heteroaryl;

[0055] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =CR 1-1 R 1-2 =NR 1-3 =N-OR 1-3 -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 -(CH2) m10 R a10 -(CH2) m14 P(O)R a14 R a15 -O(CH2) m15 P(O)R a14 R a15 or -NH(CH2) m16 P(O)R a14 R a15 The amino group, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0056] R4, R 4-1 and R 4-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2)m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 ,-(CH2) m10 R a10 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0057] Or, R 4-1 and R 4-2 Together with the carbon atoms they bond with, they form a C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0058] R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0059] Alternatively, two R5 connections can form a C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl and 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0060] R 1-1 R 1-2 R 1-3 R3, R 8-1 R 8-2 R 9-1 R 9-2 R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R a10 R a14 and R a15 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0061] y is 1, 2, 3, 4 or 5;

[0062] w can be 0, 1, 2, 3, or 4;

[0063] m1, m2, m3, m4, m5, m6, m8, m9, m10, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0064] m7 is selected from 0, 1, or 2.

[0065] In some embodiments of the present invention, the compounds are shown as those of formulas (IV-1)-(IV-6).

[0066]

[0067] In this context, cycloCy2 is selected from phenyl or 5-6-membered heteroaryl groups;

[0068] Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl;

[0069] M1 is selected from N or CR2;

[0070] R2 and R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0071] u can be 0, 1, 2, 3 or 4;

[0072] z can be 0, 1, 2, or 3.

[0073] In some embodiments of the present invention, the compounds are as shown in formula (I-1), formula (I-2), formula (A-1), formula (A-2), formula (B-1), formula (B-2), formula (C-1), or formula (C-2):

[0074]

[0075] Among them, R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0076] Rings G, M1, R 8-1 R 8-2 R 9-1 R 9-2 R1, R3, R4, R5, R a14 R a15 The definitions of z, w, and y are as described above.

[0077] In some embodiments of the present invention, the compounds are as shown in formulas (IV-1-1)-(IV-2-6):

[0078]

[0079] Among them, R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0080] Rings G, M1, R 8-1 R 8-2 R 9-1 R 9-2 R1, R3, R4, R5, R a14 R a15 The definitions of z, w, and y are as described above.

[0081] In the general formulas of this invention, ring G is selected from 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl-6-membered heterocyclic, 6-membered heteroaryl-6-membered heterocyclic, 5-membered heteroaryl-5-membered heterocyclic, 6-membered heteroaryl-5-membered heterocyclic, 6-membered heteroaryl-5-membered heterocyclic, or 6-membered heteroaryl-6-membered heteroaryl.

[0082] The 5-membered heteroaryl group is preferably thiadiazolyl (e.g., 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), oxadiazolyl (e.g., 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), furanyl, thiophene, pyrroleyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole, or pyrazolyl; more preferably... More

[0083] The 6-membered heteroaryl group is preferably pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl;

[0084] The 5-membered heteroaryl and 5-membered heterocyclic group is preferred.

[0085] 5-membered heteroaryl and six-membered heterocyclic preferred

[0086] 5-membered heteroaryl and hexa-membered heteroaryl preferred

[0087] In the general formulas of this invention, ring B is selected from C. 3-6 Cycloalkyl or 5-6 membered heterocyclic groups; preferably

[0088] In the general formulas of this invention, the ring C is selected from 5-6 membered heteroaryl or 5-6 membered heterocyclic groups, preferably.

[0089] In each of the general formulas of this invention, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, P(O)R a14 R a15 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0090] Preferably, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0091] Preferably, R1 is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, -CH2F, -CHF2, -OCH2F, -OCHF2, methyl, ethyl, propyl, isopropyl, alkylmethyl, alkylethyl, hydroxymethyl, hydroxyethyl, amino, cyclopropyl, cyclobutyl, or cyclopentyl. The methyl, ethyl, propyl, isopropyl, alkylmethyl, alkylethyl, hydroxymethyl, hydroxyethyl, amino, cyclopropyl, cyclobutyl, and cyclopentyl groups may optionally be further modified by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0092] In some embodiments of the present invention, R1 is independently selected from... Among them, the Cy ring is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, C preferred 3-6 Cycloalkyl, more preferably cyclopropyl, cyclobutyl, or cyclopentyl; R 11 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C6-10 Aryl and 5-6 heteroaryl; x is 0, 1, 2, 3, 4, 5, 6 or 7.

[0093] R in the general formulas of this invention 1-1 and R 1-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0094] R 1-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6-membered heteroaryl, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0095] In each of the general formulas of this invention, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0096] In each of the general formulas of this invention, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups; preferably, R3 is selected from hydrogen.

[0097] In each of the general formulas of this invention, R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 ,-(CH2) m10 R a10 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0098] R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 and R a10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0099] Preferably, R4 is selected from methyl, ethyl, -CH2CHF2, -CH2CH2F,

[0100] In some embodiments of the present invention, R4 is selected from methyl or -CD3; more preferably, R4 is selected from -CD3.

[0101] In each of the general formulas of this invention, R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0102] Preferably, R5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl, or...

[0103] In some embodiments of the present invention, R5 is independently selected from...

[0104] In some embodiments of the present invention, R5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl,

[0105]

[0106] In each of the general formulas of this invention, R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0107] In each of the general formulas of this invention, R7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0108] R in the general formulas of this invention 8-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0109] R 8-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0110] R in the general formulas of this invention 9-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0111] R 9-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups.

[0112] In some embodiments of the present invention, R 9-2 Selected from C1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl groups, preferably methyl groups.

[0113] In some embodiments of the present invention, R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0114] Preferably, R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from H, CH3, CN, OH or NH2.

[0115] In some embodiments of the present invention, R a14 and R a15 Each is independently selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl, preferably, R a14 and R a15 Each is independently selected from methyl or ethyl.

[0116] In certain embodiments of the present invention, cycloCy1 is selected from phenyl, benzo5-6-membered heterocyclic, 5-6-membered heteroaryl, 5-6-membered heteroaryl-5-6-membered heterocyclic, or 8-10-membered heteroaryl, preferably phenyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrimidinoneyl, pyridazinyl, pyrazinyl, indoleyl, quinolinyl, or...

[0117] In some embodiments of the present invention, X1 is selected from CH2, NH, NCH3, NCD3, CHCH3, C(CH3)2, or

[0118] The present invention also relates to a compound of the following formula (INT-1), its stereoisomer or a pharmaceutically acceptable salt thereof.

[0119]

[0120] in,

[0121] R int1 Selected from halogens, boric acids, or borate esters, preferably Cl, Br, or

[0122] Ring G, R 9-1 R 9-2 R1, R' 1-1 、R' 1-2 、R' 1-3 The definitions of y and y are as described above;

[0123] Preferably, the compound is selected from...

