Pyridine-containing polycyclic derivatives, their preparation method and applications

Abstract

The present invention relates to a pyridine-containing polycyclic derivative, its preparation method and application.In particular, the present invention relates to a compound shown in general formula (I), its preparation method and pharmaceutical composition containing the compound, and its application as a bioregulator in the preparation of drugs for treating autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrodegenerative diseases, metabolic diseases, cancer, tumors, leukemia and lymphoma, wherein each substituent in general formula (I) is as defined in the specification. JPEG2025503581000213.jpg34170

Description

[Technical field]

[0001] The present invention belongs to the field of biopharmaceuticals, specifically relates to pyridine-containing polycyclic derivatives and their preparation methods and applications. [Background technology]

[0002] MK2 (MAPK activated protein kinase 2) is a protein kinase and an important downstream molecule of the classical inflammatory signaling pathway MAPK, which regulates the expression of inflammatory factors. After cells receive inflammatory stimuli, activated p38 MAPK protein is phosphorylated, activating MK2, which causes phosphorylation of the MK2 substrate TTP and promotes the stability of proinflammatory cytokine mRNA, thereby increasing the protein expression levels of inflammatory cytokines.

[0003] In both mouse arthritis models and osteoarthritis patient chondrocytes, MK2 was activated, and the expression levels of inflammatory factors could be inhibited by inhibiting the p38-MK2 pathway by genetic or pharmacological means, suggesting that MK2 is involved in mediating the regulation of inflammation in arthritis. p38-MK2 inhibitors are expected to treat patients with relapsing, refractory, or poorly responsive rheumatoid arthritis.

[0004] Currently, only Aclaris Therapeutics' p38-MK2 inhibitor ATI-450 has entered clinical trial IIb for rheumatoid arthritis worldwide, and preliminary clinical trial results show that ATI-450 is safe and well tolerated in rheumatoid arthritis patients, and has excellent long-lasting efficacy. Other MK2 inhibitors in clinical trials include BMS' 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.

[0005] Currently published p38-MK2 (or MK2) inhibitor patent applications include Aclaris Therapeutics patents (WO-2012078684, WO-2013086208, WO-2014197846, WO-2021022186, WO-2012078687, WO 2012078673, WO 2012078674), BMS patents (WO-2020236636, WO-2018170199, WO-2016044463, WO-2018170201, WO-20181 70200, WO-2018170203, US20210198276, US20210139501, US20200148701, US20200102326), Moerae These include Matrix patents (WO-2016112292, WO-2016145234, US-10336788, WO-2014040074, WO-2018231722, WO-2012142320, WO-2016033432, WO-2013134636, WO-2011149964) and others.

[0006] As a drug, p38-MK2 inhibitors have good application prospects in the medical field. p38-MK2 inhibitors provide a safer and more effective treatment method for patients with recurrent, refractory, and poorly responsive rheumatoid arthritis to conventional treatments. p38-MK2 inhibitors have a broad-spectrum inflammation inhibitory effect (TNF / IL-6 / IL-1), and theoretically can be used to treat multiple inflammatory diseases and autoimmune diseases. p38-MK2 inhibitors are small molecule inhibitors, and compared with macromolecular drugs such as TNF monoclonal antibodies, they have the advantages of easy oral administration and good patient compliance. In addition, there are no reports of toxic side effects of JAK inhibitors, such as infections, tumors, thrombosis, and cardiotoxicity, in clinical trials. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a huge clinical need for research and development of new p38-MK2 inhibitors. [Means for solving the problem]

[0008] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows: [ka] Where: Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L1 is a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR cc (CH2) n1 -, -(CH2) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH2) n1 -, -(CH2) n S(CR aa R bb ) n1 -, -(CR aa R bb ) n (CH2) n1 NR cc -, -(CH2) n NR cc (CR aa R bb )n1 -, -(CH2) n NR cc C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR cc - and - (CH2) n NR cc S(O) m - selected from R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or R aa , R bb and R cc any two of may be joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; L2 and L3 each independently represent a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH2) n2 -, -(CH2) n2 C(O)(CR a1 R b1 ) n3 -, -(CH2) n2 C(O)NRc1 (CH2) n3 -, -(CH2) n2 (CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 O(CH2) n3 -, -(CH2) n2 O(CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 S(CH2) n3 -, -(CH2) n2 S(CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 (CH2) n3 NR c1 -, -(CH2) n2 NR c1 (CR a1 R b1 ) n3 -, -(CH2) n2 NR c1 C(O)-, -(CH2) n2 P(O) p1 R a1 -, -(CH2) n2 S(O) m1 -, -(CH2) n2 S(O) m1 NR c1 - and - (CH2) n2 NR c1 S(O) m1 - selected from R a1 , R b1 and R c1are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; R a are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, R bare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, R c are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, R b and R c are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R deach independently represents hydrogen, deuterium, halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, an alkyl group, a bridged cycloalkyl group, a deuterated alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a deuterated alkoxy group, a halogenated alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, or -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 C(O)NR hh R gg Or -(CR ee R ff ) n4 S(O)2NR hh R gg wherein the amino, alkyl, bridged cycloalkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-8 Alkyl group, C 1-8 Deuterated alkyl groups, C 1-8 Halogenated alkyl groups, C 1-8 Hydroxyalkyl group, C 1-8 Alkoxy group, C 1-8 Deuterated alkoxy group, C 1-8Halogenated alkoxy groups, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Or R ee , R ff are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; n4 is 0, 1, 2, 3 or 4; Preferably, R dare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, Or any two adjacent or non-adjacent R d are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or L3 and R d are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or R c and R d are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally 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; e is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; m1 is 0, 1, 2 or 3; p1 is 0, 1, 2 or 3.

[0009] In a preferred embodiment of the present invention, the compound is further represented by general formula (I'-1): [ka] Where: Ring D is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring E is selected from heterocyclyl groups; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; X3 is N or CR b1 is selected from L1 is a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR cc (CH2) n1 -, -(CH2) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH2) n1 -, -(CH2) n S(CR aa R bb ) n1 -, -(CR aa R bb ) n(CH2) n1 NR cc -, -(CH2) n NR cc (CR aa R bb ) n1 -, -(CH2) n NR cc C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR cc - and - (CH2) n NR cc S(O) m - selected from R aa , R bb and R cc are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; L3 is a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH2) n2 -, -(CH2) n2 C(O)(CR a1 R b1 ) n3 -, -(CH2) n2 C(O)NR c1 (CH2) n3 -, -(CH2) n2 (CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 O(CH2) n3 -, -(CH2) n2 O(CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 S(CH2) n3 -, -(CH2) n2 S(CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 (CH2) n3 NRc1 -, -(CH2) n2 NR c1 (CR a1 R b1 ) n3 -, -(CH2) n2 NR c1 C(O)-, -(CH2) n2 P(O) p1 R a1 -, -(CH2) n2 S(O) m1 -, -(CH2) n2 S(O) m1 NR c1 - and - (CH2) n2 NR c1 S(O) m1 - selected from R a1 , R b1 and R c1 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R a are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R a is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or L1 and Ra is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R b1 or R b3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c2 or R c3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R d are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, -(CRee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 S(O)R gg , -(CR ee R ff ) n4 S.R. 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)2NR hh R gg wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group or the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Or R ee , R ff is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; x is an integer from 0 to 6; e is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; n4 is 0, 1, 2, 3 or 4; n6 is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; m1 is 0, 1, 2 or 3; p1 is 0, 1, 2 or 3.

[0010] In a further preferred embodiment of the present invention, the ring D according to the present invention is 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 aryl group or 5- to 14-membered heteroaryl group, preferably ring D is 6-10Ring D is preferably selected from a pyrazolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, a pyrimidinyl group, a pyridyl group, a phenyl group, [ka] is selected from.

[0011] In a further preferred embodiment of the present invention, the ring E according to the present invention is selected from 6- to 12-membered heterocyclyl groups, preferably, the ring E is [ka] is selected from.

[0012] In a preferred embodiment of the present invention, the compound is further represented by general formula (XIV): [ka] Where: M 1 is selected from C, CH, N or absent; M 2 is selected from C, CH, N or absent; M 3 is selected from C, CH, N or absent; X3 is N or CR b1 is selected from Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L1 is a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR cc (CH2) n1 -, -(CH2) n (CR aa Rbb ) n1 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH2) n1 -, -(CH2) n S(CR aa R bb ) n1 -, -(CR aa R bb ) n (CH2) n1 NR cc -, -(CH2) n NR cc (CR aa R bb ) n1 -, -(CH2) n NR cc C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR cc - and - (CH2) n NR cc S(O) m - selected from R aa , R bb and R cc are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; L3 is a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH2) n2 -, -(CH2) n2 C(O)(CR a1 R b1 ) n3 -, -(CH2) n2 C(O)NR c1 (CH2) n3 -, -(CH2) n2 (CR a1 R b1 ) n3-, -(CR a1 R b1 ) n2 O(CH2) n3 -, -(CH2) n2 O(CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 S(CH2) n3 -, -(CH2) n2 S(CR a1 R b1 ) n3 -, -(CR a1 R b1 ) n2 (CH2) n3 NR c1 -, -(CH2) n2 NR c1 (CR a1 R b1 ) n3 -, -(CH2) n2 NR c1 C(O)-, -(CH2) n2 P(O) p1 R a1 -, -(CH2) n2 S(O) m1 -, -(CH2) n2 S(O) m1 NR c1 - and - (CH2) n2 NR c1 S(O) m1 - selected from R a1 , R b1 and R c1 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R a are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R a is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or L1 and R a is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R b1 or R b3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c2 or R c3are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Rd are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 S(O)R gg , -(CR ee R ff ) n4 S.R. 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 hhR gg Or -(CR ee R ff ) n4 S(O)2NR hh R gg wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group or the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Or R ee , R ff is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; x is an integer from 0 to 6; e is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; n4 is 0, 1, 2, 3 or 4; n6 is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; m1 is 0, 1, 2 or 3; p1 is 0, 1, 2 or 3.

[0013] In a further preferred embodiment of the present invention, ring A according to the present invention is 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, ring A is selected from a 6- to 12-membered bicyclic heterocyclyl group, a 5- to 6-membered monocyclic heteroaryl group, or a 7- to 10-membered bicyclic heteroaryl group; More preferably, ring A is selected from a pyrazolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, a pyrimidinyl group, a pyridyl group, a phenyl group, a tetrahydroquinolinyl group, a benzocyclopentyl group, a pyrrolopyrimidinyl group, a pyrrolopyridyl group, a pyrazolopyridine or an imidazopyridine.

[0014] In a further preferred embodiment of the present invention, the ring B according to the present invention is 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, ring B is selected from a 3- to 7-membered monocyclic heterocyclyl group, a 6- to 12-membered bicyclic heterocyclyl group, a 5-membered monocyclic heteroaryl group, a 6-membered monocyclic heteroaryl group, or a 7- to 14-membered heteroaryl ring; More preferably, ring B is selected from a 5-membered monocyclic nitrogen-containing heteroaryl group, a 6-membered monocyclic nitrogen-containing heteroaryl group, a 5- to 6-membered heteroaryl-fused 5- to 6-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl group, or a 5- to 6-membered heteroarylphenyl group; More preferably, ring B is pyrimidine, a pyridocyclohexyl group, a pyridocyclopentyl group, a pyrrolotriazinyl group, a pyrrolopyrimidinyl group, a pyridocyclopentenyl group, pyridine, thiazole, pyrazole, pyridopyrrolidone, pyridofuranone, pyridosulfolane, [ka] is selected from Even more preferably, ring B is selected from a thiazolyl group, an oxazolyl group, a pyrazolyl group, an imidazolyl group, a 1,2,4-thiadiazolyl group, a 1,3,4-oxadiazolyl group, a pyrimidinyl group, a pyridocyclohexyl group, a pyridocyclopentyl group, a pyrrolotriazinyl group, a pyrrolopyrimidinyl group, a pyridocyclopentenyl group, a pyridyl group, a pyridopyrrolidone, a pyridofuranone or a pyridosulfolane.

[0015] In a further preferred embodiment of the present invention, L1 according to the present invention is a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH2) n -, -(CH2) n C(O)(CR aa R bb ) n1 -, -(CH2) n C(O)NR cc (CH2) n1 -, -(CH2) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH2) n1 -, -(CH2) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH2) n1 -, -(CH2) n S(CR aa R bb ) n1 -, -(CR aa Rbb ) n (CH2) n1 NR cc -, -(CH2) n NR cc (CR aa R bb ) n1 -, -(CH2) n NR cc C(O)-, -(CH2) n P(O) p R aa -, -(CH2) n S(O) m -, -(CH2) n S(O) m NR cc - and - (CH2) n NR cc S(O) m - selected from Preferably, L1 is a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH2) n -, -(CH2) n C(O)-, -(CR aa R bb ) n O-, -O(CR aa R bb ) n1 -, -(CR aa R bb ) n S-, -S(CR aa R bb ) n1 -, -(CH2) n1 NR cc -, -NR cc (CR aa R bb ) n1 -OR-NR cc C(O)-, More preferably, L1 is a bond, -CH2-, -OCH2-, -OCD2-, -NH-, -C(O)NH-, -OCH(CH3)-, -OC(CH3)2-, -NH-CH2- or [ka] is selected from R aa, R bb and R cc are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R aa , R bb and R cc are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; Or R aa , R bb and R cc Any two of the 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy groups and C 1-6 may be further substituted with one or more substituents of halogenated alkoxy groups; Preferably, R aa , R bb and R cc Any two of the 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5- to 10-membered heteroaryl group is formed, 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3Deuterated alkoxy groups and C 1-3 It may be further substituted with one or more substituents of the halogenated alkoxy group.

[0016] In a further preferred embodiment of the present invention, the compound is further represented by general formula (XV): [ka] Where: X1 is N or CR a5 is selected from X3 is N or CR b1 is selected from R a1 , R a2 , R a3 , R a4 or R a5 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R a1 , R a2 , R a3 , R a4 and R a5 is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R aa or R bb are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R aa and R bb is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R b1 , R b2 or R b3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R b1 and R b2 The substituent is bonded to C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c1 , R c2 or R c3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R c1 and R c2 The substituent is bonded to C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R c1 and Rb2 The substituents combine to form a 3- to 12-membered heterocyclyl group or a 5- to 14-membered heteroaryl group, and the 3- to 12-membered heterocyclyl group and the 5- to 14-membered heteroaryl group are optionally substituted with deuterium, halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, a C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R 1 is hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR eeR ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 S(O)R gg , -(CR ee R ff ) n4 S.R. 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)2NR hh R gg wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Or R ee , R ff is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R 2 , R 3 or R 4 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R 1 , R 2 , R 3 and R 4 is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; n4 is 0, 1, 2, 3 or 4, and The above [ka] teeth, [ka] isn't it.

[0017] In a further preferred embodiment of the invention, the compound further comprises the general formula (XIV-A), (XIV-B) or (XIV-C): [ka] As shown in Where: X1 is N or CR a5 is selected from X2 is N or CR 2 is selected from X3 is N or CR b1 is selected from R a1 , R a2 , R a3 , R a4 or R a5 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R a1 , R a2 , R a3 , R a4 and R a5 is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R aa or R bb are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R aa and R bb is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R b1 or R b3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R c2 or R c3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R da , R db or R' da are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R da and R db is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R dc or R dd are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or R dc and R dd is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R 1 is hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 S(O)R gg , -(CR ee R ff ) n4 S.R. gg , -(CR ee R ff ) n4 C(O)NR hh R gg , -(CR ee R ff ) n4 S(O)NR hh Rgg , -(CR ee R ff ) n4 SNR hh R gg Or -(CR ee R ff ) n4 S(O)2NR hh R gg wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Or R ee , R ff is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R 2 , R 3 or R 4 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R 1 , R 2 , R 3 and R 4 is combined with C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R 7 is hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff )n4 NR hh C(O)R gg , -(CR ee R ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 S(O)R gg , -(CR ee R ff ) n4 S.R. 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)2NR hh R gg wherein the amino group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Bridged cycloalkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Or R ee , R ff is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R 6 or R 8 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Or any two adjacent or non-adjacent R 6 , R 7 and R 8 is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; n4 is 0, 1, 2, 3 or 4; n5 is 0, 1 or 2; n5' is 0, 1 or 2; n5 and n5' are not 0 at the same time. n6 is 0, 1, 2, 3 or 4.

[0018] In a further preferred embodiment of the present invention, the compound further comprises the general formula (I'-1-1), (I'-1-2), (XIV-1), (XIV-2), (XIV-A-1), (XIV-A-2), (XIV-B-1), (XIV-B-2), (XIV-C-1), (XIV-C-2), (XV-1) or (XV-2): [ka] [ka] [ka] As shown in the figure.

