Oxygen-containing heterocyclic derivative inhibitor, and preparation method therefor and use thereof

Abstract

The present invention relates to an oxygen-containing heterocyclic derivative inhibitor, and a preparation method therefor and a use thereof, and in particular to a compound, a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the compound as an inhibitor in the treatment of autoimmune diseases.

Description

Oxygen-containing heterocyclic derivative inhibitors, preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to an oxygen-containing heterocyclic derivative inhibitor and a preparation method and application thereof. BACKGROUND

[0002] TNF alpha is a member of the tumor necrosis factor (TNF) superfamily of proteins, a proinflammatory cytokine produced by macrophages and monocytes, involved in normal inflammatory and immune responses, and drives the expression of other cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6). It has proinflammatory and immunoregulatory functions and is considered a pleiotropic cytokine. TNF alpha is expressed as a membrane-bound precursor (mTNF), which requires TNF alpha-converting enzyme cleavage for release as a soluble cytokine (sTNF). mTNF alpha and sTNF alpha are symmetrical trimeric proteins with biological activity and signal through two separate tumor necrosis factor receptors 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).

[0003] TNFR1 is ubiquitously expressed and mainly promotes TNF-induced inflammatory responses, while TNFR2 expression is limited to immune cells and maintains local immune homeostasis. The TNFR1 signaling pathway uses the canonical nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAP kinase) pathways to transmit proinflammatory signals. In contrast, TNFR2 signals through a non-canonical NF-kappa B pathway, and activation of TNFR2 is very important for the proliferation, survival and lineage stability of Treg cells and thymic Treg cell development, and is associated with immune regulation. At physiological concentrations, sTNF activates TNFR1 but not TNFR2, while mTNF can activate both receptors.

[0004] 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 specific 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, such as TNF, IL-6 and IL-1, and immune cells (T cells, B cells, monocytes and macrophages), which contribute to drive chronic inflammation in the joints. Rheumatoid arthritis can lead to cumulative joint damage and irreversible disability, but can also cause extra-articular manifestations, such as rheumatoid nodules, lung involvement or vasculitis, and other systemic comorbidities. Current pharmacological treatment of RA is with symptomatic drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) and drugs targeting disease modification, known as disease-modifying antirheumatic drugs (DMARDs), consisting of small molecules and biologies. Disease modification aims to improve the patient's disease signs and symptoms and restore physical function by inhibiting the progression of cartilage and bone structure damage.

[0005] TNF-α inhibitors such as infliximab, adalimumab, etanercept, golimumab and certolizumab pegol have revolutionized the era of rheumatological immunotherapy and have become one of the most powerful weapons for the treatment of rheumatological diseases, being consistently recommended by national and international authoritative guidelines. Anti-TNF-α biologies 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 biologies have completely changed the treatment of RA, despite the great success achieved, the disease remission rate in RA is still quite low, only 25% of patients achieve remission. In addition, it has also been reported that in the treatment of anti-TNF-α combined with methotrexate for 6 months, only 25% of patients achieve low disease activity (LDA). Other limitations of anti-TNF-α biologies include the occurrence of adverse reactions, such as opportunistic infections, reactivation of latent tuberculosis and increased risk of specific malignancies (such as lymphoma), as well as the development of anti-drug antibodies (ADA) due to the immunogenicity of the drug itself, which can limit its efficacy. The high cost of biologies and the need for intravenous injection have created a huge obstacle to their widespread use in clinical practice.

[0006] To date, there are no marketed TNFα small molecule inhibitors, so there is a high clinical need for oral TNFα small molecule inhibitors. The purpose of this project is to develop an oral TNFα small molecule inhibitor with high specificity, safety and effectiveness for the treatment of rheumatological immune diseases.

[0007] Patents of small molecule inhibitors of TNFα have been reported, such as: WO2016050975A1, WO2018167176, WO2018197503, WO2020084008 (Sanofi), the most advanced one SAR-441566 is in clinical phase I, others are in preclinical development stage. The present invention needs to develop orally available small molecule inhibitors of TNFα. SUMMARY

[0008] The present invention also provides a compound as shown in general formula (II-A) or general formula (II-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0009] wherein X1 is selected from O, S or NH; X2 and X3 are each independently selected from N or CR2; M1 is selected from N or CH;

[0010] Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably, Ring A is selected from C 3-8 cycloalkyl;

[0011] Ring B is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0012] R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =CR' 1-1 R' 1- 2, =N-R' 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 NRa5 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 , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1- haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0013] R' 1-1 and R' 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0014] 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 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 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 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;

[0015] R2is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0016] R3is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are substituted;

[0017] R4is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 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 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuteroalkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group, or 5-10 membered heteroaryl group, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo group, thioxo group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuteroalkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group, and 5-10 membered heteroaryl group;

[0018] R5is independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo group, thioxo group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuteroalkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group, 5-10 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thia, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thia, C

[0019] R6is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thia, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thia, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0020] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R’ a1 , R’ a2 , R’ a3 , R’ a4 , R’ a5 , R’ a6 , R’ a7 , R’ a8 , R’ a9 , and R’ a10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 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, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0021] x is 1, 2, 3, 4 or 5; y is 0, 1 or 2; z is 0, 1, 2 or 3; u is 0, 1, 2, 3 or 4; w is 0, 1, 2, 3 or 4;

[0022] m1, m2, m3, m4, m5, m6, m8, m9, m10, m1', m2', m3', m4', m5', m6', m8', m9' and m10' are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0023] m7 and m7' are each independently selected from 0, 1, 2 or 3.

[0024] In some embodiments of the invention, the compound has the structure shown in formula (II-A-1):

[0025] in, It can be a single or double bond; M2 can be CH, CH2, N, NH, O, or S;

[0026] M3 is CH2, NH, O, or S; v is 0, 1, 2, or 3.

[0027] The present invention also provides compounds of formula (II-A-1-1), their stereoisomers or pharmaceutically acceptable salts thereof:

[0028] in:

[0029] R 1-1 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, 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, 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;

[0030] R 1-2 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, C1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0031] R 1-3 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0032] R 6-1 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0033] R 6-2 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl.

[0034] The present application also relates to a compound as shown in general formula (XI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0035] wherein:

[0036] L2is selected from -(CH2) m14 -, -0(CH2) m15 - or -NH(CH2) m16 -; wherein, when m14is 0, -(CH2) m14 is a bond; M1is selected from N or CH; M 22 , M 13 and M 14 are each independently selected from C or N;

[0037] M 15 independently selected from CH or N; M 23 independently selected from N or CR 9-1 ;

[0038] ring B is present or absent, and when present is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; X4is selected from N or CR 2-1 ;

[0039] X5is selected from N or CR 2-2 ; X6is selected from N or CR 2-3 ; X7is selected from N or CR 2-4 ;

[0040] R 2-1 , R 2-2 , R 2-3 , and R 2-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0041] R3is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0042] R4is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 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 , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0043] R5is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of R5and R6may be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0044] R6is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are substituted;

[0045] R 9-1 and R 9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 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 Ra6 -(CH2) m6 S(O) m7 R a7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 or -(CH2) m10 R a10 , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0046] or, R4and R 9-1 are linked to form a 5-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein said 5-8 membered heterocyclyl or 5-6 membered heteroaryl is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10One or more substitutions of aryl and 5-10 heteroaryl groups;

[0047] 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;

[0048] Or R a14and R a15 together with the P atom to which they are attached form a substituted or substituted 3-8 membered heterocyclyl, wherein the substitution means substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0049] the H in the above CH2may optionally be substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;

[0050] z is 0, 1, 2, or 3; u is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4;

[0051] 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, 2, or 3.

[0052] In certain embodiments of the application, the compound has the structure of Formula (XI-1) (XI-2)

[0053] wherein, is a single or double bond;

[0054] M2is CH, CH2, N, NH, O, or S;

[0055] M3is CH2, NH, O, or S;

[0056] R 6-3selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0057] R3, R4, R5, R6, R 9-2 , R a14 , R a15 , L2, X4, X5, X6, X7, M1, M2, M3, M 13 , M 14 , M 15 , M 22 , M 23 , z, v, u and w are as defined above.

[0058] In certain embodiments of the application, is

[0059] The present application also relates to a compound as illustrated in general formula (I-D), (I-E), (I-F), (I-G), (I-H), (I-I), (I-J), (I-K), (I-L), (I-M), (I-N) (I-O), (I-P), (I-Q), (I-R) or (I-S), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0060] wherein M1is selected from N or CH; M 17 is selected from N or CH; M 18 is selected from CH2, NH, O or S;

[0061] L is selected from a bond or L is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl, 5-10 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups;

[0062] L3 is selected from the key, 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, C 3-8 Cycloalkyl O-, 3-8 membered heterocyclic O-, C 6-10 aryl O- or 5-10 heteroaryl O-, the 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, C 3-8 Cycloalkyl O-, 3-8 membered heterocyclic O-, C 6-10 aryl O- or 5-10 heteroaryl O- can optionally be further replaced 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;

[0063] Ring A exists or does not exist; if it exists, it is selected from C. 3-8 Cycloalkyl, 3-8 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; preferably, ring A is selected from C 3-8 cycloalkyl;

[0064] Ring B is present or absent, when present is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;

[0065] Ring C" is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably Ring C" is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0066] Ring Cy2 is present or absent, when present is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;

[0067] Ring Cy1 is selected from substituted or unsubstituted C 3-10 cycloalkyl or substituted or unsubstituted 3-10 membered heterocyclyl; wherein the substitution means substitution with 1-4 groups selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1- 6-hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 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;

[0068] 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, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1- 6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R1is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =CR' 1-1 R' 1-2 , =N-R' 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 or -(CH2) m10 R a10 , said amino, C 1-6 1-6 alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 1-6 alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 1-6 alkyl, C 2- 2-6 alkenyl, C 2-6 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 1-6 alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said aryl and 5-10 membered heteroaryl optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0069] or R1is independently selected from -(CH2) m14 P(S)R a14 R a15 , -O(CH2) m15 P(S)R a14 R a15 or -NH(CH2) m16 P(S)R a14 R a15 ;

[0070] R' 1-1 and R' 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl is substituted;

[0071] R' 1-3 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 3- 12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0072] R2is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0073] R3is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0074] R N1 and R N2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are substituted;

[0075] R4is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 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 Ra7 -(CH2) m8 S(O)2NHR a8 -(CH2) m9 NHS(O)2R a9 -(CH2) m10 R a10 , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0076] R5is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0077] R6is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0078] R8is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0079] R 9-1 and R 9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 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 or -(CH2) m10 R a10 , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0080] or, R4and R 9-1 to form a 5-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein said 5-8 membered heterocyclyl or 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0081] 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 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C1-6 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;

[0082] Or R a14 and R a15 The P atom attached to it forms a substituted or substituted 3-8 membered heterocyclic group, wherein the substitution refers to being replaced by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or 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;

[0083] In the above CH2, H can be optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or 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 substitutions;

[0084] v1 is 1, 2, or 3; x is 1, 2, 3, 4, or 5; y is 0, 1, or 2; z is 0, 1, 2, or 3; u is 0, 1, 2, 3, or 4; w is 0, 1, 2, 3, or 4; a is 1, 2, or 3;

[0085] m1, m2, m3, m4, m5, m6, m8, m9, and m10 are each independently selected from 0, 1, 2, 3, 4, 5, or 6; m7 is independently selected from 0, 1, 2, or 3.

[0086] In certain embodiments of the application, the compound is represented by Formula (I-D-1), (I-D-2), (I-D-3), (I-D-4), (I-D-5), (I-D-6), (I-E-1), (I-E-2), (I-E-3), (I-E-4), (I-E-5), (I-E-6), (I-E-7), (I-E-8), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-F-7), (I-F-8), (I-F-9), (I-F-10), (I-H-1), (I-H-2), (I-I-1), (I-I-2), (I-J-1), (I-J-2), (I-K-1), (I-K-2), (I-L-1), (I-L-2), (I-M-1), (I-M-2), (I-N-1), (I-N-2), (I-O-1), (I-O-2), (I-P-1), (I-P-2), (I-Q-1), (I-Q-2), (I-R-1), (I-R-2), (I-S-1), or (I-S-2)

[0087] wherein L2is selected from -(CH2) m14 , -0(CH2) m15 , or -NH(CH2) m16 wherein when m14 is 0, -(CH2) m14 is a bond;

[0088] M 17 is selected from N or CH; M 18 is selected from CH2, NH, O, or S;

[0089] M 19 is selected from CH2, NH, SO2, O, or S; M 20 and M 21 are each independently selected from N or CH;

[0090] R 10-1 and R 10-2each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, 6-10 aryl or 5- to 10-membered heteroaryl;

[0091] R 6-3 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, 6-10 aryl or 5- to 10-membered heteroaryl, said amino, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, 6-10 aryl or 5- to 10-membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, 6-10One or more substitutions of aryl and 5-10 heteroaryl groups; v1 is 1, 2 or 3;

[0092] L3, Ring B, Ring C", Ring Cy1, Ring Cy2, M1, R2, R3, R4, R5, R6, R a14 R a15 The definitions of y, z, u, w, m14, m15 and m16 are as described above.

[0093] In certain embodiments of the present invention, the compounds are as shown in general formulas (ID-1-1), (ID-2-1), (IE-1-1), (IE-3-1), (IF-1-1), (IF-3-1), (IG-1-1), (IH-1-1), (II-1-1), (IJ-1-1), (IK-1-1), (IL-1-1), (IM-1-1), (IQ-1-1), (IR-1-1), or (IS-1-1).

[0094] in, It can be a single bond or a double bond;

[0095] M2 is CH, CH2, N, NH, O, or S; M3 is CH2, NH, O, or S;

[0096] v is 0, 1, 2, or 3; L2 is selected from -(CH2). m14 -O(CH2) m15 or -NH(CH2) m16 Where m14 is 0, -(CH2) m14 For key; M 17 Selected from N or CH; M 18 Selected from CH2, NH, O, or S;

[0097] Preferably, the compound is as shown in general formulas (ID-1-1-1), (ID-2-1-1), (IE-1-1-1), (IE-3-1-1), (IF-1-1-1), (IF-3-1-1), (IJ-1-1-1), (IK-1-1-1), (IL-1-1-1), (IM-1-1-1), or (IM-1-1-1-1).

[0098] or preferably, the compound is represented by formula (I-D-1-1-2), (I-D-7), (I-E-1-1-2), (I-F-1-1-2), (I-E-2-1), (I-F-2-1), (I-D-1-1-2-1), (I-D-1-1-2-2), (I-E-1-1-2-1), (I-E-1-1-2-2), (I-F-1-1-2-1), (I-F-1-1-2-2), (I-Q-1-1-1), (I-Q-1-1-2), (I-R-1-1-1), (I-R-1-1-2), (I-S-1-1-1), or (I-S-1-1-2)

[0099] wherein X4is selected from N or CR 2-1 ; X5is selected from N or CR 2-2 ;

[0100] X6is selected from N or CR 2-3 ; X7is selected from N or CR 2-4 ;

[0101] R 2-1 , R 2-2 , R 2-3 , and R 2-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, which amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, is optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl; and

[0102] R 6-1 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl; and

[0103] R 6-2 one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0104] R 6-4 and R 6-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl groups are optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0105] ring C”, ring Cy1, ring Cy2, M1, R2, R3, R4, R5, R a14 , R a15 , y, z, w, m14, m15, and m16 are defined above.

[0106] In certain embodiments of the application, the compound is represented by Formula (I-E-5)

[0107] wherein X4is selected from N or CR 2-1 ; X5is selected from N or CR 2-2 ;

[0108] X6is selected from N or CR 2-3 ; X7is selected from N or CR 2-4 ;

[0109] R 2-1 , R 2-2 , R 2-3 , and R 2-4each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0110] R1, R3, R4, R5, R6, x, z, w, and u are defined above.

[0111] In certain embodiments of the application, the compound is represented by Formula (I-E-5-1) or Formula (I-E-5-2)

[0112] wherein, is a single or double bond; M2is CH, CH2, N, NH, O, or S;

[0113] M3is CH2, NH, O, or S; v is 0, 1, 2, or 3;

[0114] R 6-3 one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0115] Preferably, the compound is as shown in general formula (I-E-5-1-1) or (I-E-5-1-2)

[0116] wherein R 6-1 one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl is optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0117] R 6-2 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0118] R 6-4 and R 6-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0119] M1, R1, R3, R4, R5, R6, x, z, w, u, X4, X5, X6and X7are defined as above.

[0120] In certain embodiments of the application, the compound is represented by the general formula (I-F-5)

[0121] wherein X4is selected from N or CR 2-1 ; X5is selected from N or CR 2-2 ;

[0122] X6is selected from N or CR 2-3 ; X7is selected from N or CR 2-4 ;

[0123] R 2-1 , R 2-2 , R 2-3 and R 2-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 Aryl or 5-10 membered heteroaryl is optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuteroalkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, one or more of which is substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0124] R1, R3, R4, R5, R6, x, z, w, and u are defined above.

[0125] In certain embodiments of the application, the compound is represented by Formula (I-F-5-1) or Formula (I-F-5-2)

[0126] wherein, is a single or double bond; M2is CH, CH2, N, NH, O, or S;

[0127] M3is CH2, NH, O, or S; v is 0, 1, 2, or 3;

[0128] R 6-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuteroalkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, said amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuteroalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuteroalkoxy, C 1-6 Haloalkoxy, C 1-6hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0129] Preferably, the compound is as shown in general formula (I-F-5-1-1) or (I-F-5-1-2)

[0130] wherein R 6-1 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0131] R 6-2 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0132] R 6-4 and R 6-5each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3-8 membered heterocyclyl, 6-10 aryl, 5-10 membered heteroaryl, said amino, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3-8 membered heterocyclyl, 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6 deutero-C1-C6alkoxy, 1-6 halo-C1-C6alkoxy, 1-6 hydroxy-C1-C6alkyl, 3-8 C3-C8cycloalkyl, 3-8 membered heterocyclyl, 6-10 one or more of aryl and 5-10 membered heteroaryl are substituted;

[0133] M1, R1, R3, R4, R5, R6, x, z, w, u, X4, X5, X6, and X7 are defined above.

[0134] In certain embodiments of the application, each R1is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, 1-6 C1-C6alkyl, 2-6 C1-C6alkenyl, 2-6 C1-C6alkynyl, 1-6 deutero-C1-C6alkyl, 1-6 halo-C1-C6alkyl, 1-6 C1-C6alkoxy, 1-6deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, =CR' 1-1 R' 1-2 , =N-R' 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) m11 C(O)OR a11 , (CH2) m12 OC(O)R a12 or -(CH2) m13 N3, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1- 6haloalkyl, C 1-6alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0135] R' 1-1 and R' 1-2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl optionally can be further substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0136] R' 1-3 is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- 6alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with deutero, halo, amino, hydroxy, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3- 12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents of aryl and 5-14 membered heteroaryl;

[0137] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 and R a12 are each independently selected from hydrogen, deutero, halo, amino, hydroxy, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl is optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0138] Preferably, each R1is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-6 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, =CR' 1-1 R' 1-2 , =N-R' 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) m11 C(O)OR a11 , (CH2) m12 OC(O)R a12 or -(CH2) m13 N3, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0139] The H in the above CH2 can be optionally replaced by deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, or 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 and 5-10 heteroaryl substitutions;

[0140] m1, m2, m3, m4, m5, m6, m8, m9, m10, m11, m12 and m13 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is independently selected from 0, 1, 2 or 3.

[0141] In some embodiments of the present 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 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)2NHRa8 -(CH2) m9 NHS(O)2R a9 or -(CH2) m10 R a10 , said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl;

[0142] R a1 , R a2 , R a3 , R a4 , R a5 , R a5 , R a6 , R a7 , R a8 , R a9 and R a10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1- hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl are substituted;

[0143] m1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5, or 6; m7 is selected from 0, 1, 2, or 3.

[0144] In certain embodiments of the application, R1is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, OR a11 , NR a31 R a41 , -CH2-OR a11 , -CH2-R a21 , -CH2-NR a31 R a41 , R a51 CO, Ra51 SO2, R a51 CONH, R a51 NHCO, R a51 SO2NH, R a51 NHSO2, =CHF, =CF2, wherein said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 3-deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by hydrogen, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, one or more of which is substituted by hydrogen, halogen, amino, cyano, hydroxy, C

[0145] R a11 , R a21 , R a31 , R a41 and R a51 are each independently selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, wherein said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted with hydrogen, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, one or more of which is optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0146] In certain embodiments of the application, R1is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, the amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3haloalkyl, C 1- 3alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 10 one or more of aryl and 5-6 membered heteroaryl;

[0147] Preferably, R1is independently selected from hydrogen, hydroxyl, methyl, -CH2F, cyano, cyclopropyl, -CH2-cyclopropyl, or amino.

[0148] In certain embodiments of the application, each R1is independently selected from H, D, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, ethenyl, propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, NH2, OH, CN, CH2F, CHF2, CF3, CH2CF3, CD3, N3, COOCH3, OCOCH3, NHCOCH3, CONHCH3, COCH3, COCF3, SO2CH3, SO2NHCH3, NHSO2CH3, SO2CH2CH3, NHSO2CH2CH3, SO2NHCH2CH3, F, Cl, OCF3, CH2OCF3, =CF2, =CHF, =CHCN, CH2CN, CH2OH,

[0149] In certain embodiments of the application, R' 1-1 and R' 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 one or more of aryl and 5-6 membered heteroaryl; preferably, R' 1-1 and R' 1-2 are each independently selected from hydrogen or fluorine.

[0150] In certain embodiments of the application, R' 1-1 and R' 1-2 are each independently selected from: hydrogen, fluorine, methyl or ethyl. In certain embodiments of the application, R' 1-3 is independently selected from: hydrogen or methyl.

[0151] In certain embodiments of the application, R2is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 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 , said amino group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuteroalkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group, or 5-10 membered heteroaryl group, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo group, thioxo group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuteroalkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C 6-10 aryl group, and 5-10 membered heteroaryl group;

[0152] R' a1 , R' a2 , R' a3 , R' a4 , R' a5 , R' a6 , R' a7 , R' a8 , R' a9 , and R' a10 are each independently selected from hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, oxo group, thioxo group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 deuteroalkyl group, C 1-6 haloalkyl group, C1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1- hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0153] m1’, m2’, m3’, m4’, m5’, m6’, m8’, m9’, and m10’ are each independently selected from 0, 1, 2, 3, 4, 5, or 6; m7’ is selected from 0, 1, 2, or 3.

