CN118510776A - Derivatives containing five-membered rings, preparation methods and applications thereof - Google Patents

Abstract

The present invention relates to a five-membered ring derivative, a preparation method and application thereof. In particular, the present invention relates to a compound represented by a general formula, a preparation method thereof and a pharmaceutical composition containing the compound, and application thereof as a bioregulator in the preparation of a drug for treating autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancer, tumors, leukemia and lymphoma, wherein each substituent in the general formula has the same definition as in the specification.

Description

Derivatives containing five-membered rings, preparation methods and applications thereof Technical Field

The present invention belongs to the field of biomedicine, and specifically relates to a five-membered ring derivative, a preparation method and application thereof.

Background Art

MK2 (MAPK activated protein kinase 2) is a protein kinase that is an important downstream molecule of the classic inflammatory signal transduction pathway MAPK and regulates the expression of inflammatory factors. After cells are stimulated by inflammatory factors, the activated p38 MAPK protein phosphorylates and activates MK2, leading to the phosphorylation of MK2 substrate TTP, promoting the stability of pro-inflammatory cytokine mRNA, thereby increasing the protein expression level of inflammatory cytokines.

In both mouse arthritis models and chondrocytes of osteoarthritis patients, MK2 is activated. Inhibiting the p38-MK2 pathway by genetic or pharmacological means can inhibit the expression of inflammatory factors, indicating that MK2 is involved in mediating the inflammatory regulation of arthritis. p38-MK2 inhibitors are expected to treat patients with relapsed, refractory rheumatoid arthritis who have poor response to existing therapies.

Currently, only Aclaris Therapeutics' p38-MK2 inhibitor ATI-450 has entered clinical stage IIb for rheumatoid arthritis. Preliminary clinical trial results show that ATI-450 is safe and well tolerated in patients with rheumatoid arthritis, with outstanding and sustained efficacy. Other MK2 inhibitors in clinical trials include BMS's CC-99677 and Moerae Matrix's MMI-0100, both of which can directly inhibit the activity of MK2, with a different mechanism from ATI-450.

The patent applications for p38-MK2 (or MK2) inhibitors that have been published include: Aclaris Therapeutics patents (WO-2012078684, WO-2013086208, WO-2014197846, WO-2021022186, WO-2012078687, WO2012078673, WO2012078674); BMS patents (WO-2020236636, WO-2018170199, WO-2016044463, WO-2018170201, WO-2018170200, WO-2018170203, US20210198276, US20210139501, US20200148701, US20200102326); Moerae Matrix patents (WO-2016112292, WO-2016145234, US-10336788, WO-2014040074, WO-2018231722, WO-2012142320, WO-2016033432, WO-2013134636, WO-2011149964), etc.

As a drug, p38-MK2 inhibitors have good application prospects in the pharmaceutical industry. p38-MK2 inhibitors provide a safer and more effective treatment for patients with rheumatoid arthritis who are relapsed, refractory, and poorly responsive to existing therapies; p38-MK2 inhibitors have a broad spectrum of anti-inflammatory effects (TNF/IL-6/IL-1), and can theoretically be used to treat a variety of inflammatory diseases and autoimmune diseases; p38-MK2 inhibitors are small molecule inhibitors, which have advantages over macromolecular drugs such as TNF monoclonal antibodies, such as oral convenience and good patient compliance. At the same time, p38-MK2 inhibitors have not been reported to have the toxic side effects of JAK inhibitors such as infection, tumors, thrombosis, and cardiac toxicity. Therefore, there is a huge clinical demand for the development of new p38-MK2 inhibitors.

Summary of the invention

The object of the present invention is to provide a compound represented by general formula (I-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I-2) has the following structure:

in:

Ring C is selected from phenyl, thiazolyl, pyrazolyl, pyrimidinyl or pyridinyl;

_L1 is selected _from a bond or -( _CH2 ) _nO ( _CRaaRbb ) _n1- ;

R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, C _1-8 alkyl or C _1-8 deuterated alkyl, wherein the C _1-8 alkyl or C _1-8 deuterated alkyl may be further substituted;

M ₅ is selected from CR ⁵ , N, NR ⁵ , O or S;

M ₆ is selected from CR ⁶ , N, NR ⁶ , O or S;

M ₇ is selected from CR ⁷ or NR ⁷ ;

M ₈ is selected from CR ⁸ , N, NR ⁸ , O or S;

M ₉ is selected from C or N;

^R5 , ^R6 and ^R8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 hydroxyalkyl, _C1-8 alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 alkoxy, _C1-8 haloalkoxy, _C1-8 hydroxyalkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or _5-14 membered heteroaryl is selected. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1-8 haloalkyl, C 1-8 hydroxyalkyl} , C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _{1-8 haloalkoxy, C 2-8 alkenyl} , C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

Preferably, R ⁵ , R ⁶ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 haloalkoxy, C _{1-6 hydroxyalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl. C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1-6 haloalkyl, C 1-6 hydroxyalkyl} , C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

^R7 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, bridged cycloalkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _{C6-14 aryl} , 5-14 membered heteroaryl, -(CReeRff) _n4C ( _O ) _Rgg , _- ( _CReeRff ) _n4NRhhC (O) _Rgg , _{- ( CReeRff ) n4S} (O) _2Rgg , _{- (} CReeRff) _n4C (O) _{NRhhRgg or} -(CR wherein _the amino, _C1-8 alkyl, bridged cycloalkyl, _{C1-8 deuterated alkyl, C1-8} haloalkyl, C1-8 alkoxy, C1-8 _haloalkoxy , _{C1-8 hydroxyalkyl} , _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _{C6-14 aryl and} 5-14 membered heteroaryl _may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl _{, C1-8} alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and _5-14 membered heteroaryl. substituted by one or more substituents selected from _3-12- membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl;

Preferred are hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _{C6-10 aryl ,} 5-10 membered heteroaryl, -( _CReeRff ) _n4C (O _{)Rgg, -(CReeRff)n4NRhhC(O)Rgg , - ( CReeRff ) n4S (} O _{) 2Rgg, -(CReeRff)n4C ( O ) NRhhRgg or -} ( _CReeRff ) _n4 S(O) ₂ NR _hh R _gg ； The amino, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C 1-6 hydroxyalkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C 1-6 alkyl} , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted by one or more substituents selected from _3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C 1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

Preferably, R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

Alternatively, any two adjacent or non-adjacent substituents of R ⁵ , R ⁶ , R ⁷ and R ⁸ are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl group may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Preferably, any two adjacent or non-adjacent substituents are linked to form a _C3-8 cycloalkyl, a 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, a _C6-10 aryl, or a 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, wherein the _C3-8 cycloalkyl, the 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, the _C6-10 aryl, or the 5-10 membered heteroaryl containing 1-3 N, O, or S atoms may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-4 alkyl, _C1-4 deuterated alkyl, _C1-4 haloalkyl, _C1-4 hydroxyalkyl, _C1-4 alkoxy, _C1-4 deuterated alkoxy, _C1-4 haloalkoxy, _C2-3 alkenyl, C substituted by one or more substituents selected from _C2-3 alkynyl, _C5-8 cycloalkyl, 5-8 membered heterocyclyl, _C6-8 aryl and 5-8 membered heteroaryl; more preferably, any two adjacent or non-adjacent substituents are linked to form Optionally, it may be further substituted with one or more of deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, cyano, oxo, thio, carboxyl, methyl, ethyl, propyl, butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl;

x is an integer from 0 to 6;

y is an integer from 0 to 6;

z is an integer from 0 to 6;

n is 0, 1, 2 or 3;

n1 is 0, 1, 2 or 3;

n4 is 0, 1, 2, 3 or 4.

In a further preferred embodiment of the present invention, the compound is further represented by general formula (VI), (X) or (XI):

in:

M ₅ is selected from CR ⁵ , N, NR ⁵ , O or S;

M ₆ is selected from CR ⁶ , N, NR ⁶ , O or S;

M ₇ is selected from CR ⁷ or NR ⁷ ;

M ₈ is selected from CR ⁸ , N, NR ⁸ , O or S;

M ₉ is selected from C or N;

^R5 , ^R6 and ^R8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 hydroxyalkyl, _C1-8 alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 alkoxy, _C1-8 haloalkoxy, _C1-8 hydroxyalkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or _5-14 membered heteroaryl is selected. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1-8 haloalkyl, C 1-8 hydroxyalkyl} , C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _{1-8 haloalkoxy, C 2-8 alkenyl} , C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

Preferably, R ⁵ , R ⁶ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 haloalkoxy, C _{1-6 hydroxyalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl. C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1-6 haloalkyl, C 1-6 hydroxyalkyl} , C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

^R7 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl _{, C1-8 hydroxyalkyl, C1-8 alkoxy, C1-8 deuterated alkoxy, C1-8 haloalkoxy, C2-8 alkenyl , C2-8 alkynyl , C3-12} cycloalkyl, _3-12 membered heterocyclyl, _{C6-14 aryl} , 5-14 membered heteroaryl, -( _{CReeRff ) n4C} (O) _Rgg , _- (CReeRff) _n4NRhhC (O) _Rgg , _{- (} CReeRff _{) n4S} (O) _2Rgg , - ₍ CReeRff) _n4C (O) _{NRhhRgg or} - _{( CReeRff ) n4} ) _n4 S(O) ₂ NR _hh R _gg ； The amino, C _1-8 alkyl, C _1-8 deuterated alkyl, C 1-8 haloalkyl, C _1-8 alkoxy, C _1-8 haloalkoxy, C 1-8 hydroxyalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C _1-8 deuterated alkoxy, C _{1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C 1-8 alkyl} , C _1-8 deuterated alkyl, C _1-8 haloalkyl, C 1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 deuterated alkoxy, C 1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C substituted by one or more substituents selected from _3-12- membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl;

Preferred are hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _{C6-10 aryl ,} 5-10 membered heteroaryl, -( _CReeRff ) _n4C (O _{)Rgg, -(CReeRff)n4NRhhC(O)Rgg , - ( CReeRff ) n4S (} O _{) 2Rgg, -(CReeRff)n4C ( O ) NRhhRgg or -} ( _CReeRff ) _n4 S(O) ₂ NR _hh R _gg ； The amino, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C 1-6 hydroxyalkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C 1-6 alkyl} , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted by one or more substituents selected from _3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C 1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

Preferably, R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

n4 is 0, 1, 2, 3 or 4;

_L1 is selected from a bond, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, -( _CH2 ) _n- , -( _CH2 ) _nC (O) _{(CRaaRbb ) n1-} , -( _CH2 ) _nC (O) _NRcc ( _{CH2 ) n1-} , -( _{CH2 ) n(CRaaRbb)n1-, -(CRaaRbb)nO ( CH2 ) n1- , - ( CH2} ) _nO ( _CRaaRbb ) _n1- , _- (CRaaRbb) _{nS ( CH2} ) _n1- , -( _CH2 ) _nS ( _{CRaaRbb ) n1-} , -( _CRaaRbb ) _n ( _CH2 ) _n1NRcc- , -( _CH2 ) _{nNRcc ( CRaaRbb ) n1-} , - _{( CH 2} ) _n NR _cc C(O)-, -(CH ₂ ) _n P(O) _p R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _cc - and -(CH ₂ ) _n NR _cc S(O) _m -;

_Raa , _Rbb and _Rcc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, any two of _Raa , _Rbb and _Rcc are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

R ^{a is} each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, any two adjacent or non-adjacent ^Ras are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

Alternatively, L ₁ and R ^a are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

R ^{b is} each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, any two adjacent or non-adjacent R ^b are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

Alternatively, L ₁ and R ^b are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

Alternatively, ^Ra and ^Rb are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may be further substituted;

R ^c is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, any two adjacent or non-adjacent R ^c are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

Alternatively, R ^b and R ^c are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

x is an integer from 0 to 6;

y is an integer from 0 to 6;

z is an integer from 0 to 6;

n is 0, 1, 2, or 3;

n1 is 0, 1, 2, or 3;

m is 0, 1, 2 or 3;

p is 0, 1, 2 or 3.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (VI-1) or (VI-2), (XI-1) or (XI-2):

In a further preferred embodiment of the present invention, the compound is further represented by general formula (VIII):

In a further preferred embodiment of the present invention, the compound is further represented by general formula (VIII-1) or (VIII-2):

In a further preferred embodiment of the present invention, the compound is further represented by general formula (IX):

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IX-1) or (IX-2):

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (VI-3) or (XI-3):

in:

R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, C _1-8 alkyl or C _1-8 deuterated alkyl, and the C _1-8 alkyl or C _1-8 deuterated alkyl may be further substituted.

In a further preferred embodiment of the present invention, _L1 is selected from a bond, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, -( _CH2 ) _n- , -( _CH2 ) _nC (O)(CRaaRbb _{) n1-} , -( _CH2 )nC(O) _NRcc ( _CH2 ) _n1- , _- ( _CH2 ) _n ( _{CRaaRbb ) n1-} , _- ( _{CRaaRbb ) nO} ( _CH2 ) _n1- , -( _CH2 ) _nO (CRaaRbb) _n1- , -( _CRaaRbb ) _nS ( _CH2 ) _{n1- ,} -( _CH2 ) _{nS(CRaaRbb)n1- , - ( CRaaRbb ) n ( CH2 )n1NRcc- , - ( CH2} ) _nNRcc ( _{CRaaRbb ) n1} -, -(CH ₂ ) _n NR _cc C(O)-, -(CH ₂ ) _n P(O) _p R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _cc - and -(CH ₂ ) _n NR _cc S(O) _m -;

Preferably, _L1 is selected from a bond, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, -( _CH2 ) _n- , -( _CH2 ) _{nC (} O)-, -( _CRaaRbb )nO- _{, -O} ( _CRaaRbb ) _n1- , -( _CRaaRbb ) _nS- , _{-S ( CRaaRbb} ) _n1- , -( _CH2 ) _{n1NRcc- , -NRcc ( CRaaRbb ) n1-} or _-NRccC (O)-;

More preferably, L ₁ is selected from a bond, -CH ₂ -, -OCH ₂ -, -OCD ₂ -, -NH-, -C(O)NH-, -OCH(CH ₃ )-, -OC(CH ₃ ) ₂ -, -NH-CH ₂ - or

R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Preferably, _Raa , _Rbb and _Rcc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy, _C1-3 haloalkoxy, _C2-4 alkenyl, C2-4 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, _C1-3 hydroxyalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _{1-3 deuterated alkoxy, C 1-3 haloalkoxy} , C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

Alternatively, any two of _Raa , _Rbb and _Rcc are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy and _C1-6 haloalkoxy;

Preferably, any two of _Raa , _Rbb and _Rcc are linked to form a _C3-8 cycloalkyl, a 3-8 membered heterocyclyl, a _C6-10 aryl or a 5-10 membered heteroaryl, and the _C3-8 cycloalkyl, the 3-8 membered heterocyclyl, the _C6-10 aryl and the 5-10 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy and _C1-3 haloalkoxy.

In a further preferred embodiment of the present invention, the compound is further represented by general formula (XII-D):

in:

_X1 is selected from N or CR ^a5 ;

_X3 is selected from N or CR ^b1 ;

^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 or ^Ra5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl;

Alternatively, any two adjacent or non-adjacent ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 and ^Ra5 are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the C3-12 cycloalkyl, the _3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl _{, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , 3-12 membered heterocyclyl ,} C6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl;

R _aa or R _bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6 haloalkoxy} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, _Raa and _Rbb are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy , C1-6} haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl;

R ^b1 , R ^b2 or R ^b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, the ^Rb1 and ^Rb2 substituents are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl} , _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl;

R ^c1 , R ^c2 or R ^c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, the R ^c1 and R ^c2 substituents are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, the R ^c1 and R ^b2 substituents are linked to form a 3-12 membered heterocyclyl or a 5-14 membered heteroaryl, and the 3-12 membered heterocyclyl and the 5-14 membered heteroaryl may be further optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

R _da , R _db , R' _da or R' _db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 alkoxy _, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, any two adjacent or non-adjacent R _da , R _db , R' _da and R' _db are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6 haloalkoxy} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl;

^R6 or ^R8 is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy _{, C1-6} haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, ^R6 and ^R8 are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl} , _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl;

n7 is 0, 1, 2 or 3;

Preferably, the Not for

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (XIII-B) or (XIII-B'):

in:

_X1 is selected from N or CR ^a5 ;

^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 or ^Ra5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl;

Alternatively, any two adjacent or non-adjacent ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 and ^Ra5 are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the C3-12 cycloalkyl, the _3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl _{, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , 3-12 membered heterocyclyl ,} C6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl;

R _aa or R _bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6 haloalkoxy} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, _Raa and _Rbb are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy , C1-6} haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl;

^Rb2 and ^Rb3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6} hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy _{, C1-6} haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

R ^c1 , R ^c2 or R ^c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, the R ^c1 and R ^c2 substituents are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, the R ^c1 and R ^b2 substituents are linked to form a 3-12 membered heterocyclyl or a 5-14 membered heteroaryl, and the 3-12 membered heterocyclyl and the 5-14 membered heteroaryl may be further optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

^R7 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _{C1-6 deuterated alkyl, C1-6 cycloalkyl} , _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl , C3-12} cycloalkyl, 3-12 membered heterocyclyl, _{C6-14 aryl} , 5-14 _membered heteroaryl, - ₍ CReeRff) _n4C ( _O )Rgg, _- (CReeRff _{) n4NRhhC} ( _O ) _{Rgg ,} - ₍ CReeRff) _n4NRhhORgg , _- ( _{CReeRff ) n4S} (O) _{wherein the} amino _{, C} 1-6 _alkyl , C 1-6 _deuterated alkyl _, C 1-6 bridged _cycloalkyl , C 1-6 haloalkyl, C _{1-6 hydroxyalkyl} , _C 1-6 _alkoxy , _{C 1-6 deuterated} alkoxy, C 1-6 haloalkoxy, C 2-6 _alkenyl , C 2-6 alkynyl, C 2-6 alkylene group is selected from the group consisting of: -(CR _ee R _ff ) _n4 S(O) _{R gg} , -(CR _ee R _ff ) _n4 SR _gg , _- (CR _ee R _ff ) _n4 C(O)NR hh R _gg , _- (CR ee R _{ff ) n4 S} (O)NR _hh R gg , -(CR _{ee R} ff _{) n4} SNR _hh R _gg or -(CR _ee R ff ) n4 S(O) 2 NR hh R gg; C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

or R _ee and R _ff are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

^R6 or ^R8 is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy _{, C1-6} haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, any two adjacent or non-adjacent R ⁶ , R ⁷ and R ⁸ are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl;

n4 is 0, 1, 2, 3 or 4.

In a further preferred embodiment of the present invention, the compound is further represented by the general formula (XII-D-1), (XII-D-2), (XIII-B-1), (XIII-B-2), (XIII-B'-1) or (XIII-B'-2):

In a further preferred embodiment of the present invention, the Ra described in the present invention ^is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, and the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, _C1-6 haloalkoxy, _{C1-6 hydroxyalkyl, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Preferably, Ra ^is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _{C1-3 deuterated alkoxy, C1-3 haloalkoxy} , _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl _{, C1-3} alkoxy, _C1-3 haloalkoxy, _C1-3 hydroxyalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. The _6-10 membered aryl and 5-10 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl.

In a further preferred embodiment of the present invention, the ^Rb of the present invention is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, and the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, _C1-6 haloalkoxy, _{C1-6 hydroxyalkyl, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Preferably, R ^{b is} each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C 1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C 1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-3 alkyl, C _{1-3 deuterated alkyl, C 1-3 haloalkyl} , C _{1-3 alkoxy, C 1-3 haloalkoxy} , C _1-3 hydroxyalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The _6-10 membered aryl and 5-10 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl.

In a further preferred embodiment of the present invention, the R ^c of the present invention is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or _5-14 membered heteroaryl, and the amino, C _1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _{3-12 membered heterocyclyl, C 6-14 aryl} or 5-14 membered heteroaryl. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Preferably, R ^c is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C 1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C 1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-3 alkyl, C _{1-3 deuterated alkyl, C 1-3 haloalkyl} , C _{1-3 alkoxy, C 1-3 haloalkoxy} , C _1-3 hydroxyalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. _6-10 membered aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _{1-3 haloalkyl, C 1-3 hydroxyalkyl} , C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

Alternatively, R ^b and R ^c are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, and the C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl.

In a further preferred embodiment of the present invention, ^R7 described in the present invention is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy, _C1-3 haloalkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl _{, 3-8} membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl, or -( _CReeRff ) _n4C (O) _{Rgg , -} (CReeRff _{) n4NRhhC} (O) _Rgg , _{- (} CReeRff) _n4S (O)2Rgg _, - _{( CReeRff} ) _n4 C(O)NR _hh R _gg or -(CR _ee R _ff ) _n4 S(O) ₂ NR _hh R _gg ;

R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

n4 is 0, 1, 2, 3 or 4.

In a further preferred embodiment of the present invention, ^R5 , ^R6 and ^R8 of the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-3 alkyl, _C1-3 deuterated alkyl, C1-3 haloalkyl, _C1-3 hydroxyalkyl, C1-3 alkoxy, _C1-3 deuterated alkoxy, _C1-3 haloalkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. The amino, _C1-3 alkyl, _C1-3 deuterated alkyl, C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, _C1-3 hydroxyalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. The invention further comprises a C _3-8 cycloalkyl, a 3-8 membered heterocyclyl, a C _6-10 aryl and a 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, a 3-8 membered heterocyclyl, a C _6-10 aryl and a 5-10 membered heteroaryl.

In a further preferred embodiment of the present invention, ^R6 of the present invention is selected from halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _{C1-6 deuterated alkyl, C1-6 haloalkyl} , C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, and the amino, _C1-6 alkyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Preferably, ^R6 is selected from halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl _, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl or _C2-6 alkynyl;

More preferably, R ⁶ is selected from fluorine.

In a further preferred embodiment of the present invention, ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 , ^Ra5 , ^Rb1 , Rb2, Rb3, ^Rc1 , ^Rc2 , ^Rc3 , ^Rda , ^Rdb , _R'da and _R'db described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, _hydroxyl , thiol, cyano, _amino , oxo, thio, carboxyl, _C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy, C1-3 haloalkoxy, C2-4 alkenyl, _C2-4 alkynyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, and the amino, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, C1-3 alkoxy, _C1-3 deuterated alkoxy, C1-3 haloalkoxy, C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. C _1-3 deuterated alkyl, C _1-3 haloalkyl, C 1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 hydroxyalkyl, C _2-4 alkenyl, C 2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C 1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C The aryl group is substituted by one or more substituents of _6-10 membered aryl and 5-10 membered heteroaryl.

The present invention further provides a method for preparing the compound of the aforementioned general formula (XII-D) or its stereoisomers and pharmaceutically acceptable salts thereof, comprising the following steps:

The general formula (M-1) reacts with the general formula (M-2) to obtain the target compound represented by the general formula (XII-D);

_X1 , _X3 , ^Ra1 , ^Ra2 , Ra3, ^Ra4 , _Raa , Rbb, Rb2, ^Rb3 , _Rc1 , ^Rc2 , ^Rc3 , ^{Rda , Rdb} , ^R'da , _R'db , _R6 , _R8 ^and n7 are as _described above.

The present invention further relates to a pharmaceutical composition, comprising a therapeutically effective dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients; further, the weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).

The present invention further relates to the use of the compound, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of drugs for treating diseases mediated by p38 kinase.

The present invention further relates to the use of the compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of drugs for treating autoimmune diseases, metabolic diseases and tumors, etc. The autoimmune diseases are selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases and atherosclerosis, etc.; the metabolic diseases are selected from diabetes and fibrotic diseases, etc.; the tumors are selected from leukemia and lymphoma, etc.

The present invention also relates to a method for treating, preventing and/or treating autoimmune diseases, metabolic diseases and tumors, etc., which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof; wherein the autoimmune disease is selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases and atherosclerosis, etc.; the metabolic disease is selected from diabetes and fibrotic diseases, etc.; the tumor is selected from leukemia and lymphoma, etc.

The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with p38 kinase-mediated diseases.

Detailed description of the invention

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 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 butyl, 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, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylbutyl Methylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which 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, n-heptyl, 4-heptyl, 1-propylbutyl, 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

The term "alkylene" refers to a divalent alkyl group formed by further replacing one hydrogen atom of an alkyl group, wherein alkyl is as defined above. For example, "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ -, etc. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through one carbon or any two carbons within the chain. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, which is a straight or branched group containing 2 to 20 carbon atoms, preferably an alkenyl group containing 2 to 12 carbon atoms, more preferably an alkenyl group containing 2 to 8 carbon atoms, further preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 4 carbon atoms. For example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

The term "alkenylene" refers to a divalent alkenyl group formed by further replacing one hydrogen atom of an alkenyl group, wherein the alkenyl group is as defined above, for example, vinylene, propenylene, butenylene, etc. The alkenylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight or branched group containing 2 to 20 carbon atoms, preferably an alkynyl group containing 2 to 12 carbon atoms, more preferably an alkynyl group containing 2 to 8 carbon atoms, further preferably an alkynyl group containing 2 to 6 carbon atoms, and most preferably an alkynyl group containing 2 to 4 carbon atoms. For example, ethynyl, propynyl, 1-butynyl, 2-butynyl or 3-butynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

The term "alkynylene" refers to a divalent alkynyl group formed by further replacing one of the hydrogen atoms of an alkynyl group, wherein the alkynyl group is as defined above. For example, ethynylene, propynylene, butynylene, etc. Alkynylidene can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan/6 yuan, 3 yuan/5 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include: wait;

It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include: wait.

The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include: wait.

The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 or 5 to 14, more preferably 7 to 10 or 5 to 10. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

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

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, C(O) or S(O) _m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 6 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclyl, optionally, substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including monocyclic heterocyclyl, spiro heterocyclyl or fused heterocyclyl.

Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyridonyl, pyranyl, tetrahydrothiopyran dioxide, wait.

Polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups; the spirocyclic, condensed and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 8 to 12 yuan. According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/5-yuan or 5-yuan/6-yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include: wait.

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 8 to 12 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 4-membered/5-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered/7-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include: wait.

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: wait.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

The term "heterocyclylalkylene" refers to a heterocyclyl group connected to an alkylene group to form a "heterocyclyl-alkylene-" group, wherein the heterocyclyl or alkyl group may be optionally substituted or unsubstituted, and the heterocyclyl and alkylene groups are as defined above.

The term "heterocyclylene" refers to a divalent heterocyclic group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heterocyclic group may be optionally substituted or unsubstituted, and the heterocyclic group is as defined above.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include: wait.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "arylene group" refers to a divalent aromatic group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the arylene group is optionally substituted or unsubstituted, and the aryl group is as defined above.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably a 5-6-membered monocyclic heteroaryl or an 8-12-membered bicyclic heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidyl or thiazolyl; more preferably tetrazolyl, pyridyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl.

Non-limiting examples of bicyclic heteroaryl groups include:

The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl groups include trifluoromethyl, -CH ₂ CF ₃ ,

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Aminocarbonyl" refers to _NH2 -C(O)-.

"Alkylaminocarbonyl" refers to an aminocarbonyl ( _NH2 -C(O)-) group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein alkyl is as defined above.

"Alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

"Alkylcarbonyl" or "acyl" refers to (alkyl)-C(O)- wherein alkyl is as previously described.

"Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carbonyl" refers to -C(O)-.

"Carboxy" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

"Ethyl acetate" means ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"TEA" refers to triethylamine.

"MeCN" refers to acetylene.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCM" refers to dichloromethane.

"DMAP" refers to 4-dimethylaminopyridine.

"DCC" refers to dicyclohexylcarbodiimide.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

Different expressions such as “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” all express the same meaning, that is, X can be any one or more of A, B, C.

The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

DETAILED DESCRIPTION

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

Example

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or deuterated water (D ₂ O), and the internal standard is tetramethylsilane (TMS).

Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

The eluent system of silica gel column chromatography and the developing solvent system of thin layer chromatography used for the intermediates and purified compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Unless otherwise specified, in the embodiments of the present invention, the ratios in the mobile phases in the HPLC chiral separation conditions and HPLC chiral analysis conditions are volume ratios.

Intermediate 1

2',3-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

2'-Chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one a (200 mg, 0.8 mmol, its synthesis method is referred to WO2014197846A1), 2-(chloromethyl)-3,5-difluoro-pyridine (157 mg, 0.96 mmol), potassium carbonate (276 mg, 1.99 mmol) and 18-crown-6 (21 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction was heated to 60 ° C and stirred for 16 hours. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one b (301 mg), yield: 99%.

MS m/z(ESI):378.1[M+H] ⁺ .

Step 2

2'-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one b (301 mg, 0.8 mmol) and N-chlorosuccinimide (117 mg, 0.88 mmol) were dissolved in isopropanol (6 mL), and the reaction was heated to 60°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one intermediate 1 (190 mg), with a yield of 57.9%.

MS m/z(ESI):412.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(s,1H),8.54(s,1H),8.07-8.13(m,1H),7.69(s,1H),6.80(s,1H), 5.48(s,2H),1.98(s,3H),1.96(s,3H).

Intermediate 2

2'-Acetyl-3-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

The preparation method of intermediate 2 was synthesized with reference to WO2014197846A1.

MS m/z(ESI):293.0[M+H] ⁺ .

Intermediate 3

2',3-Dichloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

first step

Dissolve a (10 g, 40 mmol) in a mixture of dichloroethane (600 mL) and isopropanol (400 mL). Heat the reaction solution to 60°C, add N-chlorosuccinamide (6.4 g, 50 mmol) to the reaction solution in batches, and continue stirring at 60°C for 2 hours. Concentrate the reaction solution, add isopropanol (50 mL) to the residue, and stir the mixture at 60°C for 1 hour. Cool the mixture, filter, and wash the filter cake with isopropanol. Dry the filter cake to obtain the product 2',3-dichloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one intermediate 3 (8.0 g), yield: 71%.

MS m/z(ESI):285.0[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.61(s,1H),8.52(s,1H),7.64(s,1H),6.17(d,1H),1.97(s,3H),1.86( s,3H).

