Pentacyclic derivative inhibitor, preparation method therefor and use thereof

Abstract

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

Description

Pentacyclic derivative inhibitors, methods of making and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024104680239, filed on April 17, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to a pentacyclic derivative inhibitor, a method for preparing the same and uses thereof. BACKGROUND

[0003] TNFα 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. TNFα is expressed as a membrane-bound precursor (mTNF), which requires cleavage by TNFα converting enzyme to be released as a soluble cytokine (sTNF). mTNFα and sTNFα 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).

[0004] 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-κB (NF-κB) and mitogen-activated protein kinase (MAP kinase) pathways to transmit proinflammatory signals. In contrast, TNFR2 signals through a non-canonical NF-κB 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.

[0005] TNFα is associated with the development of chronic inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis and 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 drug treatment for RA is 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 biologics. Disease modification aims to improve patients' disease signs and symptoms and restore physical function by inhibiting the progression of cartilage and bone structure damage.

[0006] TNF-α inhibitors such as infliximab, adalimumab, etanercept, golimumab and pexidartinib, etc. have ushered in a new era of rheumatological immunotherapy and have become one of the most powerful weapons for the treatment of rheumatological diseases, which are unanimously recommended by domestic and international authoritative guidelines. Anti-TNF-α biologics have been successfully used in the clinical treatment of RA, JIA, PsA, ankylosing spondylitis, psoriasis and IBD, especially Crohn's disease (CD) and ulcerative colitis (UC). Anti-TNF-α biologics have completely changed the treatment of RA, although great success has been achieved, but the disease remission rate of 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 biologics 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 biologics and the need for intravenous injection have created a huge obstacle to their widespread use in clinical practice.

[0007] So far, there is no TNFα small molecule inhibitor on the market, so there is a high clinical demand 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.

[0008] TNFα small molecule inhibitors have been patented, such as: WO2016050975A1, WO2018167176, WO2018197503, WO2020084008 (Sanofi), the most advanced of which, SAR-441566, is in clinical phase I, and the others are in preclinical development stage. The present application needs to develop orally available TNFα small molecule inhibitors. SUMMARY

[0009] The present application provides a compound as shown in general formula (I-A), general formula (I-A-1) or general formula (I-A-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0010] wherein,

[0011] M1 is selected from N or CH;

[0012] 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 1-6 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 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- haloalkoxy, C 1-6 hydroxyalkyl, C 3-8cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl;

[0013] ring A is present or absent, and when 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;

[0014] 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;

[0015] 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- 6deuteroalkoxy, 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 or -(CH2) m10 R a10 , said amino, C 1-6 alkyl, 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 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- 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 and 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, 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- 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 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, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0016] R 1-1 and R 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0017] R 1-3halogen, amino, hydroxyl, cyano, nitro, 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 haloalkoxy, C 1-6 hydroxyalkyl, 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- alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, 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, 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, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from deutero, halogen, amino, hydroxyl, cyano, nitro, C

[0018] R2is independently selected from hydrogen, deutero, 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- 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 2-6 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- 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;

[0019] R'2is 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- 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, 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;

[0020] Preferably, R’2is 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, 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, 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- 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

[0021] 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- 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- 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, 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;

[0022] 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- 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, 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 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

[0023] 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- 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- 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, C1-6 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

[0024] 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- 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 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- 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

[0025] 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 1-6alkoxy, C 1- 6deuterated alkyl, 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, said amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3- 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 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 1-6 haloalkyl, 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

[0026] 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 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkyl, 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, said amino, C m1 OR a1 , -(CH2) m2 C(O)R a2 , -(CH2) m3 NHC(O)Ra3 -(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 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;

[0027] or, R4and R 9-1 join 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 1-6deuteroalkoxy, 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 and independently substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0028] 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- cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, said amino, C 1-6 alkyl, C 2- 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;

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

[0030] y is 0, 1, or 2;

[0031] z is 0, 1, 2, or 3;

[0032] u is 0, 1, 2, 3, or 4;

[0033] w is 0, 1, 2, 3, or 4;

[0034] a is 1, 2, or 3;

[0035] 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;

[0036] m7and m7' are each independently selected from 0, 1, 2, or 3.

[0037] In certain embodiments of the application, said ring B is selected from C 3-6 cycloalkyl or 5-6 membered heterocyclyl, preferably more preferably

[0038] The present application provides a compound as shown in formula (II-2) or formula (II-2-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0039] wherein:

[0040] R 1-1 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, C1-6 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

[0041] R 1-2 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, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C1-6 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 is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0042] 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 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, C1-6 haloalkyl, 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;

[0043] 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;

[0044] 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 1-6deuteroalkyl, 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;

[0045] 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- 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, said amino, C 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 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] R’2is 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- deuteroalkoxy, C 1-6 haloalkoxy, C 1-6hydroxyalkyl, 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;

[0047] R3is independently 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0048] R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0049] R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 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, 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- 8cycloalkyl, 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

[0050] 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 2-6alkynyl, 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- 8cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, said amino, 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 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;

[0051] y is 0, 1 or 2;

[0052] z is 0, 1, 2 or 3;

[0053] w is 0, 1, 2, 3 or 4;

[0054] 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;

[0055] m7 and m7' are each independently selected from 0, 1, 2 or 3.

[0056] The present application also relates to a compound as illustrated in general formula (I-D), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0057] wherein,

[0058] M1is selected from N or CH;

[0059] 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 1-6 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 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- 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;

[0060] 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;

[0061] ring 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;

[0062] Cycloalkyl, 3-10 membered heterocyclyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0063] 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- 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 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 6-10The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, one or more substitutions; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0064] R 1-1 and R 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0065] 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with deuterium, halo, 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- alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally substituted with deuterium, halo, 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, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 one or more substituents on aryl and 5-14 membered heteroaryl;

[0066] R2is independently selected from hydrogen, deuterium, halo, 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- 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 haloalkyl, C 1-6 hydroxyalkyl, C 3- 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

[0067] 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- 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- 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, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0068] R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0069] R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8cycloalkyl, 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

[0070] 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- 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- 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

[0071] 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- deuteroalkoxy, C1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl;

[0072] 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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) m4C(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 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;

[0073] or, R4and R 9-1 are joined 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, C1-6 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

[0074] R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , 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, 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- 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

[0075] x is 1, 2, 3, 4, or 5;

[0076] y is 0, 1, or 2;

[0077] z is 0, 1, 2, or 3;

[0078] u is 0, 1, 2, 3, or 4;

[0079] w is 0, 1, 2, 3, or 4;

[0080] a is 1, 2, or 3;

[0081] m1, m2, m3, m4, m5, m6, m8, m9 and m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0082] m7 is independently selected from 0, 1, 2 or 3. In certain embodiments of the present invention, each R1 is independently selected from H, D, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, vinyl, 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,

[0083] In certain embodiments of the present invention, R 1-1 and R 1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, the amino, 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, 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 aryl and 5-6 membered heteroaryl, one or more of which is substituted; preferably, R 1-1 and R 1-2 are each independently selected from hydrogen or fluorine. In certain embodiments of the application, R 1-1 and R 1-2 are each independently selected from: hydrogen, fluorine, methyl or ethyl.

[0084] In certain embodiments of the application, R 1-3 is independently selected from: amino, hydroxyl, cyano or C 1-6 alkyl.

[0085] 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 6-10 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, 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 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- 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;

[0086] Preferably, R2is selected from hydrogen.

[0087] 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- 3haloalkyl, 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, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10The aryl or 5-6 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl;

[0088] 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 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 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 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6- 10 Aryl, 5-6 membered heteroaryl may be further substituted with hydrogen, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl, C 2- 4-alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C6-10 one or more of the aryl, 5-6 membered heteroaryl groups is optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0089] 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 or 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 1-3 alkoxy, C 1- deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 one or more of the aryl, 5-6 membered heteroaryl groups is optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C

[0090] In certain embodiments of the application, R4is selected from methyl, ethyl, -CD3, -CH2CHF2, -CH2CH2F, In certain embodiments of the application, R4is selected from COCH3.

[0091] 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 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- 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; preferably, R6is independently selected from hydrogen or fluorine. 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 In certain embodiments of the application, is selected from In certain embodiments of the application, ring C" is selected from 6 membered heteroaryl, preferably pyrimidinyl or pyridinyl, preferably

[0092] The present application further relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0093] In certain embodiments of the present application, the compound, a stereoisomer thereof, or a 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%, even more preferably 10% to 50%, even more preferably 15-40%, even more preferably 20-30%, even more preferably 20-25% by weight based on the total weight of the pharmaceutical composition.

[0094] In certain embodiments of the present application, the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered in a dosage amount 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 therebetween).

[0095] The present application further relates to the use of the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for the preparation of a TNFα inhibitor medicament.

[0096] The present application further relates to the use of the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for the preparation of a medicament for the treatment of 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, spondyloarthritides, 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.

[0097] The present application further relates to a method for the prophylaxis and / or treatment of an autoimmune disease, comprising administering to a patient a therapeutically effective amount of the compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0098] In certain embodiments of the application, the 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.

[0099] Detailed description of the application

[0100] Unless otherwise indicated, all technical and scientific terms have the same meaning as those one of ordinary skill in the art would attribute to such terms, specifically, the terms used in the specification and claims have their normal meaning to one of ordinary skill in the art.

[0101] The term "alkyl" refers to straight- or branched-chain saturated aliphatic hydrocarbon groups, which alkyl groups can optionally be substituted with one or more substituents. In particular embodiments, alkyl refers to linear saturated hydrocarbon groups having 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 branched saturated hydrocarbon groups having 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. As used herein, linear C 1-6 alkyl groups and branched C 3-6 alkyl groups are also referred to as "lower alkyl." For example, C 1-6 alkyl refers to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C 1-6Alkyl groups contain 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-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 chain isomers thereof, etc. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0102] The term "alkylene" refers to an alkyl group with one hydrogen atom 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 as described elsewhere herein.

[0103] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be located at any position within the alkenyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkenyl group is an unsaturated aliphatic hydrocarbon group having 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 straight-chain unsaturated hydrocarbon group having 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. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkenyl groups include: One of ordinary skill in the art will appreciate that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl described elsewhere herein.

[0104] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which may be located at any position within the alkynyl group, and which may be optionally substituted with one or more substituents. In a particular embodiment, the alkynyl group is a 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 straight-chain unsaturated hydrocarbon group having 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 Unless otherwise indicated, the term "alkynyl" as used herein includes both straight-chain and branched 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 unsaturated hydrocarbon group having 3 to 6 carbon atoms. 2-6 Alkynyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of alkynyl groups include: In one embodiment, the alkynyl is an optionally substituted alkynyl group described elsewhere herein.

[0105] The term "cycloalkyl" refers to saturated or partially unsaturated aliphatic monocyclic, polycyclic (two and 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, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups, in one embodiment. In one embodiment, the cycloalkyl 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, and the like.

[0106] 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 of the rings. 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. Spirocycloalkyl groups are classified as mono-, bi-, or polycycloalkyl groups, in one embodiment as mono- and bi- spirocycloalkyl groups, depending on the number of spiro atoms shared between rings of the system. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include:

[0107] The term "fused cycloalkyl" refers to all-carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but does not have a fully conjugated pi-electron system in any of the rings. In particular embodiments, the fused cycloalkyl group comprises 5 to 20 (C 5-20 ), 6 to 14 (C6-14 ) or 7 to 10 (C 7-10 ) carbon atoms. Depending on the number of rings comprising the bridge, the bridge can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged alkyl, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl is an optionally substituted bridged alkyl as described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0108] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system 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, the bridged cycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms. Depending on the number of rings comprising the bridge, the bridge can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged alkyl, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl is an optionally substituted bridged alkyl as described elsewhere herein. Non-limiting examples of bridged alkyl groups include:

[0109] 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.

[0110] 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:

[0111] 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:

[0112] 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:

[0113] 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 and which can be optionally substituted. 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),

[0114] The term "arylene" refers to a divalent aryl radical formed by the further substitution of one hydrogen atom of aryl, wherein arylene is optionally substituted or unsubstituted, and aryl is as defined above.