[0154] In certain embodiments of the application, R2is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, said aryl and 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1- alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 10 one or more of aryl and 5-6 membered heteroaryl; preferably, R2is selected from hydrogen.

[0155] In certain embodiments of the application, R’2is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH2)OR’ a11 , or OR’ a11 , said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 one or more of aryl and 5-6 membered heteroaryl are substituted;

[0156] R’ a11 independently selected from hydrogen, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3- 6cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, wherein the C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl optionally further substituted with hydrogen, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0157] In certain embodiments of the application, R3is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1- alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 10 aryl and 5-6 membered heteroaryl, one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0158] In certain embodiments of the application, R4is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 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 , said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, C6-C10aryl, or 5-6 membered heteroaryl;

[0159] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, C6-C10aryl, or 5-6 membered heteroaryl; 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl; 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl; 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 one or more of which is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 3-6 membered heterocyclyl, C6-C10aryl, or 5-6 membered heteroaryl;

[0160] Preferably, R4is selected from methyl, ethyl, -CD3, -CH2CHF2, -CH2CH2F, Preferably, R4 is selected from methyl, ethyl, -CH2CHF2, -CH2CH2F, In certain embodiments of the application, R4 is selected from hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2CF3, -CH2CHF2, -CH2CH2F, cyclopropyl, In certain embodiments of the application, R4 is selected from COCH3.

[0161] In certain embodiments of the application, R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1- 3alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 10 one or more of aryl and 5-6 membered heteroaryl; preferably, R5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl, or pyrazolyl; preferably, R5is independently selected from hydrogen, fluoro, chloro, methyl, cyano, cyclopropyl, or pyrazolyl; preferably, R5is independently selected from hydrogen, fluoro, chloro, methyl, cyano, cyclopropyl or

[0162] In certain embodiments of the application, R6is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1- 3alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 10 one or more of aryl and 5-6 membered heteroaryl; preferably, R6is independently selected from hydrogen or fluoro.

[0163] In certain embodiments of the application, R7is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1- alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 10 one or more of aryl and 5-6 membered heteroaryl; preferably, R7is independently selected from hydrogen or fluorine.

[0164] In certain embodiments of the application, R8is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 one or more of aryl and 5-6 membered heteroaryl are substituted;

[0165] Preferably, R8is selected from oxo, thioxo, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl.

[0166] In certain embodiments of the application, R 9-1 and R 9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 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 or-(CH2) m10 R a10 , said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl, is optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl;

[0167] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 and R a10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl optionally can be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 one or more of aryl and 5-6 membered heteroaryl.

[0168] In certain embodiments of the application, ring C” is selected from 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, more preferably

[0169] In certain embodiments of the application, ring C” is selected from phenyl, 5-6 membered heteroaryl, phenyl and 5-6 membered heterocyclyl, or 5-6 membered heteroaryl and 5-6 membered heterocyclyl, preferably ring C” is selected from thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, pyrimidinyl, pyridinyl, pyridazinyl, pyrazinyl, phenyl, more preferably ring C” is selected from

[0170] In certain embodiments of the application, ring C” is selected from C 3-10cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclyl and 5-6 membered heteroaryl, C 3-10 cycloalkyl and 5-6 membered heteroaryl, 4-10 membered heterocyclyl and phenyl, C 3-10 cycloalkyl and phenyl; preferably, ring C" is selected from

[0171] In certain embodiments of the application, is selected from

[0172] In certain embodiments of the application, is selected from

[0173] In certain embodiments of the application, is selected from preferably is selected from wherein Cy3is selected from C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; X8and X9are each independently selected from C or N; X 10 , X 11 and X 12 are each independently selected from C, N, O, S, NH or CH; X 13 , X 14 , X 15 and X 16 are each independently selected from CH or N;

[0174] M 17 , M 18 , M 19 , M 20 , M 21 , v1, R1, R2, x, y, R a14 , R a15 , L2, X4, X5, X6and X7are as defined above.

[0175] In certain embodiments of the application, is selected from preferably is selected from wherein Cy3is selected from C 3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; X8and X9are each independently selected from C or N; X 10 , X 11 , and X 12 are each independently selected from C, N, O, S, NH, or CH; X 13 , X 14 , X 15 , and X 16 are each independently selected from CH or N;

[0176] M 17 , M 18 , M 19 , M 20 , M 21 , v1, R1, x, R a14 , R a15 , L2, X4, X5, X6, and X7are defined as above.

[0177] In certain embodiments of the present application, is selected from wherein, R a14 and R a15 are each independently C 1-6 alkyl, preferably methyl or ethyl;

[0178] or R a14 and R a15 together with the P atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl, wherein the substitution means being substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2- 6alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0179] R L-1 and R L-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;

[0180] preferably

[0181] In certain embodiments of the application, L2is selected from a bond, -(CH2)-, -(CH2)2-, -0(CH2)-, -NH(CH2)-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, NH, Preferably, L2is selected from a bond, -(CH2), -0(CH2), or -NH(CH2); or R a14 and R a15 each independently is C 1-6 alkyl, preferably methyl or ethyl.

[0182] In certain embodiments of the application, or ring A is selected from C 3-8 cycloalkyl, preferably C 3-6 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0183] In certain embodiments of the application, or ring A is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or phenyl; more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridonyl.

[0184] In certain embodiments of the application, R 6-3 is selected from C 1-3 alkyl or C 1-3 alkyl C 3-6 cycloalkyl.

[0185] In certain embodiments of the application, R 6-3 is selected from C 1-3 alkyl, C 1-3 haloalkyl or deutero C 1-3 haloalkyl; more preferably, R 6-3 is selected from CH2F, CHF2, CF3, CDF2, In certain embodiments of the application, R 6-1 and R 6-2each independently halogen, preferably F.

[0186] In certain embodiments of the application, R 2-1 , R 2-2 , R 2-3 and R 2-4 each independently H, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 3-6 cycloalkyl, preferably H, F or methyl.

[0187] In certain embodiments of the application, the ring Cy2is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, preferably pyrazolyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyridonyl,

[0188] In certain embodiments of the application, the ring Cy2is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, preferably pyrazolyl, cyclopropyl, pyridyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, imidazolyl.

[0189] In certain embodiments of the application, the ring Cy1is selected from 4-6 membered heterocyclyl, further preferably selected from

[0190] In certain embodiments of the application, L3is selected from C 1-3 alkoxy, C 3-6 cycloalkyl O-, 4-6 membered heterocyclyl O-, C 3- 10 cycloalkyl or 4-10 membered heterocyclyl, preferably

[0191] In certain embodiments of the application, selected from preferably, selected from In certain embodiments of the application, the ring C’ is selected from 6 membered heteroaryl, preferably pyrimidinyl or pyridyl, preferably

[0192] In certain embodiments of the present application, L is a bond, O or NH. In certain embodiments of the present application, L is a bond, ring A is absent,

[0193] The present application further relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0194] In certain embodiments of the present application, the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, more further preferably 15-40%, more further preferably 20-30%, more further preferably 20-25% by weight based on the total weight of the pharmaceutical composition.

[0195] The present application further relates to a pharmaceutical composition comprising the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof as an active ingredient in an amount of 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, more further preferably 15-40%, more further preferably 20-30%, more further preferably 20-25% by weight based on the total weight of the pharmaceutical composition.

[0196] In certain embodiments of the present application, the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof is administered in a dosage of 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).

[0197] The present application further relates to the use of the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof, or the pharmaceutical composition for the preparation of a TNFα inhibitor medicament.

[0198] ​The present application further relates to the use of said compound, stereoisomer thereof or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for the treatment of an autoimmune disease, wherein said autoimmune disease is preferably selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondylarthritis, 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 biliary cholangitis, autoimmune hepatitis, lupus nephritis, Goodpasture's syndrome, autoimmune oophoritis or autoimmune orchitis.

[0199] The present application also relates to a method for the prophylaxis and / or treatment of an autoimmune disease comprising administering to a patient a therapeutically effective dose of said compound, stereoisomer thereof or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0200] In certain embodiments of the application, said autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondylarthritis, 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 biliary cholangitis, autoimmune hepatitis, lupus nephritis, Goodpasture's syndrome, autoimmune oophoritis or autoimmune orchitis.

[0201] Detailed description of the application

[0202] Unless otherwise indicated herein, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art in the field of the application, and in particular, the terms used in the specification and claims have their normal generic meanings.

[0203] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which can optionally be substituted by one or more substituents. In particular embodiments, alkyl refers to a straight-chain saturated hydrocarbon group 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 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a branched saturated hydrocarbon group of 3 to 20 (C 3-20 ), 3 to 15 (C3-15 ), 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 ) carbon atoms. As used herein, straight chain C 1-6 alkyl and branched chain C 3-6 alkyl groups are also referred to as "lower alkyl." For example, C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In one embodiment, the C 1-6 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, t-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 described elsewhere herein.

[0204] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is as defined 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 described elsewhere herein.

[0205] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon radical that contains at least one carbon-carbon double bond and the carbon-carbon double bond can be located in any position of the alkenyl group, which can be optionally substituted with one or more substituents. In particular embodiments, the alkenyl group is a straight-chain unsaturated hydrocarbon radical of 2 to 20 (C 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 ) carbon atoms, or a branched-chain unsaturated hydrocarbon radical of 3 to 20 (C 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 ) carbon atoms. Unless otherwise indicated, the term "alkenyl" as used herein encompasses both straight-chain and branched-chain alkenyl groups. For example, C 2-6 alkenyl refers to a straight-chain unsaturated hydrocarbon radical of 2 to 6 carbon atoms or a branched-chain unsaturated hydrocarbon radical of 3 to 6 carbon atoms. In one embodiment, the C 2-6 alkenyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: It will be understood by those of ordinary skill in the art that the term "alkenyl" can also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl group is an optionally substituted alkenyl group as described elsewhere herein.

[0206] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon radical that contains at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located in any position of the alkynyl group, which can be optionally substituted with one or more substituents. In particular embodiments, the alkynyl group is a straight-chain unsaturated hydrocarbon radical of 2 to 20 (C 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 ) carbon atoms, or a branched-chain unsaturated hydrocarbon radical of 3 to 20 (C 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 ) carbon atoms. Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched-chain alkynyl groups. For example, C 2-6 alkynyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched-chain unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 alkynyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.

[0207] The term "cycloalkyl" refers to saturated or partially unsaturated aliphatic monocyclic, polycyclic (two or more) cyclic groups, which can be optionally substituted with one or more substituents. In particular 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 ) carbon atoms; which can contain one or more double bonds, but does not have a fully conjugated pi-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group described elsewhere herein or a cycloalkyl group optionally fused to a heterocyclyl, aryl, or heteroaryl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc.

[0208] The term "spirocycloalkyl" refers to aliphatic polycyclic groups that share one carbon atom (termed a spiro atom) between single rings, which can contain one or more double bonds, but does not have a fully conjugated pi-electron system in any ring. In particular embodiments, the spirocycloalkyl 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. Spiroalkyl groups are classified as mono-, bi-, or polyspiroalkyl groups according to the number of spiro atoms shared between rings, in one embodiment mono- and bi-spiroalkyl groups. In one embodiment, the spiroalkyl group is an optionally substituted spiroalkyl group described elsewhere herein. Non-limiting examples of spiroalkyl groups include:

[0209] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. In particular embodiments, a fused 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. Fused cycloalkyl groups can be classified as bi-, tri-, tetra-, or polycyclic, in one embodiment bi- or tri-cyclic, further in one embodiment 3 / 5-, 4 / 5-, 5 / 5-, or 5 / 6- bicyclic alkyl groups. In one embodiment, the fused cycloalkyl group is an optionally substituted fused cycloalkyl group described elsewhere herein or a fused cycloalkyl group optionally fused to a heterocyclyl, aryl, or heteroaryl group. Non-limiting examples of fused cycloalkyl groups include:

[0210] The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. In particular embodiments, a 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. Bridged cycloalkyl groups can be classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-cyclic. In one embodiment, the bridged cycloalkyl group is an optionally substituted bridged cycloalkyl group described elsewhere herein. Non-limiting examples of bridged cycloalkyl groups include:

[0211] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atoms are optionally oxidized, the nitrogen atoms are optionally quaternized, the ring carbon atoms are optionally substituted with oxygen, but excluding ring moieties of -0-0-, -0-S-, the remaining ring atoms are carbon, which can contain one or more double bonds but do not have a fully conjugated pi-electron system. In particular embodiments, the heterocyclyl group comprises 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl 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 heterocyclyl group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, among others. Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups. In one embodiment, the heterocyclyl group is optionally substituted as described elsewhere herein, or further annelated with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0212] The term "spiroheterocyclyl" refers to polycyclic heterocyclic groups that share one atom (referred to as the spiro atom) between the rings, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, the remaining ring atoms are carbon, which can contain one or more double bonds, and no ring has a fully conjugated pi-electron system. In particular embodiments, the spiroheterocyclyl group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; the spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between the rings; mono- and bi-spiroheterocyclyl groups are preferred; in one embodiment, the spiroheterocyclyl group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl group; in one embodiment, the spiroheterocyclyl group is optionally substituted as described elsewhere herein; non-limiting examples of spiroheterocyclyl groups include:

[0213] The term "fused heterocyclyl" refers to a polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In particular embodiments, the fused heterocyclyl group comprises 5 to 20 or 6 to 14 ring atoms, in one embodiment 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl depending on the number of rings comprising the ring system; preferably bicyclic or tricyclic; in one embodiment a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl; in one embodiment, the fused heterocyclyl group is an optionally substituted fused heterocyclyl group described elsewhere herein, or can be fused to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group; non-limiting examples of fused heterocyclyl groups include:

[0214] The term "bridged heterocyclyl" refers to a polycyclic heterocyclyl group in which any two rings share two non-adjacent atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In particular embodiments, the bridged heterocyclyl group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl depending on the number of rings comprising the ring system; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment a bicyclic or tricyclic; in one embodiment, the bridged heterocyclyl group is an optionally substituted bridged heterocyclyl group described elsewhere herein; non-limiting examples of bridged heterocyclyl groups include:

[0215] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring (that is, rings which share adjacent pairs of carbon atoms) radical that has a conjugated pi-electron system, which can be optionally substituted by one or more substituents. In particular embodiments, aryl groups contain from 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, aryl can further refer to a bicyclic, tricyclic, or tetracyclic ring system in which at least one ring is aromatic, the other rings can be saturated, partially unsaturated, carbocyclic, or heterocyclic rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10heteroaryl, benzo3-10cycloalkyl, or benzo3-10heterocyclyl. In one embodiment, the aryl group is selected from benzo5-6heteroaryl, benzo3-6cycloalkyl, or benzo3-6heterocyclyl, wherein the heterocyclyl is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetrahydroanthracenyl),

[0216] The term "arylene" refers to a divalent aryl radical formed by the further replacement of one hydrogen atom of aryl with a bond, wherein arylene is optionally substituted or unsubstituted, and aryl is as defined above.

[0217] 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 particular embodiments, the heteroaryl group 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 group comprises 5 or 6 ring atoms; in particular embodiments, the heteroaryl group can further refer to a bicyclic, tricyclic, or tetracyclic ring system, 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 can 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 and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl, or heteroaryl and 3-10 membered heterocyclyl; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl is a heterocyclyl comprising 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzoindolyl, carbazolyl, biphenofuranyl, phenanthrolinyl, phenanthridinyl, phenarsenazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0218] The term "heteroarylene" refers to a divalent heteroaryl group formed by the further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is defined above.

[0219] The term "heteroalkyl" refers to stable straight-chain or branched-chain, or cyclic alkyl hydrocarbon groups, or combinations thereof, consisting of the stated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. In one embodiment, the heteroatoms O, N, and S can be placed at any interior position of the heteroalkyl group. In one embodiment, the heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which 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. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-O-CH3and -CH2-O-Si(CH3)3. In a particular embodiment, the heteroalkyl is optionally substituted heteroalkyl as described elsewhere herein.

[0220] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as previously described. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. In one embodiment, the alkoxy is optionally substituted alkoxy as described elsewhere herein.

[0221] The term "alkylacyl" refers to -C(O)-alkyl, wherein alkyl is as previously described.

[0222] The term "haloalkyl" refers to an alkyl group as previously described substituted by one or more halogens. Non-limiting examples of haloalkyl groups include trifluoromethyl, -CH2CF3,

[0223] The term "haloalkoxy" refers to an alkoxy group as previously described substituted by one or more halogens.

[0224] The term "hydroxyalkyl" refers to an alkyl group as previously described substituted by a hydroxyl group.

[0225] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), where alkyl or cycloalkyl are as previously described. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkylthio is an optionally substituted alkylthio as described elsewhere herein.

[0226] The term "haloalkylthio" refers to alkylthio substituted with one or more halogen, where alkylthio is as previously described.

[0227] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), where alkenyl is as previously described. Non-limiting examples of alkenylcarbonyl include: ethenylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl as described elsewhere herein.

[0228] The term "aminocarbonyl" refers to NH2-C(O)-.

[0229] The term "alkylaminocarbonyl" refers to aminocarbonyl (NH2-C(O)-) with one or both of the hydrogens replaced by alkyl, where alkyl is as previously described.

[0230] The term "alkylamino" refers to amino with one or both of the hydrogens replaced by alkyl, where alkyl is as previously described.

[0231] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably throughout the specification.

[0232] The term "hydroxyl" refers to the -OH group. The term "halogen" denotes fluorine, chlorine, bromine, or iodine. The term "amino" refers to -NH2.

[0233] The term "cyano" refers to -CN. The term "nitro" refers to -NO2. The term "carboxyl" refers to -C(O)OH. The term "acetyl" refers to -C(O)CH3. The term "oxo" or "keto" refers to =O. The term "mercapto" refers to -SH.

[0234] The term "hydrogen" includes protium ( 1 ), deuterium ( 2 ), tritium ( 3 ), and / or mixtures thereof. In particular embodiments, one or more positions of a compound occupied by hydrogen can be enriched in deuterium and / or tritium. Such isotopically enriched analogs can be prepared from suitably isotope-labeled starting materials available from commercial sources or prepared by known literature procedures.

[0235] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, alkylacyl groups can be substituted or unsubstituted, in one embodiment, the substituents are selected from one or more of the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, thiol, hydroxyl, nitro, cyano, azido, hydroximino, phosphonate, oxo, thioxo, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0236] The phrases "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used interchangeably and mean that X can be any one of A, B, or C, or any two of A, B, or C, or all three of A, B, and C.

[0237] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0238] In various portions of the application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be understood to be a connecting group. For example, if the structure requires a connecting group and the Markush group definition recited for that variable recites "alkyl" or "aryl," it should be understood that the "alkyl" or "aryl" respectively represents a connected alkylene group or arylene group.

[0239] In one embodiment, "substituted" means that any one or more hydrogen atoms on a particular atom is / are replaced with a substituent, as long as the valence of the particular atom is not normally exceeded, and the substituted compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that the moiety can or can not be substituted and that the nature and number of substituents, if present, are optional and can be any that are chemically feasible unless otherwise specified. It goes without saying that the substituents are only in their possible chemical locations and that one skilled in the art can determine (experimentally or theoretically) what substitutions are or are not possible without undue effort. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0240] The indefinite articles "a" and "an," as well as the word "the" when used in the present specification and claims come with the meaning "one or more."

[0241] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient.

[0242] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in a mammal and possess the desirable biological activity.

[0243] "Stereoisomer" encompasses all enantiomeric / diastereomeric / stereomerically pure and enantiomeric / diastereomeric / stereomerically enriched compounds of the present application.

[0244] "Stereomerically pure" refers to a composition comprising one stereoisomer of a compound substantially free of another stereoisomer of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. Typically, a stereomerically pure compound comprises greater than about 80% by mass of one stereoisomer of the compound and less than about 20% by mass of another stereoisomer of the compound, greater than about 90% by mass of one stereoisomer of the compound and less than about 10% by mass of another stereoisomer of the compound, greater than about 95% by mass of one stereoisomer of the compound and less than about 5% by mass of another stereoisomer of the compound, greater than about 97% by mass of one stereoisomer of the compound and less than about 3% by mass of another stereoisomer of the compound, or greater than about 99% by mass of one stereoisomer of the compound and less than about 1% by mass of another stereoisomer of the compound.

[0245] "Stereomerically enriched" refers to a composition comprising greater than about 55% by mass, greater than about 60% by mass, greater than about 70% by mass, or greater than about 80% by mass of one stereoisomer of a compound.

[0246] "Enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereomerically enriched composition of a compound having one chiral center.

[0247] "Optically active" and "enantiomerically active" refer to a molecular composition having an enantiomeric or diastereomeric 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 particular embodiments, the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer by weight of the total racemate.

[0248] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. The (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light that is 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 symbols (+) and (-) for optical rotation are not related to the absolute configuration of the molecule R and S. DETAILED DESCRIPTION

[0249] The application is further described in connection with the following examples, which are not intended to limit the scope of the application.

[0250] Examples

[0251] The structure of the compounds of the present application were determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were made on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0252] LC-MS measurements were made on an Agilent 1200 Infinity Series Mass Spectrometer. HPLC measurements were made using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm column).

[0253] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, TLC uses specification is 0.15mm-0.20mm, thin layer chromatography separation and purification product uses specification is 0.4mm-0.5mm.Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0254] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0255] Unless otherwise specified, all reactions of the present application are carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature unit is degree Celsius.

[0256] Intermediate 1

[0257] To a solution of (R)-N-(1-(5-bromopyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfmamide (500 mg, 1.50 mmol), pinacol diborane (496 mg, 1.96 mmol) and potassium acetate (443 mg, 4.51 mmol) in 1,4-dioxane (10 mL) was added 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (109 mg, 150 μmol), the reaction was vacuumed, filled with nitrogen, repeated for 3 times, then heated to 80 °C for 16 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, then dissolved in N,N-dimethylformamide (5 mL), separated and purified by reverse column chromatography to obtain (R)-(2-(1-((tert-butylsulfinyl< sulfinyl>)amino)cyclobutyl)pyrimidin-5-yl)boronic acid (273 mg, 61%). MS m / z (ESI): 298.1 [M+H] + .