[0019] In a further preferred embodiment of the present invention, R a are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R a are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0020] In a further preferred embodiment of the present invention, R b are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R b are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0021] In a further preferred embodiment of the present invention, R c are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R c are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group; Or R b and R c is combined with C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14An aryl group or a 5- to 14-membered heteroaryl group is formed, 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group.

[0022] In a further preferred embodiment of the present invention, R d are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl groups, 5-10 membered bridged cycloalkyl groups, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 Aryl group or 5-14 membered heteroaryl group or -(CR ee R ff ) n4 C(O)R gg , -(CR ee Rff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 C(O)NR hh R gg Or -(CR ee R ff ) n4 S(O)2NR hh R gg wherein the amino group, C 1-6 Alkyl groups, 5-10 membered bridged cycloalkyl groups, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; R ee , R ff , R gg and Rhh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-8 Alkyl group, C 1-8 Deuterated alkyl groups, C 1-8 Halogenated alkyl groups, C 1-8 Hydroxyalkyl group, C 1-8 Alkoxy group, C 1-8 Deuterated alkoxy group, C 1-8 Halogenated alkoxy groups, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group; Preferably, R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; Or R ee , R ff are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group optionally being substituted with deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, a C 1-6 Alkyl group, C 1-6Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; n4 is 0, 1, 2, 3 or 4.

[0023] Preferably, R d are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R d are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0024] More preferably, R d are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5-10 membered heteroaryl group or -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee Rff ) n4 S(O)2R gg , -(CR ee R ff ) n4 C(O)NR hh R gg Or -(CR ee R ff ) n4 S(O)2NR hh R gg is selected from R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; n4 is 0, 1, 2, 3 or 4.

[0025] In a further preferred embodiment of the present invention, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R c1 , R c2 and R c3 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0026] In a further preferred embodiment of the present invention, R da , R db , R' da , Rdc and R dd are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0027] In a further preferred embodiment of the present invention, R 1 and R 7 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 An aryl group or a 5-10 membered heteroaryl group or -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O)2R gg , -(CR ee R ff ) n4 C(O)NR hh R gg Or -(CR ee R ff ) n4 S(O)2NR hh R gg is selected from R ee , R ff , R gg and R hh are each independently hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, carboxyl group, C1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group; n4 is 0, 1, 2, 3 or 4.

[0028] In a further preferred embodiment of the present invention, R 2 , R 3 , R 4 , R 6 and R 8 are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 an aryl group or a 5- to 10-membered heteroaryl group, 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 3-8 Cycloalkyl groups, 3-8 membered heterocyclyl groups, C 6-10 It may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

[0029] In a further preferred embodiment of the present invention, R 2 is a halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R 2 is a halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group or C 2-6 alkynyl groups, More preferably, R 2 is selected from fluorine.

[0030] In a further preferred embodiment of the present invention, R 6 is a halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 an aryl group or a 5- to 14-membered heteroaryl group, 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl group, C 1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-12 Cycloalkyl groups, 3-12 membered heterocyclyl groups, C 6-14 may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group; Preferably, R 6 is a halogen, nitro group, hydroxy group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C 1-6 Alkyl group, C1-6 Deuterated alkyl groups, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 1-6 Alkoxy group, C 1-6 Deuterated alkoxy group, C 1-6 Halogenated alkoxy groups, C 2-6 Alkenyl group or C 2-6 alkynyl groups, More preferably, R 6 is selected from fluorine.

[0031] The present invention further provides a compound represented by general formula (M-1) or (M-2), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [ka] Where: X4 is selected from halogens, preferably chlorine or bromine; Ring D and rings E and M 1 , M 2 , M 3 , n6, L1, R a , R b3 , R c2 , R c3 , X3 and x are as described above.

[0032] The present invention further provides a method for preparing the compound of the general formula (I'-1) or its stereoisomer and its pharma- ceutically acceptable salt, the method comprising the steps of: [ka] The method includes a step of obtaining a target compound represented by general formula (I'-1) by reacting a compound represented by general formula (M-1), Where: X4 is selected from halogens, preferably chlorine or bromine; Ring D, Ring E, Ring B, L1, L3, R a , R b3 , R c2 , R c3 , X3, R d, x and e are as defined above.

[0033] The present invention further provides a method for preparing the compound of formula (XIV) or its stereoisomer and its pharma- ceutically acceptable salt, the method comprising the steps of: [ka] The method includes a step of obtaining a target compound represented by general formula (XIV) by reacting a compound represented by general formula (M-2), Where: X4 is selected from halogens, preferably chlorine or bromine; M 1 , M 2 , M 3 , L1, L3, R a , R b3 , R c2 , R c3 , X3, R d , x, e and n6 are as defined above.

[0034] The present invention further provides a method for preparing the compound of formula (XV) or its stereoisomer and its pharma- ceutically acceptable salt, the method comprising the steps of: [ka] The method includes a step of reacting the general formula (M-3) with the general formula (M-4) to obtain a target compound represented by the general formula (XV), Where: X1, X3, R a1 , R a2 , R a3 , R a4 , R aa , R bb , R b2 , R b3 , R c1 , R c2 , R c3 , R 1 , R 2 , R 3 and R 4 is as described above.

[0035] The present invention further relates to a pharmaceutical composition, which comprises a therapeutically effective amount of said compound, its stereoisomer or its pharma- ceutically acceptable salt and one or more pharma- ceutically acceptable carriers, diluents or excipients, and further wherein the weight percentage of said compound, its stereoisomer or its pharma- ceutically acceptable salt in the composition is 0.1%-95%, preferably 0.5%-85%, more preferably 1%-60%, even more preferably 10%-50%, even more preferably 15-40%, even more preferably 20-30%, and even more preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0036] The present invention further relates to the application of said compound, its stereoisomer or a pharma- ceutically acceptable salt thereof, or said pharmaceutical composition in the manufacture of a medicament for treating a p38 kinase mediated disease.

[0037] The present invention further relates to the application of said compound, its stereoisomer or its pharma- ceutically acceptable salt, or its pharmaceutical composition in the manufacture of a medicament for treating autoimmune diseases, metabolic diseases, tumors, etc., wherein the autoimmune diseases are selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, etc., the metabolic diseases are selected from diabetes mellitus, fibrodegenerative diseases, etc., and the tumors are selected from leukemia, lymphoma, etc.

[0038] The present invention further 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 amount of a compound according to the present invention, its stereoisomer or a pharma- ceutically acceptable salt 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 fibrodegenerative diseases, etc., and the tumor is selected from leukemia and lymphoma, etc.

[0039] The present invention further provides methods of treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including, but not limited to, conditions associated with p38 kinase mediated diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0041] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 8 carbon atoms, even more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 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, 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 group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, Examples include 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 from 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, and when substituted, the substituent may be substituted at any available binding site, and said substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, and in the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, halogenated alkyl, deuterated alkyl, alkyl substituted with alkoxy and alkyl substituted with hydroxy.

[0042] The term "alkylene group" refers to a divalent alkyl group formed by the further replacement of one hydrogen atom of an alkyl group, where alkyl group is as defined above. For example, a "methylene group" refers to -CH2-, an "ethylene group" refers to -(CH2)2-, a "propylene group" refers to -(CH2)3-, a "butylene group" refers to -(CH2)4-, etc. The points of attachment of the alkylene chain to the remainder of the molecule and to the group may be via one carbon or any two carbons within the chain. The alkylene group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available bonding site, and the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups or carboxylate groups, and in the present invention are preferably methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, halogenated alkyl groups, deuterated alkyl groups, alkyl groups substituted with alkoxy groups and alkyl groups substituted with hydroxy groups.

[0043] The term "alkenyl group" 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 chain group containing from 2 to 20 carbon atoms, preferably an alkenyl group containing from 2 to 12 carbon atoms, more preferably an alkenyl group containing from 2 to 8 carbon atoms, even more preferably an alkenyl group containing from 2 to 6 carbon atoms, and most preferably an alkenyl group containing from 2 to 4 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, or 3-butenyl. An alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0044] The term "alkenylene group" refers to a divalent alkenyl group formed by further replacing one hydrogen atom of an alkenyl group, where the alkenyl group is as defined above, such as a vinylene group, a propenylene group, a butenylene group, etc. The alkenylene group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0045] The term "alkynyl group" 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 chain group containing from 2 to 20 carbon atoms, preferably an alkynyl group containing from 2 to 12 carbon atoms, more preferably an alkynyl group containing from 2 to 8 carbon atoms, even more preferably an alkynyl group containing from 2 to 6 carbon atoms, and most preferably an alkynyl group containing from 2 to 4 carbon atoms, such as an ethynyl group, a propynyl group, a 1-butynyl group, a 2-butynyl group, or a 3-butynyl group. The alkynyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0046] The term "alkynylene group" refers to a divalent alkynyl group formed by further replacing one hydrogen atom of an alkynyl group, where the alkynyl group is as defined above. For example, ethynylene group, propynylene group, butynylene group, etc. The alkynylene group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0047] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the ring of the cycloalkyl group containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and even more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spiro, fused, and bridged ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0048] The term "spirocycloalkyl group" refers to a polycyclic group of 5 to 20 members in which the monocyclic rings share one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups, bisspirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 3-membered / 6-membered, 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Including, Also included are spirocycloalkyl groups in which the monospirocycloalkyl group and the heterocycloalkyl group share a spiro atom, non-limiting examples of which are: [ka] etc.

[0049] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups are: [ka] etc.

[0050] "Bridged cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and it may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered or 5-14 membered, more preferably 7-10 membered or 5-10 membered. Depending on the number of rings it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0051] [ka] The ring of the cycloalkyl group can be condensed onto the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring connected to the base skeleton is a cycloalkyl group, non-limiting examples of which include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptyl group, [ka] and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0052] The term "cycloalkylene group" refers to a divalent cycloalkyl group formed by further replacing one hydrogen atom of a cycloalkyl group, where the cycloalkylene group is optionally substituted or unsubstituted, and where cycloalkyl group is as defined above.

[0053] The term "heterocyclyl group" refers to a saturated or partially unsaturated mono- or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, C(O) or S(O). m (where m is an integer of 0 to 2), but does not include the ring moieties -OO-, -OS- or -SS-, and the other ring atoms are carbon. Preferably, the heterocyclyl group contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms or 6 to 12 ring atoms, most preferably 3 to 6 ring atoms, and even more preferably 3 to 8 membered heterocyclyl groups containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms or oxo groups, and includes monocyclic heterocyclyl groups, spiroheterocyclyl groups or fused heterocyclyl groups.

[0054] Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyridonyl, pyranyl, tetrahydrothiopyran dioxide, [ka] etc.

[0055] Polycyclic heterocyclyl groups include spirocyclic, fused ring, and bridged ring heterocyclyl groups, where such spirocyclic, fused ring, and bridged ring heterocyclyl groups are optionally linked to other groups via single bonds or further tandemly linked to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups via any two or more atoms on the ring.

[0056] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiro atom), where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2), and the other ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. It is preferably 6 to 14-membered, more preferably 8 to 12-membered. Depending on the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into monospiroheterocyclyl, bisspiroheterocyclyl or polyspiroheterocyclyl groups, preferably monospiroheterocyclyl and bisspiroheterocyclyl groups. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] etc.

[0057] The term "fused heterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and wherein one or more ring atoms is nitrogen, oxygen or S(O) m (wherein m is an integer of 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 8 to 12-membered. Depending on the number of rings that constitute it, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 4-membered / 5-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered and 6-membered / 7-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] etc.

[0058] The term "bridged heterocyclyl group" refers to a 5- to 14-membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, which may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms is not nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2), and the other ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings that it comprises, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] etc.

[0059] The ring of the heterocyclyl group may be fused onto the ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring connected to the base skeleton is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0060] Heterocyclyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylate groups.

[0061] The term "heterocyclylalkylene group" refers to a "heterocyclyl-alkylene-" formed by the joining of a heterocyclyl group and an alkylene group, where the heterocyclyl group or the alkyl group may be optionally substituted or unsubstituted, and the heterocyclyl group and the alkylene group are as defined above.

[0062] The term "heterocyclylene group" refers to a divalent heterocyclyl group formed by further replacing one hydrogen atom of a cycloalkyl group, where the heterocyclylene group may be optionally substituted or unsubstituted, and where the definition of heterocyclyl group is as set forth above.

[0063] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl groups. More preferably, it is a phenyl group. The aryl ring may be fused onto a heteroaryl group, heterocyclyl group, or cycloalkyl group, including 5- to 10-membered benzoheteroaryl groups, 3- to 8-membered benzocycloalkyl groups, and 3- to 8-membered benzoheteroalkyl groups, preferably 5- to 6-membered benzoheteroaryl groups, 3- to 6-membered benzocycloalkyl groups, and 3- to 6-membered benzoheteroalkyl groups, where the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen, oxygen, sulfur atoms, or further containing a three-membered nitrogen-containing fused ring containing a benzene ring.

[0064] Here, the ring connected to the basic skeleton is an aryl ring, and non-limiting examples thereof include: [ka] etc.

[0065] The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0066] The term "arylene group" refers to a divalent aryl group formed by further replacing one hydrogen atom of a cycloalkyl group, where the arylene group is optionally substituted or unsubstituted, and where the definition of an aryl group is as set forth above.

[0067] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- to 6-membered monocyclic heteroaryl group or an 8- to 12-membered bicyclic heteroaryl group, such as an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, a pyrazinyl group, etc., preferably a pyridyl group, an oxadiazolyl group, a triazolyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, a thiazolyl group, a pyrimidinyl group or a thiazolyl group, more preferably a tetrazolyl group, a pyridyl group, an oxadiazolyl group, a pyrazolyl group, a pyrrolyl group, a thiazolyl group and an oxazolyl group.

[0068] Non-limiting examples of said bicyclic heteroaryl groups are: [ka] Includes.

[0069] The heteroaryl ring may be fused onto an aryl, heterocyclyl or cycloalkyl ring, where the ring connected to the base skeleton is a heteroaryl ring, non-limiting examples of which are: [ka] etc.

[0070] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0071] The term "heteroarylene group" refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, where the heteroarylene group is optionally substituted or unsubstituted, and where heteroaryl group is as defined above.

[0072] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of alkyl group is as set forth above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy groups, where the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

[0073] "Halogenated alkyl group" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above. Non-limiting examples of the halogenated alkyl group include trifluoromethyl, -CH2CF3, [ka] Includes.

[0074] A "halogenated alkoxy group" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0075] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

[0076] The term "alkenylcarbonyl group" refers to -C(O)-(alkenyl group), where the definition of alkenyl group is as set forth above. Non-limiting examples of alkenylcarbonyl groups include vinylcarbonyl, propenylcarbonyl, and butenylcarbonyl groups. An alkenylcarbonyl group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylate groups.

[0077] An "aminocarbonyl group" refers to NH2-C(O)-.

[0078] An "alkylaminocarbonyl group" means that one or all of the two hydrogen atoms in an aminocarbonyl group (NH2-C(O)-) are replaced by an alkyl group, in which the alkyl group is as defined above.

[0079] The term "alkylamino group" means that one or all of the two hydrogen atoms in an amino group are substituted with an alkyl group, the definition of which is as defined above.

[0080] An "alkylcarbonyl group" or an "acyl group" refers to an (alkyl group)-C(O)-, where alkyl is as defined above.

[0081] "Hydroxy" refers to an -OH group.

[0082] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0083] An "amino group" refers to -NH2.

[0084] A "cyano group" refers to -CN.

[0085] A "nitro group" refers to --NO.sub.2.

[0086] A "carbonyl group" refers to -C(O)-.

[0087] A "carboxyl group" refers to -C(O)OH.

[0088] "THF" refers to tetrahydrofuran.

[0089] "Ethyl acetate" refers to ethyl acetate.

[0090] "MeOH" refers to methanol.

[0091] "DMF" refers to N,N-dimethylformamide.

[0092] "DIPEA" refers to diisopropylethylamine.

[0093] "TFA" refers to trifluoroacetic acid.

[0094] "TEA" refers to triethylamine.

[0095] "MeCN" refers to acetonitrile.

[0096] "DMA" refers to N,N-dimethylacetamide;

[0097] "Et2O" refers to ether.

[0098] "DCM" refers to dichloromethane;

[0099] "DMAP" refers to 4-dimethylaminopyridine.

[0100] "DCC" refers to dicyclohexylcarbodiimide.

[0101] "DCE" refers to 1,2 dichloroethane.

[0102] "DIPEA" refers to N,N-diisopropylethylamine.

[0103] "NBS" refers to N-bromosuccinimide.

[0104] "NIS" refers to N-iodosuccinimide.

[0105] "Cbz-Cl" refers to benzyl chloroformate;

[0106] "Pd2(dba)3" refers to tri(dibenzylideneacetone)dipalladium.

[0107] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0108] "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0109] "KHMDS" refers to potassium hexamethyldisilazane.

[0110] "LiHMDS" refers to lithium bistrimethylsilylamide;

[0111] "MeLi" refers to methyllithium.