Intermediate 4

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2'-(tributylstannyl)-2H-[1,4'-bipyridyl]-2-one

first step

Under nitrogen protection, intermediate 1 (500 mg, 1.21 mmol), hexabutyl ditin (1.06 g, 1.82 mmol), lithium chloride (51 mg, 1.21 mmol), tricyclohexylphosphine (68 mg, 0.24 mmol) and tris(di benzylideneacetone)dipalladium (111 mg, 0.12 mmol) were dispersed in 1,4-dioxane (8 mL). The reaction was heated to 130 ° C and stirred for 12 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2'-(tributylmethylstannyl)-2H-[1,4'-bipyridine]-2-one intermediate 4 (400 mg), yield: 49.4%.

MS m/z(ESI):668.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.78(s,1H),8.40(d,1H),7.32(td,1H),7.12(s,1H),6.35(s,1H),5.39(d, 2H),2.07(s,3H),1.92(s,3H),1.71–1.42(m,6H),1.31(h,6H),1.13(t,6H),0.96–0.83(m,9H).

Intermediate 5

(2-(2-Hydroxypropan-2-yl)thiazol-4-yl)boronic acid

first step

4-Bromothiazole-2-carboxylic acid 5A (1 g, 4.81 mmol) was dissolved in methanol (10 mL), and thionyl chloride (1.72 g, 14.42 mmol) was slowly added dropwise to the reaction solution at room temperature. After the addition was completed, the reaction was heated to 50°C and stirred for 3.5 hours. The reaction was returned to room temperature and directly concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain the product 4-bromothiazole-2-carboxylic acid methyl ester 5B (1.02 g), with a yield of 95.6%.

MS m/z(ESI):222.1,224.1[M+H] ⁺ .

Step 2

Dissolve methyl 4-bromothiazole-2-carboxylate 5B (970 mg, 4.37 mmol) in tetrahydrofuran (30 mL) and cool to 0°C. Add methylmagnesium bromide (3M, 4.37 mL) dropwise to the reaction solution, return to room temperature, and continue stirring for 5 hours. Add saturated ammonium chloride solution (15 mL) to the reaction solution, extract with ethyl acetate (15 mL×2), combine the organic phases, dry, and concentrate. The residue is separated by silica gel column chromatography (eluent system A) to obtain the product 2-(4-bromothiazol-2-yl)propane-2-ol 5C (805 mg,), yield: 83.0%.

MS m/z(ESI):222.1,224.1[M+H] ⁺ .

Step 3

2-(4-bromothiazol-2-yl)propane-2-ol 5C (100 mg, 0.45 mmol), biboronic acid pinacol ester (137.2 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (20.6 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25.8 mg, 0.05 mmol) and potassium acetate (88.4 mg, 0.9 mmol) were dissolved in anhydrous 1,4-dioxane (9 mL), replaced with nitrogen for 1 minute, and the reaction was heated to 110°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the residue was prepared by reverse phase HPLC (formic acid system) to obtain the title product (2-(2-hydroxypropane-2-yl)thiazol-4-yl)boronic acid intermediate 5 (65 mg), with a yield of 77.2%.

MS m/z(ESI):188.1[M+H] ⁺ .

Intermediate 6

2'-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridinyl]-2-one

first step

Dissolve 2,2,6-trimethyl-4H-1,3-dioxin-4-one 6A (8.16 g, 57.40 mmol) in tetrahydrofuran (60 mL) and cool to -78 °C. Add lithium bis(trimethylsilyl)amide (1 M, 63 mL) dropwise to the reaction solution. After the addition is complete, stir the reaction at -78 °C for 1 hour. Add a solution of cyclopropylcarbonyl chloride (3 g, 28.70 mmol, 2.60 mL) in tetrahydrofuran (10 mL) dropwise to the reaction solution, and stir the reaction at -78 °C for 16 hours. Add saturated ammonium chloride solution (30 mL) to the reaction solution under ice bath to quench the reaction, and adjust the pH to weak acidity with dilute hydrochloric acid. Separate the organic phase, and extract the aqueous phase with ethyl acetate (30 mL × 2). Combine the organic phases, dry, and concentrate. The residue was separated by silica gel column chromatography (eluent system B) to give the product 6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one 6B (2.93 g). Yield: 48%.

MS m/z(ESI):211.1[M+H] ⁺ .

Step 2

6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one 6B (700 mg, 3.33 mmol) and 2-chloro-4-amino-5-methylpyridine (617 mg, 4.33 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was heated to 90°C and stirred for 3.5 hours. Concentrated sulfuric acid (0.25 mL) was added to the reaction solution, and the reaction was stirred at 90°C for 1 hour. Water (10 mL) was added to the reaction solution, and the product 2'-chloro-6-cyclopropyl-4-hydroxy-5'-methyl-2H-[1,4'-bipyridine]-2-one 6C (318 mg) was obtained by reverse phase HPLC preparative separation (formic acid system), with a yield of 34.5%.

MS m/z(ESI):277.1[M+H] ⁺ .

Step 3

Dissolve 2'-chloro-6-cyclopropyl-4-hydroxy-5'-methyl-2H-[1,4'-bipyridyl]-2-one 1c (318 mg, 1.15 mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (226 mg, 1.38 mmol), potassium carbonate (397 mg, 2.87 mmol) and 18-crown-6 (30 mg, 0.11 mmol) in N,N-dimethylformamide (5 mL). Heat the reaction to 60 °C and stir for 3 hours. Add water (20 mL) to the reaction solution, and extract the aqueous phase with ethyl acetate (20 mL × 2). Combine the organic phases, dry and concentrate. The residue was separated by silica gel column chromatography (eluent system A) to give the product 2'-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridyl]-2-one intermediate 6 (380 mg) in a yield of 81%.

MS m/z(ESI):404.1[M+H] ⁺ .

Example 1

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

Under nitrogen protection, intermediate 1 (50 mg, 0.12 mmol), intermediate 5 (50.8 mg, 0.17 mmol, purity: 62%), 1,1-bis(diphenylphosphine)-1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (8.9 mg, 0.01 mmol) and cesium carbonate (79 mg, 0.24 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.3 mL). The reaction was heated to 100°C and stirred for 3 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 1 (32 mg) in a yield of 50.8%.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.15-8.05(m,1H),7.86(s,1H), 6.80(s,1H),6.06(s,1H),5.48(d,2H),2.03(s,3H),1.97(s,3H),1.55(d,6H).

Decomposition of Example 1

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 1 (30 mg, 0.06 mmol) was subjected to chiral separation (OD column) to obtain the title product 1-1 (12.0 mg, R.T = 3.597 min), yield: 40%; 1-2 (11.7 mg, R.T = 4.320 min), yield: 39.0%.

Example 1-1: MS m/z (ESI): 519.1 [M+H] ⁺ ;

Example 1-2: MS m/z (ESI): 519.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 2

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridinyl]-2-one

first step

Dissolve 2,2,6-trimethyl-4H-1,3-dioxin-4-one (10.04 g, 70.66 mmol) in tetrahydrofuran (60 mL) and cool to -78°C. Add lithium bis(trimethylsilyl)amide (1 M, 71 mL) dropwise to the reaction solution. Stir the reaction at -78°C for 1 hour. Add a solution of 2,2,2-trideuterated acetyl chloride (2.88 g, 35.33 mmol) in tetrahydrofuran (10 mL) dropwise to the reaction solution. Stir the reaction at -78°C for 16 hours. Add saturated ammonium chloride solution (30 mL) to the reaction solution under ice bath, and adjust the pH to weak acidity with dilute hydrochloric acid. Separate the organic phase, and extract the aqueous phase with ethyl acetate (30 mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give the product 2,2-dimethyl-6-(2-carbonylpropyl-3,3,3-d3)-4H-1,3-dioxin-4-one 2a (2.66 g). Yield: 40%.

MS m/z(ESI):188.1[M+H] ⁺ .

Step 2

2,2-Dimethyl-6-(2-carbonylpropyl-3,3,3-d3)-4H-1,3-dioxin-4-one 2a (2.66 g, 14.21 mmol) and 2-chloro-4-amino-5-methylpyridine (2.63 g, 18.47 mmol) were dissolved in 1,4-dioxane (20 mL). The reaction was heated to 90 ° C and stirred for 2 hours. Concentrated sulfuric acid (1.06 mL) was added to the reaction solution, and the reaction was continued to stir at 90 ° C for 1 hour. The reaction solution was concentrated, and the residue was slurried with ice water to obtain the product 2'-chloro-4-hydroxy-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridine]-2-one 2b (2.66 g), with a yield of 73.9%.

MS m/z(ESI):254.1[M+H] ⁺ .

Step 3

2'-Chloro-4-hydroxy-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one 2b (500 mg, 1.97 mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (419 mg, 2.56 mmol), potassium carbonate (544 mg, 3.94 mmol) and 18-crown-6 (521 mg, 1.97 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction was heated to 60 ° C and stirred for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give the product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one 2c (660 mg), yield: 87.9%.

MS m/z(ESI):381.1[M+H] ⁺ .

Step 4

2'-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridinyl]-2-one 2c (651 mg, 1.71 mmol) and N-chlorosuccinimide (251 mg, 1.88 mmol) were dissolved in isopropanol (2 mL). The reaction was heated to 60 °C and stirred for 3 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridinyl]-2-one 2d (560 mg) with a yield of 78.9%.

MS m/z(ESI):415.0[M+H] ⁺ .

Step 5

Preheat the oil bath to 100°C. Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one 2d (50 mg, 0.12 mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid intermediate 5 (45 mg, 0.24 mmol), cesium carbonate (78 mg, 0.24 mmol), and 1,1-bis(diphenylphosphino)diferronichloridopalladium (9 mg, 0.012 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was heated to 100°C with microwave and stirred for 3 hours. The reaction solution was filtered, and the filtrate was separated by reverse phase HPLC preparative separation (formic acid system) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridine]-2-one 2 (46 mg), yield: 76.2%.

MS m/z(ESI):522.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.10(s,1H),7.86(s,1H),6.80( s,1H),6.07(s,1H),5.48(s,2H),2.03(s,3H),1.55(d,6H).

Decomposition of Example 2

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridinyl]-2-one

Example 2 (110 mg, 0.21 mmol) was subjected to chiral separation (OD column) to give Example 2-1 (42 mg, R.T = 3.633 min, yield: 38.2%) and Example 2-2 (36 mg, R.T = 4.360 min, yield: 36.7%),

Example 2-1: MS m/z (ESI): 522.1 [M+H] ⁺ ;

Example 2-2: MS m/z (ESI): 522.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 3

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-5'-(methyl-d ₃ )-2H-[1,4'-bipyridinyl]-2-one

first step

2-Chloro-5-iodopyridin-4-amine (2 g, 7.86 mmol) and iron triacetylacetonate (416 mg, 1.18 mmol) were placed in a two-necked flask, replaced with nitrogen, and anhydrous tetrahydrofuran (30 mL) was added. After ice bathing for 10 minutes, 1 mol/L methyl-d3-magnesium iodide solution (27.5 mL) was slowly added dropwise through a syringe under stirring. After the addition was completed, the mixture was transferred to room temperature for reaction for 1 hour. Saturated ammonium chloride solution was added dropwise under ice bathing to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL), dried, concentrated, and chromatographed on a silica gel column (elution system B) to obtain the product 2-chloro-5-(methyl- _d3 )pyridin-4-amine 3b (0.140 g), with a yield of 12%.

MS m/z(ESI):146.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.85 (s, 1H), 6.53 (s, 1H), 4.24 (s, 2H).

Step 2

The target product 2′-chloro-4-hydroxy-6-methyl-5′-(methyl-d ₃ )-2H-[1,4′-bipyridinyl]-2-one 3c can be prepared by a similar process to the second step of Example 2.

MS m/z(ESI):253.8[M+H] ⁺ .

Step 3

The target product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'-(methyl-d3)-2H-[1,4'-bipyridinyl]-2-one 3d can be prepared by a similar process to the third step of Example 2.

MS m/z(ESI):381.1[M+H] ⁺ .

Step 4

The target product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'-(methyl-d3)-2H-[1,4'-bipyridine]-2-one 3e can be prepared by a similar process to the fourth step of Example 2.

MS m/z(ESI):414.8[M+H] ⁺ .

Step 5

Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'-(methyl-d3)-2H-[1,4'-bipyridine]-2-one 3e (40 mg, 0.096 mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid intermediate 5 (82 mg, 0.241 mmol, purity: 55%) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (14 mg, 0.019 mmol) and cesium carbonate (94 mg, 0.289 mmol) were dissolved in a mixture of dioxane (0.75 mL) and water (0.25 mL). The reaction was heated to 100°C and stirred for 3.5 hours. Ethyl acetate (25 mL) was added to the reaction solution, filtered through celite, and the filtrate was concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-5'-(methyl- _d3 )-2H-[1,4'-bipyridyl]-2-one 3 (44 mg), yield: 87%.

MS m/z(ESI):521.8[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.66(d,J＝27.0Hz,1H),8.60(s,1H),8.15(d,J＝19.1Hz,1H),8.10(s,1H) ,7.86(s,1H),6.80(s,1H),6.05(s,1H),5.48(s,2H),1.97(s,3H),1.55(s,6H).

Decomposition of Example 3

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-5'-(methyl-d ₃ )-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-5'-(methyl-d ₃ )-2H-[1,4'-bipyridinyl]-2-one

Example 3 (66 mg, 0.126 mmol) was subjected to chiral separation (OD column) to give the title product 3-1 (25 mg, R.T = 3.623 min), yield: 38%; 3-2 (25 mg, R.T = 4.420 min), yield: 38%.

Example 3-1, MS m/z (ESI): 521.8 [M+H] ⁺ ;

Example 3-2, MS m/z (ESI): 521.8 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Example 4

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

first step

2,2-Dimethyl-6-(2-carbonylpropyl)-4H-1,3-dioxin-4-one (2.26g, 12.3mmol) and 2,5-dichloro-4-aminopyridine 4a (1g, 6.13mmol) were dissolved in 1,4-dioxane (15mL). The reaction solution was heated to 100℃ and stirred for 3 hours. Concentrated sulfuric acid (842mg, 8.59mmol) was added to the reaction system, and stirring was continued at 100℃ for 2 hours. The crude product was concentrated and separated by silica gel column chromatography (eluent system A) to obtain the product 2',5'-dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2-one 4b (700mg), yield: 42%.

MS m/z(ESI):271.0[M+H] ⁺ .

Step 2

2',5'-Dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 4b (400 mg, 1.48 mmol) and 2-(chloromethyl)-3,5-difluoropyridine (313 mg, 1.92 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (509 mg, 3.69 mmol) and 18-crown-6 (585 mg, 2.21 mmol) were added. The reaction solution was heated to 70°C and stirred for 4 hours. Saturated sodium chloride (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the product 2',5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 4c (500 mg) in a yield of 85%.

MS m/z(ESI):398.0[M+H] ⁺ .

Step 3

2',5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridinyl]-2-one 4c (120 mg, 0.301 mmol) was dissolved in isopropanol (2 mL), and N-chlorosuccinimide (45 mg, 0.331 mmol) was added. The reaction solution was stirred at 60°C for 4 hours. The reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridinyl]-2-one 4d (83 mg), yield: 63%

MS m/z(ESI):431.9[M+H] ⁺ .

Step 4

2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 4d (40 mg, 0.092 mmol), intermediate 5 (44 mg, 0.231 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (7.5 mg, 0.009 mmol) and cesium carbonate (60 mg, 0.184 mmol) were dissolved in 1,4-dioxane/water (5:1, 1 mL), and the reaction was heated to 100 ° C and stirred for 3 hours under nitrogen protection. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 4 (27 mg) in a yield of 54%.

MS m/z(ESI):539.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.93(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.10(m,1H),6.98– 6.79(m,1H),6.10(s,1H),5.50(d,2H),2.01(s,3H),1.56(d,6H).

Decomposition of Example 4

(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 4 (27 mg, 0.050 mmol) was subjected to chiral separation (OD column) to give Example 4-1 (9.1 mg, R.T = 3.413 min, yield: 34%) and Example 4-2 (11 mg, R.T = 4.960 min, yield: 41%).

Example 4-1: MS m/z (ESI): 539.0 [M+H] ⁺ ;

Example 4-2: MS m/z (ESI): 539.0 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 5

3,5'-Dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

first step

Dissolve 2',5'-dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 4b (100 mg, 0.369 mmol) and 2-(1-chloroethyl)-3,5-difluoropyridine (98 mg, 0.553 mmol) in N,N-dimethylformamide (2 mL), add potassium carbonate (127 mg, 0.922 mmol) and 18-crown-6 (146 mg, 0.553 mmol). Heat the reaction solution to 70°C and stir for 4 hours. Add saturated sodium chloride (10 mL) to the reaction solution, extract the aqueous phase with ethyl acetate (10 mL×3), combine the organic phases, dry, and concentrate to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the product 2',5'-dichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 5a (120 mg) in a yield of 78%.

MS m/z(ESI):412.0[M+H] ⁺ .

Step 2

2',5'-Dichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2H-[1,4'-bipyridinyl]-2-one 5a (120 mg, 0.291 mmol) was dissolved in isopropanol (2 mL), and N-chlorosuccinimide (43 mg, 0.321 mmol) was added. The reaction solution was stirred at 60°C for 4 hours. The reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system A) to obtain the product 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2H-[1,4'-bipyridinyl]-2-one 5b (110 mg), with a yield of 84%.

MS m/z(ESI):446.0[M+H] ⁺ .

Step 3

2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 5b (110 mg, 0.246 mmol), intermediate 5 (115 mg, 0.616 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (21 mg, 0.025 mmol) and cesium carbonate (160 mg, 0.493 mmol) were dissolved in 1,4-dioxane/water (V:V=5:1, 1 mL), and the reaction was heated to 100°C and stirred for 3 hours under nitrogen protection. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 5 (103 mg) in a yield of 75%.

MS m/z(ESI):553.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.92(s,1H),8.59(d,1H),8.26(s,1H),8.14(s,1H),8.07(m,1H),6.62( s,1H),6.09(s,1H),6.07(d,1H),1.96(s,3H),1.73(d,3H),1.54(s,6H).

Decomposition of Example 5

(S)-3,5'-dichloro-4-(((S)-3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one, (S)-3,5'-dichloro-4-(((R)-3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one , (R)-3,5'-dichloro-4-(((R)-3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-(((S)-3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 5 (103 mg, 0.186 mmol) was subjected to chiral separation (AD column) to obtain Example 5-1 (20 mg, R.T = 4.963 min, yield: 20%), Example 5-2 (18 mg, R.T = 1.634 min, yield: 17%), Example 5-3 (21 mg, R.T = 8.047 min, yield: 20%), and Example 5-4 (18 mg, R.T = 2.141 min, yield: 17%).

Example 5-1: MS m/z (ESI): 553.0 [M+H] ⁺

Example 5-2: MS m/z (ESI): 553.0 [M+H] ⁺

Example 5-3: MS m/z (ESI): 553.0 [M+H] ⁺

Example 5-4: MS m/z (ESI): 553.0 [M+H] ⁺

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 6

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

6a (500 mg, 3.4 mmol), ethyl 2-bromo-2-methylpropionate (862.6 mg, 4.42 mmol) and potassium carbonate (1.41 g, 10.21 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the reaction was heated to 80 ° C and stirred for 16 hours. The reaction solution was filtered, saturated ammonium chloride (80 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried, and concentrated to obtain the crude product ethyl 2-(3-bromo-1H-pyrazol-1-yl)-2-methylpropionate 6b (888 mg), with a yield of 99.9%. It was used directly in the next step without further purification.

MS m/z(ESI):261.1,263.1[M+H] ⁺ .

Step 2

6b (730 mg, 2.8 mmol) was dissolved in methanol (10 mL), and sodium borohydride (423 mg, 11.2 mmol) was added to the reaction solution at 0°C. The reaction was returned to room temperature and stirred for 1 hour. The reaction solution was concentrated, and saturated ammonium chloride (25 mL) solution was added to the residue, and the aqueous phase was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried, and concentrated. The residue was subjected to reverse phase HPLC (formic acid system) to obtain the product 2-(3-bromo-1H-pyrazol-1-yl)-2-methylpropane-1-ol 6c (390 mg), with a yield of 63.7%.

MS m/z(ESI):219.1,221.1[M+H] ⁺ .

Step 3

Under nitrogen protection, 6c (400 mg, 1.83 mmol), bis(diphenylphosphino)ferrocenepalladium dichloride (602.7 mg, 2.37 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (133.6 mg, 0.18 mmol) and potassium acetate (448 mg, 4.56 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The reaction was heated to 100 ° C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was prepared by reverse phase HPLC (formic acid system) to obtain the crude product (1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)boronic acid 6d (390 mg, purity about 40%), yield: 46.4%.

MS m/z(ESI):185.1[M+H] ⁺ .

Step 4

Under nitrogen protection, intermediate 1 (40 mg, 0.1 mmol), 6d (102.7 mg, 0.22 mmol, purity about 40%), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (7.1 mg, 0.01 mmol) and cesium carbonate (94.8 mg, 0.29 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.2 mL) and water (0.1 mL). The reaction was heated to 90 ° C and stirred for 0.5 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 6 (30 mg), yield: 59.9%.

MS m/z(ESI):516.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.64(s,1H),8.60(d,1H),8.15-8.05(m,1H),7.87(d,1H),7.77(s,1H), 6.81(d,1H),6.79(s,1H),5.48(d,2H),4.97(t,1H),3.65-3.59(m,2H),2.00(s,3H),1.97(s,3H) ,1.50(s,6H).

Decomposition of Example 6

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 6 (30 mg, 0.06 mmol) was subjected to chiral separation (AD column) to obtain the title product 6-1 (13.6 mg, R.T = 6.367 min), yield: 42.5%; 6-2 (15.0 mg, R.T = 8.977 min), yield: 46.9%.

Example 6-1: MS m/z (ESI): 516.1 [M+H] ⁺ ;

Example 6-2: MS m/z (ESI): 516.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 7

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

Lithium aluminum deuteride (388 mg, 9.24 mmol) was added in batches to a solution of methyl 3,5-difluoropyridine-2-carboxylate (1.00 g, 5.78 mmol) in tetrahydrofuran (20 mL) under an ice bath. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ice cubes and the reaction solution was filtered. The filtrate was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product (3,5-difluoropyridin-2-yl)methane-d2-ol 7a (345 mg) with a yield of 40.6%.

MS m/z(ESI):148.0[M+H] ⁺ .

Step 2

Thionyl chloride (839 mg, 7.06 mmol) was added dropwise to a solution of (3,5-difluoropyridin-2-yl)methane-d2-ol 7a (346 mg, 2.35 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL) under stirring. The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (160 mL), and the organic phase was washed with saturated sodium bicarbonate and water. The organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to give the product 2-(chloromethyl-d2)-3,5-difluoropyridine 7b (150 mg), with a yield of 38.5%.

MS m/z(ESI):166.0[M+H] ⁺ .

Step 3

3-Chloro-1-(2-chloro-5-methyl-4-pyridyl)-4-hydroxy-6-methyl-pyridin-2-one (136 mg, 0.82 mmol), 2-(chloromethyl-d2)-3,5-difluoropyridine 7b (180 mg, 1.09 mmol), potassium carbonate (174 mg, 1.26 mmol) and 18-crown-6 ether (167 mg, 0.63 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction was heated to 60 ° C and stirred for 16 hours. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 7c (210 mg), yield: 80.2%.

MS m/z(ESI):414.0[M+H] ⁺ .

Step 4

Preheat the oil bath to 100°C. Under nitrogen, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 7c (50 mg, 0.12 mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid (45 mg, 0.24 mmol), cesium carbonate (78 mg, 0.24 mmol), and 1,1-bis(diphenylphosphino)diferronichloridopalladium (9 mg, 0.012 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was stirred at 100°C for 3 hours. The reaction solution was filtered and the filtrate was separated by reverse phase HPLC preparative separation (formic acid system) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 7 (38 mg) with a yield of 60.6%.

MS m/z(ESI):521.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.10(ddd,1H),7.86(s,1H),6.80( d,1H),6.06(s,1H),2.03(s,3H),2.00–1.90(m,3H),1.56(d,6H).

Decomposition of Example 7

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 7 (36 mg, 0.07 mmol) was subjected to chiral separation (OD column) to give Example 7-1 (15 mg, R.T = 3.640 min, yield: 41.7%) and Example 7-2 (13 mg, R.T = 4.357 min, yield: 36.1%),

Example 7-1: MS m/z (ESI): 521.1 [M+H] ⁺ ;

Example 7-2: MS m/z (ESI): 521.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 8

3-Chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

Intermediate 3 (350 mg, 1.23 mmol), 2-(1-chloroethyl)-3,5-difluoro-pyridine (218 mg, 1.23 mmol), potassium carbonate (509 mg, 3.68 mmol) and 18-crown-6 ether (324 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred. The reaction was heated to 60 ° C and stirred for 16 hours. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed with water twice, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 8b (280 mg), yield: 53.5%.

MS m/z(ESI):426.0[M+H] ⁺ .

Step 2

Under nitrogen protection, 2',3-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 8b (190 mg, 0.446 mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid (167 mg, 0.892 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (33 mg, 0.045 mmol) and cesium carbonate (290 mg, 0.892 mmol) were dissolved in 1,4-dioxane (2 mL) and stirred. The reaction was heated to 100°C with microwave and stirred for 3 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was washed with saturated ammonium chloride, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give the product 3-chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 8 (170 mg), yield: 71.6%.

MS m/z(ESI):533.1[M+H] ⁺ .

Decomposition of Example 8

(S)-3-Chloro-1-[2-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridinyl]-6-methyl-4-[(1S)-1-(3,5-difluoro-2-pyridinyl)ethoxy]pyridin-2-one, (S)-3-Chloro-1-[2-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridinyl]-6-methyl-4-[(1R)-1-(3,5-difluoro-2-pyridinyl)ethoxy]pyridin-2-one , (R)-3-chloro-1-[2-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridinyl]-6-methyl-4-[(1S)-1-(3,5-difluoro-2-pyridinyl)ethoxy]pyridin-2-one and (R)-3-chloro-1-[2-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridinyl]-6-methyl-4-[(1R)-1-(3,5-difluoro-2-pyridinyl)ethoxy]pyridin-2-one

Example 8 (170 mg) was subjected to chiral separation (AD column) to give the title product 8-1 (27.9 mg, R.T = 3.91 min), yield: 16.4%; 8-2 (18.0 mg, R.T = 5.667 min), yield: 10.6%; 8-3 (22.5 mg, R.T = 6.460 min), yield: 13.2%, 8-4 (26.5 mg, R.T = 6.767 min), yield: 15.6%.

Example 8-1, MS m/z (ESI): 533.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.68(s,1H),8.59(d,1H),8.16(s,1H),8.07(dd,1H),7.83(s,1H),6.59( s,1H),6.04(s,2H),2.01(s,3H),1.92(s,3H),1.73(d,3H),1.54(s,6H).

Example 8-2, MS m/z (ESI): 533.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.68(s,1H),8.60(d,1H),8.17(s,1H),8.07(dd,1H),7.84(s,1H),6.66( s,1H),6.06(d,2H),1.98(s,3H),1.94(s,3H),1.73(d,3H),1.55(d,6H).

Example 8-3, MS m/z (ESI): 533.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.68(s,1H),8.59(d,1H),8.16(s,1H),8.07(dd,1H),7.83(s,1H),6.59( s,1H),6.05(d,2H),2.01(s,3H),1.92(s,3H),1.73(d,3H),1.54(s,6H).

Example 8-4, MS m/z (ESI): 533.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.68(s,1H),8.60(d,1H),8.17(s,1H),8.07(dd,1H),7.84(s,1H),6.66( s,1H),6.06(d,2H),1.98(s,3H),1.94(s,3H),1.73(d,3H),1.55(d,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Example 9

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

9a (5 g, 29.04 mmol), di-tert-butyl carbonate (6.97 g, 31.94 mmol), triethylamine (2.94 g, 29.04 mmol) and 4-dimethylaminopyridine (1.06 g, 8.71 mmol) were dissolved in a mixed solvent of dichloromethane (35 mL) and tetrahydrofuran (35 mL). The reaction was heated to 60°C and stirred for 20 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product ethyl 2-((tert-butoxycarbonyl)amino)thiazole-4-carboxylate 9b (6.1 g) with a yield of 77.2%.

MS m/z(ESI):273.1[M+H] ⁺ .

Step 2

9b (3 g, 11.02 mmol) was dissolved in tetrahydrofuran (40 mL). Methylmagnesium bromide (3 M, 18.4 mL) was added dropwise to the reaction solution under stirring at 0°C. The reaction was returned to room temperature and stirred for 1 hour. Saturated ammonium chloride (50 mL) solution was added to the reaction solution at 0°C, and the aqueous phase was extracted with ethyl acetate (35 mL × 2). The organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product (4-(2-hydroxypropane-2-yl)thiazol-2-yl)carbamic acid tert-butyl ester 9c (2.0 g), with a yield of 70.3%.

MS m/z(ESI):259.1[M+H] ⁺ .

Step 3

9c (2 g, 7.74 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (7.45 g, 65.3 mmol, 5 mL) was added dropwise to the reaction solution under stirring. The reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2-(2-aminothiazol-4-yl)propane-2-ol 9d (675 mg), with a yield of 55.1%.

MS m/z(ESI):159.1[M+H] ⁺ .

Step 4

Tert-butyl nitrite (657.0 mg, 6.37 mmol) and copper bromide (578.1 mg, 2.59 mmol) were dissolved in acetonitrile (35 mL). 9d (630 mg, 3.98 mmol) was added to the reaction solution. The reaction was heated to 80 °C and stirred for 6 hours. Water (50 mL) and ammonia (15 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain the title product 2-(2-bromothiazol-4-yl)propane-2-ol 9e (560 mg), with a yield of 63.3%.

MS m/z(ESI):222.1,224.1[M+H] ⁺ .