[0258] Intermediate 2

[0259] First step: preparation of 1-(fluoromethyl)-3-methylenecyclobutane-1-carbonitrile

[0260] To a solution of 3-methylenecyclobutane carbonitrile (1.5 g, 16.11 mmol) in THF (20 mL) was added lithium diisopropylamide (19.3 mL, 19.33 mmol, 1M in THF) at -78 °C, the reaction was stirred at -78 °C for 30 minutes, fluoromethane iodide (3.35 g, 20.94 mmol) was added to the reaction, and the stirring was continued at -78 °C for 1 hour. The reaction was quenched with saturated ammonium chloride, extracted with EA, the organic phase was dried, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (680 mg, 33.7%).

[0261] 1 H NMR (400 MHz, CDC13) δ 5.00 (p, J = 2.5 Hz, 2H), 4.54 (d, J = 46.8 Hz, 2H), 3.31-3.20 (m, 2H), 2.90 (ddt, J = 15.3, 4.4, 2.3 Hz, 2H).

[0262] Second Step: Preparation of 1-(fluoromethyl)-3-oxocyclobutane-1-carbonitrile

[0263] Sodium periodate (2.73 g, 12.79 mmol) was added to a solution of 1-(fluoromethyl)-3- methylenecyclobutane-1-carbonitrile (400 mg, 3.20 mmol) and ruthenium trichloride monohydrate (36.03 mg, 160 μmol) in acetonitrile (4 mL), DCM (4 mL) and water (8 mL) at 0 °C and the reaction was stirred at room temperature for 4 h. The reaction was poured into water and extracted with EA, the organic phase was dried, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (318 mg, 78%). MS m / z (ESI): 128.1 [M+H] + .

[0264] [Corr. according to Rule 91 14.10.2025] Third Step: Preparation of 3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)-3-hydroxycyclobutane-1-carbonitrile

[0265] n-Butyllithium (0.73 mL, 1.84 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 5-bromo-2-iodo-pyrimidine (500 mg, 1.76 mmol) in toluene (10 mL) at -78 °C and the reaction was stirred at -78 °C for 30 min. 1-(fluoromethyl)-3-oxocyclobutane-1-carbonitrile (245.42 mg, 1.93 mmol) was added to the reaction and the reaction was stirred at -78 °C for 30 min before being allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured into water and extracted with EA, the organic phase was dried, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (160 mg, 31.8%). MS m / z (ESI): 286.1 [M+H] + .

[0266] Intermediate 3

[0267] First Step: Preparation of (1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile

[0268] Dissolve 5-bromo-2-iodopyrimidine (18 g, 63.23 mmol) in DCM (200 mL) under dry ice-acetone bath, add n-butyllithium (25.3 mL, 63.23 mmol, 2.5 mol / L in Hexanes) dropwise, stir the reaction for 1 hour, add 1-methyl-3-oxocyclobutane-1-carbonitrile (6 g, 54.98 mmol) in DCM (30 mL) dropwise and continue stirring for 1 hour. After the reaction is completed, extract the reaction with DCM (150 mL x 3), wash with saturated aqueous sodium chloride solution (200 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, purify the residue by silica gel column chromatography and chiral column separation to obtain the title compound (1.5 g, 10.2%). MS m / z (ESI): 268.1 [M+H] + .

[0269] Intermediate 4

[0270] Intermediate 5

[0271] Intermediate 6

[0272] Specifically, intermediate 6 can also be prepared according to the following intermediates 7 and 8.

[0273] Intermediate 7

[0274] First step: preparation of aminobenzenesulfonic acid 2,4,6-trimethyl ester

[0275] Stir a mixture of (tert-butoxycarbonylamino) 2,4,6-trimethyl benzenesulfonate (50 g, 158.54 mmol) in trifluoroacetic acid (100 mL) at 0 °C for 1.5 hours. Pour the mixture onto crushed ice. Filter the resulting white precipitate, wash with water (1500 mL) and dry under vacuum to obtain the title compound as a white solid (34 g, 99.6%).

[0276] Second step: preparation of 4-chloropyridin-1-ium-1-amine iodide

[0277] ​To a solution of 4-chloropyridine hydrochloride (15 g, 100.00 mmol) in water (45 mL) was added sodium bicarbonate (16.8 g, 199.99 mmol) at 0 °C and stirred for 30 min. The mixture was extracted with dichloromethane (40 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered. A solution of amino 2,4,6-trimethylbenzenesulfonate (34 g, 157.94 mmol) in dichloromethane (100 mL) was added to the filtrate. The resulting mixture was stirred at 20 °C for 12 h. Hydroiodic acid (12.79 g, 100.00 mmol) was added to the mixture and stirred for 30 min. The resulting solution was stored in the refrigerator to crystallize the title compound as an orange solid (7.5 g, 29.2%).

[0278] Third Step: Preparation of 5-chloropyrazolo[l,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester

[0279] To a solution of 4-chloropyridine hydrochloride (15 g, 100.00 mmol) in water (45 mL) was added sodium bicarbonate (16.8 g, 199.99 mmol) at 0 °C and stirred for 30 min. The mixture was extracted with dichloromethane (40 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered. A solution of amino 2,4,6-trimethylbenzenesulfonate (34 g, 157.94 mmol) in dichloromethane (100 mL) was added to the filtrate. The resulting mixture was stirred at 20 °C for 12 h. Hydroiodic acid (12.79 g, 100.00 mmol) was added to the mixture and stirred for 30 min. The resulting solution was stored in the refrigerator to crystallize the title compound as an orange solid (7.5 g, 29.2%). + .

[0280] Fourth Step: Preparation of 5-chloropyrazolo[l,5-a]pyridine-2-carboxylic acid

[0281] A mixture of 5-chloropyrazolo[l,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester (4.5 g, 16.75 mmol) in sulfuric acid (82.8 g, 844.22 mmol, 45 mL) and water (45 mL) was stirred at 110 °C for 12 h. After the reaction solution was cooled to room temperature, the pH of the mixture was adjusted to 8-9 with aqueous sodium hydroxide solution. The pH of the mixture was adjusted to 5-6 with dilute hydrochloric acid and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried in vacuum to give the title compound as a white solid (3 g, 91.1%) which was used directly in the next step. MS m / z (ESI): 197 [M+H] + .

[0282] 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 8.86-8.76 (m, 1H), 7.97 (dd, J = 8.8, 2.3 Hz, 1H), 7.18-7.07 (m, 1H), 7.03 (d, J = 0.9 Hz, 1H).

[0283] Step 5: Preparation of ethyl 5-chloropyrazolo[l,5-a]pyridine-2-carboxylate

[0284] To a solution of 5-chloropyrazolo[l,5-a]pyridine-2-carboxylic acid (3 g, 15.26 mmol) in ethanol (30 mL) was added sulfuric acid (2.99 g, 30.52 mmol, 1.63 mL), the resulting mixture was stirred at 80 °C for 12 h. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound as a white solid (3.2 g, 93.4 %). MS m / z (ESI): 225 [M+H] + .

[0285] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 7.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 7.5, 2.4 Hz, 1H), 7.08 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0286] Step 6: Preparation of ethyl 5-chloro-3-iodopyrazolo[l,5-a]pyridine-2-carboxylate

[0287] To a solution of ethyl 5-chloropyrazolo[l,5-a]pyridine-2-carboxylate (3.2 g, 14.24 mmol) in N,N-dimethylformamide (35 mL) was added N-iodosuccinimide (9.61 g, 42.73 mmol), the resulting mixture was stirred at 100 °C for 3 h. After the reaction solution was cooled to room temperature, it was diluted with water (35 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (35 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound as a white solid (4.9 g, 98.1 %). MS m / z (ESI): 350 [M+H]+ .

[0288] Step 7: Preparation of ethyl 3-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)(hydroxy)methyl)-5-chloropyrazolo[l,5-a]pyridine-2-carboxylate

[0289] Ethyl 5-chloro-3-iodopyrazolo[l,5-a]pyridine-2-carboxylate (45 g, 128.3 mmol) and isopropylmagnesium chloride-lithium chloride (1.3 M, 118 mL) were dissolved in tetrahydrofuran (300 mL) at -78 °C, and 5-bromo-2,2-difluorobenzo[d][l,3]dioxole-4-carbaldehyde (40.8 g, 154 mmol) was added dropwise. After the addition was complete, the reaction was slowly warmed to room temperature and stirred for 1 h. The reaction was completed, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a yellow solid (37 g, 58%) after purification by silica gel column chromatography.

[0290] Step 8: Preparation of dimethyl 2-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)(5-chloro-2-(ethyl oxycarbonyl)pyrazolo[l,5-a]pyridin-3-yl)methyl)propanedioate

[0291] Dimethyl propanedioate (49.92 g, 377.81 mmol), ethyl 3-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)(hydroxy)methyl)-5-chloropyrazolo[l,5-a]pyridine-2-carboxylate (37 g, 75.56 mmol), and scandium trifluoromethanesulfonate (3.72 g, 7.56 mmol) were dissolved in 1,2-dichloroethane (1500 mL), and the reaction was stirred at 80 °C for 16 h. The reaction was completed, the reaction solution was cooled to room temperature, and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a yellow solid (24 g, 52.1%) after purification by silica gel column chromatography. MS m / z (ESI): 603.2 [M+H] + .

[0292] Step 9: Preparation of ethyl 3-(l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-3-methoxy-3-oxopropyl)-5-chloropyrazolo[l,5-a]pyridine-2-carboxylate

[0293] Dimethyl 2-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)(5-chloro-2- (ethoxycarbonyl)pyrazolo[l,5-a]pyridin-3-yl)methyl)propanedioate (24 g, 39.75 mmol), water (3.58 g, 198.76 mmol) and lithium chloride (8.43 g, 198.76 mmol) were dissolved in dimethyl sulfoxide (250 mL) and stirred at 125 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound as a yellow solid (16 g, 73.7%). MS m / z (ESI): 546.2 [M+H] + .

[0294] Step 10: Preparation of methyl l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-8- chloro-3-oxo-2,3-dihydro-lH-cyclopenta[3,4]pyrazolo[l,5-a]pyridine-2-carboxylate

[0295] Potassium tert-pentoxide (6.11 g, 47.64 mmol) was added to a solution of ethyl 3-(l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-3-methoxy-3- oxopropanyl)-5-chloropyrazolo[l,5-a]pyridine-2-carboxylate (13 g, 23.82 mmol) in tetrahydrofuran (300 mL) and stirred at 75 °C for 20 min. After the reaction was completed, the reaction solution was cooled to room temperature and poured into a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (150 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound as a yellow solid (7.4 g, 62.1%). MS m / z (ESI): 499.2 [M+H] + .

[0296] Step 10: Preparation of methyl l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-8- chloro-3-oxo-2,3-dihydro-lH-cyclopenta[3,4]pyrazolo[l,5-a]pyridine-2-carboxylate

[0297] To a solution of (S)-8-chloro-3-oxo-2,3-dihydro-lH-cyclopenta[3,4]pyrrolo[l,2- c]pyrimidine-2-carboxylic acid (2.0 g, 7.62 mmol) in tetrahydrofuran (20 mL) was added 6N hydrochloric acid (20 mL) and the reaction was stirred at 60 °C for 16 hours. The reaction was cooled to room temperature and filtered. The filter cake was dried under vacuum and purified by chiral chromatography to give the title compound (1.5 g, 75.0 %). MS m / z (ESI): 218.1 [M+H] + .

[0298] Twelfth Step: Preparation of (R)-N-((S,E)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-8-chloro-l,2-dihydro-3H-cyclopenta[3,4]pyrrolo[l,5-a]pyrimidin-3- ylidene)-2-methylpropane-2-sulfmamide

[0299] To a solution of (S)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-8-chloro-l,2- dihydro-3H-cyclopenta[3,4]pyrrolo[l,5-a]pyrimidin-3-one (2.75 g, 6.23 mmol) and (R) tert-butylsulfmamide (1.51 g, 12.45 mmol) in tetrahydrofuran (30 mL) was added tetraethyl orthotitanate (7.1 g, 31.14 mmol) and the reaction was heated to reflux for 16 hours. The reaction was cooled to room temperature and poured into water. The mixture was filtered and the filter cake was washed with ethyl acetate. The combined filtrate was extracted twice with ethyl acetate and the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.45 g, 72.2 %). MS m / z (ESI): 544.2 [M+H] + .

[0300] Thirteenth Step: Preparation of (lS,3R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-8-chloro-2,3-dihydro-lH-cyclopenta[3,4]pyrrolo[l,5-a]pyrimidin-3-amine

[0301] Sodium borohydride (340 mg, 8.99 mmol) was added to a solution of (R)-N-((S,E)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-8-chloro-1,2-dihydro-3H- cyclopenta[3,4]pyrrolo[1,5-a]pyridine-3-ylidene)-2-methylpropane-2-sulfmamide (2.45 g, 4.50 mmol) in methanol (20 mL) at 0 °C. The reaction was stirred for 1 h, and then 4 M hydrochloric acid in dioxane (2 mL) was added directly to the reaction. The reaction was stirred at room temperature for 15 min. The reaction was poured into sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.75 g, 87.9%). MS m / z (ESI): 442.2 [M+H] + .

[0302] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (dd, J = 7.5, 0.8 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.39 - 7.24 (m, 2H), 6.82 (dd, J = 7.5, 2.4 Hz, 1H), 4.70 (t, J = 8.1 Hz, 1H), 4.52 (t, J = 7.5 Hz, 1H), 3.25 (dt, J = 12.6, 7.5 Hz, 1H), 2.19 (s, 2H), 2.11 (s, 1H).

[0303] Fourteenth step: Preparation of (8R,15S)-13-chloro-2,2-difluoro-7,8-dihydro-8,15- methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)- one

[0304] Tris(dibenzylideneacetone)dipalladium (51.7 mg, 56.48 μmol) was added to a solution of (1S,3R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-8-chloro-2,3- dihydro-1H-cyclopenta[3,4]pyrrolo[1,5-a]pyridin-3-amine (250 mg, 564 μmol), sodium ascorbate (336 mg, 1.69 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33 mg, 56.48 μmol) in N,N-dimethylformamide (15 mL), the reaction was vacuumed and filled with carbon monoxide gas for 2 times, heated to 110 °C for 16 hours under the protection of carbon monoxide balloon. The reaction was cooled to room temperature, poured into water, extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by silica gel column chromatography to give the title compound (75 mg, 34.1%). MS m / z (ESI): 390.2 [M+H] + .

[0305] Fifteenth Step: Preparation of (8R,15S)-13-chloro-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one

[0306] Sodium hydride (12 mg, 288.65 μmol, 60% purity) was added to a solution of (8R,15S)-13-chloro-2,2-difluoro-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2- c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one (75 mg, 192.44 μmol) in tetrahydrofuran (10 mL), the reaction was stirred for 5 minutes, deuterated iodomethane (56 mg, 384.87 μmol) was added, the reaction was stirred for 1 hour. The reaction was poured into water, extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, then purified by preparative silica gel plate to give the title compound (48 mg, 61.3%). MS m / z (ESI): 407.2 [M+H] + .

[0307] Intermediate 8

[0308] (SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (19.43 mg, 22.58 μmol) was added to a solution of (8R,15S)-13-chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (88 mg, 225.79 μmol), pinacol diborane (86.01 mg, 338.69 μmol) and potassium acetate (66.48 mg, 677.38 μmol) in 1,4-dioxane (6 mL). The reaction was evacuated, backfilled with nitrogen and repeated three times before heating to 100 °C for 3 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and purified by silica gel chromatography to give (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7,8-dihydro-8,15-methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2- c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one (84 mg, 77.3%). MS m / z (ESI): 499.1 [M+H] + .

[0309] Intermediate 9

[0310] First Step: Preparation of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole-4- carboxaldehyde

[0311] Under dry ice-acetone bath, 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (10 g, 42.2 mmol) was dissolved in dry THF (100 mL), LDA (31.6 mL, 63.3 mmol) was added dropwise and the reaction was stirred for 1 hour, dry DMF (4.9 mL, 63.3 mmol) was added dropwise and the reaction was stirred for another 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, the reaction was extracted with EtOAc (150 mL x 3), washed with saturated aqueous sodium chloride solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (9.2 g, 82.3%). MS m / z (ESI): 265.1 [M+H] + .

[0312] Step 2: Preparation of (S,E)-N-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4- yl)methylene)-2-methylpropane-2-sulfmamide

[0313] Dissolve 5-bromo-2,2-difluorobenzo[d][l,3]dioxole-4-carboxaldehyde (9.2 g, 34.7 mmol) and (S)-tert-butylsulfmamide (5.05 g, 41.7 mmol) in THF (100 mL), dropwise add tetraethyl orthotitanate (11.88 g, 52.1 mmol) and stir the reaction for 16 hours. Upon completion of the reaction, extract the reaction with EtOAc (150 mL x 3), wash with saturated aqueous sodium chloride solution (200 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain the title compound (12 g, 93.9%). MS m / z (ESI): 368.1 [M+H] + .

[0314] Step 3: Preparation of (S)-N-((R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)but-3- en-l-yl)-2-methylpropane-2-sulfmamide

[0315] [Corr. to Rule 91 14.10.2025] Dissolve (S,E)-N-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4- yl)methylene)-2-methylpropane-2-sulfmamide (10 g, 27.2 mmol) in dry DCM (200 mL), dropwise add allylmagnesium bromide (40.7 mL, 40.7 mmol, 1 mol / L in Et2O) and stir the reaction for 1 hour. Quench the reaction with saturated aqueous ammonium chloride solution, extract the reaction with DCM (150 mL x 3), wash with saturated aqueous sodium chloride solution (200 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to obtain the title compound (8.3 g, 74.5%). MS m / z (ESI): 410.1 [M+H] + .

[0316] Step 4: Preparation of (R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)but-3-en-l- amine

[0317] (S)-N-((R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)but-3-en-l- yl)-2-methylpropane-2-sulfmamide (8.3 g, 20.2 mmol) was dissolved in a solution of hydrochloric acid in dioxane (50 mL, 4.0 N) and stirred for 1 h. The reaction was concentrated and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL x 3) and then saturated aqueous sodium chloride (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried in vacuum to give the title compound (5.5 g, 88.8%). MS m / z (ESI): 306.1 [M+H] + .

[0318] Fifth Step: Preparation of (R)-N-(l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4- yl)but-3-en-l-yl)-5-chloro-2-nitroaniline

[0319] (R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)but-3-en-l-amine (5.5 g, 18 mmol), 4-chloro-2-fluoro-l-nitrobenzene (3.78 g, 21.6 mmol), and potassium carbonate (9.93 g, 71.9 mmol) were dissolved in DMF (100 mL), heated to 80 °C and stirred for 16 h. The reaction was allowed to cool to room temperature and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (5 g, 60.3%). MS m / z (ESI): 461.1 [M+H] + .

[0320] Sixth Step: Preparation of (R)-3-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-3- ((5-chloro-2-nitrophenyl)amino)propanal

[0321] (R)-N-(l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)but-3-en-l-yl)-5- chloro-2-nitroaniline (5 g, 10.8 mmol) was dissolved in a mixture of THF (150 mL) and water (150 mL), after the addition of potassium osmium (II) dihydroxide (169 mg, 0.54 mmol), the reaction was stirred for 1 hour, after the addition of sodium periodate (7 g, 32.5 mmol), the reaction was continued to stir for 16 hours. The reaction was extracted with EtOAc (150 mL x 3), the organic phase was collected and washed with saturated sodium chloride aqueous solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the title compound (4.5 g, 89.6%). MS m / z (ESI): 463.1 [M+H] + .

[0322] Step 7: Preparation of (4R)-4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-4-((5- chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxy)butanenitrile

[0323] (R)-3-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-3-((5-chloro-2- nitrophenyl)amino)propanal (4.5 g, 9.7 mmol), trimethylsilyl cyanide (1.93 g, 19.4 mmol), zinc iodide (310 mg, 0.97 mmol), and triethylamine (98 mg, 0.97 mmol) were dissolved in DCM (100 mL) and stirred for 2 hours. After the reaction was completed, the reaction was extracted with EtOAc (150 mL x 3), the organic phase was collected and washed with saturated sodium chloride aqueous solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain the title compound (5 g, 91.5%). MS m / z (ESI): 562.1 [M+H] + .

[0324] Step 8: Preparation of (lR,3S)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-7- chloro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-ol

[0325] (4R)-4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-4-((5-chloro-2- nitrophenyl)amino)-2-((trimethylsilyl)oxy)butanenitrile (5g, 8.9 mmol) and stannous chloride (8.4 g, 44.4 mmol) were dissolved in ethanol (100 mL), the reaction was stirred at 80 °C for 16 hours. After the reaction was cooled to room temperature, the pH of the reaction was adjusted to 8 using potassium hydroxide aqueous solution (1 mol / L), the reaction was extracted with EtOAc (150 mL x 3), the organic phase was collected and washed with saturated sodium chloride aqueous solution (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography, and the title compound (650 mg, 16.5%) was obtained by separation on a chiral column. MS m / z (ESI): 443.1 [M+H] + .

[0326] Step 9: Preparation of (1R,3R)-1-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-7- chloro-2,3-dihydro-lH-benzo[d]pyrrolo[l,2-a]imidazol-3-amine

[0327] (1R,3S)-1-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-7-chloro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3-ol (650 mg, 1.47 mmol), diphenyl phosphorazide (463 mg, 1.9 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (312 mg, 2.05 mmol) were dissolved in toluene (10 mL), and the reaction was stirred at 60 °C for 16 hours. After the reaction was cooled to room temperature, the reaction was extracted with EtOAc (15 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of THF (10 mL) and water (10 mL), and the reaction was stirred at 60 °C for 1 hour. After the reaction was cooled to room temperature, the reaction was extracted with EtOAc (15 mL x 3), the organic phase was collected and washed with saturated sodium chloride aqueous solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the title compound (477 mg, 74.2%). MS m / z (ESI): 442.1 [M+H] + .

[0328] Tenth step: Preparation of (8R, 15R)-12-chloro-2,2-difluoro-7,8-dihydro-8,15- methylene[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-6(15H)- one

[0329] (1R,3R)-1-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-7-chloro-2,3-dihydro-lH- benzo[d]pyrrolo[l,2-a]imidazol-3-amine (477 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium (99 mg, 0.11 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (125 mg, 0.22 mmol) and potassium carbonate (447 mg, 3.24 mmol) were dissolved in anhydrous DMF (10 mL), heated to 130 °C and stirred for 16 hours. The reaction was allowed to cool to room temperature, extracted with EtOAc (30 mL x 3), the organic phases were combined and washed with saturated aqueous sodium chloride solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (200 mg, 47.6%). MS m / z (ESI): 390.1 [M+H] + .