[0112] "n-BuLi" refers to n-butyllithium.

[0113] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0114] The various terms "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all mean the same thing, i.e., X can be one or more of A, B, C.

[0115] Any hydrogen atom described in the present invention may be replaced with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be replaced with a deuterium atom.

[0116] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes cases where the event or circumstance has occurred or not occurred. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0117] "Substituted" refers to the substitution of one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group, with the corresponding number of substituents, independently of each other. Needless to say, the substituents are only present in their possible chemical positions, and the skilled person can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, amino or hydroxy groups with free hydrogen may be unstable if they are attached to carbon atoms with unsaturated (e.g., olefinic) bonds.

[0118] A "pharmaceutical composition" is meant to contain a mixture of one or more compounds described herein or physiologically / pharmaceutical acceptable salts or prodrugs thereof with other chemical components, as well as other components such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and facilitate absorption of the active ingredient, thereby exerting a biological activity.

[0119] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is safe and effective when used in a mammalian body and possesses the desired biological activity. EXAMPLES

[0120] The present invention will now be further described in conjunction with the following examples, which are not intended to limit the scope of the present invention.

[0121] Working Example The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetometer, with the solvents being deuterated dimethylsulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or deuterated water (D2O) and the internal standard being tetramethylsilane (TMS).

[0122] 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 chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 × 4.6 mm chromatography column).

[0123] Thin layer chromatography silica gel plate used was Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, TLC used 0.15mm-0.20mm specifications, thin layer chromatography product separation and purification used 0.4mm-0.5mm specifications. Column chromatography generally used Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0124] The starting materials in the examples of the present invention are either known and commercially available or can be synthesized using or according to methods known in the art.

[0125] Unless otherwise noted, all reactions of the present invention were carried out under a dry nitrogen or argon gas atmosphere with continuous magnetic stirring, the solvents were dry solvents, and the reaction temperatures were in degrees Celsius.

[0126] The eluent system of silica gel column chromatography and the developer system of thin layer chromatography used in the purification of the intermediates and the compounds in the Examples include A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system, and the volume ratio of the solvents is adjusted according to the polarity of the compounds, and can also be adjusted by adding a small amount of alkaline or acidic reagent such as triethylamine and acetic acid.

[0127] Unless otherwise specified, in the examples of the present invention, the ratio of the mobile phase under the HPLC chiral resolution conditions and the HPLC chiral analysis conditions was a volume ratio.

[0128] Intermediate 1 2',3-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one [ka]

[0129] Step 1 2'-Chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one a (200 mg, 0.8 mmol, see WO 2014197846A1 for its synthesis), 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, the aqueous phase was extracted with ethyl acetate (20 mL x 2) and 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'-bipyridin]-2-one b (301 mg), the yield was 99%.

[0130] MS m / z (ESI): 378.1 [M+H] + .

[0131] Step 2 2'-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one b (301 mg, 0.8 mmol) and N-chlorobutanediimide (117 mg, 0.88 mmol) were dissolved in isopropanol (6 mL) and the reaction was heated to 60° C. and stirred for 16 h. After cooling to room temperature, the reaction was concentrated and 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)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one intermediate 1 (190 mg), 57.9% yield.

[0132] MS m / z (ESI): 412.1 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.60 (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).

[0133] Intermediate 2 2-(1H-pyrazol-3-yl)propan-2-ol [ka]

[0134] Step 1 Methyl 1H-pyrazole-3-carboxylate (2 g, 15.9 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Methylmagnesium chloride (1 M, 47.58 mL) was added dropwise to the reaction with stirring. After addition was complete, the reaction was allowed to warm to room temperature and continued to stir for 2 hours. Ethyl acetate (100 mL) was added to the reaction and the organic phase was washed with water and saturated ammonium chloride, dried and concentrated to give the product 2-(1H-pyrazol-3-yl)propan-2-ol intermediate 2 (840 mg), 42% yield.

[0135] MS m / z (ESI): 127.1 [M+H] + . 1 H NMR (400MHz,CDCl3) δ 7.51 (d,1H),6.64 (s,2H),6.18 (d,1H),1.62 (s,6H).

[0136] Intermediate 3 2',3-Dichloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one [ka]

[0137] Step 1 A (10 g, 40 mmol) was dissolved in a mixture of dichloroethane (600 mL) and isopropanol (400 mL). The reaction was heated to 60° C., N-chlorobutanediamide (6.4 g, 50 mmol) was added to the reaction in batches, and the reaction was continued to stir at 60° C. for 2 hours. The reaction was concentrated, isopropanol (50 mL) was added to the residue, and the mixture was stirred at 60° C. for 1 hour. The mixture was cooled, filtered, and the filter cake was washed with isopropanol. The filter cake was dried to give the product 2',3-dichloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one intermediate 3 (8.0 g), the yield was 71%.

[0138] MS m / z (ESI): 285.0 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 11.61 (s,1H),8.52 (s,1H),7.64 (s,1H),6.17 (d,1H),1.97 (s,3H),1.86 (s,3H).

[0139] Intermediate 4 1-(chloromethyl-d2)-2,4-difluorobenzene [ka]

[0140] Step 1 Methyl 2,4-difluorobenzoate 4A (0.5 g, 2.90 mmol) was dissolved in tetrahydrofuran (8 mL), stirred, and 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 for 1 hour under ice bath, the reaction solution was quenched with saturated ammonium chloride, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with saturated sodium chloride, dried, concentrated, and the residue was subjected to silica gel column chromatography (elution system B) to give (2,4-difluorophenyl)methanol-d2-ol 4B (0.4 g), the yield was 94%.

[0141] MS m / z (ESI): 147.1 [M+H] + .

[0142] Step 2 (2,4-Difluorophenyl)methanol-d2-ol 4B (400 mg, 2.74 mmol) and N,N-dimethylformamide (0.05 mL) were dissolved in dichloromethane (10 mL), stirred, and thionyl chloride (749 mg, 6.30 mmol) was slowly added dropwise to the reaction solution under ice bath. The reaction was brought to room temperature and stirred for 1 hour. The reaction solution was concentrated, the residue was diluted with saturated sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (20 mL x 3), the organic phase was combined, washed with saturated sodium chloride, dried, and concentrated to give 1-(chloromethyl-d2)-2,4-difluorobenzene intermediate 4 (0.42 g).

[0143] Intermediate 5 (2-(2-hydroxypropan-2-yl)thiazol-4-yl)boronic acid [ka]

[0144] Step 1 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 at room temperature. After the addition was complete, the reaction was heated to 50° C. and stirred for 3.5 hours. The reaction was allowed to warm to room temperature and directly concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the product methyl 4-bromothiazole-2-carboxylate 5B (1.02 g), with a yield of 95.6%.

[0145] MS m / z (ESI):222.1,224.1 [M+H] + .

[0146] Step 2 Methyl 4-bromothiazole-2-carboxylate 5B (970 mg, 4.37 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. Methylmagnesium bromide (3 M, 4.37 mL) was added dropwise to the reaction solution, and the mixture was allowed to warm to room temperature and stirred for 5 hours. Saturated ammonium chloride (15 mL) solution was added to the reaction solution, and the mixture 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 (eluent system A) to give the product 2-(4-bromothiazol-2-yl)propan-2-ol 5C (805 mg), with a yield of 83.0%.

[0147] MS m / z (ESI):222.1,224.1 [M+H] + .

[0148] Step 3 2-(4-Bromothiazol-2-yl)propan-2-ol 5C (100 mg, 0.45 mmol), bis(pinacolato)diboron (137.2 mg, 0.54 mmol), tri(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), purged with nitrogen gas for 1 min and the reaction was heated to 110 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was separated by reverse-phase HPLC (formic acid system) to obtain the title product (2-(2-hydroxypropan-2-yl)thiazol-4-yl)boronic acid intermediate 5 (65 mg), the yield was 77.2%.

[0149] MS m / z (ESI): 188.1 [M+H] + .

[0150] Intermediate 6 2-(chloromethyl-d2)-3,5-difluoropyridine [ka]

[0151] Step 1 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 ice bath. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ice and the reaction solution was filtered. The filtrate was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the product (3,5-difluoropyridin-2-yl)methane-d2-ol 6A (345 mg), the yield was 40.6%.

[0152] MS m / z (ESI): 148.0 [M+H] + .

[0153] Step 2 While stirring, thionyl chloride (839 mg, 7.06 mmol) was added dropwise to a solution of (3,5-difluoropyridin-2-yl)methan-d2-ol 6A (346 mg, 2.35 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL). The reaction was stirred at room temperature for 3 h. The reaction 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 intermediate 6 (150 mg), 38.5% yield.

[0154] MS m / z (ESI): 166.0 [M+H] + .

[0155] Intermediate 7 1-(2-Bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one [ka]

[0156] Step 1 2-Bromo-5-methyl-pyridin-4-amine 7A (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 preheated reactor at 90° C. and stirred for 3 hours. Concentrated sulfuric acid (1.8 g, 18.35 mmol) was added to the reaction and stirring was continued for 1 hour. The reaction was cooled, the supernatant removed, and water was added to the remaining oil. The mixture was stirred at room temperature for 30 minutes and filtered to give 2'-bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one 7B (1.7 g), 53% yield.

[0157] MS m / z (ESI): 296.1 [M+H]+ .

[0158] Step 3 2'-Bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one 7B (1.7 g, 5.76 mmol) was dissolved in isopropanol (40 mL) and 1,2-dichloroethane (60 mL) and heated to 60° C. and stirred. N-chlorobutanediamide (923 mg, 6.91 mmol) was added to the reaction in batches and stirring was continued for 2 hours. The reaction was concentrated and isopropanol (20 mL) was added to the residue and the mixture was heated to 60° C. and stirred for 0.5 hours. The reaction was cooled and filtered to give 1-(2-bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one intermediate 7 (1.71 g), 90.1% yield.

[0159] MS m / z (ESI): 330.9 [M+H] + .

[0160] Intermediate 8 2'-Bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one [ka]

[0161] Step 1 1-(2-Bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one Intermediate 7 (550g, 1.67mmol), Intermediate 6 (387mg, 2.34mmol), potassium carbonate (577mg, 4.17mmol) and 18-crown-6 ether (662mg, 2.50mmol) were dissolved in N,N-dimethylformamide (25mL), heated to 70°C and stirred for 3 hours. Ethyl acetate (50mL) 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'-bipyridin]-2-one intermediate 8 (540 mg), the yield was 70.6%.

[0162] MS m / z (ESI): 458.0 [M+H] + .

[0163] Intermediate 9 N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0164] Step 1 Methyl 4-fluoro-1H-pyrazole-3-carboxylate (600 mg, 4.16 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under ice bath, and methylmagnesium bromide in tetrahydrofuran (3 M, 6.9 mL, 20.7 mmol) was added dropwise to the reaction solution while stirring, and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into saturated ammonium chloride solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, and concentrated to give 2-(4-fluoro-1H-pyrazol-3-yl)propan-2-ol 9A (600 mg), and the product was used directly in the next step reaction without purification.

[0165] MS m / z (ESI): 145.1 [M+H] + .

[0166] Step 2 9A (600 mg, 4.17 mmol) was dissolved in acetonitrile (15 mL), stirred, and concentrated sulfuric acid (5 mL) was added dropwise to the reaction at 0° C., and the reaction was warmed to room temperature and stirred for 3 hours. The reaction was added to saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide intermediate 9 (510 mg), with a yield of 86.8%.

[0167] MS m / z (ESI): 186.1 [M+H] + .

[0168] Intermediate 10 2'-Bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one [ka]

[0169] Step 1 Under nitrogen gas protection, intermediate 7 (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., stirred, and intermediate 4 (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 successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 2'-bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one intermediate 10 (480 mg), the yield was 86.4%.

[0170] MS m / z (ESI): 457.0 [M+H] + .

[0171] Reference Example 1 3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5'-methyl-2H-[1,4'-bipyridin]-2-one [ka]

[0172] Step 1 2,2,6-trimethyl-4H-1,3-dioxin-4-one 1-a (8.16 g, 57.40 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to -78°C. Lithium bistrimethylsilylamide (1M, 63 mL) was added dropwise to the reaction, and after the addition was complete, the reaction was stirred at -78°C for 1 hour. Cyclopropanecarboxylic acid chloride (3 g, 28.70 mmol, 2.60 mL) in tetrahydrofuran (10 mL) was added dropwise to the reaction, and the reaction was stirred at -78°C for 16 hours. Saturated ammonium chloride solution (30 mL) was added to the reaction under ice bath to quench the reaction, and the pH was adjusted to weak acidic with dilute hydrochloric acid, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 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 6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one 1-b (2.93 g), the yield was 48%.

[0173] MS m / z (ESI): 211.1 [M+H] + .

[0174] Step 2 6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one 1-b (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 and the reaction was stirred at 90° C. for 1 hour. Water (10 mL) was added to the reaction and the product 2'-chloro-6-cyclopropyl-4-hydroxy-5'-methyl-2H-[1,4'-bipyridine]-2-one 1-c (318 mg) was obtained by fractionation and separation using reverse phase HPLC (formic acid system), with a yield of 34.5%.

[0175] MS m / z (ESI): 277.1 [M+H] + .

[0176] Step 3 2'-Chloro-6-cyclopropyl-4-hydroxy-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-c (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) were dissolved in N,N-dimethylformamide (5 mL). The reaction was heated to 60° C. and stirred for 3 hours. Water (20 mL) was added to 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 (eluent system A) to give the product 2'-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-d (380 mg), the yield was 81%.

[0177] MS m / z (ESI): 404.1 [M+H] + .

[0178] Step 4 2'-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-d (150 mg, 0.37 mmol), tributyl(1-ethoxyvinyl)stannane (148 mg, 0.41 mmol) and bistriphenylphosphine palladium dichloride (26 mg, 0.04 mmol) were dissolved in 1,4-dioxane (3 mL) and purged with nitrogen gas for 2 minutes. The reaction was heated to 130 °C in a microwave and stirred for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (3 mL) and diluted hydrochloric acid (2 M, 1 mL) was added dropwise and reacted until the raw material was completely hydrolyzed. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to weakly alkaline, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the product 2'-acetyl-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-e (90 mg), the yield was 58.9%.

[0179] MS m / z (ESI): 412.1 [M+H] + .

[0180] Step 5 2'-Acetyl-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-e (90 mg, 0.22 mmol) and N-chlorobutanediimide (32 mg, 0.24 mmol) were dissolved in isopropanol (2 mL) and the reaction was heated to 60° C. and stirred for 3 h. The reaction was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to give the product 2'-acetyl-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-f (90 mg), 92% yield.

[0181] MS m / z (ESI): 446.1 [M+H] + .

[0182] Step 6 2'-Acetyl-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-f (90 mg, 0.2 mmol) and N,N-dimethylformamide dimethyl acetal (72 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the reaction was heated to 50 °C and stirred for 16 h. Water (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated to give the crude product (E)-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(dimethylamino)acryloyl)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-g (80 mg), which was used directly in the next step reaction without purification.

[0183] MS m / z (ESI): 501.1 [M+H] + .

[0184] Step 7 (E)-3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(dimethylamino)acryloyl)-5'-methyl-2H-[1,4'-bipyridin]-2-one 1-g (80 mg, 0.16 mmol), 2-hydroxy-2-methylpropionamidine hydrochloride (33 mg, 0.24 mmol) and potassium carbonate (44 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the reaction was heated to 75° C. and stirred for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was separated by reverse phase HPLC (formic acid system) to obtain the title product 3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5'-methyl-2H-[1,4'-bipyridin]-2-one Reference Example 1 (55 mg), the yield was 63.8%.

[0185] MS m / z (ESI): 540.1 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.96 (d,1H),8.85 (s,1H),8.75 (s,1H),8.62 (d,1H),8.24 (d,1H),8.15-8.05 (m,1H),6.47 (s,1H),5.53 (d,2H),5.24 (s,1H),2.13 (s,3H),1.53 (d,6H),1.36-1.23 (m,1H),1.02-0.93 (m,1H),0.92-0.81 (m,1H),0.75-0.63 (m,2H).

[0186] Reference Example 2 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one [ka]

[0187] Step 1 Under nitrogen gas protection, intermediate 1 (50 mg, 0.12 mmol), intermediate 5 (50.8 mg, 0.17 mmol, purity: 62%), 1,1-bis(diphenylphosphino)1,1'-bisdiphenylphosphinoferrocene palladium dichloride (8.9 mg, 0.01 mmol) and cesium carbonate (79 mg, 0.24 mmol) were dissolved in a mixture of 1,4-dioxane (1 mL) and water (0.3 mL). The reaction was heated to 100° C. and stirred for 3 h. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridin]-2-one Reference Example 2 (32 mg), the yield was 50.8%.

[0188] MS m / z (ESI): 519.1 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.70 (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).