Step 5

Under nitrogen protection, 9e (24.0 mg, 0.11 mmol), intermediate 4 (60 mg, 0.09 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.6 mg, 0.009 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction was heated to 120 ° C and stirred for 5.5 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(4-(2-hydroxypropane-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 9 (25 mg,) with a yield of 53.5%.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.72(s,1H),8.61(d,1H),8.15-8.05(m,1H),8.01(s,1H),7.54(s,1H), 6.81(s,1H),5.48(d,2H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H).

Decomposition of Example 9

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 9 (50 mg, 0.096 mmol) was subjected to chiral separation (OD column) to obtain the title product 9-1 (19.0 mg, R.T = 4.630 min), yield: 38.0%; 9-2 (18.2 mg, R.T = 6.027 min), yield: 36.4%.

Example 9-1: MS m/z (ESI): 519.1 [M+H] ⁺ ;

Example 9-2: MS m/z (ESI): 519.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Example 10

3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-methyl-2H-[1,4'-bipyridyl]-2-one

first step

Intermediate 6 (110 mg, 0.27 mmol) and N-chlorosuccinimide (40.0 mg, 0.3 mmol) were dissolved in isopropanol (2 mL). The reaction was heated to 60 °C and stirred for 16 hours. Water (10 mL) was added to the reaction solution, stirred for 30 minutes, and filtered to obtain the product 2',3-dichloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridyl]-2-one 10a (104 mg), with a yield of 87.1%.

MS m/z(ESI):438.1[M+H] ⁺ .

Step 2

Under nitrogen protection, 10a (80 mg, 0.18 mmol), intermediate 5 (73.5 mg, 0.26 mol, purity: 65%), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13.4 mg, 0.02 mol) and cesium carbonate (119.0 mg, 0.37 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (0.5 mL). The reaction was heated to 100°C and stirred for 2.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5'-methyl-2H-[1,4'-bipyridyl]-2-one 10 (54 mg), yield: 54.3%.

MS m/z(ESI):545.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.69(s,1H),8.61(d,1H),8.16(s,1H),8.14-8.05(m,1H),7.90(s,1H), 6.39(s,1H),6.05(s,1H),5.52(d,2H),2.06(s,3H),1.55(d,6H),1.37-1.21(m,1H),0.98-0.91(m, 1H),0.89-0.81(m,1H),0.76-0.68(m,2H).

Decomposition of Example 10

(S)-3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 10 (54 mg, 0.099 mmol) was subjected to chiral separation (OJ column) to obtain the title product 10-1 (24.0 mg, R.T = 3.360 min), yield: 44.4%; 10-2 (24.8 mg, R.T = 3.907 min), yield: 45.9%.

Example 10-1: MS m/z (ESI): 545.1 [M+H] ⁺ ;

Example 10-2: MS m/z (ESI): 545.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 11

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

1H-pyrazole-3-carboxylic acid methyl ester (2g, 15.9mmol) was dissolved in tetrahydrofuran (50mL) and cooled to 0°C. Methylmagnesium chloride (1M, 47.58mL) was added dropwise to the reaction solution under stirring. After the addition was completed, the reaction was warmed to room temperature and stirred for 2 hours. Ethyl acetate (100mL) was added to the reaction solution, and the organic phase was washed with water and saturated ammonium chloride, dried, and concentrated to obtain the product 2-(1H-pyrazol-3-yl)propan-2-ol 11b (840mg), with a yield of 42%.

MS m/z(ESI):127.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.51(d,1H),6.64(s,2H),6.18(d,1H),1.62(s,6H).

Step 2

2-Bromo-5-methyl-pyridin-4-amine 11c (2.03 g, 10.86 mmol) and 2,2-dimethyl-6-(2-carbonylpropyl)-4H-1,3-dioxin-4-one (2 g, 10.86 mmol) were dissolved in 1,4-dioxane (80 mL) and stirred. The reaction was placed in a reactor preheated to 90°C and stirred for 3 hours. Concentrated sulfuric acid (1.8 g, 18.35 mmol) was added to the reaction solution and continued to stir for 1 hour. The reaction solution was cooled, the supernatant was removed, and water was added to the residual oil. The mixture was stirred at room temperature for 30 minutes and filtered to obtain 2'-bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 11d (1.7 g) with a yield of 53%.

MS m/z(ESI):296.1[M+H] ⁺ .

Step 3

2'-Bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 11d (1.7 g, 5.76 mmol) was dissolved in isopropanol (40 mL) and 1,2-dichloroethane (60 mL) and heated to 60°C with stirring. N-chlorosuccinamide (923 mg, 6.91 mmol) was added to the reaction solution in batches and stirring was continued for 2 hours. The reaction solution was concentrated, isopropanol (20 mL) was added to the residue, and the mixture was heated to 60°C and stirred for 0.5 hours. The reaction solution was cooled and filtered to obtain 1-(2-bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one 11e (1.71 g), with a yield of 90.1%.

MS m/z(ESI):330.9[M+H] ⁺ .

Step 4

1-(2-Bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one 11e (150 mg, 0.455 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (139 mg, 0.910 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred. 2-(Chloromethyl)-3,5-difluoro-pyridine (89 mg, 0.546 mmol) was added dropwise to the reaction solution, and heated to 80°C and stirred for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was washed with water, saturated ammonium chloride and saturated sodium chloride, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one 11f (140 mg) in a yield of 67.4%.

MS m/z(ESI):458.0[M+H] ⁺ .

Step 5

Under nitrogen protection, 11b (55 mg, 0.438 mmol), 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 11f (100 mg, 0.219 mmol), cuprous iodide (8 mg, 0.044 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (13 mg, 0.088 mmol) and cesium carbonate (143 mg, 0.438 mmol) were dissolved in N,N-dimethylformamide (5 mL) and heated to 100 °C and stirred for 16 hours. The reaction solution was filtered and the filtrate was separated using a reverse phase column. The product was separated by reverse phase HPLC (formic acid system) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 11 (40 mg) with a yield of 36%.

MS m/z(ESI):501.8[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.10(t,1H),7.78(s,1H),6.80( s,1H),6.56(d,1H),5.48(s,2H),5.08(s,1H),2.00(d,6H),1.47(s,6H).

Decomposition of Example 11

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 11 (9 mg, 0.018 mmol) was subjected to chiral separation (AS column) to give the title product 11-1 (4.1 mg, R.T = 3.287 min), yield: 45.56%; 11-2 (4.3 mg, R.T = 4.807 min), yield: 47.78%.

Example 11-1, MS m/z (ESI): 501.8 [M+H] ⁺ ;

Example 11-2, MS m/z (ESI): 501.8 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Example 12

2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

first step

2-(3-Bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid 6b (1.6 g, 6.13 mmol) was dissolved in ethanol (30 mL). Aqueous sodium hydroxide solution (1 M, 6.13 mL) was added dropwise to the reaction solution under stirring. The reaction was stirred at 25 ° C for 3 hours. The reaction solution was concentrated, and water (10 mL) and methyl tert-butyl ether (10 mL) were added to the residue. After the aqueous phase was separated, the pH was adjusted to 2 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried, and concentrated to give the product 2-(3-bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid 12a (1.4 g, yield: 98%).

MS m/z(ESI):233.0,235.0[M+H] ⁺ .

Step 2

2-(3-Bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid 12a (0.5 g, 2.15 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (0.363 mL, 4.29 mmol) was added dropwise to the reaction solution under stirring. The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated, and tetrahydrofuran (5 mL) was added to the residue to dissolve. The resulting solution was added dropwise to ammonia methanol solution (7 M, 1.23 mL) under stirring. The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated, the residue was dissolved in ethyl acetate (20 mL), the organic phase was washed with saturated ammonium chloride (10 mL), dried, and concentrated to obtain the product 2-(3-Bromo-1H-pyrazol-1-yl)-2-methylpropanamide 12b (382 mg), with a yield of 76.7%.

MS m/z(ESI):232.0,234.0[M+H] ⁺ .

Step 3

Under nitrogen protection, intermediate 4 (100 mg, 0.150 mmol), 12b (70 mg, 0.3 mmol) and bis(triphenylphosphine)palladium dichloride (11 mg, 0.015 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was heated to 130 °C with microwave and stirred for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropanamide 12 (26 mg), yield: 32.8%.

MS m/z(ESI):529.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.66(s,1H),8.60(d,1H),8.15–8.02(m,1H),7.93(d,1H),7.78(s,1H), 7.19(s,1H),6.94(s,1H),6.87(d,1H),6.79(s,1H),5.47(s,2H),2.01(s,3H),1.97(s,3H),1.75 (s,6H).

Decomposition of Example 12

(S)-2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropanamide and (R)-2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

Example 12 (26 mg) was subjected to chiral separation (AS column) to give the title product 12-1 (6.8 mg, R.T = 4.98 min), yield: 26.15%; 12-2 (6.8 mg, R.T = 8.113 min), yield: 26.15%.

Example 12-1, MS m/z (ESI): 529.1 [M+H] ⁺ ;

Example 12-2, MS m/z (ESI): 529.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Example 13

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2)'-yl)thiazol-2-yl)-2-methylpropionitrile

first step

2-Cyano-2-methyl-propionic acid methyl ester 13a (2 g, 15.73 mmol) was dissolved in aqueous ammonia (7 M, 20 mL) and stirred at 30°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 2-cyano-2-methylpropionamide 13b (1.76 g) with a yield of 100%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.64 (s, 1H), 7.42 (d, 1H), 1.49 (s, 6H).

Step 2

Under nitrogen protection, 2-cyano-2-methylpropanamide 13b (0.1 g, 0.892 mmol) and Lawesson's reagent (198 mg, 0.490 mmol) were dissolved in tetrahydrofuran (5 mL). The reaction was refluxed and stirred for 3 hours. The reaction solution was diluted with ethyl acetate (25 mL), washed with saturated brine, dried, concentrated, and purified by preparative silica gel chromatography (elution system B) to obtain the product 2-cyano-2-methylpropanesulfamide 13c (0.097 g), with a yield of 85%.

MS m/z(ESI):129.0[M+H] ⁺ .

Step 3

2-Cyano-2-methylpropanesulfonamide 13c (0.5 g, 3.90 mmol), bromoacetaldehyde diethyl acetal (845 mg, 4.29 mmol) and p-toluenesulfonic acid (67 mg, 0.39 mmol) were dissolved in ethanol (6 mL) and water (0.6 mL), heated to 100°C in a sealed tube and stirred for 20 hours. The reaction solution was concentrated to obtain a black residue which was chromatographed on a silica gel column (elution system B) to obtain compound 2-methyl-2-(thiazol-2-yl)propionitrile 13d (94 mg) with a yield of 16%.

MS m/z(ESI):153.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.78(d,1H),7.35(d,1H),1.88(s,6H).

Step 4

2-Methyl-2-(thiazol-2-yl)propionitrile 13d (0.45 g, 2.96 mmol) was dissolved in N,N-dimethylformamide (5 mL). N-bromosuccinimide (1.16 g, 6.50 mmol) was added under stirring, and the reaction was stirred at 30°C for 20 hours. The reaction solution was diluted with ethyl acetate (35 mL), washed with saturated brine, dried, concentrated, and chromatographed on a silica gel column (elution system B) to obtain the product 2-(5-bromothiazol-2-yl)-2-methylpropionitrile 13e (312 mg), with a yield of 46%.

MS m/z(ESI):230.8,232.8[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.65 (s, 1H), 1.83 (s, 6H).

Step 5

2-(5-bromothiazol-2-yl)-2-methylpropionitrile 13d (0.312 g, 1.35 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), replaced with nitrogen, cooled to -78°C in a dry ice bath, and lithium diisopropylamide (2M, 1.35 mL) was slowly added through a syringe. After the addition was completed, the reaction was stirred at -78°C for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution, stirred for 5 minutes, diluted with ethyl acetate (40 mL), washed with saturated brine, dried, and the concentrated residue was chromatographed on a silica gel column (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-2-methylpropionitrile 13f (0.147 g) with a yield of 47%.

MS m/z(ESI):230.8,232.8[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.24 (s, 1H), 1.86 (s, 6H).

Step 6

Under nitrogen protection, 3-chloro-4-[(3,5-difluoro-2-pyridyl)methoxy]-6-methyl-1-(5-methyl-2-tributylstannyl-4-pyridyl)pyridin-2-one intermediate 4 (80 mg, 0.120 mmol), 2-(4-bromothiazol-2-yl)-2-methylpropionitrile 13f (33 mg, 0.144 mmol) and bistriphenylphosphine palladium dichloride (17 mg, 0.024 mmol) were dissolved in dioxane (1.5 mL). The reaction was heated to 130 ° C with microwave and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (25 mL), filtered through celite, and concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to give the title product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2)'-yl)thiazol-2-yl)-2-methylpropionitrile 13 (30 mg) in a yield of 47%.

MS m/z(ESI):528.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.74(s,1H),8.60(s,1H),8.39(s,1H),8.10(t,1H),7.92(s,1H),6.81( s,1H),5.48(s,2H),2.04(s,3H),1.98(s,3H),1.87(s,6H).

Decomposition of Example 13

(S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2)'-yl)thiazol-2-yl)-2-methylpropionitrile and (R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2)'-yl)thiazol-2-yl)-2-methylpropionitrile

Example 13 (30 mg, 0.057 mmol) was subjected to chiral separation (OD column) to give the title product 13-1 (7 mg, R.T = 4.223 min), yield: 23%; 13-2 (7 mg, R.T = 5.453 min), yield: 23%.

Example 13-1, MS m/z (ESI): 527.8 [M+H] ⁺ .

Example 13-2, MS m/z (ESI): 527.8 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 14

2-(((3-Chloro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxy)methyl)-3,5-difluorobenzonitrile

first step

2-Amino-4,6-difluorobenzoic acid 14a (5 g, 28.9 mmol) and potassium carbonate (5.98 g, 43.3 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature. Methyl iodide (4.92 g, 34.7 mmol) was slowly added dropwise to the reaction solution under stirring. The reaction solution was stirred at 25°C for 2 hours. Water (180 mL) was added to the reaction solution and stirring was continued for 1 hour. The reaction solution was filtered to obtain the title product methyl 2-amino-4,6-difluorobenzoate 14b (3.9 g), which was used directly in the next step without purification.

MS m/z(ESI):188.0[M+H] ⁺ .

Step 2

2-Amino-4,6-difluorobenzoic acid methyl ester 14b (1 g, 5.34 mmol) was dissolved in 20% sulfuric acid solution (30 mL) and cooled to 0°C. Sodium nitrite (442 mg, 6.41 mmol) aqueous solution (4 mL) and potassium iodide (1.78 g, 10.7 mmol) aqueous solution (4 mL) were added dropwise in sequence. The reaction solution was stirred at 25°C for 4 hours. Saturated sodium sulfite (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2,4-difluoro-6-iodobenzoic acid methyl ester 14c (1.1 g), with a yield of 70%.

MS m/z(ESI):298.9[M+H] ⁺ .

Step 3

Methyl 2,4-difluoro-6-iodobenzoate 14c (2 g, 6.71 mmol) and cuprous cyanide (1.26 g, 13.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction was heated to 120 °C by microwave and stirred for 1 hour. Ethyl acetate (10 mL) was added to the reaction solution, filtered, water (30 mL) was added, and the filtrate was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product methyl 2-cyano-4,6-difluorobenzoate 14d (740 mg), with a yield of 56%.

MS m/z(ESI):198.0[M+H] ⁺ .

Step 4

Methyl 2-cyano-4,6-difluorobenzoate 14d (700 mg, 3.55 mmol) and anhydrous calcium chloride (394 mg, 3.55 mmol) were dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), and sodium borohydride (296 mg, 7.81 mmol) was added in batches under stirring. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the title product 3,5-difluoro-2-(hydroxymethyl)benzonitrile 14e (340 mg, colorless liquid), with a yield of 57%.

MS m/z(ESI):170.0[M+H] ⁺ .

Step 5

The intermediate 3 (200 mg, 0.701 mmol) was dissolved in anhydrous dichloromethane (2 mL), and triethylamine (142 mg, 1.40 mmol) was added and stirred evenly. Trifluoromethanesulfonic anhydride (297 mg, 1.05 mmol) was added to the reaction solution at 0°C, and stirring was continued at 25°C for 2 hours. The reaction solution was concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yltrifluoromethanesulfonic acid 14f (150 mg), with a yield of 51%.

MS m/z(ESI):416.9[M+H] ⁺ .

Step 6

2',3-Dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl trifluoromethanesulfonic acid 14f (120 mg, 0.288 mmol), 3,5-difluoro-2-(hydroxymethyl)benzonitrile 14e (73 mg, 0.431 mmol) and cesium carbonate (187 mg, 0.575 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction solution was heated to 70°C and stirred for 4 hours. Saturated sodium chloride (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give 14 g (74 mg) of the product 2-(((2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxy)methyl)-3,5-difluorobenzonitrile, yield: 58%.

MS m/z(ESI):436.0[M+H] ⁺ .

Step 7

2-(((2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxy)methyl)-3,5-difluorobenzonitrile 14g (65mg, 0.149mmol), intermediate 5 (70mg, 0.373mmol), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium dichloromethane complex (12mg, 0.015mmol) and cesium carbonate (97mg, 0.298mmol) were dissolved in 1,4-dioxane/water (v:v＝5:1, 1mL), and the reaction was heated to 100℃ and stirred for 3 hours under nitrogen protection. Saturated sodium chloride (10mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the title product 2-(((3-chloro-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5',6- dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxy)methyl)-3,5-difluorobenzonitrile 14 (40 mg), yield: 49%.

MS m/z(ESI):543.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.70(s,1H),8.18(s,1H),7.99(d,1H),7.97–7.90(m,1H),7.89(s,1H), 6.87(s,1H),6.05(s,1H),5.43(s,2H),2.04(s,3H),2.01(s,3H),1.55(d,6H).

Decomposition of Example 14

(S)-2-(((3-chloro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxy)methyl)-3,5-difluorobenzonitrile and (R)-2-(((3-chloro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxy)methyl)-3,5-difluorobenzonitrile

Example 14 (40 mg, 0.074 mmol) was subjected to chiral separation to obtain Example 14-1 (10.3 mg, R.T = 5.847 min, yield: 26%) and Example 14-2 (8.5 mg, R.T = 7.160 min, yield: 21%),

Example 14-1: MS m/z (ESI): 543.1 [M+H] ⁺ ;

Example 14-2: MS m/z (ESI): 543.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 34

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide

first step

Under nitrogen protection, sodium hydride (1.98 g, 49.4 mmol, purity: 60%) was dissolved in tetrahydrofuran (55 mL). Under ice bath, diethyl malonate (7.91 g, 49.4 mmol) was slowly added dropwise with stirring. The reaction slowly warmed to room temperature, 2,4-dibromothiazole (10.0 g, 41.2 mmol) was added, and the mixture was heated to 70 °C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine respectively, and the organic phase was dried and concentrated. The residue was chromatographed on a silica gel column (elution system B) to obtain the product diethyl 2-(4-bromothiazol-2-yl) malonate 34b (6.04 g), with a yield of 46%.

MS m/z(ESI):321.8[M+H] ⁺ .

Step 2

Diethyl 2-(4-bromothiazol-2-yl)malonate 34b (6.0 g, 18.6 mmol) was dissolved in dimethyl sulfoxide (30 mL), sodium chloride (2.18 g, 37.2 mmol) and pure water (671 mg, 37.2 mmol) were added, and the reaction was heated to 130°C and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine, and the organic phase was dried and concentrated to obtain the product ethyl 2-(4-bromothiazol-2-yl)acetate 34c (4.5 g), with a yield of 96%.

MS m/z(ESI):250.0[M+H] ⁺ .

Step 3

Under nitrogen protection, sodium hydride (2.40 g, 60.0 mmol, purity: 60%) was dissolved in tetrahydrofuran (20 mL) and stirred for 10 minutes in an ice bath. 2-(4-bromothiazol-2-yl)ethyl acetate 34c (5.0 g, 20.0 mmol) was slowly added to the reaction solution, and the ice bath was continued to stir for 0.5 hours. Iodomethane (11.3 g, 80.0 mmol) was added to the reaction solution, and the temperature was raised to room temperature and reacted for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated brine, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried, and concentrated. The residue was chromatographed on a silica gel column (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-2-methylpropionic acid ethyl ester 34d (3.15 g), with a yield of 57%.

MS m/z(ESI):278.0[M+H] ⁺ .

Step 4

Ethyl 2-(4-bromothiazol-2-yl)-2-methylpropanoate 34d (3.15 g, 11.3 mmol) was dissolved in aqueous ammonia (20 mL), placed in a pressure-resistant sealed tube, heated to 80°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (2.8 g), which was used directly in the next step without purification.

MS m/z(ESI):248.9[M+H] ⁺ .

Step 5

Under nitrogen protection, sodium hydride (302 mg, 7.55 mmol, purity: 60%) was dissolved in tetrahydrofuran (2 mL). A solution of 2-(4-bromothiazol-2-yl)-2-methylpropionamide 34e (1.88 g, 7.55 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction solution under stirring. The reaction was heated to 30 °C and stirred for 1 hour, then the temperature was raised to 70 °C and iodomethane (1.07 g, 7.55 mmol) was slowly added dropwise, and the reaction was continued at this temperature for 0.5 hour. The reaction solution was quenched with saturated ammonium chloride solution, and the crude product was concentrated and chromatographed on a silica gel column (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-N,2-dimethylpropionamide 34f (225 mg), with a yield of 11%.

MS m/z(ESI):262.9[M+H] ⁺ .

Step 6

Intermediate 4 (90 mg, 0.135 mmol), 2-(4-bromothiazol-2-yl)-N,2-dimethylpropanamide 34f (36 mg, 0.135 mmol) and tetrakistriphenylphosphine palladium (23 mg, 0.020 mmol) were dissolved in dioxane (2 mL) and stirred at 105°C for 16 hours under nitrogen protection. The reaction solution was concentrated and purified by preparative HPLC (formic acid system) to obtain the title product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide 34 (60 mg), yield: 71%.

MS m/z(ESI):560.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.67(s,1H),8.40(s,1H),8.17(s,1H),7.89(s,1H),7.31(dd,1H),6.57(s, 1H),6.42(s,1H),5.42(s,2H),2.77(s,3H),2.15(s,3H),2.02(s,3H),1.74(s,6H).

Decomposition of Example 34

(S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide and (R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide

Example 34 (60 mg, 0.107 mmol) was subjected to chiral separation (OD column) to give 34-1 (13 mg, R.T = 3.417 min), yield: 22%; 34-2 (13 mg, R.T = 3.880 min), yield: 22%.

Example 34-1: MS m/z (ESI): 559.8 [M+H] ⁺ ;

Example 34-2: MS m/z (ESI): 559.8 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 35

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

first step

Under nitrogen protection, intermediate 4 (135 mg, 0.202 mmol), 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (50 mg, 0.202 mmol) and tetrakistriphenylphosphine palladium (35 mg, 0.030 mmol) were dissolved in dioxane (2 mL). The reaction was heated to 105 ° C and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by preparative silica gel chromatography (elution system A) to obtain the title product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide 35 (60 mg), yield: 55%.

MS m/z(ESI):545.8[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.67(s,1H),8.46(d,1H),8.16(s,1H),8.02(s,1H),7.78–7.67(m,1H),6.82 (s,1H),5.51(d,2H),2.13(s,3H),2.08(s,3H),1.73(s,6H).

Decomposition of Example 35

(S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide and (R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

Example 35 (60 mg, 0.110 mmol) was subjected to chiral separation (OD column) to give 35-1 (18 mg, R.T = 4.387 min), yield: 30%; 35-2 (18 mg, R.T = 5.447 min), yield: 30%.

Example 35-1: MS m/z (ESI): 546.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD) δ8.67(s,1H),8.46(d,1H),8.16(s,1H),8.02(s,1H),7.78–7.67(m,1H),6.82 (s,1H),5.51(d,2H),2.13(s,3H),2.08(s,3H),1.73(s,6H).

Example 35-2: MS m/z (ESI): 546.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 36

2-(4-(3-chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

first step

Under nitrogen protection, 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (105 mg, 0.423 mmol), 3-chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2'-(tributyltin)-2H-[1,4'-bipyridine]-2-one 36a (240 mg, 0.353 mmol, its synthesis method refers to the synthesis of intermediate 4) and bistriphenylphosphine palladium dichloride (25 mg, 0.035 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was heated to 106 ° C and stirred for 14 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the product 2-(4-(3-chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide 36 (65.6 mg), yield: 33.2%.

MS m/z(ESI):560.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.69(s,1H),8.60(d,1H),8.23(d,1H),8.09-8.04(m,1H),7.93(d,1H), 7.27-7.15(m,2H),6.67-6.60(m,1H),6.09-6.03(m,1H),2.02-1.99(m,3H),1.95-1.93(m,3H),1.74-1.72(m ,3H),1.63-1.61(m,6H).

Embodiment 37

(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

Referring to the synthesis method of Example 35, the target product (4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide 37 was synthesized.

MS m/z(ESI):548.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H).

Decomposition of Example 37

(R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide and (S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

Example 37 (30 mg, 0.055 mmol) was subjected to chiral separation (OD column) to give the title product 37-1 (12 mg, R.T = 3.352 min), yield: 40.0%; 37-2 (11 mg, R.T = 5.430 min), yield: 36.7%.

Example 37-1, MS m/z (ESI): 548.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H).

Example 37-2, MS m/z (ESI): 548.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 38

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

Referring to the synthesis method of Example 35, the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropylamine 38 was synthesized.

MS m/z(ESI):549.1[M+H] ⁺ .

Decomposition of Example 38

(R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide and (S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

Example 38 (32 mg, 0.058 mmol) was subjected to chiral separation (OD column) to give the title product 38-1 (11 mg, R.T = 4.362 min), yield: 34.3%; 38-2 (12 mg, R.T = 5.423 min), yield: 37.5%.

Example 38-1, MS m/z (ESI): 549.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71(s,1H),8.61(d,1H),8.24(s,1H),8.11(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.91(s,1H),5.49(s,2H),2.01(s,3H),1.64(s,6H).

Example 38-2, MS m/z (ESI): 549.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71(s,1H),8.61(d,1H),8.24(s,1H),8.11(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.91(s,1H),5.49(s,2H),2.01(s,3H),1.64(s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 41

2-(4-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

first step

Under nitrogen protection, 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (116 mg, 0.45 mmol), biboronic acid pinacol ester (137.2 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (20.6 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25.8 mg, 0.05 mmol) and potassium acetate (88.4 mg, 0.9 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was heated to 110 ° C and stirred for 2 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the residue was prepared by reverse phase HPLC (formic acid system) to obtain the product (2-(1-amino-2-methyl-1-carbonylpropane-2-yl)thiazol-4-yl)boronic acid 41a (62 mg), with a yield of 64%.

MS m/z(ESI):215.0[M+H] ⁺ .

Step 2

Under nitrogen protection, 41a (50 mg, 0.116 mmol), 4d (30 mg, 0.139 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (9 mg, 0.012 mmol) and cesium carbonate (75 mg, 0.231 mmol) were dissolved in a mixture of dioxane (1 mL) and water (0.1 mL). The reaction was heated to 100 °C and stirred for 3 hours. Ethyl acetate (10 mL) was added to the reaction solution, filtered through celite, and the filtrate was concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to give the product 2-(4-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide 41 (25 mg), yield: 38%

MS m/z(ESI):566.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.94(s,1H),8.61(d,1H),8.33(s,1H),8.25(s,1H),8.10(d,1H),7.29( s,1H),7.19(s,1H),6.84(s,1H),5.50(d,2H),2.02(s,3H),1.63(s,6H).

Embodiment 42

2-(4-(3,5'-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide

Referring to the synthesis method of Example 41, the target product 2-(4-(3,5'-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropanamide 42 was synthesized.

MS m/z(ESI):580.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.93(s,1H),8.60(d,1H),8.32(d,1H),8.23(d,1H),8.06(t,1H),7.29( s,1H),7.19(s,1H),6.71(s,1H),6.08(d,1H),1.98(d,3H),1.73(d,3H),1.62(d,6H).

Embodiment 45

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide

Referring to the synthesis method of Example 34, the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide 45 was synthesized.

MS m/z(ESI):562.1[M+H] ⁺ .

Decomposition of Example 45

(R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridin-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide and (S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxy-2H-[1,4'-bipyridin-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide

Example 45 (30 mg, 0.053 mmol) was subjected to chiral separation (OD column) to give the title product 45-1 (12 mg, R.T = 3.397 min), yield: 40.0%; 45-2 (11 mg, R.T = 3.860 min), yield: 36.7%.

Example 45-1, MS m/z (ESI): 562.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71(s,1H),8.61(s,1H),8.24(s,1H),8.10(m,1H),7.92(s,1H),7.66( m,1H),6.81(s,1H),2.60(d,3H),2.03(s,3H),1.98(s,3H),1.63(s,6H).

Example 45-2, MS m/z (ESI): 562.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71(s,1H),8.61(s,1H),8.24(s,1H),8.10(m,1H),7.92(s,1H),7.66( m,1H),6.81(s,1H),2.60(d,3H),2.03(s,3H),1.98(s,3H),1.63(s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 46

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,N,2-trimethylpropanamide

first step

Under nitrogen protection, sodium hydride (302 mg, 7.55 mmol, 60% purity) was dissolved in tetrahydrofuran (2 mL) and stirred in an ice bath. A tetrahydrofuran solution (2 mL) of 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (1.88 g, 7.55 mmol) was added dropwise to the reaction solution, and the reaction was heated to 30°C and stirred for 1 hour, then the temperature was raised to 70°C and iodomethane (1.07 g, 7.55 mmol) was slowly added dropwise, and stirring was continued for 0.5 hour. The reaction solution was quenched with saturated ammonium chloride solution, concentrated, and separated by silica gel column chromatography (elution system B) to obtain the title product 2-(4-bromothiazol-2-yl)-N,N,2-trimethylpropanamide 46a (489 mg, light yellow solid), yield: 23%.