[0124] This invention also relates to a method for preparing a stereoisomer of a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound represented by formula (INT-1) and a compound represented by formula (INT) to prepare the compound represented by formula (I-1).

[0125]

[0126] in,

[0127] R intSelected from halogens, boric acids, or borate esters, preferably Cl, Br, or

[0128] R int1 Selected from halogens, boric acids, or borate esters, preferably Cl, Br, or

[0129] Preferably, the reaction is carried out in the presence of a base and a catalyst, wherein the base is an organic or inorganic base and the catalyst is a palladium catalyst;

[0130] Rings G, M1, R 8-1 R 8-2 R 9-1 R 9-2 R1, R' 1-1 、R' 1-2 、R' 1-3 The definitions of R3, R4, R5, z, w, and y are as described above.

[0131] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0132] In some embodiments of the invention, the compound, its stereoisomers, or its pharmaceutically acceptable salts constitute 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, even more preferably 15-40%, even more preferably 20-30%, and even more preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0133] In some embodiments of the invention, the dosage of the compound, its stereoisomers, or its pharmaceutically acceptable salts is 1 mg to 1000 mg, for example, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg (or any integer between them).

[0134] The present invention further relates to the use of the said compound, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof in the preparation of TNFα inhibitor drugs.

[0135] The present invention further relates to the use of the said compound, its stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating autoimmune diseases, wherein the autoimmune diseases are preferably selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis.

[0136] The present invention also relates to a method for treating, preventing and / or treating autoimmune diseases, comprising administering to a patient a therapeutically effective dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0137] In some embodiments of the present invention, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis.

[0138] Detailed description of the invention

[0139] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used in the specification and claims have the following meanings.

[0140] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CONH is equivalent to NHCO.

[0141] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 1 to 20 (C). 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6 Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C... 1-6 The alkyl group contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0142] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0143] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 16 carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0144] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6 Alkyne refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0145] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0146] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0147]

[0148] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include:

[0149]

[0150] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C...) 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10(e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0151]

[0152] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen, excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 10, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0153] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include:

[0154]

[0155] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include:

[0156]

[0157] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:

[0158]

[0159] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl),

[0160] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0161] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 5 to 15, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, the heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl,

[0162] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0163] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0164] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0165] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0166] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3,

[0167] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0168] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0169] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0170] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0171] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0172] The term "aminocarbonyl" refers to NH2-C(O)-.

[0173] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, wherein the definition of alkyl is as described above.

[0174] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0175] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0176] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs can be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures.

[0177] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0178] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0179] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0180] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0181] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0182] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0183] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0184] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0185] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0186] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0187] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0188] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0189] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0190] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule. Detailed Implementation

[0191] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0192] Example

[0193] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0194] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 (150×4.6mm chromatographic column).

[0195] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0196] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0197] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0198] Example 1

[0199] (7R,14R)-11-((E)-2-(5-(1-aminocyclobutyl)-1,3,4-oxadiazol-2-yl)vinyl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-

[0200] ketone

[0201]

[0202]

[0203] The above route can be further optimized as follows:

[0204] Step 1: Preparation of tert-butyl (1-(hydrazine carbonyl)cyclobutyl)carbamate

[0205]

[0206] Hydrazine hydrate (5.00 g, 84.90 mmol, 5 mL, 85%) was added dropwise to a MeOH (10 mL) solution of methyl 1-((tert-butoxycarbonyl)amino)cyclobutanecarboxylate (1 g, 4.36 mmol). The reaction mixture was heated to 60 °C and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), filtered, and the filter cake was dried under reduced pressure to give the title compound (418 mg, 41.8%). MS m / z (ESI): 230.1 [M+H] + .

[0207] Step 2: Preparation of tert-butyl (1-(5-vinyl-1,3,4-oxadiazol-2-yl)cyclobutyl)carbamate

[0208]

[0209] A solution of tert-butyl(1-(hydrazine carbonyl)cyclobutyl)carbamate (418 mg, 1.82 mmol), acrylic acid (131 mg, 1.82 mmol), triethylamine (922 mg, 9.12 mmol, 1.27 mL), and T3P (3.48 g, 5.47 mmol, 50%) in ethyl acetate (12 mL) was microwaved to 150 °C for 40 minutes. After cooling, the reaction solution was washed with 1 mL of 1 N HCl, 5 mL of water, and 5 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (51 mg, 10.5%). MS m / z (ESI): 266.1 [M+H] + .

[0210] Step 3: Preparation of 2-bromo-6-(difluoromethoxy)benzaldehyde

[0211]

[0212] Diethyl bromofluoromethylphosphonate (531 g, 1.99 mol) was dissolved in THF (4.8 L). Potassium hydroxide (1.12 kg, 19.90 mol) (dissolved in 4.8 L water) was added with stirring at 0 °C, followed by 2-bromo-6-hydroxybenzaldehyde (400 g, 1.99 mol). The reaction mixture was stirred at 0 °C for 1 hour. The organic phase of the reaction solution was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (499 g, 100%). MS m / z (ESI): 251.0 [M+H] + .

[0213] Step 4: Preparation of (S,E)-N-(2-bromo-6-(difluoromethoxy)benzylmethyl)-2-methylpropane-2-sulfinamide

[0214]

[0215] 2-Bromo-6-(difluoromethoxy)benzaldehyde (499 g, 1.99 mol) was dissolved in THF (4 L). S-tert-butylsulfinamide (289 g, 2.39 mol) and tetraethyl titanate (681 g, 2.98 mol) were added with stirring. The reaction mixture was stirred for 12 hours, quenched with water, filtered, and the filtrate was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the title compound (540 g, 77%). MS m / z (ESI): 354.2 [M+H] + .

[0216] Step 5: Preparation of N-((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0217]

[0218] (S,E)-N-(2-bromo-6-(difluoromethoxy)benzylmethyl)-2-methylpropane-2-sulfinamide (540 g, 1.52 mol) was dissolved in DCM (5 L). Allyl magnesium bromide (2.29 L, 2.29 mol, 1 M ether solution) was added with stirring at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (560 g, 93%). MS m / z (ESI): 396.0 [M+H] + .

[0219] Step 6: Preparation of (R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-ene-1-amine

[0220]

[0221] N-((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (560 g, 1.41 mol) was dissolved in DCM (3 L), and dioxane hydrochloride solution (1.5 L, 4 M) was added with stirring. The reaction solution was stirred for 2 hours, and the reaction solution was concentrated to give the title compound (464 g, 100%, crude product).

[0222] MSm / z(ESI): 292.0 [M+H] + .