[0189] Example 1 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one [ka]

[0190] Step 1 Lithium bistrimethylsilylamide (66.1 mL, 1M solution in tetrahydrofuran) was added dropwise to a solution of 2,2,6-trimethyl-4H-1,3-dioxo-4-one 1a (9.50 g, 66.8 mmol) in tetrahydrofuran (20 mL) with stirring at -50°C. After stirring the reaction at -50°C for 1 hour, 4-pentenoyl chloride (4.40 g, 37.11 mmol) was added dropwise to the reaction and stirring was continued for 1 hour. The reaction was quenched with formic acid, filtered, the filtrate was concentrated and the residue was separated by silica gel column chromatography (eluent system A) to give the title product 2,2-dimethyl-6-(2-oxohex-5-en-1-yl)-4H-1,3-dioxo-4-one 1b (3.60 g), yield 43.3%.

[0191] MS m / z (ESI): 225.1 [M+H] + .

[0192] Step 2 Under nitrogen gas protection, 1j (1.50 g, 5.89 mmol), tributylvinyltin (2.43 g, 7.66 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (431 mg, 0.59 mmol) were dissolved in 1,4-dioxane (15 mL) and sealed in a microwave tube, and the reaction was heated to 100° C. in a microwave and stirred for 2 h. The reaction was concentrated and the residue was separated by silica gel column chromatography (eluent system A) to give the title product 2-chloro-4-amino-5-vinylpyridine 1k (460 mg), the yield was 50.5%.

[0193] MS m / z (ESI): 155.0 [M+H] + .

[0194] Step 3 1b (6.70 g, 29.88 mmol) and 1k (3.08 g, 19.92 mmol) were dissolved in 1,4-dioxane (80 mL) and heated to 100° C. and stirred for 1.5 h. Concentrated sulfuric acid (4.88 g, 49.80 mmol) was slowly added dropwise to the reaction and the reaction was continued to stir at 100° C. for 2 h. The reaction was concentrated, methanol and water were added to the residue, filtered, and the filtrate was concentrated and separated by reverse phase HPLC preparative separation (formic acid system) to give the title product 6-(but-3-en-1-yl)-2'-chloro-4-hydroxy-5'-vinyl-2H-[1,4'-bipyridin]-2-one 1c (3.80 g), yield 63.0%.

[0195] MS m / z (ESI): 303.1 [M+H] + .

[0196] Step 4 Under nitrogen gas protection, 1c (334 mg, 1.11 mmol) and Grubbs 2nd generation catalyst (93 mg, 0.11 mmol) were dissolved in 1,2-dichloroethane (300 mL), and the reaction was heated to 60° C. and stirred for 2 h. Methanol (10 mL) was added to the reaction mixture, concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the title product (Z)-2-chloro-10-hydroxy-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one 1d (110 mg), yield 36.0%.

[0197] MS m / z (ESI): 275.0 [M+H] + .

[0198] Step 5 Under hydrogen gas atmosphere, 1d (300 mg, 0.19 mmol) and platinum dioxide (25 mg, 0.19 mmol) were dissolved in tetrahydrofuran (20 mL) and the reaction was stirred for 3 h at 25° C. The reaction was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to give the title product 2-chloro-10-hydroxy-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one 1e (200 mg), yield 66.2%.

[0199] MS m / z (ESI): 277.1 [M+H] + .

[0200] Step 6 1e (480 mg, 1.76 mmol) and N-chlorobutanediimide (347 mg, 2.61 mmol) were dissolved in isopropanol (20 mL) and the reaction was heated to 35° C. and stirred for 1 h. The reaction was concentrated and the residue was separated by silica gel column chromatography (eluent system A) to give the title product 2,11-dichloro-10-hydroxy-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1f (200 mg) in 64.3% yield.

[0201] MS m / z (ESI): 311.0 [M+H] + .

[0202] Step 7 1f (168 mg, 0.54 mmol), potassium carbonate (149 mg, 1.08 mmol) and intermediate 6 (119 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (5 mL) and the reaction was heated to 70° C. and stirred for 16 h. The reaction was concentrated and the residue was separated by reverse phase HPLC preparative separation (formic acid system) to give the title product 2,11-dichloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1g (172 mg) in 72.4% yield.

[0203] MS m / z (ESI): 40.1 [M+H] + .

[0204] Step 8 Under nitrogen gas protection, 1g (150 mg, 0.34 mmol), tributyl(1-ethoxyvinyl)stannane (185 mg, 0.51 mmol) and bis(triphenylphosphino)palladium dichloride (24 mg, 0.03 mmol) were dissolved in 1,4-dioxane (5 mL) and the reaction was heated to 123° C. in a microwave and stirred for 2 h. The reaction was quenched with dilute hydrochloric acid (0.6 M, 0.5 mL), stirred at room temperature for 30 min, concentrated, and the residue was separated by reverse phase HPLC preparative separation (formic acid system) to give the title product 2-acetyl-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one 1h (132 mg), 86.5% yield.

[0205] MS m / z (ESI): 448.1 [M+H] + .

[0206] Step 9 A solution of 1h (160 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) and 1,1-dimethoxy-N,N-dimethylmethylamine (2 mL) was heated to 70° C. and stirred for 16 hours. The reaction mixture was concentrated, and the residue was separated by reverse phase HPLC fractionation (formic acid system) to obtain the title product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(dimethylamino)acryloyl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one 1i (85 mg), yield 47.3%.

[0207] MS m / z (ESI): 503.2 [M+H] + .

[0208] Step 10 1i (85 mg, 0.17 mmol), 2-hydroxy-2-methylpropionamidine hydrochloride (70 mg, 0.51 mmol) and potassium carbonate (70 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (3 mL) and the reaction was heated to 75° C. and stirred for 16 h. The reaction was cooled to room temperature, filtered and the filtrate was subjected to reverse phase HPLC preparative separation (formic acid system) to give the title product 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1 (50 mg) in 54.6% yield.

[0209] MS m / z (ESI): 542.2 [M+H]+. 1 H NMR (400MHz,CD3OD) δ 8.90 (d,1H),8.86 (s,1H),8.54 (s,1H),8.46 (d,1H),8.29 (d,1H),7.73 (m,1H),6.84 (s,1H),2.90 (m,2H),2.26 (m,3H),2.04 (m,1H),1.62 (m,8H).

[0210] Division of Example 1 (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one [ka]

[0211] Example 1 (50 mg, 0.091 mmol) was subjected to chiral resolution (OD column) to obtain 1-1 (20 mg, RT=3.807 min) with a yield of 40.0% and 1-2 (20 mg, RT=7.060 min) with a yield of 40.0%.

[0212] Example 1-1: MS m / z (ESI): 542.2 [M+H] + , 1 H NMR (400MHz,CD3OD) δ 8.90 (d,1H),8.86 (s,1H),8.54 (s,1H),8.46 (d,1H),8.29 (d,1H),7.73 (m,1H),6.84 (s,1H),2.90 (m,2H),2.26 (m,3H),2.04 (m,1H),1.62 (m,8H). Example 1-2: MS m / z (ESI): 542.2 [M+H] + , 1 H NMR (400MHz,CD3OD) δ 8.90 (d,1H),8.86 (s,1H),8.54 (s,1H),8.46 (d,1H),8.29 (d,1H),7.73 (m,1H),6.84 (s,1H),2.90 (m,2H),2.26 (m,3H),2.04 (m,1H),1.62 (m,8H). HPLC chiral separation conditions:

[0213] [Table 1] HPLC chiral analysis conditions:

[0214] [Table 2]

[0215] Example 2 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one [ka]

[0216] Step 1 Under nitrogen gas protection, 2-bromo-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one 2a (50 mg, 0.10 mmol, see synthesis of 1g in Reference Example 1 for its synthesis method), intermediate 2 (20 mg, 0.15 mmol), cesium carbonate (50 mg, 0.15 mmol) and cuprous iodide (10 mg, 0.05 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 concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one 2 (41 mg), the yield was 75.0%.

[0217] MS m / z (ESI): 530.2 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.60 (m,2H),8.52 (d,1H),8.10 (m,1H),7.70 (s,1H),6.80 (s,1H),6.56 (d,1H),5.13 (s,1H),2.85 (m,2H),2.09 (m,3H),1.90 (m,1H),1.47 (m,8H).

[0218] Division of Example 2 (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azol-12-one [ka]

[0219] Example 2 (80 mg, 0.151 mmol) was subjected to chiral separation (IB column) to give 2-1 (35 mg, RT=3.677 min) in a yield of 43.7% and 2-2 (30 mg, RT=6.300 min) in a yield of 37.5%.

[0220] Example 2-1: MS m / z (ESI): 530.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.60 (m,2H),8.52 (d,1H),8.10 (m,1H),7.70 (s,1H),6.80 (s,1H),6.56 (d,1H),5.13 (s,1H),2.85 (m,2H),2.09 (m,3H),1.90 (m,1H),1.47 (m,8H). Example 2-2: MS m / z (ESI): 530.2 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.60 (m,2H),8.52 (d,1H),8.10 (m,1H),7.70 (s,1H),6.80 (s,1H),6.56 (d,1H),5.13 (s,1H),2.85 (m,2H),2.09 (m,3H),1.90 (m,1H),1.47 (m,8H). HPLC chiral separation conditions:

[0221] [Table 3] HPLC chiral analysis conditions:

[0222] [Table 4]

[0223] Example 3 N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0224] Step 1 Under nitrogen gas protection, 2a (100 mg, 0.206 mmol), intermediate 9 (52 mg, 0.280 mmol), cuprous iodide (19.64 mg, 0.103 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (23.48 mg, 0.165 mmol) and cesium carbonate (100.58 mg, 0.309 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction solution was heated to 100° C. and stirred for 0.5 hours. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 3 (90 mg), the yield was 74.1%.

[0225] MS m / z (ESI): 589.2 [M+H] + .

[0226] Division of Example 3 (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka] Chiral separation (OD column) was performed on Example 3 (90 mg, 0.152 mmol) to give 3-1 (20.4 mg, RT=3.403 min) in a yield of 22.35% and 3-2 (21.9 mg, RT=4.447 min) in a yield of 23.56%.

[0227] Example 3-1: MS m / z (ESI): 589.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.64 - 8.51 (m,3H),8.15 - 8.04 (m,2H),7.68 (s,1H),6.79 (s,1H),2.93 - 2. 76 (m,2H),2.15 - 1.89 (m,4H),1.79 (s,3H),1.57 (d,6H),1.53 -1.29 (m,2H). Example 3-2: MS m / z (ESI): 589.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.64 - 8.54 (m,3H),8.15 - 8.06 (m,2H),7.68 (s,1H),6.79 (s,1H),2.93 - 2. 76 (m,2H),2.16 - 1.89 (m,4H),1.79 (s,3H),1.57 (d,6H),1.50 - 1.29 (m,2H). HPLC chiral separation conditions:

[0228] [Table 5] HPLC Chiral Analysis Method:

[0229] [Table 6]

[0230] Example 4 N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide [ka]

[0231] The synthesis was carried out with reference to the synthesis method of Example 1, and the target product, N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 4 was obtained.

[0232] MS m / z (ESI): 583.2 [M+H] + ,

[0233] Division of Example 4 (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide and (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide [ka]

[0234] Example 4 (26 mg, 0.047 mmol) was subjected to chiral resolution (IB column) to give 4-1 (5 mg, RT=4.387 min) in a 19.23% yield, and 4-2 (5 mg, RT=5.183 min) in a 19.23% yield.

[0235] Example 4-1: MS m / z (ESI): 583.2 [M+H] + , Example 4-2: MS m / z (ESI): 583.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.94 - 8.83 (m,2H),8.61 (d,1H),8.24 (d,2H),8.16 (d,1H),8.10 (ddd,1H),6.81 (s,1H),2.98 (dd,1H),2.80 (dd,1H),2.21 - 2.05 (m,3H),1.95 - 1.82 (m,1H),1.77 (s,3H),1.60 (d,6H),1.48 - 1.29 (m,2H). HPLC chiral separation conditions:

[0236] [Table 7] HPLC chiral analysis conditions:

[0237] [Table 8]

[0238] Example 5 N-(2-(3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridin]-3-yl)propan-2-yl)acetamide [ka]

[0239] Step 1 Methylmagnesium bromide (3M, 2.61 mL) was added dropwise to a solution of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate 5a (300 mg, 1.96 mmol) in tetrahydrofuran (8 mL) at 0° C., and the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction was cooled to 0° C., and saturated ammonium chloride solution was added dropwise to the reaction to quench the reaction. The aqueous phase was extracted with ethyl acetate (25 mL×4), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography (elution system B) to give 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one 5b (173 mg), the yield was 57.65%.

[0240] MS m / z (ESI): 154.1 [M+H] + ,

[0241] Step 2 To a solution of 5b (150 mg, 0.98 mmol) in acetonitrile (2 mL), concentrated sulfuric acid (960 mg, 9.8 mmol) was added dropwise, and the reaction was warmed to room temperature and stirred for 3 h. Saturated sodium bicarbonate solution was added to the above reaction solution at 0° C. to adjust the pH to weakly alkaline. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to give N-(2-(2-carbonyl-1,2-dihydropyridin-3-yl)propan-2-yl)acetamide 5c (168 mg), the yield was 88.33%.

[0242] MS m / z (ESI): 195.2 [M+H] + ,

[0243] Step 3 Under nitrogen gas protection, intermediate 8 (60 mg, 0.13 mmol), 5c (33 mg, 0.17 mmol), cuprous iodide (10 mg, 0.05 mmol) and potassium carbonate (18 mg, 0.13 mmol) were dissolved in N,N-dimethylacetamide (1 mL) and the reaction was heated to 120° C. and stirred for 6 h. A saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by reverse phase HPLC to obtain N-(2-(3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridine]-3-yl)propan-2-yl)acetamide 5 (35 mg), the yield was 46.78%.

[0244] MS m / z (ESI): 572.2 [M+H] + ,

[0245] Division of Example 5 (S)-N-(2-(3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridin]-3-yl)propan-2-yl)acetamide and (R)-N-(2-(3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridin]-3-yl)propan-2-yl)acetamide [ka]

[0246] Chiral separation (IB column) of Example 5 (33 mg, 0.06 mmol) afforded the title product 5-1 (11.1 mg, RT=5.100 min) in 33.64% yield and 5-2 (11 mg, RT=6.173 min) in 33.33% yield.

[0247] Example 5-1, MS m / z (ESI): 572.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.68 (s,1H),8.60 (d,1H),8.14-8.04 (m,1H),7.88-7.80 (m,2H),7.75 (s,1H),7.39-7.30 (m,1H),6.79 (s,1H),6.36 (t,1H),2.07 (s,3H),2.00 (s,3H),1.81 (s,3H),1.61-1.58 (m,6H). Example 5-2, MS m / z (ESI): 572.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.68 (s,1H),8.60 (d,1H),8.14-8.04 (m,1H),7.88-7.80 (m,2H),7.75 (s,1H),7.39-7.30 (m,1H),6.79 (s,1H),6.36 (t,1H),2.07 (s,3H),2.00 (s,3H),1.81 (s,3H),1.61-1.58 (m,6H). HPLC chiral separation conditions:

[0248] [Table 9] HPLC Chiral Analysis Method:

[0249] [Table 10]

[0250] Example 6 N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0251] Step 1 Under nitrogen gas protection, 6a (4 g, 27.3 mmol) was dissolved in anhydrous acetonitrile (60 mL), N-iodosuccinimide (7.37 g, 32.8 mmol) and p-toluenesulfonic acid (235 mg, 1.36 mmol) were added, and the reaction was heated to 80° C. and stirred for 16 h. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed successively with saturated sodium sulfite solution (80 mL), water (80 mL), and saturated sodium chloride solution (80 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to give 2-chloro-3-fluoro-5-iodo-pyridin-4-amine 6b (6.5 g), with a yield of 87.4%.

[0252] MS m / z (ESI): 272.9 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.10 (s,1H),6.69 (s,2H).

[0253] Step 2 Under nitrogen gas protection, 6b (4 g, 14.7 mmol) was dissolved in 1,4-dioxane (60 mL) and water (12 mL), potassium vinyltrifluoroborate (2.36 g, 17.6 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (533 mg, 0.734 mmol) and sodium carbonate (3.89 g, 36.7 mmol) were added, and the reaction was heated to 80° C. and stirred for 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed successively with water (60 mL) and saturated sodium chloride solution (60 mL), dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 2-chloro-3-fluoro-5-vinyl-pyridin-4-amine 6c (2.1 g), 82.9% yield.

[0254] MS m / z (ESI): 173.0 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 7.98 (s,1H),6.82 (dd,1H),6.62 (s,2H),5.78 (dd,1H),5.33 (dd,1H).