[0115] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring, wherein the aromatic ring has one or more heteroatoms independently selected from O, S and N. In particular embodiments, the heteroaryl group contains 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 contains 5 or 6 ring atoms; in particular embodiments, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N. In one embodiment, the heteroaryl group is selected from a heteroaryl group with 6-10 members, a heteroaryl group with 3-10 members, or a heteroaryl group with 3-10 members, and a heterocyclyl group with 3-10 members. In another embodiment, the heteroaryl group is selected from a 5- or 6-membered heteroaryl group with 6-10 members, a 5- or 6-membered heteroaryl group with 3-6 members, and a 5- or 6-membered heterocyclyl group, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothienyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, thienopyridinyl, acridinyl, benzindolyl, carbazolyl, bibenzofuranyl, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,

[0116] The term "heteroarylene" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.

[0117] 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.

[0118] 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.

[0119] The term "alkylacyl" refers to -C(O)-alkyl, wherein alkyl is as previously described.

[0120] 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,

[0121] The term "haloalkoxy" refers to an alkoxy group as previously described substituted by one or more halogens.

[0122] The term "hydroxyalkyl" refers to an alkyl group as previously described substituted by a hydroxyl group.

[0123] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above. 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 described elsewhere herein.

[0124] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogen groups, wherein alkylthio is as defined above.

[0125] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl. In one embodiment, the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.

[0126] The term "aminocarbonyl" refers to NH2-C(O)-.

[0127] The term "alkylaminocarbonyl" refers to an aminocarbonyl (NH2-C(O)-) group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0128] The term "alkylamino" refers to an amino group in which one or both of the hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.

[0129] The term "carbonyl" refers to a -C(O)-, -(CO)-, or -C(=O)- group. All notations are used interchangeably in the specification.

[0130] The term "hydroxy" refers to an -OH group.

[0131] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0132] The term "amino" refers to -NH2.

[0133] The term "cyano" refers to -CN.

[0134] The term "oxo" or "oxo" refers to =0.

[0135] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In a particular embodiment, one or more positions occupied by hydrogen in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.

[0136] 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.

[0137] 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.

[0138] "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.

[0139] 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.

[0140] "Substituted" means that any one or more hydrogen atoms on a particular atom is / are replaced with a substituent, provided that the valency of the particular atom is not exceeded, and that the resulting compound is stable. In one embodiment, when the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that the group can or can not be substituted, and that the nature and number of substituents, if present, can be any that are chemically possible, unless otherwise specified. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be substituted, as can be determined (experimentally or theoretically) by one of skill in the art 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.

[0141] The indefinite articles "a" and "an," as well as the definite article "the," preceding singular nouns, are inclusive of both the singular and plural, unless otherwise indicated by the context.

[0142] "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 goal of a pharmaceutical composition is to facilitate administration of an active ingredient to a biological entity for the practical and efficient exertion of biological activity.

[0143] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in mammals and possess the desirable biological activity.

[0144] "Stereoisomer" encompasses all enantiomeric / diastereomeric / stereomerically pure and enantiomeric / diastereomeric / stereomerically enriched compounds of the present application.

[0145] "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.

[0146] "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.

[0147] "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.

[0148] "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.

[0149] 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(s). 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

[0150] The application is further described in connection with the following examples, which are not intended to limit the scope of the application.

[0151] Examples

[0152] The structures 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.

[0153] 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).

[0154] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, TLC uses a specification of 0.15mm-0.20mm, thin layer chromatography separation and purification product uses a specification of 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0155] 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.

[0156] Unless otherwise specified, all reactions of the present application are carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature unit is in degrees Celsius.

[0157] Intermediate 1

[0158] First step: preparation of (1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1- methylcyclobutane-1-carbonitrile

[0159] Under a dry ice-acetone bath, 5-bromo-2-iodopyrimidine (18 g, 63.23 mmol) was dissolved in DCM (200 mL), and then n-butyllithium (25.3 mL, 63.23 mmol, 2.5 mol / L in Hexanes) was added dropwise, and the reaction was stirred for 1 hour, and then a solution of 1-methyl-3-oxocyclobutane-1-carbonitrile (6 g, 54.98 mmol) in DCM (30 mL) was added dropwise, and the reaction was continued to stir for 1 hour. After the reaction was completed, the reaction solution was extracted with DCM (150 mL x 3), washed with saturated aqueous sodium chloride solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography and chiral column resolution to obtain the title compound (1.5 g, 10.2%).

[0160] MS m / z (ESI): 268.1 [M+H] + .

[0161] Reference Example 1

[0162] First step: preparation of 5-bromo-2,2-difluorobenzo[d][1,3]dioxole-4-carbaldehyde

[0163] Dissolve 5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-ylmethanol (9.2 g, 34.7 mmol) and (S)-tert-butylsulfinamide (5.05 g, 41.7 mmol) in THF (100 mL), add tetraethyl orthotitanate (11.88 g, 52.1 mmol) dropwise 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 (200 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and 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] + .

[0164] Second Step: Preparation of (S,E)-N-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4- yl)methylene)-2-methylpropane-2-sulfmamide

[0165] Dissolve 5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-ylmethanol (9.2 g, 34.7 mmol) and (S)-tert-butylsulfinamide (5.05 g, 41.7 mmol) in THF (100 mL), add tetraethyl orthotitanate (11.88 g, 52.1 mmol) dropwise 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 (200 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and 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] + .

[0166] Third Step: Preparation of N-((R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4- yl)but-3-en-l-yl)-2-methylpropane-2-sulfmamide

[0167] (S,E)-N-((5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)methylene)-2- methylpropane-2-sulfmamide (10 g, 27.2 mmol) was dissolved in dry DCM (200 mL) under ice water bath, propenyl magnesium bromide (40.7 mL, 40.7 mmol, 1 mol / L in Et20) was added dropwise and the reaction was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, the reaction was extracted with DCM (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, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (8.3 g, 74.5%). MS m / z (ESI): 410.1 [M+H] + .

[0168] Fourth Step: Preparation of (R)-l-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4- yl)but-3-en-l-amine

[0169] 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 hydrochloric acid in dioxane solution (50 mL, 4.0 N) and the reaction was stirred for 1 hour. The reaction was concentrated and extracted with EtOAc (150 mL x 3), washed with saturated aqueous sodium bicarbonate solution (200 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, concentrated, and dried to give the title compound (5.5 g, 88.8%). MS m / z (ESI): 306.1 [M+H] + .

[0170] 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

[0171] (R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)but-3-en-1-amine (5.5 g, 18 mmol), 4-chloro-2-fluoro-1-nitrobenzene (3.78 g, 21.6 mmol) and potassium carbonate (9.93 g, 71.9 mmol) were suspended in a solution of DMF (100 mL), heated to 80 °C and stirred for 16 h. The reaction was allowed to cool to room temperature, extracted with EtOAc (150 mL x 3), washed with saturated aqueous sodium chloride (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography on silica gel to give the title compound (5 g, 60.3%). MS m / z (ESI): 461.1 [M+H] + .

[0172] Step 6: Preparation of (R)-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-3-((5- chloro-2-nitrophenyl)amino)propanal

[0173] (R)-N-(1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)but-3-en-1-yl)-5-chloro-2- nitroaniline (5 g, 10.8 mmol) was dissolved in a mixture of THF (150 mL) and water (150 mL), stirred for 1 h after addition of potassium osmate dihydrate (169 mg, 0.54 mmol) and stirred for another 16 h after addition of sodium metaperiodate (7 g, 32.5 mmol). The reaction was extracted with EtOAc (150 mL x 3), washed with saturated aqueous sodium chloride (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by column chromatography on silica gel to give the title compound (4.5 g, 89.6%). MS m / z (ESI): 463.1 [M+H] + .

[0174] Step 7: Preparation of (4R)-4-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-4-((5-chloro-2- nitrophenyl)amino)-2-((trimethylsilyl)oxy)butanenitrile

[0175] (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) solution, the reaction was stirred at room temperature for 2 hours. The reaction was completed, the reaction liquid 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, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (5 g, 91.5%). MS m / z (ESI): 562.1 [M+H] + .

[0176] Eighth step: 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

[0177] (4R)-4-(5-bromo-2,2-difluorobenzo[d][l,3]dioxol-4-yl)-4-((5-chloro-2- nitrophenyl)amino)-2-((trimethylsilyl)oxy)butanenitrile (5 g, 8.9 mmol) and stannous chloride (8.4 g, 44.4 mmol) were dissolved in ethanol (100 mL) solution, the reaction was stirred at 80 °C for 16 hours. After returning to room temperature, the pH of the reaction liquid was adjusted to 8 using aqueous potassium hydroxide solution (1 mol / L), the reaction liquid 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, concentrated, and the residue was separated by chiral separation column to obtain the title compound (650 mg, 16.5%). MS m / z (ESI): 443.1 [M+H] + .

[0178] Ninth step: preparation of (lR,3R)-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-amine

[0179] Dissolve (1R,3S)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-7-chloro-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-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) in toluene (10 mL) and heat to 60 °C for 16 h. Cool the reaction to room temperature and extract with EtOAc (15 mL x 3). Dry the organic phase over anhydrous sodium sulfate, filter and concentrate. Dissolve the residue in a mixture of THF (10 mL) and water (10 mL) and heat to 60 °C for 1 h. Cool the reaction to room temperature and extract with EtOAc (15 mL x 3). Wash the organic phase with saturated aqueous sodium chloride (20 mL x 3), dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to give the title compound (477 mg, 74.2%). MS m / z (ESI): 442.1 [M+H] + .

[0180] Step 10: Preparation of (8R,15R)-12-chloro-2,2-difluoro-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

[0181] Dissolve (1R,3R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxol-4-yl)-7-chloro-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-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) in anhydrous DMF (10 mL) and heat to 130 °C for 16 h. Cool the reaction to room temperature and extract with EtOAc (30 mL x 3). Wash the organic phase with saturated aqueous sodium chloride (20 mL x 3), dry over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography to give the title compound (200 mg, 47.6%). MS m / z (ESI): 390.1 [M+H] + .

[0182] Tenth Step: Preparation of (8R, 15R)-12-chloro-2,2-difluoro-7-methyl-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

[0183] (8R, 15R)-12-chloro-2,2-difluoro-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 (100 mg, 0.26 mmol) was dissolved in dry THF (10 mL) under ice water bath, sodium hydride (21 mg, 0.52 mmol) was added and the reaction was stirred for 1 h, iodomethane (55 mg, 0.38 mmol) was added and the reaction was stirred for another 1 h. The reaction was extracted with EtOAc (15 mL x 3), washed with saturated aqueous sodium chloride solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (87 mg, 84%).

[0184] MS m / z (ESI): 404.1 [M+H] + .

[0185] Twelfth Step: Preparation of N-(l-(5-((8R, 15R)-2,2-difluoro-7-methyl-6-oxo-6,7,8, 15-tetrahydro-8, 15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfmamide

[0186] (8R,15R)-12-chloro-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4′,5′:3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one (87 mg, 0.22 mmol), (2-(1-((tert-butylsulfonamido)cyclobutyl)pyrimidin-5-yl)boronic acid (70 mg, 0.24 mmol) were added. mol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (18.5 mg, 0.02 mmol), and potassium carbonate (60 mg, 0.44 mmol) were suspended in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL) and reacted in a microwave oven at 110°C for 1 hour. The reaction solution was returned to room temperature, extracted with EtOAc (30 mL x 3), and washed with saturated sodium chloride aqueous solution (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (100 mg, 74.8%).

[0187] MS m / z(ESI):621.1[M+H] + .

[0188] Step 13: Preparation of (8R,15R)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4′,5′:3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one

[0189] N-(1-(5-((8R,15R)-2,2-difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4′,5′:3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfenamide (100 mg, 0.16 mmol) was dissolved in dioxane hydrochloride (5 mL, 4N) and stirred for 1 hour. The reaction solution was concentrated and purified by prep-HPLC to obtain the title compound (59.5 mg, 71.5%). MS m / z (ESI): 517.1 [M+H] + .