[0223] Step 10: Preparation of (R)-N-(1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-5-chloro-2-nitroaniline

[0224]

[0225] Potassium carbonate (585 g, 4.23 mol) was added to DMF (3.6 L), and (R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-amine (464 g, 1.41 mol, crude product) and 4-chloro-2-fluoro-1-nitrobenzene (297 g, 1.69 mol) were added with stirring at room temperature. The reaction mixture was stirred at 80 °C for 12 hours. After returning to room temperature, the reaction mixture was diluted with EA, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the title compound (560 g, 89%). MS m / z (ESI): 447.0 [M+H] + .

[0226] Step 7: Preparation of (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propionaldehyde

[0227]

[0228] (R)-N-(1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-5-chloro-2-nitroaniline (560 g, 1.25 mol) was dissolved in water (3.2 L) and dioxane (6.4 L). Potassium (VI) osmium tetroxide dihydrate (18 g, 48.9 mmol) was added with stirring. The reaction mixture was stirred for 1 hour. Sodium periodate (803 g, 3.75 mol) was added to the reaction mixture at 0 °C, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with EA, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the title compound (230 g, 41%). MS m / z (ESI): 449.0 [M+H] + .

[0229] Step 8: Preparation of (4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxo)butyronitrile

[0230]

[0231] (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propanal (230 g, 512 mmol) was dissolved in DCM (3 L). Trimethylcyanosilane (76 g, 767 mmol), zinc iodide (16.3 g, 51.2 mmol), and triethylamine (14.3 mL, 102 mmol) were added with stirring at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with DCM, and the organic phase was washed with saturated ammonium chloride and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (244 g, 87%). MS m / z (ESI): 548.0 [M+H] + .

[0232] Step 9: Preparation of (1R,3S)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol

[0233]

[0234] (4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxo)butyronitrile (244 g, 445 mmol) was dissolved in ethanol (3 L). Stannous chloride (422 g, 2.22 mol) was added with stirring at room temperature. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated, and the residue was dissolved in EA. Saturated sodium carbonate was added to adjust the pH of the system to 10. The mixture was filtered, and the filtrate was extracted with saturated sodium chloride. The organic phase was concentrated, and the mixture was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound (12 g, 6%). MS m / z (ESI): 429.0 [M+H] + .

[0235] Step 10: Preparation of (1R,3r)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine

[0236]

[0237] (1R,3S)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (9.5 g, 22.1 mmol) was dissolved in toluene (150 mL), and diphenyl azidophosphate (7.29 g, 26.5 mmol) was added with stirring at room temperature. 1,8-diazobisspirocyclic[5.4.0]undecyl-7-ene (4.3 mL, 28.7 mmol) was added dropwise. The reaction mixture was stirred at 50 °C for 12 hours under nitrogen atmosphere. The reaction mixture was diluted with EA, the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (PE / EA = 2 / 1) to obtain a yellow oily liquid azide compound. The above liquid was dissolved in water (20 mL) and THF (100 mL), and triphenylphosphine (8.70 g, 33.2 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 4 hours. After dilution with EA, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain the title compound (8.1 g, 85%). MS m / z (ESI): 428.0 [M+H] + .

[0238] Step 11: Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one

[0239]

[0240] (1R,3r)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (8.1 g, 18.9 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (1.09 g, 1.89 mmol) and potassium carbonate (7.83 g, 56.7 mmol) were dispersed in DMF (220 mL). The reaction solution was protected with nitrogen. Tris(dibenzylidene indeneacetone)dipalladium (3.46 g, 3.78 mmol) was added with stirring at room temperature. The reaction solution was replaced three times with dry carbon monoxide. The temperature was raised to 130 °C and the reaction was stirred for 12 hours. The reaction solution was diluted with EA and washed with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give the title compound (4 g, 56%). MS m / z (ESI): 376.1 [M+H] + .

[0241] Step 12: Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one

[0242]

[0243] (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one (1 g, 2.66 mmol) was dissolved in THF (15 mL). Sodium hydroxide (160 mg, 3.99 mmol, 60% purity) was added with stirring, followed by methyl iodoform (755 mg, 5.32 mmol). After stirring for 2 hours, the mixture was diluted with EtOAc. The organic phase was washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EtOAc / PE = 0–100%) to obtain the title compound as a yellow solid (890 mg, 86%). MS m / z (ESI): 376.1 [M+H] + .

[0244] Step 13: Preparation of tert-butyl(1-(5-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-11-yl)vinyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)carbamate

[0245]

[0246] Tert-butyl (1-(5-vinyl-1,3,4-oxadiazol-2-yl)cyclobutyl)carbamate (51 mg, 192 μmol), (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one (50 mg, 128 μmol), tetrabutylacetic acid (77 mg, 257 μmol), DavePhos (10 mg, 26 μmol), and palladium acetate (2.9 mg, 12.8 μmol) were mixed with 1,4-dioxane (2 mL), and the mixture was microwave-heated to 100 °C for 24 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (15 mg, 19%). MSm / z(ESI): 619.2 [M+H]+ .

[0247] Step 14: Preparation of (7R,14R)-11-((E)-2-(5-(1-aminocyclobutyl)-1,3,4-oxadiazol-2-yl)vinyl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one

[0248]

[0249] Under ice bath conditions, HCl / 1,4-dioxane solution (4M, 2 mL) was added to a solution of tert-butyl(1-(5-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)vinyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)carbamate (15 mg, 24 μmol) in MeOH (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the title compound (4.3 mg, 34.1%).

[0250] MSm / z(ESI): 519.2 [M+H] + .

[0251] 1 H NMR (400MHz, CDCl3) δ8.52-8.48(m,1H),7.73(d,J=8.5Hz,1H),7.68-7.60(m,2H),7.48-7.33(m,3H),7.13-6.69(m,2H),6.2 9-6.24(m,1H),5.02-4.95(m,1H),3.51(s,3H),3.50-3.42(m,1H),2.92-2.85(m,1H),2.84-2.48(m,2H),2.32-2.04(m,4H).

[0252] Other synthetic routes are completed with reference to Example 1:

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276] The NMR data for the example are shown in the table below:

[0277]

[0278]

[0279] Example 46 can also be prepared by the following method: (1S,3S)-3-amino-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)prop-1-ene-1-

[0280] 5-(5-)-1-methyl-1H-1,2,4-triazol-5-yl)-1-methylcyclobutane-1-carboxynitrile

[0281] Step 1: Preparation of (1r,3r)-3-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile

[0282]

[0283] At -78°C, n-BuLi (2.5 M, 3.34 mL) was added dropwise to a THF (30 mL) solution of 3,5-dibromo-1-methyl-1,2,4-triazole (1.92 g, 7.97 mmol). The mixture was stirred at low temperature for 0.5 h. Then, a THF (1 mL) solution of 1-methyl-3-oxocyclobutanecarboxynitrile (828 mg, 7.59 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL), extracted with ethyl acetate (30 mL x 2), the organic layers were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (906 mg, 44%). MS m / z (ESI): 271.0 [M+H] + .