[0255] Step 3 6c (1 g, 5.79 mmol) was dissolved in 1,4-dioxane (15 mL), 1b (1.30 g, 5.79 mmol) was added, and the reaction was heated to 100 °C and stirred for 2 h. Concentrated sulfuric acid (1.42 g, 0.772 mL) was added to the reaction, and the reaction was continued to stir at 100 °C for 0.5 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL), then washed successively with water (50 mL), saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 6-(but-3-en-1-yl)-2'-chloro-3'-fluoro-4-hydroxy-5'-vinyl-2H-[1,4'-bipyridin]-2-one 6d (1.1 g), 59.2% yield.

[0256] MS m / z (ESI): 321.0 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 11.13 (s,1H),8.80 (s,1H),6.29 - 6.22 (m,1H),6.08 - 6.00 (m,2H),5.67 - 5.58 (m,3H),4.95 - 4.89 (m,2H),2.19 - 2.16 (m,2H),2.13 - 2.09 (m,2H).

[0257] Step 4 6d (100 mg, 0.312 mmol) was dissolved in N,N-dimethylformamide (3 mL) and intermediate 6 (77 mg, 0.468 mmol), 18-crown-6 (124 mg, 0.468 mmol) and potassium carbonate (129 mg, 0.935 mmol) were added and the reaction was heated to 75° C. and stirred for 2 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL). The organic phase was washed successively with water (30 mL×2) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 6-(but-3-en-1-yl)-2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-3'-fluoro-5'-vinyl-2H-[1,4'-bipyridin]-2-one 6e (110 mg), the yield was 78.4%.

[0258] MS m / z (ESI): 450.1 [M+H] + ,

[0259] Step 5 6e (110 mg, 0.245 mmol) and Grubbs 2nd generation catalyst (21 mg, 0.0245 mmol) were dissolved in 1,2-dichloroethane (80 mL) and the reaction was heated to 40° C. under nitrogen gas protection and stirred for 1 h. The reaction was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give (Z)-2-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azidin-12-one 6f (95 mg), 92.1% yield.

[0260] MS m / z (ESI): 422.1 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.59 (d,1H),8.32 (s,1H),8.10 - 8.05 (m,1H),6.43 (d,1H),6.19 (d,1H),6.04 (d,1H),6.03 - 5.98 (m,1H),2.72 - 2.64 (m,2H),2.59 - 2.52 (m,1H),2.47 - 2.41 (m,1H).

[0261] Step 6 6f (95 mg, 0.225 mmol) and platinum dioxide (5 mg, 0.0225 mmol) were dissolved in tetrahydrofuran (3 mL), the reaction was flushed with hydrogen gas three times, and stirred under hydrogen gas at room temperature for 2 h. The reaction was filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 2-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 6g (90 mg), 94.3% yield.

[0262] MS m / z (ESI): 424.1 [M+H] + ,

[0263] Step 7 6g (90 mg, 0.212 mmol) and N-chlorobutanediimide (34 mg, 0.255 mmol) were dissolved in 1,2-dichloroethane (9 mL) and isopropanol (3 mL), and the reaction was heated to 60° C. and allowed to react for 2 hours. The reaction was cooled to room temperature, washed with water (20 mL), saturated sodium chloride solution (20 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to give 2,11-dichloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 6h (90 mg), yield 92.5%.

[0264] MS m / z (ESI): 458.0 [M+H] + , 1 H NMR (400MHz,CDCl3) δ 8.39 (d,1H),8.26 (s,1H),7.35 - 7.30 (m,1H),6.43 (s,1H),2.93 - 2.88 (m,1H),2.80 - 2.75 (m,1H),2.28 - 2.17 (m,3H),2.05 - 1.95 (m,1H),1.62 - 1.45 (m,2H).

[0265] Step 8 Under nitrogen gas protection, 6h (100 mg, 0.218 mmol), intermediate 9 (81 mg, 0.436 mmol), cesium carbonate (213 mg, 0.655 mmol), cuprous iodide (62 mg, 0.327 mmol) and trans-N,N-dimethyl-1,2-cyclohexanediamine (31 mg, 0.218 mmol) were dissolved in 1,4-dioxane (2 mL) and the reaction was heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with ethyl acetate (50 mL), washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reverse phase column chromatography (eluent system C) to give N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 6 (40 mg), 30.2% yield.

[0266] MS m / z (ESI): 607.2 [M+H] + ,

[0267] Division of Example 6 (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0268] Example 6 (40 mg, 0.066 mmol) was subjected to chiral separation (IB column) to give 6-1 (13.2 mg, RT=4.940 min) in a yield of 33.0% and 6-2 (15.8 mg, RT=7.710 min) in a yield of 21.3%.

[0269] Example 6-1: MS m / z (ESI): 607.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.60 (d,1H),8.50 (s,1H),8.45 (d,1H),8.13 - 8.07 (m,2H),6.86 (s,1H),3.03 - 2.98 (m,1H),2.86 - 2.80 (m,1H),2.18 - 1.99 (m,4H),1.79 (s,3H),1.61 - 1.50 (m,7H),1.40 - 1.34 (m,1H). Example 6-2: MS m / z (ESI): 607.2 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.60 (d,1H),8.50 (s,1H),8.45 (d,1H),8.13 - 8.07 (m,2H),6.86 (s,1H),3.03 - 2.98 (m,1H),2.86 - 2.80 (m,1H),2.18 - 1.99 (m,4H),1.79 (s,3H),1.61 - 1.50 (m,7H) ,1.40 - 1.34 (m,1H). HPLC chiral separation conditions:

[0270] [Table 11] HPLC Chiral Analysis Method:

[0271] [Table 12]

[0272] Example 7 N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide [ka]

[0273] Step 1 Under nitrogen gas protection, 6h (90 mg, 0.196 mmol) was dissolved in 1,4-dioxane (2 mL), tributyl(1-ethoxyvinyl)tin (75 mg, 0.206 mmol) and bistriphenylphosphinepalladium dichloride (14 mg, 0.019 mmol) were added, and the mixture was reacted in a microwave reactor at 125° C. for 2 hours. The reaction solution was cooled to room temperature, diluted hydrochloric acid (0.2 M, 1 mL) was added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate (50 mL), washed successively with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL), the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-acetyl-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 7a (90 mg), the yield was 98.4%.

[0274] MS m / z (ESI): 466.1 [M+H] + .

[0275] Step 2 Under nitrogen gas protection, 7a (90 mg, 0.193 mmol) was dissolved in N,N-dimethylformamide (2 mL), N,N-dimethylformamide dimethyl acetal (115 mg, 0.966 mmol) was added, and the reaction was heated to 55 °C and stirred for 6 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL), then washed with water (30 mL x 2), saturated sodium chloride solution (30 mL), dried, and concentrated to give 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(dimethylamino)acryloyl)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 7b (110 mg), which was used directly in the next step without purification.

[0276] MS m / z (ESI): 521.2 [M+H] + .

[0277] Step 3 Under nitrogen gas protection, 7b (110 mg, 0.211 mmol) was dissolved in N,N-dimethylformamide (3 mL), N-(1-amino-1-imino-2-methylpropan-2-yl)acetamide acetate (90 mg, 0.443 mmol, see Chemistry of Heterocyclic Compounds 2020, 56(10), 1329-1334 for its preparation) and potassium carbonate (146 mg, 1.06 mmol) were added, and the reaction was heated to 75 °C and stirred for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL), then washed successively with water (30 mL×2), saturated sodium chloride solution (30 mL), dried, concentrated, and the residue separated by preparative HPLC (formic acid system) to give N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 7 (35 mg), 27.6% yield.

[0278] MS m / z (ESI): 601.2 [M+H] + ,

[0279] Division of Example 7 (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide and (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide [ka]

[0280] Chiral separation (IB column) of Example 7 (35 mg, 0.058 mmol) afforded 7-1 (10.7 mg, RT=4.640 min) in a yield of 30.45% and 7-2 (10.4 mg, RT=5.473 min) in a yield of 29.54%.

[0281] Example 7-1: MS m / z (ESI): 601.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.92 (d,1H),8.77 (s,1H),8.60 (d,1H),8.22 (s,1H),8.10 (ddd,1H),7.93 (d,1H),6.86 (s,1H),3.05 (dd,1H),2.84 (dd,1H),2.16 (q,3H),2.07 - 1.94 (m,1H),1.76 (s,3H),1.59 (d,7H),1.49 - 1.35 (m,1H). Example 7-2: MS m / z (ESI): 601.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.92 (d,1H),8.77 (s,1H),8.60 (d,1H),8.22 (s,1H),8.10 (ddd,1H),7.93 (d,1H),6.86 (s,1H),3.05 (dd,1H),2.84 (dd,1H),2.16 (q,3H),2.07 - 1.94 (m,1H),1.76 (s,3H),1.59 (d,7H),1.49 - 1.35 (m,1H). HPLC chiral separation conditions:

[0282] [Table 13] HPLC Chiral Analysis Method:

[0283] [Table 14]

[0284] Example 8 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0285] By referring to the synthesis method of Example 6, the synthesis was carried out to obtain the target product 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 8 (20 mg), the yield was 32.1%.

[0286] MS m / z (ESI): 548.2 [M+H] + ,

[0287] Division of Example 8 (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0288] Example 8 (20 mg, 0.036 mmol) was subjected to chiral separation (IB column) to give 8-1 (10 mg, RT=4.923 min) in a 50.0% yield and 8-2 (3 mg, RT=9.473 min) in a 15% yield.

[0289] Example 8-1: MS m / z (ESI): 548.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.60 (d,1H),8.50 (s,1H),8.33 (d,1H),8.10 (ddd,1H),6.86 (s,1H),6.57 (d,1H),5.11 (s,1H),3.01 (dd,1H),2.83 (dd,1H),2.20 - 1.97 (m,4H),1.55 (d,1H),1.46 (d,6H),1.41 - 1.31 (m,1H). Example 8-2: MS m / z (ESI): 548.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.60 (d,1H),8.50 (s,1H),8.33 (d,1H),8.10 (ddd,1H),6.86 (s,1H),6.57 (d,1H),5.11 (s,1H),3.01 (dd,1H),2.83 (dd,1H),2.20 - 1.97 (m,4H),1.55 (d,1H),1.46 (d,6H),1.41 - 1.31 (m,1H). HPLC chiral separation conditions:

[0290] [Table 15] HPLC Chiral Analysis Method:

[0291] [Table 16]

[0292] Example 9 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0293] Step 1 Under nitrogen gas protection, 7b (100 mg, 0.192 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-hydroxy-2-methylpropionamidine hydrochloride (80 mg, 0.576 mmol) and potassium carbonate (133 mg, 0.960 mmol) were added, and the reaction was heated to 75 °C and stirred for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL), then washed successively with (30 mL x 2) and saturated sodium chloride solution (30 mL), the organic phase was dried, concentrated and the residue was purified by silica gel column chromatography (elution system B) to give 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 9 (50 mg), yield 46.5%.

[0294] MS m / z (ESI): 560.2 [M+H] + .

[0295] Resolution of Example 9 (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0296] Example 9 (50 mg, 0.089 mmol) was subjected to chiral resolution (IB column) to give 9-1 (15.4 mg, RT=4.973 min) in 30.8% yield and 9-2 (15.8 mg, RT=8.337 min) in 31.6% yield.

[0297] Example 9-1: MS m / z (ESI): 560.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 9.02 (d,1H),8.79 (s,1H),8.61 (d,1H),8.13 - 8.08 (m,1H),8.03 (d,1H),6.87 (s,1H),5.09 (s,1H),3.09 - 3.04 (m,1H),2.88 - 2.82 (m,1H),2.22 - 2.11 (m,3H),2.06 - 1.99 (m,1H),1.62 - 1.53 (m,1H),1.52 (s,6H),1.46 - 1.39 (m,1H).

[0298] Example 9-2: MS m / z (ESI): 560.2 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 9.02 (d,1H),8.79 (s,1H),8.61 (d,1H),8.13 - 8.08 (m,1H),8.03 (d,1H),6.87 (s,1H),5.09 (s,1H),3.09 - 3.04 (m,1H),2.88 - 2.82 (m,1H),2.22 - 2.13 (m,3H),2.06 - 1.99 (m,1H),1.62 - 1.53 (m,1H),1.52 (s,6H),1.46 - 1.39 (m,1H). HPLC chiral separation conditions:

[0299] [Table 17] HPLC Chiral Analysis Method:

[0300] [Table 18]

[0301] Example 10 3'',5'-Dichloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6''-methyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione [ka]

[0302] Step 1 Under nitrogen gas protection, 2',3,5'-trichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (150 mg, 0.49 mmol, see Intermediate 3 for its synthesis method), 5b (90 mg, 0.59 mmol) and cesium carbonate (400 mg, 1.23 mmol) were dissolved in dimethylsulfoxide (2 mL) and the reaction was heated to 120 °C and stirred for 16 h. The reaction solution was cooled to room temperature, formic acid was added dropwise to the reaction solution to adjust the pH to weak acidity, and the reaction solution was extracted with saturated sodium chloride solution and ethyl acetate (25 mL x 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'',5'-dichloro-4''-hydroxy-3-(2-hydroxypropan-2-yl)-6''-methyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione 10a (147 mg), the yield was 70.91%.

[0303] MS m / z (ESI): 422.1 [M+H] + ,

[0304] Step 2 10a (147 mg, 0.35 mmol), potassium carbonate (96 mg, 0.7 mmol) and 18-crown-6 (138 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the reaction was heated to 65° C. and stirred for 10 min. Intermediate 6 (75 mg, 0.45 mmol) was added dropwise to the reaction and the reaction was stirred at 65° C. for 2 h. Saturated sodium chloride solution was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (25 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 3'',5'-dichloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6''-methyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione 10 (127 mg), the yield was 66.17%.

[0305] MS m / z (ESI): 551.1 [M+H]+ ,

[0306] Resolution of Example 10 (S)-3'',5'-dichloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6''-methyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione and (R)-3'',5'-dichloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6''-methyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione [ka]

[0307] Chiral separation (IB column) of Example 10 (127 mg, 0.23 mmol) afforded the title product 10-1 (26.2 mg, RT=5.667 min) in 20.63% yield and 10-2 (22.1 mg, RT=7.113 min) in 17.40% yield.

[0308] Example 10-1, MS m / z (ESI): 551.1 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.97 (s,1H),8.60 (d,1H),8.16-8.06 (m,2H),7.92-7.86 (m,1H),7.75-7.68 (m,1H),6.83 (s,1H),6.45 (t,1H),5.21 (s,1H),2.03 (s,3H),1.47 (d,6H). Example 10-2, MS m / z (ESI): 551.1 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.97 (s,1H),8.60 (d,1H),8.16-8.06 (m,2H),7.92-7.86 (m,1H),7.75-7.68 (m,1H),6.83 (s,1H),6.45 (t,1H),5.21 (s,1H),2.03 (s,3H),1.47 (d,6H). HPLC chiral separation conditions:

[0309] [Table 19] HPLC Chiral Analysis Method:

[0310] [Table 20]

[0311] Example 11 3''-Chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione [ka]

[0312] Step 1 Under nitrogen gas protection, intermediate 8 (85 mg, 0.19 mmol), 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one 5b (37 mg, 0.24 mmol), cuprous iodide (18 mg, 0.09 mmol) and potassium carbonate (26 mg, 0.19 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL) and the reaction was heated to 120° C. and stirred for 5 h. A saturated ammonium chloride solution was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phases were combined, dried, concentrated, and the residue was separated by reverse phase HPLC to obtain 3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione 11 (23 mg), the yield was 23.38%.

[0313] MS m / z (ESI): 531.2 [M+H] + ,

[0314] Resolution of Example 11 (S)-3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione and (R)-3''-chloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione [ka]

[0315] Chiral separation (IB column) of Example 11 (23 mg, 0.04 mmol) afforded the title product 11-1 (7.4 mg, RT=4.833 min) in 32.17% yield and 11-2 (8.5 mg, RT=6.753 min) in 36.96% yield.

[0316] Example 11-1, MS m / z (ESI): 531.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ 8.68 (s,1H),8.60 (d,1H),8.14-8.05 (m,1H),7.88-7.82 (m,1H),7.78 (s,1H),7.72-7.66 (m,1H),6.80 (s,1H),6.42 (t,1H),5.23 (s,1H),2.07 (s,3H),2.00 (s,3H),1.49-1.44 (m,6H).