[0190] 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.32 - 8.24 (m, 2H), 7.82 - 7.71 (m, 2H), 7.64 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.14 (d, J = 6.4 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.53 (s, 2H), 3.38 (s, 3H), 2.96 (d, J = 13.6 Hz, 1H), 2.65 (ddd, J = 11.2, 9.0, 5.5 Hz, 2H), 2.21 (td, J = 10.4, 7.6 Hz, 2H), 2.09 - 1.82 (m, 2H).

[0191] Reference Example 2

[0192] First Step: Preparation of (8R, 15R)-12-chloro-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

[0193] (8R, 15R)-12-chloro-2,2-difluoro-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 (100 mg, 0.26 mmol) was dissolved in THF (10 mL) under ice water bath, sodium hydride (21 mg, 0.52 mmol, 60% purity) was added and stirred for 1 hour, iodomethane (55 mg, 0.38 mmol) was added and stirred for another 1 hour. The reaction was extracted with EtOAc (15 mL x 3), washed with saturated aqueous sodium chloride solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (90 mg, 86%).

[0194] MS m / z (ESI): 407.1 [M+H] + .

[0195] Second Step: Preparation 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[l,3]dioxolo[4',5':3,4]benzo[l,2- f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-6(15H)-one

[0196] (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), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) acetate (13 mg, 0.015 mmol) and potassium acetate (44 mg, 0.45 mmol) were suspended in 1,4-dioxane (10 mL) and reacted at 125 °C for 2 h in a microwave. The reaction was allowed to cool to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated aqueous sodium chloride (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography to give the title compound (72 mg, 98%). MS m / z (ESI): 499.1 [M+H] + .

[0197] Step 3: Preparation of (1S,3S)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6- carbonyl-6,7,8,15-tetrahydro-8,15-methyleno[1,3]dioxolo[4',5':3,4]benzo[1,2- f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-12-yl)pyrimidin-2-yl)-3-hydroxy-1- methylcyclobutan-1 -carbonitrile

[0198] (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 (35 mg, 0.07 mmol), (1s,3s)-3-(5-bromopyrimidin-2-yl)-3- hydroxy-1-methylcyclobutane-1-carbonitrile (20.7 mg, 0.77 mmol, prepared according to WO2020084008), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) (6 mg, 0.007 mmol) and potassium carbonate (19.4 mg, 0.14 mmol) were suspended in a mixture of 1,4- dioxane (10 mL) and water (2 mL) and microwaved at 110 °C for 1 hour. The reaction was allowed to cool to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated aqueous sodium chloride (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and the residue was separated by prep-HPLC to give the title compound (12.9 mg, 32.7%). MS m / z (ESI): 560.1 [M+H] + .

[0199] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 8.29 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.21 - 6.11 (m, 2H), 5.33 (d, J = 7.2 Hz, 1H), 3.51 (dt, J = 14.0, 7.2 Hz, 1H), 2.99 - 2.86 (m, 3H), 2.76 (d, J = 12.8 Hz, 2H), 1.43 (s, 3H).

[0200] Reference Example 3

[0201] First Step: Preparation of (8R,15R)-2,2-difluoro-7-methyl-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

[0202] (8R,15R)-12-chloro-2,2-difluoro-7-methyl-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 (1 g, 2.48 mmol), bis(pinacolato)diboron (1.26 g, 4.96 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl) dichloropalladium (II) (213 mg, 0.24 mmol) and potassium acetate (486 mg, 4.96 mmol) were suspended in 1,4-dioxane (10 mL) and heated at 125 °C for 2 h in a microwave reactor. The reaction was allowed to cool to room temperature, diluted with EtOAc (30 mL x 3), washed with saturated aqueous sodium chloride solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (1.1 g, 89.7%). MS m / z (ESI): 496.1 [M+H] + .

[0203] Second Step: Preparation of N-((ls,3S)-l-(5-((8R,15R)-2,2-difluoro-7-methyl-6-oxo- 6,7,8,15-tetrahydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2- a][l,4]diazocin-12-yl)pyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2- sulfinamide

[0204] (8R, 15R)-2,2-difluoro-7-methyl-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 (200 mg, 0.4 mmol), N-((ls,3s)-l-(5-bromopyrimidin-2- yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfmamide (162 mg, 0.44 mmol), bis(tricyclohexylphosphine) palladium (II) (2'-methylamino-l,l'-biphenyl-2-yl) dichloride (34.7 mg, 0.04 mmol), and potassium carbonate (112 mg, 0.81 mmol) were suspended in a mixture of 1,4-dioxane (10 mL) and water (2 mL), and the reaction was stirred at 110 °C for 1 h in a microwave. The reaction was allowed to cool to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated aqueous sodium chloride (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (218 mg, 82.7%). MS m / z (ESI): 653.1 [M+H] + .

[0205] Step 3: Preparation of (8R, 15R)-12-(2-((ls,3S)-l-amino-3- (fluoromethyl)cyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-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

[0206] N-((ls,3S)-l-(5-((8R, 15R)-2,2-difluoro-7-methyl-6-oxo-6,7,8, 15-tetrahydro-8, 15- methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-12-yl)- pyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfmamide (218 mg, 0.33 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL, 4 N) and stirred for 1 h. The reaction was concentrated and the title compound was isolated by prep-HPLC (100 mg, 55%). MS m / z (ESI): 549.1 [M+H] + .

[0207] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 8.77 (s, 2H), 8.30 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.15 (d, J = 6.4 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 4.60 (d, J = 6.0 Hz, 1H), 4.48 (d, J = 6.0 Hz, 1H), 3.52 (d, J = 6.8 Hz, 1H), 3.38 (s, 3H), 2.96 (d, J = 13.6 Hz, 1H), 2.75-2.55 (m, 3H), 2.12-2.03 (m, 2H).

[0208] Example 1

[0209] First Step: Preparation of 3-((difluoromethoxy)methyl)-3-methylcyclobutane-1-one

[0210] Diisopropylamine (166.9 g, 1.65 mol) was dissolved in tetrahydrofuran (400 mL), n-butyllithium (604 mL, 2.5 M, 1.51 mol) was added at -78 °C with stirring, after stirring for 1 hour, 3-methylene cyclobutylcarbonitrile (128 g, 1.37 mol) was added at -78 °C, stirring for 1 hour at low temperature. Iodomethane (292 g, 2.06 mol) was added dropwise at the same temperature, stirring for 1 hour at -78 °C. The reaction solution was quenched with saturated ammonium chloride, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product as the title compound (147 g, 99%). MS m / z (ESI): 108.1 [M+H] + .

[0211] Second Step: Preparation of 1-methyl-3-methylene cyclobutane-1-carboxylic acid

[0212] 1-methyl-3-methylene cyclobutane-1-carbonitrile (245.4 g, 2.29 mol) was dissolved in water (500 mL), ethanol (500 mL), KOH (514 g, 9.16 mol) was added with stirring, the reaction solution was heated to 100 °C for 12 hours, the reaction solution was concentrated, the remaining aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate, the combined organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (155 g, 54%). MS m / z (ESI): 125.1 [M+H]- .

[0213] Step 3: Preparation of (1-methyl-3-methylene cyclobutyl)methanol

[0214] Dissolve 1-methyl-3-methylene cyclobutane-1-carboxylic acid (150 g, 1.19 mol) in tetrahydrofuran (200 mL), diethyl ether (1.2 L), add lithium aluminum hydride (68 g, 1.78 mol) at 0 °C with stirring, stir the reaction solution at 0 °C for 2 hours, add water (67 mL), 15% sodium hydroxide (67 mL), water (200 mL) dropwise to the reaction solution in sequence, filter, dry the filtrate over anhydrous sodium sulfate, filter, concentrate, and separate the title compound (19 g, 14%) by silica gel column chromatography. MS m / z (ESI): 113.1 [M+H] + .

[0215] Step 4: Preparation of 1-(methoxymethyl)-1-methyl-3-methylene cyclobutane

[0216] Dissolve (1-methyl-3-methylene cyclobutyl)methanol (13.7 g, 122 mmol) in tetrahydrofuran (130 mL), add sodium hydride (7.33 g, 183 mmol, 60%) at 0 °C with stirring, add iodomethane (35 g, 244 mmol) at 0 °C, stir the reaction solution at 0 °C for 2 hours, quench the reaction solution with saturated ammonium chloride, wash the organic phase with saturated aqueous sodium chloride, and directly use the organic phase in the next step reaction. MS m / z (ESI): 127.1 [M+H] + .

[0217] Step 5: Preparation of 3-(methoxymethyl)-3-methylcyclobutane-1-one

[0218] Dissolve 1-(methoxymethyl)-1-methyl-3-methylene cyclobutane (15 g, 122.3 mmol) in water (200 mL), tetrahydrofuran (200 mL), add potassium osmate (3.59 g, 12.2 mmol) with stirring, stir the reaction solution for 1 hour, add sodium periodate (78.5 g, 367 mmol) at 0 °C, stir the reaction solution at room temperature for 12 hours, dilute the reaction solution with diethyl ether, filter, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and directly use the solution of the title compound in the next step reaction. MS m / z (ESI): 129.1 [M+H] + .

[0219] Step 6: Preparation of N-(3-(methoxymethyl)-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide

[0220] Dissolve 3-(methoxymethyl)-3-methylcyclobutane-l-one (15.3 g, 119 mmol) in tetrahydrofuran (200 mL), add tert-butylsulfonamide (17.36 g, 143 mmol), tetraethyl orthotitanate (41 g, 179 mmol) with stirring, stir for 12 hours, dilute the reaction with ethyl acetate, quench with saturated aqueous sodium chloride, filter, separate the organic phase, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography to give the title compound (20 g, 72%). MS m / z (ESI): 232.1 [M+H] + .

[0221] Step 7: Preparation of N-((ls,3s)-l-(5-bromopyrimidin-2-yl)-3- (methoxymethyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfonamide

[0222] Dissolve N-(3-(methoxymethyl)-3-methylcyclobutylidene)-2-methylpropane-2- sulfonamide (25 g, 108 mmol), 5-bromo-2-iodopyrimidine (37 g, 130 mmol) in toluene (500 mL), add n-butyllithium (52 mL, 2.5 M, 130 mmol) with stirring at -40 °C, react for 3 hours at -40 °C, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, purify by silica gel column chromatography, and separate by chiral column to give the title compound (4.9 g, 12%).

[0223] MS m / z (ESI): 390.1 [M+H] + .

[0224] Step 8: Preparation of N-((ls,3s)-l-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-oxo- 6,7,8,15-tetrahydro-8,15-methan[ 1,3 ]dioxolo[ 4 ', 5': 3, 4 ]benzo [ 1, 2 - f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-12-yl)pyrimidin-2-yl)-3- (methoxymethyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfonamide

[0225] (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 (400 mg, 0.8 mmol), N-((ls,3s)-l-(5-bromopyrimidin-2-yl)-3- (methoxymethyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfmamide (344.6 mg, 0.88 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'- biphenyl) (2'-methylamino-l,l'-biphenyl) palladium(II) (69 mg, 0.08 mmol) and potassium carbonate (222 mg, 1.6 mmol) were suspended in a mixture of 1,4- dioxane (20 mL) and water (5 mL), and microwaved at 110 °C for 1 hour. The reaction was allowed to cool to room temperature, extracted with ethyl acetate (10 mL x 3), washed with saturated aqueous sodium chloride (10 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (459 mg, 83.9%). MS m / z (ESI): 682.1 [M+H] + .

[0226] Ninth Step: Preparation of (8R, 15R)-12-(2-((ls,3S)-l-amino-3- (methoxymethyl)-3-methylcyclobutyl)pyrimidin-5-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

[0227] N-((ls,3S)-l-(5-((8R, 15R)-2,2-difluoro-7-(methyl-d3)-6-oxo-6,7,8, 15-tetrahydro-8, 15- methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-12-yl)- pyrimidin-2-yl)-3-(methoxymethyl)-3-methylcyclobutyl)-2-methylpropane-2- sulfmamide (459 mg, 0.67 mmol) was dissolved in a solution of hydrochloric acid in dioxane (10 mL, 4 N) and allowed to react at room temperature for 1 hour. Upon completion of the reaction, the reaction was concentrated and the residue was purified by prep-HPLC to give the title compound (288 mg, 73.0%).