[0330] Intermediate 10

[0331] [Rule 91 correction 14.10.2025] (8R,15R)-12-chloro-2,2-difluoro-7,8-dihydro-8,15- methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-6(15H)-one (100 mg, 0.26 mmol) was dissolved in THF (10 mL), after the addition of sodium hydride (21 mg, 0.52 mmol, 60% purity) the reaction was stirred for 1 hour, deuterated methyl iodide (55 mg, 0.38 mmol) was added and the reaction was stirred for another 1 hour. The reaction was extracted with EtOAc (15 mL x 3), the organic phase was combined and washed with saturated aqueous sodium chloride solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (8R,15R)-12-chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)- one (90 mg, 86%). MS m / z (ESI): 407.1 [M+H] + .

[0332] Intermediate 11

[0333] Dissolve (8R,15R)-12-chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-6(15H)-one (60 mg, 0.15 mmol), bis(pinacolato)diboron (56 mg, 0.22 mmol), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl] phosphine]methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (13 mg, 0.015 mmol) and potassium acetate (44 mg, 0.45 mmol) in 1,4-dioxane (10 mL), and microwave at 125 °C for 2 hours. Cool the reaction to room temperature, extract with EtOAc (30 mL x 3), combine the organic layers and wash with saturated aqueous sodium chloride (20 mL x 3), collect the organic layer, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography to give (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7,8-dihydro-8,15-methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2- f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)-one (72 mg, 98%). MS m / z (ESI): 499.1 [M+H] + .

[0334] Intermediate 12

[0335] First Step: Preparation of (S)-N-(3-cyano-3-methylcyclobutylidene)-2- methylpropane-2-sulfonamide

[0336] Dissolve 1-methyl-3-oxocyclobutane-1-carbonitrile (10.5 g, 96.38 mmol) and (S)-tert-butylsulfinamide (14 g, 115.64 mmol) in THF (400 mL), slowly add tetraethyl orthotitanate (32.98 g, 144.56 mmol), then warm to room temperature and stir for 16 hours. Quench the reaction with water, filter, extract the filtrate with ethyl acetate (150 mL x 3), combine the organic layers and wash with saturated aqueous sodium chloride (200 mL x 3), collect the organic layer, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography to give the title compound (18.50 g, 90.6%). MS m / z (ESI): 213.1 [M+H] + .

[0337] Step 2: Preparation of (S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3-cyano-3- methylcyclobutyl)-2-methylpropane-2-sulfmamide

[0338] (S)-N-(3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfmamide (2.93 g, 13.80 mmol) in DCM (20 mL) was added dropwise and stirring was continued for 1 h. The reaction was extracted with DCM (50 mL x 3), the organic phases were combined and washed with saturated aqueous sodium chloride solution (30 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The title compound (700 mg, 13.7%) was obtained by silica gel column chromatography and chiral column separation. MS m / z (ESI): 371.0 [M+H] + .

[0339] [Corr. to Rule 91 14.10.2025] Step 3: Preparation of (2-((1s,3R)-1-(((S)-tert- butylsulfinyl< sulfinyl>)amino)-3-cyano-3-methylcyclobutyl)pyrimidin-5-yl)boronic acid

[0340] PdCl2(dppf)CH2Cl2(197.1 mg, 269 μmol) was added to a solution of (S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2- sulfmamide (1 g, 2.69 mmol), potassium acetate (793 mg, 8.07 mmol) and pinacol diboron (1.02 g, 4.04 mmol) in 1,4-dioxane (10 mL). The reaction was evacuated, purged with nitrogen and repeated three times. The reaction was heated to 90 °C for 16 h. The reaction was cooled to room temperature and filtered. The filtrate was prepared by HPLC to obtain (2-((1s,3R)-1-(((S)-tert-butylsulfinyl< sulfinyl>)amino)-3-cyano-3- methylcyclobutyl)pyrimidin-5-yl)boronic acid (450 mg, 49%). MS m / z (ESI): 336.9 [M+H] + .

[0341] Intermediate 13

[0342] Dimethylphosphine oxide (15 g, 194 mmol), 5-bromo-2-iodopyridine (50 g, 176 mmol), Xantphos (10.2 g, 17.6 mmol) and triethylamine (49.1 mL, 352 mmol) were dispersed in 1,4-dioxane (500 mL), Pd2(dba)3(8.0 g, 8.81 mmol) was added with stirring, vacuumed, filled with nitrogen, the operation was repeated for 3 times, the reaction was stirred at 60 °C for 12 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, then was slurried with ethyl acetate, the filtrate was concentrated, then was separated by silica gel column chromatography to obtain (5-bromopyridin-2-yl)dimethylphosphine oxide (25 g, 61%). MS m / z (ESI): 234.0 [M+H] + .

[0343] Intermediate 14

[0344] Dimethylphosphine oxide (15 g, 194 mmol), 5-bromo-2-iodopyridine (50 g, 176 mmol), Xantphos (10.2 g, 17.6 mmol) and triethylamine (49.1 mL, 352 mmol) were dispersed in 1,4-dioxane (500 mL), Pd2(dba)3(8.0 g, 8.81 mmol) was added with stirring, vacuumed, filled with nitrogen, the operation was repeated for 3 times, the reaction was stirred at 60 °C for 12 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, then was slurried with ethyl acetate, the filtrate was concentrated, then was separated by silica gel column chromatography to obtain (5-bromopyridin-2-yl)dimethylphosphine oxide (25 g, 61%). MS m / z (ESI): 234.0 [M+H] + .

[0345] [According to Rule 91 Correction 14.10.2025] Intermediate 15

[0346] Tris(dibenzylideneacetone)dipalladium (912 mg, 996 μmol) was added to a solution of 2,5-dibromo-6-methylpyridine (5 g, 19.9 mmol), dimethylphosphine oxide (1.56 g, 19.9 mmol), Xantphos (576 mg, 996 μmol) and triethylamine (6.05 g, 59.8 mmol) in 1,4-dioxane (80 mL). The reaction was evacuated, backfilled with nitrogen, and the operation was repeated three times. The reaction was heated to 80 °C for 4 h. After the reaction was cooled to room temperature, it was poured into water (250 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel to give (5-bromo-6-methylpyridin-2-yl)dimethylphosphine oxide (4.5 g, 91.0 %). MS m / z (ESI): 248.0 [M+H] + .

[0347] Intermediate 16

[0348] Tris(dibenzylideneacetone)dipalladium (180 mg, 149 μmol) was added to a solution of 2,5-dichloropyrazine (294 mg, 1.97 mmol), dimethylphosphine oxide (169 mg, 2.17 mmol), Xantphos (172 mg, 298 μmol) and triethylamine (597 mg, 5.91 mmol) in 1,4-dioxane (15 mL). The reaction was evacuated, backfilled with nitrogen, and the operation was repeated three times. The reaction was heated to 60 °C for 16 h. After the reaction was cooled to room temperature, it was poured into water (150 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel to give (5-chloropyrazin-2-yl)dimethylphosphine oxide (120 mg, 32.1 %). MS m / z (ESI): 191.0 [M+H] + .

[0349] Intermediate 17

[0350] Tris(dibenzylideneacetone)dipalladium (308.39 mg, 336.78 μmol) and Xantphos (389.72 mg, 673.56 μmol) were added to a solution of 1-bromo-4-iodo-2-methylbenzene (2.0 g, 6.74 mmol), dimethylphosphine oxide (630.85 mg, 8.08 mmol) and potassium phosphate (1.72 g, 8.08 mmol) in 1,4-dioxane (40 mL), the reaction was vacuumed, filled with nitrogen, and the operation was repeated for 3 times, heated to 80 °C for 16 hours. After the reaction was cooled to room temperature, water (60 mL) was added, extracted with ethyl acetate (60 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain (4-bromo-3-methylphenyl)dimethylphosphine oxide (800 mg, 48.1%). MS m / z (ESI): 247.0 [M+H] + .

[0351] Intermediate 18

[0352] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (296.53 mg, 323.80 μmol) was added to a solution of (4-bromo-3-methylphenyl)dimethylphosphine oxide (800 mg, 3.24 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.23 g, 4.86 mmol) and potassium acetate (953.32 mg, 9.71 mmol) in 1,4-dioxane (15 mL), the reaction was vacuumed, filled with nitrogen, and the operation was repeated for 3 times, heated to 100 °C for 2 hours. After the reaction was cooled to room temperature, water (30 mL) was added, extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain dimethyl(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphine oxide (400 mg, 42.0%). MS m / z (ESI): 295.2 [M+H] + .

[0353] Intermediate 19

[0354] [According to Rule 91 correction 14.10.2025] 1-bromo-3-fluoro-4-iodo-2-methylbenzene (500 mg, 1.6 mmol) and dimethyl phosphine oxide (130 mg, 1.7 mmol) were dissolved in dioxane (10 mL), tris(dibenzylideneacetone)dipalladium(0) (36 mg, 39 μmol), Xantphos (46 mg, 79 μmol) and potassium phosphate (404 mg, 2 mmol) were added, vacuumed, filled with nitrogen, and the operation was repeated 3 times. The reaction was heated to 80 °C and stirred for 2 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure, and then separated by silica gel column chromatography to obtain (4-bromo-2-fluoro-3-methylphenyl)dimethyl phosphine oxide (400 mg, 95.1%). MS m / z (ESI): 265.1 [M+H] + .

[0355] Intermediate 20

[0356] Tris(dibenzylideneacetone)dipalladium (136 mg, 149 μmol) was added to a solution of 1-bromo-2-chloro-3-fluoro-4-iodo-benzene (500 mg, 1.49 mmol), dimethyl phosphine oxide (122 mg, 1.57 mmol), Xantphos (172 mg, 298 μmol) and triethylamine (301 mg, 2.98 mmol) in 1,4-dioxane (15 mL). The reaction was vacuumed, filled with nitrogen, and the operation was repeated 3 times. It was heated to 60 °C and reacted for 16 hours. After the reaction was cooled to room temperature, it was poured into water (150 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain (4-bromo-3-chloro-2-fluorophenyl)dimethyl phosphine oxide (380 mg, 89.3%). MS m / z (ESI): 285.0 [M+H] + .

[0357] Intermediate 21

[0358] Tris(dibenzylideneacetone)dipalladium (179.6 mg, 179.63 μmol) and Xantphos (227.0 mg, 392.34 μmol) were added to a solution of 3,6-dibromo-2-fluoropyridine (1.0 g, 3.92 mmol), dimethylphosphine oxide (367.46 mg, 4.71 mmol) and potassium phosphate (999.38 mg, 4.71 mmol) in 1,4-dioxane (20 mL), the reaction was vacuumed, filled with nitrogen, and the operation was repeated 3 times. The reaction was heated to 80 °C for 16 hours. After the reaction was cooled to room temperature, water (50 mL) was added, and ethyl acetate (50 mL x 3) was extracted. The organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain (5-bromo-6-fluoropyridin-2-yl)dimethylphosphine oxide (850 mg, 85.9%). MS m / z (ESI): 252.0 [M+H] + .

[0359] [According to Rule 91 correction 14.10.2025] Intermediate 22

[0360] Dimethylphosphine oxide (1.5 g, 19.4 mmol), 4-bromo-2-fluoro-1-iodobenzene (5.28 g, 17.6 mmol) and Xantphos (1.02 g, 1.76 mmol), triethylamine (4.91 mL, 35.2 mmol) were dissolved in 1,4-dioxane (50 mL), and the reaction was protected with nitrogen. Pd2(dba)3 (0.80 g, 0.88 mmol) was added with stirring, vacuumed, filled with nitrogen, and the operation was repeated 3 times. The temperature was raised to 100 °C and stirred for 12 hours. After the reaction was cooled to room temperature, it was concentrated under reduced pressure, the residue was slurried with ethyl acetate, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography to obtain (4-bromo-2-fluorophenyl)dimethylphosphine oxide (2.86 g, 65%). MS m / z (ESI): 251.1 [M+H] + .

[0361] Intermediate 23

[0362] [Rule 91 Correction 14.10.2025] 1-Bromo-2-fluoro-4-iodobenzene (2 g, 6.65 mmol), dimethylphosphine oxide (544.7 mg, 7.0 mmol), cesium carbonate (6.5 g, 19.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (304.3 mg, 332.3 μmol) and Xantphos (384.6 mg, 664.7 μmol) were added sequentially into dioxane (8 mL), then vacuumed, filled with nitrogen, and repeated for 3 times. The reaction was stirred at 100 °C for 4 h. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and then purified by silica gel column chromatography to give (4-bromo-3-fluorophenyl)dimethylphosphine oxide (1.1 g, 65.9%). MS m / z (ESI): 251.1 [M+H] + .

[0363] [Rule 91 Correction 14.10.2025][Deleted]

[0364] Reference Example 1

[0365] First Step: Preparation of 2-bromo-6-(difluoromethoxy)benzene(meth)aldehyde

[0366] Bromofluoromethylphosphonic acid diethyl ester (531 g, 1.99 mol) was dissolved in THF (4.8 L), and potassium hydroxide (1.12 kg, 19.90 mol) was added at 0 °C with stirring, followed by the addition of 2-bromo-6-hydroxybenzene(meth)aldehyde (400 g, 1.99 mol). The reaction mixture was stirred at 0 °C for 1 h. The organic phase of the reaction mixture 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] + .

[0367] Second Step: Preparation of (S,E)-N-(2-bromo-6-(difluoromethoxy)benzylidene)-2- methylpropane-2-sulfmamide

[0368] 2-Bromo-6-(difluoromethoxy)benzene(meth)aldehyde (499 g, 1.99 mol) was dissolved in THF (4 L), and S-tert-butylsulfmamide (289 g, 2.39 mol) was added with stirring, followed by the addition of tetraethyl titanate (681 g, 2.98 mol). The reaction mixture was stirred for 12 h, quenched with water, filtered, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to give the title compound (540 g, 77%). MS m / z (ESI): 354.2 [M+H] +.

[0369] Step 3: Preparation of N-((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)- 2-methylpropane-2-sulfonamide

[0370] Dissolve (S,E)-N-(2-bromo-6-(difluoromethoxy)benzylidene)-2-methylpropane-2- sulfonamide (540 g, 1.52 mol) in DCM (5 L), add allylmagnesium bromide (2.29 L, 2.29 mol, 1 M in ether) at 0 °C with stirring, stir the reaction mixture at 0 °C for 1 h, quench the reaction mixture with saturated ammonium chloride, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate to give the title compound (560 g, 93%). MS m / z (ESI): 396.0 [M+H] + .

[0371] Step 4: Preparation of (R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-amine

[0372] Dissolve N-((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-2- methylpropane-2-sulfonamide (560 g, 1.41 mol) in DCM (3 L), add hydrochloric acid in dioxane (1.5 L, 4 M) with stirring, continue to stir the reaction mixture for 2 h, concentrate the reaction mixture to give the title compound (464 g, 100%, crude). MS m / z (ESI): 292.0 [M+H] + .

[0373] Step 5: Preparation of (R)-N-(1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-5- chloro-2-nitroaniline

[0374] Add potassium carbonate (585 g, 4.23 mol) to DMF (3.6 L), add (R)-1-(2-bromo-6- (difluoromethoxy)phenyl)but-3-en-1-amine (464 g, 1.41 mol, crude) and 4-chloro-2- fluoro-1-nitro-benzene (297 g, 1.69 mol) at room temperature with stirring, stir the reaction mixture at 80 °C for 12 h, dilute the reaction mixture with EA after returning to room temperature, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to give the title compound (560 g, 89%). MS m / z (ESI): 447.0 [M+H] + .

[0375] Step 6: Preparation of (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propionaldehyde

[0376] (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, and 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] + .

[0377] Step 7: Preparation of (4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxo)butyronitrile

[0378] (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propionaldehyde (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] + .

[0379] Step 8: 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

[0380] (4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-chloro-2- nitrophenyl)amino)-2-((trimethylsilyl)oxy)butyronitrile (244 g, 445 mmol) was dissolved in ethanol (3 L), stannous chloride (422 g, 2.22 mol) was added under stirring at room temperature, the reaction was stirred at 80 °C for 12 h, the reaction was concentrated, the residue was dissolved in EA, saturated sodium carbonate was added to make the system pH 10, filtered, the filtrate was extracted with saturated sodium chloride, the organic phase was concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to give the title compound (12 g, 6%). MS m / z (ESI): 429.0 [M+H] + .

[0381] Ninth step: 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

[0382] (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), diphenylphosphoryl azide (7.29 g, 26.5 mmol) was added under stirring at room temperature, 1,8-diazobicyclo[5.4.0]undec-7-ene (4.3 mL, 28.7 mmol) was added dropwise, the reaction was stirred at 50 °C under nitrogen for 12 h, the reaction was diluted with EA, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by silica gel column chromatography (PE / EA = 2 / 1) to give the azide compound as a yellow oil. The above oil was dissolved in water (20 mL) and THF (100 mL), triphenylphosphine (8.70 g, 33.2 mmol) was added at room temperature, the reaction was stirred at 60 °C for 4 h. Diluted with EA, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, separated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give the title compound (8.1 g, 85%). MS m / z (ESI): 428.0 [M+H] + .

[0383] Tenth step: Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7- dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0384] [Corr. to Rule 91 14.10.2025] (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-bisdiphenylphosphino-9,9- dimethylxanthene (1.09 g, 1.89 mmol) and potassium carbonate (7.83 g, 56.7 mmol) were dispersed in DMF (220 mL), the reaction was protected by nitrogen, tris(dibenzylideneacetone)dipalladium (3.46 g, 3.78 mmol) was added under stirring at room temperature, the reaction was replaced by dry carbon monoxide for three times, the temperature was raised to 130 °C, the reaction was stirred for 12 hours, the reaction was diluted by EA, washed by saturated sodium chloride. The organic phase was dried by anhydrous sodium sulfate, filtered, concentrated, the residue was separated and 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] + .

[0385] Eleventh step: preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6-((1- fluorocyclopropyl)methyl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4] diazocin-5(14H)-one

[0386] (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (100 mg, 0.267 mmol) was dissolved in THF (5 mL), sodium hydride (16 mg, 0.40 mmol, 60% purity) was added under stirring at room temperature, then (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate (130 mg, 0.534 mmol) was added to the reaction, which was stirred at room temperature for 2 hours. The reaction was diluted by EA, the organic phase was washed by saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried by anhydrous sodium sulfate, filtered, concentrated, separated and purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to give the title compound (100 mg, 84%). MS m / z (ESI): 448.1 [M+H] + .

[0387] Twelfth Step: Preparation of (7R,14R)-1-(difluoromethoxy)-6-((1- fluorocyclopropyl)methyl)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7- dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one

[0388] (7R,14R)-11-chloro-1-(difluoromethoxy)-6-((1-fluorocyclopropyl)methyl)-6,7- dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (100 mg, 0.224 mmol), bis(pinacolato)diboron (114 mg, 0.448 mmol) and potassium acetate (44 mg, 0.448 mmol) were dispersed in dioxane (5 mL), the reaction was protected with nitrogen, (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-propanyl)[1,1'-biphenyl]-2-yl] phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (17 mg, 0.02 mmol) was added under stirring at room temperature, the reaction was purged with dry nitrogen for three times, the reaction was stirred at 125 °C for 2 hours under microwave, the reaction was filtered, concentrated, the residue was separated and purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to give the title compound (110 mg, 92%). MS m / z (ESI): 540.2 [M+H] + .

[0389] Thirteenth Step: Preparation of (1R,3r)-3-(5-((7R,14R)-1-(difluoromethoxy)-6-((1- fluorocyclopropyl)methyl)-5-oxo-5,6,7,14-tetrahydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-11-yl)pyrimidin-2-yl)-1-(fluoromethyl)-3- hydroxycyclobutan-1-carbonitrile

[0390] (7R,14R)-1-(difluoromethoxy)-6-((1-fluorocyclopropyl)methyl)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanoben[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (110 mg, 0.204 mmol), (1R,3r)-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)-3-hydroxycyclobutane-1-carbonitrile (88 mg, 0.306 mmol) and potassium carbonate (56 mg, 0.408 mmol) were dispersed in dioxane (5 mL) and water (1 mL), the reaction was protected with nitrogen, (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-propan-2-yl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (17 mg, 0.02 mmol) was added with stirring at room temperature, the reaction was replaced with dry nitrogen three times, and the reaction was stirred at 110 °C for 2 hours under microwave. The reaction was filtered, concentrated, and the residue was separated and purified by reverse phase column chromatography to give the title compound (60 mg, 48%). MS m / z (ESI): 619.2 [M+H] + .

[0391] The following examples were synthesized according to the above routes

[0392] The NMR data for the examples are as follows table:

[0393] Example 8 can also be prepared according to the following route

[0394] [Corrected according to Rule 91 on 14.10.2025](8R,15R)-12-(4-(dimethylphosphoryl)-3-fluorophenyl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)-one

[0395] (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)-one (185 mg, 0.37 mmol), (4-bromo-2-fluorophenyl)dimethylphosphine oxide (110 mg, 0.44 mmol), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (32 mg, 37.2 μmol) and potassium carbonate (153 mg, 1.11 mmol) were added into a mixture of 1,4-dioxane (10 mL) and water (2 mL), the reaction was stirred at 110 °C for 1 h. The reaction was cooled to room temperature, extracted with EtOAc (30 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified by silica gel column chromatography to give the title compound (40.2 mg, 20.0 %). MS m / z (ESI): 543.1 [M+H] + .

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 8.9 Hz, 1H), 7.76 (dt, J = 11.8, 7.5 Hz, 1H), 7.71 - 7.46 (m, 5H), 7.38 (d, J = 8.9 Hz, 1H), 6.08 (d, J = 6.6 Hz, 1H), 5.26 (d, J = 7.2 Hz, 1H), 3.43 (dt, J = 13.8, 7.0 Hz, 1H), 2.88 (d, J = 13.8 Hz, 1H), 1.72 - 1.64 (m, 6H).