[0317] Example 11-2, MS m / z (ESI): 531.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ 8.68 (s,1H),8.60 (d,1H),8.14-8.05 (m,1H),7.88-7.82 (m,1H),7.78 (s,1H),7.72-7.66 (m,1H),6.80 (s,1H),6.42 (t,1H),5.23 (s,1H),2.07 (s,3H),2.00 (s,3H),1.49-1.44 (m,6H). HPLC キラル separation conditions:

[0318]

Table 21

[0319]

Table 22

[0320] Example 12 N-(2-(3'',5'-dichloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-6''-methyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridin]-3-yl)propan-2-yl)acetamide [ka]

[0321] Step 1 Under nitrogen gas protection, 2',3,5'-trichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridin]-2-one (100 mg, 0.33 mmol), 5c (83 mg, 0.43 mmol) and cesium carbonate (320 mg, 0.98 mmol) were dissolved in dimethylsulfoxide (2 mL) and the reaction was heated to 120 °C and stirred for 16 h. The reaction mixture was added with saturated sodium chloride solution, adjusted to a weakly acidic pH with formic acid, and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried, and concentrated to give crude N-(2-(3'',5'-dichloro-4''-hydroxy-6''-methyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridine]-3-yl)propan-2-yl)acetamide 12a (100 mg), which was used directly in the next step reaction without further purification. MS m / z (ESI): 463.1 [M+H] + ,

[0322] Step 2 12a (27 mg, 0.06 mmol), potassium carbonate (16 mg, 0.12 mmol) and 18-crown-6 (23 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 65° C. for 15 minutes. Intermediate 6 (14 mg, 0.09 mmol) was added to the above reaction solution and stirred at 65° C. for 1 hour. Saturated sodium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (25 mL x 2). The organic phases were combined, dried, and concentrated, and the residue was separated by reverse phase HPLC to give N-(2-(3'',5'-dichloro-4''-((3,5-difluoropyridin-2-yl)methoxy-d2)-6''-methyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridin]-3-yl)propan-2-yl)acetamide 12 (15.8 mg), yield 45.77%.

[0323] MS m / z (ESI): 592.1 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.97 (s,1H),8.60 (d,1H),8.15-8.06 (m,2H),7.92-7.82 (m,2H),7.41-7.32 (m,1H),6.83 (s,1H),6.39 (t,1H),2.02 (s,3H),1.81 (s,3H),1.60 (d,6H).

[0324] Example 13 N-(2-(3''-chloro-4''-((2,4-difluorophenyl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridin]-3-yl)propan-2-yl)acetamide [ka]

[0325] Step 1 Under nitrogen gas protection, intermediate 10 (85 mg, 0.19 mmol), N-(2-(2-carbonyl-1,2-dihydropyridin-3-yl)propan-2-yl)acetamide 5c (43 mg, 0.22 mmol), cuprous iodide (18 mg, 0.09 mmol) and potassium carbonate (26 mg, 0.19 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL) and the reaction was heated to 120° C. and stirred for 3 h. Saturated sodium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (25 mL x 2). The organic phases were combined, dried, and concentrated, and the residue was separated by reverse phase HPLC to give N-(2-(3''-chloro-4''-((2,4-difluorophenyl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridine]-3-yl)propan-2-yl)acetamide 13 (40 mg), yield 37.72%.

[0326] MS m / z (ESI): 571.2 [M+H] + ,

[0327] Resolution of Example 13 (S)-N-(2-(3''-chloro-4''-((2,4-difluorophenyl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridine]-3-yl)propan-2-yl)acetamide and (R)-N-(2-(3''-chloro-4''-((2,4-difluorophenyl)methoxy-d2)-5',6''-dimethyl-2,2''-dicarbonyl-2H,2''H-[1,2':4',1''-terpyridine]-3-yl)propan-2-yl)acetamide [ka]

[0328] Example 13 (40 mg, 0.07 mmol) was subjected to chiral resolution (AD column) to give the title product 13-1 (14.6 mg, RT=5.173 min) in 36.50% yield and 13-2 (15.6 mg, RT=8.937 min) in 39.00% yield.

[0329] Example 13-1, MS m / z (ESI): 571.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.68 (s,1H),7.88-7.80 (m,2H),7.77-7.66 (m,2H),7.42-7.31 (m,2H),7.25-7.15 (m,1H),6.82 (s,1H),6.36 (t,1H),2.07 (s,3H),2.02 (s,3H),1.81 (s,3H),1.60 (d,6H). Example 13-2, MS m / z (ESI): 571.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.68 (s,1H),7.88-7.80 (m,2H),7.77-7.66 (m,2H),7.42-7.31 (m,2H),7.25-7.15 (m,1H),6.82 (s,1H),6.36 (t,1H),2.07 (s,3H),2.02 (s,3H),1.81 (s,3H),1.60 (d,6H). HPLC chiral separation conditions:

[0330] [Table 23] HPLC Chiral Analysis Method:

[0331] [Table 24]

[0332] Example 14 3''-Chloro-4''-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione [ka]

[0333] Step 1 Under nitrogen gas protection, intermediate 10 (70 mg, 0.15 mmol), 5b (28 mg, 0.18 mmol), cuprous iodide (15 mg, 0.08 mmol) and potassium carbonate (21 mg, 0.15 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL) and the reaction was heated to 120° C. and stirred for 3 h. Saturated sodium chloride solution was added to the reaction, extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, concentrated and the residue was separated by reverse phase HPLC to give 3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione 14 (35 mg), yield 43.18%.

[0334] MS m / z (ESI): 530.2 [M+H] + ,

[0335] Resolution of Example 14 (S)-3''-chloro-4''-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione and (R)-3''-chloro-4''-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5',6''-dimethyl-2H,2''H-[1,2':4',1''-terpyridine]-2,2''-dione [ka]

[0336] Chiral separation (IB column) of Example 14 (35 mg, 0.07 mmol) afforded the title product 14-1 (12.2 mg, RT=5.990 min) in 34.86% yield and 14-2 (11.9 mg, RT=9.167 min) in 34.00% yield.

[0337] Example 14-1, MS m / z (ESI): 530.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.69 (s,1H),7.88-7.82 (m,1H),7.78 (s,1H),7.74-7.65 (m,2H),7.43-7.32 (m,1H),7.24-7.16 (m,1H),6.82 (s,1H),6.42 (t,1H),5.23 (s,1H),2.07 (s,3H),2.02 (s,3H),1.46 (d,6H). Example 14-2, MS m / z (ESI): 530.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.69 (s,1H),7.88-7.82 (m,1H),7.78 (s,1H),7.74-7.65 (m,2H),7.43-7.32 (m,1H),7.24-7.16 (m,1H),6.82 (s,1H),6.42 (t,1H),5.23 (s,1H),2.07 (s,3H),2.02 (s,3H),1.46 (d,6H). HPLC chiral separation conditions:

[0338] [Table 25] HPLC Chiral Analysis Method:

[0339] [Table 26]

[0340] Example 15 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0341] Step 1 Under nitrogen gas protection, 2a (100 mg, 0.21 mmol), 5b (41 mg, 0.27 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (31 mg, 0.22 mmol), cuprous iodide (20 mg, 0.1 mmol) and cesium carbonate (134 mg, 0.41 mmol) were dissolved in 1,4-dioxane (1.5 mL) and the reaction was heated to 100 °C and stirred for 1.5 h. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (elution system B) to obtain a white solid 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 15 (105 mg), the yield was 91.38%.

[0342] MS m / z (ESI): 557.2 [M+H] + ,

[0343] Resolution of Example 15 (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0344] Chiral separation (IB column) of Example 15 (105 mg, 0.19 mmol) afforded the title product 15-1 (36.5 mg, RT=3.977 min) in 34.76% yield and 15-2 (34.3 mg, RT=5.027 min) in 32.67% yield.

[0345] Example 15-1, MS m / z (ESI): 557.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.75 (s,1H),8.60 (d,1H),8.13-8.06 (m,1H),7.88-7.82 (m,1H),7.74-7.67 (m,2H),6.80 (s,1H),6.42 (t,1H),5.21 (s,1H),3.02-2.90 (m,1H),2.88-2.77 (m,1H),2.23-2.04 (m,3H),1.95-1.82 (m,1H),1.58 (d,1H),1.47 (s,3H),1.45 (s,3H),1.42-1.32 (m,1H). Example 15-2, MS m / z (ESI): 557.2 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.75 (s,1H),8.60 (d,1H),8.13-8.06 (m,1H),7.88-7.82 (m,1H),7.74-7.67 (m,2H),6.80 (s,1H),6.42 (t,1H),5.21 (s,1H),3.02-2.90 (m,1H),2.88-2.77 (m,1H),2.23-2.04 (m,3H),1.95-1.82 (m,1H),1.58 (d,1H),1.47 (s,3H),1.45 (s,3H),1.42-1.32 (m,1H). HPLC chiral separation conditions:

[0346] [Table 27] HPLC Chiral Analysis Method:

[0347] [Table 28]

[0348] Example 16 (Z)-11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0349] The synthesis was carried out with reference to the synthesis method of Example 1 to obtain the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 16.

[0350] MS m / z (ESI): 540.2 [M+H]+ . 1 H NMR (400MHz,DMSO-d6) δ 8.99 (d,1H),8.80 (s,1H),8.66 - 8.57 (m,2H),8.26 (d,1H),8.11 (ddd,1H),6.81 (s,1H),6.53 (dd,1H),6.03 (d,1H),5.29 (s,1H),2.76 (d,2H),2.57 (dd,1H),2.00 (q,1H),1.53 (d,6H).

[0351] Resolution of Example 16 (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0352] Chiral separation (OD column) of Example 16 (20 mg, 0.037 mmol) afforded the title product 16-1 (8 mg, RT=3.623 min) in 40% yield and 16-2 (6 mg, RT=7.39 min) in 30% yield.

[0353] Example 16-1, MS m / z (ESI): 540.2 [M+H] + , Example 16-2, MS m / z (ESI): 540.2 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.99 (d,1H),8.80 (s,1H),8.66 - 8.57 (m,2H),8.26 (d,1H),8.11 (ddd,1H),6.81 (s,1H),6.53 (dd,1H),6.03 (d,1H),5.29 (s,1H),2.76 (d,2H),2.57 (dd,1H),2.00 (q,1H),1.53 (d,6H). HPLC chiral separation conditions:

[0354] [Table 29] HPLC Chiral Analysis Method:

[0355] [Table 30]

[0356] Example 17 (Z)-11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0357] The synthesis was carried out with reference to the synthesis method of Example 2 to obtain the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 17.

[0358] MS m / z (ESI): 528.2 [M+H] + .

[0359] Resolution of Example 17 (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0360] Chiral separation (OD column) of Example 17 (80 mg, 0.152 mmol) afforded the title product 17-1 (36 mg, RT=3.553 min) in 45% yield and 17-2 (38 mg, RT=5.693 min) in 47.5% yield.

[0361] Example 17-1, MS m / z (ESI): 528.2 [M+H] + , Example 17-2, MS m / z (ESI): 528.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.60 (d,1H),8.53 (d,1H),8.49 (s,1H),8.10 (td,1H),7.72 (s,1H),6.79 (s,1H),6.57 (d,1H),6.47 - 6.39 (m,1H),5.99 - 5.88 (m,1H),5.14 (s,1H),2.80 - 2.67 (m,2H),2.67 - 2.52 (m,2H),1.47 (d,6H). HPLC chiral separation conditions:

[0362] [Table 31] HPLC Chiral Analysis Method:

[0363] [Table 32]

[0364] Example 18 (Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0365] The synthesis was carried out with reference to the synthesis method of Example 3 to obtain the target product (Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 18.

[0366] MS m / z (ESI): 587.2 [M+H] + .

[0367] Resolution of Example 18 (S,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0368] Chiral separation (OD column) of Example 18 (86 mg, 0.147 mmol) afforded the title product 18-1 (32 mg, RT=3.280 min) in 37.2% yield and 18-2 (32 mg, RT=4.387 min) in 37.2% yield.

[0369] Example 18-1, MS m / z (ESI): 587.2 [M+H] + , Example 18-2, MS m / z (ESI): 587.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.59 (dd,2H),8.48 (s,1H),8.18 - 8.02 (m,2H),7.71 (s,1H),6.78 (s,1H),6.44 (d,1H),5.99 - 5.91 (m,1H),2.78 - 2.65 (m,2H),2.57 (dd,2H),1.79 (s,3H),1.58 (d,6H). HPLC chiral separation conditions:

[0370] [Table 33] HPLC Chiral Analysis Method:

[0371] [Table 34]

[0372] Example 19 (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0373] The synthesis was carried out with reference to the synthesis method of Example 15 to obtain the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 19.

[0374] MS m / z (ESI): 555.2 [M+H] + .

[0375] Resolution of Example 19 (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0376] Chiral separation (IB column) of Example 19 (76 mg, 0.137 mmol) afforded the title product 19-1 (33 mg, RT=5.147 min) in 43.4% yield and 19-2 (27 mg, RT=7.360 min) in 35.5% yield.

[0377] Example 19-1, MS m / z (ESI): 555.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.64 (s,1H),8.60 (d,1H),8.09 (td,1H),7.87 (dd,1H),7.78 (s,1H),7.70 (dd,1H),6.80 (s,1H),6.53 - 6.38 (m,2H),6.06 - 5.94 (m,1H),5.20 (s,1H),2.78 (d,2H),2.59 - 2.51 (m,2H),1.46 (d,6H). Example 19-2, MS m / z (ESI): 555.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.64 (s,1H),8.60 (d,1H),8.09 (td,1H),7.87 (dd,1H),7.78 (s,1H),7.70 (dd,1H),6.80 (s,1H),6.53 - 6.38 (m,2H),6.06 - 5.94 (m,1H),5.20 (s,1H),2.78 (d,2H),2.59 - 2.51 (m,2H),1.46 (d,6H). HPLC chiral separation conditions:

[0378] [Table 35] HPLC Chiral Analysis Method:

[0379] [Table 36]

[0380] Example 56 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0381] Step 1 56a (150 mg, 0.298 mmol, see the synthesis of 6h in Example 6 for its preparation) was dissolved in dimethylsulfoxide (1.5 mL) and 5b (137 mg, 0.895 mmol), cesium carbonate (292 mg, 0.895 mmol), ethyl 2-cyclohexanecarboxylate (51 mg, 0.298 mmol) and cuprous bromide (64 mg, 0.447 mmol) were added and the reaction was heated to 80° C. under nitrogen gas protection and stirred for 16 h. The reaction was cooled to room temperature, filtered, the filtrate was diluted with ethyl acetate (30 mL) and washed successively with water (30 mL), saturated sodium chloride solution (30 mL), dried, concentrated and the residue was purified by reverse phase column chromatography (eluent system C) to give 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 56 (30 mg), 17.5% yield.

[0382] MS m / z (ESI): 575.1 [M+H] + ,

[0383] Resolution of Example 56 (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0384] Example 56 (30 mg, 0.066 mmol) was subjected to chiral separation (OD column) to give 56-1 (13.5 mg, RT=3.543 min) in a 45.0% yield and 56-2 (13.2 mg, RT=5.707 min) in a 44.0% yield.

[0385] Example 56-1: MS m / z (ESI): 575.1 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.63 (d,1H),8.59 (d,1H),8.12 - 8.06 (m,1H),7.73 (d,1H),7.69 - 7.65 (m,1H),6.87 (s,1H),6.48 - 6.40 (m,1H),5.18 (s,1H),3.09 - 3.03 (m,1H),2.94 - 2.83 (m,1H),2.22 - 2.03 (m,4H),1.61 - 1.54 (m,1H),1.46 - 1.34 (m,7H). Example 56-2: MS m / z (ESI): 575.1 [M+H] + , 1H NMR (400MHz,DMSO-d6) δ 8.63 (d,1H),8.59 (d,1H),8.12 - 8.06 (m,1H),7.73 (d,1H),7.69 - 7.65 (m,1H),6.87 (s,1H),6.48 - 6.40 (m,1H),5.18 (s,1H),3.09 - 3.03 (m,1H),2.94 - 2.83 (m,1H),2.22 - 2.03 (m,4H),1.61 - 1.54 (m,1H),1.46 - 1.34 (m,7H). HPLC chiral separation conditions:

[0386] [Table 37] HPLC Chiral Analysis Method:

[0387] [Table 38]

[0388] Example 59 (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0389] The synthesis was carried out with reference to the synthesis method of Example 9 to obtain the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 59.

[0390] MS m / z (ESI): 558.1 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 9.02 (d,1H),8.68 (s,1H),8.60 (d,1H),8.09 (ddd,1H),8.03 (d,1H),6.87 (s,1H),6.56 (d,1H),6.09 (ddd,1H),5.07 (s,1H),2.80 (d,2H),2.72 - 2.52 (m,2H),1.59 - 1.44 (m,6H).

[0391] Example 60 (Z)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide [ka]

[0392] The synthesis was carried out with reference to the synthesis method of Example 7, to obtain the target product (Z)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azidin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 60.

[0393] MS m / z (ESI): 599.2 [M+H] + . 1 H NMR (400MHz,DMSO-d6) δ 8.93 (d,1H),8.66 (s,1H),8.60 (d,1H),8.21 (s,1H),8.09 (ddd,1H),7.93 (d,1H),6.86 (s,1H),6.58 - 6.51 (m,1H),6.14 - 6.02 (m,1H),2.87 - 2.58 (m,4H),1.76 (s,3H),1.59 (s,6H).