[0228] MS m / z (ESI): 578.1 [M+H] + .

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.29 (d, J = 8.8 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.14 (d, J = 6.4 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.55 - 3.47 (m, 1H), 3.44 (s, 2H), 3.37 (s, 3H), 2.96 (d, J = 13.6 Hz, 1H), 2.60 - 2.46 (m, 4H), 2.29 (d, J = 12.8 Hz, 2H), 1.17 (s, 3H).

[0230] Example 4

[0231] First Step: Preparation of 3-((difluoromethoxy)methyl)-3-methylcyclobutane-1-one

[0232] Dissolve 1-((difluoromethoxy)methyl)-3,3-diethoxy-1-methylcyclobutane (1.5 g, 6.30 mmol) in a mixture solvent of water (10 mL), acetone (20 mL), add p-toluenesulfonic acid (108 mg, 0.63 mmol) under stirring, heat to 60 °C for 2 hours, cool to room temperature, concentrate, add saturated sodium bicarbonate to basic, extract with diethyl ether, wash the combined organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate to give the title compound (1.0 g, 97.0%). MS m / z (ESI): 165.1 [M+H] + .

[0233] Second Step: Preparation of N-(3-((difluoromethoxy)methyl)-3-methylcyclobutylidene)-2-methylpropane-2-sulfmamide

[0234] Dissolve 3-((difluoromethoxy)methyl)-3-methylcyclobutane-l-one (1 g, 6.09 mmol) in tetrahydrofuran (20 mL), add tert-butylsulfinamide (1.11 g, 9.14 mmol) with stirring, add tetraethyl titanate (13.9 g, 60.9 mmol), stir the reaction at 20 °C for 12 hours, dilute the reaction with ethyl acetate, add saturated sodium chloride to the dilution, filter, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, and separate the title compound (1.0 g, 61.0%) by column chromatography on silica gel. MS m / z (ESI): 268.1 [M+H] + .

[0235] Third Step: Preparation of N-((ls,3s)-l-(5-bromopyrimidin-2-yl)-3-((difluoromethoxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfmamide

[0236] Dissolve N-(3-((difluoromethoxy)methyl)-3-methylcyclobutylidene)-2-methylpropane-2-sulfmamide (1 g, 3.74 mmol) and 5-bromo-2-iodopyrimidine (1.28 g, 4.49 mmol) in toluene (20 mL), add n-butyllithium (1.8 mL, 2.5 M, 4.49 mmol) with stirring at -40 °C, stir the reaction at -40 °C for 2 hours, quench with saturated ammonium chloride, extract with ethyl acetate, wash the combined organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, purify by column chromatography on silica gel, and separate the title compound (170 mg, 11.0%) by column chromatography on a chiral column. MS m / z (ESI): 411.1 [M+H] + .

[0237] Fourth Step: Preparation of N-((ls,3s)-l-(5-((8R,15R)-2,2-difluoro-7-methyl-6-oxo-6,7,8,15-tetrahydro-8,15-methano[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-12-yl)pyrimidin-2-yl)-3-((difluoromethoxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfmamide

[0238] N-((1s,3s)-1-(5-bromopyrimidin-2-yl)-3-((difluoromethoxy)methyl)-3- methylcyclobutyl)-2-methylpropane-2-sulfmamide (55 mg, 0.13 mmol), (8R,15R)- 2,2-difluoro-7-methyl-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15- methanedi oxolo [4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)-one (64 mg, 0.13 mmol) and potassium carbonate (36 mg, 0.26 mmol) were dissolved in water (0.8 mL), dioxane (4 mL), Xphos-Pd-G4 (22 mg, 0.025 mmol) was added with stirring, the flask was purged with dry nitrogen three times, the reaction was heated to 110 °C for 1 h, the reaction was concentrated, the residue was purified by silica gel column chromatography to give the title compound (88 mg, 95.0%).

[0239] MS m / z (ESI): 715.2 [M+H] + .

[0240] Fifth Step: Preparation of (8R,15R)-12-(2-((1s,3S)-1-amino-3-((difluoromethoxy)methyl)-3- methylcyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15- methanedi oxolo [4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)-one

[0241] N-((1s,3S)-1-(5-((8R,15R)-2,2-difluoro-7-methyl-6-oxo-6,7,8,15-tetrahydro-8,15- methanedi oxolo [4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-12-yl)pyrimidin- 2-yl)-3-((difluoromethoxy)methyl)-3-methylcyclobutyl)-2-methylpropane-2-sulfmamide (88.00 mg, 0.12 mmol) was dissolved in dioxane (5 mL), methanol (5 mL), hydrochloric acid dioxane (5 mL, 4 M) was added with stirring, the reaction was stirred at room temperature for 1 h, the reaction was diluted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column chromatography to give the title compound (23.8 mg, 32.0%). + .

[0242] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 2H), 8.29 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 6.74 (t, J = 76.3 Hz, 1H), 6.14 (d, J = 6.7 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 4.06 (s, 2H), 3.55 - 3.47 (m, 1H), 3.38 (s, 3H), 2.95 (d, J = 13.8 Hz, 1H), 2.52 - 2.51 (m, 2H), 2.10 - 1.95 (m, 2H), 1.13 (s, 3H).

[0243] Example 7

[0244] First Step: Preparation of 3-(benzyloxy)-l-(5-bromopyrimidin-2-yl)cyclobutanol

[0245] n-BuLi (2.5 M, 25.0 mL, 62.50 mmol) was added dropwise to a solution of 5-bromo-2-iodo-pyrimidine (17.8 g, 62.48 mmol), 3-(benzyloxy)-l-cyclobutanone (10 g, 56.75 mmol) in DCM (100 mL) at -40 °C, stirred for 10 min after dropwise addition, raised to room temperature and stirred for 16 h, quenched with saturated ammonium chloride solution (50 mL). Filtered, the filtrate was partitioned, the organic layer was washed with water (20 mL), saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (6.4 g, 33.6%).

[0246] MS m / z (ESI): 335.1 [M+H] + .

[0247] Second Step: Preparation of l-(5-bromopyrimidin-2-yl)cyclobutane-l,3-diol

[0248] Bromotrimethylsilane (0.5 mL, 3.75 mmol) was added to a solution of 3-(5- bromopyrimidin-2-yl)-3-hydroxy-cyclobutanone (0.5 g, 2.06 mmol) in DCM (10 mL) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction was diluted with DCM (50 mL) and washed with water (50 mL x 3). The combined aqueous layers were extracted with DCM (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give the title compound (0.5 g, 82% yield). MS m / z (ESI): 357.1 [M+H]+. + .

[0249] Step 3: Preparation of 3-(5-bromopyrimidin-2-yl)-3-hydroxy-cyclobutanone

[0250] Dess-Martin periodinane (17.47 g, 41 mmol) was added to a solution of 1-(5- bromopyrimidin-2-yl)cyclobutane-1,3-diol (6.73 g, 27.45 mmol) in DCM (150 mL) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction was diluted with DCM (200 mL) and washed with saturated sodium sulfite solution (50 mL) and saturated sodium bicarbonate solution (200 mL) separately. The organic layer 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 (3.65 g, 54.7% yield over two steps). MS m / z (ESI): 243.0 [M+H] + .

[0251] Step 4: Preparation of 3-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)- cyclobutanone

[0252] Imidazole (5.11 g, 75.09 mmol) was added to a solution of 3-(5-bromopyrimidin-2-yl)-3- hydroxy-cyclobutanone (3.65 g, 15.02 mmol) in DMF (55 mL) at room temperature. tert- Butyldimethylsilyl chloride (9.06 g, 60.11 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was diluted with DCM (200 mL) and washed with water (100 mL x 3). The combined aqueous layers were extracted with DCM (100 mL). The combined organic layers were 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 (4.4 g, 82%). MS m / z (ESI): 357.1 [M+H]+.

[0253] Step 5: Preparation of 3-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-1- methylcyclobutanol

[0254] Methylmagnesium iodide (3 M, 10.6 mL) was added dropwise to a solution of 3-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanone (4.4 g, 12.31 mmol) in THF (40 mL) at -78 °C, warmed to room temperature and stirred for 1 h, quenched with saturated ammonium chloride solution (40 mL), extracted with ethyl acetate (30 mL x 2), the organic layers were combined and washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.91 g, 41.4 %). MS m / z (ESI): 373.1 [M+H] + .

[0255] Sixth Step: Preparation of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)-3- (difluoromethoxy)-3-methylcyclobutyl)pyrimidine

[0256] A mixture of 3-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-1- methylcyclobutanol (0.73 g, 1.96 mmol), difluorobromomethyltrimethylsilane (2.38 g, 11.73 mmol, 1.8 mL), KOAc (1.53 g, 15.64 mmol), DCM (20 mL), water (10 mL) was stirred at room temperature for 3 days. The reaction was partitioned between water and DCM, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (475 mg, 57.4 %). MS m / z (ESI): 423.1 [M+H] + .

[0257] Seventh Step: Preparation of 1-(5-bromopyrimidin-2-yl)-3-(difluoromethoxy)-3- methylcyclobutanol

[0258] A solution of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)-3-(difluoromethoxy)-3- methylcyclobutyl)pyrimidine (475 mg, 1.12 mmol) in TBAF (1 M in THF, 1.12 mL) was stirred at room temperature for 1 h. The reaction was diluted with ethyl acetate (20 mL), washed with water (10 mL), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (222 mg, 64.0 %). MS m / z (ESI): 309.1 [M+H] + .

[0259] Eighth Step: Preparation of 1-(5-bromopyrimidin-2-yl)-3-(difluoromethoxy)-3- methylcyclobutyl 4-methylbenzenesulfonate

[0260] NaH (43 mg, 1.08 mmol, 60%) was added portionwise to a solution of 1-(5-bromopyrimidin-2-yl)-3-(difluoromethoxy)-3-methylcyclobutanol (222 mg, 0.72 mmol) in THF (14 mL) under ice-bath, stirred for 10 min, p-toluenesulfonyl chloride (205 mg, 1.08 mmol) was added, stirred at room temperature for 1 h. The reaction was poured into ice-water (20 mL), the mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (20 mL), washed with water (10 mL), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by column chromatography on silica gel to give the title compound (294 mg, 88.4%).

[0261] MS m / z (ESI): 463.1 [M+H] + .

[0262] Ninth Step: 2-(1-Azido-3-(difluoromethoxy)-3-methylcyclobutyl)-5-bromopyrimidine

[0263] Sodium azide (206 mg, 3.17 mmol) was added to a solution of 1-(5-bromopyrimidin-2-yl)-3-(difluoromethoxy)-3-methylcyclobutyl 4-methylbenzenesulfonate (294 mg, 0.63 mmol) in DMF (3 mL), heated to 80 °C in microwave for 3 h. The reaction was diluted with water (9 mL), extracted with ethyl acetate (30 mL), the organic layer was washed with water (10 mL x 2), the organic layer was used directly in the next step. MS m / z (ESI): 334.1 [M+H] + .

[0264] Ninth Step: Preparation of tert-butyl ((1s,3s)-1-(5-bromopyrimidin-2-yl)-3-(difluoromethoxy)-3-methylcyclobutyl)carbamate

[0265] 2-(1-azido-3-(difluoromethoxy)-3-methylcyclobutyl)-5-bromopyrimidine crude (212 mg, 0.63 mmol) in ethyl acetate was added triphenylphosphine (283 mg, 1.08 mmol), water (1 mL), and heated to reflux for 16 h. After the reaction was cooled, 1 M HC1 (10 mL) was added, stirred, partitioned, the aqueous layer was adjusted to pH 7-8 with saturated NaHC03solution, extracted with ethyl acetate (10 mL x 2), the combined organic layers were concentrated under reduced pressure, the residue was diluted with methanol (5 mL), di-tert-butyl dicarbonate (207 mg, 0.95 mmol) was added, stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, the residue was purified by column chromatography, then resolved by chiral column to give the title compound (72 mg, 28.3% for two steps). MS m / z (ESI): 308.1 [M+H] + .