[0284] Step 2: Preparation of (1s,3s)-3-amino-3-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)-1-methylcyclobutane-1-carboxylonitrile

[0285]

[0286] Under ice bath conditions, a DCM solution of methanesulfonyl chloride (697 mg, 6.09 mmol) in 1 mL was added dropwise to a DCM solution of (1r,3r)-3-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile (1.5 g, 5.53 mmol) and TEA (840 mg, 8.30 mmol, 1.16 mL) in 15 mL. The mixture was then stirred at room temperature for 16 hours. A 10% NaHSO4 solution (20 mL) was added to the reaction mixture, and after stirring, the mixture was separated. The organic layer was washed with water (15 mL) and saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in DMF (8 mL). Sodium azide (250 mg, 3.85 mmol) was added, and the mixture was heated to 80 °C for 2 hours. After cooling, the reaction solution was diluted with water (40 mL), extracted with ethyl acetate (30 mL x 2), and the organic layers were combined and washed with water (10 mL x 2). The organic layer solution was mixed with trimethylphosphine (5.4 mL, 1 M THF solution) and heated to 70 °C for 1 hour. After cooling, 0.5 M HCl (10 mL) was added, and the mixture was separated. The aqueous layer was adjusted to pH 8-9 with 2 M NaOH solution, extracted with ethyl acetate (20 mL x 2), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (656 mg, 44%).

[0287] MSm / z(ESI): 270.0 [M+H] + .

[0288] Step 3: Preparation of tert-butyl ((1s,3s)-1-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)-3-cyano-3-methylcyclobutyl)carbamate

[0289]

[0290] Di-tert-butyl dicarbonate (1.29 g, 5.92 mmol) and DMAP (15 mg, 118 μmol) were added to a solution of (1s, 3s)-3-amino-3-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)-1-methylcyclobutane-1-carboxynitrile (320 mg, 1.18 mmol) in 10 mL of EtOH. The mixture was heated to 50 °C and stirred for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (292 mg, 66.6%). MS m / z (ESI): 370.1 [M+H] + .

[0291] Step 4: Preparation of tert-butyl ((1s,3s)-3-cyano-3-methyl-1-(1-methyl-3-(prop-1-yn-1-yl)-1H-1,2,4-triazol-5-yl)cyclobutyl)carbamate

[0292]

[0293] Tert-butyl ((1s,3s)-1-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)-3-cyano-3-methylcyclobutyl)carbamate (292 mg, 789 μmol), propyne (3.94 mL, 1 M DMF solution), TEA (239 mg, 2.37 mmol), CuI (30 mg, 158 μmol), and palladium dichloride bis(triphenylphosphine) (111 mg, 158 μmol) were mixed and reacted under nitrogen protection by microwave heating to 90 °C for 6 hours. The reaction solution was cooled, diluted with water (20 mL), and extracted with DCM (20 mL x 2). The organic layers were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (156 mg, 60.1%).

[0294] MSm / z(ESI): 330.2 [M+H] + .

[0295] Step 5: Preparation of tert-butyl((1s,3s)-3-cyano-3-methyl-1-(1-methyl-3-((Z)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)prop-1-en-1-yl)-1H-1,2,4-triazol-5-yl)cyclobutyl)carbamate

[0296]

[0297] A solution of tert-butyl ((1s,3s)-3-cyano-3-methyl-1-(1-methyl-3-(prop-1-yn-1-yl)-1H-1,2,4-triazol-5-yl)cyclobutyl)carbamate (156 mg, 474 μmol), pinacol borane (303 mg, 2.37 mmol), and tris(triphenylphosphine)carbonylruthenium(II) hydrochloride (45 mg, 47 μmol) in toluene (2 mL) was stirred at 50 °C for 1.5 h. The reaction mixture was cooled, quenched with methanol (5 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (216 mg, 99.7%). MS m / z (ESI): 458.3 [M+H] + .

[0298] Step 6: Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one

[0299]

[0300] Under ice bath conditions, NaH (179 mg, 4.47 mmol, 60% in mineral oil) was added to a THF (20 mL) solution of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one (700 mg, 1.86 mmol), stirred for 5 minutes, and then a THF (1 mL) solution of deuterated iodomethane (540 mg, 3.73 mmol) was added. The mixture was then brought to room temperature and stirred for 16 hours. The reaction solution was quenched with water (5 mL), concentrated under reduced pressure, and the residue was separated in water (10 mL) and EtOAc (20 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give the title compound (588 mg, 80.4%). MS m / z (ESI): 393.1 [M+H] + .

[0301] Step 7: Preparation of tert-butyl((1s,3S)-3-cyano-1-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-methylcyclobutyl)carbamate

[0302]

[0303] tert-butyl ((1s,3s)-3-cyano-3-methyl-1-(1-methyl-3-((Z)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)prop-1-en-1-yl)-1H-1,2,4-triazol-5-yl)cyclobutyl)carbamate (105 mg, 230 μmol), (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6, A mixture of 7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one (90 mg, 229 μmol), XPhosPdG3 (19 mg, 23 μmol), cesium carbonate (149 mg, 458 μmol), 1,4-dioxane (2 mL), and water (0.4 mL) was microwave-heated to 100 °C and stirred for 2 hours under nitrogen protection. The reaction mixture was cooled, concentrated under reduced pressure, and the residue was separated in water (10 mL) and DCM (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (155 mg, 98.3%).

[0304] MSm / z(ESI): 688.3 [M+H] + .

[0305] Step 8: Preparation of (1S,3s)-3-amino-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-1-methylcyclobutane-1-carboxylonitrile

[0306]

[0307] TFA (1 mL) was added to a solution of tert-butyl((1s,3S)-3-cyano-1-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-methylcyclobutyl)carbamate (155 mg, 225 μmol) in DCM (2 mL) and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with DCM (10 mL), washed with saturated sodium bicarbonate solution (5 mL), concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the title compound (14 mg, 10.6%).

[0308] MSm / z(ESI): 588.2 [M+H] + .