[0397] Example 10 can also be prepared according to the following route

[0398] (8R,15R)-12-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-2,2-difluoro-7-(methyl-d3)- 7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-6(15H)-one

[0399] [Corr. According to Rule 91 14.10.2025] First step: Preparation of (4-bromo-2,3- difluorophenyl)dimethylphosphine oxide

[0400] [Corr. According to Rule 91 14.10.2025] Tris(dibenzylideneacetone)dipalladium (143.58 mg, 156.80 μmol) was added to a solution of l-bromo-2,3-difluoro-4-iodo- benzene (500 mg, 1.57 mmol), dimethylphosphine oxide (135 mg, 1.73 mmoL), triethylamine (238.0 mg, 2.35 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (181.45 mg, 313.59 μmol) in 1,4-dioxane (15 mL), the reaction was purged with nitrogen for 3 times, heated to 80 °C for 2 hours. The reaction was poured into water, extracted with ethyl acetate (50 mL x 3), the organic phase was dried, rotary evaporated and column chromatographed (petroleum ether: ethyl acetate = 4: 1) to give the title compound (350 mg, 83.0%). MS m / z (ESI): 269.0 [M+H] + .

[0401] [Rule 91 correction 14.10.2025] Second step: Preparation of (8R,15R)-12-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-6(15H)-one

[0402] [Rule 91 correction 14.10.2025] (SP-4-3)-[Bicyclohexyl[2',4',6'-tris(isopropyl)[l,l'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[l,l'-biphenyl]-2-yl]palladium (12.8 mg, 14.87 μmol) was added to a solution of (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-6(15H)-one (74.1 mg, 148.7 μmol), (4-bromo-2,3-difluorophenyl)dimethylphosphine oxide (40 mg, 148.7 μmol) and potassium carbonate (61.65 mg, 446.1 μmol) in 1,4-dioxane (3 mL) and water (0.3 mL), the reaction was purged with nitrogen 3 times, heated to 110 °C under nitrogen for 2 hours. The reaction was concentrated and directly submitted to prep-HPLC to give the title compound (55 mg, 66.0 %). MS m / z (ESI): 561.0 [M+H] + .

[0403] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 6.14 (d, J = 6.6 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.49 (dt, J = 13.9, 7.1 Hz, 1H), 2.99 - 2.91 (m, 1H), 1.79 (d, J = 13.7 Hz, 6H).

[0404] Example 11

[0405] (8R,15R)-12-(4-(dimethylphosphino)-2-fluorophenyl)-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8, 15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-6(15H)-one

[0406] (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8- dihydro-8, 15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-6(15H)-one (50 mg, 100.3 pmol), (4-bromo-3-fluorophenyl)dimethylphosphine oxide (27.71 mg, 110.4 pmol), sodium carbonate (21.27 mg, 200.7 pmol) and (SP-4-3)-[dicyclohexyl[2',4',6'-tris( isopropyl)[l,l'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[l,l'- biphenyl]-2-yl]palladium (8.63 mg, 10.0 pmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL), the reaction solution was vacuumed, filled with nitrogen, and the operation was repeated 3 times, the temperature was raised to 80 °C, and the reaction was stirred for 12 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then purified by HPLC to obtain the title compound (33.5 mg, 60.9%). MS m / z (ESI): 543.2 [M+H] + .

[0407] Example 13

[0408] [correction according to Rule 91 14.10.2025] (8R,15R)-12-(6-(dimethylphosphino)pyridin-3-yl)-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8, 15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-6(15H)-one

[0409] (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 7,8-dihydro-8,15-methan[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-6(15H)-one (37g, 74.25 mmol), (5-bromopyridin-2-yl)dimethylphosphine oxide (19.12 g, 81.68 mmol), (SP-4-3)-[dicyclohexyl[2',4',6'-tris( isopropyl)[1,1'-biphenyl]-2-yl] phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'- biphenyl]-2-yl]palladium (6.39 g, 7.43 mmol) and potassium carbonate (30.74 g, 222.76 mmol) were dissolved in a mixed solution of 1,4-dioxane (400 mL) and water (80 mL), and stirred at 110 °C for 1 hour. The reaction solution was returned to room temperature, extracted with EtOAc (300 mL x 3), and the organic phase was collected, washed with saturated aqueous sodium chloride solution (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (31.0 g, 79.5%). MS m / z (ESI): 526.1 [M+H] + . MS m / z (ESI): 526.1 [M+H] + .

[0410] 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.21 (dt, J = 8.1, 2.7 Hz, 1H), 8.04 (dd, J = 8.0, 5.1 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 6.16 (d, J = 6.6 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.52 (dt, J = 13.9, 7.0 Hz, 1H), 2.96 (d, J = 13.8 Hz, 1H), 1.73 (dd, J = 13.6, 2.1 Hz, 6H).

[0411] Example 85

[0412] [Rule 91 Correction 14.10.2025] (8R,15S)-13-(2-(1- aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one can also be prepared following two synthetic routes as follows

[0413] [Rule 91 Correction 14.10.2025] (SP-4-3)-[Bicyclohexyl[2',4',6'-tris(isopropyl)[1,1'- biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2- yl]palladium (3.2 mg, 3.69 μmol) was added to a solution of (8R,15S)-13-chloro-2,2- difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2- c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one (15 mg, 36.87 μmol), (R)-(2-(1- ((tert-butylsulfinyl)sulfanyl)amino)cyclobutyl)pyrimidin-5-yl)boronic acid (13.1 mg, 44.25 μmol) and cesium carbonate (25 mg, 76.37 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL), the reaction was evacuated, filled with nitrogen and the operation was repeated 3 times, and heated to 110 °C under microwave for 2 hours. After the reaction was cooled to room temperature, 4N hydrochloric acid in dioxane was added to the reaction, stirred at room temperature for 30 minutes, the reaction was concentrated under reduced pressure, and the title compound (10.5 mg, 54.9%) was prepared by prep-HPLC. MS m / z (ESI): 520 [M+H] + .

[0414] Example 86 can also be prepared following the route as follows

[0415] [Rule 91 Correction 14.10.2025] (1R,3s)-3-amino-3-(5-((8R,15S)-2,2-difluoro-7-(methyl- d3)-6-oxo-6,7,8,15-tetrahydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocin-13-yl)pyrimidin-2-yl)-1-methylcyclobutane-1- carbonitrile

[0416] [According to Rule 91 correction 14.10.2025] (SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (3.3 mg, 3.82 μmol) was added to a solution of (8R,15S)-13-chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one (15 mg, 38.19 μmol), (2-((1s,3R)-1-(((S)-tert-butylsulfinyl< sulfinyl>)amino)-3-cyano-3-methyl-cyclobutyl)pyrimidin-5-yl]boronic acid (15.4 mg, 45.82 μmol) and cesium carbonate (25 mg, 76.37 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL), the reaction was purged with nitrogen 3 times, and heated to 110 °C in a microwave for 2 hours. 4N Hydrochloric acid dioxane (0.5 mL) was added to the reaction, the reaction was stirred for an additional 30 minutes, and the reaction was concentrated to dryness and directly submitted to prep-HPLC to produce the title compound (13.4 mg, 66.2%). MS m / z (ESI): 545 [M+H] + .

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.85 (dd, J = 7.4, 0.9 Hz, 1H), 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.83 - 7.57 (m, 2H), 7.42 - 7.28 (m, 3H), 5.08 (d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 3.30 - 3.26 (m, 1H), 2.86 - 2.77 (m, 2H), 2.64 (d, J = 12.2 Hz, 2H), 2.53 (s, 1H), 1.47 (s, 3H).

[0418] Example 113 can also be prepared according to the following route

[0419] (8R,15S)-13-(4-(dimethylphosphoryl)-3-fluorophenyl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one

[0420] (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1 -propyl)[1,1 '-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1 '-biphenyl]-2-yl]palladium (5.18 mg, 6.02 μιηοΐ) was added to a solution of (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8- dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1 ',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (30 mg, 60.2 μιηοΐ), (4-bromo-2-fluorophenyl)dimethylphosphine oxide (22.6 mg, 90.3 μιηοΐ) and cesium carbonate (39 mg, 120 μιηοΐ) in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was evacuated, backfilled with nitrogen and repeated 3 times, then heated to 110 °C for 1 h. The reaction was concentrated under reduced pressure and purified by prep-HPLC to give (8R,15S)-13-(4-(dimethylphosphino)-3-fluorophenyl)-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1 ',2':1,5]pyrazolo[4,3-f]azocine- 6(15H)-one (15.6 mg, 31.9 %). MS m / z (ESI): 543.1 [M+H] + .

[0421] Example 114 can also be prepared according to the following route

[0422] [Amended according to Rule 91 (New Rule 14.10), Corrected 14.10.2025] (8R,15S)-13-(6-(dimethylphosphino)pyridin-3-yl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1 ',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one

[0423] [According to Rule 91 correction 14.10.2025] Methyl sulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(ll) (3.2 mg, 3.69 μmol) was added to a solution of (8R,15S)-13-chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one (15 mg, 36.87 μmol), (6-(dimethylphosphino)pyridin-3-yl)boronic acid (8.8 mg, 44.25 μmol) and cesium carbonate (25 mg, 76.37 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL), the reaction was evacuated, flushed with nitrogen and repeated 3 times, and heated to 110 °C for 2 hours under microwave. The reaction was cooled to room temperature and purified by prep-HPLC to give the title compound (8.2 mg, 42.2%). MS m / z (ESI): 526.2 [M+H] + .

[0424] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 2.2 Hz, 1H), 8.87 - 8.79 (m, 1H), 8.31 (dt, J = 8.0, 2.7 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 8.09 - 8.01 (m, 1H), 7.75 (dd, J = 2.1, 1.0 Hz, 1H), 7.34 - 7.22 (m, 2H), 5.16 (d, J = 7.0 Hz, 1H), 4.79 (d, J = 6.1 Hz, 1H), 3.29 (d, J = 6.7 Hz, 1H), 2.62 (d, J = 13.3 Hz, 1H), 1.70 (d, J = 13.5 Hz, 6H).

[0425] Example 155

[0426] (15S)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-(methyl-d3)-7H-8,15- methano[1,3]dioxolo[4',5':5,6]benzo[1,2-f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocine- 6(15H)-one can also be prepared according to the following two synthetic routes

[0427] [Corrected according to Rule 91 14.10.2025] First Step: Preparation of (E)-5-bromo-2,2-difluoro-4-(2-nitrovinyl)benzo[d][1,3]dioxole

[0428] To a solution of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole-4-carboxaldehyde (21.67 g, 81.77 mmol) in AcOH (300 mL) was added ammonium acetate (12.61 g, 163.54 mmol) and nitromethane (39.93 g, 654.17 mmol) at room temperature. The mixture was heated at 102 °C for 6 h, LCMS detected the starting material was consumed completely. The reaction was concentrated in vacuo, purified by column chromatography to give the title compound as a light yellow solid (19 g, 75.4%).

[0429] 1 H NMR (CDCI3) δ 8.28 (d, J = 13.9 Hz, 1H), 7.89 (d, J = 13.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H).

[0430] Second Step: Preparation of N-(1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-2- nitroethyl)hydroxylamine

[0431] To a solution of (E)-5-bromo-2,2-difluoro-4-(2-nitrovinyl)benzo[d][1,3]dioxole (16.6 g, 53.89 mmol) in EtOH (230 mL) was added TEA (10.91 g, 107.78 mmol, 15.03 mL) and hydroxylamine hydrochloride (7.49 g, 107.78 mmol) at 0 °C. The solution was stirred at room temperature for 2 h and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a yellow solid (16.5 g, 89.8%). MS m / z (ESI): 341.1 [M+H] + .

[0432] Third Step: Preparation of 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)ethane-1,2- diamine

[0433] To a solution of N-(l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-2- nitroethyl)hydroxylamine (16.5 g, 48.38 mmol) in MeOH (300 mL) was added Raney nickel (12.49 g) and the reaction was purged with hydrogen three times. The reaction was stirred at room temperature for 2-5 h, and the reaction was complete by LCMS. The reaction was filtered and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a light yellow solid (9.89 g, 69.3%). MS m / z (ESI): 295.1 [M+H] + .

[0434] Fourth Step: Preparation of tert-butyl (2-amino-2-(5-bromo-2,2- difluorobenzo[d][l,3]dioxol-4-yl)ethane)carbamate

[0435] [Rule 91 Correction 14.10.2025] To a solution of l-(5-bromo-2,2- difluorobenzo[d][l,3]dioxol-4-yl)ethane-l,2-diamine (9.89 g, 33.52 mmol) in DCM (200 mL) was added di-tert-butyl dicarbonate (7.31 g, 33.52 mmol) and TEA (3.39 g, 33.52 mmol, 4.67 mL) at 0 °C. The solution was stirred at room temperature for 3 h and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a light yellow oil (7.35 g, 55.5%). MS m / z (ESI): 395.1 [M+H] + .

[0436] [Rule 91 Correction 14.10.2025] Fifth Step: Preparation of tert-butyl 4-(5-bromo-2,2- difluorobenzo[d][l,3]dioxol-4-yl)-2-oxoimidazolidine-l-carboxylate

[0437] To a solution of tert-butyl (2-amino-2-(5-bromo-2,2- difluorobenzo[d][l,3]dioxol-4-yl)ethane)carbamate (10.4 g, 26.32 mmol) in DCM (200 mL) was added l,l'-carbonyldiimidazole (4.27 g, 26.32 mmol) and the reaction was heated to 50 °C and stirred for 5 h. The reaction was concentrated in vacuo and purified by column chromatography to give the title compound as a white solid (8.7 g, 78.5%). MS m / z (ESI): 421.1 [M+H] + .

[0438] [correction according to rule 91 14.10.2025] Step 6: Preparation of tert-butyl 4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-3-(5-chloro-2-nitrophenyl)-2-oxoimidazolidine-l-carboxylate

[0439] A solution of tert-butyl 4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-2-oxoimidazolidine-l-carboxylate (8.5 g, 20.18 mmol), 2-bromo-4-chloro-l-nitrobenzene (9.54 g, 40.36 mmol), cesium carbonate (10.19 g, 31.28 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.34 g, 4.04 mmol) and tris(dibenzylideneacetone)dipalladium (1.85 g, 2.02 mmol) in toluene (250 mL) was heated to 110 °C and stirred for 20 h. The reaction was concentrated in vacuo. The crude product was purified by column chromatography to give the title compound as a yellow solid (8.81 g, 75.7%). MS m / z (ESI): 576.1 [M+H] + .

[0440] Step 7: Preparation of tert-butyl 3-(2-amino-5-chlorophenyl)-4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-2-oxoimidazolidine-l-carboxylate

[0441] To a solution of tert-butyl 4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-3-(5-chloro-2-nitrophenyl)-2-oxoimidazolidine-l-carboxylate (8.8 g, 15.26 mmol) in MeOH (180 mL) was added Raney Ni (6.8 g) and the solution was replaced with hydrogen gas three times. The solution was stirred at room temperature for 2 h, filtered and concentrated in vacuo to give the title compound as a yellow solid (8.2 g, 98.3%). MS m / z (ESI): 546.1 [M+H] + .

[0442] Step 8: Preparation of l-(2-amino-5-chlorophenyl)-5-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)imidazolidine-2-one

[0443] TFA (12 mL) was added to a DCM (150 mL) solution of tert-butyl-3-(2-amino-5-chlorophenyl)-4-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-2-carbonylimidazolidine-1-carboxylic acid ester (8.2 g, 14.99 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, quenched with Na₂CO₃ solution, and the pH was adjusted to alkaline. Extraction was performed with DCM (4 × 30 mL). The combined organic layers were concentrated under vacuum and purified by column chromatography to give the title compound as a grayish-white solid (5.49 g, 82%). MS m / z (ESI): 446.1 [M+H] + .

[0444] Step 9: Preparation of 3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-6-chloro-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazolium

[0445] 1-(2-amino-5-chlorophenyl)-5-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)imidazolidine-2-one (5.49 g, 12.29 mmol) and P4S 10 A solution of 10.93 g (24.58 mmol) of toluene (80 mL) was heated at 110 °C for 18 h and concentrated under vacuum. The residue was dissolved in a solution of DCM and MeOH (V / V = 10:1), the pH was adjusted to alkaline, and the mixture was filtered. The organic layer was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to give the title compound as a grayish-white solid (4.92 g, 93.4%). MS m / z (ESI): 428.1 [M+H] + .

[0446] Step 10: Preparation of 3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-6-chloro-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazo-1-amine

[0447] To a solution of 3-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-6-chloro-2,3- dihydro-lH-benzo[d]imidazo[l,2-a]imidazole (4.64 g, 10.83 mmol) in DMF (70 mL) was added NaH (1.73 g, 43.30 mmol, 60% purity) at 0 °C and stirred for 30 min at 0 °C, then (aminooxy)diphenylphosphine oxide (3.79 g, 16.24 mmol) was added. The reaction was warmed to room temperature and stirred for another 2 h, quenched with MeOH at 0 °C and diluted with EA (300 mL), washed with saturated brine (3 x 150 mL). The organic layer was concentrated in vacuo and purified by column chromatography to give the title compound as a light brown solid (2.45 g, 51.0%). MS m / z (ESI): 443.1 [M+H] + .

[0448] Eleventh Step: Preparation of 12-chloro-2,2-difluoro-7H-8,15-methano[l,3]dioxolo[4',5':5,6]benzo[l,2-f]benzo[4,5]imidazo[2,l-c][l,2,4]triazocine-6(15H)-one

[0449] A solution of 3-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-6-chloro-2,3- dihydro-lH-benzo[d]imidazo[l,2-a]imidazole-l-amine (500 mg, 1.13 mmol), tris(dibenzylideneacetone)dipalladium (103 mg, 112.71 μmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (130.43 mg, 225.41 μmol) and N,N-diisopropylethylamine (436.99 mg, 3.38 mmol) in DMF (20 mL) was stirred under carbon monoxide atmosphere at 110 °C for 12 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (150 mg, 34%). MS m / z (ESI): 391.0 [M+H] + .

[0450] Twelfth Step: Preparation of 12-chloro-2,2-difluoro-7-(methyl-d3)-7H-8,15- methano[l,3]dioxolo[4',5':5,6]benzo[l,2-f]benzo[4,5]imidazo[2,l-c][l,2,4]triazocine-6(15H)-one

[0451] To a solution of 12-chloro-2,2-difluoro-7H-8,15-methano[l,3]dioxolo[4',5':5,6]benzo[l,2- f]benzo[4,5]imidazo[2,l-c][l,2,4]triazocine-6(15H)-one (150 mg, 384 μmol) in THF (5 mL) was added sodium hydride (30.71 mg, 767.80 μmol, 60% purity), deuterated iodomethane (110.56 mg, 767.80 μmol), the mixture was stirred at 20 °C for 14 hours. The mixture was quenched with ammonium chloride solution (3 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (100 mg, 64%). MS m / z (ESI): 408.1.2 [M+H] + .

[0452] [Corrected according to Rule 91 14.10.2025] Step 13: Preparation of N-(l-(5-((15S)-2,2-difluoro-7-methyl-6-oxo-6,15-dihydro-7H-8,15-methano[l,3]dioxolo[4',5':5,6]benzo[l,2-f]benzo[4,5]imidazo[2,l-c][l,2,4]triazocin-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfonamide

[0453] (2-(1-((tert-butylsulfinylamino)cyclobutyl)pyrimidin-5-yl)boronic acid (26.24 mg, 88.28 μmol), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-propanyl)[1,1'-biphenyl]-2-yl]phosphine] (methane sulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (6.33 mg, 7.66 μmol) and potassium carbonate (20.31 mg, 147.14 μmol) were suspended in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL), and reacted at 110 °C for 1 hour under microwave. The reaction solution was cooled to room temperature, extracted with EtOAc (10 mL x 3), washed with saturated aqueous sodium chloride solution (10 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography and chiral separation to obtain the title compound (20 mg, 43.5%). MS m / z (ESI): 625.2 [M+H] + .

[0454] Fourteenth step: Preparation of (15S)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-(methyl-d3)-7H-8,15-methano[1,3]dioxolo[4',5':5,6]benzo[1,2-f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocine-6(15H)-one

[0455] N-(1-(5-((15S)-2,2-difluoro-7-methyl-6-oxo-6,15-dihydro-7H-8,15-methano[1,3]dioxolo[4',5':5,6]benzo[1,2-f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocine-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfmamide (20 mg, 88.28 μmol 32.02) was dissolved in a solution of hydrochloric acid in dioxane (0.5 mL, 4N), and stirred for 1 hour. After the reaction solution was concentrated, prep-HPLC separation and purification were performed to obtain the title compound (10 mg, 86%). MS m / z (ESI): 521.2 [M+H] + .

[0456] 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.20 (d, J = 10.5 Hz, 2H), 7.67 - 7.60 (m, 1H), 7.53 (dd, J = 8.1, 1.6 Hz, 1H), 7.44 (dd, J = 11.8, 8.7 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.08 (s, 1H), 5.93 (t, J = 9.3 Hz, 1H), 4.15 (s, 1H), 3.68 (dt, J = 12.9, 9.0 Hz, 1H), 2.67 (s, 2H), 2.56 (d, J = 8.7 Hz, 1H), 2.17 - 1.95 (m, 2H), 1.32 - 1.21 (m, 2H).

[0457] Example 285 can also be prepared following the route below

[0458] (14S)-1-(Difluoromethoxy)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-6-(methyl-d3)- 6H-7,14-methanoben[f]benzo[4,5]imidazo[2,1-c][1,2,4]triazin-5(14H)-one

[0459] A mixture of tert-butyl N-[2-amino-2-[2-bromo-6-(difluoromethoxy)phenyl]ethyl]carbamate (4.6 g, 12.07 mmol) and N,N'-carbonyldiimidazole (1.96 g, 12.7 mmol) in dichloromethane (50 mL) was stirred at 27 °C for 30 min, then the reaction was continued to stir at 55 °C for 4 h. The reaction was concentrated and purified by silica gel chromatography to give the title compound as a white solid (4.2 g, 85.5%). MS m / z (ESI): 351.0 [M+H-56] + .