[0266] Tenth Step: Preparation of (8R, 15R)-12-(2-((1s, 3S)-1-amino-3-(difluoromethoxy)-3- methylcyclobutyl)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-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)- one

[0267] To a mixture 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 (40 mg, 80 μmol), XPhos PdG4 (6.9 mg, 8 μmol), potassium carbonate (44 mg, 0.32 mmol) in dioxane (2 mL) and water (0.4 mL) was added tert-butyl ((1s,3s)-1-(5-bromopyrimidin-2-yl)-3-(difluoromethoxy)-3- methylcyclobutyl)carbamate (33 mg, 80 μmol) under nitrogen for three times, then stirred at 100 °C for 1 h in microwave. The reaction was concentrated under reduced pressure, the residue was diluted with HC1 / MeOH (2 mL, 2 M), stirred at room temperature for 0.5 h, concentrated under reduced pressure, the residue was purified by prep-HPLC to give the title compound (18 mg, 36.4%). MS m / z (ESI): 600.2 [M+H] + .

[0268] 1H NMR (400 MHz, CDC13) δ 8.94 (s, 2H), 8.47 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.50 - 7.43 (m, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.49 (t, J = 75.4 Hz, 1H), 5.96 (d, J = 6.7 Hz, 1H), 5.06 (d, J = 7.2 Hz, 1H), 3.58 - 3.46 (m, 1H), 3.17 - 3.01 (m, 4H), 2.98 (d, J = 13.5 Hz, 1H), 1.66 (s, 3H).

[0269] Example 15

[0270] First Step: Preparation of methyl 3,3-diethoxycyclobutane-l-carboxylate

[0271] Methyl 3-oxocyclobutane carboxylate (25 g, 195 mmol) and triethyl orthoformate (60.73 g, 410 mmol, 68 mL) were dissolved in dichloromethane (200 mL), p-toluenesulfonic acid (1.68 g, 9.76 mmol) was added and the reaction was stirred at 50 °C for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give the title compound (38 g, 96%).

[0272] 1 H NMR (400 MHz, CDC13) δ 3.67 (s, 3H), 3.40 (p, J = 7.2 Hz, 4H), 2.88 (p, J = 8.6 Hz, 1H), 2.47 - 2.33 (m, 4H), 1.17 (td, J = 7.2, 6.0 Hz, 6H).

[0273] Second Step: Preparation of ((3,3-diethoxycyclobutylidene)(methoxy)methoxy)trimethylsilane

[0274] Lithium diisopropylamide (2 M, 58 mL) was dissolved in tetrahydrofuran (140 mL) and a solution of methyl 3,3-diethoxycyclobutane-l-carboxylate (19.5 g, 96.4 mmol) in tetrahydrofuran (40 mL) was added dropwise at -60 °C. After stirring for 1 h, trimethylsilyl chloride (17.81 g, 164 mmol, 21 mL) was added and the reaction was stirred at room temperature for 11 h. The reaction was concentrated under reduced pressure, diluted with petroleum ether (200 mL), quenched with ice water slowly, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (21 g, 79%).

[0275] Third Step: Preparation of methyl 3,3-diethoxy-l-(trifluoromethyl)cyclobutane-l- carboxylate

[0276] ((3,3-diethoxycyclobutyl)(methoxy)methoxy)trimethylsilane was dissolved in dichloromethane (1 L), the system was replaced with nitrogen, and the temperature was lowered to -60 °C with a dry ice-ethanol bath. N-(trimethylsilyl)bis(trifluoromethanesulfonate) imide (901 mg, 2.6 mmol, 585 μL) and 3,3-dimethyl-l-(trifluoromethyl)-l,2-benziodoxolane (42.1 g, 127.5 mmol) were added sequentially, and the reaction was slowly warmed to room temperature. The reaction was stirred for 12 h. The reaction was poured into 200 mL of saturated aqueous sodium bicarbonate solution, and the mixture was partitioned. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (13 g, 37.7%).

[0277] 1 H NMR (400 MHz, CDC13) δ 3.80 (s, 3H), 3.40 (qd, J = 7.2, 1.2 Hz, 4H), 2.82-2.73 (m, 2H), 2.63-2.53 (m, 2H), 1.17 (dt, J = 12.8, 7.2 Hz, 6H).

[0278] Fourth Step: Preparation of (3,3-diethoxy-l-(trifluoromethyl)cyclobutyl)methanol

[0279] Methyl 3,3-diethoxy-l-(trifluoromethyl)cyclobutane-l-carboxylate (8 g, 29.6 mmol) was dissolved in tetrahydrofuran (80 mL), and the temperature was lowered to 0 °C with an ice bath. Lithium aluminum hydride (2.5 M, 13.5 mL) was added slowly dropwise, and the reaction was stirred at 0 °C for 1 h. Sodium sulfate decahydrate solution was added slowly until no more bubbles were produced. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (6.8 g, 95%).

[0280] Fifth Step: Preparation of 3-(hydroxymethyl)-3-(trifluoromethyl)cyclobutan-l-one

[0281] (3,3-diethoxy-l-(trifluoromethyl)cyclobutyl)methanol (6.8 g, 28.0 mmol) was dissolved in acetone (68 mL), and p-toluenesulfonic acid (483.4 mg, 2.8 mmol) was added. The reaction was stirred at 55 °C for 4 h. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give the title compound (4.6 g, 97%).

[0282] Step 6: Preparation of 3-(((tert-butyldimethylsilyl)oxy)methyl)-3- (trifluoromethyl)cyclobutan-1-one

[0283] To a solution of 3-(hydroxymethyl)-3-(trifluoromethyl)cyclobutan-1-one (4.6 g, 27.4 mmol) in dichloromethane (50 mL) was added tert-butyldimethylsilyl chloride (4.95 g, 32.8 mmol), imidazole (3.73 g, 54.7 mmol) and 4-dimethylaminopyridine (334.3 mg, 2.7 mmol) and the reaction stirred at 50 °C for 2 h. The reaction was concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel to give the title compound (5.2 g, 67%).

[0284] 1 H NMR (400 MHz, CDC13) δ 3.90 (s, 2H), 3.30-3.12 (m, 4H), 0.89 (s, 9H), 0.09 (s, 6H).

[0285] Step 7: Preparation of 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(5- chloropyrimidin-2-yl)-3-(trifluoromethyl)cyclobutan-1-ol

[0286] To a solution of 5-chloro-2-iodo-pyrimidine (5.31 g, 22.1 mmol) and 3-(((tert- butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)cyclobutan-1-one (5.2 g, 18.4 mmol) in dichloromethane (100 mL) was added n-butyllithium (2.5 M, 9 mL) slowly at -60 °C and the reaction stirred at -60 °C for 2 h. The reaction was poured into aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (200 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and purified by flash column chromatography on silica gel to give the title compound (3.7 g, 51%). MS m / z (ESI): 397.1 [M+H] + .

[0287] Step 8: Preparation of 1-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)-3- (trifluoromethyl)cyclobutan-1-ol

[0288] Dissolve 3-(((tert-butyldimethylsilyl)oxy)methyl)-l-(5-chloropyrimidin-2-yl)-3- (trifluoromethyl)cyclobutane-l-ol (3.7 g, 9.32 mmol) in dioxane (20 mL), add 4M hydrochloric acid in dioxane (4M, 23.31 mL), and stir the reaction for 10 minutes. Concentrate the reaction under reduced pressure to give the title compound (2.7 g, crude). MS m / z (ESI): 283.0 [M+H] + .

[0289] Ninth Step: Preparation of 3-(5-chloropyrimidin-2-yl)-3-hydroxy-l- (trifluoromethyl)cyclobutane-l-carbaldehyde

[0290] Dissolve l-(5-chloropyrimidin-2-yl)-3-(hydroxymethyl)-3- (trifluoromethyl)cyclobutane-l-ol (1 g, 3.5 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (3.0 g, 23 mmol, 4 mL), cool to 0 °C, slowly add a solution of sulfur trioxide pyridine (1.7 g, 10.6 mmol) in dimethyl sulfoxide (4 mL), and stir the reaction at 0 °C for 0.5 hours. Pour the reaction into 10% aqueous citric acid (100 mL), extract with dichloromethane (100 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (1 g, crude). MS m / z (ESI): 281.0 [M+H] + .

[0291] Tenth Step: Preparation of (ls,3s)-l-(5-chloropyrimidin-2-yl)-3-ethynyl-3- (trifluoromethyl)cyclobutane-l-ol

[0292] Dissolve 3-(5-chloropyrimidin-2-yl)-3-hydroxy-l-(trifluoromethyl)cyclobutane-l- carbaldehyde (1 g, 3.6 mmol) in methanol (20 mL), add dimethyl (l-diazo-2- oxopropyl)phosphonate (1.4 g, 7.1 mmol, 1.1 mL) and potassium carbonate (1.5 g, 10.7 mmol), and stir the reaction for 13 hours. Pour the reaction into water (100 mL), extract with ethyl acetate (100 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by thin layer silica gel chromatography to give the title compound (175 mg, 17.8%). MS m / z (ESI): 277.0 [M+H] + .

[0293] Preparation of (8R, 15R)-12-(2-(1s,3S)-3-ethynyl-1-hydroxy-3- (trifluoromethyl)cyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15- metheno[l,3]dioxolo[4',5':3,4]benzo[l,2-f]benzo[4,5]imidazo[l,2-a][l,4]diazocin-6(15H)- one

[0294] (8R, 15R)-2,2-difluoro-7-methyl-12-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8- dihydro-8,15-metheno[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, 101 μmol) and (1s,3s)-1-(5-chloropyrimidin-2-yl)-3-ethynyl-3- (trifluoromethyl)cyclobutane-1-ol (30.8 mg, 111 μmol) were dissolved in a mixture of dioxane (5 mL) and water (1 mL), (SP-4-3)-[dicyclohexyl[2',4',6'-tris(1- methylethyl)[l,r-biphenyl]-2-yl]phosphine] (methanesulfonic acid) [2'-(methylamino)[l,r- biphenyl]-2-yl]palladium (8.7 mg, 10 μmol) and sodium carbonate (21.4 mg, 202 μmol) were added, the reaction was vacuumed, the system was replaced with nitrogen, the temperature was increased to 90 °C, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give the title compound (22.4 mg, 36%).

[0295] MS m / z (ESI): 610.1 [M+H] + .

[0296] 1 H NMR (400 MHz, CDC13) δ 8.95 (s, 2H), 8.47 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 5.97 (d, J = 4.4 Hz, 1H), 5.07 (s, 2H), 3.65 - 3.34 (m, 6H), 2.98 (d, J = 13.4 Hz, 1H), 2.69 (d, J = 12.7 Hz, 2H), 2.59 (s, 1H).

[0297] Example 22

[0298] Step 1: Preparation of (1s,3s)-3-(5-bromo-3-methylpyridin-2-yl)-3-hydroxy-1- methylcyclobutane-1-carbonitrile

[0299] Dissolve 5-bromo-2-iodo-3-methylpyridine (2 g, 6.71 mmol) in toluene (40 mL), drop in n-butyllithium (2.5 M, 2.95 mL) under dry ice ethanol bath, react for 1 hour, drop in 1-methyl-3-oxocyclobutane-1-carbonitrile (879.1 mg, 8.06 mmol), react for 1 hour under -78 °C, recover to room temperature and stir for 1 hour. Add saturated aqueous ammonium chloride solution (100 mL), extract with ethyl acetate (50 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate, purify the residue by column chromatography, and resolve by chiral column to obtain the title compound (500 mg, 26.5%).

[0300] MS m / z (ESI): 281.0 [M+H] + .

[0301] Step 2: Preparation of (1S,3s)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-oxo-6,7,8,15- tetrahydro-8,15-methyl[1,3]dioxolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4] diazepin-12-yl)-3-methylpyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile

[0302] Methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2'-methylamino-1,1 '-biphenyl-2-yl)palladium(II) (8.6 mg, 10.03 μιηοΐ) 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-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 (50 mg, 100.3 μιηοΐ), (1 s,3s)-3-(5-bromo-3-methylpyridin-2-yl)-3-hydroxy-1 - methylcyclobutane-1 -carbonitrile (28.21 mg, 100.3 μιηοΐ) and potassium carbonate (41.60 mg, 301.0 μιηοΐ) in 1 '4dioxane (2 mL) and water (0.2 mL), purged with nitrogen 3 times, heated to 110 °C for 1 hour. The reaction was concentrated and the residue was purified by prep-HPLC to give the title compound (30.8 mg, 53.6%). MS m / z (ESI): 573.2 [M+H] + .