MS m/z(ESI):277.0[M+H] ⁺ .

Step 2

Referring to the synthesis method of the sixth step of Example 34, the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,N,2-trimethylpropanamide 46 was synthesized.

MS m/z(ESI):573.8[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.60(d,1H),8.30(s,1H),8.13–8.05(m,1H),7.85(s,1H),6.80 (s,1H),5.48(s,2H),2.71(d,6H),2.03(s,3H),1.97(s,3H),1.62(s,6H).

Embodiment 47

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

first step

Under nitrogen protection, 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-6-methyl-2H-[1,4'-bipyridyl]-2-one 47a (100 mg, 0.230 mmol, refer to the synthesis method of 4d in Example 4), intermediate 5 (86 mg, 0.460 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (17 mg, 0.023 mmol) and cesium carbonate (150 mg, 0.46 mmol) were dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL), and the reaction was heated to 100 ° C and stirred for 2.5 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one 47 (65 mg) with a yield of 52.2%.

MS m/z(ESI):541.1[M+H] ⁺ ;

Decomposition of Example 47

(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 47 (65 mg, 0.12 mmol) was subjected to chiral separation (OD column) to give the title product 47-1 (20.8 mg, R.T = 3.333 min), yield: 32.0%; 47-2 (21.6 mg, R.T = 4.167 min), yield: 33.2%.

Example 47-1, MS m/z (ESI): 541.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.94(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.13-8.07(m,1H), 6.83(d,1H),6.10(s,1H),2.01(s,3H),1.56(s,6H).

Example 47-2, MS m/z (ESI): 541.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.94(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.13-8.07(m,1H), 6.83(d,1H),6.10(s,1H),2.01(s,3H),1.56(s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 48

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridyl]-2-one

first step

1-(2-bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one 11e (550 g, 1.67 mmol), 2-(chloromethyl-d2)-3,5-difluoropyridine 7b (387 mg, 2.34 mmol), potassium carbonate (577 mg, 4.17 mmol) and 18-crown-6 ether (662 mg, 2.50 mmol) were dissolved in N,N-dimethylformamide (25 mL) and heated to 70°C and stirred for 3 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the organic phase was washed with water and saturated sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one 48a (540 mg) in a yield of 70.6%.

MS m/z(ESI):458.0[M+H] ⁺ .

Step 2

Under nitrogen protection, 2'-bromo-3-chloro-4-((3,5-difluoro-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 48a (210 mg, 0.458 mmol), 2-(1H-pyrazol-3-yl)propane-2-ol 11b (87 mg, 0.687 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (26 mg, 0.183 mmol), cuprous iodide (17 mg, 0.092 mmol) and cesium carbonate (298 mg, 0.916 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction was heated to 100 ° C and stirred for 8 hours. Ethyl acetate (25 mL) was added to the reaction solution, and the organic phase was washed with water and saturated sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridyl]-2-one 48 (75 mg), yield: 32.5%.

MS m/z(ESI):504.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.10(t,1H),7.78(s,1H),6.80( s,1H),6.56(d,1H),5.09(s,1H),2.00(d,6H),1.48(s,6H).

Decomposition of Example 48

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 48 (140 mg, 0.278 mmol) was subjected to chiral separation (AS column) to give the title product 48-1 (54 mg, R.T = 3.28 min), yield: 38.57%; 48-2 (52 mg, R.T = 4.757 min), yield: 34.14%.

Example 48-1, MS m/z (ESI): 504.1 [M+H] ⁺ ;

Example 48-2, MS m/z (ESI): 504.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 49

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

First Step

2',5'-Dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 4b (10 g, 36.89 mmol) was dissolved in a mixture of dichloroethane (600 mL) and isopropanol (400 mL), heated to 60°C and stirred. N-chlorosuccinamide (6.2 g, 46.11 mmol) was added to the reaction solution in batches, and the reaction was continued to stir at 60°C for 2 hours. The reaction solution was concentrated, and the residue was separated by a reverse phase column (formic acid system) to obtain 2',3,5'-trichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 49a (5.1 g), with a yield of 45.3%.

MS m/z(ESI):306.8[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.72(s,1H),8.80(s,1H),7.98(s,1H),6.19(d,1H),1.90(s,3H).

Step 2

49a (300 mg, 0.982 mmol), 2-(1H-pyrazol-3-yl)propan-2-ol 11b (186 mg, 1.47 mmol) and cesium carbonate (640 mg, 1.96 mmol) were dissolved in dimethyl sulfoxide (4 mL). The reaction was heated to 110 ° C and stirred for 16 hours. The reaction solution was purified by reverse phase column (formic acid system) to obtain the product 3,5'-dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 49b (263 mg), yield: 68%.

MS m/z(ESI):395.0[M+H] ⁺ .

Step 3

3,5'-Dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one 49b (70 mg, 0.177 mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (58 mg, 0.354 mmol) and potassium carbonate (73 mg, 0.531 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction was heated to 70°C and stirred for 3 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated brine, dried, and concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to obtain the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 49 (75 mg), yield: 81%.

MS m/z(ESI):522.1[M+H] ⁺ .

Decomposition of Example 49

(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 49 (75 mg, 0.144 mmol) was subjected to chiral separation (OJ column) to give 49-1 (28 mg, R.T = 3.650 min) yield: 37%; 49-2 (28 mg, R.T = 8.937 min), yield: 37%.

Example 49-1: MS m/z (ESI): 522.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.36–7.27(m,1H),6.42( d,1H),6.40(s,1H),5.42(s,2H),2.08(s,3H),1.59(d,6H).

Example 49-2: MS m/z (ESI): 522.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.37–7.28(m,1H),6.47– 6.41(m,1H),6.40(s,1H),5.40(d,2H),2.08(s,3H),1.59(d,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 50

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 49, the target product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 50 was synthesized.

MS m/z(ESI):524.1[M+H] ⁺ .

Decomposition of Example 50

(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 50 (65 mg, 0.124 mmol) was subjected to chiral separation (OJ column) to give 50-1 (25 mg, R.T = 3.633 min) with a yield of 38%; 50-2 (25 mg, R.T = 9.053 min), with a yield of 38%.

Example 50-1: MS m/z (ESI): 524.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.36–7.29(m,1H),6.42( d,1H),6.40(s,1H),2.08(s,3H),1.59(d,6H).

Example 50-2: MS m/z (ESI): 524.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.54(s,1H),8.43(d,1H),8.40(s,1H),7.92(s,1H),7.31(dd,1H),6.42(d, 1H),6.40(s,1H),2.08(s,3H),1.59(d,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 51

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 9, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropane-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 51 was synthesized.

MS m/z(ESI):521.1[M+H] ⁺ ;

Decomposition of Example 51

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 51 (58 mg, 0.111 mmol) was subjected to chiral separation (OD column) to give the title product 51-1 (21 mg, R.T = 4.653 min), yield: 36.2%; 51-2 (22.4 mg, R.T = 6.000 min), yield: 38.6%.

Example 51-1, MS m/z (ESI): 521.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.72(s,1H),8.60(d,1H),8.13-8.08(m,1H),8.01(s,1H),7.54(s,1H), 6.81(d,1H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H).

Example 51-2, MS m/z (ESI): 521.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.72(s,1H),8.60(d,1H),8.13-8.08(m,1H),8.01(s,1H),7.54(s,1H), 6.81(d,1H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 52

5-Chloro-6-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4(3H)-one

first step

Under nitrogen protection, 2-chloro-4-iodo-5-methylpyridine 52a (2.5 g, 9.86 mmol), acetamidine hydrochloride (1.86 g, 19.7 mmol), cuprous iodide (188 mg, 0.986 mmol) and cesium carbonate (9.64 g, 29.6 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction was heated to 100 ° C and stirred for 16 hours. Acetonitrile (40 mL) was added to the reaction solution, filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to obtain the product N-(2-chloro-5-methylpyridin-4-yl)acetamidine 52b (650 mg), yield: 36%

MS m/z(ESI):184.0[M+1] ⁺ .

Step 2

52b (300 mg, 1.63 mmol) and di(2,4,6-trichlorophenyl)malonate (832 mg, 1.8 mmol) were dissolved in tetrahydrofuran (8 mL). The reaction solution was heated to 90°C and stirred for 8 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4(3H)-one 52c (180 mg) with a yield of 44%.

MS m/z(ESI):252.0[M+1] ⁺ .

Step 3

52c (180 mg, 0.715 mmol), 2-(chloromethyl)-3,5-difluoropyridine (175 mg, 1.07 mmol), potassium carbonate (247 mg, 1.79 mmol) and 18-crown-6 ether (189 mg, 0.715 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction was heated to 70 °C and stirred for 3 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the organic phase was washed with water three times, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give the product 3-(2-chloro-5-methylpyridin-4-yl)-6-((3,5-difluoropyridin-2-yl)methoxy)-2-methylpyrimidin-4(3H)-one 52d (190 mg) in a yield of 70%.

MS m/z(ESI):379.0[M+H] ⁺ .

Step 4

52d (100 mg, 0.264 mmol) and N-chlorosuccinimide (39 mg, 0.29 mmol) were dissolved in isopropanol (3 mL), and the reaction was heated to 60 °C and stirred for 6 hours. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-((3,5-difluoropyridin-2-yl)methoxy)-2-methylpyrimidin-4(3H)-one 52e (80 mg), with a yield of 73%.

MS m/z(ESI):413.0[M+H] ⁺ .

Step 5

Under nitrogen protection, 52e (80 mg, 0.194 mmol), intermediate 5 (91 mg, 0.484 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (16 mg, 0.019 mmol) and cesium carbonate (126 mg, 0.387 mmol) were dissolved in 1,4-dioxane/water (V:V=10:1, 1 mL), and the reaction was heated to 100°C and stirred for 3 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give the title product 5-chloro-6-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4(3H)-one 52 (70 mg), yield: 70%.

MS m/z(ESI):520.0[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71(s,1H),8.58(d,1H),8.17(s,1H),8.09(s,1H),8.07–8.02(m,1H), 6.07(s,1H),5.61(m,2H),2.12(s,3H),2.08(s,3H),1.56(d,6H).

Embodiment 53

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

first step

Under nitrogen protection, ethyl 4-methyl-1H-pyrazole-3-carboxylate 53a (2.5 g, 16.2 mmol) was dissolved in tetrahydrofuran (25 mL). Methylmagnesium bromide (3 M, 16.2 mL) was added dropwise to the reaction solution under ice bath and stirring. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction solution was quenched with saturated ammonium chloride, concentrated to half volume under reduced pressure, extracted with ethyl acetate, and the aqueous layer was extracted once with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated to obtain the product 2-(4-methyl-1H-pyrazol-3-yl)propan-2-ol 53b (1.89 g), which was used directly in the next step without purification.

MS m/z(ESI):141.1[M+H] ⁺ .

Step 2

49a (500 mg, 1.64 mmol), 2-(4-methyl-1H-pyrazol-3-yl)propan-2-ol 53b (344 mg, 2.45 mmol) and cesium carbonate (1.07 g, 3.27 mmol) were dissolved in dimethyl sulfoxide (7 mL), heated to 110°C and stirred for 14 hours. The reaction solution was purified by reverse phase HPLC (formic acid system) to obtain the product 3,5'-dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 53c (460 mg), yield: 69%.

MS m/z(ESI):409.1[M+H] ⁺ .

Step 3

5'-Dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one 53c (80 mg, 0.196 mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (64 mg, 0.391 mmol), potassium carbonate (81 mg, 0.586 mmol) and 18-crown-6 (77 mg, 0.293 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction was heated to 70°C and stirred for 3 hours. The reaction solution was purified by reverse phase HPLC (formic acid system) to give the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 53 (70 mg) in a yield of 67%.

MS m/z(ESI):537.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.51(s,1H),8.40(d,1H),8.23(s,1H),7.86(s,1H),7.36–7.28(m,1H),6.40( s,1H),5.41(s,2H),2.22(s,3H),2.07(s,3H),1.59(d,6H).

Decomposition of Example 53

(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 53 (65 mg, 0.121 mmol) was subjected to chiral separation (OD column) to give 53-1 (30 mg, R.T = 3.160 min) with a yield of 46%; 53-2 (30 mg, R.T = 5.810 min) with a yield of 46%.

Example 53-1: MS m/z (ESI): 537.1 [M+H] ⁺ ;

Example 53-2: MS m/z (ESI): 537.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 54

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 53, the target product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(3-(2-hydroxypropane-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 54 was synthesized.

MS m/z(ESI):538.1[M+H] ⁺ .

Decomposition of Example 54

(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

Example 54 (80 mg, 0.148 mmol) was subjected to chiral separation (OD column) to give 54-1 (31 mg, R.T = 3.160 min), yield: 39%; 54-2 (30 mg, R.T = 5.823 min), yield: 38%.

Example 54-1: MS m/z (ESI): 538.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.51(s,1H),8.40(d,1H),8.23(d,1H),7.84(s,1H),7.32(ddd,1H),6.40(d, 1H),2.22(s,3H),2.07(s,3H),1.59(d,6H).

Example 54-2: MS m/z (ESI): 538.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.51(s,1H),8.40(s,1H),8.23(s,1H),7.85(s,1H),7.32(t,1H),6.40(s, 1H),2.22(s,3H),2.07(s,3H),1.59(d,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 55

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridinyl]-2-one

first step

The reaction solution of 2-chloro-5-fluoro-pyridin-4-amine 55a (500 mg, 3.41 mmol) and 2,2-dimethyl-6-(2-carbonylpropyl)-4H-1,3-dioxin-4-one (1.26 g, 6.82 mmol) dissolved in 1,4-dioxane (5 mL) was placed in an oil bath preheated to 95°C and stirred for 2 hours. Concentrated sulfuric acid (569 mg, 5.80 mmol, 0.309 mL) was added to the reaction solution, and the reaction was continued to stir at 95°C for 1 hour. The reaction solution was cooled and the upper organic phase was removed. Water was added to the lower oily substance, and solids were precipitated after ultrasonic vibration. After filtration, 2'-chloro-5'- fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2-one 55b (0.38 g) was obtained, and the product was directly used in the next reaction without purification.

MS m/z(ESI):255.0[M+1] ⁺ .

Step 2

2'-Chloro-5'-fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 55b (0.38 g, 1.49 mmol) was dissolved in a mixture of isopropanol (4 mL) and 1,2-dichloroethane (6 mL) and heated to 60°C and stirred for 10 minutes. N-chlorosuccinamide (239.12 mg, 1.79 mmol) was added to the reaction solution in batches under stirring, and the reaction was stirred at 60°C for 1 hour. The reaction solution was concentrated, isopropanol (4 mL) was added to the residue, and after solids were precipitated under ultrasound, it was heated to 50°C and stirred for 1 hour. The reaction solution was cooled to room temperature, and the reaction solution was filtered to obtain 2',3-dichloro-5'-fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 55c (420 mg), which was used directly in the next step without purification.

MS m/z(ESI):299.2[M+1] ⁺ .

Step 3

2',3-Dichloro-5'-fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 55c (150 mg, 0.519 mmol), potassium carbonate (179 mg, 1.30 mmol) and 18-crown-6 ether (206 mg, 0.778 mmol) were dissolved in N,N-dimethylformamide (10 mL) and heated to 70°C and stirred for 10 minutes. 2-(Chloromethyl)-3,5-difluoropyridine (119 mg, 0.726 mmol) was added dropwise to the reaction solution and stirred at 70°C for 3 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the organic phase was washed with water (10 mL×2) and saturated ammonium chloride (10 mL), dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-6-methyl-2H-[1,4'-bipyridinyl]-2-one 55d (150 mg) in a yield of 69.46%.

MS m/z(ESI):416.0[M+1] ⁺ .

Step 4

Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-6-methyl-2H-[1,4'-bipyridyl]-2-one 55d (70 mg, 0.168 mmol), intermediate 5 (47 mg, 0.252 mmol), 1,1-bis(diphenylphosphino)1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (12 mg, 17 mmol) and cesium carbonate (110 mg, 0.336 mmol) were dissolved in 1,4-dioxane (1 mL), heated to 100°C and stirred for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 55 (60 mg) in a yield of 68.22%.

MS m/z(ESI):523.1[M+1] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.89(s,1H),8.60(d,1H),8.18(s,1H),8.16(d,1H),8.13–8.06(m,1H), 6.82(s,1H),6.08(s,1H),5.51(s,2H),2.08(s,3H),1.56(d,6H).

Embodiment 56

N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide

first step

2-(4-bromothiazol-2-yl)propan-2-ol 5C (440 mg, 1.98 mmol) and acetonitrile (488 mg, 11.89 mmol) were dissolved in acetic acid (952 mg, 15.85 mmol) and stirred. Concentrated sulfuric acid (1.75 g, 17.83 mmol) was added dropwise to the above reaction solution at 0°C, and the reaction temperature was raised to 20°C and stirred for 16 hours. After cooling to 0°C, saturated sodium bicarbonate solution (40 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to obtain N-(2-(4-bromothiazol-2-yl)propan-2-yl)acetamide 56a (434 mg) with a yield of 83.25%.

MS m/z(ESI):263.0[M+H] ⁺ ;

Step 2

Under nitrogen protection, N-(2-(4-bromothiazol-2-yl)propan-2-yl)acetamide 56a (100 mg, 0.38 mmol), biboronic acid pinacol ester (106 mg, 0.418 mmol), tris(dibenzylideneacetone)dipalladium (17 mg, 0.019 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22 mg, 0.046 mmol) and potassium acetate (112 mg, 1.14 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100 ° C and stirred for 1 hour. The reaction solution was filtered and the filtrate was concentrated to obtain the crude product (2-(2-acetamidopropane-2-yl)thiazol-4-yl)boronic acid 56b (83 mg), which was directly used in the next step without further purification.

MS m/z(ESI):229.1[M+H] ⁺ ;

Step 3

Under nitrogen protection, (2-(2-acetylaminopropane-2-yl)thiazol-4-yl)boronic acid 56b (83 mg, 0.362 mmol), 48a (100 mg, 0.241 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (18 mg, 0.024 mmol) and cesium carbonate (157 mg, 0.483 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (0.5 mL), and the reaction was heated to 100°C and stirred for 1.5 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (elution system B) to give N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide 56 (103 mg), yield: 75.91%.

MS m/z(ESI):562.2[M+H] ⁺ ;

Decomposition of Example 56

(S)-N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide and (R)-N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide

Example 56 (103 mg, 0.183 mmol) was subjected to chiral separation (AD column) to give the title product 56-1 (44.3 mg, R.T = 4.643 min), yield: 43.01%; 56-2 (42.4 mg, R.T = 5.823 min), yield: 41.17%.

Example 56-1, MS m/z (ESI): 562.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.14-8.07(m,1H), 7.85(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H).

Example 56-2, MS m/z (ESI): 562.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.14-8.07(m,1H), 7.85(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 57

3-Chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-4-((3-methoxybenzyl)oxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

first step

Under nitrogen protection, 11e (800 mg, 2.43 mmol), 2-(1H-pyrazol-3-yl)propan-2-ol (459 mg, 3.64 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (69 mg, 0.49 mmol), cesium carbonate (1.18 g, 3.64 mmol), and cuprous iodide (46 mg, 0.24 mmol) were dissolved in dioxane (5 mL), heated to 100 ° C and stirred for 3 hours. The reaction solution was filtered, the pH value of the filtrate was adjusted to 3 with formic acid, the reaction solution was concentrated, and the residue was separated by Prep-HPLC chromatography (formic acid system) to give the title product 3-chloro-4-hydroxy-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 57a (580 mg), yield: 63.8%.

MS m/z(ESI):375.2[M+H] ⁺ .

Step 2

3-Chloro-4-hydroxy-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 57a (50 mg, 0.13 mmol), 1-(chloromethyl)-3-methoxybenzene (42 mg, 0.27 mmol), 18-crown-6 (35 mg, 0.13 mmol), potassium carbonate (27 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction was heated to 60°C and stirred for 16 hours. The reaction solution was concentrated and the residue was separated by Prep-HPLC chromatography (eluent system A) to give the title product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-4-((3-methoxybenzyl)oxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 57 (20 mg), yield: 30.3%.

MS m/z(ESI):495.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.48(d,1H),8.40(s,1H),7.77(s,1H),7.34(t,1H),7.00(m,2H),6.91(dd, 1H),6.39(d,1H),6.14(s,1H),5.27(s,2H),3.85(s,3H),2.10(s,3H),2.00(s,3H),1.59(d,6H ).

Embodiment 58

3-Chloro-4-((2,4-difluorobenzyl)oxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((2,4-difluorobenzyl)oxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 58 was synthesized.

MS m/z(ESI):501.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.50(s,1H),8.42(s,1H),7.79(s,1H),7.58(t,1H),6.99(t,1H),6.90(m, 1H),6.40(d,1H),6.20(s,1H),5.28(s,2H),2.11(s,3H),2.04(s,3H),1.60(d,6H).

Embodiment 59

3-Chloro-4-((3,5-dichloropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((3,5-dichloropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 59 was synthesized.

MS m/z(ESI):534.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.50(m,2H),8.41(s,1H),7.80(m,2H),6.41(s,1H),6.31(s,1H),5.46(s, 2H),2.11(s,3H),2.03(s,3H),1.60(d,6H).

Embodiment 60

3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((3-(trifluoromethyl)benzyl)oxy)-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((3-(trifluoromethyl)benzyl)oxy)-2H-[1,4'-bipyridyl]-2-one 60 was synthesized.

MS m/z(ESI):533.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.54(s,1H),8.51(d,1H),7.88(s,1H),7.81(d,1H),7.77(s,2H),7.72( d,1H),6.75(s,1H),6.56(d,1H),5.48(s,2H),5.07(s,1H),2.00(s,6H),1.47(s,6H).

Embodiment 61

3-Chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((1-methyl-1H-pyrazol-3-yl)methoxy)-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((1-methyl-1H-pyrazol-3-yl)methoxy)-2H-[1,4'-bipyridine]-2-one 61 was synthesized.

MS m/z(ESI):469.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.43(d,2H),7.74(s,1H),7.39(s,1H),6.38(m,3H),5.30(s,2H),3.94(s, 3H),2.09(s,3H),2.01(s,3H),1.59(d,6H).

Embodiment 62

3-Chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,5-trifluorobenzyl)oxy)-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,5-trifluorobenzyl)oxy)-2H-[1,4'-bipyridyl]-2-one 62 was synthesized.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.44(d,2H),7.76(s,1H),7.47(d,1H),7.01(d,1H),6.39(s,1H),6.16(s, 1H),5.25(s,2H),2.11(s,3H),2.04(s,3H),1.59(d,6H).

Embodiment 63

3-Chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,3,4-trifluorobenzyl)oxy)-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,3,4-trifluorobenzyl)oxy)-2H-[1,4'-bipyridyl]-2-one 63 was synthesized.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.44(d,2H),7.75(s,1H),7.35(d,1H),7.08(d,1H),6.39(s,1H),6.18(s, 1H),5.29(s,2H),2.10(s,3H),2.04(s,3H),1.59(d,6H).

Embodiment 64

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(3-(2-hydroxypropane-2-yl)-4-methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 64 was synthesized.

MS m/z(ESI):518.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.40(d,1H),8.37(s,1H),8.25(s,1H),7.68(s,1H),7.35–7.29(m,1H),6.39( s,1H),2.21(s,3H),2.08(s,3H),2.03(s,3H),1.59(d,6H).

Decomposition of Example 64

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 64 (25 mg, 0.048 mmol) was subjected to chiral separation (OD column) to give 64-1 (11 mg, R.T = 3.107 min), yield: 44%; 64-2 (12 mg, R.T = 4.890 min), yield: 48%.

Example 64-1: MS m/z (ESI): 518.1 [M+H] ⁺ ;

Example 64-2: MS m/z (ESI): 518.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 66

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentan-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentan-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 66 was synthesized.

MS m/z(ESI):532.2[M+H] ⁺ .

Decomposition of Example 66

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentan-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentan-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 66 (80 mg, 0.027 mmol) was subjected to chiral separation (OD column) to give 66-1 (36 mg, R.T = 6.273 min), yield: 45%; 66-2 (32 mg, R.T = 7.830 min), yield: 40%.

Example 66-1: MS m/z (ESI): 532.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.51(s,1H),8.40(s,2H),7.76(s,1H),7.32(t,1H),6.40(s,1H),6.27(s, 1H),2.07(d,6H),1.79(m,4H),0.81(m,6H).

Example 66-2: MS m/z (ESI): 532.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.51(s,1H),8.40(s,2H),7.76(s,1H),7.32(t,1H),6.40(s,1H),6.27(s, 1H),2.07(d,6H),1.79(m,4H),0.81(m,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 67

3-Chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 67 was synthesized.

MS m/z(ESI):518.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.46(s,3H),7.74(s,1H),7.57(d,1H),6.36(s,2H),5.41(s,2H),2.10(s, 3H),2.03(s,3H),1.59(d,6H).

Embodiment 68

3-Chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 68 was synthesized.

MS m/z(ESI):518.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.41(m,3H),7.75(s,1H),7.59(dd,1H),6.39(d,1H),6.33(s,1H),5.46(s, 2H),2.10(s,3H),2.02(s,3H),1.59(d,6H).

Embodiment 69

3-Chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 69 was synthesized.

MS m/z(ESI):485.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.12(d,1H),8.98(d,1H),8.54(s,1H),8.51(d,1H),7.77(s,1H),6.72( s,1H),6.56(d,1H),5.63(d,2H),5.07(s,1H),2.00(s,3H),1.96(s,3H),1.48(s,6H).

Embodiment 70

3-Chloro-4-((4-chloro-2-fluorobenzyl)oxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((4-chloro-2-fluorobenzyl)oxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 70 was synthesized.

MS m/z(ESI):517.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.46(d,1H),8.40(s,1H),7.75(s,1H),7.55(t,1H),7.25(d,1H),7.17(d, 1H),6.39(d,1H),6.17(s,1H),5.29(s,2H),2.10(s,3H),2.03(s,3H),1.59(d,6H).

Embodiment 71

3-Chloro-4-((2-chloro-4-fluorobenzyl)oxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-4-((2-chloro-4-fluorobenzyl)oxy)-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 71 was synthesized.

MS m/z(ESI):517.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.47(d,1H),8.41(s,1H),7.76(s,1H),7.65(m,1H),7.20(dd,1H),7.11(d, 1H),6.39(d,1H),6.16(s,1H),5.31(s,2H),2.11(s,3H), 2.03(s,3H),1.59(d,6H)

Embodiment 72

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-methoxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

Under ice bath, 1H-pyrazole-3-carboxylic acid methyl ester (2g, 15.9mmol) and potassium carbonate (4.39g, 31.8mmol) were dissolved in N,N-dimethylformamide (20mL) and stirred, and 2-(trimethylsilyl)ethoxymethyl chloride (3.96g, 23.8mmol) was added dropwise, and the reaction was heated to room temperature and stirred for 2 hours. The reaction solution was poured into water (100mL), and the aqueous phase was extracted with methyl tert-butyl ether (50mL×2). The organic phases were combined, washed with water (50mL) and saturated sodium chloride solution (50mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid methyl ester 72a (1.6g), yield: 39.4%.

MS m/z(ESI):257.1[M+H] ⁺ .

Step 2

Dissolve 72a (1.6 g, 6.24 mmol) in anhydrous tetrahydrofuran (15 mL) and stir. Add methyl magnesium bromide tetrahydrofuran solution (3 M, 6.2 mL, 18.6 mmol) dropwise to the reaction solution under ice bath. Stir the reaction at room temperature for 2 hours, pour the reaction solution into saturated ammonium chloride solution (100 mL), and extract the aqueous phase with methyl tert-butyl ether (50 mL × 2). The organic phases are combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in turn, dried, and concentrated to obtain 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propane-2-ol 72b (1.6 g), which is used directly in the next step without purification.

MS m/z(ESI):257.1[M+H] ⁺ .

Step 3

72b (700 mg, 2.72 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and stirred. Sodium hydride (218 mg, 5.45 mmol, content 60%) was added under ice bath. The reaction was stirred at room temperature for 0.5 hours and then iodomethane (774 mg, 5.45 mmol) was added. The reaction was stirred at room temperature for 1.5 hours, and the reaction solution was poured into ice water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in turn, dried, and concentrated to obtain 3-(2-methoxypropane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 72c (720 mg), which was used directly in the next step without purification.

MS m/z(ESI):271.2[M+H] ⁺ .

Step 4

72c (720 mg, 2.66 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (1M, 20 mL, 20 mmol), and the reaction was heated to 65°C and stirred for 16 hours. The reaction solution was cooled to room temperature, poured into water (100 mL), and the aqueous phase was extracted with dichloromethane (50 mL×2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-(1-methoxy-1-methyl-ethyl)-1H-pyrazole 72d (170 mg), yield: 45.7%.

MS m/z(ESI):281.2[M+H] ⁺ .

Step 5

48a (80 mg, 0.174 mmol) was dissolved in 1,4-dioxane (2 mL), 72d (37 mg, 0.262 mmol), trans-N,N'-dimethyl 1,2-cyclohexanediamine (12 mg, 0.087 mmol), cesium carbonate (114 mg, 0.349 mmol) and cuprous iodide (50 mg, 0.262 mmol) were added, and the reaction was heated to 100 ° C and stirred for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent System C to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(3-(2-methoxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one (40 mg) 72, yield: 44.3%.

MS m/z(ESI):518.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.59(d,1H),8.56(s,1H),8.13-8.08(m,1H),7.82(s,1H), 6.81(s,1H),6.55(d,1H),3.01(s,3H),2.01(s,3H),2.00(s,3H),1.51(s,6H).

Decomposition of Example 72

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-methoxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-methoxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 72 (45 mg, 0.087 mmol) was subjected to chiral separation (OD column) to give 72-1 (8.9 mg, R.T = 3.463 min), yield: 19%; 72-2 (9.8 mg, R.T = 4.063 min), yield: 22%.