[0460] Step 2: Preparation of tert-butyl 4-[2-bromo-6-(difluoromethoxy)phenyl]-3-(5-chloro-2- nitro-phenyl)-2-oxo-imidazolidine-1-carboxylate

[0461] A mixture of tert-butyl 4-(2-bromo-6-(difluoromethoxy)phenyl)-2-oxoimidazolidine- 1 -carboxylate (5 g, 12.28 mmol), 2-bromo-4-chloro-1 -nitrobenzene (5.81 g, 24.56 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.42 g, 2.46 mmol), cesium carbonate (8.00 g, 24.56 mmol) and tris(dibenzylideneacetone)dipalladium (1.12 g, 1.23 mmol) in toluene (150 mL) was stirred at 110 °C under nitrogen atmosphere for 12 h. The reaction was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (5.2 g, 75.3%). MS m / z (ESI): 506.0 [M+H-56] + .

[0462] Third Step: Preparation of tert-butyl 3-(2-amino-5-chloro-phenyl)-4-[2-bromo-6- (difluoromethoxy)phenyl]-2-oxo-imidazolidine-1 -carboxylate

[0463] To a mixture of tert-butyl 4-[2-bromo-6-(difluoromethoxy)phenyl]-3-(5-chloro-2- nitro-phenyl)-2-oxo-imidazolidine-1 -carboxylate (5.2 g, 9.24 mmol), iron powder (1.55 g, 27.72 mmol) in ethanol (5 mL) and water (5 mL) was added ammonium chloride (1.43 g, 27.72 mmol) and the resulting mixture was stirred at 70 °C for 2 h. The mixture was filtered and concentrated, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow oil (3.3 g, 67.1 %). MS m / z (ESI): 476.0 [M+H] + .

[0464] Fourth Step: Preparation of 1 -(2-amino-5-chloro-phenyl)-5-[2-bromo-6- (difluoromethoxy)phenyl]imidazolidin-2-one

[0465] To a solution of tert-butyl 3-(2-amino-5-chloro-phenyl)-4-[2-bromo-6- (difluoromethoxy)phenyl]-2-oxo-imidazolidine-1 -carboxylate (3.3 g, 6.19 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (706.27 mg, 6.19 mmol, 6 mL), the resulting mixture was stirred at 28 °C for 3 hours. The pH of the mixture was adjusted to 8-9 with ammonia solution, and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (2 g, 74.6%). MS m / z (ESI): 432.0 [M+H] + .

[0466] Fifth Step: Preparation of 1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3- dihydro-1 H-imidazo[1,2-a]benzoimidazole

[0467] To a solution of 1-(2-amino-5-chloro-phenyl)-5-[2-bromo-6-(difluoromethoxy)phenyl] imidazolidin-2-one (2 g, 4.62 mmol) in toluene (20 mL) was added phosphorus pentasulfide (4.11 g, 9.25 mmol), the resulting mixture was stirred at 110 °C for 12 hours. The mixture was concentrated, the solid was dissolved with (dichloromethane / methanol = 10 / 1, 20 mL). The pH of the mixture was adjusted to 8-9 with sodium hydroxide aqueous solution, and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a white solid (1.2 g, 62.6%). MS m / z (ESI): 414.0 [M+H] + .

[0468] Sixth Step: Preparation of 1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-1,2- dihydroimidazo[1,2-a]benzoimidazol-3-amine

[0469] To a solution of 1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-2,3-dihydro-1H- imidazo[1,2-a]benzoimidazole (1.1 g, 2.65 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (424.43 mg, 10.61 mmol, 60% purity), O-diphenyl phosphorohydroxylamine (928.01 mg, 3.98 mmol) was added to the reaction, the resulting mixture was stirred at 25 °C for 2 hours. The mixture was quenched with ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow oil (800 mg, 70.2%). MS m / z (ESI): 429.0 [M+H] + .

[0470] Step 7: Preparation of 11-chloro-1-(difluoromethoxy)-6H-7,14-methanoben[f]benzo[4,5] imidazo[2,1-c][1,2,4]triazocine-5(14H)-one

[0471] A solution of 1-[2-bromo-6-(difluoromethoxy)phenyl]-7-chloro-1,2-dihydroimidazo[1,2- a]benzoimidazol-3-amine (700 mg, 1.63 mmol), tris(dibenzylideneacetone)dipalladium (149.19 mg, 162.92 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (188.54 mg, 325.85 μmol) and N,N-diisopropylethylamine (421.14 mg, 3.26 mmol, 567.57 μL) in N,N-dimethylformamide (15 mL) was stirred at 110 °C under carbon monoxide atmosphere for 12 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (300 mg, 48.9%). MS m / z (ESI): 377.0 [M+H] + .

[0472] Step 8: Preparation of 11-chloro-1-(difluoromethoxy)-6-(methyl-d3)-6H-7,14- methanoben[f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocine-5(14H)-one

[0473] To a solution of 11-chloro-l-(difluoromethoxy)-6H-7,14-methanoben[f]benzo[4,5]imidazo[2,l- c][l,2,4]triazocin-5(14H)-one (300 mg, 796.30 pmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (63.70 mg, 1.59 mmol, 60% purity), deuterated iodomethane (346.29 mg, 2.39 mmol), the mixture was stirred at 27 °C for 2 hours. The mixture was quenched with ammonium chloride solution (3 mL), extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (300 mg, 95.7%). MS m / z (ESI): 394.2 [M+H] + .

[0474] Step 9: Preparation of l-(difluoromethoxy)-6-(methyl-d3)-l l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6H-7,14-methanoben[f]benzo[4,5]imidazo[2,l-c][l,2,4]triazocin-5(14H)-one

[0475] To a solution of l l-chloro-l-(difluoromethoxy)-6-(methyl-d3)-6H-7,14-methanoben[f]benzo[4,5]imidazo[2,l- c][l,2,4]triazocin-5(14H)-one (300 mg, 761.83 pmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (290.19 mg, 1.14 mmol), potassium acetate (149.54 mg, 1.52 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-l,l'- biphenyl) (2'-methylamino-l,l'-biphenyl-2-yl)palladium(II) (32.78 mg, 38.09 pmol) in dioxane (5 mL) was stirred at 110 °C for 12 hours under nitrogen atmosphere. The reaction was concentrated and purified by silica gel chromatography to give the title compound as a yellow solid (280 mg, 75.7%). MS m / z (ESI): 486.2 [M+H] + .

[0476] Ninth step: preparation of (14S)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-7,14-methanobenzo[f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocin-5(14H)-one

[0477] Purification of 1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-7,14-methanobenzo[f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocin-5(14H)-one (280 mg, 576.96 μmol) by supercritical fluid chromatography gave the title compound as a yellow oil (100 mg, 206.06 μmol).

[0478] Tenth step: (14S)-1-(difluoromethoxy)-11-(4-(dimethylphosphino)-2,3-difluorophenyl)-6-(methyl-d3)-6H-7,14-methanobenzo[f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocin-5(14H)-one

[0479] Oxidation of (4-bromo-2,3-difluorophenyl)dimethylphosphine (13.3 mg, 0.049 mmol), (14S)-1-(difluoromethoxy)-6-(methyl-d3)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-7,14-methanobenzo[f]benzo[4,5]imidazo[2,1-c][1,2,4]triazocin-5(14H)-one (20 mg, 0.041 mmol) and potassium bicarbonate (12.4 mg, 0.124 mmol) were dispersed in a mixture of water (0.4 mL) and 1,4-dioxane (2 mL), the reaction was protected with nitrogen, (SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonic acid)[2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (7.1 mg, 0.008 mmol) was added with stirring at room temperature, vacuumed, filled with nitrogen, the operation was repeated 3 times, the temperature was raised to 80 °C and the reaction was stirred for 1 hour, the reaction was concentrated, the residue was separated by high performance liquid column to give the title compound as a white solid (7.5 mg, 33%). MS m / z (ESI): 548.2 [M+H] + .

[0480] 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J = 7.9, 1.5 Hz, 1H), 7.76 - 7.29 (m, 8H), 6.28 (d, J = 4.7 Hz, 1H), 4.76 (dd, J = 13.1, 4.9 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 1.79 (d, J = 13.7 Hz, 6H).

[0481] Example 38 can also be prepared following the route below

[0482] (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7,8- dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-6(15H)-one

[0483] To a solution of (8R,15R)-12-chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)- one (162 mg, 0.399 mmol) and N-methyl-4-ethynylpyrazole (212 mg, 1.995 mmol) in DMF (3 mL) were added XPhos (19 mg, 0.040 mmol), DIPEA (257 mg, 1.995 mmol), copper iodide (4 mg, 0.020 mmol) and XPhos Pd G3 (34 mg, 0.040 mmol), and the reaction was stirred at 110 °C for 16 h after purging with nitrogen three times. The reaction was cooled and diluted with water (15 mL) and extracted with ethyl acetate (30 mL). The organic layer was concentrated under reduced pressure and the residue was purified by prep-HPLC to give the title compound (49 mg, 26%). MS m / z (ESI): 477.2 [M+H] + .

[0484] 1H NMR (400 MHz, CDC13) δ 8.45 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.58-7.52 (m, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 5.90 (s, 1H), 5.07 (s, 1H), 3.92 (s, 3H), 3.50 (s, 1H), 3.04-2.84 (m, 1H).

[0485] Example 550 can also be prepared according to the following route

[0486] [Amended in accordance with Rule 91 on 14.10.2025] (7R,14S)-1-(trifluoromethoxy)-12-(6-(dimethylphosphoryl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one [0486.1][Amended in accordance with Rule 91 on 14.10.2025] First step: Preparation of ethyl 3-((2-bromo-6-(trifluoromethoxy)phenyl)(hydroxy)methyl)-5-chloropyrazolo[1,5-a]pyridine-2-carboxylate

[0487] [Amended in accordance with Rule 91 on 14.10.2025] Ethyl 5-chloro-3-iodo-pyrazolo[1,5-a]pyridine-2-carboxylate (50 g, 142.6 mmol) was dissolved in tetrahydrofuran (750 mL) and placed in a dry ice-ethanol bath. Isopropylmagnesium chloride-lithium chloride (1.3 M, 164.6 mL) was added dropwise. After 1 hour of reaction, 2-bromo-6-(trifluoromethoxy)benzaldehyde (16.11 g, 64.19 mmol) was added dropwise. The reaction was stirred at -78 °C for 1 hour and then allowed to recover to 20 °C for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (500 mL) was added. The organic phase was extracted with ethyl acetate (300 mL x 3), dried and concentrated. The title compound was obtained as a yellow solid (50 g, 71.0%) by column chromatography (petroleum ether: ethyl acetate = 4:1). MS m / z (ESI): 493.0 [M+H] + .

[0488] Second step: Preparation of dimethyl 2-[[2-bromo-6-(trifluoromethoxy)phenyl]-(5-chloro-2-ethoxycarbonyl-pyrazolo[1,5-a]pyridin-3-yl)methyl]propanedioate

[0489] [According to Rule 91 correction 14.10.2025] Dimethyl malonate (58.88 g, 445.65 mmol), ethyl 3-[[2-bromo-6-(trifluoromethoxy)phenyl]-hydroxy-methyl]-5-chloro-pyrazolo[l,5- a]pyridine-2-carboxylate (44 g, 89.13 mmol) and scandium triflate (4.39 g, 8.91 mmol) were dissolved in 1,2-dichloroethane (1.6 L) and stirred at 80 °C for 16 hours. The reaction was completed, the organic phase was dried and concentrated, and the title compound was obtained as a yellow solid (45 g, 83.1%) by column chromatography (petroleum ether: ethyl acetate = 4: 1). MS m / z (ESI): 607.0 [M+H] + .

[0490] Third Step: Preparation of Ethyl 3-[l-[2-bromo-6-(trifluoromethoxy)phenyl]-3-methoxy-3-oxo- propyl]-5-chloro-pyrazolo[l,5-a]pyridine-2-carboxylate

[0491] Dimethyl 2-[[2-bromo-6-(trifluoromethoxy)phenyl]-(5-chloro-2-ethoxycarbonyl- pyrazolo[l,5-a]pyridin-3-yl)methyl]malonate (45 g, 74.04 mmol) and lithium chloride (18.83 g, 444.26 mmol) were dissolved in dimethyl sulfoxide (500 mL) and water (50 mL) and stirred at 125 °C for 16 hours. The reaction was completed, the reaction solution was poured into water (1 L), extracted with ethyl acetate (200 mL x 3), the organic phase was dried and concentrated, and the title compound was obtained as a gray solid (35 g, 85.9%) by column chromatography (petroleum ether: ethyl acetate = 4: 1). MS m / z (ESI): 531 [M+H] + .

[0492] Fourth Step: Preparation of Methyl 3-[2-bromo-6-(trifluoromethoxy)phenyl]-l l-chloro-5- oxo-7,8-diazatricyclo[6.4.0.02,6]dodeca-l,6,9,l l-tetraene-4-carboxylate

[0493] Ethyl 3-[1-[2-bromo-6-(trifluoromethoxy)phenyl]-3-methoxy-3-oxo-propyl]-5- chloro-pyrazolo[1,5-a]pyridine-2-carboxylate (35 g, 63.67 mmol) was dissolved in tetrahydrofuran (50 mL), potassium tert-pentoxide (16.32 g, 127.34 mmol) was added, and the reaction was stirred at 75 °C for 0.5 h. The reaction was completed, and the reaction solution was poured into an aqueous ammonium chloride solution (300 mL), extracted with ethyl acetate (150 mL x 3), dried and concentrated, and the organic phase was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound as a gray solid (21 g, 65.5%). MS m / z (ESI): 503.0 [M+H] + .

[0494] Fifth step: Preparation of (S)-1-(2-bromo-6-(trifluoromethoxy)phenyl)-8-chloro-1,2- dihydro-3H-cyclopenta[3,4]pyrazolo[1,5-a]pyridine-3-one

[0495] Methyl 3-[2-bromo-6-(trifluoromethoxy)phenyl]-11-chloro-5-oxo-7,8-diazatricyclo[6.4.0.02,6]dodeca-1,6,9,11-tetraene-4-carboxylate (21 g, 41.7 mmol) was dissolved in tetrahydrofuran (100 mL) and concentrated hydrochloric acid (6 M, 100 mL), and the reaction was stirred at 60 °C for 16 h. The reaction was completed, and the reaction solution was filtered after cooling, the filtrate was extracted with ethyl acetate (100 mL x 3), dried and concentrated, and the organic phase was purified by column chromatography (dichloromethane:methanol = 20:1) and chiral column separation to obtain the title compound (6.2 g, 32.3%). MS m / z (ESI): 445.0 [M+H] + .

[0496] Sixth step: Preparation of (R)-N-((S,E)-1-(2-bromo-6-(trifluoromethoxy)phenyl)-8- chloro-1,2-dihydro-3H-cyclopenta[3,4]pyrazolo[1,5-a]pyridine-3-ylidene)-2- methylpropane-2-sulfmamide

[0497] To a solution of (S)-l-(2-bromo-6-(trifluoromethoxy)phenyl)-8-chloro-l,2- dihydro-3H-cyclopenta[3,4]pyrazolo[l,5-a]pyridin-3-one (2.6 g, 5.83 mmol) and (R)-tert-butylsulfinamide (1.41 g, 11.67 mmol) in tetrahydrofuran (50 mL) was added tetraethyl titanate (13.31 g, 58.35 mmol) and the reaction was heated to 60 °C for 16 h. The reaction was poured into water and filtered, the filter cake was washed with ethyl acetate and the combined liquids were extracted with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated in vacuo and the title compound was isolated by column chromatography (petroleum ether: ethyl acetate = 1: 1) (2.3 g, 71.8 %). MS m / z (ESI): 549.5 [M+H] + .

[0498] Step 7: Preparation of (IS,3R)-l-(2-bromo-6-(trifluoromethoxy)phenyl)-8-chloro- 2,3-dihydro-lH-cyclopenta[3,4]pyrazolo[l,5-a]pyridin-3-amine

[0499] Sodium borohydride (317.1 mg, 8.38 mmol) was added to a solution of (R)-N- ((S,E)-l-(2-bromo-6-(trifluoromethoxy)phenyl)-8-chloro-l,2-dihydro-3H- cyclopenta[3,4]pyrazolo[l,5-a]pyridine-3-ylidene)-2-methylpropane-2- sulfinamide (2.3 g, 4.19 mmol) in methanol (30 mL) at 0 °C and the reaction was stirred for 0.5 h. 4M Hydrochloric acid in dioxane (1 mL) was added directly to the reaction and it was stirred at room temperature for 15 min. The reaction was poured into sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The organic phase was dried and concentrated in vacuo and the title compound was isolated by silica gel column chromatography (1.4 g, 74.8 %). MS m / z (ESI): 446.0 [M+H] + .

[0500] Step 8: Preparation of (7R,14S)-12-chloro-l-(trifluoromethoxy)-6,7-dihydro-7,14- methanobenzo[c]pyrido[l',2':l,5]pyrazolo[4,3-f]azocine-5(14H)-one

[0501] Tris(dibenzylideneacetone)dipalladium (287.0 mg, 313.45 μmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (362.72 mg, 626.89 μmol) were added to a solution of (1S,3R)-1-(2-bromo-6-(trifluoromethoxy)phenyl)-8-chloro-2,3- dihydro-1H-cyclopenta[3,4]pyrazolo[1,5-a]pyridin-3-amine (1.4 g, 3.13 mmol), sodium ascorbate (1.86 g, 9.40 mmol) in N,N-dimethylformamide (30 mL), the reaction was purged with carbon monoxide gas for 2 times, heated to 115 °C for 16 hours under a carbon monoxide balloon. The reaction was poured into water, extracted with ethyl acetate (50 mL x 3), the organic phase was dried, concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give the title compound (770 mg, 62.39%). MS m / z (ESI): 394.0 [M+H] + .

[0502] Ninth step: Preparation of (7R,14S)-12-chloro-1-(trifluoromethoxy)-6-(methyl-d3)- 6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one

[0503] Sodium hydride (81.26 mg, 2.03 mmol, 60%) was added to a solution of (7R,14S)-12-chloro-1-(trifluoromethoxy)-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (400 mg, 1.02 mmol) in tetrahydrofuran (10 mL) at room temperature, the reaction was stirred for 5 minutes, deuterated iodomethane (294.52 mg, 2.03 mmol) was added, the reaction was stirred at room temperature for 1 hour. The reaction was poured into water, extracted with ethyl acetate (30 mL x 3), the organic phase was dried, concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (370 mg, 88.6%). MS m / z (ESI): 411.0 [M+H] + .

[0504] Tenth step: Preparation of (7R,14S)-1-(trifluoromethoxy)-12-(6-(dimethylphosphoryl)pyridin-3-yl)-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[c]pyrido[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one

[0505] [Corrected according to Rule 91 14.10.2025] Methyl sulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(ll) (6.28 mg, 7.30 pmol) was added to a solution of (7R,14S)-12-chloro-1-(trifluoromethoxy)-6-(methyl-d3)-6,7-dihydro-7,14- methylenobenzo[c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-5(14H)-one (30 mg, 73.0 pmol), (6-(dimethylphosphoryl)pyridin-3-yl)boronic acid (21.8 mg, 110 pmol) and potassium carbonate (30.3 mg, 219.0 pmol) in 1,4-dioxane (2 mL) and water (0.2 mL), the reaction was purged with nitrogen 3 times, heated to 110 °C under nitrogen for 2 hours. The reaction was concentrated and directly sent to prep-HPLC to give the title compound (25 mg, 64.6%). MS m / z (ESI): 530.0 [M+H] + .

[0506] 1 H NMR (400 MHz, DMSO-d6) d 9.07 (d, J = 2.2 Hz, 1H), 8.85 (d, J = 1.0 Hz, 1H), 8.33 (d, J = 1.3 Hz, 1H), 8.26 (dt, J = 8.1, 2.7 Hz, 1H), 8.10 - 8.02 (m, 1H), 7.64 - 7.54 (m, 2H), 7.41 (t, J = 8.2 Hz, 1H), 7.29 (dd, J = 7.4, 2.1 Hz, 1H), 5.11 (d, J = 6.9 Hz, 1H), 4.97 (d, J = 6.6 Hz, 1H), 3.35 - 3.27 (m, 1H), 2.59 - 2.51 (m, 1H), 1.70 (d, J = 13.5 Hz, 6H).

[0507] Example 63

[0508] (8R,15S)-13-(6-(dimethylphosphoryl)-2-methylpyridin-3-yl)-2,2-difluoro-7-(methyl- d3)-7,8-dihydro-8,15-methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)-one

[0509] (SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (10.0 mg, 11.6 μmol) was added to a solution of (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15- methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (58 mg, 116 μmol), (5-bromo-6-methylpyridin-2-yl)dimethylphosphine oxide (34.7 mg, 140 μmol) and cesium carbonate (114 mg, 349 μmol) in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was evacuated, backfilled with nitrogen and repeated 3 times, then heated to 110 °C for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure and purified by prep-HPLC to give the title compound (41.8 mg, 65.5%). MS m / z (ESI): 540.0 [M+H] + .

[0510] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J = 7.3, 0.9 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.37 (dd, J = 2.0, 0.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.00 (dd, J = 7.3, 2.0 Hz, 1H), 5.16 (d, J = 6.9 Hz, 1H), 4.76 (d, J = 6.2 Hz, 1H), 3.31 - 3.24 (m, 4H), 2.61 (d, J = 13.4 Hz, 1H), 1.69 (d, J = 13.5 Hz, 6H).

[0511] Example 63

[0512] (8R,15S)-13-(5-(dimethylphosphoryl)-6-fluoropyridin-2-yl)-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8,15-methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one

[0513] First Step: Preparation of (8R, 15S)-13-(5-bromo-6-fluoropyridin-2-yl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-c]pyrrolo[l',2':l,5]pyrazolo[4,3-f]azocine-6(15H)-one

[0514] (S)-[2',4',6'-tris(3-fluorophenyl)[l,r-biphenyl]-2-yl]dimethylamine (0.1 g, 0.21 mmol) was added to a solution of (8R, 15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-c]pyrrolo[l',2':l,5]pyrazolo[4,3-f]azocine-6(15H)-one (0.1 g, 0.21 mmol), 3-bromo-2-fluoro-6-iodopyridine (0.07 g, 0.24 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL). The reaction was degassed and purged with nitrogen three times, then heated to 110 °C for 1 hour. The reaction was concentrated under reduced pressure and purified by silica gel chromatography to give the title compound (0.1 g, 79.0 %). MS m / z (ESI): 545.9 [M+H] + .