[0309] 1 H NMR(400MHz, CDCl3) δ8.49(dd,J=8.2,1.2Hz,1H),7.69(d,J=8.6Hz,1H),7.65(d,J=1.7 Hz,1H),7.53-7.47(m,1H),7.42(t,J=8.2Hz,1H),7.34-7.27(m,1H),6.86(t,J=72.9Hz, 1H),6.70-6.68(m,1H),6.28(d,J=6.9Hz,1H),5.01(d,J=6.9Hz,1H),3.96(s,3H),3.51 -3.43(m,1H),3.13-3.05(m,2H),2.92-2.80(m,3H),2.66(d,J=1.2Hz,3H),1.51(s,3H).

[0310] Example 135 can also be prepared by the following method: (1S,3S)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-hydroxy-1-methylcyclobutanenitrile

[0311] Step 1: Preparation of (1S,3s)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-((4-methoxybenzyl)oxo)-1-methylcyclobutyronitrile

[0312]

[0313] The following ingredients were prepared: (1s,3s)-3-((4-methoxybenzyl)oxo)-1-methyl-3-(1-methyl-3-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)prop-1-en-1-yl)-1H-1,2,4-triazol-5-yl)cyclobutyronitrile (270 mg, 0.56 mmol, prepared according to the first five steps of Example 46), and (7R,14R)-11-chloro-1-(difluoromethoxy)-6-methyl-6 7-Dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one (200 mg, 0.51 mmol), XPhosPdG3 (43.4 mg, 51 μmol), and cesium carbonate (502 mg, 1.54 mmol) were added to a mixed solution of 1,4-dioxane (4 mL) and water (0.5 mL), respectively. The mixture was heated to 100 °C under nitrogen protection and reacted for 12 hours. The reaction solution was allowed to return to room temperature, diluted with ethyl acetate (20 mL), washed with water (10 mL), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (294 mg, 81.2%). MS m / z (ESI): 706.2 [M+H] + .

[0314] Step 2: Preparation of (1S,3s)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-hydroxy-1-methylcyclobutanenitrile

[0315]

[0316] Add (1S,3s)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-((4-methoxybenzyl)oxo)-1-methylcyclobutanenitrile (294 mg, 0.42 mmol) to TFA (2 mL), heat to 50 °C and stir for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (10 mL), concentrated under reduced pressure, and purified by prep-HPLC to give the title compound (68 mg, 27.6%). MS m / z (ESI): 586.2 [M+H] + .

[0317] 1 H NMR(400MHz,DMSO-d6)δ8.42(d,J=8.2Hz,1H),7.66-7.56(m,2H),7.49-7.41(m,1H),7 .38(t,J=8.2Hz,1H),7.31-7.26(m,1H),6.86(t,J=72.8Hz,1H),6.60(d,J=1.5Hz,1H), 6.22(d,J=7.0Hz,1H),5.41(s,1H),4.91(d,J=6.9Hz,1H),3.84(s,3H),3.48(s,3H),3 .46-3.35(m,1H),3.07-2.92(m,4H),2.83(d,J=13.5Hz,1H),2.58(s,3H),1.51(s,3H).

[0318] Example 136 can also be prepared by the following method: (1S,3S)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile

[0319] Step 1: Preparation of (1S,3s)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocyn-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-((4-methoxybenzyl)oxo)-1-methylcyclobutane-1-carboxynitrile

[0320]

[0321] The following ingredients were added: (1s,3s)-3-((4-methoxybenzyl)oxo)-1-methyl-3-(1-methyl-3-((E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)prop-1-en-1-yl)-1H-1,2,4-triazol-5-yl)cyclobutyronitrile (150 mg, 0.12 mmol), and (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6,7-dihydro -7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-5(14H)-one (123 mg, 0.31 mmol), XPhosPdG3 (26.5 mg, 31 μmol), and cesium carbonate (307 mg, 0.94 mmol) were added to a mixed solution of 1,4-dioxane (4 mL) and water (0.5 mL), respectively. The mixture was heated to 100 °C under nitrogen protection and reacted for 12 hours. The reaction solution was allowed to return to room temperature, diluted with ethyl acetate (20 mL), washed with water (10 mL), washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (222 mg, crude). MS m / z (ESI): 709.3 [M+H] + .

[0322] Step 2: Preparation of (1S,3s)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacocin-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile

[0323]

[0324] Add (1S,3s)-3-(3-((E)-2-((7R,14R)-1-(difluoromethoxy)-6-(methyl-d3)-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-11-yl)prop-1-en-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-3-((4-methoxybenzyl)oxo)-1-methylcyclobutane-1-carboxynitrile (222 mg, 0.31 mmol) to TFA (2 mL), heat to 60 °C and stir for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the title compound (41 mg, 21.4%).

[0325] MSm / z(ESI): 589.2 [M+H] + .

[0326] 1 H NMR(400MHz, CDCl3)δ8.46(dd,J=8.3,1.2Hz,1H),7.67-7.60(m,2H),7.47(dd,J=8.6,1 .8Hz,1H),7.41(t,J=8.2Hz,1H),7.34-7.28(m,1H),6.87(t,J=72.8Hz,1H),6.63(d,J=1 .3Hz,1H),6.27(d,J=7.0Hz,1H),4.99(d,J=7.0Hz,1H),4.27(s,1H),3.89(s,3H),3.51- 3.40(m,1H),3.09-2.95(m,4H),2.87(d,J=13.5Hz,1H),2.63-2.58(m,3H),1.54(s,3H).

[0327] Biological testing evaluation

[0328] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0329] I. Combining experiments

[0330] The compounds in the embodiments of the present invention showed strong binding activity to TNFα protein in experiments on the thermal shift effect on the thermostability of TNFα protein and in experiments on the effect of TNFα protein on the binding of TNFR1 receptor.

[0331] II. Cell Function Experiments

[0332] Test Example 1: Determination of the effect of the compound of the present invention on TNF-induced NF-κB phosphorylation in HEK293 cells. 1. Experimental objective: To detect the effect of the compound on TNF-induced pNF-κB levels in HEK293 cells.

[0333] 2. Experimental instruments and reagents:

[0334] 2.1 Instruments:

[0335] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), pure water system (THERMO: Pacific T II+Micropure), ice maker (Xueke Electric, IMS-150), incubator (Boxun, BC-J80S).

[0336] 2.2 Reagents:

[0337] Cell culture plates (Corning: 3599); PBS (Gibco, 10010023);

[0338] DMSO (Sigma: D2650); TNFα (MCE: HY-P7085);

[0339] PMSF (100mM) (Beyotime, ST506); trypsin (Gibco, 25200-056);

[0340] Pierce BCA Protein Assay Kit (Thermo Fisher, 23227);

[0341] Mixture of protease phosphatase inhibitors (universal, 50X) (Beyotime, P1045);

[0342] NF kappaB p65 (pS536) ELISA kit (Abcam, ab176647);

[0343] Cell line Hek293 (ATCC); DMEM (Gibco, 11995-065);

[0344] FBS serum (Gibco, 30067-334); Pen strep bispecific antibody (Gibco, 15140-122);

[0345] 3. Experimental methods:

[0346] 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%–90% confluence.