Example 72-1: MS m/z (ESI): 518.1 [M+H] ⁺ ;

Example 72-2: MS m/z (ESI): 518.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 73

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

first step

Under ice bath, methyl 4-fluoro-1H-pyrazole-3-carboxylate (600 mg, 4.16 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and a tetrahydrofuran solution of methyl magnesium bromide (3 M, 6.9 mL, 20.7 mmol) was added dropwise to the reaction solution under stirring, and the reaction was stirred at room temperature for 3 hours. The reaction solution was slowly poured into a saturated ammonium chloride solution (50 mL) under stirring, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated to obtain 2-(4-fluoro-1H-pyrazol-3-yl)propane-2-ol 73a (600 mg), which was used directly in the next step without purification.

MS m/z(ESI):145.1[M+H] ⁺ .

Step 2

73a (600 mg) was dissolved in acetonitrile (15 mL) and stirred. Concentrated sulfuric acid (5 mL) was added dropwise to the reaction solution at 0°C. The reaction was heated to room temperature and stirred for 3 hours. The reaction solution was slowly poured into a saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro-1H-pyrazol-3-yl)propane-2-yl)acetamide 73b (510 mg) with a yield of 86.8%.

MS m/z(ESI):186.1[M+H] ⁺ .

Step 3

Under nitrogen protection, 48a (80 mg, 0.174 mmol) was dissolved in 1,4-dioxane (2 mL), and then 73b (48 mg, 0.261 mmol), (trans)-dimethyl-1,2-cyclohexanediamine (12 mg, 0.087 mmol), cesium carbonate (170 mg, 0.523 mmol) and cuprous iodide (66 mg, 0.349 mmol) were added in sequence, and the reaction was heated to 100 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent System C to give N-(2-(1-(3-chloro-4-((3,5-difluoropyridin- ₂ -yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 73 (75 mg), yield: 76.1%.

MS m/z(ESI):563.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.56(d,1H),8.54(s,1H),8.11-8.06(m,2H),7.78(s,1H), 6.80(s,1H),2.01(s,3H),1.99(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H).

Decomposition of Example 73

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 73 (40 mg, 0.071 mmol) was subjected to chiral separation (OD column) to give 73-1 (18.3 mg,

R.T＝3.020min), yield: 45%; 73-2 (17.3 mg, R.T＝3.960min), yield: 43%.

Example 73-1: MS m/z (ESI): 563.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.56(d,1H),8.54(s,1H),8.12-8.06(m,2H),7.78(s,1H), 6.80(s,1H),2.00(s,3H),1.99(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H).

Example 73-2: MS m/z (ESI): 563.2 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 75

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-(2-carbonylpyrrolidin-1-yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

first step

2-(1-Benzyl-1H-pyrazol-3-yl)propan-2-ol 75a (400 mg, 1.85 mmol) and 4-chlorobutyronitrile (4.79 g, 46.24 mmol) were dissolved in trifluoroacetic acid (5 mL) and chloroform (5 mL), and the reaction was stirred at 30° C. for 48 hours. The reaction solution was concentrated, and the residue was separated by Prep-HPLC column chromatography (formic acid system) to obtain the title product N-(2-(1-benzyl-1H-pyrazol-3-yl)propan-2-yl)-4-chlorobutyramide 75b (200 mg), with a yield of 33.8%.

MS m/z(ESI):320.2[M+H] ⁺ .

Step 2

Sodium hydride (125 mg, 3.13 mmol, 60% content) was added to a tetrahydrofuran (10 mL) solution of N-[1-(1-benzylpyrazol-3-yl)-1-methyl-ethyl]-4-chlorobutyramide 75b (500 mg, 1.56 mmol) under ice bath. The reaction was stirred at 22°C for 3 hours. The reaction solution was quenched with methanol, concentrated, and separated using Prep-HPLC chromatographic column method (formic acid system) to obtain the title product 1-[1-(1-benzylpyrazol-3-yl)-1-methyl-ethyl]pyrrolidin-2-one 75c (310 mg), with a yield of 70.0%.

MS m/z(ESI):284.2[M+H] ⁺ .

Step 3

A suspension of 1-[1-(1-benzylpyrazol-3-yl)-1-methyl-ethyl]pyrrolidin-2-one 75c (300 mg, 1.06 mmol) and Pd/C (300 mg, 5% Pd content, 55% water content) in tetrahydrofuran (10 mL) and acetic acid (2 mL) was replaced with hydrogen. Stir at 25°C for 16 hours in a hydrogen environment. The reaction solution was filtered to remove palladium carbon, the filtrate was concentrated, and the title product 1-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]pyrrolidin-2-one 75d (160 mg) was separated using a Prep-HPLC column method (formic acid system) with a yield of 78.2%.

MS m/z(ESI):194.1[M+H] ⁺ .

Step 4

The product 1-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]pyrrolidin-2-one 75d (63 mg, 0.33 mmol), 48a (100 mg, 0.22 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (12 mg, 0.09 mmol), cesium carbonate (106 mg 0.33 mmol), and cuprous iodide (17 mg, 0.09 mmol) were dissolved in dioxane (2 mL). The reaction was stirred at 100° C. for 3 hours. The reaction solution was concentrated and separated by normal phase silica gel column chromatography (eluent system A) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-(2-carbonylpyrrolidin-1-yl)propane-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one 75 (86 mg), yield: 69.1%.

MS m/z(ESI):571.2[M+H] ⁺ .

Decomposition of Example 75

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-(2-carbonylpyrrolidin-1-yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-(2-carbonylpyrrolidin-1-yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

Example 75 (75 mg, 0.131 mmol) was subjected to chiral separation (OD column) to give 75-1 (30 mg, R.T = 4.527 min), yield: 40%; 75-2 (35 mg, R.T = 5.733 min), yield: 46%.

Example 75-1: MS m/z (ESI): 571.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.40(m,3H),7.71(s,1H),7.33(m,1H),6.40(d,2H),3.42(dt,2H),2.37(d, 2H),2.06(d,6H),1.95(d,2H),1.79(d,6H).

Example 75-2: MS m/z (ESI): 571.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.40(m,3H),7.71(s,1H),7.33(m,1H),6.40(d,2H),3.42(dt,2H),2.37(d, 2H),2.06(d,6H),1.95(d,2H),1.79(d,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 76

2'-(3-(1-acetyl-3-methylazetidin-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.24 g, 11.15 mmol) was added to a dichloromethane solution (50 mL) of 1-tert-butyloxycarbonyl-3-methyl-azetidine-3-carboxylic acid 76a (2.00 g, 9.29 mmol), N-methoxymethylamine hydrochloride (997 mg, 10.22 mmol) and triethylamine (2.82 g, 27.88 mmol), and the reaction solution was stirred at 25° C. for 3 hours. After the reaction was completed, the reaction solution was filtered to remove solid impurities, the filtrate was concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-[methoxy(methyl)carbamoyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester 76b (2.10 g), with a yield of 87.5%.

MS m/z(ESI):259.2[M+H] ⁺ .

Step 2

Methylmagnesium bromide (4.24 g, 11.15 mmol) was added dropwise to a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]-3-methyl-azetidine-1-carboxylate 76b (2.38 g, 9.21 mmol) in tetrahydrofuran (50 mL) at 0°C in an ice bath. After the addition was complete, the reaction solution was heated to 25°C and stirred for 2 hours. After the reaction was completed, the reaction solution was quenched with methanol and water to form a white solid, which was filtered to remove solid impurities, and the filtrate was concentrated. The residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product tert-butyl 3-acetyl-3-methylazetidine-1-carboxylate 76c (1.90 g) with a yield of 96.7%.

MS m/z(ESI):427.1[2M+H] ⁺ .

Step 3

A solution of tert-butyl 3-acetyl-3-methylazetidine-1-carboxylate 76c (4.24 g, 11.15 mmol) and N,N-dimethylformamide dimethyl acetal (8.93 g, 75.02 mmol) in N,N-dimethylformamide (15 mL) was heated to 100°C and stirred for 16 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (160 mL), washed with water and brine, the organic phases were combined and concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product tert-butyl 3-[(E)-3-(dimethylamino)propane-2-enoyl]-3-methyl-azetidine-1-carboxylate 76d (1.60 g), with a yield of 79.5%.

MS m/z(ESI):269.2[M+H] ⁺ .

Step 4

A solution of 3-[(E)-3-(dimethylamino)propane-2-enoyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester 76d (1.20 g, 4.47 mmol) and hydrazine hydrate (1.69 g, 44.72 mmol, content: 85%) in ethanol (20 mL) was heated to 50° C. and stirred for 16 hours. After the reaction was completed, the reaction solution was concentrated and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-methyl-3-(1H-pyrazol-3-yl)azetidine-1-carboxylic acid tert-butyl ester 76e (810 mg) with a yield of 76.3%.

MS m/z(ESI):475.2[2M+H] ⁺ .

Step 5

The product tert-butyl 3-methyl-3-(1H-pyrazol-3-yl)azetidine-1-carboxylate 76e (155 mg, 0.65 mmol), 48a (200 mg, 0.44 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (25 mg, 0.17 mmol), cesium carbonate (212 mg 0.65 mmol), and cuprous iodide (33 mg, 0.17 mmol) were dissolved in dioxane (3 mL). The reaction was stirred at 100 °C for 3 hours. The reaction solution was concentrated and separated by normal phase silica gel column chromatography (eluent system A) to give the title product 3-[1-[4-[3-chloro-4-[dideuterio-(3,5-difluoro-2-pyridinyl)methoxy]-6-methyl-2-carbonyl-1-pyridinyl]-5-methyl-2-pyridinyl]pyrazol-3-yl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester 76f (200 mg) with a yield of 74.6%.

MS m/z(ESI):615.2[M+H] ⁺ .

Step 6

A solution of 3-[1-[4-[3-chloro-4-[dideuterio-(3,5-difluoro-2-pyridinyl)methoxy]-6-methyl-2-carbonyl-1-pyridinyl]-5-methyl-2-pyridinyl]pyrazol-3-yl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester 76f (200 mg, 0.32 mmol) and hydrochloric acid in dioxane (4M, 1 mL) in tetrahydrofuran (3 mL) was stirred at 27 °C for 16 hours. After the reaction, the reaction solution was concentrated to obtain the title product 3-chloro-4-[dideuterio-(3,5-difluoro-2-pyridinyl)methoxy]-6-methyl-1-[5-methyl-2-[3-(3-methylazetidin-3-yl)pyrazol-1-yl]-4-pyridinyl]pyridin-2-one 76 g (150 mg), which was directly used in the next reaction without purification.

MS m/z(ESI):515.2[M+H] ⁺ .

Step 7

Acetyl chloride (73 mg, 0.93 mmol) was added dropwise to a solution of 76 g (160 mg, 0.31 mmol) of 3-chloro-4-[dideuterio-(3,5-difluoro-2-pyridinyl)methoxy]-6-methyl-1-[5-methyl-2-[3-(3-methylazetidin-3-yl)pyrazol-1-yl]-4-pyridinyl]pyridin-2-one and triethylamine (126 mg, 1.24 mmol) in dichloromethane (3 mL) under ice bath, and the mixture was heated to 25° C. and stirred for 2 hours. After the reaction, the reaction solution was concentrated and separated using Prep-HPLC column method (formic acid system) to obtain the title product 2'-(3-(1-acetyl-3-methylazetidine-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 76 (100 mg), yield: 57.8%.

MS m/z(ESI):557.2[M+H] ⁺ .

Decomposition of Example 76

(S)-2'-(3-(1-acetyl-3-methylazetidin-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-2'-(3-(1-acetyl-3-methylazetidin-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 76 (90 mg, 0.161 mmol) was subjected to chiral separation (OD column) to give 76-1 (40 mg, R.T = 4.780 min), yield: 44.4%; 76-2 (40 mg, R.T = 6.957 min), yield: 44.4%.

Example 76-1: MS m/z (ESI): 557.2 [M+H] ⁺ ;

1H NMR (400MHz, CDCl3) δ8.51(d,1H),8.38(m,2H),7.76(s,1H),7.33(m,1H),6.43(s,1H),6.36(d,1H) ,4.44(dd,2H),4.00(d,2H),2.11(s,3H),2.05(s,3H),1.96(s,3H),1.70(s,3H).

Example 76-2: MS m/z (ESI): 557.2 [M+H] ⁺ ;

1H NMR (400MHz, CDCl3) δ8.51(d,1H),8.38(m,2H),7.76(s,1H),7.33(m,1H),6.43(s,1H),6.36(d,1H) ,4.44(dd,2H),4.00(d,2H),2.11(s,3H),2.05(s,3H),1.96(s,3H),1.70(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 78

3-Chloro-4-(3,5-difluoropyridin- ₂ -yl)methoxy-d2)-2'-(4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(4-fluoro-3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one 78 was synthesized.

MS m/z(ESI):522.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.62(d,1H),8.60(d,1H),8.54(s,1H),8.12-8.06(m,1H),7.81(s,1H), 6.80(s,1H),5.20(s,1H),2.01(s,3H),1.98(s,3H),1.52(s,6H).

Decomposition of Example 78

(S)-3-Chloro-4-(3,5-difluoropyridin- ₂ -yl)methoxy-d2)-2'-(4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-(3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 78 (70 mg, 0.134 mmol) was subjected to SFC chiral separation (IB column) to give 78-1 (24 mg, R.T = 0.707 min), yield: 33%; 78-2 (30 mg, R.T = 3.134 min), yield: 43%.

Example 78-1: MS m/z (ESI): 522.1 [M+H] ⁺ ;

Example 78-2: MS m/z (ESI): 522.1 [M+H] ⁺ ;

SFC chiral separation conditions:

SFC chiral analysis method:

Embodiment 79

3-Chloro-2'-(4-chloro-3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 48, the target product 3-chloro-2'-(4-chloro-3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 79 was synthesized.

MS m/z(ESI):538.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.72(s,1H),8.60(d,1H),8.56(s,1H),8.12-8.06(m,1H),7.83(s,1H), 6.80(s,1H),5.13(s,1H),2.02(s,3H),1.98(s,3H),1.55(s,6H).

Decomposition of Example 79

(S)-3-chloro-2'-(4-chloro-3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-chloro-2'-(4-chloro-3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 79 (60 mg, 0.111 mmol) was subjected to SFC chiral separation (AD column) to give 79-1 (26 mg, R.T = 1.229 min), yield: 41%; 79-2 (26 mg, R.T = 3.311 min), yield: 41%.

Example 79-1: MS m/z (ESI): 538.1 [M+H] ⁺ ;

Example 79-2: MS m/z (ESI): 538.1 [M+H] ⁺ ;

SFC chiral separation conditions:

SFC chiral analysis method:

Embodiment 83

3-(1-(3-chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile

first step

Ethyl (1H-pyrazol-3-yl)acetate (1.5 g, 9.73 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL) and stirred. Potassium carbonate (2.69 g, 19.5 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.95 g, 11.7 mmol) were added and stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with methyl tert-butyl ether (50 mL×2). The organic phases were combined, washed with water (50 mL×2) and saturated sodium chloride solution (50 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain ethyl 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)acetate 83a (2.3 g), with a yield of 83.1%.

MS m/z(ESI):285.2[M+H] ⁺ .

Step 2

83a (2.3 g, 8.09 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) at 0°C and stirred. Sodium hydride (582 mg, 24 mmol, content: 60%) was added to the reaction solution in batches. The reaction was returned to room temperature and stirred for 0.5 hours. Iodomethane (3.44 g, 24.3 mmol) was added to the reaction solution and the reaction was stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in turn, dried, and concentrated to obtain ethyl 2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propanoate 83b (2.5 g), which was used directly in the next step without purification.

MS m/z(ESI):313.2[M+H] ⁺ .

Step 3

83b (2.5 g, 8.00 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and a tetrahydrofuran solution of lithium aluminum tetrahydride (1 M, 12 mL, 12 mmol) was added dropwise under ice bath, and the reaction was stirred at room temperature for 2 hours. Water (1 mL) and 15% sodium hydroxide solution (0.5 mL) were slowly added dropwise to the reaction solution, and the reaction was continued to stir at room temperature for 0.5 hours. The reaction solution was filtered, dried, and concentrated to obtain 2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propan-1-ol 83c (2.15 g), which was used directly in the next step without purification.

MS m/z(ESI):271.2[M+H] ⁺ .

Step 4

83c (1 g, 3.70 mmol) and triethylamine (1.12 g, 11.1 mmol) were dissolved in anhydrous dichloromethane (20 mL) and stirred. Methanesulfonyl chloride (847 mg, 7.40 mmol) was added dropwise to the reaction solution under ice bath, and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propyl methanesulfonate 83d (850 mg), yield: 66.0%.

MS m/z(ESI):349.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.50(d,1H),6.25(d,1H),5.42(s,2H),4.30(s,2H),3.58(t,2H),2.92(s, 3H),1.40(s,6H),0.91-0.87(m,2H),-0.02(s,9H).

Step 5

83d (850 mg, 2.44 mmol) was dissolved in dimethyl sulfoxide (10 mL), sodium cyanide (359 mg, 7.32 mmol) was added under stirring, and the reaction was heated to 100°C and stirred for 36 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with methyl tert-butyl ether (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-methyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)butyronitrile 83e (620 mg), yield: 91.0%.

MS m/z(ESI):280.3[M+H] ⁺ .

Step 6

83e (570 mg, 2.04 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (1M, 5 mL, 5 mmol) and heated to 50 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-methyl-3-(1H-pyrazol-3-yl)butyronitrile 83f (140 mg), yield: 46.0%.

MS m/z(ESI):150.1[M+H] ⁺ .

Step 7

83f (52 mg, 0.349 mmol), 48a (80 mg, 0.174 mmol), trans-N,N'-dimethyl 1,2-cyclohexanediamine (12 mg, 0.087 mmol), cesium carbonate (114 mg, 0.349 mmol) and cuprous iodide (50 mg, 0.262 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction mixture was heated to 100 °C and stirred for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent System C to give 3-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile 83 (30 mg), yield: 32.6%.

MS m/z(ESI):527.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.58(d,1H),8.56(s,1H),8.13-8.08(m,1H),7.81(s,1H), 6.82(s,1H),6.64(d,1H),2.95(s,2H),2.02(s,3H),2.00(s,3H),1.41(s,6H).

Decomposition of Example 83

(S)-3-(1-(3-chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile and (R)-3-(1-(3-chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile

Example 83 (30 mg, 0.060 mmol) was subjected to chiral separation (OD column) to give 83-1 (9 mg, R.T = 3.923 min), yield: 29%; 83-2 (10 mg, R.T = 5.647 min), yield: 33%.

Example 83-1: MS m/z (ESI): 527.1 [M+H] ⁺ ;

Example 83-2: MS m/z (ESI): 527.2 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 86

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-1,2,4-triazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(3-(2-hydroxypropane-2-yl)-1H-1,2,4-triazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 86 was synthesized.

MS m/z(ESI):505.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.28(s,1H),8.63(s,1H),8.60(d,1H),8.11-8.06(m,1H),7.82(s,1H), 6.80(s,1H),5.21(s,1H),2.05(s,3H),1.99(s,3H),1.53(s,6H).

Embodiment 90

N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 56, the target product N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide 90 was synthesized.

MS m/z(ESI):562.1[M+H] ⁺ ;

Decomposition of Example 90

(S)-N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide and (R)-N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide

Example 90 (50 mg, 0.089 mmol) was subjected to chiral separation (AD column) to give the title product 90-1 (17.8 mg, R.T = 4.713 min), yield: 35.60%; 90-2 (19.2 mg, R.T = 5.793 min), yield: 38.40%.

Example 90-1, MS m/z (ESI): 562.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.73(s,1H),8.61(d,1H),8.15-8.07(m,1H),7.99(s,1H),7.97(s,1H), 7.47(s,1H),6.82(s,1H),2.06(s,3H),1.99(s,3H),1.83(s,3H),1.64(s,3H),1.62(s,3H).

Example 90-2, MS m/z (ESI): 562.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.73(s,1H),8.61(d,1H),8.15-8.07(m,1H),7.99(s,1H),7.97(s,1H), 7.47(s,1H),6.82(s,1H),2.06(s,3H),1.99(s,3H),1.83(s,3H),1.64(s,3H),1.62(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 91

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxadiazole-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

first step

1-(3-Methyloxetane-3-yl)ethane-1-one 91a (1 g, 8.76 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (10 mL), and the reaction was heated to 100°C and stirred for 20 hours. The reaction solution was concentrated to obtain (E)-3-(dimethylamino)-1-(3-methyloxetane-3-yl)propane-2-ene-1-one 91b (1.23 g) with a yield of 82.97%. The product was directly used in the next step without purification.

MS m/z(ESI):170.1[M+H] ⁺ ;

Step 2

(E)-3-(Dimethylamino)-1-(3-methyloxetane-3-yl)propane-2-en-1-one 91b (1.23 g, 7.27 mmol) and hydrazine hydrate (3 mL) were dissolved in ethanol (9 mL), and the reaction was heated to 90°C and stirred for 2 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 3-(3-methyloxetane-3-yl)-1H-pyrazole 91c (778 mg), with a yield of 77.47%.

MS m/z (ESI): 139.1 [M+H] ⁺ ;

Step 3

Under nitrogen protection, 3-(3-methyloxetane-3-yl)-1H-pyrazole 91c (54 mg, 0.392 mmol), 48a (90 mg, 0.196 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (28 mg, 0.196 mmol), cuprous iodide (37 mg, 0.196 mmol) and cesium carbonate (128 mg, 0.392 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100 °C and stirred for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 3-chloro-4-((3,5-difluoro pyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxabutane-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one 91 (60 mg), yield: 59.27%.

MS m/z(ESI):516.1[M+H] ⁺ ;

Decomposition of Example 91

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxetan-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxetan-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

Example 91 (60 mg, 0.116 mmol) was subjected to chiral separation (OD column) to give the title product 91-1 (5 mg, R.T = 4.297 min), yield: 8.33%; 91-2 (17 mg, R.T = 5.570 min), yield: 28.33%.

Example 91-1, MS m/z (ESI): 516.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.62-8.60(m,2H),8.56(s,1H),8.14-8.06(m,1H),7.86(s,1H),6.80(d,1H ),6.65(d,1H),4.92-4.84(m,2H),4.49(d,2H),2.02(s,3H),2.00(s,3H),1.69(s,3H).

Example 91-2, MS m/z (ESI): 516.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.62-8.60(m,2H),8.56(s,1H),8.14-8.06(m,1H),7.86(s,1H),6.80(d,1H ),6.65(d,1H),4.92-4.84(m,2H),4.49(d,2H),2.02(s,3H),2.00(s,3H),1.69(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 93

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one

first step

At -78°C, a solution of N,N-dimethyl-1H-pyrazole-1-sulfonamide 93a (500 mg, 2.85 mmol) in tetrahydrofuran (2 mL) was added dropwise to a solution of n-butyl lithium (2.5 M, 1.26 mL) in tetrahydrofuran (4 mL) under stirring. After the reaction was stirred at -78°C for 10 minutes, dimethyl disulfide (403 mg, 4.28 mmol) was added dropwise to the reaction solution, and the reaction was heated to room temperature and stirred for 4 hours. Saturated ammonium chloride solution (30 mL) was added to the reaction solution at 0°C to quench the reaction, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to obtain N,N-dimethyl-5-(methylthio)-1H-pyrazole-1-sulfonamide 93b (489 mg) with a yield of 77.4%.

MS m/z(ESI):222.0[M+H] ⁺ ;

Step 2

N,N-dimethyl-5-(methylthio)-1H-pyrazole-1-sulfonamide 93b (300 mg, 1.36 mmol) was dissolved in a mixed solvent of acetone (5 mL) and water (5 mL) and stirred. Sodium bicarbonate (569 mg, 6.78 mmol) and potassium peroxymonosulfonate (2.08 g, 3.39 mmol) were added to the above reaction solution at 0°C. The reaction was heated to room temperature and stirred for 1 hour. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (25 mL×2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to obtain N,N-dimethyl-5-(methylsulfonyl)-1H-pyrazole-1-sulfonamide 93c (262 mg) with a yield of 76.3%.

MS m/z(ESI):254.1[M+H] ⁺ ;

Step 3

Trifluoroacetic acid (1 mL) was added dropwise to a solution of N,N-dimethyl-5-(methylsulfonyl)-1H-pyrazole-1-sulfonamide 93c (262 mg, 1.03 mmol) in dichloromethane (2 mL) at room temperature, and the reaction was stirred for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution at 0°C until pH>7, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated to give the crude product 3-(methylsulfonyl)-1H-pyrazole 93d (80 mg), which was used directly in the next step without further purification.

MS m/z(ESI):147.1[M+H] ⁺ ;

Step 4

Under nitrogen protection, 3-(methylsulfonyl)-1H-pyrazole 93d (33 mg, 0.227 mmol), 48a (80 mg, 0.174 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (25 mg, 0.174 mmol), cuprous iodide (33 mg, 0.174 mmol) and cesium carbonate (114 mg, 0.349 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100 °C and stirred for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one 93 (50 mg), yield: 54.72%.

MS m/z(ESI):524.0[M+H] ⁺ ;

Decomposition of Example 93

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

Example 93 (58 mg, 0.111 mmol) was subjected to chiral separation (OD column) to obtain the title product 93-1 (24.0 mg, R.T = 7.023 min), yield: 41.38%; 93-2 (19.0 mg, R.T = 10.733 min), yield: 32.76%.

Example 93-1, MS m/z (ESI): 524.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87(d,1H),8.68(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.03(s,1H), 7.12(d,1H),6.82(d,1H),3.37(s,3H),2.07(s,3H),2.01(s,3H).

Example 93-2, MS m/z (ESI): 524.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87(d,1H),8.68(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.03(s,1H), 7.12(d,1H),6.82(d,1H),3.37(s,3H),2.07(s,3H),2.01(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 94

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

first step

Pyrrolidine-2-one 94a (4 g, 47 mmol) was dissolved in acetonitrile (50 mL) at room temperature, and 4-dimethylaminopyridine (574 mg, 4.70 mmol) and di-tert-butyl dicarbonate (11.28 g, 51.70 mmol) were added under stirring. The reaction was stirred at 20 °C for 2 hours. The reaction was detected by TLC plate and showed that the reaction was complete. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate (100 mL). The organic phase was washed with saturated ammonium chloride, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give tert-butyl 2-carbonylpyrrolidine-1-carboxylate 94b (8 g, 43.19 mmol) with a yield of 91.90%.

MS m/z(ESI):130.0[M-55] ⁺ .

Step 2

Under nitrogen protection, tert-butyl 2-carbonylpyrrolidine-1-carboxylate 94b (1 g, 5.40 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -78 °C and stirred. Diisopropylamide lithium (2M, 3.24 mL) was added dropwise to the reaction solution. After the addition was completed, the reaction was continued to stir at -78 °C for 1 hour. 1-(1H-imidazole-1-yl)ethane-1-one (654 mg, 5.94 mmol) was added to the reaction solution at one time. After the addition was completed, the reaction was stirred at -78 °C for 1 hour. The reaction was detected by thin layer chromatography and showed that the reaction was complete. Saturated ammonium chloride solution (10 mL) was added to the reaction solution at -78 °C, and the mixture was warmed to room temperature. The organic phase was separated, dried, and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give tert-butyl 3-acetyl-2-carbonylpyrrolidine-1-carboxylate 94c (1 g). Yield: 81.50%.

MS m/z(ESI):172.0[M-55] ⁺ .

Step 3

Under nitrogen protection, tert-butyl 3-acetyl-2-carbonylpyrrolidine-1-carboxylate 94c (1 g, 4.40 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C and stirred. Sodium hydride (211 mg, 5.28 mmol, content: 60%) was added to the reaction solution. The reaction was stirred at 0°C for 0.5 hours. Methyl iodide (687 g, 19.36 mmol, 0.3 mL) was added to the reaction solution, and the reaction was stirred at 0°C for 1 hour. Ethyl acetate (20 mL) and saturated ammonium chloride (10 mL) were added to the reaction solution. The organic phase was separated, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain tert-butyl 3-acetyl-3-methyl-2-carbonylpyrrolidine-1-carboxylate 94d (1 g), yield: 94.19%.

MS m/z(ESI):242.1[M+1] ⁺ .

Step 4

3-Acetyl-3-methyl-2-carbonylpyrrolidine-1-carboxylic acid tert-butyl ester 94d (1 g, 4.15 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (10 mL) and heated to 100°C and stirred for 16 hours. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed with saturated ammonium chloride, dried, and concentrated to obtain tert-butyl 3-(3-(dimethylamino)acryloyl)-3-methyl-2-carbonylpyrrolidine-1-carboxylate 94e (1 g), which was used directly in the next step without purification.

MS m/z(ESI):197.2[M-100] ⁺ .

Step 5

3-(3-(Dimethylamino)acryloyl)-3-methyl-2-carbonylpyrrolidine-1-carboxylic acid tert-butyl ester 94e (1 g, 3.37 mmol) and hydrazine hydrate (254 mg, 6.75 mmol, content: 85%) were dissolved in ethanol (3 mL) and heated to 90°C and stirred for 2 hours. The reaction solution was concentrated and the residue was separated by reverse phase column (formic acid system) to obtain 3-methyl-3-(1H-pyrazol-3-yl)pyrrolidin-2-one 94f (0.6 g) with a yield of 67.2%.

MS m/z(ESI):166.1[M-100] ⁺ .

Step 6

Under nitrogen protection, 3-methyl-3-(1H-pyrazol-3-yl)pyrrolidin-2-one 94f (100 mg, 0.605 mmol), 48a (185 mg, 0.404 mmol), cesium carbonate (263 mg, 0.807 mmol) and cuprous iodide (15 mg, 0.081 mmol) were dissolved in 1,4-dioxane (2 mL) and heated to 100 °C and stirred for 4 hours. The reaction solution was filtered, the residue was washed with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride (10 mL), dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one 94 (80 mg), yield: 36.5%.

MS m/z(ESI):543.1[M+1] ⁺ .