[0303] Example 23

[0304] First Step: Preparation of (1 s,3s)-3-(5-bromo-3-chloropyridin-2-yl)-3-hydroxy-1 - methylcyclobutane-1 -carbonitrile

[0305] 2,5-Dibromo-3-chloropyridine (3 g, 11.06 mmol) was dissolved in toluene (60 mL), n-butyllithium (2.5 M, 4.86 mL) solution was added dropwise under dry ice ethanol bath, the reaction was stirred for 1 hour, 1 -methyl-3-oxocyclobutane-1 -carbonitrile (1.45 g, 13.27 mmol) was added, stirred for 1 hour at -78 °C, recovered to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution (100 mL) was added, extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified by column chromatography and chiral column resolution to give the title compound (800 mg, 24.0%).

[0306] MS m / z (ESI): 301.0 [M+H] + .

[0307] Second Step: Preparation of (1S,3s)-3-(3-chloro-5-((8R,15R)-2,2-difluoro-7-(methyl- d3)-6-oxo-6,7,8,15-tetrahydro-8,15-methyl[1,3]dioxolo[4',5':3,4]benzo[1,2- f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-12-yl)pyridin-2-yl)-3-hydroxy-1- methylcyclobutane-1-carbonitrile

[0308] Methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg, 10.03 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-methano[1,3]dioxolo[4',5':3,4]benzo[1,2- f]benzo[4,5]imidazo[1,2-a][1,4]diazepin-6(15H)-one (50 mg, 100.3 μmol), (1s,3s)-3- (5-bromo-3-chloropyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile (30.26 mg, 100.3 μmol) and potassium carbonate (41.60 mg, 301.0 μmol) in 1,4 dioxane (2 mL) and water (0.2 mL), purged with nitrogen 3 times, heated to 110 °C for 1 hour. The reaction was concentrated and the residue was separated by prep-HPLC to give the title compound (22.3 mg, 37.5%). MS m / z (ESI): 593.1 [M+H] + .

[0309] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.66 - 7.59 (m, 1H), 6.21 - 6.11 (m, 2H), 5.33 (d, J = 7.2 Hz, 1H), 3.56 - 3.44 (m, 2H), 3.05 - 2.79 (m, 5H), 1.34 (s, 3H).

[0310] Example 50

[0311] First Step: Preparation of (S)-N-(3-cyano-3-methylcyclobutylidene)-2- methylpropane-2-sulfonamide

[0312] 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 the reaction for 16 hours. Quench the reaction with water, filter the mixture, extract the filtrate with ethyl acetate (150 mL x 3), wash with saturated aqueous sodium chloride (200 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography to give the title compound (18.50 g, 90.6%). MS m / z (ESI): 213.1 [M+H] + .

[0313] Second Step: Preparation of (S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3- cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0314] Dissolve 5-bromo-2-iodopyrimidine (4.72 g, 16.56 mmol) in DCM (100 mL), dropwise add n-butyllithium (6.62 mL, 16.56 mmol, 2.5 mol / L in Hexanes), stir the reaction for 1 hour, dropwise add a solution of (S)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (2.93 g, 13.80 mmol) in DCM (20 mL), continue stirring the reaction for 1 hour, extract the reaction with DCM (50 mL x 3). Wash with saturated aqueous sodium chloride (30 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography and chiral column resolution to give the title compound (700 mg, 13.7%). MS m / z (ESI): 371.0 [M+H] + .

[0315] Third Step: Preparation of N-((1s,3S)-3-cyano-1-(5-((8R,15R)-2,2-difluoro-7-(methyl- d3)-6-oxo-6,7,8,15-tetrahydro-8,15-methanocyclo[1,3]dioxolo[4',5':3,4]benzo[1,2- f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2- methylpropane-2-sulfinamide

[0316] (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-methanobenzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-6(15H)-one (1.0 g, 2.00 mmol), (S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3-cyano-3- methylcyclobutyl)-2-methylpropane-2-sulfmamide (816.2 mg, 2.20 mmol), methyl sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (171.5 mg, 0.20 mmol), and potassium carbonate (828.0 mg, 6.00 mmol) were suspended in a mixture of 1,4- dioxane (20 mL) and water (4 mL), and the mixture was microwaved at 110 °C for 1 h. The reaction was allowed to cool to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated aqueous sodium chloride (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (1.10 g, 83.3%). MS m / z (ESI): 663.2 [M+H] + .

[0317] Fourth Step: Preparation of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6- carbonyl-6,7,8,15-tetrahydro-8,15-methanobenzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin- 12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carbonitrile

[0318] N-((1s,3S)-3-cyano-1-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-oxo-6,7,8,15- tetrahydro-8,15-methanobenzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-12-yl)pyrimidin- 2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfmamide (1.10 g, 1.66 mmol) was dissolved in a solution of hydrochloric acid in dioxane (10 mL, 4N) and stirred at room temperature for 1 hour. The reaction was concentrated and the title compound was isolated by prep-HPLC (433.5 mg, 46.7%). MS m / z (ESI): 559.2 [M+H] + .

[0319] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.29 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 1.7, 0.7 Hz, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 6.14 (d, J = 6.6 Hz, 1H), 5.33 (d, J = 7.2 Hz, 1H), 3.51 (dt, J = 13.9, 7.0 Hz, 1H), 2.95 (d, J = 13.8 Hz, 1H), 2.85 - 2.77 (m, 2H), 2.68 - 2.59 (m, 2H), 1.46 (s, 3H).

[0320] The other examples were prepared according to the procedure described above. The examples of the present application are summarized below

[0321] The NMR data of the examples are summarized in the table below:

[0322] Biological test evaluation

[0323] The present application is further described in conjunction with the following test examples, which are not meant to limit the scope of the present application.

[0324] I. Binding experiments

[0325] Test Example 1, Determination of the Thermal shift of TNFα protein thermal stability by the compound of the present application

[0326] 1. Purpose of the experiment: to detect the thermal stability of the compound on TNFα protein Thermal shift effect.

[0327] 2. Experimental instruments and reagents:

[0328] 2.1 Instruments:

[0329] Quantitative PCR instrument (Life: Quantstudio6 Flex), micro centrifuge (IKA: mini G);

[0330] pure water instrument (THERMO: Pacific T II+Micropure)

[0331] 2.2 Reagents:

[0332] Protein Thermal Shift TM Dye Kit (Thermofisher: 4461146); DMSO (Sigma: D2650);

[0333] PBS (Gibco, 10010023); TNFa (MCE: HY-P7085); eight-tube (Corning, 6542);

[0334] 3. Experimental method:

[0335] 1) According to the amount of the compound to be tested, calculate the amount of SYPRO Orange, dilute 1000x storage concentration of SYPRO Orange with buffer to 30x;

[0336] 2) According to the following table, configure a mixed solution containing 3x SYPRO Orange, 1x PBS (pH 7.4), 0.025 mg / mL TNFα protein:

[0337] 3) Use a pipette to mix well for ten times, and add the above mixed solution to the eight-tube, 9.5uL per tube;

[0338] 4) Dilute the compound to 2mM with DMSO, add 0.5uL of the corresponding compound to each eight-tube, add 0.5uL of DMSO to the control well, and mix well;

[0339] 5) Cover the eight-tube cover, and centrifuge the micro centrifuge for 30s;

[0340] 6) Use the melt cure function of the quantitative PCR instrument to detect the thermal melting temperature Tm of the TNF protein, set the program to rise from 25°C to 99°C at 0.05°C / s.

[0341] 7) Calculate the ΔTm value according to the obtained dissolution curve.

[0342] 4. Experimental data processing method: After using the quantitative qPCR instrument dissolution curve function, the return value Tm is obtained, ΔTm is the Tm value of the sample minus the DMSO Tm value, and the difference is the required ΔTm.

[0343] 5. Experimental results and conclusions: Through the above scheme, it is concluded that the compound of the present application has strong binding effect on TNFα protein.

[0344] Test Example 2, determination of the TNFα-TNFR1 binding ability of the compound of the present application

[0345] 1. Experimental purpose: To detect the influence of the compound on the binding of TNFα protein and TNFR1 receptor.

[0346] 2. Experimental instruments and reagents:

[0347] 2.1 Instruments:

[0348] Envision (PE-Cisbio: 2105-0020), centrifuge (Eppendorf: 5810R), water instrument (THERMO: Pacific T II+Micropure), plate washer (Thermo: WELLWASH VERSA), microporous plate oscillator (Thermo: 88882006)

[0349] 2.2 Reagents:

[0350] TNFA / TNFR1 Binding assay kits (Cisbio: 64BDTNFPEG);

[0351] DMSO (Sigma: D2650); compound plate (Thermo: 1353506);

[0352] 3. Experimental method:

[0353] 1) Resuspend Tag1-TNFα and Tag2-TNFR1 with 200uL deionized water respectively to obtain 10x storage solution.

[0354] 2) Dilute the compound to 5x final concentration with PPI Europium Detection Buffer, control the final concentration of DMSO to be 0.1%, add 2uL of compound per well;

[0355] 3) TNFα and TNFR1 were diluted to 1x with PPI Europium Detection Buffer, and 4uL was added to each well, respectively;

[0356] 4) The standard curve was prepared, and the standard solution of TNFα-TNFR1 was stored at a concentration of 1uM, and a 5-fold dilution was prepared to prepare the standard curve. The standard curve top concentration point was 200000pM, and the working concentration was 20000pM;

[0357] 5) 2uL of the standard curve was added to each well;

[0358] 6) The detection mixture was prepared: 50x Anti-Tag1 Eu and 50x Anti-Tag2 were diluted to 1x with PPI Europium Detection Buffer, and 10uL of detection was added to each well;

[0359] 7) The plate was sealed and incubated at room temperature overnight;

[0360] 8) The sealing film was removed, and Envision reading 665 / 620 was performed.

[0361] 4. Experimental data processing method:

[0362] Log(inhibitor) vs. response - Variable slope (four parameters) in Graph pad was used.

[0363] The compound concentration and the corresponding inhibition rate were subjected to non-linear regression fitting, the fitting curve was obtained, and the IC 50 value was obtained.

[0364] 5. Experimental results and conclusions: The compound of the embodiment shown in the application has strong TNFα binding effect.

[0365] II. Cell function experiment

[0366] Test Example 1, determination of the influence of the compound of the application on TNF-induced HEK293 cell NF-KB phosphorylation

[0367] 1. Experimental purpose: to detect the influence of the compound on the TNF-induced pNF-κB level of HEK293 cells.

[0368] 2. Experimental instruments and reagents:

[0369] 2.1 Instruments:

[0370] Envision (PE-Cisbio: 2105-0020); centrifuge (Eppendorf: 5810R);

[0371] Pure water instrument (THERMO: Pacific T II + Micropure);

[0372] Ice maker (Xueke Electrical, IMS-150); incubator (Bo Xun, BC-J80S)

[0373] 2.2 Reagents:

[0374] Cell culture plate (Corning: 3599); PBS (Gibco, 10010023); DMSO (Sigma: D2650);

[0375] TNF alpha (MCE: HY-P7085); PMSF (100mM) (Beyotime, ST506);

[0376] Pierce BCA Protein Assay Kit (Thermo Fisher, 23227);

[0377] Protease phosphatase inhibitor cocktail (universal, 50X) (Beyotime, P1045);

[0378] NF kappaB p65 (pS536) ELISA kit (Abeam, ab176647);

[0379] Cell line Hek293 (ATCC); DMEM (Gibco, 11995-065);

[0380] FBS serum (Gibco, 30067-334); Pen strep double antibody (Gibco, 15140-122);

[0381] Trypsin (Gibco, 25200-056);

[0382] 3. Experimental method:

[0383] 1) HepG2 cell line was cultured in complete culture medium, 37℃, 5% CO2 to 70% ~ 90% confluence.