[0394] Example 61 (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one [ka]

[0395] The synthesis was carried out with reference to the synthesis method of Example 6 to obtain the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azidin-12-one 61.

[0396] MS m / z (ESI): 546.2 [M+H] + , 1 H NMR (400MHz,DMSO-d6) δ 8.60 (d,1H),8.40 (s,1H),8.35 (d,1H),8.14-8.06 (m,1H),6.86 (s,1H),6.59 (d,1H),6.50 (d,1H),6.08-5.95 (m,1H),5.14 (s,1H),2.84-2.68 (m,3H),2.57-2.52 (m,1H),1.46 (d,6H).

[0397] Example 62 (Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide [ka]

[0398] The synthesis was carried out with reference to the synthesis method of Example 6, to obtain the target product (Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azidin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 62.

[0399] MS m / z (ESI): 605.2 [M+H] + , 1 H NMR (400MHz,CDCl3) δ 8.39 (d,1H),8.24 (s,1H),8.18 (d,1H),7.37-7.29 (m,1H),6.57 (s,1H),6.46-6.36 (m,2H),6.00-5.89 (m,1H),2.89-2.78 (m,1H),2.76-2.67 (m,2H),2.57-2.42 (m,1H),2.00 (s,3H),1.79 (s,6H).

[0400] [Table 39-1] [Table 39-2] [Table 39-3] [Table 39-4] [Table 39-5] [Table 39-6] [Table 39-7]

Table 39-8

Table 39-9

Table 39-10

Table 39-11

Table 39-12

Table 39-13

Table 39-14

Table 39-15

Table 39-16

Table 39-17

Table 39-18

Table 39-19

Table 39-20

Table 39-21

Table 39-22

Table 39-23

Table 39-24

[0401] Test evaluation of the embodiment The present invention will be further described below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0402] Test Example 1: Measurement of p38α / MK2 enzyme activity inhibitory effect of the compound of the present invention 1. Experimental Objective: The objective of this experiment was to determine the ability of compounds to inhibit p38α / MK2 enzyme activity.

[0403] 2. Laboratory equipment and reagents: 2.1 Equipment:

[0404] [Table 40] 2.2 Reagents:

[0405] [Table 41]

[0406] 3. Experimental Method: Experimental method for p38 / MK2 enzyme activity: 0.06 nM p38α (Active p38 alpha Protein), 1.2 nM MK2 (Inactive MK2) and compounds diluted in a concentration gradient were incubated for 1 hour in 1× enzyme reaction buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20). 50 nM ULight-CREBtide and 25 μM ATP (ATP Solution) were added and reacted at room temperature for 1.5 hours. An equal volume of detection and stop mixture (1× LANCE detection buffer containing 20 mM EDTA and 2 nM Europium-anti-phospho-CREB) was added, mixed uniformly, centrifuged, a sealing film was attached, and reacted at room temperature for 1 hour. The plate was read using the TR-FRET program of the EnVision instrument, and the fluorescence value of each well at 665 nm / 615 nm was detected.

[0407] Experimental method for p38 enzyme activity: 3 nM p38α (Active p38 alpha Protein) and gradient diluted compounds were incubated for 1 hour in 1× enzyme reaction buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20). 50 nM ULight-MBP and 50 μM ATP (ATP 10 mM Solution) were added and reacted at room temperature for 1.5 hours. An equal volume of detection and stop mixture (1× LANCE detection buffer containing 20 mM EDTA and 2 nM Europium-anti-P-MBP) was added, mixed uniformly, centrifuged, and a sealing film was attached, and reacted at room temperature for 1 hour. The plate was read using the TR-FRET program of the EnVision instrument, and the fluorescence value of each well at 665 nm / 615 nm was detected.

[0408] 4. How to process the experimental data: The raw data (ratio of 665 nm / 615 nm readings) was calculated to obtain the inhibition percentage using the following formula: Inhibition percentage %=[(mean value of positive control wells-value of sample wells) / (mean value of positive control wells-mean value of negative control wells)]×100, where positive control wells are enzyme reaction wells without compound, and negative control wells are reaction wells without enzyme addition.

[0409] A fitting equation analysis was performed for compound concentrations and corresponding inhibition rates using log(inhibitor) vs. response -- Variable slope (four parameters) in GraphPad Prism 6, and the compound IC was calculated by fitting the curves. 50 Got the value.

[0410] The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope) 5. Experimental Results:

[0411] [Table 42]

[0412] 6. Test conclusion: The above data demonstrate that the compounds of the examples of the present invention have relatively strong inhibitory activity against p38α / MK2 enzyme and also have extremely good selectivity.

[0413] Test Example 2: Measurement of p-Hsp27 inhibitory effect of the compounds of the present invention on U937 cells 1. Experimental Objective: The objective of this experiment is to determine the ability of the compounds of the present invention to inhibit U937 cell p-Hsp27.

[0414] 2. Laboratory equipment and reagents: 2.1 Equipment:

[0415] [Table 43] 2.2 Reagents:

[0416] [Table 44]

[0417] 3. Experimental Method: U937 was treated with 20ng / ml PMA, differentiated overnight, replaced with fresh culture medium, and U937 was left overnight. The number of U937 digests after differentiation was counted, and 25,000 cells per well were seeded into a 96-well plate until cell attachment. A concentration gradient of the compound was set up, and the cells were pretreated with the compound for 1 hour (the highest concentration of the final compound was 1μM, and it was diluted in a 3-fold concentration gradient), and 10ng / ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added and stimulated for 0.5 hours. After washing the cells with PBS, the cells were lysed with the lysis solution. The Phospho-HSP27 (S78 / S82) DuoSet IC ELISA kit was used to detect p-Hsp27 in the cell lysate, and the specific steps referred to the standard steps provided by the kit manufacturer.

[0418] 4. How to process the experimental data: Calculation of p-Hsp27 inhibition rate: Percent inhibition rate = [(mean p-Hsp27 value of positive control wells - mean p-Hsp27 value of sample wells) / (mean p-Hsp27 value of positive control wells - mean p-Hsp27 value of negative control wells)] x 100%, where positive control wells are wells without compound (DMSO-treated wells) and negative control wells are wells without LPS stimulation.

[0419] Dose-response curve fitting: A fitting equation analysis was performed for compound concentrations and corresponding inhibition rates using log(inhibitor) vs. response -- Variable slope (four parameters) in GraphPad Prism 6, and the curves were fitted to obtain compound IC 50 Got the value.

[0420] The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope) 5. Experimental Results:

[0421] [Table 45]

[0422] 6. Test conclusion: The above data demonstrate that the compounds of the examples of the present invention have relatively strong inhibitory activity against p-Hsp27 in U937 cells.

[0423] Test Example 3: Measurement of the inhibitory effect of the compounds of the present invention on the TNF-α expression level in U937 cells 1. Experimental Objective: The objective of this experiment is to determine the ability of the compounds of the present invention to inhibit the expression level of TNF-α in U937 cells.

[0424] 2. Laboratory equipment and reagents: 2.1 Equipment:

[0425] [Table 46] 2.2 Reagents:

[0426] [Table 47]

[0427] 3. Experimental Method: U937 was treated with 20ng / ml PMA, differentiated overnight, replaced with fresh culture medium, and U937 was left overnight. The number of U937 digests after differentiation was counted, and 50,000 cells per well were seeded into a 96-well plate until cell attachment. A concentration gradient of the compound was set up, and the cells were pretreated with the compound for 1 hour (the highest concentration of the final compound was 1μM, diluted with a 3-fold concentration gradient), and 10ng / ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added and stimulated for 4 hours, after which centrifugation was performed, and the culture supernatant was collected and used for subsequent detection of TNF-α concentration in the supernatant by ELISA. Detection of TNF-α concentration was performed according to the standard steps provided by the ELISA kit manufacturer.

[0428] 4. How to process the experimental data: A calibration curve was drawn using the linear regression method for the TNF-α standard, and the sample TNF-α concentrations were converted according to the calibration curve.

[0429] Calculation of inhibition rate: Percent inhibition rate = [(mean TNF-α concentration of positive control wells - mean TNF-α concentration of sample wells) / (mean TNF-α concentration of positive control wells - mean TNF-α concentration of negative control wells)] x 100%, where positive control wells are wells without compound (DMSO-treated wells) and negative control wells are medium wells.

[0430] Dose-response curve fitting: A fitting equation analysis was performed for compound concentrations and corresponding inhibition rates using log(inhibitor) vs. response -- Variable slope (four parameters) in GraphPad Prism 6, and the curves were fitted to obtain compound IC 50 The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope). 5. Experimental Results:

[0431] [Table 48]

[0432] 6. Test conclusion: The above data demonstrate that the compounds of the examples of the present invention have relatively strong inhibitory activity against the expression level of TNF-α in U937 cells.

[0433] Test Example 4: Pharmacokinetics measurement in SD rats 1. Purpose of the experiment: Using SD rats as test animals, the pharmacokinetic behavior of the compound of the present invention in the rat body (plasma) was investigated when it was orally administered at a dose of 5 mg / kg or 2 mg / kg and when it was intravenously administered at a dose of 1 mg / kg.

[0434] 2. Experimental plan: 2.1 Test Drugs: Compounds of the invention made in-house.

[0435] 2.2 Test animals: [Table 49]

[0436] 2.3 Drug Combinations: PO and 10% solutol HS15 were dissolved by ultrasonication and formulated as a clear liquid or a uniform suspension.

[0437] IV, 5% DMSO + 10% Solutol HS15 + 85% PBS was dissolved by ultrasonication and formulated as a clear solution.

[0438] 2.4 Administration method: SD rats, 3 males per group, were fasted overnight and administered po at a dose of 5 mg / kg or 2 mg / kg in a volume of 10 mL / kg, or iv at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0439] 2.5 Sampling: 0.2 mL of blood was collected from the jugular vein of rats at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration, and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration, placed in EDTA-K2 test tubes, centrifuged at 6000 rpm at 4°C for 6 minutes to separate plasma, and stored at -80°C.

[0440] 2.6 Sample Processing: 1) 20 uL of plasma sample was added to 100 uL of acetonitrile to precipitate, mixed, and then centrifuged at 3500 x g for 5 to 20 minutes.

[0441] 2) The treated supernatant solution was taken and analyzed for the concentration of the test compound by LC / MS / MS, and the LC / MS / MS analysis equipment was AB Sciex API 4000 Qtrap.

[0442] 2.7 Liquid phase analysis: ● Liquid phase conditions: Shimadzu LC-20AD pump Chromatography column: Waters Xbridge C18 5μm, 4.6 x 50mm Mobile phase: Liquid A was 0.1% formic acid in water, and liquid B was methanol. ● Flow rate: 1.0mL / min

[0443] ● Elution time: 0 to 4.0 minutes, elution solution is as follows.

[0444] [Table 50]

[0445] 3. Test results and data processing: The main pharmacokinetic parameters were calculated with WinNonlin 6.1.

[0446] [Table 51]

[0447] 4. Experimental Conclusion The pharmacokinetic measurement results in SD rats showed that the compounds of the present invention exhibited relatively good PK properties.

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Ring A is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L １ represents a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH ２ ) ｎ -, -(CH ２ ) ｎ C(O)(CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ C(O)NR ｃｃ (CH ２ ) ｎ１ -, -(CH ２ ) ｎ (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ O (CH ２ ) ｎ１ -, -(CH ２ ) ｎ O (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ S (CH ２ ) ｎ１ -, -(CH ２ ) ｎ S (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ (CH ２ ) ｎ１ N.R. ｃｃ -, -(CH ２ ) ｎ N.R. ｃｃ (CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ N.R. ｃｃ C(O)-,-(CH ２ ) ｎ P(O) ｐ R ａａ -, -(CH ２ ) ｎ S (O) ｍ -, -(CH ２ ) ｎ S (O) ｍ N.R. ｃｃ - and - (CH ２ ) ｎ N.R. ｃｃ S (O) ｍ - selected from R ａａ , R ｂｂ and R ｃｃ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; Or, R ａａ , R ｂｂ and R ｃｃ any two of may be joined to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, which cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be further substituted; L ２ and L ３ each independently represents a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH ２ ) ｎ２ -, -(CH ２ ) ｎ２ C(O)(CR ａ１ R ｂ１ ) ｎ３ -, -(CH ２ ) ｎ２ C(O)NR ｃ１ (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ O (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ O (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ S (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ S (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ (CH ２ ) ｎ３ N.R. ｃ１ -, -(CH ２ ) ｎ２ N.R. ｃ１ (CR ａ１ R ｂ１ ) ｎ３ -, -(CH ２ ) ｎ２ N.R. ｃ１ C(O)-,-(CH ２ ) ｎ２ P(O) ｐ１ R ａ１ -, -(CH ２ ) ｎ２ S (O) ｍ１ -, -(CH ２ ) ｎ２ S (O) ｍ１ N.R. ｃ１ - and - (CH ２ ) ｎ２ N.R. ｃ１ S (O) ｍ１ - selected from R ａ１ , R ｂ１ and R ｃ１ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may optionally be further substituted; R ａ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, R ｂ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, R ｃ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, R ｂ and R ｃ are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R ｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, an alkyl group, a bridged cycloalkyl group, a deuterated alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a deuterated alkoxy group, a halogenated alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, or -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ C(O)NR ｈｈ R ｇｇ Or - (CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ N.R. ｈｈ R ｇｇ wherein the amino, alkyl, bridged cycloalkyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－８ Alkyl group, C １－８ Deuterated alkyl groups, C １－８ Halogenated alkyl group, C １－８ Hydroxyalkyl group, C １－８ Alkoxy group, C １－８ Deuterated alkoxy group, C １－８ Halogenated alkoxy group, C ２－８ Alkenyl group, C ２－８ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Preferably, R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group; Or, R ｅｅ , R ｆｆ are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; n4 is 0, 1, 2, 3 or 4; Preferably, R ｄ are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, halogenated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may optionally be further substituted, Or, any two adjacent or non-adjacent R ｄ are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or, L ３ and R ｄ are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Or, R ｃ and R ｄ are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally 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; e is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; m1 is 0, 1, 2 or 3; A compound, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, wherein p1 is 0, 1, 2 or 3.

2. The compound is further represented by the general formula (I'-1): 【Chemistry 2】 Where: Ring D is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; Ring E is selected from heterocyclyl groups; Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; X ３ is N or CR ｂ１ is selected from L １ represents a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH ２ ) ｎ -, -(CH ２ ) ｎ C(O)(CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ C(O)NR ｃｃ (CH ２ ) ｎ１ -, -(CH ２ ) ｎ (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ O (CH ２ ) ｎ１ -, -(CH ２ ) ｎ O (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ S (CH ２ ) ｎ１ -, -(CH ２ ) ｎ S (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ (CH ２ ) ｎ１ N.R. ｃｃ -, -(CH ２ ) ｎ N.R. ｃｃ (CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ N.R. ｃｃ C(O)-,-(CH ２ ) ｎ P(O) ｐ R ａａ -, -(CH ２ ) ｎ S (O) ｍ -, -(CH ２ ) ｎ S (O) ｍ N.R. ｃｃ - and - (CH ２ ) ｎ N.R. ｃｃ S (O) ｍ - selected from R ａａ , R ｂｂ and R ｃｃ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; L ３ represents a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH ２ ) ｎ２ -, -(CH ２ ) ｎ２ C(O)(CR ａ１ R ｂ１ ) ｎ３ -, -(CH ２ ) ｎ２ C(O)NR ｃ１ (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ O (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ O (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ S (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ S (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ (CH ２ ) ｎ３ N.R. ｃ１ -, -(CH ２ ) ｎ２ N.R. ｃ１ (CR ａ１ R ｂ１ ) ｎ３ -, -(CH ２ ) ｎ２ N.R. ｃ１ C(O)-,-(CH ２ ) ｎ２ P(O) ｐ１ R ａ１ -, -(CH ２ ) ｎ２ S (O) ｍ１ -, -(CH ２ ) ｎ２ S (O) ｍ１ N.R. ｃ１ - and - (CH ２ ) ｎ２ N.R. ｃ１ S (O) ｍ１ - selected from R ａ１ , R ｂ１ and R ｃ１ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ａ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ａ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, L １ and R ａ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｂ１ Or R ｂ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｃ２ Or R ｃ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ Aryl groups, 5- to 14-membered heteroaryl groups, -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ OR ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S.R. 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 N.R. ｈｈ R ｇｇ wherein the amino group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl group or the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Or, R ｅｅ , R ｆｆ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; x is an integer from 0 to 6; e is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; n4 is 0, 1, 2, 3 or 4; n6 is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; m1 is 0, 1, 2 or 3; The compound according to claim 1, its stereoisomer or its pharma- ceutically acceptable salt, characterized in that p1 is 0, 1, 2 or 3.