Decomposition of Example 94

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((S)-3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one, (S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((R)-3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one , (R)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((S)-3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one and (R)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((R)-3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

Example 94 (80 mg, 0.147 mmol) was subjected to chiral separation (OJ column) to give 94A (18 mg, R.T = 4.7 min), yield: 22.5%; 94B (32 mg, R.T = 9.6 min), yield: 40%.

Example 94A, MS m/z (ESI): 543.1 [M+1] ⁺ ;

Example 94B, MS m/z (ESI): 543.1 [M+1] ⁺ .

Example 94B (32 mg, 0.059 mmol) was subjected to chiral separation (AS column) to give 94-1 (14 mg, R.T = 6.76 min), yield: 43.75%; 94-2 (12 mg, R.T = 8.987 min), yield: 37.5%.

Example 94-1, MS m/z (ESI): 543.1 [M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.55(d,2H),8.10(ddd,1H),7.81(s,1H),7.74(s,1H),6.81( d,1H),6.52(d,1H),3.31–3.20(m,2H),2.70(ddd,1H),2.11–2.02(m,1H),2.02–1.94(m,6H),1.44(s, 3H).

Example 94-2, MS m/z (ESI): 543.1 [M+1] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.55(d,2H),8.10(t,1H),7.80(s,1H),7.72(s,1H),6.80( d,1H),6.53(d,1H),3.26(dd,2H),2.71(ddd,1H),2.06(ddd,1H),2.00(d,6H),1.43(s,3H).

HPLC chiral separation conditions:

HPLC chiral separation conditions:

HPLC chiral analysis method:

HPLC chiral analysis method:

Embodiment 96

3-Chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

Methyl 2,4-difluorobenzoate 96a (0.5 g, 2.90 mmol) was dissolved in tetrahydrofuran (8 mL) and stirred. A solution of lithium aluminum deuteride (122 mg, 2.90 mmol) in tetrahydrofuran (5 mL) was added to the reaction solution under ice bath. The reaction was stirred under ice bath for 1 hour. The reaction solution was quenched with saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated. The residue was chromatographed on a silica gel column (elution system B) to obtain (2,4-difluorophenyl)methanol- _{d 2} -ol 96b (0.4 g) with a yield of 94%.

Step 2

(2,4-Difluorophenyl)methanol-d ₂ -ol 96b (400 mg, 2.74 mmol) and N,N-dimethylformamide (0.05 mL) were dissolved in dichloromethane (10 mL) and stirred. Sulfonyl chloride (749 mg, 6.30 mmol) was slowly added dropwise to the reaction solution under ice bath. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was diluted with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain 1-(chloromethyl-d2)-2,4-difluorobenzene 96c (0.42 g). The product was used directly in the next step without purification.

Step 3

Referring to the synthesis method of the second step of Example 57, the target product 3-chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-2′-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5′,6-dimethyl-2H-[1,4′-bipyridyl]-2-one 96 was synthesized.

MS m/z(ESI):503.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.55–8.44(m,1H),8.40(s,1H),7.76(s,1H),7.58(td,1H),7.02–6.95(m,1H), 6.89(ddd,1H),6.39(s,1H),6.19(d,1H),2.10(s,3H),2.03(s,3H),1.59(d,6H).

Decomposition of Example 96

(S)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 96 (25 mg, 0.050 mmol) was subjected to chiral separation (AS column) to give 96-1 (11 mg, R.T = 2.660 min), yield: 44%; 96-2 (10 mg, R.T = 3.580 min), yield: 40%.

Example 96-1: MS m/z (ESI): 503.1 [M+H] ⁺ ;

Example 96-2: MS m/z (ESI): 503.1 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 97

3-Chloro-4-((4-chloro-2-fluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 96, the target product 3-chloro-4-((4-chloro-2-fluorophenyl)methoxy- _d2 )-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 97 was synthesized.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.49(d,1H),8.41(s,1H),7.77(s,1H),7.55(t,1H),7.26–7.22(m,1H),7.17( dd,1H),6.40(s,1H),6.17(d,1H),2.10(s,3H),2.03(s,3H),1.59(d,6H).

Decomposition of Example 97

(S)-3-chloro-4-((4-chloro-2-fluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-chloro-4-((4-chloro-2-fluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 97 (60 mg, 0.115 mmol) was subjected to chiral separation (AS column) to give 97-1 (30 mg, R.T = 2.650 min), yield: 50%; 97-2 (20 mg, R.T = 3.970 min), yield: 33%.

Example 97-1: MS m/z (ESI): 519.1 [M+H] ⁺ ;

Example 97-2: MS m/z (ESI): 519.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 98

3-Chloro-4-((2-chloro-4-fluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 96, the target product 3-chloro-4-((2-chloro-4-fluorophenyl)methoxy- _d2 )-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 98 was synthesized.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.48(d,1H),8.41(s,1H),7.77(s,1H),7.65(dd,1H),7.20(dd,1H),7.14–7.06( m,1H),6.39(d,1H),6.16(d,1H),2.11(s,3H),2.04(s,3H),1.59(d,6H).

Decomposition of Example 98

(S)-3-chloro-4-((2-chloro-4-fluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-chloro-4-((2-chloro-4-fluorophenyl)methoxy-d ₂ )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 98 (60 mg, 0.115 mmol) was subjected to chiral separation (AS column) to give 98-1 (20 mg, R.T = 2.660 min), yield: 33%; 98-2 (17 mg, R.T = 3.747 min), yield: 28%.

Example 98-1: MS m/z (ESI): 519.1 [M+H] ⁺ ;

Example 98-2: MS m/z (ESI): 519.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 99

3-Chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,6-trifluorobenzyl)oxy)-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,6-trifluorobenzyl)oxy)-2H-[1,4'-bipyridyl]-2-one 99 was synthesized.

MS m/z(ESI):519.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.54(s,1H),8.51(d,1H),7.79(s,1H),7.44–7.32(m,2H),6.84(s,1H), 6.56(d,1H),5.33(s,2H),5.09(s,1H),2.02(s,6H),1.48(s,6H).

Embodiment 100

3-Chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,6-trifluorophenyl)methoxy-d2)-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 96, the target product 3-chloro-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,6-trifluorophenyl)methoxy-d2)-2H-[1,4'-bipyridine]-2-one 100 was synthesized.

MS m/z(ESI):521.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.54(s,1H),8.51(d,1H),7.79(s,1H),7.44–7.32(m,2H),6.84(s,1H), 6.56(d,1H),5.09(s,1H),2.02(s,6H),1.48(s,6H).

Embodiment 101

3-Chloro-4-((5-fluorothiazol-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

first step

Under ice bath, (5-bromothiazol-2-yl)methanol (1 g, 5.15 mmol) and imidazole (1.05 g, 15.5 mmol) were dissolved in anhydrous dichloromethane (20 mL), and tert-butyldimethylsilyl chloride (1.17 g, 7.73 mmol) was added to the reaction solution under stirring. The reaction was stirred at room temperature for 3 hours. The reaction solution was washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)thiazole 101a (1.5 g), which was used directly in the next step without purification.

Step 2

Under nitrogen protection, 101a (1.2 g, 3.89 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and a n-butyl lithium hexane solution (1.6 M, 3.16 mL) was added dropwise at -78 ° C. After stirring for 0.5 hours, N-fluorobisbenzenesulfonamide (1.60 g, 5.06 mmol) was added. The reaction was stirred at -78 ° C for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in turn, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorothiazole 101b (460 mg), with a yield of 47.8%.

MS m/z(ESI):248.1[M+H] ⁺ .

Step 3

101b (460 mg, 1.86 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (1M, 10 mL), and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain (5-fluorothiazol-2-yl)methanol 101c (190 mg), with a yield of 76.8%.

MS m/z(ESI):134.1[M+H] ⁺ .

Step 4

101c (190 mg, 1.43 mmol) and thionyl chloride (509 mg, 4.28 mmol) were dissolved in anhydrous dichloromethane (4 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried, and the filtrate was concentrated to obtain 2-(chloromethyl)-5-fluorothiazole 101d (190 mg), which was used directly in the next step without purification.

Step 5

Under nitrogen protection, 57a (150 mg, 0.400 mmol), potassium carbonate (166 mg, 1.20 mmol) and 18-crown-6 (159 mg, 0.600 mmol) were dissolved in N,N-dimethylformamide (3 mL), heated to 75°C, and 101d (190 mg, 1.25 mmol) was added dropwise under stirring. The reaction was stirred at 75°C for 1 hour, the reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, dried, and the filtrate was concentrated. The residue was purified by reverse phase chromatography with eluent System C to give 3-chloro-4-((5-fluorothiazol-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 101 (9.8 mg) in a yield of 5.0%.

MS m/z(ESI):490.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.55(s,1H),8.51(d,1H),7.78(s,1H),7.72(d,1H),6.78(s,1H),6.57( d,1H),5.56(d,2H),5.13(s,1H),2.00(s,6H),1.48(s,6H).

Embodiment 102

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(1-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2′-(3-(1-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5′,6-dimethyl-2H-[1,4′-bipyridyl]-2-one 102 was synthesized.

MS m/z(ESI):530.1[M+H] ⁺ .

Decomposition of Example 102

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(1-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(1-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 102 (35 mg, 0.066 mmol) was subjected to chiral separation (OD column) to give 102-1 (11.0 mg, R.T = 4.537 min), yield: 31%; 102-2 (13.2 mg, R.T = 8.973 min), yield: 37%.

Example 102-1: MS m/z (ESI): 527.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.54(s,1H),8.52(d,1H),8.12-8.07(m,1H),7.79(s,1H), 6.80(s,1H),6.57(d,1H),4.99(s,1H),2.03-1.96(m,8H),1.86-1.81(d,4H),1.70-1.66(d,2H).

Example 102-2: MS m/z (ESI): 527.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.54(s,1H),8.52(d,1H),8.12-8.07(m,1H),7.79(s,1H), 6.80(s,1H),6.57(d,1H),4.99(s,1H),2.03-1.96(m,8H),1.86-1.81(d,4H),1.70-1.66(d,2H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 103

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-2'-(3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

first step

72a (1.0 g, 3.90 mmol) was dissolved in methanol (15 mL) and water (5 mL), sodium hydroxide (468 mg, 11.7 mmol) was added, and the reaction was heated to 50 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The mixed solution was adjusted to pH 5 with dilute hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated to obtain 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid 103a (750 mg), which was used directly in the next step without purification.

MS m/z(ESI):243.1[M+H] ⁺ .

Step 2

103a (750 mg, 3.09 mmol) was dissolved in anhydrous dichloromethane (15 mL) and stirred, and 2,2,2-trifluoroethanol (619 mg, 6.19 mmol), 1-hydroxybenzotriazole (502 mg, 3.71 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (712 mg, 3.71 mmol) and triethylamine (939 mg, 9.28 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The reaction solution was washed with water (50 mL) and saturated sodium chloride solution (50 mL) in turn, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid-2,2,2-trifluoroethyl ester 103b (530 mg) with a yield of 52.8%.

MS m/z(ESI):325.1[M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δ8.09(d,1H),6.90(d,1H),5.52(s,2H),4.97(q,2H),3.57-3.53(m,2H), 0.86-0.82(m,2H),-0.05(s,9H).

Step 3

103b (430 mg, 1.33 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuran solution (1.3 mL, 1 M, 1.3 mmol) was added and stirred, (trifluoromethyl)trimethylsilane (943 mg, 6.63 mmol) was added dropwise to the reaction solution under ice bath, and the reaction was returned to room temperature and stirred for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1,1,1,3,3,3-hexafluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]propane-2-ol 103c (240 mg), yield: 49.7%.

MS m/z(ESI):365.0[M+H] ⁺ .

Step 4

103c (240 mg, 0.659 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (3 mL, 1 M, 3.0 mmol), and the reaction was heated to 60 ° C and stirred for 24 hours. The reaction solution was cooled to room temperature and poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 1,1,1,3,3,3-hexafluoro-2-(1H-pyrazol-3-yl)propane-2-ol 103d (55 mg), yield: 35.7%.

MS m/z(ESI):235.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ13.27(s,1H),8.27(s,1H),7.86(s,1H),6.48(s,1H).

Step 5

48a (150 mg, 0.327 mmol) was dissolved in 1,4-dioxane (3 mL), 103d (45 mg, 0.192 mmol), trans-dimethyl 1,2-cyclohexanediamine (23 mg, 0.164 mmol), cesium carbonate (213 mg, 0.654 mmol) and cuprous iodide (93 mg, 0.490 mmol) were added, and the reaction was heated to 100 ° C and stirred for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent System C to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-2'-(3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 103 (4.8 mg) in a yield of 2.2%.

MS m/z(ESI):612.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.78(d,1H),8.69(br s,1H),8.63(s,1H),8.61(d,1H),8.12-8.07(m,1H) ,7.90(s,1H),6.82-6.81(m,2H),2.05(s,3H),2.00(s,3H).

Embodiment 107

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

first step

11b (400 mg, 3.17 mmol) and acetonitrile (781 mg, 19.02 mmol) were dissolved in acetic acid (1.52 g, 25.37 mmol) and stirred. Concentrated sulfuric acid (1.52 mL, 28.54 mmol) was added dropwise to the reaction solution at 0°C. The reaction temperature was raised to 60°C and stirred for 2 hours. Saturated sodium bicarbonate solution (40 mL) was added to the reaction solution at 0°C and stirred for 0.5 hours. The aqueous phase was extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried, concentrated, and N-(2-(1H-pyrazol-3-yl)propan-2-yl)acetamide 107a (53 mg) was prepared by reverse phase HPLC (ammonium bicarbonate system) with a yield of 10%.

MS m/z(ESI):168.1[M+H] ⁺ ;

Step 2

Under nitrogen protection, N-(2-(1H-pyrazol-3-yl)propan-2-yl)acetamide 107a (17.9 mg, 0.107 mmol), 11f (35 mg, 0.077 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (2 mg, 0.015 mmol), cuprous iodide (3 mg, 0.015 mmol) and cesium carbonate (50 mg, 0.153 mmol) were dissolved in 1,4-dioxane (1.5 mL), and the reaction was heated to 100 °C and stirred for 16 hours. Saturated ammonium chloride solution (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (15 mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to give N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 107 (28.6 mg), yield: 68.8%.

MS m/z(ESI):543.1[M+H] ⁺ ;

Decomposition of Example 107

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 107 (45 mg, 0.083 mmol) was subjected to chiral separation (OD column) to give the title product 107-1 (14.9 mg, R.T = 3.14 min), yield: 33.11%; 107-2 (13.9 mg, R.T = 3.62 min), yield: 30.89%.

Example 107-1, MS m/z (ESI): 543.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.14-8.04(m,1H),7.93(s,1H), 7.77(s,1H),6.80(s,1H),6.42(d,1H),5.48(d,2H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57 (s,3H).

Example 107-2, MS m/z (ESI): 543.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.14-8.04(m,1H),7.93(s,1H), 7.77(s,1H),6.80(s,1H),6.42(d,1H),5.48(d,2H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57 (s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 108

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 107, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 108 was synthesized.

MS m/z(ESI):545.2[M+H] ⁺ ;

Decomposition of Example 108

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 108 (75 mg, 0.138 mmol) was subjected to chiral separation (OD column) to give the title product 108-1 (24.3 mg, R.T = 3.123 min), yield: 32.4%; 108-2 (24.6 mg, R.T = 3.627 min), yield: 32.8%.

Example 108-1, MS m/z (ESI): 545.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.13-8.06(m,,1H),7.93(s,1H) ,7.77(s,1H),6.80(d,1H),6.42(d,1H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H).

Example 108-2, MS m/z (ESI): 545.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.13-8.06(m,,1H),7.93(s,1H) ,7.77(s,1H),6.80(d,1H),6.42(d,1H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 109

N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

first step

Under nitrogen protection, 11e (400 mg, 1.21 mmol), potassium carbonate (503 mg, 3.64 mmol) and 18-crown-6 (481 mg, 1.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL), heated to 75 ° C with stirring, and 96c (300 mg, 1.82 mmol) was added dropwise to the reaction solution. The reaction was stirred at 75 ° C for 1 hour. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, and dried. The filtrate was concentrated and the residue was separated by silica gel column chromatography (elution system B) to give 2'-bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 109a (480 mg) with a yield of 86.4%.

MS m/z(ESI):457.0[M+H] ⁺ .

Step 2

Under nitrogen protection, 2'-bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 109a (100 mg, 0.218 mmol), 107a (73 mg, 0.437 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (31 mg, 0.218 mmol), cuprous iodide (42 mg, 0.218 mmol) and cesium carbonate (142 mg, 0.437 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100 ° C and stirred for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to give N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 109 (75 mg), yield: 63.10%.

MS m/z(ESI):544.2[M+H] ⁺ .

Decomposition of Example 109

(S)-N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 109 (75 mg, 0.138 mmol) was subjected to chiral separation (AD column) to give the title product 109-1 (27.2 mg, R.T = 4.827 min), yield: 36.27%; 109-2 (27.9 mg, R.T = 5.697 min), yield: 37.2%.

Example 109-1, MS m/z (ESI): 544.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.55(s,1H),8.49(d,1H),7.96(s,1H),7.78(s,1H),7.76-7.68(m,1H), 7.40-7.35(m,1H),7.25-7.19(m,1H),6.83(d,1H),6.43(d,1H),2.02(s,3H),2.01(s,3H),1.82(s, 3H),1.61(s,3H),1.57(s,3H).

Example 109-2, MS m/z (ESI): 544.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.55(s,1H),8.49(d,1H),7.96(s,1H),7.78(s,1H),7.76-7.68(m,1H), 7.40-7.35(m,1H),7.25-7.19(m,1H),6.83(d,1H),6.43(d,1H),2.02(s,3H),2.01(s,3H),1.82(s, 3H),1.61(s,3H),1.57(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 110

N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 109, the target product N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 110 was synthesized.

MS m/z(ESI):562.1[M+H] ⁺ .

Decomposition of Example 110

(S)-N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 110 (60 mg, 0.107 mmol) was subjected to chiral separation (OD column) to give 110-1 (19.4 mg, R.T = 4.397 min), yield: 32%; 110-2 (9.7 mg, R.T = 5.757 min), yield: 16%.

Example 110-1: MS m/z (ESI): 562.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(d,1H),8.55(s,1H),8.11(s,1H),7.79(s,1H),7.74-7.68(m,1H), 7.42-7.39(m,1H),7.24-7.19(m,1H),6.83(s,1H),2.02(s,3H),2.01(s,3H),1.80(s,3H),1.60(s, 3H),1.57(s,3H).

Example 110-2: MS m/z (ESI): 562.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(d,1H),8.55(s,1H),8.11(s,1H),7.79(s,1H),7.73-7.68(m,1H), 7.41-7.39(m,1H),7.25-7.18(m,1H),6.83(s,1H),2.02(s,3H),2.01(s,3H),1.80(s,3H),1.60(s, 3H),1.57(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 111

N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d ₂ )-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 109, the target product N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d2)-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 111 was synthesized.

MS m/z(ESI):580.2[M+H] ⁺ .

Decomposition of Example 111

(S)-N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d ₂ )-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d ₂ )-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 111 (60 mg, 0.107 mmol) was subjected to chiral separation (OD column) to give 111-1 (19.4 mg,

R.T＝4.397min), yield: 32%; 111-2 (9.7mg, R.T＝5.757min), yield: 16%.

Example 111-1: MS m/z (ESI): 580.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(d,1H),8.54(s,1H),8.10(s,1H),7.80(s,1H),7.39-7.34(m,2H), 6.84(s,1H),2.01(s,6H),1.80(s,3H),1.60(s,3H),1.57(s,3H).

Example 111-2: MS m/z (ESI): 580.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.57(d,1H),8.54(s,1H),8.10(s,1H),7.80(s,1H),7.39-7.34(m,2H), 6.84(s,1H),2.01(s,6H),1.80(s,3H),1.60(s,3H),1.57(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 112

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide

first step

Sulfuric acid (3.40 g, 34.69 mmol) was added dropwise to a solution of 73a (500 mg, 3.47 mmol) in 3-bromopropionitrile (4.65 g, 34.69 mmol) under ice bath and stirred. The reaction solution was heated to 30°C and stirred for 16 hours. The reaction solution was concentrated and the residue was separated using Prep-HPLC column method (formic acid system) to obtain the title product 3-bromo-N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112b (520 mg) with a yield of 53.9%.

MS m/z(ESI):278.0[M+H] ⁺ .

Step 2

3-Bromo-N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112b (500 mg, 1.80 mmol) and zinc powder (1.17 g, 17.98 mmol) were dissolved in acetic acid (10 mL) and tetrahydrofuran (5 mL) solution, and the reaction was stirred at 25°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by Prep-HPLC column method (formic acid system) to obtain the title product N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112c (260 mg), with a yield of 72.6%.

MS m/z(ESI):200.1[M+H] ⁺ .

Step 3

N-(2-(4-Fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112c (65 mg, 0.33 mmol), 48a (100 mg, 0.22 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (12 mg, 0.09 mmol), cesium carbonate (106 mg 0.33 mmol), and cuprous iodide (17 mg, 0.09 mmol) were dissolved in dioxane (2 mL), and the reaction was heated to 100 °C and stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated using normal phase silica gel column chromatography (eluent system A) to give the title product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112 (80 mg), yield: 63.6%.

MS m/z(ESI):577.2[M+H] ⁺ .

Decomposition of Example 112

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide

Example 112 (80 mg, 0.138 mmol) was subjected to chiral separation (OD column) to give 112-1 (31 mg, R.T = 2.840 min), yield: 38%; 112-2 (27 mg, R.T = 3.380 min), yield: 33%.

Example 112-1: MS m/z (ESI): 577.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.59(m,3H),8.11(m,1H),8.02(s,1H),7.79(s,1H),6.81(d,1H),2.09( q,2H),2.01(d,6H),1.59(d,6H),0.95(t,3H).

Example 112-2: MS m/z (ESI): 577.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.59(m,3H),8.11(m,1H),8.02(s,1H),7.79(s,1H),6.81(d,1H),2.09( q,2H),2.01(d,6H),1.59(d,6H),0.95(t,3H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 113

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2-d3

Referring to the synthesis method of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2-d3 113 was synthesized.

MS m/z(ESI):566.2[M+H] ⁺ .

Decomposition of Example 113

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2-d3 and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2-d3

Example 113 (60 mg, 0.106 mmol) was subjected to chiral separation (OD column) to give 113-1 (23 mg, R.T = 3.003 min), yield: 38%; 113-2 (27 mg, R.T = 3.943 min), yield: 33%.

Example 113-1: MS m/z (ESI): 566.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.36(m,3H),7.67(s,1H),7.33(m,1H),6.41(d,1H),6.34(s,1H),2.06(d, 6H),1.76(d,6H).

Example 113-2: MS m/z (ESI): 566.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.36(m,3H),7.67(s,1H),7.33(m,1H),6.41(d,1H),6.34(s,1H),2.06(d, 6H),1.76(d,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 114

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

first step

Under ice bath, ethyl 4,4,4-trifluorobutane-2-nonanoate 114a (2.0 g, 12.0 mmol) was dissolved in tetrahydrofuran (30 mL) and stirred. Trimethylsilylated diazomethane (2 M, 7.22 mL) was added to the reaction solution under nitrogen atmosphere. The reaction was stirred at room temperature for 2 hours. After the reaction solution was concentrated, it was chromatographed on a silica gel column (elution system B) to obtain ethyl 4-(trifluoromethyl)-1H-pyrazole-3-carboxylate 114b (1.5 g) with a yield of 60%.

MS m/z(ESI):209.1[M+H] ⁺ .

Step 2

Referring to the synthetic method of the first step of Example 73, 2-(4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-ol 114c was synthesized.

MS m/z(ESI):195.1[M+H] ⁺ .

Step 3

Referring to the synthesis method of the second step of Example 73, N-(2-(4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 114d was synthesized.

MS m/z(ESI):236.1[M+H] ⁺ .

Step 4

Referring to the synthesis method of the third step of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 114 was synthesized.

MS m/z(ESI):613.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.79(s,1H),8.48–8.34(m,2H),7.75(s,1H), 7.32(ddd,1H),6.42(s,1H),6.00( s,1H),2.11(s,3H),2.03(s,3H),1.96(s,3H),1.84(s,3H),1.59(s,3H).

Embodiment 115

N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide

Referring to the synthesis method of Example 73, the target product N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide 115 was synthesized.

MS m/z(ESI):575.2[M+H] ⁺ .

Decomposition of Example 115

(S)-N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide and (R)-N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide

Example 115 (50 mg, 0.087 mmol) was subjected to chiral separation (OD column) to give 115-1 (18 mg, R.T = 5.590 min), yield: 36%; 115-2 (16 mg, R.T = 7.427 min), yield: 32%.

Example 115-1: MS m/z (ESI): 575.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.37(m,3H),7.73(s,1H),7.32(m,1H),6.40(s,1H),2.08(s,3H),2.02(d, 6H),1.28(m,6H).

Example 115-2: MS m/z (ESI): 575.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl3) δ8.37(m,3H),7.73(s,1H),7.32(m,1H),6.40(s,1H),2.08(s,3H),2.02(d,6H ),1.28(m,6H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 116

N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 73, the target product N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 116 was synthesized.

MS m/z(ESI):579.1[M+H] ⁺ .

Decomposition of Example 116

(S)-N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 116 (70 mg, 0.107 mmol) was subjected to chiral separation (OJ column) to give 116-1 (34.3 mg, R.T = 3.080 min), yield: 48%; 116-2 (30.2 mg, R.T = 5.023 min), yield: 42%.

Example 116-1: MS m/z (ESI): 579.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.67(s,1H),8.61(d,1H),8.56(s,1H),8.14(s,1H),8.14-8.07(m,1H), 7.81(s,1H),6.81(s,1H),2.01(s,3H),2.00(s,3H),1.81(s,3H),1.60(s,3H),1.56(s,3H).

Example 116-2: MS m/z (ESI): 579.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.67(s,1H),8.61(d,1H),8.56(s,1H),8.14(s,1H),8.12-8.09(m,1H), 7.81(s,1H),6.81(s,1H),2.01(s,3H),2.00(s,3H),1.81(s,3H),1.60(s,3H),1.56(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 117

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy- _d2 )-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide 117 was synthesized.

MS m/z(ESI):559.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.60(d,1H),8.49(s,1H),8.28(d,1H),8.09(ddd,1H),8.04(s,1H),7.70( s,1H),6.80(d,1H),2.06(d,3H),2.02–1.97(m,6H),1.58(s,3H),1.53(s,3H).

Decomposition of Example 117

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 117 (120 mg, 0.215 mmol) was subjected to chiral separation (OD column) to give 117-1 (53 mg, R.T = 3.000 min), yield: 44%; 117-2 (56 mg, R.T = 3.577 min), yield: 46%.

Example 117-1: MS m/z (ESI): 559.2 [M+H] ⁺ ;

Example 117-2: MS m/z (ESI): 559.2 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 119

3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

first step

Referring to the synthesis method of Example 93, the target product 3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one 119 (75 mg) was synthesized with a yield of 65.64%.

MS m/z(ESI):523.1[M+H] ⁺ .

Decomposition of Example 119

(S)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one and (R)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one

Example 119 (75 mg, 0.143 mmol) was subjected to chiral separation (OD column) to give the title product 119-1 (24.1 mg, R.T = 6.287 min), yield: 32.13%; 119-2 (25.7 mg, R.T = 7.620 min), yield: 34.27%.

Example 119-1, MS m/z (ESI): 523.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87(d,1H),8.68(s,1H),8.03(s,1H),7.76-7.67(m,1H),7.39-7.35(m,1H ),7.24-7.18(m,1H),7.12(d,1H),6.84(d,1H),3.37(s,3H),2.07(s,3H),2.02(s,3H).

Example 119-2, MS m/z (ESI): 523.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87(d,1H),8.68(s,1H),8.03(s,1H),7.76-7.67(m,1H),7.39-7.35(m,1H ),7.24-7.18(m,1H),7.12(d,1H),6.84(d,1H),3.37(s,3H),2.07(s,3H),2.02(s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 120

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 93, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 120 was synthesized.

MS m/z(ESI):538.0[M+H] ⁺ ;

Decomposition of Example 120

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 120 (65 mg, 0.121 mmol) was subjected to chiral separation (OD column) to give the title product 120-1 (27.8 mg, R.T = 6.047 min), yield: 42.77%; 120-2 (26.0 mg, R.T = 8.483 min), yield: 40%.

Example 120-1, MS m/z (ESI): 538.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.88(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.02(s,1H), 7.11(d,1H),6.81(d,1H),3.44(q,2H),2.07(s,3H),2.00(s,3H),1.20(t,3H).

Example 120-2, MS m/z (ESI): 538.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.88(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.02(s,1H), 7.11(d,1H),6.81(d,1H),3.44(q,2H),2.07(s,3H),2.00(s,3H),1.20(t,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 121

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Referring to the synthesis method of Example 93, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 121 was synthesized.

MS m/z(ESI):552.1[M+H] ⁺ ;

Decomposition of Example 121

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 121 (75 mg, 0.136 mmol) was subjected to chiral separation (OD column) to give the title product 121-1 (27.8 mg, R.T = 5.080 min), yield: 37.07%; 121-2 (34.8 mg, R.T = 6.020 min), yield: 46.40%.

Example 121-1, MS m/z (ESI): 552.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.89(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.06(m,1H),8.02(s,1H), 7.10(d,1H),6.81(d,1H),3.60-3.51(m,1H),2.07(s,3H),2.00(s,3H),1.24(s,6H).

Example 121-2, MS m/z (ESI): 552.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.89(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.06(m,1H),8.02(s,1H), 7.10(d,1H),6.81(d,1H),3.60-3.51(m,1H),2.07(s,3H),2.00(s,3H),1.24(s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 122

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 93, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one 122 was synthesized.

MS m/z(ESI):552.1[M+H] ⁺ ;

Decomposition of Example 122

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridinyl]-2-one

Example 122 (75 mg, 0.136 mmol) was subjected to chiral separation (OD column) to give the title product 122-1 (35.1 mg, R.T = 5.693 min), yield: 46.80%; 122-2 (34.0 mg, R.T = 7.963 min), yield: 45.33%.