[0384] 2) The cells were resuspended in experimental culture medium after digestion, 40,000 cells / well / 100 μL were inoculated into 96-well cell culture plate, and cultured at 37℃, 5% CO2 overnight.

[0385] 3) The culture medium was prepared with 5x final concentration of compound and TNF protein mixture, and incubated at 37℃ incubator for 1h.

[0386] 4) Add the incubated compound and TNF protein mixture to the corresponding cell well, 25uL per well, and incubate in a 37°C incubator for 10 min. At this time, the final concentration of TNF is 25 ng / mL, and the concentration of DMSO is 0.1%.

[0387] 5) Centrifuge at 2000 rpm for 5 min, discard the supernatant, and wash the cells twice with 100 uL of PBS.

[0388] 6) Pre-cool the centrifuge at 4°C, prepare the cell lysis solution (the reagent components are included in the Elisa kit), and add an appropriate amount of protease inhibitor. Add 70 uL of lysis solution to each well and incubate on ice for 10 min.

[0389] 7) Take 5 uL of the lysis sample for BCA detection of protein concentration, and use the remaining sample for Elisa determination.

[0390] 8) Dilute the lysis sample with Elisa buffer to the appropriate multiple, and prepare the standard curve. The highest concentration point of the standard curve is 25% of the Control lysate concentration, and the remaining gradient is diluted by 2 times, for a total of 8 concentration points.

[0391] 9) Add the sample and standard curve to each well, 50 uL per well.

[0392] 10) Calculate the total volume required for the experiment, mix the Capture Antibody and Detector Antibody at a ratio of 1:1, and add 50 uL to each well. Seal the plate and incubate in a 25°C shaking incubator at 400 rpm for 1 h.

[0393] 11) Remove the liquid, dilute the 10x wash buffer with deionized water by 10 times, and add 350 uL to each well. Wash three times, and make sure to completely remove the liquid from the plate each time.

[0394] 12) Add 100 uL of TMB Substrate to each well, avoid light, and incubate in a shaking incubator at 400 rpm for 15 min to develop color.

[0395] 13) Add 100 uL of Stop solution to each well, mix well in a shaking incubator at 400 rpm for 1 min, and read OD450nm using Envision.

[0396] 4. Experimental data processing method:

[0397] Use Graph pad four-parameter log(inhibitor) vs. response--Variable slope(four parameters) to fit the compound concentration and corresponding inhibition rate in reverse non-linear manner, and calculate IC 50.

[0398] 5. Experimental results and conclusions:

[0399] The experiment of the effect of the compound of the embodiment shown in the present application on the TNF-induced pNF-κB level in HEK293 cells shows strong inhibitory effect.

[0400] Test Example 2, detection of inhibitory effect of the compound of the present application on TNF-stimulated hPBMC release of IL-8

[0401] 1. Experimental purpose:

[0402] Detect the inhibitory effect of the compound on TNF-induced hPBMC release of IL-8.

[0403] 2. Experimental instruments and reagents:

[0404] 2.1 Instruments:

[0405] Envision (PE-Cisbio: 2105-0020);

[0406] Biological safety cabinet (Sunan Tai, BSC-1604IIA2);

[0407] Cell counter (Invitrogen, Countess II)

[0408] 2.2 Reagent consumables:

[0409] hPBMC (Saili, XFB-HP010B), PBS (Gibco, 10010023), DMSO (Sigma: D2650), TNFa (MCE: HY-P7085), RPMI1640 medium (Gibco, 22400-105), FBS serum (Gibco, 30067-334);

[0410] Pen strep dual antibody (Gibco, 15140-122), cell culture plates (Coming: 3599), Human IL-8 / CXCL8 DuoSet ELISA (RD, DY208-05), DuoSet ELISA Ancillary Reagent Kit 2 (RD, DY008B), 50 mL centrifuge tubes (Coming, 430829), 2.5 uL pipette (Eppendorf, I36630F), 10 uL pipette (Eppendorf, J13131F), 100 uL pipette (Eppendorf, R22267J), 1000 uL pipette (Eppendorf, I44804F), 10 uL 12-channel electronic pipette (METTLER TOLEDO, 17013797), 300 uL 12-channel electronic pipette (Eppendorf, O51743J), 1200 uL 12-channel electronic pipette (Eppendorf, J51515K);

[0411] 3. Experimental method:

[0412] 1) Thaw hPBMC frozen stock at 37 °C water bath;

[0413] 2) Add thawed cells dropwise to 10 mL pre-warmed 1640 media (+10% FBS + 1% PS), centrifuge at 2000 rpm for 10 min;

[0414] 3) Remove supernatant from centrifuged cells, resuspend in 10 mL fresh media, mix by pipetting, count;

[0415] 4) Adjust cell density to 1*10 6 cells / mL, 100 uL / well into 96 well plate;

[0416] 5) Place plate in 37 °C incubator for 4 h;

[0417] 6) Prepare 6x final concentration compound (final concentration 1 uM Top, 3-Fold, 8 Dose) and TNF protein (final concentration 3 ng / mL) working solutions in serum-free 1640 media, then mix compound with TNFa 1 : 1, incubate in 37 °C incubator for 1 h;

[0418] 7) Add the mixed solution at the end of incubation to the corresponding well plate, 50uL per well, incubate at 37℃ for 18h, and prepare Elisa capture antibody with coating buffer at the same time, add 100uL per well to the high binding well plate, the final concentration is 4ug / mL, incubate in the refrigerator at 4℃ overnight;

[0419] 8) Elisa sample preparation: centrifuge the cell plate at 1500rpm for 10min after incubation, take the supernatant, and dilute the supernatant with dilution buffer by 15 times (6.7uL supernatant + 93.3uL dilution buffer);

[0420] 9) Prepare standard curve: the IL-8 concentration of the standard curve is 250ng / mL, 2-fold, 8-dose, 2-fold dilution is 125uL + 125uL dilution buffer;

[0421] 10) Prepare 1x wash buffer, add 300uL per well to the well plate and wash three times, and wait for 30s after adding wash buffer each time to ensure washing;

[0422] 11) Add the diluted sample and standard curve to the well plate, 100uL per well, incubate at room temperature for 2h

[0423] 12) Repeat step 10, wash the plate three times

[0424] 13) Prepare Detection antibody, the final concentration is 10ng / mL, add 100uL per well to the well plate, incubate at room temperature for 2h;

[0425] 14) Repeat step 10, wash the plate three times;

[0426] 15) Prepare SA-HRP, the final concentration is 1x, add 100uL per well to the well plate, incubate at room temperature for 30min;

[0427] 16) Repeat step 10, wash the plate three times;

[0428] 17) Add 100uL TMB solution, develop color at room temperature for 20min in the dark;

[0429] 18) Add 50uL Stop solution, shake well, and read OD450-570 when the solution is completely yellow.

[0430] 4. Experimental data processing method:

[0431] IC50 was calculated from compound concentration and corresponding inhibition rate and non-linear fitting with XLfit four parameters log(inhibitor) vs. response - Variable slope (four parameters).

[0432] 5. Experimental conclusion:

[0433] 5. Experimental conclusion: The compound of the application has a good inhibitory effect on the release of IL-8 of TNF stimulated hPBMC.

[0434] III. Pharmacokinetics determination of Balb / C mice

[0435] 1. Purpose of the study: The pharmacokinetic behavior of the compound of the application in the plasma of mice was studied at a dose of 30 mg / kg by oral administration in Balb / C mice as test animals.

[0436] 2. Experimental scheme

[0437] 2.1 Test drug: The compound of the application, self-made.

[0438] 2.2 Test animals: Balb / C Mouse (3 per example), male, Shanghai Bk Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0439] 2.3 Administration: Balb / C mice, male; after fasting overnight, p.o. at a dose of 30 mg / kg, and the administration volume was 10 mL / kg.

[0440] 2.4 Sample collection: Before and after administration of the mice, at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, 0.04 mL of blood was collected from the eye socket into an EDTA-K2 test tube, and the plasma was separated by centrifugation at 4°C at 6000 rpm for 6 min, and stored at -80°C.

[0441] 2.5 Sample processing:

[0442] 1) 20 uL of plasma sample was added to 100 uL of acetonitrile for precipitation, and after mixing, centrifugation was performed at 5000 x g for 15-20 minutes.

[0443] 2) The supernatant solution after treatment was taken for LC / MS / MS analysis of the concentration of the test compound, and the LC / MS / MS analyzer was AB Sciex API 4000.

[0444] 2.6 Liquid analysis

[0445] Liquid phase conditions: Shimadzu LC-20AD pump

[0446] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0447] Column: Waters Xbridge C18 5 μm, 4.6 X 50 mm

[0448] Mobile phase: A liquid is 0.1% formic acid aqueous solution, B liquid is methanol flow rate: 1 mL / min

[0449] Elution time: 0-4.0 minutes, eluent as follows:

[0450] 3. Test results and analysis

[0451] The main pharmacokinetic parameters were calculated by WinNonlin 6.1, and the results of the mouse pharmacokinetic experiment are shown in Table 8 below:

[0452] 4. Experimental conclusion: The compound of the present application shows good pharmacokinetic properties.

[0453] Four, Caco-2 cell permeability test of the compound

[0454] I. Experimental purpose

[0455] The purpose of this test 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.

[0456] II. Compounds and test materials

[0457] 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 use.

[0458] 2.2 Control compounds: Cimetidine, Metoprolol, Erythromycin are prepared as 10 mM stock solutions for use.

[0459] 2.3 Caco-2 cells are purchased from American Type Culture Collection (ATTC), PBS (Gibco, pH 7.4), HBSS (Sigma), DMEM medium (Gibco), Fluorescent Yellow (sigma), HEPES (Solarbio).

[0460] III. Experimental introduction

[0461] Caco-2 cells are a human colon carcinoma cell line that, under specific culture conditions, forms a tightly connected and differentiated cell layer that resembles the morphology and function of human small intestinal cells. Because of the expression of multiple types of transporters, Caco-2 cells can be used to construct an in vitro model for studying the absorption of drugs by small intestinal epithelial cells. Using the Caco-2 cell permeability model, the bidirectional permeability of the compounds was determined by adding the drug to the apical side and the basolateral side of the cell monolayer, respectively. At the same time, because the apical side of the cells expresses efflux transporters, the efflux ratio can be used to preliminarily assess whether the compound is an efflux substrate.

[0462] IV. Experimental procedures

[0463] 4.1 Preparation of transport buffer

[0464] Take 1 mL of 1M HEPES and 99 mL of HBSS to prepare a 10 mM HBSS transport buffer.

[0465] 4.2 Preparation of fluorescent yellow solution

[0466] Take 100 mL of transport buffer and 100 uL of fluorescent yellow solution (20 mM) to prepare a 20 uM fluorescent yellow working solution.

[0467] 4.3 Preparation of compound working solution

[0468] Preparation of compound working solution: Add 1 uL of compound stock solution to 999 uL of fluorescent yellow working solution to prepare a 10 uM working solution. Depending on the properties of the compound, the preparation ratio can be adjusted to adjust the final concentration.

[0469] Preparation of control compound working solution: The preparation process is consistent with that of the compound.

[0470] 4.4 Preparation of reaction termination solution

[0471] 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.

[0472] 4.5 Test procedure

[0473] a. Construction of Caco-2 cell permeability model

[0474] Remove the Caco-2 plate from the incubator. Wash the monolayer twice with preheated HBSS (25 mM HEPES, pH 7.4). Then incubate the plate at 37°C

[0475] b. Compound permeability test

[0476] 1) Assay compound transport rate from apical to basal side. Take 8 uL sample, add 72 uL HBSS to 240 uL acetonitrile containing internal standard as 0 min dosing sample on the apical side of the Transwell.

[0477] 2) Assay compound transport rate from basal to apical side. Take 8 uL sample, add 72 uL HBSS to 240 uL acetonitrile containing internal standard as 0 min dosing sample on the basal side of the Transwell.