[0515] Second Step: Preparation of (8R, 15S)-13-(5-(dimethylphosphoryl)-6-fluoropyridin-2-yl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-c]pyrrolo[l',2':l,5]pyrazolo[4,3-f]azocine-6(15H)-one

[0516] Palladium acetate (1 mg, 4.58 pmol) was added to a solution of (8R,15S)-13-(5-bromo-6-fluoropyridin-2-yl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15- methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (25 mg, 45.7 pmol), dimethylphosphine oxide (7.1 mg, 91.5 pmol), Xantphos (5.3 mg, 9.15 pmol) and potassium phosphate (24.3 mg, 114.4 pmol) in N,N-dimethylformamide (3 mL), the reaction was evacuated, flushed with nitrogen and the procedure repeated three times. The reaction was heated to 120 °C in a microwave reactor for 1 hour. The reaction was cooled to room temperature and filtered. The filtrate was purified by prep-HPLC to give the title compound (1.5 mg, 6.0%). MS m / z (ESI): 544.0 [M+H] + .

[0517] 1 H NMR (400 MHz, DMSO-d6) d 8.82 (d, J = 7.4 Hz, 1H), 8.41 - 8.34 (m, 1H), 8.28 - 8.14 (m, 3H), 7.55 (dd, J = 7.5, 2.1 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 5.17 (d, J = 7.0 Hz, 1H), 4.84 (d, J = 6.2 Hz, 1H), 3.27 - 3.25 (1H, m), 2.63 (d, J = 13.4 Hz, 1H), 1.78 (d, J = 13.8 Hz, 6H).

[0518] Example 63

[0519] (8R,15S)-13-(6-(dimethylphosphoryl)-2-fluoropyridin-3-yl)-2,2-difluoro-7-(methyl-d3)- 7,8-dihydro-8,15-methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one

[0520] (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (10 mg, 0.02 mmol), XPhos PdG4 (1.7 mg, 0.002 mmol), potassium carbonate (11 mg, 0.08 mmol) were added into a mixed solvent of 1,4-dioxane (1 mL) and water (0.2 mL) respectively, the reaction solution was vacuumed, filled with nitrogen, and the operation was repeated for 3 times, then the temperature was raised to 100 °C and stirred for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and then separated and purified by prep-HPLC to obtain the title compound (3.5 mg, 31.6%). MS m / z (ESI): 544.4 [M+H] + .

[0521] 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 7.4 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 8.18-8.00 (m, 2H), 7.67 (s, 1H), 7.00-6.92 (m, 2H), 4.97 (d, J = 7.0 Hz, 1H), 4.81 (d, J = 6.3 Hz, 1H), 3.37-3.26 (m, 1H), 2.72 (d, J = 13.2 Hz, 1H), 1.83 (s, 3H), 1.80 (s, 3H).

[0522] Example 63

[0523] (8R,15S)-13-(5-(dimethylphosphoryl)pyrazin-2-yl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro- 8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)- one

[0524] (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (5.18 mg, 6.02 μmol) was added to a solution of (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15- methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3-f]azocine-6(15H)- one (30 mg, 60.2 μmol), (5-chloropyrazin-2-yl)dimethylphosphine oxide (12.6 mg, 66.6 μmol) and cesium carbonate (39 mg, 120 μmol) in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was evacuated, backfilled with nitrogen and repeated 3 times, then heated to 110 °C for 1 hour. After cooling to room temperature, the reaction was concentrated under reduced pressure and purified by prep-HPLC to give the title compound (4.6 mg, 14.3%). MS m / z (ESI): 527.1 [M+H] + .

[0525] 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.13 (d, J = 1.4 Hz, 1H), 8.87 (d, J = 7.5 Hz, 1H), 8.32 - 8.19 (m, 2H), 7.65 (dd, J = 7.5, 2.1 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 4.84 (d, J = 6.2 Hz, 1H), 3.28 (d, J = 6.7 Hz, 1H), 2.64 (d, J = 13.4 Hz, 1H), 1.77 (d, J = 13.7 Hz, 6H).

[0526] Example 64

[0527] (8R,15S)-13-(4-(dimethylphosphoryl)-2-methylphenyl)-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8,15-methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one

[0528] Xantphos Pd G4 (4.23 mg, 4.92 pmol) was added to a solution of (8R,15S)-13- chloro-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2- c]pyrido[l',2':l,5]pyrazolo[4,3-f]azocine-6(15H)-one (20 mg, 49.17 pmol), dimethyl(3-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)phosphine oxide (21.69 mg, 73.75 pmol) and potassium carbonate (20.39 mg, 147.50 pmol) in 1,4 dioxane (1 mL) and water (0.1 mL), the reaction was evacuated, flushed with nitrogen, and the procedure repeated three times. The reaction was heated to 110 °C for 1 h. After cooling to room temperature, the reaction was concentrated under reduced pressure and purified by prep-HPLC to give the title compound (12.0 mg, 45.3%). MS m / z (ESI): 539.2 [M+H] + .

[0529] 1 H NMR (400 MHz, DMSO-d6) d 8.75 (d, J = 0.9 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.77 - 7.62 (m, 2H), 7.40 (dd, J = 7.8, 2.7 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 6.92 (dd, J = 7.3, 2.0 Hz, 1H), 5.15 (d, J = 7.0 Hz, 1H), 4.76 (d, J = 6.2 Hz, 1H), 3.36 - 3.22 (m, 1H), 2.61 (d, J = 13.4 Hz, 1H), 2.29 (s, 3H), 1.68 (d, J = 13.3 Hz, 6H).

[0530] Example 64

[0531] [Corrected according to Rule 91, as from 14.10.2025](8R,15S)-13-(4-(dimethylphosphoryl)-2- fluorophenyl)-2,2-difluoro-7-(methyl-d3)-7,8-dihydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2- c]pyrido[l',2':l,5]pyrazolo[4,3-f]azocine-6(15H)-one

[0532] (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (92.5 mg, 185 μmol), (4-bromo-3-fluorophenyl)dimethylphosphine oxide (55 mg, 220 μmol), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2- yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (16 mg, 18.6 μmol) and potassium carbonate (76.5 mg, 555 μmol) were added to a mixture of 1,4-dioxane (5 mL) and water (1 mL) and the reaction stirred at 110 °C for 1 hour. The reaction was cooled to room temperature, extracted with EtOAc (10 mL x 3), the organic phases combined, washed with saturated aqueous sodium chloride (10 mL), the organic phase collected, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The title compound was isolated and purified by prep-HPLC (15.0 mg, 30.0 %). MS m / z (ESI): 543.1 [M+H] + .

[0533] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.77 (m, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.83 - 7.68 (m, 3H), 7.61 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 5.17 (d, J = 6.9 Hz, 1H), 4.78 (d, J = 6.1 Hz, 1H), 3.31 - 3.23 (m, 1H), 2.62 (d, J = 13.4 Hz, 1H), 1.71 (d, J = 13.5 Hz, 6H).

[0534] Example 64

[0535] (8R,15S)-13-(4-(dimethylphosphoryl)-3-fluoro-2-methylphenyl)-2,2-difluoro-7-(methyl-d3)- 7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one

[0536] (8R,15S)-2,2-difluoro-7-(methyl-d3)-13-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-c]pyrrolo[1',2':1,5]pyrazolo[4,3- f]azocine-6(15H)-one (15 mg, 30 μmol) and (4-bromo-2-fluoro-3-methylphenyl)dimethyl- phosphine oxide (10 mg, 39 μmol) were dissolved in a mixture solvent of dioxane (1.5 mL) and water (0.3 mL), potassium bicarbonate (9 mg, 90.μmol) and (SP-4-3)-[dicyclohexyl[2',4',6'-tris( isopropyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'- biphenyl]-2-yl]palladium (2.6 mg, 3 μmol) were added, the reaction solution was vacuumed, filled with nitrogen, and the operation was repeated for 3 times, then the temperature was raised to 80 °C and the reaction was stirred for 1 hour. After the reaction solution was cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and then the title compound (4.6 mg, 27.4%) was separated and purified by prep-HPLC. MS m / z (ESI): 558.1 [M+H] + .

[0537] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 7.2 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.66 (dt, J = 11.8, 7.2 Hz, 1H), 7.30 (d, J = 9.4 Hz, 3H), 6.92 (d, J = 7.2 Hz, 1H), 5.15 (d, J = 7.0 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 3.28 - 3.24 (m, 1H), 2.61 (d, J = 13.4 Hz, 1H), 2.16 (s, 3H), 1.74 (d, J = 13.6 Hz, 6H).

[0538] Example 1161

[0539] Preparation of (8R,15R)-12-(4-(dimethylphosphoryl)-3-fluoro-2-methylphenyl)-2,2-difluoro- 7-(methyl-d3)-7,8-dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2- a][1,4]azocine-6(15H)-one

[0540] (SP-4-3)-[dicyclohexyl[2',4',6'-tris(isopropyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (5.18 mg, 6.02 μmol) was added to a solution of (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15- methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)- one (30 mg, 60.2 μmol), (4-bromo-3-methyl-2-fluorophenyl)dimethylphosphine oxide (24 mg, 90.3 μmol) and cesium carbonate (39 mg, 120 μmol) in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was evacuated, backfilled with nitrogen and repeated 3 times, then heated to 110 °C for 1 hour. After cooling to room temperature, the reaction was concentrated under reduced pressure and purified by prep-HPLC to give the title compound (9.3 mg, 27.6 %). MS m / z (ESI): 557.0 [M+H] + .

[0541] 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.86 - 7.36 (m, 6H), 7.31 - 7.00 (m, 2H), 6.27 (d, J = 4.8 Hz, 1H), 6.22 (d, J = 10.4 Hz, 1H), 4.75 (dd, J = 13.2, 4.8 Hz, 1H), 4.36 (d, J = 13.2 Hz, 1H), 2.83 (d, J = 10.8 Hz, 2H), 2.76 - 2.70 (m, 2H), 1.47 (d, J = 5.2 Hz, 3H).

[0542] Example 1163

[0543] (8R,15R)-12-(2-chloro-4-(dimethylphosphoryl)-3-fluorophenyl)-2,2-difluoro-7-(methyl-d3)- 7,8-dihydro-8,15-methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 6(15H)-one

[0544] (Sp-4-3)-[dicyclohexyl[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[1,1'-biphenyl]-2-yl]palladium (5.18 mg, 6.02 μmol) was added to a solution of (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15- methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)- one (30 mg, 60.2 μmol), (4-bromo-3-chloro-2-fluorophenyl)dimethylphosphine oxide (34 mg, 120 μmol), and cesium carbonate (39 mg, 120 μmol) in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction was evacuated, backfilled with nitrogen, and repeated 3 times, and then heated to 110 °C for 1 hour. After cooling the reaction to room temperature, it was concentrated under reduced pressure and purified by prep-HPLC to give the title compound (14.6 mg, 40.0%).

[0545] Example 1169

[0546] (8R,15R)-12-(2-Fluoro-6-(dimethylphosphoryl)pyridin-3-yl)-2,2-difluoro-7-(methyl-d3)-7,8- dihydro-8,15-methylene[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 6(15H)-one

[0547] Xantphos Pd G4 (8.63 mg, 10.03 pmol) was added to a solution of (8R,15R)-2,2-difluoro-7-(methyl-d3)-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8- dihydro-8,15-methano[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2- a][1,4]diazocin-6(15H)-one (50 mg, 100.34 pmol), (5-bromo-6-fluoropyridin-2- yl)dimethylphosphine oxide (30.35 mg, 120.41 pmol) and potassium carbonate (41.6 mg, 301.02 pmol) in 1,4 dioxane (2 mL) and water (0.2 mL), the reaction was evacuated, backfilled with nitrogen and repeated 3 times before heating to 110 °C for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure, purified by prep-HPLC to give the title compound (38.6 mg, 70.8%). MS m / z (ESI): 544.4 [M+H] + .

[0548] 1 H NMR (400 MHz, DMSO-d6) d 8.41 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 6.4 Hz, 1H), 7.99 (dd, J = 8.4, 2.4 Hz, 1H), 7.62 - 7.40 (m, 6H), 7.02 (d, J = 8.4 Hz, 1H), 6.27 (d, J = 4.8 Hz, 1H), 4.75 (dd, J = 13.2, 4.8 Hz, 1H), 4.63 (d, J = 5.2 Hz, 2H), 4.35 (d, J = 13.2 Hz, 1H), 1.53 (s, 3H), 1.50 (s, 3H).

[0549] Biological test evaluation

[0550] The application is further described and explained with reference to the following test examples, which are not meant to limit the scope of the application.

[0551] Instrument and reagent consumables: Envision (PE-Cisbio: 2105-0020); incubator (Bo Xun, BC-J80S); centrifuge (Eppendorf: 5810R); ice maker (Xueke Electrical, IMS-150); pure water instrument (THERMO: Pacific T II + Micropure); biological safety cabinet (Su Jingsheng, BSC-1604IIA2); cell counter (Invitrogen, Countess II); electric pipette aspirator (Easypet 3, Eppendorf); centrifuge (Eppendorf: 5810R); Apricot (SPT Labtech, S2-Pipette-384); ECHO (LABCYTE, 655); FLIPR (Molecular Devices, 5); 50mL centrifuge tube (Corning, 430829); 2.5uL pipette (Eppendorf, I36630F); 10uL pipette (Eppendorf, J13131F); 100uL pipette (Eppendorf, R22267J); 1000uL pipette (Eppendorf, I44804F); 10uL 12-channel electric pipette (METTLER TOLEDO, 17013797); 300uL 12-channel electric pipette (Eppendorf, O51743J); 1200uL 12-channel electric pipette (Eppendorf, J51515K).

[0552] I. Combined experiments

[0553] The compound of the embodiment of the present application shows strong binding effect on TNFα protein in the thermal shift experiment of thermal stability of TNFα protein and the experiment of the influence on the binding of TNFα protein and TNFR1 receptor.

[0554] II. Detection of inhibitory effect of the compound of the present application on IL-8 release of TNF stimulated hPBMC

[0555] 1. Purpose of the experiment: to detect the inhibitory effect of the compound on the IL-8 release of TNF induced hPBMC.

[0556] 2. Reagents: hPBMC (Saili, XFB-HP010B); PBS (Gibco, 10010023); DMSO (Sigma: D2650); TNFa (MCE: HY-P7085); RPMI1640 medium (Gibco, 22400-105); FBS serum (Gibco, 30067-334); Pen strep double antibody (Gibco, 15140-122); cell culture plate (Corning: 3599); Human IL-8 / CXCL8 DuoSet ELISA (RD, DY208-05); DuoSet ELISA Ancillary Reagent Kit 2 (RD, DY008B)

[0557] 3. Experimental method:

[0558] 1) Thaw the hPBMC frozen solution in a 37°C water bath;

[0559] 2) Add the thawed cells dropwise to 10 mL of preheated 1640 culture medium (+10% FBS + 1% PS), centrifuge at 2000 rpm for 10 min;

[0560] 3) Remove the supernatant of the centrifuged cells, add 10 mL of fresh culture medium, mix well, and count;

[0561] 4) Adjust the cell density to 1*10 6 cells / mL, 100uL / well into a 96-well plate;

[0562] 5) Place the well plate in a 37°C incubator for 4h;

[0563] 6) Prepare 6x final concentration compound (final concentration 1uM Top, 3-Fold, 8Dose) and TNF protein (final concentration 3ng / mL) working solution with serum-free 1640 medium, then mix the compound with TNFa 1:1, incubate in a 37°C incubator for 1h;

[0564] 7) Add the incubated mixture to the corresponding well plate, 50uL per well, incubate at 37°C for 18h, at the same time, prepare Elisa capture antibody with coating buffer, 100uL per well into high binding well plate, final concentration is 4ug / mL, incubate in a 4°C refrigerator overnight;

[0565] 8) Elisa sample preparation: centrifuge the incubated cell plate at 1500 rpm for 10 min, take the supernatant, dilute the supernatant 15 times with dilution buffer (6.7 uL supernatant + 93.3 uL dilution buffer);

[0566] 9) Prepare standard curve: the IL-8 concentration of the standard curve is 250 ng / mL, 2-fold, 8 doses, 2-fold dilution is 125 uL + 125 uL dilution buffer;

[0567] 10) Prepare 1x wash buffer, add 300 uL per well to the well plate to wash three times, and after adding the wash buffer each time, stand for 30 s to ensure washing;

[0568] 11) Add the diluted sample and standard curve to the well plate, 100 uL per well, incubate at room temperature for 2 h

[0569] 12) Repeat step 10, wash the plate three times

[0570] 13) Prepare the detection antibody, the final concentration is 10 ng / mL, add 100 uL per well to the well plate, incubate at room temperature for 2 h;

[0571] 14) Repeat step 10, wash the plate three times

[0572] 15) Prepare SA-HRP, the final concentration is 1x, add 100 uL per well to the well plate, incubate at room temperature for 30 min;

[0573] 16) Repeat step 10, wash the plate three times

[0574] 17) Add 100 uL of TMB solution, develop color at room temperature for 20 min in the dark;

[0575] 18) Add 50 uL of stop solution, shake well, and read OD450-570 after the solution turns yellow.

[0576] 4. Experimental data processing method:

[0577] Use XLfit four-parameter log(inhibitor) vs.response--Variable slope(four parameters) to calculate IC 50 .

[0578] 5. Experimental conclusion: The compound of the application has a good inhibitory effect on the release of IL-8 of TNF-stimulated hPBMC.

[0579] III. Pharmacokinetics determination of Balb / C mice

[0580] 1. Research purpose: Taking Balb / C mice as test animals, the pharmacokinetic behavior of the compound of the application in the plasma of mice is studied under the condition of oral administration at a dose of 30 mg / kg.

[0581] 2. Experimental scheme

[0582] 2.1 Test drug: The compound of the application is self-made.

[0583] 2.2 Test animals: Balb / C Mouse (3 per example), male, Shanghai Bikai Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0584] 2.3 Drug administration: Balb / C mice, male; after fasting overnight, p.o. at a dose of 30 mg / kg, and the administration volume is 10 mL / kg.

[0585] 2.4 Sample collection: Before and after administration, at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, 0.04 mL of blood is collected from the eye orbit, placed in an EDTA-K2 test tube, centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, and stored at -80°C.

[0586] 2.5 Sample processing:

[0587] 1) 20 uL of the plasma sample is added with 100 uL of acetonitrile for precipitation, and after mixing, centrifuged at 5000 x g for 15-20 min.

[0588] 2) The supernatant solution after processing is taken for LC / MS / MS analysis of the concentration of the test compound, and the LC / MS / MS analyzer is AB Sciex API 4000.

[0589] 2.6 Liquid phase analysis

[0590] Liquid phase condition: Shimadzu LC-20AD pump Mass spectrometry condition: AB Sciex API 4000 mass spectrometer

[0591] Chromatographic column: Waters Xbridge C18 5 μm, 4.6 X 50 mm

[0592] Mobile phase: A liquid is 0.1% formic acid aqueous solution, and B liquid is methanol Flow rate: 1 mL / min

[0593] Elution time: 0-4.0 min, eluent as follows:

[0594] 3. Test results and analysis: The main pharmacokinetic parameters were calculated by WinNonlin 6.1, and the pharmacokinetic test results of mice are shown in the following table:

[0595] 4. Experimental conclusion: The compound of the present application shows good pharmacokinetic properties.

[0596] Four, Caco-2 cell permeability test of the compound

[0597] 1. Purpose of the experiment: The purpose of this experiment is to test the bidirectional permeability of the compound through the Caco-2 cell model and to evaluate whether it is transported by efflux transporters.

[0598] 2. Compounds and test materials

[0599] 2.1 The test compound is configured as a 10 mM stock solution with DMSO (or other suitable solution) and stored in a refrigerator at -20°C for later use.

[0600] 2.2 Control compounds: Cimetidine, Metoprolol, Erythromycin are prepared as 10 mM stock solutions for later use.

[0601] 2.3 Caco-2 cells are purchased from the American Type Culture Collection (ATTC), PBS (Gibco, pH 7.4), HBSS (Sigma), DMEM medium (Gibco), fluorescent yellow (sigma), HEPES (Solarbio).

[0602] 3. Introduction to the experiment: Caco-2 cells are a type of human colon cancer cells that can form tight junctions and differentiate into cell layers similar in shape and function to human small intestinal cells in vitro through specific culture conditions. Because they express multiple types of transporters, they can be used to construct an in vitro model for studying drug absorption in small intestinal epithelial cells. Using the Caco-2 cell permeability model, drugs are added to the basolateral and basolateral sides of the cell monolayer, respectively, to measure the bidirectional permeability of the compound. At the same time, because the basolateral side of the cell expresses efflux transporters, the efflux ratio can be used to preliminarily evaluate whether the compound is an efflux substrate.

[0603] 4. Experimental steps

[0604] 4.1 Prepare transport buffer: Take 1 mL of 1 M HEPES and 99 mL of HBSS to prepare 10 mM HBSS transport buffer.

[0605] 4.2 Preparation of the fluorescent yellow solution: Take 100 mL of the transport buffer and 100 uL of the fluorescent yellow solution (20 mM), and prepare a 20 uM fluorescent yellow working solution.

[0606] 4.3 Preparation of the compound working solution

[0607] Preparation of the compound working solution: Add 1 uL of the compound stock solution to 999 uL of the fluorescent yellow working solution to obtain a final concentration of 10 uM. Depending on the properties of the compound, the preparation ratio can be adjusted to adjust the final concentration.

[0608] Preparation of the control compound working solution: The preparation process is consistent with that of the compound.

[0609] 4.4 Preparation of the reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution, and store it in a refrigerator at 2-8°C.

[0610] 4.5 Test procedure

[0611] a. Caco-2 cell permeability model construction: Take the Caco-2 plate from the incubator. Wash the monolayer twice with preheated HBSS (25 mM HEPES, pH 7.4), and then incubate at 37°C.

[0612] b. Compound permeability test

[0613] 1) Determine the transport rate of the compound from the apical end to the basal end. Take 8 uL of the sample, add 72 uL of HBSS to 240 uL of acetonitrile containing the internal standard as the 0-minute dosing sample after passing through the apical end of the Transwell culture end.

[0614] 2) Determine the transport rate of the compound from the basal end to the apical end. Take 8 uL of the sample, add 72 uL of HBSS to 240 uL of acetonitrile containing the internal standard as the 0-minute dosing sample after passing through the basal side of the Transwell.