Example 122-1, MS m/z (ESI): 552.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.07(m,1H),8.01(s,1H), 7.10(d,1H),6.81(s,1H),3.46-3.38(m,2H),2.06(s,3H),2.00(s,3H),1.75-1.61(m,2H),0.96(t, 3H).

Example 122-2, MS m/z (ESI): 552.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.87(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.07(m,1H),8.01(s,1H), 7.10(d,1H),6.81(s,1H),3.46-3.38(m,2H),2.06(s,3H),2.00(s,3H),1.75-1.61(m,2H),0.96(t, 3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 124

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

first step

Sodium hydride (695 mg, 17.37 mmol, content: 60%) was added to a solution of 4-fluoropyrazole 124a (1.15 g, 13.36 mmol) in tetrahydrofuran (34.8 mL) at 0°C, and N,N-dimethylsulfonyl chloride (2.11 g, 14.70 mmol, 1.58 mL) was added to the reaction solution after stirring for 20 minutes. The reaction mixture was warmed to room temperature and stirred for 40 minutes. Saturated ammonium chloride solution (30 mL) was slowly added dropwise to the reaction solution at 0°C, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124b (2.3 g), with a yield of 89.10%.

MS m/z (ESI): 194.1 [M+H] ⁺ ;

Step 2

A solution of 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124b (1 g, 5.18 mmol) in tetrahydrofuran (4 mL) was added dropwise to a solution of n-butyl lithium (2.5 M, 2.7 mL) in tetrahydrofuran (8 mL) at -78°C, and diisopropyl disulfide (1.17 g, 7.76 mmol) was added dropwise to the above reaction solution after stirring for 10 minutes. The reaction was warmed to room temperature and stirred for 16 hours. Saturated ammonium chloride solution (30 mL) was added to the reaction solution at 0°C to quench the reaction, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried, and concentrated. The residue was prepared by reverse phase HPLC to obtain 4-fluoro-5-(isopropylthio)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124c (283 mg) with a yield of 20.45%.

MS m/z(ESI):268.0[M+H] ⁺ ;

Step 3

To a solution of 4-fluoro-5-(isopropylthio)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124c (215 mg, 0.804 mmol) in dichloromethane (8 mL) was added meta-chloroperbenzoic acid (359 mg, 1.77 mmol, purity: 85%) at 0°C, the reaction was warmed to room temperature, and after stirring for 2 hours, meta-chloroperbenzoic acid (180 mg, 0.885 mmol, purity: 85%) was added, and the reaction was stirred for 2 hours. Saturated sodium carbonate (30 mL) solution was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried, and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 4-fluoro-5-(isopropylsulfonyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124d (97 mg), yield: 40.29%.

MS m/z (ESI): 300.0 [M+H] ⁺ ;

Step 4

4-Fluoro-5-(isopropylsulfonyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124d (97 mg, 0.324 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added to the reaction solution, and stirred at room temperature for 45 minutes. The reaction solution was concentrated, and the residue was prepared by reverse phase HPLC to give 4-fluoro-5-(isopropylsulfonyl)-1H-pyrazole 124e (60 mg), with a yield of 96.33%.

MS m/z(ESI):193.0[M+H] ⁺ ;

Step 5

Under nitrogen protection, 48a (45 mg, 0.098 mmol), 4-fluoro-5-(isopropylsulfonyl)-1H-pyrazole 124e (28 mg, 0.147 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (14 mg, 0.098 mmol), cuprous iodide (19 mg, 0.098 mmol) and cesium carbonate (64 mg, 0.196 mmol) were dissolved in 1,4-dioxane (1 mL), and the reaction was heated to 100 °C and stirred for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried and concentrated, and the residue was prepared by reverse phase HPLC to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 124 (45 mg), yield: 80.47%.

MS m/z(ESI):570.1[M+H] ⁺ ;

Decomposition of Example 124

(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one and (R)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridinyl]-2-one

Example 124 (57 mg, 0.1 mmol) was subjected to chiral separation (OD column) to give the title product 124-1 (24.8 mg, R.T = 5.177 min), yield: 43.51%; 124-2 (22.1 mg, R.T = 7.007 min), yield: 38.77%.

Example 124-1, MS m/z (ESI): 570.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.06(m,1H),8.02(s,1H), 6.80(d,1H),3.60-3.51(m,1H),2.07(s,3H),1.99(s,3H),1.29(d,3H),1.27(d,3H).

Example 124-2, MS m/z (ESI): 570.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.08(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.06(m,1H),8.02(s,1H), 6.80(d,1H),3.60-3.51(m,1H),2.07(s,3H),1.99(s,3H),1.29(d,3H),1.27(d,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 130

N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide

first step

Under nitrogen protection, 56b (83 mg, 0.364 mmol), intermediate 1 (100 mg, 0.243 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (18 mg, 0.024 mmol) and cesium carbonate (158 mg, 0.485 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (0.5 mL), and the reaction was heated to 100 °C and stirred for 2.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl -2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)propane-2-yl)acetamide 130 (60 mg), yield: 44.16%.

MS m/z(ESI):560.2[M+H] ⁺ ;

Decomposition of Example 130

(S)-N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide and (R)-N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide

Example 130 (60 mg, 0.107 mmol) was subjected to chiral separation (AD column) to give the title product 130-1 (23.7 mg, R.T = 4.617 min), yield: 39.50%; 130-2 (22.7 mg, R.T = 5.800 min), yield: 37.83%.

Example 130-1, MS m/z (ESI): 560.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.15-8.06(m,1H), 7.85(s,1H),6.81(s,1H),5.48(d,2H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63 (s,3H).

Example 130-2, MS m/z (ESI): 560.1 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.15-8.06(m,1H), 7.85(s,1H),6.81(s,1H),5.48(d,2H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63 (s,3H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 131

N-(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-6-methyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

first step

49a (120 mg, 0.393 mmol), 73b (73 mg, 0.393 mmol) and cesium carbonate (256 mg, 0.785 mmol) were dissolved in dimethyl sulfoxide (4 mL). The reaction was heated to 110 °C and stirred for 16 hours. The reaction solution was purified by reverse phase column (formic acid system) to obtain the product N-(2-(1-(3,5'-dichloro-4-hydroxy-6-methyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 131a (30 mg), yield: 19%.

MS m/z(ESI):454.1[M+H] ⁺ .

Step 2

N-(2-(1-(3,5'-dichloro-4-hydroxy-6-methyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 131a (30 mg, 0.066 mmol), 7b (22 mg, 0.132 mmol), 18-crown-6 ether (26 mg, 0.099 mmol) and potassium carbonate (27 mg, 0.198 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction was heated to 70°C and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL), and the organic phase was washed with saturated sodium chloride (5 mL×2), dried and concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to give the target product N-(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-6-methyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 131.

MS m/z(ESI):583.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.81(s,1H),8.63–8.57(m,2H),8.14–8.11(m,1H),8.11(s,1H),8.11–8.06(m ,1H),6.83(d,1H),2.04(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H).

Decomposition of Example 131

(S)-N-(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-6-methyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-6-methyl-2-oxo-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 131 (35 mg, 0.060 mmol) was subjected to chiral separation (OD column) to give 131-1 (13 mg, R.T = 3.033 min), yield: 37%; 131-2 (13 mg, R.T = 3.713 min), yield: 37%.

Example 131-1: MS m/z (ESI): 583.1 [M+H] ⁺ ;

Example 131-2: MS m/z (ESI): 583.1 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 134

3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Referring to the synthesis method of Example 93, the target product 3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 134 was synthesized.

MS m/z(ESI):551.1[M+H] ⁺ .

Decomposition of Example 134

(S)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

Example 134 (55 mg, 0.1 mmol) was subjected to chiral separation (AD column) to give the title product 134-1 (25.3 mg, R.T = 8.657 min), yield: 46%; 134-2 (23.2 mg, R.T = 10.253 min), yield: 42.18%.

Example 134-1, MS m/z (ESI): 551.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.89(d,1H),8.68(s,1H),8.01(s,1H),7.76-7.67(m,1H),7.39-7.34(m,1H) ),7.24-7.18(m,1H),7.10(d,1H),6.83(d,1H),3.60-3.50(m,1H),2.06(s,3H),2.01(s,3H),1.24( s,6H).

Example 134-2, MS m/z (ESI): 551.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.89(d,1H),8.68(s,1H),8.01(s,1H),7.76-7.67(m,1H),7.39-7.34(m,1H) ),7.24-7.18(m,1H),7.10(d,1H),6.83(d,1H),3.60-3.50(m,1H),2.06(s,3H),2.01(s,3H),1.24( s,6H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 136

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide

Referring to the synthesis method of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide 136 was synthesized.

MS m/z(ESI):589.2[M+H] ⁺ .

Decomposition of Example 136

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide

Example 136 (60 mg, 0.102 mmol) was subjected to chiral separation (OD column) to give 136-1 (22 mg, R.T = 2.923 min), yield: 36.7%; 136-2 (23 mg, R.T = 4.257 min), yield: 38.3%.

Example 136-1: MS m/z (ESI): 589.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.59(m,3H),8.30(s,1H),8.11(m,1H),7.79(s,1H),6.81(s,1H),2.00( d,6H),1.61(d,7H),0.58(m,4H).

Example 136-2: MS m/z (ESI): 589.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.59(m,3H),8.30(s,1H),8.11(m,1H),7.79(s,1H),6.81(s,1H),2.00( d,6H),1.61(d,7H),0.58(m,4H).

HPLC chiral separation conditions:

HPLC chiral analysis conditions:

Embodiment 139

N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide

first step

73b (150 mg, 0.810 mmol), potassium carbonate (336 mg, 2.43 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (162 mg, 0.972 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 139a (230 mg), yield: 90.0%.

MS m/z(ESI):316.1[M+H] ⁺ .

Step 2

139a (230 mg, 0.729 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under ice bath, and sodium hydride (87 mg, 2.19 mmol, content: 60%) was added under stirring. After the reaction was stirred at room temperature for 0.5 hours, iodomethane (310 mg, 2.19 mmol) was added, and then stirring was continued at room temperature for 1.5 hours. The reaction solution was poured into ice water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide 139b (190 mg), yield: 79.1%.

MS m/z(ESI):330.2[M+H] ⁺ .

Step 3

139b (190 mg, 0.577 mmol) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (1M, 4 mL), and the reaction was heated to 65 ° C and stirred for 6 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro-1H-pyrazol-3-yl)propane-2-yl)-N-methylacetamide 139c (70 mg), yield: 60.9%.

MS m/z(ESI):200.0[M+H] ⁺ .

Step 4

Under nitrogen protection, 48a (120 mg, 0.262 mmol), 139c (52 mg, 0.262 mmol), trans-N,N'-dimethyl 1,2-cyclohexanediamine (7 mg, 0.052 mmol), cuprous iodide (75 mg, 0.392 mmol) and cesium carbonate (256 mg, 0.785 mmol) were dissolved in 1,4-dioxane (3 mL), and the reaction was heated to 100 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, and the filtrate was concentrated. The residue was purified by reverse phase chromatography with eluent System C to give N-(2-(1-(3-chloro-4-((3,5-difluoropyridin- ₂ -yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide 139 (70 mg) in a yield of 46.4%.

MS m/z(ESI):577.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61(d,1H),8.54(m,2H),8.13-8.08(m,1H),7.76(s,1H),6.81(s,1H), 3.02(s,3H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.64(s,3H),1.62(s,3H).

Decomposition of Example 139

(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d ₂ )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide

Example 139 (70 mg, 0.107 mmol) was subjected to chiral separation (OJ column) to give 139-1 (34.3 mg, R.T = 3.080 min), yield: 48%; 139-2 (30.2 mg, R.T = 5.023 min), yield: 42%.

Example 139-1: MS m/z (ESI): 577.2 [M+H] ⁺ ;

Example 139-2: MS m/z (ESI): 577.2 [M+H] ⁺ ;

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 148

3-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-3-methylbutyronitrile

first step

34d (2.5 g, 8.99 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) under ice bath, and a tetrahydrofuran solution of lithium aluminum tetrahydride (1 M, 8.99 mL, 8.99 mmol) was added dropwise to the reaction solution under stirring. The reaction was stirred at 0°C for 2 hours, and water (0.4 mL), 15% sodium hydroxide solution (0.4 mL) and water (0.4 mL) were added dropwise to the reaction solution in sequence. The mixture was stirred at room temperature for 0.5 hours, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 2-(4-bromothiazol-2-yl)-2-methylpropane-1-ol 148a (450 mg), with a yield of 21.2%.

MS m/z(ESI):236.0[M+1] ⁺ .

Step 2

148a (320 mg, 1.36 mmol) and triethylamine (411 mg, 4.07 mmol) were dissolved in anhydrous dichloromethane (10 mL) under ice bath, and methylsulfonyl chloride (233 mg, 2.03 mmol) was added dropwise to the reaction solution under stirring, and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 2-(4-bromothiazol-2-yl)-2-methylpropyl methanesulfonate 148b (420 mg) with a yield of 98.6%.

MS m/z(ESI):313.9[M+1] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.17 (s, 1H), 4.38 (s, 2H), 2.95 (s, 3H), 1.50 (s, 6H).

Step 3

Under nitrogen protection, 148b (420 mg, 1.34 mmol) and sodium cyanide (131 mg, 2.67 mmol) were dissolved in dimethyl sulfoxide (6 mL), and the reaction was heated to 80 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 3-(4-bromothiazol-2-yl)-3-methylbutyronitrile 148c (240 mg), yield: 73.3%.

MS m/z(ESI):244.9[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.83 (s, 1H), 3.03 (s, 2H), 1.48 (s, 6H).

Step 4

Under nitrogen protection, 148c (55 mg, 0.225 mmol), intermediate 4 (100 mg, 0.150 mmol) and bistriphenylphosphine palladium dichloride (21 mg, 0.030 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 110 ° C by microwave and stirred for 1.5 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with water (30 mL) and saturated sodium chloride solution (30 mL) in sequence, dried, and the filtrate was concentrated. The residue was purified by reverse phase chromatography with eluent System C to give 3-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-3-methylbutyronitrile 148 (17 mg) in a yield of 20.3%.

MS m/z(ESI):542.1[M+1] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71(s,1H),8.60(d,1H),8.28(s,1H),8.12-8.07(m,1H),7.93(s,1H), 6.81(s,1H),5.49(s,2H),3.11(s,2H),2.04(s,3H),1.98(s,3H),1.54(s,3H),1.53(s,3H).

Decomposition of Example 148

(S)-3-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-3-methylbutyronitrile and (R)-3-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridinyl]-2'-yl)thiazol-2-yl)-3-methylbutyronitrile

Example 148 (17 mg, 0.031 mmol) was subjected to SFC chiral separation (AD column) to give 148-1 (8 mg, R.T = 0.792 min), yield: 47%; 148-2 (6 mg, R.T = 1.704 min), yield: 35%.

Example 148-1: MS m/z (ESI): 542.1 [M+H] ⁺ ;

Example 148-2: MS m/z (ESI): 542.1 [M+H] ⁺ ;

SFC chiral separation conditions:

SFC chiral analysis method:

Embodiment 149

N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

first step

Under nitrogen protection, 2-fluoro-4-iodo-5-methylpyridine 149a (2.5 g, 8.44 mmol), acetamidine hydrochloride (1.86 g, 19.7 mmol), cuprous iodide (188 mg, 0.986 mmol) and cesium carbonate (9.64 g, 29.6 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction was heated to 100 ° C and stirred for 16 hours. Acetonitrile (40 mL) was added to the reaction solution, filtered through diatomaceous earth, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent system A) to obtain the product N-(2-fluoro-5-methylpyridin-4-yl)acetamidine 149b (650 mg), yield: 36%

MS m/z(ESI):168.1[M+H] ⁺ .

Step 2

149b (300 mg, 1.63 mmol) and bis(2,4,6-trichlorophenyl)malonate (832 mg, 1.8 mmol) were dissolved in tetrahydrofuran (8 mL). The reaction solution was heated to 90°C and stirred for 8 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system A) to give the product 3-(2-fluoro-5-methylpyridin-4-yl)-6-hydroxy-2-methylpyrimidin-4(3H)-one 149c (180 mg) with a yield of 42.7%.

MS m/z(ESI):236.1[M+H] ⁺ .

Step 3

149c (800 mg, 3.42 mmol), 2-(chloromethyl-d2)-2,4-difluorophenyl (843 mg, 5.12 mmol), potassium carbonate (1.18 g, 8.54 mmol) and 18-crown-6 ether (903 mg, 3.42 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction was heated to 70 °C and stirred for 3 hours. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water three times, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give the product 6-((2,4-difluorophenyl)methoxy-d2)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methylpyridin-4(3H)-one 149d (820 mg), yield: 66.1%.

MS m/z(ESI):364.1[M+H] ⁺ .

Step 4

149d (800 mg, 2.20 mmol) and N-chlorosuccinimide (323 mg, 2.42 mmol) were dissolved in isopropanol (30 mL), and the reaction was heated to 60°C and stirred for 6 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the product 5-chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methylpyridin-4(3H)-one 149e (450 mg), yield: 51.4%.

MS m/z(ESI):398.1[M+H] ⁺ .

Step 5

149e (800 mg, 2.20 mmol), 73b (800 mg, 2.20 mmol) and cesium carbonate (800 mg, 2.20 mmol) were dissolved in acetonitrile (5 mL) and the reaction was heated to 80°C and stirred for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the product N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 149 (70 mg) in a yield of 76.1%.

MS m/z(ESI):563.2[M+H] ⁺ .

Decomposition of Example 149

(S)-N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 149 (70 mg, 0.124 mmol) was subjected to chiral separation (IB column) to give 149-1 (20.1 mg, R.T = 2.720 min), yield: 28.7%; 149-2 (21.1 mg, R.T = 3.863 min), yield: 30.1%.

Example 149-1: MS m/z (ESI): 563.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.50(d,2H),8.05(s,1H),7.97(s,1H),7.66-7.57(m,1H),7.32-7.24(m,1H) ),7.14-7.07(m,1H),2.11(s,3H),1.99(s,3H),1.73(s,3H),1.53(s,3H),1.50(s,3H).

Example 149-2: MS m/z (ESI): 563.2 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 150

N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 149, the target product N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 150 was synthesized.

MS m/z(ESI):545.2[M+H] ⁺ .

Decomposition of Example 150

(S)-N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 150 (70 mg, 0.128 mmol) was subjected to chiral separation (IB column) to give 150-1 (21.1 mg, R.T = 3.053 min), yield: 30.1%; 150-2 (22.7 mg, R.T = 4.670 min), yield: 32.4%.

Example 150-1: MS m/z (ESI): 545.2 [M+H] ⁺ ;

¹ H NMR(400MHz, DMSO-d ₆ )δ8.56(s,1H),8.48(d,1H),8.02(s,1H),7.97(s,1H),7.74-7.63(m,1H), 7.40-7.30(m,1H),7.23-7.12(m,1H),6.42(d,1H),2.19(s,3H),2.06(s,3H),1.82(s,3H),1.61(s, 3H),1.57(s,3H).

Example 150-2: MS m/z (ESI): 545.2 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 151

5-Chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one

Referring to the synthesis method of Example 149, the target product 5-chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one 151 was synthesized.

MS m/z(ESI):504.2[M+H] ⁺ .

Decomposition of Example 151

(S)-5-chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one and (R)5-chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one

Example 151 (60 mg, 0.120 mmol) was subjected to chiral separation (IB column) to give 151-1 (17.9 mg, R.T = 4.183 min), yield: 29.9%; 151-2 (16.1 mg, R.T = 5.350 min), yield: 27.8%.

Example 151-1: MS m/z (ESI): 504.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.56(s,1H),8.51(d,1H),8.03(s,1H),7.73-7.64(m,1H),7.39-7.29(m,1H ),7.22-7.12(m,1H),6.57(d,1H),5.10(s,1H),2.18(s,3H),2.06(s,3H),1.48(s,6H).

Example 151-2: MS m/z (ESI): 504.2 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 152

N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Referring to the synthesis method of Example 149, the target product N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 152 was synthesized.

MS m/z(ESI):564.2[M+H] ⁺ .

Decomposition of Example 152

(S)-N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

Example 152 (50 mg, 0.088 mmol) was subjected to chiral separation (IB column) to give 152-1 (17.0 mg, R.T = 3.077 min), yield: 34.0%; 152-2 (17.1 mg, R.T = 4.530 min), yield: 34.2%.

Example 152-1: MS m/z (ESI): 564.2 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.44-8.38(m,2H),8.34(d,1H),7.70(s,1H),7.33-7.27(m,1H),6.27(s,1H), 2.21(s,3H),2.14(s,3H),2.03(s,3H),1.80(s,3H),1.73(s,3H).

Example 152-2: MS m/z (ESI): 564.2 [M+H] ⁺ .

HPLC chiral separation conditions:

HPLC chiral analysis method:

Embodiment 153

N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanamide

Referring to the synthesis method of Example 149, the target product N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanamide 153 was synthesized.

MS m/z(ESI):564.2[M+H] ⁺ .

Decomposition of Example 153

(S)-N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanamide and (R)-N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanamide

Example 153 (45 mg, 0.076 mmol) was subjected to chiral separation (IB column) to give 153-1 (13.9 mg, R.T = 3.013 min), yield: 30.9%; 153-2 (10.5 mg, R.T = 4.853 min), yield: 23.3%.

Example 153-1: MS m/z (ESI): 590.2 [M+H] ⁺ ;

Example 153-2: MS m/z (ESI): 590.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.58(d,1H),8.57-8.55(m,2H),8.31(s,1H),8.09-8.04(m,1H),8.03(s,1H ),2.14(s,3H),2.06(s,3H),2.00(q,1H),1.62(s,3H),1.59(s,3H),0.62-0.52(m,4H).

HPLC chiral separation conditions:

HPLC chiral analysis method:

Example Test Evaluation

The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on p38α/MK2 enzyme activity

1. Experimental purpose: The purpose of this test case is to measure the inhibitory ability of the compound on p38α/MK2 enzyme activity.

2. Experimental instruments and reagents:

2.1 Instruments:

2.2 Reagents:

3. Experimental methods:

p38/MK2 enzyme activity assay method: In 1× enzyme reaction buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl ₂ , 2mM DTT, 0.01% Tween-20), incubate 0.06nM p38α (Active p38alpha Protein), 1.2nM MK2 (Inactive MK2) and gradient dilutions of compounds for 1 hour. Add 50nM ULight-CREBtide and 25μM ATP (ATP Solution) and react at room temperature for 1.5 hours. Add an equal volume of detection and termination mixture (1×LANCE detection buffer containing 20mM EDTA and 2nM Europium-anti-phospho-CREB), mix and centrifuge, apply sealing film, and react at room temperature for 1 hour. Read the plate using the TR-FRET program of the EnVision instrument and detect the fluorescence value of each well at 665nm/615nm.

p38 enzyme activity assay method: Incubate 3nM p38α (Active p38 alpha Protein) and compound gradient dilutions for 1 hour in 1× enzyme reaction buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl ₂ , 2mM DTT, 0.01% Tween-20). Add 50nM ULight-MBP and 50μM ATP (ATP 10mM Solution) and react at room temperature for 1.5 hours. Add an equal volume of detection and termination mixture (1×LANCE detection buffer containing 20mM EDTA and 2nM Europium-anti-P-MBP), mix and centrifuge, apply sealing film, and react at room temperature for 1 hour. Read the plate using the TR-FRET program of the EnVision instrument and detect the fluorescence value of each well at 665nm/615nm.

4. Experimental data processing method:

The raw data (665nm/615nm reading ratio) was calculated according to the following formula to obtain the inhibition rate: Inhibition rate % = [(average value of positive control wells - sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are reaction wells without compound enzymes, and the negative control wells are reaction wells without enzymes.

The log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 was used to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, and the curve was fitted to obtain the compound IC ₅₀ value.

The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC ₅₀ -X)*HillSlope))

5. Experimental results:

6. Experimental conclusion:

The above data show that the compounds of the present invention have strong inhibitory ability on p38α/MK2 enzyme activity and good selectivity.

Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on p-Hsp27 in U937 cells

1. Experimental purpose: The purpose of this test example is to test the inhibitory ability of the compounds of the present invention on p-Hsp27 of U937 cells.

2. Experimental instruments and reagents:

2.1 Instruments:

2.2 Reagents:

3. Experimental methods:

U937 cells were treated with 20ng/ml PMA for differentiation overnight, and then fresh culture medium was replaced. U937 cells were rested overnight. U937 cells were digested and counted after differentiation, and 25,000 cells were seeded in 96-well plates per well until the cells adhered to the wall. Compound concentration gradients were prepared, and cells were pretreated with compounds for 1 hour (the highest final concentration of the compound was 1μM, and the concentration gradient was diluted 3 times), and 10ng/ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added for stimulation for 0.5 hours. After washing the cells with PBS, the cells were lysed with lysis buffer. The p-Hsp27 in the cell lysate was detected using the Phospho-HSP27 (S78/S82) DuoSet IC ELISA kit. The specific steps refer to the standard steps provided by the kit manufacturer.

4. Experimental data processing method:

Calculate the p-Hsp27 inhibition rate: inhibition rate percentage = [(average p-Hsp27 in positive control wells - average p-Hsp27 in sample wells) / (average p-Hsp27 in positive control wells - average p-Hsp27 in negative control wells)] × 100%, where the positive control wells are wells without compound (DMSO-treated wells) and the negative control wells are wells without LPS stimulation.

Dose response curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to perform fitting equation analysis on compound concentration and corresponding inhibition rate, fit the curve and obtain the compound _IC50 value.

The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC ₅₀ -X)*HillSlope))

5. Experimental results:

6. Experimental conclusion:

The above data show that the compounds of the present invention have a strong inhibitory ability on p-Hsp27 of U937 cells.

Test Example 3: Determination of the inhibitory effect of the compounds of the present invention on the expression level of TNF-α in U937 cells

1. Experimental purpose: The purpose of this test example is to measure the inhibitory ability of the compounds of the present invention on the expression level of TNF-α in U937 cells.

2. Experimental instruments and reagents:

2.1 Instruments:

2.2 Reagents:

3. Experimental methods:

U937 cells were treated with 20ng/ml PMA for differentiation overnight, and then fresh culture medium was replaced. U937 cells were rested overnight. U937 cells were digested and counted after differentiation, and 50,000 cells were seeded in 96-well plates per well until the cells adhered to the wall. Compound concentration gradients were prepared, and cells were pretreated with compounds for 1 hour (the highest final concentration of the compound was 1μM, and the concentration gradient was diluted 3 times). After adding 10ng/ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) for stimulation for 4 hours, the culture supernatant was collected by centrifugation for subsequent ELISA detection of TNF-α concentration in the supernatant. TNF-α concentration detection was performed according to the standard steps provided by the ELISA kit manufacturer.

4. Experimental data processing method:

The standard curve of TNF-α standard was drawn by linear regression method, and the TNF-α concentration of the sample was converted according to the standard curve.

Calculate the inhibition rate: inhibition rate percentage = [(average TNF-α concentration in positive control wells - average TNF-α concentration in sample wells) / (average TNF-α concentration in positive control wells - average TNF-α concentration in negative control wells)] × 100%, where the positive control wells are compound-free wells (DMSO-treated wells) and the negative control wells are culture medium wells.

Dose response curve fitting: Use log(inhibitor) vs.response–Variable slope(four parameters) in GraphPad Prism 6 to fit the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC ₅₀ value. The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)).

5. Experimental results:

6. Experimental conclusion:

The above data show that the compounds of the present invention have a strong inhibitory ability on the expression level of TNF-α in U937 cells.

Test Example 4: Investigation of in vitro metabolic stability of the compounds of the present invention in human liver microsomes

1. Experimental purpose:

The purpose of this study is to evaluate the metabolic stability of the compounds in phase I and partially phase II in human liver microsomes.

2. Experimental Plan

2.1 Trial Drugs:

The compound of the present invention is self-made.

Alamethicin (Abcam), 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 BiDe Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), acetonitrile (Merck).

2.2 Drug preparation

The compound of the present invention was prepared into a 10 mM stock solution with DMSO (or other suitable solution) and stored in a -20°C refrigerator until use.

Control compound: 7-Hydroxycoumarin was prepared as a 10 mM stock solution for use.

2.3 Experimental procedures

1) Prepare buffer:

Take 4.01 mL of 1M K ₂ HPO ₄ ·3H ₂ O (AR grade) and 0.99 mL of 1M KH ₂ PO ₄ (AR grade), dissolve them in ultrapure water and make up to 50 mL to prepare a phosphate buffer with a final concentration of 100 mM.

2) Prepare compound working solution

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

Preparation of working solution of control compound: keep the same preparation process as the compound.

3) Preparation of liver microsome working solution

156.3 μL of 20 mg/mL microsomes were diluted to 5 mL with 100 mM phosphate buffer and mixed to a final concentration of 0.625 mg/mL.

4) Prepare NADPH and UDPGA

Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.

5) Prepare the punch (Alamethicin)

Weigh 1 mg of Alamethicin and add 200 μL of methanol to prepare a 5 mg/mL solution. Then take out 10 μL of the solution and add it to 990 μL of phosphate buffer (pH 7.4) to a final concentration of 50 μg/mL.

6) Prepare the reaction termination solution

Dilute the internal standard with acetonitrile (or other suitable solution) as the stop solution and store it in a refrigerator at 2-8°C.

7) Incubation process

400 μL of prepared liver microsomes, 25 μL of compound working solution (10 μM) and 25 μL of Alamethicin (50 μg/mL) were added to a 96-well plate and pre-incubated at 37°C for 10 min. Then 50 μL of prepared NADPH/UDPGA was added to start the reaction and incubated at 37°C. The total volume of the reaction system was 500 μL, and the final contents of each component were as follows:

50 μL was taken out at 0, 5, 15, 30, 60 and 120 min, and 200 μL of cold stop solution containing internal standard was added to terminate the sample reaction. The sample was centrifuged at 3500 rpm for 10 min, and the supernatant was taken for LC-MS/MS analysis.