[0347] 2) Digest and resuspend the cells in experimental culture medium, and seed 40,000 cells / well / 100μL into a 96-well cell culture plate and incubate overnight at 37°C and 5% CO2.

[0348] 3) Prepare a 5x final concentration mixture of the compound and TNF protein in the culture medium and incubate it in a 37°C incubator for 1 hour.

[0349] 4) Add the incubated compound and TNF protein mixture to the corresponding cell wells, 25 μL per well, and incubate at 37°C for 10 min. At this point, the final concentration of TNF is 25 ng / mL and the concentration of DMSO is 0.1%.

[0350] 5) Centrifuge at 2000 rpm for 5 min, discard the supernatant, and wash the cells twice with 100 uL PBS.

[0351] 6) Pre-cool the centrifuge to 4°C, prepare cell lysis buffer (reagent components are included in the ELISA kit), add an appropriate amount of protease inhibitor, add 70 μL of lysis buffer to each well, and incubate on ice for 10 minutes for lysis.

[0352] min.

[0353] 7) Take 5 μL of the lysed sample for BCA protein concentration detection, and use the remaining sample for ELISA assay.

[0354] 8) Dilute the lysed sample with ELISA buffer at appropriate ratios and prepare a standard curve. The highest concentration point of the standard curve is the 25% control lysate concentration. The remaining gradients are diluted 2-fold, for a total of 8 concentration points.

[0355] 9) Add the sample and standard curve to each well, 50 μL per well.

[0356] 10) Calculate the total volume required for the experiment. Mix Capture Antibody and Detector Antibody in a 1:1 ratio, add 50 μL to each well, seal the plate, and incubate at 25°C on a shaker at 400 rpm for 1 h.

[0357] 11) Remove the liquid, dilute 10x wash buffer 10 times with deionized water, add 350uL to each well, and wash three times, draining the liquid from the plate each time.

[0358] 12) Add 100 μL of TMB Substrate to each well, protect from light, and incubate on a shaker at 400 rpm for 15 min for color development.

[0359] 13) Add 100 μL of Stop solution to each well, shake at 400 rpm for 1 min to mix, and read the Envision value as OD 450 nm.

[0360] 4. Experimental data processing methods: Graph pad four-parameter log(inhibitor) vs. response-variable slope (four parameters) was used to fit the compound concentration, corresponding inhibition rate, and inverse nonlinearity to calculate IC. 50 .

[0361] 5. Experimental Results and Conclusions: The compounds in the examples of this invention showed a strong inhibitory effect on TNF-induced pNF-κB levels <50 nM in HEK293 cells.

[0362] Test Example 2: Detection of the inhibitory effect of the compound of the present invention on the release of IL-8 from TNF-stimulated hPBMCs.

[0363] 1. Experimental objective: To detect the inhibitory effect of the compound on TNF-induced release of IL-8 from hPBMCs.

[0364] 2. Experimental instruments and reagents:

[0365] 2.1 Instruments:

[0366] Envision (PE-Cisbio: 2105-0020); Biosafety Cabinet (Sujing Antai, BSC-1604ⅡA2); Cell Counter (Invitrogen, Countess II)

[0367] 2.2 Reagents and Consumables:

[0368] hPBMC (Saili, XFB-HP010B) PBS (Gibco, 10010023);

[0369] DMSO (Sigma: D2650); TNFa (MCE: HY-P7085);

[0370] RPMI 1640 medium (Gibco, 22400-105);

[0371] FBS serum (Gibco, 30067-334); Pen strep bispecific antibody (Gibco, 15140-122);

[0372] Cell culture plate (Corning: 3599);

[0373] Human IL-8 / CXCL8 DuoSet ELISA (RD, DY208-05);

[0374] DuoSet ELISA Ancillary Reagent Kit 2 (RD, DY008B);

[0375] 50 mL centrifuge tubes (Corning, 430829); 2.5 μL pipette (Eppendorf, I36630F);

[0376] 10µL pipette (Eppendorf, J13131F);

[0377] 100µL pipette (Eppendorf, R22267J);

[0378] 1000µL pipette (Eppendorf, I44804F);

[0379] 10uL 12-channel electric pipette (METTLER TOLEDO, 17013797);

[0380] 300uL 12-channel electric pipette (Eppendorf, O51743J);

[0381] 1200uL 12-channel electric pipette (Eppendorf, J51515K);

[0382] 3. Experimental methods:

[0383] 1) Thaw the hPBMC cryopreservation solution in a 37°C water bath;

[0384] 2) Add the thawed cells dropwise to 10 mL of preheated 1640 medium (+10% FBS+1% PS), centrifuge at 2000 rpm for 10 min;

[0385] 3) After centrifugation, remove the supernatant from the cells, add 10 mL of fresh culture medium to resuspend them, mix well by pipetting, and count them;

[0386] 4) Adjust the cell density to 1*10 6 Add cells / mL, 100uL / well to a 96-well plate;

[0387] 5) Incubate the well plate in a 37°C incubator for 4 hours;

[0388] 6) Prepare working solutions of 6x final concentration compound (final concentration 1uM Top, 3-Fold, 8Dose) and TNF protein (final concentration 3ng / mL) using serum-free 1640 medium. Then mix the compound with TNFα 1:1 and incubate at 37°C for 1h.

[0389] 7) Add the incubated mixture to the corresponding well plate, 50 μL per well, and incubate at 37°C for 18 h. At the same time, prepare the ELISA capture antibody with coating buffer, add 100 μL to each well of the high binding plate to a final concentration of 4 μg / mL, and incubate overnight at 4°C.

[0390] 8) ELISA sample preparation: Centrifuge the incubated cell plate at 1500 rpm for 10 min, collect the supernatant, and dilute the supernatant 15 times with dilution buffer (6.7 uL supernatant + 93.3 uL dilution buffer);

[0391] 9) Preparation of standard curve: The standard curve IL-8 concentration is 250 ng / mL, 2-fold, 8-dose, 2-fold dilution to 125 uL + 125 uL dilution buffer;

[0392] 10) Prepare 1x wash buffer, add 300uL to each well of the plate and wash three times. After each wash, let it stand for 30 seconds to ensure it is clean.

[0393] 11) Add the diluted sample and standard curve to each well of the plate, 100 μL, and incubate at room temperature for 2 hours.

[0394] 12) Same as step 10, wash the plate three times.

[0395] 13) Prepare the detection antibody to a final concentration of 10 ng / mL. Add 100 μL to each well of the plate and incubate at room temperature for 2 h.