[0478] 3) Combine the upper and lower apparatus and incubate in 37 °C incubator for 120 min.

[0479] 4) Take 8 uL sample from the dosing side (D side), dilute 10 times with 72 uL transport buffer, add 240 uL acetonitrile containing internal standard to stop, as the working solution of the dosing side (D side) at T120.

[0480] 5) Take 80 uL sample from the A to B receiving side (R side), add 240 uL acetonitrile containing internal standard to stop; take 100 uL sample from the B to A receiving side (R side), add 240 uL acetonitrile containing internal standard to stop.

[0481] 6) Take 20 uL sample from the basal side, add 100 uL transport buffer; take 120 uL sample from the basal side, detect the fluorescence intensity at the excitation / emission spectrum of 480 / 530 nm.

[0482] 7) Centrifuge the sample at 3500 rpm for 10 min, take the supernatant for LC-MS / MS analysis.

[0483] 4.6 Chromatographic analysis

[0484] 1) Chromatographic conditions Instrument: Shimadzu LC-30AD; Chromatographic column: Biphemyl 2.7 μm, 2.1 x 50 mm; Mobile phase: A: 0.1% formic acid water; B: 0.1% formic acid acetonitrile

[0485] Wash gradient: 0-0.7 min 5% A to 95% A, 1.2-1.5 min 95% A to 5% A;

[0486] Flow rate: 0.7 ml / min; Run time: 1.5 min; Injection volume: 5 μL.

[0487] 2) Mass spectrometric conditions

[0488] Instrument: API5500 Qtrap type liquid chromatograph mass spectrometer, AB Sciex Company;

[0489] Ion source: electrospray ionization source (ESI); drying gas: N2, temperature 420℃; electrospray voltage: 5500V; detection mode: positive ion detection; scanning mode: reaction monitoring (MRM) mode;

[0490] V. Experimental results:

[0491] The bidirectional permeability of the compound of the embodiment of the present application through the Caco-2 cell model is shown in the following table,

[0492] VI. Experimental conclusion:

[0493] From the experimental structure in the above table, it can be seen that the compound of the embodiment of the present application has high permeability.

[0494] V. In vivo pharmacodynamic study of the compound in a collagen antibody-induced mouse arthritis model

[0495] 1.1 Purpose of the experiment

[0496] To evaluate the in vivo efficacy of the compound in a collagen antibody-induced mouse arthritis model.

[0497] 1.2 Reagents

[0498] 1. Mice arthritis inducer 5-clone agent (53100, Chondrex)

[0499] 2. Tween 80 (30189828, Sinoreagent)

[0500] 3. Sodium carboxymethylcellulose (30036365, Sinoreagent)

[0501] 1.3 Experimental operation and data processing

[0502] 1.3.1 Animal procurement

[0503] BALB / c nude mice, 8-10 weeks, ♀, purchased from Shanghai Family Planning Science Institute Experimental Animal Operation Department.

[0504] 1.3.2 Establishment of CAIA model

[0505] a. After the animals adapt for 2-3 days, mark them with a disposable ear tag, and then randomly group the animals according to their weight after weighing;

[0506] b. On the experimental day (i.e. D0), inject 5-clone antibody mixture 1.0 mg into the tail vein or abdominal cavity of the animals;

[0507] 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-clone mixture and the LPS are thawed and placed on wet ice);

[0508] 1.3.3 Dosing, Weighting Score

[0509] a, D1 after LPS injection, the test drug was administered (Dosing method: oral administration; Dosing volume: 10 mL / kg; Dosing frequency: QD / BID; Dosing period: 7 days; Solvent: 0.5% CMC-Na / 1% Tween);

[0510] b, from the second day of the experiment, the mice were weighed every day, and the CAIA arthritis score of the mouse paw was scored (score from D2 to D7);

[0511] CAIA clinical score criteria (total score is the sum of 4 paws, total score 0-16)

[0512] 0 normal;

[0513] 1 ankle / tarsus / toe joint, any one part red, swollen;

[0514] 2 ankle / tarsus / toe joint, any two parts red, swollen;

[0515] 3 ankle / tarsus / toe joint, three parts have obvious redness and swelling;

[0516] 4 ankle / tarsus / toe joint maximum inflammation, swelling.

[0517] c, euthanize the animals after the experiment.

[0518] d, process the data with software such as Excel. Calculation of the percentage (%) of compound inhibition of CAIA arthritis:

[0519] TGI (%) = [1-(average arthritis score of the compound administration group at the end / average arthritis score of the solvent control group at the end)] x 100%.

[0520] 1.4 Experimental results and conclusions:

[0521] In the antibody collagen-induced mouse arthritis model, the compounds of the embodiments of the application can effectively improve the symptoms of arthritis, and the animals have good tolerance at the therapeutic dose. According to the D7 score, the relative treatment rate of the compounds of the embodiments of the application (30 mg / kg, BID) is 55% to 95%, and the relative treatment rate of some compounds is 70% to 90%.

[0522] Six, in vitro metabolic stability of the compounds of the application in mouse, rat and dog liver microsomes

[0523] 1. Purpose of the experiment: The purpose of this experiment is to evaluate the phase I and part of phase II metabolic stability of the compounds in mouse, rat and dog liver microsomes, respectively.

[0524] 2. Experimental design

[0525] 2.1 Test drug: The compound of the present application, self-made, Alamethicin (Abeam), 7-Hydroxycoumarin (Sigma), liver microsomes (XenoTech, Shanghai Quanyang Biotechnology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4), NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai Bidai Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abeam), methanol (Merck), acetonitrile (Merck).

[0526] 2.2 Drug preparation: The compound of the present application 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.

[0527] Control compound: 7-Hydroxycoumarin is prepared as a 10 mM stock solution for later use.

[0528] 2.3 Experimental procedure

[0529] 1) Preparation of buffer solution: 4.01 mL of 1M K2HPO4·3H2O (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade) are dissolved in ultrapure water and made up to 50 mL to prepare a 100 mM phosphate buffer solution.

[0530] 2) Preparation of compound working solution

[0531] Preparation of compound working solution: 2 μL of compound stock solution is added to 998 μL of phosphate buffer solution to give a final concentration of 20 μM. Depending on the properties of the compound, the preparation ratio can be adjusted to adjust the final concentration.

[0532] Preparation of control compound working solution: the preparation process is consistent with that of the compound.

[0533] 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.

[0534] 4) Preparation of NADPH and UDPGA: 33.3 mg of NADPH and 25.8 mg of UDPGA are weighed and added to 2 mL of 100 mM phosphate buffer, and the final concentration is 20 mM.

[0535] 5) Prepare the Puncturing agent (Alamethicin): Take 1 mg Alamethicin and add it to 200 μL methanol to make a 5 mg / mL solution. Take 10 μL from this solution and add it to 990 μL phosphate buffer (pH 7.4) to make a final concentration of 50 μg / mL.

[0536] 6) Prepare the reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to make the termination solution, and store it in a 2-8 °C refrigerator.

[0537] 7) Incubation procedure: Add 400 μL prepared liver microsomes, 25 μL compound working solution (10 μM) and 25 μL Alamethicin (50 μg / mL) into a 96-well plate in sequence, and pre-incubate at 37 °C for 10 min. Then add 50 μL 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:

[0538] Take 50 μL at 0, 5, 15, 30, 60 and 120 min, respectively, and add 200 μL cold termination solution containing the internal standard to terminate the sample reaction. Centrifuge at 3500 rpm for 10 min, and take the supernatant for LC-MS / MS analysis.

[0539] 2.4 Chromatographic analysis

[0540] 1) Chromatographic conditions

[0541] Instrument: Shimadzu LC-30AD; Column: C18 (50*4.6 mm, 5 μm particle size);

[0542] Mobile phase: A: 0.1% formic acid in water, B: methanol;

[0543] Wash gradient: 0.2-1.6 min 10% A to 95% A, 3.0-3.1 min 95% A to 10% A;

[0544] Flow rate: 1.0 ml / min; Run time: 4.0 min; Injection volume: 5 μL.

[0545] 2) Mass spectrometric conditions

[0546] Instrument: API 5500 Qtrap liquid chromatograph-mass spectrometer, AB Sciex Company;

[0547] Ion source: Electrospray ionization source (ESI); Dry gas: N2, temperature 500 °C;

[0548] Electrospray voltage: 5000 V; detection method: positive ion detection;

[0549] Scanning mode: reaction monitoring (MRM) mode;

[0550] 3. Experimental results and data processing

[0551] The original data is calculated according to the following formula:

[0552] Residual rate % = peak area ratio of compound to internal standard at any time point / peak area ratio of compound to internal standard at 0 minutes × 100

[0553] T 1 / 2 =0.693 / Ke, where Ke represents the elimination rate constant.

[0554] In vitro liver microsomal intrinsic clearance (CL) was calculated by Ke int ) and hepatic intrinsic clearance (CL int,liver )CL int =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation mg / mL)

[0555] CL int,liver =CL int × amount of microsomal protein in the liver (mg / g) × liver weight to body weight ratio

[0556] Based on the well-stirred model, the in vivo hepatic clearance (CL int,liver )

[0557] CL=(CL int,liver ×fu×Qh) / (CL int,liver ×fu+Qh), where fu represents the free fraction in blood and is 1 by default.

[0558] The parameters in the formula are shown in the table below.

[0559] The test results are as follows:

[0560] Experimental conclusion: The compound of the present invention has good metabolic stability.

Claims

1. A compound represented by Formula (II-2) or Formula (II-2-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ###00001### (II-2) (II-2-1). wherein: R 1-1 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, 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, can be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C R 1-2 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, can be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C R 1-3 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, 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 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, 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 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, 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 can be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; R'2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from aryl and 5-10 membered heteroaryl; R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, 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 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions selected from 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' 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, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C1-6alkoxy, C1-6deuteroalkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-8cycloalkyl, 3-8 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein the amino, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C1-6alkoxy, C1-6deuteroalkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-8cycloalkyl, 3-8 membered heterocyclyl, C6-10aryl, and 5-10 membered heteroaryl groups are optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C1-6alkoxy, C1-6deuteroalkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-8cycloalkyl, 3-8 membered heterocyclyl, C6-10aryl, or 5-10 membered heteroaryl; 1-6 2-6 2-6 1-6 1-6 1-6 1-6 1-6 1-6 3- 6-10 1-6 2- 2-6 1-6 1-6 1-6 1-6 1-6 1-6 3-8 6-10 1-6 2-6 2-6 1-6 1-6 1-6 1-6 1-6 1-6 3-8 ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​cycloalkyl, 3-8 membered heterocyclyl, C 6-10 one or more of aryl and 5-10 membered heteroaryl; y is 0, 1 or 2; z is 0, 1, 2 or 3; w is 0, 1, 2, 3 or 4; 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; m7 and m7' are each independently selected from 0, 1, 2 or 3.

2. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1-1 and R 1-2 each independently is selected from the group consisting 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, or 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 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; preferably, R 1-1 and R 1-2 each independently is selected from hydrogen or fluorine; R 1-1 and R 1-2 are each independently selected from the group consisting of hydrogen, fluorine, methyl or ethyl; preferably R 1-3 are independently selected from amino, hydroxyl, cyano or C 1-6 alkyl; preferably R 1-3 are independently selected from hydrogen or methyl.

3. The compound according to any one of claims 1 to 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein 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 6-10 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 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; preferably, R2is selected from hydrogen; Preferably, R'2 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, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -(CH2)OR' a11 OR' a11 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The aryl or 5-6 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 One or more substitutions of aryl and 5-6 membered heteroaryl; 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 3-6 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 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 one or more of hydrogen, halogen, amino, cyano, hydroxyl, C 1-3 alkyl, C 2- 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.

4. The compound according to any one of claims 1 to 3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein 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- 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- 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 aryl and 5-6 membered heteroaryl; preferably, R3is selected from hydrogen.

5. The compound according to any one of claims 1 to 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R4is selected from methyl, ethyl, -CD3, -CH2CHF2, -CH2CH2F, Preferably, R4 is selected from COCH3.

6. The compound of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein The compounds are shown below:

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

8. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the inhibition of TNFα.

9. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of 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.

Images