2.4 Chromatographic analysis

1) Chromatographic conditions

Instrument: Shimadzu LC-20 AD;

Column: Phenomenex C18 (50*4.6mm, 5μm particle size);

Mobile phase: A: 0.1% formic acid aqueous solution, B: acetonitrile;

Washing gradient: 0.2-1.6 min 5% A to 95% A, 3.0-3.1 min 95% A to 5% A;

Flow rate: 1.0ml/min;

Running time: 4.0min;

Injection volume: 5 μL.

2) Mass spectrometry conditions

Instrument: API4000 liquid chromatography-mass spectrometer, AB Sciex;

Ion source: electrospray ionization source (ESI);

Drying gas: N2, temperature 500℃;

Electrospray voltage: 5000 V;

Detection method: positive ion detection;

Scanning mode: reaction monitoring (MRM) mode;

Scan time: 0.8401s.

3. Experimental results and data processing

T _1/2 =0.693/Ke, where Ke represents the elimination rate constant.

4. Experimental Conclusion

The above data show that the compounds of the present invention exhibit good metabolic stability in human liver microsomes.

Test Example 5: Pharmacokinetics in SD rats

1. Experimental purpose:

SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) at a dose of 5 mg/kg orally and 1 mg/kg intravenously.

2. Experimental Plan

2.1 Trial Drugs:

The compound of the present invention is homemade.

2.2 Experimental Animals:

There were 3 male SD rats in each group, from Shanghai Jiesijie Experimental Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

2.3 Drug preparation:

PO, 10% solutol HS15, dissolve by ultrasound, prepare as a clear solution or homogeneous suspension.

IV, 5% DMSO + 10% Solutol HS15 + 85% PBS, sonicated to prepare a clear solution.

2.4 Dosage regimen:

There were 3 male SD rats in each group. After fasting overnight, they were given p.o. at a dose of 5 mg/kg in a dosing volume of 10 mL/kg; and i.v. at a dose of 1 mg/kg in a dosing volume of 5 mL/kg.

2.5 Sample collection:

After oral administration to rats, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours were collected; after intravenous administration to rats, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours were collected; 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-K ₂ test tube, centrifuged at 6000 rpm at 4°C for 6 min to separate plasma, and stored at -80°C.

2.6 Sample processing:

1) Add 100uL acetonitrile to 20uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5 to 20 minutes.

2) The supernatant solution after treatment is subjected to LC/MS/MS analysis to determine the concentration of the test compound. The LC/MS/MS analysis instrument is AB Sciex API 4000Qtrap.

2.7 Liquid phase analysis:

●Liquid phase conditions: Shimadzu LC-20AD pump

●Chromatographic column: Waters Xbridge C18 5μm, 4.6X 50mm Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is methanol

Flow rate: 1.0 mL/min

● Elution time: 0-4.0 minutes, eluent is as follows:

3. Test results and data processing:

The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

4. Test conclusion:

The results of the pharmacokinetic test on SD rats showed that the compound of the present invention exhibited a good PK advantage. The pharmacokinetics of the compound of the present invention were also tested on mice and beagle dogs, and the results showed that there was little difference in the PK species of the compound of the present invention.

Test Example 6: Pharmacokinetics in SD rats

1. Experimental purpose:

SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in rats (plasma and brain) at a dose of 5 mg/kg after oral administration.

2. Experimental Plan

2.1 Trial Drugs:

The compound of the present invention is self-made.

2.2 Experimental Animals:

Each group contained 12 male SD rats, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

2.3 Drug preparation:

PO, 10% solutol HS15, dissolve by ultrasound, prepare as a clear solution or homogeneous suspension.

2.4 Dosage regimen:

Each group consisted of 12 male SD rats; they were fasted overnight and administered p.o. at a dose of 5 mg/kg in a volume of 10 mL/kg.

2.5 Sample collection:

After oral administration to rats, plasma and brain tissue were collected at 0.5, 1, and 2 hours; 0.25 mL of blood was collected from the jugular vein, anticoagulated with sodium heparin, and placed on ice after blood sample collection, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.

2.6 Sample processing:

1) 50uL of plasma sample was added with 500uL of 50% methanol-acetonitrile solution containing internal standard (100ng/mL), mixed, centrifuged at 4000rpm and 4°C for 10 minutes, and analyzed by LC-MS/MS.

2) After all samples are completely thawed, weigh a certain amount of brain tissue, add 4 times the volume of 50% methanol/water, and homogenize. Transfer 50uL of the homogenized brain tissue sample to a 96-well plate, and add 500uL of 50% methanol-acetonitrile solution containing internal standard (100 ng/mL). Vortex the sample for 5 minutes, centrifuge it at 4000rpm and 4℃ for 10 minutes, and analyze it by LC-MS/MS.

3) Pipette 80uL of supernatant into 80uL of water, mix well and perform LC/MS/MS analysis on the concentration of the compound to be tested. LC/MS/MS analysis instrument: AB Sciex Triple Quad 5500+.

2.7 Liquid phase analysis:

●Chromatographic column: Synergi 4μm Fusion-RP 80ALC Column 50*2mm Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile

Flow rate: 0.8 mL/min

● Elution time: 0-2.2 minutes, the eluent is as follows:

3. Experimental results and data processing:

The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

4. Experimental Conclusion

The results of pharmacokinetic measurements in SD rats showed that the compound of the present invention had an extremely low drug concentration in the brain. The low brain-blood ratio indicated that the compound of the present invention had a poor ability to enter the brain, and the side effects such as headaches it caused were likely to be lower.

Test Example 7: PD test in Wistar rat acute inflammation model

1. Experimental purpose:

Wistar rats aged 6-8 weeks were used as test animals to study the pharmacodynamic behavior of the compound of the present invention in rats (serum) after oral administration at different doses and time points.

2. Experimental Plan

2.1 Test samples:

The compound of the present invention is self-made.

Wistar rats, Vital River Company.

2.2 Drug preparation:

An appropriate amount of compound was weighed, and the corresponding solvent 10% Solutol HS15 was added, and a suspension with a final concentration of 0.2 mg/mL was obtained by ultrasound, vortexing and stirring.

2.3 Dosage regimen:

Eight male Wistar rats were administered p.o. after overnight fasting at a dose of 1 mg/kg in a dosing volume of 5 mL/kg.

The experiment was started when the rats weighed 200-230 g. Vehicle or drug was administered 1 h, 5 h, 11 h, 17 h, and 23 h before the administration of the modeling agent LPS. Samples were collected 1 h after the tail vein injection of the modeling agent LPS or PBS.

2.4 Sample collection:

Blood was collected from the jugular vein of rats, added to a centrifuge tube, placed at room temperature for 60 minutes, and centrifuged at 8000 rpm for 5 minutes. 50 μL of the serum after centrifugation was transferred to a new labeled centrifuge tube, and 2 portions were taken, quickly frozen with dry ice, and stored in a -80°C refrigerator for detection.

2.5 Sample processing:

Serum samples: After thawing, the normal group and the 6-hour administration group were diluted 1.5 times, that is, 80.0 μL of sample was added to 40.0 μL 1x reagent diluent buffer (prepared by R&D kit); the modeling group and the 18-hour administration group were diluted 3 times, that is, 40.0 μL of sample was added to 80.0 μL 1x reagent diluent buffer.

2.6 Experimental Procedure

TNF-α test (Kit DY510):

1) Coat the test plate one day in advance: Take appropriate coating antibody and add it to PBS to obtain a coating antibody solution with a concentration of about 4.00 μg/mL, add it to the test plate, 100.0 μL per well, and place it in a 24°C incubator for overnight incubation.

2) Washing: Discard the coating solution in the test plate, add 300.0ul of wash buffer to each well, and repeat washing 3 times, removing all residual liquid in the test plate each time.

3) Blocking: Add 300.0 μL of 1× blocking buffer to each well for blocking and incubate at 24°C for at least 1 h.

4) Preparation of standard products: First, dilute the Rat TNFa standard product to 1000 pg/ml, take 4.17 μL of the standard product and add it to 495.83 μL of 1xreagent dilute, and then dilute it twice with 1xRegent dilute to prepare standard products with 8 concentrations.

5) Take out the sealed test plate and wash the plate.

6) Sample incubation: Take 100.0 μL of the diluted sample or standard into the corresponding test well of the ELISA test plate, seal it with adhesive tape and place it in a 24°C incubator for 2 hours.

7) Wash the plate.

8) Detection antibody incubation: Prepare the detection antibody working solution: Add appropriate detection antibody to 1xRegent Dilute to obtain the detection antibody solution. Add 100.0 μL of detection antibody working solution to each well, seal with new adhesive tape, and incubate in a 24°C incubator for 2 hours.

9) Wash the plate.

10) Secondary antibody HRP incubation in dark: Take appropriate amount of 40xStreptavidin-HRP and dilute it to 1x in 1xRegent Dilute. Add 100.0μL to each well and incubate in 24℃ incubator for about 20min.

11) Wash the plate and repeat step 2.

12) Color development and light protection: Mix equal volumes of color reagent A and B to prepare substrate solution, add 100.0ul to each well, and incubate at room temperature for about 20 minutes.

13) Stop: When the color develops appropriately, add 50.0 μL of STOP solution to each well.

IL-6 detection (Kit K15059D-2):

1) Reagent preparation: Preparation: Take out the reagent kit from the refrigerator and equilibrate it at room temperature for 30 minutes.

2) Prepare the standard: add 1 ml of diluent 42 to the standard, shake thoroughly, and leave at room temperature for 15-20 minutes. As the highest concentration point, make 4-fold dilutions in sequence, 7 standards + 1 Blank.

3) Prepare samples: dilute rat serum appropriately

4) Prepare the detection antibody diluent: aspirate the detection antibody and make up the volume with diluent 40.

5) Prepare the cleaning solution: prepare 1*PBS (0.05% Tween-20) for later use.

6) Prepare plate reading solution: Prepare 2* plate reading solution. (Prepare 10 minutes before the end of antibody incubation)

7) Take out the rewarmed MSD plate and Blocker H, add 150ul Block H to each well and incubate at room temperature with shaking at 800rpm for 1h.

8) Wash the MSD plate 3 times, each time with 150ul of washing solution.

9) Add 50ul of diluted samples and standards to each well, seal with sealing film, and shake at room temperature for 2h.

10) Wash the MSD plate 3 times, each time with 150ul of washing solution.

11) Add 25ul of the prepared detection antibody to each well, seal with sealing film, and shake at room temperature for 2 hours.

12) Wash the MSD plate 3 times, each time with 150ul of washing solution.

13) Add 150ul of prepared plate reader to each well and test on the machine.

3 Experimental results and conclusions:

Data processing was performed using Graph pad.

The results of the PD experiment on the Wistar rat acute inflammation model showed that the compound of the present invention exhibited an excellent PD effect and had a high inhibition rate on TNF-α and IL-6.

Claims (21)

A compound represented by general formula (I-2), its stereoisomer or a pharmaceutically acceptable salt thereof: in: Ring C is selected from phenyl, thiazolyl, pyrazolyl, pyrimidinyl or pyridinyl; _L1 is selected _from a bond or -( _CH2 ) _nO ( _CRaaRbb ) _n1- ; R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, C _1-8 alkyl or C _1-8 deuterated alkyl, wherein the C _1-8 alkyl or C _1-8 deuterated alkyl may be further substituted; M ₅ is selected from CR ⁵ , N, NR ⁵ , O or S; M ₆ is selected from CR ⁶ , N, NR ⁶ , O or S; M ₇ is selected from CR ⁷ or NR ⁷ ; M ₈ is selected from CR ⁸ , N, NR ⁸ , O or S; M ₉ is selected from C or N; ^R5 , ^R6 and ^R8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 hydroxyalkyl, _C1-8 alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 alkoxy, _C1-8 haloalkoxy, _C1-8 hydroxyalkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or _5-14 membered heteroaryl is selected. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1-8 haloalkyl, C 1-8 hydroxyalkyl} , C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _{1-8 haloalkoxy, C 2-8 alkenyl} , C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; Preferably, R ⁵ , R ⁶ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 haloalkoxy, C _{1-6 hydroxyalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl. _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl; ^R7 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, bridged cycloalkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C1-8 alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _{C6-14 aryl} , 5-14 membered heteroaryl, -(CReeRff) _n4C ( _O ) _Rgg , _- ( _CReeRff ) _n4NRhhC (O) _Rgg , _{- ( CReeRff ) n4S} (O) _2Rgg , _{- (} CReeRff) _n4C (O) _{NRhhRgg or} -(CR wherein _the amino, _C1-8 alkyl, bridged cycloalkyl, _{C1-8 deuterated alkyl, C1-8} haloalkyl, C1-8 alkoxy, C1-8 _haloalkoxy , _{C1-8 hydroxyalkyl} , _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _{C6-14 aryl and} 5-14 membered heteroaryl _may be further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl _{, C1-8} alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and _5-14 membered heteroaryl. substituted by one or more substituents selected from _3-12- membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl; Preferred are hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _{C6-10 aryl ,} 5-10 membered heteroaryl, -( _CReeRff ) _n4C (O _{)Rgg, -(CReeRff)n4NRhhC(O)Rgg , - ( CReeRff ) n4S (} O _{) 2Rgg ,} -(CReeRff _{) n4C} (O _{)NRhhRgg or -} ( _CReeRff ) _n4 S(O) ₂ NR _hh R _gg ； The amino, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C 1-6 hydroxyalkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C 1-6 alkyl} , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted by one or more substituents selected from _3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C 1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; Preferably, R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; Alternatively, any two adjacent or non-adjacent substituents of ^R5 , ^R6 , ^R7 and ^R8 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl group may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated _alkyl , _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Preferably, any two adjacent or non-adjacent substituents are linked to form a _C3-8 cycloalkyl, a 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, a _C6-10 aryl, or a 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, wherein the _C3-8 cycloalkyl, the 3-8 membered heterocyclyl containing 1-3 N, O, or S atoms, the _C6-10 aryl, or the 5-10 membered heteroaryl containing 1-3 N, O, or S atoms may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-4 alkyl, _C1-4 deuterated alkyl, _C1-4 haloalkyl, _C1-4 hydroxyalkyl, _C1-4 alkoxy, _C1-4 deuterated alkoxy, _C1-4 haloalkoxy, _C2-3 alkenyl, C substituted by one or more substituents selected from _C2-3 alkynyl, _C5-8 cycloalkyl, 5-8 membered heterocyclyl, _C6-8 aryl and 5-8 membered heteroaryl; more preferably, any two adjacent or non-adjacent substituents are linked to form Optionally, it may be further substituted with one or more of deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, cyano, oxo, thio, carboxyl, methyl, ethyl, propyl, butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl; x is an integer from 0 to 6; y is an integer from 0 to 6; z is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n4 is 0, 1, 2, 3 or 4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by general formula (VI), (X) or (XI): in: M ₅ is selected from CR ⁵ , N, NR ⁵ , O or S; M ₆ is selected from CR ⁶ , N, NR ⁶ , O or S; M ₇ is selected from CR ⁷ or NR ⁷ ; M ₈ is selected from CR ⁸ , N, NR ⁸ , O or S; M ₉ is selected from C or N; ^R5 , ^R6 and ^R8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 hydroxyalkyl, _C1-8 alkoxy, _C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-8 alkyl, _C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 alkoxy, _C1-8 haloalkoxy, _C1-8 hydroxyalkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or _5-14 membered heteroaryl is selected. C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C _{1-8 haloalkyl, C 1-8 hydroxyalkyl} , C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _{1-8 haloalkoxy, C 2-8 alkenyl} , C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; Preferably, R ⁵ , R ⁶ and R ⁸ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 haloalkoxy, C _{1-6 hydroxyalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl. C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _{1-6 haloalkyl, C 1-6 hydroxyalkyl} , C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; ^R7 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl _{, C1-8 hydroxyalkyl, C1-8 alkoxy, C1-8 deuterated alkoxy, C1-8 haloalkoxy, C2-8 alkenyl , C2-8 alkynyl , C3-12} cycloalkyl, _3-12 membered heterocyclyl, _{C6-14 aryl} , 5-14 membered heteroaryl, -( _{CReeRff ) n4C} (O) _Rgg , _{- (} CReeRff _{) n4NRhhC} (O) _Rgg , _{- (} CReeRff _{) n4S} (O) _2Rgg , - ₍ CReeRff) _n4C (O) _{NRhhRgg or} -( _{CReeR ff} ) _n4 S(O) _2NRhhRgg ; the amino, _C1-8 alkyl, C1-8 deuterated alkyl, C1-8 haloalkyl, _C1-8 alkoxy, _C1-8 haloalkoxy, C1-8 hydroxyalkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl and 5-14 _{membered heteroaryl} may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, _C1-8 alkyl, C1-8 deuterated alkyl, _C1-8 haloalkyl, C1-8 hydroxyalkyl, _{C1-8 alkoxy, C1-8 deuterated alkoxy, C1-8 haloalkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, optionally with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C1-8 alkyl , C1-8 deuterated alkyl ,} C1-8 haloalkyl, _C1-8 hydroxyalkyl, C1-8 alkoxy, C1-8 deuterated alkoxy, _C1-8 haloalkoxy, _C2-8 alkenyl, _C2-8 alkynyl, C substituted by one or more substituents selected from _3-12- membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl; Preferred are hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _{C6-10 aryl ,} 5-10 membered heteroaryl, -( _CReeRff ) _n4C (O _{)Rgg, -(CReeRff)n4NRhhC(O)Rgg , - ( CReeRff ) n4S (} O _{) 2Rgg, -(CReeRff)n4C ( O ) NRhhRgg or -} ( _CReeRff ) _n4 S(O) ₂ NR _hh R _gg ； The amino, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C 1-6 hydroxyalkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C 1-6 alkyl} , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C 1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6} haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted by one or more substituents selected from _3-8 membered cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-8 alkyl, C _1-8 deuterated alkyl, C 1-8 haloalkyl, C _1-8 hydroxyalkyl, C _1-8 alkoxy, C _1-8 deuterated alkoxy, C _1-8 haloalkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; Preferably, R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; n4 is 0, 1, 2, 3 or 4; _L1 is selected from a bond, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, -( _CH2 ) _n- , -( _CH2 ) _nC (O) _{(CRaaRbb ) n1-} , -( _CH2 ) _nC (O) _NRcc ( _{CH2 ) n1-} , -( _{CH2 ) n(CRaaRbb)n1-, -(CRaaRbb)nO ( CH2 ) n1- , - ( CH2} ) _nO ( _CRaaRbb ) _n1- , _- (CRaaRbb) _{nS ( CH2} ) _n1- , -( _CH2 ) _nS ( _{CRaaRbb ) n1-} , -( _CRaaRbb ) _n ( _CH2 ) _n1NRcc- , -( _CH2 ) _{nNRcc ( CRaaRbb ) n1-} , - _{( CH 2} ) _n NR _cc C(O)-, -(CH ₂ ) _n P(O) _p R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _cc - and -(CH ₂ ) _n NR _cc S(O) _m -; _Raa , _Rbb and _Rcc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; Alternatively, any two of _Raa , _Rbb and _Rcc are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; R ^{a is} each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; Alternatively, any two adjacent or non-adjacent ^Ras are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; Alternatively, L ₁ and R ^a are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; R ^{b is} each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; Alternatively, any two adjacent or non-adjacent R ^b are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; Alternatively, L ₁ and R ^b are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; Alternatively, ^Ra and ^Rb are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; R ^c is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; Alternatively, any two adjacent or non-adjacent R ^c are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; Alternatively, R ^b and R ^c are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; x is an integer from 0 to 6; y is an integer from 0 to 6; z is an integer from 0 to 6; n is 0, 1, 2, or 3; n1 is 0, 1, 2, or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3. The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, characterized in that the compound is further represented by general formula (VI-1), (VI-2), (XI-1) or (XI-2): The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by general formula (VIII): The compound, its stereoisomer or pharmaceutically acceptable salt thereof according to claim 4, characterized in that the compound is further represented by general formula (VIII-1) or (VIII-2): The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by general formula (IX): The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by general formula (IX-1) or (IX-2): The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by the general formula (VI-3) or (XI-3): in: R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, C _1-8 alkyl or C _1-8 deuterated alkyl, and the C _1-8 alkyl or C _1-8 deuterated alkyl may be further substituted. The compound according to any one of claims 1 to 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by the general formula (XII-D): in: _X1 is selected from N or CR ^a5 ; _X3 is selected from N or CR ^b1 ; ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 or ^Ra5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 and ^Ra5 are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the C3-12 cycloalkyl, the _3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, C1-6 deuterated alkyl, _C1-6 haloalkyl _{, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C2-6 alkenyl , C2-6 alkynyl , C3-12} cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl; R _aa or R _bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6 haloalkoxy} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, _Raa and _Rbb are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy , C1-6} haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; R ^b1 , R ^b2 or R ^b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, the ^Rb1 and ^Rb2 substituents are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl} , _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; R ^c1 , R ^c2 or R ^c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, the R ^c1 and R ^c2 substituents are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, the R ^c1 and R ^b2 substituents are linked to form a 3-12 membered heterocyclyl or a 5-14 membered heteroaryl, and the 3-12 membered heterocyclyl and the 5-14 membered heteroaryl may be further optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; R _da , R _db , R' _da or R' _db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _{1-6 haloalkoxy, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6} haloalkyl, C _1-6 alkoxy _, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent R _da , R _db , R' _da and R' _db are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6 haloalkoxy} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl; ^R6 or ^R8 is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy _{, C1-6} haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, ^R6 and ^R8 are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl} , _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; n7 is 0, 1, 2 or 3; Preferably, the Not for The compound according to any one of claims 1 to 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by the general formula (XIII-B) or (XIII-B'): in: _X1 is selected from N or CR ^a5 ; ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 or ^Ra5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent ^Ra1 , ^Ra2 , ^Ra3 , ^Ra4 and ^Ra5 are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the C3-12 cycloalkyl, the _3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl _{, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , 3-12 membered heterocyclyl ,} C6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl; R _aa or R _bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1-6 deuterated alkoxy, C 1-6 haloalkoxy} , C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, _Raa and _Rbb are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _{C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy , C1-6} haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; R ^b1 , R ^b2 or R ^b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; R ^c1 , R ^c2 or R ^c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, the R ^c1 and R ^c2 substituents are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl are optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, the R ^c1 and R ^b2 substituents are linked to form a 3-12 membered heterocyclyl or a 5-14 membered heteroaryl, and the 3-12 membered heterocyclyl and the 5-14 membered heteroaryl may be further optionally substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; ^R7 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _{C1-6 deuterated alkyl, C1-6 cycloalkyl} , _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl , C3-12} cycloalkyl, 3-12 membered heterocyclyl, _{C6-14 aryl} , 5-14 _membered heteroaryl, - ₍ CReeRff) _n4C ( _O ) _Rgg , _- (CReeRff _{) n4NRhhC} ( _O ) _Rgg , - ₍ CReeRff) _{n4NRhhORgg , -} ( _CReeRff ) _n4 S(O) _2Rgg , _{- ( CReeRff} ) _{n4S(O)Rgg, -(CReeRff)n4SRgg, -(CReeRff)n4C ( O ) NRhhRgg , - ( CReeRff ) n4S ( O ) NRhhRgg} , _{- (} CReeRff _{)n4SNRhhRgg or} -( _{CReeRff ) n4S} (O) _2NRhhRgg , wherein the amino, _{C1-6 alkyl} , C1-6 deuterated _{alkyl , C1-6} bridged _cycloalkyl , C1-6 _haloalkyl , _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _{C2-6 alkynyl} , C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; R _ee , R _ff , R _gg and R _hh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; or R _ee and R _ff are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; ^R6 or ^R8 is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy _{, C1-6} haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, any two adjacent or non-adjacent R ⁶ , R ⁷ and R ⁸ are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, wherein the C _3-12 cycloalkyl, the 3-12 membered heterocyclyl, the C _6-14 aryl and the 5-14 membered heteroaryl may be further substituted with deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl. substituted by one or more substituents of _6-14- membered aryl and 5-14-membered heteroaryl; n4 is 0, 1, 2, 3 or 4. The compound according to any one of claims 9 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the compound is further represented by the general formula (XII-D-1), (XII-D-2), (XIII-B-1), (XIII-B-2), (XIII-B'-1) or (XIII-B'-2): The compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _L1 is selected from a bond, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, -( _CH2 ) _n- , -( _CH2 ) _nC ( _O )( _{CRaaRbb ) n1-} , -(CH2) _nC (O) _NRcc ( _CH2 ) _n1- , -( _{CH2 ) n} ( _{CRaaRbb ) n1-} , -(CRaaRbb) _nO ( _CH2 ) _n1- , -( _CH2 ) _nO ( _{CRaaRbb ) n1- ,} - ₍ CRaaRbb) _nS ( _{CH2 )n1-, -(CH2)nS(CRaaRbb)n1-, -(CRaaRbb )n ( CH2 ) n1NRcc ( CH2 ) n1- , - (} CH ₂ ) _n NR _cc (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n NR _cc C(O)-, -(CH ₂ ) _n P(O) _p R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _cc - and -(CH ₂ ) _n NR _cc S(O) _m -; Preferably, _L1 is selected from a bond, a substituted or unsubstituted alkenylene, a substituted or unsubstituted alkynylene, -( _CH2 ) _n- , -( _CH2 ) _{nC (} O)-, -( _CRaaRbb )nO- _{, -O} ( _CRaaRbb ) _n1- , -( _CRaaRbb ) _nS- , _{-S ( CRaaRbb} ) _n1- , -( _CH2 ) _{n1NRcc- , -NRcc ( CRaaRbb ) n1-} or _-NRccC (O)-; More preferably, L ₁ is selected from a bond, -CH ₂ -, -OCH ₂ -, -OCD ₂ -, -NH-, -C(O)NH-, -OCH(CH ₃ )-, -OC(CH ₃ ) ₂ -, -NH-CH ₂ - or R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _{1-6 deuterated alkyl, C 1-6 haloalkyl} , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Preferably, _Raa , _Rbb and _Rcc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy, _C1-3 haloalkoxy, _C2-4 alkenyl, C2-4 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 alkoxy, _C1-3 haloalkoxy, _C1-3 hydroxyalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _{1-3 deuterated alkoxy, C 1-3 haloalkoxy} , C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl; Alternatively, any two of _Raa , _Rbb and _Rcc are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy and _C1-6 haloalkoxy; Preferably, any two of _Raa , _Rbb and _Rcc are linked to form a _C3-8 cycloalkyl, a 3-8 membered heterocyclyl, a _C6-10 aryl or a 5-10 membered heteroaryl, and the _C3-8 cycloalkyl, the 3-8 membered heterocyclyl, the _C6-10 aryl and the 5-10 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy and _C1-3 haloalkoxy. The compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that ^{Ra is} independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 hydroxyalkyl, C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, and the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl _{, C1-6} alkoxy, _C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Preferably, Ra ^is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, _C1-3 hydroxyalkyl, _C1-3 alkoxy, _C1-3 deuterated alkoxy, _C1-3 haloalkoxy, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl, wherein the amino, _C1-3 alkyl, _C1-3 deuterated alkyl, _C1-3 haloalkyl _{, C1-3} alkoxy, _C1-3 haloalkoxy, _C1-3 hydroxyalkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl or 5-10 membered heteroaryl. The _6-10 membered aryl and 5-10 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl. The compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R ^b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Preferably, R ^{b is} each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C 1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C 1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-3 alkyl, C _{1-3 deuterated alkyl, C 1-3 haloalkyl} , C _{1-3 alkoxy, C 1-3 haloalkoxy} , C _1-3 hydroxyalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. The _6-10 membered aryl and 5-10 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl. The compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R ^c is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Preferably, R ^c is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C 1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C 1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the amino, C _1-3 alkyl, C _{1-3 deuterated alkyl, C 1-3 haloalkyl} , C _{1-3 alkoxy, C 1-3 haloalkoxy} , C _1-3 hydroxyalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl. _6-10 membered aryl and 5-10 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C _1-3 alkyl, C _1-3 deuterated alkyl, C _{1-3 haloalkyl, C 1-3 hydroxyalkyl} , C _1-3 alkoxy, C _1-3 deuterated alkoxy, C _1-3 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl; Alternatively, R ^b and R ^c are linked to form a C _3-12 cycloalkyl, a 3-12 membered heterocyclyl, a C _6-14 aryl or a 5-14 membered heteroaryl, and the C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, carboxyl, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl. The compound according to any one of claims 1 to 3 or 6 to 11, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that ^R6 is selected from halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _{C1-6 haloalkoxy, C2-6 alkenyl} , _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the amino, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl _{, C1-6} alkoxy, _C1-6 haloalkoxy, _C1-6 hydroxyalkyl, _C2-6 alkenyl, C _C2-6 alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, which may be further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, C1-6 haloalkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; Preferably, ^R6 is selected from halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thio, carboxyl, _C1-6 alkyl, _C1-6 deuterated alkyl, _C1-6 haloalkyl _, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 deuterated alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl or _C2-6 alkynyl; More preferably, R ⁶ is selected from fluorine. According to any one of claims 1 to 16, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that the structure of the compound is as follows: A method for preparing the compound of general formula (XII-D) or its stereoisomers and pharmaceutically acceptable salts thereof according to claim 9, characterized in that it comprises the following steps: The general formula (M-1) reacts with the general formula (M-2) to obtain the target compound represented by the general formula (XII-D); Said _X1 , _X3 , ^Ra1 , Ra2, ^Ra3 , ^Ra4 , _Raa , Rbb, ^Rb2 , ^Rb3 , ^Rc1 , _Rc2 , ^Rc3 , _Rda ^{, Rdb} , ^R'da , _R'db , _R6 , _R8 ^and n7 are as described in claim 9. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the compound according to any one of claims 1 to 17, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a drug for treating p38 kinase-mediated diseases. Use of the compound according to any one of claims 1 to 17, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for treating autoimmune diseases, chronic inflammatory diseases, acute inflammatory conditions, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancer, tumors, leukemia and lymphoma.