[0396] 14) Same as step 10, wash the plate three times;

[0397] 15) Prepare SA-HRP to a final concentration of 1x, add 100 μL to each well of the plate, and incubate at room temperature for 30 min;

[0398] 16) Repeat step 10, washing the plate three times;

[0399] 17) Add 100 μL of TMB solution and incubate at room temperature in the dark for 20 minutes to develop color;

[0400] 18) Add 50 μL of Stop solution, shake well. After the solution turns completely yellow, measure the OD450 - 570.

[0401] 4. Experimental data processing method:

[0402] Use XLfit four - parameter log(inhibitor) vs. response--Variable slope (four parameters) to perform non - linear fitting on the compound concentration and the corresponding inhibition rate, and calculate IC 50 . The results are as follows

[0403] Example <![CDATA[IC 50 (nM)]]> 1 5.1 135 6.5

[0404] 5. Experimental conclusion: The compound of the present invention has a good inhibitory effect on the release of IL - 8 from TNF - stimulated hPBMC.

[0405] III. Pharmacokinetics determination in Balb / C mice

[0406] 1. Research purpose: Using Balb / C mice as test animals, study the pharmacokinetic behavior of the compound of the present invention in mouse plasma after oral administration at a dose of 30 mg / kg.

[0407] 2. Test protocol

[0408] 2.1 Test drug: The compound of the present invention, self - made.

[0409] 2.2 Test animals: Balb / C Mouse (3 per embodiment), male, Shanghai Bikai Laboratory Animal Co., Ltd., animal production license number (SCXK (Hu) 2013 - 0006 N0.311620400001794).

[0410] 2.3 Administration: Balb / C mice, male; after fasting overnight, administer p.o. at a dose of 30 mg / kg, and the administration volume is 10 mL / kg.

[0411] 2.4 Sample collection: Before and after drug administration in mice, at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours, collect 0.04 mL of blood from the orbital cavity, place it in an EDTA - K2 test tube, centrifuge at 4°C at 6000 rpm for 6 min to separate plasma, and store it at - 80°C.

[0412] 2.5 Sample treatment:

[0413] 1) Add 20 μL of plasma sample to 100 μL of acetonitrile for precipitation, mix well, and centrifuge at 5000×g for 15 - 20 minutes.

[0414] 2) The concentration of the analyte was analyzed by LC / MS / MS of the treated supernatant. LC / MS / MS instrument: AB Sciex API 4000

[0415] 2.6 Liquid Chromatography Analysis

[0416] Liquid phase conditions: Shimadzu LC-20AD pump

[0417] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0418] Column: Waters Xbridge C18 5μm, 4.6 x 50 mm

[0419] Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is methanol; Flow rate: 1 mL / min

[0420] Elution time: 0-4.0 minutes, eluent as follows:

[0421]

[0422] 3. Experimental Results and Analysis: The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[0423] 4. Experimental conclusion: The compounds of this invention exhibit good pharmacokinetic properties.

[0424] IV. In vivo pharmacodynamic studies of the compounds in a mouse model of collagen antibody-induced arthritis

[0425] 1.1 Experimental objective: To evaluate the in vivo efficacy of the compound in a collagen antibody-induced mouse model of arthritis.

[0426] 1.2 Experimental Instruments and Reagents

[0427] 1.2.1 Instruments

[0428] 1. Refrigerator (BCD-268TN, Haier)

[0429] 2. Biosafety cabinet (BSC-1300IIA2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[0430] 3. Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.)

[0431] 4. Electric pipetting aid (Easypet 3, Eppendorf)

[0432] 5. Constant temperature water bath (HWS-12, Shanghai Yiheng Science)

[0433] 6. Electronic balance (CPA2202S, Sartorius)

[0434] 7. Ultrasonic cleaner (115F0032, Shanghai Keda)

[0435] 8. Pure water system (Pacific TII, Thermo) 10. Magnetic stirrer (08-2G, Chijiu)

[0436] 9. Electronic balance (BSA2202S-CW, Sartorius)

[0437] 10. Ultrasonic Cleaner (115F0032, Shanghai Keda)

[0438] 11. Pure water system (Pacific TII, Thermo) 15. Magnetic stirrer (08-2G, Chijiu)

[0439] 12. Ultrasonic Cell Disruptor (JY92-IIN, Ningbo Xinzhi)

[0440] 1.2.2 Reagents

[0441] 1. Mouse arthritis induction 5-clonal compound (53100, Chondrex)

[0442] 2. Tween 80 (30189828, Sinopharm Reagent)

[0443] 3. Sodium carboxymethyl cellulose (30036365, Sinopharm Reagent)

[0444] 1.3 Experimental Operation and Data Processing

[0445] 1.3.1 Animal Procurement: BALB / c nude mice, 8-10 weeks old, female, were purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science.

[0446] 1.3.2 CAIA Model Establishment

[0447] a. After acclimatizing for 2-3 days, the animals were tagged with disposable ear tags, weighed, and randomly grouped according to their body weight; b. On the day of the experiment (D0), 1.0 mg of 5-clonal antibody mixture was injected into the tail vein or peritoneum of the animals.

[0448] c. One day later (i.e., D1), inject the animals intraperitoneally with 10ug of Escherichia coli lipopolysaccharide LPS (both 5-clone compound and LPS were thawed and placed on wet ice).

[0449] 1.3.3 Drug administration and weighing score

[0450] a. Six hours after LPS injection on day 1, the test drug was administered (administration route: oral administration; administration volume: 10 mL / kg; administration frequency: QD / BID; administration period: 7 days; solvent: 0.5% CMC-Na / 1% Tween); b. Starting from day 2 of the experiment, mice were weighed daily, and CAIA arthritis scores were assessed on their paws (scores from day 2 to day 7).

[0451] CAIA Clinical Scoring Criteria (Total score is the sum of 4 claws, total score 0-16)

[0452] 0 is normal;

[0453] 1. Redness and swelling in any part of the ankle / tarsal / toe joint;

[0454] 2. Redness and swelling in any two of the following areas: ankle / tarsal / toe joints;

[0455] 3. There is obvious redness and swelling in all three areas: ankle, tarsal, and toe joints.

[0456] 4. Maximum inflammation and swelling of the ankle / tarsal / toe joints.

[0457] c. Euthanize the animals after the experiment.

[0458] d. Process the data using software such as Excel. Calculation of the percentage (%) of CAIA arthritis inhibited by the compound: TGI (%) = [1 - (mean arthritis score at the end of the compound administration group / mean arthritis score at the end of the solvent control group)] × 100%.