3. Ring D is C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, preferably ring D is ６－１０ aryl group, a 5- to 6-membered monocyclic heteroaryl group, or a 7- to 10-membered bicyclic heteroaryl group, more preferably ring D is a pyrazolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, a pyrimidinyl group, a pyridyl group, a phenyl group, 【Chemistry 3】 3. The compound according to claim 2, its stereoisomer or a pharma- ceutically acceptable salt thereof, selected from:

4. Ring E is selected from 6- to 12-membered heterocyclyl groups, preferably Ring E is 【Chemistry 4】 The compound according to claim 2 or 3, its stereoisomer or a pharma- ceutically acceptable salt thereof, which is selected from the group consisting of:

5. The compound is further represented by general formula (XIV): 【Chemistry 5】 Where: M １ is selected from C, CH, N or absent; M ２ is selected from C, CH, N or absent; M ３ is selected from C, CH, N or absent; X ３ is N or CR ｂ１ is selected from Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L １ represents a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH ２ ) ｎ -, -(CH ２ ) ｎ C(O)(CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ C(O)NR ｃｃ (CH ２ ) ｎ１ -, -(CH ２ ) ｎ (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ O (CH ２ ) ｎ１ -, -(CH ２ ) ｎ O (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ S (CH ２ ) ｎ１ -, -(CH ２ ) ｎ S (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ (CH ２ ) ｎ１ N.R. ｃｃ -, -(CH ２ ) ｎ N.R. ｃｃ (CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ N.R. ｃｃ C(O)-,-(CH ２ ) ｎ P(O) ｐ R ａａ -, -(CH ２ ) ｎ S (O) ｍ -, -(CH ２ ) ｎ S (O) ｍ N.R. ｃｃ - and - (CH ２ ) ｎ N.R. ｃｃ S (O) ｍ - selected from R ａａ , R ｂｂ and R ｃｃ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; L ３ represents a bond, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, -(CH ２ ) ｎ２ -, -(CH ２ ) ｎ２ C(O)(CR ａ１ R ｂ１ ) ｎ３ -, -(CH ２ ) ｎ２ C(O)NR ｃ１ (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ O (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ O (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ S (CH ２ ) ｎ３ -, -(CH ２ ) ｎ２ S (CR ａ１ R ｂ１ ) ｎ３ -, - (CR ａ１ R ｂ１ ) ｎ２ (CH ２ ) ｎ３ N.R. ｃ１ -, -(CH ２ ) ｎ２ N.R. ｃ１ (CR ａ１ R ｂ１ ) ｎ３ -, -(CH ２ ) ｎ２ N.R. ｃ１ C(O)-,-(CH ２ ) ｎ２ P(O) ｐ１ R ａ１ -, -(CH ２ ) ｎ２ S (O) ｍ１ -, -(CH ２ ) ｎ２ S (O) ｍ１ N.R. ｃ１ - and - (CH ２ ) ｎ２ N.R. ｃ１ S (O) ｍ１ - selected from R ａ１ , R ｂ１ and R ｃ１ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ａ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ａ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, L １ and R ａ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｂ１ Or R ｂ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｃ２ Or R ｃ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ Aryl groups, 5- to 14-membered heteroaryl groups, -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ OR ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S.R. 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 N.R. ｈｈ R ｇｇ wherein the amino group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl group or the 5- to 14-membered heteroaryl group may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Or, R ｅｅ , R ｆｆ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; x is an integer from 0 to 6; e is an integer from 0 to 6; n is 0, 1, 2 or 3; n1 is 0, 1, 2 or 3; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; n4 is 0, 1, 2, 3 or 4; n6 is 0, 1, 2, 3 or 4; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; m1 is 0, 1, 2 or 3; The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 4, wherein p1 is 0, 1, 2 or 3.

6. Ring A is C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Preferably, Ring A is selected from a 6- to 12-membered bicyclic heterocyclyl group, a 5- to 6-membered monocyclic heteroaryl group, or a 7- to 10-membered bicyclic heteroaryl group; More preferably, ring A is selected from a pyrazolyl group, a thienyl group, a thiazolyl group, an oxazolyl group, a pyrimidinyl group, a pyridyl group, a phenyl group, a tetrahydroquinolinyl group, a benzocyclopentyl group, a pyrrolopyrimidinyl group, a pyrrolopyridyl group, a pyrazolopyridine or an imidazopyridine, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof according to claim 1.

7. Ring B is C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Preferably, Ring B is selected from a 3- to 7-membered monocyclic heterocyclyl group, a 6- to 12-membered bicyclic heterocyclyl group, a 5-membered monocyclic heteroaryl group, a 6-membered monocyclic heteroaryl group or a 7- to 14-membered heteroaryl ring; More preferably, Ring B is selected from a 5-membered monocyclic nitrogen-containing heteroaryl group, a 6-membered monocyclic nitrogen-containing heteroaryl group, a 5- to 6-membered heteroaryl-fused 5- to 6-membered cycloalkyl group, a 5- to 6-membered heteroaryl-fused 5- to 6-membered heteroaryl group, or a 5- to 6-membered heteroarylphenyl group; More preferably, ring B is pyrimidine, a pyridocyclohexyl group, a pyridocyclopentyl group, a pyrrolotriazinyl group, a pyrrolopyrimidinyl group, a pyridocyclopentenyl group, pyridine, thiazole, pyrazole, pyridopyrrolidone, pyridofuranone, pyridosulfolane, 【Chemistry 6】 is selected from The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 6, characterized in that ring B is selected from pyrimidine, a pyridocyclohexyl group, a pyridocyclopentyl group, a pyrrolotriazinyl group, a pyrrolopyrimidinyl group, a pyridocyclopentenyl group, pyridine, thiazole, pyrazole, pyridopyrrolidone, pyridofuranone or pyridosulfolane.

8. The compound is further represented by the general formula (XV): 【Chemistry 7】 Where: X １ is N or CR ａ５ is selected from X ３ is N or CR ｂ１ is selected from R ａ１ , R ａ２ , R ａ３ , R ａ４ Or R ａ５ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ａａ Or R ｂｂ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ａａ and R ｂｂ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｂ１ , R ｂ２ Or R ｂ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ｂ１ and R ｂ２ The substituent is bonded to C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｃ１ , R ｃ２ Or R ｃ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ｃ１ and R ｃ２ The substituent is bonded to C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ｃ１ and R ｂ２ The substituents are linked to form a 3- to 12-membered heterocyclyl group or a 5- to 14-membered heteroaryl group, and the 3- to 12-membered heterocyclyl group and the 5- to 14-membered heteroaryl group are optionally selected from the group consisting of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R １ is hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ Aryl groups, 5- to 14-membered heteroaryl groups, -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ OR ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S.R. 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 N.R. ｈｈ R ｇｇ wherein the amino group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Or, R ｅｅ , R ｆｆ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ２ , R ３ Or R ４ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R １ , R ２ , R ３ and R ４ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; n4 is 0, 1, 2, 3 or 4; and The above 【Chemistry 8】 teeth, 【Chemistry 9】 2. The compound according to claim 1, its stereoisomer or a pharma- ceutically acceptable salt thereof, which is not:

9. The compound may further be represented by the general formula (XIV-A), (XIV-B) or (XIV-C): 【Chemistry 10】 As shown in Where: X １ is N or CR ａ５ is selected from X ２ is N or CR ２ is selected from X ３ is N or CR ｂ１ is selected from R ａ１ , R ａ２ , R ａ３ , R ａ４ Or R ａ５ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ａａ Or R ｂｂ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ａａ and R ｂｂ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｂ１ Or R ｂ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｃ２ Or R ｃ３ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｄａ , R ｄｂ or R' ｄａ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ｄａ and R ｄｂ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｄｃ Or R ｄｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, R ｄｃ and R ｄｄ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R １ is hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ Aryl groups, 5- to 14-membered heteroaryl groups, -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ OR ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S.R. 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 N.R. ｈｈ R ｇｇ wherein the amino group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Or, R ｅｅ , R ｆｆ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ２ , R ３ Or R ４ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R １ , R ２ , R ３ and R ４ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ７ is hydrogen, deuterium, halogen, nitro group, hydroxyl group, mercapto group, cyano group, amino group, oxo group, thio group, carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ Aryl groups, 5- to 14-membered heteroaryl groups, -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ OR ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S.R. 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 N.R. ｈｈ R ｇｇ wherein the amino group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Bridged Cycloalkyl Groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Or, R ｅｅ , R ｆｆ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ６ Or R ８ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Or, any two adjacent or non-adjacent R ６ , R ７ and R ８ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; n4 is 0, 1, 2, 3 or 4; n5 is 0, 1 or 2; n5′ is 0, 1 or 2; n5 and n5' are not 0 at the same time, The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 8, wherein n6 is 0, 1, 2, 3 or 4.

10. The compound may further be represented by the general formula (I'-1-1), (I'-1-2), (XIV-1), (XIV-2), (XIV-A-1), (XIV-A-2), (XIV-B-1), (XIV-B-2), (XIV-C-1), (XIV-C-2), (XV-1) or (XV-2): 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 The compound according to any one of claims 1 to 9, its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein the compound is as shown in

11. L １ represents a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH ２ ) ｎ -, -(CH ２ ) ｎ C(O)(CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ C(O)NR ｃｃ (CH ２ ) ｎ１ -, -(CH ２ ) ｎ (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ O (CH ２ ) ｎ１ -, -(CH ２ ) ｎ O (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ S (CH ２ ) ｎ１ -, -(CH ２ ) ｎ S (CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ (CH ２ ) ｎ１ N.R. ｃｃ -, -(CH ２ ) ｎ N.R. ｃｃ (CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ N.R. ｃｃ C(O)-,-(CH ２ ) ｎ P(O) ｐ R ａａ -, -(CH ２ ) ｎ S (O) ｍ -, -(CH ２ ) ｎ S (O) ｍ N.R. ｃｃ - and - (CH ２ ) ｎ N.R. ｃｃ S (O) ｍ - selected from Preferably, L １ represents a bond, a substituted or unsubstituted alkenylene group, a substituted or unsubstituted alkynylene group, -(CH ２ ) ｎ -, -(CH ２ ) ｎ C(O)-,-(CR ａａ R ｂｂ ) ｎ O-, -O(CR ａａ R ｂｂ ) ｎ１ -, - (CR ａａ R ｂｂ ) ｎ S-, -S(CR ａａ R ｂｂ ) ｎ１ -, -(CH ２ ) ｎ１ N.R. ｃｃ --, --NR ｃｃ (CR ａａ R ｂｂ ) ｎ１ -or-NR ｃｃ C(O)—, More preferably, L １ is a bond, -CH ２ --, --OCH ２ --, --OCD ２ -, -NH-, -C(O)NH-, -OCH(CH ３ ) -, -OC(CH ３ ) ２ --NH-CH ２ -or- 【Chemistry 14】 is selected from R ａａ , R ｂｂ and R ｃｃ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R ａａ , R ｂｂ and R ｃｃ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; Or, R ａａ , R ｂｂ and R ｃｃ Any two of the groups may be combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy groups and C １－６ may be further substituted with one or more substituents of halogenated alkoxy groups; Preferably, R ａａ , R ｂｂ and R ｃｃ Any two of the groups may be combined to form C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ An aryl group or a 5- to 10-membered heteroaryl group is formed, ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy groups and C １－３ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 7 or 10, further optionally substituted with one or more substituents of halogenated alkoxy groups.

12. R ａ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R ａ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 7 or 10 to 11, which may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

13. R ｂ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R ｂ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1, 6-7 or 11-12, which may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

14. R ｃ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R ｃ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ may be further substituted with one or more substituents selected from aryl and 5- to 10-membered heteroaryl groups; Or, R ｂ and R ｃ is combined to form C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group is formed, ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1, 6 to 7 or 11 to 13, which may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 14-membered heteroaryl group.

15. R ｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, 5-10 membered bridged cycloalkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ An aryl group or a 5- to 14-membered heteroaryl group or -(CR ｅｅ R ｆｆ ) ｎ４ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ N.R. ｈｈ C(O)R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ R ｇｇ , -(CR ｅｅ R ｆｆ ) ｎ４ C(O)NR ｈｈ R ｇｇ Or - (CR ｅｅ R ｆｆ ) ｎ４ S (O) ２ N.R. ｈｈ R ｇｇ wherein the amino group, C １－６ Alkyl group, 5-10 membered bridged cycloalkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－８ Alkyl group, C １－８ Deuterated alkyl groups, C １－８ Halogenated alkyl group, C １－８ Hydroxyalkyl group, C １－８ Alkoxy group, C １－８ Deuterated alkoxy group, C １－８ Halogenated alkoxy group, C ２－８ Alkenyl group, C ２－８ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ an aryl group or a 5- to 14-membered heteroaryl group; Preferably, R ｅｅ , R ｆｆ , R ｇｇ and R ｈｈ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group; Or, R ｅｅ , R ｆｆ are linked to form a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted with deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, a C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; n4 is 0, 1, 2, 3 or 4; Preferably, R ｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R ｄ are each independently hydrogen, deuterium, a halogen, a nitro group, a hydroxyl group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ an aryl group or a 5- to 10-membered heteroaryl group, １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Alkoxy group, C １－３ Halogenated alkoxy group, C １－３ Hydroxyalkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The aryl and 5- to 10-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group, C １－３ Halogenated alkoxy group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C ３－８ Cycloalkyl group, 3-8 membered heterocyclyl group, C ６－１０ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 1 to 7 or 10 to 14, further optionally substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group.

16. R ２ is a halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ may be further substituted with one or more of the following substituents: aryl groups and 5- to 14-membered heteroaryl groups; Preferably, R ２ is a halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group or C ２－６ alkynyl groups, More preferably, R ２ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 8 to 10, wherein is selected from fluorine.

17. R ６ is a halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ aryl group or 5- to 14-membered heteroaryl group, １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C １－６ Hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ The aryl and 5- to 14-membered heteroaryl groups may optionally be substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclyl groups, C ６－１４ It may be further substituted with one or more substituents of aryl groups and 5- to 14-membered heteroaryl groups. Preferably, R ６ is a halogen, a nitro group, a hydroxy group, a mercapto group, a cyano group, an amino group, an oxo group, a thio group, a carboxyl group, C １－６ Alkyl group, C １－６ Deuterated alkyl groups, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C １－６ Alkoxy group, C １－６ Deuterated alkoxy group, C １－６ Halogenated alkoxy group, C ２－６ Alkenyl group or C ２－６ alkynyl groups, More preferably, R ６ The compound, its stereoisomer or its pharma- ceutically acceptable salt according to any one of claims 8 to 10, wherein is selected from fluorine.

18. The structure of the compound is: 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 18. The compound according to any one of claims 1 to 17, its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein:

19. A compound represented by general formula (M-1) or (M-2), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, 【Chemical 38】 Where: X ４ is selected from halogens, preferably chlorine or bromine, Ring D and ring E are as defined in claim 2, M １ , M. ２ , M. ３ and n6 are as defined in claim 5, L １ , R ａ , R ｂ３ , R ｃ２ , R ｃ３ , X ３ and x is as defined in claim 2 or 5, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

20. A method for producing the compound of formula (I'-1) according to claim 2 or a stereoisomer thereof and a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemical Formula 39】 The method includes a step of reacting a compound represented by general formula (M-1) to obtain a target compound represented by general formula (I'-1), Where: X ４ is selected from halogens, preferably chlorine or bromine, Ring D, Ring E, Ring B, L １ , L ３ , R ａ , R ｂ３ , R ｃ２ , R ｃ３ , X ３ , R ｄ , x and e are as defined in claim 2.

21. A process for preparing the compound of general formula (XIV) according to claim 5 or its stereoisomer and its pharma- ceutically acceptable salt, comprising: 【Chemistry 40】 The method includes the step of obtaining a target compound represented by general formula (XIV) by reacting a compound represented by general formula (M-2): Where: X ４ is selected from halogens, preferably chlorine or bromine, M １ , M. ２ , M. ３ , L １ , L ３ , R ａ , R ｂ３ , R ｃ２ , R ｃ３ , X ３ , R ｄ , x, e and n6 are as defined in claim 5.

22. A method for preparing a compound of general formula (XV) according to claim 8 or a stereoisomer thereof and a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemistry 41】 The method includes a step of reacting the general formula (M-3) with the general formula (M-4) to obtain a target compound represented by the general formula (XV), Where: X １ , X ３ , R ａ１ , R ａ２ , R ａ３ , R ａ４ , R ａａ , R ｂｂ , R ｂ２ , R ｂ３ , R ｃ１ , R ｃ２ , R ｃ３ , R １ , R ２ , R ３ and R ４ is as defined in claim 8.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, its stereoisomer or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents or excipients.

24. Use of the compound according to any one of claims 1 to 18, its stereoisomer or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the manufacture of a medicament for treating a p38 kinase mediated disease.

25. Application of the compound according to any one of claims 1 to 18, its stereoisomer or its pharma- ceutically acceptable salt, or the pharmaceutical composition according to claim 23 in the manufacture of a medicament for treating autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrodegenerative diseases, metabolic diseases, cancer, tumors, leukemia and lymphoma.

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