[0615] 3) After combining the upper and lower devices, incubate in a 37°C incubator for 120 min.

[0616] 4) Take 8 uL of the sample from the dosing end (D end), dilute it 10-fold with 72 uL of the transport buffer, and add 240 uL of acetonitrile containing the internal standard to terminate it as the working solution of the dosing end (D end) at T120.

[0617] 5) Take 80 uL of the A to B receiving end (R end) sample, add 240 uL of acetonitrile containing the internal standard to terminate it; take 100 uL of the B to A receiving end (R end) sample, and add 240 uL of acetonitrile containing the internal standard to terminate it.

[0618] 6) Take 20 uL of the top sample and add 100 uL of transport buffer; take 120 uL of the bottom sample and detect the fluorescence intensity at the excitation / emission spectrum of 480 / 530 nm.

[0619] 7) Centrifuge the sample at 3500 rpm for 10 min, and take the supernatant for LC-MS / MS analysis.

[0620] 4.6 Chromatographic analysis

[0621] 1) Chromatographic conditions

[0622] Instrument: Shimadzu LC-30AD; Column: Biphemyl 2.7 μm, 2.1 x 50 mm;

[0623] Mobile phase: A: 0.1% formic acid water; B: 0.1% formic acid acetonitrile

[0624] Wash gradient: 0-0.7 min 5% A to 95% A, 1.2-1.5 min 95% A to 5% A;

[0625] Flow rate: 0.7 ml / min; Run time: 1.5 min; Injection volume: 5 μL.

[0626] 2) Mass spectrometric conditions

[0627] Instrument: API5500 Qtrap type liquid chromatograph-mass spectrometer, AB Sciex Company;

[0628] Ion source: Electrospray ionization source (ESI);

[0629] Dry gas: N2, temperature 420℃; Electrospray voltage: 5500V;

[0630] Detection mode: Positive ion detection; Scanning mode: Reaction monitoring (MRM) mode;

[0631] 5, Experimental results: The bidirectional permeability of the compound of the embodiment of the application through the Caco-2 cell model is shown in the following table,

[0632] 6, Experimental conclusion: From the experimental results in the above table, it can be seen that the compound of the embodiment of the application has high permeability.

[0633] V. In vivo pharmacodynamic study of the compound in a collagen antibody-induced mouse arthritis model

[0634] 1.1 Purpose of the experiment: to evaluate the in vivo efficacy of the compound in a collagen antibody-induced mouse arthritis model.

[0635] 1.2 Reagents

[0636] 1. Mouse arthritis induced 5-clones cocktail (53100, Chondrex)

[0637] 2. Tween 80 (30189828, Sinopharm Chemical Reagent) 3. Sodium carboxymethylcellulose (30036365, Sinopharm Chemical Reagent)

[0638] 1.3 Experimental operation and data processing

[0639] 1.3.1 Animal procurement: BALB / c nude mice, 8-10 weeks, ♀, purchased from Shanghai Family Planning Science Institute Experimental Animal Operation Department.

[0640] 1.3.2 CAIA model establishment

[0641] a. After the animals adapt for 2-3 days, mark them with disposable ear tags, and after weighing the animals, randomly group them according to weight;

[0642] b. On the experimental day (i.e. D0), inject 5-clones antibody cocktail 1.0 mg into the tail vein or abdominal cavity of the animals;

[0643] c. One day later (i.e. D1), inject 10 ug of E. coli lipopolysaccharide (LPS) into the abdominal cavity of the animals (both the 5-clones cocktail and the LPS are thawed and placed on wet ice);

[0644] 1.3.3 Drug administration, weighing and scoring

[0645] a. After 6 hours of LPS injection on D1, start administering the test drug (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: QD / BID; administration period: 7 days; solvent: 0.5% CMC-Na / 1% Tween);

[0646] b. Starting on the second day of the experiment, weigh the animals and score the CAIA arthritis of the mouse paws every day (scoring from D2 to D7);

[0647] CAIA clinical scoring criteria (total score is the sum of 4 paws, total score 0-16)

[0648] 0 normal;

[0649] 1 redness and swelling in any one part of the ankle / tarsus / toe joint;

[0650] 2 redness and swelling in any two parts of the ankle / tarsus / toe joint;

[0651] 3 obvious redness and swelling in all three parts of the ankle / tarsus / toe joint;

[0652] 4 maximum inflammation and swelling of the ankle / tarsus / toe joint.

[0653] c, the animals were euthanized at the end of the experiment.

[0654] d, data were processed by Excel or other software. The calculation of the percentage (%) of compound inhibiting CAIA arthritis:

[0655] TGI (%) = [1- (the average of arthritis score of the compound administration group at the end of the experiment / the average of arthritis score of the vehicle control group at the end of the experiment)] x 100%.

[0656] 1.4 Experimental results and conclusions: In the antibody collagen-induced mouse arthritis model, the compounds of the embodiments of the present application can effectively improve the symptoms of arthritis, and the animals have good tolerance at the therapeutic dose. The relative treatment rate of the compounds of the embodiments of the present application (30 mg / kg, BID) is 25% to 96%, preferably 30% to 90% or 55% to 95%, and the relative treatment rate of some compounds is 70% to 90% according to the D7 score.

[0657] Six, in vitro metabolic stability of the compounds of the present application in mouse, rat and canine liver microsomes

[0658] 1. Purpose of the experiment: The purpose of this experiment is to evaluate the phase I and part II metabolic stability of the compounds in mouse, rat and canine liver microsomes, respectively.

[0659] 2. Experimental scheme

[0660] 2.1 Test drugs: The compounds of the present application, self-made, Alamethicin (Abeam), 7-Hydroxycoumarin (Sigma), liver microsomes (XenoTech, Shanghai Quanyang Biological Technology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4), NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai Bid Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abeam), methanol (Merck), acetonitrile (Merck).

[0661] 2.2 Drug preparation: The compounds of the present application were prepared into 10 mM stock solution with DMSO (or other suitable solution) and stored in the refrigerator at -20°C for use. The control compound: 7-Hydroxycoumarin was prepared into 10 mM stock solution for use.

[0662] 2.3 Experimental steps

[0663] 1) Preparation of buffer solution: Take 4.01 mL of 1M K2HPO4·3H2O (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dissolve in ultrapure water and dilute to 50 mL to prepare a 100 mM phosphate buffer solution.

[0664] 2) Preparation of compound working solution

[0665] Preparation of compound working solution: Add 2 μL of compound stock solution to 998 μL of phosphate buffer solution to make a final concentration of 20 μM. Depending on the properties of the compound, the preparation ratio can be adjusted appropriately to adjust the final concentration.

[0666] Preparation of control compound working solution: The same as the preparation of the compound.

[0667] 3) Preparation of liver microsomal working solution: 156.3 μL of 20 mg / mL microsomes is diluted to 5 mL with 100 mM phosphate buffer, mixed well, and the final concentration is 0.625 mg / mL.

[0668] 4) Preparation of NADPH and UDPGA: Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add to 2 mL of 100 mM phosphate buffer, and the final concentration is 20 mM.

[0669] 5) Preparation of puncher (Alamethicin): Weigh 1 mg of Alamethicin and add to 200 μL of methanol to prepare a 5 mg / mL solution. Then take 10 μL from the solution and add to 990 μL of phosphate buffer (pH 7.4) to make a final concentration of 50 μg / mL.

[0670] 6) Preparation of reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution, and store it in a 2-8°C refrigerator.

[0671] [According to Rule 91 correction 14.10.2025] 7) Incubation procedure: In a 96-well plate, add 400 μL of prepared liver microsomes, 25 μL of compound working solution (10 μM), and 25 μL of Alamethicin (50 μg / mL) in sequence, and pre-incubate at 37°C for 10 min. Then add 50 μL of prepared NADPH / UDPGA to start the reaction, and incubate at 37°C. The total volume of the reaction system is 500 μL, and the final concentrations of each component are as follows:

[0672] Take 50 μL at time points of 0, 5, 15, 30, 60 and 120 min, add 200 μL of cold termination solution containing internal standard to terminate the sample reaction, centrifuge at 3500 rpm for 10 min, and take the supernatant for LC-MS / MS analysis.

[0673] 2.4 Chromatographic analysis

[0674] 1) Chromatographic conditions

[0675] Instrument: Shimadzu LC-30AD; Column: C18 (50*4.6 mm, 5 μm particle size);

[0676] Mobile phase: A: 0.1% formic acid in water, B: methanol;

[0677] Wash gradient: 0.2-1.6 min 10% A to 95% A, 3.0-3.1 min 95% A to 10% A;

[0678] Flow rate: 1.0 ml / min; Run time: 4.0 min; Injection volume: 5 μL.

[0679] 2) Mass spectrometric conditions

[0680] Instrument: API5500 Qtrap type liquid chromatograph-mass spectrometer, AB Sciex Corporation;

[0681] Ion source: Electrospray ionization source (ESI); Dry gas: N2, temperature 500 °C;

[0682] Electrospray voltage: 5000 V; Detection mode: Positive ion detection;

[0683] Scan mode: Reaction monitoring (MRM) mode;

[0684] 3. Experimental results and data processing

[0685] The raw data was calculated according to the following formula:

[0686] Remaining rate % = peak area ratio of compound to internal standard at any time point / peak area ratio of compound to internal standard at 0 min x 100

[0687] T 1 / 2 = 0.693 / Ke, wherein Ke represents the elimination rate constant.

[0688] The in vitro liver microsomal intrinsic clearance (CL int ) and the liver intrinsic clearance (CL int,liver ) were calculated by Ke

[0689] CL int = 0.693 / T 1 / 2 / microsomal protein content (microsomal concentration mg / mL at incubation)

[0690] CL int,liver = CL intX amount of microsomal protein in liver (mg / g) X liver weight / body weight ratio

[0691] According to the well-stirred model, the in vivo liver clearance (CL int,liver )

[0692] CL = (CL int,liver X fu X Qh) / (CL int,liver X fu + Qh), wherein fu represents the free fraction in blood, and defaults to 1.

[0693] The parameters in the formula are shown in the following table.

[0694] The test results are as follows:

[0695] Experimental conclusion: The compound has good metabolic stability.

[0696] Seven, in vivo pharmacodynamic study of the compound in a rat arthritis model (CIA)

[0697] 1. Test purpose: The prepared pharmaceutical preparation is given to the animal model to treat the rat arthritis model, and the efficacy of the drug is evaluated.

[0698] 2. Test method: 6-8 week SPF female Lewis rats were used, and 8 of them were randomly selected as the normal control group, and the rest were subjected to collagen arthritis model modeling.

[0699] The acetic acid solution of bovine type II collagen was completely mixed with an equal volume of Freund's incomplete adjuvant and emulsified. The emulsion was taken 0.25 mL per animal for intradermal injection at three points on the back and tail root (two points on the back and one point on the tail root) for primary immunization (d0), and the same method was used for booster immunization on the 7th day after immunization.

[0700] The four limb arthritis scores were performed three times a week, and the highest score for each rat was 16. The volume of the hind paw was determined by the drainage method.

[0701] On the 7th day after immunization, the animals were randomly divided into solvent and treatment groups according to body weight and foot volume, with 8 animals in each group. The normal group animals were not treated; the solvent group was given solvent (0.5% CMC-Na / 1% Tween 80) 5 mL / kg by gavage; the drug group was given different doses (1 mg / kg, 3 mg / kg, 10 mg / kg) of the test substance by gavage, twice a day.

[0702] 3. Test results and conclusions: From the experimental results, it can be seen that the compound of the embodiment can effectively improve the symptoms of arthritis, and the animal tolerance is good at the treatment dose. In this model, the compound of the embodiment has a significant reduction in inhibiting clinical scores and foot volume at different doses, and even some embodiments have a dose-dependent correlation.

[0703] Eight, the inhibition effect of the compound of the application on alpha1A receptor is detected

[0704] 1. Experimental purpose: To detect the inhibitory effect of the compound on alpha1A receptor.

[0705] 2. Reagents: Cell line: CHO cell line stably expressing alpha1A receptor

[0706] PBS (Gibco, 10010023); DMSO (Sigma: D2650); cell culture plate (Corning: 3764);

[0707] 3. Experimental method:

[0708] 1) Digest and collect alpha1A-CHO cells, count and inoculate in 384-well cell plates (1.0x10 / 25μL / well) (Corning, 3764). Place the cell plate in a 5% CO2 incubator at 37°C for 16-20h.

[0709] 2) Prepare Assay Buffer according to the instructions of FLIPR Calcium 6 Assay Kit, and dilute Component A to 2xloading buffer with Assay Buffer for use;

[0710] 3) Remove the culture medium in the 384-well plate by decanting and centrifuging, and add 17.5μL Assay Buffer in the inhibition mode.

[0711] 4) Add 17.5μL / well of 2xloading buffer prepared in step 2) to the corresponding experimental wells, centrifuge and incubate at 37°C in the dark for 2 hours.

[0712] 5) Use Apricot instrument (SPT Labtech, S2-Pipette-384) to gradient dilute positive compounds and test compounds.

[0713] 6) Then use ECHO instrument (LABCYTE, 655) to dispense the compounds into 384 source plate 1 (600nL / well or 200nL / well), and then add 20μL Assay Buffer per well.

[0714] 7) Prepare 5x agonist intermediate solution (Epinephrine, final concentration 20nM) and transfer 20μL / well to the corresponding 384 source plate 2.

[0715] 8) After the end of dye incubation, add the test compound prepared in step 6 to the experimental wells (5μL / well) using the FLIPR instrument (Molecular Devices, 5) and incubate for 30 minutes.

[0716] 9) After the end of compound incubation, add the agonist intermediate solution prepared in step 7 to the experimental wells (10μL / well) and read the fluorescence signal values (excitation 470-515nm, emission 515-575nm) for 5 minutes.

[0717] 4. Experimental data processing method: use XLfit four-parameter log (inhibitor) vs. response - Variable slope (four parameters) to nonlinearly fit the compound concentration and the corresponding inhibition rate and calculate IC 50 .

[0718] 5. Experimental results and conclusions:

[0719] Conclusion: The compound of the present application has substantially no inhibitory effect on alpha1A receptor and has good safety.

Claims

A compound as shown in general formula (I-D), (I-E) or (I-F), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein M1is selected from N or CH; L is selected from the group consisting of a bond or L is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1- alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 aryl and 5-10 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1- alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6- 10 one or more of aryl and 5-10 membered heteroaryl; ring A is present or absent, and if present is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; preferably, ring A is selected from C 3-8 cycloalkyl; B is present or absent, and if present is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; R1is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =CR' 1-1 R' 1- 2, =N-R' 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 amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1- 6haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl are optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R' 1-1 and R' 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; R' 1-3 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1- alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3-12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkyl, C 3- 12 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C R2is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; R3is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6deuteroalkenyl, C2-C6hydroxyalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C2-C6deuteroalkynyl, C2-C6hydroxyalkynyl, C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl; 1-6 C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 2-6 C2-C6alkenyl, C2-C6haloalkenyl, C2-C6deuteroalkenyl, C2-C6hydroxyalkenyl, 2-6 C2-C6alkynyl, C2-C6haloalkynyl, C2-C6deuteroalkynyl, C2-C6hydroxyalkynyl, 1-6 C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 1-6 C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 1-6 C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6haloalkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, 3-8 C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl; 6-10 C6-C10aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 1-6 C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 2-6 C2-C6alkenyl, C2-C6haloalkenyl, C2-C6deuteroalkenyl, C2-C6hydroxyalkenyl, 2-6 C2-C6alkynyl, C2-C6haloalkynyl, C2-C6deuteroalkynyl, C2-C6hydroxyalkynyl, 1-6 C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 1-6 C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 1-6 C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6haloalkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, 3-8 C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl; 6-10 C6-C10aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 1- C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 2-6 C2-C6alkenyl, C2-C6haloalkenyl, C2-C6deuteroalkenyl, C2-C6hydroxyalkenyl, 2-6 C2-C6alkynyl, C2-C6haloalkynyl, C2-C6deuteroalkynyl, C2-C6hydroxyalkynyl, 1-6 C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 1-6 C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 1-6 C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6deuteroalkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6haloalkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkoxy, 1-6 C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, 3-8 C3-C6cycloalkyl, 3- to 8-membered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl; 6-10 C6-C10aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, 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 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl; R5is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1- alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 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; R8 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 9-1 and R 9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 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 or -(CH2) m10 R a10 , said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl; or, R4and R 9-1 connected to form a 5-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein said 5-8 membered heterocyclyl or 5-6 membered heteroaryl optionally can be further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; 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 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, which amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, can be optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; x is 1, 2, 3, 4 or 5; y is 0, 1 or 2; z is 0, 1, 2 or 3; u is 0, 1, 2, 3 or 4; w is 0, 1, 2, 3 or 4; a is 1, 2 or 3; 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 independently selected from 0, 1, 2 or 3. The compound as claimed in claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are as shown in general formula (I-D-1), (I-E-1), (I-F-1) or (I-F-2) wherein L2is selected from -(CH2) m14 , -0(CH2) m15 , or -NH(CH2) m16 wherein when m14is 0, -(CH2) m14 is a bond; R 6-3 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, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; Ring B, Ring C", M1, R2, R3, R4, R5, R6, R a14 R a15 The definitions of y, z, u, w, m14, m15 and m16 are as described in claim 1. The compound as claimed in claim 1 or 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are represented by general formula (I-D-1-1), (I-E-1-1) or (I-F-1-1) wherein is a single bond or a double bond; M2is CH, CH2, N, NH, O or S; M3is CH2, NH, O or S; v is 0, 1, 2 or 3; L2is selected from -(CH2) m14 , -0(CH2) m15 , or -NH(CH2) m16 wherein, when m14 is 0, -(CH2) m14 is a bond. The compound according to any one of claims 1 to 3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are represented by general formula (I-D-1-1-1), (I-E-1-1-1) or (I-F-1-1-1) or preferably, the compound is as depicted in general formula (I-D-1-1-2), (I-E-1-1-2), (I-F-1-1-2), (I-D-1-1-2-1), (I-D-1-1-2-2), (I-E-1-1-2-1), (I-E-1-1-2-2), (I-F-1-1-2-1), (I-F-1-1-2-2) wherein X4is selected from N or CR 2-1 ; X5is selected from N or CR 2-2 ; X6is selected from N or CR 2-3 ; X7is selected from N or CR 2- 4; R 2-1 , R 2-2 , R 2-3 , and R 2-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, which amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, can be optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; R 6-1 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, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 6-2 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, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 6-4 and R 6-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, can be optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; Ring C", M1, R2, R3, R4, R5, R a14 R a15 The definitions of y, z, w, m14, m15 and m16 are as described in claim 1. The compound as claimed in claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown as general formula (I-F-5) wherein X4is selected from N or CR 2-1 ; X5is selected from N or CR 2-2 ; X6is selected from N or CR 2-3 ; X7is selected from N or CR 2- 4; R 2-1 , R 2-2 , R 2-3 , and R 2-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, which amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, can be optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; the definitions of ring B, M1, R1, R3, R4, R5, R6, x, z, w and u are as described in claim 1. The compound as claimed in claim 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown as general formula (I-F-5-1) wherein, is a single bond or a double bond; M2is CH, CH2, N, NH, O or S; M3is CH2, NH, O or S; v is 0, 1, 2 or 3; R 6-3 selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, optionally can be further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl; Preferably, the compound is as shown in general formula (I-F-5-1-1) or (I-F-5-1-2) Among them, R 6-1 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, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 6-2 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, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R 6-4 and R 6-5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, can be optionally further substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl. the definitions of M1, R1, R3, R4, R5, R6, x, z, w and u are as described in claim 1; the definitions of X4, X5, X6and X7are as described in claim 5. The compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, R4is selected from methyl, ethyl, -CD3, -CH2CHF2, -CH2CH2F, The compound according to any one of claims 1 to 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, Ring C" is selected from phenyl, 5-6 membered heteroaryl, phenyl and 5-6 membered heterocyclyl, or 5-6 membered heteroaryl and 5-6 membered heterocyclyl, preferably, ring C" is selected from thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl, phenyl, More preferably, ring C" is selected from The compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, L2is selected from a bond, -(CH2), -O(CH2) or -NH(CH2); or R a14 and R a15 each independently C 1-6 alkyl, preferably methyl or ethyl; or ring A is selected from C 3-8 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; preferably ring A is selected from C 3- 8cycloalkyl, preferably C 3-6 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R 6-3 selected from C 1-3 alkyl, C 1-3 haloalkyl or deuterated C 1-3 haloalkyl; More preferably, R 6-3 selected from CH2F, CHF2, CF3, CDF2, or R 6-1 and R 6-2 each independently halogen; preferably F. The compound according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are shown below: A compound represented by formula (INT-1) or (INT-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof R int selected from halogen, boronic acid or boronic acid ester, preferably CI, Br, M1, ring B, R3, R4, R5, R6, u, w and z are as defined in claim 2; preferably the compound is selected from: A method for preparing a compound of formula (I-D-1), (I-E-1), (I-F-1) or (I-F-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: Method 1: reacting the compound represented by formula (INT) and formula (INT-3) to prepare the compound represented by formula (I-D-1); Method 2: reacting the compound represented by formula (INT) and formula (INT-1) to prepare the compound represented by formula (I-E-1); Method 3: reacting the compounds represented by formula (INT) and formula (INT-2) to prepare the compound represented by formula (I-F-1); Method 4: the compound shown as formula (INT) and formula (INT-4) are reacted to prepare the compound shown as formula (I-F-2); R int selected from halogen, boronic acid or boronic acid ester, preferably CI, Br, R int1 selected from halogen, boronic acid or boronic acid ester, preferably CI, Br, Preferably, the reaction is carried out in the presence of a base, which is an organic base or an inorganic base, and a catalyst, which is a palladium catalyst; M1, Ring C", Ring B, L2, M1, R1, R2, R3, R4, R5, R6, R 6-3 , R a14 , R a15 , x, y, z, u and w are as defined in claim 2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of a compound of any one of claims 1-10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for inhibiting TNFα. Use of a compound of any one of claims 1-10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for treating an autoimmune disease; wherein the autoimmune disease is preferably selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondylarthritis, 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 biliary cholangitis, autoimmune hepatitis, lupus nephritis, Goodpasture's syndrome, autoimmune oophoritis or autoimmune orchitis.

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