[0459] 1.4 Experimental Results and Conclusions: In an antibody-collagen-induced mouse model of arthritis, the compounds of the present invention effectively improved arthritis symptoms and were well tolerated by the animals at therapeutic doses. Oral administration of the compounds of the present invention (30 mg / kg, BID) showed a relative therapeutic rate of 55% to 95% based on the D7 score, with some compounds showing a relative therapeutic rate of 70% to 90%.

Claims

1. A compound as shown in general formula (I) or formulas (A)-(C), its stereoisomer or a pharmaceutically acceptable salt thereof: in, L1 is selected from CONH; M1 is selected from N or CR2; Cycloyl G is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =CR 1-1 R 1-2 =NR 1-3 =N-OR 1-3 -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 -(CH2) m10 R a10 -(CH2) m14 P(O)R a14 R a15 -O(CH2) m15 P(O)R a14 R a15 or -NH(CH2) m16 P(O)R a14 R a15 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Preferably, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, =CR 1-1 R 1-2 =NR 1-3 =N-OR 1-3 -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 Or -(CH2) m10 R a10 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions are selected from aryl and 5-10 heteroaryl groups; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 1-1 and R 1-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 1-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl and 5-14 heteroaryl groups, optionally covered by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 ,-(CH2) m10 R a10 The amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Alternatively, two R5 connections can form a C. 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 8-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 8-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 9-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 9-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 R a10 R a14 and R a15 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; y is 1, 2, 3, 4 or 5; z can be 0, 1, 2, or 3; w can be 0, 1, 2, 3, or 4; m1, m2, m3, m4, m5, m6, m8, m9, m10, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, or 2.

2. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are shown as those of formula (II), (II-A), (II-B), or (II-C): in, Ring B is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups; preferably C. 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-14 aryl or 5-15 membered heteroaryl; R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; u can be 0, 1, 2, 3 or 4.

3. The compound of claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are shown in formulas (I-1), (I-2), (A-1), (A-2), (B-1), (B-2), (C-1), or (C-2): Among them, R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Rings G, M1, R 8-1 R 8-2 R 9-1 R 9-2 R1, R3, R4, R5, R a14 R a15 The definitions of z, w, and y are as described in claim 1.

4. The compound according to any one of claims 1-3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The ring G is selected from 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heteroaryl-6-membered heterocyclic, 6-membered heteroaryl-6-membered heterocyclic, 5-membered heteroaryl-5-membered heterocyclic, 6-membered heteroaryl-5-membered heterocyclic, 6-membered heteroaryl-5-membered heterocyclic, or 6-membered heteroaryl-6-membered heteroaryl. The 5-membered heteroaryl group is preferably thiadiazolyl (e.g., 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), oxadiazolyl (e.g., 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), furanyl, thiophene, pyrroleyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole, or pyrazolyl; more preferably... More The 6-membered heteroaryl group is preferably pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; The 5-membered heteroaryl and 5-membered heterocyclic group is preferred. 5-membered heteroaryl and six-membered heterocyclic preferred 5-membered heteroaryl and hexa-membered heteroaryl preferred 5. The compound of claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The ring B is selected from C. 3-6 Cycloalkyl or 5-6 membered heterocyclic groups; preferably 6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, P(O)R a14 R a15 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Preferably, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Preferably, R1 is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, -CH2F, -CHF2, -OCH2F, -OCHF2, methyl, ethyl, propyl, isopropyl, alkylmethyl, alkylethyl, hydroxymethyl, hydroxyethyl, amino, cyclopropyl, cyclobutyl, or cyclopentyl. The methyl, ethyl, propyl, isopropyl, alkylmethyl, alkylethyl, hydroxymethyl, hydroxyethyl, amino, cyclopropyl, cyclobutyl, and cyclopentyl groups may optionally be further modified by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Or R1 is selected independently Among them, the Cy ring is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, C preferred 3-6 Cycloalkyl, more preferably cyclopropyl, cyclobutyl, or cyclopentyl; R 11 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl and 5-6 heteroaryl; x is 0, 1, 2, 3, 4, 5, 6 or 7; Or R 1-1 and R 1-2 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; R 1-3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl, wherein the amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6-membered heteroaryl, optionally further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Alternatively, R2 can be independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Alternatively, R3 can be independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6-membered heteroaryl groups; preferably, R3 is selected from hydrogen; Alternatively, R4 can be independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2) m1 OR a1 -(CH2) m2 C(O)R a2 -(CH2) m3 NHC(O)R a3 -(CH2) m4 C(O)NHR a4 -(CH2) m5 NR a5 R a6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 ,-(CH2) m10 R a10 The amino group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; R a1 R a2 R a3 R a4 R a5 R a6 R a7 R a8 R a9 and R a10 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Preferably, R4 is selected from methyl, ethyl, -CH2CHF2, -CH2CH2F, Preferably, R4 is selected from methyl or -CD3; more preferably, R4 is selected from -CD3; Alternatively, R5 can be independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Preferably, R5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl, Preferably, R5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl, or... Preferably, R5 is independently selected from Alternatively, R6 can be independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Or R 8-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; R 8-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Or R 9-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; R 9-2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 heteroaryl groups; or R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, said amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl or 5-6 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; Preferably, R' 1-1 、R' 1-2 and R' 1-3 Each is independently selected from H, CH3, CN, OH, or NH2; Or, R a14 and R a15 Each was independently selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl, preferably, R a14 and R a15 Each is independently selected from methyl or ethyl.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are shown below:

8. A compound represented by formula (INT-1), its stereoisomer or a pharmaceutically acceptable salt thereof. in, R int1 Selected from halogens, boric acids, or borate esters, preferably Cl, Br, or Ring G, R 9-1 R 9-2 R1, R' 1-1 、R' 1-2 、R' 1-3 The definitions of y and y are as described in claim 3; Preferably, the compound is selected from...

9. A method for preparing a stereoisomer of a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of: reacting the compound represented by formula (INT-1) and formula (INT) to prepare the compound represented by formula (I-1). in, R int Selected from halogens, boric acids, or borate esters, preferably Cl, Br, or R int1 Selected from halogens, boric acids, or borate esters, preferably Cl, Br, or Preferably, the reaction is carried out in the presence of a base and a catalyst, wherein the base is an organic or inorganic base and the catalyst is a palladium catalyst; Rings G, M1, R 8-1 R 8-2 R 9-1 R 9-2 R1, R' 1-1 、R' 1-2 、R' 1-3 The definitions of R3, R4, R5, z, w, and y are as described in claim 3.

10. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

11. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition of claim 10, in the preparation of a TNFα inhibitor medicament.

12. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 7, or the pharmaceutical composition of claim 10, in the preparation of a medicament for treating autoimmune diseases; wherein the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis.

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